TW201028381A - Pyridine derivative having ttk inhibition activity - Google Patents

Pyridine derivative having ttk inhibition activity Download PDF

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TW201028381A
TW201028381A TW098123662A TW98123662A TW201028381A TW 201028381 A TW201028381 A TW 201028381A TW 098123662 A TW098123662 A TW 098123662A TW 98123662 A TW98123662 A TW 98123662A TW 201028381 A TW201028381 A TW 201028381A
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Ken-Ichi Kusakabe
Nobuyuki Ide
Genta Tadano
Masahiko Fujioka
Sachie Tagashira
Yuki Tachibana
Takeshi Endoh
Natsuki Ishizuka
Eiichi Kojima
Naoko Yamaguchi
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Shionogi & Co
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Abstract

The object aims to provide an effective inhibitor of TTK protein kinase and an effective anti-cancer agent. The object can be achieved by a compound of the invention and inventions related to the compound (e.g., a pharmaceutical composition, a TTK inhibitor). A novel series of compounds having specific properties which are particularly useful for the preparation of a medicinal product for inhibiting the activity of TTK kinase to treat the diseases can be successfully found. Particularly, the compound is useful for the treatment of proliferative diseases (e.g., cancer) which occur in the form of a solid tumor or a hematologic tumor and in which it is known that TTK kinase is active. The compound is particularly useful for diseases including colorectal cancer, breast cancer, lung cancer, prostate cancer, pancreatic cancer, bladder cancer, renal cancer, leukemia, lymphoma and others.

Description

201028381 六、發明說明： 【發明所屬之技術領域】 本發明係關於一種具有ττκ(ττκ蛋白激酶）活性之阻 礙、抑制作用之吧咬衍生物。於其他態樣中，本發明係關 於一種包含該吡啶衍生物之醫藥。 【先前技術】 所謂蛋白質激酶係指於其他蛋白質分子上加成磷酸基 (磷酸化）之酶。蛋白質激酶具有如下之活性：使磷酸基自 豢ATP(triPh〇Sphate，三麟酸腺苷）移至蛋白質分子内之胺基 酸殘基中之羥基上，而使其共價鍵合。多數之蛋白質激酶 有.與蛋白質分子中之絲胺酸及蘇胺酸之羥基反應者（絲 胺酸/蘇胺酸激酶），與酪胺酸之羥基反應者（酪胺酸激 酶）’與該等3種全部反應者（雙重特異性激酶）。亦存在蛋 白質激酶之活性被精密地調節，蛋白質激酶本身亦由於磷 酸化而受到調節之現象。該等之調節係由於其他活化（或 抑制）蛋白質或低分子化合物之鍵結、細胞内之局部變化 • 等而發生。激酶之功能異常亦較多時候導致疾病。 TTK蛋白激酶係將成為受質之蛋白質中之絲胺酸、蘇胺 酸及酿·胺酸殘基磷酸化（例如參照非專利文獻丨）的雙重特異 性激酶。已知表現激酶活性所必須之激酶區（例如參照非 專利文獻1及2)。作為内因性受質，已知有Mad 1(例如參照 非專利文獻3)、SpcllOp(Nuflp)(例如參照非專利文獻4)、 CHK2(例如參照非專利文獻5)、Borealin(例如參照非專利 文獻6)等。TTK表現與細胞增生相關，並且於細胞週期之 141666.doc 201028381 控制中起到作用。又，於專利文獻1中記載有TTK於惡性 卵巢癌中表現之現象，以及包含測定ΤΤΚ之表現量之步驟 的篩選方法。又，於專利文獻2中有檢測ΤΤΚ活性之癌細 胞之鑑定方法，係與抑制腫瘤生長之藥劑鑑定相關之申 請，作為篩選方法，記載有利用tau、cdc25及其等之部分 肽作為受質之TTK活性測定方法。又，於專利文獻3中， 作為TTK活性之篩選方法，記載有利用p38MAPK之部分肽 作為受質之TTK活性測定方法。 作為抗癌劑之候補而為人所知之吡啶系化合物，有於專 利文獻4、5及6中記載者。作為類似之化合物，已知有專 利文獻7。於專利文獻4中揭示有具有抗癌作用之吡啶衍生 物，但吡啶2位之取代基限定於吡唑基。於專利文獻5中揭 示有具有抗癌作用之雜環衍生物。揭示吡啶衍生物作為其 中間體，而對抗癌作用並未揭示。於專利文獻6中揭示有 具有抗癌作用之吡啶衍生物，但對吡啶4位之取代基為胺 基之衍生物並未揭示。 [專利文獻1]國際公開第01/94629號手冊 [專利文獻2]國際公開第02/068444號手冊 [專利文獻3]日本專利特開2007-1 04911號公報 [專利文獻4]國際公開第2006/118231號手冊 [專利文獻5]國際公開第2006/08753 8號手冊 [專利文獻6]國際公開第2002/020495號手冊 [專利文獻7]國際公開第2006/083673號手冊 [專利文獻8]國際公開第2008/024963號手冊 141666.doc 201028381 [專利文獻9]國際公開第2005/023761號手冊 [專利文獻1〇]國際公開第2004/065378號手冊 [專利文獻U]國際公開第2004/037808號手冊 [專利文獻12]國際公開第2〇〇1/〇9〇〇74號手冊 [專利文獻13]曰本專利特開平U49678號手冊 [專利文獻14]德國專利發明第241 7916號說明書 [專利文獻15]國際公開第2009/058923號手冊 [專利文獻16]國際公開第2009/007029號手冊 [專利文獻17]國際公開第2008/156726號手冊 [專利文獻18]國際公開第2008/053812號手冊 [專利文獻19]國際公開第2008/11 5369號手冊 [專利文獻2〇]國際公開第2008/073687號手冊 [專利文獻21 ]國際公開 第2001/062233號手冊 [專利文獻22]國際公開第2009/024824號手冊 [專利文獻23]國際公開第2009/032694號手冊 [非專利文獻 1] Mills等人，J. Biol. Chem. (1992) 267, 16000-16006 [非專利文獻2] Lindberg等人，Oncogene (1993) 8, 351-359 [非專利文獻3] Liu等人，Mol. Biol· Cell. (2003) 14, 1638-51 [非專利文獻4] Friedman等人，J. Biol· Chem. (2001) 276, 17958-17967 [非專利文獻 5] Wei等人，J. Biol. Chem. (2005) 280, 141666.doc 201028381 7748-7757[Technical Field] The present invention relates to a bite derivative having a hindrance and inhibition of ττκ (ττκ protein kinase) activity. In other aspects, the invention relates to a medicament comprising the pyridine derivative. [Prior Art] The protein kinase refers to an enzyme which adds a phosphate group (phosphorylation) to other protein molecules. The protein kinase has an activity of causing a phosphate group to be covalently bonded to a hydroxyl group in an amino acid residue in a protein molecule by moving ATP (triPh〇Sphate, adenosine triphosphate) to a hydroxyl group in an amino acid residue in a protein molecule. Most of the protein kinases are those that react with the hydroxyl groups of serine and threonine in the protein molecule (serine/threonine kinase), and the hydroxyl group of tyrosine (tyrosine kinase) Three kinds of all responders (double specific kinase). There is also a phenomenon in which the activity of the protein kinase is precisely regulated, and the protein kinase itself is regulated by phosphorylation. Such regulation occurs due to other activation (or inhibition) of binding of proteins or low molecular compounds, local changes within the cell, and the like. Abnormal function of the kinase also causes disease. The TTK protein kinase system is a dual specific kinase that phosphorylates serine, threonine, and tyrosine residues in the protein of the receptor (see, for example, Non-Patent Document). A kinase region necessary for expressing kinase activity is known (for example, refer to Non-Patent Documents 1 and 2). As an internal factor, Mad 1 (for example, refer to Non-Patent Document 3), SpcllOp (Nuflp) (for example, refer to Non-Patent Document 4), CHK2 (for example, refer to Non-Patent Document 5), and Borealin (for example, refer to non-patent literature). 6) Wait. TTK expression is associated with cell proliferation and plays a role in the control of the cell cycle 141666.doc 201028381. Further, Patent Document 1 describes a phenomenon in which TTK is expressed in malignant ovarian cancer, and a screening method including a step of measuring the amount of expression of sputum. Further, Patent Document 2 discloses an identification method for cancer cells for detecting sputum activity, and relates to an application for identifying a drug for inhibiting tumor growth. As a screening method, a partial peptide using tau, cdc25, or the like is described as a substrate. TTK activity assay method. Further, in Patent Document 3, as a screening method for TTK activity, a method for measuring TTK activity using a partial peptide of p38MAPK as a substrate is described. The pyridine-based compounds which are known as candidates for anticancer agents are described in Patent Documents 4, 5 and 6. As a similar compound, Patent Document 7 is known. Patent Document 4 discloses a pyridine derivative having an anticancer action, but a substituent at the 2-position of pyridine is limited to a pyrazolyl group. Patent Document 5 discloses a heterocyclic derivative having an anticancer action. The pyridine derivative was revealed as an intermediate thereof, and the anticancer effect was not revealed. Patent Document 6 discloses a pyridine derivative having an anticancer action, but a derivative in which a substituent at the 4-position of pyridine is an amine group is not disclosed. [Patent Document 1] International Publication No. 01/94629 [Patent Document 2] International Publication No. 02/068444 [Patent Document 3] Japanese Patent Laid-Open Publication No. 2007-1 04911 [Patent Document 4] International Publication No. 2006 Handbook No. /118231 [Patent Document 5] International Publication No. 2006/08753 No. 8 Manual [Patent Document 6] International Publication No. 2002/020495 Handbook [Patent Document 7] International Publication No. 2006/083673 Handbook [Patent Document 8] International Publication No. 2008/024963, pp. PCT No. PCT Publication No. No. No. No. No. Publication No. No. No. No. No. No. No. No. No. No. No. No. No. No. No. No. No. No. No. No. No. No. No. No. No. No. No. No. No. No. No. No. No. No. No. No. No. No. No. No Handbook [Patent Document 12] International Publication No. 2/〇9〇〇74 Manual [Patent Document 13] Japanese Patent Laid-Open Publication No. U49678 [Patent Document 14] German Patent Invention No. 241 7916 [Patent Literature] 15] International Publication No. 2009/058923 [Patent Document 16] International Publication No. 2009/007029 Handbook [Patent Document 17] International Publication No. 2008/156726 Handbook [Patent Document 18] International Publication No. 2008/053812 Handbook [ Patent Document 19] International Publication No. 200 Handbook No. 8/11 5369 [Patent Document 2 〇] International Publication No. 2008/073687 [Patent Document 21] International Publication No. 2001/062233 Handbook [Patent Document 22] International Publication No. 2009/024824 Manual [Patent Document 23] [International Patent Publication No. 2009/032694] [Non-Patent Document 1] Mills et al., J. Biol. Chem. (1992) 267, 16000-16006 [Non-Patent Document 2] Lindberg et al., Oncogene (1993) 8, 351 -359 [Non-Patent Document 3] Liu et al., Mol. Biol. Cell. (2003) 14, 1638-51 [Non-Patent Document 4] Friedman et al., J. Biol. Chem. (2001) 276, 17958-17967 [Non-Patent Document 5] Wei et al., J. Biol. Chem. (2005) 280, 141666.doc 201028381 7748-7757

Cell (2008) 25, 233-246 f非專利文獻6〗jei丨uma等人 【發明内容】 [發明所欲解決之問題] 本發明之課題在於提供—種取蛋白激酶之有效之抑弟 劑，進而提供一種有效之抗癌劑。 [解決問題之技術手段] 上述課題係利用本發明中提供之化合物及其相關發明 (例如醫藥組合物、ΤΤΚ抑制料）而解決。 本申清人成功發現具有如下特定特性之新穎的—系列化 口物·抑制ΤΤΚ激酶之作用，於將治療上述疾病之醫藥品 製劑化時特別有用。特別是，本化合物可用於治療作為實 體腫瘤或血液腫瘤之任—者而產生之已知ττκ激酶為活性 癌之類之增生性疾病之治療中，尤其是可用於結腸直 腸癌、乳癌、肺癌、***癌、騰臟癌或膀胱癌及腎癌， 同樣地如白血病及淋巴瘤之類之疾病中。 因此’例如，本發明提供以下者。 (1) 一種含有由式（I)所表示之化合物、其製藥上所容許 之鹽或者其等之溶劑合物或前藥（酯、醯胺等）之具有TTK 抑制活性的醫藥組合物， [化 11]Cell (2008) 25, 233-246 f Non-patent document 6 jeje丨uma et al. [Summary of the Invention] [Problems to be Solved by the Invention] The object of the present invention is to provide an effective inhibitor for protein kinases. Further, an effective anticancer agent is provided. [Technical means for solving the problem] The above problems are solved by using the compound provided by the present invention and related inventions (e.g., pharmaceutical composition, bismuth inhibitor). The present applicant succeeded in discovering the novel-serialized substance and inhibiting the action of ΤΤΚ kinase having the following specific characteristics, and is particularly useful when formulating a pharmaceutical for treating the above diseases. In particular, the present compound can be used for the treatment of a proliferative disease in which a known ττκ kinase produced as a solid tumor or a hematological tumor is active cancer, in particular, for colorectal cancer, breast cancer, lung cancer, Prostate cancer, smear cancer or bladder cancer and kidney cancer, as in diseases such as leukemia and lymphoma. Thus, for example, the present invention provides the following. (1) A pharmaceutical composition comprising a compound represented by the formula (I), a pharmaceutically acceptable salt thereof, or a solvate or a prodrug thereof (ester, guanamine, etc.) having TTK inhibitory activity, [ 11]

14l666.doc 201028381 (式中 =氮、經取代或未經取代u基、經取代或未經取代之 =、絲代絲經取代之芳基、經取代或未經取代之雜 方基、經取代或未經取代之㈣基、經取代或未經取代之 環烯基、經取代或未經取代之雜環基、 =⑽所示基㈣中，Ra#、氫、經取代或未經取代 =基^取代或未鮮狀料、絲代或未經取代之14l666.doc 201028381 (wherein = nitrogen, substituted or unsubstituted u group, substituted or unsubstituted =, aryl substituted aryl, substituted or unsubstituted heteroaryl, substituted Or unsubstituted (tetra), substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic group, group (4) represented by =(10), Ra#, hydrogen, substituted or unsubstituted = Substituted or unfreshed, silky or unsubstituted

芳二，取代或未經取代之芳基、經取代或未經取代之雜 方土、！取代或未經取代之環烷基、經取代或 環烯基或者經取代或未經取代之雜環基）、一、 =式：-sow所示基團（式中，Rf係經取代或未經取代之院 :、經取代或未經取代之烯基、經取代或未經取代之炊 二、經取代或未經取代之芳基、經取代或未經取代之雜芳 ς其^取代或未經取代之環縣、經取代或未經取代之環 烯土或者經取代或未經取代之雜環基）、 由式· -NRbRC所示基團（式中，Rb&RC分別獨立，係氯、 經取代或未經取代之烧基、經取代或未經取代之烤基、經 =或未經取代之块基、經取代或未經取代之芳基、經取 =未經取代之雜芳基、經取代或未經取代之環烧基、經 代或未經取代之環稀基、經取代或未經取代之雜環基、 二：代或未經取代之酿基、由式：所示基團(此處， :上述定義相同)或者R、RC可與氮原子—起形成經取代 或未經取代之含氮雜環）、 由式：所示基團（式中，Rd係氫、經取代或未經 141666.doc 201028381 取代之縣嗜取代或未經取代之㈣、經取代或未經取 代之^基、經取代或未經取代之芳基、經取代或未經取代 之雜方基、經取代或未纟緣狀環㈣、經取代或未經取 代之衣烯1：㉟取代或未經取代之雜環基、、纟 取代之烷氧基或者_ΝΜκνιμ者Db c 代次未左 尺有JNRR(此處，Rb*RC與上述 同））、Aromatic, substituted or unsubstituted aryl, substituted or unsubstituted heterogeneous earth,! a substituted or unsubstituted cycloalkyl group, a substituted or cycloalkenyl group or a substituted or unsubstituted heterocyclic group), a group of the formula: -sow (wherein the Rf is substituted or not Substituted: substituted or unsubstituted alkenyl, substituted or unsubstituted fluorene, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted Unsubstituted ring, substituted or unsubstituted cycloolefin or substituted or unsubstituted heterocyclic group, a group represented by the formula -NRbRC (wherein Rb & RC are independent, respectively Chlorine, substituted or unsubstituted alkyl, substituted or unsubstituted base, = or unsubstituted block, substituted or unsubstituted aryl, taken = unsubstituted An aryl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloaliphatic group, a substituted or unsubstituted heterocyclic group, a di- or unsubstituted aryl group, and a formula: The group shown (here, the above definition is the same) or R, RC may form a substituted or unsubstituted nitrogen-containing heterocyclic ring with a nitrogen atom, : a group of the formula (wherein Rd is hydrogen, substituted or unsubstituted or substituted by 141666.doc 201028381 (4), substituted or unsubstituted, substituted or unsubstituted Aryl, substituted or unsubstituted heteroaryl, substituted or unbranched ring (IV), substituted or unsubstituted hexene 1,35 substituted or unsubstituted heterocyclic group, hydrazine substituted Alkoxy or _ΝΜκνιμ Db c has no JNRR (here, Rb*RC is the same as above),

H 由式· _N(R )C(=Q)Rd所示基團（式中，Rg係氫經取代或 未經取代线基、經取代絲經取代之烯基、經取代或未 經取代之炔基、經取代或未經取狀芳基、經取代或未經 取代之雜芳基、經取代或未經取代之⑽基、經取代或未 經取代之環縣、絲代絲絲狀雜環基或者經取代 或未經取代之醯基，…與上述定義相同）、 由式：_SRe所示基團（式中，Re係氫、經取代或未經取代之 烧基、經取代或未經取代之祕、絲代絲經取代之块 基、經取代或未經取代之芳基、經取代或未經取代之雜芳 基、經取代或未經取代之料基、經取代或未經取代之環 稀基或者經取代或未經取代之雜環基）、 或者H is a group represented by the formula: _N(R)C(=Q)Rd (wherein Rg is a substituted or unsubstituted linear group, substituted alkene substituted alkenyl group, substituted or unsubstituted Alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted (10) group, substituted or unsubstituted ring county, silky filamentous A cyclic group or a substituted or unsubstituted fluorenyl group, ... having the same meaning as defined above), a group represented by the formula: _SRe (wherein Re is hydrogen, substituted or unsubstituted alkyl, substituted or not Substituted, substituted silk, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted, substituted or unsubstituted Substituted ring or substituted or unsubstituted heterocyclic group), or

Rg&Rf與上述定義相 由式：_N(Rg)S〇2RV/i示基團（式中 同）、 R係氫、經取似未經取代之㈣、經取代或未經取代之 婦基、經#代或未經取代之炔基、經取代或未經取代之芳 基、經取代或未經取代之雜芳&'經取代或未經取代之^ 烧基、經取代或未經取代之環職、經取代或未經取代: 141666.doc 201028381 雜環基、氰基、硝基、鹵素、 由式：-C(=0)Rd所示基團（式中，…與上述定義相同）、 或者由式：_N(Rg)C(=0)Rd所示基團（式中，Rg& Rd與上述 足義相同）、 R3係氫、i素、經取代或未經取代之芳基、經取代或未經 取代之雜芳基或者經取代或未經取代之胺基、 R4係氫、齒素或者由式：_NRbRC所示基團（式中，…及… 與上述定義相同）、Rg&Rf has the following formula: _N(Rg)S〇2RV/i indicates a group (the same formula), R-hydrogen, unsubstituted (tetra), substituted or unsubstituted gynecyl , substituted or unsubstituted aryl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl & 'substituted or unsubstituted, substituted or unsubstituted Substituted ring, substituted or unsubstituted: 141666.doc 201028381 Heterocyclyl, cyano, nitro, halogen, a group represented by the formula: -C(=0)Rd (wherein...with the above definition The same), or a group represented by the formula: _N(Rg)C(=0)Rd (wherein Rg& Rd is the same as the above), R3 hydrogen, i, substituted or unsubstituted a substituted or unsubstituted heteroaryl group or a substituted or unsubstituted amino group, an R4 hydrogen group, a dentate or a group represented by the formula: _NRbRC (wherein, ... and ... are as defined above) ,

R5係氫、經取代或未經取代之烷基、經取代或未經取代之 烯基、經取代或未經取代之芳基、經取代或未經取代之雜 芳基、經取代或未經取代之環烷基、經取代或未經取代之 環缔基、經取代或未經取代之雜環基、 由式：-NRbRC所示基團（式中，…及^與上述定義相同）、 由式：<(=0)1^斤*基團（式中，^與上述定義相同）或 由式.-N(Rg)C(=〇)Rd所示基團（式中，…及…與上述定義 相同） 或者 R4和R5可與鄰接之碳原子一起形成經取代或未經取代之 環。其中，於r5係式：视…Rb係氫，rc係經取代或未 經取代之雜芳基或者經取代或未經取代之雜環基之情形 時，R3係經取代或未經取代之胺基，r1〜rS ^ 非為氫）》 ' I二者並 (2)如項目⑴所揭示之含有化合物、其製藥上所容許之 鹽或者其等之溶劑合物之具有ττκ抑制活性的醫藥組合 141666.doc 201028381 二經取代或未經取代之燒基、經取代或未經取 ==代或未經取代之芳基、經取代或未經取代 ’ 土 4取代或未經取代之環烧I、經取 代之環稀基、經取代或未經取代之雜環基、未取 ⑽:所示基團(式令，作項目⑴中之定義相同)、 相^撕汉所不基團（式中HRC與項目⑴中之定義 =:评响所示基團（式中，Rd與項目⑴中之定義相 由式：-N(Rg)C(=〇)Rd所示基 義相同）、 ，、項目⑴中之定 或者 由式· -N(Rg)S〇2Rf所示基團（式中，^及 定義相同）、 丹項目（1)中之 未經取代之雜芳基、氣基或者確基、 係虱或者經取代或未經取代之胺美 ❹ 經取…基，代或未經取代之婦 基、經取代或未經取代之環垸基、經 2雜务 婦基、經取代或未經取代之雜環基、或未左取代之環 =:、卿所示基㈣，W項目⑴中之定義 f示基團(式中，項目⑴中之定義相 141666.doc 201028381 由式：-N(Rg)C(=〇)Rd所示基團（式中，Rg&Rd與項目中 之定義相同）。 (2A)如項目⑴所揭示之含有化合物、其製藥上所容許之 鹽或者其等之溶劑合物之具有ττκ抑制活性的醫藥组合 物，其令Rl係經取代或未經取代之烧基、經取代或未經取 代之縣、經取代或未經取代之芳基、經取代或未經取代 之雜芳基、經取代或未經取代之環炫基、經取代或未經取 代之環烯基、經取代或未經取代之雜環基、 由式：挪所示基團（式中，Ra與項目⑴中之定義相同）、 由式：-NRbR、示基團(式中’ 與項目⑴中之定義 相同）、 由式：-c(=〇)Rd所示基團（式中，Rd與項目⑴中之定義相 同）、 由式.-N(Rg)C(=〇)Rc^示基團（式中，Rg與項目⑴中之 義相同）、 或者 由式：-N(Rg)S〇2Rf所示基團（式中，…及❻項目⑴ 定義相同）、 R32係經取代或未經取代之雜芳基、氰基或者硝基、 R係經取代或未經取代之胺基、 :係經取代或未經取代之烷基、經取代或未經取 、經取代或未經取代之芳基、經取代或未經取代之雜芳 ^經取代或未經取代之環院基、經取代或未經取代之環 土、麵·取代或未經取代之雜環基、 141666.doc 201028381 由式：-NRbRe所示基團（式中，Rb與項目（1)中之定義相 同，係經取代或未經取代之烯基、經取代或未經取代之 炔基、經取代或未經取代之芳基、經取代或未經取代之噻 吩、嘆TI坐、。惡唾、異嗔β坐、η比唆、哺咬、n比咬酮 '苯并嗓 唑、苯并噻唑、苯并咪唑、吲唑、吲哚、經取代或未經取 代之環烷基、經取代或未經取代之環烯基、經取代或未經 取代之醯基或者-S〇2Rf(此處，Rf與上述定義相同、 由式.-C( = 0)Rd所示基團（式中，Rd與項目中之定義相 同）或者 由式：-N(Rg)C(=0)Rd所示基團（式中，…及…與項目中 之定義相同）。 (3)如項目(1)或(2)所揭示之含有化合物、其製藥上所容 許之鹽或者其等之溶劑合物之具有ττκ抑制活性的醫藥組 合物’其中R3係經取代或未經取代之胺基，r4係氫，以 由式··视bRC所示基團(式中，妒及Rc與項目⑴中之定義 相同)或者由式“C(=〇)R、示基團(式中，Rd與項目⑴中 之定義相同）。 (4)如項目⑴至(3)中任—項所揭示之含有化合物、其棠 藥上所容許之^者其等之溶劑合物之具有TTK抑制活,Η 的醫藥組合物，其中R5係由式：_NRbRC所示基團(式中: ^與項目⑴中之定義相同，"經取代或未經取代之； 基、經取代或未經取代之雜芳基、經取代或未經取代之老 烧基、經取代或未經取代之環稀基或者經取絲未經取4 之雜環基）或者由式：_c㈣)Rd（式中，Rd係經! 141666.doc 201028381 代或未經取代之芳基、經取代或未經取代之雜芳基、經取 代或未經取代之環院基、經取代或未經取代之環埽基或者 經取代或未經取代之雜環基）。 (4A)如項目⑴至⑷中任一項記載之ττκ抑制劑之前 藥。 (5)—種由式⑴所表示之化合物、其製藥上所容許之鹽 或者其等之溶劑合物， [化 12]R5 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted a substituted cycloalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a group represented by the formula: -NRbRC (wherein, and ... are as defined above), By the formula: < (=0) 1 ^ kg * group (wherein ^ is the same as defined above) or by the formula -N (Rg) C (= 〇) Rd (in the formula, ... and ...is identical to the above definition) or R4 and R5 may form a substituted or unsubstituted ring together with an adjacent carbon atom. Wherein, in the case of r5: Rb is hydrogen, rc is substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclic group, R3 is substituted or unsubstituted amine a combination of a compound having a ττκ inhibitory activity of a compound, a pharmaceutically acceptable salt thereof, or a solvate thereof, as disclosed in the item (1), as defined in the item (1). 141666.doc 201028381 A substituted or unsubstituted alkyl, substituted or unsubstituted == substituted or unsubstituted aryl, substituted or unsubstituted 'earth 4 substituted or unsubstituted ring burned I a substituted cycloaliphatic group, a substituted or unsubstituted heterocyclic group, not taken (10): a group represented by the formula (the formula is the same as defined in the item (1)), and a group which is not a Definition of HRC and Project (1) =: The group shown in the evaluation (in the formula, Rd is the same as the definition in the item (1): -N(Rg)C(=〇)Rd has the same meaning), , In the item (1), the group represented by the formula -N(Rg)S〇2Rf (wherein, and the definition are the same), the unsubstituted heteroaryl group in the Dan item (1), Alkyl or arginyl, hydrazine or substituted or unsubstituted amides, substituted or unsubstituted thiol, substituted or unsubstituted cyclodecyl, via 2 chores, A substituted or unsubstituted heterocyclic group, or a ring which is not substituted to the left =:, a group represented by the group (4), and a definition of a group in the W item (1), f, a group (in the formula, the definition in the item (1), 141666.doc 201028381 A group represented by the formula: -N(Rg)C(=〇)Rd (wherein Rg&Rd is the same as defined in the item). (2A) A compound contained in the item (1), which is pharmaceutically acceptable A pharmaceutical composition having a ττκ inhibitory activity of a salt or a solvate thereof, which is a substituted or unsubstituted alkyl, substituted or unsubstituted sulphate, substituted or unsubstituted aryl group. a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted cyclohexyl group, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted heterocyclic group, The group shown (in the formula, Ra is the same as defined in the item (1)), and the formula: -NRbR, the group (in the formula and the item (1) The same formula), a group represented by the formula: -c(=〇)Rd (wherein Rd is the same as defined in the item (1)), and a group represented by the formula: -N(Rg)C(=〇)Rc^ (wherein Rg is the same as in the item (1)), or a group represented by the formula: -N(Rg)S〇2Rf (wherein, ... and ❻ item (1) are the same), R32 is substituted or not Substituted heteroaryl, cyano or nitro, R substituted or unsubstituted amino, : substituted or unsubstituted alkyl, substituted or unsubstituted, substituted or unsubstituted Aryl, substituted or unsubstituted heteroaryl substituted or unsubstituted ring-based, substituted or unsubstituted ring, surface-substituted or unsubstituted heterocyclic group, 141666.doc 201028381 A group represented by the formula: -NRbRe (wherein Rb is the same as defined in the item (1), a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, substituted or not Substituted aryl, substituted or unsubstituted thiophene, sigh TI sitting. Evil saliva, isoindole beta, η 唆, gnaw, n-bite ketone 'benzoxazole, benzothiazole, benzimidazole, carbazole, anthracene, substituted or unsubstituted cycloalkyl, Substituted or unsubstituted cycloalkenyl, substituted or unsubstituted fluorenyl or -S〇2Rf (wherein Rf is as defined above, and is represented by the formula: -C(=0)Rd ( Where, Rd is the same as defined in the project) or by the formula: -N(Rg)C(=0)Rd (in the formula, ... and ... are the same as defined in the project). (1) or (2) a pharmaceutical composition having a ττκ inhibitory activity of a compound, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R3 is a substituted or unsubstituted amino group, R4 is hydrogen, which is represented by the formula bRC (wherein 妒 and Rc are the same as defined in the item (1)) or by the formula "C(=〇)R, showing a group (in the formula, Rd and (1) The definition in item (1) is the same. (4) The solvate containing the compound disclosed in the item (1) to (3), and the solvate thereof, which is acceptable on the drug, has TTK inhibition activity, Η Pharmaceutical composition, where R 5 is a group represented by the formula: _NRbRC (wherein: ^ is the same as defined in the item (1), " substituted or unsubstituted; aryl, substituted or unsubstituted heteroaryl, substituted or not Substituted old alkyl, substituted or unsubstituted cycloaliphatic or unsubstituted 4-heterocyclic group) or by the formula: _c(iv))Rd (wherein Rd is via! 141666.doc 201028381 generation Or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted ring-based, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclic (4) The prodrug of the ττκ inhibitor according to any one of the items (1) to (4). (5) A compound represented by the formula (1), a pharmaceutically acceptable salt thereof, or a solvate thereof , [Chemistry 12]

(式中， R1係經取代或未經取代之院基、經取代或未經取代之稀 基、經取代或未經取代之芳基、經取代或未經取代之雜芳(wherein R1 is substituted or unsubstituted or substituted, unsubstituted or unsubstituted aryl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl

=經取代或未經取代之環垸基、經取代或未經取代之環 烯基、經取代或未經取代之雜環基、 由式：-ORa所示基團（式中a 由式.興項目（1)中之定義相同）、 所不基團（式中，^項目⑴中之定義相 由式：-NRbRc所示基團（式中， 相同）、 R及汉與項目⑴中之定義a substituted or unsubstituted cyclodecyl group, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted heterocyclic group, a group represented by the formula: -ORa (wherein a is a formula. Xing project (1) has the same definition), and no group (in the formula, ^ project (1) is defined by the formula: -NRbRc group (in the formula, the same), R and Han and project (1) definition

Rd與項目（1)中之定義相 由式：-C(=〇)Rd所示基團（式中 同）、 141666.doc -13- 201028381 之定 二式”=。)以示基團(式中，Rg與項目⑴中 義相同）、 丹項目（1)中Rd is defined by the formula in (1): -C(=〇)Rd group (the same formula), 141666.doc -13-201028381's formula "=.) to show the group ( Where, Rg is the same as in item (1)), Dan item (1)

由式：货所示基團（式令，R 或者 甲之疋義相同）、 由式：-N(Rg)S〇2Rf所 定義相同）、所丁基團（式中與項目⑴中之 R32係經取代或未經取代之雜芳基、氰基或者硝基、 響 R係氫、經取代或未經取代之芳基、經取代或㈣ 雜4芳基或者經取代或未經取代之胺基、 戈之 R4係氫、鹵素或者由式：视bRe所示基團（式中，Rbw 與項目（1)中之定義相同）、 r5係氫、經取代或未經取代之芳基、經取代或未經取代之 雜芳基、經取代或未經取狀㈣基、絲代或未經取代 之環烯基、經取代或未經取代之雜環基、 由式：-NRbRc所示基團（式中，Rb&RC與項目中之定義 相同）、From the formula: the group shown by the product (the order, R or A is the same), the formula: -N(Rg)S〇2Rf is the same as defined), the butyl group (in the formula and the R32 in the item (1) Substituted or unsubstituted heteroaryl, cyano or nitro, R-hydrogen, substituted or unsubstituted aryl, substituted or (tetra)tetraaryl or substituted or unsubstituted amine R4 is hydrogen, halogen or by the formula: the group represented by bRe (wherein Rbw is the same as defined in the item (1)), r5 hydrogen, substituted or unsubstituted aryl, Substituted or unsubstituted heteroaryl, substituted or unsubstituted (tetra), substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic group, represented by the formula: -NRbRc Group (where Rb&RC is the same as defined in the project),

Q R4和R5可與鄰接之碳原子一起形成經取代或未經取代之 環。其中，於R5係式：-NRbRe，Rb係氫，RC係經取代或未 經取代之雜芳基或者經取代或未經取代之雜環基之情形 時’ R3係經取代或未經取代之胺基）。 (6)如項目（5)所揭示之化合物、其製藥上所容許之鹽或 者其等之溶劑合物，其中R2係氰基或者硝基，R3係氫或者 經取代或未經取代之胺基，R4係氫，R5係由式：_NRbRC所 141666.doc • 14- 201028381 示基圈（式中，Rb與項目⑴中之^義相同，Re係經取代或 未經取代之芳基、經取錢未經取代之雜芳基、經取代或 未經取代之我基、經取代或未經取代之料基、或者經 取代或未經取代之雜環基）。 ⑺如項目（5)或（6)所揭示之化合物、其製藥上所容許之 鹽或者其等之溶劑合物，其中R5係由式（11)所示基團， [化 13]Q R4 and R5 may form a substituted or unsubstituted ring together with an adjacent carbon atom. Wherein, in the case where R5 is a formula: -NRbRe, Rb is hydrogen, RC is substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclic group, 'R3 is substituted or unsubstituted Amine). (6) A compound as disclosed in the item (5), a pharmaceutically acceptable salt thereof or a solvate thereof, wherein R2 is a cyano group or a nitro group, R3 is a hydrogen group or a substituted or unsubstituted amino group. R4 is hydrogen, and R5 is of the formula: _NRbRC 141666.doc • 14- 201028381 shows the base ring (wherein Rb is the same as in item (1), and Re is substituted or unsubstituted aryl, taken An unsubstituted heteroaryl group, a substituted or unsubstituted thiol, a substituted or unsubstituted base, or a substituted or unsubstituted heterocyclic group. (7) A compound disclosed in the item (5) or (6), a pharmaceutically acceptable salt thereof or a solvate thereof, wherein R5 is a group represented by the formula (11), [Chem. 13]

(Π) (式中，分別獨立，係氫、經取代或未經取代之 烧基、經取代或未經取代之烯基、絲代或未經取代之芳 基、經取代或未經取代之㈣基、絲代或未經取代之環 烧基、經取代絲經取代之環縣、經取代或未經取代之 雜環基、(Π) (wherein independently, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted (d) a cyclized or unsubstituted cycloalkyl group, a substituted ring, a substituted or unsubstituted heterocyclic group,

由式：-〇Ra所示基團（式中，^與項目⑴中之定義相同）、 由式、S〇2Rf所示基團(式巾，Rf與項目⑴中之定義相 同）、 由式：-NRbRe所示基圏（式中，Rb&Re#項目⑴中之 相同）、 由式：-C(=〇)R、示基團(式中，Rd與項目⑴中 同）、 由式：-N(Rg)C(=0)Rd所示基團（式中，Rg與項目中之定 141666.doc •15- 201028381 義相同）、 由式：_SRe所示基團（式中，Re與項目（1)中之定義相同）、 由式N(R )S〇2R所示基團（式中，Rg&Rf與項目〇)中 定義相同）、 或者RA2可鍵結於^所鍵結之碳的鄰接碳原+ i，與心 一起形成經取代或未經取代之環、 η係1〜4之整數、 RB係氫、經取代或未經取代之烷基或者經取代或未經取代 之醯基）。 (8) 如項目（5)至（7)中任一項所揭示之化合物、其製藥上 所容許之鹽或者其等之溶劑合物，其中R5係由式（ΙΠ)所示 基團， [化 14]a group represented by the formula: -〇Ra (wherein ^ is the same as defined in the item (1)), a group represented by the formula: S〇2Rf (formula, Rf is the same as defined in the item (1)), :- NRbRe indicates the basis (wherein Rb&Re# is the same in item (1)), the formula: -C(=〇)R, the group (in the formula, Rd is the same as in item (1)), :-N(Rg)C(=0)The group represented by Rd (wherein Rg is the same as 141666.doc •15-201028381 in the project), and the group represented by the formula: _SRe (in the formula, Re Same as defined in the item (1), the group represented by the formula N(R )S〇2R (wherein Rg&Rf is the same as defined in the item )), or RA2 may be bonded to the bond Adjacent carbon of the carbon + i, together with the core to form a substituted or unsubstituted ring, an integer of η 1 to 4, RB hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted醯基). (8) A compound disclosed in any one of the items (5) to (7), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R5 is a group represented by the formula (ΙΠ), [ 14]

an) Η (式中，RA1及RA2與項目（7)中之定義相同）。 (9) 如項目（5)至（8)中任一項所揭示之化合物、其製藥上 所容許之鹽或者其等之溶劑合物，其中RA1係經取代或未 經取代之雜芳基、經取代或未經取代之胺基、經取代或未 經取代之醯基、經取代或未經取代之烯基、經取代或未經 取代之烧氧基或者經取代或未經取代之炫基，ra2係經取 代或未經取代之烷氧基、經取代或未經取代之胺基、經取 代或未經取代之烧基、經取代或未經取代之烯基或者經取 141666.doc •16- 201028381 代或未經取代之块基。 (10) 如項目（5)至（9)中任_項所揭示之化合物、其製藥上 所容許之鹽或者其等之溶劑合物，其中Rl係由式：孤所 示基團（式中，1T與項目⑴中之定義相同）或者由式：_NRbRc 所示基團(式中，Rb及RC與項目⑴中之定義相同）。 (11) 如項目（5)至（10)中任一項所揭示之化合物其製藥 上所容許之鹽或者其等之溶劑合物，其中Ra係經取代或未 經取代之芳基或者經取代或未經取代之烷基，Rb係氫、經 籲取《或未經取代之烧基或者經取代或未經取代之芳基，rc 係氫或者經取代或未經取代之烧基。 (12) 如項目（5)至（11)中任一項所揭示之化合物、其製藥 上所容許之鹽或者其等之溶劑合物，其中r2係氰基。 (13) 如項目（5)至（11)中任一項所揭示之化合物其製藥 上所容許之鹽或者其等之溶劑合物，其中r2係硝基。 (14) 如項目（5)至（13)中任一項所揭示之化合物、其製藥 上所容許之鹽或者其等之溶劑合物’其中R3係經取代或未 _經取代之胺基。 (15) 如項目（5)至（13)中任一項所揭示之化合物、其製藥 上所容許之鹽或者其等之溶劑合物，其中R3係氫。 (16) 如項目（5)所揭示之化合物、其製藥上所容許之鹽或 者其等之溶劑合物，其中R2係氰基或者硝基，R3係經取代 或未經取代之雜芳基，R4係氫，R5係經取代或未經取代之 方基。 (17) 如項目（5)所揭示之化合物、其製藥上所容許之鹽或 141666.doc •17· 201028381 者其等之*劑合物’其中r2係氰基或者确基，r3係經取代 或未經取代之雜芳基，R4和R5與鄰接之碳原子一起係由式 (IV)所示基團， [化 15] (R°)mAn) Η (wherein RA1 and RA2 are the same as defined in item (7)). (9) A compound disclosed in any one of items (5) to (8), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein RA1 is a substituted or unsubstituted heteroaryl group, Substituted or unsubstituted amino group, substituted or unsubstituted fluorenyl group, substituted or unsubstituted alkenyl group, substituted or unsubstituted alkoxy group or substituted or unsubstituted slab group , ra2 is substituted or unsubstituted alkoxy, substituted or unsubstituted amino, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or taken 141666.doc • 16- 201028381 Generation or unsubstituted block base. (10) A compound disclosed in any one of items (5) to (9), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R1 is a group represented by the formula: , 1T is the same as defined in the item (1)) or a group represented by the formula: _NRbRc (wherein Rb and RC are the same as defined in the item (1)). (11) A pharmaceutically acceptable salt of the compound disclosed in any one of the items (5) to (10), or a solvate thereof, wherein the substituted or unsubstituted aryl group or substituted Or an unsubstituted alkyl group, Rb is hydrogen, an unsubstituted alkyl group or a substituted or unsubstituted aryl group, rc is hydrogen or a substituted or unsubstituted alkyl group. (12) A compound disclosed in any one of the items (5) to (11), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein r2 is a cyano group. (13) A pharmaceutically acceptable salt or a solvate thereof, wherein the compound disclosed in any one of the items (5) to (11), wherein r2 is a nitro group. (14) A compound disclosed in any one of the items (5) to (13), a pharmaceutically acceptable salt thereof or a solvate thereof, wherein R3 is a substituted or unsubstituted amino group. (15) A compound disclosed in any one of the items (5) to (13), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R3 is hydrogen. (16) A compound as disclosed in the item (5), a pharmaceutically acceptable salt thereof or a solvate thereof, wherein R2 is a cyano group or a nitro group, and R3 is a substituted or unsubstituted heteroaryl group, R4 is hydrogen and R5 is a substituted or unsubstituted square. (17) The compound disclosed in item (5), its pharmaceutically acceptable salt or 141666.doc •17· 201028381 of its *precipitate' where r2 is a cyano group or an exact group, r3 is substituted Or an unsubstituted heteroaryl group, R4 and R5 together with an adjacent carbon atom are a group represented by the formula (IV), [15] (R°) m

(IV)(IV)

式中係N 或-CH2·，RD係氫、經取代或未經取 代之烧基、絲代或未經取代之縣、經取代或未經取代 之芳基、經取代或未經取代之㈣基、經取代或未經取代 之環烧基、經取代或未經取代之環烯基、經取代或未經取 代之雜環基、 與項目（1)中之定義相同）、 ’ Rf與項目（1)中之定義相 由式.-OR所不基團（式中，Ra 由式：_s〇2Rfm示基團（式中 同）、 由式：-NRbRc所示基團（式中 相同）、Wherein N or -CH2·, RD is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted county, substituted or unsubstituted aryl, substituted or unsubstituted (IV) a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted heterocyclic group, the same as defined in the item (1), 'Rf and a project The definition in (1) is based on the formula .-OR. (In the formula, Ra is represented by the formula: _s〇2Rfm (the same formula), and the group represented by the formula: -NRbRc (the same formula) ,

Rb&RC與項目（1)中之定義Rb&RC and definition in project (1)

由式：-C(=0)Rd所示基團（式中 同）、a group represented by the formula: -C(=0)Rd (in the formula)

Rd與項目（1)中之定義相 由式：-N(Rg)C(=0)Rd所示基團（式中，Rg與項 義相同）、 目U)中之定 由式：此所示基團(式巾，項目⑴中之定 或者 義相同） 由式：-N(Rg)S〇2Rfm示基團（式中Rd is defined by the formula in (1): -N(Rg)C(=0)Rd is the group represented by the formula (wherein Rg is the same as the term), and U is the formula: The group (type towel, item (1) or the same meaning) is represented by the formula: -N(Rg)S〇2Rfm (in the formula

Rg&Ri與項目（1)中之 141666.doc •18- 201028381 定義相同）、m為1〜4之整數）。 (18) 如項目（5)所揭示之化合物、其製藥上所容許之鹽或 者其等之溶劑合物，其中Ri係由式：_〇Ra所示基團（式 中，Ra與項目（1)中之定義相同）、R2係氰基或者硝基，R4 係由式._NRbRC所示基團（式中，Rb及Rc與項目（1)中之定 義相同）。 (19) 一種醫藥組合物，其含有如項目（5)至“8)中任一項Rg&Ri is the same as 141666.doc •18- 201028381 in item (1), and m is an integer from 1 to 4). (18) A compound disclosed in the item (5), a pharmaceutically acceptable salt thereof or a solvate thereof, wherein Ri is a group represented by the formula: _〇Ra (in the formula, Ra and the item (1) The definition is the same), R2 is a cyano group or a nitro group, and R4 is a group represented by the formula: _NRbRC (wherein Rb and Rc are the same as defined in the item (1)). (19) A pharmaceutical composition comprising any one of items (5) to "8"

所揭不之化合物、其製藥上所容許之鹽或者其等之溶劑合 物。 (20)如項目（19)所揭示之醫藥組合物，其係ττκ抑制 劑。 ⑽如項目（19)所揭示之醫i组合物其係用以處理或 預防與TTK相關之疾病、損傷或者狀態的醫藥。 ⑽如項目⑴至⑷、（2A)、（19)至⑼中任一項所揭示 之醫藥組合物，其係用以治療及/或預防癌。 (23)-種癌之預防或治療方法’其特徵在於：投予 目⑴至（18)中任—項所揭示之化合物、其製藥上所容許之 鹽或者其等之溶劑合物。 州-種如項目⑴至（18)中任—項所揭示之化合物复 製藥上所容許之鹽或者其等之溶劑合物的用途，其係用； 製造癌之治療藥及/或預防藥。 、 (25)如項目⑴至（18)中任—項所揭示之化合物其 ^許之鹽或者其等之溶劑合物’其係用以咬 預防癌。 4 141666.doc •19· 201028381 例如’本發明提供以下。 卜種含有由式⑴所表示之化合物 之鹽或者其等之、、交勒丨人& 农樂上所谷許 物，、〜劑合物之具有ττκ抑制活性的醫藥組合 [化 1Α]A compound which is not disclosed, a pharmaceutically acceptable salt thereof or a solvate thereof. (20) A pharmaceutical composition according to item (19) which is a ττκ inhibitor. (10) A medical composition as disclosed in the item (19), which is a medicine for treating or preventing a disease, injury or condition associated with TTK. (10) A pharmaceutical composition according to any one of items (1) to (4), (2A), (19) to (9) for use in the treatment and/or prevention of cancer. (23) A method for the prophylaxis or treatment of a cancer according to any one of the items (1) to (18), a pharmaceutically acceptable salt thereof, or a solvate thereof. The use of a salt or a solvate thereof for a compound as disclosed in any one of the items (1) to (18), for use in the manufacture of a therapeutic and/or preventive agent for cancer. (25) The compound disclosed in any one of the items (1) to (18), wherein the salt thereof or the solvate thereof is used for bite prevention of cancer. 4 141666.doc • 19· 201028381 For example, the present invention provides the following. A pharmaceutical composition having a salt of a compound represented by the formula (1) or the like, a compound of the cultivar, a cultivar, and a pharmaceutically active compound having a ττκ inhibitory activity.

(式中，(in the formula,

、虱、㈣代或未經取代之院基、經取代或未經取代 =、經取代或未經取代以基、經取代或未經取代之 =其經取代絲經取代w、絲代或未經取代 環烯基、經取代或未經取代之雜環基、, 虱, (4) or unsubstituted, substituted or unsubstituted =, substituted or unsubstituted, substituted or unsubstituted = substituted silk substituted by w, silk or not Substituted cycloalkenyl, substituted or unsubstituted heterocyclic group,

由式OR所不基團(式中，Ra係氫、經取代或未經取代 之貌基、經取代或未經取代之縣、經取代或未經取代之 炔基、經取代絲經取叙芳基、經取代或未經取代之雜 芳基、經取代絲經取代之社基、經取代或未經取代之 環烯基或者經取代或未經取代之雜環基）、 由式：-so2R^基團(式中，Rf係經取代或未經取代之烷 基、經取代或未經取代之稀基、縣代或未經取代之块 基、經取代或未經取代之芳基、經取代或未經取代之雜芳 基、經取代或未經取代之環烧基、經取代或未經取代之環 烯基或者經取代或未經取代之雜環基）、 由式：-SORf所示基團（式中，“與上述定義相同）、 141666.doc -20- 201028381 由式：-NRbRc所示基團（式中，…及^分別獨立，係氫、 經取代或未經取代之烷基、經取代或未經取代之烯基、經 取代或未經取代之炔基、經取代或未經取代之芳基、經取 代或未經取代之雜芳基、經取代或未經取代之環烷基、經 取代或未經取代之環烯基、經取代或未經取代之雜環基或 者Rb*Re可與氮原子一起形成經取代或未經取代之含氮雜 環）、 由式：-C(=〇)Rd所示基團（式中，Rd係氫、經取代或未經 取代之烷基、經取代或未經取代之烯基、經取代或未經取 代之炔基、、經取代《未經取代之芳|、經取代|未經取代 之雜芳基、經取代或未經取代之環烷基、經取代或未經取 代之環烯基、經取代或未經取代之雜環基、經取代或未經 取代之烷氧基或者由式：_NRbRc所示基團（此處，…和RC 與上述定義相同））、 由式：-N(Rg)C(=0)Rd所示基團（式中，Rg係氫、經取代或 未經取代之烷基、經取代或未經取代之烯基、經取代或未 經取代之炔基、經取代或未經取代之芳基、經取代或未經 取代之雜芳基、經取代或未經取代之環烷基、經取代或未 經取代之環烯基、經取代或未經取代之雜環基或者經取代 或未經取代之醯基，…與上述定義相同）、 由式：-SRe所示基團（式中’ Re係氫、、經取代或未經取代之 烷基、經取代或未經取代之烯基、經取代或未經取代之炔 基、經取代或未經取代之芳基、經取代或未經取代之雜芳 基、經取代或未經取代之環烷基、經取代或未經取代之環 141666.doc •21- 201028381 稀基或者經取代或未經取代之雜環基）、 或者由式：_N(Rg)S〇2RfA示基團（式中，Rg及Rf與上述~ 義相同）、 疋 R2係氫、經取代或未經取代之烷基、經取代或未經取代之 烯基、經取代或未經取代之炔基、經取代或未經取代之芳 基、經取代或未經取代之雜芳基、經取代或未經取代之環 烷基、經取代或未經取代之環烯基、經取代或未經取代之 雜環基、氰基、硝基、南素、 由式：-c(=〇)Rd所示基團（式中，…與上述定義相同）、 或者由式：-N(Rg)C(=0)Rd所示基團（式中，Rg&Rd與上述 定義相同）、 R3係氫 '齒素、經取代或未經取代之芳基、經取代或未經 取代之雜芳基或者經取代或未經取代之胺基、 R4係氫、齒素或者由式：_NRbRC所示基團（式中，…及… 與上述定義相同）、 R5係氫、經取代或未經取代之烷基、經取代或未經取代之 烯基、經取代或未經取代之芳基、經取代或未經取代之雜 芳基、經取代或未經取代之環烷基、經取代或未經取代之 環烯基、經取代或未經取代之雜環基、 由式.-NRbRc所示基團（式中，Rb&RC與上述定義相同广 由式：-C(=〇)Rd所示基團（式中，Rd與上述定義相同）或 由式· N(R )C(-〇)R所示基團（式中，Rg&Rd與上述定義 相同） 或者 141666.doc 201028381 R4和R5可與鄰接之碳原子一起形成經取代或未經取代之 環。其中，於R5係由式：-NRbRc所示基團，Rb係氫，…係 經取代或未經取代之烷基、經取代或未經取代之芳基、經 取代或未經取代之雜芳基或者經取代或未經取代之雜環基 之情形時，R3係未經取代之胺基、 於R1係由式：-SRe所示基團之情形時（式中，Re與上述定義 相同），R5並非為由式：_C(=0)RV/f*基團（式中^上 述定義相同）、a group not represented by the formula OR (in the formula, a Ra-based hydrogen, a substituted or unsubstituted base group, a substituted or unsubstituted county, a substituted or unsubstituted alkynyl group, a substituted silk An aryl group, a substituted or unsubstituted heteroaryl group, a substituted silk substituted group, a substituted or unsubstituted cycloalkenyl group or a substituted or unsubstituted heterocyclic group), a so2R^ group (wherein Rf is a substituted or unsubstituted alkyl group, a substituted or unsubstituted dilute group, a county or unsubstituted block group, a substituted or unsubstituted aryl group, Substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocyclic group, by: -SORf The group shown (wherein "the same as defined above"), 141666.doc -20- 201028381 is a group represented by the formula: -NRbRc (wherein, ... and ^ are each independently, hydrogen, substituted or unsubstituted Alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, taken Or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic or Rb*Re together with nitrogen atom a substituted or unsubstituted nitrogen-containing heterocyclic ring), a group represented by the formula: -C(=〇)Rd (wherein, Rd is hydrogen, substituted or unsubstituted alkyl, substituted or not Substituted alkenyl, substituted or unsubstituted alkynyl, substituted "unsubstituted aryl", substituted | unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted alkoxy group or a group represented by the formula: _NRbRc (here, ... and RC are as defined above) The same)), a group represented by the formula: -N(Rg)C(=0)Rd (wherein Rg is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, Substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, taken a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted heterocyclic group or a substituted or unsubstituted fluorenyl group, which is the same as defined above, and a group represented by the formula: -SRe (wherein 'Re-hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or not Substituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted ring 141666.doc •21- 201028381 dilute or substituted or unsubstituted heterocyclic), or Formula: _N(Rg)S〇2RfA shows a group (wherein Rg and Rf are the same as defined above), 疋R2 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl , substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted a cycloalkenyl group, a substituted or unsubstituted heterocyclic group, a cyano group, a nitro group, a nitrite, a group represented by the formula: -c(=〇)Rd ( In the formula, ... is the same as defined above, or a group represented by the formula: -N(Rg)C(=0)Rd (wherein Rg&Rd is the same as defined above), R3 is hydrogen dentate, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group or a substituted or unsubstituted amine group, an R4 hydrogen group, a dentate or a group represented by the formula: _NRbRC (in the formula, And ... as defined above), R5 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted An aryl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted heterocyclic group, a group represented by the formula: -NRbRc (wherein, Rb&; RC is as broad as defined above: a group represented by -C(=〇)Rd (wherein Rd is as defined above) or a group represented by the formula: N(R)C(-〇)R ( Wherein Rg&Rd is as defined above) or 141666.doc 201028381 R4 and R5 may form a substituted or unsubstituted ring together with an adjacent carbon atom. Wherein R5 is a group represented by the formula: -NRbRc, Rb is hydrogen, ... is a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group; In the case of a substituted or unsubstituted heterocyclic group, R3 is an unsubstituted amino group, and when R1 is a group represented by the formula: -SRe (wherein Re is the same as defined above) , R5 is not a formula: _C (=0) RV / f * group (where the above definition is the same),

R1〜R5中之氫的數目為2以下）。 ⑺如項目(1’)所揭示之含有化合物、其製藥上所容許之 鹽或者其等之溶劑合物之具有ττκ抑制活性的醫藥組合 物，其中R1係經取代或未經取代之烧基、經取代或未= 代之稀基、經取代或未經取代之芳基、經取代或未經 之雜方基、經取代或未經取代之環&基 代之環稀基、經取代或未經取代之雜環或未㈣ 示基團（式中，Ra與項目（1.)中之定義相同）、…观所 由式、所示基團(式中，心與 相同）、 v J τ炙疋義 由式：-C(=〇)Rd所示基團（式中 同）、The number of hydrogens in R1 to R5 is 2 or less). (7) A pharmaceutical composition having a ττκ inhibitory activity of a compound, a pharmaceutically acceptable salt thereof, or a solvate thereof, as disclosed in the item (1), wherein R1 is a substituted or unsubstituted alkyl group, Substituted or unsubstituted aryl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted ring & cycloal, substituted or unsubstituted Substituted heterocyclic ring or unsubstituted group (in the formula, Ra is the same as defined in the item (1.)), ... by the formula, the group shown (in the formula, the heart is the same), v J τ炙疋义式:-C(=〇)Rd group (the same formula),

Rd與項目 之定義相Rd and the definition of the project

RlRd與項目（1，）中 由式：所示基團（式中 之定義相同）、 或者 141666.doc •23- 201028381 由式· -N(Rg)s〇2Rf所示基團（式中，Rg&Rf與項目〇，）中之 定義相同）、 '係經取代或未經取代之雜芳基、氣基或者蝴基、 R3係氫或者經取代或未經取代之胺基、 R5係經取代或未經取代之祕、經取代或未經取代之烯 基、經取代或未經取代之芳基、經取代或未經取代之雜芳 基、經取代或未經取代之環院基、經取代或未經取代之環 烯基、經取代或未經取代之雜環基、 ❹ 二咖示㈣式中’一項目⑺中之定義 =:(=_所示基團(式中，Rd與項目⑺t之定義相 由式：-N(Rg)C卜⑺…所示基團^ ^ ^ 之定義相同)。 （式巾〖及R與項目(Γ)中 之(鹽2=Γ)所揭示之含有化合物^ ❹ 物，其中二之溶劑合物的具有取抑制活性的醫藥組合 取代或未經取代之院基、經取代或未經取 代之烯基、經取代或未經取 之雜芳基、經取代或未經 、沒取代或未經取代 代之《基、經取代或未經取=基經取代或_ 示基團(式中，R—中之 =二、由式… Π;〜基，，—目…定義 由式―d所示基團(式中，Rd與項目〇，)中之定義相 141666.doc •24. 201028381 同）、 由式’ -N(Rg)c(=〇)Rd所示基團（式中，Rg及Rd與項目（ρ)中 之定義相同）、 或者 由式.-N(Rg)s〇2Rf所示基團（式中，Rg及Rf與項目（r)中之 定義相同）、 R/系經取代或未經取代之雜芳基、氰基或者硝基、 R3係經取代或未經取代之胺基、 R係經取代或未經取代之烷基、經取代或未經取代之烯 基、經取代或未經取代之芳基、經取代或未經取代之雜芳 基、經取代或未經取代之環烷基、經取代或未經取代之環 烯基、經取代或未經取代之雜環基、 ❿ 由式、NRV所示基團（式中，Rb與項目〇|)中之定義相 同，心系經取代或未經取代之稀基、經取代或未經取代之 炔基、經取代或未絲狀芳基、絲代或未經取代之嗓 吩、：唑、噁唑、異噁唑、吡啶、嘧啶、吡啶酮、苯并噁 =、㈣、苯㈣4 '❹、，、經取代或未經取 代之環烧基、經取代或未經取代之環㈣、經取代或未瘦 ^之醯基或者部f(此處，Rf與項目⑺中之定義相 R與項目（1·)令之定義相 由式：-匚(=0)1^所示基團（式中 同）或者RlRd and the item (1,) are represented by the formula: the group shown by the formula (the definition is the same), or 141666.doc • 23- 201028381 by the formula -N(Rg)s〇2Rf (in the formula, Rg&Rf is as defined in the item 〇,)), 'substituted or unsubstituted heteroaryl, gas or aryl, R3 hydrogen or substituted or unsubstituted amine, R5 Substituted or unsubstituted, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted ring, Substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic group, ❹ 咖 咖 ( 四 四 四 四 四 四 四 四 四 四 ' 定义 定义 定义 定义 定义 定义 定义 定义 定义 定义 定义 定义 定义 = = = 定义 = 定义The definition of the item (7)t is based on the formula: -N(Rg)CBu(7)...The definition of the group ^^^ is the same). (In the case of the towel and the R and the item (Γ) (salt 2=Γ) A compound containing a compound, wherein a pharmaceutically acceptable combination of a pharmaceutically acceptable or substituted compound, a substituted or unsubstituted alkenyl group, substituted or Substituted heteroaryl, substituted or unsubstituted, unsubstituted or unsubstituted, "substituted, unsubstituted or unsubstituted" or substituted group (in the formula, R - medium = two) From the formula... Π; 〜 base,, - 目... defined by the definition of the group represented by the formula - d (in the formula, Rd and the project 〇,) 141666.doc • 24. 201028381 same), by the formula '-N (Rg)c(=〇) a group represented by Rd (wherein Rg and Rd are the same as defined in the item (ρ)), or a group represented by the formula: -N(Rg)s〇2Rf (wherein , Rg and Rf are the same as defined in the item (r), R/ is substituted or unsubstituted heteroaryl, cyano or nitro, R3 is substituted or unsubstituted amine, R is Substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl , substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic group, ❿ by the formula, NRV represented by the formula (wherein Rb is the same as the item 〇|), Substituted or unsubstituted dilute base Substituted or unsubstituted alkynyl, substituted or unfilved aryl, substituted or unsubstituted porphin, azole, oxazole, isoxazole, pyridine, pyrimidine, pyridone, benzoxine = , (iv), benzene (tetra) 4 '❹,, substituted or unsubstituted cycloalkyl, substituted or unsubstituted ring (iv), substituted or unthined sulfhydryl or moiety f (here, Rf and project The definition of phase R in (7) is related to the definition of the item (1·) order: -匚(=0)1^ indicates the group (the same formula) or

Rg&Rd與項目（1·)中 由式：-N(Rg)C(=〇)R<^示基團（式中 之定義相同）。 141666.doc •25· 201028381 (3 )如項目（1’）或（2’）所揭示之含有化合物、其製藥上所 容許之鹽或者其等之溶劑合物之具有TTK抑制活性的醫藥 組合物，其中R3係經取代或未經取代之胺基，R4係氫，r5 係由式：-NRbRc所示基團（式中，…及尺。與項目（1,)中之定 義相同）或者由式._c(=o)Rdm示基團（式中，Rd與項目（r) 中之疋義相同）。 =)如項目（Γ)至（3，）中任一項所揭示之含有化合物、其 製樂上所谷許之鹽或者其等之溶劑合物之具有ττκ抑制活 性的醫匕藥組合物’ WR5係由式：撕bRe所示基團（式 中’ W與項目Π，）*之定義相同，Re係經取代或未經取代 之芳基、經取代或未經取代之雜芳基、經取代或未經取代 之環院基、經取代或未經取代之輯基或者經取代或未經 取代之雜環基）或者由式：_C( = 〇)Rdm示基團（式中，以係 =取代或未經取代之芳基、經取代或未經取代之雜芳基、 2代或未經取代之環Μ、經取代或未經取代之環稀基 或者經取代或未經取代之雜環基）。 參 :種由式⑴所表示之化合物、其製藥上所容許之鹽 或者其等之溶劑合物， [化 2Α]Rg&Rd and the item (1·) are represented by the formula: -N(Rg)C(=〇)R<^(), which is the same as defined in the formula. 141666.doc •25· 201028381 (3) A pharmaceutical composition having TTK inhibitory activity containing a compound, a pharmaceutically acceptable salt thereof, or a solvate thereof, as disclosed in the item (1') or (2') Wherein R3 is a substituted or unsubstituted amine group, R4 is hydrogen, and r5 is a group represented by the formula: -NRbRc (wherein, and ... is the same as defined in the item (1)) or The formula ._c(=o) Rdm shows a group (wherein Rd is the same as in the item (r)). =) A pharmaceutical composition having a ττκ inhibitory activity containing a compound, a salt thereof, or a solvate thereof, as disclosed in any one of the items (A) to (3) WR5 is represented by the formula: the group represented by the tear bRe (wherein 'W is the same as the item Π,)*, and the Re is a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted ring-based, substituted or unsubstituted substituent or substituted or unsubstituted heterocyclic group) or by the formula: _C(= 〇) Rdm (in the formula, = substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, 2nd or unsubstituted guanidine, substituted or unsubstituted cycloaliphatic or substituted or unsubstituted Ring base). a compound represented by the formula (1), a pharmaceutically acceptable salt thereof, or a solvate thereof, [Chemical 2Α]

(式中， 、、里取代或未經取代之烤 R係經取代或未經取代之烷基 ⑷ 666.doc -26- 201028381(substituted, substituted, unsubstituted or substituted in the formula R is substituted or unsubstituted alkyl (4) 666.doc -26- 201028381

基、經取代或未經取代之芳基、經取代或未經取代之雜芳 基、經取代或未經取狀㈣基、經取代絲經取代之環 烯基、經取代或未經取代之雜環基、 由式：_〇Ra所示基團（式中，Ra與項目（m之定義相同）、 由式：媽以示基團（式中，Rf與項目（1，）中之定義相 同）、 由式：-NRbRc所示基團（式中，Rb 、、丁 κ及R與項目（1，）中之定 相同）、 由式：-C(=〇)R、*基團（式令，Rd與項目⑺中之定義 同）、 由式：-N(Rg)C(=0)Rd所示基團（式_，…及…與項 之定義相同）、 由式：-SRe所示基團（式中，Re與項目（1,)中 或者 相 目（1，）中 之定義相同） 由式：·ν(，〇2·*基團（式巾，R4Rf與項 定義相同）、 5係經取代或未經取代之雜芳基、氰基或者硝基、 R3,氫、經取代或未經取代之芳基、經取代或未經取代之 雜芳基或者經取代或未經取代之胺基、 R4係氫、齒素或者由式··以妒…所示基團（式中，…及… 與項目（1，）中之定義相同）、 R5係氫、經取代或未經取代之芳基、經取代或未經取代之 雜芳基、經取代或未經取代之環烧基、經取代或未經取代 之環婦基、經取代或未經取代之雜環基、 14I666.doc •27· 201028381 由式：-NRbR<^示基團（式中 相同）、A substituted, unsubstituted or substituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted (tetra) group, a substituted silk substituted cycloalkenyl group, substituted or unsubstituted Heterocyclic group, a group represented by the formula: _〇Ra (in the formula, Ra is the same as the item (the definition of m), and the formula: the group is represented by the formula (in the formula, Rf and the definition of the item (1)) The same), a group represented by the formula: -NRbRc (wherein, Rb, and κ and R are the same as those in the item (1)), and a formula: -C(=〇)R, * group ( The formula, Rd is the same as defined in the item (7), the group represented by the formula: -N(Rg)C(=0)Rd (the formulas _, ... and ... are the same as the definition of the item), and the formula: -SRe The group shown (in the formula, Re is the same as defined in the item (1,) or in the item (1)) by the formula: · ν (, 〇 2 · * group (style towel, R4Rf is the same as the item definition) , 5 substituted or unsubstituted heteroaryl, cyano or nitro, R3, hydrogen, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or not Substituted amine group, R4 hydrogen, dentate or a group represented by the formula: (wherein, ... and ... are as defined in the item (1)), an R5-based hydrogen, a substituted or unsubstituted aryl group, substituted or unsubstituted Heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cyclo, substituted or unsubstituted heterocyclic, 14I666.doc •27· 201028381 by: -NRbR&lt ;^ shows the group (the same in the formula),

Rb&RC與項目（1，）中之定義 或者 ,4 R和R可與鄰接之碳原子_起形成經取代或未經取代之 環。其中’於R5係式：视bRe，氫，Re係經 經取代之絲、經取代絲經取狀芳基、經取代或未經 取代之雜芳基或者經取代或未經取代之雜環基之情形時， R3係未經取代之胺基、 R3、R4及H5並非同時為氫）。 (6’）如項目（5，）所揭示之化合物、其製藥上所容許之鹽或 者其等之溶劑合物，其中R2係氰基或者硝基，R3係氫或者 經取代或未經取代之胺基’ R4係氫’ R5係由式：_NRbRC所 示基團（式中’ Rb與項目（1，）中之定義相同，RC係經取代或 未經取代之芳基、經取代或未經取代之雜芳基、經取代或 未經取代之環烷基、經取代或未經取代之環烯基、或者經 取代或未經取代之雜環基）。 (7')如項目（5，）或（6')所揭示之化合物、其製藥上所容許 之鹽或者其等之溶劑合物，其中R5係由式（II)所示基團， [化 3A]Rb&RC and the definition in item (1,) Alternatively, 4 R and R may form a substituted or unsubstituted ring with an adjacent carbon atom. Wherein 'in R5' formula: as bRe, hydrogen, Re is substituted filament, substituted filament aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclic In the case where R3 is an unsubstituted amine group, R3, R4 and H5 are not simultaneously hydrogen). (6') A compound as disclosed in the item (5), a pharmaceutically acceptable salt thereof or a solvate thereof, wherein R2 is a cyano group or a nitro group, and R3 is hydrogen or substituted or unsubstituted. The amine 'R4 hydrogen' R5 is a group represented by the formula: _NRbRC (wherein Rb is the same as defined in the item (1), and the RC is substituted or unsubstituted aryl, substituted or not Substituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocyclic). (7') a compound as disclosed in the item (5,) or (6'), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R5 is a group represented by the formula (II). 3A]

(II) 141666.doc • 28· 201028381 (式中’ RA1及RA2分別獨立，係氯、經取代或未經取代之 烧基、經取代或未經取狀烯基、經取代或未經取代之块 基、經取代或未經取代之芳基、經取代或未經取代之雜芳 基、經取代或未經取代之環烧基、經取代或未經取代之環 烯基、經取代或未經取代之雜環基、 由式：-ORa所示基團（式中，Ra與項目（1，）中之定義相同卜 由式：-s〇2Rf所示基團（式中，Rf與項目（1，）中之定義相 同）、 由式：-NRbRc所示基團（式中’ Rb&RC與項目中之定義 相同）、 由式.-c(=〇)Rdm示基團（式中，Rd與項目〇，）中之定義相 同）、 由式· -N(R )C(-〇)R<V/i·示基團（式中，Rg&Rd與項目（r)中 之定義相同）、 由式：_SRe所示基團（式巾，Re與項目（Γ)中之定義相同）、 由式：-N(Rg)S〇2R>示基團（式中，Rg&Rf與項目（ι·)中之 定義相同）、 或者R可鍵結於RA1所鍵結之碳的鄰接碳原子上，與rA1 一起形成經取代或未經取代之環， η係1〜4之整數、 心氳、經取代或未經取代之燒基或者經取代或未經取代 之醯基）。 (8 )如項目（5 )至（7’）中任—項所揭示之化合物其製藥 上所今許之鹽或者其等之溶劑合物，其中r5係由式(Η”所 141666.doc •29- 201028381 不基團， [化 4A] RA：(II) 141666.doc • 28· 201028381 (wherein RA1 and RA2 are independent, chlorine, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted Blocky, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or not a substituted heterocyclic group, a group represented by the formula: -ORa (wherein Ra is the same as defined in the item (1)): a group represented by the formula: -s〇2Rf (wherein, Rf and the item) (1,) has the same definition), a group represented by the formula: -NRbRc (wherein 'Rb&RC is the same as defined in the item), and a group represented by the formula: -c(=〇)Rdm , Rd is the same as defined in the project 〇,), and is defined by the formula -N(R )C(-〇)R<V/i· (in the formula, Rg&dd and the definition in the item (r) The same formula, by the formula: _SRe shown in the group (type towel, Re is the same as defined in the item (Γ)), by the formula: -N(Rg)S〇2R> shows the group (wherein Rg&Rf and The definition in item (ι) is the same), or R may be bonded to a contiguous carbon atom of the carbon to which the RA1 is bonded, together with rA1 to form a substituted or unsubstituted ring, η is an integer of 1 to 4, palpitations, substituted or unsubstituted Base or substituted or unsubstituted thiol). (8) A pharmaceutically acceptable salt or a solvate thereof as disclosed in any one of the items (5) to (7'), wherein r5 is a compound of the formula (Η) 141666.doc • 29- 201028381 No group, [Chem. 4A] RA:

(III) (式中’ RAiRA2與項目(7.)中之定義相同)。 (9)如項目(5’m(8’)中任一項所揭示之化合物其製藥 上所容許之鹽或者其等之溶劑合物，其中尺5係由式㈣所 示基團， [化 5A](III) (wherein RAiRA2 is the same as defined in item (7.)). (9) A pharmaceutically acceptable salt of the compound disclosed in any one of the items (5'm (8'), or a solvate thereof, wherein the rule 5 is a group represented by the formula (IV). 5A]

(ΠΓ) (式中，R、RA2與項目(7，)定義相同)。 ()如項目(5 )至(9’)中任一項所揭示之化合物其製参 上所容許之鹽或去' 盟次者其等之溶劑合物，其中rA1係經取代^ 未經取代之㈣基、由式：_NRbR>示基 ％(ΠΓ) (where R and RA2 are the same as item (7,)). (a) a salt as disclosed in any one of the items (5) to (9'), or a solvate thereof, wherein the rA1 is substituted and unsubstituted (4) Base and formula: _NRbR>

Rc與項目（1，）中之定義相丄上 ^ :項目（1’）中之定義相同）、經取代或未經取代之相 基、由式：赞所示基團（式中，Ra與項目⑺中之定義本 同）或者經取代或未經取代之絲，^❹式·翁所〒 基團（式中，1T與項目（1，）中之定義相同）、由式：顿bR> 不基團(式中’Rb及項目⑺中之定義相同)、由式 -N⑽C(，R、示基團（式中，R^Rd與項目中之定義 141666.doc 201028381 相同）、由式：示基團（式中，Rg&Rf與項目 (η中之定義相同）、經取代或未經取代之烧基、經取代或 未經取代之烯基或者經取代或未經取代之炔基。 一（11 )如項目（5,)至（1〇,)中任一項所揭示之化合物、其製 藥上所容許之鹽或者其等之溶劑合物，其中R1係由式：_ORa 所不基團(式中’ Ra與項目(1，)中之定義相同)或者由式： -NRbRC所*基團(式中，…及以項目⑺中之定義相同)。 “（）如項目（5 )至（11’）中任一項所揭示之化合物、其製 藥上所谷許之鹽或者其等之溶劑合物，其中Ra係經取代或 未經取代之芳基或者經取代或未經取代之烷基，Rb係氫、 二取代或未經取代t院基或者經取代或未經取代之芳基， RC係氫或者經取代或未經取代之烷基。 “(13)如項目(5)至(12,)中任—項所揭示之化合物、其製 藥上所容許之鹽或者其等之溶劑合物，其中氮基。 (14 )如項目（5 )至（13’）中任一項所揭示之化合物、其製 ❿ #上所容許之鹽或者其等之溶劑合物，其中r2係確基。 “（15)如項目（5)至（Η·)中任—項所揭示之化合物、其製 藥上所容許之鹽或者其等之溶劑合物，其中r3係經取代或 未經取代之胺基。 ⑽如項目⑺至(15，)中任—項所揭示之化合物、其製 藥上所容許之鹽或者其等之溶劑合物，其中r3係氯。 (17’)如項目(5’)至(16’)中任—項所揭示之化合物、其製 藥上所容許之鹽或者其等之溶劑合物，r2係氰基或者硝 基，R3係經取代或未經取代之雜芳基，r4係氮，r5係經取 141666.doc * 31 - 201028381 代或未經取代之芳基。 (18’）如項目（5·)至（17，）t任一項所揭示之化合物其製 樂上所容許之鹽或者其等之溶劑合物，其中R2係氰基或者 硝基，R3係經取代或未經取代之雜芳基，R4和r5與鄰接之 碳原子一起係由式（IV)所示基團， [化 6A]Rc is equivalent to the definition in item (1); ^: the definition in item (1') is the same), the substituted or unsubstituted phase group, the formula: the group shown by (in the formula, Ra and The definition in item (7) is the same as that of the substituted or unsubstituted silk, the type of the ❹ · · Weng 〒 group (where 1T is the same as defined in the item (1)), and the formula: ton bR> Non-group (wherein 'Rb is the same as defined in item (7)), from the formula -N(10)C(, R, showing group (where R^Rd is the same as the definition in the project 141666.doc 201028381), by: A group (wherein Rg & Rf is the same as defined in the item (n), a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group or a substituted or unsubstituted alkynyl group. The compound disclosed in any one of the items (5,) to (1), or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R1 is a compound of the formula: _ORa Group (where Ra is the same as defined in item (1)) or by the formula: -NRbRC* group (in the formula, ... and the definition in item (7)). "() as item (5) a compound disclosed in any one of (11'), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the substituted or unsubstituted aryl group of Ra is substituted or unsubstituted Alkyl, Rb is hydrogen, disubstituted or unsubstituted t or substituted or unsubstituted aryl, RC is hydrogen or substituted or unsubstituted alkyl. "(13) as item (5) a compound disclosed in any one of (12), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the nitrogen group is. (14) as in any one of items (5) to (13') The compound disclosed in the item, the salt which is allowed in the preparation of the product, or the solvate thereof, wherein r2 is the base. "(15) as disclosed in item (5) to (Η·) a compound, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein r3 is a substituted or unsubstituted amino group. (10) A compound as disclosed in any one of items (7) to (15), and a pharmaceutical thereof A salt or a solvate thereof, wherein r3 is chlorine. (17') A compound as disclosed in the item (5') to (16') a pharmaceutically acceptable salt or a solvate thereof, r2 is a cyano group or a nitro group, R3 is a substituted or unsubstituted heteroaryl group, r4 is a nitrogen, and the r5 system is taken 141666.doc*31 - 201028381 A substituted or unsubstituted aryl group. (18') A salt or a solvate thereof, as permitted by a compound disclosed in any one of items (5·) to (17,) Wherein R 2 is a cyano group or a nitro group, and R 3 is a substituted or unsubstituted heteroaryl group, and R 4 and r 5 together with a contiguous carbon atom are a group represented by the formula (IV), [Chemical 6A]

丨係 經取代或未經取代之 烷基、經取代或未經取代之烯基、經取代或未經取代之芳 基、經取代或未經取狀料基、經取代絲經取代 炫基、經取代或未經取代之環稀基、經取代或未經取代之 義相同）Lanthanide substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted, substituted silk substituted leuco, Substituted or unsubstituted ring-like, substituted or unsubstituted)

雜環基、由式：.撕所示基峨中，Ra與項目⑺中C 由式：-S02Rf所示基團（式中，Rf 相 兴項目（1·)中之定義 同）、 由式：-NRbRe所示基團（式中，Rb及 相同）In the heterocyclic group, the formula shown by the formula: tearing, Ra and the item (7) in C are represented by the formula: -S02Rf (in the formula, the definition of Rf in the item (1·) is the same), :-NRbRe group (in the formula, Rb and the same)

Re與項目（1，）中之定 義 義相 由式所示基團（式中，Rd與項目〇,)中 同）、 R^Rd與項目（1，）中 由式：-N(Rg)C(=〇)Rd所示基團（式中， 之定義相同） 141666.doc -32· 201028381 由式：-SRe所示基團（式中 或者Re and the definition of the item (1,) are expressed by the formula (in the formula, Rd and the item 〇,), R^Rd and the item (1,) are: -N(Rg) C(=〇)Rd is a group represented by the formula (wherein, the definition is the same) 141666.doc -32· 201028381 by the formula: -SRe group (in the formula

Re與項目（1，）中之定義相同） =式：-N(Rg)S〇2RV斤示基團（式中，Rg&Rf與項目〇，）中之 定義相同）、„!係0〜4之整數）。 U9’）一種醫藥組合物 項所揭示之化合物、其 合物。 ，其含有如項目（5·)至（18，）中任— 製藥上所容許之鹽或者其等之溶劑 (20 )如項目（19，）g己載之醫藥組合物，其係ττκ抑制劑。 一⑵’）如項目（1，）至（4，）、（2AI)、（19,)及（2〇,)中任一項所揭 示之醫藥組合物，其係用以治療及/或預防癌。 (22')一種癌之預防或治療方法，其特徵在於··投予如項 目（5)至（18’）中任一項所揭示之化合物、其製藥上所容許 之鹽或者其等之溶劑合物。 (23，）一種如項目（5，）至（18·)中任一項所揭示之化合物、 其製藥上所容許之鹽或者其等之溶劑合物的用途，其係用 以製造癌之治療藥及/或預防藥。 (24，）如項目（^至。…中任一項所揭示之化合物、其製 藥上所容許之鹽或者其等之溶劑合物，其係用以治療及/ 或預防癌。 (25')—種癌之預防或治療方法，其特徵在於：投予如項 目（1 )至（4')及（2A’）中任一項所揭示之具有ττκ抑制活性的 醫藥組合物。 於某實施形態中，本發明係關於一種含有本發明之化合 物、其製藥上所容許之鹽、或者其等之溶劑合物之ττκ抑 141666.doc -33- 201028381 制劑。 於某實施形態中’本發明係關於一種含有本發明之化合 物、其製藥上所容許之鹽、或者其等之溶劑合物之抗癌 劑。 於某實施形態中，本發明係關於一種含有本發明之化合 物、其製藥上所容許之鹽、或者其等之溶劑合物之免疫系 統疾病治療劑。 於某實施形態中，本發明係關於一種含有本發明之化合 物、其製藥上所容許之鹽、或者其等之溶劑合物之免疫抑 制劑。 於某實施形態中，本發明係關於一種含有本發明之化合 物、其製藥上所容許之鹽、或者其等之溶劑合物之自體免 疫疾病治療劑。 本發明又係關於一種製造本發明之化合物、其製藥上所 容許之鹽、或者其等之溶劑合物的方法、系統、裝置、套 組等。 本發明又係關於一種調製含有本發明之化合物、其製藥 上所谷許之鹽、或者其等之溶劑合物的醫藥組合物之方 法、系統、裝置、套組等。 本發明又係關於一種使用本發明之化合物、其製藥上所 谷許之鹽、或者其等之溶劑合物的方法、系統、裝置、套 組等。 因此，若閱讀以下詳細說明可明白本發明之該等及其他 優點。 141666.doc •34· 201028381 [發明之效果] 本發明提供一種TTK蛋白激酶之有效之抑制劑，進而提 供一種對癌等與TTK相關之疾病、損傷或者狀態而言較為 有效的醫藥。 【實施方式】 以下，一面表示最佳形態一面對本發明加以說明。於本 說明書之整體中，單數形之表現，只要無特別說明，應理 解成亦包含其複數形之概念。因此，單數形之修飾語等 # (例如，於英語之情形時，為「a」、「an」、「the」等冠詞 等），只要無特別說明，應理解成亦包含其複數形之概 念。又，本說明書中所使用之用語，只要無特別說明，應 理解成以上述領域中通常使用之意思而使用。因此，只要 未另外定義，本說明書中所使用之所有專業用語及科學技 術用語具有與本發明所屬領域之業者通常所理解者相同之 意思。於矛盾之情形時，以本說明書（包含定義）優先。 以下對本說明書中所使用之各用語之意思加以說明。各 β 用語於本說明書中，以統一之意思使用，無論是單獨使用 之情形時，或者是與其他用語組合使用之情形時，亦以相 同之意思使用。 以下記載了本說明書中所使用之略語。 [數1] 略語 名稱 HATU 0-(7-氮雜苯并***-1-基)-l，l，3,3-四曱基脲六氟磷酸酯 HOBt 1-羥基苯并*** HOAt 1-羥基-7-氮雜苯并*** DIC NW-異丙基碳化二醯亞胺 141666.doc -35- 201028381 EDC 1-乙基-3-(3-二曱基胺基丙基)碳化二醯亞胺鹽酸鹽 DIEA N，N-二異丙基胺 TEA NMM 三乙基胺 N-曱基嗎啉 B〇C2〇 二碳酸二第三丁酯 TrCl 三苯曱基氣 LHMDS 雙(三甲基矽烧)胺基鋰 NMP N-曱基吡咯啶酮 DMSO 二曱基亞礙 THF 四氫°夫喃 DMF N，N-二曱基甲醯胺 DMA N，N-二甲基乙醯胺 MeCN 乙腈 TFA 三氟乙酸 BINAP 2,2'-雙(二苯基膦基)-1,Γ-聯萘 S-Phos 2-二環己基膦基-2’，6'-二甲氧基聯苯 X-Phos 2-二環己基膦基-2',4'，6'-三異丙基聯苯 DPPF 1,1'-雙(二苯基膦基)二茂鐵 Xantphos 9,9-二曱基-4,6-雙(二苯基膦基)二苯并哌喃 Pd(PPh3)4 四(三苯基膦)鈀 Pd2(OAc)2 乙酸鈀 Pd2(dba)3 三(二亞苄基丙酮)雙把 PdCl2(dtbpf) [1, Γ-雙(二-第三丁基膦基)二茂鐵]鈀(Π)二氣化物 PdCl2(dppf) [1，Γ-雙(二苯基膦基)二茂鐵]-二氣鈀(Π)-二氣曱烷錯合物 TosMIC 曱苯續醯基曱基胩 DEAD 偶氮二曱酸二乙酯 ADDP 1,1'-(偶氮二羰基)二哌啶 DDQ 2,3-二氯-5,6-二氣基-對苯酿i Tf20 三氟甲磺酸酐 TBAF 四丁基氟化銨 於本說明書中，所謂「鹵素」可列舉：氟、氣、溴及 埃。 於本說明書中，所謂「烷基」，包含碳數為1〜10個之直 鏈狀或支鏈狀烷基，例如可列舉：甲基、乙基、正丙基、 異丙基、正丁基、異丁基、第二丁基、第三丁基、正戊 基、異戊基、新戊基、正己基、異己基、正庚基、正辛 基、正壬基、正癸基等。例如，係碳數為1〜6或1〜4個之院 基，例如可列舉：甲基、乙基、正丙基、異丙基、正丁 141666.doc •36· 201028381 基、異丁基、第二丁基、第三丁基、正戊基、異戊基、新 戊基、正己基、異己基。 於本說明書中，所謂「烯基」，包含上述「烷基」中具 有1個或其以上之雙鍵之碳數為2~8個的直鏈狀或支鏈狀烯 例如可列舉：乙烯基、1-丙烯基、2-丙烯基、1_ 丁烯 基2-丁烯基、3-丁烯基、丨，3_丁二烯基、3_曱基_2_丁烯 基等。 於本說明書中，所謂「炔基」，包含上述「烷基」中具 有1個痞1 iv u > 、 之二鍵之碳數為2〜8個的直鍵狀或支鏈狀快 基例如可列舉：乙炔基、丙炔基、丁炔基等。進而，亦 可具有1個或其以上之雙鍵。 於本說明書中，所謂「環烷基」，包含碳數為3〜15之環 狀飽和煌基’例如可列舉：帛丙基、環丁基、環戊基、環 己基、環庚基、環辛基、交聯環式烴基、螺烴基等。例如 可列舉· ί裒丙基、環丁基、環戊基、環己基、交聯環式烴 基。 再者，於本說明書中，所謂「交聯環式烴基」，包含可 自兩個以上之環共有2個或其以上之原子的碳數為5~12之 脂肪族環除去一個氫之基。具體而言，可列舉：雙環 [2丄〇]戊基、雙環[2.2」]庚基、雙環[2 2 2]辛基及雙環 [3‘2.1]辛基、三環[2.2.10]庚基、雙環[33丨]壬烷卜金剛 烷基、2-金剛烷基等。 又，於本說明書中，所謂「螺烴基」，包含可自兩個烴 環共有1個碳原子而構成之環除去一個氫之基。具體而 141666.doc •37· 201028381 言，可列舉螺P.4j辛基等。 於本說明書中，「環烯基包 3奴數為3〜7個之環狀不飽 和月曰肪族烴基，例如可列舉： 嬙其播展丙席基、環丁烯基、環戌 烯基、環己烯基、環庚烯基 基、環戊稀基、環己稀基。環烯環丁婦 4城 職㈣基#亦包含環t具有不飽 和鍵之交聯環式烴基及螺烴基。 於本說明書中，所謂「芳基 # 匕3早環方香族烴基（例 如·本基）及多環芳香族煙基（例如： Θ 葱基、2·葱基、9·葱基、r菲基、2·菲基、3_菲二· :)、,結等)。例如可列舉:苯基或萘基U-萘基、2-萘 ^本說明書中’所謂「雜芳基」，包含單環芳香族雜環 縮合方香族雜環式基。單環芳香族雜環式基包A由 環内可含有卜4個氧 雜哀式基包含由 …氧原子、硫原子及/或氮原子之5〜8員芳 =生之亦可於可取代之任意位置上具有鍵結的基。； 合方香族雜環式基包含環内可含有W個氧原子、 φ 及/或氮原子之5〜8 g »关也_L原子 —香族雜環:個5〜8員芳香族碳環或其 上具有鍵結的基。而成之亦可於可取代之任意位置 於本說明書中， 「# (例如〜夫喃基、3 例如可列舉：°夫喃基Re is the same as defined in item (1)) = =: -N(Rg)S〇2RV shows the same group (in the formula, Rg&Rf is the same as in item 〇), „!系0~ An integer of 4) U9') A compound, a compound thereof, disclosed in the pharmaceutical composition, which contains a pharmaceutically acceptable salt or a solvent thereof as in the items (5·) to (18) (20) A pharmaceutical composition as described in item (19) g, which is a ττκ inhibitor. One (2)') as items (1,) to (4,), (2AI), (19,) and (2) The pharmaceutical composition disclosed in any one of the above, which is for treating and/or preventing cancer. (22') A method for preventing or treating cancer, characterized in that it is administered as in item (5) to A compound disclosed in any one of (18'), a pharmaceutically acceptable salt thereof, or a solvate thereof, etc. (23,) a method as disclosed in any one of items (5,) to (18) The use of a compound, a pharmaceutically acceptable salt thereof, or a solvate thereof, for the manufacture of a therapeutic and/or preventive agent for cancer. (24,) As for the item (^ to. A disclosed compound, a pharmaceutically acceptable salt thereof, or a solvate thereof, for use in the treatment and/or prevention of cancer. (25') A method of preventing or treating cancer, characterized in that: A pharmaceutical composition having ττκ inhibitory activity as disclosed in any one of items (1) to (4') and (2A'). In one embodiment, the present invention relates to a compound containing the present invention, a pharmaceutically acceptable salt thereof, or a solvate thereof, ττκ 141666.doc -33-201028381. In one embodiment, the present invention relates to a compound containing the present invention, which is pharmaceutically acceptable. An anticancer agent of a salt or a solvate thereof, etc. In one embodiment, the present invention relates to an immune system disease comprising a compound of the present invention, a pharmaceutically acceptable salt thereof, or a solvate thereof. In a certain embodiment, the present invention relates to an immunosuppressive agent comprising a compound of the present invention, a pharmaceutically acceptable salt thereof, or a solvate thereof, etc. In one embodiment, the present invention The present invention relates to a therapeutic agent for autoimmune diseases comprising a compound of the present invention, a pharmaceutically acceptable salt thereof, or a solvate thereof, etc. The present invention further relates to a method for producing a compound of the present invention which is pharmaceutically acceptable A method, system, device, kit, etc. of a salt or a solvate thereof, etc. The present invention further relates to a solvate comprising a compound of the present invention, a pharmaceutically acceptable salt thereof, or the like Method, system, device, kit, etc. of the pharmaceutical composition. The present invention further relates to a method, system, and apparatus for using the compound of the present invention, a pharmaceutically acceptable salt thereof, or a solvate thereof, The above and other advantages of the present invention will become apparent upon reading the following detailed description. 141666.doc •34· 201028381 [Effects of the Invention] The present invention provides an effective inhibitor of TTK protein kinase, and further provides a medicine which is effective for diseases, injuries or conditions related to TTK such as cancer. [Embodiment] Hereinafter, the present invention will be described with reference to the best mode. As a whole, the expression of the singular form is understood to include the concept of its plural form unless otherwise stated. Therefore, the modifier of the singular form, etc. (for example, in the case of English, the articles such as "a", "an", "the", etc.), unless otherwise specified, should be understood as including the concept of the plural form. . Further, the terms used in the present specification are to be understood as being used in the above-mentioned fields unless otherwise specified. Therefore, all of the technical terms and scientific technical terms used in the present specification have the same meaning as commonly understood by those skilled in the art to which the present invention pertains, unless otherwise defined. In the case of conflicts, this manual (including definitions) takes precedence. The meaning of each term used in the specification will be described below. Each of the β terms is used in the same meaning in the specification, and is used in the same sense when used alone or in combination with other terms. The abbreviations used in the present specification are described below. [Number 1] Abbreviation name HATU 0-(7-azabenzotriazol-1-yl)-l,l,3,3-tetradecylurea hexafluorophosphate HOBt 1-hydroxybenzotriazole HOAt 1 -hydroxy-7-azabenzotriazole DIC NW-isopropylcarbodiimide 141666.doc -35- 201028381 EDC 1-ethyl-3-(3-didecylaminopropyl) carbonized醯imine hydrochloride DIEA N,N-diisopropylamine TEA NMM Triethylamine N-mercaptomorpholine B〇C2 〇dicarbonate dibutyl TrCl Triphenyl sulfhydryl gas LHMDS double (three Acrylyl)N-based lithium NMP N-decylpyrrolidone DMSO Diterpenoid THF Tetrahydrofuran DMF N,N-dimercaptocarhamamine DMA N,N-dimethylacetamide MeCN Acetonitrile TFA trifluoroacetic acid BINAP 2,2'-bis(diphenylphosphino)-1, fluorene-binaphthalene S-Phos 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl X -Phos 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl DPPF 1,1'-bis(diphenylphosphino)ferrocene Xantphos 9,9-didecyl -4,6-bis(diphenylphosphino)dibenzopyran Pd(PPh3)4 Tetrakis(triphenylphosphine)palladium Pd2(OAc)2 Palladium acetate Pd2(dba)3 Tris(dibenzylideneacetone) ) double PdCl2 (dtbpf) [1, Γ-double (two- Tert-butylphosphino)ferrocene]palladium (deuterium) disulphide PdCl2 (dppf) [1, bis-bis(diphenylphosphino)ferrocene]-digas palladium (Π)-dioxane Alkyl complex TosMIC 曱 醯 醯 曱 曱 胩 胩 DEAD ED azodicarboxylate ADDP 1,1 '-(azodicarbonyl)dipiperidine DDQ 2,3-dichloro-5,6-di Gas-P-Benzene Brewing i Tf20 Trifluoromethanesulfonic anhydride TBAF Tetrabutylammonium fluoride In the present specification, the term "halogen" includes fluorine, gas, bromine and angstrom. In the present specification, the "alkyl group" includes a linear or branched alkyl group having 1 to 10 carbon atoms, and examples thereof include a methyl group, an ethyl group, a n-propyl group, an isopropyl group, and a n-butyl group. Base, isobutyl, t-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, n-octyl, n-decyl, n-decyl, etc. . For example, a base having a carbon number of 1 to 6 or 1 to 4, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl 141666.doc • 36· 201028381 base, isobutyl , a second butyl group, a tert-butyl group, a n-pentyl group, an isopentyl group, a neopentyl group, a n-hexyl group, an isohexyl group. In the present specification, the "alkenyl group" includes a linear or branched olefin having 2 to 8 carbon atoms having one or more double bonds in the above "alkyl group", and examples thereof include a vinyl group. , 1-propenyl, 2-propenyl, 1-butenyl 2-butenyl, 3-butenyl, anthracene, 3-butadienyl, 3-hydrazino-2-butenyl, and the like. In the present specification, the "alkynyl group" includes a straight bond or a branched fast group having 1 痞1 iv u > in the above "alkyl group" and having 2 to 8 carbon atoms in the two bonds. Examples thereof include an ethynyl group, a propynyl group, a butynyl group and the like. Further, it may have one or more double bonds. In the present specification, the "cycloalkyl group" includes a cyclic saturated fluorenyl group having a carbon number of 3 to 15, and examples thereof include a fluorenyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a ring. An octyl group, a crosslinked cyclic hydrocarbon group, a spirohydrocarbyl group or the like. For example, 裒 propyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, and crosslinked cyclic hydrocarbon group are mentioned. In the present specification, the "crosslinked cyclic hydrocarbon group" includes an aliphatic ring having 5 to 12 carbon atoms which may have two or more atoms in two or more rings, and one hydrogen group is removed. Specific examples thereof include bicyclo[2丄〇]pentyl, bicyclo[2.2"]heptyl, bicyclo[2 2 2]octyl and bicyclo[3'2.1]octyl, and tricyclo[2.2.10]g Base, bicyclo[33丨]decaneb-adamantyl, 2-adamantyl, and the like. Further, in the present specification, the "spirohydrocarbyl group" includes a group in which one hydrogen atom can be removed from a ring having two carbon atoms in two hydrocarbon rings. Specifically, 141666.doc •37· 201028381 It can be exemplified by the snail P.4j octyl and the like. In the present specification, the "cycloalkenyl group 3" is a cyclic unsaturated unsaturated menic hydrocarbon hydrocarbon group having 3 to 7 ring numbers, and examples thereof include: 嫱, its broadcast of a propyl group, a cyclobutenyl group, a cyclodecenyl group a cyclohexenyl group, a cycloheptenyl group, a cyclopentyl group, a cyclohexyl group. The cycloalkenyl ring 4 4 (4) group also contains a crosslinked cyclic hydrocarbon group and a spirohydrocarbyl group having a ring t having an unsaturated bond. In the present specification, the term "aryl group #3" is an early aromatic aromatic hydrocarbon group (for example, a base group) and a polycyclic aromatic group (for example, onion base, onion base, onion base, and onion base, r Phenylidene, phenanthrenyl, phenanthrene, phenanthrene, phenanthrene, etc., for example, phenyl or naphthyl U-naphthyl, 2-naphthyl, "the so-called "heteroaryl" in the present specification, A monocyclic aromatic heterocyclic condensed scented heterocyclic group is included. The monocyclic aromatic heterocyclic group A may contain 4 oxo groups in the ring, and may be substituted by 5 to 8 members of the oxygen atom, sulfur atom and/or nitrogen atom. A base with a bond at any position. The compound aromatic heterocyclic group contains 5 to 8 g of W oxygen atoms, φ and/or nitrogen atoms in the ring. » Guan also _L atom - Fragrant heterocyclic ring: 5 to 8 member aromatic carbon A ring or a group having a bond thereon. It can also be replaced at any position in this specification, "# (for example, ~Fanmu, 3, for example: °

mi、 夫味基）、㈣基（例如：噻吩A 3_嗟吩基)、㈣基(例如一基 基）、咪唑基（例如」， 唂基3_°比咯 .1-咪唑基、2-咪唑基、扣味 峻基（例如H坐基、3_„比0坐基'“一坐^、°比 坐暴）二唑基（例 141666.doc -38- 201028381 ，一唾· 1 _ 基、1，2,4-三唾 _3_ 基、1，2,4-三吐 _4_ 基）四唑基（例如：1-四唑基、2-四唑基、5_四唑基）、噁 坐基（例如：2-噁唑基、4-噁唑基、5-噁唑基）、異噁唑基 (例如.3_異噁唑基、4_異噁唑基、5-異噁唑基）、噻唑基 (】 2嗟唾基、4-嘆唾基、5-嘆吐基）、嘆二嗤基、異 噻坐基（例如：3_異噻唑基、4異噻唑基、5_異噻唑基）、 比啶基（例如：2_°比啶基、3-吡啶基、4·°比啶基）、噠嗪基 (例如· 3-噠°秦基、4·健嗪基）、嘧啶基（例如：2-嘧咬基、 4_嘧啶基、5·嘧啶基）、呋吖基（例如：3-呋吖基）、吡嗪基 (例如.2_吡嗪基）、噁二唑基（例如：1，3,4-噁二唑-2-基）、 苯并呋喃基（例如：2-苯并[b]呋喃基、3_苯并[b]呋喃基、 4-苯并[b]呋喃基、5_苯并[b]呋喃基、6苯并[b]呋喃基、7_ 苯并[b]呋喃基）、苯并噻吩基（例如：2苯并[b]噻吩基、％ 苯并[b]噻吩基、4-笨并[b]噻吩基、5_苯并噻吩基、6_ 苯并[b]噻吩基、7-苯并[b]噻吩基）、苯并咪唑基（例如：卜 苯并咪唑基、2-苯并咪唑基、4-笨并咪唑基、5_笨并咪唑 基）、二苯并呋喃基、苯并噁唑基、苯并噻唑基、喹噁啉 基（例如：2-喹噁啉基、5_喹噁啉基、6_喹噁啉基）、唓啉 基（例如：3·啐啉基、4-4啉基、5_咔啉基、6_啐啉基、厂 4啉基、8-4啉基）、喹唑啉基（例如：2_喹唑啉基、喹 峻啉基' 5-喧嗤啉基、6_喹唑啉基、7_喹唑啉基、啥吨 啉基）、喹啉基（例如：2-喹啉基、3-喹啉基、4·喹嘛基、5_ 喹啉基、6-喹啉基、7-喹啉基、8_喹啉基）、酞嗪基（例 如：1-酞嗪基、5-酞嗪基、6-酞嗪基）、異喹啉基（例如：卜 141666.doc •39· 201028381 異喹啉基、3-異喹啉基、4_異喹啉基、5_異喹 ㈣基Ή㈣基、8·異㈣基）、嗓呤基、^ Μ 如：2-嗓唆基、4嗓唆基、卜嗓咬基”嗓、土（例 基、啡咬基…丫咬基（例如：1个定基小丫以、)/唾 基、4个定基、9心基）、㈣基（例如： 噪基、3-十朵基、4_十朵基、5+朵基 吟、 口朵基）、異㈣基、啡嗓基（例如：1♦秦基木基、Μ 啡噻嗪基（例如：卜啡噻嗪Α、7 i '啡嗪基）或 4-啡嗟嗪基）等。^ 2_啡㈣基、3·Μ。秦基、Mi, succinyl), (d)yl (eg thiophene A 3 - fluorenyl), (tetra) (eg a base), imidazolyl (eg", fluorenyl 3 _ lb. 1-imidazolyl, 2- Imidazolyl group, deodorizing squaring base (such as H sitting base, 3_„ than 0 sitting base '“ sit ^, ° than sitting storm) diazolyl (example 141666.doc -38- 201028381, a salivary · 1 _ base, 1,2,4-tris-7-yl, 1,2,4-tris--4-yl)tetrazolyl (eg 1-tetrazolyl, 2-tetrazolyl, 5-tetrazolyl), evil Sit-based (eg, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (eg, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazole) Base), thiazolyl (] 2 嗟 sinyl, 4- sinyl, 5-sinter), succinyl, isothiazyl (eg, 3-isothiazolyl, 4 isothiazolyl, 5_) Isothiazolyl), pyridyl (for example: 2_°pyridinyl, 3-pyridyl, 4·pyridinyl), pyridazinyl (for example, 3-indylmethyl, 4·oxazinyl), Pyrimidinyl (eg, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), furazinyl (eg, 3-furazyl), pyrazinyl (eg, 2-pyrazinyl), malignant Azolyl (for example : 1,3,4-oxadiazol-2-yl), benzofuranyl (for example: 2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b] Furanyl, 5-benzo[b]furanyl, 6-benzo[b]furanyl, 7-benzo[b]furanyl), benzothienyl (eg 2 benzo[b]thienyl, % benzene And [b]thienyl, 4-benzo[b]thienyl, 5-benzothiophenyl, 6-benzo[b]thienyl, 7-benzo[b]thienyl), benzimidazolyl (eg :benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-bromoimidazolyl, dibenzofuranyl, benzoxazolyl, benzothiazolyl, quinoxalinyl (eg, 2-quinoxalinyl, 5-quinoxalinyl, 6-quinoxalinyl), porphyrin (eg, 3· porphyrin, 4-4 phenyl, 5- porphyrin, 6 _ porphyrin group, plant 4 phenyl group, 8-4 phenyl group), quinazolinyl group (for example: 2-quinazolinyl, quinolinyl group 5-pyridyl, 6-quinazolinyl, 7-quinazolinyl, xanthryl), quinolyl (for example: 2-quinolyl, 3-quinolyl, 4-quinolinyl, 5-quinolinyl, 6-quinolinyl, 7- Quinolinyl, 8-quinolinyl), pyridazinyl (eg, 1- Azinyl, 5-pyridazinyl, 6-pyridazinyl), isoquinolinyl (eg: 141666.doc •39· 201028381 isoquinolyl, 3-isoquinolinyl, 4-isoquinolyl, 5_Isoquino(tetra)ylfluorenyl(tetra)yl, 8·iso(tetra)yl), fluorenyl, ^ Μ For example: 2-mercapto, 4-mercapto, 嗓 嗓 嗓 嗓 土, soil (eg base, morphine) ...bite base (for example: 1 base small to 、, / salivation, 4 base, 9 core), (iv) base (for example: noise base, 3-ten radical, 4-10 base, 5+朵基吟, 口基基), iso(tetra)yl, morphyl (for example: 1♦ 秦基木基, Μmorphthiazinyl (eg morphinthiazinium, 7 i 'cyanoazinyl) or 4- Phenothrazinyl) and the like. ^ 2_Brown (four) base, 3·Μ. Qin Ji,

Q 於本說明書中’所謂「雜環基」，包含 個氧原子、硫原子及/或氮原子，且可取代含有1〜4 I具有鍵結之非芳香族雜環式基。又，此:位置上 式基進而可由碳數為卜4之燒基鏈㈣族雜環 列舉5〜6員環）或苯環。若為非芳 縮《環烷（可 飽和。例如係5〜8員環。例如可列舉H為飽和亦可為不 洛琳基、3,略琳基、卜…定基、2·:二：基〜 咬基…比略相咪唾琳基、…心 基、1州基、2州基、4 :基、…淋 卜比唾琳基、…琳基、“ 基、咪唾咬酮、 口比唾吩其 」L , 土、1 _ D比0坐咬基、3 - 比坐疋基、4“比唾咬基、派相、 基 娘咬基、4_㈣基、秦基、^ 基、&gt; 啉基、3w x 奈基、哌嗪酮、2-嗎 / Μ基' N_M基 '四氣Μ基、四氮咬喃基 於本說明書中，所謂「酿基」，包含甲酿基、經取代或 141666.doc 201028381 未經取代之炫基艘基、經取代或未經取代之烯基羰基、經 取代或未經取代之環烷基羰基、經取代或未經取代之環烯 基羰基、經取代或未經取代之芳基羰基、經取代或未經取 代之雜芳基羰基、經取代或未經取代之雜環基羰基。 於本說明書中，所謂「伸烷基」，包含i〜6個亞甲基連續 而成之2價基’具體而言可列舉：亞甲基、伸乙基、伸丙 基、伸丁基、伸戊基及伸己基等。 於本”兑明書中，所謂r伸烯基」，包含2~6個亞甲基連續 _ 而成之2價基’且碳_碳鍵之至少一個為雙鍵者。 於本說明書中，所謂「伸炔基」，包含2〜6個亞甲基連續 而成之2價基，且碳_碳鍵之至少一個為三鍵者。 於本說明書中，所謂「R^〇RC與氮原子一起形成之經取 代或未經取代之含氮雜環」可列舉以下環。 [化 16] 人…Rb- /、Q In the present specification, the "heterocyclic group" includes an oxygen atom, a sulfur atom and/or a nitrogen atom, and may be substituted for a non-aromatic heterocyclic group having a bond of 1 to 4 I. Further, this: the above formula may further be a 5- to 6-membered ring or a benzene ring, which may be represented by a (four-membered heterocyclic ring having a carbon number of 4). If it is non-aromatic "cycloalkane (saturated. For example, it is a 5- to 8-membered ring. For example, H may be saturated or may be linalyl, 3, lensyl, b... fixed, 2: 2: base ~ bite base... than slightly squirting, singer, heart, 1 state base, 2 state base, 4: base, ... 淋 比 比 唾 、 、 ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... Speaking, "L, soil, 1 _ D is more than 0 sitting on the base, 3 - than sitting on the base, 4" than on the base, the faction, the base bite, 4_(four) base, Qinji, ^ base, &gt; Alkyl group, 3w x-nyl group, piperazinone, 2-?/fluorenyl 'N_M-based' tetra-halogenyl group, tetra-nitrogen-based group, based on the present specification, the so-called "brewed group", including a brewing group, substituted or 141666.doc 201028381 Unsubstituted aryl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted cycloalkylcarbonyl, substituted or unsubstituted cycloalkenylcarbonyl, substituted Or an unsubstituted arylcarbonyl group, a substituted or unsubstituted heteroarylcarbonyl group, a substituted or unsubstituted heterocyclic carbonyl group. In the present specification, the term "alkylene group" includes i~6 Methylene continuous The specific two-valent group can be exemplified by methylene, ethyl, propyl, butyl, pentyl and hexyl. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; a methyl group continuously formed as a divalent group, and at least one of the carbon-carbon bonds is a triple bond. In the present specification, the term "R^〇RC is substituted or unsubstituted with a nitrogen atom to form a nitrogen-containing impurity. The ring can be exemplified by the following ring. [Chemistry 16] People...Rb- /,

No /、n〇 ArNo /, n〇 Ar

O RO R

(此處’作為H ’例如可列舉：氫、經取代或未經取代之院 基、經取代或未經取代之醯基、經取代或未經取代之胺 基、南素、隸、硝基、氰基、缓基）。 141666.doc -41 - 201028381 於本說明書中 取代或未經取代 [化 16A] ，所謂「R〜和RW與氮原子一起形成之經 之含氮雜環」可列舉以下環。(Here, 'as H' can be exemplified by hydrogen, substituted or unsubstituted thiol, substituted or unsubstituted fluorenyl, substituted or unsubstituted amine, sulphate, nitro, nitro , cyano group, slow base). 141666.doc -41 - 201028381 In the present specification, the following ring is exemplified as the "nitrogen-containing heterocyclic ring formed by R and RW together with a nitrogen atom".

(此處’作為R'，可列舉 經取代之烷 氫、經取代或未 141666.doc -42. 201028381 基、-S〇2-(Cl-C3烷基）、經取代或未經取代之烷氧基）。 於本說明書中，R〗、…及汉5中之式：c(=〇)Rd(式中， Rd與上述（Γ)中之定義相同）可分別不同。R1、R2及R5中之 式：-N(Rg)C(=〇)Rd(式中，Rg&amp;Rd與上述（1，）中之定義相 同）可分別不同。R1、R4及R5中之式：_NRbRC(式中，Rb及 Rc與上述（1，）中之定義相同）可分別不同。 於本說明書中，作為「經取代或未經取代之烷基」、「經(herein 'as R', a substituted alkane hydrogen, substituted or not 141666.doc -42. 201028381 base, -S〇2-(Cl-C3 alkyl), substituted or unsubstituted alkane Oxy). In the present specification, the formulas of R, ..., and 5: c(=〇) Rd (where Rd is the same as defined in the above (Γ)) may be different. The formula of R1, R2 and R5: -N(Rg)C(=〇)Rd (wherein Rg&amp;Rd is the same as defined in the above (1)) may be different. The formula of R1, R4 and R5: _NRbRC (wherein Rb and Rc are the same as defined in the above (1)) may be different. In this specification, as a "substituted or unsubstituted alkyl group",

取代或未經取代之烯基」、「經取代或未經取代之炔基」、 「經取代或未經取代之芳基」、「經取代或未經取代之環烷 基」、「經取代或未經取代之環烯基」、「經取代或未經取代 之雜芳基」、「經取代或未經取代之雜環基」、「經取代或未 經取代之烷氧基」、「經取代或未經取代之醯基」、「經取代 或未經取代之伸烷基」、「經取代或未經取代之伸烯基」、 「經取代或未經取代之伸炔基」或者「R^〇Re與氮原子— 起形成之經取代或未經取代之含氮雜環」中之取代基，例 如係選自由羥基、羧基、^素、函化烷基（例如：c C^CF3、c^CClO、硝基、亞硝基、氰基、烷基（例如： 曱基、乙基、異丙基、第三丁基）、稀基（例如：乙稀基）、 炔基（例如：乙炔基）、環烷基（例如：環丙基、金剛烷 基）、環燒基院基（例如：環己基甲基、金剛燒基甲基）、環 烯基（例如：環丙烯基）、芳基（例如：苯基、萘基）、芳美 烷基（例如：节基、笨乙基）、雜芳基（例如：吡啶基、呋^ 基）、雜芳基烧基（例如：吼咬基曱基）、雜環基（例如：旅 啶基）、雜環基烧基（例如：嗎啉基甲基）、烷氧基（例如： 141666.doc -43- 201028381 甲氧基、乙氧基、丙氧基、丁氧基）、鹵化烷氧基（例如： 0CF3)、烯氧基（例如：乙烯氧基、烯丙氧基）、芳氧基（例 如：苯氧基）、烷氧基羰基（例如：曱氧基羰基、乙氧基羰 基、第二丁氧基羰基）、芳基烧氧基（例如：苄氧基）、胺基 (例如·烧基胺基（例如：甲基胺基、乙基胺基、二甲基胺 基）、醯基胺基（例如：乙醯胺基、苯甲醯基胺基）、芳基烷 基胺基（例如：苄基胺基、三笨甲基胺基）、羥基胺基、烷 基胺基烷基（例如··二乙基胺基甲基）、胺磺醯基、側氧 基、胺甲醯基等所組成之群。可由丨個該取代基取代。參 於本說明書中，作為「經取代或未經取代之胺基」、「經 取代或未經取代之胺甲醯基」、「經取代或未經取代之胺磺 醯基」之取代基，可列舉：烷基、烯基、芳基、雜芳基、 烷基羰基、芳基羰基、雜芳基羰基、雜環基羰基、烷氧基 羰基、芳氧基羰基、雜芳氧基羰基、雜環氧基羰基、胺磺 醯基、胺甲醯基、烷基磺醯基、環烷基磺醯基、芳基磺醯 基、雜芳基磺醯基、雜環基磺醯基、烷基亞磺醯基、環烷 基亞磺醯基、芳基亞磺醯基、雜芳基亞磺醯基、雜環基亞_ 磺醯基、羥基、巯基、亞磺酸基、磺基、胺基等。 在本說明書中，「經取代或未經取代之環烷基烷基」、 「經取代或未經取代之芳基烷基」、「經取代或未經取代之 雜芳基烷基」、「經取代或未經取代之雜環基烷基」、「經取 代或未經取代之烷基羰基」、「經取代或未經取代之烷氧基 羰基」、「經取代或未經取代之芳基烷氧基」、「_化烷 基」、「經取代或未經取代之烷基磺醯基」、「經取代或未經 141666.doc 201028381 取代之烷氧基」及「經取代或未經取代之烷基亞磺醯基」 之烧基部分意指上述「院基」。 在本說明書中，「經取代或未經取代之烷氧基」及「鹵 化院氧基」之烷氧基部分意指上述「烷氧基」。 在本說明書中’「經取代或未經取代之烯基羰基」及 「經取代或未經取代之烯氧基」之烯基部分意指上述「烯 基」。 在本說明書中，「經取代或未經取代之環烷基羰基」及 「經取代或未經取代之環烷基烷基」之環烷基部分意指上 述「環烷基」。 在本說明書中’ Γ經取代或未經取代之環烯基羰基」之 環烯基部分意指上述「環烯基」。 於本說明書中，「經取代或未經取代之芳基烧基」、「經 取代或未經取代以基㈣」、「經取代或未經取代之芳氧 基幾基」、「絲代或未經取代之芳基料基」、「經取代或 未經取代之芳氧基」、「經取代或未經取代之芳基續醯基」 及「經取代或未經取代之芳基亞續醯基」之芳基部分意指 上述「芳基」。 「，本說W中’「經取代或未經取代之雜芳基幾基」、 ::代：未經取代之雜芳基院基」、「經取代或未經取代 及Γ基幾基」、「經取代或未經取代之雜芳基績醯基」 未經取代之雜芳基亞續醯基」之雜芳基部分 意扎上述「雜芳基」。 於本說明書中，「姆雨/上 ，、取代或未經取代之雜環基羰基」、 141666.doc -45- 201028381 「經取代絲經取代之雜環基絲」、「經取代或未經 之雜環氧基絲」、「經取代或未經取代之雜環基續酿基 及「經取代或未經取代之雜環基亞_基」之雜環基^ 意指上述「雜環基」。 77 作為本發明之化合物之製藥上所容許的鹽’可列舉以 鹽。 卜 作為驗性鹽，例如可列舉：納鹽、鉀鹽^金屬鹽；_ 鹽、鎖鹽等驗土金屬m·三甲基胺鹽、三乙基胺 鹽、二環己基胺鹽、乙醇胺鹽、二乙醇胺鹽、三乙二胺 鹽、普魯卡因鹽，胺鹽、二乙醇胺鹽或乙二胺鹽等脂 肪族胺鹽；N，N-二节基乙- 曰 下丞G一胺、卞本乙胺鹽等芳烷基胺 鹽·，Μ鹽、甲基対鹽、料鹽、異^鹽等雜環芳香 族胺鹽；四甲基録鹽、四乙基錢鹽、节基三甲基銨鹽、节 基三乙基銨鹽、节基三丁基銨鹽、甲基三辛基銨鹽、四丁 基錄鹽等四級㈣；精胺酸鹽、離胺酸鹽等驗性胺基酸越 等。 &amp; 參 作為酸性鹽，例如可料：a酸鹽、硫㈣、确酸鹽、 磷酸鹽、碳酸鹽、碳酸氫鹽、過氣酸鹽等無機酸鹽；乙酸 鹽、丙酸鹽、乳酸鹽、順丁烯二酸鹽、反丁烯二酸鹽、酒 石酸鹽、蘋果酸鹽、檸檬酸鹽、抗壞血酸料有機酸鹽； 甲續酸m項酸鹽 '笨_鹽、對甲笨姐鹽等績酸 鹽；天冬醯胺酸鹽、麩胺酸鹽等酸性胺基酸等。 所謂溶劑合物意指本發明之化合物或其製藥上所容許之 鹽的溶劑合物，例如可列舉：醇(例如：乙醇)合物或水合 141666.doc -46 - 201028381 物等。作為水合物，可列舉：丨水合物、2水合物等。 (本發明之較好之吡啶衍生物化合物） 該具有TTK抑制活性的醫藥組合物中所含之化合物、其 製藥上所容許之鹽或者其等之溶劑合物或前藥（酯、醯胺 等）中，上述取代基可為本說明書中所揭示之任意取代 基，例如可使用用以解決課題之手段中例示之任意的較好 之取代基。 考慮本發明之咬衍生物之情形時，可考慮以下要素。 本發明之較好實施形態中，例示於以下（A1)〜(A3)中。 各記號與上述記載定義相同。 (A1) 各取代基之定義，只要無特別說明，與上述項目 之定義相同 於通式[1]中， [化 17] R3 ❿ rVyr2 R人又R1 經取代或未經取代之 ' -C(=0)Rd . -N(Rg)C 經取代或未經取代之 作為 R1，可列舉：_〇Ra、_NRbRC、 芳基、經取代或未經取代之雜芳基 (=0)Rd、經取代或未經取代之烷基、 烯基、-SRe、-s〇2Rf、氫。 、盈取代或未經取代之炫 例如可列舉：-〇Ra、-NRbRc。 此處，作為Ra及Rb，可列舉 141666.doc •47- 201028381 基、經取代或未經取代之芳基、經取代或未經取代之雜芳 基、經取代或未經取代之雜環基。此處，所謂經取代或未 經取代之垸基，尤其可列舉··胺基烧基、經基燒基、燒氧 基烧基、C1-C7燒基 '酿基烧基、燒基續醯基烧基、燒基 磺醯基胺基烷基、脂肪族環狀烷基、雜芳基烷基及芳基^ 基。又，所謂脂肪族環狀烷基，可列舉：環丙基、環丁 基、環庚基、金剛院基、雙環己基、雙環壬基、及雙環辛 基作為R，可列舉：氫或者經取代或未經取代之烧基。 作為R1，例如可列舉：翁…NRbRC。此處Rb可列❹ 舉：經取代或未經取代之㈣、經取代或未經取代之芳 基、經取代或未經取代之雜環基。Re可列舉氫。 作為R ’可列舉：氰基、石肖基、經取代或未經取代之芳 基、經取代或未經取代之雜芳基、齒素、經取代或未經取 代之烯，、經取代或未經取代之炔基、_c(=〇)Rd、_N(Rg) C(-0)R、經取代或未經取代之烷基或者氫。 例如可列舉.氰基、頌基、經取代或未經取代之芳基 或者經取代或未經取代之雜芳基。 〇 例如為氰基。 作為R，可列舉：經取代或未經取代之胺基、氮、齒 素0 例如為經取代或未經取代之胺基或者氫。 例如為-NH2。 作為R4’可列舉：氫、_NRbRC、_素。 例如為氫。 141666.doc -48- 201028381 作為 R5,可列舉：_NRbRC、_c( = 〇)Rd、_N(Rg)c( = 〇)Rd、 取代或未㈣代之Μ、經取代縣鋒狀稀基或者 經取代或未經取代^基、經取代或未經取狀雜芳基、 經“ ' 氫 例如為 _NRbRC、-C(=〇)Rd或·ΝΗ(：(=0)Μ。 此處作為R，可列舉：經取代或未經取代之芳基、經 取代或未絲代之雜芳基^作為Re，可列舉氫。作為^， ❹ 可列舉：經取代或未經取代之芳基、經取代或未經取代之 雜芳基、經取代或未經取代之烷基。 作為R命J如為_NRbRC，Rb係經取代或未經取代之芳基 或者經取代或未經取代之雜芳基，Re係氫。 土 此處’作為Rb’可列舉：經取代之苯基或者經取代之嘆 吩。作為經取代之笨基或者經取狀㈣之取代基，可列 舉：雜芳基、胺基、醯基、烯基、烷氧基、烷基、烯基。 以下之實施形態亦可又為一個實施形態。 (A2) 各取代基之定義，只要無特別說明，與上述項目中 之定義相同。 於通式[1]中， [化 18] R3Substituted or unsubstituted alkenyl", "substituted or unsubstituted alkynyl", "substituted or unsubstituted aryl", "substituted or unsubstituted cycloalkyl", "substituted Or unsubstituted cycloalkenyl", "substituted or unsubstituted heteroaryl", "substituted or unsubstituted heterocyclic", "substituted or unsubstituted alkoxy", Substituted or unsubstituted thiol group, "substituted or unsubstituted alkylene group", "substituted or unsubstituted alkylene group", "substituted or unsubstituted alkynyl group" or The substituent in the "substituted or unsubstituted nitrogen-containing heterocyclic ring formed by R^〇Re and a nitrogen atom" is, for example, selected from a hydroxyl group, a carboxyl group, a compound, and a functionalized alkyl group (for example, c C^). CF3, c^CClO, nitro, nitroso, cyano, alkyl (eg fluorenyl, ethyl, isopropyl, tert-butyl), dilute (eg ethylene), alkynyl ( For example: ethynyl), cycloalkyl (eg cyclopropyl, adamantyl), cycloalkyl (eg cyclohexylmethyl, adamantylmethyl) a cycloalkenyl group (e.g., a cyclopropenyl group), an aryl group (e.g., a phenyl group, a naphthyl group), an aramidyl group (e.g., a benzyl group, a streptoethyl group), a heteroaryl group (e.g., a pyridyl group, a furyl group) a heteroarylalkyl group (for example, a thiol group), a heterocyclic group (for example, a benzyl group), a heterocyclic group (for example, morpholinomethyl group), an alkoxy group (for example, 141666. Doc -43- 201028381 methoxy, ethoxy, propoxy, butoxy), halogenated alkoxy (eg: 0CF3), alkenyloxy (eg vinyloxy, allyloxy), aryloxy a group (for example, a phenoxy group), an alkoxycarbonyl group (for example, a decyloxycarbonyl group, an ethoxycarbonyl group, a second butoxycarbonyl group), an aryloxy group (for example, a benzyloxy group), an amine group ( For example, an alkylamino group (for example, methylamino group, ethylamino group, dimethylamino group), a mercaptoamine group (for example, an etidinyl group, a benzhydrylamino group), an arylalkyl group. Amino group (for example, benzylamino group, tris-methylamino group), hydroxylamino group, alkylaminoalkyl group (for example, diethylaminomethyl group), amine sulfonyl group, pendant oxy group, amine A group consisting of thiol and the like may be substituted by one such substituent. In the present specification, as a "substituted or unsubstituted amine group", "substituted or unsubstituted amine methyl sulfhydryl", The substituent of the substituted or unsubstituted amidoxime group may, for example, be an alkyl group, an alkenyl group, an aryl group, a heteroaryl group, an alkylcarbonyl group, an arylcarbonyl group, a heteroarylcarbonyl group or a heterocyclic carbonyl group. Alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, heterocyclooxycarbonyl, aminsulfonyl, aminecarboxyalkyl, alkylsulfonyl, cycloalkylsulfonyl, arylsulfonyl , heteroarylsulfonyl, heterocyclylsulfonyl, alkylsulfinyl, cycloalkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, heterocyclyl Sulfonyl, hydroxy, decyl, sulfinate, sulfo, amine, etc. In the present specification, "substituted or unsubstituted cycloalkylalkyl", "substituted or unsubstituted aryl" Alkyl", "substituted or unsubstituted heteroarylalkyl", "substituted or unsubstituted heterocyclylalkyl", "substituted or unsubstituted" "Carbocarbonyl", "substituted or unsubstituted alkoxycarbonyl", "substituted or unsubstituted arylalkoxy", "-alkyl", "substituted or unsubstituted alkyl" The "base group" of the above-mentioned "sulfonyl group", "substituted or substituted alkoxy group substituted by 141666.doc 201028381" and "substituted or unsubstituted alkyl sulfinyl group" means. In the present specification, the alkoxy moiety of "substituted or unsubstituted alkoxy group" and "halogenated oxy group" means the above "alkoxy group". The "alkenyl group" of the "substituted or unsubstituted alkenylcarbonyl group" and the "substituted or unsubstituted alkenyloxy group" in the present specification means the above "alkenyl group". In the present specification, the "cycloalkylcarbonyl group which is substituted or unsubstituted" and the cycloalkyl moiety of the "substituted or unsubstituted cycloalkylalkyl group" mean the above "cycloalkyl group". The cycloalkenyl moiety of the "substituted or unsubstituted cycloalkenylcarbonyl group" in the present specification means the above "cycloalkenyl group". In the present specification, "substituted or unsubstituted arylalkyl", "substituted or unsubstituted aryl (4)", "substituted or unsubstituted aryloxy", "silk or Unsubstituted aryl base, "substituted or unsubstituted aryloxy", "substituted or unsubstituted aryl thiol" and "substituted or unsubstituted aryl amide" The aryl moiety of sulfhydryl means the above "aryl". "In this paper, "the substituted or unsubstituted heteroaryl group", :: generation: unsubstituted heteroaryl base, "substituted or unsubstituted and fluorenyl" "Substituted or unsubstituted heteroaryl fluorenyl group" The heteroaryl group of the unsubstituted heteroaryl group is intended to be the above-mentioned "heteroaryl group". In the present specification, "milk/upper, substituted or unsubstituted heterocyclic carbonyl", 141666.doc -45- 201028381 "substituted heterocyclic filaments substituted by silk", "substituted or not Heterocyclic alkyl, "substituted or unsubstituted heterocyclic carboxylic acid, and "substituted or unsubstituted heterocyclic phenyl" heterocyclyl ^ means the above "heterocyclic group" "." 77 A pharmaceutically acceptable salt of the compound of the present invention is exemplified by a salt. As the test salt, for example, a sodium salt, a potassium salt, a metal salt, a salt, a salt, a methane trimethylamine salt, a triethylamine salt, a dicyclohexylamine salt, and an ethanolamine salt are mentioned. , an aliphatic amine salt such as a diethanolamine salt, a triethylenediamine salt, a procaine salt, an amine salt, a diethanolamine salt or an ethylenediamine salt; an N,N-dibasic ethylidene-indenyl G-amine, a heterocyclic aromatic amine salt such as an arylalkylamine salt, a phosphonium salt, a methyl phosphonium salt, a salt or an iso-salt; a tetramethyl salt, a tetraethyl salt, a benzyl trimethyl group Ammonium salt, sulfhydryl triethylammonium salt, benzyl tributylammonium salt, methyl trioctyl ammonium salt, tetrabutyl salt, etc. (four); arginine, aminate and other test amines The more the base acid is. &amp; As an acid salt, for example, mineral acid salts such as acid salt, sulfur (tetra), acid salt, phosphate, carbonate, hydrogencarbonate, peroxy acid salt, etc.; acetate, propionate, lactate , maleic acid salt, fumarate, tartrate, malate, citrate, ascorbic acid organic acid salt; methyl acid m-acid salt 'stupid salt, a pair of stupid salt, etc. An acid salt; an acid amino acid such as aspartate or glutamate. The solvate means a solvate of the compound of the present invention or a pharmaceutically acceptable salt thereof, and examples thereof include an alcohol (e.g., ethanol) or hydrated 141666.doc-46 - 201028381. Examples of the hydrate include hydrazine hydrate, dihydrate, and the like. (Preferred pyridine derivative compound of the present invention) A compound contained in a pharmaceutical composition having TTK inhibitory activity, a pharmaceutically acceptable salt thereof, or a solvate or a prodrug thereof (ester, guanamine, etc.) In the above, the above substituent may be any substituent disclosed in the specification, and for example, any of the preferred substituents exemplified in the means for solving the problem can be used. In consideration of the case of the bite derivative of the present invention, the following elements can be considered. Preferred embodiments of the present invention are exemplified in the following (A1) to (A3). Each symbol is the same as the above definition. (A1) The definition of each substituent is the same as defined in the above formula [1], unless otherwise specified, in the formula [1], R3 ❿ rVyr2 R and R1 substituted or unsubstituted '-C ( =0) Rd. -N(Rg)C Substituted or unsubstituted as R1, exemplified by: 〇Ra, _NRbRC, aryl, substituted or unsubstituted heteroaryl (=0) Rd, Substituted or unsubstituted alkyl, alkenyl, -SRe, -s〇2Rf, hydrogen. For example, 〇Ra, -NRbRc can be cited. Here, as Ra and Rb, a 141666.doc • 47- 201028381 group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heterocyclic group may be mentioned. . Here, the substituted or unsubstituted fluorenyl group may, for example, be an amine group, a base group, an alkoxy group, a C1-C7 alkyl group, or a base. a base group, a sulfoalkylaminoalkyl group, an aliphatic cyclic alkyl group, a heteroarylalkyl group, and an aryl group. Further, examples of the aliphatic cyclic alkyl group include a cyclopropyl group, a cyclobutyl group, a cycloheptyl group, a ruthenium group, a bicyclohexyl group, a bicyclononyl group, and a bicyclooctyl group, and R may be exemplified by hydrogen or substituted. Or unsubstituted burnt base. Examples of R1 include: NRbRC. Here, Rb may be exemplified by substituted or unsubstituted (tetra), substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic group. Re can be cited as hydrogen. R ' may, for example, be cyano, schiffyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, dentate, substituted or unsubstituted alkene, substituted or unsubstituted Substituted alkynyl, _c(=〇)Rd, _N(Rg)C(-0)R, substituted or unsubstituted alkyl or hydrogen. For example, a cyano group, a fluorenyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group can be exemplified. 〇 For example, it is a cyano group. As R, a substituted or unsubstituted amino group, nitrogen, and dentate 0 such as a substituted or unsubstituted amino group or hydrogen may be mentioned. For example, -NH2. Examples of R4' include hydrogen, _NRbRC, and _. For example, hydrogen. 141666.doc -48- 201028381 As R5, _NRbRC, _c( = 〇) Rd, _N(Rg)c( = 〇)Rd, substituted or not (four) Μ, substituted county front thin base or Substituted or unsubstituted, substituted or unsubstituted heteroaryl, via " 'hydrogen such as _NRbRC, -C(=〇)Rd or ·ΝΗ(:(=0)Μ. Here as R Examples of the substituted or unsubstituted aryl group, the substituted or unsubstituted heteroaryl group, and Re may be exemplified by hydrogen. As the oxime, a substituted or unsubstituted aryl group may be mentioned. Substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl. As R, such as _NRbRC, Rb is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl And R is hydrogen. The term "as Rb" in the soil may be exemplified by a substituted phenyl group or a substituted sinter. The substituted phenyl group or the substituted (tetra) substituent may, for example, be a heteroaryl group. Amino group, mercapto group, alkenyl group, alkoxy group, alkyl group, alkenyl group. The following embodiments may also be one embodiment. (A2) The definition of each substituent is not particularly specified, Same as the definition in the above project. In the general formula [1], [Chemical 18] R3

R5 N R1R5 N R1

作為R1，可列舉·…〇Ra或·NRbRC 141666.doc -49- 201028381 作為R2，可列舉：氰基、 雜芳基。 硝基或者經取代或未經取代之 作為R3，可列舉·ΝΗ2。 作為R4 ’可列舉氫。 作為R5 ’可列舉_NRbRC。 之（B1)〜(B4)。 此處，作為R5，可料以下所表示 (B1) [化 19] RA2Examples of R1 include 〇Ra or ·NRbRC 141666.doc -49- 201028381 Examples of R2 include a cyano group and a heteroaryl group. Nitro or substituted or unsubstituted R3 is exemplified by ΝΗ2. Hydrogen is exemplified as R4'. As R5', _NRbRC can be cited. (B1) ~ (B4). Here, as R5, it can be expressed as follows (B1) [Chem. 19] RA2

ΗΗ

此處，作為RA1 , ，丨斑. 了列舉·經取代或未經取代之雜芳 基，！取代或未經取代之胺基、經取代或未經取代之酿 基、.·！取代或未經取代之稀基、經取代或未經取代之快 基，..呈取代或未經取代之烧氧基、經取代或未經取代之院 基。 作為RA1，可列舉以下所表示之取代基。 參 [化 19A]Here, as RA1, , Freckle. Listed, substituted or unsubstituted heteroaryl,! Substituted or unsubstituted amine, substituted or unsubstituted base, . Substituted or unsubstituted dilute, substituted or unsubstituted fast radical, substituted or unsubstituted alkoxy, substituted or unsubstituted. Examples of RA1 include the substituents shown below. Participation [Chem. 19A]

I41666.doc •50- 201028381I41666.doc •50- 201028381

(此處，作馬K，例如 _ ,^ L 夕〗舉.虱、經取代或未經取代之烷 基、經取代或未經取代 _ 代之醯基、經取代或未經取代之胺 基、鹵素、％基、硝其、 月I、氰基、羧基）。 作為RA2’分㈣立’可列舉：氫、經取代或未經取代 、經取代或未經取代 經取代或未經取代之 之烷氧基、經取代或未經取代之胺基(here, as a horse K, for example, _, ^ L 〗 举 虱 虱 虱, substituted or unsubstituted alkyl, substituted or unsubstituted 醯 醯, substituted or unsubstituted amine , halogen, % base, nitrate, month I, cyano, carboxyl). As the RA2' sub (four), the hydrogen group, a substituted or unsubstituted, substituted or unsubstituted alkoxy group, a substituted or unsubstituted amino group may be mentioned.

之烧基、經取代或未經取代之烯基、 炔基。 由上述（A2)定義之形態中，作為R5，可列舉以下取代 基。 (B2) 141666.doc -51- 201028381 [化 20]An alkyl group, a substituted or unsubstituted alkenyl group, an alkynyl group. In the form defined by the above (A2), the following substituents are mentioned as R5. (B2) 141666.doc -51- 201028381 [Chem. 20]

(此處，料R’例如可料：氫、絲代或未經取代之烧 基、經取代或未經取代之酿基、經取代或未經取代之胺 基、函素、經基、石肖基、氰基、㈣。作為p，可列舉： 1〜3之整數。Y可列舉：CH、。作為z，可列舉· 〇、 CH2、S、NRX。作為Rx ’例如可列舉：氫、經取代或未經 取代之烷基、經取代或未經取代之醯基、經取代或未經取 代之胺基、鹵素、羥基、硝基、氰基、羧基）。 由上述（A2)定義之形態中，作為R5，可列舉由以下之式 所表示之取代基。 (B3) [化 21] RA2(Here, the material R' can be, for example, hydrogen, silk or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted amino, functional, thiol, schwitz Examples of p include an integer of 1 to 3. Y is exemplified by CH. Examples of z include 〇, CH2, S, and NRX. Examples of Rx' include hydrogen and substituted. Or unsubstituted alkyl, substituted or unsubstituted thiol, substituted or unsubstituted amine, halogen, hydroxy, nitro, cyano, carboxy). In the form defined by the above (A2), examples of R5 include a substituent represented by the following formula. (B3) [Chem. 21] RA2

141666.doc -52. 201028381 此處，作為 L，可列舉：·〇_、-(CH2)m-〇-、-〇_(CH2)m_ 、·仰2)m-N(Rg)· ' _N(Rg)_(CH2)m_、_(cH2)m、經取代或 未紅取代之伸稀基、經取代或未經取代之伸快基。此處， R與上述（1)中之定義相同，瓜係^〜5之整數。 RA1及RA2分別與由上述(B1)所表示之rA1及rA2之定義相 同。 由上述（A2) &amp;義之形態中，作為r5，可列舉由以下式所 表示之取代基。 ❹ （B4) [化 21A] ρΑ1 RA2 此處，R、RA2與上述（7,)中之定義相同。 於其他實施形態中，可列舉以下所表示之化合物。 (A3) 夢各取代基之定義，若無特別說明，則與上述項 之定義相同。 ） 通式[la]: [化 22]141666.doc -52. 201028381 Here, as L, there are: 〇_, -(CH2)m-〇-, -〇_(CH2)m_, ·仰2)mN(Rg)· ' _N(Rg ) _(CH2)m_, _(cH2)m, a substituted or unsubstituted red, extended or unsubstituted stretching group. Here, R is the same as defined in the above (1), and the melon is an integer of ^5. RA1 and RA2 are respectively the same as the definitions of rA1 and rA2 represented by the above (B1). In the form of the above (A2) &amp; meaning, as r5, a substituent represented by the following formula may be mentioned. ❹ (B4) [Chem. 21A] ρΑ1 RA2 Here, R and RA2 are the same as defined in the above (7,). In other embodiments, the compounds shown below are mentioned. (A3) The definition of each substituent of Dream is the same as the definition of the above item unless otherwise specified. ) General formula [la]: [Chem. 22]

此處，R5可列舉由上述（A2)定義之⑻）〜_。 於其他實施形態中，本發明亦可列舉由以下（C1)〜(C4) 141666.doc -53· 201028381 所表示之形態。 (C1) [化 23]Here, R5 may be exemplified by (8)) to _ defined by the above (A2). In other embodiments, the present invention may also be exemplified by the following (C1) to (C4) 141666.doc-53·201028381. (C1) [Chem. 23]

途之特徵。 上述化合物具有發現作為TTK抑制劑之用 (此處，各取代基之定義與上述項目（1，）中之定義相同） (C2) 進而於其他實施形態中，本發明之化合物具有由 [化 24]The characteristics of the way. The above compound has been found to be used as a TTK inhibitor (herein, the definition of each substituent is the same as defined in the above item (1)) (C2) Further, in other embodiments, the compound of the present invention has a compound of 24 ]

所表示之式之結構。 (此處，各取代基之定義與上述項目（1，）中之定義相同，作 為R ’可列舉：經取代或未經取代之胺基氫、經取代或❹ 未經取代之雜芳基。作為ra，可列舉：經取代或未經取代 之雜芳基、齒素、經取代或未經取代之胺基、羥基、經取 代或未經取代之胺甲醯基、經取代或未經取代之烷氧基羰 基、幾基、經取代或未經取代之烷基）。 (C3) 進而於其他實施形態中，本發明之化合物具有由 [化 25] 141666.doc -54- 201028381The structure of the expressed formula. (Here, the definition of each substituent is the same as defined in the above item (1), and R ' may be exemplified by substituted or unsubstituted amino hydrogen, substituted or unsubstituted heteroaryl. As ra, a substituted or unsubstituted heteroaryl group, a dentate, a substituted or unsubstituted amino group, a hydroxyl group, a substituted or unsubstituted amine mercapto group, a substituted or unsubstituted group may be mentioned. Alkoxycarbonyl, a few, substituted or unsubstituted alkyl). (C3) Further, in other embodiments, the compound of the present invention has [Chem. 25] 141666.doc -54- 201028381

所表示之式之結構β 作 經 (此處，各取代基之定義與上述項目(1，)中之定義相同 為X’可列舉：_ΝΗ…〇_、韻2&quot;作為rA，可列舉 取、或未么取代之胺基、經取代或未經取代之院氧基 素、經取代或未經取代之雜環基）。 (C4) ❹ 進而於其他實施形態中’本發明之化合物具有由 [化 26]The structure of the formula β is expressed as follows (here, the definition of each substituent is the same as the definition of X- in the above item (1)): _ΝΗ...〇_, rhyme 2&quot; as rA, Or an unsubstituted amino group, a substituted or unsubstituted anthracene, a substituted or unsubstituted heterocyclic group). (C4) 进而 Further in other embodiments, the compound of the present invention has

所表示之式之結構。 (此處，各取代基之定義與上述項目（1，）中之定義相同）。 再者，進而於其他實施形態巾，本發明之化合物具有由 [化 27]The structure of the expressed formula. (Here, the definition of each substituent is the same as defined in the above item (1,)). Furthermore, in still another embodiment, the compound of the present invention has a compound of [27]

R2 R1 所表示之式之結構。此處，Rl、R2、R3與上述項目（丨,）中 之定義相同，RA1、RA2與上述項目（γ)中之定義相同。 並且，作為R〖，可列舉以下。 al : -〇Ra、_NRbRC、經取代或未經取代之烷基、或者 -C(=0)-Rd 141666.doc -55- 201028381 a2 ： -ORa a3 ： -NRbRc a4: _N(經取代或未經取代之芳基）(經取代或未經取代、 基）、-N(經取代或未經取代之烧基）（經取代或未經取代 之烷 之 烧基）、_N(經取代或未經取代之烧基）（經取代或未經取代 之雜環基）$者_N(經取代或未經取代之芳基）（經取代或 未經取代之雜環基） a5 :、·(經取代或未經取代之芳基）、_nh(經取代或未經 取代之雜環基）nNH(經*代《未經取代之⑥^) ❹ a6 .·0-(經取代或未經取代之芳基）、_〇_(經取代或未經取 代之雜環基）、或者_〇_(經取代或未經取代之烧基）。 作為R2，可列舉以下。The structure of the formula represented by R2 R1. Here, R1, R2, and R3 are the same as defined in the above item (丨,), and RA1 and RA2 are the same as defined in the above item (γ). Further, as R, the following can be cited. Al : -〇Ra, _NRbRC, substituted or unsubstituted alkyl, or -C(=0)-Rd 141666.doc -55- 201028381 a2 : -ORa a3 : -NRbRc a4: _N (substituted or not Substituted aryl) (substituted or unsubstituted, benzyl), -N (substituted or unsubstituted alkyl) (substituted or unsubstituted alkyl), _N (substituted or not) Substituted alkyl) (substituted or unsubstituted heterocyclic group) $-N (substituted or unsubstituted aryl) (substituted or unsubstituted heterocyclic group) a5 :, · ( Substituted or unsubstituted aryl), _nh (substituted or unsubstituted heterocyclic) nNH (via unsubstituted 6^) ❹ a6 .·0- (substituted or unsubstituted An aryl group, _〇_(substituted or unsubstituted heterocyclic group), or _〇_ (substituted or unsubstituted alkyl). As R2, the following are mentioned.

bl . CN、-N〇2或者經取代或未經取代之雜芳基 b2 ： -CN b3 ： -N〇2 b4 ·經取代或未經取代之雜芳基。 作為R3，可列舉以下。 〇 cl :氫 c2 : -NH2。 作為RA1 ’可列舉以下。 dl .經取代或未經取代之雜芳基、經取代或未經取代之胺 基經取代或未經取代之醯基、經取代或未經取代之烯 基、左取代或未經取代之燒氧基、經取代或未經取代之 烷基 ^ 141666.doc .56· 201028381 d2 ·、、屋取代或未經取代之雜芳基、經取代或未經取代之醯 基、經取代或未經取代之烯基 d3 .經取代或未經取代之雜芳基 d4 :經取代或未經取代之醯基 d5 :經取代或未經取代之烯基。 作為RA2 ’可列舉以下。 el :經取代或未經取代之烷氧基、經取代或未經取代之胺 基、經取代或未經取代之烷基、經取代或未經取代之烯 • 基、經取代或未經取代之炔基 e2 .經取代或未經取代之烧氧基、經取代或未經取代之胺 基、經取代或未經取代之烷基 e3 :經取代或未經取代之烷氧基 e4 :經取代或未經取代之烷基 e5 :經取代或未經取代之胺基。 作為R1、R2、R3、ra1、ra2之組合，可列舉以下。 (Rl，R2，R3 , RA1，RA2) = i (al，bl ’ cl ’ dl，el)、（a2，bl，cl，dl，el)、（a3， bl，cl , dl，el)、（a4，bl，cl，dl，el)、（a5，bl，cl， dl，el)、（a6，bl，cl ’ dl，el)、（al，b2，cl，dl， el)、（a2，b2，cl，dl，el)、（a3，b2，cl，dl，el)、 (a4 ’ b2 ’ cl ’ dl，el)、（a5，b2，cl，dl，el)、（a6， b2 ， cl ， dl ， el) 、 （ai ， b3 ， cl ， dl ， el) 、 （a2 ， b3 ， cl ， dl，el)、（a3，b3，cl，dl ’ el)、（a4，b3，cl，dl， el)、（a5，b3，cl，dl，el)、（a6，b3，cl，dl，el)、 141666.doc -57- 201028381 (a 1，b4，cl，dl，el)、（a2，b4，cl，dl，el)、 b4 ， cl ， dl ， el) 、 （a4 ， b4 ， cl ， dl ， el) 、 （a5 ， b4 d 1，el)、（a6，b4，cl，dl，el)、(a 1，bl，c2， e 1)、（a2，b 1，c2，d 1，el)、（a3，bl，c2，dl， (a4，bl，c2，dl，el)、(a5，b 1，c2，dl，e 1)、 bl ， c2 ， dl ， el) 、 （al ， b2 ， c2 ， dl ， el) 、 （a2 ， b2 dl，el)、(a3，b2，c2，dl，el)、（a4，b2，c2， el)、(a5，b2，c2，dl，el)、（a6，b2，c2，dl， (al，b3，c2，dl，el)、（a2，b3，c2，dl，el)、 b3，c2，dl，el)、（a4，b3，c2，dl，el)、（a5，b3 dl，el)、（a6，b3，c2，dl，el)、（al，b4，c2， el)、（a2，b4，c2，dl，el)、(a3，b4，c2，dl， (a4，b4，c2，dl，el)、(a5，b4，c2，dl，el)、 b4，c2，dl，e 1)、（al，b 1，c 1，d2，el)、（a2，b 1 d2，el)、(a3，bl，cl，d2，el)、（a4，bl，cl， el)、(a5，bl，cl，d2，el)、（a6，b 1，c 1，d2， (al，b2，cl，d2，el)、（a2，b2，c 1，d2，el)、 b2 ， cl ， d2 ， el) 、 （a4 ， b2 ， cl ， d2 ， el) 、 （a5 ， b2 d2，el)、（a6，b2，cl，d2，el)、(al，b3，cl， el)、（a2，b3，cl，d2，el)、(a3，b3，cl，d2， (a4，b3，c 1，d2，el)、(a5，b3，cl，d2，el)、 b3，cl，d2，el)、（al，b4，cl，d2，el)、（a2，b4 d2，el)、(a3，b4，cl，d2，el)、（a4，b4，cl el)、（a5，b4，cl，d2，el)、（a6，b4，cl，d2， (a3， ，c 1， dl， el)、 (a6， ，c2， d 1， el)、 (a3， ，c2， d 1， el)、 (a6， ，c 1， ，d2， el)、 (a3， ，c 1， ，d2， el) ' (a6， ，c 1， ，d2， el) ' 141666.doc -58 - 201028381 (al，bl，c2，d2，el)、（a2，b 1，c2，d2，el)、 bl ， c2 ， d2 ， el) 、 （a4 ， bl ， c2 ， d2 ， el) 、 （a5 ， bl d2，el)、（a6，bl，c2，d2，el)、（al，b2，c2， el)、（a2，b2，c2，d2，el)、(a3，b2，c2，d2， (a4，b2，c2，d2，el)、（a5，b2，c2，d2，el)、 b2，c2，d2，el)、（al，b3，c2，d2，el)、（a2，b3 d2，el)、(a3，b3，c2，d2，el)、（a4，b3，c2 ’ el)、(a5，b3，c2，d2，el)、（a6，b3，c2，d2， ❿ （al，b4，c2，d2，e 1)、（a2，b4，c2，d2，el)、 b4，c2，d2，el)、（a4，b4，c2，d2，el)、（a5，b4 d2，el)、（a6，b4，c2，d2，el)、(al，bl，cl， el)、（a2，b 1，c 1，d3，e 1)、（a3，b 1，c 1，d3， (a4，bl，c 1，d3，el)、（a5，b 1，c 1，d3，el)、 bl ， cl ， d3 ， el) 、 （al ， b2 ， cl ， d3 ， el) 、 （a2 ， b2 d3，el)、(a3，b2，cl，d3，el)、（a4，b2，cl， el)、(a5，b2，cl，d3，el)、（a6，b2，c 1，d3， , (al，b3，cl，d3，e 1)、（a2，b3，c 1，d3，el)、 b3，cl，d3，el)、（a4，b3，cl，d3，el)、（a5，b3 d3，el)、（a6，b3，c 1，d3，el)、(al，b4，cl， el)、（a2，b4，cl，d3，el)、（a3，b4，c 1，d3， (a4，b4，cl，d3，el)、（a5，b4，cl，d3，el)、 b4，cl，d3，el)、（al，bl，c2，d3，el)、（a2，bl d3，el)、（a3，bl，c2，d3，e 1)、（a4，b 1，c2， el)、（a5，b 1，c2，d3，e 1)、（a6，b 1，c2，d3， (a3， ，c2， d2， el)、 (a6， ，c2， d2， el)、 (a3， ，c2， d3， el)、 (a6， ，cl， d3， el)、 (a3， ，c 1， I d3， el)、 (a6， ，c2， ，d3， el)、 141666.doc -59- 201028381 (al，b2，c2，d3，el)、（a2，b2，c2，d3，el)、 b2 ， c2 ， d3 ， el) 、 （a4 ， b2 ， c2 ， d3 ， el) 、 （a5 ， b2 d3，el)、（a6，b2，c2，d3，el)、(al，b3，c2， el)、（a2，b3，c2，d3，e 1)、（a3，b3，c2，d3， (a4，b3，c2，d3，el)、(a5，b3，c2，d3，el)、 b3 ， c2 ， d3 ， el) 、 （al ， b4 ， c2 ， d3 ， el) 、 （a2 ， b4 d3，el)、(a3，b4，c2，d3，el)、（a4，b4，c2， el)、(a5，b4，c2，d3，e 1)、（a6，b4，c2，d3， (al，bl，cl，d4，el)、（a2，bl，cl，d4，el)、 bl ， cl ， d4 ， el) 、 （a4 ， bl ， cl ， d4 ， el) 、 （a5 ， bl d4，el)、（a6，bl，cl，d4，el)、(al，b2，cl， el)、（a2，b2，cl，d4，el)、(a3，b2，cl，d4， (a4，b2，cl，d4，el)、(a5，b2，cl，d4，el)、 b2 ， cl ， d4 ， el) 、 （al ， b3 ， cl ， d4 ， el) 、 （a2 ， b3 d4，el)、（a3，b3，cl，d4，el)、（a4，b3，cl， el)、(a5，b3，cl，d4，el)、（a6，b3，cl，d4， (al，b4，cl，d4，el)、（a2，b4，c 1，d4，el)、 b4 ， cl ， d4 ， el) 、 （a4 ， b4 ， cl ， d4 ， el) 、 （a5 ， b4 d4，el)、（a6，b4，cl，d4，el)、（al，bl，c2 _ el)、（a2，bl，c2，d4，el)、(a3，bl，c2，d4， (a4，bl，c2，d4，el)、（a5，b 1，c2，d4，el)、 bl ， c2 ， d4 ， el) 、 （al ， b2 ， c2 ， d4 ， el) 、 （a2 ， b2 d4，el)、(a3，b2，c2，d4，el)、（a4，b2，c2 el)、（a5，b2，c2，d4，el)、（a6，b2，c2，d4， 141666.doc -60- (a3， ，c2， d3， el)、 (a6， ，c2， d3， el)、 (a3， ，c 1， d4， el) ' (a6， ，cl， I d4， el)、 (a3， ，cl， ，d4， el) ' (a6， ，c2， ，d4， el) 'Bl. CN, -N〇2 or substituted or unsubstituted heteroaryl b2 : -CN b3 : -N〇2 b4 · substituted or unsubstituted heteroaryl. As R3, the following are mentioned. 〇 cl : hydrogen c2 : -NH2. The following is exemplified as RA1'. Dl. A substituted or unsubstituted heteroaryl, substituted or unsubstituted amino group substituted or unsubstituted fluorenyl group, substituted or unsubstituted alkenyl group, left substituted or unsubstituted burnt Alkyl, substituted or unsubstituted alkyl group 141666.doc .56· 201028381 d2 ·, house substituted or unsubstituted heteroaryl, substituted or unsubstituted thiol, substituted or unsubstituted Substituted alkenyl d3. Substituted or unsubstituted heteroaryl d4: substituted or unsubstituted fluorenyl d5: substituted or unsubstituted alkenyl group. The following is exemplified as RA2'. El: substituted or unsubstituted alkoxy group, substituted or unsubstituted amino group, substituted or unsubstituted alkyl group, substituted or unsubstituted alkene group, substituted or unsubstituted Alkynyl e2. substituted or unsubstituted alkoxy group, substituted or unsubstituted amino group, substituted or unsubstituted alkyl group e3: substituted or unsubstituted alkoxy group e4: Substituted or unsubstituted alkyl group e5: substituted or unsubstituted amine group. The combination of R1, R2, R3, ra1, and ra2 is as follows. (Rl, R2, R3, RA1, RA2) = i (al, bl ' cl ' dl, el), (a2, bl, cl, dl, el), (a3, bl, cl, dl, el), ( A4, bl, cl, dl, el), (a5, bl, cl, dl, el), (a6, bl, cl ' dl, el), (al, b2, cl, dl, el), (a2, B2,cl,dl,el), (a3,b2,cl,dl,el), (a4 ' b2 ' cl ' dl,el), (a5,b2,cl,dl,el), (a6, b2 , Cl , dl , el ) , ( ai , b3 , cl , dl , el ) , ( a2 , b3 , cl , dl , el ) , ( a3 , b3 , cl , dl ' el ) , (a4 , b3 , cl , Dl, el), (a5, b3, cl, dl, el), (a6, b3, cl, dl, el), 141666.doc -57- 201028381 (a 1, b4, cl, dl, el), ( A2, b4, cl, dl, el), b4, cl, dl, el), (a4, b4, cl, dl, el), (a5, b4 d 1, el), (a6, b4, cl, dl , el), (a 1, bl, c2, e 1), (a2, b 1, c2, d 1, el), (a3, bl, c2, dl, (a4, bl, c2, dl, el) , (a5, b 1, c2, dl, e 1), bl, c2, dl, el), (al, b2, c2, dl, el) , (a2, b2 dl, el), (a3, b2, c2, dl, el), (a4, b2, c2, el), (a5, b2, c2, dl, el), (a6, b2, c2 , dl, (al, b3, c2, dl, el), (a2, b3, c2, dl, el), b3, c2, dl, el), (a4, b3, c2, dl, el), (a5 , b3 dl, el), (a6, b3, c2, dl, el), (al, b4, c2, el), (a2, b4, c2, dl, el), (a3, b4, c2, dl, (a4, b4, c2, dl, el), (a5, b4, c2, dl, el), b4, c2, dl, e 1), (al, b 1, c 1, d2, el), (a2 , b 1 d2, el), (a3, bl, cl, d2, el), (a4, bl, cl, el), (a5, bl, cl, d2, el), (a6, b 1, c 1 , d2, (al, b2, cl, d2, el), (a2, b2, c 1, d2, el), b2, cl, d2, el), (a4, b2, cl, d2, el), ( A5 , b2 d2, el), (a6, b2, cl, d2, el), (al, b3, cl, el), (a2, b3, cl, d2, el), (a3, b3, cl, d2 , (a4, b3, c 1, d2, el), (a5, b3, cl, d2, el), b3, cl, d2, el), (al, b4, cl, d2, el), (a2, B4 d2,el), (a3,b4,cl,d 2, el), (a4, b4, cl el), (a5, b4, cl, d2, el), (a6, b4, cl, d2, (a3, , c 1, dl, el), (a6, , c2, d 1, el), (a3, , c2, d 1, el), (a6, , c 1, , d2, el), (a3, , c 1, , d2, el) ' (a6, , c 1, , d2, el) ' 141666.doc -58 - 201028381 (al, bl, c2, d2, el), (a2, b 1, c2, d2, el), bl, c2, d2, el) , (a4, bl, c2, d2, el), (a5, bl d2, el), (a6, bl, c2, d2, el), (al, b2, c2, el), (a2, b2, c2 , d2, el), (a3, b2, c2, d2, (a4, b2, c2, d2, el), (a5, b2, c2, d2, el), b2, c2, d2, el), (al , b3, c2, d2, el), (a2, b3 d2, el), (a3, b3, c2, d2, el), (a4, b3, c2 'el), (a5, b3, c2, d2, El), (a6, b3, c2, d2, ❿ (al, b4, c2, d2, e 1), (a2, b4, c2, d2, el), b4, c2, d2, el), (a4, B4, c2, d2, el), (a5, b4 d2, el), (a6, b4, c2, d2, el), (al, bl, cl, el), (a2, b 1, c 1, d3 , e 1), (a3, b 1, c 1, d3, (a4, bl, c 1, d3, el), (a5, b 1, c 1, d3, el), bl, cl, d3, el) , (al , b2 , cl , d3 , el ) , (a2 , b2 d3 , el ) , ( a3 , b2 , cl , d3 , el ) , ( a4 , b2 , cl , el ) , ( a5 , b2 , cl , d3, el), (a6, b2, c 1, d3, , (al, b3, cl, d3, e 1), (a2, b3, c 1, d3, el), b3, cl, d3, el ), (a4, b3, cl, d3, el), (a5, b3 d3, el), (a6, b3, c 1, d3, el), (al, b4, cl, el), (a2, b4 ,cl,d3,el),(a3,b4,c 1,d3, (a4,b4,cl,d3,el), (a5,b4,cl,d3,el), b4,cl,d3,el) , (al, bl, c2, d3, el), (a2, bl d3, el), (a3, bl, c2, d3, e 1), (a4, b 1, c2, el), (a5, b 1,c2,d3,e 1), (a6,b 1,c2,d3, (a3, ,c2, d2, el), (a6, ,c2, d2, el), (a3, ,c2, d3, El), (a6, ,cl, d3, el), (a3, ,c 1, I d3, el), (a6, ,c2, ,d3, el), 141666.doc -59- 201028381 (al,b2 , c2, d3, el) , (a2, b2, c2, d3, el), b2, c2, d3, el), (a4, b2, c2, d3, el), (a5, b2 d3, el), (a6, b2, c2, D3, el), (al, b3, c2, el), (a2, b3, c2, d3, e 1), (a3, b3, c2, d3, (a4, b3, c2, d3, el), ( A5, b3, c2, d3, el), b3, c2, d3, el), (al, b4, c2, d3, el), (a2, b4 d3, el), (a3, b4, c2, d3, El), (a4, b4, c2, el), (a5, b4, c2, d3, e 1), (a6, b4, c2, d3, (al, bl, cl, d4, el), (a2, Bl,cl,d4,el), bl, cl, d4, el), (a4, bl, cl, d4, el), (a5, bl d4, el), (a6, bl, cl, d4, el) , (al, b2, cl, el), (a2, b2, cl, d4, el), (a3, b2, cl, d4, (a4, b2, cl, d4, el), (a5, b2, cl , d4, el), b2, cl, d4, el), (al, b3, cl, d4, el), (a2, b3 d4, el), (a3, b3, cl, d4, el), (a4 , b3, cl, el), (a5, b3, cl, d4, el), (a6, b3, cl, d4, (al, b4, cl D4,el), (a2,b4,c 1,d4,el), b4, cl,d4,el), (a4, b4, cl, d4, el), (a5, b4 d4, el), (a6 , b4, cl, d4, el), (al, bl, c2 _ el), (a2, bl, c2, d4, el), (a3, bl, c2, d4, (a4, bl, c2, d4, El), (a5, b 1, c2, d4, el), bl, c2, d4, el), (al, b2, c2, d4, el), (a2, b2 d4, el), (a3, b2 , c2, d4, el), (a4, b2, c2 el), (a5, b2, c2, d4, el), (a6, b2, c2, d4, 141666.doc -60- (a3, , c2, D3, el), (a6, , c2, d3, el), (a3, , c 1, d4, el) ' (a6, ,cl, I d4, el), (a3, ,cl, ,d4, el ) ' (a6, ,c2, ,d4, el) '

201028381 (a 1，b3，c2，d4，el)、（a2，b3，c2，d4，el)、 b3，c2，d4，e 1)、（a4，b3，c2，d4，el)、（a5，b3 d4，el)、（a6，b3，c2，d4，el)、（al，b4，c2， el)、（a2，b4，c2，d4，el)、(a3，b4，c2，d4， (a4，b4，c2，d4，el)、(a5，b4，c2，d4，el)、 b4，c2，d4，el)、（al，bl，cl，d5，el)、（a2，bl d5，el)、(a3，bl，cl，d5，el)、（a4，bl，cl， e 1)、（a5，b 1，c 1，d5，e 1)、（a6，b 1，c 1，d5， (al，b2，cl，d5，el)、（a2，b2，cl，d5，el)、 b2，cl，d5，el)、（a4，b2，cl，d5，el)、（a5，b2 d5，el)、（a6，b2，cl，d5，el)、(al，b3，cl， el)、（a2，b3，cl，d5，el)、(a3，b3，cl，d5， (a4，b3，cl，d5，el)、（a5，b3，cl，d5，el)、 b3 ， cl ， d5 ， el) 、 （al ， b4 ， cl ， d5 ， el) 、 （a2 ， b4 d5，el)、(a3，b4，cl，d5，el)、（a4，b4，cl， el)、(a5，b4，cl，d5，el)、（a6，b4，c 1，d5， (al，bl，c2，d5，e 1)、（a2，b 1，c2，d5，el)、 bl ， c2 ， d5 ， el) 、 （a4 ， bl ， c2 ， d5 ， el) 、 （a5 ， bl d5，el)、(a6，bl，c2，d5，el)、(al，b2，c2 el)、（a2，b2，c2，d5，el)、(a3，b2，c2，d5， (a4，b2，c2，d5，el)、（a5，b2，c2，d5，el)、 b2，c2，d5，el)、（al，b3，c2，d5，el)、（a2，b3 d5，el)、(a3，b3，c2，d5，el)、（a4，b3，c2 el)、(a5，b3，c2，d5，el)、（a6，b3，c2，d5， (a3， ，c2， d4， el)、 (a6， ，cl， d5， el) ' (a3， ，cl， d5， el) ' (a6， ，c 1， d5， el)、 (a3， ，c2， 1 d5， el)、 (a6， ，c2， ，d5， el)' 141666.doc -61- 201028381 (al，b4，c2，d5，el)、（a2，b4，c2，d5，el)、 b4，c2，d5，el)、（a4，b4，c2，d5，el)、（a5，b4 d5，el)、(a6，b4，c2，d5，el)、（al，bl，cl， e2)、（a2，b 1，c 1，dl，e2)、（a3，b 1，c 1，d 1， (a4，b 1，c 1，d 1，e2)、（a5，bl，cl，dl，e2)、 bl ， cl ， dl ， e2) 、 （al ， b2 ， cl ， dl ， e2) 、 （a2 ， b2 dl，e2)、（a3，b2，cl，dl，e2)、（a4，b2，cl， e2)、（a5，b2，cl，dl，e2)、（a6，b2，cl，dl， (al，b3，cl，dl，e2)、（a2，b3，cl，dl，e2)、 b3 ， cl ， dl ， e2) 、 （a4 ， b3 ， cl ， dl ， e2) 、 （a5 ， b3 dl，e2)、（a6，b3，cl，dl，e2)、（al，b4，cl ’ e2)、（a2，b4，cl，dl，e2)、(a3，b4，cl，dl， (a4，b4，c 1，d 1，e2)、（a5，b4，cl，dl，e2)、 b4 ， cl ， dl ， e2) 、 （al ， bl ， c2 ， dl ， e2) 、 （a2 ， bl dl，e2)、(a3，bl，c2，dl，e2)、（a4，bl，c2， e2)、(a5，bl，c2，dl，e2)、（a6，bl，c2，dl， (al，b2，c2，dl，e2)、（a2，b2，c2，dl，e2)、 b2 ， c2 ， dl ， e2) 、 （a4 ， b2 ， c2 ， dl ， e2) 、 （a5 ， b2 dl，e2)、（a6，b2，c2，dl，e2)、(al，b3，c2， e2)、（a2，b3，c2，dl，e2)、(a3，b3，c2，dl， (a4，b3，c2，dl，e2)、(a5，b3，c2，dl，e2)、 b3 ， c2 ， dl ， e2) 、 （al ， b4 ， c2 ， dl ， e2) 、 （a2 ， b4 dl，e2)、(a3，b4，c2，dl，e2)、（a4，b4，c2 e2)、(a5，b4，c2，dl，e2)、（a6，b4，c2，dl， 141666.doc -62- (a3， ，c2， dl， e2)、 (a6， ，cl， dl， e2)、 (a3， ，cl， dl， e2)、 (a6， ，c2， d 1 &gt; e2)、 (a3， ，c2， ，dl， e2)、 (a6， ，c2， ，d 1， e2) '201028381 (a 1,b3,c2,d4,el), (a2,b3,c2,d4,el), b3,c2,d4,e 1), (a4,b3,c2,d4,el), (a5 , b3 d4, el), (a6, b3, c2, d4, el), (al, b4, c2, el), (a2, b4, c2, d4, el), (a3, b4, c2, d4, (a4, b4, c2, d4, el), (a5, b4, c2, d4, el), b4, c2, d4, el), (al, bl, cl, d5, el), (a2, bl d5 , el), (a3, bl, cl, d5, el), (a4, bl, cl, e 1), (a5, b 1, c 1, d5, e 1), (a6, b 1, c 1 , d5, (al, b2, cl, d5, el), (a2, b2, cl, d5, el), b2, cl, d5, el), (a4, b2, cl, d5, el), (a5 , b2 d5, el), (a6, b2, cl, d5, el), (al, b3, cl, el), (a2, b3, cl, d5, el), (a3, b3, cl, d5, (a4, b3, cl, d5, el), (a5, b3, cl, d5, el), b3, cl, d5, el), (al, b4, cl, d5, el), (a2, b4 d5 , el), (a3, b4, cl, d5, el), (a4, b4, cl, el), (a5, b4, cl, d5, el), (a6, b4, c 1, d5, (al , bl, c2, d5, e 1), ( A2, b 1, c2, d5, el), bl, c2, d5, el), (a4, bl, c2, d5, el), (a5, bl d5, el), (a6, bl, c2, d5 , el), (al, b2, c2 el), (a2, b2, c2, d5, el), (a3, b2, c2, d5, (a4, b2, c2, d5, el), (a5, b2 , c2, d5, el), b2, c2, d5, el), (al, b3, c2, d5, el), (a2, b3 d5, el), (a3, b3, c2, d5, el), (a4, b3, c2 el), (a5, b3, c2, d5, el), (a6, b3, c2, d5, (a3, c2, d4, el), (a6, , cl, d5, el ) ' (a3, ,cl, d5, el) ' (a6, ,c 1, d5, el), (a3, ,c2, 1 d5, el), (a6, ,c2, ,d5, el)' 141666 .doc -61- 201028381 (al,b4,c2,d5,el), (a2,b4,c2,d5,el), b4,c2,d5,el), (a4,b4,c2,d5,el) , (a5, b4 d5, el), (a6, b4, c2, d5, el), (al, bl, cl, e2), (a2, b 1, c 1, dl, e2), (a3, b 1,c 1,d 1, (a4,b 1,c 1,d 1,e2), (a5,bl,cl,dl,e2), bl , cl , dl , e2) , (al , b2 , cl , Dl , e2) , (a2 , b2 dl, e2), (a3, b2, cl, dl, e2), (a4, b2, cl, e2), (a5, b2, cl, dl, e2), (a6 , b2, cl, dl, (al, b3, cl, dl, e2), (a2, b3, cl, dl, e2), b3, cl, dl, e2), (a4, b3, cl, dl, e2 ), (a5, b3 dl, e2), (a6, b3, cl, dl, e2), (al, b4, cl ' e2), (a2, b4, cl, dl, e2), (a3, b4, Cl, dl, (a4, b4, c 1, d 1, e2), (a5, b4, cl, dl, e2), b4, cl, dl, e2), (al, bl, c2, dl, e2) , (a2 , bl dl, e2), (a3, bl, c2, dl, e2), (a4, bl, c2, e2), (a5, bl, c2, dl, e2), (a6, bl, c2) , dl, (al, b2, c2, dl, e2), (a2, b2, c2, dl, e2), b2, c2, dl, e2), (a4, b2, c2, dl, e2), (a5 , b2 dl, e2), (a6, b2, c2, dl, e2), (al, b3, c2, e2), (a2, b3, c2, dl, e2), (a3, b3, c2, dl, (a4, b3, c2, dl, e2), (a5, b3, c2, dl, e2), b3, c2, dl, e2), (al B4, c2, dl, e2), (a2, b4 dl, e2), (a3, b4, c2, dl, e2), (a4, b4, c2 e2), (a5, b4, c2, dl, e2) , (a6, b4, c2, dl, 141666.doc -62- (a3, ,c2, dl, e2), (a6, ,cl, dl, e2), (a3, ,cl, dl, e2), ( A6, ,c2, d 1 &gt; e2), (a3, ,c2, ,dl, e2), (a6, ,c2, ,d 1, e2) '

201028381 (al，bl，cl，d2，e2)、（a2，b 1，cl，d2，e2)、 bl ， cl ， d2 ， e2) 、 （a4 ， bl ， cl ， d2 ， e2) 、 （a5 ， bl d2，e2)、（a6，b 1，c 1，d2，e2)、（al，b2，cl， e2)、（a2，b2，cl，d2，e2)、(a3，b2，cl，d2， (a4，b2，cl，d2，e2)、（a5，b2，cl，d2，e2)、 b2，cl，d2，e2)、（al，b3，cl，d2，e2)、（a2，b3 d2，e2)、(a3，b3，cl，d2，e2)、（a4，b3，cl， e2)、(a5，b3，cl，d2，e2)、（a6，b3，cl，d2， (al，b4，cl，d2，e2)、（a2，b4，cl，d2，e2)、 b4，cl，d2，e2)、（a4，b4，cl，d2，e2)、（a5，b4 d2，e2)、（a6 .，b4，cl，d2，e2)、（al，bl，c2， e2)、（a2，bl，c2，d2，e2)、(a3，bl，c2，d2， (a4，bl，c2，d2，e2)、（a5，b 1，c2，d2，e2)、 bl ， c2 ， d2 ， e2) 、 （al ， b2 ， c2 ， d2 ， e2) 、 （a2 ， b2 d2，e2)、(a3，b2，c2，d2，e2)、（a4，b2，c2 e2)、(a5，b2，c2，d2，e2)、（a6，b2，c2，d2， (al，b3，c2，d2，e2)、（a2，b3，c2，d2，e2)、 b3，c2，d2，e2)、（a4，b3，c2，d2，e2)、（a5，b3 d2，e2)、（a6，b3，c2，d2，e2)、（al，b4，c2 e2)、（a2，b4，c2，d2，e2)、（a3，b4，c2，d2， (a4，b4，c2，d2，e2)、（a5，b4，c2，d2，e2)、 b4，c2，d2，e2)、（al，bl，cl，d3，e2)、（a2，bl d3，e2)、(a3，bl，cl，d3，e2)、（a4，bl，cl e2)、(a5，bl，cl，d3，e2)、（a6，bl，cl，d3， (a3， ，c 1， d2， e2) ' (a6， ，cl， d2， e2) ' (a3， ，cl， d2， e2) ' (a6， ，c2， d2， e2) ' (a3， ，c2， ，d2， e2)、 (a6， ，c 1， ，d3， e2)、 141666.doc -63- 201028381 (a 1，b2，cl，d3，e2)、（a2，b2，cl，d3，e2)、 b2，cl，d3，e2)、（a4，b2，cl，d3，e2)、（a5，b2 d3，e2)、(a6，b2，cl，d3，e2)、(a 1，b3，cl， e2)、（a2，b3，cl，d3，e2)、（a3，b3，c 1，d3， (a4，b3，c 1，d3，e2)、(a5，b3，cl，d3，e2)、 b3，cl，d3，e2)、（al，b4，cl，d3，e2)、（a2，b4 d3，e2) ' (a3，b4，cl，d3，e2)、（a4，b4，cl， e2)、(a5，b4，cl，d3，e2)、（a6，b4，c 1，d3， (al，bl，c2，d3，e2)、（a2，b 1，c2，d3，e2)、 bl ， c2 ， d3 ， e2) 、 （a4 ， bl ， c2 ， d3 ， e2) 、 （a5 ， bl d3，e2)、（a6，bl，c2，d3，e2)、(al，b2，c2， el) ' (a2，b2，c2，d3，e2)、(a3，b2，c2，d3， (a4，b2，c2，d3，e2)、（a5，b2，c2，d3，e2)、 b2，c2，d3，e2)、（al，b3，c2，d3，e2)、（a2，b3 d3，e2) ' (a3，b3，c2，d3，e2)、（a4，b3，c2， e2)、(a5，b3，c2，d3，e2)、（a6，b3，c2，d3， (al，b4，c2，d3，e2)、（a2，b4，c2，d3，e2)、 b4 ， c2 ， d3 ， e2) 、 （a4 ， b4 ， c2 ， d3 ， e2) 、 （a5 ， b4 d3，e2)、（a6，b4，c2，d3，e2)、（al，bl，cl _ e2)、（a2，bl，cl，d4，e2)、(a3，bl，cl，d4， (a4，b 1，c 1，d4，e2)、(a5，bl，cl，d4，e2)、 bl ， cl ， d4 ， e2) 、 （al ， b2 ， cl ， d4 ， e2) 、 （a2 ， b2 d4，e2)、(a3，b2，cl，d4，e2)、（a4，b2，cl e2)、(a5，b2，cl，d4，e2)、（a6，b2，c 1，d4， (a3， ，c 1， d3， e2) ' (a6， ，cl， d3， e2)、 (a3， ，c2， d3， e2) ' (a6， ，c2， I d3， e2)、 (a3， ，c2， ，d4， e2)、 (a6， ，c 1， ，d4， e2)、 141666.doc -64-201028381 (al, bl, cl, d2, e2), (a2, b 1, cl, d2, e2), bl, cl, d2, e2), (a4, bl, cl, d2, e2), (a5, Bl d2, e2), (a6, b 1, c 1, d2, e2), (al, b2, cl, e2), (a2, b2, cl, d2, e2), (a3, b2, cl, d2) , (a4, b2, cl, d2, e2), (a5, b2, cl, d2, e2), b2, cl, d2, e2), (al, b3, cl, d2, e2), (a2, b3 D2, e2), (a3, b3, cl, d2, e2), (a4, b3, cl, e2), (a5, b3, cl, d2, e2), (a6, b3, cl, d2, (al , b4, cl, d2, e2), (a2, b4, cl, d2, e2), b4, cl, d2, e2), (a4, b4, cl, d2, e2), (a5, b4 d2, e2) ), (a6 ., b4, cl, d2, e2), (al, bl, c2, e2), (a2, bl, c2, d2, e2), (a3, bl, c2, d2, (a4, bl) , c2, d2, e2), (a5, b 1, c2, d2, e2), bl, c2, d2, e2), (al, b2, c2, d2, e2), (a2, b2 d2, e2) , (a3, b2, c2, d2, e2), (a4, b2, c2 e2), (a5, b2, c2, d2, e2), (a6, b2, c2, d2, (al, b3, c2) D2, e2), (a2, b3, c2, d2, e2), b3, c2, d2, e2), (a4, b3, c2, d2, e2), (a5, b3 d2, e2), (a6, B3, c2, d2, e2), (al, b4, c2 e2), (a2, b4, c2, d2, e2), (a3, b4, c2, d2, (a4, b4, c2, d2, e2) , (a5, b4, c2, d2, e2), b4, c2, d2, e2), (al, bl, cl, d3, e2), (a2, bl d3, e2), (a3, bl, cl, D3, e2), (a4, bl, cl e2), (a5, bl, cl, d3, e2), (a6, bl, cl, d3, (a3, , c 1, d2, e2) ' (a6, ,cl, d2, e2) ' (a3, ,cl, d2, e2) ' (a6, ,c2, d2, e2) ' (a3, ,c2, ,d2, e2), (a6, ,c 1, , D3, e2), 141666.doc -63- 201028381 (a 1,b2,cl,d3,e2), (a2,b2,cl,d3,e2), b2,cl,d3,e2), (a4,b2 , cl, d3, e2), (a5, b2 d3, e2), (a6, b2, cl, d3, e2), (a 1, b3, cl, e2), (a2, b3, cl, d3, e2 ), (a3, b3, c 1, d3, (a4, b3, c 1, d3, e2), (a5, b3, cl, d3, e2), b3, cl, d3, e2), (al, b4 , cl, d3, e2), (a2, B4 d3,e2) ' (a3,b4,cl,d3,e2), (a4,b4,cl, e2), (a5,b4,cl,d3,e2), (a6,b4,c 1,d3, (al, bl, c2, d3, e2), (a2, b 1, c2, d3, e2), bl, c2, d3, e2), (a4, bl, c2, d3, e2), (a5, bl D3, e2), (a6, bl, c2, d3, e2), (al, b2, c2, el) ' (a2, b2, c2, d3, e2), (a3, b2, c2, d3, (a4 , b2, c2, d3, e2), (a5, b2, c2, d3, e2), b2, c2, d3, e2), (al, b3, c2, d3, e2), (a2, b3 d3, e2) ) ' (a3, b3, c2, d3, e2), (a4, b3, c2, e2), (a5, b3, c2, d3, e2), (a6, b3, c2, d3, (al, b4, C2, d3, e2), (a2, b4, c2, d3, e2), b4, c2, d3, e2), (a4, b4, c2, d3, e2), (a5, b4 d3, e2), ( A6, b4, c2, d3, e2), (al, bl, cl _ e2), (a2, bl, cl, d4, e2), (a3, bl, cl, d4, (a4, b 1, c 1 , d4, e2), (a5, bl, cl, d4, e2), bl, cl, d4, e2), (al, b2, cl, d4, e2), (a2, b2 d4, e2) , (a3, b2, cl, d4, e2), (a4, b2, cl e2), (a5, b2, cl, d4, e2), (a6, b2, c 1, d4, (a3, , c 1) , d3, e2) ' (a6, ,cl, d3, e2), (a3, ,c2, d3, e2) ' (a6, ,c2, I d3, e2), (a3, ,c2, ,d4, e2 ), (a6, , c 1, , d4, e2), 141666.doc -64-

201028381 (a 1，b3，cl，d4，e2)、（a2，b3，c 1，d4，e2)、 b3，cl，d4，e2)、（a4，b3，cl，d4，e2)、（a5，b3 d4，e2)、（a6，b3，c 1，d4，e2)、(al，b4，cl， e2)、（a2，b4，cl，d4，e2)、(a3，b4，cl，d4， (a4，b4，c 1，d4，e2)、（a5，b4，c 1，d4，e2)、 b4，cl，d4，e2)、（al，bl，c2，d4，e2)、（a2，bl d4，e2)、(a3，bl，c2，d4，e2)、（a4，bl，c2， e2)、(a5，bl，c2，d4，e2)、（a6，bl，c2，d4， (al，b2，c2，d4，e2)、（a2，b2，c2，d4，e2)、 b2，c2，d4，e2)、（a4，b2，c2，d4，e2)、（a5，b2 d4，e2)、（a6，b2，c2，d4，e2)、(al，b3，c2， e2)、（a2，b3，c2，d4，e2)、（a3，b3，c2，d4， (a4，b3，c2，d4，e2)、（a5，b3，c2，d4，e2)、 b3，c2，d4，e2)、（al，b4，c2，d4，，e2)、（a2，b4 d4，e2)、（a3，b4，c2，d4，e2)、（a4，b4，c2， e2)、(a5，b4，c2，d4，e2)、（a6，b4，c2，d4， (al，bl，cl，d5，e2)、（a2，bl，cl，d5，e2)、 bl，cl，d5，e2)、（a4，bl，cl，d5，e2)、（a5，bl d5，e2)、（a6，bl，cl，d5，e2)、(al，b2，cl ’ e2)、（a2，b2，cl，d5，e2)、（a3，b2，cl，d5， (a4，b2，c 1，d5，e2)、（a5，b2，c 1，d5，e2)、 b2，cl，d5，e2)、（al，b3，cl，d5，e2)、（a2，b3 d5，e2)、（a3，b3，cl，d5，e2)、（a4，b3，cl， e2) ' (a5，b3，cl，d5，e2)、（a6，b3，cl，d5， 141666.doc -65- (a3， ，cl， d4， e2)、 (a6， ，c2， d4， e2)、 (a3， ，c2， d4， e2)、 (a6， ，c2， d4， e2)、 (a3， ，cl， d5， e2)、 (a6， ，c 1， d5， e2)、 201028381 (al，b4，cl，d5，e2)、（a2，b4，cl，d5，e2)、 b4，cl，d5，e2)、（a4，b4，cl，d5，e2)、（a5，M d5，e2) ' (a6，b4，cl，d5，e2)、（al，bl，c2， e2)、（a2，bl，c2，d5，e2)、（a3，b 1，c2，d5， (a4，bl，c2，d5，e2)、（a5，bl，c2，d5，e2)、 bl ， c2 ， d5 ， e2) 、 （al ， b2 ， c2 ， d5 ， e2) 、 （a2 ， b2 d5，e2)、（a3，b2，c2，d5，e2)、（a4，b2，c2， e2)、(a5，b2，c2，d5，e2)、（a6，b2，c2，d5， (al，b3，c2，d5，e2)、（a2，b3，c2，d5，e2)、 b3，c2，d5，e2)、（a4，b3，c2，d5，e2)、（a5，b3 d5，e2)、（a6，b3，c2，d5，e2)、(al，b4，c2， e2)、（a2，b4，c2，d5，e2)、（a3，b4，c2，d5， (a4，b4，c2，d5，e2)、(a5，b4，c2，d5，e2)、 b4 ， c2 ， d5 ， e2) 、 （al ， bl ， cl ， dl ， e3) 、 （a2 ， bl d 1，e3)、(a3，bl，cl，dl，e3)、（a4，bl，cl ’ e3)、(a5，bl，cl，dl，e3)、（a6，bl，cl，dl， (al，b2，cl，dl，e3)、（a2，b2，c 1，d 1，e3)、 b2 ， cl ， dl ， e3) 、 （a4 ， b2 ， cl ， dl ， e3) 、 （a5 ， b2 dl，e3)、（a6，b2，cl，dl，e3)、(al，b3，cl e3)、（a2，b3，cl，dl，e3)、(a3，b3，cl，dl， (a4，b3，cl，dl，e3)、（a5，b3，c 1，d 1，e3)、 b3 ， cl ， dl ， e3) 、 （al ， b4 ， cl ， dl ， e3) 、 （a2 ， b4 dl，e3)、(a3，b4，cl，dl，e3)、（a4，b4，cl e3)、(a5，b4，cl，dl，e3)、（a6，b4，cl，dl， 141666.doc -66- (a3， ，c 1， d5， e2)、 (a6， ，c2， d5， e2)、 (a3， ，c2， d5， e2)、 (a6， ，c 1， ，dl， e3) ' (a3， ，c 1， ，dl， e3) ' (a6， ，c 1， ，dl， e3) '201028381 (a 1,b3,cl,d4,e2), (a2,b3,c 1,d4,e2), b3,cl,d4,e2), (a4,b3,cl,d4,e2), (a5 , b3 d4, e2), (a6, b3, c 1, d4, e2), (al, b4, cl, e2), (a2, b4, cl, d4, e2), (a3, b4, cl, d4) , (a4, b4, c 1, d4, e2), (a5, b4, c 1, d4, e2), b4, cl, d4, e2), (al, bl, c2, d4, e2), (a2 , bl d4, e2), (a3, bl, c2, d4, e2), (a4, bl, c2, e2), (a5, bl, c2, d4, e2), (a6, bl, c2, d4, (al, b2, c2, d4, e2), (a2, b2, c2, d4, e2), b2, c2, d4, e2), (a4, b2, c2, d4, e2), (a5, b2 d4) , e2), (a6, b2, c2, d4, e2), (al, b3, c2, e2), (a2, b3, c2, d4, e2), (a3, b3, c2, d4, (a4, B3, c2, d4, e2), (a5, b3, c2, d4, e2), b3, c2, d4, e2), (al, b4, c2, d4, e2), (a2, b4 d4, e2) ), (a3, b4, c2, d4, e2), (a4, b4, c2, e2), (a5, b4, c2, d4, e2), (a6, b4, c2, d4, (al, bl, Cl,d5,e2), (a2, bl, cl, d5, E2), bl, cl, d5, e2), (a4, bl, cl, d5, e2), (a5, bl d5, e2), (a6, bl, cl, d5, e2), (al, b2, Cl ' e2), (a2, b2, cl, d5, e2), (a3, b2, cl, d5, (a4, b2, c 1, d5, e2), (a5, b2, c 1, d5, e2 ), b2, cl, d5, e2), (al, b3, cl, d5, e2), (a2, b3 d5, e2), (a3, b3, cl, d5, e2), (a4, b3, cl , e2) ' (a5, b3, cl, d5, e2), (a6, b3, cl, d5, 141666.doc -65- (a3, ,cl, d4, e2), (a6, ,c2, d4, E2), (a3, , c2, d4, e2), (a6, , c2, d4, e2), (a3, , cl, d5, e2), (a6, , c 1, d5, e2), 201028381 ( Al, b4, cl, d5, e2), (a2, b4, cl, d5, e2), b4, cl, d5, e2), (a4, b4, cl, d5, e2), (a5, M d5, E2) ' (a6, b4, cl, d5, e2), (al, bl, c2, e2), (a2, bl, c2, d5, e2), (a3, b 1, c2, d5, (a4, Bl, c2, d5, e2), (a5, bl, c2, d5, e2), bl, c2, d5, e2), (al, b2, c2, d5, e2), (a2, b2 d5, e 2), (a3, b2, c2, d5, e2), (a4, b2, c2, e2), (a5, b2, c2, d5, e2), (a6, b2, c2, d5, (al, b3) , c2, d5, e2), (a2, b3, c2, d5, e2), b3, c2, d5, e2), (a4, b3, c2, d5, e2), (a5, b3 d5, e2), (a6, b3, c2, d5, e2), (al, b4, c2, e2), (a2, b4, c2, d5, e2), (a3, b4, c2, d5, (a4, b4, c2, D5, e2), (a5, b4, c2, d5, e2), b4, c2, d5, e2), (al, bl, cl, dl, e3), (a2, bl d 1, e3), (a3 , bl, cl, dl, e3), (a4, bl, cl ' e3), (a5, bl, cl, dl, e3), (a6, bl, cl, dl, (al, b2, cl, dl, E3), (a2, b2, c 1, d 1, e3), b2, cl, dl, e3), (a4, b2, cl, dl, e3), (a5, b2 dl, e3), (a6, B2, cl, dl, e3), (al, b3, cl e3), (a2, b3, cl, dl, e3), (a3, b3, cl, dl, (a4, b3, cl, dl, e3) , (a5, b3, c 1, d 1, e3), b3, cl, dl, e3), (al, b4, cl, dl, e3), (a2, b4 dl, e3), (a 3, b4, cl, dl, e3), (a4, b4, cl e3), (a5, b4, cl, dl, e3), (a6, b4, cl, dl, 141666.doc -66- (a3, , c 1, d5, e2), (a6, , c2, d5, e2), (a3, , c2, d5, e2), (a6, , c 1, , dl, e3) ' (a3, , c 1 , ,dl, e3) ' (a6, ,c 1, ,dl, e3) '

201028381 (a 1，bl，c2，dl，e3)、（a2，b 1，c2，dl，e3)、 bl ， c2 ， dl ， e3) 、 （a4 ， bl ， c2 ， dl ， e3) 、 （a5 ， bl dl，e3)、（a6，b 1，c2，d 1，e3)、(al，b2，c2， e3)、（a2，b2，c2，dl，e3)、(a3，b2，c2，dl， (a4，b2，c2，dl，e3)、（a5，b2，c2，dl，e3)、 b2 ， c2 ， dl ， e3) 、 （al ， b3 ， c2 ， dl ， e3) 、 （a2 ， b3 dl，e3)、（a3，b3，c2，dl，e3)、（a4，b3，c2， e3)、（a5，b3，c2，dl，e3)、（a6，b3，c2，dl， (al，b4，c2，dl，e3)、（a2，b4，c2，dl，e3)、 b4，c2，dl，e3)、（a4，b4，c2，dl，e3)、（a5，b4 dl，e3)、（a6，b4，c2，dl，e3)、（al，bl，cl， e3)、（a2，bl，cl，d2，e3)、(a3，bl，cl，d2， (a4，bl，c 1，d2，e3)、(a5，bl，cl，d2，e3)、 bl ， cl ， d2 ， e3) 、 （al ， b2 ， cl ， d2 ， e3) 、 （a2 ， b2 d2，e3)、(a3，b2，cl，d2，e3)、（a4，b2，cl e3)、(a5，b2，cl，d2，e3)、（a6，b2，cl，d2， (al，b3，cl，d2，e3)、（a2，b3，cl，d2，e3)、 b3，cl，d2，e3)、（a4，b3，cl，d2，e3)、（a5，b3 d2，e3)、（a6，b3，c 1，d2，e3)、（al，b4，cl e3)、（a2，b4，cl，d2，e3)、（a3，b4，cl，d2， (a4，b4，c 1，d2，e3)、（a5，b4，cl，d2，e3)、 b4，cl，d2，e3)、（al，bl，c2，d2，e3)、（a2，bl d2，e3)、(a3，bl，c2，d2，e3)、（a4，bl，c2 e3)、（a5，bl，c2，d2，e3)、（a6，bl，c2，d2， (a3， ，c2， dl， e3)、 (a6， ，c2， dl， e3) ' (a3， ，c2， d2， e3)、 (a6， ，cl， d2， e3)、 (a3， ，cl， 1 d2 » e3)、 (a6， ，c2， ，d2， e3) ' 141666.doc -67- 201028381 (a 1，b2，c2，d2，e3)、（a2，b2，c2，d2，e3)、 b2，c2，d2，e3)、（a4，b2，c2，d2，e3)、（a5，b2 d2，e3)、（a6，b2，c2，d2，e3)、(al，b3，c2， e3)、（a2，b3，c2，d2，e3)、(a3，b3，c2，d2， (a4，b3，c2，d2，e3)、（a5，b3，c2，d2，e3)、 b3 ， c2 ， d2 ， e3) 、 （al ， b4 ， c2 ， d2 ， e3) 、 （a2 ， b4 d2，e3)、(a3，b4，c2，d2，e3)、（a4，b4，c2， e3)、(a5，b4，c2，d2，e3)、（a6，b4，c2，d2， (al，bl，cl，d3，e3)、（a2，bl，cl，d3，e3)、 bl ， cl ， d3 ， e3) 、 （a4 ， bl ， cl ， d3 ， e3) 、 （a5 ， bl d3，e3)、（a6，b 1，c 1，d3，e3)、（al，b2，cl， e3)、（a2，b2，cl，d3，e3)、(a3，b2，cl，d3， (a4，b2，c 1，d3，e3)、(a5，b2，cl，d3，e3)、 b2，cl，d3，e3)、（al，b3，cl，d3，e3)、（a2，b3 d3 ， e3) 、 (a3 ， b3 ， cl ， d3 ， e3) 、 （a4 ， b3 ， cl ， e3)、(a5，b3，cl，d3，e3)、（a6，b3，c 1，d3， (al，b4，cl，d3，e3)、（a2，b4，cl，d3，e3)、 b4，cl，d3，e3)、、（a4，b4，cl，d3，e3)、(a5 cl，d3，e3)、（a6，b4，cl，d3，e3)、（al，bl，c2 e3)、（a2，b 1，c2，d3，e3)、（a3，bl，c2，d3， (a4，bl，c2，d3，e3)、（a5，b 1，c2，d3，e3)、 bl ， c2 ， d3 ， e3) 、 （al ， b2 ， c2 ， d3 ， e3) 、 （a2 ， b2 d3，e3)、(a3，b2，c2，d3，e3)、（a4，b2，c2 e3)、(a5，b2，c2，d3，e3)、（a6，b2，c2，d3， U1666.doc -68 · (a3， ，c2， d2， e3)、 (a6， ，c2， d2， e3)、 (a3， ，cl， d3， e3) ' (a6， ，cl， I d3， e3) ' (a3， ，b4， ，d3， e3) ' (a6， ，c2， ，d3， e3) &gt;201028381 (a 1, bl, c2, dl, e3), (a2, b 1, c2, dl, e3), bl, c2, dl, e3), (a4, bl, c2, dl, e3), (a5 , bl dl, e3), (a6, b 1, c2, d 1, e3), (al, b2, c2, e3), (a2, b2, c2, dl, e3), (a3, b2, c2, Dl, (a4, b2, c2, dl, e3), (a5, b2, c2, dl, e3), b2, c2, dl, e3), (al, b3, c2, dl, e3), (a2, B3 dl, e3), (a3, b3, c2, dl, e3), (a4, b3, c2, e3), (a5, b3, c2, dl, e3), (a6, b3, c2, dl, ( Al, b4, c2, dl, e3), (a2, b4, c2, dl, e3), b4, c2, dl, e3), (a4, b4, c2, dl, e3), (a5, b4 dl, E3), (a6, b4, c2, dl, e3), (al, bl, cl, e3), (a2, bl, cl, d2, e3), (a3, bl, cl, d2, (a4, bl) , c 1,d2,e3), (a5, bl, cl, d2, e3), bl, cl, d2, e3), (al, b2, cl, d2, e3), (a2, b2 d2, e3) , (a3, b2, cl, d2, e3), (a4, b2, cl e3), (a5, b2, cl, d2, e3), (a6, b2, cl, d2) , (al, b3, cl, d2, e3), (a2, b3, cl, d2, e3), b3, cl, d2, e3), (a4, b3, cl, d2, e3), (a5, b3 D2, e3), (a6, b3, c 1, d2, e3), (al, b4, cl e3), (a2, b4, cl, d2, e3), (a3, b4, cl, d2, (a4 , b4, c 1, d2, e3), (a5, b4, cl, d2, e3), b4, cl, d2, e3), (al, bl, c2, d2, e3), (a2, bl d2, E3), (a3, bl, c2, d2, e3), (a4, bl, c2 e3), (a5, bl, c2, d2, e3), (a6, bl, c2, d2, (a3, , c2) , dl, e3), (a6, , c2, dl, e3) ' (a3, ,c2, d2, e3), (a6, ,cl, d2, e3), (a3, ,cl, 1 d2 » e3) , (a6, , c2, , d2, e3) ' 141666.doc -67- 201028381 (a 1,b2,c2,d2,e3), (a2,b2,c2,d2,e3), b2,c2,d2 , e3), (a4, b2, c2, d2, e3), (a5, b2 d2, e3), (a6, b2, c2, d2, e3), (al, b3, c2, e3), (a2, B3, c2, d2, e3), (a3, b3, c2, d2, (a4, b3, c2, d2, e3), (a5, b3, c2, d2, e3), b3, c2, d2, e3) , (al B4, c2, d2, e3), (a2, b4 d2, e3), (a3, b4, c2, d2, e3), (a4, b4, c2, e3), (a5, b4, c2, d2, e3) ), (a6, b4, c2, d2, (al, bl, cl, d3, e3), (a2, bl, cl, d3, e3), bl, cl, d3, e3), (a4, bl, cl , d3 , e3) , (a5 , bl d3 , e3 ) , (a6 , b 1, c 1, d3, e3), (al, b2, cl, e3), (a2, b2, cl, d3, e3) , (a3, b2, cl, d3, (a4, b2, c 1, d3, e3), (a5, b2, cl, d3, e3), b2, cl, d3, e3), (al, b3, cl , d3, e3), (a2, b3 d3, e3), (a3, b3, cl, d3, e3), (a4, b3, cl, e3), (a5, b3, cl, d3, e3), ( A6, b3, c 1, d3, (al, b4, cl, d3, e3), (a2, b4, cl, d3, e3), b4, cl, d3, e3), (a4, b4, cl, D3, e3), (a5 cl, d3, e3), (a6, b4, cl, d3, e3), (al, bl, c2 e3), (a2, b 1, c2, d3, e3), (a3 , bl, c2, d3, (a4, bl, c2, d3, e3), (a5, b 1, c2, d3, e3), bl, c2, d3, e3), (al, b2 , c2 , d3 , e3) , (a2 , b2 d3 , e3 ) , (a3 , b2 , c2 , d3 , e3 ) , ( a4 , b2 , c2 e3 ) , ( a5 , b2 , c2 , d3 , e3 ) , (a6,b2,c2,d3, U1666.doc -68 · (a3, ,c2, d2, e3), (a6, ,c2, d2, e3), (a3, ,cl, d3, e3) ' (a6 , ,cl, I d3, e3) ' (a3, ,b4, ,d3, e3) ' (a6, ,c2, ,d3, e3) &gt;

201028381 (al，b3，c2，d3，e3)、（a2，b3，c2，d3，e3)、 b3，c2，d3，e3)、（a4，b3，c2，d3，e3)、（a5，b3 d3，e3)、（a6，b3，c2，d3，e3)、（al，b4，c2， e3)、（a2，b4，c2，d3，e3)、(a3，b4，c2，d3， (a4，b4，c2，d3，e3)、（a5，b4，c2，d3，e3)、 b4，c2，d3，e3)、（al，bl，cl，d4，e3)、（a2，bl d4，e3)、(a3，bl，cl，d4，e3)、（a4，bl，cl， e3)、(a5，bl，cl，d4，e3)、（a6，bl，cl，d4， (al，b2，cl，d4，e3)、（a2，b2，cl，d4，e3)、 b2，cl，d4，e3)、（a4，b2，cl，d4，e3)、（a5，b2 d4，e3)、(a6，b2，cl，d4，e3)、(al，b3，cl， e3)、（a2，b3，cl，d4，e3)、（a3，b3，cl，d4， (a4，b3，c 1，d4，e3)、（a5，b3，cl，d4，e3)、 b3，cl，d4，e3)、（al，b4，cl，d4，e3)、（a2，b4 d4，e3)、(a3，b4，cl，d4，e3)、（a4，b4，cl e3)、（a5，b4，c 1，d4，e3)、（a6，b4，cl，d4， (al，bl，c2，d4，e3)、（a2，bl，c2，d4，e3)、 bl，c2，d4，e3)、（a4，bl，c2，d4，e3)、（a5，bl d4，e3)、（a6，bl，c2，d4，e3)、(al，b2，c2 e3) ' (a2，b2，c2，d4，e3)、（a3，b2，c2，d4， (a4，b2，c2，d4，e3)、（a5，b2，c2，d4，e3)、 b2，c2，d4，e3)、（al，b3，c2，d4，e3)、（a2，b3 d4，e3)、(a3，b3，c2，d4，e3)、（a4，b3，c2 e3)、(a5，b3，c2，d4，e3)、（a6，b3，c2，d4， (a3， ，c2， d3， e3) ' (a6， ，c 1， d4， e3)、 (a3， ，c 1， d4， e3) ' (a6， ，c 1， d4， e3) ' (a3， ，c2， 丨d4， e3)、 (a6， ，c2， ，d4， e3)、 141666.doc -69- 201028381 (al，b4，c2，d4，e3)、（a2，b4，c2，d4，e3)、 b4 ， c2 ， d4 ， e3) 、 （a4 ， b4 ， c2 ， d4 ， e3) 、 （a5 ， b4 d4，e3)、（a6，b4，c2，d4，e3)、(al，bl，cl， e3)、（a2，bl，cl，d5，e3)、（a3，b 1，c 1，d5， (a4，b 1，c 1，d5，e3)、(a5，bl，cl，d5，e3)、 bl ， cl ， d5 ， e3) 、 （al ， b2 ， cl ， d5 ， e3) 、 （a2 ， b2 d5，e3)、(a3，b2，cl，d5，e3)、（a4，b2，cl， e3) ' (a5，b2，cl，d5，e3)、（a6，b2，c 1，d5， (al，b3，cl，d5，e3)、（a2，b3，cl，d5，e3)、 b3，cl，d5，e3)、（a4，b3，cl，d5，e3)、（a5，b3 d5，e3)、（a6，b3，cl，d5，e3)、(al，b4，cl， e3)、（a2，b4，cl，d5，e3)、(a3，b4，cl，d5， (a4，b4，c 1，d5，e3)、(a5，b4，cl，d5，e3)、 b4 ， cl ， d5 ， e3) 、 （al ， bl ， c2 ， d5 ， e3) 、 （a2 ， bl d5，e3)、(a3，bl，c2，d5，e3)、（a4，bl，c2， e3)、(a5，bl，c2，d5，e3)、（a6，bl，c2，d5， (al，b2，c2，d5，e3)、（a2，b2，c2，d5，e3)、 b2 ， c2 ， d5 ， e3) 、 （a4 ， b2 ， c2 ， d5 ， e3) 、 （a5 ， b2 d5 ， e3) 、 （a6 ， b2 ， c2 ， d5 ， e3) 、 (al ， b3 ， c2 ， e3) ' (a2，b3，c2，d5，e3)、(a3，b3，c2，d5， (a4，b3，c2，d5，e3)、（a5，b3，c2，d5，e3)、 b3 ， c2 ， d5 ， e3) 、 （al ， b4 ， c2 ， d5 ， e3) 、 （a2 ， b4 d5，e3)、(a3，b4，c2，d5，e3)、（a4，b4，c2 e3)、(a5，b4，c2，d5，e3)、（a6，b4，c2，d5， 141666.doc -70- (a3， ，c2， d5， e3) ' (a6， ，cl， d5， e3) &gt; (a3， ，cl， d5， e3) ' (a6， ，c2， 'd5， e3) &gt; (a3， ，c2， ，d5， e3) ' (a6， ，c2， ，d5， e3) '201028381 (al, b3, c2, d3, e3), (a2, b3, c2, d3, e3), b3, c2, d3, e3), (a4, b3, c2, d3, e3), (a5, b3) D3, e3), (a6, b3, c2, d3, e3), (al, b4, c2, e3), (a2, b4, c2, d3, e3), (a3, b4, c2, d3, (a4) , b4, c2, d3, e3), (a5, b4, c2, d3, e3), b4, c2, d3, e3), (al, bl, cl, d4, e3), (a2, bl d4, e3) ), (a3, bl, cl, d4, e3), (a4, bl, cl, e3), (a5, bl, cl, d4, e3), (a6, bl, cl, d4, (al, b2, Cl, d4, e3), (a2, b2, cl, d4, e3), b2, cl, d4, e3), (a4, b2, cl, d4, e3), (a5, b2 d4, e3), ( A6, b2, cl, d4, e3), (al, b3, cl, e3), (a2, b3, cl, d4, e3), (a3, b3, cl, d4, (a4, b3, c 1, D4, e3), (a5, b3, cl, d4, e3), b3, cl, d4, e3), (al, b4, cl, d4, e3), (a2, b4 d4, e3), (a3, B4,cl,d4,e3), (a4,b4,cl e3), (a5,b4,c 1,d4,e3), (a6,b4,cl,d4, (al,bl,c2,d4,e3) ), (a2, bl, c2, d4, e3), bl , c2, d4, e3), (a4, bl, c2, d4, e3), (a5, bl d4, e3), (a6, bl, c2, d4, e3), (al, b2, c2 e3) ' (a2, b2, c2, d4, e3), (a3, b2, c2, d4, (a4, b2, c2, d4, e3), (a5, b2, c2, d4, e3), b2, c2, d4 , e3), (al, b3, c2, d4, e3), (a2, b3 d4, e3), (a3, b3, c2, d4, e3), (a4, b3, c2 e3), (a5, b3) , c2, d4, e3), (a6, b3, c2, d4, (a3, , c2, d3, e3) ' (a6, , c 1, d4, e3), (a3, , c 1, d4, e3 ) ' (a6, ,c 1, d4, e3) ' (a3, ,c2, 丨d4, e3), (a6, ,c2, ,d4, e3), 141666.doc -69- 201028381 (al,b4, C2, d4, e3), (a2, b4, c2, d4, e3), b4, c2, d4, e3), (a4, b4, c2, d4, e3), (a5, b4 d4, e3), ( A6, b4, c2, d4, e3), (al, bl, cl, e3), (a2, bl, cl, d5, e3), (a3, b 1, c 1, d5, (a4, b 1, c 1,d5,e3), (a5, bl, cl, d5, e3), bl, cl, d5, e3), (al, b2, cl, d5, e3), (a2, b2 d 5, e3), (a3, b2, cl, d5, e3), (a4, b2, cl, e3) ' (a5, b2, cl, d5, e3), (a6, b2, c 1, d5, ( Al, b3, cl, d5, e3), (a2, b3, cl, d5, e3), b3, cl, d5, e3), (a4, b3, cl, d5, e3), (a5, b3 d5, E3), (a6, b3, cl, d5, e3), (al, b4, cl, e3), (a2, b4, cl, d5, e3), (a3, b4, cl, d5, (a4, b4) , c 1,d5,e3), (a5,b4,cl,d5,e3), b4 , cl , d5 , e3) , (al , bl , c2 , d5 , e3 ) , (a2 , bl d5 , e3 ) , (a3, bl, c2, d5, e3), (a4, bl, c2, e3), (a5, bl, c2, d5, e3), (a6, bl, c2, d5, (al, b2, c2) , d5, e3), (a2, b2, c2, d5, e3), b2, c2, d5, e3), (a4, b2, c2, d5, e3), (a5, b2 d5, e3), (a6 , b2 , c2 , d5 , e3) , (al , b3 , c2 , e3) ' (a2, b3, c2, d5, e3), (a3, b3, c2, d5, (a4, b3, c2, d5, E3), (a5, b3, c2, d5, e3), b3, c2, d5, e3), (al, b4, c2, d5, e3), (a2, B4 d5, e3), (a3, b4, c2, d5, e3), (a4, b4, c2 e3), (a5, b4, c2, d5, e3), (a6, b4, c2, d5, 141666. Doc -70- (a3, ,c2, d5, e3) ' (a6, ,cl, d5, e3) &gt; (a3, ,cl, d5, e3) ' (a6, ,c2, 'd5, e3) &gt ; (a3, ,c2, ,d5, e3) ' (a6, ,c2, ,d5, e3) '

201028381 (al，bl，cl，dl，e4)、（a2，b 1，c 1，d 1，e4)、 bl ， cl ， dl ， e4) 、 （a4 ， bl ， cl ， dl ， e4) 、 （a5 ， bl dl，e4)、（a6，b 1，c 1，d 1，e4)、（al，b2，cl， e4)、（a2，b2，cl，dl，e4)、（a3，b2，c 1，d 1， (a4，b2，c 1，d 1，e4)、（a5，b2，c 1，d 1，' e4)、 b2，cl，dl，e4)、（al，b3，cl，dl，e4)、（a2，b3 dl，e4)、(a3，b3，cl，dl，e4)、（a4，b3，cl， e4)、(a5，b3，cl，dl，e4)、（a6，b3，cl，d 1， (a 1，b4，c 1，d 1，e4)、（a2，b4，cl，dl，e4)、 b4，cl，dl，e4)、（a4，b4，cl，dl，e4)、（a5，b4 dl，e4)、（a6，b4，c 1，d 1，e4)、（al，bl，c2 ’ e4)、（a2，b 1，c2，d 1，e4)、（a3，b 1，c2，d 1， (a4，bl，c2，dl，e4)、（a5，b 1，c2，d 1，e4)、 bl ， c2 ， dl ， e4) 、 （al ， b2 ， c2 ， dl ， e4) 、 （a2 ， b2 dl，e4)、(a3，b2，c2，dl，e4)、（a4，b2，c2 e4)、（a5，b2，c2，dl，e4)、（a6，b2，c2，dl， (al，b3，c2，dl，e4)、（a2，b3，c2，dl，e4)、 b3，c2，dl，e4)、（a4，b3，c2，dl，e4)、（a5，b3 dl，e4)、（a6，b3，c2，dl，e4)、(al，b4 .，c2 e4)、（a2，b4，c2，dl，e4)、(a3，b4，c2，dl， (a4，b4，c2，dl，e4)、（a5，b4，c2，dl，e4)、 b4，c2，dl，e4)、（al，bl，cl，d2，e4)、（a2，bl d2，e4)、（a3，bl，cl，d2，e4)、（a4，bl，cl e4)、(a5，bl，cl，d2，e4)、（a6，bl，cl，d2， (a3， ，c 1， dl， e4)、 (a6， ，c 1， dl， e4)、 (a3， ，cl， dl， e4)、 (a6， ，c2， dl， e4) ' (a3， ，c2， d 1 5 e4)、 (a6， ，cl， ，d2， e4)、 141666.doc -71 - 201028381 (al，b2，cl，d2，e4)、（a2，b2，cl，d2，e4)、 b2 ， cl ， d2 ， e4) 、 （a4 ， b2 ， cl ， d2 ， e4) 、 （a5 ， b2 d2，e4)、（a6，b2，c 1，d2，e4)、(al，b3，cl， e4)、（a2，b3，cl，d2，e4)、（a3，b3，c 1，d2， (a4，b3，cl，d2，e4)、（a5，b3，cl，d2，e4)、 b3，cl，d2，e4)、（al，b4，cl，d2，e4)、（a2，b4 d2，e4)、(a3，b4，cl，d2，e4)、（a4，b4，cl， e4)、(a5，b4，cl，d2，e4)、（a6，b4，c 1，d2， (al，bl，c2，d2，e4)、（a2，b 1，c2，d2，e4)、 bl ， c2 ， d2 ， e4) 、 （a4 ， bl ， c2 ， d2 ， e4) 、 （a5 ， bl d2，e4)、（a6，bl，c2，d2，e4)、（al，b2，c2， e4)、（a2，b2，c2，d2，e4)、(a3，b2，c2，d2， (a4，b2，c2，d2，e4)、(a5，b2，c2，d2，e4)、 b2 ， c2 ， d2 ， e4) 、 （al ， b3 ， c2 ， d2 ， e4) 、 （a2 ， b3 d2，e4)、(a3，b3，c2，d2，e4)、（a4，b3，c2， e4)、(a5，b3，c2，d2，e4)、（a6，b3，c2，d2， (al，b4，c2，d2，e4)、（a2，b4，c2，d2，e4)、 b4，c2，d2，e4)、（a4，b4，c2，d2，e4)、（a5，b4 d2，e4)、（a6，b4，c2，d2，e4)、（al，bl，cl : e4)、（a2，bl，cl，d3，e4)、（a3，bl，cl，d3， (a4，bl，cl，d3，e4)、（a5，b 1，c 1，d3，e4)、 bl，cl，d3，e4)、（al，b2，cl，d3，e4)、（a2，b2 d3，e4)、(a3，b2，cl，d3，e4)、（a4，b2，cl e4)、(a5，b2，cl，d3，e4)、（a6，b2，c 1，d3， 141666.doc •72- (a3， ，c 1， d2， e4)、 (a6， ，cl， d2， e4)、 (a3， ，c2， d2， e4)、 (a6， ，c2， _ d2， e4)、 (a3， ，c2， ，d3， e4)、 (a6， ，cl， ，d3， e4)、201028381 (al, bl, cl, dl, e4), (a2, b 1, c 1, d 1, e4), bl, cl, dl, e4), (a4, bl, cl, dl, e4) , ( A5 , bl dl, e4), (a6, b 1, c 1, d 1, e4), (al, b2, cl, e4), (a2, b2, cl, dl, e4), (a3, b2, c 1,d 1, (a4,b2,c 1,d 1,e4), (a5,b2,c 1,d 1,' e4), b2,cl,dl,e4),(al,b3,cl , dl, e4), (a2, b3 dl, e4), (a3, b3, cl, dl, e4), (a4, b3, cl, e4), (a5, b3, cl, dl, e4), ( A6, b3, cl, d 1, (a 1, b4, c 1, d 1, e4), (a2, b4, cl, dl, e4), b4, cl, dl, e4), (a4, b4, Cl, dl, e4), (a5, b4 dl, e4), (a6, b4, c 1, d 1, e4), (al, bl, c2 'e4), (a2, b 1, c2, d 1 , e4), (a3, b 1, c2, d 1, (a4, bl, c2, dl, e4), (a5, b 1, c2, d 1, e4), bl, c2, dl, e4), (al , b2 , c2 , dl , e4) , (a2 , b2 dl , e4 ) , (a3 , b2 , c2 , dl , e4 ) , (a4 , b2 , c2 e4 ) , (a5 , b2 , c2 , dl , e4), (a6, b2 C2, dl, (al, b3, c2, dl, e4), (a2, b3, c2, dl, e4), b3, c2, dl, e4), (a4, b3, c2, dl, e4), ( A5, b3 dl, e4), (a6, b3, c2, dl, e4), (al, b4., c2 e4), (a2, b4, c2, dl, e4), (a3, b4, c2, dl , (a4, b4, c2, dl, e4), (a5, b4, c2, dl, e4), b4, c2, dl, e4), (al, bl, cl, d2, e4), (a2, bl D2, e4), (a3, bl, cl, d2, e4), (a4, bl, cl e4), (a5, bl, cl, d2, e4), (a6, bl, cl, d2, (a3, , c 1, dl, e4), (a6, , c 1, dl, e4), (a3, ,cl, dl, e4), (a6, ,c2, dl, e4) ' (a3, ,c2, d 1 5 e4), (a6, ,cl, ,d2, e4), 141666.doc -71 - 201028381 (al,b2,cl,d2,e4), (a2,b2,cl,d2,e4), b2, Cl , d2 , e4) , (a4 , b2 , cl , d2 , e4 ) , (a5 , b2 d2 , e4 ) , (a6 , b2 , c 1, d2 , e4 ) , ( al , b3 , cl , e4 ) , (a2, b3, cl, d2, e4), (a3, b3, c 1, d2, (a4, b3, cl, d2, e4), (a5, b3, cl, d2, e4), b3, cl D2, e4), (al, b4, cl, d2, e4), (a2, b4 d2, e4), (a3, b4, cl, d2, e4), (a4, b4, cl, e4), (a5 , b4, cl, d2, e4), (a6, b4, c 1, d2, (al, bl, c2, d2, e4), (a2, b 1, c2, d2, e4), bl, c2, d2 , e4), (a4, bl, c2, d2, e4), (a5, bl d2, e4), (a6, bl, c2, d2, e4), (al, b2, c2, e4), (a2, B2, c2, d2, e4), (a3, b2, c2, d2, (a4, b2, c2, d2, e4), (a5, b2, c2, d2, e4), b2, c2, d2, e4) , (al, b3, c2, d2, e4), (a2, b3 d2, e4), (a3, b3, c2, d2, e4), (a4, b3, c2, e4), (a5, b3, c2) , d2, e4), (a6, b3, c2, d2, (al, b4, c2, d2, e4), (a2, b4, c2, d2, e4), b4, c2, d2, e4), (a4 , b4, c2, d2, e4), (a5, b4 d2, e4), (a6, b4, c2, d2, e4), (al, bl, cl: e4), (a2, bl, cl, d3, E4), (a3, bl, cl, d3, (a4, bl, cl, d3, e4), (a5, b 1, c 1, d3, e4), bl, cl, d3, e4), (al, B2 Cl,d3,e4), (a2,b2 d3,e4), (a3,b2,cl,d3,e4), (a4,b2,cl e4), (a5,b2,cl,d3,e4),( A6,b2,c 1,d3, 141666.doc •72- (a3, ,c 1, d2, e4), (a6, ,cl, d2, e4), (a3, ,c2, d2, e4), ( A6, ,c2, _ d2, e4), (a3, ,c2, ,d3, e4), (a6, ,cl, ,d3, e4),

201028381 (a 1，b3，cl，d3，e4)、（a2，b3，c 1，d3，e4)、 b3，cl，d3，e4)、（a4，b3，cl，d3，e4)、（a5，b3 d3，e4)、（a6，b3，cl，d3，e4)、（al，b4，cl， e4)、（a2，b4，c 1，d3，e4)、（a3，b4，c 1，d3， (a4，b4，c 1，d3，e4)、（a5，b4，c 1，d3，e4)、 b4 ， cl ， d3 ， e4) 、 （al ， bl ， c2 ， d3 ， e4) 、 （a2 ， bl d3，e4)、(a3，bl，c2，d3，e4)、（a4，bl，c2， e4)、(a5，bl，c2，d3，e4)、（a6，bl，c2，d3， (al，b2，c2，d3，e4)、（a2，b2，c2，d3，e4)、 b2，c2，d3，e4)、（a4，b2，c2，d3，e4)、（a5，b2 d3，e4)、（a6，b2，c2，d3，e4)、(al，b3，c2， e4)、（a2，b3，c2，d3，e4)、（a3，b3，c2，d3， (a4，b3，c2，d3，e4)、（a5，b3，c2，d3，e4)、 b3，c2，d3，e4)、（al，b4，c2，d3，e4)、（a2，b4 d3，e4)、(a3，b4，c2，d3 » e4)、（a4，b4，c2， e4)、（a5，b4，c2，d3，e4)、（a6，b4，c2，d3， (al，bl，cl，d4，e4)、（a2，b 1，c 1，d4，e4)、 bl ， cl ， d4 ， e4) 、 （a4 ， bl ， cl ， d4 ， e4) 、 （a5 ， bl d4，e4)、（a6，b 1，c 1，d4，e4)、（al，b2，cl e4)、（a2，b2，cl，d4，e4)、(a3，b2，cl，d4， (a4，b2，c 1，d4，e4)、(a5，b2，cl，d4，e4)、 b2，cl，d4，e4) ' (al，b3，cl，d4，e4)、（a2，b3 d4，e4)、(a3，b3，cl，d4，e4)、（a4，b3，cl e4)、(a5，b3，cl，d4，e4)、（a6，b3，c 1，d4， (a3， ，cl， d3， e4)、 (a6， ，c2， d3， e4)、 (a3， ，c2， d3， e4)、 (a6， ，c2， d3， e4)、 (a3， ，cl， d4， e4)、 (a6， ，cl， 丨d4， e4)、 141666.doc -73- 201028381 (al，b4，cl，d4，e4)、（a2，b4，cl，d4，e4)、 b4，cl，d4，e4)、（a4，b4，cl，d4，e4)、（a5，b4 d4，e4)、（a6，b4，c 1，d4，e4)、(al，bl，c2， e4)、（a2，b 1，c2，d4，e4)、(a3，bl，c2，d4， (a4，bl，c2，d4，e4)、(a5，bl，c2，d4，e4)、 bl ， c2 ， d4 ， e4) 、 （al ， b2 ， c2 ， d4 ， e4) 、 （a2 ， b2 d4，e4)、（a3，b2，c2，d4，e4)、（a4，b2，c2， e4)、(a5，b2，c2，d4，e4)、（a6，b2，c2，d4， (al，b3，c2，d4，e4)、（a2，b3，c2，d4，e4)、 b3，c2，d4，e4)、（a4，b3，c2，d4，e4)、（a5，b3 d4，e4)、（a6，b3，c2，d4，e4)、(al，b4，c2， e4)、（a2，b4，c2，d4，e4)、(a3，b4，c2，d4， (a4，b4，c2，d4，e4)、(a5，b4，c2，d4，e4)、 b4，c2，d4，e4)、（al，bl，cl，d5，e4)、（a2，bl d5，e4)、(a3，bl，cl，d5，e4)、（a4，bl，cl ! e4)、(a5，bl，cl，d5，e4)、（a6，b 1，c 1，d5， (al，b2，cl，d5，e4)、（a2，b2，cl，d5，e4)、 b2，cl，d5，e4)、（a4，b2，cl，d5，e4)、（a5，b2 d5，e4)、（a6，b2，cl，d5，e4)、（al，b3，cl e4)、（a2，b3，cl，d5，e4)、(a3，b3，cl，d5， (a4，b3，cl，d5，e4)、（a5，b3，c 1，d5，e4)、 b3，cl，d5，e4)、（al，b4，cl，d5，e4)、（a2，b4 d5，e4)、（a3，b4，cl，d5，e4)、（a4，b4，cl e4)、(a5，b4，cl，d5，e4)、（a6，b4，c 1，d5， 141666.doc -74- (a3， ，cl， d4， e4)、 (a6， ，c2， d4， e4)、 (a3， ，c2， d4， e4) &gt; (a6， ，cl， ，d5， e4)、 (a3， ，cl， ，d5， e4)、 (a6， ，cl， ，d5， e4)、201028381 (a 1,b3,cl,d3,e4), (a2,b3,c 1,d3,e4), b3,cl,d3,e4), (a4,b3,cl,d3,e4), (a5 , b3 d3, e4), (a6, b3, cl, d3, e4), (al, b4, cl, e4), (a2, b4, c 1, d3, e4), (a3, b4, c 1, D3, (a4, b4, c 1, d3, e4), (a5, b4, c 1, d3, e4), b4, cl, d3, e4), (al, bl, c2, d3, e4), ( A2 , bl d3, e4), (a3, bl, c2, d3, e4), (a4, bl, c2, e4), (a5, bl, c2, d3, e4), (a6, bl, c2, d3) , (al, b2, c2, d3, e4), (a2, b2, c2, d3, e4), b2, c2, d3, e4), (a4, b2, c2, d3, e4), (a5, b2) D3, e4), (a6, b2, c2, d3, e4), (al, b3, c2, e4), (a2, b3, c2, d3, e4), (a3, b3, c2, d3, (a4) , b3, c2, d3, e4), (a5, b3, c2, d3, e4), b3, c2, d3, e4), (al, b4, c2, d3, e4), (a2, b4 d3, e4) ), (a3, b4, c2, d3 » e4), (a4, b4, c2, e4), (a5, b4, c2, d3, e4), (a6, b4, c2, d3, (al, bl, Cl,d4,e4), (a2, b 1, c 1, d4, e4), bl, cl, d4, e4), (a4, bl, cl, d4, e4), (a5, bl d4, e4), (a6, b 1, c 1,d4,e4), (al,b2,cl e4), (a2,b2,cl,d4,e4), (a3,b2,cl,d4, (a4,b2,c 1,d4,e4) , (a5, b2, cl, d4, e4), b2, cl, d4, e4) ' (al, b3, cl, d4, e4), (a2, b3 d4, e4), (a3, b3, cl, D4, e4), (a4, b3, cl e4), (a5, b3, cl, d4, e4), (a6, b3, c 1, d4, (a3, , cl, d3, e4), (a6, , c2, d3, e4), (a3, , c2, d3, e4), (a6, , c2, d3, e4), (a3, , cl, d4, e4), (a6, , cl, 丨d4, E4), 141666.doc -73- 201028381 (al, b4, cl, d4, e4), (a2, b4, cl, d4, e4), b4, cl, d4, e4), (a4, b4, cl, D4, e4), (a5, b4 d4, e4), (a6, b4, c 1, d4, e4), (al, bl, c2, e4), (a2, b 1, c2, d4, e4), (a3, bl, c2, d4, (a4, bl, c2, d4, e4), (a5, bl, c2, d4, e4), bl, c2, d4, e4), (al, b2, c2, D4, e4), (a2, b2 d4, e4), (a3, b2, c2, d4, e4), (a4, b2, c2, e4), (a5, b2, c2, d4, e4), (a6 , b2, c2, d4, (al, b3, c2, d4, e4), (a2, b3, c2, d4, e4), b3, c2, d4, e4), (a4, b3, c2, d4, e4) ), (a5, b3 d4, e4), (a6, b3, c2, d4, e4), (al, b4, c2, e4), (a2, b4, c2, d4, e4), (a3, b4, C2, d4, (a4, b4, c2, d4, e4), (a5, b4, c2, d4, e4), b4, c2, d4, e4), (al, bl, cl, d5, e4), ( A2, bl d5, e4), (a3, bl, cl, d5, e4), (a4, bl, cl ! e4), (a5, bl, cl, d5, e4), (a6, b 1, c 1 , d5, (al, b2, cl, d5, e4), (a2, b2, cl, d5, e4), b2, cl, d5, e4), (a4, b2, cl, d5, e4), (a5 , b2 d5, e4), (a6, b2, cl, d5, e4), (al, b3, cl e4), (a2, b3, cl, d5, e4), (a3, b3, cl, d5, ( A4, b3, cl, d5, e4), (a5, b3, c 1, d5, e4), b3, cl, d5, e4), (al, b4, cl, d5, e4), (a2, b4 d5 , e4), (a3, b4, cl, d5, e4), A4, b4, cl e4), (a5, b4, cl, d5, e4), (a6, b4, c 1, d5, 141666.doc -74- (a3, , cl, d4, e4), (a6, , c2, d4, e4), (a3, , c2, d4, e4) &gt; (a6, ,cl, ,d5, e4), (a3, ,cl, ,d5, e4), (a6, ,cl, , d5, e4),

201028381 (a 1，bl，c2，d5，e4)、（a2，b 1，c2，d5，e4)、 bl，c2，d5，e4)、（a4，bl，c2，d5，e4)、（a5，bl d5，e4)、（a6，b 1，c2，d5，e4)、（al，b2，c2， e4)、（a2，b2，c2，d5，e4)、(a3，b2，c2，d5， (a4，b2，c2，d5，e4)、（a5，b2，c2，d5，e4)、 b2，c2，d5，e4)、（al，b3，c2，d5，e4)、（a2，b3 d5，e4)、(a3，b3，c2，d5，e4)、（a4，b3，c2， e4) ' (a5，b3，c2，d5，e4)、（a6，b3，c2，d5， (al，b4，c2，d5，e4)、（a2，b4，c2，d5，e4)、 b4，c2，d5，e4).、（a4，b4，c2，d5，e4)、（a5，b4 d5，e4)、（a6，b4，c2，d5，e4)、(al，bl，cl e5) ' (a2，bl，cl，dl，e5)、（a3，bl，cl，dl， (a4，b1，c1，d1，e5)、（a5，b 1，c1，d1，e5)、 bl，cl，dl，e5)、（al，b2，cl，dl，e5)、（a2，b2 dl，e5)、(a3，b2，cl，dl，e5) ' (a4，b2，cl e5)、(a5，b2，cl，dl，e5)、（a6，b2，cl，dl， (al，b3，cl，dl，e5)、（a2，b3，c 1，d 1，e5)、 b3，cl，dl，e5)、（a4，b3，cl，dl，e5)、（a5，b3 dl，e5)、（a6，b3，c 1，d 1，e5)、（al，b4，cl e5)、（a2，b4，cl，dl，e5)、（a3，b4，c 1，dl， (a4，b4，c 1，dl，e5)、(a5，b4，cl，dl，e5)、 b4，cl，dl，e5)、（al，bl，c2，dl，e5)、（a2，bl dl，e5)、(a3，bl，c2，dl，e5)、（a4，bl，c2 e5)、(a5，bl，c2，dl，e5)、（a6，bl，c2，dl， (a3， ，c2， d5， e4)、 (a6， ，c2， d5， e4)、 (a3， ，c2， dl -e5) ' (a6， ，c 1， dl， e5)、 (a3， ，c 1， ，d 1， e5)、 (a6， ，c2， ，dl， e5)、 141666.doc -75- 、（a2 ， b2 ， c2 ， dl ， e5) 、 （a3 ， b2 ， c2 ， dl ， e5) 、 （a5 ， b2 ， c2 ， ，dl，e5)、(al，b3，c2，dl， ，e5)、（a3，b3，c2，dl，e5)、 、（a5 ， b3 ， c2 ， dl ， e5) 、 （a6 ， b4 ， c2 ， dl ， e5) 、 （a2 ， b4 ， c2 ， ，dl，e5)、（a4，b4，c2，dl， ，e5) ' (a6，b4，c2，dl，e5)、 、（a2，b 1，c 1，d2，e5)、（a3， bl ， cl ， d2 ， e5) 、 （a5 ， bl ， cl ， ，d2，e5)、（al，b2，cl，d2， ，e5)、（a3，b2，c 1，d2，e5)、 、(a5，b2，cl，d2，e5)、（a6， b3 ， cl ， d2 ， e5) 、 （a2 ， b3 ， c1 ， ，d2，e5)、（a4，b3，c 1，d2， ，e5)、（a6，b3，cl，d2，e5)、 、（a2，b4，c 1，d2，e5)、(a3 ’ b4 ， cl ， d2 ， e5) 、 （a5 ， b4 ， cl ， ，d2，e5)、(al，bl，c2，d2， ，e5)、（a3，bl，c2，d2，e5)、 、(a5，bl，c2，d2，e5)、（a6， b2 ， c2 ， d2 ， e5) 、 （a2 ， b2 ， c2 ， ，d2，e5)、（a4，b2，c2，d2， ，e5)、（a6，b2，c2，d2，e5)、 201028381 (a 1，b2，c2，dl，e5) b2，c2，dl，e5)、（a4， dl ， e5) ' (a6 ， b2 ， c2 e5)、（a2，b3，c2，dl (a4，b3，c2，d 1，e5) b3 ， c2 ， dl ， e5) 、 （al ， dl ， e5) 、 (a3 ， b4 ， c2 e5) 、 (a5 ， b4 ， c2 ， dl (al，bl，cl，d2，e5) bl，cl，d2，e5) ' (a4， d2 ， e5) 、 （a6 ， bl ， cl e5) 、 （a2 ， b2 ， cl ， d2 (a4，b2，cl，d2，e5) b2 ， cl ， d2 ， e5) 、 （al ， d2 ， e5) 、 (a3 ， b3 ， cl e5) 、 (a5 ， b3 ， cl ， d2 (al，b4，cl，d2，e5) b4 ， cl ， d2 ， e5) 、 （a4 ， d2 ， e5) 、 （a6 ， b4 ， cl e5) 、 （a2 ， bl ， c2 ， d2 (a4，b 1，c2，d2，e5) b 1，c2，d2，e5)、（al， d2 ， e5) 、 (a3 ， b2 ， c2 e5) 、 (a5 ， b2 ， c2 ， d2 141666.doc -76-201028381 (a 1, bl, c2, d5, e4), (a2, b 1, c2, d5, e4), bl, c2, d5, e4), (a4, bl, c2, d5, e4), (a5 , bl d5, e4), (a6, b 1, c2, d5, e4), (al, b2, c2, e4), (a2, b2, c2, d5, e4), (a3, b2, c2, d5) , (a4, b2, c2, d5, e4), (a5, b2, c2, d5, e4), b2, c2, d5, e4), (al, b3, c2, d5, e4), (a2, b3) D5, e4), (a3, b3, c2, d5, e4), (a4, b3, c2, e4) ' (a5, b3, c2, d5, e4), (a6, b3, c2, d5, (al , b4, c2, d5, e4), (a2, b4, c2, d5, e4), b4, c2, d5, e4)., (a4, b4, c2, d5, e4), (a5, b4 d5, E4), (a6, b4, c2, d5, e4), (al, bl, cl e5) ' (a2, bl, cl, dl, e5), (a3, bl, cl, dl, (a4, b1, C1, d1, e5), (a5, b 1, c1, d1, e5), bl, cl, dl, e5), (al, b2, cl, dl, e5), (a2, b2 dl, e5), (a3, b2, cl, dl, e5) ' (a4, b2, cl e5), (a5, b2, cl, dl, e5), (a6, b2, cl, dl, (al, b3, cl, dl , e5), (a2, b3, c 1, d 1, e5), b3 Cl, dl, e5), (a4, b3, cl, dl, e5), (a5, b3 dl, e5), (a6, b3, c 1, d 1, e5), (al, b4, cl e5) , (a2, b4, cl, dl, e5), (a3, b4, c 1, dl, (a4, b4, c 1, dl, e5), (a5, b4, cl, dl, e5), b4, Cl, dl, e5), (al, bl, c2, dl, e5), (a2, bl dl, e5), (a3, bl, c2, dl, e5), (a4, bl, c2 e5), ( A5, bl, c2, dl, e5), (a6, bl, c2, dl, (a3, , c2, d5, e4), (a6, c2, d5, e4), (a3, , c2, dl - E5) ' (a6, ,c 1, dl, e5), (a3, ,c 1, ,d 1, e5), (a6, ,c2, ,dl, e5), 141666.doc -75-, (a2 , b2 , c2 , dl , e5) , (a3 , b2 , c2 , dl , e5 ) , ( a5 , b2 , c2 , , dl , e5 ) , ( al , b3 , c2 , dl , , e5 ) , (a3 , b3, c2, dl, e5), (a5, b3, c2, dl, e5), (a6, b4, c2, dl, e5), (a2, b4, c2, , dl, e5), (a4 , b4, c2, dl, , e5) ' (a6, b4, c2, dl, e5), , (a2, b 1, c 1, d2, e5), (a3 Bl, cl, d2, e5), (a5, bl, cl, , d2, e5), (al, b2, cl, d2, , e5), (a3, b2, c 1, d2, e5), , ( A5, b2, cl, d2, e5), (a6, b3, cl, d2, e5), (a2, b3, c1, , d2, e5), (a4, b3, c 1, d2, e5), (a6, b3, cl, d2, e5), , (a2, b4, c 1, d2, e5), (a3 ' b4 , cl , d2 , e5 ) , (a5 , b4 , cl , , d2 , e5 ) , (al, bl, c2, d2, , e5), (a3, bl, c2, d2, e5), , (a5, bl, c2, d2, e5), (a6, b2, c2, d2, e5) , (a2, b2, c2, , d2, e5), (a4, b2, c2, d2, , e5), (a6, b2, c2, d2, e5), 201028381 (a 1, b2, c2, dl, E5) b2, c2, dl, e5), (a4, dl, e5) ' (a6, b2, c2 e5), (a2, b3, c2, dl (a4, b3, c2, d 1, e5) b3 , C2 , dl , e5) , ( al , dl , e5) , (a3 , b4 , c2 e5 ) , (a5 , b4 , c2 , dl (al, bl, cl, d2, e5) bl, cl, d2, e5 ) ' (a4, d2 , e5) , (a6 , bl , cl e5) , (a2 B2 , cl , d2 (a4, b2, cl, d2, e5) b2 , cl , d2 , e5) , ( al , d2 , e5 ) , ( a3 , b3 , cl e5 ) , (a5 , b3 , cl , d2 ) (al, b4, cl, d2, e5) b4, cl, d2, e5), (a4, d2, e5), (a6, b4, cl e5), (a2, bl, c2, d2 (a4, b 1 , c2, d2, e5) b 1, c2, d2, e5), (al, d2, e5), (a3, b2, c2 e5), (a5, b2, c2, d2 141666.doc -76-

201028381 (al，b3，c2，d2，e5)、（a2，b3，c2，d2，e5)、 b3，c2，d2，e5)、（a4，b3，c2，d2，e5)、（a5，b3 d2，e5)、（a6，b3，c2，d2，e5)、（al，b4，c2， e5)、（a2，b4，c2，d2，e5)、（a3，b4，c2，d2， (a4，b4，c2，d2，e5)、（a5，b4，c2，d2，e5)、 b4，c2，d2，e5)、（al，bl，cl，d3，e5)、（a2，bl d3，e5)、(a3，bl，cl，d3，e5)、（a4，bl，cl， e5)、(a5，bl，cl，d3，e5)、（a6，bl，cl，d3， © (al，b2，cl，d3，e5)、（a2，b2，cl，d3，e5)、 b2，cl，d3，e5)、（a4，b2，cl .，d3，e5)、（a5，b2 d3，e5)、（a6，b2，c 1，d3，e5)、（al，b3，cl ’ e5)、（a2，b3，cl，d3，e5)、（a3，b3，cl，d3， (a4，b3，c 1，d3，e5)、(a5，b3，cl，d3，e5)、 b3 ， cl ， d3 ， e5) 、 （al ， b4 ， cl ， d3 ， e5) 、 （a2 ， b4 d3，e5)、(a3，b4，cl，d3，e5)、（a4，b4，cl， e5)、(a5，b4，cl，d3，e5)、（a6，b4，cl，d3， (al，bl，c2，d3，e5)、（a2，b 1，c2，d3，e5)、 bl，c2，d3，e5)、（a4，bl，c2，d3，e5)、（a5，bl d3，e5)、（a6，bl，c2，d3，e5)、(al，b2，c2 e5)、（a2，b2，c2，d3，e5)、（a3，b2，c2，d3， (a4，b2，c2，d3，e5)、(a5，b2，c2，d3，e5)、 b2，c2，d3，e5)、（al，b3，c2，d3，e5)、（a2，b3 d3，e5)、(a3，b3，c2，d3，e5)、（a4，b3，c2 e5)、(a5，b3，c2，d3，e5)、（a6，b3，c2，d3， 141666.doc •77- (a3， ，c2， d2， e5)、 (a6， ，c 1， d3， e5)、 (a3， ，c 1， d3， e5)、 (a6， ，c 1， d3， e5) ' (a3， ，c2， 1 d3， e5) ' (a6， ，c2， ，d3， e5)、 201028381 (al，b4，c2，d3，e5)、（a2，b4，c2，d3，e5)、 b4，c2，d3，e5)、（a4，b4，c2，d3，e5)、（a5，b4 d3，e5)、（a6，b4，c2，d3，e5)、(al，bl，cl， e5) ' (a2，bl，cl，d4，e5)、(a3，bl，cl，d4， (a4，b 1，c 1，d4，e5)、(a5，bl，cl，d4，e5)、 bl ， cl ， d4 ， e5) 、 （al ， b2 ， cl ， d4 ， e5) 、 （a2 ， b2 d4，e5)、(a3，b2，cl，d4，e5)、（a4，b2，cl， e5)、（a5，b2，cl，d4，e5)、（a6，b2，c 1，d4， (al，b3，cl，d4，e5)、（a2，b3，c 1，d4，e5)、 b3，cl，d4，e5)、（a4，b3，cl，d4，e5)、（a5，b3 d4，e5)、（a6，b3，cl，d4，e5)、(al，b4，cl， e5)、（a2，b4，cl，d4，e5)、(a3，b4，cl，d4， (a4，b4，c 1，d4，e5)、（a5，b4，cl，d4，e5)、 b4 ， cl ， d4 ， e5) 、 （al ， bl ， c2 ， d4 ， e5) 、 （a2 ， bl d4，e5)、(a3，bl，c2，d4，e5)、（a4，bl，c2， e5)、(a5，bl，c2，d4，e5)、（a6，bl，c2，d4， (al，b2，c2，d4，e5)、（a2，b2，c2，d4，e5)、 b2，c2，d4，e5)、（a4，b2，c2，d4，e5)、（a5，b2 d4，e5)、（a6，b2，c2，d4，e5)、(al，b3，c2， e5)、（a2，b3，c2，d4，e5)、（a3，b3，c2，d4， (a4，b3，c2，d4，e5)、(a5，b3，c2，d4，e5)、 b3 ， c2 ， d4 ， e5) 、 （al ， b4 ， c2 ， d4 ， e5) 、 （a2 ， b4 d4，e5)、(a3，b4，c2，d4，e5)、（a4，b4，c2 e5)、(a5，b4，c2，d4，e5)、（a6，b4，c2，d4， 141666.doc -78 - (a3， ，c2， d4， e5) ' (a6， ，c 1， d4， e5)、 (a3， ，c 1， d4， e5)、 (a6， ，c2， 1 d4， e5) ' (a3， ，c2， ，d4， e5) ' (a6， ，c2， ，d4， e5) '201028381 (al, b3, c2, d2, e5), (a2, b3, c2, d2, e5), b3, c2, d2, e5), (a4, b3, c2, d2, e5), (a5, b3) D2, e5), (a6, b3, c2, d2, e5), (al, b4, c2, e5), (a2, b4, c2, d2, e5), (a3, b4, c2, d2, (a4) , b4, c2, d2, e5), (a5, b4, c2, d2, e5), b4, c2, d2, e5), (al, bl, cl, d3, e5), (a2, bl d3, e5) ), (a3, bl, cl, d3, e5), (a4, bl, cl, e5), (a5, bl, cl, d3, e5), (a6, bl, cl, d3, © (al, b2) , cl, d3, e5), (a2, b2, cl, d3, e5), b2, cl, d3, e5), (a4, b2, cl., d3, e5), (a5, b2 d3, e5) , (a6, b2, c 1, d3, e5), (al, b3, cl ' e5), (a2, b3, cl, d3, e5), (a3, b3, cl, d3, (a4, b3, c 1,d3,e5), (a5,b3,cl,d3,e5), b3, cl,d3, e5), (al, b4, cl, d3, e5), (a2, b4 d3, e5), (a3, b4, cl, d3, e5), (a4, b4, cl, e5), (a5, b4, cl, d3, e5), (a6, b4, cl, d3, (al, bl, c2, D3, e5), A2, b 1, c2, d3, e5), bl, c2, d3, e5), (a4, bl, c2, d3, e5), (a5, bl d3, e5), (a6, bl, c2, d3) , e5), (al, b2, c2 e5), (a2, b2, c2, d3, e5), (a3, b2, c2, d3, (a4, b2, c2, d3, e5), (a5, b2) , c2, d3, e5), b2, c2, d3, e5), (al, b3, c2, d3, e5), (a2, b3 d3, e5), (a3, b3, c2, d3, e5), (a4, b3, c2 e5), (a5, b3, c2, d3, e5), (a6, b3, c2, d3, 141666.doc • 77- (a3, , c2, d2, e5), (a6, , c 1, d3, e5), (a3, , c 1, d3, e5), (a6, , c 1, d3, e5) ' (a3, ,c2, 1 d3, e5) ' (a6, ,c2 , ,d3, e5), 201028381 (al,b4,c2,d3,e5), (a2,b4,c2,d3,e5), b4,c2,d3,e5), (a4,b4,c2,d3, E5), (a5, b4 d3, e5), (a6, b4, c2, d3, e5), (al, bl, cl, e5) ' (a2, bl, cl, d4, e5), (a3, bl , cl, d4, (a4, b 1, c 1, d4, e5), (a5, bl, cl, d4, e5), bl, cl, d4, e5), (al, b2, cl, d4, e5 ), (a2 , b2 d4, e5), (a3, b2, cl, d4, e5), (a4, b2, cl, e5), (a5, b2, cl, d4, e5), (a6, b2, c 1, d4) , (al, b3, cl, d4, e5), (a2, b3, c 1, d4, e5), b3, cl, d4, e5), (a4, b3, cl, d4, e5), (a5, B3 d4, e5), (a6, b3, cl, d4, e5), (al, b4, cl, e5), (a2, b4, cl, d4, e5), (a3, b4, cl, d4, ( A4, b4, c 1, d4, e5), (a5, b4, cl, d4, e5), b4, cl, d4, e5), (al, bl, c2, d4, e5), (a2, bl d4) , e5), (a3, bl, c2, d4, e5), (a4, bl, c2, e5), (a5, bl, c2, d4, e5), (a6, bl, c2, d4, (al, B2, c2, d4, e5), (a2, b2, c2, d4, e5), b2, c2, d4, e5), (a4, b2, c2, d4, e5), (a5, b2 d4, e5) , (a6, b2, c2, d4, e5), (al, b3, c2, e5), (a2, b3, c2, d4, e5), (a3, b3, c2, d4, (a4, b3, c2) , d4, e5), (a5, b3, c2, d4, e5), b3, c2, d4, e5), (al, b4, c2, d4, e5), (a2, b4 d4, e5), (a3 , b4 C2, d4, e5), (a4, b4, c2 e5), (a5, b4, c2, d4, e5), (a6, b4, c2, d4, 141666.doc -78 - (a3, , c2, d4 , e5) ' (a6, ,c 1, d4, e5), (a3, ,c 1, d4, e5), (a6, ,c2, 1 d4, e5) ' (a3, ,c2, ,d4, e5 ) ' (a6, ,c2, ,d4, e5) '

201028381 (al，bl，cl，d5，e5)、（a2，bl，cl，d5，e5)、 bl，cl，d5，e5)、（a4，bl，cl，d5，e5)、（a5，bl d5，e5)、(a6，bl，cl，d5，e5)、(al，b2，cl， e5)、（a2，b2，cl，d5，e5)、（a3，b2，cl，d5， (a4，b2，c 1，d5，e5)、（a5，b2，cl，d5，e5)、 b2，cl，d5，e5)、（al，b3，cl，d5，e5)、（a2，b3 d5，e5)、(a3，b3，cl，d5，e5)、（a4，b3，cl， e5)、（a5，b3，cl，d5，e5)、（a6，b3，c 1，d5， (al，b4，cl，d5，e5)、（a2，b4，cl，d5，e5)、 b4，cl，d5，e5)、（a4，b4，cl，d5，e5)、（a5，b4 d5，e5)、（a6，b4，cl，d5，e5)、（al，bl，c2， e5)、（a2，b 1，c2，d5，e5)、（a3，bl，c2，d5， (a4，bl，c2，d5，e5)、（a5，bl，c2，d5，e5)、 bl ， c2 ， d5 ， e5) 、 （al ， b2 ， c2 ， d5 ， e5) 、 （a2 ， b2 d5，e5)、(a3，b2，c2，d5，e5)、（a4，b2，c2 e5)、（a5，b2，c2，d5，e5)、（a6，b2，c2，d5， (al，b3，c2，d5，e5)、（a2，b3，c2，d5，e5)、 b3，c2，d5，e5)、（a4，b3，c2，d5，e5)、（a5，b3 d5，e5)、（a6，b3，c2，d5，e5)、(al，b4，c2 e5)、（a2，b4，c2，d5，e5)、（a3，b4，c2，d5， (a4，b4，c2，d5，e5)、（a5，b4，c2，d5，e5)、 b4 ， c2 ， d5 ， e5)° 進而於其他實施形態中，本發明之化合物具有由 [化 27A] (a3， ，cl， d5， e5)、 (a6， ，c 1， d5， e5)、 (a3， ，c 1， d5， e5)、 (a6， ，c2， d5， e5)、 (a3， ，c2， d5， e5)、 (a6， 141666.doc -79- 201028381 RA&lt;八入/R2 所表示之式之結構。此處H R3與上述項目(1.)中 之定義相同，rai、rA2與上述項目(7，)中之定義相同。 並且，作為R1 ’可列舉以下。 a'l ： -ORa ^ -NRbRc &gt; m ^ + t取代或未經取代之烷基、或者 -C(=0)-Rd a'2 ： -〇Ra a，3 : -NRbRc a 4 . -N(經取代或未經取代之芳基κ經取代或未經取代之 烧基）、_Ν(經取代或未經取代之烧基）（經取代或未經取代 之烧基）、-Ν(經取代或未經取代之絲）（經取代或未經取 代之雜環基）、或者_叫經取代或未經取代之芳基）（經取代 或未經取代之雜環基） a’5 : ·ΝΗ(經取代或未經取代之芳基）、_ΝΗ(經取代或未經 取代之雜環基）、或者-ΝΗ(經取代或未經取代之烷基） a，6: -〇·(經取代或未經取代之芳基）、_〇_(經取代或未經取 代之雜環基）、或者_〇_(經取代或未經取代之烷基）。 作為R2，可列舉以下。201028381 (al, bl, cl, d5, e5), (a2, bl, cl, d5, e5), bl, cl, d5, e5), (a4, bl, cl, d5, e5), (a5, bl D5, e5), (a6, bl, cl, d5, e5), (al, b2, cl, e5), (a2, b2, cl, d5, e5), (a3, b2, cl, d5, (a4 , b2, c 1, d5, e5), (a5, b2, cl, d5, e5), b2, cl, d5, e5), (al, b3, cl, d5, e5), (a2, b3 d5, E5), (a3, b3, cl, d5, e5), (a4, b3, cl, e5), (a5, b3, cl, d5, e5), (a6, b3, c 1, d5, (al, B4,cl,d5,e5), (a2,b4,cl,d5,e5), b4,cl,d5,e5), (a4,b4,cl,d5,e5), (a5,b4 d5,e5) , (a6, b4, cl, d5, e5), (al, bl, c2, e5), (a2, b 1, c2, d5, e5), (a3, bl, c2, d5, (a4, bl, C2, d5, e5), (a5, bl, c2, d5, e5), bl, c2, d5, e5), (al, b2, c2, d5, e5), (a2, b2 d5, e5), ( A3, b2, c2, d5, e5), (a4, b2, c2 e5), (a5, b2, c2, d5, e5), (a6, b2, c2, d5, (al, b3, c2, d5, E5), (a2 B3, c2, d5, e5), b3, c2, d5, e5), (a4, b3, c2, d5, e5), (a5, b3 d5, e5), (a6, b3, c2, d5, e5) , (al, b4, c2 e5), (a2, b4, c2, d5, e5), (a3, b4, c2, d5, (a4, b4, c2, d5, e5), (a5, b4, c2, D5, e5), b4, c2, d5, e5) ° Further, in other embodiments, the compound of the present invention has [Chemical 27A] (a3, , cl, d5, e5), (a6, , c 1, d5) , e5), (a3, , c 1, d5, e5), (a6, , c2, d5, e5), (a3, , c2, d5, e5), (a6, 141666.doc -79- 201028381 RA&lt; The structure of the equation represented by the eight-input/R2. Here, H R3 is the same as defined in the above item (1.), and rai and rA2 are the same as defined in the above item (7,). Further, the following is exemplified as R1'. A'l : -ORa ^ -NRbRc &gt; m ^ + t substituted or unsubstituted alkyl group, or -C(=0)-Rd a'2 : -〇Ra a,3 : -NRbRc a 4 . N (substituted or unsubstituted aryl κ substituted or unsubstituted alkyl), Ν (substituted or unsubstituted alkyl) (substituted or unsubstituted alkyl), -Ν ( Substituted or unsubstituted silk) (substituted or unsubstituted heterocyclic group), or _called substituted or unsubstituted aryl group (substituted or unsubstituted heterocyclic group) a'5 : ΝΗ (substituted or unsubstituted aryl), ΝΗ (substituted or unsubstituted heterocyclic), or - ΝΗ (substituted or unsubstituted alkyl) a, 6: -〇· (substituted or unsubstituted aryl), _〇_ (substituted or unsubstituted heterocyclic group), or _〇_ (substituted or unsubstituted alkyl group). As R2, the following are mentioned.

b'l : -CN、-N〇2或者經取代或未經取代之雜芳基 b'2 ： -CN b'3 ： -N〇2 b'4 :經取代或未經取代之雜芳基。 141666.doc -80 - 201028381 作為R3，可列舉以下。 c，l :氫 c，2 : -NH2 〇 作為RA1 ’可列舉以下。 d，l : 基、 基、 經取代或未經取代之雜芳基 經取代或未經取代之醯基、 經取代或未經取代之烷氧基 燒基 ‘經取代或未經取代之胺 經取代或未經取代之烯 、經取代或未經取代之B'l : -CN, -N〇2 or substituted or unsubstituted heteroaryl b'2 : -CN b'3 : -N〇2 b'4 : substituted or unsubstituted heteroaryl . 141666.doc -80 - 201028381 As R3, the following can be cited. c, l : hydrogen c, 2 : -NH 2 〇 As RA1 ', the following can be cited. d,l: a substituted or unsubstituted aryl group, a substituted or unsubstituted alkoxyalkyl group, a substituted or unsubstituted amine group, a substituted or unsubstituted amine Substituted or unsubstituted alkene, substituted or unsubstituted

m取代或纽取狀㈣基、經取代或未經取代之醯 基、經取代或未經取代之烯基 d’3 :經取代或未經取代之雜芳基 d’4 .經取代或未經取代之醯基 d'5 .經取代或未經取代之烯基。 作為RA2，可列舉以下。 e’l :經取代或未經取代之烧氧基 '經取代或未經取代之胺 基、經取代&amp;未經取代tΜ、經取代或未經取代之締 基、經取代或未經取代之炔基 e’2 :經取代或未經取代之烷氧基、經取代或未經取代之胺 基、經取代或未經取代之烷基 e'3 :經取代或未經取代之烷氧基 e'4 :經取代或未經取代之烷基 e’5 :經取代或未經取代之胺基。 作為R1、R2、R3、RA1、RA2之組合，可列舉以下。 (Rl，R2，R3，RA1，rA2) = 141666.doc -81 · 201028381 (a，l， b，l， c，l， (a'3， b'l &gt; c'l (a，5， b'l， c'l (a'l， b'2， c'l (a'3 &gt; b’2， c'l (a，5， b，2， c'l (a'l， b，3， c'l (a'3， b'3， c'l (a，5， b’3， c'l (a'l &gt; b'4， c'l (a，3， b，4， c'l (a'5， b，4， c'l (a'l， b'l， c'2 (a，3， b'l， c'2 (a，5， b'l， c'2 (a'l &gt; b'2， c'2 (a'3 &gt; b'2， c'2 (a'5， b'2， c'2 (a’l， b，3， c'2 (a，3， b'3， c'2 (a'5， b，3， c'2 (a'l， b，4， c'2 (a’3， b'4， c'2 (a'5 &gt; b'4， c'2 d’l， e'l)、 (a'2 d'l， e'l)、 (a'4 d'l， e'l)、 (a，6 d'l &gt; e'l)、 (a'2 d’l， e'l)、 (a'4 d'l， e'l)、 (a'6 d'l， e'l)、 (a'2 d，l， e'l)、 (a'4 d'l， e'l) ' (a'6 d'l， e'l)、 (a'2 d'l， e'l)、 (a’4 d'l， e’l)、 (a'6 d'l， e'l)、 (a'2 d'l， e'l)、 (a'4 d’l， e'l)、 (a'6 d'l， e'l) ' (a'2 d'l， e'l) ' (a'4 d'l， e'l)、 (a'6 d'l， e'l)、 (a'2 d'l， e'l) &gt; (a'4 d'l， e'l)、 (a'6 d，l， e'l) ' (a'2 d'l， e'l) ' (a'4 d'l， e'l)、 (a'6 b'l ， c'l ， d'l b，l ， c，l ， d'l b，l ， c，l ， d'l b，2 ， c'l ， d'l b，2 ， c，l ， d'l b，2 ， c'l ， d'l b，3，c'l，d'l b，3，c'l，d'l b，3 ， c'l ， d'l b'4 ， c'l ， d'l b'4 ， c'l ， d'l b，4 ， c'l ， d'l b，l ， c，2 ， d'l b，l ， c'2 ， d'l b，l ， c'2 ， d'l b'2 ， c'2 ， d'l b，2 ， c，2 ， d'l b，2 ， c'2 ， d'l b'3，c'2，d’l b，3 ， c'2 ， d'l b'3 ， c，2 ， d'l b'4 ， c，2 ， d'l b'4 ， c，2 ， d，l b，4 ， c，2 ， d'l e'l)、 e'l)、 e'l)、 e'l)、 e'l)、 e'l) ' e'l)、 e'l) &gt; e'l) ' e'l) ' e'l)、 e'l) ' e'l)、 e'l)、 e'l)、 e'l)、 e'l)、 e'l)、 e'l) ' e'l)、 e'l)、 e'l)、 e'l) ' ，e'l)、 141666.doc -82- 201028381 (a，l b，l， c'l， d'2 e'l)、 (a'3 b'l， c'l d'2， e，l)、 (a'5 b'l &gt; c'l d'2， e'l)、 (a'l b'l &gt; c'l d'2， e'l)、 (a'3 b'2， c'l d'2 e'l) ' (a'5 b'2， c'l d'2 e'l)、 (a'l b'3， c'l d'2， e'l) ' (a'3 b'3， c'l d'2 e'l)、 (a'5 b'3， c'l d'2 e'l)、 (a'l b'4， c'l d'2 e'l)、 (a’3 b，4， c'l d'2 e'l)、 (a'5 b'4 &gt; c'l d'2 e'l)、 (a'l b'l， c'2 d'2 e'l)、 (a'3 b'l， c'2 d'2 e'l) &gt; (a’5 b'l， c'2 d'2 e'l)、 (a'l b'2， c'2 d'2 e'l) ' (a’3 b'2 - c'2 d'2 e'l)、 (a'5 b，2， c'2 d'2 e'l) &gt; (a'l b，3， c'2 d'2 e'l)、 (a'3 b’3， c'2 d'2 e'l)、 (a'5 b'3， c'2 d'2 e'l) &gt; (a'l b'4 &gt; c'2 d'2 e'l) &gt; (a'3 b'4 &gt; c'2 d'2 e'l)' (a'5 b'4 &gt; c'2 d'2 e'l)、 (a'2， b，l， c'l， d，2， e'l)、 (a'4， b'l， c'l， d'2， e'l)、 (a'6， b'l， c，l， d'2， e'l)、 (a'2， b，2， c'l， d'2， e'l)、 (a，4， b'2 - c'l， d'2， e'l)、 (a'6， b'2， c'l， d'2， e'l)、 (a'2 &gt; b’3， c'l， d'2， e'l)、 (a'4 &gt; b，3， c'l， d'2， e'l) ' (a，6， b'3， c'l， d，2， e'l)、 (a，2， b，4， c'l， d，2， e'l)、 (a'4， b'4， c'l， d'2 &gt; e'l)、 (a'6 &gt; b'4， c'l， d，2， e'l)、 (a'2， b'l， c，2， d，2， e'l)、 (a'4， b'l， c，2， d'2 &gt; e'l) ' (a'6， b'l， c，2， d'2， e'l)、 (a'2 &gt; b，2， c，2， d'2， e'l) ' (a'4， b'2， c'2， d'2， e'l)、 (a，6， b，2， c'2， d，2， e'l)、 (a，2， b'3 &gt; c'2， d'2 - e'l) &gt; (a’4， b，3， c'2， d'2， e'l)、 (a'6， b，3， c，2， d'2， e'l)、 (a'2， b’4， c，2， d’2， e'l)、 (a'4， b’4， c’2， d-2， e'l) ' (a，6， b'4， c'2， d'2， e'l)、M-substituted or substituted (tetra), substituted or unsubstituted fluorenyl, substituted or unsubstituted alkenyl d'3: substituted or unsubstituted heteroaryl d'4. substituted or not Substituted fluorenyl d'5. substituted or unsubstituted alkenyl group. As RA2, the following are mentioned. E'l : substituted or unsubstituted alkoxy 'substituted or unsubstituted amino, substituted & unsubstituted tΜ, substituted or unsubstituted, substituted or unsubstituted Alkynyl e'2: substituted or unsubstituted alkoxy group, substituted or unsubstituted amino group, substituted or unsubstituted alkyl group e'3: substituted or unsubstituted alkoxylate Base e'4: substituted or unsubstituted alkyl group e'5: substituted or unsubstituted amine group. The combination of R1, R2, R3, RA1, and RA2 is as follows. (Rl, R2, R3, RA1, rA2) = 141666.doc -81 · 201028381 (a,l, b,l, c,l, (a'3, b'l &gt; c'l (a,5, B'l, c'l (a'l, b'2, c'l (a'3 &gt; b'2, c'l (a,5, b,2, c'l (a'l, b ,3, c'l (a'3, b'3, c'l (a,5, b'3, c'l (a'l &gt; b'4, c'l (a,3, b, 4, c'l (a'5, b,4, c'l (a'l, b'l, c'2 (a,3, b'l, c'2 (a,5, b'l, C'2 (a'l &gt; b'2, c'2 (a'3 &gt; b'2, c'2 (a'5, b'2, c'2 (a'l, b,3, C'2 (a,3, b'3, c'2 (a'5, b,3, c'2 (a'l, b,4, c'2 (a'3, b'4, c' 2 (a'5 &gt; b'4, c'2 d'l, e'l), (a'2 d'l, e'l), (a'4 d'l, e'l), ( a,6 d'l &gt; e'l), (a'2 d'l, e'l), (a'4 d'l, e'l), (a'6 d'l, e'l ), (a'2 d,l, e'l), (a'4 d'l, e'l) ' (a'6 d'l, e'l), (a'2 d'l, e 'l), (a'4 d'l, e'l), (a'6 d'l, e'l), (a'2 d'l, e'l), (a'4 d'l , e'l), (a'6 d'l, e'l) ' (a'2 d'l, e'l) ' (a'4 d'l, e'l), (a'6 d 'l, e'l), ( A'2 d'l, e'l) &gt; (a'4 d'l, e'l), (a'6 d,l, e'l) ' (a'2 d'l, e'l ) ' (a'4 d'l, e'l), (a'6 b'l , c'l , d'l b,l , c,l , d'l b,l , c,l , d 'l b,2 , c'l , d'l b,2 , c,l , d'l b,2 , c'l , d'l b,3,c'l,d'l b,3, C'l,d'l b,3 , c'l , d'l b'4 , c'l , d'l b'4 , c'l , d'l b,4 , c'l , d' l b,l , c,2 , d'l b,l , c'2 , d'l b,l , c'2 , d'l b'2 , c'2 , d'l b,2 , c , 2, d'l b, 2, c'2, d'l b'3, c'2, d'l b, 3, c'2, d'l b'3, c, 2, d'l B'4 , c,2 , d'l b'4 , c,2 , d,lb,4 , c,2 , d'l e'l), e'l), e'l), e'l ), e'l), e'l) ' e'l), e'l) &gt; e'l) ' e'l) ' e'l), e'l) ' e'l), e' l), e'l), e'l), e'l), e'l), e'l) 'e'l), e'l), e'l), e'l) ' ,e 'l), 141666.doc -82- 201028381 (a, lb, l, c'l, d'2 e'l), (a'3 b'l, c'l d'2, e, l), (a'5 b'l &gt; c'l d'2, e'l), (a'l b'l &gt; c'l d'2, e'l), (a'3 b'2,C'l d'2 e'l) ' (a'5 b'2, c'l d'2 e'l), (a'l b'3, c'l d'2, e'l) ' (a'3 b'3, c'l d'2 e'l), (a'5 b'3, c'l d'2 e'l), (a'l b'4, c'l d '2 e'l), (a'3 b,4, c'l d'2 e'l), (a'5 b'4 &gt; c'l d'2 e'l), (a'l B'l, c'2 d'2 e'l), (a'3 b'l, c'2 d'2 e'l) &gt; (a'5 b'l, c'2 d'2 e 'l), (a'l b'2, c'2 d'2 e'l) ' (a'3 b'2 - c'2 d'2 e'l), (a'5 b, 2, C'2 d'2 e'l) &gt; (a'l b,3, c'2 d'2 e'l), (a'3 b'3, c'2 d'2 e'l), (a'5 b'3, c'2 d'2 e'l) &gt; (a'l b'4 &gt; c'2 d'2 e'l) &gt; (a'3 b'4 &gt; C'2 d'2 e'l)' (a'5 b'4 &gt; c'2 d'2 e'l), (a'2, b,l, c'l, d,2, e' l), (a'4, b'l, c'l, d'2, e'l), (a'6, b'l, c, l, d'2, e'l), (a' 2, b, 2, c'l, d'2, e'l), (a, 4, b'2 - c'l, d'2, e'l), (a'6, b'2, C'l, d'2, e'l), (a'2 &gt; b'3, c'l, d'2, e'l), (a'4 &gt; b,3, c'l, D'2, e'l) ' (a,6, b'3, c'l, d,2, e'l), (a,2, b,4, c'l, d,2, e' l), (a'4, b'4, c'l, d'2 &gt; e'l), (a'6 &gt; b'4, c'l, d,2, e'l), (a'2 , b'l, c,2, d,2, e'l), (a'4, b'l, c,2, d'2 &gt; e'l) ' (a'6, b'l, c,2, d'2, e'l), (a'2 &gt; b,2, c,2, d'2, e'l) ' (a'4, b'2, c'2, d '2, e'l), (a,6, b,2, c'2, d,2, e'l), (a,2, b'3 &gt; c'2, d'2 - e' l) &gt; (a'4, b,3, c'2, d'2, e'l), (a'6, b,3, c,2, d'2, e'l), (a '2, b'4, c, 2, d'2, e'l), (a'4, b'4, c'2, d-2, e'l) ' (a,6, b'4 , c'2, d'2, e'l),

141666.doc -83- 201028381 (a，l ， b，l ， c'l ， d，3 ， (a'3 ， b'l ， c，l ， d，3 ， (a，5 ， b，l ， c'l ， d'3 (a'l ， b，2 ， c'l ， d，3 (a'3，b'2，c'l，d'3 (a'5 ， b'2 ， c'l ， d，3 (a'l ， b'3 ， c'l ， d，3 (a，3 ， b'3 ， c'l ， d，3 (a，5 ， b'3 ， c'l ， d'3 (a'l ， b，4 ， c’l ， d，3 (a，3 ， b，4 ， c'l ， d'3 (a，5 ， b'4 ， c'l ， d'3 (a'l ， b'l ， c，2 ， d，3 (a，3 ， b'l ， c'2 ， d’3 (a，5 ， b'l ， c'2 ， d，3 (a'l ， b'2 ， c，2 ， d'3 (a，3 ， b，2 ， c.2 ， d，3 (a，5，b，2，c'2，d'3 (a'l ， b'3 ， c，2 ， d，3 (a，3，b'3，c'2，d'3 (a'5 ， b'3 ， c，2 ， d，3 (a'l ， b，4 ， c’2 ， d，3 (a，3，b'4，c'2，d，3 (a，5 ， b'4 ， c，2 ， d'3 e'l)、 e，l)、 e'l) ' e'l)、 e'l)、 e'l)、 e'l)、 e'l)、 e'l)、 e'l)、 e'l)、 e'l)、 e'l)、 e'l)、 e'l)、 e'l)、 e'l)、 e'l) ' e'l)、 e'l) ' e'l)、 e'l)、 e'l)、 e'l)、141666.doc -83- 201028381 (a,l , b,l , c'l , d,3 , (a'3 , b'l , c,l , d,3 , (a,5 , b,l , C'l , d'3 (a'l , b,2 , c'l , d,3 (a'3,b'2,c'l,d'3 (a'5 , b'2 , c' l , d, 3 (a'l , b'3 , c'l , d, 3 (a,3 , b'3 , c'l , d,3 (a,5 , b'3 , c'l , D'3 (a'l , b,4 , c'l , d,3 (a,3 , b,4 , c'l , d'3 (a,5 , b'4 , c'l , d' 3 (a'l , b'l , c, 2 , d, 3 (a,3 , b'l , c'2 , d'3 (a,5 , b'l , c'2 , d,3 ( A'l , b'2 , c,2 , d'3 (a,3 , b,2 , c.2 , d,3 (a,5,b,2,c'2,d'3 (a' l , b'3 , c, 2 , d, 3 (a, 3, b'3, c'2, d'3 (a'5 , b'3 , c, 2 , d, 3 (a'l , b,4 , c'2 , d,3 (a,3,b'4,c'2,d,3 (a,5 , b'4 , c,2 , d'3 e'l), e, l), e'l) ' e'l), e'l), e'l), e'l), e'l), e'l), e'l), e'l), e' l), e'l), e'l), e'l), e'l), e'l), e'l) 'e'l), e'l) 'e'l), e' l), e'l), e'l),

e'l) ·&gt; (a'2， b'l， c'l， d'3 e'l) (a，4， b'l， c'l &gt; d'3 e'l) (a'6， b'l， c'l， d'3 e'l) (a，2， b'2， c'l， d'3 e'l) (a’4， b，2， c'l， d’3 e'l) Λ (a'6， b'2， c，l， d'3 e'l) X (a'2， b，3， c'l， d'3 e'l) Λ (a，4， b，3， c'l， d'3 e'l) (a’6， b'3， c'l， d'3 e'l) (a，2， b，4， c'l， d'3 e'l) 、 (a'4， b'4， c'l， d'3 e'l) (a'6， b，4， c'l， d'3 e'l) (a，2， b'l， c'2， d'3 e'l) 、 (a'4， b'l， c，2， d'3 e'l) &gt; (a'6， b'l， c，2， d'3 e'l) (a'2 &gt; b，2， c'2， d'3 e'l) 、 (a'4， b，2， c，2， d'3 e'l) 、 (a'6， b'2， c，2， d'3 e'l) 、 (a'2， b'3， c，2， d'3 e'l) &gt; (a'4， b，3， c，2， d'3 e'l) Λ (a，6， b'3， c'2， d，3 e'l) &gt; (a'2， b'4， c，2， d'3 e'l) &gt; (a，4， b'4， c，2， d'3 ，e'l) 、 (a'6， b，4， c'2， d'3 141666.doc • 84- 201028381 (a'l，b'l (a'3 ， b，l (a'5 ， b'l (a'l &gt; b'2 (a，3 ， b'2 (a'5 ， b'2 (a'l ， b'3 (a'3 ， b，3 ❹（a'5 ， b，3 (a'l ， b'4 (a'3 ， b'4 (a'5 ， b，4 (a'l ， b'l (a'3 » b'l (a'5 ， b'l (a'l ^ b'2 w (a'3 ， b'2 (a'5 ， b，2 (a'l » b'3 (a'3 ， b，3 (a'5，b'3 (a'l &gt; b'4 (a，3，b，4 (a'5 ， b'4 141666.doc c'l， d'4， e'l)、 (a，2， b'l， c'l， d'4 e'l)、 c'l， d'4， e'l)、 (a'4， b’l， c'l， d'4 e'l)、 c'l， d，4， e’l)、 (a'6， b'l &gt; c'l， d'4 e'l)、 c’l， d，4， e'l)、 (a’2， b'2， c'l， d'4 e'l)、 c'l， d'4， e'l)、 (a'4， b'2 &gt; c'l， d'4 e'l)、 c'l， d'4， e'l)、 (a'6， b'2， c'l， d'4 e'l)、 c'l， d'4， e'l)、 (a'2 &gt; b'3， c'l， d'4 e'l)、 c'l， d，4， e'l)、 (a’4， b'3， c'l， d'4 e'l)、 c'l， d'4 &gt; e'l)、 (a'6， b'3， c'l， d'4 e'l)、 c'l， d'4， e'l)、 (a'2， b'4， c'l， d'4 e'l)、 c'l， d'4， e'l)、 (a'4， b'4 &gt; c'l， d'4 e'l)、 c'l， d'4， e'l)、 (a'6， b'4， c'l， d'4 e'l)、 c'2， d'4， e'l)、 (a'2 &gt; b'l， c'2， d'4 e'l)、 c'2， d'4， e'l)、 (a'4 &gt; b'l， c'2， d'4 e'l)、 c'2， d，4， e'l)、 (a'6， b'l， c，2， d'4 e'l)、 c'2， d，4， e'l)、 (a'2 - b，2， c'2， d'4 e'l) &gt; c'2 &gt; d'4， e'l)、 (a’4， b'2， c，2， d'4 e'l) ' c’2， d'4， e'l)、 (a’6， b'2， c'2， d'4 e'l)、 c，2， d，4， e'l)、 (a'2， b'3， c'2， d'4 e'l)、 c，2， d，4， e'l)、 (a'4， b，3， c，2， d'4 e'l)、 c，2， d，4， e'l)、 (a'6， b'3 » c，2， d'4 e'l) ' c'2， d'4， e'l) (a'2， b，4， c，2， d'4 e'l)、 c，2， d'4， e'l) (a'4 &gt; b’4， c'2， d'4 e'l)、 c，2， d'4， e'l) (a'6， b'4， c'2， d'4 e'l)、 -85- 201028381 (a'l， b'l， c'l 5 d，5， e'l)、 (a'3， b'l， c'l ， d’5， e'l)、 (a'5， b'l， c'l ， d，5， e'l) ' (a'l， b'2， c'l ) d’5， e'l)、 (a'3， b，2， c'l 5 d'5， e'l)、 (a，5， b'2， c'l ， d，5， e'l)、 (a’l， b，3， c'l 9 d，5， e'l) &gt; (a，3， b，3， c'l i d，5， e'l)、 (a'5 &gt; b，3， c'l 9 d，5， e’l)、 (a'l， b，4， c'l 1 d，5， e'l) ' (a，3， b，4， c'l 5 d'5， e'l)、 (a'5， b'4， c'l d'5， e'l)、 (a'l， b’l， c，2 d'5 &gt; e'l)、 (a'3， b'l， c，2 d'5， e'l)、 (a'5， b'l， c'2 d，5， e'l)、 (a'l， b，2， c'2 d'5， e'l) ' (a，3， b，2， c'2 d'5， e'l)、 (a'5， b'2， c'2 ) d'5， e'l)、 (a'l， b'3， c'2 5 d，5， e'l)、 (a，3， b，3， c'2 5 d'5， e’l)、 (a，5， b'3， c'2 ) d'5， e'l) ' (a，l， b'4， c'2 5 d'5， e'l)、 (a'3 &gt; b，4， c'2 1 d'5， e'l)、 (a，5， b'4， c'2 y d，5， e'l)、 (a'2，b'l，c'l，d'5，e，l)、 (a'4， b'l， c'l， d'5 e'l) ' (a'6， b，l， c'l， d'5 5 e'l)、 (a'2， b'2， c，l， d'5 ， e'l) ' (a'4， b，2， c'l， d'5 5 e'l)、 (a'6， b'2 » c'l， d'5 9 e'l)、 (a，2， b，3， c'l， d'5 &gt; e'l) ' (a'4， b，3， c'l， d'5 9 e'l)、 (a'6， b，3， c'l &gt; d'5 e'l) ' (a，2， b，4， c'l， d'5 e'l)、 (a’4， b，4， c'l， d'5 ， e'l)、 (a’6， b，4， c'l， d'5 e'l)、 (a'2， b'l， c，2， d'5 e'l) ' (a'4 - b'l &gt; c'2， d'5 e'l)、 (a'6， b'l， c'2， d'5 e’l)、 (a，2， b'2， c’2， d'5 ? e'l) ' (a'4， b'2， c’2， d'5 5 e'l) ' (a'6， b，2， c'2， d'5 ? e'l)、 (a'2， b，3， c’2， d'5 ， e'l)、 (a，4， b'3 &gt; c，2， d'5 9 e'l)、 (a'6， b，3， c'2， d'5 5 e'l)、 (a，2， b'4， c，2， d'5 e'l)、 (a，4， b，4， c'2 &gt; d'5 e'l)、 (a'6， b，4， c，2， d'5 ， e'l) ' 141666.doc -86- 201028381E'l) ·&gt; (a'2, b'l, c'l, d'3 e'l) (a,4, b'l, c'l &gt; d'3 e'l) (a '6, b'l, c'l, d'3 e'l) (a,2, b'2, c'l, d'3 e'l) (a'4, b,2, c'l , d'3 e'l) Λ (a'6, b'2, c,l, d'3 e'l) X (a'2, b,3, c'l, d'3 e'l) Λ (a,4, b,3, c'l, d'3 e'l) (a'6, b'3, c'l, d'3 e'l) (a,2, b,4, C'l, d'3 e'l) , (a'4, b'4, c'l, d'3 e'l) (a'6, b,4, c'l, d'3 e' l) (a, 2, b'l, c'2, d'3 e'l) , (a'4, b'l, c, 2, d'3 e'l) &gt; (a'6, B'l, c,2, d'3 e'l) (a'2 &gt; b,2, c'2, d'3 e'l) , (a'4, b,2, c,2, D'3 e'l) , (a'6, b'2, c, 2, d'3 e'l) , (a'2, b'3, c, 2, d'3 e'l) &gt ; (a'4, b,3, c,2, d'3 e'l) Λ (a,6, b'3, c'2, d,3 e'l) &gt; (a'2, b '4, c, 2, d'3 e'l) &gt; (a,4, b'4, c,2, d'3 ,e'l) , (a'6, b,4, c'2 , d'3 141666.doc • 84- 201028381 (a'l,b'l (a'3 , b,l (a'5 , b'l (a'l &gt; b'2 (a,3 , b '2 (a'5 , b'2 (a'l , b'3 (a'3 , b, 3 ❹ (a'5 , b, 3 (a'l , b'4 (a'3 , b'4 ( A'5 , b,4 (a'l , b'l (a'3 » b'l (a'5 , b'l (a'l ^ b'2 w (a'3 , b'2 (a '5 , b, 2 (a'l » b'3 (a'3 , b, 3 (a'5, b'3 (a'l &gt; b'4 (a,3,b,4 (a' 5, b'4 141666.doc c'l, d'4, e'l), (a,2, b'l, c'l, d'4 e'l), c'l, d'4, E'l), (a'4, b'l, c'l, d'4 e'l), c'l, d, 4, e'l), (a'6, b'l &gt; c 'l, d'4 e'l), c'l, d, 4, e'l), (a'2, b'2, c'l, d'4 e'l), c'l, d '4, e'l), (a'4, b'2 &gt; c'l, d'4 e'l), c'l, d'4, e'l), (a'6, b' 2, c'l, d'4 e'l), c'l, d'4, e'l), (a'2 &gt; b'3, c'l, d'4 e'l), c 'l, d, 4, e'l), (a'4, b'3, c'l, d'4 e'l), c'l, d'4 &gt; e'l), (a' 6, b'3, c'l, d'4 e'l), c'l, d'4, e'l), (a'2, b'4, c'l, d'4 e'l ), c'l, d'4, e'l), (a'4, b'4 &gt; c'l, d'4 e'l), c'l, d'4, e'l), (a'6, b'4, c'l, d'4 e'l), c'2, d'4, e' l), (a'2 &gt; b'l, c'2, d'4 e'l), c'2, d'4, e'l), (a'4 &gt; b'l, c' 2, d'4 e'l), c'2, d, 4, e'l), (a'6, b'l, c, 2, d'4 e'l), c'2, d, 4, e'l), (a'2 - b, 2, c'2, d'4 e'l) &gt; c'2 &gt; d'4, e'l), (a'4, b' 2, c, 2, d'4 e'l) ' c'2, d'4, e'l), (a'6, b'2, c'2, d'4 e'l), c, 2, d, 4, e'l), (a'2, b'3, c'2, d'4 e'l), c, 2, d, 4, e'l), (a'4, b,3, c,2, d'4 e'l), c,2, d,4, e'l), (a'6, b'3 » c,2, d'4 e'l) ' C'2, d'4, e'l) (a'2, b,4, c,2, d'4 e'l), c,2, d'4, e'l) (a'4 &gt ; b'4, c'2, d'4 e'l), c, 2, d'4, e'l) (a'6, b'4, c'2, d'4 e'l), -85- 201028381 (a'l, b'l, c'l 5 d,5, e'l), (a'3, b'l, c'l, d'5, e'l), (a '5, b'l, c'l , d,5, e'l) ' (a'l, b'2, c'l ) d'5, e'l), (a'3, b, 2 , c'l 5 d'5, e'l), (a,5, b'2, c'l, d,5, e'l), (a'l, b,3, c'l 9 d , 5, e 'l) &gt; (a,3, b,3, c'l id,5, e'l), (a'5 &gt; b,3, c'l 9 d,5, e'l), ( A'l, b,4, c'l 1 d,5, e'l) ' (a,3, b,4, c'l 5 d'5, e'l), (a'5, b' 4, c'l d'5, e'l), (a'l, b'l, c, 2 d'5 &gt; e'l), (a'3, b'l, c, 2 d' 5, e'l), (a'5, b'l, c'2 d, 5, e'l), (a'l, b, 2, c'2 d'5, e'l) ' ( a,3, b,2, c'2 d'5, e'l), (a'5, b'2, c'2) d'5, e'l), (a'l, b'3 , c'2 5 d,5, e'l), (a,3, b,3, c'2 5 d'5, e'l), (a,5, b'3, c'2 ) d '5, e'l) ' (a,l, b'4, c'2 5 d'5, e'l), (a'3 &gt; b,4, c'2 1 d'5, e' l), (a,5, b'4, c'2 yd,5, e'l), (a'2,b'l,c'l,d'5,e,l), (a'4 , b'l, c'l, d'5 e'l) ' (a'6, b,l, c'l, d'5 5 e'l), (a'2, b'2, c, l, d'5 , e'l) ' (a'4, b, 2, c'l, d'5 5 e'l), (a'6, b'2 » c'l, d'5 9 E'l), (a,2, b,3, c'l, d'5 &gt; e'l) ' (a'4, b,3, c'l, d'5 9 e'l), (a'6 b,3, c'l &gt; d'5 e'l) ' (a,2, b,4, c'l, d'5 e'l), (a'4, b,4, c'l , d'5 , e'l), (a'6, b, 4, c'l, d'5 e'l), (a'2, b'l, c, 2, d'5 e'l ) ' (a'4 - b'l &gt; c'2, d'5 e'l), (a'6, b'l, c'2, d'5 e'l), (a, 2, B'2, c'2, d'5 ? e'l) ' (a'4, b'2, c'2, d'5 5 e'l) ' (a'6, b,2, c' 2, d'5 ? e'l), (a'2, b, 3, c'2, d'5, e'l), (a,4, b'3 &gt; c,2, d'5 9 e'l), (a'6, b,3, c'2, d'5 5 e'l), (a,2, b'4, c,2, d'5 e'l), ( a,4, b,4, c'2 &gt; d'5 e'l), (a'6, b,4, c,2, d'5 , e'l) ' 141666.doc -86- 201028381

(a丨1 b'l， c'l， d'l e’2) (a，2， b'l， c'l， d'l e'2) ' (a，3 b'l， c，l， d'l e'2) 、 (a'4， b'l， c'l， d'l e，2)、 (a'5 b'l， c'l， d'l e'2) (a'6， b'l， c'l， d'l e'2)、 (a丨1 b，2， c'l， d'l e'2) (a'2， b'2， c’l， d'l e’2)、 (a，3 b'2， c'l， d’l e'2) (a'4， b，2， c'l， d'l e'2)、 (a'5 b，2， c'l， d'l e'2) (a'6， b'2， c'l， d'l e，2)、 (a'l b'3， c’l， d'l e'2) (a'2， b'3， c'l， d'l e'2) ' (a'3 b，3， c’l， d'l e'2) (a'4， b'3， c'l， d'l e'2)、 (a'5 b'3 &gt; c'l， d'l e'2) (a'6， b'3， c'l &gt; d'l e'2)、 (a'l b'4， c'l， d'l e'2) (a'2， b'4， c'l， d'l e'2) &gt; (a'3 b'4， c'l， d'l e'2) (a’4， b'4， c'l， d'l e，2)、 (a丨5 b，4， c'l， d'l e'2) (a，6， b'4， c'l， d'l e，2)、 (a'l b'l， c'2， d'l e'2) 、 (a'2， b'l， c'2， d'l e'2) &gt; (a，3 b’l， c，2， d'l e'2) 、 (a'4 &gt; b'l， c'2， d'l e'2) ' (a'5 b'l， c'2， d'l e'2) Λ (a'6， b'l， c'2， d'l e'2)、 (a，l b，2， c，2， d，l e'2) (a，2， b，2， c，2， d'l e'2)、 (a'3 b'2 &gt; c，2， d'l e'2) (a'4， b，2， c'2， d'l e'2) ' (a'5 b'2， c，2， d'l e'2) 、 (a，6， b，2， c，2， d'l e，2)、 (a'l b'3， c，2， d'l e'2) 、 (a，2， b，3， c'2， d'l e'2)、 (a'3 b'3， c'2 &gt; d'l e'2) 、 (a'4， b，3， c'2， d'l e，2)、 (a'5 b'3， c'2， d'l ，e，2) Λ (a'6， b'3， c'2， d'l e'2)、 (a'l b'4， c，2， d'l ，e'2) N (a'2， b'4， c'2， d'l e'2) ' (a'3 b'4 &gt; c'2， d'l ，e，2) 、 (a'4， b'4， c'2， d'l e'2) ' (a'5，b'4，c'2，d，l，e'2)、（a'6，b'4，c'2，d'l，e，2)、 141666.doc -87- 201028381 (a'l， (a，3， (a'5， (a'l &gt; (a，3， (a'5， (a'l， (a'3， (a'5， (a'l ’ (a'3， (a'5， (a'l， (a'3， (a'5， (a'l， (a'3 (a'5 (a'l (a'3 (a’5 (a'l (a’3 (a'5 b'l ， c，l ， d'2 ， b，l ， c，l ， d'2 ， b'l ， c'l ， d'2 b'2，c'l，d，2 b，2 ， c，l ， d'2 b'2 ， c'l ， d'2 b'3 ， c，l ， d'2 b'3 ， c’l ， d，2 b'3 ， c'l ， d，2 b，4 ， c'l ， d’2 b，4 ， c'l ， d，2 b，4 ， c'l ， d，2 b，l ， c，2 ， d'2 b'l ， c，2 ， d，2 b'l ， c'2 ， d'2 b'2 ， c，2 ， d'2 b'2 ， c'2 ， d，2 ，b'2，c，2，d'2 ，b，3 ， c'2 ， d，2 ，b'3，c，2，d'2 ，b，3，c'2，d，2 ，b'4，c，2，d，2 ，b'4，c，2，d’2， ，b，4，c'2，d，2， e，2)、 (a'2， b’l， e，2)、 (a，4， b'l e，2)、 (a，6， b'l e，2)、 (a'2 &gt; b'2 e'2)、 (a，4， b’2 e，2)、 (a，6， b'2 e'2)、 (a，2， b'3 e，2)、 (a，4， b'3 e，2)、 (a'6， b'3 e，2)、 (a，2， b'4 e'2)、 (a，4， b'4 e，2)、 (a，6， b'4 e，2)、 (a'2， b'l e'2) ' (a'4， b'l e，2)、 (a，6， b'l e'2)、 (a，2， b'2 e'2) &gt; (a'4， b'2 e，2)、 (a，6， b'2 e'2)、 (a'2， b'3 e'2) &gt; (a，4， b'3 e'2)、 (a'6， b'3 e，2)、 (a，2， b'4 e，2)、 (a，4， b'4 e，2)、 (a，6， b'4 c'l， d'2， e'2) c'l， d'2， e'2) c'l， d，2， e'2) c'l， d'2 &gt; e'2) c'l， d’2， e'2) c'l， d，2， e'2) c'l， d，2， e'2) c，l， d，2， e'2) c'l， d，2， e'2) c，l， d'2 &gt; e'2) c'l， d，2， e'2) c'l， d'2， e'2) c，2， d，2， e'2) c，2， d，2， e'2) c，2， d'2， e'2) c'2， d'2， e'2) c'2， d'2， e'2) c'2， d，2， e'2) c'2， d，2， e'2) c'2， d'2， e'2) c'2， d，2， e'2) c，2， d，2， e'2) ，c'2， d，2， e'2) ，c'2， d'2， e'2) 141666.doc -88- 201028381 (a'l，b'l，c'l，d，3， (a'3 ， b，l ， c’l ， d，3 ， (a'5 ， b'l ， c，l ， d，3 ， (a'l ， b，2 ， c'l ， d，3 ， (a，3，b，2，c'l，d，3， (a'5，b，2，c'l，d，3， (a'l，b'3，c，l，d，3， (a'3，b，3，c'l，d，3， ® (a'5，b，3，c，l，d，3， (a'l ， b'4 ， c'l ， d'3 ， (a，3，b，4，c，l，d，3， (a'5，b'4，c'l，d'3， (a，l ， b，l ， c，2 ， d'3 ， (a'3 ， b'l ， c'2 ， d，3 ， (a，5，b，l，c'2，d'3， (a'l，b'2，c'2，d，3， ’ （a’3，b'2，c'2，d'3， (a’5 ， b，2 ， c，2 ， d'3 ， (a'l，b，3，c'2，d'3， (a'3，b'3，c，2，d，3， (a，5，b'3，c'2，d，3， (a'l，b，4，c'2，d'3， (a'3，b'4，c'2，d'3， (a'5 ， b'4 ， c'2 ， d'3 ， e，2)、 e’2)、 e，2)、 e'2) &gt; e，2)、 e'2)、 e，2)、 e'2) ' e'2)、 e'2) ' e，2)、 e’2)、 e'2)、 e，2)、 e'2) ' e'2) ' e'2)、 e，2)、 e'2)、 e'2) &gt; e'2)、 e'2)、 e'2)、 e’2)、 e'2) (a，2， b'l c'l d'3 e'2) ·&gt; (a，4， b'l c'l d'3 e'2) (a，6， b'l c，l d'3 e'2) (a，2， b'2 c'l d'3 e'2) (a，4， b，2 c'l d，3 e'2) (a'6， b'2 c'l d'3 e'2) &gt; (a，2， b'3 c'l d'3 e'2) 、 (a'4， b'3 c'l d'3 e'2) X (a，6， b，3 c'l d'3 e'2) 、 (a'2， b'4 c'l d'3 e'2) (a，4， b'4 c'l d'3 e'2) % (a'6， b'4 c'l d'3 e’2) 、 (a，2， b'l c'2 d'3 e'2) (a'4， b'l c'2 d'3 e'2) (a'6， b'l c'2 d'3 e'2) \ (a，2， b'2 c'2 d'3 e'2) N (a'4 &gt; b'2 c'2 d'3 e'2) 、 (a'6， b'2 c'2 d'3 e'2) &gt; (a'2， b'3 c'2 d'3 e'2) 、 (a'4， b’3 c'2 d'3 e'2) &gt; (a'6 &gt; b'3 c’2 d'3 e'2) &gt; (a'2， b'4 c'2 d'3 e'2) (a'4， b'4 c'2 d’3 e'2) 、 (a'6， b'4 c'2 d'3 141666.doc -89- 201028381 (a，l， b，l， c'l (a，3， b，l， c'l (a'5， b'l， c'l (a，l， b，2， c'l (a，3， b'2， c'l (a，5， b，2， c'l (a'l， b，3， c'l (a，3， b'3， c'l (a'5 &gt; b，3， c'l (a'l， b，4， c'l (a，3， b，4， c'l (a'5 &gt; b'4， c'l (a’l， b丨1， c'2 (a'3， b，l， c'2 (a'5， b'l， c'2 (a'l， b，2， c'2 (a，3， b，2， c'2 (a’5， b，2， c'2 (a'l， b，3， c'2 (a'3， b'3， c'2 (a，5， b，3， c'2 (a'l， b，4， c'2 (a'3， b'4， c'2 (a，5， b，4， c'2 d'4， e'2) ' (a，2， d，4， e'2)、 (a’4， d，4， e'2)、 (a'6 d'4， e'2) ' (a'2 d，4， e，2)、 (a'4 d'4 &gt; e'2) &gt; (a'6 d，4， e'2)、 (a'2 d'4， e’2)、 (a'4 d'4， e，2)、 (a'6 d，4， e'2) ' (a'2 d'4， e，2)、 (a'4 d，4， e'2) ' (a'6 d'4， e'2)、 (a'2 d'4 &gt; e'2) ' (a'4 d'4， e'2) ' (a'6 d'4， e'2)、 (a'2 d，4， e，2)、 (a'4 d，4， e’2)、 (a'6 d，4， e'2) ' (a'2 d’4， e'2)、 (a'4 d'4， e，2)、 (a'6 d，4， e'2) &gt; (a'2 d，4， e'2)、 (a'4 d，4， e'2)、 (a'6 b'l， c'l， d'4， b'l， c'l， d'4 b'l， c'l， d'4 b'2， c'l， d'4 b，2， c'l， d'4 b'2， c'l， d'4 b，3， c'l &gt; d'4 b'3， c'l， d'4 b，3， c'l， d'4 b，4， c'l， d'4 b'4 &gt; c'l - d'4 b'4， c'l， d'4 b'l， c'2， d'4 b'l， c’2， d'4 b'l， c，2， d'4 b'2， c'2， d'4 b'2， c'2， d'4 b，2， c，2， d'4 b'3， c'2， d'4 b'3， c，2， d'4 b，3， c'2， d'4 b'4 - c，2， d'4 ，b，4， ，c，2， d'4 ，b'4 ， c，2， d'4 e'2)、 e'2)、 e'2) ' e'2) ' e'2)、 e'2)、 e，2)、 e'2) ' e'2)、 e'2)、 e'2)、 e，2)、 e'2)、 e'2) ' e，2)、 e，2)、 e'2)、 e'2) ' e'2) ' e'2)、 e’2)、 e，2)、 ，e，2)、 ，e'2)、 141666.doc -90- ❿ 201028381 (a，l ， b，l (a'3，b'l (a，5，b'l (a，l ， b，2 (a'3 ， b’2 (a'5 » b'2 (a'l ， b，3 (a'3 ， b'3 (a，5 ， b'3 (a，l ， b’4 (a'3 ， b'4 (a，5 ， b，4 (a'l ， b'l (a，3，b’l (a，5，b’l (a'l，b'2 (a，3 ， b，2 (a’5 ， b'2 (a'l &gt; b'3 (a'3 ， b，3 (a，5 ， b'3 (a'l * b'4 (a'3 ， b'4 (a，5 ， b，4 c，l， d'5 ，e’2) (a'2， b'l， c'l， d，5， e'2)、 c'l， d'5 ，e'2) (a'4， b'l &gt; c'l， d'5， e'2) ' c'l， d'5 ，e，2) 、 (a，6， b'l， c丨1， d'5， e，2)、 c'l， d’5 ，e'2) (a'2 &gt; b，2， c'l， d，5， e'2) ' c'l， d'5 ，e'2) (a'4， b，2， c'l， d，5， e'2)、 c'l， d'5 ，e，2) &gt; (a'6， b'2， c'l， d'5， e'2)、 c’l， d'5 ，e'2) &gt; (a'2 &gt; b'3， c'l， d'5， e-2)、 c'l， d'5 ，e'2) &gt; (a，4， b'3， c'l &gt; d'5， e丨2)、 c'l， d'5 ，e'2) (a'6， b'3， c'l， d'5， e'2)、 c'l， d'5 ，e'2) 、 (a'2， b'4， c'l， d'5 &gt; e'2) ' c’l， d'5 ，e'2) Λ (a'4， b'4， c'l， d'5， e'2) ' c'l， d'5 ，e'2) (a'6， b'4， c'l， d，5， e’2)、 c'2， d'5 ，e'2) 、 (a'2 &gt; b'l， c，2， d'5， e，2)、 c’2， d'5 ，e'2) (a'4， b'l， c’2， d，5， e，2)、 c'2， d'5 ，e，2) (a丨6， b'l， c'2， d'5， e'2)、 c'2， d'5 ，e'2) (a'2， b'2， c，2， d'5， e，2)、 c'2， d'5 ，e'2) (a'4， b'2， c'2， d'5， e'2) ' c'2 - d'5 » e'2) 、 (a'6， b'2 &gt; c'2， d'5， e'2)、 c，2， d'5 ，e'2) (a'2 » b'3， c'2， d，5， e'2)、 c'2， d'5 ’ e，2) Λ (a，4， b'3， c'2， d，5， e'2)、 c'2， d'5 &gt; e'2) (a'6， b'3， c，2， d'5， e'2)、 c’2， d'5 ，e，2) 、 (a'2 &gt; b，4， c'2， d，5， e'2)、 c'2， d'5 ，e，2) (a，4， b'4， c'2， d'5， e，2)、 c'2， d'5 ，e，2) 、 (a，6， b'4， c，2， d，5， e，2)、 141666.doc -91- 201028381 (a'l ， b'l ， c'l ， d'l (a，3 ， b'l ， c，l ， d，l (a，5 ， b'l ， c，l ， d，l (a，l ， b'2 ， c'l ， d，l (a’3 ， b'2 ， c'l ， d，l (a'5，b，2，c'l，d'l (a'l ， b'3 ， c'l ， d，l (a'3，b，3，c'l，d'l (a'5，b'3，c，l，d'l (a'l ， b'4 ， c'l ， d'l (a，3 ， b'4 ， c'l ， d'l (a'5，b'4，c'l，d'l (a'l ， b'l ， c'2 ， d'l (a，3 ， b'l ， c'2 ， d'l (a，5，b'l，c，2，d'l (a'l ， b，2 ， c，2 ， d，l (a’3，b，2，c’2，d，l (a'5，b'2，c_2，d'l (a，l ， b，3 ， c'2 ， d’l (a'3，b，3，c，2，d，l (a'5，b，3，c'2，d，l (a，l ， b'4 ， c'2 ， d'l (a，3，b'4，c'2，d'l (a，5，b，4，c，2，d'l e，3)、 (a，2， b'l e，3)、 (a，4， b'l e，3)、 (a，6， b'l e'3)、 (a，2， b’2 e'3)、 (a'4， b'2 e'3) ' (a丨6， b'2 e'3) &gt; (a'2， b'3 e，3)、 (a'4 &gt; b'3 e'3) ' (a'6， b'3 e，3)、 (a，2， b'4 e，3)、 (a，4， b'4 e'3)、 (a，6， b'4 e’3)、 (a'2， b'l e，3)、 (a'4， b'l e'3) ' (a，6， b'l e'3) ' (a'2， b'2 e’3)、 (a'4， b'2 e'3)、 (a'6 &gt; b'2 e'3) ' (a，2， b'3 e'3)、 (a'4， b'3 e'3) ' (a'6， b'3 e'3)、 (a'2 &gt; b'4 ，e，3)、 (a'4， b'4 ，e，3)、 (a，6， b'4 ，c’ 1， d，l， e’3)、 ，c'l， d'l， e，3)、 ，c，l， d'l， e，3)、 ，c，l， d'l， e，3)、 ，c'l， d'l， e'3)、 ，c，l， d'l， e'3) ' ，c'l， d'l， e，3)、 ，c'l， d'l， e’3)、 ，c，l， d'l， e，3)、 ，c'l， d'l， e'3)、 ，c'l， d’l， e，3)、 ，c'l， d'l， e，3)、 ，c，2， d'l， e，3)、 ，c'2， d'l， e'3) ' ，c'2， d'l， e'3) ' ，c，2， d'l， e'3)、 ，c，2， d’l， e'3)、 ，c'2， d'l， e'3)、 ，c'2， d，l， e，3)、 ，c'2， d'l， e'3)、 ，c，2， d'l， e'3)、 ，c'2， d，l， e，3)、 ，c，2， d'l， e'3) &gt; ，c'2， d'l » e，3)、 141666.doc -92- 201028381 (a，l ， b'l ， c，l ， d，2 (a，3 ， b，l ， c，l ， d'2 (a'5 ， b，l ， c'l ， d'2 (a'l ， b，2 ， c'l ， d'2 (a，3 ， b，2 ， c'l ， d'2 (a，5，b'2，c，l，d'2 (a'l ， b'3 ， c'l ， d'2 (a'3，b'3，c'l，d'2 φ (a，5 ， b，3 ， c’l ， d'2 (a'l ， b'4 ， c'l ， d'2 (a'3 ， b，4 ， c'l ， d'2 (a'5 ， b'4 ， c'l ， d，2 (a，l ， b'l ， c，2 ， d'2 (a'3 ， b'l ， c，2 ， d'2 (a'5 ， b，l ， c'2 ， d'2 (a’l ， b'2 ， c'2 ， d'2 ® (a'3，b，2，c'2，d'2 (a'5 ， b'2 ， c，2 ， d'2 (a'l，b'3，c'2，d'2 (a'3 ， b'3 ， c'2 ， d'2 (a，5 ， b'3 ， c'2 ， d'2 (a'l ， b'4 ， c'2 ， d'2 (a，3 ， b，4 ， c，2 ， d，2 (a'5 ， b'4 ， c'2 ， d'2 e，3) N (a，2， b，l， c，l， d，2， e，3)、 e'3) (a，4， b，l， c'l， d，2， e，3)、 e'3) (a'6， b，l， c'l， d，2， e，3)、 e'3) 、 (a'2， b'2， c，l， d'2， e，3)、 e'3) X (a’4， b'2， c'l， d，2， e'3) ' e'3) 、 (a'6， b'2， c'l &gt; d'2， e，3)、 e'3) 、 (a'2， b'3， c'l， d'2， e'3) ' e'3) 、 (a'4， b'3， c'l， d'2， e'3) ' e'3) (a，6， b'3， c'l， d，2， e'3) ' e’3) 、 (a'2， b，4， c'l， d'2， e'3)、 e’3) (a'4 - b'4， c'l， d'2， e'3)、 e'3) (a'6， b'4， c'l， d'2 &gt; e'3) ' e’3) N (a'2， b，l， c'2 &gt; d，2， e'3)、 e'3) (a'4， b'l - c'2， d'2， e，3)、 e'3) 、 (a，6， b'l， c'2， d'2， e'3) ' e’3) (a，2， b'2 - c'2， d，2， e'3)、 e'3) % (a'4， b'2， c’2， d'2， e'3)、 e'3) (a'6， b'2， c'2， d'2， e'3) ' e'3) 、 (a，2， b'3， c，2， d'2， e'3)、 e'3) 、 (a'4， b'3， c’2， d'2， e，3)、 e'3) (a'6， b'3， c'2， d'2， e，3)、 e'3) (a'2 &gt; b'4， c，2， d'2 &gt; e'3)、 e'3) (a'4， b'4， c，2， d'2， e’3)、 e'3) &gt; (a'6 &gt; b'4， c'2， d'2， e’3)、 141666.doc -93- 201028381 (a'l， b'l， c，l， d'3， e'3) &gt; (a'3， b，l， c'l， d'3， e'3) ' (ar5， b'l， c'l， d'3， e'3) ' (a'l， b'2， c'l » d’3， e'3) ' (a，3， b'2， c'l， d'3 &gt; e'3)、 (a'5， b，2， c'l， d，3， e，3)、 (a'l &gt; b，3， c，l， d，3， e’3)、 (a'3， b，3， c’l， d，3， e，3)、 (a’5， b’3， c'l， d，3， e'3) ' (a'l， b'4， c'l， d，3， e'3)、 (a，3， b，4， c'l， d'3， e'3) ' (a'5 » b，4， c'l， d'3， e'3)、 (a，l， b'l， c'2， d'3， e，3)、 (a'3， b’l， c'2， d'3 &gt; e，3)、 (a，5， b’l， c'2， d，3， e，3)、 (a'l， b，2， c'2， d，3， e'3) &gt; (a'3， b'2， c'2， d，3， e'3)、 (a'5， b'2， c’2， d'3， e，3)、 (a'l， b'3， c'2， d，3， e，3)、 (a'3， b'3， c'2， d'3， e，3)、 (a'5 &gt; b，3， c'2 &gt; d'3， e’3)、 (a'l， b，4， c，2， d，3， e丨3)、 (a，3， b'4， c'2 » d，3， e'3) ' (a，5， b'4， c'2， d'3， e，3)、 (a'2， b，l， c'l， d'3， e'3) &gt; (a’4， b’l， c'l， d，3， e，3)、 (a'6， b'l， c'l， d，3， e'3)、 (a，2， b，2， c'l， d，3， e’3)、 (a，4， b'2， c'l， d’3， e，3)、 (a，6， b’2， c’l， d'3， e'3) ' (a’2， b’3， c'l， d'3， e，3)、 (a’4， b'3， c’l， d，3， e，3)、 (a'6， b'3， c’l， d'3， e'3)、 (a，2， b，4， c’l， d'3， e'3)、 (a'4， b，4， c'l » d，3， e，3)、 (a'6， b，4， c'l， d，3， e'3) ' (a，2， b'l， c，2， d，3， e'3) ' (a'4 &gt; b'l &gt; c'2 &gt; d'3， e'3)、 (a'6， b'l， c，2， d'3， e，3)、 (a'2， b，2， c，2， d，3， e'3)、 (a'4 &gt; b，2， c'2， d，3， e'3)、 (a'6， b'2， c，2， d，3， e，3)、 (a'2 &gt; b，3， c'2， d，3， e'3) ' (a，4， b，3， c'2， d，3， e，3)、 (a，6， b，3， c，2， d，3， e’3)、 (a'2， b，4， c'2， d'3， e'3)、 (a，4， b'4， c，2， d'3， e'3) ' (a'6，b'4，c'2，d，3，e'3)、 141666.doc •94- 201028381 (a'l ， b，l ， c，l ， d，4 (a，3 ， b，l ， c，l ， d’4 (a'5 ， b'l ， c，l ， d，4 (a，l ， b，2 ， c'l ， d，4 (a，3，b，2，c，l，d，4 (a，5 ， b，2 ， c，l ， d，4 (a，l ， b，3 ， c，l ， d，4 (a，3，b，3，c，l，d'4 ❿（a，5 ， b，3 ， c'l ， d'4 (a，l ， b，4 ， c'l ， d，4 (a'3 ， b，4 ， c'l ， d，4 (a'5 ， b'4 ， c'l ， d'4 (a'l ， b'l ， c'2 ， d'4 (a'3，b'l，c，2，d'4 (a'5，b'l，c'2，d'4 (a'l，b'2，c，2，d'4 ’ （a’3 ， b'2 ’ c，2 ， d'4 (a'5，b'2，c'2，d，4 (a'l ， b'3 ， c'2 ， d'4 (a，3，b'3，c，2，d，4 (a'5，b，3，c'2，d'4 (a'l ， b'4 ， c'2 ， d'4 (a'3，b'4，c'2，d，4 (a'5 ， b，4 ， c'2 ， d'4 e，3)、 e'3)、 e'3)、 e'3)、 e'3)、 e'3)、 e'3) ' e'3)、 e'3)、 e'3) ' e，3)、 e'3) ' e'3) ' e'3)、 e'3)、 e'3) &gt; e，3)、 e'3)、 e'3) ' e'3)、 e，3)、 e'3) ' e'3)、 e'3) ' e，3) (a，2， b，l， c’l， d'4 e'3) 、 (a’4， b，l， c，l， d’4 e'3) (a'6， b'l &gt; c，l， d，4 e'3) 、 (a，2， b’2， c'l， d'4 e，3) 、 (a，4， b'2， c'l， d'4 e'3) (a'6， b'2， c'l， d'4 e'3) (a'2， b'3， c'l， d'4 e'3) &gt; (a'4， b'3， c'l， d'4 e'3) 、 (a，6， b'3， c'l， d'4 e'3) &gt; (a'2， b，4， c'l， d'4 e'3) (a'4 » b'4， c'l， d'4 e'3) N (a，6， b'4， c'l， d'4 e'3) 、 (a'2， b'l， c'2， d'4 e'3) (a'4， b'l， c'2， d'4 e'3) 、 (a'6， b'l， c'2， d'4 e'3) (a'2 &gt; b'2， c'2， d'4 e'3) Λ (a，4， b'2， c'2， d'4 e'3) X (a'6， b'2， c，2， d'4 e'3) 、 (a'2， b，3， c，2， d'4 e'3) (a，4， b'3， c'2， d'4 e'3) (a'6， b'3， c'2， d'4 e'3) (a'2， b，4， c'2， d'4 e，3) (a丨4， b'4， c，2， d'4 e'3) N (a'6 &gt; b'4， c'2， d'4 141666.doc -95- 201028381 (a’l， b'l， c，l， d'5 (a，3， b'l， c’l， d'5 (a，5， b'l， c'l， d'5 (a，l， b'2， c'l， d'5 (a'3， b，2， c'l， d'5 (a'5， b'2， c'l， d'5 (a'l， b’3， c'l， d'5 (a'3 &gt; b'3， c'l， d'5 (a'5， b'3 &gt; c'l， d'5 (a'l， b，4， c，l， d'5 (a'3， b，4， c'l， d'5 (a'5， b，4， c'l， d'5 (a'l， b’l， c'2， d'5 (a'3， b'l， c'2， d'5 (a，5， b'l， c，2， d'5 (a，l， b'2 &gt; c，2， d'5 (a'3 » b，2， c'2， d'5 (a，5， b，2， c'2， d'5 (a，l， b'3， c'2， d'5 (a'3 &gt; b，3， c，2， d’5 (a'5 &gt; b，3， c，2， d'5 (a'l， b'4， c，2， d'5 (a，3， b'4， c'2， d'5 (a，5， b'4， c，2， d'5 e’3)、（a'2，b'l，c'l，d'5， e'3)、（a'4，b'l，c'l，d，5 e'3)、（a’6，b'l，c'l，d'5 e，3)、（a’2，b，2，c’l，d'5 e'3) 、 （a'4 ， b，2 ， c’l ， d，5 e，3) 、 （a’6 ， b'2 ， c’l ， d，5 e，3)、（a，2，b'3，c'l，d，5 e，3) 、 （a'4 ， b，3 ， c'l ， d'5 e'3)、（a，6，b，3，c'l，d'5 e，3)、（a，2，b，4，c’l，d'5 e，3)、（a'4，b，4，c'l，d，5 e，3) 、 （a，6 ， b'4 ， c’l ， d，5 e，3) 、 （a'2 ， b，l ， c'2 ， d，5 e'3)、（a，4，b'l，c'2，d，5 e'3) 、 （a'6 ， b，l ， c，2 ， d，5 e，3)、（a'2，b'2，c'2，（Γ5 e，3)、（a'4，b'2，c'2，d'5 e'3)、（a，6，b'2，c，2，d，5 e'3)、（a丨2，b，3，c，2，d，5 e，3) 、 （a'4 ， b，3 ， c'2 ， d'5 e'3)、（a'6，b'3，c，2，d，5 e，3)、（a，2，b'4，c'2，d'5 e，3)、（a’4，b，4，c’2，d'5 e'3) 、 （a'6 ， b，4 ， c，2 ， d'5 e'3) ' e，3)、 e'3)、 e，3)、 e，3)、 e'3) ' e，3)、 e，3)、 e'3) ' e，3)、 e'3) &gt; e，3)、 e，3)、 e'3)、 e'3) ' e'3) ' e'3)、 e'3) &gt; e'3)、 e，3)、 e'3) ' e，3)、 e'3)、 ，e，3)、 141666.doc -96- 201028381 (a'l ， b，l ， c'l ， d'l (a，3 ， b，l ， c'l ， d'l (a'5 ， b'l ， c'l ， d'l (a’l ， b'2 ， c'l ， d’l (a'3，b'2，c'l，d'l (a'5 ， b'2 ， c，l ， d'l (a'l ， b'3 ， c'l ， d'l (a'3，b'3，c，l，d'l ❿（a'5 ， b，3 ， c'l ， d’l (a，l ， b，4 ， c'l ， d'l (a'3 ， b'4 ， c'l ， d'l (a，5 ， b，4 ， c，l ， d'l (a'l ， b，l ， c'2 ， d'l (a，3 ， b'l ， c'2 ， d'l (a，5 ， b，l ， c'2 ， d'l (a'l ， b'2 ， c'2 ， d'l m 零 （a，3 ， b'2 ， c'2 ， d，l (a'5 ， b，2 ， c'2 ， d'l (a'l ， b，3 ， c'2 ， d'l (a，3，b，3，c，2，d'l (a，5，b，3，c，2，d'l (a'l ， b，4 ， c，2 ， d'l (a，3，b’4，c'2，d'l (a*5 ， b’4 ， c’2 ， d'l e'4) &gt; (a，2， b'l， c'l， d'l e'4) ' e'4) (a’4， b'l c'l d'l e'4)、 e'4) 、 (a'6， b'l c'l d'l e，4)、 e'4) 、 (a，2， b'2 c'l d'l e，4)、 e'4) 、 (a，4， b'2 c'l d'l e，4)、 e'4) 、 (a'6， b'2 c'l d’l e'4) ' e'4) (a，2， b'3 c'l d'l e'4) ' e'4) (a'4， b'3 c'l d'l e'4)、 e'4) 、 (a'6， b'3 c'l d’l e'4)、 e'4) &gt; (a'2， b'4 c'l d'l e'4)、 e'4) (a'4 &gt; b'4 c'l d'l e'4)、 e'4) (a'6， b'4 c'l d'l e丨4)、 e'4) &gt; (a'2， b'l c’2 d'l e丨4)、 e'4) X (a，4， b'l c’2 d'l e，4)、 e'4) (a’6， b'l c'2 d'l e’4)、 e'4) (a'2， b'2 c'2 d'l e'4) ' e'4) (a丨4， b'2 c'2 d'l e'4)、 e'4) (a'6 5 b'2 c'2 d'l e'4) ' e'4) 、 (a，2， b’3 c'2 d'l e’4)、 e'4) (a，4， b'3 c'2 d'l e，4)、 e'4) (a'6， b’3 c'2 d'l e'4) &gt; e'4) &gt; (a'2， b'4 c'2 d'l e'4) ' e'4) (a'4， b'4 c'2 d'l e'4)、 e'4) (a'6， b'4 c'2 d'l e'4) &gt; 141666.doc -97- 201028381 (a，l，b，l，c，l，d’2， (a，3，b，l，c'l，d'2， (a，5， b'l， c'l， d'2 (a，l， b，2， c’l， d'2 (a，3， b'2， c'l， d'2 (a，5， b'2， c'l， d'2 (a，l， b’3， c’l， d'2 (a'3， b'3， c'l， d'2 (a'5， b'3， c'l， d'2 (a，l， b，4， c’l， d'2 (a，3， b'4， c'l， d'2 (a'5， b，4， c'l， d'2 (a，l， b'l， c'2 &gt; d'2 (a'3， b'l， c'2， d'2 (a，5， b'l， c'2， d'2 (a，l， b，2， c，2， d'2 (a，3， b'2， c'2， d'2 (a，5， b，2， c，2， d'2 (a'l， b，3， c'2， d'2 (a，3， b'3， c，2， d'2 (a'5 &gt; b'3， c'2， d'2 (a'l &gt; b，4， c'2， d'2 (a'3 &gt; b'4， c，2， d'2 (a'5 &gt; b'4， c'2， d'2 e'4)、（a’2，b'l，c’l，d'2， e'4)、（a'4，b'l，c'l，d’2， e，4) 、 （a'6 ， b'l ， c'l ， d'2 e，4) 、 （a，2 ， b'2 ， c’l ， d，2 e'4)、（a，4，b，2，c'l，d'2 e，4)、（a'6，b，2，c，l，d'2 e'4) 、 （a，2 ， b，3 ， c'l ， d'2 e*4) 、 （a'4 ， b'3 ， c'l ， d，2 e，4) 、 （a，6 ， b，3 ， c，l ， d'2 e'4) 、 （a'2 ， b'4 ， c'l ， d，2 e'4) 、 （a，4 ， b，4 ， c'l ， d，2 e-4) 、 （a，6 ， b，4 ， c'l ， d'2 e，4) 、 （a'2 ， b'l ， c，2 ， d，2 e，4) 、 （a'4 ， b’l ， c，2 ， d，2 e'4) 、 （a，6 ， b’l ， c，2 ， d’2 e，4)、（a，2，b'2，c'2，d'2 e，4)、（a'4，b'2，c'2，d，2 e'4) 、 （a'6 ， b，2 ， c，2 ， d'2 e'4) 、 （a'2 ， b，3 ， c，2 ， d，2 e，4) 、 （a，4 ， b'3 ， c'2 ， d'2 e，4)、（a'6，b，3，c'2，d'2 e'4) 、 （a'2 ， b'4 ， c，2 ， d，2 e'4)、（a，4，b'4，c'2，d，2 e'4)、（a'6，b，4，c'2，d'2 e丨4)、 e'4) ' e'4) &gt; e，4)、 e，4)、 e，4)、 e，4)、 e'4)、 e'4)、 e'4) ' e，4)、 e，4)、 e，4)、 e，4)、 e，4)、 e'4) ' e，4)、 e'4)、 e'4)、 e-4)、 e'4)、 e'4)、 e'4)、 e'4)、 141666.doc •98· 201028381 (a'l， (a'3， (a丨5， (a'l， (a'3， (a'5， (a'l， (a’3， ❿(a'5， (a'l， (a，3， (a丨5， (a'l， (a'3， (a丨5， (a丨 1， w (a'3， (a'5， (a，l， (a’3， (a'5， (a'l ' (a丨3， (a'5， b'l c'l， d'3 e'4)、 b'l c'l， d'3 e'4)、 b'l c'l， d'3 e'4) ' b'2 c'l， d'3 e'4) &gt; b'2 c'l， d'3 e'4)、 b'2 c'l， d'3 e'4) &gt; b，3 c'l， d'3 e'4) ' b'3 c'l， d'3 e’4)、 b'3 c'l， d'3 e'4) ' b'4 c'l， d'3 e'4) ' b'4 c'l， d'3 e'4) ' b'4 c'l， d'3 e'4)、 b'l c'2， d'3 e，4)、 b’l c，2， d'3 e'4)、 b'l c，2， d'3 e'4)、 b'2 c，2， d'3 e'4)、 b'2 c'2， d'3 e'4)、 b’2 c'2， d'3 e'4)、 b'3 c'2， d'3 e'4)、 b'3 c，2， d'3 e'4) ' b’3 c，2， d'3 e，4)、 b'4 c'2， d'3 e'4)、 b'4 c'2， d'3 ，e'4)、 b'4 c'2 &gt; d'3 ，e'4)、 (a'2， b'l c'l &gt; d'3， (a'4， b'l c，l， d'3， (a’6， b'l c'l， d'3 (a'2， b'2 c'l， d'3 (a'4 » b'2 c'l， d’3 (a，6， b'2 c'l， d’3 (a，2， b'3 c'l， d'3 (a'4， b'3 c'l， d'3 (a'6， b'3 c'l， d’3 (a'2， b'4 c'l， d'3 (a'4， b'4 c'l， d'3 (a'6 » b'4 c'l， d'3 (a'2， b'l c'2， d'3 (a'4， b'l c'2， d'3 (a'6， b'l c'2， d'3 (a'2， b'2 c'2， d'3 (a'4， b'2 c，2， d'3 (a，6， b'2 c'2 &gt; d'3 (a，2， b'3 c'2， d'3 (a’4， b'3 c'2， d’3 (a'6， b’3 c'2， d'3 (a，2， b'4 ，c’2， d'3 (a’4， b'4 ，c’2， d’3 (a'6， b'4 ，c'2， d'3 e，4)、 e'4) ' e'4)、 e'4)、 e'4) &gt; e'4)、 e'4)、 e，4)、 e'4)、 e'4)、 e'4) &gt; e'4) ' e'4) ' e丨4)、 e'4)、 e'4) ' e，4)、 e'4) ' e，4)、 e，4)、 e'4)、 e'4) ' e，4)、 e，4)、 141666.doc -99- 201028381 (a'l， (a'3， (a'5 (a'l (a'3 (a'5 (a'l (a，3 (a'5 (a'l (a'3 (a'5 (a'l (a丨3 (a'5 (a'l (a'3 (a丨5 (a'l (a'3 (a'5 (a'l (a'3 (a'5 b，l， c' 1， d'4， b'l， c’ 1， d'4， b，l， c丨1， d，4， b'2， c，l， d'4， b，2， c· 1， d'4， b，2， c，l， d，4， b'3， c，l， d'4 » b，3， c，l， d，4， b，3， c，l， d'4， b'4， c，l， d，4， b'4， c'l， d'4， b'4， c'l， d'4， b'l， c，2， d'4， b'l， c，2， d'4， b'l， c，2， d’4， b'2 &gt; c'2， d'4， b，2， c，2， d’4， b，2， c'2， d'4， b'3， c'2， d'4， b，3， c'2， d，4， b，3， c，2， d，4， b'4， c'2， d，4， b，4， c，2， d'4， ，b'4 ， c'2， d，4， e，4)、 (a，2， b'l， e'4)、 (a'4， b'l e'4)、 (a'6， b'l e'4)、 (a，2， b'2 e，4)、 (a'4， b'2 e’4)、 (a’6， b'2 e，4)、 (a，2， b'3 e'4)、 (a'4， b'3 e'4)、 (a'6， b'3 e，4)、 (a，2， b'4 e’4)、 (a，4， b'4 e'4)、 (a’6， b'4 e'4) ' (a’2， b'l e'4)、 (a，4， b'l e'4) ' (a，6， b'l e，4)、 (a'2， b'2 e'4) ' (a，4， b’2 e'4)、 (a’6， b'2 e'4)、 (a'2， b'3 e'4)、 (a'4， b'3 e丨4)、 (a'6， b'3 e'4)、 (a，2， b'4 e'4) ' (a'4， b'4 e'4) ' (a，6， b'4 c'l， d，4， e'4)、 c'l， d，4， e'4) &gt; c'l， d'4， e，4)、 c，l， d'4， e'4) ' c'l， d'4， e'4) ' c，l， d，4， e，4)、 c'l， d，4， e’4)、 c'l， d，4， e'4) ' c'l， d'4， e'4)、 c，l， d'4， e'4)、 c'l， d，4， e'4) ' c'l， d'4， e'4)、 c’2， d'4， e'4)、 c，2， d，4， e，4)、 c'2， d，4， e，4)、 c’2， d'4， e'4)、 c'2， d，4， e，4)、 c，2， d，4， e’4)、 c'2， d，4， e'4)、 c'2， d，4， e，4)、 c，2， d，4， e'4) ' c'2， d'4， e，4)、 c，2， d'4， e'4)、 ，c'2， d’4， e，4)、 141666.doc -100- 201028381 (a'l，b'l， (a'3，b'l， (a，5，b'l， (a'l ， b'2 ， (a'3，b'2， (a，5，b，2， (a'l，b'3， (a'3，b'3， ❿（a'5，b'3， (a'l，b'4， (a'3，b，4， (a丨5 ， b'4 ， (a'l，b'l， (a，3，b，l， (a'5，b'l， (a'l，b，2， w (a'3，b'2， (a丨5 ， b'2 ， (a'l ， b'3 ， (a，3，b'3， (a'5，b'3， (a'l，b'4， (a'3 ， b'4 ， (a，5 ， b'4 ， c'l ， d'5 ， e，4) 、 （a'2 ， c'l ， d’5 ， e'4) 、 （a'4 ， c'l ， d'5 ， e'4) 、 （a'6 ， c'l ， d'5 ， e’4) 、 （a'2 ， c’l ， d，5 ， e’4) 、 （a'4 ， c'l ， d'5 ， e，4) 、 （a'6 ， c'l ， d'5 ， e，4) 、 （a，2 ， c'l ， d'5 ， e'4) 、 （a'4 ， c'l ， d'5 ， e'4) 、 （a'6 ， c'l ， d，5 ， e，4) 、 （a'2 ， c'l ， d'5 ， e'4) 、 （a'4 ， c'l ， d'5 ， e，4) 、 （a'6 ， c，2，d，5，e'4)、（a'2， c'2 ， d，5 ， e，4) 、 （a，4 ， c'2 ， d'5 ， e，4) 、 （a，6 ， c'2，d'5，e'4)、（a，2， c，2 ， d，5 ， e'4) 、 （a'4 ， c'2 ， d’5 ， e'4) 、 （a'6 ， c'2 ， d’5 ， e，4) 、 （a'2 ， c'2 ， d'5 ， e'4) 、 （a'4 ， c'2 ， d，5 ， e'4) 、 （a，6 ， c'2 ， d'5 ， e'4) 、 （a，2 ， c'2，d，5，e'4)、（a'4， c'2，d'5，e'4)、（a'6， b'l c'l， d'5 e'4) ' b'l c'l， d'5 e'4)、 b'l c'l， d'5 e'4) ' b'2 c'l， d'5 e，4)、 b'2 c'l， d'5 e'4)、 b'2 c'l， d'5 e'4)、 b'3 c'l， d'5 e'4)、 b'3 c'l， d'5 e-4)、 b'3 c'l， d'5 e丨4)、 b'4 c，l， d'5 e，4)、 b'4 c'l， d'5 e'4) ' b'4 c'l， d'5 e丨4)、 b'l c'2， d'5 e丨4)、 b'l c'2， d'5 e'4)、 b'l c，2， d'5 e'4)、 b'2 c'2， d'5 e'4)、 b'2 c'2， d，5 e丨4)、 b'2 c'2， d'5 e'4) ' b'3 c，2， d’5 e'4)、 b'3 c，2， d，5 e'4)、 b'3 c'2， d'5 e'4) ' b'4 c，2， d'5 e，4)、 b'4 c'2， dr5 e丨4)、 b'4 c'2， d'5 e'4)、 141666.doc -101 - 201028381 (a'l，b'l，c，l，d'l，e，5)、 (a'3 ， b'l ， c'l ， d，l ， e'5)、 (a，5 ， b'l ， c'l ， d'l ， e，5)、 (a，l ， b'2 ， c'l ， d'l ， e，5)、 (a'3，b'2，c’l，d'l，e'5)、 (a，5 ， b，2 ， c’l ， d’l ， e，5)、 (a，l ， b'3 ， c'l ， d'l ， e'5)、 (a'3，b，3，c’l，d'l，e'5)、 (a'5 ， b，3 ， c'l ， d'l ， e，5)、 (a，l ， b，4 ， c，l ， d'l ， e，5)、 (a，3 ， b，4 ， c'l ， d'l ， e，5)、 (a，5 ， b’4 ， c'l ， d'l ， e，5)、 (a，l，b'l，c'2，d'l，e'5)、 (a'3，b'l，c'2，d，l，e'5)、 (a，5，b'l，c，2，d'l，e，5)、 (a’l ， b，2 ， c'2 ， d'l ， e'5)、 (a'3，b'2，c-2，d-1，e，5)、 (a'5，b'2，c，2，d丨 1，e'5)、 (a'l ， b'3 ， c'2 ， d'l ， e，5)、 (a'3 ， b'3 ， c'2 ， d，l ， e'5)、 (a'5 ， b'3 ， c，2 ， d'l ， e，5)、 (a'l ， b，4 ， c'2 ， d'l ， e'5)、 (a'3 ， b'4 ， c，2 ， d，l ， e，5)、 (a'5，b'4，c，2，d，l，e，5)、 (a'2， b'l， c'l， d'l ， e，5)、 (a，4， b'l， c'l， d'l 5 e'5)、 (a'6， b'l， c，l， d'l ， e，5)、 (a'2， b，2， c'l， d'l 5 e，5)、 (a'4， b，2， c'l， d'l ， e-5)、 (a，6， b，2， c，l， d'l 5 e'5) ' (a'2， b，3， c'l， d'l 9 e，5)、 (a'4 5 b，3， c'l， d'l 5 e'5)、 (a，6， b，3， c'l， d'l ， e'5)、 (a，2， b，4， c'l， d'l 5 e'5)、 (a'4， b，4， c，l， d'l e，5)、 (a，6， b'4， c'l， d'l e'5) ' (a'2 » b'l &gt; c'2 » d'l e，5)、 (a，4， b'l， c，2， d'l e，5)、 (a'6 « b'l， c'2， d'l e'5)、 (a'2 &gt; b，2， c'2， d，l ， e'5) ' (a'4， b，2， c'2， d'l 9 e'5) ' (a，6， b'2， c，2， d'l 9 e'5)、 (a'2 » b，3， c'2， d，l 5 e，5)、 (a，4， b，3， c'2， d'l ， e'5) &gt; (a'6， b'3， c，2， d'l 9 e'5)、 (a'2， b，4， c'2， d'l ， e，5)、 (a'4 &gt; b’4， c'2， d'l 9 e'5)、 (a'6， b，4， c，2， d'l 9 e'5) ' -102- 141666.doc 201028381(a丨1 b'l, c'l, d'l e'2) (a,2, b'l, c'l, d'l e'2) ' (a,3 b'l, c, l, d'l e'2) , (a'4, b'l, c'l, d'l e, 2), (a'5 b'l, c'l, d'l e'2) (a'6, b'l, c'l, d'l e'2), (a丨1 b,2, c'l, d'l e'2) (a'2, b'2, c 'l, d'l e'2), (a,3 b'2, c'l, d'l e'2) (a'4, b,2, c'l, d'l e'2) , (a'5 b,2, c'l, d'l e'2) (a'6, b'2, c'l, d'l e,2), (a'l b'3, c 'l, d'l e'2) (a'2, b'3, c'l, d'l e'2) ' (a'3 b,3, c'l, d'l e'2) (a'4, b'3, c'l, d'l e'2), (a'5 b'3 &gt; c'l, d'l e'2) (a'6, b'3, C'l &gt; d'l e'2), (a'l b'4, c'l, d'l e'2) (a'2, b'4, c'l, d'l e' 2) &gt; (a'3 b'4, c'l, d'l e'2) (a'4, b'4, c'l, d'l e, 2), (a丨5 b, 4, c'l, d'l e'2) (a,6, b'4, c'l, d'l e,2), (a'l b'l, c'2, d'l e '2) , (a'2, b'l, c'2, d'l e'2) &gt; (a,3 b'l, c,2, d'l e'2) , (a'4 &gt; b'l, c'2, d'l e'2) ' (a'5 b'l, c'2, d'l e'2) Λ (a' 6, b'l, c'2, d'l e'2), (a, lb, 2, c, 2, d, l e'2) (a, 2, b, 2, c, 2, d 'l e'2), (a'3 b'2 &gt; c,2, d'l e'2) (a'4, b,2, c'2, d'l e'2) ' (a '5 b'2, c, 2, d'l e'2) , (a,6, b,2, c,2, d'l e,2), (a'l b'3, c,2 , d'l e'2) , (a,2, b,3, c'2, d'l e'2), (a'3 b'3, c'2 &gt; d'l e'2) , (a'4, b,3, c'2, d'l e,2), (a'5 b'3, c'2, d'l, e,2) Λ (a'6, b' 3, c'2, d'l e'2), (a'l b'4, c, 2, d'l, e'2) N (a'2, b'4, c'2, d' l e'2) ' (a'3 b'4 &gt; c'2, d'l , e, 2) , (a'4, b'4, c'2, d'l e'2) ' ( A'5,b'4,c'2,d,l,e'2), (a'6,b'4,c'2,d'l,e,2), 141666.doc -87- 201028381 (a'l, (a,3, (a'5, (a'l &gt; (a,3, (a'5, (a'l, (a'3, (a'5, (a'l ' (a'3, (a'5, (a'l, (a'3, (a'5, (a'l, (a'3 (a'5 (a'l (a'3 (a' 5 (a'l (a'3 (a'5 b'l , c,l , d'2 , b,l , c,l , d'2 , b'l , c'l , d'2 b' 2, c'l, d, 2 b, 2, c, l D'2 b'2 , c'l , d'2 b'3 , c,l , d'2 b'3 , c'l , d,2 b'3 , c'l , d,2 b,4 , c'l , d'2 b,4 , c'l , d,2 b,4 , c'l , d,2 b,l , c,2 , d'2 b'l , c,2 , d , 2 b'l , c'2 , d'2 b'2 , c, 2 , d'2 b'2 , c'2 , d, 2 , b'2, c, 2, d'2 , b, 3, c'2, d, 2, b'3, c, 2, d'2, b, 3, c'2, d, 2, b'4, c, 2, d, 2, b'4, c,2,d'2, ,b,4,c'2,d,2, e,2), (a'2, b'l, e,2), (a,4, b'l e, 2), (a,6, b'l e,2), (a'2 &gt; b'2 e'2), (a,4, b'2 e,2), (a,6, b' 2 e'2), (a, 2, b'3 e, 2), (a, 4, b'3 e, 2), (a'6, b'3 e, 2), (a, 2, B'4 e'2), (a,4, b'4 e,2), (a,6, b'4 e,2), (a'2, b'l e'2) ' (a' 4, b'l e,2), (a,6, b'l e'2), (a,2, b'2 e'2) &gt; (a'4, b'2 e,2), (a,6, b'2 e'2), (a'2, b'3 e'2) &gt; (a,4, b'3 e'2), (a'6, b'3 e, 2), (a, 2, b'4 e, 2), (a, 4, b'4 e , 2), (a,6, b'4 c'l, d'2, e'2) c'l, d'2, e'2) c'l, d,2, e'2) c' l, d'2 &gt; e'2) c'l, d'2, e'2) c'l, d,2, e'2) c'l, d,2, e'2) c,l , d,2, e'2) c'l, d,2, e'2) c,l, d'2 &gt; e'2) c'l, d,2, e'2) c'l, D'2, e'2) c,2, d,2, e'2) c,2, d,2, e'2) c,2, d'2, e'2) c'2, d' 2, e'2) c'2, d'2, e'2) c'2, d,2, e'2) c'2, d,2, e'2) c'2, d'2, E'2) c'2, d,2, e'2) c,2, d,2, e'2) ,c'2, d,2, e'2) ,c'2, d'2, E'2) 141666.doc -88- 201028381 (a'l,b'l,c'l,d,3, (a'3, b,l, c'l, d,3, (a'5 B'l , c,l , d,3 , (a'l , b,2 , c'l , d,3 , (a,3,b,2,c'l,d,3, (a'5 ,b,2,c'l,d,3, (a'l,b'3,c,l,d,3, (a'3,b,3,c'l,d,3, ® (a '5,b,3,c,l,d,3, (a'l , b'4 , c'l , d'3 , (a,3,b,4,c,l,d,3, ( A'5, b'4, c'l, d'3, (a, l, b, l, c, 2, D'3 , (a'3 , b'l , c'2 , d,3 , (a,5,b,l,c'2,d'3, (a'l,b'2,c'2 ,d,3, ' (a'3,b'2,c'2,d'3, (a'5 , b,2 , c,2 , d'3 , (a'l,b,3,c '2,d'3, (a'3,b'3,c,2,d,3, (a,5,b'3,c'2,d,3, (a'l,b,4, C'2,d'3, (a'3,b'4,c'2,d'3, (a'5, b'4, c'2, d'3, e,2), e'2 ), e, 2), e'2) &gt; e, 2), e'2), e, 2), e'2) ' e'2), e'2) ' e, 2), e' 2), e'2), e, 2), e'2) ' e'2) ' e'2), e, 2), e'2), e'2) &gt; e'2), e '2), e'2), e'2), e'2) (a, 2, b'l c'l d'3 e'2) ·&gt; (a,4, b'l c'l D'3 e'2) (a,6, b'l c,l d'3 e'2) (a,2, b'2 c'l d'3 e'2) (a,4, b, 2 c'l d,3 e'2) (a'6, b'2 c'l d'3 e'2) &gt; (a,2, b'3 c'l d'3 e'2) , (a'4, b'3 c'l d'3 e'2) X (a,6, b,3 c'l d'3 e'2) , (a'2, b'4 c'l d '3 e'2) (a,4, b'4 c'l d'3 e'2) % (a'6, b'4 c'l d'3 e'2) , (a,2, b 'l c'2 d'3 e'2) (a'4, b'l c'2 d'3 e'2) (a'6 B'l c'2 d'3 e'2) \ (a,2, b'2 c'2 d'3 e'2) N (a'4 &gt; b'2 c'2 d'3 e' 2) , (a'6, b'2 c'2 d'3 e'2) &gt; (a'2, b'3 c'2 d'3 e'2) , (a'4, b'3 C'2 d'3 e'2) &gt; (a'6 &gt; b'3 c'2 d'3 e'2) &gt; (a'2, b'4 c'2 d'3 e'2 ) (a'4, b'4 c'2 d'3 e'2) , (a'6, b'4 c'2 d'3 141666.doc -89- 201028381 (a,l, b,l, C'l (a,3, b,l, c'l (a'5, b'l, c'l (a,l, b,2, c'l (a,3, b'2, c' l (a,5, b,2, c'l (a'l, b,3, c'l (a,3, b'3, c'l (a'5 &gt; b,3, c'l (a'l, b,4, c'l (a,3, b,4, c'l (a'5 &gt; b'4, c'l (a'l, b丨1, c'2 ( A'3, b,l, c'2 (a'5, b'l, c'2 (a'l, b,2, c'2 (a,3, b,2, c'2 (a' 5, b, 2, c'2 (a'l, b, 3, c'2 (a'3, b'3, c'2 (a,5, b,3, c'2 (a'l, b,4, c'2 (a'3, b'4, c'2 (a,5, b,4, c'2 d'4, e'2) ' (a,2, d,4, e '2), (a'4, d, 4, e'2), (a'6 d'4, e'2) ' (a'2 d,4, e,2), (a'4 d' 4 &gt; e'2) &gt; ( A'6 d,4, e'2), (a'2 d'4, e'2), (a'4 d'4, e,2), (a'6 d,4, e'2) ' (a'2 d'4, e, 2), (a'4 d, 4, e'2) ' (a'6 d'4, e'2), (a'2 d'4 &gt; e '2) ' (a'4 d'4, e'2) ' (a'6 d'4, e'2), (a'2 d,4, e,2), (a'4 d,4 , e'2), (a'6 d,4, e'2) ' (a'2 d'4, e'2), (a'4 d'4, e, 2), (a'6 d ,4, e'2) &gt; (a'2 d,4, e'2), (a'4 d,4, e'2), (a'6 b'l, c'l, d'4 , b'l, c'l, d'4 b'l, c'l, d'4 b'2, c'l, d'4 b,2, c'l, d'4 b'2, c 'l, d'4 b,3, c'l &gt; d'4 b'3, c'l, d'4 b,3, c'l, d'4 b,4, c'l, d' 4 b'4 &gt; c'l - d'4 b'4, c'l, d'4 b'l, c'2, d'4 b'l, c'2, d'4 b'l, c,2, d'4 b'2, c'2, d'4 b'2, c'2, d'4 b,2, c,2, d'4 b'3, c'2, d' 4 b'3, c,2, d'4 b,3, c'2, d'4 b'4 - c,2, d'4 ,b,4, ,c,2, d'4 ,b' 4 , c, 2, d'4 e'2), e'2), e'2) ' e'2) ' e'2), e'2), e, 2), e'2) ' e '2), e'2), e'2), e 2), e'2), e'2) 'e, 2), e, 2), e'2), e'2) 'e'2) 'e'2), e'2), e, 2), ,e,2), ,e'2), 141666.doc -90- ❿ 201028381 (a,l , b,l (a'3,b'l (a,5,b'l (a, l , b, 2 (a'3 , b'2 (a'5 » b'2 (a'l , b,3 (a'3 , b'3 (a,5 , b'3 (a,l , B'4 (a'3 , b'4 (a,5 , b,4 (a'l , b'l (a,3,b'l (a,5,b'l (a'l,b' 2 (a,3 , b,2 (a'5 , b'2 (a'l &gt; b'3 (a'3 , b,3 (a,5 , b'3 (a'l * b'4 (a'3 , b'4 (a,5 , b,4 c,l, d'5 ,e'2) (a'2, b'l, c'l, d,5, e'2), C'l, d'5 , e'2) (a'4, b'l &gt; c'l, d'5, e'2) ' c'l, d'5 , e, 2) , (a ,6, b'l, c丨1, d'5, e,2), c'l, d'5, e'2) (a'2 &gt; b,2, c'l, d,5, E'2) ' c'l, d'5 , e'2) (a'4, b, 2, c'l, d, 5, e'2), c'l, d'5, e, 2 ) &gt; (a'6, b'2, c'l, d'5, e'2), c'l, d'5, e'2) &gt; (a'2 &gt; b'3, c 'l, d'5, e-2), c'l, d'5, e'2) &gt; (a,4, b'3, c'l &gt; d'5, e丨2), c'l, d'5, e'2) (a'6, b'3, c'l, d'5, e'2), c'l, d'5, e'2) , (a'2, b'4, c'l, d'5 &gt; e'2) ' c'l, d'5 , e'2) Λ (a'4, b'4, c'l, D'5, e'2) 'c'l, d'5, e'2) (a'6, b'4, c'l, d,5, e'2), c'2, d'5 ,e'2) , (a'2 &gt; b'l, c,2, d'5, e,2), c'2, d'5 , e'2) (a'4, b'l, C'2, d,5, e,2), c'2, d'5,e,2) (a丨6, b'l, c'2, d'5, e'2), c'2 , d'5 , e'2) (a'2, b'2, c, 2, d'5, e, 2), c'2, d'5, e'2) (a'4, b' 2, c'2, d'5, e'2) ' c'2 - d'5 » e'2) , (a'6, b'2 &gt; c'2, d'5, e'2) , c, 2, d'5 , e'2) (a'2 » b'3, c'2, d, 5, e'2), c'2, d'5 ' e, 2) Λ (a ,4, b'3, c'2, d,5, e'2), c'2, d'5 &gt; e'2) (a'6, b'3, c,2, d'5, E'2), c'2, d'5, e, 2), (a'2 &gt; b, 4, c'2, d, 5, e'2), c'2, d'5, e , 2) (a, 4, b'4, c'2, d'5, e, 2), c'2, d'5, e, 2) , (a,6, b'4, c 2, d,5, e,2), 141666.doc -91- 201028381 (a'l , b'l , c'l , d'l (a,3 , b'l , c,l , d,l (a,5 , b'l , c,l , d,l (a,l , b'2 , c'l , d,l (a'3 , b'2 , c'l , d,l (a '5,b,2,c'l,d'l (a'l , b'3 , c'l , d,l (a'3,b,3,c'l,d'l (a'5 , b'3, c, l, d'l (a'l , b'4 , c'l , d'l (a,3 , b'4 , c'l , d'l (a'5,b '4,c'l,d'l (a'l , b'l , c'2 , d'l (a,3 , b'l , c'2 , d'l (a,5,b'l ,c,2,d'l (a'l , b,2 , c,2 , d,l (a'3,b,2,c'2,d,l (a'5,b'2,c_2 , d'l (a,l , b,3 , c'2 , d'l (a'3,b,3,c,2,d,l (a'5,b,3,c'2,d ,l (a,l , b'4 , c'2 , d'l (a,3,b'4,c'2,d'l (a,5,b,4,c,2,d'l e,3), (a,2, b'l e,3), (a,4, b'l e,3), (a,6, b'l e'3), (a,2, b '2 e'3), (a'4, b'2 e'3) ' (a丨6, b'2 e'3) &gt; (a'2, b'3 e,3), (a' 4 &gt; b'3 e'3) ' (a'6, b'3 e,3), (a,2, b'4 e,3) (a,4, b'4 e'3), (a,6, b'4 e'3), (a'2, b'l e,3), (a'4, b'l e'3 ) ' (a,6, b'l e'3) ' (a'2, b'2 e'3), (a'4, b'2 e'3), (a'6 &gt; b'2 E'3) ' (a,2, b'3 e'3), (a'4, b'3 e'3) ' (a'6, b'3 e'3), (a'2 &gt; B'4, e, 3), (a'4, b'4, e, 3), (a, 6, b'4, c' 1, d, l, e'3), c'l, D'l, e,3), ,c,l, d'l, e,3), ,c,l, d'l, e,3), ,c'l, d'l, e'3) , ,c,l, d'l, e'3) ' ,c'l, d'l, e,3), ,c'l, d'l, e'3), ,c,l, d' l, e, 3), , c'l, d'l, e'3), , c'l, d'l, e, 3), , c'l, d'l, e, 3), , c,2, d'l, e,3), ,c'2, d'l, e'3) ' ,c'2, d'l, e'3) ' ,c,2, d'l, E'3), ,c,2, d'l, e'3), ,c'2, d'l, e'3), ,c'2, d,l, e,3), ,c' 2, d'l, e'3), ,c,2, d'l, e'3), ,c'2, d,l, e,3), ,c,2, d'l, e' 3) &gt; , c'2, d'l » e, 3), 141666. Doc -92- 201028381 (a,l , b'l , c,l , d,2 (a,3 , b,l , c,l , d'2 (a'5 , b,l , c'l , D'2 (a'l , b,2 , c'l , d'2 (a,3 , b,2 , c'l , d'2 (a,5,b'2,c,l,d' 2 (a'l , b'3 , c'l , d'2 (a'3, b'3, c'l, d'2 φ (a,5 , b,3 , c'l , d'2 (a'l , b'4 , c'l , d'2 (a'3 , b,4 , c'l , d'2 (a'5 , b'4 , c'l , d, 2 (a ,l , b'l , c,2 , d'2 (a'3 , b'l , c,2 , d'2 (a'5 , b,l , c'2 , d'2 (a'l , b'2 , c'2 , d'2 ® (a'3,b,2,c'2,d'2 (a'5 , b'2 , c,2 , d'2 (a'l, B'3,c'2,d'2 (a'3 , b'3 , c'2 , d'2 (a,5 , b'3 , c'2 , d'2 (a'l , b' 4 , c'2 , d'2 (a,3 , b,4 , c,2 , d,2 (a'5 , b'4 , c'2 , d'2 e,3) N (a, 2 , b,l, c,l, d,2, e,3), e'3) (a,4, b,l, c'l, d,2, e,3), e'3) (a '6, b,l, c'l, d,2, e,3), e'3) , (a'2, b'2, c,l, d'2, e,3), e'3 ) X (a'4, b'2, c'l, d, 2, e'3) ' e'3) , (a'6, b'2, c'l &gt; d'2, e, 3), e'3) , (a'2, b'3, c 'l, d'2, e'3) ' e'3) , (a'4, b'3, c'l, d'2, e'3) ' e'3) (a,6, b' 3, c'l, d, 2, e'3) ' e'3) , (a'2, b, 4, c'l, d'2, e'3), e'3) (a'4 - b'4, c'l, d'2, e'3), e'3) (a'6, b'4, c'l, d'2 &gt; e'3) ' e'3) N (a'2, b,l, c'2 &gt; d,2, e'3), e'3) (a'4, b'l - c'2, d'2, e,3), e '3) , (a,6, b'l, c'2, d'2, e'3) ' e'3) (a,2, b'2 - c'2, d,2, e'3 ), e'3) % (a'4, b'2, c'2, d'2, e'3), e'3) (a'6, b'2, c'2, d'2, E'3) ' e'3) , (a,2, b'3, c,2, d'2, e'3), e'3) , (a'4, b'3, c'2, D'2, e, 3), e'3) (a'6, b'3, c'2, d'2, e, 3), e'3) (a'2 &gt; b'4, c ,2, d'2 &gt; e'3), e'3) (a'4, b'4, c,2, d'2, e'3), e'3) &gt; (a'6 &gt ; b'4, c'2, d'2, e'3), 141666.doc -93- 201028381 (a'l, b'l, c,l, d'3, e'3) &gt; (a '3 b,l, c'l, d'3, e'3) ' (ar5, b'l, c'l, d'3, e'3) ' (a'l, b'2, c'l » D'3, e'3) ' (a,3, b'2, c'l, d'3 &gt; e'3), (a'5, b,2, c'l, d,3, e , 3), (a'l &gt; b,3, c,l, d,3, e'3), (a'3, b,3, c'l, d,3, e,3), ( A'5, b'3, c'l, d,3, e'3) ' (a'l, b'4, c'l, d,3, e'3), (a,3, b, 4, c'l, d'3, e'3) ' (a'5 » b,4, c'l, d'3, e'3), (a,l, b'l, c'2, D'3, e, 3), (a'3, b'l, c'2, d'3 &gt; e, 3), (a, 5, b'l, c'2, d, 3, e ,3), (a'l, b,2, c'2, d,3, e'3) &gt; (a'3, b'2, c'2, d,3, e'3), ( A'5, b'2, c'2, d'3, e, 3), (a'l, b'3, c'2, d,3, e,3), (a'3, b' 3, c'2, d'3, e, 3), (a'5 &gt; b, 3, c'2 &gt; d'3, e'3), (a'l, b, 4, c, 2, d,3, e丨3), (a,3, b'4, c'2 » d,3, e'3) ' (a,5, b'4, c'2, d'3, e,3), (a'2, b,l, c'l, d'3, e' 3) &gt; (a'4, b'l, c'l, d,3, e,3), (a'6, b'l, c'l, d,3, e'3), (a ,2, b,2, c'l, d,3, e'3), (a,4, b'2, c'l, d'3, e,3), (a,6, b'2 , c'l, d'3, e'3) ' (a'2, b'3, c'l, d'3, e, 3), (a'4, b'3, c'l, d ,3, e,3), (a'6, b'3, c'l, d'3, e'3), (a,2, b,4, c'l, d'3, e'3 ), (a'4, b,4, c'l » d,3, e,3), (a'6, b,4, c'l, d,3, e'3) ' (a,2 , b'l, c,2, d,3, e'3) ' (a'4 &gt; b'l &gt; c'2 &gt; d'3, e'3), (a'6, b' l, c, 2, d'3, e, 3), (a'2, b, 2, c, 2, d, 3, e'3), (a'4 &gt; b, 2, c'2 , d,3, e'3), (a'6, b'2, c,2, d,3, e,3), (a'2 &gt; b,3, c'2, d,3, E'3) ' (a,4, b,3, c'2, d,3, e,3), (a,6, b,3, c,2, d,3, e'3), ( A'2, b,4, c'2, d'3, e'3), (a,4, b'4, c,2, d'3, e'3) ' (a'6,b' 4, c'2, d, 3, e'3), 141666.doc •94- 201028381 (a'l , b,l , c,l , d,4 (a,3 , b,l , c,l , d'4 (a'5 , b'l , c, l , d, 4 (a,l , b,2 , c'l , d,4 (a,3,b,2,c,l,d,4 (a,5 , b,2 , c,l , d,4 (a,l , b,3 , c,l , d,4 (a,3,b,3,c,l,d'4 ❿(a,5 , b,3 , c'l , d '4 (a,l , b,4 , c'l , d,4 (a'3 , b,4 , c'l , d,4 (a'5 , b'4 , c'l , d'4 (a'l , b'l , c'2 , d'4 (a'3, b'l, c, 2, d'4 (a'5, b'l, c'2, d'4 (a 'l,b'2,c,2,d'4 ' (a'3 , b'2 ' c,2 , d'4 (a'5,b'2,c'2,d,4 (a' l , b'3 , c'2 , d'4 (a,3,b'3,c,2,d,4 (a'5,b,3,c'2,d'4 (a'l , B'4 , c'2 , d'4 (a'3, b'4, c'2, d, 4 (a'5, b, 4, c'2, d'4 e, 3), e' 3), e'3), e'3), e'3), e'3), e'3) 'e'3), e'3), e'3) 'e,3), e' 3) ' e'3) ' e'3), e'3), e'3) &gt; e,3), e'3), e'3) ' e'3), e,3), e '3) ' e'3), e'3) ' e,3) (a,2, b,l, c'l D'4 e'3) , (a'4, b,l, c,l, d'4 e'3) (a'6, b'l &gt; c,l, d,4 e'3) , (a,2, b'2, c'l, d'4 e,3) , (a,4, b'2, c'l, d'4 e'3) (a'6, b'2, C'l, d'4 e'3) (a'2, b'3, c'l, d'4 e'3) &gt; (a'4, b'3, c'l, d'4 e '3) , (a,6, b'3, c'l, d'4 e'3) &gt; (a'2, b,4, c'l, d'4 e'3) (a'4 » b'4, c'l, d'4 e'3) N (a,6, b'4, c'l, d'4 e'3) , (a'2, b'l, c'2 , d'4 e'3) (a'4, b'l, c'2, d'4 e'3) , (a'6, b'l, c'2, d'4 e'3) ( A'2 &gt; b'2, c'2, d'4 e'3) Λ (a,4, b'2, c'2, d'4 e'3) X (a'6, b'2 , c,2, d'4 e'3) , (a'2, b,3, c,2, d'4 e'3) (a,4, b'3, c'2, d'4 e '3) (a'6, b'3, c'2, d'4 e'3) (a'2, b,4, c'2, d'4 e,3) (a丨4, b' 4, c, 2, d'4 e'3) N (a'6 &gt; b'4, c'2, d'4 141666.doc -95- 201028381 (a'l, b'l, c,l , d'5 (a,3, b'l, c'l, d'5 (a,5, b'l, c'l, d'5 (a,l, b'2, c'l, d '5 (a'3 b,2, c'l, d'5 (a'5, b'2, c'l, d'5 (a'l, b'3, c'l, d'5 (a'3 &gt; b '3, c'l, d'5 (a'5, b'3 &gt; c'l, d'5 (a'l, b,4, c,l, d'5 (a'3, b, 4, c'l, d'5 (a'5, b,4, c'l, d'5 (a'l, b'l, c'2, d'5 (a'3, b'l, C'2, d'5 (a,5, b'l, c,2, d'5 (a,l, b'2 &gt; c,2, d'5 (a'3 » b,2, c '2, d'5 (a,5, b,2, c'2, d'5 (a,l, b'3, c'2, d'5 (a'3 &gt; b,3, c, 2, d'5 (a'5 &gt; b,3, c,2, d'5 (a'l, b'4, c,2, d'5 (a,3, b'4, c'2 , d'5 (a,5, b'4, c,2, d'5 e'3), (a'2, b'l, c'l, d'5, e'3), (a' 4, b'l, c'l, d, 5 e'3), (a'6, b'l, c'l, d'5 e, 3), (a'2, b, 2, c' l,d'5 e'3) , (a'4 , b,2 , c'l , d,5 e,3) , (a'6 , b'2 , c'l , d,5 e,3 ), (a, 2, b'3, c'l, d, 5 e, 3), (a'4, b, 3, c'l, d'5 e'3), (a, 6, b , 3, c'l, d'5 e, 3), (a, 2, b, 4, c'l, d'5 e, 3), A'4,b,4,c'l,d,5 e,3) , (a,6 , b'4 , c'l , d,5 e,3) , (a'2 , b,l , C'2 , d,5 e'3), (a,4,b'l,c'2,d,5 e'3) , (a'6 , b,l , c,2 , d,5 e , 3), (a'2, b'2, c'2, (Γ5 e, 3), (a'4, b'2, c'2, d'5 e'3), (a, 6, B'2,c,2,d,5 e'3), (a丨2,b,3,c,2,d,5 e,3) , (a'4 , b,3 , c'2 , D'5 e'3), (a'6, b'3, c, 2, d, 5 e, 3), (a, 2, b'4, c'2, d'5 e, 3), (a'4,b,4,c'2,d'5 e'3) , (a'6 , b,4 , c,2 , d'5 e'3) ' e,3), e'3 ), e,3), e,3), e'3) ' e,3), e,3), e'3) ' e,3), e'3) &gt; e,3), e, 3), e'3), e'3) 'e'3) 'e'3), e'3) &gt; e'3), e, 3), e'3) 'e, 3), e '3), ,e,3), 141666.doc -96- 201028381 (a'l , b,l , c'l , d'l (a,3 , b,l , c'l , d'l ( A'5 , b'l , c'l , d'l (a'l , b'2 , c'l , d'l (a'3, b'2, c'l, d'l (a' 5 , b'2 , c,l , d'l (a'l , b'3 , c'l , d' l (a'3,b'3,c,l,d'l ❿(a'5 , b,3 , c'l , d'l (a,l , b,4 , c'l , d'l (a'3 , b'4 , c'l , d'l (a,5 , b,4 , c,l , d'l (a'l , b,l , c'2 , d'l (a ,3, b'l , c'2 , d'l (a,5 , b,l , c'2 , d'l (a'l , b'2 , c'2 , d'l m zero (a ,3, b'2 , c'2 , d,l (a'5 , b,2 , c'2 , d'l (a'l , b,3 , c'2 , d'l (a,3 ,b,3,c,2,d'l (a,5,b,3,c,2,d'l (a'l , b,4 , c,2 , d'l (a,3,b '4,c'2,d'l (a*5 , b'4 , c'2 , d'l e'4) &gt; (a,2, b'l, c'l, d'l e' 4) ' e'4) (a'4, b'l c'l d'l e'4), e'4), (a'6, b'l c'l d'l e, 4), E'4) , (a,2, b'2 c'l d'l e,4), e'4) , (a,4, b'2 c'l d'l e,4), e' 4) , (a'6, b'2 c'l d'l e'4) ' e'4) (a,2, b'3 c'l d'l e'4) ' e'4) ( A'4, b'3 c'l d'l e'4), e'4), (a'6, b'3 c'l d'l e'4), e'4) &gt; (a '2, b'4 c'l d'l e'4), e'4) (a'4 &gt; b'4 c'l d'l e'4), e'4) (a'6, B'4 c'l d'l e丨4), e'4) &gt; (a'2, b'l c'2 d'l e丨4), e'4) X (a,4, b'l c'2 d'l e, 4), e'4) (a'6, b'l c'2 d'l e'4), e'4) (a'2, b'2 c'2 d'l e'4) ' e '4) (a丨4, b'2 c'2 d'l e'4), e'4) (a'6 5 b'2 c'2 d'l e'4) ' e'4) , (a,2, b'3 c'2 d'l e'4), e'4) (a,4, b'3 c'2 d'l e,4), e'4) (a'6 , b'3 c'2 d'l e'4) &gt; e'4) &gt; (a'2, b'4 c'2 d'l e'4) ' e'4) (a'4, B'4 c'2 d'l e'4), e'4) (a'6, b'4 c'2 d'l e'4) &gt; 141666.doc -97- 201028381 (a,l, b,l,c,l,d'2, (a,3,b,l,c'l,d'2, (a,5, b'l, c'l, d'2 (a,l, b,2, c'l, d'2 (a,3, b'2, c'l, d'2 (a,5, b'2, c'l, d'2 (a,l, b' 3, c'l, d'2 (a'3, b'3, c'l, d'2 (a'5, b'3, c'l, d'2 (a,l, b,4, C'l, d'2 (a,3, b'4, c'l, d'2 (a'5, b,4, c'l, d'2 (a,l, b'l, c' 2 &gt; d'2 (a'3, b'l, c'2, d'2 (a,5, b'l, c'2, d'2 (a,l, b,2, c,2 , d'2 (a,3, b'2, c'2, D'2 (a,5, b,2, c,2, d'2 (a'l, b,3, c'2, d'2 (a,3, b'3, c,2, d' 2 (a'5 &gt; b'3, c'2, d'2 (a'l &gt; b,4, c'2, d'2 (a'3 &gt; b'4, c,2, d '2 (a'5 &gt; b'4, c'2, d'2 e'4), (a'2, b'l, c'l, d'2, e'4), (a'4 , b'l, c'l, d'2, e, 4) , (a'6 , b'l , c'l , d'2 e, 4) , (a, 2 , b'2 , c' l , d, 2 e'4), (a, 4, b, 2, c'l, d'2 e, 4), (a'6, b, 2, c, l, d'2 e'4 ), (a, 2, b, 3, c'l , d'2 e*4) , (a'4 , b'3 , c'l , d, 2 e, 4) , (a,6 , b ,3, c,l, d'2 e'4) , (a'2 , b'4 , c'l , d,2 e'4) , (a,4 , b,4 , c'l , d , 2 e-4) , (a,6 , b,4 , c'l , d'2 e,4) , (a'2 , b'l , c,2 , d,2 e,4) , ( A'4 , b'l , c,2 , d,2 e'4) , (a,6 , b'l , c,2 , d'2 e,4), (a,2,b'2, C'2,d'2 e,4),(a'4,b'2,c'2,d,2 e'4) , (a'6 , b,2 , c,2 , d'2 e '4) , (a'2 b,3 , c,2 , d,2 e,4) , (a,4 , b'3 , c'2 , d'2 e,4), (a'6,b,3,c'2, D'2 e'4) , (a'2 , b'4 , c, 2 , d, 2 e'4), (a, 4, b'4, c'2, d, 2 e'4), (a'6,b,4,c'2,d'2 e丨4), e'4) ' e'4) &gt; e,4), e,4), e,4), e,4 ), e'4), e'4), e'4) 'e,4), e,4), e,4), e,4), e,4), e'4) 'e,4 ), e'4), e'4), e-4), e'4), e'4), e'4), e'4), 141666.doc •98· 201028381 (a'l, ( A'3, (a丨5, (a'l, (a'3, (a'5, (a'l, (a'3, ❿(a'5, (a'l, (a,3, (a丨5, (a'l, (a'3, (a丨5, (a丨1, w (a'3, (a'5, (a,l, (a'3, (a'5 , (a'l ' (a丨3, (a'5, b'l c'l, d'3 e'4), b'l c'l, d'3 e'4), b'l c 'l, d'3 e'4) ' b'2 c'l, d'3 e'4) &gt; b'2 c'l, d'3 e'4), b'2 c'l, d '3 e'4) &gt; b,3 c'l, d'3 e'4) ' b'3 c'l, d'3 e'4), b'3 c'l, d'3 e' 4) ' b'4 c'l, d'3 e'4) ' b'4 c'l, d'3 e'4) ' b'4 c'l, d'3 e'4), b' l c'2, d'3 e,4), b' Lc,2, d'3 e'4), b'l c,2, d'3 e'4), b'2 c,2, d'3 e'4), b'2 c'2, d '3 e'4), b'2 c'2, d'3 e'4), b'3 c'2, d'3 e'4), b'3 c,2, d'3 e'4 ) ' b'3 c,2, d'3 e,4), b'4 c'2, d'3 e'4), b'4 c'2, d'3 ,e'4), b' 4 c'2 &gt; d'3 , e'4), (a'2, b'l c'l &gt; d'3, (a'4, b'l c,l, d'3, (a '6, b'l c'l, d'3 (a'2, b'2 c'l, d'3 (a'4 » b'2 c'l, d'3 (a,6, b' 2 c'l, d'3 (a,2, b'3 c'l, d'3 (a'4, b'3 c'l, d'3 (a'6, b'3 c'l, D'3 (a'2, b'4 c'l, d'3 (a'4, b'4 c'l, d'3 (a'6 » b'4 c'l, d'3 (a '2, b'l c'2, d'3 (a'4, b'l c'2, d'3 (a'6, b'l c'2, d'3 (a'2, b' 2 c'2, d'3 (a'4, b'2 c,2, d'3 (a,6, b'2 c'2 &gt; d'3 (a,2, b'3 c'2 , d'3 (a'4, b'3 c'2, d'3 (a'6, b'3 c'2, d'3 (a,2, b'4 ,c'2, d'3 (a'4, b'4, c'2, d'3 (a'6, b'4, c'2, d'3 e, 4), e'4) 'e'4), e'4 ), e'4) &gt; e'4), e'4), e, 4), e'4), e'4), e '4) &gt; e'4) ' e'4) ' e丨4), e'4), e'4) ' e,4), e'4) ' e,4), e,4), E'4), e'4) 'e,4), e,4), 141666.doc -99- 201028381 (a'l, (a'3, (a'5 (a'l (a'3 ( A'5 (a'l (a,3 (a'5 (a'l (a'3 (a'5 (a'5 (a'5 (a'3 (a'5 (a'5 5 (a'l (a'3 (a'5 (a'l (a'3 (a'5 b,l, c' 1, d'4, b'l, c' 1, d'4, b ,l, c丨1, d,4, b'2, c,l, d'4, b,2, c· 1, d'4, b,2, c,l,d,4, b'3 , c,l, d'4 » b,3, c,l, d,4, b,3, c,l, d'4, b'4, c,l, d,4, b'4, c 'l, d'4, b'4, c'l, d'4, b'l, c,2, d'4, b'l, c,2, d'4, b'l, c,2 , d'4, b'2 &gt; c'2, d'4, b,2, c,2, d'4, b,2, c'2, d'4, b'3, c'2, D'4, b,3, c'2, d,4, b,3, c,2, d,4, b'4, c'2, d,4, b,4, c,2, d' 4, , b'4 , c'2, d, 4, e, 4), (a, 2, b'l, e'4), (a'4, b'l e'4), (a' 6, b'l e'4), (a, 2, b'2 e, 4), (a'4, b'2 E'4), (a'6, b'2 e, 4), (a, 2, b'3 e'4), (a'4, b'3 e'4), (a'6, b '3 e,4), (a,2, b'4 e'4), (a,4, b'4 e'4), (a'6, b'4 e'4) ' (a'2 , b'l e'4), (a,4, b'l e'4) ' (a,6, b'l e,4), (a'2, b'2 e'4) ' (a , 4, b'2 e'4), (a'6, b'2 e'4), (a'2, b'3 e'4), (a'4, b'3 e丨4), (a'6, b'3 e'4), (a,2, b'4 e'4) ' (a'4, b'4 e'4) ' (a,6, b'4 c'l , d,4, e'4), c'l, d,4, e'4) &gt; c'l, d'4, e,4), c,l, d'4, e'4) ' C'l, d'4, e'4) ' c,l, d,4, e,4), c'l, d,4, e'4), c'l, d,4, e'4 ) ' c'l, d'4, e'4), c,l, d'4, e'4), c'l, d,4, e'4) ' c'l, d'4, e '4), c'2, d'4, e'4), c, 2, d, 4, e, 4), c'2, d, 4, e, 4), c'2, d'4 , e'4), c'2, d,4, e,4), c,2, d,4, e'4), c'2, d,4, e'4), c'2, d ,4, e,4), c,2, d,4, e'4) ' c'2, d'4, e,4), c,2 , d'4, e'4), , c'2, d'4, e, 4), 141666.doc -100- 201028381 (a'l,b'l, (a'3,b'l, ( a,5,b'l, (a'l , b'2 , (a'3,b'2, (a,5,b,2, (a'l,b'3, (a'3,b '3, ❿ (a'5, b'3, (a'l, b'4, (a'3, b, 4, (a丨5, b'4, (a'l, b'l, ( a,3,b,l, (a'5,b'l, (a'l,b,2, w (a'3,b'2, (a丨5 , b'2 , (a'l , B'3 , (a,3,b'3, (a'5,b'3, (a'l,b'4, (a'3 , b'4 , (a,5 , b'4 , c 'l , d'5 , e, 4) , (a'2 , c'l , d'5 , e'4 ) , (a'4 , c'l , d'5 , e'4 ) , (a '6, c'l , d'5 , e'4) , (a'2 , c'l , d, 5 , e'4 ) , (a'4 , c'l , d'5 , e, 4 ), (a'6, c'l, d'5, e, 4), (a, 2, c'l, d'5, e'4), (a'4, c'l, d'5 , e'4) , (a'6 , c'l , d, 5 , e, 4) , (a'2 , c'l , d'5 , e'4 ) , (a'4 , c'l , d'5 , e, 4) , (a'6 , c, 2, d, 5, e '4), (a'2, c'2 , d, 5 , e, 4) , (a, 4 , c'2 , d' 5, e, 4), (a, 6 , c'2, d'5, e'4), (a, 2, c, 2, d, 5, e'4), (a'4, c' 2, d'5, e'4), (a'6, c'2, d'5, e, 4), (a'2, c'2, d'5, e'4), (a' 4, c'2, d,5, e'4) , (a,6 , c'2 , d'5 , e'4) , (a,2 , c'2,d,5,e'4) , (a'4, c'2, d'5, e'4), (a'6, b'l c'l, d'5 e'4) ' b'l c'l, d'5 e '4), b'l c'l, d'5 e'4) ' b'2 c'l, d'5 e,4), b'2 c'l, d'5 e'4), b '2 c'l, d'5 e'4), b'3 c'l, d'5 e'4), b'3 c'l, d'5 e-4), b'3 c'l , d'5 e丨4), b'4 c,l, d'5 e,4), b'4 c'l, d'5 e'4) ' b'4 c'l, d'5 e丨4), b'l c'2, d'5 e丨4), b'l c'2, d'5 e'4), b'l c,2, d'5 e'4), b '2 c'2, d'5 e'4), b'2 c'2, d,5 e丨4), b'2 c'2, d'5 e'4) ' b'3 c,2 , d'5 e'4), b'3 c,2, d,5 e'4), b'3 c'2, d'5 e'4) ' b'4 c,2, d'5 e , 4), b'4 c'2, dr5 e丨4), b'4 c'2, d'5 e'4), 141666.doc -101 - 201028381 (a'l,b'l,c, l, d'l, e, 5), (a'3, b'l, c'l, d, l, e'5), (a, 5, b'l, c'l, d'l, e,5), (a,l , b'2 , c'l , d'l , e,5), (a'3,b'2,c'l,d'l,e'5), ( a,5, b,2, c'l, d'l, e,5), (a,l, b'3, c'l, d'l, e'5), (a'3,b, 3, c'l, d'l, e'5), (a'5, b, 3, c'l, d'l, e, 5), (a, l, b, 4, c, l, D'l , e, 5), (a, 3, b, 4, c'l, d'l, e, 5), (a, 5, b'4, c'l, d'l, e, 5), (a, l, b'l, c'2, d'l, e'5), (a'3, b'l, c'2, d, l, e'5), (a, 5, b'l, c, 2, d'l, e, 5), (a'l, b, 2, c'2, d'l, e'5), (a'3, b'2, C-2, d-1, e, 5), (a'5, b'2, c, 2, d丨1, e'5), (a'l, b'3, c'2, d' l , e, 5), (a'3, b'3, c'2, d, l, e'5), (a'5, b'3, c, 2, d'l, e, 5) , (a'l, b, 4, c'2, d'l, e'5), (a'3, b'4, c, 2, d, l, e, 5), (a'5, B'4,c,2,d,l,e,5), (a'2 B'l, c'l, d'l, e,5), (a,4, b'l, c'l, d'l 5 e'5), (a'6, b'l, c, l, d'l , e, 5), (a'2, b, 2, c'l, d'l 5 e, 5), (a'4, b, 2, c'l, d'l , E-5), (a,6, b,2, c,l, d'l 5 e'5) ' (a'2, b,3, c'l, d'l 9 e,5), ( A'4 5 b,3, c'l, d'l 5 e'5), (a,6, b,3, c'l, d'l , e'5), (a,2, b, 4, c'l, d'l 5 e'5), (a'4, b, 4, c, l, d'l e, 5), (a,6, b'4, c'l, d 'l e'5) ' (a'2 » b'l &gt; c'2 » d'l e,5), (a,4, b'l, c,2, d'l e,5), (a'6 « b'l, c'2, d'l e'5), (a'2 &gt; b,2, c'2, d,l , e'5) ' (a'4, b ,2, c'2, d'l 9 e'5) ' (a,6, b'2, c,2, d'l 9 e'5), (a'2 » b,3, c'2 , d,l 5 e,5), (a,4, b,3, c'2, d'l , e'5) &gt; (a'6, b'3, c,2, d'l 9 E'5), (a'2, b, 4, c'2, d'l, e, 5), (a'4 &gt; b'4, c'2, d'l 9 e'5), (a'6, b,4, c,2, d'l 9 e'5) ' -102- 141666.doc 201028381

(a'l b'l， c'l， d'2， e'5) (a'2， b'l &gt; c'l， d'2 (a'3 5 b'l， c'l， d，2， e'5) (a'4， b，l， c，l， d'2 (a'5 5 b’l， c'l， d，2， e'5) (a丨6， b'l， c'l， d'2 (a'l b，2， c’l d'2， e'5) 、 (a，2， b'2 c'l d'2 (a'3 b'2， c'l d'2， e'5) 、 (a'4， b'2 c'l d'2 (a'5 b'2， c'l d，2， e'5) (a'6， b'2 c'l d'2 (a'l 5 b，3， c'l d，2， e'5) &gt; (a，2， b'3 c'l d'2 (a'3 b'3， c'l d'2 &gt; e’5) (a'4， b'3 c'l d'2 (a'5 b'3， c'l d'2， e'5) (a'6， b'3 c'l d'2 (a'l b'4， c'l d'2， e'5) 、 (a'2， b'4 c'l d'2 (a'3 b'4， c'l d'2， e’5) 、 (a'4， b'4 c'l d'2 (a'5 b'4， c'l d'2， e'5) 、 (a'6， b'4 c'l d'2 (a'l b'l， c'2 d'2， e'5) (a，2， b'l c'2 d'2 (a'3 b'l， c，2 d'2 &gt; e'5) (a'4， b'l c'2 d'2 (a'5 b'l， c'2 d'2， e'5) (a'6， b'l c'2 d'2 (a'l b'2 &gt; c'2 d，2， e'5) 、 (a，2， b'2 c'2 d’2 (a’3 b'2， c'2 d'2， e'5) 、 (a'4， b'2 c'2 d'2 (a'5 b'2， c'2 d，2， e'5) (a，6， b'2 c'2 d'2 (a'l b，3， c'2 d'2， e'5) 、 (a'2， b'3 c'2 d'2 (a'3 b，3， c'2 d，2， e'5) &gt; (a’4， b'3 c'2 d'2 (a'5 b'3， c'2 d，2， e'5) 、 (a，6， b'3 c'2 d'2 (a'l 5 b'4， c'2 d，2， e'5) (a'2， b'4 c'2 d'2 (a'3 9 b'4， c'2 d'2， e'5) 、 (a，4， b'4 c'2 d'2 (a'5 5 b'4 &gt; c'2 d'2 &gt; e'5) &gt; (a，6， b'4 c'2 d'2 e'5)、 e'5)、 e'5)、 e，5)、 e'5) &gt; e，5)、 e'5)、 e'5)、 e'5)、 e'5)、 e'5)、 e'5)、 e，5)、 e，5)、 e'5)、 e'5) ' e'5)、 e，5)、 e'5)、 e'5) &gt; e，5)、 e'5) ' e'5)、 e'5) ' 141666.doc -103- 201028381 (a'l ， b'l ， c，l (a'3， b'l， c'l (a，5， b'l &gt; c'l (a'l， b'2， c'l (a，3， b，2， c'l (a'5， b'2， c'l (a'l， b'3， c'l (a，3， b，3， c'l (a，5， b，3， c'l (a'l， b，4， c'l (a，3， b，4， c'l (a'5， b'4， c'l (a'l &gt; b'l， c'2 (a'3 &gt; b'l， c'2 (a'5 &gt; b'l &gt; c'2 (a'l， b'2 &gt; c'2 (a'3 « b，2， c'2 (a，5， b'2， c'2 (a'l， b'3， c'2 (a'3 &gt; b，3， c'2 (a，5， b'3， c'2 (a，l， b，4， c'2 (a，3， b’4， c'2 (a，5， b，4， c'2 ,d，_3， e 5) ' ，d'3， e，5)、 ，d'3， e'5) &gt; ，d'3， e'5)、 ，d，3， e，5)、 ，d'3， e，5)、 ，d'3， e'5) ' ，d，3， e，5)、 ，d，3， e'5) ' ，d'3， e'5) &gt; ，d'3， e，5)、 ，d，3， e'5)、 ，d'3， e，5)、 ，d'3， e'5)、 ，d'3， e'5)、 ，d'3， e'5)、 ，d'3， e'5) ' ，d，3， e'5)、 ，d'3， e'5)、 ，d'3， e'5) ' ，d，3， e，5)、 ，d'3， e'5) ' ，d，3， e，5)、 ，d，3， e，5)、 (a，2， b'l， c'l (a，4， b'l， c'l (a'6， b'l， c'l (a，2， b，2， c'l (a'4， b'2， c’l (a'6， b，2， c'l (a，2， b，3， c'l (a，4， b'3， c'l (a丨6， b'3 &gt; c'l (a'2， b'4， c'l (a'4， b'4， c'l (a，6， b，4， c'l (a'2 « b'l， c'2 (a，4， b'l， c'2 (a，6， b，l， c'2 (a，2， b，2， c'2 (a'4， b，2， c'2 (a，6， b，2， c'2 (a，2， b，3， c'2 (a'4， b'3， c'2 (a'6， b'3， c'2 (a'2， b，4， c'2 (a，4， b，4， c'2 (a'6， b，4， c'2 ，d'3，e’5)、 ，d'3 ， e，5)、 ，d，3，e'5)、 ，d'3，e，5)、 ，d，3，e，5)、 ，d'3，e'5)、 ，d'3 ， e'5)、 ，d'3，e，5)、 ，d，3，e丨5)、 ，d'3，e丨5)、 ，d，3，e'5)、 ，d'3，e，5)、 ，d'3，e，5)、 ，d，3，e，5)、 ，d，3，e’5)、 ，d，3，e'5)、 ，d'3，e'5)、 ，d'3，e，5)、 ，d，3，e，5)、 ，d，3，e，5)、 ，d'3，e'5)、 ，d'3，e，5)、 ，d，3，e，5)、 ，d'3，e，5)、 141666.doc •104- 201028381 (a'l b'l ) c' 1， d，4， e'5) (a，2， b'l， c， 1， d'4 (a'3 b'l 5 c'l， d，4， e'5) (a，4， b，l， c，l， d'4 (a'5 b'l 5 c'l， d'4， e'5) 、 (a'6， b'l， c， 1， d'4 (a'l b'2 1 c，l， d，4， e'5) (a'2， b'2， c· 1 d'4 (a'3 b'2 1 c’l， d'4， e'5) &gt; (a，4， b，2， c' 1 d'4 (a'5 b'2 ) c'l， d'4， e'5) (a’6， b'2， c， 1 d'4 (a'l b丨3 J c'l， d，4， e'5) (a，2， b'3， c 1 d'4 (a'3 b'3 ， c'l， d'4， e'5) (a’4， b'3 &gt; c 1 d'4 (a'5 b'3 c'l， d，4， e'5) (a'6， b，3， c' 1 d'4 (a'l b'4 c'l， d'4， e'5) (a'2 &gt; b'4， c 1 d'4 (a'3 b，4 5 c'l， d，4， e'5) (a'4， b'4， c 1 d'4 (a'5 b'4 c'l， d'4 &gt; e'5) (a，6， b'4， c 1 d'4 (a'l b'l c，2， d'4， e'5) (a'2 &gt; b'l， c 2 d'4 (a'3 b'l c'2， d'4， e'5) % (a'4， b'l， c 2 d'4 (a'5 b'l c'2， d'4， e'5) 、 (a’6， b，l， c 2 d'4 (a'l b'2 c'2， d'4， e'5) (a'2， b，2， c 2 d'4 (a'3 b'2 c'2， d'4， e'5) (a'4， b，2， c 2 d'4 (a'5 b'2 c'2， d'4， e'5) (a'6， b'2， c'2 d'4 (a'l b'3 c’2， d'4， e'5) (a’2， b，3， c 2 d'4 (a'3 b'3 c，2， d'4， e'5) 、 (a'4， b'3， c 2 d'4 (a'5 b'3 c'2， d'4， e'5) 、 (a'6 &gt; b'3， c '2 d'4 (a'l b’4 c'2， d'4， e'5) 、 (a'2， b'4， c'2 d'4 (a’3 b'4 c'2， d'4， e'5) (a'4， b'4， c '2 d’4 (a'5 b'4 ， c'2， d'4， e'5) (a'6， b'4， c '2 d'4 e’5)、 e，5)、 e，5)、 e'5)、 e'5)、 e'5) ' e'5)、 e'5)、 e'5)、 e'5) ' e'5) ' e，5)、 e，5)、 e'5) ' e，5)、 e，5)、 e'5) ' e'5) ' e'5)、 e'5)、 e'5) ' e'5)、 e'5)、 e'5)、 141666.doc 105· 201028381 (a，l，b'l，c'l，d'5，e'5)、（a'2，b，l，c'l，d'5，e'5)、 (a'3 ， b'l ， c，l ， d'5 ， e，5) 、 （a'4 ， b，l ， c，l ， d'5 ， e'5)、 (a，5 ， b，l ， c，l ， d'5 ， e'5) 、 （a，6 ， b，l ， c'l ， d'5 ， e'5)、 (a’l，b，2，c'l，d，5，e，5)、（a'2，b，2，c，l，d'5，e'5)、 (a'3，b，2，c'l，d，5，ef5)、（a，4，b，2，c'l，d'5，e，5)、 (a'5，b，2，c'l，d'5，e，5)、（a'6，b'2，c'l，d，5，e'5)、 (a'l，b'3，c'l，d，5，e，5)、（a'2，b，3，c'l，d'5，e'5)、 (a，3，b'3，c'l，d'5，e，5)、（a'4，b'3，c'l，d，5，e'5)、 (a'5，b，3，c'l，d'5，e，5)、（a，6，b，3，c'l，d，5，e，5)、 (a'l，b'4，c'l，d，5，e'5)、（a'2，b，4，c，l，d'5，e'5)、 (a，3，b，4，c'l，d'5，e'5)、（a，4，b'4，c'l，d，5，e，5)、 (a'5，b’4，c'l，d’5，e’5)、（a'6，b'4，c’l，d'5，e'5)、 (a'l ， b'l ， c，2 ， d'5 ， e'5) 、 （a'2 ， b’l ， c'2 ， d’5 ， e'5)、 (a，3，b，l，c，2，d'5，e'5)、（a'4，b，l，c，2，d，5，e'5)、 (a'5 ， b’l ， c’2 ， d'5 ， e'5) 、 （a'6 ， b'l ， c’2 ， d'5 ， e'5)、 (a'l，b'2，c'2，d'5，e'5)、（a'2，b，2，c'2，d，5，e'5)、 (a，3，b，2，c，2，d'5，e，5)、（a，4，b'2，c，2，d'5，e'5)、 (a'5 ， b'2 ， c'2 ， d'5 ， e'5) 、 （a’6 ， b，2 ， c，2 ， d，5 ， e'5)、 (a'l，b，3，c，2，d'5，e'5)、（a，2，b'3，c'2，d，5，e，5)、 (a’3，b'3，c，2，d'5，e’5)、（a’4，b'3，c'2，d'5，e’5)、 (a，5，b，3，c'2，d，5，e，5)、（a'6，b'3，c'2，d'5，e'5)、 (a'l，b'4，c，2，d，5，e，5)、（a'2，b'4，c，2，d'5，e'5)、 (a'3，b，4，c，2，d，5，e'5)、（a'4，b，4，c，2，d，5，e，5)、 (a，5 ， b，4 ， c'2 ， d'5 ， e，5) 、 （a'6 ， b'4 ， c'2 ， d'5 ， e，5)。 •106- 141666.doc 201028381 於其他實施形態中，本發明提供一種含有上述任一項所 揭示之化合物、其製藥上所容許之鹽或者其等之溶劑合 物、或其前藥（例如，酯類、醯胺類）的醫藥組合物。 於本說明書中，所謂「前藥」「前藥化合物」係指具有 可化學性或代謝性分解之基，藉由水解或加溶劑分解或者 於生理條件下進行分解而顯示藥學活性的本發明之化合物 之衍生物。於該技術領域中已知有各種各樣形態之前藥。 關於此種前藥衍生物之例，可參照以下之文獻（a)〜(f)。式 β (I)之化合物之前藥係藉由利用式⑴之化合物中存在的官能 基於生物體内***則放出母化合物之改質方法進行改質而 製造。例如，前藥包含式（I)之化合物中之羥基、硫氫基或 者胺基分別與若於生物體内***則再生出自由羥基、胺 基、或者硫氫基之基鍵結之式（I)的化合物。前藥之例並不 限定於該等，包含式（I)之化合物中之羥基官能基的酯（例 如乙酸酯、甲酸酯、及苯曱酸酯衍生物）、胺基甲酸酯（例 如Ν，Ν-二甲基胺基羰基）等。 (a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42. p. 309-396, edited by K. Widder, et al. (Academic Press, 1985)； (b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen ； (c) H. Bundgaard, Chapter 5 「Design and Application of Prodrugs」，by H. Bundgaard p. 113-191 (1991); (d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1 - 141666.doc -107- 201028381 38 (1992)； (e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77,285 (1988);及 (f) N. Kakeya，et al.，Chem Pharm Bull, 32,692 (1984)。 個刚藥基之例係於人或動物體内***而產生母酸 (parent acid)之可藥學容許的酯之可體内（in viv〇)***之酯 基。例如，刖藥基與鍵結其之羧基一起，形成如Ci 6烷基 酯或C!·6環烷基酯，例如曱基、乙基、丙基、異丙基、正 丁基或環戊基之g曰，C丨_6院氧基曱酯，例如甲氧基曱酯； Cl·6烷醯氧基甲酯，例如特戊醯氧甲酯；酞基酯；（：3.8環烷 氧基羰氧基Cw烷基酯，例如環己基羰氧基乙酯；-二 氧戊環-2-基曱酯，例如5_曱基q，％:氧戊環_2_基甲酯； C〗-6烷氧基羰氧基乙酯，例如丨_甲氧基羰氡基乙酯；胺基 羰基曱S曰及其單-或二烷基）變型，例如NN_二甲基 胺基幾基甲S曰及N-乙基胺基羰基甲酯之類的可藥學容許之 酯，及經取代或未經取代之雜環式基之可藥學容許之酯。 於-個實施形態中’前藥可列舉：與選自如異丙基或環戊 基之類之Cw烷基、或者如N·甲基四氫吡啶基之類之可經 取代之雜環式基中者的酯。 包含上述列舉之具體化合物之任意化合物的本發明之醫 藥組合物之特徵亦在於係TTK抑制劑。因此，提供一種藉 由對必須抑制TTK之患者投予而發揮藥效之任意的醫藥組 合物。 、 於其他實施形態中，本發明提供一種醫藥，其係用以處 141666.doc -108- 201028381 理或預防癌或免疫疾病，且包含上述列舉之具體化合物之 任意化合物。 (製造方法） 以下例示本發明之化合物之通常製造法。又，萃取、純 化等，進行利用通常之有機化學實驗進行之處理即可。 以下，記載本發明之化合物之製造方法。 本發明之化合物之合成可一面參照該領域中眾所周知之 方法一面實施。 原料化合物可利用市售之化合物，或者於專利文獻3〜專 利文獻23中記載者，此外可利用本說明書中記載者以及於 本說明書中另外引用之文獻中記載者以及其他眾所周知之 化合物。 本發明之化合物中可存在互變異構物、位置異構物、光 學異構物’本發明包含該等，包含所有可能之異構物及其 等之混合物。 欲取得本發明之化合物時，以鹽之形態獲得本發明之化 合物之情形時，可直接純化，又，以自由之形態獲得之情 形時，可使其溶解或懸浮於適當有機溶劑中，添加酸或 驗’利用通常之方法形成鹽。 又，本發明之化合物及其製藥上所容許之鹽有時亦以與 水或各種溶劑之加成物（水合物或溶劑合物）之形態存在， 該等加成物亦包含於本發明中。 該等之衍生物係於體内轉換活化者，於本說明書令亦稱 為「前藥」。作為前藥之例，理解為例如除上述鹽、溶劑 141666.doc -109. 201028381 物之外，亦包含酯（例如烷基酯等）、醯胺等。 本發明之化合物之例於實施例中列舉各種，業者亦可參 考等，製造、使用本發明之未例示之化合物。 本發明亦係關於一種製造本發明之化合物之系統、裝 -套組。理解成此種系統、裝置、套組之構成要件可利 用該領域中眾所周知者，業者可進行適宜設計。 [化 28] 1)(a'l b'l, c'l, d'2, e'5) (a'2, b'l &gt; c'l, d'2 (a'3 5 b'l, c'l, d,2, e'5) (a'4, b,l, c,l, d'2 (a'5 5 b'l, c'l, d,2, e'5) (a丨6, B'l, c'l, d'2 (a'l b,2, c'l d'2, e'5) , (a,2, b'2 c'l d'2 (a'3 b '2, c'l d'2, e'5) , (a'4, b'2 c'l d'2 (a'5 b'2, c'l d, 2, e'5) (a '6, b'2 c'l d'2 (a'l 5 b,3, c'l d,2, e'5) &gt; (a,2, b'3 c'l d'2 (a '3 b'3, c'l d'2 &gt; e'5) (a'4, b'3 c'l d'2 (a'5 b'3, c'l d'2, e'5 ) (a'6, b'3 c'l d'2 (a'l b'4, c'l d'2, e'5) , (a'2, b'4 c'l d'2 ( A'3 b'4, c'l d'2, e'5) , (a'4, b'4 c'l d'2 (a'5 b'4, c'l d'2, e' 5) , (a'6, b'4 c'l d'2 (a'l b'l, c'2 d'2, e'5) (a, 2, b'l c'2 d'2 (a'3 b'l, c,2 d'2 &gt; e'5) (a'4, b'l c'2 d'2 (a'5 b'l, c'2 d'2, e '5) (a'6, b'l c'2 d'2 (a'l b'2 &gt; c'2 d,2, e'5) , (a,2, b'2 c'2 d '2 (a'3 b'2, c'2 d'2, e'5) , (a'4, b'2 c'2 d'2 (a'5 b'2, c'2 d, 2 , e' 5) (a,6, b'2 c'2 d'2 (a'l b,3, c'2 d'2, e'5) , (a'2, b'3 c'2 d'2 (a'3 b,3, c'2 d,2, e'5) &gt; (a'4, b'3 c'2 d'2 (a'5 b'3, c'2 d,2, E'5) , (a,6, b'3 c'2 d'2 (a'l 5 b'4, c'2 d,2, e'5) (a'2, b'4 c'2 D'2 (a'3 9 b'4, c'2 d'2, e'5) , (a,4, b'4 c'2 d'2 (a'5 5 b'4 &gt; c' 2 d'2 &gt; e'5) &gt; (a,6, b'4 c'2 d'2 e'5), e'5), e'5), e,5), e'5) &gt; e,5), e'5), e'5), e'5), e'5), e'5), e'5), e,5), e,5), e'5 ), e'5) ' e'5), e, 5), e'5), e'5) &gt; e, 5), e'5) ' e'5), e'5) ' 141666. Doc -103- 201028381 (a'l , b'l , c,l (a'3, b'l, c'l (a,5, b'l &gt; c'l (a'l, b'2 , c'l (a,3, b,2, c'l (a'5, b'2, c'l (a'l, b'3, c'l (a,3, b,3, c 'l (a,5, b,3, c'l (a'l, b,4, c'l (a,3, b,4, c'l (a'5, b'4, c'l (a'l &gt; b'l, c'2 (a'3 &gt; b'l, c'2 (a'5 &gt; b'l &gt; c'2 (a'l, b'2 &gt; C'2 (a'3 « b,2, c'2 (a,5, b'2, C'2 (a'l, b'3, c'2 (a'3 &gt; b,3, c'2 (a,5, b'3, c'2 (a,l, b,4, c '2 (a,3, b'4, c'2 (a,5, b,4, c'2 ,d,_3, e 5) ' ,d'3, e,5), ,d'3, E'5) &gt; , d'3, e'5), ,d,3, e,5), ,d'3, e,5), ,d'3, e'5) ' ,d,3 , e,5), ,d,3, e'5) ' ,d'3, e'5) &gt; ,d'3, e,5), ,d,3, e'5), ,d' 3, e, 5), , d'3, e'5), , d'3, e'5), , d'3, e'5), , d'3, e'5) ' ,d, 3, e'5), , d'3, e'5), , d'3, e'5) ' ,d,3, e,5), ,d'3, e'5) ' ,d, 3, e, 5), , d, 3, e, 5), (a, 2, b'l, c'l (a, 4, b'l, c'l (a'6, b'l, C'l (a,2, b,2, c'l (a'4, b'2, c'l (a'6, b,2, c'l (a,2, b,3, c' l (a,4, b'3, c'l (a丨6, b'3 &gt; c'l (a'2, b'4, c'l (a'4, b'4, c'l (a,6, b,4, c'l (a'2 « b'l, c'2 (a,4, b'l, c'2 (a,6, b,l, c'2 (a ,2, b,2, c'2 (a'4, b,2 C'2 (a,6, b,2, c'2 (a,2, b,3, c'2 (a'4, b'3, c'2 (a'6, b'3, c' 2 (a'2, b,4, c'2 (a,4, b,4, c'2 (a'6, b,4, c'2,d'3,e'5), ,d' 3, e, 5), , d, 3, e'5), , d'3, e, 5), , d, 3, e, 5), , d'3, e'5), , d' 3, e'5), , d'3, e, 5), , d, 3, e丨5), , d'3, e丨5), ,d,3,e'5), ,d' 3,e,5), ,d'3,e,5), ,d,3,e,5), ,d,3,e'5), ,d,3,e'5), ,d' 3,e'5), ,d'3,e,5), ,d,3,e,5), ,d,3,e,5), ,d'3,e'5), ,d' 3,e,5), ,d,3,e,5), ,d'3,e,5), 141666.doc •104- 201028381 (a'l b'l ) c' 1, d,4, E'5) (a,2, b'l, c, 1, d'4 (a'3 b'l 5 c'l, d,4, e'5) (a,4, b,l, c ,l, d'4 (a'5 b'l 5 c'l, d'4, e'5) , (a'6, b'l, c, 1, d'4 (a'l b'2 1 c,l, d,4, e'5) (a'2, b'2, c· 1 d'4 (a'3 b'2 1 c'l, d'4, e'5) &gt; (a,4, b,2, c' 1 d'4 (a'5 b'2 ) c'l, d '4, e'5) (a'6, b'2, c, 1 d'4 (a'l b丨3 J c'l, d,4, e'5) (a,2, b'3 , c 1 d'4 (a'3 b'3 , c'l, d'4, e'5) (a'4, b'3 &gt; c 1 d'4 (a'5 b'3 c' l, d,4, e'5) (a'6, b,3, c' 1 d'4 (a'l b'4 c'l, d'4, e'5) (a'2 &gt; B'4, c 1 d'4 (a'3 b,4 5 c'l, d,4, e'5) (a'4, b'4, c 1 d'4 (a'5 b'4 C'l, d'4 &gt; e'5) (a,6, b'4, c 1 d'4 (a'l b'l c,2, d'4, e'5) (a'2 &gt; b'l, c 2 d'4 (a'3 b'l c'2, d'4, e'5) % (a'4, b'l, c 2 d'4 (a'5 b 'l c'2, d'4, e'5) , (a'6, b,l, c 2 d'4 (a'l b'2 c'2, d'4, e'5) (a '2, b,2, c 2 d'4 (a'3 b'2 c'2, d'4, e'5) (a'4, b,2, c 2 d'4 (a'5 b '2 c'2, d'4, e'5) (a'6, b'2, c'2 d'4 (a'l b'3 c'2, d'4, e'5) (a '2, b,3, c 2 d'4 (a'3 b'3 c,2, d'4, e'5) , (a'4, b'3, c 2 d'4 (a'5 B'3 c'2, d'4, e'5) , (a'6 &gt; b'3, c '2 d'4 (a'l b'4 c'2, d'4, e'5 ), (a'2, b'4, c'2 d'4 (a'3 b'4 c'2, d'4, e '5) (a'4, b'4, c '2 d'4 (a'5 b'4 , c'2, d'4, e'5) (a'6, b'4, c '2 D'4 e'5), e,5), e,5), e'5), e'5), e'5) 'e'5), e'5), e'5), e' 5) ' e'5) ' e,5), e,5), e'5) ' e,5), e,5), e'5) ' e'5) ' e'5), e' 5), e'5) 'e'5), e'5), e'5), 141666.doc 105· 201028381 (a,l,b'l,c'l,d'5,e'5) , (a'2, b, l, c'l, d'5, e'5), (a'3, b'l, c, l, d'5, e, 5), (a'4, b,l , c,l , d'5 , e'5), (a,5 , b,l , c,l , d'5 , e'5) , (a,6 , b,l , c' l , d'5 , e'5), (a'l, b, 2, c'l, d, 5, e, 5), (a'2, b, 2, c, l, d'5, E'5), (a'3, b, 2, c'l, d, 5, ef5), (a, 4, b, 2, c'l, d'5, e, 5), (a' 5,b,2,c'l,d'5,e,5), (a'6,b'2,c'l,d,5,e'5), (a'l,b'3, C'l,d,5,e,5), (a'2,b,3,c'l,d'5,e'5), (a,3,b'3,c'l,d' 5,e,5), (a'4,b'3,c'l,d,5,e'5), (a'5,b,3,c'l,d'5,e,5) , (a, 6, b, 3, c'l, d, 5, e, 5), (a'l, b'4, c'l, d, 5, e'5), (a'2, b, 4, c, l, D'5,e'5), (a,3,b,4,c'l,d'5,e'5), (a,4,b'4,c'l,d,5,e, 5), (a'5, b'4, c'l, d'5, e'5), (a'6, b'4, c'l, d'5, e'5), (a' l , b'l , c, 2 , d'5 , e'5) , (a'2 , b'l , c'2 , d'5 , e'5 ) , (a, 3, b, l, c, 2, d'5, e'5), (a'4, b, l, c, 2, d, 5, e'5), (a'5, b'l, c'2, d' 5, e'5), (a'6, b'l, c'2, d'5, e'5), (a'l, b'2, c'2, d'5, e'5) , (a'2, b, 2, c'2, d, 5, e'5), (a, 3, b, 2, c, 2, d'5, e, 5), (a, 4, B'2, c, 2, d'5, e'5), (a'5, b'2, c'2, d'5, e'5), (a'6, b, 2, c, 2, d, 5, e'5), (a'l, b, 3, c, 2, d'5, e'5), (a, 2, b'3, c'2, d, 5, e,5), (a'3, b'3, c, 2, d'5, e'5), (a'4, b'3, c'2, d'5, e'5), ( a,5,b,3,c'2,d,5,e,5), (a'6,b'3,c'2,d'5,e'5), (a'l,b' 4,c , 2, d, 5, e, 5), (a'2, b'4, c, 2, d'5, e'5), (a'3, b, 4, c, 2, d, 5 , e'5), (a'4, b, 4, c, 2, d, 5, e, 5), (a, 5, b, 4, c'2, d'5, e, 5), (a'6, b'4, c'2, d'5, e, 5). In another embodiment, the present invention provides a pharmaceutically acceptable salt or a solvate thereof, or a prodrug thereof (for example, an ester), which comprises a compound disclosed in any one of the above, a pharmaceutically acceptable salt thereof, or the like Pharmaceutical compositions of the class of guanamines. In the present specification, the term "prodrug" and "prodrug compound" means a substance having chemically or metabolically decomposable groups, which exhibits pharmaceutically active activity by hydrolysis or solvolysis or decomposition under physiological conditions. a derivative of a compound. Various forms of prodrugs are known in the art. For examples of such prodrug derivatives, reference may be made to the following documents (a) to (f). The prodrug of the compound of the formula β (I) is produced by modifying the functional group present in the compound of the formula (1) by a modification method in which the parent compound is released based on in vivo division. For example, a prodrug comprises a formula in which a hydroxyl group, a sulfhydryl group or an amine group in a compound of the formula (I) is bonded to a radical of a free hydroxyl group, an amine group or a sulfhydryl group, respectively, if it is cleaved in a living body (I) )compound of. Examples of prodrugs are not limited to these, including esters of hydroxy functional groups (e.g., acetate, formate, and benzoate derivatives), urethanes in the compounds of formula (I) ( For example, hydrazine, hydrazine-dimethylaminocarbonyl, and the like. (a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42. p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen; (c) H. Bundgaard, Chapter 5 "Design and Application of Prodrugs", by H. Bundgaard p. 113-191 (1991); (d) H Bundgaard, Advanced Drug Delivery Reviews, 8, 1 - 141666.doc -107- 201028381 38 (1992); (e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); and (f) N Kakeya, et al., Chem Pharm Bull, 32, 692 (1984). An example of a rigid drug base is an in vivo cleavable ester group which is cleaved in a human or animal body to produce a pharmaceutically acceptable ester of a parent acid. For example, a guanidine group, together with a carboxyl group bonded thereto, forms, for example, a Ci 6 alkyl ester or a C -6 cycloalkyl ester such as a decyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group or a cyclopentane group.曰 曰, 丨 6 院 院 院 院 院 院 院 , , , , , 6 6 6 6 6 6 6 6 6 6 6 6 Cl 6 Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl 6 Cl Cl Alkoxycarbonyl Cw alkyl ester, such as cyclohexylcarbonyloxyethyl ester; - dioxolane-2-yl decyl ester, such as 5-indolyl q, %: oxolane-2-yl methyl ester; C -6-alkoxycarbonyloxyethyl ester, such as 丨-methoxycarbonylmethyl ester; amine carbonyl 曱S曰 and its mono- or dialkyl) variants, such as NN-dimethylamino Pharmaceutically acceptable esters such as hydrazino and N-ethylaminocarbonylmethyl, and pharmaceutically acceptable esters of substituted or unsubstituted heterocyclic groups. In the present embodiment, the prodrug may be exemplified by a heterocyclic group which may be substituted with a Cw alkyl group selected from, for example, isopropyl or cyclopentyl or a N.methyltetrahydropyridyl group. The ester of the middle. The pharmaceutical composition of the present invention comprising any of the specific compounds enumerated above is also characterized by being a TTK inhibitor. Therefore, there is provided a pharmaceutical composition which exerts pharmacological effects by administering to a patient who must inhibit TTK. In other embodiments, the invention provides a medicament for use in the treatment of a cancer or an immune disease, and any compound comprising the specific compounds listed above. (Manufacturing Method) The usual production method of the compound of the present invention is exemplified below. Further, extraction, purification, and the like may be carried out by a usual organic chemistry experiment. Hereinafter, a method for producing the compound of the present invention will be described. The synthesis of the compounds of the present invention can be carried out while referring to methods well known in the art. The raw material compound can be used as a commercially available compound, or it can be described in Patent Document 3 to Patent Document 23, and other known compounds can be used as described in the specification and in the literature cited elsewhere in the specification. Tautomers, positional isomers, optical isomers may be present in the compounds of the invention. The invention encompasses such materials, including all possible isomers and mixtures thereof. When the compound of the present invention is obtained in the form of a salt, it can be directly purified, and when it is obtained in a free form, it can be dissolved or suspended in a suitable organic solvent, and an acid is added. Or check 'use the usual method to form a salt. Further, the compound of the present invention and a pharmaceutically acceptable salt thereof are sometimes present in the form of an adduct (hydrate or solvate) with water or various solvents, and such adducts are also included in the present invention. . These derivatives are those that are activated in vivo and are also referred to as "prodrugs" in this specification. As an example of the prodrug, it is understood that, for example, in addition to the above salt and solvent 141666.doc-109.201028381, an ester (e.g., an alkyl ester or the like), a guanamine or the like is also included. Examples of the compound of the present invention are listed in the examples, and the compounds which are not exemplified in the present invention can be produced and used by reference. The invention also relates to a system, kit, kit for making a compound of the invention. It is understood that the components of such systems, devices, and kits can be utilized in the art and can be suitably designed. [化 28] 1)

❹❹

HNHN

CC

^ 各5己號與上述定義相同，由式（A1)及式（NH-RbRc) 表不之化口物可使用眾所周知之化合物，可使用由眾所 周知之化合物利用常法衍生之化合物。） 參 係使由式（A1)所表不之化合物與由式（NHRbRC)所表示 之化合物㈣及縮合劑之存在下進行反應，製造由式（A:) 所表示之化合物的步驟。 作為反應溶劑，可列舉：Dmf、nmp、dma、二甲基 M、芳香族_(例如甲笨、笨、二甲笨等）、飽和烴^ (例如環己烷、己烷等)、南化烴類(例如二氣甲烷、氣仿、 Ά二氣乙烧等）、_類（例如四氫。夫喃、二乙基n 烷、1，2-一甲氧基乙院等）、醋類（例如乙酸甲冑' 乙酸乙 酯等）、酮類（例如丙酮、甲某 T基乙基酮等）、腈類（例如乙腈 141666.doc -110· 201028381 等）、8?·類（例如甲7两拿、楚_•丁餘&amp;、 r ^乙醇第二丁醇專）、水及其等之混 合溶劑等。 作為鹼，例如可列舉：金屬氫化物（例如氫化鈉等）、金 屬氫氧化物（例如氫氧化納、氫氧化卸、氯氧化經、氯氧 化銷等）金屬碳酸鹽（例如碳酸納、碳酸舞、碳酸鏠等）、 金屬醇鹽（例如甲醇鈉、乙醇鈉、第三丁醇鉀等）、碳酸氫 鈉、金屬鈉、有機胺（例如三乙基胺、二異丙基乙基胺、 DBU、2,6·二甲基吡啶等）、吡啶、烷基鋰（n BuU、“卜 # BuU、tert-BuLi)等。驗未必必須使用，可視情況使用。 作為縮合劑，可使用DCC(二環己基碳化二醯亞胺）、 BOP(苯并三唾小基氧基·三（二甲基胺基）鱗六氣鱗酸 醋）、PyBOP、PyBrop、HATU、DppA(疊氮基磷酸二苯 S曰）W SC(1-乙基-3-(3-一甲基胺基丙基）碳化二醯亞胺鹽 酸鹽）、DMT-MM等。又，該等之試劑例如可與H〇Su(N•羥 基丁二醯亞胺）、HOBt、HOAt等組合使用。 較好的是，作為反應溶劑可使用醚類（例如四氫咬喃、 二***、二噁烷等）、N，N-二甲基甲醯胺、N•甲基吡咯啶 酮、N，N-二甲基乙醯胺，作為鹼，可使用有機胺（例如三 乙基胺、二異丙基乙基胺、DBU、2,6-二曱基吡咬等），作 為縮合劑，可使用HATU或PyBOP。反應溫度、反應時間 並無特別限定’通常係於室溫下實施反應，有時亦於反應 進行較慢之情形時藉由加溫而促進反應。 以下例示於R5中導入取代基之製造方法。 [化 29] 141666.doc -111- 201028381^ Each of the five numbers is the same as defined above, and a well-known compound can be used as the chemical substance represented by the formula (A1) and the formula (NH-RbRc), and a compound derived by a conventional method can be used by a conventionally known compound. The step of reacting a compound represented by the formula (A1) with a compound (IV) represented by the formula (NHRbRC) and a condensing agent to produce a compound represented by the formula (A:). Examples of the reaction solvent include Dmf, nmp, dma, dimethyl M, aromatic _ (for example, stupid, stupid, dimethyl, etc.), saturated hydrocarbon (e.g., cyclohexane, hexane, etc.), and nanhua. Hydrocarbons (eg, di-methane, gas, bismuth, etc.), _ (for example, tetrahydrogen, phoranyl, diethyl n-alkane, 1,2-methoxymethoxy, etc.), vinegar (e.g., methyl acetate 'ethyl acetate, etc.), ketones (such as acetone, methyl T-ethyl ethyl ketone, etc.), nitriles (such as acetonitrile 141666.doc -110· 201028381, etc.), 8? (such as A 7 Two, Chu _• Ding Yu &amp;, r ^ ethanol second butanol special), water and other mixed solvents. Examples of the base include a metal hydride (for example, sodium hydride or the like), a metal hydroxide (for example, sodium hydroxide, hydrogen hydroxide, chlorine oxychloride, chlorine oxyfluoride, etc.) metal carbonate (for example, sodium carbonate, carbonic acid dance). , cesium carbonate, etc.), metal alkoxides (such as sodium methoxide, sodium ethoxide, potassium butoxide, etc.), sodium hydrogencarbonate, sodium metal, organic amines (such as triethylamine, diisopropylethylamine, DBU , 2,6·lutidine, etc.), pyridine, alkyl lithium (n BuU, “Bu # BuU, tert-BuLi), etc. It may not be necessary to use it, and it may be used as it is. As a condensing agent, DCC can be used. Cyclohexylcarbodiimide), BOP (benzotrisinyloxy·tris(dimethylamino)scale hexahydrate), PyBOP, PyBrop, HATU, DppA (azidophosphoric acid diphenyl) S曰) W SC (1-ethyl-3-(3-monomethylaminopropyl)carbodiimide hydrochloride), DMT-MM, etc. Further, such reagents may be, for example, H〇 Su(N•hydroxybutanediimide), HOBt, HOAt, etc. are used in combination. Preferably, an ether (for example, tetrahydroanthracene, two) can be used as the reaction solvent. Ether, dioxane, etc.), N,N-dimethylformamide, N.methylpyrrolidone, N,N-dimethylacetamide, as a base, an organic amine such as triethyl can be used. As the condensing agent, HATU or PyBOP can be used as the condensing agent. The reaction temperature and reaction time are not particularly limited 'usually at room temperature When the reaction is carried out, the reaction may be promoted by heating while the reaction is slow. A method for introducing a substituent into R5 is exemplified below. [Chem. 29] 141666.doc -111- 201028381

(式中，各記號與上述定義相同，由式（B1)、式（RdCOCl)所 表示之化合物、由式（RdNCO)所表示之化合物及由式 (RfS02Cl)所表示之化合物可使用眾所周知之化合物，可使 用由眾所周知之化合物利用常法衍生之化合物。） 若使由式（B1)所表示之化合物於1)所記載之鹼存在下， 與由式（R2-S02C1)所表示之化合物進行反應，則可製造化 合物（B2)。 又，若使由式（B1)所表示之化合物，與由式（R2NCO)所 表示之化合物，於1)所記載之鹼存在下進行反應，則可製 造由式（B3)所表示之化合物。 進而，若使由式（B1)所表示之化合物，與由式（R2COCl) 所表示之化合物於1)所記載之鹼之存在下進行反應，則可 製造由式（B4)所表示之化合物。任一種反應亦可使用1)所 記載之溶劑，反應溫度、反應時間並無特別限定，通常係 於室溫下實施反應，有時亦於反應進行較慢之情形時藉由 141666.doc -112- 201028381 加溫而促進反應。較好的是，溶劑為二氯甲烧等南化飽和 煙類’笨、甲苯等芳香族烴類，或THF等醚類。 於R5中導入由式（-NRbRC)所示基團之情形時，可根據以 下進行製造。 3) [化 30] rVyr2 + &lt; ~~~~^ WR2 φ TfO人N 义 R1 c R、人N 人 R1 、C1 &quot; 〇2 (式中，各記號與上述定義相同，由式（C1)及式（HN_RbRC) 所表示之化合物可使用眾所周知之化合物，可使用由眾所 周知之化合物利用常法衍生之化合物。） 其係使由式（C1)所表示之化合物，與由式（HNRbRC)所 表示之化合物進行反應，製造由式（C2)所表示之化合物的 步驟。反應可於1)所記載之溶劑中進行。較好的是NMP、 • DMA、DMSO、二°惡烧、甲苯、乙醇等醇類。可於反應溫 度為自5(TC至所使用之溶劑回流之溫度下實施，反應速度 較慢之情形時，可使用微波反應裝置升溫至25〇。(：左右。 作為驗’可使用1)所記載之驗，亦可不使用。 作為本發明之其他製造方法，可列舉以下。 4) [化 31] 141666.doc -113- 201028381(wherein each symbol is the same as defined above, and a compound represented by the formula (B1), the formula (RdCOCl), a compound represented by the formula (RdNCO), and a compound represented by the formula (RfS02Cl)) may be a known compound. A compound derived from a well-known compound by a usual method can be used.) The compound represented by the formula (B1) is reacted with a compound represented by the formula (R2-S02C1) in the presence of a base described in 1). Then, the compound (B2) can be produced. Further, when a compound represented by the formula (B1) is reacted with a compound represented by the formula (R2NCO) in the presence of a base described in 1), the compound represented by the formula (B3) can be produced. Further, when a compound represented by the formula (B1) is reacted with a compound represented by the formula (R2COCl) in the presence of a base described in 1), a compound represented by the formula (B4) can be produced. The solvent described in 1) may be used in any of the reactions. The reaction temperature and the reaction time are not particularly limited, and the reaction is usually carried out at room temperature, and sometimes 141666.doc-112 when the reaction is slow. - 201028381 Heating to promote the reaction. Preferably, the solvent is an aromatic hydrocarbon such as a stinky or toluene such as methylene chloride or an ether such as THF. When a group represented by the formula (-NRbRC) is introduced into R5, it can be produced as follows. 3) [化30] rVyr2 + &lt; ~~~~^ WR2 φ TfO person N meaning R1 c R, person N person R1, C1 &quot; 〇2 (wherein the symbols are the same as defined above, by the formula (C1 And a compound represented by the formula (HN_RbRC), a well-known compound can be used, and a compound derived from a well-known compound by a usual method can be used.) The compound represented by the formula (C1), and the compound represented by the formula (HNRbRC) The step in which the compound represented by the reaction is carried out to produce a compound represented by the formula (C2). The reaction can be carried out in the solvent described in 1). Preferred are alcohols such as NMP, • DMA, DMSO, dioxane, toluene, and ethanol. When the reaction temperature is from 5 (TC to the temperature at which the solvent used is refluxed, and the reaction rate is slow, the temperature can be raised to 25 Torr using a microwave reactor. (: Left and right. As the test can be used 1) The test may not be used. As another manufacturing method of the present invention, the following may be mentioned. 4) [31] 141666.doc -113- 201028381

RA2 D2RA2 D2

由式（D1)及式（D2)所表示 知，可使用由眾所周知之 (式中，各記號與上述定義相同，由 之化合物可使用眾所周知之化合物 化合物利用常法衍生之化合物。） 其係使由式（D1)所砉彔夕外人&amp; &amp; k』/T_、~ i _From the formula (D1) and the formula (D2), it is known to use a compound which is well-known (wherein each symbol is the same as defined above, and a compound which is known to be a compound which can be synthesized by a usual method can be used.) By the formula (D1), the foreigner &amp;&amp; k』/T_, ~ i _

之化合物的步驟。The step of the compound.

香族烴類（例如甲苯、苯等）。 鹼可使用1)所言己載之驗。較好的是可使用金屬驗（例如 碳酸鈉、碳酸鈣、碳酸铯、聽化鈉、氟化鉀、氟化鉋、 乙酸鉀、乙酸鈉等）、金屬酵鹽（第三丁醇鈉、第三丁醇鉀 等）、有機胺（例如三乙基胺、二異丙基乙基胺、DBU、 2,6-二甲基吡啶等）。 於把觸媒（例如：Pd(PPh3)4、pdCl2(氣化鈀）、Aromatic hydrocarbons (eg toluene, benzene, etc.). The base can be tested using 1). It is preferred to use a metal test (for example, sodium carbonate, calcium carbonate, barium carbonate, sodium, potassium fluoride, fluorinated planer, potassium acetate, sodium acetate, etc.), metal nitrate (sodium butoxide, first) Potassium tributoxide, etc.), organic amines (eg, triethylamine, diisopropylethylamine, DBU, 2,6-lutidine, etc.). For the catalyst (for example: Pd (PPh3) 4, pdCl2 (gasified palladium),

Pd2(dba)3、Pd(dba)2、Pd(OAc)2、PdCl2(dppf)、PdCl2(PPh3)2 等）與膦配位基（例如：pph3(三苯基膦）、BINAP、Pd2(dba)3, Pd(dba)2, Pd(OAc)2, PdCl2(dppf), PdCl2(PPh3)2, etc.) and phosphine ligands (eg, pph3 (triphenylphosphine), BINAP,

Xantphos、S-Phos、X-Phos、DPPF、t-Bu3P(三第三 丁基三 苯基鱗）、二鄰甲苯基膦等）之存在下，使用之溶劑可於回 流之溫度下反應《反應進行較慢之情形時可使用微波反應 裝置進而使其升溫。 141666.doc •114- 201028381 作為本發明之其他製造方法’可列舉以下 5) [化 32] R3In the presence of Xantphos, S-Phos, X-Phos, DPPF, t-Bu3P (tri-tert-butyltriphenyl scale), di-o-tolylphosphine, etc., the solvent used can react at reflux temperature. In the case of slower conditions, a microwave reactor can be used to raise the temperature. 141666.doc •114- 201028381 As another manufacturing method of the present invention, the following can be cited. 5) [Chem. 32] R3

R2 N E1R2 N E1

E3 R1 +E3 R1 +

n’、r1 E4 Me Me E2 R2 ^1-Β(〇Η)2 rain', r1 E4 Me Me E2 R2 ^1-Β(〇Η)2 rai

Μβ^〇'Β-β，〇Ί^Μβ Me~TO' B'〇4~Me Me Me E6Μβ^〇'Β-β,〇Ί^Μβ Me~TO' B'〇4~Me Me Me E6

E7E7

R^-LG (式中，各記號與上述定義相同，由式（ei)及式所表示 參 之化合物可使用眾所周知之化合物，亦可使用由眾所周知 之化合物利用常法衍生之化合物。「LG」意指離去基可 列舉：齒素、-OMs、-〇Ts、-OTf、_〇Ns 等。此處，「Ms」 表不甲磺醯基、「Ts」表示對曱苯磺醯基、「Tf」表示三氟 曱磺醯基、「Ns」表示鄰硝基苯磺醯基。） 使由式（E1)所表示之化合物與由式（E2)所表示之化合物 、行反應，製造由式（E3)所表示之化合物的步驟可依歡上 述3)記載進行。 可將由式（E3)所表示之化合物之羥基轉換成離去基製 141666.doc -115- 201028381 造由式（E4)所表示之化合物。繼而，若使由式（E4)所表示 之化合物與由式（RA1-B(OH)2)所表示之化合物於鈐木偶合 (Suzuki Coupling)反應之條件下進行反應，則可製造由式 (E5)所表示之化合物。或者，若使由式（E4)所表示之化合 物與由式（RA1-SnBu3)所表示之化合物於Stille偶合反應之 條件下進行反應，則可製造由式（E5)所表示之化合物。鈴 木偶合反應、及Stille偶合反應可使用上述4)中使用之鈀觸 媒、溶劑、及鹼而實施，於Stille偶合反應之情形時亦可 不使用鹼。 又，可將由式（E4)所表示之化合物之離去基轉換成硼 酸，製造由式（E7)所表示之化合物後，繼而與由式（RA1-LG)所表示之化合物進行反應，製造由式（E5)所表示之化 合物。此時，對式（E7)之轉換可使用由式（E4)及式（E6)所 表示之化合物，與自式（E4)向式（E5)轉換中使用之鈀觸 媒、溶劑、及驗而實施。 作為本發明之其他製造方法，可列舉以下。 6) [化 32A]R^-LG (wherein the symbols are the same as defined above, and the compound represented by the formula (ei) and the formula may be a known compound, or a compound derived from a well-known compound by a usual method may be used. "LG" It means that the leaving group can be exemplified by dentate, -OMs, -〇Ts, -OTf, _〇Ns, etc. Here, "Ms" represents no methylsulfonyl group, and "Ts" represents sulfonate, "Tf" represents a trifluorosulfonyl group, and "Ns" represents an o-nitrophenylsulfonyl group.) A compound represented by the formula (E1) is reacted with a compound represented by the formula (E2) to produce The step of the compound represented by the formula (E3) can be carried out in accordance with the above 3). The hydroxyl group of the compound represented by the formula (E3) can be converted into a leaving group. 141666.doc -115- 201028381 A compound represented by the formula (E4) can be produced. Then, if the compound represented by the formula (E4) is reacted with a compound represented by the formula (RA1-B(OH)2) under the reaction of Suzuki Coupling, the formula ( Compound represented by E5). Alternatively, a compound represented by the formula (E5) can be produced by reacting a compound represented by the formula (E4) with a compound represented by the formula (RA1-SnBu3) under the conditions of a coupling reaction of Stille. The Suzuki coupling reaction and the Stille coupling reaction can be carried out using the palladium catalyst, the solvent, and the base used in the above 4), and in the case of the Stille coupling reaction, the base may not be used. Further, the leaving group of the compound represented by the formula (E4) can be converted into boric acid, and the compound represented by the formula (E7) can be produced, and then reacted with a compound represented by the formula (RA1-LG) to produce a compound represented by the formula (E5). In this case, the conversion of the formula (E7) can be carried out using the compound represented by the formula (E4) and the formula (E6), and the palladium catalyst, solvent, and test used in the conversion from the formula (E4) to the formula (E5). And implementation. Other production methods of the present invention include the following. 6) [Chem. 32A]

H2NI 人N 人 R1 F1 (式中，各記號與上述定義相同，由式（F1)及式（F2)所表示 之化合物可使用眾所周知之化合物，亦可使用由眾所周知 之化合物利用常法衍生之化合物。） 141666.doc -116- 201028381 其係使由式（F1)所砉_ 合物於_媒之存在/之化合物與由式(F2)所表示之化 化合物的步驟。該步驟可:應，製造由式㈣所表示之 可以與上述句同樣之條件實施。 作為其他製造方法， _ 步酿胺化。 乂下例示R之取代基之側鏈的進-7) [化 32B]H2NI human N human R1 F1 (wherein each symbol is the same as defined above, and a compound represented by the formula (F1) and the formula (F2) may be a known compound, or a compound derived from a well-known compound by a usual method may be used. 141666.doc -116- 201028381 The step of formulating a compound represented by the formula (F1) in the presence of a medium and a compound represented by the formula (F2). This step can be carried out, and the manufacturing can be carried out under the same conditions as those described above by the formula (4). As a further manufacturing method, _ step amination. Subsequent to the side chain of the substituent of R, -7) [Chemical 32B]

G2 (式中，各記號與上述定義相同，由式（G1)及式（NH_RbRc) 所表示之化合物可使用眾所周知之化合物，亦可使用由眾 所周知之化合物利用常法衍生之化合物。） 其係使由式（G1)所表示之化合物與由式（NHRbRC)所表 示之化合物於驗及縮合劑之存在下反應，製造由式（G2)所 表示之化合物的步驟。該步驟可以與上述〇同樣之條件實 施。 以下例示於R1中導入取代基之製造方法。 8) [化 33] 141666.doc •117· 201028381 RVxR2 H2N人N人U3 FA1G2 (wherein each symbol is the same as defined above, and a compound represented by the formula (G1) and the formula (NH_RbRc) may be a known compound, or a compound derived from a well-known compound by a usual method may be used.) A step of producing a compound represented by the formula (G2) by reacting a compound represented by the formula (G1) with a compound represented by the formula (NHRbRC) in the presence of a test agent and a condensing agent. This step can be carried out under the same conditions as the above. Hereinafter, a method for producing a substituent introduced into R1 will be exemplified. 8) [Chem. 33] 141666.doc •117· 201028381 RVxR2 H2N Ren N U3 FA1

RaONaRaONa

HNHN

,Rb 、RC, Rb, RC

FA4 R2 / RcFA4 R2 / Rc

Rb1-LGRb1-LG

Rbl-LGRbl-LG

(式中，各記號與上述定義相同，由式（fai)所表示之化人 物可使用眾所周知之化合物，亦可使^ 物利用常法衍生之化合物。「LG」意指離去基。以與乂 義相同，係獨立選擇者。作為Ra，可列舉幻_3 若使由式（FA1)所表示之化合物與由式（Ra〇N_表示之 化合物進行反應，則可製造化合物（FA2)。Ra〇Na可藉由 Ra〇H與鈉或氫化鈉進行反應而調製。此時，溶劑可使用 NMP、DMF、四氫呋喃、Ra〇H等，通常於反應溫度為室 溫下實施，但可根據反應進行適宜變更。式（FA1)之化合 物可於RaONa之調製前或調製後之任一情形時添加。添加 式（FA1)後，通常於加溫條件下實施反應。於反應進行較 慢之情形時’可利用微波反應裝置，反應溫度亦可升溫至 250°C左右。 若使由式（FA2)所表示之化合物與式（Rbl-LG)(「LG」意 指離去基）進行反應，則可製造化合物（FA3)。較好的是， 離去基可列舉鹵基或〇Tf基。反應可以與上述6)之方法同 樣之條件實施。 141666.doc • 118 - 201028381 若使由式（FA1)所表示之化合物與由式（HN-RbRe)所表示 之化合物進行反應，則可製造化合物（FA4)。於反應速度 較慢之情形時，可使用微波反應裝置升溫至250度左右。 作為鹼可使用1)所記載之鹼，亦可不使用。作為溶劑，較 好的是 NMP、DMA、DMSO 等。 若使由式（FA4)所表示之化合物與式（Rbl-LG)(「LG」意 指離去基）進行反應，則可製造化合物（FA5)。反應可以與 製造化合物（FA4)時之條件同樣之方法製造。(In the formula, each symbol is the same as defined above, and a person represented by the formula (fai) may use a well-known compound, or may use a compound derived from a conventional method. "LG" means a leaving group. The same is true for the same, and is an independent selector. As Ra, the compound (FA2) can be produced by reacting a compound represented by the formula (FA1) with a compound represented by the formula (Ra〇N_). Ra〇Na can be prepared by reacting Ra〇H with sodium or sodium hydride. In this case, the solvent can be NMP, DMF, tetrahydrofuran, Ra〇H, etc., usually at a reaction temperature of room temperature, but according to the reaction. The compound of the formula (FA1) can be added before or after the preparation of the RaONa. After the addition of the formula (FA1), the reaction is usually carried out under heating conditions. 'The microwave reaction apparatus can be used, and the reaction temperature can be raised to about 250 ° C. If the compound represented by the formula (FA2) is reacted with the formula (Rbl-LG) ("LG" means a leaving group), then A compound (FA3) can be produced. Preferably, it is The group may be a halogen group or a fluorene Tf group. The reaction can be carried out under the same conditions as the method of the above 6). 141666.doc • 118 - 201028381 If the compound represented by the formula (FA1) is made by the formula (HN-RbRe) When the compound is reacted, the compound (FA4) can be produced. When the reaction rate is slow, the temperature can be raised to about 250 degrees using a microwave reactor. The base described in 1) may be used as the base, or may not be used. As the solvent, NMP, DMA, DMSO or the like is preferable. When the compound represented by the formula (FA4) is reacted with the formula (Rbl-LG) ("LG" means a leaving group), the compound (FA5) can be produced. The reaction can be carried out in the same manner as in the case of producing the compound (FA4).

作為其他方法，以下例示於R2中導入取代基之製造方 法。作為轉換R2之方法，可列舉以下。As another method, a method for introducing a substituent into R2 is exemplified below. As a method of converting R2, the following are mentioned.

(式中，各記號與上述定義相同，由式（H1)所表示之化合 物、由式（HC三CRH1)所表示之化合物、由式 (HRH2C=CRH3RH4、（RH6〇)2BRH2C=CRH3RH4)所表示之化合 物及由式（hc(=o)rH5)所表示之化合物可使用眾所周知之 化合物，亦可使用由眾所周知之化合物利用常法衍生之化 141666.doc -119- 201028381 合物。此處，作為RH1、rH2、rH3、rH4及rH5，可列舉作 為烷基、芳基、炔基、烯基、羰基等之適當任意取代基。 該等之取代基於本說明書中例示。又，RH6為烷基或芳 基，可分別與硼原子一起形成環。） 由式（H2)所表示之化合物可將式（H1)鹵化而製造。所謂 該情形時之鹵素（式（H2)之X)意指碘、溴、氣或氟，例如 可使用N-碘丁二醯亞胺、N-溴丁二醯亞胺、N-氯丁二醢亞 胺、Selectfluor、或鹵化納與Chloramine-T(氣胺T)之組合 等鹵化。進行向式（H3)、式（H4)及式（H5)之轉換時，作為 式（H2)之X，較好的是溴或碘。對反應溶劑、反應溫度並 無特別限制，例如可使用二氣曱烷等鹵化烴類、四氫呋喃 等醚類、或乙酸等作為溶劑，反應溫度可自室溫於加熱回 流條件下實施。 由式（H3)所表示之化合物可藉由例如於上述4)中使用之 鈀觸媒、鹼及碘化銅（I)之存在下，使由式（HRh2C= CRH3RH4)所表示之化合物進行反應而製造。對反應溶劑、 反應溫度並無特別限制，例如可使用DMF、DMA、或二甲 氧基乙烷、二噁烷、四氫呋喃等醚類，甲苯、苯等芳香族 烴類等作為溶劑，反應溫度可自室溫於加熱回流條件下實 施。 由式（H4)所表示之化合物可藉由例如於上述4)中使用之 鈀觸媒及鹼存在下，使由式（HRH2C=CRH3RH4)或 ((RH60)2BRH2C=CRH3RH4)所表示之化合物進行反應而製 造。對反應溶劑、反應溫度並無特別限制，例如可使用 141666.doc -120- 201028381 NMP、DMF、DMA、二甲氧基乙烷、二噁烷、四氫呋喃、 甲苯、苯等作為溶劑，反應溫度可自室溫於加熱回流條件 下實施。(wherein each symbol is the same as defined above, and the compound represented by the formula (H1), the compound represented by the formula (HC3 CRH1), and the formula (HRH2C=CRH3RH4, (RH6〇)2BRH2C=CRH3RH4) As the compound represented by the formula (hc(=o)rH5), a well-known compound can be used, and a compound which is derived from a well-known compound by a usual method, 141666.doc-119-201028381 can also be used. RH1, rH2, rH3, rH4, and rH5 may, for example, be any suitable substituents such as an alkyl group, an aryl group, an alkynyl group, an alkenyl group, or a carbonyl group. The substitutions are based on the description in the specification. Further, RH6 is an alkyl group or The aryl group may form a ring together with a boron atom, respectively.) The compound represented by the formula (H2) can be produced by halogenating the formula (H1). The halogen in this case (X of the formula (H2)) means iodine, bromine, gas or fluorine, and for example, N-iodobutylimine, N-bromosuccinimide, N-chlorobutane can be used. Halogenation of ruthenium, Selectfluor, or a combination of halogenated sodium and Chloramine-T (aeroline T). When the conversion to the formula (H3), the formula (H4) and the formula (H5) is carried out, as the X of the formula (H2), bromine or iodine is preferred. The reaction solvent and the reaction temperature are not particularly limited. For example, a halogenated hydrocarbon such as dioxane or an ether such as tetrahydrofuran or acetic acid or the like can be used as a solvent, and the reaction temperature can be carried out at room temperature under heating and reflux conditions. The compound represented by the formula (H3) can be reacted with a compound represented by the formula (HRh2C=CRH3RH4) by, for example, a palladium catalyst, a base and copper (I) iodide used in the above 4). And manufacturing. The reaction solvent and the reaction temperature are not particularly limited, and for example, DMF, DMA, or an ether such as dimethoxyethane, dioxane or tetrahydrofuran, or an aromatic hydrocarbon such as toluene or benzene can be used as a solvent, and the reaction temperature can be used. It is carried out from room temperature under heating under reflux. The compound represented by the formula (H4) can be subjected to a compound represented by the formula (HRH2C=CRH3RH4) or ((RH60)2BRH2C=CRH3RH4), for example, in the presence of a palladium catalyst and a base used in the above 4). Manufactured by reaction. The reaction solvent and the reaction temperature are not particularly limited. For example, 141666.doc -120-201028381 NMP, DMF, DMA, dimethoxyethane, dioxane, tetrahydrofuran, toluene, benzene or the like can be used as a solvent, and the reaction temperature can be used. It is carried out from room temperature under heating under reflux.

由式（H5)所表示之化合物可藉由例如於上述4)中使用之 鈀觸媒、及鹼之存在下，於一氧化碳氣體環境下使一級 胺、二級胺、水或醇進行反應而製造對應之醯胺、羧酸、 酯。對反應溶劑、反應溫度並無特別限制，例如可使用 NMP、DMF、DMA、二甲氧基乙烷、二噁烷、四氫呋喃、 曱苯、苯等作為溶劑，反應溫度可自室溫於加熱回流條件 下實施。 . R4和R5與鄰接之碳原子一起形成環之化合物例如可利用 以下方式製造。 10) [化 35]The compound represented by the formula (H5) can be produced by reacting a primary amine, a secondary amine, water or an alcohol in a carbon monoxide gas atmosphere, for example, in the presence of a palladium catalyst used in the above 4) and a base. Corresponding to decylamine, carboxylic acid, ester. The reaction solvent and the reaction temperature are not particularly limited. For example, NMP, DMF, DMA, dimethoxyethane, dioxane, tetrahydrofuran, toluene, benzene or the like can be used as a solvent, and the reaction temperature can be from room temperature to heating under reflux conditions. Implemented below. A compound in which R4 and R5 form a ring together with an adjacent carbon atom can be produced, for example, in the following manner. 10) [Chem. 35]

(式中，各記號與上述定義相同，由式（II)所表示之化合 物、由式（NeCCR2=CHR3)所表示之化合物、NaORa、RaOH 可使用眾所周知之化合物，亦可使用由眾所周知之化合物 利用常法衍生之化合物。作為Ra，可列舉C1-3烷基。） 由式（12)所表示之化合物可於NaORa存在下，使由 NeCCR2CHR3所表示之化合物與由式（II)所表示之化合物 進行反應而製造12。RaONa可藉由RaOH與鈉或氫化鈉進行 141666.doc -121 - 201028381 反應而調製。此時，溶劑較好的是Ra〇H，通常於反應溫 度為室溫下實施，但可根據反應進行適宜變更。由式 (NsCCR2CHR3)所表示之化合物可於Ra〇Na之調製前或調 製後之任一情形時添加。 於其他實施形態中，例如可利用以下方式製造。 11) [化 36](In the formula, each symbol is the same as defined above, and a compound represented by the formula (II), a compound represented by the formula (NeCCR2=CHR3), NaORa, RaOH may be a known compound, or may be used by a well-known compound. A compound derived from a conventional method. As Ra, a C1-3 alkyl group is exemplified. The compound represented by the formula (12) can be a compound represented by the formula (II) and a compound represented by the formula (II) in the presence of NaORa. The reaction was carried out to produce 12. RaONa can be prepared by reacting RaOH with sodium or sodium hydride in 141666.doc -121 - 201028381. In this case, the solvent is preferably Ra?H, and it is usually carried out at a reaction temperature of room temperature, but may be appropriately changed depending on the reaction. The compound represented by the formula (NsCCR2CHR3) can be added before or after the modulation of Ra?Na. In other embodiments, for example, it can be produced in the following manner. 11) [Chem. 36]

(式中，各記號與上述定義相同，由式（J1)所表示之化合 物、由式（n=ccr2=chr3)所表示之化合物、Na〇Ra、Ra〇H 可使用眾所周知之化合物，亦可使用由眾所周知之化合物 利用常法衍生之化合物《作為Ra，可列舉c i _3燒基。） 由式（J2)所表示之化合物可於乙酸銨存在下，使由 N5CCR2CHR3所表示之化合物與由式（J1)所表示之化合物 進行反應而製造。此時，溶劑可使用甲醇、乙醇、丙醇等 醇類，甲苯、苯等芳香族烴類，二噁烷等醚類對該等並 無特別限制。作為反應溫度，通常於50〜100度下實施，並 無特別限制，可根據反應進行選擇。 於其他實施形態中，本發明之化合物可利用以下方式製 造。 12) [化 37] 141666.doc •122- 201028381(In the formula, each symbol is the same as defined above, and a compound represented by the formula (J1), a compound represented by the formula (n=ccr2=chr3), Na〇Ra, Ra〇H may be used, or a known compound may be used. A compound derived from a well-known compound by a usual method is used. As Ra, a ci _3 alkyl group can be cited. The compound represented by the formula (J2) can be a compound represented by N5CCR2CHR3 in the presence of ammonium acetate. The compound represented by J1) is produced by reacting. In this case, the solvent may be an alcohol such as methanol, ethanol or propanol, an aromatic hydrocarbon such as toluene or benzene, or an ether such as dioxane, which is not particularly limited. The reaction temperature is usually carried out at 50 to 100 °C, and is not particularly limited, and may be selected depending on the reaction. In other embodiments, the compounds of the present invention can be produced in the following manner. 12) [Chem. 37] 141666.doc •122- 201028381

(式中，各記號與上述定義相同，由式（κι)所表示之化合 物、由式（r3c(=o)h)所表示之化合物、由式（r2ch2c=n) 所表示之化合物、NaORa、RaOH可使用眾所周知之化合 物，亦可使用由眾所周知之化合物利用常法衍生之化合 物。作為Ra，可列舉C1-3烷基。） Φ 可於NaORa之存在下，使由式（R3C(=0)H)所表示之化合 物、由式（R2CH2C=N)所表示之化合物，與由式（K1)所表示 之化合物進行反應而製造K2。RaONa可藉由RaOH與鈉或 氫化鈉進行反應而調製。此時，溶劑較好的是RaOH，反 應溫度通常於室溫下實施，但可根據反應進行適宜變更。 由式（K1)所表示之化合物、由式（r3c(=o)h)所表示之化合 物、及由式（R2CH2C=N)所表示之化合物較好的是於RaONa 之調製後添加。 m 本發明之製造可藉由對上述較好之實施形態加以適宜改 變、或者組合、或者附加眾所周知之技術而實施。 本發明之化合物可使用保護基而進行保護。例如，代表 性而言，表示鹵素（I、Br、C卜F等）、低級（此處，代表性 而言，表示C1-C6，但並不限定於此）烷氧基、低級烷硫 基、低級烷基磺醯氧基、芳基磺醢氧基等。）中，可藉由 於該領域利用眾所周知之方法將適宜之取代基保護來製 造。作為此種保護基，例如可列舉：乙氧基羰基、第三丁 141666.doc -123 - 201028381 氧基幾基、乙醢基、苄基等Protective Groups in Organic Synthesis, T. W. Green著，John Wiley &amp; Sons Inc. (1981 年）等中記載之保護基。保護基之導入及離去方法可為有 機合成化學中常用之方法[例如參照Protective Groups in Organic Synthesis，T. W. Greene著，John Wiley &amp; Sons Inc. (1981年）]等中記載之方法或者依據該等而獲得。又， 各取代基中所含之官能基之轉換，除上述製造法以外亦可 利用眾所周知之方法[例如Comprehensive Organic Transformations，R. C. Larock著（1989年）等]進行，本發明 之化合物中亦有可將其作為合成中間體進而導入至新穎之 衍生物中者。上述各製造法之中間體及目標化合物可賦予 至有機合成化學中常用之純化法，例如中和、過濾、萃 取、清洗、乾燥、濃縮、再結晶、各種層析法等中而進行 分離純化。又，就中間體而言，亦可不進行特別純化而供 於下一反應。 (TTK蛋白激酶） 所謂「TTK蛋白激酶」係指專利文獻3中所記載、定義 之酶，例如可列舉含有作為Genbank NM_003 3 1 8而登陸之 胺基酸排列，或者於該胺基酸排列中，缺失、加成、*** 或取代1個或數個胺基酸而成且具有激酶活性之胺基酸排 列的多肽等。此處，就較好之胺基酸排列而言，可採用專 利文獻3中列舉之任意者。此處，所謂「TTK蛋白激酶之 活性」及「TTK活性」意指蘇胺酸及/或絲胺酸及/或酪胺 酸之磷酸化。例如，可列舉p38MAPK(參照專利文獻3)中 141666.doc -124- 201028381 第180號之蘇胺酸及/或第182號之酪胺酸之磷酸化。TTK活 性可使用專利文獻3之篩選方法中所使用之測定方法進行 測定。多肽是否具有激酶活性，例如可藉由使多肽、ΤΤΚ 活性測定用受質及磷酸基供體接觸，測定ΤΤΚ活性，與相 同條件之野生型ΤΤΚ蛋白激酶之ΤΤΚ活性進行比較而研 究。可利用眾所周知之ΤΤΚ活性測定用受質及磷酸供體。 又，亦可使用本發明所記載之新穎ΤΤΚ活性測定用受質。 就ΤΤΚ活性而言，可參考非專利文獻1中記載者。並且， ® ΤΤΚ活性之測定例如可列舉專利文獻3中所記載者。並 且，ΤΤΚ蛋白激酶可為具有ΤΤΚ蛋白激酶活性之多肽， 即，可為含有作為激酶活性區而眾所周知之專利文獻3中 記載之胺基酸排列中，可缺失、加成、***或取代1個或 數個胺基酸，且具有激酶活性之胺基酸排列的多肽。多肽 之總長或修飾基之加成、胺基酸殘基之改變等可視需要適 宜選擇，並不僅限定於本說明書中所記載之排列。因此， 於本說明書中，僅稱為「ΤΤΚ」時，只要無特別註釋，亦 @ 理解成與該「ΤΤΚ蛋白激酶」定義相同使用。再者，ΤΤΚ 有以下別名，亦可參照此。 ΤΤΚ—ΤΤΚ蛋白激酶（TTK PROTEIN KINASE) hMPSl —人單極紡錘體 l(human MONOPOLARSPINDLE 1) PYT—磷酸酪胺酸-精選 蘇胺酸激酶 (PHOSPHOTYROSINE-PICKED THREONINE KINASE) MPS1L1—單極紡錘體 1-狀 l(MONOPOLARSPINDLE 1-LIKE 1) 141666.doc -125 - 201028381 ESK—ESK、小白鼠ESK(=EC STY激酶）之同系物（ESK ; MOUSE HOMOLOG OF ESK(=EC STY Kinase)) 利用本發明之筛選方法獲得之化合物或其鹽可發揮治療 或預防與TTK活性上升相關發病之疾病的作用。例如，根 據本發明之篩選方法，可篩選對與TTK活性上升相關而發 病之癌、免疫疾病等有效之治療劑或預防劑的候補化合 物。 作為上述「癌」，可例示實質癌、血管瘤、血管内皮 瘤、肉瘤、卡波西氏肉瘤（kaposi sarcoma)及造血器官腫瘤 等各種惡性新生物，包含大腸癌及肝癌等，進而亦包含該 等癌之轉移。本發明成功發現具有如下特定特性之新穎的 一系列化合物：抑制TTK激酶之作用，於將治療上述疾病 之醫藥品製劑化時特別有用。特別是，本化合物可用於作 為實體腫瘤或血液腫瘤之任一者而產生的已知TTK激酶為 活性之如癌之類之增生性疾病之治療中，尤其是可用於結 腸直腸癌、乳癌、肺癌、***癌、胰臟癌或膀胱癌及腎 癌，同樣地如白血病及淋巴瘤之類之疾病中。 作為「免疫疾病」，例如可例示異位、哮喘、風濕、膠 原病、過敏等。 又，利用本發明之化合物或其鹽，提供一種用以治療或 預防與TTK蛋白激酶相關之疾病，例如TTK蛋白激酶參與 之癌、免疫疾病等的醫藥組合物。 上述醫藥組合物之一個特徵在於含有本發明之化合物或 其鹽作為有效成分。因此，該醫藥組合物對與TTK蛋白激 141666.doc •126- 201028381 酶相關發病之疾病，發揮可經由抑制該酶之活性而起作用 ，優異，果。例如，本發明之醫藥組合物對癌、免疫疾病 等尤其是與TTK活性相關而發病之癌、免疫疾病等，發揮 可經由抑制該酶之活性而起作用之優異效果。使用該醫藥 組合物治療或預防癌之情形時，亦可於實施通常之癌症产 療法，例如放射線療法、化學療法、尤其是用以使_細 胞事先感應化之DNA劣化劑之同時或其之前使用。(wherein each symbol is the same as defined above, a compound represented by the formula (κι), a compound represented by the formula (r3c(=o)h), a compound represented by the formula (r2ch2c=n), NaORa, As the RaOH, a well-known compound can be used, and a compound derived from a well-known compound by a usual method can also be used. As Ra, a C1-3 alkyl group can be cited.) Φ can be obtained by the formula (R3C(=0) in the presence of NaORa. H) The compound represented by the formula (R2CH2C=N) is reacted with a compound represented by the formula (K1) to produce K2. RaONa can be prepared by reacting RaOH with sodium or sodium hydride. In this case, the solvent is preferably RaOH, and the reaction temperature is usually carried out at room temperature, but may be appropriately changed depending on the reaction. The compound represented by the formula (K1), the compound represented by the formula (r3c(=o)h), and the compound represented by the formula (R2CH2C=N) are preferably added after the preparation of RaONa. m The manufacture of the present invention can be carried out by appropriately changing the above-described preferred embodiments, or by combining or adding well-known techniques. The compounds of the invention may be protected using a protecting group. For example, it is a halogen (I, Br, C, F, etc.), and a lower level (herein, it is a C1-C6, but is not limited to this), alkoxy, lower alkylthio , lower alkylsulfonyloxy, arylsulfonyloxy and the like. In this case, it can be produced by the use of well-known methods in the field to protect the appropriate substituents. Examples of such a protective group include an ethoxycarbonyl group, a third group of 141666.doc-123-201028381, an oxy group, an ethyl group, a benzyl group, and the like, Protective Groups in Organic Synthesis, TW Green, John Wiley &amp;; Protecting groups described in Sons Inc. (1981) and others. The method of introducing and removing the protecting group may be a method generally used in organic synthetic chemistry [for example, refer to the method described in Protective Groups in Organic Synthesis, TW Greene, John Wiley &amp; Sons Inc. (1981)] or the like. Wait and get. Further, the conversion of the functional group contained in each substituent may be carried out by a known method (for example, Comprehensive Organic Transformations, RC Larock (1989), etc.) in addition to the above production method, and the compound of the present invention may also be used. It is introduced as a synthetic intermediate into a novel derivative. The intermediates and target compounds of the above various production methods can be subjected to purification methods commonly used in organic synthetic chemistry, such as neutralization, filtration, extraction, washing, drying, concentration, recrystallization, various chromatography, and the like. Further, in the case of the intermediate, it may be supplied to the next reaction without special purification. (TTK protein kinase) The term "TTK protein kinase" refers to an enzyme described and defined in Patent Document 3, and examples thereof include an amino acid array which is deposited as Genbank NM_003 3 18 or in the amino acid array. A polypeptide which is deleted, added, inserted or substituted with one or several amino acids and has a kinase-active amino acid arrangement. Here, as for the preferred amino acid arrangement, any of those listed in Patent Document 3 can be employed. Here, the "activity of TTK protein kinase" and "TTK activity" mean phosphorylation of threonine and/or serine and/or tyrosine. For example, p18MAPK (refer to Patent Document 3) 141666.doc-124-201028381 No. 180 of threonine and/or 182th tyrosine phosphorylation. The TTK activity can be measured by the measurement method used in the screening method of Patent Document 3. Whether or not the polypeptide has a kinase activity can be measured by, for example, contacting a polypeptide, a ruthenium activity measurement target, and a phosphate donor, and measuring the ruthenium activity, and comparing it with the ΤΤΚ activity of wild-type ΤΤΚ protein kinase under the same conditions. A well-known substrate for the measurement of the activity and the phosphate can be used. Further, the substrate for measuring the activity of the novel oxime activity described in the present invention can also be used. For the hydrazine activity, the one described in Non-Patent Document 1 can be referred to. Further, for example, the measurement of the activity of the ® ΤΤΚ is described in Patent Document 3. Further, the prion protein kinase may be a polypeptide having prion protein kinase activity, that is, an amino acid sequence described in Patent Document 3 which is known as a kinase active region, and may be deleted, added, inserted or substituted. Or a plurality of amino acid-containing polypeptides having a kinase-active amino acid array. The total length of the polypeptide or the addition of the modifying group, the change of the amino acid residue, and the like may be appropriately selected as needed, and are not limited to the arrangement described in the present specification. Therefore, in the present specification, when it is simply referred to as "ΤΤΚ", it is understood to be used in the same manner as the definition of "ΤΤΚ protein kinase" unless otherwise noted. Furthermore, ΤΤΚ has the following alias, and can also refer to this. TTK PROTEIN KINASE hMPSl — human MONOPOLARSPINDLE 1 PYT-phosphotyrosine-selective sulphate kinase (PHOSPHOTYROSINE-PICKED THREONINE KINASE) MPS1L1—monopolar spindle 1- Isomorphism (MONOPOLARSPINDLE 1-LIKE 1) 141666.doc -125 - 201028381 ESK-ESK, homolog of ESK (=EC STY kinase) (ESK; MOUSE HOMOLOG OF ESK (=EC STY Kinase)) The compound obtained by the screening method or a salt thereof can exert a function of treating or preventing a disease associated with an increase in TTK activity. For example, according to the screening method of the present invention, candidate compounds which are effective therapeutic or prophylactic agents for cancers, immune diseases, and the like which are associated with an increase in TTK activity can be screened. Examples of the "cancer" include various malignant neoplasms such as parenchymal carcinoma, hemangioma, hemangioendothelioma, sarcoma, kaposi sarcoma, and hematopoietic organ tumor, including colorectal cancer and liver cancer, and the like. The transfer of cancer. The present inventors have succeeded in discovering a novel series of compounds having the specific properties of inhibiting the action of TTK kinase, which is particularly useful in formulating pharmaceuticals for treating the above diseases. In particular, the present compound can be used in the treatment of a proliferative disease such as cancer in which a known TTK kinase is produced as a solid tumor or a blood tumor, and particularly useful for colorectal cancer, breast cancer, lung cancer. , prostate cancer, pancreatic cancer or bladder cancer and kidney cancer, as well as diseases such as leukemia and lymphoma. Examples of the "immune disease" include ectopic, asthma, rheumatism, collagen disease, and allergy. Further, the compound of the present invention or a salt thereof provides a pharmaceutical composition for treating or preventing a disease associated with TTK protein kinase, for example, a cancer involving TTK protein kinase, an immune disease, or the like. One of the above pharmaceutical compositions is characterized by containing a compound of the present invention or a salt thereof as an active ingredient. Therefore, the pharmaceutical composition acts on a disease associated with the TTK protein 141666.doc • 126-201028381 enzyme, and acts by inhibiting the activity of the enzyme, which is excellent. For example, the pharmaceutical composition of the present invention exhibits an excellent effect of inhibiting the activity of the enzyme, such as cancer, immune diseases, and the like, particularly cancers and immune diseases which are associated with TTK activity. When the pharmaceutical composition is used for the treatment or prevention of cancer, it can also be used at the same time as or before the conventional cancer-producing therapy, such as radiation therapy, chemotherapy, especially a DNA degradation agent for inducing _ cells to be inductively induced. .

上述醫藥組合物中上述化合物或其鹽之含量可根據治療 目的之疾病、患者之年齡、體重等而適宜調節，可為治療 上之有效量，較理想的是，於低分子化合物或高分子化合 物之情料’例如為請心则mg，較好的是請i〜⑽ mg，於多肽或其衍生物之情形時，例如為〇 〇〇〇ι〜ι〇〇〇 mg，較好的是0.001〜100 mg，於核酸或其衍生物之情形 時，例如為〇.〇〇〇01〜100„1§，較好的是〇〇〇〇1〜1〇叫。/ 上述醫藥組合物可進而含有可穩定保持上述化合物或其 鹽之各種助劑。具體而言，可列舉：呈現直至有效成分到 達成為送達對象之部位為止之期間抑制有效成分分解之性 質的藥學上可容許之助劑、賦形劑、黏合劑、穩定劑、緩 衝劑、溶解辅助劑、等張劑等。 上述醫藥組合物之投予形態根據有效成分之種類；成為 投予對象之個體、器官、局部部位、組織；成為投予對象 之個體之年齡、體重等而適宜選擇^作為上述投予形態， 可列舉：皮下注射、肌肉注射、靜脈注射、局部投予等。 又，上述醫藥組合物之投予量亦根據有效成分之種類； 141666.doc -127· 201028381 成為投予對象之個體、器官、局部部位、組織；成為投予 對象之個體之年齡、體重等而適宜選擇◦作為投予並無特 別限定，有效成分為低分子化合物或高分子化合物之情形 時，作為上述有效成分之量’例如可列舉以0 mg/kg體重、較好的是〇.〇〇1〜1〇〇 mg/kg體重，多肽或其衍 生物之情形時’例如0.0001〜1000 mg/kg體重、較好的是 0.001〜100 mg/kg體重，核酸或其衍生物之情形時，例如 0·00001〜100 mg/kg體重、較好的是0.0001〜10 mg/kg體重j 次投予量之方式，每天投予複數次，例如1〜3次。 _ (醫藥） 本發明之化合物或其製藥上所容許之鹽亦可直接單獨投 予，但較好的是通常作為各種醫藥製劑提供。又，該等醫 藥製劑用於動物及人。 投予路徑較好的是使用治療時最有效果者，可列舉口服 或例如直腸内、口腔内、皮下、肌肉内、靜脈内等非口 服。 作為投予形態，有膠囊劑、錠劑、顆粒劑、粉劑、糖漿_ 劑、乳劑、栓劑、注射劑等。口服投予適當之例如乳劑= 糖裂劑之類之液體調製物可使用水，蔑糖、山梨糖醇、果 糖等糖類，聚乙二醇、丙二醇等二醇類，芝麻油、撤揽 ’由、大豆油等油類，對羥基苯甲酸酯類等防腐劑，草莓香 料、薄荷等香料類等而製造。又，膠囊劑、錠劑、粉劑、 顆粒劑等可使用乳糖、葡萄糖、蔑糖、甘露醇等賦形劑， 殿粉、海藻酸鈉等崩解劑，硬脂酸鎮、滑石等潤滑劑，聚 141666.doc •128· 201028381 乙稀醇、㈣基纖維素、明料黏合劑，脂肪酸s旨等界面 活性劑，甘油等塑化劑等而製造。 非口服投予適當之製劑較好的S包含含有與接受者 (recipient)之血液等張之活性化合物的㈣水性製劑。例 如’於注射劑之情科，使用包含鹽溶液、葡萄糖溶液或 鹽水與葡萄糖溶液之混合物之載體等而調製注射用溶液。 局部製劑係使活性化合物溶解或懸浮於1種或其以上之 介質中命J如礦物油、石油、多元醇等或局部醫藥製劑所 使用之其他基劑中而調製。 用以腸内投予之製劑可使用通常之載體，例如可可脂、 氫化脂肪、氫化脂肪幾酸等而調製，製成栓劑而提供。 於本發明t ’非口服劑中亦可添加選自口服劑中所例示 醇員’由類、香料類、防腐劑（包含抗氧化劑）、賦形 劑、崩解劑、潤滑劑、黏合劑、界面活性劑、塑化劑等令 之1種或其以上之輔助成分。The content of the above compound or a salt thereof in the above pharmaceutical composition can be appropriately adjusted depending on the disease for the purpose of treatment, the age, body weight, and the like of the patient, and can be a therapeutically effective amount, and preferably, a low molecular compound or a high molecular compound. The facts are, for example, mg for the heart, preferably i~(10) mg, in the case of a polypeptide or a derivative thereof, for example, 〇〇〇〇ι~ι〇〇〇mg, preferably 0.001. ～100 mg, in the case of a nucleic acid or a derivative thereof, for example, 〇.〇〇〇01~100„1§, preferably 〇〇〇〇1~1 〇./ The above pharmaceutical composition may further contain The auxiliaries which are capable of stably retaining the above-mentioned compound or a salt thereof, and pharmaceutically acceptable additives which inhibit the decomposition of the active ingredient until the active ingredient reaches the site to be delivered are exemplified. a drug, a binder, a stabilizer, a buffer, a dissolution aid, an isotonic agent, etc. The administration form of the above pharmaceutical composition is based on the type of the active ingredient; the individual, the organ, the local part, and the tissue to be administered; The age, body weight, and the like of the subject to be administered are appropriately selected. The above-mentioned administration form may be, for example, subcutaneous injection, intramuscular injection, intravenous injection, topical administration, etc. Further, the administration amount of the above pharmaceutical composition is also effective. 141666.doc -127· 201028381 The individual, the organ, the local part, and the tissue to be administered, and the age, weight, and the like of the individual to be administered are appropriately selected. The administration is not particularly limited, and the active ingredient is not particularly limited. In the case of a low molecular compound or a polymer compound, the amount of the above-mentioned effective ingredient 'is, for example, 0 mg/kg body weight, preferably 〇.〇〇1 to 1〇〇mg/kg body weight, polypeptide or In the case of a derivative, for example, 0.0001 to 1000 mg/kg body weight, preferably 0.001 to 100 mg/kg body weight, in the case of a nucleic acid or a derivative thereof, for example, 0·00001 to 100 mg/kg body weight, preferably It is a method of administration of 0.0001 to 10 mg/kg body weight j times, and is administered a plurality of times per day, for example, 1 to 3 times. _ (Pharmaceutical) The compound of the present invention or a pharmaceutically acceptable salt thereof can also be directly administered alone. But more It is usually provided as various pharmaceutical preparations. Moreover, such pharmaceutical preparations are used for animals and humans. The route of administration is preferably the most effective when used for treatment, and may be exemplified by oral or intrarectal, intraoral, subcutaneous, and intramuscular. Oral, intravenous, etc. Non-oral. As a dosage form, there are capsules, troches, granules, powders, syrups, emulsions, suppositories, injections, etc. Oral administration such as emulsion = cleavage agent or the like Liquid preparations may use water, sugars such as sucrose, sorbitol, fructose, glycols such as polyethylene glycol and propylene glycol, sesame oil, oils such as soybean oil, soybean oil, etc., and anti-corrosion of parabens. It is produced by using a fragrance such as a strawberry flavor or a mint. Further, for capsules, troches, powders, granules, and the like, excipients such as lactose, glucose, sucrose, and mannitol, disintegrators such as fenya powder and sodium alginate, and lubricants such as stearic acid and talc may be used. Poly 141666.doc •128· 201028381 Made of ethylene glycol, (tetra) cellulose, clear binder, fatty acid s, etc., surfactants, plasticizers such as glycerin. Non-oral administration of a suitable preparation Preferably, S comprises (4) an aqueous preparation containing an isotonic active compound with blood of the recipient. For example, in the case of an injection, a solution containing a salt solution, a glucose solution or a mixture of saline and a glucose solution or the like is used to prepare an injection solution. The topical preparation is prepared by dissolving or suspending the active compound in one or more mediums such as mineral oil, petroleum, polyol, or the like, or other bases used in topical pharmaceutical preparations. The preparation for enteral administration can be prepared by using a usual carrier such as cocoa butter, hydrogenated fat, hydrogenated fatty acid or the like to prepare a suppository. In the t 'non-oral agent of the present invention, an alcoholic agent selected from the group consisting of an oral agent, a fragrance, a preservative (including an antioxidant), an excipient, a disintegrant, a lubricant, a binder, and the like may be added. An auxiliary component of one or more of a surfactant, a plasticizer, or the like.

本發月之化合物或其製藥上所容許之鹽的有效用量及投 予數根據技予形態、患者之年齡、體重、應治療之症狀 的法質或嚴重度等而不同，通常而言投予量為每天 曰0 mg/人，較好的是5〜500 mg/人，投予次數較好 的是1天1次或分割投予。 發月之化口物較好的是篩選使用ρ38ΜΑρκ狀之具有 酶活丨生抑制作用之化合物之情形時的，以 ，受檢物質之情形時的螢光值為基準’具有受檢物質之抑 '為1 μΜ以下、較好的是G.l μΜ以下、更好的是0.01 141666.doc •129· 201028381 μΜ以下之值者，或者筛選癌細胞增生抑制化合物（A549分 析）之情形時，具有10 ηΜ〜10 μΜ之範圍内、較好的是未滿 10 μΜ、更好的是未滿1 μΜ之IC50值的化合物。 就與製劑化相關之進一步之資訊而言，可參照 Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990年第 5卷 第25.2章。 本發明亦係關於一種製造本發明之醫藥組合物之系統、 裝置、套組。可理解成此種系統、裝置、套組之構成要件 可利用該領域中眾所周知者，業者可進行適宜設計。 本發明亦係關於一種使用本發明之化合物、其製藥上所 容許之鹽、或者其等之溶劑合物之系統、裝置、套組。可 理解成此種系統、裝置、套組之構成要件可利用該領域中 眾所周知者，業者可進行適宜設計。 本發明之化合物係具有作為醫藥之有用性之化合物。此 處，作為醫藥之有用性，包含代謝穩定性較好之方面，藥 物代謝酶之衍生亦較少之方面，抑制代謝其他藥劑之藥物 代謝酶亦較小之方面，口服吸收性較高之化合物之方面， 間隙較小之方面，或為了表現藥效半生期足夠長之方面 等。 本說明書中引用之科學文獻、專利、專利申請等之參考 文獻的整體以與分別具體記載者相同之程度地於本說明書 中作為參考而引用。 [實施例] 141666.doc -130· 201028381 以下，利用實施例對本發明加以更詳細之說明，但並非 由該實施例等而限定本發明之技術範圍》 使用機器及測定條件等係採用下述所記載者。 LC/MS分析使用Waters公司之系統（ZQ2000質量檢測 器；1525 HPLC泵；2996光電二極體陣列檢測器；2777自 動採樣器）。分析使用逆相C18管柱（Phenomenex，Luna C18(2)，4·〇χ50 mm, 5 μΜ)，使用水/ 乙腈（0.1% 甲酸）作為 溶析溶劑。溶析條件係以流速3 mL/分鐘，以5〜100%乙腈 ® (3分鐘線性梯度）、及100%乙腈（1分鐘）而實施。記載之 LC/MS tR表示LC/MS分析之目標化合物之滯留時間（分 鐘），峰值檢測使用254 nm之UV。 逆相等分試樣液相層析法使用Waters公司之系統實施 (ZQ 2000質量檢測器；2525 HPLC泵；2996光電二極鱧陣 列檢測器；2777自動採樣器）。使用逆相C18管柱 (Phenomenex, Luna C18(2), 21.5x50 mm, 5 μΜ)，使用水/ 乙腈（0.1%甲酸）作為溶析溶劑。溶析條件係以流速25 mL/ 分鐘，以10-100%乙腈（5分鐘線性梯度）、及100%乙腈（2 分鐘）而實施。 矽膠層析法使用山善（YFLC-Wprep2XY)、Molitec(Purif-α2)、或 Isco公司（Combi Flash Companion)之系統。管柱使 用山善之Hi-Flash eolumn(S〜5 L)，溶析溶劑使用己烧/乙 酸乙酯或者氣仿/甲醇。 1H NMR 光譜使用 Varian Gemini-300(300 MHz)、或 Bruker AV-400(400 MHz)進行測定。化學位移以TMS(四甲 141666.doc -131 - 201028381 基矽烷）為内部標準，以δ值（ppm)進行記載。分析結果中 使用s:單峰、d:雙峰、t:三重峰、q:四重峰、m:多 重峰、br :寬作為略語。 微波反應裝置使用Biotage公司之initiator 8或initiator 60 ° (評價方法） 使用p38 MAPK肽之具有TTK激酶活性抑制作用之化合 物的篩選 將 1·〇 μΐ 受檢物質（溶劑：10%(v/v) DMSO)、5 μΐ 之 TTK 溶液（組成·· 4 pg/ml 之 TTK、25 mM 之 Tris-HCl、pH 值為 7.5、5 mM之β-甘油磷酸酯、2 mM之DTT、0.1 mM之 Na3V04、5 mM 之 MgCl2、0.1%(w/v)BSA)、5 μΐ 受質溶液 (組成：60 μΜ之ρ38 MAPK肽、60 μΜ之 ATP、25 mM之 Tris-HCl、pH值為7.5、5 mM之β-甘油填酸酯、2 mM之 DTT、0.1 mM之Na3V04、5 mM之MgCl2、0.1%(w/v) BSA) 於聚丙烯製384孔微量滴定盤（康寧公司）中混合，放入至恆 溫濕潤器中。以溫度為25°C、濕度為95%靜置一晚後，添 加50 μΐ反應停止液（組成：25 mM之Tris-HCl、pH值為 7·5、100 mM 之 EDTA、0.01%(v/v) Triton X-100、 0.1%(w/v)BSA)加以混合。 自此處抽取1.7 μΐ，於聚丙烯製384孔微量滴定盤（康寧 公司）中與60 μΐ反應停止液混合後，將40 μΐ移至384孔黑色 NeutrAvidin板（Pias公司）中，加以密封後於室溫下培養30 分鐘。將板於100 μΐ TTBS(組成：10 mM之Tris、40 mM之 141666.doc -132- 201028381The effective amount of the compound of the present month or the pharmaceutically acceptable salt thereof and the amount of the administration vary depending on the technical form, the age, weight of the patient, the circumstance or severity of the symptom to be treated, etc., usually administered The amount is mg0 mg/person per day, preferably 5 to 500 mg/person, and the number of administrations is preferably once a day or divided. It is preferable to use a compound having a ρ38ΜΑρκ-like compound having an inhibitory effect on the activity of the enzyme, so that the fluorescence value in the case of the substance to be tested is based on the fact that it has the substance to be tested. 'When it is 1 μΜ or less, preferably G1 μΜ or less, more preferably 0.01 141666.doc •129· 201028381 μΜ or less, or when screening cancer cell proliferation inhibitory compounds (A549 analysis), it has 10 In the range of η Μ 10 10 μΜ, preferably less than 10 μΜ, more preferably a compound having an IC50 value of less than 1 μΜ. For further information on formulation, refer to Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press, Vol. 5, No. 25.2. The invention also relates to a system, apparatus, kit for making a pharmaceutical composition of the invention. It can be understood that the components of such a system, apparatus, and kit can be utilized by those skilled in the art, and the operator can make an appropriate design. The invention also relates to a system, apparatus, kit for using a compound of the invention, a pharmaceutically acceptable salt thereof, or a solvate thereof. It can be understood that the components of such systems, devices, and kits can be utilized by those skilled in the art and can be suitably designed. The compound of the present invention has a compound useful as a medicine. Here, as the usefulness of the medicine, the aspect in which the metabolic stability is better, the derivative of the drug-metabolizing enzyme is also less, the drug-metabolizing enzyme which inhibits the metabolism of other agents is also small, and the compound which is orally absorbed is high. In terms of the smaller gap, or in order to show that the half-life of the drug is long enough. The entire contents of the references, such as the scientific literature, patents, patent applications, and the like, which are incorporated herein by reference in their entirety in their entireties in the the the the the the [Examples] 141666.doc -130· 201028381 Hereinafter, the present invention will be described in more detail by way of examples, but the technical scope of the present invention is not limited by the examples and the like. Recorder. The LC/MS analysis used a system from Waters Corporation (ZQ2000 mass detector; 1525 HPLC pump; 2996 photodiode array detector; 2777 autosampler). The analysis used a reverse phase C18 column (Phenomenex, Luna C18 (2), 4·〇χ 50 mm, 5 μΜ) using water/acetonitrile (0.1% formic acid) as the solvent for the dissolution. The elution conditions were carried out at a flow rate of 3 mL/min with 5 to 100% acetonitrile ® (3 minute linear gradient) and 100% acetonitrile (1 min). The LC/MS tR is reported as the residence time (minutes) of the target compound for LC/MS analysis, and the peak detection uses UV at 254 nm. Reverse equivalence fractions were performed using liquid chromatography using a Waters system (ZQ 2000 mass detector; 2525 HPLC pump; 2996 photodiode array detector; 2777 autosampler). A reverse phase C18 column (Phenomenex, Luna C18 (2), 21.5 x 50 mm, 5 μΜ) was used, using water/acetonitrile (0.1% formic acid) as the solvent for the dissolution. The elution conditions were carried out at a flow rate of 25 mL/min with 10-100% acetonitrile (5 minute linear gradient) and 100% acetonitrile (2 min). For the gelatin chromatography, a system of Yamatake (YFLC-Wprep2XY), Molitec (Purif-α2), or Isco Corporation (Combi Flash Companion) was used. The column uses Hi-Flash eolumn (S~5 L), and the solvent used is hexane/ethyl acetate or gas/methanol. 1H NMR spectra were measured using a Varian Gemini-300 (300 MHz) or Bruker AV-400 (400 MHz). The chemical shift is described by TMS (tetramethyl 141666.doc -131 - 201028381 decane) as an internal standard, and is recorded in δ (ppm). In the analysis results, s: single peak, d: doublet, t: triplet, q: quartet, m: multiplet, br: wide are used as abbreviations. Microwave reaction apparatus using Biotage's initiator 8 or initiator 60 ° (evaluation method) Screening of compounds having inhibition of TTK kinase activity using p38 MAPK peptide 1·〇μΐ Test substance (solvent: 10% (v/v) DMSO), 5 μΐ of TTK solution (composition·4 pg/ml of TTK, 25 mM of Tris-HCl, pH 7.5, 5 mM β-glycerophosphate, 2 mM DTT, 0.1 mM Na3V04, 5 mM MgCl2, 0.1% (w/v) BSA), 5 μΐ substrate (composition: 60 μM ρ38 MAPK peptide, 60 μM ATP, 25 mM Tris-HCl, pH 7.5, 5 mM Β-glycerolate, 2 mM DTT, 0.1 mM Na3V04, 5 mM MgCl2, 0.1% (w/v) BSA) were mixed in a 384-well microtiter plate (Corning) made of polypropylene and placed in In a constant temperature humidifier. After standing at a temperature of 25 ° C and a humidity of 95% for one night, 50 μM reaction stop solution was added (composition: 25 mM Tris-HCl, pH 7.5, 100 mM EDTA, 0.01% (v/) v) Triton X-100, 0.1% (w/v) BSA) is mixed. 1.7 μΐ was taken from here and mixed with 60 μΐ reaction stop solution in a polypropylene 384-well microtiter plate (Corning), and 40 μM was transferred to a 384-well black NeutrAvidin plate (Pias), sealed and then sealed. Incubate for 30 minutes at room temperature. Plate in 100 μΐ TTBS (composition: 10 mM Tris, 40 mM 141666.doc -132- 201028381

Tris-HCl、150 mM之NaCl2、〇.〇5%(v/v) Tween 20)中清洗3 次後，添加40 μΐ之1次抗體溶液（Anti-phosphop38抗體_ 28B10(Cell Signaling公司，#9216))於室溫下培養1小時。 同樣於100 μΐ之TTBS中清洗3次後，添加40 μΐ之2次抗體溶 液（Eu-Nl labeled Anti-mouse IgG(Perkin Elmer 公司， #AD0124))，於室溫下培養30分鐘》將板於100 μΐ之TTBS 中清洗5次後，添加40 μΐ增強液（Perkin Elmer公司），於室 溫下培養5分鐘，利用ARVO(Perkin Elmer公司）測定615 • nm之螢光值。以無受檢物質之情形之螢光值為基準，計算 受檢物質之抑制活性，獲得表示TTK激酶活性抑制作用之 化合物作為TTK活性抑制劑之候補化合物。 癌細胞增生抑制化合物之篩選 利用添加有10%之FBS(Hyclone公司）之D-MEM(拿卡萊 公司（Nacalai Tesque Inc.))(以下稱為培養液），將調整成適 當濃度之細胞浮動液（RERF-LC-AI、A549 : lxl04/ml、 MRC5 : 3xl04/ml 與 lxl05/ml)以 100 μΐ/孔添加至 96 孔板 (以下稱為孔板），於37度C02培養箱中培養1天。將96孔分 析塊内顯示TTK激酶活性抑制作用之1 0 mM之化合物 (100% DMSO溶液）添加2 μΐ至998 μΐ培養液中，製作20 μΜ 溶液，以二倍稀釋系列調製10濃度。其次，向準備細胞之 孔板之各孔中，每次添加100 μΐ/孔之上述化合物稀釋液， 使其成為200 μΐ/孔。其後，進而於37度C02培養箱中培養3 天。向孔板之各孔每次添加1 〇 μΐ之細胞數測定用WST-8套 組（Kishida化學）溶液，於C02培養箱内進行1〜4小時呈色反 141666.doc -133- 201028381 應。利用微盤分析儀測定450 nm(參照波長為620 nm)之吸 光度後，以無受檢物質之情形時之吸光度值為基準，計算 受檢物質之抑制活性，選擇以癌細胞顯示增生抑制作用之 化合物。 (實施例1) 實施例1-1 4-胺基-5-氰基-6-乙氧基-N-苯基甲基吡啶醯胺 [化 1001]After washing 3 times with Tris-HCl, 150 mM NaCl2, 〇.〇5% (v/v) Tween 20), add 40 μM of antibody solution (Anti-phosphop38 antibody _ 28B10 (Cell Signaling, Inc., #9216 )) Incubate for 1 hour at room temperature. After washing 3 times in 100 μM TTBS, 40 μM of antibody solution (Eu-Nl labeled Anti-mouse IgG (Perkin Elmer, Inc., #AD0124)) was added and incubated at room temperature for 30 minutes. After washing 5 times with 100 μM of TTBS, 40 μM of enhancement solution (Perkin Elmer) was added, and the mixture was incubated at room temperature for 5 minutes, and the fluorescence value of 615 • nm was measured by ARVO (Perkin Elmer). The inhibitory activity of the test substance is calculated based on the fluorescence value of the test substance, and a compound which exhibits an inhibitory effect on the activity of TTK kinase is obtained as a candidate compound of the TTK activity inhibitor. Screening of cancer cell proliferation-inhibiting compounds Using D-MEM (Nacalai Tesque Inc.) (hereinafter referred to as a culture solution) supplemented with 10% FBS (Hyclone), cells adjusted to an appropriate concentration were floated. The solution (RERF-LC-AI, A549: lxl04/ml, MRC5: 3xl04/ml and lxl05/ml) was added to a 96-well plate (hereinafter referred to as a well plate) at 100 μM/well and cultured in a 37°C02 incubator. 1 day. A 10 mM compound (100% DMSO solution) showing inhibition of TTK kinase activity in a 96-well assay block was added to a medium of 2 μM to 998 μM to prepare a 20 μL solution, and a concentration of 10 was prepared in a double dilution series. Next, 100 μM/well of the above compound dilution was added to each well of the prepared cell plate to make it 200 μM/well. Thereafter, it was further cultured for 3 days in a 37 degree CO 2 incubator. The number of cells added with 1 〇 μΐ to each well of the well plate was measured with a WST-8 kit (Kishida Chemical) solution, and the color was reversed in a C02 incubator for 1 to 4 hours. 141666.doc -133- 201028381 should be used. After measuring the absorbance at 450 nm (reference wavelength: 620 nm) using a microdisk analyzer, the inhibitory activity of the test substance is calculated based on the absorbance value in the absence of the test substance, and the growth inhibition effect of the cancer cells is selected. Compound. (Example 1) Example 1-1 4-Amino-5-cyano-6-ethoxy-N-phenylmethylpyridinamide [Chemical 1001]

向4_胺基_5_氰基-6-乙氧基吡啶甲酸（US20060173050 A1，實施例 104A)(50 mg，0.24 mmol)、三乙基胺（49 mg， 67 pL，0.48 mmol)、及苯胺（27 mg，26 pL，0.29 mmol)之 NMP(1.5 mL)溶液中添加HATU(119 mg，0.3 12 mol)，搜拌 16小時。向反應溶液中添加水及乙酸乙酯進行分離後，以 乙酸乙醋萃取水相’以飽和碳酸氫納水溶液、〇 · 1 m〇l/L鹽 酸及飽和食鹽水對合併之有機相進行清洗，以硫酸鎂加以 乾燥。將有機相過濾後，進行減壓濃縮，利用逆相等分試 樣液相層析法（C18管柱，水/乙猜/0.1%甲酸；1〇_1 〇〇%梯 度）純化所獲得之殘渣’獲得標題化合物（2〇 9 mg，〇 〇74 mmol，31%)，為白色固體。 1H-NMR (300 MHz, DMSO-d6) δ 1.35 (t, J=6.0 Hz), 4.58 (q? J —6.0 Hz? 2H), 7,14 (s, 2H), 7.14 (t, J=9.〇 Hz) 7 37 (t 141666.doc -134- 201028381 J=9.0 Hz)，7.77 (d，2H, J=9.0 Hz), 10.04 (s，1H)。 MS(ESI)m/z=283 (M+H)+。 實施例1-2 4-胺基-5-氰基-6-乙氧基-N-(4-甲氧基苄基）甲基《比啶醯胺 [化 1002]To 4-amino-5-cyano-6-ethoxypicolinic acid (US20060173050 A1, Example 104A) (50 mg, 0.24 mmol), triethylamine (49 mg, 67 pL, 0.48 mmol), and HATU (119 mg, 0.312 mol) was added to a solution of aniline (27 mg, 26 pL, 0.29 mmol) in NMP (1.5 mL). After adding water and ethyl acetate to the reaction solution for separation, the aqueous phase was extracted with ethyl acetate to wash the combined organic phase with saturated aqueous sodium hydrogencarbonate solution, 〇·1 m〇l/L hydrochloric acid and saturated brine. Dry with magnesium sulfate. After filtering the organic phase, it was concentrated under reduced pressure, and the obtained residue was purified by reverse phase separation liquid chromatography (C18 column, water/b/0.1% formic acid; 1 〇 1 〇〇% gradient). 'The title compound (2 〇 9 mg, 〇〇 74 mmol, 31%) was obtained as white solid. 1H-NMR (300 MHz, DMSO-d6) δ 1.35 (t, J = 6.0 Hz), 4.58 (q? J - 6.0 Hz? 2H), 7,14 (s, 2H), 7.14 (t, J=9 .〇Hz) 7 37 (t 141666.doc -134- 201028381 J=9.0 Hz), 7.77 (d, 2H, J=9.0 Hz), 10.04 (s, 1H). MS (ESI) m / z = 283 (M+H)+. Example 1-2 4-Amino-5-cyano-6-ethoxy-N-(4-methoxybenzyl)methyl "pyridinium amide" [Chem. 1002]

標題化合物係依據實施例1 -1之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 1.31 (t, J=6.9 Hz, 3H), 3.72 (s, 3H), 4.39 (d, J=6.3 Hz, 2H), 4.48 (q, J=7.2 Hz, 2H), 6.87 (d, J=8.7 Hz, 2H), 7.06 (s, 1H), 7.22 (d, J=8.7 Hz，2H)，7.31 (br，2H), 8.96 (t，J=6.0 Hz, 1H)。 實施例1-3 4-胺基-N-(4-胺基苄基）-5-氰基-6-乙氧基甲基&quot;比啶醯胺 [化 1003]The title compound was synthesized according to the method of Example 1-1. 1H-NMR (300 MHz, DMSO-d6) δ 1.31 (t, J = 6.9 Hz, 3H), 3.72 (s, 3H), 4.39 (d, J = 6.3 Hz, 2H), 4.48 (q, J = 7.2 Hz, 2H), 6.87 (d, J=8.7 Hz, 2H), 7.06 (s, 1H), 7.22 (d, J=8.7 Hz, 2H), 7.31 (br, 2H), 8.96 (t, J=6.0) Hz, 1H). Example 1-3 4-Amino-N-(4-aminobenzyl)-5-cyano-6-ethoxymethyl&quot;Bipyridylamine [Chem. 1003]

標題化合物係依據實施例1-1之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 1.30 (t, J=7.2 Hz, 3Η), 4.27 (d, J=6.3 Hz, 2H), 4.46 (q, J=7.2 Hz, 2H), 4.96 (s, 2H), 6.48 (d, J=8.4 Hz, 2H), 6.94 (d, J=8.4 Hz, 2H), 7.05 (s，1H), 7.33 (br，2H)，8.80 (t，J=6.9 Hz, 1H)。 141666.doc -135· 201028381 實施例1-4 N-(3-乙醯胺苄基）-4-胺基-5-氰基-6-乙氧基甲基吼啶醯胺 [化 1004]The title compound was synthesized according to the method of Example 1-1. 1H-NMR (300 MHz, DMSO-d6) δ 1.30 (t, J = 7.2 Hz, 3 Η), 4.27 (d, J = 6.3 Hz, 2H), 4.46 (q, J = 7.2 Hz, 2H), 4.96 ( s, 2H), 6.48 (d, J=8.4 Hz, 2H), 6.94 (d, J=8.4 Hz, 2H), 7.05 (s,1H), 7.33 (br,2H), 8.80 (t, J=6.9 Hz, 1H). 141666.doc -135· 201028381 Example 1-4 N-(3-Acetylbenzyl)-4-amino-5-cyano-6-ethoxymethyl acridineamine [Chem. 1004]

標題化合物係依據實施例1-1之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 1.30 (t, J=6.0 Hz, 3H), 1.99 (s, 3H), 4.42 (d, J=6.0 Hz, 2H), 4.49 (q, J=6.0 Hz, 2H), 6.94 (d, J=6.0 Hz, 1H), 7.07 (s, 1H), 7.21 (t, J=6.0 Hz, 1H), 7.33 (brs, 2H), 7.41 (s, 1H), 7.49 (d, J=6.0 Hz, 1H), 9.04 (t，J=6.0 Hz，1H)。 MS(ESI)m/z=354 (M+H)+。 實施例1-5 4-胺基-5-氰基-6-乙氧基-N-(噻唑-2-基）甲基吼啶醯胺 [化 1005]The title compound was synthesized according to the method of Example 1-1. 1H-NMR (300 MHz, DMSO-d6) δ 1.30 (t, J = 6.0 Hz, 3H), 1.99 (s, 3H), 4.42 (d, J = 6.0 Hz, 2H), 4.49 (q, J = 6.0) Hz, 2H), 6.94 (d, J=6.0 Hz, 1H), 7.07 (s, 1H), 7.21 (t, J=6.0 Hz, 1H), 7.33 (brs, 2H), 7.41 (s, 1H), 7.49 (d, J=6.0 Hz, 1H), 9.04 (t, J=6.0 Hz, 1H). MS (ESI) m / z = 354 (M+H)+. Example 1-5 4-Amino-5-cyano-6-ethoxy-N-(thiazol-2-yl)methyl acridineamine [Chemical 1005]

標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=290 (M+H)+。 LC/MS tR=1.38 min。 實施例1-6 141666.doc -136- 201028381 N-(3-乙醢胺苯基）-4-胺基-5-氰基-6-乙氧基甲基。比啶醯胺 [化 1006]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 290 (M + H) +. LC/MS tR = 1.38 min. Example 1-6 141666.doc -136- 201028381 N-(3-acetamidophenyl)-4-amino-5-cyano-6-ethoxymethyl. Bipyridylamine [Chem. 1006]

標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=340 (M+H)+。 魯 LC/MS tR= 1.25 min。 實施例1-7 4 -胺基-5-亂基-N-(3,4 -二甲乳基苯乙基）-6 -乙氧基曱基σ比 咬醢胺 [化 1007]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 340 (M + H) +. Lu LC/MS tR = 1.25 min. Example 1-7 4 -Amino-5-ranyl-N-(3,4-dimethylphenylethyl)-6-ethoxyindolyl σ ratio Oleamine [Chem. 1007]

標題化合物係依據實施例1-1之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 1.28-1.35 (m, 3H), 2.90 (q, 2H, J=9.0 Hz), 4.35 (q, 2H, J=9.0 Hz), 5.73 (s, 1H), 6.49 (s, 2H), 7.27 (d, 1H, J=9.0 Hz), 7.52 (d, 1H, J=9.0 Hz)，8.01 (s, 1H)，9.24 (s, 1H)。 mp 223-226。。° MS(ESI)m/z=324 (M+H)+。 141666.doc -137- 201028381 LC/MS tR=1.92 min 〇 實施例1-8 4-胺基-5-氰基-6-乙氧基-N-(噻吩-2-基甲基）曱基吡啶醯胺 [化 1008]The title compound was synthesized according to the method of Example 1-1. 1H-NMR (300 MHz, DMSO-d6) δ 1.28-1.35 (m, 3H), 2.90 (q, 2H, J = 9.0 Hz), 4.35 (q, 2H, J = 9.0 Hz), 5.73 (s, 1H ), 6.49 (s, 2H), 7.27 (d, 1H, J=9.0 Hz), 7.52 (d, 1H, J=9.0 Hz), 8.01 (s, 1H), 9.24 (s, 1H). Mp 223-226. . ° MS (ESI) m/z = 324 (M+H)+. 141666.doc -137- 201028381 LC/MS tR=1.92 min 〇Example 1-8 4-Amino-5-cyano-6-ethoxy-N-(thiophen-2-ylmethyl)decylpyridine Guanamine [Chemical 1008]

標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=303 (M+H)+。 LC/MS tR=1.48 min。 實施例1-9 4-胺基-N-(4-氣苯乙基）-5-氰基-6-乙氧基甲基啦啶醯胺 [化 1009]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 303 (M+H)+. LC/MS tR = 1.48 min. Example 1-9 4-Amino-N-(4-phenethylethyl)-5-cyano-6-ethoxymethyl-byrylamine [Chem. 1009]

標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=345 (M+H)+。 LC/MS tR=l.77 min。 實施例1-10 4-胺基-5-氰基-6-乙氧基-N-(2-異丙氧基乙基）甲基》比啶 醯胺 141666.doc -138- 201028381 [化 1010]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 345 (M + H) +. LC/MS tR = 1.77 min. Example 1-10 4-Amino-5-cyano-6-ethoxy-N-(2-isopropoxyethyl)methyl"pyridinium 141666.doc -138- 201028381 [Chemical 1010 ]

標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=293 (M+H)+。 實施例1-11The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 293 (M + H) +. Example 1-11

Ν-(3-(1Η-咪唑-1-基）丙基）-4-胺基-5-氰基-6-乙氧基甲基 吡咬醯胺 [化 1011]Ν-(3-(1Η-imidazol-1-yl)propyl)-4-amino-5-cyano-6-ethoxymethylpyridinium [Chemical 1011]

標題化合物係依據實施例1 -1之方法而合成。 MS(ESI)m/z=315 (M+H)+。The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 315 (M + H) +.

LC/MS tR=0.99 min 〇 實施例1-12 4-胺基-5-氰基-6-乙氧基-N-(3-羥基苯基）甲基°比啶醯胺 [化 1012]LC/MS tR=0.99 min 实施 Example 1-12 4-Amino-5-cyano-6-ethoxy-N-(3-hydroxyphenyl)methyl-pyridinium amide [Chemical 1012]

標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=299 (M+H)+。 LC/MS tR=1.33 min。 141666.doc -139- 201028381 實施例1-13 Ν-(2-(1Η-吲哚-3-基）乙基）_4-胺基-5-氰基-6-乙氧基曱基 °比啶醯胺 [化 1013]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 299 (M+H)+. LC/MS tR = 1.33 min. 141666.doc -139- 201028381 Example 1-13 Ν-(2-(1Η-indol-3-yl)ethyl)-4-amino-5-cyano-6-ethoxyindolylpyridinium Guanamine [Chemical 1013]

標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=350 (Μ+Η)+。 LC/MS tR=1.53 min。 實施例1-14 4-胺基-N-((l -节基D比嘻咬-3-基）曱基）-5 -氛基-6-乙乳基 曱基°比咬醯胺 [化 1014]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 350 (Μ + Η) +. LC/MS tR = 1.53 min. Example 1-14 4-Amino-N-((l-p-group D is more than -3-yl) fluorenyl)-5-aryl-6-ethyl thiol thiol 1014]

標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=366 (M+H)+。 LC/MS tR=l.64 min 〇 實施例1 -15 4-胺基-5-氰基-6-乙氧基-N-(呋喃-2-基甲基）甲基吡啶醯胺 141666.doc -140- 201028381 [化 1015]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 366 (M+H)+. LC/MS tR=1.44 min 〇 Example 1 -15 4-Amino-5-cyano-6-ethoxy-N-(furan-2-ylmethyl)methylpyridinamide 141666.doc -140- 201028381 [化1015]

標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=287 (M+H)+。 LC/MS tR=1.40 min。 實施例1-16The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 287 (M+H)+. LC/MS tR = 1.40 min. Example 1-16

4-胺基-5-氰基-6-乙氧基-N-(l-苯基乙基）甲基&quot;比啶醯胺 [化 1016]4-amino-5-cyano-6-ethoxy-N-(l-phenylethyl)methyl&quot;bipyridylamine [1016]

標題化合物係依據實施例1 -1之方法而合成。 MS(ESI)m/z=311 (M+H)+。 LC/MS tR=1.71 min。The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 311 (M + H) +. LC/MS tR = 1.71 min.

實施例1-17 4-胺基-5-氰基-6-乙氧基-N-(4-氟苄基）曱基。比啶醯胺 [化 1017]Example 1-17 4-Amino-5-cyano-6-ethoxy-N-(4-fluorobenzyl)indenyl. Bipyridylamine [Chem. 1017]

標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=314 (Μ+Η)+。 LC/MS tR=l.59 min。 141666.doc -141 - 201028381 實施例1-18 4-胺基-5-氰基-N-環己基-6-乙氧基曱基°比咬酿私: [化 1018]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 314 (Μ + Η) +. LC/MS tR = 1.59 min. 141666.doc -141 - 201028381 Example 1-18 4-Amino-5-cyano-N-cyclohexyl-6-ethoxy fluorenyl °°Bitter: [Chem. 1018]

標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=289 (M+H)+。 LC/MS Ir=1.76 min 〇 實施例卜19 4-胺基-5-氰基-6-乙氧基-N-(2-(噻吩-2-基）乙基）曱基〇比 啶醯胺 [化 1019]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 289 (M+H)+. LC/MS Ir=1.76 min 〇Example 19 19 Amino-5-cyano-6-ethoxy-N-(2-(thien-2-yl)ethyl)indolylpyridinium amide [化1019]

標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=317 (M+H)+。 LC/MS tR=1.56 min。 實施例1-20 4-胺基-5-氰基-6-乙氧基-N-(3-(2-側氧基吡咯啶_丨_基）丙 基）甲基吡啶醯胺 141666.doc -142- 201028381 [化 1020]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 317 (M+H)+. LC/MS tR = 1.56 min. Example 1-20 4-Amino-5-cyano-6-ethoxy-N-(3-(2-o-oxypyrrolidinyl)-propyl)methylpyridinium 141666.doc -142- 201028381 [化1020]

標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=331 (M+H)+。 LC/MS tR=0.98 min。 實施例1-21 4-胺基-5-亂基-6-乙氧基-N-(2-苯氧基乙基）甲基°比β定酿胺 [化 1021]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 331 (M+H)+. LC/MS tR = 0.98 min. Example 1-21 4-Amino-5-ranyl-6-ethoxy-N-(2-phenoxyethyl)methyl ° ratio β determinate [Chem. 1021]

標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=327 (Μ+Η)+。The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 327 (Μ + Η) +.

LC/MS tR=1.59 min 〇 實施例1-22 4-胺基-5 -亂基-6 -乙氧基-N-(0th °定-2-基甲基）甲基°比0定酿胺 [化 1022]LC/MS tR=1.59 min 〇 Example 1-22 4-Amino-5-ranyl-6-ethoxy-N-(0th °-di-2-ylmethyl)methyl ° ratio [化1022]

標題化合物係依據實施例1_1之方法而合成。 141666.doc -143 - 201028381 MS(ESI)m/z=297 (M+H)+。 LC/MS tR=1.14 min。 實施例1-23 N-(2-乙醯胺乙基）-4-胺基-5-氰基-6-乙氧基曱基吡啶醯胺 [化 1023]The title compound was synthesized according to the method of Example 1_1. 141666.doc -143 - 201028381 MS (ESI) m/z = 297 (M+H)+. LC/MS tR = 1.14 min. Example 1-23 N-(2-acetamidoethyl)-4-amino-5-cyano-6-ethoxymercaptopyridine amine [Chemical 1023]

標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=292 (M+H)+。 LC/MS tR=0.82 min。 實施例1-24 4-胺基-5-乳基-6-乙氧基(秦-1-基曱基）曱基。比唆酿胺 [化 1024]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 292 (M+H)+. LC/MS tR = 0.82 min. Example 1-24 4-Amino-5-lacty-6-ethoxy(qin-1-ylindenyl)fluorenyl. Than brewing amine [化1024]

標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=347 (M+H)+。 LC/MS tR=l.77 min。 實施例1-25 4-胺基-N-(2 -亂基）-5-亂基-6-乙氧基曱基β比α定酿胺 141666.doc -144- 201028381 [化 1025]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 347 (M+H)+. LC/MS tR = 1.77 min. Example 1-25 4-Amino-N-(2-disyl)-5-ranyl-6-ethoxyindolyl β ratio α-nitramine 141666.doc -144- 201028381 [Chemical 1025]

標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=331 (M+H)+。 LC/MS tR=1.74 min。 實施例1-26 ® 4-胺基-5-氰基-6-乙氧基-N-(2-甲氧基苄基）甲基&quot;比啶醯胺 [化 1026]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 331 (M+H)+. LC/MS tR = 1.74 min. Example 1-26 ® 4-Amino-5-cyano-6-ethoxy-N-(2-methoxybenzyl)methyl &quot;Bipyridylamine [Chem. 1026]

標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=327 (Μ+Η)+。 LC/MS tR=1.61 min。 實施例1-27 4-胺基-5-氰基-6-乙氡基-N-(2-曱基苄基）曱基吼啶醯胺 [化 1027]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 327 (Μ + Η) +. LC/MS tR = 1.61 min. Example 1-27 4-Amino-5-cyano-6-ethylindenyl-N-(2-mercaptobenzyl)indolyl acridineamine [Chemical 1027]

標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=311 (M+H)+。 141666.doc -145- 201028381 LC/MS tR=1.67 min。 實施例1-28 4-胺基-5-氰基-6-乙氧基-N-(3-曱氧基苄基）甲基。比啶醯胺 [化 1028]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 311 (M + H) +. 141666.doc -145- 201028381 LC/MS tR=1.67 min. Example 1-28 4-Amino-5-cyano-6-ethoxy-N-(3-decyloxybenzyl)methyl. Bipyridylamine [Chemical 1028]

標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=327 (M+H)+。 LC/MS tR=l.55 min。 實施例1-29 4-胺基-N-(4-氣苄基）-5-氰基-6-乙氧基曱基。比啶醯胺 [化 1029]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m/z = 327 (M+H)+. LC/MS tR = 1.55 min. Example 1-29 4-Amino-N-(4-abenzyl)-5-cyano-6-ethoxyindenyl. Bipyridylamine [Chemical 1029]

標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=331 (Μ+Η)+。 LC/MS tR=1.73 min。 實施例1-30 4-胺基-5-氰基-6-乙氧基-N-(4-甲基苄基）曱基η比啶醯胺 [化 1030]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 331 (Μ + Η) +. LC/MS tR = 1.73 min. Example 1-30 4-Amino-5-cyano-6-ethoxy-N-(4-methylbenzyl)indolyl n-pyridiniumamine [Chemical 1030]

141666.doc •146- 201028381 標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=310 (M+H)+。 LC/MS tR=1.66 min。 實施例1-31 4 -胺基-N-(3-氯节基）-5 -氮基-6-乙氧基甲基°比咬酿胺 [化 1031]141666.doc • 146- 201028381 The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 310 (M + H) +. LC/MS tR = 1.66 min. Example 1-31 4-Amino-N-(3-chlorobenzyl)-5-nitro-6-ethoxymethyl ° ratio biting amine [Chemical 1031]

標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=345 (M+H)+。 LC/MS tR=1.77 min。 實施例1-32 4-胺基-N-(2-氣苯乙基）-5-氰基-6-乙氧基曱基吼啶醯胺 [化 1032]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 345 (M + H) +. LC/MS tR = 1.77 min. Example 1-32 4-Amino-N-(2-cephenethyl)-5-cyano-6-ethoxymercaptoacylamine [Chemical 1032]

標題化合物係依據實施例1 -1之方法而合成。 MS(ESI)m/z=345 (M+H)+。 LC/MS tR=l.77 min。 實施例1-33 4-胺基-5-氰基-6-乙氧基-N-(2-曱氧基苯乙基）甲基吼啶 醯胺 141666.doc -147- 201028381 [化 1033]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 345 (M + H) +. LC/MS tR = 1.77 min. Example 1-33 4-Amino-5-cyano-6-ethoxy-N-(2-decyloxyphenethyl)methyl acridine decylamine 141666.doc -147- 201028381 [Chem. 1033]

標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=341(M+H)+。 LC/MS tR=1.67 min。 實施例1-34 4-胺基-5-氰基-6-乙氧基-N-(2-(。比啶-4-基）乙基）甲基《比 咬酿胺 [化 1034]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 341 (M + H) +. LC/MS tR = 1.67 min. Example 1-34 4-Amino-5-cyano-6-ethoxy-N-(2-(.pyridin-4-yl)ethyl)methyl" Ratio Bitter Amine [Chemical 1034]

標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=312 (Μ+Η)+。 LC/MS tR=1.08 min。 實施例1-35 4-胺基-5-氰基-6-乙氧基-N-(吡啶-4-基甲基）甲基吡啶醯胺 [化 1035]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 312 (Μ + Η) +. LC/MS tR = 1.08 min. Example 1-35 4-Amino-5-cyano-6-ethoxy-N-(pyridin-4-ylmethyl)methylpyridiniumamine [Chemical 1035]

標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=298 (M+H)+。 141666.doc -148- 201028381 LC/MS tR=1.05 min。 實施例1-36 4 -胺基-5 -氮基-6-乙氣基-N-(2 -( 0比咬-3 -基）乙基）曱基Dthi 啶醯胺 [化 1036]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 298 (M + H) +. 141666.doc -148- 201028381 LC/MS tR=1.05 min. Example 1-36 4-Amino-5-nitro-6-ethionyl-N-(2-(0-bito-3-yl)ethyl)decyl Dthi pyridine amine [Chemical 1036]

標題化合物係依據實施例1 -1之方法而合成。 MS(ESI)m/z=312 (M+H)+。 LC/MS tR=1.10 min。 實施例1-37 4-胺基-5-乱基-6-乙氧基-Ν-(π比咬-3-基甲基）甲基°比咬酿胺 [化 1037]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 312 (M + H) +. LC/MS tR = 1.10 min. Example 1-37 4-Amino-5-ranyl-6-ethoxy-indole-(π ratio -3-ylmethyl)methyl ° ratio biting amine [Chemical 1037]

標題化合物係依據實施例1 -1之方法而合成。 MS(ESI)m/z=298 (Μ+Η)+。 LC/MS tR=1.08 min。 實施例1-38 4-胺基-5-氰基-6-乙氧基-N-(2-(吼啶-2-基）乙基）甲基。比 唆酿胺 141666.doc -149- 201028381 [化 1038]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 298 (Μ + Η) +. LC/MS tR = 1.08 min. Example 1-38 4-Amino-5-cyano-6-ethoxy-N-(2-(acridin-2-yl)ethyl)methyl. Ratio 唆 胺 141666.doc -149- 201028381 [化 1038]

標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=312 (M+H)+。 LC/MS tR=1.27 min。 實施例1-39 4-胺基-5-氰基-6-乙氧基-N-(2-(哌啶-1-基）乙基）甲基吼 啶醯胺 [化 1039]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 312 (M + H) +. LC/MS tR = 1.27 min. Example 1-39 4-Amino-5-cyano-6-ethoxy-N-(2-(piperidin-1-yl)ethyl)methyl hydrazinamide [Chemical 1039]

標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=318 (M+H).。 LC/MS tR=1.42 min。 實施例1-40 4-胺基-5-氰基-6-乙氧基-N-(2-(N-嗎琳基）乙基）曱基β比u定 醯胺 [化 1040]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 318 (M + H). LC/MS tR = 1.42 min. Example 1-40 4-Amino-5-cyano-6-ethoxy-N-(2-(N-morphinyl)ethyl)indenyl β-r-decylamine [1040]

Ον〜 標題化合物係依據實施例1-1之方法而合成。 141666.doc -150- 201028381 MS(ESI)m/z=320 (M+H)+。 LC/MS tR=1.01 min。 實施例1-41 4-胺基-N-丁基-5-氰基-6-乙氧基甲基吡啶醯胺 [化 1041]Ον~ The title compound was synthesized according to the method of Example 1-1. 141666.doc -150- 201028381 MS (ESI) m/z = 320 (M+H)+. LC/MS tR = 1.01 min. Example 1-41 4-Amino-N-butyl-5-cyano-6-ethoxymethylpyridinamide [Chem. 1041]

標題化合物係依據實施例1 -1之方法而合成。 MS(ESI)m/z=263 (M+H)+。 LC/MS tR=l.53 min。 實施例1-42 4-胺基-5-氰基-6-乙氧基-N-(4-苯基丁基）甲基吨啶醯胺 [化 1042]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 263 (M+H)+. LC/MS tR = 1.53 min. Example 1-42 4-Amino-5-cyano-6-ethoxy-N-(4-phenylbutyl)methyl oxalylamine [Chemical 1042]

標題化合物係依據實施例1 -1之方法而合成。 MS(ESI)m/z=339 (M+H)+。 LC/MS tR=1.87 min。 實施例1-43 4-胺基-5-氰基-N-(2,5-二氣苄基）-6-乙氧基曱基吼啶醯胺 141666.doc -151- 201028381 [化 1043]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 339 (M+H)+. LC/MS tR = 1.87 min. Example 1-43 4-Amino-5-cyano-N-(2,5-di-benzyl)-6-ethoxymercaptoacylamine 141666.doc -151- 201028381 [Chem. 1043]

標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=365 (M+H)+。 LC/MS tR=1.88 min。 實施例1-44 N-(5-乙醯胺-2-曱氧基苯基）-4-胺基-5-氰基-6-乙氧基曱 基Π比咬醯胺 [化 1044]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m/z = 356 (M+H)+. LC/MS tR = 1.88 min. Example 1-44 N-(5-Acetylamine-2-decyloxyphenyl)-4-amino-5-cyano-6-ethoxyindoleylpyridinium octaamine [Chemical 1044]

標題化合物係依據實施例1 -1之方法而合成。 MS(ESI)m/z=370 (M+H)+。 LC/MS tR=l_36 min 〇 實施例1-45 4-胺基-N-(5-胺甲醯基-2-甲氧基苯基）-5-氰基-6-乙氧基 甲基吡啶醯胺 [化 1045]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 370 (M+H)+. LC/MS tR=l_36 min 〇Example 1-45 4-Amino-N-(5-Aminomethylindenyl-2-methoxyphenyl)-5-cyano-6-ethoxymethylpyridine Guanamine [1045]

141666.doc •152- 201028381 標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=356 (M+H)+。 LC/MS tR=1.27 min。 實施例1-46 1-(4-胺基-5-氰基-6-乙氧基甲基吡啶醯基）哌啶-4-甲醯胺 [化 1046]141666.doc • 152- 201028381 The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 356 (M+H)+. LC/MS tR = 1.27 min. Example 1-46 1-(4-Amino-5-cyano-6-ethoxymethylpyridinyl)piperidine-4-carboxamide [Chemical 1046]

標題化合物係依據實施例1 -1之方法而合成。 MS(ESI)m/z=318 (M+H)+。 LC/MS tR=0.72 min。 實施例1-47 1-(4-胺基-5-氰基-6-乙氧基甲基吡啶醯基）哌啶-3-甲醯胺 [化 1047]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 318 (M + H) +. LC/MS tR = 0.72 min. Example 1-47 1-(4-Amino-5-cyano-6-ethoxymethylpyridinyl)piperidine-3-carboxamide [Chemical 1047]

標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=318 (M+H)+。 LC/MS tR=0.80 min。 實施例1-48 4-胺基-5-氰基-6-乙氧基-N-(3-氟苄基）曱基吼啶醯胺 141666.doc -153- 201028381 [化 1048]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 318 (M + H) +. LC/MS tR = 0.80 min. Example 1-48 4-Amino-5-cyano-6-ethoxy-N-(3-fluorobenzyl)decyl acridineamide 141666.doc -153- 201028381 [Chem. 1048]

標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=315 (M+H)+。 LC/MS tR=1.58 min。 實施例1-49 4-胺基-5-氰基-N-(2-(二甲基胺基）乙基）-6-乙氧基曱基吼 啶醯胺 [化 1049]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 315 (M + H) +. LC/MS tR = 1.58 min. Example 1-49 4-Amino-5-cyano-N-(2-(dimethylamino)ethyl)-6-ethoxymercaptopurine [Chem. 1049]

標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=278 (M+H)+。 LC/MS tR=l.04 min。 實施例1-50 4-胺基-5-氰基-N-(4-(二甲基胺基）苄基）-6-乙氧基曱基吼 咬醯胺 [化 1050]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m/z = 278 (M+H)+. LC/MS tR = 1.04 min. Example 1-50 4-Amino-5-cyano-N-(4-(dimethylamino)benzyl)-6-ethoxymercaptopurine octopamine [Chemical 1050]

標題化合物係依據實施例1-1之方法而合成。 141666.doc -154- 201028381 MS(ESI)m/z=340 (M+H)+。 LC/MS tR=1.62 min。 實施例1-51 4-胺基-5-氰基-N-(2,5-二甲氧基苄基）-6-乙氧基甲基》比啶 醯胺 [化 1051]The title compound was synthesized according to the method of Example 1-1. 141666.doc -154- 201028381 MS (ESI) m/z = 340 (M+H)+. LC/MS tR = 1.62 min. Example 1-51 4-Amino-5-cyano-N-(2,5-dimethoxybenzyl)-6-ethoxymethyl"pyridinium amide [Chemical 1051]

標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=357 (M+H)+。 LC/MS tR=l.60 min。 實施例1-52 4-胺基-5-氰基-6-乙氧基-N-(2-氟苄基）甲基吼啶醯胺 [化 1052]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 357 (M+H)+. LC/MS tR = 1.60 min. Example 1-52 4-Amino-5-cyano-6-ethoxy-N-(2-fluorobenzyl)methyl acridineamine [Chemical 1052]

標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=315 (M+H)+。 LC/MS tR=l.60 min。 實施例1-53 4-胺基-5-氰基-N-(3,4-二氟苄基）-6-乙氧基甲基吼啶醯胺 141666.doc -155- 201028381 [化 1053]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 315 (M + H) +. LC/MS tR = 1.60 min. Example 1-53 4-Amino-5-cyano-N-(3,4-difluorobenzyl)-6-ethoxymethyl acridineamine 141666.doc -155- 201028381 [Chem. 1053]

標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=333 (M+H)+。 LC/MS tR=1.63 min 〇 實施例1-54 4-胺基-5-氮基-6-乙氧基-N-(4-二氟曱氧基节基）甲基°比 咬醯胺 [化 1054]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m/z = 333 (M+H)+. LC/MS tR=1.63 min 〇 Example 1-54 4-Amino-5-nitro-6-ethoxy-N-(4-difluorodecyloxy) methyl group than octopamine [ 1054]

標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=381 (M+H)+。 LC/MS tR=l.85 min 〇 實施例1-55 4-胺基-5-氰基-N-(環己基甲基）-6-乙氧基曱基吼啶醯胺 [化 1055]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 381 (M+H)+. LC/MS tR=l.85 min 实施 Example 1-55 4-Amino-5-cyano-N-(cyclohexylmethyl)-6-ethoxymercaptoacylamine [Chemical 1055]

標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=303 (M+H)+。 141666.doc -156- 201028381 LC/MS tR=1.88 min。 實施例1-56 4-胺基-5-亂基-6-乙氧基-N-((四氮-2H -0比0南-4-基）曱基） 甲基吡啶醯胺 [化 1056]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 303 (M+H)+. 141666.doc -156- 201028381 LC/MS tR=1.88 min. Example 1-56 4-Amino-5-ranyl-6-ethoxy-N-((tetrazo-2H-0 to 0-N--4-yl)indolyl)methylpyridiniumamine [1056] ]

標題化合物係依據實施例1 -1之方法而合成。 MS(ESI)m/z=305 (M+H)+。 LC/MS tR=1.28 min。 實施例1-57 4-胺基-5-氰基-N-(2,5-二甲基苄基）-6-乙氧基甲基吼 啶醯胺 [化 1057]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 305 (M+H)+. LC/MS tR = 1.28 min. Example 1-57 4-Amino-5-cyano-N-(2,5-dimethylbenzyl)-6-ethoxymethyl hydrazinamide [Chemical 1057]

標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=325 (M+H)+。 LC/MS tR=l.82 min。 實施例1-58 4-胺基-5-氰基-6-乙氧基-N-(5-氟-2-甲基苄基）曱基吼啶 醯胺 141666.doc -157- 201028381 [化 1058]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 325 (M+H)+. LC/MS tR = 1.82 min. Example 1-58 4-Amino-5-cyano-6-ethoxy-N-(5-fluoro-2-methylbenzyl)-decyl acridineamide 141666.doc -157- 201028381 1058]

標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=329 (M+H)+。 LC/MS tR=1.69 min。 實施例1-59 4-胺基-5-氰基-6-乙氧基-N-((5-甲基吼嗪-2-基）曱基）曱 基0比咬酿胺 [化 1059]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m/z = 329 (M+H)+. LC/MS tR = 1.69 min. Example 1-59 4-Amino-5-cyano-6-ethoxy-N-((5-methylpyridazin-2-yl)indenyl) fluorenyl group 0 to bite amine [Chemical 1059]

標題化合物係依據實施例1 -1之方法而合成。 MS(ESI)m/z=313 (M+H)+。 LC/MS tR=1.08 min。 實施例1-60 4-胺基-5-氰基-6-乙氧基-N-((2S)-2-苯基環丙基）甲基》比 咬醯胺 [化 1060]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 313 (M+H)+. LC/MS tR = 1.08 min. Example 1-60 4-Amino-5-cyano-6-ethoxy-N-((2S)-2-phenylcyclopropyl)methyl" Ratio Leptinamine [Chemical 1060]

標題化合物係依據實施例1 -1之方法而合成 141666.doc -158- 201028381 MS(ESI)m/z=323 (M+H)+。 LC/MS tR=1.75 min。 實施例1-61 4-胺基-5-氰基-N-(3,5-二曱基苄基）-6-乙氧基甲基吡 。定酿胺 [化 1061]The title compound was synthesized according to the method of Example 1-1. 141. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> LC/MS tR = 1.75 min. Example 1-61 4-Amino-5-cyano-N-(3,5-dimercaptobenzyl)-6-ethoxymethylpyrene. Dilute amine [Chem. 1061]

標題化合物係依據實施例1 -1之方法而合成。 MS(ESI)m/z=325 (M+H)+。 LC/MS tR=1.82 min。 實施例1-62 Ν-(2-(1Η-°比咯-1-基）乙基）-4-胺基-5-氰基-6-乙氧基甲基 °比啶醯胺 [化 1062]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 325 (M+H)+. LC/MS tR = 1.82 min. Example 1-62 Ν-(2-(1Η-°Byr-1-yl)ethyl)-4-amino-5-cyano-6-ethoxymethyl-pyridinium amide [Chemical 1062] ]

標題化合物係依據實施例1 -1之方法而合成。 MS(ESI)m/z=300 (M+H)+。 LC/MS tR=1.44 min。 實施例1-63 4-胺基-N-(苯并[d]異噁唑-3-基）-5-氰基-6-乙氧基曱基吼 咬醢胺 141666.doc -159- 201028381 [化 1063]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 300 (M + H) +. LC/MS tR = 1.44 min. Example 1-63 4-Amino-N-(benzo[d]isoxazol-3-yl)-5-cyano-6-ethoxyindolyl guanamine 141666.doc -159- 201028381 [化1063]

標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=324 (M+H)+。 LC/MS tR=1.73 min。 實施例1-64 4-((4-胺基-5-氰基-6-乙氧基甲基吡啶醯胺）甲基）苯甲酸 甲酯 [化 1064]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m/z = 324 (M+H)+. LC/MS tR = 1.73 min. Example 1-64 4-((4-Amino-5-cyano-6-ethoxymethylpyridinium)methyl)benzoic acid methyl ester [Chemical 1064]

標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=355 (M+H)+。 LC/MS tR=1.51 min。 實施例1-65 4-(4-胺基-5-氰基-6-乙氧基甲基吡啶醯胺）丁酸甲酯 [化 1065]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 355 (M+H)+. LC/MS tR = 1.51 min. Example 1-55 4-(4-Amino-5-cyano-6-ethoxymethylpyridiniumamine) methyl butyrate [Chemical 1065]

標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=307 (M+H)+。 141666.doc •160- 201028381 LC/MS tR=1.22 min。 實施例1-66 5-(4-胺基-5-氰基-6-乙乳基甲基°比唆酿胺）_4_側氧基戍酸 甲酯 [化 1066]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 307 (M + H) +. 141666.doc •160- 201028381 LC/MS tR=1.22 min. Example 1-66 5-(4-Amino-5-cyano-6-ethyllacylmethyl ° ratio enthalpy amine) _4_side oxydecanoic acid methyl ester [Chemical 1066]

標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=335 (M+H)+。 LC/MS tR= 1.18 min。 實施例1-67 4-胺基-5-氰基-N-(3-(二甲基胺基）节基）-6-乙氧基甲基η比 啶醯胺 [化 1067]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 335 (M+H)+. LC/MS tR = 1.18 min. Example 1-67 4-Amino-5-cyano-N-(3-(dimethylamino)benzyl)-6-ethoxymethylη ratio Hexylamine [Chemical 1067]

標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=340 (Μ+Η)+ 〇 LC/MS tR=l.65 min。 實施例1-68 4-胺基-5-氰基-6-乙氧基-Ν·(噻唑-2-基甲基）甲基吡啶醯胺 141666.doc -161 - 201028381 [化 1068]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 340 ( Μ + Η) + 〇 LC/MS tR = 1.65 min. Example 1-68 4-Amino-5-cyano-6-ethoxy-oxime (thiazol-2-ylmethyl)methylpyridinium 141666.doc -161 - 201028381 [Chem. 1068]

標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=304 (M+H)+。 LC/MS tR=1.15 min。 實施例1-69 4-胺基-5-氰基-N-((2,3-二氫苯并呋喃-2-基）曱基）-6-乙氧 基甲基吡啶醯胺 [化 1069]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 304 (M + H) +. LC/MS tR = 1.15 min. Example 1-69 4-Amino-5-cyano-N-((2,3-dihydrobenzofuran-2-yl)indolyl)-6-ethoxymethylpyridiniumamine [Chemical 1069] ]

標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=339 (M+H)+。 LC/MS tR=1.63 min。 實施例1-70 4-胺基-5-氰基-N-(2,3-二甲氧基苄基）-6-乙氧基甲基吼啶 隨胺 [化 1070]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 339 (M+H)+. LC/MS tR = 1.63 min. Example 1-70 4-Amino-5-cyano-N-(2,3-dimethoxybenzyl)-6-ethoxymethyl acridine with an amine [1070]

標題化合物係依據實施例1-1之方法而合成。 141666.doc •162· 201028381 MS(ESI)m/z=357 (M+H)+。 LC/MS tR=1.54 min。 實施例1-71 4-胺基-N-(2-(2-氣苯基）-2-(二甲基胺基）乙基）-5-氰基-6-乙氧基甲基°比啶醯胺 [化 1071]The title compound was synthesized according to the method of Example 1-1. 141666.doc •162· 201028381 MS (ESI) m/z = 357 (M+H)+. LC/MS tR = 1.54 min. Example 1-71 4-Amino-N-(2-(2-phenylphenyl)-2-(dimethylamino)ethyl)-5-cyano-6-ethoxymethyl ° ratio Pyridinamine [1071]

標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=388 (M+H)+。 LC/MS tR=1.70 min。 實施例1-72 4-胺基-5-氰基-6-乙氧基-N-(2-(吼嗪·2-基氧基）苄基）甲 基》比咬醯胺 [化 1072]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 388 (M+H)+. LC/MS tR = 1.70 min. Example 1-72 4-Amino-5-cyano-6-ethoxy-N-(2-(pyridazine-2-yloxy)benzyl)methyl" than octadecylamine [1072]

標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=391 (Μ+Η)+。 LC/MS tR=l.42 min。 實施例1-73 4-胺基-5-氰基-6-乙氧基-N-(2-乙基苯并[d]噁唑-5-基）甲 141666.doc • 163- 201028381 基β比咬蕴胺 [化 1073]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 391 (Μ + Η) +. LC/MS tR = 1.42 min. Example 1-73 4-Amino-5-cyano-6-ethoxy-N-(2-ethylbenzo[d]oxazol-5-yl)methyl 141666.doc • 163- 201028381 Specific bite amine [化1073]

標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=352 (Μ+Η)+。 LC/MS tR=1.64 min。 實施例1-74 4-胺基-5-氰基-N-(2-((5-((二甲基胺基）曱基）呋喃-2-基） 曱硫基）乙基）-6-乙氧基甲基吼啶醯胺 [化 1074]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 352 (Μ + Η) +. LC/MS tR = 1.64 min. Example 1-74 4-Amino-5-cyano-N-(2-((5-((dimethylamino)indolyl)furan-2-yl) sulfonyl)ethyl)-6 -ethoxymethyl acridinium [Chemical 1074]

標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=404 (M+H)+。 LC/MS tR=1.42 min。 實施例1-75 4-胺基-5-乳基-6-乙氧基-N-((2-(嗟吩-2-基）嗟唾-4-基）曱 基）甲基吡啶醯胺 [化 1075]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 404 (M + H) +. LC/MS tR = 1.42 min. Example 1-75 4-Amino-5-lacty-6-ethoxy-N-((2-(indol-2-yl)pyran-4-yl)indolyl)methylpyridinium [1075]

141666.doc -164- 201028381 標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=386 (M+H)+。 LC/MS tR=1.65 min 〇 實施例1-76 4-胺基-5-氰基-6-乙氧基-N-(4-(N-嗎啉基）苄基）曱基。比啶 醯胺 [化 1076]141666.doc -164- 201028381 The title compound was synthesized according to the method of Example 1-1. MS (ESI) m/z = 386 (M+H)+. LC/MS tR = 1.65 min </RTI> Example 1-76 4-Amino-5-cyano-6-ethoxy-N-(4-(N-morpholinyl)benzyl) fluorenyl. Bipyridylamine [Chem. 1076]

標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=382 (Μ+Η)+。 LC/MS tR=1.41 min。 實施例1-77 Ν-(4-(1Η-。比唑-1-基）苄基）-4-胺基-5-氰基-6-乙氧基甲基 吡啶醯胺 _ [化 1077]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 382 (Μ + Η) +. LC/MS tR = 1.41 min. Example 1-77 Ν-(4-(1Η-.Bizozol-1-yl)benzyl)-4-amino-5-cyano-6-ethoxymethylpyridinamide _ [1077]

標題化合物係依據實施例1 -1之方法而合成。 MS(ESI)m/z=363 (M+H)+。 LC/MS tR=l_46 min。 實施例1-78 141666.doc 165- 201028381 4-胺基-N-(苯并[d]噻唑-2-基甲基）-5-氰基-6-乙氧基甲基 0比咬酿胺 [化 1078]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 363 (M+H)+. LC/MS tR = l_46 min. Example 1-78 141666.doc 165- 201028381 4-Amino-N-(benzo[d]thiazol-2-ylmethyl)-5-cyano-6-ethoxymethyl 0 than nibble amine [化1078]

標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=354 (Μ+Η)+ 〇 LC/MS tR=1.52 min。 實施例1-79 4-胺基-5-氰基-6-乙氧基-N-((3-甲基吼啶-2-基）甲基）曱 基0比咬醯胺 [化 1079]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 354 ( Μ + Η) + 〇 LC/MS tR = 1.52 min. Example 1-79 4-Amino-5-cyano-6-ethoxy-N-((3-methylacridin-2-yl)methyl)fluorenyl group 0 to octaamine [Chemical 1079]

標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=312 (M+H)+。 LC/MS tR=1.43 min。 實施例1-80 4-胺基-5-氰基-N-(環丙基甲基）-6-乙氧基曱基吼啶醯胺 [化 1080]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 312 (M + H) +. LC/MS tR = 1.43 min. Example 1-80 4-Amino-5-cyano-N-(cyclopropylmethyl)-6-ethoxymercaptoacylamine [Chem. 1080]

141666.doc -166- 201028381 標題化合物係依據實施例1 -1之方法而合成。 MS(ESI)m/z=261 (M+H)+。 LC/MS tR=1.41 min 〇 實施例1-81 4-胺基-5-氰基-N-(2,5-二氣卞基）·6 -乙氧基甲基^比咬酿胺 [化 1081]141666.doc -166- 201028381 The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 261 (M + H) +. LC/MS tR=1.41 min 〇Example 1-81 4-Amino-5-cyano-N-(2,5-dioxamethyl)·6-ethoxymethyl^ 1081]

標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=333 (Μ+Η)+。 LC/MS tR=l_62 min。 實施例1-82 4-胺基-5-亂基-6-乙氣基-N-(4-(4-甲基π辰嗪_ι_基）节美）甲 基0比咬酿胺 [化 1082]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 333 (Μ + Η) +. LC/MS tR = l_62 min. Example 1-82 4-Amino-5-ranyl-6-ethane group-N-(4-(4-methyl π- oxazinyl)-methyl) 1028]

標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=395 (M+H)+。 LC/MS tR=l.28 min。 實施例1-83 4-胺基-5-氰基-N-((l，5-二甲基_1Η-η比嗅_3_基）曱美）6乙 141666.doc -167- 201028381 氧基甲基吡啶醯胺 [化 1083]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 495 (M+H)+. LC/MS tR = 1.28 min. Example 1-83 4-Amino-5-cyano-N-((l,5-dimethyl-1Η-η than odor-3-yl) 曱美)6B 141666.doc -167- 201028381 Oxygen Methylpyridiniumamine [Chemical 1083]

標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=315 (M+H)+。 LC/MS tR=1.15 min。 實施例1-84 4-胺基-5 -乳基-6-乙乳基-N- (1 -甲基旅咬-4-基）曱基°比咬 醯胺 [化 1084]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 315 (M + H) +. LC/MS tR = 1.15 min. Example 1-84 4-Amino-5-lactyl-6-ethyllacyl-N-(1-methylbend-4-yl)thiol ratio octoate [1084]

標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=304 (M+H)+。 LC/MS tR=0.99 min ° 實施例1-85 4-胺基-5-亂基-6-乙氧基-N-(3-(4-甲基σ底嗓-1-基）丙基）甲 基°比咬醢胺 [化 1085]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 304 (M + H) +. LC/MS tR=0.99 min ° Example 1-85 4-Amino-5-ranyl-6-ethoxy-N-(3-(4-methylσ-indol-1-yl)propyl) Methyl ° ratio to guanamine [1085]

141666.doc -168 - 201028381 標題化合物係依據實施例1 -1之方法而合成。 MS(ESI)m/z=347 (M+H)+。 LC/MS tR=0.87 min。 實施例1-86 4-胺基-5-氰基-6-乙氧基-N-((l-甲基-1H-苯并[d]咪唑-2-基）甲基）甲基1•比啶醯胺 [化 1086]141666.doc -168 - 201028381 The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 347 (M+H)+. LC/MS tR = 0.87 min. Example 1-86 4-Amino-5-cyano-6-ethoxy-N-((l-methyl-1H-benzo[d]imidazol-2-yl)methyl)methyl 1• Bis-pyridylamine [1086]

標題化合物係依據實施例1 -1之方法而合成。 MS(ESI)m/z=351 (M+H)+。 LC/MS tR=l.32 min。 實施例1-87 4-胺基-5-氰基-N-(3,5-二甲氧基苯乙基）-6-乙氧基甲基吼 咬醢胺 〇 [化 1087]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 351 (M + H)+. LC/MS tR = 1.32 min. Example 1-87 4-Amino-5-cyano-N-(3,5-dimethoxyphenethyl)-6-ethoxymethylhydrazine Amylin 〇 [Chemical 1087]

標題化合物係依據實施例1 -1之方法而合成。 MS(ESI)m/z=371 (M+H)+。 LC/MS tR=1.60 min。 實施例1-88 141666.doc -169- 201028381 Ν-(2-(1Η-咪唑-1-基）乙基）-4-胺基-5-氰基-6-乙氧基曱基 °比唆醯胺 [化 1088]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 371 (M+H)+. LC/MS tR = 1.60 min. Example 1-88 141666.doc -169- 201028381 Ν-(2-(1Η-imidazol-1-yl)ethyl)-4-amino-5-cyano-6-ethoxy fluorenyl ° Guanamine [1088]

標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=301 (M+H)+。 LC/MS tR=0.90 min。 實施例1-89 4-胺基-N-苄基-5-氰基-6-乙氧基-N-甲基甲基吡啶醯胺 [化 1089]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 301 (M+H)+. LC/MS tR = 0.90 min. Example 1-89 4-Amino-N-benzyl-5-cyano-6-ethoxy-N-methylmethylpyridiniumamine [Chemical 1089]

標題化合物係依據實施例1-1之方法而合成。 1H-NMR (300 MHz, DMSO-d6 δ 1.10 (t, J=6.9 Hz, 3H), 1.30 (t, J=6.9 Hz, 3H), 2.84 (s, 3H), 2.88 (s, 3H), 4.02 (q, 2H), 4.33 (q, 2H), 4.54 (s, 2H), 4.62 (s, 2H), 6.45 (s, 1H), 4.62 (s, 1H), 7.24-7.39 (m, 6H)。 實施例1-90 4-胺基-5-氰基-6-乙氧基-N-(4-(曱基磺醯基）苄基）曱基》比 啶醯胺 141666.doc •170- 201028381 [化 1090]The title compound was synthesized according to the method of Example 1-1. 1H-NMR (300 MHz, DMSO-d6 δ 1.10 (t, J = 6.9 Hz, 3H), 1.30 (t, J = 6.9 Hz, 3H), 2.84 (s, 3H), 2.88 (s, 3H), 4.02 (q, 2H), 4.33 (q, 2H), 4.54 (s, 2H), 4.62 (s, 2H), 6.45 (s, 1H), 4.62 (s, 1H), 7.24-7.39 (m, 6H). Example 1-90 4-Amino-5-cyano-6-ethoxy-N-(4-(indolylsulfonyl)benzyl)indolylpyridinium 141666.doc •170- 201028381 [化1090]

標題化合物係依據實施例1 -1之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 1.32 (t, J=6.9 Hz, 3H), 3.18 (s, 3H), 3.32 (s, 2H), 4.48-4.57 (m, 4H), 7.07 (s, 1H), .7.33 (br, 2H), 7.54 (d, J=8.4 Hz, 2H), 7.88 (d, 2H), 9.19 (t, φ J=6.3 Hz, 1H) 〇 實施例1-91 4-胺基-5-氰基-6-乙氧基-N-(4-胺磺醯基苄基）曱基&quot;比啶 '醯胺 [化 1091]The title compound was synthesized according to the method of Example 1-1. 1H-NMR (300 MHz, DMSO-d6) δ 1.32 (t, J = 6.9 Hz, 3H), 3.18 (s, 3H), 3.32 (s, 2H), 4.48-4.57 (m, 4H), 7.07 (s , 1H), .7.33 (br, 2H), 7.54 (d, J=8.4 Hz, 2H), 7.88 (d, 2H), 9.19 (t, φ J=6.3 Hz, 1H) 〇Example 1-91 4 -amino-5-cyano-6-ethoxy-N-(4-amine sulfonylbenzyl) fluorenyl &quot;bipyridine' amide [Chemical 1091]

標題化合物係依據實施例1-1之方法而合成。 1H NMR (300 MHz, DMSO-d6) δ 1.32 (t, J=6.9 Hz, 3H), 4.47-4.54 (m 4H), 7.07 (s, 1H), 7.30 (s, 1H), 7.33 (br, 2H), 7.45 (d, J=8.1 Hz, 2H), 7.76 (d, 2H), 9.15 (t, J=6.3 Hz, 1H)。 實施例1-92 4-胺基-5-氰基-6-乙氧基-N-(4-((N-嗎啉基）磺醯基）苄基） 甲基吡啶醯胺 141666.doc -171 - 201028381 [化 1092]The title compound was synthesized according to the method of Example 1-1. 1H NMR (300 MHz, DMSO-d6) δ 1.32 (t, J = 6.9 Hz, 3H), 4.47-4.54 (m 4H), 7.07 (s, 1H), 7.30 (s, 1H), 7.33 (br, 2H) ), 7.45 (d, J=8.1 Hz, 2H), 7.76 (d, 2H), 9.15 (t, J=6.3 Hz, 1H). Example 1-92 4-Amino-5-cyano-6-ethoxy-N-(4-((N-morpholinyl)sulfonyl)benzyl)methylpyridinium 141666.doc - 171 - 201028381 [化1092]

標題化合物係依據實施例1-1之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 1.32 (t, J=6.9 Hz, 3H), 2.84 (m, 4H), 3.62 (m, 4H), 4.51 (q, 2H), 4.58 (d, J=6.6 Hz, 2H), 7.00 (s, 1H), 7.34 (br, 2H), 7.55 (d, J=8.1 Hz, 2H), 7.70 (d, 2H)，9.20 (t，J=6.3 Hz，1H)。 實施例1-93 4-胺基-N-(3-胺基节基）-5-氰基-6-乙氧基甲基°比啶醯胺 [化 1093]The title compound was synthesized according to the method of Example 1-1. 1H-NMR (300 MHz, DMSO-d6) δ 1.32 (t, J = 6.9 Hz, 3H), 2.84 (m, 4H), 3.62 (m, 4H), 4.51 (q, 2H), 4.58 (d, J =6.6 Hz, 2H), 7.00 (s, 1H), 7.34 (br, 2H), 7.55 (d, J=8.1 Hz, 2H), 7.70 (d, 2H), 9.20 (t, J=6.3 Hz, 1H ). Example 1-93 4-Amino-N-(3-aminophenyl)-5-cyano-6-ethoxymethyl-pyridinium amide [Chemical 1093]

標題化合物係依據實施例1-1之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 1.31 (t, J=6.9 Hz, 3H), 4.33 (d, J=6.3 Hz, 2H), 4.48 (q, 2H), 5.02 (br, 2H), 6.40- 6.46 (m, 3H), 6.93 (t, J=7.5 Hz, 1H), 7.08 (s, 1H), 7.32 (br, 2H), 8.89 (t，J=6.3 Hz，1H)。 實施例1-94 4-胺基-2-乙氧基- 6-(嗎淋-4-幾基）於驗腈 [化 1094]The title compound was synthesized according to the method of Example 1-1. 1H-NMR (300 MHz, DMSO-d6) δ 1.31 (t, J = 6.9 Hz, 3H), 4.33 (d, J = 6.3 Hz, 2H), 4.48 (q, 2H), 5.02 (br, 2H), 6.40- 6.46 (m, 3H), 6.93 (t, J=7.5 Hz, 1H), 7.08 (s, 1H), 7.32 (br, 2H), 8.89 (t, J=6.3 Hz, 1H). Example 1-94 4-Amino-2-ethoxy-6-(N-Phenyl-4-yl) in the nitrile [Chemical 1094]

141666.doc -172- 201028381 標題化合物係依據實施例1-1之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 1.29 (t，J=7.2 Hz，3H), 3.40-3.62 (m, 8H), 4.30 (q, 2H), 6.47 (s, 1H), 7.25 (br, 2H)。 實施例1-95 4-胺基-2-乙氧基-6-(&quot;比咯啶-1-羰基）菸鹼腈 [化 1095]141666.doc -172- 201028381 The title compound was synthesized according to the method of Example 1-1. 1H-NMR (300 MHz, DMSO-d6) δ 1.29 (t, J = 7.2 Hz, 3H), 3.40-3.62 (m, 8H), 4.30 (q, 2H), 6.47 (s, 1H), 7.25 (br , 2H). Example 1-95 4-Amino-2-ethoxy-6-(&quot;pyrrolidine-1-carbonyl)nicotinonitrile [Chemical 1095]

標題化合物係依據實施例1-1之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 1.30 (t, J=6.9 Hz, 3H), 1.82 (m, 4H), 3.42 (dd, J=6.9 Hz, 2H), 3.60 (dd, J=6.9 Hz, 2H), 4.32 (q，2H)，6.89 (s，1H)，7.22 (br，2H)。 實施例1-96 4-胺基-N-(3-甲基胺甲醯基苯基）-5-氰基-6-乙氧基甲基 • D比咬醢胺 [化 1096]The title compound was synthesized according to the method of Example 1-1. 1H-NMR (300 MHz, DMSO-d6) δ 1.30 (t, J = 6.9 Hz, 3H), 1.82 (m, 4H), 3.42 (dd, J = 6.9 Hz, 2H), 3.60 (dd, J=6.9 Hz, 2H), 4.32 (q, 2H), 6.89 (s, 1H), 7.22 (br, 2H). Example 1-96 4-Amino-N-(3-methylamine-mercaptophenyl)-5-cyano-6-ethoxymethyl • D is a bit of decylamine [Chemical 1096]

標題化合物係依據實施例1-1之方法而合成。 MS(ESI)m/z=340 (M+H)+。 LC/MS tR=1.49 min。 實施例1-97 141666.doc • 173- 201028381 4-胺基-N-(5-胺甲醯基-2-氣苯基）-5-氰基-6-乙氧基曱基 0比咬醯胺 [化 1097]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 340 (M + H) +. LC/MS tR = 1.49 min. Example 1-97 141666.doc • 173- 201028381 4-Amino-N-(5-Aminomethylindol-2-Phenylphenyl)-5-cyano-6-ethoxyindolyl group 0 Amine [1097]

標題化合物係依據實施例1 -1之方法而合成。 MS(ESI)m/z=359 (M+H)+。 LC/MS tR=1.68 min。 實施例卜98 5-(4-胺基-5-氰基-6-乙氧基甲基吡啶醯胺）-1Η-吲哚-3-甲 醯胺 [化 1098]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 359 (M+H)+. LC/MS tR = 1.68 min. Example 98 5-(4-Amino-5-cyano-6-ethoxymethylpyridinium)-1Η-indole-3-carboxamide [Chemical 1098]

標題化合物係依據實施例1 -1之方法而合成。 MS(ESI)m/z=365 (M+H)+。 LC/MS tR=1.33 min。 實施例1-99 4-胺基-N-(5-胺甲酿基- 2-(N-嗎琳基）苯基）-5 -氰基_6-乙 氧基甲基吡啶醯胺 141666.doc -174- 201028381 [化 1099]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m/z = 356 (M+H)+. LC/MS tR = 1.33 min. Example 1-99 4-Amino-N-(5-aminoglycolyl-2-(N-morphinyl)phenyl)-5-cyano-6-ethoxymethylpyridinium 141666. Doc -174- 201028381 [化1099]

標題化合物係依據實施例1 -1之方法而合成。 MS(ESI)m/z=411 (M+H)+。 LC/MS tR=1.47 min。 實施例1-100 N-(4-胺基-5-氰基-6-乙氧基ϋ比咬-2-基）-2-苯基乙醯胺 [化 1100]The title compound was synthesized according to the method of Example 1-1. MS (ESI) m / z = 411 (M + H) +. LC/MS tR = 1.47 min. Example 1-100 N-(4-Amino-5-cyano-6-ethoxyindole than butyl-2-yl)-2-phenylacetamide [Chemical 1100]

標題化合物係依據US 20060173050 Al(Abbott Laboratories， 實施例1B)之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 1.30 (t, J=7.2 Hz, 3H), 3.70 (s, 2H), 4.33 (q, 2H), 6.91 (br, 2H), 7.15 (s, 1H), 7.23-7.31 (m, 5H)，10.33 (br，1H)。 實施例1 -1 〇 1 N-(4-胺基-5-氰基-6-乙氧基n比咬_2-基）乙醯胺 [化 1101]The title compound was synthesized according to the method of US 20060173050 Al (Abbott Laboratories, Example 1B). 1H-NMR (300 MHz, DMSO-d6) δ 1.30 (t, J = 7.2 Hz, 3H), 3.70 (s, 2H), 4.33 (q, 2H), 6.91 (br, 2H), 7.15 (s, 1H) ), 7.23-7.31 (m, 5H), 10.33 (br, 1H). Example 1 -1 〇 1 N-(4-Amino-5-cyano-6-ethoxy n-bito-2-yl)acetamide [Chem. 1101]

141666.doc •175- 201028381 標題化合物係依據US 20060173050 Al(Abbott Laboratories ’ 實施例1B)之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 1.29 (t, J=7.2 Hz, 3H), 2.06 (s, 3H), 4.31 (q, 2H), 6.91 (br, 2H), 7.17 (s, 1H), 10.11 (s’ 1H” 實施例1-102 Ν，Ν·-(6-溴-5-氰基吡啶-2,4-二基）二乙醯胺 [化 1102]141666.doc • 175- 201028381 The title compound was synthesized according to the method of US 20060173050 Al (Abbott Laboratories 'Example 1B). 1H-NMR (300 MHz, DMSO-d6) δ 1.29 (t, J = 7.2 Hz, 3H), 2.06 (s, 3H), 4.31 (q, 2H), 6.91 (br, 2H), 7.17 (s, 1H) ), 10.11 (s' 1H" Example 1-102 Ν,Ν·-(6-bromo-5-cyanopyridine-2,4-diyl)diacetamide [Chemical 1102]

標題化合物係使用4,6-二胺基-2-菸鹼腈，依據US 20060173050 Al(Abbott Laboratories，實施例 1B)之方法而 合成。 1H-NMR (300 MHz, DMSO-d6) δ 2.12 (s, 3H), 2.32 (s, 3H), 8_01 (s，1H)，11.02 (s, 1H)，12.40 (s，1H)。 實施例1-103 4-胺基-2-乙氧基-6-(2-侧氧基吼哈咬-1-基）於驗猜 [化 1103]The title compound was synthesized according to the method of US 20060173050 Al (Abbott Laboratories, Example 1B) using 4,6-diamino-2-nicotinonitrile. 1H-NMR (300 MHz, DMSO-d6) δ 2.12 (s, 3H), 2.32 (s, 3H), 8_01 (s, 1H), 11.02 (s, 1H), 12.40 (s, 1H). Example 1-103 4-Amino-2-ethoxy-6-(2-side-oxyha-habita-1-yl) was tested [Chem. 1103]

向三氟甲磺酸4-胺基-5-氰基-6-乙氧基吡啶-2-基酯（1〇〇 mg，0.321 mmol)、Pd2(dba)3(l4.7 mg，0.016 mmol)、 141666.doc •176- 201028381 BINAP(20 mg，0.032 mmol)、Cs2C03(碳酸铯）（146 mg， 0.449 mmol)之甲本（1.5 mL)&gt;谷液中添加2· 〇比洛n定酮（55 mg，0.049 mmol)，於加熱回流下攪拌10小時。向反應溶 液中添加水及乙酸乙酯進行分離後，以乙酸乙醋萃取水 相’將合併之有機相以水及飽和食鹽水進行清洗，以硫酸 鎮加以乾燥。將有機相過遽後’進行減壓濃縮，利用中壓 管柱層析法（氣仿：曱醇=98 : 2)對所獲得之殘逢進行純 化’獲得標題化合物（37 mg ’ 0· 1 50 nimol，47%)，為黃色 ❹固體。 1H-NMR (300 MHz，DMSO-dg) δ 1.3〇 (t，j=6.9 Hz, 3H), 1.98 (m, J=7.2 Hz, 2H), 2.54 (m, 2H), 3.93 (t, J=6.9 Hz, 2H)，6.90 (br, 2H), 7.37 (s，1H)。 實施例1-104 4-胺基-2-乙氧基-6-(3 -甲基-2-側氧基咪e坐咬-i_基）於 鹼腈 [化 1104] ❿4-Amino-5-cyano-6-ethoxypyridin-2-yl trifluoromethanesulfonate (1 〇〇 mg, 0.321 mmol), Pd2 (dba) 3 (14.7 mg, 0.016 mmol) ), 141666.doc • 176- 201028381 BINAP (20 mg, 0.032 mmol), Cs2C03 (barium carbonate) (146 mg, 0.449 mmol) of the base (1.5 mL) &gt; Add 2· 〇 比洛洛定The ketone (55 mg, 0.049 mmol) was stirred for 10 hours under reflux. Water and ethyl acetate were added to the reaction solution for separation, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and saturated brine and dried over sodium sulfate. After the organic phase was dried, it was concentrated under reduced pressure, and the residue obtained was purified by medium pressure column chromatography (methanol: methanol: 98: 2) to obtain the title compound (37 mg ' 0·1 50 nimol, 47%), yellow solid. 1H-NMR (300 MHz, DMSO-dg) δ 1.3 〇 (t, j = 6.9 Hz, 3H), 1.98 (m, J = 7.2 Hz, 2H), 2.54 (m, 2H), 3.93 (t, J = 6.9 Hz, 2H), 6.90 (br, 2H), 7.37 (s, 1H). Example 1-104 4-Amino-2-ethoxy-6-(3-methyl-2-oxo-oxy-4-e-bito-i-yl) in an alkali nitrile [Chemical 1104] ❿

標題化合物係使用甲基咪唑啶-2-酮，依據實施例1-103之 方法而合成。 1H-NMR (3〇〇 MHz, DMSO-d6) δ 1.3〇 (t, J=6.9 Hz, 3H), 2.76 (s, 3H), 3.40 (t, J=7.8 Hz, 2H), 3.89 (t, J=7.8 Hz, 3H), 4.33 (q, 2H), 6.73 (br, 2H), 7·18 (s，1H)。 141666.doc -177· 201028381 實施例1-105 4-胺基-2-乙氧基-6-(2-側氧基咪唑啶-1-基）菸鹼腈 [化 1105]The title compound was synthesized according to the method of Example 1-103 using methyl imidazolidin-2-one. 1H-NMR (3〇〇MHz, DMSO-d6) δ 1.3〇(t, J=6.9 Hz, 3H), 2.76 (s, 3H), 3.40 (t, J=7.8 Hz, 2H), 3.89 (t, J = 7.8 Hz, 3H), 4.33 (q, 2H), 6.73 (br, 2H), 7·18 (s, 1H). 141666.doc -177· 201028381 Example 1-105 4-Amino-2-ethoxy-6-(2-trioxyimidazolidine-1-yl)nicotinonitrile [Chemical 1105]

標題化合物係使用咪唑啶-2-酮，依據實施例1-103之方法 而合成。 1H-NMR (300 MHz, DMSO-d6) δ 1.30 (t J=6.9 Hz, 3H), 3.96 (t, J=6.6 Hz, 2H), 4.32 (q, 2H), 6.70 (s, 1H), 7.18 (s, 1H)，7.25 (s，1H)。 實施例1-106 1-(4-胺基-5-氰基-6-乙氧基&quot;比啶-2-基）-3-曱脲 [化 1106]The title compound was synthesized according to the procedure of Example 1-103 using imidazolidin-2-one. 1H-NMR (300 MHz, DMSO-d6) δ 1.30 (t J = 6.9 Hz, 3H), 3.96 (t, J = 6.6 Hz, 2H), 4.32 (q, 2H), 6.70 (s, 1H), 7.18 (s, 1H), 7.25 (s, 1H). Example 1-106 1-(4-Amino-5-cyano-6-ethoxy&quot;bipyridin-2-yl)-3-indoleure [Chemical 1106]

向 4,6-二胺基-2-乙氧基菸鹼腈（US 20060173050 Al)(50 mg，0.281 mmol)及 DIEA(72.6 mg，98 pL，0.562 mmol)之 THF(1.0 mL)溶液中於0°C下添加三光氣（28.5 mg，0.096 mmol)，攪:拌20分鐘。繼而，添加二甲基胺（THF中2 mol/L，0.28 mL，0.562 mmol)，進而授拌1小時。向反應 溶液中添加水及乙酸乙酯進行分離後，以乙酸乙酯萃取水 相，將合併之有機相以水及飽和食鹽水進行清洗，以硫酸 141666.doc -178- 201028381 鎂加以乾燥。將有機相過濾後，進行減壓濃縮，以己烷/ 乙酸乙酯使所獲得之殘渣固化，藉此獲得標題化合物（12 5 mg，0.053 mmol，19%) ° 1H-NMR (300 MHz, DMSO-d6) δ 1.29 (t, J=6.9 Hz, 3H), 2.66 (d, J=4.5 Hz, 3H), 6.61 (s, 1H), 6.76 (br, 2H), 7.09 (d, J=4.5 Hz, 1H)，8.91 (s，1H)。 實施例1-107 1-(4-胺基-5-氰基-6-乙氧基。比》定-2-基）-3-苯基腺 〇 [化 1107]To a solution of 4,6-diamino-2-ethoxynicotinonitrile (US 20060173050 Al) (50 mg, 0.281 mmol) and DIEA (72.6 mg, 98 pL, 0.562 mmol) in THF (1.0 mL) Add triphosgene (28.5 mg, 0.096 mmol) at 0 °C, stir: mix for 20 minutes. Then, dimethylamine (2 mol/L in THF, 0.28 mL, 0.562 mmol) was added, and the mixture was further stirred for 1 hour. After water and ethyl acetate were added to the reaction solution for separation, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water and saturated brine, and dried over magnesium sulfate 141666.doc -178 - 201028381. After the organic phase was filtered, EtOAc (EtOAc m. -d6) δ 1.29 (t, J=6.9 Hz, 3H), 2.66 (d, J=4.5 Hz, 3H), 6.61 (s, 1H), 6.76 (br, 2H), 7.09 (d, J=4.5 Hz , 1H), 8.91 (s, 1H). Example 1-107 1-(4-Amino-5-cyano-6-ethoxy. Ratio: Din-2-yl)-3-phenyl gland 〇 [Chemical 1107]

標題化合物係使用苯胺，依據實施例1-106之方法而合 成。 MS(ESI)m/z=298 (M+H)+。 LC/MS tR=1.82 min 〇 φ 實施例1-108 1-(4-胺基-5-氰基-6-乙氧基吼啶-2-基）-3-苄基脲 [化 1108]The title compound was synthesized according to the procedure of Example 1-106 using aniline. MS (ESI) m / z = 298 (M + H) +. LC/MS tR=1.82 min 〇 φ Example 1-108 1-(4-Amino-5-cyano-6-ethoxyacridin-2-yl)-3-benzylurea [Chem. 1108]

標題化合物係使用苄基胺，依據實施例1 -1 〇6之方法而合 成。 1H-NMR (300 MHz, DMSO-d6) δ 1.19 (t, J=6.9 Hz, 3H), 141666.doc -179- 201028381 4.09 (q，2H)，4.32 (d，J=5.7 Hz, 2H)，6.53 (s，1H)，6_79 (br， 2H)，7.25-7.34 (m，5H), 7.80 (t，1H)，9.06 (s，1H)。 實施例1-109 N - (4 -胺基· 5 -氣基-6 -乙氧基〇比咬-2 -基）甲項酿胺 [化 1109]The title compound was synthesized according to the method of Example 1-1, using benzylamine. 1H-NMR (300 MHz, DMSO-d6) δ 1.19 (t, J = 6.9 Hz, 3H), 141666.doc -179 - 201028381 4.09 (q, 2H), 4.32 (d, J = 5.7 Hz, 2H), 6.53 (s, 1H), 6_79 (br, 2H), 7.25-7.34 (m, 5H), 7.80 (t, 1H), 9.06 (s, 1H). Example 1-109 N-(4-Amino·5-ylyl-6-ethoxyindole-biti-2-yl)carboxamide [Chem. 1109]

向4,6-二胺基-2_乙氧基於驗腈（3〇 mg，0.281 mmol)及 DMAP(5 mg ’ 0.041 mmol)之吡啶（ι·〇 mL)溶液中添加甲續 醯氣（38.5 mg，0.33 6 mmol) ’攪拌16小時。向反應溶液中 添加水及乙酸乙酯進行分離後’以乙酸乙酯萃取水相，將 合併之有機相以水及飽和食鹽水進行清洗，以硫酸鎂加以 乾燥。將有機相過濾後，進行減壓濃縮，利用矽膠層析法 (氯仿：甲醇=98: 2)對所獲得之殘渣進行純化，藉此獲得 標題化合物（31.5 mg，0.123 mmol，73%)。 1H-NMR (300 MHz，DMS〇-d6) δ uo (t，J=6 9 Hz，3H) 4.31 (q, 2H), 5.86 (s, 1H), 6.88 (br, 2H), l〇.5g (s, 1H) 〇 實施例1-110 N-(4-胺基-5-氰基-6-乙氧基n比啶_2_基）苯磺醯胺 [化 1110]Add 4,6-diamino-2-ethoxylate to a solution of nitrile (3 〇mg, 0.281 mmol) and DMAP (5 mg '0.041 mmol) in pyridine (ι·〇mL). Mg, 0.33 6 mmol) 'Stirring for 16 hours. Water and ethyl acetate were added to the reaction solution for separation. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and brine, and dried over magnesium sulfate. After the organic phase was filtered, the residue was evaporated, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 1H-NMR (300 MHz, DMS〇-d6) δ uo (t, J=6 9 Hz, 3H) 4.31 (q, 2H), 5.86 (s, 1H), 6.88 (br, 2H), l〇.5g (s, 1H) 〇 Example 1-110 N-(4-Amino-5-cyano-6-ethoxy n-pyridyl-2-yl)benzenesulfonamide [Chemical 1110]

141666.doc -180- 201028381 標題化合物係依據實施例1-109之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 1.12 (t, J=7.2 Hz, 3H), 4.03 (q, 2H), 5.92 (s 1H), 6.88 (br, 2H), 7.57-7.65 (m, 3H), 7.86-7.89 (m, 2H)，11.12 (s，1H)。 實施例1-111 N-(4-胺基-5-氰基-6-乙氧基》比啶-2-基）-1-苯基甲磺醯胺 [化 1111]141666.doc -180- 201028381 The title compound was synthesized according to the method of Example 1-109. 1H-NMR (300 MHz, DMSO-d6) δ 1.12 (t, J = 7.2 Hz, 3H), 4.03 (q, 2H), 5.92 (s 1H), 6.88 (br, 2H), 7.57-7.65 (m, 3H), 7.86-7.89 (m, 2H), 11.12 (s, 1H). Example 1-111 N-(4-Amino-5-cyano-6-ethoxy)pyridin-2-yl)-1-phenylmethanesulfonamide [Chemical 1111]

? 2 N ❿? 2 N ❿

H LH L

Me 標題化合物係依據實施例1-109之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 1.36 (t, J=6.9 Hz, 3H), 4.41 (q, 2H), 4.81 (s, 2H), 5.79 (s, 1H), 6.91 (br, 2H), 7.26-7.37 (m，5H)，10.50 (s，1H)。 實施例1-112 4-胺基-5-氰基-6-乙氧基甲基吡啶醯肼 [化 1112]The Me title compound was synthesized according to the method of Example 1-109. 1H-NMR (300 MHz, DMSO-d6) δ 1.36 (t, J = 6.9 Hz, 3H), 4.41 (q, 2H), 4.81 (s, 2H), 5.79 (s, 1H), 6.91 (br, 2H) ), 7.26-7.37 (m, 5H), 10.50 (s, 1H). Example 1-112 4-Amino-5-cyano-6-ethoxymethylpyridinium [Chemical Formula 1112]

向4·胺基-5-氣基_6_乙氧基0比咬甲酸甲醋（us 20060173050 Al)(185 mg，0.836 mmol)之乙醇（2 mL)溶液 中添加肼水合物（837 mg，16.7 mol) ’於加熱回流下授摔2 小時。將反應溶液冷卻至0°C ’將所獲得之固體過澹分 141666.doc -181 - 201028381 離，藉此獲得標題化合物（146 mg，〇·66 mmol，79%)。 1H-NMR (300 MHz，DMSO-d6) δ 1.29 (t，J=7.2 Hz，3H)， 4.48 (q，J=7.2 Hz，2H)，4.56 (d，J=3.6 Hz，2H), 7.01 (s， 1H)，7.27 (br，2H)，9.70 (br，1H)。 實施例1-113 Ν' -乙酿基-4-胺基-5-氣基-6-乙氧基甲基〇比咬酿耕 [化 1113]Add hydrazine hydrate (837 mg, to a solution of 4·Amino-5-carbyl-6-ethoxy 0 to methyl acetate (us 20060173050 Al) (185 mg, 0.836 mmol) in ethanol (2 mL). 16.7 mol) 'Take for 2 hours under heating and reflux. The reaction solution was cooled to 0 ° C. The obtained solid was partitioned from 141 666. doc - 181 - 201028381, whereby the title compound (146 mg, 〇· 66 mmol, 79%) was obtained. 1H-NMR (300 MHz, DMSO-d6) δ 1.29 (t, J = 7.2 Hz, 3H), 4.48 (q, J = 7.2 Hz, 2H), 4.56 (d, J = 3.6 Hz, 2H), 7.01 ( s, 1H), 7.27 (br, 2H), 9.70 (br, 1H). Example 1-113 Ν'-Ethyl-4-amino-5-yl-6-ethoxymethyl hydrazine ratio bittering [Chem. 1113]

HATU, NMM DMF,室溫 MeHATU, NMM DMF, room temperature Me

向4-胺基-5-氰基-6-乙氧基曱基〇比咬醯肼（7〇 mg，0.316 mmol)、乙酸（24.7 mg’ 24 μί’ 0.411 mm〇l)及ΝΜΜ(70·3 mg ’ 76 pL，0.695 mmol)之 DMF(l.〇 mL)溶液中添加 HATU(144 mg，0·379 mmol)，擾拌3小時。向反應溶液中 添加水及乙酸乙酯進行分離後，以乙酸乙酯萃取水相，將 合併之有機相以水及飽和食鹽水進行清洗，以硫酸鎂加以 乾燥。將有機相過濾後，進行減壓濃縮，以己烷/乙酸乙 酯使所獲得之殘渣固化’藉此獲得標題化合物（74 5 mg， 0.283 mmol，90%) ° 1H-NMR (300 MHz, DMSO-d6) δ 1.30 (t, J=6.9 Hz, 3H), 1·90 (s, 3H)，4.49 (q, 2H), 7.03 (s，ih)，7.37 (br, 2H), 9.95 (s，1H)，10.14 (s, 1H)。 實施例1-114 4-胺基-2-乙氧基-6-(5-曱基-l，3,4_噁二唑_2_基）菸鹼腈 141666.doc -182- 201028381 [化 1114]To 4-amino-5-cyano-6-ethoxyindolyl hydrazine (7 〇 mg, 0.316 mmol), acetic acid (24.7 mg '24 μί' 0.411 mm 〇l) and hydrazine (70· Add HATU (144 mg, 0·379 mmol) to a solution of 3 mg '76 pL, 0.695 mmol) in DMF (1. 〇mL) and stir for 3 hours. Water and ethyl acetate were added to the reaction solution for separation, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and brine and dried over magnesium sulfate. After the organic phase was filtered, EtOAc (EtOAc m. -d6) δ 1.30 (t, J=6.9 Hz, 3H), 1·90 (s, 3H), 4.49 (q, 2H), 7.03 (s, ih), 7.37 (br, 2H), 9.95 (s, 1H), 10.14 (s, 1H). Example 1-114 4-Amino-2-ethoxy-6-(5-fluorenyl-l,3,4-oxadiazole-2-yl)nicotinonitrile 141666.doc -182- 201028381 1114]

向Ν'-乙酿基·4_胺基_5_氰基_6_乙氧基曱基吡啶醯肼（6〇 mg，0.228 mmol)及四溴化碳（227 mg，0.684 mmol)之二氣 甲烧（2.0 mL)溶液中添加三苯基膦（179 mg，0.684 mmol)Ν'-Ethyl- 4-amino-5-cyano-6-ethoxymercaptopyridinium (6 〇 mg, 0.228 mmol) and carbon tetrabromide (227 mg, 0.684 mmol) Add triphenylphosphine (179 mg, 0.684 mmol) to a gas-fired (2.0 mL) solution

授拌2小時。向反應溶液中添加水及二氣甲烷，進行分離 後，以二氣甲烷萃取水相，以硫酸鎂加以乾燥。將有機相 過漉後’進行減壓濃縮，利用中壓矽膠層析法（己烷：乙 酸乙酯=1 : 1)對所獲得之殘渣進行純化，藉此獲得白色固 體。以包含0.1% TFA之乙腈··水=1 : i溶液稀釋所獲得之 化合物，於40。(：下攪拌2小時。向反應溶液中添加水及乙 酸乙醋進行分離後，以乙酸乙醋萃取水相，將合併之有機 相以水及飽和食鹽水進行清洗，以硫酸鎮加以乾燥。將有 機相過濾後，進行減壓濃縮，以甲醇/水使所獲得之殘渣 固化，藉此獲得標題化合物（1〇 2 mg，〇 〇42， 18%)，為白色固體。 1H NMR (300 MHz, DMSO-d6) δ 1.34 (t, J=6.9 Hz, 3H), 2.59 (s, 3H), 4.42 (q, 2H), 7.16 (s, 1H), 7.42 (br, 2H) 〇 實施例1-115 心胺基專苯甲酿基·5·氰基-6-乙氧基甲基-比咬醯肼 141666.doc -183· 201028381 [化 1115]Mix for 2 hours. Water and di-methane were added to the reaction solution, and after separation, the aqueous phase was extracted with di-methane and dried over magnesium sulfate. After the organic phase was dried, it was concentrated under reduced pressure, and the obtained residue was purified by medium pressure gel chromatography (hexane: ethyl acetate = 1 : 1) to obtain a white solid. The obtained compound was diluted at 40 with an acetonitrile·water = 1:1 solution containing 0.1% TFA. (: stirring for 2 hours. After adding water and ethyl acetate to the reaction solution for separation, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water and saturated brine, and dried with sulfuric acid. After the organic phase was filtered, the residue was evaporated,jjjjjjjjjjjjjj DMSO-d6) δ 1.34 (t, J=6.9 Hz, 3H), 2.59 (s, 3H), 4.42 (q, 2H), 7.16 (s, 1H), 7.42 (br, 2H) 〇Example 1-115 Heart amine-based benzoin-based ·5·cyano-6-ethoxymethyl-specific biting 141666.doc -183· 201028381 [Chemical 1115]

標題化合物係依據實施例1-113之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 1.32 (t, J=6.9 Hz, 3H), 4.55 (q, 2H), 7.07 (s, 1H), 7.38 (br5 2H), 7.49-7.62 (m, 3H), 7.88-7.91 (m，2H)，10.40 (s，1H)，10.52 (s，1H)。The title compound was synthesized according to the method of Example 1-113. 1H-NMR (300 MHz, DMSO-d6) δ 1.32 (t, J = 6.9 Hz, 3H), 4.55 (q, 2H), 7.07 (s, 1H), 7.38 (br5 2H), 7.49-7.62 (m, 3H), 7.88-7.91 (m, 2H), 10.40 (s, 1H), 10.52 (s, 1H).

實施例1-116 Q 4-胺基-2-乙氧基-6-(5-苯基-1，3,4-噁二唑_2-基）菸鹼腈 [化 1116]Example 1-116 Q 4-Amino-2-ethoxy-6-(5-phenyl-1,3,4-oxadiazol-2-yl)nicotinonitrile [Chemical 1116]

標題化合物係使用4-胺基-Ν'-苯甲酿基-5-氰基-6-乙氧基甲 基吡啶醯肼，依據實施例1-114之方法而合成。The title compound was synthesized according to the method of Example 1-114 using 4-amino-indole--bromo-bromo-5-cyano-6-ethoxymethylpyridinium.

1H-NMR (300 MHz, DMSO-d6) δ 1.38 (t, J=6 9 Hz 3H) 4.48 (q, 2H), 7.28 (s, 1H), 7.48 (br, 2H), 7.62-7.90 (m, 7H), 8.06 (m，2H) o 實施例1-117 4-胺基-5-氰基-6-乙氧基-N'-(2-(4-甲氧基笨基）乙醯）曱基 吡啶醯肼 141666.doc -184- 201028381 [化 1117]1H-NMR (300 MHz, DMSO-d6) δ 1.38 (t, J = 6 9 Hz 3H) 4.48 (q, 2H), 7.28 (s, 1H), 7.48 (br, 2H), 7.62-7.90 (m, 7H), 8.06 (m, 2H) o Example 1-117 4-Amino-5-cyano-6-ethoxy-N'-(2-(4-methoxyphenyl)ethylhydrazine) Pyridinium 醯肼 666 666666.doc -184- 201028381 [Chemical 1117]

標題化合物係依據實施例1-113之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 1.29 (t, J=6.9 Hz, 3H), 3.45 (s, 2H), 3.73 (s, 3H), 4.48 (q, J=7.2 Hz, 2H), 6.87 (d, J=8.7 Hz, 2H), 7.03 (s, 1H), 7.23 (d, J=8.7 Hz), 7.36 (br, 參 1H)，10.22 (br，2H)。 實施例1-118 4-胺基-2-乙基胺基-6-(5-(4-甲氧基节基）-1，3,4-噁二唑-2-基）菸鹼腈 [化 1118]The title compound was synthesized according to the method of Example 1-113. 1H-NMR (300 MHz, DMSO-d6) δ 1.29 (t, J = 6.9 Hz, 3H), 3.45 (s, 2H), 3.73 (s, 3H), 4.48 (q, J = 7.2 Hz, 2H), 6.87 (d, J=8.7 Hz, 2H), 7.03 (s, 1H), 7.23 (d, J=8.7 Hz), 7.36 (br, ref. 1H), 10.22 (br, 2H). Example 1-118 4-Amino-2-ethylamino-6-(5-(4-methoxybenzyl)-1,3,4-oxadiazol-2-yl)nicotinonitrile [ 1118]

標題化合物係使用4-胺基-5-氰基-6-乙氧基-N，-(2-(4-甲氧 基苯基）乙醯）甲基吡啶醯肼，依據實施例1-114之方法而合 成。 1H-NMR (300 MHz，DMSO-d6) δ 1.33 (t，J=6 9 Ηζ，π)， 3.73 (s，3H)，4.29 (s，2H)，4.40 (q，2H)，6.92 (d，J=8 7 Hz， 2H)，7.14 (s，1H)，7_26 (d，2H)，7.41 (br，2H)。 實施例1-119 4-胺基-2·乙氧基-6-(3-甲基·1,2,4-噁二唑-5-基）終驗腈 141666.doc • 185- 201028381 [化 1119]The title compound was 4-amino-5-cyano-6-ethoxy-N,-(2-(4-methoxyphenyl)acetamidine)methylpyridinium, according to Example 1-114. The method is synthesized. 1H-NMR (300 MHz, DMSO-d6) δ 1.33 (t, J = 6 9 Ηζ, π), 3.73 (s, 3H), 4.29 (s, 2H), 4.40 (q, 2H), 6.92 (d, J=8 7 Hz, 2H), 7.14 (s, 1H), 7_26 (d, 2H), 7.41 (br, 2H). Example 1-119 4-Amino-2·ethoxy-6-(3-methyl·1,2,4-oxadiazol-5-yl) final nitrile 141666.doc • 185- 201028381 1119]

向4-胺基-5-氰基-6-乙氧基吡啶甲酸曱酯（100 mg，0.452 mmol)及碳酸鉀（131 mg，0.949 mmol)之甲苯（2.0 mL)溶液 中添加乙醢胺肪（70 mg，0.949 mmol)，於加熱回流下揽拌 6小時。向反應溶液中添加水及乙酸乙酯進行分離後，以 乙酸乙酯萃取水相，以硫酸鎂加以乾燥。將有機相過濾 後，進行減壓濃縮，以己烷/乙酸乙酯使所獲得之殘渣固 化，藉此獲得標題化合物（86.3 mg，0.352 mmol，78%)， 為白色固體。 1H-NMR (300 MHz, DMSO-d6) δ 1.34 (t, J = 6.9 Hz, 3H), 4.43 (q，2H), 7.25 (s, 1H)，7.53 (br，2H)。 實施例1-120 4-胺基-6-(5-胺基-1Η-»比唑-3-基）-2-乙氧基菸鹼腈 [化 1120]Adding acetamidine to a solution of 4-amino-5-cyano-6-ethoxypyridinecarboxylic acid decyl ester (100 mg, 0.452 mmol) and potassium carbonate (131 mg, 0.949 mmol) in toluene (2.0 mL) (70 mg, 0.949 mmol), stirred under reflux for 6 h. After water and ethyl acetate were added to the reaction solution for separation, the aqueous phase was extracted with ethyl acetate and dried over magnesium sulfate. After the organic phase was filtered, EtOAc mjjjjjjjjjjj 1H-NMR (300 MHz, DMSO-d6) δ 1.34 (t, J = 6.9 Hz, 3H), 4.43 (q, 2H), 7.25 (s, 1H), 7.53 (br, 2H). Example 1-120 4-Amino-6-(5-amino-1Η-»bisazol-3-yl)-2-ethoxynicotinonitrile [Chemical 1120]

向乙腈（26 kL，0.475 mmol)之 THF(2.0 mL)溶液中於 -78°C 下添加 LDA(THF 中 2 mol/L，475 μί，0.475 mmol)。 攪拌5分鐘後，於相同溫度下添加4-胺基-5-氰基-6-乙氧基 0比0定曱酸曱醋（100 mg，0.452 mmol)，於一整夜一面升溫 141666.doc •186- 201028381 一面進行攪拌。向反應溶液中添加水及乙酸乙酯進行分離 後’以乙酸乙酯萃取水相，以硫酸鎂加以乾燥。將有機相 過據後’進行減壓濃縮，利用管柱層析法（氣仿：甲醇 =98 : 2)對所獲得之殘渣進行純化，藉此獲得4_胺基_6_(2_ 氰基乙酿）-2 -乙氧基於驗腈（34.2 mg，0.149 mmol)。 向所獲得之化合物之乙醇（1.5 mL)溶液中添加肼水合物 (7.8 mg，0.156 mmol)，於加熱回流下攪拌3小時。向反應 备液中添加水及乙酸乙酯進行分離後，以乙酸乙酯萃取水 ® 相，以硫酸鎂加以乾燥。將有機相過濾後，進行減壓濃 縮’利用管柱層析法（氣仿：曱醇=98 : 2)對所獲得之殘渣 進行純化’藉此獲得標題化合物（9.2 mg，〇.〇37 mm〇1， 8°/〇 2 步驟）。 1H-NMR (300 MHz, DMSO-d6) δ 1.31 (t, J=6.9 Hz, 3H), 4.42 (q，2H)，5.79 (br，1H)，6.93 (br，2H)。 實施例1 -121 4-胺基-6-(2-氰基-1-亞肼基乙基）-2-乙氧基菸鹼腈To a solution of acetonitrile (26 kL, 0.475 mmol) in THF (2.0 mL), EtOAc (EtOAc (EtOAc) After stirring for 5 minutes, 4-amino-5-cyano-6-ethoxy 0 to 0 decanoic acid vinegar (100 mg, 0.452 mmol) was added at the same temperature, and the temperature was raised overnight. •186- 201028381 Stir on one side. After adding water and ethyl acetate to the reaction solution for separation, the aqueous phase was extracted with ethyl acetate and dried over magnesium sulfate. After the organic phase was passed through, the residue was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (methanol: methanol = 98: 2) to obtain 4-amino group _6_(2_ cyano Stuffed - 2 - ethoxylated nitrile (34.2 mg, 0.149 mmol). To a solution of the obtained compound in ethanol (1.5 mL) was added hydrazine hydrate (7.8 mg, 0.156 mmol). After water and ethyl acetate were added to the reaction mixture for separation, the water was extracted with ethyl acetate and dried over magnesium sulfate. The organic phase was filtered, and then concentrated under reduced pressure. The residue obtained was purified by column chromatography (methanol: methanol: 98: 2) to give the title compound (9.2 mg, 〇. 〇37 mm 〇 1, 8° / 〇 2 steps). 1H-NMR (300 MHz, DMSO-d6) δ 1.31 (t, J = 6.9 Hz, 3H), 4.42 (q, 2H), 5.79 (br, 1H), 6.93 (br, 2H). Example 1 -121 4-Amino-6-(2-cyano-1-indenylethyl)-2-ethoxy nicotinic nitrile

標題化合物係作為實施例1 -120之副產物而獲得。 1H-NMR (300 MHz, DMSO-d6) δ 1.33 (t, J=6.9 Hz, 3H), 3.88 (s, 2H), 4.42 (q, 2H), 6.81 (s, 1H), 6.88 (br, 2H), 7.70 (br，2H)。 141666.doc -187- 201028381 實施例1-122 N-(3-(4-胺基-5·氰基-6-乙氧基吡啶-2-基）-1Η-吡唑-5-基） 乙醯胺 [化 1122]The title compound was obtained as a by-product of Example 1-120. 1H-NMR (300 MHz, DMSO-d6) δ 1.33 (t, J = 6.9 Hz, 3H), 3.88 (s, 2H), 4.42 (q, 2H), 6.81 (s, 1H), 6.88 (br, 2H) ), 7.70 (br, 2H). 141666.doc -187- 201028381 Example 1-122 N-(3-(4-Amino-5.cyano-6-ethoxypyridin-2-yl)-1Η-pyrazole-5-yl) B Guanamine [Chemical 1122]

向4-胺基-5-氰基-6-乙氧基曱基吡啶醯肼（30 mg，0.123 mmol)、乙酸（11.1 mg，11 μΕ，0.185 mmol)及ΝΜΜ(33·6 mg ’ 36 μί，0·332 mmol)之 DMF(l.〇 mL)溶液中添加 HATU(56.3 mg ’ 0.148 mmol)，攪拌15小時。向反應溶液 中添加水及乙酸乙酯進行分離後，以乙酸乙酯萃取水相， 將合併之有機相以水及飽和食鹽水進行清洗，以硫酸鎂加 以乾燥。將有機相過濾後，進行減壓濃縮，利用管柱層析 法（氣仿：曱醇=19 : 1)對所獲得之殘渣進行純化，藉此獲 得標題化合物（2.8 mg，0.0099 mmol，8%)。 1H-NMR (遍 MHz，DMS0-d6) δ 134 (t, J=6 9 Hz，3H)，To 4-amino-5-cyano-6-ethoxymercaptopyridinium (30 mg, 0.123 mmol), acetic acid (11.1 mg, 11 μM, 0.185 mmol) and hydrazine (33·6 mg ' 36 μί HATU (56.3 mg '0.148 mmol) was added to a solution of 0.332 mmol) in DMF (1. EtOAc) and stirred for 15 hr. After water and ethyl acetate were added to the reaction solution for separation, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water and brine, and dried over magnesium sulfate. After the organic phase was filtered, the residue was evaporated to purified crystals crystals crystals eluted ). 1H-NMR (passing MHz, DMS0-d6) δ 134 (t, J=6 9 Hz, 3H),

(s，1H)，10.49 (s, 1H), 12.88 (s，1H)。 實施例1-123(s, 1H), 10.49 (s, 1H), 12.88 (s, 1H). Example 1-123

苯曱醯胺 -5-基） 141666.doc 188- 201028381 [化 1123]Benzoylamine -5-yl) 141666.doc 188- 201028381 [Chem. 1123]

標題化合物係依據實施例1-122之方法而合成。 1H-NMR (300-MHz，DMSO-D δ 134 (t，J=6.9 Hz 3H) 4.55 (q, 2H), 6.73 (s, 1H), 7.09 (s, 2H), 7.50-7.60 (m, 3H), φ 8.02 (d，J=7.8 Hz, 2H)，10.96 (br，1H)。 實施例1-124 N-(3-(4-胺基-5-氰基-6-乙氧基吡啶-2-基）-1 Η-11比唑-5-基）-2-(4-甲氧基苯基）乙醯胺 [化 1124]The title compound was synthesized according to the method of Example 1-122. 1H-NMR (300-MHz, DMSO-D δ 134 (t, J=6.9 Hz 3H) 4.55 (q, 2H), 6.73 (s, 1H), 7.09 (s, 2H), 7.50-7.60 (m, 3H) ), φ 8.02 (d, J = 7.8 Hz, 2H), 10.96 (br, 1H). Example 1-124 N-(3-(4-Amino-5-cyano-6-ethoxypyridine- 2-yl)-1 Η-11-pyrazol-5-yl)-2-(4-methoxyphenyl)acetamide [Chemical 1124]

標題化合物係依據實施例1-122之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 1.31 (t, J=6.9 Hz, 3H), 3.54 (s, 2H), 3.72 (s, 3H), 4.49 (q, 2H), 6.66 (br, 1H), 6.86-6.89 (d, 2H), 7.06 (br, 2H), 7.24 (d, J=9.0 Hz, 2H), 10.72 (s，lH)。 實施例1-125 N-(3-(4-胺基-5-氰基-6-乙氧基》比啶-2-基）-1Η-吼唑-5-基） 甲磺醯胺 141666.doc -189- 201028381 [化 1125]The title compound was synthesized according to the method of Example 1-122. 1H-NMR (300 MHz, DMSO-d6) δ 1.31 (t, J = 6.9 Hz, 3H), 3.54 (s, 2H), 3.72 (s, 3H), 4.49 (q, 2H), 6.66 (br, 1H) ), 6.86-6.89 (d, 2H), 7.06 (br, 2H), 7.24 (d, J=9.0 Hz, 2H), 10.72 (s, lH). Example 1-125 N-(3-(4-Amino-5-cyano-6-ethoxy)pyridin-2-yl)-1Η-indazol-5-yl)methanesulfonamide 141666. Doc -189- 201028381 [化1125]

向4-胺基-6-(5-胺基-1Η-η比唾-3-基）-2-乙氧基終驗腈（3 〇 mg，0.123 mmol)之°比啶u.o mL)溶液中添加甲磺醯氣 (18·3 mg，0·160 mmol)，攪拌16小時。向反應溶液中添加 水及乙酸乙酯進行分離後，以乙酸乙酯萃取水相，將合併 之有機相以水及飽和食鹽水進行清洗，以硫酸鎂加以乾 燥。將有機相過濾後’進行減壓濃縮，利用矽膠層析法 (氯仿.曱醇=19 ·· 1)對所獲得之殘渣進行純化，藉此獲得 標題化合物（8.6 mg，0.027 mmol，22%；)。 1H-NMR (300 MHz, DMSO-dg) δ 1.32 (t, J=6 9 Hz, 3H) 4.51 (q, 2H), 6.40 (s, 1H), 6.82 (s, 1H), 7.08 (br, 2H), 9.95 (s，1H)，13.06 (s，1H)。 實施例1-126 魯 N-(3-(4-胺基-5-氰基-6-乙氧基吡啶_2_基）_1Η·β比唑_5_基） 苯磺醯胺 [化 1126]To a solution of 4-amino-6-(5-amino-1Η-η than spani-3-yl)-2-ethoxyl far-nitrile (3 〇mg, 0.123 mmol) in a ratio of pyridine uo mL) Methanesulfonate (18. 3 mg, 0. 160 mmol) was added and stirred for 16 hours. Water and ethyl acetate were added to the reaction solution for separation, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and brine and dried over magnesium sulfate. After the organic phase was filtered, the title compound was obtained (yield: </RTI> </ RTI> </ RTI> </ RTI> <RTIgt; ). 1H-NMR (300 MHz, DMSO-dg) δ 1.32 (t, J = 6 9 Hz, 3H) 4.51 (q, 2H), 6.40 (s, 1H), 6.82 (s, 1H), 7.08 (br, 2H) ), 9.95 (s, 1H), 13.06 (s, 1H). Example 1-126 Lu N-(3-(4-Amino-5-cyano-6-ethoxypyridine_2-yl)_1Η·β-pyrazole-5-yl) Benzenesulfonamide [Chemical 1126] ]

141666.doc •190- 201028381 標題化合物係依據實施例1-125之方法而合成。 1H-NMR (300 MHz，DMSO-d6) δ 1.29 (t j=6 9 Hz 3H) 4.47 (q, 2H), 6.38 (d, J=2.1 Hz, 1H), 6.64 (s, 1H), 7.06 (br, 2H)，7.52-7.64 (m，3H)，7.79 (m, 2H)，10.60 (br，1H)。 實施例1-127 4-胺基-6-(3-胺基苯基）-2 -乙氧基終驗腈 [化 1127]141666.doc • 190-201028381 The title compound was synthesized according to the method of Example 1-125. 1H-NMR (300 MHz, DMSO-d6) δ 1.29 (tj = 6 9 Hz 3H) 4.47 (q, 2H), 6.38 (d, J = 2.1 Hz, 1H), 6.64 (s, 1H), 7.06 (br , 2H), 7.52-7.64 (m, 3H), 7.79 (m, 2H), 10.60 (br, 1H). Example 1-127 4-Amino-6-(3-aminophenyl)-2-ethoxy terminal nitrile [Chemical 1127]

向二氟甲續酸4-胺基-5 -氰基-6-乙氧基n比咬·2_基酯（1〇〇 mg，0.321 mmol)、Pd(PPh3)4(18.5 mg，0.016 mmol)及 2 mol/L 碳酸納水溶液（650 pL，1.284 mmol)之 THF(1.5 mL) 參 溶液中添加3-胺基苯基蝴酸（48.3 mg，0.353 mm〇i)，於加 熱回流下攪拌5小時。向反應溶液中添加水及乙酸乙酯進 行分離後，以乙酸乙酯萃取水相，將合併之有機相以水及 飽和食鹽水進行清洗，以硫酸鎂加以乾燥。將有機相過濾 後，進行減壓濃縮，利用中壓矽膠層析法（己烷/乙酸乙 酯；20-50%梯度）對所獲得之殘渣進行純化，獲得標題化 合物（53.6 mg，〇_211 mmol，15%)。 1H-NMR (300 MHz, DMSO-d6) δ 1.35 (t, J=6.9 Hz, 3H) (44 (q，2H)，5.23 (br，2H)，6.61 (m，1H)，6 73 (s，1H)， 6.99-7.15 (m，5H)。 實施例1-128 141666.doc -191 - 201028381 4-胺基- 6-(2-胺基苯基）-2 -乙氧基於驗腈 [化 1128]4-Difluoro-5-cyano-6-ethoxy n-bito-2-yl ester (1 〇〇 mg, 0.321 mmol), Pd(PPh3) 4 (18.5 mg, 0.016 mmol) And 2 mol/L sodium carbonate aqueous solution (650 pL, 1.284 mmol) in THF (1.5 mL). Add 3-aminophenyl phthalic acid (48.3 mg, 0.353 mm〇i) to the solution and stir under heating and reflux. hour. After water and ethyl acetate were added to the reaction solution for separation, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water and brine and dried over magnesium sulfate. After the organic phase was filtered, EtOAc (EtOAc m.) M, 15%). 1H-NMR (300 MHz, DMSO-d6) δ 1.35 (t, J = 6.9 Hz, 3H) (44 (q, 2H), 5.23 (br, 2H), 6.61 (m, 1H), 6 73 (s, 1H), 6.99-7.15 (m, 5H). Example 1-128 141666.doc -191 - 201028381 4-Amino-6-(2-aminophenyl)-2-ethoxyl in nitrile [1128] ]

標題化合物係依據實施例1-127之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 1.33 (t, J = 6.9 Hz, 3H), 4.33 (q, 2H), 6.11 (br, 2H), 6.56-6.73 (m, 3H), 6.99 (br, 2H)，7.08 (ddd，J=8.4 Hz, 1.2 Hz，1H), 7.27 (dd，J=7.8 Hz， 1.2 Hz，1H)。 實施例1-129 4,6'-二胺基-6-乙氧基-2,3·-聯吡啶-5-曱腈 [化 1129]The title compound was synthesized according to the method of Example 1-127. 1H-NMR (300 MHz, DMSO-d6) δ 1.33 (t, J = 6.9 Hz, 3H), 4.33 (q, 2H), 6.11 (br, 2H), 6.56-6.73 (m, 3H), 6.99 (br , 2H), 7.08 (ddd, J = 8.4 Hz, 1.2 Hz, 1H), 7.27 (dd, J = 7.8 Hz, 1.2 Hz, 1H). Example 1-129 4,6'-Diamino-6-ethoxy-2,3·-bipyridyl-5-indolecarbonitrile [Chemical 1129]

標題化合物係依據實施例1-127之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 1.34 (t, J=6.9 Hz, 3H), 4.43 (q, 2H), 6.41 (br, 2H), 6.50 (d, J=8.7 Hz, 2H), 6.69 (s, 1H), 6.87 (br, 2H), 7.89 (dd, J=8.4, 2.4 Hz, 1H), 8.53 (d, 1H)。 實施例1-130 4-胺基-2-乙氧基-6-(lH-吡唑-3-基）菸鹼腈 141666.doc -192- 201028381 [化 1130]The title compound was synthesized according to the method of Example 1-127. 1H-NMR (300 MHz, DMSO-d6) δ 1.34 (t, J = 6.9 Hz, 3H), 4.43 (q, 2H), 6.41 (br, 2H), 6.50 (d, J = 8.7 Hz, 2H), 6.69 (s, 1H), 6.87 (br, 2H), 7.89 (dd, J=8.4, 2.4 Hz, 1H), 8.53 (d, 1H). Example 1-130 4-Amino-2-ethoxy-6-(lH-pyrazol-3-yl)nicotinonitrile 141666.doc -192- 201028381 [Chem. 1130]

標題化合物係依據實施例1-127之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 1.34 (t, J=6.9 Hz, 3H), 4.45 (q, 2H), 6.69-7.06 (m, 4H), 7.79 (s, 1H), 13.06 (s, 1H) 〇 實施例1-131 4-胺基-2-乙氧基-6-(噁唑-2-基）菸鹼腈 [化 1131]The title compound was synthesized according to the method of Example 1-127. 1H-NMR (300 MHz, DMSO-d6) δ 1.34 (t, J = 6.9 Hz, 3H), 4.45 (q, 2H), 6.69-7.06 (m, 4H), 7.79 (s, 1H), 13.06 (s , 1H) 〇Example 1-131 4-Amino-2-ethoxy-6-(oxazol-2-yl)nicotinonitrile [Chemical 1131]

標題化合物係依據實施例1-127之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 1.34 (t, J=6.9 Hz, 3H), 4.43 (q, 2H), 7.14 (s, 1H), 7.30 (br, 2H), 7.43 (s 1H), 8.28 (s, 1H) 〇 實施例1-132 4-胺基-2-乙氧基-6-(噻唑-2-基）菸鹼腈 [化 1132]The title compound was synthesized according to the method of Example 1-127. 1H-NMR (300 MHz, DMSO-d6) δ 1.34 (t, J = 6.9 Hz, 3H), 4.43 (q, 2H), 7.14 (s, 1H), 7.30 (br, 2H), 7.43 (s 1H) , 8.28 (s, 1H) 〇 Example 1-132 4-Amino-2-ethoxy-6-(thiazol-2-yl)nicotinonitrile [Chemical 1132]

標題化合物係依據實施例1-127之方法而合成。 141666.doc •193- 201028381 1H-NMR (300 MHz, DMSO-d6) δ 1.36 (t, J=6.9 Hz, 3H), 4.44 (q, 2H), 7.18 (s, 1H), 7.30 (br, 2H), 7.89 (d, J=3.0 Hz, 1H), 7.98 (d，1H)。 實施例1-133 4-胺基-6-乙氧基-2,3'-聯吡啶-5-腈 [化 1133]The title compound was synthesized according to the method of Example 1-127. 141666.doc •193- 201028381 1H-NMR (300 MHz, DMSO-d6) δ 1.36 (t, J=6.9 Hz, 3H), 4.44 (q, 2H), 7.18 (s, 1H), 7.30 (br, 2H) ), 7.89 (d, J=3.0 Hz, 1H), 7.98 (d, 1H). Example 1-133 4-Amino-6-ethoxy-2,3'-bipyridyl-5-carbonitrile [Chemical 1133]

標題化合物係依據實施例1-127之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 1.36 (t, J=6.9 Hz, 3H), 4.47 (q, 2H), 6.91 (s, 1H), 7.15 (br, 2H), 7.52 (dd, J=7.8, 4.5 Hz, 1H), 8.25 (m, 1H), 8.63 (m, 1H), 9.09 (d, J=2.1 Hz, 1H)。 實施例1-134 4-胺基-6-(苯并[d]噻唑-2-基）-2-乙氧基菸鹼腈 [化 1134]The title compound was synthesized according to the method of Example 1-127. 1H-NMR (300 MHz, DMSO-d6) δ 1.36 (t, J = 6.9 Hz, 3H), 4.47 (q, 2H), 6.91 (s, 1H), 7.15 (br, 2H), 7.52 (dd, J = 7.8, 4.5 Hz, 1H), 8.25 (m, 1H), 8.63 (m, 1H), 9.09 (d, J = 2.1 Hz, 1H). Example 1-134 4-Amino-6-(benzo[d]thiazol-2-yl)-2-ethoxynicotinonitrile [Chem. 1134]

標題化合物係依據實施例1 -127之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 1.40 (t, J=6.9 Hz, 3H), 4.49 (q, 2H), 7.39 (s, 1H), 7.40 (br, 2H), 7.54 (m, 2H), 8.07-8.18 (m，2H)。 141666.doc -194· 201028381 實施例1-135 4 -胺基-6 -乙氧基-2,聯π比咬_5 -赌 [化 1135]The title compound was synthesized according to the method of Example 1-127. 1H-NMR (300 MHz, DMSO-d6) δ 1.40 (t, J = 6.9 Hz, 3H), 4.49 (q, 2H), 7.39 (s, 1H), 7.40 (br, 2H), 7.54 (m, 2H) ), 8.07-8.18 (m, 2H). 141666.doc -194· 201028381 Example 1-135 4 -Amino-6-ethoxy-2, π ratio bite_5 - gambling [Chem. 1135]

向三氟甲磺酸4-胺基-5-氰基-6-乙氧基吡啶-2·基酯（1〇〇 mg，0.321 mmol)及 Pd(PPh3)4(18.5 mg’ 0.016 mmol)之甲 ® 苯（2 mL)溶液中添加三丁基（2-吡啶基）錫（153.5 mg，0.417 mmol)，於加熱回流下搜拌5小時。向反應溶液中添加水及 乙酸乙醋進行分離後，以乙酸乙酯萃取水相，將合併之有 機相以水及飽和食鹽水進行清洗，以硫酸鎂加以乾燥。將 有機相過濾後’進行減壓濃縮，以氣仿使所獲得之殘渣固 化’藉此獲得標題化合物（27 4 mg，0.114 mmol，36%)。 1H-NMR (300 MHz, DMSO-d6) δ 1.37 (t, J=6.9 Hz, 3H), 瞻 4.49 (q，2H)，7.19 (br，2H)，7.43-7.47 (m，2H)，7.94 (m， J=7.8 Hz，2.1，1H)，8.27 (d，J=7.8 Hz, 1H)，8.64 (m, J=4.8 Hz，1H)。 實施例1-136 4-胺基-2-乙氧基_6_((三甲基矽烷基）乙炔基）菸鹼腈 [化 1136]4-Amino-5-cyano-6-ethoxypyridin-2-yl trifluoromethanesulfonate (1 mg, 0.321 mmol) and Pd(PPh3)4 (18.5 mg '0.016 mmol) To a solution of methyl benzene (2 mL), tributyl(2-pyridyl)tin (153.5 mg, 0.417 mmol) was added, and the mixture was stirred under reflux for 5 hours. After adding water and ethyl acetate to the reaction solution for separation, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water and saturated brine and dried over magnesium sulfate. After the organic phase was filtered, the title compound (27 4 mg, 0.114 mmol, 36%) was obtained. 1H-NMR (300 MHz, DMSO-d6) δ 1.37 (t, J = 6.9 Hz, 3H), prospect 4.49 (q, 2H), 7.19 (br, 2H), 7.43-7.47 (m, 2H), 7.94 ( m, J = 7.8 Hz, 2.1, 1H), 8.27 (d, J = 7.8 Hz, 1H), 8.64 (m, J = 4.8 Hz, 1H). Example 1-136 4-Amino-2-ethoxy_6-((trimethyldecyl)ethynyl)nicotinonitrile [Chemical 1136]

141666.doc -195- 201028381 向二氣甲崎酸4 -胺基-5-氣基-6-乙氧基β比咬-2 -基S旨（100 mg，0.321 mmol)、PdCl2(PPh3)4(11.2 mg，0.016 mmol)、 峨化銅（3.0 mg，0.016 mmol)、三乙基胺（97.4 mg，0.963 mmol)及四丁基氟化敍（5.9 mg，0.016 mmol)之 DMF(2 mL) 溶液中添加三甲基矽烷基乙炔（94.6 mg，0.963 mmol)，於 4〇°C下授拌3小時。向反應溶液中添加水及乙酸乙酯進行 分離後，以乙酸乙酯萃取水相，將合併之有機相以水及飽 和食鹽水進行清洗，以硫酸鎂加以乾燥。將有機相過濾 後，進行減壓濃縮，利用中壓矽膠層析法（己烷/乙酸乙 酯；20-50%梯度）對所獲得之殘渣進行純化，獲得標題化 合物（65.5 mg，0.253 mmol，79%)。 1H-NMR (300 MHz, DMSO-d6) δ 0.23 (s, 9Η), 1.28 (t, J=6.9 Hz，3H)，4.29 (q, 2H)，6.50 (s，1H)，7·13 (br，2H)。 實施例1-137 4-胺基-2-乙氧基-6-(異噪峻-3-基胺基）於驗腈 [化 1137]141666.doc -195- 201028381 to 2-dicarbazate 4-amino-5-yl-6-ethoxyβ ratio 2-base S (100 mg, 0.321 mmol), PdCl2 (PPh3) 4 ( 11.2 mg, 0.016 mmol), copper telluride (3.0 mg, 0.016 mmol), triethylamine (97.4 mg, 0.963 mmol) and tetrabutylfluoride (5.9 mg, 0.016 mmol) in DMF (2 mL) Trimethyldecyl acetylene (94.6 mg, 0.963 mmol) was added and the mixture was stirred at 4 ° C for 3 hours. After water and ethyl acetate were added to the reaction solution for separation, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water and saturated brine and dried over magnesium sulfate. After the organic phase was filtered, EtOAcjjjjjjjjjj 79%). 1H-NMR (300 MHz, DMSO-d6) δ 0.23 (s, 9 Η), 1.28 (t, J = 6.9 Hz, 3H), 4.29 (q, 2H), 6.50 (s, 1H), 7·13 (br , 2H). Example 1-137 4-Amino-2-ethoxy-6-(isophoric-3-ylamino) in a nitrile [Chemical 1137]

標題化合物係依據實施例1 -145之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 1.31 (t, J=6.9 Hz, 3H), 4.33 (q, 2H)，6.42 (s，1H), 6.58 (d, J=i.8 Hz, 1H)，6.74 (br, 2H)，8.66 (d，J=1.8 Hz，1H)，9.81 (s，ih)。 實施例1-138 141666.doc • 196· 201028381 4-胺基-2-乙氧基- 6-(°惡β坐-2-基胺基）终驗猜 [化 1138]The title compound was synthesized according to the method of Example 1-145. 1H-NMR (300 MHz, DMSO-d6) δ 1.31 (t, J = 6.9 Hz, 3H), 4.33 (q, 2H), 6.42 (s, 1H), 6.58 (d, J = i.8 Hz, 1H ), 6.74 (br, 2H), 8.66 (d, J = 1.8 Hz, 1H), 9.81 (s, ih). Example 1-138 141666.doc • 196· 201028381 4-Amino-2-ethoxy- 6-(°Iso-β-ylamino group) final test [Chem. 1138]

標題化合物係依據實施例1-145之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 1.30 (t, J=7.2 Hz, 3H), 4.33 (q, 2H), 6.85 (br, 2H), 7.04 (s, 2H), 7.72 (s, 1H), 10.54 (s，1H)。 實施例1-139 4-胺基- 6-(3 -氰基-2 -乙氧基-6-(°惡e坐-2-基胺基）n比咬-4-基 胺基）-2 -乙氧基於驗猜 [化 1139]The title compound was synthesized according to the method of Example 1-145. 1H-NMR (300 MHz, DMSO-d6) δ 1.30 (t, J = 7.2 Hz, 3H), 4.33 (q, 2H), 6.85 (br, 2H), 7.04 (s, 2H), 7.72 (s, 1H) ), 10.54 (s, 1H). Example 1-139 4-Amino-6-(3-cyano-2-ethoxy-6-(°oxe-2-ylamino)n-biti-4-ylamino)-2 -Ethoxylation in the test [Chemical 1139]

標題化合物係作為實施例1-138之副產物而分離。 1H-NMR (300 MHz, DMSO-d6) δ 1.17 (t, J=6.9 Hz, 3H), 1.32 (t, J=6.9 Hz, 3H), 4.30 (q, 2H), 4.40 (q, 2H), 6.05 (s, 1H), 6.77 (br, 2H), 7.05 (s, 1H), 7.74 (s, 1H), 9.10 (s, 1H), 9.42 (br，1H)。 實施例1-140 4 -胺基-2-乙氧基- 6-(雀吐-2-基胺基）於驗腈 I41666.doc -197- 201028381 [化 1140]The title compound was isolated as a by-product of Example 1-138. 1H-NMR (300 MHz, DMSO-d6) δ 1.17 (t, J = 6.9 Hz, 3H), 1.32 (t, J = 6.9 Hz, 3H), 4.30 (q, 2H), 4.40 (q, 2H), 6.05 (s, 1H), 6.77 (br, 2H), 7.05 (s, 1H), 7.74 (s, 1H), 9.10 (s, 1H), 9.42 (br, 1H). Example 1-140 4-Amino-2-ethoxy-6-(anthran-2-ylamino) in a nitrile I41666.doc -197- 201028381 [Chem. 1140]

標題化合物係依據實施例1-145之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 1.35 (t, J=7.2 Hz, 3H), 4.49 (q, 2H), 5.91 (s, 1H), 6.70 (br, 2H), 7.02 (d, J=3.6 Hz, 1H)，7.34 (d，J=3.6 Hz, 1H), 11.20 (s，1H)。 實施例1-141 4-胺基-2-乙氧基-6-(4-甲基噻唑-2-基胺基）菸鹼腈 [化 1141]The title compound was synthesized according to the method of Example 1-145. 1H-NMR (300 MHz, DMSO-d6) δ 1.35 (t, J = 7.2 Hz, 3H), 4.49 (q, 2H), 5.91 (s, 1H), 6.70 (br, 2H), 7.02 (d, J = 3.6 Hz, 1H), 7.34 (d, J = 3.6 Hz, 1H), 11.20 (s, 1H). Example 1-141 4-Amino-2-ethoxy-6-(4-methylthiazol-2-ylamino)nicotinonitrile [Chem. 1141]

標題化合物係依據實施例1-145之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 1.35 (t, J=6 9 Hz, 3H), 4.49 (q, 2H), 5.89 (s, 1H), 6.58 (s, 1H), 6.68 (br, 2H), 11.18 (br, 1H)。 實施例1-142 2-(4-胺基-5-氰基-6-乙氧基吡啶-2-基胺基）°塞°坐-5-甲酸 甲酯 [化 1142]The title compound was synthesized according to the method of Example 1-145. 1H-NMR (300 MHz, DMSO-d6) δ 1.35 (t, J = 6 9 Hz, 3H), 4.49 (q, 2H), 5.89 (s, 1H), 6.58 (s, 1H), 6.68 (br, 2H), 11.18 (br, 1H). Example 1-142 2-(4-Amino-5-cyano-6-ethoxypyridin-2-ylamino) °°°-5-carboxylic acid methyl ester [Chem. 1142]

141666.doc -198- 201028381 標題化合物係依據實施例1-145之方法而合成。 1H-NMR (300 MHz, DMSO-dg) § 1.38 (t, J=6.9 Hz, 3H), 3.77 (s, 3H), 4.53 (q, 2H), 5.99 (s, 1H), 6.85 (br, 2H), 8.03 (s，1H)。 實施例1-143 2-(4-胺基-5-氰基-6-乙氧基&quot;比咬-2·基胺基）噻唑_5_甲酸 [化 1143]141666.doc -198- 201028381 The title compound was synthesized according to the method of Example 1-145. 1H-NMR (300 MHz, DMSO-dg) § 1.38 (t, J = 6.9 Hz, 3H), 3.77 (s, 3H), 4.53 (q, 2H), 5.99 (s, 1H), 6.85 (br, 2H) ), 8.03 (s, 1H). Example 1-143 2-(4-Amino-5-cyano-6-ethoxy&quot;bital-2-ylamino)thiazole_5-carboxylic acid [Chemical 1143]

向2-(4 -胺基-5-氰基-6-乙氧基&quot;比咬-2-基胺基）嘆嗤-5-甲 酸甲酯（210 mg，1.316 mmol)之DMF溶液（2 mL)中添加2 mol/L氫氧化鈉水溶液（1.32 mL，2.63 mmol)，於50°C下擾 拌5小時。向反應溶液中添加1〇%檸檬酸水溶液及乙酸乙To a solution of 2-(4-amino-5-cyano-6-ethoxy&quot;biti-2-ylamino) sulphate-5-carboxylic acid methyl ester (210 mg, 1.316 mmol) in DMF (2 2 mol/L aqueous sodium hydroxide solution (1.32 mL, 2.63 mmol) was added to the mL), and the mixture was stirred at 50 ° C for 5 hours. Add 1% citric acid aqueous solution and acetic acid B to the reaction solution

酯，進行分離後’以乙酸乙酯萃取水相，將合併之有機相 以水及飽和食鹽水進行清洗，以硫酸鎂加以乾燥。將有機 相過濾後，進行減壓濃縮。使用乙酸乙酯清洗所獲得之殘 &gt;査’獲得標題化合物（185 mg，0.61 mmol，46%)，為黃色 固體。 1H-NMR (300 MHz, DMSO-d6) δ 1.38 (t, J=6.9 Hz, 3H), 4.52 (q，2H)，6.00 (s，ih), 6.85 (br，2H)，7.95 (s, 1H)，11.68 (br, 1H)。 實施例1-144 4-胺基-2·乙氧基苯基胺基）菸鹼腈 141666.doc -199- 201028381 [化 1144]After the ester was separated, the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and brine and dried over magnesium sulfate. The organic phase was filtered and concentrated under reduced pressure. The title compound (185 mg, 0.61 mmol, 46%) 1H-NMR (300 MHz, DMSO-d6) δ 1.38 (t, J = 6.9 Hz, 3H), 4.52 (q, 2H), 6.00 (s, ih), 6.85 (br, 2H), 7.95 (s, 1H) ), 11.68 (br, 1H). Example 1-144 4-Amino-2·ethoxyphenylamino) Nicotinonitrile 141666.doc -199- 201028381 [Chem. 1144]

於5 mL微波反應容器中添加三氟曱磺酸4-胺基-5-氰基-6-乙氧基吡啶-2-基酯（US 20060173050 A1，實施例 104 A) (100 mg，0.35 mmol)、三乙基胺（4 3 mg，56 pL， 0.42 mmol)及苯胺（99 mg，98 μί，1.06 mmol)之DMSO(1.8 mL)溶液進行覆蓋，使用Biotage Optimizer反應裝置，於 1 80°C下攪拌30分鐘。向反應溶液中添加水及乙酸乙酯進 行分離後，以乙酸乙酯萃取水相，將合併之有機相以水、 0.1 mol/L鹽酸及飽和食鹽水進行清洗，以硫酸鎂加以乾 燥。將有機相過濾後，進行減壓濃縮，利用中壓矽膠層析 法（己烷/乙酸乙酯；10-70%梯度）對所獲得之殘渣進行純 化，獲得標題化合物（14 mg，0.055 mmol，16%)，為白色 固體。 1H-NMR (300 MHz，DMSO-d6) δ 1.30 (t, J=6.0 Hz, 3H)， 4.32 (q, J=6.0 Hz, 2H), 5.71 (s, 1H), 6.46 (s, 1H), 6.91 (t, J=6.0 Hz, 1H), 7.25 (t, J=6 Hz, 2H), 7.49 (d, J=6.0 Hz, 2H), 9.03 (s，1H)。 MS(ESI)m/z=255 (M+H)+。 LC/MS tR=2.00 min。 實施例1-145 4-胺基-2-乙氧基-6-(4-(噁唑-5-基）苯基胺基）菸鹼腈 141666.doc •200· 201028381 [化 1145]4-Amino-5-cyano-6-ethoxypyridin-2-yl trifluorosulfonate was added to a 5 mL microwave reaction vessel (US 20060173050 A1, Example 104 A) (100 mg, 0.35 mmol) , a solution of triethylamine (43 mg, 56 pL, 0.42 mmol) and aniline (99 mg, 98 μί, 1.06 mmol) in DMSO (1.8 mL) using a Biotage Optimizer reactor at 180 °C Stir for 30 minutes. After water and ethyl acetate were added to the reaction solution for separation, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water, 0.1 mol/L hydrochloric acid and brine, and dried over magnesium sulfate. After the organic phase was filtered, EtOAcjjjjjjjjj 16%), as a white solid. 1H-NMR (300 MHz, DMSO-d6) δ 1.30 (t, J = 6.0 Hz, 3H), 4.32 (q, J = 6.0 Hz, 2H), 5.71 (s, 1H), 6.46 (s, 1H), 6.91 (t, J=6.0 Hz, 1H), 7.25 (t, J=6 Hz, 2H), 7.49 (d, J=6.0 Hz, 2H), 9.03 (s, 1H). MS (ESI) m / z = 255 (M + H) +. LC/MS tR = 2.00 min. Example 1-145 4-Amino-2-ethoxy-6-(4-(oxazol-5-yl)phenylamino)nicotinonitrile 141666.doc •200· 201028381 [Chem. 1145]

+ h2n+ h2n

Pd(OAc)2, BINAP OS2OO3 二噁烷，130°CPd(OAc)2, BINAP OS2OO3 dioxane, 130°C

於5 mL微波反應容器中添加三氟甲磺酸4-胺基-5-氱基-6-乙氧基吼0定-2-基酯（200 mg，0_643 mmol)、Pd(OAc)2 (14.4 mg，0.064 mmol)、BINAP(60 mg，0.096 mmol)、 Cs2C〇3(碳酸飽）(293 mg，0.900 mmol)及 4-(°惡》坐-5-基）苯 ® 胺（60 mg，0.964 mmol)之二°惡烧溶液進行覆蓋’使用 Biotage Optimizer反應裝置，於130 °C下加熱授拌1小時。 向反應溶液中添加水及乙酸乙酯進行分離後，以乙酸乙酯 萃取水相，將合併之有機相以水、10%檸檬酸及飽和食鹽 水進行清洗，以硫酸鎂加以乾燥。將有機相過濾後，進行 減麼濃縮，利用中壓管柱層析法（矽膠、己烷/乙酸乙酯 4 : 1〜3 ·· 1梯度）對所獲得之殘渣進行純化，獲得標題化合 物（47 mg，23%)，為白色固體。 9 1H-NMR (400 MHz, DMSO-d6) δ 1.34 (t, J=6.8 Hz, 3H), 4.36 (q, J=6.8 Hz, 2H), 5.77 (s, 1H), 6.52 (s, 2H), 7.53 (s, 1H), 7.64 (dd, J=8.8 Hz, 16.8 Hz, 4H), 8.36 (s, 1H), 9.29 (s，1H)。 MS(ESI)m/z=322 (M+H)+。 LC/MS tR=1.86 min。 實施例1-146 3-(4-胺基-5-氰基-6-乙氧基》比啶-2·基胺基）苯磺醯胺 141666.doc -201· 201028381 [化 1146]Add 4-amino-5-mercapto-6-ethoxyindole-2-yl trifluoromethanesulfonate (200 mg, 0_643 mmol) and Pd(OAc)2 in a 5 mL microwave reaction vessel. 14.4 mg, 0.064 mmol), BINAP (60 mg, 0.096 mmol), Cs2C〇3 (carbonated) (293 mg, 0.900 mmol) and 4-(°Ethyl-5-yl)benzene® amine (60 mg, 0.964 mmol) of the 2° smoldering solution was covered and covered with a Biotage Optimizer reaction apparatus and heated at 130 ° C for 1 hour. After water and ethyl acetate were added to the reaction solution for separation, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water, 10% citric acid and brine, and dried over magnesium sulfate. After the organic phase was filtered, the residue was purified and purified using EtOAc EtOAc EtOAc EtOAc 47 mg, 23%) as a white solid. 9 1H-NMR (400 MHz, DMSO-d6) δ 1.34 (t, J = 6.8 Hz, 3H), 4.36 (q, J = 6.8 Hz, 2H), 5.77 (s, 1H), 6.52 (s, 2H) , 7.53 (s, 1H), 7.64 (dd, J=8.8 Hz, 16.8 Hz, 4H), 8.36 (s, 1H), 9.29 (s, 1H). MS (ESI) m / z = 322 (M+H)+. LC/MS tR = 1.86 min. Example 1-146 3-(4-Amino-5-cyano-6-ethoxy)pyridin-2-ylamino)benzenesulfonamide 141666.doc -201· 201028381 [Chem. 1146]

標題化合物係依據實施例1-145之方法而合成。 1H-NMR (300 MHz, DMSO.D δ 1.29 (t, J=6.9 Hz, 3H)， 4.35 (q, 2H), 5.48 (br, 2H), 5.72 (s, 1H), 6.52 (br, 2H), 7.11-7.56 (m, 4H)，8.34 (t, J=l.8 Hz，1H)，9.40 (s, ih)。 實施例1-147 4-(4-胺基-5-氰基-6-乙氧基°比咬-2-基胺基）苯確醯胺 [化 1147]The title compound was synthesized according to the method of Example 1-145. 1H-NMR (300 MHz, DMSO.D δ 1.29 (t, J=6.9 Hz, 3H), 4.35 (q, 2H), 5.48 (br, 2H), 5.72 (s, 1H), 6.52 (br, 2H) , 7.11-7.56 (m, 4H), 8.34 (t, J=l.8 Hz, 1H), 9.40 (s, ih). Example 1-147 4-(4-Amino-5-cyano-6 -ethoxyl group than bit-2-ylamino)benzamine [1147]

標題化合物係依據實施例1-145之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 1.33 (t, J=6.9 Hz, 3H), 4.35 (q, 2H), 5.79 (s, 1H), 6.60 (br, 2H), 7.14 (s, 2H), 7.69 (s，4H)，9.48 (s，1H)。 實施例1-148 4-胺基-2_乙氧基-6-(4-(甲基磺醯基;)苯基胺基）菸鹼腈 [化 1148]The title compound was synthesized according to the method of Example 1-145. 1H-NMR (300 MHz, DMSO-d6) δ 1.33 (t, J = 6.9 Hz, 3H), 4.35 (q, 2H), 5.79 (s, 1H), 6.60 (br, 2H), 7.14 (s, 2H) ), 7.69 (s, 4H), 9.48 (s, 1H). Example 1-148 4-Amino-2-ethoxy-6-(4-(methylsulfonyl)phenylamino)nicotinonitrile [Chem. 1148]

標題化合物係依據實施例1 -145之方法而合成。 141666.doc -202- 201028381 1H-NMR (300 MHz, DMSO-d6) δ 1.34 (t, J=6.9 Hz, 3H), 4.36 (q, 2H), 5.82 (s, 1H), 6.65 (br, 2H), 7.78 (s, 4H), 9.64 (s，1H)。 實施例卜149 4-胺基-2-乙氧基-6-(3-(甲基續醯基）苯基胺基）於驗腈 [化 1149]The title compound was synthesized according to the method of Example 1-145. 141666.doc -202- 201028381 1H-NMR (300 MHz, DMSO-d6) δ 1.34 (t, J=6.9 Hz, 3H), 4.36 (q, 2H), 5.82 (s, 1H), 6.65 (br, 2H) ), 7.78 (s, 4H), 9.64 (s, 1H). EXAMPLE 149 4-Amino-2-ethoxy-6-(3-(methylthenyl)phenylamino)in the nitrile [Chem. 1149]

標題化合物係依據實施例1-145之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 1.32 (t, J=6.9 Hz, 3H)， 3.16 (s, 3H), 4.39 (q, 2H), 5.75 (s, 1H), 6.60 (br, 2H), 7.40-7.64 (m, 4H)，8.53 (s, 1H), 9.55 (s, 1H)。 實施例卜150 4-胺基-6-(3,4-二曱氧基苯乙基胺基）-2-乙氧基菸鹼腈 [化 1150]The title compound was synthesized according to the method of Example 1-145. 1H-NMR (300 MHz, DMSO-d6) δ 1.32 (t, J = 6.9 Hz, 3H), 3.16 (s, 3H), 4.39 (q, 2H), 5.75 (s, 1H), 6.60 (br, 2H) ), 7.40-7.64 (m, 4H), 8.53 (s, 1H), 9.55 (s, 1H). EXAMPLES 150 4-Amino-6-(3,4-dimethoxyphenethylamino)-2-ethoxynicotinonitrile [Chemical 1150]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=343 (M+H)+。 LC/MS tR=1.63 min。 實施例1-151 4-胺基-6-(4-氣苯乙基胺基乙氧基菸驗猜 141666.doc -203 · 201028381 [化 1151]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 343 (M+H)+. LC/MS tR = 1.63 min. Example 1-151 4-Amino-6-(4-gasphenethylamino ethoxy cigarette test 141666.doc -203 · 201028381 [Chem. 1151]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=316 (M+H)+。 LC/MS tR=2.28 min。 實施例1-152 6-(3-( 1H-咪唑-1-基）丙基胺基）-4-胺基-2-乙氧基菸鹼腈 [化 1152]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 316 (M + H) +. LC/MS tR = 2.28 min. Example 1-152 6-(3-( 1H-imidazol-1-yl)propylamino)-4-amino-2-ethoxynicotinonitrile [Chemical 1152]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=287 (M+H)+。 LC/MS tR=0.78 min。 實施例1-153 4-胺基-2-乙氧基-6-(2-側氧基氮雜環庚烷-3-基胺基）菸鹼腈 [化 1153]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 287 (M+H)+. LC/MS tR = 0.78 min. Example 1-153 4-Amino-2-ethoxy-6-(2-oxooxyazepane-3-ylamino) Nicotinonitrile [Chem. 1153]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=290 (M+H)+。 LC/MS tR=1.43 min 〇 141666.doc -204- 201028381 實施例1-154 4-胺基-2-乙氧基-6-(3-(曱基（苯基）胺基）丙基胺基）菸 鹼腈 [化 1154]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 290 (M + H) +. LC/MS tR=1.43 min 〇 141666.doc -204-201028381 Example 1-154 4-Amino-2-ethoxy-6-(3-(indolyl(phenyl)amino)propylamino Nicotinonitrile [Chemical 1154]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=326 (M+H)+。 LC/MS tR=l .58 min。 實施例1-155 6-(2-(1 Η-0引朵-3-基）乙基胺基）-4-胺基-2-乙氧基於驗腈 [化 1155]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 326 (M+H)+. LC/MS tR = 1.58 min. Example 1-155 6-(2-(1 Η-0-exyl-3-yl)ethylamino)-4-amino-2-ethoxy group in the nitrile [Chemical 1155]

標題化合物係依據實施例1 -144之方法而合成。 MS(ESI)m/z=322 (M+H)、 LC/MS tR=2.00 min。 實施例1-156 4-胺基-2-乙氧基-6-(3-(2-側氧基&quot;比洛咬基）丙基胺基） 菸鹼腈 141666.doc 205- 201028381 [化 1156]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m/z = 422 (M+H). Example 1-156 4-Amino-2-ethoxy-6-(3-(2-oxooxy&quot; piroxicamyl) propylamino) Nicotine nitrile 141666.doc 205- 201028381 1156]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=304 (M+H)+。 LC/MS tR=1.37 min。 實施例1-157 4 -胺基-2 -乙氧基-6 - ( °比。定-2 -基甲基胺基）於驗猜 [化 1157]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 304 (M + H) +. LC/MS tR = 1.37 min. Example 1-157 4 -Amino-2 -ethoxy-6 - ( ° ratio -1 -ylmethylamino group) in the test [Chem. 1157]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=270 (M+H)+。 LC/MS tR=2.71 min。 實施例1-158 N-(2-(4-胺基-5-氰基-6-乙氧基°比啶-2-基胺基）乙基）乙 醯胺 [化 1158]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 270 (M+H)+. LC/MS tR = 2.71 min. Example 1-158 N-(2-(4-Amino-5-cyano-6-ethoxy~pyridin-2-ylamino)ethyl)ethylamine [Chem. 1158]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=264 (M+H)+。 141666.doc -206· 201028381 LC/MS tR=1.12 min 〇 實施例1-159 心胺基·2·乙氧基·6_(5十夫味冬基）-^^3基胺基辦 鹼腈 [化 1159]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m/z =264 (M+H)+. 141666.doc -206· 201028381 LC/MS tR=1.12 min 〇Example 1-159 Heart amine · 2 · ethoxy · 6_(5 十夫味冬基)-^^3 base amine base nitrile [ 1159]

φ 標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=311 (Μ+Η)+。 LC/MS tR=1.64 min。 實施例1 -16 0 4-胺基-2-乙氧基-6-(2-甲氧基苯乙基胺基）菸鹼腈 [化 1160]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 311 (Μ + Η) +. LC/MS tR = 1.64 min. Example 1 - 16 0 4-Amino-2-ethoxy-6-(2-methoxyphenethylamino)nicotinonitrile [Chemical 1160]

標題化合物係依據實施例1 -14 4之方法而合成。 MS(ESI)m/z=313 (M+H)+。 LC/MS tR=2.16 min 〇 實施例1-161 4-私基- 6-(2,3- 一虱Η-ip -2_基胺基）-2 -己氧基終驗腈 141666.doc -207- 201028381 [化 1161]The title compound was synthesized according to the method of Example 1-14. MS (ESI) m / z = 313 (M+H)+. LC/MS tR=2.16 min 〇 Example 1-161 4-Pelement- 6-(2,3- 虱Η-ip -2-ylamino)-2-hexyloxy final nitrile 141666.doc - 207- 201028381 [化1161]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=295 (M+H)+。 LC/MS tR=2.20 min。 實施例1-162 6-(2-( 1H-咪唑-5-基）乙基胺基）-4-胺基-2-乙氧基菸鹼腈 [化 1162]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 295 (M + H) +. LC/MS tR = 2.20 min. Example 1-162 6-(2-( 1H-imidazol-5-yl)ethylamino)-4-amino-2-ethoxynicotinonitrile [Chem. 1162]

標題化合物係依據實施例1 -144之方法而合成。 MS(ESI)m/z=273 (M+H)+。 LC/MS tR=0_79 min。 實施例1-163 4-胺基-2-乙乳基-6-(2-(ntt咬-3-基）乙基胺基）於驗猜 [化 1163]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 273 (M+H)+. LC/MS tR = 0_79 min. Example 1-163 4-Amino-2-ethylidyl-6-(2-(ntt -3-yl)ethylamino) was tested [Chem. 1163]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=284 (M+H)+。 LC/MS tR=0.88 min。 141666.doc •208· 201028381 實施例1 -164 4-胺基-2-乙氧基-6-(2-(°比啶-2-基）乙基胺基）菸鹼腈 [化 1164]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 284 (M+H)+. LC/MS tR = 0.88 min. 141666.doc •208· 201028381 Example 1-164 4-Amino-2-ethoxy-6-(2-(pyridin-2-yl)ethylamino) Nicotinonitrile [Chem. 1164]

標題化合物係依據實施例1-144之方法而合成 MS(ESI)m/z=284 (M+H)+。 LC/MS tR=0.86 min。 實施例1-165 4-胺基-6-( 丁基胺基）-2 -乙氧基於驗猜 [化 1165] NH,The title compound was synthesized according to the method of Example 1-144 MS (ESI) m/z = 284 (M+H)+. LC/MS tR = 0.86 min. Example 1-165 4-Amino-6-(butylamino)-2-ethoxyl assay [Chem. 1165] NH,

Me 標題化合物係依據實施例1 -144之方法而合成。 MS(ESI)m/z=235 (M+H)+。 LC/MS tR=2.03 min。 實施例1-166 4-3*基·2 -乙氧基_6-(4-笨基丁基胺基）於驗猜 [化 1166]The Me title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 235 (M+H)+. LC/MS tR = 2.03 min. Example 1-166 4-3*-based 2-ethoxy- 6-(4-p-butylbutylamino) was tested [Chem. 1166]

標題化合物係依據實施例1-144之方法而合成 141666.doc -209- 201028381 MS(ESI)m/z=311 (M+H)+。 LC/MS tR=2.36 min。 實施例1-167 4-胺基-6-(2,5-二氣苄基胺基）-2-乙氧基菸鹼腈 [化 1167]The title compound was synthesized according to the method of Example 1-144. 141. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> LC/MS tR = 2.36 min. Example 1-167 4-Amino-6-(2,5-dioxabenzylamino)-2-ethoxynicotinic nitrile [Chem. 1167]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=337 (M+H)+。 LC/MS tR=2.29 min。 實施例1-168 3 - ( 4 -胺基-5 -亂基-6 -乙氧基°比°定-2 -基胺基）-4 -甲乳基苯 甲醯胺 [化 1168]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 337 (M+H)+. LC/MS tR = 2.29 min. Example 1-168 3 - ( 4 -Amino-5-ranyl-6-ethoxyl ratio -2 -ylamino)-4 -methyllactophenamide Amidoxime [Chem. 1168]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=328 (M+H)+。 LC/MS tR=l.38 min。 實施例1-169 4-胺基-2-乙氧基-6-(3-(羥基甲基）哌啶-1-基）菸鹼醯胺 141666.doc -210· 201028381 [化 1169]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m/z = 328 (M+H)+. LC/MS tR = 1.38 min. Example 1-169 4-Amino-2-ethoxy-6-(3-(hydroxymethyl)piperidin-1-yl)nicotinamide 141666.doc -210· 201028381 [Chem. 1169]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=277 (M+H)+。 LC/MS tR=1.60 min。 實施例1-170 1-(4 -胺基-5-乱基-6-乙乳基°比σ定-2-基）娘定-4-甲酿胺 [化 1170]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 277 (M+H)+. LC/MS tR = 1.60 min. Example 1-170 1-(4-Amino-5-ranyl-6-ethylidene ratio σ=-2-yl) Niangding-4-cartoamine [Chem. 1170]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=290 (Μ+Η)+。 LC/MS tR=1.27 min。 ❹ 實施例1-171 4-胺基- 6-(4 -卞基旅咬-1-基）-2-乙氧基於驗猜 [化 1171]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 290 (Μ + Η) +. LC/MS tR = 1.27 min.实施 Example 1-171 4-Amino- 6-(4-indolyl-Butyl-1-yl)-2-ethoxylated test [Chem. 1171]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=337 (M+H)+。 LC/MS tR=2.62 min 〇 141666.doc -211- 201028381 實施例1-172 1-(4-胺基-5-氰基-6-乙氧基吡啶-2-基）哌啶-3-曱醯胺 [化 1172]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 337 (M+H)+. LC/MS tR=2.62 min 〇 141666.doc -211-201028381 Example 1-172 1-(4-Amino-5-cyano-6-ethoxypyridin-2-yl)piperidine-3-indole Guanamine [Chemical 1172]

標題化合物係依據實施例1 -14 4之方法而合成。 MS(ESI)m/z=290 (M+H)+。 LC/MS tR=l_34 min。 實施例1-173 N-(l-(4-胺基-5-氰基-6-乙氧基η比咬_2_基）β比略咬_3-基）乙 醢胺 [化 1173]The title compound was synthesized according to the method of Example 1-14. MS (ESI) m / z = 290 (M + H) +. LC/MS tR = l_34 min. Example 1-173 N-(l-(4-Amino-5-cyano-6-ethoxy η than bite_2_yl) β ratio slightly biting _3-yl) acetamide [Chem. 1173]

標題化合物係依據實施例1 -144之方法而合成。 MS(ESI)m/z=290 (Μ+Η)+。 LC/MS tR=l.32 min。 實施例1-174 6-(1Η-吲哚-5-基胺基）-4-胺基乙氧基菸鹼腈 [化 1174]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 290 (Μ + Η) +. LC/MS tR = 1.32 min. Example 1-174 6-(1Η-吲哚-5-ylamino)-4-aminoethoxy nicotine nitrile [Chemical 1174]

141666.doc -212- 201028381 標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=294 (M+H)+。 LC/MS tR=1.79 min。 實施例1-175 4-胺基-6-(4-二甲基胺基节基胺基）-2-乙氧基菸鹼腈 [化 1175]141666.doc -212- 201028381 The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 294 (M + H) +. LC/MS tR = 1.79 min. Example 1-175 4-Amino-6-(4-dimethylaminosuccinylamino)-2-ethoxynicotinonitrile [Chem. 1175]

Me 標題化合物係依據實施例1 -144之方法而合成。 MS(ESI)m/z=312 (M+H)+。 LC/MS tR=2.17 min。 實施例1-176 4 -胺基- 6-(3,4 -二風1苯乙基胺基）-2-乙氧基於驗猜 [化 1176]The Me title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 312 (M + H) +. LC/MS tR = 2.17 min. Example 1-176 4 -Amino-6-(3,4-dipho-1 phenylethylamino)-2-ethoxyl was tested [Chem. 1176]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=351 (M+H)+。 LC/MS tR=2.41 min。 實施例1-177 4-胺基-2-乙氧基-6-(4-甲基苯乙基胺基）菸鹼腈 141666.doc -213- 201028381 [化 1177]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 351 (M + H)+. LC/MS tR = 2.41 min. Example 1-177 4-Amino-2-ethoxy-6-(4-methylphenethylamino)nicotinonitrile 141666.doc -213- 201028381 [Chem. 1177]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=297 (M+H)+。 LC/MS tR=2.27 min。 實施例1-178 4-胺基- 6-(2，5-二甲氧基节基胺基）-2 -乙氧基於驗猜 [化 1178]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 297 (M+H)+. LC/MS tR = 2.27 min. Example 1-178 4-Amino-6-(2,5-dimethoxyoxylamino)-2-ethoxyl assay [Chem. 1178]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=329 (M+H)+。 LC/MS tR=1.98 min。 實施例1-179 N-(2-(4-胺基-5-亂基-6-乙氧基11比咬-2-基胺基）苯基）乙 醯胺 [化 1179]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m/z = 329 (M+H)+. LC/MS tR = 1.98 min. Example 1-179 N-(2-(4-Amino-5-ranyl-6-ethoxy 11-buty-2-ylamino)phenyl)ethylamine [Chem. 1179]

標題化合物係依據實施例1-144之方法而合成。 141666.doc -214- 201028381 MS(ESI)m/z=312 (M+H)+。 LC/MS tR=2.17 min。 實施例1-180 4-胺基-6-(苯并[c][l,2,5]噻二唑-4-基胺基）-2-乙氧基菸 鹼腈 [化 1180]The title compound was synthesized according to the method of Example 1-144. 141666.doc -214- 201028381 MS (ESI) m/z = 312 (M+H)+. LC/MS tR = 2.17 min. Example 1-180 4-Amino-6-(benzo[c][l,2,5]thiadiazol-4-ylamino)-2-ethoxynicotinic nitrile [Chemical 1180]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=313 (Μ+Η)+。 LC/MS tR=2.15 min。 實施例1-181 4-胺基-2-乙氧基- 6-((2S)-2-苯基環丙基胺基）於驗腈 [化 1181]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 313 (Μ + Η) +. LC/MS tR = 2.15 min. Example 1-181 4-Amino-2-ethoxy-6-((2S)-2-phenylcyclopropylamino) in a nitrile [Chem. 1181]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=295 (M+H)+。 LC/MS tR=2.16 min 〇 實施例1-182 4-((4-胺基-5-氰基-6-乙氧基°比啶-2-基胺基）甲基）苯甲酸 甲酯 141666.doc -215- 201028381 [化 1182]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 295 (M + H) +. LC/MS tR=2.16 min 〇 1-182 4-((4-Amino-5-cyano-6-ethoxy~pyridin-2-ylamino)methyl)benzoic acid methyl ester 141666 .doc -215- 201028381 [化1182]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=327 (M+H)+。 LC/MS tR=1.91 min。 實施例1-183 (R)-2-乙醯胺-6-(4-胺基-5-氰基-6-乙氧基β比咬2基胺笑） 己酸甲酯 [化 1183]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m/z = 327 (M+H)+. LC/MS tR = 1.91 min. Example 1-183 (R)-2-Ethylamine-6-(4-Amino-5-cyano-6-ethoxyβ-biti 2-amineamine) Methyl hexanoate [Chem. 1183]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=364 (Μ+Η)+。 LC/MS tR=1.44 min。 實施例1-184 4-胺基-2-乙氧基-6-(2-(4-甲基哌嗪-1-基）乙基胺基）菸 鹼腈 [化 1184]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 364 (Μ + Η) +. LC/MS tR = 1.44 min. Example 1-184 4-Amino-2-ethoxy-6-(2-(4-methylpiperazin-1-yl)ethylamino)nicotinonitrile [Chemical 1184]

141666.doc -216- 201028381 標題化合物係依據實施例1 -1 44之方法而合成。 MS(ESI)m/z=305 (M+H).。 LC/MS tR_=0.70 min。 實施例1 -1 8 5 4-胺基-6-((4-节基嗎啉-2-基）甲基胺基）-2_乙氧基菸鹼腈 [化 1185]141666.doc -216- 201028381 The title compound was synthesized according to the method of Example 1-4. MS (ESI) m / z = 305 (M + H). LC/MS tR_=0.70 min. Example 1 -1 8 5 4-Amino-6-((4-pyromorpholin-2-yl)methylamino)-2-ethoxy nicotine nitrile [Chemical 1185]

標題化合物係依據實施例1 -144之方法而合成。 MS(ESI)m/z=368 (M+H)+。 LC/MS tR=l.〇3 min。 實施例1-186 4-胺基-2 -乙氧基- 6-(4-(°比唆-4-基甲基）娘嗪_ι_基）柊驗腈 [化 1186]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m/z = 368 (M+H)+. LC/MS tR = l. 〇 3 min. Example 1-186 4-Amino-2-ethoxy- 6-(4-(°-pyrimidin-4-ylmethyl)anthropazine _ι_yl) oxime nitrile [Chemical 1186]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=339 (M+H)+。 LC/MS tR=0.84 min。 實施例1-187 4-胺基-2-乙氧基-6-(4-氟苯乙基胺基）菸鹼腈 141666.doc -217- 201028381 [化 1187]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 339 (M+H)+. LC/MS tR = 0.84 min. Example 1-187 4-Amino-2-ethoxy-6-(4-fluorophenethylamino)nicotinonitrile 141666.doc -217- 201028381 [Chem. 1187]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=3〇l (m+H)+。 LC/MS tR=2.13 min 〇 實施例1-188 4-胺基-2-乙氧基甲基-1 Η-苯并[d]味峻_2·基）甲美 胺基）於驗睛 [化 1188]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 3 〇 l (m + H) +. LC/MS tR = 2.13 min 〇 Example 1-188 4-Amino-2-ethoxymethyl-1 hydrazine-benzo[d]methylene-2·yl)methanosamine) 1188]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=323 (M+H)+。 LC/MS tR=0.96 min 〇 實施例1-189 4-胺基-6-(2-(3,5-二甲基異噁唑-4-基）乙基胺基）_2_乙氧 基菸鹼腈 [化 1189]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 323 (M+H)+. LC/MS tR=0.96 min 〇 Example 1-189 4-Amino-6-(2-(3,5-dimethylisoxazol-4-yl)ethylamino)_2-ethoxy smoke Alkali nitrile [1189]

標題化合物係依據實施例1-144之方法而合成。 141666.doc -218- 201028381 MS(ESI)m/z=302 (M+H)+。 LC/MS tR=1.71 min。 實施例1-190 4 -胺基- 6- (2-環己基乙基胺基）-2-乙氧基於驗猜 [化 1190] NH2 nThe title compound was synthesized according to the method of Example 1-144. 141666.doc -218- 201028381 MS (ESI) m/z = 302 (M+H)+. LC/MS tR = 1.71 min. Example 1-190 4 -Amino-6-(2-cyclohexylethylamino)-2-ethoxylated test [Chemical 1190] NH2 n

CuNvC H kCuNvC H k

MeMe

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=289 (M+H)+。 LC/MS tR=2.53 min。 實施例1-191 4-胺基-6-(6,7-二曱氧基-3,4-二氫異喹啉-2(1H)-基）-2-乙 氧基菸鹼腈 [化 1191]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 289 (M+H)+. LC/MS tR = 2.53 min. Example 1-191 4-Amino-6-(6,7-didecyloxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-ethoxynicotinonitrile 1191]

標題化合物係依據實施例1 -1 44之方法而合成。 MS(ESI)m/z=355 (M+H)+。 LC/MS tR=2.06 min 〇 實施例1-192 4-胺基-2-乙氧基-6-(噻吩-2-基甲基胺基）菸鹼腈 141666.doc -219· 201028381 [化 1192]The title compound was synthesized according to the method of Example 1-4. MS (ESI) m / z = 355 (M+H)+. LC/MS tR=2.06 min 〇 Example 1-192 4-Amino-2-ethoxy-6-(thiophen-2-ylmethylamino)nicotinonitrile 141666.doc -219· 201028381 [Chemical 1192 ]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=275 (M+H)+。 LC/MS tR=1.86 min 〇 實施例1-193 4-胺基-2-乙氧基-6-(4-經基苯基胺基）路驗猜 [化 1193]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 275 (M+H)+. LC/MS tR=1.86 min 实施 Example 1-193 4-Amino-2-ethoxy-6-(4-phenylphenylamino) path test [Chem. 1193]

標題化合物係依據實施例1 -144之方法而合成。 1H-NMR (400 MHz，DMSO-d6) δ 1.29 (t，J=6 8 Hz 3h) 4.29 (q，J=6.8 Hz, 2H)，5.55 (s，1H)，6.30 (s，2H)，6 7〇 (/ J=8.4 Hz，2H)，7.20 (d，J=8.4 Hz, 2H)，8.62 (s Λ ’ 1H), 9.12 (br s，1H)。 MS(ESI)m/z=271 (M+H)+。 LC/MS tR=l.49 min。 實施例1-194 4-胺基-6-(苄基（甲基）胺基）_2-乙氧基菸鹼腈 141666.doc -220- 201028381 [化 1194]The title compound was synthesized according to the method of Example 1-144. 1H-NMR (400 MHz, DMSO-d6) δ 1.29 (t, J = 6 8 Hz 3h) 4.29 (q, J = 6.8 Hz, 2H), 5.55 (s, 1H), 6.30 (s, 2H), 6 7〇(/ J=8.4 Hz, 2H), 7.20 (d, J=8.4 Hz, 2H), 8.62 (s Λ ' 1H), 9.12 (br s, 1H). MS (ESI) m / z = 271 (M+H)+. LC/MS tR = 1.49 min. Example 1-194 4-Amino-6-(benzyl(methyl)amino)_2-ethoxynicotinonitrile 141666.doc -220- 201028381 [Chem. 1194]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=283 (M+H)+。 LC/MS tR=2.23 min 〇 實施例卜195 4 -胺基- 6- (苯并[d]°塞σ坐-2-基胺基）-2 -乙氧基於驗猜 [化 1195]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 283 (M+H)+. LC/MS tR=2.23 min 实施 Example 195 4 -Amino-6-(benzo[d]° σσ坐-2-ylamino)-2-ethoxyl. [Chem. 1195]

標題化合物係依據實施例1 -1 44之方法而合成。 MS(ESI)m/z=312 (M+H)+。 LC/MS tR=2.17 min。 實施例1-196 4-胺基-2-乙氧基-6-(甲基（苯基）胺基）菸鹼腈 [化 1196]The title compound was synthesized according to the method of Example 1-4. MS (ESI) m / z = 312 (M + H) +. LC/MS tR = 2.17 min. Example 1-196 4-Amino-2-ethoxy-6-(methyl(phenyl)amino)nicotinonitrile [Chem. 1196]

e 標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=269 (M+H)+。 LC/MS tR=2.23 min。 141666.doc -221 - 201028381 實施例1-197 4-胺基-2-乙氧基_6_(4-甲氧基苄基胺基）菸鹼腈 [化 1197]e The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 269 (M+H)+. LC/MS tR = 2.23 min. 141666.doc -221 - 201028381 Example 1-117 4-Amino-2-ethoxy_6-(4-methoxybenzylamino)nicotinonitrile [Chemical 1197]

標題化合物係依據實施例1 · 144之方法而合成。 MS(ESI)m/z=299 (M+H)+。 LC/MS tf 1.95 min 〇 實施例1-198 4-胺基-2·乙氧基_6-(吡咯啶-1-基）菸鹼腈 [化 1198]The title compound was synthesized according to the method of Example 1 - 144. MS (ESI) m / z = 299 (M+H)+. LC/MS tf 1.95 min 实施 Example 1-198 4-Amino-2·ethoxy 6-(pyrrolidin-1-yl)nicotinonitrile [Chem. 1198]

標題化合物係依據實施例1 _ 144之方法而合成。 MS(ESI)m/z=233 (M+H)+。 LC/MS tR=1.97 min。 實施例1-199 4·胺基-2-乙氧基_6_(N_嗎啉基）菸鹼腈 [化 1199]The title compound was synthesized according to the method of Example 1 - 144. MS (ESI) m / z = 233 (M+H)+. LC/MS tR = 1.97 min. Example 1-199 4·Amino-2-ethoxy_6_(N_morpholinyl)nicotinonitrile [Chem. 1199]

標題化合物係依據實施例1 _ 144之方法而合成。 141666.doc -222- 201028381 MS(ESI)m/z=249 (M+H)+。 LC/MS tR=1.59 min。 實施例1-200 4-胺基- 6-(4 -氣苯基胺基）-2 -乙氧基务驗猜 [化 1200]The title compound was synthesized according to the method of Example 1 - 144. 141666.doc -222- 201028381 MS (ESI) m/z = 249 (M+H)+. LC/MS tR = 1.59 min. Example 1-200 4-Amino-6-(4-oxophenylamino)-2-ethoxylate test [Chem. 1200]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=289 (M+H)+。 LC/MS tR=2.13 min。 實施例1-201 4-胺基-2-乙乳基- 6-(曱基（丙基）胺基）於驗猜 [化 1201]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 289 (M+H)+. LC/MS tR = 2.13 min. Example 1-201 4-Amino-2-ethylidyl- 6-(fluorenyl (propyl)amino group) was investigated [Chem. 1201]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=235 (M+H)+。 LC/MS tR=2.16 min。 實施例1-202 4-胺基-2-乙氧基- 6-(丙基胺基）於驗猜 141666.doc -223 - 201028381 [化 1202]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 235 (M+H)+. LC/MS tR = 2.16 min. Example 1-202 4-Amino-2-ethoxy- 6-(propylamino) was tested 141666.doc -223 - 201028381 [Chem. 1202]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=221 (M+H)+。 LC/MS tR=1.84 min。 實施例1-203 4-胺基- 6-(2-(二甲基胺基）乙基胺基）-2 -乙氧基於驗猜 [化 1203]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 221 (M+H)+. LC/MS tR = 1.84 min. Example 1-203 4-Amino-6-(2-(dimethylamino)ethylamino)-2-ethoxylated test [Chem. 1203]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=250 (M+H)+。 LC/MS tR=0.73 min。 實施例1-204 4-胺基-2-乙乳基- 6-(2 -甲氧基乙基胺基）於驗猜 [化 1204]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 250 (M + H) +. LC/MS tR = 0.73 min. Example 1-104 4-Amino-2-ethylidyl-6-(2-methoxyethylamino) was tested [Chem. 1204]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=237 (M+H)+。 LC/MS tR=1.44 min。 141666.doc -224- 201028381 實施例1-205 4 -胺基-2-乙氧基-6-(4 -曱基略π秦-1-基）於驗猜 [化 1205]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 237 (M+H)+. LC/MS tR = 1.44 min. 141666.doc -224- 201028381 Example 1-205 4-Amino-2-ethoxy-6-(4-indolyl π-qyl-1-yl) was tested [Chem. 1205]

標題化合物係依據實施例1 -14 4之方法而合成。 MS(ESI)m/z=262 (Μ+Η)+。 LC/MS tR=0.79 min。 實施例1-206 4-胺基-6-(環戍基胺基）-2-乙氧基菸鹼腈 [化 1206]The title compound was synthesized according to the method of Example 1-14. MS (ESI) m / z = 262 (Μ + Η) +. LC/MS tR = 0.79 min. Example 1-206 4-Amino-6-(cyclodecylamino)-2-ethoxynicotinic nitrile [Chem. 1206]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=247 (M+H)+。 LC/MS tR=1.99 min。 實施例1-207 4-胺基-2-乙氧基-6-((1-曱基-1Η-η比咯-2-基）曱基胺基）菸 驗猜 [化 1207]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 247 (M+H)+. LC/MS tR = 1.99 min. Example 1-207 4-Amino-2-ethoxy-6-((1-indolyl-1Η-ηpyrrol-2-yl)nonylamino) Smoking Quiz [Chem. 1207]

141666.doc -225- 201028381 標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=272 (M+H)+。 LC/MS tR=1.65 min。 實施例1-208 4 -胺基-2-乙氧基- 6-(甲基胺基）於驗猜 [化 1208]141666.doc -225- 201028381 The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 272 (M+H)+. LC/MS tR = 1.65 min. Example 1-208 4 -Amino-2-ethoxy- 6-(methylamino) was tested [Chem. 1208]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=193 (M+H)+。 LC/MS tR = 1.35 min。 實施例1-209 4-胺基-2-乙氧基- 6- (2-輕基乙基胺基）於驗猜 [化 1209]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 193 (M+H)+. LC/MS tR = 1.35 min. Example 1-209 4-Amino-2-ethoxy- 6-(2-light-ethylethylamino) was tested [Chem. 1209]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=223 (M+H)+。 LC/MS tR=l.11 min。 實施例1-210 4-胺基- 6-(二曱基胺基）-2 -乙氧基於驗猜 141666.doc -226- 201028381 [化 1210]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 223 (M+H)+. LC/MS tR = 1.11 min. Example 1-110 4-Amino-6-(didecylamino)-2-ethoxy group was tested. 141666.doc -226- 201028381 [Chem. 1210]

e 標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=207 (M+H)+。 LC/MS tR=1.78 min。 實施例1 -211 4-(4-胺基-5-亂基-6-乙氧基°比咬-2-基）痕°秦-1-甲酸第三 丁酯 [化 1211]e The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 207 (M+H)+. LC/MS tR = 1.78 min. Example 1 -211 4-(4-Amino-5-ranyl-6-ethoxyl ratio butyl-2-yl) trace t-butyl-1-carboxylic acid tert-butyl ester [Chemical 1211]

標題化合物係依據實施例1 -144之方法而合成。 MS(ESI)m/z=348 (M+H)+。 ❷ LC/MS tR=2.11 min 〇 實施例1-212 4-胺基-2-乙氧基-6-(4-氟笨基胺基）菸鹼腈 [化 1212]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 348 (M+H)+. ❷ LC/MS tR=2.11 min 实施 Example 1-212 4-Amino-2-ethoxy-6-(4-fluorophenylamino)nicotinonitrile [Chemical 1212]

標題化合物係依據實施例1 -1 44之方法而合成。 MS(ESI)m/z=273 (M+H)+。 141666.doc -227- 201028381 LC/MS tR=2.01 min。 實施例1-213 4-胺基-6-(3-氣苯基胺基）-2-乙氧基终驗猜 [化 1213]The title compound was synthesized according to the method of Example 1-4. MS (ESI) m / z = 273 (M+H)+. 141666.doc -227- 201028381 LC/MS tR=2.01 min. Example 1-113 4-Amino-6-(3-phenylphenylamino)-2-ethoxy group final test [Chem. 1213]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=289 (M+H)+。 LC/MS tR=2.19 min。 實施例1-214 4-胺基-2-乙氧基-6-(3-羥基苯基胺基）菸鹼猜 [化 1214]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 289 (M+H)+. LC/MS tR = 2.19 min. Example 1-214 4-Amino-2-ethoxy-6-(3-hydroxyphenylamino)nicotine guess [Chem. 1214]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=271 (M+H)+。 LC/MS tR=1.57 min。 實施例1-215 6-(4-乙醯苯基胺基）-4-胺基-2-乙氧基菸鹼腈 [化 1215]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 271 (M+H)+. LC/MS tR = 1.57 min. Example 1-215 6-(4-Ethylphenylamino)-4-amino-2-ethoxynicotinonitrile [Chemical 1215]

141666.doc -228- 201028381 標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=297 (M+H)+。 LC/MS tR=1.75 min。 實施例1-216 4-胺基-2-乙氧基_6_(4_甲硫基）苯基胺基）菸鹼腈 [化 1216]141666.doc -228- 201028381 The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 297 (M+H)+. LC/MS tR = 1.75 min. Example 1-216 4-Amino-2-ethoxy_6-(4-methylthio)phenylamino)nicotinonitrile [Chemical 1216]

標題化合物係依據實施例1 · 144之方法而合成。 MS(ESI)m/z=301 (M+H)+。 LC/MS tR=2.13 min。 實施例1 -217 4-胺基-2-乙氧基-6-(3-(甲硫基）苯基胺基）菸鹼腈 [化 1217]The title compound was synthesized according to the method of Example 1 - 144. MS (ESI) m / z = 301 (M+H)+. LC/MS tR = 2.13 min. Example 1 -217 4-Amino-2-ethoxy-6-(3-(methylthio)phenylamino)nicotinonitrile [Chem. 1217]

標題化合物係依據實施例1 -144之方法而合成。 MS(ESI)m/z=301 (M+H)+。 LC/MS tR=2.14 min。 實施例1-218 4-胺基-6-(4·(4,5·二孰_1Η-σ米β坐-1-基）苯基胺基）-2-乙氧 基於驗猜 141666.doc -229- 201028381 [化 1218]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 301 (M+H)+. LC/MS tR = 2.14 min. Example 1-118 4-Amino-6-(4·(4,5·2孰_1Η-σ米ββ-1-yl)phenylamino)-2-ethoxyl was tested at 141666.doc -229- 201028381 [Chem. 1218]

標題化合物係依據實施例1-144之方法而人成 MS(ESI)m/z=389 (M+H)+。 LC/MS tR=2.10 min。 實施例1-219The title compound was obtained according to the method of Example 1-144 to MS (ESI) m/z = 389 (M+H)+. LC/MS tR = 2.10 min. Example 1-219

鹼腈 [化 1219]Alkali nitrile [Chemical 1219]

標題化合物係依據實施例1 -144之方法而合成。 MS(ESI)m/z=347 (M+H)+。 LC/MS tR=l.79 min。 實施例1-220 4-胺基-2 -乙氧基-6-(4-(N-嗎琳基）苯基胺基）於驗猜 [化 1220]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 347 (M+H)+. LC/MS tR = 1.79 min. Example 1-220 4-Amino-2-ethoxy-6-(4-(N-morphinyl)phenylamino) was investigated [Chem. 1220]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=340 (M+H)+。 141666.doc -230· 201028381 LC/MS tR=1.59 min。 實施例1-221 4-胺基-6-(4-苯甲醯基苯基胺基）-2-乙氧基菸鹼腈 [化 1221]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 340 (M + H) +. 141666.doc -230· 201028381 LC/MS tR=1.59 min. Example 1-221 4-Amino-6-(4-benzylidenylphenylamino)-2-ethoxynicotinonitrile [Chemical 1221]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=359 (M+H)+。 LC/MS tR=2.18 min。 實施例1-222 4-胺基-2-乙氧基-6-(2-曱基啥琳-6-基胺基）於驗猜 [化 1222]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 359 (M+H)+. LC/MS tR = 2.18 min. Example 1-222 4-Amino-2-ethoxy-6-(2-mercaptopurin-6-ylamino) Assay [Chem. 1222]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=320 (M+H)+。 LC/MS tR=l.09 min。 實施例1-223 4-胺基-6-(苯并[dHl ,3]二氧雜環戊烯-5-基胺基）-2-乙氧 基於驗腈 141666.doc -231 - 201028381 [化 1223]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 320 (M + H) +. LC/MS tR = 1.09 min. Example 1-223 4-Amino-6-(benzo[dHl,3]dioxol-5-ylamino)-2-ethoxyl in nitrile 141666.doc -231 - 201028381 1223]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=299 (M+H)+。 LC/MS tR=1.88 min。 實施例1-224 4 -胺基-2 -乙氧基-6 - ( 2 -甲基-1Η -11引π朵-5 -基胺基）於驗猜 [化 1224]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 299 (M+H)+. LC/MS tR = 1.88 min. Example 1-224 4-Amino-2-ethoxy-6-(2-methyl-1Η-11-indolyl-5-ylamino) Assay [Chem. 1224]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=308 (Μ+Η)+。 LC/MS tR=1.91 min。 實施例1-225 4-胺基- 6-(4 -亂基苯基胺基）-2 -乙氧基务驗猜 [化 1225]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 308 (Μ + Η) +. LC/MS tR = 1.91 min. Example 1-25 4-Amino-6-(4-oxylphenylamino)-2-ethoxylate test [Chem. 1225]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=280 (M+H)+。 LC/MS tR=l.85 min。 141666.doc -232- 201028381 實施例1-226 4-胺基-2-乙氧基-6-(對甲苯基胺基）菸鹼腈 [化 1226]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m/z = 280 (M+H)+. LC/MS tR = 1.85 min. 141666.doc -232- 201028381 Example 1-226 4-Amino-2-ethoxy-6-(p-tolylamino)nicotinonitrile [Chemical 1226]

標題化合物係依據實施例1 -144之方法而合成。 MS(ESI)m/z=269 (M+H)+。 參 LC/MS tR=2.13 min。 實施例1-227 4-胺基-6-(4-(二甲基胺基）苯基胺基）-2-乙氧基菸鹼腈 [化 1227]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 269 (M+H)+. Reference LC/MS tR = 2.13 min. Example 1-227 4-Amino-6-(4-(dimethylamino)phenylamino)-2-ethoxynicotinonitrile [Chemical 1227]

標題化合物係依據實施例1 -1 44之方法而合成。 MS(ESI)m/z=298 (M+H)+。 LC/MS tR=1.07 min。 實施例1-228 4-胺基-6-(2-氣苯基胺基）-2-乙氧基菸鹼腈 [化 1228]The title compound was synthesized according to the method of Example 1-4. MS (ESI) m / z = 298 (M + H) +. LC/MS tR = 1.07 min. Example 1-228 4-Amino-6-(2-phenylphenylamino)-2-ethoxynicotinonitrile [Chemical 1228]

標題化合物係依據實施例1-144之方法而合成。 141666.doc -233 - 201028381 MS(ESI)m/z=289 (M+H)+。 LC/MS tR=2.18 min。 實施例1-229 4 -胺基- 6- (聯苯-3-基胺基）-2 -乙氧基於驗猜 [化 1229]The title compound was synthesized according to the method of Example 1-144. 141666.doc -233 - 201028381 MS (ESI) m/z = 289 (M+H)+. LC/MS tR = 2.18 min. Example 1-229 4 -Amino-6-(biphenyl-3-ylamino)-2-ethoxy group was tested [Chemical 1229]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=331 (M+H)+。 LC/MS tR=2.41 min。 實施例1-230 4-胺基-2-乙氧基- 6-(3 -甲氧基苯基胺基）於驗猜 [化 1230]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 331 (M+H)+. LC/MS tR = 2.41 min. Example 1-230 4-Amino-2-ethoxy-6-(3-methoxyphenylamino) was tested [Chem. 1230]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=285 (M+H)+。 LC/MS tR=1.95 min 〇 實施例1-231 4 -胺基-2 -乙氧基-6 - (4 -頌基苯基胺基）於驗猜 [化 1231]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 285 (M+H)+. LC/MS tR = 1.95 min 实施 Example 1-231 4 -Amino-2 -ethoxy-6 - (4-nonylphenylamino) was tested [Chem. 1231]

Me 141666.doc •234- 201028381 標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=300 (M+H)+。 LC/MS tR=2.00 min。 實施例1-232 4-胺基-2-乙氧基-6-(1-甲基-1H-吲哚-5-基胺基）菸鹼腈 [化 1232]Me 141666.doc • 234- 201028381 The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 300 (M + H) +. LC/MS tR = 2.00 min. Example 1-232 4-Amino-2-ethoxy-6-(1-methyl-1H-indol-5-ylamino)nicotinonitrile [Chemical 1232]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=308 (M+H)+。 LC/MS tR=2.00 min。 實施例1-233 3-(4-(4-胺基-5-亂基-6-乙氧基吼。定-2-基胺基）苯氧基）嘆 吩-2-曱酸甲酯 [化 1233]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m/z = 308 (M+H)+. LC/MS tR = 2.00 min. Example 1-233 3-(4-(4-Amino-5-ranyl-6-ethoxyindole.din-2-ylamino)phenoxy)-thin-2-carboxylate [ 1233]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=411 (M+H)+。 LC/MS tR=2.13 min。 實施例1-234 4-胺基-2-乙氧基-6-(4-苯氧基苯基胺基）菸鹼腈 141666.doc -235 - 201028381 [化 1234]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 411 (M + H) +. LC/MS tR = 2.13 min. Example 1-234 4-Amino-2-ethoxy-6-(4-phenoxyphenylamino)nicotinonitrile 141666.doc -235 - 201028381 [Chem. 1234]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=347 (M+H)+。 LC/MS tR=2.35 min。 實施例1-235 4-(4 -胺基-5 -亂基-6-乙氧基D比咬-2 -基胺基）-N，N -二曱基 苯磺醯胺 [化 1235]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 347 (M+H)+. LC/MS tR = 2.35 min. Example 1-235 4-(4-Amino-5-ranyl-6-ethoxy D ratio -2-amino-amino)-N,N-dimercaptobenzenesulfonamide [Chemical 1235]

標題化合物係依據實施例1 -144之方法而合成。 MS(ESI)m/z=362 (M+H)+。 LC/MS tR=l.79 min 〇 實施例1-236 4 -胺基-2-乙氧基- 6- (3 -侧氧基-1，3 -二風異苯并D夫喃-5 -基 胺基）菸鹼腈 [化 1236]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 362 (M+H)+. LC/MS tR = 1.79 min 〇 Example 1-236 4 -Amino-2-ethoxy- 6-(3-oxo-oxy-1,3-dithiaisobenzo D-propan-5- Amino) nicotine nitrile [1236]

標題化合物係依據實施例1-144之方法而合成。 141666.doc -236- 201028381 MS(ESI)m/z=311 (M+H)+。 LC/MS tR=l_64 min。 實施例1-237 4-胺基-2-乙氧基-6-( 1-(甲基磺醯基）吲哚啉-5-基胺基）菸 鹼腈 [化 1237]The title compound was synthesized according to the method of Example 1-144. 141666.doc -236- 201028381 MS (ESI) m/z = 311 (M+H)+. LC/MS tR = l_64 min. Example 1-137 4-Amino-2-ethoxy-6-(1-(methylsulfonyl)porphyrin-5-ylamino)nicotinonitrile [Chemical 1237]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=374 (M+H)+。 LC/MS tR=1.75 min。 實施例1-238 4-胺基-2-乙氧基-6-(喹噁啉-6-基胺基）菸鹼腈 [化 1238]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 374 (M + H)+. LC/MS tR = 1.75 min. Example 1-238 4-Amino-2-ethoxy-6-(quinoxalin-6-ylamino)nicotinonitrile [Chemical 1238]

標題化合物係依據實施例1 -144之方法而合成。 MS(ESI)m/z=307 (M+H)+。 LC/MS tR=l.55 min。 實施例1-239 4-胺基-6-(苯并[d]噁唑-6-基胺基）-2-乙氧基菸鹼腈 141666.doc •237- 201028381 [化 1239]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 307 (M + H) +. LC/MS tR = 1.55 min. Example 1-139 4-Amino-6-(benzo[d]oxazol-6-ylamino)-2-ethoxynicotinonitrile 141666.doc •237- 201028381 [Chem. 1239]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=296 (M+H)+。 LC/MS tR=1.65 min。 實施例1-240 4-胺基-2-乙氧基-6-(3-(噁唑-5-基）苯基胺基）菸鹼腈 [化 1240]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 296 (M + H) +. LC/MS tR = 1.65 min. Example 1-240 4-Amino-2-ethoxy-6-(3-(oxazol-5-yl)phenylamino)nicotinonitrile [Chemical 1240]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=322 (M+H)+。 LC/MS tR = l.80 min。 實施例1-241 6-(4-(1 H-°比咯-1-基）苯基胺基）-4-胺基-2-乙氧基菸鹼腈 [化 1241]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 322 (M+H)+. LC/MS tR = l.80 min. Example 1-241 6-(4-(1H-°pyrrol-1-yl)phenylamino)-4-amino-2-ethoxynicotinonitrile [Chemical 1241]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=320 (M+H)+。 LC/MS tR=2.19 min。 141666.doc -238- 201028381 實施例1-242 6-(4-(( 1H-&quot;比唑-1-基）曱基）苯基胺基）-4-胺基-2-乙氧基菸 鹼腈 [化 1242]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 320 (M + H) +. LC/MS tR = 2.19 min. 141666.doc -238- 201028381 Example 1-242 6-(4-((1H-&quot;Biazol-1-yl)indolyl)phenylamino)-4-amino-2-ethoxymethane Alkali nitrile [Chemical 1242]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=267 (M+H)+。 LC/MS tR=l_77 min。 實施例1-243 3-(4-胺基-5-氰基-6-乙氧基吡啶-2-基胺基）苯曱酸甲酯 [化 1243]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 266 (M+H)+. LC/MS tR = l_77 min. Example 1-243 Methyl 3-(4-amino-5-cyano-6-ethoxypyridin-2-ylamino)benzoate [Chemical 1243]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=313 (M+H)+。 LC/MS tR=l.95 min。 實施例1-244 6-(4-(1Η-»比唑-1-基）苯基胺基）-4-胺基-2-乙氧基菸鹼腈 [化 1244]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 313 (M+H)+. LC/MS tR = 1.95 min. Example 1-244 6-(4-(1Η-»Bazol-1-yl)phenylamino)-4-amino-2-ethoxynicotinonitrile [Chemical 1244]

141666.doc -239- 201028381 標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=321 (M+H)+。 LC/MS tR=1.87 min。 實施例1-245 4 -胺基-6 - ( 4 -壤己基苯基胺基）-2 -乙乳基於驗猜 [化 1245]141666.doc -239- 201028381 The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 321 (M + H) +. LC/MS tR = 1.87 min. Example 1-245 4-Amino-6-(4-oxalylphenylamino)-2-ethylemulsion based on the test [Chem. 1245]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=337 (M+H)+。 LC/MS tR=2.72 min。 實施例1-246 6-(3-乙醯苯基胺基）-4-胺基-2-乙氧基菸鹼腈 [化 1246]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 337 (M+H)+. LC/MS tR = 2.72 min. Example 1-246 6-(3-Ethylphenylamino)-4-amino-2-ethoxynicotinonitrile [Chem. 1246]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=297 (M+H)+。 LC/MS tR=1.81 min 〇 實施例1-247 4 -胺基-2 -乙氧基-6 - ( 2 -側氧基-2 Η -苯并ntb喃-6 -基胺基）於 鹼腈 141666.doc -240- 201028381 [化 1247]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 297 (M+H)+. LC/MS tR=1.81 min 〇 Example 1-247 4 -Amino-2-ethoxy-6-(2-o-oxo-2-indole-benzonb- yl-6-ylamino) 141666.doc -240- 201028381 [Chem. 1247]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=323 (M+H)+。 LC/MS tR=1.70 min。 實施例1-248 參 4-(4-胺基-5-吼基-6-乙乳基nt|j 〇定-2-基胺基）-N-(3,4 -二甲 基異噁唑-5-基）苯磺醯胺 [化 1248]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 323 (M+H)+. LC/MS tR = 1.70 min. Example 1-248 Reference 4-(4-Amino-5-mercapto-6-ethylidyl nt|j 〇 -2--2-ylamino)-N-(3,4-dimethylisoxazole -5-yl) benzenesulfonamide [Chemical 1248]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=429 (M+H)+。 LC/MS tR=l.84 min。 實施例1-249 4 -胺基-2-乙氧基-6-(4-(6-甲基苯并[d]嗔B坐-2 -基）苯基胺 基）於驗腈 [化 1249]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m/z = 422 (M+H)+. LC/MS tR = 1.84 min. Example 1-249 4-Amino-2-ethoxy-6-(4-(6-methylbenzo[d]indole B-n-yl)phenylamino) was assayed for nitrile [1249] ]

標題化合物係依據實施例1-144之方法而合成。 141666.doc -241 · 201028381 MS(ESI)m/z=402 (M+H)+。 LC/MS tR=2.89 min。 實施例1-250 4 -胺基-2-乙氧基- 6-(啥琳-6-基胺基）於驗猜 [化 1250]The title compound was synthesized according to the method of Example 1-144. 141666.doc -241 · 201028381 MS(ESI) m/z = 402 (M+H)+. LC/MS tR = 2.89 min. Example 1-50 4-Amino-2-ethoxy- 6-(啥琳-6-ylamino) was tested [Chemical 1250]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=306 (M+H)+。 LC/MS tR=l.25 min。 實施例1-251 4 -胺基- 6- (苯并[&lt;1]嘆唾-6-基胺基）-2 -乙乳基於驗猜 [化 1251]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 306 (M + H) +. LC/MS tR = 1.25 min. Example 1-251 4-Amino-6-(benzo[&lt;1] sin-6-ylamino)-2-ethylemulsion based on the test [Chem. 1251]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=312 (M+H).。 LC/MS tR=1.81 min。 實施例1-252 6-(4-(11^-11 米β坐-1 -基）苯基胺基）-4-胺基-2-乙氧基於驗猜 141666.doc -242- 201028381 [化 1252]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 312 (M + H). LC/MS tR = 1.81 min. Example 1-252 6-(4-(11^-11 m β-l-yl)phenylamino)-4-amino-2-ethoxy group was tested 141666.doc -242- 201028381 1252]

標題化合物係依據實施例1 -14 4之方法而合成。 MS(ESI)m/z=321 (M+H)+。 LC/MS tR=1.28 min。 實施例1-253 4-胺基-6-(2,3-二氫-1H-茚-5-基胺基）-2-乙氧基菸鹼腈 [化 1253]The title compound was synthesized according to the method of Example 1-14. MS (ESI) m / z = 321 (M + H) +. LC/MS tR = 1.28 min. Example 1-253 4-Amino-6-(2,3-dihydro-1H-indol-5-ylamino)-2-ethoxynicotinic nitrile [Chemical 1253]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=295 (M+H)+。 LC/MS tR=2.48 min。 實施例1-254 4-胺基- 6-(2，3-二氫苯并β夫喃-5-基胺基）-2 -乙氧基於驗猜 [化 1254]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 295 (M + H) +. LC/MS tR = 2.48 min. Example 1-254 4-Amino-6-(2,3-dihydrobenzo-β-pentan-5-ylamino)-2-ethoxyl assay [Chem. 1254]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=297 (M+H)+。 LC/MS tR=1.95 min。 141666.doc -243 - 201028381 實施例1-255 (R)-2 -乙酿胺-3-(4-(4 -胺基-5 -亂基-6-乙氧基°比唆-2-基胺 基）苯基）丙酸曱酯 [化 1255]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 297 (M+H)+. LC/MS tR = 1.95 min. 141666.doc -243 - 201028381 Example 1-255 (R)-2 - Ethylamine-3-(4-(4-amino-5-ranyl-6-ethoxy) 唆-2-yl Amino)phenyl)propanoic acid decyl ester [Chemical 1255]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=398 (M+H)+。 LC/MS tR=1.66 min。 實施例1-256 4-胺基-2-乙氧基·6-(4-((Ν-嗎啉基）磺醯基）苯基胺基）菸 驗腈 [化 1256]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 398 (M+H)+. LC/MS tR = 1.66 min. Example 1-256 4-Amino-2-ethoxy-6-(4-((indolyl-morpholino)sulfonyl)phenylamino) citric acid [Chemical 1256]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=404 (Μ+Η)+。 LC/MS tR=1.85 min。 實施例1-257 4-胺基- 6-(4-(4-^苯乳基）苯基胺基）-2-乙氧基於驗猜 141666.doc •244- 201028381 [化 1257]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 404 (Μ + Η) +. LC/MS tR = 1.85 min. Example 1-157 4-Amino-6-(4-(4-(phenylphenyl)phenylamino)-2-ethoxyl was tested 141666.doc •244- 201028381 [Chem. 1257]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=381 (M+H)+。 LC/MS tR=2.76 min。 實施例1-258 4-胺基-2-乙氧基-6-(4-(5-甲基苯并[d]噁唑-2-基）苯基胺 基）於驗腈 [化 1258]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 381 (M+H)+. LC/MS tR = 2.76 min. Example 1-258 4-Amino-2-ethoxy-6-(4-(5-methylbenzo[d]oxazol-2-yl)phenylamine) was tested on nitrile [Chem. 1258]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=386 (M+H)+。The title compound was synthesized according to the method of Example 1-144. MS (ESI) m/z = 386 (M+H)+.

LC/MS tR=2.67 min。 實施例1-259 4-胺基-2-乙氧基-6-(4-(5-乙基苯并[d]噁唑-2-基）苯基胺 基）於驗腈 [化 1259]LC/MS tR = 2.67 min. Example 1-259 4-Amino-2-ethoxy-6-(4-(5-ethylbenzo[d]oxazol-2-yl)phenylamine) was tested on nitrile [Chem. 1259]

141666.doc - 245 - 201028381 標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=400 (M+H)+。 LC/MS tR=2.91 min。 實施例卜260 4-胺基-2-乙氧基-6-(2-(3-甲氧基苯基）苯并[d]噁唑-5-基 胺基）菸鹼腈 [化 1260]141666.doc - 245 - 201028381 The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 400 (M + H) +. LC/MS tR = 2.91 min. EXAMPLE 260 4-Amino-2-ethoxy-6-(2-(3-methoxyphenyl)benzo[d]oxazol-5-ylamino)nicotinonitrile [Chemical 1260]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=402 (M+H)+。 LC/MS tR=2.48 min ° 實施例1-261 4-胺基-2-乙氧基-6-(2-(4-氟苯基）苯并[d]噁唑-5-基胺基） 於驗腈 [化 1261]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 402 (M + H) +. LC/MS tR = 2.48 min ° Example 1-261 4-Amino-2-ethoxy-6-(2-(4-fluorophenyl)benzo[d]oxazol-5-ylamino) For nitrile [Chemical 1261]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=390 (M+H)+。 LC/MS tR=2.58 min。 實施例1-262 4 -胺基- 6- (2，3 -二甲基唾°惡琳-6-基胺基）-2 -乙氧基於驗猜 141666.doc -246- 201028381 [化 1262]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 390 (M+H)+. LC/MS tR = 2.58 min. Example 1-262 4-Amino-6-(2,3-dimethylsaphthyl-6-ylamino)-2-ethoxylate 147666.doc -246- 201028381 [Chem. 1262]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=335 (M+H)+。 LC/MS tR=1.80 min 〇 實施例1-263 4-胺基-2-乙氧基-6-(2-甲基苯并[d]噁唑-6-基胺基）菸 鹼腈 [化 1263]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 335 (M+H)+. LC/MS tR=1.80 min 〇 Example 1-263 4-Amino-2-ethoxy-6-(2-methylbenzo[d]oxazol-6-ylamino) Nicotine nitrile 1263]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=310 (M+H)+。 LC/MS tR=l.84 min。 實施例1-264 4-胺基-2-乙氧基-6-(2-乙氧基苯并[d]噁唑-6-基胺基）菸 鹼腈 [化 1264]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 310 (M + H) +. LC/MS tR = 1.84 min. Example 1-164 4-Amino-2-ethoxy-6-(2-ethoxybenzo[d]oxazol-6-ylamino)nicotinonitrile [Chem. 1264]

標題化合物係依據實施例1-144之方法而合成。 141666.doc -247- 201028381 1H NMR (300 MHz, DMSO) δ 1.28-1.35 (m, 3H), 2.90 (q, 2H, J=9.0 Hz), 4.35 (q, 2H, J=9.0 Hz), 5.73 (s, 1H), 6.49 (s, 2H), 7.27 (d, 1H, J=9.0 Hz), 7.52 (d, 1H, J=9.0 Hz), 8.01 (s，1H)，9.24 (s，1H)。 mp 223-226〇C MS(ESI)m/z=324 (M+H)+。 LC/MS tR=1.92 min 〇 實施例1-265 4-胺基-6-(4-((4,6-二甲基嘧啶-2-基）（甲基）胺基）苯基胺 基）-2 -乙氧基於驗腈 [化 1265]The title compound was synthesized according to the method of Example 1-144. 141666.doc -247- 201028381 1H NMR (300 MHz, DMSO) δ 1.28-1.35 (m, 3H), 2.90 (q, 2H, J = 9.0 Hz), 4.35 (q, 2H, J = 9.0 Hz), 5.73 (s, 1H), 6.49 (s, 2H), 7.27 (d, 1H, J=9.0 Hz), 7.52 (d, 1H, J=9.0 Hz), 8.01 (s,1H), 9.24 (s,1H) . Mp 223-226 〇C MS (ESI) m/z = 324 (M+H)+. LC/MS tR=1.92 min 〇 Example 1-265 4-Amino-6-(4-((4,6-dimethylpyrimidin-2-yl)(methyl)amino)phenylamino) -2 - ethoxylation in nitrile [Chemical 1265]

標題化合物係依據實施例1 · 144之方法而合成。 MS(ESI)m/z=39 1 (M+H)+ 〇 LC/MS tR=1.90 min。 實施例1-266 4-胺基-6-(4-(4,5-二氫噁唑-2-基）苯基胺基）_2-乙氧基菸 鹼腈 [化 1266]The title compound was synthesized according to the method of Example 1 - 144. MS (ESI) m/z = 39 (495). Example 1-266 4-Amino-6-(4-(4,5-dihydrooxazol-2-yl)phenylamino)_2-ethoxynicotinic nitrile [Chem. 1266]

標題化合物係依據實施例1-144之方法而合成。 141666.doc •248· 201028381 MS(ESI)m/z=324 (M+H)+。 LC/MS tR=1.21 min。 實施例1-267 4-胺基-6-(4-(3,5-二曱基-1H-吼唑-1-基）苯基胺基）-2-乙 氧基菸鹼腈 [化 1267]The title compound was synthesized according to the method of Example 1-144. 141666.doc • 248· 201028381 MS (ESI) m/z = 324 (M+H)+. LC/MS tR = 1.21 min. Example 1-267 4-Amino-6-(4-(3,5-dimercapto-1H-indazol-1-yl)phenylamino)-2-ethoxynicotinic nitrile [Chemical 1267 ]

MeMe

Me 標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=349 (M+H)+ 〇 LC/MS tR=2.01 min。 實施例1-268 4-胺基-2-乙氧基-6-(4-(N-嗎啉基）甲基）苯基胺基）菸鹼腈 [化 1268]The Me title compound was synthesized according to the method of Example 1-144. MS (ESI) m/z = 495 (MH): Example 1-268 4-Amino-2-ethoxy-6-(4-(N-morpholinyl)methyl)phenylamino)nicotinonitrile [Chemical 1268]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=354 (M+H)+。 LC/MS tR=l.68 min。 實施例1-269 4-胺基-6-(4-(2,6-二曱基（N-嗎啉基））苯基胺基）-2-乙氧基 菸鹼腈 141666.doc -249- 201028381 [化 1269]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m / z = 354 (M+H)+. LC/MS tR = 1.68 min. Example 1-169 4-Amino-6-(4-(2,6-diamidino(N-morpholinyl))phenylamino)-2-ethoxynicotinonitrile 141666.doc -249 - 201028381 [化1269]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=368 (M+H)+。 LC/MS tR=2.02 min ° 實施例1-270 4-胺基-2-乙氧基-6-(2-乙基苯并[d]噁唑-5-基胺基）菸 鹼腈 [化 1270]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m/z = 368 (M+H)+. LC/MS tR=2.02 min ° Example 1-170 4-Amino-2-ethoxy-6-(2-ethylbenzo[d]oxazol-5-ylamino) Nicotine nitrile 1270]

標題化合物係依據實施例1-144之方法而合成。 MS(ESI)m/z=324 (M+H)+。 LC/MS tR=1.99 min。 實施例1_271 6-(4-(1,3,4-噁二唑-2-基）笨基胺基）_4_胺基-2-乙氧基菸 驗猜 [化 1271]The title compound was synthesized according to the method of Example 1-144. MS (ESI) m/z = 324 (M+H)+. LC/MS tR = 1.99 min. Example 1-271 6-(4-(1,3,4-oxadiazol-2-yl)phenylamino)-4-amino-2-ethoxy oxime [1271]

141666.doc -250. 201028381 標題化合物係使用4-(1,3，4-噁二唑-2-基）苯胺（w〇 2004087641 A1 ’參考例17)，依據實施例1-145而合成。 1H-NMR (300 MHz, DMSO-d6) δ 1.33 (t, J=6.0 Hz, 3H), 4.37 (q, J=6.0 Hz, 2H), 5.82 (s, 1H), 6.60 (s, 2H), 7.77 (d, J=6.0 Hz, 2H), 7.90 (d, J=6.0 Hz, 2H), 9.22 (s, 1H), 9.55 (s, 1H)。 MS(ESI)m/z=323 (M+H)+。 LC/MS tR=1.66 min。 ® 實施例1-272 4-胺基-2-乙氧基-6-(4-(5-甲基-1,3,4-噁二唑-2-基）笨基胺 基）菸鹼腈 [化 1272]141666.doc -250. 201028381 The title compound was synthesized according to Example 1-145 using 4-(1,3,4-oxadiazol-2-yl)phenylamine (w 〇 2004087641 A1 'Reference Example 17). 1H-NMR (300 MHz, DMSO-d6) δ 1.33 (t, J = 6.0 Hz, 3H), 4.37 (q, J = 6.0 Hz, 2H), 5.82 (s, 1H), 6.60 (s, 2H), 7.77 (d, J=6.0 Hz, 2H), 7.90 (d, J=6.0 Hz, 2H), 9.22 (s, 1H), 9.55 (s, 1H). MS (ESI) m / z = 323 (M+H)+. LC/MS tR = 1.66 min. ® Example 1-172 4-Amino-2-ethoxy-6-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenylamino) Nicotine Nitrile [化1272]

標題化合物係使用4-(5-曱基-1,3,4-噁二唑-2-基）苯胺（WO φ 2004087641 A1，參考例20)，依據實施例1-145合成。 1H-NMR (300 MHz, DMSO-d6) δ 1.35 (t, J=6.8 Hz, 3H), 2.55 (s, 3H), 4.38 (q, J=6.8 Hz, 2H), 5.82 (s, 1H), 6.61 (bs, 2H), 7.76 (d, J=8.8 Hz, 2H), 7.85 (d, J=8.8 Hz, 2H), 9.51 (s, 1H)。 MS(ESI)m/z=337 (M+H)+。 LC/MS tR=l.65 min。 實施例1-273 141666.doc -251- 201028381 4-(4-胺基-5-氰基-6-乙氧基吡啶-2-基胺基）苯曱酸曱酯 [化 1273]The title compound was synthesized according to Example 1-145 using 4-(5-mercapto-1,3,4-oxadiazol-2-yl)aniline (WO φ 2004 087 641 A1, Reference Example 20). 1H-NMR (300 MHz, DMSO-d6) δ 1.35 (t, J = 6.8 Hz, 3H), 2.55 (s, 3H), 4.38 (q, J = 6.8 Hz, 2H), 5.82 (s, 1H), 6.61 (bs, 2H), 7.76 (d, J=8.8 Hz, 2H), 7.85 (d, J=8.8 Hz, 2H), 9.51 (s, 1H). MS (ESI) m / z = 337 (M+H)+. LC/MS tR = 1.65 min. Example 1-273 141666.doc -251- 201028381 4-(4-Amino-5-cyano-6-ethoxypyridin-2-ylamino)benzoic acid oxime ester [Chem. 1273]

標題化合物係依據實施例1-145之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 1.34 (t, J = 7.2 Hz, 3H), 3.80 (s, 3H), 4.37 (q, J=7.2 Hz, 2H), 5.82 (s, 1H), 6.57 (s, 2H), 7.07 (s, 1H), 7.69 (d, J=8.8 Hz, 2H), 7.79 (d, J=8.8 Hz，2H)，8.93 (s, 1H), 9·35 (s, 1H)。 MS(ESI)m/z=313 (M+H)+。 LC/MS tR=l_99 min。 實施例1-274 4-(4-胺基-5-氰基-6-乙氧基吼啶-2-基胺基）苯甲酸 [化 1274]The title compound was synthesized according to the method of Example 1-145. 1H-NMR (300 MHz, DMSO-d6) δ 1.34 (t, J = 7.2 Hz, 3H), 3.80 (s, 3H), 4.37 (q, J = 7.2 Hz, 2H), 5.82 (s, 1H), 6.57 (s, 2H), 7.07 (s, 1H), 7.69 (d, J=8.8 Hz, 2H), 7.79 (d, J=8.8 Hz, 2H), 8.93 (s, 1H), 9·35 (s , 1H). MS (ESI) m / z = 313 (M+H)+. LC/MS tR = l_99 min. Example 1-274 4-(4-Amino-5-cyano-6-ethoxyoxaridin-2-ylamino)benzoic acid [Chemical 1274]

向4-(4-胺基-5-氰基-6-乙氧基吡啶-2-基胺基）苯曱酸曱酯 (605 mg，1.94 mmol)之DMSO溶液中添加2 mo 1/L氫氧化鈉 水溶液（3.87 mL，7.75 mmol)，於50°C下加熱攪拌1小時。 向反應溶液中添加10%檸檬酸水溶液及乙酸乙酯，進行分 離後，以乙酸乙酯萃取水相，將合併之有機相以水及飽和 食鹽水進行清洗，以硫酸鎂加以乾燥。將有機相過濾後， 進行減壓濃縮，藉此獲得標題化合物（77 mg，77%)，為黃 141666.doc -252- 201028381 色固體。 1H-NMR (300 MHz, DMSO-d6) δ 1.38 (t, J=6.9 Hz, 3H), 4.41 (q, J=6.9 Hz, 2H), 5.85 (s, 1H), 6.64 (s, 2H), 7.70 (d, J=8.7 Hz, 2H), 7.88 (d, J=8.7 Hz, 2H), 9.51 (s, 1H), 12.51 (bs，1H)。 MS(ESI)m/z=299 (M+H)+。 LC/MS tR=1.64 min。 實施例1-275 β 4-(4-胺基-5-氰基-6-乙氧基&quot;比啶-2-基胺基）-N-苯基苯甲 醯胺 [化 1275]Add 2 mol of 1/L hydrogen to a solution of 4-(4-amino-5-cyano-6-ethoxypyridin-2-ylamino)benzoate oxalate (605 mg, 1.94 mmol) in DMSO An aqueous solution of sodium oxide (3.87 mL, 7.75 mmol) was stirred at 50 ° C for 1 hour. After adding a 10% aqueous citric acid solution and ethyl acetate to the reaction solution, the mixture was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and saturated brine and dried over magnesium sulfate. After the organic phase was filtered, EtOAcjjjjjjjjjjj 1H-NMR (300 MHz, DMSO-d6) δ 1.38 (t, J = 6.9 Hz, 3H), 4.41 (q, J = 6.9 Hz, 2H), 5.85 (s, 1H), 6.64 (s, 2H), 7.70 (d, J=8.7 Hz, 2H), 7.88 (d, J=8.7 Hz, 2H), 9.51 (s, 1H), 12.51 (bs, 1H). MS (ESI) m / z = 299 (M+H)+. LC/MS tR = 1.64 min. Example 1-175 β 4-(4-Amino-5-cyano-6-ethoxy&quot;bipyridin-2-ylamino)-N-phenylbenzamide [Chemical 1275]

DIC, HOAt NMP,室溫DIC, HOAt NMP, room temperature

向4-(4-胺基-5-氰基-6-乙氧基°比啶-2-基胺基）苯甲酸To 4-(4-Amino-5-cyano-6-ethoxy~pyridin-2-ylamino)benzoic acid

(50.1 mg，0.168 mmol)、苯胺（18.8 mg ’ 18 gL，0.202 mmol)及HOAt(4.6 mg，0.034 mmol)之 NMP溶液中添加二 異丙基碳化二醯亞胺（25.5 mg，31 pL，0.202 mmol)，於 室溫下搜拌3小時。向反應溶液中添加水及乙酸乙酯進行 分離後，以乙酸乙酯萃取水相，將合併之有機相以水及飽 和食鹽水進行清洗，以硫酸鎂加以乾燥。將有機相過濾 後’進行減壓濃縮，利用逆相等分試樣液相層析法（C18管 柱，水/乙腈/0.1%曱酸梯度）對所獲得之殘渣進行純化，獲 得標題化合物（18.7 mg，3〇%)，為黃色固體。 141666.doc •253 - 201028381 1H-NMR (300 MHz, DMSO-d6) δ 1.36 (t, J=6.8 Hz, 3H), 4.40 (q, J=6.8 Hz, 2H), 5.82 (s, 1H), 6.59 (s, 2H), 7.08 (t, J=7.2 Hz, 1H), 7.34 (t, J=8.0 Hz, 2H), 7.71 (d, J=8.4 Hz, 2H), 7.78 (d, J=8.0 Hz, 2H), 7.93 (d, J=8.4 Hz, 2H), 9.45 (s, 1H), 10.03 (s，1H)。 實施例1-276 4-(4 -胺基-5-氮基-6-乙氧基D比咬-2 -基胺基）-N-甲基苯甲 醯胺 [化 1276](50.1 mg, 0.168 mmol), aniline (18.8 mg '18 gL, 0.202 mmol) and HOAt (4.6 mg, 0.034 mmol) in NMP solution with diisopropylcarbodiimide (25.5 mg, 31 pL, 0.202) Mmmol), mix for 3 hours at room temperature. After water and ethyl acetate were added to the reaction solution for separation, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water and saturated brine and dried over magnesium sulfate. After the organic phase was filtered, the residue was purified under reduced pressure, and purified residue was purified eluting with EtOAc EtOAc EtOAc Mg, 3〇%), as a yellow solid. 141666.doc •253 - 201028381 1H-NMR (300 MHz, DMSO-d6) δ 1.36 (t, J=6.8 Hz, 3H), 4.40 (q, J=6.8 Hz, 2H), 5.82 (s, 1H), 6.59 (s, 2H), 7.08 (t, J=7.2 Hz, 1H), 7.34 (t, J=8.0 Hz, 2H), 7.71 (d, J=8.4 Hz, 2H), 7.78 (d, J=8.0 Hz, 2H), 7.93 (d, J=8.4 Hz, 2H), 9.45 (s, 1H), 10.03 (s, 1H). Example 1-176 4-(4-Amino-5-nitro-6-ethoxy D-bito-2-aminocarbyl)-N-methylbenzamide Amidoxime [Chem. 1276]

標題化合物係依據實施例1-275之方法而合成。 MS(ESI)m/z=312 (M+H)+。 LC/MS tR=1.42 min。 實施例1-277 4-(4-胺基-5-氰基-6-乙氡基吡啶-2-基胺基）-N，N-二曱基 苯甲醯胺 [化 1277]The title compound was synthesized according to the method of Example 1-275. MS (ESI) m / z = 312 (M + H) +. LC/MS tR = 1.42 min. Example 1-177 4-(4-Amino-5-cyano-6-ethenylpyridin-2-ylamino)-N,N-dimercaptobenzamide [Chem. 1277]

標題化合物係依據實施例1 -275之方法而合成。 MS(ESI)m/z=326 (M+H)+。 LC/MS tR=1.54 min。 141666.doc -254- 201028381 實施例1-278 4-(4-胺基-5-氰基-6-乙氧基。比啶-2-基胺基）-N-異丙基苯 甲醯胺 [化 1278]The title compound was synthesized according to the method of Example 1-275. MS (ESI) m / z = 326 (M+H)+. LC/MS tR = 1.54 min. 141666.doc -254- 201028381 Example 1-178 4-(4-Amino-5-cyano-6-ethoxy.bipyridin-2-ylamino)-N-isopropylbenzimidamide [化1278]

標題化合物係依據實施例1-275之方法而合成。 MS(ESI)m/z=340 (M+H)+。 LC/MS tR=1.72 min。 實施例1-279 4-(4-胺基-5-氰基-6-乙氧基。比啶-2-基胺基）-N-丁基苯甲 醯胺 [化 1279]The title compound was synthesized according to the method of Example 1-275. MS (ESI) m / z = 340 (M + H) +. LC/MS tR = 1.72 min. Example 1-179 4-(4-Amino-5-cyano-6-ethoxy.bipyridin-2-ylamino)-N-butylbenzimidamide [Chem. 1279]

標題化合物係依據實施例1-275之方法而合成。 MS(ESI)m/z=354 (M+H)+。 LC/MS tR=l.86 min。 實施例1-280 4-胺基-2-乙氧基-6-(4-(嗎啉-4-羰基）苯基胺基）菸鹼腈 141666.doc -255 - 201028381 [化 1280]The title compound was synthesized according to the method of Example 1-275. MS (ESI) m / z = 354 (M+H)+. LC/MS tR = 1.86 min. Example 1-180 4-Amino-2-ethoxy-6-(4-(morpholin-4-carbonyl)phenylamino)nicotinonitrile 141666.doc -255 - 201028381 [Chem. 1280]

標題化合物係依據實施例1-275之方法而合成。 MS(ESI)m/z=366 (M+H)+。 LC/MS tR=1.51 min。 實施例1-281 2-(4-(4-胺基-5-氰基-6-乙氧基吡啶-2-基胺基）苯甲醯胺） 乙酸第三丁基酯 [化 1281]The title compound was synthesized according to the method of Example 1-275. MS (ESI) m / z = 366 (M+H)+. LC/MS tR = 1.51 min. Example 1-181 2-(4-(4-Amino-5-cyano-6-ethoxypyridin-2-ylamino)benzamide) Tert-butyl acetate [Chem. 1281]

標題化合物係依據實施例1-275之方法而合成。 MS(ESI)m/z=412 (M+H)+。 LC/MS tR=1.92 min。 實施例1-282 2-(4-(4-胺基-5-氰基-6-乙氧基°比啶-2-基胺基）苯甲醯胺） 乙酸 [化 1282]The title compound was synthesized according to the method of Example 1-275. MS (ESI) m / z = 412 (M+H)+. LC/MS tR = 1.92 min. Example 1-282 2-(4-(4-Amino-5-cyano-6-ethoxy~pyridin-2-ylamino)benzamide) Acetic acid [Chemical 1282]

標題化合物係依據實施例1-275之方法而合成。 141666.doc -256- 201028381 1H-NMR (300 MHz, DMSO-d6) δ 1.34 (t, J=7.2 Hz, 3H), 3.90 (d, J=6.0 Hz, 2H), 4.36 (q, J=7.2 Hz, 2H), 5.79 (s, 1H), 7.63 (d, J=8.0 Hz, 2H), 7.79 (d, J=8.0 Hz, 2H), 8.61 (s, 1H)，9.38(s, 1H)。 MS(ESI)m/z=356 (M+H)+。 LC/MS tR=1.32 min。 實施例1-283 4-(4 -胺基-5-氛基-6-乙氧基定-2 -基胺基）_N-节基苯曱 β 醯胺 [化 1283]The title compound was synthesized according to the method of Example 1-275. 141666.doc -256- 201028381 1H-NMR (300 MHz, DMSO-d6) δ 1.34 (t, J = 7.2 Hz, 3H), 3.90 (d, J = 6.0 Hz, 2H), 4.36 (q, J = 7.2 Hz, 2H), 5.79 (s, 1H), 7.63 (d, J=8.0 Hz, 2H), 7.79 (d, J=8.0 Hz, 2H), 8.61 (s, 1H), 9.38 (s, 1H). MS (ESI) m / z = 356 (M+H)+. LC/MS tR = 1.32 min. Example 1-283 4-(4-Amino-5-enyl-6-ethoxylated-2-ylamino)_N-pyridylphenylhydrazine β-decylamine [Chemical 1283]

標題化合物係依據實施例1-275之方法而合成。 MS(ESI)m/z=388 (Μ+Η)+。 LC/MS tR=1.91 min。 ❹ 實施例1-284 4-(4_胺基-5-氰基-6-乙氧基吡啶-2-基胺基）-N-(嗟唑_2- 基）苯甲醯胺 [化 1284]The title compound was synthesized according to the method of Example 1-275. MS (ESI) m / z = 388 (Μ + Η) +. LC/MS tR = 1.91 min.实施 Example 1-284 4-(4-Amino-5-cyano-6-ethoxypyridin-2-ylamino)-N-(carbazole-2-yl)benzamide [1284] ]

標題化合物係依據實施例1-275之方法而合成。 MS(ESI)m/z=381 (M+H)+。 141666.doc •257- 201028381 LC/MS tR=l_82 min。 實施例1-285 4-(4 -胺基-5-亂基-6-乙氧基°比咬-2-基胺基）-N-(4-甲氧基 苯基）苯甲醯胺 [化 1285]The title compound was synthesized according to the method of Example 1-275. MS (ESI) m / z = 381 (M+H)+. 141666.doc •257- 201028381 LC/MS tR=l_82 min. Example 1-185 4-(4-Amino-5-ranyl-6-ethoxy~biti-2-ylamino)-N-(4-methoxyphenyl)benzamide [ 1285]

標題化合物係依據實施例1-275之方法而合成。 MS(ESI)m/z=404 (M+H)+。 LC/MS tR=l_93 min。 實施例1-286 4-(4-胺基-5-氰基-6-乙氧基吼啶-2-基胺基）-N-(2-(N-嗎啉 基）乙基）苯曱醯胺 [化 1286]The title compound was synthesized according to the method of Example 1-275. MS (ESI) m / z = 404 (M + H) +. LC/MS tR = l_93 min. Example 1-286 4-(4-Amino-5-cyano-6-ethoxyoxaridin-2-ylamino)-N-(2-(N-morpholinyl)ethyl)phenylhydrazine Guanamine [Chemical 1286]

標題化合物係依據實施例1-275之方法而合成。 MS(ESI)m/z=411 (M+H)+。 LC/MS tR=0.89 min 〇 實施例1-287 4 - ( 4 -胺基-5 -乳基-6 -乙氧基n比咬-2 -基胺基）-N - ( 2 -經基乙 基）苯甲醯胺 141666.doc -258- 201028381 [化 1287]The title compound was synthesized according to the method of Example 1-275. MS (ESI) m / z = 411 (M + H) +. LC/MS tR = 0.89 min 〇 Example 1-187 4 - (4-amino-5-lacyl-6-ethoxy n-bito-2-ylamino)-N-(2-N-based Benzomethane 141666.doc -258- 201028381 [Chem. 1287]

標題化合物係依據實施例1-275之方法而合成。 MS(ESI)m/z=342 (M+H)+。 LC/MS tR=1.21 min。 實施例1-288 4-(4-胺基-5-氰基-6-乙氧基吼啶-2-基胺基）-2-甲氧基苯 甲酸曱酯 [化 1288]The title compound was synthesized according to the method of Example 1-275. MS (ESI) m / z = 342 (M + H) +. LC/MS tR = 1.21 min. Example 1-288 4-(4-Amino-5-cyano-6-ethoxyacridin-2-ylamino)-2-methoxybenzoic acid oxime ester [Chemical 1288]

標題化合物係依據實施例1-145之方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 1.31 (t, J=7.2 Hz, 3H), 3.71 (s, 3H), 3.78 (s, 3H), 4.38 (q, J=7.2 Hz, 2H), 5.81 (s, 1H), 6.61 (s, 2H), 7.09 (d, J=8.6 Hz, 1H), 7.51 (s, 1H), 7.64 (d, J=8.6 Hz, 1H)，9.45 (s，1H)。 MS(ESI)m/z=343 (M+H)+。 LC/MS tR=l.79 min。 實施例1-289 4-(4 -胺基-5-乳基-6-乙乳基°比α定-2-基胺基）-2-甲氧基苯 甲酸 141666.doc -259- 201028381 [化 1289]The title compound was synthesized according to the method of Example 1-145. 1H-NMR (400 MHz, DMSO-d6) δ 1.31 (t, J = 7.2 Hz, 3H), 3.71 (s, 3H), 3.78 (s, 3H), 4.38 (q, J = 7.2 Hz, 2H), 5.81 (s, 1H), 6.61 (s, 2H), 7.09 (d, J=8.6 Hz, 1H), 7.51 (s, 1H), 7.64 (d, J=8.6 Hz, 1H), 9.45 (s, 1H) ). MS (ESI) m / z = 343 (M+H)+. LC/MS tR = 1.79 min. Example 1-289 4-(4-Amino-5-lacyl-6-ethylidene ratio α-di-2-ylamino)-2-methoxybenzoic acid 141666.doc -259- 201028381 [ 1289]

標題化合物係使用4-胺基-2-曱氧基苯曱酸曱酯，利用實 施例1-145之方法進行胺基化後，依據實施例1-274之方法 進行水解而合成。 1H-NMR (400 MHz, DMSO-d6) δ 1.32 (t, J=7.1 Hz, 3H), 3.79 (s, 3H), 4.38 (q, J=7.1 Hz, 2H), 5.81 (s, 1H), 6.59 (s, 2H), 7.06 (d, J=8.6 Hz, 1H), 7.50 (s, 1H), 7.64 (d, J=8.6 Hz，1H)，9.42 (s，1H)，12.0 (s，1H)。 MS(ESI)m/z=329 (M+H)+。 LC/MS tR=1.53 min。 實施例1-290 4-(4-胺基-5-氰基-6-乙氧基》比啶-2-基胺基）-2-甲氧基苯 甲醯胺 [化 1290]The title compound was synthesized by the method of Example 1-174, using the ethylamine of 4-amino-2- phenoxybenzoate, which was subjected to amination by the method of Example 1-145. 1H-NMR (400 MHz, DMSO-d6) δ 1.32 (t, J = 7.1 Hz, 3H), 3.79 (s, 3H), 4.38 (q, J = 7.1 Hz, 2H), 5.81 (s, 1H), 6.59 (s, 2H), 7.06 (d, J=8.6 Hz, 1H), 7.50 (s, 1H), 7.64 (d, J=8.6 Hz, 1H), 9.42 (s, 1H), 12.0 (s, 1H) ). MS (ESI) m/z = 329 (M+H)+. LC/MS tR = 1.53 min. Example 1-190 4-(4-Amino-5-cyano-6-ethoxy)pyridin-2-ylamino)-2-methoxybenzenecarbamidine [Chemical 1290]

標題化合物係使用實施例1-289之化合物’依據實施例1-275之方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 1.32 (t, J=7.1 Hz, 3H), 3.07 (s, 3H), 4.39 (q, J=7.1 Hz, 2H), 5.82 (s, 1H), 6.58 (s, 2H), 7.10 (d, J=8.6 Hz, 1H), 7.28 (s, 1H), 7.48 (s, 1H), 7.54 14l666.doc •260- 201028381 (s，1H)，7.78 (d，J=8.6 Hz，1H), 9.44 (s，1H)。 MS(ESI)m/z=328 (M+H)+。 LC/MS tR=1.43 min。 mp : 135-138。。。 實施例1-291 4-(4 -胺基-5-氰基-6-乙氧基吼°定-2-基胺基）-2-乙氧基苯 曱酸甲酯 [化 1291]The title compound was synthesized according to the method of Example 1-275 using the compound of Example 1-289. 1H-NMR (400 MHz, DMSO-d6) δ 1.32 (t, J = 7.1 Hz, 3H), 3.07 (s, 3H), 4.39 (q, J = 7.1 Hz, 2H), 5.82 (s, 1H), 6.58 (s, 2H), 7.10 (d, J=8.6 Hz, 1H), 7.28 (s, 1H), 7.48 (s, 1H), 7.54 14l666.doc •260- 201028381 (s,1H),7.78 (d , J = 8.6 Hz, 1H), 9.44 (s, 1H). MS (ESI) m/z = 328 (M+H)+. LC/MS tR = 1.43 min. Mp: 135-138. . . Example 1-191 4-(4-Amino-5-cyano-6-ethoxyindole-2-ylamino)-2-ethoxybenzoic acid methyl ester [Chemical 1291]

標題化合物係依據實施例1-145之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 1.32-1.37 (m，6H), 3.73 (s, 3H), 4.01-4.08 (m, 2H), 4.39 (q, J=7.2 Hz, 2H), 5.82 (s, 1H), 6.42 (s, 2H), 7.11 (d, J=9.6 Hz, 1H), 7.52 (s, 1H), 7.52 (J=9.6 Hz, 1H)，9.44 (s, 1H)。 MS(ESI)m/z=357 (M+H)+。 LC/MS tR=1.99 min。 實施例1-292 4-(4 -胺基-5-亂基-6-乙氧基&quot;比°定-2 -基胺基）-2-乙氧基苯 甲酸 141666.doc •261 · 201028381 [化 1292]The title compound was synthesized according to the method of Example 1-145. 1H-NMR (300 MHz, DMSO-d6) δ 1.32-1.37 (m, 6H), 3.73 (s, 3H), 4.01-4.08 (m, 2H), 4.39 (q, J = 7.2 Hz, 2H), 5.82 (s, 1H), 6.42 (s, 2H), 7.11 (d, J=9.6 Hz, 1H), 7.52 (s, 1H), 7.52 (J=9.6 Hz, 1H), 9.44 (s, 1H). MS (ESI) m / z = 357 (M+H)+. LC/MS tR = 1.99 min. Example 1-292 4-(4-Amino-5-ranyl-6-ethoxy&quot;t-but-2-ylamino)-2-ethoxybenzoic acid 141666.doc •261 · 201028381 [化1292]

標題化合物係使用4-胺基-2-乙氧基苯甲酸甲醋’利用實施 例1-145之方法進行胺基化後，依據實施例卜274之方法進 行水解而合成。 1H-NMR (300 MHz, DMSO-d6) δ 1.31-1.37 (m, 6H), 4.〇6 (q，J=6.8 Hz，2H)，4.38 (q，J=7.2 Hz，2H)，5.81 (s，m)， 6,61 (s, 2H), 7.07 (d，J=8.0 Hz, 1H)，7.51 (s，1H)，7.64 (d， J=8.8 Hz，1H)，9.41 (s，1H)，11.94 (s，1H)。 MS(ESI)m/z=343 (M+H)+。 LC/MS tR=1.74 min。 實施例1-293 4-(4-胺基-5-氰基-6-乙氧基°比啶-2-基胺基）-2-乙氧基笨 甲醯胺 [化 1293]The title compound was synthesized by the method of Example 1-145 using a 4-amino-2-ethoxybenzoic acid methyl acetate. 1H-NMR (300 MHz, DMSO-d6) δ 1.31-1.37 (m, 6H), 4. 〇6 (q, J = 6.8 Hz, 2H), 4.38 (q, J = 7.2 Hz, 2H), 5.81 ( s,m), 6,61 (s, 2H), 7.07 (d,J=8.0 Hz, 1H), 7.51 (s,1H), 7.64 (d, J=8.8 Hz,1H), 9.41 (s,1H) ), 11.94 (s, 1H). MS (ESI) m / z = 343 (M+H)+. LC/MS tR = 1.74 min. Example 1-193 4-(4-Amino-5-cyano-6-ethoxy~pyridin-2-ylamino)-2-ethoxy benzylcarbamide [Chem. 1293]

標題化合物係使用實施例1492之化合物，依據實施例1-275之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 1.33 (t, J=7.2 Hz, 6H), 1.42 (t, J=6.8 Hz, 3H), 4.15 (q, J=6.8 Hz, 2H), 4.39 (q, 141666.doc • 262· 201028381 J=7.2 Hz, 2H), 5.80 (s, 1H), 6.59 (s, 2H), 7.09 (s, J=8.8 Hz, 1H), 7.33 (s, 1H), 7.45 (s, 1H), 7.53 (s, 1H), 7.53 (s, 1H), 7.80 (d，J=8.8 Hz，1H)，9.38 (s，1H)。 實施例l-294 4-胺基-2-乙氡基-6-(4-(4-甲基噁唑-5-基）苯基胺基）於 驗腈 [化 1294]The title compound was synthesized according to the procedure of Example 1-129 using the compound of Example 1492. 1H-NMR (300 MHz, DMSO-d6) δ 1.33 (t, J = 7.2 Hz, 6H), 1.42 (t, J = 6.8 Hz, 3H), 4.15 (q, J = 6.8 Hz, 2H), 4.39 ( q, 141666.doc • 262· 201028381 J=7.2 Hz, 2H), 5.80 (s, 1H), 6.59 (s, 2H), 7.09 (s, J=8.8 Hz, 1H), 7.33 (s, 1H), 7.45 (s, 1H), 7.53 (s, 1H), 7.53 (s, 1H), 7.80 (d, J = 8.8 Hz, 1H), 9.38 (s, 1H). Example 1-294 4-Amino-2-ethinyl-6-(4-(4-methyloxazol-5-yl)phenylamino) nitrite [Chem. 1294]

標題化合物係使用4-(4-甲基噁唑-5-基）苯胺（WO 200025780，實施例266 B部分），依據實施例丨·145之方法 而合成。 1H-NMR (400 MHz, DMSO-d6) d 1.32 (t, J=7.1 Hz, 3H), 2.33 (s, 3H), 4.35 (q, J=7.1 Hz, 2H), 5.76 (s, 1H), 6.51 (s, 2H), 7.51 (d, J=8.6 Hz, 1H), 7.66 (d, J=8.6 Hz, 1H), 8.24 ® (s, 1H), 9.27 (s, 1H) 〇 MS(ESI)m/z=336 (M+H)+。 LC/MS tR=1.90 min o 實施例1-295 4-胺基-6-(4-(2,4-二甲基噁唑-5_基）苯基胺基）-2-乙氧基 菸鹼腈 141666.doc -263- 201028381 [化 1295]The title compound was synthesized according to the procedure of Example 145 using 4-(4-methyloxazol-5-yl)aniline (WO 200025780, Part 266 Part B). 1H-NMR (400 MHz, DMSO-d6) d 1.32 (t, J = 7.1 Hz, 3H), 2.33 (s, 3H), 4.35 (q, J = 7.1 Hz, 2H), 5.76 (s, 1H), 6.51 (s, 2H), 7.51 (d, J=8.6 Hz, 1H), 7.66 (d, J=8.6 Hz, 1H), 8.24 ® (s, 1H), 9.27 (s, 1H) 〇MS(ESI) m/z = 336 (M+H)+. LC/MS tR = 1.90 min o Example 1-195 4-Amino-6-(4-(2,4-dimethyloxazol-5-yl)phenylamino)-2-ethoxy Alkali nitrile 141666.doc -263- 201028381 [Chemical 1295]

標題化合物係使用4-(2,4-二甲基噁唑-5-基）苯胺卩.厂 Iwanowicz et al., Bioorg. Med. Chem. Lett. 2002, 13 (12), 2059-2063.)，依據實施例1-145之方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 1.32 (t, J=6.8 Hz, 3H), 2.26 (s, 3H), 2.38 (s, 3H), 4.34 (q, J=6.8 Hz, 2H), 5.75 (s, 1H), 6.49 (s, 2H), 7.45 (d, J=8.3 Hz, 2H), 7.64 (d, J=8.3 Hz, 2H)，9.24 (s，1H)。 MS(ESI)m/z=350 (M+H)+。 LC/MS tR=1.93 min。 mp : 151-153。。。 實施例1-296 4-胺基-2-乙氧基-6-(4-(2-甲基噁唑-5-基）苯基胺基）菸 鹼腈 [化 1296]The title compound is 4-(2,4-dimethyloxazol-5-yl)aniline oxime. Iwanowicz et al., Bioorg. Med. Chem. Lett. 2002, 13 (12), 2059-2063.) And synthesized according to the method of Example 1-145. 1H-NMR (400 MHz, DMSO-d6) δ 1.32 (t, J = 6.8 Hz, 3H), 2.26 (s, 3H), 2.38 (s, 3H), 4.34 (q, J = 6.8 Hz, 2H), 5.75 (s, 1H), 6.49 (s, 2H), 7.45 (d, J = 8.3 Hz, 2H), 7.64 (d, J = 8.3 Hz, 2H), 9.24 (s, 1H). MS (ESI) m / z = 350 (M + H) +. LC/MS tR = 1.93 min. Mp: 151-153. . . Example 1-196 4-Amino-2-ethoxy-6-(4-(2-methyloxazol-5-yl)phenylamino)nicotinonitrile [Chemical 1296]

標題化合物係使用4-(2-甲基噁唑-5-基）苯胺（E. J. Iwanowicz et al., Bioorg. Med. Chem. Lett. 2002, 13 (12), 2059-2063.)，依據實施例1-145之方法而合成。 141666.doc -264- 201028381 1H-NMR (300 MHz, DMSO-d6) 5 1.34 (t, J=6.8 Hz, 3H), 2.45 (s, 3H), 4.35 (q, J=6.8 Hz, 2H), 5.76 (s, 1H), 6.51 (bs, 2H), 7.36 (s, 1H), 7.55 (d, J=8.4 Hz, 2H), 7.64 (d, J=8.4 Hz, 2H), 9.26 (s, 1H)。 MS(ESI)m/z=336 (M+H)+。 LC/MS tR=1.89 min。 實施例1-297 4-胺基-6-(4-(4,5-二甲基噁唑-2-基）苯基胺基）-2-乙氧基 .β 於驗腈 [化 1297]The title compound was 4-(2-methyloxazol-5-yl)aniline (EJ Iwanowicz et al., Bioorg. Med. Chem. Lett. 2002, 13 (12), 2059-2063.), according to the examples. Synthesized by the method of 1-145. 141666.doc -264- 201028381 1H-NMR (300 MHz, DMSO-d6) 5 1.34 (t, J = 6.8 Hz, 3H), 2.45 (s, 3H), 4.35 (q, J = 6.8 Hz, 2H), 5.76 (s, 1H), 6.51 (bs, 2H), 7.36 (s, 1H), 7.55 (d, J=8.4 Hz, 2H), 7.64 (d, J=8.4 Hz, 2H), 9.26 (s, 1H) ). MS (ESI) m / z = 336 (M + H) +. LC/MS tR = 1.89 min. Example 1-197 4-Amino-6-(4-(4,5-dimethyloxazol-2-yl)phenylamino)-2-ethoxyl.β in nitrile [Chemical 1297]

標題化合物係使用4-(4,5-二曱基噁唑-2-基）苯胺，依據實 施例1 -14 5之方法而合成。 MS(ESI)m/z=350 (M+H)+。 LC/MS tR=2.13 min。 實施例1-298 4 -胺基-2 -乙乳基- 6- (3 -曱乳基-4-(5 -甲基°惡〇坐-2 -基）苯基 胺基）菸鹼腈 [化 1298]The title compound was synthesized according to the method of Example 1 - 14 5 using 4-(4,5-dimercaptooxazol-2-yl)aniline. MS (ESI) m / z = 350 (M + H) +. LC/MS tR = 2.13 min. Example 1-198 4-Amino-2-ethyllactyl-6-(3-anthracene-4-(5-methyl-carboindolin-2-yl)phenylamino)nicotinic nitrile [ 1298]

MeMe

141666.doc - 265 - 201028381 標題化合物係使用3-甲氧基-4-(5-甲基噁唑-2-基）苯胺（依 據WO 199850358 A1而合成），依據實施例1-145之方法而 合成。 MS(ESI)m/z=336 (M+H)+。 LC/MS tR=2_02 min。 實施例1-299 4 -胺基-2 -乙氧基-6 - ( 3 -經基-4 -(嗯°坐-5 -基）苯基胺基）於 鹼腈 [化 1299]141666.doc - 265 - 201028381 The title compound was synthesized using 3-methoxy-4-(5-methyloxazol-2-yl)aniline (according to WO 199850358 A1) according to the method of Example 1-145. synthesis. MS (ESI) m / z = 336 (M + H) +. LC/MS tR = 2_02 min. Example 1-199 4-Amino-2-ethoxy-6-(3-carbyl-4-(yt-6-yl)phenylamino) to an alkali nitrile [Chemical 1299]

步驟1 : 2-羥基-4-硝基苯曱醛 向2-甲氧基-4-硝基苯甲醛（3.1 g，17.1 mmol)之二氯甲 烷（20 mL)溶液中，於-78°C下添加BBr3(DCM中1 mol/L， 17.1 mL，17.1 mmol)，升溫至室溫後，攪拌6小時。向反 應溶液中添加水及乙酸乙酯，進行分離。以乙酸乙酯萃取 水相，將合併之有機相以水及飽和食鹽水進行清洗，以硫 酸鎂加以乾燥。將有機相過濾後，進行減壓濃縮，藉此獲 得標題化合物（2.6 g，15.6 mmol，91%)，為白色固體。 1H-NMR (400 MHz, DMSO-d6) δ 7.69 (dd, J=1.6 Hz, 8.8 Hz, 1H), 7.75 (d, J=1.6 Hz, 1H), 7.83 (d, J=8.8 Hz, 1H), 141666.doc -266- 201028381 10.35 (s, 1H), 11.58 (s, 1H) ° 步驟2 : 5-頌基-2-(»惡唾-5-基）苯紛 向2-輕基-4-硝基苯甲搭（532 mg，3.18 mmol)及破酸钟 (879 mg ’ 6.36 mmol)之甲醇（1〇瓜乙）溶液中添加 TosMIC(622 mg，6,36 mmol) ’加熱回流ό小時。將反應溶 液以1 mol/L鹽酸進行中和，繼而添加水及乙酸乙酯進行 分離。以乙酸乙酯萃取水相’將合併之有機相以水、〇 i mol/L鹽酸及飽和食鹽水進行清洗，以硫酸鎂加以乾燥。 修 將有機相過濾後’進行減壓濃縮，利用中壓矽膠層析法 (乙酸乙酯·己烷；1〇_50〇/。梯度）對所獲得之殘渣進行純化， 獲得標題化合物（187 mg ’ 0.91 mmol，28%)，為白色固 體。 1H-NMR (400 MHz, DMSO-d6) δ 7.65-7.76 (m, 3H), 7.8u 7·84 (m, 1H), 8.53 (s, 1H)，11.50 (s，1H)。 步驟3 : 5-胺基-2-(°惡e坐_5_基）笨紛 向5-頌基-2-(°惡唾-5-基）苯盼（1〇〇 mg，0 485 mmol)之甲 醇-THF=1 : 1(4 mL)溶液中添加1〇% Pd_c粉末（1〇 mg)，於 風乳％境下於至溫下授拌4小時。對反應液進行砍藤土 過濾，將溶劑減壓濃縮。利用中壓矽膠層析法（乙酸乙醋 己烷；10-70。/。梯度）對所獲得之殘渣進行純化，獲得標題 化合物（68.4 mg，0.39 mmo卜80%)，為黃色固體。 1H-NMR (400 MHz, DMSO-d6) δ 5.31 (Sj 2H), 6.14 (dd J=1.6 Hz, 8.4 Hz, 1H), 6.18 (d, J=1.6 Hz, 1H), 7.18 (s, lH) 7.25 (d, J=8.6 Hz，1H)，8.16 (s，1H)，9.83 (s，1H)。 141666.doc -267- 201028381 步驟4 :標題化合物 使用5-胺基-2·(噁也-5-基）苯酚，依據實施例ι_145之方 法而合成。 MS(ESI)m/z=338 (M+H)+。 LC/MS tR=1.65 min。 實施例1-300 4-胺基-2-乙氧基-6-(3-(2-(N-嗎啉基）乙氧基）_4-(噁唑-5-基）苯基胺基）於驗腈 [化 1300]Step 1 : 2-Hydroxy-4-nitrobenzaldehyde to 2-methoxy-4-nitrobenzaldehyde (3.1 g, 17.1 mmol) in dichloromethane (20 mL) BBr3 (1 mol/L in DCM, 17.1 mL, 17.1 mmol) was added, and the mixture was stirred at room temperature for 6 hours. Water and ethyl acetate were added to the reaction solution to carry out separation. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and brine and dried over magnesium sulfate. After the organic layer was filtered, EtOAcjjjjjjjjjj 1H-NMR (400 MHz, DMSO-d6) δ 7.69 (dd, J = 1.6 Hz, 8.8 Hz, 1H), 7.75 (d, J = 1.6 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H) , 141666.doc -266- 201028381 10.35 (s, 1H), 11.58 (s, 1H) ° Step 2: 5-Mercapto-2-(» oxasin-5-yl)benzene to 2-light base-4 TosMIC (622 mg, 6,36 mmol) was added to a solution of -nitrobenzazole (532 mg, 3.18 mmol) and a spent acid clock (879 mg ' 6.36 mmol) in methanol (1 36 〇 '). . The reaction solution was neutralized with 1 mol/L hydrochloric acid, followed by the addition of water and ethyl acetate. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water, EtOAc &lt After the organic phase was filtered, the residue was purified under reduced pressure. EtOAc (EtOAc: EtOAc: EtOAc '0.91 mmol, 28%) as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 7.65-7.76 (m, 3H), 7.8 u 7.84 (m, 1H), 8.53 (s, 1H), 11.50 (s, 1H). Step 3: 5-Amino-2-(°E.sup._5_yl) is awkward to 5-mercapto-2-(°carbo-5-yl)benzene (1 〇〇 mg, 0 485 mmol) To the methanol-THF = 1 : 1 (4 mL) solution, 1% Pd_c powder (1 〇 mg) was added, and the mixture was stirred for 4 hours at a temperature of the air. The reaction solution was filtered with chopped vine, and the solvent was concentrated under reduced pressure. The residue obtained was purified by EtOAc EtOAc (EtOAc:EtOAc) 1H-NMR (400 MHz, DMSO-d6) δ 5.31 (Sj 2H), 6.14 (dd J = 1.6 Hz, 8.4 Hz, 1H), 6.18 (d, J = 1.6 Hz, 1H), 7.18 (s, lH) 7.25 (d, J=8.6 Hz, 1H), 8.16 (s, 1H), 9.83 (s, 1H). 141666.doc -267- 201028381 Step 4: The title compound was synthesized according to the method of Example ι 145 using 5-amino-2-((-5-yl) phenol. MS (ESI) m / z = 338 (M+H)+. LC/MS tR = 1.65 min. Example 1-300 4-Amino-2-ethoxy-6-(3-(2-(N-morpholinyl)ethoxy)-4-(oxazol-5-yl)phenylamino) For nitrile [Chemical 1300]

步驟1 : 4-(2-(5-硝基-2-(噁唆-5-基）苯氧基）乙基）嗎琳 向 5-硝基-2-(噁唑-5-基）苯盼（71.3 mg，0.346 mmol)、2-(N-嗎琳基）乙醇（45.4 mg，0.346 mmol)及PPh3(三苯基 膦）（109 mg’ 0.415 mmol)之 THF(1.5 mL)溶液中添加 DEAD(72.3 mg，0.415 mmol)，於室溫下攪拌12小時。添 加水及乙酸乙酯將反應溶液分離。以乙酸乙酯萃取水相， 將合併之有機相以水及飽和食鹽水進行清洗，以硫酸鎂加 以乾燥9將有機相過濾、後’進行減壓濃縮，利用中壓梦膠 層析法（乙酸乙酯-己烷；20-100%梯度）對所獲得之殘造 141666.doc -268 · 201028381 進行純化’獲得標題化合物（72.2 mg，0.226 mmol， 65%) ’為黃色固體。 1H-NMR (400 MHz, DMSO-d6) δ 2.47-2.51 (m, 4H), 2.82-2.84 (m, 2H), 3.58-3.60 (m, 4H), 4.39-4.42 (m, 2H), 7.91» 7.95 (m，3H)，8.07 (s, 1H)，8.59 (s，1H)。 MS(ESI)m/z=320 (M+H)+ °Step 1: 4-(2-(5-Nitro-2-(oxo-5-yl)phenoxy)ethyl)morphine to 5-nitro-2-(oxazol-5-yl)benzene Add (71.3 mg, 0.346 mmol), 2-(N-morphinyl)ethanol (45.4 mg, 0.346 mmol) and PPh3 (triphenylphosphine) (109 mg '0.415 mmol) in THF (1.5 mL) DEAD (72.3 mg, 0.415 mmol) was stirred at room temperature for 12 h. The reaction solution was separated by adding water and ethyl acetate. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and brine, dried over magnesium sulfate, and the organic phase was filtered, and then concentrated under reduced pressure, using medium pressure gel chromatography (acetic acid) Ethyl acetate-hexane; 20-100% gradient) </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 1H-NMR (400 MHz, DMSO-d6) δ 2.47-2.51 (m, 4H), 2.82-2.84 (m, 2H), 3.58-3.60 (m, 4H), 4.39-4.42 (m, 2H), 7.91» 7.95 (m, 3H), 8.07 (s, 1H), 8.59 (s, 1H). MS (ESI) m / z = 320 (M + H) + °

步驟2 : 4-(2-(5-胺基-2-(噁唑-5-基）苯氧基）乙基）嗎啉 向4-(2-(5-硝基·2-(噁唑-5-基）苯氧基）乙基）嗎啉（70 mg， 0.219 mmol)之甲醇-THF=1 : 1(2 mL)溶液中添加 10% Pd-C 粉末（10 mg) ’於氫氣環境下，於室溫下攪拌4小時。對反 應液進行矽藻土過濾，將溶劑減壓濃縮。以固化（乙醇/醚） 對所獲得之殘渣進行純化’獲得標題化合物（44.8 mg， 0.155 mmol，71%)，為白色固體。 1H-NMR (400 MHz, DMSO-d6) δ 2.44-2.56 (m, 4H), 2.75-2.87 (m, 2H), 3.55-3.63 (m, 4H), 4.06-4.14 (m, 2H), 5.46 (brs, 2H), 6.25 (d, J=7.2 Hz, 1H), 6.32 (s, 1H), 7.33 (d, J=7.2 Hz, 1H)，7.39 (s, 1H), 8.19 (s, 1H)。 MS(ESI)m/z=290 (M+H)+。 步驟3 :標題化合物 使用4-(2-(5-胺基-2-(噁唑-5-基）笨氧基）乙基）嗎啉，依 據實施例1-145之方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 1.33 (t, J=6.8 Hz, 3H), 2.44-2.55 (m, 4H), 2.82 (brs, 2H), 3.59 (brs, 4H), 4.17 (brs, 2H), 4.39 (q, J=6.8 Hz, 2H), 5.77 (s, 1H), 6.54 (s, 2H), 7.10 141666.doc -269- 201028381 (d，J=8.1 Hz, 1H)，7·56 (d，J=8」Hz，1H)，7 59 (s，1H)， 7.65 (s，1H)，8_31 (s，1H), 9.30 (s，1H) 0 MS(ESI)m/z=451 (M+H)+。 LC/MS tR=1.08 min。 mp : 123_124〇C。 實施例1-301 2-(4-(4-胺基-5-氰基-6-乙氧基„比啶_2_基胺基）苯基）乙酸 乙酯 [化 1301]Step 2: 4-(2-(5-Amino-2-(oxazol-5-yl)phenoxy)ethyl)morpholine to 4-(2-(5-nitro.2-(oxazole) -5-yl)phenoxy)ethyl)morpholine (70 mg, 0.219 mmol) in methanol-THF = 1: 1 (2 mL) was added 10% Pd-C powder (10 mg) in a hydrogen atmosphere The mixture was stirred at room temperature for 4 hours. The reaction solution was filtered through Celite, and the solvent was concentrated under reduced pressure. The residue obtained was purified by EtOAc (EtOAc:EtOAc) 1H-NMR (400 MHz, DMSO-d6) δ 2.44-2.56 (m, 4H), 2.75-2.87 (m, 2H), 3.55-3.63 (m, 4H), 4.06-4.14 (m, 2H), 5.46 ( Brs, 2H), 6.25 (d, J=7.2 Hz, 1H), 6.32 (s, 1H), 7.33 (d, J=7.2 Hz, 1H), 7.39 (s, 1H), 8.19 (s, 1H). MS (ESI) m / z = 290 (M + H) +. Step 3: The title compound was synthesized using 4-(2-(5-amino-2-(oxazol-5-yl)phenyloxy)ethyl)morpholine according to the procedure of Example 1-145. 1H-NMR (400 MHz, DMSO-d6) δ 1.33 (t, J = 6.8 Hz, 3H), 2.44-2.55 (m, 4H), 2.82 (brs, 2H), 3.59 (brs, 4H), 4.17 (brs , 2H), 4.39 (q, J=6.8 Hz, 2H), 5.77 (s, 1H), 6.54 (s, 2H), 7.10 141666.doc -269- 201028381 (d, J=8.1 Hz, 1H), 7 · 56 (d, J=8" Hz, 1H), 7 59 (s, 1H), 7.65 (s, 1H), 8_31 (s, 1H), 9.30 (s, 1H) 0 MS (ESI) m/z =451 (M+H)+. LC/MS tR = 1.08 min. Mp : 123_124〇C. Example 1-101 2-(4-(4-Amino-5-cyano-6-ethoxy)pyridin-2-ylamino)phenyl)acetic acid ethyl ester [Chem. 1301]

標題化合物係依據實施例1-145之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 1.18 (d，J=6.9 Hz，3H)， 1.31 (t, J=7.2 Hz, 3H), 3.57 (s, 2H), 4.01-4.11 (s, 2H), 4.32 (d, J=6.9 Hz, 2H), 5.71 (s, 1H), 6.45 (s, 2H), 7.14 (d, J=8.7The title compound was synthesized according to the method of Example 1-145. 1H-NMR (300 MHz, DMSO-d6) δ 1.18 (d, J = 6.9 Hz, 3H), 1.31 (t, J = 7.2 Hz, 3H), 3.57 (s, 2H), 4.01-4.11 (s, 2H ), 4.32 (d, J=6.9 Hz, 2H), 5.71 (s, 1H), 6.45 (s, 2H), 7.14 (d, J=8.7

Hz, 2H)，7.45 (d, J=8.7 Hz，2H)，9.03 (s，ih)。 MS(ESI)m/z=341 (M+H)+。 LC/MS tR=2.07 min。 實施例1-302 4-胺基-2-乙氧基-6-(2-側氧基-2,3-二氫苯并[d]。惡唾-5-基 胺基）菸鹼腈 141666.doc -270- 201028381 [化 1302]Hz, 2H), 7.45 (d, J=8.7 Hz, 2H), 9.03 (s, ih). MS (ESI) m / z = 341 (M+H)+. LC/MS tR = 2.07 min. Example 1-302 4-Amino-2-ethoxy-6-(2-o-oxy-2,3-dihydrobenzo[d]. Oxa-5-ylamino) Nicotinonitrile 141666 .doc -270- 201028381 [化1302]

標題化合物係依據實施例1-145之方法而合成。 MS(ESI)m/z=312 (M+H)+。 LC/MS tR=1.27 min 〇 實施例1-303 參 4-胺基-2-乙氧基-6-(2-側氧基吲哚啉-5-基胺基）菸鹼腈 [化 1303]The title compound was synthesized according to the method of Example 1-145. MS (ESI) m / z = 312 (M + H) +. LC/MS tR=1.27 min 实施 Example 1-103 -4-amino-2-ethoxy-6-(2- oxo oxalin-5-ylamino)nicotinonitrile [Chem. 1303]

標題化合物係依據實施例1 -14 5之方法而合成。 MS(ESI)m/z=310 (M+H)+。 LC/MS tR=1.39 min 〇 實施例1-304 4-胺基-6-(2,3-二侧氧基吲哚啉-5-基胺基）-2-乙氧基菸 驗腈 [化 1304]The title compound was synthesized according to the method of Example 1 - 14 5 . MS (ESI) m / z = 310 (M + H) +. LC/MS tR=1.39 min 〇 Example 1-304 4-Amino-6-(2,3-di- oxooxalin-5-ylamino)-2-ethoxy oxime nitrile 1304]

標題化合物係依據實施例1-145之方法而合成。 MS(ESI)m/z=324 (M+H)+。 141666.doc -271 - 201028381 LC/MS tR=1.49 min。 實施例1-305 4-(4-胺基-5-氰基-6-乙氧基吡啶_2_基胺基）苯曱醯胺 [化 1305]The title compound was synthesized according to the method of Example 1-145. MS (ESI) m/z = 324 (M+H)+. 141666.doc -271 - 201028381 LC/MS tR=1.49 min. Example 1-305 4-(4-Amino-5-cyano-6-ethoxypyridin-2-ylamino)benzamide [Chem. 1305]

標題化合物係依據實施例1-145之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 1.33 (t, J=6.9 Hz, 3H), 4.35 (q, 2H), 5.78 (s, 1H), 6.56 (br5 2H), 7.10 (br, 1H), 7.59 (d, J=9.0 Hz，2H), 7.70-7.80 (m，3H)，9.34 (s，1H)。 實施例1-306 3-(4-胺基-5-氰基-6-乙氧基吡啶-2-基胺基）苯甲醯胺 [化 1306]The title compound was synthesized according to the method of Example 1-145. 1H-NMR (300 MHz, DMSO-d6) δ 1.33 (t, J = 6.9 Hz, 3H), 4.35 (q, 2H), 5.78 (s, 1H), 6.56 (br5 2H), 7.10 (br, 1H) , 7.59 (d, J=9.0 Hz, 2H), 7.70-7.80 (m, 3H), 9.34 (s, 1H). Example 1-306 3-(4-Amino-5-cyano-6-ethoxypyridin-2-ylamino)benzimidamide [Chem. 1306]

標題化合物係依據實施例1-145之方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 1.31 (t, J=7.2 Hz, 3H), 4.37 (q, J=7.2 Hz, 2H), 5.73 (s, 1H), 6.48 (s, 2H), 7.25 (s, 1H), 7.31 (t, J=8.0 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.60 (d, J=9.2 Hz, 1H), 7.85 (s，1H), 8.16 (s，1H), 9.19 (s，1H)。 MS(ESI)m/z=297 (M+H)+。 LC/MS tR=l.34 min o 實施例1-307 141666.doc -272- 201028381 4-胺基-2-乙氧基-6-(4-甲氧基苯基胺基）菸鹼腈 [化 1307]The title compound was synthesized according to the method of Example 1-145. 1H-NMR (400 MHz, DMSO-d6) δ 1.31 (t, J = 7.2 Hz, 3H), 4.37 (q, J = 7.2 Hz, 2H), 5.73 (s, 1H), 6.48 (s, 2H), 7.25 (s, 1H), 7.31 (t, J=8.0 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.60 (d, J=9.2 Hz, 1H), 7.85 (s,1H), 8.16 (s, 1H), 9.19 (s, 1H). MS (ESI) m / z = 297 (M+H)+. LC/MS tR=l.34 min o Example 1-107 141666.doc -272- 201028381 4-Amino-2-ethoxy-6-(4-methoxyphenylamino)nicotinonitrile [ 1307]

標題化合物係依據實施例1-145之方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 1.31 (t, J=7.2 Hz, 3H), 3.72 (s, 3H), 4.48 (q, J=7.2 Hz, 2H), 5.62 (s, 1H), 6.34 (s, 2H), 6.52 (d, J=8.4 Hz, 2H), 6.55 (d, J=8.4 Hz, 2H), 8.80 (s，1H)。 MS(ESI)m/z=285 (M+H)+。 LC/MS tR=1.91 min 〇 實施例1-308 4_胺基-6-(3-氯-4-(5-(羥基甲基）呋喃-2-基）苯基胺基）-2-乙氧基菸鹼腈 [化 1308]The title compound was synthesized according to the method of Example 1-145. 1H-NMR (400 MHz, DMSO-d6) δ 1.31 (t, J = 7.2 Hz, 3H), 3.72 (s, 3H), 4.48 (q, J = 7.2 Hz, 2H), 5.62 (s, 1H), 6.34 (s, 2H), 6.52 (d, J=8.4 Hz, 2H), 6.55 (d, J=8.4 Hz, 2H), 8.80 (s, 1H). MS (ESI) m / z = 285 (M+H)+. LC/MS tR=1.91 min 〇 Example 1-308 4_Amino-6-(3-chloro-4-(5-(hydroxymethyl)furan-2-yl)phenylamino)-2-ethyl Oxynicotinonitrile [Chemical 1308]

標題化合物係依據實施例1-145之方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 1.36 (t, J=6.8 Hz, 3H), 4.39 (q, J=6.8 Hz, 2H), 4.46 (d, J=4.0 Hz, 2H), 5.28 (s, 1H), 5.76 (s, 2H), 6.42 (d, J=4.0 Hz, 1H)} 6.59 (s, 2H), 6.89 (d, J=2.8 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.70 (d, J=8.8 Hz, 1H)，7.97 (s, 1H)，9.43 (s，1H)。 141666.doc -273 - 201028381 MS(ESI)m/z=385 (M+H)+。 LC/MS tR=2.00 min 〇 實施例卜309 4-胺基-2-乙氧基-6-(4-(5-(經基甲基）喔u坐_2-基）苯基胺 基）於驗腈 [化 1309]The title compound was synthesized according to the method of Example 1-145. 1H-NMR (400 MHz, DMSO-d6) δ 1.36 (t, J = 6.8 Hz, 3H), 4.39 (q, J = 6.8 Hz, 2H), 4.46 (d, J = 4.0 Hz, 2H), 5.28 ( s, 1H), 5.76 (s, 2H), 6.42 (d, J=4.0 Hz, 1H)} 6.59 (s, 2H), 6.89 (d, J=2.8 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.70 (d, J=8.8 Hz, 1H), 7.97 (s, 1H), 9.43 (s, 1H). 141666.doc -273 - 201028381 MS (ESI) m/z = 385 (M+H)+. LC/MS tR=2.00 min 〇Example 309 4-Amino-2-ethoxy-6-(4-(5-(ylaminomethyl)喔u~_2-yl)phenylamino) For nitrile [Chemical 1309]

標題化合物係依據實施例1-145之方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 1.35 (t, J=6.8 Hz, 3H), 4.35-4.43 (m, 2H), 4.46 (s, 1H), 4.74 (s, 1H), 5.79 (s, 1H), 5.55 (bs, 2H), 6.64 (d, J=8.4 Hz, 1H), 6.83 (s, 1H), 7.11 (bsy 1H), 7.35 (s, 1H), 7.57-7.69 (m, 3H), 7.82 (d, J=8.4 Hz, 1H)，9.39 (s，1H)。 MS(ESI)m/z=368 (M+H)+。 LC/MS tR=l_69 min。 實施例1-310 4-胺基-2-乙氧基-6-(4-(噁唑-2·基）苯基胺基）菸鹼腈 [化 1310]The title compound was synthesized according to the method of Example 1-145. 1H-NMR (400 MHz, DMSO-d6) δ 1.35 (t, J = 6.8 Hz, 3H), 4.35-4.43 (m, 2H), 4.46 (s, 1H), 4.74 (s, 1H), 5.79 (s , 1H), 5.55 (bs, 2H), 6.64 (d, J=8.4 Hz, 1H), 6.83 (s, 1H), 7.11 (bsy 1H), 7.35 (s, 1H), 7.57-7.69 (m, 3H ), 7.82 (d, J=8.4 Hz, 1H), 9.39 (s, 1H). MS (ESI) m/z = 368 (M+H)+. LC/MS tR = l_69 min. Example 1-110 4-Amino-2-ethoxy-6-(4-(oxazol-2yl)phenylamino)nicotinonitrile [Chemical 1310]

141666.doc •274· 201028381 步驟1 : 2-(4-硝基笨基）噁唑 向4-蛾苯胺（1.0 g ’ 1.66 mmol)、2-(三丁基錫烷基）噁唑 (1.29 g，3.61 mmol)之曱苯溶液（10 mL)中添加 Pd(PPh3)4(464 mg ’ 0.402 mmol) ’ 於 l〇〇°C 下授拌 4小時。 向反應溶液中添加水及乙酸乙酯進行分離後，以乙酸乙g旨 萃取水相，將合併之有機相以水及飽和食鹽水進行清洗， 以硫酸鎂加以乾燥。將有機相過濾後，進行減壓濃縮。利 用中壓矽膠層析法（乙酸乙酯：己烷=3: 1)對所獲得之殘 ❹ &gt;查進行純化’獲得標題化合物（3 16 mg，41 %)，為白色固 體0 1H-NMR (400 MHz, DMSO-d6) δ 8.06-8.08 (m, 3H) 8 35 8.37 (m，3H)。 MS(ESI)m/z=191 (M+H)+。 LC/MS tR=1.67 min。 步驟2 : 4-(°惡唾-2-基）苯胺141666.doc •274· 201028381 Step 1: 2-(4-Nitrophenyl)oxazole to 4-Mothaniline (1.0 g ' 1.66 mmol), 2-(tributylstannyl)oxazole (1.29 g, 3.61 Pd(PPh3)4 (464 mg '0.402 mmol)' was added to the benzene solution (10 mL) of mmol) and mixed at 4 °C for 4 hours. Water and ethyl acetate were added to the reaction solution, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and brine, and dried over magnesium sulfate. After the organic phase was filtered, it was concentrated under reduced pressure. The residue obtained was purified by medium pressure EtOAc (EtOAc: hexane = 3:1) to give the title compound (3 16 mg, 41%) as white solids. (400 MHz, DMSO-d6) δ 8.06-8.08 (m, 3H) 8 35 8.37 (m, 3H). MS (ESI) m / z = 191 (M+H)+. LC/MS tR = 1.67 min. Step 2: 4-(°Ethoster-2-yl)aniline

將2-(4-碗基笨基）嗯唆⑽mg，4〇2 及ι〇%纪碳 U50 mg)之THF-甲醇溶液（1 : i，6叫於氣氣環境下，於 室溫下授拌4小時。狀應溶液進行⑦藻土過㈣，進行 減壓濃縮。利用中㈣膠層析法（乙酸乙_ :己统_2 對所獲得之殘法進行純化’獲得標題化 ：§，) 25%)，為白色固體。 g MS(ESI)m/z=161 (M+H)+ ° LC/MS tR=0.93 min 〇 步驟3 :標題化合物 141666.doc -275- 201028381 使用4-(噁唑-2-基）苯胺，依據實施例1-145之方法而合 成。 1H-NMR (400 MHz, DMSO-d6) δ 1.33 (t，J=7.2 Hz，3H)， 4.38 (q, J=7.2 Hz, 2H), 5.81 (s, 1H), 6.57 (s, 1H), 7.32 (s, 1H), 7.71 (d, J=8.4 Hz, 2H), 7.88 (d, J=8.4 Hz, 2H), 8.13 (s, 1H)，9.23 (s, 1H)。 MS(ESI)m/z=322 (M+H)+。 LC/MS tR=1.89 min。 實施例1-311 5-(4-(4 -胺基-5-氣基-6-乙氧基e比咬-基胺基）未基）咬喃-2-甲酸甲酯 [化 1311]2-(4-bowl base stupid) 唆 (10) mg, 4 〇 2 and ι〇% carbon U50 mg) in THF-methanol solution (1: i, 6 is called in a gas atmosphere, at room temperature Mix for 4 hours. The solution should be subjected to 7 algae (4), and concentrated under reduced pressure. Using the medium (4) gel chromatography (acetic acid B_: hexa-2 to purify the obtained residue method) to obtain the title: §, ) 25%) as a white solid. g MS (ESI) m/z = 161 (M+H) + </RTI> &lt;&quot;&&&&&&&&&&&&&&&&&&&& Synthesized according to the method of Example 1-145. 1H-NMR (400 MHz, DMSO-d6) δ 1.33 (t, J = 7.2 Hz, 3H), 4.38 (q, J = 7.2 Hz, 2H), 5.81 (s, 1H), 6.57 (s, 1H), 7.32 (s, 1H), 7.71 (d, J=8.4 Hz, 2H), 7.88 (d, J=8.4 Hz, 2H), 8.13 (s, 1H), 9.23 (s, 1H). MS (ESI) m / z = 322 (M+H)+. LC/MS tR = 1.89 min. Example 1-311 5-(4-(4-Amino-5-carbyl-6-ethoxye-butyl-amino-amino)-pyridyl) methyl benzoate-2-carboxylate [Chemical 1311]

標題化合物係依據實施例1-145之方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 1.35 (t, J=7.2 Hz, 3H), 4.37 (q, J=7.2 Hz, 2H), 5.78 (s, 1H), 6.54 (s, 2H), 7.01 (d, J=4.4 Hz, 1H), 7.39 (d, J=4.4 Hz, 1H), 7.71 (dd, J=9.2 Hz, 15.6 Hz, 4H)，9.37 (s，1H)。 MS(ESI)m/z=379 (M+H)+。 LC/MS tR=2.16 min。 實施例l-3 12 2-(4-(4-胺基-5-氰基-6·乙氧基&quot;比啶-2-基）胺基苯基）噻唑- 141666.doc -276- 201028381 5-甲酸乙酯 [化 1312]The title compound was synthesized according to the method of Example 1-145. 1H-NMR (400 MHz, DMSO-d6) δ 1.35 (t, J = 7.2 Hz, 3H), 4.37 (q, J = 7.2 Hz, 2H), 5.78 (s, 1H), 6.54 (s, 2H), 7.01 (d, J=4.4 Hz, 1H), 7.39 (d, J=4.4 Hz, 1H), 7.71 (dd, J=9.2 Hz, 15.6 Hz, 4H), 9.37 (s, 1H). MS (ESI) m / z = 379 (M+H)+. LC/MS tR = 2.16 min. Example l-3 12 2-(4-(4-Amino-5-cyano-6.ethoxy)&quot;bipyridin-2-yl)aminophenyl)thiazole - 141666.doc -276- 201028381 5-ethyl formate [Chemical 1312]

標題化合物係依據實施例1-145之方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 1.31-1.37 (m, 6H), 4.31-4.41 (m, 4H), 5.80 (s, 1H), 6.57 (bs, 2H), 7.73 (d, J=8.8 Hz, ❹ 2H)，7.88 (d, J=8.8 Hz，2H)，8.46 (s，1H)，9.46 (s，1H)。 MS(ESI)m/z=41〇 (m+H)+。 LC/MS tR=2.21 min o 實施例1-313 4-胺基-2-乙氧基_6_(3_甲氧基_4-(噁唑-5-基）笨基胺基）菸 鹼腈 [化 1313]The title compound was synthesized according to the method of Example 1-145. 1H-NMR (400 MHz, DMSO-d6) δ 1.31-1.37 (m, 6H), 4.31-4.41 (m, 4H), 5.80 (s, 1H), 6.57 (bs, 2H), 7.73 (d, J= 8.8 Hz, ❹ 2H), 7.88 (d, J = 8.8 Hz, 2H), 8.46 (s, 1H), 9.46 (s, 1H). MS (ESI) m / z = 41 〇 (m + H) +. LC/MS tR=2.21 min o Example 1-313 4-Amino-2-ethoxy_6-(3-methoxy-4-(oxazol-5-yl)phenylamino) Nicotinonitrile [Chem. 1313]

標題化合物係依據實施例1 -145之方法而合成。 MS(ESI)m/z=352 (M+H)+。 LC/MS tR=1.91 min。 實施例1-314 4-胺基-2-乙氧基-6-(2-甲基苯并[d]噁唑-5-基胺基）菸 鹼腈 I41666.doc -277· 201028381 [化 1314]The title compound was synthesized according to the method of Example 1-145. MS (ESI) m / z = 352 (M + H) +. LC/MS tR = 1.91 min. Example 1-114 4-Amino-2-ethoxy-6-(2-methylbenzo[d]oxazol-5-ylamino)nicotinonitrile I41666.doc -277· 201028381 [Chemical 1314] ]

標題化合物係依據實施例1-145之方法而合成。 MS(ESI)m/z=310 (M+H)+。 LC/MS tR=1.79 min。 實施例1-315 4-胺基-6-(苯并[d]噁唑-5-基胺基）-2-乙氧基柊驗猜 [化 1315]The title compound was synthesized according to the method of Example 1-145. MS (ESI) m / z = 310 (M + H) +. LC/MS tR = 1.79 min. Example 1-315 4-Amino-6-(benzo[d]oxazol-5-ylamino)-2-ethoxy oxime [Chemical 1315]

標題化合物係依據實施例1-145之方法而合成。 MS(ESI)m/z=296 (M+H)+。 LC/MS tR=1.72 min。 實施例1-316 4-胺基-6-(2-丁基苯并[d]噁唑-6-基胺基乙氧基 鹼腈 [化 1316]The title compound was synthesized according to the method of Example 1-145. MS (ESI) m / z = 296 (M + H) +. LC/MS tR = 1.72 min. Example 1-116 4-Amino-6-(2-butylbenzo[d]oxazol-6-ylaminoethoxy ethoxynitrile [Chemical 1316]

標題化合物係依據實施例1-145之方法而合成。 MS(ESI)m/z=352 (M+H)+。 141666.doc -278- 201028381 LC/MS tR=2.25 min。 實施例1-317 4-胺基-2-乙氧基-6-(2-苯基苯并[d]噁唑-6-基胺基）菸 鹼腈 [化 1317]The title compound was synthesized according to the method of Example 1-145. MS (ESI) m / z = 352 (M + H) +. 141666.doc -278- 201028381 LC/MS tR=2.25 min. Example 1-317 4-Amino-2-ethoxy-6-(2-phenylbenzo[d]oxazol-6-ylamino)nicotinonitrile [Chem. 1317]

標題化合物係依據實施例1-145之方法而合成。 MS(ESI)m/z=372 (M+H)+ ° LC/MS tR=2.31 min。 實施例1-318 4-胺基-2-乙氧基-6-(2-丙基苯并[d]噁唑-6-基胺基）菸 鹼腈 [化 1318]The title compound was synthesized according to the method of Example 1-145. MS (ESI) m/z = 372 (MH+) Example 1-118 4-Amino-2-ethoxy-6-(2-propylbenzo[d]oxazol-6-ylamino)nicotinonitrile [Chemical 1318]

標題化合物係依據實施例1 -145之方法而合成。 MS(ESI)m/z=338 (M+H)+。 LC/MS tR=2.07 min。 實施例1-319 4-胺基-2-乙氧基-6-(4-(噻唑-2-基）苯基胺基）菸鹼腈 141666.doc -279- 201028381 [化 1319]The title compound was synthesized according to the method of Example 1-145. MS (ESI) m / z = 338 (M+H)+. LC/MS tR = 2.07 min. Example 1-319 4-Amino-2-ethoxy-6-(4-(thiazol-2-yl)phenylamino)nicotinonitrile 141666.doc -279- 201028381 [Chem. 1319]

標題化合物係依據實施例1-145之方法而人&amp; MS(ESI)m/z=338 (M+H)+。 LC/MS tR=2.05 min 〇 實施例1-320 4-胺基-2-乙氧基-6-(4-甲醯基苯基胺基）於驗猜 [化 1320]The title compound was obtained according to the method of Example 1-145. &&lt;&quot;&gt;&gt; MS (ESI) m/z = 338 (M+H)+. LC/MS tR=2.05 min 实施 Example 1-320 4-Amino-2-ethoxy-6-(4-methylnonylphenylamino) was tested [Chem. 1320]

標題化合物係依據實施例1-145之方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 1.36 (t, J=6.8 Hz, 3H), 4.38 (q, J=6.8 Hz, 2H), 5.86 (s, 1H), 6.68 (s, 2H), 7.76-7.81 (m, 4H), 6.48 (s，1H), 9.66 (s, 1H)，9.81 (s，1H) 〇 MS(ESI)m/z=283 (M+H)+。 LC/MS tR=l.77 min。 實施例1-321 N-(4-(4-胺基-5-氰基-6-乙氧基D比咬-2-基胺基）_2_經基苯 基）丙醯胺 141666.doc -280- 201028381 [化 1321]The title compound was synthesized according to the method of Example 1-145. 1H-NMR (400 MHz, DMSO-d6) δ 1.36 (t, J = 6.8 Hz, 3H), 4.38 (q, J = 6.8 Hz, 2H), 5.86 (s, 1H), 6.68 (s, 2H), 7.76-7.81 (m, 4H), 6.48 (s, 1H), 9.66 (s, 1H), 9.81 (s, 1H) 〇MS (ESI) m/z = 283 (M+H)+. LC/MS tR = 1.77 min. Example 1-321 N-(4-(4-Amino-5-cyano-6-ethoxy D-biti-2-ylamino)_2-phenylphenyl)propanamide 141666.doc - 280- 201028381 [Chem. 1321]

標題化合物係依據實施例1 -145之方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 1.08 (t, J=7.6 Hz, 3H), 1.31 (t, J=6.8 Hz, 3H), 2.36 (q, J=7.6 Hz, 2H), 2.36 (q, J=6.8 Hz, 2H), 5.86 (s, 1H), 6.40 (s, 2H), 6.89 (d, J=8.8 Hz, 1H), 7.06 (s, 1H), 7.46 (d, J=8.8 Hz, 1H), 8.87 (s, 1H), 9.17 (s, 1H)，9.71 (s，1H)。 MS(ESI)m/z=342 (M+H)、 LC/MS tR=1.57 min。 實施例1-322 4-(4 -胺基-5-氰基-6-乙氧基比e定-2-基胺基）-2-甲氧基苯 續醯胺 [化 1322]The title compound was synthesized according to the method of Example 1-145. 1H-NMR (400 MHz, DMSO-d6) δ 1.08 (t, J = 7.6 Hz, 3H), 1.31 (t, J = 6.8 Hz, 3H), 2.36 (q, J = 7.6 Hz, 2H), 2.36 ( q, J=6.8 Hz, 2H), 5.86 (s, 1H), 6.40 (s, 2H), 6.89 (d, J=8.8 Hz, 1H), 7.06 (s, 1H), 7.46 (d, J=8.8 Hz, 1H), 8.87 (s, 1H), 9.17 (s, 1H), 9.71 (s, 1H). MS (ESI) m/z = 342 (M+H). Example 1-322 4-(4-Amino-5-cyano-6-ethoxyl ratio e-diyl-2-ylamino)-2-methoxybenzene Continuum amide [Chem. 1322]

步驟1 : 2-甲氧基-4_硝基苯磺醯胺 向2-甲氧基-4-硝基苯·ι·磺醢氣（2.0 g’ 7.95 mmol)之二 噁烷（20 mL)溶液中添加28%氨水（9.2 mL)，於室溫下搜捧 141666.doc •281 201028381 4小時。添加水及乙酸乙酿將反應溶液分離。以乙酸乙醋 萃取水相’將合併之有機相以水及飽和食鹽水進行清洗了 以硫酸鎮加以乾燥。將有機相過濾後’進行減壓濃縮，以 乙醇使所獲得之殘渣固化，獲得標題化合物（1 82 g，7 Μ mmol，99%)，為黃色固體。 1H-NMR (400 MHz, DMSO-d6) δ 4.03 (s 扣、7 以, JH)，7.46 (s，2Η), 7.89-7.99 (m，3H)。 ’ MS(ESI)m/z=233 (M+H)、 步驟2 : 4-胺基-2-甲氧基苯磺醯胺 向2-甲氧基-4-硝基苯磺醯胺（1.0 g，4 31 mm〇1)之曱醇· THF=1 ·· 3(20 mL)溶液中添加 10% Pd_C 粉末（1〇〇 mg)，於 氫氣環境下’於室溫下攪拌4小時。對反應液進行石夕藻土 過濾’將溶劑減壓濃縮。利用中壓矽膠層析法（氣仿/甲 醇；2-10%梯度）對所獲得之殘渣進行純化，獲得標題化合 物（227 mg ’ 1 · 12 mmol，26%)，為黃色固體。 1H-NMR (400 MHz, DMSO-d6) δ 3.76 (s, 3H), 5.80 (s, 2H), 6.11 (d, J=8.4 Hz, 1H), 6.24 (s, 1H), 6.57 (brs, 2H), 7.33 (d，J=8.4 Hz, 1H)。 MS(ESI)m/z=203 (M+H)+。 步驟3 :標題化合物 使用4·胺基-2-甲氧基苯績醯胺，依據實施例ι_ΐ45之方 法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 1.32 (t, J=7.2 Hz, 3H), 3.86 (s, 3H), 4.38 (q, J=7.2 Hz, 2H), 5.80 (s, 1H), 6.61 (s, 141666.doc •282· 201028381 2H), 7.06 (d, J=9.2 Hz, 1H), 7.56-7.58 (m, 2H), 9.46 (s, 1H)。 MS(ESI)m/z=364 (M+H)+。 mp : 150-153。。。 實施例1-323 N-(4-(4-胺基-5-氰基-6-乙氧基吼啶-2-基胺基）-2-曱氧基 苯基）-N-曱基磺醯基甲磺醯胺 [化 1323]Step 1: 2-Methoxy-4-nitrobenzenesulfonamide to 2-methoxy-4-nitrobenzene·methanesulfonate (2.0 g' 7.95 mmol) in dioxane (20 mL) Add 28% ammonia water (9.2 mL) to the solution and search for 141666.doc •281 201028381 for 4 hours at room temperature. Water and acetic acid were added to separate the reaction solution. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and saturated brine. After the organic phase was filtered, the residue was evaporated to dryness crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 1H-NMR (400 MHz, DMSO-d6) δ 4.03 (s, s, 7 s, JH), 7.46 (s, 2 Η), 7.89-7.99 (m, 3H). ' MS (ESI) m / z = 233 (M + H), Step 2: 4-amino-2-methoxybenzenesulfonamide to 2-methoxy-4-nitrobenzenesulfonamide (1.0 g, 4 31 mm 〇1) decyl alcohol·THF = 1 · 3 (20 mL) was added 10% Pd_C powder (1 〇〇 mg), and stirred under a hydrogen atmosphere for 4 hours at room temperature. The reaction solution was subjected to filtration with celite, and the solvent was concentrated under reduced pressure. The residue obtained was purified by EtOAc EtOAc (EtOAc (EtOAc) 1H-NMR (400 MHz, DMSO-d6) δ 3.76 (s, 3H), 5.80 (s, 2H), 6.11 (d, J = 8.4 Hz, 1H), 6.24 (s, 1H), 6.57 (brs, 2H) ), 7.33 (d, J = 8.4 Hz, 1H). MS (ESI) m / z = 203 (M+H)+. Step 3: The title compound was synthesized according to the procedure of Example ι. 1H-NMR (400 MHz, DMSO-d6) δ 1.32 (t, J = 7.2 Hz, 3H), 3.86 (s, 3H), 4.38 (q, J = 7.2 Hz, 2H), 5.80 (s, 1H), 6.61 (s, 141666.doc •282· 201028381 2H), 7.06 (d, J=9.2 Hz, 1H), 7.56-7.58 (m, 2H), 9.46 (s, 1H). MS (ESI) m / z = 364 (M + H) +. Mp : 150-153. . . Example 1-123 N-(4-(4-Amino-5-cyano-6-ethoxyacridin-2-ylamino)-2-methoxyphenyl)-N-decylsulfonate Mercaptomethylsulfonamide [Chemical 1323]

步驟1 : N-(2-甲氧基-4-硝基苯基）-N-(甲基磺醯基）甲磺 醯胺 向2-曱氧基-4-硝基苯胺（2.0 g，7.95 mmol)、三乙基胺 (2.71 g，3.71 mL，21.4 mmol)及 DMAP(218 mg，1.78 mmol)之二氣曱炫（50 mL)溶液中添加甲績醢氣（2.45 g， 1.68 mL，21.4 mmol)，於室溫下攪拌5小時。添加水及乙 酸乙酯將反應溶液分離。以乙酸乙酯萃取水相，將合併之 有機相以水及飽和食鹽水進行清洗，以硫酸鎂加以乾燥。 將有機相過濾後，進行減壓濃縮，以乙醇/乙酸乙酯使所 獲得之殘渣固化，獲得標題化合物（3 .4 g，10.5 mmol， 141666.doc •283 - 201028381 59%)，為黃色固體。 1H-NMR (400 MHz，DMSO-d6) δ 3.54 (s，6H)，4.01 (s, 3H), 7.82 (d, J=8.4 Hz, 1H), 7.87 (dd, J=2.0 Hz, 8.4 Hz, 1H), 7.93 (d，J=2.0 Hz, 1H) ° MS(ESI)m/z=325 (M+H)+。 步驟2 : N-(4-胺基-2-曱氧基苯基）-N-(甲基磺醯基）甲續 醯胺 向N-(2-曱氧基-4-硝基苯基）-N-(曱基磺醯基）曱磺醯胺 (2.0 g，6.17 mmol)之曱醇-THF=1 : 1(40 mL)溶液中添加 10% Pd-C粉末（200 mg)，於氫氣環境下，於室溫下搜拌4 小時。對反應液進行矽藻土過濾，將溶劑減壓濃縮。使所 獲得之殘渣固化（乙醇/醚），獲得標題化合物（1.51 g，5.13 mmol，83%)，為白色固體。 1H-NMR (400 MHz, DMSO-d6) δ 3.36 (s, 6H), 3.71 (s, 3H), 5.55 (s, 2H), 6.11 (dd, J=2.0 Hz, 8.4 Hz, 1H), 6.25 (d, J=2.0 Hz, 1H)，6.96 (d，J=8.4 Hz，1H)。 MS(ESI)m/z=295 (M+H)+。 步驟3:標題化合物 使用N-(4 -胺基-2-甲氧基笨基）-Ν-(曱基續醯基）甲續醯 胺，依據實施例1-145之方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 1.32 (t, J=6.8 Hz, 3H), 3.43 (s,6H), 3.82 (s, 3H), 4.39 (q, J=6.8 Hz, 2H), 5.79 (s, 1H), 6.58 (s, 2H), 7.06 (d, J=8.〇 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H)，7.56 (s，1H), 9.36 (s，1H) 〇 141666.doc -284- 201028381 MS(ESI)m/z=456 (M+H)+。 mp : 242-245。。° 實施例1-324 N-(4-(4-胺基-5-乳基-6-乙氧基n比咬-2-基胺基）-2-甲氧基 苯基）乙醯胺 [化 1324] 〇Step 1: N-(2-Methoxy-4-nitrophenyl)-N-(methylsulfonyl)methanesulfonamide to 2-decyloxy-4-nitroaniline (2.0 g, 7.95 Methyl hydrazine (2.45 g, 1.68 mL, 21.4) was added to a solution of triethylamine (2.71 g, 3.71 mL, 21.4 mmol) and DMAP (218 mg, 1.78 mmol) in dioxane (50 mL). Methyl), stirred at room temperature for 5 hours. The reaction solution was separated by adding water and ethyl acetate. The aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with water and brine and dried over magnesium sulfate. After the organic phase was filtered, EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj . </ RTI> <RTIgt; 1H), 7.93 (d, J = 2.0 Hz, 1H) ° MS (ESI) m/z = 325 (M+H)+. Step 2: N-(4-Amino-2-methoxyphenyl)-N-(methylsulfonyl)methyl hydrazine to N-(2-decyloxy-4-nitrophenyl) -N-(fluorenylsulfonyl)furfurylamine (2.0 g, 6.17 mmol) in methanol-THF = 1: 1 (40 mL) was added 10% Pd-C powder (200 mg) in hydrogen Under the environment, mix for 4 hours at room temperature. The reaction solution was filtered through Celite, and the solvent was concentrated under reduced pressure. The residue obtained was crystallized (EtOAc/EtOAc) 1H-NMR (400 MHz, DMSO-d6) δ 3.36 (s, 6H), 3.71 (s, 3H), 5.55 (s, 2H), 6.11 (dd, J=2.0 Hz, 8.4 Hz, 1H), 6.25 ( d, J = 2.0 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H). MS (ESI) m / z = 295 (M + H) +. Step 3: The title compound was synthesized according to the procedure of Example 1-145 using N-(4-amino-2-methoxyphenyl)-indole-(indole). 1H-NMR (400 MHz, DMSO-d6) δ 1.32 (t, J = 6.8 Hz, 3H), 3.43 (s, 6H), 3.82 (s, 3H), 4.39 (q, J = 6.8 Hz, 2H), 5.79 (s, 1H), 6.58 (s, 2H), 7.06 (d, J=8.〇Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.56 (s,1H), 9.36 (s , 1H) 〇 141666.doc -284- 201028381 MS (ESI) m/z = 456 (M+H)+. Mp: 242-245. . ° Example 1-324 N-(4-(4-Amino-5-lacty-6-ethoxy n-butyl-2-ylamino)-2-methoxyphenyl)acetamide [ 1324] 〇

步驟1 : N-(2-甲氧基-4-硝基苯基）乙醯胺 向2-曱氧基-4-硝基苯胺（2.0 g，7.95 mmol)及吡啶（20 1111〇之二氣甲烷（5〇1111〇溶液中，於0°〇下添加乙醯氯（2.24 g ’ 2.0 mL，28.5 mmol) ’於室溫下檟:拌8小時。添加水及 φ 乙酸乙酯將反應溶液分離。以乙酸乙酯萃取水相，將合併 之有機相以水及飽和食鹽水進行清洗，以硫酸鎂加以乾 燥。將有機相過濾後，進行減壓濃縮，以乙醇/醚使所獲 得之殘渣固化，獲得標題化合物（3.75 g，17.8 mmol， 74%) ° 1H-NMR (400 MHz, DMSO-d6) δ 2.16 (s, 3Η), 3.96 (s, 6H), 7.77 (d, J=2.4 Hz, 1H), 7.85 (dd, J=2.4 Hz, 8.8 Hz, 1H), 8.35 (d, J=8.8 Hz, 1H), 9.56 (s，1H)。 141666.doc -285- 201028381 MS(ESI)m/z=211 (M+H)+ 〇 步驟2 : N-(4-胺基-2-曱氧基苯基）乙醯胺 向N_(2-甲氧基冬墙基苯基）乙醢胺（2 〇 g，6 17職〇1)之 甲醇-THF = 1 : 3(2〇 mL)溶液中添加1〇% pd c粉末⑽〇 mg)’於氫氣環境下’於室溫下㈣4小時。對反應液進行 矽藻土過濾，將溶劑減壓濃縮》利用中壓矽膠層析法（氣 仿/曱醇；2-10%梯度）對所獲得之殘渣進行純化，獲得標 題化合物（718 mg ’ 3.98 mmol，84%)，為黃色非晶體。 1H-NMR (400 MHz，DMSO-d6) δ 1.95 (s，3H)，4.95 (s, 2H) 6.07 (dd, J-1.6 Hz, 8.4 Hz, 1H), 6.24 (d, J=1.6 Hz, 1H) 7.25 (d，J=8.4 Hz, 1H)，8.72 (s，1H)。 MS(ESI)m/z=181 (M+H)+。 步驟3 :使用標題化合物N-(4-胺基-2-甲氧基苯基）乙酿 胺，依據實施例1-145之方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 1.30 (t, J=6.8 Hz, 3H), 2.03 (s, 3H), 3.79 (s, 3H), 4.36 (q, J=6.8 Hz, 2H), 5.71 (s, 1H), 6.44 (s, 2H), 6.92 (d, J=8.4 Hz, 1H), 7.39 (s, 1H), 7.70 (d，J=8.4 Hz, 1H), 8.99 (s，1H)，9.02 (s, 1H)。 MS(ESI)m/z=342 (M+H)+。 mp : 219-221。。。 實施例l-325 4-胺基-2-乙氧基-6-(3-甲氧基-4-(甲基磺醯基）苯基胺基） 菸鹼腈 141666.doc -286- 201028381 [化 1325] OMeStep 1: N-(2-Methoxy-4-nitrophenyl)acetamidine to 2-decyloxy-4-nitroaniline (2.0 g, 7.95 mmol) and pyridine (20 1111 bismuth) Add methane chloride (2.24 g '2.0 mL, 28.5 mmol) in a solution of methane (5〇1111〇) at room temperature. Mix at room temperature for 8 hours. Add water and φ ethyl acetate to separate the reaction solution. The aqueous phase is extracted with ethyl acetate, and the combined organic phases are washed with water and brine, and dried over magnesium sulfate. The organic phase is filtered and concentrated under reduced pressure to solidify the residue with ethanol/ether. The title compound was obtained (3.75 g, 17.8 mmol, 74%) ° 1H-NMR (400 MHz, DMSO-d6) δ 2.16 (s, 3 Η), 3.96 (s, 6H), 7.77 (d, J = 2.4 Hz, 1H), 7.85 (dd, J=2.4 Hz, 8.8 Hz, 1H), 8.35 (d, J=8.8 Hz, 1H), 9.56 (s, 1H). 141666.doc -285- 201028381 MS(ESI)m/ z=211 (M+H)+ 〇Step 2: N-(4-Amino-2-decyloxyphenyl)acetamide to N_(2-methoxy-winter phenyl)acetamide ( 2 〇g, 6 17 jobs 1) methanol-THF = 1 : 3 (2 〇 mL) solution added 1% pd c powder (10) 〇 mg) 'under hydrogen atmosphere' (4) 4 hours at room temperature. The reaction solution was filtered through celite, and the solvent was concentrated under reduced pressure. The residue obtained was purified by medium pressure gel chromatography (gas/methanol; 2-10% gradient). The title compound (718 mg ' 3.98 mmol, 84%) was obtained as yellow crystals. 1H-NMR (400 MHz, DMSO-d6) δ 1.95 (s, 3H), 4.95 (s, 2H) 6.07 (dd, J-1.6 Hz, 8.4 Hz, 1H), 6.24 (d, J=1.6 Hz, 1H) 7.25 (d, J=8.4 Hz, 1H), 8.72 (s, 1H) MS (ESI) m/z = 181 (M+ H) + Step 3: The title compound N-(4-Amino-2-methoxyphenyl)ethylamine was used according to the procedure of Example 1-145. 1H-NMR (400 MHz, DMSO- D6) δ 1.30 (t, J=6.8 Hz, 3H), 2.03 (s, 3H), 3.79 (s, 3H), 4.36 (q, J=6.8 Hz, 2H), 5.71 (s, 1H), 6.44 ( s, 2H), 6.92 (d, J=8.4 Hz, 1H), 7.39 (s, 1H), 7.70 (d, J=8.4 Hz, 1H), 8.99 (s, 1H), 9.02 (s, 1H). MS (ESI) m / z = 342 (M + H) +. Mp: 219-221. . . Example 1-325 4-Amino-2-ethoxy-6-(3-methoxy-4-(methylsulfonyl)phenylamino) Nicotinonitrile 141666.doc -286-201028381 [ 1325] OMe

Pd/Ct H2 THRMeOH,室溫 〇 〇 OMePd/Ct H2 THRMeOH, room temperature 〇 〇 OMe

、ONa DMSO, 130 °C, ONa DMSO, 130 °C

步驟1 : 2-甲氧基-1-甲基磺醯基-4-硝基苯 向1-氯-2-曱氧基-4-硝基苯（3.0 g，16.0 mmol)之 Φ DMSO(15 mL)溶液中添加曱亞磺酸鈉（1.80 g，17.6 mmol)，於130°C下攪拌17小時。添加水及乙酸乙酯，將反 應溶液分離。以乙酸乙酯萃取水相，將合併之有機相以水 及飽和食鹽水進行清洗，以硫酸鎮加以乾燥。將有機相過 濾後，進行減壓濃縮，利用中壓矽膠層析法（己烷/乙酸乙 酯；20-70%梯度）對所獲得之殘渣進行純化，獲得標題化 合物（411 mg，1.78 mmol，11%)。 1H-NMR (400 MHz, DMSO-d6) δ 3.32 (s, 3Η), 4.09 (s, 3H), 參 7.97 (dd, J=1.6 Hz, 8.4 Hz, 1H), 8.00 (d, J=1.6 Hz, 1H), 8.06 (d，J=8.4 Hz, 1H)。 MS(ESI)m/z=232 (M+H)+。 步驟2 : 3-甲氧基-4-(甲基磺醯基）苯胺 向2-甲氧基-1-曱基磺醯基-4-硝基苯（200 mg，0.865 mmol)之曱醇-THF=1 : 1(6 mL)溶液中添加10% Pd-C粉末 (20 mg)，於氫氣環境下，於室溫下攪拌4小時。對反應液 進行矽藻土過濾，將溶劑減壓濃縮。利用中壓矽膠層析法 141666.doc 287- 201028381 (己炫/乙酸乙酯；10_80%梯度）對所獲得之殘渣進行純化， 獲得標題化合物（164 mg，0.815 mmol，94%)。 1H-NMR (400 MHz, DMSO-d6) δ 3.05 (s, 3Η), 3.80 (s, 3H), 6.07 (s, 2H), 6.19 (dd, J=1.6 Hz, 8.8 Hz, 1H), 6.27 (d, J=1.6 Hz, 1H)，7.38 (d，J=8_8 Hz，1H)。 MS(ESI)m/z=202 (M+H).。 步驟3 .標題化合物 使用3-甲氧基-4-(曱基磺醯基）苯胺，依據實施例卜145之 方法而合成。 ❿ 1H-NMR (400 MHz，DMSO-d6) δ 1.32 (t，J=6.8 Hz，3H)， 3.15 (s, 3H), 3.90 (s, 3H), 4.39 (q, J=6.8 Hz, 2H), 5.83 (s, 1H), 6.66 (s, 2H), 7.17 (d, J=8.8 Hz, lH), 7.63 (d, J=8.8 Hz，1H), 7.66 (s, 1H)，9.60 (s，1H)。 MS(ESI)m/z=363 (M+H)+。 mp :236-238°C。 實施例1-326 4-胺基-2-乙氧基-6-(4-(1-甲基-1H-吡唑基）苯基胺基）G 菸鹼腈 [化 1326] nh2Step 1: 2-methoxy-1-methylsulfonyl-4-nitrobenzene to 1-chloro-2-indolyl-4-nitrobenzene (3.0 g, 16.0 mmol) in Φ DMSO (15 Sodium sulfinium sulfinate (1.80 g, 17.6 mmol) was added to the solution, and stirred at 130 ° C for 17 hours. Water and ethyl acetate were added to separate the reaction solution. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water and brine, and dried over silica. After the organic phase was filtered, EtOAcjjjjjjjjjj 11%). 1H-NMR (400 MHz, DMSO-d6) δ 3.32 (s, 3 Η), 4.09 (s, 3H), s. 7.97 (dd, J=1.6 Hz, 8.4 Hz, 1H), 8.00 (d, J=1.6 Hz , 1H), 8.06 (d, J = 8.4 Hz, 1H). MS (ESI) m / z = 232 (M + H) +. Step 2: 3-Methoxy-4-(methylsulfonyl)aniline to 2-methoxy-1-indolylsulfonyl-4-nitrobenzene (200 mg, 0.865 mmol) of decyl alcohol - 10% Pd-C powder (20 mg) was added to a solution of THF = 1 : 1 (6 mL), and stirred under a hydrogen atmosphere at room temperature for 4 hours. The reaction solution was filtered through Celite, and the solvent was concentrated under reduced pressure. The residue obtained was purified by EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc 1H-NMR (400 MHz, DMSO-d6) δ 3.05 (s, 3 Η), 3.80 (s, 3H), 6.07 (s, 2H), 6.19 (dd, J=1.6 Hz, 8.8 Hz, 1H), 6.27 ( d, J = 1.6 Hz, 1H), 7.38 (d, J = 8_8 Hz, 1H). MS (ESI) m / z = 202 (M + H). Step 3. The title compound was synthesized according to the method of Example 145 using 3-methoxy-4-(decylsulfonyl)aniline. ❿ 1H-NMR (400 MHz, DMSO-d6) δ 1.32 (t, J = 6.8 Hz, 3H), 3.15 (s, 3H), 3.90 (s, 3H), 4.39 (q, J = 6.8 Hz, 2H) , 5.83 (s, 1H), 6.66 (s, 2H), 7.17 (d, J=8.8 Hz, lH), 7.63 (d, J=8.8 Hz, 1H), 7.66 (s, 1H), 9.60 (s, 1H). MS (ESI) m / z = 363 (M+H)+. Mp: 236-238 °C. Example 1-326 4-Amino-2-ethoxy-6-(4-(1-methyl-1H-pyrazolyl)phenylamino) G Nicotinonitrile [Chemical 1326] nh2

il + h2n 、'N 人。Il + h2n , 'N people.

DMSO, 180°CDMSO, 180 ° C

PhNTf2, Et3N THF,室溫PhNTf2, Et3N THF, room temperature

DMF, 80 °CDMF, 80 °C

DIEADIEA

Pd(OAc)2, S-Phos K2C〇3Pd(OAc)2, S-Phos K2C〇3

Me 141666.doc •288- 201028381 步驟1 . 4 -胺基-2-乙氧基- 6- (4 -經基苯基胺基）於驗猜（實 施例1-193) 於20 mL微波反應容器中，向三氟曱磺酸4-胺基-5-氰基-6-乙氧基。比咬-2 -基S旨（1.50 g，4.82 mmol)及4-胺基苯盼 -(1.5 8 g，14.5 mmol)之DMSO溶液（10 mL)中添加三乙基胺 (732 mg 1 1.0 mL » 7.23 mmol)進行覆蓋，使用 Biotage Optimizer反應裝置，於180°C下攪拌30分鐘。向反應溶液 中添加水及乙酸乙酯進行分離後，以乙酸乙酯萃取水相， ® 將合併之有機相以水、0.1 mol/L鹽酸水溶液及飽和食鹽水 進行清洗，以硫酸鎂加以乾燥。將有機相過濾後，進行減 壓濃縮。使所獲得之殘渣溶解於二氣甲烷中，過濾除去不 溶物，進行減壓濃縮，藉此獲得標題化合物（1.30 g， 86%)，為茶色非晶體。 1H-NMR (400 MHz, DMSO-d6) δ 1.29 (t, J=6.8 Hz, 3H), 4.29 (q, J=6.8 Hz, 2H), 5.55 (s, 1H), 6.30 (s, 2H), 6.70 (d, J=8.4 Hz, 2H), 7.20 (d, J=8.4 Hz, 2H), 8.62 (s, 1H), 9.12 w (brs, 1H)。 MS(ESI)m/z=271 (M+H)+。 LC/MS tR=1.49 min。 步驟2 :三氟曱磺酸4-(4-胺基-5-氰基-6-乙氧基》比啶-2-基胺基）苯基S旨 向4 -胺基-2-乙氧基- 6- (4 -經基苯基胺基）於驗猜（1.11 g， 4.11mmol)及PhNTf2(N-苯基雙（三氟曱磺醯胺））（1.76 g， 4.93 mmol)之THF溶液（20 mL)中添加三乙基胺（1.04 g， 141666.doc -289- 201028381 i.42mL，H).3mmol)，於室溫下攪拌16小時。向反應溶液 中添加水及乙酸乙g旨進行分離後，以乙酸乙醋萃取水相， 將合併之有機相以水、Gl md/L鹽酸水溶液及飽和食鹽水 進行清洗，以硫酸鎂加以乾燥。將有機相過濾後，進行減 壓濃縮。使所獲得之殘渣溶解於乙酸乙酯：己烷=1 : 5溶 液中，過濾除去不溶物，進行減壓濃縮，藉此獲得標題化 合物（1.16 g，70%)，為茶色非晶體。 1H-NMR (400 MHz, DMSO-d6) δ 1.34 (t, J=6.8 Hz, 3H), 4.35 (q, J=6.8 Hz, 2H), 5.77 (s, 1H), 6.58 (s, 2H), 7.37 (d, ® J-9.2 Hz, 2H), 7.71 (d, J=9.2 Hz, 2H), 9.38 (s, 1H) ° MS(ESI)m/z=403 (M+H)+。 LC/MS tR=2.37 min 〇 步驟3，標題化合物 向三氟曱磺酸4-(4-胺基-5_氰基_6_乙氧基吡啶_2_基胺基） 苯基酯（90.0 mg，0.224 mmol)、卜甲基_4_(4 4 5 5_四曱基_ 1，3,2-二氡雜硼烷-2-基）-1Η-吡唑（69 9 mg，〇 336 mm〇1)、 S-Ph〇s(18.4 mg，0.045 mmol)及Pd(OAc)2(5 〇2 mg，〇 〇22 β 111111〇1)之乙腈、/谷液（3111]^)中添加2111〇1/1^碳酸卸水溶液（336 PL，0.671 mm〇l) ’於90°C下攪拌6小時。向反應溶液中添 加水及乙酸乙酯進行分離後，以乙酸乙酯萃取水相，將合 併之有機相以水及飽和食鹽水進行清洗，以硫酸鎂加以乾 燥。將有機相過濾後，進行減壓濃縮。利用中壓矽膠層析 法（乙酸乙酯：己烷=1 : 1)對所獲得之殘渣進行純化獲 得標題化合物（26 mg，35%)。 141666.doc •290· 201028381 1H-NMR (400 MHz, DMSO-d6) δ 1.33 (t, J=6.8 Hz, 3H), 3.85 (s, 3H), 4.34 (q, J=6.8 Hz, 2H), 5.72 (s, 1H), 6.44 (s, 2H), 7.47 (dd, J=8.8 Hz, 16.4 Hz, 4H), 7.78 (s, 1H), 8.02 (s，1H)，9.04 (s，1H)。 MS(ESI)m/z=335 (M+H)+。 LC/MS tR=1.72 min。 實施例1-327 4-胺基-2-乙氧基-6-(4-(噻吩-2-基）苯基胺基）菸鹼腈 ® [化 1327]Me 141666.doc •288- 201028381 Step 1. 4 -Amino-2-ethoxy- 6-(4-propylphenylamino) was investigated (Example 1-193) in a 20 mL microwave reaction vessel Medium, 4-amino-5-cyano-6-ethoxy group of trifluorosulfonium sulfonate. Triethylamine (732 mg 1 1.0 mL) was added to the DMSO solution (10 mL) of the 2-(2)-based (1.50 g, 4.82 mmol) and 4-aminophene- (1.5 8 g, 14.5 mmol) DMSO solution (10 mL) » 7.23 mmol) Covered and stirred at 180 ° C for 30 minutes using a Biotage Optimizer reactor. Water and ethyl acetate were added to the reaction solution for separation, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water, 0.1 mol/L aqueous hydrochloric acid and brine, and dried over magnesium sulfate. After the organic phase was filtered, it was concentrated under reduced pressure. The obtained residue was dissolved in methylene chloride, and then filtered to remove insoluble material, and concentrated under reduced pressure to give the title compound (1.30 g, 86%) as a brown crystal. 1H-NMR (400 MHz, DMSO-d6) δ 1.29 (t, J = 6.8 Hz, 3H), 4.29 (q, J = 6.8 Hz, 2H), 5.55 (s, 1H), 6.30 (s, 2H), 6.70 (d, J=8.4 Hz, 2H), 7.20 (d, J=8.4 Hz, 2H), 8.62 (s, 1H), 9.12 w (brs, 1H). MS (ESI) m / z = 271 (M+H)+. LC/MS tR = 1.49 min. Step 2: 4-(4-Amino-5-cyano-6-ethoxy)pyridin-2-ylamino)phenyl S-trifluorosulfonate is intended to 4-amino-2-ethoxy -6-(4-Pentylphenylamino)-test (1.11 g, 4.11 mmol) and PhNTf2 (N-phenylbis(trifluorosulfonamide)) (1.76 g, 4.93 mmol) in THF Triethylamine (1.04 g, 141666.doc -289 - 201028381 i.42 mL, H). 3 mmol) was added to the solution (20 mL) and stirred at room temperature for 16 hr. After the water and the acetic acid were added to the reaction solution for separation, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water, aq. After the organic phase was filtered, it was concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate:hexane = 1 :5, and then filtered to remove insoluble material, and concentrated under reduced pressure to give the title compound (1.16 g, 70%). 1H-NMR (400 MHz, DMSO-d6) δ 1.34 (t, J = 6.8 Hz, 3H), 4.35 (q, J = 6.8 Hz, 2H), 5.77 (s, 1H), 6.58 (s, 2H), 7.37 (d, ® J-9.2 Hz, 2H), 7.71 (d, J=9.2 Hz, 2H), 9.38 (s, 1H) ° MS (ESI) m/z = 403 (M+H)+. LC/MS tR=2.37 min 〇 Step 3, title compound to 4-(4-amino-5-cyano-6-ethoxypyridin-2-ylamino)phenyl ester of trifluorosulfonium sulfonate (90.0 Mg, 0.224 mmol), methyl _4_(4 4 5 5_tetradecyl _ 1,3,2-dioxaborane-2-yl)-1 Η-pyrazole (69 9 mg, 〇336 mm〇1 Add 2111〇1 to acetonitrile and / glutamic acid (3111)^ of S-Ph〇s (18.4 mg, 0.045 mmol) and Pd(OAc)2 (5 〇2 mg, 〇〇22 β 111111〇1) /1^ Aqueous solution of carbonic acid (336 PL, 0.671 mm 〇l) was stirred at 90 ° C for 6 hours. Water and ethyl acetate were added to the reaction solution for separation, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and brine and dried over magnesium sulfate. After the organic phase was filtered, it was concentrated under reduced pressure. The residue obtained was purified by EtOAc (EtOAc:EtOAc) 141666.doc •290· 201028381 1H-NMR (400 MHz, DMSO-d6) δ 1.33 (t, J=6.8 Hz, 3H), 3.85 (s, 3H), 4.34 (q, J=6.8 Hz, 2H), 5.72 (s, 1H), 6.44 (s, 2H), 7.47 (dd, J=8.8 Hz, 16.4 Hz, 4H), 7.78 (s, 1H), 8.02 (s, 1H), 9.04 (s, 1H). MS (ESI) m / z = 335 (M+H)+. LC/MS tR = 1.72 min. Example 1-327 4-Amino-2-ethoxy-6-(4-(thiophen-2-yl)phenylamino) Nicotinonitrile® [Chem. 1327]

標題化合物係依據實施例1 -326之方法而合成》 1H-NMR (400 MHz, DMSO-d6) δ 1.34 (t, J=6.8 Hz, 3H), 4.36 (q, J=6.8 Hz, 2H), 5.76 (s, 1H), 6.49 (s, 2H), 7.10 (d, J=3.6 Hz, 1H), 7.39 (d, J=3.2 Hz, 1H), 7.44 (d, J=4.8 Hz, ❹ 1H), 7·57 (dd，J=8.8 Hz, 14.8 Hz，4H)，9.21 (s，1H)。 MS(ESI)m/z=337 (M+H)+。 LC/MS tR=2.37 min o 實施例1-328 4-胺基-2-乙氧基-6-(4-嗟吩-3-基）苯基胺基）於驗腈 141666.doc -291- 201028381 [化 1328]The title compound was synthesized according to the method of Example 1-326. 1H-NMR (400 MHz, DMSO-d6) δ 1.34 (t, J = 6.8 Hz, 3H), 4.36 (q, J = 6.8 Hz, 2H), 5.76 (s, 1H), 6.49 (s, 2H), 7.10 (d, J=3.6 Hz, 1H), 7.39 (d, J=3.2 Hz, 1H), 7.44 (d, J=4.8 Hz, ❹ 1H) , 7·57 (dd, J=8.8 Hz, 14.8 Hz, 4H), 9.21 (s, 1H). MS (ESI) m / z = 337 (M+H)+. LC/MS tR=2.37 min o Example 1-328 4-Amino-2-ethoxy-6-(4-pursin-3-yl)phenylamino) in nitrile 141666.doc -291- 201028381 [化1328]

標題化合物係依據實施例i_326之方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 1.34 (t, J=7.2 Hz, 3H), 4.36 (q, J=7.2 Hz, 2H), 5.75 (s, 1H), 6.48 (s, 2H), 7.75-7.74 (m, 6H), 7.74 (s，1H)，9.14 (s，1H)。 MS(ESI)m/z=337 (M+H)+。 LC/MS tR=2.33 min o 實施例1-329 4-胺基-2-乙氧基-6-(4-(1-三異丙基矽烷基-1H-吡咯-3-基）苯基胺基）於驗腈 [化 1329]The title compound was synthesized according to the method of Example i_326. 1H-NMR (400 MHz, DMSO-d6) δ 1.34 (t, J = 7.2 Hz, 3H), 4.36 (q, J = 7.2 Hz, 2H), 5.75 (s, 1H), 6.48 (s, 2H), 7.75-7.74 (m, 6H), 7.74 (s, 1H), 9.14 (s, 1H). MS (ESI) m / z = 337 (M+H)+. LC/MS tR = 2.33 min o Example 1-129 4-Amino-2-ethoxy-6-(4-(1-triisopropyldecyl-1H-pyrrol-3-yl)phenylamine Base) for nitrile [1329]

標題化合物係依據實施例1 -326之方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 1.07 (d, J=7.2 Hz, 18H), 1.33 (d, J=7.2 Hz, 3H), 1.52 (q, J=7.2 Hz, 3H), 4.34 (q, J=7.2 Hz, 2H), 5.70 (s, 1H), 6.41 (s, 2H), 6.57 (s, 1H), 6.83 (s，1H)，7.18 (s, 1H)，7.74 (s, 5H)，8.99 (s，1H)。 MS(ESI)m/z=476 (M+H)+。 LC/MS tR=3.16 min。 141666.doc -292· 201028381 實施例1-330 6-(4-(1 Η-D比洛-3-基）苯基胺基）-4-胺基-2-乙氧基於驗腈 [化 1330]The title compound was synthesized according to the method of Example 1-326. 1H-NMR (400 MHz, DMSO-d6) δ 1.07 (d, J = 7.2 Hz, 18H), 1.33 (d, J = 7.2 Hz, 3H), 1.52 (q, J = 7.2 Hz, 3H), 4.34 ( q, J=7.2 Hz, 2H), 5.70 (s, 1H), 6.41 (s, 2H), 6.57 (s, 1H), 6.83 (s, 1H), 7.18 (s, 1H), 7.74 (s, 5H) ), 8.99 (s, 1H). MS (ESI) m / z = 476 (M+H)+. LC/MS tR = 3.16 min. 141666.doc -292· 201028381 Example 1-330 6-(4-(1 Η-D-Bial-3-yl)phenylamino)-4-amino-2-ethoxy group in nitrile [Chemical 1330] ]

向4-胺基-2-乙氧基- 6-(4-(1-三異丙基梦烧基-1Η-π比略_3_ 基）苯基胺基）於驗腈（28 mg，0.059 mmol)中添加TBAF · 1 mol/LTHF溶液（71 μι，0.071 mmol)，於室溫下授拌4小 時。向反應溶液中添加水及乙酸乙酯進行分離後，以乙酸 乙酯萃取水相，將合併之有機相以水及飽和食鹽水進行清 洗，以硫酸鎂加以乾燥。將有機相過濾後，進行減壓濃 縮。使所獲得之殘渣溶解於乙酸乙酯：己烷: 5溶液 中’過濾除去不溶物，進行減壓濃縮，藉此獲得標題化合 物（14.5 mg，77%)，為白色固體。 1H-NMR (400 MHz, DMSO-d6) δ 1.33 (t, J=7.2 Hz, 6H) 4.34 (m，2H)，5.70 (s，1H)，6.39 (q，J=7.6 Hz，3H)，6.76 (s 1H)，7·13 (s，1H), 7.43 (s，4H)，8.95 (s，1H)。 MS(ESI)m/z=320 (M+H)+。 LC/MS tR=1.92 min。 實施例1-331 6-(4-(1Η-«·比唑-4-基）笨基胺基）_4_胺基_2乙氧基菸鹼腈 141666.doc -293- 201028381 [化 1331]To 4-nityl-2-ethoxy-6-(4-(1-triisopropylmethyloxyalkyl-1Η-π 比略_3_yl)phenylamine) for nitrile (28 mg, 0.059 Add TBAF · 1 mol/L THF solution (71 μm, 0.071 mmol) to mmol) and mix for 4 hours at room temperature. Water and ethyl acetate were added to the reaction solution for separation, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and brine, and dried over magnesium sulfate. After the organic phase was filtered, it was concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate: hexane: 5 (yield: EtOAc). 1H-NMR (400 MHz, DMSO-d6) δ 1.33 (t, J = 7.2 Hz, 6H) 4.34 (m, 2H), 5.70 (s, 1H), 6.39 (q, J = 7.6 Hz, 3H), 6.76 (s 1H), 7·13 (s, 1H), 7.43 (s, 4H), 8.95 (s, 1H). MS (ESI) m / z = 320 (M + H) +. LC/MS tR = 1.92 min. Example 1-31 6-(4-(1Η-«·Bizozol-4-yl)phenylamino)-4-amino-2-ethoxynicotinonitrile 141666.doc -293- 201028381 [Chem. 1331]

標題化合物係依據實施例1-326之方法而合成。 1H-NMR (400 MHz，DMSO-d6) δ 1.34 (t, J=7.2 Hz, 3H)， 4.35 (q, J=7.2 Hz, 2H), 5.73 (s, 1H), 6.44 (s, 2H), 7.51 (s, 4H), 7.88 (bs, 1H), 8.08 (bs, 1H), 9.04 (s, 1H), 12.84 (s, 1H)。 MS(ESI)m/z=321 (M+H)+。 LC/MS tR=1.58 min。 實施例1-332 4-胺基-2-乙氧基- 6-(4-( e夫鳴-2-基）苯基胺基）於驗腈 [化 1332]The title compound was synthesized according to the method of Example 1-326. 1H-NMR (400 MHz, DMSO-d6) δ 1.34 (t, J = 7.2 Hz, 3H), 4.35 (q, J = 7.2 Hz, 2H), 5.73 (s, 1H), 6.44 (s, 2H), 7.51 (s, 4H), 7.88 (bs, 1H), 8.08 (bs, 1H), 9.04 (s, 1H), 12.84 (s, 1H). MS (ESI) m / z = 321 (M + H) +. LC/MS tR = 1.58 min. Example 1-332 4-Amino-2-ethoxy- 6-(4-(e-f-but-2-yl)phenylamino) in a nitrile [Chemical 1332]

標題化合物係依據實施例1-326之方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 1.33 (t, J=7 2 Hz 3Η), 4.35 (q, J=7.2 Hz, 2H), 5.75 (s, 1H), 6.49 (s, 2H), 6.55 (s, 1H), 6.78 (d, J=3.2 Hz, 1H), 7.59 (s, 1H), 7.67 (s, 1H), 9.20 (s，1H)。 MS(ESI)m/z=321 (M+H)+。 LC/MS tR=2.28 min。 實施例1-333 14t666.doc -294- 201028381 4-胺基-2-乙氧基-6-(4-(吱喃-3-基）笨基胺基）終驗腈 [化 1333]The title compound was synthesized according to the method of Example 1-326. 1H-NMR (400 MHz, DMSO-d6) δ 1.33 (t, J = 7 2 Hz 3 Η), 4.35 (q, J = 7.2 Hz, 2H), 5.75 (s, 1H), 6.49 (s, 2H), 6.55 (s, 1H), 6.78 (d, J=3.2 Hz, 1H), 7.59 (s, 1H), 7.67 (s, 1H), 9.20 (s, 1H). MS (ESI) m / z = 321 (M + H) +. LC/MS tR = 2.28 min. Example 1-33 14t666.doc -294- 201028381 4-Amino-2-ethoxy-6-(4-(indol-3-yl)phenylamino) final nitrile [Chem. 1333]

標題化合物係依據實施例1-326之方法而合成。 1H-NMR (400 MHz，DMSO-d6) δ 1.34 (t，J=7.2 Hz，3H)， 4.36 (q, J=7.2 Hz, 2H), 5.75 (s, 1H), 6.47 (s, 2H), 6.91 (s, φ 1H), 7.54 (q, J=8.4 Hz, 1H), 7.70 (s, 1H), 8.09 (s, 1H), 9.12 (s，lH)。 實施例1-3 34 2-(4-(4-胺基-5-氰基-6-乙氧基》比咬-2-基胺基）苯基）_1H_ 吡咯-1 -甲酸第三丁酯 [化 1334]The title compound was synthesized according to the method of Example 1-326. 1H-NMR (400 MHz, DMSO-d6) δ 1.34 (t, J = 7.2 Hz, 3H), 4.36 (q, J = 7.2 Hz, 2H), 5.75 (s, 1H), 6.47 (s, 2H), 6.91 (s, φ 1H), 7.54 (q, J=8.4 Hz, 1H), 7.70 (s, 1H), 8.09 (s, 1H), 9.12 (s, lH). Example 1-3 34 2-(4-(4-Amino-5-cyano-6-ethoxy) butyl-2-ylamino)phenyl)_1H_pyrrole-1 -carboxylic acid tert-butyl ester [Chem. 1334]

標題化合物係依據實施例1 -326之方法而合成。 1H NMR (400 MHz, d6-DMSO) δ 1.30-1.33 (m, 12H), 4.35 (q, J=7.2 Hz, 2H), 5.75 (s, 1H), 6.19 (s, 1H), 6.25 (d, J=3.2 Hz, 1H), 6.48 (s5 1H), 7.20 (d, J=4.4 Hz, 2H), 7.30 (s, 1H), 7.51 (d, J=4.4 Hz, 2H), 9.12 (s, 1H)。 MS(ESI)m/z=420 (M+H)+。 141666.doc -295- 201028381 LC/MS tR=2.58 min。 實施例1-335 6-(4-(lH-&quot;比咯-2-基）苯基胺基）_4-胺基-2-乙氧基菸鹼腈 [化 1335]The title compound was synthesized according to the method of Example 1-326. 1H NMR (400 MHz, d6-DMSO) δ 1.30-1.33 (m, 12H), 4.35 (q, J = 7.2 Hz, 2H), 5.75 (s, 1H), 6.19 (s, 1H), 6.25 (d, J=3.2 Hz, 1H), 6.48 (s5 1H), 7.20 (d, J=4.4 Hz, 2H), 7.30 (s, 1H), 7.51 (d, J=4.4 Hz, 2H), 9.12 (s, 1H) ). MS (ESI) m / z = 420 (M + H) +. 141666.doc -295- 201028381 LC/MS tR=2.58 min. Example 1-35 6-(4-(lH-&quot;Byrrol-2-yl)phenylamino)-4-amino-2-ethoxynicotinonitrile [Chemical 1335]

標題化合物係藉由使2-(4-(4-胺基-5-氰基-6-乙氧基吼咬-2-基胺基）苯基）-1Η-吡咯-1-甲酸第三丁酯溶解於TFA :二氣 曱烷=1 : 1溶液中後，進行減壓濃縮而獲得。 1H-NMR (400 MHz, DMSO-d6) δ 1.36 (t, J=6.8 Hz, 3H), 4.38 (q, J=6.8 Hz, 2H), 5.86 (s, 1H), 6.68 (s, 2H), 7.76-7.81 (m, 5H)，6.48 (s, 1H), 9.66 (s，1H)，9.81 (s, 1H)。 MS(ESI)m/z=320 (M+H)+。 LC/MS tR=2.02 min ° 實施例1-336 4-胺基-6-(4-(3,5-二甲基異噁唑-4-基）苯基胺基）-2-乙氧 基於驗猜 [化 1336]The title compound is obtained by making 2-(4-(4-amino-5-cyano-6-ethoxyindole-2-ylamino)phenyl)-1Η-pyrrole-1-carboxylic acid tert-butyl The ester was dissolved in TFA: dioxane = 1 : 1 solution, and then concentrated under reduced pressure. 1H-NMR (400 MHz, DMSO-d6) δ 1.36 (t, J = 6.8 Hz, 3H), 4.38 (q, J = 6.8 Hz, 2H), 5.86 (s, 1H), 6.68 (s, 2H), 7.76-7.81 (m, 5H), 6.48 (s, 1H), 9.66 (s, 1H), 9.81 (s, 1H). MS (ESI) m / z = 320 (M + H) +. LC/MS tR=2.02 min ° Example 1-136 4-Amino-6-(4-(3,5-dimethylisoxazol-4-yl)phenylamino)-2-ethoxy Guessing [Chemical 1336]

標題化合物係依據實施例1-326之方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 1.33 (t, J=7.2 Hz, 3H), 141666.doc -296- 201028381 2.22 (s, 3H), 2.39 (s, 3H), 4.36 (q, J=7.2 Hz, 2H), 5.77 (s, 1H), 6.49 (s, 2H), 7.27 (d, J=8.4 Hz, 2H), 7.63 (d, J=8.4 Hz，2H)，9·19 (s，1H)。 實施例1-337 4-胺基-2-乙氧基- 6-(4-( e比咬-2-基）苯基胺基）於驗猜 [化 1337]The title compound was synthesized according to the method of Example 1-326. 1H-NMR (400 MHz, DMSO-d6) δ 1.33 (t, J = 7.2 Hz, 3H), 141666.doc -296- 201028381 2.22 (s, 3H), 2.39 (s, 3H), 4.36 (q, J =7.2 Hz, 2H), 5.77 (s, 1H), 6.49 (s, 2H), 7.27 (d, J=8.4 Hz, 2H), 7.63 (d, J=8.4 Hz, 2H), 9·19 (s , 1H). Example 1-137 4-Amino-2-ethoxy- 6-(4-(e-Bit-2-yl)phenylamino) was tested [Chem. 1337]

步驟1 : 4-胺基-2-乙氧基-6-(4-(4,4,5,5-四曱基-1，3,2-二 氧雜硼烷-2-基）苯基胺基）菸鹼腈 向三氟甲磺酸4-(4-胺基-5-氰基-6-乙氧基吡啶-2-基胺基） 苯基酯（500 mg，1.24 mmol)、雙（頻哪醇根基）二硼（473 mg ’ 1.864 mmol)及 PdCl2(dppf)(l〇l mg，0.124 mmol)之 DMF溶液（l〇 mL)中添加乙酸鉀（610 mg，6.21 mmol)，於 8〇°C下攪拌6小時。向反應溶液中添加水及乙酸乙酯進行 分離後，以乙酸乙酯萃取水相，將合併之有機相以水及飽 和食鹽水進行清洗，以硫酸鎂加以乾燥。將有機相過濾 後，進行減壓濃縮。利用中壓矽膠層析法（乙酸乙酯·己 烷-1 . 2)對所獲得之殘渣進行純化獲得標題化合物卩31 mg，49%)，為黃色固體。 141666.doc -297. 201028381 1H-NMR (400 MHz，DMSO-d6) δ 1.27 (s, 2H)，1.33 (t， J=6.8 Hz, 3H), 4.34 (q, J=6.8 Hz, 2H), 5.77 (s, 1H), 6.51 (s, 2H)，7.56 (s，4H)，9.25 (s，1H) 〇 步驟2 :標題化合物 向4-胺基-2-乙氧基-6-(4·(4,4,5,5-四甲基-1,3,2-二氧雜硼 炫基）本基胺基）私驗猜（50 mg，0.131 mmol)、2 -溴。比π定 (17.3 mg，0.110 mmol)及 Pd(PPh3)4(12.7 mg，0.0109 mmol)之DMF溶液（10 mL)中添加2 mol/L碳酸鈉水溶液（164 μί，0.329 mmol)，於80°C下攪拌6小時。向反應溶液中添〇 加水及乙酸乙酯進行分離後，以乙酸乙酯萃取水相，將合 併之有機相以水及飽和食鹽水進行清洗，以硫酸鎂加以乾 燥。將有機相過濾'後’進行減壓濃縮。利用逆相等分試樣 液相層析法（C18管柱’水/乙腈/0.1%甲酸梯度）對所獲得之 殘渣進行純化，獲得標題化合物（〖2.0 mg，33%)，為黃色 固體。 1H-NMR (400 MHz, DMSO-d6) δ 1.36 (t, J=6.8 Hz, 3H), 4.39 (q, J=6.8 Hz, 2H), 5.80 (s, 1H), 6.52 (s, 2H), 7.25-7.28 ^ (m, 1H), 7.67 (d, J=8.8 Hz, 2H), 7.82 (d, J=7.2 Hz, 1H), 7.89 (d5 J=8.4 Hz, 1H), 8.02 (d, J=8.4 Hz, 2H), 8.16 (s, 1H)，8.6 (d，J=3.6 Hz，1H)，9.29 (s，1H)。 MS(ESI)m/z=332 (M+H)+。 LC/MS tR=1.33 min。 實施例1-338 4-胺基-6-(4-(1-(2-(二曱基胺基）乙基）-1Η-吧唑-4-基）笨 141666.doc •298· 201028381 基胺基-2-乙氧基於驗猜 [化 1338]Step 1: 4-Amino-2-ethoxy-6-(4-(4,4,5,5-tetradecyl-1,3,2-dioxaborolan-2-yl)phenyl Amino)nicotinic nitrile to 4-(4-amino-5-cyano-6-ethoxypyridin-2-ylamino)phenyl trifluoromethanesulfonate (500 mg, 1.24 mmol), double Potassium acetate (610 mg, 6.21 mmol) was added to the DMF solution (1 〇 mL) of diboron (473 mg ' 1.864 mmol) and PdCl 2 (dppf) (10 mg, 0.124 mmol). Stir at 6 ° C for 6 hours. After water and ethyl acetate were added to the reaction solution for separation, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water and saturated brine and dried over magnesium sulfate. After the organic phase was filtered, it was concentrated under reduced pressure. The residue obtained was purified by EtOAc EtOAc (EtOAc) 141666.doc -297. 201028381 1H-NMR (400 MHz, DMSO-d6) δ 1.27 (s, 2H), 1.33 (t, J = 6.8 Hz, 3H), 4.34 (q, J = 6.8 Hz, 2H), 5.77 (s, 1H), 6.51 (s, 2H), 7.56 (s, 4H), 9.25 (s, 1H) 〇 Step 2: title compound to 4-amino-2-ethoxy-6-(4· (4,4,5,5-tetramethyl-1,3,2-dioxaboronyl)-based amino group (50 mg, 0.131 mmol), 2-bromo. Add 2 mol/L sodium carbonate aqueous solution (164 μί, 0.329 mmol) to π (17.3 mg, 0.110 mmol) and Pd(PPh3)4 (12.7 mg, 0.0109 mmol) in DMF (10 mL) at 80 ° Stir for 6 hours at C. After adding water and ethyl acetate to separate the mixture, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water and brine and dried over magnesium sulfate. The organic phase was filtered and then concentrated under reduced pressure. The residue obtained was purified by EtOAc EtOAc (EtOAc) elute 1H-NMR (400 MHz, DMSO-d6) δ 1.36 (t, J = 6.8 Hz, 3H), 4.39 (q, J = 6.8 Hz, 2H), 5.80 (s, 1H), 6.52 (s, 2H), 7.25-7.28 ^ (m, 1H), 7.67 (d, J=8.8 Hz, 2H), 7.82 (d, J=7.2 Hz, 1H), 7.89 (d5 J=8.4 Hz, 1H), 8.02 (d, J =8.4 Hz, 2H), 8.16 (s, 1H), 8.6 (d, J = 3.6 Hz, 1H), 9.29 (s, 1H). MS (ESI) m / z = 332 (M+H)+. LC/MS tR = 1.33 min. Example 1-338 4-Amino-6-(4-(1-(2-(didecylamino)ethyl)-1Η-barrazol-4-yl) stupid 141666.doc •298· 201028381 Amino-2-ethoxy group test [Chemical 1338]

步驟1 : 2-(4-溴-1H-吡唑-1-基）-Ν,Ν-二曱基乙胺 向 4- 臭-1Η-〇比 °坐（200 mg，1.36 mmol)及碳酸錄（93 1 mg，2.86 mmol)之 DMF溶液（2 mL)中添加 2 -氣-Ν,Ν-二甲基 乙胺鹽酸鹽（196 mg，1.36 mmol)，於40°C下授拌6小時。 向反應溶液中添加水及乙酸乙酯進行分離後，以乙酸乙酯 萃取水相，將合併之有機相以水及飽和食鹽水進行清洗， 以硫酸鎂加以乾燥。將有機相過濾後，進行減壓濃縮，藉 此獲得標題化合物（189 mg，0.867 mmol，64%)，為無色 油0 1H-NMR (400 MHz, DMSO-d6) δ 2.15 (s，6H)，2.62 (t, J=6.4 Hz, 2H), 4.18 (t, J=6.4 Hz, 2H), 7.50 (s, 1H), 7.95 (s, 1H)。 步驟2 :標題化合物 向2-(4-溴-1H-吡唑-1-基）-Ν,Ν-二甲基乙胺（57.4 mg， 0.263 mmol)、4-胺基-2-乙氧基-6-(4-(4,4,5,5-四甲基-1，3,2-二氧雜硼烷-2-基）苯基胺基）菸鹼腈（100 mg，0.263 141666.doc -299- 201028381 mmol)及 Pd(PPh3)4(30.4 mg’ 0.026 mm〇l)之 THF 溶液（1 mL)中添加2 mol/L碳酸鈉水溶液（394 pL，0.789 mmol)， 於90 C下授拌7小時。向反應溶液中添加水及乙酸乙酯進 行分離後，以乙酸乙酯萃取水相’將合併之有機相以水及 飽和食鹽水進行清洗’以硫酸鎂加以乾燥。將有機相過濾 後’進行減壓濃縮。利用中壓矽膠層析法（己烷/乙酸乙酯 50-100%梯度）對所獲得之殘渣進行純化，獲得標題化合物 (13.5 mg，0.034 mmol，13%)，為白色固體。 1H-NMR (400 MHz, DMSO-d6) δ 1.33 (t, J=7.2 Hz, 3H), 2.17 (s, 6H), 2.66 (t, J=6.4 Hz, 2H), 4.18 (t, J=6.4 Hz, 2H), 4.34 (q, J=6.8 Hz, 2H), 5.71 (s, 1H), 6.44 (s, 2H), 7.48 (dd, J=9.2 Hz, 19.2 Hz, 4H), 7.78 (s, 1H), 8.07 (s, 1H), 9.05 (s, 1H) 〇 MS(ESI)m/z=392 (M+H)+。 LC/MS tR=1.01 min。 實施例1-339 4-胺基-2-乙氧基- 6-(4-(°¾咬-5-基）苯基胺基）終驗腈 [化 1339]Step 1: 2-(4-Bromo-1H-pyrazol-1-yl)-indole, Ν-dimercaptoethylamine to 4- odor-1Η-〇 ratio (200 mg, 1.36 mmol) and carbonated (93 1 mg, 2.86 mmol) in DMF solution (2 mL) was added 2- gas-purine, hydrazine-dimethylethylamine hydrochloride (196 mg, 1.36 mmol), and stirred at 40 ° C for 6 hours. . After water and ethyl acetate were added to the reaction solution for separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and brine, and dried over magnesium sulfate. After the organic phase was filtered, EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 2.62 (t, J=6.4 Hz, 2H), 4.18 (t, J=6.4 Hz, 2H), 7.50 (s, 1H), 7.95 (s, 1H). Step 2: the title compound to 2-(4-bromo-1H-pyrazol-1-yl)-indole, hydrazine-dimethylethylamine (57.4 mg, 0.263 mmol), 4-amino-2-ethoxy -6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamino)nicotinonitrile (100 mg, 0.263 141666. Doc -299- 201028381 mmol) and Pd(PPh3)4(30.4 mg' 0.026 mm〇l) in THF (1 mL) were added 2 mol/L sodium carbonate aqueous solution (394 pL, 0.789 mmol) at 90 C Mix for 7 hours. After water and ethyl acetate were added to the reaction solution for separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and saturated brine. The organic phase was filtered and concentrated under reduced pressure. The residue obtained was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc 1H-NMR (400 MHz, DMSO-d6) δ 1.33 (t, J = 7.2 Hz, 3H), 2.17 (s, 6H), 2.66 (t, J = 6.4 Hz, 2H), 4.18 (t, J = 6.4 Hz, 2H), 4.34 (q, J=6.8 Hz, 2H), 5.71 (s, 1H), 6.44 (s, 2H), 7.48 (dd, J=9.2 Hz, 19.2 Hz, 4H), 7.78 (s, 1H), 8.07 (s, 1H), 9.05 (s, 1H) 〇MS (ESI) m/z = 392 (M+H)+. LC/MS tR = 1.01 min. Example 1-339 4-Amino-2-ethoxy- 6-(4-(°3⁄4 bit-5-yl)phenylamino) final nitrile [Chem. 1339]

標題化合物係使用對應之芳基鹵化物，依據實施例1-337 之方法（步驟2)而合成。 1H-NMR (400 MHz, DMSO-d6) δ 1.35 (t, J=6.8 Hz, 3H), 141666.doc -300- 201028381 4.38 (q, J=6.8 Hz, 2H), 5.80 (s, 1H), 6.55 (s, 2H), 7.70-7.76 (m，4H)，9.11 (s, 3H)，9.31 (s，1H) 〇 MS(ESI)m/z=333 (M+H)+。 LC/MS tR=1.70 min。 實施例1-340 4-胺基-2-乙氧基-6-(4-(吼啶-3-基）苯基胺基）菸鹼腈 [化 1340]The title compound was synthesized according to the method of Example 1-137 (Step 2) using the corresponding aryl halide. 1H-NMR (400 MHz, DMSO-d6) δ 1.35 (t, J = 6.8 Hz, 3H), 141666.doc -300 - 201028381 4.38 (q, J = 6.8 Hz, 2H), 5.80 (s, 1H), 6.55 (s, 2H), 7.70-7.76 (m, 4H), 9.11 (s, 3H), 9.31 (s, 1H) 〇MS (ESI) m/z = 333 (M+H)+. LC/MS tR = 1.70 min. Example 1-340 4-Amino-2-ethoxy-6-(4-(acridin-3-yl)phenylamino)nicotinonitrile [Chemical 1340]

標題化合物係使用對應之芳基鹵化物，依據實施例1-337 之方法（步驟2)而合成。 1H-NMR (400 MHz, DMSO-d6) δ 1.35 (t, J=6.8 Hz, 3H), 4.38 (q, J=6.8 Hz, 2H), 5.79 (s, 1H), 6.52 (s, 2H), 7.43-7.46 (m, 1H), 7.67 (s, 3H), 8.04 (d, J=8.0 Hz, 1H), 8.50 (d, J=3.6 Hz，1H), 8.87 (s，1H), 9.25 (s, 1H)。 ❹ MS(ESI)m/z=332 (M+H)+。 LC/MS tR=1.22 min。 實施例1-341 4-胺基-2 -乙氧基- 6-(4-(吼咬-4-基）苯基胺基）終驗猜 [化 1341]The title compound was synthesized according to the method of Example 1-137 (Step 2) using the corresponding aryl halide. 1H-NMR (400 MHz, DMSO-d6) δ 1.35 (t, J = 6.8 Hz, 3H), 4.38 (q, J = 6.8 Hz, 2H), 5.79 (s, 1H), 6.52 (s, 2H), 7.43-7.46 (m, 1H), 7.67 (s, 3H), 8.04 (d, J=8.0 Hz, 1H), 8.50 (d, J=3.6 Hz, 1H), 8.87 (s,1H), 9.25 (s , 1H). ❹ MS (ESI) m/z = 332 (M+H)+. LC/MS tR = 1.22 min. Example 1-41 4-Amino-2-ethoxy- 6-(4-(indol-4-yl)phenylamino) final test [Chem. 1341]

141666.doc - 301 - 201028381 標題化合物係使用對應之芳基鹵化物，依據實施例1 _337 之方法（步驟2)而合成。 1H-NMR (400 MHz，DMSO-(j6) δ 1.35 (t, J=7.2 Hz，3H)， 4·38 (q，J=7.2 Hz，2H)，5.79 (s，iH)，6 54 (s，2H), 7.61-7.78 (m, 5H), 8.15 (s, 1H), 8.57 (d, J=5.2 Hz, 2H), 9.33 (s, 1H) 〇 MS(ESI)m/z=332 (M+H)+。 LC/MS tR=1.05 min o 實施例1-342 4-胺基-6-(4-(2,4-二甲基噻唑_5·基）苯基胺基）_2-乙氧基 終驗腈 [化 1342]141666.doc - 301 - 201028381 The title compound was synthesized according to the method of Example 1_337 (Step 2) using the corresponding aryl halide. 1H-NMR (400 MHz, DMSO-(j6) δ 1.35 (t, J = 7.2 Hz, 3H), 4·38 (q, J = 7.2 Hz, 2H), 5.79 (s, iH), 6 54 (s , 2H), 7.61-7.78 (m, 5H), 8.15 (s, 1H), 8.57 (d, J=5.2 Hz, 2H), 9.33 (s, 1H) 〇MS(ESI)m/z=332 (M +H)+ LC/MS tR=1.05 min o Example 1-342 4-Amino-6-(4-(2,4-dimethylthiazole-5(phenyl)phenylamino)_2-B Alkyl final nitrile [Chemical 1342]

標題化合物係使用對應之芳基鹵化物，依據實施例1-337 之方法（步驟2)而合成。 1H-NMR (400 MHz, DMSO-d6) δ 1.33 (t, J=6.8 Hz, 3H), 2.36 (s, 3H), 2.60 (s, 3H), 4.35 (q, J=6.8 Hz, 2H), 5.76 (s, 1H), 6.50 (s, 2H), 7.33 (d, J=8.0 Hz, 1H), 7.54-7.62 (m, 4H)，9.23 (s，1H)。 MS(ESI)m/z=366 (M+H)+。 LC/MS tR=1.98 min o 實施例1-343 141666.doc -302- 201028381 4-胺基-2-乙氧基-6-(4-(1-曱基-1H-咪唑-5-基）苯基胺基） 菸鹼腈 [化 1343]The title compound was synthesized according to the method of Example 1-137 (Step 2) using the corresponding aryl halide. 1H-NMR (400 MHz, DMSO-d6) δ 1.33 (t, J = 6.8 Hz, 3H), 2.36 (s, 3H), 2.60 (s, 3H), 4.35 (q, J = 6.8 Hz, 2H), 5.76 (s, 1H), 6.50 (s, 2H), 7.33 (d, J=8.0 Hz, 1H), 7.54-7.62 (m, 4H), 9.23 (s, 1H). MS (ESI) m / z = 366 (M+H)+. LC/MS tR=1.98 min o Example 1-433 141666.doc -302-201028381 4-Amino-2-ethoxy-6-(4-(1-mercapto-1H-imidazol-5-yl) Phenylamino) Nicotinonitrile [Chemical 1343]

標題化合物係使用對應之芳基鹵化物，依據實施例1-337 之方法（步驟2)而合成。 ❿ 1H-NMR (400 MHz, DMSO-d6) δ 1.34 (t，J=6.8 Hz, 3H)， 3.67 (s, 3H), 4.34-4.39 (m, 2H), 5.77 (s, 1H), 6.51 (s, 2H), 6.98 (s, 1H), 7.38 (d, J=8.4 Hz, 2H), 7.58-7.65 (m, 3H), 9.21 (s，1H)。 MS(ESI)m/z=335 (M+H)+。 LC/MS tR=l.〇5 min。 實施例1-344 2-乙氧基-6-(4-(°比嗓-2-基）苯基胺基）-4-(°比嗓-2-基胺基） ❿ 菸驗腈 [化 1344]The title compound was synthesized according to the method of Example 1-137 (Step 2) using the corresponding aryl halide. ❿ 1H-NMR (400 MHz, DMSO-d6) δ 1.34 (t, J = 6.8 Hz, 3H), 3.67 (s, 3H), 4.34-4.39 (m, 2H), 5.77 (s, 1H), 6.51 ( s, 2H), 6.98 (s, 1H), 7.38 (d, J=8.4 Hz, 2H), 7.58-7.65 (m, 3H), 9.21 (s, 1H). MS (ESI) m / z = 335 (M+H)+. LC/MS tR = l. 〇 5 min. Example 1-344 2-Ethoxy-6-(4-(°-pyridin-2-yl)phenylamino)-4-(°-pyridin-2-ylamino) ❿ 1344]

標題化合物係使用對應之芳基鹵化物，依據實施例1 -337 之方法（步驟2)而合成。 1H-NMR (400 MHz, DMSO-d6) δ 1.41 (t, J=6.8 Hz, 3H), 141666.doc -303 - 201028381 4.48 (q, J=6.8 Hz, 2H), 7.31 (s, 1H), 7.84 (d, J=8.8 Hz, 2H), 8.13 (d, J=8.8 Hz, 2H), 8.20 (d, J=2.4 Hz, 1H), 8.32 (s, 1H), 8.53 (d, J=2.4 Hz, 1H), 8.61 (s, 1H), 8.67 (s, 1H), 9.22 (s, 1H), 9.53 (s，1H)，9.94 (s，1H)。 MS(ESI)m/z=411 (M+H)+。 LC/MS tR=1.97 min。 實施例1-345 4-胺基-2-乙氧基-6-(4-(咐•嗪-2-基）苯基胺基）菸鹼腈 [化 1345]The title compound was synthesized according to the method of Example 1-337 (Step 2) using the corresponding aryl halide. 1H-NMR (400 MHz, DMSO-d6) δ 1.41 (t, J = 6.8 Hz, 3H), 141666.doc -303 - 201028381 4.48 (q, J = 6.8 Hz, 2H), 7.31 (s, 1H), 7.84 (d, J=8.8 Hz, 2H), 8.13 (d, J=8.8 Hz, 2H), 8.20 (d, J=2.4 Hz, 1H), 8.32 (s, 1H), 8.53 (d, J=2.4 Hz, 1H), 8.61 (s, 1H), 8.67 (s, 1H), 9.22 (s, 1H), 9.53 (s, 1H), 9.94 (s, 1H). MS (ESI) m / z = 411 (M + H) +. LC/MS tR = 1.97 min. Example 1-345 4-Amino-2-ethoxy-6-(4-(indoloxazin-2-yl)phenylamino)nicotinonitrile [Chemical 1345]

標題化合物係使用對應之芳基鹵化物，依據實施例1-337 之方法（步驟2)而合成。 1H-NMR (400 MHz, DMSO-d6) δ 1.36 (t, J=7.2 Hz, 3H), 4.39 (q, J=7.2 Hz, 2H), 5.81 (s, 1H), 6.56 (s, 2H), 7.72 (d, J=8.4 Hz, 2H), 8.08 (d, J=8.4 Hz, 2H), 8.51 (s, 1H), 8.64 (s, 1H)，9.19 (s, 1H)，9.38 (s，1H)。 MS(ESI)m/z=333 (M+H)+ 0 LC/MS tR=1.82 min。 實施例1-346 2-乙氧基-6-(4-(2-乙氧基》比啶-4-基）苯基胺基）-4-(2-乙氧 基°比咬-4-基胺基）於驗猜 141666.doc -304- 201028381 [化 1346]The title compound was synthesized according to the method of Example 1-137 (Step 2) using the corresponding aryl halide. 1H-NMR (400 MHz, DMSO-d6) δ 1.36 (t, J = 7.2 Hz, 3H), 4.39 (q, J = 7.2 Hz, 2H), 5.81 (s, 1H), 6.56 (s, 2H), 7.72 (d, J=8.4 Hz, 2H), 8.08 (d, J=8.4 Hz, 2H), 8.51 (s, 1H), 8.64 (s, 1H), 9.19 (s, 1H), 9.38 (s, 1H) ). MS (ESI) m/z = 437 (MH+) Example 1-346 2-Ethoxy-6-(4-(2-ethoxy)pyridin-4-yl)phenylamino)-4-(2-ethoxyl ratio -4- Amino group) in the test 141666.doc -304- 201028381 [Chem. 1346]

標題化合物係使用對應之芳基鹵化物，依據實施例1-337 之方法（步驟2)而合成。 1H-NMR (400 MHz, DMSO-d6) δ 1.29-1.41 (m, 9H), 4.26-4.34 (m, 4H), 4.45 (q, J=6.8 Hz, 2H), 6.38 (s, 1H), 6.51 (s, 1H), 6.82-6.83 (m, 1H), 7.05 (s, 1H), 7.27-7.29 (m, 1H), 7.72-7.78 (m, 5H), 7.98 (d, J=6.0 Hz, 1H), 8.60 (d, J=5.2 Hz, 1H)，9.67 (s，1H)。 MS(ESI)m/z=497 (M+H)+。 LC/MS tR=2.09 min。 實施例1-347 4-胺基-6-(聯苯-4-基胺基）-2-乙氧基菸鹼腈 [化 1347]The title compound was synthesized according to the method of Example 1-137 (Step 2) using the corresponding aryl halide. 1H-NMR (400 MHz, DMSO-d6) δ 1.29-1.41 (m, 9H), 4.26-4.34 (m, 4H), 4.45 (q, J = 6.8 Hz, 2H), 6.38 (s, 1H), 6.51 (s, 1H), 6.82-6.83 (m, 1H), 7.05 (s, 1H), 7.27-7.29 (m, 1H), 7.72-7.78 (m, 5H), 7.98 (d, J=6.0 Hz, 1H ), 8.60 (d, J = 5.2 Hz, 1H), 9.67 (s, 1H). MS (ESI) m / z = 495 (M + H)+. LC/MS tR = 2.09 min. Example 1-147 4-Amino-6-(biphenyl-4-ylamino)-2-ethoxynicotinonitrile [Chem. 1347]

標題化合物係使用苯基硼酸，依據實施例1-326之方法而 合成。 1H-NMR (400 MHz, DMSO-d6) d 1.34 (t, J=7.2 Hz, 3H), 4.38 (q, J=7.2 Hz, 2H), 5.77 (s, 1H), 6.50 (s, 2H), 7.30 (t, 141666.doc -305- 201028381 J=7.2 Hz, 1H), 7.43 (t, J=8.0 Hz, 2H), 7.58-7.65 (m, 6H), 9.18 (s，1H)。 MS(ESI)m/z=331 (M+H)+。 LC/MS tR=2.44 min。 實施例1-348 4-胺基-2-乙氧基-6-(4-(異-惡嗤-3-基）苯基胺基）於驗腈 [化 1348]The title compound was synthesized according to the procedure of Example 1-326 using phenyl boronic acid. 1H-NMR (400 MHz, DMSO-d6) d 1.34 (t, J = 7.2 Hz, 3H), 4.38 (q, J = 7.2 Hz, 2H), 5.77 (s, 1H), 6.50 (s, 2H), 7.30 (t, 141666.doc -305- 201028381 J=7.2 Hz, 1H), 7.43 (t, J=8.0 Hz, 2H), 7.58-7.65 (m, 6H), 9.18 (s, 1H). MS (ESI) m / z = 331 (M+H)+. LC/MS tR = 2.44 min. Example 1-48 4-Amino-2-ethoxy-6-(4-(iso-oxan-3-yl)phenylamino) as a nitrile [Chem. 1348]

標題化合物係使用對應之方基_化物，依據實施例1 _ 3 3 7 之方法（步驟2)而合成。 1H-NMR (400 MHz, DMSO-d6) δ 1.34 (t, J=6.8 Hz, 3H), 4-37 (q, J=6.8 Hz, 2H), 5.79 (s, 1H), 6.55 (s, 2H), 7.07 (s, 1H), 7.69 (d, J = 8.8 Hz, 2H), 7.79 (d, J=8.8 Hz, 2H), 8.93 (s，1H)，9.35 (s，1H)。 MS(ESI)m/z=322 (M+H)+。 ❹ LC/MS tR=2.11 min。 實施例1-349 4-胺基-2 -乙氧基- 6-(4_(l -曱基-1H-咪唑-2-基）胺基）於 鹼腈 [化 1349]The title compound was synthesized according to the method of Example 1 - 3 3 7 (Step 2) using the corresponding base group. 1H-NMR (400 MHz, DMSO-d6) δ 1.34 (t, J = 6.8 Hz, 3H), 4-37 (q, J = 6.8 Hz, 2H), 5.79 (s, 1H), 6.55 (s, 2H) ), 7.07 (s, 1H), 7.69 (d, J = 8.8 Hz, 2H), 7.79 (d, J = 8.8 Hz, 2H), 8.93 (s, 1H), 9.35 (s, 1H). MS (ESI) m / z = 322 (M+H)+. ❹ LC/MS tR = 2.11 min. Example 1-495 4-Amino-2-ethoxy- 6-(4-(l-indolyl-1H-imidazol-2-yl)amino) in the alkali nitrile [Chem. 1349]

141666.doc -306- 201028381 標題化合物係使用對應之芳基鹵化物，依據實施例1 -337 之方法（步驟2)而合成。 1H-NMR (400 MHz, DMSO-d6) δ 1.34 (t, J=6.8 Hz, 3H), 3.74 (s, 3H), 4.36 (t, J=6.8 Hz, 2H), 5.78 (s, 1H), 6.53 (s, 2H), 6.96 (s, 1H), 7.21 (s5 1H), 7.62 (dd, J=8.0 Hz, 19.6 Hz, 4H), 8.15 (s，1H)，9.28 (s，1H)。 MS(ESI)m/z=335 (M+H)+。 LC/MS tR=0.88 min 0 ❹ 實施例1-350 4-胺基-2-乙氧基-6-(4-(1-甲基-1H-°米°坐-4-基）苯基胺基） 菸鹼腈 [化 1350]141666.doc -306- 201028381 The title compound was synthesized according to the method of Example 1-337 (Step 2) using the corresponding aryl halide. 1H-NMR (400 MHz, DMSO-d6) δ 1.34 (t, J = 6.8 Hz, 3H), 3.74 (s, 3H), 4.36 (t, J = 6.8 Hz, 2H), 5.78 (s, 1H), 6.53 (s, 2H), 6.96 (s, 1H), 7.21 (s5 1H), 7.62 (dd, J=8.0 Hz, 19.6 Hz, 4H), 8.15 (s, 1H), 9.28 (s, 1H). MS (ESI) m / z = 335 (M+H)+. LC/MS tR=0.88 min 0 实施 Example 1-350 4-Amino-2-ethoxy-6-(4-(1-methyl-1H-°m)-4-phenyl)phenylamine Base) Nicotinonitrile [Chemical 1350]

標題化合物係使用對應之芳基鹵化物，依據實施例1 _33 7 φ 之方法（步驟2)而合成。 1H-NMR (400 MHz, DMSO-d6) δ 1.33 (t, J=6.8 Hz, 3H), 3.67 (s, 3H), 4.35 (t, J=6.8 Hz, 2H), 5.72 (s, 1H), 6.44 (s, 2H)，7.49-7.62 (m，7H), 9_05 (s, 1H)。 MS(ESI)m/z=335 (M+H)+。 LC/MS tR=0.99 min ° 實施例1-351 4-胺基-2-乙氧基-6-(4-(2-乙氧基吼啶-4-基）苯基胺基）菸 141666.doc 307- 201028381 鹼腈 [化 1351]The title compound was synthesized according to the method of Example 1 - 33 7 φ (Step 2) using the corresponding aryl halide. 1H-NMR (400 MHz, DMSO-d6) δ 1.33 (t, J = 6.8 Hz, 3H), 3.67 (s, 3H), 4.35 (t, J = 6.8 Hz, 2H), 5.72 (s, 1H), 6.44 (s, 2H), 7.49-7.62 (m, 7H), 9_05 (s, 1H). MS (ESI) m / z = 335 (M+H)+. LC/MS tR=0.99 min ° Example 1-351 4-Amino-2-ethoxy-6-(4-(2-ethoxyoxaridin-4-yl)phenylamino) sm. Doc 307- 201028381 Alkali nitrile [Chemical 1351]

標題化合物係使用對應之芳基鹵化物，依據實施例1 -337 之方法（步驟2)而合成。 1H-NMR (400 MHz, DMSO-d6) δ 1.32-1.36 (m, 6H), 4.31-4.40 (m, 4H), 5.79 (s, 1H), 6.55 (s, 2H), 7.33 (s, 1H), 7.67- 7.72 (m，4H)，7.67-7.72 (m, 4H), 9·31 (s，1H)。 MS(ESI)m/z=360 (M+H)、 LC/MS tR=1.21 min o 實施例1-352 4-胺基-6-(4-(2,6-二甲基n比啶-4-基）苯基胺基）-2-乙氧基 於驗腈 [化 1352]The title compound was synthesized according to the method of Example 1-337 (Step 2) using the corresponding aryl halide. 1H-NMR (400 MHz, DMSO-d6) δ 1.32-1.36 (m, 6H), 4.31-4.40 (m, 4H), 5.79 (s, 1H), 6.55 (s, 2H), 7.33 (s, 1H) , 7.67- 7.72 (m, 4H), 7.67-7.72 (m, 4H), 9·31 (s, 1H). MS (ESI) m / z = 360 (M + H), LC / MS t R = 1.21 min o Example 1-352 4-amino-6-(4-(2,6-dimethyl n-pyridin- 4-yl)phenylamino)-2-ethoxyl for the nitrile [Chemical 1352]

標題化合物係使用對應之芳基鹵化物，依據實施例1 -337 之方法（步驟2)合成。 1H-NMR (400 MHz, DMSO-d6) δ 1.35 (t, J=7.2 Hz, 3H), 2.45 (s, 6H), 5.79 (s, 1H), 6.54 (s, 2H), 7.22 (s, 1H), 7.26 (d, J=5.6, 1H), 7.70 (dd, J=8.8 Hz, 24.0 Hz, 4H), 8.15 (d, 141666.doc -308- 201028381 J=5.6 Hz, 1H)，9.31 (s，1H)。 MS(ESI)m/z=376 (M+H)+。 LC/MS tR=2_19 min。 實施例1-353 4-胺基-2-乙氧基-6-(4-(噁唑-5-基）苯基胺基）菸鹼酸曱酯 [化 1353]The title compound was synthesized according to the method of Example 1-337 (Step 2) using the corresponding aryl halide. 1H-NMR (400 MHz, DMSO-d6) δ 1.35 (t, J = 7.2 Hz, 3H), 2.45 (s, 6H), 5.79 (s, 1H), 6.54 (s, 2H), 7.22 (s, 1H) ), 7.26 (d, J=5.6, 1H), 7.70 (dd, J=8.8 Hz, 24.0 Hz, 4H), 8.15 (d, 141666.doc -308- 201028381 J=5.6 Hz, 1H), 9.31 (s , 1H). MS (ESI) m / z = 376 (M+H)+. LC/MS tR = 2_19 min. Example 1-353 4-Amino-2-ethoxy-6-(4-(oxazol-5-yl)phenylamino) nicotinic acid decyl ester [Chem. 1353]

/TO/TO

二。惡院，100oCtwo. Hospital, 100oC

OMe ^^νη2 Pd(OAc)2, BINAP CS2CO3 步驟1 : 2-氣-6-乙氧基吡啶-4-胺OMe ^^νη2 Pd(OAc)2, BINAP CS2CO3 Step 1: 2-Ga-6-ethoxypyridin-4-amine

於20 mL微波反應容器中，向2,6-二氯吡啶-4-胺（1.86 g，11.4 mmol)之乙醇（12 mL)溶液中添加60%氫化鋼（301 mg，12.5 mmol)進行覆蓋，使用 Biotage Optimizer反應裝 置，於1 50°C下攪拌1小時。向反應溶液中添加水及乙酸乙 酯進行分離後，以乙酸乙酯萃取水相，將合併之有機相以 水及飽和食鹽水進行清洗，以硫酸鎂加以乾燥。將有機相 過濾後，進行減壓濃縮。以乙酸乙酯/醚使所獲得之殘渣 固化，藉此獲得標題化合物（1.08 g，6.3 mmol，55%)，為 無色油。 1H-NMR (300 MHz, DMSO-d6) δ 1.22 (t, J=7.2 Hz, 3H), 4.11 (q, J=7.2 Hz, 2H), 5.74 (s, 1H), 6.18 (s, 1H), 6.25 (s, 141666.doc •309- 201028381 2H)。 MS(ESI)m/z=173 (M+H)+。 步驟2 · 6 -氣-2-乙乳基-3 -蛾°比咬-4 -胺 向2 -氣-6-乙氧基0比唆-4-胺（50 mg，0.131 mmol)及填化 納（3.02 g，20.2 mmol)之乙酸溶液（30 mL)中添加氯胺 (Chloramine)-T(4.59 g，20.2 mmol)，於室溫下授拌 4 小 時。向反應溶液中添加2 mol/L氫氧化納水溶液（60 mL)及 乙酸乙酯，進行分離後，以乙酸乙酯萃取水相，將合併之 有機相以水、10% NaHS03水溶液及飽和食鹽水進行清 洗，以硫酸鎂加以乾燥。將有機相過濾後，進行減壓濃 縮。使所獲得之殘渣溶解於己烷：乙酸乙酯: 1溶液 中，過濾除去不溶物後，利用中壓矽膠層析法（己烷：乙 酸乙酯=20 : 1)進行純化，獲得標題化合物（3.05 g， 61 %)，為無色油。 1H-NMR (300 MHz, DMSO-d6) δ 1.32 (t, J = 7.2 Hz, 3H), 4.26 (q，J=7.2 Hz，2H), 6.39 (s, 1H)，6.44 (s，2H)。 MS(ESI)m/z=299 (M+H)+。 LC/MS tR=1.33 min。 步驟3 : 4-胺基-6-氣-2-乙氧基菸鹼酸甲酯 向 6 -氯-2 -乙氧基-3-磁°比咬-4-胺（200 mg，0.670 mmol)、 DPPF(37.1 mg，0.067 mmol)及 Pd(OAc)2(7.52 mg，0.033 mmol)之曱醇溶液（2 mL)中添加三乙基胺（203 mg，279 pL，2.01 mmol)，於60°C下攪拌5小時。向反應溶液中添 加水及乙酸乙酯進行分離後，以乙酸乙酯萃取水相，將合 141666.doc -310- 201028381 併之有機相以水及飽和食鹽水進行清洗，以硫酸鎮加以乾 燥。將有機相過濾後，進行減壓濃縮。利用中壓矽膠層析 法（己烷：乙酸乙酯=7 : 3)對所獲得之殘渣進行純化，獲 得標題化合物（106 mg，69%)，為白色固體。 1H-NMR (400 MHz, DMSO-d6) δ 1.25 (t, J=6.8 Hz, 3H), 3.75 (s, 3H), 4.23 (q, J=6.8 Hz, 2H), 6.39 (brs, 1H)，7.14 (s，2H)。 MS(ESI)m/z=231 (M+H)+。 ® LC/MS tR=1.92 min ° 步驟4:標題化合物 使用4-胺基-6-氣-2-乙氧基菸鹼酸甲酯（步驟3，900 mg， 3.90 mmol)、及4-(噁唑-5-基）苯胺，依據實施例1-145之方 法而合成（1.38 g，80%)。 1H-NMR (400 MHz, DMSO-d6) 1.32 (t, J=7.2 Hz, 3H), 3.70 (s, 3H), 4.32 (q, J=7.2 Hz, 2H), 5.77 (s, 1H), 6.96 (s, 2H), 7.51 (s, 1H), 7.60-7.69 (m, 4H), 8.35 (s, 1H), 9.12 (s, 1H)。 MS(ESI)m/z=355 (M+H)+ 0 LC/MS tR=1.93 min 〇 實施例1-354 4-胺基-2-乙氧基_6_(4-(噁唑-5-基）苯基胺基）菸鹼酸 141666.doc • 311· 201028381 [化 1354]60% hydrogenated steel (301 mg, 12.5 mmol) was added to a solution of 2,6-dichloropyridin-4-amine (1.86 g, 11.4 mmol) in ethanol (12 mL) in a 20 mL microwave reaction vessel. The mixture was stirred at 150 ° C for 1 hour using a Biotage Optimizer reaction apparatus. Water and ethyl acetate were added to the reaction solution for separation, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and brine and dried over magnesium sulfate. The organic phase was filtered and concentrated under reduced pressure. The residue obtained was solidified with ethyl acetate / ethyl ether toield to afforded the title compound (1.08 g, 6.3 mmol, 55%) as a colorless oil. 1H-NMR (300 MHz, DMSO-d6) δ 1.22 (t, J = 7.2 Hz, 3H), 4.11 (q, J = 7.2 Hz, 2H), 5.74 (s, 1H), 6.18 (s, 1H), 6.25 (s, 141666.doc • 309- 201028381 2H). MS (ESI) m / z = 173 (M+H)+. Step 2 · 6 -Gas-2-ethylidyl-3 - Moth ° bite -4 -amine to 2- gas-6-ethoxy 0 to 唆-4-amine (50 mg, 0.131 mmol) and fill Chloramine (Tilamine)-T (4.59 g, 20.2 mmol) was added to a solution of sodium (3.02 g, 20.2 mmol) in acetic acid (30 mL) and stirred at room temperature for 4 hours. 2 mol/L aqueous sodium hydroxide solution (60 mL) and ethyl acetate were added to the reaction solution, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were combined with water, 10% aqueous NaHS03 and saturated brine. It was washed and dried with magnesium sulfate. After the organic phase was filtered, it was concentrated under reduced pressure. The obtained residue was dissolved in hexane:ethyl acetate: 1 solution, and the insoluble material was removed by filtration, and then purified by medium-pressure gel chromatography (hexane: ethyl acetate = 20:1) to give the title compound ( 3.05 g, 61 %), colorless oil. 1H-NMR (300 MHz, DMSO-d6) δ 1.32 (t, J = 7.2 Hz, 3H), 4.26 (q, J = 7.2 Hz, 2H), 6.39 (s, 1H), 6.44 (s, 2H). MS (ESI) m / z = 299 (M+H)+. LC/MS tR = 1.33 min. Step 3: 4-Amino-6-Gas-2-ethoxynicotinic acid methyl ester to 6-chloro-2-ethoxy-3-pyrene-4-amine (200 mg, 0.670 mmol) Add DPethyl (203 mg, 279 pL, 2.01 mmol) to DPPF (37.1 mg, 0.067 mmol) and Pd(OAc) 2 (7.52 mg, 0.033 mmol) in methanol (2 mL) at 60 ° Stir for 5 hours at C. After water and ethyl acetate were added to the reaction solution for separation, the aqueous phase was extracted with ethyl acetate, and the organic phase was washed with water and saturated brine, and dried over sodium sulfate. After the organic phase was filtered, it was concentrated under reduced pressure. The residue obtained was purified by EtOAc EtOAc (EtOAc:EtOAc: 1H-NMR (400 MHz, DMSO-d6) δ 1.25 (t, J = 6.8 Hz, 3H), 3.75 (s, 3H), 4.23 (q, J = 6.8 Hz, 2H), 6.39 (brs, 1H), 7.14 (s, 2H). MS (ESI) m / z = 231 (M + H) +. ® LC/MS tR=1.92 min ° Step 4: The title compound was used in 4-amino-6-gly-2-ethoxynicotinic acid methyl ester (Step 3, 900 mg, 3.90 mmol), and 4- (Evil Zyrid-5-yl)aniline was synthesized according to the method of Example 1-145 (1.38 g, 80%). 1H-NMR (400 MHz, DMSO-d6) 1.32 (t, J = 7.2 Hz, 3H), 3.70 (s, 3H), 4.32 (q, J = 7.2 Hz, 2H), 5.77 (s, 1H), 6.96 (s, 2H), 7.51 (s, 1H), 7.60-7.69 (m, 4H), 8.35 (s, 1H), 9.12 (s, 1H). MS (ESI) m / z = 355 (M + H) + &lt;&quot;&&&&&&&&&&&&&&&&&&&& Phenylamino)nicotinic acid 141666.doc • 311· 201028381 [Chemical 1354]

NaOH水溶液 DMSO,室溫NaOH aqueous solution DMSO, room temperature

向4-胺基-2-乙氧基-6-(4-(噁唑-5-基）苯基胺基）菸鹼酸曱 醋（200 mg，0.564 mmol)之 DMSO溶液（2 mL)中添加 2 N 氫 氧化鈉水溶液（847 pL，1.69 mmol)，於室溫下攪拌一整 夜。向反應溶液中添加1 0%檸檬酸水溶液及乙酸乙酯，進 行分離後，以乙酸乙酯萃取水相，將合併之有機相以水及 飽和食鹽水進行清洗，以硫酸鎂加以乾燥。將有機相過渡 後，進行減壓濃縮。利用中壓矽膠層析法（己烷：乙酸乙 酯=5 : 1)對所獲得之殘渣進行純化，獲得標題化合物（105 mg，5 5%)，為黃色固體。 1H-NMR (400 MHz, DMSO-d6) δ 1.35 (t, J=6.8 Hz, 3H), 4.39 (q, J=6.8 Hz, 2H), 5.79 (s, 1H), 7.24 (s, 2H), 7.52 (s, 1H), 7.64 (dd, J=8.4 Hz, 22.8 Hz, 4H), 8.36 (s, 1H), 9.15 (s, 1H)。 MS(ESI)m/z=341 (M+H)+。 LC/MS tR=1.76 min。 實施例1-355 4-胺基-2-乙氧基-6-(4-(噁唑-5-基）苯基胺基）-N-苯基菸 驗醯胺 141666.doc -312- 201028381 [化 1355]To 4-amino-2-ethoxy-6-(4-(oxazol-5-yl)phenylamino) nicotinic acid vinegar (200 mg, 0.564 mmol) in DMSO (2 mL) A 2 N aqueous sodium hydroxide solution (847 pL, 1.69 mmol) was added and stirred at room temperature overnight. After adding 10% aqueous citric acid solution and ethyl acetate to the reaction solution, the mixture was separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and brine and dried over magnesium sulfate. After the organic phase was transferred, it was concentrated under reduced pressure. The residue obtained was purified by EtOAc EtOAc (EtOAc:EtOAc) 1H-NMR (400 MHz, DMSO-d6) δ 1.35 (t, J = 6.8 Hz, 3H), 4.39 (q, J = 6.8 Hz, 2H), 5.79 (s, 1H), 7.24 (s, 2H), 7.52 (s, 1H), 7.64 (dd, J=8.4 Hz, 22.8 Hz, 4H), 8.36 (s, 1H), 9.15 (s, 1H). MS (ESI) m / z = 341 (M+H)+. LC/MS tR = 1.76 min. Example 1-55 4-Amino-2-ethoxy-6-(4-(oxazol-5-yl)phenylamino)-N-phenyl oxime phthalamide 141666.doc -312- 201028381 [化1355]

向4-胺基-2-乙氧基-6-(4-(噁唑-5-基）苯基胺基）菸鹼酸 (20 mg，0.059 mmol)、NMM(7.13 mg &gt; 7.75 pL，0.071 mmol)及苯胺（6.6 mg，0.071 mmol)之NMP溶液中添加 HATU(26.8 mg，0.071 mol)，授拌4小時。向反應溶液中添 加水後，進行減壓濃縮，利用逆相等分試樣液相層析法 (C18管柱，水/乙腈/0.1%曱酸梯度）對所獲得之殘渣進行純 化，獲得標題化合物（6.8 mg，28%)，為白色固體。 MS(ESI)m/z=416 (M+H)+。 LC/MS tR=2.94 min 〇 實施例1-356. 4 -胺基-2-乙乳基-6-(4-(11 惡β坐-5-基）笨基胺基）於驗酿胺 [化 1356]To 4-amino-2-ethoxy-6-(4-(oxazol-5-yl)phenylamino)nicotinic acid (20 mg, 0.059 mmol), NMM (7.13 mg &gt; 7.75 pL, HATU (26.8 mg, 0.071 mol) was added to a solution of 0.071 mmol) and aniline (6.6 mg, 0.071 mmol) in NMP for 4 hours. After adding water to the reaction solution, the residue was concentrated under reduced pressure, and the residue obtained was purified by reverse phase liquid chromatography (C18 column, water / acetonitrile / 0.1% decanoic acid gradient) to give the title compound. (6.8 mg, 28%) as a white solid. MS (ESI) m / z = 416 (M + H) +. LC/MS tR=2.94 min 〇Example 1-356. 4-Amino-2-ethyllacyl-6-(4-(11 oxaβ-s--5-yl)phenylamino) 1356]

標題化合物係依據實施例1-355之方法而合成。 MS(ESI)m/z=340 (Μ+Η)+。 LC/MS tR=1.97 min。 實施例1-357 4-胺基-2-乙氧基-N-甲基-6-(4-噁唑-5-基）苯基胺基）菸鹼 141666.doc -313- 201028381 醯胺 [化 1357]The title compound was synthesized according to the procedure of Example 1-355. MS (ESI) m / z = 340 (Μ + Η) +. LC/MS tR = 1.97 min. Example 1-57 4-Amino-2-ethoxy-N-methyl-6-(4-oxazol-5-yl)phenylamino)nicotine 141666.doc -313-201028381 Amidoxime [ 1357]

標題化合物係依據實施例1-355之方法而合成。 MS(ESI)m/z=354 (M+H)+。 LC/MS tR=2.17 min 〇 實施例1-358 4-胺基-2-乙氧基-N，N-二甲基-6-(4-(噁唑_5_基）苯基胺 基）菸鹼醯胺 [化 1358]The title compound was synthesized according to the procedure of Example 1-355. MS (ESI) m / z = 354 (M+H)+. LC/MS tR = 2.17 min 〇 Example 1-558 4-Amino-2-ethoxy-N,N-dimethyl-6-(4-(oxazol-5-yl)phenylamino) Nicotine amide [Chemical 1358]

標題化合物係依據實施例1-355之方法而合成。 MS(ESI)m/z=368 (M+H)+。 LC/MS tR=1.93 min。 實施例1-359 4-胺基-2-乙氧基-N-異丙基-6-(4-(。惡。坐基）苯基胺基） 菸鹼醯胺 [化 1359]The title compound was synthesized according to the procedure of Example 1-355. MS (ESI) m/z = 368 (M+H)+. LC/MS tR = 1.93 min. Example 1-359 4-Amino-2-ethoxy-N-isopropyl-6-(4-(.oxanyl)phenylamino) Nicotinamide [Chem. 1359]

141666.doc -314- 201028381 標題化合物係依據實施例1-355之方法而合成。 MS(ESI)m/z=382 (M+H)+。 LC/MS tR=2.63 min。 實施例1-360 4 -胺基-N - 丁基-2-乙氧基- 6-(4 -11 惡唾-5-基）苯基胺基）於驗 醯胺 [化 1360]141666.doc -314- 201028381 The title compound was synthesized according to the procedure of Example 1-355. MS (ESI) m / z = 382 (M+H)+. LC/MS tR = 2.63 min. Example 1-160 4-Amino-N-butyl-2-ethoxy- 6-(4 -11 oxasin-5-yl)phenylamino) in the presence of decylamine [Chemical 1360]

標題化合物係依據實施例1-355之方法而合成。 MS(ESI)m/z=396 (M+H)+。 LC/MS tR=2.79 min。 實施例1-361 4-胺基-N-(環丙基甲基）-2-乙氧基-6-(4-(噁唑-5-基）苯基 胺基）菸鹼醯胺 參 [化 1361]The title compound was synthesized according to the procedure of Example 1-355. MS (ESI) m / z = 396 (M+H)+. LC/MS tR = 2.79 min. Example 1-361 4-Amino-N-(cyclopropylmethyl)-2-ethoxy-6-(4-(oxazol-5-yl)phenylamino)nicotinium amide 1361]

標題化合物係依據實施例1-355之方法而合成。 MS(ESI)m/z=394 (M+H)+。 LC/MS tR=2.66 min。 實施例1-362 4 -胺基-2 -乙氧基-N-(2-曱氧基乙基）-6-(4-(°惡0坐-5-基）苯 141666.doc -315- 201028381 基胺基）菸鹼醯胺 [化 1362]The title compound was synthesized according to the procedure of Example 1-355. MS (ESI) m / z = 394 (M+H)+. LC/MS tR = 2.66 min. Example 1-162 4-Amino-2-ethoxy-N-(2-decyloxyethyl)-6-(4-(°oxo-5-yl)benzene 141666.doc -315- 201028381 amide amino) nicotine amide [Chemical 1362]

標題化合物係依據實施例1-355之方法而合成。 MS(ESI)m/z=398 (M+H)+。 LC/MS tR=2.27 min。 實施例1-363 4 -胺基-2-乙氧基-N-(2-(N-嗎琳基）乙基）-6-(4-(°惡〇坐-5_ 基）苯基胺基）菸鹼醯胺 [化 1363]The title compound was synthesized according to the procedure of Example 1-355. MS (ESI) m / z = 398 (M+H)+. LC/MS tR = 2.27 min. Example 1-163 4-Amino-2-ethoxy-N-(2-(N-morphinyl)ethyl)-6-(4-(°〇?-5-yl)phenylamino Nicotine amide [Chemical 1363]

標題化合物係依據實施例1-355之方法而合成。 MS(ESI)m/z=453 (M+H)+。 LC/MS tR=1.33 min。 實施例1-364 4 -胺基-2-乙氧基-N-(2 -甲基績酿基乙基- 6- (4-( °惡°坐-5-基） 苯基胺基）菸鹼醯胺 [化 1364]The title compound was synthesized according to the procedure of Example 1-355. MS (ESI) m / z = 453 (M+H)+. LC/MS tR = 1.33 min. Example 1-364 4-Amino-2-ethoxy-N-(2-methyl-glycosylethyl-6-(4-(°(°-5-yl)phenylamino)) Alkaline amide [Chemical 1364]

141666.doc -316- 201028381 標題化合物係依據實施例1-355之方法而合成。 MS(ESI)m/z=446 (M+H)+。 LC/MS tR=2.99 min。 實施例1-365 2-(4-胺基-2-乙氧基-6-(4-(噁唑-5-基）苯基胺基）菸鹼醯 胺）乙酸第三丁酯 [化 1365]141666.doc -316- 201028381 The title compound was synthesized according to the method of Example 1-355. MS (ESI) m / z = 446 (M+H)+. LC/MS tR = 2.99 min. Example 1-365 2-(4-Amino-2-ethoxy-6-(4-(oxazol-5-yl)phenylamino)nicotinium decylamine) tert-butyl acetate [Chemical 1365] ]

標題化合物係依據實施例1-355之方法而合成。 MS(ESI)m/z=454 (M+H)+。 LC/MS tR=2.82 min 〇 實施例1-366 2-(4-胺基-2-乙氧基-6-(4-(噁唑-5-基）苯基胺基）菸鹼醯 胺）乙酸 ⑩ [化1366]The title compound was synthesized according to the procedure of Example 1-355. MS (ESI) m / z = 454 (M + H) +. LC/MS tR = 2.82 min 〇 Example 1-366 2-(4-Amino-2-ethoxy-6-(4-(oxazol-5-yl)phenylamino) nicotinamide Acetic acid 10 [Chemical 1366]

標題化合物係藉由使2-(4-胺基-2-乙氧基-6-(4-(噁唑-5-基） 苯基胺基）菸鹼醯胺）乙酸第三丁酯溶解於TFA :二氣曱烷 =1 : 1溶液中後，進行減壓濃縮而獲得。 1H-NMR (400 MHz, DMSO-d6) δ 1.42 (t, J=7.2 Hz, 3H), 3.96 (d, J=3.2 Hz, 2H), 4.44 (q, J=7.2 Hz, 2H), 7.50 (s, 141666.doc -317· 201028381 1H), 7.59-7.68 (m, 4H), 8.35 (s, 1H), 8.45 (s, 1H), 9.08 (s, 1H)。 MS(ESI)m/z=398 (M+H)+。 LC/MS tR=1.55 min。 實施例1-367 (4 -胺基-2 -乙氧基-6 - ( 4 - ( e 惡0坐-5 -基）苯基胺基）n比°定-3 基）(Ν-嗎啉基）胺基甲酮 [化 1367]The title compound is prepared by dissolving 2-(4-amino-2-ethoxy-6-(4-(oxazol-5-yl)phenylamino)nicotinium amide) TFA: After dioxane = 1 : 1 solution, it was obtained by concentration under reduced pressure. 1H-NMR (400 MHz, DMSO-d6) δ 1.42 (t, J = 7.2 Hz, 3H), 3.96 (d, J = 3.2 Hz, 2H), 4.44 (q, J = 7.2 Hz, 2H), 7.50 ( s, 141666.doc -317· 201028381 1H), 7.59-7.68 (m, 4H), 8.35 (s, 1H), 8.45 (s, 1H), 9.08 (s, 1H). MS (ESI) m / z = 398 (M+H)+. LC/MS tR = 1.55 min. Example 1-367 (4-Amino-2-ethoxy-6-(4-(e oxaxyl-5-yl)phenylamino)n) °-3 base) (Ν-morpholine) Aminomethanone [Chemical 1367]

標題化合物係依據實施例1-355之方法而合成。 MS(ESI)m/z=410 (Μ+Η)+。 LC/MS tR = 1.89 min。 實施例1-368 4-胺基-N-(2-氣苯基）-2-乙氧基-6-(4-(噁唑-5-基）苯基胺 基）於驗醯胺 [化 1368]The title compound was synthesized according to the procedure of Example 1-355. MS (ESI) m / z = 410 (Μ + Η) +. LC/MS tR = 1.89 min. Example 1-368 4-Amino-N-(2-phenylphenyl)-2-ethoxy-6-(4-(oxazol-5-yl)phenylamino) 1368]

標題化合物係依據實施例1-355之方法而合成。 MS(ESI)m/z=450 (M+H)+。 LC/MS tR=3.27 min。 141666.doc -318- 201028381 實施例1-369 4-胺基-N-(3-氯苯基）-2-乙氧基-6-(4-(噁唑-5-基）苯基胺 基）菸鹼醯胺 [化 1369]The title compound was synthesized according to the procedure of Example 1-355. MS (ESI) m / z = 450 (M + H) +. LC/MS tR = 3.27 min. 141666.doc -318- 201028381 Example 1-369 4-Amino-N-(3-chlorophenyl)-2-ethoxy-6-(4-(oxazol-5-yl)phenylamino Nicotine amide [Chemical 1369]

標題化合物係依據實施例1-355之方法而合成。 MS(ESI)m/z=450 (M+H)+。 LC/MS tR=3.24 min。 實施例1-370 4-胺基-N-(4-氯苯基）-2-乙氧基-6-(4-(噁唑-5-基）苯基胺 基）菸鹼醯胺 [化 1370]The title compound was synthesized according to the procedure of Example 1-355. MS (ESI) m / z = 450 (M + H) +. LC/MS tR = 3.24 min. Example 1-370 4-Amino-N-(4-chlorophenyl)-2-ethoxy-6-(4-(oxazol-5-yl)phenylamino)nicotinium amide 1370]

標題化合物係依據實施例1-355之方法而合成。 MS(ESI)m/z=450 (M+H)+。 LC/MS tR=3.21 min。 實施例1-371 4-胺基-2-乙氧基-N-(4-曱氧基苯基）-6-(4-(噁唑-5-基）苯 基胺基）菸鹼醯胺 141666.doc .319· 201028381 [化 1371]The title compound was synthesized according to the procedure of Example 1-355. MS (ESI) m / z = 450 (M + H) +. LC/MS tR = 3.21 min. Example 1-71 4-Amino-2-ethoxy-N-(4-decyloxyphenyl)-6-(4-(oxazol-5-yl)phenylamino)nicotinamide 141666.doc .319· 201028381 [Chemical 1371]

標題化合物係依據實施例1-355之方法而合成。 MS(ESI)m/z=446 (M+H)+。 LC/MS tR=2.84 min。 實施例1-372 4-胺基-N-(蒽-2-基）-2-乙氧基-6-(4-(噁唑-5-基）苯基胺 基）菸鹼醯胺 [化 1372]The title compound was synthesized according to the procedure of Example 1-355. MS (ESI) m / z = 446 (M+H)+. LC/MS tR = 2.84 min. Example 1-172 4-Amino-N-(indol-2-yl)-2-ethoxy-6-(4-(oxazol-5-yl)phenylamino)nicotinium amide 1372]

標題化合物係依據實施例1-355之方法而合成。 MS(ESI)m/z=516 (M+H)+。 LC/MS tR=3.60 min。 實施例1-373 4-胺基-2-乙氧基-6-(4-(噁唑-5-基）笨基胺基）-N-(4-苯氧 基苯基）终驗醯胺 [化 1373]The title compound was synthesized according to the procedure of Example 1-355. MS (ESI) m / z = 516 (M + H) +. LC/MS tR = 3.60 min. Example 1-173 4-Amino-2-ethoxy-6-(4-(oxazol-5-yl)phenylamino)-N-(4-phenoxyphenyl)-final amine [化1373]

141666.doc -320· 201028381 標題化合物係依據實施例1-355之方法而合成。 MS(ESI)m/z=508 (M+H)+。 LC/MS tR=3.35 min。 實施例1-374 4-胺基-2-乙氧基-N-(4-(3-氟苄氧基）苯基）-6-(4-(噁唑-5-基）苯基胺基）菸鹼醯胺 [化 1374]141666.doc -320· 201028381 The title compound was synthesized according to the method of Example 1-355. MS (ESI) m / z = 508 (M + H) +. LC/MS tR = 3.35 min. Example 1-174 4-Amino-2-ethoxy-N-(4-(3-fluorobenzyloxy)phenyl)-6-(4-(oxazol-5-yl)phenylamino Nicotine amide [Chemical 1374]

標題化合物係依據實施例1-355之方法而合成。 MS(ESI)m/z=574 (M+H)+。 LC/MS tR=3.47 min。 實施例1-375 4-胺基-N-(4-苯曱醯基苯基）-2-乙氧基-6-(4-(噁唑-5-基） 苯基胺基）菸鹼醯胺 [化 1375] 〇The title compound was synthesized according to the procedure of Example 1-355. MS (ESI) m / z = 574 (M+H)+. LC/MS tR = 3.47 min. Example 1-375 4-Amino-N-(4-phenylmercaptophenyl)-2-ethoxy-6-(4-(oxazol-5-yl)phenylamino)nicotine oxime Amine [Chemical 1375] 〇

標題化合物係依據實施例1-355之方法而合成。 MS(ESI)m/z=520 (M+H)+。 LC/MS tR=3.17 min。 141666.doc -321 - 201028381 實施例1-376 4-(4-胺基-2-乙氧基-6-(4-(噁唑-5-基）苯基胺基）菸鹼醯 胺）-2-經基苯甲酸苯醋 [化 1376]The title compound was synthesized according to the procedure of Example 1-355. MS (ESI) m / z = 520 (M+H)+. LC/MS tR = 3.17 min. 141666.doc -321 - 201028381 Examples 1-376 4-(4-Amino-2-ethoxy-6-(4-(oxazol-5-yl)phenylamino)nicotinamide)- 2-Phenylbenzoic acid Benzene vinegar [Chemical 1376]

標題化合物係依據實施例1-355之方法而合成。 MS(ESI)m/z=552 (M+H)+ 〇 LC/MS tR=3.40 min 〇 實施例1-377 4-胺基-2-乙氧基-N-(4-( °惡°坐-5-基）苯基）-6-(4-(嗔&gt;»坐-5-基）苯基胺基）菸鹼醯胺 [化 1377]The title compound was synthesized according to the procedure of Example 1-355. MS (ESI) m / z = 552 (M + H) + 〇 LC / MS tR = 3.40 min 〇 Example 1-177 4-Amino-2-ethoxy-N-(4-( ° -5-yl)phenyl)-6-(4-(嗔&gt;»坐-5-yl)phenylamino)nicotinium amide [Chemical 1377]

標題化合物係依據實施例1-355之方法而合成。 MS(ESI)m/z=483 (M+H). 0 LC/MS tR=2.77 min 〇 實施例1-378 4-胺基-2-乙氧基_N-(3-(噁唑-5-基）苯基）-6-(4-(噁唑-5-基）胺基苯基）終驗酿胺 141666.doc • 322· 201028381 [化 1378]The title compound was synthesized according to the procedure of Example 1-355. MS (ESI) m / z = 483 (M + H). </RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; -yl)phenyl)-6-(4-(oxazol-5-yl)aminophenyl) final amine 141666.doc • 322· 201028381 [Chemical 1378]

標題化合物係依據實施例1-355之方法而合成。 MS(ESI)m/z=483 (M+H)+ 〇 LC/MS tR=2_79 min 〇 實施例1-379 (E)-3-(4-(4-胺基-2-乙氧基-6-(4-(噁唑-5-基）笨基胺基）菸 鹼醯胺）苯基）丙烯酸乙酯 [化 1379] 〇The title compound was synthesized according to the procedure of Example 1-355. MS (ESI) m / z = 483 (M + H) + 〇 LC / MS tR = 2 - 79 min 〇 Example 1-179 (E)-3-(4-(4-Amino-2-ethoxy- 6-(4-(oxazol-5-yl)phenylamino)nicotinium decyl)phenyl)ethyl acrylate [Chemical 1379] 〇

標題化合物係依據實施例1-355之方法而合成。 MS(ESI)m/z=514 (M+H)+。 LC/MS tR=3.16 min 〇 實施例1-380 4-胺基-N-苄基乙氧基-6-(4-(噁唑-5-基）苯基胺基）菸 驗醯胺 [化 1380]The title compound was synthesized according to the procedure of Example 1-355. MS (ESI) m / z = 514 (M + H) +. LC/MS tR=3.16 min 〇Example 1-380 4-Amino-N-benzylethoxy-6-(4-(oxazol-5-yl)phenylamino) acetonide 1380]

141666.doc - 323 · 201028381 標題化合物係依據實施例1-355之方法而合成。 MS(ESI)m/z=430 (M+H)+。 LC/MS tR=2.77 min。 實施例1-381 6-乙氧基-5-乙炔基-N2-(4-(噁唑-5-基）苯基）吼啶-2,4-二胺 [化 1381]141666.doc - 323 · 201028381 The title compound was synthesized according to the method of Example 1-355. MS (ESI) m / z = 430 (M + H) +. LC/MS tR = 2.77 min. Example 1-181 6-Ethoxy-5-ethynyl-N2-(4-(oxazol-5-yl)phenyl)acridine-2,4-diamine [Chem. 1381]

步驟1 : 6-氯-2-乙氧基-3-((三曱基矽烷基）乙炔基）吡啶-4-胺 向 6-亂-2-乙乳基-3-埃。比 σ定 _4-胺（200 mg ’ 0.670 minol)、 PdCl2(PPh3)2(23.5 mg，0.033 mmol)、Cul(埃化銅）（12.8 mg，0.067 mmol)及 Et3N(136 mg，0.186 mmol)之 DMF 溶液 中添加三曱基矽烷基乙炔（99 mg，1.01 mmol)，於室溫下 攪拌1小時。向反應溶液中添加水及乙酸乙酯進行分離 後，以乙酸乙酯萃取水相，將合併之有機相以水及飽和食 鹽水進行清洗，以硫酸鎂加以乾燥。將有機相過濾後，進 141666.doc -324· 201028381 行減壓濃縮’利用中壓管柱層析法（矽膠、己烷/乙酸乙酯 50 : 1)對所獲得之殘渣進行純化，獲得標題化合物（117 mg，65%)，為黃色固體。 1H-NMR (400 MHz, DMS〇-d6) δ 0.21 (s, 9H), 1.26 (t, J=6.8 Hz，3H)，4.22 (q，J=6.8 Hz，2H)，6.36 (s，1H)。 MS(ESI)m/z=267 (M+H)+。 LC/MS tR=2_62 min 〇 步驟2〜3 :標題化合物 添加6-氯-2·乙氧基-3-((三甲基矽烷基）乙炔基；)吡啶_4_胺 (50 mg，0.186 mmol)、Pd(〇Ac)2(4.18 mg , 0.019 mmol)、 ΒΙΝΑΡ(17·4 mg，0.028 mmol)、Cs2C03(碳酸铯）（85 mg， 0.260 mmol)及 4-(噁唑-5-基）苯胺（44.7 mg，0.279 mmol)之 二噁烷（1 mL)溶液，於11·(Γ〇下攪拌i〇小時。向反應溶液中 添加水及乙酸乙酯進行分離後，以乙酸乙酯萃取水相，將 合併之有機相以水、1 〇%檸檬酸及飽和食鹽水進行清洗， 以硫酸鎂加以乾燥。將有機相過濾後，進行減壓濃縮，利 用中壓管柱層析法（矽膠、己烷/乙酸乙酯4: 1〜3: i梯度） 對殘渣進行純化。 使獲得之化合物溶解於甲醇（1 mL)中，添加碳酸鉀（16 9 mg，0.122 mmol)，於室溫下攪拌18小時。向反應溶液中 添加水及乙酸乙酯進行分離後’以乙酸乙酯萃取水相，將 合併之有機相以水及飽和食鹽水進行清洗，以硫酸鎂加以 乾燥。將有機相過濾後’進行減壓濃縮，以乙酸乙酯：己 烷=1 . 2使殘渣固化，藉此獲得標題化合物（16 mg， 141666.doc -325- 201028381 18%)，為茶色固體。 1H-NMR (400 MHz, DMSO-d6) δ 1.36 (t, J=6.8 Hz, 3H), 4.36 (q, J=6.8 Hz, 2H), 5.82 (s, 1H), 6.16 (s, 2H), 7.50 (s, 1H), 760 (d, J=8.4 Hz, 2H), 7.69 (d, J=8.4 Hz, 2H), 8.35 (s, 1H), 9.11 (s，1H)。 MS(ESI)m/z=321 (M+H)+。 LC/MS tR=2_42 min。 實施例1-382 6-乙氧基-N2-(4-( n惡°坐-5-基）苯基）-5-(苯基乙快基）°比咬_ 2,4-二胺 [化 1382]Step 1: 6-Chloro-2-ethoxy-3-((tridecyldecyl)ethynyl)pyridin-4-amine To 6-ran-2-ethyllacyl-3- anthracene. Ratio σ 4-amine (200 mg '0.670 minol), PdCl2 (PPh3) 2 (23.5 mg, 0.033 mmol), Cul (copper copper) (12.8 mg, 0.067 mmol) and Et3N (136 mg, 0.186 mmol) Trimethyl decyl acetylene (99 mg, 1.01 mmol) was added to the DMF solution and stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction solution for separation. The aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with water and brine and dried over magnesium sulfate. After the organic phase was filtered, 141666.doc -324·201028381 was concentrated under reduced pressure. The residue obtained was purified by medium pressure column chromatography (gel, hexane/ethyl acetate 50:1). Compound (117 mg, 65%) was obtained as a yellow solid. 1H-NMR (400 MHz, DMS 〇-d6) δ 0.21 (s, 9H), 1.26 (t, J = 6.8 Hz, 3H), 4.22 (q, J = 6.8 Hz, 2H), 6.36 (s, 1H) . MS (ESI) m / z = 266 (M+H)+. LC/MS tR=2_62 min 〇 Steps 2 to 3: the title compound was added 6-chloro-2·ethoxy-3-((trimethyldecyl)ethynyl;)pyridine-4-amine (50 mg, 0.186) Methyl), Pd(〇Ac)2 (4.18 mg, 0.019 mmol), hydrazine (17.4 mg, 0.028 mmol), Cs2C03 (barium carbonate) (85 mg, 0.260 mmol) and 4-(oxazol-5-yl) A solution of aniline (44.7 mg, 0.279 mmol) in dioxane (1 mL) was stirred at EtOAc (EtOAc). The aqueous phase is washed with water, 1% by weight of citric acid and saturated brine, and dried over magnesium sulfate. The organic phase is filtered and concentrated under reduced pressure using medium pressure column chromatography , hexane/ethyl acetate 4: 1~3: i gradient) Purification of the residue. The obtained compound was dissolved in methanol (1 mL), and potassium carbonate (16 9 mg, 0.122 mmol) was added at room temperature After stirring for 18 hours, water and ethyl acetate were added to the reaction solution for separation. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water and saturated brine. The title compound (16 mg, 141666.doc - 325 - 201028381 18%) was obtained after the organic phase was filtered. ), as a tan solid. 1H-NMR (400 MHz, DMSO-d6) δ 1.36 (t, J = 6.8 Hz, 3H), 4.36 (q, J = 6.8 Hz, 2H), 5.82 (s, 1H), 6.16 (s, 2H), 7.50 (s, 1H), 760 (d, J=8.4 Hz, 2H), 7.69 (d, J=8.4 Hz, 2H), 8.35 (s, 1H), 9.11 (s, 1H) MS (ESI) m / z = 321 (M + H) +. LC / MS tR = 2 - 42 min. Example 1-382 6-ethoxy-N2-(4-( n ° ° sit-5-yl Phenyl)-5-(phenylethyl fast radical) ° bite _ 2,4-diamine [化1382]

步驟1 : 6-氣-2-乙氧基-3-(苯基乙炔基）&quot;比啶-4-胺 向 6-氣-2-乙氧基-3-埃1比咬-4-胺（100 mg，0.33 5 mmol)、 PdCl2(PPh3)2(ll-8 mg，0.017 mmol)、Cul(6.4 mg，0.033 mmol)及 Et3N(67.8 mg，0.093 mmol)之 DMF 溶液中添加苯 基乙炔（51 mg，55 μι，0.502 mmol)，於室溫下攪:拌1小 141666.doc -326- 201028381 時。向反應溶液中添加水及乙酸乙酯進行分離後，以乙酸 乙酯萃取水相，將合併之有機相以水及飽和食鹽水進行清 洗’以硫酸鎂加以乾燥。將有機相過濾後，進行減壓濃 縮’利用中壓管柱層析法（矽膠，己烷：乙酸乙酯=5〇 : i &gt; 對所獲得之殘渣進行純化，獲得標題化合物（41 mg， 45%)’為茶色油。 1H-NMR (400 MHz，DMSO-d6) δ 1.31 (t，J=6.8 Hz, 3H)， 4.28 (q, J=6.8 Hz, 2H), 6.39 (s, 1H), 6.63 (s, 2H), 7.37-7.42 ® (m，3H)，7.57 (d, J=6.0 Hz，2H)。 MS(ESI)m/z=273 (M+H)+。 LC/MS tR=2.45 min o 步驟2 :標題化合物 添加6 -氣-2-乙氧基-3-(苯基乙快基）〇比咬-4-胺（5〇 ， 0.183 mmol) ^ Pd(OAc)2(4.12 mg &gt; 0.018 mmol) &gt; BINAP(17.1 mg ’ 0.027 mmol)、Cs2C03(碳酸铯）（84 mg， _ 0.257 mmol)及 4-(°惡0坐-5-基）笨胺（44.0 mg，0.275 mmol)之 二嗔烷（1 mL)溶液，於110°C下攪拌7小時》向反應溶液中 添加水及乙酸乙酯進行分離後，以乙酸乙酯萃取水相，將 合併之有機相以水及飽和食鹽水進行清洗，以硫酸鎮加以 乾燥。將有機相過漶後，進行減壓濃縮，利用中壓管柱層 析法（胺基矽膠，己烷：乙酸乙酯=4 : 對殘潰進行純 化，獲得標題化合物（25 mg，34%)，為茶色固體。 1H-NMR (400 MHz, DMSO-d6) δ 1.38 (t, J=6.8 Hz, 3H), 4.36 (q，J=6.8 Hz，2H)，5.85 (s，1H)，6.09 (s，1H)，7.32-7.40 141666.doc -327- 201028381 (m, 3H), 7.50-7.54 (m, 3H), 7.60 (d, J=8.4 Hz, 2H), 7.71 (d, J=8.4 Hz, 2H)，8.35 (s，1H)，9.05 (s，1H)。 MS(ESI)m/z=397 (M+H)+。 LC/MS tR=2.42 min ° 實施例1-383 (E)-6-乙氧基-N2-(4-(噁唑-5-基）苯基）-5-苯乙烯基比啶-2,4-二胺 [化 1383]Step 1: 6-Gas-2-ethoxy-3-(phenylethynyl)&quot;bipyridin-4-amine to 6-gas-2-ethoxy-3-ang-1 ratio butyl-4-amine Add phenylacetylene (100 mg, 0.33 5 mmol), PdCl2 (PPh3) 2 (ll-8 mg, 0.017 mmol), Cul (6.4 mg, 0.033 mmol) and Et3N (67.8 mg, 0.093 mmol) in DMF 51 mg, 55 μιη, 0.502 mmol), stir at room temperature: mix 1 small 141666.doc -326- 201028381. After water and ethyl acetate were added to the reaction solution for separation, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water and saturated brine. After the organic phase was filtered, the title compound (41 mg, m. m. 45%) 'for brown oil. 1H-NMR (400 MHz, DMSO-d6) δ 1.31 (t, J = 6.8 Hz, 3H), 4.28 (q, J = 6.8 Hz, 2H), 6.39 (s, 1H) , 6.63 (s, 2H), 7.37-7.42 ® (m, 3H), 7.57 (d, J = 6.0 Hz, 2H) MS (ESI) m/z = 273 (M+H) + LC/MS tR =2.45 min o Step 2: Add the title compound to 6-gas-2-ethoxy-3-(phenylethyl)-pyridinium-4-amine (5 〇, 0.183 mmol) ^ Pd(OAc) 2 ( 4.12 mg &gt; 0.018 mmol) &gt; BINAP (17.1 mg '0.027 mmol), Cs2C03 (barium carbonate) (84 mg, _ 0.257 mmol) and 4-(°oxo-5-yl) strepamine (44.0 mg, 0.275 mmol) of dioxane (1 mL) was stirred at 110 ° C for 7 hours. After adding water and ethyl acetate to the reaction mixture, the aqueous phase was extracted with ethyl acetate. Wash the water and saturated brine, and dry it with sulfuric acid. After the organic phase is passed through, concentrate under reduced pressure and use medium pressure tube. Chromatography (Amino phthalocyanine, hexane: EtOAc = EtOAc: EtOAc: EtOAc (EtOAc) 1.38 (t, J=6.8 Hz, 3H), 4.36 (q, J=6.8 Hz, 2H), 5.85 (s, 1H), 6.09 (s, 1H), 7.32-7.40 141666.doc -327- 201028381 (m , 3H), 7.50-7.54 (m, 3H), 7.60 (d, J=8.4 Hz, 2H), 7.71 (d, J=8.4 Hz, 2H), 8.35 (s, 1H), 9.05 (s, 1H) MS (ESI) m / z = 397 (M + H) +. LC / MS tR = 2.42 min ° Example 1-183 (E)-6-ethoxy-N2-(4-(oxazole-5) -yl)phenyl)-5-styrylidine-2,4-diamine [Chemical 1383]

步驟1 : 6-氯-2-乙氧基-3-(苯基乙快基）&lt;»比咬_4-胺 向 6-氣-2-乙氧基-3-碘吡啶 _4_ 胺（200 mg，0.670 mmol)、Step 1: 6-Chloro-2-ethoxy-3-(phenylethyl carbyl) &lt;» than bite 4-amine to 6-gas-2-ethoxy-3-iodopyridine_4_amine ( 200 mg, 0.670 mmol),

Pd2(dba)3(30.7 mg，0.033 mmol)、P(t-Bu)3(13.6 mg， 0.067 mmol)及二環己基甲基胺（262 mg，287 叫，134 mmol)之二鳴烧溶液中添加苯乙烯（1〇5 mg，115 0， mmol) ’於120°C下攪拌6小時。向反應溶液中添加水及乙 酸乙酯進行分離後，以乙酸乙酯萃取水相，將合併之有機 相以水及飽和食鹽水進行清洗，以硫酸鎂加以乾燥。將有 機相過濾後，進行減壓濃縮，利用中壓管柱層析法（矽 141666.doc -328- 201028381 膠’己烧··乙酸乙酯=1 : 1)對所獲得之殘逢進行純化，獲 得標題化合物（13 5 mg，73%)，為黃色固艘。 1H-NMR (400 MHz, DMSO-d6) δ 1.31 (t, J=6.8 Hz, 3H), 4.28 (q, J=6.8 Hz, 2H), 6.39 (s, 1H), 6.63 (s, 2H), 7.37-7.42 (m，3H)，7.57 (d，J=6.0 Hz, 2H)。 MS(ESI)m/z=273 (M+H)+。 LC/MS tR=2.45 min。 步驟2 :標題化合物 ® 標題化合物係使用6-氣-2-乙氧基-3-(苯基乙炔基）吡啶_ 4-胺以及4-(噁唑-5-基）苯胺，依據實施例1-145之方法而合 成（18%)。 1H-NMR (400 MHz, DMSO-d6) δ 1.42 (t, J=6.8 Hz, 3H), 4.39 (q, J=6.8 Hz, 2H), 5.83 (s, 1H), 6.05 (s, 2H), 7.09-7.24 (m, 2H), 7.32 (t J=7.2 Hz, 2H), 7.48 (s, 1H), 7.52-7.59 (m, 4H), 7.72 (d, J=7.2 Hz, 2H), 8.15 (s, 1H), 8.42 (s, 1H), 8.91 (s，1H)。 ’ MS(ESI)m/z=399 (M+H)+。 LC/MS tR=2.48 min。 實施例1-384 (E)-6-乙氧基-N2-(4-(噁唑-5-基）苯基）-5-(2-(°比啶-2-基） 乙烯基）吡啶-2,4-二胺 141666.doc •329- 201028381 [化 1384]Pd2(dba)3 (30.7 mg, 0.033 mmol), P(t-Bu)3 (13.6 mg, 0.067 mmol) and dicyclohexylmethylamine (262 mg, 287, 134 mmol) in a smouldering solution Styrene (1 〇 5 mg, 1150, mmol) was added and stirred at 120 ° C for 6 hours. Water and ethyl acetate were added to the reaction solution for separation, and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with water and brine and dried over magnesium sulfate. After filtering the organic phase, it was concentrated under reduced pressure, and the obtained residue was purified by medium-pressure column chromatography (矽141666.doc -328-201028381, gelatin-hexane ethyl acetate = 1:1). The title compound (13 5 mg, 73%) was obtained as a yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ 1.31 (t, J = 6.8 Hz, 3H), 4.28 (q, J = 6.8 Hz, 2H), 6.39 (s, 1H), 6.63 (s, 2H), 7.37-7.42 (m, 3H), 7.57 (d, J = 6.0 Hz, 2H). MS (ESI) m / z = 273 (M+H)+. LC/MS tR = 2.45 min. Step 2: The title compound was used as the title compound using 6-gas-2-ethoxy-3-(phenylethynyl)pyridine-4-amine and 4-(oxazol-5-yl)aniline according to Example 1. Synthesis (18%) by the method of -145. 1H-NMR (400 MHz, DMSO-d6) δ 1.42 (t, J = 6.8 Hz, 3H), 4.39 (q, J = 6.8 Hz, 2H), 5.83 (s, 1H), 6.05 (s, 2H), 7.09-7.24 (m, 2H), 7.32 (t J=7.2 Hz, 2H), 7.48 (s, 1H), 7.52-7.59 (m, 4H), 7.72 (d, J=7.2 Hz, 2H), 8.15 ( s, 1H), 8.42 (s, 1H), 8.91 (s, 1H). ' MS (ESI) m/z = 399 (M+H)+. LC/MS tR = 2.48 min. Example 1-384 (E)-6-Ethoxy-N2-(4-(oxazol-5-yl)phenyl)-5-(2-(pyridin-2-yl)vinyl)pyridine -2,4-diamine 141666.doc •329- 201028381 [Chemical 1384]

標題化合物係依據實施例1-383之方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 1.42 (t, J=7.2 Hz, 3H), 4.41 (q, J=7.2 Hz, 2H), 5.86 (s, 1H), 6.07 (s, 2H), 7.12-7.14 (m, 1H), 7.25 (d, J=16.8 Hz, 1H), 7.49 (s, 1H), 7.54-7.74 (m, 7H), 8.34 (s, 1H)，8.50 (s，1H), 8.98 (s，1H)。 MS(ESI)m/z=400 (M+H)+。 LC/MS tR=1.27 min。 實施例1-385 (E)-6-乙氧基-N2-(4-(噁唑_5-基）苯基）-5-(2-(。比啶·4-基） 乙烯基）吡啶-2,4-二胺 [化 1385]The title compound was synthesized according to the method of Example 1-383. 1H-NMR (400 MHz, DMSO-d6) δ 1.42 (t, J = 7.2 Hz, 3H), 4.41 (q, J = 7.2 Hz, 2H), 5.86 (s, 1H), 6.07 (s, 2H), 7.12-7.14 (m, 1H), 7.25 (d, J=16.8 Hz, 1H), 7.49 (s, 1H), 7.54-7.74 (m, 7H), 8.34 (s, 1H), 8.50 (s, 1H) , 8.98 (s, 1H). MS (ESI) m / z = 400 (M + H) +. LC/MS tR = 1.27 min. Example 1-85 (E)-6-Ethoxy-N2-(4-(oxazole-5-yl)phenyl)-5-(2-(.pyridin-4-yl)vinyl)pyridine -2,4-diamine [化1385]

標題化合物係依據實施例1-383之方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 1.44 (t, J=6.8 Hz, 3H), 4.40 (q, J=6.8 Hz, 2H), 5.83 (s, 1H), 6.22 (s, 2H), 7.18 (d, J=16.4 Hz, 1H), 7.42 (d, J=16.4 Hz, 1H), 7.49 (s, 2H), 7.59 (d, J=8.4 Hz, 2H), 7.72 (d, J=8.4 Hz, 2H), 8.15 (s, 1H), 8_34 (s, 1H)，8.44 (s，1H), 9.00 (s，1H)。 141666.doc - 330- 201028381 MS(ESI)m/z=400 (M+H)+。 LC/MS tR=1.18 min。 實施例1-386 (E)-6-乙氧基-N2-(4-(噁唑-5-基）苯基）-5-(2-〇b 啶-3-基） 乙烯基）吡啶-2,4-二胺 [化 1386]The title compound was synthesized according to the method of Example 1-383. 1H-NMR (400 MHz, DMSO-d6) δ 1.44 (t, J = 6.8 Hz, 3H), 4.40 (q, J = 6.8 Hz, 2H), 5.83 (s, 1H), 6.22 (s, 2H), 7.18 (d, J=16.4 Hz, 1H), 7.42 (d, J=16.4 Hz, 1H), 7.49 (s, 2H), 7.59 (d, J=8.4 Hz, 2H), 7.72 (d, J=8.4 Hz, 2H), 8.15 (s, 1H), 8_34 (s, 1H), 8.44 (s, 1H), 9.00 (s, 1H). 141666.doc - 330- 201028381 MS (ESI) m/z = 400 (M+H)+. LC/MS tR = 1.18 min. Example 1-86 (E)-6-Ethoxy-N2-(4-(oxazol-5-yl)phenyl)-5-(2-indobyridin-3-yl)vinyl)pyridine- 2,4-diamine [Chemical 1386]

標題化合物係依據實施例1-383之方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 1.44 (t, J=7.2 Hz, 3H), 4.40 (q, J=7.2 Hz, 2H), 5.83 (s, 1H), 6.14 (s, 2H), 7.23 (s, 2H), 7.32-7.36 (m, 1H), 7.49 (s, 1H), 7.59 (d, J=8.8 Hz, 2H), 7.72 (d, J=8.8 Hz, 2H), 7.99 (d, J=8.4 Hz, 1H), 8.15 (s，1H), 8.34 (s, 1H), 8.69 (s, 1H), 8.95 (s, 1H)。 MS(ESI)m/z=400 (M+H)+。 ^ LC/MS tR= 1.30 min o 實施例1-387 6-乙氧基卞2-(4-(噁唑-5-基）苯基）吡啶-2,4-二胺 [化 1387]The title compound was synthesized according to the method of Example 1-383. 1H-NMR (400 MHz, DMSO-d6) δ 1.44 (t, J = 7.2 Hz, 3H), 4.40 (q, J = 7.2 Hz, 2H), 5.83 (s, 1H), 6.14 (s, 2H), 7.23 (s, 2H), 7.32-7.36 (m, 1H), 7.49 (s, 1H), 7.59 (d, J=8.8 Hz, 2H), 7.72 (d, J=8.8 Hz, 2H), 7.99 (d , J = 8.4 Hz, 1H), 8.15 (s, 1H), 8.34 (s, 1H), 8.69 (s, 1H), 8.95 (s, 1H). MS (ESI) m / z = 400 (M + H) +. ^ LC/MS tR = 1.30 min o Example 1-187 6-ethoxyindole 2-(4-(oxazol-5-yl)phenyl)pyridine-2,4-diamine [Chem. 1387]

標題化合物係使用丙烯腈，依據實施例K383之方法而合 141666.doc -331 - 201028381 成，其結果係作為副產物而獲得。 1H-NMR (400 MHz, DMSO-d6) δ 1.30 (t, J=7.2 Hz, 3H), 4.21 (q, J=7.2 Hz, 2H), 5.42 (s, iH), 5.72 (s, 2H), 5.68 (s, 1H), 7.46 (s, 1H), 7.56 (d, J=8.8 Hz, 2H), 7.70 (d, J=8.8The title compound was obtained by the method of Example K383 using acrylonitrile, 141666.doc - 331 - 201028381, and the result was obtained as a by-product. 1H-NMR (400 MHz, DMSO-d6) δ 1.30 (t, J = 7.2 Hz, 3H), 4.21 (q, J = 7.2 Hz, 2H), 5.42 (s, iH), 5.72 (s, 2H), 5.68 (s, 1H), 7.46 (s, 1H), 7.56 (d, J=8.8 Hz, 2H), 7.70 (d, J=8.8

Hz, 2H)，8.16 (s, 1H), 8.32 (s, 1H)，8.75 (s，1H)。 MS(ESI)m/z=297 (M+H)+。 LC/MS tR=0.89 min。 實施例1-388 (E)-3-(4-胺基-2-乙氧基_6-(4-(鳴°坐-5-基）笨基胺基）τι比咬_ 3-基）丙烯酸第三丁酯 [化 1388]Hz, 2H), 8.16 (s, 1H), 8.32 (s, 1H), 8.75 (s, 1H). MS (ESI) m / z = 297 (M+H)+. LC/MS tR = 0.89 min. Example 1-188 (E)-3-(4-Amino-2-ethoxy-6-(4-(Nas-s--5-yl)-phenylamino) τι than bit _ 3-yl) Tert-butyl acrylate [Chemical 1388]

標題化合物係依據實施例1-383之方法而合成。 1H-NMR (400 MHz，DMSO-d6) δ 1.38 (t，J=7.2 Hz, 3H)， 1.47 (s，9H)，4.38 (q，J=7.2 Hz，2H)，5.81 (s，ih)，6.19 (s， 2H), 6.33 (d, J=15.6 Hz, 1H), 7.50 (s, 1H), 7.59-7.71 (m, 5H)，8.35 (s, 1H)，9.10 (s，1H)。 MS(ESI)m/z=423 (M+H)+。 LC/MS tR=2.46 min。 實施例卜389 (E)-3-(4-胺基-2-乙氧基-6-(4-噁唑-5-基）笨基胺基）吼啶_ 3-基）丙烯酸 141666.doc -332- 201028381 [化 1389] νη2 ο H 、 標題化合物係藉由使（E)-3-(4-胺基-2·乙氧基_6_(4_(n惡唑_5_ 基）苯基胺基）吡啶-3-基）丙烯酸第三丁酯溶解於TFA :二氣 曱烷=1 : 1溶液中後，進行減壓濃縮而獲得。 1H-NMR (400 MHz, DMSO-d6) δ 1.40 (t, J=7.2 Hz, 3H), ❿ 4·39 U，】=7.2 Hz，2H)，5.83 (s, 1H)，6.41 (d，j=15.6 Hz, 1H)，7.51 (s，1H)，7.59-7.72 (m，5H)，8.35 (s，1H)，9.10 (s, 1H)。 實施例1-3 90 6·乙乳基-5-硝基-Ν2-(4-(β惡〇坐-5-基）苯基）&gt;»比咬）_2,4_二胺 [化 1390]The title compound was synthesized according to the method of Example 1-383. 1H-NMR (400 MHz, DMSO-d6) δ 1.38 (t, J = 7.2 Hz, 3H), 1.47 (s, 9H), 4.38 (q, J = 7.2 Hz, 2H), 5.81 (s, ih), 6.19 (s, 2H), 6.33 (d, J = 15.6 Hz, 1H), 7.50 (s, 1H), 7.59-7.71 (m, 5H), 8.35 (s, 1H), 9.10 (s, 1H). MS (ESI) m / z = 423 (M+H)+. LC/MS tR = 2.46 min. EXAMPLE 389 (E)-3-(4-Amino-2-ethoxy-6-(4-oxazol-5-yl)phenylamino)pyridin-3-yl)acrylic acid 141666.doc -332- 201028381 [?1389] νη2 ο H , the title compound by (E)-3-(4-amino-2.ethoxy_6_(4_(noxazole-5-yl)phenylamine) The tert-butyl pyridyl-3-yl) acrylate was dissolved in a solution of TFA: dioxane = 1 : 1 and then concentrated under reduced pressure. 1H-NMR (400 MHz, DMSO-d6) δ 1.40 (t, J = 7.2 Hz, 3H), ❿ 4·39 U,] = 7.2 Hz, 2H), 5.83 (s, 1H), 6.41 (d, j =15.6 Hz, 1H), 7.51 (s, 1H), 7.59-7.72 (m, 5H), 8.35 (s, 1H), 9.10 (s, 1H). Example 1-3 90 6 · ethyl lactyl-5-nitro-indole 2-(4-(β oxazeto-5-yl)phenyl)&gt;» than bite) _2,4-diamine [Chemical 1390 ]

步驟1 : 6-氯-2-乙氧基-3-硝基吡啶-4-胺 向 2,6-一 氣-3-硝基 °比淀-4-胺（500 mg’ 2.40 mmol)之乙 醇溶液（1 : 1，20 mL)中添加60%氫化鈉（116 mg，2.8 mmol)，於室溫下撲掉6小時。向反應溶液中添加水及乙酸 乙醋進行分離後，以乙酸乙酯萃取水相，將合併之有機相 以水及飽和食鹽水進行清洗，以硫酸鎂加以乾燥。將有機 相過濾後’進行減壓濃縮，利用中壓管柱層析法（矽膠， 141666.doc -333 · 201028381 己烷：乙酸乙酯=5 : 1)對所獲得之殘渣進行純化，獲得標 題化合物（470 mg，90%) 〇 1H-NMR (400 MHz, DMS〇-d6) δ 1.31 (t, J=6.8 Hz, 3H), 4.35 (q，J=6.8 Hz, 2H)，6.55 (s, 1H), 7.55 (s, 2H)。 MS(ESI)m/z=218 (M+H)+ 〇 LC/MS tR=l_88 min。 步驟2 :標題化合物 標題化合物係使用6 -氣-2-乙氧基-3-硝基α比咬_4_胺以及 4-(噁唑-5-基）苯胺’依據實施例1_145之方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 1.34 (t, J=6.8 Hz, 3H), 4.40 (q, J=6.8 Hz, 2H), 5.86 (s, 1H), 7.30 (d, 2H), 7.31 (s, 2H)，7.55 (s，1H), 7.65 (s，4H)，8.37 (s，1H)，9.45 (s, 1H)。 MS(ESI)m/z=342 (M+H)+ 〇 LC/MS tR=1.85 min o 實施例1-391 6-乙氧基-N2-(3-甲氧基-4-(噁唑-5-基）苯基）_5_硝基吼啶_ 2,4-二胺 [化 1391]Step 1: 6-Chloro-2-ethoxy-3-nitropyridin-4-amine to 2,6-mono--3-nitro-proton-4-amine (500 mg ' 2.40 mmol) in ethanol (1: 1,20 mL) was added 60% sodium hydride (116 mg, 2.8 mmol) and allowed to stand at room temperature for 6 hours. After the water and the acetic acid were added to the reaction solution for separation, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water and brine, and dried over magnesium sulfate. After the organic phase was filtered, the residue was concentrated under reduced pressure, and the residue obtained was purified by medium-pressure column chromatography (yield: 141666.doc-333 · 201028381 hexane: ethyl acetate = 5:1) to obtain the title. Compound (470 mg, 90%) 〇1H-NMR (400 MHz, DMS 〇-d6) δ 1.31 (t, J = 6.8 Hz, 3H), 4.35 (q, J = 6.8 Hz, 2H), 6.55 (s, 1H), 7.55 (s, 2H). MS (ESI) m/z = 218 (M + H) + Step 2: The title compound was used as the title compound using 6-gas-2-ethoxy-3-nitro-alpha ratio _4-amine and 4-(oxazol-5-yl)aniline according to the method of Example 1-145. synthesis. 1H-NMR (400 MHz, DMSO-d6) δ 1.34 (t, J = 6.8 Hz, 3H), 4.40 (q, J = 6.8 Hz, 2H), 5.86 (s, 1H), 7.30 (d, 2H), 7.31 (s, 2H), 7.55 (s, 1H), 7.65 (s, 4H), 8.37 (s, 1H), 9.45 (s, 1H). MS (ESI) m / z = 342 (M + H) + 〇 LC/MS tR = 1.85 min o Example 1-391 6-ethoxy-N2-(3-methoxy-4-(oxazole) 5-yl)phenyl)_5_nitroacridine_ 2,4-diamine [Chemical 1391]

標題化合物係使用3-甲氧基-4-(噁唑-5-基）苯胺，依據實施 例1-390之方法而合成。 1H-NMR (400 MHz，DMSO-d6) δ 1·35 (t，J=6.8 Hz，3H)， 141666.doc -334- 201028381 3.04 (s, 3H), 4.45 (q, J=6.8 Hz, 2H), 5.90 (s, 1H), 7.20 (d, J=8.4 Hz, 1H), 7.31 (s, 2H), 7.41 (s, 1H), 7.53 (s, 1H), 7.61 (d，J=8.4 Hz，1H)，8.35 (s，1H), 9.48 (s，1H)。 MS(ESI)m/z=372 (M+H)+。 LC/MS tR=1.92 min。 實施例1-392 2-乙氧基-6-(4-(噁唑-5-基）苯基胺基）-3-三氟甲基吡啶-4-基胺基甲酸第三丁酯 ® [化 1392] Ο Ο 〇The title compound was synthesized according to the procedure of Example 1-190 using 3-methoxy-4-(oxazol-5-yl)aniline. 1H-NMR (400 MHz, DMSO-d6) δ 1·35 (t, J = 6.8 Hz, 3H), 141666.doc -334 - 201028381 3.04 (s, 3H), 4.45 (q, J = 6.8 Hz, 2H ), 5.90 (s, 1H), 7.20 (d, J=8.4 Hz, 1H), 7.31 (s, 2H), 7.41 (s, 1H), 7.53 (s, 1H), 7.61 (d, J=8.4 Hz , 1H), 8.35 (s, 1H), 9.48 (s, 1H). MS (ESI) m / z = 372 (M+H)+. LC/MS tR = 1.92 min. Example 1-392 2-Ethoxy-6-(4-(oxazol-5-yl)phenylamino)-3-trifluoromethylpyridin-4-ylaminocarbamic acid tert-butyl ester® [ 139 ] Ο 〇

步驟1 . 6 -氣-2-乙氧基-3 -磁ntL。定-4 -基胺基曱酸第二丁酉旨 向6-氣-2-乙氧基-3-破11比咬-4-胺（500 mg，1.68 mmol)及 Boc2〇(377 mg，1·73 mmol)之 THF 溶液（2 mL)中於 0°C 下添 加 1.0 mol/L之 LHMDS THF溶液（3.68 mL，3·68 mmol)，擾 拌2小時後，進而於室溫下攪拌1.5小時。向反應溶液中添 加水及乙酸乙酯進行分離後，以乙酸乙酯萃取水相，將合 併之有機相以水及飽和食鹽水進行清洗，以硫酸鎂加以乾 燥。將有機相過濾後，進行減壓濃縮，利用中壓管柱層析 141666.doc -335- 201028381 法（矽膠，己烷：乙酸乙酯=20 : 1)對所獲得之殘渣進行純 化’獲得標題化合物（576 mg，1.45 mmo卜86%)，為黃色 固體。 1H-NMR (400 MHz, DMSO-d6) δ 1.19 (t, J=7.2 Hz, 3H), 1.35 (s, 9H), 4.16 (q, J=7.2 Hz, 2H), 7.34 (s, 1H), 7.90 (s, 1H)。 MS(ESI)m/z=399 (M+H)+。 LC/MS tR=3.06 min。 步驟2 : 6-氣-2-乙氧基-3-三氟曱基n比咬_4_基碳酸第三 丁酯 向6-氣·2-乙氧基-3-碘吡啶-4-基胺基曱酸第三丁酯（217 mg，0.544 mmol)及2,2-二氟_2_氟磺醯基乙酸甲酯（366 mg ’ 241 吣，1.91 mmol)之DMF溶液（2 mL)中添加 CuI(U4 mg，0.S99 mm〇l)’於70t：下攪拌5小時。向反應溶液中添 加水及乙酸乙酯進行分離後，以乙酸乙酯萃取水相，將合 併之有機相以水及飽和食鹽水進行清洗，以硫酸鎂加以乾 燥。將有機相過濾後，進行減壓濃縮，利用中壓管柱層析 法（石夕膠’己院：乙酸乙S旨=1G : υ對所獲得之殘潰進行純 化，獲得標題化合物（141 mg，0.414職〇1，76%)，為白 色固體》 m-NMR (40〇 MHz，DMS〇_d6) δ i 3i (t，j=7 2 Hz，扭), 1.46 (s, 9H), 4.40 (q, J=7.2 Hz, 2H), 7.29 (s, 1H), 9.39 (Sj 步驟3 ·標題化合物 141666.doc 336· 201028381 於5 mL微波反應容器中，添加6-氣-2-乙氧基-3-三氟曱 基。比π定-4-基碳酸第三丁 S旨（140 mg，0.411 mmol)、 Pd(OAc)2(9.22 mg，0·041 mmol)、BINAP(38.4 mg，0.062 mmol)、Cs2C〇3(碳酸絶）（187 mg，0.575 mmol)及 4-(〇惡0坐-5-基）苯胺（99 mg，0.616 mmol)之二°惡烧溶液，進行覆 蓋，使用Biotage Optimizer反應裝置，於120°C下授拌30分 鐘。向反應溶液中添加水及乙酸乙酯進行分離後，以乙酸 乙酯萃取水相，將合併之有機相以水及飽和食鹽水進行清 © 洗，以硫酸鎂加以乾燥。將有機相過濾後，進行減壓濃 縮，利用中壓管柱層析法（矽膠，己烷：乙酸乙酯=10 : 1) 對所獲得之殘渣進行純化，獲得標題化合物（24 mg，0.052 mmol，13%)，為白色固體。 1H-NMR (400 MHz, DMSO-d6) δ 1.35 (t, J=7.2 Hz, 3H), 1.47 (s, 9H), 4.42 (q, J=7.2 Hz, 2H), 6.73 (s, 1H), 7.55 (d, 1H), 7.67 (d, J=8.4 Hz, 2H), 7.76 (d, J=8.4 Hz, 2H), 8.38 (s，1H)，8_75 (s，1H), 9.70 (s, 1H)。 ’ MS(ESI)m/z=465 (M+H)+。 LC/MS tR=2.85 min。 實施例1-393 6-乙氧基-N2-(4-(噁唑-5-基）苯基）-5-(三氟苯基）。比啶-2,4- 二胺 [化 1393]Step 1. 6 -Gas-2-ethoxy-3 - Magnetic ntL. 4-Bistyl decanoic acid dibutyl hydrazine intended to 6-gas-2-ethoxy-3-deuterium 11 butyl-4-amine (500 mg, 1.68 mmol) and Boc2 〇 (377 mg, 1· A solution of 1.0 mmol/L of LHMDS in THF (3.68 mL, 3.68 mmol) was added to a solution of EtOAc (2 mL), and then stirred at room temperature for 1.5 hr. Water and ethyl acetate were added to the reaction solution for separation, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and brine and dried over magnesium sulfate. The organic phase was filtered, and concentrated under reduced pressure. The obtained residue was purified by medium-pressure column chromatography 141666. doc - 335 - 201028 381 ( hexane, hexane: ethyl acetate = 20: 1). Compound (576 mg, 1.45 mmo, 86%) as a yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ 1.19 (t, J = 7.2 Hz, 3H), 1.35 (s, 9H), 4.16 (q, J = 7.2 Hz, 2H), 7.34 (s, 1H), 7.90 (s, 1H). MS (ESI) m/z = 399 (M+H)+. LC/MS tR = 3.06 min. Step 2: 6-Gas-2-ethoxy-3-trifluorodecyl n to 6-gas·2-ethoxy-3-iodopyridin-4-yl a solution of tert-butyl amide (217 mg, 0.544 mmol) and methyl 2,2-difluoro-2-fluorosulfonate (366 mg '241 吣, 1.91 mmol) in DMF (2 mL) CuI (U4 mg, 0.S99 mm〇l)' was added and stirred at 70 t: for 5 hours. Water and ethyl acetate were added to the reaction solution for separation, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and brine and dried over magnesium sulfate. The organic phase was filtered, and concentrated under reduced pressure. The title compound (141 mg) was obtained from the residue obtained by the medium pressure column chromatography method (Shixijia's Institute: acetic acid B S = 1G: υ). , 0.414, 1,76%), as a white solid, m-NMR (40〇MHz, DMS〇_d6) δ i 3i (t, j=7 2 Hz, twist), 1.46 (s, 9H), 4.40 (q, J=7.2 Hz, 2H), 7.29 (s, 1H), 9.39 (Sj Step 3 • Title Compound 141666.doc 336· 201028381 Add 6-Gas-2-Ethoxy in a 5 mL Microwave Reaction Vessel -3-trifluoroindolyl group. π-but-4-yl carbonate tert-butylate (140 mg, 0.411 mmol), Pd(OAc) 2 (9.22 mg, 0·041 mmol), BINAP (38.4 mg, 0.062 Methane), Cs2C〇3 (carbonate) (187 mg, 0.575 mmol) and 4-(oxo 0--5-yl) aniline (99 mg, 0.616 mmol) in hexane solution, covered with Biotage The Optimizer reaction apparatus was stirred at 120 ° C for 30 minutes. After adding water and ethyl acetate to the reaction solution for separation, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water and saturated brine. Wash and dry with magnesium sulfate. Organic After filtration, the residue was purified under EtOAcqqqqqlililililililililili , as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 1.35 (t, J = 7.2 Hz, 3H), 1.47 (s, 9H), 4.42 (q, J = 7.2 Hz, 2H), 6.73 (s, 1H), 7.55 (d, 1H), 7.67 (d, J=8.4 Hz, 2H), 7.76 (d, J=8.4 Hz, 2H), 8.38 (s,1H),8_75 (s,1H) , </ RTI> <RTIgt; Oxazol-5-yl)phenyl)-5-(trifluorophenyl).pyridin-2,4-diamine [Chemical 1393]

141666.doc -337- 201028381 向2_乙氧基-6-(4-(噁唑-5-基）苯基胺基）_3_三氟甲基0比 咬-4-基胺基甲酸第三丁酯（17 mg，〇 op mm〇1)中添加 TFA :二氣甲烷=1 : 1溶液，於室溫下攪拌i小時。對反應 溶液進行減壓濃縮，以己烧：乙酸乙酯=2〇 : 1使所獲得之 殘座固化’藉此獲得標題化合物（6.7 mg，0.018 mmol， 50%)，為桃色固體。 1H-NMR (400 MHz，DMSO-d6) δ 1.30 (t, J=6.9 Hz，3H)， 4.32 (q, J=6.9 Hz, 2H), 5.79 (s, 1H), 6.14 (s, 2H), 7.51 (s, 1H), 7.51-7.67 (m, 4H), 8.35 (s, 1H), 9.10 (s, 1H) ° MS(ESI)m/z=365 (M+H)+。 LC/MS tR=2.20 min 〇 實施例1-394 5-氣-6-乙氧基_]^2-(4-(噁唑-5-基）苯基）吡啶-2,4-二胺 [化 1394]141666.doc -337- 201028381 to 2_ethoxy-6-(4-(oxazol-5-yl)phenylamino)_3_trifluoromethyl 0-biti-4-ylaminocarboxylic acid To the butyl ester (17 mg, 〇op mm〇1) was added TFA: di-methane methane = 1 : 1 solution, and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure. EtOAc (EtOAc: EtOAc) 1H-NMR (400 MHz, DMSO-d6) δ 1.30 (t, J = 6.9 Hz, 3H), 4.32 (q, J = 6.9 Hz, 2H), 5.79 (s, 1H), 6.14 (s, 2H), 7.51 (s, 1H), 7.51-7.67 (m, 4H), 8.35 (s, 1H), 9.10 (s, 1H) ° MS (ESI) m/z = 365 (M+H)+. LC/MS tR=2.20 min 〇 Example 1-194 5-Ga-6-ethoxy-]^2-(4-(oxazol-5-yl)phenyl)pyridine-2,4-diamine [ 1394]

步驟1 : 3,6-二氯-2-乙氧基吡啶-4-胺 向 2-氣-6-乙氧基 〇 比。定_4_ 胺（400 mg，2.32 mmol)之 DMF 溶液（10 mL)中添加N-氣丁二醯亞胺（340 mg，340 mmol) ’ 於室溫下攪拌一整夜。向反應溶液中添加水及乙酸乙酯進 行分離後’以乙酸乙酯萃取水相，將合併之有機相以水及 飽和食鹽水進行清洗，以硫酸鎂加以乾燥。將有機相過濾 後’進行減壓濃縮。利用中壓矽膠層析法（己烷：乙酸乙 141666.doc - 338 - 201028381 醋=10 ·· 1)對所獲得之殘渣進行純化，獲得標題化合物 (367 mg ’ 1.77 mmol，61%)，為白色固體。 1H-NMR (300 MHz, DMSO-d6) δ 1.30 (t, J=7.2 Hz, 3H), 4.27 (q，J=7.2 Hz，2H)，6.43 (s，1H)，6.57 (s，2H)。 MS(ESI)m/z=207 (M+H)+ ° LC/MS tR=2.00 min。 步驟2 ·標題化合物 標題化合物係使用3,6-二氣-2-乙氧基η比唆-4-胺（200 ® mg，〇.966 mmol)及4·(噁唑-5-基）笨胺，依據實施例ι_145 之方法而合成（34mg，11%)。 1H-NMR (400 MHz, DMSO-d6) δ 1.35 (t, J=7.2 Hz, 3H), 4.33 (q, J=7.2 Hz, 2H), 5.90 (s, 1H), 6.02 (s, 2H), 7.48 (s, 1H), 7.58 (d, J=8.8 Hz, 2H), 7.67 (d, J=8.8 Hz, 2H), 8.33 (s, 1H)，8.89 (s, 1H)。 MS(ESI)m/z=331 (M+H)+。 LC/MS tR=2.05 min。 ® 實施例1-395 5·氣-6-乙氧基-N -(3 -甲乳基-4-(噪π坐_5 -基）苯基）°比咬· 2,4-二胺 [化 1395]Step 1: 3,6-Dichloro-2-ethoxypyridin-4-amine to 2- gas-6-ethoxy oxime. N-gas dimethylimine (340 mg, 340 mmol) was added to a solution of _4_amine (400 mg, 2.32 mmol) in DMF (10 mL) and stirred at room temperature overnight. After water and ethyl acetate were added to the reaction solution for separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and brine, and dried over magnesium sulfate. The organic phase was filtered and concentrated under reduced pressure. The residue obtained was purified by EtOAc (EtOAc: EtOAc: EtOAc EtOAc EtOAc EtOAc White solid. 1H-NMR (300 MHz, DMSO-d6) δ 1.30 (t, J = 7.2 Hz, 3H), 4.27 (q, J = 7.2 Hz, 2H), 6.43 (s, 1H), 6.57 (s, 2H). MS (ESI) m/z = 207 (MH) Step 2 · Title compound The title compound is 3,6-dioxa-2-ethoxy η than 唆-4-amine (200 ® mg, 966.966 mmol) and 4 · (oxazol-5-yl) The amine was synthesized according to the method of Example ι 145 (34 mg, 11%). 1H-NMR (400 MHz, DMSO-d6) δ 1.35 (t, J = 7.2 Hz, 3H), 4.33 (q, J = 7.2 Hz, 2H), 5.90 (s, 1H), 6.02 (s, 2H), 7.48 (s, 1H), 7.58 (d, J=8.8 Hz, 2H), 7.67 (d, J=8.8 Hz, 2H), 8.33 (s, 1H), 8.89 (s, 1H). MS (ESI) m / z = 331 (M+H)+. LC/MS tR = 2.05 min. ® Example 1-395 5. Gas-6-ethoxy-N-(3-methyllacyl-4-(noise π sitting-5-yl)phenyl) ° bite · 2,4-diamine [ 1395]

標題化合物係使用3,6·二氣-2-乙氧基吡啶_4_胺以及3-甲氧 141666.doc -339- 201028381 基-4-(噁唑-5-基）苯胺，依據實施例1-145之方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 1.34 (t, J=7.2 Hz, 3H), 3.92 (s, 3H), 4.38 (q, J=7.2 Hz, 2H), 5.92 (s, 1H), 6.05 (s, 2H), 7.13 (d, J=8.4 Hz, 1H), 7.35 (s, 1H), 7.54 (d, J=8.4 Hz, 1H)，7.76 (s，1H), 8.31 (s, 1H)，8.95 (s，1H)。 MS(ESI)m/z=361 (M+H)+。 LC/MS tR=2.09 min o 實施例1-396 4-(4-胺基-5-氣-6-乙氧基°比啶-2-基胺基）-2-甲氧基苯甲 酸甲酯 [化 1396]The title compound is 3,6·dioxa-2-ethoxypyridine-4-amine and 3-methoxy 141666.doc-339-201028381 -4-(oxazol-5-yl)aniline, according to the examples Synthesized by the method of 1-145. 1H-NMR (400 MHz, DMSO-d6) δ 1.34 (t, J = 7.2 Hz, 3H), 3.92 (s, 3H), 4.38 (q, J = 7.2 Hz, 2H), 5.92 (s, 1H), 6.05 (s, 2H), 7.13 (d, J=8.4 Hz, 1H), 7.35 (s, 1H), 7.54 (d, J=8.4 Hz, 1H), 7.76 (s,1H), 8.31 (s, 1H) ), 8.95 (s, 1H). MS (ESI) m / z = 361 (M + H) +. LC/MS tR=2.09 min o Example 1-196 4-(4-Amino-5-gas-6-ethoxy~pyridin-2-ylamino)methyl-2-methoxybenzoate [化1396]

標題化合物係使用3,6-二氣-2-乙氧基吡啶-4-胺以及對應之 苯胺衍生物，依據實施例1-145之方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 1.33 (t, J=6.8 Hz, 3H), 3.71 (s, 3H), 3.79 (s, 3H), 4.36 (q, J=6.8 Hz, 2H), 5.94 (s, 1H), 6.10 (s, 2H), 7.06 (d, J=9.2 Hz, 1H), 7.54 (s, 1H), 7.63 (d, J=9.2 Hz, 1H)，9.12 (s, 1H)。 MS(ESI)m/z=352 (M+H)+。 LC/MS tR=l.95 min o 實施例1-397 6-乙氧基-5-氟-N2-(4-(噁唑-5-基）苯基）吡啶_2,4-二胺 141666.doc • 340· 201028381 實施例1-398 6-乙氧基-3-氟-&gt;^2-(4-(噁唑-5-基）苯基）。比啶-2,4-二胺 [化 1397] /Γ〇The title compound was synthesized according to the method of Example 1-145 using 3,6-dis- 2 - oxypyridin-4-amine and the corresponding aniline derivative. 1H-NMR (400 MHz, DMSO-d6) δ 1.33 (t, J = 6.8 Hz, 3H), 3.71 (s, 3H), 3.79 (s, 3H), 4.36 (q, J = 6.8 Hz, 2H), 5.94 (s, 1H), 6.10 (s, 2H), 7.06 (d, J=9.2 Hz, 1H), 7.54 (s, 1H), 7.63 (d, J=9.2 Hz, 1H), 9.12 (s, 1H) ). MS (ESI) m / z = 352 (M + H) +. LC/MS tR = 1.95 min o Example 1-197 6-ethoxy-5-fluoro-N2-(4-(oxazol-5-yl)phenyl)pyridine 2,4-diamine 141666 .doc • 340· 201028381 Examples 1-398 6-Ethoxy-3-fluoro-&gt;^2-(4-(oxazol-5-yl)phenyl). Bisidine-2,4-diamine [Chemical 1397] /Γ〇

νη2Ηη2

二噁烷，120°CDioxane, 120 ° C

Pd(OAc)2, BINAP CS2CO3 參 froPd(OAc)2, BINAP CS2CO3 cf fro

步驟1 . 6 -乳-2-乙氧基-3 -氣D比咬-4 -胺以及2 -氯-6-乙氧 基-3-氟吡啶-4-胺之混合物 向2-氯-6-乙氧基η比咬-4-胺（400 mg，2.32 mmol)之 DMF ：乙腈溶液（1 : 1，10 mL)中添加 Selectfluor(R)(985 mg，2.78 mmol)，於室溫下擾拌一整夜。向反應溶液中添 加水及乙酸乙酯進行分離後，以乙酸乙酯萃取水相，將合 併之有機相以水及飽和食鹽水進行清洗，以硫酸鎂加以乾 燥。將有機相過濾後，進行減壓濃縮。利用中壓矽膠層析 法（己烷：乙酸乙酯=20 : 1)對所獲得之殘渣進行純化，獲 得標題化合物（117 mg，0.614 mmol，27%)之混合物，為 黃色油。 MS(ESI)m/z=191 (M+H).。 LC/MS tR=1.75 / 1.82 min。 步驟2 :標題化合物 141666.doc •341- 201028381 於5 mL微波反應容器中，添加6_氯_2·乙氡基_3_氟吡啶· 4-胺以及2-氣-6-乙氧基_3·氟吡啶·4-胺之混合物（117 mg， 0.614 mmol)、Pd(〇Ac)2(13.8 mg，0.061 mmol)、 BINAP(57.3 mg ’ 0.092 mmol)、Cs2C03(碳酸铯）（280 mg， 0.859 mmol)及 4-(n惡 e坐 _5_ 基）苯胺（147 mg，0.921 mmol)之 二°惡烧溶液’進行覆蓋，使用Biotage Optimizer反應裝 置’於120C下授拌30分鐘。向反應溶液中添加水及乙酸 乙酯進行分離後’以乙酸乙酯萃取水相，將合併之有機相 以水及飽和食鹽水進行清洗，以硫酸鎂加以乾燥。將有機© 相過濾後’進行減壓濃縮，利用逆相等分試樣液相層析法 (C18管柱’水/乙腈/〇·ι%甲酸梯度）對所獲得之殘渣進行純 化’分別獲得6·乙氧基-5-氟-N2-(4-(噁唑·5·基）苯基）吡啶_ 2,4-二胺（8.1 mg ’ 〇·〇26 mmol ’ 4%，黃色固體）以及 6_ 乙氧 基-3-氟-N2-(4-(噁唑-5-基）苯基）》比啶 _2,4-二胺（19.4 mg， 0.062 mmol &gt; 10%，橙色固體）。 6-乙氧基-5-氟-N2-(4-(噁唑-5-基）笨基）吡啶·2,4·二胺之 物性資料； Θ 1H-NMR (400 MHz, DMSO-d6) δ 1.34 (t, J=6.8 Hz, 3H), 4.32 (q, J=6.8 Hz, 2H), 5.83 (d, J=4.8 Hz, 1H), 5.99 (s, 2H), 7.46 (s, 1H), 7.56 (d, J=8.8 Hz, 2H), 7.64 (d, J=8.8 Hz, 2H)，8.32 (s, 1H), 8.77 (s, 1H)。 MS(ESI)m/z=315 (M+H)+。 LC/MS tR=1.82 min。 6-乙氧基-3-氟-Ν2·(4-(噁唑-5-基）笨基）吡啶_2,4_二胺之 141666.doc 342- 201028381 物性資料； 1H-NMR (400 MHz, DMSO-d6) δ 1.28 (t, J=6.8 Hz, 3H), 4.16 (q, J=6.8 Hz, 2H), 5.59 (d, J=3.2 Hz, 1H), 5.91 (s, 2H), 7.49 (s, 1H), 7.58 (d, J=8.8 Hz, 2H), 7.79(d,J=8.8 Hz，2H), 8.34 (s，1H), 8.56 (s，1H)。 MS(ESI)m/z=315 (M+H)+。 LC/MS tR=1.78 min o 實施例1-399 2-乙氧基-6-(4-(°惡e坐-5-基）苯基胺基）於驗猜 [化 1399]Step 1. 6 - a mixture of lacto-2-ethoxy-3- gas D to bite 4-amine and 2-chloro-6-ethoxy-3-fluoropyridin-4-amine to 2-chloro-6 -Ethoxy η was added to the DMF:400 mg, 2.32 mmol of DMF: acetonitrile solution (1:1,10 mL) with the addition of Selectfluor(R) (985 mg, 2.78 mmol) at room temperature Mix all night. Water and ethyl acetate were added to the reaction solution for separation, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and brine and dried over magnesium sulfate. After the organic phase was filtered, it was concentrated under reduced pressure. The residue obtained was purified by EtOAc EtOAc (EtOAc:EtOAc) MS (ESI) m / z = 191 (M+H). LC/MS tR = 1.75 / 1.82 min. Step 2: Title Compound 141666.doc • 341- 201028381 In a 5 mL microwave reaction vessel, add 6-chloro-2·ethinyl_3_fluoropyridine·4-amine and 2-gas-6-ethoxy_ 3. A mixture of fluoropyridine·4-amine (117 mg, 0.614 mmol), Pd(〇Ac) 2 (13.8 mg, 0.061 mmol), BINAP (57.3 mg '0.092 mmol), Cs2C03 (barium carbonate) (280 mg, 0.859 mmol) and 4-(n-e-e-sodium _5-yl) aniline (147 mg, 0.921 mmol) in hexanes solution were overlaid and mixed using a Biotage Optimizer reaction apparatus at 120 C for 30 minutes. Water and ethyl acetate were added to the reaction solution for separation. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and brine, and dried over magnesium sulfate. After the organic phase was filtered, 'concentrated under reduced pressure, and the obtained residue was purified by reverse phase equal liquid chromatography (C18 column 'water/acetonitrile/〇·ι% formic acid gradient'). Ethoxy-5-fluoro-N2-(4-(oxazole·5·yl)phenyl)pyridine 2,4-diamine (8.1 mg '〇·〇26 mmol ' 4%, yellow solid) and 6_Ethoxy-3-fluoro-N2-(4-(oxazol-5-yl)phenyl)"pyridin-2,4-diamine (19.4 mg, 0.062 mmol &gt; 10%, orange solid). Physical properties of 6-ethoxy-5-fluoro-N2-(4-(oxazol-5-yl)phenyl)pyridine 2,4·diamine; Θ 1H-NMR (400 MHz, DMSO-d6) δ 1.34 (t, J=6.8 Hz, 3H), 4.32 (q, J=6.8 Hz, 2H), 5.83 (d, J=4.8 Hz, 1H), 5.99 (s, 2H), 7.46 (s, 1H) , 7.56 (d, J = 8.8 Hz, 2H), 7.64 (d, J = 8.8 Hz, 2H), 8.32 (s, 1H), 8.77 (s, 1H). MS (ESI) m / z = 315 (M + H) +. LC/MS tR = 1.82 min. 6-ethoxy-3-fluoro-indole 2·(4-(oxazol-5-yl)phenyl)pyridine 2,4-diamine 141666.doc 342- 201028381 Physical data; 1H-NMR (400 MHz δ δ δ δ δ δ δ (s, 1H), 7.58 (d, J = 8.8 Hz, 2H), 7.79 (d, J = 8.8 Hz, 2H), 8.34 (s, 1H), 8.56 (s, 1H). MS (ESI) m / z = 315 (M + H) +. LC/MS tR=1.78 min o Example 1-139 2-Ethoxy-6-(4-(°(e)-yl-5-yl)phenylamino) was tested [Chem. 1399]

於5 mL微波反應容器中，添加三氟甲磺酸5-氰基-6-乙氧 基°比咬-2-基 S旨（H. Zhao et al·, J. Med· Chem. 2006，49 (15)， 4455-4458 ; US 20060173050 A1， 實施例 154A)(l〇〇 ⑩ mg，0.33 8 mmol)、DIEA(65.1 mg，0.504 mmol)及苯胺（8 1 mg，0.506 mmol)之NMP(1.5 mL)溶液，進行覆蓋，使用 Biotage Optimizer反應裝置，於150°C下攪拌30分鐘。向反 應溶液中添加水及乙酸乙酯進行分離後，以乙酸乙酯萃取 水相，將合併之有機相以水及飽和食鹽水進行清洗，以硫 酸鎂加以乾燥。將有機相過濾後，進行減壓濃縮，利用中 壓矽膠層析法（己烷/乙酸乙酯；10-70%梯度）對所獲得之殘 渣進行純化，獲得標題化合物（53 mg，0.173 mmol， 141666.doc -343- 201028381 51%)，為固體。 1H-NMR (400 MHz, DMSO-d6) δ 1.37 (t, J=7.1 Hz, 3H), 4.44 (q, J=7.1 Hz, 2H), 6.47 (d, J=8.6 Hz, 1H), 7.56 (s, 1H), 7.68 (d, J=8.6 Hz, 1H), 7.77 (d, J=8.6 Hz, 1H), 7.82 (d, J=8.6 Hz，1H)，8.37 (s, 1H)，9.95 (s，1H)。 MS(ESI)m/z=307 (M+H)+。 LC/MS tR=1.98 min o 實施例1-400 2 -乙氧基- 6- (4 -°比。定-4-基）苯基胺基）終驗·猜 [化 1400]In a 5 mL microwave reaction vessel, 5-cyano-6-ethoxyl trifluoromethanesulfonate was added to the ratio of chito-2-yl (H. Zhao et al., J. Med. Chem. 2006, 49). (15), 4455-4458; US 20060173050 A1, Example 154A) (10 mg, 0.33 8 mmol), DIEA (65.1 mg, 0.504 mmol) and aniline (8 1 mg, 0.506 mmol) of NMP (1.5 The mL) solution was covered and stirred at 150 ° C for 30 minutes using a Biotage Optimizer reaction apparatus. Water and ethyl acetate were added to the reaction solution for separation, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and brine, and dried over magnesium sulfate. After the organic phase was filtered, EtOAcjjjjjjjjjjjj 141666.doc -343- 201028381 51%), as solid. 1H-NMR (400 MHz, DMSO-d6) δ 1.37 (t, J = 7.1 Hz, 3H), 4.44 (q, J = 7.1 Hz, 2H), 6.47 (d, J = 8.6 Hz, 1H), 7.56 ( s, 1H), 7.68 (d, J=8.6 Hz, 1H), 7.77 (d, J=8.6 Hz, 1H), 7.82 (d, J=8.6 Hz, 1H), 8.37 (s, 1H), 9.95 ( s, 1H). MS (ESI) m / z = 307 (M + H) +. LC/MS tR=1.98 min o Example 1-400 2-Ethoxy-6-(4-fluoropyrene-4-yl)phenylamine) Final test·guess [Chem. 1400]

Pd(QAc)2, BINAP CS2CO3 二噁烷，120°CPd(QAc)2, BINAP CS2CO3 dioxane, 120°C

於5 mL微波反應容器中，添加三氟甲磺酸5-氰基-6-乙氧 基0比0定-2-基酿（200 mg，0.675 mmol)、Pd(OAc)2(15.2 mg，0.068 mmol)、ΒΙΝΑΡ(63·1 mg * 0.101 mmol)、 Cs2C03(碳酸铯）(308 mg，0.945 mmol)及 4-(吡啶-4-基）苯 胺（13 8 mg，0.810 mmol)之二噁烷（2 mL)溶液’進行覆 蓋，使用Biotage Optimizer反應裝置，於120°C下擾拌1小 時。向反應溶液中添加水及乙酸乙酯進行分離後，以乙酸 乙酯萃取水相，將合併之有機相以水及飽和食鹽水進行清 洗，以硫酸鎂加以乾燥。將有機相過濾後’進行減壓濃 縮，以乙酸乙酯使所獲得之殘渣固化’藉此獲得標題化合 物（50 mg，23%)，為黃色固體。 141666.doc -344- 201028381 1H-NMR (400 MHz, DMSO-d6) δ 1.40 (d, J=7.2 Hz, 3H), 4.47 (q, J=7.2 Hz, 2H), 6.52 (d, J=8.8 Hz, 1H), 7.70 (d, J=5.6 Hz，2H)，7.83 (s，5H), 8.60 (d, J=5.6 Hz，2H)。 MS(ESI)m/z=317 (M+H)+。 LC/MS tR=1.14 min。 實施例l-4〇l 2-乙氧基-6-(3-甲氧基-4-(噁唑-5-基）苯基胺基）菸鹼腈 [化 1401]Add 5 - cyano-6-ethoxy 0-butan-2-yl trifluoromethanesulfonate (200 mg, 0.675 mmol) and Pd(OAc) 2 (15.2 mg, in a 5 mL microwave reaction vessel. 0.068 mmol), hydrazine (63.1 mg * 0.101 mmol), Cs2C03 (barium carbonate) (308 mg, 0.945 mmol) and 4-(pyridin-4-yl)aniline (13 8 mg, 0.810 mmol) of dioxane (2 mL) solution was overlaid and scrambled at 120 °C for 1 hour using a Biotage Optimizer reaction apparatus. Water and ethyl acetate were added to the reaction solution for separation, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and brine, and dried over magnesium sulfate. After the organic phase was filtered, the title compound was obtained (yield: EtOAc) 141666.doc -344- 201028381 1H-NMR (400 MHz, DMSO-d6) δ 1.40 (d, J = 7.2 Hz, 3H), 4.47 (q, J = 7.2 Hz, 2H), 6.52 (d, J = 8.8 Hz, 1H), 7.70 (d, J=5.6 Hz, 2H), 7.83 (s, 5H), 8.60 (d, J = 5.6 Hz, 2H). MS (ESI) m / z = 317 (M+H)+. LC/MS tR = 1.14 min. Example l-4〇1-Ethoxy-6-(3-methoxy-4-(oxazol-5-yl)phenylamino)nicotinonitrile [Chem. 1401]

標題化合物係使用三氟甲磺酸5-氰基-6-乙氧基°比啶-2-基 酯以及對應之苯胺衍生物，依據實施例1 -399之方法而合 成。 1H-NMR (400 MHz, DMSO-d6) δ 1.36 (t, J=7.1 Hz, 3H), 3.82 (s, 3H), 4.47 (q, J-7.1 Hz, 2H), 6.52 (d, J=8.6 Hz, ❹ 1H)，7.20 (d, J=8.6 Hz, 1H)，7.58 (s, 1H)，7.70 (d，J=8.3The title compound was synthesized according to the method of Example 1-399 using 5-cyano-6-ethoxyl-pyridin-2-yl trifluoromethanesulfonate and the corresponding aniline derivative. 1H-NMR (400 MHz, DMSO-d6) δ 1.36 (t, J = 7.1 Hz, 3H), 3.82 (s, 3H), 4.47 (q, J-7.1 Hz, 2H), 6.52 (d, J=8.6 Hz, ❹ 1H), 7.20 (d, J=8.6 Hz, 1H), 7.58 (s, 1H), 7.70 (d, J=8.3

Hz, 1H)，7.87 (d，J=8.3 Hz，1H)，10.06 (s，1H)。 MS(ESI)m/z=337 (M+H)+。 LC/MS tR=2.05 min 〇 實施例1-402 4-(5-氰基-6-乙氧基吡啶-2-基胺基）-2-甲氧基苯甲酸曱酯 141666.doc -345- 201028381 [化 1402]Hz, 1H), 7.87 (d, J = 8.3 Hz, 1H), 10.06 (s, 1H). MS (ESI) m / z = 337 (M+H)+. LC/MS tR=2.05 min </RTI> Example 1-402 4-(5-Cyano-6-ethoxypyridin-2-ylamino)-2-methoxybenzoic acid oxime ester 141666.doc -345- 201028381 [Chem. 1402]

9、N ? 標題化合物係依據三氟曱磺酸5-氰基-6-乙氧基°比°定-2-基 酯以及對應之苯胺衍生物，依據實施例1 -399之方法而合 成。 1H-NMR (400 MHz, DMSO_d6) δ 1.36 (t，J = 7.1 Hz，3H)， 3.78 (s, 3H), 3.93 (s, 3H), 4.49 (q, J=7.1 Hz, 2H), 6.49 (d, J=8.6 Hz, 1H), 7.25 (d, J=8.6 Hz, 1H), 7.42 (s, 1H), 7.63 (d，J=8.6 Hz, 1H)，7.83 (d，J=8.6 Hz, 1H)，9.97 (s，1H)。 MS(ESI)m/z=308 (M+H)+。 LC/MS tR=1.98 min。 實施例1-403 2 -乙氧基- 6- (4-(1-甲基-1H -n比唾-4-基）笨基胺基）於驗赌 [化 1403]The title compound was synthesized according to the method of Example 1-399, based on the 5-cyano-6-ethoxyl trifluorosulfonium sulfonate and the corresponding aniline derivative. 1H-NMR (400 MHz, DMSO_d6) δ 1.36 (t, J = 7.1 Hz, 3H), 3.78 (s, 3H), 3.93 (s, 3H), 4.49 (q, J = 7.1 Hz, 2H), 6.49 ( d, J=8.6 Hz, 1H), 7.25 (d, J=8.6 Hz, 1H), 7.42 (s, 1H), 7.63 (d, J=8.6 Hz, 1H), 7.83 (d, J=8.6 Hz, 1H), 9.97 (s, 1H). MS (ESI) m/z = 308 (M+H)+. LC/MS tR = 1.98 min. Example 1-403 2-Ethoxy-6-(4-(1-methyl-1H-n-pyran-4-yl)phenylamino) gambling [Chem. 1403]

標題化合物係使用三氟甲磺酸5-氰基-6-乙氧基吡啶-2-基 酯，依據實施例1-326之方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 1.38 (d, J=7.2 Hz, 6H), 4.41-4.47 (m, 2H), 6.43 (s, 1H), 7.53 (d, J=8.0 Hz, 2H), 7.63 (d, J=8.0 Hz, 2H), 7.78-7.81 (s, 2H), 8.06 (s, 1H), 9.78 (s, 1H)。 141666.doc -346· 201028381 MS(ESI)m/z=320 (M+H)+。 LC/MS tR=l_95 min。 實施例1-404 6-(4-( 1H-&quot;比唑-4-基）苯基胺基）-2-乙氧基菸鹼腈 [化 1404]The title compound was synthesized according to the method of Example 1-326 using 5-cyano-6-ethoxypyridin-2-yl trifluoromethanesulfonate. 1H-NMR (400 MHz, DMSO-d6) δ 1.38 (d, J = 7.2 Hz, 6H), 4.41-4.47 (m, 2H), 6.43 (s, 1H), 7.53 (d, J = 8.0 Hz, 2H ), 7.63 (d, J=8.0 Hz, 2H), 7.78-7.81 (s, 2H), 8.06 (s, 1H), 9.78 (s, 1H). 141666.doc -346· 201028381 MS (ESI) m/z = 320 (M+H)+. LC/MS tR = l_95 min. Example 1-404 6-(4-( 1H-&quot;Biazol-4-yl)phenylamino)-2-ethoxynicotinonitrile [Chemical 1404]

φ 標題化合物係使用三氟甲磺酸5-氰基-6-乙氧基吡啶-2·基 酯，依據實施例1 -326之方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 1.38 (d, J=7.2 Hz, 6H), 4.44 (d, J=7.2 Hz, 2H), 6.44 (d, J=8.4 Hz, 1H), 7.58 (d, J=8.54 Hz, 4H), 7.14 (d, J=8.4 Hz, 2H), 7.78-7.81 (s, 2H), 8.06 (s，1H)，9.78 (s，1H)。 MS(ESI)m/z=306 (M+H)+。 LC/MS tR=1.75 min。 實施例1-405 2-乙氧基-6-(4-(1-異丁基-1H-吡唑-4-基）苯基胺基）菸 鹼腈 [化 1405]The title compound was synthesized according to the method of Example 1-326 using 5-cyano-6-ethoxypyridin-2-yl trifluoromethanesulfonate. 1H-NMR (400 MHz, DMSO-d6) δ 1.38 (d, J = 7.2 Hz, 6H), 4.44 (d, J = 7.2 Hz, 2H), 6.44 (d, J = 8.4 Hz, 1H), 7.58 ( d, J = 8.54 Hz, 4H), 7.14 (d, J = 8.4 Hz, 2H), 7.78-7.81 (s, 2H), 8.06 (s, 1H), 9.78 (s, 1H). MS (ESI) m / z = 306 (M + H) +. LC/MS tR = 1.75 min. Example 1-405 2-Ethoxy-6-(4-(1-isobutyl-1H-pyrazol-4-yl)phenylamino)nicotinonitrile [Chem. 1405]

標題化合物係使用三氟甲磺酸5-氰基-6-乙氧基吡啶-2-基 141666.doc -347- 201028381 酯，依據實施例1 -326之方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 0.86 (d, J=7.2 Hz, 6H), 1.38 (t, J=7.2 Hz, 3H), 2.10-2.17 (m, 1H), 3.91 (d, J=7.2 Hz, 2H), 4.44 (q, J=7.2 Hz, 2H), 6.44 (d, J=8.4 Hz, 1H) 7.54 (d, J=8.8 Hz, 2H), 7.64 (d, J=8.8 Hz, 2H), 7.79 (d, J=8.4 Hz, 1H)，7.83 (s，1H)，8.09 (s，1H)，9.78 (s，1H)。 MS(ESI)m/z=362 (M+H)+。 LC/MS tR=2.33 min。 實施例1-406 4-胺基-6-节基-2-乙氧基於驗腈 [化 1406]The title compound was synthesized according to the method of Example 1-326, using 5-(?? 1H-NMR (400 MHz, DMSO-d6) δ 0.86 (d, J = 7.2 Hz, 6H), 1.38 (t, J = 7.2 Hz, 3H), 2.10-2.17 (m, 1H), 3.91 (d, J =7.2 Hz, 2H), 4.44 (q, J=7.2 Hz, 2H), 6.44 (d, J=8.4 Hz, 1H) 7.54 (d, J=8.8 Hz, 2H), 7.64 (d, J=8.8 Hz , 2H), 7.79 (d, J=8.4 Hz, 1H), 7.83 (s, 1H), 8.09 (s, 1H), 9.78 (s, 1H). MS (ESI) m / z = 362 (M+H)+. LC/MS tR = 2.33 min. Example 1-406 4-Amino-6-benzyl-2-ethoxyl to nitrile [Chem. 1406]

向三氟甲磺酸4-胺基-5-氰基-6-乙氧基吡啶-2-基酯（1〇〇4-Amino-5-cyano-6-ethoxypyridin-2-yl trifluoromethanesulfonate (1〇〇

mg，0.321 mmol)及 Pd(PPh3)4(19 mg，0.016 mmol)之 THF 溶液中添加苄基溴化辞（1 mol/L之THF溶液，0.771 mL， 0.39 mol)，於50°C下攪拌8小時。向反應溶液中添加水及 乙酸乙酯進行分離後，以乙酸乙酯萃取水相，將合併之有 機相以水及飽和食鹽水進行清洗，以硫酸鎂加以乾燥。將 有機相過濾後，進行減壓濃縮，利用逆相等分試樣液相層 析法（C18管柱，水/乙腈/01%甲酸梯度）對所獲得之殘渣進 行純化’獲得標題化合物（7 9 mg，0.03 1 mmol，1〇%)，為 茶色固體。 141666.doc •348- 201028381 MS(ESI)m/z=254 (M+H)+。 LC/MS tR=2.22 min。 實施例1-407 4 -胺基-2-乙氧基-6-苯氧基於驗猜 [化 1407]Add benzyl bromide (1 mol/L THF solution, 0.771 mL, 0.39 mol) to THF solution of mg, 0.321 mmol) and Pd(PPh3)4 (19 mg, 0.016 mmol), stir at 50 °C 8 hours. Water and ethyl acetate were added to the reaction solution for separation, and the aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with water and saturated brine and dried over magnesium sulfate. The organic phase was filtered, and concentrated under reduced pressure. The obtained residue was purified by reversed-element liquid chromatography (C18 column, water / acetonitrile / 1% formic acid gradient) to give the title compound (7 9 Mg, 0.03 1 mmol, 1% by weight), as a tan solid. 141666.doc • 348- 201028381 MS (ESI) m/z = 254 (M+H)+. LC/MS tR = 2.22 min. Example 1-407 4 -Amino-2-ethoxy-6-phenoxy assay [Chem. 1407]

Pd(OAc)2 K3PO4 2-(二-第三丁基膦基〉聯笨 二噁烷，回流Pd(OAc)2 K3PO4 2-(di-t-butylphosphino)-linked stupid dioxane, reflux

向三氟甲磺酸4-胺基-5-氰基-6-乙氧基吼啶-2-基酯（100 mg，0.321 mmol)、Pd(OAc)2(4.0 mg，0.016 mmol)、2-(二-第三丁基膦基）聯苯（7_2 mg，0.024 mmol)及磷酸鉀 (136 mg，0·642 mmol)之二°惡烧（1.5 mL)溶液中添加苯酴 (45 mg，0.48 mol)，加熱回流6小時。向反應溶液中添加 水及乙酸乙酯進行分離後，以乙酸乙酯萃取水相，將合併 之有機相以水及飽和食鹽水進行清洗，以硫酸鎂加以乾 燥。將有機相過濾後，進行減壓濃縮，利用逆相等分試樣 液相層析法（C18管柱，水/乙腈/0.1%甲酸梯度）對所獲得之 殘逢進行純化，獲得標題化合物（35.7 mg，0.14 mmol， 44%)，為茶色固體。 MS(ESI)m/z=256 (M+H)+。 LC/MS tR=3.06 min。 實施例1-408 4 -胺基-2-氯-6-(4 -經基苯基胺基）於驗猜 141666.doc -349- 201028381 [化 1408]4-Amino-5-cyano-6-ethoxyacridin-2-yl trifluoromethanesulfonate (100 mg, 0.321 mmol), Pd(OAc) 2 (4.0 mg, 0.016 mmol), 2 Add phenylhydrazine (45 mg, bis(tert-butylphosphino)biphenyl (7_2 mg, 0.024 mmol) and potassium phosphate (136 mg, 0·642 mmol) in a solution of bismuth (1.5 mL) 0.48 mol), heated to reflux for 6 hours. Water and ethyl acetate were added to the reaction solution for separation, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and brine and dried over magnesium sulfate. The organic phase was filtered, and concentrated under reduced pressure. The obtained residue was purified by reverse phase liquid chromatography (C18 column, water / acetonitrile / 0.1% formic acid gradient) to give the title compound (35.7 Mg, 0.14 mmol, 44%), as a brown solid. MS (ESI) m / z = 256 (M + H) +. LC/MS tR = 3.06 min. Example 1-408 4 -Amino-2-chloro-6-(4-phenylphenylamino) was tested 141666.doc -349- 201028381 [Chem. 1408]

濃HCl 室温Concentrated HCl room temperature

步驟1 : 4 -胺基-2-氣-6-侧乳基-1,6 -二風0比0定-3-甲猜 向3 -胺基-4，4 -二亂基-3 - 丁酸乙醋（5.0 g，27.9 mmol)中 添加濃鹽酸（12 mol/L)(20 mL)，於室溫下攪拌1小時。將 反應溶液過濾，將所獲得之殘渣以水進行清洗，藉此獲得 標題化合物（5.0 g，29·5 mmol，定量），為白色固體。 1H-NMR (400 MHz, DMSO-d6) δ 5.80 (s, 1H), 7.01 (s, 2H), 11.6 (s，1H)。 MS(ESI)m/z=170 (M+H)+。 步驟2 :三氟甲磺酸4-胺基-6-氣-5-氰基&quot;比啶-2-基酯 向4 -胺基-2 -氣-6-側氧基-1,6 -二氮α比咬-3-甲猜（4.7 g， 27.7 mmol)及三乙基胺（7.1 g，9·7 mL，69.8 mmol)之 THF(40 mL)溶液中添加PhNTf2(N-苯基雙（三氟曱磺醯 胺））（12.0 g，33.5 mmol)，於室溫下攪拌16小時。向反應 溶液中添加水及乙酸乙酯進行分離後，以乙酸乙酯萃取水 相，將合併之有機相以碳酸氫納水溶液及飽和食鹽水進行 清洗，以硫酸鎂加以乾燥。將有機相過濾後，進行減壓濃 縮，利用中壓矽膠層析法（己烷/乙酸乙酯；5-50%梯度）對 所獲得之殘渣進行純化，獲得標題化合物（4.82 g，16 141666.doc -350· 201028381 mmol，5 8%)，為白色固體。 1H-NMR (400 MHz，DMSO-d6) δ 6.67 (s，1H)，8.07 (brs， 2H)。 MS(ESI)m/z=302 (M+H)+。 步驟3 :標題化合物 於5 mL微波反應容器十，添加三氟甲磺酸4-胺基-6-氯-5-氰基吡啶-2-基酯（625 mg，2.07 mmol)、DIEA(268 mg， 2.07 mmol)及胺基苯酚（339 mg，3.11 mmol)之 DMSO(5 ® mL)溶液，進行覆蓋，使用Biotage Optimizer反應裝置， 於180°C下加熱攪拌。向反應溶液中添加水及乙酸乙酯進 行分離後，以乙酸乙酯萃取水相。將合併之有機相以碳酸 氫鈉水溶液及飽和食鹽水進行清洗，以硫酸鎂加以乾燥。 將有機相過濾後，進行減壓濃縮，利用中壓矽膠層析法 (己烷/乙酸乙酯；10-70%梯度）對所獲得之殘渣進行純化， 獲得標題化合物（249 mg，0_956 mmol，46%) ’為茶色固 體。 1H-NMR (400 MHz，DMSO-d6) δ 5.79 (s, 1H)，6.61 (s，1H) 6.69 (s, 2H)，6.73 (d，J=9.0 Hz，2H)，7.09 (d，J=9.〇 Ήζ 2H)，8.96 (s，1H)，9·27 (s，1H)。 MS(ESI)m/z=261 (M+H)+。 LC/MS tR=1.44 min。 實施例1-409 三氟甲磺酸4-(4-胺基-6-氣-5-氰基吡啶-2-基胺基）笨基西旨 141666.doc -351 - 201028381 [化 1409]Step 1: 4 -Amino-2-gas-6-side-milk-1,6-two winds 0 to 0 -3--3- guess 3 -amino-4,4 -disorder-3 - Concentrated hydrochloric acid (12 mol/L) (20 mL) was added to ethyl acetate (5.0 g, 27.9 mmol) and stirred at room temperature for 1 hour. The reaction solution was filtered, and the obtained residue was washed with water, mjjjjjj 1H-NMR (400 MHz, DMSO-d6) δ 5.80 (s, 1H), 7.01 (s, 2H), 11.6 (s, 1H). MS (ESI) m / z = 170 (M + H) +. Step 2: 4-Amino-6-gas-5-cyano &lt;bipyridin-2-yl triflate to 4-amino-2- gas-6-sideoxy-1,6- Addition of PhNTf2 (N-phenyl double) to a solution of nitro-α-α (4.3 g, 27.7 mmol) and triethylamine (7.1 g, 9·7 mL, 69.8 mmol) in THF (40 mL) (Trifluorosulfonamide) (12.0 g, 33.5 mmol), stirred at room temperature for 16 h. Water and ethyl acetate were added to the reaction solution for separation, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with aqueous sodium hydrogen carbonate and brine and dried over magnesium sulfate. After the organic phase was filtered, EtOAc was evaporated,jjjjjjjjj Doc -350· 201028381 mmol, 5 8%) as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 6.67 (s, 1H), 8.07 (brs, 2H). MS (ESI) m / z = 302 (M + H) +. Step 3: The title compound was added to a 5 mL microwave reaction vessel. Add 4-amino-6-chloro-5-cyanopyridin-2-yl trifluoromethanesulfonate (625 mg, 2.07 mmol), DIEA (268 mg) , 2.07 mmol) and a solution of aminophenol (339 mg, 3.11 mmol) in DMSO (5 ® mL), covered with a Biotage Optimizer reactor and heated at 180 °C. After water and ethyl acetate were added to the reaction solution for separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with aqueous sodium hydrogencarbonate and brine and dried over magnesium sulfate. After the organic phase was filtered, EtOAc (EtOAc m. 46%) 'is a brown solid. 1H-NMR (400 MHz, DMSO-d6) δ 5.79 (s, 1H), 6.61 (s, 1H) 6.69 (s, 2H), 6.73 (d, J = 9.0 Hz, 2H), 7.09 (d, J = 9. 〇Ήζ 2H), 8.96 (s, 1H), 9·27 (s, 1H). MS (ESI) m / z = 261 (M + H) +. LC/MS tR = 1.44 min. Example 1-409 4-(4-Amino-6-a-5-cyanopyridin-2-ylamino)trifluoromethanesulfonate 141666.doc -351 - 201028381 [Chem. 1409]

向4-胺基-2-氣-6-(4-經基苯基胺基）於驗猜（22 1 mg， 0.848 mmol)及三乙基胺（172 mg，235 pL，1.70 mmol)之 二氣甲烷：THF=1 : 1(4 mL)溶液中添加PhNTf2(N-苯基雙 (三氟甲磺醢胺））（394 mg，1·10 mmol)，於室溫下攪拌8小 時。向反應溶液中添加水及乙酸乙酯進行分離後，以乙酸 乙酯萃取水相，將合併之有機相以碳酸氫鈉水溶液及飽和 食鹽水進行清洗，以硫酸鎂加以乾燥。將有機相過濾後， 進行減壓濃縮，利用中壓矽膠層析法（己烷/乙酸乙酯；10-70%梯度）對所獲得之殘渣進行純化，獲得標題化合物（261 mg，0.67 mmol，79%)，為白色固體。 1H-NMR (400 MHz, DMSO-d6) δ 6.05 (s, 1H), 6.96 (s, 2H), 7.40 (d, J=9.0 Hz, 2H), 7.60 (d, J=9.0 Hz, 2H), 9.63 (s, 1H)。 MS(ESI)m/z=393 (M+H)+。 LC/MS tR=2.35 min。 實施例1 -410 4-(4-胺基-6-氣-5-氰基吡啶-2-基胺基）苯甲酸曱酯 實施例1-411 4-胺基-3-氰基-6-(4-(曱氧基羰基）苯基胺基）。比啶曱酸 甲酯 141666.doc •352· 201028381 [化 1410]To 4-amino-2- gas-6-(4-phenylphenylamino), guess (22 1 mg, 0.848 mmol) and triethylamine (172 mg, 235 pL, 1.70 mmol) Gas methane: THF = 1: 1 (4 mL) was added with PhNTf2 (N-phenylbis(trifluoromethanesulfonamide)) (394 mg, 1·10 mmol), and stirred at room temperature for 8 hours. Water and ethyl acetate were added to the reaction solution for separation, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with aqueous sodium hydrogen carbonate and brine and dried over magnesium sulfate. After the organic phase was filtered, EtOAc EtOAc m. 79%), as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 6.05 (s, 1H), 6.96 (s, 2H), 7.40 (d, J = 9.0 Hz, 2H), 7.60 (d, J = 9.0 Hz, 2H), 9.63 (s, 1H). MS (ESI) m / z = 393 (M+H)+. LC/MS tR = 2.35 min. Example 1-410 4-(4-Amino-6-a-5-cyanopyridin-2-ylamino)benzoic acid oxime ester Example 1-411 4-Amino-3-cyano-6- (4-(decyloxycarbonyl)phenylamino). Methylpyridinium methyl ester 141666.doc •352· 201028381 [Chem. 1410]

向二氣甲績酸4-(4 -胺基-6-氯-5-亂基α比咬-2-基胺基）苯醋 (12.9 mg，0_033 mmol)及三乙基胺（10 mg，0.099 mmol)之 甲醇溶液中添加 PdCl2(dppf)(3 mg，0.0033 mmol)，於一氧 化碳環境下加熱回流8小時。向反應溶液中添加水及乙酸 ^ 乙酯進行分離後，以乙酸乙酯萃取水相，將合併之有機相 以碳酸氫鈉水溶液及飽和食鹽水進行清洗，以硫酸鎂加以 乾燥。將有機相過濾後，進行減壓濃縮，利用逆相等分試 樣液相層析法（C18管柱，水/乙腈/0.1%甲酸梯度）對所獲得 之殘 &gt;查進行純化’獲得4 - ( 4 -胺基-6 -氯-5 -乱基Dit α定-2 -基胺 基）苯甲酸甲酯（1.7 mg，0.052 mmol，17%)及4-胺基-3-氰 基-6-(4-(甲氧基羰基）苯基胺基）吡啶甲酸曱酯（1_9 mg， 0.058 mmol，18%)° φ 4-(4-胺基-6-氯-5-氰基吡啶-2-基胺基）苯甲酸曱酯之物性 資料； MS(ESI)m/z=303 (M+H)+。 LC/MS tR=1.85 min。 4-胺基-3-氰基-6-(4-(甲氧基羰基）苯基胺基）吼啶曱酸甲 酯之物性資料； MS(ESI)m/z=327 (M+H)+。 LC/MS tR=1.68 min。 141666.doc -353- 201028381 實施例1-412 4-胺基-2-氣-6-(4-(噁唑-5-基）苯基胺基）菸鹼腈 [化 1412]4-(4-Amino-6-chloro-5-acyl-α-butyl-2-ylamino)phenyl vinegar (12.9 mg, 0_033 mmol) and triethylamine (10 mg, PdCl 2 (dppf) (3 mg, 0.0033 mmol) was added to a methanol solution of 0.099 mmol), and heated under reflux for 8 hours under carbon monoxide. Water and ethyl acetate were added to the reaction solution for separation, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with aqueous sodium hydrogen carbonate and brine and dried over magnesium sulfate. After filtering the organic phase, it was concentrated under reduced pressure, and purified by reverse phase equal liquid chromatography (C18 column, water/acetonitrile/0.1% formic acid gradient). Methyl 4-(4-amino-6-chloro-5-acyl Dit α-di-2-amino)benzoate (1.7 mg, 0.052 mmol, 17%) and 4-amino-3-cyano-6 -(4-(Methoxycarbonyl)phenylamino)pyridinecarboxylic acid decyl ester (1-9 mg, 0.058 mmol, 18%) ° φ 4-(4-Amino-6-chloro-5-cyanopyridine-2 -physical data of decylamino)benzoate; MS (ESI) m/z = 303 (M+H)+. LC/MS tR = 1.85 min. Physical properties of methyl 4-amino-3-cyano-6-(4-(methoxycarbonyl)phenylamino) acridinium hydride; MS (ESI) m/z = 327 (M+H) +. LC/MS tR = 1.68 min. 141666.doc -353- 201028381 Examples 1-412 4-Amino-2- gas-6-(4-(oxazol-5-yl)phenylamino)nicotinonitrile [Chemical 1412]

Pd(OAc)2, BINAP CS2〇〇3Pd(OAc)2, BINAP CS2〇〇3

TfO N Cl 二鳴烧，120 °C 於5 mL微波反應容器中，添加三氟曱磺酸4-胺基-6-氣-5-氰基 °比咬-2-基 S旨（100 mg，0.331 mmol)及 4-(°惡唾-5-基） 苯胺（106 mg，0.663 mmol)之 DMSO(1.5 mL)溶液，進行覆 蓋，使用Biotage Optimizer反應裝置，於180°C下加熱授 拌。向反應溶液中添加水及乙酸乙酯進行分離後，以乙酸 乙酯萃取水相，將合併之有機相以碳酸氫鈉水溶液及飽和 食鹽水進行清洗，以硫酸鎂加以乾燥。將有機相過濾後， 進行減壓濃縮，利用逆相等分試樣液相層析法（C18管柱， 水/乙腈/0.1%甲酸梯度）對所獲得之殘渣進行純化，獲得標 題化合物（10.3 mmol，0.033 mmol，10%)，為茶色固體。 MS(ESI)m/z=312 (M+H)+。 LC/MS tR=1.72 min。 實施例1-413 4 -胺基- 2- (異丁基胺基）-6-(4-( D惡β坐-5-基）苯基胺基）於 驗猜 141666.doc -354- 201028381 [化 1413]TfO N Cl dioxin, 120 °C in a 5 mL microwave reaction vessel, adding 4-amino-6-ethane-5-cyanosulfonate to trimethylsulfonate. A solution of 0.331 mmol) and 4-(°cain-5-yl) aniline (106 mg, 0.663 mmol) in DMSO (1.5 mL) was applied, and then applied to the mixture using a Biotage Optimizer reaction apparatus at 180 °C. Water and ethyl acetate were added to the reaction solution for separation, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with aqueous sodium hydrogen carbonate and brine and dried over magnesium sulfate. After the organic phase was filtered, the title compound (10.3 mmol, m. , 0.033 mmol, 10%), as a tan solid. MS (ESI) m / z = 312 (M + H) +. LC/MS tR = 1.72 min. Example 1-113 4-Amino-2-(isobutylamino)-6-(4-(Doxo-β-yl-5-yl)phenylamino) is judged 141666.doc -354- 201028381 [Chem. 1413]

於5 mL微波反應容器中，添加三氟甲磺酸4-胺基-6-氯-5 -氰基0比0定-2-基S旨（7.8 mg，0.025 mmol)、三乙基胺（2 _ 8 mg，0.0275 mmol)及異 丁基胺（5.5 mg，0.075 mmol)之 NMP(0.13 mL)溶液，進行覆蓋，使用 Biotage Optimizer反 應裝置，於180°C下加熱攪拌30分鐘。向反應溶液中添加 水及乙酸乙酯進行分離後，以乙酸乙酯萃取水相，將合併 之有機相以碳酸氫鈉水溶液及飽和食鹽水進行清洗，以硫 酸鎂加以乾燥。將有機相過濾後，進行減壓濃縮，利用逆 相等分試樣液相層析法（C18管柱，水/乙腈/0.1%甲酸梯度） 對所獲得之殘渣進行純化，獲得標題化合物（3.8 mg， 0.011 mmol，44%)，為茶色固體。 MS(ESI)m/z=349 (M+H)+。 LC/MS tR=1.83 min。 實施例1-414 4-胺基-2-曱氧基-6-(4-(噁唑-5-基）苯基胺基）菸鹼腈 [化 1414]Add 4-amino-6-chloro-5-cyanomethyl trifluoromethanesulfonate to butyl-2-yl S (7.8 mg, 0.025 mmol) and triethylamine in a 5 mL microwave reaction vessel. A solution of 2 _ 8 mg, 0.0275 mmol) and isobutylamine (5.5 mg, 0.075 mmol) in NMP (0.13 mL) was applied, and the mixture was heated and stirred at 180 ° C for 30 minutes using a Biotage Optimizer reaction apparatus. Water and ethyl acetate were added to the reaction solution for separation, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with aqueous sodium hydrogen carbonate and brine and dried over magnesium sulfate. After the organic phase was filtered, the residue was evaporated to dryness crystals crystals crystals , 0.011 mmol, 44%), as a brown solid. MS (ESI) m/z = 495 (M+H)+. LC/MS tR = 1.83 min. Example 1-414 4-Amino-2-indolyl-6-(4-(oxazol-5-yl)phenylamino)nicotinonitrile [Chemical 1414]

PhNTf2, Et3N DCMPhNTf2, Et3N DCM

步驟1 :三氟甲磺酸4-胺基-5-氰基-6-甲氧基吡啶-2-基酯 141666.doc •355· 201028381 標題化合物係使用4-胺基-2-甲氧基-6-側氧基-1，6-二氫 吡啶-3-腈（Leibigs Ann. Chem. 1986，533-544.)，依據實施 例1-408(步驟2)之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 3.86 (s, 3H), 6.32 (s, 1H), 7.68 (s, 2H)。 MS(ESI)m/z=298 (M+H)+。 步驟2 :標題化合物 標題化合物係使用三氟曱磺酸4-胺基-5-氰基-6-甲氧基 吡啶-2-基酯及4-(噁唑-2-基）苯胺，依據實施例1-145之方 法而合成。 MS(ESI)m/z=308 (M+H)+。 LC/MS tR=1.72 min 〇 實施例1-415 4 -胺基-2-甲氧基- 6- (3 -甲氧基- 4- (°惡唾·- 5-基）苯基胺基）於 驗腈 [化 1415]Step 1: 4-Amino-5-cyano-6-methoxypyridin-2-yl trifluoromethanesulfonate 141666.doc •355· 201028381 The title compound is 4-amino-2-methoxy -6-Phenoxy-1,6-dihydropyridine-3-carbonitrile (Leibigs Ann. Chem. 1986, 533-544.) was synthesized according to the method of Example 1-408 (Step 2). 1H-NMR (300 MHz, DMSO-d6) δ 3.86 (s, 3H), 6.32 (s, 1H), 7.68 (s, 2H). MS (ESI) m / z = 298 (M + H) +. Step 2: title compound The title compound was obtained using 4-amino-5-cyano-6-methoxypyridin-2-yl trifluorosulfonate and 4-(oxazol-2-yl)aniline according to the implementation. Synthesis by the method of Example 1-145. MS (ESI) m/z = 308 (M+H)+. LC/MS tR = 1.72 min 〇 Example 1-415 4 -Amino-2-methoxy- 6-(3-methoxy-4-(( 恶 · -7-yl)phenylamino) For nitrile [Chemical 1415]

標題化合物係使用三氟甲磺酸4-胺基-5-氰基-6-曱氧基 吡啶-2-基酯及3-曱氧基-4-(噁唑-2-基）苯胺，依據實施例1-145之方法而合成。 MS(ESI)m/z=338 (M+H)+。 LC/MS tR=1.76 min。 實施例1 -416 141666.doc -356- 201028381 4 -胺基-2-異丙氧1基- 6- (4-(11 惡π坐-5-基）苯基胺基）私驗猜 [化 1416]The title compound is 4-amino-5-cyano-6-methoxypyridin-2-yl trifluoromethanesulfonate and 3-decyloxy-4-(oxazol-2-yl)aniline. The method of Example 1-145 was synthesized. MS (ESI) m / z = 338 (M+H)+. LC/MS tR = 1.76 min. Example 1 -416 141666.doc -356- 201028381 4 -Amino-2-isopropyloxy 1 -6-(4-(11 oxa π--5-yl)phenylamino) 1416]

步驟1 · 4 -胺基-2 -異丙氧基-6 -側乳基-1，6 -二鼠°比α定-3 -甲腈 於20 mL微波反應容器中，添加3-胺基-4,4-二氰基-3-丁 浠乙 S旨（5 00 mg，2.79 mmol)及氫化鈉（60% wt，167 mg， 4.19 mmol)之異丙醇（10 mL)溶液，進行覆蓋，使用 Biotage Optimizer反應裝置，於170°C下加熱授拌30分鐘。 恢復至室溫後，以2 mol/L鹽酸進行中和，向反應溶液中 添加水及乙酸乙酯，進行分離。對不溶物進行矽藻土過濾 ® 後，以乙酸乙酯萃取水相。將合併之有機相以碳酸氫鈉水 溶液及飽和食鹽水進行清洗，以硫酸錢加以乾燥。將有機 相過濾後，進行減壓濃縮，利用逆相等分試樣液相層析法 (C18管柱，水/乙腈/0.1%曱酸梯度）對所獲得之殘渣進行純 化，獲得標題化合物（253 mg，1.31 mmol，47%)，為白色 固體。 1H-NMR (300 MHz, DMSO-d6) δ 1.24 (d, J=6.3 Hz, 6H), 5.18 (dt, J=6.3 Hz, 1H), 5.18 (s, 1H), 6.54 (s, 2H), 10.74 (s, 141666.doc -357- 201028381 1H)。 MS(ESI)m/z=194 (M+H)+。 步驟2 :三氟甲磺酸4-胺基氰基_6_異丙氧基吡啶_2_ 基醋 標題化合物係使用4-胺基-2-異丙氧基_6_侧氧基-1，6-二 氫°比咬-3_甲腈，依據實施例1-408(步驟2)之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 1.29 (d, J=6.3 Hz, 6H), 5.07 (dt，J=6.3 Hz, 1H)，6.26 (s，1H)，7.63 (brs，1H)。 MS(ESI)m/z=326 (M+H)+。 ❹ 步驟3 :標題化合物 標題化合物係使用三氟甲磺酸4-胺基-5-氰基-6-異丙氧 基吡啶-2-基酯及4-(噁唑-2-基）苯胺，依據實施例1-145之 方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 1.33 (d, J=6.0 Hz, 6H), 5.18-5.26 (m, 1H), 5.74 (s, 1H), 6.49 (s, 2H), 7.52 (s, 1H), 7.59-7.63 (m, 4H)，8.35 (s, 1H), 9.27 (s，1H)。Step 1 · 4 -Amino-2-isopropoxy-6 - flavonyl-1,6-di- azole ratio α-1,3-carbonitrile in a 20 mL microwave reaction vessel with 3-amino group added - A solution of 4,4-dicyano-3-butanoxime S (500 mg, 2.79 mmol) and sodium hydride (60% wt, 167 mg, 4.19 mmol) in isopropyl alcohol (10 mL). The mixture was heated and heated at 170 ° C for 30 minutes using a Biotage Optimizer reaction apparatus. After returning to room temperature, it was neutralized with 2 mol/L hydrochloric acid, and water and ethyl acetate were added to the reaction solution to carry out separation. After the insoluble material was subjected to diatomaceous earth filtration ® , the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with aqueous sodium bicarbonate solution and saturated brine and dried over EtOAc. After the organic phase was filtered, the residue was purified under reduced pressure. Mg, 1.31 mmol, 47%) as a white solid. 1H-NMR (300 MHz, DMSO-d6) δ 1.24 (d, J = 6.3 Hz, 6H), 5.18 (dt, J = 6.3 Hz, 1H), 5.18 (s, 1H), 6.54 (s, 2H), 10.74 (s, 141666.doc -357- 201028381 1H). MS (ESI) m / z = 194 (M + H) +. Step 2: 4-Aminocyano-6-isopropoxypyridin-2-yl vinegar trifluoromethanesulfonic acid The title compound is 4-amino-2-isopropoxy-6-sideoxy-1. 6-Dihydrogen ratio bite-3_carbonitrile was synthesized according to the method of Example 1-408 (Step 2). 1H-NMR (300 MHz, DMSO-d6) δ 1.29 (d, J = 6.3 Hz, 6H), 5.07 (dt, J = 6.3 Hz, 1H), 6.26 (s, 1H), 7.63 (brs, 1H). MS (ESI) m / z = 326 (M+H)+. ❹ Step 3: The title compound The title compound is 4-amino-5-cyano-6-isopropoxypyridin-2-yl trifluoromethanesulfonate and 4-(oxazol-2-yl)aniline. Synthesized according to the method of Example 1-145. 1H-NMR (300 MHz, DMSO-d6) δ 1.33 (d, J = 6.0 Hz, 6H), 5.18-5.26 (m, 1H), 5.74 (s, 1H), 6.49 (s, 2H), 7.52 (s , 1H), 7.59-7.63 (m, 4H), 8.35 (s, 1H), 9.27 (s, 1H).

Q MS(ESI)m/z=308 (M+H)+。 LC/MS tR=1.72 min。 實施例1-417 5 -胺基-2 -異丙氧基- 6- (3 -甲氧基-4-(嗯0坐-5-基）本基基） 菸鹼腈 141666.doc -358· 201028381 [化 1417]Q MS (ESI) m/z = 308 (M+H)+. LC/MS tR = 1.72 min. Example 1-417 5-Amino-2-isopropoxy- 6-(3-methoxy-4-(hm-O--5-yl)benyl) Nicotinonitrile 141666.doc-358· 201028381 [Chem. 1417]

標題化合物係使用三氟甲磺酸4-胺基-5-氰基-6-異丙氧 基吡啶-2-基酯及3 -甲氧基-4-(噁唑-2-基）苯胺，依據實施 例1-145之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 1.31 (d, J=6.0 Hz, 6H), φ 3.90 (s, 3H), 5.31 (dt, J=6.0 Hz, 1H), 5.77 (s, 1H), 6.52 (s, 2H), 7.18 (dd, J=3.0, 9.0 Hz, 1H), 7.38 (s, 1H), 7.47 (d, J=3.0 Hz, 1H), 7.57 (d, J=9.0 Hz, 1H), 8.33 (s, 1H), 9.31 (s, 1H)。 MS(ESI)m/z=366 (M+H)+。 LC/MS tR=2.03 min。 實施例1-418 4-胺基-2-異丙氧基-6-(2-曱基苯并[d]噁唑-5-基胺基）菸 φ 絵:腈 [化 1418]The title compound is 4-amino-5-cyano-6-isopropoxypyridin-2-yl trifluoromethanesulfonate and 3-methoxy-4-(oxazol-2-yl)aniline. Synthesized according to the method of Example 1-145. 1H-NMR (300 MHz, DMSO-d6) δ 1.31 (d, J = 6.0 Hz, 6H), φ 3.90 (s, 3H), 5.31 (dt, J = 6.0 Hz, 1H), 5.77 (s, 1H) , 6.52 (s, 2H), 7.18 (dd, J=3.0, 9.0 Hz, 1H), 7.38 (s, 1H), 7.47 (d, J=3.0 Hz, 1H), 7.57 (d, J=9.0 Hz, 1H), 8.33 (s, 1H), 9.31 (s, 1H). MS (ESI) m / z = 366 (M+H)+. LC/MS tR = 2.03 min. Example 1-418 4-Amino-2-isopropoxy-6-(2-mercaptobenzo[d]oxazol-5-ylamino) Tobacco φ 絵: Nitrile [Chemical 1418]

標題化合物係使用三氟甲磺酸4-胺基-5-氰基-6-異丙氧 基吡啶-2-基酯以及對應之苯胺衍生物，依據實施例1-145 之方法而合成。 MS(ESI)m/z=324 (M+H)+。 141666.doc •359- 201028381 LC/MS tR=1.92 min。 實施例1-419The title compound was synthesized according to the method of Example 1-145 using 4-amino-5-cyano-6-isopropoxypyridin-2-yl trifluoromethanesulfonate and the corresponding aniline derivative. MS (ESI) m/z = 324 (M+H)+. 141666.doc •359- 201028381 LC/MS tR=1.92 min. Example 1-419

基）菸鹼腈 [化 1419]Nicotinic nitrile [Chemical 1419]

Me-N 標題化合物係使用三氟甲磺酸4-(4-胺基_5-氮基_6_異丙 氧基吡啶-2-基胺基）苯基酯，依據實施例1-326之方法而合 成。 1H-NMR (400 MHz, DMSO-d6) δ 1.33 (d, J=5.6 Hz, 6H), 3.85 (s, 2H), 5.08-5.28 (m, 2H), 5.72 (s, 1H), 6.43 (s, 2H), 7.49-7.51 (m, 4H), 7.79 (s, 1H), 8.03 (d, J=8.8 Hz, 9.04 (s, 1H)。 MS(ESI)m/z=349 (M+H)+。 LC/MS tR=l‘87 min。 實施例1-420 4-胺基-6-(4-(1-異丁基-1Η-»比唑-4-基）苯基胺基）_2_異丙 氧基於驗腈 [化 1420]The title compound of Me-N is 4-(4-amino-5-nitro-6-isopropoxypyridin-2-ylamino)phenyl ester of trifluoromethanesulfonate according to Examples 1-326. The method is synthesized. 1H-NMR (400 MHz, DMSO-d6) δ 1.33 (d, J = 5.6 Hz, 6H), 3.85 (s, 2H), 5.08-5.28 (m, 2H), 5.72 (s, 1H), 6.43 (s , 2H), 7.49-7.51 (m, 4H), 7.79 (s, 1H), 8.03 (d, J=8.8 Hz, 9.04 (s, 1H). MS (ESI) m/z = 349 (M+H) LC/MS tR = 1 '87 min. Example 1-420 4-Amino-6-(4-(1-isobutyl-1Η-»bazol-4-yl)phenylamino)_2 _Isopropoxy group in the test of nitrile [Chemical 1420]

Me，Me 141666.doc -360- 201028381 標題化合物係使用三氟甲磺酸4-(4-胺基-5-氰基·6-異丙 氧基11比咬-2-基胺基）笨基醋，依據實施例1-326之方法而合 成。 1H-NMR (400 MHz, DMSO-d6) δ 0.86 (d, J=6.4 Hz, 6H), 1.32 (t, J=6.0 Hz, 6H), 2.01-2.16 (m, 1H), 3.90 (d, J=7.6 Hz, 2H), 5.24 (t, J=6.0 Hz, 1H), 5.71 (s, 1H), 6.42 (s, 2H), 7.48 (s, 4H)，7.80 (s，2H)，8.06 (s, 1H)，9.03 (s，1H)。 MS(ESI)m/z=391 (M+H)、 e LC/MS tR=2.26 min o 實施例1-421 4-胺基-6-(4-(1-苄基-1Η-«比唑-4-基）苯基胺基）-2-異丙氧 基於驗腈 [化 1421]Me,Me 141666.doc -360- 201028381 The title compound uses 4-(4-amino-5-cyano-6-isopropoxy 11-but-2-ylamino)trifluoromethanesulfonate Vinegar was synthesized according to the method of Examples 1-326. 1H-NMR (400 MHz, DMSO-d6) δ 0.86 (d, J = 6.4 Hz, 6H), 1.32 (t, J = 6.0 Hz, 6H), 2.01-2.16 (m, 1H), 3.90 (d, J =7.6 Hz, 2H), 5.24 (t, J=6.0 Hz, 1H), 5.71 (s, 1H), 6.42 (s, 2H), 7.48 (s, 4H), 7.80 (s, 2H), 8.06 (s , 1H), 9.03 (s, 1H). MS (ESI) m/z = 391 (M + H), e LC / MS t R = 2.26 min o Example 1-421 4-amino-6-(4-(1-benzyl-1Η-« azole 4-yl)phenylamino)-2-isopropoxy in the nitrile [Chemical 1421]

標題化合物係使用三氟甲磺酸4-(4-胺基-5-氰基-6-異丙 氧基吡啶-2-基胺基）苯基酯，依據實施例1-326之方法而合 成。 1H-NMR (400 MHz, DMSO-d6) δ 1.32 (d, J=6.0 Hz, 6H), 5.23 (t, J=6.0 Hz, 1H), 5.33 (s, 2H), 5.71 (s, 1H), 6.42 (s, 2H), 7.26-7.37 (m, 5H), 7.48 (s, 4H), 7.85 (s, 1H), 8.18 (s, 1H), 9.05 (s, 1H)。 MS(ESI)m/z=425 (M+H)+。 141666.doc •361 - 201028381 LC/MS tR=2.26 min。 實施例1-422 4-胺基-2-異丙氧基-6-(4-(l-(2-(N-嗎啉基）乙基比 唑-4-基）苯基胺基）菸鹼腈 [化 1422] Γ~~\The title compound was synthesized according to the method of Example 1-326 using 4-(4-amino-5-cyano-6-isopropoxypyridin-2-ylamino)phenyl trifluoromethanesulfonate. . 1H-NMR (400 MHz, DMSO-d6) δ 1.32 (d, J = 6.0 Hz, 6H), 5.23 (t, J = 6.0 Hz, 1H), 5.33 (s, 2H), 5.71 (s, 1H), 6.42 (s, 2H), 7.26-7.37 (m, 5H), 7.48 (s, 4H), 7.85 (s, 1H), 8.18 (s, 1H), 9.05 (s, 1H). MS (ESI) m / z = 425 (M+H)+. 141666.doc • 361 - 201028381 LC/MS tR = 2.26 min. Example 1-422 4-Amino-2-isopropoxy-6-(4-(l-(2-(N-morpholinyl)ethylbisoxazol-4-yl)phenylamino) Alkali nitrile [Chemical 1422] Γ~~\

C 標題化合物係使用三氟甲磺酸4-(4-胺基-5-氰基-6-異丙 氧基吡啶-2-基胺基）苯基酯，依據實施例1-326之方法而合 成。 1H NMR (400 MHz, DMSO-d6) δ 1.32 (d, J=6.0 Hz, 6H), 2.41 (s, 4H), 2.73 (t, J=6.4 Hz, 2H), 3.55 (s, 4H), 4.22 (t, J=6.4 Hz, 2H), 5.24 (t, J=6.0 Hz, 1H), 5.72 (s, 1H), 6.42 (s, 2H), 7.48 (dd, J=8.4 Hz, 14.8 Hz, 4H), 7.80 (s, 1H), 8.09 (s, 1H)，9.04 (s，1H)。 MS(ESI)m/z=448 (M+H)+。 LC/MS tR=1.10 min。 實施例1-423 4-胺基-2-異丙氧基-6-(4-(1,3,5-三甲基-1H-吡唑-4-基）苯 基胺基）菸鹼腈 [化 1423]The title compound is 4-(4-amino-5-cyano-6-isopropoxypyridin-2-ylamino)phenyl trifluoromethanesulfonate according to the method of Example 1-326. synthesis. 1H NMR (400 MHz, DMSO-d6) δ 1.32 (d, J = 6.0 Hz, 6H), 2.41 (s, 4H), 2.73 (t, J = 6.4 Hz, 2H), 3.55 (s, 4H), 4.22 (t, J=6.4 Hz, 2H), 5.24 (t, J=6.0 Hz, 1H), 5.72 (s, 1H), 6.42 (s, 2H), 7.48 (dd, J=8.4 Hz, 14.8 Hz, 4H ), 7.80 (s, 1H), 8.09 (s, 1H), 9.04 (s, 1H). MS (ESI) m / z = 448 (M+H)+. LC/MS tR = 1.10 min. Example 1-423 4-Amino-2-isopropoxy-6-(4-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenylamino) Nicotine Nitrile [化1423]

Me Me 141666.doc • 362· 201028381 標題化合物係使用三氟甲磺酸4-(4-胺基-5-氰基-6-異丙 氧基吡啶-2-基胺基）苯基酯，依據實施例1-326之方法而合 成。 1H NMR (400 MHz, DMSO-d6) δ 1.3 1 (d, J=6.4 Hz, 6H), 2.11 (s, 3H), 2.20 (s, 3H), 3.68 (s, 3H), 5.20-5.27 (m, 1H), 5.74 (s, 1H), 6.43 (s, 2H), 7.14 (d, J=8.4 Hz, 2H), 7.53 (d, J=8.4 Hz, 2H)，9.05 (s, 1H)。 MS(ESI)m/z=377 (M+H)+。 Φ LC/MS tR=1.91 min。 實施例1-424 6-(4-( 1H-n比唑-4-基）苯基胺基）-4-胺基-2-異丙氧基菸 驗猜Me Me 141666.doc • 362· 201028381 The title compound is 4-(4-amino-5-cyano-6-isopropoxypyridin-2-ylamino)phenyl trifluoromethanesulfonate, based on The synthesis was carried out in the same manner as in Example 1-326. 1H NMR (400 MHz, DMSO-d6) δ 1.3 1 (d, J = 6.4 Hz, 6H), 2.11 (s, 3H), 2.20 (s, 3H), 3.68 (s, 3H), 5.20-5.27 (m , 1H), 5.74 (s, 1H), 6.43 (s, 2H), 7.14 (d, J=8.4 Hz, 2H), 7.53 (d, J=8.4 Hz, 2H), 9.05 (s, 1H). MS (ESI) m / z = 377 (M+H)+. Φ LC/MS tR = 1.91 min. Example 1-424 6-(4-( 1H-n-Bizozol-4-yl)phenylamino)-4-amino-2-isopropoxy oxime

[化 1424][Chem. 1424]

APrOH NMP, 160 °CAPrOH NMP, 160 °C

Pd(OAc)2, Xantphos CS2CO3 二噁烷，100 °cPd(OAc)2, Xantphos CS2CO3 dioxane, 100 °c

步驟1 . 4 -胺基-2-&gt;臭-6-(4 -&gt;臭苯基胺基）於驗猜 於5 mL微波反應容器中，向4,6-二胺基-2-溴菸鹼腈（300 mg，0.864 mmol)、1 -漠-4-破苯（1.33 g，4.69 mmol)、 Xantphos(272 mg，0.469 mmol)及碳酸铯（2.14 g，6.57 141666.doc -363 - 201028381 mmol)之二 °惡烧（10 mL)溶液中添加 Pd(OAc)2(52.7 mg， 0.235 mmol)進行覆蓋，使用Biotage Optimizer反應裝置， 於1 〇〇°C下攪拌1小時。向反應溶液中添加水及乙酸乙酯進 行分離後，以乙酸乙酯萃取水相，將合併之有機相以水及 飽和食鹽水進行清洗，以硫酸鎂加以乾燥。將有機相過濾 後，進行減壓濃縮。利用中壓矽膠層析法（己烷：乙酸乙 酯=1 : 1)對所獲得之殘渣進行純化，獲得標題化合物（656 mg，3 8%)，為黃色固體。 1H-NMR (400 MHz, DMSO-d6) δ 6.04 (s, 1H), 6.86 (s, 2H), 7.38 (d, J=8.8 Hz, 2H), 7.47 (d, J=8.8 Hz, 2H), 9.45 (s, 1H)。 MS(ESI)m/z=367 (M+H)+。 步驟2 . 4 -胺基- 6- (4 -&gt;臭苯基胺基）-2 -異丙氧基务驗猜 於20 mL微波反應容器中，向4-胺基-2-溴-6-(4-溴苯基胺 基）菸鹼腈（2.0 g，5·43 mmol)及異丙醇（12 mL)之NMP(4 mL)溶液中添加60%敷化鈉（261 mg，10.9 mmol)進行覆 蓋，使用Biotage Optimizer反應裝置，於160°C下授拌30分 鐘。向反應溶液中添加水及乙酸乙酯進行分離後，以乙酸 乙S旨萃取水相，將合併之有機相以水及飽和食鹽水進行清 洗，以硫酸鎂加以乾燥。將有機相過濾後，進行減壓濃 縮。利用中壓矽膠層析法（己烷：乙酸乙酯=1 : 1)對所獲 得之殘渣進行純化，獲得標題化合物（1.25 g，3.59 mmol，66%)，為白色固體。 1H-NMR (400 MHz, DMSO-d6) δ 1.29 (d, J=6.4 Hz, 6H), 141666.doc --364 - 201028381 5.19 (dt, J=6.4 Hz, 1H), 5.70 (s, 1H), 6.47 (s, 2H), 7.40 (d, J-8.8 Hz，2H)，7.48 (d, J=8.8 Hz, 2H)，9..16 (s，1H)。 MS(ESI)m/z=347 (M+H)+。 步驟3 :標題化合物 於5 mL微波反應容器中，向4-胺基-6-(4-溴苯基胺基）-2- 異丙氧基於驗腈（300 mg，0.864 mmol)、4-(4,4,5,5-四甲Step 1. 4 -Amino-2-&gt;Smell-6-(4-&gt;odor phenylamino group) was guessed in a 5 mL microwave reaction vessel to 4,6-diamino-2-bromo Nicotinonitrile (300 mg, 0.864 mmol), 1-di-4-benzene (1.33 g, 4.69 mmol), Xantphos (272 mg, 0.469 mmol) and cesium carbonate (2.14 g, 6.57 141666.doc -363 - 201028381 Pd(OAc) 2 (52.7 mg, 0.235 mmol) was added to a solution of m.sub.2 (10 mL), and was stirred at 1 ° C for 1 hour using a Biotage Optimizer apparatus. After water and ethyl acetate were added to the reaction solution for separation, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water and brine and dried over magnesium sulfate. After the organic phase was filtered, it was concentrated under reduced pressure. The residue obtained was purified by EtOAc EtOAc (EtOAc) 1H-NMR (400 MHz, DMSO-d6) δ 6.04 (s, 1H), 6.86 (s, 2H), 7.38 (d, J = 8.8 Hz, 2H), 7.47 (d, J = 8.8 Hz, 2H), 9.45 (s, 1H). MS (ESI) m / z = 367 (M+H)+. Step 2. 4 -Amino- 6-(4 -> odorant phenylamino)-2 -isopropoxy chemistry is judged in a 20 mL microwave reaction vessel to 4-amino-2-bromo-6 Add 60% sodium sulphate (261 mg, 10.9 mmol) to a solution of (4-bromophenylamino)nicotinonitrile (2.0 g, 5.43 mmol) and isopropanol (12 mL) in NMP (4 mL) Covering was carried out using a Biotage Optimizer reaction apparatus and mixing at 160 ° C for 30 minutes. After water and ethyl acetate were added to the reaction solution for separation, the aqueous phase was extracted with acetic acid, and the combined organic phases were washed with water and brine, and dried over magnesium sulfate. After the organic phase was filtered, it was concentrated under reduced pressure. The residue obtained was purified by EtOAc EtOAcjjjjjjj 1H-NMR (400 MHz, DMSO-d6) δ 1.29 (d, J = 6.4 Hz, 6H), 141666.doc -364 - 201028381 5.19 (dt, J=6.4 Hz, 1H), 5.70 (s, 1H) , 6.47 (s, 2H), 7.40 (d, J-8.8 Hz, 2H), 7.48 (d, J = 8.8 Hz, 2H), 9..16 (s, 1H). MS (ESI) m / z = 347 (M+H)+. Step 3: The title compound was taken in a 5 mL microwave reaction vessel to 4-amino-6-(4-bromophenylamino)-2-isopropoxy to the nitrile (300 mg, 0.864 mmol), 4-( 4,4,5,5-four

基-1,3,2- —氧雜蝴烧-2-基）-1H-0比0坐-1 -曱酸第：丁酿（381 mg，1.30 mmol)及 2 mol/L碳酸鉀水溶液 〇 3〇 ，2 59 mmol)之THF(3 mL)溶液中添加二氣⑴广雙^第三丁基 鱗基）一戊鐵]把（11)(28.2 mg ’ 0.043 mmol)進行覆蓋，使用 Biotage Optimizer反應裝置’於120°C下攪拌30分鐘。向反 應溶液中添加水及乙酸乙酯進行分離後，以乙酸乙醋萃取 水相，將合併之有機相以水及飽和食鹽水進行清洗，以硫 酸鎂加以乾燥。將有機相過濾後，進行減壓濃縮。利用令 壓石夕膠層析法（己烧：乙酸乙醋=1 : 1)對所獲得之殘潰進 行純化，獲得標題化合物（189 mg，0.S65 mm〇1，65%)， 為白色固體。 1H-NMR (400 MHz, DMSO-d6) δ 1.32 (d, J=6.4 Hz, 6H) 5.21-5.27 (m，1H)，5.71 (s，1H)，6·42 (s，2H), 7.50 (s 4H) 7.86 (s，1H)，8.09 (s，1H)，9.63 (s，1H)，12.85 (s，ih)。 MS(ESI)m/z=335 (M+H)+。 LC/MS tR=1.68 min 〇 實施例1-425 6-(4-(1-乙醯基- IH-0比《•坐-4 -基）苯基胺基）胺基異丙 141666.doc -365- 201028381 氧基菸鹼腈 [化 1425]Base-1,3,2-oxaxan-2-yl)-1H-0 to 0--1 -decanoic acid: butyl (381 mg, 1.30 mmol) and 2 mol/L aqueous potassium carbonate solution 3 〇, 2 59 mmol) of THF (3 mL) was added with hexane (1) bis-bis-tert-butyl fluorenyl)-pental-iron] (11) (28.2 mg '0.043 mmol), using Biotage Optimizer The reaction apparatus was stirred at 120 ° C for 30 minutes. Water and ethyl acetate were added to the reaction solution, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and saturated brine and dried over magnesium sulfate. After the organic phase was filtered, it was concentrated under reduced pressure. The obtained residue was purified by EtOAc (EtOAc:EtOAc:EtOAc) solid. 1H-NMR (400 MHz, DMSO-d6) δ 1.32 (d, J = 6.4 Hz, 6H) 5.21-5.27 (m, 1H), 5.71 (s, 1H), 6·42 (s, 2H), 7.50 ( s 4H) 7.86 (s, 1H), 8.09 (s, 1H), 9.63 (s, 1H), 12.85 (s, ih). MS (ESI) m / z = 335 (M+H)+. LC/MS tR=1.68 min 〇Example 1-425 6-(4-(1-Ethyl-IH-0 than "•s--4-yl)phenylamino)aminoisopropyl 141666.doc - 365- 201028381 oxynicotinonitrile [Chemical 1425]

向6-(4-(1Η-。比唑-4-基）苯基胺基）-4-胺基-2-異丙氧基於 驗腈（50 mg ’ 0.150 mmol)i吼咬溶液中添加乙醯氣（12.9 mg，11.7 pL，0.164 mmol)，於室溫下攪拌2小時。向反應 溶液中添加水及乙酸乙酯進行分離後，以乙酸乙酯萃取水 相，將合併之有機相以碳酸氫鈉水溶液及飽和食鹽水進行 清洗’以硫酸鎂加以乾燥。將有機相過濾後，進行減壓浪 縮，以己烷：乙酸乙酯=5 : 1使所獲得之殘渣固化，獲得 標題化合物（42 mg ’ 0.112 mmol，75%)，為黃色固體。 1H NMR (400 MHz, DMSO-d6) δ j 33 (d5 J=6.0 Hz, 6H), 2.65 (s，3H)，5.22-5.28 (m，1H)，5.74 (s，1H)，6 47 (s，2H)， 7.57 (d, J=8.4 Hz, 2H), 7.68 (d} j=8.4 Ήζ, 2H), 8.33 (s, 1H)，8.75 (s，1H), 9.16 (s，1H) 〇 MS(ESI)m/z=377 (M+H)+。 LC/MS tR=2.14 min。 實施例1-426 4-胺基-2-異丙氧基-6-(4-(1-(2-甲氧基乙醯基）_1H_吡唑、 4-基）苯基胺基）菸鹼腈 14l666.doc 366 - 201028381 [化 1426]Add 6 to 6-(4-(1Η-.boxazol-4-yl)phenylamino)-4-amino-2-isopropoxy to the nitrile (50 mg ' 0.150 mmol) i bite solution Helium (12.9 mg, 11.7 pL, 0.164 mmol) was stirred at room temperature for 2 h. After water and ethyl acetate were added to the reaction solution for separation, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with aqueous sodium hydrogen carbonate and brine, and dried over magnesium sulfate. After the organic phase was filtered, EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 1H NMR (400 MHz, DMSO-d6) δ j 33 (d5 J=6.0 Hz, 6H), 2.65 (s, 3H), 5.22-5.28 (m, 1H), 5.74 (s, 1H), 6 47 (s , 2H), 7.57 (d, J=8.4 Hz, 2H), 7.68 (d} j=8.4 Ήζ, 2H), 8.33 (s, 1H), 8.75 (s, 1H), 9.16 (s, 1H) 〇MS (ESI) m/z = 377 (M+H)+. LC/MS tR = 2.14 min. Example 1-426 4-Amino-2-isopropoxy-6-(4-(1-(2-methoxyethenyl)_1H-pyrazole, 4-yl)phenylamino) Alkali nitrile 14l666.doc 366 - 201028381 [Chem. 1426]

標題化合物係使用2-甲氧基乙醯氣，依據實施例1-425之方 法而合成。 1H NMR (400 MHz, DMSO-d6) δ 1.33 (d, 3=6.4 Hz, 6H), 3.43 (s, 3H), 4.88 (s, 2H), 5.22-5.28 (m, 1H), 5.75 (s, 1H), φ 6.47 (s, 2H), 7.58 (d, J=8.4 Hz, 2H), 7.69 (d, J=8.4 Hz, 2H), 8.35 (s, 1H)，8.78 (s, 1H), 9.07 (s，1H)。 MS(ESI)m/z=407 (M+H)+。 LC/MS tR=2.07 min。 實施例1-427 4-胺基-2-異丙氧基-6-(4-(°比啶-4-基）苯基胺基）菸鹼腈 [化 1427]The title compound was synthesized according to the method of Example 1-425 using 2-methoxyethylhydrazine. 1H NMR (400 MHz, DMSO-d6) δ 1.33 (d, 3 = 6.4 Hz, 6H), 3.43 (s, 3H), 4.88 (s, 2H), 5.22-5.28 (m, 1H), 5.75 (s, 1H), φ 6.47 (s, 2H), 7.58 (d, J=8.4 Hz, 2H), 7.69 (d, J=8.4 Hz, 2H), 8.35 (s, 1H), 8.78 (s, 1H), 9.07 (s, 1H). MS (ESI) m / z = 407 (M+H)+. LC/MS tR = 2.07 min. Example 1-427 4-Amino-2-isopropoxy-6-(4-(pyridin-4-yl)phenylamino)nicotinonitrile [Chem. 1427]

標題化合物係使用三氟甲磺酸4-(4-胺基-5-氰基-6-異丙氧 基吡啶-2-基胺基）苯基酯，依據實施例1-337之方法而合 成。 1H-NMR (400 MHz，DMSO-d6) δ 1.34 (d，J=6.〇 Hz，6H)， 5.21-5.29 (m，1H)，5.77 (s，1H)，6.54 (s，2H)，7.67-7.78 (m， 5H)，8.56 (d，J=6.0 Hz，2H)，9.32 (s，1H)。 141666.doc -367- 201028381 MS(ESI)m/z=346 (M+H)+。 LC/MS tR=1.12 min。 實施例1-428 4-胺基-2-異丙氧基-6-(4-(°比咬-3-基）苯基胺基）終驗腈 [化 1428]The title compound was synthesized according to the method of Example 1-137 using 4-(4-amino-5-cyano-6-isopropoxypyridin-2-ylamino)phenyl trifluoromethanesulfonate. . 1H-NMR (400 MHz, DMSO-d6) δ 1.34 (d, J = 6. 〇 Hz, 6H), 5.21-5.29 (m, 1H), 5.77 (s, 1H), 6.54 (s, 2H), 7.67 -7.78 (m, 5H), 8.56 (d, J = 6.0 Hz, 2H), 9.32 (s, 1H). 141666.doc -367- 201028381 MS (ESI) m/z = 346 (M+H)+. LC/MS tR = 1.12 min. Example 1-288 4-Amino-2-isopropoxy-6-(4-(°-But-3-yl)phenylamino) Final Acetonitrile [Chemical 1428]

標題化合物係使用三氟曱績酸4-(4-胺基-5-氰基-6-異丙氧 基吡啶-2-基胺基）苯基酯，依據實施例1-337之方法而合 成。 1H-NMR (400 MHz, DMSO-d6) δ 1.34 (d，J=6.0 Hz，6H)， 5.23-5.29 (m, 1H), 5.79 (s, 1H), 6.53 (s, 2H), 7.56-7.77 (m, 6H)，9.12 (s，1H)，9.31 (s，1H)。 MS(ESI)m/z=347 (M+H)+。 LC/MS tR=1.78 min。 實施例1-429 4-胺基-2-異丙氧基-6-(4-(°比咬_5-基）苯基胺基）於驗腈 [化 1429]The title compound was synthesized according to the method of Example 1-137 using 4-(4-amino-5-cyano-6-isopropoxypyridin-2-ylamino)phenyl ester of trifluoromethane. . 1H-NMR (400 MHz, DMSO-d6) δ 1.34 (d, J = 6.0 Hz, 6H), 5.23-5.29 (m, 1H), 5.79 (s, 1H), 6.53 (s, 2H), 7.56-7.77 (m, 6H), 9.12 (s, 1H), 9.31 (s, 1H). MS (ESI) m / z = 347 (M+H)+. LC/MS tR = 1.78 min. Example 1-429 4-Amino-2-isopropoxy-6-(4-(° ratio _5-yl)phenylamino) in the nitrile [Chem. 1429]

標題化合物係使用三氟甲磺酸4-(4-胺基-5-氰基-6-異丙氧 基《•比唆_2_基胺基）苯基酯，依據實施例1 -337之方法而合 141666.doc -368 - 201028381 ' 成。 1H-NMR (400 MHz, DMSO-d6) δ 1.34 (d, J=6.0 Hz, 6H), 5.23-5.29 (m, 1H), 5.77 (s, 1H), 6.50 (s, 2H), 7.43-7.46 (m, 1H), 7.67 (s, 4H), 8.04 (d, J=8.4 Hz, 1H), 8.50 (d, J=4.8 Hz，1H)，8_88 (s，1H)，9.24 (s，1H)。 MS(ESI)m/z=346 (M+H)+。 LC/MS tR=1.35 min。 實施例1-430 Ο 6-(4-(lH-吡唑-3-基）苯基胺基）-4-胺基-2-異丙氧基菸 驗腈 [化 1430]The title compound is 4-(4-amino-5-cyano-6-isopropoxy[•bi-2-ylamino)phenyl ester of trifluoromethanesulfonate according to Example 1-337. Method and 141666.doc -368 - 201028381 '成成. 1H-NMR (400 MHz, DMSO-d6) δ 1.34 (d, J = 6.0 Hz, 6H), 5.23-5.29 (m, 1H), 5.77 (s, 1H), 6.50 (s, 2H), 7.43-7.46 (m, 1H), 7.67 (s, 4H), 8.04 (d, J=8.4 Hz, 1H), 8.50 (d, J=4.8 Hz, 1H), 8_88 (s, 1H), 9.24 (s, 1H) . MS (ESI) m / z = 346 (M + H) +. LC/MS tR = 1.35 min. Example 1-430 Ο 6-(4-(lH-pyrazol-3-yl)phenylamino)-4-amino-2-isopropoxy oxime Acetonitrile [Chemical 1430]

標題化合物係使用三氟甲磺酸4-(4-胺基-5-氰基-6-異丙氧 基吡啶-2-基胺基）苯基酯，依據實施例1-337之方法而合 參 成0 MS(ESI)m/z=335 (M+H)+ 〇 LC/MS tR=l.75 min。 實施例1-431 4-胺基-2-異丙氧基-6-(4-( 1-(2-曱氧基乙基）_ 1H-n比唑-4-基）苯基胺基）菸鹼腈 141666.doc -369- 201028381 [化 1431]The title compound was obtained using 4-(4-amino-5-cyano-6-isopropoxypyridin-2-ylamino)phenyl trifluoromethanesulfonate according to the method of Example 1-137. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Example 1-431 4-Amino-2-isopropoxy-6-(4-(1-(2-oximeoxyethyl)-1H-n-pyrazol-4-yl)phenylamino) Nicotinonitrile 141666.doc -369- 201028381 [Chemical 1431]

標題化合物係使用三氟曱磺酸4_(4_胺基_5_氰基_6•異丙 氧基吡啶-2-基胺基）苯基酯，依據實施例ι_337之方法而合 成。 1H-NMR (400 MHz, DMSO-d6) δ 1.32 (d, J=6.0 Hz, 6H), 3.70 (t, J=4.2 Hz, 2H), 4.25 (t, J=4.2 Hz, 2H), 5.21-5.26 (m, 1H), 5.71 (s, 1H), 6.42 (s, 2H), 7.46-7.51 (m, 4H), 7.81 (s，1H), 8.05 (s，1H), 9.04 (s，1H)。 MS(ESI)m/z=393 (M+H)+。 LC/MS tR=1.90 min。 實施例1-432 4-胺基-2-異丙氧基-6-(4-(3-甲基異噁唑-5-基）苯基胺基） 菸鹼腈 [化 1432]The title compound was synthesized according to the method of Example ι-337 using 4-(4-amino-5-cyano-6-isopropoxypyridin-2-ylamino)phenyl ester of trifluoromethanesulfonic acid. 1H-NMR (400 MHz, DMSO-d6) δ 1.32 (d, J = 6.0 Hz, 6H), 3.70 (t, J = 4.2 Hz, 2H), 4.25 (t, J = 4.2 Hz, 2H), 5.21- 5.26 (m, 1H), 5.71 (s, 1H), 6.42 (s, 2H), 7.46-7.51 (m, 4H), 7.81 (s, 1H), 8.05 (s, 1H), 9.04 (s, 1H) . MS (ESI) m / z = 393 (M+H)+. LC/MS tR = 1.90 min. Example 1-432 4-Amino-2-isopropoxy-6-(4-(3-methylisoxazol-5-yl)phenylamino) Nicotinonitrile [Chemical 1432]

THF, 50 °C 涉驟1-1)THF, 50 °C involved in step 1-1)

141666.doc -370- 201028381 h2n141666.doc -370- 201028381 h2n

Me HO—&lt; MeMe HO—&lt; Me

步驟1-1 : 1-(4-碘苯基）丁烷-1,3-二酮 向乙酸乙 S旨（788 mg，0.875 mL，8.94 mmol)之 THF 溶液 中添加60%氫化納（533 mg，22.2 mmol)，其次添加1-(4-蛾 苯基）乙酮（1.0 g，4.06 mmol)、18-冠-6(32.2 mg，0.122 mmol)及乙醇（2滴），於40°C下攪拌6小時。向反應溶液中 φ 添加1 mol/L鹽酸水溶液及乙酸乙酯，進行分離後，以乙 酸乙酯萃取水相，將合併之有機相以水及飽和食鹽水進行 清洗，以硫酸鎂加以乾燥。將有機相過濾後，進行減壓濃 縮。利用中壓矽膠層析法（乙酸乙酯：己烷=4 : 1)對所獲 得之殘渣進行純化，獲得標題化合物（1.11 g，95%)，為黃 色固體。 1H-NMR (400 MHz, DMSO-d6) δ 2.20 (s, 3H), 6.57 (s, 2H), 7.72 (d，J=6.4 Hz, 2H)，7.91 (d，J=6.4 Hz，2H)。 MS(ESI)m/z=289 (M+H)+。 LC/MS tR=2.43 min。 步驟1-2: 5-(4-碘苯基）-3-甲基異噁唑 向 1-(4-埃苯基）丁院-1,3-二酮（500 mg，1 _74 111111〇1)之 0比 °定溶液中添加肢鹽酸鹽（145 mg，2.08 mmol)，於室溫下攪; 拌3小時。向反應溶液中添加水及乙酸乙酯進行分離後， 以乙酸乙酯萃取水相，將合併之有機相以水及飽和食鹽水 進行清洗，以硫酸鎂加以乾燥。將有機相過濾後，進行減 141666.doc -371 - 201028381 壓濃縮。利用中壓矽膠層析法（乙酸乙酯：己烷=2 : 1)對 所獲得之殘渣進行純化，獲得標題化合物（305 mg， 62%)，為黃色油。 1H-NMR (400 MHz, DMSO-d6) δ 1.96 (s, 3H), 7.21 (s, 1H), 7.28 (d, J=8.0 Hz, 2H), 7.73 (d，J=8.0 Hz, 2H)。 MS(ESI)m/z=286 (M+H)+。 LC/MS tR=1.64 min。 步驟2-1 : 4,6-二胺基-2-異丙氧基菸鹼腈 於20 mL微波反應容器中，向4,6-二胺基-2-溴菸鹼腈（1.0 g，4.69 mmol)之異丙醇（10 mL)溶液中添加60%氫化納（563 mg，23.5 mmol)，進行覆蓋，使用 Biotage Optimizer 反應 裝置，於160°C下攪拌30分鐘。向反應溶液中添加水及乙 酸乙酯進行分離後，以乙酸乙酯萃取水相，將合併之有機 相以水及飽和食鹽水進行清洗，以硫酸鎮加以乾燥。將有 機相過濾後，進行減壓濃縮。利用中壓矽膠層析法（己 烷：乙酸乙酯=5 : 1)對所獲得之殘渣進行純化，獲得標題 化合物（560 mg，2.91 mmol，62%)，為白色固體。 1H-NMR (400 MHz, DMSO-d6) δ 1.24 (d, J=6.4 Hz, 6H), 5.17-5.24 (m, 1H), 5.32 (s, 1H), 6.12 (s, 2H), 6.17 (s, 2H)。 步驟2-2 :標題化合物 於5 mL微波反應容器中，向4,6-二胺基-2-異丙氧基菸鹼 腈（100 mg，0.520 mmol)、5-(4-碘苯基）-3-曱基異噁唑（148 mg，0.520 mmol)、Xantphos(60.2 mg，0.104 mmol)及碳酸 141666.doc •372· 201028381 铯（237 mg，0.728 mmol)之二噁烷（3 mL)溶液中添加Step 1-1: 1-(4-Iodophenyl)butane-1,3-dione to 60% sodium hydride (533 mg) in THF (78 mg, 0.875 mL, 8.94 mmol) in THF , 22.2 mmol), followed by addition of 1-(4-mothenyl)ethanone (1.0 g, 4.06 mmol), 18-crown-6 (32.2 mg, 0.122 mmol) and ethanol (2 drops) at 40 ° C Stir for 6 hours. After a 1 mol/L hydrochloric acid aqueous solution and ethyl acetate were added to the reaction solution, the mixture was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and brine and dried over magnesium sulfate. After the organic phase was filtered, it was concentrated under reduced pressure. The residue obtained was purified by EtOAc EtOAc (EtOAc:EtOAc: 1H-NMR (400 MHz, DMSO-d6) δ 2.20 (s, 3H), 6.57 (s, 2H), 7.72 (d, J = 6.4 Hz, 2H), 7.91 (d, J = 6.4 Hz, 2H). MS (ESI) m / z = 289 (M+H)+. LC/MS tR = 2.43 min. Step 1-2: 5-(4-Iodophenyl)-3-methylisoxazole to 1-(4-Ethyl) Dingyuan-1,3-dione (500 mg, 1 _74 111111〇1 Add 0 mg of the hydrochloride salt (145 mg, 2.08 mmol) to the solution and stir at room temperature; mix for 3 hours. After water and ethyl acetate were added to the reaction solution for separation, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water and brine and dried over magnesium sulfate. After the organic phase was filtered, the concentration was reduced by 141666.doc -371 - 201028381. The residue obtained was purified by EtOAc EtOAc (EtOAc:EtOAc) 1H-NMR (400 MHz, DMSO-d6) δ 1.96 (s, 3H), 7.21. (s, 1H), 7.28 (d, J = 8.0 Hz, 2H), 7.73 (d, J = 8.0 Hz, 2H). MS (ESI) m / z = 286 (M+H)+. LC/MS tR = 1.64 min. Step 2-1: 4,6-Diamino-2-isopropoxy nicotine nitrile in a 20 mL microwave reaction vessel to 4,6-diamino-2-bromonicotinonitrile (1.0 g, 4.69 60% of sodium hydride (563 mg, 23.5 mmol) was added to a solution of mmol) in isopropyl alcohol (10 mL), and the mixture was stirred and stirred at 160 ° C for 30 minutes using a Biotage Optimizer reaction apparatus. Water and ethyl acetate were added to the reaction solution for separation, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and brine, and dried over EtOAc. After filtering the organic phase, it was concentrated under reduced pressure. The residue obtained was purified by EtOAc EtOAc (EtOAcjjjjjjj 1H-NMR (400 MHz, DMSO-d6) δ 1.24 (d, J = 6.4 Hz, 6H), 5.17-5.24 (m, 1H), 5.32 (s, 1H), 6.12 (s, 2H), 6.17 (s , 2H). Step 2-2: The title compound was taken in a 5 mL microwave reaction vessel to 4,6-diamino-2-isopropoxynicotinonitrile (100 mg, 0.520 mmol), 5-(4-iodophenyl) -3-mercaptoisoxazole (148 mg, 0.520 mmol), Xantphos (60.2 mg, 0.104 mmol) and 141666.doc • 372· 201028381 铯 (237 mg, 0.728 mmol) in dioxane (3 mL) Add in

Pd(OAc)2(11.7 mg ’ 0.052 mmol)，進行覆蓋，使用 BiotagePd(OAc)2 (11.7 mg '0.052 mmol), covered, using Biotage

Optimizer反應裝置，於120°C下攪拌1小時。向反應溶液中 添加水及乙酸乙酯進行分離後’以乙酸乙醋萃取水相，將 合併之有機相以水及飽和食鹽水進行清洗，以硫酸鎂加以 乾燥。將有機相過濾後，進行減壓濃縮。利用逆相等分試 樣液相層析法（C18管柱，水/乙腈/〇丨甲酸梯度）對所獲得 之殘渣進行純化，獲得標題化合物（17 8 mg，1〇%)，為白 # 色固體。 1H-NMR (400 MHz，DMSO-d6) δ 1.34 (d, J=6.0 Hz, 6H), 2.26 (s, 3H), 5.21-5.27 (m, 1H), 5.78 (s, 1H), 6.54 (s, 2H), 6.59 (s，1H)，7.70 (dd, J=8.8 Hz, 16.4 Hz，4H)，9.38 (s, 1H)。 ’ MS(ESI)m/z=350 (M+H)+。 LC/MS tR=2*15 min 〇 實施例1_433 4-胺基-2-異丙氧基-6_(4-(5_甲基吡唑_3•基）苯基胺 基）菸鹼腈 [化 1433]The Optimizer reaction apparatus was stirred at 120 ° C for 1 hour. Water and ethyl acetate were added to the reaction solution for separation. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and brine and dried over magnesium sulfate. After the organic phase was filtered, it was concentrated under reduced pressure. The residue obtained was purified by reverse phase-division liquid chromatography (C18 column, water / acetonitrile / hydrazide gradient) to give the title compound (17 8 mg, 1%) as white color solid. 1H-NMR (400 MHz, DMSO-d6) δ 1.34 (d, J = 6.0 Hz, 6H), 2.26 (s, 3H), 5.21-5.27 (m, 1H), 5.78 (s, 1H), 6.54 (s , 2H), 6.59 (s, 1H), 7.70 (dd, J = 8.8 Hz, 16.4 Hz, 4H), 9.38 (s, 1H). ' MS (ESI) m/z = 350 (M+H)+. LC/MS tR=2*15 min 〇Example 1_433 4-Amino-2-isopropoxy-6-(4-(5-methylpyrazole-3-yl)phenylamino)nicotinonitrile 1433]

141666.doc -373- 201028381 向1-(4-碘苯基）丁烷-丨，％二酮（470 mg，1.63 mmol)之甲 醇溶液中添加肼水合物（82 mg，1.631 mmol)，於室溫下授 拌3小時。向反應溶液中添加水及乙酸乙酯進行分離後， 以乙酸乙酯萃取水相，將合併之有機相以水及飽和食鹽水 進行清洗，以硫酸鎂加以乾燥。將有機相過濾後，進行減 壓濃縮。利用中壓矽膠層析法（乙酸乙酯：己烷=2 : 1)對 所獲得之殘渣進行純化，獲得標題化合物（288 mg， 62%)，為黃色固體。 1H-NMR (400 MHz, DMSO-d6) δ 2.26 (s, 3H), 6.44 (s, 1H), 7.73 (d, J=7.6 Hz, 2H), 7.76 (d, J=7.6 Hz, 2H), 12.64 (s, 1H)。 MS(ESI)m/z=285 (M+H)+。 LC/MS tR = 1.93 min。 步驟2 :標題化合物 標題化合物係依據實施例1-432(步驟2-2)之方法而合 成。 1H-NMR (400 MHz, DMSO-d6) δ 1.32 (d, J=6.0 Hz, 6H), 2.23 (s, 3H), 5.22-5.26 (m, 1H), 5.73 (s, 1H), 6.35 (s, 1H), 6.44 (s, 2H), 7.52 (d, J=8.4 Hz, 2H), 7.63 (d, J=8.4 Hz, 2H)，9.11 (s，1H)。 MS(ESI)m/z=349 (M+H)+。 LC/MS tR=l-79 min o 實施例1-434 6-(4-(111-13米e坐-4_基）苯基胺基）-4 -胺基-2 -異丙氧基於 141666.doc -374· 201028381 驗腈141666.doc -373- 201028381 Add hydrazine hydrate (82 mg, 1.631 mmol) to a solution of 1-(4-iodophenyl)butane-indole, 5% diketone (470 mg, 1.63 mmol) in methanol. Warm mixing for 3 hours. After water and ethyl acetate were added to the reaction solution for separation, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water and brine and dried over magnesium sulfate. After the organic phase was filtered, it was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc: 1H-NMR (400 MHz, DMSO-d6) δ 2.26 (s, 3H), 6.44 (s, 1H), 7.73 (d, J = 7.6 Hz, 2H), 7.76 (d, J = 7.6 Hz, 2H), 12.64 (s, 1H). MS (ESI) m / z = 285 (M+H)+. LC/MS tR = 1.93 min. Step 2: title compound The title compound was synthesized according to the procedure of Example 1-432 (Step 2-2). 1H-NMR (400 MHz, DMSO-d6) δ 1.32 (d, J = 6.0 Hz, 6H), 2.23 (s, 3H), 5.22-5.26 (m, 1H), 5.73 (s, 1H), 6.35 (s , 1H), 6.44 (s, 2H), 7.52 (d, J=8.4 Hz, 2H), 7.63 (d, J=8.4 Hz, 2H), 9.11 (s, 1H). MS (ESI) m/z = 495 (M+H)+. LC/MS tR=1-79 min o Example 1-341 6-(4-(111-13 m e-s--4-yl)phenylamino)-4-amino-2-isopropoxy group at 141666 .doc -374· 201028381

[化 1434][Chem. 1434]

步驟1 : 4-(4-碘苯基）-1Η-咪唑Step 1: 4-(4-iodophenyl)-1Η-imidazole

向 4-碘苯曱醛（1.0 g，4.31 mmol)及TosMIC(765 mg， 3·92 mmol)之乙醇溶液中添加氰化納（19.2 mg，0.392 mmol)，於室溫下攪拌1小時，進行減壓濃縮。將所獲得之 黃色固體移至20 mL微波反應容器中，添加7 Μ氨·甲醇溶 液（1 5 mL)，進行覆蓋，使用Biotage Optimizer反應裝置， 於ll〇°C下攪拌10小時。向反應溶液中添加水及乙酸乙酯 進行分離後，以乙酸乙酯萃取水相，將合併之有機相以水 及飽和食鹽水進行清洗，以硫酸鎂加以乾燥。將有機相過 濾後，進行減壓濃縮。利用中壓矽膠層析法（乙酸乙酯： 己烷=1 : 1)對所獲得之殘渣進行純化，獲得標題化合物 (5 3 0 mg，50%)，為淡黃色固體。 1H-NMR (400 MHz, DMSO-d6) δ 7.59-7.74 (m, 6H), 12.8 141666.doc -375 - 201028381 (brs, 1H) 〇 MS(ESI)m/z=271 (M+H)+。 LC/MS tR=0.81 min。 步驟2 : 4-(4-碘苯基）-1-三苯甲基·ιη-咪唾 向4-(4-碘苯基）-1Η-咪峻（373 mg’ ΐ·38 mm〇1)&amp;三苯曱 基氣（501 mg ’ 1.80 mmol)之DMF溶液中添加三乙基胺（28〇 mg，383 μί ’ 2·76 mmol)，於室溫下攪拌6小時。向反應 溶液中添加水及乙酸乙醋進行分離後，以乙酸乙醋萃取水Add sodium cyanide (19.2 mg, 0.392 mmol) to a solution of 4-iodobenzaldehyde (1.0 g, 4.31 mmol) and TosMIC (765 mg, 3.92 mmol) in ethanol, and stir at room temperature for 1 hour. Concentrate under reduced pressure. The obtained yellow solid was transferred to a 20 mL microwave reaction vessel, and 7 Μ ammonia·methanol solution (15 mL) was added, covered, and stirred at ll 〇 ° C for 10 hours using a Biotage Optimizer reaction apparatus. Water and ethyl acetate were added to the reaction solution for separation, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and brine, and dried over magnesium sulfate. The organic phase was filtered and concentrated under reduced pressure. The residue obtained was purified by EtOAc EtOAc (EtOAc:EtOAc: 1H-NMR (400 MHz, DMSO-d6) δ 7.59-7.74 (m, 6H), 12.8 141666.doc -375 - 201028381 (brs, 1H) 〇MS(ESI) m/z=271 (M+H)+ . LC/MS tR = 0.81 min. Step 2: 4-(4-iodophenyl)-1-tritylmethyl·ιη-mipropion to 4-(4-iodophenyl)-1Η-mi (373 mg' ΐ·38 mm〇1) Triethylamine (28 mg, 383 μί '2·76 mmol) was added to a solution of triphenylsulfonyl (501 mg ' 1.80 mmol) in DMF and stirred at room temperature for 6 hours. After adding water and ethyl acetate to the reaction solution for separation, the water was extracted with ethyl acetate.

相’將合併之有機相以水及飽和食鹽水進行清洗，以硫酸 鎂加以乾燥。將有機相過濾後’進行減壓濃縮。利用中壓 矽膠層析法（乙酸乙酯：己烷=2: 1)對所獲得之殘潰進行 純化，獲得標題化合物（617 mg，87%)，為白色固體。 lH-NMR(400 MHz，DMSO_d6”7.15-7.l7(m6H)7.38-7.50 (m, 1H)，7.55 (d，J=8.4 Hz，2H)，7.66 (d, J=8.4 Hz， 2H)。The combined organic phase was washed with water and saturated brine and dried over magnesium sulfate. After the organic phase was filtered, it was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc) lH-NMR (400 MHz, DMSO_d6) 7.15-7.l7 (m6H) 7.38-7.50 (m, 1H), 7.55 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 8.4 Hz, 2H).

步驟3 : 4-胺基-2 -異丙氧基-6-(4-(1-三笨甲基米〇坐_ 4-基）苯基胺基）菸鹼腈 使用4,6-二胺基-2-異丙氧基菸驗腈（j 1〇 mg，〇 572 mmol)及4-(4-埃苯基）-1-三苯甲基-1H-咪嗤，依據實旅例ι_ 432(步驟 2-2)而合成（105 mg，32%)。 1H-NMR (400 MHz，DMSO-d6) δ 1.30 (d，J=6 4 Hz, 6H)， 5.19-5.23 (m，1H)，5.69 (s, 1H)，6.41 (s，ijj)，7.17 (d，J=6.4 Hz，6H), 7.31-7.48 (m，13H)，7.62-7.64 (m，2H)。 MS(ESI)m/z=577 (M+H)+。 141666.doc -376· 201028381 LC/MS min 〇 步驟4 :標題化合物 向4-胺基-2-異丙氧基_6_(4_(1三苯甲基_1H咪唑_4基） 苯基胺基）菸鹼腈（17 mg，〇.037 mm〇1)中添加TFA :二氣甲 烧=4 : 1溶液’於室溫下攪拌3小時。將反應溶液減壓濃 縮，利用中壓石夕膠層析法（氣仿：甲醇：水=64 : 12 : 1)對 所獲得之殘渣進行純化，獲得標題化合物（19 mg，0.057 mmol，33%) o β 1H_NMR (400 MHz，DMSO-d6) δ 1.33 (d，J=6.0 Hz, 6Η)， 5.22-5.28 (m, 1H), 5.73 (s, 1H), 6.24 (s, 2H), 7.48-7.56 (m, 4H), 7.67-7.70 (m, 2H), 9.03 (s, 1H), 12.08 (s, 1H) ° MS(ESI)m/z=335 (M+H)+。 LC/MS tR=1.01 min。 實施例1-435 4-胺基-6-(4-( 1-(3-(二甲基胺基）丙基）_ιη·〇比唑-4-基）苯 基胺基）-2-異丙氧基於驗腈 •[化 1435]Step 3: 4-Amino-2-isopropoxy-6-(4-(1-triphenylmethylpyridinyl-4-yl)phenylamino)nicotinonitrile using 4,6-diamine Alkyl-2-isopropoxyacetonitrile (j 1 〇 mg, 〇 572 mmol) and 4-(4-Ethyl)-1-trityl-1H-imidine, according to the actual example ι_ 432 (Step 2-2) and synthesized (105 mg, 32%). 1H-NMR (400 MHz, DMSO-d6) δ 1.30 (d, J = 6 4 Hz, 6H), 5.19-5.23 (m, 1H), 5.69 (s, 1H), 6.41 (s, ijj), 7.17 ( d, J = 6.4 Hz, 6H), 7.31-7.48 (m, 13H), 7.62 - 7.64 (m, 2H). MS (ESI) m / z = 577 (M+H)+. 141666.doc -376· 201028381 LC/MS min 〇Step 4: title compound to 4-amino-2-isopropoxy-6-(4-(1triphenylmethyl-1H imidazole-4-yl)phenylamino To the nicotinic nitrile (17 mg, 〇.037 mm〇1), TFA was added: a two-gas-fired = 4:1 solution was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure. o β 1H_NMR (400 MHz, DMSO-d6) δ 1.33 (d, J = 6.0 Hz, 6 Η), 5.22-5.28 (m, 1H), 5.73 (s, 1H), 6.24 (s, 2H), 7.48- 7.56 (m, 4H), 7.67-7.70 (m, 2H), 9.03 (s, 1H), 12.08 (s, 1H) ° MS (ESI) m/z = 335 (M+H)+. LC/MS tR = 1.01 min. Example 1-435 4-Amino-6-(4-(1-(3-(dimethylamino)propyl)-yl)-indoleazole-4-yl)phenylamino)-2-iso Propoxy in the test of nitrile • [Chemical 1435]

標題化合物係依據實施例1-338之方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 1.32 (d, J=6.0 Hz, 6H), 1.92 (t, J=6.8 Hz, 2H), 2.16 (s, 6H), 2.19 (t, J=6.8 Hz, 2H), 141666.doc -377 - 201028381 4.11 (t, J=6.8 Hz, 2H), 5.21-5.27 (m, 1H), 5.71 (s, 1H), 6.41 (s, 2H), 7.48 (s, 4H), 7.80 (s, 1H), 8.06 (s, 1H), 9.03 (s, 1H)。 MS(ESI)m/z=420 (M+H)+。 LC/MS tR=1.10 min。 實施例1-436 4-胺基-6-(4-(噁唑-5-基）苯基胺基）-2-丙氧基菸鹼腈 [化 1436]The title compound was synthesized according to the method of Example 1-338. 1H-NMR (400 MHz, DMSO-d6) δ 1.32 (d, J = 6.0 Hz, 6H), 1.92 (t, J = 6.8 Hz, 2H), 2.16 (s, 6H), 2.19 (t, J = 6.8 Hz, 2H), 141666.doc -377 - 201028381 4.11 (t, J=6.8 Hz, 2H), 5.21-5.27 (m, 1H), 5.71 (s, 1H), 6.41 (s, 2H), 7.48 (s , 4H), 7.80 (s, 1H), 8.06 (s, 1H), 9.03 (s, 1H). MS (ESI) m / z = 420 (M + H) +. LC/MS tR = 1.10 min. Example 1-436 4-Amino-6-(4-(oxazol-5-yl)phenylamino)-2-propoxynicotinonitrile [Chemical 1436]

步驟1 : 4-胺基-2-丙氧基-6-側氧基-1,6-二氫吡啶-3-腈 標題化合物係依據實施例1-416(步驟1)之方法而合成。 1H NMR (300 MHz, DMSO-d6) δ 0.95 (t, J=7.2 Hz, 3H), 1.63-1.75 (m, 2H), 4.19 (t, J=6.9 Hz, 2H), 5.53 (s, 1H), 6.60 (s, 2H)，10.83 (s，1H)。 MS(ESI)m/z=194 (M+H)+。 步驟2:三氟甲磺酸4-胺基-5-氰基-6-丙氧基吡啶-2-基酯 標題化合物係使用4 -胺基-2-丙氧基-6 -侧氧基-1，6 -— IL 吡啶-3-腈，依據實施例1-408(步驟2)之方法而合成。 1H NMR (300 MHz, DMSO-d6) δ 0.92 (t, J=7.2 Hz, 3H), 141666.doc -378- 201028381 1.63-1.75 (m, 2H), 4.20 (t, J=6.6 Hz, 2H), 6.29 (s, 1H), 7.66 (brs, 2H) ° MS(ESI)m/z=326 (M+H)+。 步驟3 :標題化合物 依據實施例1-416(步驟3)之方法而合成。 1H NMR (300 MHz, DMSO-d6) δ 0.97 (t, J=6.0 Hz, 3H), 1.67-1.76 (m, 2H), 4.25 (t, J=6.0 Hz, 2H), 5.75 (s, 1H), 6.53 (s, 2H), 7.52 (s, 1H), 7.60 (d, J=9.0 Hz, 2H), 7.65 (d, ❹ J=9.0 Hz，2H)，8.35 (s, 1H), 9_29 (s，1H)。 MS(ESI)m/z=336 (M+H)+。 LC/MS tR=1.99 min。 實施例1-437 4-胺基-6-(3-甲氧基-4-(噁唑-5-基）苯基胺基）-2-丙氧基菸 驗猜 [化 1437]Step 1: 4-Amino-2-propoxy-6-oxo-1,6-dihydropyridine-3-carbonitrile The title compound was synthesized according to the procedure of Example 1-416 (Step 1). 1H NMR (300 MHz, DMSO-d6) δ 0.95 (t, J = 7.2 Hz, 3H), 1.63-1.75 (m, 2H), 4.19 (t, J = 6.9 Hz, 2H), 5.53 (s, 1H) , 6.60 (s, 2H), 10.83 (s, 1H). MS (ESI) m / z = 194 (M + H) +. Step 2: 4-Amino-5-cyano-6-propoxypyridin-2-yl trifluoromethanesulfonate The title compound is 4-amino-2-propoxy-6-sideoxy-- 1,6--IL pyridine-3-carbonitrile was synthesized according to the method of Example 1-408 (Step 2). 1H NMR (300 MHz, DMSO-d6) δ 0.92 (t, J = 7.2 Hz, 3H), 141666.doc -378 - 201028381 1.63-1.75 (m, 2H), 4.20 (t, J = 6.6 Hz, 2H) , 6.29 (s, 1H), 7.66 (brs, 2H) ° MS (ESI) m/z = 326 (M+H)+. Step 3: The title compound was synthesized according to the method of Example 1-416 (Step 3). 1H NMR (300 MHz, DMSO-d6) δ 0.97 (t, J = 6.0 Hz, 3H), 1.67-1.76 (m, 2H), 4.25 (t, J = 6.0 Hz, 2H), 5.75 (s, 1H) , 6.53 (s, 2H), 7.52 (s, 1H), 7.60 (d, J=9.0 Hz, 2H), 7.65 (d, ❹ J=9.0 Hz, 2H), 8.35 (s, 1H), 9_29 (s , 1H). MS (ESI) m / z = 336 (M + H) +. LC/MS tR = 1.99 min. Example 1-437 4-Amino-6-(3-methoxy-4-(oxazol-5-yl)phenylamino)-2-propoxyacetic acid test [Chem. 1437]

標題化合物係使用三氟甲磺酸4-胺基-5-氰基-6-丙氧基 吡啶-2-基酯及對應之苯胺衍生物，依據實施例1-145之方 法而合成。 MS(ESI)m/z=366 (M+H)+。 LC/MS tR=2.05 min。 實施例1-438 141666.doc -379- 201028381 4-胺基-6-(4-(噁唑-5-基）苯基胺基）-2-苯乙氧基菸鹼腈 [化 1438]The title compound was synthesized according to the method of Example 1-145 using 4-amino-5-cyano-6-propoxypyridin-2-yl trifluoromethanesulfonate and the corresponding aniline derivative. MS (ESI) m / z = 366 (M+H)+. LC/MS tR = 2.05 min. Example 1-438 141666.doc -379- 201028381 4-Amino-6-(4-(oxazol-5-yl)phenylamino)-2-phenylethoxy nicotine nitrile [Chem. 1438]

步驟1 · 4 -胺基-2 -苯乙氧基-6 -側氧基-1，6 -二氣11比。定-3 -猜 標題化合物係依據實施例1-416(步驟1)之方法而合成。 1H NMR (300 MHz, DMSO-d6) δ 2.97 (t, J=6.9 Hz, 2H), 4.39 (t, J=6.9 Hz, 2H), 5.51 (s, 1H), 6.60 (s, 2H), 7.16-7.30 (m，5H), 10.78 (s, 1H)。 MS(ESI)m/z=256 (M+H)+。 步驟2 :三氟曱磺酸4-胺基-5-氰基-6-苯乙氧基-比啶-2-基醋 標題化合物係使用4-胺基-2-苯乙氧基-6-側氧基-1,6-二 氫吡啶-3-腈，依據實施例1-408(步驟2)之方法而合成。 1H NMR (300 MHz, DMSO-d6) δ 3.00 (t, J=6.9 Hz, 2H), 4.42 (t, J=6.9 Hz, 2H), 6.29 (s, 1H), 7.18-7.30 (m, 5H), 7.66 (s, 2H)。 MS(ESI)m/z=388 (M+H)+。 步驟3 :標題化合物 依據實施例1-416(步驟3)之方法而合成。 141666.doc -380- 201028381 1H NMR (300 MHz, DMSO-d6) δ 3.04 (t, J=6.0 Hz, 2H), 4.52 (t, J=6.0 Hz, 2H), 5.78 (s, 1H), 6.57 (s, 2H), 7.24-7.33 (m，5H)，7.54 (s, 1H)，7.60 (d，J=9.〇 Hz, 2H), 7.65 (d， J=9.0 Hz，2H)，8.39 (s, 1H)，9.31 (s，1H)。 MS(ESI)m/z=398 (M+H)+。 LC/MS tR=2.17 min。 mp : 217-220。。。 實施例1-439 Φ 4-胺基-6-(3-甲氧基-4-(噁唑-5-基）苯基胺基）-2-苯乙氧基 於驗腈 [化 1439]Step 1 · 4 -Amino-2-phenylethoxy-6-c-oxy-1,6-diox 11 ratio. The title compound was synthesized according to the method of Example 1-416 (Step 1). 1H NMR (300 MHz, DMSO-d6) δ 2.97 (t, J = 6.9 Hz, 2H), 4.39 (t, J = 6.9 Hz, 2H), 5.51 (s, 1H), 6.60 (s, 2H), 7.16 -7.30 (m,5H), 10.78 (s, 1H). MS (ESI) m / z = 256 (M + H) +. Step 2: 4-Amino-5-cyano-6-phenylethoxy-pyridin-2-yl vinegar trifluorosulfonate The title compound was 4-amino-2-phenylethoxy-6- The pendant oxy-1,6-dihydropyridine-3-carbonitrile was synthesized according to the method of Example 1-408 (Step 2). 1H NMR (300 MHz, DMSO-d6) δ 3.00 (t, J = 6.9 Hz, 2H), 4.42 (t, J = 6.9 Hz, 2H), 6.29 (s, 1H), 7.18-7.30 (m, 5H) , 7.66 (s, 2H). MS (ESI) m / z = 388 (M+H)+. Step 3: The title compound was synthesized according to the method of Example 1-416 (Step 3). 141666.doc -380- 201028381 1H NMR (300 MHz, DMSO-d6) δ 3.04 (t, J = 6.0 Hz, 2H), 4.52 (t, J = 6.0 Hz, 2H), 5.78 (s, 1H), 6.57 (s, 2H), 7.24-7.33 (m, 5H), 7.54 (s, 1H), 7.60 (d, J=9.〇Hz, 2H), 7.65 (d, J=9.0 Hz, 2H), 8.39 ( s, 1H), 9.31 (s, 1H). MS (ESI) m / z = 398 (M+H)+. LC/MS tR = 2.17 min. Mp: 217-220. . . Example 1-439 Φ 4-Amino-6-(3-methoxy-4-(oxazol-5-yl)phenylamino)-2-phenylethoxy group in the test of nitrile [Chem. 1439]

標題化合物係使用三氟曱績酸4-胺基-5-氰基-6-苯乙氧 基吡啶-2-基酯及對應之苯胺衍生物，依據實施例1-145之 方法而合成。 MS(ESI)m/z=428 (M+H)+ 0 LC/MS tR=2.23 min 〇 實施例1-440 4-胺基-2-(環丙基甲氧基）-6·(4_(噁唑-5-基）苯基胺基）菸 驗腈 141666.doc -381- 201028381 [化 1440] νη2 οThe title compound was synthesized according to the method of Example 1-145 using 4-amino-5-cyano-6-phenethyloxypyridin-2-yl ester as the corresponding aniline derivative. MS (ESI) m / z = 428 (M + H) + &lt;&quot;&&&&&&&&&&&&&&&&&&&&& Oxazol-5-yl)phenylamino)nicotinonitrile 141666.doc -381- 201028381 [Chemical 1440] νη2 ο

CNCN

Pd(OAc)2, BINAP CS2CO3 二噁烷，120 0cPd(OAc)2, BINAP CS2CO3 dioxane, 120 0c

步驟1 . 4 -胺基-2 -環丙基甲乳基-6 -侧氧基-1，6 -二鼠。比 咬-3 -甲猜 標題化合物係依據實施例1-416(步驟1)之方法而合成。 lHNMR(300 MHz，DMSO-d6)S0_28-0.32 (m,2H)，0.47-0.55 (m, 2H), 1.13-1.26 (m, 1H), 4.06 (d, J=6.9 Hz, 2H), 5.50 (s，1H)，6.58 (s，2H)，10.75 (brs，1H)。 MS(ESI)m/z=206 (M+H)+。 步驟2 :三氟曱磺酸4-胺基-5-氰基-6-環丙基甲氧基吡啶-2 -基醋 標題化合物係使用4-胺基-2-環丙基甲氧基-6-側氧基-1,6-二氫吡啶-3-甲腈，依據實施例1-408(步驟2)之方法而 合成。 1H NMR (300 MHz, DMSO-d6) δ 0.30-0.35 (m, 2H), 0.52-0.58 (m, 2H), 1.17-1.29 (m, 1H), 4.10 (d, J=7.5 Hz, 2H), 6.29 (s, 1H)，7.65 (brs, 1H)。 MS(ESI)m/z=338 (M+H)+。 141666.doc -382- 201028381 步驟3 :標題化合物 依據實施例1-416(步驟3)之方法而合成。 1H NMR (300 MHz, DMSO-d6) δ 0.31-0.36 (m, 2H), 0.52-0.58 (m, 2H), 1.20-1.29 (m, 1H), 4.15 (d, J=6.0 Hz, 2H), 5.75 (s, 1H), 6.53 (s, 2H), 7.52 (s, 1H), 7.64-7.58 (m, 4H), 8.35 (s，1H)，9.27 (s, 1H)。 MS(ESI)m/z=348 (M+H)+。 LC/MS tR=1.97 min。 φ mp : 167-170〇C。 實施例1-441 4-胺基-2-(環丙基曱氧基）-6-(3-甲氧基-4-(噁唑-5-基）苯 基胺基）菸鹼腈 [化 1441]Step 1. 4 -Amino-2 -cyclopropylmethyllacyl-6-sideoxy-1,6-dimur. The title compound was synthesized according to the method of Example 1-416 (Step 1). lHNMR (300 MHz, DMSO-d6) S0_28-0.32 (m, 2H), 0.47-0.55 (m, 2H), 1.13-1.26 (m, 1H), 4.06 (d, J = 6.9 Hz, 2H), 5.50 ( s, 1H), 6.58 (s, 2H), 10.75 (brs, 1H). MS (ESI) m / z = 206 (M + H) +. Step 2: 4-Amino-5-cyano-6-cyclopropylmethoxypyridine-2-yl vinegar trifluorosulfonate The title compound is 4-amino-2-cyclopropylmethoxy- 6-Sideoxy-1,6-dihydropyridine-3-carbonitrile was synthesized according to the method of Example 1-408 (Step 2). 1H NMR (300 MHz, DMSO-d6) δ 0.30-0.35 (m, 2H), 0.52-0.58 (m, 2H), 1.17-1.29 (m, 1H), 4.10 (d, J = 7.5 Hz, 2H), 6.29 (s, 1H), 7.65 (brs, 1H). MS (ESI) m / z = 338 (M+H)+. 141666.doc -382- 201028381 Step 3: The title compound was synthesized according to the method of Example 1-416 (Step 3). 1H NMR (300 MHz, DMSO-d6) δ 0.31-0.36 (m, 2H), 0.52-0.58 (m, 2H), 1.20-1.29 (m, 1H), 4.15 (d, J = 6.0 Hz, 2H), 5.75 (s, 1H), 6.53 (s, 2H), 7.52 (s, 1H), 7.64-7.58 (m, 4H), 8.35 (s, 1H), 9.27 (s, 1H). MS (ESI) m / z = 348 (M+H)+. LC/MS tR = 1.97 min. φ mp : 167-170〇C. Example 1-441 4-Amino-2-(cyclopropyl decyloxy)-6-(3-methoxy-4-(oxazol-5-yl)phenylamino)nicotinonitrile 1441]

甲氧基吡啶-2-基酯及對應之苯胺衍生物’依據實施例1_ 145之方法而合成。 lHNMR(300 MHz,DMSO-d6)S〇.28-0.35 (m，2H)，〇.52- 0.58 (m，2H)，1.24-1.32 (m，1H), 3.92 (s，3H)，4.20 (d， J=6.0 Hz, 2H), 5.78 (s, 1H), 6.55 (s, 2H), 7.04-7.10 (m, 1H), 7.37 (s, 1H), 7.56 (d, J=9.〇 Hz, 1H), 7.68 (d, J=3.〇 Hz, 1H)，8.32 (s, 1H)，9.33 (s，1H)。 141666.doc -383 - 201028381 MS(ESI)m/z=378 (M+H)+。 LC/MS tR=2.05 min ° 實施例1-442 4-胺基-2-異丁氧基-6-(4-(噁唑-5-基）苯基胺基）菸鹼腈 [化 1442]Methoxypyridin-2-yl ester and the corresponding aniline derivative were synthesized according to the method of Example 1-145. lHNMR (300 MHz, DMSO-d6) S〇.28-0.35 (m, 2H), 〇.52-0.58 (m, 2H), 1.24-1.32 (m, 1H), 3.92 (s, 3H), 4.20 ( d, J=6.0 Hz, 2H), 5.78 (s, 1H), 6.55 (s, 2H), 7.04-7.10 (m, 1H), 7.37 (s, 1H), 7.56 (d, J=9.〇Hz , 1H), 7.68 (d, J=3.〇Hz, 1H), 8.32 (s, 1H), 9.33 (s, 1H). 141666.doc -383 - 201028381 MS (ESI) m/z = 378 (M+H)+. LC/MS tR=2.05 min ° Example 1-442 4-Amino-2-isobutoxy-6-(4-(oxazol-5-yl)phenylamino)nicotinonitrile [Chem. 1442]

步驟1 . 4 -胺基-2 -異丁氧基-6 -侧氧基-1，6 -二氮D比咬-3 -曱腈 標題化合物係依據實施例1-416(步驟1)之方法而合成。 1H NMR (300 MHz, DMSO-d6) δ 0.93 (d, J=6.3 Hz, 6H), 1.90-2.01 (m, 1H), 3.98 (d, 3=6.6 Hz, 2H), 5.50 (s, 1H),❿ 6.58 (s，1H)，10.77 (s，1H)。 MS(ESI)m/z=208 (M+H)+。 步驟2:三氟甲磺酸4-胺基-5-氰基-6-異丁氧基吡啶-2-基酯 標題化合物係使用4·胺基-2-異丁氧基-6-側氧基-1,6-二 氫吡啶-3-腈，依據實施例1-408(步驟2)之方法而合成。 1H NMR (300 MHz, DMSO-d6) δ 0.93 (d, J=6.6 Hz, 6H), 141666.doc -384· 201028381 1.95-2.03 (m, 1H), 4.03 (d, J=6.6 Hz, 2H), 6.29 (s, 1H), 7.66 (s，2H)。 MS(ESI)m/z=340 (M+H)+。 步驟3 :標題化合物 依據實施例1-416(步驟3)之方法而合成。 1H NMR (300 MHz’ DMSO-d6) δ 〇 97 (d，J=6 〇 Hz，6H)， 1.97-2.08 (m，1H)，4.08 (d，J=6 〇 Hz，2H)，5.75 (s，1H)， 7.53 (s，1H)，7.60 (d, J=9.〇 Hz，2H), 7.65 (d，J=9.0 Hz, ❹ 2H), 8.35 (s，1H)，9.28 (s，1H)。 MS(ESI)m/z=350 (M+H)+。 LC/MS tR=2.13 min。 實施例1-443 4-胺基-2-異丁氧基-6-(3-甲氧基_4_(嗯唾_5_基）苯基胺基） 於驗腈 [化 1443]Step 1. 4 -Amino-2-isobutoxy-6-o-oxy-1,6-diaza-D-bite-3-phthalonitrile The title compound is according to the method of Example 1-416 (Step 1) And synthesis. 1H NMR (300 MHz, DMSO-d6) δ 0.93 (d, J = 6.3 Hz, 6H), 1.90-2.01 (m, 1H), 3.98 (d, 3 = 6.6 Hz, 2H), 5.50 (s, 1H) , ❿ 6.58 (s, 1H), 10.77 (s, 1H). MS (ESI) m / z = 208 (M + H) +. Step 2: 4-Amino-5-cyano-6-isobutoxypyridin-2-yl trifluoromethanesulfonate The title compound uses 4·amino-2-isobutoxy-6-side oxygen The benzyl-1,6-dihydropyridine-3-carbonitrile was synthesized according to the method of Example 1-408 (Step 2). 1H NMR (300 MHz, DMSO-d6) δ 0.93 (d, J = 6.6 Hz, 6H), 141666.doc -384 · 201028381 1.95-2.03 (m, 1H), 4.03 (d, J = 6.6 Hz, 2H) , 6.29 (s, 1H), 7.66 (s, 2H). MS (ESI) m / z = 340 (M + H) +. Step 3: The title compound was synthesized according to the method of Example 1-416 (Step 3). 1H NMR (300 MHz' DMSO-d6) δ 〇97 (d, J=6 〇Hz, 6H), 1.97-2.08 (m,1H), 4.08 (d, J=6 〇Hz, 2H), 5.75 (s ,1H), 7.53 (s,1H), 7.60 (d, J=9.〇Hz, 2H), 7.65 (d, J=9.0 Hz, ❹ 2H), 8.35 (s, 1H), 9.28 (s, 1H) ). MS (ESI) m / z = 350 (M + H) +. LC/MS tR = 2.13 min. Example 1-43 4-Amino-2-isobutoxy-6-(3-methoxy-4-yl (Humene _5-yl)phenylamino) was tested on nitrile [Chem. 1443]

標題化合物係使用三氟甲磺酸4-胺基-5-氰基-6-異丁氧基 吡啶-2-基酯及對應之笨胺衍生物，依據實施例1-145之方 法而合成。 1H NMR (300 MHz, DMSO-d6) δ 0.96 (d, J=6.0 Hz, 6H), 1.98-2.07 (m, 1H), 3.92 (s, 3H), 4.12 (d, J=6.0 Hz, 2H), 5.77 (s, 1H), 6.56 (s, 2H), 7.09 (d, J=9.0 Hz, 1H), 7.37 (s, 141666.doc •385 - 201028381 1H), 7.55 (d, J=9.0 Hz, 1H), 7.71 (s, 1H), 8.32 (s, 1H), 9.34 (s, 1H)。 MS(ESI)m/z=380 (M+H)+。 LC/MS tR=2.20 min。 實施例1-444 4-胺基-2-节氧基-6-(4-(噁唑-5-基）苯基胺基）菸鹼腈 [化 1444]The title compound was synthesized according to the method of Example 1-145 using 4-amino-5-cyano-6-isobutoxypyridin-2-yl trifluoromethanesulfonate and the corresponding phenantamine derivative. 1H NMR (300 MHz, DMSO-d6) δ 0.96 (d, J = 6.0 Hz, 6H), 1.98-2.07 (m, 1H), 3.92 (s, 3H), 4.12 (d, J = 6.0 Hz, 2H) , 5.77 (s, 1H), 6.56 (s, 2H), 7.09 (d, J=9.0 Hz, 1H), 7.37 (s, 141666.doc •385 - 201028381 1H), 7.55 (d, J=9.0 Hz, 1H), 7.71 (s, 1H), 8.32 (s, 1H), 9.34 (s, 1H). MS (ESI) m / z = 380 (M + H) +. LC/MS tR = 2.20 min. Example 1-444 4-Amino-2-hydroxy-6-(4-(oxazol-5-yl)phenylamino)nicotinonitrile [Chemical 1444]

步驟1 : 4-胺基-2-苄氧基-6-側氧基-1,6-二氫吼啶-3-腈 標題化合物係依據實施例1-416(步驟1)之方法而合成。 1H NMR (300 MHz, DMSO-d6) δ 5.32 (s，2H)，5.55 (s, 1H), 6.65 (s，2Η)，7.27-7.44 (m, 5Η)，10.88 (s，1Η)。 MS(ESI)m/z=242 (M+H)+。 步驟2 :三氟甲磺酸4-胺基-5-氰基-6-苄氧基吼啶-2-基酯 標題化合物係使用4 -胺基-2 -节氧基-6 -側氧基-1,6 -二乳 吡啶-3-腈，依據實施例1-408(步驟2)之方法而合成。 1H NMR (300 MHz, DMSO-d6) δ 5.33 (s, 2H), 6.33 (s, 1H), 7.28-7.44 (m，5H)，7.70 (brs, 1H)。 141666.doc -386· 201028381 MS(ESI)m/z=374 (M+H)+。 步驟3 :標題化合物 依據實施例1 -416(步驟3)之方法而合成。 1H NMR (300 MHz, DMSO-d6) δ 5.40 (s, 2H), 5.77 (s, 1H), 6.59 (s, 2H), 7.29-7.45 (m, 5H), 7.52 (s, 1H), 7.58 (brs, 4H), 8.35 (s，1H)，9.32 (s，1H)。 MS(ESI)m/z=384 (M+H)+。 LC/MS 1^=2-06 min o ❿ 實施例1-445 4-胺基-2-节氧基-6-(3-甲氧基-4-(噁唑-5-基）苯基胺基）菸 鹼腈 [化 1445]Step 1: 4-Amino-2-benzyloxy-6-o-oxy-1,6-dihydroacridin-3-carbonitrile The title compound was synthesized according to the procedure of Example 1-416 (Step 1). 1H NMR (300 MHz, DMSO-d6) δ 5.32 (s, 2H), 5.55 (s, 1H), 6.65 (s, 2 Η), 7.27-7.44 (m, 5 Η), 10.88 (s, 1 Η). MS (ESI) m/z = 242 (M+H)+. Step 2: 4-Amino-5-cyano-6-benzyloxyacridin-2-yl trifluoromethanesulfonate The title compound is 4-amino-2-phenoxy-6-sideoxy -1,6-dilacidopyridine-3-carbonitrile was synthesized according to the method of Example 1-408 (Step 2). 1H NMR (300 MHz, DMSO-d6) δ 5.33 (s, 2H), 6.33 (s, 1H), 7.28-7.44 (m, 5H), 7.70 (brs, 1H). 141666.doc -386· 201028381 MS (ESI) m/z = 374 (M+H)+. Step 3: The title compound was synthesized according to the method of Example 1-416 (Step 3). 1H NMR (300 MHz, DMSO-d6) δ 5.40 (s, 2H), 5.77 (s, 1H), 6.59 (s, 2H), 7.29-7.45 (m, 5H), 7.52 (s, 1H), 7.58 ( Brs, 4H), 8.35 (s, 1H), 9.32 (s, 1H). MS (ESI) m / z = 384 (M+H)+. LC/MS 1^=2-06 min o 实施 Example 1-445 4-Amino-2-ethoxy-6-(3-methoxy-4-(oxazol-5-yl)phenylamine Nicotinic nitrile [化1445]

標題化合物係使用三氟甲磺酸4-胺基-5-氰基-6-节氧基 吡啶-2-基酯及對應之苯胺衍生物，依據實施例U45之方 法而合成。 MS(ESI)m/z=414 (M+H)+。 LC/MS tR=2.13 min。 實施例1-446 4-胺基-6-(4-(噁唑-5-基）苯基胺基）-2-侧氧基-1，2-二氫吡 咬-3-腈 [化 1446] 141666.doc • 387 - 201028381The title compound was synthesized according to the method of Example U45 using 4-amino-5-cyano-6- hydroxypyridin-2-yl trifluoromethanesulfonate and the corresponding aniline derivative. MS (ESI) m / z = 414 (M + H) +. LC/MS tR = 2.13 min. Example 1-446 4-Amino-6-(4-(oxazol-5-yl)phenylamino)-2-oxooxy-1,2-dihydropyridin-3-nitrile [Chemical 1446 ] 141666.doc • 387 - 201028381

標題化合物係依據實施例1-3 10(步驟2)之方法而合成。 MS(ESI)m/z=294 (M+H)+。 LC/MS tR=1.04 min。 實施例1-447 4-胺基-6-(4-(噁唑-5-基）苯基胺基）-2-苯氧基菸鹼腈 [化 1447]The title compound was synthesized according to the method of Example 1-3 10 (Step 2). MS (ESI) m / z = 294 (M + H) +. LC/MS tR = 1.04 min. Example 1-447 4-Amino-6-(4-(oxazol-5-yl)phenylamino)-2-phenoxynicotinonitrile [Chem. 1447]

Pd(OAc)2, Xantphos 〇S^C〇3Pd(OAc)2, Xantphos 〇S^C〇3

步驟1 : 5-(4-碘苯基）噁唑 向 4-碘苯甲醛（9.74 g，42.0 mmol)及 TosMIC(9,02 g， 46.2 mmol)之曱醇（90 mL)溶液中添加碳酸钟（6.38 g，46.2 mmol)，於力ο熱回流下攪:拌3小時。將反應溶液注入至冰水 中，濾取析出之固體。使所獲得之殘渣溶解於甲醇中，進 行減壓濃縮而使其固化後，以甲醇：水=1 : 1溶液進行清 洗，藉此獲得標題化合物（9.9 g，36.5 mmol，87%)，為褐 141666.doc -388 - 201028381 色固體。 1H-NMR (400 MHz, DMSO-d6) δ 7.47 (d, J=8.0 Hz, 2H), 7.70 (s，1H), 7.78 (d, J=8.0 Hz，2H)，8.43 (s, 1H)。 MS(ESI)m/z=272(M+H)+。 步驟2 : 4-胺基-2-漠-6-(4-(n惡e坐-5-基）苯基胺基）於驗猜 向 4,6-二胺基-2-溴於驗腈（2.5 g，11.7 mmol)、5-(4-埃苯 基）°惡嗤（3.18 g，11.7 mmol)、Xantphos(679 mg，1.17 mmol)及碳酸絶（5·35 g，16.4 mmol)之二嗓院（25 mL)溶液 Ο 中添加Pd(OAc)2(132 mg，0.587 mmol)，於 100°c 下攪拌 1 小時。向反應溶液中添加10%擰檬酸水溶液及乙酸乙酯進 行分離後，以乙酸乙酯萃取水相，將合併之有機相以水、 飽和破酸氬納水溶液及飽和食鹽水進行清洗，以硫酸錢加 以乾燥。將有機相過濾後，進行減壓濃縮。利用矽膠層析 法（氣仿：甲醇：水=64 : 9 : 1)對所獲得之殘渣進行純 化，獲得標題化合物（525 mg，1.47 mmol，13%) ’為黃色 固體》 • 1H-NMR (400 MHz, DMSO-d6) δ 6.09 (s, 1H), 6.88 (s, 2H), 7.54 (s, 1H), 7.59 (d, J=8.4 Hz, 2H), 7.64 (d, J=8.4 Hz, 2H)，8.36 (s, 1H)，9.55 (s，1H)。 MS(ESI)m/z=356 (M+H)+。 步驟3 :標題化合物 於5 mL微波反應容器中，向4-胺基-2-溴-6-(4-(噁唑-5-基）苯基胺基）於驗腈（80 mg，0.225 mmol)及苯盼（254 mg， 2.70 mmol)之NMP溶液中添加60%氫化納（64·7 mg，2.70 141666.doc -389- 201028381 mmol)進行覆蓋’使用Biotage Optimizer反應裝置，於 1 60°C下攪拌30分鐘。向反應溶液中添加水及乙酸乙酯進 行分離後，以乙酸乙酯萃取水相，將合併之有機相以水及 飽和食鹽水進行清洗，以硫酸鎂加以乾燥。將有機相過滤 後’進行減壓濃縮。利用中壓矽膠層析法（己烷：乙酸乙 酯=1 : 1)對所獲得之殘渣進行純化，獲得標題化合物（15 5 mg，0_042 mmol，19%)，為白色固體。 1H-NMR (400 MHz，DMSO-d6) δ 5_82 (s，1H)，6.74 (s, 2H)， 7.24-7.26 (m, 6H), 7.36 (t, J=7.1 Hz, 1H), 7.54-7.44 (m, 3H)，8.33 (s, 1H)，9.32 (s，1H)。 實施例1-448 4·胺基-6-(4-(噁唑-5-基）苯基胺基）菸鹼腈 [化 1448]Step 1: 5-(4-iodophenyl)oxazole Adding carbonic acid to a solution of 4-iodobenzaldehyde (9.74 g, 42.0 mmol) and TosMIC (9,02 g, 46.2 mmol) in methanol (90 mL) (6.38 g, 46.2 mmol), stir under heat reflux: mix for 3 hours. The reaction solution was poured into ice water, and the precipitated solid was collected by filtration. The obtained residue was dissolved in methanol, and concentrated under reduced pressure to solidified, and then washed with methanol:water = 1:1 to give the title compound (9.9 g, 36.5 mmol, 87%) as brown 141666.doc -388 - 201028381 Color solid. 1H-NMR (400 MHz, DMSO-d6) δ 7.47 (d, J = 8.0 Hz, 2H), 7.70 (s, 1H), 7.78 (d, J = 8.0 Hz, 2H), 8.43 (s, 1H). MS (ESI) m/z = 272 (M+H)+. Step 2: 4-Amino-2-indol-6-(4-(noxo-s--5-yl)phenylamino) is tested for 4,6-diamino-2-bromo (2.5 g, 11.7 mmol), 5-(4-Ethylphenyl) oxime (3.18 g, 11.7 mmol), Xantphos (679 mg, 1.17 mmol) and carbonic acid (5·35 g, 16.4 mmol) Pd(OAc) 2 (132 mg, 0.587 mmol) was added to the broth (25 mL) solution and stirred at 100 ° C for 1 hour. After adding 10% aqueous solution of citric acid and ethyl acetate to the reaction solution, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water, saturated aqueous solution of argon sulfate and saturated brine to sulfuric acid. The money is dried. After the organic phase was filtered, it was concentrated under reduced pressure. The residue obtained was purified by silica gel chromatography (methanol:methanol:water = 64 : 9 : 1) to give the title compound (525 mg, 1.47 mmol, 13%) as a yellow solid. 400 MHz, DMSO-d6) δ 6.09 (s, 1H), 6.88 (s, 2H), 7.54 (s, 1H), 7.59 (d, J=8.4 Hz, 2H), 7.64 (d, J=8.4 Hz, 2H), 8.36 (s, 1H), 9.55 (s, 1H). MS (ESI) m / z = 356 (M+H)+. Step 3: The title compound was taken in a 5 mL microwave reaction vessel to 4-amino-2-bromo-6-(4-(oxazol-5-yl)phenylamino) as the nitrile (80 mg, 0.225 mmol) And 60% sodium hydride (64·7 mg, 2.70 141666.doc -389- 201028381 mmol) was added to the benzene solution (254 mg, 2.70 mmol) in NMP solution using a Biotage Optimizer reactor at 1 60 °C. Stir for 30 minutes. After water and ethyl acetate were added to the reaction solution for separation, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water and brine and dried over magnesium sulfate. The organic phase was filtered and concentrated under reduced pressure. The residue obtained was purified by EtOAc EtOAc (EtOAc:EtOAc 1H-NMR (400 MHz, DMSO-d6) δ 5_82 (s, 1H), 6.74 (s, 2H), 7.24-7.26 (m, 6H), 7.36 (t, J = 7.1 Hz, 1H), 7.54-7.44 (m, 3H), 8.33 (s, 1H), 9.32 (s, 1H). Example 1-448 4·Amino-6-(4-(oxazol-5-yl)phenylamino)nicotinonitrile [Chemical 1448]

於5 mL微波反應容中’向4 -胺基-2 -漠-6-(4-(°惡β坐- 5-基）苯基胺基）於驗腈（39.4 mg，〇_111 mmol)，甲酸（25.5 mg，21 μί，0.553 mmol)及三乙基胺（112 mg，153 μΧ， 1.11 mmol)之 DMF 溶液中添加 PdCl2(PPh3)2(3.9 mg，0.0055 mmol)進行覆蓋，使用Biotage Optimizer反應裝置，於70°C 下攪拌1小時。向反應溶液中添加水及乙酸乙酯進行分離 後，以乙酸乙酯萃取水相，將合併之有機相以水及飽和食 鹽水進行清洗’以硫酸鎂加以乾燥。將有機相過濾後，進 行減壓濃縮。利用中壓矽膠層析法（己烷：乙酸乙酯=1 ·· 141666.doc •390- 201028381 i)對所獲得之殘渣進行純化，獲得標題化合物（3 2 mg， 〇·〇12 mmol，10%)，為白色固體。 1H-NMR (400 MHz, DMSO-d6) δ 6.11 (s, 1H), 6.60 (s, 2H) 7.52 (s，1H)，7.61 (d，J=8.6 Hz，2H), 7_67 (d，J=8‘6 Hz 2H)，8.18 (s，1H)，8.36 (s，1H)，9.32 (s, 1H)。 實施例1-449 4-胺基-6-(聯苯-4-基胺基）-2-溴菸鹼腈 [化 1449]Determination of nitrile (39.4 mg, 〇_111 mmol) in a 5 mL microwave reaction volume to 4-amino-2-ision-6-(4-(°-β-s- 5-yl)phenylamino) Add PdCl2(PPh3)2 (3.9 mg, 0.0055 mmol) to DMF solution of formic acid (25.5 mg, 21 μί, 0.553 mmol) and triethylamine (112 mg, 153 μM, 1.11 mmol), using Biotage Optimizer The reaction apparatus was stirred at 70 ° C for 1 hour. After water and ethyl acetate were added to the reaction solution for separation, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water and saturated brine. After the organic phase was filtered, it was concentrated under reduced pressure. The residue obtained was purified by EtOAc (EtOAc: EtOAc: EtOAc (EtOAc) %), as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 6.11 (s, 1H), 6.60 (s, 2H) 7.52 (s, 1H), 7.61 (d, J = 8.6 Hz, 2H), 7_67 (d, J = 8'6 Hz 2H), 8.18 (s, 1H), 8.36 (s, 1H), 9.32 (s, 1H). Example 1-449 4-Amino-6-(biphenyl-4-ylamino)-2-bromonicotinonitrile [Chem. 1449]

標題化合物係使用4-碘聯苯，依據實施例1-447(步驟2)之 方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 6.11 (s，1H)，6.85 (s，2H)， 7.32 (t, J=7.6 Hz, 1H), 7.44 (t, J=7.6 Hz, 2H), 7.51 (d, J=7.6 Hz，2H)，7.64 (t，J=7.6 Hz, 4H)，9·47 (s，1H)。 實施例1-450 4-胺基-2-(2-甲氧基乙氧基）-6-(4-(噁唑-5-基）苯基胺基） 菸鹼腈 [化 1450]The title compound was synthesized according to the method of Example 1-427 (Step 2) using 4-iodobiphenyl. 1H-NMR (400 MHz, DMSO-d6) δ 6.11 (s, 1H), 6.85 (s, 2H), 7.32 (t, J = 7.6 Hz, 1H), 7.44 (t, J = 7.6 Hz, 2H), 7.51 (d, J = 7.6 Hz, 2H), 7.64 (t, J = 7.6 Hz, 4H), 9·47 (s, 1H). Example 1-450 4-Amino-2-(2-methoxyethoxy)-6-(4-(oxazol-5-yl)phenylamino) Nicotinonitrile [Chem. 1450]

標題化合物係使用對應之醇衍生物’依據實施例1 - 141666.doc -391 - 201028381 447(步驟3)之方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 3.32 (s, 3H), 3.68 (t, J=4.5 Hz, 2H), 4.43 (t, J=4.5 Hz, 2H), 5.78 (s, 1H), 6.56 (s, 2H)，7.53 (s，1H), 7.63 (s, 4H), 8.36 (s，1H), 9.31 (s, 1H)。 實施例1-451 4-胺基-2-(2-(N-嗎啉基）乙氧基）-6-(4-(噁唑_5_基）笨基胺 基）菸鹼腈 [化 1451]The title compound was synthesized according to the method of Example 1-141666.doc-391 - 201028381 447 (Step 3) using the corresponding alcohol derivative. 1H-NMR (400 MHz, DMSO-d6) δ 3.32 (s, 3H), 3.68 (t, J = 4.5 Hz, 2H), 4.43 (t, J = 4.5 Hz, 2H), 5.78 (s, 1H), 6.56 (s, 2H), 7.53 (s, 1H), 7.63 (s, 4H), 8.36 (s, 1H), 9.31 (s, 1H). Example 1-451 4-Amino-2-(2-(N-morpholinyl)ethoxy)-6-(4-(oxazole-5-yl)phenylamino) Nicotine Nitrile 1451]

標題化合物係使用對應之醇衍生物，依據實施例1 -447(步 驟3)之方法而合成。 MS(ESI)m/z=407 (M+H) + LC/MS tR=l.〇2 min。 實施例1-452 4-胺基-6-(4-(噁唑-5-基）苯基胺基）-2-(四氫·2Η_吡喃-4-基氧基）於驗腈 [化 1452]The title compound was synthesized according to the method of Example 1-447 (Step 3) using the corresponding alcohol derivative. MS (ESI) m / z = 407 (M + H) + Example 1-452 4-Amino-6-(4-(oxazol-5-yl)phenylamino)-2-(tetrahydro-2Η-pyran-4-yloxy) in a nitrile [ 1452]

標題化合物係使用對應之醇衍生物，依據實施例1_447(步 驟3)之方法而合成。 141666.doc -392- 201028381 MS(ESI)m/z=3 78(M+H)+ LC/MS tR=1.83 min。 實施例1-453 4-胺基-2-(環戊氧基）-6-(4-(噁唑-5-基）苯基胺基）菸鹼腈 [化 1453]The title compound was synthesized according to the method of Example 1-447 (Step 3) using the corresponding alcohol derivative. 141666.doc -392- 201028381 MS (ESI) m/z =3 78 (M+H) Example 1-453 4-Amino-2-(cyclopentyloxy)-6-(4-(oxazol-5-yl)phenylamino)nicotinonitrile [Chem. 1453]

φ 標題化合物係使用對應之醇衍生物，依據實施例1-447(步 驟3)之方法而合成。 MS(ESI)m/z=362 (M+H)+。 LC/MS tR=2.26 min 〇 實施例1-454 4-胺基-2-(2-(二甲基胺基）乙氧基）-6-(4-(噁唑-5-基）苯基 胺基）菸鹼腈 [化 1454]The title compound of φ was synthesized according to the method of Example 1-447 (Step 3) using the corresponding alcohol derivative. MS (ESI) m / z = 362 (M+H)+. LC/MS tR = 2.26 min 〇 Example 1-454 4-Amino-2-(2-(dimethylamino)ethoxy)-6-(4-(oxazol-5-yl)phenyl Amino)nicotinic nitrile [Chemical 1454]

標題化合物係使用對應之醇衍生物，依據實施例1 -447(步驟3)之方法而合成。 MS(ESI)m/z=365 (M+H) + LC/MS tR=1.01 min。 實施例1-455 141666.doc -393 - 201028381 4_胺基-2-(3-甲氧基苯氧基）-6-(4-(噁唑-5-基）苯基胺基） 菸鹼腈 [化 1455]The title compound was synthesized according to the method of Example 1-447 (Step 3) using the corresponding alcohol derivative. MS (ESI) m/z = 356 (M+H) Example 1-455 141666.doc -393 - 201028381 4_Amino-2-(3-methoxyphenoxy)-6-(4-(oxazol-5-yl)phenylamino) Nicotine Nitrile [1455]

標題化合物係使用對應之苯酚衍生物，依據實施例1_ 447(步驟3)之方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 3.78 (s, 3H), 5.84 (s, 1H), 6.74 (s, 2H), 6.81 (d, J=8.1 Hz, 1H), 6.85 (s, 1H), 6.94 (d, J=8.1 Hz, 1H), 7.30 (s, 4H), 7.40 (t, J=8.1 Hz, 1H), 7.46 (s, 1H)，8.34 (s, 1H)，9.34 (s, 1H)。 實施例1-456 4-胺基-2-(4-甲氧基苯氧基）-6-(4-(噁唑-5-基）苯基胺基） 於驗腈 [化 1456]The title compound was synthesized according to the method of Example 1-447 (Step 3) using the corresponding phenol derivative. 1H-NMR (400 MHz, DMSO-d6) δ 3.78 (s, 3H), 5.84 (s, 1H), 6.74 (s, 2H), 6.81 (d, J = 8.1 Hz, 1H), 6.85 (s, 1H) ), 6.94 (d, J=8.1 Hz, 1H), 7.30 (s, 4H), 7.40 (t, J=8.1 Hz, 1H), 7.46 (s, 1H), 8.34 (s, 1H), 9.34 (s , 1H). Example 1-456 4-Amino-2-(4-methoxyphenoxy)-6-(4-(oxazol-5-yl)phenylamino) was tested on nitrile [Chem. 1456]

標題化合物係使用對應之苯酚衍生物，依據實施例1 _ 447(步驟3)之方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 3.85 (s, 3H), 5.80 (s, 1H), 6.71 (s, 2H), 7.04 (d, J=8.6 Hz, 2H), 7.15 (d, J=8.6 Hz, 141666.doc -394· 201028381 2H), 7.25 (d, J=8.6 Hz, 2H), Ί.29 (d, J=8.6 Hz, 2H), 7.42 (s，1H), 8.35 (s, 1H), 9.31 (s, 1H)。 實施例1-457 4-胺基-2-(3 -氟苯氧基）-6-(4-(噁唑-5-基）苯基胺基）菸 鹼腈 [化 1457]The title compound was synthesized according to the method of Example 1 - 447 (Step 3) using the corresponding phenol derivative. 1H-NMR (400 MHz, DMSO-d6) δ 3.85 (s, 3H), 5.80 (s, 1H), 6.71 (s, 2H), 7.04 (d, J = 8.6 Hz, 2H), 7.15 (d, J =8.6 Hz, 141666.doc -394· 201028381 2H), 7.25 (d, J=8.6 Hz, 2H), Ί.29 (d, J=8.6 Hz, 2H), 7.42 (s,1H), 8.35 (s , 1H), 9.31 (s, 1H). Example 1-457 4-Amino-2-(3-fluorophenoxy)-6-(4-(oxazol-5-yl)phenylamino)nicotinonitrile [Chem. 1457]

❹ 標題化合物係使用對應之苯酚衍生物，依據實施例1-447(步驟3)之方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 5.85 (s, 1H), 6.78 (s, 2H), 7.11 (d, J=7.6 Hz, 1H), 7.19-7.28 (m, 4H), 7.32 (d, J=8.6 Hz, 2H), 7.47 (s, 1H), 7.54 (q, J=7.6 Hz, 1H), 8.35 (s, 1H), 9.36 (s，1H)。 ❿ 實施例1-458 4-胺基-2-(4-氟苯氧基）-6-(4-(噁唑-5-基）苯基胺基）於 鹼腈 [化 1458]标题 The title compound was synthesized according to the method of Example 1-447 (Step 3) using the corresponding phenol derivative. 1H-NMR (400 MHz, DMSO-d6) δ 5.85 (s, 1H), 6.78 (s, 2H), 7.11 (d, J = 7.6 Hz, 1H), 7.19-7.28 (m, 4H), 7.32 (d , J=8.6 Hz, 2H), 7.47 (s, 1H), 7.54 (q, J=7.6 Hz, 1H), 8.35 (s, 1H), 9.36 (s, 1H).实施 Example 1-458 4-Amino-2-(4-fluorophenoxy)-6-(4-(oxazol-5-yl)phenylamino) in an alkali nitrile [Chemical 1458]

標題化合物係使用對應之苯酚衍生物，依據實施例1 141666.doc • 395 · 201028381 447(步驟3)之方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 5.82 (s, 1H), 6.75 (s, 2H), 7.21-7.37 (m, 8H), 7.45 (s, 1H), 8.35 (s, 1H), 9.34 (s, 1H)。 實施例1-459 4-胺基-2-(4-(二甲基胺基）苯氧基）-6-(4-(噁唑-5-基）苯基 胺基）菸鹼腈 [化 1459]The title compound was synthesized according to the method of Example 1 141666.doc • 395 · 201028381 447 (Step 3) using the corresponding phenol derivative. 1H-NMR (400 MHz, DMSO-d6) δ 5.82 (s, 1H), 6.75 (s, 2H), 7.21-7.37 (m, 8H), 7.45 (s, 1H), 8.35 (s, 1H), 9.34 (s, 1H). Example 1-459 4-Amino-2-(4-(dimethylamino)phenoxy)-6-(4-(oxazol-5-yl)phenylamino)nicotinonitrile 1459]

標題化合物係使用對應之苯酚衍生物，依據實施例1-447(步驟3)之方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 2.91 (s, 6H), 5.56 (s, 1H), 6.24 (s, 2H), 6.74 (d, J=8.6 Hz, 2H), 7.23 (d, J=8.6 Hz, 2H), 7.38 (d, J=8.6 Hz, 2H), 7.42 (s, 1H), 7.54 (d, J=8.6 Hz, 2H)，8.13 (s，1H), 8.34 (s, 1H), 9.02 (s，1H)。 實施例1-460 4 -胺基- 6- (4 -&gt;臭苯基胺基）-2 -苯氧基於驗猜 [化 1460]The title compound was synthesized according to the method of Example 1-447 (Step 3) using the corresponding phenol derivative. 1H-NMR (400 MHz, DMSO-d6) δ 2.91 (s, 6H), 5.56 (s, 1H), 6.24 (s, 2H), 6.74 (d, J = 8.6 Hz, 2H), 7.23 (d, J =8.6 Hz, 2H), 7.38 (d, J=8.6 Hz, 2H), 7.42 (s, 1H), 7.54 (d, J=8.6 Hz, 2H), 8.13 (s, 1H), 8.34 (s, 1H) ), 9.02 (s, 1H). Example 1-460 4 -Amino- 6-(4 -&gt;odorophenylamino)-2-phenoxy group was tested [Chem. 1460]

141666.doc -396- 201028381 於20 mL微波反應容器中，向4-胺基-2-溴-6-(4-溴苯基胺 基）於驗腈（實施例1-424 ·步驟1)(600 mg，1.630 mmol)及 苯酚（767 mg，8.15 mmol)之NMP(6 mL)溶液中添加60%氫 化鈉（196 mg，8.15 mmol)進行覆蓋，使用Biotage Optimizer反應裝置，於160°C下擾拌30分鐘。向反應溶液 中添加水及乙酸乙酯進行分離後，以乙酸乙酯萃取水相， 將合併之有機相以水及飽和食鹽水進行清洗，以硫酸鎂加 以乾燥。將有機相過濾後，進行減壓濃縮。利用中壓矽膠 Φ 層析法（己烷：乙酸乙酯=1 : 1)對所獲得之殘渣進行純 化，獲得標題化合物（578 mg，1.52 mmol，93%)，為黃色 固體。 1H-NMR (400 MHz，DMSO-d6) δ 5.78 (s，1H)，6.73 (s，2H)， 7.04 (d, J=8.6 Hz, 2H), 7.10 (d, J=8.6 Hz, 2H), 7.21 (d, J=7.6 Hz, 2H), 7.34 (t, J=7.6 Hz, 1H), 7.49 (t, J=7.6 Hz, 2H), 9.24 (s，1H)。 實施例1-461 4 -胺基-2-笨乳基- 6- (4-(比咬-4-基）苯基胺基）於驗猜 [化 1461]141666.doc -396- 201028381 In a 20 mL microwave reaction vessel, test the nitrile to 4-amino-2-bromo-6-(4-bromophenylamino) (Example 1-424 · Step 1) 600 mg, 1.630 mmol) and phenol (767 mg, 8.15 mmol) in NMP (6 mL) were added with 60% sodium hydride (196 mg, 8.15 mmol), and the mixture was applied at 160 °C using Biotage Optimizer. Mix for 30 minutes. After water and ethyl acetate were added to the reaction solution for separation, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water and brine, and dried over magnesium sulfate. After the organic phase was filtered, it was concentrated under reduced pressure. The residue obtained was purified by EtOAc EtOAc (EtOAc:EtOAc: 1H-NMR (400 MHz, DMSO-d6) δ 5.78 (s, 1H), 6.73 (s, 2H), 7.04 (d, J = 8.6 Hz, 2H), 7.10 (d, J = 8.6 Hz, 2H), 7.21 (d, J=7.6 Hz, 2H), 7.34 (t, J=7.6 Hz, 1H), 7.49 (t, J=7.6 Hz, 2H), 9.24 (s, 1H). Example 1-461 4-Amino-2-bromo-based- 6-(4-(Bite-4-yl)phenylamino) is judged [Chem. 1461]

於5 mL微波反應容器中，向4-胺基-6-(4-溴苯基胺基）-2-苯氧基於鹼腈（100 mg，0.262mmol)、°比咬-4-基硼酸（97 141666.doc -397- 201028381 mg，0.787 mmol)及 4 mol/L 碳酸鉀水溶液（197 μΣ，0.787 mmol)之二嗔烧（1 mL)溶液中添加 Pd(PPh3)4(60.6 mg， 0.052 mmol)進行覆蓋，使用Biotage Optimizer反應裝置， 於150°C下攪拌30分鐘。向反應溶液中添加水及乙酸乙酯 進行分離後，以乙酸乙酯萃取水相，將合併之有機相以水 及飽和食鹽水進行清洗，以硫酸鎂加以乾燥。將有機相過 濾後，進行減壓濃縮。利用中壓矽膠層析法（己烷：乙酸 乙酯=1 : 1〜1 : 2)對所獲得之殘渣進行純化，獲得標題化 合物（9.3 mg，0.025 mmol，9%)，為黃色固體。 1H-NMR (400 MHz, DMSO-d6) δ 5.85 (s, 1H), 6.76 (s, 2H), 7.24 (d, J=8.1 Hz, 2H), 7.28 (d, J = 8.1 Hz, 2H), 7.34-7.41 (m，3H), 7.49-7.58 (m，4H)，8.56 (br s，2H), 9.35 (s，1H)。 實施例1-462 4-胺基-6-(4-((1-甲基-1H-咪唑-5-基）乙炔基）苯基胺基）-2-苯氧基菸鹼腈 [化 1462]To a 4-amino-6-(4-bromophenylamino)-2-phenoxy group in a 5 mL microwave reaction vessel to a base nitrile (100 mg, 0.262 mmol) at a ratio of -4--4-boronic acid ( 97 141666.doc -397- 201028381 mg,0.787 mmol) and 4 mol/L potassium carbonate solution (197 μΣ, 0.787 mmol) in dioxane (1 mL) was added Pd(PPh3)4 (60.6 mg, 0.052 mmol) Covering was carried out using a Biotage Optimizer reaction apparatus at 150 ° C for 30 minutes. Water and ethyl acetate were added to the reaction solution for separation, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and brine, and dried over magnesium sulfate. The organic phase was filtered and concentrated under reduced pressure. The residue obtained was purified by EtOAc EtOAc (EtOAc:EtOAc) 1H-NMR (400 MHz, DMSO-d6) δ 5.85 (s, 1H), 6.76 (s, 2H), 7.24 (d, J = 8.1 Hz, 2H), 7.28 (d, J = 8.1 Hz, 2H), 7.34-7.41 (m, 3H), 7.49-7.58 (m, 4H), 8.56 (br s, 2H), 9.35 (s, 1H). Example 1-462 4-Amino-6-(4-((1-methyl-1H-imidazol-5-yl)ethynyl)phenylamino)-2-phenoxynicotinonitrile [Chemical 1462] ]

於5 mL微波反應容器中，向4-胺基-6-(4-溴苯基胺基）_2-苯氧基於驗腈（100 mg，0.262 mmol)、5 -乙块基-l-曱基-1H-味口坐（55_7 mg，0.525 mmol)、Cul(5.0 mg，0.026 mmol)及三乙基胺（53.1 mg，73 μι，0.525 mmol)之 DMF(1 141666.doc •398- 201028381 niL)溶液中添加 PdCl2(PPh3)2(9.2 mg，0.013 mmol)進行覆 蓋，使用Biotage Optimizer反應裝置，於l〇〇°C下授掉分 鐘。向反應溶液中添加水及乙酸乙酯進行分離後，以乙酸 乙酯萃取水相，將合併之有機相以水及飽和食鹽水進行清 洗，以硫酸鎂加以乾燥。將有機相過濾後，進行減壓濃 縮。利用中壓矽膠層析法（己烷：乙酸乙酯=1 : 1〜丨：2)對 所獲得之殘渣進行純化，獲得標題化合物（7.0 mg，〇.〇17 mmol，7%)，為褐色固體。 ® 1H-NMR (400 MHz, DMSO-d6) δ 3.66 (s, 3Η), 5.83 (S} 1H), 6·77 (s，2H)，7.00-7.66 (m，11H)，9.38 (s，1H)。 實施例1-463 4-胺基-6-(4-(1-甲基-1H-&quot;比唑-4-基）苯基胺基）-2-苯氧基 菸鹼腈 [化 1463]In a 5 mL microwave reaction vessel, 4-amino-6-(4-bromophenylamino)_2-phenoxy was assayed for nitrile (100 mg, 0.262 mmol), 5-ethylidene-l-fluorenyl -1H-Digestive (55_7 mg, 0.525 mmol), Cul (5.0 mg, 0.026 mmol) and triethylamine (53.1 mg, 73 μιη, 0.525 mmol) of DMF (1 141666.doc •398- 201028381 niL) PdCl 2 (PPh 3 ) 2 (9.2 mg, 0.013 mmol) was added to the solution for covering, and the mixture was dispensed at 10 ° C using a Biotage Optimizer reaction apparatus. Water and ethyl acetate were added to the reaction solution for separation, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and brine, and dried over magnesium sulfate. After the organic phase was filtered, it was concentrated under reduced pressure. The residue obtained was purified by EtOAc (EtOAc:EtOAc:EtOAc: solid. ® 1H-NMR (400 MHz, DMSO-d6) δ 3.66 (s, 3Η), 5.83 (S} 1H), 6·77 (s, 2H), 7.00-7.66 (m, 11H), 9.38 (s, 1H) ). Example 1-463 4-Amino-6-(4-(1-methyl-1H-&quot;Biazol-4-yl)phenylamino)-2-phenoxy Nicotinonitrile [Chem. 1463]

標題化合物係使用對應之硼酸頻哪醇酯，依據實施例1 -461之方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 3.84 (s, 3H), 5.79 (s, 1H), 6.66 (s, 2H), 7.13 (s, 4H), 7.22 (d, J=7.6 Hz, 2H), 7.34 (t, J=7.6 Hz, 1H), 7.49 (t, J=7.6 Hz, 2H), 7.70 (s, 1H), 7.95 (s, 1H), 9.07 (s，1H)。 實施例1-464 141666.doc -399- 201028381 4,6 -二胺基-2-苯氧基务驗猜 [化 1464]The title compound was synthesized according to the method of Example 1-461 using the corresponding boronic acid pinacol ester. 1H-NMR (400 MHz, DMSO-d6) δ 3.84 (s, 3H), 5.79 (s, 1H), 6.66 (s, 2H), 7.13 (s, 4H), 7.22 (d, J = 7.6 Hz, 2H ), 7.34 (t, J=7.6 Hz, 1H), 7.49 (t, J=7.6 Hz, 2H), 7.70 (s, 1H), 7.95 (s, 1H), 9.07 (s, 1H). Example 1-464 141666.doc -399- 201028381 4,6-Diamino-2-phenoxy verification [Chem. 1464]

NaH -- Η,ΝNaH -- Η, Ν

ΝΜΡ, 160 0C 於20 mL微波反應容器中，向4,6-二胺基-2-溴菸鹼腈（1.0 g，4.69 mmol)及苯紛（2.2 g，23.5 mmol)之 NMP(10 mL)溶 液中添加60%氫化鈉（563 mg，23.5 mmol)，進行覆蓋，使 用Biotage Optimizer反應裝置，於160°C下授拌1小時。向 反應溶液中添加水及乙酸乙酯進行分離後，以乙酸乙酯萃 取水相，將合併之有機相以水及飽和食鹽水進行清洗，以 硫酸鎂加以乾燥。將有機相過濾後，進行減壓濃縮，以己 烷：乙酸乙酯=5 : 1溶液使其固化，藉此獲得標題化合物 (905 mg，4.00 mmol，85%)，為灰色固體。 1H-NMR (400 MHz，DMSO-d6) δ 5.43 (s，1H)，6.25 (s，2H), 6.37 (s, 2H), 7.10 (d, J=7.8 Hz, 2H), 7.18 (t, J=7.8 Hz, 1H), 7.38 (t, J=7.8 Hz, 2H)。 實施例1-465 4 - ( 4 -胺基-5 -亂基-6 -苯氧基°比咬-2 -基胺基）苯甲酸曱醋 [化 1465]ΝΜΡ, 160 0C In a 20 mL microwave reaction vessel, 4,6-diamino-2-bromonicotinonitrile (1.0 g, 4.69 mmol) and benzene (2.2 g, 23.5 mmol) of NMP (10 mL) 60% sodium hydride (563 mg, 23.5 mmol) was added to the solution, and the mixture was covered with a Biotage Optimizer reaction apparatus at 160 ° C for 1 hour. Water and ethyl acetate were added to the reaction solution for separation, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and brine and dried over magnesium sulfate. After the organic phase was filtered, EtOAc mjjjjjjjjj 1H-NMR (400 MHz, DMSO-d6) δ 5.43 (s, 1H), 6.25 (s, 2H), 6.37 (s, 2H), 7.10 (d, J = 7.8 Hz, 2H), 7.18 (t, J =7.8 Hz, 1H), 7.38 (t, J=7.8 Hz, 2H). Example 1-465 4 - (4-Amino-5-ranyl-6-phenoxy~biti-2-amino-amino)benzoic acid vinegar [Chemical 1465]

141666.doc -400- 201028381 於5 mL微波反應容器中，向4,6-二胺基-2-苯氧基菸鹼腈 (300 mg，1.33 mmol)、4-破苯甲酸曱醋（382 mg，1.46 mmol)、Xantphos(77 mg，0.133 mmol)及礙酸鉋（605 mg， 1.86 mmol)之二 °惡烧（3 mL)溶液中添加 Pd(OAc)2(14.9 mg， 0.066 mmol)進行覆蓋，使用Biotage Optimizer反應裝置， 於120°C下攪拌1小時。向反應溶液中添加10%檸檬酸水溶 液及乙酸乙酯進行分離後，以乙酸乙酯萃取水相，將合併 之有機相以水、飽和碳酸氫鈉水溶液及飽和食鹽水進行清 ❹ 洗，以硫酸鎂加以乾燥。將有機相過濾後，進行減壓濃 縮。利用矽膠層析法（己烷：乙酸乙酯=1 : 1)對所獲得之 殘邊進行純化，獲得標題化合物（168 mg，0.466 mmol， 35%)，為白色固體。 1H-NMR (400 MHz, DMSO-d6) δ 3.77 (s, 3H), 5.87 (s, 1H), 6.82 (s, 2H), 7.20-7.26 (m, 4H), 7.36 (t, J=7.3 Hz, 1H), 7.54-7.48 (m, 4H), 9.54 (s，1H)。 實施例1-466 @ 4-(4 -胺基-5-亂基-6-苯氧基n比e定-2-基胺基）苯甲酸乙酉旨 [化 1466]141666.doc -400- 201028381 4,6-Diamino-2-phenoxynicotinonitrile (300 mg, 1.33 mmol), 4-bromobenzoic acid vinegar (382 mg) in a 5 mL microwave reaction vessel Pf(OAc)2 (14.9 mg, 0.066 mmol) was added to a solution of Xantphos (77 mg, 0.133 mmol) and acid turbid (605 mg, 1.86 mmol) in a 2° solution (3 mL). The mixture was stirred at 120 ° C for 1 hour using a Biotage Optimizer reaction apparatus. After the 10% aqueous citric acid solution and ethyl acetate were added to the reaction solution for separation, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water, a saturated aqueous sodium hydrogen carbonate solution and brine. Magnesium is dried. After the organic phase was filtered, it was concentrated under reduced pressure. The residue obtained was purified by EtOAc (EtOAc:EtOAc) 1H-NMR (400 MHz, DMSO-d6) δ 3.77 (s, 3H), 5.87 (s, 1H), 6.82 (s, 2H), 7.20-7.26 (m, 4H), 7.36 (t, J = 7.3 Hz , 1H), 7.54-7.48 (m, 4H), 9.54 (s, 1H). Example 1-466 @ 4-(4-Amino-5-ranyl-6-phenoxy n-e-di-2-ylamino)benzoic acid Ethyl group [Chem. 1466]

標題化合物係使用對應之芳基鹵化物，依據實施例1-465之方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 1.28 (t, J=7.2 Hz, 3H), 141666.doc -401 · 201028381 4.23 (q, J=7.2 Hz，2H), 5·87 (s，1H)，6.83 (s，2H)，7.22-7.53 (m，9H)，9.65 (s，1H) » 實施例1-467 4-(4-胺基-5-氰基-6-苯氧基《比啶-2-基胺基）苯甲酸 [化 1467]The title compound was synthesized according to the method of Example 1-465 using the corresponding aryl halide. 1H-NMR (400 MHz, DMSO-d6) δ 1.28 (t, J = 7.2 Hz, 3H), 141666.doc -401 · 201028381 4.23 (q, J=7.2 Hz, 2H), 5·87 (s, 1H) ), 6.83 (s, 2H), 7.22 - 7.53 (m, 9H), 9.65 (s, 1H) » Example 1-467 4-(4-Amino-5-cyano-6-phenoxy" Pyridin-2-ylamino)benzoic acid [Chemical 1467]

標題化合物係依據實施例1-354之方法，將4-(4-胺基-5-氰基-6-苯氧基吡啶-2-基胺基）苯甲酸甲酯進行水解而合 成。 1H-NMR (400 MHz, DMSO-d6) δ 5.86 (s, 1H), 6.81 (s, 2H), 7.21 (d, J=8.1 Hz, 2H), 7.24 (d, J=8.1 Hz, 2H), 7.37 (t, J=7.1 Hz，1H), 7.54-7.46 (m, 4H), 9.50 (s，1H)。 實施例1-468 4-(4-胺基-5-氰基-6-苯氧基《比啶-2-基胺基）苯甲醯胺 [化 1468]The title compound was obtained by hydrolysis of methyl 4-(4-amino-5-cyano-6-phenoxypyridin-2-ylamino)benzoate according to the procedure of Example 1-354. 1H-NMR (400 MHz, DMSO-d6) δ 5.86 (s, 1H), 6.81 (s, 2H), 7.21 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 8.1 Hz, 2H), 7.37 (t, J=7.1 Hz, 1H), 7.54-7.46 (m, 4H), 9.50 (s, 1H). Example 1-468 4-(4-Amino-5-cyano-6-phenoxy"pyridin-2-ylamino)benzimidamide [Chem. 1468]

向4-(4-胺基-5-氰基-6-苯氧基。比啶-2-基胺基）苯曱酸（100 mg，0.289 mmol)、1-乙基-3-(3-二甲基胺基丙基）碳化二醯 亞胺鹽酸鹽（83 mg ’ 0.433 mmol)及 HOBt(11.7 mg ’ 0.087 141666.doc -402- 201028381 mmol)之DMF(1 mL)溶液中添加28%氨水（1 mL)攪拌2小 時。向反應溶液中添加水及乙酸乙酯進行分離後，以乙酸 乙酯萃取水相，將合併之有機相以〇. i N鹽酸、飽和碳酸 氫鈉水溶液及飽和食鹽水進行清洗，以硫酸鎂加以乾燥。 將有機相過濾後，進行減壓濃縮。將所獲得之殘渣以己 烧.乙酸乙酯=2 . 1溶液進行清洗，藉此獲得標題化合物 (37.4 mg，0.108 mmol，38%)，為白色固體。 1H-NMR (400 MHz, DMS〇-d6) δ 5.84 (s, 1H), 6.76 (s, 2H), ❿ 7·〇7 (br s，1H)，7.16 (d，J=8.6 Hz, 2H)，7.23 (d, J=8.1 Hz, 2H), 7.35 (t, J—8.1 Hz, 1H), 7.44-7.53 (m, 4H), 7.70 (br s 1H)，9.35 (s，1H)。 實施例1_469 4-(4-胺基-5-氣基-6-本氧基n比n定_2-基胺基）_N-乙基苯甲 醯胺 [化 1469]To 4-(4-Amino-5-cyano-6-phenoxy.pyridin-2-ylamino)benzoic acid (100 mg, 0.289 mmol), 1-ethyl-3-(3- Add 28% to dimethylaminopropyl)carbodiimide hydrochloride (83 mg '0.433 mmol) and HOBt (11.7 mg '0.087 141666.doc -402- 201028381 mmol) in DMF (1 mL) Ammonia (1 mL) was stirred for 2 hours. After adding water and ethyl acetate to the reaction solution for separation, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with MgSO. dry. After the organic phase was filtered, it was concentrated under reduced pressure. The obtained residue was washed with EtOAc EtOAc EtOAc (EtOAc) 1H-NMR (400 MHz, DMS〇-d6) δ 5.84 (s, 1H), 6.76 (s, 2H), ❿ 7·〇7 (br s,1H), 7.16 (d, J=8.6 Hz, 2H) , 7.23 (d, J = 8.1 Hz, 2H), 7.35 (t, J - 8.1 Hz, 1H), 7.44 - 7.53 (m, 4H), 7.70 (br s 1H), 9.35 (s, 1H). Example 1-473 4-(4-Amino-5-carbyl-6-n-oxyl-n-n-t- 2-ylamino)_N-ethylbenzamide [Chem. 1469]

標題化合物係使用對應之胺衍生物，依據實施例1_468之 方法而合成。 1H-NMR (400 MHz, DMSO-dg) δ 1.09 J=7 2 Hz 3H) 3.21-3.27 (m, 2H), 5.84 (s, 1H), 6.76 (s, 2H), 7.16-7.52 (m, 9H)，8.17 (t, J=4.8 Hz, 1H)，9.35 (s，1H) 〇 實施例1-470 141666.doc -403 - 201028381 4-(4-胺基-5-氰基-6-苯氧基吼啶-2-基胺基）-N-(氰基曱 基）苯甲醯胺 [化 1470]The title compound was synthesized according to the method of Example 1-468 using the corresponding amine derivative. 1H-NMR (400 MHz, DMSO-dg) δ 1.09 J=7 2 Hz 3H) 3.21-3.27 (m, 2H), 5.84 (s, 1H), 6.76 (s, 2H), 7.16-7.52 (m, 9H ), 8.17 (t, J = 4.8 Hz, 1H), 9.35 (s, 1H) 〇 Example 1-470 141666.doc -403 - 201028381 4-(4-Amino-5-cyano-6-phenoxy Acridine-2-ylamino)-N-(cyanoindolyl)benzamide [Chemical 1470]

標題化合物係使用對應之胺衍生物，依據實施例1-468之 方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 4.24 (d, J=5.2 Hz, 2H), 5.85 (s, 1H), 6.80 (s, 2H), 7.20-7.53 (m, 9H), 8.88 (t, J=4.8 Hz，1H)，9.45 (s，1H)。 實施例1-471 4-(4-胺基-5-氰基-6-苯氧基。比啶-2-基胺基）-N-(2-(二曱基 胺基）乙基）苯曱醯胺 [化 1471]The title compound was synthesized according to the method of Example 1-468 using the corresponding amine derivative. 1H-NMR (400 MHz, DMSO-d6) δ 4.24 (d, J = 5.2 Hz, 2H), 5.85 (s, 1H), 6.80 (s, 2H), 7.20-7.53 (m, 9H), 8.88 (t , J = 4.8 Hz, 1H), 9.45 (s, 1H). Example 1-471 4-(4-Amino-5-cyano-6-phenoxy.pyridin-2-ylamino)-N-(2-(didecylamino)ethyl)benzene Guanamine [Chemical 1471]

標題化合物係使用對應之胺衍生物，依據實施例1 -468之 方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 2.20 (s, 6H), 2.40 (t, J=6.4 Hz, 2H), 3.32 (t, J=6.4 Hz, 2H), 5.84 (s5 1H), 6.76 (s, 2H), 7.17-7.52 (m, 9H), 8.11 (t, J=4.8 Hz, 1H), 9.36 (s, 1H)。 I41666.doc -404· 201028381 實施例1-472 4-(4-胺基-5-氰基-6-苯氧基β比咬-2-基胺基）_N-(2-曱氧基 乙基）苯甲醯胺 [化 1472]The title compound was synthesized according to the method of Example 1-468 using the corresponding amine derivative. 1H-NMR (400 MHz, DMSO-d6) δ 2.20 (s, 6H), 2.40 (t, J = 6.4 Hz, 2H), 3.32 (t, J = 6.4 Hz, 2H), 5.84 (s5 1H), 6.76 (s, 2H), 7.17-7.52 (m, 9H), 8.11 (t, J = 4.8 Hz, 1H), 9.36 (s, 1H). I41666.doc -404· 201028381 Examples 1-472 4-(4-Amino-5-cyano-6-phenoxyβ butyl-2-ylamino)_N-(2-decyloxyethyl) )benzamide [1,472]

標題化合物係使用對應之胺衍生物，依據實施例1-468之 ® 方法而合成。 1H-NMR (400 MHz，DMSO-d6) δ 3.26 (s，3H), 3.37-3.42 (m, 4H), 5.84 (s, 1H), 6.76 (s, 2H), 7.16-7.52 (m, 9H), 8.22 (t，J=4.8 Hz，1H)，9.36 (s, 1H)。 實施例1-473 4-(4-胺基-5-氰基-6-苯氧基e比咬-2-基胺基）·Ν-甲氧基苯 曱醯胺 [化 1473]The title compound was synthesized according to the method of Example 1-68 using the corresponding amine derivative. 1H-NMR (400 MHz, DMSO-d6) δ 3.26 (s, 3H), 3.37-3.42 (m, 4H), 5.84 (s, 1H), 6.76 (s, 2H), 7.16-7.52 (m, 9H) , 8.22 (t, J = 4.8 Hz, 1H), 9.36 (s, 1H). Example 1-473 4-(4-Amino-5-cyano-6-phenoxye ratio butyl-2-ylamino)·Ν-methoxyphenyl guanamine [Chem. 1473]

標題化合物係使用對應之胺衍生物，依據實施例1-468&amp; 方法而合成。 1H-NMR (400 MHz，DMSO-d6) δ 3.66 (s，3H)，5.84 (s，1H)’ 6.79 (s，2Η), 7.17-7.53 (m, 9Η)，9.40 (s, 1Η)，Π.46 (s， 1H)。 141666.doc -405- 201028381 實施例1-474 4-(4-胺基-5-氰基-6-苯氧基&quot;比啶-2-基胺基）苯并醯肼 [化 1474]The title compound was synthesized according to the procedure of Example 1-468 &amp; 1H-NMR (400 MHz, DMSO-d6) δ 3.66 (s, 3H), 5.84 (s, 1H)' 6.79 (s, 2 Η), 7.17-7.53 (m, 9 Η), 9.40 (s, 1 Η), Π .46 (s, 1H). 141666.doc -405- 201028381 Examples 1-474 4-(4-Amino-5-cyano-6-phenoxy&quot;bipyridin-2-ylamino)benzoindole [Chemical 1474]

標題化合物係使用對應之胺衍生物，依據實施例1-468之 方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 4.37 (s, 2H), 5.83 (s, 1H), 6.76 (s，2H), 7.15-7.55 (m, 9H)，9.35 (s，1H)，9.55 (s，lH)。 實施例卜475 4_胺基-6-(4-(甲基磺醯基）苯基胺基）-2-苯氧基菸鹼腈 [化 1475]The title compound was synthesized according to the method of Example 1-468 using the corresponding amine derivative. 1H-NMR (400 MHz, DMSO-d6) δ 4.37 (s, 2H), 5.83 (s, 1H), 6.76 (s, 2H), 7.15-7.55 (m, 9H), 9.35 (s, 1H), 9.55 (s, lH). Example 475 4_Amino-6-(4-(methylsulfonyl)phenylamino)-2-phenoxynicotinonitrile [Chem. 1475]

標題化合物係使用對應之芳基_化物，依據實施例1 _465 之方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 3.06 (s, 3H), 5.88 (s, 1H), 6.87 (s, 2H), 7.24 (d, J=7.6 Hz, 2H), 7.42-7.30 (m, 5H), 7.52 (t, J=7.6 Hz, 2H), 9-64 (s，ih)。 實施例1-476 4-胺基-6-(4-(3-側氧基哌嗪-l-基）苯基胺基）_2_苯氧基菸 鹼腈 141666.doc •406- 201028381 [化 1476] ΟThe title compound was synthesized according to the method of Example 1 to 465 using the corresponding aryl group. 1H-NMR (400 MHz, DMSO-d6) δ 3.06 (s, 3H), 5.88 (s, 1H), 6.87 (s, 2H), 7.24 (d, J = 7.6 Hz, 2H), 7.42-7.30 (m , 5H), 7.52 (t, J=7.6 Hz, 2H), 9-64 (s, ih). Example 1-476 4-Amino-6-(4-(3-oxopiperazin-1-yl)phenylamino)_2-phenoxynicotinonitrile 141666.doc •406- 201028381 1476] Ο

標題化合物係使用對應之芳基鹵化物，依據實施例丨-465 之方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 3.25 (s, 4H), 3.55 (s, 2H), φ 5·68 (s, 1H), 6.55-6.63 (m, 4H), 7.01-7.48 (m, 7H), 7.98 (s, 1H)，8.79 (s, 1H)。 實施例1-477 5-(4-胺基-5-氰基-6-苯氧基e比咬_2_基胺基）_n-(&quot;比咬-4-基）°塞吩-2-甲醯胺 [化 1477]The title compound was synthesized according to the method of Example 丨-465 using the corresponding aryl halide. 1H-NMR (400 MHz, DMSO-d6) δ 3.25 (s, 4H), 3.55 (s, 2H), φ 5·68 (s, 1H), 6.55-6.63 (m, 4H), 7.01-7.48 (m , 7H), 7.98 (s, 1H), 8.79 (s, 1H). Example 1-177 5-(4-Amino-5-cyano-6-phenoxye than bit _2-ylamino)_n-(&quot;Bite-4-yl)°Cet-2 -carbamamine [Chemical 1477]

標題化合物係使用對應之芳基鹵化物，依據實施例1-465 之方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 5.86 (s, 1H), 6.41 (d, J=3.2 Hz，1H)，6.86 (s，2H), 7.19-7.67 (m，8H), 8.41 (d, J=4.8 Hz，2H), 10.04 (s，1H), 10.63 (br s，1H)。 實施例1-478 4-胺基-6-(4-((4-曱基哌嗪-1-基）甲基）苯基胺基）_2-苯氧 14I666.doc •407- 201028381 基菸鹼腈 [化 1478]The title compound was synthesized according to the method of Example 1-465 using the corresponding aryl halide. 1H-NMR (400 MHz, DMSO-d6) δ 5.86 (s, 1H), 6.41 (d, J = 3.2 Hz, 1H), 6.86 (s, 2H), 7.19-7.67 (m, 8H), 8.41 (d , J=4.8 Hz, 2H), 10.04 (s, 1H), 10.63 (br s, 1H). Example 1-478 4-Amino-6-(4-((4-mercaptopiperazin-1-yl)methyl)phenylamino)_2-phenoxy 14I666.doc • 407- 201028381 Nitrile [Chemical 1478]

標題化合物係使用對應之芳基南化物’依據實施例1 _465 之方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 2.13 (s, 3H), 2.27 (br s, 8H), 3.26 (s, 2H), 5.77 (s, 1H), 6.64-7.46 (m, 11H), 9.13 (slH)。 實施例1-479 4-胺基-2-苯氧基-6-(4-(哌嗪_i_基曱基;)苯基胺基）菸鹼腈 [化 1479]The title compound was synthesized according to the method of Example 1 to 465 using the corresponding aryl amide. 1H-NMR (400 MHz, DMSO-d6) δ 2.13 (s, 3H), 2.27 (br s, 8H), 3.26 (s, 2H), 5.77 (s, 1H), 6.64-7.46 (m, 11H), 9.13 (slH). Example 1-179 4-Amino-2-phenoxy-6-(4-(piperazine-i-ylindenyl)phenylamino) Nicotinonitrile [Chem. 1479]

標題化合物係使用對應之芳基函化物，依據實施例i _465 之方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 2.19 (br s, 4H), 2.64 (br s, 4H), 3.24 (s, 2H), 5.78 (s, 1H), 6.62-7.46 (m, 11H), 9.03 (s 1H)。 實施例1-480 2-(4-(4-胺基-6-氣-5-氰基n比啶·2·基胺基）苯氧基）乙酸 141666.doc -408- 201028381 [化 1480]The title compound was synthesized according to the method of Example i_465 using the corresponding aryl compound. 1H-NMR (400 MHz, DMSO-d6) δ 2.19 (br s, 4H), 2.64 (br s, 4H), 3.24 (s, 2H), 5.78 (s, 1H), 6.62-7.46 (m, 11H) , 9.03 (s 1H). Example 1-480 2-(4-(4-Amino-6-a-5-cyano n-pyridin-2-ylamino)phenoxy)acetic acid 141666.doc -408- 201028381 [Chem. 1480]

向4-胺基-2-氣-6-(4-羥基苯基胺基）菸鹼腈（210 mg， 0.806 mmol)及碳酸鉀（334 mg，2.42 mmol)之 DMF(3 mL)溶 液中添加2-&gt;臭乙酸甲醋（185 mg，114 μΙ&gt;，1.21 mmol)授拌 3小時。向反應溶液中添加水及乙酸乙酯進行分離後，以 乙酸乙酯萃取水相，將合併之有機相以水及飽和食鹽水進 行清洗，以硫酸鎂加以乾燥。將有機相過濾後，進行減壓 濃縮。利用中壓矽膠層析法（己烷：乙酸乙酯=1 : 1)對所 獲得之殘渣進行純化，藉此獲得標題化合物（144 mg， 0.433 mmol，540/〇)，為白色固體。 ❹ 1H-NMR (400 MHz, DMSO-d6) δ 3.70 (s, 3H), 4.76 (s, 2H), 5.89 (s, 1H), 6.78 (s, 2H), 6.91 (d, J=8.8 Hz, 2H), 7.27 (d, J=8.8 Hz, 2H)，9.16 (s，1H)。 實施例1-481 2-(4-(4-胺基-5-氰基-6-苯氧基吼啶-2-基胺基）苯氧基） 乙酸 [化 1481]Add to a solution of 4-amino-2- gas-6-(4-hydroxyphenylamino)nicotinonitrile (210 mg, 0.806 mmol) and potassium carbonate (334 mg, 2.42 mmol) in DMF (3 mL) 2-&gt; Odor acetic acid methyl vinegar (185 mg, 114 μΙ&gt;, 1.21 mmol) was mixed for 3 hours. After water and ethyl acetate were added to the reaction solution for separation, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water and brine, and dried over magnesium sulfate. After the organic phase was filtered, it was concentrated under reduced pressure. The residue obtained was purified by EtOAc EtOAc (EtOAc:EtOAc) ❹ 1H-NMR (400 MHz, DMSO-d6) δ 3.70 (s, 3H), 4.76 (s, 2H), 5.89 (s, 1H), 6.78 (s, 2H), 6.91 (d, J = 8.8 Hz, 2H), 7.27 (d, J=8.8 Hz, 2H), 9.16 (s, 1H). Example 1-481 2-(4-(4-Amino-5-cyano-6-phenoxyacridin-2-ylamino)phenoxy)acetic acid [Chemical 1481]

141666.doc -409- 201028381 標題化合物係使用2-(4-(4-胺基-6-氣-5-氰基®比咬_2_基胺 基）苯氧基）乙酸曱酯，依據實施例1-460之方法而合成（作 為羧酸而獲得）。 1H-NMR (400 MHz, DMSO-d6) δ 4.29 (s, 2H), 5.68 (s, 1H), 6.57-6.60 (m，4H)，7.03-7.47 (m，9H)，8.90 (s，1H)。 實施例1-482 2-(4-(4-胺基-5-氰基-6-苯氧基吼啶-2-基胺基）苯氧基）乙 醯胺 [化 1482]141666.doc -409- 201028381 The title compound is based on the use of 2-(4-(4-amino-6-a-5-cyano)-bito-2-amino)phenoxy)acetate. Synthesis (obtained as a carboxylic acid) by the method of Example 1-460. 1H-NMR (400 MHz, DMSO-d6) δ 4.29 (s, 2H), 5.68 (s, 1H), 6.57-6.60 (m, 4H), 7.03-7.47 (m, 9H), 8.90 (s, 1H) . Example 1-482 2-(4-(4-Amino-5-cyano-6-phenoxyacridin-2-ylamino)phenoxy)ethylamine [Chemical 1482]

標題化合物係使用2-(4-(4-胺基-5-氰基-6-苯氧基吡啶-2-基胺基）苯氧基）乙酸曱酯及氣化錢，依據實施例1-468之方 法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 4.29 (s, 2H), 5.68 (s, 1H), 6.57-6.60 (m，4H)，7.03-7.47 (m，9H), 8.90 (s，1H)。 實施例1-483 (Z)-4-胺基-6-(4-( 1-(曱氧基亞胺基）乙基）苯基胺基）-2-苯 氧基菸鹼腈 141666.doc -410- 201028381 [化 1483]The title compound was obtained by using 2-(4-(4-amino-5-cyano-6-phenoxypyridin-2-ylamino)phenoxy)acetic acid decyl ester and gasification, according to Example 1- Synthesized by the method of 468. 1H-NMR (400 MHz, DMSO-d6) δ 4.29 (s, 2H), 5.68 (s, 1H), 6.57-6.60 (m, 4H), 7.03-7.47 (m, 9H), 8.90 (s, 1H) . Example 1-383 (Z)-4-Amino-6-(4-(1-(decyloxyimino)ethyl)phenylamino)-2-phenoxynicotinonitrile 141666.doc -410- 201028381 [化1483]

Pd(OAc)2, Xantphos OS2CO3Pd(OAc)2, Xantphos OS2CO3

二噁烷J20°CDioxane J20 ° C

步驟1 · (Z)-l-(4_破苯基）乙闕O-甲基月亏 向4-碘苯乙酮（210 mg，0.806 mmol)及0-甲基胲（1.15 g，24.4 mmol)之乙醇（20 mL)溶液中添加D比咬（2.57 g， 3 2.5 mmol)，於80°C下攪拌30分鐘。向反應溶液中添加 1 0%檸檬酸水溶液及乙酸乙酯，進行分離後，以乙酸乙酯 萃取水相，將合併之有機相以水及飽和食鹽水進行清洗， 以硫酸鎂加以乾燥。將有機相過濾後，進行減壓濃縮。利 用中壓矽膠層析法（己烷：乙酸乙酯=10 : 1)對所獲得之殘 φ 渣進行純化，藉此獲得標題化合物（2.04 g，7.42 mmol， 91%)，為褐色固體。 1H-NMR (300 MHz, DMSO-d6) δ 2.13 (s, 3H), 3.90 (s, 3H), 7.44 (d, J=8.4 Hz, 2H)，7·75 (d，J=8.4 Hz, 2H)。 MS(ESI)m/z=276 (M+H)+。 步驟2 :標題化合物 標題化合物係使用（Z)-l-(4-碘苯基）乙酮Ο-甲基肟，依據 實施例1 -465之方法而合成。 141666.doc -411 - 201028381 1H-NMR (400 MHz，DMSO-d6) δ 2_07 (s，3H), 3·86 (s，3H)， 5.83 (s, 1H), 6.72 (s, 2H), 7.16 (d, J=7.1 Hz, 2H), 7.23 (br s, 4H), 7.32 (t, J=7.1 Hz, 1H), 7.49 (t, J=7.1 Hz, 2H), 9.27 (s，1H)。 實施例1-484 4-胺基-6-(1-側氧基-1，3-二氫異苯并呋喃-5-基胺基）-2-苯 氧基菸鹼腈 [化 1484]Step 1 · (Z)-l-(4_Phenyl) Ethyl O-Methyl Deficient to 4-Iodoacetophenone (210 mg, 0.806 mmol) and 0-methylindole (1.15 g, 24.4 mmol To a solution of ethanol (20 mL) was added D to bite (2.57 g, 3 2.5 mmol) and stirred at 80 ° C for 30 minutes. After adding 10% aqueous citric acid solution and ethyl acetate to the reaction solution, the mixture was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and brine and dried over magnesium sulfate. After the organic phase was filtered, it was concentrated under reduced pressure. The residue obtained was purified by EtOAc EtOAc (EtOAc:EtOAc) 1H-NMR (300 MHz, DMSO-d6) δ 2.13 (s, 3H), 3.90 (s, 3H), 7.44 (d, J = 8.4 Hz, 2H), 7·75 (d, J = 8.4 Hz, 2H ). MS (ESI) m / z = 276 (M + H) +. The title compound was synthesized according to the method of Example 1-465 using (Z)-l-(4-iodophenyl)ethanone oxime-methylhydrazine. 141666.doc -411 - 201028381 1H-NMR (400 MHz, DMSO-d6) δ 2_07 (s, 3H), 3·86 (s, 3H), 5.83 (s, 1H), 6.72 (s, 2H), 7.16 (d, J=7.1 Hz, 2H), 7.23 (br s, 4H), 7.32 (t, J=7.1 Hz, 1H), 7.49 (t, J=7.1 Hz, 2H), 9.27 (s, 1H). Example 1-484 4-Amino-6-(1-oxo-1,3-dihydroisobenzofuran-5-ylamino)-2-phenyloxynicotinonitrile [Chemical 1484]

標題化合物係使用對應之芳基_化物，依據實施例1 _465 之方法而合成。 1H-NMR (400 MHz，DMSO_d6) δ 4·97 (s，2H), 5.89 (s，1H)， 6.88 (s, 2Η), 7.17 (d, J=7.6 Hz, 1H), 7.24 (d, J=7.6 Hz, 2H), 7.47-7.39 (m, 3H), 7.53 (t, J=7.6 Hz, 2H), 9.73 (s5 1H)。 實施例1-485 4-胺基-6-(1,3-二侧氧基異叫丨鳴琳-5-基胺基）-2-苯氧基於 驗腈 [化 1485]The title compound was synthesized according to the method of Example 1 to 465 using the corresponding aryl group. 1H-NMR (400 MHz, DMSO_d6) δ 4·97 (s, 2H), 5.89 (s, 1H), 6.88 (s, 2 Η), 7.17 (d, J = 7.6 Hz, 1H), 7.24 (d, J =7.6 Hz, 2H), 7.47-7.39 (m, 3H), 7.53 (t, J=7.6 Hz, 2H), 9.73 (s5 1H). Example 1-185 4-Amino-6-(1,3-di- oxy-iso- oxindole-5-ylamino)-2-phenoxy group for nitrile [Chem. 1485]

141666.doc -412- 201028381 標題化合物係使用對應之芳基鹵化物，依據實施例卜 465之方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 5.89 (s, 1H), 6.90 (s, 2H), 7.19-7.25 (m, 3H), 7.33 (t, 1=7,3 Hz, 1H), 7.45 (s, 1H), 7.49 (t, J=7.3 Hz, 2H), 7.60 (d, J=8.6 Hz, 1H), 9.77 (s, 1H), 10.99 (br s，1H)。 實施例1-486 4-胺基-2-苯氧基-6-(4-(1，1-二氧基硫嗎啉基）苯基胺基） ❿ 菸驗腈 [化 1486]141666.doc -412- 201028381 The title compound was synthesized according to the method of Example 465 using the corresponding aryl halide. 1H-NMR (400 MHz, DMSO-d6) δ 5.89 (s, 1H), 6.90 (s, 2H), 7.19-7.25 (m, 3H), 7.33 (t, 1=7,3 Hz, 1H), 7.45 (s, 1H), 7.49 (t, J = 7.3 Hz, 2H), 7.60 (d, J = 8.6 Hz, 1H), 9.77 (s, 1H), 10.99 (br s, 1H). Example 1-486 4-Amino-2-phenoxy-6-(4-(1,1-dioxythiomorpholinyl)phenylamino) 烟 Cigarette nitrile [Chem. 1486]

QQ

標題化合物係使用對應之芳基鹵化物，依據實施例1 -465之方法而合成。 ❹ 1H-NMR (400 MHz, DMSO-d6) δ 3.14 (s，4H)，3.75 (s，4H), 5.51 (s, 1H), 6.41 (s, 2H), 7.06 (d, J=8.1 Hz, 2H), 7.11-7.22 (m, 5H)，7.40 (t, J=8.1 Hz, 2H)，8.22 (s，1H)。 實施例1-487 4-胺基-6-(1-側氧基-1,2,3,4-四氫異喹啉-6-基胺基）-2-苯 氧基於驗腈 141666.doc -413- 201028381 [化 1487]The title compound was synthesized according to the method of Example 1-465 using the corresponding aryl halide. ❹ 1H-NMR (400 MHz, DMSO-d6) δ 3.14 (s, 4H), 3.75 (s, 4H), 5.51 (s, 1H), 6.41 (s, 2H), 7.06 (d, J = 8.1 Hz, 2H), 7.11-7.22 (m, 5H), 7.40 (t, J = 8.1 Hz, 2H), 8.22 (s, 1H). Example 1-187 4-Amino-6-(1-o-oxy-1,2,3,4-tetrahydroisoquinolin-6-ylamino)-2-phenoxy group for nitrile 141666.doc -413- 201028381 [化1487]

PhNTf2t EI3N HlPhNTf2t EI3N Hl

Pd(OAc)2l Xantphos CS2CO3Pd(OAc)2l Xantphos CS2CO3

二噁烷，120oCDioxane, 120oC

步驟1 :二氣曱續酸1-側氧基-1，2,3，4 -四虱異喧琳-6 -基酯 向 6-羥基-3,4-二氫異啥琳-l(2H)-_(500 mg，3.06 mmol) 及三乙基胺（620 mg，8 50 pL，6.1 3 mmol)之 THF(5 mL)溶 液中添加PhNTf2(N-苯基雙（三氟甲磺醯胺））（1.64 g，4.59 mmol)，於室溫下攪拌2小時。向反應溶液中添加水及乙酸 乙酯進行分離後，以乙酸乙酯萃取水相，將合併之有機相 以水及飽和食鹽水進行清洗，以硫酸镁加以乾燥。將有機 相過濾後，進行減壓濃縮。利用中壓矽膠層析法（己烷： 乙酸乙酯=1 : 3)對所獲得之殘渣進行純化，藉此獲得標題 化合物（355 mg，1.20 mmol，39%)，為白色固體。 1H-NMR (400 MHz, DMSO-d6) δ 2.97 (t，J=6.4 Hz，2H)， 3.39 (t, J=6.4 Hz, 2H), 7.42 (d, J = 8.8 Hz, 1H), 7.49 (brs, 1H), 7.99 (d, J=8.8 Hz, 1H)，8.12 (s，1H)。 步驟2 : 標題化合物係使用三氟甲磺酸1-側氧基-1，2,3，4-四氫異 喹啉-6-基酯，依據實施例1-465之方法而合成。 141666.doc • 414· 201028381 1H-NMR (400 MHz, DMSO-d6) δ 2.50 (br s, 2H), 3.25 (br s, 2H), 5.85 (s, 1H), 6.77 (s, 2H), 7.03 (d, J=8.1 Hz, 1H), 7.11 (s, 1H), 7.23 (d, J=7.6 Hz, 2H), 7.33 (t, J=7.6 Hz, 1H), 7.43 (d, J=8.1 Hz, 1H), 7.48 (t, J=7.6 Hz, 2H), 7.58 (s, 1H), 9.38 (s, 1H) 〇 實施例1-488 4-胺基-2-苯氧基-6-(4-(哌嗪-1_基）苯基胺基）菸鹼腈 [化 1488]Step 1: Dioxin acid 1-terpoxy-1,2,3,4-tetraisoindolin-6-yl ester to 6-hydroxy-3,4-dihydroisoindole-l (2H Adding PhNTf2 (N-phenylbis(trifluoromethanesulfonamide) to a solution of -((500 mg, 3.06 mmol) and triethylamine (620 mg, 8 50 pL, 6.1 3 mmol) in THF (5 mL) )) (1.64 g, 4.59 mmol), stirred at room temperature for 2 hours. Water and ethyl acetate were added to the reaction solution for separation, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and brine and dried over magnesium sulfate. The organic phase was filtered and concentrated under reduced pressure. The residue obtained was purified by EtOAc EtOAc (EtOAc:EtOAc) 1H-NMR (400 MHz, DMSO-d6) δ 2.97 (t, J = 6.4 Hz, 2H), 3.39 (t, J = 6.4 Hz, 2H), 7.42 (d, J = 8.8 Hz, 1H), 7.49 ( Brs, 1H), 7.99 (d, J=8.8 Hz, 1H), 8.12 (s, 1H). Step 2: The title compound was synthesized according to the procedure of Example 1-465, using 1-l-oxy-1,2,3,4-tetrahydroisoquinolin-6-yl trifluoromethanesulfonate. 141666.doc • 414· 201028381 1H-NMR (400 MHz, DMSO-d6) δ 2.50 (br s, 2H), 3.25 (br s, 2H), 5.85 (s, 1H), 6.77 (s, 2H), 7.03 (d, J=8.1 Hz, 1H), 7.11 (s, 1H), 7.23 (d, J=7.6 Hz, 2H), 7.33 (t, J=7.6 Hz, 1H), 7.43 (d, J=8.1 Hz , 1H), 7.48 (t, J = 7.6 Hz, 2H), 7.58 (s, 1H), 9.38 (s, 1H) 〇 Example 1-488 4-Amino-2-phenoxy-6-(4 -(piperazin-1-yl)phenylamino)nicotinic nitrile [Chemical 1488]

〇-〇h hO〇-〇h hO

NaHNaH

NMP, 160 °CNMP, 160 °C

步驟1 : 4-胺基-2-氣-6-(4-(哌嗪基）苯基胺基）菸鹼腈 於5 mL微波反應容器中’向三氟曱績酸4_胺基_6_氯_5_ 氰基 °比咬-2-基 S旨（250 mg ’ 0.829mm〇l)及 DIEA(118 mg， 0.912 mmol)之DMSO(3 mL)溶液中添加4_(4_甲基哌嗪_卜 基）苯胺（317 mg，1.66 mmol)進行覆蓋，使用Bi〇tage Optimizer反應裝置，於15〇°C下攪拌3〇分鐘。向反應溶液 中添加水及乙酸乙醋進行分離後，以乙酸乙醋萃取水相， 將合併之有機相以水及飽和食鹽水進行清洗，以硫酸鎂加 以乾燥。將有機相過滤後，進行減墨遭縮。利用中壓石夕膠 層析法（己烷.乙酸乙知1 . 3)對所獲得之殘渣進行純 141666.doc -415- 201028381 化’獲得標題化合物（56.9 mg，0.173 mmo卜21%)，為褐 色固體。 1H-NMR (400 MHz, DMSO-d6) δ 2.93 (brs, 4H), 3.54 (brs, 4H), 4.61 (brs, 1H), 5.88 (s, 1H), 6.50 (d, J=8.0 Hz, 2H), 6.72 (d，J=8.0 Hz，2H)，6.73 (s，2H)。 步驟2 :標題化合物 於5 mL微波反應容器中，向4_胺基·2_氣_6_(4_(哌嗪 基）苯基胺基）菸鹼腈（56.9 mg，0.173 mmol)及苯酚（81 mg，0.865 mmol)之NMP(1 mL)溶液中添加60%氫化鈉❿ (20.8 mg，0.865 mmol)進行覆蓋，使用 Bi〇tage 〇ptimizer 反應裝置，於160 C下攪拌1小時。向反應溶液中添加水及 乙酸乙酯進行分離後，以乙酸乙酯萃取水相，將合併之有 機相以水及飽和食鹽水進行清洗，以硫酸鎂加以乾燥。將 有機相過濾後，進行減壓濃縮。利用中壓矽膠層析法（己 烷：乙酸乙酯=1 : 1〜〇 : 1)對所獲得之殘渣進行純化，獲 得標題化合物（23.6 mg，〇.〇61 mm〇1，35%)，為茶色固 體。 1H-NMR (400 MHz, DMSO-d6) δ 2.83 (s, 4H), 3.34 (s, 4H), 4.60 (br s, 1H), 5.70 (s, lH), 6.48 (d, J=8.6 Hz, 2H), 6.58 (s, 2H), 6.68 (d, J=8.6 Hz, 2H), 7.15 (d, J=7.6 Hz, 2H), 7.21 (t,】=7·6 Hz，1H), 7.41 (t，j=7 6 Hz，2H)。 實施例1-489 4-胺基-6-(4-(1-甲 終驗猜 基-1H-咪唑_5·基）苯基胺基）2苯氧基 141666.doc -416- 201028381 [化 1489]Step 1: 4-Amino-2- gas-6-(4-(piperazinyl)phenylamino)nicotinic nitrile in a 5 mL microwave reaction vessel 'to a trifluoro acid 4-amino group -6 _Chloro_5_Cyano group added 4-(4-methylpiperazine) to a solution of -2-(S) (250 mg '0.829mm〇l) and DIEA (118 mg, 0.912 mmol) in DMSO (3 mL) The aniline (317 mg, 1.66 mmol) was overlaid and stirred at 15 ° C for 3 Torr using a Bi〇tage Optimizer reactor. After the water and ethyl acetate were added to the reaction solution for separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and brine, and dried over magnesium sulfate. After the organic phase is filtered, the ink is reduced. The obtained residue was subjected to pure 141666.doc -415 - 201028381 by medium pressure stone chromatography (hexane, acetic acid, hexane, hexane) to obtain the title compound (56.9 mg, 0.173 mmo, 21%). It is a brown solid. 1H-NMR (400 MHz, DMSO-d6) δ 2.93 (brs, 4H), 3.54 (brs, 4H), 4.61 (brs, 1H), 5.88 (s, 1H), 6.50 (d, J=8.0 Hz, 2H ), 6.72 (d, J = 8.0 Hz, 2H), 6.73 (s, 2H). Step 2: The title compound was taken in a 5 mL microwave reaction vessel to 4-amino-2 gas (6-(4-piperazinyl)phenylamino)nicotinonitrile (56.9 mg, 0.173 mmol) and phenol (81) A solution of 60 mg of sodium hydride (20.8 mg, 0.865 mmol) was added to a solution of EtOAc (1 mL), and then stirred at 160 C for 1 hour using a Bi〇tage 〇ptimizer apparatus. Water and ethyl acetate were added to the reaction solution for separation, and the aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with water and saturated brine and dried over magnesium sulfate. After the organic phase was filtered, it was concentrated under reduced pressure. The residue obtained was purified by EtOAc (EtOAc: EtOAc: EtOAc: It is a brown solid. 1H-NMR (400 MHz, DMSO-d6) δ 2.83 (s, 4H), 3.34 (s, 4H), 4.60 (br s, 1H), 5.70 (s, lH), 6.48 (d, J = 8.6 Hz, 2H), 6.58 (s, 2H), 6.68 (d, J=8.6 Hz, 2H), 7.15 (d, J=7.6 Hz, 2H), 7.21 (t,]=7·6 Hz, 1H), 7.41 ( t, j = 7 6 Hz, 2H). Example 1-89 4-Amino-6-(4-(1-methyl-predictive-1H-imidazole-5(yl))phenylamino)2phenoxy 141666.doc -416- 201028381 1489]

標題化合物係使用4-胺基-6-(4-溴苯基胺基）_2_苯氧基終驗 腈及5-溴-1-甲基-1H-咪唑，依據實施例丨-42^步驟3)之方 法而合成。 1H NMR (400 MHz, DMSO-d6) δ 3.40 (s, 3H), 5.83 (s, 1H), 6.71 (s, 2H), 6.95 (s, 1H), 7.04 (d, J=8.4 Hz, 3H), 7.33 (d, J=8.4 Hz, 1H), 7.47-7.50 (m, 2H), 7.72 (s, 1H), 9.26 (s, 1H)。 MS(ESI)m/z=383 (M+H)+。 LC/MS tR=1.07 min。 實施例1-490 4-胺基-6-(4-(1·(2-(二甲基胺基）乙基）-1Η-吼唑-4-基）苯 基胺基）-2-苯氧基終驗腈 [化 1490]The title compound is 4-amino-6-(4-bromophenylamino)-2-phenoxy final nitrile and 5-bromo-1-methyl-1H-imidazole, according to the procedure 丨-42^ 3) The method is synthesized. 1H NMR (400 MHz, DMSO-d6) δ 3.40 (s, 3H), 5.83 (s, 1H), 6.71 (s, 2H), 6.95 (s, 1H), 7.04 (d, J = 8.4 Hz, 3H) , 7.33 (d, J=8.4 Hz, 1H), 7.47-7.50 (m, 2H), 7.72 (s, 1H), 9.26 (s, 1H). MS (ESI) m / z = 381 (M+H)+. LC/MS tR = 1.07 min. Examples 1-490 4-Amino-6-(4-(1·(2-(dimethylamino)ethyl)-1Η-oxazol-4-yl)phenylamino)-2-benzene Alkyl final nitrile [Chemical 1490]

標題化合物係使用4-胺基-6-(4-溴苯基胺基）-2-笨氧基菸鹼 腈及2-(4-溴-1Η-°比吐-1-基）-N，N-二甲基乙胺，依據實施例 1-424(步驟3)之方法而合成。 141666.doc • 417- 201028381 1H NMR (400 MHz, DMSO-d6) d 2.17 (s, 6H), 2.66 (t, J=6.4 Hz, 2H), 4.17 (t, J=6.4 Hz, 2H), 5.79 (s, 1H), 6.64 (s, 2H), 7.13 (s, 4H), 7.22 (d, J=8.4 Hz, 2H), 7.33 (d, J=7.6 Hz, 1H), 7.49 (t, J=8.0 Hz, 2H), 7.70 (s, 1H), 7.99 (s, 1H), 9.08 (s，1H)。 MS(ESI)m/z=440 (M+H)+。 LC/MS tR=1.13 min。 實施例1-491 4-胺基-6-(4-溴苯基胺基）-2-(3-(羥基甲基）苯氧基）菸 © 鹼腈 [化 1491]The title compound is 4-amino-6-(4-bromophenylamino)-2- phenoxy nicotine nitrile and 2-(4-bromo-1 fluorenylpyran-1-yl)-N. N-dimethylethylamine was synthesized according to the method of Example 1-424 (Step 3). 141666.doc • 417- 201028381 1H NMR (400 MHz, DMSO-d6) d 2.17 (s, 6H), 2.66 (t, J=6.4 Hz, 2H), 4.17 (t, J=6.4 Hz, 2H), 5.79 (s, 1H), 6.64 (s, 2H), 7.13 (s, 4H), 7.22 (d, J=8.4 Hz, 2H), 7.33 (d, J=7.6 Hz, 1H), 7.49 (t, J= 8.0 Hz, 2H), 7.70 (s, 1H), 7.99 (s, 1H), 9.08 (s, 1H). MS (ESI) m / z = 440 (M + H) +. LC/MS tR = 1.13 min. Example 1-491 4-Amino-6-(4-bromophenylamino)-2-(3-(hydroxymethyl)phenoxy) Tobacco © Alkali Nitrile [Chem. 1491]

標題化合物係使用4-胺基-2-溴-6-(4-溴苯基胺基）菸鹼腈 (實施例1-424之步驟1)及3-(羥基甲基）苯酚，依據實施例1-460之方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 4.54 (d, J=5.1 Hz, 2H), 5.31 (t, J=5.1 Hz, 1H), 5.77 (s, 1H), 6.72 (s, 2H), 7.04-7.15 (m, 6H), 7.27 (d, J=7.8 Hz, 1H), 7.43 (t, J=7.8 Hz, 1H), 9.23 (s, 1H)。 實施例1-492 4-胺基-2-(3-(羥基甲基）苯氧基）-6-(4-(1-甲基-ΙΗ-吼峻-4-基）苯基胺基）菸鹼腈 141666.doc -418· 201028381 [化 1492]The title compound is 4-amino-2-bromo-6-(4-bromophenylamino)nicotinonitrile (Step 1 of Examples 1-424) and 3-(hydroxymethyl)phenol, according to the examples. Synthesized by the method of 1-460. 1H-NMR (400 MHz, DMSO-d6) δ 4.54 (d, J = 5.1 Hz, 2H), 5.31 (t, J = 5.1 Hz, 1H), 5.77 (s, 1H), 6.72 (s, 2H), 7.04-7.15 (m, 6H), 7.27 (d, J=7.8 Hz, 1H), 7.43 (t, J=7.8 Hz, 1H), 9.23 (s, 1H). Example 1-492 4-Amino-2-(3-(hydroxymethyl)phenoxy)-6-(4-(1-methyl-indole-indol-4-yl)phenylamino) Nicotinonitrile 141666.doc -418· 201028381 [化1492]

標題化合物係使用4-胺基-6-(4-溴苯基胺基）-2-(3-(羥基甲 基）苯氧基）菸鹼腈及硼酸頻哪醇酯衍生物，依據實施例1-326(步驟3)之方法而合成。The title compound is 4-amino-6-(4-bromophenylamino)-2-(3-(hydroxymethyl)phenoxy)nicotinonitrile and boronic acid pinacol ester derivative, according to the examples. Synthesized by the method of 1-326 (step 3).

1H-NMR (400 MHz, DMSO-d6) δ 3.82 (s, 3H), 4.55 (br s, 2H), 5.43 (br s, 1H), 5.78 (s, 1H), 6.60 (s, 2H), 7.05 (d, J=7.6 Hz, 1H), 7.11-7.18 (m, 5H), 7.26 (d, J=7.6 Hz, 1H), 7.42 (t, J=7.6 Hz, 1H), 7.69 (s, 1H), 7.92 (s, 1H), 9.07 (s, 1H)。 實施例1-493 4-胺基-2-(苯并[d][l，3]二氧雜環戊烯-5-基氧基）-6-(4-溴 苯基胺基）菸鹼腈 [化 1493]1H-NMR (400 MHz, DMSO-d6) δ 3.82 (s, 3H), 4.55 (br s, 2H), 5.43 (br s, 1H), 5.78 (s, 1H), 6.60 (s, 2H), 7.05 (d, J=7.6 Hz, 1H), 7.11-7.18 (m, 5H), 7.26 (d, J=7.6 Hz, 1H), 7.42 (t, J=7.6 Hz, 1H), 7.69 (s, 1H) , 7.92 (s, 1H), 9.07 (s, 1H). Example 1-193 4-Amino-2-(benzo[d][l,3]dioxol-5-yloxy)-6-(4-bromophenylamino)nicotine Nitrile [Chemical 1493]

標題化合物係使用4-胺基-2-溴-6-(4-溴笨基胺基）菸鹼腈 (實施例1-424之步驟1)及苯并[d][l，3]二氧雜環戍烯_5_酵， 依據實施例1-460之方法而合成。 1H-NMR (400 MHz，DMSO-d6) δ 5·77 (s，iH)，6.09 (s，2H)， 141666.doc -419- 201028381 6.66 (dd, J=8.1, 2.0 Hz, 1H), 6.70 (s, 2H), 6.89 (d, J=2.0 Hz, 1H), 7.00 (d, J=8.1 Hz, 1H), 7.12 (d, J=9.1 Hz, 2H), 7.18 (d, J=9_l Hz, 2H)，9.24 (s，ih) 〇 實施例1-494 4-胺基-2-(苯并[d][l，3]二氧雜環戊烯_5_基氧基 甲基-1Η-°比唑-4-基）苯基胺基）菸鹼腈 [化 1494]The title compound is 4-amino-2-bromo-6-(4-bromophenylamino)nicotinonitrile (Step 1 of Examples 1-424) and benzo[d][l,3]dioxane. Heterocyclic terpene _5_ leaven, synthesized according to the method of Examples 1-460. 1H-NMR (400 MHz, DMSO-d6) δ 5·77 (s, iH), 6.09 (s, 2H), 141666.doc -419 - 201028381 6.66 (dd, J=8.1, 2.0 Hz, 1H), 6.70 (s, 2H), 6.89 (d, J=2.0 Hz, 1H), 7.00 (d, J=8.1 Hz, 1H), 7.12 (d, J=9.1 Hz, 2H), 7.18 (d, J=9_l Hz , 2H), 9.24 (s, ih) 〇 Example 1-194 4-Amino-2-(benzo[d][l,3]dioxol-5-yloxymethyl-1Η -°bazol-4-yl)phenylamino)nicotinic nitrile [Chemical 1494]

標題化合物係使用4-胺基-2-(苯并[d][l，3]二氧雜環戍婦_5_ 基氧基）-6-(4-溴苯基胺基）菸鹼腈及硼酸頻哪醇_衍生物， 依據實施例1 ·326(步驟3)之方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 3.85 (s，3Η), 5.77 (s 1Η) 6.11 (s, 2H), 6.68-6.60 (m, 3H), 6.90 (d, J=2.5 jjz ijj) 6.98 (d, J=8.1 Hz, 1H)，7.20 (s，4H)，7.70 (s, 1H)，7 95 (s, 1H), 9.07 (s，1H)。 實施例1-495 4,6-二胺基-2-(萘-2-基氧基）菸鹼腈 [化 1495]The title compound is 4-amino-2-(benzo[d][l,3]dioxanthene-5-yloxy)-6-(4-bromophenylamino)nicotinonitrile and The boronic acid pinacol derivative was synthesized according to the method of Example 1 326 (Step 3). 1H-NMR (400 MHz, DMSO-d6) δ 3.85 (s, 3 Η), 5.77 (s 1 Η) 6.11 (s, 2H), 6.68-6.60 (m, 3H), 6.90 (d, J=2.5 jjz ijj) 6.98 (d, J=8.1 Hz, 1H), 7.20 (s, 4H), 7.70 (s, 1H), 7 95 (s, 1H), 9.07 (s, 1H). Example 1-495 4,6-Diamino-2-(naphthalen-2-yloxy)nicotinonitrile [Chem. 1495]

141666.doc •420· 201028381 標題化合物係使用2-萘酚’依據實施例1-464之方法而合 成。 1H-NMR (400 MHz, DMSO-d6) δ 5.46 (s, 1H), 6.25 (s, 2H), 6.43 (s5 2H), 7.31 (dd, J=9.1, 2.0 Hz, 1H), 7.55-7.46 (m, 2H)，7.64 (s, 1H), 7.96-7.87 (m，3H)。 實施例1-496 4-(4 -胺基-5-氰基- 6- (萘-2-基氧基）u比咬-2-基胺基）苯甲 酿胺 ❹ [化1496]141666.doc • 420· 201028381 The title compound was synthesized according to the method of Example 1-464 using 2-naphthol. 1H-NMR (400 MHz, DMSO-d6) δ 5.46 (s, 1H), 6.25 (s, 2H), 6.43 (s5 2H), 7.31 (dd, J=9.1, 2.0 Hz, 1H), 7.55-7.46 ( m, 2H), 7.64 (s, 1H), 7.96-7.87 (m, 3H). Example 1-496 4-(4-Amino-5-cyano-6-(naphthalen-2-yloxy)u butyl-2-ylamino)benzamide Aromatic amine 化 [4961]

標題化合物係使用4,6-二胺基-2-(萘_2-醯氧基）菸鹼腈及4-碘苯曱醯胺，依據實施例1_465之方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 5.88 (s, 1H), 6.80 (s, 2H), 6.99 (s, 1H), 7.12 (d, J=8.6 Hz, 2H), 7.23 (d, J=8.6 Hz, 2H), 7.43 (d, J=9.1 Hz, 1H), 7.52-7.58 (m, 3H), 7.76 (s, 1H)，7.91-7.95 (m, 1H)，8.07-8.01 (m, 2H), 9.33 (s，1H)。 實施例1-497 4-(4-胺基·5-氰基-6-(2-甲氧基苯氧基）e比啶_2-基胺基）苯 甲酸曱酯 141666.doc • 421 - 201028381 [化 1497]The title compound was synthesized according to the method of Example 1-465 using 4,6-diamino-2-(naphthalene-2- methoxy) nicotinonitrile and 4-iodobenzamine. 1H-NMR (400 MHz, DMSO-d6) δ 5.88 (s, 1H), 6.80 (s, 2H), 6.99 (s, 1H), 7.12 (d, J = 8.6 Hz, 2H), 7.23 (d, J =8.6 Hz, 2H), 7.43 (d, J=9.1 Hz, 1H), 7.52-7.58 (m, 3H), 7.76 (s, 1H), 7.91-7.95 (m, 1H), 8.07-8.01 (m, 2H), 9.33 (s, 1H). Example 1-197 4-(4-Amino-5-cyano-6-(2-methoxyphenoxy)epyridin-2-ylamino)benzoate 141666.doc • 421 - 201028381 [Chem. 1497]

標題化合物係使用4,6-二胺基-2-(2-甲氧基苯氧基）菸鹼 腈，依據實施例1-465之方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 3.70 (s, 3H), 3.77 (s, 3H), 5.84 (s, 1H), 6.77 (s, 2H), 7.05 (t, J=7.3 Hz, 1H), 7.17-7.25 (m, 4H), 7.35 (t, J=7.3 Hz, 1H), 7.49 (d, J=8.6 Hz, 2H), 9.51 (s，1H)。 實施例1_498 4,6-二胺基-2-(金剛烷_1-基胺基）菸鹼腈 [化 1498]The title compound was synthesized according to the method of Example 1-465 using 4,6-diamino-2-(2-methoxyphenoxy)nicotinonitrile. 1H-NMR (400 MHz, DMSO-d6) δ 3.70 (s, 3H), 3.77 (s, 3H), 5.84 (s, 1H), 6.77 (s, 2H), 7.05 (t, J = 7.3 Hz, 1H ), 7.17-7.25 (m, 4H), 7.35 (t, J = 7.3 Hz, 1H), 7.49 (d, J = 8.6 Hz, 2H), 9.51 (s, 1H). Example 1_498 4,6-Diamino-2-(adamantane-1-ylamino)nicotinonitrile [Chemical 1498]

於20 mL微波反應容器中，向4,6-二胺基-2-溴菸鹼腈（2.0 莒’9.39 111111〇1)之]^]\4?(2〇1111〇溶液中添加1-金剛燒胺（4.26 g ’ 28.2 mmol)進行覆蓋，使用 Bi〇tage 〇ptimizer 反應裝 置’於250 C下攪拌1小時。向反應溶液中添加水及乙酸乙 醋進行分離後，以乙酸乙酯萃取水相，將合併之有機相以 水及飽和食鹽水進行清洗，以硫酸鎂加以乾燥。將有機相 過滤後’進行減壓濃縮，利用中壓矽膠層析法（己烷：乙 141666.doc 201028381 酸乙酯=1 : 1)進行純化，藉此獲得標題化合物（1.57 g， 5.54 mmol，59%)，為白色固體。 1H-NMR (400 MHz, DMSO-d6) δ 1.65 (q，J=11.3 Hz, 6H)， 2.02 (s, 3H), 2.07 (s, 6H), 4.56 (s, 1H), 5.07 (s, 1H), 5.81 (s，2H), 5.83 (s，2H)。 實施例1-499 參 4 -胺基-2 -(金剛烧-1 -基胺基）-6-(4-(1-曱基-1Η - °比α坐-4 _ 基）苯基胺基）菸鹼腈 [化 1499]Add 1 -6-diamino-2-bromonicotinonitrile (2.0 莒 '9.39 111111〇1) to ^]\4? (2〇1111〇 solution in a 20 mL microwave reaction vessel) The amine was dried (4.26 g ' 28.2 mmol) and covered with a Bi〇tage 〇ptimizer reactor at 250 C for 1 hour. Water and ethyl acetate were added to the reaction solution for separation, and the aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with water and saturated brine and dried over magnesium sulfate. After the organic phase was filtered, and then concentrated under reduced pressure, using medium pressure gel chromatography (hexane: 141666.doc 201028381 acid B The title compound (1.57 g, 5.54 mmol, 59%) was obtained as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 1.65 (q, J = 11.3 Hz, 6H), 2.02 (s, 3H), 2.07 (s, 6H), 4.56 (s, 1H), 5.07 (s, 1H), 5.81 (s, 2H), 5.83 (s, 2H). Examples 1-499 4-Amino-2 -(adamantan-1 -ylamino)-6-(4-(1-indolyl-1Η- ° than α-s--4-yl)phenylamino)nicotinic nitrile [ 1499]

步驟1 . 4 -胺基-2-(金剛炫&gt;-1-基胺基）-6-(4 -漠苯基胺基） 於驗腈 於5 mL微波反應容器中，向4,6-二胺基-2-(金剛烷-1-基 胺基）於驗腈（300 mg，1.06 mmol)、1-溴-4-埃苯（300 mg， 1.06 mmol) ' Xantphos(61.3 mg，0.106 mmol)及碳酸铯 (483 mg，1.48 mmol)之二°惡烧（3 mL)溶液中添加 141666.doc -423- 201028381Step 1. 4 -Amino-2-(金刚炫&gt;-1-ylamino)-6-(4-diphenylamino) was tested in a 5 mL microwave reaction vessel to 4,6- Diamino-2-(adamantan-1-ylamino)-acetonitrile (300 mg, 1.06 mmol), 1-bromo-4-ethylbenzene (300 mg, 1.06 mmol) 'Xantphos (61.3 mg, 0.106 mmol) And cesium carbonate (483 mg, 1.48 mmol) in a two-degree smoldering (3 mL) solution added 141666.doc -423- 201028381

Pd(OAc)2(11.9 mg’ 〇·〇53 mmol)進行覆蓋，使用 Bi〇tage Optimizer反應裝置，於120°C下攪拌1小時。向反應溶液中 添加水及乙酸乙酯進行分離後，以乙酸乙醋萃取水相，將 合併之有機相以水及飽和食鹽水進行清洗，以硫酸鎂加以 乾燥。將有機相過濾後’進行減壓濃縮。利用中壓矽膠層 析法（己烷··乙酸乙酯=1 : 1)對所獲得之殘渣進行純化， 獲得標題化合物（142.8 mg，0.326 mmol，31%)，為黃色固 體。 1H-NMR (400 MHz，DMSO-d6) δ 1.63 (brs, 6H)，1.97 (brs，❹ 3H), 2.04 (brs, 6H), 4.83 (s, 1H), 5.43 (s, 1H), 6.16 (s, 2H), 7.34 (d, J = 8.8 Hz, 2H), 7.46 (d, J=8.8 Hz, 2H), 8.85 (s, 1H)。 步驟2 :標題化合物 向4-胺基-6-(4-溴苯基胺基）_2_異丙氧基菸鹼腈（14 g， 3.19 mmol)、1-甲基 _4-(4,4,5,5-四甲基-1，3,2-二氧雜硼烷 _ 2基）1H比坐（997 mg，4.79 mmol)及2 mol/L碳酸卸水溶 液（3.19 mL，6.38 mmol)iDMF(1〇 mL)溶液中添加二氯 G [1，1’_雙（二-第三丁基膦基）二茂鐵]把⑴）（2〇8叫，〇 319 mmol)’於9〇°C下攪拌1小時。向反應溶液中添加水及乙酸 乙酯進行分離後，以乙酸乙酯萃取水相，將合併之有機相 以水及飽和食鹽水進行清洗，以硫酸鎂加以乾燥 。將有機 相過濾後，進行減壓濃縮。利用中壓矽膠層析法（己烷： 乙酸乙s曰-1 . 1)對所獲得之殘渣進行純化使用乙酸乙酯 使其固化’藉此獲得標題化合物（1 16 g，2 64 mm〇1， 141666.doc -424- 201028381 83%)，為白色固體。 1H-NMR (400 MHz, DMSO-d6) δ 1.66 (br s, 6H)，2 〇4 (fc 3H)，2.08 (br s，6H), 3.85 (s，3H)，4.81 (s，m)，5 45 ( ’ 1H), 6.10 (s, 2H), 7.40 (d, J=8.6 Hz, 2H), 7 46 r , T ’ (α，J=8.6Pd(OAc) 2 (11.9 mg' 〇·〇 53 mmol) was covered, and stirred at 120 ° C for 1 hour using a Bi〇tage Optimizer reaction apparatus. Water and ethyl acetate were added to the reaction solution for separation, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and brine and dried over magnesium sulfate. After the organic phase was filtered, it was concentrated under reduced pressure. The residue obtained was purified by EtOAc (EtOAc:EtOAc) 1H-NMR (400 MHz, DMSO-d6) δ 1.63 (brs, 6H), 1.97 (brs, ❹ 3H), 2.04 (brs, 6H), 4.83 (s, 1H), 5.43 (s, 1H), 6.16 ( s, 2H), 7.34 (d, J = 8.8 Hz, 2H), 7.46 (d, J = 8.8 Hz, 2H), 8.85 (s, 1H). Step 2: The title compound is 4-amino-6-(4-bromophenylamino)_2-isopropoxy nicotinonitrile (14 g, 3.19 mmol), 1-methyl_4- (4, 4) ,5,5-tetramethyl-1,3,2-dioxaborane _ 2)) 1H than sitting (997 mg, 4.79 mmol) and 2 mol/L aqueous solution (3.19 mL, 6.38 mmol) iDMF (1〇mL) solution added with dichloro G [1,1'-bis(di-t-butylphosphino)ferrocene] (1)) (2〇8, 〇319 mmol)' at 9〇° Stir for 1 hour at C. Water and ethyl acetate were added to the reaction solution for separation, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and brine, and dried over magnesium sulfate. The organic phase was filtered and concentrated under reduced pressure. The residue obtained was purified by medium pressure tannin chromatography (hexane: ethyl acetate s -1 -1) using ethyl acetate to solidify, whereby the title compound (1 16 g, 2 64 mm 〇1) was obtained. , 141666.doc -424- 201028381 83%), as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 1.66 (br s, 6H), 2 〇4 (fc 3H), 2.08 (br s, 6H), 3.85 (s, 3H), 4.81 (s, m), 5 45 ( ' 1H), 6.10 (s, 2H), 7.40 (d, J=8.6 Hz, 2H), 7 46 r , T ' (α, J=8.6

Hz，2H)，7.74 (s，1H)，8_00 (s，1H)，8·71 (s，iH) o 實施例1-500 -2-基胺基μHz, 2H), 7.74 (s, 1H), 8_00 (s, 1H), 8·71 (s, iH) o Example 1-500 -2-ylamino group μ

4-[6-(金剛烧-1-基胺基）-4 -胺基-5-氰基_n比咬 苯甲醯胺 [化 1500]4-[6-(Adamant-1-ylamino)-4-amino-5-cyano-n-bit benzophenone [Chem. 1500]

標題化合物係使用4,6-二胺基-2-(金剛烷_丨_基胺&amp; )&amp; 及4-碘苯曱醯胺，依據實施例1-499(步驟、 X方法而合 成。The title compound was synthesized according to the procedure of Example 1-49 using 4,6-diamino-2-(adamantane- s-ylamine &amp;&amp;&amp;&amp;&amp;

1H-NMR (400 MHz，DMSO-d6) δ 1 68 (s，6Ή) 2 04 2 (m, 9H)，4.89 (s，1H)，5.52 (s, 1H)，6.22 (s，2H), 7 i2 〇 1H)，7.61 (d，J=8.1 Hz, 2H)，7.76 (d，J=8」Hz，2H)，7 8〇 (s，1H)，9.04 (s, 1H)。 實施例l-5〇l 2-(金剛烷-1-基胺基）-4-胺基-6-(4-乙炔基_苯基胺基）於 鹼腈 141666.doc -425- 201028381 [化 1501]1H-NMR (400 MHz, DMSO-d6) δ 1 68 (s, 6 Ή) 2 04 2 (m, 9H), 4.89 (s, 1H), 5.52 (s, 1H), 6.22 (s, 2H), 7 I2 〇1H), 7.61 (d, J = 8.1 Hz, 2H), 7.76 (d, J = 8" Hz, 2H), 7 8 〇 (s, 1H), 9.04 (s, 1H). Example l-5〇l 2-(adamantan-1-ylamino)-4-amino-6-(4-ethynyl-phenylamino) in alkali nitrile 141666.doc -425- 201028381 1501]

步驟1 : 2-(金剛烷-1-基胺基）-4-胺基-6-(4-三曱基矽烷基 乙炔基-苯基胺基）-菸鹼腈 標題化合物係依據實施例1-499(步驟1)之方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 0.19 (s，9H), 1.65 (brs， 6H), 1.97 (s, 3H), 2.06 (brs, 6H), 4.87 (s, 1H), 5.47 (s, 1H), 6.19 (s, 2H), 7.26 (d, J=8.8 Hz, 2H), 7.55 (d, J=8.8 Hz, 2H)，9.00 (s，1H)。 步驟2 :標題化合物 向2-(金剛烷-1-基胺基）_4_胺基·6_(4_三甲基矽烷基乙炔 0 基-本基胺基）-於驗腈（113.6 111§，0.249 111111〇1)之1'1^(2 1111^) 溶液中添加 TBAF(1 m〇l/L THF 溶液，374 μί，0.374 mmol) ’於室溫下攪拌5分鐘。向反應溶液中添加水及乙酸 乙醋進行分離後’以乙酸乙酯萃取水相，將合併之有機相 以水及飽和食鹽水進行清洗，以硫酸鎂加以乾燥。將有機 相過濾後’進行減壓濃縮’利用中壓矽膠層析法（己烷： 乙酸乙酯=2 : 1)進行純化，藉此獲得標題化合物（3 1.1 mg，0.081 mmo卜33%)，為白色固體。 141666.doc •426- 201028381 1H-NMR (400 MHz，DMSO-d6) δ 1.66 (s，6H)，2.07 (s, 9H)， 3.98 (s，1H)，4.87 (s，1H)，5.48 (s, 1H)，6.20 (s, 2H)，7.30 (d，J=7.6 Hz，2H)，7.56 (d，J=7.6 Hz, 2H)，8.99 (s, 1H)。 實施例1-502 4-[4 -胺基-5-氮基- 6- (3 -經基-金剛烧-1·基胺基）-α比咬- 2_ 基胺基]-苯甲醯胺 [化 1502]Step 1: 2-(Adamantyl-1-ylamino)-4-amino-6-(4-tridecylfluorenylethynyl-phenylamino)-nicotinonitrile The title compound is based on Example 1. Synthesized by the method of -499 (Step 1). 1H-NMR (400 MHz, DMSO-d6) δ 0.19 (s, 9H), 1.65 (brs, 6H), 1.97 (s, 3H), 2.06 (brs, 6H), 4.87 (s, 1H), 5.47 (s , 1H), 6.19 (s, 2H), 7.26 (d, J=8.8 Hz, 2H), 7.55 (d, J=8.8 Hz, 2H), 9.00 (s, 1H). Step 2: The title compound is taken to 2-(adamantan-1-ylamino)-4-amino-6-(4-trimethyldecylalkylethynyl-yl-ylamino)-acetonitrile (113.6 111 §, Add TBAF (1 m〇l/L THF solution, 374 μί, 0.374 mmol) to the solution of 0.249 111111〇1) in 1'1^(2 1111^). Stir at room temperature for 5 minutes. After adding water and acetic acid to the reaction solution for separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and brine and dried over magnesium sulfate. After the organic phase was filtered, the title compound (3 1.1 mg, 0.081 mmo, 33%) was purified by EtOAc (EtOAc: EtOAc) It is a white solid. 141666.doc • 426- 201028381 1H-NMR (400 MHz, DMSO-d6) δ 1.66 (s, 6H), 2.07 (s, 9H), 3.98 (s, 1H), 4.87 (s, 1H), 5.48 (s , 1H), 6.20 (s, 2H), 7.30 (d, J = 7.6 Hz, 2H), 7.56 (d, J = 7.6 Hz, 2H), 8.99 (s, 1H). Example 1-502 4-[4-Amino-5-nitro-6-(3-carbyl-adamantel-1-ylamino)-α ratio biting- 2_ylamino]-benzamide [化1502]

標題化合物係使用4,6-二胺基-2-(3-羥基-金剛烷_丨_基胺基） 菸鹼腈及4-碘苯甲醯胺，依據實施例1-499(步驟丨）之方法 而合成。 1H-NMR (400 MHz，DMSO-d6) δ 1.45-1.66 (m，6H)，j 93_ 2.06 (m，6H)，2·18 (s，2H)，4.56 (s, 1H)，4.97 (s，1H)，5 52 (s, 1H), 6.22 (s，2H)，7.12 (s，1H)，7.60 (d，J=8.i hz，2H)， 7.77 (d, J=8.1 Hz, 3H)，9.04 (s，1H)。 實施例1-503 4,6-二胺基-2-(第三丁基胺基）菸鹼腈 [化 1503]The title compound is 4,6-diamino-2-(3-hydroxy-adamantane-indole-amino) nicotine nitrile and 4-iodobenzamide, according to Examples 1-499 (step 丨) The method is synthesized. 1H-NMR (400 MHz, DMSO-d6) δ 1.45-1.66 (m, 6H), j 93_ 2.06 (m, 6H), 2·18 (s, 2H), 4.56 (s, 1H), 4.97 (s, 1H),5 52 (s, 1H), 6.22 (s,2H), 7.12 (s,1H), 7.60 (d,J=8.i hz,2H), 7.77 (d, J=8.1 Hz, 3H) , 9.04 (s, 1H). Example 1-503 4,6-Diamino-2-(t-butylamino)nicotinonitrile [Chem. 1503]

於20 mL微波反應容器中，向4,6-二胺基-2-溴菸鹼腈（2.〇 141666.doc -427- 2010283814,6-Diamino-2-bromonicotinonitrile in a 20 mL microwave reaction vessel (2. 〇 141666.doc -427- 201028381

析法（己烷：乙酸乙酯=2 : 1)進行純化， ，利用中壓矽膠層 ，藉此獲得標題化 合物（1.77 g，8.62 mmol，92%)，為無色油。 1H-NMR (400 MHz, DMSO-d6) δ 1.37 (s, 9H), 4.74 (s, 1H), 5.08 (s，1H)，5.79 (s, 2H)，5.83 (s，2H) 〇 實施例1-5 04 4-(4_胺基-6-(第三丁基胺基）-5-氰基《•比咬_2_基胺基）苯甲 [化 1504]The title compound (1.77 g, 8.62 mmol, 92%) was obtained as a colorless oil. 1H-NMR (400 MHz, DMSO-d6) δ 1.37 (s, 9H), 4.74 (s, 1H), 5.08 (s, 1H), 5.79 (s, 2H), 5.83 (s, 2H) 〇 Example 1 -5 04 4-(4_Amino-6-(t-butylamino)-5-cyano-••biter_2_ylamino)benz [Chemical 1504]

標題化合物係使用4,6-二胺基-2-(第三丁基胺基）菸鹼腈及 4_蛾苯甲醯胺，依據實施例1_499(步驟1)之方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 1.43 (s, 9H), 5.09 (s, 1H), 5.54 (s, 1H), 6.21 (s, 2H), 7.10 (s, 1H), 7.56 (d, J=8.6 Hz, 2H)，7.77 (d，J=8.6 Hz, 3H), 9.02 (s, 1H)。 實施例1-505 4-胺基-6-(4-溴苯基胺基）-2-(第三丁基胺基）菸鹼腈 141666.doc • 428· 201028381 [化 1505]The title compound was synthesized according to the method of Example 1-499 (Step 1) using 4,6-diamino-2-(t-butylamino)nicotinonitrile and 4-mothbenzamide. 1H-NMR (400 MHz, DMSO-d6) δ 1.43 (s, 9H), 5.09 (s, 1H), 5.54 (s, 1H), 6.21 (s, 2H), 7.10 (s, 1H), 7.56 (d , J=8.6 Hz, 2H), 7.77 (d, J=8.6 Hz, 3H), 9.02 (s, 1H). Example 1-505 4-Amino-6-(4-bromophenylamino)-2-(t-butylamino)nicotinonitrile 141666.doc • 428· 201028381 [Chem. 1505]

標題化合物係使用4,6-二胺基_2_(第三丁基胺基）菸鹼腈， 依據實施例1-499(步驟1)之方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 1.39 (s, 9H), 5.04 (s, 1H), 5.47 (s, 1H), 6.16 (s, 2H), 7.38 (d, J=8.6 Hz, 2H), 7.45 (d, 參 J=8.6 Hz, 2H), 8.85 (s, 1H)。 實施例1-506 4-胺基-2-(第三丁基胺基）-6-(4-(1-甲基-1H-°比&quot;坐-4-基）苯 基胺基）菸鹼腈 [化 1506]The title compound was synthesized according to the procedure of Example 1-499 (Step 1) using 4,6-diamino-2-[(t-butylamino) nicotinonitrile. 1H-NMR (400 MHz, DMSO-d6) δ 1.39 (s, 9H), 5.04 (s, 1H), 5.47 (s, 1H), 6.16 (s, 2H), 7.38 (d, J = 8.6 Hz, 2H ), 7.45 (d, see J=8.6 Hz, 2H), 8.85 (s, 1H). Example 1-506 4-Amino-2-(t-butylamino)-6-(4-(1-methyl-1H-° ratio &quot;Stilt-4-yl)phenylamino) Alkali nitrile [1506]

® 標題化合物係使用4,6-二胺基-2-(第三丁基胺基）菸鹼腈， 依據實施例1-499之方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 1.42 (s, 9H), 3.84 (s, 3H), 5.01 (s, 1H), 5.48 (s, 1H), 6.10 (s, 2H), 7.43 (s, 4H), 7.78 (s, 1H), 8.03 (s, 1H), 8.69 (s，1H)。 實施例1-507 4-胺基- 2-(第三丁基胺基）-6-(4-(°比唆-4-基）苯基胺基）务 驗腈 141666.doc • 429· 201028381 [化 1507]The title compound was synthesized according to the procedure of Example 1-499 using 4,6-diamino-2-(t-butylamino)nicotinonitrile. 1H-NMR (400 MHz, DMSO-d6) δ 1.42 (s, 9H), 3.84 (s, 3H), 5.01 (s, 1H), 5.48 (s, 1H), 6.10 (s, 2H), 7.43 (s , 4H), 7.78 (s, 1H), 8.03 (s, 1H), 8.69 (s, 1H). Example 1-507 4-Amino-2-(tert-butylamino)-6-(4-(°-pyrimidin-4-yl)phenylamino) Examined nitrile 141666.doc • 429· 201028381 [化1507]

標題化合物係使用4,6-二胺基-2-(第三丁基胺基）菸鹼腈及 吡啶-4-硼酸，依據實施例1-499之方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 1.44 (s, 9H), 5.08 (s, 1H), 5.55 (s, 1H), 6.20 (s, 2H), 7.68-7.63 (m, 4H), 7.73 (d, J=8.1 Hz, 2H), 8.56 (d, J=5.1 Hz，2H), 8.99 (s，1H)。 實施例1-508 (E)-3-(4-(4 -胺基- 6- (第二丁基胺基）-5 -亂基σ比0定-2 -基胺 基）苯基）丙烯酸曱酯 [化 1508] ΗThe title compound was synthesized according to the method of Example 1-499 using 4,6-diamino-2-(t-butylamino)nicotinonitrile and pyridine-4-boronic acid. 1H-NMR (400 MHz, DMSO-d6) δ 1.44 (s, 9H), 5.08 (s, 1H), 5.55 (s, 1H), 6.20 (s, 2H), 7.68-7.63 (m, 4H), 7.73 (d, J=8.1 Hz, 2H), 8.56 (d, J=5.1 Hz, 2H), 8.99 (s, 1H). Example 1-508 (E)-3-(4-(4-Amino-6-(2-butylamino)-5-rangue σ?0-2-1-amino)phenyl)acrylic acid Oxime ester [Chemical 1508] Η

NaH THF,室溫NaH THF, room temperature

Ο Ο A.^P-〇EtΟ Ο A.^P-〇Et

I 、/ I OEtI , / I OEt

Pd(OAc)2, Xantphos CS^〇3 二-惡校·，120oCPd(OAc)2, Xantphos CS^〇3 II-Evil School, 120oC

步驟1 : (E)-3-(4-碘苯基）丙烯酸曱酯 向2-(二乙氧基磷醯基）乙酸曱酯（3.26 g，2.85 mL，15.5 mmol)及 60%氫化納（620 mg，25.8 mmol)之THF(100 mL)溶 液中添加4-碘苯甲醛（3.0 g，12.9 mmol)，於室溫下攪拌1 小時。將反應溶液放入至冰檸檬酸水中，濾取析出之固 141666.doc -430· 201028381 體，藉此獲得標題化合物（3.7 g，l2·8 mmo卜99%)，為白 色固體。 1H-NMR (400 MHz, DMSO-d6) δ 3.69 (s, 3H), 6.63 (d, J=16.4 Hz, 1H) 7.48 (d, J=8.4 Hz, 2H), 7.57 (d, J=16.4 Hz, 1H)，7.76 (d, J=8.4 Hz, 2H)。 步驟2 :標題化合物 向4,6-二胺基-2-(第三丁基胺基）菸鹼腈（28〇 mg，136 mmol)、（E)-3-(4-碘苯基）丙烯酸曱酯（393 mg，L36Step 1: (E) 3-(4-iodophenyl) decyl acrylate to decyl 2-(diethoxyphosphonyl)acetate (3.26 g, 2.85 mL, 15.5 mmol) and 60% sodium hydride ( 4- iodobenzaldehyde (3.0 g, 12.9 mmol) was added to a solution of 620 mg (25.8 mmol) in THF (100 mL) and stirred at room temperature for 1 hour. The reaction solution was poured into ice citric acid water, and the precipitated solid 141666.doc - 430· 201028381 was collected by filtration to give the title compound (3.7 g, s. 1H-NMR (400 MHz, DMSO-d6) δ 3.69 (s, 3H), 6.63 (d, J = 16.4 Hz, 1H) 7.48 (d, J = 8.4 Hz, 2H), 7.57 (d, J = 16.4 Hz , 1H), 7.76 (d, J = 8.4 Hz, 2H). Step 2: title compound to 4,6-diamino-2-(t-butylamino)nicotinonitrile (28 mg, 136 mmol), (E)-3-(4-iodophenyl)acrylic acid Oxime ester (393 mg, L36

mmol)、Xantphos(79 mg，0.136 mmol)及碳酸铯（622 mg， 1.91 mmol)之二噁烷（5 mL)溶液中添加 Pd(OAc)2(15 3 mg， 0.068 mmol)，於加熱回流下攪拌2小時。向反應溶液中添 加水及乙酸乙酯進行分離後，以乙酸乙酯萃取水相，將合 併之有機相以水及飽和食鹽水進行清洗，以硫酸鎂加以乾 燥。將有機相過濾後’進行減壓濃縮。利用中壓矽膠層析 法（己烷：乙酸乙酯=2 : 1)對所獲得之殘渣進行純化，獲 得標題化合物（73.0 mg，0.200 mmol，15%)，為黃色固 體。 1H-NMR (400 MHz, DMSO-d6) δ 1.43 (s, 9H), 3.70 (s, 3H), 5.09 (s, 1H), 5.54 (s, 1H), 6.22 (s, 2H), 6.45 (d, J=15.7 Hz, 1H)，7.60-7.54 (m，5H)，9.05 (s，1H)。 實施例1-509 (E)-3-(4-(4-胺基-6-(第三丁基胺基）_5•氰基^比啶_2•基胺 基）苯基）丙烯酸 141666.doc -431. 201028381 [化 1509]Pd(OAc)2 (15 3 mg, 0.068 mmol) was added to a solution of Xantphos (79 mg, 0.136 mmol) and cesium carbonate (622 mg, 1.91 mmol) in dioxane (5 mL). Stir for 2 hours. Water and ethyl acetate were added to the reaction solution for separation, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and brine and dried over magnesium sulfate. After the organic phase was filtered, it was concentrated under reduced pressure. The residue obtained was purified by EtOAc (EtOAc:EtOAc) 1H-NMR (400 MHz, DMSO-d6) δ 1.43 (s, 9H), 3.70 (s, 3H), 5.09 (s, 1H), 5.54 (s, 1H), 6.22 (s, 2H), 6.45 (d , J=15.7 Hz, 1H), 7.60-7.54 (m, 5H), 9.05 (s, 1H). Example 1-509 (E)-3-(4-(4-Amino-6-(t-butylamino)-5(cyano)pyridin-2-ylamino)phenyl)acrylic acid 141666. Doc -431. 201028381 [化1509]

NaOH水溶液HO DMSO,室溫NaOH aqueous solution HO DMSO, room temperature

向（E)-3-(4-(4-胺基- 6-(第三丁基胺基）-5_氰基α比咬_2_基 胺基）苯基）丙烯酸甲酯（66.4 mg，0.182 mmol)之DMS 0(3 mL)溶液中添加1 m〇l/L氫氧化鈉水溶液（1.5 mL)，於室溫 下授拌2小時。向反應溶液中添加水及謎進行分離後，以 醚清洗水相。以1 N鹽酸水溶液使水相成為酸性，利用乙 酸乙S旨進行卒取。將合併之有機相以水及飽和食鹽水進行 清洗，以硫酸鎂加以乾燥。將有機相過濾後，進行減壓濃 縮，藉此獲得標題化合物（63.9 mg，0.182 mmol，1〇0%)， 為黃色非晶體。 1H-NMR (400 MHz, DMSO-d6) δ 1.41 (s, 9H), 5.07 (s, 1¾) 5.53 (s，1H)，6.19 (s，2H), 6.33 (d，J=15.6 Hz，1H)，7.48 (d, J=15.6 Hz，1H)，7.51-7.56 (m，4H)，9·01 (s，1H)。 實施例1-510 (E)-3-(4-(4-胺基-6-(第三丁基胺基）-5-氰基°比啶-2-基胺 基）苯基）丙烯醯胺 [化 1510]To (E)-3-(4-(4-Amino-6-(tert-butylamino)-5-cyano-α-bito-2-amino)phenyl) acrylate (66.4 mg A 0.1 m 〇l/L aqueous sodium hydroxide solution (1.5 mL) was added to a solution of 0.18 mmol of DMS 0 (3 mL), and the mixture was stirred at room temperature for 2 hours. After adding water and mystery to the reaction solution, the aqueous phase was washed with ether. The aqueous phase was made acidic with a 1 N aqueous solution of hydrochloric acid, and stroke was carried out by using acetic acid ethyl acetate. The combined organic phases were washed with water and saturated brine and dried over magnesium sulfate. After the organic phase was filtered, the title compound (63.9 mg, 0.182 mmol, 1% 0%) was obtained as a yellow crystal. 1H-NMR (400 MHz, DMSO-d6) δ 1.41 (s, 9H), 5.07 (s, 13⁄4) 5.53 (s, 1H), 6.19 (s, 2H), 6.33 (d, J = 15.6 Hz, 1H) , 7.48 (d, J = 15.6 Hz, 1H), 7.51 - 7.56 (m, 4H), 9·01 (s, 1H). Example 1-510 (E)-3-(4-(4-Amino-6-(t-butylamino)-5-cyano)pyridin-2-ylamino)phenyl)propene oxime Amine [1010]

〇 hh2〇 hh2

氨水，HATU TEA DMF,室溫 141666.doc • 432- 201028381 向（E)-3-(4-(4-胺基-6-(第三丁基胺基）-5-氰基。比啶-2-基 胺基）苯基）丙烯酸（63.9 mg，0.182 mmol)、HATU(104 mg，0.273 mmol)及三乙基胺（55.2 mg，0.546 mmol)之 DMF(1 mL)溶液中添加28%氨水（1 mL)攪拌2小時。向反應 溶液中添加水及乙酸乙酯進行分離後，以乙酸乙酯萃取水 相’將合併之有機相以10%檸檬酸水溶液、飽和碳酸氫鈉 水溶液及飽和食鹽水進行清洗，以硫酸鎂加以乾燥。將有 機相過濾後，進行減壓濃縮，藉此獲得標題化合物（5 1.4 Φ mg，0.147 mmol，81%)，為黃色固體。 1H-NMR (400 MHz，DMSO-d6) δ 1.43 (s，9H), 5.07 (s，1H)， 5.53 (s, 1H), 6.18 (s, 2H), 6.47 (d, J=15.7 Hz, 1H), 6.98 (s, 1H), 7.33 (d, J=15.7 Hz, 1H), 7.43 (d, J=8.1 Hz, 3H), 7.54 (d，J=8.1 Hz，2H)，8.97 (s, 1H)。 實施例1-511 4,6-二胺基- 2-(第三戊基胺基）終驗腈 [化 1511]Ammonia, HATU TEA DMF, room temperature 141666.doc • 432- 201028381 to (E)-3-(4-(4-amino-6-(t-butylamino)-5-cyano. Add 28% aqueous ammonia to a solution of 2-aminoamino)phenyl)acrylic acid (63.9 mg, 0.182 mmol), HATU (104 mg, 0.273 mmol) and triethylamine (55.2 mg, 0.546 mmol) in DMF (1 mL) (1 mL) was stirred for 2 hours. After adding water and ethyl acetate to the reaction solution for separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution and brine, and then dry. After the organic phase was filtered, the title compound was obtained (jjjjjjjj 1H-NMR (400 MHz, DMSO-d6) δ 1.43 (s, 9H), 5.07 (s, 1H), 5.53 (s, 1H), 6.18 (s, 2H), 6.47 (d, J = 15.7 Hz, 1H ), 6.98 (s, 1H), 7.33 (d, J = 15.7 Hz, 1H), 7.43 (d, J = 8.1 Hz, 3H), 7.54 (d, J = 8.1 Hz, 2H), 8.97 (s, 1H) ). Example 1-511 4,6-Diamino-2-(tripentylamino) final nitrile [Chemical 1511]

標題化合物係使用第三戊基胺，依據實施例1 _5〇3之方法 而合成（86%)。 1H-NMR (400 MHz, DMSO-d6) δ 0.756 (t, J=7.2 Hz, 3H), 1.31 (s，6H)，1.79 (q，J=7.2 Hz，2H)，4.59 (s，1H)，5.06 (s， 1H)，5.80 (s，2H)，5.82 (s，2H)。 141666.doc -433- 201028381 實施例1-512 4-(4-胺基-5-氰基- 6-(第二戊基胺基）u比β定_2-基胺基）苯曱 醯胺 [化 1512]The title compound was synthesized according to the method of Example 1 _ 5 〇 3 (86%) using the third amylamine. 1H-NMR (400 MHz, DMSO-d6) δ 0.756 (t, J = 7.2 Hz, 3H), 1.31 (s, 6H), 1.79 (q, J = 7.2 Hz, 2H), 4.59 (s, 1H), 5.06 (s, 1H), 5.80 (s, 2H), 5.82 (s, 2H). 141666.doc -433- 201028381 Example 1-512 4-(4-Amino-5-cyano-6-(second amylamino)u~ββ_2-ylamino)benzamide [化1512]

標題化合物係使用4,6-二胺基-2-(第三戊基胺基）菸鹼腈及 4_碘苯甲醯胺，依據實施例1-499(步驟1)之方法而合成。 ❹ 1H-NMR (400 MHz, DMSO-d6) δ 0.82 (t, J=7.3 Hz, 3H), 1.36 (s, 6H), 1.85 (q, J=7.3 Hz, 2H), 4.93 (s, 1H), 5.53 (s, 1H), 6.22 (s, 2H), 7.10 (s, 1H), 7.53 (d, J=8.6 Hz, 2H), 7.76 (d，J=8.6 Hz, 3H)，9.02 (s，1H)。 實施例1-513 4,6-二胺基-2-(2,4,4-三甲基戊烷-2-基胺基）菸鹼腈 [化 1513]The title compound was synthesized according to the method of Example 1-499 (Step 1) using 4,6-diamino-2-(t-pentylamino)nicotinonitrile and 4-iodobenzamide. ❹ 1H-NMR (400 MHz, DMSO-d6) δ 0.82 (t, J = 7.3 Hz, 3H), 1.36 (s, 6H), 1.85 (q, J = 7.3 Hz, 2H), 4.93 (s, 1H) , 5.53 (s, 1H), 6.22 (s, 2H), 7.10 (s, 1H), 7.53 (d, J=8.6 Hz, 2H), 7.76 (d, J=8.6 Hz, 3H), 9.02 (s, 1H). Example 1-513 4,6-Diamino-2-(2,4,4-trimethylpentan-2-ylamino)nicotinonitrile [Chemical 1513]

標題化合物係使用2,4,4-三甲基戊烷-2-胺，依據實施例1_ 503之方法而合成（24%)。 1H-NMR (400 MHz, DMSO&gt;d6) δ 0.944 (s, 9H), 1.43 (s, 6H), 1.80 (s, 2H), 4.67 (s, 1H), 5.05 (s, 1H), 5.78 (s, 2H), 5.81 (s，2H)。 141666.doc -434- 201028381 實施例1-514 4-(4-胺基-5-氰基-6-(2,4,4-三甲基戊烧-2-基胺基）ϋ比咬-2-基胺基）苯甲醯胺 [化 1514]The title compound was synthesized according to the method of Example 1-503 (24%) using 2,4,4-trimethylpentane-2-amine. 1H-NMR (400 MHz, DMSO &gt; d6) δ 0.944 (s, 9H), 1.43 (s, 6H), 1.80 (s, 2H), 4.67 (s, 1H), 5.05 (s, 1H), 5.78 (s , 2H), 5.81 (s, 2H). 141666.doc -434- 201028381 Example 1-514 4-(4-Amino-5-cyano-6-(2,4,4-trimethylpentan-2-ylamino)pyrene-bite- 2-ylamino)benzamide [Chemical 1514]

標題化合物係使用4,6-二胺基-2-(2,4,4·三甲基戊烷-2-基 φ 胺基）菸鹼腈及4-碘苯曱醯胺，依據實施例1-499(步驟1)之 方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 0.96 (s, 9H), 1.46 (s, 6H), 1.87 (s, 2H), 4.97 (s, 1H), 5.52 (s, 1H), 6.20 (s, 2H), 7.10 (s, 1H), 7.53 (d, J=8.6 Hz, 2H), 7.76 (d, J=8.6 Hz, 2H), 7.80 (s，1H), 9.03 (s，1H)。 實施例1-515 4 -胺基-2-(異丙基胺基）-6-(4-(°惡唾-5 -基）苯基胺基）於 ❿ 驗腈 [化 1515]The title compound is 4,6-diamino-2-(2,4,4·trimethylpentan-2-ylφ-amino)nicotinonitrile and 4-iodobenzamide, according to Example 1. Synthesized by the method of -499 (Step 1). 1H-NMR (400 MHz, DMSO-d6) δ 0.96 (s, 9H), 1.46 (s, 6H), 1.87 (s, 2H), 4.97 (s, 1H), 5.52 (s, 1H), 6.20 (s , 2H), 7.10 (s, 1H), 7.53 (d, J=8.6 Hz, 2H), 7.76 (d, J=8.6 Hz, 2H), 7.80 (s, 1H), 9.03 (s, 1H). Example 1-515 4-Amino-2-(isopropylamino)-6-(4-(°oxasin-5-yl)phenylamino) in acetonitrile [Chemical 1515]

於5 mL微波反應容器中，向4-胺基-2-溴-6-(4-(噁唑-5-基）苯基胺基）菸鹼腈（100 mg，0.281 mmol)之NMP(1 mL)溶 液中添加異丙基胺（664 mg，11.2 mmol)進行覆蓋，使用 141666.doc -435- 201028381To a 4-amino-2-bromo-6-(4-(oxazol-5-yl)phenylamino)nicotinonitrile (100 mg, 0.281 mmol) NMP in a 5 mL microwave reaction vessel Add isopropylamine (664 mg, 11.2 mmol) to the solution to cover the solution, using 141666.doc -435- 201028381

Biotage Optimizer反應裝置’於1 50°C下授拌1小時。向反 應溶液中添加水及乙酸乙酯進行分離，藉由過濾將不溶物 除去後，以乙酸乙酯萃取水相。將合併之有機相以水及飽 和食鹽水進行清洗，以硫酸鎂加以乾燥，過濾後進行減壓 濃縮。利用中壓矽膠層析法（己烷：乙酸乙酯=1 : 1)對所 獲得之殘渣進行純化，獲得標題化合物（8.0 mg，0.024 mmol ’ 9°/。）’為黃褐色固體。 1H-NMR (400 MHz, DMSO-d6) δ 1.21 (d, J = 6.6 Hz, 6H), 4.16-4.27 (m, 1H), 5.47 (s, 1H), 5.82 (d, J=7.6 Hz, 1H), 6.14 (s, 2H), 7.51 (s, 1H), 7.58 (d, J=8.6 Hz, 2H), 7.73 (d, J=8.6 Hz, 2H), 8.34 (s，1H)，9.02 (s, 1H)。 實施例1-516 4-胺基-2-(環戊基胺基）-6-(4-(噁唑-5-基）苯基胺基）菸 鹼腈 [化 1516]The Biotage Optimizer reaction unit was stirred at 1 50 ° C for 1 hour. Water and ethyl acetate were added to the reaction solution for separation, and the insoluble matter was removed by filtration, and then the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The residue obtained was purified by EtOAc EtOAc (EtOAc:EtOAc) 1H-NMR (400 MHz, DMSO-d6) δ 1.21 (d, J = 6.6 Hz, 6H), 4.16-4.27 (m, 1H), 5.47 (s, 1H), 5.82 (d, J = 7.6 Hz, 1H ), 6.14 (s, 2H), 7.51 (s, 1H), 7.58 (d, J=8.6 Hz, 2H), 7.73 (d, J=8.6 Hz, 2H), 8.34 (s,1H), 9.02 (s , 1H). Example 1-516 4-Amino-2-(cyclopentylamino)-6-(4-(oxazol-5-yl)phenylamino)nicotinonitrile [Chem. 1516]

標題化合物係使用環戊基胺，依據實施例1 -5 1 5之方法 而合成。 1H-NMR (400 MHz, DMSO-d6) δ 1.50-1.61 (br m, 4H), 1.65-1.74 (br m, 2H), 1.93-2.00 (br m, 2H), 4.25-4.35 (m, 1H), 5.49 (s, 1H), 5.93 (d, J=7.1 Hz, 1H), 6.16 (s, 2H), 7.51 (s, 1H), 7.58 (d, J=8.6 Hz, 2H), 7.77 (d, J=8.6 Hz, 2H), 141666.doc -436· 201028381 8_33 (s, 1H)，9.04 (s，1H)。 實施例1-517 4-胺基-2-(二甲基胺基）_6_(4_(噁唑_5_基）苯基胺基）菸 鹼腈 [化 1517]The title compound was synthesized according to the method of Example 1 - 5 15 using cyclopentylamine. 1H-NMR (400 MHz, DMSO-d6) δ 1.50-1.61 (br m, 4H), 1.65-1.74 (br m, 2H), 1.93-2.00 (br m, 2H), 4.25-4.35 (m, 1H) , 5.49 (s, 1H), 5.93 (d, J=7.1 Hz, 1H), 6.16 (s, 2H), 7.51 (s, 1H), 7.58 (d, J=8.6 Hz, 2H), 7.77 (d, J=8.6 Hz, 2H), 141666.doc -436· 201028381 8_33 (s, 1H), 9.04 (s, 1H). Example 1-517 4-Amino-2-(dimethylamino)-6-(4-(oxazol-5-yl)phenylamino)nicotinonitrile [Chem. 1517]

標題化合物係使用二曱基胺，依據實施例1-515之方法而 合成。 1H-NMR (400 MHz, DMSO-d6) δ 3.13 (s, 6H), 5.60 (s, 1H), 6.19 (s, 2H), 7.50 (s, 1H), 7.59 (d, J=8.6 Hz, 2H), 7.72 (d, J=8.6 Hz，2H)，8.35 (s, 1H), 9.08 (s，1H)。 實施例1-518 4,6-二胺基-2-(苯基胺基）菸鹼腈 [化 1518]The title compound was synthesized according to the procedure of Example 1-515 using dimethanolamine. 1H-NMR (400 MHz, DMSO-d6) δ 3.13 (s, 6H), 5.60 (s, 1H), 6.19 (s, 2H), 7.50 (s, 1H), 7.59 (d, J = 8.6 Hz, 2H ), 7.72 (d, J=8.6 Hz, 2H), 8.35 (s, 1H), 9.08 (s, 1H). Example 1-518 4,6-Diamino-2-(phenylamino)nicotinonitrile [Chemical 1518]

Φ 於20 mL微波反應容器中，向4,6-二胺基-2-漠菸鹼腈（2.0 g·，9.39 mmol)之 NMP(10 mL)溶液中添加苯胺（1.05 g， 11.3 mmol)進行覆蓋，使用Biotage Optimizer反應裝置， 於230°C下授拌2小時。向反應溶液中添加水及乙酸乙酯進 行分離後’以乙酸乙酯萃取水相，將合併之有機相以水及 141666.doc •437- 201028381 飽和食鹽水進行清洗，以硫酸鎂加以乾燥。將有機相過滤 後’進行減壓濃縮，利用中壓矽膠層析法（己烷：乙酸乙 S曰-1 . 1)進行純化，藉此獲得標題化合物（1.2 e，$ 5 5 mmol，59%)，為褐色固體。 1H-NMR (400 MHz，DMSO-d6) δ 5.28 (s，1H)，6.02 (s，2H), 6.04 (s, 2H), 6.88 (t, J=7.6 Hz, 1H), 7.19 (t, J=7.6 Hz, 2H), 7.59 (d，J=7.6 Hz, 2H)，8.04 (s, 1H)。 實施例1-519 4-(4-胺基-5_氰基_6-(苯基胺基）n比咬_2-基胺基）苯甲醯胺 [化 1519]Φ Add aniline (1.05 g, 11.3 mmol) to a solution of 4,6-diamino-2-nicotinonitrile (2.0 g·, 9.39 mmol) in NMP (10 mL) in a 20 mL microwave reaction vessel. Coverage was carried out for 2 hours at 230 ° C using a Biotage Optimizer reaction apparatus. After the water and ethyl acetate were added to the reaction solution for separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and 141666.doc. 437 - 201028381 saturated brine and dried over magnesium sulfate. After the organic phase was filtered, the title compound (1.2 e, $5 5 mmol, 59%) was purified by EtOAc (EtOAc: EtOAc (EtOAc) ) is a brown solid. 1H-NMR (400 MHz, DMSO-d6) δ 5.28 (s, 1H), 6.02 (s, 2H), 6.04 (s, 2H), 6.88 (t, J = 7.6 Hz, 1H), 7.19 (t, J =7.6 Hz, 2H), 7.59 (d, J=7.6 Hz, 2H), 8.04 (s, 1H). Example 1-519 4-(4-Amino-5-cyano-6-(phenylamino)n ratio _2-ylamino)benzimidamide [Chemical 1519]

標題化合物係使用4,6-二胺基-2-(苯基胺基）菸鹼腈及4-碘苯甲醯胺，依據實施例1-499(步驟1)之方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 5.70 (s, 1H), 6.38 (s, 2H), 7.05 (t, J=7.6 Hz, 1H), 7.08 (brs, 1H), 7.31 (t, J=7.6 Hz, 2H), 7.49 (d, J=7.6 Hz, 2H), 7.53 (d, J=8.6 Hz, 2H), 7.63 (d，J=8.6 Hz, 2H), 7.75 (s, 1H), 8.49 (s, 1H), 9.16 (s，1H)。 實施例1-520 4-胺基- 6-(4-漠苯基胺基）-2-(苯基胺基）於驗腈 141666.doc -438- 201028381 [化 1520]The title compound was synthesized according to the procedure of Example 1-499 (Step 1) using 4,6-diamino-2-(phenylamino)nicotinonitrile and 4-iodobenzamide. 1H-NMR (400 MHz, DMSO-d6) δ 5.70 (s, 1H), 6.38 (s, 2H), 7.05 (t, J = 7.6 Hz, 1H), 7.08 (brs, 1H), 7.31 (t, J =7.6 Hz, 2H), 7.49 (d, J=7.6 Hz, 2H), 7.53 (d, J=8.6 Hz, 2H), 7.63 (d, J=8.6 Hz, 2H), 7.75 (s, 1H), 8.49 (s, 1H), 9.16 (s, 1H). Example 1-520 4-Amino-6-(4-diphenylamino)-2-(phenylamino) in a nitrile 141666.doc -438- 201028381 [Chem. 1520]

標題化合物係使用4,6-二胺基-2-(苯基胺基）菸鹼腈，依 據實施例1 -499之方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 5.63 (s, 1H), 6.34 (s, 2H), 7.04 (t, J=7.3 Hz, 1H), 7.21 (d, J=8.6 Hz, 2H), 7.29 (t, J=7.3 Hz, 2H), 7.46-7.40 (m, 4H), 8.46 (s, 1H), 9.02 (s, 1H)。 實施例1-521 4-胺基-2-(苯基胺基）-6-(4-(吡啶-4-基）笨基胺基）菸鹼腈 [化 1521]The title compound was synthesized according to the procedure of Example 1-499 using 4,6-diamino-2-(phenylamino)nicotinonitrile. 1H-NMR (400 MHz, DMSO-d6) δ 5.63 (s, 1H), 6.34 (s, 2H), 7.04 (t, J = 7.3 Hz, 1H), 7.21 (d, J = 8.6 Hz, 2H), 7.29 (t, J=7.3 Hz, 2H), 7.46-7.40 (m, 4H), 8.46 (s, 1H), 9.02 (s, 1H). Example 1-521 4-Amino-2-(phenylamino)-6-(4-(pyridin-4-yl)phenylamino)nicotinonitrile [Chemical 1521]

標題化合物係使用4,6-二胺基-2-(苯基胺基）菸鹼腈及吡啶-4-硼酸，依據實施例1-499之方法而合成。 1H-NMR (400 MHz，DMSO-d6) δ 5_71 (s，1H), 6.38 (s，2H)， 7.04 (t, J=7.3 Hz, 1H), 7.32 (t, J=7.3 Hz, 2H), 7.51 (d, J=7.3 Hz, 2H), 7.56 (d, 3=8.6 Hz, 2H), 7.64-7.61 (m, 4H), 8.48 (s，1H)，8.56 (d，J=4.5 Hz, 2H), 9.16 (s，1H)。 實施例1-522 141666.doc •439- 201028381 (E)-3-(4-(4-胺基- 5-1基-6-(苯基胺基）〇比唆_2_基胺基）笨 基）丙烯醯胺 [化 1522]The title compound was synthesized according to the procedure of Example 1-499 using 4,6-diamino-2-(phenylamino)nicotinonitrile and pyridine-4-boronic acid. 1H-NMR (400 MHz, DMSO-d6) δ 5_71 (s, 1H), 6.38 (s, 2H), 7.04 (t, J = 7.3 Hz, 1H), 7.32 (t, J = 7.3 Hz, 2H), 7.51 (d, J=7.3 Hz, 2H), 7.56 (d, 3=8.6 Hz, 2H), 7.64-7.61 (m, 4H), 8.48 (s,1H), 8.56 (d, J=4.5 Hz, 2H ), 9.16 (s, 1H). Example 1-522 141666.doc • 439- 201028381 (E)-3-(4-(4-Amino-5-1-yl-6-(phenylamino)pyrene 唆_2_ylamino) Stupid base) acrylamide [Chemical 1522]

標題化合物係使用4,6-二胺基-2-(苯基胺基）菸鹼腈，依 據實施例1 - 5 1 0之方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 5.69 (s, 1H), 6.34 (s, 2H), 6.42 (d, J=16.2 Hz, 1H), 6.96 (s, 1H), 7.04 (t, J=7.1 Hz, 1H), 7.27-7.34 (m, 5H), 7.44-7.54 (m, 5H), 8.45 (s, 1H), 9.12 (s，1H)。 實施例1-523 4-胺基- 2-(4-經基苯基胺基）-6-(4-(1-曱基-1H-n比0坐-4-基） 苯基胺基）菸鹼腈 [化 1523]The title compound was synthesized according to the procedure of Example 1 - 5 10 using 4,6-diamino-2-(phenylamino)nicotinonitrile. 1H-NMR (400 MHz, DMSO-d6) δ 5.69 (s, 1H), 6.34 (s, 2H), 6.42 (d, J = 16.2 Hz, 1H), 6.96 (s, 1H), 7.04 (t, J =7.1 Hz, 1H), 7.27-7.34 (m, 5H), 7.44-7.54 (m, 5H), 8.45 (s, 1H), 9.12 (s, 1H). Example 1-523 4-Amino- 2-(4-phenylphenylamino)-6-(4-(1-indolyl-1H-n ratio 0--4-yl)phenylamino group) Nicotinonitrile [Chemical 1523]

標題化合物係使用4,6·二胺基-2-(4-羥基苯基胺基）菸鹼 腈，依據實施例1_499之方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 3.84 (s, 3H), 5.54 (s5 1H), 6.17 (s，2H)，6.71 (d，J=8.1 Hz, 2H), 7.25 (t，J=8.1 Hz, 4H)， 141666.doc -440- 201028381 7.40 (d, J=8.1 Hz, 2H), 7.72 (s, 1H), 7.95 (s, 1H), 8.05 (s, 1H)，8.78 (br s, 1H), 9.18 (s，1H)。 實施例1-524 6-乙氧基-5-(1-甲基-1H-&quot;比唑-4-基）-N2-(4-(噁唑-5-基）苯 基）吡啶-2,4-二胺 [化 1524]The title compound was synthesized according to the method of Example 1-499 using 4,6-diamino-2-(4-hydroxyphenylamino)nicotinonitrile. 1H-NMR (400 MHz, DMSO-d6) δ 3.84 (s, 3H), 5.54 (s5 1H), 6.17 (s, 2H), 6.71 (d, J = 8.1 Hz, 2H), 7.25 (t, J = 8.1 Hz, 4H), 141666.doc -440- 201028381 7.40 (d, J=8.1 Hz, 2H), 7.72 (s, 1H), 7.95 (s, 1H), 8.05 (s, 1H), 8.78 (br s , 1H), 9.18 (s, 1H). Example 1-524 6-Ethoxy-5-(1-methyl-1H-&quot;Biazol-4-yl)-N2-(4-(oxazol-5-yl)phenyl)pyridine-2 ,4-diamine [Chemical 1524]

步驟1 : 6 -氣-2 -乙氧基- 3-(1-甲基-1H-0比唾-4-基）0比咬-4-基胺基曱酸第三丁酯Step 1: 6-Gas-2-Ethoxy-3-(1-methyl-1H-0 than sal-4-yl)0 is more than tert-butyl-4-ylamino decanoate

向6-氣-2-乙氧基-3-碘吡啶-4-基胺基曱酸第三丁酯（200 mg，0.502 mmol)、1-甲基-4-(4,4,5,5-四甲基-1，3,2-二氧雜 蝴烧-2-基）-1Η-η比 °坐（157 mg，0.753 mmol)及 2 mol/L 碳酸 鈉水溶液（753 kL’ 1.51 mmol)之THF(4 mL)溶液中添加 Pd(PPh3)4(58 mg，0.050 mmol)，於加熱回流下授拌6巧 時。向反應溶液中添加水及乙酸乙酯進行分離後，以 乙酯萃取水相’將合併之有機相以水及飽和食鹽水進行、▲ 洗，以硫酸鎂加以乾燥。將有機相過濾後，進行滅壓 縮。利用中壓矽膠層析法（己烷：乙酸乙酯=1 :丨）對所 141666.doc -441 - 201028381 得之殘渣進行純化，獲得標題化合物（126 mg，0.357 mmol，71%)，為黃色固體。 1H-NMR (400 MHz, DMSO-d6) δ 1.30 (t, J=7.2 Hz, 3H), 1.42 (s, 9H), 3.89 (s, 3H), 4.26 (q, J=7.2 Hz, 2H), 7.50 (s, 1H)，7.55 (s, 1H), 7.86 (s, 1H), 8.20 (s, 1H)。 MS(ESI)m/z=353 (M+H)+。 LC/1V1S tR=2.47 min 〇 步驟2 : 2-乙氧基-3-(卜甲基-1H-吡唑-4-基）-6-(4-(噁唑-5-基）苯基胺基）吡啶-4-基胺基曱酸第三丁酯 於5 mL微波反應容中’向6-氣-2-乙氧基-3 - (1 -曱基_ 1H-吡唑-4-基）η比啶-4-基胺基甲酸第三丁酯（126 mg，0.357 mmol)、Pd(OAc)2(8.0 mg，0.036 mmol)、BINAP(33 mg， 0.054 mmol)及 Cs2C03(碳酸铯）（163 mg，0.50 mmol)之二0惡 烷（2 mL)溶液中添加4-(噁唑-5-基）苯胺（86 mg，0.536 mmol)進行覆蓋，使用Biotage Optimizer反應裝置，於 120°C下攪拌1小時。向反應溶液中添加水及乙酸乙酯進行 分離後，以乙酸乙酯萃取水相，將合併之有機相以水及飽 和食鹽水進行清洗，以硫酸鎂加以乾燥。將有機相過濾 後’進行減壓濃縮，以乙酸乙酯使所獲得之殘渣固化，獲 侍標題化合物（86·6 mg，5 1%)，為黃色固體。 1H-NMR (4〇〇 MHz, DMSO-d6) δ 1.31 (t, J=7.2 Hz, 3H), !-44 (s, 9H), 3.89 (s, 3H), 4.33 (q, J=7.2 Hz, 2H), 7.09 (s, !H), 7.49 (s, 1H), 7.60-7.65 (m, 3H), 7.77-7.79 (m, 3H), 8·34 (s，1H)，9.31 (s, 1H)。 141666.doc -442· 201028381 MS(ESI)m/z=477 (M+H)+。 LC/MS tR=2.32 min。 步驟3 :標題化合物 向2-乙氧基-3-(1-甲基-1H-吡唑-4-基）-6-(4-(噁唑-5-基） 苯基胺基）吡啶-4-基胺基曱酸第三丁酯（60 mg，0.126 mmol)之二氯甲烧（5 mL)溶液中添加三氟乙酸（5 mL)，於 室溫下攪拌1小時。將反應溶液減壓濃縮，以乙酸乙酯使 所獲得之殘渣固化，獲得標題化合物（41.3 mg，0.110 ❿ mmol，87%) 〇 1H-NMR (400 MHz, DMSO-d6) δ 1.29 (t, J=6.8 Hz, 3H), 3.86 (s, 3H), 4.27 (q, J=6.8 Hz, 2H), 5.43 (s, 2H), 5.89 (s, 1H), 7.48 (d, J=8.0 Hz, 2H), 7.57 (d, J=8.4 Hz, 2H), 7.71-7.73 (m, 3H)，8.32 (s, 1H)，8.82 (s, 1H)。 MS(ESI)m/z=377 (M+H)+。 LC/MS tR=1.56 min。 實施例1-525 ® 4-胺基-6-(4-(噁唑-5-基）苯基胺基）-2-苯基菸鹼腈 [化 1525]To 6-gas-2-ethoxy-3-iodopyridin-4-ylamino decanoic acid tert-butyl ester (200 mg, 0.502 mmol), 1-methyl-4-(4,4,5,5 -Tetramethyl-1,3,2-dioxole-2-yl)-1Η-η ratio (157 mg, 0.753 mmol) and 2 mol/L sodium carbonate solution (753 kL '1.51 mmol) Pd(PPh3)4 (58 mg, 0.050 mmol) was added to a solution of THF (4 mL), and the mixture was stirred under reflux. Water and ethyl acetate were added to the reaction solution for separation, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and saturated brine, and washed with magnesium sulfate. After the organic phase was filtered, the pressure was reduced. The residue obtained from 141666. doc - 441 - 201028381 was purified by EtOAc (EtOAc: EtOAc: EtOAc) solid. 1H-NMR (400 MHz, DMSO-d6) δ 1.30 (t, J = 7.2 Hz, 3H), 1.42 (s, 9H), 3.89 (s, 3H), 4.26 (q, J = 7.2 Hz, 2H), 7.50 (s, 1H), 7.55 (s, 1H), 7.86 (s, 1H), 8.20 (s, 1H). MS (ESI) m / z = 353 (M+H)+. LC/1V1S tR=2.47 min 〇Step 2: 2-Ethoxy-3-(dimethyl-1H-pyrazol-4-yl)-6-(4-(oxazol-5-yl)phenylamino) Pyridyl-4-ylaminophosphonic acid tert-butyl ester in 6 mL microwave reaction volume 'to 6-gas-2-ethoxy-3-(1-indolyl-1H-pyrazol-4-yl)η Tetidine-4-ylaminocarbamic acid tert-butyl ester (126 mg, 0.357 mmol), Pd(OAc) 2 (8.0 mg, 0.036 mmol), BINAP (33 mg, 0.054 mmol) and Cs2C03 (barium carbonate) (163 Add 4-(oxazol-5-yl)aniline (86 mg, 0.536 mmol) to a solution of mg, 0.50 mmol) in dioxane (2 mL) and use a Biotage Optimizer apparatus to stir at 120 °C. 1 hour. After water and ethyl acetate were added to the reaction solution for separation, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water and saturated brine and dried over magnesium sulfate. After the organic phase was filtered, the title compound was obtained (jjjjjjjjjjj 1H-NMR (4〇〇MHz, DMSO-d6) δ 1.31 (t, J=7.2 Hz, 3H), !-44 (s, 9H), 3.89 (s, 3H), 4.33 (q, J=7.2 Hz , 2H), 7.09 (s, !H), 7.49 (s, 1H), 7.60-7.65 (m, 3H), 7.77-7.79 (m, 3H), 8·34 (s, 1H), 9.31 (s, 1H). 141666.doc -442· 201028381 MS (ESI) m/z = 477 (M+H)+. LC/MS tR = 2.32 min. Step 3: The title compound is 2-ethoxy-3-(1-methyl-1H-pyrazol-4-yl)-6-(4-(oxazol-5-yl)phenylamino)pyridine- Trichloroacetic acid (5 mL) was added to a solution of EtOAc (EtOAc) (EtOAc) The reaction solution was concentrated under reduced pressure. EtOAcjjjjjjjjjjjjjjjjjjjjjjjj =6.8 Hz, 3H), 3.86 (s, 3H), 4.27 (q, J=6.8 Hz, 2H), 5.43 (s, 2H), 5.89 (s, 1H), 7.48 (d, J=8.0 Hz, 2H ), 7.57 (d, J=8.4 Hz, 2H), 7.71-7.73 (m, 3H), 8.32 (s, 1H), 8.82 (s, 1H). MS (ESI) m / z = 377 (M+H)+. LC/MS tR = 1.56 min. Example 1-525 ® 4-Amino-6-(4-(oxazol-5-yl)phenylamino)-2-phenylnicotinonitrile [Chemical 1525]

於5 mL微波反應容器中，向4-胺基-2-溴-6-(4-(噁唑-5-基）苯基胺基）菸鹼腈（80 mg，0.225 mmol)、苯基硼酸（82 mg，0.674 mmol)及 2 mol/L 碳酸卸水溶液（0.337 mL)之二 141666.doc -443 - 201028381 口惡烧（1 mL)溶液中覆蓋Pd(PPh3)4(51.9 mg，0_〇45 mmol)， 使用Biotage Optimizer反應裝置，於150°C下攪拌30分鐘。 向反應溶液中添加水及乙酸乙酯進行分離後，以乙酸乙醋 萃取水相，將合併之有機相以水及飽和食鹽水進行清洗， 以硫酸鎂加以乾燥。將有機相過濾後，進行減壓濃縮。利 用中壓矽膠層析法（己烷：乙酸乙酯=1: 2)對所獲得之殘 /查進行純化’獲得標題化合物（26.4 mg，0.075 mmol， 33%)，為白色固體。 1H-NMR (400 MHz, DMSO-d6) δ 6.18 (s, 1H), 6.63 (s, 2H), 7.52 (d, J=4.5 Hz, 4H), 7.62 (d, J=8.6 Hz, 2H), 7.74 (d, J=8.6 Hz, 2H), 7.82-7.78 (m, 2H), 8.35 (s, 1H), 9.42 (s, 1H)。 實施例1-526 4-胺基-6-(4-(噁唑-5-基）苯基胺基）-2,3'-聯吡啶-3-曱腈 [化 1526]4-Amino-2-bromo-6-(4-(oxazol-5-yl)phenylamino)nicotinonitrile (80 mg, 0.225 mmol), phenylboronic acid in a 5 mL microwave reaction vessel (82 mg, 0.674 mmol) and 2 mol/L aqueous solution of carbonic acid (0.337 mL) 141666.doc -443 - 201028381 Oral burning (1 mL) solution covered with Pd(PPh3)4 (51.9 mg, 0_〇 45 mmol), stirred at 150 ° C for 30 minutes using a Biotage Optimizer reactor. Water and ethyl acetate were added to the reaction solution for separation, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and brine, and dried over magnesium sulfate. After the organic phase was filtered, it was concentrated under reduced pressure. The residue obtained was purified by EtOAc (EtOAc:EtOAc:EtOAc) 1H-NMR (400 MHz, DMSO-d6) δ 6.18 (s, 1H), 6.63 (s, 2H), 7.52 (d, J = 4.5 Hz, 4H), 7.62 (d, J = 8.6 Hz, 2H), 7.74 (d, J=8.6 Hz, 2H), 7.82-7.78 (m, 2H), 8.35 (s, 1H), 9.42 (s, 1H). Example 1-526 4-Amino-6-(4-(oxazol-5-yl)phenylamino)-2,3'-bipyridine-3-indoleonitrile [Chemical 1526]

標題化合物係使用對應之硼酸，依據實施例1 -499之方 法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 6.20 (s, 1H), 6.72 (s, 2H), 7.53 (s, 1H), 7.56 (t, 1=6.6 Hz, 1H), 7.63 (d, J=8.6 Hz, 2H), 7.71 (d, J=8.6 Hz, 2H), 8.19 (d, J=6.6 Hz, 1H), 8.36 (s, 1H), 8.70 (d，J=6.6 Hz, 1H), 8.98 (s，1H)，9.48 (s，1H)。 141666.doc -444 - 201028381 實施例1-527 4_胺基-2-(3-(經基甲基）苯基）-6-(4-(噁唑-5-基）苯基胺基） 於驗腈 [化 1527]The title compound was synthesized according to the method of Example 1-499 using the corresponding boronic acid. 1H-NMR (400 MHz, DMSO-d6) δ 6.20 (s, 1H), 6.72 (s, 2H), 7.53 (s, 1H), 7.56 (t, 1 = 6.6 Hz, 1H), 7.63 (d, J =8.6 Hz, 2H), 7.71 (d, J=8.6 Hz, 2H), 8.19 (d, J=6.6 Hz, 1H), 8.36 (s, 1H), 8.70 (d, J=6.6 Hz, 1H), 8.98 (s, 1H), 9.48 (s, 1H). 141666.doc -444 - 201028381 Example 1-527 4-Amino-2-(3-(radiomethyl)phenyl)-6-(4-(oxazol-5-yl)phenylamino) For nitrile [Chemical 1527]

標題化合物係使用對應之硼酸，依據實施例1-499之方 法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 4.60 (d, J=5.6 Hz, 2H), 5.31 (t, J=5.6 Hz, 1H), 6.IB (s, 1H), 6.62 (s, 2H), 7.43-7.50 (m, 2H), 7.52 (s, 1H), 7.62 (d, J=8.6 Hz, 2H), 7.66 (d, J=6.6 Hz, 1H), 7.73 (d, J=8.6 Hz, 2H), 7.76 (s, 1H), 8.36 (s, 1H)，9.41 (s，1H)。 實施例1-528 4-胺基-6-(4-(噁唑-5-基）苯基胺基）-2-(噻吩-3-基）菸鹼腈 [化 1528]The title compound was synthesized according to the method of Example 1-499 using the corresponding boronic acid. 1H-NMR (400 MHz, DMSO-d6) δ 4.60 (d, J = 5.6 Hz, 2H), 5.31 (t, J = 5.6 Hz, 1H), 6. IB (s, 1H), 6.62 (s, 2H ), 7.43-7.50 (m, 2H), 7.52 (s, 1H), 7.62 (d, J=8.6 Hz, 2H), 7.66 (d, J=6.6 Hz, 1H), 7.73 (d, J=8.6 Hz) , 2H), 7.76 (s, 1H), 8.36 (s, 1H), 9.41 (s, 1H). Example 1-528 4-Amino-6-(4-(oxazol-5-yl)phenylamino)-2-(thiophen-3-yl)nicotinonitrile [Chemical 1528]

標題化合物係使用對應之硼酸，依據實施例1_499之方法 而合成。 1H-NMR (400 MHz, DMSO-d6) δ 6.11 (s, 1H), 6.60 (s, 2H), 7.54 (s, 1H), 7.69-7.63 (m, 4H), 7.75 (d, J=8.6 Hz, 2H), 8.18 (s, 1H)，8.37 (s，1H)，9.39 (s, 1H)。 141666.doc -445- 201028381 實施例1-529 (E)-4-胺基-6-(4-(噁唑-5-基）苯基胺基）-2-(1-丙烯基）菸 驗猜 [化 1529]The title compound was synthesized according to the method of Example 1-499 using the corresponding boronic acid. 1H-NMR (400 MHz, DMSO-d6) δ 6.11 (s, 1H), 6.60 (s, 2H), 7.54 (s, 1H), 7.69-7.63 (m, 4H), 7.75 (d, J = 8.6 Hz , 2H), 8.18 (s, 1H), 8.37 (s, 1H), 9.39 (s, 1H). 141666.doc -445- 201028381 Example 1-529 (E)-4-Amino-6-(4-(oxazol-5-yl)phenylamino)-2-(1-propenyl) cigarette test Guess [化1529]

標題化合物係使用對應之硼酸，依據實施例1-499之方法 而合成。 @ 1H-NMR (400 MHz, DMSO-d6) δ 1.96 (d, J=6.6 Hz, 3H), 6.00 (s, 1H), 6.48 (s, 2H), 6.60 (d, J=14.1 Hz, 1H), 6.97 (dd, J=14.1, 6.6 Hz, 1H), 7.53 (s, 1H), 7.64 (d, J=8.6 Hz, 2H)，7.75 (d, J=8.6 Hz，2H), 8.36 (s, 1H)，9.28 (s, 1H)。 實施例1-530 4-胺基- 6-(4-(11 惡嗤-5-基）苯基胺基）-2-(1-戊快基）终驗猜 [化 1530]The title compound was synthesized according to the method of Example 1-499 using the corresponding boronic acid. @ 1H-NMR (400 MHz, DMSO-d6) δ 1.96 (d, J = 6.6 Hz, 3H), 6.00 (s, 1H), 6.48 (s, 2H), 6.60 (d, J = 14.1 Hz, 1H) , 6.97 (dd, J=14.1, 6.6 Hz, 1H), 7.53 (s, 1H), 7.64 (d, J=8.6 Hz, 2H), 7.75 (d, J=8.6 Hz, 2H), 8.36 (s, 1H), 9.28 (s, 1H). Example 1-530 4-Amino- 6-(4-(11 oxaindole-5-yl)phenylamino)-2-(1-pentyl) final test [Chem. 1530]

於5 mL微波容器中，向4-胺基-2-溴-6-(4-(噁唑-5-基）苯 基胺基）於驗腈（100 mg，0.281 mmol)、1-戊炔（38 mg， 0.562 mmol)、三乙基胺（56.8 mg，0.562 mmol)、及 Cul(5.35 ，0.028 mmol)之 DMF(1 mL)溶液中添加 PdCl2(PPh3)2(9.9 mg，0.014 mmol)進行覆蓋，使用 Bi〇tage 141666.doc -446· 201028381In a 5 mL microwave vessel, 4-amino-2-bromo-6-(4-(oxazol-5-yl)phenylamino) was assayed for nitrile (100 mg, 0.281 mmol), 1-pentyne. PdCl2(PPh3)2 (9.9 mg, 0.014 mmol) was added to a solution of (38 mg, 0.562 mmol), triethylamine (56.8 mg, 0.562 mmol), and Cul (5.35, 0.028 mmol) in DMF (1 mL). Covered, using Bi〇tage 141666.doc -446· 201028381

Optimizer反應裝置，於7(TC下攪拌2小時。向反應溶液令 添加水及乙酸乙醋進行分離後’以乙酸乙酯萃取水相，將 合併之有機相以水及飽和食鹽水進行清洗，以硫酸鎂加以 乾燥。將有機相過濾後，進行減壓濃縮。利用中壓矽膠層 析法（己烷··乙酸乙酯=1 : 1)對所獲得之殘渣進行純化， 獲仔標題化合物（33.9 mg ’ 0.099 mmol，35%)，為白色固 體。 1H-NMR (400 MHz, DMSO-d6) § 1.04 (t, J=7.1 Hz, 3H), • 1-59 (dt, J=7.1, 7.1 Hz, 2H), 2.48 (t, J=7.1 Hz, 2H), 6.11 (s, 1H), 6.62 (s, 2H), 7.53 (s, 1H), 7.62 (s, 4H), 8.37 (s, 1H), 9.35 (s, 1H) 〇 實施例1-531 4_胺基-6-(4-(噁唑-5-基）苯基胺基）_2-戊基菸鹼腈 [化 1531]The Optimizer reaction apparatus was stirred at 7 (TC for 2 hours. After adding water and ethyl acetate to the reaction solution, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water and saturated brine. The organic layer was filtered, and then concentrated under reduced pressure. The obtained residue was purified by EtOAc EtOAc EtOAc Mg ' 0.099 mmol, 35%) as a white solid. 1H-NMR (400 MHz, DMSO-d6) § 1.04 (t, J=7.1 Hz, 3H), • 1-59 (dt, J=7.1, 7.1 Hz , 2H), 2.48 (t, J=7.1 Hz, 2H), 6.11 (s, 1H), 6.62 (s, 2H), 7.53 (s, 1H), 7.62 (s, 4H), 8.37 (s, 1H) , 9.35 (s, 1H) 〇Example 1-531 4_Amino-6-(4-(oxazol-5-yl)phenylamino)_2-pentylnicotinonitrile [Chemical 1531]

向4-胺基-6-(4-( D惡嗤-5-基）苯基胺基）-2-(1-戊快基）於臉 腈（25 mg，0.073 mmol)之 THF :甲醇=1 : 1(2 mL)溶液中 添加10%把碳（3.1 mg)，於氫氣環境下，於室溫下授拌5小 時。對反應溶液進行石夕藻土過渡，使用己烧：乙酸乙酯 =3 : 1溶液清洗所獲得之殘渣，藉此獲得標題化合物（10.4 mg，0.030 mmol，41%)，為白色固體。 141666.doc -447- 201028381 1H-NMR (400 MHz, DMSO-d6) δ 0.83-0.93 (br m，3H), l. 27-1.39 (br m, 4H), 1.66-1.78 (br m, 2H), 2.63-2.73 (br m, 2H), 5.99 (s, 1H), 6.45 (s, 2H), 7.52 (s, 1H), 7.60 (d, J=7.1 Hz, 2H), 7.70 (d, J=7.1 Hz, 2H), 8.35 (s, 1H), 9.25 (s, 1H)。 實施例1-532 Ν·(5-氰基-6-乙氧基吡啶-3-基）苯甲醯胺 [化 1532]To 4-Amino-6-(4-(Doxin-5-yl)phenylamino)-2-(1-pentyl) in a face nitrile (25 mg, 0.073 mmol) in THF:MeOH = Add 10% carbon (3.1 mg) to a 1 : 1 (2 mL) solution and mix for 5 hours at room temperature under hydrogen atmosphere. The reaction solution was subjected to a celite-branched residue, and the obtained residue was washed with ethyl acetate (ethyl acetate = 3:1) to give the title compound (10.4 mg, 0.030 mmol, 41%) as white solid. 141666.doc -447- 201028381 1H-NMR (400 MHz, DMSO-d6) δ 0.83-0.93 (br m,3H), l. 27-1.39 (br m, 4H), 1.66-1.78 (br m, 2H) , 2.63-2.73 (br m, 2H), 5.99 (s, 1H), 6.45 (s, 2H), 7.52 (s, 1H), 7.60 (d, J=7.1 Hz, 2H), 7.70 (d, J= 7.1 Hz, 2H), 8.35 (s, 1H), 9.25 (s, 1H). Example 1-532 Ν·(5-Cyano-6-ethoxypyridin-3-yl)benzamide [Chemical 1532]

步驟1 . 3 -&gt;臭-2-乙氧基-5 -石肖基β比0定 向3-漠_2-氣-5-硝基°比咬（100 mg，0.281 mmol)之乙醇（4 mL)溶液中添加20%乙醇鈉-乙醇溶液（2.3 mL)，於室溫下 ❹ 攪拌1小時。向反應溶液中添加水及乙酸乙酯進行分離 後，以乙酸乙酯萃取水相，將合併之有機相以水及飽和食 鹽水進行清洗，以硫酸鎂加以乾燥。將有機相過濾後，進 行減壓濃縮，藉此獲得標題化合物（942 mg，3.81 mmol， 91%) ’為淡黃色固體。 1H-NMR (400 MHz, DMSO-d6) δ 1.37 (t, J=6.8 Hz, 3H), 4 51 (q, J=6.8 Hz, 2H), 8.75 (d, J=2.0 Hz, 1H), 9.02 (d, 141666.doc -448- 201028381 J=2.0 Hz, 1H)。 MS(ESI)m/z=247 (M+H)+。 步驟2 · 2 -乙氧基-5 -石肖基洛驗猜 向3-溴-2-乙氧基-5-硝基。比〇定（900 mg，3.64 mmol)之 DMF(9 mL)溶液中添加 CuCN(392 mg，4.37 mmol)，於加 熱回流下攪拌1.5小時。向反應溶液中添加飽和碳酸氫鈉 水溶液及乙酸乙酯，進行分離後，以乙酸乙酯萃取水相， 將合併之有機相以水及飽和食鹽水進行清洗，以硫酸鎂加 ® 以乾燥。將有機相過濾後，進行減壓濃縮。利用中壓矽膠 層析法（己烧：乙酸乙S旨=5 : 1)對所獲得之殘潰進行純 化，獲得標題化合物（498 mg，2.58 mmol，71%)，為白色 固體。 1H-NMR (400 MHz, DMSO-d6) δ 1.39 (br, 3H), 4.58 (br, 3H)，9.12 (s, 1H), 9.27 (s，1H)。 MS(ESI)m/z=194 (M+H)+。 步驟3 : 5-胺基-2-乙氧基菸鹼腈 向2 -乙氧基-5-石肖基於驗腈（464 mg，2.40 mmol)之乙酸乙 酉旨：曱醇=1 : 1(6 mL)溶液中添加10%紅碳（46 mg)，於氫 氣環境下，於室溫下攪拌3小時。對反應溶液進行矽藻土 過濾，進行減壓濃縮。使用己烷清洗所獲得之殘渣，藉此 獲得標題化合物（3 65 mg，2_24 mmol，93%)，為淡黃色固 體。 1H-NMR (400 MHz, DMSO-d6) δ 1.28 (t, J=7.2 Hz, 3H), 4.27 (q, J=7.2 Hz, 2H), 5.16 (s, 2H), 7.32 (d, J=2.8 Hz, 141666.doc -449- 201028381 1H)，7.78 (d，J=2.8 Hz, 1H)。 MS(ESI)m/z=164 (M+H)+。 步驟4 :標題化合物 向5-胺基-2 -乙氧基於驗腈（41 mg，0.25 1 mmol)及三乙基 胺（38 mg，0.377 mmol)之THF(1 mL)溶液中添加苯甲醯氣 (3 8.9 mg，0.276 mmol)，於室溫下攪拌1小時。向反應溶 液中添加10%檸檬酸水溶液及乙酸乙酯，進行分離後，以 乙酸乙酯萃取水相，將合併之有機相以水及飽和食鹽水進 行清洗，以硫酸鎂加以乾燥。將有機相過濾後，進行減壓 濃縮，使用己烷/乙酸乙酯使其固化，藉此獲得標題化合 物（54.4 mg，0.204 mmol，81%)，為白色固體。 1H-NMR (400 MHz, DMSO-d6) δ 1.37 (t, J=7.2 Hz, 3H), 4.45 (q, J=7.2 Hz, 2H), 7.54-7.65 (m, 3H), 7.97 (d, J=7.2 Hz, 2H), 8.54 (d, J=2.8 Hz, 1H), 8.73 (d, J=2.8 Hz, 1H), 10.54 (s, 1H)。 MS(ESI)m/z=268 (M+H)+。 實施例1-533 5-苄基胺基-2-乙氧基菸鹼腈 [化 1533]Step 1. 3 -&gt;Smell-2-ethoxy-5-stone-shallow β is 0-oriented 3-di-_2-gas-5-nitro-bito (100 mg, 0.281 mmol) ethanol (4 mL) A 20% sodium ethoxide-ethanol solution (2.3 mL) was added to the solution, and the mixture was stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction solution for separation. The aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with water and brine and dried over magnesium sulfate. After the organic phase was filtered, EtOAcjjjjjjjjjj 1H-NMR (400 MHz, DMSO-d6) δ 1.37 (t, J = 6.8 Hz, 3H), 4 51 (q, J = 6.8 Hz, 2H), 8.75 (d, J = 2.0 Hz, 1H), 9.02 (d, 141666.doc -448- 201028381 J=2.0 Hz, 1H). MS (ESI) m / z = 247 (M+H)+. Step 2 · 2-Ethoxy-5-stone succinol assay to 3-bromo-2-ethoxy-5-nitro. To a solution (900 mg, 3.64 mmol) of DMF (9 mL) was added CuCN (392 mg, 4.37 mmol). To the reaction solution, a saturated aqueous solution of sodium hydrogencarbonate and ethyl acetate were added and the mixture was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and saturated brine and dried over magnesium sulfate. After the organic phase was filtered, it was concentrated under reduced pressure. The residue obtained was purified by EtOAc (EtOAc:EtOAc:EtOAc) 1H-NMR (400 MHz, DMSO-d6) δ 1.39 (br, 3H), 4.58 (br, 3H), 9.12 (s, 1H), 9.27 (s, 1H). MS (ESI) m / z = 194 (M + H) +. Step 3: 5-Amino-2-ethoxy nicotinic nitrile to 2-acetoxy-5-salt based on nitrile (464 mg, 2.40 mmol) of ethyl acetate: sterol = 1 : 1 (6 10% red carbon (46 mg) was added to the solution, and the mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere. The reaction solution was filtered through Celite, and concentrated under reduced pressure. The residue obtained was washed with hexane to give the title compound (3 65 mg, 2-24 mmol, 93%) as pale yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ 1.28 (t, J = 7.2 Hz, 3H), 4.27 (q, J = 7.2 Hz, 2H), 5.16 (s, 2H), 7.32 (d, J = 2.8 Hz, 141666.doc -449- 201028381 1H), 7.78 (d, J = 2.8 Hz, 1H). MS (ESI) m / z = 164 (M+H)+. Step 4: Addition of the title compound to the 5-amino-2-ethoxy group in a solution of the nitrile (41 mg, 0.25 1 mmol) and triethylamine (38 mg, 0.377 mmol) in THF (1 mL) Gas (3 8.9 mg, 0.276 mmol) was stirred at room temperature for 1 hour. After adding a 10% aqueous citric acid solution and ethyl acetate to the reaction solution, the mixture was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and brine, and dried over magnesium sulfate. After the organic phase was filtered, EtOAc mjjjjjjjj 1H-NMR (400 MHz, DMSO-d6) δ 1.37 (t, J = 7.2 Hz, 3H), 4.45 (q, J = 7.2 Hz, 2H), 7.54-7.65 (m, 3H), 7.97 (d, J =7.2 Hz, 2H), 8.54 (d, J=2.8 Hz, 1H), 8.73 (d, J=2.8 Hz, 1H), 10.54 (s, 1H). MS (ESI) m / z = 268 (M + H) +. Example 1-533 5-Benzylamino-2-ethoxynicotinic nitrile [Chemical 1533]

向5-胺基-2 -乙氧基於驗腈（50 mg，0.306 mmol)及三乙基 胺（46.5 mg，0.460 mmol)之THF(1 mL)溶液中添加演化节 141666.doc -450- 201028381 基（57.6 mg，40 pL，0.337 mmol)，於室溫下授掉 j 時。向反應溶液中添加水及乙酸乙酯進行分離後，以乙酸 乙酯萃取水相，將合併之有機相以水及飽和食鹽水進行清 洗，以硫酸鎂加以乾燥。將有機相過濾後，進行減壓濃 縮。利用中壓矽膠層析法（己烷：乙酸乙酯=2 : 1)對所獲 得之殘渣進行純化，獲得標題化合物（28 mg，〇丨丨丨 mmol，3 6%) ’為黃色油。 1H-NMR (400 MHz，DMSO-d6) δ 1·29 (t, J=7.2 Hz，3H)， • 4.25-4.31 (m, 4H), 6.39 (t5 J=6.0 Hz, 1H), 7.23-7.41 (m, 6H)，7.83 (d，J=2.8 Hz, 1H)。 實施例1-534 2-乙氧基-5-(苯基胺基）菸鹼腈 [化 1534]Addition of the evolutionary section to the 5-amino-2-ethoxyl group in a solution of the nitrile (50 mg, 0.306 mmol) and triethylamine (46.5 mg, 0.460 mmol) in THF (1 mL) 141666.doc -450 - 201028381 Base (57.6 mg, 40 pL, 0.337 mmol), when j was given at room temperature. Water and ethyl acetate were added to the reaction solution for separation, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and brine, and dried over magnesium sulfate. After the organic phase was filtered, it was concentrated under reduced pressure. The residue obtained was purified by EtOAc (EtOAc:EtOAc) 1H-NMR (400 MHz, DMSO-d6) δ 1·29 (t, J = 7.2 Hz, 3H), • 4.25-4.31 (m, 4H), 6.39 (t5 J=6.0 Hz, 1H), 7.23-7.41 (m, 6H), 7.83 (d, J = 2.8 Hz, 1H). Example 1-534 2-Ethoxy-5-(phenylamino)nicotinonitrile [Chemical 1534]

標題化合物係使用溴苯，依據實施例1 -499(步驟1)之方法 而合成。 1H-NMR (400 MHz, DMSO-d6) δ 1.35 (t, J=7.2 Hz, 3H), 4.39 (q, J-7.2 Hz, 2H), 6.85 (t, J=7.6 Hz, 1H), 6.99 (d, J=7.6 Hz, 2H), 7.24 (t, J=7.6 Hz, 2H), 7.91 (d, J=2.8 Hz, 1H)，8.22 (m，2H)。 實施例1-535 2-乙氧基-5-(4-(噁唑-5-基）苯基胺基）菸鹼腈 14l666.doc •451 - 201028381 [化 1535]The title compound was synthesized according to the procedure of Example 1-499 (Step 1) using bromobenzene. 1H-NMR (400 MHz, DMSO-d6) δ 1.35 (t, J = 7.2 Hz, 3H), 4.39 (q, J-7.2 Hz, 2H), 6.85 (t, J = 7.6 Hz, 1H), 6.99 ( d, J = 7.6 Hz, 2H), 7.24 (t, J = 7.6 Hz, 2H), 7.91 (d, J = 2.8 Hz, 1H), 8.22 (m, 2H). Example 1-535 2-Ethoxy-5-(4-(oxazol-5-yl)phenylamino)nicotinonitrile 14l666.doc •451 - 201028381 [Chem. 1535]

標題化合物係使用5-(4-溴苯基）噁唑，依據實施例 499(步驟1)之方法而合成。 1H-NMR (400 MHz, DMSO-d6) δ 1.36 (t, J=7.2 Hz, 3H), 4.41 (q, J=7.2 Hz, 2H), 7.05 (d, J=8&gt;4 Hz, 2H), 7.47 (s, 1H), 7.58 (d, J=8.4 Hz, 2H), 8.00 (d, J=2.8 Hz, 1H), 8.27 (d，J=2.8 Hz，1H)，8.33 (s，1H)，8.50 (s, 1H)。 實施例1-536 4-胺基-6-苯甲醯基-2-乙氧基菸鹼腈 [化 1536]The title compound was synthesized according to the method of Example 499 (Step 1) using 5-(4-bromophenyl)oxazole. 1H-NMR (400 MHz, DMSO-d6) δ 1.36 (t, J = 7.2 Hz, 3H), 4.41 (q, J = 7.2 Hz, 2H), 7.05 (d, J = 8 &gt; 4 Hz, 2H), 7.47 (s, 1H), 7.58 (d, J=8.4 Hz, 2H), 8.00 (d, J=2.8 Hz, 1H), 8.27 (d, J=2.8 Hz, 1H), 8.33 (s, 1H), 8.50 (s, 1H). Example 1-536 4-Amino-6-benzylidene-2-ethoxynicotinonitrile [Chemical 1536]

+ (v /&gt;-B{0H)2+ (v /&gt;-B{0H)2

CO (5 atm) PdCKPPh^jqco、水溶液 THF, 120 °CCO (5 atm) PdCKPPh^jqco, aqueous solution THF, 120 °C

於耐壓反應容器中’向三氟曱磺酸4_胺基_5_氰基_6_乙 乳基D比咬-2-基醋（1〇〇 mg，0.281 mmol)、苯基棚酸（43.1 mg ’ 0.353 mmol)及碳酸鉀（133 mg，0.964 mmol)之 THF(l〇 mL)溶液中添加 pdCl2(PPh3)2(6.77 mg，0.0096 mmol)，使用 chemistation(PPV型）反應裝置，以 120°C/5 atm攪拌8小時。向反應溶液中添加水及乙酸乙酯進行分離 後’以乙酸乙醋萃取水相，將合併之有機相以水及飽和食 鹽水進行清洗’以硫酸鎂加以乾燥。將有機相過濾後，進 141666.doc -452- 201028381 行減壓濃縮。利用逆相等分試樣液相層析法（C 1 8管柱， 水/乙腈/0.1%甲酸梯度）對所獲得之殘渣進行純化，以乙酸 乙酯使其固化，藉此獲得標題化合物（6.3 mg，0.024 mmol，7%)，為白色固體。 1H-NMR (400 MHz, DMSO-d6) δ 1.26 (t, J=7.0 Hz, 3H), 4.26 (q, J=7.0 Hz, 2H), 6.90 (s, 1H), 7.36 (s, 2H), 7.51 (t, J=7.6 Hz, 2H), 7.64 (t, J=7.6 Hz, 1H), 7.95 (d, J=7.6 Hz, 2H)。 ❿ 實施例1-537 (E)-3-{4-[6-(金剛烷-1-基胺基）-4-胺基-5-氰基-n比啶-2-基 胺基]-2-氰基甲氧基苯*}-Ν-(2-甲氧基乙基）-丙烯醯胺 [化 1537]In a pressure-resistant reaction vessel, 'to trifluoromethanesulfonic acid 4-amino _5-cyano-6-ethyl lactyl D to bite-2-yl vinegar (1 〇〇 mg, 0.281 mmol), phenyl linalic acid (43.1 mg '0.353 mmol) and potassium carbonate (133 mg, 0.964 mmol) in THF (10 mL) were added pdCl2(PPh3)2 (6.77 mg, 0.0096 mmol) using a chemistation (PPV type) reaction apparatus. Stir at 120 ° C / 5 atm for 8 hours. Water and ethyl acetate were added to the reaction solution for separation. The aqueous phase was extracted with ethyl acetate and the combined organic phases were washed with water and saturated brine. After the organic phase was filtered, it was concentrated under reduced pressure at 141666.doc -452 - 201028381. The obtained residue was purified by EtOAc (EtOAc (EtOAc) (EtOAc) Mg, 0.024 mmol, 7%) as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 1.26 (t, J = 7.0 Hz, 3H), 4.26 (q, J = 7.0 Hz, 2H), 6.90 (s, 1H), 7.36 (s, 2H), 7.51 (t, J=7.6 Hz, 2H), 7.64 (t, J=7.6 Hz, 1H), 7.95 (d, J=7.6 Hz, 2H).实施 Examples 1-537 (E)-3-{4-[6-(Adamantyl-1-ylamino)-4-amino-5-cyano-n-pyridin-2-ylamino]- 2-cyanomethoxybenzene*}-indole-(2-methoxyethyl)-acrylamide [Chemical 1537]

(步驟2)(Step 2)

141666.doc -453 - 201028381141666.doc -453 - 201028381

步驟1 : 4-溴-2-羥基苯甲醛 向2-甲氧基-4-溴苯甲醛（1.0 g，4.65 mmol)之二氣甲烷 (10 mL)溶液中，於0°C 下添加BBr3(DCM中 1 mol/L，5.58 mL，5.5 8 mmol)，升溫至室溫後攪拌一整夜。向反應溶液 中添加水及乙酸乙酯，進行分離。以乙酸乙酯萃取水相， 將合併之有機相以水及飽和食鹽水進行清洗，以硫酸鎂加 以乾燥。將有機相過濾後，進行減壓濃縮，利用中壓矽膠 層析法（己烷/乙酸乙酯；20-50%乙酸乙酯梯度）對所獲得之 殘渣進行純化，藉此獲得標題化合物（0.94 g，4.65 mmol，100%)，為無色油。 1H-NMR (400 MHz, CDC13) δ 7.15 (s, 1H), 7.18 (d, J=6.1 Hz, 1H), 7.41 (d, J=8.3 Hz, 1H), 9.85 (s, 1H), 11.11 (s, 1H)。 步驟2 : (E)-3-(4-溴-2-羥基苯基）丙烯酸乙酯 向2-(二乙氧基填酿基）乙酸乙醋（1.15 g，5.12 mmol)及 60% 氫化納（223 mg，5.58 mmol)之 DMF(10 mL)溶液中添 加4-溴-2-羥基苯甲醛（935 mg，4.65 mmol)，於室溫下攪拌 141666.doc -454- 201028381 一整夜。向反應溶液中添加水及乙酸乙醋進行分離。以&amp; 酸乙酯萃取水相，將合併之有機相以水及飽和食鹽水進行 清洗，以硫酸鎂加以乾燥。將有機相過濾後，進行減壓濃 縮，利用中壓矽膠層析法（己烷/乙酸乙酯；20-50%乙酸乙 酯梯度）對所獲得之殘渣進行純化，藉此獲得標題化合物 (884 mg ’ 3.26 mmol，70%)，為白色固趙。 1H-NMR (400 MHz, CDC13) δ 1.36 (t，J=7.1 Hz，3H)，4.31 (q, J=7.1 Hz, 2H), 6.66 (d, J=16.4 Hz, 1H), 7.03 (d, J=8.1 Hz, 1H), 7.08 (s, 1H), 7.31 (d, J=8.3 Hz, 1H), 7.91 (s, 1H), 7.99 (d, J=16.4 Hz，1H)。 MS(ESI)m/z=271 (M+H)+。 LC/MS tR=1.94 min。 步驟3 : (E)-3-(4-溴-2-(甲氧基曱氧基）苯基）丙烯酸乙酯 向（E)-3_(4-溴-2-經基苯基）丙稀酸乙酯（15〇 mg，0.553 mmol)及碳酸鉀（107 mg，0.775 mmol)之DMF(2 mL)溶液中 添加氣曱基甲基謎（53.5 mg，0.664 mmol)後，於室溫下擾 拌一整夜。向反應溶液中添加水及乙酸乙酯進行分離。以 乙酸乙醋萃取水相，將合併之有機相以水及飽和食鹽水進 行清洗’以硫酸鎂加以乾燥。將有機相過濾後進行減壓濃 縮’利用中壓矽膠層析法（己烷/乙酸乙酯；2〇_5〇%乙酸乙 醋梯度）對所獲得之殘渣進行純化，藉此獲得標題化合物 (164 mg ’ 0.520 mmol，94%)。 1H-NMR (400 MHz, CDC13) δ 1.34 (t, J=6.9 Hz, 3H), 3.50 (s, 3H), 4.27 (q5 J=6.9 Hz, 2H), 5.24 (s, 2H), 6.48 (d, 141666.doc •455 · 201028381 J = 15.9 Hz, 1H), 7.15 (d, J=8.3 Hz, 1H), 7.34 (s, 1H), 7.38 (d, J=8.3 Hz, 1H)，7.93 (d，J=15.9 Hz, 1H)。 MS(ESI)m/z=315 (M+H)+ 〇 LC/MS tR=2.32 min。 步驟4 : (E)-3-{4-[6-(金剛烷-1-基胺基）-4-胺基-5-氰基-&quot;比咬-2-基胺基]-2-曱氧基甲氧基笨基}-丙稀酸乙醋 於5 mL微波反應容器中，向2-(金剛烧-1-基胺基）-4,6-二 胺於驗腈（147 mg，0.520 mmol)、（E)-3-(4-溴-2-(曱氧基曱 氧基）苯基）丙烯酸乙酯（147 mg，0.520 mmol)、Step 1 : 4-Bromo-2-hydroxybenzaldehyde to 2-methoxy-4-bromobenzaldehyde (1.0 g, 4.65 mmol) in di-methane (10 mL). 1 mol/L, 5.58 mL, 5.5 8 mmol) in DCM, and allowed to warm to room temperature and stirred overnight. Water and ethyl acetate were added to the reaction solution to carry out separation. The aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with water and brine and dried over magnesium sulfate. After the organic phase was filtered, the title compound was obtained (yield from EtOAc (EtOAc) g, 4.65 mmol, 100%), as a colorless oil. 1H-NMR (400 MHz, CDC13) δ 7.15 (s, 1H), 7.18 (d, J = 6.1 Hz, 1H), 7.41 (d, J = 8.3 Hz, 1H), 9.85 (s, 1H), 11.11 ( s, 1H). Step 2: Ethyl (E)-3-(4-bromo-2-hydroxyphenyl)acrylate to 2-(diethoxylated) ethyl acetate (1.15 g, 5.12 mmol) and 60% hydrogen. (223 mg, 5.58 mmol) in DMF (10 mL) was added 4-bromo-2-hydroxybenzaldehyde (935 mg, 4.65 mmol) and stirred at room temperature 141666.doc -454 - 201028381 overnight. Water and ethyl acetate were added to the reaction solution for separation. The aqueous phase was extracted with &amp; ethyl acetate, and the combined organic phases were washed with water and brine and dried over magnesium sulfate. After the organic phase was filtered, the title compound was obtained (yield: m. Mg ' 3.26 mmol, 70%), white solid Zhao. 1H-NMR (400 MHz, CDC13) δ 1.36 (t, J = 7.1 Hz, 3H), 4.31 (q, J = 7.1 Hz, 2H), 6.66 (d, J = 16.4 Hz, 1H), 7.03 (d, J=8.1 Hz, 1H), 7.08 (s, 1H), 7.31 (d, J=8.3 Hz, 1H), 7.91 (s, 1H), 7.99 (d, J=16.4 Hz, 1H). MS (ESI) m / z = 271 (M+H)+. LC/MS tR = 1.94 min. Step 3: (E)Ethyl 3-(4-bromo-2-(methoxymethoxy)phenyl)acrylate to (E)-3_(4-bromo-2-phenylphenyl)propene Adding gas methyl-based mystery (53.5 mg, 0.664 mmol) to a solution of ethyl acetate (15 mg, 0.553 mmol) and potassium carbonate (107 mg, 0.775 mmol) in DMF (2 mL) Mix all night. Water and ethyl acetate were added to the reaction solution for separation. The aqueous phase was extracted with ethyl acetate and the combined organic phases were washed with water and saturated brine. The organic phase was filtered and concentrated under reduced pressure. The residue obtained was purified using EtOAc (EtOAc/EtOAc: EtOAc 164 mg '0.520 mmol, 94%). 1H-NMR (400 MHz, CDC13) δ 1.34 (t, J=6.9 Hz, 3H), 3.50 (s, 3H), 4.27 (q5 J=6.9 Hz, 2H), 5.24 (s, 2H), 6.48 (d , 141666.doc •455 · 201028381 J = 15.9 Hz, 1H), 7.15 (d, J=8.3 Hz, 1H), 7.34 (s, 1H), 7.38 (d, J=8.3 Hz, 1H), 7.93 (d , J = 15.9 Hz, 1H). MS (ESI) m/z = 315 (MH+) Step 4: (E)-3-{4-[6-(Adamantyl-l-ylamino)-4-amino-5-cyano-&quot;biti-2-ylamino]-2-曱oxymethoxyphenyl}-acrylic acid in acetonitrile in a 5 mL microwave reaction vessel to 2-(adamant-1-ylamino)-4,6-diamine in a nitrile (147 mg, 0.520 mmol), ethyl (E)-3-(4-bromo-2-(decyloxydecyloxy)phenyl)acrylate (147 mg, 0.520 mmol),

Xantphos(30.1 mg ’ 0.052 mmol)及碳酸鉋（237 g，0.729 mmol)之二噁烷（1.5 mL)溶液中添加Pd(OAc)2(5.84 mg， 0.026 mmol)進行覆蓋’使用Biotage Optimizer反應裝置， 於120°C下攪拌1小時。向反應溶液中添加水及乙酸乙酯進 行分離後’以乙酸乙酯萃取水相，將合併之有機相以水及 飽和食鹽水進行清洗’以硫酸鎂加以乾燥。將有機相過濾 後，進行減壓濃縮。利用中壓矽膠層析法（氣仿/甲醇；5_ 10%氯仿梯度）對所獲得之殘渣進行純化，獲得標題化合物 (97·1 mg，36%)，為茶色固體。 MS(ESI)m/z=518 (M+H)+。 LC/MS tR=2.77 min 〇 步驟5 : (E)-3-{4-[6_(金剛烷-i_基胺基）_4_胺基_5_氰基_ 。比啶-2-基胺基]-2-氰基甲氧基苯基}_丙烯酸乙酯 向（E)-3-{4-[6-(金剛烷_丨_基胺基）_4_胺基_5_氰基比啶_2_ 基胺基]-2-曱氧基曱氧基笨基卜丙稀酸乙酯（1〇呂，193 141666.doc •456· 201028381 mmol)之THF/乙醇溶液（1 : 1，10 mL)中添加濃鹽酸（1.0 mL)，於50°C下攪拌一整夜。對反應溶液進行減壓濃縮， 獲得脫保護體（985 mg)。 向所獲得之脫保護體（400 mg，0.784 mmol)及碳酸鉀 (434 mg，3.14 mmol)之 DMF (2 mL)溶液中添加漠乙腈（188 mg，1.5 7 mmol)後，於室溫下授拌一整夜。向反應溶液中 添加水及乙酸乙酯，進行分離。以乙酸乙酯萃取水相，將 合併之有機相以水及飽和食鹽水進行清洗，以硫酸鎂加以 Φ 乾燥。將有機相過濾後，進行減壓濃縮，利用中壓矽膠層 析法（氯仿/甲醇；5-10%氣仿梯度）對所獲得之殘渣進行純 化，藉此獲得標題化合物（217 mg，0.423 mmol，54%)。 1H-NMR (400 MHz，DMSO_d6) δ 1.24 (t，J=7.1 Hz，3H)， 1.64 (s, 6H), 2.06 (s, 9H), 4.16 (t, J=7.1 Hz, 2H), 4.89 (s, 1H), 5.19 (s, 2H), 5.54 (s, 1H), 6.26 (s, 2H), 6.45 (d, J=15.9 Hz, 1H), 6.89 (s, 1H), 7.61 (s, 2H), 7.74 (d, J=15.9 Hz, 1H), 9.17 (s，1H)。 _ 步驟6 :標題化合物 向（E)-3-{4-[6-(金剛烷-1-基胺基）-4-胺基-5-氰基-n比啶-2-基胺基]-2-氰基甲氧基苯基}-丙烯酸乙酯（30 mg，0.059 mmol)之THT7曱醇溶液（1 : 1，1·0 mL)中添加2 mol/L氫氧 化經水溶液（100 μι，0.40 mmol)，於室温下攪;拌6小時。 將反應溶液濃縮，獲得對應之羧酸。 向所獲得之羧酸（28 mg，0.05 8 mmol)、DIEA( 11 mg， 0.087 mmol)及 2-曱氧基乙基胺（6.5 mg，0.087 mmol)之 141666.doc -457· 201028381 NMP(0.50 mL)溶液中添加 HATU(33 mg, 0.087 mol)攪拌 4 小時。向反應溶液中添加水及乙酸乙酯進行分離後，以乙 酸乙酯萃取水相’將合併之有機相以飽和碳酸氫鈉水溶 液、0.1 mol/L鹽酸及飽和食鹽水進行清洗，以硫酸鎂加以 乾燥。將有機相過濾後’進行減壓濃縮，利用逆相等分試 樣液相層析法（C 1 8管柱；水/乙腈/〇. 1 %曱酸；1 〇_ 1 〇〇%梯 度）對所獲得之殘渣進行純化’獲得標題化合物（12 mg， 0.021 mmol，37%)，為茶色固體。 1H-NMR (400 MHz, DMSO-de) δ 1.67 (br, 6H), 2.09 (br, 9H), 3.27 (s, 3H), 3.34-3.40 (m, 4H), 4.90 (s, 1H), 5.16 (s, 2H), 5.53 (s, 1H), 6.24 (s, 2H), 6.64 (d, 1H, J=12 Hz), 6.89 (s, 1H), 7.43 (d, 1H, J=6 Hz), 7.57 (d, 1H, J=12 Hz), 7.68 (d, 1H, J=6 Hz), 7.71 (d, 1H, J=6Hz), 8.10 (m, 1H), 9.11 (s, 1H)。 實施例1-538 2-(金剛烷-1-基胺基）-4-胺基-6-[3 -氰基曱氧基_4_((e)-3-羥基丙烯基-苯基胺基]-菸鹼腈 [化 1538]Add Pd(OAc)2 (5.84 mg, 0.026 mmol) to a solution of Xantphos (30.1 mg '0.052 mmol) and a carbonated (237 g, 0.729 mmol) in dioxane (1.5 mL) using a Biotage Optimizer reaction apparatus. Stir at 120 ° C for 1 hour. After water and ethyl acetate were added to the reaction solution for separation, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water and saturated brine. After the organic phase was filtered, it was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc) MS (ESI) m / z = 518 (M + H) +. LC/MS tR=2.77 min 〇 Step 5: (E)-3-{4-[6_(adamantane-i-ylamino)_4_amine_5-cyano_. Ethylpyridin-2-ylamino]-2-cyanomethoxyphenyl}-ethyl acrylate to (E)-3-{4-[6-(adamantane-indole-ylamino)-4-amine THF/ethanol of benzyl 5-(cyanopyridin-2-ylamino)-2-oxooxyoxyphenyl stearate (1 〇, 193 141666.doc •456· 201028381 mmol) Concentrated hydrochloric acid (1.0 mL) was added to the solution (1:1, 10 mL) and stirred at 50 ° C overnight. The reaction solution was concentrated under reduced pressure to give a deprotected material (985 mg). Add acetonitrile (188 mg, 1.5 7 mmol) to a solution of the obtained deprotected material (400 mg, 0.784 mmol) and potassium carbonate (434 mg, 3.14 mmol) in DMF (2 mL) Mix all night. Water and ethyl acetate were added to the reaction solution to carry out separation. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water and brine, and then dried with magnesium sulfate. After the organic phase was filtered, EtOAc (EtOAc m. , 54%). 1H-NMR (400 MHz, DMSO_d6) δ 1.24 (t, J = 7.1 Hz, 3H), 1.64 (s, 6H), 2.06 (s, 9H), 4.16 (t, J = 7.1 Hz, 2H), 4.89 ( s, 1H), 5.19 (s, 2H), 5.54 (s, 1H), 6.26 (s, 2H), 6.45 (d, J=15.9 Hz, 1H), 6.89 (s, 1H), 7.61 (s, 2H) ), 7.74 (d, J = 15.9 Hz, 1H), 9.17 (s, 1H). _ Step 6: title compound to (E)-3-{4-[6-(adamantan-1-ylamino)-4-amino-5-cyano-n-pyridin-2-ylamino] Add 2 mol/L aqueous solution of hydrogen peroxide (100 μιη) to a solution of ethyl 2-cyanomethoxyphenyl}-acrylate (30 mg, 0.059 mmol) in THT7 sterol solution (1:1,0 mL) , 0.40 mmol), stir at room temperature; mix for 6 hours. The reaction solution was concentrated to obtain the corresponding carboxylic acid. To the obtained carboxylic acid (28 mg, 0.05 8 mmol), DIEA (11 mg, 0.087 mmol) and 2-decyloxyethylamine (6.5 mg, 0.087 mmol) 141666.doc -457· 201028381 NMP (0.50 Add HATU (33 mg, 0.087 mol) to the solution and stir for 4 hours. After adding water and ethyl acetate to the reaction solution, the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium hydrogencarbonate, 0.1 mol/L hydrochloric acid and brine, and then evaporated. dry. After filtering the organic phase, 'concentrate under reduced pressure, using reverse equal fraction liquid chromatography (C 18 column; water / acetonitrile / hydrazine. 1% citric acid; 1 〇 _ 1 〇〇% gradient) The residue obtained was purified to give the title compound (12 mg, <RTIgt; 1H-NMR (400 MHz, DMSO-de) δ 1.67 (br, 6H), 2.09 (br, 9H), 3.27 (s, 3H), 3.34-3.40 (m, 4H), 4.90 (s, 1H), 5.16 (s, 2H), 5.53 (s, 1H), 6.24 (s, 2H), 6.64 (d, 1H, J=12 Hz), 6.89 (s, 1H), 7.43 (d, 1H, J=6 Hz) , 7.57 (d, 1H, J=12 Hz), 7.68 (d, 1H, J=6 Hz), 7.71 (d, 1H, J=6Hz), 8.10 (m, 1H), 9.11 (s, 1H). Example 1-538 2-(Adamantyl-1-ylamino)-4-amino-6-[3-cyanomethoxy@4_((e)-3-hydroxypropenyl-phenylamino) ]-Nicotine nitrile [Chemical 1538]

向（E)-3-{4-[6-(金剛院-1-基胺基）_4_胺基-5-氰基-«»比咬- 2-基胺基]-2-氰基甲氧基苯基}-丙烯酸乙酯（3〇 mg, 0.060 mmol)之二氣甲烧（1.0 mL)溶液中於-78°C下添加 141666.doc -458- 201028381 DIBAL(THF 中 0.99 mol/L，0.128 mL ’ 0.127 mmol)，於相 同溫度下授拌4小時。向反應溶液中添加水進行石夕藻土過 濾後’及添加乙酸乙酯進行分離。以乙酸乙酯萃取水相， 將合併之有機相以水及飽和食鹽水進行清洗，以硫酸鎂加 以乾燥。將有機相過濾'後，進行減壓濃縮，利用逆相等分 試樣液相層析法（C18管柱；水/乙腈/〇」％甲酸；1〇_1〇〇% 梯度）對所獲得之殘渣進行純化，藉此獲得標題化合物 (10.9 mg，0.023 mmol，38%)，為茶色固體。 ❿To (E)-3-{4-[6-(金刚院-1-ylamino)_4_amino-5-cyano-«» bicone-2-ylamino]-2-cyanomethyl Add 141666.doc -458- 201028381 DIBAL (0.99 mol/L in THF) in a solution of oxyphenyl}-ethyl acrylate (3 〇mg, 0.060 mmol) in dioxin (1.0 mL) at -78 °C. , 0.128 mL '0.127 mmol), and mixed for 4 hours at the same temperature. Water was added to the reaction solution to carry out filtration of Shixiazao soil, and ethyl acetate was added thereto for separation. The aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with water and brine and dried over magnesium sulfate. After filtering the organic phase, it was concentrated under reduced pressure, and obtained by reverse phase separation liquid chromatography (C18 column; water / acetonitrile / hydrazine % carboxylic acid; 1 〇 1 〇〇 % gradient) The residue was purified to give the title compound (10.9 mg, <RTIgt; ❿

1H-NMR (400 MHz, DMSO-d6) δ 1.64 (br, 6H), 1.92-2.07 (br, 9H), 3.39 (s, 3H), 4.10 (bs, 2H), 4.84 (s, 1H), 5.10 (s, 2H), 5.50 (s, 1H), 6.16 (s, 2H), 6.20-6.24 (m, 1H), 6.68 (d, 1H, J=12.0 Hz), 6.88 (s, 1H), 7.37 (d, 1H, J=6.0 Hz), 7.46 (d，1H，J=6.0 Hz)，8.88 (s，1H) » MS(ESI)m/z=471 (M+H)+。 LC/MS tR=1.91 min。 實施例1-539 2-(金剛烷-1-基胺基）-4-胺基-6-{3·甲氧基-4-[(Ε)·2-(5-甲 基-[1，3,4]噁二唑-2-基）-乙烯基]-苯基胺基}-菸鹼腈 [化 1539] (步驟1)1H-NMR (400 MHz, DMSO-d6) δ 1.64 (br, 6H), 1.92-2.07 (br, 9H), 3.39 (s, 3H), 4.10 (bs, 2H), 4.84 (s, 1H), 5.10 (s, 2H), 5.50 (s, 1H), 6.16 (s, 2H), 6.20-6.24 (m, 1H), 6.68 (d, 1H, J = 12.0 Hz), 6.88 (s, 1H), 7.37 ( d, 1H, J = 6.0 Hz), 7.46 (d, 1H, J = 6.0 Hz), 8.88 (s, 1H) » MS (ESI) m/z = 471 (M+H)+. LC/MS tR = 1.91 min. Example 1-539 2-(Adamantyl-1-ylamino)-4-amino-6-{3.methoxy-4-[(Ε)·2-(5-methyl-[1, 3,4]oxadiazol-2-yl)-vinyl]-phenylamino}-nicotinonitrile [Chemical 1539] (Step 1)

(步驟2) Burgess 試劑 THF, MW150X 74% ΜΛνΤΝΗ2 Η(Step 2) Burgess Reagent THF, MW150X 74% ΜΛνΤΝΗ2 Η

HATU, D1EA NMP，室溫 69% 141666.doc -459- 201028381HATU, D1EA NMP, room temperature 69% 141666.doc -459- 201028381

步驟1 : (E)-N'-乙醯基-3-(4-溴-2-曱氧基苯基）丙烯醯肼 向（E)-3-(4-溴-2-曱氧基苯基）丙烯酸（150 mg，0.583 mmol)、DIEA(98.0 mg，0.759 mmol)及乙醯肼（56.2 mg， 0.759 mmol)之 NMP(3 mL)溶液中添加 HATU(288 mg， 0.759 mol)攪拌4小時。向反應溶液中添加水及乙酸乙酯進 行分離後，將所獲得之固體過濾分離，藉此獲得標題化合 物（127 mg，0.405 mmol，69%)，為白色固體。 1H-NMR (400 MHz, DMSO-d6) δ 1.88 (s, 3H), 3.88 (s, 3H), 6.74 (d, J = 16.2 Hz, 1H), 7.19 (d, J=8.6 Hz, 1H), 7.28 (s, 1H), 7.47 (d, J=8.6 Hz, 1H), 7.62 (d, J=16.2 Hz, 1H), 10.02 (brs, 2H)。 步驟2 : (E)-2-(4-溴-2-曱氧基苯乙稀基）-5-曱基-1,3,4-噁 於5 mL微波反應容器中，向（E)-N’-乙醯基-3-(4-溴-2-甲 氧基苯基）丙烯酿肼（150 mg，0.553 mmol)之THF(2 mL)溶 液中添加Burgess試劑（53.5 mg，0.664 mmol)進行覆蓋，使 用Biotage Optimizer反應裝置，於150°C下撲:拌1〇分鐘。向 反應溶液中添加水及乙酸乙酯進行分離。以乙酸乙酯萃取 水相，將合併之有機相以水及飽和食鹽水進行清洗，以硫 141666.doc -460- 201028381 酸鎂加以乾燥。將有機相過濾後，進行減壓濃縮，利用中 壓矽膠層析法（己烷/乙酸乙酯；10-50%乙酸乙酯梯度）對所 獲付之殘、/查進行純化’藉此獲得標題化合物（36.2 mg， 0,123 mmol，77°/〇)，為白色固體。 1H-NMR (400 MHz, DMSO-d6) δ 2.52 (s, 3H), 3.90 (s, 3H), 7.19 (d, J=8.1 Hz, 1H), 7.27 (d, J=16.9 Hz, 1H), 7.29 (s, 1H), 7.61 (d, J=16.9 Hz, 1H), 7.73 (d, J=7.8 Hz, 1H) ° 步驟3 :標題化合物 於5 mL微波反應容器中’向2_(金剛烧_i_基胺基）_4,6_二 胺洛鹼腈（84 mg，0.298 mmol)、（E)-2-(4-漠-2-曱氧基苯乙 烯基）-5-曱基-l，3,4-噁二唑（88 mg，0.298 mmol)、Step 1: (E)-N'-Ethyl-3-(4-bromo-2-indolylphenyl)propene oxime to (E)-3-(4-bromo-2-indolylbenzene Add HATU (288 mg, 0.759 mol) to a solution of acrylic acid (150 mg, 0.583 mmol), DIEA (98.0 mg, 0.759 mmol) and acetamidine (56.2 mg, 0.759 mmol) in NMP (3 mL) for 4 hours. . After water and ethyl acetate were added to the reaction mixture, and the obtained solid was separated by filtration, the title compound (127 mg, 0.405 mmol, 69%) was obtained as white solid. 1H-NMR (400 MHz, DMSO-d6) δ 1.88 (s, 3H), 3.88 (s, 3H), 6.74 (d, J = 16.2 Hz, 1H), 7.19 (d, J = 8.6 Hz, 1H), 7.28 (s, 1H), 7.47 (d, J = 8.6 Hz, 1H), 7.62 (d, J = 16.2 Hz, 1H), 10.02 (brs, 2H). Step 2: (E)-2-(4-Bromo-2-indolylphenidyl)-5-mercapto-1,3,4-oxin in a 5 mL microwave reaction vessel, to (E)- Add Burgess reagent (53.5 mg, 0.664 mmol) to a solution of N'-acetamido-3-(4-bromo-2-methoxyphenyl)propene (150 mg, 0.553 mmol) in THF (2 mL) Coverage was carried out using a Biotage Optimizer reaction apparatus at 150 ° C for 1 minute. Water and ethyl acetate were added to the reaction solution for separation. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and saturated brine and dried over s s s s s After the organic phase was filtered, it was concentrated under reduced pressure, and purified by medium pressure gel chromatography (hexane/ethyl acetate; 10-50% ethyl acetate gradient). The title compound (36.2 mg, 0,123 mmol, 77 / /) 1H-NMR (400 MHz, DMSO-d6) δ 2.52 (s, 3H), 3.90 (s, 3H), 7.19 (d, J = 8.1 Hz, 1H), 7.27 (d, J = 16.9 Hz, 1H), 7.29 (s, 1H), 7.61 (d, J = 16.9 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H) ° Step 3: The title compound in a 5 mL microwave reaction vessel 'to 2_(金刚烧_ I_ylamino)) 4,6-diamine lysine nitrile (84 mg, 0.298 mmol), (E)-2-(4-indol-2-nonyloxystyryl)-5-fluorenyl-l , 3,4-oxadiazole (88 mg, 0.298 mmol),

Xantphos(17.3 mg，0.030 mmol)及碳酸鉋（136 g，0.417 mmol)之二噁烧（1.5 mL)溶液中添加 pd(〇Ac)2(3.35 mg， 0.015 mmol)進行覆蓋，使用Bi〇tage 〇ptimizer反應裝置， 於120C下授掉1小時。向反應溶液中添加水及乙酸乙醋進 行分離後，以乙酸乙酯萃取水相，將合併之有機相以水及 飽和食鹽水進行清洗’以硫酸鎂加以乾燥。將有機相過濾 後’進行減壓濃縮。利用逆相等分試樣液相層析法（C18管 柱；水/乙腈/0· 1 %甲酸；1 〇- 100〇/〇梯度）對所獲得之殘渣進 行純化’獲得標題化合物（12 mg，0.024 mmol，8%)，為 茶色固體。 1H-NMR (400 MHz, DMSO-d6) δ 1.66 (br, 6H), 2.06-2.09 (br, 9H), 2.51 (s, 3H), 3.86 (s, 3H), 4.88 (s, 1H), 5.55 (s, 1H), 6.24 (s, 2H), 6.83 (s, 1H), 7.02 (d, 1H, J=12 Hz), 7.48- 141666.doc -461 · 201028381 7.64 (m，3H)，9.01 (s，1H)。 實施例1-540 2-(金剛烧-1-基胺基）-4-胺基-6 - [4-((E)-3 -二甲基胺基-丙 烯基）-3-曱氧基苯基胺基]-菸驗腈 [化 1540]Add Pd(〇Ac)2 (3.35 mg, 0.015 mmol) to a solution of Xantphos (17.3 mg, 0.030 mmol) and carbonated (136 g, 0.417 mmol) in dioxane (1.5 mL) using Bi〇tage 〇 The ptimizer reaction apparatus was given at 120 C for 1 hour. After water and ethyl acetate were added to the reaction solution for separation, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water and brine, and dried over magnesium sulfate. The organic phase was filtered and concentrated under reduced pressure. The residue obtained was purified by reverse-phased liquid chromatography (C18 column; water / acetonitrile / 0. 1% formic acid; 1 〇 - 100 〇 / 〇 gradient) to give the title compound (12 mg, 0.024 mmol, 8%), a brown solid. 1H-NMR (400 MHz, DMSO-d6) δ 1.66 (br, 6H), 2.06-2.09 (br, 9H), 2.51 (s, 3H), 3.86 (s, 3H), 4.88 (s, 1H), 5.55 (s, 1H), 6.24 (s, 2H), 6.83 (s, 1H), 7.02 (d, 1H, J=12 Hz), 7.48- 141666.doc -461 · 201028381 7.64 (m, 3H), 9.01 ( s, 1H). Example 1-540 2-(Adamant-1-ylamino)-4-amino-6-[4-((E)-3-dimethylamino-propenyl)-3-decyloxy Phenylamino]-smoke nitrile [Chemical 1540]

EtOEtO

DCM, -78 °C MeCTDCM, -78 °C MeCT

(步驟1) DIBAL 91%(Step 1) DIBAL 91%

(步驟4〉 Pd(OAc)2, Xantphos, CS2CO3 二噁烷，MW120°C 13% (步驟2) MsCI, TEA DCM 76%(Step 4) Pd(OAc)2, Xantphos, CS2CO3 Dioxane, MW120°C 13% (Step 2) MsCI, TEA DCM 76%

MsO*MsO*

MeQMeQ

MeO* (步驟3)MeO* (Step 3)

Me'N^le Η THF, 50 °C 定量 步驟1 : (E)-3-(4-溴-2-甲氧基苯基）-2-丙烯-1-醇 向（E)-3-(4-溴-2-曱氧基苯基）丙烯酸乙酯（100 mg，0.351 mmol)之二氣曱烧（1 ·0 mL)溶液中，於-78°C下添加 DIBAL(THF 中 0.99 mol/L，0.744 mL，0.736 mmol)，於相 同溫度下攪拌4小時。向反應溶液中添加水，進行矽藻土 過濾後，及添加乙酸乙酯進行分離。以乙酸乙酯萃取水 相，將合併之有機相以水及飽和食鹽水進行清洗，以硫酸 鎂加以乾燥。將有機相過濾後，進行減壓濃縮，藉此獲得 標題化合物（77.5 mg，0.3 19 mmol，91 %)，為白色固體。 1H-NMR (400 MHz, DMSO-d6) δ 3.81 (s, 3H), 4.08 (s, 2H), 4.87 (s, 1H), 6.35 (dt, J=16.2, 4.6 Hz, 1H), 6.71 (d, J=16.2 141666.doc -462- 201028381Me'N^le Η THF, 50 °C Quantification step 1: (E)-3-(4-bromo-2-methoxyphenyl)-2-propen-1-ol to (E)-3-( DIBAL (0.99 mol/THF) was added to a solution of ethyl 4-bromo-2-indolyl phenyl) acrylate (100 mg, 0.351 mmol) in dioxane (1·0 mL) at -78 °C. L, 0.744 mL, 0.736 mmol), stirred at the same temperature for 4 h. Water was added to the reaction solution, and the mixture was filtered through celite, and ethyl acetate was added thereto for separation. The aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water and brine and dried over magnesium sulfate. After the organic phase was filtered, EtOAcjjjjjjjjj 1H-NMR (400 MHz, DMSO-d6) δ 3.81 (s, 3H), 4.08 (s, 2H), 4.87 (s, 1H), 6.35 (dt, J = 16.2, 4.6 Hz, 1H), 6.71 (d , J=16.2 141666.doc -462- 201028381

Hz，1H)，7.08 (d，J=8.3 Hz，1H)，7.15 (s，1H)，7.38 (d, J=8.3 Hz，1H)。 步驟2 . (E)-3-(4-溴2-甲氧基苯基）烯丙基甲確酸酯 向（E)-3-(4-邊-2-甲氧基苯基）2-丙埽·醇（2〇〇 mg，〇 823 mmol)及三乙基胺（125 mg，〇.171 mL，j 23 mm〇1)之二氯 甲院（1.5 mL)溶液中’於〇C下添加甲績酿氯（104 mg， 0.0710 mL，0_905 mmol) ’於相同溫度下擾拌4小時。向反 應浴液中添加水及乙酸乙醋’進行分離。以乙酸乙醋萃取 ® 水相’將合併之有機相以水及飽和食鹽水進行清洗，以硫 酸鎂加以乾燥。將有機相過濾後，進行減壓濃縮，藉此獲 得標題化合物（200 mg，0.622 mmol，76%)，為無色油。 1H-NMR (400 MHz, DMSO-D δ 3.82 (s，3H)，4.37 (br， 2H)，6.39-6.46 (m, 1H), 6.86 (d, J=15 7 Hz，1H)，7.10 (d， J=8.1 Hz, 1H), 7.19 (s，1H), 7.42 (d，J=8.1 Hz，1H)。 步驟3 : (E)-3-(4-溴-2-甲氧基笨基）_N,N_2_二甲基丙稀_ 1-胺 β 向（E)-3-(4-溴2-曱氧基笨基）烯丙基曱磺酸酯（6〇4 mg， 0.188 mmol)之THF(1.0 mL)溶液中於室溫下添加二甲基胺 (THF中 1 mol/L，0.470 mL，0.940 mm〇i)，於相同溫度下 攪拌2小時後，升溫至50°C進而攪拌3小時。向反應溶液中 添加水及乙酸乙酯進行分離。以乙酸乙酯萃取水相，將合 併之有機相以水及飽和食鹽水進行清洗，以硫酸鎂加以乾 燥。將有機相過遽後’進行減壓濃縮，藉此獲得標題化合 物（58.3 mg)。 141666.doc -463- 201028381 1H-NMR (400 MHz, DMSO-d6) δ 2.13 (s, 6H), 2.97 (d, J=6.1 Hz, 2H), 3.81 (s, 3H), 6.22-6.29 (m, 1H), 6.65 (d, J=15.9 Hz, 1H), 7.08 (d, J=8.1 Hz, 1H), 7.15 (s, 1H), 7.41 (d, J=8.1 Hz, 1H)。 步驟4 :標題化合物 利用與實施例1-539之步驟3同樣之方法實施，獲得標題 化合物（11.6 mg，13%)。 1H-NMR (400 MHz, DMSO-d6) δ 1.64 (br，6H), 1 93-2 07 (br, 9H), 2.28 (s, 6H), 3.17 (m, 2H), 3.77 (s, 3H), 4.82 (s, 1H), 5.49 (s, 1H), 6.15 (s, 2H), 6.05-6.25 (m, 2H), 6.17- 6.22 (m, 1H), 6.71 (d, 1H, J=12.0 Hz), 6.76 (s, 1H), 7.32 (s5 1H)，8.78 (s，1H)。 實施例1-541 2-(金剛烧-1-基胺基）-4-胺基-6-[4-(2-側氧基_丨，2_二氫0比 啶-4-基）-苯基胺基]-菸鹼腈 [化 1541]Hz, 1H), 7.08 (d, J = 8.3 Hz, 1H), 7.15 (s, 1H), 7.38 (d, J = 8.3 Hz, 1H). Step 2. (E)-3-(4-Bromo-2-methoxyphenyl)allylcarboxylic acid ester to (E)-3-(4-Butyl-2-methoxyphenyl)2- Propionate alcohol (2〇〇mg, 〇823 mmol) and triethylamine (125 mg, 171.171 mL, j 23 mm〇1) in a solution of dichlorocarbyl (1.5 mL) Add a blend of chlorine (104 mg, 0.0710 mL, 0_905 mmol) 'stirred for 4 hours at the same temperature. Water and ethyl acetate were added to the reaction bath for separation. Extraction with ethyl acetate (aqueous phase) The combined organic phases were washed with water and saturated brine and dried over magnesium sulfate. After the organic phase was filtered, EtOAcjjjjjjjjj 1H-NMR (400 MHz, DMSO-D δ 3.82 (s, 3H), 4.37 (br, 2H), 6.39-6.46 (m, 1H), 6.86 (d, J = 15 7 Hz, 1H), 7.10 (d) , J = 8.1 Hz, 1H), 7.19 (s, 1H), 7.42 (d, J = 8.1 Hz, 1H) Step 3: (E)-3-(4-Bromo-2-methoxyphenyl) _N,N_2_dimethylpropan-1-amine β to (E)-3-(4-bromo-2-indolylphenyl)allyl sulfonate (6〇4 mg, 0.188 mmol) Add dimethylamine (1 mol/L in THF, 0.470 mL, 0.940 mm〇i) to THF (1.0 mL) at room temperature, stir at the same temperature for 2 hours, then warm to 50 ° C and stir. To the reaction solution, water and ethyl acetate were added to separate the mixture, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and brine, and dried over magnesium sulfate. The title compound (58.3 mg) was obtained. 2H), 3.81 (s, 3H), 6.22-6.29 (m, 1H), 6.65 (d, J=15.9 Hz, 1H), 7.08 (d, J=8.1 Hz, 1H), 7.15 (s, 1H), 7.41 (d, J=8.1 Hz, 1H) Step 4: The title compound (11.6 mg, 13%) was obtained from the title compound (11.6 g, DMSO-d6) δ 1.64 (br, 6H), 1 93- 2 07 (br, 9H), 2.28 (s, 6H), 3.17 (m, 2H), 3.77 (s, 3H), 4.82 (s, 1H), 5.49 (s, 1H), 6.15 (s, 2H), 6.05-6.25 (m, 2H), 6.17- 6.22 (m, 1H), 6.71 (d, 1H, J = 12.0 Hz), 6.76 (s, 1H), 7.32 (s5 1H), 8.78 (s, 1H). Example 1-541 2-(Adamant-1-ylamino)-4-amino-6-[4-(2-o-oxy-oxime, 2-dihydro-2-pyridin-4-yl)- Phenylamino]-nicotinonitrile [Chemical 1541]

TIPSCI 咪唑 I DCM,室溫 99%TIPSCI imidazole I DCM, room temperature 99%

H2NH2N

Pd(PPh3)4, KOAc .............. - I » DME,回流 涉驟2)Pd(PPh3)4, KOAc .............. - I » DME, reflux Step 2)

141666.doc -464- 201028381141666.doc -464- 201028381

(步驟 3) OTIPS(Step 3) OTIPS

4-溴-2-(三異丙基秒氧基）„比咬 向 4-溴吡啶-2-醇（l.oo g，5.75 mmol)及咪唑（783 mg， 11.5 mmol)之二氯甲烷（1〇 mL)溶液中於0°C下添加氯化三4-bromo-2-(triisopropylsecondoxy)-dichloromethane (b.o.g., 5.75 mmol) and imidazole (783 mg, 11.5 mmol). 1 〇 mL) solution was added with chlorination at 0 ° C

異丙基碎烧基（1.66 g，1.85 mL，8.62 mmol)，於室溫下搜 拌一整夜。向反應溶液中添加水及乙酸乙酯進行分離。以 乙酸乙酯萃取水相’將合併之有機相以水及飽和食鹽水進 行清洗’以硫酸鎂加以乾燥《將有機相過濾後，進行減壓 濃縮’利用中壓矽膠層析法（己烷：乙酸乙酯=3 : 1}對所 獲得之殘渣進行純化，藉此獲得標題化合物（丨79 g，5 7() mmol，99%)，為無色油。 1H-NMR (400 MHz, DMSO-d6) δ 1.02 (d, J=5.1 Hz, 18H) 1.32 (br, 3H), 6.76 (d, J=8.3 Hz, 1H), 7.85 (d j=8 3 H 1H)，8.17 (s, 1H)。 步驟1 : 2-(金剛烷-1-基胺基）-4-胺基·6·(4_漠苯基胺基） 於驗猜 利用與實施例1-539之步驟3同樣之方法實施，獲得標題 化合物（1.10 g，41%)。 1H-NMR (400 MHz, DMSO-d6) δ 1.62 (s，6H)，2 03 ( 9H) 4.83 (s，1Η)，5.44 (s, 1Η), 6.14 (s，2Η)，7.34 (d, J=8 6 Ηζ 2H)，7·46 (d，J=8.6 Hz，2H)，8·85 (s，1H)。 141666.doc -465- 201028381 步驟2 : 2-(金剛烷-1_基胺基）_4_胺基_6_[4_(4,4,5,5_四甲 基-[1，3,2]二氧雜硼院_2_基）_苯基胺基]-於驗腈 向2-(金剛烷_ι_基胺基胺基_6_(4_溴苯基胺基）菸鹼腈 (2.32 g ’ 5_29 mmol)、雙戊醯二硼（4.03 g，15.9 mmol)、 X-Phos(505 mg，1.06 mmol)及 Pd2dba3(485 mg，0.530 mmol)之二噁烧（3 mL)溶液中添加乙酸钟〇 56 g，15 9 mmmol) ’於加熱回流下授拌6小時。向反應溶液中添加水 及乙酸乙酯進行分離後’以乙酸乙酯萃取水相，將合併之 有機相以水及飽和食鹽水進行清洗，以硫酸鎂加以乾燥。 將有機相過濾後’進行減壓濃縮。利用中壓矽膠層析法 (己烷：乙酸乙酯=4 : 1)對所獲得之殘渣進行純化，獲得 標題化合物（2.36 g，78%)，為茶色固體。 1H-NMR (400 MHz，DMSO-d6) δ 1.26 (s, 12H), 1.67 (brs， 6H), 2.08 (brs, 9H), 3.99-4.05 (m, 1H), 4.87 (s, 1H), 5.53 (s, 1H), 6.17 (s, 2H), 7.52 (t, d=8.1 Hz, 2H), 7.60 (d, J=8.1 Hz，2H), 8.95 (s，1H)。 步驟3 :標題化合物 向2-(金剛烷-i_基胺基）_4_胺基-6_[4_(4,4 5 5•四曱基_ [1，3,2] 一氧雜蝴烧-2-基）-苯基胺基]-於驗腈（3〇〇 mg，0.61 8 mmol)、4-溴-2-(三異丙基矽氧基）吡咬（245 mg，0.742 mmol)及 PdCl2(dtbpf)(40.3 mg，0.062 mmol)之 THF(3.0 mL)溶液中添加 2 m〇1/L碳酸鈉（〇 433 mL，0.865 mmmol)， 於加熱回流下攪拌6小時。向反應溶液中添加水及乙酸乙 醋進行分離後，以乙酸乙酯萃取水相，將合併之有機相以 141666.doc -466- 201028381 水及飽和食鹽水進行清洗，以硫酸鎂加以乾燥。將有機相 過濾後，進行減壓濃縮。利用逆相等分試樣液相層析法 (C18管柱；水/乙腈/〇 1%甲酸；1〇1〇〇%乙腈梯度）對所獲 付之殘/查進行純化’獲得標題化合物（65.5 mg，0.145 mmol，23%)，為茶色固體。 1H-NMR (400 MHz, DMSO-d6) δ 1.67 (6Η, s), 1.99-2.09 (9H, m), 3.18 (1H, s), 4.88 (1H, s), 5.51 (1H, s), 6.21 (2H, s)，6.50 (2H，s), 7.40 (1H，s)，7.56-7.64 (4H, m), 9.02 (1H, # s)，11.49 (1H，s)。 MS(ESI)m/z=453 (M+H)+。 LC/MS tR=1.89 min。 實施例1-542 2-(金剛烷-1-基胺基）-4-胺基-6-[4-(l-氰基甲基-2-側氧Isopropyl calcined base (1.66 g, 1.85 mL, 8.62 mmol) was taken at room temperature overnight. Water and ethyl acetate were added to the reaction solution for separation. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and saturated brine. The dried organic layer was dried over magnesium sulfate. Ethyl acetate = 3: 1} The obtained residue was purified to give the title compound ( </ </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; δ 1.02 (d, J=5.1 Hz, 18H) 1.32 (br, 3H), 6.76 (d, J=8.3 Hz, 1H), 7.85 (dj=8 3 H 1H), 8.17 (s, 1H). 1 : 2-(adamantan-1-ylamino)-4-amino 6·(4_ hydroxyphenylamino) was determined by the same method as in the step 3 of Example 1-539. The title compound (1.10 g, 41%). 1H-NMR (400 MHz, DMSO-d6) δ 1.62 (s, 6H), 2 03 (9H) 4.83 (s, 1 Η), 5.44 (s, 1 Η), 6.14 ( s, 2Η), 7.34 (d, J=8 6 Ηζ 2H), 7·46 (d, J=8.6 Hz, 2H), 8.85 (s, 1H). 141666.doc -465- 201028381 Step 2: 2-(adamantan-1-ylamino)_4_amine _6_[4_(4,4,5,5-tetramethyl-[1,3,2]dioxaborin_2_yl) _Phenylamino]--tested nitrile to 2-(adamantane_ι _Aminoaminoamino-6-(4-bromophenylamino)nicotinonitrile (2.32 g '5_29 mmol), dipentazone diboron (4.03 g, 15.9 mmol), X-Phos (505 mg, 1.06 mmol) And Pd2dba3 (485 mg, 0.530 mmol) in dioxo (3 mL) solution, add acetic acid clock 〇 56 g, 15 9 mmmol) 'mixed under heating and reflux for 6 hours. Add water and acetic acid to the reaction solution. After the ester was separated, the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and saturated brine and dried over magnesium sulfate. The organic phase was filtered and then concentrated under reduced pressure. The residue was purified by EtOAc (EtOAc:EtOAc) s, 12H), 1.67 (brs, 6H), 2.08 (brs, 9H), 3.99-4.05 (m, 1H), 4.87 (s, 1H), 5.53 (s, 1H), 6.17 (s, 2H), 7.52 (t, d = 8.1 Hz, 2H), 7.60 (d, J = 8.1 Hz, 2H), 8.95 (s, 1H). Step 3: The title compound to 2-(adamantane-i-ylamino)_4_amino-6-[4_(4,4 5 5•tetradecyl_[1,3,2] oxaza- 2-yl)-phenylamino]--nitrile (3 〇〇 mg, 0.61 8 mmol), 4-bromo-2-(triisopropyl decyloxy) pyridine (245 mg, 0.742 mmol) and To a solution of PdCl2 (dtbpf) (40.3 mg, 0.062 mmol) in THF (3.0 mL), 2 m?? After the water and the acetic acid were added to the reaction mixture for separation, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with 141666.doc -466 - 201028381 water and saturated brine, and dried over magnesium sulfate. The organic phase was filtered and concentrated under reduced pressure. Purification of the residue obtained by reverse phase equilibration liquid chromatography (C18 column; water / acetonitrile / hydrazine 1% formic acid; 1 〇 1% acetonitrile gradient) to give the title compound (65.5 Mg, 0.145 mmol, 23%), as a brown solid. 1H-NMR (400 MHz, DMSO-d6) δ 1.67 (6 Η, s), 1.99-2.09 (9H, m), 3.18 (1H, s), 4.88 (1H, s), 5.51 (1H, s), 6.21 (2H, s), 6.50 (2H, s), 7.40 (1H, s), 7.56-7.64 (4H, m), 9.02 (1H, # s), 11.49 (1H, s). MS (ESI) m / z = 453 (M+H)+. LC/MS tR = 1.89 min. Example 1-542 2-(Adamantyl-1-ylamino)-4-amino-6-[4-(1-cyanomethyl-2-oxooxy)

基-1,2-二氫》比啶-4-基）-苯基胺基]-菸鹼腈 [化 1542]Base-1,2-dihydro"pyridin-4-yl)-phenylamino]-nicotinonitrile [Chemical 1542]

向2-(金剛烷-1-基胺基）-4-胺基-6·[4-(2-側氧基-1,2-二氫 吡啶-4-基）-笨基胺基]-菸鹼腈（40 mg，0.〇88 mmol)及碳酸 鉀（25.7 mg，0.186 mmol)之 DMF(1.0 mL)溶液中添加 2-溴 乙腈（12.7 11^，7.39 41^’0.106 111111111〇1)’於室溫下攪拌4 小時。向反應溶液中添加水及乙酸乙醋進行分離後’以乙 141666.doc -467 - 201028381 酸乙醋萃取水相，將合併之有機相以水及飽和食鹽水進行 清洗，以硫酸鎂加以乾燥。將有機相過濾後，進行減壓濃 縮。利用逆相等分試樣液相層析法（C 1 8管柱；水/乙腈/ 0.1%甲酸；10-100%乙腈梯度）對所獲得之殘渣進行純化， 獲得標題化合物（18.6 mg，0.038 mmol，43%)，為黃色固 1H-NMR (400 MHz, DMSO-d6) δ 1.67 (6Η, s), 2.07-2.10 (9H, m), 4.90 (1H, s), 5.03 (2H, s), 5.53 (1H, s), 6.23 (2H, s), 6·71 (2H, s)，7_64 (4H, s)，7.80 (1H, s)，9.06 (1H, s)。 MS(ESI)m/z=492 (M+H)+。 LC/MS tR=2.06 min o 實施例1-543 (E)-3-(5-{4-[6-(金剛烷-1-基胺基）-4-胺基-5-氰基--比啶-2-基胺基]-苯基}-l-甲基-1H-咪唑-2-基）-丙烯醯胺 [化 1543] (步驟1)To 2-(adamantan-1-ylamino)-4-amino-6-[4-(2-o-oxy-1,2-dihydropyridin-4-yl)-phenylamino]- 2-Bromoacetonitrile (12.7 11^, 7.39 41^'0.106 111111111〇1) was added to a solution of nicotinic nitrile (40 mg, 〇88 mmol) and potassium carbonate (25.7 mg, 0.186 mmol) in DMF (1.0 mL) 'Stirring at room temperature for 4 hours. After adding water and ethyl acetate to the reaction solution for separation, the aqueous phase was extracted with ethyl acetate 141666.doc -467 - 201028381, and the combined organic phases were washed with water and saturated brine and dried over magnesium sulfate. After the organic phase was filtered, it was concentrated under reduced pressure. The residue obtained was purified using EtOAc EtOAc (EtOAc (EtOAc) , 43%), as a yellow solid 1H-NMR (400 MHz, DMSO-d6) δ 1.67 (6 Η, s), 2.07-2.10 (9H, m), 4.90 (1H, s), 5.03 (2H, s), 5.53 (1H, s), 6.23 (2H, s), 6·71 (2H, s), 7_64 (4H, s), 7.80 (1H, s), 9.06 (1H, s). MS (ESI) m / z = 492 (M + H) +. LC/MS tR=2.06 min o Example 1-543 (E)-3-(5-{4-[6-(adamantan-1-ylamino)-4-amino-5-cyano-- Bipyridin-2-ylamino]-phenyl}-l-methyl-1H-imidazol-2-yl)-propenylamine [Formula 1543] (Step 1)

NaH OEt Ο 〇 OEtNaH OEt Ο 〇 OEt

Me DMF, 0 °C 89%Me DMF, 0 °C 89%

141666.doc •468- 201028381 步驟1 ·. (E)-3-(5-溴-1-曱基-1H-咪唑-2-基）丙烯酸乙酯 向2-(二乙氧基磷醢基）乙酸乙酯（818 mg，3.65 mmol)及 60% 氫化鈉（159 mg，3.97 mmol)之 DMF(2 mL)溶液中，於 〇°C下添加5-溴_ι_甲基-1H-咪唑-2-曱醛（300 mg，1.59 mmol)，於相同溫度下授拌1小時。向反應溶液中添加水及 乙酸乙酯進行分離。以乙酸乙酯萃取水相，將合併之有機 相以水及飽和食鹽水進行清洗，以硫酸鎂加以乾燥。將有 機相過濾後，進行減壓濃縮，利用中壓矽膠層析法（己烷/ 乙酸乙酯；40-50%乙酸乙酯梯度）對所獲得之殘渣進行純 化’藉此獲得標題化合物（3 65 mg，1.41 mmol，89%)，為 白色固體。 1H-NMR (400 MHz, DMS〇-d6) δ 1.24 (t, J=6.9 Hz, 4H), 3.70 (s, 3H), 4.18 (q, J=6.9 Hz, 2H), 6.58 (d, J=15.4 Hz, 1H)，7·21 (s，1H), 7.53 (d，J=15.4 Hz, 1H)。 MS(ESI)m/z=259 (M+H).。 LC/MS tR=1.27 min 〇 步驟2 : (E)-3-(5-{4-[6-(金剛烷-丨-基胺基）_4-胺基_5_氟 基-吼啶-2-基胺基]-笨基}-1_甲基·1H_咪唑_2•基）_丙烯酸 乙酯 利用與實施例1-541之步驟3同樣之方法實施，獲得標題 化合物（28.1 mg，30%)，為白色固體。 MS(ESI)m/z=538 (M+H)+。 LC/MS tR=2.10 min 〇 步驟3 :標題化合物 141666.doc •469- 201028381 向（E)-3-{4-[6-(金剛烷-1_基胺基）-4-胺基-5-氰基-°比啶-2-基胺基]-2-氰基曱氧基笨基卜丙烯酸乙酯（28.1 mg ’ 0.052 mmol)之THF/曱醇溶液（1 : 1，l.o mL)中添加2 mol/L氫氧 化鈉水溶液（100 pL，0.200 mmol)，於50。(3下攪拌6小時。 將反應溶液濃縮，獲得對應之羧酸。 向所獲得之羧酸、DIEA(33.8 mg，0.261 mmol)及 HATU(49.7 mg，0.131 mol)之 NMP(0.50 mL)溶液中添加 28。/。氨水（0.50 mL) ’攪拌4小時。向反應溶液中添加水及 乙酸乙酯進行分離後，以乙酸乙酯萃取水相，將合併之有 機相以飽和碳酸氫鈉水溶液、〇」mol/L鹽酸及飽和食鹽水 進行清洗’以硫酸鎂加以乾燥。將有機相過濾後’進行滅 壓濃縮，利用逆相等分試樣液相層析法（c i 8管柱；水/乙 腈/0.1%甲酸；1〇-1〇〇%梯度）對所獲得之殘渣進行純化， 獲得標題化合物（5.9 mg，0.012 mm〇i，22%)，為黃色固 體》 1H-NMR (400 MHz，DMSO-d6) δ 1.67 (br, 6H)，2.06-2.11 (br m, 9H), 3.79 (s, 3H), 4.92 (s, iH), 5.52 (s, iH), 6.24 (br, 1H), 6.97 (d, 1H, 1=15.7 Hz), 7.4l (d, 2H, J.g.i Hz), 7.47 (d，1H，J=15.7 Hz)，7.56 (s，1H)，7 74 (d，2H，J=8」 Hz)，7.85 (s，1H)，7.99 (s, 1H)，9.11(s，1H)。 ’ MS(ESI)m/z=509 (M+H)+。 LC/MS tR=1.60 min。 實施例1-544 4-胺基-2-(環己基胺基）-6·(4-(ΐ_(2_(甲基磺醯基）乙基）_ 141666.doc -470- 201028381 1Η-η比唑-4-基）苯基胺基）菸鹼腈 [化 1544] ❿141666.doc •468- 201028381 Step 1 · (E)-3-(5-Bromo-1-indolyl-1H-imidazol-2-yl)ethyl acrylate to 2-(diethoxyphosphonium) Ethyl acetate (818 mg, 3.65 mmol) and 60% sodium hydride (159 mg, 3.97 mmol) in DMF (2 mL) EtOAc. 2-furfural (300 mg, 1.59 mmol) was stirred at the same temperature for 1 hour. Water and ethyl acetate were added to the reaction solution for separation. The aqueous phase was extracted with EtOAc. EtOAc was evaporated. After the organic phase was filtered, the title compound was obtained (yield from EtOAc (EtOAc/EtOAc) 65 mg, 1.41 mmol, 89%) as a white solid. 1H-NMR (400 MHz, DMS〇-d6) δ 1.24 (t, J=6.9 Hz, 4H), 3.70 (s, 3H), 4.18 (q, J=6.9 Hz, 2H), 6.58 (d, J= 15.4 Hz, 1H), 7·21 (s, 1H), 7.53 (d, J = 15.4 Hz, 1H). MS (ESI) m / z = 259 (M+H). LC/MS tR=1.27 min 〇Step 2: (E)-3-(5-{4-[6-(adamantane-indole-ylamino)-4-amino-5-fluoro-acridine-2 Ethylamino]-p-yl}-1-methyl-1H-imidazole-2-yl)-ethyl acrylate was carried out in the same manner as in Step 3 of Example 1-451 to give the title compound (28.1 mg, 30 %), as a white solid. MS (ESI) m / z = 538 (M+H)+. LC/MS tR=2.10 min 〇 Step 3: title compound 141666.doc • 469 - 201028381 to (E)-3-{4-[6-(adamantan-1-ylamino)-4-amino-5 -Cyano-pyridylpyridin-2-ylamino]-2-cyanomethoxyoxyphenyl acrylate (28.1 mg '0.052 mmol) in THF / methanol (1:1, 1 mL) A 2 mol/L aqueous solution of sodium hydroxide (100 pL, 0.200 mmol) was added at 50. (3 stirring for 6 hours. The reaction solution was concentrated to obtain the corresponding carboxylic acid. To the obtained carboxylic acid, DIEA (33.8 mg, 0.261 mmol) and HATU (49.7 mg, 0.131 mol) in NMP (0.50 mL) Add 28% aqueous ammonia (0.50 mL) and stir for 4 hours. After adding water and ethyl acetate to the reaction solution for separation, the aqueous phase is extracted with ethyl acetate, and the combined organic phases are saturated aqueous sodium hydrogen carbonate and hydrazine. "mol/L hydrochloric acid and saturated brine were washed" and dried with magnesium sulfate. After filtering the organic phase, it was concentrated by pressure quenching, using reverse equal fraction liquid chromatography (ci 8 column; water / acetonitrile / The residue obtained was purified to give the title compound (5.9 mg, <RTI ID=0.0></RTI> </RTI> <RTIgt; D6) δ 1.67 (br, 6H), 2.06-2.11 (br m, 9H), 3.79 (s, 3H), 4.92 (s, iH), 5.52 (s, iH), 6.24 (br, 1H), 6.97 ( d, 1H, 1 = 15.7 Hz), 7.4l (d, 2H, Jgi Hz), 7.47 (d, 1H, J = 15.7 Hz), 7.56 (s, 1H), 7 74 (d, 2H, J = 8 Hz), 7.85 (s, 1H), 7.99 (s, 1H), 9.11 (s, 1) H). MS (ESI) m/z = 509 (M + H) +. LC/MS t R = 1.60 min. Example 1-544 4-amino-2-(cyclohexylamino)-6. 4-(ΐ_(2_(methylsulfonyl)ethyl)_ 141666.doc -470- 201028381 1Η-ηBizozol-4-yl)phenylamino)nicotinic nitrile [Chemical 1544] ❿

(步驟υ TsCI,吡啶 DCM, 0 °C 50%(Step υ TsCI, pyridine DCM, 0 °C 50%

42% (步驟2)42% (Step 2)

K2C03 88%K2C03 88%

步驟1 : 4-甲基苯磺酸2-(甲基磺醯基）乙酯 向2-(甲基磺醢基）乙醇（1.00 g，8.05 mmol)及吡啶（765 mg，9.67 mmol)之二氯甲烧（10 mL)溶液中，於室溫下添 加對曱苯磺醯氣（1.69 g，8.86 mmol)攪拌一整夜。向反應 溶液中添加水及乙酸乙酯進行分離。以乙酸乙酯萃取水 ® 相，將合併之有機相以飽和碳酸氫鈉水溶液及飽和食鹽水 進行清洗，以硫酸鎂加以乾燥。將有機相過濾後，進行減 壓濃縮，藉此獲得標題化合物（1.39 g，4.99 mmol， 62%) ° 1H-NMR (400 MHz, DMSO-d6) δ 2.42 (s, 3Η), 3.00 (s, 3H), 3.58 (t, J=5.1 Hz, 2H), 4.38 (t, J=5.1 Hz, 2H), 7.50 (d, J=7.8 Hz, 2H)，7.84 (d, J=7.8 Hz，2H)。 MS(ESI)m/z=279 (M+H)+。 141666.doc -471 - 201028381 LC/MS ^=1.38 min 〇 步驟2 : 4-溴-1-(2-(甲基確醯基）乙基）比唑 向 4-漠-1Η-» 比。坐（1.33 g，4.76 mm〇i)及碳酸鉀（7〇5 mg， 5.10 mmol)之DMF(10 mL)溶液中於室溫下添加4_甲基苯磺 酸2-(甲基磺醯基）乙酯（500 mg ’ 3.40 mmol)攪拌一整夜。 向反應 &gt;合液中添加水及乙酸乙醋進行分離。以乙酸乙g旨萃 取水相’將合併之有機相以飽和碳酸氫納水溶液及飽和食 鹽水進行清洗，以硫酸鎮加以乾燥。將有機相過渡後，進 行減壓濃縮，使所獲得之殘渣固化，藉此獲得標題化合物 (761 mg，3.01 mmol，88%)，為白色固體。 1H-NMR (400 MHz, DMSO-d6) 6 2.89 (s, 3H), 3.68 (t J=6.6 Hz, 2H), 4.54 (t, J=6.6 Hz, 2H), 7.58 (s, 1H), 8.02 (S) 1H) 〇 MS(ESI)m/z=253 (M+H)+。 LC/MS tR=0.97 min。 步驟3 :標題化合物 利用與實施例1-541之步驟3同樣之方法實施，獲得標題 化合物（70.3 mg，42°/〇)，為茶色固體。 1H-NMR (400 MHz, DMSO-d6) δ 1.15-1.34 (5H，m), 1.6〇_ 1.73 (4H, m), 1.89 (2H, br s), 2.87 (3H, s), 3.72 (2H, t J=6.4 Hz), 3.85 (3H, s), 4.56 (2H, t, J = 6.4 Hz), 5.45 (ih s), 5.70 (1H, d, J=8.0 Hz), 6.10 (2H, s), 7.16 (1H, s), 7.39 (3H，q，J=8.0 Hz), 7.90 (1H，s), 8.14 (1H，s)，8.83 (1H, s) 〇 MS(ESI)m/z=480 (M+H)+。 141666.doc •472- 201028381 LC/MS tR=1.54 min。 實施例1-545 4-胺基-6-(3-(氰基甲氧基）-4-(1-甲基-1Η-»比唑-4-基）苯基 胺基）-2-(環己基胺基）菸鹼腈 [化 1545]Step 1: 2-(methylsulfonyl)ethyl 4-methylbenzenesulfonate to 2-(methylsulfonyl)ethanol (1.00 g, 8.05 mmol) and pyridine (765 mg, 9.67 mmol) In a solution of chloroform (10 mL), toluene sulfonate (1.69 g, 8.86 mmol) was added at room temperature overnight. Water and ethyl acetate were added to the reaction solution for separation. The water was extracted with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium hydrogen sulfate and brine and dried over magnesium sulfate. After the organic phase was filtered, EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 3H), 3.58 (t, J=5.1 Hz, 2H), 4.38 (t, J=5.1 Hz, 2H), 7.50 (d, J=7.8 Hz, 2H), 7.84 (d, J=7.8 Hz, 2H) . MS (ESI) m/z = 277 (M+H)+. 141666.doc -471 - 201028381 LC/MS^=1.38 min 〇 Step 2: 4-Bromo-1-(2-(methyl-decyl)ethyl)pyrazole to 4-Moist-1Η-» ratio. Add 2-(methylsulfonyl) 4-methylbenzenesulfonate at room temperature in a solution of (1.33 g, 4.76 mm〇i) and potassium carbonate (7〇5 mg, 5.10 mmol) in DMF (10 mL) Ethyl acetate (500 mg ' 3.40 mmol) was stirred overnight. Water and ethyl acetate were added to the reaction &gt; mixture to separate. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with a saturated aqueous solution of sodium hydrogencarbonate and brine and dried over EtOAc. After the organic phase was combined, the title compound (761 mg, 3.01 mmol, 88%) was obtained as white solid. 1H-NMR (400 MHz, DMSO-d6) 6 2.89 (s, 3H), 3.68 (t J = 6.6 Hz, 2H), 4.54 (t, J = 6.6 Hz, 2H), 7.58 (s, 1H), 8.02 (S) 1H) 〇MS (ESI) m/z = 253 (M+H)+. LC/MS tR = 0.97 min. The title compound (70.3 mg, 42 / /) was obtained as a brown solid. 1H-NMR (400 MHz, DMSO-d6) δ 1.15-1.34 (5H, m), 1.6〇_ 1.73 (4H, m), 1.89 (2H, br s), 2.87 (3H, s), 3.72 (2H, t J=6.4 Hz), 3.85 (3H, s), 4.56 (2H, t, J = 6.4 Hz), 5.45 (ih s), 5.70 (1H, d, J=8.0 Hz), 6.10 (2H, s) , 7.16 (1H, s), 7.39 (3H, q, J=8.0 Hz), 7.90 (1H, s), 8.14 (1H, s), 8.83 (1H, s) 〇MS(ESI)m/z=480 (M+H)+. 141666.doc •472- 201028381 LC/MS tR=1.54 min. Example 1-545 4-Amino-6-(3-(cyanomethoxy)-4-(1-methyl-1Η-»bisoxazol-4-yl)phenylamino)-2-( Cyclohexylamino)nicotinic nitrile [Chemical 1545]

PdCI2(dppf).CH2CI2,K2C(VJc溶液 n〇2DMF,80°CPdCI2(dppf).CH2CI2, K2C (VJc solution n〇2DMF, 80°C

步驟2) Fe, NH4CIStep 2) Fe, NH4CI

NH2NH2

涉驟5)Step 5)

步驟1 : 4-(2-曱氧基-4-硝基苯基）-1-甲基-1H-吼唑 向1_甲基_4-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基）-111-0 比0坐（15.4 g，74.1 mmol)、1-溴-2-曱氧基-4-硝基苯（15.6 g，67.4 mmol)及 PdCl2(dppf) · CH2C12(2.75 g，3.37 mmol) 之DMF(150 mL)溶液中添加2 mol/L碳酸鉀（50.6 mL，101 mmmol)，於80°C下擾拌6小時。向反應溶液中添加水及乙 酸乙酯進行分離後，以乙酸乙酯萃取水相，將合併之有機 141666.doc •473- 201028381 相以水及飽和食鹽水進行清洗，以硫酸鎂加以乾燥。將有 機相過渡後’進行減壓濃縮，以二氣甲烷/醚使其固化， 藉此獲得標題化合物（8 68 g，37 2 mm〇1，55%)，為茶色 固體。 1H-NMR (400 MHz, DMSO-d6) δ 3.89 (s, 3H), 4.00 (s, 3H), 7.79-7.87 (m, 3H), 8.06 (s, 1H), 8.32 (s, 1H) 〇 MS(ESI)m/z=234 (M+H)+ 〇 LC/MS 4==1.60 min 〇 步驟2 : 3-甲氧基曱基_1H吡唑_4_基）苯胺 向4-(2-甲氧基-4-硝基苯基甲基-1H_吡唑g， 37.2 mmol)及還原鐵（6.24 g，112 mmol)之乙醇/氣仿/水 (120 mL/50 mL/20 mL)溶液中添加氣化銨（3.98 g，74.4 mmol)，於加熱回流下授拌6小時。向反應溶液中添加水及 氣仿，進行分離。以氣仿萃取水相，以硫酸鎂加以乾燥。 將有機相過渡後，進行減壓濃縮，利用中壓碎膠層析法 (己烷/乙酸乙酯；50-75%乙酸乙酯梯度）對所獲得之殘渣進 行純化，藉此獲得標題化合物（4.34 g，21.4 mmol， 57%)，為黃色固體。 1H-NMR (400 MHz，DMSO-d6) δ 3.75 (s，3H)，3.81 (s, 3H) 5.07 (s, 2H), 6.18 (d, J=8.1 Hz, 1H), 6.28 (s, 1H), 7.19 (d J=8.1 Hz，1H), 7.67 (s’ 1H)，7.83 (s, 1H)。 MS(ESI)m/z=204 (M+H)+。 LC/MS tR=0.36 min ° 步驟3 : 4-胺基-2-氣-6-(3-甲氧基-4-(1-甲基_1幵-吼0坐_4 141666.doc -474- 201028381 基）苯基胺基）於驗腈 於5 mL微波反應容器中，向四氟曱磺酸4_胺基_6_氣-5- 氰基0比唆-2-基醋（80 mg，0.266 mmol)及3-曱氧基-4-(1-曱 基-1Η-°比峻-4-基）苯胺（81 mg’ 0.399 mmol)之 DMSO(1.0 mL)溶液中添加DIEA(5 1.5 mg，0.399 mmol)進行覆蓋，使 用Biotage Optimizer反應裝置，於160°C下攪拌45分鐘。向 反應溶液中添加水及乙酸乙酯進行分離。以乙酸乙酯萃取 水相’將合併之有機相以水及飽和食鹽水進行清洗，以硫 酸鎂加以乾燥。將有機相過濾後，進行減壓濃縮，利用中 壓矽膠層析法（己烷/乙酸乙酯；70-100%乙酸乙酯梯度）對 所獲传之殘逢進彳于純化，藉此獲得標題化合物（61.5 mg， 0.173 mmol，65%)，為茶色油。 1H-NMR (400 MHz, DMSO-d6) δ 3.84 (s, 9H), 6.06 (s, 1H), 6.85 (s, 2H), 6.99 (d, J=8.3 Hz, 1H), 7.22 (s, 1H), 7.49 (d, J=8.3 Hz，1H)，7.81 (s，1H)，8.01 (s，1H)，9.39 (s, 1H)。 步驟4 : 4-胺基-2-(環己基胺基）-6-(3-羥基-4-(1-曱基-1H-'比唑-4-基）苯基胺基）菸鹼腈 於20 mL微波反應容器中，向4-胺基-2·氣-6-(3-甲氧基-4-(1-甲基-lH-η比唑-4-基）苯基胺基）菸鹼腈（300 mg，0.846 mmol)之NMP(8.0 mL)溶液中添加環己胺（419 mg，4.23 mmol)進行覆蓋，使用Biotage Optimizer反應裝置，於 2 4 5 C下授掉2小時。向反應溶液中添加水及乙酸乙醋，進 行分離。以乙酸乙酯萃取水相，將合併之有機相以水及飽 和食鹽水進行清洗，以硫酸鎂加以乾燥。將有機相過滤 141666.doc -475 - 201028381 後，進行減壓濃縮，利用逆相等分試樣液相層析法（ci8管 柱；水/乙腈/0.1%甲酸；10_100%梯度）對所獲得之殘渣進 行純化’獲得標題化合物（34 mg，〇 〇84 mmol，1〇%)，為 白色固體。 MS(ESI)m/z=404 (M+H).。 步驟5 :標題化合物 向4-胺基·2-(環己基胺基）冬(3·經基_4_(1甲基-ih_d^_ 4-基）苯基胺基）於驗腈（19.8 mg，〇_軸^)及碳酸卸 (33.9 mg，0.245 mm〇1)之DMF(3 〇社）溶液中添加溴乙腈 (17.7 mg’ 0.147 _〇1)後，於5〇t下搜掉一整夜。向反應 溶液中添加水及乙酸旨進行分離。以乙酸乙_萃取水 相，將合併之有機相以水及鮮食以進行清洗以硫酸 鎂加以乾燥。將有機相過錢，進行減壓濃縮，利用逆相 等分試樣液相層析法(C18管柱；水/乙腈/〇 ι%甲酸W 鮮/。梯度m所獲得之錢進行純化，藉此獲得標題化合 物(6.7 1^’0.015顏。1，31%)，為茶色非晶體。 1H-NMR (4〇〇 MHz，DMS〇_d6) δ ! μ] μ 阳叫⑴ K73 (3H，m)&gt;1*92 (2^ br S)&gt;3^ (3H, s), 5.12 (iH, s) 5.46 (1H，s)，5.75 (1H d，J=6 8 H ， ΰ·13 (2H, s), 7.21 (1H, S)，7.44 (1H，d，】=8.G HZ)，7.58 (1H，d，；=8·〇 Hz), 7 8〇 (1H, s)，8.01 (1H，s)，8.96 (1H, s)。 141666.doc -476- 201028381 [表 1-1]Step 1: 4-(2-decyloxy-4-nitrophenyl)-1-methyl-1H-indazole to 1-methyl-4-(4,4,5,5-tetramethyl- 1,3,2-Dioxaborolan-2-yl)-111-0 (0. 5 g, 74.1 mmol), 1-bromo-2-indolyl-4-nitrobenzene (15.6 g, 67.4 mmol) and PdCl2 (dppf) · CH2C12 (2.75 g, 3.37 mmol) in DMF (150 mL) was added 2 mol/L potassium carbonate (50.6 mL, 101 mmmol) and was stirred at 80 °C for 6 hours. After the water and ethyl acetate were added to the reaction solution for separation, the aqueous phase was extracted with ethyl acetate. The combined organic 141666.doc: 473 - 201028381 was washed with water and saturated brine and dried over magnesium sulfate. After the organic phase was transferred, the residue was concentrated under reduced pressure, and then purified to m. m. m. 1H-NMR (400 MHz, DMSO-d6) δ 3.89 (s, 3H), 4.00 (s, 3H), 7.79-7.87 (m, 3H), 8.06 (s, 1H), 8.32 (s, 1H) 〇MS (ESI) m/z = 234 (M+H) + 〇LC/MS 4 = = 1.60 min 〇 Step 2: 3-methoxyindolyl-1H pyrazole _4 yl) aniline to 4-(2- Methoxy-4-nitrophenylmethyl-1H-pyrazole g, 37.2 mmol) and reduced iron (6.24 g, 112 mmol) in ethanol/methanol/water (120 mL/50 mL/20 mL) Ammonium vaporification (3.98 g, 74.4 mmol) was added thereto, and the mixture was stirred under heating and reflux for 6 hours. Water and gas were added to the reaction solution to carry out separation. The aqueous phase was extracted with a gas pattern and dried over magnesium sulfate. After the organic phase was combined, the residue was purified under reduced pressure. 4.34 g, 21.4 mmol, 57%) as a yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ 3.75 (s, 3H), 3.81 (s, 3H) 5.07 (s, 2H), 6.18 (d, J = 8.1 Hz, 1H), 6.28 (s, 1H) , 7.19 (d J=8.1 Hz, 1H), 7.67 (s' 1H), 7.83 (s, 1H). MS (ESI) m / z = 204 (M + H) +. LC/MS tR=0.36 min ° Step 3: 4-Amino-2- gas-6-(3-methoxy-4-(1-methyl-1幵-吼0 sitting_4 141666.doc -474 - 201028381 base) phenylamine) in a 5 mL microwave reaction vessel, to 4-fluoroindolesulfonic acid 4_amine _6_gas-5-cyano 0 唆-2-yl vinegar (80 mg , 0.266 mmol) and 3-methoxy-4-(1-indolyl-1Η-° 峻 -4--4-yl) aniline (81 mg ' 0.399 mmol) in DMSO (1.0 mL) was added DIEA (5 1.5 The mg, 0.399 mmol) was covered and stirred at 160 ° C for 45 minutes using a Biotage Optimizer reaction apparatus. Water and ethyl acetate were added to the reaction solution for separation. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and saturated brine and dried over magnesium sulfate. After the organic phase was filtered, it was concentrated under reduced pressure, and purified by medium pressure gel chromatography (hexane/ethyl acetate; 70-100% ethyl acetate gradient). The title compound (61.5 mg, 0.173 mmol, 65%) was obtained as a brown oil. 1H-NMR (400 MHz, DMSO-d6) δ 3.84 (s, 9H), 6.06 (s, 1H), 6.85 (s, 2H), 6.99 (d, J = 8.3 Hz, 1H), 7.22 (s, 1H) ), 7.49 (d, J=8.3 Hz, 1H), 7.81 (s, 1H), 8.01 (s, 1H), 9.39 (s, 1H). Step 4: 4-Amino-2-(cyclohexylamino)-6-(3-hydroxy-4-(1-indolyl-1H-'pyazol-4-yl)phenylamino)nicotinonitrile In a 20 mL microwave reaction vessel, to 4-amino-2 gas-6-(3-methoxy-4-(1-methyl-lH-n-bisoxazol-4-yl)phenylamine) To a solution of nicotinic nitrile (300 mg, 0.846 mmol) in NMP (8.0 mL) was added with hexanes (419 mg, 4.23 mmol), and then applied to the apparatus for 2 hours at 2 4 5 C using a Biotage Optimizer reaction apparatus. Water and ethyl acetate were added to the reaction solution for separation. The aqueous phase was extracted with ethyl acetate and the combined organics were washed with water and brine and dried over magnesium sulfate. After the organic phase was filtered 141666.doc - 475 - 201028381, it was concentrated under reduced pressure, and obtained by reverse phase separation liquid chromatography (ci8 column; water / acetonitrile / 0.1% formic acid; 10-100% gradient) The residue was purified to give the title compound (m. MS (ESI) m / z = 404 (M + H). Step 5: The title compound is taken to 4-amino-2-(cyclohexylamino) winter (3. thiol_4_(1methyl-ih_d^-4-yl)phenylamine) for nitrile (19.8 mg) Add bromoacetonitrile (17.7 mg ' 0.147 _ 〇 1) to DMF (3 〇 ) ) solution of 碳酸 _ axis ^) and carbonic acid unloading (33.9 mg, 0.245 mm 〇 1), and then search for it at 5 〇t night. Water and acetic acid were added to the reaction solution for separation. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and fresh water and dried over magnesium sulfate. The organic phase was passed, concentrated under reduced pressure, and purified by reverse phase equal liquid chromatography (C18 column; water / acetonitrile / oxime formic acid W fresh / gradient m). The title compound (6.7 1^'0.015 pi.1, 31%) was obtained as a brown amorphous. 1H-NMR (4 〇〇 MHz, DMS 〇 _d6) δ ! μ] μ 阳 (1) K73 (3H, m) &gt;1*92 (2^ br S)&gt;3^ (3H, s), 5.12 (iH, s) 5.46 (1H, s), 5.75 (1H d, J=6 8 H , ΰ·13 (2H , s), 7.21 (1H, S), 7.44 (1H,d,]=8.G HZ), 7.58 (1H,d,;=8·〇Hz), 7 8〇(1H, s), 8.01 ( 1H, s), 8.96 (1H, s). 141666.doc -476- 201028381 [Table 1-1]

表1-1中記載之化合物係依據上述記載之實施例1-145之 方法而合成。 實施例編號The compounds described in Table 1-1 were synthesized in accordance with the methods of Examples 1-145 described above. Example number

RR

實施例1 — 54 6Example 1 - 54 6

實施例1 一 5 4 7Example 1 A 5 4 7

物性資料_ 1H-NMR {300 HHz# DMSO-d6) 5 5.72 (s, 1H), 6.58 (s, 1H)7 6.66 is, 2H), 7.18-7.21 (mf 2H), 7.28-7.29 {mf 2H) , 7*42-7.45 (m, 2H), 7.77 (bxs, 2H&gt;, 9·51 (s, 1H&gt;. MS (ESI) m/z » 352 (M+H)+. 1H-NMR (300MHz # DMSO-de) 54.29 {a r 5,6S (s, 1H&gt;, 6.57 &lt;s, 4H&gt;, 7.03-7.47 (m, 9H), 8.90 (s, 1H).Physical data _ 1H-NMR {300 HHz# DMSO-d6) 5 5.72 (s, 1H), 6.58 (s, 1H)7 6.66 is, 2H), 7.18-7.21 (mf 2H), 7.28-7.29 {mf 2H) , 7*42-7.45 (m, 2H), 7.77 (bxs, 2H&gt;, 9·51 (s, 1H&gt;. MS (ESI) m/z » 352 (M+H)+. 1H-NMR (300MHz # DMSO-de) 54.29 {ar 5,6S (s, 1H&gt;, 6.57 &lt;s, 4H&gt;, 7.03-7.47 (m, 9H), 8.90 (s, 1H).

實施例1 — 5 4 8 1H-NMR (300MHz, DMSO-dg) δ 5.84 (s, 1H) , 6.13-6.42 (m, 4H&gt;, 6,75 &lt;s, 2H) , 7.22-7.54 (mr dH) r 9.35 &lt;s, 1H) , 11.50 (s, 1H).Example 1 - 5 4 8 1H-NMR (300MHz, DMSO-dg) δ 5.84 (s, 1H), 6.13-6.42 (m, 4H&gt;, 6,75 &lt;s, 2H), 7.22-7.54 (mr dH ) r 9.35 &lt;s, 1H) , 11.50 (s, 1H).

實施例1 一 5 4 9Example 1 a 5 4 9

MS (ESI) m/z « 344 &lt;M+H)+, X*C/M3 tR * 1.73 xoln.MS (ESI) m/z « 344 &lt;M+H)+, X*C/M3 tR * 1.73 xoln.

實施例1 — 5 5 0 477- 1H-KMR (400 MHz, DMSO-de) 5 3.50 (s t 3H), 5.89 (s, 1H) r 6.75 &lt;s, 2H), 6.90 (d, J = 8.0 Hz, 1H) , 7.06 (s, 1H) f 7.20-7.29 (m, SH), 7.43-7.47 (m, 2H) , 8.29 (s, 1H) , 9.35 {s, 1H). MS (ESI) m/z « 400 (M+H)+. I.C/MS tR - 1,88 min. 141666.doc 201028381 實施例編號 R 物性資料 1H-KHR &lt;400 MH2 ,DMSO-de) 53.36 (sf 3H), 3.67 (S, 3H), 5,89 (sr 1H) f 0 6.80-6.82 (m, 3H), 7.00 (s, 1H), 實施例1 7.19-7.20 (m. 2H) , 7.28-7.30 (m, 5 5 1 IVftTW || X 2H); 7.42 -7.46 (m, 2H), 9.45 (sr MeO入 1H). MS (£SI) m/z = 391 (M+H) +- LC/MS tR : -1.82 min. 0 HS (ESI) m/z « 337 (M+H) + 實施例1 - H2N&quot;Nf LC/MS tR = » 1.50 min. 5 5 2 Jl Λ MeO 1H-NMR (400 MHz, DHSO-de) δ 3.47 3H&gt;, 5.70 (s, 1M) 7 6,45 (d, jl Ί lHfJ«6Hz) , 6.55U, 2H&gt;, 6,81 (s, 1H)# 7.16-7.42^, 6H),8.53 8,73 (S, 1H). 實施例i — 5 5 3 實施例1 5 5 4Example 1 - 5 5 0 477- 1H-KMR (400 MHz, DMSO-de) 5 3.50 (st 3H), 5.89 (s, 1H) r 6.75 &lt;s, 2H), 6.90 (d, J = 8.0 Hz , 1H) , 7.06 (s, 1H) f 7.20-7.29 (m, SH), 7.43-7.47 (m, 2H) , 8.29 (s, 1H) , 9.35 {s, 1H). MS (ESI) m/z « 400 (M+H)+. IC/MS tR - 1,88 min. 141666.doc 201028381 Example No. R Physical data 1H-KHR &lt;400 MH2 , DMSO-de) 53.36 (sf 3H), 3.67 (S , 3H), 5,89 (sr 1H) f 0 6.80-6.82 (m, 3H), 7.00 (s, 1H), Example 1 7.19-7.20 (m. 2H), 7.28-7.30 (m, 5 5 1 IVftTW || X 2H); 7.42 -7.46 (m, 2H), 9.45 (sr MeO into 1H). MS (£SI) m/z = 391 (M+H) +- LC/MS tR : -1.82 min. 0 HS (ESI) m/z « 337 (M+H) + Example 1 - H2N &quot;Nf LC/MS tR = » 1.50 min. 5 5 2 Jl Λ MeO 1H-NMR (400 MHz, DHSO-de) δ 3.47 3H&gt;, 5.70 (s, 1M) 7 6,45 (d, jl Ί lHfJ«6Hz), 6.55U, 2H&gt;, 6,81 (s, 1H)# 7.16-7.42^, 6H), 8.53 8, 73 (S, 1H). Example i - 5 5 3 Example 1 5 5 4

實施例1 一 5 5 5Example 1 a 5 5 5

MeOMeO

MeOMeO

1H-NMR &lt;400 MHz, DMSO-d6) 53.44 (s, 3H), 4.27 (a, 2H), 5.77 &lt;s, XH), 6.61 (m, 4H), 6.92 &lt;s, 1H), 7.16-7.42 (in, 7H) , 8.93 {s, 1H). MS (ESI) m/z = 407 (M+H&gt;+. LC/MS tR = 1.81 min. 實施例1 一 5 5 61H-NMR &lt;400 MHz, DMSO-d6) 53.44 (s, 3H), 4.27 (a, 2H), 5.77 &lt;s, XH), 6.61 (m, 4H), 6.92 &lt;s, 1H), 7.16 -7.42 (in, 7H), 8.93 {s, 1H). MS (ESI) m/z = 407 (M+H&gt;+. LC/MS tR = 1.81 min. Example 1 - 5 5 6

ΜθΟΜθΟ

MS (ESI) m/z = 476 (ΜΦΗ&gt;+. LC/MS tR - 1.28 min. 實施例1 — 5 5 7MS (ESI) m/z = 476 ( Μ Φ Η &gt; +. LC/MS tR - 1.28 min. Example 1 - 5 5 7

MS (ESI) m/z « 447 (M+H}+. LC/MS tn = 3.30 min. MS (ESI) m/z = 433 {M+H)+. LC/MS tR * 3.65 min. 實施例1 一 5 5 8 0.MS (ESI) m/z « 447 (M + H) +. LC/MS tn = 3.30 min. MS (ESI) m/z = 433 (M+H)+. LC/MS tR * 3.65 min. 1 a 5 5 8 0.

MeOMeO

141666.doc 478- 201028381141666.doc 478- 201028381

實施例編號 實施例3.— 5 5 9Example No. Example 3.— 5 5 9

R _物性資料 MS (ESI) m/z » 448 (M+H)+. LC/MS 1.23 min. 〇 MeOR _physical data MS (ESI) m/z » 448 (M+H)+. LC/MS 1.23 min. 〇 MeO

實施例1 — 5 6 0Example 1 - 5 6 0

實施例1 — 5 6 1Example 1 - 5 6 1

實施例1 — 5 6 2Example 1 - 5 6 2

MeMe

實施例1 一 5 6 3Example 1 a 5 6 3

Me、Me,

實施例1 一 5 6 4Example 1 a 5 6 4

1H-NHR &lt;400 MHSK, DMSO-de) δ 5.79 &lt;1H, s&gt; , 6.65 (2H, s) , 7.13 (3H, df J - 8.0 Hz)# 7,21 (5H, t, J » 8,0 Hz) , 7.34 (1H； tr J = 8.0 Hz) λ 7.49 (2H, t, J* 8,0 Hz), 7,78 (2H, , 8.01 (1H, s), 9.06 (1H, s), 12.84 &lt;1H, s&gt;. 1H-NMR {400 MHz, OMSO-d6) δ 5.81 (1H, s)# 6.69 (2H, s), 7.20 (6H, ddf J * 16.8, 8.4 Hz), 7.33 &lt;4H, dd, J « 16.8, 8.4 Hz), 7.50 &lt;3H, t, J « 8.0 Hs〇 , 8·16 (1H, s》，8.53 (2H, s),9.17 (1H, s). 1H-NHII (400 MHz, DMSO-ds) δ 1.98 (OH, s) , 2.52 (1H, d, J « 15.7 Hz), 3.60 (4H, s&gt;, 5.14 (2H, s), 5.83 (1H, 8) , 6.71 (3H, s) , 7.03 《4H, d, J = 8.0 Hi) , 7.21 &lt;10H, dt J » 8.0 Hz) , 7,32 &lt;2H, t, J « 6.8 Hz) , 7.48 (3H, t, J = 6.8 Hz) , 7.72 (1H, s) r 8.18 (XHy b), 9.26 (1H, s). XH-NMR &lt;400 MHz, DMSO-d6&gt; δ 2.17 &lt;6H, s》，2.S6 (SH, t, J 雄 6.4 Hz&gt; , 4.17 (3H, tf J » 6.4 Hz) , 5.79 (1H, s), 6.64 (2H, s), 7.13 (SH, s) , 7.22 (3H, d, J = 7.6 Hjc) , 7.34 (1H, t, J ^ 1.2 Hz), 7.49 (3H, t, J « 7.6 Hz), 7.70 &lt;1H, 3), 7.99 &lt;lHr s), 9,08 UH, s)， 1H-NMR (400 MHz, DMSO-dg) δ 3.43 《3H, s&gt; , 4.87 {2h, s&gt; , 5*82 (1H, s&gt; , 6· 69 (2H, s) , 7.18-7,23 (SH, m) r 7.35 (4H, d, J = 6.0 Hz) , 7.51 (2Hr t, J - 7.6 Hz) , 8.27 (1H, s) , 8.71 (1H, s)f 9.18 (1H# s). 141666.doc 479- 201028381 實施例編號 實施例1 - 5 6 51H-NHR &lt;400 MHSK, DMSO-de) δ 5.79 &lt;1H, s&gt; , 6.65 (2H, s) , 7.13 (3H, df J - 8.0 Hz) # 7,21 (5H, t, J » 8 , 0 Hz) , 7.34 (1H; tr J = 8.0 Hz) λ 7.49 (2H, t, J* 8,0 Hz), 7,78 (2H, , 8.01 (1H, s), 9.06 (1H, s) , 12.84 &lt;1H, s&gt;. 1H-NMR {400 MHz, OMSO-d6) δ 5.81 (1H, s)# 6.69 (2H, s), 7.20 (6H, ddf J * 16.8, 8.4 Hz), 7.33 &lt;;4H, dd, J « 16.8, 8.4 Hz), 7.50 &lt;3H, t, J « 8.0 Hs〇, 8·16 (1H, s), 8.53 (2H, s), 9.17 (1H, s). 1H -NHII (400 MHz, DMSO-ds) δ 1.98 (OH, s) , 2.52 (1H, d, J « 15.7 Hz), 3.60 (4H, s&gt;, 5.14 (2H, s), 5.83 (1H, 8) , 6.71 (3H, s) , 7.03 "4H, d, J = 8.0 Hi) , 7.21 &lt;10H, dt J » 8.0 Hz) , 7,32 &lt;2H, t, J « 6.8 Hz) , 7.48 (3H , t, J = 6.8 Hz) , 7.72 (1H, s) r 8.18 (XHy b), 9.26 (1H, s). XH-NMR &lt;400 MHz, DMSO-d6&gt; δ 2.17 &lt;6H, s》, 2.S6 (SH, t, J 6.4 Hz), 4.17 (3H, tf J » 6.4 Hz), 5.79 (1H, s), 6.64 (2H, s), 7.13 (SH, s), 7.22 (3H, d, J = 7.6 Hjc) , 7.34 (1H, t, J ^ 1.2 Hz), 7.49 (3H, t, J « 7.6 Hz), 7.70 &lt;1H, 3), 7.99 &lt;lHr s), 9,08 UH, s), 1H-NMR (400 MHz, DMSO-dg) δ 3.43 "3H, s&gt; , 4.87 {2h, s&gt; , 5*82 (1H, s&gt; , 6 · 69 (2H, s) , 7.18-7,23 (SH, m) r 7.35 (4H, d, J = 6.0 Hz) , 7.51 (2Hr t, J - 7.6 Hz) , 8.27 (1H, s) , 8.71 (1H, s)f 9.18 (1H# s). 141666.doc 479- 201028381 Example Numbering Example 1 - 5 6 5

實施例3 -566Example 3 -566

實施例1 - 5 6 7Example 1 - 5 6 7

物性資料_ 1H-NMR (400 MHz, DMSO-d6) δ 2,41 (4Η, s) , 2.72 (2Hf t, J * β.4 Η*), 3.55 (4H, ά, J « 4.4 Hz) , 4.21 {2Hf t, J « 6.4 Hz) , 5.79 UH, s) , €.64 (2H, s) , 7.14 (5Hf s) , 7.22 (2H, d, J « 7.6 Hz), 7.33 (1H, t, J = 7.2 Hz) , 1.49 (2H, t, J « 8,0 Hz) , 7.71 (1H, s&gt; , 8-00 UH, s&gt; , 9·07 (1H, s》· 1H-NMR (400 MHz, DMSO-d6) δ 3.91 (3H, s) , 5.86 (1H, s) , 6.77 (2H, s), 7.24 (2H, d, J « 8.0 Hz) , 7.29-7,38 (3H, m&gt; , 7.43 &lt;2H, d, J * 8.8 Hz), 7,52 (2H, t, J « 7.6 Hz) , 7.81 (XH, d, J = 3.2 Hz) f 8.15 (1H, s), 8,68 &lt;1H, d# J - 3-2 Hz) , 9.40 (XH, s). 1H-NMR (400 MHz, DMSO-d6) 6 5,86 (1H, s&gt;, 6.76 (2H, s), 7.23-7,44 &lt;6H, m&gt; , 7，S3 {2H, fc, J = 7·6 Ha〇 , 7.68-7.76 (2Hf m)f 8.15 (2H, s), 8.61 (1H, d, J « 4.4 Hz) , 9.39 &lt;1H, s&gt; . 實施例1 - 5 6 8 MVNMePhysical data _ 1H-NMR (400 MHz, DMSO-d6) δ 2,41 (4Η, s) , 2.72 (2Hf t, J * β.4 Η*), 3.55 (4H, ά, J « 4.4 Hz) , 4.21 {2Hf t, J « 6.4 Hz) , 5.79 UH, s) , €.64 (2H, s) , 7.14 (5Hf s) , 7.22 (2H, d, J « 7.6 Hz), 7.33 (1H, t, J = 7.2 Hz) , 1.49 (2H, t, J « 8,0 Hz) , 7.71 (1H, s&gt; , 8-00 UH, s&gt; , 9·07 (1H, s)· 1H-NMR (400 MHz , DMSO-d6) δ 3.91 (3H, s) , 5.86 (1H, s) , 6.77 (2H, s), 7.24 (2H, d, J « 8.0 Hz) , 7.29-7,38 (3H, m&gt; , 7.43 &lt;2H, d, J * 8.8 Hz), 7,52 (2H, t, J « 7.6 Hz) , 7.81 (XH, d, J = 3.2 Hz) f 8.15 (1H, s), 8,68 &lt;;1H,d# J - 3-2 Hz) , 9.40 (XH, s). 1H-NMR (400 MHz, DMSO-d6) 6 5,86 (1H, s&gt;, 6.76 (2H, s), 7.23-7 ,44 &lt;6H, m&gt; , 7,S3 {2H, fc, J = 7·6 Ha〇, 7.68-7.76 (2Hf m)f 8.15 (2H, s), 8.61 (1H, d, J « 4.4 Hz ), 9.39 &lt;1H, s&gt; . Example 1 - 5 6 8 MVNMe

實施例3 — 5 β 9Example 3 - 5 β 9

1H-NMR (400 MHz, DMSO-d€) δ 3.X0 (3H, s&gt; , 3.26 i3H, s) , 5.42 (1H, 3), 5.83 (1H, s), 6.77 (2H, s)r 7,03 (2H, d, J - 8.4 Hz) , 7.23 {6H, t, J * 8.4 Has), 7.50 (2H, t, J = 8.0 Hz), 9.40 (1H, s). 1H-HHR (400 MHz, DMSO-d6) δ 3.84 (4H, d, J « 13.6 Hz) , 4.22 (2H, s), 5.18 &lt;1H, s), 5.78 (1H, s), 6.64 (2H, s) , 7.13 (4H, s) , 7.21 (2H, d, J « 8.0 Hz), 7.35 (1H, dt J ^ 7.2 Hz) , 7.49 (2H, t, J « 8,0 Hz) , 7.74 (XH, s) , 7.95 (1H, s) , 9*08 (1H, s) * 141666.doc 480· 2010283811H-NMR (400 MHz, DMSO-d €) δ 3.X0 (3H, s&gt;, 3.26 i3H, s), 5.42 (1H, 3), 5.83 (1H, s), 6.77 (2H, s)r 7 ,03 (2H, d, J - 8.4 Hz) , 7.23 {6H, t, J * 8.4 Has), 7.50 (2H, t, J = 8.0 Hz), 9.40 (1H, s). 1H-HHR (400 MHz , DMSO-d6) δ 3.84 (4H, d, J « 13.6 Hz) , 4.22 (2H, s), 5.18 &lt;1H, s), 5.78 (1H, s), 6.64 (2H, s) , 7.13 (4H , s) , 7.21 (2H, d, J « 8.0 Hz), 7.35 (1H, dt J ^ 7.2 Hz) , 7.49 (2H, t, J « 8,0 Hz) , 7.74 (XH, s) , 7.95 ( 1H, s) , 9*08 (1H, s) * 141666.doc 480· 201028381

實施例編號Example number

R 實施例】-5 7 0R Example]-5 7 0

實施例Ϊ — 5 7 1Example Ϊ — 5 7 1

物性資料_ (400 mz, DMSO-de) 6 1.36-1.66 &lt;7H/ m) f 3*55 &lt;1Η, br s), 3,72-3.75 (1H, m) f 3.91-3.95 (1H# m) , 4.27 {2H, s) , 4.53 {1H, s) , 5.78 (1H, s) , 6,63 (2H, s) , 7.13 (4H, s), 7*21· &lt;2H, d, J 皿 8.0 Hz&gt; , U2 &lt;1H, t, J « 7.6 Hz) , 7.48 (2H, J * 7.6 Hz), 7*73 (1H, s), 7.98 &lt;1H, s), 9.07 (1H, a), 1H - NMR (400 MHz, DMSO-de) δ 3.74-3.75 (2H, m) f 4.11-4.14 (2H, m) f 4.94 (lHf s) , 5.78 (XH, s) , 6.64 &lt;1H, s) # 7*12 (4H, s) , 7.21 (2Hf d, J = 8.4 Hz) r 7,32-7.36 &lt;1H? m) f 7,47-7.51 (2Bf m), 7.71 (1H, a)f 7,96 {in, s), 9.07 (XH, s), 141666.doc 481 - 201028381 [表 1-2]Physical data _ (400 mz, DMSO-de) 6 1.36-1.66 &lt;7H/ m) f 3*55 &lt;1Η, br s), 3,72-3.75 (1H, m) f 3.91-3.95 (1H# m) , 4.27 {2H, s) , 4.53 {1H, s) , 5.78 (1H, s) , 6,63 (2H, s) , 7.13 (4H, s), 7*21· &lt;2H, d, J 8.0 Hz&gt; , U2 &lt;1H, t, J « 7.6 Hz) , 7.48 (2H, J * 7.6 Hz), 7*73 (1H, s), 7.98 &lt;1H, s), 9.07 (1H, a), 1H-NMR (400 MHz, DMSO-de) δ 3.74-3.75 (2H, m) f 4.11-4.14 (2H, m) f 4.94 (lHf s) , 5.78 (XH, s) , 6.64 &lt;1H , s) # 7*12 (4H, s) , 7.21 (2Hf d, J = 8.4 Hz) r 7,32-7.36 &lt;1H? m) f 7,47-7.51 (2Bf m), 7.71 (1H, a)f 7,96 {in, s), 9.07 (XH, s), 141666.doc 481 - 201028381 [Table 1-2]

表1-2中記載之化合物係依據上述記載之實施例1-499之 方法而合成。 實施例編號 實施例1 - 5 7 2The compounds described in Table 1-2 were synthesized in accordance with the methods of Examples 1-49 described above. Example No. Example 1 - 5 7 2

實施例1 _ 5 7 3Example 1 _ 5 7 3

0 實施例1 一 5 7 4 h2n0 Example 1 A 5 7 4 h2n

物性資料_ 1H-NKR (400 MHz, DHSO-de) δ 1.21 {Bt 7H) , 1.61 (S, 11H), 2.08 (d, J = 14.1 Hzf 18H), 2.39 (s, 7H&gt;, 3.55 {t, J * IX,6 Uzf 12H), 4.43 (s# 3H), 4.87 (sf 1H), 5.51 (sr 1H) , 6,23 (s, 2H) , 7.47 (df J = 8.1 Hz, 1H&gt; , 7.60 (tf J = 9.0 Hz, 3H) # 9.XI (s, 1H). MS (£SX) m/z = 528 (M+H)+. LC/HS tR = X.14 tain. 1H-NMR (400 MHz, DMSO-de) δ 1.66 {s, 6H), 2.07 (s, 9H), 3.11 {s, 3H), 4.94 (s, 1H), 5.54 (sf 1H), 6.31 (sf 2H) , 7.70 (d, J « 8.6 Hse , 2H) , 7.77 (d, J = 8.6 Hz , 2H) , 9.32 (s, 1H). HS (ESI) m/z « 438 (M+H)+, LC/MS tR = 2.16 min, 1H-NMR (400 MHz, DMSO-de) δ 1.67 (br, 6B) f 1,90-2.17 (br m, 9H) r 2· 69 (sf 3H) , 4.85 &lt;s, 1H) r 5.48 (s, 1H) , 6.16 {s, 2H&gt; , 6.97 (bs,lH&gt; , 7.21 (s,lH) , 7.29(d, 2H, J ^ 7,5Hz) , 7.45 (bs, 1H, ) f 7.57 (d, 2H, J » 7,5 Hz} , 8.93 iH) · 141666.doc 482- 201028381Physical data _ 1H-NKR (400 MHz, DHSO-de) δ 1.21 {Bt 7H) , 1.61 (S, 11H), 2.08 (d, J = 14.1 Hzf 18H), 2.39 (s, 7H&gt;, 3.55 {t, J * IX,6 Uzf 12H), 4.43 (s# 3H), 4.87 (sf 1H), 5.51 (sr 1H) , 6,23 (s, 2H) , 7.47 (df J = 8.1 Hz, 1H&gt;, 7.60 ( Tf J = 9.0 Hz, 3H) # 9.XI (s, 1H). MS (£SX) m/z = 528 (M+H)+. LC/HS tR = X.14 tain. 1H-NMR (400 MHz, DMSO-de) δ 1.66 {s, 6H), 2.07 (s, 9H), 3.11 {s, 3H), 4.94 (s, 1H), 5.54 (sf 1H), 6.31 (sf 2H) , 7.70 (d , J « 8.6 Hse , 2H) , 7.77 (d, J = 8.6 Hz , 2H) , 9.32 (s, 1H). HS (ESI) m/z « 438 (M+H)+, LC/MS tR = 2.16 Min, 1H-NMR (400 MHz, DMSO-de) δ 1.67 (br, 6B) f 1,90-2.17 (br m, 9H) r 2· 69 (sf 3H) , 4.85 &lt;s, 1H) r 5.48 (s, 1H) , 6.16 {s, 2H&gt; , 6.97 (bs,lH&gt; , 7.21 (s,lH) , 7.29(d, 2H, J ^ 7,5Hz) , 7.45 (bs, 1H, ) f 7.57 ( d, 2H, J » 7,5 Hz} , 8.93 iH) · 141666.doc 482- 201028381

實施例編號 R 物性資料_ 1H-NMR (400 MHz, DMSO-de) δ 1.69 {br, 6H) , 1.90-2.18 (br m, 9H), 4.96 (Bf 1H), 5.57 (sf 1H&gt;, 6.33 {&amp;f 2H), 6.97 (bs,lH)# 7,S0-7-7S&lt;m, 2H&gt;, 7.77 (d, 2H, J » 6.0Hz) , 7-90 (d, 2Hr J * 6.0 Hz), 8·04 (s, 1H&gt;, $,41 (s, 1H)· 1H-NHR (400 MHz, DMSO-dg) δ 1.64 (br, 6H), 2.07 (br , 9H) , 4.91 (s, 1H), 5,50 (s, 1H) f 6.29 (br, 2H), 6.52 (d, 1H, J«12Hje), 7,10 {s, 1H), 7.47-7.68 (m, 5H), 9.15 {s, IB). 實施例1 5 7 5Example No. R Physical data _ 1H-NMR (400 MHz, DMSO-de) δ 1.69 {br, 6H), 1.90-2.18 (br m, 9H), 4.96 (Bf 1H), 5.57 (sf 1H&gt;, 6.33 { &amp;f 2H), 6.97 (bs,lH)# 7,S0-7-7S&lt;m, 2H&gt;, 7.77 (d, 2H, J » 6.0Hz), 7-90 (d, 2Hr J * 6.0 Hz) , 8·04 (s, 1H&gt;, $,41 (s, 1H)· 1H-NHR (400 MHz, DMSO-dg) δ 1.64 (br, 6H), 2.07 (br , 9H) , 4.91 (s, 1H ), 5,50 (s, 1H) f 6.29 (br, 2H), 6.52 (d, 1H, J«12Hje), 7,10 {s, 1H), 7.47-7.68 (m, 5H), 9.15 {s , IB). Example 1 5 7 5

實施例1 5 76Example 1 5 76

0 1H-N] {br, MR (400 MHz r DMSO-de) δ 1,67 6H) , 2.09 (br , 9H) , 4.93 (s, 實施例1 - 1H)# 5.51 (a, IH), 6-28 Cs, 2H), 5 7 7 6.52 lfi), 7.38 i&lt;it lHf J * 12Η3；) , 7.02 (sf 7*26 (d, IH, J * 6.0Hz), -7.54 {m, 4H), 9,21 (s, IH). 1H-NMR (400 HHz, DMSO~de) δ 1.65 ihxt 6H) f 1.99-2.08 (br, 9H) , 3.83 &lt;s, 3H), 4.87 (s, XH), 5.55 (s, 1H), S.23 U, 2H) , 6.32 id, 1H, J =9.0Hz), 6.80 (s, lH)f 7.48 (s, 2H) , 7.73 &lt;d, 1H, J = 9.0Hz) , 9.01 is, 1H). 實施例l 5 780 1H-N] {br, MR (400 MHz r DMSO-de) δ 1,67 6H) , 2.09 (br , 9H) , 4.93 (s, Example 1 - 1H) # 5.51 (a, IH), 6 -28 Cs, 2H), 5 7 7 6.52 lfi), 7.38 i&lt;it lHf J * 12Η3;) , 7.02 (sf 7*26 (d, IH, J * 6.0Hz), -7.54 {m, 4H), 9,21 (s, IH). 1H-NMR (400 HHz, DMSO~de) δ 1.65 ihxt 6H) f 1.99-2.08 (br, 9H) , 3.83 &lt;s, 3H), 4.87 (s, XH), 5.55 (s, 1H), S.23 U, 2H), 6.32 id, 1H, J = 9.0Hz), 6.80 (s, lH)f 7.48 (s, 2H) , 7.73 &lt;d, 1H, J = 9.0 Hz) , 9.01 is, 1H). Example l 5 78

實施例i 5 7 9Example i 5 7 9

1H-NMR (400 MHz, DMSO*d«} δ X.66 {br, 6H) , 1.99-2.09 Cm , 9H) f 3.82 &lt;s, 3H), 4,86 U, IH) f 5.53 (s, 1H), 6.20 (s, 2H), 6,47 (d, 1H, J * 12Hz), 6.78 (sr IH), 6.90 {bsrlH), 7,34-7.50(m, 3H)/7,57 (d, IH, 12Hz), 8.95 {s# IH). 實施例1 一 5 8 0 0 (X 1H-KMR (400 mzf DMSO-d«) δ 1.67 (br, 6H), 1.99-2.09(m, 9H)f 4.88 (s, IH), 5.50 (s, IH), 6.20 (s, 2H) , 6,77 &lt;d, IH, σ « 30 Hz), 7.53-7.61&lt;m, 5H},7.87 (s, XH&gt;, 0.04 (sf IH)* 141666.doc 483- 201028381 實施例編號1H-NMR (400 MHz, DMSO*d«} δ X.66 {br, 6H) , 1.99-2.09 Cm , 9H) f 3.82 &lt;s, 3H), 4,86 U, IH) f 5.53 (s, 1H), 6.20 (s, 2H), 6,47 (d, 1H, J * 12Hz), 6.78 (sr IH), 6.90 {bsrlH), 7,34-7.50(m, 3H)/7,57 (d , IH, 12Hz), 8.95 {s# IH). Example 1 158 0 0 (X 1H-KMR (400 mzf DMSO-d«) δ 1.67 (br, 6H), 1.99-2.09 (m, 9H) f 4.88 (s, IH), 5.50 (s, IH), 6.20 (s, 2H) , 6,77 &lt;d, IH, σ « 30 Hz), 7.53-7.61&lt;m, 5H}, 7.87 (s , XH&gt;, 0.04 (sf IH)* 141666.doc 483- 201028381 Example Number

R 實施例1 一 5 8 1R Example 1 A 5 8 1

實施例1 一 5 8 2Example 1 a 5 8 2

物性資料_ 1H-NMR (400 MHz, DMSO-de) δ 1,67 (br, 6H), 1.99-2.09(m, 9H&gt;, 4.86 (s, XH), 5.49 {s, 1H), 6.17 (sf 2H) , €.69 (d, 1H, J » 24 Hz) r 7.53-7.71 (m, 5H), 7.81 (s, 1H), 8.94 &lt;s, 1H), MS (ESI) m/z « 535 &lt;M+H)+. LC/MS tR - 2.52 min. 實施例1 — 5 8 3Physical data _ 1H-NMR (400 MHz, DMSO-de) δ 1,67 (br, 6H), 1.99-2.09 (m, 9H&gt;, 4.86 (s, XH), 5.49 {s, 1H), 6.17 (sf 2H) , €.69 (d, 1H, J » 24 Hz) r 7.53-7.71 (m, 5H), 7.81 (s, 1H), 8.94 &lt;s, 1H), MS (ESI) m/z « 535 &lt;M+H)+. LC/MS tR - 2.52 min. Example 1 - 5 8 3

MS (£31) m/z » 517 (M+H&gt;+. LC/MS tR == 2.13 min. 賁施例1 — 5 8 4MS (£31) m/z » 517 (M+H&gt;+. LC/MS tR == 2.13 min. 贲Example 1 — 5 8 4

MS (£SX) m/z = 553 (M+H)+. LC/MS tR «= 1.63 min. 實施例1 — 5 8 5MS (£SX) m/z = 553 (M+H)+. LC/MS tR «= 1.63 min. Example 1 - 5 8 5

MS (ESI) m/z « 572 (M+H)+, LC/MS tR — 1.60 min. 實施例1 — 5 8 6MS (ESI) m/z « 572 (M+H)+, LC/MS tR - 1.60 min. Example 1 - 5 8 6

MS (ESI) m/z « 473 (M+H)+. LC/MS tR * 2.05 min. 實施例1 — 5 8 7MS (ESI) m/z « 473 (M+H) +. LC/MS tR * 2.05 min. Example 1 - 5 8 7

HS (£SX) m/z = 487 (Μ4·Η) + . LC/MS tR = 2.21 min. 實施例1 一 5 8 8HS (£SX) m/z = 487 (Μ4·Η) + . LC/MS tR = 2.21 min. Example 1 A 5 8 8

MeO 1H-NMR (400 MHz, DMSO-de) δ 1.65 〇&gt;r, 6H&gt; , 1.99-2 · 08 &lt;br , 9H) , [ 88 (sr 1H), 5.25 (s, 2H), 5.54 (sf XH) , 6.23 (sr 2H) , 6.35 &lt;d, 1H, J « 12Hz) , 6.92 (s, 1H) , 7.52(d, lHf or « 6Hz) f 7.58 (d, lHf J « 6.0Hz), 7·79 &lt;&lt;i, 1H, 9.06 &lt;s, 1H). 141666.doc 484- 201028381 實施例編號MeO 1H-NMR (400 MHz, DMSO-de) δ 1.65 〇&gt;r, 6H&gt;, 1.99-2 · 08 &lt;br , 9H) , [ 88 (sr 1H), 5.25 (s, 2H), 5.54 ( Sf XH) , 6.23 (sr 2H) , 6.35 &lt;d, 1H, J « 12Hz) , 6.92 (s, 1H) , 7.52(d, lHf or « 6Hz) f 7.58 (d, lHf J « 6.0Hz), 7·79 &lt;i, 1H, 9.06 &lt;s, 1H). 141666.doc 484- 201028381 Example number

R 實施例1 一 5 8 9R Example 1 A 5 8 9

物性資料_ 1H-NMR (400 MHs, DMSO-de) δ 1.66 ihr, 6H) , X . 99~2.08 (br , 9H) , 4.87 &lt;s, 1·Η&gt;, 5,23 &lt;sr 2H&gt;, (a, 1H) r 6.20 (sf 2H) , 6.47 (df 1H, J =12Hz&gt;, 6.90 {s, 1H), 6.95 {bs, 1H), 7.38-7.65 (m, 4H), 9.00 (sf IB). 1H-NMR (400 MHz, DMSO〇 δ 1.65 &lt;br, 6H) , 1.99*2*07 (br r 9H) #Physical data _ 1H-NMR (400 MHs, DMSO-de) δ 1.66 ihr, 6H) , X . 99~2.08 (br , 9H) , 4.87 &lt;s, 1·Η&gt;, 5,23 &lt;sr 2H&gt; , (a, 1H) r 6.20 (sf 2H) , 6.47 (df 1H, J =12Hz&gt;, 6.90 {s, 1H), 6.95 {bs, 1H), 7.38-7.65 (m, 4H), 9.00 (sf IB 1H-NMR (400 MHz, DMSO 〇 δ 1.65 &lt; br, 6H), 1.99*2*07 (br r 9H) #

實施例1 -5 9 0 4.83 (s, 1H&gt;, 5.49 (s, 1H), 6.16 &lt;s, 2H), 6.47 &lt;d, 1H, J = 12Hz&gt;, 6.47 (d, 1H, d « 12H2), 6.68 (a, 1H) r 6.84 (bs, 1H) , 7.25-7.41 (mf 3H) , 7*56 (d, 1H, d * 12Hz) , 8.84 (s, 1H),Example 1 -5 9 0 4.83 (s, 1H&gt;, 5.49 (s, 1H), 6.16 &lt;s, 2H), 6.47 &lt;d, 1H, J = 12Hz&gt;, 6.47 (d, 1H, d « 12H2 ), 6.68 (a, 1H) r 6.84 (bs, 1H) , 7.25-7.41 (mf 3H) , 7*56 (d, 1H, d * 12Hz) , 8.84 (s, 1H),

實施例i — 5 9 1Example i - 5 9 1

OMe MS (ESI) m/z = 503 (M+H)+. I.C/MS tR * 1.95 min. 0 MS (KSI&gt; m/z - 473 LC/MS tR » 2.09 min. 實施例1 一 5 9 2 J 人OMe MS (ESI) m/z = 503 (M+H) +. IC/MS tR * 1.95 min. 0 MS (KSI&gt; m/z - 473 LC/MS tR » 2.09 min. Example 1 A 5 9 2 J people

〇 MS (ESI) m/z « 487 (M+H)4.〇 MS (ESI) m/z « 487 (M+H)4.

141666.doc 485- 201028381141666.doc 485- 201028381

MS &lt;£S1) m/z * 559 (M+H)+. LC/HS tR » 2.18 min. 實施例1 — 5 9 8MS &lt; £S1) m/z * 559 (M+H) +. LC/HS tR » 2.18 min. Example 1 - 5 9 8

實施例1 — 5 9 9Example 1 - 5 9 9

MS &lt;£SX) m/z = 443 (M+H)+. LC/MS tR = 2.01 min. 實施例編號 R 物性資料 0 MS (ESI) m/x « 501 &lt;M+H)+. ΗζνΛ^ΧΧ LC/HS tn - 2.23 min. 實施例+1 — 5 9 5 Me 丫J Me 本 Q MS (ESI) m/st = 541 (M+H) + .MS &lt; £SX) m/z = 443 (M+H) +. LC/MS tR = 2.01 min. Example No. R Physical data 0 MS (ESI) m/x « 501 &lt;M+H)+. ΗζνΛ^ΧΧ LC/HS tn - 2.23 min. Example +1 — 5 9 5 Me 丫J Me This Q MS (ESI) m/st = 541 (M+H) + .

MeO 實施例1 — 6 0 0 1H-KMR (400 MHz, DMSO-d6) δ 1.66 (br, 6H) , 1.99-2.08 (br, 9H) , 4.87 (s, 1H), 5,23 (s, 2H), 5.51 (s, 1H) , 6.20 (s, 2H&gt; , 6.43 (d, 1H, J * 12Hz) , 6.90 {sf 1H) , 7.38-7.65 (m, 3H), 9.00 &lt;s, 1H), 9.30 (s, 1H). 486- 141666.doc 201028381MeO Example 1 - 6 0 0 1H-KMR (400 MHz, DMSO-d6) δ 1.66 (br, 6H), 1.99-2.08 (br, 9H), 4.87 (s, 1H), 5,23 (s, 2H ), 5.51 (s, 1H), 6.20 (s, 2H&gt;, 6.43 (d, 1H, J * 12Hz), 6.90 {sf 1H), 7.38-7.65 (m, 3H), 9.00 &lt;s, 1H), 9.30 (s, 1H). 486- 141666.doc 201028381

實施例編號Example number

R 實施例1 一 6 0 1R Example 1 A 6 0 1

實施例1 — 6 0 2Example 1 - 6 0 2

物性資料_1H-NMR &lt;400 MHz, DMSO-de) δ 1.67 (br, 6H) , 1.99-2.08 , 3.23-3.24 &lt;mr 4H}, 3.43 (s, 3H&gt;, 4.76 (s, 1H) f 4*87 [st in), 5·23 (s, 2B), 5.51 {s, 1H&gt;r 6.19 (s, 2H) , 6.54 (d, 1H, σ = 9.0 H2) , 6.89 (s, im r 7.38 (d, lHr d « 9.0 Hz) f 7.61-7.64 2H&gt;, 8.0S (ba, XH), 9.OX ist 1H), 1H-NMR (400 MHz, DMSO-de) δ 1.64 (hr, 6H) , 1.99-2.05 (br; 9H) , 2.30 &lt;m, 2.T2 &lt;m, 210, 3.10 (m, 2H) , 3.60 (ία, 2B) , 3.43 &lt;s, 3H), 4.66 &lt;s, 1H), 4.78 {s, XH), 5.17 (s, 2H), 5*44 &lt;s, 1H)r 6.06 (&amp;t 2H&gt;, 6.81 {af 1H) # €.99 (dt 1H, J =6,0 Hz), 7,30 (d, 1H, d = 6,0 Ha) ,7,81 (bs, IS), 8.62 (s, 1H). 實施例1 6 0 3Physical property data_1H-NMR &lt;400 MHz, DMSO-de) δ 1.67 (br, 6H), 1.99-2.08, 3.23-3.24 &lt;mr 4H}, 3.43 (s, 3H&gt;, 4.76 (s, 1H) f 4*87 [st in), 5·23 (s, 2B), 5.51 {s, 1H&gt;r 6.19 (s, 2H) , 6.54 (d, 1H, σ = 9.0 H2) , 6.89 (s, im r 7.38 (d, lHr d « 9.0 Hz) f 7.61-7.64 2H&gt;, 8.0S (ba, XH), 9.OX ist 1H), 1H-NMR (400 MHz, DMSO-de) δ 1.64 (hr, 6H), 1.99-2.05 (br; 9H) , 2.30 &lt;m, 2.T2 &lt;m, 210, 3.10 (m, 2H) , 3.60 (ία, 2B) , 3.43 &lt;s, 3H), 4.66 &lt;s, 1H), 4.78 {s, XH), 5.17 (s, 2H), 5*44 &lt;s, 1H)r 6.06 (&amp;t 2H&gt;, 6.81 {af 1H) # €.99 (dt 1H, J = 6,0 Hz), 7,30 (d, 1H, d = 6,0 Ha) , 7,81 (bs, IS), 8.62 (s, 1H). Example 1 6 0 3

1H-NMR (400 MHz, DHSO-d^) δ 1.62 (br, 6H&gt; , 1.98*2.05 {hr, 9H) , 3.57 (s, 2H&gt;, 4·96 &lt;s, 1H&gt;, 5.51 (s, 1H), 6.33 (s, 2H), 6,60 &lt;d, 1H, J =12.0 Hz) , 7.16 {sf 1H), 7.44-7.47 (hi, 2H) , 7.62-7.70 &lt;xn. 3H), 9.40 Is, 1H). 實施例1 一 6 04 F3crf0 1H-N1 &lt;br, 1H), 6.62 XH), 1H). 4R (400 MHz, DHSO-d6) δ 1.63 6H}, S.OWbr, 9H), 4.96 U, 5.51 {s, 1H), €.34 (s, 2H), (dr 1H, J* 12.0 Hz), 7.17 (s, 7.23-7.71 (m, 5H), 9.40 (s, iB-m (brr ^EK (400 MHz, DMSO-de) δ 1.67 6H&gt;, 2.08{br, 9H&gt;, 3.16 (s, 3H}, 3,39 4H}, 4*95 &lt;3, lHi, 5.51 (s, 1H), 6.33 (s, 2H&gt;, 6.61 (d, XH, XZUz) r 7.48 (d, XH, J -12.0 Hz) , 7.51 (s, 1H) , 7.59 (df 1H, J = 6.0 Hz&gt; , 7 ·Τ1 1H, J : 6.0 Hz) f 9.30 (sf 1H). 實施例1 — 6 0 51H-NMR (400 MHz, DHSO-d^) δ 1.62 (br, 6H&gt;, 1.98*2.05 {hr, 9H) , 3.57 (s, 2H&gt;, 4·96 &lt;s, 1H&gt;, 5.51 (s, 1H), 6.33 (s, 2H), 6,60 &lt;d, 1H, J = 12.0 Hz), 7.16 {sf 1H), 7.44-7.47 (hi, 2H), 7.62-7.70 &lt;xn. 3H), 9.40 Is, 1H). Example 1 A 6 04 F3crf0 1H-N1 &lt;br, 1H), 6.62 XH), 1H). 4R (400 MHz, DHSO-d6) δ 1.63 6H}, S.OWbr, 9H) , 4.96 U, 5.51 {s, 1H), €.34 (s, 2H), (dr 1H, J* 12.0 Hz), 7.17 (s, 7.23-7.71 (m, 5H), 9.40 (s, iB-m (brr ^EK (400 MHz, DMSO-de) δ 1.67 6H&gt;, 2.08{br, 9H&gt;, 3.16 (s, 3H}, 3,39 4H}, 4*95 &lt;3, lHi, 5.51 (s, 1H), 6.33 (s, 2H&gt;, 6.61 (d, XH, XZUz) r 7.48 (d, XH, J -12.0 Hz), 7.51 (s, 1H), 7.59 (df 1H, J = 6.0 Hz), 7 ·Τ1 1H, J : 6.0 Hz) f 9.30 (sf 1H). Example 1 - 6 0 5

141666.doc 487- 201028381 實施例編號 R 物性資料141666.doc 487- 201028381 Example number R Physical data

MS &lt;£SX) m/z = 483 {H+H)+. LC/MS tR = 2*01 min- 實施例I — 606MS &lt; £SX) m/z = 483 {H+H)+. LC/MS tR = 2*01 min - Example I - 606

實施例1 — 6 0 8Example 1 - 6 0 8

Me MS (ESI) m/z * 516 (M+H)+. LC/MS fcR =» 1.61 min. 0 1H-NMR (400 MHz, DMSO«d6) δ 1.67 (br, 6H) , 2.08 (br, 9H) , 3-27 (s, 3H&gt;, 3,36 &lt;m, 4H&gt;, 4.87 U, 1H&gt;, 5.50 (s, 1H), 6.20 {s, 2H), 6.47 實施例1 - Cl (d, 1H, J * 9 Hz&gt;, 7.36 (s, 1H&gt;, 6 0 9 L 7.45 (d, 1H, J * 6 Hz), 7.54 (d, Me^C ) 1H, J « 12 Hz), 7.67 (d, 1H, J = 6 Hz) , 8*12 (m, 1H) , 9-02 (s, 1H). 9,71 &lt;s, 1H).Me MS (ESI) m/z * 516 (M+H)+. LC/MS fcR =» 1.61 min. 0 1H-NMR (400 MHz, DMSO«d6) δ 1.67 (br, 6H) , 2.08 (br, 9H), 3-27 (s, 3H&gt;, 3,36 &lt;m, 4H&gt;, 4.87 U, 1H&gt;, 5.50 (s, 1H), 6.20 {s, 2H), 6.47 Example 1 - Cl (d , 1H, J * 9 Hz&gt;, 7.36 (s, 1H&gt;, 6 0 9 L 7.45 (d, 1H, J * 6 Hz), 7.54 (d, Me^C ) 1H, J « 12 Hz), 7.67 ( d, 1H, J = 6 Hz) , 8*12 (m, 1H) , 9-02 (s, 1H). 9,71 &lt;s, 1H).

實施例1 — 6 10Example 1 - 6 10

1H-NMR (400 MHz, DMSO-de) 61,68 (br, 6H) , 2.09 {br, 9H) , 2.96 (sr 3H&gt;, 3.27 &lt;s, 3H), 3.40 (m, 4H), 4.$0 (s, XH), 5.50 (s, 1H), 6.23 (s, 2H) , 6,48 (d, 1H, J = 12 Hz) f 7.12 (s, 1H) # 7.49 (d, !Hr J *： 6 Hz) , 7.75 (ά, 1H, J « 12 Hz) , 7.95 (d, 1H, J ~ 6 Hz), 8.12 (mf 1H), 9.08 &lt;s, 1H), 141666.doc 488· 201028381 實施例編號 R 物性資料 實施例1 — 6 111H-NMR (400 MHz, DMSO-de) 61,68 (br, 6H), 2.09 {br, 9H), 2.96 (sr 3H&gt;, 3.27 &lt;s, 3H), 3.40 (m, 4H), 4. $0 (s, XH), 5.50 (s, 1H), 6.23 (s, 2H) , 6,48 (d, 1H, J = 12 Hz) f 7.12 (s, 1H) # 7.49 (d, !Hr J * : 6 Hz) , 7.75 (ά, 1H, J « 12 Hz) , 7.95 (d, 1H, J ~ 6 Hz), 8.12 (mf 1H), 9.08 &lt;s, 1H), 141666.doc 488· 201028381 Example No. R Physical Data Example 1 - 6 11

1H-HMR (400 MHz, 0MSO-d6) δ 1.66 &lt;br, 6H&gt; , 1.76 (df 3HrJ « 3.0 Hz) r 1.99-2.09 (hr, 9H&gt; , 4.90 &lt;s, 1H&gt; , 5.31 (d, 1H, J * 3-0 Hx) , 5.53 (s, iH) , 6*24 2H&gt; / 6.50 &lt;dL, 1H, J * 12.0 Hz) , 6.97 (s, 1H) , 7.00 (bs, IH), 7,44 (d, lUt J«6.0 Hz) r 7.50 {bs, IH) , 7.54 (ά, IH, J= X2.0 Hz), 7.65 (d, IH, J * 6*0 Hz) , 9.11 &lt;s, IH)-1H-HMR (400 MHz, 0MSO-d6) δ 1.66 &lt;br, 6H&gt; , 1.76 (df 3HrJ « 3.0 Hz) r 1.99-2.09 (hr, 9H&gt; , 4.90 &lt;s, 1H&gt; , 5.31 (d, 1H, J * 3-0 Hx) , 5.53 (s, iH) , 6*24 2H&gt; / 6.50 &lt;dL, 1H, J * 12.0 Hz) , 6.97 (s, 1H) , 7.00 (bs, IH), 7,44 (d, lUt J«6.0 Hz) r 7.50 {bs, IH) , 7.54 (ά, IH, J= X2.0 Hz), 7.65 (d, IH, J * 6*0 Hz) , 9.11 &lt;;s, IH)-

0 1H-NMR (400 MHz, DMSO-d«) δ 1.67 (hrf 6H),2.08 {br, 9H) , 3.05-3.11 Cm, IH), 3.17-3.55 (m, 4B&gt;, 4.95 實施例1 - HOf (sf IH), 5.51 (s, IH), 6.31 is, 6 12 J H J 2H) ,6.67 {d, IH, J * 12 Hz) , 7.49 HO〆 f3co’ (ά, IH^ J » 12 Hz) , 7.52 {s, IH), 7.60 &lt;df IH, J = 6 Hz), 7.70 (d, IH, J * 6 Hz), 9.29 (Bf IH). 實施例 6 130 1H-NMR (400 MHz, DMSO-d«) δ 1.67 (hrf 6H), 2.08 {br, 9H), 3.05-3.11 Cm, IH), 3.17-3.55 (m, 4B&gt;, 4.95 Example 1 - HOf (sf IH), 5.51 (s, IH), 6.31 is, 6 12 JHJ 2H) , 6.67 {d, IH, J * 12 Hz) , 7.49 HO〆f3co' (ά, IH^ J » 12 Hz) , 7.52 {s, IH), 7.60 &lt;df IH, J = 6 Hz), 7.70 (d, IH, J * 6 Hz), 9.29 (Bf IH). Example 6 13

MeO 1H-NMR &lt;400 MHz, DHSO-dg) δ 1.65 &lt;br, €H) t 1.93-2,07 {br, 9H) , 3.39 (s, 3H) , 4.09 (d, 2H, «7*6.0 Hz), 4.82 (s, IH), 5.18 (s, 2H), 5*48 (sr IH), 6.13 &lt;s, 2H), 6.17-6.22 {m, IH) , 6.74 &lt;d, IH, 12.0 Hz), 6.87 &lt;s, IH) , 7.32 (d, IH, J * 6.0 Hz) , 7.44 (df IH, 6.0 Hz) , 8.79 (s, IH).MeO 1H-NMR &lt;400 MHz, DHSO-dg) δ 1.65 &lt;br, €H) t 1.93-2,07 {br, 9H) , 3.39 (s, 3H) , 4.09 (d, 2H, «7* 6.0 Hz), 4.82 (s, IH), 5.18 (s, 2H), 5*48 (sr IH), 6.13 &lt;s, 2H), 6.17-6.22 {m, IH) , 6.74 &lt;d, IH, 12.0 Hz), 6.87 &lt;s, IH), 7.32 (d, IH, J * 6.0 Hz), 7.44 (df IH, 6.0 Hz), 8.79 (s, IH).

實施例1 — 6 14Example 1 - 6 14

1H-NMR &lt;400 MHz, DHSO-d*) δ 1.64 (br, 6H), 1.93-2,07 (br r 9H), 2.28 &lt;sf 6H), 3-17 (m, 2H) , 3.77 (S, 3H), 4.82 (s, IH), 5.49 (s, 1H&gt;, 6.15 {sf 2H&gt; r 6.05-6.25 2H), 6.17-6.22 (mf IH), €.71 (d, IH, J = 12 Hz) r 6.76 (s, IH) , 7.32 {s, IH), 8.78 (s, IH). 141666.doc 489- 201028381 實施例編號1H-NMR &lt;400 MHz, DHSO-d*) δ 1.64 (br, 6H), 1.93-2, 07 (br r 9H), 2.28 &lt;sf 6H), 3-17 (m, 2H) , 3.77 ( S, 3H), 4.82 (s, IH), 5.49 (s, 1H&gt;, 6.15 {sf 2H&gt; r 6.05-6.25 2H), 6.17-6.22 (mf IH), €.71 (d, IH, J = 12 Hz) r 6.76 (s, IH) , 7.32 {s, IH), 8.78 (s, IH). 141666.doc 489- 201028381 Example Number

R 實施例1 — 6 15R Example 1 - 6 15

物性資料_ 1H-NMR (400 MHz, DMSO-d6) δ 1.67 6Η&gt; , 2-08 (br, 9Η&gt;, 3-26 (s, 3Η), 3.40 (mf 4Η&gt;, 3.40 (sr 3Η&gt;, 4.02 {sf 2Η)f 4.88 {sf 1Η), 5.50 (s, 1H) , 6,21 (s, 2H) , 6.46 (df 1H, J = 12 Hz) , 7.30 (s, 1H) , 7.46-7.50 (mt 2H), 7.77 (d, 1H, J « 6 Hz), 8.13 (hsf 1H&gt; , 9.05 (s, 1H) . 9.59 (s, 1H)Physical data _ 1H-NMR (400 MHz, DMSO-d6) δ 1.67 6Η&gt;, 2-08 (br, 9Η&gt;, 3-26 (s, 3Η), 3.40 (mf 4Η&gt;, 3.40 (sr 3Η&gt;, 4.02) {sf 2Η)f 4.88 {sf 1Η), 5.50 (s, 1H) , 6,21 (s, 2H) , 6.46 (df 1H, J = 12 Hz) , 7.30 (s, 1H) , 7.46-7.50 (mt 2H), 7.77 (d, 1H, J « 6 Hz), 8.13 (hsf 1H&gt; , 9.05 (s, 1H) . 9.59 (s, 1H)

實施例1 一 6 16 XH-NMR (400 MHz, DMSO»d6) 6 1.67 (for, 6H) , 1.76 (df 3H, J * 3 Hz), 2.09 (br , 9H) , 3.27 &lt;s, 3H) , 3.40 (m, 4H) , 4.90 (s, 1H&gt; , 5.32 (d, XH, J * 3 Hz&gt; , 5.53 (s, 1H) , 6·24 (s, 2H) # 6.55 (d, 1H, J = 12 Hz) , 6.96 (s, 1H) , 7.43 (d, 1H, J» 6 Hz) , 7.54 (d, 1H, J = 12 Hz) f 7.67 [df 1H, J » 6 Hz&gt; , 8.15 &lt;bs, 1H&gt; , 9.12 (s, 1H). 實施例1 — MeO^^0^· 1H-MMR (400 MHz, DMSO-de) δ 1.59 &lt;br, 6H&gt;, 2.00 (br, 9H) , 3.27 (&amp;r 3H&gt;, 3·40 &lt;m, 4H), 4,77 (s, 1H&gt;, 6 17 5.33 {s, 1H), 6.10 (s, 2H), 6.93 (d, IH, J = 6 Hz) , 7.42 (d, 1H, J « 6 Hz&gt; , 7.52 (s, 1H) , 8.62 (a, 1H&gt; . 1H-NME &lt;400 MHz, DHSO-d6) δ 1.66 (br, 6H}, 2.07(br, 9H), 3.27 (s, 3H), 3.40 (m, 4H), 4.92 &lt;s, 1H&gt;, 5.51 &lt;s, 1H), 6.28 is, 2H), 6,53 (d, 1H, J « 12 Hz)y 6.96-7.1 (m, 1H), 7.16 (s, 1H), 7.51 (m, 2H), 7.75 &lt;mf 1H} , 8.17 (bs, 1H&gt; , 9.22Example 1 - 6 16 XH-NMR (400 MHz, DMSO»d6) 6 1.67 (for, 6H), 1.76 (df 3H, J * 3 Hz), 2.09 (br, 9H), 3.27 &lt;s, 3H) , 3.40 (m, 4H) , 4.90 (s, 1H&gt; , 5.32 (d, XH, J * 3 Hz&gt; , 5.53 (s, 1H) , 6·24 (s, 2H) # 6.55 (d, 1H, J = 12 Hz) , 6.96 (s, 1H) , 7.43 (d, 1H, J» 6 Hz) , 7.54 (d, 1H, J = 12 Hz) f 7.67 [df 1H, J » 6 Hz&gt; , 8.15 &lt; Bs, 1H&gt;, 9.12 (s, 1H). Example 1 - MeO^^0^· 1H-MMR (400 MHz, DMSO-de) δ 1.59 &lt;br, 6H&gt;, 2.00 (br, 9H), 3.27 (&amp;r 3H&gt;, 3·40 &lt;m, 4H), 4,77 (s, 1H&gt;, 6 17 5.33 {s, 1H), 6.10 (s, 2H), 6.93 (d, IH, J = 6 Hz) , 7.42 (d, 1H, J « 6 Hz&gt; , 7.52 (s, 1H) , 8.62 (a, 1H&gt; . 1H-NME &lt;400 MHz, DHSO-d6) δ 1.66 (br, 6H}, 2.07(br, 9H), 3.27 (s, 3H), 3.40 (m, 4H), 4.92 &lt;s, 1H&gt;, 5.51 &lt;s, 1H), 6.28 is, 2H), 6,53 (d, 1H , J « 12 Hz)y 6.96-7.1 (m, 1H), 7.16 (s, 1H), 7.51 (m, 2H), 7.75 &lt;mf 1H} , 8.17 (bs, 1H&gt; , 9.22

MeOMeO

490- 實施例1 6 18 (s, 1H). 141666.doc 201028381490- Example 1 6 18 (s, 1H). 141666.doc 201028381

實施例編號 實施例1 - 6 19 實施例1 — 6 2 0 實施例1 — 6 2 1 實施例1 — 6 2 2 實施例1 -6 2 3 實施例1 -6 2 4EXAMPLES Example 1 - 6 19 Example 1 - 6 2 0 Example 1 - 6 2 1 Example 1 - 6 2 2 Example 1 - 6 2 3 Example 1 -6 2 4

KK

物性資料_ 1H-HMR {400 MHzr OMSO-de) δ 1.58 (br, 6Η) , 1.71-1.80 (m, 4Η) f 2.00 (bxf 9H&gt; , 2.23 (»i, 1H) , 2.72 (m, 2H), 3.40 {m, 2H), 4,81 (s, 1H), 5.38 (s, 1H), 6.15 (s, 2H&gt;, 6.80 i&amp;f 1H), 7.09 (d, 1H, J = 6 Hz), 7,31 (s, 1H) ; 747 (d, 1H, J*6 Hz), 7,68 (s, 1H), 8,79 (s, 1H). MS (ESI) ift/z « 542 (H*fH) + . LC/MS tR s 1.92 min.Physical data _ 1H-HMR {400 MHzr OMSO-de) δ 1.58 (br, 6Η) , 1.71-1.80 (m, 4Η) f 2.00 (bxf 9H&gt; , 2.23 (»i, 1H) , 2.72 (m, 2H) , 3.40 {m, 2H), 4,81 (s, 1H), 5.38 (s, 1H), 6.15 (s, 2H&gt;, 6.80 i&amp;f 1H), 7.09 (d, 1H, J = 6 Hz), 7,31 (s, 1H) ; 747 (d, 1H, J*6 Hz), 7,68 (s, 1H), 8,79 (s, 1H). MS (ESI) ift/z « 542 (H *fH) + . LC/MS tR s 1.92 min.

MS (ESI) m/z = 528 (H-fH) + . LC/MS tR * 1*86 min.MS (ESI) m/z = 528 (H-fH) + . LC/MS tR * 1*86 min.

MS (ESI) m/z « 572 (M+H)+. LC/MS tR = 1.83 roin*MS (ESI) m/z « 572 (M+H)+. LC/MS tR = 1.83 roin*

MS &lt;£SI) m/z « 558 (H+H&gt;+. LC/MS tR * 1,70 min*MS &lt;£SI) m/z « 558 (H+H&gt;+. LC/MS tR * 1,70 min*

141666.doc 491 - 201028381 實施例編號141666.doc 491 - 201028381 Example number

R 實施例1 — 6 2 5R Example 1 - 6 2 5

實施例1 - 6 2 6Example 1 - 6 2 6

實施例1 - 6 2 7 ΟExample 1 - 6 2 7 Ο

實施例1 - 6 2 8Example 1 - 6 2 8

實施例1 — 6 2 9Example 1 - 6 2 9

實施例1 - 6 3 0 N —Example 1 - 6 3 0 N —

物性資料_ 1H-HHR (400 MHz, DMSO-d6) δ 1.65 (hr, 6H) , 1.70 (d, 3H, J = 3 Hz) f 2.07 (br, 9H) , 4.10 (s, 2H) , 4.84 {s, 2H), 5.25 (d, 1H, J « 3 Hz), 5.48 &lt;s, XH), 6.16 &lt;3, 2H&gt;, 6.19-6.25 《m, 1H) , 6-67 (d, 1H, J « 12 Hz) , 6.98 (s, 1H) , 7.35-7.50 &lt;m, 2H&gt;, 8.89 (s, 1H). XH-NMR (400 mzf DHSO-d«) δ 1 · 67 (s, 6H), 2.08 (S/ 9H), 4.87 (s# 1H)r 5.49 (s, 1H), 6.17 (s, 2H), 6.43 (d, 1H, J * 15.7 Hz) , 6,96 (s, XH) , 7.34 (d, lHr J = 15.7 Hz), 7.39-7.48 (m, 3H) # 7.58 (d, 2H, J -8.6 Hz), 8.99 (s, 1H). 1H-NMR (400 MHz, DHSO-de) δ 1.61 &lt;s, 6H&gt;, 2.01-2.07 (m, 9H), 4.27 (s, 2H), 4.87 (s, 1H), 5.51 (s, 110, 6.18 (s, 2H&gt; , 7,51 &lt;d, 1H, J -8.6Hz), 7,64-7.57 (m# 2H) , 8.24 {st 1H), 9.10 (s, 1H). 1E-NMR (400 MHz, DMS0-d6) δ 1.63 (a, 6H&gt;, 2.01-2.09 (mf 9H&gt; , 4.36 &lt;s, 1H), 5.50 {S, 1H), 6.14 (s, 2H) , 7.69-7.59 (m, 6H), 8.54 (d, 2H, J - 5.6 Hz)f 9.00 (s, 1H). 1H-NMR (400 MHz, DHSO-d«) δ 1.69 (s, 6H), 2.10 (s, 9H), 4,97 (s, 1H), 5.55 &lt;s, 1H), 6.34 (s, 2H) r 7.53 2Hr J * 5,1 Hz) , 8.25 (sf 2H), 9,23 (s, 1H), 1H-KHR (400 MHz, DHSO-d«) δ 1.66 &lt;7H, s), 2-04-2.07 (9H, m), 2.41 &lt;4H, s)f 2.70-2.74 (2H, m) f 4.22 (2H, t, J = 6.4 Hz) , 4.80 (1H, s), 5.44 (1H, s) r 6.08 (2H, s) , 7.43 &lt;4H, dd# J » 22.4, 8.0 Hz), 7.75 (1H, s), 8.06 &lt;1H, s&gt;, 8,71 &lt;1H, s). 141666.doc 492· 201028381Physical data _ 1H-HHR (400 MHz, DMSO-d6) δ 1.65 (hr, 6H) , 1.70 (d, 3H, J = 3 Hz) f 2.07 (br, 9H) , 4.10 (s, 2H) , 4.84 { s, 2H), 5.25 (d, 1H, J « 3 Hz), 5.48 &lt;s, XH), 6.16 &lt;3, 2H&gt;, 6.19-6.25 "m, 1H), 6-67 (d, 1H, J « 12 Hz) , 6.98 (s, 1H) , 7.35-7.50 &lt;m, 2H&gt;, 8.89 (s, 1H). XH-NMR (400 mzf DHSO-d«) δ 1 · 67 (s, 6H) , 2.08 (S/ 9H), 4.87 (s# 1H)r 5.49 (s, 1H), 6.17 (s, 2H), 6.43 (d, 1H, J * 15.7 Hz) , 6,96 (s, XH) , 7.34 (d, lHr J = 15.7 Hz), 7.39-7.48 (m, 3H) # 7.58 (d, 2H, J -8.6 Hz), 8.99 (s, 1H). 1H-NMR (400 MHz, DHSO-de) δ 1.61 &lt;s, 6H&gt;, 2.01-2.07 (m, 9H), 4.27 (s, 2H), 4.87 (s, 1H), 5.51 (s, 110, 6.18 (s, 2H&gt;, 7,51 &lt; d, 1H, J - 8.6 Hz), 7, 64-7.57 (m# 2H) , 8.24 {st 1H), 9.10 (s, 1H). 1E-NMR (400 MHz, DMS0-d6) δ 1.63 (a, 6H&gt;, 2.01-2.09 (mf 9H&gt;, 4.36 &lt;s, 1H), 5.50 {S, 1H), 6.14 (s, 2H), 7.69-7.59 (m, 6H), 8.54 (d, 2H, J - 5.6 Hz)f 9.00 (s, 1H). 1H-NMR (400 MHz, DHSO-d«) δ 1.69 (s, 6H), 2.10 (s, 9H), 4,97 (s, 1H), 5.55 &lt; s, 1H), 6.34 (s, 2H) r 7.53 2Hr J * 5,1 Hz) , 8.25 (sf 2H), 9,23 (s, 1H), 1H-KHR (400 MHz, DHSO-d«) δ 1.66 &lt;7H, s), 2 -04-2.07 (9H, m), 2.41 &lt;4H, s)f 2.70-2.74 (2H, m) f 4.22 (2H, t, J = 6.4 Hz) , 4.80 (1H, s), 5.44 (1H, s) r 6.08 (2H, s) , 7.43 &lt;4H, dd# J » 22.4, 8.0 Hz), 7.75 (1H, s), 8.06 &lt;1H, s&gt;, 8,71 &lt;1H, s). 141666.doc 492· 201028381

實施例編號 R 物性資料 1H-N MR (400 她z, DMSO*-d6) δ 1.64 ΠΗ, s) , 2.03-2,07 (9Hf in) , 4.80 實施例1 — {1H, B) f S.44 (1H, s), 6*08 (2H, 6 3 1 IQ S) f 7*45 (5H, s), 7.81 (IK, s), 8.06 (1H, s) , 8.69 (1H, s) , 12,85 UH, s).Example No. R Physical data 1H-N MR (400 herz, DMSO*-d6) δ 1.64 ΠΗ, s) , 2.03-2, 07 (9Hf in) , 4.80 Example 1 - {1H, B) f S. 44 (1H, s), 6*08 (2H, 6 3 1 IQ S) f 7*45 (5H, s), 7.81 (IK, s), 8.06 (1H, s) , 8.69 (1H, s) , 12,85 UH, s).

m-mm. &lt;400 mhx, 〇Mso-d6) δ 1.65 《6H, s&gt;, 2.05-2.08 &lt;9H, m) , 4.83 &lt;1H, s), 4.88 (2H, s), 5.47 (lHf s), 6.13 (2Hf s) f 7,52 (2Uf df J =» 8.4 Hz) , 7,63 (2H, df 8.4 Hat), 8.32 (1H, s&gt;, 8.7? (1H, s&gt;, 8.83 (lHf b). 實施例i — 6 3 3M-mm. &lt;400 mhx, 〇Mso-d6) δ 1.65 "6H, s&gt;, 2.05-2.08 &lt;9H, m) , 4.83 &lt;1H, s), 4.88 (2H, s), 5.47 (lHf s), 6.13 (2Hf s) f 7,52 (2Uf df J =» 8.4 Hz) , 7,63 (2H, df 8.4 Hat), 8.32 (1H, s&gt;, 8.7? (1H, s&gt;, 8.83 ( lHf b). Example i - 6 3 3

實施例1 — 6 34Example 1 - 6 34

實施例1 一 6 3 5Example 1 A 6 3 5

1H-HMR (400 MHz, OMSO-de) δ 1.65 《6H, s) , 2·05-2*11 (9U, m) f 4.83 (1H, s)f 5.47 (XHf s&gt;, 6.X3 (1H, s&gt; , 7·52 d, 0Γ = 8·4 Hz&gt; , 7,62 (1H, d, J « 8.4 Hz) t 8.30 (1H, s), 8.73 (1H； B), 8.82 (lg, s)&gt; IH-tW依 &lt;400 MH»# DHSO-ds) δ 1.18 &lt;3H, t, J = 6.8 Hz) , 1.65 &lt;7H, s&gt; , 2,05-2.07 &lt;9H, m), 2,73 (3H, s), 2.89 (2H, s) , 4,06 (2H, tr J « 6.8 Hz), 4,83 (1H, b) f 5,47 (1H, s), 6.13 (2Hr s) , 7,52 (2H, d, J = 8.4 Hz) , 7.62 (2Hf d, J « 8.4 Hz) , 7.94 &lt;1Η, s)r 8.33 (2Hf s), 8.74 (2Hr s), Θ.83 (2H, s). XH-NHR (400 MH%, DHSO-d6&gt; δ 1.66 &lt;€H, a) r 2.08 (9H, s), 3.55 (3H, S) r 4.84 (1H, s) , 5,47 (1H, s&gt; ,6.14 (2H, s), 7,57 (4Hf dd, J « 29.€, 8.4 Hz) , 8.38 (18, s) , 8.63 (1H, s), 8.83 &lt;lHf s). 141666.doc 493 - 201028381 實施例編號1H-HMR (400 MHz, OMSO-de) δ 1.65 "6H, s) , 2·05-2*11 (9U, m) f 4.83 (1H, s)f 5.47 (XHf s&gt;, 6.X3 (1H , s&gt; , 7·52 d, 0Γ = 8·4 Hz&gt; , 7,62 (1H, d, J « 8.4 Hz) t 8.30 (1H, s), 8.73 (1H; B), 8.82 (lg, s )&gt;IH-tW&lt;400MH»# DHSO-ds) δ 1.18 &lt;3H, t, J = 6.8 Hz) , 1.65 &lt;7H, s&gt; , 2,05-2.07 &lt;9H, m) , 2,73 (3H, s), 2.89 (2H, s) , 4,06 (2H, tr J « 6.8 Hz), 4,83 (1H, b) f 5,47 (1H, s), 6.13 ( 2Hr s) , 7,52 (2H, d, J = 8.4 Hz) , 7.62 (2Hf d, J « 8.4 Hz) , 7.94 &lt;1Η, s)r 8.33 (2Hf s), 8.74 (2Hr s), Θ .83 (2H, s). XH-NHR (400 MH%, DHSO-d6&gt; δ 1.66 &lt;€H, a) r 2.08 (9H, s), 3.55 (3H, S) r 4.84 (1H, s) , 5,47 (1H, s&gt; , 6.14 (2H, s), 7,57 (4Hf dd, J « 29.€, 8.4 Hz) , 8.38 (18, s) , 8.63 (1H, s), 8.83 &lt;;lHf s). 141666.doc 493 - 201028381 Example Number

R 實施例1 — 6 3 6R Example 1 - 6 3 6

實施例1 一 6 3 7Example 1 A 6 3 7

實施例1 一 6 3 8Example 1 A 6 3 8

實施例1 — 6 3 9Example 1 - 6 3 9

實施例1 — 6 4 0Example 1 - 6 4 0

物性資料_ 1H-KMR (400 HH27 DMSO-de) δ 1.64 {SHf s&gt;, 2.03-2.08 &lt;9H, m&gt;, 3.82 &lt;3H, s), 4.86 (1H, s), 5-49 (XH, s) , 6,17 (2H, 5) , 6.30 (1H, s&gt; , 7.36 (2H, d, J^e.OHz), 7.42 (1H, s) , 7.62 (2H, d, J* 8.0 Hz) , 8.95 (1H, S) ·_ 1H-NMR (400 HBzt DMSO-d6) δ 1.23-1.43 &lt;4H, m) f 1.55-1.68 &lt;6H, m) , 2.03-2.07 (9Bf m), 3.70-3.75 (XH, m) , 3.91-3.95 (XH, m) t 4.28 &lt;2H# 3), 4.53 (1H, s), 4.80 (1H, S), 5.44 (XH, s), 6.08 (2H, s&gt;, 7.43 (4H, dd, J = 21.2, 8.0 Hz), 7.78 &lt;1H, s&gt;, 8.03 (1H, s), 8.72 ilUf S). XH-NMR (400 MHz, DMSO-d6) δ 1.66 (6Hf s), 2.05-2.08 (9U, m), 4.76 {2Ht a), 4.81 &lt;1H, s), 5.45 (1H, S&gt;, 6.10 (1H, s)r 7.26 (1H, s}, 7.4X-7.49 (5H, m&gt;, 7.79 (1H, s), 8*02 (1H, s), 8.73 (XH, s). 1H-NMR (400 MHs, DMSO-d6) δ 1.66 &lt;7H, s), 2,08-2.08 (9H, m&gt; , 3.74-3.77 (2H, m) , 4.14 (2Bt J « 5.4 Hz) , 4.81 (1H, s) , 4.92 (1H, t, J = 5.4 Hz) r 5.44 (1H, s) , 6.10 {2H, s), 7.44 (4H, ddf J * 22.0, 8.8 Hz), 7.77 (1H, s), 8.02 (lHf g), 8,72 (1H, s) -_ 1H-NHR (400 MHz, DHSO-d6) δ 1.61 &lt;6H, a)f 1.98-2.12 {9H, m) f 3.83 (3H, s), 4.98 (1H, s) , 5.57 (XH, s) f 6.41 (2H, s), 7.86 (1H, d, J κ 4.0 Hz) , 7,93 (1H, s) , 8.36 (1H, d, J = 4.0 Hz), 9.49 (1H, s). 141666.doc 494· 201028381Physical data _ 1H-KMR (400 HH27 DMSO-de) δ 1.64 {SHf s&gt;, 2.03-2.08 &lt;9H, m&gt;, 3.82 &lt;3H, s), 4.86 (1H, s), 5-49 (XH , s) , 6,17 (2H, 5) , 6.30 (1H, s&gt; , 7.36 (2H, d, J^e.OHz), 7.42 (1H, s) , 7.62 (2H, d, J* 8.0 Hz ), 8.95 (1H, S) · _ 1H-NMR (400 HBzt DMSO-d6) δ 1.23-1.43 &lt;4H, m) f 1.55-1.68 &lt;6H, m) , 2.03-2.07 (9Bf m), 3.70 -3.75 (XH, m) , 3.91-3.95 (XH, m) t 4.28 &lt;2H# 3), 4.53 (1H, s), 4.80 (1H, S), 5.44 (XH, s), 6.08 (2H, s&gt;, 7.43 (4H, dd, J = 21.2, 8.0 Hz), 7.78 &lt;1H, s&gt;, 8.03 (1H, s), 8.72 ilUf S). XH-NMR (400 MHz, DMSO-d6) δ 1.66 (6Hf s), 2.05-2.08 (9U, m), 4.76 {2Ht a), 4.81 &lt;1H, s), 5.45 (1H, S&gt;, 6.10 (1H, s)r 7.26 (1H, s}, 7.4 X-7.49 (5H, m&gt;, 7.79 (1H, s), 8*02 (1H, s), 8.73 (XH, s). 1H-NMR (400 MHs, DMSO-d6) δ 1.66 &lt;7H, s ), 2,08-2.08 (9H, m&gt; , 3.74-3.77 (2H, m) , 4.14 (2Bt J « 5.4 Hz) , 4.81 (1H, s) , 4.92 (1H, t, J = 5.4 Hz) r 5.44 (1H, s) , 6.10 {2H, s), 7.44 (4H, ddf J * 22.0, 8.8 Hz), 7.77 (1H, s), 8.02 (lHf g), 8,72 (1H, s) -_1H-NHR (400 MHz, DHSO-d6) δ 1.61 &lt;6H, a)f 1.98-2.12 {9H, m) f 3.83 (3H, s), 4.98 (1H, s) , 5.57 (XH, s) f 6.41 (2H, s), 7.86 (1H, d, J κ 4.0 Hz), 7,93 (1H, s) , 8.36 (1H, d, J = 4.0 Hz), 9.49 (1H, s). 141666.doc 494· 201028381

實施例編號 R 物性資料 1H«K HR (400 mzt DMSO-dc) δ 1.66 〇 (6H, s) r 2 »05, -2.09 {9H, m) f 3.73 實施例1.- MeO^ (3tt, s&gt; f 3.78 (3E； s) / 4-91 &lt;1H, 6 4 1 i 1 s), 5.56 (1H, S), 6.28 (2H, s), MeO’ 6.81 UH, s), 7.62 (2H, S&gt; / 9.12 (1H, β). XH-NMR {400 MHz, DMSO-c^) δ 1.66 (6Η, a) f 2.06*2.10 (9H, m) t 3,91 (3H, s&gt;, 4.89 {1H, s&gt;, 5.53 (lHr s} , 6.22 {2Hf s) f 7,71 (4H# dd, J =19.6, 8.4 Hz) , 7.89 (1H, s) , 8.23 UH, s) , 8.69 C1H, d# J « 3-6 Hz), 9.06 &lt;1H, s), 1H-NMR (400 MHz, DMSO-de) δ 1.66 (6H, a) f 2.06-2.09 (9H, m), 4.87 (1H, s), 5.51 {1H, S&gt;, 6.20 &lt;2H, s) r 7.68 (4H, s), 8.98 &lt;1H, s), 9.08 (2H, 3), 9.12 (1H, 3). 實施例1 -6 4 2Example No. R Physical property 1H «K HR (400 mzt DMSO-dc) δ 1.66 〇(6H, s) r 2 »05, -2.09 {9H, m) f 3.73 Example 1.- MeO^ (3tt, s&gt ; f 3.78 (3E; s) / 4-91 &lt;1H, 6 4 1 i 1 s), 5.56 (1H, S), 6.28 (2H, s), MeO' 6.81 UH, s), 7.62 (2H, S&gt; / 9.12 (1H, β). XH-NMR {400 MHz, DMSO-c^) δ 1.66 (6Η, a) f 2.06*2.10 (9H, m) t 3,91 (3H, s&gt;, 4.89 { 1H, s&gt;, 5.53 (lHr s} , 6.22 {2Hf s) f 7,71 (4H# dd, J = 19.6, 8.4 Hz), 7.89 (1H, s) , 8.23 UH, s) , 8.69 C1H, d# J « 3-6 Hz), 9.06 &lt;1H, s), 1H-NMR (400 MHz, DMSO-de) δ 1.66 (6H, a) f 2.06-2.09 (9H, m), 4.87 (1H, s) , 5.51 {1H, S&gt;, 6.20 &lt;2H, s) r 7.68 (4H, s), 8.98 &lt;1H, s), 9.08 (2H, 3), 9.12 (1H, 3). Example 1 -6 4 2

實施例1 -6 4 3Example 1 -6 4 3

實施例1 — 644Example 1 - 644

實施例1 -6 4 5Example 1 -6 4 5

實施例1 — 646Example 1 - 646

1H-NHR (400 MHz, BMSO-de) 6 1.66 (6H, s)r 2.06-2,09 (9H, m), 4.86 《1H, s), 5.50 &lt;lHf s&gt;, 6.18 &lt;2H, s} , 7.45 (1H, s&gt;, 7.62 (4B, dd, J « 17.6, 8.0 Hk) , 8.00 (1H, d, J » 8.0 Hs), 8.50 &lt;1H, s), 8.83 &lt;1H, s&gt;, 8·93 (1H, s&gt;. 1H-NMR (400 MHz, DHSO-ds) δ 1.67 (6H, s&gt;, 2.07-2.09 (9H, m) , 3.69 (3H, s&gt;, 4.72 &lt;2H, s)y 4.88 (1H, s) , 5.51 (IE, s), 6.2X &lt;2H, b) f 6.62 (2H, s) , 7.63 (4H, s) , 7.70 (1H, d, J « 7.2 Hz) , 9.04 (1H, s), 1H-NMR (400 MHz, DMS0-d6) 5 1.67 (6fi, s) t 2.05*2,09 {5H, m) , 3.87 (3H, S)f 4.90 (1H, s), 5.54 &lt;1H, s&gt;, 6.24 (2H, b) t 6.79 (lHf s&gt;, 7,32 (1H, s), 7.50 (1H, s), 7.67 (lHr d, J 8.0 Hz) 7 7.78 (1H, d, J *= 8.0 Has} , 9·04 (1H, S}, 141666.doc 495- 201028381 實施例編號1H-NHR (400 MHz, BMSO-de) 6 1.66 (6H, s)r 2.06-2,09 (9H, m), 4.86 "1H, s), 5.50 &lt;lHf s&gt;, 6.18 &lt;2H, s } , 7.45 (1H, s&gt;, 7.62 (4B, dd, J « 17.6, 8.0 Hk) , 8.00 (1H, d, J » 8.0 Hs), 8.50 &lt;1H, s), 8.83 &lt;1H, s&gt; , 8·93 (1H, s&gt;. 1H-NMR (400 MHz, DHSO-ds) δ 1.67 (6H, s&gt;, 2.07-2.09 (9H, m), 3.69 (3H, s&gt;, 4.72 &lt; 2H, s)y 4.88 (1H, s) , 5.51 (IE, s), 6.2X &lt;2H, b) f 6.62 (2H, s) , 7.63 (4H, s) , 7.70 (1H, d, J « 7.2 Hz ), 9.04 (1H, s), 1H-NMR (400 MHz, DMS0-d6) 5 1.67 (6fi, s) t 2.05*2,09 {5H, m) , 3.87 (3H, S)f 4.90 (1H, s), 5.54 &lt;1H, s&gt;, 6.24 (2H, b) t 6.79 (lHf s&gt;, 7,32 (1H, s), 7.50 (1H, s), 7.67 (lHr d, J 8.0 Hz) 7 7.78 (1H, d, J *= 8.0 Has} , 9·04 (1H, S}, 141666.doc 495- 201028381 Example number

R 實施例1 — 6 4 7R Example 1 - 6 4 7

實施例1 — 6 4 8Example 1 - 6 4 8

實施例1 _ 6 4 9Example 1 _ 6 4 9

物性資料_ 1H-HMR (400 MHz, DMSO-de) δ 1.61 (3Η, d, J = 12.8 Hz) , 1.81 (3H, d, J * 12.8 Hz), 2.05-2,08 (9H, m), 3.23 (3H, s), 4.95 (XH, s)r 5.11 (2H, s), 5.58 (1H, s), 6.31 (1H, d, J « 7.6 Hz) , 6,39 (2H, s) , 6.78 (1H, s) , 7.44 {1H# d, J = 7.6 Hz), 9.05 &lt;1H, s). 1H-HMR (400 MHz, 0MSO-de) δ 1.68 (6Hf e)y 2.05-2,09 (9H, m) , 3.66 (3H, s), 4.82 (1H, s&gt;, 5.45 (1H, s), 6.10 (2H, s), 7.45-7.60 (6H, m) , 8.74 (1H, s). MS &lt;SSI) m/z = 434 (M+H) LC/MS tR = 1.58 min. 實施例1 一 6 5 0Physical data _ 1H-HMR (400 MHz, DMSO-de) δ 1.61 (3Η, d, J = 12.8 Hz) , 1.81 (3H, d, J * 12.8 Hz), 2.05-2,08 (9H, m), 3.23 (3H, s), 4.95 (XH, s)r 5.11 (2H, s), 5.58 (1H, s), 6.31 (1H, d, J « 7.6 Hz) , 6,39 (2H, s) , 6.78 (1H, s), 7.44 {1H# d, J = 7.6 Hz), 9.05 &lt;1H, s). 1H-HMR (400 MHz, 0MSO-de) δ 1.68 (6Hf e)y 2.05-2,09 ( 9H, m) , 3.66 (3H, s), 4.82 (1H, s&gt;, 5.45 (1H, s), 6.10 (2H, s), 7.45-7.60 (6H, m) , 8.74 (1H, s). MS &lt;SSI) m/z = 434 (M+H) LC/MS tR = 1.58 min. Example 1 A 6 5 0

實施例1 — 6 5 1Example 1 - 6 5 1

實施例1 一 6 5 2Example 1 a 6 5 2

1H-NHR (400 HHz, DMSO-de) δ 1.65 (6Η, s), 2.04-2.08 (9Η, m&gt; , 3.64 &lt;3Η, s), 4.85 (1Η, s), 5.48 (1H, a), 6.16 (2Hf a) f 6.95 (tnf s), 7.33 (2H, df J = 8.0Hz), 7.58 (2H, dt J = 8.0 Hz) , 7.67 (1H, s) , 8.90 (1H, s)._ 1H-NMR (400 MHz, DMSO-de) 6 1.67 (6tt, s), 2.06*2.09 &lt;9H, , 3.29 (3H, s) , 4.89 UH, s) , 5.24 (2H, s) , 5.51 (1H, s) , 6,21 (2H, s), 6.58-6.62 &lt;2H, π〇 , 7.63«·7·71 (6Hy m), 9.04 (1H, s). XH-NMR (400 MHz, DMSO-d^) δ 1.73 (6H, s&gt;, 2.12-2*15 (9H, m) , 4.58 (2H, s)/ 5.57 (lRf s), 6.59-6.63 (3H, m), 7.25 (IB, s&gt;, 7.67 (7H, d, J = 5.6 Hz), 9.11 (XH, s). 141666.doc 496- 2010283811H-NHR (400 HHz, DMSO-de) δ 1.65 (6Η, s), 2.04-2.08 (9Η, m&gt; , 3.64 &lt;3Η, s), 4.85 (1Η, s), 5.48 (1H, a), 6.16 (2Hf a) f 6.95 (tnf s), 7.33 (2H, df J = 8.0Hz), 7.58 (2H, dt J = 8.0 Hz), 7.67 (1H, s) , 8.90 (1H, s)._ 1H -NMR (400 MHz, DMSO-de) 6 1.67 (6tt, s), 2.06*2.09 &lt;9H, , 3.29 (3H, s) , 4.89 UH, s) , 5.24 (2H, s) , 5.51 (1H, s) , 6,21 (2H, s), 6.58-6.62 &lt;2H, π〇, 7.63«·7·71 (6Hy m), 9.04 (1H, s). XH-NMR (400 MHz, DMSO-d ^) δ 1.73 (6H, s&gt;, 2.12-2*15 (9H, m), 4.58 (2H, s)/ 5.57 (lRf s), 6.59-6.63 (3H, m), 7.25 (IB, s&gt;, 7.67 (7H, d, J = 5.6 Hz), 9.11 (XH, s). 141666.doc 496- 201028381

實施例編號 物性資料 1H-NMR &lt;400 MHz, DMSO-d6) δ 1.59-1.69 (6Hf m) , 2.01-2.08 &lt;9Hr 實施例1 — 6 5 3 Μθ~Ν % m), 3.87 (3H, s&gt;, 4.85 &lt;XH, B) r 5.45 (1H, s) , 6.18 (2H, s) f 7.49 (1H, dt J =8,0 Η»), 7.82 (1H, d, J« 8.0 Hz) ,7.88 &lt;1H, s&gt; , 8.13 {1H, s), 8-61 UH, s) f 8.87 (lHf s). 實施例1 -6 54EXAMPLES No. 1H-NMR &lt;400 MHz, DMSO-d6) δ 1.59-1.69 (6Hf m) , 2.01-2.08 &lt;9Hr Example 1 - 6 5 3 Μθ~Ν % m), 3.87 (3H, s&gt;, 4.85 &lt;XH, B) r 5.45 (1H, s) , 6.18 (2H, s) f 7.49 (1H, dt J =8,0 Η»), 7.82 (1H, d, J« 8.0 Hz) , 7.88 &lt;1H, s&gt;, 8.13 {1H, s), 8-61 UH, s) f 8.87 (lHf s). Example 1 -6 54

MeOMeO

1H-NMR &lt;400 MHz, 0MSO-de) δ 1.66 &lt;6H, s) A 2-06-2.09 (9H, m&gt; , 3.29 (3H, s) f 4.88 &lt;1H, 3), 5.24 (2H, s&gt;, 5.52 (lHr s), 6.21 (2Uf s), 6.58-6.62 (2H, m) , 7.60-7.70 (5H# m), 9.04 (lHr s). 實施例1 -6 5 51H-NMR &lt;400 MHz, 0MSO-de) δ 1.66 &lt;6H, s) A 2-06-2.09 (9H, m&gt; , 3.29 (3H, s) f 4.88 &lt;1H, 3), 5.24 (2H , s&gt;, 5.52 (lHr s), 6.21 (2Uf s), 6.58-6.62 (2H, m), 7.60-7.70 (5H# m), 9.04 (lHr s). Example 1 -6 5 5

實施例1 一 6 5 6Example 1 A 6 5 6

實施例1 一 6 5 7Example 1 A 6 5 7

XH-NMR (400 MHz, DMSO-de) δ 1*65 (6H, B), 2.04-2.08 (9Hr &amp;) f 2.37 (6H, &amp;) f 2.86 (2H, s) f 4,43 {2H, s), 4.84 (1H, s), 5.49 (1H, a) f 6.15 &lt;2H, s) , 6.87 &lt;1H, d, J « 7.6 Hz) 7 7.50 (2H, d, 〇r» 8.0 Hx) , 7.59 (2H, d, CT = 8.0 Hz) , 7.93 &lt;1H, df 7.6 Hz) f 8.24 (1H, s&gt; , 8.39 (XH, s)f 8.88 (lHr s). 1H-NMR (400 MHz, DMSO-de) δ 1.66 (6H, s), 2.04-2.08 (9Hf m&gt; , 2.88 (3H, s) , 3.72 (2H, t, J ^ 6.4 Hz) f 4.55 (2H, t, J*=6.4Hz), 4*81 {1H, s)r 5.45 (1H, s)f 6.10 《2H, s&gt;, 7.45 (4H, dd, 0Γ a 25.2, 8.0 Ha), 7.85 (1H, s), 8.15 (1H, s), 8.74 (1H, s&gt; , 1H-NMR (400 MHz, DMSO-de) δ 1.65 (6H, s) , 2.05-2.08 (9H„ , 3.72 (2H, s) r 4.30 (2H, s) , 4.B6 (2H, d, J = 18,4 H2&gt; , 5,48 UH, s&gt; , 6.14 &lt;2H, s&gt; , 6,88 (1H, d, J « 8*4 Hjk), 7.50-7.59 (4H, m) f 7.93 (1H, d, J =8,4 Hz) , β.38 (1H, s&gt; , 8.86 (1H, s). 141666.doc 497- 201028381 實施例編號XH-NMR (400 MHz, DMSO-de) δ 1*65 (6H, B), 2.04-2.08 (9Hr &amp;) f 2.37 (6H, &amp;) f 2.86 (2H, s) f 4,43 {2H , s), 4.84 (1H, s), 5.49 (1H, a) f 6.15 &lt;2H, s) , 6.87 &lt;1H, d, J « 7.6 Hz) 7 7.50 (2H, d, 〇r» 8.0 Hx ), 7.59 (2H, d, CT = 8.0 Hz), 7.93 &lt;1H, df 7.6 Hz) f 8.24 (1H, s&gt; , 8.39 (XH, s)f 8.88 (lHr s). 1H-NMR (400 MHz , DMSO-de) δ 1.66 (6H, s), 2.04-2.08 (9Hf m> , 2.88 (3H, s) , 3.72 (2H, t, J ^ 6.4 Hz) f 4.55 (2H, t, J*=6.4 Hz), 4*81 {1H, s)r 5.45 (1H, s)f 6.10 "2H, s&gt;, 7.45 (4H, dd, 0Γ a 25.2, 8.0 Ha), 7.85 (1H, s), 8.15 (1H , s), 8.74 (1H, s&gt; , 1H-NMR (400 MHz, DMSO-de) δ 1.65 (6H, s) , 2.05-2.08 (9H„ , 3.72 (2H, s) r 4.30 (2H, s) , 4.B6 (2H, d, J = 18,4 H2&gt; , 5,48 UH, s&gt; , 6.14 &lt;2H, s&gt; , 6,88 (1H, d, J « 8*4 Hjk), 7.50 -7.59 (4H, m) f 7.93 (1H, d, J = 8, 4 Hz), β.38 (1H, s&gt;, 8.86 (1H, s). 141666.doc 497- 201028381 Example number

R 實施例1 —6 5 8R Example 1 - 6 5 8

實施例1 — 6 5 9Example 1 - 6 5 9

實施例1 — 6 6 0Example 1 - 6 6 0

實施例i — 6 6 1Example i - 6 6 1

物性資料_ 1H-HHR &lt;400 MHz, DMSO»d«) δ 1.66 (6Η, a) , 2.05-2.08 {9H, m&gt; , 4.85 (1H, s), 5.04 (2H, s), 5.47 (1H, s&gt;, 6.14 (2H, s&gt; f 6.59 (1H, d, J « 9.2 Hz) , 7.42 (2H, d, J = 8.0 Ha), 7.57 (2H, dt J « 8.0 Hz) , 7.87 (1H, d, J - 9.2 Hz) , 8.09 &lt;1H, s) , 8.85 (1H, 0) ·_ 1H-NMR (400 MHz, DHSO-d6) δ 1.65 《6H, s&gt;, 2.D5-2.08 (9H, m) f 4.58 (2Hr 3&gt;, 4.83 (1H, s), 5.47 (1H, s), 6.12 (2H, s), 6.47 (1H, dt J » 9.2 Hz) , 7.20 {1H, s) , 7.40 (2H, d, J = 8.4 Hz), 7.55 (2H, d, J ~ 8.4Hz), 7.65 (1H, s), 7.78 (1H, d, J = 9.2 Hz) , 7.91 (1H, s&gt; , 8.82 (1H, s) ._ 1H-NMR (400 MHz, DMSO-d6) δ 1,65 (6H, s&gt; , 1.99-2.06 (12H, m) , 4.78 (1H, s), 5.39 (1H, &amp;) t 6.05 (2H, s) , 7.43 (4H, dd, J = 20.4f 9.2 Hr), 8.64 (1H, s), 9.81 (1H, s). 1H-NHR (400 MHz, DMSO-dg) δ 1.62 (6H, s&gt;, 2.02-2,06 &lt;9H, m&gt;, 2.21 (6H, s&gt;, 3.10 (2H, s), 3.78 (3H, s), 4.79 (lHf s), 5.46 (1H, s), 6.07 (2Hf s), 6.45-6.48 &lt;1H, m), 6.65-6.69 &lt;1H, m), 6.81 &lt;1H, s), 7.29 (XH, d, J = 8.0 Hz) , 7.83 (1H, d, J « 8.4 Hz) , 8.66 (1H, s) , 9.19 (lHr s). 實施例1 — 6 6 2Physical data _ 1H-HHR &lt;400 MHz, DMSO»d«) δ 1.66 (6Η, a) , 2.05-2.08 {9H, m&gt; , 4.85 (1H, s), 5.04 (2H, s), 5.47 (1H , s&gt;, 6.14 (2H, s&gt; f 6.59 (1H, d, J « 9.2 Hz) , 7.42 (2H, d, J = 8.0 Ha), 7.57 (2H, dt J « 8.0 Hz) , 7.87 (1H, d, J - 9.2 Hz) , 8.09 &lt;1H, s) , 8.85 (1H, 0) · _ 1H-NMR (400 MHz, DHSO-d6) δ 1.65 "6H, s&gt;, 2.D5-2.08 (9H , m) f 4.58 (2Hr 3&gt;, 4.83 (1H, s), 5.47 (1H, s), 6.12 (2H, s), 6.47 (1H, dt J » 9.2 Hz) , 7.20 {1H, s) , 7.40 (2H, d, J = 8.4 Hz), 7.55 (2H, d, J ~ 8.4Hz), 7.65 (1H, s), 7.78 (1H, d, J = 9.2 Hz), 7.91 (1H, s&gt; , 8.82 (1H, s) ._ 1H-NMR (400 MHz, DMSO-d6) δ 1,65 (6H, s&gt;, 1.99-2.06 (12H, m), 4.78 (1H, s), 5.39 (1H, & t 6.05 (2H, s) , 7.43 (4H, dd, J = 20.4f 9.2 Hr), 8.64 (1H, s), 9.81 (1H, s). 1H-NHR (400 MHz, DMSO-dg) δ 1.62 (6H, s&gt;, 2.02-2, 06 &lt;9H, m&gt;, 2.21 (6H, s&gt;, 3.10 (2H, s), 3.78 (3H, s), 4.79 (lHf s), 5.46 (1H, s ), 6.07 (2Hf s), 6.45-6.48 &lt;1H, m), 6.65-6.69 &lt;1H, m), 6.81 &lt;1H, s), 7.29 (XH, d, J = 8.0 Hz) , 7.83 (1H, d, J « 8.4 Hz) , 8.66 (1H, s) , 9.19 (lHr s). Example 1 - 6 6 2

MeO、MeO,

om 0Om 0

1H-KMR (400 MHz, DMSO»d6&gt; δ 1.63 (6H, s&gt; , 2.02-2.07 (9H, m&gt; , 3,25 (3H, s) , 3.44-3.46 (2H, m) , 3.86 《3H, s)f 4.82 (1H, s), 5.47 (lHf s) , 6.14 (2H, s) , 6.87 (1H, s), 7.42 (1H, J = 9.2 Hz) , 8.06 (1H, d, J = 9.2 Hz&gt; , 8·76 (1H, s&gt; , 9.02 (1H, S)# 9.64 (1H, s). 141666.doc 498- 2010283811H-KMR (400 MHz, DMSO»d6&gt; δ 1.63 (6H, s&gt;, 2.02-2.07 (9H, m&gt;, 3,25 (3H, s), 3.44-3.46 (2H, m), 3.86 "3H, s)f 4.82 (1H, s), 5.47 (lHf s) , 6.14 (2H, s) , 6.87 (1H, s), 7.42 (1H, J = 9.2 Hz) , 8.06 (1H, d, J = 9.2 Hz) ; , 8·76 (1H, s&gt; , 9.02 (1H, S)# 9.64 (1H, s). 141666.doc 498- 201028381

實施例編號Example number

R 實施例1 — 6 6 3R Example 1 - 6 6 3

實施例1 — 6 6 4Example 1 - 6 6 4

物性資料 1H-NMR (400 MHz, DHSO-de) δ 1.65 {6Η, s) , 2.04-2.08 (9Hr m&gt; , 4.83 (1H, s) r 5.46 (1H, s&gt;, 6.14 (2H, s) , 6.42 {1H, d, J =* 9.6 Hz) , 7.40 (2H, d, J« 7.2 Hz) , 7.51-7.58 (3H, m) , 7.76 (1H, d, J = 9.6 Hz) , 8-80 (1H, s). MS mSl) m/z * 525 I.C/MS tR « 2.07 min. 實施例1 — 6 6 5Physical property 1H-NMR (400 MHz, DHSO-de) δ 1.65 {6Η, s) , 2.04-2.08 (9Hr m), 4.83 (1H, s) r 5.46 (1H, s&gt;, 6.14 (2H, s) , 6.42 {1H, d, J = * 9.6 Hz), 7.40 (2H, d, J« 7.2 Hz), 7.51-7.58 (3H, m), 7.76 (1H, d, J = 9.6 Hz), 8-80 ( 1H, s). MS mSl) m/z * 525 IC/MS tR « 2.07 min. Example 1 - 6 6 5

實施例i -6 6 6Example i -6 6 6

1H-NHR (400 HHz, DHSO-d^) δ 1.08 &lt;3Η, t, J » 7.2 Η») , 1.67 (6Η, s) f 2.09 (9Η, s) , 3.19 (2Η, q? «Τ * 7.2 Η2), 4.96 (1Η, β), 5.56 (XHf S), 6,34 (2Η, s) f 7.66 (2Η, d, J « 8.0 Has) Λ 7.77 (2Η, d, J « 8.0 Hz) f 9.36&lt;1H, s) ._ HS (ESI) m/z » 44€ 《M+H&gt;+. LC/MS tR « a .48 min. 實施例.1 一 6 6 71H-NHR (400 HHz, DHSO-d^) δ 1.08 &lt;3Η, t, J » 7.2 Η») , 1.67 (6Η, s) f 2.09 (9Η, s) , 3.19 (2Η, q? «Τ * 7.2 Η2), 4.96 (1Η, β), 5.56 (XHf S), 6,34 (2Η, s) f 7.66 (2Η, d, J « 8.0 Has) Λ 7.77 (2Η, d, J « 8.0 Hz) f 9.36 &lt;1H, s) ._ HS (ESI) m/z » 44€ "M+H&gt;+. LC/MS tR « a .48 min. Example.1 a 6 6 7

實施例1 一 6 6 8Example 1 A 6 6 8

XH«NMR (400 MHz, DHSO-d«) δ 1.65 {6Hf s&gt; , 1.99-2.07 U2H, m) , 4*87 (1H, s&gt;, 5.55 (1H, s&gt;, 6.22 {2U, s) , 7.43 (1H, br b) , 7.55-7.57 &lt;1H, m) , 7.66-7.70 (lHr m), 8*11 {1H, br e) # 8.30 (1H, s) , 9.15 (1H, s), 12,04 (1H, s) ·_ 1H*MMR &lt;400 MHz, DHSO-d6) δ 1*67 (6H, s&gt; , 2.09 {9H, br s) , 3,08 (4Hf s), 4.91 (1H, s), 5.55 (1H, a), 6.28 (3H7 s&gt;, 7.26 (lHr s&gt; , 7.60 &lt;1Η, s&gt;, 1.11 (2H# si, 8.29 (1H, s), 9.22 (1H, s). 141666.doc 499- 201028381 實施例編號 實施例1 -6 6 9 物性資料 1H-N1 MR &lt;400 MHz, DMSO-de) δ 1.68 0 &lt;6H, s), 2.06- 2.09 (9H, m), 4.90 (1H, S) / 5.31 (1H, s&gt;, 5.54 (1H, s), 6.24 (2E, s), 6.90 (1H, s), MeO」 7.38 (1H, s), 7.53 (1H, s), 7.77 (1H, s) / 7.95 (1H, s), 9,09 (1H, s). XH-NMR (400 MHz, DMSO-d6&gt; δ 1 68 《6Η, s), 2,06-2.09 (9Η, π〇 ,XH«NMR (400 MHz, DHSO-d«) δ 1.65 {6Hf s&gt; , 1.99-2.07 U2H, m) , 4*87 (1H, s&gt;, 5.55 (1H, s&gt;, 6.22 {2U, s), 7.43 (1H, br b) , 7.55-7.57 &lt;1H, m) , 7.66-7.70 (lHr m), 8*11 {1H, br e) # 8.30 (1H, s) , 9.15 (1H, s), 12,04 (1H, s) ·_ 1H*MMR &lt;400 MHz, DHSO-d6) δ 1*67 (6H, s&gt; , 2.09 {9H, br s) , 3,08 (4Hf s), 4.91 ( 1H, s), 5.55 (1H, a), 6.28 (3H7 s&gt;, 7.26 (lHr s&gt;, 7.60 &lt;1Η, s&gt;, 1.11 (2H# si, 8.29 (1H, s), 9.22 (1H, s 141666.doc 499- 201028381 Example No. Example 1 -6 6 9 Physical data 1H-N1 MR &lt;400 MHz, DMSO-de) δ 1.68 0 &lt;6H, s), 2.06- 2.09 (9H, m ), 4.90 (1H, S) / 5.31 (1H, s&gt;, 5.54 (1H, s), 6.24 (2E, s), 6.90 (1H, s), MeO" 7.38 (1H, s), 7.53 (1H, s), 7.77 (1H, s) / 7.95 (1H, s), 9,09 (1H, s). XH-NMR (400 MHz, DMSO-d6 > δ 1 68 "6Η, s), 2,06- 2.09 (9Η, π〇,

MeO 實施例1 6 70MeO Example 1 6 70

MeO 實施例1 6 7 1 2.79-2.82 (2Η, m) , 3.50-3.54 (2Η, m&gt;, 3.58 (3Η, s), 4.89 (1Η, s&gt; , 5.24 (2Η, S), 5.53 (1Η, s), 6.24 (2Η, , 6.72-6.77 (1Η, m)# 6.89 (1Η, s&gt;, 7.53 (1Η, S), 7.73-7.79 (2Hy m) , 8.14-8.17 &lt;1Η, m) , 9.09 (1Η, s&gt; . 1H-NMR (400 MHz, DMSO-d6) δ X.68 (6H, a) , 2.06-2.09 {9H, m) , 3.44 &lt;3H, s&gt; , 4.29 &lt;2H, d, J = 5.2 Hat), 4.91 (!Hf s), 5.32 (2fi, s), 5.55 (1H, a), 6.26 (2H, s), 6.94 (1H, s) , 7.77-7.84 (2Hr m&gt;, 8.60 (lHf s), 9.17 (1H, s). 實施例1 — 0 HzN'y 1H-NMR (400 MHz, DMSO-dg) δ 1.61-1.76 (6H, m) , 2.06-2.09 (9Hr m) , 4.89 (1H, s) , 5.52 (1H, s), 6.25 (2H, s) , 6.98 (XH, d, J = 9.2 6 7 2 HO) Hz) , 7.09 (1H, s&gt; , 7.66 (2H, « 9.2 Hz) , 8*15 (1H, s) , 8.98 s), 13.24 (1H, s). d, J (1H,MeO Example 1 6 7 1 2.79-2.82 (2Η, m) , 3.50-3.54 (2Η, m&gt;, 3.58 (3Η, s), 4.89 (1Η, s&gt; , 5.24 (2Η, S), 5.53 (1Η, s), 6.24 (2Η, , 6.72-6.77 (1Η, m)# 6.89 (1Η, s&gt;, 7.53 (1Η, S), 7.73-7.79 (2Hy m) , 8.14-8.17 &lt;1Η, m) , 9.09 (1Η, s&gt; . 1H-NMR (400 MHz, DMSO-d6) δ X.68 (6H, a) , 2.06-2.09 {9H, m) , 3.44 &lt;3H, s&gt; , 4.29 &lt;2H, d , J = 5.2 Hat), 4.91 (!Hf s), 5.32 (2fi, s), 5.55 (1H, a), 6.26 (2H, s), 6.94 (1H, s), 7.77-7.84 (2Hr m&gt;, 8.60 (lHf s), 9.17 (1H, s). Example 1 - 0 HzN'y 1H-NMR (400 MHz, DMSO-dg) δ 1.61-1.76 (6H, m) , 2.06-2.09 (9Hr m) , 4.89 (1H, s), 5.52 (1H, s), 6.25 (2H, s), 6.98 (XH, d, J = 9.2 6 7 2 HO) Hz) , 7.09 (1H, s&gt; , 7.66 (2H, « 9.2 Hz) , 8*15 (1H, s) , 8.98 s), 13.24 (1H, s). d, J (1H,

LC/MS tR * 1 · 92 min. 實施例i 6 7 4LC/MS tR * 1 · 92 min. Example i 6 7 4

MeO 141666.doc 500- 201028381MeO 141666.doc 500- 201028381

實施例編號Example number

R 實施例1 一 6 7 6R Example 1 A 6 7 6

實施例1 _ 6 7 6 Ο h2nExample 1 _ 6 7 6 Ο h2n

σ f3ct 實施例1 一 6 7 7σ f3ct embodiment 1 a 6 7 7

實施例1 一 6 78 ο σΝ^ΜβExample 1 A 6 78 ο σΝ^Μβ

實施例1 一 6 7 9Example 1 A 6 7 9

物性資料_ 1H-NMR &lt;400 mz, DMSO-d&lt;) δ 1.67 (€H, s), 2.06-2.09 (9Hf m&gt;, 4.92 (1H, s) t 5.IB &lt;2H, s), 5.55 (XH, s) f 6*27 (2H, b) f 6.87 (1H, s)r 7.43 (2H, s)； 7,73-7.81 {2H, m), 9.17 (1H, s). 1H-NMR (400 mzf DMSO-de) δ 1.66 (7H# s)# 2.05-2.09 m), 4,80-4.91 (2H, m) , 5.55 &lt;1H, s), 6.27 &lt;2H, s), 6.85 (1H, s), 7.14 (1H, s), 7.51 (IH, s), 7,69-7.75 (1H, m) f 7.96 &lt;1H, s), 9.08 (1H, a) &gt; ___ 1H-NMR (400 MHz, DMSO-de) δ 1.01 (6H, dt J * 6.4 Hz) f 1*67 ($Uf s), 2,05-2.09 (9H, m&gt; , 3.57 (1H, s) r 3.86 {2H, d, J « 6,4 Ha) , 4.90 (1H, s) , 5.53 &lt;1H, s), 6.25 (2H, a)r 6. SO (1H, s), 7.42 (2H, s&gt; , 7.68 (1H, d, J = 8.4 Hz) , 7.79 (1H, d, J » 8.4 Hz) f 9.02 (1H, a). 1H-NMR (400 MHz, DMSO-de) $ 1.67-1.78 U1H, fti) , 2.07*2.09 (9H, m), 4.92 (1H, s), 5.32-5.37 (1H, S.S5 &lt;1H, s), 6·27 (2H, s&gt;, 6.97 (1H, s), 7.30 (1H, s)r 7·41 UH, 7.74 dd, J « 34.4, 8.4 Hz), 9.17 {1H, s), XH-NMR &lt;400 MHz, DMSO-de) δ 1,67 C6H, s) , 2,06-2.09 (9H, m) , 3,69 (1H, s) t 4,90 (2H, s), 5.55 (1H, s), 6,25 (2H, s), 6.85 &lt;1H, s)r 7,41 (3H, d, J * 14.8 Hz),7.70-7.80 (2H, m), 9.10 (1H, s). 141666.doc 501 - 201028381 實施例編號 R 物性資料Physical property data_1H-NMR &lt;400 mz, DMSO-d&lt;) δ 1.67 (€H, s), 2.06-2.09 (9Hf m&gt;, 4.92 (1H, s) t 5.IB &lt;2H, s), 5.55 (XH, s) f 6*27 (2H, b) f 6.87 (1H, s)r 7.43 (2H, s); 7,73-7.81 {2H, m), 9.17 (1H, s). 1H- NMR (400 mzf DMSO-de) δ 1.66 (7H# s)# 2.05-2.09 m), 4,80-4.91 (2H, m) , 5.55 &lt;1H, s), 6.27 &lt;2H, s), 6.85 (1H, s), 7.14 (1H, s), 7.51 (IH, s), 7,69-7.75 (1H, m) f 7.96 &lt;1H, s), 9.08 (1H, a) &gt; ___ 1H- NMR (400 MHz, DMSO-de) δ 1.01 (6H, dt J * 6.4 Hz) f 1*67 ($Uf s), 2,05-2.09 (9H, m&gt; , 3.57 (1H, s) r 3.86 { 2H, d, J « 6,4 Ha) , 4.90 (1H, s) , 5.53 &lt;1H, s), 6.25 (2H, a)r 6. SO (1H, s), 7.42 (2H, s&gt; , 7.68 (1H, d, J = 8.4 Hz), 7.79 (1H, d, J » 8.4 Hz) f 9.02 (1H, a). 1H-NMR (400 MHz, DMSO-de) $1.67-1.78 U1H, fti) , 2.07*2.09 (9H, m), 4.92 (1H, s), 5.32-5.37 (1H, S.S5 &lt;1H, s), 6·27 (2H, s&gt;, 6.97 (1H, s), 7.30 (1H, s)r 7·41 UH, 7.74 dd, J « 34.4, 8.4 Hz), 9.17 {1H, s), XH-NMR &lt;400 MHz, DMSO-de) δ 1,67 C6H, s) , 2,06-2.09 (9H, m) , 3,69 (1H, s) t 4,90 (2H, s), 5.55 (1H, s), 6,25 (2H, s), 6.85 &lt;1H, s)r 7,41 (3H, d, J * 14.8 Hz), 7.70- 7.80 (2H, m), 9.10 (1H, s). 141666.doc 501 - 201028381 Example No. R Physical data

實施例1 -6 8 0 XH-KMR (400 MH2, DMSO-dEe) 5 X.16-1.39 (2H, m), 1.67 &lt;9H, s), 2.05-2.09 (11H, m&gt;, 3.88-3.95 (4H, m)r 4.$0 &lt;1H, s), 5*53 (1H, s&gt;, 6·25 &lt;2H, s&gt;, 6,80 &lt;1H, s), 7.38 &lt;2H, d, 6.8 , 7,73 &lt;2H, dd, J * 38.0, 8.4 Hz), 9.02 (1H, s).Example 1 -6 8 0 XH-KMR (400 MH2, DMSO-dEe) 5 X.16-1.39 (2H, m), 1.67 &lt;9H, s), 2.05-2.09 (11H, m&gt;, 3.88-3.95 (4H, m)r 4.$0 &lt;1H, s), 5*53 (1H, s&gt;, 6·25 &lt; 2H, s&gt;, 6,80 &lt;1H, s), 7.38 &lt; 2H, d, 6.8, 7,73 &lt;2H, dd, J * 38.0, 8.4 Hz), 9.02 (1H, s).

實施例i — 6 8 3Example i - 6 8 3

1H-HMR (400 MHz, DMSO-d6) δ 1.64 (brm, 6H) , 1.77 (d, 3H, J= 6.6 Hz&gt; , 2.01-2.05 &lt;m, 9H), 3.87 (s, 3H), 4.82 (s, 1H&gt; , 5,30 (qf 1H, J = 6.6 Hz), 5.4θ (s, 1H), 6.14 (s, 2H&gt;, 7.00 (s, 1H) , 7.44 (br, 2H) , 7.78 (s, 1H)# 7.98 (s, 1H), 8.83 (s, 1H). MS (ESX) tn/ss = 509 + . LC/MS tR « 2.32 min. 實施例1 — 6 8 41H-HMR (400 MHz, DMSO-d6) δ 1.64 (brm, 6H), 1.77 (d, 3H, J= 6.6 Hz&gt;, 2.01-2.05 &lt;m, 9H), 3.87 (s, 3H), 4.82 ( s, 1H&gt;, 5,30 (qf 1H, J = 6.6 Hz), 5.4θ (s, 1H), 6.14 (s, 2H&gt;, 7.00 (s, 1H), 7.44 (br, 2H), 7.78 (s , 1H)# 7.98 (s, 1H), 8.83 (s, 1H). MS (ESX) tn/ss = 509 + . LC/MS tR « 2.32 min. Example 1 - 6 8 4

1H-NMR (400 MHz, DMSO-d6) δ 1.66 (br, 6H) , 2.06-2.10 (brm, 9H), 3.76 &lt;s, 3H), 4.90 (s, 1H) , 5.33 ◎ (br, 1H) f 5.51 {s, 1H&gt; , 6.23 (bra, 2H) , 6.75 (d, 1H, J« 15.7 Hz) , 7.38 (d, 2H, J = 7.6 Hz) , 7.57 (s, 1H), 7.58 {dt 1H, J » 15.7 Hz) , 7.70 (d, 2H, J « 7.6 H«), 9.05 1H)* MS (ESX) m/z « 510 (M+H)+. XiC/MS tR - 1.69 min. 141666.doc 502- 201028381 實施例編號 實施例1 -6 8 51H-NMR (400 MHz, DMSO-d6) δ 1.66 (br, 6H), 2.06-2.10 (brm, 9H), 3.76 &lt;s, 3H), 4.90 (s, 1H), 5.33 ◎ (br, 1H) f 5.51 {s, 1H&gt; , 6.23 (bra, 2H) , 6.75 (d, 1H, J« 15.7 Hz) , 7.38 (d, 2H, J = 7.6 Hz), 7.57 (s, 1H), 7.58 {dt 1H , J » 15.7 Hz) , 7.70 (d, 2H, J « 7.6 H«), 9.05 1H)* MS (ESX) m/z « 510 (M+H)+. XiC/MS tR - 1.69 min. 141666. Doc 502-201028381 Example Numbering Example 1 -6 8 5

物性資料_ MS (ESI) m/z 462 (M+H)+. LC/MS tR = 1.77 min.Physical property data _ MS (ESI) m/z 462 (M+H)+. LC/MS tR = 1.77 min.

[表 1-3][Table 1-3]

表1-3中記載之化合物係依據上述記載之實施例1-499之 ® 方法而合成。 實施例編號 《 物性資料_ 1H-NMR (400 MHs, DMSO-de) δ Χ.4Χ (s, 9H&gt;, 3.01 (s, 3H), 4.35 (s, 2H) , 5.09 (s, 1H) , 5.53 (s, 1H), 6.22 (s, 2H&gt; , 7-39 (d, J = 7.3 Hse , 1H&gt; , 7.48 (d, J= 7.3 Η*, 1H) f 7.91 (sr 1H) , 9.12 (s, 1H). MS (ESI) m/a « 3S1 (M+H&gt;+. LC/MS tR * 1,56 min. 1H-NMR (400 MHk, DHSO-de) δ 1.41 (s, 9H), 3.25 (s, 3H), 3.52 (s,The compounds described in Tables 1-3 were synthesized in accordance with the methods of the above-described Examples 1-499. Example No. "Material data _ 1H-NMR (400 MHs, DMSO-de) δ Χ.4Χ (s, 9H&gt;, 3.01 (s, 3H), 4.35 (s, 2H), 5.09 (s, 1H), 5.53 (s, 1H), 6.22 (s, 2H&gt;, 7-39 (d, J = 7.3 Hse , 1H&gt; , 7.48 (d, J= 7.3 Η*, 1H) f 7.91 (sr 1H) , 9.12 (s, 1H). MS (ESI) m/a « 3S1 (M+H&gt;+. LC/MS tR * 1,56 min. 1H-NMR (400 MHk, DHSO-de) δ 1.41 (s, 9H), 3.25 ( s, 3H), 3.52 (s,

實施例l - _〇 6 8 7 A»/t J·OA , Aaj tExample l - _〇 6 8 7 A»/t J·OA , Aaj t

5.09 (sf 1H&gt;, 5.53 &lt;sr XH), 6.22 (s, 2H) f 7.42 (d, J » 7.8 Hz f 1H) r 7.49 (d, J « 7.8 Hz, 2H) , 7.88 (s. 實施例1 - 6 8 85.09 (sf 1H&gt;, 5.53 &lt;sr XH), 6.22 (s, 2H) f 7.42 (d, J » 7.8 Hz f 1H) r 7.49 (d, J « 7.8 Hz, 2H) , 7.88 (s. Example 1 - 6 8 8

1H&gt;, 9.13 (s, 1H&gt;. MS (ESI) m/z » 395 (H+H)+* LC/HS tR * 1.62 min, 1H-NMR &lt;400 MHz, DMSO-d6) $ 1.43 (sf 9H}, 3.12 (s, 3H), 5,16 (s, 1H) , 5.57 (s, 1H) , 6.31 (sr 2H), 7.72 (d, J * 8.6 Hz, 2H) f 7.76 (d, J * 8.6 Hz, 2H&gt;, 9,32 (s, 1H). MS (ESI) m/z «360 (M+H)*· LC/MS tR =» 1.71 min, 141666.doc 503 - 201028381 實施例編號 R 物性資料 實施例1 - 0 h2h^^Y% 1H-NMR (400 MHz, DMSO-de) δ 1.44 (s, 9H), 3.83 (s, 3H), 5.08 (s, 1H) t 5,57 (S/ XH), 6.22 (s, 2H), 6.4θ (d, 1H# J = 12 Hz) , €.91 (&amp;r 6 8 9 1H) , β.99 &lt;s, 1H) , 7.25-7.39 (m, 3H) , 7.58 (d, 1H, J = 12 Hz) , 9.00 (s, 1H)· 實施例1 — 0 MeO^^ 1H-NMR (400 MHz, DMSO-de) δ 1.43 (s, 9H), 3.26 (s, 3H), 3.77(8, 3H) , 5.08 (s, 1H), 5.57 (s, 1H), 6.20 (s, 2H), 6,55 (d, 1H, J ® 12.0 6 9 0 ^ Xj 6*98 (s, iH&gt;,7·25(&lt;1, 1H, Ο1， MeO^^ * 9.0 Hz) , 7.38 (d, 1H, J = 9.0 Hz), 1H, J^ia.OHz), 8.94 (s, 1H). MS (ESI) m/z == 420 (M+H) + . LC/MS tR * 1.62 min. 實施例l — 6 9 11H&gt;, 9.13 (s, 1H&gt;. MS (ESI) m/z » 395 (H+H)+* LC/HS tR * 1.62 min, 1H-NMR &lt;400 MHz, DMSO-d6) $ 1.43 (sf 9H}, 3.12 (s, 3H), 5,16 (s, 1H), 5.57 (s, 1H), 6.31 (sr 2H), 7.72 (d, J * 8.6 Hz, 2H) f 7.76 (d, J * 8.6 Hz, 2H&gt;, 9,32 (s, 1H). MS (ESI) m/z «360 (M+H)*· LC/MS tR =» 1.71 min, 141666.doc 503 - 201028381 Example Number R Physical Properties Example 1 - 0 h2h^^Y% 1H-NMR (400 MHz, DMSO-de) δ 1.44 (s, 9H), 3.83 (s, 3H), 5.08 (s, 1H) t 5,57 (S / XH), 6.22 (s, 2H), 6.4θ (d, 1H# J = 12 Hz) , €.91 (&amp;r 6 8 9 1H) , β.99 &lt;s, 1H) , 7.25-7.39 (m, 3H), 7.58 (d, 1H, J = 12 Hz), 9.00 (s, 1H)· Example 1 - 0 MeO^^ 1H-NMR (400 MHz, DMSO-de) δ 1.43 (s, 9H ), 3.26 (s, 3H), 3.77 (8, 3H), 5.08 (s, 1H), 5.57 (s, 1H), 6.20 (s, 2H), 6,55 (d, 1H, J ® 12.0 6 9 0 ^ Xj 6*98 (s, iH&gt;, 7·25 (&lt;1, 1H, Ο1, MeO^^ * 9.0 Hz), 7.38 (d, 1H, J = 9.0 Hz), 1H, J^ia. OHz), 8.94 (s, 1H). MS (ESI) m/z == 420 (M+H) + . LC/MS tR * 1.62 min. Example l - 6 9 1

實施例1 - 6 9 2Example 1 - 6 9 2

MS &lt;£SX) m/z » 409 (M+H)+. LC/MS tR = 1.74 min * MS (ESI) m/z » 493 十H) + ·MS &lt;£SX) m/z » 409 (M+H)+. LC/MS tR = 1.74 min * MS (ESI) m/z » 493 T H) + ·

141666.doc 504- 201028381141666.doc 504- 201028381

實施例編號 R 物性資料Example No. R Physical data

1H-NMR (400 MHz, DMSO-de) δ 1.44 (s, 9H)r 4.25 (sr 2H)r 5.18 (s, 1H) , 5.55 (sf XH) , 6.32 (s, 2B) f 6.59 (df 1H, J « 12 Hz) , 7,54-7,70 (m, 3H)f 7.81 (s, XH), S.82 (b»f 1H), 9.36 (s, 1H). 1H-NHR &lt;400 MHz, DHSO-dg) δ 1.43 Cs, 9H) t 3*34 (sf 3H), 3.74 (s, 2H), 4.12 (s, 2H), S.08 (sf 1H),5.57 (s, 1H), 6.22 (s, 2H)f 6.49 (d, 1H, J« 12 Hz) , 6.90*7.00 (m, 2H)# 7.25 &lt;d, 1H, J * 6 Hz), 7.40 (s, 2H) , 7*61 &lt;d, 1H, J « 12 Hz), 8.93 (s, 1H&gt;. 0 MS &lt;ESI&gt; m/z » 499 (M+H)+.實施例1 一 7 0 11H-NMR (400 MHz, DMSO-de) δ 1.44 (s, 9H) r 4.25 (sr 2H) r 5.18 (s, 1H) , 5.55 (sf XH) , 6.32 (s, 2B) f 6.59 (df 1H, J « 12 Hz) , 7,54-7,70 (m, 3H)f 7.81 (s, XH), S.82 (b»f 1H), 9.36 (s, 1H). 1H-NHR &lt;400 MHz , DHSO-dg) δ 1.43 Cs, 9H) t 3*34 (sf 3H), 3.74 (s, 2H), 4.12 (s, 2H), S.08 (sf 1H), 5.57 (s, 1H), 6.22 (s, 2H)f 6.49 (d, 1H, J« 12 Hz) , 6.90*7.00 (m, 2H)# 7.25 &lt;d, 1H, J * 6 Hz), 7.40 (s, 2H) , 7*61 &lt;d, 1H, J « 12 Hz), 8.93 (s, 1H&gt;. 0 MS &lt;ESI&gt; m/z » 499 (M+H)+. Example 1 A 7 0 1

LC/HS tR * 1.89 min. 實施例1 7 0 2LC/HS tR * 1.89 min. Example 1 7 0 2

141666.doc 505 - 201028381 實施例編號141666.doc 505 - 201028381 Example number

R 實施例1 一 7 0 3R Example 1 A 7 0 3

物性資料__ MS (ESI) m/z = 431 (M+H)+. LC/MS tR = 1.50 min. 1H-N MR (400 MHz, DHSO»de) δ 1.42 u, 9H)r 2.37 (s, 6H&gt;f 3-29 &lt;m, 2H), 3.78 (s, 3H), 5.04 (Bt 1H), 實施例1 — Π 5.54 (s, XH), 6.15 (m, 1H), 6.16 7 0 4 Me {»/ 2H)7 6.76 (d, 1H, J =12 Hz), 6.96 (3/ 1H), 7.15 (d, 1H# J - 6 Hz), 7.36 (d, 1H, J = 6 Hz)# 8.80 (s, XH). 實施例1 - 〇 Π 1H-NMR (400 MH«, DHSO-de) δ 1.36 is, 9B) f 3.8S (s, 3H), 5,02 (s, 1H), 5.59 (s, 1H), 6.14 (s, 2H), 6.53 {d, 1H, J « 12.0 Hz) , 7.01 {s , 7 0 5 OMe 1H&gt; , 7.07 (d, 1H, J : 6,0 Hz&gt; , 7.19 &lt;s, 1H) , 7.36 (df 1H# 12.0 Hz), 7.43 &lt;s, XH) , 7.78 (d, 1H, J = 6.0 Hz), 7.93 &lt;s, 1H). 1H-NMR (400 MHss, DHS0-d6&gt; δ 1.36 &lt;s, 9H) , 3.17 &lt;s, 3H) , 3.27-3.40 (m, 4H), 3.86 (s, 3H), 5.01 (s, 1H) , S,B9 (Bf 1H) , 6.13 (s, 2H), 6.61 &lt;d, 1H, J = 12.0 Hz) , 7.08 (d, 1H, J « 6.0 Hz) , 7.19 &lt;s, 1H) , 7.37 (d, 1H, J = 12.0 Hz) , 7,78 {d, 1H, J=6.0 Hz) # 7.93 (s, 1H) , 8.04 (bs, 1H). 實施例1 7 0 6Physical data __ MS (ESI) m/z = 431 (M+H)+. LC/MS tR = 1.50 min. 1H-N MR (400 MHz, DHSO»de) δ 1.42 u, 9H)r 2.37 (s , 6H&gt;f 3-29 &lt;m, 2H), 3.78 (s, 3H), 5.04 (Bt 1H), Example 1 - Π 5.54 (s, XH), 6.15 (m, 1H), 6.16 7 0 4 Me {»/ 2H)7 6.76 (d, 1H, J =12 Hz), 6.96 (3/ 1H), 7.15 (d, 1H# J - 6 Hz), 7.36 (d, 1H, J = 6 Hz)# 8.80 (s, XH). Example 1 - 〇Π 1H-NMR (400 MH«, DHSO-de) δ 1.36 is, 9B) f 3.8S (s, 3H), 5,02 (s, 1H), 5.59 (s, 1H), 6.14 (s, 2H), 6.53 {d, 1H, J « 12.0 Hz) , 7.01 {s , 7 0 5 OMe 1H&gt; , 7.07 (d, 1H, J : 6,0 Hz) , 7.19 &lt;s, 1H) , 7.36 (df 1H# 12.0 Hz), 7.43 &lt;s, XH) , 7.78 (d, 1H, J = 6.0 Hz), 7.93 &lt;s, 1H). 1H-NMR (400 MHss, DHS0-d6&gt; δ 1.36 &lt;s, 9H) , 3.17 &lt;s, 3H) , 3.27-3.40 (m, 4H), 3.86 (s, 3H), 5.01 (s, 1H) , S, B9 ( Bf 1H) , 6.13 (s, 2H), 6.61 &lt;d, 1H, J = 12.0 Hz) , 7.08 (d, 1H, J « 6.0 Hz) , 7.19 &lt;s, 1H) , 7.37 (d, 1H, J = 12.0 Hz) , 7,78 {d, 1H, J=6.0 Hz) # 7.93 (s, 1H) , 8.04 (bs, 1H). Example 1 7 0 6

OMe 實施例1 — 7 0 7OMe Example 1 - 7 0 7

1H-NMR (400 MHz, DMSO-de) δ 1.42 (s, 9H), 3.05 {s, 3H)f 5.10 (s# 1H), 5.54 (s, 1H)# 6.24 (sy 2H), 7.25 (d, J = 15.2 Hz, XH) , 7.38 &lt;d, J = 15.2 Ha, 1H) , 7.58 (brs, 4H), 9,10 (s, 1H), MS (ESI) m/z « 386 (M+H)+ -I*C/MS tR - 1.80 min. 141666.doc 506- 201028381 實施例編號 實施例1 — 7 0 81H-NMR (400 MHz, DMSO-de) δ 1.42 (s, 9H), 3.05 {s, 3H)f 5.10 (s# 1H), 5.54 (s, 1H)# 6.24 (sy 2H), 7.25 (d, J = 15.2 Hz, XH) , 7.38 &lt;d, J = 15.2 Ha, 1H) , 7.58 (brs, 4H), 9,10 (s, 1H), MS (ESI) m/z « 386 (M+H ) + -I*C/MS tR - 1.80 min. 141666.doc 506- 201028381 Example Number Example 1 - 7 0 8

物性資料_ MS 《ESI) m/z = 415 (M+H)+. IiC/MS « 1.77 min. 實施例1 -7 0 9Physical data _ MS "ESI" m/z = 415 (M+H)+. IiC/MS « 1.77 min. Example 1 -7 0 9

1K-NMR &lt;400 MHz, DMSO-d6) δ 1.44 &lt;9H, s), 5.02 (2Uf a) f 5,10 &lt;1H, s) , 5.55 (1H, s) t 6.22 {2H, s), 6.74 (2H, s) , 7.66 (4H, J « 8.4 H«) r 7.79 (lHf d, J « 6.4 Hz) , 9,05 &lt;1H, s).1K-NMR &lt;400 MHz, DMSO-d6) δ 1.44 &lt;9H, s), 5.02 (2Uf a) f 5,10 &lt;1H, s) , 5.55 (1H, s) t 6.22 {2H, s) , 6.74 (2H, s) , 7.66 (4H, J « 8.4 H«) r 7.79 (lHf d, J « 6.4 Hz) , 9,05 &lt;1H, s).

141666.doc 實施例1 - 7 10 1H-NMR (400 mzf DMSO-dg) δ 1.43 o K {9H, 3), 4.48 (2H, S) , 4.66 (2Bf s&gt; , 5.14 (XH, , 5*56 (1H, s), H 6.27 (2Hf s&gt; , 7.46 UH, d, J « B,4 Hz), 7.57 (1H, d, J » 8.4 Hz) , 7,98 (1H, s), 9.26 (1H, s). 實施例1 - 7 1 ί141666.doc Example 1 - 7 10 1H-NMR (400 mzf DMSO-dg) δ 1.43 o K {9H, 3), 4.48 (2H, S) , 4.66 (2Bf s&gt; , 5.14 (XH, , 5*56 (1H, s), H 6.27 (2Hf s&gt; , 7.46 UH, d, J « B,4 Hz), 7.57 (1H, d, J » 8.4 Hz) , 7,98 (1H, s), 9.26 (1H , s). Example 1 - 7 1 ί

1H-NMR &lt;400 MHz, DMSO-d6) δ 1，44 (9H, s), 3,06 &lt;3H, s&gt;, 3.58 (2H, t, J « 6.8 Uz), 4.29 (2H, t, J « 6.8Hz), 5.09 (lHf s), 5.54 (1H, $), €.21 (2H, &amp;)f 6.66 (2H, $}, 7.64*7.73 (5H, m&gt;, 9.02 (1H, s). 實施例1 一 7 121H-NMR &lt;400 MHz, DMSO-d6) δ 1,44 (9H, s), 3,06 &lt;3H, s&gt;, 3.58 (2H, t, J « 6.8 Uz), 4.29 (2H, t, J « 6.8Hz), 5.09 (lHf s), 5.54 (1H, $), €.21 (2H, &amp;)f 6.66 (2H, $}, 7.64*7.73 (5H, m&gt;, 9.02 (1H, s ). Example 1 - 7 12

1H-KHR &lt;400 MHz, DMS0»d6) δ 1,43 (9H, s&gt;, 2.87 (3H, s), 3.68-3.74 {2H, m), 4.54-4.57 (2H, m), 5*02 &lt;1Η, B) f 5.48 (1H, s), 6.11 (2H, &amp;) f 7.46 (5H, s&gt;, 7.89 (1H, s&gt;, 8.17 &lt;1H, s) f 8.73 {1U, s). 實施例1 - 7 131H-KHR &lt;400 MHz, DMS0»d6) δ 1,43 (9H, s&gt;, 2.87 (3H, s), 3.68-3.74 {2H, m), 4.54-4.57 (2H, m), 5*02 &lt;1Η, B) f 5.48 (1H, s), 6.11 (2H, &amp;) f 7.46 (5H, s&gt;, 7.89 (1H, s&gt;, 8.17 &lt;1H, s) f 8.73 {1U, s) Example 1 - 7 13

1H-NMR &lt;400 MH2, DMSO»d«) δ 1.34 3.87 《3H, &lt;1H, 5,22 (2H, S&gt;, 5·44 UH, s&gt;, 6.06 (2H, a) t 7.21 {1H, d, Hz), 7.36 (1H, s) , 7.58 (1H, dr J =7.6 Hz) , 7.87 (1H, s) f 7.93 (!Hr s), 8.12 (1H, s). 507- 201028381 實施例編號 實施例1 - 7 14 實施例1 - 7 151H-NMR &lt;400 MH2, DMSO»d«) δ 1.34 3.87 "3H, &lt;1H, 5,22 (2H, S&gt;, 5·44 UH, s&gt;, 6.06 (2H, a) t 7.21 {1H , d, Hz), 7.36 (1H, s), 7.58 (1H, dr J = 7.6 Hz), 7.87 (1H, s) f 7.93 (!Hr s), 8.12 (1H, s). 507- 201028381 Example Numbering Example 1 - 7 14 Example 1 - 7 15

物性資料—————_— MS (ESI) m/z = 392 (M+H)+. LC/MS tR » 1.87 min. MS (ESI) m/z « 378 (M+H)+. LC/MS tR » 1.61 min. 實施例1 - 7 16Physical data——————— MS (ESI) m/z = 392 (M+H)+. LC/MS tR » 1.87 min. MS (ESI) m/z « 378 (M+H)+. LC /MS tR » 1.61 min. Example 1 - 7 16

實施例1 -. 7 17Example 1 -. 7 17

實施例1 - 7 18Example 1 - 7 18

XH-NMR (400 MHz, DMSO-d6) δ 1.44 (s, 9H&gt;, 3.86 (s, 3H&gt;, 5·05 (s# 1H), 5.15 (s, 2H), 5.55 &lt;s, 1H)f 6,15 (br, 2H&gt; # 7.06 {a r IB) , 7.34 (d, 1H, J = 8.6 Hz&gt;, 7.50 &lt;d, 1H, J * 8.6 H2) f 7.83 (s, 1H) , 8.03 (s, 1H), 8.82 (s, 1H). MS &lt;£SI) m/z = 417 &lt;M+H)+. LC/MS tn = 1,82 min-1H-NMH (400 MHz, DHSO-dg) δ 1.43 (s, 3,63 (s, 3H&gt;, 3.82 (s, 3H), 4.99 (a, 1H), 5.53 (s, 1H&gt;f 6.10 (s, 2H), 6.39 (s, 1H), 6.68 (S, 1H) , 6.95 (s, 1H) f 7.06 (d, 1H, J=8.1Hz)f 7.14 (s, IB), 7.36 (d7 1H# a = 8.1 Hz), 8-59 (s, 1H). MS (ESI) m/z « 391 (M+H&gt;+. LC/MS tR ^ 2.22 min. 1H-NMR (400 MHz, DMS0-d6) δ 1-43 (s, 9H), 3.64 (s, 3H), 5.05 (br, 1H), 5.10 (s, 2H), 5.54 (s, 1H), 6.40 &lt;s, 1H), 6,72 (s, 1H), 7.04 (s, XH) , 7.14 (s, 1H) , 7.25 (d# 1H, J » 7.6 Hz), 7.42 (d, 1H, J * 7.6 Hz), 8,74 (s, 1H), MS (ESI) m/z « 416 (M+H)+. LC/MS » 2.16 min. 141666.doc 508 - 201028381 實施例編號XH-NMR (400 MHz, DMSO-d6) δ 1.44 (s, 9H&gt;, 3.86 (s, 3H&gt;, 5·05 (s# 1H), 5.15 (s, 2H), 5.55 &lt;s, 1H)f 6,15 (br, 2H&gt;# 7.06 {ar IB) , 7.34 (d, 1H, J = 8.6 Hz&gt;, 7.50 &lt;d, 1H, J * 8.6 H2) f 7.83 (s, 1H) , 8.03 (s , 1H), 8.82 (s, 1H). MS &lt;£SI) m/z = 417 &lt;M+H)+. LC/MS tn = 1,82 min-1H-NMH (400 MHz, DHSO-dg δ 1.43 (s, 3,63 (s, 3H&gt;, 3.82 (s, 3H), 4.99 (a, 1H), 5.53 (s, 1H&gt;f 6.10 (s, 2H), 6.39 (s, 1H), 6.68 (S, 1H) , 6.95 (s, 1H) f 7.06 (d, 1H, J=8.1Hz)f 7.14 (s, IB), 7.36 (d7 1H# a = 8.1 Hz), 8-59 (s, 1H). MS (ESI) m/z « 391 (M+H&gt;+. LC/MS tR^ 2.22 min. 1H-NMR (400 MHz, DMS0-d6) δ 1-43 (s, 9H), 3.64 ( s, 3H), 5.05 (br, 1H), 5.10 (s, 2H), 5.54 (s, 1H), 6.40 &lt;s, 1H), 6,72 (s, 1H), 7.04 (s, XH) , 7.14 (s, 1H) , 7.25 (d# 1H, J » 7.6 Hz), 7.42 (d, 1H, J * 7.6 Hz), 8,74 (s, 1H), MS (ESI) m/z « 416 (M +H)+. LC/MS » 2.16 min. 141666.doc 508 - 201028381 Example number

K 實施例1 -7X9K Example 1 -7X9

實施例1 -7 2 0Example 1 -7 2 0

物性資料____ 1H-NMR (400 MHz, DMSO〇 δ 1.44 (sf 9H&gt;, 3*25 (s, 3H), 3.72 (m, 2H) , 4.27 (m, 2H) ,5.05 (tor, 1H), S.iS S.55 &lt;s, 1H&gt;, 6·14 &lt;br, 2H), 7.06 (s, XH), 7.35 (d, inr J « 7,6 Hz) , 7.51 {dr lHf J * 7.6 Hz), 7.86 (s, 1H), 8.06 (a, 1H), 8.83 (&amp;, 1H). MS (£SX) m/z « 461 LC/MS » 1.85 min. 1H-NMR &lt;400 棚DMSO-de) δ 1.43 (stf 9H) , 1.79 {d, 3Hr J = 6.1 Hz), 3*87 U, 3Η&gt;, 5·05 &lt;s, 1H&gt;, 5·30 (q, XH, J « 6.1 Hz) , 5.54 (s, 1H), 6·；15 2H&gt;, 7·12 7,35 (df XHf J * 8.6 Hz) , 7.49 &lt;d, 1H, J* 8-6 Hz) , 7,82 (s, 1H) , 8,01 (s, 1H) , 8.83 (s, 1H&gt;. MS &lt;£SI) m/z = 431 (M+H)+. LC/MS tR * 1.91 min.Physical data ____ 1H-NMR (400 MHz, DMSO 〇 δ 1.44 (sf 9H&gt;, 3*25 (s, 3H), 3.72 (m, 2H), 4.27 (m, 2H), 5.05 (tor, 1H), S.iS S.55 &lt;s, 1H&gt;, 6·14 &lt;br, 2H), 7.06 (s, XH), 7.35 (d, inr J « 7,6 Hz) , 7.51 {dr lHf J * 7.6 Hz), 7.86 (s, 1H), 8.06 (a, 1H), 8.83 (&amp;, 1H). MS (£SX) m/z « 461 LC/MS » 1.85 min. 1H-NMR &lt;400 shed DMSO -de) δ 1.43 (stf 9H) , 1.79 {d, 3Hr J = 6.1 Hz), 3*87 U, 3Η&gt;, 5·05 &lt;s, 1H&gt;, 5·30 (q, XH, J « 6.1 Hz) , 5.54 (s, 1H), 6·; 15 2H&gt;, 7·12 7,35 (df XHf J * 8.6 Hz) , 7.49 &lt;d, 1H, J* 8-6 Hz) , 7,82 (s, 1H) , 8,01 (s, 1H) , 8.83 (s, 1H&gt;. MS &lt;£SI) m/z = 431 (M+H)+. LC/MS tR * 1.91 min.

1H-NMR &lt;400 MHz, DMSO-de&gt; δ 1.47 (s, 9H), 5.58 (sf 1H)f 6.21 {sf 1H&gt;, {d, 2H, J=8*6Hz&gt;, 6·85 (sf 2H) r 7.50 (df 2Hf J « 8,6 Bz), 7.80 (s, 1H), 8.25 {a, 1H).1H-NMR &lt;400 MHz, DMSO-de&gt; δ 1.47 (s, 9H), 5.58 (sf 1H)f 6.21 {sf 1H&gt;, {d, 2H, J=8*6Hz&gt;, 6·85 (sf 2H ) r 7.50 (df 2Hf J « 8,6 Bz), 7.80 (s, 1H), 8.25 {a, 1H).

MS (HSX) m/z « 348 (M+H)+. LC/MS * 1.36 min. 1H-NMR (300 MHz, CDC13&gt; 51.43 &lt;s, 9H&gt;, 3.66 (s, 4H&gt;, 5.05 (s, 1H)f 5.52 (s, XH), 6.17 (S/ 2H), 6.97 實施例1 - (s, 1H) , 7.35 (d, 2H, J * 8.6 Hz), 7 2 2 Me tx 7.56 (d, 2H, J « 8.6 Sz&gt; , 7.65 (e, 1H), 8,86 (s, Ifi). MS (ESI) m/z = 362 (H+H)+. LC/MS tR * 1.26 min.MS (HSX) m/z « 348 (M+H)+. LC/MS * 1.36 min. 1H-NMR (300 MHz, CDC13&gt; 51.43 &lt;s, 9H&gt;, 3.66 (s, 4H&gt;, 5.05 (s , 1H)f 5.52 (s, XH), 6.17 (S/ 2H), 6.97 Example 1 - (s, 1H), 7.35 (d, 2H, J * 8.6 Hz), 7 2 2 Me tx 7.56 (d, 2H, J « 8.6 Sz&gt; , 7.65 (e, 1H), 8,86 (s, Ifi). MS (ESI) m/z = 362 (H+H)+. LC/MS tR * 1.26 min.

141666.doc 509- 201028381 [表 1-4] nh2141666.doc 509- 201028381 [Table 1-4] nh2

N NH 表1-4中記載之化合物係依據上述記載之實施例1-541之 步驟3及步驟4之方法而合成。 實施例編號 R 物性資料_ Μχ 1H-NWH (400 imz, 0MSO-d6&gt; δ 1-15 {brs, 1H)f 1.33 (brs, 4H), 1.63 O (brs, 1H), 1.74 {brs, 2H), 1.92 (brs, 2H) , 3.12 (s, 3H&gt;, 3.79 (s, 實施例1 一 7 24N NH The compounds described in Tables 1-4 were synthesized in accordance with the procedures of Steps 3 and 4 of Examples 1-541 described above. Example No. R Physical data _ Μχ 1H-NWH (400 imz, 0MSO-d6&gt; δ 1-15 {brs, 1H)f 1.33 (brs, 4H), 1.63 O (brs, 1H), 1.74 {brs, 2H) , 1.92 (brs, 2H) , 3.12 (s, 3H&gt;, 3.79 (s, Example 1 - 7 24

1B&gt; , 5.50 (s, 1H&gt; , 5.94 (dl, 〇r: 7.3 Hz, 1H) , 6.26 (s, 2H) ,7.70 (d, J « 8.6 Hz , 2H) , 7.88 {d, J =« 8.6 Hz , 2H&gt;, 9.38 &lt;s, 1H). MS (BSI) m/z = 386 (M+H)+. LC/MS tR * 1.84 min. 1H-NMR (400 MHz, DMSO-de) 6 1,07-1.22 (br, 1H) , 1.24-1.38 {br, 4H) , 1.63-1.66 (brr 1H) ,1.75 (brsf 2H), 1.91 (brs, 2H)f 3,02 (s, 3H) , 3,81 (brs, 1H&gt; , 4,36 實施例1 — 7 2 5 (brs, 2H&gt;, 5.47 (s, 1H) , 5.85 (d, ^e~NvJl J® 7,8 Hz, 1H&gt; , 6·18 (s, r 7·45 ❹ (df J = 8·3 Hz, 1Η) , 7.56 (d, J » 8.3 Ha, 1H) , 8.01 (s, 1H) , 9.17 (s, 1H). MS (ESI) m/z *« 377 (H+H)+. LC/MS tR =* 1.61 min. 510- 141666.doc 201028381 實施例編號1B&gt; , 5.50 (s, 1H&gt;, 5.94 (dl, 〇r: 7.3 Hz, 1H), 6.26 (s, 2H), 7.70 (d, J « 8.6 Hz , 2H) , 7.88 {d, J =« 8.6 Hz , 2H&gt;, 9.38 &lt;s, 1H). MS (BSI) m/z = 386 (M+H)+. LC/MS tR * 1.84 min. 1H-NMR (400 MHz, DMSO-de) 6 1 , 07-1.22 (br, 1H) , 1.24-1.38 {br, 4H) , 1.63-1.66 (brr 1H) , 1.75 (brsf 2H), 1.91 (brs, 2H)f 3,02 (s, 3H) , 3 , 81 (brs, 1H&gt;, 4, 36 Example 1 - 7 2 5 (brs, 2H&gt;, 5.47 (s, 1H), 5.85 (d, ^e~NvJl J® 7,8 Hz, 1H&gt;, 6 · 18 (s, r 7·45 ❹ (df J = 8·3 Hz, 1Η), 7.56 (d, J » 8.3 Ha, 1H), 8.01 (s, 1H), 9.17 (s, 1H). MS ( ESI) m/z *« 377 (H+H)+. LC/MS tR =* 1.61 min. 510- 141666.doc 201028381 Example number

R 實施例1 一 7 2 6R Example 1 A 7 2 6

實施例1 -7 2 7Example 1 -7 2 7

物性資料_ 1H-NMR (400 MHz, OMSO-cfe) δ 1.15 (brs, 1H&gt;, 1.26-1.39 (br, 4H), 1,63 (brs , 1H) , 1.75 &lt;brs, 3H), 1.91 (fcrs, 2H&gt;, 3,24 ύ, 4H), 3·52 (brs, 2H), 3.62 (brs, 3H), 3.81 (bra, 1H) r 4.43 (a, 2H) , 5.47 (s, 1H), 5.86 (d, J* 7.3 Hz, 1H&gt; , 6,19 &lt;s, , 7·47 » 8·3 Hz, iH&gt; , 7.56 (d, a « 8.3 Hz, 1H&gt; , 8.00 (s, XH), 9.19 (sf IH), MS &lt;£SX) m/« - 421 (M+H)+. LC/MS tR « 1*68 min* MS (ESI) m/« * 308 (M+H)+. LC/MS tR « 2.00 min.Physical data _ 1H-NMR (400 MHz, OMSO-cfe) δ 1.15 (brs, 1H&gt;, 1.26-1.39 (br, 4H), 1,63 (brs, 1H), 1.75 &lt;brs, 3H), 1.91 ( Fcrs, 2H&gt;, 3,24 ύ, 4H), 3·52 (brs, 2H), 3.62 (brs, 3H), 3.81 (bra, 1H) r 4.43 (a, 2H) , 5.47 (s, 1H), 5.86 (d, J* 7.3 Hz, 1H&gt;, 6,19 &lt;s, , 7·47 » 8·3 Hz, iH&gt; , 7.56 (d, a « 8.3 Hz, 1H&gt; , 8.00 (s, XH) , 9.19 (sf IH), MS &lt;£SX) m/« - 421 (M+H)+. LC/MS tR « 1*68 min* MS (ESI) m/« * 308 (M+H)+ . LC/MS tR « 2.00 min.

1H-NMER (40Q MHz, DMSO-ds) δ 1.16 (brs, 1H), 1.33 (brs, 4H&gt;, 1.64 (brs, 1H), 1.74 (brsr 2H), 1.92 (brs, 2H) , 3.05 (s, 3H&gt; , 3.80 &lt;s, 〇 〇 lfi), 5.46 (s, 1H) , 5.87 &lt;d, J=7.81H-NMER (40Q MHz, DMSO-ds) δ 1.16 (brs, 1H), 1.33 (brs, 4H&gt;, 1.64 (brs, 1H), 1.74 (brsr 2H), 1.92 (brs, 2H) , 3.05 (s, 3H&gt; , 3.80 &lt;s, 〇〇lfi), 5.46 (s, 1H) , 5.87 &lt;d, J=7.8

實施例 1 — MeHz, im, 6.19 u, 2H&gt;, 7·26 (d, &lt;J 7 2 8 |1 » 15.7 Hz, 1H) , 7.38 &lt;d, J * 15.7 # Hz, r 7.56 J » 7·8 Hz, 2H&gt; , 7.74 {df J « 7.8 Hz, 2H&gt; , 9.17 (3, 1H&gt; . MS (ESI) m/« *= 412 (M+H) + . LC/MS tR * X.84 min* 1H-NMR {400 MHz, DMSO-de) δ 1.14 (brs, 1H) f 1.33 (brs,仰，1.58 (d, σ^β.βΗζ, 3H) , 1.65 (brs/ 1H), 1.75 (brs, 2H&gt;, 1.91 (bxs, 2H&gt;, 〇 3.82 (brs, 1H&gt; , 4.41-4.56 (m, 2H), 實施例 1 — ' 5.37 (d, J = 6.8 Hz, 1H) , 5.49 {s, 7 2 9 XH)r 5-87 (d# J*6.8 Hz, 1H) , 6.22 (st 2H) , 7.54 (dy J =« 8.1 1H), 7.73 (df J « 8.X He, 1H) , 7.95 (St 9.29 ：LH&gt;· MS (ESI) m/z * 416 LC/MS tR * 1,82 min. 511 - 141666.doc 201028381 實施例編號_R_物性資料_ 1H-NMR (400 HHz, DMSO_d«) δ 1.18 (s, 3H) , 1.19 &lt;s, 3H) , 1.21-1.37 (s, 5H) f 1.S3 (br, XH&gt; , 1.74 (brs, 2H) ,1.91 (br&amp;, 2B) r 3.16 (s, 1H), Q 3.81 &lt;s, 1H) , 4^27-4.42 (in, 3H), 實施例 1 — 5.47 &lt;3, 1H) , 5.84 (d, J « 7,3 Hz , 730 Me 1H) , 6.18 (sr 2H) , 7.45 &lt;dr J * 7.6Example 1 - MeHz, im, 6.19 u, 2H&gt;, 7·26 (d, &lt;J 7 2 8 |1 » 15.7 Hz, 1H) , 7.38 &lt;d, J * 15.7 # Hz, r 7.56 J » 7·8 Hz, 2H&gt;, 7.74 {df J « 7.8 Hz, 2H&gt; , 9.17 (3, 1H&gt; . MS (ESI) m/« *= 412 (M+H) + . LC/MS tR * X. 84 min* 1H-NMR {400 MHz, DMSO-de) δ 1.14 (brs, 1H) f 1.33 (brs, sag, 1.58 (d, σ^β.βΗζ, 3H), 1.65 (brs/ 1H), 1.75 ( Brs, 2H&gt;, 1.91 (bxs, 2H&gt;, 〇3.82 (brs, 1H&gt;, 4.41-4.56 (m, 2H), Example 1 - ' 5.37 (d, J = 6.8 Hz, 1H), 5.49 {s, 7 2 9 XH)r 5-87 (d# J*6.8 Hz, 1H) , 6.22 (st 2H) , 7.54 (dy J =« 8.1 1H), 7.73 (df J « 8.X He, 1H) , 7.95 ( St 9.29 : LH &gt; MS (ESI) m / z * 416 LC / MS tR * 1, 82 min. 511 - 141666.doc 201028381 Example number _R_physical data _ 1H-NMR (400 HHz, DMSO_d«) δ 1.18 (s, 3H) , 1.19 &lt;s, 3H) , 1.21-1.37 (s, 5H) f 1.S3 (br, XH&gt; , 1.74 (brs, 2H) , 1.91 (br&amp;, 2B) r 3.16 (s, 1H), Q 3.81 &lt;s, 1H) , 4^27-4.42 (in, 3H), Example 1 - 5.47 &lt;3, 1H) , 5.84 (d, J « 7,3 Hz , 730 Me 1H) , 6.18 (sr 2H) , 7.45 &lt; Dr J * 7.6

Hz , 1H) y 7.6S (d, J « 7.6 Hz , 1H), 7.88 (Bf 1H)A 9.17 (s, XH), MS (ESI) m/z « 405 (M+H)+. liC/MS Or x . / mm , 實施例1 - 0 1 MS (ESI) m/z = 421 (M+H)+. LC/MS ta = 1.65 min. 7 3 1 0人 Me」 八* 1H-KMR {400 MHz, DMSO-d6) δ 1.14 (brs, 1H) , 1.31 (tors, 4H&gt; , 1.58-1.67 (br, 1H) , 1.75 (brs, 2H) , 1.91 (brs, 2H), 3.82 (brs, 〇 1H), 4.28 (a, 2H), 5.47 (s, 1H), 實施例 1 — ΗΝ^ΐΓ^Ι 5.86 {ά, J «= 8.1 H27 1H) , 6.18 (s, 7 3 2 2H) , 7.46 (d# J= 8.3 Hz, 1H) , 7.54 (d, J « 8.3 Hz, 1H) , 8.04 &lt;s, 1H&gt; , 8.19 (s, 1H), 9.18 (s, 1H). MS &lt;ESX) m/z : 363 (M+H)+. LC/MS tR « 1.46 min. 實施例1 -7 3 3Hz , 1H) y 7.6S (d, J « 7.6 Hz , 1H), 7.88 (Bf 1H)A 9.17 (s, XH), MS (ESI) m/z « 405 (M+H)+. liC/MS Or x . / mm , Example 1 - 0 1 MS (ESI) m/z = 421 (M+H)+. LC/MS ta = 1.65 min. 7 3 1 0 people Me" 八* 1H-KMR {400 MHz, DMSO-d6) δ 1.14 (brs, 1H) , 1.31 (tors, 4H&gt; , 1.58-1.67 (br, 1H) , 1.75 (brs, 2H) , 1.91 (brs, 2H), 3.82 (brs, 〇1H ), 4.28 (a, 2H), 5.47 (s, 1H), Example 1 - ΗΝ^ΐΓ^Ι 5.86 {ά, J «= 8.1 H27 1H) , 6.18 (s, 7 3 2 2H) , 7.46 (d# J = 8.3 Hz, 1H), 7.54 (d, J « 8.3 Hz, 1H) , 8.04 &lt;s, 1H&gt; , 8.19 (s, 1H), 9.18 (s, 1H). MS &lt;ESX) m/z : 363 (M+H)+. LC/MS tR « 1.46 min. Example 1 -7 3 3

MS &lt;ESX) m/z « 495 (M+H)+. LC/MS tR » 1.71 min. 實施例1 -7 3 4MS &lt;ESX) m/z « 495 (M+H)+. LC/MS tR » 1.71 min. Example 1 -7 3 4

MS (ESI) m/z » 437 (M+H)+. LC/MS tR * X,55 min. 512· 141666.doc 201028381MS (ESI) m/z » 437 (M+H)+. LC/MS tR * X, 55 min. 512· 141666.doc 201028381

物性資料_ MS &lt;£SI) ta/z a 504 (M-fΗ)+. 1.C/HS tR * 1.77 min. 實施例編號 實施例1.-7 3 5Physical property data_MS &lt;£SI) ta/z a 504 (M-fΗ)+. 1.C/HS tR * 1.77 min. Example No. Example 1.-7 3 5

OO

實施例1 M 7 3 6Example 1 M 7 3 6

Me〇-^N MS (£S1) m/z * 493 I*C/MS tR « 1.86 min.Me〇-^N MS (£S1) m/z * 493 I*C/MS tR « 1.86 min.

實施例1 -7 3 7Example 1 -7 3 7

M3 (BS1) m/z « 507 &lt;M+H)+. I*C/MS tR = 1.98 min. 0 MS (BSD m/z ® 495 (M+H)+. LC/MS = 1.50 min. 實施例l - 7 3 8 XH-NHR (400 HBz, DMSO-de) δM3 (BS1) m/z « 507 &lt;M+H)+. I*C/MS tR = 1.98 min. 0 MS (BSD m/z ® 495 (M+H)+. LC/MS = 1.50 min. Example l - 7 3 8 XH-NHR (400 HBz, DMSO-de) δ

MeO*MeO*

實施例1 -7 3 9 1.14-1.87 &lt;m, 10Η&gt; , 2·93 《s, 3H&gt; , 3.32 (s, 3H), 3.68 {m, 2H), 3.86 (取，1H&gt;, 4.09 &lt;m, 5.35 (s, 1H) , 5.63 (d, 1H, J « 6 Hz) , 6.02 (ar 2H), 6.95 (d, XH, J * 6 Ha), 7.48 (s, 1H), 7.53 idf 1H, J « 6 Hz), 8.71 (af 1H).Example 1 -7 3 9 1.14-1.87 &lt;m, 10Η&gt;, 2·93 "s, 3H&gt;, 3.32 (s, 3H), 3.68 {m, 2H), 3.86 (take, 1H&gt;, 4.09 &lt; m, 5.35 (s, 1H) , 5.63 (d, 1H, J « 6 Hz) , 6.02 (ar 2H), 6.95 (d, XH, J * 6 Ha), 7.48 (s, 1H), 7.53 idf 1H, J « 6 Hz), 8.71 (af 1H).

實施例1 -7 4 0Example 1 -7 4 0

MeOMeO

IXIX

M e人。 XH-NMR (400 HHz, DMSO-de) δ 1.13-1,87 (m, 10B) r 2.07 {s, 3H), 3.34 (s, 3H)f 3.65 (m, 2H), 3.83 (m, 1H), 4.08 (m, 2H), 5.35 (s, 1H) f 5.60 (d, 1H, 〇r « 6 Hz) f 5.99 (sf 2B), 6*92 (d, 1H, J « 6 Ha), 7,31 (d, 1H, J = 6 Hz), 8.67 (s, 1H). 8.93 (s, 1H). 513- 141666.doc 201028381 實施例編號M e person. XH-NMR (400 HHz, DMSO-de) δ 1.13-1,87 (m, 10B) r 2.07 {s, 3H), 3.34 (s, 3H)f 3.65 (m, 2H), 3.83 (m, 1H) , 4.08 (m, 2H), 5.35 (s, 1H) f 5.60 (d, 1H, 〇r « 6 Hz) f 5.99 (sf 2B), 6*92 (d, 1H, J « 6 Ha), 7, 31 (d, 1H, J = 6 Hz), 8.67 (s, 1H). 8.93 (s, 1H). 513- 141666.doc 201028381 Example number

R 實施例1 一 7 4 1R Example 1 A 7 4 1

NH2 實施例1 一 7 4 2NH2 Example 1 A 7 4 2

物性資料_ 1H-KMR (400 MHz, DMSO-d6) δ 1.14-1,86 &lt;m, 10Η&gt;, 3,82-3.96 (m, 1Η) , 5.44 (s, 1H) , 5.75 &lt;d, 1H, J * 6 Hx) , 6.16 (s, 2H) , 7.25 (s, 2H) Λ 7,33 (d, 1H, J » 6 Hz), 7.38 (df 1H, J » 6 Hz) , 7.99 &lt;s, 2H) . 9.15 (3, XH) ·_ MS (ESI) m/z « 489 (M+H)+. I*C/MS tR » 1.60 min. 1H-NMR (400 MHz, DMSO-d«) δ 〇〇 X.17-1.94 (m, X〇H) , 3.75-3.90 實施例 i — &lt;mr 1H), 5.48 (s, 1H), 5.94 (d# 1H, 7 4 3 2 Ij j J * 6 Hz) , 6.23 (s, 2H) , 7.13 (s, 2H&gt; , 7,64 (d, 2H, «Τ * 6 Hz) , 7.81 (d, 2H, J = 6 Hz), 9.25 (s, 1H&gt;Physical data _ 1H-KMR (400 MHz, DMSO-d6) δ 1.14-1,86 &lt;m, 10Η&gt;, 3,82-3.96 (m, 1Η), 5.44 (s, 1H) , 5.75 &lt;d, 1H, J * 6 Hx) , 6.16 (s, 2H) , 7.25 (s, 2H) Λ 7,33 (d, 1H, J » 6 Hz), 7.38 (df 1H, J » 6 Hz) , 7.99 &lt; s, 2H) . 9.15 (3, XH) ·_ MS (ESI) m/z « 489 (M+H)+. I*C/MS tR » 1.60 min. 1H-NMR (400 MHz, DMSO-d« δ 〇〇X.17-1.94 (m, X〇H) , 3.75-3.90 Example i - &lt;mr 1H), 5.48 (s, 1H), 5.94 (d# 1H, 7 4 3 2 Ij j J * 6 Hz) , 6.23 (s, 2H) , 7.13 (s, 2H&gt; , 7,64 (d, 2H, «Τ * 6 Hz), 7.81 (d, 2H, J = 6 Hz), 9.25 (s, 1H&gt ;

實施例i — 7 4 6 1H-NMR (400 MHz, DMSO-de) δ 1.17-1.92 (m, l〇H) # 3.02 (s# 3H), 3.35 (nw 2H), 3,58 (m, 2H), 3.84 (mr 1H), 5.16 (sf 2H), 5.49 (s, 1H) , 5.66 (d, 1H, J - 6 Hz) , 6.23 (s, 2H) , 6.51 (d, 1H, J = 12 Hz), 7,12 (sf 1H)f 7.46 (d, 1H, 6Example i - 7 4 6 1H-NMR (400 MHz, DMSO-de) δ 1.17-1.92 (m, l〇H) # 3.02 (s# 3H), 3.35 (nw 2H), 3,58 (m, 2H ), 3.84 (mr 1H), 5.16 (sf 2H), 5.49 (s, 1H) , 5.66 (d, 1H, J - 6 Hz) , 6.23 (s, 2H) , 6.51 (d, 1H, J = 12 Hz ), 7,12 (sf 1H)f 7.46 (d, 1H, 6

Hz) , 7.61 (dr 1H# J = 12 Hz) , 7.77 (d, 1H, J - B Hz) f 8.29 (bs, 1H&gt; # 9.22 (s, 1H}. 514- 141666.doc 201028381 實施例編號Hz) , 7.61 (dr 1H# J = 12 Hz) , 7.77 (d, 1H, J - B Hz) f 8.29 (bs, 1H&gt;# 9.22 (s, 1H}. 514- 141666.doc 201028381 Example number

R 實施例1 — 7 4 7R Example 1 - 7 4 7

物性資料_ 1H-KMK &lt;400 MHz, DMSO-d6) δ 1,17-1.93 (m, 10H) , 3,27 (s, 3H), 3.35 (m, 4H)r 3.85 (mf 1H) , 5.16 (Bf 2H), 5.49 (s, 1H), 5.87 (bs, 1H)f 6.22 (&amp;f 2H)f 6.56 &lt;d, XB, J « 12 Hz)f 7*11 (sf 1H), 7.44 (df 1H, J « 6 Hz) , 7.57 (d, 1H, J « 12 Hz) r 7.77 (d, 1H, J 6 Hz) , 8.07 (bsf 1H), &amp;.2X {sf 1H).Physical data _ 1H-KMK &lt;400 MHz, DMSO-d6) δ 1,17-1.93 (m, 10H) , 3,27 (s, 3H), 3.35 (m, 4H)r 3.85 (mf 1H) , 5.16 (Bf 2H), 5.49 (s, 1H), 5.87 (bs, 1H)f 6.22 (&amp;f 2H)f 6.56 &lt;d, XB, J « 12 Hz)f 7*11 (sf 1H), 7.44 ( Df 1H, J « 6 Hz) , 7.57 (d, 1H, J « 12 Hz) r 7.77 (d, 1H, J 6 Hz) , 8.07 (bsf 1H), &amp;.2X {sf 1H).

實施例1 — 7 4 8 賁施例i — 7 4 9Example 1 - 7 4 8 Example i - 7 4 9

1H-NMR (400 MHz, DMSO-de) 5 1,17-2.00 (m, 10H) , 3.16 (s t 3H), 3.92 &lt;sr 3H)f 5.49 (s, 1H), 5,92 (bs, 1H), 6.3D {Bf 2H), 7.25 (B, IB) f 7.57 (ra, 1H), 7.67 (m, 1H), 9.35 is, XH). MS (ESI) m/z « 541 (M+H)+· LC/MS tR = 1.76 min.1H-NMR (400 MHz, DMSO-de) 5 1,17-2.00 (m, 10H), 3.16 (st 3H), 3.92 &lt;sr 3H)f 5.49 (s, 1H), 5,92 (bs, 1H ), 6.3D {Bf 2H), 7.25 (B, IB) f 7.57 (ra, 1H), 7.67 (m, 1H), 9.35 is, XH). MS (ESI) m/z « 541 (M+H) +· LC/MS tR = 1.76 min.

實施例i 7 5 2Example i 7 5 2

7,73 (4H, dd, J « 18.4, 8.4 Hz), 8.15 (lHt s)# 9,10 &lt;1H, s). in-mm (4〇o mhz, onso-de) δ ι.ΐβ {6H, d, J = 6.4 Hz&gt;, 1.34 (5H, br B) r 1.64-1.76 &lt;3H, m) f 1.94 &lt;2H, br s&gt; , 3.83 (1H, br s) , 4.02-4.11 (1H, m) , 5.47 (1H, a) , 5,85 (IK, d, J = 7.2 H«) f 6.17 (2H, s) r 7.71 (4H, s) , 8.00 (1H, df J « 7.2 Hz), 9.09 (1H, s). 141666.doc 515- 201028381 實施例編號7,73 (4H, dd, J « 18.4, 8.4 Hz), 8.15 (lHt s)# 9,10 &lt;1H, s). in-mm (4〇o mhz, onso-de) δ ι.ΐβ { 6H, d, J = 6.4 Hz&gt;, 1.34 (5H, br B) r 1.64-1.76 &lt;3H, m) f 1.94 &lt;2H, br s&gt; , 3.83 (1H, br s) , 4.02-4.11 (1H , m) , 5.47 (1H, a) , 5,85 (IK, d, J = 7.2 H«) f 6.17 (2H, s) r 7.71 (4H, s) , 8.00 (1H, df J « 7.2 Hz) , 9.09 (1H, s). 141666.doc 515- 201028381 Example Number

R 實施例1 — 7 5 3R Example 1 - 7 5 3

實施例1 一 7 54Example 1 a 7 54

物性資料_ 1H—HMR (400 MHz, DHSO&quot;d6) δ 1.19-1.34 &lt;9H, m), 1.64-1.99 (10Η, m)7 3.71 (lHf br s)f 3.82 (1H, br s) , 4.60 (1H, d, J = 3.2 Hz) , 5.47 (1H, s&gt; , 5.85 &lt;lHy d, J »7.2 Hz) r 6.17 (2H, s) , 7.71 (4H, 3) , 7,96 (1H, d, J « 7.2 Hz) , 9,09 (1H, s) ·__ 1H-NMR (400 MHz, DMSO-de) δ 1.18 (1H, br s) , 1.35 (4H, br s), 1.65-1.77 (3H, m), 1.94 (2Hf s), 3.03 (3H, a) , 3.66 (2H# d, J « 6.4 Ha:) , 3.82 (1H, br s) , 5.47 (1H, s), 5.88 (XH, d, J = 6.8 Hz) , 6.18 (2H, S), 7.73 (4H, s) , 8.52 &lt;1H, s), 9.14 (1H, s). 1H-NHR (400 MHz, DMSO-de) δ 1.14-1.35 &lt;8H, m&gt; , 1.62-1,75 (3H, 9 m) , 1.90 (2H, br s) , 3.87 (1H, brPhysical data _ 1H—HMR (400 MHz, DHSO&quot;d6) δ 1.19-1.34 &lt;9H, m), 1.64-1.99 (10Η, m)7 3.71 (lHf br s)f 3.82 (1H, br s) , 4.60 (1H, d, J = 3.2 Hz), 5.47 (1H, s&gt; , 5.85 &lt;lHy d, J »7.2 Hz) r 6.17 (2H, s) , 7.71 (4H, 3) , 7,96 (1H, d, J « 7.2 Hz) , 9,09 (1H, s) ·__ 1H-NMR (400 MHz, DMSO-de) δ 1.18 (1H, br s) , 1.35 (4H, br s), 1.65-1.77 ( 3H, m), 1.94 (2Hf s), 3.03 (3H, a), 3.66 (2H# d, J « 6.4 Ha:) , 3.82 (1H, s s) , 5.47 (1H, s), 5.88 (XH, d, J = 6.8 Hz), 6.18 (2H, S), 7.73 (4H, s) , 8.52 &lt;1H, s), 9.14 (1H, s). 1H-NHR (400 MHz, DMSO-de) δ 1.14 -1.35 &lt;8H, m&gt; , 1.62-1,75 (3H, 9 m) , 1.90 (2H, br s) , 3.87 (1H, br

實施例 1 — H2M人s) , 5.44 (1H, s) , 5.79 (1H, d, JExample 1 - H2M person s), 5.44 (1H, s), 5.79 (1H, d, J

7 5 5 II J =&gt; 7.6 Hz) , 6.13 (2H, s) , 7,11 (1H, s&gt; , 7.31 &lt;1H, d, J = 7.6 Hz), 7.48-7.55 (3H7 m), 8.92 &lt;XHr s). 0 1H-NMR (400 MHz, DHSO-d6) δ 1,22-1.30 &lt;5H, m) t 1.59 (1H, br s&gt; , 1.71 (2H, br s) , 1.82 &lt;2H, br 實施例1 一 s) , 2.26 (3H, s) , 3.76 (1H, br s), 5.46 &lt;1H, s) , 5.69 (1H, d, J = 7.6 7 5 6 τ * Me Hz), 6.09 (2H, s), 7.15 (1H# s), 7.62 (1H, df J= 7.8 Hz) , 7,71 (1H, s) , 7.81 (2H, d, J « 7.8 Hz) , 8.01 (lHf s}. 0 1H-NMR (400 MHz, DMSO-d6) δ 1.18 (2H, br s) r 1.31-1,38 (5H, m), 1.64-1.68 (3H, m), 1,76 (2H, br 實施例1 - hct^ 产 s) , 1.94 (2H, br s) , 3.83 &lt;2H, br 7 5 7 H 1 s) f 4.52 (2H, br s) , 5.46 (1H, s), 5.87 {1H, d, J = 7,2 Hz) , 6.17 (2H, s)/ 7.71 &lt;4H, s), 8.26 &lt;1H, s&gt;, 9*10 (1H, s)* -516- 141666.doc 201028381 實施例編號 K 物性資料 實施例I — 7 5 8 ocf3 實施例1 — 7597 5 5 II J => 7.6 Hz) , 6.13 (2H, s) , 7,11 (1H, s&gt; , 7.31 &lt;1H, d, J = 7.6 Hz), 7.48-7.55 (3H7 m), 8.92 &lt;XHr s). 0 1H-NMR (400 MHz, DHSO-d6) δ 1,22-1.30 &lt;5H, m) t 1.59 (1H, br s&gt;, 1.71 (2H, br s) , 1.82 &lt; 2H, br Example 1 s), 2.26 (3H, s), 3.76 (1H, br s), 5.46 &lt;1H, s), 5.69 (1H, d, J = 7.6 7 5 6 τ * Me Hz) , 6.09 (2H, s), 7.15 (1H# s), 7.62 (1H, df J= 7.8 Hz) , 7,71 (1H, s) , 7.81 (2H, d, J « 7.8 Hz) , 8.01 (lHf s}. 0 1H-NMR (400 MHz, DMSO-d6) δ 1.18 (2H, br s) r 1.31-1,38 (5H, m), 1.64-1.68 (3H, m), 1,76 (2H, Br Example 1 - hct^ s), 1.94 (2H, br s) , 3.83 &lt; 2H, br 7 5 7 H 1 s) f 4.52 (2H, s s) , 5.46 (1H, s), 5.87 { 1H, d, J = 7,2 Hz) , 6.17 (2H, s)/ 7.71 &lt;4H, s), 8.26 &lt;1H, s&gt;, 9*10 (1H, s)* -516- 141666.doc 201028381 Example No. K Physical Data Example I - 7 5 8 ocf3 Example 1 - 759

1H-NMR (400 MHz, DMSO-de) δ X.15-1.33 (5H, ta) f 1.61-1.87 (4H, m&gt; r 3.75 (1H, br s) , 5.72《1H, s》， 5.89 (XHf d, J » 7.2 Hz) # 6.24 (2H, s), 7.37 (1H, B} f 7.79-7,82 (2H, m), 8.04 (1H, a), 8.43 (1H, d, J »8.4 Uz) f 8.68 &lt;XR, s). 1H-NMR (400 mzt DHSO-d6) $ 1.32-1.38 (5Hf m) , 1.65-1*69 (1H, m) f 1.76 {2H, br s) , 1.94 (2H, br s&gt; , 3.82 &lt;1H, br s&gt; , S.46 &lt;1H, s&gt; , 5.87 (1H, dr 〇T » 7,2 H«) , 6.17 (2H, s) , 7.73 (4H, s) , 8.25 (1H, s), 9.XI (1H, s). • 實施例i 一 ΥΊ 1H-NMR (400 MHz, OMSO-de) $ X.15-1.34 (5Hr m) f X.62-1,66 &lt;XH, m), 1.75 (2H, s&gt;, 1.91 (2H, s), 3.81(:111,3),3.88 1313),5.65 UH, s) , 5·85 (1H, d, J * 7.6 Hz}, 7 6 0 OMe 6.13 {2K, s&gt;, 7.18 (1H, s&gt; x 7.43-7.48 (2Hf m), 7.90 (XHf s), 8.00 (1H, s&gt; , 8.32 (1H, d, J « 8.4 Hz), 實施例1 一 7 6 11H-NMR (400 MHz, DMSO-de) δ X.15-1.33 (5H, ta) f 1.61-1.87 (4H, m&gt; r 3.75 (1H, br s) , 5.72 "1H, s", 5.89 (XHf d, J » 7.2 Hz) # 6.24 (2H, s), 7.37 (1H, B} f 7.79-7,82 (2H, m), 8.04 (1H, a), 8.43 (1H, d, J »8.4 Uz f 8.68 &lt;XR, s). 1H-NMR (400 mzt DHSO-d6) $ 1.32-1.38 (5Hf m) , 1.65-1*69 (1H, m) f 1.76 {2H, br s) , 1.94 ( 2H, br s&gt; , 3.82 &lt;1H, br s&gt; , S.46 &lt;1H, s&gt; , 5.87 (1H, dr 〇T » 7,2 H«) , 6.17 (2H, s) , 7.73 (4H , s) , 8.25 (1H, s), 9.XI (1H, s). • Example i ΥΊ 1H-NMR (400 MHz, OMSO-de) $ X.15-1.34 (5Hr m) f X. 62-1,66 &lt;XH, m), 1.75 (2H, s&gt;, 1.91 (2H, s), 3.81 (:111,3), 3.88 1313), 5.65 UH, s), 5·85 (1H, d, J * 7.6 Hz}, 7 6 0 OMe 6.13 {2K, s&gt;, 7.18 (1H, s&gt; x 7.43-7.48 (2Hf m), 7.90 (XHf s), 8.00 (1H, s&gt; , 8.32 (1H , d, J « 8.4 Hz), Example 1 A 7 6 1

1H-NMR (400 MHz, DMSO-de) δ 1.16 (1H, br s&gt; , 1.34 (4Hf br s), 1.65-1.74 (3H, n〇 , 1.93 (2H, br s) # 3.07 &lt;3H, l&gt;r s} , 3.82 {1H, br 3&gt;, 4.30 &lt;2H, s&gt;, S.S3 &lt;1H, 5.81 (1H, s), 6.17 (2H, s) f 6.65 s}, 7.60 &lt;2H, s&gt;, 7.80 &lt;3H, br s), 9.29 (!Hr s). 141666.doc 517- 201028381 實施例編號1H-NMR (400 MHz, DMSO-de) δ 1.16 (1H, br s&gt;, 1.34 (4Hf br s), 1.65-1.74 (3H, n〇, 1.93 (2H, br s) # 3.07 &lt;3H, l&gt ;rs} , 3.82 {1H, br 3&gt;, 4.30 &lt;2H, s&gt;, S.S3 &lt;1H, 5.81 (1H, s), 6.17 (2H, s) f 6.65 s}, 7.60 &lt; 2H, s&gt;, 7.80 &lt;3H, br s), 9.29 (!Hr s). 141666.doc 517- 201028381 Example number

R 實施例1 — 7 6 2R Example 1 - 7 6 2

實施例1 — 7 6 3Example 1 - 7 6 3

實施例1 — 7 6 4Example 1 - 7 6 4

實施例1 — 7 6 5Example 1 - 7 6 5

MeO 物性資料_ 1H-NMR (400 MHz, DMSO*d6) δ 1.15-Χ.32 (5Hf m&gt; , 1.60-1.73 (3H, xn) r 1.89 (2H, s) t 3.07 (3H, s), 3.58 (2Bf t, J « 6.8 Hz) r 3.80 &lt;3B, s) , 3.89 (1H, br s) , 4.28 (2H, t, J- 6.4 Hz) , 5.49 (1H, s) , 5.78 (1H, d, J = 7.2 Hz) t 6,18 &lt;2H, s), 6.47-6.50 &lt;2H# m) # 7.21-7-23 (2H, m) f 7,53 (1H, d, J = 8.0 Hz) , 7,64 (IH, dr J = 6.8 Hz) , 9,05 (1H, s). 1H-NMR (400 MHz, DMSO-d6) δ 1.17 {1H, br s) , 1.28-1.44 (8H, m), 1.63 &lt;1H, d, J=rl2.4 H«) , 1.75 (3H, s&gt; , 1.88 (2H, s&gt;, 3.87 (1H, s), 4.15 (2H, q, J = S.8 H*&gt; , 5·48 UH, s) , 5.84 (1H, d, J = 7.2 Hz) , 6.21 &lt;2H, s), 7.14 (lHr s&gt;, 7.34 (1H, s) , 7.47 (1H, s), 7.57 (1H, d, J =8.0 Hz) , 7.77 ClHf d, J= 8.0 Hz), 9,11 (1H, s) ·_ 1H-NMR (400 MHz, DMSO-d6) δ 1.17 &lt;1H, br s) , X.31-1.36 &lt;4H, m), X.63-1.77 (2H, m&gt;, 1.94 (3H, br s), 2.88 (3H, s) r 3.73 (2Ut t, J -6,8 Hz) , 4.55 (2H, t, 6.8 Hz) f 5,42 (1H, s) , 5.75 UH, d, J = 7,2 Hz) r 6.07 (2H, a) f 7.41 (2Hr d, J * 8.4 Hz) , 7.63 (2H, d, J «* 8.4 Hz), 7.87 (1H, s), 8.17 &lt;1H, s), 8,83 (1H, s? ._ 1H-KMR (400 MHz, DMSO-cU) δ 1.17 &lt;1H, br s) , 1.31 (4H, br s&gt; , 1.59 (1H, br s) , 1.71 (2H, br s) , 1.88 (2H, br s) , 3.85 (3H, s) , 5.24 (2Hf s) , 5.43 &lt;1H, s) , 5.69 (lHf br s), 6.07 &lt;2H, s)f 7.18 (1H, s), 7,40 (1H, br s) f 7.47 (lHf br s) , 7.81 (1H, 5), 8.01 (1H, s), 8,83 (1H, s). 141666.doc 518- 201028381 實施例編號 實施例1 7 6 6MeO Physical Data _ 1H-NMR (400 MHz, DMSO*d6) δ 1.15-Χ.32 (5Hf m&gt; , 1.60-1.73 (3H, xn) r 1.89 (2H, s) t 3.07 (3H, s), 3.58 (2Bf t, J « 6.8 Hz) r 3.80 &lt;3B, s) , 3.89 (1H, br s) , 4.28 (2H, t, J- 6.4 Hz) , 5.49 (1H, s) , 5.78 (1H, d , J = 7.2 Hz) t 6,18 &lt;2H, s), 6.47-6.50 &lt;2H# m) # 7.21-7-23 (2H, m) f 7,53 (1H, d, J = 8.0 Hz ), 7,64 (IH, dr J = 6.8 Hz), 9,05 (1H, s). 1H-NMR (400 MHz, DMSO-d6) δ 1.17 {1H, br s) , 1.28-1.44 (8H, m), 1.63 &lt;1H, d, J=rl2.4 H«) , 1.75 (3H, s&gt; , 1.88 (2H, s&gt;, 3.87 (1H, s), 4.15 (2H, q, J = S. 8 H*&gt; , 5·48 UH, s) , 5.84 (1H, d, J = 7.2 Hz), 6.21 &lt;2H, s), 7.14 (lHr s&gt;, 7.34 (1H, s), 7.47 (1H , s), 7.57 (1H, d, J = 8.0 Hz), 7.77 ClHf d, J = 8.0 Hz), 9,11 (1H, s) ·_ 1H-NMR (400 MHz, DMSO-d6) δ 1.17 &lt;;1H, br s) , X.31-1.36 &lt;4H, m), X.63-1.77 (2H, m&gt;, 1.94 (3H, br s), 2.88 (3H, s) r 3.73 (2Ut t, J -6,8 Hz) , 4.55 (2H, t, 6.8 Hz) f 5,42 (1H, s) , 5.75 UH, d, J = 7,2 Hz) r 6.07 (2H, a) f 7.41 (2Hr d, J * 8.4 Hz) , 7.63 (2H, d, J «* 8.4 Hz), 7.87 (1H, s), 8.17 &lt;1H, s), 8,83 (1H, s? ._ 1H-KMR (400 MHz, DMSO-cU) δ 1.17 &lt;1H, br s) , 1.31 (4H, br s&gt; , 1.59 (1H, br s) , 1.71 (2H, br s) , 1.88 (2H, br s) , 3.85 (3H, s) , 5.24 (2Hf s) , 5.43 &lt;;1H, s) , 5.69 (lHf br s), 6.07 &lt;2H, s)f 7.18 (1H, s), 7,40 (1H, br s) f 7.47 (lHf br s) , 7.81 (1H, 5 ), 8.01 (1H, s), 8,83 (1H, s). 141666.doc 518- 201028381 Example Numbering Example 1 7 6 6

物性資料_ 1H-HMR (400 MHz, DHSO-de) δ 1.29-1.35 (5Η,ια), X.59-1.63 (1Η, η〇, α.72 (2Η, br s) , 1.85 {2H, br s) , 3.87 (1H, s), 5.45 (1H, s), 5.86 (1H; d, J« 7.2 Hz) , g.25 (2H, s&gt;, 7·40 (2H, s&gt;, 7.80 &lt;2H, d, J =9.2 Hz&gt;, 8.18 UH, s&gt;, 9.28 &lt;1H, s).Physical data _ 1H-HMR (400 MHz, DHSO-de) δ 1.29-1.35 (5Η, ια), X.59-1.63 (1Η, η〇, α.72 (2Η, br s) , 1.85 {2H, br s) , 3.87 (1H, s), 5.45 (1H, s), 5.86 (1H; d, J« 7.2 Hz) , g.25 (2H, s&gt;, 7·40 (2H, s&gt;, 7.80 &lt; 2H, d, J = 9.2 Hz&gt;, 8.18 UH, s&gt;, 9.28 &lt;1H, s).

實施例1 — Μβ—ΝΊ 1H-KMR (400 MHz, DMSO»d«》 δ 1.16-1.29 (5Hf m) f 1,54-1.58 (1H, m) , 1.70 (2H, br s) , 1.82 (2H, fcr s), 2.21 (3H, a), 3,85 (4H, s), 7 6 7 Me 5.19 {int ai t 5.53 (1H, d, J * 8.0 Hz) , 5.98 (2Hf B) f 7.30 &lt;1H, d, J =8.0 Hz) , 7.40 {2H, s) , 7.79 (1H, s), 7.89 (1H, s), 8.05 &lt;1H, s)- 實施例1 7 6 8Example 1 - Μβ-ΝΊ 1H-KMR (400 MHz, DMSO»d«》 δ 1.16-1.29 (5Hf m) f 1,54-1.58 (1H, m) , 1.70 (2H, br s) , 1.82 (2H , fcr s), 2.21 (3H, a), 3,85 (4H, s), 7 6 7 Me 5.19 {int ai t 5.53 (1H, d, J * 8.0 Hz) , 5.98 (2Hf B) f 7.30 &lt;;1H, d, J = 8.0 Hz) , 7.40 {2H, s) , 7.79 (1H, s), 7.89 (1H, s), 8.05 &lt;1H, s) - Example 1 7 6 8

1H-NMR (400 MHz, DMSO-de) δ 1.10-1.29 (5H, m) , 1.S7 UH, d, *7 =* 11.2 Hz) , 1.70 (2H, br a) , 1.83 (2H, fcr s&gt; , 2·22 &lt;3H, s&gt; , 3*18 &lt;1H, s) , 3.78 &lt;3H, br s) , 4.X6 (2Hf s) r 5.21 (1H, s), 5.52 (1H, d, J«7.2 Hz) f 5,99 (2H, s) , 7.32 (1H, d, J « 8.0 Hz) , 7.42 (2H, s) , 7.82 (1H, s) , 7.89 (1H, s&gt;, 8.07 &lt;1H, s&gt;, 8.15 (1H, s),1H-NMR (400 MHz, DMSO-de) δ 1.10-1.29 (5H, m) , 1.S7 UH, d, *7 =* 11.2 Hz) , 1.70 (2H, br a) , 1.83 (2H, fcr s&gt ; , 2·22 &lt;3H, s&gt; , 3*18 &lt;1H, s) , 3.78 &lt;3H, br s) , 4.X6 (2Hf s) r 5.21 (1H, s), 5.52 (1H, d, J«7.2 Hz) f 5,99 (2H, s) , 7.32 (1H, d, J « 8.0 Hz) , 7.42 (2H, s) , 7.82 (1H, s) , 7.89 (1H, s&gt;, 8.07 &lt;1H, s&gt;, 8.15 (1H, s),

實施例1 — 7 6 9Example 1 - 7 6 9

1H-NHR (400 MHz, DMSO-de) δ 1.05-1*29 (5H, m) , 1.53-1*56 (1H, m) , 1·66-1,68 (2H, m) f 1,79-1.82 (2H, m) , 3.69 (lHr br s) , 3.87 (3H, s), 5.48 (XH, s)f 5.75 &lt;1Η, d, J = 7.2 Hz), 6.21 (2H, s) f 7.71 (2H, dd, J = 33.6, 8.0 Hz), 7.93 &lt;2H, s), 8.21 (1H, s), 8.87 (1H, s). 141666.doc 519· 201028381 實施例編號1H-NHR (400 MHz, DMSO-de) δ 1.05-1*29 (5H, m) , 1.53-1*56 (1H, m) , 1·66-1,68 (2H, m) f 1,79 -1.82 (2H, m) , 3.69 (lHr br s) , 3.87 (3H, s), 5.48 (XH, s)f 5.75 &lt;1Η, d, J = 7.2 Hz), 6.21 (2H, s) f 7.71 (2H, dd, J = 33.6, 8.0 Hz), 7.93 &lt; 2H, s), 8.21 (1H, s), 8.87 (1H, s). 141666.doc 519· 201028381 Example Number

R 實施例1 - 7 7 0R Example 1 - 7 7 0

實施例1 - 7 7 1Example 1 - 7 7 1

實施例1 - 7 7 2Example 1 - 7 7 2

Me—NMe-N

OMe 物性資料_ 1H-NMR (400 MHz, DHSO-d6) δ 1.16 (m, 1H), 1.29-1.35 (mf 4H)f 1.63 (m, 1ΪΠ , 1.73 {m, 2H) , 1.92 &lt;m, 2H ) , 3.83 (sf 3H) , 3.83 (brs, 1H), 5.41 (s, 1H) , 5.72 (d, 1H, J = 7.6 Hz) , 6.05 (st 2H} , 7.39 {d, 2H, J =8.1 Hx) , 7.60 (df 2H, J * 8.1 Hz) r 7.76 (S, 1H), 8.01 (s, 1H), 8.80 (S, 1H). MS (ESI) m/z = 388 (M+H)+. LC/MS tR « 1.65 min. 1H-KMR (400 MHz, DMSO-d6) δ 1.17 (m, 1H), 1.24-1.32 (m, 3H), 1.62 (m# 1H), 1.73 {m, 2H), 1.89 (mf 2H), 3.85 (3, 6H&gt;, 3.91 (m, 1H)7 5.45 (s, 1H) , 5.70 (d, 1H, J = 7.6 Hz)7 6.10 (s, 2H&gt;, 7.16 (s, 1H), 7,35 (d, XH, J = 8.3 H«&gt; , 7,39 &lt;d, 1H, J « 8.3 Hz) , 7.80 (s, IH) , 8.00 (s, 1H), 8.81 (s, 1H). MS (ESI) m/z * 418 &lt;M-fH) + . I«C/MS tR = 2.07 min. 1H-NMR ¢400 MHz, DMSO-d6) δ 1-16 (m, XH), 1.30 {mt 4H), 1.62 (m, 1H&gt;, 1.73 {mf 2H), 1.88 (m, 2H), 3.82 (br, 1H) f 3.86 (s, 3H) ,3.87 (s, 3H) , 5.48 (s, 1H) , 5.68 (d, XH, J * 6-6 Hz) , 6.02 (s, 2H) , 7.04 (df 1H, J =» 8.1 Hz&gt; , 7·17 (s, 1H) , 7.73 (s, 1H) , 7.84 &lt;s, 1H) , 7.95 {d, 1H, J » 8.1 Hz), 8.10 (sf 1H). MS (ESI) m/z « 418 (M+H)\ LC/MS fcR « 1·72 min. 141666.doc 520- 201028381 實施例編號OMe Physical Properties _ 1H-NMR (400 MHz, DHSO-d6) δ 1.16 (m, 1H), 1.29-1.35 (mf 4H)f 1.63 (m, 1ΪΠ , 1.73 {m, 2H) , 1.92 &lt;m, 2H ), 3.83 (sf 3H) , 3.83 (brs, 1H), 5.41 (s, 1H) , 5.72 (d, 1H, J = 7.6 Hz) , 6.05 (st 2H} , 7.39 {d, 2H, J =8.1 Hx ), 7.60 (df 2H, J * 8.1 Hz) r 7.76 (S, 1H), 8.01 (s, 1H), 8.80 (S, 1H). MS (ESI) m/z = 388 (M+H)+. LC/MS tR « 1.65 min. 1H-KMR (400 MHz, DMSO-d6) δ 1.17 (m, 1H), 1.24-1.32 (m, 3H), 1.62 (m# 1H), 1.73 {m, 2H), 1.89 (mf 2H), 3.85 (3, 6H&gt;, 3.91 (m, 1H)7 5.45 (s, 1H), 5.70 (d, 1H, J = 7.6 Hz) 7 6.10 (s, 2H&gt;, 7.16 (s, 1H), 7,35 (d, XH, J = 8.3 H«&gt; , 7,39 &lt;d, 1H, J « 8.3 Hz) , 7.80 (s, IH) , 8.00 (s, 1H), 8.81 ( s, 1H). MS (ESI) m/z * 418 &lt;M-fH) + . I«C/MS tR = 2.07 min. 1H-NMR ¢400 MHz, DMSO-d6) δ 1-16 (m, XH), 1.30 {mt 4H), 1.62 (m, 1H&gt;, 1.73 {mf 2H), 1.88 (m, 2H), 3.82 (br, 1H) f 3.86 (s, 3H) , 3.87 (s, 3H) , 5.48 (s, 1H) , 5.68 (d, XH, J * 6-6 Hz) , 6.02 (s, 2H) , 7.04 (df 1H, J =» 8.1 Hz&gt; , 7·17 (s, 1H), 7.73 (s, 1H) , 7 .84 &lt;s, 1H) , 7.95 {d, 1H, J » 8.1 Hz), 8.10 (sf 1H). MS (ESI) m/z « 418 (M+H)\ LC/MS fcR « 1·72 Min. 141666.doc 520- 201028381 Example number

R 實施例1 -7 7 3R Example 1 -7 7 3

物性資料_ 1H-NMR (300 ΗΗζ, CDC13) δ 1.17 (m, XH), 1.24-1,35 imT 4H) , 1.62 (mf 1H)? 1.74 (m, 2H), 1.91 (m, 2H), 2.33 (a, 3H), 3,87 (s, 3H), 3.87 &lt;m, 1H) , 5.41 (s, XH) , 5.72 (ά, 1H, 7.1 Hz) , 6.07 (s, 2H) , 7.19 (d, 1H, J * B.6 H2) , 7.43 (d, lHf J = 8.6 Bz) f 7.53 (Br 1H), 7.59 (s, 1H), 7,85 (a, 1H), 8.76 (s&gt; 1H). MS (BSD m/z « 402 &lt;M+H) + ·Physical Properties _ 1H-NMR (300 ΗΗζ, CDC13) δ 1.17 (m, XH), 1.24-1, 35 imT 4H) , 1.62 (mf 1H)? 1.74 (m, 2H), 1.91 (m, 2H), 2.33 (a, 3H), 3,87 (s, 3H), 3.87 &lt;m, 1H) , 5.41 (s, XH) , 5.72 (ά, 1H, 7.1 Hz) , 6.07 (s, 2H) , 7.19 (d , 1H, J * B.6 H2) , 7.43 (d, lHf J = 8.6 Bz) f 7.53 (Br 1H), 7.59 (s, 1H), 7,85 (a, 1H), 8.76 (s&gt; 1H) MS (BSD m/z « 402 &lt;M+H) + ·

I*C/HS tn » 1.78 min. MS {ESI) m/z « 457 實施例1 - X*C/HS tR * 1.26 min. 7 7 4 H2N Me (XI*C/HS tn » 1.78 min. MS {ESI) m/z « 457 Example 1 - X*C/HS tR * 1.26 min. 7 7 4 H2N Me (X

IH-liMR (400 imzf DMSO-de) δ 1.17 {m, 1H&gt;, 1.36 (mi 4H), 1.64 (m, 1H), 1.75 (m, 2H) , 1*95 (m, 2H), 3*84 〇», 1H&gt;, 3·87 &lt;s, 3H&gt;, S.43 (s, 1H) , 5*86 (dr 1H, J - 6.6 Hz), 6.17 (sf 2H) , 7.15 (d, 1H, J « 8.6 Hz) , 7,50 &lt;t, 1H, 8.3 Hz&gt; , 7.79 (s, 1H&gt; 〆 7.98 (d, 1H, J » 8·β Hz&gt; , 8.02 (s, 1H), 9.07 (s, 1H). MS (£SX) m/z ® 406 {Μ+·Η) + .IH-liMR (400 imzf DMSO-de) δ 1.17 {m, 1H&gt;, 1.36 (mi 4H), 1.64 (m, 1H), 1.75 (m, 2H) , 1*95 (m, 2H), 3*84 〇», 1H&gt;, 3·87 &lt;s, 3H&gt;, S.43 (s, 1H), 5*86 (dr 1H, J - 6.6 Hz), 6.17 (sf 2H) , 7.15 (d, 1H, J « 8.6 Hz) , 7,50 &lt;t, 1H, 8.3 Hz&gt; , 7.79 (s, 1H&gt; 〆7.98 (d, 1H, J » 8·β Hz&gt; , 8.02 (s, 1H), 9.07 (s , 1H). MS (£SX) m/z ® 406 {Μ+·Η) + .

LC/MS tR = 2.00 min. 實施例1 - Μβ-Ν^ η 1H-NMR (400 MHz, DHSO-d6&gt; δ 1.13 (mf 1H), 1.27 (m, 4H), 1.59 (m, 1H&gt;, 1.72 (m, 2H&gt;, 1.8J5 (in, 3.76《m, 3.8S U, 3H), S.48 (s, 1H) , 5.70 (df lHf J = 8,1 Hz), 6,09 (s, 2H) r 7.27 (d, 1H, J « 8*1 7 7 6 F Hz&gt; , 7.41 (d, 1H, J篇 , 7.85 (sf 1H) , 7.S2 (t, 1H, J = 8.1 Hz), 8.13 (s, 1H), 8.41 (s, 1H). MS (ESI) m/z = 406 {M+H)+. XiC/MS tR - 2Λ9 min. 141666.doc 521 - 201028381 實施例編號 實施例1 — 7 7 7</ RTI> <RTIgt; (m, 2H&gt;, 1.8J5 (in, 3.76"m, 3.8SU, 3H), S.48 (s, 1H), 5.70 (df lHf J = 8,1 Hz), 6,09 (s, 2H) r 7.27 (d, 1H, J « 8*1 7 7 6 F Hz&gt; , 7.41 (d, 1H, J, 7.85 (sf 1H) , 7.S2 (t, 1H, J = 8.1 Hz), 8.13 ( s, 1H), 8.41 (s, 1H). MS (ESI) m/z = 406 {M+H) +. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> 141666.doc 521 - 201028381 Example Numbering Example 1 - 7 7 7

物性資料_ MS (£SX) m/z » 482 (M+H&gt;+. IiC/MS tR - 1.96 min.Physical Data _ MS (£SX) m/z » 482 (M+H&gt;+. IiC/MS tR - 1.96 min.

1H-NMR (400 MHz, DMSO-de) δ 1.16 {m, 1H&gt;, 1.31 {m, 4H), 1.59 (m, 1H&gt; r 1.71 (me 2H), 1.86 (m, 2H), 3.88 (s, 4H), 5.45 (s, 1H&gt;, 5.81 &lt;d, 1H, J ** 7,6 Hz) , 6.21 &lt;s, 2H), 7.31 (d, 1H, J = 8*6 Hi) , 7*50 (s, 1H), 7*80 (s, 2H), 8.20 (s, 1H), d.18 (s, XH). MS (ESI) m/z ® 456 (M+H)+. LC/HS tR = 2.15 min. 實施例1 - v _/Λΐ OMe MS (ESI) m/z » 487 (M-VH) + , LC/MS tR * 1.26 min. 7 7 9 h2n Me Ok1H-NMR (400 MHz, DMSO-de) δ 1.16 {m, 1H&gt;, 1.31 {m, 4H), 1.59 (m, 1H&gt; r 1.71 (me 2H), 1.86 (m, 2H), 3.88 (s, 4H), 5.45 (s, 1H&gt;, 5.81 &lt;d, 1H, J ** 7,6 Hz), 6.21 &lt;s, 2H), 7.31 (d, 1H, J = 8*6 Hi) , 7* 50 (s, 1H), 7*80 (s, 2H), 8.20 (s, 1H), d.18 (s, XH). MS (ESI) m/z ® 456 (M+H)+. LC/ HS tR = 2.15 min. Example 1 - v _/Λΐ OMe MS (ESI) m/z » 487 (M-VH) + , LC/MS tR * 1.26 min. 7 7 9 h2n Me Ok

實施例1 一 7 8 0 XH-NMR (400 MHz, DMSO-d6) δ 1.14 &lt;m, XH) , 1.30 (m, 4H) , 1,38 &lt;t, 3H, J»6.6Hz)f 1.61 (m, 1H) , 1.73 (m, 2H&gt; , 1.89 (mf 2H) , 3.82 (br, 1H&gt; , 3.85 {Sf 3H) , 4.14 (q, 2H, J«6.6 Hz) , 5.47 (af 1H) , 5.69 {d, 1H, J =* 7.1 Ha:) , 6.03 {sf 2H) , 7.03 (d, 1H, 7.16 {», 1H) t 7.58 (sr 1H) , 7.82 (s, 1H) , 7.95 (d, 1H, or = 8-1 Hz) # 8.09 (s, XH). HS (ESI) m/z » 432 (M+H)+. X.C/MS tR « 1.72 min. 實施例1 — 7 8 1Example 1 780 XH-NMR (400 MHz, DMSO-d6) δ 1.14 &lt; m, XH), 1.30 (m, 4H), 1,38 &lt;t, 3H, J»6.6 Hz)f 1.61 (m, 1H), 1.73 (m, 2H&gt;, 1.89 (mf 2H), 3.82 (br, 1H&gt;, 3.85 {Sf 3H) , 4.14 (q, 2H, J«6.6 Hz) , 5.47 (af 1H) , 5.69 {d, 1H, J =* 7.1 Ha:) , 6.03 {sf 2H) , 7.03 (d, 1H, 7.16 {», 1H) t 7.58 (sr 1H) , 7.82 (s, 1H) , 7.95 (d, 1H, or = 8-1 Hz) # 8.09 (s, XH). HS (ESI) m/z » 432 (M+H)+. XC/MS tR « 1.72 min. Example 1 — 7 8 1

實施例1 一 7 8 2Example 1 A 7 8 2

MS (ESI) m/z » 388 (M+H)+. LC/MS tR « 1.25 min. 522- 141666.doc 201028381 [表 1-5]MS (ESI) m/z » 388 (M+H)+. LC/MS tR « 1.25 min. 522- 141666.doc 201028381 [Table 1-5]

表1-5中記載之化合物係依據上述記載之實施例1-541之 步驟3及步驟4之方法而合成。 實施例編號The compounds described in Tables 1-5 were synthesized in accordance with the procedures of Steps 3 and 4 of Examples 1-541 described above. Example number

實施例1 — 7 8 3Example 1 - 7 8 3

Ο 實施例1 — 7 8 4实施 Example 1 - 7 8 4

實施例1 — 7 8 5Example 1 - 7 8 5

物性資料_ 1H-NMR (400 HHx, DMSO-d6&gt; 6 X.55-1.68 &lt;br, 2H)f 1,77-1,86 (b£, 2H) , 3*12 (St, 3H) , 3.42-3.45 &lt;br, , 4-02 &lt;brs, 1H&gt; , S.52 (s, 1H) , 6.2X &lt;df J* 7.3 Η», 1H) , 6.28 (s, 2H) , 7.72 &lt;d, « 8.3 Ha, 2H), 7.85 (df J == 8.3 fi«, 2H&gt; , 9,38 (S/ 1H). MS (ESI) m/z = 388 (M+H)+. LC/MS tR « 1-27 mia. 1H-NHR &lt;400 HH«, PMSO-cfc) 6 1.62 &lt;2H7 d, J * 8,4 Hz) , 1,85 (2Hf d, J * 12.4 Hz) f 3,91 &lt;2H, d, J = 9.6 Hz) , 4.06 (1H, s) , 5.49 (1H, s&gt; , 6.11-6-1S 6.53-6.57 《2H, m) r 7.39 (1H, d, 6.8 Hz) f 7,61 &lt;2H, d, J «= 8.4 Hz&gt; , 7,73 &lt;2H, d, J » 8.4 Hz) f 9.09 (1H； s), 1H-NMR (400 MHss, DMS0-d6) δ 1,18-1.24 (2H, m&gt; , 1.59-1.64 &lt;2H, m) , 1.S3-X.86 (2H, m) f 3.89-3.93 (2H, m&gt; , 4,01-4.09 (1H, m) f 5,01 (2H, s&gt; , 5.49 (1H, s&gt; , 6,13-6.20 (3H, m) , 6.77 (2H, s&gt; , 7.66-7.80 (4H, m), 9.14 (1H, s). 141666.doc 523 - 201028381 實施例編號 R 物性資料 實施例1 - 1H-NMR (400 MHz, DMSO-d6) δ 1,54-1-62 &lt;2Η, m) , 1.80 (2Η, d, «X « 12-0 Hz) , 3.86 (8Η, d, σ « 4.0 Ηζ&gt; ,4,02 &lt;2Hf br s) , 5.49 &lt;1Η, s&gt; , 7 8 6 5.96 (2Η, df J= 7.6 Hz) , 6.04 &lt;3H# OMe s) f 7.06 (1H, d, J * 7.6 Hz) f 7.17 (IE, s) f 7.76 (1H, s&gt; , 7.85-7*89 (3H, m&gt;, 8.11 (1H, s). 實施例1 7 8 7Physical data _ 1H-NMR (400 HHx, DMSO-d6 &gt; 6 X.55-1.68 &lt;br, 2H)f 1,77-1,86 (b£, 2H) , 3*12 (St, 3H) , 3.42-3.45 &lt;br, , 4-02 &lt;brs, 1H&gt; , S.52 (s, 1H) , 6.2X &lt;df J* 7.3 Η», 1H) , 6.28 (s, 2H) , 7.72 &lt;;d, « 8.3 Ha, 2H), 7.85 (df J == 8.3 fi«, 2H&gt; , 9,38 (S/ 1H). MS (ESI) m/z = 388 (M+H)+. LC/ MS tR « 1-27 mia. 1H-NHR &lt;400 HH«, PMSO-cfc) 6 1.62 &lt;2H7 d, J * 8,4 Hz) , 1,85 (2Hf d, J * 12.4 Hz) f 3 ,91 &lt;2H, d, J = 9.6 Hz) , 4.06 (1H, s) , 5.49 (1H, s&gt; , 6.11-6-1S 6.53-6.57 "2H, m) r 7.39 (1H, d, 6.8 Hz f 7,61 &lt;2H, d, J «= 8.4 Hz&gt; , 7,73 &lt;2H, d, J » 8.4 Hz) f 9.09 (1H; s), 1H-NMR (400 MHss, DMS0-d6) δ 1,18-1.24 (2H, m&gt; , 1.59-1.64 &lt; 2H, m) , 1.S3-X.86 (2H, m) f 3.89-3.93 (2H, m&gt; , 4,01-4.09 (1H, m) f 5,01 (2H, s&gt; , 5.49 (1H, s&gt; , 6,13-6.20 (3H, m) , 6.77 (2H, s&gt; , 7.66-7.80 (4H, m), 9.14 (1H, s). 141666.doc 523 - 201028381 Example No. R Physical Properties Example 1 - 1H-NMR (400 MHz, DMSO-d6) δ 1,54-1-62 &lt;2Η, m) , 1.8 0 (2Η, d, «X « 12-0 Hz) , 3.86 (8Η, d, σ « 4.0 Ηζ&gt; , 4,02 &lt;2Hf br s) , 5.49 &lt;1Η, s&gt; , 7 8 6 5.96 ( 2Η, df J= 7.6 Hz) , 6.04 &lt;3H# OMe s) f 7.06 (1H, d, J * 7.6 Hz) f 7.17 (IE, s) f 7.76 (1H, s&gt; , 7.85-7*89 ( 3H, m&gt;, 8.11 (1H, s). Example 1 7 8 7

Me-~N,Me-~N,

1H-KMR (400 ΜΗ ss, DMSO-d«) δ 1.55-1.63 (2H, ia&gt; , 1.74-1.79 &lt;2H, m) , 3.84 (5H, s) , 3.95 (2H, br s), 5.47 (1H, s&gt; , 6.11-6.X5 (3H, m) f 6.92-6.99 (2Hf m) f 7,47 (1H, d, J * 8.4 Hz) , 7.72 (1H, s) , 8.02 (2H, d, J « 16.4 Hz), 10.24 (1H, s). 實施例1 — 7 8 81H-KMR (400 ΜΗ ss, DMSO-d«) δ 1.55-1.63 (2H, ia&gt;, 1.74-1.79 &lt;2H, m), 3.84 (5H, s), 3.95 (2H, br s), 5.47 ( 1H, s&gt; , 6.11-6.X5 (3H, m) f 6.92-6.99 (2Hf m) f 7,47 (1H, d, J * 8.4 Hz) , 7.72 (1H, s) , 8.02 (2H, d , J « 16.4 Hz), 10.24 (1H, s). Example 1 – 7 8 8

實施例1 - 7 8 9Example 1 - 7 8 9

1H-2JMR (400 MHe/ DMSO-de) ί5 1.54-1.61 (2Η, m) , 1*79 (2Η, d., J * 10.8 Hz) , 3.87 &lt;5H, s&gt; , 3.95-4.04 (2H, m), 5.23 &lt;2H, s), 5-51 (1H, s) f 5.98 (1H, d, J « 7.2 Hz) , 6.07 (2H, S) , 7.19 (1H, d, J « 7.2 Hz) , 7.36 (1H, s) , 7.86 (1H, s) r 7.92-7.98 (2Hf m) , 8.11 (1H, s)- MS &lt;ESX) m/z ® 390 &lt;M+H)+. LC/MS tR = 1.30 min. 實施例1 — 7 9 01H-2JMR (400 MHe/ DMSO-de) ί5 1.54-1.61 (2Η, m) , 1*79 (2Η, d., J * 10.8 Hz) , 3.87 &lt;5H, s&gt; , 3.95-4.04 (2H, m), 5.23 &lt;2H, s), 5-51 (1H, s) f 5.98 (1H, d, J « 7.2 Hz) , 6.07 (2H, S) , 7.19 (1H, d, J « 7.2 Hz) , 7.36 (1H, s) , 7.86 (1H, s) r 7.92-7.98 (2Hf m) , 8.11 (1H, s)- MS &lt;ESX) m/z ® 390 &lt;M+H)+. LC/ MS tR = 1.30 min. Example 1 - 7 9 0

1H-NMR &lt;400 MHz, DMSO-d6) δ X.25 (t, 3H, J » 6.8 Hz) , 1.61 (mf 2H), 1.81 &lt;m, 2H&gt; , 3.43 (s, 3H&gt; , 3.89 (m, 2H&gt;, 4*08 (bna, 1H) f 4.17 &lt;q, 2H, J* 6,8 Hz) , 5.28 (s, 2H) , 5.51 {at 1H) , 6.09 {df 1H, J * 6.1 Hz&gt; , 6.22 (s, 2H) , 6.49 (d, 1H, J = 15.7 He) , 7.18 (s, 1H), 7.63 (s, 2H), 7.85 (d, lHf J= 15.7 Hz) , 9.19 (s, 1H&gt; , MS &lt;SSI) m/z « 468 &lt;M+H)+. LC/MS tR « 1.87 min. 141666.doc -524- 2010283811H-NMR &lt;400 MHz, DMSO-d6) δ X.25 (t, 3H, J » 6.8 Hz), 1.61 (mf 2H), 1.81 &lt;m, 2H&gt;, 3.43 (s, 3H&gt;, 3.89 ( m, 2H&gt;, 4*08 (bna, 1H) f 4.17 &lt;q, 2H, J* 6,8 Hz) , 5.28 (s, 2H) , 5.51 {at 1H) , 6.09 {df 1H, J * 6.1 Hz&gt; , 6.22 (s, 2H) , 6.49 (d, 1H, J = 15.7 He) , 7.18 (s, 1H), 7.63 (s, 2H), 7.85 (d, lHf J= 15.7 Hz) , 9.19 (s , 1H&gt; , MS &lt;SSI) m/z « 468 &lt;M+H)+. LC/MS tR « 1.87 min. 141666.doc -524- 201028381

實施例編號Example number

R 實施例1 一 7 9 1R Example 1 A 7 9 1

實施例1 — 7 9 2Example 1 - 7 9 2

實施例1 一 7 9 3Example 1 A 7 9 3

物性資料_(400 MHz, DMSO-d6) δ 1.25 3Η, J = 6.8 Ηζ&gt; , 1.61 (m, , 1.83 &lt;m, 2Η) , 3.42 &lt;m, 2Η&gt; f 3.90 &lt;d, 2Η, J = 9,1 Hz) , 4.04 (m, 1Η&gt; , 4.17 (q, 2H, J » 6.8 Hz) , 5.20 (s, 2H) , 5.53 (s, 1H) , 6.15 (ά, 1H, J =7,6 Hz), 6.26 (S, 2H&gt;, 6.S2 &lt;d, 1H, 〇r = 16.2 , 7.09 (S, , 7.70{d, 1H, J « 7,6 Hz) , 7.75 (s, 1H), 7.77 (d, 1H# J « 16.2 Hz) , 9,30 (st 1H). MS (ESI) m/z = 463 (M+H)+. LC/MS tR « 1.81 min. 1H-NMR (400 MHz, DMSO-de) δ 1.61 (m, 2H) , 1.82 (m, 2H) , 3.90 (d, 2H, J = 8.6 Hz) Λ 4.07 (brs, 1H) , 5.25 (s, 2H) , 5.50 (s, 1H) , 6.08 (d, 1H, σ * 7.6 Hz) , 6.19 (s, 2H) t 6.50 (df lHr 16.2 Hz) , 6.94 (s, 1H) ,7.15 (s, 1H) , 7.43 {df 1H, J = 7,6 Hz), 7,44 (s, IH), 7.63 (9, XH)f 7*65 (d, 1H, J 16.2 Hz) , 9.11 {S, 1H). MS (ESI) m/z « 439 (M+H}+. LC/MS tR ® 1.21 min. 1H-NMR &lt;400 MHz, DHSO-de) δ 1.61 (m, 2H&gt;, 1.83 (m, 2H&gt;# 3.27 (s, 3B)f 3.42 (s, 3H), 3,91 (m, 2H), 4.07 (brs, 1H) , 5.25 (sf 2H) f 5.49 (sf 1H) f 6.08 (d, 1H, J=7.1Hz)f 6.19 2H&gt; , 6·55 &lt;d, J 篇 15.7 Hz) , 7.13 {s, 1H) f 7,41 &lt;d, 1H, J « 8.1 Η»), 7.64 (d, XH, J = 15.7 Hz) , 7.65 (d, 1H, J = 7.1 fiz) , 8.05 &lt;br, 1H), 9.11 (s, 1H). MS &lt;£S1) m/z = 497 (M+H)+, LC/HS » 1.80 min. 141666.doc 525 - 201028381 實施例編號Physical property data_(400 MHz, DMSO-d6) δ 1.25 3Η, J = 6.8 Ηζ&gt; , 1.61 (m, , 1.83 &lt;m, 2Η), 3.42 &lt;m, 2Η&gt; f 3.90 &lt;d, 2Η, J = 9,1 Hz) , 4.04 (m, 1Η&gt; , 4.17 (q, 2H, J » 6.8 Hz) , 5.20 (s, 2H) , 5.53 (s, 1H) , 6.15 (ά, 1H, J = 7, 6 Hz), 6.26 (S, 2H&gt;, 6.S2 &lt;d, 1H, 〇r = 16.2, 7.09 (S, , 7.70{d, 1H, J « 7,6 Hz) , 7.75 (s, 1H) , 7.77 (d, 1H# J « 16.2 Hz) , 9,30 (st 1H). MS (ESI) m/z = 463 (M+H)+. LC/MS tR « 1.81 min. 1H-NMR (400 MHz, DMSO-de) δ 1.61 (m, 2H) , 1.82 (m, 2H) , 3.90 (d, 2H, J = 8.6 Hz) Λ 4.07 (brs, 1H) , 5.25 (s, 2H) , 5.50 (s , 1H) , 6.08 (d, 1H, σ * 7.6 Hz) , 6.19 (s, 2H) t 6.50 (df lHr 16.2 Hz) , 6.94 (s, 1H) , 7.15 (s, 1H) , 7.43 {df 1H, J = 7,6 Hz), 7,44 (s, IH), 7.63 (9, XH)f 7*65 (d, 1H, J 16.2 Hz) , 9.11 {S, 1H). MS (ESI) m/ z « 439 (M+H}+. LC/MS tR ® 1.21 min. 1H-NMR &lt;400 MHz, DHSO-de) δ 1.61 (m, 2H&gt;, 1.83 (m, 2H&gt;# 3.27 (s, 3B )f 3.42 (s, 3H), 3,91 (m, 2H), 4.07 (brs, 1H), 5.25 (sf 2H) f 5.49 (sf 1H) f 6.08 (d, 1H, J=7.1Hz)f 6.19 2H &gt; , 6·55 &lt;d, J, 15.7 Hz), 7.13 {s, 1H) f 7,41 &lt;d, 1H, J « 8.1 Η»), 7.64 (d, XH, J = 15.7 Hz) , 7.65 (d, 1H, J = 7.1 fiz) , 8.05 &lt;br, 1H), 9.11 (s, 1H). MS &lt;£S1) m/z = 497 (M+H)+, LC/HS » 1.80 min. 141666.doc 525 - 201028381 Example number

R 實施例1 — 7 9 4R Example 1 - 7 9 4

實施例1 — 7 9 5Example 1 - 7 9 5

實施例1 — 7 9 6Example 1 - 7 9 6

物性資料_ 1H-HMR (400 MHz, DMSO-de) δ 1.61 (m, 3,27 U, 3H) , 3.90 (St, 2H&gt; , 4.06 (s, 1H&gt; , 5.16 (Br 2H), 5.51 (s, 1H&gt;, 6.14 (d, lHf J * 8.6 Hz) , 6.22 (s, 2H), 6.56 (d, 1H, J^lS.lHz), 7.09 (s, 1H) , 7.47 (d, 1H, J = 8.6Hz), 7.57 (dt 1H, J « 15.7 Hz) , 7.74 (d, 1H, J^8.6Hz), 8.07 (s, 1H) , 9.21 &lt;s, 1H). MS (£SZ) m/z = 492 (M+H)+. LC/MS tR =« 1.31 min. 1H-NMR (400 MHz, DMSO-de) δ 1.62 (m, 2H) , 1.85 (m, 2H) , 3.45 (tf 2H, J « IX.4 Hz), 3.55 (s, 3H), 3.93 (m, 2H&gt;, 4.06 (br, 1H), 5.46 &lt;s, © 1H&gt; , 6.09 (d, 1H, J*7.1Hz), 6.14 (s, 2H) , 7.63 (d, 2H, J « 8.6 Hz), 7.67 {df 2H, J « 8,6 Hz) , 8.42 &lt;s, 1H), 8.69 (B, 1H), 8.94 (s, XH). MS &lt;ESX) m/z ~ 454 (M+H)+, LC/MS : 3L * 31 1H-NMR (400 MHz, DMSO-de) δ 1.62 (mf 2H) f 1.84 (m, 2H) , 3.42 (t, 3H# J = 11.9 Hz), 3.76 (m, 2H) , 3.92 (d, 2H, J = 10.1 Hz) , 4.06 (br, 1H), 4.14 ist 2H) , 4.92 &lt;brsf 1H) , 5.44 (s, 1H) r 6.04 (cl, 1H, J * 7.1 Hz), 6,09 (s, 2H&gt; , 7.42 (d, 2H7 J = 8.1 Hz) , 7.59 (d, 2H, J = 8.1 Hz) , 7.80 {a, 1H&gt;, 8.05 (s, 1H), 8.82 (s, ^ 1H) . MS (ESI) m/z = 420 &lt;M4-H)+ . LC/MS tR = 1.04 min. 141666.doc 526· 201028381Physical data _ 1H-HMR (400 MHz, DMSO-de) δ 1.61 (m, 3,27 U, 3H), 3.90 (St, 2H&gt; , 4.06 (s, 1H&gt;, 5.16 (Br 2H), 5.51 (s , 1H&gt;, 6.14 (d, lHf J * 8.6 Hz), 6.22 (s, 2H), 6.56 (d, 1H, J^lS.lHz), 7.09 (s, 1H), 7.47 (d, 1H, J = 8.6Hz), 7.57 (dt 1H, J « 15.7 Hz) , 7.74 (d, 1H, J^8.6Hz), 8.07 (s, 1H) , 9.21 &lt;s, 1H). MS (£SZ) m/z = 492 (M+H)+. LC/MS tR = « 1.31 min. 1H-NMR (400 MHz, DMSO-de) δ 1.62 (m, 2H), 1.85 (m, 2H), 3.45 (tf 2H, J « IX.4 Hz), 3.55 (s, 3H), 3.93 (m, 2H&gt;, 4.06 (br, 1H), 5.46 &lt;s, © 1H&gt; , 6.09 (d, 1H, J*7.1Hz), 6.14 (s, 2H) , 7.63 (d, 2H, J « 8.6 Hz), 7.67 {df 2H, J « 8,6 Hz) , 8.42 &lt;s, 1H), 8.69 (B, 1H), 8.94 (s, MS &lt;ESX) m/z ~ 454 (M+H)+, LC/MS : 3L * 31 1H-NMR (400 MHz, DMSO-de) δ 1.62 (mf 2H) f 1.84 (m, 2H ), 3.42 (t, 3H# J = 11.9 Hz), 3.76 (m, 2H), 3.92 (d, 2H, J = 10.1 Hz), 4.06 (br, 1H), 4.14 ist 2H) , 4.92 &lt;brsf 1H ), 5.44 (s, 1H) r 6.04 (cl, 1H, J * 7.1 Hz), 6,09 (s, 2H&gt;, 7.42 (d, 2H7 J = 8.1 Hz), 7.59 (d, 2H, J = 8 .1 Hz) , 7.80 {a, 1H&gt;, 8.05 (s, 1H), 8.82 (s, ^ 1H) . MS (ESI) m/z = 420 &lt; M4-H)+ . LC/MS tR = 1.04 Min. 141666.doc 526· 201028381

實施例編號Example number

R 實施例1 一 7 9 7R Example 1 A 7 9 7

實施例1 — 7 9 8Example 1 - 7 9 8

實施例1 一 7 9 9Example 1 A 7 9 9

物性資料_ in-mm &lt;400 MHz, DMSO-d«) δ 1.37 (ra, 2H), 1.62 (mr 2H), 1.71 (m, 2H), 1.83 (mt 2H), 2.10 (mr 1H), 3·27 (s, 310, = Hz), 3.91 {mf 4H&gt;, 4.03 (mf XH), 5.49 {9f 1H) , 6.11 (d, 1H, J « 7.1 Hz), 6.20 &lt;s, 2H) f 6,SI (d, 1H, J «15.7 Hz), 6.95 (s, 1H) , 7.39 (d, IK, J « 8.1 Hz) , 7.61 {ύ, in, J « 8*1 Has) , 7.65 (ά, XBr 15.7 Hz), 8.01 (s, 1H&gt; # 9.04 (s, 1H). MS (ESI) m/z « 551 (H+H)+. LC/HS tR = 1.43 min. 1H-NMR (400 MHz, DMSO-de) δ 1.07 (m, 2H)r 1.17-1.31 (m, 3H), 1.60-1.75 &lt;m, 5H), 1.82 (br, 5H), 3.26 (s, 3H&gt; , 3.80 (d, 2H, J»4.5 Hz), 3,91 &lt;m, 2H), 4.06 &lt;s, 1H), 5.48 (s, 1H&gt; , 6.10 &lt;d, 1H, Jw7.6 Hz) , 6.20 (sr 2H&gt; , 6,50 &lt;d# 1H, J =15,7 Hz), 6.94 (Bf IB) ,7,38 (d, 1H, J = 8.6 Hz) , 7.59 (d, XH, J = 8.6 Hz) , 7.66 1H, J» 15,7 Hz&gt; , 8.00 (s, 1H)# 9,03 (s, 1H). MS m/2 « 549 (H+H) + . LC/HS tR - 1.89 min. 1H-NMR &lt;400 MH2, DMSO-de) δ 1.62 2H&gt; , 1·78 (d, 3H, J » 6·3· , 1.84 (m, 2H), 3,27 &lt;s, 3H)7 3.92 imt 2H) f 4.06 (br, 1H&gt;, S.29 (q, 1H, J = 6.1 Hz) , 5.51 (s, 1H) r 6.15 &lt;d, 1H, J » 6.S Hz&gt; , 6.23 &lt;s, 2fl&gt; , 6.58 (d, 1H, J = 15.7 Hz) r 7.18 (s, XH) , 7.47 (d, 1H, J * 7.6 Hz) , 7.54 &lt;d, lHr J « 15.7 Hz) , 7.74 (d, 1H, J«7.6Hz)# 8*11 (sf 1H) , 9.22 &lt;s, 1H). MS &lt;ESX&gt; m/z =* 506 (M+H)+. LC/MS tR * 1.36 xnin. 141666.doc 527- 201028381 實施例編號Physical property_in-mm &lt;400 MHz, DMSO-d«) δ 1.37 (ra, 2H), 1.62 (mr 2H), 1.71 (m, 2H), 1.83 (mt 2H), 2.10 (mr 1H), 3 · 27 (s, 310, = Hz), 3.91 {mf 4H&gt;, 4.03 (mf XH), 5.49 {9f 1H) , 6.11 (d, 1H, J « 7.1 Hz), 6.20 &lt;s, 2H) f 6 ,SI (d, 1H, J «15.7 Hz), 6.95 (s, 1H) , 7.39 (d, IK, J « 8.1 Hz) , 7.61 {ύ, in, J « 8*1 Has) , 7.65 (ά, XBr 15.7 Hz), 8.01 (s, 1H&gt;# 9.04 (s, 1H). MS (ESI) m/z « 551 (H+H)+. LC/HS tR = 1.43 min. 1H-NMR (400 MHz, DMSO-de) δ 1.07 (m, 2H)r 1.17-1.31 (m, 3H), 1.60-1.75 &lt;m, 5H), 1.82 (br, 5H), 3.26 (s, 3H&gt;, 3.80 (d, 2H , J»4.5 Hz), 3,91 &lt;m, 2H), 4.06 &lt;s, 1H), 5.48 (s, 1H&gt;, 6.10 &lt;d, 1H, Jw7.6 Hz), 6.20 (sr 2H&gt; , 6,50 &lt;d# 1H, J =15,7 Hz), 6.94 (Bf IB) , 7,38 (d, 1H, J = 8.6 Hz) , 7.59 (d, XH, J = 8.6 Hz) , 7.66 1H, J» 15,7 Hz&gt;, 8.00 (s, 1H)# 9,03 (s, 1H). MS m/2 « 549 (H+H) + . LC/HS tR - 1.89 min. 1H-NMR &lt;400 MH2, DMSO-de) δ 1.62 2H&gt;, 1·78 (d, 3H, J » 6·3· , 1.84 (m, 2H), 3,27 &lt;s, 3H)7 3.92 imt 2H) f 4.06 (br , 1H&gt;, S.29 (q, 1H, J = 6.1 Hz), 5.51 (s, 1H) r 6.15 &lt;d, 1H, J » 6.S Hz&gt; , 6.23 &lt;s, 2fl&gt; , 6.58 ( d, 1H, J = 15.7 Hz) r 7.18 (s, XH) , 7.47 (d, 1H, J * 7.6 Hz) , 7.54 &lt;d, lHr J « 15.7 Hz) , 7.74 (d, 1H, J«7.6 Hz)# 8*11 (sf 1H) , 9.22 &lt;s, 1H). MS &lt;ESX&gt; m/z =* 506 (M+H)+. LC/MS tR * 1.36 xnin. 141666.doc 527- 201028381 Example number

R 實施例1 8 0 0R Example 1 8 0 0

實施例1 — 8 0 1Example 1 - 8 0 1

實施例1 — 8 0 2Example 1 - 8 0 2

物性資料_ 1H-NMR (400 MHz, DMSO-de) δ 1.41 (t, 3H, J « 6.6 Hi) # 1.62 (m, 2H), X.83 (m, 2H), 3.26 (s, 3H), 3,91 (m, 2H), 4.07 (mr 3H), 5.49 (s, 1H) f 6.09 (d, 1H, J = 7.1Hz), 6.20 (s# 2H) , 6.54 (d, 1H, J « 15.7 Hz) f 7,05 {s, 1H) , 7.38 (d# 1H, J * 8.1 Hz) , 7.50 (d, 1H, J « 8.1 Hz) , 7.60 (d, IH, J 篇 1S.7 HaO , 8.04 (s, , 9,04 &lt;s, 1H&gt; · MS (£SX) m/z « 481 (M+H)+. LC/MS tR « 1.36 min. 1H-NMR (400 UBTir DHSO-d^) δ 1.02 (d, 6H, J * 5.6 Hx) , 1.62 &lt;mf 2H), 1.84 (mt 2H) , 2Λ2 (in, 1H) r 3.27 (s, 3H) , 3.77 (d, 2H, J * 5,1 Hz&gt; , 3.92 &lt;m, 2H), 4.07 (s, 1H), 5.49 (s, 1H&gt; , 6*11 (d, 1H, J - 7.1 Hz), 6.20 (s, 2H), 6.53 d 1H, J»1S.7 Hz) , 6.97 (s, XH) , 7.39 (d, lH, J » 8.1 Hz) , 7.58 (d, 1H, 8,1 Hz), 7.67 {ά, 1H, J = 15.7 Hz) , 8.02 (s, 1H), 9.04 (s, 1H), MS &lt;£SI) m/z = 509 (M+H)+, LC/MS tR — 1.61 min. 1H-NMR (400 MHzf DHSO-^de) δ 1.61 (m, 2H&gt;, 1.83 (mf 2H&gt;, 3.85 (s, €H) , 3.90 (m, 2H) , 4.11 (br, 1H&gt; , 5.48 &lt;s, 1H&gt; , 6.00 (d, 1H, J ® 7.1 Hz), 6.12 (s, 2H), 7.08 (s, 1H), 7.40 (m, 2H), 7.81 (s, 1H), 8.00 (s# 1H), 8.82 (s, 1H), MS (ESI) m/z = 420 (M+H)+. LC/MS tit =s 1.56 min. 141666.doc 528- 201028381 實施例編號 K 物性資料Physical data _ 1H-NMR (400 MHz, DMSO-de) δ 1.41 (t, 3H, J « 6.6 Hi) # 1.62 (m, 2H), X.83 (m, 2H), 3.26 (s, 3H), 3,91 (m, 2H), 4.07 (mr 3H), 5.49 (s, 1H) f 6.09 (d, 1H, J = 7.1Hz), 6.20 (s# 2H) , 6.54 (d, 1H, J « 15.7 Hz) f 7,05 {s, 1H) , 7.38 (d# 1H, J * 8.1 Hz) , 7.50 (d, 1H, J « 8.1 Hz), 7.60 (d, IH, J 1S.7 HaO , 8.04 ( s, , 9,04 &lt;s, 1H&gt; · MS (£SX) m/z « 481 (M+H)+. LC/MS tR « 1.36 min. 1H-NMR (400 UBTir DHSO-d^) δ 1.02 (d, 6H, J * 5.6 Hx) , 1.62 &lt;mf 2H), 1.84 (mt 2H) , 2Λ2 (in, 1H) r 3.27 (s, 3H) , 3.77 (d, 2H, J * 5,1 Hz&gt; , 3.92 &lt;m, 2H), 4.07 (s, 1H), 5.49 (s, 1H&gt;, 6*11 (d, 1H, J - 7.1 Hz), 6.20 (s, 2H), 6.53 d 1H, J»1S.7 Hz) , 6.97 (s, XH) , 7.39 (d, lH, J » 8.1 Hz) , 7.58 (d, 1H, 8,1 Hz), 7.67 {ά, 1H, J = 15.7 Hz) , 8.02 (s, 1H), 9.04 (s, 1H), MS &lt;£SI) m/z = 509 (M+H)+, LC/MS tR — 1.61 min. 1H-NMR (400 MHzf DHSO-^ De) δ 1.61 (m, 2H&gt;, 1.83 (mf 2H&gt;, 3.85 (s, €H), 3.90 (m, 2H), 4.11 (br, 1H&gt;, 5.48 &lt;s, 1H&gt;, 6.00 (d, 1H, J ® 7.1 Hz), 6.12 (s, 2H), 7.08 (s, 1H), 7.40 (m, 2H), 7.81 (s, 1H), 8.00 (s# 1H), 8.82 (s, 1H), MS (ESI m/z = 420 (M+H)+. LC/MS tit = s 1.56 min. 141666.doc 528- 201028381 Example No. K Physical data

實施例1 — 8 0 3 1H-KMR (400 MHz, DMSO-de) δ 1.62 (m, 2H&gt; , 1.83 (m, 2H) , 3.40 (t, 2H, J « 12.1 Hz), 3.55 (s, 3H&gt;, 3.90 (Bf 5H), 4.10 (br, XH)f 5.50 (s, 1H) , 6.05 idf 1H, J = 7.6 Hz) , 6.17 (IB, 2H&gt; f 7.13 (s^ 1H) , 7.SI (d, 1H, J * 8.1 H«) , 7.62 {d, 1H, J = 8.1 Hz), 8.44 &lt;s, XH), 8,47 (s, 1H), 8.96 (s, XH)* MS (£SI) m/z = 484 (M+H&gt;+. LC/HS tR « 1.51 min * 實施例1 一 HO-y -N，^X 1H-NMR (400 MHz, DMSO-dfi) δ 1.61 (m, 2H) , 1.83 (mf 2H) f 3*38 (t, 2Bf J « 11.6 Hz) r 3.76 (br, 2H&gt; , 3.85 (s, 3H) f 3.88 {t, 2H, J= 10.6 Hz), 4.11 (br, 1H) , 4-15 (br, 2H) , 5.48 8 04 《s, , €；,00 (d, 1H, CT = 7,6 Hs〇 , 6.12 (s, 2H), 7.09 (s, 1H), 7.38 (dt 1H, J « 8.6 Hz) , 7.43 (d, 1H, J»8.6Ha), 7.84 {s, 1H) , 8.03 is, 1H)r 8.82 (s, XH). MS (ESI) m/z = 406 (M+H)+. LC/MS tft « 1*06 min.Example 1 - 8 0 3 1H-KMR (400 MHz, DMSO-de) δ 1.62 (m, 2H&gt;, 1.83 (m, 2H), 3.40 (t, 2H, J « 12.1 Hz), 3.55 (s, 3H&gt;;, 3.90 (Bf 5H), 4.10 (br, XH)f 5.50 (s, 1H) , 6.05 idf 1H, J = 7.6 Hz) , 6.17 (IB, 2H&gt; f 7.13 (s^ 1H) , 7.SI ( d, 1H, J * 8.1 H«) , 7.62 {d, 1H, J = 8.1 Hz), 8.44 &lt;s, XH), 8,47 (s, 1H), 8.96 (s, XH)* MS (£ SI) m/z = 484 (M+H&gt;+. LC/HS tR « 1.51 min * Example 1 HO-y -N, ^X 1H-NMR (400 MHz, DMSO-dfi) δ 1.61 (m, 2H) , 1.83 (mf 2H) f 3*38 (t, 2Bf J « 11.6 Hz) r 3.76 (br, 2H&gt; , 3.85 (s, 3H) f 3.88 {t, 2H, J= 10.6 Hz), 4.11 ( Br, 1H) , 4-15 (br, 2H) , 5.48 8 04 "s, , €;,00 (d, 1H, CT = 7,6 Hs〇, 6.12 (s, 2H), 7.09 (s, 1H ), 7.38 (dt 1H, J « 8.6 Hz) , 7.43 (d, 1H, J»8.6Ha), 7.84 {s, 1H) , 8.03 is, 1H)r 8.82 (s, XH). MS (ESI) m /z = 406 (M+H)+. LC/MS tft « 1*06 min.

實施例1 一 8 0 5 1B-NMR (400 MHz, DMSO-de) δ 1.03 {s, 3H) , 1.05 (Bt 3H) f 1.61 (m, 2H) r 183 (m, 2H), 2.15 (m, 1H) f N 3.39 (t, 2Hf J=10.6Hz), 3.80 (d,Example 1 - 8 0 5 1B-NMR (400 MHz, DMSO-de) δ 1.03 {s, 3H) , 1.05 (Bt 3H) f 1.61 (m, 2H) r 183 (m, 2H), 2.15 (m, 1H) f N 3.39 (t, 2Hf J=10.6Hz), 3.80 (d,

Me~Ns^N^^ 2H, J« 6.1 Hz) , 3.86 (s, 3H) , 3.88 實施例 1 T Ί (tf 2H, J*10.6Hz) , 4.08 (br, 1H), 8 0 6 9 Φ 5.46 (s, 1H) , 6.00 (d, 1H,Me~Ns^N^^ 2H, J« 6.1 Hz) , 3.86 (s, 3H) , 3.88 Example 1 T Ί (tf 2H, J*10.6Hz) , 4.08 (br, 1H), 8 0 6 9 Φ 5.46 (s, 1H) , 6.00 (d, 1H,

Mey^ Hz) f 6.12 (br, 2H) , €.99 (s, 1H),Mey^ Hz) f 6.12 (br, 2H) , €.99 (s, 1H),

Me 7,41 &lt;br, 2H), 7.83 (st 1H) ,7.97 (s, 1H), 8,78 (s7 1H). MS (ESI) m/z » 462 (M+H)+. LC/MS tR « 1.69 min. 529· 141666.doc 201028381 實施例編號Me 7,41 &lt;br, 2H), 7.83 (st 1H) , 7.97 (s, 1H), 8,78 (s7 1H). MS (ESI) m/z » 462 (M+H)+. LC/ MS tR « 1.69 min. 529· 141666.doc 201028381 Example number

R 實施例1 — 8 0 7R Example 1 - 8 0 7

MeMe

實施例1 — 8 0 8Example 1 - 8 0 8

實施例1 — 8 0 9Example 1 - 8 0 9

物性資料_ 1H-NMR (400 MHzr DMSO-de) δ 0,97 (s, 3H), 0.98 (s, 2H), 1.62 (m, 2H)f X.83 &lt;m, 2H) , 2.00 (to, XH), 3.61 {d, 2H, J = 5.6 Hz) , 3.90 (sf 5H) , 4.10 &lt;br, 1H) f 5.50 {a t XH), 6.07 (br, 1H) , 6.18 (br, 2H) ,7.13 (s, XH) , 7-51 (d, 1H, J « 7.6 Hz), 7.62 {d, 1H, J « 7.6 Hz) , 8.45 (s, 1H), 8.49 &lt;sr 1H), 8.96 (sy 1H). MS (ESI) m/z = 526 (M+H)+. LC/MS tR « 1.61 min. 1H-HMR (400 MHz, DMSO-de) δ 1.20-X.32 (m, 4H), 1,40 {tt, 2H# J«12.0H2：)# 1.61 (tt, 2H, J»12.0 Hz), X.76 (m, 2H), 1.84 (mf 4H), 3.40 (t, 2H, J « 11.1 Hz&gt; , 3.70 (t,❿ 1H# 11.1 Hz) , 3.90 (a, 5H) , 4.10 (brf 1H) , 5.50 &lt;sf 1H) , 6.06 &lt;br, 1H) , 6.18 (br, 2H) , 7.13 (s, 1H&gt; , 7.51 (d, 1H, J-8.6HZ), 7.63 (d, 1H, J * 8.6 Hz) , 8.46 &lt;s, 2H) , 8.96 (s, 1H). MS (ESI) m/z = 552 &lt;M+H)+. LC/MS fcR 1.73 min. MS (ESI) m/z « 502 (M+H)+. I.C/MS tR - 2.01 min. 141666.doc 530- 201028381Physical data _ 1H-NMR (400 MHzr DMSO-de) δ 0,97 (s, 3H), 0.98 (s, 2H), 1.62 (m, 2H)f X.83 &lt;m, 2H) , 2.00 (to , XH), 3.61 {d, 2H, J = 5.6 Hz), 3.90 (sf 5H) , 4.10 &lt;br, 1H) f 5.50 {at XH), 6.07 (br, 1H) , 6.18 (br, 2H) , 7.13 (s, XH) , 7-51 (d, 1H, J « 7.6 Hz), 7.62 {d, 1H, J « 7.6 Hz) , 8.45 (s, 1H), 8.49 &lt;sr 1H), 8.96 (sy 1H). MS (ESI) m/z = 526 (M+H)+. LC/MS tR « 1.61 min. 1H-HMR (400 MHz, DMSO-de) δ 1.20-X.32 (m, 4H), 1,40 {tt, 2H# J«12.0H2:)# 1.61 (tt, 2H, J»12.0 Hz), X.76 (m, 2H), 1.84 (mf 4H), 3.40 (t, 2H, J « « 11.1 Hz&gt;, 3.70 (t, ❿ 1H# 11.1 Hz), 3.90 (a, 5H), 4.10 (brf 1H), 5.50 &lt;sf 1H) , 6.06 &lt;br, 1H) , 6.18 (br, 2H) , 7.13 (s, 1H&gt;, 7.51 (d, 1H, J-8.6HZ), 7.63 (d, 1H, J * 8.6 Hz), 8.46 &lt;s, 2H) , 8.96 (s, 1H). MS (ESI) m/z = 552 &lt;M+H)+. LC/MS fcR 1.73 min. MS (ESI) m/z « 502 (M+H)+. IC/MS tR - 2.01 min. 141666.doc 530- 201028381

實施例編號Example number

R 實施例1 — 8 10R Example 1 - 8 10

實施例1 — 8 11Example 1 - 8 11

MeO 實施例1 — 8 12MeO Example 1 - 8 12

物性實料_ 1H-KMR (400 MHz, DMSO-de) δ 1,61 (m, 2H), 1.84 (m, 2H)y 3.2S (s, 3H) , 3.41 (t, 2H, J» 11.6Hz)f 3-71 (br, 2H) , 3.90 (m, 2H), 4,07 (bz, 1H) , 4.27 (hrf ZB) f 5.13 (s, 2H&gt; , 5.49 (s, 1H) , 6.05 {d, 1H, J 7.1 Hz), €.15 (S, 2H), 7.X7 (S, 1H), 7.49 &lt;d, 1H, J * 8.6 Hx) , 7.57 (d, 1H, 7.85 {s, IB) f 8.05 (S, 1H), 8.96 (s, 1H). MS (£$I) m/z « 489 (M+H)+. IiC/MS &lt;：r — 1.35 min. 1H-NHR (400 MHz, DMSO-de) δ 1.61 (m, 2H) , 1.83 (m, 2H) , 3.63 (s, 3H), 3,82 (sr 3H》，3.50 (m, 2H&gt;, 4,11 (br, 1H) , 5.47 &lt;s, 1H) , 5,97 &lt;dr 1H, J « 7.6 Hz) , 6.09 (s, 2H), 6.39 &lt;s, 1H), 6.68 {&amp;t 1H&gt;, 7*05 (S, 11« , 7*13 (s, 1H) , 7.29 iH, J ® 8.6 Hz) f 7.34 (dr in, J * 8,6 Hz) f 8.73 〇f 1H). MS (ESI) m/z « 552 + . LC/HS tR = 1.73 min. 1H-KMR (400 MHz, DMSO-de) δ 1.61 (m, 2H) , 1.77 (df 3Hf J » 6.6 Hz) f 1.82 (m, 2H), 3.25 (s, 3H), 3.42 (t, 2H, J « 9.6 Hs) f 3,71 (t, 2H, J « 4.5 Hz) , 3-91 (t, 2H, J = 9.6 Hz) , 4.10 (m, 1H) , 4.29 (t, 2Hf J « 4.5 Hz) , 5,22 1H, J » 6,6 Hz), 5*48 &lt;s, 1H) , 6.06 &lt;d, 1H, J m 7.S Hz), 6.15 Cs, 2H) , 7.26 (s, 2H), 1.47 (d, 1H, J * 8-6 Hz) f 7.S6 (d, 1H, 8.6 Hz) , 7.83 (s, 1H) , 8.03 (s, 1H)r 8.97 (s, 1H). HS (ESI) m/z « 503 (M+H)+. LC/MS tR « 1.4€ xnin. 141666.doc 531 - 201028381 [表 1-6]Physical properties _ 1H-KMR (400 MHz, DMSO-de) δ 1,61 (m, 2H), 1.84 (m, 2H)y 3.2S (s, 3H) , 3.41 (t, 2H, J» 11.6Hz )f 3-71 (br, 2H) , 3.90 (m, 2H), 4,07 (bz, 1H) , 4.27 (hrf ZB) f 5.13 (s, 2H&gt; , 5.49 (s, 1H) , 6.05 {d , 1H, J 7.1 Hz), €.15 (S, 2H), 7.X7 (S, 1H), 7.49 &lt;d, 1H, J * 8.6 Hx) , 7.57 (d, 1H, 7.85 {s, IB ) f 8.05 (S, 1H), 8.96 (s, 1H). MS (£$I) m/z « 489 (M+H)+. IiC/MS &lt;:r — 1.35 min. 1H-NHR (400 MHz, DMSO-de) δ 1.61 (m, 2H) , 1.83 (m, 2H) , 3.63 (s, 3H), 3,82 (sr 3H), 3.50 (m, 2H&gt;, 4,11 (br, 1H) ), 5.47 &lt;s, 1H) , 5,97 &lt;dr 1H, J « 7.6 Hz) , 6.09 (s, 2H), 6.39 &lt;s, 1H), 6.68 {&amp;t 1H&gt;, 7*05 (S, 11« , 7*13 (s, 1H) , 7.29 iH, J ® 8.6 Hz) f 7.34 (dr in, J * 8,6 Hz) f 8.73 〇f 1H). MS (ESI) m/z « 552 + . LC/HS tR = 1.73 min. 1H-KMR (400 MHz, DMSO-de) δ 1.61 (m, 2H) , 1.77 (df 3Hf J » 6.6 Hz) f 1.82 (m, 2H), 3.25 ( s, 3H), 3.42 (t, 2H, J « 9.6 Hs) f 3,71 (t, 2H, J « 4.5 Hz) , 3-91 (t, 2H, J = 9.6 Hz) , 4.10 (m, 1H ) , 4.29 (t, 2Hf J « 4.5 Hz) , 5, 22 1H, J » 6,6 Hz), 5*48 &lt;s, 1H) , 6.06 &lt;d, 1H, J m 7.S Hz), 6.15 Cs, 2H) , 7.26 (s, 2H), 1.47 (d, 1H, J * 8-6 Hz) f 7.S6 (d, 1H, 8.6 Hz), 7.83 (s, 1H), 8.03 (s, 1H)r 8.97 (s, 1H). HS (ESI) m/z « 503 (M+H)+. LC/MS tR « 1.4€ xnin. 141666.doc 531 - 201028381 [Table 1-6]

表1-6中記載之化合物係依據上述記載之實施例1-545之 步驟4之方法而合成。又，實施例1-813係依據實施例1-525 之方法而合成。 實施例編號The compounds described in Tables 1-6 were synthesized in accordance with the method of Step 4 of Examples 1-545 described above. Further, Examples 1-813 were synthesized in accordance with the methods of Examples 1-525. Example number

R 物性資料 實施例1 一 8 13R Physical properties Example 1 A 8 13

1H-NME (400 MH2, DMSO-de) δ 3.84 (s, 3H)# 3.93 (s, 3H)r 5.96 (s, 1H) , 6,43 (sr 2H) , 7.48 (d, J * 7.8 Hz, 2U) f 7.57 (d, J = 7.8 H« # 2H), 7.78 (sf 1H) , 8.01 (sr 1H) , 8.04 (s, XH), 8,28 &lt;s, XH)f 9.05 (S,1H-NME (400 MH2, DMSO-de) δ 3.84 (s, 3H)# 3.93 (s, 3H)r 5.96 (s, 1H) , 6,43 (sr 2H) , 7.48 (d, J * 7.8 Hz, 2U) f 7.57 (d, J = 7.8 H« # 2H), 7.78 (sf 1H) , 8.01 (sr 1H) , 8.04 (s, XH), 8,28 &lt;s, XH)f 9.05 (S,

1H). MS (ESI) m/z » 371 LC/MS tR * 1.10 min. 實施例1 — 8 141H). MS (ESI) m/z » 371 LC/MS tR * 1.10 min. Example 1 - 8 14

•、NH•, NH

OH 1H-HMR (400 HHz# DMSO-d6) δ 3.84 (s, 3H), 5.54 &lt;s, 1H); 6.17 (s, 2H) , 6.71 (d, 2H, 8.6 Hz) , 7.25 (t, 4H, J = 7.8 Hz) , 7,40 (dt 2H f J- 8.1 Hz) , 7.72 (s, 1H) , 7.95 (S, XH) , 8,05 (S/ 1H) f 8.78 (s, 1H), 9.18 (brs, 1H). 實施例1 一 8 15OH 1H-HMR (400 HHz# DMSO-d6) δ 3.84 (s, 3H), 5.54 &lt;s, 1H); 6.17 (s, 2H), 6.71 (d, 2H, 8.6 Hz), 7.25 (t, 4H) , J = 7.8 Hz) , 7,40 (dt 2H f J- 8.1 Hz) , 7.72 (s, 1H) , 7.95 (S, XH) , 8,05 (S/ 1H) f 8.78 (s, 1H), 9.18 (brs, 1H). Example 1 A 8 15

*、NH*, NH

F F MS (ESI) m/z « 424 (M+H)+. LC/MS tR * 1.35 min.F F MS (ESI) m/z « 424 (M+H)+. LC/MS tR * 1.35 min.

實施例1 一 8 16 NH !Example 1 A 8 16 NH !

OH MS (ESI) m/z = 456 (M+H)+. X.C/MS tR » 1.30 min. 實施例1 - 8 17OH MS (ESI) m/z = 456 (M+H) +. X.C/MS tR » 1.30 min. Example 1 - 8 17

*、NH*, NH

MS (ESI) m/z =： 444 (M+H) + . X»C/MS tR « m join·MS (ESI) m/z =: 444 (M+H) + . X»C/MS tR « m join·

Me 个 MeMe 141666.doc -532- 201028381 實施例編號 ϋ 物性資料_ 1H-NMR (400 mzf DHSO-de) δ 5.78 (s, 1H) # 6.68 (s, 2H) , 7.09 &lt;d, 2H,Me Me Me 141666.doc -532- 201028381 Example No. ϋ Physical data _ 1H-NMR (400 mzf DHSO-de) δ 5.78 (s, 1H) # 6.68 (s, 2H) , 7.09 &lt;d, 2H,

J = 8-6 Hz) , 7.17 (d, 2H, J « 8-6J = 8-6 Hz) , 7.17 (d, 2H, J « 8-6

Hz) , 7.26 (d, 2Hf J = 8.1 Hz) , 7.54 {d, 2H, J « 8.i Hz&gt; , 7.S7 ⑷ 1H&gt; , 7.92 &lt;s, 1H), 9.09 (s, 1H). MS (ESI) m/z » 417 (M+H)*. LC/MS ^ X.88 min. 1H-3SMR (400 MHz, DMSO-d«) b 3.85 (s, 3H), 5.66 Cs, 1H), €.30 &lt;s, 2H) , 7.01 (t, 1H, J = 7.1 Hz) r 7.27 * (d, 2H, J * 7.6 Has) , 7.32 &lt;d, 2H,Hz) , 7.26 (d, 2Hf J = 8.1 Hz) , 7.54 {d, 2H, J « 8.i Hz&gt; , 7.S7 (4) 1H&gt; , 7.92 &lt;s, 1H), 9.09 (s, 1H). MS (ESI) m/z » 417 (M+H)*. LC/MS^ X.88 min. 1H-3SMR (400 MHz, DMSO-d«) b 3.85 (s, 3H), 5.66 Cs, 1H) , €.30 &lt;s, 2H) , 7.01 (t, 1H, J = 7.1 Hz) r 7.27 * (d, 2H, J * 7.6 Has) , 7.32 &lt;d, 2H,

NH 實施例 1 一 工 J - 8.6 Hz) , 7.45 (d, 2H# J « 8.1 8 19 «z) , 7.55 {d, 2H, J « 7.6 Hz) , 7.76NH Example 1 I work J - 8.6 Hz) , 7.45 (d, 2H# J « 8.1 8 19 «z) , 7.55 {d, 2H, J « 7.6 Hz) , 7.76

(s, 1H) , 8.00 (sf 1H) , 8.39 (s, 1H), 8.88 {sf 1H), MS (ESI) m/z * 382 (M+H)+. LC/MS tR « 1.61 min.(s, 1H) , 8.00 (sf 1H) , 8.39 (s, 1H), 8.88 {sf 1H), MS (ESI) m/z * 382 (M+H)+. LC/MS tR « 1.61 min.

1H-NMR (400 MHz, DMSO-de) δ 3.83 (st 3H), 5.79 (s, 1H)# 6.71 (s, 2H) , 7.05 (d, 2H, J» 8.1 Has) , 7.20 (d, 2H, J * 8.1 Hz) , 7.43 (d, 2K, 8.1 Hz) , 7,53 (s# 2H) , 7,72 (s, 1H) , 7,91 isf 1H) , 7.95 (d, 2H, J » 8.1 Hz), 9-14 {Bf 1H). MS &lt;KSI) m/z * 462 (M+H)+. LC/MS tR » 1.35 min. 1H-NMR &lt;400 MHz, DMSO-d«) δ 3.85 (s, 3H), 5.80 (s, 1H), 6.56 (s, 2H) r 6.97 (d, 2H, J « 8.1 Hz) , 7.05 (d, 2H, J « 8.1 Hz) , 7,54 (t, 2H, 實施例 1 - 又 J = 7,1 Hz) f 7.61 (d, 2S, J * 7.1 8 2 1 Γ'ΐΙ Bz) t 7*67 (t, 1H, σ«7,3Η»), 7,71 (s, 1H) , 7.$7 (s, 1H) , 9.06 (s, 1H). MS (BSD m/z = 399 (M+H)+. I.C/MS fcR « 1.85 min. 533 - 141666.doc 201028381 實施例編號 R 物性資料 MS (ESI) m/z = 389 (H+H)+. 實施例1 — NH A LC/MS tR 0.87 min. 8 2 2 0 Η MS (ESI) m/z « 412 + . 實施例1 — NH Λ LC/MS tR * 1.53 min. 8 2 3 y OMe1H-NMR (400 MHz, DMSO-de) δ 3.83 (st 3H), 5.79 (s, 1H) # 6.71 (s, 2H) , 7.05 (d, 2H, J» 8.1 Has) , 7.20 (d, 2H, J * 8.1 Hz) , 7.43 (d, 2K, 8.1 Hz) , 7,53 (s# 2H) , 7,72 (s, 1H) , 7,91 isf 1H) , 7.95 (d, 2H, J » 8.1 Hz), 9-14 {Bf 1H). MS &lt;KSI) m/z * 462 (M+H)+. LC/MS tR » 1.35 min. 1H-NMR &lt;400 MHz, DMSO-d«) δ 3.85 (s, 3H), 5.80 (s, 1H), 6.56 (s, 2H) r 6.97 (d, 2H, J « 8.1 Hz) , 7.05 (d, 2H, J « 8.1 Hz) , 7,54 (t , 2H, Example 1 - again J = 7,1 Hz) f 7.61 (d, 2S, J * 7.1 8 2 1 Γ 'ΐΙ Bz) t 7*67 (t, 1H, σ«7,3Η»), 7,71 (s, 1H) , 7.$7 (s, 1H) , 9.06 (s, 1H). MS (BSD m/z = 399 (M+H)+. IC/MS fcR « 1.85 min. 533 - 141666.doc 201028381 Example No. R Physical property MS (ESI) m/z = 389 (H+H) +. Example 1 - NH A LC/MS tR 0.87 min. 8 2 2 0 Η MS (ESI) m/ z « 412 + . Example 1 - NH Λ LC/MS tR * 1.53 min. 8 2 3 y OMe

MeMe

實施例1 —8 2 8Example 1 - 8 2 8

MS (ESI) m/z = 389 (M+H&gt;+. LC/MS tR = 2.01 min. *、0 Λ MS &lt;ESI) m/z = 404 (M+H)+. 實施例1 一 LC/MS tR 1.02 min. 8 2 9 Me 141666.doc 534- 201028381 MS (£SX) m/z = 432 &lt;H+H)+. &quot;0 I LC/MS tR - 1.33 min. 實施例1 — rS 8 3 1 Me人。MS (ESI) m/z = 389 (M+H&gt;+. LC/MS tR = 2.01 min. *, 0 Λ MS &lt;ESI) m/z = 404 (M+H)+. Example 1 LC /MS tR 1.02 min. 8 2 9 Me 141666.doc 534- 201028381 MS (£SX) m/z = 432 &lt;H+H)+. &quot;0 I LC/MS tR - 1.33 min. Example 1 - rS 8 3 1 Me people.

、0 LC/MS tR =* 1.14 min. 實施例編號 R 物性資料 *、0 MS (BSI) m/^ » 440 (Μ+Η&gt;+· LC/MS tR * 1.46 min. 實施例1 — 〇 8 3 0 τ ΝΗ Me VN&quot; 人 實施例i 8 3 4 實施例i B 3 5 MS (ESI) m/z « 404 (M+H)+. LC/MS tR « 1.04 min.0 LC/MS tR = * 1.14 min. Example No. R Physical data*, 0 MS (BSI) m/^ » 440 (Μ+Η&gt;+· LC/MS tR * 1.46 min. Example 1 - 〇8 3 0 τ ΝΗ Me VN&quot; Human Example i 8 3 4 Example i B 3 5 MS (ESI) m/z « 404 (M+H)+. LC/MS tR « 1.04 min.

實施例i 一 836Example i a 836

MS (BSX) m/z « 390 (M+H)+. LC/MS ts. « 1.05 min. 實施例1 一 8 3 7MS (BSX) m/z « 390 (M+H)+. LC/MS ts. « 1.05 min. Example 1 A 8 3 7

*、NH*, NH

MS (ESI) m/z » 400 &lt;M+H)+. LC/MS tR » 1.78 min. 535 - 141666.doc 201028381 實施例編號 R 物性資料 MS (ESI) m/z = 376 (H+H) +. 實施例1 - LC/MS tR —1.46 min. 8 3 8 *、N，_ Λ MS (ESI) m/z = 417 (M+H)+. 實施例1 - LC/MS tR =0.88 min. 8 3 9 V Me MS (£SX) m/z - 364 (M+H)+. LC/MS tR « 1.13 min. 實施例1 -8 4 0MS (ESI) m/z » 400 &lt;M+H)+. LC/MS tR: 1.78 min. 535 - 141666.doc 201028381 Example No. R Physical Properties MS (ESI) m/z = 376 (H+H +. Example 1 - LC/MS tR - 1.46 min. 8 3 8 *, N, _ Λ MS (ESI) m/z = 417 (M+H) +. Example 1 - LC/MS tR = 0.88 Min. 8 3 9 V Me MS (£SX) m/z - 364 (M+H)+. LC/MS tR « 1.13 min. Example 1 -8 4 0

實施例1 -S 4 1Example 1 -S 4 1

MS (ESI) m/z = 377 &lt;M+H&gt;+· ItC/MS tR = 1.56 min. 實施例1 -8 4 2 、〇Med0Me HS (ESI) m/z « 379 (M+H&gt;+. LC/MS tR = 1.71 min. MS (ESI) m/2 « 365 實施例1 - 傘、 X.C/MS tR » 1.60 min 8 4 3 .OMe 實施例1 _ 8 4 4MS (ESI) m/z = 377 &lt;M+H&gt;+· ItC/MS tR = 1.56 min. Example 1 -8 4 2 〇Med0Me HS (ESI) m/z « 379 (M+H&gt;+ LC/MS tR = 1.71 min. MS (ESI) m/2 « 365 Example 1 - Umbrella, XC/MS tR » 1.60 min 8 4 3 .OMe Example 1 _ 8 4 4

HS (ESI) m/z = 405 (M+H)+. X.C/HS tR - 1.58 min. 實施例1 一 8 4 5HS (ESI) m/z = 405 (M+H) +. X.C/HS tR - 1.58 min. Example 1 A 8 4 5

MS (ESI) m/z = 405 (M+H)+. LC/MS tR * 1.37 min.MS (ESI) m/z = 405 (M + H) +. LC/MS tR * 1.37 min.

OH *、0 MS (ESI) m/z » 419 (M+H)+. 實施例1 — 8 4 6OH *, 0 MS (ESI) m/z » 419 (M+H) +. Example 1 - 8 4 6

OMe 141666.doc 536- 201028381OMe 141666.doc 536- 201028381

實施例1 _ 8 5 2Example 1 _ 8 5 2

MS (£S1) m/z » 404 &lt;M+H)+. XtC/MS tR « 1.03 min, 實施例編號 R 物性資料 實施例1 — 8 4 7 、0 Φ Me MS (ESX) LC/MS tK m/z = 460 &lt;M-fH) + . =1.58 min * MS (ESX) m/z « 417 &lt;M+H)+, 、Γ LC/MS fcR * 0.99 min. 實施例1 - rS 8 48 、Me MS (ESI) m/z = 418 (M+H)+. 實施例1 - ΜΗ Λ LC/MS tR » 1.35 min. 8 4 9 ΟΜβMS (£S1) m/z » 404 &lt;M+H)+. XtC/MS tR « 1.03 min, Example No. R Physical Data Example 1 - 8 4 7 , 0 Φ Me MS (ESX) LC/MS tK m/z = 460 &lt; M-fH) + . = 1.58 min * MS (ESX) m/z « 417 &lt; M+H)+, Γ LC/MS fcR * 0.99 min. Example 1 - rS 8 48 , Me MS (ESI) m/z = 418 (M+H) +. Example 1 - ΜΗ Λ LC/MS tR » 1.35 min. 8 4 9 ΟΜβ

實施例1 -8 5 3 1H-KMR (400 MHz, DMSO-d6) δ 1.14 &lt;m, 1H)f 1.34 (mr 2U) r 1.55 (mf 2U) f 1.65 (m, 1H), 1.73 (m, 2H), 1.81 (mf 2B), 2.96 {s, 3H&gt;, 3,84 (s, 3H&gt;, 4.19 (m, 1H), 5.54 {s, 1H&gt; , 6.09 (s, 2H) , 7.40 (dr 2H, J « 8,6 Hz) , 7.57 (dr 2H, J« 8.6 Hz), 7.76 (», 1H), 8.02 (s# 1H&gt;, 8.83 (S/ 1H). MS (SSI) m/a = 402 (M+H)+. LC/HS = 1*84 min* 537 - 141666.doc 201028381Example 1 -8 5 3 1H-KMR (400 MHz, DMSO-d6) δ 1.14 &lt;m, 1H)f 1.34 (mr 2U) r 1.55 (mf 2U) f 1.65 (m, 1H), 1.73 (m, 2H), 1.81 (mf 2B), 2.96 {s, 3H&gt;, 3,84 (s, 3H&gt;, 4.19 (m, 1H), 5.54 {s, 1H&gt; , 6.09 (s, 2H) , 7.40 (dr 2H , J « 8,6 Hz) , 7.57 (dr 2H, J« 8.6 Hz), 7.76 (», 1H), 8.02 (s# 1H&gt;, 8.83 (S/ 1H). MS (SSI) m/a = 402 (M+H)+. LC/HS = 1*84 min* 537 - 141666.doc 201028381

表1-7中記載之化合物係依據上述記載之實施例1-488之 步驟2及1-499之步驟1之方法而合成。又，實施例1-858、 1-864及1-872係依據實施例1-525之方法而合成。 實施例編號 R 物性資料 丰、 MS (ESI) m/z - 339 (M+H)+. 實施例1 — NH L Μα LC/MS tR « 1.37 min. 8 5 4 l£Me MS (ESI) m/z =* 353 (H+H) + . 實施例1 - *、¥H l LC/MS tR » 1.53 min» 8 5δ (jU^e 1H-NMR (400 MHz, DMSO-de) δThe compounds described in Tables 1-7 were synthesized in accordance with the procedures of Step 2 of Examples 1-488 described above and Step 1 of 1-499. Further, Examples 1-858, 1-864 and 1-872 were synthesized in accordance with the methods of Examples 1-525. Example No. R Physical property, MS (ESI) m/z - 339 (M+H) +. Example 1 - NH L Μα LC/MS tR « 1.37 min. 8 5 4 l £Me MS (ESI) m /z =* 353 (H+H) + . Example 1 - *, ¥H l LC/MS tR » 1.53 min» 8 5δ (jU^e 1H-NMR (400 MHz, DMSO-de) δ

實施例1 -8 5 6 1&lt;57«2.09 (m, 14H), 4.10 (br sf 1H) f 5.38 (d, 1H, 0Γ = 6.6 H2) , 5.49 (s, 1H) , 6.26 &lt;s, 2H) , 7.08 (brs, 1H) , 7.82-7.67 &lt;m, 5H) , 9.14 (s, 1H). 538- 141666.doc 201028381Example 1 -8 5 6 1&lt;57«2.09 (m, 14H), 4.10 (br sf 1H) f 5.38 (d, 1H, 0Γ = 6.6 H2) , 5.49 (s, 1H) , 6.26 &lt;s, 2H ), 7.08 (brs, 1H), 7.82-7.67 &lt;m, 5H) , 9.14 (s, 1H). 538- 141666.doc 201028381

實施例編號 實施例1 — 8 5 7 實施例1 — 8 5 8 實施例1 -8 5 9 _R_物性資料_ 1H-NMR (4〇〇 MBs, DMSO-de) 5 5.86 &lt;1H, s), 6.80 (2H, s), 7.09 (1H, s) , 7.18 (3H, d, J = 7.2 Hz) , 7.28 i3H, d, J * 7.2 Hz), 7.53 (4H, t, 8.0 Hz) , 7.70 (XH, s) , 9.37 (1H, s). ΙΗ-JSfMR (400 MHz , DMSO-d6) 5 0.62 &lt;2H, br s) , 0.94 (2H, d, J « 6.0 Hz) , 1,74 (1H, hr a) , 6.00 {XH, s), β.40-6.50 (3H, m) f 6.60 (1H, df J » 14.4 Hz) , 7,13 (1H, s) , 7.65 (2Hf d, J = 7.6 Hz&gt; , 7,79 (3H, d, J = 7.6 Bz) t 9.30 (1H, s). MS &lt;ES1) m/z * 337 &lt;M+H)+* I.C/MS tR « 1*23 min*EXAMPLES EXAMPLES Example 1 - 8 5 7 Example 1 - 8 5 8 Example 1 -8 5 9 _R_physical data _ 1H-NMR (4 〇〇 MBs, DMSO-de) 5 5.86 &lt;1H, s) , 6.80 (2H, s), 7.09 (1H, s), 7.18 (3H, d, J = 7.2 Hz), 7.28 i3H, d, J * 7.2 Hz), 7.53 (4H, t, 8.0 Hz), 7.70 ( XH, s), 9.37 (1H, s). ΙΗ-JSfMR (400 MHz, DMSO-d6) 5 0.62 &lt;2H, br s) , 0.94 (2H, d, J « 6.0 Hz) , 1,74 (1H , hr a) , 6.00 {XH, s), β.40-6.50 (3H, m) f 6.60 (1H, df J » 14.4 Hz) , 7,13 (1H, s) , 7.65 (2Hf d, J = 7.6 Hz&gt; , 7,79 (3H, d, J = 7.6 Bz) t 9.30 (1H, s). MS &lt;ES1) m/z * 337 &lt;M+H)+* IC/MS tR « 1* 23 min*

•、NH•, NH

實施例1 — 860 *、 NH 6Me MS (£S1) LC/MS tR m/z « 365 * 1.50 min. 實施例1 -8 6 1 本、 NH Φ MS (ESI) I-C/MS tR m/z « 365 (H+H) + · « 1.56 min. Me 實施例1 -8 6 2 *、NH % MS (ESI) LC/MS tR m/z » 363 (H+H)+. »： 1.44 min. 實施例i — 8 6 3 ^NHj!?Me &lt;^VMe MS (ESI) LC/MS tR m/z = 405 « 1,87 min. 實施例i 一 864 、N,Me j 0 MS &lt;£SI》 IiC/HS fcR m/z = 365 (M+H)+. » 1.S3 min. 141666.doc 539- 201028381 實施例編號Example 1 - 860 *, NH 6Me MS (£S1) LC/MS tR m/z « 365 * 1.50 min. Example 1 -8 6 1 This, NH Φ MS (ESI) IC/MS tR m/z « 365 (H+H) + · « 1.56 min. Me Example 1 -8 6 2 *, NH % MS (ESI) LC/MS tR m/z » 363 (H+H)+. »: 1.44 min. Example i - 8 6 3 ^NHj!?Me &lt;^VMe MS (ESI) LC/MS tR m/z = 405 « 1,87 min. Example i 864, N, Me j 0 MS &lt; £SI IiC/HS fcR m/z = 365 (M+H)+. » 1.S3 min. 141666.doc 539- 201028381 Example number

R ·、 實施例1 — 8 6 5R ·, Example 1 - 8 6 5

NHNH

Wle 个 Me Me 實施例1 — 8 6 6Wle Me Me Example 1 - 8 6 6

實施例1 一 8 6 7Example 1 A 8 6 7

賁施例1 — 8 6 8Example 1 - 8 6 8

•、NH•, NH

實施例1 — 8 6 9Example 1 - 8 6 9

物性資料_ 1H-NMR &lt;400 HH2, DMSO-d^) δ 0.88 (10H, s), 1.01-1.15 &lt;2H, m), 1.28-1.37 (XH, m) , 1.79-1.83 (2H, m) , 1.97-2-01 (2H, m), 3.71-3.80 (1H, m), 5.47 (1H, s&gt;, 5.87 (1H, d, J * 8.0 Hz), 6.17 &lt;2H, br s), 7.07 (1H, s) , 7.67-7,77 (5H, m&gt; , 9.08 &lt;1H, a) ,_ 1H-NMR C400 MHk, DMSO-de) δ 5.83 (1H, s), 6.10 (2H, s)/ 6.66-6.75 (3H, m), 6.90 (1H; s), 6.99 &lt;1H, d, J « 8.4 Hz) , 7.10 (1H, s) , 7.25 (2H, d, J « 8.4 Hz) , 7.54 &lt;2H, dt J* 8.4 Hz) , 7.74 (1H, s) , 9.37 (1H, S? ·___ 1H-HMR (400 MHz, DMSO-d6) δ 1.23 (1H, s), X.66-1.71 (2H, m), 1.98-2.10 &lt;5H, n〇 , 3.96 (1H, s), 5.50 (1H, s&gt;, 6.20 (2H, s), 7.12 (1H, s), 7.73 (6H, dd, J= 36.0, 8.0 Hz), 9.12 (1H, s&gt;. 1H-NMR (400 MHz, DMSO-d6) δ 1.51-1.70 &lt;5H, «〇, 1.97 (4H, br s) , 3.17 &lt;4H, s) , 4.77 (1H, br s) f 5.46 (1H, s) , 5.66 (1H, df ^=7.2 Hz), 6.17 (2Hf s)f 7.08 (1H, s), 7.71 (5H, s) , 9.11 (1H, s). MS (ESI) m/z = 348 (M+H)+. 1*C/MS tR « 1.49 min. 實施例1 — 8 7 0Physical property _ 1H-NMR &lt;400 HH2, DMSO-d^) δ 0.88 (10H, s), 1.01-1.15 &lt;2H, m), 1.28-1.37 (XH, m) , 1.79-1.83 (2H, m ), 1.97-2-01 (2H, m), 3.71-3.80 (1H, m), 5.47 (1H, s&gt;, 5.87 (1H, d, J * 8.0 Hz), 6.17 &lt;2H, br s), 7.07 (1H, s), 7.67-7,77 (5H, m&gt;, 9.08 &lt;1H, a) , _ 1H-NMR C400 MHk, DMSO-de) δ 5.83 (1H, s), 6.10 (2H, s ) / 6.66-6.75 (3H, m), 6.90 (1H; s), 6.99 &lt;1H, d, J « 8.4 Hz) , 7.10 (1H, s) , 7.25 (2H, d, J « 8.4 Hz) , 7.54 &lt;2H, dt J* 8.4 Hz) , 7.74 (1H, s) , 9.37 (1H, S? ·___ 1H-HMR (400 MHz, DMSO-d6) δ 1.23 (1H, s), X.66- 1.71 (2H, m), 1.98-2.10 &lt;5H, n〇, 3.96 (1H, s), 5.50 (1H, s&gt;, 6.20 (2H, s), 7.12 (1H, s), 7.73 (6H, dd , J= 36.0, 8.0 Hz), 9.12 (1H, s&gt;. 1H-NMR (400 MHz, DMSO-d6) δ 1.51-1.70 &lt;5H, «〇, 1.97 (4H, br s) , 3.17 &lt;4H , s) , 4.77 (1H, br s) f 5.46 (1H, s) , 5.66 (1H, df ^=7.2 Hz), 6.17 (2Hf s)f 7.08 (1H, s), 7.71 (5H, s) , 9.11 (1H, s). MS (ESI) m/z = 348 (M+H) +. 1*C/MS tR « 1.49 min. Example 1 - 8 7 0

*、NH*, NH

1H-HMR (400 MHz, DMSO-d6) δ 0.94 (2H, br s) , 1.61-1.76 (8H# m),3.18-3.20 (2Hf m) r 5.45 &lt;1H, s), 6,15 (2H, s) , 6.48 (XH, br s) , 7.09 (1H, br s&gt;, 7.72-7-79 (5H, m),9.08 (1H, s). 141666.doc 540· 2010283811H-HMR (400 MHz, DMSO-d6) δ 0.94 (2H, br s) , 1.61-1.76 (8H# m), 3.18-3.20 (2Hf m) r 5.45 &lt;1H, s), 6,15 (2H , s), 6.48 (XH, br s) , 7.09 (1H, br s&gt;, 7.72-7-79 (5H, m), 9.08 (1H, s). 141666.doc 540· 201028381

實施例編號 實施例1 — 8 7 1 實施例1 一 8 7 2 實施例1 8 7 3Example No. Example 1 - 8 7 1 Example 1 - 8 7 2 Example 1 8 7 3

RR

物性資料_ 1H-NMR (400 MHzf DMSO-de) δ Χ.6Χ-1.69 {4Η, m&gt; , 1.95-X.S9 (2Hf m&gt; , 3.74 (1H, br s) , 3.83 (1H, br s), 5.51 (1H, &amp;) r 5.98 (1H, s) r 6.22 (2H, &amp;) t 7.10 (XHf s) , 7.65 &lt;2H, d, J = 8.4 Hz} , 7,75 &lt;3H, d, J *= 8.4 Hz) , 9.12 (XH, a). 1H-KMR (400 MHz, DMSO-de) 5 0.99-X.25 (5H, m&gt;, 1.62-1.70 (5H, ffi) f 1.87 (1H, br s) , 2.59 (2Ut d# J» 6.8 , 6·02 &lt;1H, , 6.49 &lt;2H, s)f 7.13 (1H, s), 7.65 (2H, d, J ^ 8.4 Hz) , 7.79 (3H, d, 8.4 Hz), 9.32 (XH, s).Physical data _ 1H-NMR (400 MHzf DMSO-de) δ Χ.6Χ-1.69 {4Η, m&gt; , 1.95-X.S9 (2Hf m&gt; , 3.74 (1H, br s) , 3.83 (1H, br s) , 5.51 (1H, &amp;) r 5.98 (1H, s) r 6.22 (2H, &amp;) t 7.10 (XHf s) , 7.65 &lt;2H, d, J = 8.4 Hz} , 7,75 &lt;3H, d, J *= 8.4 Hz) , 9.12 (XH, a). 1H-KMR (400 MHz, DMSO-de) 5 0.99-X.25 (5H, m&gt;, 1.62-1.70 (5H, ffi) f 1.87 ( 1H, br s) , 2.59 (2Ut d# J» 6.8 , 6·02 &lt;1H, , 6.49 &lt; 2H, s)f 7.13 (1H, s), 7.65 (2H, d, J ^ 8.4 Hz) , 7.79 (3H, d, 8.4 Hz), 9.32 (XH, s).

1H-NMR (400 MHz, OMSO-dfe) δ 1*52-1.60 (mr 10H), 1.91 (br sf 2H) , 4.03 (tor s, IH), 5*47 (sf 1H), 5.B2 (d, 1H, J - 7*6 Hz&gt; , 6.18 (S, 2H) , 7.10 (s, IH), 7.71 (d, 2H, J =8,1 Hz) , 7.73 (d, 2H, J= 8,1 Hz&gt; , 7.79 (s, IH), 9.10 (s, 1H). MS (ESI) m/z ^ 365 {M+H)' LC/MS t» « 1.57 min. 1H-NMR (400 MHz, DMSO*d£) δ 1.64 (mf 2H) , 1.89 (m, 2H) f 2.16 (t, 2Mf J * 10.6 Hz), 2.30 (s, 3H)r 2.90 *、MH 丄 (m, 2H, J » 9.6 Ha〇 , 3,83 {3b:rr 1H&gt; , 5.48 (st IK), 6.06 (df IH, J«7.1 實施例i — 8 74 〇 Hz), 6.19 (s; 2H), 7.11 (s, IH), V 7.S8 (d, 2H, J = 8.6 , 7.75 (d, Me 2H, J * 8.6 Sz) f 7.79 (s, XH) , 9.11 (s, IH). MS (SSX) m/z « 366 (H+H&gt;+. LC/MS tR — 0,60 min. 141666.doc 541 - 201028381 實施例編號1H-NMR (400 MHz, OMSO-dfe) δ 1*52-1.60 (mr 10H), 1.91 (br sf 2H) , 4.03 (tor s, IH), 5*47 (sf 1H), 5.B2 (d , 1H, J - 7*6 Hz&gt; , 6.18 (S, 2H) , 7.10 (s, IH), 7.71 (d, 2H, J = 8, 1 Hz) , 7.73 (d, 2H, J= 8,1 Hz&gt;, 7.79 (s, IH), 9.10 (s, 1H). MS (ESI) m/z ^ 365 {M+H)' LC/MS t» « 1.57 min. 1H-NMR (400 MHz, DMSO* d£) δ 1.64 (mf 2H) , 1.89 (m, 2H) f 2.16 (t, 2Mf J * 10.6 Hz), 2.30 (s, 3H)r 2.90 *, MH 丄(m, 2H, J » 9.6 Ha〇 , 3,83 {3b:rr 1H&gt; , 5.48 (st IK), 6.06 (df IH, J«7.1 Example i - 8 74 〇Hz), 6.19 (s; 2H), 7.11 (s, IH), V 7.S8 (d, 2H, J = 8.6, 7.75 (d, Me 2H, J * 8.6 Sz) f 7.79 (s, XH) , 9.11 (s, IH). MS (SSX) m/z « 366 (H +H&gt;+. LC/MS tR — 0,60 min. 141666.doc 541 - 201028381 Example number

RR

*、NH 實施例1 — 8 7 5*, NH Example 1 - 8 7 5

OH 物性資料_ 1H-NHR (400 MHz, DMSO-d6) δ 1.25-1.44 (m, 4H) , X . 90 {brm, 4H), 3.79 (hr, 1H) , 4.63 (br, 1H) , 5.47 (s, XH) , 5,87 (d, 1H, J * 7.1 Hz), 6.17 &lt;s, 2H), 7.10 (s, 1H), 7.71 2H, J = 8,1 Hz&gt; , *7.76 (d, 2H, J « 8.1 Hz), 7.79 (brf 1H) , 9.11 (Bt 1H). MS &lt;£SX) m/z « 367 (M+H)+ · LC/MS tR « 0.86 min. 實施例1 — 8 7 6OH Physical Properties _ 1H-NHR (400 MHz, DMSO-d6) δ 1.25-1.44 (m, 4H), X. 90 {brm, 4H), 3.79 (hr, 1H), 4.63 (br, 1H), 5.47 ( s, XH), 5,87 (d, 1H, J * 7.1 Hz), 6.17 &lt;s, 2H), 7.10 (s, 1H), 7.71 2H, J = 8,1 Hz&gt;, *7.76 (d, 2H, J « 8.1 Hz), 7.79 (brf 1H) , 9.11 (Bt 1H). MS &lt;£SX) m/z « 367 (M+H)+ · LC/MS tR « 0.86 min. Example 1 - 8 7 6

MS (ESI) m/z « 352 (M+H)+. LC/MS tR « 1,58 min.MS (ESI) m/z « 352 (M+H)+. LC/MS tR « 1,58 min.

* 、〇 1H-NMR (400 MHl DMSO-dg) δ 1.67 On, , 2.03 &lt;η», 2H&gt; , 3.S3 J® 9.6 Hz) , 3.91 (m, 2H) , 5.15 (br, 1H), 5.79 (Bf 1H), 6.59 (s, 2H), 實施例1 一 8 7 7 Λ 7.14 &lt;sr XH) , 7.59 (d, 2Hf J: *=8.1 〔。〕 Hz) , 7.80 &lt;d, 2Hr J = 8,1 Hz), {br, 1H), 9.38 (s, XH). MS &lt;£SI) m/r * 354 (H+H)+. LC/MS tR » 1. IS min. 7.80 O*, 〇1H-NMR (400 MHl DMSO-dg) δ 1.67 On, , 2.03 &lt;η», 2H&gt;, 3.S3 J® 9.6 Hz), 3.91 (m, 2H), 5.15 (br, 1H), 5.79 (Bf 1H), 6.59 (s, 2H), Example 1 - 8 7 7 Λ 7.14 &lt;sr XH) , 7.59 (d, 2Hf J: *=8.1 [.] Hz) , 7.80 &lt;d, 2Hr J = 8,1 Hz), {br, 1H), 9.38 (s, XH). MS &lt;£SI) m/r * 354 (H+H)+. LC/MS tR » 1. IS min. 7.80 O

141666.doc 542- 201028381 [表 1-8]141666.doc 542- 201028381 [Table 1-8]

R1H 表1-8中記載之化合物係依據上述記載之實施例1-488之 步驟2及1-515之方法而合成。又，實施例1-890、1-891、 1-893、1-894及1-895係依據實施例1-525之方法而合成。R1H The compounds described in Tables 1-8 were synthesized in accordance with the procedures of Steps 2 and 1-515 of Examples 1-488 described above. Further, Examples 1-890, 1-891, 1-893, 1-894, and 1-895 were synthesized in accordance with the methods of Examples 1-525.

實施例編號 R1 R2 實施例1 一 8 7 8Example No. R1 R2 Example 1 A 8 7 8

實施例1 — 8 8 0Example 1 - 8 8 0

物性資料_ 1H-NMR (400 MHz, DHSO-d6) δ Χ.53 (tors, 4H) f 1*68 (brs, 2H) , 1.94 (brs, 2H) r 4.26 (brs, 3H), 5.48 (s, XH) , 6.00 (d, J =* 6.1 Hz, 1H) , 6,18 &lt;sf 2H) r 7- 4$ (df J - 8.3 Hz, XH), 7.50 (d, J = 8.3 Hz, 1H), 8.08 {sr 1H) , 8.18 &lt;s, 1H) , 9.17 (sf 1H). MS (ZS1) m/z « 349 (M+H) + . LC/MS tR = 1.87 min. 1B-KMR (400 MHx, DMSO-dc) 6 0.56 (3, 2&amp;)f 0.92 (s, 2tt) ,1.74 (mf XH) , 3.82 (s, 3H) , 6.01 (s, 1H) , 6.47 (d, 1H, J = 12 Hz), 6.SO (s, 2H) , 6.70 (d, IH, J = X2 H«) , 6-91 (», 1H) , 7.02 (d, 1H, 6 Hz) , 7.40 (&amp;t 1H), 7.42 (B, 1H) ,7.59 (d, 1H, J * 12 Hz), 7,71 &lt;sf 1H) 9.32 (s, 1H). 1H-HMR &lt;400 MH*, DMS〇-d6) $ 5.69 (s, lH)r 6.34 (B, 2H) , 6.42 (d, 1H, J « 16*2 Η») , 6,96 (s, 1H) , 7.04 {t, 1H, J ® 7*1 Ha) r 7.26-7.34 (m, 5H) , 7,54-7,44 (mr 5H) , 8.45 (s, 1H) , 9,12 (s, 1H). • 543 - 141666.doc 201028381 實施例編號 妒 R2 實施例1 一 8 8 1Physical data _ 1H-NMR (400 MHz, DHSO-d6) δ Χ.53 (tors, 4H) f 1*68 (brs, 2H) , 1.94 (brs, 2H) r 4.26 (brs, 3H), 5.48 (s , XH) , 6.00 (d, J =* 6.1 Hz, 1H) , 6,18 &lt;sf 2H) r 7- 4$ (df J - 8.3 Hz, XH), 7.50 (d, J = 8.3 Hz, 1H ), 8.08 {sr 1H) , 8.18 &lt;s, 1H) , 9.17 (sf 1H). MS (ZS1) m/z « 349 (M+H) + . LC/MS tR = 1.87 min. 1B-KMR ( 400 MHx, DMSO-dc) 6 0.56 (3, 2&amp;) f 0.92 (s, 2tt) , 1.74 (mf XH) , 3.82 (s, 3H) , 6.01 (s, 1H) , 6.47 (d, 1H, J = 12 Hz), 6.SO (s, 2H) , 6.70 (d, IH, J = X2 H«) , 6-91 (», 1H) , 7.02 (d, 1H, 6 Hz) , 7.40 (&amp; t 1H), 7.42 (B, 1H), 7.59 (d, 1H, J * 12 Hz), 7,71 &lt;sf 1H) 9.32 (s, 1H). 1H-HMR &lt;400 MH*, DMS〇- D6) $ 5.69 (s, lH)r 6.34 (B, 2H) , 6.42 (d, 1H, J « 16*2 Η») , 6,96 (s, 1H) , 7.04 {t, 1H, J ® 7 *1 Ha) r 7.26-7.34 (m, 5H) , 7,54-7,44 (mr 5H) , 8.45 (s, 1H) , 9,12 (s, 1H). • 543 - 141666.doc 201028381 Implementation Example number 妒R2 Example 1 A 8 8 1

實施例1 — 8 8 2Example 1 - 8 8 2

實施例1 — 8 8 3 Μθ—Ν iExample 1 - 8 8 3 Μ θ - Ν i

*、NH*, NH

實施例1 — 8 8 4 Μβ~ΝExample 1 - 8 8 4 Μβ~Ν

OMeOMe

物性資料_ 1H-HMR &lt;400 HH«, DMSO-de) δ 1.32 (6H, d, J - 6.0 Hz), 1.92 &lt;2H, t, J = 6.0 Hz), 2.13 (6H, s) , 2.19 (2H, t, J ^ 6,8 Hz), 4.11 (2H# t, J » 6.8 Hz), 5.24 (lHf tf J = 6,0 Hz&gt; , 5.71 (1H, s), 6.40 &lt;2H, s&gt; , 7.47《5H, s), 7.80 (1H, s&gt; , 8.06 {1H, s), 9.03 (XH, s). 1H-HMR (400 MHz, DMSO»d6) δ 1&lt;32 (6H, d, J » 6.0 Hz), 3.70 (3H, s&gt; , 5.08 {2H, s), 5.71 (1H, s) , 6.41 (2H, s), 7.49 (5H, d, J * 3,6 Hz), 7.86 (1H, s) , 8.08 ClHr s), 9.04 (XH, s). 1H-NMR (400 MHz, DMSO-de) 5 1.51 (1H# br s) , 1.63 {3H, br s), 1.86 (1H, br s) , 2,20 (3Hf s), 3.66-3.70 (1H, m), 3.76-3.79 (1H, m), 3.85 &lt;3H, s), 4.02 (2H, br s), 5.15 (1H, s) f 5.67 (1H# d, J « 8.0 Hz) , 6,02 (2Hf s), 7.31 (2H, s&gt; , 7.42 UH, s); 7.80 &lt;1H, s&gt; , 7.94 (1H, s), 8.07 (XH, s). 1H-NHR (400 MHz, DMSO*d6) δ 1*58-1.64 &lt;3H, m&gt; , 1.94-1.99 (3H, m), 3.42-3.48 (2H, m) r 3.86 (€Hf s), 5.08 (1H, br s), 5.69 (1H, s) # 6.38 {2H, s), 7.10 (1H, df J - 8.0 Hz), 7.19 (1H, s) , 7.6X (1H, d# J « 8.0 Hz) , 7.86 (1H, s), 8.13-8.15 (2H, m). 141666.doc 544- 201028381Physical property _ 1H-HMR &lt;400 HH«, DMSO-de) δ 1.32 (6H, d, J - 6.0 Hz), 1.92 &lt;2H, t, J = 6.0 Hz), 2.13 (6H, s) , 2.19 (2H, t, J ^ 6,8 Hz), 4.11 (2H# t, J » 6.8 Hz), 5.24 (lHf tf J = 6,0 Hz&gt; , 5.71 (1H, s), 6.40 &lt;2H, s&gt ; , 7.47 "5H, s), 7.80 (1H, s&gt; , 8.06 {1H, s), 9.03 (XH, s). 1H-HMR (400 MHz, DMSO»d6) δ 1 &lt;32 (6H, d, J » 6.0 Hz), 3.70 (3H, s&gt; , 5.08 {2H, s), 5.71 (1H, s), 6.41 (2H, s), 7.49 (5H, d, J * 3,6 Hz), 7.86 ( 1H, s), 8.08 ClHr s), 9.04 (XH, s). 1H-NMR (400 MHz, DMSO-de) 5 1.51 (1H# br s) , 1.63 {3H, br s), 1.86 (1H, br s) , 2,20 (3Hf s), 3.66-3.70 (1H, m), 3.76-3.79 (1H, m), 3.85 &lt;3H, s), 4.02 (2H, br s), 5.15 (1H, s ) f 5.67 (1H# d, J « 8.0 Hz) , 6,02 (2Hf s), 7.31 (2H, s&gt; , 7.42 UH, s); 7.80 &lt;1H, s&gt; , 7.94 (1H, s), 8.07 (XH, s). 1H-NHR (400 MHz, DMSO*d6) δ 1*58-1.64 &lt;3H, m&gt; , 1.94-1.99 (3H, m), 3.42-3.48 (2H, m) r 3.86 (€Hf s), 5.08 (1H, br s), 5.69 (1H, s) # 6.38 {2H, s), 7.10 (1H, df J - 8.0 Hz), 7.19 (1H, s) , 7.6X (1H , d# J « 8.0 Hz), 7.86 (1H, s), 8.13-8.15 (2H, m). 141666.doc 544- 201028381

141666.doc 實施例編號 R*141666.doc Example number R*

實施例1 一 8 8 6Example 1 A 8 8 6

R2 物性資料_ 1H-NMR (400 DHSO-d6) δ 1.66 (m, 2H), 1.9S Cmf 2H) , 3.43 (s, 3H) , 3.53 (t, 2H, J » 8*6 Hz&gt; , 3·85 (m, 2H) , 5.22 imt 1H) , 5.26 Cs, 2H&gt; , 5,78 (s, 1H} , 6·51 (d, 1H, J « 15-7 Hz) , 6.57 (s, 2H), 6.96 (a, 1H&gt;, 7.28-7.34 (m, 2H&gt; , 7,45 (st 1H) , 7.46 {ά, XH, J » 7.1 Hz) , 7.64 &lt;d, XH, J « 15.7 Ha), 9,36 (b, 1Ά), MS &lt;ESI) m/z « 440 (M+H) + . LC/MS = 1.33 min, 1H-NMR {400 MH:, DMSO-de) 5 1.66 &lt;m, 2H&gt;, 1.98 («I, 2H) f 3.27 (s, 3H) , 3.43 (s, 3H) , 3.53 (t, 2Hf J » 8.6 Hz), 3,87 (t, 2H, J « 5.6 Hz), 5.24 (br, 1H), 5.26 、0 (3, 2H) , 5,78 &lt;s, 1H) , 6.56 0&lt;d, 1H, J * 15.7 Hz) , 6.57 ^ (s, 2H) r 7,30 (8t 1H) , 7.33 (d, 1H, J = 8.6 Hz&gt;, 7.44 &lt;d, 1H, J = 8.6 Hz&gt;, 7.64 &lt;d, 1H, J * 15,7 Hz) , 8.07 (br, 1H), 9.36 (s, 1H). MS (ESI) m/z = 498 (M+H)+. LC/MS tR « 1.47 min.R2 Physical Properties _ 1H-NMR (400 DHSO-d6) δ 1.66 (m, 2H), 1.9S Cmf 2H) , 3.43 (s, 3H) , 3.53 (t, 2H, J » 8*6 Hz), 3· 85 (m, 2H) , 5.22 imt 1H) , 5.26 Cs, 2H&gt; , 5,78 (s, 1H} , 6·51 (d, 1H, J « 15-7 Hz) , 6.57 (s, 2H), 6.96 (a, 1H&gt;, 7.28-7.34 (m, 2H&gt;, 7,45 (st 1H), 7.46 {ά, XH, J » 7.1 Hz) , 7.64 &lt;d, XH, J « 15.7 Ha), 9 , 36 (b, 1Ά), MS &lt;ESI) m/z « 440 (M+H) + . LC/MS = 1.33 min, 1H-NMR {400 MH:, DMSO-de) 5 1.66 &lt;m, 2H&gt;, 1.98 («I, 2H) f 3.27 (s, 3H) , 3.43 (s, 3H) , 3.53 (t, 2Hf J » 8.6 Hz), 3,87 (t, 2H, J « 5.6 Hz), 5.24 (br, 1H), 5.26, 0 (3, 2H), 5,78 &lt;s, 1H) , 6.56 0&lt;d, 1H, J * 15.7 Hz) , 6.57 ^ (s, 2H) r 7,30 (8t 1H) , 7.33 (d, 1H, J = 8.6 Hz&gt;, 7.44 &lt;d, 1H, J = 8.6 Hz&gt;, 7.64 &lt;d, 1H, J * 15,7 Hz) , 8.07 (br, 1H ), 9.36 (s, 1H). MS (ESI) m/z = 498 (M+H)+. LC/MS tR « 1.47 min.

545 - 201028381 實施例編號 R1 實施例1 — 8 8 7545 - 201028381 Example Number R1 Example 1 - 8 8 7

實施例1 一 8 8 8Example 1 A 8 8 8

Ra 物性資料_ &lt;400 HHz, DMSO-d6) δ 1.66 (mr 2Η), 2.02 (m, 2Η&gt; , 3.53 (t, 2H, J = 9.6 Hz), 3.76 (mf 2H} f 3-8θ (br, 2H), 4,14 (br, 2H), 4.92 (brs, 1H) , 5.15 &lt;brs, 1H) y 5.71 (s, 1H) , 6.47 (br, 2H) , 7.48 (s, 4H), 7.81 is, 1H) 7 S.06 &lt;S, XH), 9.08 (s, 1H). MS (ESI) m/z « 421 (Μ+Η&gt; +, LC/MS tR =* 1.34 min, 1H-NMR (400 MHz, DMSO»d6) δ 1.23 (q, 2H, J - 10.8 Hz), 1.40 (q# 2H, J « 11.6 Hz:), 1.96 (d, 2H, J * 10.8 Hz), 2.05 (d, 2H, J * 1X.6 Hz), 3.12 (br, 1H) , 3.26 (s, 3H), 3.7€ (br, 2H), 3.83 (br, 1H), 4.15 &lt;br, 2H), 4.92 &lt;br, 1H) , 5.43 (s, 1H), 5.81 idt IH, J « 7.1 OMe Hz) , 6.08 (s, 2H) , 7.40 (d; 2H, J = 7,6 Hz) , 7,59 (d, 2H, J » 7·δ Hz&gt; , 7·78 (s, 1H) , 8.03 &lt;s, 1H) , 8.80 (sr 1H). MS (ESI) m/z » 448 (M+H)+. LC/MS tR «= 1.26 min.Ra Physical Data_ &lt;400 HHz, DMSO-d6) δ 1.66 (mr 2Η), 2.02 (m, 2Η&gt;, 3.53 (t, 2H, J = 9.6 Hz), 3.76 (mf 2H} f 3-8θ (br , 2H), 4,14 (br, 2H), 4.92 (brs, 1H) , 5.15 &lt;brs, 1H) y 5.71 (s, 1H) , 6.47 (br, 2H) , 7.48 (s, 4H), 7.81 Is, 1H) 7 S.06 &lt;S, XH), 9.08 (s, 1H). MS (ESI) m/z « 421 (Μ+Η&gt; +, LC/MS tR =* 1.34 min, 1H-NMR (400 MHz, DMSO»d6) δ 1.23 (q, 2H, J - 10.8 Hz), 1.40 (q# 2H, J « 11.6 Hz:), 1.96 (d, 2H, J * 10.8 Hz), 2.05 (d, 2H, J * 1X.6 Hz), 3.12 (br, 1H), 3.26 (s, 3H), 3.7€ (br, 2H), 3.83 (br, 1H), 4.15 &lt;br, 2H), 4.92 &lt; Br, 1H), 5.43 (s, 1H), 5.81 idt IH, J « 7.1 OMe Hz) , 6.08 (s, 2H) , 7.40 (d; 2H, J = 7,6 Hz), 7,59 (d, 2H, J » 7·δ Hz&gt; , 7·78 (s, 1H) , 8.03 &lt;s, 1H) , 8.80 (sr 1H). MS (ESI) m/z » 448 (M+H)+. LC /MS tR «= 1.26 min.

141666.doc 546· 201028381 實施例編號 R* 實施例1 — 8 8 9141666.doc 546· 201028381 Example Number R* Example 1 - 8 8 9

實施例1 — 8 9 0Example 1 - 8 9 0

R2 物性資料_ 1H-HMR (400 MHz, DMSO*de) δ 3.51 (s, 3H&gt;, 3.84 (s, 3H) , 5.86 (s, 1H) , €.73 (s, 2H) , β.75 (t, 1H； σ ^ ΒΛ Hz) , 6.98 {s, 1H) , 7.20 (df lHf J =* 8·6 Hz} , 7,26 (d, 2H, J « 8.1 Hz&gt; , *7&gt;53·《心 2Hf J « 8.1 Hz), 7,72 (s, 1H) , 7.93 (sf 1H) , 9.15 (a f 1H), MS &lt;ESI&gt; 成/z = 447 &lt;M+H)+, LC/HS tR « 1.97 min. 1H-NMR (400 HHz, DMSO-dte) δ 0.56 (in, 0.93 (m, 2H&gt; , 1.75 (brm, 1H) , 3.84 (st 3H) , 3*85 (s, 3H) , 5.97 (s, 1H) , 6.42 &lt;sr 2H) , 6.48 (ddf 1H, J - 15,7, 6.2 Hz), 6.70 &lt;d, 1H, J 雄 15.7 , 6.98 (df lHf J « 7,6 Hz), 7.45 (d, 1H, J » 7.6 Hz), 7.63 (s, 1H&gt; , 7.81 &lt;s, 1H&gt; , 8.00 (s, XH) , 9.07 (s, 1H). MS (ESI) m/z * 387 (M+H)+. LC/HS tR =： 1.54 min. 1H-NMH (400 MHz, DMSO-de) 6 1.12 Cs, 9H), 3.86 (s, 3H) , 3.90 (s, 3H&gt; , 6.00 (s, 1H) f 6.45 (s, 2H) , 6.52 (d, 1H, J * 15.7 Hz) , 6.97 (d, 1H, J * 7.1 Hz) , 7.05 (d, 1H, J ® 15.7 Hz) , 7.4€ (d, Μβ 5 1H, J * 7.1 Hz) , 7.71 (s, 1H) , 7.82 (s, 1H) , 8,01 i&amp;t 1H) , 9.11 &lt;s, IS), MS (ESI) m/z » 403 (M+H) +. LC/MS tft == 1.91 min.R2 Physical Data _ 1H-HMR (400 MHz, DMSO*de) δ 3.51 (s, 3H&gt;, 3.84 (s, 3H), 5.86 (s, 1H) , €.73 (s, 2H), β.75 ( t, 1H; σ ^ ΒΛ Hz) , 6.98 {s, 1H) , 7.20 (df lHf J =* 8·6 Hz} , 7,26 (d, 2H, J « 8.1 Hz&gt; , *7&gt;53· Heart 2Hf J « 8.1 Hz), 7,72 (s, 1H) , 7.93 (sf 1H) , 9.15 (af 1H), MS &lt;ESI&gt; into /z = 447 &lt;M+H)+, LC/HS tR « 1.97 min. 1H-NMR (400 HHz, DMSO-dte) δ 0.56 (in, 0.93 (m, 2H&gt;, 1.75 (brm, 1H), 3.84 (st 3H) , 3*85 (s, 3H) , 5.97 (s, 1H) , 6.42 &lt;sr 2H) , 6.48 (ddf 1H, J - 15,7, 6.2 Hz), 6.70 &lt;d, 1H, J male 15.7, 6.98 (df lHf J « 7,6 Hz ), 7.45 (d, 1H, J » 7.6 Hz), 7.63 (s, 1H&gt;, 7.81 &lt;s, 1H&gt;, 8.00 (s, XH), 9.07 (s, 1H). MS (ESI) m/z * 387 (M+H)+. LC/HS tR =: 1.54 min. 1H-NMH (400 MHz, DMSO-de) 6 1.12 Cs, 9H), 3.86 (s, 3H), 3.90 (s, 3H&gt; , 6.00 (s, 1H) f 6.45 (s, 2H) , 6.52 (d, 1H, J * 15.7 Hz), 6.97 (d, 1H, J * 7.1 Hz), 7.05 (d, 1H, J ® 15.7 Hz), 7.4€ (d, Μβ 5 1H, J * 7.1 Hz), 7.71 (s, 1H), 7.82 (s, 1H) , 8,01 i&amp;t 1H ), 9.11 &lt;s, IS), MS (ESI) m/z » 403 (M+H) +. LC/MS tft == 1.91 min.

141666.doc 547- 201028381 實施例編號 R1 R2 實施例1 一 8 9 2141666.doc 547- 201028381 Example number R1 R2 Example 1 A 8 9 2

物性資料‘_ 1H-HMR {400 MHz, DMSO«d6) δ 3.52 (s, 3H), 3.55 (s, 3H) , 5.89 {Bt 1H), 6.74-6.83 (m, 3H) 7 7.08 (S, 1H) 7 7.27 &lt;d, 2H, J * 7.1 Hz) , 7.37 &lt;d, 1H, J * 7,6 Hz) , 7.51 (dt 2H, J * 7.1Hz), 8.32 (s, 1H) f 8.38 (s, 1H), 9.28 (s, 1H). MS (ESI) m/z * 511 (M+H) + . LC/MS tR - 2.11 min- 實施例1 — 8 9 3Physical data '_ 1H-HMR {400 MHz, DMSO«d6) δ 3.52 (s, 3H), 3.55 (s, 3H) , 5.89 {Bt 1H), 6.74-6.83 (m, 3H) 7 7.08 (S, 1H 7 7.27 &lt;d, 2H, J * 7.1 Hz) , 7.37 &lt;d, 1H, J * 7,6 Hz) , 7.51 (dt 2H, J * 7.1Hz), 8.32 (s, 1H) f 8.38 ( s, 1H), 9.28 (s, 1H). MS (ESI) m/z * 511 (M+H) + . LC/MS tR - 2.11 min - Example 1 - 8 9 3

1H-NMR (400 MHz, DMSO-d6&gt; δ 0.08 (m, 2H), 0.45 (mf 2H) , 0.78 {m, 1H) , 1.66 (m, 2H) , 2.82 (xn, 2H) , 3.88 {&amp;t 6H&gt; , 6.01 is, 1H) , ¢.44 (s, © 2H), 7.04 (d, 1H, J « 8.6 Hz)7 7,47 (d, 1H, J * 8.6 Hz) , 7.62 (sf 1H&gt; , 7,84 (s, XH&gt; , 8.03 (s, 1H) , 9.10 isf XH). MS (ESI) m/z = 389 (M+H) + . LC/MS tR = 1.41 min. XH-NMR (400 MHz, DMSO-de) δ 0.95 (st 9H), 1.58 (t,1H-NMR (400 MHz, DMSO-d6 &gt; δ 0.08 (m, 2H), 0.45 (mf 2H), 0.78 {m, 1H), 1.66 (m, 2H), 2.82 (xn, 2H), 3.88 {&amp; t 6H&gt; , 6.01 is, 1H) , ¢.44 (s, © 2H), 7.04 (d, 1H, J « 8.6 Hz) 7, 7,47 (d, 1H, J * 8.6 Hz) , 7.62 (sf 1H&gt) ; , 7,84 (s, XH&gt; , 8.03 (s, 1H) , 9.10 isf XH). MS (ESI) m/z = 389 (M+H) + . LC/MS tR = 1.41 min. XH-NMR (400 MHz, DMSO-de) δ 0.95 (st 9H), 1.58 (t,

XMeMe 2H, J « 8.3 Hz) , 2.66 &lt;t, 2H, J * 8.3 Hz), 3.85 (s, 3H) , 3.86 (s, 3H&gt; , 5.98 {s, 1H) , 5.42 (sf 2H) r 6.95 (d, XH, J « 8,6 Hz) , 7.44 (d, in, J « 8,6 Hz) , 7.67 (s, 1H) , 7.81 (s, 1H) , 8.00 (s, 1H), 9.08 (s, 1H). MS (ESX) m/z « 405 (M+H) +.XMeMe 2H, J « 8.3 Hz) , 2.66 &lt;t, 2H, J * 8.3 Hz), 3.85 (s, 3H) , 3.86 (s, 3H&gt; , 5.98 {s, 1H) , 5.42 (sf 2H) r 6.95 (d, XH, J « 8,6 Hz) , 7.44 (d, in, J « 8,6 Hz) , 7.67 (s, 1H) , 7.81 (s, 1H) , 8.00 (s, 1H), 9.08 ( s, 1H). MS (ESX) m/z « 405 (M+H) +.

LC/MS tR = 1.S9 min. 141666.doc 548- 201028381LC/MS tR = 1.S9 min. 141666.doc 548- 201028381

實施例編號 R1 R2 實施例1 _ 8 9 5Example No. R1 R2 Example 1 _ 8 9 5

實施例1 — 8 9 6Example 1 - 8 9 6

*、MH*, MH

實施例1 一 8 9 7Example 1 A 8 9 7

OMeOMe

*、NH*, NH

物性資料_ 1H-NMR (400 MHz, DMSO-de) 50,94 (s, 3H), 0.96 {sf 3H) , 2.19 (brm, 1H) r 2,57 (d, 2Ht J =* 6,6 Hz) , 3.85 (sf 6H) , 5.98 (a, 1H) , 6.42 (sf 2H), 7.01 (d, IH, J = 9.1 Has) r 7.45 {dr XHr J * 9.1 Hz) , 7.62 (s, 1H) , 7.81 {&amp;t in) f 8.00 (s, 1H) , 9.09 &lt;s, XH). MS &lt;ESI) m/z = 377 &lt;M+H) + . LC/MS tR * a,34 min. 1H-NMR (400 MBs, DMSO~d6) δ 1.14 s, 1H&gt; # 1.27-1.37 (m, 4H), 1.62-1,65 (mf 1H) , 1.73 (br Bt 2H&gt;, 1.89 (br Bf 2H) , 2*76 (s, 3H) r 3.78 (br 3/ 1H) f 4.30 &lt;s, 2H) r 5,48 (s, 1H)f 5.89 (df J » 7.3 Η*, 1H) , 6.26 (s, 2H&gt; , 7,63 {d, J * 9.1 Hzr 1H&gt;, 7.69 &lt;d, J * 8.6 Η», 1H), 7.91 {sf 1H), 9-35 {s, 1H). MS (ESZ) m/z ^ 413 (M+H) + . LC/MS tR = 1.84 min. ΧΗ-ΙΏίΏΙ (400 MHz, DMSO-de) δ 3.84 &lt;s, 3H&gt;, 3·86 (s, 3H) , 5.62 (6, 1H) , 6*21 (s, 2H), 6.92 &lt;tr J ® 6.8 Hz, 1H)7 6.99 (df J * 7.8 Hz, 1H), 7.17-7.20 (me 3H), 7.55 (d, J » 7.8 Hz, 3H)r 7.85 (s, 1H) , 7.94 &lt;s, XH), 8.11 (s, 1H) f 8.25 {sf 1H), MS (ESI) m/z * 412 (M-fH) + . LC/MS tR = 1.59 min. 141666.doc 549- 201028381 實施例編號 R1 實施例1 — 8 9 8Physical data _ 1H-NMR (400 MHz, DMSO-de) 50,94 (s, 3H), 0.96 {sf 3H) , 2.19 (brm, 1H) r 2,57 (d, 2Ht J =* 6,6 Hz ), 3.85 (sf 6H) , 5.98 (a, 1H), 6.42 (sf 2H), 7.01 (d, IH, J = 9.1 Has) r 7.45 {dr XHr J * 9.1 Hz) , 7.62 (s, 1H) , 7.81 {&amp;t in) f 8.00 (s, 1H) , 9.09 &lt;s, XH). MS &lt;ESI) m/z = 377 &lt;M+H) + . LC/MS tR * a,34 min 1H-NMR (400 MBs, DMSO~d6) δ 1.14 s, 1H&gt;# 1.27-1.37 (m, 4H), 1.62-1, 65 (mf 1H) , 1.73 (br Bt 2H&gt;, 1.89 (br Bf 2H ), 2*76 (s, 3H) r 3.78 (br 3/ 1H) f 4.30 &lt;s, 2H) r 5,48 (s, 1H)f 5.89 (df J » 7.3 Η*, 1H) , 6.26 ( s, 2H&gt;, 7,63 {d, J * 9.1 Hzr 1H&gt;, 7.69 &lt;d, J * 8.6 Η», 1H), 7.91 {sf 1H), 9-35 {s, 1H). MS (ESZ m/z ^ 413 (M+H) + . LC/MS tR = 1.84 min. ΧΗ-ΙΏίΏΙ (400 MHz, DMSO-de) δ 3.84 &lt;s, 3H&gt;, 3·86 (s, 3H) , 5.62 (6, 1H) , 6*21 (s, 2H), 6.92 &lt;tr J ® 6.8 Hz, 1H)7 6.99 (df J * 7.8 Hz, 1H), 7.17-7.20 (me 3H), 7.55 (d , J » 7.8 Hz, 3H)r 7.85 (s, 1H) , 7.94 &lt;s, XH), 8.11 (s, 1H) f 8.25 {sf 1H), MS (ESI) m/z * 412 (M-fH ) +. LC/MS tR = 1.59 min. 141666.doc 549- 201028381 Example number R1 Example 1 - 8 9 8

Me-NMe-N

OMeOMe

實施例1 — 9 0 0Example 1 - 9 0 0

Me-NMe-N

^ 物性資料_ 1H-NHR (400 MHz, DMSO-de) δ 3.S6 (s, 6H), 5.63 (s, 1H) , 6.21 (sf 2H) , 6.38 (d, *、 J» 6.0 Hz, 1H) , 6,96-7.00 NH Ϊ &lt;m, 3H&gt; , 7.17 (s, 1H&gt; , 7.65 (dt J « 8.0 Hz, 1H) , 7.83 (», 2H) , 8.09 (s, XH) , 8.15 (s, 1H). MS《ESI) m/z - 428 (M+H) + . LC/MS tR « 1.24 min. 1H-NMH (400 MHz, DMSO-d6&gt; δ 1.53-1.62 &lt;m, 2H&gt;, 1.79 {ύ, J = 12.6 Ha：, 2H) , 3.87 (s, 3H), 4.01 (br s# 1H&gt;, 5.23 &lt;s, 2H) , 5.51 (s, 1H) # ^NH 5.98 Cd, J « 8.0 Hz, 1H), 6.07 (s, 2H) , 7.19 (d, J = 8.0 Hz, 1H) , 7.36 &lt;s, 1H), 7.86 &lt;s, 1H&gt; , 7.93 (d, J = 8.3 Hz, 1H) f 7.98 (s, 1H), 8.11 (at 1H). MS《ESI&gt; m/z « 445 &lt;M+H&gt; + . LC/MS tR = 1.21 min. 1H-NMR (400 MHz, DMSO-de) δ 1.55 (br s, 1H) , 1.87 (br s, XH) , 2,05-2.26 (m, 4H), 3.84 (s, 3H), 4.02 (br sf 1H) , 5,47 (a, 1H) , 5.65 (s, 2H) , 5.94 (d, J = 7,8 Hje, 1H) , 6.17 (s, 2H) , 6.92 {d, J = 7.8 Hz, 1H), 6.99 (s, XH&gt; # 7.42 id, J « 8.4 Hz, 1H) , 7.71 (s, 1H) , 8.00 {s, 1H&gt; , 8.08 (S, 1H&gt; , 10.31 (s, 1H). MS &lt;ESX) m/z » 402 (M-fH) + . LC/MS tR = 1,42 min.^ Physical data _ 1H-NHR (400 MHz, DMSO-de) δ 3.S6 (s, 6H), 5.63 (s, 1H), 6.21 (sf 2H) , 6.38 (d, *, J» 6.0 Hz, 1H ) , 6,96-7.00 NH Ϊ &lt;m, 3H&gt; , 7.17 (s, 1H&gt; , 7.65 (dt J « 8.0 Hz, 1H) , 7.83 (», 2H) , 8.09 (s, XH) , 8.15 ( s, 1H). MS "ESI" m/z - 428 (M+H) + . LC/MS tR « 1.24 min. 1H-NMH (400 MHz, DMSO-d6 &gt; δ 1.53-1.62 &lt;m, 2H&gt; , 1.79 {ύ, J = 12.6 Ha:, 2H) , 3.87 (s, 3H), 4.01 (br s# 1H&gt;, 5.23 &lt;s, 2H) , 5.51 (s, 1H) # ^NH 5.98 Cd, J « 8.0 Hz, 1H), 6.07 (s, 2H), 7.19 (d, J = 8.0 Hz, 1H), 7.36 &lt;s, 1H), 7.86 &lt;s, 1H&gt;, 7.93 (d, J = 8.3 Hz , 1H) f 7.98 (s, 1H), 8.11 (at 1H). MS "ESI" m/z « 445 &lt;M+H&gt; + . LC/MS tR = 1.21 min. 1H-NMR (400 MHz, DMSO -de) δ 1.55 (br s, 1H) , 1.87 (br s, XH) , 2,05-2.26 (m, 4H), 3.84 (s, 3H), 4.02 (br sf 1H) , 5,47 (a , 1H) , 5.65 (s, 2H) , 5.94 (d, J = 7,8 Hje, 1H) , 6.17 (s, 2H) , 6.92 {d, J = 7.8 Hz, 1H), 6.99 (s, XH&gt;# 7.42 id, J « 8.4 Hz, 1H) , 7.71 (s, 1H) , 8.00 {s, 1H&gt; , 8.08 (S, 1H&gt; , 10.31 (s, 1H). MS &lt;ESX) m/z » 402 (M-fH) + . LC/MS tR = 1,42 min.

*、NH*, NH

141666.doc 550- 201028381 實施例編號 妒 實施例1 - 9 0 1141666.doc 550- 201028381 Example Number 妒 Example 1 - 9 0 1

Me-Ν’Me-Ν’

OMeOMe

實施例1 — 9 0 2Example 1 - 9 0 2

Me 一 NMe a N

OMe 實施例1 — 9 0 3OMe Example 1 - 9 0 3

Me~NMe~N

R2 物性資料_ 1H-NHR (400 MHz7 DMSO-d6) δ 1 * 56 (br s f 1H), 1.90-1*93 (m, 1H) r 2.12 (br s, 3H) , 2,25-2,30 (m, 1H) , 3.86-3*87 (mf 6H), 4.08 {br s, 1H), 5.48 &lt;s, XH) , 5.66 (»f 2H) r 5.80 (d, J - 7.2 Hz, 1H) , 6.04 (s, 2H), 7.02 (dt J » 8.0 Hz, 1H) , 7.17 (s, 1H) , 7.73 (s7 XH) , 7.83 (s, 2H) , 8,10 (Bt 1H). MS (ESX) m/z « 4X6 (M4*H)+. LC/MS tR « 1.59 min. 1H-KMR &lt;400 MHz, DMSO-de) δ 1.18-1.41 (m, 4H), 1,86 (br sr 4H)r 3.86-3.88 (m, 6H) , 4.56 (br s, 1H) , 5.47 {s, 1H) , 5.68 (d, J = 7,8 Hz, 1H) , 6,01 (S, 2H) , 7.03 (df J * 7.8 Hz, 1H), 7.17 (s, 1H) , 7.74 (s, 1H) , 7,83 (sf 1H) , 7.92 &lt;d, J « 7,8 Hz, 1H), 8.08 (sf 1H&gt;. MS (ESI) m/z 434 LC/MS tR « 1.0X min, 1H-NMR (400 DMSO-d6) δ 1.16-1.38 {ra, 5H) r 1*69-1,72 (xn, 3H), 1.95-1.99 (mt 2H) , 3.85 &lt;sf 6H) , 4,74 (s, 1H) f 5.46 、NH W , 6.1S U, 2H&gt; , 6,24 (br s, 1H&gt; , 6.93 (d, J - 7.8 k^A〇H Hz, 1H) , 6.99 (sf 1H) f 7.46 {d, J = 7,8 Hz, 1H)y 7.72 &lt;s, XH&gt; , 7.99 (s, 1H) , 8,04 (sf 1H&gt;, 10,36 (s, 1H), MS (ESX) m/z « 420 &lt;M+H) +. LC/MS tR - 0.99 min.R2 Physical Properties _ 1H-NHR (400 MHz7 DMSO-d6) δ 1 * 56 (br sf 1H), 1.90-1*93 (m, 1H) r 2.12 (br s, 3H) , 2,25-2,30 (m, 1H), 3.86-3*87 (mf 6H), 4.08 {br s, 1H), 5.48 &lt;s, XH) , 5.66 (»f 2H) r 5.80 (d, J - 7.2 Hz, 1H) , 6.04 (s, 2H), 7.02 (dt J » 8.0 Hz, 1H) , 7.17 (s, 1H) , 7.73 (s7 XH) , 7.83 (s, 2H) , 8,10 (Bt 1H). MS (ESX m/z « 4X6 (M4*H)+. LC/MS tR « 1.59 min. 1H-KMR &lt;400 MHz, DMSO-de) δ 1.18-1.41 (m, 4H), 1,86 (br sr 4H )r 3.86-3.88 (m, 6H) , 4.56 (br s, 1H) , 5.47 {s, 1H) , 5.68 (d, J = 7,8 Hz, 1H) , 6,01 (S, 2H) , 7.03 (df J * 7.8 Hz, 1H), 7.17 (s, 1H), 7.74 (s, 1H), 7,83 (sf 1H) , 7.92 &lt;d, J « 7,8 Hz, 1H), 8.08 (sf 1H&gt;. MS (ESI) m/z 434 LC/MS tR « 1.0X min, 1H-NMR (400 DMSO-d6) δ 1.16-1.38 {ra, 5H) r 1*69-1,72 (xn, 3H ), 1.95-1.99 (mt 2H) , 3.85 &lt;sf 6H) , 4,74 (s, 1H) f 5.46 , NH W , 6.1SU , 2H&gt; , 6,24 (br s, 1H&gt; , 6.93 (d , J - 7.8 k^A〇H Hz, 1H) , 6.99 (sf 1H) f 7.46 {d, J = 7,8 Hz, 1H)y 7.72 &lt;s, XH&gt; , 7.99 (s, 1H) , 8 ,04 (sf 1H&gt;, 10,36 ( s, 1H), MS (ESX) m/z « 420 &lt;M+H) +. LC/MS tR - 0.99 min.

、NHNH

*、NH*, NH

OH 141666.doc 551 - 201028381 實施例編號 R1 實施例1 — 9 0 4OH 141666.doc 551 - 201028381 Example Number R1 Example 1 - 9 0 4

實施例1 一 9 0 5Example 1 A 9 0 5

實施例1 — 9 0 6Example 1 - 9 0 6

R2 物性資料 _ 1H-NMR &lt;400 MHz, DMSO-dfi) δ 1.24-1.35 (m, 2H)f 1.74 (hr a, 4H), 3.54 is, 1H&gt;, 3.86-3-88 (m, 6H) , 4.73 (Sf 1H) , 5.48 {s, 1H) # 6.02 (s, 2H), 7.05 (df J « 8.3 Hz, 1H) , 7.17 (g, 1H) , 7.71 (s, 1H), 7.83 (d, J » 7.8 Hz, 1H), 7.91 (d, J » 7.8 Hz, 1H), 7.97 (d, J = 7.8 Η», 1H), 8.09 (B, 1H). MS (ESI) m/z - 434 (M+H)+. LC/MS tK * 1.09 min. 1H-NMR (400 MHz, DMSO-de) δ 1.53-1.57 &lt;m, 1H), 1.90-1.93 (m, 1H), 2.11 (br s, 3H&gt;, 2 - 25-2,29 &lt;m, 1H&gt;, 3.87 {s, 3H&gt;, 4.06《i&gt;r s, 1H) , 5.23 (s, 2H&gt; , 5.49 (S, 1H) , 5.66 (s, 2H) f 5.82 &lt;&lt;i, J « 7,2 Hz, 1H&gt; , 6.08 [sf 2H) , 7.14 &lt;d, 〇r « 8.3 Hz, 1H) , 7.36 (s# 1H) , 7.85 (s, 1H) , 7.90 (d, J = 8.3 Hz, 1H) , 7.95 (s, 1H) , 8.10 is, 1H), MS (ESI) m/z « 441 (Μ4·Η) + . I«C/MS = 1.62 min. 1H-HMR (400 MHz, DMSO-d6) δ 1.16-1.35 &lt;m, 4H&gt;, 1.74 &lt;br s, 2H&gt;, 1.99 (s, 1H&gt;, 3.54 &lt;s, 1H) , 3.87 (s, 4H), 4.74 &lt;s, 1H) , 5.24 (a, 2H), JT 5.49 (s, 1H), 6.06 (br s, j j 2H), 7.17 (d, J ^ 7.8 Hz, 1H) , 7.36 (s, XH) , 7.85 (s# 1H) , 7,94-7.98 (m, 1H), 8.09 (s, XH). MS (ESI) m/z « 459 (M+H)' LC/MS tR = X.ll min. ώ0ΗR2 physical property _ 1H-NMR &lt;400 MHz, DMSO-dfi) δ 1.24-1.35 (m, 2H)f 1.74 (hr a, 4H), 3.54 is, 1H&gt;, 3.86-3-88 (m, 6H) , 4.73 (Sf 1H) , 5.48 {s, 1H) # 6.02 (s, 2H), 7.05 (df J « 8.3 Hz, 1H) , 7.17 (g, 1H) , 7.71 (s, 1H), 7.83 (d, J » 7.8 Hz, 1H), 7.91 (d, J » 7.8 Hz, 1H), 7.97 (d, J = 7.8 Η», 1H), 8.09 (B, 1H). MS (ESI) m/z - 434 ( M+H)+. LC/MS tK* 1.09 min. 1H-NMR (400 MHz, DMSO-de) δ 1.53-1.57 &lt;m, 1H), 1.90-1.93 (m, 1H), 2.11 (br s, 3H&gt;, 2 - 25-2, 29 &lt;m, 1H&gt;, 3.87 {s, 3H&gt;, 4.06 "i&gt;rs, 1H), 5.23 (s, 2H&gt;, 5.49 (S, 1H), 5.66 (s , 2H) f 5.82 &lt;i, J « 7,2 Hz, 1H&gt; , 6.08 [sf 2H) , 7.14 &lt;d, 〇r « 8.3 Hz, 1H) , 7.36 (s# 1H) , 7.85 ( s, 1H), 7.90 (d, J = 8.3 Hz, 1H), 7.95 (s, 1H), 8.10 is, 1H), MS (ESI) m/z « 441 (Μ4·Η) + . I«C/ MS = 1.62 min. 1H-HMR (400 MHz, DMSO-d6) δ 1.16-1.35 &lt;m, 4H&gt;, 1.74 &lt;br s, 2H&gt;, 1.99 (s, 1H&gt;, 3.54 &lt;s, 1H) , 3.87 (s, 4H), 4.74 &lt;s, 1H) , 5.24 (a, 2H), JT 5.49 (s, 1H), 6.06 (br s, jj 2H), 7.1 7 (d, J ^ 7.8 Hz, 1H) , 7.36 (s, XH) , 7.85 (s# 1H) , 7,94-7.98 (m, 1H), 8.09 (s, XH). MS (ESI) m/ z « 459 (M+H)' LC/MS tR = X.ll min. ώ0Η

、NHNH

141666.doc -552- 201028381 實施例編號 R* R2 實施例1 一 9 0 7141666.doc -552- 201028381 Example number R* R2 Example 1 A 9 0 7

khh ΦKhh Φ

實施例1 — 9 0 8Example 1 - 9 0 8

*、 ΝΗ*, ΝΗ

0Η0Η

實施例1 — 9 0 9Example 1 - 9 0 9

Me-NMe-N

ΟΗ 物性資料 _ 1H-NMR (400 MHz, DHSO-dg) δ X . 57 (q, J « IX . 6 Hz , 2H), X.78 &lt;d, J = 11.6 Hz, 2H), 3.86 (a, 4H), 4,02 (br sr 1H), 4.82 (q, J » 7.8 f 2H) , 5.44 (s, 1H) , 5.98 (4, J « 7.8 Hz, 1H)f 6.07 (sf 2H)r 7,18 (dt J « 8,6 1H) , 7.34 (sr 1H) , 7.66 (sr XH), 7.82 (d, J « 8-6 Hz, 1H) , 7.87 (s, 1H) # 8.12 (sf 1H). MS (ESI) m/z » 488 (M+H)+. X-C/HS tK ^ 1.47 min. 1H-HMR (400 MHz, DHSO-d6) δ 1.31-1.44 &lt;m, 6H&gt;, 1.92 (br s, 2H) F 3.83 &lt;br s, / 3-94 &lt;br s, 4H&gt; , 4.63 (s, 1H&gt; f 5.30 (s, 2H5 , 5.56 (s, 1H) , 5.77 (s, IH) , 6.12 (s, 2H&gt; , 7.23 {stf 1H) , 7.43 {sf 1H), 7.91 (s, IH), 8.07-8,03 (m, 2H) , 8.15 (sf IH). MS &lt;ESI&gt; m/z “S9 &lt;M+l〇 + . LC/MS tR « X.02 min. 1H-NMR &lt;400 MHz, DMSO-d6) 6 1.51-1.74 (m, 8H&gt; , 3,76 (s, 1H&gt; , 3.S5 (s, 3H) , 4.38 &lt;s, 1H&gt; , S.47 &lt;s, IH) , S.S8 (dr J « 7.6 Hz, IH) , 6.18 (s, 2H) , 6,92-6.99 {m, 2H) , 7.47 (d, J « 7.6 Hz, IH) , 7.72 (s, IH) , 8.00 (s, IB), 8.07 (S, IH), 10.38 (sf 1H&gt;. MS &lt;ESI) m/2 » 420 (M+H)' LC/HS i:R ® 0-98 min. 141666.doc 553 - 201028381 實施例編號 R1 實施例1 一 9 10物 Physical data _ 1H-NMR (400 MHz, DHSO-dg) δ X . 57 (q, J « IX . 6 Hz , 2H), X.78 &lt;d, J = 11.6 Hz, 2H), 3.86 (a , 4H), 4,02 (br sr 1H), 4.82 (q, J » 7.8 f 2H) , 5.44 (s, 1H) , 5.98 (4, J « 7.8 Hz, 1H)f 6.07 (sf 2H)r 7 ,18 (dt J « 8,6 1H) , 7.34 (sr 1H) , 7.66 (sr XH), 7.82 (d, J « 8-6 Hz, 1H) , 7.87 (s, 1H) # 8.12 (sf 1H) MS (ESI) m/z » 488 (M+H)+. XC/HS tK ^ 1.47 min. 1H-HMR (400 MHz, DHSO-d6) δ 1.31-1.44 &lt;m, 6H&gt;, 1.92 (br s, 2H) F 3.83 &lt;br s, / 3-94 &lt;br s, 4H&gt; , 4.63 (s, 1H&gt; f 5.30 (s, 2H5 , 5.56 (s, 1H) , 5.77 (s, IH) , 6.12 (s, 2H&gt;, 7.23 {stf 1H) , 7.43 {sf 1H), 7.91 (s, IH), 8.07-8,03 (m, 2H) , 8.15 (sf IH). MS &lt;ESI&gt; m/ z "S9 &lt;M+l〇+ . LC/MS tR « X.02 min. 1H-NMR &lt;400 MHz, DMSO-d6) 6 1.51-1.74 (m, 8H&gt;, 3,76 (s, 1H&gt;; , 3.S5 (s, 3H) , 4.38 &lt;s, 1H&gt; , S.47 &lt;s, IH) , S.S8 (dr J « 7.6 Hz, IH) , 6.18 (s, 2H) , 6 , 92-6.99 {m, 2H) , 7.47 (d, J « 7.6 Hz, IH) , 7.72 (s, IH) , 8.00 (s, IB), 8.07 (S, IH), 10.38 (sf 1H>. MS&lt;ESI) m/2 » 420 (M+H)' LC/HS i: R ® 0-98 min. 141666.doc 553 - 201028381 Example No. R1 Example 1 A 9 10

Me—Ν'Me-Ν'

實施例1 — 9 11Example 1 - 9 11

Me 一 ΝMe 一 Ν

OMeOMe

R2 物性資料_ 1H-NMR &lt;400 MHz Y DMSO-d6) δ 1,50 (br s, 4H&gt; , 1.67 (s, 2H) , X, 91 (s, 2H) , 3,84 (s, 3H) , 4.21 (br 1H) , 5.47 (s, 1H), 5.98 {dt J = 7.2 Hz, 1R) , 6.16 &lt;s, 2H) , 6.94 (d, J * 8.4 Hz, 1H), 7.01 (sr 1H), 7.42 (dr J * 8.4 Hzf 1H&gt; , 7.73 (s, 1H) , 8.00 &lt;s, 1H&gt;, 8.09 (sf 1H). MS (ESI) m/z « 390 (H-fH) + . LC/MS ta B 1.28 min. 1H-NMR &lt;400 MHz, DMSO-de) δ 1*52 (br s, 4H) , 1.68 (s, 2H) f 1.93 (st 2H) , 3.86 (sf 3H) , 3.88 (s, 3H) , 4.28 (br s, 1H) , 5.50 (s, 1H) , 5.81 (df J « 6.4 Hz, 1H), 6.03 (s, 2H), 7.07 (d, J ® 8.2 Hz, 1H) f 7.18 &lt;s, 1H) , 7.70 (3f IB) t 7.85 {st 1H) r 7.91 (d, J « 8.2 Hz, 1H), 8.10 (S, 1H). MS 《ESI) m/z = 404 (M+H)+ . LC/MS tR = 1.43 min. XH-NMR &lt;400 MHz, DMSO-d6) δ 1.51-1.74 (m, 8H) , 3.76 (br s, 1H), 3.87 (s, 4H), 4.40 (s, 1H) # 5.23 (s, 2H) # 5.51 is, 1H) , 5.54 (d, J -7.8 Hz, 1H) , 6.09 (s, 2H), 7.17 (d, J « 8.4 Hz, XH), 7.36 {», 1H) , 7.86 iaf 1H) f 7.96 (sf 1H) , 7.99 (d, J = 8.4 Hz, 1H) , 8.10 (s, XH). MS (ESI) m/z « 459 (M+H) + . LC/MS tR = 1.05 min,R2 physical property _ 1H-NMR &lt;400 MHz Y DMSO-d6) δ 1,50 (br s, 4H&gt; , 1.67 (s, 2H) , X, 91 (s, 2H) , 3,84 (s, 3H ), 4.21 (br 1H) , 5.47 (s, 1H), 5.98 {dt J = 7.2 Hz, 1R) , 6.16 &lt;s, 2H) , 6.94 (d, J * 8.4 Hz, 1H), 7.01 (sr 1H ), 7.42 (dr J * 8.4 Hzf 1H&gt;, 7.73 (s, 1H) , 8.00 &lt;s, 1H&gt;, 8.09 (sf 1H). MS (ESI) m/z « 390 (H-fH) + . LC /MS ta B 1.28 min. 1H-NMR &lt;400 MHz, DMSO-de) δ 1*52 (br s, 4H) , 1.68 (s, 2H) f 1.93 (st 2H) , 3.86 (sf 3H) , 3.88 (s, 3H) , 4.28 (br s, 1H) , 5.50 (s, 1H) , 5.81 (df J « 6.4 Hz, 1H), 6.03 (s, 2H), 7.07 (d, J ® 8.2 Hz, 1H) f 7.18 &lt;s, 1H) , 7.70 (3f IB) t 7.85 {st 1H) r 7.91 (d, J « 8.2 Hz, 1H), 8.10 (S, 1H). MS "ESI" m/z = 404 ( M+H)+ . LC/MS tR = 1.43 min. XH-NMR &lt;400 MHz, DMSO-d6) δ 1.51-1.74 (m, 8H), 3.76 (br s, 1H), 3.87 (s, 4H) , 4.40 (s, 1H) # 5.23 (s, 2H) # 5.51 is, 1H) , 5.54 (d, J -7.8 Hz, 1H) , 6.09 (s, 2H), 7.17 (d, J « 8.4 Hz, XH ), 7.36 {», 1H), 7.86 iaf 1H) f 7.96 (sf 1H) , 7.99 (d, J = 8.4 Hz, 1H) , 8.10 (s, XH). MS ( ESI) m/z « 459 (M+H) + . LC/MS tR = 1.05 min,

OH 141666.doc 554- 201028381OH 141666.doc 554- 201028381

141666.doc 實施例編號141666.doc Example number

R2 物性資料_ 1H-NMR (400 MHz, DMSO-de) δ 1.23 (br s, 1H), 1.57 (br Bf 1H), 1.94 (br s, , 2,14 (s, 2H} , 2.27 1H) f 3.18 (Bt 1H) , 3.76 {s, 2H) , 3.85 {8, 2H) , 4.08 &lt;s, %IH 3H) , 5.52 (s, 1H&gt; , 5.67 is, 0 2H&gt; f 5.86 (d# J « 7.3 Hz, 1H) f 6.09 (s, 2H) # 7.01 &lt;d, J = 8.6 Hz, 1H) , 7.16 (s# 1H), 7.80 (d, σ ^ 5.2 Hz, 2H), 8.04 (d, J » 8.6 Hz, 2H), 8.07 (s, 1H). MS (£SX) m/z « 446 (M+H) + . 1»C/MS fcR 篇 mitt· 1H-NMR (400 mzf DMSO-dc) δ 1,51 (B, 4H), 1.67 {st 2H) , 1,91 (s, 2H) # 3,8? (s, 3H) , 4.22-4.27 imt 1H), 5.23 (&amp;, 2H) , 5.50 (s, 1H), 5*83 &lt;d, J = 6.0 Hz, 1H), 6.06 (3, 2H) , 7.19 (d, J = 8.4 Hz, 1H) , 7.36 &lt;s, XH), 7.86 &lt;s, 1H) , 7.92 (s, 1H) f 7.97 (d, J « 8.4 Hzf 1H), 8.10 {Bt 1H). MS (ESI) m/z » 429 &lt;M+H) + . LC/MS tR « 1.45 min. 0 555 · 201028381 實施例編號 R1R2 Physical Properties _ 1H-NMR (400 MHz, DMSO-de) δ 1.23 (br s, 1H), 1.57 (br Bf 1H), 1.94 (br s, , 2,14 (s, 2H} , 2.27 1H) f 3.18 (Bt 1H) , 3.76 {s, 2H) , 3.85 {8, 2H) , 4.08 &lt;s, %IH 3H) , 5.52 (s, 1H&gt; , 5.67 is, 0 2H&gt; f 5.86 (d# J « 7.3 Hz, 1H) f 6.09 (s, 2H) # 7.01 &lt;d, J = 8.6 Hz, 1H) , 7.16 (s# 1H), 7.80 (d, σ ^ 5.2 Hz, 2H), 8.04 (d, J » 8.6 Hz, 2H), 8.07 (s, 1H). MS (£SX) m/z « 446 (M+H) + . 1»C/MS fcR mitt· 1H-NMR (400 mzf DMSO-dc) δ 1,51 (B, 4H), 1.67 {st 2H) , 1,91 (s, 2H) # 3,8? (s, 3H) , 4.22-4.27 imt 1H), 5.23 (&amp;, 2H) , 5.50 (s, 1H), 5*83 &lt;d, J = 6.0 Hz, 1H), 6.06 (3, 2H), 7.19 (d, J = 8.4 Hz, 1H) , 7.36 &lt;s, XH), 7.86 &lt;;s, 1H) , 7.92 (s, 1H) f 7.97 (d, J « 8.4 Hzf 1H), 8.10 {Bt 1H). MS (ESI) m/z » 429 &lt;M+H) + . LC/MS tR « 1.45 min. 0 555 · 201028381 Example number R1

實施例1 — 9 16Example 1 - 9 16

R- 物性資料_ 1H-NMR (400 MHz, DMSO-d6) δ 1.16 (br s, 1H) , 1.30 (tr J « 8.6 Hz, 4H), X.61 (df J = 12.0 Ha, 1H) , 1.73 (sf 2H) , 1.89 (8, 2H) , 2.90 {$, 3H) , 3.75 (tf J « 6,8 Hz, 3H) , 4.58 (t, J = 6*8 Hz, 2H&gt; # 5.24 (s, 2H) , S.5i (s, 1H} , S-70 (d, J = 8·4 Hz, 1H) , 6.06 (s, 2H&gt; , 7.18 (d, J - 8.4 Hz, XH), 7.38 &lt;s, 1H) , 7.96 (s, 2H) , 8.05 (d7 J = B.4 Hz, XH)y 8.25 &lt;s, 1H). MS (ESI) m/z = 535 (M+H) + , LC/HS tR = X.34 min. ltt-NMR (400 MHz, DMSO-d6) δ 1.51 (s, 4H), 1.68 (sr 2H) , 1.91 {st 2H) , 2r89 (sf 3H) , 3.74 (t, J « 6,0 Hz, 2H) , 4.22-4.27 (m, 1H), 4.57 (t, J = 6.0 Hz, 2H), 5.24 (s, 2H) , 5.50 (s, 1H), 5.84 (df J = 6.6 Hz, 1H), 6.06 (s, 2H) , 7.21 (d, J « 8.0 Hz, 1H) , 7.37 &lt;s, XH) y 7.96 {d, J « 8.0 Hz, 2H), 8*02 &lt;df J * 8.8 Hz, 1H), 8.25 (s, 1H). MS (ESI) m/z « 521 {M+H) +. LC/MS tR = 1.37 min.R- Physical data _ 1H-NMR (400 MHz, DMSO-d6) δ 1.16 (br s, 1H) , 1.30 (tr J « 8.6 Hz, 4H), X.61 (df J = 12.0 Ha, 1H) , 1.73 (sf 2H) , 1.89 (8, 2H) , 2.90 {$, 3H) , 3.75 (tf J « 6,8 Hz, 3H) , 4.58 (t, J = 6*8 Hz, 2H&gt;# 5.24 (s, 2H), S.5i (s, 1H}, S-70 (d, J = 8·4 Hz, 1H), 6.06 (s, 2H&gt;, 7.18 (d, J - 8.4 Hz, XH), 7.38 &lt; s, 1H) , 7.96 (s, 2H) , 8.05 (d7 J = B.4 Hz, XH)y 8.25 &lt;s, 1H). MS (ESI) m/z = 535 (M+H) + , LC /HS tR = X.34 min. ltt-NMR (400 MHz, DMSO-d6) δ 1.51 (s, 4H), 1.68 (sr 2H), 1.91 {st 2H) , 2r89 (sf 3H) , 3.74 (t, J « 6,0 Hz, 2H) , 4.22-4.27 (m, 1H), 4.57 (t, J = 6.0 Hz, 2H), 5.24 (s, 2H) , 5.50 (s, 1H), 5.84 (df J = 6.6 Hz, 1H), 6.06 (s, 2H) , 7.21 (d, J « 8.0 Hz, 1H) , 7.37 &lt;s, XH) y 7.96 {d, J « 8.0 Hz, 2H), 8*02 &lt; Df J * 8.8 Hz, 1H), 8.25 (s, 1H). MS (ESI) m/z « 521 {M+H) +. LC/MS tR = 1.37 min.

、NHNH

♦、♦,

NHNH

141666.doc - 556- 201028381141666.doc - 556- 201028381

實施例編號 R1 實施例1 —9 17Example No. R1 Example 1 - 9 17

實施例1 —9 18Example 1 - 9 18

82 物性資料_1H-NMR (400 MHz, DMSO— δ 1.13-1.32 (m, 58),1.59-1,62 (m, 1H) y 1,71 (B, 2H) , 1,85 (af 2H) , 3.76 (sf 3H) , 4.14 {Bf 2H) , 4.93 {br sr 1H), 5.47 (β, 1H), 5.83 (d, J » 7.6 Hzf 1H), 6.14 (s, 2H&gt; , 6-94 (d, J = 8.2 Hz, Xfl) , 7.01 (s, 1H), 7.49 (d, J » 8.2 Hz, 1H), 7.74 is, XH) # 8.01 (&amp;, 1H), 8.06 (af XH) , 10.39 (br s, 1H&gt; , MS &lt;ESI&gt; m/z » 434 {M+H} + . LC/HS tR = 1-25 min. 1H-NMR (400 MHz, DMSOO 6 1.17-1.35 (m, 5H), 1.73 &lt;br S/ 3H) , 1.99 (br s, 1H&gt;, 3.87 (br sr 5H) , 4,75 (s, IH) , 5.23 ist 2¾) , 5.49NHΪ (s, IH) , 6.05 &lt;br s, 3H) r [\ 7.17 (d, J » 7.8 Hs# IH), 7.35 isf IH) # 7.85 isf IH), 7.98-7.93 (m, 2H) 7 8.09 (a, IH). MS (ESI) m/z » 459 (M+H) + , LC/MS tR » 1.X3 min.82 Physical and chemical data_1H-NMR (400 MHz, DMSO - δ 1.13-1.32 (m, 58), 1.59-1,62 (m, 1H) y 1,71 (B, 2H), 1,85 (af 2H) , 3.76 (sf 3H) , 4.14 {Bf 2H) , 4.93 {br sr 1H), 5.47 (β, 1H), 5.83 (d, J » 7.6 Hzf 1H), 6.14 (s, 2H&gt; , 6-94 (d , J = 8.2 Hz, Xfl) , 7.01 (s, 1H), 7.49 (d, J » 8.2 Hz, 1H), 7.74 is, XH) # 8.01 (&amp;, 1H), 8.06 (af XH) , 10.39 ( Br s, 1H&gt; , MS &lt;ESI&gt; m/z » 434 {M+H} + . LC/HS tR = 1-25 min. 1H-NMR (400 MHz, DMSOO 6 1.17-1.35 (m, 5H) , 1.73 &lt;br S/ 3H) , 1.99 (br s, 1H&gt;, 3.87 (br sr 5H) , 4,75 (s, IH) , 5.23 ist 23⁄4) , 5.49NHΪ (s, IH) , 6.05 &lt; Br s, 3H) r [\ 7.17 (d, J » 7.8 Hs# IH), 7.35 isf IH) # 7.85 isf IH), 7.98-7.93 (m, 2H) 7 8.09 (a, IH). MS (ESI) m/z » 459 (M+H) + , LC/MS tR » 1.X3 min.

*、NH*, NH

141666.doc 557· 201028381 實施例編號 π141666.doc 557· 201028381 Example number π

實施例i — 9 2 0Example i - 9 2 0

實施例1 一 9 2 1Example 1 A 9 2 1

R2 物性資料_ XH-NMR (400 MHz, DMSO*d6) δ 1.16 (br sf 1H) , 1.29 (t, J«8.8Hz, 4H&gt; , 1.60-1.63 (m, 1H) f 1,72 &lt;s, 2H) , 1,88 (Sf 2H&gt; , 3.78 (S, 3H) , 4.1$ (s, 2H) , 4.96 (s# 1H) f 5.23 (s, 2H) , 5.49 (s, 1H) , 5.69 (d, J = 7.1 Hz, 1H), 6.05 (s, 2H), 7.17 &lt;d, J ^ 7.1 Hz, XH) , 7.36 (s, XH) , 7.87 (s, 1H) , 7.94 (s, 1H) , 8.01 (d, J « 8.6 Hz, 1H). MS (ESI) m/z * 473 (M+H) + . I.C/MS tR « 1.42 min. 1H-NMR (400 MHz, DMSO-de) δ 1.15-1.36 &lt;m, 5H), 1,63 (df J = 12.0 He, 1H) , 1-75 (s, 2H) , 1.91 (s, 2H) , 3.28 (t, J = 6.4 Hz, 1H), 3,53 (t, J »= 6.4 Hz, 1H) , 3.82 {sr 1H) , 5.50 (s, 1H) , 5.89 (d, J « 8.0 Hz, 1H), 6.25 (st 2H&gt; , 7,56 {dd, J = 26.X, 8.5 Has, 2H) , 7.96 {s, XH), 9.33 (s# 1H). MS (ESI) m/z - 398 (M+H) + . LC/MS tR « X.78 min. XH-HMR &lt;400 MHz, DMSO-d6&gt; δ 1.15*1.34 (mf 5H) , 1,64 (d, J « 12.8 Hz, 1H&gt; r 1.75 (s, 2H) , 1.91 (s, 2H) , 3.80 {ar XH) , 4.33 (s, 2H) f 5.50 (S/ 1H) , 5.89 (d, J «= 7.6 Hz, 1H) , 6.25 (s, 2H&gt; , 7.64-7.58 (m, 4H) , 7.95 iaf 1H)# 9.35 (s, 1H), MS (ESI) m/2 * 399 (M+I〇 + · LC/MS tR x . &lt;55 mxn.R2 Physical Properties _ XH-NMR (400 MHz, DMSO*d6) δ 1.16 (br sf 1H) , 1.29 (t, J«8.8Hz, 4H&gt; , 1.60-1.63 (m, 1H) f 1,72 &lt;s , 2H) , 1,88 (Sf 2H&gt; , 3.78 (S, 3H) , 4.1$ (s, 2H) , 4.96 (s# 1H) f 5.23 (s, 2H) , 5.49 (s, 1H) , 5.69 ( d, J = 7.1 Hz, 1H), 6.05 (s, 2H), 7.17 &lt;d, J ^ 7.1 Hz, XH) , 7.36 (s, XH) , 7.87 (s, 1H) , 7.94 (s, 1H) , 8.01 (d, J « 8.6 Hz, 1H). MS (ESI) m/z * 473 (M+H) + . IC/MS tR « 1.42 min. 1H-NMR (400 MHz, DMSO-de) δ 1.15 -1.36 &lt;m, 5H), 1,63 (df J = 12.0 He, 1H) , 1-75 (s, 2H) , 1.91 (s, 2H) , 3.28 (t, J = 6.4 Hz, 1H), 3,53 (t, J »= 6.4 Hz, 1H) , 3.82 {sr 1H) , 5.50 (s, 1H) , 5.89 (d, J « 8.0 Hz, 1H), 6.25 (st 2H&gt; , 7,56 { Dd, J = 26.X, 8.5 Has, 2H) , 7.96 {s, XH), 9.33 (s# 1H). MS (ESI) m/z - 398 (M+H) + . LC/MS tR « X .78 min. XH-HMR &lt;400 MHz, DMSO-d6&gt; δ 1.15*1.34 (mf 5H) , 1,64 (d, J « 12.8 Hz, 1H&gt; r 1.75 (s, 2H) , 1.91 (s, 2H) , 3.80 {ar XH) , 4.33 (s, 2H) f 5.50 (S/ 1H) , 5.89 (d, J «= 7.6 Hz, 1H) , 6.25 (s, 2H&gt; , 7.64-7.58 (m, 4H) ) , 7 .95 iaf 1H)# 9.35 (s, 1H), MS (ESI) m/2 * 399 (M+I〇 + · LC/MS tR x . &lt;55 mxn.

*、NH*, NH

141666.doc 558- 201028381141666.doc 558- 201028381

實施例編號 扪 實施例1 一 9 2 2Example No. 实施 Example 1 A 9 2 2

實施例1 — 9 2 3Example 1 - 9 2 3

R2 物性資料_ 1H-NMR &lt;400 MHz, DMSO-dg) δ 1.07-1.16 &lt;m, 1H), 1,27-1,36 (mf 2H), 1.44-1.67 (m, 5B) f 1.85 {d, J » 10,0 Hz, 2H) r 3,23 &lt;t, J » 6.4 Hz, 2H) , 3.89 (br &amp;, 1H&gt;, 5.44 &lt;s, 1H&gt;, 5.81 (d, J = 7.6 Hz, 1H), 6.19 (s, 2H) , 7.34 (d, J = 8.0 Hz, 1H&gt;, 7.62 (d, J * 8.0 Hz, XH) , 8.31 (s, 1H), 9.22 (s, 1H). MS (ESI) m/z « 398 (M+H) ^. I.C/MS fcR ; 1.77 mint. 1H-NHR &lt;400 HBzf 0MSO-d6&gt; δ 1.15 (br s, 1H), 1.29-1.33 &lt;m, 4H) , 1.63 &lt;d, a « 12.0 Hz, IE) , 1.73 (s, 2H) , 1,90 (s, 2H) r 2.17 (s, 3H), 2,92 (t, J « 6.0 Hz, 2H), 3.85 (br s, 4H), 4.24 (t, J « 6.0 Η*, 2H), 5.47 (sr 1H) , 5.73 (d# J = 8.1 Hz, 1H) , 6.07 (s, 2H) f 7.07 (d, J = 8,3 Hz, 1H&gt;, 7.23 (s, 1H) , 7.60 (s, 1H), 7.84 (s, 1H) , 8.02 Cd, J *： 8.3 Hz, 1H&gt; , 8.10 (sv 1H). MS &lt;ESX) m/z » 478 {M+H) + . LC/MS a 1^82 min.R2 physical property _ 1H-NMR &lt;400 MHz, DMSO-dg) δ 1.07-1.16 &lt;m, 1H), 1,27-1,36 (mf 2H), 1.44-1.67 (m, 5B) f 1.85 { d, J » 10,0 Hz, 2H) r 3,23 &lt;t, J » 6.4 Hz, 2H) , 3.89 (br &amp;, 1H&gt;, 5.44 &lt;s, 1H&gt;, 5.81 (d, J = 7.6 Hz, 1H), 6.19 (s, 2H), 7.34 (d, J = 8.0 Hz, 1H&gt;, 7.62 (d, J * 8.0 Hz, XH), 8.31 (s, 1H), 9.22 (s, 1H) MS (ESI) m/z « 398 (M+H) ^. IC/MS fcR ; 1.77 mint. 1H-NHR &lt;400 HBzf 0MSO-d6&gt; δ 1.15 (br s, 1H), 1.29-1.33 &lt; m, 4H) , 1.63 &lt;d, a « 12.0 Hz, IE) , 1.73 (s, 2H) , 1,90 (s, 2H) r 2.17 (s, 3H), 2,92 (t, J « 6.0 Hz, 2H), 3.85 (br s, 4H), 4.24 (t, J « 6.0 Η*, 2H), 5.47 (sr 1H) , 5.73 (d# J = 8.1 Hz, 1H) , 6.07 (s, 2H) f 7.07 (d, J = 8,3 Hz, 1H&gt;, 7.23 (s, 1H), 7.60 (s, 1H), 7.84 (s, 1H) , 8.02 Cd, J *: 8.3 Hz, 1H&gt; , 8.10 (sv 1H). MS &lt;ESX) m/z » 478 {M+H) + . LC/MS a 1^82 min.

、NHNH

*、NH*, NH

141666.doc 559- 201028381 實施例編號 R1 實施例1 — 9 24141666.doc 559- 201028381 Example Number R1 Example 1 - 9 24

實施例1 — 9 2 5Example 1 - 9 2 5

R2 物性資料_ 1H-NMR (400 HH2/ DMSO-de) δ l.XO-1.16 (TO, 1H&gt; , 1.28- 1,37 (ια, 2H) r 1.43- 1-69 (m, 5H) # 1.86 {d, J « 11-2 Ha, 2H) f 3,89 (br s, 1H) , 4.29 (&lt;3, J * 4.4 Hzr 2H) , 5,44 (s, 1H) , 5.85 (d, J = 8.6 Hz, 1H), 6.22 (s, 2H), 7.37 (d, J = 8.6 Hz, 1H), 7.63-7.65 (m,2H) , 8.34 &lt;s, 1H) , 9.23 (s, 1H). MS (ESI) m/z = 399 (M+H) + . 1UC/MS tR = 1,60 min. 1H-NHR (400 MHz, DMSO-d6) δ 1.06-1.15 (m, 1H&gt; , 1.28- 1.37 (m, 2H) Λ 1.43- 1.68 (m, 5H) # X.86 (d, J » 10.0 Ha:, 2H) f 2.80 {s, 3H&gt;, 3,89 &lt;br s, 1H&gt;, 4.28 (s, 2H) , 5.45 (s, 1H) # 5.86 (dt J « 7.8 Hz, 1H), 6.23 (s, 2H) , 7.40 (d, J = 8.6 Hz, 1H) , 7.60 (d, J == 8.6 Hz, 1H) , 8.47 (s, 1H), 9.27 (s, 1H), MS (ESI) m/z « 413 (M+H) + . LC/MS fcR = 1-84 min.R2 Physical Properties _ 1H-NMR (400 HH2/ DMSO-de) δ l.XO-1.16 (TO, 1H&gt; , 1.28- 1,37 (ια, 2H) r 1.43- 1-69 (m, 5H) # 1.86 {d, J « 11-2 Ha, 2H) f 3,89 (br s, 1H) , 4.29 (&lt;3, J * 4.4 Hzr 2H) , 5,44 (s, 1H) , 5.85 (d, J = 8.6 Hz, 1H), 6.22 (s, 2H), 7.37 (d, J = 8.6 Hz, 1H), 7.63-7.65 (m, 2H), 8.34 &lt;s, 1H), 9.23 (s, 1H). MS (ESI) m/z = 399 (M+H) + . 1UC/MS tR = 1,60 min. 1H-NHR (400 MHz, DMSO-d6) δ 1.06-1.15 (m, 1H&gt;, 1.28- 1.37 (m, 2H) Λ 1.43- 1.68 (m, 5H) # X.86 (d, J » 10.0 Ha:, 2H) f 2.80 {s, 3H&gt;, 3,89 &lt;br s, 1H&gt;, 4.28 ( s, 2H) , 5.45 (s, 1H) # 5.86 (dt J « 7.8 Hz, 1H), 6.23 (s, 2H) , 7.40 (d, J = 8.6 Hz, 1H), 7.60 (d, J == 8.6 Hz, 1H) , 8.47 (s, 1H), 9.27 (s, 1H), MS (ESI) m/z « 413 (M+H) + . LC/MS fcR = 1-84 min.

141666.doc 560- 201028381 實施例編號 R1 實施例1 一 9 2 6141666.doc 560- 201028381 Example Number R1 Example 1 A 9 2 6

實施例1 — 9 2 7Example 1 - 9 2 7

R2 物性資料 1H-HMR (400 MHz, DMSO-^) δ 1.16 (br s, 1H) , 1.29 (br s, 4H)f 1.61 (d, J = 12.0 Hz, 1H) , 1.73 {s, 2H) , 1.88 (st 2H) , 3,10 (9f 3H), 3.76-3*78 {m, 3H) , 4.IS (t, J « 4.4 Hz, 2H)# 4,94 &lt;Sf 1H) f 5,37 (s# 2H) , 5,44 (s, 1H) , 5*70 (d, a = 7.3 Hz, 1H) , 6.07 (S, 2H) , 7.18 (d, J = 8.3 HZ/ 1H)f 7.47 (sf 1H) , 7,82 (s, 1H) , 7.87 (s, 1H) , 7.9»4 (d, J = 8.3 Hz, 1H), 8.13 (s, XH). MS (ESI) m/z * 526 &lt;M+H) + . LC/MS tR » 1*35 min. 1H-NMR &lt;400 MHz, DHSO-d6) δ 1-15-1.33 , 62 (d, J = 12.4 Hz, 1H) , 1.73 ts, 2m , 1·8穿（s, 2H&gt; , 2.20 (sr 3H) , 3.86 (s, 4H) , 5.38 (s, 2H) , 5.47 (s, 1H&gt; , 5.68 (d, J * 7.2 Hz, 1H), 6.05 Csr 2H), 7.10 (d, J * 7,2 Hz, 1H) r 7,29 (s, IS) , 7.69 (s, 1H) , 7.83 (sf 1H) , 7.94 (d, J » 8.2 Hz, 1H), 8.09 (sf 1H). MS (ESI) m/z » 464 &lt;M+H) + . ZC/HS tR » 1.74 min.R2 physical property 1H-HMR (400 MHz, DMSO-^) δ 1.16 (br s, 1H) , 1.29 (br s, 4H)f 1.61 (d, J = 12.0 Hz, 1H) , 1.73 {s, 2H) , 1.88 (st 2H) , 3,10 (9f 3H), 3.76-3*78 {m, 3H) , 4.IS (t, J « 4.4 Hz, 2H)# 4,94 &lt;Sf 1H) f 5, 37 (s# 2H) , 5,44 (s, 1H) , 5*70 (d, a = 7.3 Hz, 1H) , 6.07 (S, 2H) , 7.18 (d, J = 8.3 HZ/ 1H)f 7.47 (sf 1H) , 7,82 (s, 1H) , 7.87 (s, 1H) , 7.9»4 (d, J = 8.3 Hz, 1H), 8.13 (s, XH). MS (ESI) m/z * 526 &lt;M+H) + . LC/MS tR » 1*35 min. 1H-NMR &lt;400 MHz, DHSO-d6) δ 1-15-1.33, 62 (d, J = 12.4 Hz, 1H), 1.73 ts, 2m, 1·8 wear (s, 2H&gt;, 2.20 (sr 3H), 3.86 (s, 4H), 5.38 (s, 2H), 5.47 (s, 1H&gt;, 5.68 (d, J * 7.2 Hz , 1H), 6.05 Csr 2H), 7.10 (d, J * 7,2 Hz, 1H) r 7,29 (s, IS) , 7.69 (s, 1H) , 7.83 (sf 1H) , 7.94 (d, J » 8.2 Hz, 1H), 8.09 (sf 1H). MS (ESI) m/z » 464 &lt;M+H) + . ZC/HS tR » 1.74 min.

、NHNH

141666.doc 561 - 201028381 實施例編號 R1 實施例1 — 9 2 8141666.doc 561 - 201028381 Example number R1 Example 1 - 9 2 8

R3 物性資料_ XH-NMR (400 MHz, DMSO-d6) δ 1.18 &lt;br s# 2H) , 1.34 (br sf 3H) , 1.63 &lt;d, J « 11.4 Hz, 1H&gt; , 1.73 &lt;s, 2H) , 1.93 (s, 2H) , 2.89 is, 3H) , 3.73 (t, J « 6.6 Hz, 2H) , 3,86 (br s, , 4.57{t, J = 6.6 2H) , 5.12 &lt;s, 2H) r 5.47 (s, 1H), 5.73 (d, J = 7.8 Hz, 1H) , 6*13 (s# 2H&gt; , 7.22 &lt;s, 1H) , 7.46 (d, J = 8-6 Hz, 1H) , 7.61 (d# J » 8.6 H:s# , 7,91 1H&gt; , 8·1ι7 &lt;8/ 1H), 8.97 (s, 1H). MS &lt;SSI) m/z » 535 &lt;M+H)+. I.C/MS tR - 1.64 min.R3 Physical Properties _ XH-NMR (400 MHz, DMSO-d6) δ 1.18 &lt;br s# 2H) , 1.34 (br sf 3H) , 1.63 &lt;d, J « 11.4 Hz, 1H&gt; , 1.73 &lt;s, 2H) , 1.93 (s, 2H) , 2.89 is, 3H) , 3.73 (t, J « 6.6 Hz, 2H) , 3,86 (br s, , 4.57{t, J = 6.6 2H) , 5.12 &lt;s , 2H) r 5.47 (s, 1H), 5.73 (d, J = 7.8 Hz, 1H) , 6*13 (s# 2H&gt; , 7.22 &lt;s, 1H) , 7.46 (d, J = 8-6 Hz , 1H) , 7.61 (d# J » 8.6 H:s# , 7,91 1H&gt; , 8·1ι7 &lt;8/ 1H), 8.97 (s, 1H). MS &lt;SSI) m/z » 535 &lt; M+H)+. IC/MS tR - 1.64 min.

1H-NMR {400 MHz, DMSO-de) δ 1.18 (br s, 1H) , 1,32 (br S, 4H) , 1.61 {df J * 11.2 Hz, 1H) f 1,73 (br sf 2H) f 1.90 (br s, 2H) y 2.86 (s, 3H) , 3,72 (t, J = 6.6 Hz, 2H&gt; , 3.88 (br s, 1H) f 4.56 (t, J * 6.6 Hz, 2H) , 4.73 {ddt J * 8.1 # 17.7 Hz , 2H), 5.47 (sf 1H) , 5.73 (d, J * 7.8 Hz, 1H) , 6.13 U, 2H), 7.15 &lt;s, 1H)r 7.47 {άά, J =7.8, 23.5 Hz, 2H), 7,88 {s, 1H) r 8.08 (3, XH) , 8.89 (S, 1H). MS &lt;ESI&gt; m/z * 578 (M+H) + . 1.C/MS tR « 1.83 min. MS (ESI) m/z 雄 479 (M+H) + . LC/MS fcR = 1.74 min. *、NH &amp; F 實施例1-9314-胺基-2-(環己基胺基）-6-(4-(1-甲基-1Η-η比唑-4-基）-2-(曱基磺醯基曱氧基）苯基胺基）菸鹼腈 141666.doc -562- 201028381 [化 1931]1H-NMR {400 MHz, DMSO-de) δ 1.18 (br s, 1H) , 1,32 (br S, 4H) , 1.61 {df J * 11.2 Hz, 1H) f 1,73 (br sf 2H) f 1.90 (br s, 2H) y 2.86 (s, 3H) , 3,72 (t, J = 6.6 Hz, 2H&gt; , 3.88 (br s, 1H) f 4.56 (t, J * 6.6 Hz, 2H) , 4.73 {ddt J * 8.1 # 17.7 Hz , 2H), 5.47 (sf 1H) , 5.73 (d, J * 7.8 Hz, 1H) , 6.13 U, 2H), 7.15 &lt;s, 1H)r 7.47 {άά, J = 7.8, 23.5 Hz, 2H), 7,88 {s, 1H) r 8.08 (3, XH) , 8.89 (S, 1H). MS &lt;ESI&gt; m/z * 578 (M+H) + . C/MS tR « 1.83 min. MS (ESI) m/z s. 479 (M+H) + . LC/MS fcR = 1.74 min. *, NH &amp; F Example 1-9314-Amino-2-( Cyclohexylamino)-6-(4-(1-methyl-1Η-η-pyrazol-4-yl)-2-(indolylsulfonyloxy)phenylamino)nicotinonitrile 141666. Doc -562- 201028381 [化1931]

BrBr

NHBoc OH (步驟1) MeS 八 Cl k2co3 DMF, 60°C 75%NHBoc OH (Step 1) MeS Eight Cl k2co3 DMF, 60 ° C 75%

NHBocNHBoc

(步驟2) m-CPBA CHCb,室溫 83%(Step 2) m-CPBA CHCb, room temperature 83%

NHNH

00

(步驟5) TfO N NH(Step 5) TfO N NH

Pd(〇Ac)2 BINAP, Cs2C03 二噁烷，回流 23% ❹ 步驟1 : 4-溴-2-(曱硫基甲氧基）苯基胺基甲酸第三丁酯 向4-溴-2-羥基苯基胺基曱酸第三丁酯（5.00 g，17.4 mmol)及石炭酸钟（5.04 g，36.4 mmol)之 DMF(50 mL)溶液中 添加氯曱基甲基硫化物（1.68 g，17.4 mmol)後，於90°C下 攪拌6小時。向反應溶液中添加水及乙酸乙酯進行分離。 以乙酸乙酯萃取水相，將合併之有機相以水及飽和食鹽水 進行清洗，以硫酸鎂加以乾燥。將有機相過濾後，進行減 141666.doc -563 - 201028381 壓濃縮，利用中壓矽膠層析法(己烷：乙酸乙酯=5 : ”對 所獲得之殘渣進行純化，藉此獲得標題化合物（4 g， 17·4 mmol ’ 75%)，為黃色油。 1H-NMR (400 MHz, DMSO-d6) δ 1.44 (s, 9H), 2.18 (s, 3H), 5.33 (s, 2H), 7.10 (dd, J=8.5, 2.1 Hz, 1H), 7.26 (d, J=2.1Pd(〇Ac)2 BINAP, Cs2C03 Dioxane, reflux 23% ❹ Step 1: 3-bromo-2-(decylthiomethoxy)phenylcarbamic acid tert-butyl ester to 4-bromo-2- Add chloromethyl methyl sulfide (1.68 g, 17.4 mmol) to a solution of hydroxyphenylamino decanoic acid tert-butyl ester (5.00 g, 17.4 mmol) and a carbolic acid clock (5.04 g, 36.4 mmol) in DMF (50 mL). After that, it was stirred at 90 ° C for 6 hours. Water and ethyl acetate were added to the reaction solution for separation. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and brine and dried over magnesium sulfate. After the organic phase was filtered, the residue obtained was purified by 141666.doc - 563 - 201028381, and the residue obtained was purified by medium pressure gel chromatography (hexane: ethyl acetate = 5:) to obtain the title compound ( 4 g, 17·4 mmol '75%) as a yellow oil. 1H-NMR (400 MHz, DMSO-d6) δ 1.44 (s, 9H), 2.18 (s, 3H), 5.33 (s, 2H), 7.10 (dd, J=8.5, 2.1 Hz, 1H), 7.26 (d, J=2.1

Hz, 1H), 7.59 (d, J=8.5 Hz，1H)，8.09 (s, 1H)。 步驟2 : 4-溴-2-(甲基績酿基甲氧基）笨基胺基甲酸第三 丁酯 向4_溴_2_(甲硫基曱氧基）苯基胺基甲酸第三丁酯（3.5〇 © g，10.1 mmol)之氣仿（40mL)溶液中添加 mCpBA(45i 2^6.lmmol)，於室溫下攪拌3小時。向反應溶液中添加碳酸 氫鈉水溶液進行分離後，以乙酸乙酯萃取水相，將合併之 有機相以飽和碳酸氫鈉水溶液及飽和食鹽水進行清洗，以 硫酸鎂加以乾燥。將有機相過濾後，進行減壓濃縮，利用 中壓矽膠層析法（己烷：乙酸乙酯=丨：丨）對所獲得之殘渣 進行純化，藉此獲得標題化合物（3」9 g，83%)，為白色固 體。 〇 1H-NMR (400 MHz, DMSO-d6) δ 1.43 (s, 9H), 3.12 (s, 3H), 5-36 (s, 2H), 7.50-7.52 (m, 1H), 7.58 (d, J=7.8 Hz, 1H), 7.66 (d，J=7.8 Hz，1H), 8.41 (s, 1H)。 步驟3 : 4-(1-甲基-1Η-η比唑-4-基）_2_(甲基磺醯基曱氧基） 苯基胺基甲酸第三丁酯 向1-甲基-4-(4,4,5,5-四甲基_l，3,2-二氧雜硼烷_2·基）-ll·l_ 吡唑（821 mg，3.94 mmol)、4-溴-2-(甲基磺醯基甲氧基）苯 14-1666.doc -564- 201028381 基胺基甲酸第三丁酯（1·〇〇 g，2.63 mmol)及pd(OAc)2(59.0 mg ’ 0.263 mmol)之乙腈（10 mL)溶液中添加2 M碳酸鉀 (3.95 mL ’ 7.89 mmmol)，於加熱回流下授拌6小時。向反 應溶液中添加水及乙酸乙酯進行分離後，以乙酸乙酯萃取 水相’將合併之有機相以水及飽和食鹽水進行清洗，以硫 酸鎮加以乾燥。將有機相過濾後’進行減壓濃縮，以己 烷：乙酸乙酯=5 : 1使其固化，藉此獲得標題化合物（784 mg，2.06 mmol，78%)，為白色固體。 • 1H-NMR (400 MHz, DMSO-d6) δ 1.45 (s, 9H), 3.11 (s, 3H), 3.84 (s, 3H), 5.36 (s, 2H), 7.19 (d, J=8.1 Hz, 1H), 7.43 (s, 1H), 7.55 (d, J=8.1 Hz, 1H), 7.84 (s, 1H), 8.08 (s, 1H), 8.25 (s, 1H)。 步驟4 : 4-(1-甲基-1H-吡唑-4-基）-2-(甲基磺醯基甲氧基） 苯胺 向4-(1-甲基_1Η_&quot;比唑-4-基）-2-(甲基磺醯基甲氧基）苯基 籲 胺基甲酸第三丁酯（821 mg，3.94 mmol)之甲醇（10 mL)溶 液中添加4 N鹽酸二噁烷溶液（6 69 mL，26.7 mmmol)於 50 C下攪拌2小時。向反應溶液中添加碳酸氫鈉水溶液及 乙酸乙酯進行分離後，以乙酸乙酯萃取水相，將合併之有 機相以水及飽和食鹽水進行清洗，以硫酸鎂加以乾燥。將 有機相過濾後’進行減壓濃縮，以己烧：乙酸乙酯=9 ·· 1 使其固化’藉此獲得標題化合物（472 mg，！ .68 mmol， 97%)，為淡黃色固體。 1H-NMR (400 MHz, DMSO-d6) δ 3.11 (s, 3H), 3.81 (s, 3H), 141666.doc •565- 201028381 4.88 (s, 2H), 5.25 (s, 2H), 6.67 (d, J=7.8 Hz, 1H), 6.98 (d, J=7.8 Hz, 1H)，7.23 (s, 1H)，7.71 (s, 1H), 7·92 (s, 1H)。 MS(ESI)m/z=282 (M+H)+。 LC/MS tR=0_70 min o 步驟5 :標題化合物 向二氟甲績酸4-胺基-5-氛基- 6-(環己基胺基）吼咬-2-基 酯（230 mg ’ 0.631 mmol)、4-(1-甲基-1H-吡唑-4-基）-2-(甲 基項醯基曱氧基）苯胺（213 mg，0.750 mmol)、ΒΙΝΑΡ(59·0 mg，0.095 mmol)及碳酸铯（288 mg，0.884 mmol)之二噁烷 (2.0 mL)溶液中添加 Pd(OAc)2(14.2 mg，〇·〇63 mmol)，於 90C下攪拌6小時。向反應溶液中添加水及乙酸乙醋進行 分離後，以乙酸乙酯萃取水相，將合併之有機相以水及飽 和食鹽水進行清洗’以硫酸鎮加以乾燥。將有機相過漉 後’進行減壓濃縮。利用逆相等分試樣液相層析法（C1 8管 柱；水/乙腈/0.1%曱酸；10-100%梯度）對所獲得之殘造進 行純化，獲得標題化合物（71.6 mg，0.144 mmol，23%)， 為白色固體。 1H-NMR (400 MHz, DMSO-d6) δ 1.27-1.32 (m&gt; 5H), 1.61 (d, J=11.2 Hz, 1H), 1.72 (s, 2H), 1.88 (s, 2H), 3.11 (s, 3H), 3.86 (br s, 4H), 5.37 (s, 2H), 5.45 (s, 1H), 5.7〇 (d, J=7.8Hz, 1H), 7.59 (d, J=8.5 Hz, 1H), 8.09 (s, 1H). Step 2: 4-bromo-2-(methyl-branched methoxy)-p-butylaminocarbamic acid tert-butyl ester to 4_bromo-2-(methylthiocarbonyloxy)phenylcarbamic acid tert-butyl MCpBA (45i 2^6.lmmol) was added to a solution of the ester (3.5 mL, g, 10.1 mmol), and the mixture was stirred at room temperature for 3 hours. After the aqueous solution of sodium hydrogencarbonate was added to the reaction solution for separation, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with saturated aqueous sodium hydrogen carbonate and brine and dried over magnesium sulfate. After the organic phase was filtered, the residue was purified under reduced pressure. m.j. %), as a white solid. 〇1H-NMR (400 MHz, DMSO-d6) δ 1.43 (s, 9H), 3.12 (s, 3H), 5-36 (s, 2H), 7.50-7.52 (m, 1H), 7.58 (d, J =7.8 Hz, 1H), 7.66 (d, J=7.8 Hz, 1H), 8.41 (s, 1H). Step 3: 4-(1-methyl-1Η-η-pyrazol-4-yl)_2_(methylsulfonylmethoxy) phenylaminocarbamic acid tert-butyl ester to 1-methyl-4-( 4,4,5,5-tetramethyl-l,3,2-dioxaborane-2·yl)-ll·l_pyrazole (821 mg, 3.94 mmol), 4-bromo-2-(A) Sulfosyl methoxy)benzene 14-1666.doc -564- 201028381 tert-butyl carbamic acid (1·〇〇g, 2.63 mmol) and pd(OAc) 2 (59.0 mg '0.263 mmol) 2 M potassium carbonate (3.95 mL '7.99 mmmol) was added to a solution of acetonitrile (10 mL), and the mixture was stirred under reflux for 6 hours. Water and ethyl acetate were added to the reaction solution for separation, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water and saturated brine, and dried over sulfuric acid. After the organic phase was filtered, EtOAc was evaporated,jjjjjjjjj • 1H-NMR (400 MHz, DMSO-d6) δ 1.45 (s, 9H), 3.11 (s, 3H), 3.84 (s, 3H), 5.36 (s, 2H), 7.19 (d, J=8.1 Hz, 1H), 7.43 (s, 1H), 7.55 (d, J=8.1 Hz, 1H), 7.84 (s, 1H), 8.08 (s, 1H), 8.25 (s, 1H). Step 4: 4-(1-Methyl-1H-pyrazol-4-yl)-2-(methylsulfonylmethoxy)aniline to 4-(1-methyl-1Η_&quot;Bizozole-4- Add 4 N Hydrochloric acid dioxane solution to a solution of tert-butyl 2-(methylsulfonylmethoxy)phenyl-p-hydroxycarbamate (821 mg, 3.94 mmol) in methanol (10 mL) 69 mL, 26.7 mmmol) was stirred at 50 C for 2 hours. After the sodium hydrogencarbonate aqueous solution and ethyl acetate were added to the reaction solution for separation, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water and saturated brine and dried over magnesium sulfate. After the organic phase was filtered, the title compound (472 mg, EtOAc, EtOAc, EtOAc) 1H-NMR (400 MHz, DMSO-d6) δ 3.11 (s, 3H), 3.81 (s, 3H), 141666.doc •565- 201028381 4.88 (s, 2H), 5.25 (s, 2H), 6.67 (d , J = 7.8 Hz, 1H), 6.98 (d, J = 7.8 Hz, 1H), 7.23 (s, 1H), 7.71 (s, 1H), 7.92 (s, 1H). MS (ESI) m/z = 282 (M+H)+. LC/MS tR=0_70 min o Step 5: the title compound to difluoromethic acid 4-amino-5-enyl- 6-(cyclohexylamino)indole-2-yl ester (230 mg ' 0.631 mmol , 4-(1-methyl-1H-pyrazol-4-yl)-2-(methylindolyl methoxy)aniline (213 mg, 0.750 mmol), hydrazine (59·0 mg, 0.095 mmol) And a solution of cesium carbonate (288 mg, 0.884 mmol) in dioxane (2.0 mL) was added Pd(OAc) 2 (14.2 mg, 〇·〇 63 mmol), and stirred at 90 ° C for 6 hours. After adding water and ethyl acetate to the reaction solution for separation, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water and saturated brine. After the organic phase was passed through, it was concentrated under reduced pressure. The residue obtained was purified by reverse phase-division liquid chromatography (C1 8 column; water / acetonitrile / 0.1% decamic acid; 10-100% gradient) to give the title compound (71.6 mg, 0.144 mmol , 23%), as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 1.27-1.32 (m&gt; 5H), 1.61 (d, J = 11.2 Hz, 1H), 1.72 (s, 2H), 1.88 (s, 2H), 3.11 (s , 3H), 3.86 (br s, 4H), 5.37 (s, 2H), 5.45 (s, 1H), 5.7〇 (d, J=7.8

Hz, 1H), 6.08 (s, 2H), 7.17 (d, J=8.3 Hz, 1H), 7.46 (s&gt; 1H), 7-85 (d, J=8.1 Hz, 2H), 7.94 (d, J=8.3 Hz, iH), 8.11 (s5 1H)。 MS(ESI)m/z=496 (M+H)+。 141666.doc -566 - 201028381 LC/MS tR=1.53 min 〇 (實施例2) 實施例2-1 N-(3-氰基-2-乙氧基·4十夫喃_2_基）.節并⑴2仲比咬· 7-基）乙醯胺 [化 2001]Hz, 1H), 6.08 (s, 2H), 7.17 (d, J=8.3 Hz, 1H), 7.46 (s&gt; 1H), 7-85 (d, J=8.1 Hz, 2H), 7.94 (d, J =8.3 Hz, iH), 8.11 (s5 1H). MS (ESI) m/z = 495 (M+H)+. 141666.doc -566 - 201028381 LC/MS tR=1.53 min 〇 (Example 2) Example 2-1 N-(3-Cyano-2-ethoxy-4fef-2-yl). And (1) 2 zhongbi bite · 7-base) acetamidine [Chemical 2001]

向N(1側氧基_2,3-二氫_ιη·茚·5-基）乙酿胺（1〇〇 mg， 0·529 mmol)及2十夫喃_2_基亞甲基）丙二猜（76 2叫，ο· mmol)之乙醇（2 mL)溶液中添加乙醇鈉（75 6 mg，i u mmol) ’於室溫下攪拌2小時。濾取析出之固體，利用中壓 石夕膠層析法（氣仿.甲醇=19 : 1)進行純化，獲得標題化合 物（8.5 mg，0.024 mmol，5%)。To N (1 side oxy 2,3-dihydro-_ηη·茚·5-yl) ethylamine (1 〇〇 mg, 0·529 mmol) and 2 hexan-2-amethylene) Add sodium ethoxide (75 6 mg, iu mmol) to a solution of propylene (76 oz, ο. mmol) in ethanol (2 mL) and stir at room temperature for 2 hours. The precipitated solid was filtered and purified using EtOAc EtOAc (EtOAc)

1H-NMR (300 MHz, DMSO-d6) δ 1.44 (t, J=6.9 Hz, 3H), 2.11 (s, 3H), 4.16 (s, 2H), 4.61 (q, 2H), 6.87 (dd, J=3.6, 1.8 Hz, 1H), 7.55 (d, J=3.6 Hz, 1H), 7.67 (dd, 1H), 7.88 (d, J=8.4 Hz, 1H)，8.05 (m，1H), 8.13 (d, 1H)，10.26 (s, 1H)。 實施例2-2 Ν-(3·氰基-2 -曱氧基-4-苯基- 5H-節并[1，2-b] °比唆-7-基）乙 醯胺 141666.doc -567- 201028381 [化 2002]1H-NMR (300 MHz, DMSO-d6) δ 1.44 (t, J = 6.9 Hz, 3H), 2.11 (s, 3H), 4.16 (s, 2H), 4.61 (q, 2H), 6.87 (dd, J =3.6, 1.8 Hz, 1H), 7.55 (d, J=3.6 Hz, 1H), 7.67 (dd, 1H), 7.88 (d, J=8.4 Hz, 1H), 8.05 (m, 1H), 8.13 (d , 1H), 10.26 (s, 1H). Example 2-2 Ν-(3·Cyano-2-indolyl-4-phenyl-5H-gangrene [1,2-b] ° 唆-7-yl) acetamidine 141666.doc - 567- 201028381 [Chemical 2002]

標題化合物係依據實施例2-1之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 2.09 (s，3H)，3.84 (s，2H)， 4.15 (s, 3H), 7.56-7.73 (m, 6H), 7.93-7.95 (m, 2H), 10.24 (s，1H)。 實施例2-3 4-(0夫鳴-2-基）-2,7-二甲氧基-511-節并[1，2-13]〇比1&gt;定-3-赌 [化 2003]The title compound was synthesized according to the method of Example 2-1. 1H-NMR (300 MHz, DMSO-d6) δ 2.09 (s, 3H), 3.84 (s, 2H), 4.15 (s, 3H), 7.56-7.73 (m, 6H), 7.93-7.95 (m, 2H) , 10.24 (s, 1H). Example 2-3 4-(0f-but-2-yl)-2,7-dimethoxy-511-knot [1,2-13] 〇1 1&gt; -3- gambling [Chem. 2003]

標題化合物係依據實施例2 -1之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 3.87 (s, 3H), 4.13 (s, 5H), 6.87 (dd, J=3.9, 2.1 Hz, 1H), 7.09 (dd, J=8.7, 2.1 Hz, 1H), 7.29 (d, J=2.1 Hz, 1H), 7.54 (d, J=3.6 Hz, 1H), 7.88 (d, J=8.4 Hz, 1H), 8_12 (d, J=1.5 Hz, 1H)。 實施例2-4 7-氯-4-(呋喃-2-基）-2-甲氧基-5H-茚并[l,2-b]°比咬_3_腊 [化 2004]The title compound was synthesized according to the method of Example 2-1. 1H-NMR (300 MHz, DMSO-d6) δ 3.87 (s, 3H), 4.13 (s, 5H), 6.87 (dd, J=3.9, 2.1 Hz, 1H), 7.09 (dd, J=8.7, 2.1 Hz , 1H), 7.29 (d, J=2.1 Hz, 1H), 7.54 (d, J=3.6 Hz, 1H), 7.88 (d, J=8.4 Hz, 1H), 8_12 (d, J=1.5 Hz, 1H ). Example 2-4 7-Chloro-4-(furan-2-yl)-2-methoxy-5H-indole [l,2-b]° ratio bite_3_ wax [Chem. 2004]

OMe 141666.doc -568- 201028381 標題化合物係依據實施例2-1之方法而合成。 1H-NMR (300 MHz，DMSO-d6) δ 4.12 (s，3H)，4_15 (s，2H)， 6.88 (dd, J=3.6, 1.8 Hz, 1H), 7.54-7.57 (m, 2H), 7.78 (d, 1H), 7.93 (d，J=8.1 Hz，1H)，8.14 (d，J=1.8 Hz，1H)。 實施例2-5 7 -氟*-4-(0夫喃_2·基）·2_曱氧基_5H-節并[1，2_b]n比„定_3_腈 [化 2005]OMe 141666.doc -568- 201028381 The title compound was synthesized according to the method of Example 2-1. 1H-NMR (300 MHz, DMSO-d6) δ 4.12 (s, 3H), 4_15 (s, 2H), 6.88 (dd, J = 3.6, 1.8 Hz, 1H), 7.54-7.57 (m, 2H), 7.78 (d, 1H), 7.93 (d, J = 8.1 Hz, 1H), 8.14 (d, J = 1.8 Hz, 1H). Example 2-5 7-Fluoro*-4-(0-propan-2-yl)·2_decyloxy_5H-gangrene[1,2_b]n ratio „定_3_onitrile [Chemical 2005]

標題化合物係依據實施例2-1之方法而合成。 1H-NMR (300 MHz，DMSO-d6) δ 4.13 (s，3H)，4.17 (s，2H) 6.88 (dd, J=3.6, 1.8 Ηζ，1Η)，7.36 (dd，1Η)，7.55-7.58 (m 2H), 7.98 (d，J=8.7, 2.4 Hz, 1H)，8.14 (s, 1H)。 實施例2-6 4-(呋喃-2-基）-2,8_二曱氧基-5H-茚并[l，2-b]吡啶_3-腈 [化 2006]The title compound was synthesized according to the method of Example 2-1. 1H-NMR (300 MHz, DMSO-d6) δ 4.13 (s, 3H), 4.17 (s, 2H) 6.88 (dd, J = 3.6, 1.8 Ηζ, 1 Η), 7.36 (dd, 1 Η), 7.55-7.58 ( m 2H), 7.98 (d, J = 8.7, 2.4 Hz, 1H), 8.14 (s, 1H). Example 2-6 4-(furan-2-yl)-2,8-dimethoxy-5H-indeno[l,2-b]pyridine-3-nitrile [Chem. 2006]

標題化合物係依據實施例2-1之方法而合成。 1H-NMR (300 MHz，DMSO-d6) δ 3.88 (s，3H)，4·〇7 (s 2H) 4.15 (s，3Η), 6.88 (dd，J=3.9, 1·8 Ηζ，1Η), 7·13 (dd, J=8 4 5.4 Hz, 1H), 7.44 (d, J=2.4 Hz, 1H), 7.55-7.62 (m, 2H) 141666.doc -569- 201028381 8.13 (d，1H)。 實施例2-7 7-溴-4-(呋喃-2-基）-2-甲氧基-5H-茚并[l，2-b]。比啶-3-腈 [化 2007]The title compound was synthesized according to the method of Example 2-1. 1H-NMR (300 MHz, DMSO-d6) δ 3.88 (s, 3H), 4·〇7 (s 2H) 4.15 (s, 3Η), 6.88 (dd, J=3.9, 1·8 Ηζ, 1Η), 7·13 (dd, J=8 4 5.4 Hz, 1H), 7.44 (d, J=2.4 Hz, 1H), 7.55-7.62 (m, 2H) 141666.doc -569- 201028381 8.13 (d, 1H). Example 2-7 7-Bromo-4-(furan-2-yl)-2-methoxy-5H-indole[l,2-b]. Bis-pyridine-3-carbonitrile [Chemical 2007]

標題化合物係依據實施例2 -1之方法而合成。 1H-NMR (300 MHz，DMSO-d6) δ 4.12 (s，3H)，4.14 (s，2H)， 6.88 (dd, J=3.3, 1.5 Hz, 1H), 7.56 (d, J=3.6 Hz, 1H), 7.68 (dd, J=8.4, 1.8 Hz, 1H), 7.86 (d, J=8.1 Hz, 1H), 7.91 (d, 1H)，8.14 (d，J=1.8 Hz，1H)。 實施例2-8 4-(呋喃-2-基）-2-甲氧基-7-(N-嗎啉基）-5H-茚并[l，2-bp比 咬-3-曱猜 [化 2008]The title compound was synthesized according to the method of Example 2-1. 1H-NMR (300 MHz, DMSO-d6) δ 4.12 (s, 3H), 4.14 (s, 2H), 6.88 (dd, J = 3.3, 1.5 Hz, 1H), 7.56 (d, J = 3.6 Hz, 1H ), 7.68 (dd, J=8.4, 1.8 Hz, 1H), 7.86 (d, J=8.1 Hz, 1H), 7.91 (d, 1H), 8.14 (d, J=1.8 Hz, 1H). Example 2-8 4-(furan-2-yl)-2-methoxy-7-(N-morpholinyl)-5H-indole[l,2-bp ratio 曱-3-曱猜[化2008]

標題化合物係依據實施例2-1之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 3.77 (m, 4H), 4.09 (s, 2H), 4.12 (s5 3H), 6.86 (dd, 1H), 7.13 (dd, 1H), 7.24 (d, 1H), 7.51 (d, J=4.2 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 8.12 (s, 1H) 〇 141666.doc -570- 201028381 實施例2-9 4-(呋喃-2-基）-2-甲氧基-7-(2-(N-嗎啉基）乙基胺基）_5H-茚并[l，2-b]吡啶-3-甲腈 [化 2009]The title compound was synthesized according to the method of Example 2-1. 1H-NMR (300 MHz, DMSO-d6) δ 3.77 (m, 4H), 4.09 (s, 2H), 4.12 (s5 3H), 6.86 (dd, 1H), 7.13 (dd, 1H), 7.24 (d, 1H), 7.51 (d, J=4.2 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 8.12 (s, 1H) 〇141666.doc -570- 201028381 Example 2-9 4-(furan -2-yl)-2-methoxy-7-(2-(N-morpholinyl)ethylamino)_5H-indolo[l,2-b]pyridine-3-carbonitrile [Chemical 2009]

1H-NMR (300 MHz, DMSO-d6) δ 2.44 (m, 4H), 3.60 (m, • 4H), 4.02 (s, 2H), 4.09 (s, 3H)} 6.34 (dd, 1H), 6.76 (m, 1H), 6.85 (m, 2H), 7.47 (d, J=4.5 Hz, 1H), 7.68 (d, J=8.1 Hz, 1H), 8.09 (d, 1H)。 實施例2-10 7-胺基-4-(咬0南-2-基）-2-曱氧基- 5H-Bp并[1,2-b]0比咬-3-猜 [化 2010]1H-NMR (300 MHz, DMSO-d6) δ 2.44 (m, 4H), 3.60 (m, • 4H), 4.02 (s, 2H), 4.09 (s, 3H)} 6.34 (dd, 1H), 6.76 ( m, 1H), 6.85 (m, 2H), 7.47 (d, J=4.5 Hz, 1H), 7.68 (d, J=8.1 Hz, 1H), 8.09 (d, 1H). Example 2-10 7-Amino-4-(Bist 0-Nan-2-yl)-2-decyloxy-5H-Bp and [1,2-b]0 ratio bite-3-gues [Chemical 2010]

標題化合物係依據實施例2-1之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 3.98 (s, 2H), 4.08 (s, 3H), 5.92 (br, 2H), 6.68 (dd, J=8.4, 2.1 Hz, 1H), 6.80 (br, 1H), 6.83 (dd, J=3.6, 1.8 Hz, 1H), 7.47 (d, J=3.6 Hz, 1H), 7.64 (d, J=8.4 Hz, 1H)，8.08 (d, 1H)。 實施例2-11 N-(2-胺基-3-氰基-4-(呋喃-2-基）-5H-茚并[l，2-bp比啶-7- 141666.doc •571 - 201028381 基）乙醯胺 [化 2011]The title compound was synthesized according to the method of Example 2-1. 1H-NMR (300 MHz, DMSO-d6) δ 3.98 (s, 2H), 4.08 (s, 3H), 5.92 (br, 2H), 6.68 (dd, J=8.4, 2.1 Hz, 1H), 6.80 (br , 1H), 6.83 (dd, J=3.6, 1.8 Hz, 1H), 7.47 (d, J=3.6 Hz, 1H), 7.64 (d, J=8.4 Hz, 1H), 8.08 (d, 1H). Example 2-11 N-(2-Amino-3-cyano-4-(furan-2-yl)-5H-indole[l,2-bppyridin-7- 141666.doc •571 - 201028381 Ethylamine [Chemical 2011]

Me、j rOQ οMe, j rOQ ο

NH4OAc 二噁烷，室溫NH4OAc dioxane, room temperature

向N-(l-侧氧基-2,3-二氫_1H-茚-5-基）乙醯胺（100 mg， 0.529 mmol)及 2-(呋喃·2-基亞甲基）丙二腈（76.2 mg，0.529 mmol)之乙醇（2 mL)溶液中添加乙醇鈉（75.6 mg，1.11 mmol) ’於室溫下攪拌2小時。濾取析出之固體，利用中壓 矽膠層析法（氣仿：甲醇=19 : 1)進行純化，獲得標題化合 物（8.5 mg，0.024 mmol，5%)。 1H-NMR (300 MHz, DMSO-d6) δ 2.10 (s, 3Η), 4.04 (s, 2H), 6.82-6.85 (m, 2H), 7.43 (d, J=3.6 Hz, 1H), 7.65 (dd, J=9.〇 Hz, 1H), 7.78 (d, J=9.0 Hz, 1H), 7.97 (d, 1H), 8.06 (s, 1H), 10.21 (s, 1H)。 實施例2-12 6-(4-(1 H-咪唑-1-基）苯基）-2-甲氧基-4-(5-曱基呋喃_2_ 基）菸鹼腈 [化 2012]To N-(l-Sideoxy-2,3-dihydro-1H-indol-5-yl)acetamide (100 mg, 0.529 mmol) and 2-(furan-2-ylmethylene)propane To a solution of the nitrile (76.2 mg, 0.529 mmol) in EtOAc (2 mL), EtOAc. The precipitated solid was filtered and purified using EtOAc EtOAc (EtOAc: EtOAc) 1H-NMR (300 MHz, DMSO-d6) δ 2.10 (s, 3 Η), 4.04 (s, 2H), 6.82-6.85 (m, 2H), 7.43 (d, J = 3.6 Hz, 1H), 7.65 (dd , J=9.〇Hz, 1H), 7.78 (d, J=9.0 Hz, 1H), 7.97 (d, 1H), 8.06 (s, 1H), 10.21 (s, 1H). Example 2-12 6-(4-(1H-imidazol-1-yl)phenyl)-2-methoxy-4-(5-fluorenylfuran-2-yl)nicotinonitrile [Chem. 2012]

141666.doc -572- 201028381 向1-(4-(1 Η-咪唑-1·基）苯基）乙酮（3 72 mg » 2.0 mmol) ' 5-甲基0夫喝-2-甲搭（440 mg，4.0 mmol)及丙二腈（264 mg ’ 4.0 mmol)之甲醇（1〇 mL)溶液中添加乙醇鈉（130 mg，2.4 mmol)，於室溫下攪拌一整夜。濾取析出之固體，以乙酸 乙S曰及乙醇進行清洗’藉此獲得標題化合物（206.7 mg， 0.58 mmol &gt; 29%) 〇 1H-NMR (300 MHz, DMSO-d6) δ 2.42 (s, 3H), 4.10 (s, 3H), 6.46 (d, J=3.5 Hz, 1H), 7.15 (s, 1H), 7.58 (d, J=3.5 Hz, • 1H)，7.83 (d, J=8.7 Hz, 2H)，7.87 (s，1H)，7.96 (s，1H)，8.34 (d, J=8.7 Hz，2H)，8.41 (s，3H)。 實施例2-13 6-(4 -〉臭本基）-4-(0夫味-2-基）-2 -甲氧基终驗睛 [化 2013]141666.doc -572- 201028381 To 1-(4-(1 Η-imidazole-1.yl)phenyl)ethanone (3 72 mg » 2.0 mmol) ' 5-Methyl 0 Fu 2-2-( To a solution of 440 mg, 4.0 mmol) and malononitrile (264 mg '4.0 mmol) in methanol (1 mL) was added sodium ethoxide (130 mg, 2.4 mmol) and stirred at room temperature overnight. The precipitated solid was collected by filtration and washed with ethyl acetate and ethyl alcohol to afford the title compound (206.7 mg, 0.58 mmol &gt; 29%) 〇1H-NMR (300 MHz, DMSO-d6) δ 2.42 (s, 3H ), 4.10 (s, 3H), 6.46 (d, J=3.5 Hz, 1H), 7.15 (s, 1H), 7.58 (d, J=3.5 Hz, • 1H), 7.83 (d, J=8.7 Hz, 2H), 7.87 (s, 1H), 7.96 (s, 1H), 8.34 (d, J = 8.7 Hz, 2H), 8.41 (s, 3H). Example 2-13 6-(4 -> Stinyl)-4-(0 fut-2-yl)-2-methoxy end-finishing eye [Chem. 2013]

標題化合物係依據實施例2-12之方法而合成。 1H-NMR (300 MHz，CDC13) δ 4.16 (s，3H)，6.63 (dd，J=3.7 1.8 Hz，1H)，7.60-7.67 (m，4H)，7.82 (s，1H)，7·98 (d，J=8 9 Hz，2H)。 實施例2-14 6-(4-胺基苯基）-4-(°夫喃-2 -基）-2-甲氧基终驗赌 141666.doc -573 - 201028381 [化 2014]The title compound was synthesized according to the method of Example 2-12. 1H-NMR (300 MHz, CDC13) δ 4.16 (s, 3H), 6.63 (dd, J = 3.7 1.8 Hz, 1H), 7.60-7.67 (m, 4H), 7.82 (s, 1H), 7·98 ( d, J = 8 9 Hz, 2H). Example 2-14 6-(4-Aminophenyl)-4-(°f-am-2-yl)-2-methoxy end gambling 141666.doc -573 - 201028381 [Chem. 2014]

標題化合物係依據實施例2-12之方法而合成。 1H-NMR (300 MHz, CDC13) δ 4.17 (s，3H)，6·65 (dd，J=3.7, 1.8 Hz, 1H), 7.15 (d, J=8.6 Hz, 2H), 7.58 (d, J=3.7 Hz, 1H), 7.68 (d, J=1.8 Hz, 1H), 7.79 (s, 1H), 8.05 (d, J=8.6 Hz, 2H)。 實施例2-15 N-(4-(5 -氰基- 4-(吱n南-2-基）-6 -甲氧基°比咬-2-基）苯基）乙 醯胺 [化 2015]The title compound was synthesized according to the method of Example 2-12. 1H-NMR (300 MHz, CDC13) δ 4.17 (s, 3H), 6·65 (dd, J=3.7, 1.8 Hz, 1H), 7.15 (d, J=8.6 Hz, 2H), 7.58 (d, J =3.7 Hz, 1H), 7.68 (d, J=1.8 Hz, 1H), 7.79 (s, 1H), 8.05 (d, J=8.6 Hz, 2H). Example 2-15 N-(4-(5-Cyano-4-(吱n-Nan-2-yl)-6-methoxy~biti-2-yl)phenyl)acetamide [Chemical 2015 ]

標題化合物係依據實施例2-12之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 2.09 (s, 3H), 4.12 (s, 3H), 6.83 (dd, J=1.7, 3.7 Hz, 1H), 7.65 (d, J=3.7 Hz, 1H), 7.76 (d, J=8.7 Hz, 2H), 7.95 (s, 1H), 8.07 (d, J=1.7 Hz, 1H), 8.21 (d，J=8.7 Hz，2H)，10.21 (s, 1H)。 實施例2-16 N-(4-(5-氰基-4-(呋喃-2-基）-6-甲氧基吨啶-2_基）苯基）甲 141666.doc -574· 201028381 確醯胺 [化 2016]The title compound was synthesized according to the method of Example 2-12. 1H-NMR (300 MHz, DMSO-d6) δ 2.09 (s, 3H), 4.12 (s, 3H), 6.83 (dd, J=1.7, 3.7 Hz, 1H), 7.65 (d, J=3.7 Hz, 1H ), 7.76 (d, J=8.7 Hz, 2H), 7.95 (s, 1H), 8.07 (d, J=1.7 Hz, 1H), 8.21 (d, J=8.7 Hz, 2H), 10.21 (s, 1H) ). Example 2-16 N-(4-(5-Cyano-4-(furan-2-yl)-6-methoxytung-2-yl)phenyl)methyl 141666.doc -574· 201028381 Guanamine [Chemical 2016]

標題化合物係依據實施例2-12之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 3.10 (s, 3H), 4.12 (s, 3H), 6.84 (dd, J=3.3, 1.6 Hz, 1H), 7.36 (d, J=8.5 Hz, 2H), 7.65 (d, J=3.3 Hz, 1H), 7.95 (s, 1H), 8.08 (d, J=1.6 Hz, 1H), 8.23 (d，J=8.5 Hz, 2H), 10.16 (s, 1H)。 實施例2-17 N-(4-(5-氰基-6-甲氧基-4-(5-甲基呋喃-2-基）吡啶-2-基） 苯基）乙醯胺 [化 2017]The title compound was synthesized according to the method of Example 2-12. 1H-NMR (300 MHz, DMSO-d6) δ 3.10 (s, 3H), 4.12 (s, 3H), 6.84 (dd, J=3.3, 1.6 Hz, 1H), 7.36 (d, J=8.5 Hz, 2H ), 7.65 (d, J=3.3 Hz, 1H), 7.95 (s, 1H), 8.08 (d, J=1.6 Hz, 1H), 8.23 (d, J=8.5 Hz, 2H), 10.16 (s, 1H) ). Example 2-17 N-(4-(5-Cyano-6-methoxy-4-(5-methylfuran-2-yl)pyridin-2-yl)phenyl)acetamide [Chemical 2017 ]

標題化合物係依據實施例2-12之方法而合成。 1H-NMR (300 MHz，DMSO-d6) δ 2.09 (s，3H)，2.44 (s，3H)， 4.11 (s, 3H), 6.47 (d, J=3.3 Hz, 1H), 7.55 (d, J=3.3 Hz, 1H), 7.76 (d, J=8.5 Hz, 2H), 7.88 (s, 1H), 8.19 (d, J=8.5 Hz，2H)，10.23 (s，1H)。 實施例2-18 141666.doc -575 - 201028381 6-(2-羥基苯基）-2-甲氧基-4-(5-甲基呋喃-2-基）菸鹼腈 [化 2018]The title compound was synthesized according to the method of Example 2-12. 1H-NMR (300 MHz, DMSO-d6) δ 2.09 (s, 3H), 2.44 (s, 3H), 4.11 (s, 3H), 6.47 (d, J = 3.3 Hz, 1H), 7.55 (d, J =3.3 Hz, 1H), 7.76 (d, J=8.5 Hz, 2H), 7.88 (s, 1H), 8.19 (d, J=8.5 Hz, 2H), 10.23 (s, 1H). Example 2-18 141666.doc -575 - 201028381 6-(2-Hydroxyphenyl)-2-methoxy-4-(5-methylfuran-2-yl)nicotinonitrile [Chemical 2018]

標題化合物係依據實施例2-12之方法而合成。 MS(ESI)m/z=307 (M+H)+。 LC/MS tR=2.6.8 min ° 實施例2-19 6-(4-羥基苯基）-2-甲氧基-4-(5-甲基呋喃-2-基）菸鹼腈 [化 2019]The title compound was synthesized according to the method of Example 2-12. MS (ESI) m / z = 307 (M + H) +. LC/MS tR = 2.6.8 min ° Example 2-19 6-(4-hydroxyphenyl)-2-methoxy-4-(5-methylfuran-2-yl)nicotinonitrile [Chemical 2019 ]

標題化合物係依據實施例2 -12之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 2.43 (s，3H)，4.09 (s，3H) 6.45 (d, J=3.4 Hz, 1H), 6.91 (d, J=8.7 Hz, 2H), 7.52 (d J=3.4 Hz, 1H)，7.81 (s，1H)，8.10 (d，J=8.7 Hz，2H)。 實施例2-20 N-(4-(5-氰基-6-甲氧基-4-(5-甲基咬喃-2-基）n比咬_2-基） 3-(4-甲氧基节氧基）苯基）乙醯胺 141666.doc • 576· 201028381 [化 2020]The title compound was synthesized according to the method of Example 2-12. 1H-NMR (300 MHz, DMSO-d6) δ 2.43 (s, 3H), 4.09 (s, 3H) 6.45 (d, J = 3.4 Hz, 1H), 6.91 (d, J = 8.7 Hz, 2H), 7.52 (d J = 3.4 Hz, 1H), 7.81 (s, 1H), 8.10 (d, J = 8.7 Hz, 2H). Example 2-20 N-(4-(5-Cyano-6-methoxy-4-(5-methyl-n-butan-2-yl)n than bite 2-yl) 3-(4-A Oxyoxyphenol)phenyl)acetamide 141666.doc • 576· 201028381 [Chemical 2020]

標題化合物係依據實施例2-12之方法而合成。 MS(ESI)m/z=484 (M+H)+。 LC/MS tR=2.83 min。 實施例2-21 N-(4-(5 -氮基-6-曱氧基- 4- (5 -甲基α夫喃-2 -基）π比0定-2 -基）-3-羥基苯基）乙醯胺 [化 2021]The title compound was synthesized according to the method of Example 2-12. MS (ESI) m / z = 484 (M + H) +. LC/MS tR = 2.83 min. Example 2-21 N-(4-(5-Nitro-6-methoxy-4-(5-methylα-pentan-2-yl)π ratio 0-but-2-yl)-3-hydroxyl Phenyl) acetamidine [2021]

標題化合物係依據實施例2-12之方法而合成。 MS(ESI)m/z=364 (Μ+Η)+。 LC/MS tR=2.18 min。 實施例2-22 N-(4-(5 -氰基-6-甲氧基-4-(5 -甲基0夫喃-2 -基）α比0定-2-基）_ 3-氟苯基）乙醯胺 141666.doc 577- 201028381 [化 2022]The title compound was synthesized according to the method of Example 2-12. MS (ESI) m / z = 364 (Μ + Η) +. LC/MS tR = 2.18 min. Example 2-22 N-(4-(5-Cyano-6-methoxy-4-(5-methyloxafuran-2-yl)α ratio 0-but-2-yl)-3-fluoro Phenyl)acetamide 141666.doc 577- 201028381 [Chem. 2022]

標題化合物係依據實施例2-12之方法而合成。 MS(ESI)m/z=366 (M+H).。 LC/MS tR=2.38 min 〇 實施例2-23 6-(4-溴苯基）-2-乙氧基-4-(5-甲基《夫喃-2-基）終驗腈 [化 2023]The title compound was synthesized according to the method of Example 2-12. MS (ESI) m/z = 366 (M+H). LC/MS tR=2.38 min 〇 Example 2-23 6-(4-bromophenyl)-2-ethoxy-4-(5-methyl "flan-2-yl" final nitrile [2023 ]

標題化合物係依據實施例2-12之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 1.42 (t, J=7.0 Hz, 3H), 2.44 (s, 3H), 4.58 (q, J=7.0 Hz, 2H), 6.47 (d, J=3.6 Hz, 1H), 7.58 (d, J=3.6 Hz, 1H), 7.75 (d, J=8.5 Hz, 2H), 7.94 (s, 1H), 8.16 (d，J=8.5 Hz，2H)。 實施例2-24 6-(4-胺基苯基）-2-乙氡基-4-(5-甲基呋喃-2-基）菸鹼腈 141666.doc -578- 201028381 [化 2024]The title compound was synthesized according to the method of Example 2-12. 1H-NMR (300 MHz, DMSO-d6) δ 1.42 (t, J = 7.0 Hz, 3H), 2.44 (s, 3H), 4.58 (q, J = 7.0 Hz, 2H), 6.47 (d, J = 3.6 Hz, 1H), 7.58 (d, J=3.6 Hz, 1H), 7.75 (d, J=8.5 Hz, 2H), 7.94 (s, 1H), 8.16 (d, J=8.5 Hz, 2H). Example 2-24 6-(4-Aminophenyl)-2-ethinyl-4-(5-methylfuran-2-yl)nicotinonitrile 141666.doc -578- 201028381 [Chem. 2024]

標題化合物係依據實施例2-12之方法而合成。 1H-NMR (300 MHz, CDC13) δ 1.49 (t, J=7.l Hz, 3H), 2.45 (s, 3H), 4.61 (q, J=7.1 Hz, 2H), 6.22 (d, J=3.6 Hz, 1H), φ 6.92 (d, J=8.2 Hz, 2H), 7.49 (d, J=3.6 Hz, 1H), 7.68 (s, 1H)，7.99 (d，J=8.2 Hz, 2H)。 實施例2-25 6-(4-胺基苯基）-2-甲氧基-4-(5-甲基呋喃-2-基）菸鹼腈 [化 2025]The title compound was synthesized according to the method of Example 2-12. 1H-NMR (300 MHz, CDC13) δ 1.49 (t, J=7.l Hz, 3H), 2.45 (s, 3H), 4.61 (q, J=7.1 Hz, 2H), 6.22 (d, J=3.6 Hz, 1H), φ 6.92 (d, J=8.2 Hz, 2H), 7.49 (d, J=3.6 Hz, 1H), 7.68 (s, 1H), 7.99 (d, J=8.2 Hz, 2H). Example 2-25 6-(4-Aminophenyl)-2-methoxy-4-(5-methylfuran-2-yl)nicotinonitrile [Chemical 2025]

標題化合物係依據實施例2-1 2之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 2.42 (s, 3H), 4.07 (s, 3H), 5.82 (s, 2H), 6.44 (d, J=3.5 Hz, 1H), 6.67 (d, J=8.7 Hz, 2H), 7.48 (d, J=3.5 Hz, 1H), 7.71 (s, 1H), 7.97 (d, J=8.7 Hz，3H)。 實施例2-26 N-(4_(5 -氣基- 4-( 0夫味-2-基）-6 -曱氧基0比0定基）苯基）-2- 甲氧基乙醯胺 141666.doc - 579- 201028381 [化 2026]The title compound was synthesized according to the method of Example 2-1. 1H-NMR (300 MHz, DMSO-d6) δ 2.42 (s, 3H), 4.07 (s, 3H), 5.82 (s, 2H), 6.44 (d, J = 3.5 Hz, 1H), 6.67 (d, J =8.7 Hz, 2H), 7.48 (d, J=3.5 Hz, 1H), 7.71 (s, 1H), 7.97 (d, J=8.7 Hz, 3H). Example 2-26 N-(4_(5-Gasyl-4-(0-yote-2-yl)-6-decyloxy 0- to 0-decyl)phenyl)-2-methoxyacetamide 141666 .doc - 579- 201028381 [化2026]

向6-(4-胺基苯基）-2-甲氧基-4-(5-曱基呋喃-2-基）菸鹼腈 (58.3 mg，0.2 mmol)、DIC(37.9 mg，47 pL，0.30 mmol) 及 HOBt(40.5 mg，0.30 mmol)之 DMF(2 mL)溶液中添力口甲 氧基乙酸（27 mg，23 μι，0.3 mmol)，於室溫下攪拌一整 夜。向反應溶液中添加水及乙酸乙酯進行分離後，以乙酸 乙酯萃取水相。將合併之有機相以碳酸氫鈉水溶液及飽和 食鹽水進行清洗，以硫酸鎂加以乾燥。將有機相過濾後， 進行減壓濃縮，利用逆相等分試樣液相層析法（水/乙腈/ 0.3%甲酸；10-100%梯度）進行純化，藉此獲得標題化合物 (73 mg，0.20 mmol，100%)，為黃色固體。 1H-NMR (300 MHz, DMSO-d6) δ 4.05 (s, 2H), 4.13 (s, 3H), 5.49 (d, J=6.9 Hz, 3H), 6.84 (dd, J=3.5, 1.8 Hz, 1H), 7.67 (d, J=3.5 Hz, 1H), 7.87 (d, J=8.7 Hz, 2H), 7.99 (s, 1H), 8.08 (d, J = 1.8 Hz, 1H), 8.24 (d, J=8.7 Hz, 2H), 10.05 (s, 1H)。 實施例2-27 N-(4-(5-氰基-6-甲氧基-4-(噻唑-2-基）°比啶-2-基）苯基）乙 醯胺 141666.doc -580- 201028381 [化 2027]To 6-(4-Aminophenyl)-2-methoxy-4-(5-fluorenylfuran-2-yl)nicotinonitrile (58.3 mg, 0.2 mmol), DIC (37.9 mg, 47 pL, A solution of 0.30 mmol) and HOBt (40.5 mg, 0.30 mmol) in DMF (2 mL) Water and ethyl acetate were added to the reaction solution for separation, and then the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with aqueous sodium bicarbonate and brine and dried over magnesium sulfate. After the organic phase was filtered, the title compound was obtained (yield: EtOAc, EtOAc (EtOAc) M, 100%) as a yellow solid. 1H-NMR (300 MHz, DMSO-d6) δ 4.05 (s, 2H), 4.13 (s, 3H), 5.49 (d, J=6.9 Hz, 3H), 6.84 (dd, J=3.5, 1.8 Hz, 1H ), 7.67 (d, J=3.5 Hz, 1H), 7.87 (d, J=8.7 Hz, 2H), 7.99 (s, 1H), 8.08 (d, J = 1.8 Hz, 1H), 8.24 (d, J =8.7 Hz, 2H), 10.05 (s, 1H). Example 2-27 N-(4-(5-Cyano-6-methoxy-4-(thiazol-2-yl)~pyridin-2-yl)phenyl)acetamide 141666.doc -580 - 201028381 [Chem. 2027]

ΟΟ

Me人Ν Η 標題化合物係依據實施例2-12之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 2.22 (s，3Η)，4.08 (s 3Η) 7.17 (s, 1Η), 7.46 (d, J=3.0 Hz, 1H), 7.63 (d, J=8.5 Hz 2H), 7.91 (s, 1H), 7.96 (d, J=3.0 Hz, 1H), 8.11 (d5 J=8.5 Hz，2H)。 實施例2-28 3-(5 -氰基-6-甲氧基-4-(5 -甲基0夫嗔-2-基）n比咬_2-基）異。惡 唑）-5·甲酸 [化 2028]Me human Ν 标题 The title compound was synthesized according to the method of Example 2-12. 1H-NMR (300 MHz, DMSO-d6) δ 2.22 (s, 3 Η), 4.08 (s 3 Η) 7.17 (s, 1 Η), 7.46 (d, J=3.0 Hz, 1H), 7.63 (d, J=8.5 Hz 2H), 7.91 (s, 1H), 7.96 (d, J=3.0 Hz, 1H), 8.11 (d5 J=8.5 Hz, 2H). Example 2-28 3-(5-Cyano-6-methoxy-4-(5-methyloxafu-2-yl)n is more specific than 2-amino-2-yl). Oxazole-5-carboxylic acid [Chemical 2028]

標題化合物係依據實施例2-12之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 2.41 (s, 3H), 6.43 (d, J=3.6 Hz, 1H), 7.20 (s, 2H), 7.46 (d, 1=3.6 Hz, 1H), 7.55 (s, 1H)，7.58 (s，1H)。 實施例2-29 6-(4-乙醯胺苯基）-2-胺基-4-(呋喃-2-基）-N-甲基菸鹼 141666.doc •581· 201028381 酿胺 [化 2029]The title compound was synthesized according to the method of Example 2-12. 1H-NMR (300 MHz, DMSO-d6) δ 2.41 (s, 3H), 6.43 (d, J = 3.6 Hz, 1H), 7.20 (s, 2H), 7.46 (d, 1 = 3.6 Hz, 1H), 7.55 (s, 1H), 7.58 (s, 1H). Example 2-29 6-(4-Acetylaminophenyl)-2-amino-4-(furan-2-yl)-N-methylnicotine 141666.doc •581· 201028381 Amine (Chemical 2029) ]

步驟1 : 6-(4-乙醯胺苯基）-2-胺基-4-(呋喃-2-基）菸鹼酸 烯丙醋 向1^-(4-乙醯基苯基）乙醯胺（3 00 111§，1.69 111111〇1)、〇夫11南-2-甲醛（195 mg，2.03 mmol)及2-氰基乙酸烯丙酯（254 mg， 2.03 mmol)之甲苯（3 mL)溶液中添加乙酸銨（522 mg，6.77 mmol)，於力口熱回流下授拌3小時。慮取析出之固體，以醚 進行清洗，藉此獲得標題化合物（289 mg ’ 0.766 mmol ’ 45%)。 MS(ESI)m/z=378 (M+H)、 步驟2 : 6-(4-乙醯胺苯基）-2-胺基-4-(呋喃-2-基）菸鹼酸 向6-(4-乙醯胺苯基）-2-胺基-4-(呋喃-2-基）菸鹼酸烯丙酯 (115 mg，0.305 mmol)及嗎琳（132 mg，1.53 mmol)之 THF(1.5 mL)溶液中添加 Pd(PPh3)4(17_3 mg，0.015 mmol)，於室溫下擾拌3小時。向反應溶液中添力口水及乙酸 乙酯進行分離後，以乙酸乙酯萃取水相，將合併之有機相 141666.doc -582 - 201028381 以水及飽和食鹽水進行清洗，以硫酸鎂加以乾燥。將有機 相過遽後，進行減壓濃縮。以甲醇/水使所獲得之殘渣固 化，藉此獲得標題化合物。 MS(ESI)m/z=338 (Μ+Η)+。 步驟3 .標題化合物 向6-(4-乙酿胺苯基）_2_胺基_4-(呋喃-2-基）菸鹼酸（1〇〇 mg ’ 0.237 mmol)、曱基胺（MeOH 中 400/〇 ; 10 pL)及 HOBt(32 mg，0.237 mmol)之 DMF(1.5 mL)溶液中添力口 EDC( 192 mg ’ 0.237 mmol)，於室溫下攪拌3小時。向反應 溶液中添加水及乙酸乙酯進行分離後，以乙酸乙酯萃取水 相’將合併之有機相以水、飽和碳酸氫納水溶液及飽和食 鹽水進行清洗’以硫酸鎂加以乾燥。將有機相過濾後，進 行減壓濃縮。以乙醇/己烷使所獲得之殘渣固化，藉此獲 得標題化合物（67.6 mg，0.193 mmol，81%)。 1H-NMR (300 MHz, DMSO-d6) δ 2.07 (s, 3H)，2.72 (d, J=4.8 Hz, 3H), 5.80 (br, 2H), 6.62 (dd, J=3.3, 1.8 Hz, 1H), 6.86 (d, J=2.7 Hz, 1H), 7.35 (s, 1H), 7.67 (d, J=8.7 Hz, 2H), 7.82 (d, J=0.9 Hz, 1H), 7.98 (d, J=9.0 Hz, 2H), 8.30 (m, 1H)，10.06 (s，1H)。 實施例2-30 6-(4·已醯胺苯基）-2-胺基-4-(5-甲基呋喃-2-基）菸鹼酸 腈（nicotinonitrile) 141666.doc - 583 - 201028381 [化 2030]Step 1: 6-(4-Acetylaminophenyl)-2-amino-4-(furan-2-yl)nicotinic acid allyl vinegar to 1^-(4-ethylmercaptophenyl)acetamidine Amine (3 00 111 §, 1.69 111111 〇 1), Wolff 11 South-2-carbaldehyde (195 mg, 2.03 mmol) and 2-cyanoacetic acid allyl ester (254 mg, 2.03 mmol) in toluene (3 mL) Ammonium acetate (522 mg, 6.77 mmol) was added to the solution and the mixture was stirred for 3 hours under hot reflux. The precipitated solid was taken up and washed with ether to give the title compound (289 mg </ RTI> MS (ESI) m / z = 378 (M + H), Step 2: 6-(4-acetamidophenyl)-2-amino-4-(furan-2-yl)nicotinic acid to 6- (4-Ethylaminophenyl)-2-amino-4-(furan-2-yl) nicotinic acid allyl ester (115 mg, 0.305 mmol) and morphine (132 mg, 1.53 mmol) in THF ( Pd(PPh3)4 (17_3 mg, 0.015 mmol) was added to the solution of 1.5 mL) and scrambled for 3 hours at room temperature. After the reaction solution was added with a solution of water and ethyl acetate, the aqueous phase was extracted with ethyl acetate, and the combined organic phases 141666.doc - 582 - 201028381 were washed with water and saturated brine and dried over magnesium sulfate. After the organic phase was passed through, it was concentrated under reduced pressure. The residue obtained was solidified with methanol/water, whereby the title compound was obtained. MS (ESI) m / z = 338 (Μ + Η) +. Step 3. The title compound is given to 6-(4-ethylaminophenyl)-2-amino-5-(furan-2-yl)nicotinic acid (1 〇〇 mg '0.237 mmol), decylamine (MeOH) 400 〇; 10 pL) and HOBt (32 mg, 0.237 mmol) in DMF (1.5 mL) was added EtOAc ( EtOAc. Water and ethyl acetate were added to the reaction solution for separation, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water, saturated aqueous sodium hydrogencarbonate and saturated brine. After the organic phase was filtered, it was concentrated under reduced pressure. The residue obtained was solidified with ethanol / hexane to give the title compound (67.6 mg, 0.193 mmol, 81%). 1H-NMR (300 MHz, DMSO-d6) δ 2.07 (s, 3H), 2.72 (d, J = 4.8 Hz, 3H), 5.80 (br, 2H), 6.62 (dd, J=3.3, 1.8 Hz, 1H ), 6.86 (d, J=2.7 Hz, 1H), 7.35 (s, 1H), 7.67 (d, J=8.7 Hz, 2H), 7.82 (d, J=0.9 Hz, 1H), 7.98 (d, J = 9.0 Hz, 2H), 8.30 (m, 1H), 10.06 (s, 1H). Example 2-30 6-(4·Acetylamino)-2-amino-4-(5-methylfuran-2-yl)nicotinonitrile nicotinonitrile 141666.doc - 583 - 201028381 [ 2030]

標題化合物係依據實施例2-29(步驟1)之方法而合成。 MS(ESI)m/z=380 (M+H)+。 LC/MS tR=1.72 min。 實施例2-31 6-(4-乙醯胺苯基）-2-胺基-4_(呋喃-2-基）菸鹼醯胺 [化 2031]The title compound was synthesized according to the method of Example 2-29 (Step 1). MS (ESI) m / z = 380 (M + H) +. LC/MS tR = 1.72 min. Example 2-31 6-(4-Acetylaminophenyl)-2-amino-4-(furan-2-yl)nicotinamide [Chem. 2031]

標題化合物係依據實施例2-29(步驟1)之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 2.07 (s, 3H), 5.79 (br, 2H), 6.64 (dd, J=3.3, 1.8 Hz, 1H), 7.01 (dd, J=3.6, 0.6 Hz, 1H), 7.34 (s, 1H), 7.52 (br, 1H), 7.67 (d, J=8.7 Hz, 2H), 7.83 (dd, 1H), 7.98 (d, J=8.7 Hz, 2H), l〇.〇6 (s, 1H) 〇 實施例2-32 N-(4-(6 -胺基- 4-(e夫喃-2 -基）-5-(1,3,4-σ惡-—α坐-2-基）。比咬 _ 2-基）苯基）乙醯胺 141666.doc -584· 201028381 [化 2032]The title compound was synthesized according to the method of Example 2-29 (Step 1). 1H-NMR (300 MHz, DMSO-d6) δ 2.07 (s, 3H), 5.79 (br, 2H), 6.64 (dd, J=3.3, 1.8 Hz, 1H), 7.01 (dd, J=3.6, 0.6 Hz , 1H), 7.34 (s, 1H), 7.52 (br, 1H), 7.67 (d, J=8.7 Hz, 2H), 7.83 (dd, 1H), 7.98 (d, J=8.7 Hz, 2H), l 〇.〇6 (s, 1H) 〇Example 2-32 N-(4-(6-Amino-4-(e-pentan-2-yl)-5-(1,3,4-σ--- —α坐-2-yl).Bite _ 2-yl)phenyl)acetamide 141666.doc -584· 201028381 [Chem. 2032]

向Ν-(4-(6-胺基-4-(呋喃-2-基）-5-(肼羰基）吡啶-2_基）苯 基）乙醯胺（依據實施例2-29而合成）（30 mg，0.085 mmol)之 原甲酸三甲酯（1 mL)溶液中添加三氟乙酸（1滴）’於加熱回 流下攪拌6小時。濾取析出之固體，以乙酸乙酯進行清 洗’藉此獲得標題化合物（11.4 mg，0.032 mmol，37%)， 為淡黃色固體。 .Ν人 ΝΗ2Ν-(4-(6-Amino-4-(furan-2-yl)-5-(indolylcarbonyl)pyridin-2-yl)phenyl)acetamide (synthesized according to Examples 2-29) (30 mg, 0.085 mmol) of a solution of trimethyl orthoformate (1 mL) was added with trifluoroacetic acid (1 drop). The precipitated solid was filtered, washed with ethyl acetate. </RTI> </ RTI> The title compound (11.4 mg, 0.032 mmol, 37%) was obtained as a pale yellow solid. Ν人 ΝΗ2

1H-NMR (300 MHz, DMSO-d6) δ 2.10 (s, 3H), 6.69 (dd, J=3.6, 1.8 Hz, 1H), 7.28 (dd, J=3.6 Hz, 1H), 7.77 (d, J=8.7 Hz, 2H), 7.91 (dd, 1H), 8.13 (s, 1H), 8.23 (d, J=8.7 Hz, 2H), 8.56 (s, 1H)，8.63 (d, 1H), 10.22 (s, 1H)。 實施例2-33 φ 6-(4-乙醯胺苯基）-2-甲氧基-4-(5-甲基呋喃-2-基）菸鹼 醯胺 [化2033]1H-NMR (300 MHz, DMSO-d6) δ 2.10 (s, 3H), 6.69 (dd, J=3.6, 1.8 Hz, 1H), 7.28 (dd, J=3.6 Hz, 1H), 7.77 (d, J =8.7 Hz, 2H), 7.91 (dd, 1H), 8.13 (s, 1H), 8.23 (d, J=8.7 Hz, 2H), 8.56 (s, 1H), 8.63 (d, 1H), 10.22 (s , 1H). Example 2-33 φ 6-(4-Acetylaminophenyl)-2-methoxy-4-(5-methylfuran-2-yl)nicotinium amide [Chemical 2033]

於5 mL微波反應容器中，向N-(4-(5-氰基-6-甲氡基-4- 141666.doc •585· 201028381 (5-曱基呋喃-2-基）吡啶-2·基）苯基）乙醯胺（3 〇〇 mg，0.576 mmol)之乙醇（3 mL)溶液中添加氫氧化鉀（646 mg，115 mmol)進行覆蓋’使用Biotage Optimizer反應裝置，於 100C下加熱攪拌20分鐘。向反應溶液中添加水及乙酸乙 酯進行分離後’以乙酸乙酯萃取水相，將合併之有機相以 破酸氫納水溶液及飽和食鹽水進行清洗，以硫酸鎂加以乾 燥。將有機相過濾後，進行減壓濃縮。 向所獲得之殘渣之吡啶（2 mL)溶液中添加乙醯氣（90.4 mg，0’082 mL·，1.152 mmol)，於室溫下授拌一整夜。向 反應溶液中添加水及乙酸乙酯進行分離後，以乙酸乙酯萃 取水相，將合併之有機相以水、飽和碳酸氫鈉水溶液及飽 和食鹽水進行清洗，以硫酸鎂加以乾燥。將有機相過濾 後進行減壓濃縮。利用石夕膠層析法（氯仿：曱醇=98 : 2) 對所獲得之殘渣進行純化，使用己烷/乙酸乙酯使其固 化，藉此獲得標題化合物（63 9 mg，〇 175 。 1H-NMR (3〇〇 MHz, DMSO-d6) δ 2.08 (s, 3H), 2.38 (s, 3H), 3.98 (s，3H)，6.29 (m，1H)，7.03 (d，J=3.3 Hz, 1H)，7.56 (br, 1H), 7.70-7.73 (m, 2H), 7.88 (br, 1H), 8.09 (d, J=8.7 Hz, 2H), 10.13 (s, 1H)。 實施例2-34 6-(4-乙醯胺苯基）_2_乙氧基_4_(5甲基呋喃_2基）菸鹼 醯胺 141666.doc •586· 201028381 [化 2034]In a 5 mL microwave reaction vessel, N-(4-(5-cyano-6-methylindolyl-4- 141666.doc •585· 201028381 (5-decylfuran-2-yl)pyridine-2· Add potassium hydroxide (646 mg, 115 mmol) to a solution of phenyl)acetamide (3 〇〇mg, 0.576 mmol) in ethanol (3 mL). Use a Biotage Optimizer reactor and heat and stir at 100 °C. 20 minutes. Water and ethyl acetate were added to the reaction solution for separation. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with aqueous sodium hydrogen sulfate and brine and dried over magnesium sulfate. After the organic phase was filtered, it was concentrated under reduced pressure. Ethylene gas (90.4 mg, 0'082 mL·, 1.152 mmol) was added to a solution of the obtained residue in pyridine (2 mL), and the mixture was stirred overnight at room temperature. Water and ethyl acetate were added to the reaction solution for separation. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water, saturated aqueous sodium hydrogen carbonate and brine and dried over magnesium sulfate. The organic phase was filtered and concentrated under reduced pressure. The residue obtained was purified by EtOAc (EtOAc: EtOAc: EtOAc: EtOAc) -NMR (3〇〇MHz, DMSO-d6) δ 2.08 (s, 3H), 2.38 (s, 3H), 3.98 (s, 3H), 6.29 (m, 1H), 7.03 (d, J = 3.3 Hz, 1H), 7.56 (br, 1H), 7.70-7.73 (m, 2H), 7.88 (br, 1H), 8.09 (d, J=8.7 Hz, 2H), 10.13 (s, 1H). Example 2-34 6-(4-acetamidophenyl)_2_ethoxy_4_(5-methylfuran-2-yl)nicotinamide 141666.doc •586· 201028381 [Chemical 2034]

MeMe

標題化合物係依據實施例2-33之方法而合成。The title compound was synthesized according to the method of Example 2-33.

1H-NMR (300 MHz，DMSO-d6) δ 1.36 (t，J=6.9 Hz, 3H)， 2.07 (s, 3H), 2.38 (s, 3H), 4.46 (q, 2H), 6.29 (dd, J=3.3, 0.9 Hz, 1H), 7.01 (d, J=3.3 Hz, 1H), 7.51 (br, 1H), 7.68 (s, 1H), 7.70 (d, J=9.0 Hz, 2H), 7.84 (br, 1H), 8.05 (d5 J=8.7 Hz, 2H), 10.10 (s，1H)。 實施例2-3 5 Ν-(4·(5 -氛基-4-(5-甲基咬e南-2-基）-6-側取l基-1，6-二氣〇比 啶-2-基）苯基）乙醯胺 [化 2035]1H-NMR (300 MHz, DMSO-d6) δ 1.36 (t, J = 6.9 Hz, 3H), 2.07 (s, 3H), 2.38 (s, 3H), 4.46 (q, 2H), 6.29 (dd, J =3.3, 0.9 Hz, 1H), 7.01 (d, J=3.3 Hz, 1H), 7.51 (br, 1H), 7.68 (s, 1H), 7.70 (d, J=9.0 Hz, 2H), 7.84 (br , 1H), 8.05 (d5 J=8.7 Hz, 2H), 10.10 (s, 1H). Example 2-3 5 Ν-(4·(5-Alityl-4-(5-methyl acetoin-2-yl)-6-side 1 group-1,6-diazepidine- 2-yl)phenyl)acetamidine [Chemical 2035]

於20 mL微波反應容器中，向N-(4-乙醯苯基）乙醯胺 (1.77 g，10 mmol)、5-曱基呋喃-2_ 甲醛（1_19 mL，12 mmol)及2-氰基乙酸甲醋（1.06 mL，12 mmol)之二0惡院（3 mL)溶液中添加乙酸敍（3.08 g，40 mmol)進行覆蓋，使用 Biotage Optimizer反應裝置，於140°C下加熱攪拌1〇分鐘。 141666.doc -587- 201028381 藉此獲得標題化合 濾取析出之固體，使用曱醇進行清先 物（833 mg，2.50 mmol，25%)。 MS(ESI)m/z=334 (M+H)+。 LC/MS tR=2.57 min。 實施例2-3 6 N_(4_(5_氰基小甲基_4_(5•甲基咬喃_2_基）_6_側氧基]，6_ 二氫吡啶-2-基）苯基）乙醯胺 [化 2036]N-(4-Ethylphenyl)acetamide (1.77 g, 10 mmol), 5-mercaptofuran-2-formaldehyde (1_19 mL, 12 mmol) and 2-cyano group in a 20 mL microwave reaction vessel Acetic acid (3.08 g, 40 mmol) was added to a solution of methyl acetate (1.06 mL, 12 mmol) in a dioxin (3 mL), and the mixture was heated and stirred at 140 ° C for 1 min using a Biotage Optimizer reactor. . 141666.doc -587- 201028381 The title compound was obtained by filtration, and the residue was purified using decyl alcohol (833 mg, 2.50 mmol, 25%). MS (ESI) m/z = 334 (M+H)+. LC/MS tR = 2.57 min. Example 2-3 6 N_(4_(5-cyano small methyl_4_(5•methyl-bran-2-yl)_6_sideoxy],6-dihydropyridin-2-yl)phenyl) Acetamine [Chemical 2036]

向N-(4-(5-氰基-4-(5-甲基呋喃_2-基）_6_側氧基-1，6_二氫 吡啶-2-基）苯基）乙醯胺（167 mg，0.5 mm〇i)及碳酸鉀（138 mg，1.0 mmol)之DMF(2 mL)溶液中添加碘甲烷（37叫， 0.6 mmol)，於室溫下攪拌2小時。濾取析出之固體，利用 逆相等分試樣液相層析法（水/乙腈/0·3%甲酸；10-100。/。梯 度）進行純化’藉此獲得標題化合物（19.3 mg，0.056 mmol ’ 11 °/〇)，為淡黃色固體。 1H-NMR (300 MHz，DMSO-d6) δ 2.08 (s，3H)，2.38 (s，3H)， 3.29 (s, 3H), 6.46 (dd, J=〇.9 Hz, 3.6 Hz, 1H), 6.62 (s, 1H), 7.50 (d, J=8.4 Hz, 2H), 7.56 (d, J=3.6 Hz, 1H), 7.33 (d, J=8.4 Hz, 2H)，10.21 (s，ih)。 MS(ESI)m/z=348 (M+H)+。 141666.doc -588 - 201028381 LC/MS tR=1.74 min。 實施例2-37 N-(4-(5 -鼠基-4-(5 -乙基0夫咕-2 -基）-6 -側氧基-1,6 -二氮0比 啶-2-基）苯基）乙醯胺 [化 2037]To N-(4-(5-cyano-4-(5-methylfuran-2-yl)-6-sideoxy-1,6-dihydropyridin-2-yl)phenyl)acetamidamine ( To a solution of 167 mg, 0.5 mm 〇i) and potassium carbonate (138 mg, 1.0 mmol) in DMF (2 mL). The precipitated solid was collected by filtration and purified using reversed-e- s s s s s s s s s s s s s s s s s s s s s s s s s s s s ' 11 ° / 〇), a pale yellow solid. 1H-NMR (300 MHz, DMSO-d6) δ 2.08 (s, 3H), 2.38 (s, 3H), 3.29 (s, 3H), 6.46 (dd, J = 〇.9 Hz, 3.6 Hz, 1H), 6.62 (s, 1H), 7.50 (d, J=8.4 Hz, 2H), 7.56 (d, J=3.6 Hz, 1H), 7.33 (d, J=8.4 Hz, 2H), 10.21 (s, ih). MS (ESI) m / z = 348 (M+H)+. 141666.doc -588 - 201028381 LC/MS tR=1.74 min. Example 2-37 N-(4-(5-N-Mercapto-4-(5-ethyl-Of-2)-yloxy-1,6-diaza-2-pyridin-2- Phenyl) acetamidine [Chemical 2037]

標題化合物係依據實施例2-35之方法而合成。 MS(ESI)m/z=348 (M+H)+。 LC/MS tR=1.88 min。 實施例2-3 8 2-(6-(4-乙醯胺苯基）-3-氰基-4-(5-甲基呋喃-2-基）吡啶-2-醯氧基）乙酸乙酯 [化 2038]The title compound was synthesized according to the method of Example 2-35. MS (ESI) m / z = 348 (M+H)+. LC/MS tR = 1.88 min. Example 2-3 8 2-(6-(4-Ethylaminophenyl)-3-cyano-4-(5-methylfuran-2-yl)pyridin-2-yloxy)acetate [化2038]

Ο 標題化合物係依據實施例2 - 3 6之方法而合成。 MS(ESI)m/z=420 (M+H)+。 LC/MS tR=2.47 min。 實施例2-3 9 141666.doc -589- 201028381 2-(6-(4 -乙酿胺苯基）-3-乳基-4-(5-甲基0夫喃-2-基）。比咬-2-醯氧基）乙酸 [化 2039]标题 The title compound was synthesized according to the methods of Example 2 - 3 6 . MS (ESI) m / z = 420 (M + H) +. LC/MS tR = 2.47 min. Example 2-3 9 141666.doc -589- 201028381 2-(6-(4-Ethylaminophenyl)-3-lacyl-4-(5-methyloxam-2-yl). Bite-2-decyloxy)acetic acid [Chemical 2039]

標題化合物係依據實施例2-36之方法而合成。 MS(ESI)m/z=392 (M+H)+。 LC/MS tR=2.05 min。 實施例2-40 2-(6-(4-乙醯胺苯基）-3-氰基-4-(5-甲基呋喃-2-基）吡啶-2-醢氧基）乙醯胺 [化 2040]The title compound was synthesized according to the method of Example 2-36. MS (ESI) m / z = 392 (M+H)+. LC/MS tR = 2.05 min. Example 2-40 2-(6-(4-Ethylaminophenyl)-3-cyano-4-(5-methylfuran-2-yl)pyridin-2-yloxy)acetamide [ 2040]

標題化合物係依據實施例2-36之方法而合成。 MS(ESI)m/z=391 (M+H)+。 LC/MS tR=l.87 min。 實施例2-41 三氟曱磺酸6-(4-乙醯胺苯基）-3-氰基-4-(5-甲基呋喃-2-基）D比- 2 -基醋 141666.doc -590- 201028381 [化 2041]The title compound was synthesized according to the method of Example 2-36. MS (ESI) m / z = 391 (M+H)+. LC/MS tR = 1.87 min. Example 2-41 6-(4-Ethylaminophenyl)-3-cyano-4-(5-methylfuran-2-yl)D-trifluoroacetate 141666.doc -590- 201028381 [化2041]

向N-(4-(5 -乱基- 4- (5 -曱基0夫喃-2 -基）-6 -侧氧基-1,6 -二氮 。比咬-2-基）苯基）乙醯胺（4.96 g，14.9 mmol)2D比咬（100 mL)溶液中添加三氟甲績酸酐（3.76 mL，22.3 mmol)，於室 溫下攪拌2小時。將反應溶液放入至水中，濾取析出之固 體，使用乙酸乙酯進行清洗，藉此獲得標題化合物（5.38 g，11.6 mmol，78%)，為黃色固體。 MS(ESI)m/z=466 (M+H)+。 LC/MS tR=2.81 min 〇 實施例2-42 N-(4-(5 -氮基- 4-(5 -甲基0夫0南-2 -基）-6-(N-嗎琳基）nit 〇定- 2-基）苯基）乙醯胺 [化 2042]To N-(4-(5-disorganyl-4-(5-fluorenyl)-oxa-2-yl)-6-o-oxy-1,6-diaza. Ethylamine (4.96 g, 14.9 mmol) 2D was added to a solution of bite (100 mL), trifluoromethane anhydride (3.76 mL, 22.3 mmol), and stirred at room temperature for 2 hours. The reaction solution was poured into water, and the crystals crystals crystals crystals crystals crystals MS (ESI) m / z = 466 (M+H)+. LC/MS tR = 2.81 min 〇 Example 2-42 N-(4-(5-Aza- 4-(5-methyl-O-O-O-N-N-yl)-6-(N-Merline) Nit -定- 2-yl)phenyl)acetamidine [Chemical 2042]

向三氟甲磺酸6-(4-乙醯胺苯基）-3-氰基-4-(5-曱基呋喃-2-基）D比咬-2-基 S旨（93 mg，0.2 mmol)及碳酸鉀（41 mg， 141666.doc -591 - 201028381 0.30 mmol)之 DMA(1 mL)溶液中添加嗎琳（21 μι 5 0.24 mmol)，於室溫下授拌4小時。將反應溶液放入至水中，滤 取析出之固體，使用乙酸乙酯進行清洗，藉此獲得標題化 合物（40.5 mg，0.10 mmol，50%)，為黃色固體。 MS(ESI)m/z=403 (M+H)+。 LC/MS tR=2.38 min。 實施例2-43 N-(4-(6-胺基-5-氰基-4-(5-曱基呋喃-2-基）吼啶-2-基）苯 基）乙醯胺 [化 2043]To 6-(4-acetamidophenyl)-3-cyano-4-(5-fluorenylfuran-2-yl)D trifluoromethanesulfonate ratio (93 mg, 0.2) Methyl (21 μιη 5 0.24 mmol) was added to a solution of potassium carbonate (41 mg, 141666.doc -591 - 201028381 0.30 mmol) in DMA (1 mL) and stirred at room temperature for 4 hours. The reaction solution was poured into water, and the obtained solid crystals were evaporated. MS (ESI) m / z = 403 (M + H)+. LC/MS tR = 2.38 min. Example 2-43 N-(4-(6-Amino-5-cyano-4-(5-fluorenylfuran-2-yl)acridin-2-yl)phenyl)acetamide [Chemical 2043] ]

於20 mL微波反應容器中，向N-(4-乙醯基苯基）乙醯胺 (1.0 g，5.64 mmol)、5-曱基0夫喃-2-曱搭（746 mg，6.77 mmol)及丙二腈（447 mg，6.77 mmol)之二 口惡烧（10 mL)溶液 中添加乙酸銨（2.17 g，28.2 mmol)進行覆蓋，使用Biotage Optimizer反應裝置，於150°C下加熱授拌1〇分鐘。渡取析 出之固體，使用甲醇進行清洗，藉此獲得標題化合物（597 mg，1.80 mmol，32%)。 1H-NMR (300 MHz, DMSO-d6) δ 2.08 (s, 3Η), 2.41 (s, 3H), 6.41 (dd, 1H), 6.89 (br, 2H), 7.41 (d, J=3.6 Hz, 1H), 7.44 (s, 1H), 7.71 (d, J=8.7 Hz, 2H), 8.06 (d, J=8.7 Hz, 2H), 141666.doc -592- 201028381 10.16 (br，1H)。 實施例2-44 N-(4-(5 -氰基-6-乙氧基-4-(*Ό南-3-基）n比咬_2_基）苯美）乙 醯胺 [化 2044]N-(4-Ethylphenyl)acetamide (1.0 g, 5.64 mmol) in a 20 mL microwave reaction vessel, 5-fluorenyl ketone-2-sulfonate (746 mg, 6.77 mmol) Ammonium acetate (2.17 g, 28.2 mmol) was added to a solution of malondionitrile (447 mg, 6.77 mmol) in two cauldrons (10 mL), and the mixture was heated at 150 ° C using a Biotage Optimizer reactor. Minutes. The precipitated solid was taken and washed with methanol to give the title compound (597 mg, 1.80 mmol, 32%). 1H-NMR (300 MHz, DMSO-d6) δ 2.08 (s, 3 Η), 2.41 (s, 3H), 6.41 (dd, 1H), 6.89 (br, 2H), 7.41 (d, J = 3.6 Hz, 1H ), 7.44 (s, 1H), 7.71 (d, J=8.7 Hz, 2H), 8.06 (d, J=8.7 Hz, 2H), 141666.doc -592- 201028381 10.16 (br, 1H). Example 2-44 N-(4-(5-Cyano-6-ethoxy-4-(*Ό南-3-yl)n ratio _2_yl) phenylene) acetamidine [Chemical 2044] ]

標題化合物係依據實施例2-12之方法而合成。 1H-NMR (300 MHz，DMSO-d6) δ 1_43 (t，j=7.i Hz，3H)， 2.09 (s, 3H), 4.61 (q, J=7.1 Hz, 2H), 7.27 (d, J=1.0 Hz, 1H), 7.75 (d, J=8.7 Hz, 2H), 7.85 (s, 1H), 7.95 (d, J=1.0The title compound was synthesized according to the method of Example 2-12. 1H-NMR (300 MHz, DMSO-d6) δ 1_43 (t,j=7.i Hz, 3H), 2.09 (s, 3H), 4.61 (q, J=7.1 Hz, 2H), 7.27 (d, J =1.0 Hz, 1H), 7.75 (d, J=8.7 Hz, 2H), 7.85 (s, 1H), 7.95 (d, J=1.0

Hz, 1H), 8.22 (d, J=8.7 Hz, 2H), 8.57 (s, 1H), 10.24 (s 1H)。 實施例2-45 6-(4-溴苯基）-2-曱氧基-4-苯基菸鹼腈 [化 2045]Hz, 1H), 8.22 (d, J=8.7 Hz, 2H), 8.57 (s, 1H), 10.24 (s 1H). Example 2-45 6-(4-Bromophenyl)-2-decyloxy-4-phenylnicotinonitrile [Chem. 2045]

標題化合物係依據實施例2-12之方法而合成。 1H-NMR (300 MHz, CDC13) δ 4.20 (s，3H)，7 46 (s，1H)， 7.50-7.58 (m，3H)，7.60-7.68 (m，4H)，7.98 (d, J=8 5 Hz， 141666.doc •593- 201028381 2H)。 實施例2 - 4 6 6-(4-胺基苯基）-2-甲氧基-4-苯基菸鹼腈 [化 2046]The title compound was synthesized according to the method of Example 2-12. 1H-NMR (300 MHz, CDC13) δ 4.20 (s, 3H), 7 46 (s, 1H), 7.50-7.58 (m, 3H), 7.60-7.68 (m, 4H), 7.98 (d, J=8 5 Hz, 141666.doc •593- 201028381 2H). Example 2 - 4 6 6-(4-Aminophenyl)-2-methoxy-4-phenylnicotinonitrile [Chemical 2046]

標題化合物係依據實施例2-12之方法而合成。 1H-NMR (300 MHz, CDC13) δ 3.99 (br s, 2H), 4.18 (s, 3H), 6.76 (d, J=8.5 Hz, 2H), 7.36 (s, 1H), 7.48-7.57 (m, 3H), 7.61-7.68 (m, 2H), 7.97 (d，J=8.5 Hz, 2H)。 實施例2-47 N-(4-(5-氰基-6-甲氧基-4-苯基咕啶-2-基）苯基）乙醯胺 [化 2047]The title compound was synthesized according to the method of Example 2-12. 1H-NMR (300 MHz, CDC13) δ 3.99 (br s, 2H), 4.18 (s, 3H), 6.76 (d, J = 8.5 Hz, 2H), 7.36 (s, 1H), 7.48-7.57 (m, 3H), 7.61-7.68 (m, 2H), 7.97 (d, J = 8.5 Hz, 2H). Example 2-47 N-(4-(5-Cyano-6-methoxy-4-phenylacridin-2-yl)phenyl)acetamide [Chem. 2047]

標題化合物係依據實施例2-12之方法而合成。 1H-NMR (300 MHz，DMSO-d6) δ 2.09 (s，3H)，4,15 (s，3H), 7.57-7.65 (m, 3H), 7.71-7.79 (m, 5H), 8.25 (d, J=8.4 Hz, 2H), 10.22 (s，1H)。 實施例2-48 Ν-(4·(5-氰基-6-曱氧基-4-苯基&quot;比啶-2-基）笨基）甲確醯胺 141666.doc •594- 201028381 [化 2048]The title compound was synthesized according to the method of Example 2-12. 1H-NMR (300 MHz, DMSO-d6) δ 2.09 (s, 3H), 4, 15 (s, 3H), 7.57-7.65 (m, 3H), 7.71-7.79 (m, 5H), 8.25 (d, J = 8.4 Hz, 2H), 10.22 (s, 1H). Example 2-48 Ν-(4·(5-Cyano-6-fluorenyloxy-4-phenyl&quot;bipyridin-2-yl)phenyl)carbazide 141666.doc •594- 201028381 [ 2048]

標題化合物係依據實施例2 -12之方法而合成β 1H-NMR (300 MHz，DMSO-d6) δ 3.09 (s，3Η)，4.15 〇 3Η) 7.34 (d，J=8.4 Hz, 2Η)，7.55-7.65 (m，3Η)，7.70-7.78 (m 3Η)，8.26 (d，J=8.4 Ηζ，2Η)，10.14 (s，1Η)。 實施例2-49 6-(4-溴苯基）-2-甲氧基-4-(嗟吩-2-基）於驗腈 [化 2049]The title compound was synthesized according to the method of Example 2-12 to synthesize β 1H-NMR (300 MHz, DMSO-d6) δ 3.09 (s, 3 Η), 4.15 〇 3 Η) 7.34 (d, J = 8.4 Hz, 2 Η), 7.55 -7.65 (m, 3 Η), 7.70-7.78 (m 3 Η), 8.26 (d, J = 8.4 Ηζ, 2 Η), 10.14 (s, 1 Η). Example 2-49 6-(4-Bromophenyl)-2-methoxy-4-(porphin-2-yl) in the nitrile [Chemical 2049]

標題化合物係依據實施例2-1 2之方法而合成。 1H-NMR (300 MHz, CDC13) δ 4.18 (s, 3H), 7.22 (t, J=4.5 Hz, 1H), 7.53 (s, 1H), 7.56 (d, J=4.5 Hz, 1H), 7.63 (d, J=7.7 Hz, 2H), 7.92-7.99 (m，3H)。 實施例2-50 6-(4_胺基苯基）-2-甲氧基-4-(噻吩-2-基）菸鹼腈 [化 2050]The title compound was synthesized according to the method of Example 2-1. 1H-NMR (300 MHz, CDC13) δ 4.18 (s, 3H), 7.22 (t, J=4.5 Hz, 1H), 7.53 (s, 1H), 7.56 (d, J=4.5 Hz, 1H), 7.63 ( d, J = 7.7 Hz, 2H), 7.92-7.99 (m, 3H). Example 2-50 6-(4-Aminophenyl)-2-methoxy-4-(thiophen-2-yl)nicotinonitrile [Chemical 2050]

141666.doc -595- 201028381 標題化合物係依據實施例2-12之方法而合成。 1H-NMR (300 MHz, CDC13) δ 4.16 (s, 3H), 6.88 (d, J=8.6 Hz, 2H), 7.21 (dd, J=5.1, 3.8 Hz, 1H), 7.48 (s, 1H), 7.57 (dd, J=5.1, 1.1 Hz, 1H), 7.88 (dd, J=3.8, 1.1 Hz, 1H), 7.96 (d, J=8.6 Hz, 2H) ° 實施例2-51 N-(4-( 5-氰基_6_曱氧基-4-(嘆吩-2 -基）〇比咬-2 -基）苯基）乙 醯胺 [化 2051]141666.doc -595- 201028381 The title compound was synthesized according to the method of Example 2-12. 1H-NMR (300 MHz, CDC13) δ 4.16 (s, 3H), 6.88 (d, J = 8.6 Hz, 2H), 7.21 (dd, J=5.1, 3.8 Hz, 1H), 7.48 (s, 1H), 7.57 (dd, J=5.1, 1.1 Hz, 1H), 7.88 (dd, J=3.8, 1.1 Hz, 1H), 7.96 (d, J=8.6 Hz, 2H) ° Example 2-51 N-(4- (5-cyano-6-indolyl-4-(infrath-2-yl)pyridinyl-2)-phenyl)acetamidamine [Chemical 2051]

標題化合物係依據實施例2-12之方法而合成。 MS(ESI)m/z=350 (M+H)+。 LC/MS tR=2.32 min。 實施例2-52 N-(4-(5-氟基-6-甲氧基- 4-(β塞吩-2-基）〇比咬_2_基）苯義）甲 石黃酿胺 [化 2052]The title compound was synthesized according to the method of Example 2-12. MS (ESI) m / z = 350 (M + H) +. LC/MS tR = 2.32 min. Example 2-52 N-(4-(5-Fluoro-6-methoxy-4-(β-cephen-2-yl)pyridinyl)-2-phenyl)pyrene) 2052]

標題化合物係依據實施例2-12之方法而合成。 141666.doc •596- 201028381 1H-NMR (300 MHz, DMSO-d6) δ 3.09 (s, 3H), 4.13 (s, 3H), 7.34 (dd, J=4.9, 3.6 Hz, 1H), 7.35 (d, J=8.8 Hz, 2H), 7.84 (s, 1H), 7.97 (d, J=4.9 Hz, 1H), 8.00 (d, J=3.6 Hz, 1H), 8.25 (d, J=8.8 Hz，2H)，10.16 (s, 1H)。 實施例2-53 N-(4-(5-氰基-6-甲氧基-4-(1-甲基-1H-&quot;比咯-2-基）》比啶-2-基）苯基）乙醯胺 [化 2053]The title compound was synthesized according to the method of Example 2-12. 141666.doc •596- 201028381 1H-NMR (300 MHz, DMSO-d6) δ 3.09 (s, 3H), 4.13 (s, 3H), 7.34 (dd, J=4.9, 3.6 Hz, 1H), 7.35 (d , J=8.8 Hz, 2H), 7.84 (s, 1H), 7.97 (d, J=4.9 Hz, 1H), 8.00 (d, J=3.6 Hz, 1H), 8.25 (d, J=8.8 Hz, 2H ), 10.16 (s, 1H). Example 2-53 N-(4-(5-Cyano-6-methoxy-4-(1-methyl-1H-&quot;bibut-2-yl)"pyridin-2-yl)benzene Ethylamine (Chemical 2053)

標題化合物係依據實施例2-12之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 2.09 (s, 3H), 3.75 (s, 3H), 4.12 (s, 3H), 6.22 (dd, J=3.5, 1.6 Hz, 1H), 6.60 (dd, J=3.5, 1.5 Hz, 1H), 7.11 (dd, J=1.5, 1.6 Hz, 1H), 7.68 (s, 1H), 7.74 φ (d，J=8.5 Hz, 2H)，8.22 (d，J=8.5 Hz，2H)，10.21 (s，1H)。 實施例2-54 6-(4-溴苯基）-2-甲氧基-4·(1Η-»比咯-2-基）菸鹼腈 [化 2054]The title compound was synthesized according to the method of Example 2-12. 1H-NMR (300 MHz, DMSO-d6) δ 2.09 (s, 3H), 3.75 (s, 3H), 4.12 (s, 3H), 6.22 (dd, J=3.5, 1.6 Hz, 1H), 6.60 (dd , J=3.5, 1.5 Hz, 1H), 7.11 (dd, J=1.5, 1.6 Hz, 1H), 7.68 (s, 1H), 7.74 φ (d, J=8.5 Hz, 2H), 8.22 (d, J = 8.5 Hz, 2H), 10.21 (s, 1H). Example 2-54 6-(4-Bromophenyl)-2-methoxy-4·(1Η-»Byr-2-yl)nicotinonitrile [Chemical 2054]

標題化合物係依據實施例2-12之方法而合成。 141666.doc •597· 201028381 1H-NMR (300 MHz, DMSO-d6) δ 4.13 (s, 3H), 6.39 (dd, J=3.6, 1.5 Hz, 1H), 7.30 (d, J=1.5 Hz, 1H), 7.34 (d, J=3.6 Hz, 1H), 7.82 (d, J=8.8 Hz, 2H), 8.05 (s, 1H), 8.22 (d, J = 8.8 Hz，2H)。 實施例2-55 N-(4-(5-氰基-6-曱氧基-4-(1 Η-&quot;比咯-2-基）》比啶-2-基）苯 基）乙醯胺 [化 2055]The title compound was synthesized according to the method of Example 2-12. 141666.doc •597· 201028381 1H-NMR (300 MHz, DMSO-d6) δ 4.13 (s, 3H), 6.39 (dd, J=3.6, 1.5 Hz, 1H), 7.30 (d, J=1.5 Hz, 1H ), 7.34 (d, J=3.6 Hz, 1H), 7.82 (d, J=8.8 Hz, 2H), 8.05 (s, 1H), 8.22 (d, J = 8.8 Hz, 2H). Example 2-55 N-(4-(5-Cyano-6-fluorenyl-4-(1 Η-&quot;birol-2-yl)"pyridin-2-yl)phenyl)acetamidine Amine [Chemical 2055]

標題化合物係依據實施例2-12之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 2.09 (s, 3H), 4.09 (s, 3H), 6.32-6.37 (m, 1H), 7.21-7.30 (m, 2H), 7.75 (d, J=8.6 Hz, 2H), 7.92 (s, 1H), 8.19 (d, J=8.6 Hz, 2H), 10.21 (s, 1H), 11.97 (s，1H)。 0 實施例2-56 N-(4-(5-氰基-6-乙基胺基_4-(lH-°比咯-2·基）°比啶-2-基）苯 基）乙醯胺 [化 2056]The title compound was synthesized according to the method of Example 2-12. 1H-NMR (300 MHz, DMSO-d6) δ 2.09 (s, 3H), 4.09 (s, 3H), 6.32-6.37 (m, 1H), 7.21-7.30 (m, 2H), 7.75 (d, J = 8.6 Hz, 2H), 7.92 (s, 1H), 8.19 (d, J=8.6 Hz, 2H), 10.21 (s, 1H), 11.97 (s, 1H). 0 Example 2-56 N-(4-(5-Cyano-6-ethylamino] 4-(lH-°pyrrol-2-yl)-pyridin-2-yl)phenyl)acetamidine Amine [Chemical 2056]

141666.doc -598· 201028381 標題化合物係依據實施例2-42之方法而合成。 MS(ESI)m/z=346 (M+H)+。 LC/MS tR=2.25 min 〇 實施例2-57 N-(4-(6-胺基-5-氰基-4-(1Η-。比咯-2-基）°比啶-2-基）苯基） 乙醯胺 [化 2057]141666.doc -598· 201028381 The title compound was synthesized according to the method of Example 2-42. MS (ESI) m / z = 346 (M + H) +. LC/MS tR=2.25 min 〇 Example 2-57 N-(4-(6-Amino-5-cyano-4-(1Η-.pyr-2-yl))pyridin-2-yl) Phenyl) acetamidine [Chemical 2057]

標題化合物係依據實施例2-43之方法而合成。 MS(ESI)m/z=318 (M+H)+。 LC/MS tR=l.44 min。 實施例2-5 8 N-(4-(5-氰基-6-甲氧基-4-(5-甲基異噁唑-3-基）吡啶-2-基）苯基）乙醯胺 [化 2058]The title compound was synthesized according to the method of Example 2-43. MS (ESI) m / z = 318 (M + H) +. LC/MS tR = 1.44 min. Example 2-5 8 N-(4-(5-Cyano-6-methoxy-4-(5-methylisoxazol-3-yl)pyridin-2-yl)phenyl)acetamide [化2058]

MeMe

標題化合物係依據實施例2-12之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 2.09 (s, 3H), 2.55 (s, 3H), 4.15 (s, 3H), 7.00 (s, 1H), 7.76 (d, J=8.7 Hz, 2H), 7.95 (s, 141666.doc -599- 201028381 1H), 8.24 (d, J=8.7 Hz, 2H), 10.26 (s, 1H) 〇 實施例2-59 6-胺基-4-(呋喃_2-基）-2-甲氧基菸鹼腈 [化 2059]The title compound was synthesized according to the method of Example 2-12. 1H-NMR (300 MHz, DMSO-d6) δ 2.09 (s, 3H), 2.55 (s, 3H), 4.15 (s, 3H), 7.00 (s, 1H), 7.76 (d, J = 8.7 Hz, 2H ), 7.95 (s, 141666.doc -599- 201028381 1H), 8.24 (d, J=8.7 Hz, 2H), 10.26 (s, 1H) 〇Example 2-59 6-Amino-4-(furan_ 2-yl)-2-methoxynicotinonitrile [Chemical 2059]

1) NaOMe, MeOH,回流 2) DDQ,曱笨，回流1) NaOMe, MeOH, reflux 2) DDQ, stupid, reflux

向2-°夫喃丙烯腈（5.〇 g，42.0 mmol)及丙二腈（2.77 g， 42.0 mmol)之曱醇（2〇〇 mL)溶液中添加甲醇鈉（2 27邑， 42.0 mm0|)，於加熱回流下攪拌8小時。向反應溶液中添加 水及乙酸乙酯進行分離後，以乙酸乙酯萃取水相。將合併 之有機相以碳酸氫鈉水溶液及飽和食鹽水進行清洗，以硫 酸鎂加以乾燥。將有機相過濾後，進行減壓濃縮，利用中 壓矽膠層析法（己烷/乙酸乙酯；50_80%梯度）對所獲得之殘 渣進行純化，藉此獲得淡黃色固體（2.83 g)。 向所獲得之化合物之甲苯（120 mL)溶液中添加dDq(2 96 g，13.0 mmol)，於加熱回流下攪拌2小時。向反應溶液中 添加二噁烷（100 mL)，將不溶物過濾分離後，進行減壓濃 縮。以曱醇/水使所獲得之殘渣固化，藉此獲得標題化人 物（2.75 g，12.8 mmol，30%)，為淡黃色固體。 1H-NMR (300 MHz, DMSO-d6) δ 3.60 (s, 3H), 6.03.6 09 (m, 1H), 6.33-6.35 (m, 1H), 7.55 (s, 1H), 8.〇2 (brs5 1H), 8· 13 (brs，1H) o 實施例2 - 6 0 14l666.doc •600· 201028381 4-乙醯胺-N-(5-氰基-4-(呋喃-2-基）-6-甲氧基吨啶-2-基） 苯甲醯胺 [化 2060]Add sodium methoxide (2 27 邑, 42.0 mm0|) to a solution of 2-° acrylonitrile (5. g, 42.0 mmol) and malononitrile (2.77 g, 42.0 mmol) in methanol (2 mL) The mixture was stirred under heating and reflux for 8 hours. After adding water and ethyl acetate to the reaction solution for separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with aqueous sodium hydrogencarbonate solution and brine, and dried over magnesium sulfate. After the organic phase was filtered, the residue was evaporated, mjjjjjjj dDq (2 96 g, 13.0 mmol) was added to a solution of the obtained compound in toluene (120 mL), and the mixture was stirred under reflux for 2 hours. Dioxane (100 mL) was added to the reaction solution, and the insoluble material was separated by filtration and then concentrated under reduced pressure. The residue obtained was solidified with decyl alcohol / water to give titled product (2.75 g, 12.8 mmol, 30%) as pale yellow solid. 1H-NMR (300 MHz, DMSO-d6) δ 3.60 (s, 3H), 6.03.6 09 (m, 1H), 6.33-6.35 (m, 1H), 7.55 (s, 1H), 8.〇2 ( Brs5 1H), 8· 13 (brs, 1H) o Example 2 - 6 0 14l666.doc •600· 201028381 4-Acetylamine-N-(5-cyano-4-(furan-2-yl)- 6-methoxy oxaridin-2-yl) benzamide [Chemical 2060]

標題化合物係使用6-胺基-4-( β夫喃-2-基）-2-甲氧基终驗腈 及對應之羧酸，依據實施例2-26之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 2.13 (s, 3H), 4.08 (s, 3H), 6.84 (dd, J=3.5, 1.8 Hz, 1H), 7.51 (d, J=3.5 Hz, 1H), 7.75 (d, J=8.7 Hz, 2H), 8.02 (d, J=8.7 Hz, 2H), 8.08 (d, J=1.8 Hz，1H), 8·38 (s，1H)，10.34 (s，1H)。 實施例2-61 4-溴-N-(5-氰基-4-(呋喃-2-基）-6-甲氧基&quot;比啶-2-基）苯甲 醯胺 [化 2061]The title compound was synthesized according to the method of Example 2-26 using 6-amino-4-(β-f- -2-yl)-2-methoxyl. 1H-NMR (300 MHz, DMSO-d6) δ 2.13 (s, 3H), 4.08 (s, 3H), 6.84 (dd, J=3.5, 1.8 Hz, 1H), 7.51 (d, J=3.5 Hz, 1H ), 7.75 (d, J=8.7 Hz, 2H), 8.02 (d, J=8.7 Hz, 2H), 8.08 (d, J=1.8 Hz, 1H), 8·38 (s, 1H), 10.34 (s , 1H). Example 2-61 4-Bromo-N-(5-cyano-4-(furan-2-yl)-6-methoxy&quot;bipyridin-2-yl)benzamide [Chem. 2061]

標題化合物係使用6-胺基-4-(吱喃-2-基）-2-曱氧基終驗腈 及對應之羧酸，依據實施例2-26之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 4.08 (s, 3H), 6.85 (dd, J=3.6, 1.6 Hz, 1H), 7.53 (d, J=3.6 Hz, 1H), 7.80 (d, J=8.5 141666.doc -601- 201028381The title compound was synthesized according to the method of Example 2-26 using 6-amino-4-(indol-2-yl)-2-decyloxyl. 1H-NMR (300 MHz, DMSO-d6) δ 4.08 (s, 3H), 6.85 (dd, J = 3.6, 1.6 Hz, 1H), 7.53 (d, J = 3.6 Hz, 1H), 7.80 (d, J =8.5 141666.doc -601- 201028381

Hz，2H)，7.98 (d，J=8.5 Hz，2H)，8·10 (d, J=1.6 Hz，1H)， 8.38 (s，1H)，11.21 (s，1H)。 實施例2-62 2-(4-乙醯胺苯基）-Ν·(5-氰基-4-(呋喃-2-基）-6-甲氧基0比 啶-2-基）乙醯胺 [化 2062]Hz, 2H), 7.98 (d, J = 8.5 Hz, 2H), 8·10 (d, J = 1.6 Hz, 1H), 8.38 (s, 1H), 11.21 (s, 1H). Example 2-62 2-(4-Ethylaminophenyl)-indole·(5-cyano-4-(furan-2-yl)-6-methoxy 0-pyridin-2-yl)acetamidine Amine [Chemical 2062]

標題化合物係使用6-胺基-4-(呋喃-2-基）-2-甲氧基菸鹼猜 及對應之羧酸，依據實施例2-26之方法而合成。 1H-NMR (300 MHz, CDC13) δ 2.15 (s，3H)，3.76 (s，2H) 3.99 (s, 3Η)，6.58 (dd，J=3.2，1.3 Hz, 1Η)，7.29 (d，J=8.4The title compound was synthesized according to the method of Example 2-26 using 6-amino-4-(furan-2-yl)-2-methoxynicotinate as the corresponding carboxylic acid. 1H-NMR (300 MHz, CDC13) δ 2.15 (s, 3H), 3.76 (s, 2H) 3.99 (s, 3Η), 6.58 (dd, J=3.2, 1.3 Hz, 1Η), 7.29 (d, J= 8.4

Hz, 2H), 7.49 (d, J=3.2 Hz, 1H), 7.57-7.63 (m, 3H), 8.31 (s&gt; 1H)，9.00 (s，1H)，9.06 (s，1H)。 實施例2-63 5-氰基-4-(呋喃-2·基）-6-曱氧基-N-(4-甲氧基苄基）曱基 0比唆酿胺 實施例2-64 4-(呋喃-2-基）-2-曱氧基-6-(4-甲氧基苄基胺基）菸鹼腈 [化 2063]Hz, 2H), 7.49 (d, J=3.2 Hz, 1H), 7.57-7.63 (m, 3H), 8.31 (s&gt; 1H), 9.00 (s, 1H), 9.06 (s, 1H). Example 2-63 5-Cyano-4-(furan-2yl)-6-methoxy-N-(4-methoxybenzyl)indenyl 0 to anthraquinone Example 2-64 4 -(furan-2-yl)-2-decyloxy-6-(4-methoxybenzylamino)nicotinonitrile [Chemical 2063]

141666.doc •602· 201028381141666.doc •602· 201028381

步驟1 : 6-溴-4-(呋喃-2-基）-2-甲氧基菸鹼腈 向6-胺基-4-(吱鳴-2-基）-2-甲氧基於驗腈（215 mg，1.〇〇 mmol)及埃化銅（186 mg，1.30 mmol)之乙腈（8 mL)溶液中 添加亞硝酸第三丁酯（134 mg，0.152 mol)，於50°C下授拌 籲 6小時。將反應溶液以氯仿稀釋後，過濾不溶物，進行減 壓濃縮。利用中壓矽膠層析法（己烷/乙酸乙酯；20-50%梯 度）對所獲得之殘渣進行純化，獲得標題化合物（148 mg， 0.53 mmol，53%)，為黃色固體。 1H-NMR (300 MHz, CDC13) δ 4.07 (s, 3Η), 6.60-6.61 (m, 1H), 7·57 (s, 1H)，7.59-7.62 (m，2H)。 步驟2 :標題化合物 向6·溴-4-(咬喃-2-基）-2-甲氧基菸鹼腈（5〇 mg，〇.179 φ mmo1)、pdCl2(PPh3)2(19 mg，0.027 mmol)、二苯基膦基丙 烧（11.1 mg ’ 0.027 mmol)及三乙基胺（90.6 mg，0.125 mmol)之DMF(2 mL)溶液中添加4_甲氧基苄基胺（27 mg， 0·19 mol)，於8(TC下攪拌6小時。向反應溶液中添加水及 乙酸乙酯進行分離後，以乙酸乙酯萃取水相，將合併之有 機相以水及飽和食鹽水進行清洗，以硫酸鎂加以乾燥。將 有機相過濾後，進行減壓濃縮，利用中壓矽膠層析法（己 烷/乙酸乙酯；10-50°/。梯度）對所獲得之殘渣進行純化，獲 得5-氰基-4-(呋喃_2_基）_6_甲氧基_N(4甲氧基苄基）甲基 141666.doc •603- 201028381 0比咬醯胺（21.0 mg，0_057 mmol，32%) ’為淡黃色固體； 又，獲得夫喃-2-基）-2-甲氧基-6-(4-甲氧基苄基胺基）於 鹼腈（24.8 mg，0.074 mmo卜 41%)，為黃色油。 5 -氛基-4-( β夫喃-2-基）-6-甲氧基-N-(4-甲氧基节基）甲基 吡啶醯胺之物性資料： 1H-NMR (300 MHz, CDC13) δ 3.84 (s, 3H), 4.10 (Sj 3H), 4.66 (d, 3=6.2 Hz, 2H), 6.67 (dd, J=3.7, 1.7 Hz, 1H), 6.93 (d, J=8.7 Hz, 2H), 7.33 (d, J=8.7 Hz, 2H), 7.65 (d, J = 3.7 Hz, 1H), 7.72 (d, J=1.7 Hz, 1H), 7.96-7.99 (br m, 1H), 8.34 (s, 1H) 〇 4-(呋喃-2-基）-2-曱氧基-6-(4-甲氧基苄基胺基）菸鹼腈之 物性資料： 1H-NMR (300 MHz, CDC13) δ 3.84 (s, 3H), 4.01 (s, 3H), 4.55 (s, 2H), 6.47 (s, 1H), 6.57 (dd, J=3.6, 1.8 Hz, 1H), 6.92 (d, J=8.7 Hz, 2H), 7.30 (d, J=8.7 Hz, 2H), 7.51 (d, J=3.6 Hz, 1H), 7.55 (d，J=1.8 Hz, 1H)。 實施例2-65 N-(4-(4-胺基-5-氰基-6-甲氧基》比啶-2-基）苯基）乙醯胺 [化 2065]Step 1: 6-Bromo-4-(furan-2-yl)-2-methoxynicotinonitrile to 6-amino-4-(oxime-2-yl)-2-methoxyl Add butyl nitrite (134 mg, 0.152 mol) to a solution of 215 mg, 1. 〇〇mmol) and copper (186 mg, 1.30 mmol) in acetonitrile (8 mL) and mix at 50 °C. Call for 6 hours. After the reaction solution was diluted with chloroform, the insoluble material was filtered and concentrated under reduced pressure. The residue was purified using EtOAc EtOAc (EtOAc:EtOAc: 1H-NMR (300 MHz, CDC13) δ 4.07 (s, 3 Η), 6.60-6.61 (m, 1H), 7·57 (s, 1H), 7.59-7.62 (m, 2H). Step 2: The title compound is given to bromo-4-(bromo-2-yl)-2-methoxynicotinonitrile (5 〇 mg, 〇.179 φ mmo1), pdCl 2 (PPh3) 2 (19 mg, Add 4-methoxybenzylamine (27 mg) to a solution of 0.027 mmol), diphenylphosphinopropane (11.1 mg '0.027 mmol) and triethylamine (90.6 mg, 0.125 mmol) in DMF (2 mL) , 0·19 mol), stirred at 8 (TC for 6 hours). After adding water and ethyl acetate to the reaction solution for separation, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were taken with water and saturated brine. After washing, it was dried over magnesium sulfate, and the organic phase was filtered, and concentrated under reduced pressure, and the residue obtained was purified by medium pressure gel chromatography (hexane/ethyl acetate; 10-50 ° / gradient). Obtained 5-cyano-4-(furan-2-yl)-6-methoxy_N(4-methoxybenzyl)methyl 141666.doc • 603- 201028381 0-bite guanamine (21.0 mg, 0_057 mmol , 32%) 'as a pale yellow solid; again, obtained fufen-2-yl)-2-methoxy-6-(4-methoxybenzylamino) in alkali nitrile (24.8 mg, 0.074 mmo 41%), yellow oil. Physical properties of 5-amino-4-(β-furan-2-yl)-6-methoxy-N-(4-methoxyoxy)methylpyridiniumamine: 1H-NMR (300 MHz, CDC13) δ 3.84 (s, 3H), 4.10 (Sj 3H), 4.66 (d, 3=6.2 Hz, 2H), 6.67 (dd, J=3.7, 1.7 Hz, 1H), 6.93 (d, J=8.7 Hz (2, H), 7. 8.34 (s, 1H) Physical properties of 4-(furan-2-yl)-2-decyloxy-6-(4-methoxybenzylamino)nicotinonitrile: 1H-NMR (300 MHz, CDC13) δ 3.84 (s, 3H), 4.01 (s, 3H), 4.55 (s, 2H), 6.47 (s, 1H), 6.57 (dd, J=3.6, 1.8 Hz, 1H), 6.92 (d, J =8.7 Hz, 2H), 7.30 (d, J=8.7 Hz, 2H), 7.51 (d, J=3.6 Hz, 1H), 7.55 (d, J=1.8 Hz, 1H). Example 2-65 N-(4-(4-Amino-5-cyano-6-methoxy)pyridin-2-yl)phenyl)acetamide [Chem. 2065]

T幻 ----- me n me r* Η Η 向三氟曱磺酸4-胺基-5-氱基-6·甲氧基°比啶-2-基酯（60 mg，0.202 mmol)、Pd(PPh3)4(ll_6 mg，0.010 mmol)及 2 141666.doc -604- 201028381 mol/L 碳酸納水溶液（〇4 mL，〇.g〇8 mmol)之 THF(1.5 mL) 溶液中添加4-乙醯胺苯基硼酸頻哪醇酯（79 ，0.303 mol)，於加熱回流下攪拌4小時。向反應溶液中添加水及 乙酸乙醋進行分離後’以乙酸乙酯萃取水相，將合併之有 機相以水及飽和食鹽水進行清洗，以硫酸鎂加以乾燥。將 有機相過濾後’進行減壓濃縮，以乙酸乙酯使所獲得之殘 /查固化，藉此獲得標題化合物（41 mg，0.145 mmol，T------ me n me r* Η 4- 4-Amino-5-mercapto-6-methoxy-pyridin-2-yl trifluorosulfonate (60 mg, 0.202 mmol) , Pd(PPh3)4(ll_6 mg, 0.010 mmol) and 2 141666.doc -604- 201028381 mol/L sodium carbonate aqueous solution (〇4 mL, 〇.g〇8 mmol) in THF (1.5 mL) Ethylamine phenylboronic acid pinacol ester (79, 0.303 mol) was stirred under heating and reflux for 4 hours. After adding water and ethyl acetate to the reaction solution for separation, the aqueous phase was extracted with ethyl acetate, and the combined organic phases were washed with water and saturated brine and dried over magnesium sulfate. After the organic phase was filtered, the title compound (41 mg, 0.145 mmol,

6.81 (s, 1H), 6.98 (br, 2H), 7.67 (d, J=8.7 Hz, 2H), 7.88 (d, J=8.7 Hz，2H), 10.10 (s，iH)。 實施例2-66 N-(4-(4-乙醯胺-5-氰基_6-甲氧基吡啶-2-基）苯基）乙醯胺 [化 2066]6.81 (s, 1H), 6.98 (br, 2H), 7.67 (d, J=8.7 Hz, 2H), 7.88 (d, J=8.7 Hz, 2H), 10.10 (s, iH). Example 2-66 N-(4-(4-Ethylamine-5-cyano-6-methoxypyridin-2-yl)phenyl)acetamide [Chem. 2066]

標題化合物係使用N-(4-(4-胺基-5-氰基-6-甲氧基吡啶-2-基）苯基）乙醯胺，利用實施例2-26之方法進行乙醯化而合 成。 1H-NMR (3〇〇 MHz, DMSO-d6) δ 2.08 (s, 3H), 2.49 (s, 3H), 4.08 (s, 3H), 7.74 (d, J=9.0 Hz, 2H), 7.99-8.03 (m, 3H), 10.19 (s, 1H), 10.39 (s, 1H)。 141666.doc -605 · 201028381 實施例2-67 N-(4-(4-胺基-5-氰基-6-乙氧基吼啶-2-基）苯基）乙醯胺 [化 2067]The title compound was subjected to acetylation using N-(4-(4-amino-5-cyano-6-methoxypyridin-2-yl)phenyl)acetamide as described in Example 2-26. And synthesis. 1H-NMR (3〇〇MHz, DMSO-d6) δ 2.08 (s, 3H), 2.49 (s, 3H), 4.08 (s, 3H), 7.74 (d, J=9.0 Hz, 2H), 7.99-8.03 (m, 3H), 10.19 (s, 1H), 10.39 (s, 1H). 141666.doc -605 · 201028381 Example 2-67 N-(4-(4-Amino-5-cyano-6-ethoxyacridin-2-yl)phenyl)acetamide [Chem. 2067]

標題化合物係依據實施例2-65之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 1.35 (t, J=6.9 Hz，3H)， 2.07 (s, 3H), 4.46 (q, 2H), 6.81 (s, 1H), 6.97 (br, 2H), 7.68 (d，J=9.0 Hz，2H)，7.87 (d, J=9.0 Hz, 2H), 10.11 (s，1H)。 實施例2-68 4-胺基_6-(4-胺基苯基）-2-乙氧基菸鹼腈 [化 2068]The title compound was synthesized according to the method of Example 2-65. 1H-NMR (300 MHz, DMSO-d6) δ 1.35 (t, J = 6.9 Hz, 3H), 2.07 (s, 3H), 4.46 (q, 2H), 6.81 (s, 1H), 6.97 (br, 2H) ), 7.68 (d, J = 9.0 Hz, 2H), 7.87 (d, J = 9.0 Hz, 2H), 10.11 (s, 1H). Example 2-68 4-Amino-6-(4-aminophenyl)-2-ethoxynicotinonitrile [Chemical 2068]

標題化合物係依據實施例2-65之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 1.34 (t, J=6.9 Hz, 3H), 4.42 (q, 2H), 5.57 (br, 2H), 6.59 (d, J=8.7 Hz, 2H), 6.65 (s, 1H)，6.79 (br，2H)，7.65 (d，J=8.7 Hz, 2H)。 實施例2-69 6-(4 -乙酿基0比唤-1-基）-4-胺基-乙氧基於驗猜 141666.doc -606· 201028381 [化 2069]The title compound was synthesized according to the method of Example 2-65. 1H-NMR (300 MHz, DMSO-d6) δ 1.34 (t, J = 6.9 Hz, 3H), 4.42 (q, 2H), 5.57 (br, 2H), 6.59 (d, J = 8.7 Hz, 2H), 6.65 (s, 1H), 6.79 (br, 2H), 7.65 (d, J = 8.7 Hz, 2H). Example 2-69 6-(4-Ethyl-based 4-yl-1-yl)-4-amino-ethoxy group was tested 141666.doc -606· 201028381 [Chem. 2069]

標題化合物係依據實施例2-144之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 1.28 (t, J=6.9 Hz, 3H), 2.02 (s, 3H), 3.41-4.52 (m, 8H), 4.28 (q, 2H), 5.54 (s, 1H), 6.40 (br, 2H)。The title compound was synthesized according to the method of Example 2-144. 1H-NMR (300 MHz, DMSO-d6) δ 1.28 (t, J = 6.9 Hz, 3H), 2.02 (s, 3H), 3.41-4.52 (m, 8H), 4.28 (q, 2H), 5.54 (s , 1H), 6.40 (br, 2H).

實施例2-70 N-(4-(4-胺基-6-氣-5-氰基吡啶-2-基）苯基）乙醯胺 [化 2070]Example 2-70 N-(4-(4-Amino-6-a-5-cyanopyridin-2-yl)phenyl)acetamide [Chem. 2070]

141666.doc -607- 201028381 [化 2071]141666.doc -607- 201028381 [Chem. 2071]

標題化合物係依據實施例2-65之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 1.36 (t, J=6.9 Hz, 3H), 3.11 (s, 3H), 4.32 (s, 2H), 4.47 (q, 2H), 6.83 (s, 1H), 7.00 (br, 2H)} 7.70 (d, J=8.7 Hz, 2H), 7.93 (d, J=8.7 Hz, 2H), 10.61 (s，1H)。 實施例2-72 N-(4-(4-胺基-5-氰基-6-乙氧基《比啶-2-基）苯基）-2-環丙基 乙醯胺 [化 2072]The title compound was synthesized according to the method of Example 2-65. 1H-NMR (300 MHz, DMSO-d6) δ 1.36 (t, J = 6.9 Hz, 3H), 3.11 (s, 3H), 4.32 (s, 2H), 4.47 (q, 2H), 6.83 (s, 1H ), 7.00 (br, 2H)} 7.70 (d, J=8.7 Hz, 2H), 7.93 (d, J=8.7 Hz, 2H), 10.61 (s, 1H). Example 2-72 N-(4-(4-Amino-5-cyano-6-ethoxy"pyridin-2-yl)phenyl)-2-cyclopropylacetamide [Chem. 2072]

標題化合物係依據實施例2-65之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 0.20 (m, 2H), 0.48 (m, 2H), 1.07 (m, 1H), 1.35 (t, J=6.9 Hz, 3H), 2.23 (d, J=6.9 Hz, 2H), 4.46 (q, 2H), 6.81 (s, 1H), 6.97 (br, 2H), 7.71 (d, J=8.7 Hz，2H)，7.88 (d，J=8.7 Hz，2H), 10.00 (s, 1H)。 實施例2-73 4-胺基-2 -乙氧基-6-苯基於驗腈 141666.doc -608- 201028381 [化 2073]The title compound was synthesized according to the method of Example 2-65. 1H-NMR (300 MHz, DMSO-d6) δ 0.20 (m, 2H), 0.48 (m, 2H), 1.07 (m, 1H), 1.35 (t, J = 6.9 Hz, 3H), 2.23 (d, J =6.9 Hz, 2H), 4.46 (q, 2H), 6.81 (s, 1H), 6.97 (br, 2H), 7.71 (d, J=8.7 Hz, 2H), 7.88 (d, J=8.7 Hz, 2H ), 10.00 (s, 1H). Example 2-73 4-Amino-2-ethoxy-6-phenyl in nitrile 141666.doc -608- 201028381 [Chem. 2073]

標題化合物係依據實施例2-65之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 1.36 (t, J=6.9 Hz, 3H), 4.47 (q, 2H), 6.87 (s, 1H), 7.04 (br, 2H), 7.42-7.52 (m, 3H), 7.93 (d，J=8.4, 1.8 Hz，2H)。 實施例2-74 4-胺基-6-(4-胺基苯基）-2-異丙氧基菸鹼腈 [化 2074]The title compound was synthesized according to the method of Example 2-65. 1H-NMR (300 MHz, DMSO-d6) δ 1.36 (t, J = 6.9 Hz, 3H), 4.47 (q, 2H), 6.87 (s, 1H), 7.04 (br, 2H), 7.42-7.52 (m , 3H), 7.93 (d, J=8.4, 1.8 Hz, 2H). Example 2-74 4-Amino-6-(4-aminophenyl)-2-isopropoxy nicotine nitrile [Chemical 2074]

標題化合物係依據實施例2-65之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 1.32 (d, J=6.0 Hz, 6H), 5.41 (m, 1H), 5.57 (br, 2H), 6.60 (d, J=8.7 Hz, 2H), 6.64 (s, 1H)，6.76 (br，1H)，7.64 (d，J=8.7 Hz, 2H)。 實施例2-75 4-胺基-6-(4-胺基苯基）-2-丙氧基菸鹼腈 [化 2075]The title compound was synthesized according to the method of Example 2-65. 1H-NMR (300 MHz, DMSO-d6) δ 1.32 (d, J = 6.0 Hz, 6H), 5.41 (m, 1H), 5.57 (br, 2H), 6.60 (d, J = 8.7 Hz, 2H), 6.64 (s, 1H), 6.76 (br, 1H), 7.64 (d, J = 8.7 Hz, 2H). Example 2-75 4-Amino-6-(4-aminophenyl)-2-propoxynicotinonitrile [Chem. 2075]

標題化合物係依據實施例2-65之方法而合成。 141666.doc -609- 201028381 1H-NMR (300 MHz, DMSO-dg) δ 0.98 (t, J=6 9 Hz 3H) 1.74 (m, 2H), 4.34 (t, 2H), 5.55 (br, 2H), 6.60 (d, J=8.7 Hz, 2H), 6.66 (s, 1H), 6.78 (br, 2H), 7.65 (d，J=8.7 Hz，2H)。 實施例2-76 4-胺基-6-(4-胺基苯基）-2-(環丙基甲氧基）終驗腈 [化 2076]The title compound was synthesized according to the method of Example 2-65. 141666.doc -609- 201028381 1H-NMR (300 MHz, DMSO-dg) δ 0.98 (t, J = 6 9 Hz 3H) 1.74 (m, 2H), 4.34 (t, 2H), 5.55 (br, 2H) , 6.60 (d, J=8.7 Hz, 2H), 6.66 (s, 1H), 6.78 (br, 2H), 7.65 (d, J=8.7 Hz, 2H). Example 2-76 4-Amino-6-(4-aminophenyl)-2-(cyclopropylmethoxy)-final nitrile [Chemical 2076]

標題化合物係依據實施例2-65之方法而合成。 1H-NMR (300 MHz, DMSO-d6) δ 0.35 (m, 2H), 0.55 (m, 2H), 1.28 (m, 1H), 4.23 (d, J=7.2 Hz, 2H), 5.55 (br, 2H), 6.60 (d, J=8.7 Hz, 2H), 6.66 (s, 1H), 6.78 (br, 2H), 7.64 (d, J=8.7 Hz, 2H)。 實施例2-77 N-(4-(4-胺基-5-氰基-6-苯氧基。比啶-2-基）苯基）乙醯胺 [化 2077]The title compound was synthesized according to the method of Example 2-65. 1H-NMR (300 MHz, DMSO-d6) δ 0.35 (m, 2H), 0.55 (m, 2H), 1.28 (m, 1H), 4.23 (d, J = 7.2 Hz, 2H), 5.55 (br, 2H) ), 6.60 (d, J=8.7 Hz, 2H), 6.66 (s, 1H), 6.78 (br, 2H), 7.64 (d, J=8.7 Hz, 2H). Example 2-77 N-(4-(4-Amino-5-cyano-6-phenoxy.pyridin-2-yl)phenyl)acetamidamine [Chemical 2077]

標題化合物係依據實施例2-65之方法而合成。 MS(ESI)m/z=303 (Μ+Η)+。 LC/MS tR=2.01 min。 實施例2-78 141666.doc •610· 201028381 N-(4-(4 -胺基-5-吼基-6-苯基n比α定-2-基）苯基）乙酿胺 [化 2078]The title compound was synthesized according to the method of Example 2-65. MS (ESI) m / z = 303 (Μ + Η) +. LC/MS tR = 2.01 min. Example 2-78 141666.doc • 610· 201028381 N-(4-(4-Amino-5-mercapto-6-phenyln~α-but-2-yl)phenyl)ethinamide [Chemical 2078] ]

標題化合物係依據實施例2-65之方法而合成。 MS(ESI)m/z=329 (Μ+Η)+。 LC/MS tR=1.48 min。 ❿The title compound was synthesized according to the method of Example 2-65. MS (ESI) m / z = 329 (Μ + Η) +. LC/MS tR = 1.48 min. ❿

141666.doc 611 - 201028381 [表l]141666.doc 611 - 201028381 [Table l]

表1中記載之化合物係依據實施例2-12之方法而合成。 實施例編號___R____物性資料_ 1H-NMR (300MHZ, DMSO-Gf6) d 4.X3 (s, 3H). 6.85 (dd, J = 3.6, 1.6 Hz, 1H) , 7.52 (t, J =» 8.0 Hz, 1H), 7.71-7.78 (m, 2H), 8.06-8.14 (m, 2H) , 8.28 J = 6.9 Hz, 1H), 8.42-8-46 (m, 1H)·__ 1H-NMR (300MHZ, DMSO-d6) d 4.12 (S, 3H), 5.31 (s, 2H), 6.73 (d, J = 7.2 Ez, 1H), 6.83 (dd, J » 3.6, 1,8 Hz, 1H), 7.19 (t, J = 7.2 Hz, 1H) . 7.36 (d, J = 7.2 Hz, 1H), 7.43 (d, J = 1.8 Hz, 1H), 7.63 (d, J » 3.6 Hz, 1H), 7.86 (a, 1H), 8.08 (s, 1H)._ 1H-NMR (300MHz, DMSO-d«) d 4.17 (S, 3H), 6.85-6.88 (m, 1H) , 7.13 (t, J = 8.1 Hz, 1H), 7.36-7.46 (m, 2H), 7.70-7.79 (m, 3H), 7.80 (d, J * 8.1 Hz, 1H), 8.06-8.13 (m, 2H), 8.15 (s, 1H), 8.46 (d, J - 8.1 Hz, 1H), 8.72 (s, 1H), 10.44 (S, 1H) ,__ 1H-NHR (300MHz, DHSO-d6&gt; d 3.05 (S. 3H), 4.14 (s, 3H), 6.85 (dd, J = 3.6, 1.6 Hz, 1H), 7.40 (d, J * 8.0 Hz, 1H) , 7.53 {t. J=8.0 Hzr 1H) , 7,67 (d, J - 3.6 Hz, 1H), 7.95-7.99 &lt;m, 2H), 8.09-8.14 (m, 2H), 9.96 &lt;s, 1H&gt;. 實施例27 9The compounds described in Table 1 were synthesized according to the methods of Examples 2-12. Example No. ___R____ Physical Data _ 1H-NMR (300MHZ, DMSO-Gf6) d 4.X3 (s, 3H). 6.85 (dd, J = 3.6, 1.6 Hz, 1H), 7.52 (t, J =» 8.0 Hz, 1H), 7.71-7.78 (m, 2H), 8.06-8.14 (m, 2H) , 8.28 J = 6.9 Hz, 1H), 8.42-8-46 (m, 1H)·__ 1H-NMR (300MHZ , DMSO-d6) d 4.12 (S, 3H), 5.31 (s, 2H), 6.73 (d, J = 7.2 Ez, 1H), 6.83 (dd, J » 3.6, 1,8 Hz, 1H), 7.19 ( t, J = 7.2 Hz, 1H) . 7.36 (d, J = 7.2 Hz, 1H), 7.43 (d, J = 1.8 Hz, 1H), 7.63 (d, J » 3.6 Hz, 1H), 7.86 (a, 1H), 8.08 (s, 1H)._ 1H-NMR (300MHz, DMSO-d«) d 4.17 (S, 3H), 6.85-6.88 (m, 1H) , 7.13 (t, J = 8.1 Hz, 1H) , 7.36-7.46 (m, 2H), 7.70-7.79 (m, 3H), 7.80 (d, J * 8.1 Hz, 1H), 8.06-8.13 (m, 2H), 8.15 (s, 1H), 8.46 (d , J - 8.1 Hz, 1H), 8.72 (s, 1H), 10.44 (S, 1H), __ 1H-NHR (300MHz, DHSO-d6&gt; d 3.05 (S. 3H), 4.14 (s, 3H), 6.85 (dd, J = 3.6, 1.6 Hz, 1H), 7.40 (d, J * 8.0 Hz, 1H), 7.53 {t. J=8.0 Hzr 1H) , 7,67 (d, J - 3.6 Hz, 1H), 7.95-7.99 &lt;m, 2H), 8.09-8.14 (m, 2H), 9.96 &lt;s, 1H&gt;. Example 27 9

實施例2 —8 0Example 2 - 8 0

實施例 2 — 141666.doc 612- 201028381Example 2 - 141666.doc 612- 201028381

實施例2 —8 3Example 2 - 8 3

實施例2 —8 4Example 2 - 8 4

實施例2 —8 5Example 2 - 8 5

實施例2 —8 6Example 2 - 8 6

實施例2 —8 7Example 2 - 8 7

1H-NMR {300MH2, DMSO-d6) &lt;1 2.09 (s, 3H), 4.14 (s, 3H), 6.85 (dd, J * 3.6, 1.6 Hz, 1H), 7.47 (t, J =» 8.0 Hz, 1H), 7.66 {d. J * 3,6 Hz, 1H) , 7.82 ('d, J = 8,0 HZ, 1H), 7.90 (&lt;3, J = 8.0 Hz, 1H), 7.93 (s, 1H) , 8.10 (d, J - 1.6 Hz, 1H). 8.39 (s. 1H), 10,15 (s, 1H), 1H-NMR (300MHz, DMSO-dtt) d 1.07 (t, J * 7.1 Hz, 3H), 3.09-3.18 (m, 2H), 4.13 (s, 3H), 6.18 (t, J = 5.4 Hz, 1H), 6,85 (¢3. J * 3.6, 1.6 Hz, 1H), 7.40 (t, J 7.8 Hz# 1H), 7.61 (fl, J * 7.8 Hz, 1H), 7.65 (&lt;i, J = 3.6 Hz、1H.), 7.76 {d, J - 7.8 H2, 1H), 7.91 (S, 1H) , 8.10 (d, J * 1.6 Hz, 1H), 8.21 (s. 1H), 8&gt;66 (s, 1H)♦ 1H-NMR (300MHz, DMSO-d6) 3,90 (s, 3H), 4.13 (s, 3H), 6.85 (dd, J = 3.6, 1.8 Hz, 1H), 7.70 (d, J « 3.6 Hz, 1H) , 8.10 (d, J » 8.5 Hz. 2H) , 8.10 (d, J = 1.8 Hz, 1H), 8.38 (d, J » 8.S Ha, 2H)» 1H-NMR (300MHJS, DMS0-tf6) d3.92 (s, 3H). 4.15 (s, 3H), 6.86 (dd, J - 3.6, 1.9 Hz, 1H). 7.69-7.77 (m, 2H) , 8.06-8.15 (m, 3H) . 8.52 (a, J 篇 a.2 Hz, 1H&gt;, 8.74 (s, 1H) · 1H-NMR (300MHz, DMSO-(J6) d 1.07 (t, J » 7.1 Hz. 3H), 3.09-3.18 {m, 2H), 4.12 {s, 3H), 6.25 (t, J « 5.4 Hz. 1H), 6.83 (dd, J = 3.6, 1.6 Hz, 1H), 7.57 (d# J -8.β HZ. 2H), 7.64 (d, J » 3.6 Hz, 1H), 7.92 (s, 1H). 8.07(&lt;3UJ* 1.6 Hz, 1H), 8.15 (d, J » 8·8 Hz, 2H). 8.83 (S, 1H). 141666.doc 613 - 201028381 141666.doc 實施例2 8 81H-NMR {300MH2, DMSO-d6) &lt;1 2.09 (s, 3H), 4.14 (s, 3H), 6.85 (dd, J * 3.6, 1.6 Hz, 1H), 7.47 (t, J =» 8.0 Hz , 1H), 7.66 {d. J * 3,6 Hz, 1H) , 7.82 ('d, J = 8,0 HZ, 1H), 7.90 (&lt;3, J = 8.0 Hz, 1H), 7.93 (s , 1H) , 8.10 (d, J - 1.6 Hz, 1H). 8.39 (s. 1H), 10,15 (s, 1H), 1H-NMR (300MHz, DMSO-dtt) d 1.07 (t, J * 7.1 Hz, 3H), 3.09-3.18 (m, 2H), 4.13 (s, 3H), 6.18 (t, J = 5.4 Hz, 1H), 6,85 (¢3. J * 3.6, 1.6 Hz, 1H), 7.40 (t, J 7.8 Hz# 1H), 7.61 (fl, J * 7.8 Hz, 1H), 7.65 (&lt;i, J = 3.6 Hz, 1H.), 7.76 {d, J - 7.8 H2, 1H), 7.91 (S, 1H) , 8.10 (d, J * 1.6 Hz, 1H), 8.21 (s. 1H), 8&gt;66 (s, 1H)♦ 1H-NMR (300MHz, DMSO-d6) 3,90 (s , 3H), 4.13 (s, 3H), 6.85 (dd, J = 3.6, 1.8 Hz, 1H), 7.70 (d, J « 3.6 Hz, 1H), 8.10 (d, J » 8.5 Hz. 2H) , 8.10 (d, J = 1.8 Hz, 1H), 8.38 (d, J » 8.S Ha, 2H)» 1H-NMR (300MHJS, DMS0-tf6) d3.92 (s, 3H). 4.15 (s, 3H) , 6.86 (dd, J - 3.6, 1.9 Hz, 1H). 7.69-7.77 (m, 2H) , 8.06-8.15 (m, 3H) . 8.52 (a, J a.2 Hz, 1H&gt;, 8.74 (s , 1H) · 1H-NMR (300MHz, DMSO-(J6) d 1.07 (t, J » 7.1 Hz. 3H), 3.09-3.18 {m, 2H), 4.12 {s, 3H), 6.25 (t, J « 5.4 Hz. 1H), 6.83 (dd, J = 3.6, 1.6 Hz , 1H), 7.57 (d# J -8.β HZ. 2H), 7.64 (d, J » 3.6 Hz, 1H), 7.92 (s, 1H). 8.07 (&lt;3UJ* 1.6 Hz, 1H), 8.15 ( d, J » 8·8 Hz, 2H). 8.83 (S, 1H). 141666.doc 613 - 201028381 141666.doc Example 2 8 8

1H-NMR {300MHz, DMSO-d6) d 2,08 (s, 3H), 2.45 {s, 3H), 4.04 &lt;s, 3H), 6.82 (dd# J » 3.7, 1.8 Hz, 1H), 7·56-7.62 (m, 5H), 8.07 1H), 10*09 (st 1H). 實施例2 — 8 9 Η〇γΙ 0 σ· 1H-NMR (300ΜΗΖ, DMSO-d6) d 4.15 (s, 3H), 6.86 (dd, J &lt;· 3.6, 1.9 Hz, 1H), 7.71 (d, J » 3.6Hz, 1H), 8.07-8.14 (m, 4H), 8.37 (d, J -8.5 Hz, 2H). 實施例2 — 9 0 9 1H-NMR (300MHz# DMSO-d6) d 4.14 (s, 3H) r 6·85 (dd, J » 3.6, 1*9 η〇Α^ σ· Hz, 1H), 7.65-7.76 (m. 2H), 8-05-8.14 (m, 3H) , 8.48 (cl, J -8.0 Hz. 1H), 8.73 (s, 1H). 1H-NMR {300MH2, DMSO- -de) d 2.82 (d, J = 4.7 Hz, 3H), 4. 15 (s. 3H), * 6.86 (dd. J « 3·7, 1· 8 Hz, 1H), 實施例2 — 9 1 Μβ.ΝγΧΧ 7.72 (d# J * 3.7 Hz, 1H), 7.99 0 (d, J »» 8 .5 Hz, 2H), 8*09-8.12 (in. 2H}, 8 .34 (d, J = 8 -5 Hz, 2H), 8.60 (q, J *» 4 · 7 Hz, XH). 實施例29 2 1H-NMR (300MHz, DMSO-d6 ά 2.84 (d, J= 4.5 Hz, 3H), 4.16 (s, 3H), 6.86 {dd, J = 3.5, 1.8 Hz, 1H), 7-65 (t, J * 7.6 Hz. 1H), 7.68 (d, J = 3.5 Hz, 1H), 7.98 (d, J =7.6 Hz, 1H) r 8.09 (s, 1H) , 8.11 &lt;d. J » 1.8 Hz, 1H), 8.39 (d, J =7.6 Hz, 1H), 8.61 (s, 1H) , 8.64 實施例2 —9 31H-NMR {300MHz, DMSO-d6) d 2,08 (s, 3H), 2.45 {s, 3H), 4.04 &lt;s, 3H), 6.82 (dd# J » 3.7, 1.8 Hz, 1H), 7 · 56-7.62 (m, 5H), 8.07 1H), 10*09 (st 1H). Example 2 - 8 9 Η〇γΙ 0 σ· 1H-NMR (300ΜΗΖ, DMSO-d6) d 4.15 (s, 3H ), 6.86 (dd, J &lt;· 3.6, 1.9 Hz, 1H), 7.71 (d, J » 3.6Hz, 1H), 8.07-8.14 (m, 4H), 8.37 (d, J -8.5 Hz, 2H) Example 2 - 9 0 9 1H-NMR (300MHz# DMSO-d6) d 4.14 (s, 3H) r 6·85 (dd, J » 3.6, 1*9 η〇Α^ σ· Hz, 1H), 7.65-7.76 (m. 2H), 8-05-8.14 (m, 3H), 8.48 (cl, J -8.0 Hz. 1H), 8.73 (s, 1H). 1H-NMR {300MH2, DMSO- -de) d 2.82 (d, J = 4.7 Hz, 3H), 4. 15 (s. 3H), * 6.86 (dd. J « 3·7, 1· 8 Hz, 1H), Example 2 - 9 1 Μβ.ΝγΧΧ 7.72 (d# J * 3.7 Hz, 1H), 7.99 0 (d, J »» 8 .5 Hz, 2H), 8*09-8.12 (in. 2H}, 8 .34 (d, J = 8 -5 Hz , 2H), 8.60 (q, J *» 4 · 7 Hz, XH). Example 29 2 1H-NMR (300MHz, DMSO-d6 ά 2.84 (d, J = 4.5 Hz, 3H), 4.16 (s, 3H) ), 6.86 {dd, J = 3.5, 1.8 Hz, 1H), 7-65 (t, J * 7.6 Hz. 1H), 7.68 (d, J = 3.5 Hz, 1H), 7.98 (d, J = 7.6 Hz, 1H) r 8.09 (s, 1H) , 8.11 &lt;d. J » 1.8 Hz, 1H), 8.39 (d, J = 7.6 Hz, 1H), 8.61 (s, 1H), 8.64 Example 2 - 9 3

(q, J » 4.5 Hz, 1H) ._ 1H-NMR (300MHz, DMSO-d6) d 3.28 {t, J - 5.5 Hz, 2H) , 3.29 (s. 3H), 3.51 (t. J » 5.5 Hz, 2H), 4.09 (s, 3H) , 6.41 (t, J =&gt; 5.5 Hz. 1H), 6.72 (d, J - 8.7 Hz, 2H), 6.81 (dd, J =» 3.5, 1.7 Hz, 1H), 7,59 (d, J « 3.5 Hz, 1H) , 7.79 (S, 1H), 8,03 (d, J = 8.7 Hz, 2H), 8.04 (d, J =* 1.7 Hz. 1H). 614- 201028381(q, J » 4.5 Hz, 1H) ._ 1H-NMR (300MHz, DMSO-d6) d 3.28 {t, J - 5.5 Hz, 2H) , 3.29 (s. 3H), 3.51 (t. J » 5.5 Hz , 2H), 4.09 (s, 3H), 6.41 (t, J => 5.5 Hz. 1H), 6.72 (d, J - 8.7 Hz, 2H), 6.81 (dd, J =» 3.5, 1.7 Hz, 1H ), 7,59 (d, J « 3.5 Hz, 1H), 7.79 (S, 1H), 8,03 (d, J = 8.7 Hz, 2H), 8.04 (d, J =* 1.7 Hz. 1H). 614- 201028381

141666.doc 實施例2 —94141666.doc Example 2 - 94

實施例2 —9 5 實施例2 —9 6Example 2 - 9 5 Example 2 - 9 6

1H-NMR ( 300MHz, DMSO-de) d 3.17 (s, 2H}, 4.13 (S, 3H), 6.84 (dd, J = 3.6, 1.2 H2, 1H), 7.66 (d, J 3.« Hz, 1H), 7.83 (d, J = 8.5 Hz, 2H), 7.98 (S, 1H), 8.08 (d, J = 1.2 Hz, 1H), 8.24 (d, J - 8.5 Hz, 2H). 1H-NMR (300MHz, DMSO-d6) ά 0.87 (d, J = 6.9 Hz, 3K), 0.94 (d, J =6.9 Hz, 3H&gt; , 1.91-2.00 (m, 1H), 3·15 (d. J « 6.0 Hz, 1H&gt;, 4.13 (s, 3H), 6.84 {dd, J = 3.4, 1.8 Hz, 1H), 7.66 (ά, J« 3.4 Hz, 1H), 實施例2 —9 71H-NMR (300MHz, DMSO-de) d 3.17 (s, 2H}, 4.13 (S, 3H), 6.84 (dd, J = 3.6, 1.2 H2, 1H), 7.66 (d, J 3.« Hz, 1H ), 7.83 (d, J = 8.5 Hz, 2H), 7.98 (S, 1H), 8.08 (d, J = 1.2 Hz, 1H), 8.24 (d, J - 8.5 Hz, 2H). 1H-NMR (300MHz , DMSO-d6) ά 0.87 (d, J = 6.9 Hz, 3K), 0.94 (d, J = 6.9 Hz, 3H&gt;, 1.91-2.00 (m, 1H), 3·15 (d. J « 6.0 Hz, 1H&gt;, 4.13 (s, 3H), 6.84 {dd, J = 3.4, 1.8 Hz, 1H), 7.66 (ά, J« 3.4 Hz, 1H), Example 2 - 9 7

7.84 id. J = 8. 4 Hz, 2H), 7.98 (S, 1H), 8,08 (d, J= 1 .8 Hz , 1H), 8.23 (d. J K 8, 4 Hz, 2H). MS (ESI) m/z as 341 (M+H&gt;+. LC/MS tR » 2 • 13 min. 1H-NM R (300MHz, DMSO- -d6) d 0*92 it, j ss 7.3 ； Hz, 3H), 1,64 (tt, J e 7 .3, 7.5 Hz ,2H) ,2.64 (t. J * 7 • 5 Uz r 2H) ,4.12 (s. 3H), 6.84 (dd # J = 3, ,5,1* 8 Hz, 1H), 7.37 (d. J * a. 2 Hz, 2H). 7.67 (d. J » 3, ,5 Hz ,1H), 7.98 (s, 1H), 8*08 (d. J as 1. 8 Hz0 1H). a, 16 (儿j 寒 B*2 Hzr 2H) ♦ 實施例2 —9 87.84 id. J = 8. 4 Hz, 2H), 7.98 (S, 1H), 8,08 (d, J = 1. 8 Hz, 1H), 8.23 (d. JK 8, 4 Hz, 2H). MS (ESI) m/z as 341 (M+H&gt;+. LC/MS tR » 2 • 13 min. 1H-NM R (300MHz, DMSO- -d6) d 0*92 it, j ss 7.3 ; Hz, 3H ), 1,64 (tt, J e 7 .3, 7.5 Hz , 2H) , 2.64 (t. J * 7 • 5 Uz r 2H) , 4.12 (s. 3H), 6.84 (dd # J = 3, , 5,1* 8 Hz, 1H), 7.37 (d. J * a. 2 Hz, 2H). 7.67 (d. J » 3, , 5 Hz , 1H), 7.98 (s, 1H), 8*08 ( d. J as 1. 8 Hz0 1H). a, 16 (children's cold B*2 Hzr 2H) ♦ Example 2 - 9 8

Me 1H-NMR (300MHz, DMSO-d«) d 1,25 (d, J = 7.0 Hz, 6H), 2.93-3.03 (m, 1H), 4.12 (sf 3H), 6.84 (dd, J - 3.4, 1.5 Hz, 1H), 7.42 (d, J « 8.4 Hz, 2H) , 7.66 (d, J - 3.4 Hz. 1H)# 7.96 (s. 1H), 8.08 (d, J * 1,5 Hz, 1H) , 8.15 (d, J = 8.4 Hz, 2H). -615- 201028381 實施例2 — 9 9Me 1H-NMR (300MHz, DMSO-d«) d 1,25 (d, J = 7.0 Hz, 6H), 2.93-3.03 (m, 1H), 4.12 (sf 3H), 6.84 (dd, J - 3.4, 1.5 Hz, 1H), 7.42 (d, J « 8.4 Hz, 2H), 7.66 (d, J - 3.4 Hz. 1H)# 7.96 (s. 1H), 8.08 (d, J * 1,5 Hz, 1H) , 8.15 (d, J = 8.4 Hz, 2H). -615- 201028381 Example 2 - 9 9

1H-NMR {300 MHz, DMSO-d6) 6 4.14 (s, 3H), 6.83-6*85 (m# 1H) , 7.15 (S, 1H)· 7·71 (d, J*3.6H2, ：LH), 7.86 (df J * 8.8 Hzt 2H), 7.89 (brs, 1H), 8.08 {brs, 2H) , 8.40 (d, J » 8.8 Hz, 2H) , 8*42 (s, 1H).1H-NMR {300 MHz, DMSO-d6) 6 4.14 (s, 3H), 6.83-6*85 (m# 1H) , 7.15 (S, 1H)· 7·71 (d, J*3.6H2, :LH ), 7.86 (df J * 8.8 Hzt 2H), 7.89 (brs, 1H), 8.08 {brs, 2H) , 8.40 (d, J » 8.8 Hz, 2H) , 8*42 (s, 1H).

[表2][Table 2]

表2中記載之化合物係依據實施例2-26之方法而合成。 實施例編號_Η_物性資料_ 實施例2 — MS (ESI) m/2 - 406 (M+H) + . 10 0 LC/MS tu = 2.21 min.The compounds described in Table 2 were synthesized according to the methods of Examples 2-26. Example No. _Η_physical data_Example 2 - MS (ESI) m/2 - 406 (M+H) + . 10 0 LC/MS tu = 2.21 min.

實施例2 -- 10 3Example 2 - 10 3

MS (ESI) m/z - 440 (M+H)+. LC/MS tR = 2.67 min.MS (ESI) m/z - 440 (M+H) +. LC/MS tR = 2.67 min.

實施例2 - 〇 MS (ESI) rn/z - 408 (M+H) + . 10 6 MeS'^s^'* LC/HS tB - 2.40 min. 616- 141666.doc 201028381 實施例 2 - Μβ H MS (ESI) m/z - 378 (M+H)*.Example 2 - 〇MS (ESI) rn/z - 408 (M+H) + . 10 6 MeS'^s^'* LC/HS tB - 2.40 min. 616-141666.doc 201028381 Example 2 - Μβ H MS (ESI) m/z - 378 (M+H)*.

10 7 T^* LC/MS tR = 2.05 min. OH10 7 T^* LC/MS tR = 2.05 min. OH

-617- 141666.doc 0 201028381 ο 實施例 2 — ιΐ^γ^·* MS (ESI) m/z = 469 (M+H)*. 12 0 MeO^Jl^N LC/MS tR * 2.82 min.-617- 141666.doc 0 201028381 ο Example 2 - ιΐ^γ^·* MS (ESI) m/z = 469 (M+H)*. 12 0 MeO^Jl^N LC/MS tR * 2.82 min.

實施例2 12 3 MS (ESI) m/z * 446 (M+H}+· LC/MS tR « 2.10 min. 實施例2 -12 4 0^· OH MS (ESI) LC/MS tR m/z * * 2 * 36 440 (M+H) + . min. 實施例2 — 12 5 0 MS {ESI} LC/MS tR m/z * * 2.36 374 (H+R)+, min. 實施例2 -12 6 0 MS (ESI) LC/MS tR m/z « -2.54 426 {M+H)+. min. 實施例2 _ 12 7 CXa* MS (ESI) LC/MS tR m/z « 2.07 425 (M+H)+. min. 實施例2 -1 2 8 Me 丫 MS (ESI) LC/MS tR m/z * * 1.78 405 (M+H)' min. 實施例2 -12 9 MS (ESI) LC/MS tR m/z w =2.33 394 (M+H)+. min. 實施例2 -13 0 Μ 广 ^Μβ MS (ESI) LC/MS tR m/z « » 2,93 481 (M+H)' min. 618- 141666.doc 201028381Example 2 12 3 MS (ESI) m/z * 446 (M+H} +· LC/MS tR « 2.10 min. Example 2 -12 4 0^· OH MS (ESI) LC/MS tR m/z * * 2 * 36 440 (M+H) + . min. Example 2 - 12 5 0 MS {ESI} LC/MS tR m/z * * 2.36 374 (H+R)+, min. Example 2 - 12 6 0 MS (ESI) LC/MS tR m/z « -2.54 426 {M+H)+. min. Example 2 _ 12 7 CXa* MS (ESI) LC/MS tR m/z « 2.07 425 ( M+H)+. min. Example 2 -1 2 8 Me 丫MS (ESI) LC/MS tR m/z * * 1.78 405 (M+H)' min. Example 2 -12 9 MS (ESI) LC/MS tR m/zw = 2.33 394 (M+H)+. min. Example 2 -13 0 Μ 广Μβ MS (ESI) LC/MS tR m/z « » 2,93 481 (M+H )' min. 618- 141666.doc 201028381

實施例2 -13 1 MS (ESI) 3LC/MS ts m/z « * 2.59 440 (M+H&gt;*. 實施例2 — 13 2 MS (ESI) LC/MS tR m/z « * 2.X7 440 (M+H)+. m±n. 實施例2 — 13 3 Me 0 σ MS (ESI) LC/MS tR m/z雄 «2-73 4B1 iM+H”. min. 實施例2 -13 4 MS (ESI) LC/MS tR m/z » =2,78 434 (M+H)+. min. 實施例2 — 1 3 5 MS (ESI) LC/MS tR m/z * * 2.68 445 (M+H) + , min* 實施例2 - 13 6 MS (ESI) LC/MS tn m/z » =2.33 386 (M+H)' min. 實施例2 -13 7 α1* Me MS (ESI) LC/MS tn m/z e * 2.59 413 (M+H) + . m±n. 實施例2 -13 8 0 MS (ESI) LC/HS tn m/z雄 « 1.97 400 (M+H广 min. 實施例2 — 13 9 Η MS (ESI) LC/MS tR m/z * *1.99 450 (M+H)+. min* 實施例2 -14 0 MS (ESI) LC/MS tn m/z = ** 2.29 428 (M4H}\ min. 實施例2 — 14 1 〈'ν^* MS (ESI) LC/MS t» m/z = 雄 2.01 426 (M+H)\ Hiin. 141666.doc 619- 201028381 實施例2 -14 2 ^~ΝΗ 0 Η\^Α· 0 MS (ESI) LC/MS tR m/z « * 1.72 446 (M+H)' min. 實施例2 -14 3 Ο 〇\Ν MS (ESI) LC/MS tR m/z * « 1.94 423 (M+H)*. min. 實施例2 — 144 0 MS (ESI) LC/MS tR m/z * =a 1.99 416 &lt;M+H) + . min. 實施例2 — 14 5 〇&lt;Λ MS (ESI) LC/MS t5 m/z « * 2^19 497 (M+H) + . min. 實施例2 14 6Example 2 - 13 1 MS (ESI) 3 LC/MS ts m/z « * 2.59 440 (M+H&gt;*. Example 2 - 13 2 MS (ESI) LC/MS tR m/z « * 2.X7 440 (M+H)+. m±n. Example 2 - 13 3 Me 0 σ MS (ESI) LC/MS tR m/z male «2-73 4B1 iM+H". min. Example 2 -13 4 MS (ESI) LC/MS </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; M+H) + , min* Example 2 - 13 6 MS (ESI) LC/MS tn m/z » = 2.33 386 (M+H)' min. Example 2 - 13 7 α1* Me MS (ESI) LC/MS tn m/ze * 2.59 413 (M+H) + . m±n. Example 2 - 13 8 0 MS (ESI) LC/HS tn m/z male « 1.97 400 (M+H broad min. Example 2 - 13 9 Η MS (ESI) LC/MS tR m/z * *1.99 450 (M+H)+. min* Example 2 - 14 0 MS (ESI) LC/MS tn m/z = * * 2.29 428 (M4H}\min. Example 2 - 14 1 <'ν^* MS (ESI) LC/MS t» m/z = male 2.01 426 (M+H)\ Hiin. 141666.doc 619- 201028381 Example 2 -14 2 ^~ΝΗ 0 Η\^Α· 0 MS (ESI) LC/MS tR m/z « * 1.72 446 (M+H)' min. Example 2 -14 3 Ο 〇\Ν MS (ESI) LC/MS tR m/z * « 1.94 423 (M+H)*. min. Example 2 — 144 0 MS (ESI) mp. ^19 497 (M+H) + . min. Example 2 14 6

MS (ESI) m/z = 401 (M+H)+. LC/MS tR - 2.31 min. 實施例2 14 7MS (ESI) m / z = 401 (M + H) +. LC / MS tR - 2.31 min. Example 2 14 7

MS (ESI) OT/z 416 (M+H) LC/MS tR » 2.81 min. 實施例2 14 8 f3c〆MS (ESI) OT/z 416 (M+H) LC/MS t s: 2.81 min. Example 2 14 8 f3c〆

OO

Me MS (ESI) xn/z = 444 (M+H) + . LC/MS tR = 2.61 min. 實施例2 14 9Me MS (ESI) xn/z = 444 (M+H) + . LC/MS tR = 2.61 min. Example 2 14 9

MS (ESI) rn/z - 417 (M+H) LC/MS tR - 1.78 min. 實施例2 15 0MS (ESI) rn/z - 417 (M+H).

MS (ESI) m/z « 450 (M+H)+. LC/MS tR » 2.83 m±n. 實施例2 1 5 1 cr1· MS (ESI) m/z 388 (M+H)+. LC/MS tR - 2.55 min·MS (ESI) m/z « 450 (M+H)+. LC/MS tR: 2.83 m±n. Example 2 1 5 1 cr1· MS (ESI) m/z 388 (M+H)+. LC /MS tR - 2.55 min·

141666.doc 620- 201028381 實施例2 -15 4 o Me MS (ESI) LC/MS tR m/z » * 2.71 404 (M+H) + . min. 實施例2 -15 5 Me、 〇 MS (ESI) LC/MS tR m/z * 篇 3·02 432 (M+H) + . min. 實施例2 — MS (ESI) m/2 * 418 (M+H) + . 15 6 Me LC/MS tn * 2.91 min·141666.doc 620-201028381 Example 2 -15 4 o Me MS (ESI) LC/MS tR m/z » * 2.71 404 (M+H) + . min. Example 2 -15 5 Me, 〇MS (ESI LC/MS tR m/z * Part 3·02 432 (M+H) + . min. Example 2 - MS (ESI) m/2 * 418 (M+H) + . 15 6 Me LC/MS tn * 2.91 min·

實施例 2 ― &lt;TTl f MS (ESI) ra/z - 416 (M+H) + . 16 2 LC/MS t8 - 2.79 min. 實施例2 —1 6 5Example 2 - &lt;TTl f MS (ESI) ra/z - 416 (M+H) + . 16 2 LC/MS t8 - 2.79 min. Example 2 - 1 6 5

實施例2 —16 6 實施例2 -167 MS (ESI) m/z - 390 (M+H)+, LC/MS tR = 2.59 min. MS (ESI) m/z = 402 (M+H)+. LC/MS tR - 2.67 min. MS (ESI) m/z * 390 (M+H)*. LC/MS tR « 2.61 rain.Example 2 - 16 6 Example 2 -167 MS (ESI) m/z - 390 (M+H)+, LC/MS tR = 2.59 min. MS (ESI) m/z = 402 (M+H)+ LC/MS tR - 2.67 min. MS (ESI) m/z * 390 (M+H)*. LC/MS tR « 2.61 rain.

621 - 141666.doc 201028381 實施例2 — 16 8 MS (ESI) LC/MS tR m/z * 430 (M+H&gt;+. » 2·51 min. 實施例2 — 16 9 MS (ESI) LC/MS tR m/z 416 (M+H)+, «« 2.43 min· 實施例2 — 17 0 MS (ESI) Lc/m tR m/z » 388 (M+H)+. « 2.43 min. 實施例2 — 17 1 D1* MS (ESI) LC/MS t« m/z * 410 (M+H)*· 2·35 min. 實施例2 -17 2 MS (ESI) LC/MS tR m/z « 426 (M+H)+. » 2.21 min. 實施例2 -17 3 MS (£SI) LC/MS tR m/z * 452 (M+H)' * 2.71 min. 實施例2 — 17 4 MS (ESI) LC/MS t8 m/z = 470 (M+H)*. =3.12 min. 實施例2 — 17 5 aj〇^· MS (ESI) LC/MS tR m/z = 551 (M+H)+. « 2,47 niln. 實施例2 — 17 6 f&gt;i-° 〇 W MS (ESI) LC/MS tB m/z * 543 (M+H)+. » 2*55 min. 實施例2 -17 7 MS (ESI) LC/MS tR m/z « 563 (M+H)+. =2·53 min. 實施例2 — 17 8 、〇-《 MS (ESI) LC/MS tB m/z : 485 (M+H)+. =» 3.28 min. 實施例2 — 17 9 MS (ESI) LC/MS tn m/z =388 (M+H)+. » 2 M 53 ntln. 622- 141666.doc 201028381621 - 141666.doc 201028381 Example 2 - 16 8 MS (ESI) LC/MS tR m/z * 430 (M+H &gt; +. » 2·51 min. Example 2 - 16 9 MS (ESI) LC/ MS tR m/z 416 (M+H)+, «« 2.43 min· Example 2 - 17 0 MS (ESI) Lc/m tR m/z » 388 (M+H)+. « 2.43 min. Example 2 — 17 1 D1* MS (ESI) LC/MS t« m/z * 410 (M+H)*· 2·35 min. Example 2 -17 2 MS (ESI) LC/MS tR m/z « 426 (M+H)+. » 2.21 min. Example 2 -17 3 MS (£SI) LC/MS tR m/z * 452 (M+H)' * 2.71 min. Example 2 - 17 4 MS ( ESI) LC/MS t8 m/z = 470 (M+H)*.=3.12 min. Example 2 - 17 5 aj〇^· MS (ESI) LC/MS tR m/z = 551 (M+H) +. « 2,47 niln. Example 2 - 17 6 f&gt;i-° 〇W MS (ESI) LC/MS tB m/z * 543 (M+H)+. » 2*55 min. Example 2 -17 7 MS (ESI) LC/MS tR m/z « 563 (M+H)+. = 2.53 min. Example 2 - 17 8 〇 - MS (ESI) LC/MS tB m/z : 485 (M+H)+. =» 3.28 min. Example 2 - 17 9 MS (ESI) LC/MS tn m/z = 388 (M+H) +. » 2 M 53 ntln. 622- 141666. Doc 201028381

實施例 2 - O MS (ESI) m/z - 452 (M+H) + . 18 0 LC/MS ts » 2-83 min.Example 2 - O MS (ESI) m/z - 452 (M+H) + . 18 0 LC/MS ts » 2-83 min.

實施例 2 — 兄 MS (ESI) m/z ~ 422 (M+H) + . 18 6 Me0^v^〇v^v&gt; LC/MS tR - 2.29 min. 0 實施例 2 - MS (ESI) m/z - 446 (M+H) + , 187 XT* LC/MS tR * 2*41 min.Example 2 - Brother MS (ESI) m/z ~ 422 (M+H) + . 18 6 Me0^v^〇v^v&gt; LC/MS tR - 2.29 min. 0 Example 2 - MS (ESI) m /z - 446 (M+H) + , 187 XT* LC/MS tR * 2*41 min.

實施例2 — 1 8 8 MS (ESI) m/z - 401 (M+H)+. LC/MS tR ® 1,64 m±n* 實施例 2 — MS (ESI&gt; m/z * 4i4 (Μ+Η} + · 18 9 LC/MS tR » 2.33 min. N Me 實施例2 — Me 0 MS (ESI) m/z = 419 (M+H)+. 19 0 LC/MS tft » 2.07 mitu 實施例2 - Μχλ MS (ESI) m/z * 426 (M+H)+. 19 1 LC/MS t» a» 2.03 in±n * 623 - 141666.doc 201028381Example 2 - 1 8 8 MS (ESI) m/z - 401 (M+H) +. LC/MS tR ® 1,64 m±n* Example 2 - MS (ESI&gt; m/z * 4i4 (Μ +Η} + · 18 9 LC/MS tR » 2.33 min. N Me Example 2 - Me 0 MS (ESI) m/z = 419 (M+H) +. 19 0 LC/MS tft » 2.07 mitu Example 2 - Μχλ MS (ESI) m/z * 426 (M+H)+. 19 1 LC/MS t» a» 2.03 in±n * 623 - 141666.doc 201028381

Ο 實施例2 — 0 MS (ESI) m/a = 378 (M+H)+. 19 2 LC/MS tR *1.85 min. 實施例2 - MS (ESI) ro/z = 362 (M+H)+. 19 3 LC/MS t* «* 2.64 min. 實施例2 — 0 MS (ESI) m/z = 376 (M+H)*. 19 4 LC/MS ta * 2.82 min* 實施例2 — Γ ϊ MS (ESI) m/z = 391 (M+H)+. 19 5 LC/MS tR * 1.60 min. 實施例2 — “η ί MS (ESI) m/z » 364 (M+H)+. 19 6 LC/MS tR =2*28 min [表3]实施 Example 2 - 0 MS (ESI) m/a = 378 (M+H) +. 19 2 LC/MS tR *1.85 min. Example 2 - MS (ESI) ro/z = 362 (M+H) +. 19 3 LC/MS t* «* 2.64 min. Example 2 - 0 MS (ESI) m/z = 376 (M+H)*. 19 4 LC/MS ta * 2.82 min* Example 2 - Γ ϊ MS (ESI) m/z = 391 (M+H) +. 19 5 LC/MS tR * 1.60 min. Example 2 - "η ί MS (ESI) m/z » 364 (M+H)+. 19 6 LC/MS tR = 2*28 min [Table 3]

RR

表3中記載之化合物係依據實施例2-12之方法而合成。 實施例編號 R 物性資料 實施例2 ~ 19 9 拿 MS (ESI) m/z * 362 (M+H)+, LC/MS tR * 2.65 min.. 實施例2 — 2 0 0 Me Me ¥ 拿 MS (ESI) m/z * 362 (M+H)+. LC/MS tR » 2.67 m±n.. 實施例2 — 2 0 1 參. MS (ESI) rn/z »334 (M+H)+. LC/MS tR = 2.32 min.. -624- I41666.doc 201028381 實施例2 — 2 0 2 OH 離 MS (ESI) LC/MS tR m/z «364 (M+H)' » 1,90 min. 實施例2 — MS (ESI) m/z =378 (M+H)+. 2 0 3 * LC/MS « 1*88 min^ 實施例2 —2 0 4The compounds described in Table 3 were synthesized according to the methods of Examples 2-12. EXAMPLES R Physical properties Examples 2 to 19 9 Take MS (ESI) m/z * 362 (M+H)+, LC/MS tR * 2.65 min.. Example 2 - 2 0 0 Me Me ¥ Take MS (ESI) m/z * 362 (M+H)+. LC/MS tR » 2.67 m±n.. Example 2 — 2 0 1 Reference. MS (ESI) rn/z »334 (M+H)+ LC/MS tR = 2.32 min.. -624- I41666.doc 201028381 Example 2 - 2 0 2 OH from MS (ESI) LC/MS tR m/z «364 (M+H)' » 1,90 min Example 2 - MS (ESI) m/z = 378 (M+H) +. 2 0 3 * LC/MS « 1*88 min^ Example 2 - 2 0 4

MS (ESI) m/z *410 iM+H)' LC/MS tR * 1.76 min.MS (ESI) m/z *410, iM+H)' LC/MS tR * 1.76 min.

實施例2 —2 0 5Example 2 - 2 0 5

MS (ESI) m/z =348 fM+H)+. LC/MS tR » 1.95 min. 實施例2 —2 0 6MS (ESI) m/z </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt;

MS(ESI) m/z =383 (M+H)+. LC/MS tR = 2.01 min.MS (ESI) m/z = 384 (M+H) +. LC/MS tR = 2.01 min.

❿ 實施例2 — nh2 0=&lt;κ MS (ESI) m/z - 377 (M+H)+. 2 0 9 LC/MS ta = 1.78 min. 141666.doc 625- 201028381 實施例2 — 2 10 實施例2 2 11 IH-NMR (300MHZ, DMSO-d6) δ 2.10 (S, 3H), 4.16 (s, 3H) , 7·39 (m, 1H), 7.52 (mr 1H) , 7.74 (ύ, J = 8.4 Hz, iH), 7.79 (d, J » 8.7 Hz, 2H), 7.88 (d, J = 7.2 Hz, 1H), 8.09 (S, 1H) , 8.16 (s, 1H) r 8.27 (d, J = 8.4 Hz, 1H&gt;, 10·26 (br, J « 1H) &gt;_ IH-NMR (300MHz, DMSO-df6) δ 2.09 (s, 3H), 4.16 (S· 3H), 7.67 (s, 1H), 7.78 (d, J * 9.3 Hz# 1H), 8.14 {s, 1H)# 8.23 (d, J * 9.3 Hz, 1H)# 8,53 (s# 1H)# 10.25 (br# 1H). 實施例2 -2 12 * MS (ESI) m/z « 282 (M+H) + * LC/MS tR » 2.08 min. 實施例2 ~ 2 13 Υ 拿 IH-NMR {300MHz, DMSO-d6) δ 1.14-1.28 (m, 4H) , 2,08 (s, 3H), 2.16 (m# 1H) , 4.07 (s, 3H), 7.09 (sr 1H) , 7.71 (d, J « 8.7 Hz, 2H), 8·15 (d, J = 8.7 Hz # 2H) , 10.18 (hr, 1H).实施 Example 2 — nh2 0=&lt;κ MS (ESI) m/z - 377 (M+H)+. 2 0 9 LC/MS ta = 1.78 min. 141666.doc 625- 201028381 Example 2 — 2 10 Example 2 2 11 IH-NMR (300 MHZ, DMSO-d6) δ 2.10 (S, 3H), 4.16 (s, 3H), 7·39 (m, 1H), 7.52 (mr 1H), 7.74 (ύ, J = 8.4 Hz, iH), 7.79 (d, J » 8.7 Hz, 2H), 7.88 (d, J = 7.2 Hz, 1H), 8.09 (S, 1H) , 8.16 (s, 1H) r 8.27 (d, J = 8.4 Hz, 1H&gt;, 10·26 (br, J « 1H) &gt;_ IH-NMR (300MHz, DMSO-df6) δ 2.09 (s, 3H), 4.16 (S· 3H), 7.67 (s, 1H ), 7.78 (d, J * 9.3 Hz# 1H), 8.14 {s, 1H)# 8.23 (d, J * 9.3 Hz, 1H)# 8,53 (s# 1H)# 10.25 (br# 1H). Example 2 - 2 12 * MS (ESI) m/z « 282 (M+H) + * LC/MS tR » 2.08 min. Example 2 ~ 2 13 Υ IH-NMR {300MHz, DMSO-d6) δ 1.14 -1.28 (m, 4H) , 2,08 (s, 3H), 2.16 (m# 1H) , 4.07 (s, 3H), 7.09 (sr 1H) , 7.71 (d, J « 8.7 Hz, 2H), 8 · 15 (d, J = 8.7 Hz # 2H) , 10.18 (hr, 1H).

[表4][Table 4]

表4中記載之化合物係依據實施例2-29之方法而合成。 實施例編號 R 物性資料 實施例2 — 严N * MS (ESI) m/Z =319 (M+H)+. 2 14 LC/MS tr 雄 0.88 min* 實施例2 — ΗΝ 丫 Ν * MS(ESI) m/Z = 319 {M+H)+. 2 15 LC/MS tR » 0^85 min. -626- 141666.doc 201028381The compounds described in Table 4 were synthesized according to the methods of Examples 2-29. Example No. R Physical Data Example 2 - Severe N*MS (ESI) m/Z = 319 (M+H) +. 2 14 LC/MS tr Male 0.88 min* Example 2 - ΗΝ 丫Ν * MS (ESI m/Z = 319 {M+H)+. 2 15 LC/MS tR » 0^85 min. -626- 141666.doc 201028381

實施例2 -2 16 尸N 刚 * MS (ESI) m/z «333 (M+H)+* LC/MS tR * 0.79 min. 實施例2 -2 17 Me Me 蟑.. MS (ESI) m/z »422 (M+H)% X#C&gt;/MS tr^ η 2.07 DdjLzx· 實施例2 — 2 18 本 MS (ESI) m/z *318 (M+H)+· LC/MS tR * 1.60 min. 實施例2 — 2 19 广ΝΗ 9 # MS (ESI) m/z »322 (M+H)+. LC/MS tn * 0.71 min* 實施例2 — 2 2 0 瘳 1H NMR (300MHz, DMSO-d6) dL 2·08 (s# 3H), 7.12 (br, 2fi), 7.61 (s, 1H&gt;, 7.67 (s, 1H) , 7.73 (d, J « 9.0 Hz, 2H) , 8*08 (d# j « 9.0 Hz , 2H&gt;, 8.46《s, 1H), 10.19 (s, 1H)* 實施例2 — 2 2 1 5^Me 9 * 1H-NMR (300MHz, DMSO-d6) 6 1.9? (S&gt; 3H), 2.05 (S, 3H), 2.22 (m, 2H), 3.45-3.70 (m, 4H) , 3.84 (m, 1H), 6.84 (br, 2H), 7.17 (dt. J =23.4 Hz, 1H), 7.65 (dd, J =* 8.7 Hz, 2H}, 8·02 (fla, J = 8.7, 1.8 HZ, 2H), 10-11 (S, 1H). 實施例2 — 22 2 〇^Μβ * 1H-NMR {300MHz, DMSO-d«) δ 2.08 (s, 3H), 2.19 (S, 3H), 4.08 (S, 3H), 7.74 (d, J * 9.Ό Hz, 3H), 7.99-8.03 (m, 3H), 10.19 (s, 1H), 10.39 (s, 1H). 實施例2 -2 2 3 Me iΝ 拿 1H-NMR (300MHz, 0MSO-&lt;f6) δ 2.07 (s, 3H), 2.33-2.92 (m, 6H), 2.39 (S, 3H). 3.52 (m, XH&gt;, 6.78 {br, 2H), 7.20 (s, 1H), 7.68 (d, J * 8.7 Hz, 2H) , 7.99 (d, J » 8.7 Hz, 2H), 10.13 (s, 1H). 141666.doc 627- 201028381 實施例2 - 2 2 4 〇9 實施例2 — 2 2 5Example 2 - 2 16 Corpse N Just * MS (ESI) m/z «333 (M+H) + * LC/MS tR * 0.79 min. Example 2 - 2 17 Me Me 蟑.. MS (ESI) m /z »422 (M+H)% X#C&gt;/MS tr^ η 2.07 DdjLzx· Example 2 - 2 18 MS (ESI) m/z *318 (M+H)+· LC/MS tR * 1.60 min. Example 2 - 2 19 广ΝΗ 9 # MS (ESI) m/z »322 (M+H)+. LC/MS tn * 0.71 min* Example 2 - 2 2 0 瘳1H NMR (300MHz, DMSO-d6) dL 2·08 (s# 3H), 7.12 (br, 2fi), 7.61 (s, 1H&gt;, 7.67 (s, 1H), 7.73 (d, J « 9.0 Hz, 2H) , 8*08 (d# j « 9.0 Hz , 2H&gt;, 8.46 "s, 1H), 10.19 (s, 1H)* Example 2 - 2 2 1 5^Me 9 * 1H-NMR (300MHz, DMSO-d6) 6 1.9? S&gt; 3H), 2.05 (S, 3H), 2.22 (m, 2H), 3.45-3.70 (m, 4H), 3.84 (m, 1H), 6.84 (br, 2H), 7.17 (dt. J = 23.4 Hz , 1H), 7.65 (dd, J = * 8.7 Hz, 2H}, 8·02 (fla, J = 8.7, 1.8 HZ, 2H), 10-11 (S, 1H). Example 2 - 22 2 〇^ Μβ * 1H-NMR {300MHz, DMSO-d«) δ 2.08 (s, 3H), 2.19 (S, 3H), 4.08 (S, 3H), 7.74 (d, J * 9.Ό Hz, 3H), 7.99 -8.03 (m, 3H), 10.19 (s, 1H), 10.39 (s, 1H). Example 2 - 2 2 3 Me iΝ 1H-NMR (300 MHz, 0MSO-&lt;f6) δ 2.07 (s, 3H), 2.33-2.92 (m, 6H), 2.39 (S, 3H). 3.52 (m, XH&gt;, 6.78 {br, 2H), 7.20 (s, 1H), 7.68 (d, J * 8.7 Hz, 2H), 7.99 (d, J » 8.7 Hz, 2H), 10.13 (s, 1H). 141666.doc 627- 201028381 Example 2 - 2 2 4 〇9 Implementation Example 2 — 2 2 5

1H-NMR (300 MHz, DMSO-de) δ 2.07 (S, 3H), 6.76-6.78 (in, 1H) , 6.94 (S, 2H), 7.49-7.50 (m, 2H) , 7.71 (dU J - .8.7 Hz, 2H) , 8..00 (s, 1H), 8.07 (d, J » 8.7 Hz, 2H), 10.15 (s, 1H).___ 1H-NMR (300 MHz, DMSO-d6) δ 2.07 (S. 3H), 6,99 (S, 2H), 7.26-7.29 (m, 1H), 7.30 (s, 1H), 7.70 (d, J - 8.7 Hz, 2H), 7.83-7.87 (m, 2H), 8.07 {d, J » 8.7 Hz, 2H), 10.15 (s, 1H). 1H-NMR (300 MHz, DMSO-de) δ 2.07 (s, 3H), 6.91 (s. 2H), 7.32 (s 實施例2 — 2 2 6 m 1H), 7.60-7.62 (m, 1H), 7.70 (d, J * 8.7 Hz. 2H), 7.74-7.76 (m, 1H), 8.09 (d, J = 8.7 Hz, 2H), 8.14-8.15 (m, 1H) , 10.17 (s, 1H). 1H-NMR (300 MHz, DMSO-de) δ 2,08 r=\ «γΝ (S, 3H), 6.88 (s, 2H), 7.19 (s. 實施例2 - IH}, 7.59 (df J == 8 - 7 Hz, 2H), 2 2 7 7.74 (d, J =* 8.7 Hz, 2H), 8.06-8.15 (m. 2H), 10.20 (a. 1H). 1H-NMR (300 MHz, DMSO-de) δ 1.60-2.10 (m, 6H) , 2.07 (s. 1H}# 實施例2 — Q 3.35-3,47 (m. IH) , 6.74 {S, 2H), 2 2 8 Y ♦ 7.12 (s, IH)r 7.70 (d, J * * 8,6 Hz, 2H) , 7.91 (d, J 10.27 (s, iH). 8.6 Hz, 2H), [表5]1H-NMR (300 MHz, DMSO-de) δ 2.07 (S, 3H), 6.76-6.78 (in, 1H), 6.94 (S, 2H), 7.49-7.50 (m, 2H), 7.71 (dU J - . 8.7 Hz, 2H), 8..00 (s, 1H), 8.07 (d, J » 8.7 Hz, 2H), 10.15 (s, 1H).___ 1H-NMR (300 MHz, DMSO-d6) δ 2.07 ( S. 3H), 6,99 (S, 2H), 7.26-7.29 (m, 1H), 7.30 (s, 1H), 7.70 (d, J - 8.7 Hz, 2H), 7.83-7.87 (m, 2H) , 8.07 {d, J » 8.7 Hz, 2H), 10.15 (s, 1H). 1H-NMR (300 MHz, DMSO-de) δ 2.07 (s, 3H), 6.91 (s. 2H), 7.32 (s implementation Example 2 — 2 2 6 m 1H), 7.60-7.62 (m, 1H), 7.70 (d, J * 8.7 Hz. 2H), 7.74-7.76 (m, 1H), 8.09 (d, J = 8.7 Hz, 2H ), 8.14-8.15 (m, 1H), 10.17 (s, 1H). 1H-NMR (300 MHz, DMSO-de) δ 2,08 r=\ «γΝ (S, 3H), 6.88 (s, 2H) , 7.19 (s. Example 2 - IH}, 7.59 (df J == 8 - 7 Hz, 2H), 2 2 7 7.74 (d, J =* 8.7 Hz, 2H), 8.06-8.15 (m. 2H) , 10.20 (a. 1H). 1H-NMR (300 MHz, DMSO-de) δ 1.60-2.10 (m, 6H) , 2.07 (s. 1H}# Example 2 - Q 3.35-3,47 (m. IH ), 6.74 {S, 2H), 2 2 8 Y ♦ 7.12 (s, IH)r 7.70 (d, J * * 8,6 Hz, 2H) , 7.91 (d, J 10.27 (s, iH). 8.6 Hz , 2H), [Table 5]

141666.doc -628- 201028381 表5中記載之化合物係依據實施例2-12之方法而合成。 實施例編號 R 物性資料 實施例2 — 2 2 9 ·、0 Λ Me’ Me MS (ESI) LC/MS tR m/z =376 (M+H)+. =2.46 mill· 實施例2 — MS (ESI) m/z =376 (M+H)+. 2 3 0 k^Me LC/MS tm » 2*49 min. 實施例2 .— 2 3 1 、0 MS (ESI) LC/KES m/z «390 (M+H)' * 2.58 min. 實施例2 — .、0 L^Me Me MS (ESI) m/z *390 (H+H)+. 2 3 2 LC/MS tR » 2.62 m±n.141666.doc -628- 201028381 The compounds described in Table 5 were synthesized according to the methods of Examples 2-12. Example No. R Physical property Example 2 - 2 2 9 ·, 0 Λ Me' Me MS (ESI) LC/MS tR m/z = 376 (M+H) +. = 2.46 mill· Example 2 - MS ( ESI) m/z = 376 (M+H) +. 2 3 0 k^Me LC/MS tm » 2*49 min. Example 2 - 2 3 1 , 0 MS (ESI) LC/KES m/z «390 (M+H)' * 2.58 min. Example 2 - ., 0 L^Me Me MS (ESI) m/z *390 (H+H)+. 2 3 2 LC/MS tR » 2.62 m± n.

實施例 2 — *、0 MS (ESI) m/z »378 (M+H) + . 2 3 3 LC/MS tR = 1.83 min.Example 2 —*, 0 MS (ESI) m/z »378 (M+H) + . 2 3 3 LC/MS tR = 1.83 min.

O 實施例 2 - y MS (ESI) m/z *390 (M+H)*. 2 3 6 ^Me LC/MS tR - 2,66 min.O Example 2 - y MS (ESI) m/z * 390 (M+H)*. 2 3 6 ^Me LC/MS tR - 2, 66 min.

實施例 2 — f MS (ESI) m/z =404 (M+H)*. 2 3 7 LC/MS t„ * 2.74 min.Example 2 - f MS (ESI) m/z = 404 (M+H)*. 2 3 7 LC/MS t„ * 2.74 min.

Me 實施例 2 — 、〇 Me MS《ESI) m/z -404 (M+H)*. 2 3 8 Me LC/MS tR = 2.76 min. 141666.doc 629- 201028381 [表6]Me Example 2 — 〇 Me MS“ESI) m/z -404 (M+H)*. 2 3 8 Me LC/MS tR = 2.76 min. 141666.doc 629- 201028381 [Table 6]

表6中記載之化合物係依據實施例2-42之方法而合成。 實施例編號 R 物性資料 實施例2 — 2 3 9 MS (ESI) LC/MS t* m/2 ;387 &lt;M+H)+, « 2.79 min. 實施例2 — 2 4 0 MS (ESI) LC/MS tR m/z =347 (M+H)+. » 2.35 min» 實施例2 — 2 4 1 *、口八 Me MS (ESI) LC/MS tR m/z «361 (M+H)+. « 2.54 min. 實施例2 -2 4 2 *、〜爲 Me MS (ESI) LG/MS tR m/z =361 (M+H)+. * 2*53 min * 實施例2 — 2 4 3 ，、NJ〇 Η MS (ESI) LC/MS tR m/z =409 (M+H)+, »2.72 min. 實施例2 — 2 44 MS (ESI) LC/MS tR m/z «423 (M+H)+. =2.74 min. 實施例2 — 2 4 5 k^-NH MS (ESI) LC/MS tR m/z = 402 (M+H)+. « 1.31 min. 實施例2 — 2 4 6 Ί ^Ν、Μβ MS (ESI) LC/MS tR m/Z * 416 (M+H)+. s 1.29 fii±n. 實施例2 ~ 2 4 7 ^ΝΌΗ MS {ESI) LC/MS tR m/z « 418 (M+H)+. a* 2.11 min* 實施例2 — 2 4 8 、〇 MS (ESI) LC/MS tR m/z = 419 (M+H) + . =2.74 min* 實施例2 — 2 4 9 •Ό HS (ESI) LC/MS tR m/z = 402 (M+H)+. » 2,96 min. -630- 141666.doc 201028381 實施例2 -2 5 0 Η MS {ESI) LC/MS tR m/z * 391 (M+H)+. « 2.37 min* 實施例2 — 2 5 1 Χ-Ν, Me MS (ESI) LC/MS tR m/z « 430 (H+H}+· * 1.86 min* 實施例2 -2 5 2 MS (ESI) LC/MS tR m/z « 478 (M+H广 * 2.69 min. 實施例2 — 2 5 3 MS (ESI) LC/MS tR m/z * 429 (M+H)+. » 2*25 mi.n* 實施例2 — 2 54 *ν jL\ Ν MS (ESI) LC/HS tR m/z = 373 (M+H)+. * 2.15 mi.n«The compounds described in Table 6 were synthesized according to the method of Example 2-42. Example No. R Physical Properties Example 2 - 2 3 9 MS (ESI) LC/MS t* m/2; 387 &lt;M+H)+, &quot; 2.79 min. Example 2 - 2 4 0 MS (ESI) LC/MS tR m/z = 347 (M+H) +. » 2.35 min» Example 2 - 2 4 1 *, 八八Me MS (ESI) LC/MS tR m/z «361 (M+H) +. « 2.54 min. Example 2 - 2 4 2 *, ~ is Me MS (ESI) LG/MS tR m/z = 361 (M+H) +. * 2*53 min * Example 2 - 2 4 3,, NJ〇Η MS (ESI) LC/MS tR m/z = 409 (M+H)+, »2.72 min. Example 2 - 2 44 MS (ESI) LC/MS tR m/z «423 ( M+H)+.=2.74 min. Example 2 - 2 4 5 k^-NH MS (ESI) LC/MS tR m/z = 402 (M+H) +. « 1.31 min. Example 2 - 2 4 6 Ί ^Ν, Μβ MS (ESI) LC/MS tR m/Z * 416 (M+H)+. s 1.29 fii±n. Example 2 ~ 2 4 7 ^ΝΌΗ MS {ESI) LC/MS tR m/z « 418 (M+H)+. a* 2.11 min* Example 2 - 2 4 8 〇MS (ESI) LC/MS tR m/z = 419 (M+H) + . =2.74 min* Example 2 - 2 4 9 • Ό HS (ESI) LC/MS tR m/z = 402 (M+H) +. » 2,96 min. -630- 141666.doc 201028381 Example 2 -2 5 0 Η MS {ESI) LC/MS tR m/z * 391 (M+H)+. « 2.37 min* implementation 2 — 2 5 1 Χ-Ν, Me MS (ESI) LC/MS tR m/z « 430 (H+H}+· * 1.86 min* Example 2 -2 5 2 MS (ESI) LC/MS tR m /z « 478 (M+H broad* 2.69 min. Example 2 - 2 5 3 MS (ESI) LC/MS tR m/z * 429 (M+H) +. » 2*25 mi.n* Example 2 — 2 54 *ν jL\ Ν MS (ESI) LC/HS tR m/z = 373 (M+H)+. * 2.15 mi.n«

OH 實施例22 5 8 ·、 MS (ESI) m/z 441 (Μ+Η) + · LC/MS tR = 1·72 min· 實施例2 -2 5 9 、ίί Ό〇 MS (ESI) m/z * 460 (M+H)+. LC/MS tR » 1.91 min· 實施例22 6 0 n Me ^Me MS (ESI) m/z » 389 (M+H) + . LC/HS tR * 2.49 min. 實施例22 6 1 MS (ESI) m/z « 405 (M+H)+* LC/MS “ * 2·26 min. 實施例22 6 2 *、 MS (ESI) m/z * 413 (M+H)+· LC/MS tR « 2.16 min. 141666.doc 631 - 201028381 實施例2 — 2 6 3 MS (ESI) LC/HS tK m/z m 419 (M+H)+· » 2,29 min* 實施例2 -2 6 4 Me •、^0 MS (ESI) LC/MS tF m/z - 437 {M+H)+. =2,48 min. 實施例2 — 2 6 5 〇 MS (ESI) LC/MS ts m/z « 473 (M+H)' « 2,41 min· 實施例2 — 2 6 6 γΟ MS (ESI) LC/MS tR m/z * 415 (M+H)+. » 2.74 min. 實施例2 — 2 6 7 MS (ESI) LC/MS tR m/z - 386 (M+H)+. « 1.91 min. 實施例2 — 2 6 8 Η MS (SSI) LC/MS tR m/z = 443 (M+H)+. * 2.44 min. 實施例2 — 26 9 Η MS (ESI) LC/MS tR m/z * 407 (M+H)+. -2.20 min. 實施例2 — 2 7 0 0 MS (ESI) LC/MS tR m/z - 458 (M+H广 =1.74 min. 實施例2 — 2 7 1 :：χ/- Η MS (ESI) LC/MS tR m/z = 483 (M+H)+. =2.03 min. 實施例2 ~ 2 7 2 0 MS (ESI) LC/MS tR m/z = 496 (M+H)+. =1.98 min. 實施例2 — 2 7 3 Me MS (ESI) LC/MS tR m/z « 447 (M+H)+. « 2.11 min. 實施例2 -2 7 4 MS (ESI) LC/MS tR m/z - 424 (M+H)*. « 1,89 min. 賁施例2 -2 7 5 •Ό MS (ESI) LC/HS tR m/z = 3?9 (M+H)+. -2« 46 mi.n · 632 · 141666.doc 201028381 實施例22 7 6 *、 N Me MS (ESI) m/z = 400 (M+H)+. LC/MS tR « 1.95 min, 實施例22 7 7 Λ! MS (ESI) m/z = 453 (M+H)*. LC/MS tR = 2,24 min. 實施例22 7 8 ·、α MS (ESI) m/z » 430 (M+H)+-LC/MS tR * 2.03 min.OH Example 22 5 8 ·, MS (ESI) m/z 441 (Μ+Η) + · LC/MS tR = 1·72 min· Example 2 - 2 5 9 , ίί Ό〇MS (ESI) m/ z * 460 (M+H)+. LC/MS tR: 1.91 min· Example 22 6 0 n Me ^Me MS (ESI) m/z » 389 (M+H) + . LC/HS tR * 2.49 min Example 22 6 1 MS (ESI) m/z « 405 (M+H)+* LC/MS "* 2·26 min. Example 22 6 2 *, MS (ESI) m/z * 413 (M +H)+· LC/MS tR « 2.16 min. 141666.doc 631 - 201028381 Example 2 — 2 6 3 MS (ESI) LC/HS tK m/zm 419 (M+H)+· » 2,29 min * Example 2 - 2 6 4 Me •, ^0 MS (ESI) LC/MS tF m/z - 437 {M+H)+. = 2,48 min. Example 2 - 2 6 5 〇MS (ESI LC/MS ts m/z « 473 (M+H)' « 2,41 min· Example 2 — 2 6 6 γΟ MS (ESI) LC/MS tR m/z * 415 (M+H)+. » 2.74 min. Example 2 - 2 6 7 MS (ESI) LC/MS tR m/z - 386 (M+H) +. « 1.91 min. Example 2 - 2 6 8 Η MS (SSI) LC/MS tR m / z = 443 (M + H) +. * 2.44 min. Example 2 - 26 9 Η MS (ESI) LC/MS tR m/z * 407 (M+H)+. -2.20 min. 2 — 2 7 0 0 MS (ESI) LC/MS tR m/z - 458 (M+H = 1.74 min. 2 — 2 7 1 ::χ/- Η MS (ESI) LC/MS tR m/z = 483 (M+H)+. = 2.03 min. Example 2 ~ 2 7 2 0 MS (ESI) LC/MS tR m/z = 496 (M+H)+. =1.98 min. Example 2 - 2 7 3 Me MS (ESI) LC/MS tR m/z « 447 (M+H)+. « 2.11 min. Example 2 - 2 7 4 MS (ESI) LC/MS tR m/z - 424 (M+H)*. « 1,89 min. 贲Example 2 -2 7 5 •Ό MS (ESI) LC/HS tR m/z = 3?9 (M+H)+. -2« 46 mi.n · 632 · 141666.doc 201028381 Example 22 7 6 *, N Me MS (ESI) m/z = 400 (M+H +. LC/MS tR « 1.95 min, Example 22 7 7 Λ! MS (ESI) m/z = 453 (M+H)*. LC/MS tR = 2, 24 min. Example 22 7 8 · , α MS (ESI) m/z » 430 (M+H)+-LC/MS tR * 2.03 min.

Me 實施例2 —2 7 9Me Example 2 - 2 7 9

MS &lt;£SX) m/z * 449 (M+H) + , LC/MS tR * 2,66 min. 實施例22 8 0 Nώβ HN1 MS (ESI) m/z - 427 (M+H)+. LC/MS tR = 1.58 min. 實施例22 8 1 MS (ESI) m/z «* 427 (M+H}' LC/MS tR * 2.29 min. 實施例22 8 2MS &lt; £SX) m/z * 449 (M+H) + , LC/MS tR * 2, 66 min. Example 22 8 0 Nώβ HN1 MS (ESI) m/z - 427 (M+H)+ LC/MS tR = 1.58 min. Example 22 8 1 MS (ESI) m/z «* 427 (M+H}' LC/MS tR* 2.29 min. Example 22 8 2

MS (ESI) m/z « 438 (M+H)' LC/MS tK » 1*87 min.MS (ESI) m/z « 438 (M+H)' LC/MS tK » 1*87 min.

SN 實施例2 —2 8 6SN Example 2 - 2 8 6

MS (ESI) m/z » 438 (M+H) LC/MS tR »1.97 min.MS (ESI) m/z » 438 (M+H) LC/MS tR: 1.97 min.

141666.doc 633 - 201028381 實施例 2 - MS (ESI) m/z - 389 (M+H) + . 289 H LC/MS t* = 2.48 min.141666.doc 633 - 201028381 Example 2 - MS (ESI) m/z - 389 (M+H) + . 289 H LC/MS t* = 2.48 min.

實施例2 -2 9 2 Me MS (ESI) m/z : 415 (M+H)+. LC/MS tR « 2.68 min. 實施例2 — 2 9 3 ·、00 MS (ESI) m/z * 417 (M+H)+. ) LC/MS tR « Ι.βΟ min.Example 2 - 2 9 2 MS (ESI) m/z: 415 (M+H) +. LC/MS tR « 2.68 min. Example 2 - 2 9 3 ·, 00 MS (ESI) m/z * 417 (M+H)+. ) LC/MS tR « Ι.βΟ min.

實施例2 — 2 9 7 xo MS (ESI) LC/MS tR m/z -=2.00 470 (M+H)4. min. 實施例2 — 2 9 8 X^OH MS (ESI) LC/MS tR m/z = * 1*82 431 (H+H)+. min. 實施例2 -2 9 9 fMe —N 、Me MS (ESI) LC/MS tR m/z » ;2.31 458 (M+H)+. a 實施例2 -3 0 0 、 Me V-N / 'Me MS (ESI) LC/MS tn m/z * =1.96 430 (M+H}+. min* 141666.doc 634- 201028381Example 2 - 2 9 7 xo MS (ESI) LC/MS tR m/z - = 2.00 470 (M+H) 4. min. Example 2 - 2 9 8 X^OH MS (ESI) LC/MS tR m/z = * 1*82 431 (H+H)+. min. Example 2 - 2 9 9 fMe — N , Me MS (ESI) LC/MS tR m/z » ; 2.31 458 (M+H) +. a Example 2 -3 0 0 , Me VN / 'Me MS (ESI) LC/MS tn m/z * =1.96 430 (M+H}+. min* 141666.doc 634- 201028381

實施例 2 — *、f/〜\ MS (ESI) m/z = 415 (M+H) + , 3 0 5 LC/MS tR = 2.70 min.Example 2 - *, f/~\ MS (ESI) m/z = 415 (M+H) + , 3 0 5 LC/MS tR = 2.70 min.

實施例 2 - *、N^一~\ MS (ESI) m/z = 429 (M+H) + . 3 0 6 LC/MS tR » 2.82 min. 實施例 2 — MS (ESI) Kl/z » 527 (M+H) + . 3 0 7 LC/MS tR - 2.51 min.Example 2 - *, N^一~\ MS (ESI) m/z = 429 (M+H) + . 3 0 6 LC/MS tR » 2.82 min. Example 2 - MS (ESI) Kl/z » 527 (M+H) + . 3 0 7 LC/MS tR - 2.51 min.

OHOH

實施例 2 — ^Ny^sV°'v&lt;M® MS (ESI) m/z * 461 (M+H)*. 3 10 Me O MeMe LC/MS tR · 2.38 min.Example 2 - ^Ny^sV°'v&lt;M® MS (ESI) m/z * 461 (M+H)*. 3 10 Me O MeMe LC/MS tR · 2.38 min.

實施例 2 — *fe MS (ESI} Kl/Z = 391 (M+H)4. 3 11 N ^ LC/MS tR * 1.75 min. 實施例2 — 3 12 實施例2 — 3 13Example 2 - *fe MS (ESI} Kl/Z = 391 (M+H) 4. 3 11 N ^ LC/MS tR * 1.75 min. Example 2 - 3 12 Example 2 - 3 13

Me Me MS (ESI) m/z » 379 (M+H)' LC/MS tR ^ 1.99 min. MS (ESI) m/z » &lt;M+H) + · LC/MS tR = 1*90 min* 實施例2 -3 14Me Me MS (ESI) m/z » 379 (M+H)' LC/MS tR ^ 1.99 min. MS (ESI) m/z » &lt;M+H) + · LC/MS tR = 1*90 min * Example 2 - 3 14

Me MS (ESI) m/z = 389 &lt;M+H) + . LC/MS tn * 2.44 min. 635 - 141666.doc 201028381 實施例2 — 3 15 Me MS (ESI) LC/MS tR m/z = »1*68 391 (M+H)+. min. 實施例2 — 3 16 Me Η MS (ESI) LC/MS tR m/z « » 1,84 404 (H+H)+. min. 實施例2 - MS (ESI) m/z « 375 (M+H)+. 3 17 Η LC/MS tR =2.31 min. 實施例2 — Ί0Μβ MS (ESI) m/z « 405 (M+H)\ 3 18 Η 1 LG/MS t» « 1,84 min. 實施例2 — MS (ESI) m/z =* 403 (M+H)+. 3 19 Η LC/MS tK « 2.64 min. 實施例2 — ^N^V^Me MS (ESI) m/z = 405 (M+H)+. 3 2 0 Η 1 Μ ΟΗ LC/MS tR ® 1.84 min. 實施例2 — MS (ESI) m/z * 405 (M+H)+. 3 2 1 Me LC/MS tH » 2.10 min. 實施例2 — MS (ESI) m/z : 403 (M+H)+. 3 2 2 Η Ae LC/MS tR » 2*63 min* .Me 實施例 2 — Γ MS (ESI) m/z « 446 {Μ+Η} + · 3 2 3 *、$八LC/MS tn » 2.18 min.Me MS (ESI) m/z = 389 &lt;M+H) + . LC/MS tn * 2.44 min. 635 - 141666.doc 201028381 Example 2 - 3 15 Me MS (ESI) LC/MS tR m/z = »1*68 391 (M+H)+. min. Example 2 — 3 16 Me Η MS (ESI) LC/MS tR m/z « » 1,84 404 (H+H)+. min. Example 2 - MS (ESI) m/z « 375 (M+H) +. 3 17 Η LC/MS tR = 2.31 min. Example 2 - Ί0Μβ MS (ESI) m/z « 405 (M+H)\ 3 18 Η 1 LG/MS t» « 1,84 min. Example 2 - MS (ESI) m/z =* 403 (M+H)+. 3 19 Η LC/MS tK « 2.64 min. Example 2 — ^N^V^Me MS (ESI) m/z = 405 (M+H)+. 3 2 0 Η 1 Μ ΟΗ LC/MS tR ® 1.84 min. Example 2 - MS (ESI) m/z * 405 (M+H)+. 3 2 1 Me LC/MS tH: 2.10 min. Example 2 - MS (ESI) m/z: 403 (M+H)+. 3 2 2 Η Ae LC/MS tR » 2*63 min* .Me Example 2 - Γ MS (ESI) m/z « 446 {Μ+Η} + · 3 2 3 *, $8 LC/MS tn » 2.18 min.

Me 實絶例2 — 3 2 4 *、N，VMe H OH MS (ESI} LC/MS tR m/z = 39i (M+H)' =1,70 min. 實施例2 -3 2 5 Η MS (ESI) LC/MS tK m/z = 391 (M+H)' =1.66 m±n. 實施例2 -3 2 6 Me Me MS (ESI) LC/MS tR m/z « 432 (M+H)+· * 1.88 min. 實施例2 — 3 2 7 H MS (ESI) LC/MS tR m/z * 419 (M+H)+. * 1,99 min. 實施例2 — 3 2 8 .OH H MS (ESI) LC/MS tR m/z « 407 (M+H)，· =1*44 min. 實施例2 ~ 3 2 9 MS (ESI) LC/MS U m/z « 417 (M+H)+. « 2.10 min. 636- 141666.doc 201028381Me Example 2 - 3 2 4 *, N, VMe H OH MS (ESI} LC/MS tR m/z = 39i (M+H)' = 1, 70 min. Example 2 -3 2 5 Η MS (ESI) LC/MS tK m/z = 391 (M+H)' =1.66 m±n. Example 2 -3 2 6 Me Me MS (ESI) LC/MS tR m/z « 432 (M+H +· * 1.88 min. Example 2 - 3 2 7 H MS (ESI) LC/MS tR m/z * 419 (M+H) +. * 1,99 min. Example 2 - 3 2 8 .OH H MS (ESI) LC/MS tR m/z « 407 (M+H), · =1*44 min. Example 2 ~ 3 2 9 MS (ESI) LC/MS U m/z « 417 (M+ H)+. « 2.10 min. 636- 141666.doc 201028381

實施例2 — 3 3 0 Η MS (ESI) LC/MS t8 m/z ® 430 (M+H)+. * 1.88 xnin. 實施例2 — 3 3 1 *、Ν力 Η MS (ESI) LC/MS tM m/2 « 387 (K+H)+. ® 2*41 I&amp;1.XI. 實施例2 — 3 3 2 MS (ESI) LC/MS tR m/z » 387 (M+H}+. » 2.33 實施例2 — 3 3 3 Υ° MS (ESI) LC/MS tR m/z * 401 (M+H)+. » 2.58 min· 實施例2 -3 3 4 MS (ESI) LC/MS ts m/z = 429 (M+H)+. » 2.85 min* 實施例2 — 3 3 5 MS (ESI) LC/MS tR m/z 雄 459 (M+H)+. ，2·37 min. 實施例2 — 3 3 6 Η MS (ESI) LC/MS t8 m/z » 417 (M+H)+. =1*99 min. 實施例2 -3 3 7 MS {ESI) LC/HS tR m/z = 431 (M+H)+* a 2.04 min« 實施例2 — 3 3 8 MS (ESI) LC/MS tK m/z ® 426 (M+H”. « 2.20 min. 實施例2 — 3 3 9 MS (ESI) LC/MS tR m/z = 413 « 2.16 min* 實施例2 — 3 4 0 Η MS (ESI) LC/MS tR m/z « 426 (M+H)*. » 2 »21 lain* 實施例2 — 3 4 1 Η MS (ESI) LC/MS tR m/z » 437 (M+tt}+. « 2.51 min. 實施例2 ~ 3 4 2 MS (ESI) LC/MS tR m/z * 458 (M4-H} + . 2.08 min. 141666.doc 637- 201028381 實施例23 4 3Example 2 - 3 3 0 Η MS (ESI) LC/MS t8 m/z ® 430 (M+H) +. * 1.88 xnin. Example 2 - 3 3 1 *, Ν Η MS (ESI) LC/ MS tM m/2 « 387 (K+H)+. ® 2*41 I&amp;1.XI. Example 2 - 3 3 2 MS (ESI) LC/MS tR m/z » 387 (M+H}+ » 2.33 Example 2 - 3 3 3 Υ° MS (ESI) LC/MS tR m/z * 401 (M+H) +. » 2.58 min· Example 2 -3 3 4 MS (ESI) LC/MS Ts m/z = 429 (M+H)+. » 2.85 min* Example 2 - 3 3 5 MS (ESI) LC/MS tR m/z Male 459 (M+H)+., 2.37 min. Example 2 — 3 3 6 Η MS (ESI) LC/MS t8 m/z » 417 (M+H)+. =1*99 min. Example 2 - 3 3 7 MS {ESI) LC/HS tR m /z = 431 (M+H)+* a 2.04 min« Example 2 - 3 3 8 MS (ESI) LC/MS tK m/z ® 426 (M+H". « 2.20 min. Example 2 - 3 3 9 MS (ESI) LC/MS tR m/z = 413 « 2.16 min* Example 2 - 3 4 0 Η MS (ESI) LC/MS tR m/z « 426 (M+H)*. » 2 » 21 lain* Example 2 - 3 4 1 Η MS (ESI) LC/MS tR m/z » 437 (M+tt}+. « 2.51 min. Example 2 ~ 3 4 2 MS (ESI) LC/MS tR m/z * 458 (M4-H} + . 2.08 min. 141666.doc 637- 201028381 Example 2343

O MS (ESI) nt/z = 506 (M+H) + , LC/MS tR = 2.10 min.O MS (ESI) nt/z = 506 (M+H) + , LC/MS tR = 2.10 min.

實施例2 3 4 6 實施例23 4 7 丨 MS (ESI) m/a » 442 (M+H)+. LC/MS tR « 2.08 rain. MS (ESI) m/z = 430 (M+H)+. LC/MS ta « 1.85 min. 實施例2 3 4 8 實施例2 3 4 9 MS (ESI) m/z = 465 (M+H)+. LC/MS tR = 2.43 min. MS (ESI) m/z = 452 (M+H)+. LC/MS tR - 2.02 min.Example 2 3 4 6 Example 23 4 7 丨MS (ESI) m/a » 442 (M+H)+. LC/MS tR « 2.08 rain. MS (ESI) m/z = 430 (M+H) LC/MS ta « 1.85 min. Example 2 3 4 8 Example 2 3 4 9 MS (ESI) m/z = 465 (M+H)+. LC/MS tR = 2.43 min. MS (ESI) m/z = 452 (M+H)+. LC/MS tR - 2.02 min.

Me 實施例23 5 2Me Example 23 5 2

MS (ESI) rn/z » 481 (M+H) LC/MS tR - 2.22 min. 實施例2 3 5 3 MS (ESI) m/z = 474 (M+H)+. LC/MS tn * 1.99 min. 實施例23 5 4MS (ESI) rn/z: 481 (M+H)::::::::::::::: Min. Example 23 5 4

MS (ESI) ro/z = 478 (M+H)+. LC/MS tR = 2.14 min. 141666.doc -638- 201028381 參 實施例2 —3 5 5 MS (ESI) m/z = 419 (M+H)+. LC/MS tR * 2.27 min. 實施例2 —3 5 6MS (ESI): m/z = 419 (M): +H)+. LC/MS tR * 2.27 min. Example 2 - 3 5 6

MeMe

/OMe N H MS (ESI) m/z 405 (M+H)+. LC/MS tR = 2.18 min. 實施例23 5 7 MS (ESI) m/z * 371 LC/MS tR = 2.05 rain· 實施例2 —3 5 8/OMe NH MS (ESI) m/z 405 (M+H) +. LC/MS </RTI> </RTI> 2 — 3 5 8

Me 〇 MS (ESI) m/z * 433 (M+H) + . LC/MS tR » 2.11 min. 實施例23 5 9 N Me ；N-Me MS (ESI) m/z « 430 (M+H) + · LC/MS tR » 1.95 min.Me 〇MS (ESI) m/z * 433 (M+H) + . LC/MS tR » 2.11 min. Example 23 5 9 N Me ; N-Me MS (ESI) m/z « 430 (M+H ) · · LC/MS tR » 1.95 min.

實施例23 6 2Example 23 6 2

MS (ESI) m/Z « 433 (M+H) + · LC/MS tR « 1.88 min. 實施例23 6 3 'OMe MS (ESI) m/z = 460 (M+H)1 LC/MS tR = 1.92 min. 實施例23 6 4 Ό、 d、b MS (ESI) m/z » 494 (M+H) + . LC/MS tR « 2.02 min. 實施例23 6 5MS (ESI) m/Z « 433 (M+H) + · LC/MS tR « 1.88 min. Example 23 6 3 'OMe MS (ESI) m/z = 460 (M+H)1 LC/MS tR = 1.92 min. Example 23 6 4 Ό, d, b MS (ESI) m/z » 494 (M+H) + . LC/MS tR « 2.02 min. Example 23 6 5

CF3 MS (ESI) m/z » 469 (M+H) + . LC/MS frR « 2,65 min. 實施例23 6 6CF3 MS (ESI) m/z » 469 (M+H) + . LC/MS frR « 2, 65 min. Example 23 6 6

HH

O MS (ESI) m/z - 433 (M+H)' LC/MS tR » 1.96 min. 實施例23 6 7O MS (ESI) m/z - 433 (M+H)' LC/MS tR: 1.96 min. Example 23 6 7

MeOMeO

MS (ESI) m/z * 43X (M+H)* LC/MS tn * 2.32 min* 141666.doc -639- 201028381 實施例2 — 3 6 8 實施例2 3 6 9 實施例2 — 3 7 0 實施例2 — 3 7 1 實施例2 — 3 7 2 實施例2 3 7 3 實施例2 — 3 7 4 實施例2 — 3 7 5MS (ESI) m/z * 43X (M+H) * LC/MS tn * 2.32 min * 141666.doc -639 - 201028381 Example 2 - 3 6 8 Example 2 3 6 9 Example 2 - 3 7 0 Example 2 - 3 7 1 Example 2 - 3 7 2 Example 2 3 7 3 Example 2 - 3 7 4 Example 2 - 3 7 5

MS (ESI) m/z = 444 (M+H)+. LC/MS tR = 2.06 min. MS (ESI) m/z = 372 (M+H)+. LC/MS tR = 2.24 min. MS (ESI) m/z = 452 (M+H)+. LC/MS tR = 2.01 min. MS (ESI) m/z = 427 (M+H)+. LC/MS tR * 1,62 min. MS (ESI) m/z - 427 (M+H)+. LC/MS tn s 2.33 mxn. MS (ESI) m/z » 437 (M+H)+. LC/MS tH * 2.53 min. MS (ESI) m/2 = 449 (M+H)+. LC/MS t* « 2,68 min. MS (ESI) m/z = 444 {M+H)+. LC/MS tR = 1.57 min.MS (ESI) m/z = 444 (M+H) +. LC/MS: s. MS (ESI) m/z = 427 (M+H) +. LC/MS tR * 1,62 min. MS (M). MS (ESI) m/z » 437 (M+H)+. LC/MS tH * 2.53 min. MS (ESI) m/2 = 449 (M+H)+. LC/MS t* « 2,68 min. MS (ESI) m/z = 444 {M+H)+. LC/MS tR = 1.57 min.

377 Me LC/MS tR - 2.15 min.377 Me LC/MS tR - 2.15 min.

(實施例3)TTK分析及A549分析之結果 以下表示TTK分析及A549分析之結果之代表性者。表中 IC5G係以μΜ表示。 -640- 141666.doc 201028381 表7 [表 7-1](Example 3) Results of TTK analysis and A549 analysis The following are representative of the results of TTK analysis and A549 analysis. The IC5G in the table is expressed in μΜ. -640- 141666.doc 201028381 Table 7 [Table 7-1]

實施例 TTK tCsoi/iM) A549lCs〇&lt;jUM) 實施例 TTKIC50(/&lt;M) A549 IC^iuU) 1-1 42.173 1-169 1.536 1-2 0.312 1-174 0.498 1.0&lt;1C5D^ 10 1-3 0.703 t-187 3.881 1-4 0.398 1-191 2.769 1-β 0.688 1-193 0.147 1-8 0.235 1-215 0.024 1-12 0.399 1-236 0-044 1-24 0.735 1-237 0.054 1~33 0.803 1-238 0.065 1-41 1.703 t-239 0.0H 1-43 0.897 1-252 0.042 t.O&lt;ICsoS 10 1-44 0.212 1-264 0.009 1.0 &lt;IC50^ 10 t-45 0.142 1-271 0.014 1-51 0.350 1-273 0.043 t-δδ 1.822 1*288 0.010 1.0 &lt; IC50 1 10 t-75 o.eta 1-290 0.017 t.O&lt;ICso^ 10 1-77 0.976 1-293 0.018 0,1 &lt;1〇3〇^ 1.0 1-81 0.508 1-296 0,034 1,0&lt;ICso!S 10 1-90 0.568 1-305 0.012 1.0&lt;ϊ〇5〇^ 10 1-91 0.445 1-309 0.037 1*0 &lt; ϊ〇5〇 ^ 10 t-93 0.685 1-313 0.013 ICso ^ 0,1 t-98 0.169 1-326 0.015 1.0 &lt; ICSD S 10 1-99 0.671 1-330 0.017 0.1 &lt;10^5 1.0 t-100 4.200 1-331 0.011 0,1 &lt;IC50^ 1.0 1-103 12.140 1-339 0.008 1.0&lt;IC565 10 1-105 2.107 1-340 0.004 ?.〇 &lt; ICse ^ 10 1-108 3J55 1-341 0.02B 1,0&lt;ICso^1〇 1-112 8.565 1-343 o.oto i.o&lt;ic$0^io 1-120 3.709 1-350 0.023 1.0&lt;ICso^ 10 1-123 1.064 1-356 0.145 t-129 10.963 1-384 0.847 t.O &lt; ICSD ^ 10 t-130 3.526 t-390 0.012 1-131 7.065 1-391 0.007 1-132 0J26 1-399 0.050 t«137 1.484 1.0 &lt;10^110 1-400 0.028 1.0 &lt; IC50 5 10 1-140 0,174 1-403 0.035 1.0 &lt; ICS0 ^ 10 1-145 0.017 1-412 0.551 1-146 0.133 1-414 0.055 1-148 0.044 1*417 0.022 0.1 &lt;ic50^ 1.0 141666.doc -641 - 201028381 [表 7-2] 實施例 TTK ICW (U M) A549 ICW (μ M) 1-419 0.012 1,0 &lt; Ι〇5〇 ά 10 1-422 0.012 1.0 &lt; IC50 £ 10 1-424 0.002 0.1 &lt; IC50 ^ t.o 1-427 0.004 0.1 &lt; IC5〇 &lt; 1.0 1-435 0.005 0.1 &lt; IC50 &lt; 1.0 1-436 0.018 t.0&lt;IC5〇&lt; 10 1-437 0.043 0.1 &lt;1CS0^ 1.0 1-447 0,013 0.1 &lt; icso ^ t.o 1-450 0.025 1.0&lt;ICs〇&lt;：10 1-451 0.014 1.0&lt;iu 10 1-452 0.012 1.0&lt;Ι〇5〇ί：10 1—455 0.009 1.0&lt;IC50^ 10 1-456 0.011 0.1 &lt; ic5〇 ^ t.o 1-461 0.008 0.1 &lt; icso s t.o 1-463 0.005 0.1 &lt; 1C50 &lt; 1.0 1-464 1.602 t.0&lt;IC5O^ 10 1-468 0.002 1.0&lt;Ι〇5〇110 1-469 0.007 1,0&lt;ICso£ 10 1-472 0.009 t.o &lt; ICs〇 S 10 1»47β 0.006 1.0&lt;ICso5 10 1-477 0.090 1.0&lt;IC5〇S 10 1-478 0.033 t.O&lt;ICso5 to 1-479 0.020 1.0 &lt;1050$ 10 1-482 0.005 t.o &lt;ICS01 10 1-483 0.089 t.o &lt; IC5〇 S 10 1-484 0.030 1.0 &lt; ICso 5 10 1-489 0.005 0.1 &lt; 1CS0 S 10 1-490 0.008 0.1 &lt;ic50 1 1.0 t»402 0.003 0.1 &lt;ic50i t.o 1-494 0.007 0.1 &lt; IC5〇 5 1.0 1-499 0.067 0.1 &lt; IC5〇 ^ 1,0 1-500 0.006 0,1 &lt; IC50 ^ 1.0 1-504 0.005 1.0&lt;ICsol 10 1-506 0.010 t.O&lt;IC5〇i 10 1-507 0.012 0.1 &lt;1CS0S 1.0 1-510 0.006 OJ &lt; IC5〇 1 1.0 1-516 0.008 1.0&lt;IC5〇^ to 1-519 0.003 1.0&lt;ICs〇^ 10 1-521 0.014 0.1 &lt; IC50 s 1.0 t-524 0.060 t.o &lt;Ι〇5〇^ to 實施例 TTK IC50(//M) A549 !CS0 (μΜ) 1-526 0.073 1-529 0.084 1.0&lt;IC5〇^10 1-530 0.186 1-531 0.525 t.O &lt; IC50 &lt;； 10 1-533 13.389 &lt; ICS0 彡 10 1-537 0.003 ICS0 ^ 0.1 1-538 0.005 0.1 &lt; IC50 &lt; 1.0 1-539 0.020 1.0 &lt; IC50 S 10 1-540 0.011 1.0&lt;ICsoS to 1-541 0.007 0.1 &lt;IO50 i 1.0 1-542 0.003 ICso 1 0.1 1-543 0.005 0.1 &lt;Ι〇5〇1 1.0 1-544 0.004 o.t &lt;Ι〇50^ 1.0 1-545 0.004 0.1 &lt; ICsqU.O 1-547 0.005 t.o &lt;ic50i 10 1-548 0.009 1.0&lt;IC5〇110 1-549 0.012 1.0&lt;IC5〇110 1-550 0.043 0.1 &lt;IC50H.O 1-551 0.021 1.0&lt;IC5O5 10 1-552 0.014 t.O&lt;ICsoS10 1-554 0.006 1.0&lt;IC5〇^10 1-555 0.010 0_t &lt; ICjo 1 1·0 1-556 0.010 1.0&lt;!Cso5 10 1-557 0.007 t.0&lt;IC5O^ 10 1-55« 0,013 1.0 &lt; IC50 &lt; 10 1-559 0.007 0.1 &lt; ICs〇 ^ 1.0 1-560 0,005 0,1 &lt;IC50&lt; 1.0 1-561 0.055 0.1 &lt;Ι〇5〇^ 1.0 1-562 0.005 0.1 &lt; IC5〇 s 1.0 1-563 0.006 0.1 &lt;icM &lt;, 1.0 t-564 0.015 0.1 &lt; IC50 S 1,0 1-565 0.017 0.1 &lt;ICS0^ 1,0 1-568 0.058 0.1 &lt;ICS01 1.0 1-587 0.018 0,1 &lt;IC50^ 1.0 1-568 0.005 1*0 &lt; IC5〇^ 10 1-569 0.015 0.1 &lt;IC56S 1.0 1-570 0.040 0.1 &lt; ICso^S 1.0 t-571 0.005 0.1 &lt; ICso s t.o 1-572 0,007 1.0 &lt; ICso ^ 10 1-573 0.008 t*0 &lt; ICs〇 ^ 10 642- 141666.doc 201028381 [表 7-3]EXAMPLE TTK tCsoi/iM) A549lCs〇&lt;jUM) Example TTKIC50(/&lt;M) A549 IC^iuU) 1-1 42.173 1-169 1.536 1-2 0.312 1-174 0.498 1.0&lt;1C5D^ 10 1 -3 0.703 t-187 3.881 1-4 0.398 1-191 2.769 1-β 0.688 1-193 0.147 1-8 0.235 1-215 0.024 1-12 0.399 1-236 0-044 1-24 0.735 1-237 0.054 1 ~33 0.803 1-238 0.065 1-41 1.703 t-239 0.0H 1-43 0.897 1-252 0.042 t.O&lt;ICsoS 10 1-44 0.212 1-264 0.009 1.0 &lt;IC50^ 10 t-45 0.142 1- 271 0.014 1-51 0.350 1-273 0.043 t-δδ 1.822 1*288 0.010 1.0 &lt; IC50 1 10 t-75 o.eta 1-290 0.017 t.O&lt;ICso^ 10 1-77 0.976 1-293 0.018 0 , 1 &lt;1〇3〇^ 1.0 1-81 0.508 1-296 0,034 1,0&lt;ICso!S 10 1-90 0.568 1-305 0.012 1.0&lt;ϊ〇5〇^ 10 1-91 0.445 1-309 0.037 1*0 &lt; ϊ〇5〇^ 10 t-93 0.685 1-313 0.013 ICso ^ 0,1 t-98 0.169 1-326 0.015 1.0 &lt; ICSD S 10 1-99 0.671 1-330 0.017 0.1 &lt; 10^5 1.0 t-100 4.200 1-331 0.011 0,1 &lt;IC50^ 1.0 1-103 12.140 1-339 0.008 1.0&lt;IC565 10 1-105 2.107 1-340 0.004 ?.〇 &Lt; ICse ^ 10 1-108 3J55 1-341 0.02B 1,0&lt;ICso^1〇1-112 8.565 1-343 o.oto i.o&lt;ic$0^io 1-120 3.709 1-350 0.023 1.0&lt ;ICso^ 10 1-123 1.064 1-356 0.145 t-129 10.963 1-384 0.847 tO &lt; ICSD ^ 10 t-130 3.526 t-390 0.012 1-131 7.065 1-391 0.007 1-132 0J26 1-399 0.050 t«137 1.484 1.0 &lt;10^110 1-400 0.028 1.0 &lt; IC50 5 10 1-140 0,174 1-403 0.035 1.0 &lt; ICS0 ^ 10 1-145 0.017 1-412 0.551 1-146 0.133 1-414 0.055 1-148 0.044 1*417 0.022 0.1 &lt;ic50^ 1.0 141666.doc -641 - 201028381 [Table 7-2] Example TTK ICW (UM) A549 ICW (μ M) 1-419 0.012 1,0 &lt; Ι 〇5〇ά 10 1-422 0.012 1.0 &lt; IC50 £ 10 1-424 0.002 0.1 &lt; IC50 ^ to 1-427 0.004 0.1 &lt;IC5〇&lt; 1.0 1-435 0.005 0.1 &lt; IC50 &lt; 1.0 1- 436 0.018 t.0&lt;IC5〇&lt; 10 1-437 0.043 0.1 &lt;1CS0^ 1.0 1-447 0,013 0.1 &lt; icso ^ to 1-450 0.025 1.0&lt;ICs〇&lt;:10 1-451 0.014 1.0&lt ;iu 10 1-452 0.012 1.0&lt;Ι〇5〇ί:10 1—455 0.009 1.0&lt;IC50^ 10 1-456 0.011 0.1 &lt; Ic5〇^ to 1-461 0.008 0.1 &lt; icso s to 1-463 0.005 0.1 &lt; 1C50 &lt; 1.0 1-464 1.602 t.0&lt;IC5O^ 10 1-468 0.002 1.0&lt;Ι〇5〇110 1- 469 0.007 1,0&lt;ICso£ 10 1-472 0.009 to &lt; ICs〇S 10 1»47β 0.006 1.0&lt;ICso5 10 1-477 0.090 1.0&lt;IC5〇S 10 1-478 0.033 t.O&lt;ICso5 to 1-479 0.020 1.0 &lt;1050$ 10 1-482 0.005 to &lt;ICS01 10 1-483 0.089 to &lt; IC5〇S 10 1-484 0.030 1.0 &lt; ICso 5 10 1-489 0.005 0.1 &lt; 1CS0 S 10 1-490 0.008 0.1 &lt;ic50 1 1.0 t»402 0.003 0.1 &lt;ic50i to 1-494 0.007 0.1 &lt; IC5〇5 1.0 1-499 0.067 0.1 &lt; IC5〇^ 1,0 1-500 0.006 0,1 &lt; IC50 ^ 1.0 1-504 0.005 1.0&lt;ICsol 10 1-506 0.010 t.O&lt;IC5〇i 10 1-507 0.012 0.1 &lt;1CS0S 1.0 1-510 0.006 OJ &lt; IC5〇1 1.0 1-516 0.008 1.0&lt;IC5〇^ to 1-519 0.003 1.0&lt;ICs〇^ 10 1-521 0.014 0.1 &lt; IC50 s 1.0 t-524 0.060 to &lt;Ι〇5〇^ to Example TTK IC50(//M) A549 !CS0 (μΜ) 1-526 0.073 1-529 0.084 1.0&lt;IC5〇^10 1-530 0.186 1-531 0.525 tO &lt; IC50 &lt;; 10 1-533 13.389 &lt; ICS0 彡10 1-537 0.003 ICS0 ^ 0.1 1-538 0.005 0.1 &lt; IC50 &lt; 1.0 1-539 0.020 1.0 &lt; IC50 S 10 1-540 0.011 1.0&lt;ICsoS To 1-541 0.007 0.1 &lt;IO50 i 1.0 1-542 0.003 ICso 1 0.1 1-543 0.005 0.1 &lt;Ι〇5〇1 1.0 1-544 0.004 ot &lt;Ι〇50^ 1.0 1-545 0.004 0.1 &lt; ICsqU.O 1-547 0.005 to &lt;ic50i 10 1-548 0.009 1.0&lt;IC5〇110 1-549 0.012 1.0&lt;IC5〇110 1-550 0.043 0.1 &lt;IC50H.O 1-551 0.021 1.0&lt;IC5O5 10 1-552 0.014 t.O&lt;ICsoS10 1-554 0.006 1.0&lt;IC5〇^10 1-555 0.010 0_t &lt; ICjo 1 1·0 1-556 0.010 1.0&lt;!Cso5 10 1-557 0.007 t.0&lt ;IC5O^ 10 1-55« 0,013 1.0 &lt; IC50 &lt; 10 1-559 0.007 0.1 &lt; ICs〇^ 1.0 1-560 0,005 0,1 &lt;IC50&lt; 1.0 1-561 0.055 0.1 &lt;Ι〇5〇 ^ 1.0 1-562 0.005 0.1 &lt; IC5〇s 1.0 1-563 0.006 0.1 &lt;icM &lt;, 1.0 t-564 0.015 0.1 &lt; IC50 S 1,0 1-565 0.017 0.1 &lt;ICS0^ 1,0 1 -568 0.058 0.1 &lt;ICS01 1.0 1-587 0.018 0,1 &lt;IC50^ 1.0 1-568 0.005 1*0 &lt; IC5〇^ 10 1-569 0.015 0.1 &lt;IC56S 1.0 1-570 0.040 0.1 &lt; ICso^S 1.0 t-571 0.005 0.1 &lt; ICso s to 1-572 0,007 1.0 &lt; ICso ^ 10 1-573 0.008 t*0 &lt; ICs〇^ 10 642- 141666.doc 201028381 [Table 7-3]

實施例 TTK 1C50(#iM) A549 ICjoUiM) 1-574 0.004 0.1 &lt;Ι〇5〇^ 1.0 1-575 0.006 t.O &lt; ICS0 110 1-576 0.007 1.0&lt;IC5〇^ 10 1-577 0.008 0.1 &lt;I〇s〇^ 1.0 1*578 0.035 0.1 &lt; ICS0 £ 1.0 1-579 0.006 0.1 &lt; ICS0 £ 1.0 1-580 0.005 0.1 &lt;!CS0^ 1.0 1-581 0.005 t.O&lt;ICsoi 10 t - 582! 0.029 0.1 &lt;1C50-S 1.0 1-583 0.010 IC50 ά 0.1 1-584 0.007 1,0 &lt;IC50S 10 1-585 0.009 0.1 &lt; ic50 &lt;, 1.0 1-58S 0.005 0.1 &lt;IC50^ 1,0 1*587 0.005 0.1 &lt;IC50i 1,0 1-589 0.006 0.1 &lt; ICs〇 ά 1.0 1-591 0.007 0.1 &lt; ICS0 s t.0 ί-592 0.006 0.1 &lt;1CS0^ 1.0 1-593 0.007 0.1 &lt;IC50^ 1.0 1-594 0.005 0,1 &lt;IC5〇^ 1.0 1-595 0.011 0.1 &lt;1C50^ 1.0 1-697 0.00$ 0.1 &lt; ICS0 ^ 1.0 1-598 0.008 0.1 &lt;ICs〇S 1.0 1-599 0.009 0.1 &lt; ICso i t.0 1-600 0.005 0.1 &lt;1CS0^ 1.0 t-601 0,039 0.1 &lt; !Cs〇 ^ 10 1-602 0.008 1.0&lt;iCso5 10 1-603 0.006 0.1 &lt;Ι〇5〇ί 1.0 1-β04 0.005 0,1 &lt; ICs〇 ^ 1.0 1-605 0.004 OJ &lt; ICso ά 1.0 1-606 0.008 0.1 &lt;1050^1.0 t-607 0.017 1 ·0&lt;〗〜！ 10 1-609 0.004 0.1 &lt; ICso 11.0 1-610 0.090 0.1 &lt; ICso S 1.0 1-611 0,005 ICTO ^ 0.1 1-612 0.005 0,1 &lt; ICso ^ 1-0 1-613 0.00$ 0.1 &lt; IC50 ^ 1-614 0.011 1.0 &lt;!C50i 10 1-615 0.004 0.1 &lt;1C50S 1.0 1-616 0.006 ICso ^ 01 1-617 0.010 t.O &lt;IC50S 10 實施例 TTK !CS0(/iM) AS49 ΙΟ» (//Μ) 1-618 0.007 ΟΛ &lt; IGs〇 11.0 1-619 0.004 〈Κ^Ι 10 1-620 0.004 0.1 &lt; ICgo ^ 1.0 1-621 0.006 0.1 &lt;ICS011.0 卜622 0.008 0.1 &lt; ICso ^ 1-0 1-623 0.008 0,1 &lt; ICso 5 1-624 0.004 0Λ &lt; ICso ^ 1.0 t-625 0.010 0.1 &lt; 1C50 ^ 1-0 0.004 0.1 &lt; 1CS0 1 1.0 1-S27 0.013 0.1 &lt; IGS0 ^ 1.0 1-628 0.094 0,1 &lt; IC50 S 1.0 1-629 0.013 1.0 &lt;1C50^ 10 1*630 0.012 0.1 &lt; ICso ^ 1.0 1-631 0.006 0.1 &lt;1050^1.0 1-632 0.008 0,1 &lt; ICso i 1.0 1-633 0.009 0.1 &lt; 1C50 5 1.0 1-634 0.083 0.1 &lt;1〇5〇^ 1.0 1-635 0.006 0.1 &lt; ICso ^ 1.0 1-638 0.004 0.1 &lt; 1CS0 i 1.0 1-637 0.009 0.1 &lt; ICso i 1.0 1-636 0.017 0.1 &lt; ICso ^ 1.0 1-639 0.043 0.1 &lt; IC50 ^ 1.0 1-641 0.007 0.1 &lt; IC50 5 1.0 1-642 0.004 0.1 &lt; ICs〇 1 1.0 1-643 0.006 0.1 &lt; ICso 1 1,0 1-644 0.006 1.0&lt;1C50$ 10 1*645 0.004 0.1 &lt; IC50 &lt; 1.0 1-64β 0.031 0.1 &lt;iCwl1.0 1-650 0.024 0.1 &lt; ICso ^ 1-0 1-651 0.005 0,1 &lt; lCgo 1 1.0 1-652 0.031 t.O &lt;ICS01 10 1-653 0.003 0.1 &lt; ICso! 1,0 1-854 0.007 0.1 &lt; ICso i 1.0 卜655 0.00$ 1,0 &lt; ICso s to 1-856 0.005 0.1 &lt; ICso 5 1,0 1-657 0.006 1.0&lt;ICM^ 10 1-658 0.007 0.1 &lt; ICS0 ^ 10 1-659 0.036 0.1 &lt; ICso iS 1.0 1-663 9,005 0,1 &lt; ICS0 ^ 10 1-664 0.006 0.1 &lt; IOg〇 S 1Λ 141666.doc 643 - 201028381 [表 7-4] 實施例 TTK ICse (// M) A549 IC5〇 CjU M) 1-865 0.013 1.0&lt;IC5〇110 Ι-6β6 0.005 1.0&lt;1C50i 10 1-667 0.007 1.0&lt;Ι〇5〇1 10 1-868 0.005 O.t &lt; IC50 5 1.0 1-669 0.007 0.1 &lt; ICS0 5 1.0 1-670 0.004 O.t &lt; IC50 5 1.0 1-671 0.005 0.1 &lt; ICs〇 1 1.0 1-672 0.010 1.0 &lt; IGso 5 10 1-673 0.004 0.1 &lt;ICS01 t.o 1-674 0.003 0.1 &lt; 1CS0 £ 1.0 1-675 0.006 0.1 &lt; ICs〇 ^ 1.0 1-678 0.008 0.1 &lt; IC5〇 5 t.o 1-677 0.010 1.0&lt;Ι〇5〇^ 10 1-678 0.007 0.1 &lt; IC50 1 1.0 1-679 0.010 1.0 &lt; IC5〇 110 1-080 0.009 0.1 &lt; IC5〇 ^ t.o 1-681 0.005 0.1 &lt; ICS0 ^ 1.0 1-682 0.Q03 0.1 &lt; ICs〇 ^ t.0 1-683 0.003 O.t &lt; IC5〇 ^ 1.0 1-684 0.005 0.1 &lt; IC50 1 t.o 1-686 0.007 0.1 &lt; IC5〇 ^ 1.0 t-687 0.006 o.t &lt; ic50 ^ t.o 1-688 0.014 1.0&lt;ICg〇^10 1-689 0.010 0.1 &lt; ic5〇 &lt; t.o 1-690 0.030 0.1 &lt; IC5〇 1 1.0 1-691 0.010 0.1 &lt; ICs〇 1 hO 1-692 0.012 1.0&lt;1CM&lt;；10 1-693 0.006 1.0&lt;lCs〇i 10 1-694 0.011 1*0 &lt; ICS0 ^ 10 1-695 0.009 1.0 &lt;ICs〇^ 10 1-696 0.008 1.0&lt;1C5〇110 1-697 0,005 1.0&lt;ICSO£10 1-698 o.ooe 0.1 &lt; IC50 ^ t.o 1-699 0.006 1.0&lt;IC5〇ll0 1-700 0.010 0.1 &lt; IC50 ^ t.o 1-701 0.008 0.1 &lt; IC50 1 t.o 1-702 0.005 1,0&lt;IC5oi10 1-703 0.009 1.0&lt;Ι〇5〇^10 1-704 0.015 1.0&lt;Ι〇5〇110 1-705 0.010 1.0&lt;Ι〇5〇110 實施例 TTKIC50(ilM) A549 ICs〇(/iM) 1-706 0.011 1.0&lt;lC5Oi10 t-707 0.006 1.0&lt;IC5O^10 1-708 0.011 1,0 &lt; !Cs〇 ά 10 1-709 0.005 0.1 &lt; IC5〇 1 1.0 1-710 0.006 0.1 &lt; ICso 1 1.0 1-711 0.003 0Λ &lt; IC50 &lt; 1.0 1-712 0.007 1.0 &lt;Ι〇5〇^ 10 1-713 0.006 O.t &lt; ICS0 1 1.0 1-714 0.008 1.0 &lt;1CS0^ 10 1-715 0.011 1.0 &lt;1056 5 10 1-718 0.005 O.t &lt;ICS0^ 1.0 1-717 0.013 1.0&lt;Ι〇5〇5：10 1-718 0.015 1.0&lt;Ι〇5〇110 ι-m 0.006 O.t &lt; IC50^ 1.0 1-720 0.007 O.t &lt;lCg〇5 1.0 1-722 0.005 1.0&lt;1〇5〇&lt; 10 1-723 0.004 1.0 &lt;IC5〇^ 10 1-724 0.008 ι,ο &lt;ι〇5〇^ i〇 1-725 0.004 o.t &lt; IC5〇 ^ t.o 1-726 0.006 0.1 &lt; ICs〇 &lt; 1.0 1-728 0.009 1.0&lt;ICs〇^10 1-72S 0.003 o.t &lt; rc50 ^ 1.0 1-730 0.007 1.0&lt;IC5〇i10 1-731 0.015 0.1 &lt; ICso ^ 1.0 1-732 0.005 o.t &lt; ic50 &lt; 1.0 1-733 0.006 0,t &lt; IC5〇 ^ 1.0 1-734 0.013 O.t &lt; IC50&lt; 1.0 1-735 0.004 O.t &lt; ICs〇 ^ 10 1-736 0.008 o.t &lt; icso 11.0 1-737 o.ooe 1.0 &lt;IC50i 10 1-738 0.010 O.t &lt; IC50 ^ 1.0 1-739 0.007 1.0 &lt;1〇5〇^ 10 1-740 0.017 1.0 &lt;IC50^ 10 1*741 o.ooe t.o &lt;1C501 10 1-742 0.008 1.0 &lt;IC50^ 10 1-743 0.008 1_0 &lt;!Cs〇i 10 1-745 0.022 0.1 &lt; IC50 &lt; 1.0 1*746 0.008 1,〇&lt;IC501 10 1*747 0.007 O.t &lt; ICS0 £ 1.0 1-749 0.010 1.0 &lt;ic50i 10 644- 141666.doc 201028381 [表 7-5]EXAMPLE TTK 1C50(#iM) A549 ICjoUiM) 1-574 0.004 0.1 &lt;Ι〇5〇^ 1.0 1-575 0.006 tO &lt; ICS0 110 1-576 0.007 1.0&lt;IC5〇^ 10 1-577 0.008 0.1 &lt ;I〇s〇^ 1.0 1*578 0.035 0.1 &lt; ICS0 £ 1.0 1-579 0.006 0.1 &lt; ICS0 £ 1.0 1-580 0.005 0.1 &lt;!CS0^ 1.0 1-581 0.005 t.O&lt;ICsoi 10 t - 582! 0.029 0.1 &lt;1C50-S 1.0 1-583 0.010 IC50 ά 0.1 1-584 0.007 1,0 &lt;IC50S 10 1-585 0.009 0.1 &lt; ic50 &lt;, 1.0 1-58S 0.005 0.1 &lt;IC50^ 1 , 0 1*587 0.005 0.1 &lt;IC50i 1,0 1-589 0.006 0.1 &lt; ICs〇ά 1.0 1-591 0.007 0.1 &lt; ICS0 s t.0 ί-592 0.006 0.1 &lt;1CS0^ 1.0 1-593 0.007 0.1 &lt;IC50^ 1.0 1-594 0.005 0,1 &lt;IC5〇^ 1.0 1-595 0.011 0.1 &lt;1C50^ 1.0 1-697 0.00$ 0.1 &lt; ICS0 ^ 1.0 1-598 0.008 0.1 &lt;ICs〇S 1.0 1-599 0.009 0.1 &lt; ICso i t.0 1-600 0.005 0.1 &lt;1CS0^ 1.0 t-601 0,039 0.1 &lt; !Cs〇^ 10 1-602 0.008 1.0&lt;iCso5 10 1-603 0.006 0.1 &lt;;Ι〇5〇ί 1.0 1-β04 0.005 0,1 &lt; ICs〇^ 1.0 1-605 0.004 OJ &lt; ICso ά 1.0 1-606 0.008 0.1 &lt;1050^1.0 t-607 0.017 1 ·0&lt;〗 ~! 10 1-609 0.004 0.1 &lt; ICso 11.0 1-610 0.090 0.1 &lt; ICso S 1.0 1-611 0,005 ICTO ^ 0.1 1-612 0.005 0,1 &lt; ICso ^ 1-0 1-613 0.00$ 0.1 &lt; IC50 ^ 1-614 0.011 1.0 &lt;!C50i 10 1-615 0.004 0.1 &lt;1C50S 1.0 1-616 0.006 ICso ^ 01 1-617 0.010 tO &lt;IC50S 10 Example TTK !CS0(/iM) AS49 ΙΟ» (/ /Μ) 1-618 0.007 ΟΛ &lt; IGs〇11.0 1-619 0.004 〈Κ^Ι 10 1-620 0.004 0.1 &lt; ICgo ^ 1.0 1-621 0.006 0.1 &lt;ICS011.0 Bu 622 0.008 0.1 &lt; ICso ^ 1-0 1-623 0.008 0,1 &lt; ICso 5 1-624 0.004 0Λ &lt; ICso ^ 1.0 t-625 0.010 0.1 &lt; 1C50 ^ 1-0 0.004 0.1 &lt; 1CS0 1 1.0 1-S27 0.013 0.1 &lt; IGS0 ^ 1.0 1-628 0.094 0,1 &lt; IC50 S 1.0 1-629 0.013 1.0 &lt;1C50^ 10 1*630 0.012 0.1 &lt; ICso ^ 1.0 1-631 0.006 0.1 &lt;1050^1.0 1-632 0.008 , 1 &lt; ICso i 1.0 1-633 0.009 0.1 &lt; 1C50 5 1.0 1-634 0.083 0.1 &lt;1〇5〇^ 1.0 1-635 0.006 0.1 &lt; ICso ^ 1.0 1-638 0.004 0.1 &lt; 1CS0 i 1.0 1-637 0.009 0.1 &lt; ICso i 1.0 1-636 0.017 0.1 &lt; ICso ^ 1.0 1-639 0.043 0.1 &lt; IC50 ^ 1.0 1-641 0.007 0.1 &lt; IC50 5 1.0 1-642 0.004 0.1 &lt; ICs〇1 1.0 1-643 0.006 0.1 &lt; ICso 1 1,0 1-644 0.006 1.0&lt;1C50$ 10 1* 645 0.004 0.1 &lt; IC50 &lt; 1.0 1-64β 0.031 0.1 &lt;iCwl1.0 1-650 0.024 0.1 &lt; ICso ^ 1-0 1-651 0.005 0,1 &lt; lCgo 1 1.0 1-652 0.031 tO &lt; ICS01 10 1-653 0.003 0.1 &lt; ICso! 1,0 1-854 0.007 0.1 &lt; ICso i 1.0 Bu 655 0.00$ 1,0 &lt; ICso s to 1-856 0.005 0.1 &lt; ICso 5 1,0 1- 657 0.006 1.0&lt;ICM^ 10 1-658 0.007 0.1 &lt; ICS0 ^ 10 1-659 0.036 0.1 &lt; ICso iS 1.0 1-663 9,005 0,1 &lt; ICS0 ^ 10 1-664 0.006 0.1 &lt; IOg〇S 1Λ 141666.doc 643 - 201028381 [Table 7-4] Example TTK ICse (// M) A549 IC5〇CjU M) 1-865 0.013 1.0&lt;IC5〇110 Ι-6β6 0.005 1.0&lt;1C50i 10 1-667 0.007 1.0&lt;Ι〇5〇1 10 1-868 0.005 Ot &lt; IC50 5 1.0 1-669 0.007 0.1 &lt; ICS0 5 1.0 1-670 0.004 Ot &lt; IC50 5 1.0 1-671 0.005 0.1 &lt; ICs〇1 1.0 1-672 0.010 1.0 &lt; IGso 5 10 1-673 0.004 0.1 &lt;ICS01 to 1-674 0.003 0.1 &lt; 1CS0 £ 1.0 1-675 0.006 0.1 &lt; ICs〇^ 1.0 1-678 0.008 0.1 &lt; IC5〇5 to 1-677 0.010 1.0&lt;Ι〇5〇^ 10 1-678 0.007 0.1 &lt; IC50 1 1.0 1-679 0.010 1.0 &lt; IC5〇110 1-080 0.009 0.1 &lt; IC5〇^ to 1-681 0.005 0.1 &lt; ICS0 ^ 1.0 1-682 0.Q03 0.1 &lt; ICs〇^ t.0 1-683 0.003 Ot &lt; IC5〇^ 1.0 1-684 0.005 0.1 &lt; IC50 1 to 1-686 0.007 0.1 &lt; IC5〇^ 1.0 t-687 0.006 ot &lt; ic50 ^ to 1-688 0.014 1.0&lt;ICg〇^10 1-689 0.010 0.1 &lt;ic5〇&lt; to 1-690 0.030 0.1 &lt; IC5〇1 1.0 1-691 0.010 0.1 &lt; ICs〇1 hO 1-692 0.012 1.0&lt;1CM&lt;;10 1-693 0.006 1.0&lt;lCs〇 i 10 1-694 0.011 1*0 &lt; ICS0 ^ 10 1-695 0.009 1.0 &lt;ICs〇^ 10 1-696 0.008 1.0&lt;1C5〇110 1-697 0,005 1.0&lt;ICSO£10 1-698 o. Ooe 0.1 &lt; IC50 ^ to 1-699 0.006 1.0&lt;IC5〇ll0 1-700 0.010 0.1 &lt; IC50 ^ to 1-701 0.008 0.1 &lt; IC50 1 to 1-702 0.005 1,0&lt;IC5oi10 1-703 0.009 1.0&lt;Ι〇5〇^10 1-704 0.015 1.0&lt;Ι〇5〇110 1-705 0.010 1.0&lt;Ι〇5〇110 Real Example TTKIC50(ilM) A549 ICs〇(/iM) 1-706 0.011 1.0&lt;lC5Oi10 t-707 0.006 1.0&lt;IC5O^10 1-708 0.011 1,0 &lt; !Cs〇ά 10 1-709 0.005 0.1 &lt; IC5〇1 1.0 1-710 0.006 0.1 &lt; ICso 1 1.0 1-711 0.003 0Λ &lt; IC50 &lt; 1.0 1-712 0.007 1.0 &lt;Ι〇5〇^ 10 1-713 0.006 Ot &lt; ICS0 1 1.0 1-714 0.008 1.0 &lt;1CS0^ 10 1-715 0.011 1.0 &lt;1056 5 10 1-718 0.005 Ot &lt;ICS0^ 1.0 1-717 0.013 1.0&lt;Ι〇5〇5:10 1-718 0.015 1.0&lt ;Ι〇5〇110 ι-m 0.006 Ot &lt; IC50^ 1.0 1-720 0.007 Ot &lt;lCg〇5 1.0 1-722 0.005 1.0&lt;1〇5〇&lt; 10 1-723 0.004 1.0 &lt;IC5〇 ^ 10 1-724 0.008 ι,ο &lt;ι〇5〇^ i〇1-725 0.004 ot &lt; IC5〇^ to 1-726 0.006 0.1 &lt;ICs〇&lt; 1.0 1-728 0.009 1.0&lt;ICs〇 ^10 1-72S 0.003 ot &lt; rc50 ^ 1.0 1-730 0.007 1.0&lt;IC5〇i10 1-731 0.015 0.1 &lt; ICso ^ 1.0 1-732 0.005 ot &lt; ic50 &lt; 1.0 1-733 0.006 0,t &lt; IC5〇^ 1.0 1-734 0.013 Ot &lt;IC50&lt; 1.0 1-735 0.004 Ot &lt; ICs〇^ 10 1-736 0.008 ot &lt; icso 11 .0 1-737 o.ooe 1.0 &lt;IC50i 10 1-738 0.010 Ot &lt; IC50 ^ 1.0 1-739 0.007 1.0 &lt;1〇5〇^ 10 1-740 0.017 1.0 &lt;IC50^ 10 1*741 o .ooe to &lt;1C501 10 1-742 0.008 1.0 &lt;IC50^ 10 1-743 0.008 1_0 &lt;!Cs〇i 10 1-745 0.022 0.1 &lt; IC50 &lt; 1.0 1*746 0.008 1,〇&lt;IC501 10 1*747 0.007 Ot &lt; ICS0 £ 1.0 1-749 0.010 1.0 &lt;ic50i 10 644- 141666.doc 201028381 [Table 7-5]

實施例 TTK IC50(/1M) Α549 ICs〇(/iM) 實施例 1 rrxiCsoiiiM) A549 ICsoCilM) 卜750 0.006 0.1 &lt; IC50 ύ 1.0 1-791 0.043 0,1 &lt; IC5Q 5 1.0 1-751 0.006 0,1 &lt; ICS011.0 1-793 0.043 0.1 &lt; ic50 ^ 1,0 1-752 0.009 1,0&lt;lCso^10 1-794 0.02S 0.1 &lt;Ι〇5〇^ 1.0 1-753 0.007 1.0&lt;1CS〆 to 1-795 0Λ11 0.1 &lt;ICS0&lt;： 1,0 1-754 0.005 1-796 0.005 0.1 &lt; ICso ^ 1.0 1-755 0.005 1.0 &lt;1050 5 10 1-797 0.013 1.0 &lt;ICs〇l 10 1-756 0.00$ 0,1 &lt; IC50 ^ t.o 1-798 0.01$ 1*0 &lt;1050 1 10 1-757 0.004 1.O&lt;IC50ltO 1-799 0.007 0.1 &lt; ICS0 1 1,0 1-758 0.006 1.0 &lt;10^110 1-800 0.010 0.1 &lt;tC5〇iS 1Λ 1-759 0.005 1.0&lt;Ι〇5〇ί to 1-801 0.010 0.1 &lt; ICso 11,0 1-760 0.004 0.1 &lt;IC50lt.O t-802 0.004 0.1 &lt; ICso 5 1.0 1-761 0.010 1,0 &lt;10〆 10 1-803 0.003 0,1 &lt; ICso 11Λ 1-762 0.002 0.1 &lt;ICs〇^ 1.0 1-804 0.005 0.1 &lt; iCso 1 1.0 1-763 0.005 0.1 &lt; IC50 1 1.0 1-808 0.007 0.1 &lt; IC50^ 1.0 1-764 0.003 0.1 &lt;ICsoS 1.0 1-807 0.005 0.1 &lt; ICso ^ 1-0 1-765 0.006 0.1 &lt;1C5〇11.0 1-808 0.005 0.1 &lt; IC50 £. 1Λ 1-786 0.008 1.0 &lt;icwi 10 1-809 0.01? 0.1 &lt; ICso ^ 1.0 1-767 0.007 1.0&lt;ICso^10 1-810 0.010 0.1 &lt; ICs〇 ^ 1-768 0.004 1,0&lt;1C50^ 10 1-811 0.006 1,0 &lt; ICso 5 10 1*769 0.005 0,1 &lt;ICs〇^ 1,0 1-812 0.005 0,1 &lt; ICso &lt; 1,0 1-770 0.011 OJ &lt; IC50 ^ 1,0 1-814 0.012 1.0 &lt; ICso ^ 10 1-771 0.008 0.1 &lt; 1CS0 1 1.0 1-815 0.010 0.1 &lt; ICS0 1 1,0 1-772 0.009 o.t &lt; ICso i t.o 1-816 0.012 O.t &lt; Ι〇5〇 £ 1Λ 1-773 0-008 1.0&lt;1〇5〇1 10 1-817 0.013 1.0 &lt; ICso ^ 10 卜774 0.007 1.0 &lt;1050 &lt;10 1*818 0.035 0.1 &lt; IC5〇 &lt; 1.0 1-775 0.007 1.0&lt;IC50110 1-819 0.009 1.0 &lt; ICso S 10 1-778 0.003 0.1 &lt; ICS0 ^ 1.0 1-820 0.005 1.0 &lt; 1〇5〇 iS 10 1-777 0.006 0.1 &lt;IC50lt.O 1-821 o.ote O.t &lt;IC5〇 ^ 1.0 1-778 0.010 1.0&lt;ICW5 10 1-823 0.015 0.1 &lt; ICW £ 1.0 1-779 0.004 1.0 &lt; 1C〆 10 1-824 0.043 0.1 &lt; ICso 彡 1.0 1-780 0.007 1.0&lt;IC50^ to 1-825 0.008 1.0&lt;1〇5〇£10 1-781 0.003 IC50 SI 0.1 1-826 0.011 1.0&lt;1C50^10 1-782 ο.οοβ 0.1 &lt;1CS0 ^ 1.0 1-827 0.011 1.0 &lt;IC50^ 10 1-7B3 0-010 1.0 &lt;1050 110 1-828 0.028 0.1 &lt; ICso i 1.0 1-784 0.007 1.0&lt;1〇5〇^ 10 1-829 0.006 1,0 &lt; ICso ^ 10 1-785 0.006 0,1 &lt;Ι〇5〇^ 1,0 1-830 0.008 1.0 &lt;Ϊ〇50110 1-780 0.009 0.1 &lt; 1CS0 1 t.o 1-831 0.005 O.t &lt; ICg〇 ^ 1.0 1-787 0.0QS 1.0 &lt;10^110 1-832 0.005 0.1 &lt;iCw^1.0 1-788 0.003 0.1 &lt; ICS0 1 1.0 1-833 0.066 O.t &lt; ICg〇 11,0 1-789 0.005 0.1 &lt;Ι〇5〇11.0 1-834 0.017 1.0&lt;ΙΟΜ110 141666.doc 645- 201028381 [表 7-6] 實施例 TTKlCs^M) Α549 1C；» (&quot;Μ) 1-835 0,006 0,1 &lt; 1C50 5 1,0 1-838 0.014 1.0&lt;lC5〇^10 1-840 0.016 1*0 &lt;ic50i 10 1-841 0.008 1.0 &lt; IC50 S 10 1-842 0.011 1.0 &lt;IC50110 1-843 0.017 1.0 &lt;IC501 10 1-844 0.018 1.0&lt;IC5〇S10 1-845 0.004 0.1 &lt; IC50 1 1.0 1-846 0.007 0.1 &lt;ICS0^ 1.0 1-848 0.011 1.0&lt;IC5o^ 10 1-849 0,023 0.1 &lt; ICS0 11.0 1-851 0.039 0.1 &lt; IC50 i 1.0 1-853 0.006 1.0&lt;IC5〇^ 10 1-854 0.015 1.0 &lt; IO50 ^ 10 ΙΗΒδδ 0.018 1.0&lt;IC5〇&lt; 10 1-857 0.007 1.0 &lt;!Csoi 10 1-859 0.005 0.1 &lt; JCspi： 1.0 1-880 0.007 1-0&lt;ic505 10 1»8β1 0.006 1.0 &lt; ICS0 1 10 1-862 0.008 1.0&lt;IC5〇l 10 1-863 0.009 1.0&lt;IC5〇^ 10 1-864 0.008 1.0&lt;IC5〇&lt; to 1-865 0.007 1.0 &lt;ICS0 &lt;： 10 1-866 0.006 1.0&lt;IC5〇^ 10 1»8β7 0.007 1.0 &lt; IC50 £ 10 1-868 0.005 0.1 &lt; 1C50 S 1.0 1-869 0.018 1.〇&lt;IC50l 10 1-872 0.017 1.0&lt;IC50i 10 1-873 0.019 1.0&lt;ICso5 10 1-874 0.018 1.0 &lt; ICs〇 10 1-875 0.007 1.0&lt;lC5O^10 1-876 0.011 0.1 &lt; !C50 1 1.0 1-877 0.008 1.0 &lt;IC5〇l 10 1-878 0.004 0.1 &lt; ICs〇 &lt; 1.0 1-880 0.006 1.0 &lt;IC50S 10 1-881 0.005 0,1 &lt;1〇5〇5 1.0 1-882 0.008 1.0&lt;IC5〇i to 1-884 0.007 0.1 &lt;1〇5〇5 1.0 1-886 0.038 0.1 &lt; ICso ^ 1.0 1-887 0.005 o.i &lt; icS0s 1Λ 實施例 TTKICao〇/M) A549 IC50 (am 1-888 0.006 0.1 &lt; 1C50 5 1,0 1-889 0.005 1.0&lt;1〇5〇£ 10 I-890 0.012 1.0&lt;1〇5〇^ 10 1-891 0.013 1.0&lt;ICS0110 1-892 0.006 1.0&lt;lC50i 10 1-896 0.005 0.1 &lt; IC50 &lt; 1.0 1-890 0.005 0.1 &lt; ICS0 1 1*0 1-902 0.009 0.1 &lt; ICS0 1 1-905 0.004 0.1 &lt; ICS0 ^ 1.0 1-9〇e 0.005 0.1 &lt; IGso 左 1.0 1-90? 0.008 0.1 &lt; ICg〇 1 1,0 1-908 0.004 0.1 &lt; IC50 ^ 1.0 1-912 0.004 0.1 &lt;ICS0^ 1.0 1-914 0.005 0.1 &lt; IC50 &lt; 1.0 1-915 0.004 0.1 &lt; IC50 i 1-0 1-916 0.005 0.1 &lt; IC50 &lt; 1.0 1-918 0.007 0.1 &lt; IC$〇 ^ 1,0 1-919 O.DOS 0.1 &lt; ICg0 ^ 1.0 1-920 0.005 0.1 &lt; ICso ^ 1.0 1-931 0.010 0,1 &lt; ICs〇l 1.0 646 · 141666.doc 201028381 [表 7-7] 實施例 ΤΤΚ ICso (μ Μ) A549 1C9, (μ Μ) 2-1 2J77 2-3 1.261 2-15 9.380 1.0 &lt;ICsoS 10 2-17 2.900 2-20 2細 2-22 4J35 2-44 11,138 2»5β 23.000 2-67 9.190 2-76 6.186 2-84 6.341 2-94 5Λ51 1.0&lt;IC5〇l10 2*99 5.408 2-114 5.130 1.0&lt;ICso£ 10 2-125 9.242 1.0 &lt;ICM^ 10 2-129 5.95D 2-136 3J68 2-144 0.870 2-167 1.878 2-179 2J99 2-191 1,940 2-194 2.461 2-230 6.Ζ64 2-239 2.200 2-245 9.230 1,0&lt;IC50110 2-267 2.369 2-377 3.562EXAMPLE TTK IC50(/1M) Α549 ICs〇(/iM) Example 1 rrxiCsoiiiM) A549 ICsoCilM) 750 0.006 0.1 &lt; IC50 ύ 1.0 1-791 0.043 0,1 &lt; IC5Q 5 1.0 1-751 0.006 0, 1 &lt; ICS011.0 1-793 0.043 0.1 &lt; ic50 ^ 1,0 1-752 0.009 1,0&lt;lCso^10 1-794 0.02S 0.1 &lt;Ι〇5〇^ 1.0 1-753 0.007 1.0&lt; 1CS〆to 1-795 0Λ11 0.1 &lt;ICS0&lt;: 1,0 1-754 0.005 1-796 0.005 0.1 &lt; ICso ^ 1.0 1-755 0.005 1.0 &lt;1050 5 10 1-797 0.013 1.0 &lt;ICs〇l 10 1-756 0.00$ 0,1 &lt; IC50 ^ to 1-798 0.01$ 1*0 &lt;1050 1 10 1-757 0.004 1.O&lt;IC50ltO 1-799 0.007 0.1 &lt; ICS0 1 1,0 1- 758 0.006 1.0 &lt;10^110 1-800 0.010 0.1 &lt;tC5〇iS 1Λ 1-759 0.005 1.0&lt;Ι〇5〇ί to 1-801 0.010 0.1 &lt; ICso 11,0 1-760 0.004 0.1 &lt; IC50lt.O t-802 0.004 0.1 &lt; ICso 5 1.0 1-761 0.010 1,0 &lt;10〆10 1-803 0.003 0,1 &lt; ICso 11Λ 1-762 0.002 0.1 &lt;ICs〇^ 1.0 1-804 0.005 0.1 &lt; iCso 1 1.0 1-763 0.005 0.1 &lt; IC50 1 1.0 1-808 0.007 0.1 &lt; IC50^ 1.0 1-764 0.003 0.1 &lt;ICsoS 1.0 1-807 0.005 0.1 &l t; ICso ^ 1-0 1-765 0.006 0.1 &lt;1C5〇11.0 1-808 0.005 0.1 &lt; IC50 £. 1Λ 1-786 0.008 1.0 &lt;icwi 10 1-809 0.01? 0.1 &lt; ICso ^ 1.0 1- 767 0.007 1.0&lt;ICso^10 1-810 0.010 0.1 &lt; ICs〇^ 1-768 0.004 1,0&lt;1C50^ 10 1-811 0.006 1,0 &lt; ICso 5 10 1*769 0.005 0,1 &lt; ICs〇^ 1,0 1-812 0.005 0,1 &lt; ICso &lt; 1,0 1-770 0.011 OJ &lt; IC50 ^ 1,0 1-814 0.012 1.0 &lt; ICso ^ 10 1-771 0.008 0.1 &lt; ICso ^ 10 1-771 0.008 0.1 &lt; 1CS0 1 1.0 1-815 0.010 0.1 &lt; ICS0 1 1,0 1-772 0.009 ot &lt; ICso i to 1-816 0.012 Ot &lt; Ι〇5〇£ 1Λ 1-773 0-008 1.0&lt;1〇5 〇1 10 1-817 0.013 1.0 &lt; ICso ^ 10 774 0.007 1.0 &lt;1050 &lt;10 1*818 0.035 0.1 &lt;IC5〇&lt; 1.0 1-775 0.007 1.0&lt;IC50110 1-819 0.009 1.0 &lt; ICso S 10 1-778 0.003 0.1 &lt; ICS0 ^ 1.0 1-820 0.005 1.0 &lt; 1〇5〇iS 10 1-777 0.006 0.1 &lt;IC50lt.O 1-821 o.ote Ot &lt;IC5〇^ 1.0 1 -778 0.010 1.0&lt;ICW5 10 1-823 0.015 0.1 &lt; ICW £ 1.0 1-779 0.004 1.0 &lt; 1C〆10 1-824 0.043 0.1 &lt; ICso 彡1.0 1-780 0.007 1.0&lt;IC5 0^ to 1-825 0.008 1.0&lt;1〇5〇£10 1-781 0.003 IC50 SI 0.1 1-826 0.011 1.0&lt;1C50^10 1-782 ο.οοβ 0.1 &lt;1CS0 ^ 1.0 1-827 0.011 1.0 &lt;IC50^ 10 1-7B3 0-010 1.0 &lt;1050 110 1-828 0.028 0.1 &lt; ICso i 1.0 1-784 0.007 1.0&lt;1〇5〇^ 10 1-829 0.006 1,0 &lt; ICso ^ 10 1-785 0.006 0,1 &lt;Ι〇5〇^ 1,0 1-830 0.008 1.0 &lt;Ϊ〇50110 1-780 0.009 0.1 &lt; 1CS0 1 to 1-831 0.005 Ot &lt; ICg〇^ 1.0 1 -787 0.0QS 1.0 &lt;10^110 1-832 0.005 0.1 &lt;iCw^1.0 1-788 0.003 0.1 &lt; ICS0 1 1.0 1-833 0.066 Ot &lt; ICg〇11,0 1-789 0.005 0.1 &lt;Ι 〇5〇11.0 1-834 0.017 1.0&lt;ΙΟΜ110 141666.doc 645- 201028381 [Table 7-6] Example TTKlCs^M) Α549 1C;» (&quot;Μ) 1-835 0,006 0,1 &lt; 1C50 5 1,0 1-838 0.014 1.0&lt;lC5〇^10 1-840 0.016 1*0 &lt;ic50i 10 1-841 0.008 1.0 &lt; IC50 S 10 1-842 0.011 1.0 &lt;IC50110 1-843 0.017 1.0 &lt; IC501 10 1-844 0.018 1.0&lt;IC5〇S10 1-845 0.004 0.1 &lt; IC50 1 1.0 1-846 0.007 0.1 &lt;ICS0^ 1.0 1-848 0.011 1.0&lt;IC5o^ 10 1-849 0,02 3 0.1 &lt; ICS0 11.0 1-851 0.039 0.1 &lt; IC50 i 1.0 1-853 0.006 1.0&lt;IC5〇^ 10 1-854 0.015 1.0 &lt; IO50 ^ 10 ΙΗΒδδ 0.018 1.0&lt;IC5〇&lt; 10 1-857 0.007 1.0 &lt;!Csoi 10 1-859 0.005 0.1 &lt; JCspi: 1.0 1-880 0.007 1-0&lt;ic505 10 1»8β1 0.006 1.0 &lt; ICS0 1 10 1-862 0.008 1.0&lt;IC5〇l 10 1- 863 0.009 1.0&lt;IC5〇^ 10 1-864 0.008 1.0&lt;IC5〇&lt; to 1-865 0.007 1.0 &lt;ICS0 &lt;: 10 1-866 0.006 1.0&lt;IC5〇^ 10 1»8β7 0.007 1.0 &lt IC50 £ 10 1-868 0.005 0.1 &lt; 1C50 S 1.0 1-869 0.018 1. 〇 &lt;IC50l 10 1-872 0.017 1.0&lt;IC50i 10 1-873 0.019 1.0&lt;ICso5 10 1-874 0.018 1.0 &lt; ICs〇10 1-875 0.007 1.0&lt;lC5O^10 1-876 0.011 0.1 &lt; !C50 1 1.0 1-877 0.008 1.0 &lt;IC5〇l 10 1-878 0.004 0.1 &lt;ICs〇&lt; 1.0 1-880 0.006 1.0 &lt;IC50S 10 1-881 0.005 0,1 &lt;1〇5〇5 1.0 1-882 0.008 1.0&lt;IC5〇i to 1-884 0.007 0.1 &lt;1〇5〇5 1.0 1-886 0.038 0.1 &lt; ICso ^ 1.0 1-887 0.005 oi &lt; icS0s 1Λ Example TTKICao〇/M) A549 IC50 (a m 1-888 0.006 0.1 &lt; 1C50 5 1,0 1-889 0.005 1.0&lt;1〇5〇£ 10 I-890 0.012 1.0&lt;1〇5〇^ 10 1-891 0.013 1.0&lt;ICS0110 1-892 0.006 1.0&lt;lC50i 10 1-896 0.005 0.1 &lt; IC50 &lt; 1.0 1-890 0.005 0.1 &lt; ICS0 1 1*0 1-902 0.009 0.1 &lt; ICS0 1 1-905 0.004 0.1 &lt; ICS0 ^ 1.0 1- 9〇e 0.005 0.1 &lt; IGso Left 1.0 1-90? 0.008 0.1 &lt; ICg〇1 1,0 1-908 0.004 0.1 &lt; IC50 ^ 1.0 1-912 0.004 0.1 &lt;ICS0^ 1.0 1-914 0.005 0.1 &lt IC50 &lt; 1.0 1-915 0.004 0.1 &lt; IC50 i 1-0 1-916 0.005 0.1 &lt; IC50 &lt; 1.0 1-918 0.007 0.1 &lt; IC$〇^ 1,0 1-919 O.DOS 0.1 &lt; ICg0 ^ 1.0 1-920 0.005 0.1 &lt; ICso ^ 1.0 1-931 0.010 0,1 &lt; ICs〇l 1.0 646 · 141666.doc 201028381 [Table 7-7] Example ΤΤΚ ICso (μ Μ) A549 1C9, (μ Μ) 2-1 2J77 2-3 1.261 2-15 9.380 1.0 &lt;ICsoS 10 2-17 2.900 2-20 2fine 2-22 4J35 2-44 11,138 2»5β 23.000 2-67 9.190 2-76 6.186 2-84 6.341 2-94 5Λ51 1.0&lt;IC5〇l10 2*99 5.408 2-114 5.130 1.0&lt;ICso£ 10 2-125 9.242 1.0 &Lt;ICM^ 10 2-129 5.95D 2-136 3J68 2-144 0.870 2-167 1.878 2-179 2J99 2-191 1,940 2-194 2.461 2-230 6.Ζ64 2-239 2.200 2-245 9.230 1, 0&lt;IC50110 2-267 2.369 2-377 3.562

(實施例4) CYP3A4螢光MBI試驗 CYP3A4螢光MBI試驗係利用代謝反應研究化合物之增 強CYP3A4抑制的試驗，酶係使用大腸桿菌表現CYP3A4， 以CYP3A4酶將7-苄氧基三氟甲基香豆素（BFC，benzyloxy trifuoromethyl coumarin)脫节基化，以生成發出螢光之代 謝物7-經基三氟甲基香豆素（HFC，hydroxy trifuoromethyl coumarin)的反應為指標而進行。 反應條件如以下所示：受質，5.6 μιηοΙ/L 7-BFC ;預反 •647- 141666.doc 201028381 應時間’ 0或3 0分鐘；反應時間，15分鐘；反廡溫产， 25t(室溫）·’ CYP3A4含量（大腸桿菌表現酶），預反應時 62_5 pmol/mL，反應時6.25 pmol/mL(10倍稀釋時）；受檢 藥物濃度 ’ 0.625、1.25、2.50、5.00、1〇.〇、2〇 〇 pmol/L(6點）。 於96孔板中’向K-Pi緩衝液（pH值為7.4)中以上述預反應 之組成添加酶、受檢藥物溶液作為預反應液，以用受質與 K-Pi緩衝液將其1/1〇稀釋之方式將其一部分移行至另一 ％ 孔板上，添加作為補酶之NADPH，開始作為指標之反應Θ (無預反應），反應特定時間後，藉由添加乙腈：〇 5 Tris(二經基胺基甲烧）=4 : 1而停止反應。又，向剩餘預反 應液中亦添加NADPH而開始預反應（有預反應），預反應特 定時間後，以用受質與K-Pi緩衝液將其1/1〇稀釋之方式將 一部分移行至另一板中，開始作為指標之反應。反應特定 時間後’藉由添加乙腈：〇 5 mol/L Tris(三經基胺基甲 烷）=4 : 1而停止反應。對進行了各個指標反應之板利用 螢光分析儀測定代謝物7-HFC之螢光值（Ex=42〇 nm， ®(Example 4) CYP3A4 fluorescent MBI assay The CYP3A4 fluorescent MBI assay uses a metabolic reaction to study a compound that enhances CYP3A4 inhibition. The enzyme uses E. coli to express CYP3A4 and the CYP3A4 enzyme to 7-benzyloxytrifluoromethyl. The degradation of BFC (benzyloxy trifuoromethyl coumarin) is carried out by the reaction of producing a fluorescent metabolite 7-hydroxytrifuoromethyl coumarin (HFC). The reaction conditions are as follows: substrate, 5.6 μιηοΙ/L 7-BFC; pre-reverse •647- 141666.doc 201028381 should be time '0 or 30 minutes; reaction time, 15 minutes; ruminant temperature, 25t (room Temperature)· CYP3A4 content (E. coli expression enzyme), 62_5 pmol/mL in pre-reaction, 6.25 pmol/mL in reaction (10-fold dilution); concentration of tested drug '0.625, 1.25, 2.50, 5.00, 1〇. 〇, 2〇〇pmol/L (6 points). In a 96-well plate, add the enzyme and the test drug solution as a pre-reaction solution to the K-Pi buffer (pH 7.4) in the above-mentioned pre-reaction composition, and use the substrate with K-Pi buffer. /1〇Dilution method, part of it is transferred to another % plate, NADPH as a supplemental enzyme is added, and the reaction Θ (no pre-reaction) is started as an indicator. After a specific time, by adding acetonitrile: 〇5 Tris The reaction was stopped (diaminomethylcarbazide) = 4:1. Further, NADPH is also added to the remaining pre-reaction solution to start the pre-reaction (pre-reaction), and after a certain period of pre-reaction, a part of the substrate is transferred to the K-Pi buffer to dilute it to 1/1 至 to In the other board, the reaction as an indicator begins. After the reaction for a certain period of time, the reaction was stopped by adding acetonitrile: 〇 5 mol/L Tris (trimethylaminomethane) = 4:1. The fluorescence of the metabolite 7-HFC was measured using a fluorescence analyzer for the plate in which each indicator was reacted (Ex=42〇 nm, ®

Em=535 nm)。 以僅將作為溶解藥物之溶劑之DMS〇添加於反應系統中 者作為對照（100%)，算出添加受檢藥物溶液之各自濃度下 之殘存活性（％)’使用濃度與抑制率，藉由對數模型之逆 推定算出1C”。將1(^0值之差為5 μΜ以上之情形記為（+)， 將3 μΜ以下之情形記為㈠。 (結果） 141666.doc -648· 201028381 1-330 ：(-) 1-447 ：(-) 1-494 :(-) 1-541 ：(-) 1-550 ：(-) 1-560 :(-) 1-566 :(-) 1-583 ：(-) ❿ 1-597 ：(-) 1-631 ：(-) 1-646 ：(-) 1-818:(-) 1-821 ：(-) 1-824 :(-)。 (實施例5)CYP抑制試驗 使用市售混合人類肝臟微粒體，作為人主要CYP5分子 ® 種（CYP1A2、2C9、2C19、2D6、3A4)之典型性受質代謝 反應，以7-乙氧基試鹵靈之Ο-脫乙基化（CYP1A2)、甲苯磺 丁脲之甲基-羥基化（CYP2C9)、美芬妥英之4'-羥基化 (CYP2C19)、右美沙芬之Ο脫甲基化（CYP2D6)、特非那定 之羥基化（CYP3A4)作為指標，對各個代謝物生成量由受 檢化合物抑制之程度進行評價。Em=535 nm). As a control (100%), DMS hydrazine which is only a solvent for dissolving the drug is added as a control (100%), and the residual activity (%) at each concentration of the test drug solution added is calculated as the use concentration and the inhibition rate, by logarithm The inverse estimation of the model is calculated as 1C". 1 (the case where the difference between the values of ^0 is 5 μΜ or more is denoted as (+), and the case where 3 μΜ or less is referred to as (1). (Result) 141666.doc -648· 201028381 1- 330 :(-) 1-447 :(-) 1-494 :(-) 1-541 :(-) 1-550 :(-) 1-560 :(-) 1-566 :(-) 1-583 :(-) ❿ 1-597 :(-) 1-631 :(-) 1-646 :(-) 1-818:(-) 1-821 :(-) 1-824 :(-). Example 5) CYP inhibition test using commercially available mixed human liver microsomes as a typical metabolic reaction of human major CYP5 molecule® (CYP1A2, 2C9, 2C19, 2D6, 3A4) with 7-ethoxy resorufin Then de-ethylation (CYP1A2), methyl-hydroxylation of tolbutamide (CYP2C9), 4'-hydroxylation of fenfluramine (CYP2C19), demethylation of dextromethorphan (CYP2D6) , hydroxylation of terfenadine (CYP3A4) as an indicator, the amount of each metabolite produced by the test The degree of inhibition was evaluated.

反應條件如以下所示：受質，0.5 μιηοΙ/L乙氧基試鹵靈 (CYP1A2)、100 μηιοΙ/L 甲苯磺丁脲（CYP2C9)、50 μπιοΙ/L 141666.doc -649- 201028381 S-美芬妥英（CYP2C19)、5 μιηοΙ/L右美沙芬（CYP2D6)、1 μιηοΙ/L特非那定（CYP3A4);反應時間，15分鐘；反應溫 度’ 37°C ;酶，混合人類肝臟微粒體 0.2 mg蛋白質/ mL ;受檢藥物濃度，i.0、5.0、10、20 Mmol/L(4點）》 於96孔板中，作為反應溶液，向50 mM Hepes緩衝液中 以上述組成各添加5種受質、人類肝臟微粒體、受檢藥 物，添加作為補酶之NADPH，開始作為指標之代謝反 應，於37°C下反應15分鐘後，藉由添加曱醇/乙腈=1/1 (v/v)溶液而停止反應。於3000 rpm、15分鐘之離心操作 後，利用螢光多標記計數儀對離心上清液中之試鹵靈 (CYP1A2代謝物）進行定量，以LC/MS/MS對曱苯磺丁脲羥 基化物（CYP2C9代謝物）、美芬妥英4’羥基化物（CYP2C19 代謝物）、右羥嗎喃（CYP2D6代謝物）、特非那定醇體 (CYP3A4代謝物）進行定量。 以僅將作為溶解藥物之溶劑之DMSO添加於反應系統中 者作為對照（100%)，算出添加有受檢藥物溶液之各個濃度 下之殘存活性（％)，使用濃度與抑制率，藉由對數模型之 逆推定算出IC50。 (結果） 1-566 : 5種（&gt;10 μΜ) 1-574 : 5種（&gt;10 μΜ) 1-578 : 5種（&gt;10 μΜ) 1-582 : 5種（&gt;10 μΜ) 1-589 : 5種（&gt;10 μΜ) 141666.doc •650· 201028381 1-638: 5種（&gt;1〇 μΜ) 1-653 : 5種（&gt;1〇 μΜ) 1-659 : 5種（&gt;1〇 μΜ) 1-794 : 5 種（&gt;1〇 μΜ) 1-796 : 5種（&gt;1〇 μΜ) 1-804 : 5種（&gt;1〇 μΜ)。 (實施例6) FAT試驗 將20 μί冷凍保存之鼠傷寒沙門氏桿菌（Salmonella ® typhimurium TA98株、TA100株）接種於10 mL液體營養培 養基（2.5% Oxoid nutrient broth No.2)上，於 37°C下振盛預 培養10小時。TA98株係對9 mL菌液進行離心（2000xg，10 分鐘）而除去培養液，使菌懸浮於9 mL之Micro F緩衝液 (K2HP〇4 : 3.5 g/L、KH2P〇4 : 1 g/L、（NH4)2S04 : 1 g/L、 檸檬酸三鈉二水合物：0.25 g/L、MgS04 · 7H20 : 0.1 g/L)，添加於110 mL之Exposure培養基（包含生物素：8 pg/mL，組胺酸·· 0_2 pg/mL、葡萄糖：8 mg/mL之MieroF ® 緩衝液）中，TA100株係對於3.16 mL菌液而添加於120 mL 之Expo sure培養基中，調製試驗菌液。試驗物質係DMSO 溶液（自最高用量50 mg/mL以2倍公比稀釋8階段），作為陰 性對照係DMSO，作為陽性對照，係於非代謝活化條件 下，對於TA98株使50 pg/mL之4-硝基喹啉-1-氧化物DMSO 溶液、對於TA100株使0.25 pg/mL之2_(2_呋喃基）-3-(5-硝 基_2_呋喃基）丙烯醯胺DMSO溶液，於代謝活化條件下， 對於TA98株使4〇 pg/mL之2-胺基蒽DMSO溶液、對於 141666.doc -651- 201028381 TA100株使20 pg/mL之2-胺基蒽DMSO溶液各12 pL，與588 μΐ^試驗菌液（代謝活化條件下為498 pL試驗菌液與90 pL之 S9 mix之混合液）混合，於37°C下振盪培養90分鐘。將暴露 試驗物質之菌液460 pL混合於2300 gL之Indicator培養基 (包含生物素：8 pg/mL、組胺酸：0.2 pg/mL、葡萄糖：8 mg/mL、漠曱盼紫：37.5 pg/mL之MicroF緩衝液）中，以每 次50 pL微板48孔之用量進行分注，於37°C下靜置培養3 天。包含藉由胺基酸（組胺酸）合成酶基因之突變而獲得增 生能力之菌的孔由於pH值變化而自紫色變色成黃色，因此 計算每一次用量48孔中之變色成黃色之菌增生孔，與陰性 對照群加以比較而進行評價。 (結果） 1-427 ：(-) 1-456 ：(-) 1-463 ：(-) 1-544 ：(-) 1-560 ：(-) 1-601 ：(-) 1-631 ：(-) 1-690 ：(-) 1-711 :(-) 1-764 ：(-) 1-771 :㈠。 (實施例7)溶解性試驗 141666.doc -652- 201028381 化合物之溶解度係於添加I。/。DMSO之條件下而決定。 以DMSO調製1〇 化合物溶液，將6 μί化合物溶液添加 至594从乙之1?11值為6.8之人工腸液（25〇1111^之0.2 111〇1/1^磷酸 二氫鉀試液中添加0.2 mol/L之NaOH試液118 mL，添加水 成為1000 mL)中。於25°C下靜置16小時後，對混合液進行 抽氣過濾。將濾液以甲醇/水= 1/1稀釋2倍，利用絕對校準 曲線法’使用HPLC或LC/MS/MS測定濾液中濃度。 (結果） ❿ 1-137 ： &gt;1〇 μΜ 1-343 ： &gt;ΐ〇 μΜ 1-687 ： &gt;ΐ〇 μΜ 1-740 ： &gt;1〇 μΜ 1-757 ； &gt;1〇 μΜ 1-851 ： &gt;1〇 μΜ 1-859 : &gt;1〇 μΜ。 (實施例8)代謝穩定性試驗 ® 使用市售之混合人類肝臟微粒體，使對象化合物反應一 定時間，藉由反應樣品與未反應樣品之比較而算出殘存 率，評價由肝代謝之程度。 於包含人類肝臟微粒禮0.5 mg蛋白質/mL之0.2 mL緩衝 液（50 mmol/L tris-HCl pH值為 7.4，150 mmol/L氣化钾， 10 mmol/L氯化鎂）中，於1 mmol/LNADPH存在下，於37°C 下反應〇分鐘或者30分鐘（氧化性反應）。反應後，向1〇〇 pL 甲醇/己腈=1/1 (v/v)溶液中添加5 0 pL反應液’進行混合’ 141666.doc -653- 201028381 以3 000 rpm離心1 5分鐘。將其離心上清液中之試驗化合物 以LC/MS/MS進行定量，以0分鐘反應時之化合物量為 100%來計算反應後試驗化合物之殘存量。 (結果） 1-510 : &gt;90% 1-567 ： &gt;90% 1-627 ： &gt;90% 1-628 ： &gt;90% 1-691 ： &gt;90% 1-796 ： &gt;90% 1-804 ： &gt;90% 1-818 ： &gt;90% 1-851 ： &gt;90% 1-902 ： &gt;90% 1-908 ： &gt;90%。 (實施例9) hERG試驗 以心電圖QT間隔延長之風險評價為目的，使用表現 human ether-a-go-go related gene(hERG)通道之 HEK293 細 胞，研究對心室再極化過程中起到重要作用之延遲整流K+ 電流（IKr)之作用。 使用全自動膜片钳系統（Patch Xpress 7000A, Axon Instruments Inc.)，利用全細胞膜片鉗法，將細胞保持為 -8 0 mV之膜電位後，記錄施加2秒鐘之+ 5 0 mV去極化刺 激，進而施加2秒鐘之-50 mV再極化刺激時誘導之IKr。產 141666.doc -654- 201028381 生之電流穩定後，使以目標濃度（1 ·〇 μΜ)溶解受檢物質之 細胞外液（\玨(31:137 111111〇1/1^、{^1:4 111111〇1/1^、€牡(312· 2Η20 : 1.8 mmol/L、MgCl2 · 6H2〇 : 1 mmol/L、葡萄糖： 10 mmol/L ' HEPES(4-(2-hydroxyethyl)-l-piperazineethanesulfonic acid，4-(2-經乙基）-1 -派&quot;秦乙石黃酸）：1 〇 mmol/L、pH值 =7.4)於室溫條件下，適用於細胞1〇分鐘。自所獲得之 IKr ’ 使用解析軟體（DataXpress ver. 1，Molecular DevicesThe reaction conditions are as follows: substrate, 0.5 μιηοΙ/L ethoxylated resorufin (CYP1A2), 100 μηιοΙ/L tolbutamide (CYP2C9), 50 μπιοΙ/L 141666.doc -649- 201028381 S-美Fentoying (CYP2C19), 5 μιηοΙ/L dextromethorphan (CYP2D6), 1 μιηοΙ/L terfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature '37 °C; enzyme, mixed human liver microsomes 0.2 mg protein/mL; concentration of the test drug, i.0, 5.0, 10, 20 Mmol/L (4 points) in a 96-well plate, as a reaction solution, added to the above composition in 50 mM Hepes buffer Five kinds of receptors, human liver microsomes, and tested drugs were added as NADPH as a supplemental enzyme, and began to act as an indicator of metabolic reaction. After reacting at 37 ° C for 15 minutes, add sterol / acetonitrile = 1 / 1 ( The solution was stopped by v/v) solution. After centrifugation at 3000 rpm for 15 minutes, the resorufin (CYP1A2 metabolite) in the centrifugation supernatant was quantified using a fluorescent multilabel counter to LC/MS/MS versus phenylbenzenebutazone hydroxylate. (CYP2C9 metabolite), mefenicin 4' hydroxylate (CYP2C19 metabolite), dextromethorphan (CYP2D6 metabolite), terfenadine alcohol (CYP3A4 metabolite) were quantified. As a control (100%), only DMSO which is a solvent for dissolving the drug was added to the reaction system, and the residual activity (%) at each concentration to which the test drug solution was added was calculated, and the concentration and the inhibition rate were used, by logarithm The inverse of the model is estimated to calculate the IC50. (Result) 1-566 : 5 species (&gt; 10 μΜ) 1-574 : 5 species (&gt; 10 μΜ) 1-578 : 5 species (&gt; 10 μΜ) 1-582 : 5 species (&gt; 10 μΜ 1-589 : 5 species (&gt;10 μΜ) 141666.doc •650· 201028381 1-638: 5 species (&gt;1〇μΜ) 1-653 : 5 species (&gt;1〇μΜ) 1-659 : Five species (&gt;1〇μΜ) 1-794 : 5 species (&gt;1〇μΜ) 1-796 : 5 species (&gt;1〇μΜ) 1-804 : 5 species (&gt;1〇μΜ). (Example 6) FAT test 20 μί frozen-preserved Salmonella typhimurium (Salmonella ® typhimurium TA98 strain, TA100 strain) was inoculated on 10 mL of liquid nutrient medium (2.5% Oxoid nutrient broth No. 2) at 37°. Pre-culture for 10 hours under C. The TA98 strain was centrifuged (2000×g, 10 minutes) to remove the culture solution, and the bacteria were suspended in 9 mL of Micro F buffer (K2HP〇4: 3.5 g/L, KH2P〇4: 1 g/L). , (NH4)2S04: 1 g/L, trisodium citrate dihydrate: 0.25 g/L, MgS04 · 7H20: 0.1 g/L), added to 110 mL of Exposure medium (containing biotin: 8 pg/mL) In the MieroF ® buffer of histidine·· 0_2 pg/mL and glucose: 8 mg/mL, the TA100 strain was added to 120 mL of Exposure medium for 3.16 mL of bacterial solution to prepare a test bacterial solution. The test substance was DMSO solution (8 stages diluted from the highest dose of 50 mg/mL in 2 times the ratio), as the negative control system DMSO, as a positive control under non-metabolic activation conditions, and 50 pg/mL for the TA98 strain. 4-nitroquinoline-1-oxide DMSO solution, 0.25 pg/mL of 2-(2-furanyl)-3-(5-nitro-2-furanyl) acrylamide DMSO solution for TA100 strain, Under metabolic activation conditions, 4 pg/mL of 2-amino guanidine DMSO solution for TA98 strain and 12 pL of 20 pg/mL of 2-amino guanidine DMSO solution for 141666.doc-651-201028381 TA100 strain The mixture was mixed with 588 μΐ^ test bacterial solution (mixture of 498 pL of test bacterial solution and 90 pL of S9 mix under metabolic activation conditions), and cultured at 37 ° C for 90 minutes with shaking. Mix 460 pL of the test substance-exposed bacterial solution in 2300 gL of Indicator medium (containing biotin: 8 pg/mL, histidine: 0.2 pg/mL, glucose: 8 mg/mL, indifference purple: 37.5 pg/ In mL of MicroF buffer), the injection was performed at a dose of 48 wells per 50 pL of microplate, and the culture was allowed to stand at 37 ° C for 3 days. The pores containing the bacteria having the proliferative ability by the mutation of the amino acid (histidine acid) synthase gene are changed from purple to yellow due to the change in pH, so that the color of the yellow-colored bacteria in each of the 48 wells is calculated. The wells were compared with the negative control group for evaluation. (Result) 1-427 :(-) 1-456 :(-) 1-463 :(-) 1-544 :(-) 1-560 :(-) 1-601 :(-) 1-631 :( -) 1-690 : (-) 1-711 : (-) 1-764 : (-) 1-771 : (a). (Example 7) Solubility test 141666.doc -652- 201028381 The solubility of the compound is based on the addition of I. /. Determined under the conditions of DMSO. Prepare a 1 〇 compound solution in DMSO, and add 6 μί of the compound solution to 594. Add 0.2 mol from the artificial intestinal juice of 6.8 with a value of 6.8 (25〇1111^0.2 111〇1/1^ potassium dihydrogen phosphate). /L NaOH test solution 118 mL, add water to 1000 mL). After standing at 25 ° C for 16 hours, the mixture was subjected to suction filtration. The filtrate was diluted 2-fold with methanol/water = 1/1 and the concentration in the filtrate was determined by absolute calibration curve method using HPLC or LC/MS/MS. (Result) ❿ 1-137 : &gt;1〇μΜ 1-343 : &gt;ΐ〇μΜ 1-687 : &gt;ΐ〇μΜ 1-740 : &gt;1〇μΜ 1-757 ; &gt;1〇μΜ 1 -851 : &gt;1〇μΜ 1-859 : &gt;1〇μΜ. (Example 8) Metabolic stability test ® Using a commercially available mixed human liver microsome, the target compound was allowed to react for a certain period of time, and the residual rate was calculated by comparing the reaction sample with the unreacted sample, and the degree of metabolism by the liver was evaluated. In a 0.2 mL buffer containing human liver particles 0.5 mg protein/mL (50 mmol/L tris-HCl pH 7.4, 150 mmol/L potassium carbonate, 10 mmol/L magnesium chloride) at 1 mmol/L NADPH In the presence, the reaction is carried out at 37 ° C for a minute or 30 minutes (oxidative reaction). After the reaction, 50 liter of the reaction mixture was added to a solution of 1 〇〇 pL of methanol/hexanenitrile = 1/1 (v/v) and mixed. 141666.doc - 653 - 201028381 was centrifuged at 3 000 rpm for 15 minutes. The test compound in the supernatant was counted by LC/MS/MS, and the residual amount of the test compound after the reaction was calculated by taking the amount of the compound at the time of the reaction for 0 minutes to be 100%. (Result) 1-510 : &gt;90% 1-567 : &gt;90% 1-627 : &gt;90% 1-628 : &gt;90% 1-691 : &gt;90% 1-796 : &gt;90 % 1-804 : &gt;90% 1-818 : &gt;90% 1-851 : &gt;90% 1-902 : &gt;90% 1-908 : &gt;90%. (Example 9) The hERG test was performed for the risk assessment of QT interval prolongation of electrocardiogram, and HEK293 cells expressing human ether-a-go-go related gene (hERG) channels were used to study the role of ventricular repolarization. Delayed rectification of K+ current (IKr). Using a fully automated patch clamp system (Patch Xpress 7000A, Axon Instruments Inc.), using a whole-cell patch clamp method to hold the cells at a membrane potential of -8 0 mV, record + 2 0 mV depolarization for 2 seconds. Stimulation, and then the induction of IKr induced by repolarization stimulation for 2 seconds at -50 mV. 141666.doc -654- 201028381 After the current is stabilized, the extracellular fluid of the test substance is dissolved at the target concentration (1 · 〇μΜ) (\玨(31:137 111111〇1/1^, {^1: 4 111111〇1/1^,€牡(312· 2Η20 : 1.8 mmol/L, MgCl2 · 6H2〇: 1 mmol/L, glucose: 10 mmol/L 'HEPES(4-(2-hydroxyethyl)-l-piperazineethanesulfonic Acid, 4-(2-ethylidene)-1 -pyry &quot;Qinethene citrate): 1 〇mmol/L, pH=7.4) Applicable to cells for 1 于 at room temperature. IKr 'Using analytic software (DataXpress ver. 1, Molecular Devices

Corporation) ’以保持膜電位之電流值為基準，測量最大 _ 尾電流之絕對值。進而’算出對應用受檢物質前之最大尾 電流之抑制率’與媒體應用群（〇· 1〇/〇二甲基亞礙溶液）加以 比較，評價受檢物質對IKr之影響。 (結果） 1-456 ： &lt;10% 1-463 ： &lt;10% 1-574 ： &lt;10% 1-577 ： &lt;10% ® 1-628 ： &lt;10% 1-636 ： &lt;10% 1-656 ： &lt;10% 1-686 ： &lt;10% 1-711 ： &lt;10% 1-771 ： &lt;10% 1-781 : &lt;10%。 (實施例10 :製劑例1 錠劑） 141666.doc •655· 201028381 利用常法製造包含如下組成之錠劑。 本發明之化合物 100 mg 乳糖 60 mg 馬鈴薯殿粉 30 mg 聚乙烯醇 2 mg 硬脂酸鎂 1 mg 焦油色素 微量。 (實施例11 :製劑例2 粉劑） 利用常法製造包含如下組成之粉劑。 本發明之化合物 150 mg 乳糖 280 mg o (實施例12 :製劑例3 糖漿劑） 利用常法製造包含如下組成之糖漿劑 o 本發明之化合物 100 mg 純化白糖 40 g 對羥基苯甲酸乙酯 40 mg 對羥基苯甲酸丙酯 ，„ ιυ mg 巧克力香料 „ . u· l cc 向其中添加水使總量為1 00 cc。 如以上所示，使用本發明之較好實施形態例示本發明， 但本發明並不應限定於該實施形態 *肝释。可理紐太 發明應僅由申請專利範圍解釋其範圍。可理解業 發明之具體之較好實施形態之記載，基於本發明之 技術常識而實施等價範圍。可理解本說 ° θ中引用之專 141666.doc -656 - 201028381 利、專利申請及文獻，其内容本身具體而言與本說明書中 記載者同樣地，其内容應作為對本說明書之參考而引用。 [產業上之可利用性] 本發明提供一種用以處理TTK激酶依存性疾病之醫藥、 其中所使用之化合物、其製藥上所容許之鹽、或者其等之 溶劑合物。本發明之化合物如上述實施例之記載所示，顯 示出優異之TTK激酶抑制作用。Corporation) Measure the absolute value of the maximum _ tail current based on the current value of the membrane potential. Further, 'the calculation of the inhibition rate of the maximum tail current before the application of the test substance' was compared with the media application group (〇·1〇/〇 dimethyl acetamide solution), and the influence of the test substance on IKr was evaluated. (Result) 1-456 : &lt;10% 1-463 : &lt;10% 1-574 : &lt;10% 1-577 : &lt;10% ® 1-628 : &lt;10% 1-636 : &lt; 10% 1-656 : &lt;10% 1-686 : &lt;10% 1-711 : &lt;10% 1-771 : &lt;10% 1-781 : &lt;10%. (Example 10: Formulation Example 1 Lozenge) 141666.doc • 655· 201028381 A tablet containing the following composition was produced by a usual method. The compound of the present invention 100 mg Lactose 60 mg Potato powder 30 mg Polyvinyl alcohol 2 mg Magnesium stearate 1 mg Tar pigment A trace amount. (Example 11: Formulation Example 2 Powder) A powder containing the following composition was produced by a usual method. Compound of the present invention 150 mg Lactose 280 mg o (Example 12: Formulation Example 3 syrup) A syrup comprising the following composition was prepared by a usual method. o The compound of the present invention 100 mg Purified white sugar 40 g Ethyl p-hydroxybenzoate 40 mg Propyl p-hydroxybenzoate, „ ιυ mg chocolate flavor „ . u· l cc Add water to it so that the total amount is 100 cc. As described above, the present invention is exemplified by a preferred embodiment of the present invention, but the present invention is not limited to the embodiment. The management of the New Yorker should be construed only by the scope of the patent application. The description of the specific preferred embodiments of the invention will be understood to be equivalent to the technical scope of the invention. It is to be understood that the contents of the specification 141666.doc-656-201028381, the patent application and the literature, the contents of which are specifically the same as those described in the specification, should be referred to as references to the present specification. [Industrial Applicability] The present invention provides a pharmaceutical for treating a TTK kinase-dependent disease, a compound to be used, a pharmaceutically acceptable salt thereof, or a solvate thereof. As shown in the above examples, the compound of the present invention shows an excellent TTK kinase inhibitory action.

141666.doc 657-141666.doc 657-

Claims (1)

201028381 七、申請專利範圍： 1’ 種含有化合物、其製藥上所容許之鹽或者其等之溶劑 合物之具有ττκ抑制活性的醫藥組合物，該化合物由式 (I)所示： [化1] R3201028381 VII. Patent application scope: 1' A pharmaceutical composition having a ττκ inhibitory activity containing a compound, a pharmaceutically acceptable salt thereof or a solvate thereof, which is represented by the formula (I): R3 R係氫、經取代或未經取代之烷基、經取代或未經取 代之烯基、經取代或未經取代之芳基、經取代或未經取 代之雜芳基、經取代或未經取代之環烷基、經取代或未 經取代之環烯基、經取代或未經取代之雜環基、 由式：-0Ra所示基團（式中，Ra係氫、經取代或未經取 代之烷基、經取代或未經取代之烯基、經取代或未經取 代之炔基、經取代或未經取代之芳基、經取代或未經取 代之雜芳基、經取代或未經取代之環烷基、經取代或未 經取代之環烯基或者經取代或未經取代之雜環基）、 由式· -S〇2Rf所示基團（式中，Rf係經取代或未經取代 之烷基、經取代或未經取代之烯基、經取代或未經取代 之炔基、經取代或未經取代之芳基、經取代或未經取代 之雜芳基、經取代或未經取代之環烷基、經取代或未經 取代之環烯基或者經取代或未經取代之雜環基）、 由式：-SORf所示基團（式中，以與上述定義相同）、 141666.doc 201028381 由式所示基團（式中，^及rc分別獨 經取代或未經取代之烷基、經取 ，、虱、 婭你a + 4 %代及禾經取代之烯基、 、-、i取代或未經取代之块基、經取代或未經取代之 經取代或未經取狀雜芳基、經取代或未經取代之^燒 基、經取代或未經取代之環烯基、經取代或未經取代: =或者·可與氣原子一起形成經取代或 代之含氮雜環）、 響 由式：_C(=0)R、示基圏（式令，Rd係氣、經取代或未 經取代之㈣、縣代絲經取狀料、經取代或未 經取代之炔基、經取代或未經取狀芳基、經取代或未 經取代之料基、經取代或未經取代之料基、經 或未經取代之«基、經取代或未經取代之雜環基、唾 ^代或b未經取代之貌氧基或者由式：视V所示基團（此 處，R和Re與上述定義相同））、 由式：,⑽=_所示基困（式中，Rg係氯、經取 代或未經取代之烧基、經取代或未經取代之㈣、㈣ 鲁 代或未經取代之块基、經取代或未經取代之芳基、經取 代或未經取狀㈣基、經取代絲絲代之環烧基、 經取代或未絲狀環縣、絲代或未經取代之雜環 基或者經取代絲㈣代之絲，_±料義相同）、 由式：所示基團（式中，Re係氫、經取代或未經取 代之烧基、經取代或未經取代之烯基、經取代或未經取 代之快基、縣代或未經取代之芳基、纟鋒代或未經取 代之雜芳基、經取代或未經取代之觀基、經取代或未 141666.doc -2- 201028381 經取代之環烯基或者經取代或未經取代之雜環基）、 或者由式：-N(Rg)S〇2Rfm示基團（式中，…及Rf與上 述定義相同）、 R2係氫、經取代或未經取代之娱λ基、經取代或未經取 代之烯基、經取代或未經取代之炔基、經取代或未經取 代之方基、經取代或未經取代之雜芳基、經取代或未經 取代之環烷基、經取代或未經取代之環烯基、經取代或 未經取代之雜環基、氰基、硝基、處素、R is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted a substituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted heterocyclic group, a group represented by the formula: -0Ra (wherein, Ra-based hydrogen, substituted or unsubstituted Substituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or not a substituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group or a substituted or unsubstituted heterocyclic group), a group represented by the formula -S〇2Rf (wherein Rf is substituted or Unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted Or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted or unsubstituted heterocyclic), a group represented by the formula: -SORf (wherein, as defined above), 141666.doc 201028381 a group represented by the formula (wherein, ^ and rc are each independently substituted or unsubstituted alkyl group, taken , 虱, 娅, a + 4 % generation and a substituted alkenyl, -, i-substituted or unsubstituted block, substituted or unsubstituted substituted or unsubstituted heteroaryl, Substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted: = or · may form a substituted or substituted nitrogen-containing heterocyclic ring with a gas atom) By the formula: _C (=0) R, 圏 圏 (formula, Rd gas, substituted or unsubstituted (four), county silk extract, substituted or unsubstituted alkynyl, substituted Or unsubstituted aryl, substituted or unsubstituted base, substituted or unsubstituted base, unsubstituted or substituted unsubstituted, substituted or unsubstituted heterocyclic group, saliva Substituted or b unsubstituted oxy group or by the formula: as shown in the group of V (where R and Re are the same as defined above), by the formula:, (10) = _ Wherein Rg is chloro, substituted or unsubstituted alkyl, substituted or unsubstituted (d), (iv) or substituted unsubstituted, substituted or unsubstituted aryl, substituted or substituted The same is true for the unsubstituted (tetra) group, the substituted ring, the substituted or unfilamented ring, the substituted or unsubstituted heterocyclic group or the substituted silk (four). , by the formula: a group (wherein Re is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted fast radical, county or Unsubstituted aryl, hydrazone or unsubstituted heteroaryl, substituted or unsubstituted base, substituted or not substituted 141666.doc -2- 201028381 substituted or alkenyl or substituted or Unsubstituted heterocyclic group), or represented by the formula: -N(Rg)S〇2Rfm (wherein, and Rf are as defined above), R2 hydrogen, substituted or unsubstituted λ Alkenyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted Instead heteroaryl, the substituted or unsubstituted cycloalkyl, substituted or non-substituted cycloalkenyl, the substituted or unsubstituted heterocyclic group, a cyano group, a nitro group, the pigment, 由式：-C(=0)Rd所示基團（式中，Rd與上述定義相 同）、 或者由式：_N(Rg)C(=〇)Rd所示基團（式中，…及“與 上述定義相同）、 R係氫、齒素、經取代或未經取代之芳基、經取代或 未經取代之雜芳基或者經取代或未經取代之胺基、 R4係氫、i素或者由式：视bRe所示基團（式中， Re與上述定義相同）、 =、經取代或未經取代之烧基、經取代或未經! ==經取代或未經取代之芳基、經取代或未㈣ 唾取代:;稀ΓΓ或未經取代之環烧基、經取代或; 環縣、經取代或未經取代之雜環基、 同)由式· 基團（式中，Rbm上述定義才 Rd與上述定義相 由式：-C(=〇)Rd所示基團（式中 同）或 141666.doc 201028381 由式：-N(Rg)C(=〇)Rd所示基團（式中，R%Rd與上述 定義相同）、 或者 起形成經取代或未經取代 R4和R5可與鄰接之碳原子一 之環、 其中，當R5係由式：-NRbRC所示基團，Rb係氫， 經取代或未經取代之烷基、經取代或未經取代之芳基a group represented by the formula: -C(=0)Rd (wherein Rd is as defined above), or a group represented by the formula: _N(Rg)C(=〇)Rd (wherein, ... and " R1 is hydrogen, dentate, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted amine, R4 hydrogen, i Or by the formula: a group represented by bRe (wherein Re is the same as defined above), =, a substituted or unsubstituted alkyl group, substituted or not! == substituted or unsubstituted aryl group Substituted or not (iv) salic substituted:; dilute or unsubstituted cycloalkyl, substituted or; ring, substituted or unsubstituted heterocyclic, the same) by a group (in the formula, Rbm is defined by the above definition by the formula: -C (= 〇) Rd group (the same formula) or 141666.doc 201028381 by the formula: -N (Rg) C (= 〇) Rd a group (wherein R%Rd is as defined above), or a ring which forms a substituted or unsubstituted R4 and R5 which may be bonded to an adjacent carbon atom, wherein R5 is a group represented by the formula: -NRbRC , Rb hydrogen The substituted or unsubstituted alkyl, substituted or unsubstituted aryl group of 經取代或未經取代之雜芳基或者經取代或未經取代二菊 環基時’ R3係未經取代之胺基、 Re與上述定義相 團（式中，Rd與上 富R係由式：-SRe所示基團（式中， 同）時，R5並非由式：&lt;(=〇)Μ所示基 述定義相同）、 R〜R5中之氫的數目為2以下。 2. :請求項1之含有化合物、其製藥上所容許之鹽或者其 之溶劑合物之具有ττκ抑制活性的醫藥組合物盆中 ^經取代或未經取代之炫基、經取代或未經取代^ Μ經取代或未經取代之芳基、經取代或未經取代之雜 未經取代之環燒基、經取代或未經取代 展烯基、經取代或未經取代之雜環基、 同)由式：臂所示基峨中，^請求们t之定義相 R及Rc與請求項1中之 ，R與請求項1中之定 由式：-NRby所示基團（式中， 定義相同）、 由式：-C(=〇)Rd所示基團（式中 141666.doc 201028381 義相同）、 …及Rd與請求 由式.-N(Rg)C(=〇)Rd所示基團（式中 項1中之定義相同）、 或者 八汉興請求 -N(Rg)S〇2Rf 所 中之定義相同） ^係經取代或未經取代之雜芳基、氰基或者確基 r3係氫或者經取代或未經取代之胺基、a substituted or unsubstituted heteroaryl group or a substituted or unsubstituted dirylianyl group, 'R3 is an unsubstituted amine group, and Re is a group as defined above (wherein, Rd and the upper R-rich system are When the group represented by :-SRe (in the formula, the same formula), R5 is not defined by the formula: &lt;(=〇) Μ is the same as defined in the formula), and the number of hydrogens in R to R5 is 2 or less. 2. A substituted or unsubstituted thiol, substituted or unsubstituted, in a pharmaceutical composition having a ττκ inhibitory activity of a compound containing the compound, a pharmaceutically acceptable salt thereof or a solvate thereof Substituted Μ substituted or unsubstituted aryl, substituted or unsubstituted hetero unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclic, The same formula: in the base shown by the arm, ^ request the definition of the phase R and Rc and the request item 1, R and the claim 1 in the formula: -NRby group (in the formula, The definition is the same), the group represented by the formula: -C(=〇)Rd (where 141666.doc 201028381 is the same), ... and Rd and the request are represented by the formula .-N(Rg)C(=〇)Rd a group (the same as defined in item 1 in the formula), or a Ba Hanxing request -N(Rg)S〇2Rf has the same definition) ^ is a substituted or unsubstituted heteroaryl, cyano or exact group R3 is hydrogen or substituted or unsubstituted amine group, V係經取代或未經取狀以、經取代或未經取代之 埽基、經取代或未㈣狀緑、纟緣代絲經取代之 雜芳^、經取代或未經取代之環燒基、經取代或未經取 代之環烯基、經取代或未經取代之雜環基、 由式：-NW所示基團（式中，Rb&amp;RC與請求们中之 定義相同）、 ^與請求項1中之定 由式：_C( = 〇)Rd所示基團（式中 義相同）或者 中’ Rg&amp;Rd與請求 由式：_N(Rg)C(=〇)Rd所示基團（式 項1中之定義相同）。 3.如請求項丨之含有化合物、其製藥上所容許之鹽或者其 等之溶劑合物之具有TTK抑制活性的醫藥組合物，其中 R3係經取代或未經取代之胺基，R4係氫，R5係由式. -NRY所示基團（式中與請求们中之定義㈣） 或者由式：-(：(=0)Μ所示基團（式中，Rd與請求項1中之 定義相同）。 141666.doc 201028381 4.如請求们之含有化合物、其製藥上所容許之鹽或者其 等之溶劑合物之具有TTK抑制活性的醫藥組合物，其中 R5係由式：-NRY所示基團（式中，Rb與請求们中之定 義相同，Re係經取代或未經取代之芳基、經取代或未經 取代之雜芳基 '經取代或未經取代之環烧基、經取代或 未經取代之輯基或者經取代或未經取代之雜環基）或者 由式：脅咖所示基團（式中，Rd係經取代或未經取代 之芳基、經取代或未經取代之雜芳基、經取代或未經取 代之環燒基、經取代或未經取代之環稀基或者經取代或 未經取代之雜環基）。 5. φ -種該化合物係由式⑴所示化合物、其製藥上所容許之 鹽或者其等之溶劑合物， [化2]V-substituted or unsubstituted, substituted or unsubstituted fluorenyl, substituted or unsubstituted (tetra) green, fluorene substituted, heteroaryl, substituted or unsubstituted cycloalkyl a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted heterocyclic group, a group represented by the formula: -NW (wherein Rb&amp;RC is the same as defined in the request), ^ and The request 1 is determined by the formula: _C (= 〇) Rd (the same meaning in the formula) or the middle ' Rg &amp; Rd and the request is represented by the formula: _N (Rg) C (= 〇) Rd (The definition in Equation 1 is the same). 3. A pharmaceutical composition having TTK inhibitory activity as claimed in claim 3, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R3 is a substituted or unsubstituted amine group, and R4 is hydrogen. R5 is a group represented by the formula -NRY (in the formula and the definition in the request (4)) or a group represented by the formula: -(:(=0)Μ (in the formula, Rd and claim 1) The definition is the same.) 141666.doc 201028381 4. A pharmaceutical composition having TTK inhibitory activity of a compound, a pharmaceutically acceptable salt thereof or a solvate thereof, wherein R5 is a formula: -NRY a group (wherein Rb is as defined in the request, Re is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl' substituted or unsubstituted cycloalkyl, a substituted or unsubstituted substituent or a substituted or unsubstituted heterocyclic group) or a group represented by the formula: a aryl group substituted or unsubstituted, or substituted or Unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted a ring-like or a substituted or unsubstituted heterocyclic group. 5. φ - a compound which is a compound represented by the formula (1), a pharmaceutically acceptable salt thereof or a solvate thereof, ] (I) 式中 ❹ =1係絲代或未絲狀㈣、經取代或未經取代之 經取:或未經取代之芳基、經取代或未經取代之 Si: 未經取代之環燒基、經取代或未經取 烤土經取代或未經取代之雜環基、 同)由式：臂所示基峨中，Ra與請求们中之定義相 由式：·_所示基團（式中，Rf與請求们中之定義 141666.doc 6- 201028381 相同）、 由式：-NRbRCm示基團（式中， 定義相同）、 w與請求们中之 由式：-CpCOR*^示基團（式 中’ R與請求項ιφ夕a 義相同）、 月士谓i中之定 由式：-N(Rg)C(=〇)Rd 所 W中之定義相同）、 K式中，RgW與請求(I) where ❹ is =1 silky or unfilved (tetra), substituted or unsubstituted, or unsubstituted aryl, substituted or unsubstituted Si: unsubstituted ring burn a substituted, unsubstituted or unsubstituted heterocyclic group, the same formula: in the group represented by the arm, Ra is defined by the formula: (where Rf is the same as the definition in the request 141666.doc 6- 201028381), by the formula: -NRbRCm shows the group (in the formula, the definition is the same), w and the formula in the request: -CpCOR*^ a group (wherein 'R is the same as the request item ιφ 夕 a), and the formula of the yueshi is i: -N(Rg)C(=〇)Rd is the same as defined in W), K is RgW and request 由式：-SRe所示基團（式中，Re 同）、 與凊求項1中之定義相 或者 由式：-N(Rg)S02Rf所示基阐 中之定義相同）、 基團（式中’請求項i ^係經取代或未經取代之雜芳基、氰基或者硝基、 R係氫、經取代或未經取代 代之雜茹篡代之方基、經取代或未經取 代之雜方基或者絲代或未絲代之胺基、 R4係氫、齒素或者由式：卿所示 &quot;請求項1中之定義相同）、 及 R5係氫、經取代志击Λ 代次未經取代之芳基、經取代 代之雜芳基、經取获$ n U未&amp;取 代或未經取代之環烷基、經 經取代之環縣、經取代或未經取代之雜環基、 由式.-NRbRC所示基團（式中，Rb&amp;R 定義相同）、 月☆峭1〒之 或者 ί R可與鄰接之碳原子一起形成經取代或未經取代 141666.doc 201028381 之環； 其中’當R5係式：_NRbRe’ Rb係氫，經取代 &amp;取代之燒基、經取代或未經取代之芳基、經取代或未 經取代之雜芳基或者經取代或未經取代之雜環基時，y 係未經取代之胺基、 R3、R4及R5並非同時為氫。 6.如請求項5之化合物、其製藥上所容許之鹽或者其等之 /合劑°物’其中R2係氣基或者硝基，R3係氫或者經取代 或未經取代之胺基，R4係氫，R5係由式：NRbRe所干 團（式中1與請求们中之定義相同，Re係經取代或; 經取代之芳基、經取代或未經取代之雜芳基、經取代或 未A取代之環院基、經取代或未經取代之環烯基、或 經取代或未經取代之雜環基）。 / I如請求項5之化合物、其製藥上所容許之鹽或者其等之 溶劑合物’其中尺5係由式(II)所示基團： [化3] (Π) Rb 式中’ Ra丨及RA2分別獨立為氫、經取代或未經取代之 烧基、經#代或未經取代之料、經取代或未經取代之 快基、經取代或未、經取代之芳I、經取代或未經取代之 雜方基、經取代或未經取代之環烧基、經取代或未經取 141666.doc 201028381 代之環烯基、經取代或未經取代之雜枣基 由式：-ORa所示基團（式中，Ra^二，' 同） 、凊未項1中之定義相 中之定義 由式：-S〇2Rf所示基團（式中，， 相同）、 由式：-NRbRc所示基團（式中，Rb 定義相同）、 與睛求们中之 e 由式：-C(=〇)Rd所示基 M ^ Λ興靖求項1中之令 義相同）、 r 由式：_N(Rg)C(=0)Rd所示基團（式中 項1中之定義相同）、 團（式中，Rd與請求項1 Rg&amp;Rd與請求 義相 由式：-SRe所示基團（式中，Re與請求項1中 同）、 由式：_N(Rg)S〇2Rf所示基團（式中，^及作請求们 中之定義相同）、 ▲或者RA2可鍵結於尺幻所鍵結之碳的鄰接碳原子上，與 R 一起形成經取代或未經取代之環、 η係1〜4之整數、 R係氫、經取代或未經取代之烷基或者經取代或未經 取代之醯基。 8_如凊求項5之化合物、其製藥上所容許之鹽或者其等之 冷劑合物’其中R5係由式（ΙΠ)所示基團： 14I666.doc (III) 201028381 [化4] raIFrom the formula: -SRe group (in the formula, Re the same), the definition phase in the claim 1 or the definition of the formula shown in the formula: -N(Rg)S02Rf), group (form) The 'request item i ^ is a substituted or unsubstituted heteroaryl group, a cyano group or a nitro group, a R-type hydrogen group, a substituted or unsubstituted cyclamate group, substituted or unsubstituted The heterocyclic group or the silky or unsubstituted amino group, the R4 hydrogen, the dentate or the formula: "The same as defined in the claim 1", and the R5 hydrogen, replaced by the scorpion a sub-unsubstituted aryl group, a substituted heteroaryl group, a substituted n n &amp; substituted or unsubstituted cycloalkyl group, substituted ring county, substituted or unsubstituted a ring group, a group represented by the formula: -NRbRC (wherein Rb&amp;R is the same), a month ☆ 〒1 or ί R may form a substituted or unsubstituted group with adjacent carbon atoms 141666.doc 201028381 Ring; wherein 'when R5 is: _NRbRe' Rb is hydrogen, substituted &amp; substituted alkyl, substituted or unsubstituted aryl, taken The substituted or unsubstituted heteroaryl or substituted or unsubstituted with time of heterocyclyl, y based non-substituted amino group, R3, R4 and R5 are not simultaneously hydrogen. 6. A compound according to claim 5, a pharmaceutically acceptable salt thereof, or a mixture thereof, wherein R2 is a gas group or a nitro group, R3 is hydrogen or a substituted or unsubstituted amine group, R4 is a compound Hydrogen, R5 is a dry group of the formula: NRbRe (wherein 1 is the same as defined in the request, Re is substituted or; substituted aryl, substituted or unsubstituted heteroaryl, substituted or not A substituted ring-based, substituted or unsubstituted cycloalkenyl group, or substituted or unsubstituted heterocyclic group). / I. The compound of claim 5, a pharmaceutically acceptable salt thereof or a solvate thereof, wherein the rule 5 is a group represented by the formula (II): [Chemical Formula 3] (Π) Rb where 'Ra丨 and RA2 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted, substituted or unsubstituted fast radical, substituted or unsubstituted aryl I, Substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted 141666.doc 201028381 substituted cycloalkenyl, substituted or unsubstituted heterozygous base: The group represented by -ORa (in the formula, Ra^2, 'same), and the definition in the phase defined by the term 1 are defined by the formula: -S〇2Rf (in the formula, the same), by the formula :- NRbRc shows a group (wherein Rb has the same definition), and the e in the eye is the same as the formula in the formula: -C(=〇)Rd, M ^ Λ兴靖1) , r is represented by the formula: _N(Rg)C(=0)Rd (the definition in item 1 is the same), group (in the formula, Rd and request item 1 Rg&amp;Rd and the request meaning phase: a group represented by -SRe In the case where Re is the same as in Request Item 1, the group represented by the formula: _N(Rg)S〇2Rf (wherein, ^ is the same as defined in the request), ▲ or RA2 can be bonded to the ruler Adjoining carbon atoms of the bonded carbon, together with R, form a substituted or unsubstituted ring, an integer of η series 1 to 4, an R-based hydrogen, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted Substituted thiol. 8_A compound of claim 5, a pharmaceutically acceptable salt thereof or a cold pharmaceutically acceptable compound thereof, wherein R5 is a group represented by the formula (ΙΠ): 14I666.doc (III) 201028381 [Chemical 4] raI Η 式中，RA1及RA2與請求項7中之定義相同。 9. 如凊求項5之化合物、其製藥上所容許之鹽或者其等之 溶劑合物，其中R5係由式（ΙΙΓ)所示基團： [化5]In the formula, RA1 and RA2 are the same as those defined in claim 7. 9. A compound according to claim 5, a pharmaceutically acceptable salt thereof or a solvate thereof, wherein R5 is a group represented by the formula (ΙΙΓ): (m，） 式中，R 1及RA2與請求項7中之定義相同。 10·如请求項5之化合物、其製藥上所容許之鹽或者其等3 ’合劑D物，其中rai係經取代或未經取代之雜芳基、^ 式…NRVm示基團（式中，Rb及Rc與請求項1中之—, 相同）、由式、C(=0)R、示基團（式中，Rd與請求項」 之疋義相同）、經取代或未經取代之稀m七 7基團（式中，Ra與請求们中之定義相同）或者經取代. 未經取代之烧基，R、由式 广 與請求項1中之定義如门 關U中’ ! 中，心與:求:：、二式广 月♦嚷1中之定義相同）、 ㈣)Rd所示基團（式中HRd與請求们中之^ 同)、由式，sew所示基團(式中，咖與二: 14t666.doc 201028381 11. 12. Ο 13. 項1中之定義相同）、經取代或未經取代之院基、經取代 或未經取狀:基或者纟轉代或未經取代之炔基。 如凊求項5之化合物、其製藥上所容許之鹽或者其等之 ’合劑口物，其中R1係由式：_〇R&gt;示基團（式中，Ra與請 未广中之定義相同)或者由式：遞bRe所示基團(式中， R及…與請求項1中之定義相同）。 月求項5之化合物、其製藥上所容許之鹽或者其等之 办劑合物’其中Ra係經取代或未經取代之芳基或者經取 代或未經取代之烷基，Rb係氫、經取代或未經取代之烷 基或者經取代或未經取代之芳基，Re係氫或者經取代或 未經取代之烧基。 如請求項5之化合物、其製藥上所容許之鹽或者其等之 溶劑合物’其中R2係氰基。 14. 如請求項5之化合物、其製藥上所容許之鹽或者其等之 溶劑合物·，其中R2係硝基。(m,) where R 1 and RA 2 are the same as defined in claim 7. 10. The compound of claim 5, a pharmaceutically acceptable salt thereof, or a 3' mixture D thereof, wherein rai is a substituted or unsubstituted heteroaryl group, a formula of NRVm (wherein Rb and Rc are the same as -, in the request item 1, by the formula, C(=0)R, the group (wherein Rd is the same as the claim), substituted or unsubstituted m 7 7 group (in the formula, Ra is the same as defined in the request) or substituted. Unsubstituted base, R, by the formula and the definition of claim 1 such as the gate in the U! Heart and: Seek::, the two formulas are the same as the definition in 嚷1), (4)) the group represented by Rd (where HRd is the same as the requester), the formula, the group shown by sew中,咖与二: 14t666.doc 201028381 11. 12. Ο 13. The definition in item 1 is the same), substituted or unsubstituted yard, substituted or untaken: base or 纟 or not Substituted alkynyl group. A compound of claim 5, a pharmaceutically acceptable salt thereof, or a mixture thereof, wherein R1 is represented by the formula: _〇R&gt; (in the formula, Ra is the same as defined in the broadest sense) Or by the formula: the group represented by bRe (wherein R and ... are the same as defined in claim 1). A compound of claim 5, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, wherein the Ra is substituted or unsubstituted aryl or substituted or unsubstituted alkyl, Rb is hydrogen, A substituted or unsubstituted alkyl group or a substituted or unsubstituted aryl group, Re is a hydrogen or a substituted or unsubstituted alkyl group. A compound of claim 5, a pharmaceutically acceptable salt thereof or a solvate thereof, wherein R2 is a cyano group. 14. A compound according to claim 5, a pharmaceutically acceptable salt thereof or a solvate thereof, wherein R2 is a nitro group. 15. 如請求項5之化合物、其製藥上所容許之鹽或者其等之 /合劑α物，其中R3係經取代或未經取代之胺基。 16·如明求項5之化合物、其製藥上所容許之鹽或者其等之 溶劑合物，其中R3係氫。 如月求項5之化合物、其冑藥上所容許之鹽或者其等之 溶劑合物，其中V係氰基或者硝u係經取代或未經 取代之雜芳U係氫，R5係經取代或未經取代之芳 18.如請求項5之化合物、 其製藥上所容許之鹽或者其等之 141666.doc •11- 201028381 溶劑合物，其中Rm或者罐基’ 經取代或未經 取代之雜芳基，R4和R5與鄰接之碳原子一起為由式 所示基團： [化6] (R°)m·15. The compound of claim 5, a pharmaceutically acceptable salt thereof, or a mixture thereof, wherein R3 is a substituted or unsubstituted amine group. A compound according to claim 5, which is a pharmaceutically acceptable salt thereof or a solvate thereof, wherein R3 is hydrogen. A compound of claim 5, a salt which is permissible on a drug or a solvate thereof, wherein the V-based cyano group or the nitrate-based substituted or unsubstituted heteroaryl U-based hydrogen, R5 is substituted or Unsubstituted aryl 18. The compound of claim 5, a pharmaceutically acceptable salt thereof, or the like, 141666.doc • 11- 201028381 solvate wherein Rm or the tank base is substituted or unsubstituted The aryl group, R4 and R5 together with the adjacent carbon atom is a group represented by the formula: [Chem. 6] (R°) m· (IV) 式中，X係-NH-、-〇-或_ch2_，rD係經取代或未經取 代之烷基、經取代或未經取代之烯基、經取代或未經取 代之芳基、經取代或未經取代之雜芳基、經取代或未經 取代之環烷基、經取代或未經取代之環烯基、經取代或 未經取代之雜環基、由式·· _〇Ra所示基團（式中，Ra與請 求項1中之定義相同）、 ' β 由式：-s〇2Rfm示基團（式中，Rf與請求項】*之定義 相同）、 由式：m斤示基團（式中W與請求们中之 定義相同）、 由式卜C(=〇)Rd所示基團（式中，…與請求項 義相同）、 疋 由式·· -N⑽C(，Rd所示基團（式中，^及^與 項1中之定義相同）、 ~ π t 由式：-SRe所示基團（式中，Re與請求項1中之〜 同)或者 尺羲相 由式·· -N⑽SOW所*基團（式巾，R%Rf與請求項] 141666.doc 12- 201028381 中之定義相同）、m係0〜4之整數。 19. 一種醫藥組合物’其含有如請求項5至18中任一項之化 合物、其製藥上所容許之鹽或者其等之溶劑合物。 20. 如請求項19之醫藥組合物，其係ττκ抑制劑。 21. 如請求項丄至斗、19及20中任一項之醫藥組合物其係用 以 &gt;台療及/或預防癌。 22. —種癌之預防或治療方法，其特徵在於：投予如請求項 5至18中任一項之化合物、其製藥上所容許之鹽或者其 等之溶劑合物。 23. —種如請求項5至18中任一項之化合物、其製藥上所容 許之鹽或者其等之溶劑合物的用途，其係用以製造癌之 治療藥及/或預防藥。 24. 如請求項5至18中任一項之化合物、其製藥上所容許之 鹽或者其等之溶劑合物，其係用以治療及，或預防癌。 25· 一種癌之預防或治療方法，其特徵在於：投予如請求項 1至4中任一項之具有ττκ抑制活性之醫藥組合物。 141666.doc •13- 201028381 四、指定代表圖： (一) 本案指定代表圖為：（無） (二) 本代表圖之元件符號簡單說明： 五、本案若有化學式時，請揭示最能顯示發明特徵的化學式：(IV) wherein X is -NH-, -〇- or _ch2_, rD is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl , substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclic, by formula _ a group represented by 〇Ra (wherein, Ra is the same as defined in claim 1), 'β is represented by the formula: -s〇2Rfm is the same as defined in the formula (wherein Rf is the same as the request term)*, : m indicates the group (where W is the same as defined in the request), the group represented by the formula C(=〇) Rd (wherein, ... is the same as the claim), and the formula is - N(10)C(, the group represented by Rd (wherein ^ and ^ are the same as defined in item 1), ~ π t is a group represented by the formula: -SRe (wherein Re is the same as in the request item 1) Or a formula of the formula: ·N(10)SOW* group (style towel, R%Rf and request item) 141666.doc 12-201028381 has the same definition), m is an integer of 0 to 4. 19. A medical combination 'There is a claim 5 A compound according to any one of 18, a pharmaceutically acceptable salt thereof or a solvate thereof, etc. 20. The pharmaceutical composition according to claim 19, which is a ττκ inhibitor. The pharmaceutical composition according to any one of the items 19 and 20, which is used for &lt;Taiwan therapy and/or for preventing cancer. 22. A method for preventing or treating cancer, characterized in that the administration is as claimed in claims 5 to 18. A compound, a pharmaceutically acceptable salt thereof, or a solvate thereof, etc. 23. A compound according to any one of claims 5 to 18, a pharmaceutically acceptable salt thereof or a solvent thereof The use of the substance for the manufacture of a therapeutic or a prophylactic agent for cancer. The compound of any one of claims 5 to 18, a pharmaceutically acceptable salt thereof or a solvate thereof, For the treatment or prevention of cancer. A method for preventing or treating cancer, which comprises administering a pharmaceutical composition having ττκ inhibitory activity according to any one of claims 1 to 4. 141666.doc • 13- 201028381 IV. Designated representative map: (1) The representative representative of the case is: No) (ii) of the present symbol elements representative diagram of a brief description: Fifth, if the case of formula, please disclosed invention features most indicative of the formula: 141666.doc141666.doc
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