TW378208B - Pharmacologically active N-phenyl-4-(4-pyridyl)-2-pyrimidineamine derivatives - Google Patents

Pharmacologically active N-phenyl-4-(4-pyridyl)-2-pyrimidineamine derivatives Download PDF

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TW378208B
TW378208B TW83108147A TW83108147A TW378208B TW 378208 B TW378208 B TW 378208B TW 83108147 A TW83108147 A TW 83108147A TW 83108147 A TW83108147 A TW 83108147A TW 378208 B TW378208 B TW 378208B
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Taiwan
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amine
benzene
pyridine
group
chloro
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TW83108147A
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Chinese (zh)
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Juerg Zimmermann
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Novartis Ag
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Abstract

N-phenyl-2-pyrimidineamine derivatives of formula I (I) wherein the substituents are as defined below. Those compounds can be used, for example, in the treatment of tumour diseases. An N-phenyl-2-pyrimidineamine derivative of formula I or salts thereof, (I), wherein R0 is hydrogen, halogen, C1-C4-alkoxy or C1-C4-alkyl, R1 is: (a) N-(amino-C1-C4-alkyl)-aminoformyl; (b) N-(hydroxyl-C1-C4-alkyl)-aminoformyl; c piperidino which is unsubstituted or substituted by amino-C1-C4-alkyl; (d) morpholino; or (e) C1-C7-alkylamino which is substituted by morpholino, hydroxyl-C1-C4-alkylamino, imidazolyl, amino, hydroxyl or carboxyl; R2 is C1-C4-alkyl, chloro, trifluoromethyl, carboxyl or one of the following free radicals: -CO2R3 or -C(=O)-NH-(CH2)n-R4a (wherein R3 is C1-C3-alkyl, R4n is hydroxyl, amino or imidazolyl and n is 2 or 3).

Description

五、發明説明（ A 7 B7V. Description of the invention (A 7 B7

ίί 渺。A ----------f — (請先W讀背面之注$項再填寫本頁) 經濟部中央梂準局貝工消費合作社印製 實施例4 :在110°下，將20毫克（0.063毫摩爾）N-(3-氯-苯氯斗B比啶>2-嘧啶胺與1毫升伸乙二胺攪拌26小 時。濃縮並層析（二氯甲烷：甲醇：濃氨水溶液= 80:20:1)，產生Ν<3-氯·苯>4«[2*(2-胺-乙-胺>4·吡啶]-2-嘧啶 胺，Rr= 0.15 (二氯甲院：甲醇：濃氣水溶液=80:20:1)， FAB-MS: 341 (M"+l)-> 實施例5 :利用類似於實施例4之方法，由50毫克 (0.157毫摩爾）Ν-(ί-三氟甲-苯Μ-(2-氯*4-1此啶淀胺及 1毫升伸乙二胺製得Ν·( 3-三氟甲-苯Μ-[ 2-( 2·胺-乙-胺>4^比 啶]嘧啶胺；Rr=0.15 (二氯甲烷：甲醇：濃氨水溶液= 80:20:1) » FAB-MS: 375 (ί^+Η) » 實施例6 :將8〇毫克（0·24毫摩爾）Ν-(3-氯-苯j_4»(2·竣冰 吡啶>·2·喷啶胺、7〇.8毫克（0.36毫摩爾）氫氯化队乙_N，_ (3-二甲胺丙)·羰二亞胺及42毫克（0·%毫摩爾）N_翔我 本紙張尺度適用中國國家梂準（CNS ) A4规格（210X：297公釐） 訂 線 -51 - 經濟部中央標準局員工消費合作社印製 A7 B7 五、發明説明（） 本發明有關N-苯-4-( 4_吡啶>2-嘧啶胺衍生物、其製備 方法、含這些化合物之醫藥及其在製備治療溫血動物之 醫藥組成物上之用途。 本發明有關化學式I之N-苯-2-喃啶胺衍生物及其鹽ίί Miao. A ---------- f — (please read the note $ on the back before filling this page) Printed by Shellfish Consumer Cooperative of Central Bureau of Standards, Ministry of Economic Affairs Example 4: At 110 °, the 20 mg (0.063 mmol) of N- (3-chloro-benzyl chloride B-pyridine > 2-pyrimidinamine and 1 ml of ethylenediamine were stirred for 26 hours. Concentrated and chromatographed (dichloromethane: methanol: concentrated ammonia) Aqueous solution = 80: 20: 1), producing N < 3-chloro · benzene > 4 «[2 * (2-amine-ethyl-amine > 4 · pyridine] -2-pyrimidinamine, Rr = 0.15 (dichloro A hospital: methanol: concentrated gas solution = 80: 20: 1), FAB-MS: 341 (M " + l)-> Example 5: Using a method similar to that in Example 4, from 50 mg (0.157 mmol) ) Ν- (ί-trifluoromethyl-benzene M- (2-chloro * 4-1 this pyrimidine and 1 ml of ethylenediamine to obtain N · (3-trifluoromethyl-benzene M- [2- ( 2 · Amine-Ethyl-Amine > 4 ^ pyridine] pyrimidineamine; Rr = 0.15 (dichloromethane: methanol: concentrated ammonia solution = 80: 20: 1) »FAB-MS: 375 (ί ^ + Η)» Example 6: 80 mg (0.24 mmol) of N- (3-chloro-benzene j_4 »(2. Junpyridine >.2; Pendiamine, 70.8 mg (0.36 mmol) Hydrochlorinated team B _N, _ (3-dimethylamine propyl) · carbodiimide and 42 mg (0 ·% Moore) N_Xiangwo This paper size is applicable to China National Standards (CNS) A4 specifications (210X: 297 mm) Ordering line -51-Printed by A7 B7, Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs The invention relates to N-benzene-4- (4-pyridine > 2-pyrimidinamine derivatives, a preparation method thereof, a medicine containing these compounds, and its use in preparing a medicinal composition for treating warm-blooded animals. The invention relates to a chemical formula N-benzene-2-anuridine amine derivatives and their salts

Ri 式（I)中之 R〇爲氫、鹵素、低級烷氧基或低級烷基，Ri in the formula (I) is hydrogen, halogen, lower alkoxy or lower alkyl,

Ri爲 a) N_(胺{远級烷>胺甲醯基， b) N·(羥-低級烷)·胺甲醯基， c) 肼基， d) 未被取代或被胺基取代之環己-胺基， e) 未被取代或被胺-低級烷基取代之六氫吡畊基， f) 嗎啉基，或 g) 低級烷胺基（被嗎啉基、經-低級烷胺基、氰基、咪唑 基、胍基、胺基、低級烷醯基胺基、低級烷胺·簾胺基、 甲咪基、二-低級烷胺-環己基、羧基、低級烷氧羰基、胺 甲醯基、N-羥-胺甲醯基、羥基、低級烷氧基、二羥磷醸 氧基、六氫吡畊基、低級烷醯-六氫吡畊基、甲醯六氫吡 畊基、脯胺醯基醯胺基取代或被一化學式H2N-CH(R)· C(=0)-NH-之自由基取代（式中R爲氫、Q-C4烷基、苄 本紙張尺度適用中國國家標準（CNS ) A4洗格（2丨Ο X 297公釐） (請先聞讀背面之注意事項再填寫本頁) •裝· 訂 線Ri is a) N_ (amine {far alkyl > carbamoyl), b) N · (hydroxy-lower alkane) · carbamoyl, c) hydrazine, d) unsubstituted or substituted with amine Cyclohexyl-amino, e) hexahydropyridyl, unsubstituted or substituted with amine-lower alkyl, f) morpholinyl, or g) lower alkylamino (substituted by morpholinyl, via-lower alkylamine) Cyano, cyano, imidazolyl, guanidino, amine, lower alkylamino, lower alkylamine curtainamine, methylimidyl, di-lower alkylamine-cyclohexyl, carboxyl, lower alkoxycarbonyl, amine Formamyl, N-hydroxy-aminoformamyl, hydroxyl, lower alkoxy, dihydroxyphosphoranyl, hexahydropyridyl, lower alkanoyl-hexahydropyridyl, formyl hexahydropyridyl 、 Proline fluorenyl amine group or substituted by a free radical of the chemical formula H2N-CH (R) · C (= 0) -NH- (where R is hydrogen, Q-C4 alkyl, benzyl paper, scale applicable Chinese National Standard (CNS) A4 Washing grid (2 丨 〇 X 297 mm) (Please read the precautions on the back before filling in this page)

U -4- 經濟部中央標準局員工消費合作社印製 5 p正本ϊν'，曰 五、發明説明（） ——----j 珀醯亞胺溶於3毫升二甲基甲醯胺中，並在室溫下攪拌 2.5小時。然後在0°下，在30分鐘內，將反應混合物逐 滴加入一 〇·77毫升（11.8毫摩爾）伸乙二胺溶於2毫升 二甲基甲醯胺之溶液中。在室溫下攪拌14小時之後，將 反應混合物倒進50毫升醋酸乙酯中，並用30毫升水萃 取。將有機相乾燥（硫酸鈉）並濃縮。從異丙醇/鹽酸 乙醇溶液中結晶，產生氫氯化N-[3-氯-苯>4-{2-[Ν·(2-胺· 乙）·胺羰]冰吡啶}-2-嘧啶胺；熔點：161 - 163°，FAB-MS: 369 (IVf+H)» 起始原料係以下列方式製得： 階段6.1 ：在60°下，將50毫克（0.16毫摩爾）N-(3-氯-苯>4-(2-氰·4-Ι>比啶>2-喃啶胺在5毫升乙醇及5毫升2N氫 氧化鈉溶液中攪拌2小時。冷卻至室溫並過濾之後，將 留在濾紙上之物質用乙醇/水（少1)淸洗，並在50°及高 眞空下乾燥，產生Ν-(3-氯-苯)-4>(2魂>4·批啶>2·嘧啶胺之鈉 鹽；熔點：>250°，(二氯甲烷：甲醇=9:1) » 實施例7 ：利用類似於實施例6之方法，由100毫克（0.3 毫摩爾）Ν-[3·氯-苯]+(2-羧冰吡啶>2-嘧啶胺、88.5毫升 (0.46毫摩爾）氫氯化N-乙-NH3-二甲胺丙羯二亞胺、53 毫克（0.46毫摩爾）N-經琥珀醯亞胺及0.9毫升（14毫摩 爾）乙醇胺製得N-[ 3-氯-苯H-{ 2-[ N-( 2-羥-乙）·胺羰H-吡 啶}-2-嘧啶胺；熔點：206°，FAB-MS:370(M++H)。 HI m·· m ·1 m I^^^^1 - nn In nn ϋ ^SJ (請先閲讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公廣） -52- 經濟部中夬樣準局員工消費合作社印製 A7 B7 五、發明説明（） 基、羥甲基、1-羥-乙基、锍甲基、2-甲硫-乙基、吲瞬-3-基-甲基、苯-甲基、4·羥-苯-甲基、胺甲酿-甲基、2-胺甲醋-乙 基、羧·甲基、2-殘-乙基、4·胺-丁基、3-胍-丙基或R爲1H-咪哗冰基-甲基），及R2爲CrC6烷基、CrC3烷氧基、氯、 溴、碘、三氟甲基、羥基、苯基、胺基、單（CrC3烷）胺 基、二（CrC^)胺基、C2C4焼醯基、丙烯氧基、羧基、殘_ 甲氧基、乙氧簾-甲氧基、對胺苯磺醯胺基、Ν，Ν·二（CrC3 烷）對胺苯磺醯胺基、N-甲-六氫吡畊基、六氫吡啶基、1H-咪哗.1·基、1H-三哩-1·基、1H-苯幷咪嗤-2-基、1·養基、環戊 基、3,4·二甲-节基或下列化學式中之一自由基： -C02R3 ' -NH-C(=0)-R3 ' -N(R3)-C(=0)-R4 ' -0-(CH2)n-N(R3>R4 ' -C(=0>NH-(CH2)n-R4a' -QO^NH-CCH^-NCRa^ ' -CH(CH3)-NH-CHO ' -C(CH3)=N-OH ' -C(CH3)=N-0-CH3' -C(CH3)-NH2' -NH-CH2-C(=0)-N(R3)-R4 'U -4- Original 5 p printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs ϊν ', the fifth, description of the invention () -------- j Permethimide is dissolved in 3 ml of dimethylformamide, And stirred at room temperature for 2.5 hours. The reaction mixture was then added dropwise over 30 minutes at 0 ° to a solution of 10.77 ml (11.8 mmol) of ethylenediamine in 2 ml of dimethylformamide. After stirring at room temperature for 14 hours, the reaction mixture was poured into 50 ml of ethyl acetate and extracted with 30 ml of water. The organic phase was dried (sodium sulfate) and concentrated. Crystallization from isopropanol / hydrochloric acid ethanol solution to produce hydrochlorinated N- [3-chloro-benzene> 4- {2- [N · (2-amine · ethyl) · aminocarbonyl] iceridine} -2- Pyrimidinamine; melting point: 161-163 °, FAB-MS: 369 (IVf + H) »The starting material was prepared in the following manner: Stage 6.1: 50 mg (0.16 mmol) N- ( 3-Chloro-benzene > 4- (2-cyan · 4-I > pyridine > 2-pyrimidinamine was stirred in 5 ml of ethanol and 5 ml of 2N sodium hydroxide solution for 2 hours. Cool to room temperature and filter After that, the material remaining on the filter paper was washed with ethanol / water (less 1), and dried at 50 ° and high air to produce N- (3-chloro-benzene) -4 > (2 soul > 4 · Batch of pyridine> 2 · Sodium salt of pyrimidinamine; Melting point:> 250 °, (dichloromethane: methanol = 9: 1) »Example 7: Using a method similar to Example 6, from 100 mg (0.3 mmol) Mol) N- [3 · chloro-benzene] + (2-carboxypyridine > 2-pyrimidinamine, 88.5 ml (0.46 mmol) hydrochloride N-ethyl-NH3-dimethylamine propanedimine, 53 mg (0.46 mmol) of N-N- [3-chloro-benzene H- {2- [N- (2-hydroxy-ethyl) · amine prepared from succinimine and 0.9 ml (14 mmol) of ethanolamine Carbonyl H-pyridine} -2-pyrimidinamine; melting point: 206 °, FAB-MS: 370 (M ++ H). HI m ·· m · 1 m I ^^^^ 1-nn In nn ϋ ^ SJ (Please read the Note: Please fill in this page again.) This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210X 297 public broadcasting) -52- Printed by A7 B7, Employee Consumer Cooperative of China Prototype Bureau, Ministry of Economic Affairs Hydroxymethyl, 1-hydroxy-ethyl, fluorenylmethyl, 2-methylthio-ethyl, indoxy-3-yl-methyl, benzene-methyl, 4.hydroxy-benzene-methyl, aminomethyl -Methyl, 2-aminomethyl acetate-ethyl, carboxymethyl, 2-residual-ethyl, 4-amino-butyl, 3-guanidine-propyl, or R is 1H-imidyl-methyl ), And R2 is CrC6 alkyl, CrC3 alkoxy, chlorine, bromine, iodine, trifluoromethyl, hydroxyl, phenyl, amine, mono (CrC3 alkyl) amino, bis (CrC ^) amino, C2C4 Fluorenyl, acryloxy, carboxyl, residual methoxy, ethoxy curtain-methoxy, p-aminobenzenesulfonamido, Ν, Ν · bis (CrC3 alkane) p-aminobenzenesulfonamido, N -Methyl-hexahydropyridyl, hexahydropyridyl, 1H-imidazol.1 · yl, 1H-trimile-1 · yl, 1H-benzimidamidin-2-yl, 1 · phyllyl, cyclopentyl Base, 3,4 · Dijia- Or one of the following chemical formulas: -C02R3 '-NH-C (= 0) -R3' -N (R3) -C (= 0) -R4 '-0- (CH2) nN (R3 > R4' -C (= 0 > NH- (CH2) n-R4a '-QO ^ NH-CCH ^ -NCRa ^' -CH (CH3) -NH-CHO '-C (CH3) = N-OH' -C (CH3 ) = N-0-CH3 '-C (CH3) -NH2' -NH-CH2-C (= 0) -N (R3) -R4 '

(式中R3及R4各自獨立，爲Crc3烷基’ W爲羥基、 胺基或味哩基，X爲氧或硫，^^爲1、2或3，II爲2或 3，R5爲氫、CrC3烷基、CrC3烷氧基、氯、溴、碘或三氟 甲基，R«爲1H-咪哗-1·基或嗎啉基及R7爲CiA院基或爲 未被取代或被〇C3烷基、鹵素或三氟甲基單-取代之苯 基）。 鹵素R〇爲氟、溴、碘或最好爲氯。 低級烷氧基R〇宜爲甲氧基。 本紙浪尺度逍用中國國家揉準（CNS ) A4规格（210X297公羡） C ——： ο I-— — 裝 —訂 I I I n ^ I (請先聞讀背面之注意事項再填寫本瓦) 經濟部中央橾準局員工消費合作杜印裝 A7 B7_ 五、發明説明（) 低級烷基R〇宜爲甲基。 自由基R中之胺-低級烷基宜爲〇>胺-C2-C3烷基。 自由基R,中之羥-低級烷基宜爲ω·經-CrC3烷基。 被胺基取代之環己-胺基宜爲4-胺·環己-胺基。二-低級 烷胺-環己基爲被取代之低級烷基自由基R,之一部份時， 宜爲4-二·低級烷胺-環己基，較適宜者爲4·二甲胺-環己 基。 六氫吡畊基K宜爲1-六氫吡阱基。被胺-低級烷基取 代之六氮H比哄基Ri宜爲4~( 2-胺-乙)-六氨B比讲小基。 嗎啉基Κ及自由基R!中之嗎啉基宜爲4-嗎啉基 (其中之自由價由氮延伸出）。被嗎啉基取代之低級烷 胺基札宜爲2·嗎啉·4·基-乙胺基。 在自由基R,中之羥-低級烷胺基宜爲2-羥-乙胺基。 被羥·低級烷胺基取代之低級烷胺基宜爲3<2遇-乙胺>丙-1-基胺基。 在自由基R2中之咪唑基R/宜爲1Η-咪唑I基。 在自由基&中之低級烷醯基胺基宜爲乙醯基胺基。 在自由基&中之低級烷胺-簾胺基宜爲甲胺屬胺基。 在自由基&中之二-低級烷胺基宜爲二甲胺基。 在自由基札中之甲醯-六氫吡畊基宜爲冬甲酿·六氫吡 畊基。 被氰基、咪唑基、胍基、胺基、低級烷醯基胺棊、 低級烷胺-幾胺基、甲脒基、二-低級烷胺-環己基、羧基、 低級烷氧羰基、胺甲醯基、N-羥-胺甲醯基、羥基、低級 烷氧基、二羥磷醯氧基、六氫吡畊基、低級烷醯·六氫吡 本紙張尺度適用中國國家橾準（CNS ) A4规格（210X297公釐） 〇 . ο ! I —. I I I 1 I 裝 II —訂— I I I I I 線 I (請先聞讀背面之注意事項再填寫本頁) -6- A7 B7 經濟部中央標隼局貝工消費合作杜印製 五、發明説明（） 畊基、甲醯六氫吡阱基、脯胺醯基醯胺基取代或被一化 學式H2N_CH(R)*C(=0)-NH-之自由基取代之低級烷胺基Rl 宜爲被這些取代基取代之二-或三-甲胺基（取代基宜在to· 位置）。被羥基取代之低級烷基&亦宜爲2-涇-丙基。 化學式h2n-ch(r)-c(=o>之自由基（式中之R如上述 之定義）宜爲下列任何一蛋白質中之胺基酸之醯基自由 基：甘胺酸、丙胺酸、纈胺酸、白胺酸、異白胺酸、苯 丙胺酸、絲胺酸、蘇胺酸、半胱胺酸、甲硫胺酸、色胺 酸、酪胺酸、醯胺天門冬酸、醯胺麩胺酸、天門冬酸、 麩胺酸、離胺酸、精胺酸及組織胺酸，特別是天然之組 態者，較適宜者爲（L>組態者。 在本文之範圍內，'低級"一詞代表含高至（含）7 個，較適宜者爲高至（含）4個碳原子之自由基。 除非在相關內容中另外指定，低級烷基宜爲甲基或 乙基。 化學式I之化合物可與酸生成酸加成鹽，例如與無 機酸（像鹽酸、硫酸或磷酸），或與適合之有機羧酸或 磺酸，例如脂族單_或二·羧酸（像三氟醋酸、醋酸、丙 酸、羥乙酸、琥珀酸、順丁烯二酸、反丁烯二酸、羥順 丁烯二酸、蘋果酸、酒石酸、檸檬酸、草酸）、或胺基 酸（像精胺酸或離胺酸）、芳族羧酸（像苯甲酸、2-苯氧· 苯甲酸、2·乙醯氧-苯甲酸、柳酸、4_胺柳酸）、芳-脂族羧 酸（像苯乙醇酸或肉桂酸）、雜芳族羧酸（像菸雉酸或 異蘇蜍酸）、脂族磺酸（例如甲磺酸、乙磺酸或2_羥-乙 擴酸）或芳族磺酸（例如苯磺酸、對-甲苯磺酸或萘-2-磺 ----------^— (請先聞讀背面之注意事項再填寫本頁) ,tr ο 線— 本紙張尺度適用中國國家梂準（CNS ) A4規格（210 X 297公釐） -7- 經濟部中央揉準局員工消費合作社印製 A7 B7 五、發明説明（） 酸）°可生成單-、二·酸加成鹽或，若在自由基Rl中有其 它鹼基，像胺基或胍基存在的話，生成多-酸加成鹽。 含酸基（例如自由基Rl中之一自由羧基）之化學式 I之化合物可形成金屬鹽或銨鹽，像鹸金屬鹽或鹸土金屬 鹽（例如鈉鹽、鉀鹽、鎂鹽或鈣鹽），或與氨或適合之 有機胺’像第三單胺（例如三乙胺或三（2-羥乙）胺），或 雜環鹸（例如N-乙-六氫吡啶或N,N，_二甲-六氫吡畊）形成 銨鹽。 擁有酸基及鹸基之化學式I之化合物可生成內鹽。 爲了單離或純化之目的，以及在化合物進一步用作 中間體之情況中，亦可使用不爲醫藥上接受之鹽類。然 而’祇有在醫藥上可接受之無毒性鹽類才可使用在醫療 上，因此那些爲適宜者》 鑑於自由形式與其鹽（亦包括，例如在新穎化合物 之純化或爲了確認那些化合物時可用作中間體之鹽）形 式之新穎化合物間之緊密關係，在適當及有利的情況 下’上文及下文中提到之任何自由化合物，當然亦包括 其相當之鹽。 化學式I之化合物展現有價値的藥理性質：例如， 它們以高度選擇性抑制酶蛋白質激酶C。靠燐脂-及鈣之 蛋白質激酶C以許多形式存在於細胞內，並參與各種基 本作用’像訊號傳遞、增殖及分化，以及激素及神經傳 遞素之釋放。該酶之活化係利用受質媒介之細胞膜燐脂 水解作用或直接與一些腫瘤促進活性物質作用而達成。 細胞對受質媒介之訊號傳遞之敏感性可因修飾蛋白質激 本紙伕尺度適用中國國家梂準（CMS ) A4規格（21 〇 X 297公釐） (請先閱讀背面之注$項再球寫本頁) •裝. 線 經濟部中央樣隼局員工消費合作杜印製 A7 _ _ B7五、發明説明（） 酶C (作爲一訊號傳遞素）之活性而受到實質地影響。 能影響蛋白質激酶C活性之化合物可用作抑制腫瘤、抗 炎、免疫調節及抗菌之有效成份，且甚至爲有價値之對 抗動脈硬化以及心臓血管系統及中樞神經系統病症之藥 劑。 從前，依照 T. Uchida 及 C. R. Filbum 在"J. Biol. Chem. 259,12311-4(1984)”中描述之方法純化之豬腦蛋白質激酶C 被用來測定蛋白質激酶C之抑制作用，且蛋白質激酶C 之抑制作用係依照D. Fabbro等人在"Arck Biochem. Biophys. 239,102- 111(1985)"中描述之方法測定。 從前使用之豬腦蛋白質激酶C係爲各種次型（同 型）蛋白質激酶C(PKC)之混合物。若在以上試驗中用 純重組基因之同型取代豬腦蛋白質激酶C，則發現化學 式I之化合物優先抑制％傳統之〃同型（X，而對其它 |傳統之〃同型β·1、β·2及γ及特別是 '非傳統之〃同 型δ、ε及η及，非典型之〃異構重整形ζ之抑制程度 較小，且在某些情況中幾乎不抑制。 重組基因之PKC同型已利用下列方法選殖、表現及 純化： 各種蛋白質之生產（藉助桿狀病毒），及其選殖及 從S®昆蟲綑胞中之單離係利用如M. D. Summers及G. E. Smith 在"A Manual method for baculovirus vectors and insect cell culture procedure”, Texas Agricul. Exptl. Station Bull. (1987)，1555 中描述之 方法進行。在Sf9細胞內表現PKC-α (牛的）、PKC-βΙ (人的）、ΡΚΟβ2(人的）及PKC-γ (人/牛的混種）之 (請先閱讀背面之注意事項再填寫本頁) *裝· 、1Τ ο 線— 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐） -9- A7 B7 五、發明説明（） 重組基因病毒之建造及單離係利用Stabel等人在S.Stabel， M. Liyanage and D. Frith, "Expression of protein kinase C isozymes in insect cells and isolation of recombinant proteins", Meth. Neurosc. (1993)] 中描述之方法達成。PKC同型在Sf9細胞內之生產係利 用Stabel等人所描述之方法（參見上述）進行，及酶之純 化係依照 McGlynn 等人在刊物[E. McGlyrn^ Liebetanz^ S. Reutener, J. Wood, N. B. Lydon, H. Hofstetter, M. Vanek, T. Meyer and D. Fabbro, "Expression and partial characterization of rat protein kinase C-d and protein kinase C-i in insect cells using recombinant baculovirus", J. Cell. Biochem. 49, 239 - 250 (1992)]中描述之方法實施。重組基因 ΡΚΟδ (大老鼠的）、ΡΚ(%ε (大老鼠的）、ΡΚΟζ(大老鼠 的）及PKC-η (小老鼠的）之生產，及其表現及純化，分 別依照 Liyanage 等人["Protein kinase C group B members PKC-表-e， -i and PKC-1: Comparison of properties of recombinant proteins in vitro and in vivo”，Biochent J. 283, 781 - 787 (1992)】及 McGtynn 等人描述之 方法（參見上述）進行，額外之特點是用PAc360轉移載 體表現 PKC-η [V. Luckow and M. D. Summers, "Trends in the development of baculovirus expression"，Biotechnology 6，47 - 55 (1988)】。 利用上述方法得到之重組基因之PKC同型之活性測 定係在沒有脂體及鈣（輔因子）存在情況下進行。使用 在沒有輔因子存在下磷醯化之硫酸魚精蛋白作爲基質。 酶之活性反映32p從>[32p】-atp轉移至硫酸魚精蛋白之轉 移。硫酸魚精蛋白爲一各含四個c-端精胺酸殘基之多肽 混合物。磷酸鹽之倂入係在下列條件下測定：ΙΟΟμΙ反應 本紙張尺度適用中國國家標準（CNS ) A4規格（2丨〇><297公釐） (請先閱讀背面之注意事項再填寫本頁) -裝. 0 〇 -線— -10- 經濟部中央樣率局員工消費合作社印製 A 7 B7 五、發明説明（） 混合物含最後濃度之20mM TRIS-HC1 pH 7.4、10 mM Mg[N03]2、0.5毫克/毫升硫酸魚精蛋白、ΙΟμΜΑΤΡ (0.1 μΟϊ γ-[32Ρ]-ΑΤΡ ； 10 Ci/mol l Amersham, Little Chalfont, United(Wherein R3 and R4 are each independently C1, C3, alkyl, W is a hydroxyl group, an amine group, or a glutamyl group, X is oxygen or sulfur, ^^ is 1, 2 or 3, II is 2 or 3, R5 is hydrogen, CrC3 alkyl, CrC3 alkoxy, chlorine, bromine, iodine or trifluoromethyl, R «is 1H-imidyl-1 · yl or morpholinyl and R7 is CiA or is unsubstituted or substituted by OC3 Alkyl, halogen or trifluoromethyl mono-substituted phenyl). Halogen Ro is fluorine, bromine, iodine or preferably chlorine. Lower alkoxy Ro is preferably methoxy. The scale of this paper is free to use Chinese National Standard (CNS) A4 (210X297). C ——: ο I-— — Binding — Binding III n ^ I (Please read the precautions on the back before filling in this tile) Economy Consumers' cooperation with the Central Bureau of Standards and Commerce of the People's Republic of China Du Duanzhuang A7 B7_ 5. Description of the invention () The lower alkyl R0 should be methyl. The amine-lower alkyl group in the radical R is preferably O > amine-C2-C3 alkyl group. In the radical R, the hydroxy-lower alkyl group is preferably an omega-CrC3 alkyl group. The cyclohexyl-amino group substituted with an amine group is preferably a 4-amine cyclohexyl-amine group. When di-lower alkylamine-cyclohexyl is part of the substituted lower alkyl radical R, 4-di · lower alkylamine-cyclohexyl is preferred, and 4 · dimethylamine-cyclohexyl is more suitable . Hexahydropyridyl K is preferably 1-hexahydropyridyl. The hexanitrogen H specific group Ri replaced by an amine-lower alkyl group is preferably a 4- (2-amine-ethyl) -hexamine B ratio small group. The morpholinyl in the morpholinyl K and the radical R! Is preferably 4-morpholinyl (wherein the free valence is extended by nitrogen). The lower alkylamino substituted with morpholinyl is preferably 2 · morpholin · 4 · yl-ethylamino. In the radical R, the hydroxy-lower alkylamino group is preferably a 2-hydroxy-ethylamino group. The lower alkylamino group substituted with a hydroxy · lower alkylamino group is preferably a 3 < 2 encounter-ethylamine > prop-1-ylamino group. The imidazolyl R / in the free radical R2 is preferably a l-imidazole I group. The lower alkylamino group in the radical & is preferably an ethylamino group. The lower alkylamine-curtain group in the radical & is preferably a methylamine group. The bis-lower alkylamino group in the radical & is preferably a dimethylamine group. The formamidine-hexahydropyridine in the free radical is preferably Dongjiamei · hexahydropyridine. By cyano, imidazolyl, guanidino, amine, lower alkylamino, amido, lower alkylamine-chimine, methylamido, di-lower alkylamine-cyclohexyl, carboxyl, lower alkoxycarbonyl, amido Fluorenyl, N-hydroxy-carbamyl, hydroxy, lower alkoxy, dihydroxyphosphono, hexahydropyridyl, lower alkane · hexahydropyridine This paper is applicable to China National Standards (CNS) A4 Specification (210X297mm) 〇. Ο! I —. III 1 I Pack II — Book — IIIII Line I (Please read the notes on the back before filling this page) -6- A7 B7 Central Bureau of Standards, Ministry of Economic Affairs Printed by Shelley Consumers Co., Ltd. 5. Description of the invention () Cultivated base, formamidine hexahydropyridyl, proline amidino, amido, or substituted by a chemical formula H2N_CH (R) * C (= 0) -NH- The radical-substituted lower alkylamino group R1 is preferably a di- or tri-methylamino group substituted by these substituents (the substituent is preferably at the to · position). Lower alkyl & substituted with hydroxy is also preferably 2-fluorene-propyl. The free radical of the chemical formula h2n-ch (r) -c (= o > (where R is as defined above) should be a fluorenyl radical of an amino acid in any of the following proteins: glycine, alanine, Valine acid, leucine, isoleucine, phenylalanine, serine, threonine, cysteine, methionine, tryptophan, tyrosine, ammonium aspartic acid, amidine Glutamate, aspartic acid, glutamic acid, lysine, arginine and histamine, especially those with natural configuration, are more suitable (L > configuration. Within the scope of this article, ' The term "lower" refers to radicals containing up to 7 carbon atoms, more preferably up to and including 4 carbon atoms. Unless otherwise specified in the relevant context, lower alkyl groups are preferably methyl or ethyl Compounds of formula I can form acid addition salts with acids, for example with inorganic acids (like hydrochloric acid, sulfuric acid or phosphoric acid), or with suitable organic carboxylic acids or sulfonic acids, such as aliphatic mono- or di-carboxylic acids (like Trifluoroacetic acid, acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, fumaric acid, hydroxymaleic acid, malic acid, tartaric acid Acid, citric acid, oxalic acid), or amino acids (like spermine or lysine), aromatic carboxylic acids (like benzoic acid, 2-phenoxy · benzoic acid, 2 · acetamido-benzoic acid, willow Acid, 4-aminosalicylic acid), aryl-aliphatic carboxylic acids (such as phenylglycolic acid or cinnamic acid), heteroaromatic carboxylic acids (such as nicotinic acid or isosucic acid), aliphatic sulfonic acids (such as methanesulfonic acid) Acid, ethanesulfonic acid or 2-hydroxy-ethanedetic acid) or aromatic sulfonic acid (such as benzenesulfonic acid, p-toluenesulfonic acid or naphthalene-2-sulfonic acid ---------- ^ — (Please First read the notes on the back and then fill out this page), tr ο line — this paper size applies to China National Standards (CNS) A4 specifications (210 X 297 mm) -7- Printed by the Staff Consumer Cooperative of the Central Bureau of the Ministry of Economic Affairs Preparation of A7 B7 V. Description of the invention () Acid) ° can form mono-, di-acid addition salts or, if there are other bases in the free radical R1, such as amine or guanidino, poly-acid addition Compounds of formula I containing acid groups (such as one of the free carboxyl groups in the free radical R1) can form metal or ammonium salts, such as osmium metal or earth metal salts (such as sodium, potassium, magnesium, or Calcium salt), or Ammonia or a suitable organic amine 'like a third monoamine (such as triethylamine or tris (2-hydroxyethyl) amine), or a heterocyclic ring (such as N-ethyl-hexahydropyridine or N, N, _dimethyl- Hexahydropyridine) forms ammonium salts. Compounds of formula I possessing acid and fluorenyl groups can form internal salts. For the purpose of isolation or purification, and in the case where the compound is further used as an intermediate, it can also be used as Pharmaceutically acceptable salts. However, 'only non-toxic salts that are pharmaceutically acceptable can be used medically, so those are suitable.' Given that free forms and their salts (also include, for example, the purification of novel compounds or for Identify the close relationship between the novel compounds in the form of those compounds that can be used as intermediate salts) and, where appropriate and advantageous, any of the free compounds mentioned above and below, including their equivalent salts, of course. Compounds of formula I exhibit valuable pharmacological properties: for example, they inhibit the enzyme protein kinase C with high selectivity. Protein kinase C, which relies on lipids and calcium, exists in cells in many forms and participates in a variety of basic functions' like signal transmission, proliferation, and differentiation, as well as the release of hormones and neurotransmitters. The activation of the enzyme is achieved by the hydrolysis of cell membrane lipids by the mediator or by directly interacting with some tumor-promoting active substances. The sensitivity of the cells to the signal transmission of the substrate can be modified by the modified protein. The paper is sized according to the Chinese National Standard (CMS) A4 (21 × 297 mm). (Please read the note on the back before writing the ball. Page) • Equipment. Consumers' cooperation of the Central Bureau of Samples of the Ministry of Online Economics, printed A7 _ _ B7 V. Description of the invention () The activity of enzyme C (as a signal transmitter) is substantially affected. Compounds that can affect the activity of protein kinase C can be used as effective ingredients for suppressing tumors, anti-inflammatory, immunomodulation and antibacterial, and even valuable anti-arteriosclerosis and heart vascular and central nervous system disorders. Previously, pig brain protein kinase C purified according to the method described by T. Uchida and CR Filbum in " J. Biol. Chem. 259,12311-4 (1984) "was used to determine the inhibitory effect of protein kinase C, and Inhibition of protein kinase C was determined according to the method described by D. Fabbro et al. In "Arck Biochem. Biophys. 239, 102-111 (1985)". The previously used pig brain protein kinase C system has various subtypes (isotypes) ) A mixture of protein kinase C (PKC). If pig brain protein kinase C is replaced with the isotype of a pure recombinant gene in the above test, it is found that the compound of formula I preferentially inhibits the% traditional 〃 isoform (X, and other | traditional 〃 isoforms β · 1, β · 2, and γ, and especially the 'non-traditional' isoforms δ, ε, and η, and the atypical 〃 isomeric reforming ζ have less degree of inhibition, and in some cases hardly The PKC isoforms of recombinant genes have been selected, expressed and purified using the following methods: Production of various proteins (with the help of baculoviruses), their selection and the use of isolated lines from S® insect bundles such as MD Summers and GE Smith at " A Manual method for baculovirus vectors and insect cell culture procedure ", Texas Agricul. Exptl. Station Bull. (1987), 1555. PKC-α (bovine), PKC-βΙ were expressed in Sf9 cells (Human), PKOβ2 (Human) and PKC-γ (Human / Cow Hybrid) (Please read the precautions on the back before filling this page) * Packing · ， 1Τ ο — This paper is applicable to China Standard (CNS) A4 specification (210X297 mm) -9- A7 B7 V. Description of the invention () The construction and isolation of the recombinant gene virus were made by Stabel et al. In S. Stabel, M. Liyanage and D. Frith, " Expression of protein kinase C isozymes in insect cells and isolation of recombinant proteins ", Meth. Neurosc. (1993)] was achieved. The production of PKC isoforms in Sf9 cells was by the method described by Stabel et al. (See above) ), And the purification of the enzyme was performed according to McGlynn et al. [E. McGlyrn ^ Liebetanz ^ S. Reutener, J. Wood, NB Lydon, H. Hofstetter, M. Vanek, T. Meyer and D. Fabbro, " Expression and pa rtial characterization of rat protein kinase C-d and protein kinase C-i in insect cells using recombinant baculovirus ", J. Cell. Biochem. 49, 239-250 (1992)]. Production of recombinant genes PKOδ (big rat), PK (% ε (big rat), PKOζ (big rat), and PKC-η (small rat)), their performance and purification, according to Liyanage et al. [&Quot; Protein kinase C group B members PKC-Table-e, -i and PKC-1: Comparison of properties of recombinant proteins in vitro and in vivo ", Biochent J. 283, 781-787 (1992)] and McGtynn et al. The method (see above) was performed, with the additional feature of expressing PKC-η with a PAc360 transfer vector [V. Luckow and MD Summers, " Trends in the development of baculovirus expression ", Biotechnology 6, 47-55 (1988)]. The determination of the PKC isoform activity of the recombinant gene obtained by the above method was performed in the absence of liposomes and calcium (cofactors). Phosphoprotamine sulfate was used as a substrate in the absence of cofactors. Enzyme activity Reflects the transfer of 32p from > [32p] -atp to protamine sulfate. Protamine sulfate is a peptide mixture containing four c-terminal spermine residues. Incorporation of phosphate Measured under the following conditions: ΙΟΟμΙ reaction This paper size applies the Chinese National Standard (CNS) A4 specification (2 丨 〇 > < 297mm) (Please read the precautions on the back before filling this page)-Pack. 0 〇 -Line — -10- Printed by the Consumer Cooperatives of the Central Sample Rate Bureau of the Ministry of Economic Affairs A 7 B7 V. Description of the invention () The mixture contains the final concentration of 20mM TRIS-HC1 pH 7.4, 10 mM Mg [N03] 2, 0.5 mg / ml Protamine sulfate, 10 μΜΑΤΡ (0.1 μΟϊ γ- [32Ρ] -ΑΤΡ; 10 Ci / mol l Amersham, Little Chalfont, United

Kingdom)、各種濃度之抑制化合物及0.5 - 2.5單位之酶 (一單位爲，在一分鐘及每毫克蛋白質中，將一塵摩爾 32P從上述之γ-[32Ρ]-ΑΤΡ轉移至組織蛋白HI [Sigma^ V-S型] 之酶量）酶。反應於酶之加入起始並在32°C下轉移。反 應時間爲20分鐘。然後反應用50微升液體滴在P81層 析紙（Whatman» Maidstone, United Kingdom)上而終止。用 J. J. Witt 及 R. Roskoski 在"Rapid protein kinase assay using phospho-cellulose-paper absorption' Anal. Biochem. 66, 253 - 258 (1975)中描述 之淸洗操作法去除未結合之γ·[32ρ]·ΑΤΡ及核苷酸片段後， 基質磷醯化係利用閃爍測量法測定。在該試驗中，化學 式I之化合物能在一低至從0.1至0.5微摩爾/升，通常 大約從0.1至1.0微摩爾/升之ic5()値抑制《•同型之蛋 白質激酶C(PKC)。相對地，其它同型之PKC通常僅能在 顯然很高的濃度下（即在高至多於300倍之濃度下）被 抑制。 基於上述之蛋白質激酶C之抑制效果，化學式I之 化合物可預期地展現抗增殖性質，此性質可直接在下述 之另一試驗中加以證實（其中化學式I之化合物對人類 T24膀胱癌細胞生長之抑制效果被測定）。在一 37°C增 濕培養器及含5% C02之空氣（體積比）中，在加入5% (體積/體積）牛胚胎血淸之伊格（Eagle)氏最少必需培 養基中培養那些細胞。將癌細胞（1000- 1500)播種於96 本紙張尺度適用t國國家榡準（CNS ) Α4規格（210X297公釐） ---------裝— (請先閱讀背面之注$項再填寫本頁)Kingdom), various concentrations of inhibitory compounds and 0.5-2.5 units of enzyme (one unit is, in one minute and per milligram of protein, one mole of 32P is transferred from the above-mentioned γ- [32P] -ATP to the tissue protein HI [ Sigma ^ VS type] enzyme amount) enzyme. The reaction starts with the addition of the enzyme and is transferred at 32 ° C. The reaction time was 20 minutes. The reaction was then stopped by dropping 50 microliters of liquid onto a P81 layer (Whatman »Maidstone, United Kingdom). Unbound γ · [32ρ] was removed using the washing procedure described by JJ Witt and R. Roskoski in " Rapid protein kinase assay using phospho-cellulose-paper absorption 'Anal. Biochem. 66, 253-258 (1975). · After ATP and nucleotide fragments, matrix phosphorylation was determined by scintillation measurement. In this test, the compound of formula I is capable of inhibiting isotype protein kinase C (PKC) at a level as low as 0.1 to 0.5 micromoles / liter, usually from about 0.1 to 1.0 micromoles / liter. In contrast, other isoforms of PKC can usually be inhibited only at significantly higher concentrations (i.e., at concentrations up to 300 times higher). Based on the above-mentioned inhibitory effect of protein kinase C, the compound of formula I can be expected to exhibit anti-proliferative properties, which can be confirmed directly in another experiment described below (wherein the compound of formula I inhibits the growth of human T24 bladder cancer cells The effect is measured). Those cells were cultured in a 37 ° C humidified incubator and 5% CO 2 in air (volume ratio) with Eagle's minimum culture medium containing 5% (v / v) bovine embryo blood pupa. Cancer cells (1000-1500) were sown on 96 paper sizes. Applicable to national standards (CNS) Α4 size (210X297 mm) --------- install— (please read the note on the back first) (Fill in this page again)

>1T 〇 線| -11 - 經齊邹中夬樣隼馬貝工消费合作社印製 A7 B7 五、發明説明（） 洞微量滴定板中，並在上述條件下過夜培養。第一天， 將一連串稀釋之測試化合物加入。在上述條件下將滴定 板培養五天。在該期間內對照培養物進行至少四次細胞 ***。培養之後，將細胞與3·3%(重量/體積）戊二醛 水溶液混合，用水淸洗並用0.05% (重量/體積）甲基藍 水溶液染色。淸洗之後，將染料用3% (重量/體積）鹽 酸水溶液析流。然後使用一光度計（Titertek Multiskan)，在 665nm波長下測定每洞之光密度（〇D)，其與細胞數目成 正比。IC50値係用一電腦系統，利用以下公式計算， 〇〇紹（漏組）-0〜（起始値） -X 1〇〇 〇仏5 (對照組）-〇%5 (起始値） IC50値之定義爲有效成份之濃度（即在培養期終止 時，每洞之細胞數目僅爲對照培養物中細胞數目之50% 時之有效成份濃度）。在化學式I之化合物之情況中， 如此確定之IC5e値爲大約從0.01至10微摩爾/升，通 常爲大約從0.01至1微摩爾/升。 化學式I之化合物之抗腫瘤活性亦可在活體內證 實： 用皮下移植人類膀胱腫瘤T24之Balb/C無毛小雌鼠 來測定抗腫瘤活性。第零天，將動物經口麻醉後，將一 大約25毫克之固態腫瘤植入動物左腰皮膚下，並利甩縫 合夾將切開之小傷口縫合。移植後第六天，將老鼠隨機 分成六隻一組並開始治療。治療進行15天，每天以口或 由腹膜內給藥一次各種劑量之溶於二甲亞楓/Tween 80/ 氯化鈉水溶液之化學式I之化合物。腫瘤用游標尺一週 測量兩次並計算出腫瘤體積。在該試驗中，與未經治療 (請先閱讀背面之注^^項再填寫本頁) -裝 、?τ> 1T 〇 Line | -11-Printed by Qi Zouzhong, sample-like Mabeigong Consumer Cooperative A7 B7 V. Description of the invention () In a microtiter plate and cultured overnight under the above conditions. On the first day, a series of diluted test compounds was added. The titration plate was cultured under the above conditions for five days. Control cultures undergo at least four cell divisions during this period. After incubation, the cells were mixed with a 3.3% (w / v) glutaraldehyde aqueous solution, washed with water and stained with a 0.05% (w / v) methyl blue aqueous solution. After rinsing, the dye was eluted with a 3% (w / v) aqueous hydrochloric acid solution. Then use a photometer (Titertek Multiskan) to measure the optical density (OD) of each hole at a wavelength of 665 nm, which is proportional to the number of cells. The IC50 is calculated using a computer system using the following formula: 〇〇 绍 (missing group)-0 ~ (starting)-X 100: 5 (control group)-0% 5 (starting) IC50 The definition of tritium is the concentration of effective ingredients (that is, the concentration of effective ingredients at the end of the culture period when the number of cells per well is only 50% of the number of cells in the control culture). In the case of the compound of formula I, the IC5e 値 thus determined is from about 0.01 to 10 micromoles / liter, usually from about 0.01 to 1 micromole / liter. The antitumor activity of the compound of formula I can also be confirmed in vivo: The antitumor activity was determined by subcutaneously transplanting Balb / C hairless female mice with human bladder tumor T24. On day zero, after the animal was anesthetized by mouth, a solid tumor of about 25 mg was implanted under the skin of the left waist of the animal, and the small wound was sutured with a clip. On the sixth day after transplantation, the mice were randomly divided into groups of six and treatment was started. The treatment was carried out for 15 days. Oral or intraperitoneal administration was performed once a day in various doses of a compound of the formula I dissolved in dimethylsulfoxide / Tween 80 / sodium chloride aqueous solution. Tumors were measured twice a week with a vernier and tumor volume was calculated. In this test, and without treatment (please read the note ^^ on the back before filling this page)-loading,? Τ

G 〇 線— 本紙張尺度適用中國圃家標準（CNS ) Α4規格（210Χ297公釐） -12- 經濟部中央樣準局負工消費合作社印製 A7 B7________ 五、發明説明（） 之對照組動物比較，結果顯示，經口或由腹膜內給藥一 化學式I之化合物使腫瘤平均體積顯著地減小。 基於上述之性質，化學式I之化合物可特別用作抑 制腫瘤之有效成份，例如治療膀胱及皮膚腫瘤。化學式I 之化合物與其它化學醫療藥物合用來治療癌症時，其可 預防抗藥性（複藥抗藥性）之發展或消除對其它化學治 療藥物已存在之抗藥性。它們亦適用於上述之蛋白質激 酶C調節劑之其它用途，並可特別用來治療對蛋白質激 酶C抑制有反應之病症。 一些化學式I之化合物亦抑制表皮生長因子（EPF)之 受質之酪胺酸激酶活性。該受質特異之酶活性在許多哺 乳動物細胞（包括人類細胞，特別是表皮細胞、免疫系 統細胞及中樞及末梢神經系統細胞）內之訊號傳遞上扮 演一關鍵角色。在各種類型細胞的情況中，受質關聯之 酪胺酸蛋白質激酶（EGF-R-TPK)之EGF-誘發之活化爲細胞 ***，進而細胞增殖之一必要條件。EGF-受質特異之酪胺 酸激酶抑制劑之加入能抑制那些細胞之複製。 EGF-受質特異之酪胺酸蛋白質激酶（EGF-R-TPK)之抑 制可，例如，利用E. McGtynn等人刊於"Europ. J. Biochem. 207,265-275(1992)”之方法證實。本發明之化合物，例如， 在一從0.1至ΙΟμΜ之濃度下抑制50%之酶活性（IC50)。 抑制表皮細胞生長因子（EGF)受質之酪胺酸激酶活 性之化學式I之化合物因此可用於，例如，治療良性或 惡性腫瘤。它們能使腫瘤退化並可預防轉移性蔓延及微 體轉移之成長。它們可特別用於表皮細胞過度增殖（牛 本紙張尺度適用中國國家標準（CNS ) Μ规格（210><297公釐） (請先閲讀背面之注項再填寫本頁) 裝. 、1Τ 線 -13 - 哩齊印中矢*參苟員二消费合阼狂印說 A7 B7 五、發明説明（） 皮癬）之情況、上皮性質之贅瘤之治療（例如乳癌之治 療）之治療上及白血病之情況。若牽涉到蛋白質激酶 時，此化合物亦可用於治療免疫系統失調症及炎性病 症。再者，若牽涉到蛋白質激酶之訊號傳遞時，那些化 學式I之化合物可用於治療中樞或末梢神經系統失調病 症。 化學式I之化合物及其鹽類亦抑制酵素ρ34Λ2/環化物 BA^cyclineB04113)激酶。除了其它cdc2-關聯之激酶之外， 該激酶控制細胞***之特異期，特別是從Gr期至S·期之 轉變，且更特別的是從G2-期至M-期之轉變。 依照時間先後順序，一眞核細胞之周期包含間息期 及M-期。間息期伴隨有細胞之變大。依照時間先後順 序，間息期部份包含Gr期、S·期及G2.期。在Gr期（G = 隙）內，細胞內發生生物合成演變。在S-期（合成期） 內，DNA倍增。然後細胞進入Gr期，G2-期因有絲***之 開始而終止。 依照時間先後順序，M-期部份包含細胞核***（有 絲***）及胞體漿***（細胞漿移動）。 上述之酵素應化物B^ycycIineB0*13)激酶之抑制 可利用以下試驗證實： 使用1〇μΜ之1-甲-腺嘌呤誘發海盤車卵母細胞進入 Μ-期》然後將卵母細胞冷凍在液態氮中並存儲在-8〇°C。 必要時，將卵母細胞均質化並離心，如在”D. Arionetal.， Cell 55, 371 - 378 (1988)” 及"V· Rialet and L· Meijer，Anticancer Res· 11， 1581 · 1590 (1991)” 中所描述。爲了純化 P34〇dc2/cycline Bcdc13 本紙張尺度適用中國國家梯準（CNS ) A4规格（210X297公羡） c ----------裝— (請先閏讀背面之注項再填寫本頁) 訂 〇 線— -14- 經濟部中央橾隼局員工消費合作社印裝 A 7 B7 五、發明説明（） 激酶，將卵母細胞上淸液加入P9eKshs-Sephar〇Se樹脂顆粒中 (由重組基因之人類蛋白質p9eKShs製備），如在"L.Azzi et al., Eur. J. Biochem. 203, 353 360 (1992)"所描述。在 4°C 下恆 速旋轉30分鐘後，將顆粒徹底淸洗並用自由蛋白質 ρ9〇^ (3毫克/毫升）析流活性之p34〇de2/cycline Bcdcl3激 酶。將析流出之激酶用組織蛋白HI爲基質進行試驗，如 在 ”L. Meijer et al·，EMBO J· 8, 2275 - 2282 (1989)及 EMBO J. 10, 1545 - 1554 (1991)"中所描述。在該試驗中，化學式I之化 合物及其鹽類展現一大約從0.0005至2，在大多數情況 中，大約從0.001至0.4之抑制濃度ICso値〔微摩爾/ 升〕。 該發現亦預期化學式I之化合物及其鹽類可用來治 療高度增殖的病症，像腫瘤及牛皮癣。 化學式I之化合物亦抑制HIV病毒之生產（如以下 試驗所示），並因而可用作對抗免疫不全疾病AIDS之藥 劑。人體感染mv且出現最初病徵後，接著是可長達數 年之臨床潛伏期。潛伏期過後，進入熟知之AIDS階段且 通常導致死亡。潛伏期歸因於幾個因素：免疫之反應、 病毒在淋巴結或其它組織內之黏合及進入分子及病毒潛 伏期階段（在此期中感染細胞不能完成病毒細胞周期， 此即爲何感染病毒不能生產且感染無法蔓延的原因）》 該階段之分子潛伏期已用細胞模式加以硏究，像ACH-2 細胞系[K. Clouse et al., J. Immunol. 142, 431 (1989)]及 U1 細胞系 [T. Folks et al.，J. Immunol. 140, 117 (1988)]。那些細胞用 fflV-1 病 毒感染，但僅有少量的感染病毒。然而，若那些細胞用 本紙浪尺度適用中國國家棣準（CNS〉A4規格（210 X 297公釐） ------------裝-- (請先聞讀背面之注意事項再填寫本頁) 訂 〇 線| A7 B7 五、發明説明（） 生理相關因子刺激（這些因子在AIDS患者身上是增多 的），像用腫瘤壞死因子、中間白血球素-6等刺激，或 受化學感應體，像佛伯醇（phorbol)二酯（例如13-0-乙醯-12-0-正十四醯·佛伯醇）刺激，即能產生大量的病毒。 ACH-2及U1細胞爲兩種不同細胞族之代表，爲HIV感染 目標，即淋巴細胞及巨噬細胞。 迄今，尙無法有效地防止由HIV感染進展到AIDS 發病。已做了許多嚐試以防止AIDS發病後之病毒複製 (即在病毒大量產生之階段）。相對地，化學式I之化 合物能干擾細胞之作用（導致被HIV潛伏感染之細胞活 化），而不傷害正常細胞演變，像細胞***。 若上述之U1或ACH_2細胞作爲病毒潛伏期之模 式，由13-0-乙醯-12-正十四醯-佛伯醇或由腫瘤壞死因子-ex 誘發之HIV病毒之生產，可有效地用化學式I之化合物 抑制（在一大約從0.001至1微摩爾/升，例如在0.03 微摩爾/升之濃度下）之事實可得到證明。 較適宜者爲化學式（la)之化合物 (請先閱讀背面之注意事項再填寫本頁) .裝. 訂 線 經濟部中央樣準局員工消費合作社印製Line G 〇 — This paper size is in accordance with the Chinese Garden Standard (CNS) A4 specification (210 × 297 mm) -12- Printed by A7 B7 ________ of the Central Cooperative Bureau of the Ministry of Economic Affairs 5. Comparison of control animals The results show that oral administration of a compound of formula I by oral or intraperitoneal treatment significantly reduces the average tumor volume. Based on the above-mentioned properties, the compound of the formula I can be particularly used as an effective ingredient for suppressing tumors, such as treating bladder and skin tumors. When the compound of formula I is used in combination with other chemotherapeutic drugs to treat cancer, it can prevent the development of resistance (re-drug resistance) or eliminate the resistance that already exists to other chemotherapeutic drugs. They are also suitable for other uses of the above-mentioned protein kinase C modulators, and are particularly useful for treating conditions that are responsive to protein kinase C inhibition. Some compounds of formula I also inhibit the tyrosine kinase activity of epidermal growth factor (EPF). This substrate-specific enzyme activity plays a key role in signal transmission in many mammalian cells, including human cells, especially epidermal cells, immune system cells, and central and peripheral nervous system cells. In the case of various cell types, the EGF-induced activation of the cytosolic tyrosine protein kinase (EGF-R-TPK) is a necessary condition for cell division and cell proliferation. The addition of EGF-substance-specific tyrosine kinase inhibitors can inhibit the replication of those cells. EGF-substance-specific tyrosine protein kinase (EGF-R-TPK) inhibition can be confirmed, for example, by the method published by E. McGtynn et al. &Quot; Europ. J. Biochem. 207,265-275 (1992) " Compounds of the present invention, for example, inhibit 50% of the enzyme activity (IC50) at a concentration from 0.1 to 10 μM. Compounds of formula I that inhibit the activity of epidermal growth factor (EGF) substrates of tyrosine kinase are therefore useful In, for example, the treatment of benign or malignant tumors. They can degenerate tumors and prevent the spread of metastatic and micrometastasis. They can be used in particular for the excessive proliferation of epidermal cells (both paper standards apply to Chinese National Standards (CNS) M Specifications (210 > < 297mm) (Please read the notes on the back before filling out this page) Packing., 1T line-13-Mile Qi Yin Zhongya * Seng Gou 2 Consumption Hexie A7 B7 Fifth, Description of the invention () Dermatophytes), epithelial neoplasms (such as the treatment of breast cancer) and leukemia. If protein kinase is involved, this compound can also be used to treat immune system disorders and inflammation STD Furthermore, if the signal transmission of protein kinase is involved, those compounds of formula I can be used to treat disorders of the central or peripheral nervous system. The compounds of formula I and their salts also inhibit the enzyme ρ34Λ2 / cycline BA ^ cyclineB04113) kinase In addition to other cdc2-associated kinases, this kinase controls the specific phase of cell division, particularly the transition from the Gr phase to the S · phase, and more specifically the transition from the G2-phase to the M-phase. According to time In order, the cycle of a nuclear cell includes the interphase and the M-phase. The interphase is accompanied by the growth of the cells. According to the chronological order, the interphase includes the Gr phase, S · phase, and G2. Phase. In the Gr phase (G = gap), biosynthetic evolution occurs in the cell. In the S-phase (synthesis phase), DNA is multiplied. Then the cell enters the Gr phase, and the G2- phase is terminated by the beginning of mitosis. According to the chronological order, The M-phase part includes nuclear division (mitosis) and cytosolic division (cytoplasmic movement). The inhibition of the above-mentioned enzyme response B ^ ycycIineB0 * 13) kinase can be confirmed by the following tests: Use 10μ 1-A-adenine induces Ocarina oocytes to enter the M-phase. Then the oocytes are frozen in liquid nitrogen and stored at -80 ° C. If necessary, the oocytes are homogenized and centrifuged. As described in "D. Arionetal., Cell 55, 371-378 (1988)" and "V. Rialet and L. Meijer, Anticancer Res. 11, 1581 · 1590 (1991)". In order to purify P34〇dc2 / cycline Bcdc13, this paper size is applicable to China National Standard (CNS) A4 specification (210X297 public envy) c ---------- install — (Please read the notes on the back before filling This page) Order line — -14- A 7 B7 printed by the Consumer Cooperative of the Central Government Bureau of the Ministry of Economic Affairs 5. Description of the invention () Kinase, add oocyte supernatant to P9eKshs-Sephar〇Se resin particles (from Recombinant human protein preparation of p9eKShs), as described in " L. Azzi et al., Eur. J. Biochem. 203, 353 360 (1992) ". After rotating at a constant speed for 30 minutes at 4 ° C, the particles were thoroughly rinsed and the active p34ode2 / cycline Bcdcl3 kinase was eluted with free protein ρ90 (3 mg / ml). The eluted kinase was tested using tissue protein HI as a substrate, as described in "L. Meijer et al., EMBO J. 8, 2275-2282 (1989) and EMBO J. 10, 1545-1554 (1991) " Described. In this test, the compound of formula I and its salts exhibit an inhibitory concentration ICso 値 [micromole / liter] of from about 0.0005 to 2, in most cases, from about 0.001 to 0.4. This finding also Compounds of formula I and their salts are expected to be useful in the treatment of highly proliferative conditions, such as tumors and psoriasis. Compounds of formula I also inhibit the production of HIV virus (as shown in the tests below) and can therefore be used as an anti-immune disease AIDS Drugs. Human infection with mv and initial symptoms, followed by a clinical incubation period that can last for several years. After the incubation period, it enters the well-known AIDS stage and usually leads to death. The incubation period is due to several factors: the immune response, the presence of the virus Adhesion in lymph nodes or other tissues and entering the molecular and viral incubation phase (during this period infected cells cannot complete the viral cell cycle, which is why infected viruses cannot produce Reasons why the infection cannot spread) The molecular latency of this stage has been studied using cell models, such as the ACH-2 cell line [K. Clouse et al., J. Immunol. 142, 431 (1989)] and the U1 cell line [ T. Folks et al., J. Immunol. 140, 117 (1988)]. Those cells were infected with the fflV-1 virus, but only a small amount of the virus was infected. However, if those cells use the paper scale, the Chinese national standard is applicable. (CNS> A4 specification (210 X 297 mm) ------------ install-(please read the precautions on the back before filling out this page) Order 〇 Line | A7 B7 V. Invention Explanation () Stimulation of physiological related factors (these factors are increased in AIDS patients), such as stimulation with tumor necrosis factor, interleukin-6, etc., or by chemosensors, such as phorbol diesters (for example 13-0-acetam-12-0-n-tetramethylpyrene · foberol) can produce a large amount of virus. ACH-2 and U1 cells are representative of two different cell families, which are the targets of HIV infection, namely Lymphocytes and macrophages. So far, tadpoles have not been effective in preventing the progression from HIV infection to the onset of AIDS. Many attempts have been made to Prevent the replication of the virus after the onset of AIDS (that is, in the period when the virus is produced in large quantities). In contrast, the compound of formula I can interfere with the function of the cell (resulting in the activation of cells infected with HIV latent infection) without harming normal cell evolution, such as cell division. If the above U1 or ACH_2 cells are used as a virus incubation mode, the production of HIV virus induced by 13-0-acetam-12-n-tetradecano-foberol or tumor necrosis factor-ex can be effectively used. The fact that the compound of formula I is inhibited (at a concentration of approximately from 0.001 to 1 micromole / liter, for example at a concentration of 0.03 micromole / liter) can be proved. More suitable is the compound of the chemical formula (la) (Please read the precautions on the back before filling this page). Packing. Printing

XX (la) 式（la)中艮爲 a) N-(胺-低級烷>胺甲醯基 b) N·(羥-低級烷)·胺甲醯基 c) 肼基， 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） -16- 五、發明説明（） A7 B7 經濟部令夬揉準局員工消費合作社印敦XX (la) In formula (la), a) N- (amine-lower alkane) > carbamoyl group b) N · (hydroxy-lower alkane) · carbamoyl group c) hydrazine group, this paper standard is applicable China National Standard (CNS) A4 specification (210X297 mm) -16- V. Description of invention () A7 B7 Order of the Ministry of Economic Affairs, Consumer Affairs Cooperative, India

d) 環己·胺基（其未被取代或被胺基取代），或 e) 低級烷胺基（其被氰基、咪唑基、胍基、胺基、低級 烷醯基胺基、低級烷胺-羰胺基、甲咪基、二-低級烷胺-環 己基、羧基、低級烷氧羰基、胺甲醯基' N-羥-胺甲醯 基、羥基、低級烷氧基、二羥磷醯氧基、六氫吡畊基、 低級烷醯-六氫吡阱基、甲醯六氫吡阱基、脯胺醯基醯胺 基取代或被一化學式H2N-CH(R)_C(=0)-NH-之自由基（式中 R爲氫、CrC4院基、苄基、羥甲基、1_經-乙基、锍甲基、 2- 甲硫·乙基、吲餐3-基-甲基、苯-甲基、4>羥-苯-甲基、胺甲 醢-甲基、2-胺甲醯-乙基、羧·甲基、2-羧-乙基、冬胺-丁基、 3- 胍-丙基或R爲1H-咪唑基·甲基）取代），及 R2爲CrC6院基、CrC3烷氧基、氯、溴、碘、三氟甲基、 羥基、苯基、胺基、單（CrC3烷）胺基、二（CrC3垸）胺基、 C2-C4院醯基、丙烯氧基、羧基、殘-甲氧基、乙氧簾-甲氧 基、對胺苯磺醸胺基、N，N-二（CrC3院）對胺苯磺醯胺基、 N-甲-六氫吡阱基、六氫吡啶基、1H-咪唑-1-基、1H-***-1-基、1H-苯幷咪唑-2-基、1-萘基、環戊基、3,冬二甲-节基或 下列化學式中之一式的自由基： -C02R3' -NH-C(=0)-R3 ' -N(R3)-C(=0)-R4 ' -CKCH2)n-N(R3>R4 ' -0(=0)-^-(0¾^¾^ ' -CH(CH3)-NH-CHO > -C(CH3)=N-0H ' -C(CH3)=N-0-CH3 ' -C(CH3)-NH2 > 、\i—/~\ Jd) cyclohexylamino (which is unsubstituted or substituted with amine), or e) lower alkylamino (which is substituted by cyano, imidazolyl, guanidyl, amine, lower alkylamino, lower alkyl) Amine-carbonylamino, methylimidyl, di-lower alkylamine-cyclohexyl, carboxyl, lower alkoxycarbonyl, carbamoyl 'N-hydroxy-aminoformyl, hydroxyl, lower alkoxy, dihydroxyphosphorus Ethyloxy, hexahydropyridyl, lower alkylpyridine-hexahydropyridyl, formamidine hexahydropyridyl, proline amidino, amido, or substituted with a chemical formula H2N-CH (R) _C (= 0 ) -NH- radical (wherein R is hydrogen, CrC4 alkyl, benzyl, hydroxymethyl, 1-methyl-ethyl, fluorenylmethyl, 2-methylthio · ethyl, indium 3-yl- Methyl, benzene-methyl, 4 > hydroxy-benzene-methyl, carbamate-methyl, 2-carbamate-ethyl, carboxymethyl, 2-carboxy-ethyl, winteramine-butyl , 3-guanidine-propyl or R is 1H-imidazolylmethyl) substitution), and R2 is CrC6 alkyl, CrC3 alkoxy, chlorine, bromine, iodine, trifluoromethyl, hydroxyl, phenyl, amine Group, mono (CrC3 alkyl) amino group, bis (CrC3 垸) amino group, C2-C4 alkyl group, acryloxy group, carboxyl group, residual-methoxy group, ethoxy group -Methoxy, p-aminobenzenesulfonamido, N, N-di (CrC3) p-aminobenzenesulfonamido, N-methyl-hexahydropyridyl, hexahydropyridyl, 1H-imidazole-1 -Radical, 1H-triazol-1-yl, 1H-benzimidazol-2-yl, 1-naphthyl, cyclopentyl, 3, winter dimethyl-benzyl or one of the following chemical formulas:- C02R3 '-NH-C (= 0) -R3' -N (R3) -C (= 0) -R4 '-CKCH2) nN (R3 > R4' -0 (= 0)-^-(0¾ ^ ¾ ^ '-CH (CH3) -NH-CHO > -C (CH3) = N-0H' -C (CH3) = N-0-CH3 '-C (CH3) -NH2 >, \ i— / ~ \ J

-N -m 及 -X-CH2-C(=〇)—N N—R7 本紙張尺度適用中國國家榡準（CNS ) A4说格（2丨Ο X 297公釐） (讀先閎讀背面之注^^項再填寫本頁) 裝-N -m and -X-CH2-C (= 〇) —NN—R7 This paper size applies to China National Standard (CNS) A4 scale (2 丨 〇 X 297 mm) (^^ items, then fill out this page)

、1T 〇 線- -17- 經濟部中夬樣隼局員工消費合作社印製 A7 _B7_五、發明説明（） (式中R3及R4各自獨，爲CVC3院基，X爲氧或硫， 111爲1、2或3，11爲2或3，尺5爲氫、（：1-(^院基、€14 院氧基、氯、溴、碘或三氟甲基，Re爲ΙΗ-咪嗤-N基或嗎 啉基及R?爲CrC3烷基或爲未被取代或被CrC3烷基、鹵 素或三氟甲基單取代之苯基）； 及其鹽類。 一較適宜之族群包含化學式I之化合物及其鹽類， 其中之 R〇爲氫、鹵素、低級烷氧基或低級烷基， Ri爲 a) N-(胺-低級烷>胺甲醸基， b) N_(羥·低級烷>胺甲醯基， c) 肼基， d) 六氫吡畊基（其未被取代或被胺·低級烷基取代）， e) 嗎啉基，或 f) 低級烷胺基（其被嗎啉基、羥-低級烷胺基、咪唑基、 胍基、胺基、低級烷醯基胺基、低級烷胺-幾胺基、甲咪 基、羧基、低級烷氧羰基、胺甲醯基、N-羥-胺甲醯基、 羥基、二羥磷醯氧基取代或被一化學式h2nch(r>c(=〇v NH-之自由基（式中R爲氫）取代），及 R2爲氯、三氟甲基、羧基、一化學式-C02R3之自由基 (式中R3爲烷基）或一化學式-C(=0>NIMCH2)n-R4a 之自由基（式中η爲2或3及IV爲羥基、胺基或咪唑 基）。 (請先W讀背面之注$項再填寫本頁) -裝· 訂 〇 -線| 本紙張尺度適用中國國家橾準（CNS ) Α4说格（210Χ297公釐〉 -18- 經濟部中央樣隼局員工消費合作社印製 A7 B7 五、發明説明（） 另一適宜之族群包含化學式I之化合物及其鹽類， 其中之 R〇爲氫， R,爲 a) N-(胺·低級烷)·胺甲酸基， b) lsK經-低級烷胺甲醯基， c) 肼基，或 d) 低級烷胺基（其被咪唑基、胍基、胺基、低級烷醯基 胺基、低級烷胺-羰胺基、甲咪基、羧基、低級烷氧羰 基、胺甲醯基、N-徑-胺甲醯基、羥基、二羥磷醯氧基取 代或被一化學式H2N-CH(R>C(=〇VNH-之自由基取代（式中 R爲氫）），及 r2爲氯或三氟甲基。 較適宜者爲化學式I之化合物及其鹽類，其中之 R〇爲氫、氯、低級烷基或低級烷氧基， R!爲Ν·( ω·胺忑2-(：3烷)-胺甲醯基、Ν-( ω·羥-C2-C3烷胺甲醯 基、肼基、2-羥-丙胺基或直鏈之QrC3烷胺基（其在ω·位 置被嗎啉基、〇>羥-低級烷胺基、咪唑基、胍基、胺基、 低級烷醯基胺基、甲咪基、羧基、低級烷氧羰基、胺甲 醯基、Ν-羥-胺甲醯基、羥基取代或被二羥磷醯氧基取 代），及 R2爲氯、三氟甲基、羧基、一化學式-C02R3之自由基 (式中R3爲CrC3烷基）或一化學式 之自由基（式中η爲2或3及R/爲羥基、胺基或咪唑 基）。 本紙張尺度適用中國國家梯準（〇奶）厶4規格（210父297公釐） (請先閱讀背面之注意ί項再填寫本頁) -裝· 訂 G •線| -19- 經殊部中央榡準局員工消費合作杜印衷 A7^__B2-五、發明説明（） 較適宜者特別爲化學式I之化合物及其鹽類’其中 之 氏）爲氫， R丨爲Ν·( ω·胺-c2-c3烷）-胺甲醯基、N-( 〇>羥七2-<：3烷 >胺甲醯 基、肼基、2-經-丙胺基或直鏈之C2-C3烷胺基（其在》·位 置被咪唑基、胍基、胺基、低級烷酿基胺基、甲咪基、 羧基、低級烷氧羰基、胺甲醸基、Ν-羥·胺甲醯基、羥基 取代或被二羥磷醸氧基取代），及 心爲氯或三氟甲基。 特別適宜者爲化學式I之化合物及其鹽類，其中之 &爲氫、氯、甲基或甲氧基， &爲Ν-( ω·胺-C2-C3烷)《胺甲醯基、N-( 羥-(：2-(：3烷 >胺甲醯 基、肼基、2-羥-丙胺基或直鏈之C2-C3烷胺基（其在ω·位 置被4·嗎啉基、ω>羥-乙胺基、1Η-咪唑·1·基、1Η-咪唑冰 基、胍基、胺基、乙醯基胺基、甲咪基、羧基、乙氧羰 基、胺甲醯基、Ν-羥-胺甲酿基、羥基或二羥磷醯氧基取 代），及 爲氯、三氟甲基、羧基、一化學式*C02R3之自由基 (式中R3爲甲基）或一化學式之自 由基（式中η爲2或3及R/爲羥基、胺基或1H-咪嗤-4-基）。 更特別適宜者爲在實施例中描述之化學式I之化合 物。 本紙張尺度適用中國國家標準（CNS ) Α4規格（210Χ297公釐） (請先閲讀背面之注意Ϋ項再瑱寫本頁) -裝- 訂 〇 線— -20- A7 B7 五、發明説明（） 化學式I之化合物及其鹽類係依照本質上已知方法 製備。本發明之製備化學式I之N-苯-2-嘧啶胺衍生物之 方法係實施如下： a)將一化學式II之化合物 ^ss.C(=0)-CH=CH-N(Rg)-R9 N^J (Π)1T 〇 Line -17 -17 Printed by the Consumers' Cooperative of the China Bureau of Economic Affairs of the Ministry of Economic Affairs A7 _B7_ V. Description of the invention () (where R3 and R4 are independent, they are CVC3 hospitals, X is oxygen or sulfur, 111 Is 1, 2 or 3, 11 is 2 or 3, foot 5 is hydrogen, (: 1-(^ courtyard, € 14 courtyard oxygen, chlorine, bromine, iodine or trifluoromethyl), Re is 1Η-midazo -N group or morpholinyl group and R? Is CrC3 alkyl group or phenyl group which is unsubstituted or monosubstituted by CrC3 alkyl group, halogen or trifluoromethyl group); and salts thereof. A more suitable group includes a chemical formula Compounds of I and their salts, wherein R0 is hydrogen, halogen, lower alkoxy or lower alkyl, and Ri is a) N- (amine-lower alkane > carbamoyl, b) N_ (hydroxy ·· Lower alkyl > carbamoyl, c) hydrazine, d) hexahydropyridyl (which is unsubstituted or substituted with amine · lower alkyl), e) morpholinyl, or f) lower alkylamino ( It is morpholinyl, hydroxy-lower alkylamino, imidazolyl, guanidyl, amine, lower alkylamidoamino, lower alkylamine-chimineamino, methylimidyl, carboxyl, lower alkoxycarbonyl, aminomethyl Fluorenyl, N-hydroxy-aminomethylamino, hydroxy, dihydroxyphosphoryloxy Or is replaced by a chemical formula h2nch (r > c (= 0v NH- radical (where R is hydrogen)), and R2 is chlorine, trifluoromethyl, carboxyl, a chemical formula -C02R3 radical (formula Where R3 is alkyl) or a radical of the formula -C (= 0> NIMCH2) n-R4a (wherein η is 2 or 3 and IV is hydroxyl, amine or imidazolyl). (Please read W Note $ item and fill out this page)-Binding and ordering ○ -line | This paper size applies to China National Standards (CNS) Α4 grid (210 × 297 mm) -18- Printed by A7, Consumer Sample Cooperative of the Central Sample Bureau of the Ministry of Economic Affairs B7 V. Description of the invention () Another suitable group includes compounds of formula I and their salts, wherein R0 is hydrogen and R is a) N- (amine · lower alkane) · carbamic acid group, b) lsK Via-lower alkylamine formamyl, c) hydrazine, or d) lower alkylamino (which is imidazolyl, guanidyl, amine, lower alkylamino, lower alkylamine-carbonylamino, methylimide Group, carboxyl group, lower alkoxycarbonyl group, carbamoyl group, N-diameter-carbamoyl group, hydroxyl group, dihydroxyphosphoranyloxy group or substituted with a chemical formula of H2N-CH (R > C (= 〇VNH- Group substitution (where R is hydrogen ), And r2 is chloro or trifluoromethyl. More suitable are compounds of the formula I and their salts, wherein R0 is hydrogen, chlorine, lower alkyl or lower alkoxy, and R! Is N · (ω · Amine hydrazone 2-(: 3 alkane) -amine formamidine group, N- (ω · hydroxy-C2-C3 alkyl amine formamidine group, hydrazine group, 2-hydroxy-propylamine group or linear QrC3 alkylamino group ( It is morpholino, hydroxy-lower alkylamino, imidazolyl, guanidyl, amine, lower alkylamidoamino, methylimidyl, carboxyl, lower alkoxycarbonyl, and carbamate at the omega position. Group, N-hydroxy-aminomethylamino, hydroxy substituted or substituted with dihydroxyphosphoryloxy), and R2 is chlorine, trifluoromethyl, carboxyl, a radical of the formula -C02R3 (where R3 is a CrC3 alkane Radical) or a free radical of a chemical formula (wherein η is 2 or 3 and R / is a hydroxyl group, an amine group or an imidazolyl group). The size of this paper is applicable to China National Standard (0 Milk) 规格 4 (210 father 297 mm) (Please read the note on the back before filling this page)-Binding · Order G • Thread | -19- Jingshu Department Du Yinzhong A7 ^ __ B2-Employees' Cooperative Cooperation of the Central and Central Bureau of Commerce of the People's Republic of China 5. Description of the invention () The compounds which are particularly suitable are compounds of the formula I and their salts (wherein) is hydrogen, and R 丨 is N · (ω · amine -c2-c3 alkane) -carbamoyl, N- (〇 > hydroxy hepta 2- <: 3 alkane > carbamoyl, hydrazine, 2-trans-propylamino or straight chain C2-C3 Alkylamino groups (which are in the "·" position are imidazolyl, guanidyl, amine, lower alkylamino, imimidyl, carboxyl, lower alkoxycarbonyl, carbamoyl, N-hydroxy · aminocarbamyl , Hydroxy substituted or substituted with dihydroxyphosphoryloxy), and the heart is chlorine or trifluoromethyl. Particularly suitable are compounds of formula I and their salts, wherein & is hydrogen, chlorine, methyl or methyl Oxygen, & is N- (ω · amine-C2-C3 alkane), carbamoyl, N- (hydroxy-(: 2-(: 3 alkane) > carbamoyl, hydrazine, 2-hydroxy -Alanine or a linear C2-C3 alkylamino group (which is replaced by 4 · morpholine at the omega position , Ω > hydroxy-ethylamino, 1-imidazolyl-1, 1-imidazolyl, guanidyl, amine, acetamidoamino, methylimidyl, carboxyl, ethoxycarbonyl, carbamoyl, (N-hydroxy-aminomethylamino, hydroxy, or dihydroxyphosphoryloxy), and is chlorine, trifluoromethyl, carboxyl, a radical of the formula * C02R3 (where R3 is methyl) or a formula of Free radicals (wherein η is 2 or 3 and R / is hydroxyl, amine or 1H-imidino-4-yl). More particularly suitable are the compounds of formula I described in the examples. This paper is for China National Standard (CNS) A4 Specification (210 × 297 mm) (Please read the note on the back before writing this page)-Binding-Book 〇 Line--20- A7 B7 V. Description of Invention () Compounds of Chemical Formula I and The salts are prepared according to a method known per se. The method for preparing the N-phenyl-2-pyrimidinylamine derivative of Chemical Formula I of the present invention is implemented as follows: a) A compound of Chemical Formula II ^ ss.C (= 0 ) -CH = CH-N (Rg) -R9 N ^ J (Π)

Ri (式Π中R«及心各自獨立，爲低級烷基及R,如上述 定義，除了參與反應之基以外，存在於化學式Π之化合 物中之官能基，必要時，爲被保護形式）或此化合物之 鹽與一化學式ΠΙ之化合物 (請先聞讀背面之注意事項再填寫本頁) •裝.Ri (in the formula, R «and R are independent of each other, are lower alkyl and R, as defined above, except for the group participating in the reaction, the functional group present in the compound of the formula Π, if necessary, in a protected form) or The salt of this compound and a compound of formula II (please read the precautions on the back before filling this page).

訂 (式ffl中心及R2如上述定義，除了參與反應之胍基以 外，存在於化學式m之化合物中之官能基，必要時，爲 被保護形式）或其鹽反應，並去除任何存在之保護基， 或 b)爲了製備化學式I之化合物（其中之&具有上述c)、 d)或g)之意義，且R〇及R2各具有上述意義中任何一個 意義），將一化學式IV之化合物 本紙張尺度適用中國國家標準（CNS ) A4规格（210X：297公釐） 線 ^齊郎中夬樣隼局員工消費合作枉印聚 -21 - 五、發明説明（） A7 B7(The center of formula ffl and R2 are as defined above, in addition to the guanidino group participating in the reaction, the functional group existing in the compound of chemical formula m, if necessary, in a protected form) or its salt, and remove any existing protective groups , Or b) In order to prepare a compound of formula I (wherein & has the meaning of c), d) or g) above, and R0 and R2 each have any of the above meanings, a compound of formula IV is Paper size applies to China National Standard (CNS) A4 specification (210X: 297 mm) Line ^ Qilang Zhongyang Prototype Bureau Employee Consumption Cooperation Seal -21-V. Description of Invention () A7 B7

經濟部中央標準局貝工消費合作杜印裝 (式IV中Y爲一離去基，且心及R2如上述定義，除 了參與反應之離去基以外，存在於化學式IV之化合物中 之官能基，必要時，爲被保護形式）或其鹽與一化學式 V之胺反應 H2N-R12 (V) (式V中R12爲胺基或未被取代或胺基-取代之環己基， 或爲低級烷基（其被嗎啉基、羥·低級烷胺基、氰基、咪 唑基、胍基、胺基、低級烷醯基胺基、低級烷胺-羰胺 基、甲脒基、二-低級烷胺-環己基、羧基、低級烷氧羰 基、胺甲醯基、N-羥-胺甲醯基、羥基、低級烷氧基、二 羥磷醯氧基、六氫吡阱基、低級烷酸-六氫毗阱基、甲醯 六氫吡阱基、脯胺醯基醴胺基取代或被一化學式h2n-CH(RK：(=〇>NH-之自由基取代（式中R爲氫、（VC4烷 基、苄基、羥甲基、1-羥-乙基、锍甲基、2-甲硫-乙基、吲 嗓·3·基-甲基、苯-甲基、4-羥-苯-甲基、胺甲醯-甲基、2_胺甲 醯·乙基、殘·甲基、2-殘-乙基、4-胺-丁基、3·胍·丙基或R爲 1Η-咪唑冰基·甲基），存在於R,2中之官能基，必要時， 爲被保護形式），並去除任何存在之保護基，或 C)爲了製備化學式I之化合物（其中之&爲N·(胺·低級 烷>胺甲醯基或N-(羥-低級烷)-胺甲醯基，且^及R2各 具有上述意義中任何一個意義），將一化學式IX之羧酸 (請先閱讀背面之注意事項再填寫本頁) -裝· 訂 線 本紙張尺度適用中國國家梂準（CNS ) A4洗格（210X297公釐） -22- 五、發明説明（） A7 B7Du Yinzhuang, Co-worker, Consumer Product Cooperation, Central Bureau of Standards, Ministry of Economic Affairs , If necessary, in the protected form) or a salt thereof with an amine of formula V2H2N-R12 (V) (where R12 is an amine group or an unsubstituted or amine-substituted cyclohexyl group, or a lower alkane (Which is morpholinyl, hydroxy · lower alkylamino, cyano, imidazolyl, guanidyl, amine, lower alkylamino, lower alkylamine-carbonylamino, formamidine, di-lower alkyl Amine-cyclohexyl, carboxyl, lower alkoxycarbonyl, carbamoyl, N-hydroxy-aminoformyl, hydroxyl, lower alkoxy, dihydroxyphosphoryloxy, hexahydropyridyl, lower alkanoic acid- Hexahydropyridyl, formamidine hexahydropyridyl, proline amidino, amido, or substituted with a free radical of the formula h2n-CH (RK: (= 〇> NH- (where R is hydrogen, (VC4 alkyl, benzyl, hydroxymethyl, 1-hydroxy-ethyl, fluorenylmethyl, 2-methylthio-ethyl, indole-3.yl-methyl, benzene-methyl, 4-hydroxy- Benzene-methyl, Carboxamidine-methyl, 2_ Carbamate · ethyl, residue · methyl, 2-residue-ethyl, 4-amine-butyl, 3 · guanidine · propyl, or R is 1Η-imidazolebenzyl · methyl), present in R, 2 Functional groups in the protected form, if necessary), and remove any protective groups present, or C) in order to prepare compounds of formula I (wherein & is N · (amine · lower alkane) > Or N- (hydroxy-lower alkane) -carbamoyl, and ^ and R2 each have any of the above meanings), a carboxylic acid of formula IX (please read the precautions on the back before filling this page)- Binding and binding The paper size is applicable to China National Standards (CNS) A4 Washing (210X297mm) -22- V. Description of the invention () A7 B7

(式IX中R〇及R2各具有上述意義中任何一個意義，存 在於R2中之官能基，必要時，爲被保護形式）或其一反 應性酸衍生物與一化學式X之胺 H2N-R13 (X) (式X中之r13爲胺-低級烷基或經-低級烷基、胺基或經 基，必要時，爲被保護形式）反應，並去除任何存在之 保護基，或 d)爲了製備化學式I之化合物（其中之&爲嗎啉基，或 爲六氫吡阱基（其未被取代或被胺-低級烷基取代），且 R〇及R2各具有上述意義中任何一個意義），將一化學式 IV之化合物 (請先Η讀背面之注意事項再填寫本頁) •裝 訂 經奇邹中央樣隼局員工消費合作社印裝(R0 and R2 in formula IX each have any of the above meanings, the functional group existing in R2, if necessary, is a protected form) or a reactive acid derivative thereof and an amine H2N-R13 of formula X (X) (r13 in formula X is amine-lower alkyl or via-lower alkyl, amine or via, if necessary, in a protected form) reaction, and remove any protective groups present, or d) in order Preparation of a compound of formula I (wherein & is a morpholinyl group or a hexahydropyridyl group (which is unsubstituted or substituted with an amine-lower alkyl group), and R0 and R2 each have any of the above meanings ), A compound of formula IV (please read the notes on the back before filling out this page)

(式IV中之Y爲一離去基，且R〇及R2如上述定義， 除了參與反應之離去基以外，存在於化學式IV之化合物 中之官能基，必要時，爲被保護形式）或其鹽與嗎啉反 應，或與六氫吡畊（其未被取代或被胺-低級烷基取代） 反應，並去除任何存在之保護基，或 本紙張尺度適用中國國家標準（CNS ) Α4規格（210Χ297公釐） 線 -23 - A7 B7 五、發明説明（） e)爲了製備化學式I之化合物（其中之心爲_C〇2r3、 或-C(=0)-NH-(CH2)n-N(R3)-R4,其中之符號 及取代基各如上述定義），將—化學式XI之羧酸(Y in formula IV is a leaving group, and R0 and R2 are as defined above, except for the leaving group participating in the reaction, the functional group present in the compound of chemical formula IV, if necessary, is a protected form) or Its salt reacts with morpholine, or with hexahydropyrine (which is unsubstituted or substituted with amine-lower alkyl), and removes any existing protective groups, or this paper size applies the Chinese National Standard (CNS) A4 specification (210 × 297 mm) Line-23-A7 B7 V. Description of the invention () e) In order to prepare the compound of formula I (where the heart is _C〇2r3, or -C (= 0) -NH- (CH2) nN ( R3) -R4, wherein the symbols and substituents are as defined above), the carboxylic acid of formula XI

經濟部十央樣隼局貝工消费合作社印裂 (式XI中之R〇及&如上述定義，其存在之官能基，必 要時，爲被保護形式）或其一反應性羧酸衍生物利用適 當的方法酯化或醯胺化，並去除任何存在之保護基， 且，需要時，將依照方法a-e中任何一個方法得到之一 化學式I之化合物轉化成其鹽，或將所得之化學式I化 合物之鹽轉化成自由化合物。 上述製備方法變化類型之進行方式詳述於下： 一般性： 化學式I之最終產物可含取代基，該取代基亦可作 爲製備其它化學式I之最終產物之起始原料中之保護 基。所以，在本文範圍內，除非內容中另有指示，僅有 易於去除之基（其並非所要之特定化學式I之最終產物 之一組成）稱爲'^保護基' 保護基以及其引入及去除的方式描述於，例如， "Protective Groups in Organic Chemistry", Plenmn Press, London, New York 1972 及”Methoden der organischen Chemie' Houben-Weyl, 4th edition» Vol. 15/1，Georg-Thieme-Verlag^ Stuttgart 1774 及 Theodora W. Greene, "Protective Groups in Organic Synthesis", John Wiley & Sons, New (請先閲讀背面之注意事項再填寫本頁) -裝· 訂 線 c 本紙張尺度適用中國國家標準（CNS ) A4洗格（210X297公釐） -24- 經濟部中央標率局員工消費合作杜印製 A7 _B7_ 五、發明説明（） York 1981中。保護基之特徵爲其可易於去除，即，例如 以溶劑分解、還原、光解及在生理條件下去除，不會發 生不期望之次級反應。 羥基-保護基爲，例如，醯基自由基，像未被取代或 被取代之，例如鹵素-取代之低級烷醯基，像2,2·二氯乙醯 基或碳酸半酯之醯基自由基，特別是第三丁氧羰基、未 被取代或被取代之苄氧羰基，例如4-硝苄氧羰基或二苯 基甲氧羰基，或2-國-低級烷氧羰基，像2,2,2-三氯乙氧羰 基，及三苯甲基或甲醯基，或有機矽烷基或錫烷基自由 基，及易於去除之醚化基，像第三·低級烷基，例如第三 丁基、2-蹲-或2·噻-脂族或-環脂族烴自由基，特別是1-低級烷氧-低級烷基或1-低級烷硫·低級烷基，例如甲氧甲 基、1-甲氧-乙基、1-乙氧·乙基、甲硫甲基、1·甲硫乙基或 1-乙硫乙基，或含5或6環原子之2-〇f-或2-噻-環烷 基，例如四氫呋喃基或2-四氫哌喃基或相當之噻基相似 物，及未被取代或被取代之1-苯-低級烷基，像未被取代 或被取代之苄基或二苯基甲基，苯基自由基之適合的取 代基爲，例如，鹵素（像氯）、低級烷氧基（像甲氧 基）及/或硝基。 一被保護之胺基可爲，例如，一易於斷裂之醯基胺 基、芳甲胺基、醚化锍胺基、2-醯-低級稀-1-基-胺基、矽烷 胺基或錫烷胺基形式或一疊氮基形式。 在一相當之醯基胺基中，醯基爲，例如，一含，例 如，高至18個碳原子之有機羧酸之醯基自由基，特別是 一烷羧酸之醯基自由基（其未被取代或被，例如，鹵素 (請先W讀背面之_注項再填寫本頁) .裝· 訂 線 本紙張尺度適用中國國家標準（CNS ) A4规格（2丨0><297公釐） -25- 經濟部中夬樣隼局貝工消費合作社印製 A7 B7 五、發明説明（) 或芳基取代），或一苯甲酸（其未被取代或被，例如， 鹵素、低級烷氧基或硝基取代）或一碳酸半酯之醯基自 由基。這種醯基爲，例如，低級烷醯基（像甲醸基、乙 醸基或丙醯基）、_-低級烷醯基（像2-鹵-乙醯基，特別 是2-氯-、2·溴-、2-碘-、2,2,2-三氟或2,2,2-三氯·乙醯基）、 未被取代或被，例如，鹵素、低級烷氧基或硝基取代之 苄醯基（例如苄醯基、4-氯苄醯基、4-甲氧苄醯基或4·硝 苄醯基），或低級烷氧羰基（其在低級烷基自由基之1-位置分枝或宜在1-或2-位置被取代），特別是第三-低級 烷氧羰基（例如第三丁氧羰基）、含一或二個芳基自由 基之芳甲氧羰基（其芳基自由基宜爲未被取代或被，例 如，低級烷基（特別是第三-低級烷基像第三丁基）、低 級烷氧基（像甲氧基）、羥基、鹵素（例如氯）及/或 硝基單或多取代之苯基），像未被取代或被取代之苄氧 羰基（例如4·硝苄氧羰基）、或被取代之二苯基甲氧羰 基（例如二苯甲氧羰基或二（4-甲氧苯）甲氧羰基）、芳醯 甲氧羰基（其中之芳醯基宜爲苄醯基，爲未被取代或 被，例如，鹵素像溴取代之苄醯基），例如苄醯甲氧羰 基、2-_他級院氧親基（例如2,2,2-三氯乙氧幾基、2-溴乙 氧羰基或2-碘乙氧羰基）、或2-(三取代之矽烷）乙氧幾 基（其中之取代基各自獨立，爲一脂烴、芳脂烴、環脂 烴或芳烴自由基（其未被取代或被，例如，低級烷基、 低級烷氧基、芳基、鹵素或硝基取代，且包含高至15個 碳原子），像相當之未被取代或被取代之低級烷基、苯_ 低級烷基、環烷基或苯基），例如2_三-低級烷矽烷乙氧 (請先聞讀背面之注意事項再填寫本頁) .裝. 訂 C 線- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） -26- 經濟部中央揉準局貝工消费合作社印製 A7 _B7_—_ 五、發明説明（） 羰基，像2-三甲矽烷乙氧羰基或2·(二-正丁-甲-抄烷>乙氧 羰基，或2-三芳矽烷乙氧羰基，像2-三苯矽烷乙氧羰 基。 其它適合作爲胺基-保護基之醯基自由基亦爲有機磷 酸、膦酸或亞膦酸之相當自由基，像二-低級烷磷醯基 (例如二甲磷醯基、二乙磷醯基、二正丙磷醯基或二異 丙磷醯基）、二環烷磷醯基（例如二環己磷醯基）、未 被取代或被取代之二苯磷醯基（例如二苯磷醯基）、未 被取代或被取代之，例如，被硝基取代之二（苯·低級烷) 磷醯基，例如二苄磷醯基或二（4·硝苄）磷醢基、未被取代 或被取代之苯氧苯膦醯基，例如苯氧苯膦醯基、二-低級 烷亞膦醢基’例如二乙亞膦醯基，或未被取代或被取代 之二苯亞膦醯基，例如二苯亞膦醯基。 在一芳甲胺基（其爲一單-、二-或，特別是，三-芳甲 胺基）中，芳基自由基特別爲未被取代或被取代之苯基 自由基。這種基爲，例如，节-、二苯基甲-及，特別是， 三苯甲-胺基。 胺基中之醚化锍基（其用以保護胺基）特別爲芳硫 基或芳-低級烷硫基（其中芳基特別爲未被取代或被取代 之苯基，例如，被低級烷基（像甲基或第三丁基）、低 級烷氧基（像甲氧基）、鹵素（像氯）及/或硝基取代 之苯基）。一相當之胺基護基爲，例如，4-硝苯硫基。 在一 2-醯-低級1-儲-1-基自由基（其可用作胺基·保護 基）中，醯基爲，例如，一低級烷羧酸之相當自由基、 一苯甲酸之相當自由基（其未被取代或被取代，例如， 本紙張尺度適用中國國家梂準（CNS ) A4規格（210X297公釐） 83. 3.10,000 . - * - ---------裝-------- 訂.--：---- (請先聞讀背面之注意事項再填寫本I) -27- 經濟部中央梯準局貝工消费合作社印製 A7 _B7_ 五、發明説明（） 被低級烷基（像甲基或第三丁基）、低級烷氧基（像甲 氧基）、鹵素（像氯）及/或硝基取代）、或特別是一 碳酸半酯（像一碳酸低級烷基半酯）之相當自由基。相 當之保護基特別爲Μ氏級烷醯-丙-1-烯-2-基，例如1_乙醯·丙 -1-儲-2~^或級院氧凝-丙-1-稀-2-基，例如1-乙氧簾-丙-1-嫌-2-¾。 偏愛之胺基-保護基爲碳酸半酯之醯基自由基，特別 是第三丁氧羰基、未被取代或被取代之苄氧羰基，例 如，如所示者，例如4-硝-节氧羰基或二苯基甲氧羰基、 或2-鹵級烷氧羰基，像2,2,2-三氯乙氧羰基，及三苯甲 基或甲醯基》保護基（其非所期望之化學式I之最終產 物之組成）之去除係利用本質上已知方法實施，例如利 用溶劑解（特別是水解、醇解或酸解），或利用還原 (特別是氫解或化學還原）逐步或同時完成。 一被保護之胺基係利用本質上已知方法釋放且，視 保護基之性質而定，可利用各種方法，最好是用溶劑解 或還原達成。2-鹵-低級烷氧羰胺基（適當時，在2-溴-低 級烷氧羰胺基轉化成2-碘-低級烷氧羰胺基之後）、芳醯 甲氧羰胺基或4·硝苄氧羰胺基可，例如，用一適合之化 學還原劑像鋅處理***（在一適合之羧酸，像醋酸水溶 液的存在下處理）。芳醣甲氧羰胺基亦可用一親核劑處 理而***（宜用成鹽劑，像硫酚鈉處理），及4·硝-苄氧 羰胺基亦可用一鹼金屬二亞硫磺酸鹽處理而***（例如 用二亞硫磺酸鈉處理）。未被取代或被取代之二苯基甲 氧羰胺基、第三-低級烷氧羰胺基或2-三-取代之矽烷乙氧 本紙張尺度適用中國國家標準（CNS ) A4洗格（210X297公釐） 83. 3.10,000 ---------(、裝---_—tir---------《V (锖先閲讀背面之注意事項再填寫本頁) -28- A7 _B7__ 五、發明说明（） 羰胺基可用一適合之酸處理而***，例如用甲酸或三氟 醋酸處理，未被取代或被取代之苄氧羰胺基係，例如， 利用氫解處理，即用氫在一適合之氫化觸媒，像鈀觸媒 的存在下處理，未被取代或被取代之三芳甲胺基或甲醯 基胺基係，例如，用一酸，像一礦物酸（例如鹽酸）或 一有機酸（例如甲酸、醋酸或三氟醋酸）處理，適當時 在水的存在下處理，及被一有機矽烷基保護之胺基可， 例如，利用水解或醇解而釋放。一被2-鹵乙醸基，例 如，2-氯乙醯基保護之胺基可用硫脲在一鹼的存在下處理 而釋放，或用一硫脲之硫羥酸鹽，像鹼金屬硫羥酸鹽處 理，接著將形成之縮合產物溶劑解，像醇解或水解。一 被2-取代之矽烷乙氧羰基保護之胺基亦可用一產生氟離 子之氫氟酸鹽處理而轉化成自由胺基。 經濟部中央標準局員工消費合作社印製 (請先聞讀背面之注意事項再埃寫本頁) 被適合之醯基、有機矽烷基或未被取代或被取代之 1-苯·®級烷基保護之羥基，係利用類似於釋放相當被保護 之胺基的方法釋放。被未取代或取代之1-苯-低級烷基 (例如苄基）保護之羥基宜利用觸媒氫化法釋放，例如 在一鈀/碳觸媒的存在下氫化。被2,2-二氯乙醯基保護之 羥基係，例如，利用鹼性水解釋放，及被第三·低級烷基 或2-喂-或2-噻·脂烴或-環脂烴自由基醚化之羥基係利用 酸解釋放，例如用一礦物酸或一強羧酸（例如三氟醋 酸）處理。被一有機矽烷基自由基（例如三甲矽烷基） 醚化之羥基亦可’例如，利用一產生氟離子之氫氟酸鹽 (例如氟化四丁銨）處理而釋放。 本紙張尺度適用中國國家標率（CNS ) A4说格（210X297公釐） -29- 經濟部中央櫺準局員工消費合作社印製 A7 B7 五、發明説明（） 方法a: Rs及R9最好各爲甲基。 化學式π化合物中之自由官能基（其最好是被易於 去除之保護基保護）特別爲自由基艮中之胺基及1H_吲 哚基之亞胺基。亞胺基可，例如，用苄基保護。 化學式m中之自由官能基（其最好是被易於去除之 保護基保護）特別爲胺基，但也爲羥基及羧基。 化學式Π或ΠΙ化合物之鹽宜爲一酸加成鹽，例如 一硝酸鹽或在化學式I之最終產物中述及之酸加成鹽中 之一。 反應係在一適合的溶劑或分散劑中進行，例如在一 適合的醇（像2-甲氧-乙醇）或一適合的低級烷醇（例如 異丙醇或異丁醇）中，在從室溫（大約20°c )至150°c之 溫度及迴流下進行。特別是，當一化學式Π或特別是ffl 之化合物用爲鹽時，該鹽宜在原處，利用一適合之鹼， 像一鹼金屬氫氧化物（例如氫氧化鈉）之加入轉化成自 由化合物。 化學式Π之起始原料，係用一化學式VI之化合物 (請先閲讀背面之注$項再填寫本頁) •裝· 訂 線 〇Printed by the Shiyang Bureau of the Ministry of Economic Affairs, Shellfish Consumer Cooperative (where R0 and & in the formula XI are as defined above, their functional groups are present, if necessary, in a protected form) or a reactive carboxylic acid derivative thereof Esterify or amidate by appropriate methods, and remove any existing protecting groups, and, if necessary, convert one of the compounds of formula I obtained according to any one of methods ae into its salt, or convert the obtained formula I Compound salts are converted into free compounds. The method of carrying out the above-mentioned variations of the preparation method is described in detail as follows: General: The final product of Chemical Formula I may contain a substituent, and the substituent may also serve as a protective group in the starting materials for preparing other final products of Chemical Formula I. Therefore, within the scope of this document, unless otherwise indicated in the content, only those groups that are easily removable (which is not one of the final products of the specific formula I desired) are called '^ protecting groups' protecting groups and their introduction and removal. Methods are described in, for example, " Protective Groups in Organic Chemistry ", Plenmn Press, London, New York 1972 and "Methoden der organischen Chemie 'Houben-Weyl, 4th edition» Vol. 15/1, Georg-Thieme-Verlag ^ Stuttgart 1774 and Theodora W. Greene, " Protective Groups in Organic Synthesis ", John Wiley & Sons, New (Please read the precautions on the back before filling out this page)-Binding · Binding Line c This paper is in accordance with Chinese national standards ( CNS) A4 Washing (210X297 mm) -24- Consumption Cooperation of Employees of the Central Standards Bureau of the Ministry of Economic Affairs Printed A7 _B7_ V. Description of the Invention () York 1981. The protective group is characterized by being easily removable, ie, With solvolysis, reduction, photolysis and removal under physiological conditions, undesired secondary reactions do not occur. Hydroxyl-protecting groups are, for example, fluorenyl radicals, Unsubstituted or substituted, such as halogen-substituted lower alkylfluorenyl groups, such as 2,2 · dichloroethylfluorenyl or fluorenyl radicals of carbonic acid half esters, especially tertiary butoxycarbonyl, unsubstituted or Substituted benzyloxycarbonyl, such as 4-nitrobenzyloxycarbonyl or diphenylmethoxycarbonyl, or 2-nation-lower alkoxycarbonyl, like 2,2,2-trichloroethoxycarbonyl, and trityl Or methylamino, or organosilyl or stannyl radicals, and easily removable etherifying groups, like tertiary · lower alkyl, such as tertiary butyl, 2-squat- or 2-thio-aliphatic or -Cycloaliphatic hydrocarbon radicals, especially 1-lower alkoxy-lower alkyl or 1-lower alkanethio · lower alkyl, such as methoxymethyl, 1-methoxy-ethyl, 1-ethoxy · ethyl Methyl, methylthiomethyl, 1 · methylthioethyl or 1-ethylthioethyl, or 2-0f- or 2-thia-cycloalkyl containing 5 or 6 ring atoms, such as tetrahydrofuryl or 2-tetrahydro Hydropiperanyl or equivalent thiol analogs, and unsubstituted or substituted 1-benzene-lower alkyl, like unsubstituted or substituted benzyl or diphenylmethyl, phenyl radical Suitable substituents are, for example, halogen (like chlorine , Lower alkoxy (like methoxy), and / or nitro. A protected amine group can be, for example, a fluorenylamino group that is easy to break, arylmethylamino, etherified fluorenylamino, 2- Amidine-lower di-l-yl-amino, silylamine or stannylamine or azide. In a comparable fluorenylamino group, the fluorenyl group is, for example, a fluorenyl radical containing an organic carboxylic acid having, for example, up to 18 carbon atoms, in particular a fluorenyl radical of an alkanecarboxylic acid (which It has not been replaced or replaced, for example, halogen (please read the _note on the back side before filling this page). Binding and binding The paper size is applicable to China National Standard (CNS) A4 specification (2 丨 0 > < 297) (Centi) -25- Printed by the Ministry of Economic Affairs, Shellfish Consumer Cooperative, A7, B7 5. Description of the invention () or aryl substitution), or monobenzoic acid (which is not substituted or replaced by, for example, halogen, lower alkane (Oxy or nitro substituted) or a fluorenyl radical of a half carbonate. Such fluorenyl groups are, for example, lower alkylfluorenyl groups (such as methylfluorenyl, ethylfluorenyl, or propylfluorenyl), _-lower alkylfluorenyl groups (such as 2-halo-ethylfluorenyl, especially 2-chloro-, 2 · bromo-, 2-iodo-, 2,2,2-trifluoro or 2,2,2-trichloro · ethylfluorenyl), unsubstituted or substituted, for example, halogen, lower alkoxy or nitro Substituted benzamidine (for example, benzamidine, 4-chlorobenzyl, 4-methoxybenzyl, or 4-nitrobenzyl), or lower alkoxycarbonyl (which is 1- 1 in lower alkyl radicals) Branched or preferably substituted at the 1- or 2-position), especially tertiary-lower alkoxycarbonyl (eg, third butoxycarbonyl), arylmethoxycarbonyl containing one or two aryl radicals (which Aryl radicals are preferably unsubstituted or substituted, for example, lower alkyl (especially third-lower alkyl like third butyl), lower alkoxy (like methoxy), hydroxyl, halogen (such as chlorine ) And / or nitro mono- or poly-substituted phenyl), like unsubstituted or substituted benzyloxycarbonyl (such as 4 · nitrobenzyloxycarbonyl), or substituted diphenylmethoxycarbonyl (such as diphenyl Methoxycarbonyl or bis (4-methoxybenzene) methoxy Group), arylfluorenylmethoxycarbonyl (wherein the arylfluorenyl group is preferably benzylfluorenyl, which is unsubstituted or substituted, for example, halogen is like benzylfluorenyl substituted with bromine), such as benzylfluorenylmethoxycarbonyl, 2-_ other Grade oxyphilic groups (eg 2,2,2-trichloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl), or 2- (trisubstituted silane) ethoxyquinyl (where The substituents are each independently an aliphatic, araliphatic, cycloaliphatic, or aromatic hydrocarbon radical (which is unsubstituted or substituted with, for example, lower alkyl, lower alkoxy, aryl, halogen, or nitro, And contains up to 15 carbon atoms), like equivalent unsubstituted or substituted lower alkyl, benzene_ lower alkyl, cycloalkyl, or phenyl), such as 2_tri-lower silane siloxyethoxy (please Read the precautions on the back before filling in this page). Packing. Order C line-This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) -26- Printed by the Central Labor Bureau of the Ministry of Economic Affairs Preparation of A7 _B7 _—_ V. Description of the invention () Carbonyl, like 2-trimethylsilylethoxycarbonyl or 2 · (di-n-butyl-methyl-pyrane > ethoxycarbonyl, or 2- Arylsilane ethoxycarbonyl, like 2-triphenylsilane ethoxycarbonyl. Other fluorenyl radicals suitable as amine-protecting groups are also equivalent free radicals of organic phosphoric acid, phosphonic acid or phosphinic acid, like di-lower alkanes Phosphonium (such as dimethylphosphonium, diethylphosphonium, di-n-propylphosphonium or diisopropylphosphonium), dicycloalkanoyl (such as dicyclohexylphosphonium), Substituted or substituted diphenylphosphonium groups (such as diphenylphosphonium groups), unsubstituted or substituted, for example, bis-substituted (benzene · lower alkyl) phosphino groups, such as dibenzylphosphonium groups Or di (4 · nitrobenzyl) phosphonium, unsubstituted or substituted phenoxyphenylphosphinofluorenyl, such as phenoxyphenylphosphinofluorenyl, di-lower alkylphosphinephosphonium fluorenyl 'such as diethylphosphinephosphonium Group, or unsubstituted or substituted diphenylphosphinofluorenyl, such as diphenylphosphinofluorenyl. In an arylmethylamino group (which is a mono-, di-, or, in particular, a tri-arylmethylamino group), the aryl radical is particularly an unsubstituted or substituted phenyl radical. Such groups are, for example, benzyl-, diphenylmethyl- and, in particular, triphenylmethylamine. The etherified fluorenyl group in the amine group (which is used to protect the amine group) is particularly an arylthio group or an aryl-lower alkylthio group (wherein the aryl group is particularly an unsubstituted or substituted phenyl group, for example, a lower alkyl group) (Like methyl or third butyl), lower alkoxy (like methoxy), halogen (like chlorine), and / or nitro-substituted phenyl). A comparable amine protecting group is, for example, 4-nitrophenylthio. In a 2-fluorene-lower 1-stor-1-yl radical (which can be used as an amine-protecting group), the fluorenyl group is, for example, the equivalent of a lower alkyl carboxylic acid and the equivalent of a benzoic acid Free radicals (which are not substituted or substituted, for example, this paper size applies to China National Standards (CNS) A4 specifications (210X297 mm) 83. 3.10,000.-*---------- equipment -------- Order .--: ---- (Please read the notes on the back before filling in this I) -27- Printed by the Shellfish Consumer Cooperative of the Central Elevator Bureau of the Ministry of Economic Affairs A7 _B7_ V. Description of the invention () Substituted by lower alkyl (like methyl or third butyl), lower alkoxy (like methoxy), halogen (like chlorine) and / or nitro), or especially half carbonate (Like a lower alkyl half carbonate) quite free radical. The equivalent protective group is especially M-class alkane-prop-1-en-2-yl, such as 1-acetamidine · prop-1-store-2 ~ ^ or grade oxo-prop-1-en-2- -Based, such as 1-ethoxy curtain-prop-1--1--2--2-. Preferred amine-protecting groups are fluorenyl radicals of half carbonate, especially tertiary butoxycarbonyl, unsubstituted or substituted benzyloxycarbonyl, for example, as shown, such as 4-nitro-benzyloxy Carbonyl or diphenylmethoxycarbonyl, or 2-haloalkoxycarbonyl, like 2,2,2-trichloroethoxycarbonyl, and trityl or formamyl protecting groups (which are not the desired chemical formula The composition of the final product of I) is removed by a method known per se, such as by solvolysis (especially hydrolysis, alcoholysis or acidolysis), or by reduction (especially hydrogenolysis or chemical reduction) stepwise or simultaneously . A protected amine group is released by a method known per se and, depending on the nature of the protecting group, various methods can be used, preferably by solvolysis or reduction. 2-halo-lower alkoxycarbonylamino group (after conversion of 2-bromo-lower alkoxycarbonylamino group to 2-iodo-lower alkoxycarbonylamino group, if appropriate), arylfluorenylmethoxycarbonylamino group or 4 · Nitrobenzyloxycarbonyl can be cleaved, for example, with a suitable chemical reducing agent like zinc (treated in the presence of a suitable carboxylic acid, like aqueous acetic acid). Aromatic sugar methoxycarbonylamino groups can also be cleaved by treatment with a nucleophile (preferably with a salt-forming agent such as sodium thiophenolate), and 4 · nitro-benzyloxycarbonylamino groups can also be treated with an alkali metal disulfite Splitting when treated (eg, with sodium disulfite). Unsubstituted or substituted diphenylmethoxycarbonylamino, tertiary-lower alkoxycarbonylamino, or 2-tri-substituted silylethoxy This paper is sized to the Chinese National Standard (CNS) A4 (210X297) Mm) 83. 3.10,000 --------- (, install ---_- tir --------- "V (锖 Please read the precautions on the back before filling this page) -28- A7 _B7__ 5. Description of the invention () The carbonylamino group can be split with a suitable acid treatment, such as formic acid or trifluoroacetic acid, unsubstituted or substituted benzyloxycarbonylamino group, for example, using hydrogen Decomposition treatment, that is, treatment with hydrogen in the presence of a suitable hydrogenation catalyst, such as a palladium catalyst, unsubstituted or substituted triarylmethylamino or methylamino system, for example, using an acid, such as a Treatment with a mineral acid (such as hydrochloric acid) or an organic acid (such as formic acid, acetic acid, or trifluoroacetic acid), where appropriate in the presence of water, and an amine group protected by an organosilyl group, for example, by hydrolysis or alcoholysis And release. An amine group protected by 2-haloacetamidine, for example, 2-chloroacetamidine can be released by treatment with thiourea in the presence of a base, Alternatively, it can be treated with a thiouric acid salt of a thiourea, like an alkali metal thiourate, and then the formed condensation product is solvolyzed, like alcoholysis or hydrolysis. An amine group protected by a 2-substituted silane ethoxycarbonyl group is also Can be treated with a hydrofluoric acid salt that generates fluoride ions and converted into free amine groups. Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before writing this page) Silyl or unsubstituted or substituted 1-benzene · grade alkyl-protected hydroxyl is released by a method similar to the release of a fairly protected amine group. Unsubstituted or substituted 1-benzene-lower alkyl (Eg benzyl) protected hydroxyl groups should be released by catalytic hydrogenation, such as hydrogenation in the presence of a palladium / carbon catalyst. Hydroxy groups protected by 2,2-dichloroethenyl, for example, by alkaline hydrolysis Release and hydroxyl groups etherified with a third · lower alkyl or 2-Hy- or 2-thia · aliphatic or -cycloaliphatic radical are explained by acid, for example with a mineral acid or a strong carboxylic acid ( (Such as trifluoroacetic acid). It is treated with an organosilyl radical (such as trimethylsilane). The etherified hydroxyl group can also be released, for example, by treatment with a fluoride ion-generating hydrofluoric acid salt (such as tetrabutylammonium fluoride). This paper size is applicable to China National Standard (CNS) A4 scale (210X297) (%) -29- Printed by A7 B7 of the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs 5. Description of the Invention () Method a: Rs and R9 are preferably methyl groups. Free functional groups in compounds of chemical formula π (which are preferably Protected by protective groups that are easily removed) are especially the amine group in the radical radical and the imino group of 1H_indolyl group. The imine group can be protected, for example, with a benzyl group. The free functional group in the chemical formula m (the most Fortunately, it is protected by a protective group that can be easily removed. In particular, it is an amine group, but also a hydroxyl group and a carboxyl group. The salt of the compound of Formula II or III is preferably an acid addition salt, such as one of the nitrate salts or the acid addition salt mentioned in the final product of Chemical Formula I. The reaction is carried out in a suitable solvent or dispersant, for example in a suitable alcohol (like 2-methoxy-ethanol) or a suitable lower alkanol (such as isopropanol or isobutanol) in a secondary chamber. Temperature (about 20 ° c) to 150 ° c under reflux. In particular, when a compound of formula II or especially ffl is used as a salt, the salt is preferably converted into a free compound in situ by the addition of a suitable base, such as an alkali metal hydroxide (such as sodium hydroxide). The starting material of chemical formula Π is a compound of chemical formula VI (please read the note on the back before filling this page) • Binding and Binding

(式VI中之R,如上述定義，其存在之官能基，必要 時，爲被保護形式）或其鹽與一化學式ΥΠ之化合物 本紙張尺度適用中國國家橾準（CNS ) A4規格（210X297公釐） -30- 經濟部中央橾準局員工消費合作杜印製 A7 B7 五、發明説明（） 〇RlO .¾ Η--Ν (VII) \ ORu (式νπ中之Ru)及R„各爲低級烷基，且其它取代基如 上述定義）反應製得，製備方法類似於歐洲專利申請案 (申請案號233 461)中描述之方法。化學式VII之化合 物之典型代表爲N，N-二甲基甲醯胺二甲醇縮乙醛及N，N-二甲基甲醯胺二乙醇縮乙醛。屄應係將化學式VI及νπ 之反應物在沒有溶劑或，必要時，在一溶劑的存在下， 在一大約從5(TC至150°C之溫度（例如110°C)下加熱1-24小時而完成。 另一方法，化學式Π之起始原料亦可用一化學式VI 之化合物與化學式H>C(=〇M>CH2-CH3之甲酸乙酯反應， 並將形成之產物與一化學式H-N(R*>R9 (式中之取代基如 上述定義）反應而製得。 化學式ΙΠ之起始原料係用一化學式Vffl之苯胺衍生 物 (請先閱讀背面之注意事項再填寫本頁) -裝.(R in formula VI, as defined above, its existing functional group, if necessary, is in a protected form) or its salt and a compound of formula ΥΠ This paper applies the Chinese National Standard (CNS) A4 specification (210X297) PCT) -30- Consumption cooperation between employees of the Central Bureau of Standards, Ministry of Economic Affairs, printed A7 B7 V. Description of the invention () 〇RlO .¾ Η--N (VII) \ ORu (Ru in the formula νπ) and R „are Lower alkyl, and other substituents as defined above, are prepared by a reaction method similar to that described in European Patent Application (Application No. 233 461). A typical representative of the compound of formula VII is N, N-dimethyl Methylformamide dimethanol acetal and N, N-dimethylformamide diethanol acetal. The reactants of formula VI and νπ should be in the absence of a solvent or, if necessary, in the presence of a solvent Then, it is completed by heating at a temperature of about 5 (TC to 150 ° C, for example, 110 ° C) for 1-24 hours. Alternatively, the starting material of chemical formula Π can also use a compound of chemical formula VI and chemical formula H & gt C (= 〇M > CH2-CH3 ethyl formate, and the formed product is reacted with a chemical HN (R * > R9 (substituent in the formula is as defined above)). The starting material of chemical formula III is an aniline derivative of chemical formula Vffl (please read the precautions on the back before filling this page) -Loading.

(式νπι中之11〇及R2如上述定義）與氰胺（NC-NH2)反 應以酸加成鹽形式製得。反應係在一適合的溶劑或分散 劑，例如一適合的醇（例如一低級烷醇，像乙醇）中完 成，例如 〇0在等摩爾量之成鹽酸（例如硝酸）之存在下， 或 本紙張尺度適用中國國家揉準（CNS ) Α4規格（210Χ297公釐）(11 and R2 in the formula νπι are as defined above) are reacted with cyanamide (NC-NH2) in the form of an acid addition salt. The reaction is carried out in a suitable solvent or dispersant, such as a suitable alcohol (such as a lower alkanol, such as ethanol), such as 0.00 in the presence of an equimolar amount of hydrochloric acid (such as nitric acid), or the paper Standards apply to China National Standard (CNS) A4 (210 × 297 mm)

\)y C -31 - 經濟部中央標準局貝工消费合作社印製 A7 B7 五、發明説明（） β)在一澄淸，例如60%，過量之礦物酸，像鹽酸之存在 下，當反應完全時，加入一所要之成鹽酸之銨鹽，例如 硝酸銨， 在一從大約室溫至150°C之溫度下（例如在迴流下）。 方法b : 化學式IV化合物中之一離去基Y爲反應性酯化羥 基，例如用一強無機酸或有機酸酯化之羥基，像用一礦 物酸，例如一氫鹵酸（像鹽酸、氫溴酸或氫碘酸）及硫 酸或一硫醯齒（例如硫酸氟），或用一強有機磺酸，像 一低級烷磺酸（其未被取代或被，例如，鹵素像氟取 代）或一芳族磺酸，例如一苯磺酸（其未被取代或被低 級烷基像甲基、鹵素像溴及/或硝基取代），例如一甲 磺酸、三氟甲磺酸或對甲苯磺酸。Y宜爲鹵素，特別 是，氯。 反應宜在一過量之化學式V之胺（其，適當時，亦 可作爲溶劑），及，必要時，一惰性溶劑，像二甲亞砜 之存在下，在一從室溫至+150°c之溫度（例如在110°C) 下進行。 化學式IV之起始原料，可利用，例如，類似於方法 a之方法製備。例如，可先用間-氯··過苯甲酸在一適合之 溶劑，像二氯甲烷中，例如在迴流下，將4-乙醯·吡啶氧 化成N-氧化4-乙酿-吡啶。然後用***在一適合之惰 性溶劑’像甲苯中，例如在大約100 °C下，將N·氧化4-乙醯-吡啶轉化成4-乙醯-2-氯·吡啶。然後將得到之4-乙醯-2- (請先閲讀背面之注^^項再填寫本頁) 裝· 訂 9. 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 83. 3.10,000 -32- 經濟部中央標準局貝工消费合作社印製 A7 B7___ 五、發明説明（) 氯-吡啶與一化學式II之化合物（方法a中所示者）反 應，產生一類似於化學式II (在以上方法a中所示，其 中艮爲氯者）之化合物。然後利用類似於方法a之方 法，將如此得到之化合物與一化學式ΙΠ之化合物反應生 成化學式IV之起姶原料 或者’化學式IV之起始原料可用化學式VII之二甲 基甲醯胺二乙醇縮乙醛（其，例如，同時作爲溶劑）’ 例如在大約ll〇°C下，將N•氧化4-乙醯·吡啶轉化成3-二 甲胺·ΗΝ·氧-吡啶>2-丙烯-，像3·二甲胺-KN·氧冰吡啶> 2-丙嫌-1-酮，然後將其與一化學式^之R2-苯-胍（其中之 R2如上述定義者），或最好與一適合之鹽（例如一硝酸 鹽，其在一適合之溶劑，像異丙醇中），且在一適合之 鹼，像氫氧化鈉的之存在下，例如在迴流下反應生成一 類似於化學式IV (其中之Y爲氧基者）之N-氧-吡啶基 化合物。然後將如此得到之N-氧-η比啶基化合物用氧氯化 磷轉化成一化學式IV之化合物（其中之Υ爲氯）。與 ***之反應可，例如，不用溶劑，在大約l〇〇°C下進 行。或者同時使用***與一適合之胺，像二異丙 胺，在一適合之溶劑（例如，一氯化烴，像氯仿）中， 在大約室溫下進行。另一個可能性爲，使用***在 一適合之溶劑，像氯仿、甲苯或二甲苯中，在高溫下 (例如在迴流下）進行。 方法c: (請先閱讀背面之注$項再填寫本頁) •裝. 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公嫠} -33- 83. 3.10,000 經濟部中央標準局負工消費合作社印製 A7 B7 _ 五、發明説明（） 化學式IX化合物之自由基私中之自由官能基（其 最好被易於去除之保護基保護），特別爲羧基，以及胺 基。 一化學式IX之化合物之反應性衍生物特別爲一反應 性（活化）酯、一反應性酐或一反應性環醸胺。 一化學式IX之酸之反應性（活化）酯特別爲在酯化 自由基之鍵聯碳原子上不飽和之酯，例如乙烯酯型，像 乙烯酯本身（其可，例如，用醋酸乙烯酯將一相當之酯 轉酯化而製得；活化乙烯酯法）、胺甲醯酯乙烯酯（其 可，例如，用一異Of唑離子試劑處理相當之酸而製得；1-2»0f唑離子或伍得瓦（Woodward)法）、或1-低級烷氧乙烯 酯（其可，例如，用一低級烷氧乙炔處理相當之酸而製 得；乙氧乙炔法）、或甲脒基類之醋，像N，N，-二-取代之 甲脒酯（其可，例如，用一適合之N，N’-二·取代之羰二亞 胺，例如Ν,Ν·-二環己羰二亞胺處理相當之酸而製得；羰 二亞胺法）、或Ν，Ν·二-取代之甲脒酯（其可，例如，用 一 Ν，Ν-二·取代之氰胺處理相當之酸而製得；氰胺法）、 適合之芳醋，特別是適合被電子吸引取代基取代之苯醋 (其可，例如，用一適合之取代之酚，例如冬硝酚、4_甲 磺酿-S&、2,4,5·三氯酚、2Λ4,5,6«五氯酚或4-苯重氮酚，在 一縮合劑，像N，NV二環己羰二亞胺之存在下處理相當之 酸而製得；活化芳酯法）、氰甲酯（其可，例如，用氯 乙膪在一鹸的存在下處理相當之酸而製得；氰甲酯 法）、硫酯，特別是未被取代或被取代（例如硝基_取 代）之本硫酯（其可，例如，用未被取代或被取代（例 本紙張纽逋用中國國家榡率（CNS )八4财_ (2 J 0 x 297公董） 83. 3.10,000 V,..-裝-----^—訂- (請先閲讀背面之注意事項再填寫本頁) * 34 *- 經濟部中央揉準局員工消费合作社印製 A7 _B7____ 五、發明説明（） 如硝基-取代）之硫酚處理相當之酸而製得，尤其是利用 酐或羰二亞胺法；活化硫酯法）、胺酯或醯胺酯（其 可，例如，用一 N-羥-胺基或N-羥-醯胺基化合物，例如 N-羥-琥珀醯亞胺、N-羥-六氫吡啶、N-羥撒醯亞胺或1-羥-苯幷***處理相當之酸而製得，例如利用酐或羰二亞胺 法；活化N-羥基酯法）或矽烷酯（其可，例如，用一矽 烷化劑，例如六甲二矽疊氮烷處理相當之酸而製得，且 其易與羥基反應，而不與胺基反應）。 一化學式IX之酸之酐可爲那些酸之對稱酐或宜爲混 合酐，例如用無機酸（像醯鹵，特別是醯氯）生成之酐 (其可，例如，用硫磺醯氯、五氯化磷或草醯氯處理相 當之酸而製得；醯氯法），用疊氮化合物生成之酐（其 可，例如，由一相當之酸酯，利用相當之醯肼且其用亞 硝酸處理而製得；疊氮化合物法），用碳酸半衍生物生 成之酐，像用相當之酯（例如碳酸低級烷半酯）生成之 酐（其可，例如，用鹵甲酸低級烷酯（像氯甲酸低級烷 酯）或1-低級烷氧幾_2·低級烷氧-1,2-二氫喹啉（例如1·低 級院氧幾-2-乙氧-1,2-二氫唾琳）處理相當之酸而製得；混 合〇·院碳酸酐法），或用二鹵化，特別是二氯化磷酸生 成之酐（其可，例如，用***處理相當之酸而製 得；***法），或用有機酸生成之酐，像用有機殘 酸生成之混合酐（其可，例如，用一未被取代或被取代 之低級院-或苯垸·殘醯齒，例如苯乙醯氯、三甲基乙醯氯 或三氟乙醯氯處理相當之酸而製得；混合羧酸酐法）， 或用有機磺酸生成之混合酐（其可，例如，用—適合之 本紙張尺度適用中國國家標準（CNS ) A4规格（210X297公釐） (請先閲讀背面之注意事項再填寫本頁) -裝. 線 -35- 經濟部中央橾準局員工消費合作社印策 A7 B7 五、發明説明（） 有機醯氯，像一低級烷·或芳-磺醯氯（例如甲磺醯氯或對 甲苯磺醯氯）處理一相當之酸之鹽，像一鹸金屬鹽而製 得；混合磺酸酐法）及對稱酐（其可，例如，在一羰二 亞胺或1-二乙胺丙炔的存在下，縮合相當之酸而製得； 對稱酐法）。 適合之環醯胺特別爲含具芳族性質之5員重氮環之 醯胺，像用咪唑類生成之醯胺，例如咪唑（其可，例 如，用Ν,Ν’-羰二咪唑處理相當之酸而製得；咪唑化物 法），或用吡唑類生成之醯胺，例如3,5-二甲吡唑（其 可，例如，利用醯肼，用乙醯丙酮處理而製得；吡唑化 物法）。 化學式IX之酸之衍生物（其用作醯化劑）亦可在原 處生成。例如，Ν，Ν’-二-取代之甲脒酯可在一適合之Ν，Ν-二-取代之羰二亞胺（例如Ν，Ν’-二環己羰二亞胺）之存在 下，在化學式X之起始原料及作爲醯化劑之酸之混合物 反應中生成。除此之外，作爲醯化劑之酸之胺酯或醯胺 酯可在要被醯化之化學式X之起始原料存在下生成，即 在一 Ν,Ν’-二-取代之羰二亞胺（例如Ν,Ν*-二環己羰二亞 胺）之存在下，及一 Ν-羥-胺或Ν-羥-醯胺（例如Ν-羥琥 珀醯亞胺）之存在下，適當時在一適合之鹼（例如4-二 甲胺吡啶）之存在下，使一相當之酸及胺基起始原料之 混合物反應。 反應之實施係利用化學式IX化合物之反應性羧酸衍 生物與一化學式X之化合物反應，參與反應之胺基爲被 保護形式。在一較適宜形式之反應中，在室溫下，將一 (請先閱讀背面之注意事項再填寫本頁) •裝· 訂 線 本紙張尺度適用中國國家標準（CNS > Α4規格（210Χ297公釐） -36- 經濟部中央標準局員工消费合作社印製 B7_ 五、發明説明（） 化學式IX之起始原料溶於二甲基甲醯胺之溶液與氫氯化 N_乙二甲胺丙二亞胺及N-羥琥珀醯亞胺一起攪拌 數小時，然後將如此得到之反應混合物逐滴加入一化學 式X之胺溶於二甲基甲醸胺之溶液中。 反應可利用一本質上已知方法進行，反應條件特別 視醯化劑之羧基是否已經活化及如何活化而定，通常在 一適合之溶劑或稀釋劑或其混合液之存在下，及，必要 時，在一縮合劑（例如當參與反應之羧基爲一酐形式 時，亦可爲一酸結合劑）之存在下，在冷卻或加熱下 (例如在一從大約_30°C至大約+150°C，特別是大約從 0°C至+100°C，最好是從室溫（大約+20°C )至+70°C之溫 度範圍內），在一開放或封閉的反應容器及/或在一惰 性氣體（例如氮氣）氣壓下進行。常用之縮合劑爲，例 如，羰二亞胺（例如N，N’-二乙-、Ν,Ν*-二丙-、N，N*-二環己-或N-乙-NH3-二甲胺丙>羰二亞胺）、適合之羰基化合物 (例如羰二咪唑）或1，2-喂唑離子化合物（例如2-乙-5-苯-1,2-巧嗤-3’-磺酸鹽及過氯酸2-第三丁-5-甲-異Of唑或一適合 之醯基胺基化合物（例如2-乙氧_1·乙氧羰-1，2-二氫喹 啉）。常用之酸結合縮合劑爲，例如，鹼金屬碳酸鹽或 碳酸氫鹽，例如碳酸鈉或碳酸鉀或碳酸氫鈉或碳酸氫鉀 (常與一硫酸鹽一起），或有機鹸，像常用之吡啶或空 間位阻三-低級烷胺，例如N，N-二異丙-N-乙胺。 化學式IX之起始原料係利用，例如，相當之3-氰-D比 啶基化合物之水解而製得。氰基水解成羧基係在一適合 之溶劑中進行，像在醇（像乙醇）中進行，例如在一適 裝 訂 線 (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） -37- 經濟部中央揉準局員工消費合作社印製 A7 B7 五、發明説明（） 合之鹸中，像在氫氧化鈉水溶液中，在從室溫至+150°c (例如在60°c )之溫度下實施。3-氰-吡啶基化合物由相 當之N-氧-啦啶基化合物製得。爲了此目的，先將N-氧基 轉化成一離去基（例如用與一適合之反應性羧酸衍生物 或磺酸衍生物反應，例如與一適合之低級烷醯氯、低級 烷酸酐（像醋酸酐）、N，N-二甲·胺甲醯氯、甲苯磺醯氯、 甲磺醯氯或三氟甲磺醯氯反應之方法）。然後用一適合 之親核劑（其在相對於吡啶氮之鄰位上作用）將氰基引 進。引進氰基之親核劑爲，例如，一適合之氰矽烷像氰 三-低級院-砍烷（例如氰三甲矽烷）。氰基之引入係在一 適合之溶劑中，像在乙膊中進行，在大約從〇°C至150°C， 宜在大約從室溫至l〇〇°C之溫度下進行。 N-氧-吡啶基化合物係用一適合之氧化劑（像一適合 之過酸，例如適合之過苯甲酸，像特別是間-氯·過苯甲 酸）將一相當之吡啶基化合物氧化而製得，反應在一惰 性溶劑，像二氯甲烷中，在室溫下進行。 方法d: 方法d以類似於方法b之方法進行。 方法e: 方法e以類似於方法c之方法進行。例如，化學式 XI之化合物可在一強酸，像濃硫酸（其同時作爲一結合 水元素之試劑）之存在下，用所需之醇Rr〇H (其可同時 作爲溶劑）酯化。或者，一化學式XI化合物之反應性羧 (請先Μ讀背面之注意事項再填寫本頁) -裝- 訂 線 本紙張尺度適用中國國家揉準（CNS ) Α4規格（210Χ297公釐） -38- 經濟部中央標隼局貝工消费合作社印製 A7 B7 五、發明説明（） 酸衍生物（例如一適合之酯，像甲酯）可用一化學式 H2N-(CH2)n-R4a 或 H2N-(CH2)n-N(R3)-R4 之胺予以醯胺化。 化學式I之化合物之酸加成鹽係利用常用之方法製 得，例如，用一酸或一適合之離子交換劑處理。 酸加成鹽可利用常用之方法轉化成自由化合物，例 如用一適合之鹼性試劑處理。 異構體混合物可利用本質上已知方法分離成各別異 構體，例如利用分段結晶法、層析法等。 上述之方法（包括去除保護基之方法及額外之方法 措施），除非另有說明，係利用一本質上已知方法進 行，例如在適宜之惰性溶劑或稀釋劑之存在或不存在 下，必要時，在縮合劑或觸媒之存在下，在降溫或升溫 下（例如在從大約-20 °C至大約150 °C，特別是從大約 〇°C至大約+70°C，最好是從大約+10°C至大約+50°C之一 溫度範圍內，主要在室溫下），在一適合之容器及，必 要時，在一惰性氣壓，例如一氮氣壓力下進行。 考慮分子中之所有取代基，必要時（例如若有易於 水解之自由基時），要使用特別溫和之反應條件，像反 應時間要短、使用低濃度之溫和酸性或鹼性試劑、化學 計量比率、選擇適合之觸媒、溶劑、溫度條件及/或壓 力條件。 本發明亦有關那些形式之製備方法，即在這些方法 中任何一階段得到之爲中間體之化合物用作起始原料並 進行其餘的步驟，或使步驟在任何階段中止或在反應條 件下生成起始原料或以反應性衍生物或鹽形式使用。依 ! I I I I I I I 裝— I —訂 I I I —線 (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（210 X 297公釐） -39- A7 _B7__ 五、發明説明（） 照本製備方法，使用之起始原料宜爲那些能生成上述之 特別有價値之化合物者。 本發明有關偏好之化學式la之化合物及其鹽之製備 方法\) y C -31-Printed by A7 B7, Shellfish Consumer Cooperative, Central Standards Bureau, Ministry of Economic Affairs 5. Description of the invention () β) In a clear solution, such as 60%, an excess of mineral acid, such as hydrochloric acid, when reacted When complete, add a desired ammonium salt to form hydrochloric acid, such as ammonium nitrate, at a temperature from about room temperature to 150 ° C (eg, under reflux). Method b: A leaving group Y in a compound of formula IV is a reactive esterified hydroxyl group, such as a hydroxyl group with a strong inorganic acid or an organic acid ester, like a mineral acid, such as a hydrohalic acid (like hydrochloric acid, hydrogen Bromic acid or hydroiodic acid) and sulfuric acid or monothiosulfate (such as fluorine sulfate), or with a strong organic sulfonic acid, like a lower alkanesulfonic acid (which is unsubstituted or substituted, for example, halogen like fluorine) or An aromatic sulfonic acid, such as benzenesulfonic acid (which is unsubstituted or substituted with a lower alkyl like methyl, halogen like bromine, and / or nitro), such as monomethanesulfonic acid, trifluoromethanesulfonic acid, or p-toluene Sulfonic acid. Y is preferably halogen, in particular, chlorine. The reaction is preferably in an excess of the amine of formula V (which, if appropriate, can also be used as a solvent), and, if necessary, an inert solvent, such as dimethylsulfoxide, at a temperature from room temperature to + 150 ° c Temperature (eg 110 ° C). The starting material of formula IV can be prepared, for example, by a method similar to method a. For example, m-chloro ·· perbenzoic acid can be first oxidized with 4-acetamidine · pyridine to N-oxidized 4-ethyl-pyridine in a suitable solvent, such as methylene chloride, for example, under reflux. N · oxide 4-acetamidine-pyridine is then converted to 4-acetamidine-2-chloro · pyridine with phosphorus oxychloride in a suitable inert solvent 'like toluene, for example, at about 100 ° C. Then you will get 4-acetyl 醯 -2- (please read the note ^^ on the back before filling this page). Binding and binding 9. This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 83. 3.10,000 -32- Printed by A7 B7___, Shellfish Consumer Cooperative, Central Bureau of Standards, Ministry of Economic Affairs 5. Description of the Invention () Chloro-pyridine reacts with a compound of formula II (shown in method a) to produce a compound similar to formula II (Shown in Method a above, where Gen is chlorine). Then, using a method similar to method a, the compound thus obtained is reacted with a compound of formula III to form the starting material of chemical formula IV or the starting material of chemical formula IV. Aldehyde (which, for example, serves simultaneously as a solvent) ', for example, converts N • oxidized 4-acetamidine · pyridine to 3-dimethylamine · NH · oxy-pyridine > 2-propylene- at approximately 110 ° C, Like 3 · dimethylamine-KN · oxopyridine > 2-propan-1-one, and then combine it with R2-benzene-guanidine (where R2 is as defined above), or preferably with A suitable salt (for example, a nitrate in a suitable solvent, such as isopropanol), and a suitable base, such as sodium hydroxide, for example, reacts under reflux to form a chemical formula similar to N-oxy-pyridyl compound of IV (where Y is oxygen). The N-oxy-?-Pyridinyl compound thus obtained is then converted with phosphorus oxychloride to a compound of formula IV (wherein Υ is chlorine). The reaction with phosphorus oxychloride can be performed, for example, without using a solvent at about 100 ° C. Alternatively, phosphorus oxychloride is used with a suitable amine, such as diisopropylamine, in a suitable solvent (e.g., a monochlorinated hydrocarbon, such as chloroform) at about room temperature. Another possibility is to use phosphorus oxychloride in a suitable solvent, such as chloroform, toluene or xylene, at elevated temperatures (e.g., under reflux). Method c: (Please read the note on the back before filling in this page) • Packing. This paper size is applicable to China National Standard (CNS) A4 specification (210X297) 嫠 -33- 83. 3.10,000 Central Bureau of Standards, Ministry of Economic Affairs A7 B7 printed by the Consumer Cooperatives _ V. Description of the invention () The free functional group in the free radical of the compound of the chemical formula IX (which is preferably protected by a protective group that can be easily removed), especially a carboxyl group and an amine group. The reactive derivative of the compound of IX is in particular a reactive (activated) ester, a reactive anhydride or a reactive cyclic amidine. The reactive (activated) ester of an acid of formula IX is particularly Unsaturated esters bonded to carbon atoms, such as vinyl esters, like vinyl esters themselves (which can be prepared, for example, by transesterification of a comparable ester with vinyl acetate; activated vinyl ester method), carbamate Ester vinyl esters (which can be prepared, for example, by treating equivalent acids with an isoofazole ion reagent; 1-2 »0fazole ion or Woodward method), or 1-lower alkoxyethylene esters ( It can, for example, treat the phase with a lower alkoxyacetylene Made from an acid; ethoxyacetylene method), or vinegars of the formyl group, like N, N, -di-substituted formamyl esters (which can, for example, use a suitable N, N'-di · Substituted carbodiimides, such as those prepared by treating Ν, Ν · -dicyclohexylcarbodiimide; equivalent carbodiimide method), or N, N · di-substituted formazan esters (which may be For example, it is prepared by treating equivalent acid with mono-, N-di-substituted cyanamide; cyanamide method), suitable aromatic vinegar, especially phenyl vinegar suitable for substitution by electron attracting substituent (which can, for example, , Using a suitable substituted phenol, such as winter phenol, 4_methanesulfonate-S &, 2,4,5 · trichlorophenol, 2Λ4,5,6 «pentachlorophenol or 4-benzenediazophenol, Prepared by treating a comparable acid in the presence of a condensing agent, such as N, NV dicyclohexamethylene diimide; activated aryl ester method), cyanomethyl ester (which can, for example, be used with Prepared in the presence of equivalent acids; cyanomethyl method), thioesters, especially unsubstituted or substituted (eg, nitro-substituted) thioesters (which can, for example, be unsubstituted or substituted Replace (for example, paper China National Standards Rate (CNS) 8 4 _ (2 J 0 x 297 public directors) 83. 3.10,000 V, ..- installation ----- ^-order- (please read the precautions on the back before filling (This page) * 34 *-Printed by A7 _B7____ of the Consumer Cooperatives of the Central Bureau of the Ministry of Economic Affairs of the Ministry of Economic Affairs 5. Description of the invention (such as nitro-substituted) is prepared by treating thiophenol with equivalent acid, especially using anhydride or carbonyl Imine method; activated thioester method), amine ester or amidoester (which may, for example, use an N-hydroxy-amino or N-hydroxy-amido compound, such as N-hydroxy-succinimine, N-hydroxy-hexahydropyridine, N-hydroxysallimide or 1-hydroxy-benzotriazole is prepared by treating equivalent acids, for example, using the anhydride or carbodiimide method; activated N-hydroxyester method) or Silane esters (which can be prepared, for example, by treating a comparable acid with a silylating agent, such as hexamethyldisilazane, and which easily reacts with hydroxyl groups without reacting with amine groups). The anhydrides of the acids of Formula IX may be those of symmetric anhydrides or preferably mixed anhydrides, such as anhydrides formed from inorganic acids (such as halogens, especially halogens) (which may, for example, be sulfuric acid, pentachloro Phosphorus or chlorammonium chloride is prepared by treating equivalent acids; chlorination method), an anhydride generated with an azide compound (which may, for example, be made from an equivalent acid ester, using equivalent hydrazine, and treated with nitrous acid). And produced; azide method), an anhydride produced using a carbonic acid half derivative, like an anhydride produced using an equivalent ester (such as a lower alkyl halfcarbonate) (which can be, for example, a lower alkyl haloformate (such as chlorine Lower alkyl formate) or 1-lower alkoxy group_2 · lower alkoxy group-1,2-dihydroquinoline (eg 1 · lower alkoxy group-2-ethoxy-1,2-dihydrosialine) Prepared by treating equivalent acids; mixed with carbonic anhydride method), or by dihalogenation, especially anhydrides generated from phosphoric acid dichloride (which can be prepared, for example, by treating equivalent acids with phosphorus oxychloride; Phosphorus oxychloride method), or an anhydride produced with an organic acid, such as a mixed anhydride produced with an organic residual acid (which can be, for example, Substituted or substituted lower-grade hospitals-or benzene, residual teeth, such as phenylacetic acid chloride, trimethylacetic acid chloride, or trifluoroacetic acid chloride to treat equivalent acids; mixed carboxylic anhydride method), or use Organic sulfonic acid-based mixed anhydride (which can, for example, be used-suitable for the size of this paper to apply Chinese National Standard (CNS) A4 specifications (210X297 mm) (Please read the precautions on the back before filling out this page)-Packing. Line-35-Industrial Consumer Cooperative Cooperative A7 B7 of the Central Bureau of Standards, Ministry of Economic Affairs 5. Description of the Invention () Organic thorium chloride, like a lower alkane · or aryl-sulfonyl chloride (such as methanesulfonyl chloride or p-toluenesulfonyl chloride) ) Prepared by treating an equivalent acid salt like a metal salt; mixed sulfonic anhydride method) and symmetric anhydride (which can, for example, be in the presence of monocarbonyldiimine or 1-diethylaminepropyne, Prepared by condensing equivalent acids; symmetrical anhydride method). Suitable cyclic amidines are especially amines containing a 5-membered diazo ring having aromatic properties, such as amidines generated from imidazoles, such as imidazole (which may, for example, be treated with Ν, Ν'-carbonyldiimidazole equivalent Acid); imidazolium method), or pyrimidines generated from pyrazoles, such as 3,5-dimethylpyrazole (which can be prepared, for example, by using hydrazine and acetamidine; Zod method). Derivatives of the acids of formula IX, which are used as hydrating agents, can also be formed in situ. For example, N, N'-di-substituted formazan esters can be in the presence of a suitable N, N-di-substituted carbodiimide (e.g., N, N'-dicyclohexamethylenediimide), It is formed in the reaction of a mixture of the starting material of Chemical Formula X and an acid as a hydrating agent. In addition, amine esters or amine esters of acids as amidines can be formed in the presence of the starting material of the chemical formula X to be amidined, that is, a N, N'-di-substituted carbodiimide In the presence of an amine (such as N, N * -dicyclohexamethylenediimide) and the presence of an N-hydroxy-amine or N-hydroxy-amidamine (such as N-hydroxysuccinimide), as appropriate A comparable mixture of an acid and an amine-based starting material is reacted in the presence of a suitable base, such as 4-dimethylaminopyridine. The reaction is carried out by using a reactive carboxylic acid derivative of a compound of formula IX with a compound of formula X, and the amine group participating in the reaction is in a protected form. In a more suitable form of the reaction, at room temperature, read one (please read the precautions on the back before filling this page). • Binding and binding. The paper size applies to Chinese national standards (CNS > Α4 size (210 × 297). %) -36- Printed by the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs, B7_ V. Description of the invention () Solution of the starting material of chemical formula IX dissolved in dimethylformamide and hydrochloride N_ethylenedimethylamine propane The imine and N-hydroxysuccinimide are stirred together for several hours, and then the reaction mixture thus obtained is added dropwise to a solution of the amine of formula X dissolved in dimethylformamide. The reaction can utilize an essentially known The method is carried out, and the reaction conditions depend in particular on whether and how the carboxyl group of the chelating agent has been activated, usually in the presence of a suitable solvent or diluent or a mixture thereof, and, if necessary, a condensing agent (such as when When the carboxyl group participating in the reaction is in the form of an anhydride, it can also be an acid binding agent, under cooling or heating (for example, from about _30 ° C to about + 150 ° C, especially from about 0 ° C to + 100 ° C, preferably from Temperature (about + 20 ° C to + 70 ° C), in an open or closed reaction vessel and / or under an inert gas (such as nitrogen) pressure. Common condensing agents are, for example, Carbodiimide (eg N, N'-diethyl-, N, N * -dipropane-, N, N * -dicyclohexyl- or N-ethyl-NH3-dimethylamine propane > ), Suitable carbonyl compounds (such as carbonyldiimidazole) or 1,2-pyrazolium ionic compounds (such as 2-ethyl-5-benzene-1,2-carbo-3'-sulfonate and perchloric acid 2- Tertiary but-5-methyl-isoOfazole or a suitable fluorenylamino compound (such as 2-ethoxy_1 · ethoxycarbonyl-1,2-dihydroquinoline). Common acid-binding condensing agents are , For example, alkali metal carbonates or bicarbonates, such as sodium carbonate or potassium carbonate or sodium bicarbonate or potassium bicarbonate (often with monosulfate), or organic pyrene, like commonly used pyridine or sterically hindered tri-lower Alkylamines, such as N, N-diisopropyl-N-ethylamine. The starting materials of Chemical Formula IX are prepared, for example, by hydrolysis of equivalent 3-cyano-D than pyridyl compounds. Hydrolysis of cyano to carboxyl In a suitable solvent, like in (Like ethanol), for example, in a suitable gutter (please read the precautions on the back before filling out this page) This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) -37- Central Ministry of Economic Affairs A7 B7 printed by the Consumer Cooperatives of the Prospective Bureau V. Description of the invention () In the combination, it is implemented in a sodium hydroxide aqueous solution at a temperature from room temperature to + 150 ° c (for example, at 60 ° c). 3 -Cyano-pyridyl compounds are prepared from equivalent N-oxy-laridinyl compounds. For this purpose, the N-oxy group is first converted to a leaving group (for example with a suitable reactive carboxylic acid derivative or sulfonic acid). Acid derivatives, such as with a suitable lower alkane chloride, lower alkanoic anhydride (like acetic anhydride), N, N-dimethylaminocarbamyl chloride, tosylsulfonium chloride, methanesulfonyl chloride or trifluoromethanesulfonate醯 Chlorine reaction method). The cyano group is then introduced with a suitable nucleophile which acts in the ortho position relative to the pyridine nitrogen. The nucleophile introduced with cyano is, for example, a suitable cyanosilane such as cyano-lower-grade choloalkane (for example, cyanotrimethylsilane). The introduction of cyano is performed in a suitable solvent, such as in a solvent, at a temperature of about 0 ° C to 150 ° C, preferably at a temperature of about room temperature to 100 ° C. N-oxy-pyridyl compounds are prepared by oxidizing a comparable pyridyl compound with a suitable oxidant (such as a suitable peracid, such as a suitable perbenzoic acid, especially m-chloro · perbenzoic acid). The reaction is carried out in an inert solvent, such as dichloromethane, at room temperature. Method d: Method d is performed in a similar manner to method b. Method e: Method e is performed in a manner similar to method c. For example, a compound of formula XI can be esterified with the desired alcohol RroH (which can also be used as a solvent) in the presence of a strong acid, such as concentrated sulfuric acid (which also serves as a reagent that binds water). Or, a reactive carboxyl compound of a compound of formula XI (please read the notes on the back before filling this page)-binding-bookbinding This paper size applies to China National Standard (CNS) A4 (210 × 297 mm) -38- Printed by A7 B7, Shellfish Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention () Acid derivatives (such as a suitable ester, such as methyl ester) can use a chemical formula H2N- (CH2) n-R4a or H2N- (CH2 The amine of nN (R3) -R4 is amidated. Acid addition salts of compounds of formula I are prepared by conventional methods, for example, by treatment with an acid or a suitable ion exchanger. Acid addition salts can be converted into free compounds using conventional methods, such as treatment with a suitable alkaline reagent. The mixture of isomers can be separated into individual isomers by a method known per se, for example, by fractional crystallization, chromatography, and the like. The above methods (including methods for removing protective groups and additional method measures), unless otherwise specified, are performed by a method known per se, such as in the presence or absence of a suitable inert solvent or diluent, if necessary , In the presence of a condensing agent or catalyst, under cooling or heating (for example, from about -20 ° C to about 150 ° C, especially from about 0 ° C to about +70 ° C, preferably from about Temperature range from + 10 ° C to about + 50 ° C, mainly at room temperature), in a suitable container and, if necessary, under an inert gas pressure, such as a nitrogen pressure. Consider all the substituents in the molecule, if necessary (for example, if there are free radicals that are easy to hydrolyze), use particularly mild reaction conditions, such as shorter reaction time, use of mild acid or alkaline reagents at low concentrations, stoichiometric ratio 2. Select the appropriate catalyst, solvent, temperature conditions and / or pressure conditions. The present invention also relates to methods of preparing those forms, that is, compounds obtained as intermediates at any stage of these methods are used as starting materials and the remaining steps are carried out, or the steps are stopped at any stage or formed under reaction conditions The starting materials are used either in the form of reactive derivatives or salts. According to! IIIIIII Packing — I — Order III — Line (Please read the precautions on the back before filling this page) This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) -39- A7 _B7__ V. Explanation of the invention () According to the preparation method, the starting materials used are preferably those capable of forming the above-mentioned particularly valuable hydrazone compounds. Preparation method of preferred compound of formula la and salt thereof according to the present invention

經濟部中央櫺隼局負工消费合作社印製 式la中之艮爲 a) 1SK胺-低級烷 >胺甲醯基， b) N-(羥-低級烷>胺甲醯基， c) 肼基， d) 環己_胺基（其未被取代或被胺基取代），或 e) 低級烷胺基（其被氰基、咪唑基、胍基、胺基、低級 烷醯基胺基、低級烷胺-羰胺基、甲脒基、二-低級烷胺·環 己基、羧基、低級烷氧羰基、胺甲醯基、N·羥-胺甲醯 基、羥基、低級烷氧基、二羥磷醯氧基、六氫吡阱基、 低級烷醯-六氫吡阱基、甲醯六氫吡畊基、脯胺醯基釀胺 基取代或被一化學式H2N-CH(R)-C(=0)~NH-之自由基取代 (式中R爲氫、CrC4烷基、苄基、羥甲基、1-經·乙基、 锍甲基、2-甲硫-乙基、吲瞭-3_基-甲基、苯-甲基、4-羥-苯-甲 基、胺甲酿-甲基、2-胺甲醯-乙基、殘-甲基、2-竣-乙基、4· 胺-丁基、3-胍-丙基或R爲1H4米唑-4-基-甲基），及 R2爲CrC6烷基、CrC3烷氧基、氯、溴、碘、三氟甲基、 羥基、苯基、胺基、單（CrC3院）胺基、二（(^<：3烷）胺基、 (請先聞讀背面之注意事項再填寫本莧) -裝. ,*! 線 本紙張尺度適用中國國家標準（CNS ) Μ規格（210X297公釐） -40- A 7 B7 五、發明説明（） c2-c4烷醯基、丙烯氧基、羧基、羧-甲氧基、乙氧幾-甲氧 基、對胺苯磺醯胺基、N，N-二（crc3烷）對胺苯磺醯胺基、 N_甲-六氫吡畊基、六氫吡啶基、1H-咪唑-1-基、1H-***-1-基、1H-苯幷咪唑·2·基、1-萘基、環戊基、3,4>二甲-苄基或 下列化學式中之一式的自由基： -C02R3 ' -NH-C(=0)-R3 ' -N(R3)-C(=0)-R4 ' -0-(CH2)n-N(R3)-R4 ' -C^-NH^CHaVNCRa)^ ' -CH(CH3)-NH-CHO ' -C(CH3)=N-OH ' -C(CH3)=N-0-CH3' -C(CH3>NH2' -NH-CH2-C(=0)-N(R3>R4 ' 、仰丄火、-XKCH2)m-R6 及In the printed formula la printed by the Central Government Bureau of the Ministry of Economic Affairs of the Consumer Cooperative, a) 1) amine-lower alkane > carbamoyl, b) N- (hydroxy-lower alkane > carbamoyl, c) Hydrazine, d) cyclohexylamino (which is unsubstituted or substituted with amine), or e) lower alkylamino (which is substituted by cyano, imidazolyl, guanidyl, amine, lower alkylamino) , Lower alkylamine-carbonylamino, methylamidino, di-lower alkylamine · cyclohexyl, carboxyl, lower alkoxycarbonyl, aminomethylamino, N · hydroxy-aminomethylamino, hydroxyl, lower alkoxy, Dihydroxyphosphinoyloxy, hexahydropyridyl, lower alkylpyridine-hexahydropyridyl, methylpyridine hexahydropyridyl, prolylpyridylamine or substituted with a chemical formula H2N-CH (R)- C (= 0) ~ NH- radical substitution (where R is hydrogen, CrC4 alkyl, benzyl, hydroxymethyl, 1-Ethyl, ethyl, methyl, 2-methylthio-ethyl, ind 3-methyl-methyl, benzene-methyl, 4-hydroxy-benzene-methyl, carbamate-methyl, 2-carboxamidine-ethyl, residual-methyl, 2-end-ethyl , Amine-butyl, 3-guanidine-propyl, or R is 1H4 mizol-4-yl-methyl), and R2 is CrC6 alkyl, CrC3 alkoxy, chlorine, bromine, iodine, Fluoromethyl, hydroxy, phenyl, amine, mono (CrC3) amine, di ((^ <: 3 alkyl) amine, (please read the precautions on the back before filling in this 苋)-Pack. , *! The size of the paper is applicable to Chinese National Standards (CNS) M specifications (210X297 mm) -40- A 7 B7 V. Description of the invention () c2-c4 alkylfluorenyl, propyleneoxy, carboxyl, carboxy-methoxy Ethoxy, ethoxy-methoxy, p-aminobenzenesulfonamido, N, N-di (crc3 alkane) p-aminobenzenesulfonamido, N-methyl-hexahydropyridyl, hexahydropyridyl, 1H-imidazol-1-yl, 1H-triazol-1-yl, 1H-benzimidazol-2-yl, 1-naphthyl, cyclopentyl, 3,4 > dimethyl-benzyl or one of the following chemical formulae Free radicals of the formula: -C02R3 '-NH-C (= 0) -R3' -N (R3) -C (= 0) -R4 '-0- (CH2) nN (R3) -R4' -C ^- NH ^ CHaVNCRa) ^ '-CH (CH3) -NH-CHO' -C (CH3) = N-OH '-C (CH3) = N-0-CH3' -C (CH3 > NH2 '-NH-CH2- C (= 0) -N (R3 > R4 ', Yangbeihuo, -XKCH2) m-R6 and

-X~CH2-C(=0)—N N—R7 ---------裝— (請先閱讀背面之注項再填寫本页) 經濟部中央樣隼局員工消費合作杜印製 (式中之R3及R4各自獨立，爲c, -C3烷基，X爲氧或 硫，111爲1、2或3，11爲2或3，1^爲氫、（：1-(：3院基、 CrQ院氧基、氯、溴、碘或三氟甲基，1^爲1H-咪嗤-1-基 或嗎啉基及R7爲〇(：3烷基或爲未被取代或被（^心烷 基、鹵素或三氟甲基單取代之苯基），該方法包括 a)將一化學式Π之化合物 XC^-CH^H-NiRgh-Rg Ν (Π)-X ~ CH2-C (= 0) —NN—R7 --------- install— (Please read the note on the back before filling out this page) Printed by the Consumer Co-operation of the Central Sample Bureau of the Ministry of Economic Affairs (Wherein R3 and R4 are each independently c, -C3 alkyl, X is oxygen or sulfur, 111 is 1, 2 or 3, 11 is 2 or 3, 1 ^ is hydrogen, (: 1-(: 3 Yuan, CrQ, oxygen, chlorine, bromine, iodine, or trifluoromethyl, 1 ^ is 1H-imidino-1-yl or morpholinyl, and R7 is 0 (: 3 alkyl or unsubstituted or is (^ Alkyl, halogen, or trifluoromethyl mono-substituted phenyl), the method includes a) converting a compound of formula XC ^ -CH ^ H-NiRgh-Rg Ν (Π)

(式Π中1^及1各自獨立，爲低級烷基及Rl如上述 定義’除了參與反應之基以外，存在於化學式Π之化合 物中之官能基，必要時，爲被保護形式）或其鹽與一化 學式Ilia之化合物 本紙張尺度逋用中國國家梯準（CNS ) A4洗格（210X；Z97公釐） 、tr 線 -41 - 五、發明説明（ NH V—]m2 Η A7 B7 (nia) (式Ilia中之R2如上述定義，除了參與反應之胍基以 外，存在於化學式ma之化合物中之官能基，必要時’ 爲被保護形式）或這其鹽反應，並去除任何存在之保護 基，或 b)爲了製備化學式I之化合物（其中之札具有上述c) 至e)之意義中任何一意義，且R2具有上述意義中任何 一意義），將一化學式IVa之化合物(1 ^ and 1 in formula Π are each independently lower alkyl and R1 are as defined above. Except for the group participating in the reaction, the functional group present in the compound of chemical formula Π, if necessary, is a protected form) or a salt thereof And a compound of the formula Ilia, this paper uses Chinese National Standard (CNS) A4 (210X; Z97 mm), tr line -41-5. Description of the invention (NH V—] m2 Η A7 B7 (nia) (R2 in formula Ilia is as defined above. Except for the guanidyl group participating in the reaction, the functional group present in the compound of the formula ma, if necessary, is a protected form) or its salt is reacted, and any existing protecting group is removed. , Or b) In order to prepare a compound of formula I (wherein Z has any of the meanings of c) to e) above, and R2 has any of the meanings above, a compound of formula IVa

(IVa) 經濟部中央橾準局貝工消費合作社印製 (式IVa中Y爲一離去基，且R2如上述定義，除了參 與反應之離去基以外，存在於化學式IVa之化合物中之 官能基，必要時，爲被保護形式）或其鹽與一化學式V 之胺反應 h2n-r12 (V) (式V中R12爲胺基或未被取代或胺基-取代之環己基， 或爲低級烷基（其被氰基、咪唑基、胍基、胺基、低級 烷酿基胺基、低級烷胺_羰胺基、甲脒基、二·低級烷胺-環 己基、羧基、低級烷氧羰基、胺甲釀基、N-羥-胺甲釀 基、羥基、低級烷氧基、二羥磷醯氧基、六氫吡阱基、 低級烷醯-六氫吡畊基、甲醯六氫吡阱基、脯胺醯基釀胺 ,t . G ----------^-------IT------^1 (请先閲讀背面之.注意事項再填寫本頁) 本紙张尺度適用中國國家標準（CNS) A4规格（210Χ：297公釐） -42- 經濟部中央樣隼局員工消費合作社印製 A7 B7 五、發明説明（） 基取代或被一化學式h2n-ch(r)-c(=o>nh-之自由基取代 (式中R爲氫、（VC4烷基、苄基、羥甲基、1-羥-乙基、 锍甲基、2-甲硫-乙基、吲瞬-3-基-甲基、苯-甲基、4-羥-苯-甲 基、胺甲酿-甲基、2-胺甲醯-乙基、殘-甲基、2-殘-乙基、4-胺-丁基、3-胍-丙基或R爲1H-咪唑4-基-甲基），存在於 R12中之官能基，必要時，爲被保護形式），並去除任何 存在之保護基，或 c)爲了製備化學式I之化合物（其中之R,爲N_(胺·•低級 烷)胺甲醯基或N-(羥-低級烷>胺甲醯基，且112具有上述 意義中任何一意義），將一化學式IXa之羧酸 (請先閲讀背面之注意事項再填寫本頁) 裝.(IVa) Printed by the Shellfish Consumer Cooperative of the Central and Quarantine Bureau of the Ministry of Economic Affairs Group, if necessary, in a protected form) or a salt thereof with an amine of formula V2h2n-r12 (V) (where R12 is an amine group or an unsubstituted or amine-substituted cyclohexyl group, or a lower Alkyl (which is cyano, imidazolyl, guanidyl, amine, lower alkylamino, lower alkylamine-carbonylamino, formamidine, di · lower alkylamine-cyclohexyl, carboxyl, lower alkoxy Carbonyl, aminomethyl, N-hydroxy-aminomethyl, hydroxy, lower alkoxy, dihydroxyphosphoryloxy, hexahydropyridyl, lower alkanoyl-hexahydropyridyl, formamidine hexahydro Pyridyl, Proline and Ammonium, t.G ---------- ^ ------- IT ------ ^ 1 (Please read the back first. Cautions (Fill in this page again) This paper size is in accordance with Chinese National Standard (CNS) A4 (210 ×: 297 mm) -42- Printed by A7 B7, Consumer Cooperatives of the Central Sample Bureau of the Ministry of Economy A chemical h2n-ch (r) -c (= o > nh- radical substitution (where R is hydrogen, (VC4 alkyl, benzyl, hydroxymethyl, 1-hydroxy-ethyl, fluorenylmethyl, 2- Methylthio-ethyl, indoxy-3-yl-methyl, benzene-methyl, 4-hydroxy-benzene-methyl, aminomethyl-methyl, 2-aminomethyl-ethyl, residual-methyl , 2-residual-ethyl, 4-amine-butyl, 3-guanidine-propyl, or R is 1H-imidazol 4-yl-methyl), a functional group present in R12, if necessary, in a protected form ), And remove any protective groups present, or c) in order to prepare a compound of formula I (wherein R is N_ (amine · lower alkyl) carbamoyl or N- (hydroxy-lower alkyl) > Base, and 112 has any of the above meanings), a carboxylic acid of the chemical formula IXa (please read the precautions on the back before filling this page).

R2 (式IXa中之&具有上述意義中任何一個意義）或其一 反應性酸衍生物與一化學式X之胺反應 H2N-Rb (X) (式X中之R13爲胺-低級烷基或羥-低級烷基、胺基或羥 基，必要時，爲被保護形式），並去除任何存在之保護 基，且，需要時，將依照方法a-c中任何一個方法得到 之一化學式I之化合物轉化成其鹽，或將一得到之化學 式I之化合物之鹽轉化成自由化合物。 本發明亦有關新穎的起始原料及/或中間體及其製 備方法。所使用之起始原料及選擇之反應條件宜爲，能 得到本申請案中描述之偏好之化合物者。 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 訂 線 -43 - 經濟部中央標隼局員工消費合作社印袋 A7 B7 五、發明説明（） 本發明亦有關一治療罹患腫瘤疾病之溫血動物之方 法，該方法包括對一需要這種治療之溫血動物施予一有 效抑制腫瘤劑量之化學式I之化合物或其在醫藥上可接 受之鹽。本發明亦有關化學式I之化合物或其一在醫藥 上可接受之鹽在抑制溫血動物中之蛋白質激酶C上或在 製備醫藥組成物（用於醫療人體或動物體）上之用途。 視物種、年齡、個別情況、給藥方式及個別臨床徵候而 定，對一大約70公斤體重之溫血動物施予一有效劑量， 例如每日劑量爲大約1 - 1000毫克，特別是50 - 500毫 克。 本發明亦有關醫藥組成物，其含一有效量，特別是 預防或治療上述病症中之一之有效量，的有效成份與在 醫藥上可接受之載體（適用於局部給藥、經腸給藥（例 如口服或經直腸給藥）或非經腸給藥者，且可爲無機物 或有機物，固體或液體）。口服用者特別爲錠劑或明膠 膠囊，其包含有效成份與稀釋劑（例如乳糖、葡萄糖、 蔗糖、甘露糖醇、葡萄糖醇、纖維素及/或甘油）及/ 或潤滑劑（例如矽石、滑石、硬脂酸或其鹽類，像硬脂 酸鎂或硬脂酸鈣）及/或聚乙二醇，錠劑亦可包含黏合 劑，例如矽酸鎂鋁、澱粉（像玉米、小麥或米澱粉）、 明膠、甲基纖維素、羧甲基纖維素鈉及/或聚乙烯吡咯 啶酮，及，需要時，分解劑（例如澱粉、洋菜、海藻酸 或其一鹽像海藻酸鈉）及/或起泡混合物、或吸附劑、 染料、調味劑及增甜劑。本發明之藥理活性化合物也可 以非經腸形式或輸液方式使用。這種溶液宜爲等滲水溶 本纸張尺度速用中國國家橾準（CNS ) Α4規格（210Χ297公釐） (請先閱讀背面之注意事項再填寫本頁) -'δ -44- 經濟部中央標準局員工消費合作社印裝 A7 B7 五、發明説明（） 液或懸浮液，例如在凍乾之組成物（僅含有效成份或有 效成份與一載體，例如與甘露糖醇一起使用）之情況 中，可在使用之前調製。醫藥組成物可經滅菌處理及/ 或可含輔藥（例如防腐劑、安定劑、增濕劑及/或乳化 劑、助溶劑、調節滲透壓之鹽類及/或緩衝液）。本醫 藥組成物（需要時，可含其它藥理活性物質，像抗生 素）係利用本質上已知方法製備，例如利用傳統之混 合、製粒、製糖劑、溶解或冷凍乾燥方法，且含大約從 1%至100%，特別是從大約〗％至大約20%之有效成 份。 下列實施例在無任何限制下說明本發明。Rr値係在 矽膠薄層板（莫克公司，Darmstadt，德國）上測定。所使 用之析流混合液中之析流液比率係以體積比（體積/體 積）表示，及溫度係以°C表示。 縮寫： cone.:濃的 HV :高眞空 RF:迴流 RT:室溫 h :小時 有關核磁共振光譜（NMRspectra)之縮寫具有下列意義： br:寬的 d:二重峰 Η :氫 (請先閱讀背面之注意事項再填寫本頁) •裝. ，1Τ 線 本紙張尺度適用中國國家梂準（CNS ) Α4规格（210Χ297公釐） -45- 經涛部中夬樣隼局員工消費合作社印製 A7 _B7____ 五、發明説明（） m :多重峰 s:單峰 實施例1 =在100°下，將50毫克（0.143毫摩爾）N-(3-三氟甲-苯)冬(2-氯+吡啶)-2·嘧啶胺在1毫升3-胺-1-丙醇中 攪拌44小時。利用蒸發濃縮且層析（二氯甲烷：甲醇= 9:1)，產生Ν-( 3-三氟甲-苯)斗[2>( 3-羥-丙-胺>4-吡啶]-2-嘧啶 胺；Rf=0.1 (二氯甲烷：甲醇=95:5) ，FAB^MS: 390，熔 點：158-163。。 起始原料係以下列方式製得： 階段1.1 :在氮氣下，將24.61克（177_62毫摩爾）2-氯+ 氰-吡啶置於1.25升***中，並加入120毫升（22%於四 氫呋喃中，353毫摩爾）氯化甲基鎂。在室溫下，將紅色 懸浮液攪拌40小時，倒入1.25升冰/水及250毫升6N HC1中，並在室溫下攪拌14小時。用***及二氯甲烷萃 取，用MgS04乾燥並濃縮，產生4-乙酸-2-氯啶；Rf=0.5 (二氯甲烷：甲醇=9:1)。 或者，4-乙酿-2-氯-此啶可利用下列方法製得： 在100。下，將5.0克（36·5毫摩爾）N-氧化4-乙醯· 吡啶及6·64毫升（73毫摩爾）***在5〇毫升甲苯 中攪拌2小時。在50°下，將反應混合物攪入500毫升 10Ν氫氧化鈉溶液中，用醋酸乙酯萃取並用唐矽爾（Tonsil) (富路卡公司：膨土一矽酸鋁膠體水溶液）處理《濃縮 本紙張尺度適用中國國家標準（CNS ) A4规格（210X297公釐） — II I 裝— I I 訂— I I 線 (請先聞讀背面之注意事項再填寫本頁) -46- 唆齊印中夬樣隼苟員工消費合作社印敦 A7 B7___ 五、發明説明（） 並結晶（***/正己烷），產生4_乙醯-2·氯-吡陡；熔 點：35。，FAB-MS: 156 (λΤ+H) 〇 所使用之Ν·氧化4-乙醯-Π比陡係利用下方法製備： 將11.0毫升（100毫摩爾）乙醯-吡啶及31·3克 (100毫摩爾）55%間-氯·過苯甲酸在2〇〇毫升二氯甲烷中 迴流沸騰16小時。用2〇〇毫升***沉澱’產生Ν-氧化 4-乙酸-D比啶；熔點：132- 133°。 階段1.2 ：在110。下，將16.2克（104.2毫摩爾）‘乙醯-2-氯-吡啶與116毫升二甲基甲醸胺二乙醇縮乙醛攪拌1小 時。冷卻至〇°，過濾並在60°及高眞空下乾燥，產生3-二甲胺-1-( 2-氯-4·吡啶）-2·丙烯-1-酮；1H-NMR (二甲亞砜）： 階段1.3:將6.3克（15〇毫摩爾）氰胺（50%於水中）加 入一 16.1克（100毫摩爾）3-三氟甲·苯胺溶於35毫升乙 醇之懸浮液中。然後將7.0毫升硝酸（65%，0.1摩爾）加 入此棕色溶液中，並將反應混合物迴流加熱20小時。然 後冷卻至0°並過濾，並將留在濾紙上之物質用乙醇淸 洗，並在6〇°及高眞空下乾燥，產生硝酸3-三氟甲-苯-胍；1H-NMR (二甲亞砜）：7.6 (7H，m)，9.9 (lH^s)。 階段1.4:將150毫克（0.71毫摩爾）3-二甲胺2-氯4·此 啶>2-丙烯-1-酮懸浮在I·5毫升2-丙醇中。加入190毫克 (0.712毫摩爾）硝酸3-三氟甲-苯·胍及3〗毫克（0.783毫 本紙張尺度適用中國國家樣準（CNS ) A4规格（210X297公釐） I I 1 11 訂-—I I I 線 (請先閱讀背面之注意事項再填寫本頁) -47- 經齊部中夹*""員工消费合作社印裝 A7 _B7__ 五、發明説明（） 摩爾）氫氧化鈉，並在迴流下將反應混合物攪拌18小 時。然後冷卻至室溫並過濾，並將留在濾紙上之物質用 2-丙醇及水淸洗，並在50°及高眞空下乾燥，產生N-(3-三氟甲-苯>4·(2-氯·4-吡啶)-2-嘧啶胺；熔點：169-171% Rf = 0.67 (二氯甲烷：甲醇=95:5)，FAB^MS: 351 (Nf+H)。 實施例2 ·‘利用類似於實施例1之方法，由20毫克 ( 0.063毫摩爾）NK3-氯-苯)斗(2-氯冬B比啶>2-嘧啶胺及1毫 升3-胺-1·丙醇製得Μ3-氯-苯M^[2-(3-羥-丙-胺吡啶]-2-嘧 啶胺；熔點：144 - 147°，Rf = 0.12 (二氯甲烷：甲醇= 95:5)，FAB>MS: 356 (NT+H)。 起始原料係以下列方式製得： 階段2.1 ：利用類似於階段1.4之方法，由150毫克（0.7 毫摩爾）3-二甲胺2-氯冰吡啶>2-丙烯-1-釀及165毫克 (0.71毫摩爾）硝酸3-氯-苯-胍製得NK3-氯-苯>4*(2·氯冰吡 啶>2-嘧啶胺；熔點：196- 198°，Rf=0.7(二氯甲烷：甲醇 =95:5)。 或者，N-(3-氯-苯2-氯冰吡啶>2·喷啶胺可利用下列 方法製得： 在110°下，將10.0克（32毫摩爾）N-(3-氯·苯>4-(N-氧-4_1此啶>2-嘧啶胺在100毫升***中攪梓24小時。 在50°下，將反應混合物攪入2N氫氧化鈉溶液中，並 用四氫呋喃萃取。將剩留物濃縮並結晶（四氫呋喃/乙 本紙張尺度適用中國國家揉率（CNS > A4规格（210X297公釐） ——- 0 —.1 I I I I I I I I I —— I I 訂 I I I I —.線 I (請先閱讀背面之注意事項再填寫本頁) -48-R2 (& in formula IXa has any of the above meanings) or a reactive acid derivative thereof reacts with an amine of formula X H2N-Rb (X) (R13 in formula X is an amine-lower alkyl or Hydroxy-lower alkyl, amine or hydroxy, if necessary, in a protected form), and remove any protective groups present, and, if necessary, convert a compound of formula I obtained according to any of the methods ac to A salt thereof, or a salt of a compound of formula I obtained as a free compound. The present invention also relates to novel starting materials and / or intermediates and methods for their preparation. The starting materials used and the reaction conditions chosen should preferably be those which give the preferred compounds described in this application. This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm). Thread-43-Printed bags A7 B7 of the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention () The invention also relates to the treatment of a tumor disease A method for warm-blooded animals, which method comprises administering to a warm-blooded animal in need of such treatment a tumor-suppressing dose of a compound of formula I or a pharmaceutically acceptable salt thereof. The present invention also relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof to inhibit protein kinase C in a warm-blooded animal or to prepare a pharmaceutical composition (for use in treating human or animal body). Depending on the species, age, individual situation, mode of administration, and individual clinical signs, an effective dose is administered to a warm-blooded animal of approximately 70 kg body weight, such as a daily dose of about 1 to 1000 mg, especially 50 to 500 Mg. The present invention also relates to a medicinal composition, which contains an effective amount, especially an effective amount for preventing or treating one of the above-mentioned conditions, an effective ingredient and a pharmaceutically acceptable carrier (suitable for local administration, enteral administration) (Eg oral or rectal) or parenteral, and can be inorganic or organic, solid or liquid). Oral users are especially lozenges or gelatin capsules containing active ingredients and diluents (such as lactose, glucose, sucrose, mannitol, glucosyl alcohol, cellulose and / or glycerol) and / or lubricants (such as silica, Talc, stearic acid or salts thereof, like magnesium stearate or calcium stearate) and / or polyethylene glycol. Lozenges may also contain binders such as magnesium aluminum silicate, starch (like corn, wheat or Rice starch), gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, and, if necessary, decomposing agents (such as starch, agar, alginic acid or a salt thereof such as sodium alginate) ) And / or foaming mixtures, or adsorbents, dyes, flavoring agents and sweeteners. The pharmacologically active compounds of the present invention can also be used parenterally or by infusion. This solution should be an isotonic water-soluble paper. China National Standards (CNS) Α4 size (210 × 297 mm) (Please read the precautions on the back before filling this page) -'δ -44- Central Ministry of Economic Affairs Standard Bureau employee consumer cooperative printed A7 B7 V. Description of the invention () Liquid or suspension, such as in the case of lyophilized composition (containing only active ingredients or active ingredients with a carrier, such as used with mannitol) , Can be modulated before use. Pharmaceutical compositions may be sterilized and / or may contain adjuvants (such as preservatives, stabilizers, moisturizers and / or emulsifiers, co-solvents, salts and / or buffers to adjust osmotic pressure). The pharmaceutical composition (if necessary, may contain other pharmacologically active substances, such as antibiotics) is prepared by a method known per se, such as using traditional mixing, granulating, sugar-making, dissolving or freeze-drying methods, and contains about 1 % To 100%, especially from about 20% to about 20% of active ingredients. The following examples illustrate the invention without any limitation. Rr 値 is measured on a thin silicone sheet (Mock, Darmstadt, Germany). The eluent ratio in the eluent mixture used is expressed in volume ratio (volume / volume), and the temperature is expressed in ° C. Abbreviations: cone .: concentrated HV: high radon RF: reflux RT: room temperature h: hours Abbreviations related to NMRspectra have the following meanings: br: broad d: double peak Η: hydrogen (please read first Note on the back, please fill out this page again) • Packing., 1T line paper size is applicable to China National Standards (CNS) A4 specification (210 × 297 mm) -45- Printed by A7, Consumer Samples Cooperative of China Bureau of Economic Affairs, Ministry of Economic Affairs _B7____ V. Description of the invention () m: Multiplet s: Singlet Example 1 = 50 mg (0.143 mmol) of N- (3-trifluoromethyl-benzene) winter (2-chloro + pyridine) at 100 ° ) -2. Pyrimidineamine was stirred in 1 ml of 3-amine-1-propanol for 44 hours. Concentrated by evaporation and chromatographed (dichloromethane: methanol = 9: 1) to produce N- (3-trifluoromethyl-benzene) bucket [2 > (3-hydroxy-propane-amine > 4-pyridine] -2 -Pyrimidinamine; Rf = 0.1 (dichloromethane: methanol = 95: 5), FAB ^ MS: 390, melting point: 158-163 ... The starting materials were prepared in the following manner: Stage 1.1: Under nitrogen, the 24.61 g (177_62 mmol) of 2-chloro + cyano-pyridine was placed in 1.25 liters of ether, and 120 ml (22% in tetrahydrofuran, 353 mmol) of methylmagnesium chloride were added. At room temperature, the red color was suspended The solution was stirred for 40 hours, poured into 1.25 liters of ice / water and 250 ml of 6N HC1, and stirred at room temperature for 14 hours. Extracted with ether and dichloromethane, dried over MgS04 and concentrated to give 4-acetic acid-2-chloro Pyridine; Rf = 0.5 (dichloromethane: methanol = 9: 1). Alternatively, 4-ethyl-dichloro-2-chloro-dipyridine can be prepared by the following method: at 100 ° C, 5.0 g (36 · 5 mmol) Mole) N-oxidized 4-acetamidine · pyridine and 6.64 ml (73 mmol) of phosphorus oxychloride were stirred in 50 ml of toluene for 2 hours. At 50 °, the reaction mixture was stirred into 500 ml of 10N hydroxide Sodium solution, extracted with ethyl acetate and Tonsil (Fluka: bentonite-aluminum silicate colloidal water solution) treatment "Concentrated paper size applicable to China National Standard (CNS) A4 specification (210X297 mm) — II I equipment — II order — II (Please read the precautions on the reverse side before filling out this page) -46- 唆 Simultaneous Printing in China 夬 Sample Gou Staff Consumer Cooperatives Indun A7 B7___ 5. Description of the invention () and crystallization (ether / n-hexane), producing 4 _Acetyl-2 · chloro-pyridine; melting point: 35 °, FAB-MS: 156 (λΤ + H) 〇 oxidized 4-acetamidine-II ratio steep system is prepared by the following method: 11.0 ml (100 mmol) acetamidine-pyridine and 31.3 g (100 mmol) of 55% m-chloro-perbenzoic acid were boiled under reflux in 2000 ml of dichloromethane for 16 hours. Precipitated with 200 ml of diethyl ether ' N-oxidized 4-acetic acid-D bipyridine was produced; melting point: 132-133 °. Stage 1.2: at 110 °, 16.2 g (104.2 mmol) of 'acetamidine-2-chloro-pyridine and 116 ml of dimethyl Methylamine diethanol acetal was stirred for 1 hour. Cooled to 0 °, filtered and dried at 60 ° under high vacuum to produce 3-dimethylamine-1- (2-chloro-4 · pyridine -2 · propen-1-one; 1H-NMR (dimethyl sulfoxide): stage 1.3: adding 6.3 g (150 mmol) of cyanamide (50% in water) to 16.1 g (100 mmol) of 3- Trifluoromethyl · aniline was dissolved in a suspension of 35 ml of ethanol. 7.0 ml of nitric acid (65%, 0.1 mole) was then added to the brown solution, and the reaction mixture was heated at reflux for 20 hours. It was then cooled to 0 ° and filtered, and the material remaining on the filter paper was washed with ethanol and dried at 60 ° under high airspace to produce 3-trifluoromethyl-benzene-guanidine nitrate; 1H-NMR (dimethylformate Sulfoxide): 7.6 (7H, m), 9.9 (lH ^ s). Stage 1.4: 150 mg (0.71 mmol) of 3-dimethylamine 2-chloro4. This pyridine> 2-propan-1-one was suspended in 1.5 ml of 2-propanol. Add 190 mg (0.712 mmol) of 3-trifluoromethyl-benzene-guanidine nitrate and 3 mg (0.783 mmol). This paper size applies to China National Standard (CNS) A4 (210X297 mm) II 1 11 Order-III (Please read the precautions on the back before filling this page) -47- Printed in the Ministry of Economic Affairs * " " A7 _B7__ printed by the Consumer Cooperative Fifth, the description of the invention () mole) sodium hydroxide, and under reflux The reaction mixture was stirred for 18 hours. It was then cooled to room temperature and filtered, and the substance remaining on the filter paper was washed with 2-propanol and water, and dried at 50 ° under high airspace to produce N- (3-trifluoromethyl-benzene> 4 (2-chloro · 4-pyridine) -2-pyrimidinamine; melting point: 169-171% Rf = 0.67 (dichloromethane: methanol = 95: 5), FAB ^ MS: 351 (Nf + H). 2 · 'Using a method similar to Example 1, from 20 mg (0.063 mmol) of NK3-chloro-benzene) bucket (2-chlorotocopherol B-pyridine> 2-pyrimidinamine and 1 ml of 3-amine-1. M3-chloro-benzene M ^ [2- (3-hydroxy-propan-aminopyridine] -2-pyrimidinamine was prepared from propanol; melting point: 144-147 °, Rf = 0.12 (dichloromethane: methanol = 95: 5 ), FAB> MS: 356 (NT + H). The starting materials were prepared in the following manner: Phase 2.1: Using a method similar to phase 1.4, from 150 mg (0.7 mmol) of 3-dimethylamine 2-chloro NK3-Chloro-benzene made from ice-pyridine> 2-propen-1-ol and 165 mg (0.71 mmol) of 3-chloro-benzene-guanidine nitrate> 4 * (2.chloropyridine) 2-pyrimidinamine Melting point: 196-198 °, Rf = 0.7 (dichloromethane: methanol = 95: 5). Alternatively, N- (3-chloro-benzene-2-chloropyridine) > 2 · Pyridinamine can be prepared by the following method Got: at 110 ° 10.0 g (32 mmol) of N- (3-chloro · benzene> 4- (N-oxy-4_1 this pyridine) 2-pyrimidinamine was stirred in 100 ml of phosphorus oxychloride for 24 hours. At 50 ° Next, the reaction mixture was stirred into a 2N sodium hydroxide solution and extracted with tetrahydrofuran. The residue was concentrated and crystallized (tetrahydrofuran / ethyl paper size applies to the Chinese national kneading rate (CNS > A4 specification (210X297 mm) —— -0 —.1 IIIIIIIII —— II Order IIII —. Line I (Please read the precautions on the back before filling this page) -48-

五、發明説明（） ls.^''pJ^.-x'i'iT^T9rrr-,i,t'*^,tli,1" 醇），產生N-(3-氯-苯Η-(2·氯~4-吡啶>2-嘧啶胺；熔點： 196- 198。，Rf=〇.7(二氯甲烷：甲醇=95:5)。 所使用之N-( 3-氯-苯>4-( N-氧冬吡啶)-2-嘧啶胺係利用 下列方法製備： 在室溫下，將10克（35.4毫摩爾）Ν-(3·氯-苯>4*(4·吡 啶>2-嘧啶胺及11.1克（35.4毫摩爾）間-氯過苯甲酸在 5〇0毫升二氯甲烷中攪拌5小時。將剰留物濃縮並結晶 (醋酸），產生Ν·(3-氯苯VKN-氧斗吡啶>2-嘧啶胺；熔 點：274 - 275°，Rf=0.6(二氯甲烷：甲醇=9:1)。 階段2.2 ：利用類似於階段1.3之方法，由4.1毫升（0.04 摩爾）3-氯-苯胺及3.3克（0.078摩爾）氰胺（50%於水 中）製得硝酸3·氯-苯-胍；1H-NMR(二甲亞碘）：7.2-7.7 (7H，m)，9.5(lH，br，s)。 實施例3 ：下列化合物係利用類似於上述之方法，及本質 上已知之單純轉化反應製備。V. Description of the invention () ls. ^ '' PJ ^ .- x'i'iT ^ T9rrr-, i, t '* ^, tli, 1 " alcohol) to produce N- (3-chloro-phenylhydrazone- ( 2. Chlorine ~ 4-pyridine >2-pyrimidinamine; melting point: 196-198 °, Rf = 0.7 (dichloromethane: methanol = 95: 5). N- (3-chloro-benzene) used 4- (N-oxopyridine) -2-pyrimidinamine is prepared by the following method: At room temperature, 10 g (35.4 mmol) of N- (3 · chloro-benzene > 4 * (4 · pyridine > 2-pyrimidinamine and 11.1 g (35.4 mmol) of m-chloroperbenzoic acid were stirred in 5000 ml of dichloromethane for 5 hours. The retentate was concentrated and crystallized (acetic acid) to give N · (3- Chlorobenzene VKN-oxopyridine >2-pyrimidinamine; melting point: 274-275 °, Rf = 0.6 (dichloromethane: methanol = 9: 1). Stage 2.2: Using a method similar to stage 1.3, from 4.1 ml (0.04 moles) of 3-chloro-aniline and 3.3 g (0.078 moles) of cyanamide (50% in water) to produce 3 · chloro-benzene-guanidine nitrate; 1H-NMR (dimethyl iodide): 7.2-7.7 (7H , M), 9.5 (lH, br, s). Example 3: The following compounds were prepared using a method similar to that described above, and a simple conversion reaction known per se.

b) Ν·( 3-氯·苯>4-[ 2-( 2-羧-乙•胺吡啶]-2-嘧啶胺，熔點186 -188〇C 本紙張尺度適用中國國家標準（CNS ) Λ4規格（2丨0><297公释） I---------多------ΐτ------0 I (請先閲讀背面之注意事項再填寫本頁) -49- 經濟部中央揉準局員工消費合作社印裝 A 7 B7 五、發明説明（） h) N-( 3-三氟甲-苯)-4-[ 2-( 2-乙氧幾-乙-胺>4-啦啶]-2-喃啶胺， i) N-( 3-氯-苯)冰[2·( 2-咪唑-1-基乙-胺比啶】-24^啶胺， j) N-( 3-氯-苯)·4·[ 2·( 2-乙醯胺-乙·胺 >4"% 啶]-2·1® 啶胺， k) Ν-( 3-氯-苯)》4·[ 2·肼·4-吡啶】-2-嘧啶胺， l) Ν-(3-氯-苯)斗[2»(2-胍-乙·胺>4»吡啶]-2-嘧啶胺， m) Ν-( 3-氯-苯>4-[ 2-{ 2-(甲胺-羰胺)-乙-胺Μ-吡啶]-2-嘧啶胺， η) Ν·< 3-氯-苯>4·[ 2·( 2-甲脒·乙-胺Μ·%啶】-2禮啶胺， 〇) Ν·< 3-氯-苯Η·[ 2Κ 2-甘胺醯胺-乙-胺啶]-2铺啶胺， ρ) Ν·( 3-氯-苯>4-[ 2-( N-{ 2-胺-乙}-胺羰吡啶]-2-嘧啶胺（亦 參見實施例6)， q) Ν·( 3-氯-苯>4-[ 2~( N-{ 2-羥-乙}-胺羰>4-吡啶]-2-嘧啶胺（亦 參見實施例7)， r) N-( 3_氯-苯>4·[ 2·( N-{ 3-胺-丙-l-基}-胺羰>4-吡啶>2-嘧啶胺 (亦參見實施例9)， s) N-( 3-氯·苯Η>[ 2·( N-{ 3-羥·丙}-胺羰M-吡啶]-2·喃啶胺（亦 參見實施例8)， t) N<3-氯-苯>4·[2-{ 2<N-羥-胺甲醯)-乙·胺}斗吡啶]-2-嘧啶 胺， u) Ν·(3-氯-苯>4>[2-{ 3-(Ν·羥-胺甲醯 >丙-胺}斗吡啶]-2-嘧啶 胺， ν) Ν·( 3-氯-苯>4·[ 2-{ 2·(二羥-磷醯氧)乙-胺}~4_吡啶]-2-嘧啶 胺， w) Ν-( 3-氯-苯>4·[ 2-{ 3-(二羥-磷醯氧)·丙-胺}-4-吡啶]-2-嘧啶 胺， 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） ----------裝— (請先閱讀背面之注$項再填寫本頁) 訂 線 -50- 五、發明説明（ A 7 B7b) Ν · (3-chloro · benzene) 4- [2- (2-carboxy-ethyl • aminopyridine] -2-pyrimidinamine, melting point 186 -188 ° C This paper is applicable to Chinese National Standard (CNS) Λ4 Specifications (2 丨 0 > < 297 public release) I --------- Multiple ------ ΐτ ------ 0 I (Please read the precautions on the back before filling this page ) -49- Printed by the Consumer Cooperatives of the Central Bureau of the Ministry of Economic Affairs of the Consumer Cooperatives A 7 B7 V. Description of the invention () h) N- (3-trifluoromethyl-benzene) -4- [2- (2-ethoxy- Ethyl-amine > 4-laridine] -2-uridineamine, i) N- (3-chloro-benzene) ice [2 · (2-imidazol-1-ylethyl-aminepyridine] -24 ^ pyridine Amine, j) N- (3-Chloro-benzene) · 4 · [2 · (2-Acetylamine-Ethylamine > 4 "% pyridine) -2 · 1® pyridineamine, k) Ν- (3 -Chloro-benzene)》 4 [[2 · hydrazine · 4-pyridine] -2-pyrimidinamine, l) Ν- (3-chloro-benzene) bucket [2 »(2-guanidine-ethyl · amine > 4» Pyridine] -2-pyrimidinamine, m) N- (3-chloro-benzene) 4- [2- {2- (methylamine-carbonylamine) -ethyl-amine M-pyridine] -2-pyrimidinamine, η ) Ν · < 3-Chloro-benzene > 4 · [2 · (2-formamidine · ethyl-amine M ·% pyridine] -2 Limonidine, 〇) Ν · < 3-chloro-benzeneΗ · [2Κ 2-Glycosamine-ethyl-aminopyridine] -2 pyridamine, ρ) Ν · (3-chloro-benzene) 4- [2- (N- {2-amine-ethyl} -aminecarbonyl Pyridine ] -2-pyrimidinamine (see also Example 6), q) Ν · (3-chloro-benzene > 4- [2 ~ (N- {2-hydroxy-ethyl} -aminecarbonyl > 4-pyridine] -2-pyrimidinamine (see also Example 7), r) N- (3-chloro-benzene) > 4 [[2 · (N- {3-amine-propan-l-yl} -aminecarbonyl > 4 -Pyridine > 2-pyrimidinamine (see also Example 9), s) N- (3-chloro · phenylhydrazone > [2 · (N- {3-hydroxy · propyl} -aminocarbonyl M-pyridine] -2 · Aminopyridamine (see also Example 8), t) N < 3-Chloro-benzene > 4. [2- {2 < N-hydroxy-amine formamidine) -ethyl · amine} pyridine] -2- Pyrimidine amine, u) Ν · (3-chloro-benzene) > [2- {3- (Ν · hydroxy-amine formamidine > propyl-amine} pyridine] -2-pyrimidine amine, ν) Ν · (3-Chloro-benzene) 4 [[2- {2 ((Dihydroxy-phosphoranox) ethyl-amine] ~ 4-pyridine] -2-pyrimidinamine, w) Ν- (3-chloro-benzene) ; 4 · [2- {3- (Dihydroxy-phosphoramidyloxy) · propyl-amine} -4-pyridine] -2-pyrimidinamine, this paper size applies to China National Standard (CNS) A4 specification (210X297 mm) ---------- Installation— (Please read the note on the back before filling in this page) Thread-50- 5. Description of the invention (A 7 B7

ίί 渺。A ----------f — (請先W讀背面之注$項再填寫本頁) 經濟部中央梂準局貝工消費合作社印製 實施例4 :在110°下，將20毫克（0.063毫摩爾）N-(3-氯-苯氯斗B比啶>2-嘧啶胺與1毫升伸乙二胺攪拌26小 時。濃縮並層析（二氯甲烷：甲醇：濃氨水溶液= 80:20:1)，產生Ν<3-氯·苯>4«[2*(2-胺-乙-胺>4·吡啶]-2-嘧啶 胺，Rr= 0.15 (二氯甲院：甲醇：濃氣水溶液=80:20:1)， FAB-MS: 341 (M"+l)-> 實施例5 :利用類似於實施例4之方法，由50毫克 (0.157毫摩爾）Ν-(ί-三氟甲-苯Μ-(2-氯*4-1此啶淀胺及 1毫升伸乙二胺製得Ν·( 3-三氟甲-苯Μ-[ 2-( 2·胺-乙-胺>4^比 啶]嘧啶胺；Rr=0.15 (二氯甲烷：甲醇：濃氨水溶液= 80:20:1) » FAB-MS: 375 (ί^+Η) » 實施例6 :將8〇毫克（0·24毫摩爾）Ν-(3-氯-苯j_4»(2·竣冰 吡啶>·2·喷啶胺、7〇.8毫克（0.36毫摩爾）氫氯化队乙_N，_ (3-二甲胺丙)·羰二亞胺及42毫克（0·%毫摩爾）N_翔我 本紙張尺度適用中國國家梂準（CNS ) A4规格（210X：297公釐） 訂 線 -51 - 經濟部中央標準局員工消費合作社印製 5 p正本ϊν'，曰 五、發明説明（） ——----j 珀醯亞胺溶於3毫升二甲基甲醯胺中，並在室溫下攪拌 2.5小時。然後在0°下，在30分鐘內，將反應混合物逐 滴加入一 〇·77毫升（11.8毫摩爾）伸乙二胺溶於2毫升 二甲基甲醯胺之溶液中。在室溫下攪拌14小時之後，將 反應混合物倒進50毫升醋酸乙酯中，並用30毫升水萃 取。將有機相乾燥（硫酸鈉）並濃縮。從異丙醇/鹽酸 乙醇溶液中結晶，產生氫氯化N-[3-氯-苯>4-{2-[Ν·(2-胺· 乙）·胺羰]冰吡啶}-2-嘧啶胺；熔點：161 - 163°，FAB-MS: 369 (IVf+H)» 起始原料係以下列方式製得： 階段6.1 ：在60°下，將50毫克（0.16毫摩爾）N-(3-氯-苯>4-(2-氰·4-Ι>比啶>2-喃啶胺在5毫升乙醇及5毫升2N氫 氧化鈉溶液中攪拌2小時。冷卻至室溫並過濾之後，將 留在濾紙上之物質用乙醇/水（少1)淸洗，並在50°及高 眞空下乾燥，產生Ν-(3-氯-苯)-4>(2魂>4·批啶>2·嘧啶胺之鈉 鹽；熔點：>250°，(二氯甲烷：甲醇=9:1) » 實施例7 ：利用類似於實施例6之方法，由100毫克（0.3 毫摩爾）Ν-[3·氯-苯]+(2-羧冰吡啶>2-嘧啶胺、88.5毫升 (0.46毫摩爾）氫氯化N-乙-NH3-二甲胺丙羯二亞胺、53 毫克（0.46毫摩爾）N-經琥珀醯亞胺及0.9毫升（14毫摩 爾）乙醇胺製得N-[ 3-氯-苯H-{ 2-[ N-( 2-羥-乙）·胺羰H-吡 啶}-2-嘧啶胺；熔點：206°，FAB-MS:370(M++H)。 HI m·· m ·1 m I^^^^1 - nn In nn ϋ ^SJ (請先閲讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公廣） -52- 經濟部中央樣隼局員工消費合作社印製 A7 __B7_ 五、發明説明（） 實施例8 :利用類似於實施例6之方法，由80毫克（0.24 毫摩爾）N-[3-氯-苯]-4-(2-羧*4·吡啶>2·嘧啶胺、70毫克 (0.36毫摩爾）氫氯化N-乙-N，-( 3-二甲胺丙 > 羰二亞胺、42 毫克（0.36毫摩爾）N-羥琥珀醯亞胺及0.7毫升（11.8毫 摩爾）胺丙醇製得N-[ 3-氯-苯]冰[2气N-( 3-羥-丙)胺羰)·4-吡 啶]-2-嘧啶胺；熔點：152- 153°，FAB-MS: 384(1^+11)。 實施例9 ：利用類似於實施例6之方法，由50毫克（0.15 毫摩爾）Ν-[3·氯·苯]·4-(2·羧4·吡啶>2-嘧啶胺、44毫克 (0.22毫摩爾）氫氯化Ν-乙-ΝΗ3-二甲胺丙)羯二亞胺、26 毫克（0.22毫摩爾）Ν-羥琥珀醯亞胺及0.48 p升（7.3毫 摩爾）二胺丙烷製得氫氯化Ν-[ 3-氯-苯]冬[2< Ν-{ 3-胺-丙-1-基}-胺羰>4-吡啶]_2_嘧啶胺；熔點173 - 178°，FAB-MS:383 (1VT+H)。 實施例10 :利用類似於實施例1之方法，由500毫克 (1.5毫摩爾）N-[3-氯-苯>4-(2-氯-WI比啶>2-嘧啶胺及1毫 升（16.3毫摩爾）胺乙醇製得N-[3-氯-苯H-[2-(2-經-乙-胺> 比啶]-2-嘧啶胺；熔點：180 - 181。，FAB-MS: 342 (1VT+H)。 實施例11 :利用類似於實施例1之方法，由6.4克（丨9.6 毫摩爾）Ν_[ 3-羧-苯ΡΗ 2-氯+吡啶>2-嘧啶胺及12毫升 (160毫摩爾）3-胺丙醇，在從乙醇/1N鹽酸中結晶之 後，製得怵[3-羧_苯】斗[2-(3-羥-丙··胺)斗吡啶]-2-嘧啶胺，熔 點：258-259。，FAB-MS: 366 (\Γ+Η)。 (請先閱讀背面之注意事項再填寫本X) -裝 訂 線 本紙張尺度適用中國國家橾率（CNS ) Α4規格（2丨0 X 297公釐） -53- A 7 B7 經濟部中央標隼局負工消費合作社印裝 五、發明説明（) 起始原料係以下列方式製得： 階段11.1 :利用類似於階段1.3之方法，由24.4克（148 毫摩爾）胺苯甲酸乙酯、10.25毫升（150毫摩爾）65%硝 酸及9_66克（230毫摩爾）98%氰胺製得硝酸3-乙氧羰· 苯-胍；'H-NMR (DMSO, D20): 1.3 (t,3H), 4.3 (q,2H), 7.4 - 7.9 (ιΜΗ)。 mm 11.2：利用類似於階段1.4之方法，由14.5克（53.7 毫摩爾）硝酸3-乙氧裁-苯-胍、11.3克（517毫摩爾）3-二 甲胺-1-(2-氯~4-卩比陡)-2-丙嫌-1-醒及2.4克（60毫摩爾）氮氧 化鈉製得N-[3-乙氧羰-苯]-K2-氯-4-吡啶>2·嘧啶胺；熔點·’ 149 - 150°，FAB-MS: 355 (ΝΓ+Η)。 階段11.3:將9.4克（26.5毫摩爾）N-[3-乙氧簾·苯]“Κ2-氯 •4*此啶>2-喷啶胺及50毫升2Ν氫氧化鈉溶液在300毫升 乙醇中迴流沸騰1小時。冷卻至室溫之後，將反應混合 物酸化（4Ν鹽酸）並過濾。在50°及高眞空下乾燥之 後，得到檸檬黃色Ν-[3-羧-苯]~4-(2-氯冰吡啶>2-嘧啶胺晶 體；熔點：267 - 268°，FAB>MS: 327 (ΝΤ+Η)。 Λ mm 12：將 2.0 克（5·4 毫摩爾）N-[3-羧·苯ρΚ2-(3-羥-丙-胺>4·吡啶>2·嘧啶胺及0.28毫升（5.4毫摩爾）濃硫酸 在150毫升甲醇中迴流沸騰24小時。冷卻至室溫之後， 將反應混合物濃縮成一半體積，用1〇〇毫升醋酸乙酯稀 (讀先閱讀背面之注項再填寫本頁) 装---- 訂 線. 本紙張尺度逋用中國國家橾準（CNS ) A4規格（210X297公董） -54- 經濟部t央橾準局貝工消費合作社印氧 A7 _B7_五、發明説明（） 釋並用緩衝液（pH7)萃取兩次（每次50毫升）。將有機 相乾燥（Na2S04)並濃縮。結晶後產生N-[3-甲氧簾-苯]_4-[2-(3-羥-丙-胺 >4·®：啶】-2-嘧啶胺；熔點：162 - 163°，FAB-MS: 380 (NT+H)。 實施例13 :利用類似於實施例1之方法，由300毫克 (0.95毫摩爾）N-[3·氯-苯H-(2-氯冬吡啶>2-嘧啶胺及3毫 升（32.3毫摩爾）胺丁醇製得N-[3-氯-苯經-丁-胺 4·Β比陡】-2癌啶胺；熔點：136- 139°，FAB-MSJTOOVf+H)。 實施例14 :利用類似於實施例1之方法，由50毫克 (0.16毫摩爾）Ν-[3·氯-苯]_4_( 2-氯冬吡啶>2·嘧啶胺及350 毫克（3.15毫摩爾）組織胺（即2·(咪哗冰基)-乙-胺）製得 熔融態之N-[ 3-氯-苯H-{ 2-[ 2-(咪唑-4-基)*乙-胺H-Bfc啶}-2-嘧 啶胺；熔點：140 - 146°，FAB-MS: 392 (NT+H)。 實施例15 :利用類似於實施例1之方法，由1.16克 (3.91毫摩爾）N-[3-甲-苯H-(2-氯>4_吡啶>2-赌啶胺及23毫 升（304.9毫摩爾）3-胺丙醇製得N-[3-甲-苯]冰[2-(3·羥-丙-胺 >4-吡啶]-2-嘧啶胺；熔點：138 - 139°，FAB-MS.· 336 (IvT+H)- 起始原料係以下列方式製得： (請先閲讀背面之注$項再填寫本頁) -裝· 訂 線 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） -55- 經濟郎中夬樣隼局員工消費合作社印聚 A7 _B7 __ 五、發明説明（） 階段15.1 :利用類似於階段1.3之方法，由2.02毫升 (18.7毫摩爾）間-甲苯胺、1.95毫升（29.9毫摩爾）濃鹽 酸及0.89克（37.3毫摩爾）98%氰胺，用0.47克（37.3 毫摩爾）硝酸銨沉澱之後，製得硝酸3-甲-苯·胍；W-NMR (DMSO): 2.3 (s,3H), 7.0 - 7.5 (m,8H), 9.5 (br,s,lH) ° 階段15·2:利用類似於階段1.4之方法，由1.09克（5.17 毫摩爾）硝酸3-甲-苯-胍、1.09克（5·17毫摩爾）3-二甲胺· 1~(2-氯冰吡啶>2-丙烯-1-酮及0.23克（5.68毫摩爾）氫氧化 鈉製得Ν-【3-甲-苯】冰(2-氯>4·吡啶)-2-嘧啶胺；1H-NMR(DMSO): 2.3 (s,3H), 6.8 (d,lH), 7.2(t,lH), 7.6 (m,2H), 7.7 (s,lH), 8.1 (m,lH), 8.2 (s,lH), 8.6 (d,lH), 8.7 (d,lH), 9.8 (s,lH) > 實施例16 :利用類似於實施例1之方法，由168.8毫 (0.53毫摩爾）N-[3-氯-苯>4<2-氯吡啶>2-嘧啶胺及113.2 毫克（1.06毫摩爾）5-胺戊醇製得N-[3-氯-苯H-[2-(5-羥-戊-胺)冰吡啶 1-24^ 啶胺；FAB-MS: 384 (NT+H)，298。 實施例17 :在140°下，將500毫克（1,4毫摩爾）N-[3-乙氧羰-苯>4·(2邊4·啦啶>2-嘧啶胺在1毫升3-胺丙醇中攪 拌15小時。層析（矽膠，二氯甲烷：甲醇=9:1 )之 後，產生Ν-[3·{Ν-(3-羥-丙 >胺-羰卜苯H-[2-(3-羥-丙-胺>4-11 比 啶]-2-嘧啶胺；熔點：153 - 154°，FAB-MS: 423 (λΓ+Η)。 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐） -U ----------1------1Τ------^1 (請先聞讀背面之注$項再填寫本頁) -56- 經濟部中央揉準局員工消費合作社印製 A7 B7_ 五、發明说明（） 實施例18 :在90°下，將100毫克（0.26毫摩爾）N-[3-甲氧羰-苯H-[ 2K 3邊-丙-胺Μ-吡啶]-2-嘧啶胺及0.5毫升1.3-二胺-丙烷攪拌24小時’然後用20毫升醋酸乙酯稀釋並 用2X10毫升氯化鈉溶液萃取。將有機相乾燥，濃縮並從 二氯甲烷/***中結晶’得到Ν-[ΜΝ-(3-胺·丙 > 胺羰卜苯]-4-[2-(3-羥-丙·胺)斗吡啶]-2-嘧啶胺；熔點：169-170°，FAB-MS: 422(ΝΤ+Η)。 實施例19 :利用類似於實施例18之方法，由100毫克 (0.26毫摩爾）Ν·[3-甲氧羰-苯Η-[ 2>( 3-經-丙-胺>4-吡啶]-2-嘧 啶胺及150毫克（U5毫摩爾）組織胺（即2-(咪唑>4-基)· 乙-胺）製得Ν-[ 3·{ 2-咪唑冬基·乙)胺羰}-苯]·4_[ 3-羥- 丙·胺 >4·吡啶]-2-嘧啶胺；熔點：181 - 186°，FAB-MS: 459 (ΝΤ+Η)» 實施例20 :利用類似於實施例1之方法，由300毫克 (0.9毫摩爾）Ν-[ 3-氯-6·甲-苯]-K 2-氯吡啶>2-嘧啶胺及 5.3毫升（70.65毫摩爾）3-胺丙醇製得Ν·[ 3-氯-6·甲-苯]+ [2-(3-經-丙-胺)·4-吡啶]-2-嘧啶胺；熔點：117-119°，FAB-MS: 370 (ΝΤ+Η)。 起始原料係以下列方式製得： 階段20.1 ：利用類似於階段1.3之方法，由10.0克（60.62 毫摩爾）5-氯-2-甲-胺、9.45毫升（113毫摩爾）濃鹽酸及 U ----------裝------訂------線| (請先聞讀背面之注意事項再填寫本頁) 本紙张尺度適用中國固家梂準（CNS )八4规格（210Χ297公釐） -57- A7 _B7___ 五、發明说明（） 5.94克（141.2毫摩爾）98%氰胺，用11.3克（141.2毫摩 爾）硝酸銨沉澱之後，製得硝酸5-氯-2-甲•苯·胍；lH_NMR (DMSO): 2.2 (s,3H), 7.2 - 7.4 (m,7H) ° 階段20.2 ：利用類似於階段1.4之方法，由1.75克（7.12 毫摩爾）硝酸3-氯·6·甲-苯-胍、1.5克（7.12毫摩爾）3·二 甲胺-M2·氯>4·卩比啶)·2-丙烯-1-酮及0.31克（7.83毫摩爾）氫 氧化鈉製得Ν-[3-氯各甲·苯】冰(2-氯冰吡啶）-2-嘧啶胺；1!!-NMR (DMSO): 2.2 (s,3H), .71 (d x d, 1H), 73 (d, 1H), 7.6 (d,lH), 7.8 (<UH)，8.05 (dx 屯 1H)，8.15 (s，1H)，8.6 ㈣ 2H), 9.2 (s，lH)。 實施例21 ：利用類似於實施例1之方法，由300毫克 (0.85毫摩爾）N-[ 3,6·二氯-苯]冰(2-氯-4-吡啶>2-嘧啶胺及 5.0毫升（66.55毫摩爾）3-胺丙醇製得N-[3,6-二氯-苯】冬[2-(3-經-丙胺比啶]-2-嘧啶胺；熔點：130- 132°，FAB-MS:390 (ivr+H) = 起始原料係以下列方式製得： 經濟部中央樣準局貝工消費合作社印製 (請先閱讀背面之注$項再填寫本頁) 階段21.1 ：利用類似於階段1·3之方法，由1〇.〇克（61.72 毫摩爾）2,5-二氯-苯胺、8.25毫升（98.7毫摩爾）濃鹽酸 及5.19克（123.4毫摩爾）98%氰胺，用9.88克（123.4毫 摩爾）硝酸銨沉澱之後，製得硝酸2,5·二氯-苯-胍；1H-NMR (DMSO): 7.4 - 7.7 ㈣7Η)。 本紙張尺度適用中國國家標準（CNS ) Α4規格（21 〇 X 297公釐） • 58- 趣濟部中央榡準局貝工消費合作、社印製 A7 B7 五、發明説明（） 階段21.2 :利用類似於階段1.4之方法，由1.9克（7.12 毫摩爾）硝酸3,6-二氯-苯-胍、1_5克（7.12毫摩爾）3-二甲 胺-H2-氯4-吡啶>2-丙烯-1-酮及0.31克（7.83毫摩爾）氫氧 化鈉製得Ν-[3,6·二氯-苯]>4-(2-氯4-吡啶>2-嘧啶胺；W-NMR (DMSO): 7.25 (d X d, 1H), 7.6 (d, 1H), 7.7 (d, 1H), 8.05 (m, 2H), 8.2 (s, 1H), 8_6 1H), 8.7 (山 1H)，9.25 (s，1H)。 實施例22 :利用類似於實施例1之方法，由300毫克 (0·86毫摩爾）N-[3-氯各甲氧-苯PK 2-氯4·吡啶>2-嘧啶胺 及5.1毫升（67.4毫摩爾）3-胺丙醇製得N-[ 3-氯-6-甲氧-苯Η-[2·(3-羥-丙-胺吡啶]-2-嘧啶胺；熔點：131-133°， FAB-MS: 386 (NT+H) ° 起始原料係以下列方式製得： 階段22.1 ：利用類似於階段1.3之方法，由10.0克（63,45 毫摩爾）5-氯-2-甲氧-苯胺、8.5毫升（101.5毫摩爾）濃鹽 酸及5.3克（126.9毫摩爾）98%氰胺，用10.2克（126.9 毫摩爾）硝酸銨沉澱之後，製得硝酸5·氯-2-甲氧-苯-胍； W-NMR (DMSO): 3.9 (¾ 3H)，7.2 _ 7.4 (取 7H)。 階段22.2 ：利用顙似於階段I.4之方法，由1.S7克（7.12 毫摩爾）硝酸3-氯·6·甲氧-苯-胍、1.5克（7·12毫摩爾）3-二甲胺-1-(2-氯冬啦啶>*2-丙烯-1-酮及0.31克（7·82毫摩爾） 氫氧化鈉製得Ν·[ 3-氯-6·甲氧-苯]-4-( 2-氯-4-吡啶>2-喃啶胺； 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 裝 訂 II 線 (請先閱讀背面之注意事項再填寫本頁)ίί Miao. A ---------- f — (please read the note $ on the back before filling this page) Printed by Shellfish Consumer Cooperative of Central Bureau of Standards, Ministry of Economic Affairs Example 4: At 110 °, the 20 mg (0.063 mmol) of N- (3-chloro-benzyl chloride B-pyridine > 2-pyrimidinamine and 1 ml of ethylenediamine were stirred for 26 hours. Concentrated and chromatographed (dichloromethane: methanol: concentrated ammonia) Aqueous solution = 80: 20: 1), producing N < 3-chloro · benzene > 4 «[2 * (2-amine-ethyl-amine > 4 · pyridine] -2-pyrimidinamine, Rr = 0.15 (dichloro A hospital: methanol: concentrated gas solution = 80: 20: 1), FAB-MS: 341 (M " + l)-> Example 5: Using a method similar to that in Example 4, from 50 mg (0.157 mmol) ) Ν- (ί-trifluoromethyl-benzene M- (2-chloro * 4-1 this pyrimidine and 1 ml of ethylenediamine to obtain N · (3-trifluoromethyl-benzene M- [2- ( 2 · Amine-Ethyl-Amine > 4 ^ pyridine] pyrimidineamine; Rr = 0.15 (dichloromethane: methanol: concentrated ammonia solution = 80: 20: 1) »FAB-MS: 375 (ί ^ + Η)» Example 6: 80 mg (0.24 mmol) of N- (3-chloro-benzene j_4 »(2. Junpyridine >.2; Pendiamine, 70.8 mg (0.36 mmol) Hydrochlorinated team B _N, _ (3-dimethylamine propyl) · carbodiimide and 42 mg (0 ·% Moore) N_Xiangwu This paper size is applicable to China National Standards (CNS) A4 specifications (210X: 297 mm) Order line -51-Original 5 p printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs ϊν ', Description of the invention () -------- j Permethimine is dissolved in 3 ml of dimethylformamide and stirred at room temperature for 2.5 hours. Then, the reaction mixture is stirred at 0 ° within 30 minutes. A solution of 10.77 ml (11.8 mmol) of ethylenediamine in 2 ml of dimethylformamide was added dropwise. After stirring at room temperature for 14 hours, the reaction mixture was poured into 50 ml of ethyl acetate. And extracted with 30 ml of water. The organic phase was dried (sodium sulfate) and concentrated. Crystallized from an isopropanol / hydrochloric acid ethanol solution to produce hydrochlorinated N- [3-chloro-benzene> 4- {2- [ Ν · (2-amine · ethyl) · aminocarbonyl] pyridine} -2-pyrimidineamine; melting point: 161-163 °, FAB-MS: 369 (IVf + H) »The starting materials were prepared in the following manner: Stage 6.1: 50 mg (0.16 mmol) of N- (3-chloro-benzene > 4- (2-cyano-4-I > pyridine > 2-pyrimidinamine) in 5 ml of ethanol at 60 ° And 5 ml of 2N sodium hydroxide Stir for 2 hours in medium. After cooling to room temperature and filtering, the material remaining on the filter paper is washed with ethanol / water (less 1), and dried at 50 ° and high air to produce N- (3-chloro-benzene ) -4 > (2 souls > 4 · piridine > 2 · sodium salt of pyrimidinamine; melting point:> 250 °, (dichloromethane: methanol = 9: 1) »Example 7: Utilize similar to the implementation The method of Example 6 consisted of 100 mg (0.3 mmol) of N- [3 · chloro-benzene] + (2-carboxypyridine > 2-pyrimidinamine, 88.5 ml (0.46 mmol) of hydrochloride N-ethyl- NH3-dimethylamine propanedimine, 53 mg (0.46 mmol) N-N- [3-chloro-benzeneH- {2- [via succinimide and 0.9 ml (14 mmol) ethanolamine N- (2-hydroxy-ethyl) · aminocarbonylH-pyridine} -2-pyrimidinamine; melting point: 206 °, FAB-MS: 370 (M ++ H). HI m ·· m · 1 m I ^^^^ 1-nn In nn ϋ ^ SJ (Please read the precautions on the back before filling out this page) This paper size applies Chinese National Standard (CNS) A4 (210X 297) (Guangdong) -52- Printed by A7 __B7_ of the Consumer Cooperatives of the Central Bureau of Samples of the Ministry of Economic Affairs 5. Description of the Invention () Example 8: Using a method similar to Example 6, from 80 mg (0.24 mmol) N- [3- Chloro-benzene] -4- (2-carboxy * 4 · pyridine> 2 · pyrimidinamine, 70 mg (0.36 mmol) hydrochloride N-ethyl-N,-(3-dimethylamine propane) > N- [3-Chloro-benzene] ice [2-gas N- (3-hydroxy- (C) Amine carbonyl) · 4-pyridine] -2-pyrimidinamine; melting point: 152-153 °, FAB-MS: 384 (1 ^ + 11). Example 9: Using a method similar to Example 6, from 50 Mg (0.15 mmol) N- [3 · chloro · benzene] · 4- (2 · carboxy4 · pyridine > 2-pyrimidinamine, 44 mg (0.22 mmol) hydrochloride N-ethyl-ΝΗ3-dimethyl Amine propyl) sulfodiimide, 26 mg (0.22 mmol) of N-hydroxysuccinimide and 0.48 p liter (7.3 mmol) of diamine propane to produce hydrochloride N- [3-chloro-benzene] dong [2 < Ν- {3-amine-prop-1-yl} -aminecarbonyl > 4-pyridine] _2_pyrimidineamine; melting point 173-178 °, FAB-MS : 383 (1VT + H). Example 10: Using a method similar to Example 1, from 500 mg (1.5 mmol) of N- [3-chloro-benzene> 4- (2-chloro-WI ratio) ; 2-Pyrimidinamine and 1 ml (16.3 mmol) of amine ethanol to prepare N- [3-chloro-benzene H- [2- (2-Cyclo-ethyl-amine > Bipyridine] -2-pyrimidinamine; melting point : 180-181., FAB-MS: 342 (1VT + H). Example 11: Using a method similar to that in Example 1, 6.4 g (9.6 mmol) of N_ [3-carboxy-benzene PZ 2-chloro + Pyridine > 2-pyrimidinamine and 12 ml (160 mmol) of 3-aminopropanol, after crystallizing from ethanol / 1N hydrochloric acid, 怵 [3-carboxy_benzene] do [2- (3-hydroxyl -Propylamine · Pyridine] -2-pyrimidinamine, melting point: 258-259., FAB-MS: 366 (\ Γ + Η). (Please read the precautions on the back before filling in this X)-Binding line This paper size is applicable to China National Standard (CNS) Α4 specification (2 丨 0 X 297 mm) -53- A 7 B7 Printing by the Central Laboratories Bureau of the Ministry of Economic Affairs and Consumer Cooperatives Made in the following way: Stage 11.1: Using a method similar to stage 1.3, nitric acid was prepared from 24.4 g (148 mmol) of ethyl amine benzoate, 10.25 ml (150 mmol) of 65% nitric acid and 9-66 g (230 mmol) of 98% cyanamide. 3-ethoxycarbonyl · benzene-guanidine; 'H-NMR (DMSO, D20): 1.3 (t, 3H), 4.3 (q, 2H), 7.4-7.9 (ιΜΗ). mm 11.2: Using a method similar to stage 1.4, from 14.5 g (53.7 mmol) of 3-ethoxysulfate-benzene-guanidine nitrate, 11.3 g (517 mmol) of 3-dimethylamine-1- (2-chloro ~ N- [3-ethoxycarbonyl-benzene] -K2-chloro-4-pyridine was prepared from 2-propan-1-propane and 2.4 g (60 mmol) of sodium oxynitride. 2 Pyrimidine amine; melting point '149-150 °, FAB-MS: 355 (NΓ + Η). Stage 11.3: Put 9.4 g (26.5 mmol) of N- [3-ethoxy curtain · benzene] "K2-chloro • 4 * this pyridine" and 2-pyridinamine and 50 ml of 2N sodium hydroxide solution in 300 ml of ethanol Boiling at medium reflux for 1 hour. After cooling to room temperature, the reaction mixture was acidified (4N hydrochloric acid) and filtered. After drying at 50 ° under high vacuum, lemon yellow N- [3-carboxy-benzene] ~ 4- (2 -Chloropyridine > 2-pyrimidinamine crystal; melting point: 267-268 °, FAB > MS: 327 (NT + Ν). Λ mm 12: 2.0 g (5.4 mmol) of N- [3-carboxyl Benzene ρΚ2- (3-hydroxy-propane-amine> 4. Pyridine> 2. Pyrimidineamine and 0.28 ml (5.4 mmol) of concentrated sulfuric acid were boiled in 150 ml of methanol under reflux for 24 hours. After cooling to room temperature, The reaction mixture was concentrated to half the volume and diluted with 100 ml of ethyl acetate (read the note on the back and then fill out this page). ---- Threading. This paper uses China National Standards (CNS) A4 Specifications (210X297 public director) -54- Printed oxygen A7 _B7_ by the Central Bureau of quasi-government Shellfish Consumer Cooperatives of the Ministry of Economic Affairs 5. Description of the invention () Release and extract twice with buffer solution (pH7) (50 ml each time). Organic phase Dry (Na2S04) and concentrate. N- [3-methoxy curtain-benzene] _4- [2- (3-hydroxy-propane-amine > > 4 · ®: pyridine] -2-pyrimidinamine; melting point: 162-163 °, FAB-MS: 380 (NT + H). Example 13: Using a method similar to Example 1, from 300 mg (0.95 mmol) of N- [3 · chloro-benzene H- (2- N- [3-chloro-benzene via -but-amine 4 · B ratio] from clopyridine & 2-pyrimidylamine and 3 ml (32.3 mmol) amine butanol] -2 carcinidamine; melting point: 136 -139 °, FAB-MSJTOOVf + H). Example 14: Using a method similar to that in Example 1, from 50 mg (0.16 mmol) of N- [3 · chloro-benzene] _4_ (2-chlorototopyridine)> 2. Pyrimidinamine and 350 mg (3.15 mmol) of histamine (that is, 2 · (imidazolyl) -ethyl-amine) to prepare N- [3-chloro-benzene H- {2- [2- (Imidazol-4-yl) * ethyl-amine H-Bfcpyridine} -2-pyrimidinamine; melting point: 140-146 °, FAB-MS: 392 (NT + H). Example 15: Use similar to Example 1 The method consists of 1.16 g (3.91 mmol) of N- [3-methyl-benzene H- (2-chloro> 4-pyridine) 2-pyrimidinamine and 23 ml (304.9 mmol) of 3-amine propanol. Preparation of N- [3-methyl-benzene] ice [2- (3-Hydroxy-propane-amine> 4-pyridine] -2-pyrimidineamine; Point: 138-139 °, FAB-MS. · 336 (IvT + H)-The starting material is made in the following way: (Please read the note on the back before filling this page)-Binding and binding paper The standard is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) -55- Economy Langzhong sample sample bureau employee consumer cooperative printed A7 _B7 __ V. Description of the invention () Phase 15.1: Use a method similar to phase 1.3, by 2.02 ml (18.7 mmol) of m-toluidine, 1.95 ml (29.9 mmol) of concentrated hydrochloric acid, and 0.89 g (37.3 mmol) of 98% cyanamide, precipitated with 0.47 g (37.3 mmol) of ammonium nitrate to obtain nitric acid 3-methyl-benzene-guanidine; W-NMR (DMSO): 2.3 (s, 3H), 7.0-7.5 (m, 8H), 9.5 (br, s, lH) ° Stage 15 · 2: Use similar to stage 1.4 The method consists of 1.09 g (5.17 mmol) of 3-methyl-benzene-guanidine nitrate and 1.09 g (5.17 mmol) of 3-dimethylamine · 1 ~ (2-chloropyridine > 2-propene-1 -Ketone and 0.23 g (5.68 mmol) of sodium hydroxide to prepare N- [3-methyl-benzene] ice (2-chloro> 4.pyridine) -2-pyrimidinamine; 1H-NMR (DMSO): 2.3 ( s, 3H), 6.8 (d, lH), 7.2 (t, lH), 7.6 (m, 2H), 7.7 (s, lH), 8.1 (m, lH), 8.2 (s, lH), 8.6 (d, lH), 8.7 (d, lH), 9.8 (s, lH) > Example 16: Using a method similar to Example 1, from 168.8 mmol (0.53 mmol) N -[3-Chloro-benzene> 4 < 2-chloropyridine > 2-pyrimidinamine and 113.2 mg (1.06 mmol) of 5-aminopentanol to prepare N- [3-chloro-benzene H- [2- ( 5-Hydroxy-pentyl-amine) bepyridine 1-24 ^ pyridamine; FAB-MS: 384 (NT + H), 298. Example 17: 500 mg (1,4 mmol) of N- [3-ethoxycarbonyl-benzene > 4 · (2-side 4 · radiidine > 2-pyrimidine amine) in 1 ml at 140 ° -Aminopropanol was stirred for 15 hours. After chromatography (silica gel, dichloromethane: methanol = 9: 1), N- [3 · {N- (3-hydroxy-propane > amine-carbonylbenzene benzene H- [2- (3-Hydroxy-propyl-amine)> 4-11 Bipyridine] -2-pyrimidinamine; Melting point: 153-154 °, FAB-MS: 423 (λΓ + Η). This paper size applies to Chinese national standards (CNS) Α4 specification (210X297 mm) -U ---------- 1 ------ 1Τ ------ ^ 1 (Please read the note $ on the back before filling (This page) -56- Printed by A7 B7_, a consumer cooperative of the Central Bureau of the Ministry of Economic Affairs of the People's Republic of China. V. Description of the invention () Example 18: 100 mg (0.26 mmol) of N- [3-methoxycarbonyl at 90 ° -Benzene H- [2K 3-side-propyl-amine M-pyridine] -2-pyrimidinamine and 0.5 ml 1.3-diamine-propane stirred for 24 hours' then diluted with 20 ml ethyl acetate and extracted with 2 × 10 ml sodium chloride solution The organic phase was dried, concentrated and crystallized from dichloromethane / diethyl ether to obtain N- [MN- (3-amine · propane > amine carbonylbenzene] -4- [2- (3-hydroxy-propane · amine ) Pyridine] -2-pyrimidinamine; melting point: 169-170 °, FAB-MS: 422 (NT + Η). Example 19: Using a method similar to that of Example 18, 100 mg (0.26 mmol) of N · [3-methoxycarbonyl-phenylhydrazone- [ 2> (3-Propyl-amine> 4-pyridine] -2-pyrimidinamine and 150 mg (U5 mmol) of histamine (ie 2- (imidazole> 4-yl) · ethyl-amine) Ν- [3 · {2-imidazolyl · ethyl) aminocarbonyl} -benzene] · 4_ [3-hydroxy-propyl · amine > 4 · pyridine] -2-pyrimidinamine; melting point: 181-186 °, FAB -MS: 459 (NT + Η) »Example 20: Using a method similar to Example 1, from 300 mg (0.9 mmol) of N- [3-chloro-6 · methyl-benzene] -K 2-chloropyridine > Preparation of N · [3-chloro-6 · methyl-benzene] + [2- (3-Chloro-propane-amine) · 4- from 2-pyrimidinamine and 5.3 ml (70.65 mmol) of 3-aminopropanol Pyridine] -2-pyrimidinamine; melting point: 117-119 °, FAB-MS: 370 (NT + Η). The starting materials were prepared as follows: Stage 20.1: Using a method similar to stage 1.3, from 10.0 g (60.62 mmol) 5-chloro-2-methyl-amine, 9.45 ml (113 mmol) of concentrated hydrochloric acid and U ---------- pack -------- order ------ Line | (Please read the precautions on the back before filling out this page) This paper size applies to China Furniture Standard (CNS) 8-4 (210 × 297 mm) -57- A7 _B7___ 5. Description of the Invention () 5.94 g (141.2 mmol) 98% cyanamide, after precipitation with 11.3 g (141.2 mmol) ammonium nitrate, 5-Chloro-2-methyl-benzene-guanidine nitrate was obtained; lH-NMR (DMSO): 2.2 (s, 3H), 7.2-7.4 (m, 7H) ° Stage 20.2: Using a method similar to stage 1.4, 1.75 g (7.12 mmol) 3-chloro · 6 · methyl-benzene-guanidine nitrate, 1.5 g (7.12 mmol) of 3 · dimethylamine-M2 · chloro > 4 · piperidine) · 2-propen-1-one And 0.31 g (7.83 mmol) of sodium hydroxide to prepare N- [3-chlorogallylbenzene] ice (2-chloropyridine) -2-pyrimidinamine; 1 !!-NMR (DMSO): 2.2 (s , 3H), .71 (dxd, 1H), 73 (d, 1H), 7.6 (d, lH), 7.8 (< UH), 8.05 (dxtun 1H), 8.15 (s, 1H), 8.6 ㈣ 2H ), 9.2 (s, lH). Example 21: Using a method similar to Example 1, from 300 mg (0.85 mmol) of N- [3,6 · dichloro-benzene] ice (2-chloro-4-pyridine > 2-pyrimidinamine and 5.0 N- [3,6-dichloro-benzene] dong [2- (3-Ca-propylamine than pyridine] -2-pyrimidine amine was prepared from milliliter (66.55 mmol) of 3-amine propanol; melting point: 130-132 ° , FAB-MS: 390 (ivr + H) = The starting materials are prepared in the following way: Printed by the Shell Sample Consumer Cooperative of the Central Samples Bureau of the Ministry of Economic Affairs (please read the note on the back before filling this page) Stage 21.1 : Using a method similar to stage 1.3, from 10.0 g (61.72 mmol) of 2,5-dichloro-aniline, 8.25 ml (98.7 mmol) of concentrated hydrochloric acid and 5.19 g (123.4 mmol) of 98% Cyanamine was precipitated with 9.88 g (123.4 mmol) of ammonium nitrate to obtain 2,5 · dichloro-benzene-guanidine nitrate; 1H-NMR (DMSO): 7.4-7.7 (7㈣7). This paper size applies to Chinese national standards (CNS) Α4 specification (20.1 × 297 mm) • 58- Printed by Aberdeen Consumer Cooperative, Central Bureau of Quasi-Ministry of Interest, and printed by A7 B7 V. Description of the invention () Stage 21.2: Use a method similar to stage 1.4, Made from 1.9 g (7.12 mmol) of nitric acid 3, 6-Dichloro-benzene-guanidine, 1-5 g (7.12 mmol) of 3-dimethylamine-H2-chloro 4-pyridine> 2-propen-1-one and 0.31 g (7.83 mmol) of sodium hydroxide Ν- [3,6 · dichloro-benzene] > 4- (2-chloro4-pyridine >2-pyrimidinamine; W-NMR (DMSO): 7.25 (d X d, 1H), 7.6 (d, 1H), 7.7 (d, 1H), 8.05 (m, 2H), 8.2 (s, 1H), 8_6 1H), 8.7 (Mountain 1H), 9.25 (s, 1H). Example 22: Use similar to the example Method 1, consisting of 300 mg (0.86 mmol) of N- [3-chloroisomethoxy-benzene PK 2-chloro4 · pyridine> 2-pyrimidinamine and 5.1 ml (67.4 mmol) of 3-amine propionate N- [3-chloro-6-methoxy-phenylhydrazone- [2 · (3-hydroxy-propane-aminopyridine] -2-pyrimidinamine); melting point: 131-133 °, FAB-MS: 386 ( NT + H) ° The starting material was prepared in the following way: Stage 22.1: Using a method similar to stage 1.3, from 10.0 g (63,45 mmol) of 5-chloro-2-methoxy-aniline, 8.5 ml ( 101.5 mmol) of concentrated hydrochloric acid and 5.3 g (126.9 mmol) of 98% cyanamide, precipitated with 10.2 g (126.9 mmol) of ammonium nitrate, to obtain 5.chloro-2-methoxy-benzene-guanidine nitrate; W- NMR (DMSO): 3.9 (¾ 3H), 7.2 _ 7.4 (take 7H). Stage 22.2: Using a method similar to that in stage I.4, 1.S7 g (7.12 mmol) of nitric acid 3-chloro · 6 · methoxy-benzene-guanidine, 1.5 g (7.12 mmol) of 3-di Methylamine-1- (2-chlorodongoladine)> * 2-propen-1-one and 0.31 g (7.82 mmol) of sodium hydroxide to prepare N · [3-chloro-6 · methoxy-benzene ] -4- (2-chloro-4-pyridine >2-pyrimidinamine; This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) binding II line (please read the precautions on the back before filling (This page)

-59- 經濟部中央樣準局負工消費合作杜印裝 A7 B7_ _ 五、發明説明（） 'H-NMR (DMSO): 3.9 (s, 3H), 7.1 (d, 1H), 7.7 (d, 1H), 8.1 (d x d, 1H), 8.2 (s, 1H), 8.3 (s, 1H)，8.5 (s, 1H), 8.6 (cUH)，8.75 (<UH>。 實施例23 :利用類似於實施例1之方法，由100毫克 ((U1毫摩爾）N-[3-氯-苯]冰(2-氯》4-吡啶)-2-嘧啶胺及500 毫克（5.63毫摩爾）六氫吡畊，在層析（二氯甲烷：甲醇 =95:5)之後從熔融物中製得义[3_氯_苯丨4-[2·(卜六氫吡 畊 M-吡啶]-2-嘧啶胺；熔點：175 - 1800，FAB^MS: 367 (M++H) 〇 實施例24 :利用類似於實施例1之方法，由100毫克 (0.31毫摩爾）N-[3-氯-苯]>4-( 2-氯吡啶>2-嘧啶胺及1.0 毫升（7.5毫摩爾）4-(2-胺·乙Η馬啉製得N-[3-氯-苯PK2-[2-{4-嗎啉}乙-胺]4-吡啶>2-嘧啶胺；熔點：176-186°，FAB-MS: 411 (M"+H)〇 實施例25 :利用類似於實施例1之方法，由100毫克 (0.32毫摩爾）N-[ 3-氯·苯]冬(2-氯吡啶>2-嘧啶胺及1.0 毫升（7,4毫摩爾）1-( 2-胺-乙)_六氫吡畊製得N-[ 3-氯-苯]>4-{2·[Μ2-胺-乙六氫吡畊-1-基）H-吡啶}-2-嘧啶胺；熔點： 250° > FAB-MS: 410 (IVT+H) ° 實施例26 :利用類似於實施例1之方法，由100毫克 (0.32毫摩爾）N-[ 3-氯-苯PK 2-氯冬吡啶>2·嘧啶胺及1.0 毫升（8.35毫摩爾）2<3-胺-丙胺)-乙醇製得N-[3-氯·苯]冰 (請先閱讀背面之注意Ϋ項再填寫本頁) •裝- 訂 線 本紙張尺度逋用中國國家橾準（CNS ) A4規格（210X297公釐） -60- 經濟部中央梂準局員工消費合作社印製 Α7 Β7 五、發明説明（） { 2-[3-(2-羥-乙-胺）·丙胺H-吡啶}_2_喃啶胺；熔點：143-150°，FAB-MS: 399 (M++H)。 實施例27 :利用類似於實施例1之方法，由1〇〇毫克 (0.315毫摩爾）N-[3-氯-苯Η-(2·氯-4-吡啶)-2-喷啶胺及ι·〇 毫升（9.97毫摩爾）4-胺-嗎啉意外地製得Ν-[3-氯-苯]_4-[2-(4-嗎啉 >4-吡啶]-2-嘧啶胺；熔點·· 163 - 169°，FAB-MS: 268 (Μ++Η) » 實施例28:錠劑（每一顆含20毫克之有效成份，例如實 施例1-27所述之化學式I化合物中之一化合物）係用下 列組成以常用之方式製備： 組成： 有效成份 20毫克 小麥澱粉 60毫克 乳糖 50毫克 矽膠 5毫克 滑石 9毫克 硬脂酸鎂 1毫克 145毫克 製備方法：將有效成份與一部份小麥澱粉、乳糖及矽膠 混合，並將混合物強制通過一篩網。在一水浴中，用5 倍量的水將另一部份小麥澱粉作成一糊，並將粉末混合 物與糊捏合直到形成一稍具塑性之塊體爲止。 本紙張尺度適用中國國家標準（CNS )八4規格（210X297公釐） 83. 3.10,000 (請先聞讀背面之注$項再填寫本頁) 裝· 訂 -61 - A7 B7_ 五、發明説明（） 將塑性塊體壓過一大約3毫米網目大小之篩網並乾 燥，並再將形成之乾顆粒強制通過一篩網。摻合剩餘之 小麥澱粉、滑石及硬脂酸鎂，並將混合物壓擠成錠劑， 每顆重145毫克且製有一斷裂凹痕。 實施例29:膠囊（每顆含10毫克之有效成份，例如實施 例卜27所述之化學式I化合物中之一化合物）係以常用 之方式製備如下： 組成： 有效成份 2500毫克 滑石 200毫克 矽膠 50毫克 製備方法：將有效成份與滑石及矽膠緊密混合，並將混 合物強制通過一 0.5毫米網目大小之篩網，並以11毫克 之份量，裝入適當大小之硬明膠膠囊內。 I 裝 訂rr (請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局貝工消費合作社印製 本紙張尺度適用中國國家標準（CNS ) A4規格（210 X 297公釐） 83. 3. 10,000 -62--59- Duty-installed A7 B7__ Printing of the Central Bureau of Procurement, Ministry of Economic Affairs _ V. Description of Invention () 'H-NMR (DMSO): 3.9 (s, 3H), 7.1 (d, 1H), 7.7 (d , 1H), 8.1 (dxd, 1H), 8.2 (s, 1H), 8.3 (s, 1H), 8.5 (s, 1H), 8.6 (cUH), 8.75 (< UH >. Example 23: Utilize similar In the method of Example 1, 100 mg ((U1 mmol) of N- [3-chloro-benzene] ice (2-chloro >> 4-pyridine) -2-pyrimidinamine and 500 mg (5.63 mmol) of hexahydro Pycnogenol was prepared from the melt after chromatography (dichloromethane: methanol = 95: 5) [3_chloro_benzene 丨 4- [2 · (buhexahydropyridine M-pyridine] -2- Pyrimidinamine; melting point: 175-1800, FAB ^ MS: 367 (M ++ H). Example 24: Using a method similar to Example 1, from 100 mg (0.31 mmol) of N- [3-chloro-benzene ] > 4- (2-chloropyridine) > 2-pyrimidinamine and 1.0 ml (7.5 mmol) of 4- (2-amine · acetoline to obtain N- [3-chloro-benzene PK2- [2- {4-morpholine} ethyl-amine] 4-pyridine >2-pyrimidinamine; melting point: 176-186 °, FAB-MS: 411 (M " + H). Example 25: Use similar to that of Example 1 Method by 100 mg (0.32 mmol) of N- [3-chloro · benzene] dong (2-chloropyridine > 2-pyrimidine Amine and 1.0 ml (7,4 mmol) of 1- (2-amine-ethyl) _hexahydropyridine to obtain N- [3-chloro-benzene] > 4- {2 · [Μ2-amine-ethane-6 Hydropyridine-1-yl) H-pyridine} -2-pyrimidinamine; melting point: 250 ° > FAB-MS: 410 (IVT + H) ° Example 26: Using a method similar to Example 1, starting from 100 Mg (0.32 mmol) of N- [3-chloro-benzenePK 2-chloropyridine > 2 · pyrimidinamine and 1.0 ml (8.35 mmol) of 2 < 3-amine-propylamine) -ethanol to obtain N- [3 -Chlorine · benzene] Ice (please read the note on the back before filling this page) • Binding-Paper size of the booklet, using China National Standard (CNS) A4 (210X297 mm) -60- Central Ministry of Economic Affairs Printed by the Consumers' Cooperative of the quasi-station Bureau A7 B7 V. Description of the invention () {2- [3- (2-hydroxy-ethyl-amine) · propylamine H-pyridine} _2_pyrimidineamine; melting point: 143-150 °, FAB-MS: 399 (M ++ H). Example 27: Using a method similar to Example 1, from 100 mg (0.315 mmol) of N- [3-chloro-phenylhydrazone- (2.chloro- 4-pyridine) -2-pyrimidinamine and 1 · mL (9.97 mmol) 4-amine-morpholine unexpectedly produced N- [3-chloro-benzene] _4- [2- (4-morpholine) > 4-pyridine] -2-pyrimidinamine; melting point · 163-169 °, FAB-MS: 268 (Μ ++ Η) »Example 28: Lozenges (each containing 20 mg of active ingredient, such as one of the compounds of formula I described in Examples 1-27) are used The following composition is prepared in the usual way: Composition: Active ingredient 20 mg wheat starch 60 mg lactose 50 mg silicone 5 mg talc 9 mg magnesium stearate 1 mg 145 mg Preparation method: The active ingredient is mixed with a portion of wheat starch, lactose and Silicone is mixed and the mixture is forced through a sieve. In a water bath, make another part of wheat starch into a paste with 5 times the amount of water, and knead the powder mixture with the paste until a slightly plastic mass is formed. The size of this paper applies to China National Standard (CNS) 8-4 specifications (210X297 mm) 83. 3.10,000 (please read the note on the back before filling in this page) Binding-Binding -61-A7 B7_ V. Description of the invention () Press the plastic block through a sieve with a mesh size of about 3 mm and dry, and then force the formed dry particles through a sieve. The remaining wheat starch, talc and magnesium stearate were blended, and the mixture was extruded into tablets, each weighing 145 mg and made with a break dent. Example 29: Capsules (each containing 10 mg of an active ingredient, such as one of the compounds of the formula I described in Example 27) were prepared in a conventional manner as follows: Composition: Active ingredient 2500 mg talc 200 mg silicone 50 Preparation method of milligrams: The active ingredients are mixed closely with talc and silicone, and the mixture is forced through a 0.5 mm mesh sieve and filled into hard gelatin capsules of appropriate size in an amount of 11 milligrams. I Binding rr (Please read the notes on the back before filling out this page) Printed by the Central Standards Bureau of the Ministry of Economic Affairs, Shellfish Consumer Cooperative, this paper is printed in accordance with China National Standard (CNS) A4 (210 X 297 mm) 83. 3. 10,000 -62-

Claims (1)

六、申ΊΤίίΙ面 輕濟_中夬榡準局員工消費合作衽印製 1. 一種式(I)之Ν-苯-2-嘧啶胺衍生物或其鹽Sixth, the application of light and light _ _ printed by the China Consumers' Association Bureau of consumer cooperation 1. A N-benzene-2-pyrimidinamine derivative of the formula (I) or its salt 式(I)中 R〇爲氫、鹵素、CrC4院氧基或Ci_C4院基， Ri爲· a) N-(胺-CrC4烷)-胺甲醯基’ b) N-(羥-CrC4烷)-胺甲醯基’ c) 未被取代之或被胺-CrC4^基取代之六氫吡明:基’ d) 嗎啉基，或 e) 被嗎啉基、羥-CVC4烷胺基、咪唑基、胺基、羧基或 羥基取代之CrC7垸胺基，及 &爲(：1-(：4院基、氯、三氟甲基' 羧基或下列式中之一 自由基： -C02R3 或-C(=0)-NH-(CH2VR4a (式中R3爲CrC3烷基，R/爲羥基、胺基或咪唑基及η 爲2或3)。 2-如申請專利範圍第1項式(I)之化合物或其醫藥上可接 受之鹽，式(I)中 R〇爲氬， Ri爲： a)N-(胺-〇(：4烷>胺甲醯基， 本紙張尺度適用中國國家梯準（CNS ) Λ4規格（210X297公釐） (請先閱讀背面之注意事項再填寫本頁) 、-* - -63- 經濟部中央標準局員工消費合作社印裝 Ss8 C8 D8 丨 1 *........... 1 ........................... _丨__ — A、申請專利範圍 b) N-(羥-〇(：4烷 >胺甲醯基，或 c) 被咪唑基、胺基、羧基或羥基取代之CrC7院胺基， 及 爲氯或三氟甲基。 3. 如申請專利範圍第1項式(I)之化合物或其醫藥上可接 受之鹽，式(I)中 爲氫， R丨爲N-( ©胺-C2-C3烷>·胺甲醯基' N-( 羥-C2-C3烷 >胺甲 醯基、2-羥-丙胺基或直鏈CVC3烷胺基（其在位置被 咪唑基、胺基、羧基或羥基取代），及 R2爲氯或三氟甲基。 4. 如申請專利範圍第1項式①之化合物或其醫藥上可接 受之鹽，式(I)中 Ro爲氫、氯、甲基或甲氧基， R丨爲Ν-( ω·胺-QrC3烷 >胺甲醯基、N-( 〇>羥-C2-C3烷)·胺甲 醯基、2_羥-丙胺基或直鏈C2_C3烷胺基（其在ω_位置被 4-嗎啉基、〇>經-乙胺基、1Η-咪唑-1-基、1Η-咪唑斗基、 胺基、羧基或羥基取代），及 R2爲氯、三氟甲基、羧基、式-C02R3之自由基（式中 R3爲甲基）或式-C(=0)-NH-(CH2VR4a之自由基（式中η 爲2或3及R/爲羥基、胺基或1114沐哗冰基）^ 本紙张尺度適用中國國家標準（CNS > Λ4現格（210Χ297公婕） (請先閱讀背面之注意事項再填寫本莧) 訂 -64- 經濟部中央標準局員工消費合作社印製 SVoSGo c88 D8 六、申請專利範圍 5. 如申請專利範圍第1項之化合物，其爲^(3_氯_苯>4_[2_ (3·經-丙-胺批啶]_2-嘧啶胺或其醫藥上可接受之鹽。 6. 如申請專利範圍第1項式⑴之化合物或其醫藥上可接 受之鹽，其係選自 N-(3-三氟甲-苯>4-[2-(3-羥-丙-胺M-吡啶]-2-嘧啶胺， N<3-氯-苯)-4~[2-(2-胺-乙-胺)冬吡啶]-2-嘧啶胺， Ν·(3-三氟甲-苯>4-[2-(2-胺-乙-胺>4-吡啶]-2-嘧啶胺， Ν-[3-氯-苯]斗{2-[ Ν-( 2-胺-乙>胺羰Η-吡啶卜2-嘧啶胺， Ν-[3-氯-苯]·4-{2-[Ν-(2-羥-乙)胺羰Η-吡啶}·2-嘧啶胺， Ν-[3_氯-苯]-4-{2.-[Ν-(3·經-丙)-胺幾]·4-ϋ比陡} -2·喃淀胺， Ν-[3·氯-苯]-4-{2-[Ν-(3-胺-丙-1-基>胺羰]-4-吡啶}-2-嘧啶胺， Ν-[3-氯-苯]冰[2-(2-羥-乙-胺)·4-吡啶]-2-嘧啶胺， 羥-丙-胺VW比啶]-2-嘧啶胺， N-P-审氧^羰-苯]冰[2-(3-羥-丙-胺>4-吡啶]-2-嘧啶胺， N-[3-氯-苯H-[2-(4-羥· 丁-胺)斗吡啶]-2確啶胺， N-[3-氯-苯(咪唑基)_乙-胺>4-吡啶}-2痛啶胺， * 一 N-[3-甲-苯H-[2-(3-羥-丙-胺M-吡啶]-2-嘧啶胺， N-[3-fe苯]-4-[2-(5-羥-戊·胺)斗吡啶]-2-嘧啶胺， N-{3-[N-(3-羥-丙)胺-羰]-苯}·4-[2-(3-羥-丙-胺M-吡啶]-2-嘧啶 胺， Ν-{3-[Ν-(3-胺·丙)胺羰]-苯}·4-[2·(3-羥-丙-胺>4-吡啶]-2-嘧啶 胺， Ν-{3-[Ν-(2-咪唑斗基-乙)-胺羰]-苯Η-[2-(3-羥-丙-胺Μ-吡啶]-2- 嘧啶胺， 本紙張尺度適用中國國家標準（CNS ) Λ4規格（210Χ297公釐） (請先閲讀背面之注意事項再填寫本頁) 訂 -65- 队％3 s D8六、申請專利範圍 N-[3-氯-6-甲-苯>4-[2-(3-羥-丙-胺)-4-吡啶]-2-嘧啶胺， N-[3,6-二氯-苯]-4-[2-(3-經-丙-胺)-4-D比啶]-2-嚼啶胺， N-[3·氯-6·甲氧-本]~4-[2_(3-經-丙-胺)-4-11 比陡]·2·嚼陡胺， Ν-[3-氯-苯]·4-[2-(1-六氫吡畊>4-D比陡]-2-嘧啶胺， N-[3-氯-苯H-{2-[2-(4-嗎啉)乙-胺H-吡啶}-2-嘧啶胺， N-[3-氯-苯]-4-{2-[4-(2-胺-乙六氫吡哄-1-基]-4-吡啶}-2-嘧啶 胺， N-[3_氯-本]-4-{2·[3-(2·經-乙-胺)丙胺]~4-卩比陡} -2-喷淀胺及 Ν-[3-氯-苯]斗[2-(4-嗎啉>4-吡陡]-2-嘧啶胺.，及選自其醫藥 上可接受之鹽。 7. —種治療溫血動物（包括人類）腫瘤之醫藥組成物， 該組成物含一有效對抗腫瘤劑量之申請專利範圍第1 至6項中任一項式(I)之化合物或該化合物（至少含一 個成鹽基）之醫藥上可接受之鹽連同一醫藥載體。 (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) Λ4规格（2丨0Χ297公席） -66 -In formula (I), R0 is hydrogen, halogen, CrC4oxy or Ci_C4, and Ri is: a) N- (amine-CrC4alkane) -carbamoyl 'b) N- (hydroxy-CrC4alkane) -Aminoformamyl 'c) hexahydropyrimidine: unsubstituted or substituted with amine-CrC4 ^ ::' morpholinyl, or e) morpholinyl, hydroxy-CVC4 alkylamino, imidazole Group, amine group, carboxyl group or hydroxy-substituted CrC7fluorenylamino group, and & is (: 1-(: 4 alkyl group, chlorine, trifluoromethyl 'carboxyl group or one of the following formulas: -C02R3 or- C (= 0) -NH- (CH2VR4a (where R3 is a CrC3 alkyl group, R / is a hydroxyl group, an amine group, or an imidazolyl group, and η is 2 or 3). 2- If the scope of the patent application is the first formula (I) Compound or a pharmaceutically acceptable salt thereof, in the formula (I), Ro is argon, and Ri is: a) N- (amine-〇 (: 4 alkane) > carbamoyl group, this paper standard applies to the Chinese national ladder Standard (CNS) Λ4 specification (210X297 mm) (Please read the precautions on the back before filling out this page),-*--63- Printed Ss8 C8 D8 丨 1 * ... ........ 1 ................. _ 丨 __ — A. Patent application scope b) N- (hydroxyl- (: 4 alkane > carbamoyl group, or c) CrC7 amine group substituted with imidazolyl group, amine group, carboxyl group or hydroxyl group, and is chloro or trifluoromethyl group. The compound of (I) or a pharmaceutically acceptable salt thereof, wherein in formula (I) is hydrogen, and R 丨 is N- (© amine-C2-C3 alkane) > amino formamyl 'N- (hydroxy-C2- C3 alkyl> carbamoyl, 2-hydroxy-propylamino, or linear CVC3 alkylamino (which is substituted in position with an imidazolyl, amino, carboxyl, or hydroxyl group), and R2 is chloro or trifluoromethyl. 4 . For example, the compound of formula (1) or a pharmaceutically acceptable salt thereof in the scope of patent application, in formula (I), Ro is hydrogen, chlorine, methyl or methoxy, and R 丨 is N- (ω · amine-QrC3 Alkyl > carbamoyl, N- (〇 > hydroxy-C2-C3 alkane), carbamoyl, 2-hydroxy-propylamino or straight-chain C2_C3 alkylamino (is it 4- at the ω_ position? (Phenyl, 0 > substituted with -ethylamino, 1'-imidazol-1-yl, 1'-imidazolide, amino, carboxyl or hydroxy), and R2 is chlorine, trifluoromethyl, carboxyl, formula -C02R3 Radical (where R3 is methyl) or -C (= 0) -NH- (CH2VR4a radical (where η is 2 or 3 and R / Hydroxyl, amine or 1114 Mubo ice-based) ^ This paper size is applicable to Chinese national standards (CNS > Λ4 current grid (210 × 297)) (Please read the notes on the back before filling in this card) Order-64- Ministry of Economic Affairs SVoSGo c88 D8 printed by the Consumer Standards Cooperative of the Central Bureau of Standards 6. Scope of patent application 5. For the compound of scope 1 of the patent application, it is ^ (3_chloro_benzene > 4_ [2_ (3 · jing-propyl-amine Pyrimidine] _2-pyrimidinamine or a pharmaceutically acceptable salt thereof. 6. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to item 1 of the scope of the patent application, which is selected from N- (3-trifluoromethyl-benzene > 4- [2- (3-hydroxy-propane- Amine M-pyridine] -2-pyrimidinamine, N < 3-chloro-benzene) -4 ~ [2- (2-amine-ethyl-amine) winter pyridine] -2-pyrimidinamine, Ν · (3-trifluoro Methylbenzene> 4- [2- (2-amine-ethyl-amine)> 4-pyridine] -2-pyrimidinamine, N- [3-chloro-benzene] pyridine {2- [Ν- (2-amine -B > Aminocarbonylpyridine-pyridine-2-pyrimidineamine, N- [3-chloro-benzene] · 4- {2- [N- (2-hydroxy-ethyl) aminocarbonylpyridine-pyridine} · 2-pyrimidine Amine, Ν- [3_chloro-benzene] -4- {2 .- [Ν- (3 · Jing-Propyl) -amine chloride] · 4-Hydroxypyridine} -2 · Nanamine, Ν- [3 · Chloro-benzene] -4- {2- [N- (3-amine-prop-1-yl > aminecarbonyl] -4-pyridine} -2-pyrimidinamine, Ν- [3-chloro-benzene] ice [2- (2-Hydroxy-ethyl-amine) · 4-pyridine] -2-pyrimidinamine, hydroxy-propane-amine VW pyridine] -2-pyrimidinamine, NP-triol ^ carbonyl-benzene] ice [2 -(3-hydroxy-propane-amine > 4-pyridine] -2-pyrimidinamine, N- [3-chloro-benzeneH- [2- (4-hydroxy · but-amine) pyridine] -2 veridine Amine, N- [3-chloro-benzene (imidazolyl) _ethyl-amine> 4-pyridine} -2 amidinamine, * N- [3-methyl-benzene H- [2- (3-hydroxy- Propyl-amine M-pyridine] -2-pyrimidinamine, N- [3-febenzene] -4- [2- (5-hydroxy-pentamidine) pyridine] -2- Pyridinamine, N- {3- [N- (3-hydroxy-propyl) amine-carbonyl] -benzene} · 4- [2- (3-hydroxy-propyl-amine M-pyridine] -2-pyrimidinamine, Ν -{3- [Ν- (3-amine · propyl) aminocarbonyl] -benzene} · 4- [2 · (3-hydroxy-propane-amine > 4-pyridine] -2-pyrimidineamine, Ν- {3 -[N- (2-imidazolyl-ethyl) -aminocarbonyl] -phenylhydrazone- [2- (3-hydroxy-propane-amine M-pyridine] -2-pyrimidinamine, this paper size applies to Chinese national standards ( CNS) Λ4 specification (210 × 297 mm) (Please read the precautions on the back before filling this page) Order -65- Team% 3 s D8 VI. Application scope of patent N- [3-Chloro-6-methyl-benzene > 4- [2- (3-hydroxy-propyl-amine) -4-pyridine] -2-pyrimidinamine, N- [3,6-dichloro-benzene] -4- [2- (3-mer-propane- Amine) -4-D is higher than pyridine] -2-pyridinamine, N- [3 · chloro-6 · methoxy-benzyl] ~ 4- [2_ (3-mer-propyl-amine) -4-11 ] · 2 · Chrysosamine, Ν- [3-chloro-benzene] · 4- [2- (1-Hydroxypyrine > 4-D specific steep] -2-pyrimidinamine, N- [3-chloro -Benzene H- {2- [2- (4-morpholine) ethyl-amine H-pyridine} -2-pyrimidinamine, N- [3-chloro-benzene] -4- {2- [4- (2- Amine-ethanehexahydropyridin-1-yl] -4-pyridine} -2-pyrimidinamine, N- [3-chloro-benzyl] -4- {2 · [3- (2 · jing-ethyl-amine) Propylamine] ~ 4-pyridine ratio} -2-sprayamine and N- [3-chloro-benzene] pyridine [2- (4-morpholine > 4-pyridoxine) -2-pyrimidineamine. And which is selected from a pharmaceutically acceptable salt thereof. 7. A medicinal composition for treating tumors in warm-blooded animals (including humans), the composition containing a compound of formula (I) or the compound (1) in any one of the claims 1 to 6 of the patent application range effective against tumors A pharmaceutically acceptable salt containing at least one salt-forming group) and the same pharmaceutical carrier. (Please read the precautions on the back before filling out this page) The paper size applies to the Chinese National Standard (CNS) Λ4 specification (2 丨 0 × 297 seats) -66-
TW83108147A 1993-10-01 1994-09-05 Pharmacologically active N-phenyl-4-(4-pyridyl)-2-pyrimidineamine derivatives TW378208B (en)

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