TWI280240B - Substituted 8-arylquinoline phosphodiesterase-4 inhibitors - Google Patents

Substituted 8-arylquinoline phosphodiesterase-4 inhibitors Download PDF

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TWI280240B
TWI280240B TW089127506A TW89127506A TWI280240B TW I280240 B TWI280240 B TW I280240B TW 089127506 A TW089127506 A TW 089127506A TW 89127506 A TW89127506 A TW 89127506A TW I280240 B TWI280240 B TW I280240B
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alkyl
phenyl
cns
national standard
methyl
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Denis Deschenes
Daniel Dube
Michel Gallant
Yves Girard
Patrick Lacombe
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Merck Frosst Canada Ltd
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Abstract

Novel substituted 8-arylquinolines, wherein the aryl group at the 8-position contains a substituent substituted-alkenyl group, are PDE4 inhibitors.

Description

1280240 經濟部智慧財產局員工消費合作社印製 A7 五、發明說明（1 ) 發明背t 發明範園 本發明係針對經取代8-芳基喳啉化合物。特定言之，本 發明係針對經取代8-芳基喳啉，其係爲磷酸雙酯酶-4抑制 ^ 其中在心位置之芳基含有取代基取代之烯基。 相關背景 激素爲多方面影嚮細胞活性之化合物。在許多方面，激 素係充作信使，以觸發特定細胞回應與活性。但是，藉由 敦素所產生之泎多作用，不會藉由僅只是該激素之單一作 用所造成。而是，該激素首先結合至受體，藉以觸發第二 種化合物釋出’其繼續影嚮該細胞之活性。在此情節中， 該激素係被稱爲第一信使，而第二種化合物係被稱爲第二 仏使。％腺：y:單磷酸鹽（腺苷3，，5，_環狀單磷酸鹽，，，cAMP„或 環狀AMP )係被稱爲激素之第二信使，包括腎上腺素、胰 增血糖素、降血鈣素、促腎上腺皮質激素、向脂素、促黃 骨豆生成激素、正腎上腺素、甲狀旁腺激素、甲狀腺刺激激 素及後葉加壓素。因此，CAMP會媒介對激素之細胞回應。 裱AMP亦會媒介對各種神經遞質之細胞回應。 鱗酸雙醋酶（”PDE”）爲一種酶族群，其會使3，，5,環狀核甞酸 生物代谢成5’核：y：單磷酸鹽，於是使cAMp第二信使之活性 、、.；止 種特定嶙酸雙酯酶，磷酸雙酯酶-4 (，，PDE4，，，亦稱 爲PDE IV )，其係爲南親和力、專一性、第iv型pde ’已產生作爲發展新穎抗氣喘與消炎化合物可能標的之重 要性已知PDE4係以至少四種同功酶存在，其每一種均被 -4 - _ 从托口电垴田由J w煙進A4振格-—--- (請先閱讀背面之注意事項再填寫本頁) 裝 訂： 1280240 A7 B7 五、發明說明（2 ) (請先閱讀背面之注音？事項再填寫本頁) 不同基因編碼。此四種已知PDE4基因產物之每一種，咸認 在過敏性及/或炎性回應中，係扮演不同角色。因此，咸 信PDE4，特別是會產生有害回應之專一 PDE4異構重組物， 將其抑制可有利地影嚮過敏反應與發炎病徵。一般期望提 供會抑制PDE4活性之新穎化合物與組合物。 關於使用PDE4抑制劑之一項主要顧慮，係爲嘔吐之副作 用，其已被發現於數種候選化合物中，如在C. Bumouf等人 r’Bumouf 丨)，Ann· Rep. In Med· Chem” 33 ·· 91-109 (1998)中所述者。 B. Hughes 等人，Br· J· Pharmacol·，1^8 : 1183-1191 (1996) ; M. J· Perry 等 人，Cell Biochem· Biophys” 29^ : 113-132 (1998) ; S· B· Christensen 等人 ，J. Med· Chem·，丑：821-835 (1998);及 Bumouf 係描述因各種化合 物所顯示不期望副作用之嚴重性之廣泛變型。如在 M. D· Houslay 等人，Adv· In Pharmacol” 44_ : 225-342 (1998)與 D· Spina 等人，Adv· In Pharmacol·，赶：33-89 (1998)中所述者，對於治療用 PDE4抑制劑之研究，有很大重要性。 國際專利公告WO 9422852描述喳啉作爲PDE4抑制劑。 A. H. Cook 等人，J. Chem· Soc·，413-417 (1943)係描述 r-吡啶基喹 經濟部智慧財產局員工消費合作社印製 琳。其他4琳化合物係描述於Kei Manabe等人，J. Org. Chem·， 58(24) ·· 6692-6700 (1993) ; Kei Manabe 等人，J. Am. Chem. Soc·，115(12) :5324-5325 (1993);及 Kei Manabe 等人，J· Am. Chem. Soc·，114(17): 6940-6941 (1992)中。 包含環系統之化合物，係被不同研究人員描述爲對多種 療法與利用性有效。例如，國際專利公告WO 98/25883係描 述酮基苯甲驢胺類作爲calpain抑制劑，歐洲專利公告 -5- 本紙張尺度適用中國國家標準（CNS)A4規格（21G X 297公爱) 1280240 經濟部智慧財產局員工消費合作社印製 A7 五、發明說明（3 ) EP 811610 與美國專利 5,679,712、5,693,672 及 5,747,541 描述經取 代之苯甲醯基胍鈉通道阻斷劑，美國專利5,736,297描述可作 爲光敏性組合物使用之環系統。 美國專利 5,491，147、5,608,070、5,622,977、5,739，144、5,776,958 、5,780,477、5,786,354、5,798,373、5,849,770、5,859,034、 5,8ό6,593、5,891，896，及國際專利公告 w〇 95/35283，描述 PDE4抑制劑，其係爲三取代之芳基或雜芳基苯基衍生物。 美國專利5,580,888描述PDE4抑制劑，其係爲苯乙烯基衍生物 。美國專利5,550，137描述PDE4抑制劑，其係爲苯基胺基羰基 衍生物。美國專利5,340,827描述PDE4抑制劑，其係爲苯基羧 醯胺化合物。美國專利5,780,478描述PDE4抑制劑，其係爲四 取代之苯基衍生物。國際專利公告w〇 %/〇〇215描述經取代 之肋衍生物，其可作爲PDE4抑制劑使用。美國專利5,633,257 描述PDE4抑制劑，其係爲環（烷基與烯基）苯基_晞基（芳基 與雜芳基）化合物。 但疋’仍然需要新穎化合物與組合物，於治療上抑制 PDE4 ’只有最少之副作用。 發明摘诚 本發明係針對新穎經取代8-芳基喹啉，其係爲PDE4抑制 劑’其中在8-位置之芳基係被經取代之烯基取代。本發明 亦提供一種醫藥組合物，其包含有效量之新穎經取代8-芳 基4淋’及藥學上可接受之載劑。本發明進一步提供一種 在甫乳動物中治療以下病症之方法，例如氣喘、慢性枝氣 官炎、慢性阻塞肺病（COPD)、嗜伊紅肉芽瘤、牛皮癖，及 -6 - 姆尺度適用中國而標準格⑵〇 x 297 — (請先閱讀背面之注意事項再填寫本頁) 裝------ 訂·1·-------#_ 12802401280240 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed A7 V. INSTRUCTIONS (1) Inventions The invention is directed to substituted 8-arylporphyrin compounds. In particular, the present invention is directed to a substituted 8-arylporphyrin which is a phosphodiesterase-4 inhibitor wherein the aryl group at the heart position contains a substituent-substituted alkenyl group. Related Background Hormones are compounds that affect cell activity in many ways. In many ways, the hormone acts as a messenger to trigger specific cellular responses and activities. However, the many effects produced by Duncan are not caused by the mere use of the hormone alone. Rather, the hormone first binds to the receptor, thereby triggering the release of the second compound, which continues to affect the activity of the cell. In this episode, the hormone is referred to as the first messenger and the second compound is referred to as the second messenger. % gland: y: monophosphate (adenosine 3,5,_cyclic monophosphate, cAMP or cyclic AMP) is called the second messenger of hormones, including adrenaline, glucagon Calcitonin, adrenocorticotropic hormone, lipotropin, hormonal-producing hormone, norepinephrine, parathyroid hormone, thyroid stimulating hormone, and vasopressin. Therefore, CAMP mediates cells of hormones. In response, 裱AMP also mediates cellular responses to various neurotransmitters. Phytate diacetate ("PDE") is an enzyme group that metabolizes 3,5, cyclic nucleosides to 5' nucleus. :y: monophosphate, thus making the activity of cAMp second messenger, stopping the specific citrate diesterase, phosphodiesterase-4 (,, PDE4, also known as PDE IV) For the affinity of the South, the specificity, the iv type pde 'has been produced as a possible marker for the development of novel anti-asthmatic and anti-inflammatory compounds. The PDE4 line is known to exist in at least four isozymes, each of which is -4 - _ from托口电垴田 by J w 烟 into A4 振格----- (Please read the notes on the back and then fill out this Binding: 1280240 A7 B7 V. Invention description (2) (Please read the phonetic transcription on the back side and then fill out this page) Different gene codes. Each of these four known PDE4 gene products is known to be allergic and/or Or the inflammatory response plays a different role. Therefore, PDE4, especially the specific PDE4 isoforms that produce harmful responses, can effectively inhibit allergic reactions and inflammatory symptoms. It is generally expected to provide inhibition. Novel compounds and compositions of PDE4 activity. A major concern with the use of PDE4 inhibitors is the side effect of vomiting, which has been found in several candidate compounds, as in C. Bumouf et al. r'Bumouf(R), Ann·Rep. In Med·Chem” 33 ·· 91-109 (1998). B. Hughes et al., Br J. Pharmacol, 1^8: 1183-1191 (1996); M. J. Perry et al., Cell Biochem Biophys" 29^: 113-132 (1998); S·B · Christensen et al, J. Med Chem, ugly: 821-835 (1998); and Bumouf describe a wide variety of the severity of undesirable side effects exhibited by various compounds, as in M. D. Houslay et al. Adv· In Pharmacol” 44_ : 225-342 (1998) and D. Spina et al., Adv. In Pharmacol., ed.: 33-89 (1998), for the study of therapeutic PDE4 inhibitors, Great importance. International Patent Publication WO 9422852 describes porphyrins as PDE4 inhibitors. A. H. Cook et al., J. Chem. Soc., 413-417 (1943) describes r-pyridylquine Printed by the Ministry of Economic Intelligence's Intellectual Property Office employee consumption cooperative. Other 4 Lin compounds are described in Kei Manabe et al., J. Org. Chem., 58(24) · 6692-6700 (1993); Kei Manabe et al., J. Am. Chem. Soc., 115(12) : 5324-5325 (1993); and Kei Manabe et al., J. Am. Chem. Soc., 114(17): 6940-6941 (1992). Compounds containing a ring system are described by various researchers as being effective for a variety of therapies and uses. For example, International Patent Publication WO 98/25883 describes ketobenzamide as a calpain inhibitor, European Patent Publication-5- This paper scale applies to China National Standard (CNS) A4 specification (21G X 297 public) 1280240 Economy Ministry of Intellectual Property, Employees, Consumer Cooperatives, Printed A7 V. Illustrated (3) EP 811610 and U.S. Patent Nos. 5,679,712, 5,693,672 and 5,747,541, the disclosure of which is incorporated herein by reference to U.S. Pat. The ring system used in the composition. PDE4 inhibitors are described in U.S. Patents 5,491,147, 5,608,070, 5,622,977, 5,739,144, 5,776,958, 5,780,477, 5,786,354, 5,798,373, 5,849,770, 5,859,034, 5,8,6,593, 5,891,896, and International Patent Publication No. 95/35283 It is a trisubstituted aryl or heteroaryl phenyl derivative. U.S. Patent No. 5,580,888 describes PDE4 inhibitors which are styryl derivatives. U.S. Patent 5,550,137 describes PDE4 inhibitors which are phenylaminocarbonyl derivatives. U.S. Patent 5,340,827 describes PDE4 inhibitors which are phenyl carboxy guanamine compounds. U.S. Patent No. 5,780,478 describes PDE4 inhibitors which are tetrasubstituted phenyl derivatives. International Patent Publication WO 〇 %/〇〇 215 describes substituted rib derivatives which can be used as PDE4 inhibitors. U.S. Patent 5,633,257 describes PDE4 inhibitors which are ring (alkyl and alkenyl) phenyl-fluorenyl (aryl and heteroaryl) compounds. However, there is still a need for novel compounds and compositions that therapeutically inhibit PDE4' with minimal side effects. SUMMARY OF THE INVENTION The present invention is directed to a novel substituted 8-arylquinoline which is a PDE4 inhibitor wherein the aryl group at the 8-position is substituted with a substituted alkenyl group. The invention also provides a pharmaceutical composition comprising an effective amount of a novel substituted 8-aryl 4' and a pharmaceutically acceptable carrier. The present invention further provides a method for treating the following conditions in a suckling animal, such as asthma, chronic gastroenteritis, chronic obstructive pulmonary disease (COPD), eosinophilic granuloma, psoriasis, and -6-mm scale for China Standard grid (2)〇x 297 — (Please read the notes on the back and fill out this page) 装 订 订·1·-------#_ 1280240

五、發明說明（4 ) (請先閱讀背面之注意事項再填寫本頁) /、他良性或惡性增生性皮膚病，内毒素休克（及有關聯之症 狀，譬如在馬中之板層炎與急性腹痛.）、敗血性休克、潰瘍 性結腸炎、克隆氏病、心肌與腦部之再灌注傷害、炎性關 即炎、骨質疏鬆症、慢性絲球體性腎炎、異位性皮炎、蓴 麻療、成人呼吸困難徵候簇、幼兒呼吸困難徵候簇、在動 物中之慢性阻塞肺病、尿崩症、過敏性鼻炎、過敏性結合 膜炎、春季結合膜炎、動脈再狹窄、動脈粥瘤硬化、神經 性發炎、疼痛、咳嗽、風濕性關節炎、關節黏連脊椎炎、 移植排斥與移植物對宿主疾病、胃酸過度分泌，細菌、眞 菌或病毒所引致之敗血病或敗血性休克、發炎及細胞活素 所媒介慢性組織變性，骨關節炎、癌症、惡病質、肌肉消 耗、抑鬱、記憶力減弱、單極性抑鬱、具有發炎成份之急 性與慢性神經變性病症、巴金生氏病、阿耳滋海默氏疾病 、脊髓外傷、頭部傷害、多發性硬化、腫瘤生長及正常組 織之癌侵入，其方式是投予有效量之新穎經取代8-芳基喹 琳’或會在活體内形成該新穎經取代8_芳基喹啉之先質化 合物。 mm簡述 經濟部智慧財產局員工消費合作社印製 圖1爲本發明化合物一般結構之化學示意圖。 圖 2 爲 6·[1-曱基·1-(甲磺醯基）乙.基]_8·[3-[(Ε)-2-[3-甲基-1，2,4 二唆-5-基]-2-[4-(甲磺醯基）苯基]乙晞基]苯基]喳啉苯磺酸鹽形 式Α多晶型物之X-射線粉末繞射之計數對〇 $之圖表。 圖3爲6-[1-甲基小(甲磺醯基）乙基]-8-[3-[(E)-2-[3-甲基-1，2,4』号 二吐-5-基]-2-[4-(甲續醯基）苯基]乙晞基]苯基]喳琳苯續酸鹽形 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 1280240 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明（5 ) 式B多晶型物之X-射線粉末繞射之計數對〇 ^之圖表。 圖4爲6-〇甲基-1-(甲磺醯基）乙基]_8_[3_[(Ε)_2_ρ·甲基]，2,4_气 二唆-5-基]-2-[4-(甲續醯基）笨基]乙烯基]苯基]喳啉苯磺酸鹽之 形式Α多晶型物（底部軌跡）與形式β (上方軌跡）之χ-射線粉 末繞射之比較。 圖5爲6-[1-曱基·1·(甲磺醯基）乙基]冬[3_[⑹_2_[3_甲基·U4^号 一唑-5-基]-2-[4-(甲磺酿基）苯基]乙烯基]苯基]喳啉苯磺酸鹽形 式Α多晶型物之X射線粉末繞射之區別特徵吸收峰之圖表。 圖6爲6-[1-甲基-1-(甲績醯基）乙基]各[3_[(ε)_2·[3_甲基—up号 一唑-5-基]-2-[4-(甲磺醯基）苯基]乙烯基]苯基]。奎啉苯磺酸鹽形 式B多晶型物之X射線粉末繞射之區別特徵吸收峰之圖表。 發明詳述 本發明化合物係以式（I):V. Description of invention (4) (Please read the precautions on the back and fill out this page) /, his benign or malignant proliferative skin disease, endotoxin shock (and related symptoms, such as lamellar inflammation in horses) Acute abdominal pain.), septic shock, ulcerative colitis, Crohn's disease, myocardial and brain reperfusion injury, inflammatory inflammatory inflammation, osteoporosis, chronic spheroid nephritis, atopic dermatitis, castor Treatment, adult dyspnea syndrome, dyspnea syndrome in children, chronic obstructive pulmonary disease in animals, diabetes insipidus, allergic rhinitis, allergic conjunctivitis, spring-binding membranous inflammation, arterial restenosis, atherosclerosis, Neuroinflammation, pain, cough, rheumatoid arthritis, joint adhesion spondylitis, transplant rejection and graft-to-host disease, hypersecretion of gastric acid, septicemia or septic shock, inflammation caused by bacteria, sputum or virus And cytokines are chronic tissue degeneration, osteoarthritis, cancer, cachexia, muscle wasting, depression, memory loss, unipolar depression, acute inflammatory components Chronic neurodegenerative disorders, Parkinson's disease, Alzheimer's disease, spinal cord trauma, head injury, multiple sclerosis, tumor growth, and cancer invasion of normal tissues by administering an effective amount of novel replacement 8 -Arylquinoline' may form a precursor compound of the novel substituted 8_arylquinoline in vivo. Brief description of the Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing Figure 1 is a chemical schematic diagram of the general structure of the compound of the present invention. Figure 2 is 6·[1-indolyl·1-(methylsulfonyl)ethyl]yl]_8·[3-[(Ε)-2-[3-methyl-1,2,4 唆-5 -N-[4-(methylsulfonyl)phenyl]ethinyl]phenyl]porphyrin benzenesulfonate form X-ray powder diffraction of ruthenium polymorphs chart. Figure 3 is 6-[1-methyl small (methylsulfonyl) ethyl]-8-[3-[(E)-2-[3-methyl-1,2,4] No. -Based on the basis of the Chinese National Standard (CNS) A4 specification (210 X 297 mm) for the paper size of -2-[4-(methyl phenyl) phenyl] ethenyl] phenyl] phthalocyanine 1280240 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (5) The graph of the X-ray powder diffraction of the polymorphic form B of the formula B. Figure 4 is 6-fluorenylmethyl-1-(methylsulfonyl)ethyl]_8_[3_[(Ε)_2_ρ·methyl], 2,4-azepine-5-yl]-2-[4 - (A) basement] vinyl] phenyl] porphyrin benzene sulfonate form Α polymorph (bottom trajectory) and form β (upper trajectory) χ-ray powder diffraction comparison. Figure 5 is 6-[1-indolyl·1·(methylsulfonyl)ethyl] winter [3_[(6)_2_[3_methyl·U4^号-azole-5-yl]-2-[4-( A chart showing the difference in characteristic absorption peaks of X-ray powder diffraction of a polymorphic form of a sulfonyl)phenyl]vinyl]phenyl]porphyrin besylate. Figure 6 is 6-[1-methyl-1-(methylindolyl)ethyl][3_[(ε)_2·[3_methyl-up-monoazol-5-yl]-2-[ 4-(Methanesulfonyl)phenyl]vinyl]phenyl]. A chart showing the difference in characteristic absorption peaks of X-ray powder diffraction of quinolate besylate form B polymorph. DETAILED DESCRIPTION OF THE INVENTION The compounds of the invention are of formula (I):

S3- 、丫 R3 r2 (I) 或其藥學上可接受之鹽表示，其中 • si，s2及S3係獨立爲Η、-OH、函素、<丨-C6烷基、-N02、-CN或、C「C6烷氧基，其中烷基與烷氧基係視情況被1-5個取 -8- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ------------·-裝--------k---------# C請先閱境背面之注咅？事項再填寫本頁} 1280240 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（6 ) 代基取代’其中各取代基係獨立爲自素或0H ; 〜爲11、0H、卣素、羰基或<1-(：6烷基、_環^<6烷基、-CrC6烯基、-Ci-C：6烷氧基、芳基、雜芳基、-CN、雜環基 C3-C6烷基、-胺基、-(^-(^烷胺基、烷基）(CrC6燒基) 胺基、-C〗-C6燒基（氧基）q -c6烷基、_c(0)NH(芳基）、-C(0)NH( 雜芳基）、-S〇nNH(芳基）、-S〇nNH(雜芳基）、_s〇nNH(Ci七6烷基) 、-C(O)N(C0 -C6 烷基）(CVC6 烷基）、-NH_SOn -(q -C6 烷基）、-SOn - (q -c6 烷基）、-(Cl -C6 烷基）-aC(CN)-二烷胺基或 _(C1 _c6 烷基）_ SOnKC! -C6烷基），其中任何基團係視情況被M個取代基取 代；其中各取代基係獨立爲鹵素、-0H、-CN、&燒基 、-環 c3-c6燒基、-C(〇x雜環基 c3_c6虎基）、<(0)_0_((^%烷 基）、-c(0)-芳氧基_Cl夂烷氧基、_((VC6烷基）(CJ6烷基）胺 基、環烷基氧基、醯基、醯氧基、-環c3-c6烷基、雜環基 Cs-C6烷基、芳基、雜芳基、羰基、胺甲醯基或_s〇n_(CrC6 燒基）； A 爲 CH、C-酯或 C-R4 ; R2與R3係獨立爲芳基、雜芳基、η、鹵素、-CN、·€ι-(：6 燒基、雜環基C>6烷基、-CrC6烷氧基、羰基、胺甲醯基、 -C(0)0H、烷基）-SOn-(CrC6烷基）、-C(〇)N(c〇-c6烷基 )(C0 -C：6坑基）或-C! -C6烷基醯基胺基，其中任何基團係視情 況被1-5個取代基取代，其中各取代基係獨立爲芳基、雜芳 基、鹵素、-N02、-C(0)0H、羰基、-CN、-CrC6烷基、-S0n_ 仰必垸基）、_S(V(芳基）、芳氧基、碌芳基氧基、 乳基、N-氧化物、-C(0)·雜環基C3 -C6燒基、_NH-環c3 _C6燒基 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ------------Aw ---- (請先閱讀背面之注咅？事項再填寫本頁) 訂-L------- #. 經濟部智慧財產局員工消費合作社印製 1280240 A7 _____B7_ 五、發明說明（7 ) 、胺基、-OH或_(CVC6烷基）(C(rc6烷基）胺基、c6烷 基）(C〇-C6燒基）取代基，其中各取代基係獨立視情況被_〇H 、Ci -C6烷氧基、-C! -C6烷基、-環c3 -c6烷基、芳氧基、-C(0)0H 、¢:(0)0((^-C6烷基）、_ 素、-N〇2、_CN、-SKCi_c6烷基）或 -C(0)-N(Cq -C6 燒基）(C〇 -C6 燒基）取代； R2與R3之一必須爲芳基或雜芳基，視情況經取代； 當R2與R3均爲芳基或雜芳基時，則r2與r3可視情況被硫 基、氧基或（匸丨·4烷基）橋基連接，以形成稠合之三環系統； &爲芳基、-C! -C6烷基、雜芳基、、羰基、胺甲醯基 、-(q-c6燒基）-son-(c!_c6烷基）、-C(0)N(C()a烷基）(C()-C6烷基） 或-C6燒基醯基胺基，其中任何基團係視情況被1-5個取 代基取代’其中各取代基係獨立爲羰基、_CN、_素、-c(〇)(cvc6：fe 基）、基）、烷基、 C6烷基）、-〇H、（^-(：6烷氧基或-(C(rc6烷基）(Cg-C6烷基）胺基； η係獨立爲0，1或2 ;及 &或&可視情況藉一個鍵結連接至&，以形成環。 一方面，本發明化合物係以式①或其藥學上可接受之鹽 表示，其中 S1，S2 及 S3 係獨立爲 η、-OH、_ 素、_C1_C6 烷基、-N〇2、_ CN或-C0烷氧基，其中烷基與烷氧基係視情況被丨_5個取 代基取代；其中各取代基係獨立爲_素或〇H ; R!爲Η、OH、鹵素、羰基或-Ci _c6烷基…環& _C6烷基、一 晞基、-c「C6：fe氧基、芳基、雜芳基、_CN、-雜環基 CVG：6烷基、-胺基、-CrC6烷胺基、_(CrC6烷基）(CrC6烷基） -10- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱） --------------------訂---------· (請先閱讀背面之注意事項再填寫本頁) 1280240S3-, 丫R3 r2 (I) or a pharmaceutically acceptable salt thereof, wherein • si, s2 and S3 are independently Η, -OH, a lignin, <丨-C6 alkyl, -N02, -CN Or, C "C6 alkoxy, wherein the alkyl group and the alkoxy group are taken 1-5 depending on the case - the paper is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) --- ---------·-装--------k---------# CPlease read the note on the back of the first page? Please fill out this page again} 1280240 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 V. Inventive Note (6) Substituent substitution 'where each substituent is independent of itself or 0H; ~ is 11, 0H, halogen, carbonyl or <1-(: 6 alkyl, _ ring ^ < 6 alkyl, -CrC6 alkenyl, -Ci-C: 6 alkoxy, aryl, heteroaryl, -CN, heterocyclic C3-C6 alkyl, -amino , -(^-(^ alkylamino, alkyl) (CrC6 alkyl) Amino, -C--C6 alkyl (oxy) q-c6 alkyl, _c(0)NH(aryl), - C(0)NH(heteroaryl), -S〇nNH(aryl), -S〇nNH(heteroaryl), _s〇nNH(Ci-7-alkyl), -C(O)N(C0 - C6 alkyl) (CVC6 alkyl), -NH_SOn - (q -C6 alkyl), -SOn - (q -c6 alkane , -(Cl -C6 alkyl)-aC(CN)-dialkylamino or _(C1 _c6 alkyl)_SOnKC!-C6 alkyl), wherein any group is optionally substituted by M substituents Wherein each substituent is independently halogen, -OH, -CN, & alkyl, -cycloc3-c6 alkyl, -C (〇x heterocyclyl c3_c6), <(0)_0_(( ^% alkyl), -c(0)-aryloxy-Cl夂 alkoxy, _((VC6 alkyl)(CJ6 alkyl)amine, cycloalkyloxy, decyl, decyloxy, a cyclo c3-c6 alkyl group, a heterocyclic group Cs-C6 alkyl group, an aryl group, a heteroaryl group, a carbonyl group, an amine formazan group or a _s〇n_ (CrC6 alkyl group); A is a CH, a C-ester or a C -R4; R2 and R3 are independently aryl, heteroaryl, η, halogen, -CN, -1:6 alkyl, heterocyclic C>6 alkyl, -CrC6 alkoxy, carbonyl, Aminomethyl thiol, -C(0)0H, alkyl)-SOn-(CrC6 alkyl), -C(〇)N(c〇-c6 alkyl) (C0-C: 6 pit) or -C a -C6 alkylmercaptoamine group, wherein any group is optionally substituted with from 1 to 5 substituents, wherein each substituent is independently aryl, heteroaryl, halogen, -N02, -C(0) 0H, carbonyl, -CN, -CrC6 alkyl, -S0n_ 垸 垸 base), _S (V (aryl), aryloxy, arylaryloxy, lactyl, N-oxide, -C(0)·heterocyclyl C3 -C6 alkyl, _NH-ring c3 _C6 burning basic paper scale for China Standard (CNS) A4 specification (210 X 297 mm) ------------Aw ---- (Read the note on the back first? Matters fill out this page) Order-L------- #. Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1280240 A7 _____B7_ V. Description of Invention (7), Amino, -OH or _(CVC6 Alkyl a (C(rc6 alkyl)amino, c6 alkyl)(C〇-C6 alkyl) substituent wherein each substituent is independently _〇H, Ci-C6 alkoxy, -C! C6 alkyl, -cycloc3 -c6 alkyl, aryloxy, -C(0)0H, ¢:(0)0((^-C6 alkyl), _ 素, -N 〇2, _CN, -SKCi_c6 Alkylate or -C(0)-N(Cq-C6 alkyl) (C〇-C6 alkyl) substituted; one of R2 and R3 must be aryl or heteroaryl, optionally substituted; when R2 is When R3 is an aryl or heteroaryl group, then r2 and r3 may be optionally bonded to a thio, oxy or (匸丨.4 alkyl) bridging group to form a fused tricyclic system; & aryl , -C! -C6 alkyl, heteroaryl, carbonyl, amine carbaryl, -(q-c6 alkyl)-son-(c!_c6 alkyl), -C(0)N(C() Aalkyl)(C()-C6 alkyl) or -C6 alkylamino group, wherein any group is optionally substituted with from 1 to 5 substituents, wherein each substituent is independently carbonyl, _CN, _素, -c(〇)(cvc6:f E group), group), alkyl group, C6 alkyl group, -〇H, (^-(:6 alkoxy or -(C(rc6 alkyl)(Cg-C6 alkyl)amine group; η system independent 0, 1 or 2; and & or & optionally by a bond to & to form a ring. In one aspect, the compound of the invention is represented by Formula 1, or a pharmaceutically acceptable salt thereof, wherein S1 , S2 and S3 are independently η, -OH, _, _C1_C6 alkyl, -N〇2, _CN or -C0 alkoxy, wherein alkyl and alkoxy are optionally 丨5 substituents Substituent; wherein each substituent is independently _ or 〇H; R! is Η, OH, halogen, carbonyl or -Ci _c6 alkyl... ring & _C6 alkyl, monodecyl, -c "C6:fe oxygen Base, aryl, heteroaryl, _CN, -heterocyclyl CVG: 6 alkyl, -amino, -CrC6 alkylamino, _(CrC6 alkyl) (CrC6 alkyl) -10- This paper scale applies to China National Standard (CNS) A4 Specification (210 X 297 public) -------------------- Order ---------· (Please read the back first Note on this page again) 1280240

經濟部智慧財產局員工消費合作社印製 五、發明說明（8 ) 月女土、-q -C6 ：1元基（氧基）q -c6 烷基、-C(〇)NH(芳基）、-C(〇)NH( 雜万基）、-SOnNH(方基）、-SOnNH(雜芳基）、-S〇nNH(Ci _c6 烷基） 、-c(o)n(c0-c：6烷基）(C(rC6烷基）、烷基）、μα -c6 烷基 ） 、 -(q -c6 烷基）_〇-c(cn)-二 烷胺基 ，或 -(Ci-C6 烷基 )-SOrT(Cl 烷基）’其中任何基團係視情況被丨_5個取代基取 代，其中各取代基係獨立爲自素、_〇H、_CN、A烷基 、-% C3-C6：fe 基、-c(0)(雜環基 c3-c6 燒基）、-C⑼_0_(C(rCr^ 基）、-c(0)-方氧基、-Cl-C4 氧基、_(c〇_C6烷基）(c〇_C6烷基) 胺基、環燒基氧基、S!基、醯氧基、環垸基、雜環基 CVC6烷基、芳基、雜芳基、羰基、胺甲醯基或_S(v(Ci_c6 烷基）； A 爲 CH ; &與R3係獨立爲芳基、雜芳基、Η、鹵素、_CN、（厂q 烷基、雜壤基A 烷基、-C! -C：6烷氧基、羰基、胺甲醯基、 -C(0)0H、-((:厂仏烷基）-SOn-(CVC6烷基）、_c(0)N(C(rC6燒基） (C0-C0烷基）或-Cl-C0烷基醯基胺基，其中任何基團係視情況 被1-5個取代基取代，其中各取代基係獨立爲芳基、雜芳基 、鹵素、-N02、-C(0)0H、羰基、TN、_CrC6烷基、·3〇η_ (CrC6烷基）、-S0n-(芳基）、_芳氧基、·雜芳基氧基、完 氧基、N-氧化物、-c(0)-雜環基cs -C：6烷基、-NH-環c3 -c6烷基 、胺基、-oh 或-(cvc6烷基）((：〇%烷基）胺基、_c(0>n(C(^C6 烷基）(c0-C6烷基）取代基，其中各取代基係獨立視情況被_ 0H 、 q-c6 烷 氧基、 -Ci-c6 烷基 、-環 CrC6 烷基、 _芳氧基 、-C(0)0H、-C(0)0(CrC6 烷基）、_ 素、_N〇2、-CN、-S(V(Ci ^ -11 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -----------裝--------訂---------. (請先閱讀背面之注意事項再填寫本頁) 1280240 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明（9 烷基）或<(ο)_ν((^ c0烷基)(C() %烷基）取代； R2與R3 (必項爲芳基或雜芳基，視情況經取代； 當R#R3均爲芳基或雜芳基時，則R2 硫基、氧基或(c「c4垸基）橋基連接，以形成稠合三== ;及 η係獨立爲〇, 1或2。 在此方面之-，具體實施例中，本發明化合物係 或其藥學上可接受之鹽表示，其中 s2 及 s3 係獨 乂爲 Η、-ΟΗ、鹵素、a -C6 烷基、_ν〇2、_ CN或必々烷氧基，其中烷基與烷氧基係視情況被υ個取 代基取代；其中各取代基係獨立爲自素或〇Η; 心爲-C：6烷基，視情況被個取代基取代；其中各取 代基係獨立爲卣素、-0H、\CN、-C(〇)(雜環基Crq烷基）、_ c(〇KKcQ-C6：fe基）、_c(0)_0_芳基、烷氧基、環烷基氧基、醯 基、醞氧基、.環q-C：6烷基、雜環基心々烷基、芳基、雜 芳基、羰基、胺甲醯基或_S〇n_(Ci_C6烷基）、-(c〇-C6烷基）(c〇_ Cg说基）胺基； A 爲 CH ; R2與R3係獨立爲芳基、雜芳基、Η、鹵素、-CN、-Ci -C6 燒基、雜環基C3_6烷基、-CrC6烷氧基、羰基、胺甲醯基、 -C(0)0H、-(q -c6 烷基）-SOn -(Ci -c6 烷基）、-C(0)N(C〇 -c6 烷基）(c0 -c6烷基）或-CrC6烷基醯基胺基，其中任何基團係視情況被 1-5個取代基取代，其中各取代基係獨立爲芳基、雜芳基、 鹵素、-N02、-C(0)0H、羰基、-CN、-CrC6烷基、-SOn-(Cr -12- 本紙張尺度適用中國國家標準（CNS)A4規格（210 x 297公釐） -丨丨丨 ^ --^---.-----^illlllll (請先閱讀背面之注意事項再填寫本頁) 1280240 經濟部智慧財產局員工消費合作社印製 A7 五、發明說明（10) c6燒基）、-S〇n-(芳基）、_〇_芳基、_〇雜芳基、c⑹完氧基、 N-氧化物、-C(0>雜環基C3_C6烷基、_贿_環&⑽基、胺基 OH或（C0 C6 k基)(c〇七6故基）胺基、_c(〇) N(c〇 ^少充基）(c。_ c6垸基）取代基，其中各取代基係獨立視情況被_〇H、c「C6 燒氧基、-C厂c6燒基、-環c3_c6烷基、芳氧基、_c(〇)〇H、_ C_(C「⑽基）、_素、播2、_CN、_s〇n(CiC6炫基）或-€(0)-Ν((^-(：6烷基）(C〇_c6烷基）取代； R2與R3i-必須爲芳基或雜芳基，視情況經取代； 、當R#R3均爲芳基或雜芳基時，則〜與~可視情況藉由 硫基、氧基或（c「c4燒基）橋基連接，以形成稠合三環系統； η係獨立爲〇，1或2。 在此方面之另-項具體實施例中，本發明化合物係以式① 或其藥學上可接受之鹽表示，其中Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Printing, V. Inventions (8) Month, -q-C6: 1-membered (oxy)q-c6 alkyl, -C(〇)NH(aryl), -C(〇)NH(杂万基), -SOnNH(方基), -SOnNH(heteroaryl), -S〇nNH(Ci_c6 alkyl), -c(o)n(c0-c:6 Alkyl) (C(rC6 alkyl), alkyl), μα-c6 alkyl), -(q-c6 alkyl)_〇-c(cn)-dialkylamino, or -(Ci-C6 alkane Any of the groups of -SOrT(Cl alkyl)' is optionally substituted with 丨5 substituents, wherein each substituent is independently 自, 〇H, _CN, A alkyl, -% C3- C6: fe group, -c(0) (heterocyclyl c3-c6 alkyl), -C(9)_0_(C(rCr^yl), -c(0)-aryloxy, -Cl-C4 oxy, _( c〇_C6 alkyl)(c〇_C6 alkyl)amino, cycloalkyloxy, S!, decyloxy, cyclodecyl, heterocyclo CVC6 alkyl, aryl, heteroaryl, Carbonyl, carbamoyl or _S (v(Ci_c6 alkyl); A is CH; & R3 is independently aryl, heteroaryl, hydrazine, halogen, _CN, (factory q alkyl, hetero-based A alkyl group, -C! -C:6 alkoxy group, carbonyl group, amine methyl group, -C(0) 0H, -((: 仏alkyl)-SOn-(CVC6 alkyl), _c(0)N(C(rC6 alkyl) (C0-C0 alkyl) or -Cl-C0 alkyl mercaptoamine , wherein any group is optionally substituted with from 1 to 5 substituents, wherein each substituent is independently aryl, heteroaryl, halogen, -N02, -C(0)0H, carbonyl, TN, _CrC6 alkyl , ·3〇η_ (CrC6 alkyl), -S0n-(aryl), _aryloxy, heteroaryloxy, oxy, N-oxide, -c(0)-heterocyclyl cs -C: 6 alkyl, -NH-cyclo c3 -c6 alkyl, amine, -oh or -(cvc6 alkyl)((:〇%alkyl)amine, _c(0>n(C(^C6) Alkyl)(c0-C6 alkyl) substituent wherein each substituent is independently _ 0H , q-c6 alkoxy, -Ci-c6 alkyl, -cycloCrC6 alkyl, _aryloxy, -C(0)0H, -C(0)0(CrC6 alkyl), _, _N〇2, -CN, -S(V(Ci ^ -11 - This paper scale applies to China National Standard (CNS) A4 Specifications (210 X 297 mm) -----------Install--------Book---------. (Please read the notes on the back and fill in the form. Page) 1280240 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed V. Description of the Invention (9 Alkyl) Or <(ο)_ν((^ c0 alkyl)(C() % alkyl) substituted; R2 and R3 (must be an aryl or heteroaryl group, optionally substituted; when R#R3 is aryl Or a heteroaryl group, the R2 thio group, the oxy group or the (c "c4 fluorenyl" bridging group are bonded to form a fused triple ==; and the η system is independently 〇, 1 or 2. In this aspect, in a specific embodiment, the compound of the present invention or a pharmaceutically acceptable salt thereof, wherein s2 and s3 are mono-, oxime, halogen, a-C6 alkyl, _ν〇2 Or alkoxy, wherein the alkyl group and the alkoxy group are optionally substituted by one substituent; wherein each substituent is independently a self or a ruthenium; the core is a -C: 6 alkyl group, as the case may be. Substituted by a substituent; each of the substituents is independently halogen, -OH, \CN, -C(〇) (heterocyclyl Crq alkyl), _c(〇KKcQ-C6:fe), _c( 0) _0_aryl, alkoxy, cycloalkyloxy, decyl, decyloxy, cyclocC:6 alkyl, heterocyclyl cardinyl, aryl, heteroaryl, carbonyl, amine Mercapto or _S〇n_(Ci_C6 alkyl), -(c〇-C6 alkyl)(c〇_Cg) group; A is CH; R2 and R3 are independently aryl, heteroaryl , hydrazine, halogen, -CN, -Ci -C6 alkyl, heterocyclic C3_6 alkyl, -CrC6 alkoxy, carbonyl, amidyl, -C(0)0H, -(q -c6 alkyl) -SOn -(Ci-c6 alkyl), -C(0)N(C〇-c6 alkyl)(c0-c6 alkyl) or -CrC6alkyldecylamino, any of which Substituting 1-5 substituents, wherein each substituent is independently aryl, heteroaryl, halogen, -N02, -C(0)0H, carbonyl, -CN, -CrC6 alkyl, -SOn -(Cr -12- This paper scale applies to China National Standard (CNS) A4 specification (210 x 297 mm) -丨丨丨^ --^---.-----^illlllll (Please read the back Note: Please fill out this page again) 1280240 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 V. Invention description (10) c6 alkyl), -S〇n-(aryl), _〇_aryl, _〇 Aryl, c(6)-terminated oxy, N-oxide, -C(0>heterocyclyl C3_C6 alkyl, _ bri-ring & (10) group, amine OH or (C0 C6 k group) (c〇7 6 Amino group, _c(〇)N(c〇^lessly charged) (c. _ c6 fluorenyl) substituent, wherein each substituent is independently _〇H, c "C6 alkoxy, - C plant c6 alkyl, -cyclo c3_c6 alkyl, aryloxy, _c (〇) 〇 H, _ C_ (C "(10) base), _ 素, broadcast 2, _CN, _s〇n (CiC6 炫) or - €(0)-Ν((^-(:6 alkyl)(C〇_c6 alkyl) substituted; R2 and R3i- must be aryl or heteroaryl, as the case may be;; when R#R3 Aryl Or a heteroaryl group, then ~ and ~ may be linked by a thio group, an oxy group or a (c "c4 alkyl group" bridging group to form a fused tricyclic system; the η system is independently 〇, 1 or 2. In another embodiment of this aspect, the compound of the invention is represented by Formula 1 or a pharmaceutically acceptable salt thereof, wherein

SpM\係獨立爲Η、_0Η、卣素、_C「C6烷基、·Ν〇2、_ CN或-Cl-C6烷氧基，其中該烷基與烷氧基係視情況被w個 取代基取代；其中各取代基係獨立爲自素或〇h; h爲-環（：3七6烷基，視情況被丨-5個取代基取代；其中各 取代基係獨立爲自素、-OH、-CN、C(〇)(雜環基C3-C6燒基) 、-C(0HMGVC6燒基卜c(0>0-芳基、烷氧基、環烷基氧基 、醯基、醯氧基、-環q-c：6烷基.、雜環基q夂烷基、芳基 、雜方基、談基、胺甲酿基或-S〇n -(Ci -C6 ：)t完基）· A 爲 CH ; R2與尺3係獨立爲芳基、雜芳基、Η、卣素、_CN…Ci-C6 基、雜環基C：3 — 6烷基、-q-C6烷氧基、羰基、胺甲醯基、 -13- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ------------^--------訂---------^^1 (請先閱讀背面之注音？事項再填寫本頁) 128〇24〇 A7 B7 五、 發明說明（11 ) -C(〇)〇H、-(Ci -C6 烷基）-SOn -(Ci -C6 烷基）、-C(0)N((VC6 烷基 XCV c6烷基）或-CrC6烷基醯基胺基，其中任何基團係視情況被 1-5個取代基取代，其中各取代基係獨立爲芳基、雜芳基、 鹵素、-N02、-C(0)0H、羰基、_CN、-CrC6烷基、-SOn-(Cr 烷基）、-SOn-(芳基）、-ο-芳基、-ο-雜芳基、C!七6烷氧基、 N-氧化物、-c(0)-雜環基c3 -C6烷基、-NH-環c3 -C6烷基、胺基 、-OH 或-(c0-C6烷基 XCo-C6烷基）胺基、_C(0)-N(CVC6烷基）(c0-C6 fe基）取代基，其中各取代基係獨立視情況被_0H、Cl -c6 燒氧基、-q -C6烷基、-環c3 -C6烷基、芳氧基、-C(0)0H、-c(0)-0(C「C6 烷基）、鹵素…n〇2、_CN、-SOn-(CrC6 烷基）或-C(o)-N(C()-C6烷基）(CG-C6烷基）取代； R2與R3之一必須爲芳基或雜芳基，視情況經取代； 當反2與R3均爲芳基或雜芳基時，則r2與可視情況被硫 基、氧基或（q-c：4烷基）橋基連接，以形成稠合三環系統； 及 η係獨立爲〇，1或2。 於此方面之又另一項具體實施例中，本發明化合物係以 式（I)或其藥學上可接受之鹽表示，其中SpM\ is independently Η, Η, 卣, _C "C6 alkyl, Ν〇 2, _ CN or -Cl-C6 alkoxy, wherein the alkyl and alkoxy are optionally substituted by w Substituted; wherein each substituent is independently arginine or 〇h; h is a ring: (3-7 hexyl, optionally substituted with 丨-5 substituents; wherein each substituent is independently arginine, -OH , -CN, C(〇)(heterocyclyl C3-C6 alkyl), -C(0HMGVC6 alkyl b) (0>0-aryl, alkoxy, cycloalkyloxy, decyl, oxime a group, a ring qc: 6 alkyl group, a heterocyclic group q 夂 alkyl group, an aryl group, a heteroaryl group, a cyclyl group, an amine methyl group or a -S〇n - (Ci - C6 :) t group) A is CH; R2 and 尺3 are independently aryl, heteroaryl, anthracene, halogen, _CN...Ci-C6 group, heterocyclic group C: 3-6 alkyl, -q-C6 alkoxy, carbonyl , Aminomethyl thiol, -13- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) ------------^-------- ---------^^1 (Please read the phonetic on the back? Please fill out this page again) 128〇24〇A7 B7 V. Description of invention (11) -C(〇)〇H,-(Ci -C6 alkyl)-SOn -(Ci -C6 alkyl), -C(0)N((V a C6 alkyl XCV c6 alkyl) or a -CrC6 alkyldecylamino group, wherein any group is optionally substituted with from 1 to 5 substituents, wherein each substituent is independently aryl, heteroaryl, halogen, -N02, -C(0)0H, carbonyl, _CN, -CrC6 alkyl, -SOn-(Cr alkyl), -SOn-(aryl), -o-aryl, -o-heteroaryl, C !-7-alkoxy, N-oxide, -c(0)-heterocyclyl c3 -C6 alkyl, -NH-cyclo c3 -C6 alkyl, amine, -OH or -(c0-C6 alkyl XCo-C6 alkyl)amino, _C(0)-N(CVC6 alkyl)(c0-C6 fe) substituent wherein each substituent is independently alkoxy by -OH, Cl-c6, - q-C6 alkyl, -cyclo c3 -C6 alkyl, aryloxy, -C(0)0H, -c(0)-0 (C"C6 alkyl", halogen...n〇2, _CN, -SOn -(CrC6 alkyl) or -C(o)-N(C()-C6 alkyl) (CG-C6 alkyl) substituted; one of R2 and R3 must be aryl or heteroaryl, optionally substituted When both trans 2 and R 3 are aryl or heteroaryl, then r 2 may be optionally attached to a thio, oxy or (qc:4 alkyl) bridging group to form a fused tricyclic system; Independent is 〇, 1 or 2. Another aspect of this aspect Embodiment, the compounds of the present invention is based in formula (I) or a pharmaceutically acceptable salt thereof of, where

SpS2及s3係獨立爲Η、-ΟΗ、鹵素、-Ci_c6烷基、_Ν〇2、_ CN或-q-c：6烷氧基，其中該烷基與烷氧基係視情況被丨_5個 取代基取代；纟中各取代基係獨立爲_素或0H;SpS2 and s3 are independently Η, -ΟΗ, halogen, -Ci_c6 alkyl, _Ν〇2, _CN or -qc:6 alkoxy, wherein the alkyl group and the alkoxy group are optionally substituted by 丨5 Substituent; each substituent in the oxime is independently _ or 0H;

Ri烏-CyC：6晞基，視情況被1-5個取代基取代；其中各取 代基係獨立爲_素、-OH、-CN、_c(0)(雜環基C3%烷基）、-c(〇HMcvC6坑基）、-c(0)-a芳基、燒氧基、環统基氧基、醯 ---1------------ (請先閱讀背面之注意事項再填寫本頁) 1Τ---------舞 經 濟 部 智 慧 財 產 局 員 工 消 費 合 作 社 印 製Ri-CyC: 6 fluorenyl, optionally substituted with 1-5 substituents; wherein each substituent is independently _, -OH, -CN, _c(0) (heterocyclyl C3% alkyl), -c (〇HMcvC6 pit base), -c(0)-a aryl, alkoxy, cyclooxy, 醯---1------------ (Read first Note on the back side of this page) 1Τ---------Ministry of the Ministry of Education, Intellectual Property Bureau, employee consumption cooperative printing

1280240 經濟部智慧財產局員工消費合作社印製 A7 _____B7_ 五、發明說明（12 ) 基、醯氧基、-環c3-c6烷基、雜環基c3-c6烷基、芳基、雜 芳基、羰基、胺甲醯基或-SOn-(CrC6烷基）； A 爲 CH ; R2與R3係獨立爲芳基、雜芳基、Η、鹵素、-CN、-CrC6 燒基、雜環基c3_6烷基、-q-q烷氧基、羰基、胺甲醯基、 -C(0)0H、-(q -C6 烷基）-SOn -(q -C6 烷基）、<(0)Ν(<ν(：6 烷基）(C〇 -Cg燒基）或-q -c6烷基醯基胺基，其中任何基團係視情況被 1-5個取代基取代，其中各取代基係獨立爲芳基、雜芳基、 i 素、-N02、-C(0)0H、羰基、-CN、-Ci-C6烷基、-SOn-(Cr 基）、-SOn-(芳基）、-0·芳基、-〇_雜芳基、CrC6烷氧基、 N-氧化物、-C(0>雜環基& %烷基、_而_環A%烷基、胺基 、-0H 或-(C〇 —C6烷基）(C(rC6烷基）胺基、C6烷基）(C0-C0燒基）取代基’其中各取代基係獨立視情況被_〇H、& _C6 L氧基、-CrCg烷基、-環C3-C6烷基、芳氧基、-C(〇)〇H、-QOKxq-q燒基）、鹵素、-N〇2、-CN、-S(V(Ci-c6烷基）或-C(0)-N(CVC6 烷基）(C0-C6烷基）取代； 尺2與R3之一必須爲芳基或雜芳基，視情況經取代； 當R2與R3均爲芳基或雜芳基時，則汉2與化可視情況被硫 基氧基或（C1 烷基）橋基連接，以形成稠合三環系統； η係獨立爲〇, 1或2。 在此方面之另一項具體實施例中，本發明化合物係以式⑴ 或其藥學上可接受之鹽表示，其中 ^2及\係獨立爲Η、_0Η、南素、々夂烷基、％、_ CN或-C丨-C6烷氧基’纟"亥统基與烷氧基係視情況被w個 -15- 木紙張尺度適用中國國家標準（CNS)A4規格（21〇 x 297公釐 --------------------訂— (請先閱讀背面之注意事項再填寫本頁) 1280240 A7 ----------B7_____ 五、發明說明（13 ) "_ 取代基取代；其中各取代基係獨立爲_素或OH ; h爲雜芳基，視情況被丨_5個取代基取代；其中各取代基 係獨立爲_素、_0H、_CN、_c(0)(雜環基烷基）、_c(⑺_ CKCo-c：6貌基）、_c⑼办芳基、烷氧基、環烷基氧基、醯基 、醯氧基、_環（：3(6烷基、雜環基烷基、芳基、雜芳 基、羰基、胺甲醯基或-S〇n_(Ci_C6烷基）； A 爲 CH ; R2與R3係獨立爲芳基、雜芳基、Η、鹵素、-CN、-q -C6 烷基、雜環基A-6烷基、-q-q烷氧基、羰基、胺曱醯基、 -C(0)0H、-(CrCg烷基）-SOn-(CrC6烷基）、-C(0)N(C〇-C6烷基 )(C0-C6fe基）或-C0烷基醯基胺基，其中任何基團係視情 況被1-5個取代基取代，其中各取代基係獨立爲芳基、雜芳 基、鹵素、-N02、-C(0)0H、羰基、_CN、-CrQ烷基、-S〇n- (CVC6燒基）、-S〇n-(芳基）、-芳氧基、_〇雜芳基、Cl_c6烷氧基 、N-氧化物、-c(0)-雜環基C3 -C6烷基、-NH-環c3 _c6烷基、胺 基、-0H 或-(C(TC6 烷基）(C(rC6 烷基）胺基、-C(O)-N(C0-C6 烷基） (C0-C：6垸基）取代基，其中各取代基係獨立視情況被-〇H、 CrC6fe氧基、-CrQ烷基、-環c3-c6烷基、-芳氧基、_c(0)0H 、-¢:(0)0((^ -c6 烷基）、_ 素、-N02、-CN、-SOn-A -C6 烷基）或 -C(O)-N(C0-C6烷基）(CG-C6烷基）取代； R2與R3之一必須爲芳基或雜芳基，視情況經取代； 當&與R3均爲芳基或雜芳基時，則r2與r3可視情況被硫 基、氧基或（q -C4烷基）橋基連接，以形成稠合三環系統； η喺獨立爲〇, 1或2。 -16-- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） " -------------·-裝 (請先閱讀背面之注意事項再填寫本頁) 訂---------#· 經濟部智慧財產局員工消費合作社印製 1280240 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（14) 在此方面之又再另一項具體實施例中，本發明化合物係 以式⑴或其藥學上可接受之鹽表示，其中 S!，S2及S3係獨立爲Η、-0H、鹵素、-q -C6烷基、-N02、-CN或_Ci 烷氧基，其中該烷基與烷氧基係視情況被μ5個 取代基取代； 其中各取代基係獨立爲_素或0Η ; 心爲胺基、-q -C：6烷胺基或_(Ci -C6烷基xq -C6烷基）胺基， 其中任何基團係視情況被1-5個取代基取代；其中各取代基 係獨立爲_素、-OH、-CN、-C(0)(雜環基c3_c6烷基）、_c(〇)_ 〇-(CG-C6：fe基）、-c(0>0-芳基、烷氧基、環烷基氧基、醯基 、S盈氧基、-環q-C6烷基、雜環基c3-C6烷基、芳基、雜芳 基、羰基、胺甲醯基或-c6烷基）； A 爲 CH ; R2與R3係獨互爲芳基、雜芳基、Η、鹵素、-cn、-C6 烷基、雜锿基q 烷基、-C6烷氧基、羰基、胺甲醯基、 -C(0)0H、-(Ci -C6烷基）-S0n-(c〗-C6烷基）、-CCCONCCo-C^烷基）(c0- c0烷基）或-q-C：6烷基醯基胺基，其中任何基團係視情況被 1-5個取代基取代，其中各取代基係獨立爲芳基、雜芳基、 商素、-N02、-C(0)0H、羰基、-CN、-Ci-C6烷基…S(V(Ci_ c6燒基）、-S0n-(芳基）、-芳氧基、-〇_雜芳基、Ci_c6烷氧基、 N-氧化物、-C(〇)-雜環基c3_C6烷基、-Nh^C3_C6烷基、胺基 、-OH 或-(C〇 -C6 烷基）(C〇 -C6 烷基）胺基、-c(O)-N(C0 -C6 烷基）(C0 - c0烷基）取代基，其中各取代基係獨立視情況被_〇H、CrQ 燒氧基、-c「c6燒基、-環c3-c6烷基、·芳氧基…c(〇)〇H、- -17- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ------------裝--------訂---------· (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 1280240 A7 ______B7____ 五、發明說明（15 ) C(0)0(CrC6 烷基）、鹵素、·Ν02、-CN、-SOnXq-Cg 烷基）或-c(o)-n(cvc6 烷基）(C(rc6烷基）取代·， 心與R3之一必須爲芳基或雜芳基，視情況經取代； 當與反3均爲芳基或雜芳基時，則R2與r3可視情況被硫 基、氧基或（c1-4烷基）橋基連接，以形成稠合三環系統； η係獨立爲〇, 1或2。 在此方面之一項具體實施例中，本發明化合物係以式⑴ 或其藥學上可接受之鹽表示，其中1280240 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed A7 _____B7_ V. Inventive Note (12) Base, oxime, cyclo-c3-c6 alkyl, heterocyclic c3-c6 alkyl, aryl, heteroaryl, A carbonyl group, an amine carbenyl group or a -SOn-(CrC6 alkyl group); A is CH; R2 and R3 are independently aryl, heteroaryl, anthracene, halogen, -CN, -CrC6 alkyl, heterocyclic c3_6 alkane Base, -qq alkoxy group, carbonyl group, amine carbenyl group, -C(0)0H, -(q-C6 alkyl)-SOn-(q-C6 alkyl), <(0)Ν(< ν(:6 alkyl)(C〇-Cg alkyl) or -q-c6alkyldecylamino, wherein any group is optionally substituted with from 1 to 5 substituents, wherein each substituent is independently Aryl, heteroaryl, i, -N02, -C(0)0H, carbonyl, -CN, -Ci-C6 alkyl, -SOn-(Cr), -SOn-(aryl), -0 · aryl, -〇_heteroaryl, CrC6 alkoxy, N-oxide, -C (0>heterocyclyl & % alkyl, _ while _ ring A% alkyl, amine, -OH or -(C〇-C6 alkyl)(C(rC6 alkyl)amino, C6 alkyl)(C0-C0 alkyl) substituent 'wherein each substituent is independently _〇H, & _C6 L Oxy, -CrCg alkyl - a ring C3-C6 alkyl, aryloxy, -C(〇)〇H, -QOKxq-q alkyl), halogen, -N〇2, -CN, -S(V(Ci-c6 alkyl) or -C(0)-N(CVC6 alkyl)(C0-C6 alkyl) substituted; one of the ampules 2 and R3 must be an aryl or heteroaryl group, optionally substituted; when both R2 and R3 are aryl or In the case of a heteroaryl group, the Han 2 is optionally linked to a thiooxy group or a (C1 alkyl) bridging group to form a fused tricyclic system; the η system is independently 〇, 1 or 2. In this respect In a specific embodiment, the compound of the present invention is represented by the formula (1) or a pharmaceutically acceptable salt thereof, wherein ^2 and \ are independently Η, Η, 南, decyl, %, _CN or - C丨-C6 alkoxy '纟"Hermitage and alkoxy groups are considered to be -15-wood scales according to Chinese National Standard (CNS) A4 specifications (21〇x 297 mm---- ---------------- Order - (Please read the notes on the back and fill in this page) 1280240 A7 ----------B7_____ V. Description of invention (13 "_ Substituent substitution; wherein each substituent is independently _ or OH; h is a heteroaryl group, optionally substituted by 丨5 substituents; The substituents are independently _, _0H, _CN, _c(0) (heterocyclylalkyl), _c((7)_ CKCo-c:6 phenotype), _c(9) aryl, alkoxy, cycloalkyloxy , fluorenyl, decyloxy, _ ring (: 3 (6 alkyl, heterocyclylalkyl, aryl, heteroaryl, carbonyl, amine carbaryl or -S〇n_(Ci_C6 alkyl); A is CH ; R 2 and R 3 are independently aryl, heteroaryl, anthracene, halogen, -CN, -q -C6 alkyl, heterocyclic A-6 alkyl, -qq alkoxy, carbonyl, aminyl -C(0)0H, -(CrCgalkyl)-SOn-(CrC6 alkyl), -C(0)N(C〇-C6 alkyl)(C0-C6fe) or -C0 alkyl fluorenyl Amino group, wherein any group is optionally substituted by 1 to 5 substituents, wherein each substituent is independently aryl, heteroaryl, halogen, -N02, -C(0)0H, carbonyl, _CN, - CrQ alkyl, -S〇n- (CVC6 alkyl), -S〇n-(aryl), -aryloxy, 〇-heteroaryl, Cl_c6 alkoxy, N-oxide, -c(0 )-heterocyclyl C3 -C6 alkyl, -NH-cyclo c3 _c6 alkyl, amine,-0H or -(C(TC6 alkyl)(C(rC6 alkyl)amino, -C(O)- N(C0-C6 alkyl) (C0-C: 6 fluorenyl) substituent in which each substituent is unique视H, CrC6feoxy, -CrQ alkyl, -cycloc3-c6 alkyl, -aryloxy, _c(0)0H, -¢:(0)0((^-c6 alkyl), as appropriate , _, -N02, -CN, -SOn-A -C6 alkyl) or -C(O)-N(C0-C6 alkyl) (CG-C6 alkyl) substituted; one of R2 and R3 must be An aryl or heteroaryl group, optionally substituted; when both & R3 are aryl or heteroaryl, then r2 and r3 may be optionally attached to a thio, oxy or (q-C4 alkyl) bridging group. To form a fused tricyclic system; η喺 is independently 〇, 1 or 2. -16-- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) " -------------·-Installation (please read the precautions on the back) Fill in this page) Order---------#· Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Printed 1280240 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Printed A7 B7 V. Invention Description (14) In this regard In still another embodiment, the compound of the present invention is represented by the formula (1) or a pharmaceutically acceptable salt thereof, wherein the S!, S2 and S3 are independently oxime, -OH, halogen, -q-C6 alkyl , -N02, -CN or _Ci alkoxy, wherein the alkyl group and the alkoxy group are optionally substituted by μ5 substituents; wherein each substituent is independently _ or 0 Η; the heart is an amine group, -q a -C: 6 alkylamino group or a _(Ci-C6 alkylxq-C6 alkyl)amino group, wherein any group is optionally substituted with 1 to 5 substituents; wherein each substituent is independently _, -OH, -CN, -C(0) (heterocyclyl c3_c6 alkyl), _c(〇)_〇-(CG-C6:fe group), -c(0>0-aryl, alkoxy, Cycloalkyloxy, fluorenyl, S-oxyl, -cyclo q-C6 alkyl, heterocyclyl c3-C6 alkane , aryl, heteroaryl, carbonyl, aminecarakilidinyl or -c6 alkyl); A is CH; R2 and R3 are each independently aryl, heteroaryl, anthracene, halogen, -cn, -C6 alkyl , hydrazino-based q-alkyl, -C6 alkoxy, carbonyl, aminemethanyl, -C(0)0H, -(Ci-C6 alkyl)-S0n-(c--C6 alkyl), -CCCONCCo -C^alkyl)(c0-c0 alkyl) or -qC:6alkyldecylamino, wherein any group is optionally substituted with from 1 to 5 substituents, wherein each substituent is independently aryl , heteroaryl, quotient, -N02, -C(0)0H, carbonyl, -CN, -Ci-C6 alkyl...S(V(Ci_ c6 alkyl), -S0n-(aryl), -aryl Oxy, -〇-heteroaryl, Ci_c6 alkoxy, N-oxide, -C(〇)-heterocyclyl c3_C6 alkyl, -Nh^C3_C6 alkyl, amine, -OH or -(C〇 -C6 alkyl)(C〇-C6 alkyl)amino, -c(O)-N(C0-C6 alkyl)(C0-c0 alkyl) substituent, wherein each substituent is independently taken as appropriate 〇H, CrQ alkoxy, -c "c6 alkyl, -cycloc3-c6 alkyl, aryloxy...c(〇)〇H, - -17- This paper scale applies to China National Standard (CNS) A4 Specifications (210 X 297 mm) ------------Package-------- order ---------· (Please read the note on the back and fill out this page) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1280240 A7 ______B7____ V. Invention description (15) C(0)0(CrC6 Alkyl), halogen, Ν02, -CN, -SOnXq-Cg alkyl) or -c(o)-n(cvc6 alkyl) (C(rc6 alkyl) substituted, one of the heart and R3 must be aromatic Or a heteroaryl group, optionally substituted; when both R3 and R3 are aryl or heteroaryl, R2 and r3 may be optionally bonded to a thio, oxy or (c1-4 alkyl) bridging group, A fused tricyclic system is formed; the η system is independently 〇, 1 or 2. In a specific embodiment of this aspect, the compound of the present invention is represented by the formula (1) or a pharmaceutically acceptable salt thereof, wherein

Si，S2及S3係獨立爲Η、-0Η、鹵素、-C6烷基、-Ν02、-CN或-q -C：6烷氧基，其中該烷基與烷氧基係視情況被1-5個 取代基取代；其中各取代基係獨立爲自素或〇H ;Si, S2 and S3 are independently Η, -0Η, halogen, -C6 alkyl, -Ν02, -CN or -q-C:6 alkoxy, wherein the alkyl group and the alkoxy group are optionally 1- Substituted by 5 substituents; wherein each substituent is independently self- or 〇H;

Ri爲-CrC6烷基、-環c3-C6烷基、-C2-C6烯基、-q-q烷氧 基、芳基、雜芳基、-CN、-雜環基C3-C6烷基、-胺基、-Cl-C6：fe胺基、-(ci-c6烷基XCVQ烷基）胺基、_c「C6烷基（氧基 -c6 烷基、-C(0)NH(芳基）、_C(0)NH(雜芳基）、·8〇ηΝΗ(芳基）、 -SOnNH(雜芳基）、_s〇nNH(Ci_C6烷基）、_c(〇)n((VC6烷基）(c〇· C6燒基）、-NH-SO/CrQ烷基）、-SOn-(CVC6烷基）、-胺甲醯基 、-(CrC6 烷基）-〇_c(CN)-二烷胺基或-(Ci % 烷基 >s〇n _(Ci_C6 烷 基）’其中任何基團係視情況被1-5個取代基取代；其中各 取代基係獨立爲鹵素、-0H、_CN、烷氧基、環烷基氧基、 臨基、醯氧基、-環c3-c6烷基、雜環基c3_c6烷基、芳基、 雜芳基、羰基、胺甲醯基或_s〇n_(Cl _c6烷基）； A 爲 CH ; 心爲芳基，視情況被1-5個取代基取代，其中各取代基係 -18-— 本紙張尺度適用中國國家標準（CNS)A4規格（21〇 X 297公釐） I--------I ---I----訂--------I (請先閱讀背面之注意事項再填寫本頁) 1280240 A7 經濟部智慧財產局員工消費合作社印製 五、發明說明（16 ) 獨互爲芳基、雜芳基、鹵素、-N02、-C(0)0H、羰基、_CN 、-CpC6燒基、-S〇n-(Cl_c6烷基）、-S〇n_(芳基）、-芳氧基、·〇_ 雜芳基、q-c：6烷氧基、N-氧化物、-c(0)_雜環基c3_C6烷基、 -騰環CVC：6烷基、胺基、_〇H或-(CVC6烷基XC(rC6烷基）胺基 、-c(〇>N(C(rC6烷基xc〇_C6烷基）取代基，其中各取代基係獨 立視情況被-OH、CVC6烷氧基、-CrC6烷基、dtcvc6烷基 、-芳氧基、-C(0)0H、-C(0)0(CrC6烷基）、ή 素、·N〇2、-CN 、-s〇n -(C! -c6 燒基）或-C(0)-N(c〇 -C6 燒基）(C(rC6 力完基）取代； 汉3爲雜芳基，視情況被1-5個取代基取代，其中各取代基 係獨iL爲芳基、雜芳基、鹵素、_N〇2、_c(〇)〇H、羰基、 -CN、A-C：6 烷基、-S〇n_(c「C6 烷基）、-S(V(芳基）、_芳氧基 、办雜芳基、C「C6烷氧基、N_氧化物、-c(0)·雜環基c3_c 烷基、-ΝΗ-ί衣C3 -C6烷基、胺基、-OH或-(CG -c6烷基）(cG -c6烷 基）胺基、-C(0>N(CVC6烷基）(CG-C6烷基）取代基，其中各取 代基係獨立視情況被_0H、Cl -A烷氧基、-q -c0烷基、-環 c3-c6烷基、·芳氧基、_C(0)0H、_c(0)0(Ci-C6烷基）、_ 素、_ N〇2、，CN、-SOn-(Cl-C6烷基）或-c(o)-n(cvc6垸基…义烷基） 取代；及 η係獨立爲〇，1或2。 在此方面之又另一項具體實施例中，本發明化合物係以 式⑴或其藥學上可接受之鹽表示，其中 Si，S2& S3係獨立爲 Η、-ΟΗ、函素、-CrC6烷基、-Ν〇2、 CN或-C6燒氧基，其中該烷基與烷氧基係視情況被個 取代基取代；其中各取代基係獨立爲卣素或〇H ; -------------·裝---- (請先閱讀背面之注意事項再填寫本頁) 訂--- -19- 經濟部智慧財產局員工消費合作社印製 1280240 A7 ^ ----—--------- 五、發明說明（17 ) 心A鹵素、羰基、-c「c6烷基、-環c3_c6烷基、_CrC6烯基 、、-C「C6燒氧基、芳基、雜芳基、.、♦環基&以充基、 -胺基、-CVC6烷胺基、-(Cl-C6烷基）(CrC6烷基）胺基、 烷基（氧基X：〆6烷基、-C(0)NH(芳基）、_c(〇)NH(雜芳基）、_ S〇nNH(芳基）、-S〇nNH(雜芳基）、_s〇nNH(Ci _C6 烷基）、_c(〇)n(c〇· C6 烷基 XC0 -C6 烷基）、·8〇η -(CVC6 烷基）…scv(Ci a 烷基） 、-胺甲醞基、-(C! -C：6烷基）-0-C(CN)-二烷胺基或气Ci _c6烷基）· SOn-^ -c0烷基），其中任何基團係視情況被M個取代基取 代；其中各取代基係獨立爲鹵素、_〇H、_CN、_c(〇)(雜環基 C3-C6烷基）、-QPKHCo-C^烷基）、-C(0)_0-芳基、烷氧基、環 烷基氧基、醯基、醯氧基、-環C3 %烷基、雜環基烷 基、芳基、雜芳基、羰基、胺甲醯基或_s〇n_(Ci _c6烷基）； A 爲 CH ; 以2爲芳基’視情況被1-5個取代基取代，其中各取代基係 獨王爲芳基、雜芳基、鹵素、-N02、-C(0)0H、羰基、-CN 、-C「C6燒基、^(^-((:丨义烷基）、-SOn-(芳基）、-芳氧基、-〇-雜芳基、q _C6烷氧基、Ν-氧化物、-C(O)-雜環基C3 -C6烷基、 -NH-環C3 -C6烷基、胺基、-OH或-(CVC6烷基XCq -C6烷基）胺基 、-C(0>N(CtrC6烷基）(C〇 -C6烷基）取代基，其中各取代基係獨 立視情況被-OH、4<：6烷氧基、-CVC6烷基、-環c3-c6烷基 、-芳氧基、-C(0)0H、-(:(0)0((^-06烷基）、卣素、-N02、-CN 、-SOn -(C! -C6 烷基）或-C(O)-N(C0 -C6 烷基）(C0 -C6 烷基）取代；Ri is -CrC6 alkyl, -cycloc3-C6 alkyl, -C2-C6 alkenyl, -qq alkoxy, aryl, heteroaryl, -CN, -heterocyclyl C3-C6 alkyl, -amine , -Cl-C6: fe amine, -(ci-c6 alkyl XCVQ alkyl)amine, _c"C6 alkyl (oxy-c6 alkyl, -C(0)NH(aryl), _C (0) NH(heteroaryl), ·8〇ηΝΗ(aryl), -SOnNH(heteroaryl), _s〇nNH(Ci_C6 alkyl), _c(〇)n((VC6 alkyl)(c〇 · C6 alkyl), -NH-SO/CrQ alkyl), -SOn-(CVC6 alkyl), -aminemethanyl, -(CrC6 alkyl)-oxime-c(CN)-dialkylamino or -(Ci % alkyl >s〇n _(Ci_C6 alkyl)' wherein any group is optionally substituted with from 1 to 5 substituents; wherein each substituent is independently halogen, -OH, -CN, alkoxy , cycloalkyloxy, imyl, decyloxy, cyclo-c3-c6 alkyl, heterocyclyl c3_c6 alkyl, aryl, heteroaryl, carbonyl, aminecaraki or _s〇n_(Cl _c6 alkyl); A is CH; the core is aryl, optionally substituted with 1-5 substituents, wherein each substituent is -18-- This paper scale applies to China National Standard (CNS) A4 specification (21〇X 297 mm) I--------I ---I----book--- -----I (Please read the note on the back and fill out this page) 1280240 A7 Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperative Printed 5, Invention Description (16) Individually aryl, heteroaryl, halogen, -N02, -C(0)0H, carbonyl, _CN, -CpC6 alkyl, -S〇n-(Cl_c6 alkyl), -S〇n_(aryl), -aryloxy, 〇_heteroaryl , qc: 6 alkoxy, N-oxide, -c(0)-heterocyclyl c3_C6 alkyl, -Teng ring CVC: 6 alkyl, amine, 〇H or -(CVC6 alkyl XC (rC6) Alkyl)amino, -c(〇>N(C(rC6alkylxc〇_C6 alkyl) substituent, wherein each substituent is independently taken up by -OH, CVC6 alkoxy, -CrC6 alkyl , dtcvc6 alkyl, -aryloxy, -C(0)0H, -C(0)0(CrC6 alkyl), halogen, ·N〇2, -CN, -s〇n -(C! -c6 Substituted with -C(0)-N(c〇-C6 alkyl) (C(rC6)); Han 3 is heteroaryl, optionally substituted with 1-5 substituents, each substitution The monolithic iL is aryl, heteroaryl, halogen, _N〇2, _c(〇)〇H, carbonyl, -CN, AC:6 alkyl, -S〇n_(c "C6 alkyl", -S (V(aryl), _aryloxy, heteroaryl, C"C6 Oxy, N_oxide, -c(0).heterocyclyl c3_c alkyl, -ΝΗ-ί C3 -C6 alkyl, amine, -OH or -(CG -c6 alkyl) (cG -c6 Alkyl)amino, -C(0>N(CVC6 alkyl)(CG-C6 alkyl) substituent, wherein each substituent is independently taken by the _0H, Cl-A alkoxy, -q-c0 Alkyl, -cycloc3-c6 alkyl, aryloxy, _C(0)0H, _c(0)0(Ci-C6 alkyl), _, _N〇2, CN, -SOn-( Cl-C6 alkyl) or -c(o)-n(cvc6 fluorenyl...alkyl); and η is independently 〇, 1 or 2. In still another specific embodiment of this aspect, the compound of the present invention is represented by the formula (1) or a pharmaceutically acceptable salt thereof, wherein the Si, S2 & S3 series are independently ruthenium, osmium, a cyclin, a -CrC6 alkane a base, -Ν〇2, CN or -C6 alkoxy, wherein the alkyl group and the alkoxy group are optionally substituted by a substituent; wherein each substituent is independently a halogen or 〇H; ----- --------·装---- (Please read the notes on the back and fill out this page) Order --- -19- Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1280240 A7 ^ --- ----------- V. Description of the invention (17) Heart A halogen, carbonyl, -c "c6 alkyl, -cyclo c3_c6 alkyl, _CrC6 alkenyl, -C"C6 alkoxy, Aryl, heteroaryl, ., ♦ ring group & radical, -amino group, -CVC6 alkylamino group, -(Cl-C6 alkyl)(CrC6 alkyl)amino group, alkyl group (oxyl X : 〆6 alkyl, -C(0)NH(aryl), _c(〇)NH(heteroaryl), _S〇nNH(aryl), -S〇nNH(heteroaryl), _s〇nNH (Ci _C6 alkyl), _c(〇)n(c〇·C6 alkylXC0-C6 alkyl), ·8〇η -(CVC6 alkyl)...scv(Ci a alkyl),-aminecarboxamido ,- (C! -C: 6 alkyl)-0-C(CN)-dialkylamino or gas Ci_c6 alkyl)·SOn-^-c0 alkyl), wherein any group is optionally substituted by M Substituent; wherein each substituent is independently halogen, 〇H, _CN, _c(〇) (heterocyclyl C3-C6 alkyl), -QPKHCo-C^alkyl), -C(0)_0-aryl Alkyl, alkoxy, cycloalkyloxy, decyl, decyloxy, -cycloC3 % alkyl, heterocyclylalkyl, aryl, heteroaryl, carbonyl, aminecaraki or _s〇n_ (Ci _c6 alkyl); A is CH; 2 is aryl 'optionally substituted with 1-5 substituents, wherein each substituent is aryl, heteroaryl, halogen, -N02, -C(0 )0H, carbonyl, -CN, -C "C6 alkyl, ^(^-((: 丨) alkyl, -SOn-(aryl), -aryloxy, -〇-heteroaryl, q_C6 Alkoxy, oxime-oxide, -C(O)-heterocyclyl C3 -C6 alkyl, -NH-cyclo C3 -C6 alkyl, amine, -OH or -(CVC6 alkyl XCq -C6 alkyl Amino, -C(0>N(CtrC6 alkyl)(C〇-C6 alkyl) substituent, wherein each substituent is independently taken up by -OH, 4<:6 alkoxy, -CVC6 alkyl , -cycloc3-c6 alkyl, -aryloxy, -C(0)0H, -(:(0)0((^- 06 alkyl), halogen, -N02, -CN, -SOn-(C!-C6 alkyl) or -C(O)-N(C0-C6 alkyl)(C0-C6 alkyl);

R3爲芳基，視情況被1-5個取代基取代，其中各取代基係 獨立爲芳基、雜芳基、鹵素、-N02、-C(0)0H、羰基、-CN -20 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） --------訂---------· (請先閱讀背面之注意事項再填寫本頁) 五、 經濟部智慧財產局員工消費合作社印製 1280240 發明說明（18) 、-CVC6烷基、-S(V(CrC6烷基）、-SOn-(芳基）、·芳氧基、-0-雖芳基、C「C6烷氧基、N-氧化物、-C(0)-雜環基C3 -C6烷基、 -NH-環C3 -C6烷基、胺基、-oh或-(CG -C6烷基XCVQ烷基）胺基 、-c(o)-N(cG-c6烷基）(c0-c6烷基）取代基，其中各取代基係獨 立視情況被-OH、q -C6烷氧基、A -C6烷基、-環C3-C6烷基 、-芳氧基、_C(0)0H、-0(0)0((^-4烷基）、自素、-N02、-CN 、-son-(c「c6烷基）或-C(0)_N(C(rC6烷基）(C(rC6烷基）取代；及 η係獨立爲〇, 1或2。 於此方面之又再另一項具體實施例中，本發明化合物係 以式（I)或其藥學上可接受之鹽表示，其中 Si，S2 及 S3 係獨立爲 η、-0Η、鹵素、-C! -C6 $完基、-Ν〇2、-CN或-C6烷氧基，其中該烷基與烷氧基係視情況被丨_5個 取代基取代；其中各取代基係獨立爲_素或0H ; 心爲i素、羰基、-C6烷基、-環C3-C6烷基、-C2-C6烯基 、-q -C6烷氧基、芳基、雜芳基、-CN、-雜環基c3-c6烷基 、-胺基、-q -c6烷胺基、-(q -c6烷基）((vc6烷基）胺基、-q -C：6烷基（氧基）q -c6烷基、-C(0)NH(芳基）、-C(0)NH(雜芳基）、-SOnNH(芳基）、-SOnNH(雜芳基）、-SOnNHOVQ烷基）、_ C(0)N(C〇-C6烷基）((：〇-(：6烷基）、-NH-SOn-(CVC6烷基）、-S〇n_(Ci -C：6坑基）、-胺甲酿基、-(c〗-C6虎基）-0-C(CN)-二貌胺基或 C0烷基）-SOn -(q 燒基），其中任何基團係視情況被丨_5個取 代基取代；其中各取代基係獨立爲鹵素、-OH、_CN、_e(Q)( 雜環基C：3 -C：6燒基）、-C(O)-O-(C0-C6纟充基）、-C(0)-〇-芳基、垸氧 基、環烷基氧基、醯基、醯氧基、-環C3-C6烷基、雜環基 -21 - 本紙張尺度適用中國國豕橾準（CNS)A4規格（210 X 297公釐） (請先閱讀背面之注意事項再填寫本頁) 裝 訂--- 經濟部智慧財產局員工消費合作社印製 1280240 A7 ___B7____ 五、發明說明（19) crC6垸基、芳基、雜芳基、羰基、胺甲醯基或-SCVO^ -C6 院基）； A 爲 CH ; 爲羰基，視情況被1個取代基取代，其中取代基爲芳基 、雜芳基、-C(0)0H、羰基、-Ci-Cg烷基、-〇-芳基、-0-雜芳 基、-〇-((VC6烷基）、-雜環基C3-C6烷基、-NH_環c3-c6烷基、 胺基、-OH或-(C0-C6烷基）(CG_C6烷基）胺基取代基，其中各取 代基係獨立視情況被-oh、-0% -c6烷基）、-q -c6烷基、-環 C3-C6烷基、-〇(芳基）、-C(0)0H、·QopKrQ烷基）、_素、-N02、-CN、-SOnKCrQ 烷基）、-環 C3-C6 烷基或-C(0)-N(c〇-C6 燒基）(cG_c6烷基）取代； R3爲芳基，視情況被1-5個取代基取代，其中各取代基係 獨立爲芳基、雜芳基、鹵素、·Ν02、-C(0)0H、羰基、-CN 、-crC6烷基、-SOnKCrQ烷基）、-SOn-(芳基）、-芳氧基、-α 雜芳基、CrC6烷氧基、Ν-氧化物、毛(0)-雜環基C3-C6烷基、 _N；Hi c3_c6烷基、胺基、_〇h或-(C()-C6烷基）(C()_c6烷基）胺基 、烷基xq-q烷基）取代基，其中各取代基係獨 立視情況被-OH、CrC6烷氧基、-CrC6烷基、-環C3-C6烷基 、-芳氧基、-C(0)0H、-0(0)0((^-C6烷基）、鹵素、-N02、-CN 、·δοηΆ·(：6烷基）或-CXOH^CVC^烷基）(cvc6烷基）取代；及 n係獨立爲0, 1或2。 在此方面之又另一項具體實施例中，本發明化合物係以 式（I)或其藥學上可接受之鹽表示，其中Si，S2及s3係獨立爲 Η ΌΗ、鹵素、-CVC6烷基、-N02、-CN 或-CrC6烷氧基， -22-- 本紙張尺度適用中國國家標準（CNS)A4規格（21G X 297公爱） -----------'脅裝--------訂--- (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 !28〇24〇 ΚΙ ^------- ---Β7 —------- 五、發明說明（2〇) 其中該淀基與烷氧基係視情況被1-5個取代基取代；其中各 取代基係獨立爲_素或0Η ; h爲_素、羰基、<丨-C6烷基、-環C3 -C6烷基、-C2 -C6烯基 、-c〗-c6烷氧基、芳基、雜芳基、_CN、_雜環基烷基、 ，胺基、-q -c6烷胺基、_(Cl _c6烷基）(Ci夂烷基）胺基、& a烷 基（氧基）Ci -c0 烷基、-C(0)NH(芳基）、-C(0)NH(雜芳基）、-SOnNH( 芳基）、-S〇nNH(雜芳基）、-SOnNH% -C6 烷基）、-C(0)N(C〇-CV^ 基）(C〇-C6 燒基）、-顧·％ _(Ci _c6 燒基）、_S(V(C「C6 垸基）、_胺 甲酿基、-(q -C6烷基）-〇-C(CN)c烷胺基或-(C! -C6烷基）-S〇n· (crC0燒基），其中任何基團係視情況被u個取代基取代； 其中各取代基係獨立爲鹵素、_〇H、-CN、-C(0)(雜環基c3 -C6虎基）、-〇：(0)-〇-((：()-〇：6烷基）、-C(0)-0-芳基、烷氧基、環烷 基氧基、醯基、醯氧基、·環C3_C6烷基、雜環基C3-C6烷基 、芳基、雜芳基、羰基、胺甲醯基或-S〇n-(CrC6烷基）； A 爲 CH ; 化爲胺甲醯基，視情況被丨_2個取代基取代，其中各取代 基係獨立爲羰基、-CN…Ci _C6烷基…s〇n-(CrC6烷基）、_〇_ 芳基、-α雜芳基、_c(0)·雜環基c3 _c6烷基…NH-環c3 烷基 、胺基、-OH或-c! -C6烷基（胺基）取代基，其中各取代基係 獨立視情況被-0H、-0(CrC6烷基）、·〇(芳基）、-C〇〇H、- C(X)(crc6 烷基）、卣素、-n〇2、-cn 或-ccco-nccvq 烷基）(C〇-C6烷基）取代；R3 is an aryl group, optionally substituted by 1 to 5 substituents, wherein each substituent is independently aryl, heteroaryl, halogen, -N02, -C(0)0H, carbonyl, -CN-20 - The paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -------- order---------· (please read the notes on the back and fill out this page) V. Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Printed 1280240 Description of Invention (18), -CVC6 alkyl, -S(V(CrC6 alkyl), -SOn-(aryl), ·aryloxy, -0- Although aryl, C "C6 alkoxy, N-oxide, -C(0)-heterocyclyl C3 -C6 alkyl, -NH-cyclo C3 -C6 alkyl, amine, -oh or -(CG -C6 alkyl XCVQ alkyl)amino, -c(o)-N(cG-c6 alkyl)(c0-c6 alkyl) substituent, wherein each substituent is independently -OH, q-C6 as appropriate Alkoxy, A-C6 alkyl, -cyclo C3-C6 alkyl, -aryloxy, _C(0)0H, -0(0)0((^-4 alkyl), arginine, -N02, -CN, -son-(c"c6 alkyl) or -C(0)_N(C(rC6 alkyl)(C(rC6 alkyl) substituted; and η is independently 〇, 1 or 2. In this respect In yet another specific embodiment, the compounds of the invention are (I) or a pharmaceutically acceptable salt thereof, wherein Si, S2 and S3 are independently η, -0, halogen, -C! -C6 $, -Ν〇2, -CN or -C6 alkoxy a group wherein the alkyl group and the alkoxy group are optionally substituted by 丨5 substituents; wherein each substituent is independently _ or 0H; the core is i, carbonyl, -C6 alkyl, -cyclo C3- C6 alkyl, -C2-C6 alkenyl, -q-C6 alkoxy, aryl, heteroaryl, -CN, -heterocyclyl c3-c6 alkyl, -amino group, -q-c6 alkylamino group , -(q -c6 alkyl)((vc6 alkyl)amino, -q -C:6 alkyl(oxy)q-c6 alkyl, -C(0)NH(aryl), -C( 0) NH(heteroaryl), -SOnNH(aryl), -SOnNH(heteroaryl), -SOnNHOVQalkyl), _C(0)N(C〇-C6 alkyl)((:〇-( :6 alkyl), -NH-SOn-(CVC6 alkyl), -S〇n_(Ci-C: 6 pit base), -amine methyl alcohol, -(c)-C6 tiger base)-0-C (CN)-dimorphoamine or C0 alkyl)-SOn-(q alkyl), wherein any group is optionally substituted with 丨5 substituents; wherein each substituent is independently halogen, -OH, _CN, _e(Q) (heterocyclic group C: 3 -C: 6 alkyl), -C(O)-O-(C0-C6纟), -C(0)-〇-芳, decyloxy, cycloalkyloxy, decyl, decyloxy, -cyclo C3-C6 alkyl, heterocyclyl-21 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 () Please read the note on the back and fill out this page. Binding --- Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1280240 A7 ___B7____ V. Description of Invention (19) crC6 fluorenyl, aryl, heteroaryl , carbonyl, carbamoyl or -SCVO^-C6); A is CH; is carbonyl, optionally substituted by 1 substituent, wherein the substituent is aryl, heteroaryl, -C(0)0H , carbonyl, -Ci-Cg alkyl, -〇-aryl,-0-heteroaryl, -〇-((VC6 alkyl), -heterocyclyl C3-C6 alkyl, -NH_cyclo c3-c6 An alkyl, amino, -OH or -(C0-C6 alkyl)(CG_C6 alkyl)amino substituent wherein each substituent is independently -oh, -0% -c6 alkyl), -q -c6 alkyl, -cyclo C3-C6 alkyl, - fluorene (aryl), -C(0)0H, · QopKrQ alkyl), _ s, -N02, -CN, -SOnKCrQ alkyl), - ring C3-C6 alkyl or -C(0)-N(c〇-C6 alkyl) (cG_c6 alkyl) substituted; R3 is aryl, optionally 1-5 substituents Substituted, wherein each substituent is independently aryl, heteroaryl, halogen, Ν02, -C(0)0H, carbonyl, -CN, -crC6 alkyl, -SOnKCrQ alkyl), -SOn-(aryl) , -aryloxy, -α heteroaryl, CrC6 alkoxy, oxime-oxide, hair (0)-heterocyclyl C3-C6 alkyl, _N; Hi c3_c6 alkyl, amine, 〇h Or a -(C()-C6 alkyl)(C()-c6 alkyl)amino, alkyl xq-q alkyl) substituent wherein each substituent is independently taken up by -OH, CrC6 alkoxy, -CrC6 alkyl, -cyclo C3-C6 alkyl, -aryloxy, -C(0)0H, -0(0)0((^-C6 alkyl), halogen, -N02, -CN, ·δοηΆ ((6 alkyl) or -CXOH^CVC^alkyl) (cvc6 alkyl) substituted; and n is independently 0, 1 or 2. In still another embodiment of this aspect, the compound of the present invention is represented by the formula (I) or a pharmaceutically acceptable salt thereof, wherein the Si, S2 and s3 are independently anthracene, halogen, -CVC6 alkyl , -N02, -CN or -CrC6 alkoxy, -22-- This paper scale applies to China National Standard (CNS) A4 specification (21G X 297 public) ----------- --------Book --- (Please read the note on the back and fill out this page) Printed by the Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative! 28〇24〇ΚΙ ^------- --Β7 —------- V. Description of the invention (2〇) wherein the aryl group and the alkoxy group are optionally substituted by 1 to 5 substituents; wherein each substituent is independently _ or 0 Η h is _ 素, carbonyl, < 丨-C6 alkyl, -cyclo C3 -C6 alkyl, -C 2 -C 6 alkenyl, -c -c6 alkoxy, aryl, heteroaryl, _CN, _ Heterocyclylalkyl, an amine group, a -q-c6 alkylamino group, a _(Cl _c6 alkyl)(Ci 夂alkyl)amino group, & a alkyl (oxy)Ci-c0 alkyl group, - C(0)NH(aryl), -C(0)NH(heteroaryl), -SOnNH(aryl), -S〇nNH(heteroaryl), -SOnNH%-C6 alkyl), -C (0)N(C〇-CV^ base )(C〇-C6 alkyl), -Gu·% _(Ci_c6 alkyl), _S(V(C"C6 fluorenyl), _amine methyl, -(q -C6 alkyl)-〇- C(CN)calkylamino or -(C!-C6 alkyl)-S〇n·(crC0 alkyl), wherein any group is optionally substituted by u substituents; wherein each substituent is independently Halogen, _〇H, -CN, -C(0) (heterocyclyl c3 -C6), 〇:(0)-〇-((:()-〇:6 alkyl), -C( 0)-0-aryl, alkoxy, cycloalkyloxy, decyl, decyloxy, cyclo C3_C6 alkyl, heterocyclic C3-C6 alkyl, aryl, heteroaryl, carbonyl, amine Mercapto or -S〇n-(CrC6 alkyl); A is CH; is converted to an amine carbenyl group, optionally substituted by 丨_2 substituents, wherein each substituent is independently a carbonyl group, -CN...Ci _C6 alkyl...s〇n-(CrC6 alkyl), _〇_ aryl, -αheteroaryl, _c(0)·heterocyclyl c3 _c6 alkyl...NH-ring c3 alkyl, amine group, - OH or -c! -C6 alkyl (amino) substituent, wherein each substituent is independently -0H, -0(CrC6 alkyl), 〇(aryl), -C〇〇H, - C(X)(crc6 alkyl), halogen, -n〇2, -cn or -ccco-nccvq alkyl) (C〇 -C6 alkyl) substitution;

R3爲芳基，視情況被1-5個取代基取代，其中各取代基係 獨立爲芳基、雜芳基、鹵素、-N〇2、-C(〇)〇H、羰基、-CN -23- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ------------裝--------訂--------- (請先閱讀背面之注意事項再填寫本頁) 1280240 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（21 )R3 is an aryl group, optionally substituted by 1 to 5 substituents, wherein each substituent is independently aryl, heteroaryl, halogen, -N〇2, -C(〇)〇H, carbonyl, -CN- 23- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) ------------Installation--------Set------- -- (Please read the note on the back and fill out this page) 1280240 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 V. Invention description (21)

、-ci-c6燒基、4〇11_((：1七6烷基）…s〇n_(芳基）、-芳氧基、-〇_ 雜芳基、q-C6烷氧基、N-氧化物、-C(0)-雜環基C3-C6烷基、 _NH-環C3 _C6烷基、胺基、-0H或-(C〇 -C6烷基XQ -C6烷基）胺基 、eC(〇)-N(C(rC6烷基）((^(6烷基）取代基，其中各取代基係獨 立視情況被-OH、CVC6烷氧基、-CrC6烷基、-環C3-C6烷基 、-芳氧基、-C(0)0H、-C(0)0(CrC6 烷基）、_ 素、·Ν02、-CN 、-SOdCrC^烷基）或-C(0)-N(C()-C6烷基）(c〇_C6烷基）取代；及 η係獨立爲〇, 1或2。 在此方面之又另一項具體實施例中，本發明化合物係以 式（I)或其藥學上可接受之鹽表示，其中 Si，S2 及 S3 係獨立爲 η、_〇Η、鹵素、-C! ·<Ζ：6 燒基、-Ν02、-CN或-C^C：6烷氧基，其中該烷基與烷氧基係視情況被1-5個 取代基取代；其中各取代基係獨立爲_素或〇H ; 心爲_素、羰基、-q-Q烷基、-環C3-C6烷基、-CyC6烯基 、-q -c6烷氧基、芳基、雜芳基、-CN、_雜環基c3-C6烷基、 -胺基、-Ci -c6烷胺基、-(q _c6烷基）(Cl _c6烷基）胺基、_Ci _c6烷 基（氧基)C「C0 烷基、-C(0)NH(芳基）、雜芳基）、·8〇ηΝΗ( 芳基）、-SOnNH(雜芳基）、-S〇nNH(Cl _c6 烷基）、-C(〇)N(C〇 _c6 烷 基）(C(rC6 ；l充基）、-NH-SOn -(Ci -C6 烷基）、-SOn -(C! -C6 烷基）、-胺 甲醒基、烷基）_〇-C(CN)^烷胺基或((:丨义烷基）-SOn-(C! -C6垸基），其中任何基團係視情況被1-5個取代基取代； 其中各取代基係獨立爲鹵素、_〇H、-CN、_c(〇)(雜環基& _ c6烷基）、-C(0)-0-(C(rC6烷基）、_c(0)-0-芳基、烷氧基、環烷 基氧基、醯基、醯氧基、-環C3_C6烷基、雜環基C3_C6烷基 -24- 本紙張尺度適用中國國家標準（CNS)A4規格（21〇 x 297公爱） ------------裝---- (請先閱讀背面之注意事項再填寫本頁) 訂---------啤 128〇24〇 A7 ^ 1~-----B7^_______ 五、發明說明（22 ) 、芳基、雜芳基、羰基、胺甲醯基或_S〇n_(Ci_C6烷基）； A 爲 CH ; (請先閱讀背面之注意事頊再填寫本頁) R2與各獨立爲芳基，視情況經取代，藉由硫基、氧纂 或（〇丨-C4燒基）橋基互相連接，以形成稠合三環系統；及 η係獨立爲〇, 1或2。 在此方面又另一項具體實施例中，本發明化合物係以式⑴ 或其藥學上可接受之鹽表示，其中 S!，S2及S3係獨立爲Η、-ΟΗ、鹵素、-C6燒基、_Ν〇、_ CN或-(^-(^烷氧基；, -ci-c6 alkyl, 4〇11_((:1-7-hexyl)...s〇n_(aryl), -aryloxy, -〇_heteroaryl, q-C6 alkoxy, N- Oxide, -C(0)-heterocyclyl C3-C6 alkyl, _NH-cyclo C3 -C6 alkyl, amine,-0H or -(C〇-C6 alkyl XQ-C6 alkyl)amine, eC (〇)-N(C(rC6 alkyl)((^(6 alkyl)) substituent, wherein each substituent is independently -OH, CVC6 alkoxy, -CrC6 alkyl, -cyclo C3-C6 Alkyl, -aryloxy, -C(0)0H, -C(0)0(CrC6 alkyl), _ 素, Ν02, -CN, -SOdCrC^alkyl) or -C(0)-N (C()-C6 alkyl) (c〇_C6 alkyl) substituted; and η is independently 〇, 1 or 2. In still another embodiment of this aspect, the compound of the invention is of the formula ( I) or a pharmaceutically acceptable salt thereof, wherein Si, S2 and S3 are independently η, 〇Η, halogen, -C! ·<Ζ:6 alkyl, -Ν02, -CN or -C^ C: 6 alkoxy, wherein the alkyl group and the alkoxy group are optionally substituted by 1 to 5 substituents; wherein each substituent is independently _ or 〇H; the core is _, carbonyl, -qQ alkane Base, -cyclo C3-C6 alkyl, -CyC6 alkenyl, -q-c6 alkoxy, aryl, hetero , -CN, _heterocyclyl c3-C6 alkyl, -amino, -Ci-c6 alkylamino, -(q-c6 alkyl)(Cl _c6 alkyl)amine, _Ci _c6 alkyl (oxy C"C0 alkyl, -C(0)NH(aryl), heteroaryl), ·8〇ηΝΗ(aryl), -SOnNH(heteroaryl), -S〇nNH(Cl _c6 alkyl) , -C(〇)N(C〇_c6 alkyl) (C(rC6;l), -NH-SOn-(Ci-C6 alkyl), -SOn-(C!-C6 alkyl), - amine ketone, alkyl) 〇 C -C(CN) alkylamine or ((: decyl)-SOn-(C! -C6 fluorenyl), wherein any group is optionally - 5 substituents substituted; wherein each substituent is independently halogen, _〇H, -CN, _c(〇) (heterocyclyl & _ c6 alkyl), -C(0)-0-(C( rC6 alkyl), _c(0)-0-aryl, alkoxy, cycloalkyloxy, decyl, decyloxy, -cyclo C3_C6 alkyl, heterocyclic C3_C6 alkyl-24- paper scale Applicable to China National Standard (CNS) A4 specification (21〇x 297 public) ------------Install---- (Please read the note on the back and fill out this page) ------- beer 128〇24〇A7 ^ 1~-----B7^_______ V. Description of invention (22), aryl, heteroaryl, carbonyl , Aminoguanidinyl or _S〇n_(Ci_C6 alkyl); A is CH; (Please read the note on the back and fill out this page) R2 and each are independently aryl, as appropriate, by sulfur The base, oxonium or (〇丨-C4 alkyl) bridging groups are interconnected to form a fused tricyclic system; and the η series is independently 〇, 1 or 2. In still another specific embodiment of this aspect, the compound of the present invention is represented by the formula (1) or a pharmaceutically acceptable salt thereof, wherein the S!, S2 and S3 are independently oxime, -fluorene, halogen, -C6 alkyl , _Ν〇, _ CN or -(^-(^ alkoxy;

Ri爲_素、羰基、-C!-C6烷基、_環C3-C6烷基、_c2c6烯基 、-<VC6烷氧基、芳基、雜芳基、-CN、_雜環基C3_C6统基、 •胺基、-C! -C6烷胺基、-(q -C6烷基）(C! -C6烷基）胺基、& &烷 基（氧基）q % 烷基、-C(0)NH(芳基）、-C(0)NH(雜芳基）、_s〇nNH( 芳基）、-SOnNH(雜芳基）、-SOJHA-q 烷基）、-C(O)N(C0-C〆 基）(C(rC6 烷基）、-NH-SOn -(q -C6 烷基）、-SOn -(q _C6 烷基）、-胺 甲醯基、-(Ci -C6燒基）-0-C(CN)-二燒胺基或-C6燒基）_s〇n_ (Ci -C6 fe基），其中任何基團係視情況被Μ個取代基’取代； 經濟部智慧財產局員工消費合作社印製 其中各取代基係獨立爲鹵素、-OH、-CN、-C(0)(雜環基c3 -C6烷基）、-C(0)-0-(CVC6烷基）、-C(0)-0-芳基、烷氧基、環烷 基氧基、醯基、醯氧基、-環C3 -C6烷基、雜環基c3 -c6烷基 、芳基、雜芳基、羰基、胺甲醯基或-SOn-iq -c6烷基）； A 爲 CH ; R2爲-(Ci 烷基）-SOn -(Ci -C6烷基），視情況被1-5個取代基 取代，其中各取代基係獨立爲鹵素、-N02、-COOH、羰基、 -25- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） !28〇240 A7 i *經濟部智慧財產局員工消費合作社印製 五、發明說明（23) -CN、-CrC6烷基、-SOn-Cq-C^烷基）、-Ο芳基、-0-雜芳基、-C(〇>雜環基C3 -C6烷基、-NH-環C3 -C6烷基、胺基、-0H或-C6烷基（胺基）取代基，其中各取代基係獨立視情況被-oh、 -Ο% -C6 烷基）、-0(芳基）、-C00H、-COCKC厂c6 烷基）、_ 素、 -N02、-CN 或-(：(0)-Ν((ν〇6烷基）(CVC6烷基）取代； R3爲芳基視，情況被1-5個取代基取代，其中各取代基係 獨立爲芳基、雜芳基、鹵素、-N02、-C(0)0H、羰基、-CN 、-坑基、-S0n-(C「C6：fe 基）、-S0n-(芳基）、-芳氧基、-〇-雜芳基、Q -C6燒氧基、N-氧化物、-C(0)-雜環基C3 -C6燒基、 -NH-環C3-C6烷基、胺基、-oh或-(CVC6烷基）(C()-C6烷基）胺基 、-C(0)-N(CVC6烷基）(cG-c6烷基）取代基，其中各取代基係獨 亙視情況被-OH、Cl -C6烷氧基、-Ci -C6烷基、-環c3 -C6烷基 、-芳氧基、-C(0)0H、-C(0)0(C「C6 烷基）、_ 素、-N〇2、_CN 、-SOn-(C「C6燒基）或-cx〇>N(C(rC6烷基）(C(rc6烷基）取代；及 η係獨立爲〇, 1或2。 在此方面之又另一項具體實施例中，本發明化合物係以 式⑴或其藥學上可接受之鹽表示，其中 S】，S2及s3係獨立爲Η、-0Η、鹵素、_C1 烷基、·ν〇2、· CN或-q -C0烷氧基，其中該烷基與烷氧基係視情況被丨_5個 取代基取代；其中各取代基係獨立爲_素或〇H ;Ri is _, carbonyl, -C!-C6 alkyl, _cyclo C3-C6 alkyl, _c2c6 alkenyl, -<VC6 alkoxy, aryl, heteroaryl, -CN, _heterocyclyl C3_C6 Alkyl, -amino group, -C!-C6 alkylamino group, -(q-C6 alkyl)(C!-C6 alkyl)amino group, && alkyl (oxy)q % alkyl group, -C(0)NH(aryl), -C(0)NH(heteroaryl), _s〇nNH(aryl), -SOnNH(heteroaryl), -SOJHA-q alkyl), -C( O) N(C0-C fluorenyl) (C(rC6 alkyl), -NH-SOn-(q-C6 alkyl), -SOn-(q _C6 alkyl), -aminemethanyl, -(Ci -C6 alkyl)-0-C(CN)-dialkylamine or -C6 alkyl)_s〇n_ (Ci-C6 fe), wherein any group is optionally substituted by a substituent; The Ministry of Intellectual Property's employee consumption cooperative printed the substituents independently as halogen, -OH, -CN, -C(0) (heterocyclyl c3 -C6 alkyl), -C(0)-0-(CVC6 Alkyl), -C(0)-0-aryl, alkoxy, cycloalkyloxy, decyl, decyloxy, -cyclo C3 -C6 alkyl, heterocyclyl c3 -c6 alkyl, aromatic Alkyl, heteroaryl, carbonyl, carbamoyl or -SOn-iq-c6 alkyl; A is CH; R2 is -(Ci alkyl)-SOn-(Ci-C6 Alkyl), optionally substituted with 1-5 substituents, each of which is independently halogen, -N02, -COOH, carbonyl, -25- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) !28〇240 A7 i *Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (23) -CN, -CrC6 alkyl, -SOn-Cq-C^alkyl), -Ο芳,-0-heteroaryl, -C(〇>heterocyclyl C3 -C6 alkyl, -NH-cyclo C3 -C6 alkyl, amine,-0H or -C6 alkyl (amino) substituent , wherein each substituent is independently -oh, -Ο% -C6 alkyl), -0(aryl), -C00H, -COCKC plant c6 alkyl), _, -N02, -CN or - (:(0)-Ν((ν〇6 alkyl)(CVC6 alkyl) substituted; R3 is aryl, and the case is substituted by 1-5 substituents, wherein each substituent is independently aryl, heteroaryl Base, halogen, -N02, -C(0)0H, carbonyl, -CN, -pile, -S0n-(C "C6:fe"), -S0n-(aryl), -aryloxy, -〇 -heteroaryl, Q-C6 alkoxy, N-oxide, -C(0)-heterocyclyl C3 -C6 alkyl, -NH-cyclo C3-C6 alkyl, amine, -oh or -( CVC6 alkyl)(C()-C6 Amino, -C(0)-N(CVC6 alkyl)(cG-c6 alkyl) substituent wherein each substituent is mono-independently -OH, Cl-C6 alkoxy, -Ci- C6 alkyl, -cycloc3 - C6 alkyl, -aryloxy, -C(0)0H, -C(0)0 (C"C6 alkyl", _, -N〇2, _CN, -SOn - (C "C6 alkyl" or -cx 〇 > N (C (rC6 alkyl) (C (rc6 alkyl) substituted; and η is independently 〇, 1 or 2. In still another embodiment of this aspect, the compound of the present invention is represented by the formula (1) or a pharmaceutically acceptable salt thereof, wherein the S, S2 and s3 are independently oxime, -0 oxime, halogen, _C1 alkyl , ν 〇 2, · CN or -q -C0 alkoxy, wherein the alkyl group and the alkoxy group are optionally substituted by 丨 5 substituents; wherein each substituent is independently _ or 〇H;

Rl爲卣素、羰基、-C1-C6烷基、·環C3_C6烷基、-C2-C6烯基 、-Cl_C6 ：^氧基、芳基、雜芳基、_CN、_雜環基C3-C6烷基 、-胺基、义义烷胺基、_(C「C6烷基）(Ci_C6烷基）胺基、 C0烷基（氧基）(：1夂烷基…c(〇)NH(芳基）、七⑼簡(雜芳基）、_ -26- - _ 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ------------裝---- (請先閱讀背面之注意事項再填寫本頁) 訂--- #· 128〇24〇 經濟部智慧財產局員工消費合作社印製 A7 B7 1、發明說明（24) 3011丽（芳基）、-80111^(雜芳基）、-8011丽((：1-(：6烷基）、-C(0)N(C〇-C6烷基）(Cq-C6烷基）、-NH-SOn-(q -C6烷基）、-SOn-(q -C6烷基）、-胺甲醯基、-(C! -C6烷基）-〇_C(CN)-二烷胺基或-(q -c6烷基vsOnKq -c6烷基），其中任何基團係視情況被μ5個取 代基取代；其中各取代基係獨立爲鹵素、-OH、-CN、-C(0)( 雜環基 c3 -C6 燒基）、-(：(0)-0·(〇：〇 -C6 燒基）、-C(0)-0-芳基、垸氧 基、環烷基氧基、醯基、醯氧基、-環c3 -c6烷基、雜環基 c3-c6烷基、芳基、雜芳基、羰基、胺甲醯基或-SO^q -c6 基）； A 爲 CH ; R2爲-C(0)N-(C〇-C6烷基）(C0-C6烷基），視情況被1-5個取代 基取代，其中各取代基係獨立爲鹵素、-N02、-COOH、羰 基、-CN、-CVq烷基、-SOn-A-Cg烷基）、芳氧基、-雜芳基 氧基、-C(0)-雜環基C3-C6烷基、-NH-環C3-C6烷基、胺基、-0H或-C6烷基（胺基）取代基，其中各取代基係獨立視情 況被-OH、-0(C「C6 烷基）、-〇(芳基）、-C〇〇H、-COCKq -C6 烷 基）、_ 素、-N02、-CN 或 Τ(0)-Ν((ν〇6 烷基）(C(rC6 烷基）取代； R*3爲芳基，視情況被1-5個取代基取代，其中各取代基係 獨立爲芳基、雜芳基、鹵素、-NO]、-C(0)〇H、馥基、-CN 、-CrC6燒基、-S〇n-(Cl-C6垸基）、-SOn-(芳基）、-芳氧基、0-雜芳基、Ci -C：6烷氧基、N-氧化物、-C(0)-雜環基c3 -c6烷基、 -NH-環C3 -C6烷基、胺基、-OH或-(CG -C6烷基）(cG -C6烷基）胺基 、-QC^-N^Co-C6燒基）(C〇-C6燒基）取代基，其中各取代基係獨 ϋ視情況被·ΟΗ、（3丨-C：6 氧基、-CrC：6燒基、·環c3 -c6燒基 -27- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -----------^裝--------訂--------- (請先閱讀背面之注意事項再填寫本頁) 1280240 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（25) 、-芳氧基、<(0)〇H、-C(0)0(Ci-C6烷基）、自素、-N02、-CN 、-son-(c「c6烷基）或-C(0)_N(C()_C6烷基）(C(rc6烷基）取代；及 n係獨立爲0, 1或2。 在此方面之又另一項具體實施例中，本發明化合物係以 式（I)或其藥學上可接受之鹽表示，其中 Si，S2及S3係獨立爲Η、-OH、鹵素、-CrC6烷基、-N02、-CN或_crC6烷氧基，其中該烷基與烷氧基係視情況被1-5個 取代基取代；其中各取代基係獨立爲_素或0H ;Rl is halogen, carbonyl, -C1-C6 alkyl, cyclo C3_C6 alkyl, -C2-C6 alkenyl, -Cl_C6:oxy, aryl, heteroaryl, _CN, _heterocyclyl C3-C6 Alkyl, -amino, iminoalkylamino, _(C "C6 alkyl" (Ci_C6 alkyl) amine, C0 alkyl (oxy) (: 1 夂 alkyl ... c (〇) NH (fang Base), seven (9) Jane (heteroaryl), _ -26- - _ This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) ------------ ---- (Please read the notes on the back and fill out this page) Order--- #·128〇24〇Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Print A7 B7 1. Invention Description (24) 3011 Li (Fang) Base), -80111^(heteroaryl), 8-011 丽((: 1-(:6 alkyl), -C(0)N(C〇-C6 alkyl)(Cq-C6 alkyl), - NH-SOn-(q-C6 alkyl), -SOn-(q-C6 alkyl), -aminecarbamyl, -(C!-C6 alkyl)-indole_C(CN)-dialkylamino Or -(q-c6 alkyl vsOnKq-c6 alkyl), wherein any group is optionally substituted with μ5 substituents; wherein each substituent is independently halogen, -OH, -CN, -C(0) ( Heterocyclic group c3 -C6 alkyl), -(:(0)-0·(〇:〇-C6 alkyl) , -C(0)-0-aryl, decyloxy, cycloalkyloxy, decyl, decyloxy, cyclo-c3 -c6 alkyl, heterocyclyl c3-c6 alkyl, aryl, hetero Aryl, carbonyl, aminemethanyl or -SO^q-c6); A is CH; R2 is -C(0)N-(C〇-C6 alkyl)(C0-C6 alkyl), as appropriate Substituted by 1-5 substituents, each of which is independently halogen, -N02, -COOH, carbonyl, -CN, -CVq alkyl, -SOn-A-Cg alkyl), aryloxy, -hetero Aryloxy, -C(0)-heterocyclyl C3-C6 alkyl, -NH-cyclo C3-C6 alkyl, amine, -OH or -C6 alkyl (amino) substituents, wherein each substitution The base system is independently -OH, -0 (C "C6 alkyl", - fluorene (aryl), -C〇〇H, -COCKq -C6 alkyl), _, -N02, -CN or Τ (0)-Ν((ν〇6 alkyl)(C(rC6 alkyl) substituted; R*3 is aryl, optionally substituted with 1-5 substituents, wherein each substituent is independently aryl, Heteroaryl, halogen, -NO], -C(0)〇H, fluorenyl, -CN, -CrC6 alkyl, -S〇n-(Cl-C6 fluorenyl), -SOn-(aryl), -aryloxy, 0-heteroaryl, Ci-C:6 alkoxy, N-oxide, -C(0)-heterocyclyl c3 -c6 alkyl -NH-cyclo C3 -C6 alkyl, amine, -OH or -(CG -C6 alkyl)(cG-C6 alkyl)amino, -QC^-N^Co-C6 alkyl) (C〇 -C6 alkyl) substituent in which each substituent is monotonously ΟΗ, (3丨-C: 6 oxy, -CrC: 6 alkyl, cycloc3 -c6 alkyl -27- paper The scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -----------^装--------订--------- (please Read the notes on the back and fill out this page. 1280240 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Print A7 B7 V. Invention Description (25), -Aryloxy, <(0)〇H,-C(0) 0 (Ci-C6 alkyl), arginine, -N02, -CN, -son-(c"c6 alkyl) or -C(0)_N(C()_C6 alkyl) (C(rc6 alkyl) Substituted; and n is independently 0, 1 or 2. In still another specific embodiment of this aspect, the compound of the present invention is represented by the formula (I) or a pharmaceutically acceptable salt thereof, wherein the Si, S2 and S3 are independently oxime, -OH, halogen, -CrC6 An alkyl group, -N02, -CN or _crC6 alkoxy group, wherein the alkyl group and the alkoxy group are optionally substituted by 1 to 5 substituents; wherein each substituent is independently _ or 0H;

Ri爲i素、羰基、-C6烷基、-環C3-C6烷基、-c2-c6烯基 、-CrC6烷氧基、芳基、雜芳基、-CN、-雜環基烷基 、·胺基、-C〗-c6烷胺基、-(c! -C6烷基XC! -C6烷基）胺基、-C6烷基（氧基）Ci -C6烷基、-C(0)NH(芳基）、-C(0)NH(雜芳基）、_ QOMCo-Cg烷基）(C〇-C6烷基）、-NH-SOn-(q -C6烷基）、-SOn-(C! -C6烷基）、-胺甲醯基、-(q -C6烷基）-〇-C(CN)-二烷胺基或_(Ci _ 匸6 fe基）-SOn-(Ci -C：6燒基），其中任何基團係視情況被丨_5個取 代基取代；其中各取代基係獨立爲鹵素、_QH、-CN、 雜環基C3-c0ί完基）、-ccco-CHCo-C6燒基）、-c(0)_0_芳基、烷氧 基、環基氧基、醯基、醯氧基、-環c3 -C6貌基、雜環基 CrGfe基、芳基、雜芳基、談基、胺甲酿基或-SQ。·％ _c6 烷基）； A 爲 CH ; R2 爲-CN ; 汉3爲芳基’視情況被1-5個取代基取代，其中各取代基係 -28- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -----------裝--------訂--------- (請先閱讀背面之注意事項再填寫本頁) 1280240 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（26 ) 獨立爲芳基、雜芳基、s素、·N〇2、七(〇輝、窥基、 、-Ci -c6 烷基、_s〇n-(Ci _c6 烷基）、_s〇n_(芳基）、_芳氧基、·〇· 雜芳基、CA燒氧基、N_氧化物、_c(0)_雜環基C3_C6烷基、 -NH-環-C0燒基、胺基、_0H或_(c〇 a垸基）(c〇 a燒基）胺基 、-c(〇)-n(c0-c6垸基瓜-⑽基）取代基，其中各取代基係獨 立視情況被-OH、以6燒氧基、_以6燒基、^基 、-芳氧基、-c(0)0H、-C(0)0(Cl_C6烷基）、_ 素、_N〇2、_cn 、-SOn-A-C6烷基）或_C(0)_N(C(rC6烷基 Xc〇_c6烷基）取代；及 η係獨立爲〇, 1或2。 在此方面之又另一項具體實施例中，本發明化合物係以 式⑴或其藥學上可接受之鹽表示，其中 SpS2及s3係獨立爲Η、-ΟΗ、ί素、-Ci-C6烷基、_Ν〇2… CN或-C「C6：^氧基，其中該燒基與垸氧基係視情況被卜⑽ 取代基取代；其中各取代基係獨立爲_素或〇Η ; 心爲-C0烷基，視情況被υ個取代基取代；其中各取 代基係獨立爲^素、-OH、-CN、-Cl_C0烷基、_環〇3_^烷基 、-C(〇X雜環基（：3-(：6 淀基）、-C(0>a(CVC6 烷基）、_c⑼6_ 芳& 基、-C「C6烷氧基、-(Co-C：6烷基XCo-C6烷基）胺基、環烷基氧 基、醯基、醯氧基、-環C3-C：6烷基、雜環基c3_C6烷基二芳 基、雜芳基、羰基、胺甲醯基或-S〇n-(Ci _C6烷基）； A 爲 CH， R2與R3各獨立爲芳基或雜芳基，其中每—個係視情況被卜 5個取代基取代，其中各取代基係獨立爲芳基、雜芳基、 卣素、-N〇2、-C(0)0H、窥基、_CN、_Ci_c6燒基、 -----------裝--------訂--------- (請先閱讀背面之注意事項再填寫本頁) -29 1280240 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（27) C6燒基）、-SOn-(芳基）、芳氧基、-雜芳基氧基、Cl_c6烷氧基 、N-氧化物、-C(0)-雜環基c3 -c6烷基、-NH-環C3 -C6烷基、胺 基、-0H 或-(C0-C6 烷基烷基）胺基、-C(0)-N(C〇-C6 烷基 )(C〇-C6烷基）取代基，其中各取代基係獨立視情況被_〇H、 CrC$氧基、-CrQ烷基、-環c3-C6烷基、芳氧基、-c(0)0H 、-C(0)0(C「C6 烷基）、鹵素、-N〇2、-CN、_s〇n-(CrC6 烷基） 或-C(0)_N(C〇 -C6 fe 基）(C〇 -C6 统基）取代； R2與&可視情況被硫基、氧基或（Cl_C4烷基）橋基連接， 以形成稠合三環系統；及 η係獨立爲〇, 1或2 ; 在此方面之又另一項具體實施例中，本發明化合物係以 式⑴或其藥學上可接受之鹽表示，其中 8^82*83各爲 Η ; 心爲-C0烷基，視情況被ι_5個取代基取代；其中各取 代基係獨j!爲自素、-OH、-CN、-C〗-C；6燒基、環c3 -C6燒基 、-C(〇X雜環基 q-C6 烷基）、·(：(0)-0_% 烷基）、_c(〇> 芳氧 基、_ci Ά 氧基、-(CQ -C：6烷基XCo -C：6烷基）胺基、環烷基氧 基、SS基、Sf氧基、-環(：3_(：6烷基、雜環基c3-c6烷基、芳 基、雜芳基、羰基、胺甲醯基或-C6烷基）； A 爲 CH， &與&各獨立爲芳基或雜芳基，其中各視情況被μ5個取 代基取代，其中各取代基係獨立爲芳基、雜芳基、_素、_ N02、-C(0)0H、羰基、-CN、-Cl-C6烷基、·δ〇η_((ν〇6烷基） 、-S〇n-(芳基）、芳氧基、-雜芳基氧基、q-(：6垸氧基、Ν-氧 -30- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -----------裝--------訂--------- (請先閱讀背面之注意事項再填寫本頁) 1280240 五、發明說明（28) 化物-c(o>雜壤基燒基、视_環^以充基、胺基、_ 0H或-(Co% 基）(C(rC6垸基）胺基、_c⑼谭〇必燒基⑽（6 t基）取代基，其中各取代基係獨立視情況被_0H、c厂q烷 氧基、-CrC6烷基、-環c3_c6垸基、芳氧基、七⑼阳、_ c’(c「c6燒基）、自素、N〇2、心、_s〇n_(c〜完基… c(o)-N(cG -c6 烷基）(C(rC6 烷基）取代； 匕與A可視情況被硫基、氧基或（Ci-C4烷基）橋基連接， 以形成稠合三環系統；及 η係獨立爲〇, 1或2。 於本文中使用之”烷基，， 團，例如烷氧基、烷醯基 (請先閱讀背面之注音？事 4 項再填. 經濟部智慧財產局員工消費合作社印製 以及其他具有字首”烷（alk)，，之基 ^ 烯基、炔基等，係意謂碳鏈， 其可爲線性或分枝狀或其組合。烷基之實例包括甲基、乙 基、丙基、異丙基、丁基、第二_與第三_ 丁基、戊基、己 基、庚基等。”烯基”、，，炔基”及其他類似術語，係包括含 有至少一個不飽和C-C鍵結之碳鏈。 環：k基一^係意謂未含有雜原子之碳環，且包括單*、 二-及三環狀飽和碳環，以及稠合環系統。此種稠合環系統 可包含一個部份或完全不飽和之環，譬如苯環，以形成稠 合環系統，譬如苯幷稠合碳環。環烷基包括稠合環系統， 譬如螺稠合環系統。環烷基之實例包括環丙基、環丁基、 環戊基、環己基、十氫萘、金剛烷、氫茚基、茚基、第基 、1，2,3,4-四氫莕等。同樣地，”環晞基，，係意謂未含有雜原 子，而含有至少一個非芳族〇C雙鍵之碳環，且包括單·、 雙-及三環狀部份飽和碳環，以及苯幷稠合之環晞煙類。環 -31 - 本紙張尺度適用中國國家標準（CNS)A4規格（21〇 X 297公釐） 裝— 寫本頁〕 訂— 1280240 A7Ri is i, carbonyl, -C6 alkyl, -cyclo C3-C6 alkyl, -c2-c6 alkenyl, -CrC6 alkoxy, aryl, heteroaryl, -CN, -heterocyclylalkyl, -Amino group, -C--C6 alkylamino group, -(c!-C6 alkyl XC!-C6 alkyl)amino group, -C6 alkyl (oxy)Ci-C6 alkyl group, -C(0) NH(aryl), -C(0)NH(heteroaryl), _QOMCo-Cg alkyl)(C〇-C6 alkyl), -NH-SOn-(q-C6 alkyl), -SOn- (C! -C6 alkyl), -aminemethanyl, -(q-C6 alkyl)-oxime-C(CN)-dialkylamino or _(Ci _ 匸6 fe)-SOn-(Ci -C: 6 alkyl), wherein any group is optionally substituted with 丨5 substituents; wherein each substituent is independently halogen, _QH, -CN, heterocyclic C3-c0ί), -ccco -CHCo-C6 alkyl), -c(0)_0_aryl, alkoxy, cyclooxy, decyl, decyloxy, -cycloc3 -C6 phenanthyl, heterocyclyl CrGfe, aryl , heteroaryl, cyclyl, amineyl or -SQ. · % _c6 alkyl); A is CH; R2 is -CN; Han 3 is aryl 'Substituted by 1-5 substituents, each substituent is -28- This paper scale applies to Chinese national standards (CNS A4 size (210 X 297 mm) -----------Install--------Book--------- (Please read the notes on the back and fill in This page) 1280240 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 V. Description of invention (26) Independently aryl, heteroaryl, s-, 〇N〇2, seven (〇辉, 窥基, , - Ci-c6 alkyl, _s〇n-(Ci_c6 alkyl), _s〇n_(aryl), _aryloxy, 〇·heteroaryl, CA alkoxy, N_oxide, _c(0 )_heterocyclyl C3_C6 alkyl, -NH-cyclo-C0 alkyl, amine,_0H or _(c〇a垸)(c〇a alkyl)amine, -c(〇)-n(c0) a -c6 fluorenyl-(10) group substituent wherein each substituent is independently -OH, 6 alkyloxy, _6 alkyl, yl, -aryloxy, -c(0)0H , -C(0)0(Cl_C6 alkyl), _, _N〇2, _cn, -SOn-A-C6 alkyl) or _C(0)_N (C(rC6 alkyl Xc〇_c6 alkyl) Substituting; and η is independent of 〇, 1 or 2. In this respect In another embodiment, the compound of the present invention is represented by the formula (1) or a pharmaceutically acceptable salt thereof, wherein the SpS2 and s3 are independently Η, -ΟΗ, 素, -Ci-C6 alkyl, _Ν〇2 CN or -C"C6:^oxy, wherein the alkyl and the oxime are optionally substituted by a substituent of (10); wherein each substituent is independently _ or 〇Η; the core is -C0 alkyl, Substituted by a substituent; wherein each substituent is independently: -, -OH, -CN, -Cl_C0 alkyl, _cycloindole 3 - alkyl, -C (〇X heterocyclic (: 3- (:6 decyl), -C(0>a(CVC6 alkyl), _c(9)6_aryl& base, -C "C6 alkoxy, -(Co-C:6 alkylXCo-C6 alkyl)amino group , cycloalkyloxy, fluorenyl, decyloxy, -cyclo C3-C:6 alkyl, heterocyclyl c3_C6 alkyldiaryl, heteroaryl, carbonyl, aminecaraki or -S〇n- (Ci _C6 alkyl); A is CH, R2 and R3 are each independently aryl or heteroaryl, each of which is optionally substituted by 5 substituents, wherein each substituent is independently aryl, hetero Aryl, halogen, -N〇2, -C(0)0H, scouring, _CN, _Ci_c6 alkyl, ----------- loaded------- -Order--------- (Please read the note on the back and fill out this page) -29 1280240 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed A7 B7 V. Invention Description (27) C6 Burning Base) , -SOn-(aryl), aryloxy, -heteroaryloxy, Cl_c6 alkoxy, N-oxide, -C(0)-heterocyclyl c3 -c6 alkyl, -NH-ring C3 -C6 alkyl, amine, -OH or -(C0-C6 alkylalkyl)amino, -C(0)-N(C〇-C6 alkyl)(C〇-C6 alkyl) substituent, Wherein each substituent is independently _〇H, CrC$oxy, -CrQ alkyl, -cycloc3-C6 alkyl, aryloxy, -c(0)0H, -C(0)0(C) "C6 alkyl", halogen, -N〇2, -CN, _s〇n-(CrC6 alkyl) or -C(0)_N(C〇-C6 fe) (C〇-C6); R2 and & can be optionally linked by a thio, oxy or (Cl_C4 alkyl) bridging group to form a fused tricyclic system; and the η is independently 〇, 1 or 2; another specific in this regard In the examples, the compound of the present invention is represented by the formula (1) or a pharmaceutically acceptable salt thereof, wherein 8^82*83 is each oxime; the heart is a -C0 alkyl group, which is optionally substituted with ι_5 substituents; Substituent groups are pure, -OH, -CN, -C--C; 6 alkyl, ring c3 - C6 alkyl, -C (〇X heterocyclic q-C6 alkyl), ( :(0)-0_% alkyl), _c(〇> aryloxy, _ci Άoxy, -(CQ-C:6 alkylXCo-C:6 alkyl)amino, cycloalkyloxy , SS group, Sf oxy group, - ring (: 3_(:6 alkyl, heterocyclic group c3-c6 alkyl, aryl, heteroaryl, carbonyl, aminecarboxamyl or -C6 alkyl); A is CH, & and & are each independently aryl or heteroaryl, each optionally substituted by μ5 substituents, wherein each substituent is independently aryl, heteroaryl, _, _ N02, -C (0)0H, carbonyl, -CN, -Cl-C6 alkyl, ·δ〇η_((ν〇6 alkyl), -S〇n-(aryl), aryloxy, -heteroaryloxy , q-(:6垸oxy, Ν-oxy-30- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -----------Install--- -----Order--------- (Please read the note on the back and then fill out this page) 1280240 V. Description of invention (28) Compound-c (o> miscellaneous base base, view _ Rings with a base, an amine group, _ 0H or -(Co% group) (C(rC6 fluorenyl)amine group, _c(9) Tanzanite base (10) (6 t group) substituent, wherein each substituent is independently _0H, c alkoxy, -CrC6 alkyl, -cycloc3_c6 fluorenyl, aryloxy, seven (9) Yang, _ c' (c "c6 alkyl"), self-prime, N〇2, heart, _s〇n_(c~complete... c(o)-N(cG-c6 alkyl) (C(rC6 alkyl) Substituting; 匕 and A may optionally be attached to a thio, oxy or (Ci-C4 alkyl) bridging group to form a fused tricyclic system; and the η system is independently 〇, 1 or 2. As used herein, "alkyl, group, such as alkoxy, alkanoyl (please read the phonetic on the back first, then refill 4 items. Printed by the Ministry of Economic Affairs, Intellectual Property Office, Consumer Cooperatives, and others with prefixes) Alken, alkoxy, alkynyl, etc., are meant to be carbon chains, which may be linear or branched or combinations thereof. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl. Base, butyl, second-and third-butyl, pentyl, hexyl, heptyl, etc. "alkenyl", ", alkynyl" and other similar terms, including at least one unsaturated CC bond Carbon chain. Ring: k-based is a carbon ring that does not contain a hetero atom, and includes a mono-, di-, and tricyclic saturated carbocyclic ring, and a fused ring system. Such a fused ring system may contain one a partially or fully unsaturated ring, such as a benzene ring, to form a fused ring system, such as a benzoquinone fused carbocyclic ring. The cycloalkyl group includes a fused ring system, such as a spiro fused ring system. Examples of cycloalkyl groups include Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthalene, adamantane, hydroquinone, mercapto, base, 1,2,3,4-tetrahydroanthracene, etc. Similarly, "cyclononyl" means a carbocyclic ring containing no at least one non-aromatic 〇C double bond, and includes a single, Double- and triple-ring partially saturated carbocyclic rings, as well as benzoquinone-fused ringworms. Ring-31 - This paper scale applies to China National Standard (CNS) A4 specification (21〇X 297 mm). This page] set — 1280240 A7

經濟部智慧財產局員工消費合作社印製 烯基之實例包括環己缔基、。 ”環烷基氧基丨丨—, 土 接至氧基連接原子切特別敘m係包㈣ ^，除非另有特別敘述，否則係包括烷美 接至氧基連接原子。 < C仿砭基！| ，方基” 一詞，哈非η 士 u 糸非另有特別敘述，否則係包括多環$ # ，以及單環系統，例如苯基或茶基。 ^系麵 ”务乳基π —詞，除非s 士 統，以及單環系味:二！特別敘述，否則係包括多環系 ，連接至連接位置。 、接原子 :c。必统基’’一詞，包括含有…山個或無碳原子之 烷基。、未具有碳原子之烷基爲氫原子取代基，或-直接鐘 結-依孩烷基是否爲末端或橋接部份而定。 雜一柯，除非另有特別敘述，否則係包括一或多個c 、S«原子。例如，雜環燒基與雜芳基，係包括環系统， =含有-或多個Q、SU原子在該環中，包括此種原子之 匕合物此4原子係置換環碳原子。因此，例如雜環基q 烷基係爲五員環，含有5個至無碳原子。 — 雜方基t實例包括例如吡啶基、喳啉基、異喳啉基、次 呼基yM基、㈣基、基”夫喃基、苯幷咬喃基 、二苯幷呋喃基、4吩基、苯幷p塞吩基、吡咯基、吲哚基 、吡唑基、啕唑基、呤唑基、異呤唑基、噻唑基、異噻吐 基、咪唑基、苯幷咪唑基、呤二唑基、噻二唑基、三唑基 、四唑基。 -32- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -----------裝---------訂--------- (請先閱讀背面之注意事項再填寫本頁) [280240Examples of alkenyl groups printed by the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs include cyclohexyl. "Cycloalkyloxyanthracene", the ring attached to the oxy group is specifically referred to as the m-system package (IV). Unless otherwise specified, it includes alkaloid to an oxy-bonding atom. <C-like fluorenyl The word "|, square", is not specifically described otherwise, otherwise it includes polycyclic $#, and a single ring system such as phenyl or tea. ^系面" 乳乳基π-word, unless s 士士, and single-ring odor: two! Special description, otherwise it includes a polycyclic system, connected to the connection position., Atomic: c. The term includes an alkyl group containing a mountain or a carbon-free atom, an alkyl group having no carbon atom as a hydrogen atom substituent, or a direct-knot-dependent alkyl group depending on whether it is a terminal or bridging moiety. Hetero-ke, unless otherwise specified, includes one or more c, S« atoms. For example, heterocycloalkyl and heteroaryl, including ring systems, = containing - or multiple Q, SU atoms in In the ring, a tetravalent system including such an atom is substituted for a ring carbon atom. Thus, for example, a heterocyclic q alkyl group is a five-membered ring containing from 5 to no carbon atoms. Including, for example, pyridinyl, porphyrinyl, isoindolyl, sulphonyl yM, (tetra), cyclyl, benzoquinone, diphenylfuranyl, 4 phenyl, benzoquinone p-phene Base, pyrrolyl, fluorenyl, pyrazolyl, oxazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazepine, imidazolyl, benzimidazole Base, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl. -32- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) -----------Install---------Book ------ --- (Please read the notes on the back and fill out this page) [280240

五、發明說明（30) 經濟部智慧財產局員工消費合作社印製 π雜芳氧基”一詞，除非另有特別敘述，否則係描述雜芳 基，經過氧基連接原子連接至連接位置。 雜芳基(Cl.6)垸基之實例，包括例如咬喃基甲基、咬喃基 乙基、嘧吩基曱基、噻吩基乙基、吡唑基甲基、呤唑基甲 基、嘮唑基乙&、異呤唑基甲基、嘍唑基甲基、嘧唑基乙 基、咪唑基甲基、咪唑基乙基、苯幷咪唑基甲基、呤二唑 基甲基、呤二唑基乙基、嘍二唑基甲基”塞二唑基乙基、 二唑基甲基、三唑基乙基、四唑基甲基、四唑基乙基、吡 啶基甲基、吡啶基乙基、嗒畊基甲基、嘧啶基甲基、吡畊 基甲基、喳啉基甲基、異喳啉基甲基及喳喏啉基甲基。 雜環基<：3_7烷基之實例，包括例如一氮四圜基、四氫吡 咯基、穴氫吡哫基、六氫吡畊基、嗎福啉基、四氫呋喃基 一氫咪嗅基、四氫p比略-2-酮、六氫p比淀·2-酮及硫代嗎福 啉基。 芳基（Cu)烷基之實例，包括例如苯基π!·6)烷基與萘基 (Cl - 6 )燒基。 _環基-7纟元羰基（Cl· g)燒基之實例，包括例如一氮四圜 基羰基（Cl·6)烷基、四氫吡咯基羰基（Ci6)烷基、六氫吡啶 基羰基（C丨_6)烷基、六氫吡畊基羰基烷基、嗎福啉基 黢基（Cl ·6)烷基及硫代嗎福啉基羰基（Cl _ 6)烷基。 π胺”一詞，除非另有特別敘述，否則係包括一級、二級 及三級胺類。 除非另述及’否則’’胺甲酿基，，一詞，係用以包括· NHC(0)0Ci _C4烷基與-(^⑼期^丨-C4烷基。 -33 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ------------裝--------訂---------^w. (請先閱讀背面之注意事項再填寫本頁) 1280240 A7 經 濟 部 智 慧 財 產 局 員 工 消 費 合 作 社 印 製 五、發明說明（31) _素” 一詞，包括氟、氣、溴及碘原子。 視情況經取代”一詞，係意欲包括經取代與未經取代。 Q此例如視情況經取代之芳基，可表示五氟苯基或苯環 再者取代可在任何基團處施行。例如，經取代之芳基 (Ci-6)烷基，係包括在芳基上取代，以及在烷基上取代。 本文中所述之化合物，含有一或多個雙鍵，且因此可導 致順/反異構物，以及其他構形異構物。本發明包括所有 此種可能之異構物，以及此種異構物之混合物。 本又中所述之化合物，可含有一或多個不對稱中心，且 因此可導致非對映異構物與光學異構物。本發明係包括所 有此種可能之非對映異構物，以及其外消旋混合物，並實 質上純之經解析對掌異構物，所有可能之幾何異構物及其 樂學上可接受之鹽。上文式"系經顯示，而未具有明確立體 化學在某些位置上。本發明係包括式j及其藥學上可接受鹽 之所有立體異構物。再者，立體異構物之混合物，以及締 立體異構物，亦包含在内。在用以製備此種： “匆“成程序期間，或在使用熟諳此藝者所已知之消旋 作用或差向異構化作用程序時，此種程 心' 體異構物之混合物。 ’ 1爲^ ••藥學上可接受之鹽”一詞，係指製自 机㈡头学上可接受之血 母鹼或酸之鹽。當本發明化合物爲酸 … —4A #祖 時’其相應鹽可合 罝地製自樂學上可接受之無毒鹼，包括 . , L ^ „ 與機鹼與有機鹽。 何生自此種操機鹼之鹽，包括鋁、銨、 ^ ^ ^ , 約、銅（銅與亞銅） 、鐵、亞鐵、鋰、鎂、錳（錳與亞鐘）、 )神、鈉、鋅及其類V. Description of invention (30) The term “pi-heteroaryloxy” printed by the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs, unless otherwise specified, describes the heteroaryl group, which is attached to the connection position via an oxy linking atom. Examples of aryl (Cl. 6) fluorenyl groups include, for example, butylmethyl, cumylethyl, pyrenyl fluorenyl, thienylethyl, pyrazolylmethyl, oxazolylmethyl, fluorene Azylylene &,isoxazolylmethyl, oxazolylmethyl, pyrazolylethyl, imidazolylmethyl, imidazolylethyl, benzimidazylmethyl, oxadiazolylmethyl, hydrazine Diazolylethyl, oxadiazolylmethyl"-oxadiazolylethyl, oxadiazomethyl, triazolylethyl, tetrazolylmethyl, tetrazolylethyl, pyridylmethyl, pyridine Alkylethyl, hydrazine methyl, pyrimidinylmethyl, pyridylmethyl, porphyrinylmethyl, isoindolylmethyl and porphyrinylmethyl. Examples of the heterocyclic group <:3_7 alkyl group include, for example, a nitrotetradecyl group, a tetrahydropyrrolyl group, a hydropyridyl group, a hexahydropyridinyl group, a morpholinyl group, a tetrahydrofuranyl-hydromethanol group, Tetrahydrop-pyridin-2-one, hexahydrop-pyridyl-2-keto and thio-norporinyl. Examples of the aryl (Cu) alkyl group include, for example, a phenyl π!·6)alkyl group and a naphthyl (Cl-6) alkyl group. Examples of the cyclyl-7-membered carbonyl (Cl.g.) alkyl group include, for example, a nitrogen tetradecylcarbonyl (Cl.6) alkyl group, a tetrahydropyrrolylcarbonyl (Ci6) alkyl group, and a hexahydropyridylcarbonyl group. (C丨_6) alkyl, hexahydropyranylcarbonylalkyl, morpholinylfluorenyl (Cl.6)alkyl, and thiomorpholinecarbonyl(Cl-6)alkyl. The term "π-amine", unless otherwise stated, includes primary, secondary and tertiary amines. Unless otherwise stated, the term 'other' is used to include NHC (0). ) 0Ci _C4 alkyl and -(^(9) period 丨-C4 alkyl. -33 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) ---------- -------------------------^w. (Please read the notes on the back and fill out this page) 1280240 A7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed five (31) The term "_", including fluorine, gas, bromine and iodine atoms. The term "substituted as appropriate" is intended to include both substituted and unsubstituted. Q. For example, an optionally substituted aryl group. Further, a pentafluorophenyl group or a benzene ring may be substituted at any group. For example, a substituted aryl (Ci-6) alkyl group includes a substitution on an aryl group and a substitution on an alkyl group. The compounds described herein contain one or more double bonds and may therefore result in cis/trans isomers, as well as other conformational isomers. The invention includes all such possibilities. And mixtures of such isomers. The compounds described herein may contain one or more asymmetric centers, and thus may result in diastereomers and optical isomers. The invention includes all Such a possible diastereomer, as well as a racemic mixture thereof, and substantially pure analytically resolved palmomer, all possible geometric isomers and their orally acceptable salts. The formula " is shown to have no clear stereochemistry at certain positions. The present invention includes all stereoisomers of formula j and its pharmaceutically acceptable salts. Further, mixtures of stereoisomers, and The stereoisomers are also included. When used to prepare such: "hurry" procedures, or when using the racemic or epimerization procedures known to those skilled in the art, such Cheng Xin' a mixture of isomers. '1 is a pharmaceutically acceptable salt'. It refers to a salt of a blood base or an acid that is acceptable for the first time. For the acid... 4A #祖时' its corresponding salt can be combined Affordable non-toxic bases, including . , L ^ „ with organic bases and organic salts. Hesheng from this organic salt, including aluminum, ammonium, ^ ^ ^, about, copper (copper and cuprous) , iron, ferrous, lithium, magnesium, manganese (manganese and Asian clocks), god, sodium, zinc and the like

-----------裝--------訂--------- (請先閱讀背面之注意事項再填寫本頁) 1280240 經濟部智慧財產局員工消費合作社印製 A7 五、發明說明（32 ) 似鹽。特佳者爲銨、钲、雜 ^ ^ Λ 巧餐、鉀及鈉鹽。衍生自藥學上可 接受之有機然毒驗之骑 句紅 ， 皿 包括一級、二級及三級胺類，以 及環狀胺類，及經取代$脸 、 代'^知類，譬如天然生成與合成之細 取代胺類等之鹽。可自並/ 、 ^ J目其形成鹽怎其他藥學上可接受之古 機無毒鹼，包括離子交換， 技、 有 人换树I日，例如精胺酸、甜菜鹼、 啡驗、膽驗、N，N’-二；其r … 一 、 下基乙一觖、二乙胺、2-二乙胺基 醇、2- —甲胺基乙醇、乙醢险 r 一0、 乙％胺、乙一胺、N_乙基嗎福啉、 N-乙基六氫❹、葡萄糖胺、胺基葡萄糖、組胺酸、 胺、異丙胺、離胺酸、甲基葡萄糖胺、嗎福啦、六 、六氫㈣、聚胺樹脂、普魯卡因、嗓呤、3,7_二甲基黃，、 呤、二乙版、二曱胺、三丙胺、丁三醇胺等。 當本發明化合物爲鹼性時，其相應鹽可合宜地製自藥取 上可接受之無毒酸，包括無機與有機酸。此種酸包括例： 醋故、苯績酸' 苯甲酸、樟腦績酸、摔樣酸、乙统續酸、 反丁晞二酸、葡萄糖酸、越胺酸、氯漠酸、鹽酸 '声 酸、乳酸、順丁缔二酸、蘋果酸、苯乙醇酸、甲燒：酸、、 黏故、硝酸、雙羥茶酸、泛酸、磷酸、琥s白酸、硫酸、酒 石酸 '對-甲苯磺酸等。特佳爲苯磺酸、檸檬酸、氫溴酸、 鹽酸、順丁烯二酸、磷酸、硫酸及酒石酸。 本發明之醫藥組合物包含以式〗表示之化合物（或並藥學 上：接受之鹽)作爲活性成份’藥學上可接受之載劑：選； 2其他治療成份或佐劑。此種其他治療成份，包括例如〇 白二烯素受體拮抗劑，η)白三晞素生物合成抑制劑，邱皮 質類固醇，iv)H1受體拮抗劑，杉2腎上腺素受體催動劑， — — — — —--Awi ·11111--^------I-- (請先閱讀背面之注意事項再填寫本頁〕 -35 1280240 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明（33 ) VI) COX-2選擇性抑制劑，vii)史塔汀（statin)，vUi)非類固醇消 炎藥物（"NSAID”），及ix)M2/M3拮抗劑。此等組合物包括適用 於口腔、直腸、局部及非經腸（包括皮下、肌内及靜脈内） 投藥之組合物，惟在任何特定情況中最適合之途徑，係依 活性成份正被投予之特定宿主，及病症之性質與嚴重性而 定。此等醫藥組合物可合宜地以單位劑量形式呈現，並藉 製藥技藝中所習知之任何方法製成。 含有式I化合物之乳膏、軟膏、膠凍、溶液或懸浮液，可 被採用於局部用途。漱口水與漱口藥係包含在本發明目的 之局部使用範圍内。 每天約0.001毫克/公斤至約140毫克/公斤體重之劑量程 度，可用於治療症狀，譬如氣喘、慢性枝氣管炎、慢性阻 基肺病（COPD)、嗜伊紅肉芽瘤、牛皮癖，及其他良性或惡 性J曰生性皮膚病’内毒素休克（及有關聯之症狀，譬如在馬 中之板層炎與急性腹痛）、敗血性休克、潰瘍性結腸炎、克 隆氏病、心肌與腦部之再灌注傷害、炎性關節炎、骨質疏 鬆症、慢性絲球體性腎炎、異位性皮炎、蓴麻疹、成人呼7 吸困難徵候簇、幼兒呼吸困難徵候簇、在動物中之慢性阻 塞肺病、尿崩症、過敏性鼻炎、過敏性結合膜炎、春季辞 合膜炎、動脈再狹窄、動脈粥瘤硬化、神經性發炎、疼痛 、咳漱、風濕性關節炎、關節黏連脊椎炎、移植排斥與移 植物對很主疾病、胃酸之過度分泌，細菌、眞菌或病主、斤 引致之敗血病或敗血性休克、發炎，及細胞活素所媒介、 慢性組織變性、骨關節炎、癌症、惡病質、肌肉消耗\抑 -36- 表紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ------------裝--------訂---------· (請先閱讀背面之注咅？事項再填寫本頁) l28〇24〇 A7 經濟部智慧財產局員工消費合作社印製 五、發明說明（34) '、記憶力減弱、單極性抑鬱、具有炎性成份之急性與慢 陡神、“工夂性病纟、巴金生氏病、阿耳滋海默氏疾病、脊髓 =傷、頭部傷害、多發性硬化、腫瘤生長及正常組織之癌 侵入，其對PDE4抑制作用具回應性，或者，每位病人每天 :勺〇.〇5笔士至約7克。例如，發炎可經由每千克體重每天投 :約〇·〇1笔克至50 φ克化合物，或者，每位病人每天約〇 5 毛克至、为2.5克’而經有效地治療。再者，應明暸的是，本 發明之PDE4抑制用化合物，可在預防上有效劑量程度下投 藥，以預防上文列舉之症狀。 可與載劑物質合併，以產生單一劑量形式之活性成份之 量，係依待治療之宿主及特定投藥模式而改變。例如，欲 供口服投予人類之配方，可合宜地含有約〇·5毫克至約5克 活性劑，與適當且合宜量之載劑物質捧配，此載劑物質可 從全部組合物之約5至約95百分比改變。單位劑量形式通 常係含有約0.01亳克至約1000毫克間之活性成份，典型上爲 〇·〇1毫克、0.05毫克、〇·25毫克、i毫克、5毫克、25毫克、 5〇愛克、100毫克、200毫克、3〇〇毫克、4〇〇毫克、5〇〇毫克 、600毫克、800毫克或1000毫克。 但是’應明瞭的是，對任何特定病人之特定劑量程度， 係依多種因素而定，包括特、財、—般健康狀態、性 別、飲食、投藥時間、投藥途徑、排泄速率、藥物組合及 接受治療之特定疾病之嚴重性。 ☆實用上，可將以式〗表示之本發明化合物或其藥學上可接 受之鹽，作爲活性成份，根冑習用I藥接配技術，與醫藥-----------Install--------Book--------- (Please read the notes on the back and fill out this page) 1280240 Ministry of Economic Affairs Intellectual Property Office staff Consumer Cooperatives Print A7 V. Invention Description (32) Salt-like. Particularly good are ammonium, strontium, miscellaneous ^ ^ 巧 chocolate, potassium and sodium salts. Derived from a pharmaceutically acceptable organic poison test, the dish includes primary, secondary and tertiary amines, as well as cyclic amines, and substituted by $ face, generation '^ know, such as natural generation and A finely divided salt of an amine or the like is synthesized. It can be self-contained, and it can form other pharmaceutically acceptable ancient non-toxic bases, including ion exchange, technology, and some people change trees, such as arginine, betaine, morphine, biliary test, N , N'-di; its r ... I, the lower group of ethyl hydrazine, diethylamine, 2-diethylamino alcohol, 2-methylaminoethanol, ethyl hydrazine r - 0, ethylamine, ethylamine, N_Ethylmorpholine, N-ethylhexahydroindole, glucosamine, aminoglucose, histidine, amine, isopropylamine, lysine, methylglucosamine, phloem, hexa-hexahydro (IV) , polyamine resin, procaine, hydrazine, 3,7-dimethyl yellow, hydrazine, diethyl phthalate, diamine, tripropylamine, tributylamine and the like. When the compound of the present invention is basic, the corresponding salt can be conveniently prepared from a pharmaceutically acceptable non-toxic acid, including inorganic and organic acids. Examples of such acids include: vinegar, benzoic acid's benzoic acid, camphoric acid, falling acid, acetylated acid, butyl succinic acid, gluconic acid, valine acid, chloroform acid, hydrochloric acid , lactic acid, cis-concanic acid, malic acid, phenylglycolic acid, methyl ketone: acid, viscous, nitric acid, bishydroxyic acid, pantothenic acid, phosphoric acid, arsenoic acid, sulfuric acid, tartaric acid 'p-toluenesulfonic acid Wait. Particularly preferred are benzenesulfonic acid, citric acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, and tartaric acid. The pharmaceutical composition of the present invention comprises a compound represented by the formula (or pharmaceutically acceptable: acceptable salt) as an active ingredient' pharmaceutically acceptable carrier: selected; 2 other therapeutic ingredients or adjuvants. Such other therapeutic ingredients include, for example, leucovorin receptor antagonists, η) white triterpenoid biosynthesis inhibitors, qi corticosteroids, iv) H1 receptor antagonists, cedar 2 adrenergic receptor stimulants, — — — —---Awi ·11111--^------I-- (Please read the note on the back and fill out this page) -35 1280240 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 5 , invention instructions (33) VI) COX-2 selective inhibitors, vii) statin, vUi) non-steroidal anti-inflammatory drugs ("NSAID"), and ix) M2/M3 antagonists. The composition includes compositions suitable for oral, rectal, topical and parenteral (including subcutaneous, intramuscular and intravenous) administration, but the most suitable route in any particular case depends on the particular host into which the active ingredient is being administered. And the nature and severity of the condition. These pharmaceutical compositions may conveniently be presented in unit dosage form and prepared by any of the methods known in the pharmaceutical art. Creams, ointments, gels containing the compound of formula I , solution or suspension, can be used for topical use Mouthwash and mouthwash are included in the topical application range of the present invention. A dosage of from about 0.001 mg/kg to about 140 mg/kg body weight per day can be used to treat symptoms such as asthma, chronic bronchitis, chronic obstruction. Basal lung disease (COPD), eosinophilic granuloma, psoriasis, and other benign or malignant J-derived skin diseases 'endotoxic shock (and related symptoms, such as lamellar inflammation and acute abdominal pain in horses), defeat Hemorrhagic shock, ulcerative colitis, Crohn's disease, myocardial and brain reperfusion injury, inflammatory arthritis, osteoporosis, chronic glomerulonephritis, atopic dermatitis, urticaria, adult respiratory symptoms Clusters, dyspnea syndrome in children, chronic obstructive pulmonary disease in animals, diabetes insipidus, allergic rhinitis, allergic membranous inflammation, spring phlegm, arterial restenosis, atherosclerosis, neuropathic inflammation, pain , cough, rheumatoid arthritis, joint adhesion spondylitis, transplant rejection and grafts are very common diseases, excessive secretion of gastric acid, bacteria, sputum or disease, jin Septicemia or septic shock, inflammation, and cytokine mediators, chronic tissue degeneration, osteoarthritis, cancer, cachexia, muscle consumption\-36- Table paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) ------------Package--------Book---------· (Please read the note on the back first? Page) l28〇24〇A7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (34) ', memory weakening, unipolar depression, acute and slow steepness with inflammatory ingredients, "work-related disease, Parkinson's disease, Alzheimer's disease, spinal cord injury, head injury, multiple sclerosis, tumor growth, and cancer invasion of normal tissues, which are responsive to PDE4 inhibition, or, per patient per day: Spoon 〇 〇 5 pens to about 7 grams. For example, inflammation can be administered per kilogram of body weight per day: from about 1 gram to 50 gram gram of compound, or from about 5 gram per day to 2.5 grams per patient per day. Further, it should be understood that the PDE4 inhibiting compound of the present invention can be administered at a prophylactically effective dose level to prevent the symptoms listed above. The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending upon the host to be treated and the particular mode of administration. For example, a formulation intended for oral administration to humans may conveniently contain from about 5 mg to about 5 g of active agent, suitably admixed with a suitable amount of carrier material, such carrier 5 to about 95 percent change. The unit dosage form will usually contain from about 0.01 gram to about 1000 mg of active ingredient, typically 〇·〇 1 mg, 0.05 mg, 〇·25 mg, i mg, 5 mg, 25 mg, 5 〇, 100 mg, 200 mg, 3 mg, 4 mg, 5 mg, 600 mg, 800 mg or 1000 mg. However, it should be understood that the specific dose level for any particular patient depends on a number of factors, including special, financial, general health status, gender, diet, time of administration, route of administration, rate of excretion, combination of drugs, and acceptance. The severity of the particular disease being treated. ☆ In practical use, the compound of the present invention represented by the formula or a pharmaceutically acceptable salt thereof can be used as an active ingredient, and the drug can be used in combination with the drug.

本紙張尺度適用中國國家標準（CNS)A4規格（210 X ___________--------訂--------- (請先閱讀背面之注意事項再填寫本頁) -37- l28〇24〇 經濟部智慧財產局員工消費合作社印製 A7 發明說明（35 ) 載劑合併成密切互混物。載 投藥之製劑形式而定，例如:可知取極多種形式，依所要 因此，本發明之醫藥組合物=經腸(包括靜脈内）。 位呈現’譬如膠囊、爲囊劑=於：：投藥之不連續單 成份。再者，此等組合物可以粉二，、3:預疋量之活性 在水性液體中之懸浮液，以非 以顆粒，以溶液，以 化-，或以水在油中型液體乳化液呈現 &lt; 一般劑量形式以外，以式！ 、 ，、 又所棱出 受之鹽，亦可藉由受控釋出方：二：：或其藥學上可接 等組合物可藉任何製藥學方法製備。:般=置投[此 包括使活性成份與載劑產生結又&amp; ’此種万法 種必要成份一般而言 二:：，其係構成-或多 炊：載= 劑或兩者均勻且密切混合而製成了 …、後，可6且地將產物製成所要呈現之形弋 因此，本發明之醫藥組合物可包含' 與式“匕合物或藥學上可接受之鹽 予:接受（載劑 上可接受之鹽，亦可包含在併用一°物或其樂學 合物之《组合物中。 “種其他治療活性化 :採：之醫藥載劑，可爲例如固體、液體或氣體。固體 載叙貫例包括乳糖、白陶土、藏糖、滑石 '明膠、壤脂 :::、阿拉伯膠、硬脂酸鎂及硬脂酸。液體載劑之實例 馬糖漿、花生油、橄檀油及水。氣體恭、 化碳與氮。 “载劑《實例包括二氧 在省備口服劑量形式之組合物時，任何合宜醫藥媒質均 裝--------訂----- (請先閱讀背面之注意事項再填寫本頁) -38 - 1280240 A7 B7 五、發明說明（36 可採用。例如，水、二、， 劑、著色劑等，可用以形〔/甴類、醇類、矯味劑、防腐 酏劑及溶液；而馨七H成口服液體製劑，譬如懸浮液、 粒化劑、潤滑劑、黏人制；极日目性纖維素、稀釋劑、 服固體製劑，譬如粉末二膠==載劑’可用以形成口 於投藥，故其係爲較佳&quot;片劑。由於片劑與膠囊易 藥載劑。可視情況將片十/置早位’其中係採用固體醫 塗覆。 M措由標準水性或非水性技術進行 p11么明組合物之片劑，可藉由壓縮或模製製成，視 -機哭中，/Γ! 或佐劑。壓縮片劑可經由在適 田機中〜自由流動形式之 訂 粒壓縮，視情況與黏合劑 刀/如私末或顆 性或分散劑混合而製成。模製二可〕：：釋劑、表面活 體稀釋劑濕潤之粉末狀化合 ：：已使用惰性液 聲 I丄：係含有约°，1毫克至約崎 成h，而各局囊劑或膠囊較佳 克活性成份。 〇·ι毫克至約5。。毫 ::非:腸投藥之本發明醫藥組合物，可被製成活性化 :物在水中之溶液或懸浮液。可包含適當界面活性劑，例 如搜丙基纖維素。分散液亦可在甘油、液態聚乙二醇及立 ::由類中之混合物内製成。再者，可加入防腐劑以防止微 生物之不利生長。 、適合可注射用途之本發明醫藥組合物，包括無菌水溶液 或分散液。再者，此等組合物可呈無菌粉末形式，以供此 -39- 本纸張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 1280240 經 濟 部 智 慧 財 產 局 員 工 消 費 合 作 社 印 製 -40- A7 五、發明說明（37, ，二囷可/王射溶液或分散液之臨時製備。在所有情況中， 供可容易注射Γ:是無菌的，且必須有效地流動’以提 須安定；因：二等醫藥組合物於製造與儲存條件下必 八囷），/7染作用。載劑可爲溶劑或分散媒質，含有例如水 、了Λ酉手、夕 一 夕70醇（例如甘油、丙二醇及液態聚乙二醇）、植 物油，及其適當混合物。 溶^ ^醫藥組合物可呈適合局部用途之形式，例如氣 ^礼㈢、軟霄、洗劑、撒粉或其類似物。再者，此等 ：可呈適合經皮裝置之形式。此等配方可利用以幻表 ：明化合物或其藥學上可接受之鹽，經由習用加工 :二：：：以作爲實例，乳膏或軟膏係經由將親 浪厶 士、7 ，伴隨耆約5重量。。至約10重量。。之化合物 此:1成，以產生具有所要稠度之乳膏或軟膏。 制·.1月（醫藥組合物可呈適合直腸投藥之形式，其中載 ㈣爲固體。此混人物圭时 、 口又彳係形成早位劑量栓劑。適當載劑 及其他常用於此項技藝之物質。栓劑可合宜 知組合物與已軟化或熔解之載劑混合，接著在 杈〃中冷卻與成形而製成。 提及之載劑成份以外’上述醫藥配方可按適 二二或多種其他載劑成份’譬如稀釋劑、緩衝 綱、表面活性劑、增稠劑、潤⑽ 配万《轉受者之錢成等滲性。含有藉 = 本紙張尺度適用中_家標準（CNS)A4規格⑵Q χ挪公益 ------------裝--------訂---------^«^1 (請先閱讀背面之注咅？事項再填寫本頁} 1280240 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（38) 物或其藥學上可接受鹽之組合物，亦可被製成粉末或液體 濃縮物形式。 已發現本發明之化合物與醫藥組合物，顯示作爲pDE4抑 制劑之生物活性。因此，本發明之另一方面，係爲在哺乳 動物中治療例如氣喘、慢性枝氣管炎、慢性阻塞肺病（C0PD) 、嗜伊紅肉芽瘤、牛皮癬，及其他良性或惡性增生性皮膚 病’内毒素休克（及有關聯之症狀，譬如在馬中之板層炎與 急性腹痛）、敗血性休克、潰瘍性結腸炎、克隆氏病、心肌 與腦邵心再灌注傷害、炎性關節炎、骨質疏鬆症、慢性絲 球髌性腎炎、異位性皮炎、蓴麻疹、成人呼吸困難徵候簇 、幼兒呼吸困難徵候簇、在動物中之慢性阻塞肺病、尿崩 症、過敏性鼻炎、過敏性結合膜炎、春季結合膜炎、動脈 再狹窄、動脈粥瘤硬化、神經性發炎、疼痛、咳嗷、風濕 性關節炎、關節黏連脊椎炎、移植排斥與移植物對宿主疾 病Θ酸之過度分泌，細菌、眞菌或病毒所引致之敗血病 或敗血性休克、發炎，及細胞活素所媒介之慢性組織變性 ，骨關節炎、癌症、惡病質、肌肉消耗、抑#、記憶力減 弱、單極性抑镫，具有炎性成份之急性與慢性神經變性病 、·' 至生氏病阿耳滋海默氏疾病、脊髓外傷、頭部傷 害、多發性硬化、M瘤生長及正常組織之癌侵入_易於經過 PDE4同功酶之抑制作用及所造成提高之cCAMP含量而接受 改吾^病-其方式是投予有效量之本發明化合物。”哺乳動 物 3，包括人類以及其他動物，例如狗、貓、馬、豬 牛因此，應明瞭的是，人類以外哺乳動物之治療，係 ___________裝--------訂--------- (請先閱讀背面之注意事項再填寫本頁) -41 - 1280240 經濟部智慧財產局員工消費合作社印製 A7 Β7 五、發明說明（39 ) 爲與上文所列舉人類疾患實例之臨床相互關聯疾患之治療。 再者，如前述，本發明化合物可與其他治療化合物合併 使用。特定言之，本發明PDE4抑制化合物之組合，可有利 地使用於與i)白三烯素受體拮抗劑，Π)白三晞素生物合成 抑制劑，iii) COX-2選擇性抑制劑，iv)史塔汀（statin)， v) NSAID，vi) M2/M3拮抗劑，Vii)皮質類固醇，viii) H1 (組織 胺）受體拮抗劑，及ix) /52腎上腺素受體催動劑之組合上。 於另一方面，已發現本發明化合物可在哺乳動物系統中 以新陳代4丨產物形成。例如，實例19，（5-{(Ε)-2-(3-{6-[1-甲基· W曱續si基）乙基]-8-4啉基}苯基）小[4_(甲磺醯基）苯基]乙晞 基}-1，2,4』号二吐-3-基）甲醇：This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X ___________--------order--------- (please read the notes on the back and fill out this page) -37- L28〇24〇Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Printed A7, Inventories (35) Carriers are combined into a close intermix. Depending on the form of the drug to be administered, for example, it can be seen in many forms. The pharmaceutical composition of the invention = enteral (including intravenous). The position is presented as 'capsules like capsules, as capsules> in:: discontinuous single ingredients for administration. Further, these compositions can be powdered two, 3: A suspension of an amount of activity in an aqueous liquid, in the form of a non-particle, a solution, a chemical-, or an oil-in-oil liquid emulsion, in the form of a general dosage form, in the form of a formula The salt may also be prepared by any controlled method by controlled release: two:: or its pharmaceutically acceptable composition.: General = placement [This includes causing the active ingredient to form a knot with the carrier. Also &amp; 'The necessary ingredients of this type of law are generally two::, its composition - or more : The carrier or the two are uniformly and intimately mixed to form a product, and then the product can be made into a shape to be presented. Therefore, the pharmaceutical composition of the present invention may comprise a 'combination with a compound or A pharmaceutically acceptable salt: acceptable (a carrier-acceptable salt, may also be included in the composition in combination with a one-degree or its music composition. "Other therapeutic activation: the drug: The agent may be, for example, a solid, a liquid or a gas. Solids include lactose, kaolin, sugar, talc 'gelatin, loam::: gum arabic, magnesium stearate and stearic acid. Liquid carrier Examples of horse syrup, peanut oil, olive oil and water. Gas Christine, carbon and nitrogen. "Carrier" Examples include dioxins in the preparation of oral dosage form of the composition, any suitable pharmaceutical media are loaded ----- ----Book----- (Please read the note on the back and then fill out this page) -38 - 1280240 A7 B7 V. Invention Description (36 can be used. For example, water, two, agents, colorants, etc. , can be used to form [ / steroids, alcohols, flavors, antiseptic agents and solutions; and Xin Qi H into oral solution Body preparations, such as suspensions, granulating agents, lubricants, adhesives; polar Japanese cellulose, thinner, solid preparations, such as powdered di-glue == carrier' can be used to form a mouth for administration, so It is a preferred &quot;tablet. Because of the tablet and capsule easy drug carrier. It can be used in the case of tablet 10/premise where it is coated with solid medicine. M is made by standard aqueous or non-aqueous technology. The tablet of the composition can be made by compression or molding, and can be crying, / Γ! or adjuvant. The compressed tablet can be compressed by a free-flowing form in a suitable machine, as the case may be. It is made by mixing with a binder knife/such as a smear or a dispersing agent. Molding can be:: release agent, surface active diluent wet powdered combination:: has used inert liquid sound I 丄: contains about °, 1 mg to about saki into h, and each capsule or capsule is better Grams of active ingredients. 〇·ι mg to about 5. . </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; Suitable surfactants can be included, such as propylcellulose. The dispersion can also be prepared in a mixture of glycerin, liquid polyethylene glycol, and diatoms. Further, a preservative may be added to prevent unfavorable growth of the microorganism. Pharmaceutical compositions of the invention suitable for injectable use, including sterile aqueous solutions or dispersions. Furthermore, these compositions may be in the form of a sterile powder for use on this -39- paper scale in accordance with the Chinese National Standard (CNS) A4 specification (210 X 297 mm). 1280240 Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative -40- A7 V. INSTRUCTIONS (37, , Temporary preparation of a solution or dispersion of bismuth/king solution. In all cases, it can be easily injected Γ: it is sterile and must flow effectively 'to be Stability; due to: second-class pharmaceutical composition under the conditions of manufacture and storage must be eight), / 7 dyeing effect. The carrier can be a solvent or dispersion medium containing, for example, water, hands, 70 alcohols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof. The pharmaceutical composition may be in a form suitable for topical use, such as a gas (3), soft palate, lotion, dusting or the like. Furthermore, these: can be in the form of a suitable transdermal device. These formulations can be utilized in a magical form: a clear compound or a pharmaceutically acceptable salt thereof, which is processed by conventional use: two::: as an example, a cream or ointment is passed through a gentleman, 7 , accompanied by about 5 weight. . Up to about 10 weights. . Compounds: 10% to produce a cream or ointment of the desired consistency. January. (The pharmaceutical composition may be in a form suitable for rectal administration, in which (4) is a solid. This mixed character, mouth and sputum forms an early dose suppository. Suitable carriers and other commonly used in this technique A suppository can be prepared by mixing a composition with a softened or melted carrier, followed by cooling and shaping in a crucible. In addition to the carrier ingredients mentioned above, the above-mentioned pharmaceutical formula can be adapted to two or more other loadings. Ingredients such as thinner, buffer, surfactant, thickener, moist (10) with 10,000 "transfer recipient's money into isotonicity. Contains borrowing = this paper scale applies _ home standard (CNS) A4 specification (2) Q χ 公益 公益 ------------------------------------------------------------------------------------------------------------------------------------------------------------------ This page} 1280240 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed A7 B7 V. INSTRUCTIONS (38) The composition of the substance or its pharmaceutically acceptable salt may also be in the form of a powder or a liquid concentrate. The compound of the invention and a pharmaceutical composition exhibit biological activity as a pDE4 inhibitor. Therefore, another aspect of the present invention In terms of treatment in mammals such as asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), eosinophilic granuloma, psoriasis, and other benign or malignant proliferative skin diseases endotoxin shock (and associated Symptoms, such as lamellar inflammation and acute abdominal pain in horses, septic shock, ulcerative colitis, Crohn's disease, myocardial and cerebral reperfusion injury, inflammatory arthritis, osteoporosis, chronic sputum Nephritis, atopic dermatitis, urticaria, adult dyspnea syndrome, dyspnea syndrome in children, chronic obstructive pulmonary disease in animals, diabetes insipidus, allergic rhinitis, allergic conjunctivitis, spring-associated membranous inflammation, Arterial restenosis, atheroma, atherosclerosis, neuropathic inflammation, pain, cough, rheumatoid arthritis, joint adhesion spondylitis, transplant rejection and graft-to-host disease over-secretion of niacin, bacteria, sputum or virus Caused by septicemia or septic shock, inflammation, and chronic tissue degeneration mediated by cytokines, osteoarthritis, cancer, cachexia, muscle wasting, inhibition #, memory weakening, unipolar sputum, acute and chronic neurodegenerative diseases with inflammatory components, · 'Student's disease Alzheimer's disease, spinal cord trauma, head injury, multiple sclerosis, M tumor growth And cancer invasion of normal tissues _ susceptible to inhibition by PDE4 isozyme and resulting increased cCAMP content - by administering an effective amount of a compound of the invention." Mammals 3, including humans and Other animals, such as dogs, cats, horses, and pigs, should therefore be aware that the treatment of mammals other than humans is ___________-------------------- Please read the notes on the back and fill out this page.) -41 - 1280240 Ministry of Economic Affairs, Intellectual Property Office, Staff and Consumer Cooperatives, Print A7 Β7 V. Description of Invention (39) For the clinical interrelated problems with the human cases listed above. treatment. Further, as described above, the compounds of the present invention can be used in combination with other therapeutic compounds. In particular, the combination of the PDE4 inhibitory compounds of the present invention can be advantageously used in combination with i) leukotriene receptor antagonist, Π) white triterpene biosynthesis inhibitor, iii) COX-2 selective inhibitor, iv) Statin, v) NSAID, vi) M2/M3 antagonist, Vii) corticosteroid, viii) H1 (histamine) receptor antagonist, and ix) /52 adrenergic receptor agonist combination on. In another aspect, it has been discovered that the compounds of the invention can be formed in a mammalian system with a novel product. For example, Example 19, (5-{(Ε)-2-(3-{6-[1-methyl·W曱si-si)ethyl]-8-4 phenyl}}phenyl) small [4_( Methanesulfonyl)phenyl]ethinyl}-1,2,4′′di- -3-yl)methanol:

OH 其係爲PDE4抑制劑，當投予實例丨4時 -42 - -----------裝--------訂--------- (請先閱讀背面之注意事項再填寫本頁) 水^紙張尺唐滴用中國國定淮 4- η V V-/I V ί 7 f - t ·OH is a PDE4 inhibitor, when the case is given 丨4-42 - ----------- loaded-------- ordered--------- (please Read the precautions on the back and fill out this page.) Water ^ Paper ruler Tang drops with Chinese national standard Huai 4- η V V-/IV ί 7 f - t ·

Μ 公 97 y- X U 1280240 ΚΙ ---__Β7 五、發明說明（4〇 )Μ公 97 y- X U 1280240 ΚΙ ---__Β7 V. Invention description (4〇)

該實例19係於活體内以新陳代謝產物形成。因此，本發 明係包括前體藥物，在對哺乳動物投予此種前體藥物之後 ，於活體内，以新陳代謝產物形成PDE4抑制劑。再者，衣 發明係包括一種藉由投予前體藥物以在活體内形成有敦量 之藉由式I所述PDE4抑制劑之步驟之治療方法。 於本文中使用之縮寫，具有下文表列之意義。未表列於 下文之縮寫，具有如一般使用之意義，除非另有特別敘述。 (請先閱讀背面之注音ρ事項再填寫本頁) ----訂--------- 經濟部智慧財產局員工消費合作社印製This Example 19 was formed in vivo as a metabolite. Accordingly, the present invention encompasses prodrugs which, after administration of such prodrugs to mammals, form PDE4 inhibitors in vivo as metabolites. Further, the invention includes a method of treating a prodrug by a step of administering a PDE4 inhibitor of the formula I in vivo. Abbreviations used herein have the meanings listed below. Abbreviations not listed below have the meaning as they are used in general, unless otherwise stated. (Please read the note on the back and then fill out this page) ----Book--------- Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative

Ac = 乙臨基 Bn = 节基 cAMP 環狀腺苷單磷酸鹽 DBU = 1,8-二氮雙環幷[5·4·0]十一-7-烯 DIBAL = 氫化二異丁基鋁 DMAP = 4-(二甲胺基）吡啶 DMF = Ν，Ν-二甲基甲醯胺 Et3 N = 三乙胺 GST 谷胱甘肽轉移酶 HMDS 六甲基二矽氮化物 -43- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 1280240 A7 B7 五、發明說明（41 ) 經濟部智慧財產局員工消費合作社印製 LDA = 鋰二異丙基胺 m-CPBA = 間氯過苯甲酸 MMPP = 單過氧鄰苯二甲酸 MPPM = 單過氧鄰苯二曱酸，鎂鹽6H20 Ms = 甲fe橫S盛基=甲橫酿基（mesyl) = S〇2 Me MsO = 甲燒橫酸鹽=甲續酸鹽（mesylate) NSAID = 非類固醇消炎藥物 o-Tol = 鄰-甲苯基 OXONE® = 2KHS05 ·ΚΗ8〇4 ·Κ28〇4 PCC = 氯基鉻酸吡錠 PDC = 重鉻酸吡錠 PDE 磷酸雙酯酶 Ph = 苯基 Phe = 苯二基 PMB = 對-甲氧基苄基 Pye = ρ比淀二基 r.t. = 室溫 Rac. = 外消旋 SAM = 胺基磺醯基或磺醯胺或so2nh2 SEM = 2-(三甲基矽烷基）乙氧基甲氧基 SPA = 閃爍近發檢測 TBAF = 氣化四•正-丁基按 Th = 2-或3-嘧吩基 TFA = 三氟醋酸 TFAA = 三氟醋酸酐 THF = 四氫吱喃 Thi = 。塞吩二基 TLC = 薄層層析法 TMS-CN = 氰化三甲基矽烷 TMSI 碘化三甲基矽烷 Tz = 1H (或2H)-四唑-5-基 CAN 硝酸南歸按 c3h5 = 晞丙基 44- — 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ------------^--------訂---- (請先閱讀背面之注意事項再填寫本頁) 1280240 A7 B7 --— 五、發明說明（42 ) fe基縮寫 Me = 甲基 Et = 乙基 n-Pr = 正-丙基 i-Pr = 異丙基 n-Bu = 正-丁基 i-Bu = 異丁基 s-Bu = 第二丁基 t-Bu = 第三丁基 c-Pr = ?衣丙基 c-Bu = 環丁基 c-Pen = 環戊基 c-Hex = 環己基 ------------^ — (請先閱讀背面之注音？事項再填寫本頁) 証實生物活性之檢測 在人類全血液中LPS與FMLP-所引致之TNF-沈與LTB4檢測 全血液係提供蛋白質與富含細胞環境，適於消炎化合物（ 譬如PDE4-選擇性抑制劑）之生物化學功效研究。正常未經 刺激之人類血液，並未含有可測得含量之^與。 在以LPS刺激時，經活化之單細胞會表現且分泌“，高 達8小時，而血漿含量仍然保持安定達24小時。已發表之 研究已t正實’經由PDE4抑制作用，藉由增加胞rtcAMp&amp;/ 或提高腺#基環化酶活性’抑制讯厂江，係發生在轉錄階 層下。LTB4合成亦對胞内CAMP之含量很敏感，且可完全被 PDE4-選擇性抑制劑所抑制。因在全血液之⑽刺激之以小 時期間内’只有極少LTB4產生，故對於藉由經活化之嗜中 性白血球合成LTB4，必須進行另—次Lps刺激，接著爲人 類全血液之瓣激發。因此，利用相同血液試樣，能夠藉 訂--- 嫌· 經濟部智慧財產局員工消費合作社印製 -45- 經濟部智慧財產局員工消費合作社印製 A280240 A7 ^----—-— R7 _ 五、發明說明（43 ) 下述程序’評估化合物對於贿活性之兩種替代標記物在 全血液中之功效。 藉由靜脈穿刺健康人類志願者（男性與女性），在肝燐脂 化之試管中，收集新鮮血液。此等被實驗者未具有明瞭症 狀，，且在血液收集之前至少4天，未服用任何nsaid。將 500微升血液液份與2微升媒劑（DMS〇)或2微升待測化合物 ’在不同濃度下，於37。(：下預培養15分鐘。接著添加1〇微 升媒劑（PBS)作爲空白試驗，或添加1〇微升Lps (1微克/毫 升最後濃度，# L-2630 (Sigma化學公司（St· Louis，M〇))，得自 大細4干血清型0111 : B4 ;在〇·ι〇’0 W/VBSA (在PBS中）中稀釋 。在37 C下培養24小時後，將另一份1〇微升pBS (空白試驗） 或10微升LPS (1微克/毫升最後濃度）添加至血液中，並在 37°C下培養30分鐘。然後以10微升PBS (空白試驗）或1〇微升 fMLP (1 &quot;M 取後濃度 ’ # ρ·35〇6 (Sigma);在 1。。w/v BSA (於 PBS 中）中稀釋）’在37 C下使血液激發15分鐘。使血液試樣於4 °C下，在1500x克下離心1〇分鐘，以獲得血漿。將5〇微升血 漿液份與200微升甲醇混合，以供蛋白質沉澱，並按上述離 心。使用酶免疫檢測套件（# 520111，得自Cayman化學公司 (Ann Arbor，MI)，根據製造者程序，檢測上層清液之[τβ4。 在已稀釋之血漿（於PBS中）中，·使用ELISA套件（Cistron生物 科技公司（Pine，Brook，NJ)，根據製造者程序，檢測TNF- π。 實例1-42之1&lt;：50値，大致範圍爲〇.〇4 &quot;Μ至8.71 &quot;Μ。 於活體内之抗過敏活性 本發明化合物已對於在IgE所媒介之過敏性肺發炎上之作 -46 •一 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -----------裝--------訂--------- (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 l28〇24〇 A7 --—------B7__— 五、發明說明（44 ) 用進行測試’該發炎係經由抗原被已敏化之天竺鼠吸入而 引致。首先，於溫和環磷醯胺所引致之免疫抑制下，藉由 腹膜腔内注射抗原與氫氧化鋁及百日咳疫苗之組合，使天 竺氣對卵清蛋白敏化。於稍後兩週與四週，給予追加劑量 足抗原。於六週時，趁在腹膜腔内投予之抗組織胺劑（新安 替根（mepyramine))掩護下，以氣溶膠化之卵清蛋白，使動物 激發。於又48小時後，進行枝氣管肺胞灌洗（BAL)，並計算 嗜伊紅血球及其他白血球在BAL流體中之數目。亦移除肺 臟’以供組織學檢查炎性傷害。在抗原激發之後，於48小 時期間，實例化合物之投藥（0·001·10毫克/公斤，腹膜腔内 或口服），達到三次，會導致顯著降低嗜伊紅血球過多現象 及其他炎性白血球之蓄積。在以實例化合物處理之動物肺 臟上，亦只有較少炎性傷害。 以SPA爲基礎之PDE活性檢測擬案 會抑制藉由第IV型cAMP專一磷酸二酯酶使CAMP水解成 AMP之化合物’係在96-井板格式上，按下述進行篩檢： 在96井板上，於30°C下，添加待測化合物（溶於2微升 DMSO中），188毫升受質緩衝劑，其含有[2,8-3H]腺站3，，5，-環 狀磷酸鹽（cAMP，100 nM 至 50 # M)，10 mM MgCl2，1 mM EDTA ，50 mM Tris，pH 7·5。藉由添加10毫升人類重組PDE4 (其量 係經控制’因此在10分鐘内形成〜1〇〇/。產物），引發反應。 於10分鐘後，藉由添加1毫克PDE-SPA珠粒（Amersham Pharmacia Biotech 公司（Piscataway，NJ)，使反應停止。於 Wallac Microbeta® 96-井板計數器（EG&amp;G Wallac公司（Gaithersburg，MD))上，將所產 -47- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -------------------訂--------- (請先閱讀背面之注意事項再填寫本頁) 1280240 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（45 ) 生之AMP產物定量。於酶不存在下之信號，係定義爲背景 。100%活性係被定義爲酶與DMSO存在下所檢出之信號， 其中背景係被扣除。因此，計算出抑制作用百分比。q 値係使用標準4-參數/多重結合位置方程式，自十點滴定 ，以非線性回歸吻合取近似値。 實例M2之IC5 0値，係以100 nM cAMP，使用製自桿狀病毒 / Sf-9表現系統之人類重組磷酸二酯酶IVa (met_248)之經純化 GST融合蛋白質測定。實例1_42之冗⑼値，其一般範圍爲 〇·14ηΜ至10·24ηΜ，惟其中一項實例具有IC5〇値爲1〇9nM。 下文實例係意欲作爲本發明某些較佳具體實施例之説明 ，而非意謂本發明之限制。 除非另有特別敛述’否則貫驗程序均在下述條件下施行 。全邵操作均在室溫或環境溫度下進行-意即在18_25°C範圍 之溫度下。溶劑蒸發係使用迴轉式蒸發器，在減壓（6〇〇_4〇〇〇 巴斯卡：4.5-30毫米Hg)下，使用高達60。(：之浴溫進行。反應 過程係藉薄層層析法（TLC)追蹤，而反應時間僅爲説明而給 丁。溶點並未經校正’而nd’’表示分解。所予之溶點，係爲 對於按所述製成之物質所獲得者。在一些製備中，多晶型 現象可造成具有不同熔點物質之單離。所有最後產物之結 構與純度’係藉由至少一種下列技術確認··丁Lc、質量光 譜法、核磁共振(NMR)光譜測定法或微量分析數據。產率 僅爲説明而給予。當給予時，NMR數據係呈主要診斷質子 之6値形式，以相對於作爲内標準之四甲基矽烷（丁MS)每百 萬份之份數（ppm)表示，於300 MHz，400 MHz或500 MHz下，使 -48 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ------------裂--------訂----- (請先閱讀背面之注意事項再填寫本頁) 1280240Ac = ethionyl Bn = nodal cAMP cyclic adenosine monophosphate DBU = 1,8-diazabicycloindole [5·4·0] eleven-7-ene DIBAL = diisobutylaluminum hydride DMAP = 4-(Dimethylamino)pyridine DMF = Ν, Ν-dimethylformamide Et3 N = triethylamine GST glutathione transferase HMDS hexamethyldiazine nitride-43- This paper size applies to China National Standard (CNS) A4 Specification (210 X 297 mm) 1280240 A7 B7 V. Description of Invention (41) Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed LDA = Lithium Diisopropylamine m-CPBA = m-chloroperbenzene Formic acid MMPP = monoperoxyphthalic acid MPPM = monoperoxy phthalic acid, magnesium salt 6H20 Ms = 甲fe transverse S Shengji = mesyl (mesyl) = S〇2 Me MsO = A burnt Acid salt = mesylate NSAID = non-steroidal anti-inflammatory drug o-Tol = o-tolyl OXONE® = 2KHS05 · ΚΗ8〇4 · Κ28〇4 PCC = chlorochromic pyridinium PDC = dichromate Ingot PDE phosphodiesterase Ph = phenyl Phe = phenylenediyl PMB = p-methoxybenzyl Pye = ρ than precipitated diyl rt = room temperature Rac. = racemic SAM = aminosulfonyl or sulfonate Amine or so2nh2 SEM = 2-(trimethyldecyl)ethoxymethoxy SPA = scintillation detection TBAF = gasification tetra•n-butyl as Th = 2- or 3-pyrimenyl TFA = three Fluoroacetic acid TFAA = trifluoroacetic anhydride THF = tetrahydrofuran Thi = . Teflon Diyl TLC = Thin Layer Chromatography TMS-CN = Trimethyldecane cyanide TMSI Trimethyl decyl iodide Tz = 1H (or 2H)-tetrazole-5-yl CAN Nitrate N3 according to c3h5 = 晞Propyl 44- — This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ------------^--------Book---- (Please read the notes on the back and fill out this page) 1280240 A7 B7 --- V. Description of invention (42 ) fe base abbreviation Me = methyl Et = ethyl n-Pr = n-propyl i-Pr = different Propyl n-Bu = n-butyl i-Bu = isobutyl s-Bu = second butyl t-Bu = tert-butyl c-Pr = ? propyl c-Bu = cyclobutyl c- Pen = cyclopentyl c-Hex = cyclohexyl ------------^ — (please read the phonetic transcription on the back? Then fill out this page) Confirm the detection of biological activity in human whole blood LPS TNF-Sink and LTB4 Detection with FMLP- The Whole Blood Line provides protein and cell-rich environments for biochemical efficacy studies of anti-inflammatory compounds such as PDE4-selective inhibitors. Normally unstimulated human blood does not contain measurable levels. Upon stimulation with LPS, activated single cells will behave and secrete "up to 8 hours, while plasma levels remain stable for up to 24 hours. Published studies have been t-real" via PDE4 inhibition by increasing rtcAMp& / or improve glandular cyclase activity 'inhibition of the plant, the line occurs in the transcriptional hierarchy. LTB4 synthesis is also sensitive to intracellular CAMP content, and can be completely inhibited by PDE4-selective inhibitors. During the whole blood (10) stimulation, there is very little LTB4 produced during the hour. Therefore, for the synthesis of LTB4 by activated neutrophils, another Lps stimulation must be performed, followed by stimulation of the human whole blood flap. Therefore, use The same blood sample, can be borrowed - suspected - Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing -45 - Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing A280240 A7 ^------- R7 _ 5, DESCRIPTION OF THE INVENTION (43) The following procedure 'evaluates the efficacy of two alternative markers for the activity of a compound in brix activity in whole blood. By venipuncture healthy human volunteers (male and female) in the liver In the test tube, fresh blood was collected. These subjects did not have the symptoms, and did not take any nsaid at least 4 days before blood collection. 500 microliters of blood and 2 microliters of vehicle (DMS〇 ) or 2 μl of test compound 'at different concentrations, at 37. (: pre-culture for 15 minutes. Then add 1 〇 microliter medium (PBS) as a blank test, or add 1 〇 microliter Lps (1 μg) /ml final concentration, # L-2630 (Sigma Chemical Company (St. Louis, M〇)), obtained from large fine 4 dry serotype 0111: B4; in 〇·ι〇'0 W/VBSA (in PBS) Diluted in medium. After incubation for 24 hours at 37 C, add another 1 μL of microliter pBS (blank test) or 10 μl of LPS (1 μg/ml final concentration) to the blood and incubate at 37 °C. 30 minutes. Then take 10 μl PBS (blank test) or 1 〇 microliter fMLP (1 &quot;M after concentration ' # ρ·35〇6 (Sigma); at 1. w/v BSA (in PBS) In the middle of dilution) 'The blood is excited for 15 minutes at 37 C. The blood sample is centrifuged at 1500 x g for 1 minute at 4 ° C to obtain plasma. 5 〇 microliter of plasma solution Mix with 200 μl of methanol for protein precipitation and centrifuge as described above. Use the Enzyme Immunoassay Kit (# 520111, available from Cayman Chemical Company (Ann Arbor, MI), according to the manufacturer's program, to detect the supernatant [τβ4] In diluted plasma (in PBS), TNF-π was detected using an ELISA kit (Cineron Biotech, Inc. (Pine, Brook, NJ) according to the manufacturer's program. Example 1-42 1 &lt;: 50 値, the approximate range is 〇.〇4 &quot;Μ to 8.71 &quot;Μ. Anti-allergic activity in vivo The compounds of the present invention have been used for IgE-mediated allergic lung inflammation -46 • A paper scale applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) --- --------装--------Book--------- (Please read the notes on the back and fill out this page) Printed by the Intellectual Property Office of the Ministry of Economic Affairs L28〇24〇A7 ---------B7__— V. INSTRUCTIONS (44) Tests were conducted. 'This inflammation is caused by the inhalation of antigen by sensitized guinea pigs. First, under the immunosuppression induced by mild cyclophosphamide, the combination of the antigen and the aluminum hydroxide and the pertussis vaccine is used to sensitize the egg white protein to the ovalbumin. Additional doses of the foot antigen were given in the next two weeks and four weeks. At six weeks, the animals were challenged with aerosolized ovalbumin under the cover of an antihistamine (mepyramine) administered intraperitoneally. After another 48 hours, the tracheal tracheal lavage (BAL) was performed and the number of eosinophils and other white blood cells in the BAL fluid was calculated. The lungs are also removed for histological examination of inflammatory injuries. After antigen challenge, the administration of the example compound (0·001·10 mg/kg, intraperitoneal or oral) was achieved three times during the 48-hour period, which resulted in a significant reduction in eosinophilia and accumulation of other inflammatory white blood cells. . There is also less inflammatory damage on the lungs of animals treated with the example compounds. The SPA-based PDE activity assay will inhibit the hydrolysis of CAMP to AMP by type IV cAMP-specific phosphodiesterase' in a 96-well format and screen as follows: On the plate, at 30 ° C, add the test compound (dissolved in 2 μl of DMSO), 188 ml of buffer, containing [2,8-3H] gland 3,5,-cyclic phosphate Salt (cAMP, 100 nM to 50 # M), 10 mM MgCl2, 1 mM EDTA, 50 mM Tris, pH 7.5. The reaction was initiated by the addition of 10 ml of human recombinant PDE4 (the amount of which was controlled to form ~1 〇〇/. product in 10 minutes). After 10 minutes, the reaction was stopped by the addition of 1 mg of PDE-SPA beads (Amersham Pharmacia Biotech, Inc. (Piscataway, NJ). The Wallac Microbeta® 96-well plate counter (EG&amp;G Wallac (Gaithersburg, MD) ), the -47- paper size will be applied to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ------------------- Order -- ------- (Please read the notes on the back and fill out this page) 1280240 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperatives Print A7 B7 V. Invention Description (45) Quantification of raw AMP products. The underlying signal is defined as the background. The 100% active line is defined as the signal detected in the presence of the enzyme and DMSO, where the background is subtracted. Therefore, the percent inhibition is calculated. q 値 is using standard 4-parameters/ Multiple binding position equations, titrated from ten points, approximated by nonlinear regression. Example IC2 of the M2 0値, with 100 nM cAMP, using human recombinant phosphodiester from the baculovirus/Sf-9 expression system Purified GST fusion protein assay for enzyme IVa (met_248). Example 1_42 redundancy (9)値, the general range is 〇·14ηΜ to 10·24ηΜ, but one of the examples has an IC5〇値 of 1〇9nM. The following examples are intended to be illustrative of some preferred embodiments of the invention, rather than Limitations of the invention. Unless otherwise specifically stated, otherwise the procedure is performed under the following conditions. The whole operation is carried out at room temperature or ambient temperature - meaning at a temperature in the range of 18-25 ° C. Solvent evaporation is used. Rotary evaporator, under reduced pressure (6 〇〇 _ 4 〇〇〇 Baska: 4.5-30 mm Hg), using up to 60. (: bath temperature. The reaction process by thin layer chromatography ( TLC) is traced, and the reaction time is only given to the description. The melting point is uncorrected 'and 'nd'' indicates decomposition. The melting point is obtained for the substance prepared according to the above. In the preparation, the polymorphism can cause the separation of substances with different melting points. The structure and purity of all the final products are confirmed by at least one of the following techniques: Dc, mass spectrometry, nuclear magnetic resonance (NMR) spectrometry Or microanalysis data. Yield is only instructions When administered, the NMR data is in the form of a 6 値 major diagnostic proton expressed in parts per million (ppm) relative to the internal standard tetramethyl decane (butyl MS) at 300 MHz, 400 At -MHz or 500 MHz, make -48 - the paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ------------ Crack -------- Order----- (Please read the notes on the back and fill out this page) 1280240

五、發明說明（明） 用所指示之溶劑測得。用於仏號形狀之^用&amp;寫爲：s·單 重線；d.二重線；t.三重線；m•多重線；br•寬廣等。此外 ，’’Arn表示芳香族信號。化學付號具有其常用意義；下列 縮寫亦被使用：v (體積），w (重量），b.p.(沸點），m.p·(溶 點），L (升），(毫升），g (克），mg (毫克），md (莫耳）， mmol (毫莫耳），eq (當量）。 合成方法 本發明化合物可根據下述方法製備。取代基均與式I中相 同，除非其中另有定義。 圖TF 1 酮合成 E—Ar1· ^--------訂--- (請先閱讀背面之注意事項再填寫本頁} 經濟部智慧財產局員工消費合作社印製V. Description of the invention (明) Measured with the indicated solvent. For the shape of the nickname &amp; is written as: s · single line; d. double line; t. triple line; m • multiple lines; br • broad and so on. Further, ''Arn) indicates an aromatic signal. Chemical paying has its usual meaning; the following abbreviations are also used: v (volume), w (weight), bp (boiling point), mp · (melting point), L (liter), (ml), g (g), Mg (mg), md (mole), mmol (mole), eq (equivalent). Synthetic method The compound of the present invention can be produced according to the method described below. The substituents are the same as in Formula I unless otherwise defined. Figure TF 1 Ketone Synthesis E-Ar1· ^-------- Order--- (Please read the notes on the back and fill out this page) Printed by the Intellectual Property Office of the Ministry of Economic Affairs

ArX XAr1Y . V ArArX XAr1Y . V Ar

VII S02Me f SMeVII S02Me f SMe

VIII -49- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 1280240VIII -49- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1280240

五、發明說明（47) 其中鹵素，Η γ=鹵素，Η (請先閱讀背面之注意事項再填寫本頁) (甲硫基）苯甲醛 Ε==親電子基團 Ar=芳基或雜芳基 參考上文圖TFl ’及下文圖示^，醇中間物玎可經由芳 基或雜芳基金屬物種ΠΙ，譬如有機鎂鹵化物，與4_(甲硫基） 苯甲酸(A)，在有機溶劑譬如THF中反應而製成。醇中間物 II亦可經由以鹼或有機金屬，譬如正-丁基鋰，在有機溶劑 譬如THF中’接著以4-(甲硫基）苯甲趁，處理芳基或雜芳基 氫化物或溴化物IV而製成。或者，醇中間物π亦可藉由下 列化學轉變而製成··丨）以鹼或有機金屬，譬如正β 丁基鋰， 經濟部智慧財產局員工消費合作社印製 在有機溶劑譬如THF中，接著以親電子試劑，譬如丙酮或4一 (甲硫基）苯甲醛，處理芳基或雜芳基二氫化物、_化物-氫 化物或二卣化物V ; 2)後續處理係以鹼或有機金屬，譬如 正-丁基鋰，在有機溶劑譬如TIiF中，接著爲親電子試劑， 譬如丙酮或4-(甲硫基）苯曱醛，其中第一次或第二次轉變必 須使用4-(甲硫基）苯甲醛，作爲親電子試劑。砜·醇νι可經 由以氧化劑，譬如生氧劑（0xone)，在溶劑中，譬如thf/ MeOH/I^O之混合物中，使硫化物_醇H氧化而製成。酮類 vii與viii可經由以氧化劑，譬如Mn〇2，在溶劑譬如CH2 % 中，個別使醇類π與νι氧化而製成。砜-酮νιπ亦可經由以 氧化劑，譬如Oxone，在溶劑中，譬如THF/Me〇H/H2〇之混合 物中，使硫化物-酮VII氧化而製成。 -50- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） [280240V. Inventive Note (47) where halogen, Η γ = halogen, Η (please read the note on the back and fill out this page) (Methylthio) benzaldehyde oxime == electrophilic group Ar = aryl or heteroaryl Referring to Figure TFl ' and the following diagram ^, the alcohol intermediate 玎 can be via an aryl or heteroaryl metal species, such as an organomagnesium halide, and 4_(methylthio)benzoic acid (A), in organic It is prepared by reacting a solvent such as THF. The alcohol intermediate II can also be treated with an aryl or heteroaryl hydride via a base or an organometallic such as n-butyllithium in an organic solvent such as THF followed by 4-(methylthio)benzhydrazide or Made from bromide IV. Alternatively, the alcohol intermediate π can also be made by the following chemical transformations: in an organic solvent such as THF, with an alkali or an organic metal such as n-butyl butyl lithium, the Ministry of Economic Affairs, Intellectual Property Office, and the Consumer Cooperative. The aryl or heteroaryl dihydride, the hydride-dihydride or the di- sulphide V is then treated with an electrophile such as acetone or 4-mono(methylthio)benzaldehyde; 2) the subsequent treatment is base or organic a metal, such as n-butyllithium, in an organic solvent such as TIiF, followed by an electrophile such as acetone or 4-(methylthio)benzofural, wherein the first or second transition must use 4-( Methylthio)benzaldehyde, as an electrophile. The sulfone alcohol ν can be produced by oxidizing sulfide-alcohol H with an oxidizing agent such as an oxygen generating agent (0xone) in a solvent such as a mixture of thf/MeOH/I^O. The ketones vii and viii can be produced by oxidizing the alcohols π and νι individually with an oxidizing agent such as Mn 〇 2 in a solvent such as CH 2 %. The sulfone-ketone νιπ can also be produced by oxidizing the sulfide-ketone VII with a oxidizing agent such as Oxone in a solvent such as THF/Me〇H/H2. -50- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) [280240

、發明說明（48 ) 圖示1表 酮類, invention description (48) Figure 1 table ketones

rVrV

Ar SOnMe VI! (n=〇) ▽HI (n=2) 酮Ar SOnMe VI! (n=〇) ▽HI (n=2) ketone

Ar FJ〇rCH h3c〇rCH2 K1 K2 K3 酮 h3cAr FJ〇rCH h3c〇rCH2 K1 K2 K3 ketone h3c

ch2 h3c XT2 K7 0 2 K4 K5Ch2 h3c XT2 K7 0 2 K4 K5

Me〇2S a 2 K10Me〇2S a 2 K10

h3c HO, H3C hr K6H3c HO, H3C hr K6

•CH〇 H3C, HO•CH〇 H3C, HO

,ch2 N 2 CH, K11 經濟部智慧財產局員工消費合作社印製 酮Kl ㈣M㈣甲續醯基)]笨基 酮K1係藉下述程序製備。 步驟1:(4·氟苯基)[4-甲硫基）苯基]酮 於t(甲硫基）苯甲搭(2.5克，16.4毫莫耳）在THF(100毫升）中 之-78τ溶液内’逐滴添加4•敦苯基溴化鎂（ι〇Μ，在THF中 ，19.7冗升，19.7耄莫耳）。將所形成之溶液於_78。〇下攪拌3 小時’並以NH4C1之飽和水溶液，使反應淬滅。然後，將 混合物以EtOAc及HC1 10。/。稀釋，萃取及洗滌（NaHC〇3 (飽和 酮 I----11------------訂--------- (請先閱讀背面之注意事項再填寫本頁) -51 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 1280240 A7 _______B7__ 五、發明說明（49 ) ，鹽水）。將有機相以^^^804脱水乾燥及濃縮。然後將殘留 物以Μη02(28·6克，330毫莫耳）在CH2C12(150毫升）中處理， (請先閱讀背面之注意事項再填寫本頁) 並將反應物於室溫下攪拌過夜。使混合物經過矽膠填充柱 (EtOAc)過濾，，產生2.6克（4_氟苯基）[4-甲硫基）苯基]酮化合 物0 步驟2 : (4-氟苯基）[4-(甲磺醯基）苯基]酮 於得自本步驟1之硫化物-換言之係爲（4-氟苯基）[4_甲硫基） 苯基]酮-(2.0 克，8.1 毫莫耳）在 THF/Me0H/H20 (80/40/40 毫升） 中之溶液内’添加〇xone (7.5克，12.2毫莫耳）。將混合物於 室溫下攪拌4小時，以NaHC〇3 (飽和），使反應淬滅，並以 EtOAc稀釋。將有機相以NaHC〇3(飽和）、鹽水洗滌，以 Na? SO*脱水乾燥，過濾及濃縮。結晶化作用（c% % /己烷） 產生（4-氟苯基）[4-(曱磺醯基）苯基]|同，K1酮化合物，爲白色 固體。 酮K2 (1-甲基-1H-咪唑-2-基）[4-甲硫基）苯基；]酮酮 K2係藉下述程序製備。 經濟部智慧財產局員工消費合作社印製 步驟1 : (1-甲基-1H-咪唑-2-基）[4·(甲硫基）苯基]甲醇 於N-甲基咪唑（1〇·〇克，122毫莫耳）在5〇〇毫升THF中，於-78 C下之落液内，逐滴添加正-丁基鋰（2·5Μ，在己烷中， 48.7毫升，118毫莫耳），並將所形成之溶液於_78。〇下攪拌 30分鐘。然後，於-78。(：下添加4_(甲硫基 U。毫莫耳)，並將混合物揽掉直到藉TLC得知(已止 ’並以nh4ci(飽和）使反應淬滅。然後，將混合物以Et〇Ac 52 _ 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱) ------ 經濟部智慧財產局員工消費合作社印製 1280240 A7 ----------B7___ 五、發明說明（50 ) 稀釋，萃取與洗滌（NaHC03(飽和），鹽水）。將有機相以 MgS〇4脱水乾燥，過濾及濃縮。結晶化作用（Et〇Ac /己烷）產 生（1-甲基-1H-咪唑-2-基）[4-(曱硫基）苯基]甲醇。 步驟2 : (1-甲基_1H-咪唑_2•基）[4-(甲硫基）苯基]酮 於得自本步驟1之醇（25·7克，111毫莫耳）在Et〇Ac(25〇毫升) 與CH2 (¾ (250毫升）中之溶液内，添加Mn〇2 (14〇克，丨66莫耳) ’並將反應物於室溫下攪拌過夜。使混合物經過矽膠填充 柱（EtOAc)過濾、，產生酮幻。 酮K3 (4-甲磺醯基）(苯基）酉同 酮K3係藉下述程序製備。 步驟1 : (4-甲硫基）(苯基）甲醇 於4-(甲硫基）苯甲醛（1 〇克，6.5毫莫耳）在THF (20毫升）中 ’在0 C下之溶液内，添加苯基氯化鎂（2M，THF，3.5毫升 ’ 7·〇毫莫耳）。於室溫下0.5小時後，將混合物以飽和NH4C1 溶液中和，以水稀釋，並以段2〇萃取。將有機萃液洗滌 (ho)、（鹽水），脱水乾燥（MgS〇4)，過濾及濃縮。經由在 己/ Et2〇中激烈攪拌及過濾，產生（4-甲硫基）(苯基）甲醇 ，爲白色固體。 步驟2: (4-甲硫基X苯基）g同 (4-甲硫基）(苯基）酮係按下文K4程序之步驟2，經由以 Μη〇2處理得自本步驟1之…甲硫基X苯基）甲醇而獲得。 步驟3 : (4-甲續醯基）(苯基）g同 於得自本步驟2之（4-甲硫基）(苯基）酮（〇·98克，4.3毫莫耳） -53- 本紙張尺度適用中國國豕標準（CNS)A4規格（21〇 X 297公爱） •-----------·I----丨丨1Τ--------- (請先閱讀背面之注意事項再填寫本頁) 1280240 A7 經濟部智慧財產局員工消費合作社印製 五、發明說明（S1 ) 在CHC13 (10毫升）中，太卞、、、 ^ ^ 在〇 c下之落液内，添加mCPBA (間_氣過 苯甲酸)(7 5 10笔莫耳)。於室溫下〇·5小時後，將Ca卿)2 (1.7克’ 23毫莫耳)添加至混合物中’將其攪拌卜&quot;争。於 Celite®上過遽，及濃縮，產生酮们，爲白色固體。 酮K4 (1’3-p塞吱基）[4-(甲硫基）苯基]酮 酮K4係藉下述程序製備。 步驟1 ·· (1，3-噻唑-2_基）[4-(甲硫基）苯基]甲醇 於嘍唑（5.0克，58·7亳莫耳）在THF(25〇毫升）中之溶液 逐滴添加正-丁基鋰（2·5Μ，在己烷中，23·5毫升，58·7 毫莫耳），並將所形成之溶液於下攪拌1〇分鐘。然後 ，於-78°C下添加4-(甲硫基）苯甲醛（71毫升，53·4毫莫耳）。 將所形成之混合物搅拌，直到完成爲止，並以NH4Ci之飽和 水洛液使反應 &gt;午滅。然後，將混合物以Et〇Ac及HC1 1〇。〇稀 釋，萃取與洗滌(NaHC〇3(飽和），鹽水）。將有機相以MgS(^ 脱水乾燥及濃縮。然後，將殘留物藉急驟式層析純化（8〇〇。 CH2C12 / 20。。EtOAc)，產生（1，3〜塞，坐_2_基）[4_(甲硫基）苯基]甲 醇。 步驟2 : (1，3-噻唑-2-基）[4-(甲硫基）苯基]嗣 於得自本步驟1之（1，3-P塞唑-2-基）[4-(甲硫基）苯基]甲醇（1〇〇 克’ 42.1笔莫耳）在EtOAc (250毫升）中之溶液内，添加 Mn〇2 (70克’ 843宅莫耳），並將反應物於25°c下檀拌過夜。 使混合物經過矽膠填充柱（Et0Ac)過濾，以形成似锎化合物。 酮K5 -54- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ------------Μ--------訂--------- (請先閱讀背面之注意事項再填寫本頁) Α7, ch2 N 2 CH, K11 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing ketone Kl (four) M (four) A continued sulfhydryl)] stupid ketone K1 is prepared by the following procedure. Step 1: (4. Fluorophenyl) [4-methylthio)phenyl]one in t(methylthio)benzene (2.5 g, 16.4 mmol) in THF (100 mL) -78. In the solution, 4 • phenylphenylmagnesium bromide (ι〇Μ, in THF, 19.7 liters, 19.7 Torr) was added dropwise. The resulting solution was at -78. The mixture was stirred for 3 hours while the reaction was quenched with a saturated aqueous solution of NH4Cl. Then, the mixture was treated with EtOAc and HCl. /. Dilution, extraction and washing (NaHC〇3 (saturated ketone I----11------------ order--------- (please read the notes on the back and fill in again) This page) -51 - This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1280240 A7 _______B7__ V. Invention description (49), brine). Dehydrate the organic phase with ^^^804 and Concentrate. The residue is then treated with Μη02 (28·6 g, 330 mmol) in CH2C12 (150 mL). (Please read the back note and fill out this page) and stir the reaction at room temperature. After overnight, the mixture was filtered through a pad of silica gel (EtOAc) to give 2.6 g of (4-fluorophenyl)[4-methylthiophenyl) ketone compound 0 Step 2: (4-fluorophenyl)[4- (Methanesulfonyl)phenyl]one in the sulfide obtained in this step 1 - in other words (4-fluorophenyl)[4-methylthio)phenyl]one - (2.0 g, 8.1 mmol) ) Add 〇xone (7.5 g, 12.2 mmol) in a solution in THF/Me0H/H20 (80/40/40 mL). The mixture was stirred at room temperature for 4 hr. The organic phase was washed with EtOAc (aq.), brine, dried over Na? Crystallization (c% % / hexane) gave (4-fluorophenyl)[4-(nonylsulfonyl)phenyl]|, a K1 ketone compound as a white solid. Ketone K2 (1-methyl-1H-imidazol-2-yl)[4-methylthio)phenyl;]ketone K2 was prepared by the following procedure. Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Print Step 1: (1-Methyl-1H-imidazol-2-yl)[4·(methylthio)phenyl]methanol in N-methylimidazole (1〇·〇 Gram, 122 mM) n-butyllithium (2.5 mM in hexane, 48.7 mL, 118 mmol) in 5 mL of THF in a drop of -78 C ) and the resulting solution was at _78. Stir under the arm for 30 minutes. Then, at -78. (: Add 4_(methylthio-U.m.), and take the mixture off until it is known by TLC (stopping 'and quenching the reaction with nh4ci (saturation). Then, the mixture is EtEAc 52 _ This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public) ------ Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1280240 A7 ----------B7___ five , invention instructions (50) dilution, extraction and washing (NaHC03 (saturated), brine). The organic phase is dehydrated and dried with MgS〇4, filtered and concentrated. Crystallization (Et〇Ac / hexane) production (1-A -1H-imidazol-2-yl)[4-(indolyl)phenyl]methanol Step 2: (1-methyl-1H-imidazolium-2-yl)[4-(methylthio)phenyl The ketone is added to the solution of the alcohol (25. 7 g, 111 mmol) obtained in this step 1 in Et 〇Ac (25 〇 ml) and CH 2 (3⁄4 (250 ml), Mn 〇 2 (14 〇)克,丨66莫耳) 'The reaction was stirred at room temperature overnight. The mixture was filtered thru a packed pad (EtOAc) to give the ketone. Ketone K3 (4-methylsulfonyl) (phenyl) The ketone K3 system was prepared by the following procedure: Step 1: (4-Methylthio)(phenyl)methanol in 4-(methylthio)benzaldehyde (1 g, 6.5 mmol) in THF (20 mL) in EtOAc (20 mL) Magnesium chloride (2M, THF, 3.5 ml '7·〇 mmol). After 0.5 h at room temperature, the mixture was neutralized with saturated NH4C1 solution, diluted with water and extracted with EtOAc. Washing (ho), (brine), dehydration drying (MgS〇4), filtration and concentration. (4-methylthio)(phenyl)methanol was obtained as a white solid by vigorous stirring and filtration in hexane / Et2. Step 2: (4-Methylthio X phenyl) g with (4-methylthio) (phenyl) ketone is carried out according to step 2 of the following K4 procedure, obtained by the treatment of Μη〇2... Obtained with methylthioxylphenyl)methanol. Step 3: (4-methylindoleyl)(phenyl)g is the same as (4-methylthio)(phenyl)ketone obtained from this step 2 (〇· 98g, 4.3 millimoles) -53- This paper size applies to China National Standard (CNS) A4 specification (21〇X 297 public). -------------I----丨丨1Τ--------- (Please read the notes on the back and fill out this page) 128024 0 A7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (S1) In CHC13 (10 ml), too,,, ^ ^ in the falling liquid under 〇c, add mCPBA Benzoic acid) (7 5 10 moles). After 5 hours at room temperature, Ca qing) 2 (1.7 g '23 mM) was added to the mixture 'stirring it'. It was dried over Celite® and concentrated to give the ketone as a white solid. The ketone K4 (1'3-p decyl)[4-(methylthio)phenyl] ketone K4 was prepared by the following procedure. Step 1 ···(1,3-thiazol-2-yl)[4-(methylthio)phenyl]methanol in oxazole (5.0 g, 58·7 mmol) in THF (25 mL) To the solution was added n-butyllithium (2.5 mM in hexane, 23.5 ml, 58. 7 mmol), and the resulting solution was stirred for 1 hr. Then, 4-(methylthio)benzaldehyde (71 ml, 53.4 mmol) was added at -78 °C. The resulting mixture was stirred until completion and the reaction was quenched with NH4Ci saturated broth. Then, the mixture was subjected to Et〇Ac and HC1 1〇. 〇 diluted, extracted and washed (NaHC〇3 (saturated), brine). The organic phase was dried and concentrated with EtOAc (EtOAc) (EtOAc) [4_(Methylthio)phenyl]methanol. Step 2: (1,3-thiazol-2-yl)[4-(methylthio)phenyl]anthracene obtained from this step 1 Add Mn〇2 (70 g' in a solution of P-pyrazol-2-yl)[4-(methylthio)phenyl]methanol (1 g of '42.1 mol) in EtOAc (250 mL) 843 house Moule), and the reaction mixture was sanded at 25 ° C overnight. The mixture was filtered through a silicone packed column (Et0Ac) to form a quinone-like compound. Ketone K5 -54- This paper scale applies to Chinese national standards (CNS) )A4 size (210 X 297 mm) ------------Μ--------Book--------- (Please read the notes on the back first) Fill in this page) Α7

!28〇240 五、發明說明（52 ) (I，3-噻唑-2-基）[4-(甲磺醯基）苯基;jg同 酮K5係藉下述程序製備。 於K4 (1，3-遠唆-2-基）[4-(甲硫基）苯基]酮（8·2克，34·7毫莫耳） 在 THF/MeOH/H2〇(350/175/175 毫升）中之溶液内，添加 〇x〇ne (42.6克，69.4毫莫耳）。將反應物於25°C下攪拌3小時，並以 NaHC〇3之飽和水溶液使反應淬滅。然後，將所形成之混合 物以EtOAc稀釋，萃取與洗滌飽和），鹽水）。將有 機相以MgS〇4脱水乾燥及濃縮。然後使殘留物藉結晶化作 用純化（EtOAc /己烷），產生（1，3_p塞唑-2_基）[4•(甲磺醯基）苯基] 酮。 酮K6 [5-(1-輕基-1-甲基乙基H，3_噻唑_2_基][4_(甲磺醯基）苯基]酮 酮K6係藉下述程序製備。 步驟1 : 0(1-羥基-1-甲基乙基&gt;;1，3•嘧唑·2·基][4-(曱硫基）苯基] 酮 於嘧唑（1.0克，12.0毫莫耳）在THF (100毫升）中之_78Χ：溶液 内，逐滴添加正-丁基鋰（2.3 Μ，在己烷中，5·3毫升，12.3 毫莫耳），並將所形成之溶液於_78。(：下攪拌1〇分鐘。然後 於-78°C下添加4·(曱硫基）苯曱醛（7.1毫升，53·4毫莫耳）。將 所形成之混合物於室溫下攪拌10分鐘，並在_78。〇下冷卻。 逐滴添加正-丁基鋰（2_3 Μ，在己烷中，5.3毫升，12·3毫莫 耳），並將所形成之溶液於25。〇下攪拌1〇分鐘，及以丙酉同 (3.0毫升）使反應淬滅。然後，將混合物以&amp;〇触及HC1 1〇〇。 稀釋，萃取與洗滌（NaHCOd飽和），鹽水）。將有機相以 -55- 巧張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱) ' ---- ------------^裝--------訂---------^9. (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製!28〇240 V. INSTRUCTION DESCRIPTION (52) (I,3-thiazol-2-yl)[4-(methylsulfonyl)phenyl; jg homoketone K5 was prepared by the following procedure. K4 (1,3- farin-2-yl)[4-(methylthio)phenyl]one (8.2 g, 34·7 mmol) in THF/MeOH/H 2 〇 (350/175 Add 〇x〇ne (42.6 g, 69.4 mmol) to the solution in /175 ml). The reaction was stirred at 25 &lt;0&gt;C for 3 h and quenched with aq. The resulting mixture was then diluted with EtOAc, extracted and washed with brine, brine. The organic phase was dehydrated and concentrated with MgS 4 . The residue was then purified by crystallization (EtOAc / hexanes) to afford (1,3.sup. Ketone K6 [5-(1-Lightyl-1-methylethyl H,3-thiazole-2-yl][4-(methylsulfonyl)phenyl]ketone K6 was prepared by the following procedure: Step 1 : 0 (1-hydroxy-1-methylethyl); 1,3 • pyrazole 2·yl][4-(indolyl)phenyl]one in pyrazole (1.0 g, 12.0 mmol) n-Butyllithium (2.3 Torr in hexane, 5.3 ml, 12.3 mmol) was added dropwise in _78 Χ: THF (100 mL), and the resulting solution was _78. (: stirring for 1 minute. Then add 4·(indolyl)benzaldehyde (7.1 ml, 53.4 mmol) at -78 ° C. The resulting mixture was allowed to stand at room temperature. Stir for 10 minutes and cool at _78. Under ice, add n-butyllithium (2_3 Μ in hexanes, 5.3 mL, 12·3 mmol) and the resulting solution was at 25. The mixture was stirred for 1 minute, and the reaction was quenched with acetonitrile (3.0 mL). The mixture was then taken to &lt;RTI ID=0.0&gt;&&&&&&&&&&&&&&& Applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 public) with -55- Qiao Zhang scale ' ---- - -----------^装--------Book---------^9. (Please read the notes on the back and fill out this page) Property Bureau employee consumption cooperative printing

1280240 五、發明說明（53 ) g 〇4脱水乾爍，及濃縮。然後將殘留物以Μη〇2 (2〇·4克， 235笔莫耳）在cf^ciyuo毫升）中處理，並將反應物於室溫 下技拌過夜。然後’將所形成之混合物經過矽膠填充柱 (EtOAc)過濾。急驟式層析（9〇% CH2C12/1〇% Et〇Ac)產生[^…羥 基-1-甲基乙基）-1，3-Ρ塞唑-2-基][4-(甲硫基）苯基]酮。 步驟2 : 〇(1-羥基-1-甲基乙基唑1基][4_(甲磺醯基）苯 基]酮 於得自本步驟1之硫化物·意即[5_(1_羥基小甲基乙基）-i，3-噻 唑-2-基][4-(甲硫基）苯基]酮七7克，5 8毫莫耳）在THF/Me〇H/ I^O (100/50/50毫升）中之溶液内，添加〇x〇ne (7 1克，ι15毫莫 耳）。將反應物於25°C下攪拌3小時，及以NaHC03之飽和水 落液使反應坪滅。然後，將混合物以Et〇Ac稀釋，萃取與洗 滌(NaHCOj(飽和），鹽水）。將有機相以MgS〇4脱水乾燥及濃 縮。然後’藉由結晶化作用（Et〇Ac /己燒），使殘留物純化 ，產生酮K6。 酮K7 (6-甲基-3-吡啶基）[4-(甲磺醯基）苯基]酮 酮K7係藉下述程序製備。 步驟1 : (6-甲基-3-吡啶基）[4-(曱硫基）苯基；|甲醇 於3_溴基-6-甲基吡啶（760毫克，1當量）在THF (20毫升）中 ’於-78°C下之溶液内，慢慢添加正-丁基鋰在己烷中之溶 液（1.1當：)。然後’將落液揽摔30分鐘。接著慢慢添加4-( 硫基甲基）苯曱醛（738毫克，U當量）。使溶液溫熱至室溫 。添加NH4 C1 (飽和）’然後爲水及EtOAc。分離有機相，以 -56- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -----------AW- ^--------訂--------- (請先閱讀背面之注音？事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 !28〇240 Α7 Β7 經濟部智慧財產局員工消費合作社印製 五、發明說明（541280240 V. INSTRUCTIONS (53) g 〇4 Dehydrated and dried, and concentrated. The residue was then treated with Μη〇2 (2 〇·4 g, 235 moles) in cf^ciyuo ml) and the reaction was stirred overnight at room temperature. The resulting mixture was then filtered through a pad of silica (EtOAc). Flash chromatography (9〇% CH2C12/1〇% Et〇Ac) yields [^.hydroxy-1-methylethyl)-1,3-oxazol-2-yl][4-(methylthio) Phenyl] ketone. Step 2: 〇(1-hydroxy-1-methylethyl azole 1 yl)[4_(methylsulfonyl)phenyl]one is obtained from the sulfide obtained in this step 1 means that [5_(1_hydroxyl is small) Methyl ethyl)-i,3-thiazol-2-yl][4-(methylthio)phenyl]one 7 7 g, 5 8 mmoles in THF/Me〇H/I^O (100 Add 〇x〇ne (7 1 g, ι 15 mmol) to the solution in /50/50 ml). The reaction was stirred at 25 ° C for 3 hours, and the reaction was quenched with saturated aqueous NaHC.sub.3. Then, the mixture was diluted with Et〇Ac, extracted and washed (NaHCOj (saturated), brine). The organic phase was dehydrated and concentrated with MgS 4 . The residue is then purified by crystallization (Et〇Ac / hexane) to yield the ketone K6. Ketone K7 (6-methyl-3-pyridyl)[4-(methylsulfonyl)phenyl]ketone Ketone K7 was prepared by the following procedure. Step 1: (6-Methyl-3-pyridyl)[4-(indolyl)phenyl;|methanol in 3-bromo-6-methylpyridine (760 mg, 1 eq.) in THF (20 mL A solution of n-butyllithium in hexane (1.1 when:) was slowly added to the solution at -78 °C. Then 'drop the drop for 30 minutes. Then 4-(thiomethyl)benzofural (738 mg, U equivalent) was added slowly. Allow the solution to warm to room temperature. NH4Cl (saturated) was added followed by water and EtOAc. Separation of the organic phase to -56- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -----------AW- ^-------- --------- (Please read the phonetic on the back? Please fill out this page again) Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative! 28〇240 Α7 Β7 Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, Printed Five , invention description (54

MgS04脱水乾燥及濃縮。經由以醚/己烷沉澱，獲得巧甲基 -3-峨咬基）[4-(甲硫基）苯基]甲醇，將其使用於下一步驟，無 需進一步純化。 步驟2 : (6-甲基-3-吡啶基）[4-(甲磺醯基）苯基]甲醇 按照上文步驟2之程序，但以得自本步驟丨之硫化物 (6-甲基-3_吡啶基）[4-(甲硫基）苯基]甲醇，取代（4_氟苯基）[4_(甲 硫基）苯基]酮，作爲起始物質，獲得（6-甲基_3•吡啶基）[4•(甲 磺醯基）苯基]甲醇。 步驟3 ·· (6-甲基-3-吡啶基）[4-(甲磺醯基）苯基]酮 按照上文S同K2步驟2之程序，但以得自本步驟2之（6-甲基_ 3-吡哫基）[4-(甲磺醯基）苯基]甲醇，取代（丨_甲基-1H_咪唑·2-基 )[4-(甲硫基）苯基]甲醇，作爲起始物質，獲得酮…。 酮K8 (5·甲基-2-吡啶基）[4-(甲磺醯基）苯基]酉同 酮K8係按照酮K7所述程序製成，但以2-溴基-5-甲基毗啶 取代3-溴基-6_甲基吡啶。 酮K9 雙-[(4-甲磺醯基）苯基]酮 酮K9係按照酮K7所述程序製成，但以4-溴基硫代甲苯醚 取代3-溴基-6-甲基吡啶，及在硫;f匕物-氧化步驟中，使用兩 倍量之Oxone。 酮K10 (2-吡啶基）[4-甲磺醯基）苯基]酮 酮K10係按照酮K7所述程序製成，但以2-溴基吡啶取代3- -57- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -----------裝--------訂--------- (請先閱讀背面之注意事項再填寫本頁) 1280240 酮Κ11 A7 Β7 五、發明說明（55 ) 溴基-6-甲基p比淀 [5-(1-羥基-1-甲基乙基）-2_哺啶基][4-(甲磺醯基）苯基]酮 酮K11係藉下述程序製備。 步驟1 : [5-(1-羥基-1-甲基乙基&gt;2_说啶基][4_(甲硫基）苯基]甲 醇 於2,5-二溴基吡哫（5.12克，1當量）在醚中，於·78。〇下之懸 浮液内，慢慢添加在己烷中之正_ 丁基鋰（1〇5當量）。將所 形成之黃橘色沉澱物攪拌30分鐘，然後添加丙酮（1.54毫升 ，1·〇5當量）。將此溶液在-78乇下再保持3〇分鐘。將在己烷 中之正-丁基鋰（U當量）慢慢地注入所形成之橘色懸浮液中 。然後，將此懸浮液在-78°C下攪拌i小時。然後，添加4_( 甲石鳥基）苯甲醛（2.85笔升，U當量）。使所形成之懸浮液溫 熱至-35°C，並以NI^Cl(飽和）溶液，使反應淬滅。添加水 與EtOAc，並將有機層以MgS〇4脱水乾燥，蒸發及藉急驟式 層析純化（EtOAc)，獲得[5-(1-羥基+甲基乙基&gt;2^比啶基][4_(甲 硫基）苯基]甲醇。 步驟2 : [5·(1-羥基-1-甲基乙基»比啶基][4·(甲磺醯基）苯基] 甲醇 按照上文關於酮Κ1步驟2所述之程序，但以得自本步驟1 之硫化物意即[5-(1-經基小甲基乙基）·24啶基][4_(甲硫基）苯 基]甲醇-取代（4-氟苯基）[4-(甲硫基）苯基]酮，作爲起始物質 ’獲得0(1-經基-1-甲基乙基）-2·咐啶基][4-(甲磺醯基）苯基]甲 醇。 -58- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 裝--------訂--------- (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 1280240 A7 五、發明說明（56 ) 酉同 步驟3 : [5·(1每基小甲基乙基）-2-吡啶基][4·(甲 績SS基）冬基] 按照上文關於_Κ2步驟2所述之程序，但以得自本步躁2 ([5仆經基-1-甲基乙基&gt;2_峨咬基][4_(甲續酿基）苯幻甲醇， 取代0-甲基-1Η♦坐絲)[4_(甲硫基）苯基]甲醇，作爲起始物 質，獲得酮Κ11 用以製備本發明化合物之硼燒酸酯化合物，可 所示之圖式2製成： 根據下文 圖式2 石朋燒酸S旨合成 (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製The MgS04 is dehydrated, dried and concentrated. By precipitating with ether/hexane, [4-(methylthio)phenyl]methanol was obtained as the methyl-3-carbazide, which was used in the next step without further purification. Step 2: (6-Methyl-3-pyridinyl)[4-(methylsulfonyl)phenyl]methanol according to the procedure of Step 2 above, but with the sulphide from this step (6-methyl -3_pyridyl)[4-(methylthio)phenyl]methanol, substituted (4-fluorophenyl)[4-(methylthio)phenyl]one, as starting material, (6-methyl) _3•pyridyl)[4•(methylsulfonyl)phenyl]methanol. Step 3 · · (6-methyl-3-pyridyl)[4-(methylsulfonyl)phenyl]one according to the procedure of Step 2 above with K2, but obtained from this step 2 (6- Methyl-3-pyridinyl)[4-(methylsulfonyl)phenyl]methanol, substituted (丨-methyl-1H-imidazole-2-yl)[4-(methylthio)phenyl]methanol As a starting material, a ketone is obtained. Ketone K8 (5.methyl-2-pyridyl)[4-(methylsulfonyl)phenyl]nonanone K8 was prepared according to the procedure described for ketone K7, but with 2-bromo-5-methyl Pyridine is substituted for 3-bromo-6-methylpyridine. Keto K9 bis-[(4-methylsulfonyl)phenyl]ketoone K9 was prepared according to the procedure described for ketone K7, but 3-bromothiotoluene ether was substituted for 3-bromo-6-methylpyridine. And in the sulphur;f sputum-oxidation step, twice the amount of Oxone is used. Ketone K10 (2-pyridyl)[4-methylsulfonyl)phenyl]ketoone K10 was prepared according to the procedure described for ketone K7, but substituted with 2-bromopyridine 3--57- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -----------Package--------Book--------- (Please read the back Note: Please fill in this page again) 1280240 Ketone oxime 11 A7 Β7 V. Description of invention (55) Bromo-6-methyl p-precipitate [5-(1-hydroxy-1-methylethyl)-2-carboxinyl [4-(Methanesulfonyl)phenyl]ketone K11 was prepared by the following procedure. Step 1: [5-(1-Hydroxy-1-methylethyl&gt; 2_sayridinyl][4-(methylthio)phenyl]methanol in 2,5-dibromopyridinium (5.12 g, 1 equivalent) In an ether, slowly add butyl butyllithium (1 〇 5 equivalents) in hexane in a suspension of 〇. Stir the resulting yellow orange precipitate for 30 minutes. Then, acetone (1.54 ml, 1·〇5 equivalent) was added. This solution was kept at -78 Torr for an additional 3 minutes, and n-butyllithium (U equivalent) in hexane was slowly injected. The orange suspension was then stirred. The suspension was stirred at -78 ° C for 1 hour. Then, 4_(methylstone) benzaldehyde (2.85 liters, U equivalent) was added to form the resulting suspension. The reaction was quenched with EtOAc (EtOAc) (EtOAc)EtOAc. , [5-(1-hydroxy+methylethyl&gt;2^pyridinyl][4-(methylthio)phenyl]methanol was obtained. Step 2: [5·(1-hydroxy-1-methyl-ethyl) Ketopyridinyl][4·(methylsulfonyl)phenyl]methanol according to the above steps for ketone oxime 1 2 the procedure described, but substituted with the sulfide obtained in this step 1 means [5-(1-carbamicmethylethyl)·24 pyridine][4-(methylthio)phenyl]methanol- (4-Fluorophenyl)[4-(methylthio)phenyl]one, as starting material 'obtained 0 (1-alkyl-1-methylethyl)-2· aridinyl][4- (Methanesulfonyl) phenyl]methanol -58- The paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm). -- (Please read the note on the back and then fill out this page) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1280240 A7 V. Invention description (56) Same as step 3: [5·(1 per base small methyl B Base)-2-pyridyl][4·(A) SS-based winter base] Follow the procedure described above for _Κ2, step 2, but from this step 躁2 ([5 servile-based-1- Methyl ethyl group &gt; 2_ 峨 base] [4_(methyl succinyl) benzene phantom methanol, substituted 0-methyl-1 Η 坐 sit) [4_(methylthio)phenyl]methanol, as the starting Substance, obtaining ketone oxime 11 The boron sulphonate compound used to prepare the compound of the present invention can be prepared as shown in the following formula 2: According to the following formula 2 Please read the notes on the back and fill out this page. Printed by the Intellectual Property Office of the Ministry of Economic Affairs.

Br Br 0LBr Br 0L

-59 本紙張尺度適用中國國家標準（CNS)A4規格（210 χ 297公釐） 裝--------訂---------. 1280240 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明（57 ) 酮（VII或VIII) Ar η硼燒酸S旨（XII) K2 h2ca#n^ ch3 0 B1 K4 h2c々 0 B2 K8 jHrCH3 H2C 八 N H3C ^Λ0Η 2 B3 K11 h2〇V CH3 2 B4 芳基溴化物IX與X，可經由以鹼， 譬如 t-BuOK 或 LiHMDS ’在有機溶劑譬如THF中，處理溴化芊基鳞XI，接著添加 酮VII或VIII至反應混合物中而製成。在IX中之硫化物，可 經由以Oxone，在溶劑譬如THF/MeOH/H2 0之混合物中處理， 而被轉化成颯X。硼烷酸酯XII可於鹼，譬如KOAc，及觸媒 ’譬如PdCl2 (dppf)存在下，在譬如DME之溶劑中，經由將芳 基溴化物X與2,3-二甲基丁二醇二硼燒一起加熱而製成。 硼烷酸酯B1 3-{(Ε)-2-(1-曱基-1H-咪吐-2-基）-2-[4-(曱磺醯基）苯基]乙晞基}苯 基硼燒酸2,3-二甲基丁二醇酯 硼烷酸酯B1係藉下述程序製備。 歹马水1 · (E/Z)-2-(3-&gt;臭本基）小(1-甲基-1H-味唆-2-基）-1-[4-(甲硫 基）苯基]乙締 於（3-溴基芊基）(三苯基）溴化辚（1〇 2克，19 9毫莫耳）在 -60- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱） -----------裝--------訂--------- (請先閱讀背面之注意事項再填寫本頁) l28〇240-59 This paper size is applicable to China National Standard (CNS) A4 specification (210 297 297 mm). Installation--------Book---------. 1280240 A7 B7 Ministry of Economic Affairs Intellectual Property Office staff Consumer Cooperatives Printing 5, Inventions (57) Ketones (VII or VIII) Ar η borax acid S (XII) K2 h2ca#n^ ch3 0 B1 K4 h2c々0 B2 K8 jHrCH3 H2C Eight N H3C ^Λ0Η 2 B3 K11 h2〇V CH3 2 B4 aryl bromide IX and X, which can be treated by treating a ruthenium bromide scale XI with a base such as t-BuOK or LiHMDS 'in an organic solvent such as THF, followed by addition of a ketone VII or VIII to the reaction Made from the mixture. The sulfide in IX can be converted to 飒X by treatment with Oxone in a solvent such as a mixture of THF/MeOH/H20. Borane XII can be obtained by the addition of aryl bromide X and 2,3-dimethylbutanediol in the presence of a base such as KOAc and a catalyst such as PdCl2 (dppf) in a solvent such as DME. Boron is fired together to make it. Borane B1 3-{(Ε)-2-(1-indolyl-1H-mito-2-yl)-2-[4-(indolyl)phenyl]ethenyl}phenyl Borane acid 2,3-dimethylbutylene glycol borane B1 was prepared by the following procedure.歹马水1 · (E/Z)-2-(3-&gt; stinky base) small (1-methyl-1H-miso-2-yl)-1-[4-(methylthio)benzene ]](3-bromodecyl)(triphenyl)phosphonium bromide (1〇2g, 19 9mmol) at -60- This paper scale applies to China National Standard (CNS) A4 specification ( 210 X 297 public) -----------Install--------Book--------- (Please read the notes on the back and fill out this page) l28 〇240

(請先閱讀背面之注意事項再填寫本頁) THF(200毫升）與CH3CN(50毫升）中，於25Ό下之溶液内，逐 滴添加t-BU〇K(l.〇M在THF中，19.9毫升，19.9毫莫耳），並將 所形成之紅色溶液於室溫下攪拌2〇分鐘。然後，於此所形 成 &lt; 亞烷基化合物中，在25°C下添加酮K2 (4.4克，18.9亳莫 耳）。將所形成之混合物在60。(：下攪拌2天，並以NH4C1(飽 和）使反應 &gt;平滅。然後，將混合物以Ac稀釋。將有機相 以NaHC〇3 (飽和）、鹽水洗滌，以MgS〇4脱水乾燥，過濾及 濃縮’並直接使用於下一個本步驟2中。 步驟2 ·· (E)-2-(3-溴苯基）-1-(1-甲基-1H-咪嗅-2-基）-1-[4-(甲續醯 基）苯基]乙烯 m 於得自本步驟1之粗製硫化物-意即（E/Z)-2-(3-溴苯基 甲基·1Η·咪唑-2_基）-1-[4-(曱硫基）苯基]乙烯_(18·9毫莫耳）在 THF/MeOH/H2 0 (200/100/励毫升）中之溶液内，添加 〇x〇ne (23 2 克’ 37.8毫莫耳）。將混合物於室溫下攪拌4小時，以 NaHC〇3 (飽和）使反應淬滅，並以Et〇Ac稀釋。將有機相以 NaHC〇3 (飽和）、鹽水洗滌，以N^SO4脱水乾燥，過濾、及濃 縮。急驟式層析（95% EtOAc / 5% Et3N)產生（Ε)-2·(3-溴苯基）_卜 經濟部智慧財產局員工消費合作社印製 (1-甲基-1Η-咪唑-2-基）小[4-(甲磺醯基）苯基]乙晞（單一異構物） ，爲泡沫物。 步驟3 : 3-{(Ε)-2-(1-甲基-1Η-咪唑-2-基）-2-[4-(甲磺醯基）苯基]乙 烯基}苯基硼烷酸2,3-二甲基丁二醇酯 將得自本步驟2之溴化物-意即（Ε)-2-(3-溴苯基）-1-(丨-甲基_1Η-咪峻-2-基）-1-[4-(甲續醯基）苯基]乙晞-(2·〇克；4.8毫莫耳）、 2,3-二甲基丁二醇二硼烷（1·5克；5·8毫莫耳）、K0Ac (1·65克 -61 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 1280240 A7 B7 經濟部智慧財產局員工消費合作社却製 五、發明說明（59 ) ;16·8 *莫耳）及PdCl2(dppf)(0.2克；0·24毫莫耳）在50毫升 DMF中之懸浮液，於9〇Ό下攪拌4小時。使所形成之混合物 冷卻至皇溫，以EtOAc稀釋，以Η2 Ο (3χ)、鹽水洗滌，以 Na2S04脱水乾燥，過濾及濃縮。急驟式層析（95%Et〇Ac% / $ % Et3 N)產生硼烷酸酯Bi，爲泡沫物。 硼烷酸酯B2 3-{(Ε/Ζ)-2-(1，3”塞唑-2-基）-2-[4-(甲磺醯基）苯基]乙晞基}苯基硼烷 酸2,3-二甲基丁二醇酯 硼燒酸酯B2係藉下述程序製備。 步驟1 ·· (E/Z)-2-(3-溴苯基）-1-(1，3-違嗤-2-基）-1-[4-(甲硫基）苯基] 乙烯 於（3-溴基+基）(三苯基）溴化銹（44.5克，86.9毫莫耳）在 THF(500毫升）與DMF(200毫升）中，於π下之溶液内，逐滴 添加LiHMDS (1.0M在THF中，86.9毫升，86.9毫莫耳），並將 所开&gt; 成之紅色溶液於室溫下攪拌2〇分鐘。然後，在所形成 之亞烷基化合物中，於〇°C下添加酮K4 (18.6克，79.0毫莫耳） 。將混合物攪拌直到藉TLC顯示已完成爲止，並以ΝΗ4α ( 飽和）使反應淬滅。然後，將混合物以Et0Ac稀釋。將有機 相以NaHC〇3 (飽和）、鹽水洗滌，以MgS〇4脱水乾燥，過滤及 濃縮。急驟式層析（CH2 %)產生（E/Z)-2-(3-溴苯基)+(1，3…塞唾_ 2-基）小[4-(甲硫基）苯基]乙晞（異構物之丨·5比1混合物）。 步蘇2.取2)-2-(3-溴豕基）-1-(1，3-違哇-2-基]-1-[4-(甲續@蠢基）苯 基]乙締 於得自本步驟1之硫化物-意即（E/Z)-2-(3-溴苯基）+(1，3·嘍唑_ -62- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -----------裝--------訂--------- (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 1280240 A7 ---------_B7___ 五、發明說明（60 ) 2_基）++(甲硫基）苯基]乙晞-(24·8克，63.9毫莫耳）在THF/ Μ_/Η2〇_/300/300毫升）中之溶液内，添加〇_(78 5克， 128耄莫耳）。將所形成之反應混合物在室溫下攪拌過夜。 知所形成之混合物以NaHC03 (飽和）使反應淬滅，並以EtOAc 稀釋。將有機相以NaHC03 (飽和）、鹽水洗滌，以Na2 s〇4脱 水乾燥，過濾及濃縮，產生（E/Z)-2_(3_溴苯基Η·(1，3巧塞唑么基 )-1- [4 -(甲磺醯基）苯基]乙晞（異構物之3比2混合物）。 步.驟3 ·· 3-{(Ε/Ζ)·2-(1，34唑-2-基）-2-[4-(甲磺醯基）苯基]乙烯基} 苯基硼烷酸2,3-二甲基丁二醇酯 將得自本步驟2之溴化物（Ε/Ζ)-2-(3-溴苯基）小(1，3_嘍唑_2-基）-1-[4-(甲磺醯基）苯基]乙晞（15 〇克，35·7毫莫耳）、2,3_二甲基 丁二醇二硼烷（1〇·9克，42.8毫莫耳）、KOAc (12.3克，125毫莫 耳）及PdCl2(dppf)(1.46克，1.78毫莫耳）在350毫升DMF中之懸 浮液’於90°C下揽拌4小時。將所形成之混合物冷卻至室溫 ’以EtOAc稀釋，以Η2 Ο (3x)、鹽水洗滌，以Na2 S04脱水乾 燥’過濾及濃縮。急驟式層析（甲苯/丙酮9/1)產生硼烷酸 酯B2 (異構物之3比1混合物），爲泡沫物。 硼烷酸酯B3 3-{(E)-2-(5-甲基-2-吡啶基）-2-[4-(甲磺醯基）苯基]乙烯基}苯基硼 烷酸2,3-二曱基.丁二醇酯 硼烷酸酯B3係藉下述程序製備。 步驟1 : (E)-2-(3-溴苯基）-1-(5-甲基-2-吡啶基）_1-[4-(甲磺醯基） 苯基]乙烯 按照關於步驟1硼烷酸酯B1所述之程序，但以酮K8取代 -63- 本纸張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） &quot; -----------^.—I—^--------- (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社邱製 l28〇24〇 A7 ^—______B7_ __ 五、發明說明（61 ) 酮K2，作爲起始物質，在藉急驟式層析分離異構物後，獲 得（Ε)-2·(3-溴苯基）-1-(5-甲基-2·吡啶基）-1-[4-(甲磺醯基）苯基]乙 缔。 步驟2 : 3-{(E)-2-(5-甲基-2·吡啶基）-2-[4·(曱磺醯基）苯基]乙烯 基}苯基硼烷酸2,3-二甲基丁二醇酯 按照關於硼烷酸酯B1步驟3所述之程序，但以得自本步 驟1之溴化物（E)-2-(3-溴苯基）-1-(5-甲基-2-p比淀基）小[4-(甲確醯 基）苯基]乙烯，取代（E)-2-(3-溴苯基）-1-(1-甲基]H_咪唑-2-基）小 [4-(甲磺醯基）苯基]乙烯，作爲起始物質，獲得石朋燒酸酉旨B3 〇 硼烷酸酯B4 3-{(Ε)-2-(5_(1·羥基-1-甲基乙基）-2-吡啶基）-2-[4-(甲磺醯基）苯基] 乙晞基}苯基硼烷酸2,3-二甲基丁二醇酯 硼烷酸酯B4係藉下述程序製備。 步驟1 : (E)-2-(3-溴苯基）小[5-(1-羥基-1-甲基乙基）-2-吡啶基]-1-[4-(甲績醯基）苯基]乙晞 按照爛燒酸酯B1步驟1所述之程序，但以酮K11取代酮K2 ’作爲起始物質，在藉急驟式層析分離異構物後，獲得（E)_ 2-(3-溴苯基）小[5-(1-羥基小甲基乙基）-2-吡啶基]-1-[4-(甲磺醯基) 苯基]乙烯。 步驟2 : 3-{(Ε)-2-(5-(1-羥基小甲基乙基）-2-吡啶基）-2-[4&lt;甲磺 醯基）苯基]乙晞基}苯基硼烷酸2,3-二甲基丁二醇酯 按照硼烷酸酯B1步驟3所述之程序，但以得自本步驟1之 溴化物（E)-2-(3-溴苯基）-1-[5-(1-經基-1-甲基乙基）-2_响啶基]小[4-( 甲磺醯基）苯基]乙烯，取代（E)-2-(3-溴苯基）小(1-甲基-1H·咪唑- -64- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） — ϋ n I— —ϋ ϋ I ϋ ϋ ϋ ϋ n I n hso, · ϋ ϋ ·ϋ ϋ ϋ I ϋ I (請先閱讀背面之注意事項再填寫本頁) 1280240 A7 B7 五、發明說明（62 ) 2-基）-1-[4-(甲磺醯基）苯基]乙烯， 酸酯B4。 作爲起始物質，獲得 石朋燒 用以製備本發明化合物之芳其 ,.. 兔凑化物，可根據下文所 之圖式3與4製成：圖式3 吟二嗓合成(Please read the notes on the back and fill out this page.) In THF (200 ml) and CH3CN (50 ml), add t-BU〇K (l.〇M in THF) in a solution at 25 Torr. 19.9 ml, 19.9 mmoles, and the resulting red solution was stirred at room temperature for 2 min. Then, in the &lt;alkylene compound formed herein, ketone K2 (4.4 g, 18.9 mmol) was added at 25 °C. The resulting mixture was at 60. (The mixture was stirred for 2 days, and the reaction was quenched with NH4C1 (sat). Then, the mixture was diluted with Ac. The organic phase was washed with NaHC 〇 3 (saturated), brine, dried over MgSO 4 and filtered. And concentrated' and used directly in the next step 2. Step 2 · · (E)-2-(3-bromophenyl)-1-(1-methyl-1H-amisole-2-yl)- 1-[4-(methylsulfonyl)phenyl]ethene m is obtained from the crude sulfide obtained in this step 1 - that is, (E/Z)-2-(3-bromophenylmethyl·1Η·imidazole- 2_yl)-1-[4-(indolyl)phenyl]ethene_(18·9 mmol) in THF/MeOH/H 2 0 (200/100/ml), 〇 X〇ne (23 2 g '37.8 mmol). The mixture was stirred at room temperature for 4 hours, quenched with NaHC EtOAc ( sat.) and diluted with Et EtOAc. (saturated), washed with brine, dried over N~SO4, filtered, and concentrated. Flash chromatography (95% EtOAc / 5% Et3N) yields (Ε)-2·(3-bromophenyl) Printed by the Intellectual Property Office Staff Consumer Cooperative (1-methyl-1Η-imidazol-2-yl) small [4-(methylsulfonyl)phenyl]acetamidine (single difference) Structure), as a foam. Step 3: 3-{(Ε)-2-(1-methyl-1Η-imidazol-2-yl)-2-[4-(methylsulfonyl)phenyl]ethene 2,3-dimethylbutylene glycol phenylboronic acid will be obtained from bromide of this step 2 - meaning (Ε)-2-(3-bromophenyl)-1-(丨-甲Η Η 咪 咪 咪 咪 -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- -1- Alcohol diborane (1.5 g; 5·8 mmol), K0Ac (1·65 g-61 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1280240 A7 B7 Economy The Ministry of Intellectual Property's staff consumption cooperatives produced five, invention instructions (59); 16·8 * Mo Er) and PdCl2 (dppf) (0.2 g; 0 · 24 mmol) in 50 ml of DMF suspension, The mixture was stirred for 4 hours. The resulting mixture was cooled to EtOAc (EtOAc) EtOAc (EtOAc)EtOAc. Ac% / $ % Et3 N) produces boranoate Bi as a foam. Borane B2 3-{(Ε/Ζ)-2-(1,3"pyrazol-2-yl)-2- [4-(methylsulfonyl)phenyl]acetamidine } Phenyl 2,3-dimethyl-borane acid butylene glycol ester B2 burn boron alloys prepared by the following procedure. Step 1 ···(E/Z)-2-(3-bromophenyl)-1-(1,3-indol-2-yl)-1-[4-(methylthio)phenyl]ethene (3-Bromo+yl)(triphenyl)bromide rust (44.5 g, 86.9 mmol) in THF (500 mL) and DMF (200 mL) in π (1.0 M in THF, 86.9 mL, 86.9 mmol), and the red solution was stirred at room temperature for 2 min. Then, in the alkylene compound formed, ketone K4 (18.6 g, 79.0 mmol) was added at 〇 °C. The mixture was stirred until the completion by TLC and the reaction was quenched with EtOAc 4 sat. Then, the mixture was diluted with Et0Ac. The organic phase was washed with NaHC 〇3 (sat.), brine, dried over Flor. Rapid chromatography (CH 2 %) yields (E/Z)-2-(3-bromophenyl)+(1,3...sept-2-yl)small [4-(methylthio)phenyl]B晞 (the mixture of isomers · 5 to 1 mixture). Step 2: Take 2)-2-(3-bromoindolyl)-1-(1,3-violan-2-yl)-1-[4-(methyl continued@stupyl)phenyl] The sulfide obtained from this step 1 means (E/Z)-2-(3-bromophenyl)+(1,3·carbazole _-62- This paper scale applies to China National Standard (CNS) A4 Specifications (210 X 297 mm) -----------Install--------Order--------- (Please read the notes on the back and fill out this page. ) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1280240 A7 ---------_B7___ V. Invention Description (60 ) 2_Base)++(Methylthio)phenyl]Ethyl-(24· 8 g, 63.9 mmol (in THF / Μ _ / Η 2 〇 / / 300 / 300 ml) in the solution, added 〇 (78 5 g, 128 耄 Mo). The resulting reaction mixture was stirred at room temperature overnight. The resulting mixture was quenched with NaHC.sub.3 (sat.) and diluted with EtOAc. The organic phase was washed with NaHC03 (sat.), brine, dried over Na 2 s s 4, filtered and concentrated to give (E/Z)-2 (3 bromophenyl hydrazide (1,3). -1- [4-(Methanesulfonyl)phenyl]acetamidine (a mixture of 3 to 2 isomers). Step 3. 3 - 3 (Ε /Ζ)·2-(1,34 azole 2-yl)-2-[4-(methylsulfonyl)phenyl]vinyl}phenylboronic acid 2,3-dimethylbutylene glycol will be obtained from bromide of this step 2 /Ζ)-2-(3-bromophenyl) small (1,3-oxazol-2-yl)-1-[4-(methylsulfonyl)phenyl]acetamidine (15 g, 35· 7 mM), 2,3-dimethylbutanediol diborane (1 〇·9 g, 42.8 mmol), KOAc (12.3 g, 125 mmol) and PdCl2 (dppf) (1.46 g) , 1.78 mmol) suspension in 350 ml of DMF 'mixed at 90 ° C for 4 hours. The resulting mixture was cooled to room temperature' diluted with EtOAc, washed with Η 2 Ο (3×), brine. Na2 S04 dehydration drying 'filtration and concentration. Flash chromatography (toluene/acetone 9/1) yields borane B2 (3 to 1 mixture of isomers) as a foam. Borate B3 3-{ (E)-2-(5-methyl-2-pyridyl)-2-[ 4-(Methanesulfonyl)phenyl]vinyl}phenylboronic acid 2,3-dimercaptobutylate boranoate B3 was prepared by the following procedure: Step 1: (E)- 2-(3-Bromophenyl)-1-(5-methyl-2-pyridyl)_1-[4-(methylsulfonyl)phenyl]ethylene as described in relation to Step 1 Borane B1 Procedure, but replaced by ketone K8 -63- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) &quot; -----------^.—I—^- -------- (Please read the note on the back and then fill out this page) Ministry of Economic Affairs Intellectual Property Bureau employees consumption cooperatives Qiu system l28〇24〇A7 ^-______B7_ __ V. Description of invention (61) Ketone K2, As a starting material, after separation of the isomer by flash chromatography, (Ε)-2·(3-bromophenyl)-1-(5-methyl-2.pyridyl)-1-[4 -(Methanesulfonyl)phenyl]ethyl bromide Step 2: 3-{(E)-2-(5-methyl-2.pyridyl)-2-[4·(sulfonyl)phenyl ] vinyl}phenylboronic acid 2,3-dimethylbutylene glycol according to the procedure described for step 3 of boranoate B1, but with bromide (E)-2- derived from this step 1. (3-bromophenyl)-1-(5-methyl-2-p ratio) [4-(methyl-decyl)phenyl]ethene, substituted (E)-2-(3-bromophenyl)-1-(1-methyl]H-imidazol-2-yl) small [4-( Methanesulfonyl)phenyl]ethylene, as a starting material, is obtained as a starting material, B3 borane boranoate B4 3-{(Ε)-2-(5_(1·hydroxy-1-methyl-ethyl) 2,3-pyridyl)-2-[4-(methylsulfonyl)phenyl]ethanoyl}phenylboronic acid 2,3-dimethylbutylene glycol borane B4 Prepared by the following procedure. Step 1: (E)-2-(3-Bromophenyl)sodium [5-(1-hydroxy-1-methylethyl)-2-pyridyl]-1-[4-(methylphenyl) Phenyl]acetone is obtained according to the procedure described in Step 1 of the rotten acid ester B1, but the ketone K11 is substituted for the ketone K2' as a starting material, and after separation of the isomer by flash chromatography, (E)_ 2- (3-Bromophenyl) small [5-(1-hydroxysodiummethylethyl)-2-pyridyl]-1-[4-(methylsulfonyl)phenyl]ethene. Step 2: 3-{(Ε)-2-(5-(1-hydroxysodiummethylethyl)-2-pyridyl)-2-[4&lt;methylsulfonyl)phenyl]ethenyl}benzene 2,3-Dimethylbutylene glycol boranoate according to the procedure described in Step 3 of boranoate B1, but with the bromide (E)-2-(3-bromophenyl) obtained from this step 1. )-1-[5-(1-Pylan-1-methylethyl)-2-oxinyl]sodium [4-(methylsulfonyl)phenyl]ethene, substituted (E)-2-( 3-Bromophenyl) small (1-methyl-1H.imidazole--64- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) — ϋ n I—ϋ ϋ I ϋ ϋ ϋ ϋ n I n hso, · ϋ ϋ ·ϋ ϋ ϋ I ϋ I (Please read the note on the back and fill out this page) 1280240 A7 B7 V. Description of invention (62) 2-base)-1-[4- (Methanesulfonyl) phenyl]ethylene, ester B4. As a starting material, Sipentane is obtained to prepare a compound of the present invention, and a rabbit compound can be produced according to the following schemes 3 and 4: Figure 3

7F7F

p-MeOPhOH + CI^CN ^ P'Me〇ph〇^cN Xlliap-MeOPhOH + CI^CN ^ P'Me〇ph〇^cN Xllia

RCN XIIIRCN XIII

Ql«_j MeOgS XV NH,Ql«_j MeOgS XV NH,

Me02SMe02S

XVIXVI

XIVXIV

R 巧二唑（XVI)R diazole (XVI)

Me 0X1 p-MeOPhOCH2 〇X2 ------------裝--------訂--------- (請先閱讀背面之注音？事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 參考上文圖式3，腈中間物XIIIa可於鹼譬如碳酸鉀存在 下，在譬如丙酮之溶劑中，經由以氣乙腈，使4•甲氧基酚 烷基化而製成。醯胺-肟XIV可在溶劑譬如甲醇中，於鹼譬 如醋酸鈉存在下，經由以羥胺處理腈χιΙΙ而製成。噚二唑 XVI之形成，可在譬如DMF之溶劑中，經由以羰基二咪唑 ’使芳基醋酸XV活化，接著添加醯胺-肟ΧΙν，及接著將反 應混合物加熱而達成。 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 1280240 經濟部智慧財產局員工消費合作社印製 A7 _ B7 五、發明說明（63 ) 圖式4 芳基溴化物合成Me 0X1 p-MeOPhOCH2 〇X2 ------------装--------Book--------- (Please read the phonetic on the back? Page) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing reference to Figure 3 above, the nitrile intermediate XIIIa can be made in the presence of a base such as potassium carbonate in a solvent such as acetone, via a gas acetonitrile, 4 methoxy Made by phenol alkylation. The guanamine-oxime XIV can be prepared by treating the nitrile oxime with hydroxylamine in a solvent such as methanol in the presence of a base such as sodium acetate. The formation of the oxadiazole XVI can be achieved by activating the aryl acetic acid XV with carbonyldiimidazole in a solvent such as DMF, followed by the addition of guanamine-oxime, and then heating the reaction mixture. This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1280240 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing A7 _ B7 V. Invention description (63) Figure 4 aryl bromide synthesis

參考上文圖式4，於鹼存在下，譬如六氫吡啶，在譬如甲 苯之溶劑中，醛XVII經由與芳基醋酸XV —起加熱而縮合， 產生不飽和酸XVIIIa。經由以二氣化亞硫醯及鹼譬如三乙 胺，在譬如甲苯之溶劑中處理，當場形成XVIIIa之氯化醯 後，接著添加胺至反應混合物中，產生醯胺XVIIIb。4二 唑-乙烯XVIIIc可經由將0X1與XVII，於鹼譬如六氫吡啶存 在下，在譬如甲苯之溶劑中，一起加熱而形成。 -66- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -----------^裝--------訂--------- (請先閱讀背面之注意事項再填寫本頁) 1280240Referring to Figure 4 above, in the presence of a base such as a hexahydropyridine, in a solvent such as toluene, the aldehyde XVII is condensed by heating with an aryl acetic acid XV to produce an unsaturated acid XVIIIa. The indoleamine XVIIIb is produced by treatment with disulfide sulfite and a base such as triethylamine in a solvent such as toluene to form XVIIIa ruthenium chloride on the spot, followed by addition of an amine to the reaction mixture. The 4diazole-ethylene XVIIIc can be formed by heating OX0 and XVII in the presence of a base such as hexahydropyridine in a solvent such as toluene. -66- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) -----------^装--------Book ------ --- (Please read the notes on the back and fill out this page) 1280240

A7 B7 五、發明說明（64 ) 圖式4附錄 芳基漠化物合成A7 B7 V. INSTRUCTIONS (64) Appendix 4 aryl desertification synthesis

XVlIlf (AB6) 參考上文圖式4附綠，在譬如THF之溶劑中，以重氮甲烷 處理酸XVIIIa，產生甲酯XVIIId。在譬如THF之溶劑中，使 用DIBAL-H，使酯XVIIId還原，獲得烯丙基醇XVIIIe。使用 試劑，譬如氣化甲烷磺醯與三乙胺，在譬如THF之溶劑中 ，使XVIIIe中之醇基轉化成脱離基，譬如甲燒續酸根，接 著在譬如DMF之溶劑中，以親核試劑，譬如二甲胺置換， 產生化合物XVIIIf。 芳基溴化物AB1 (E)-3-(3-溴苯基）-2-[4-(甲磺醯基）苯基]-2-丙烯酸 芳基溴化物AB1係藉下述程序製備。於3-溴基苯甲醛（12.9 克，70毫莫耳）在甲.苯（100毫升）中之溶液内，添加4-(甲磺 醯基）苯基醋酸（15克，70毫莫耳）與六氫吡啶（2毫升）。於過 -67- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ϋ ϋ ϋ ϋ ϋ ϋ -ϋ I I · ϋ ϋ ϋ ·ϋ ϋ I I 一OJI ·ϋ ·ϋ I &gt;1 ϋ ϋ n I (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 經濟部智慧財產局員工消費合作社印製 1280240 A7 ---------BT__ 五、發明說明（65 ) 夜回流後，使混合物冷卻至室溫。在如此形成之漿液中， 添加甲苯（10毫升）。過濾獲得（E)-3-(3-溴苯基）-2-[4-(甲磺醯基) 苯基]-2-丙晞酸，爲白色固體。 芳基溴化物AB2 (E)-N-異丙基-3-(3-溴苯基)-2-[4-(甲磺醯基）苯基]-2-丙烯醯胺 芳基溴化物AB2係藉下述程序製備。於AB1 (24.9克，65毫 莫耳）在曱苯（250毫升）中之溶液内，添加二氣化亞硫醯（14 3 毫升，196毫莫耳）與三乙胺（34毫升，245毫莫耳）。於室溫 下攪拌0.5小時後，添加異丙胺（28毫升，327毫莫耳）。於室 溫下再2小時後，使混合物冷卻至〇。〇，並以飽和Nh4 Ci溶 液中和，然後以EtOAc萃取。將有機萃液洗滌（h2 〇，鹽水) ，脱水乾燥（MgSOJ，過濾及濃縮。藉急驟式層析純化（己 烷：EtOAc 1 : 1至純EtOAc)，產生（E)-N-異丙基-3-(3-溴苯基）-2- [4-(甲續醯基）苯基]-2-丙締醯胺。 芳基溴化物AB3 (E)-3-(3-&gt;臭苯基）-2-[4·(甲橫醯基）苯基]-2-丙稀醯胺 芳基溴化物AB3係按照關於芳基溴化物AB2所述之程序製 成，但以氫氧化銨取代異丙胺，作爲起始物質。 芳基溴化物AB4 (E)-N-(第三-丁基）-3-(3-溴苯基)-2_[4-(甲磺醯基）苯基]_2_丙晞醯胺 芳基溴化物AB4係按照關於芳基溴化物AB2所述之程序製 成，但以第三-丁基胺取代異丙胺，作爲起始物質。 芳基溴化物AB5 (Ε)-1_(3·溴苯基）-2-(3-甲基-1，2,4』号二唑-5-基）-2-[4-(甲磺醯基）苯 -68- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） --------------------訂--------- (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 1280240 A7 __B7 _ 五、發明說明（66) 基]乙缔 芳基溴化物AB5係藉下述程序製備。 步驟1 (圖式3 ’呤二唑Οχι) : 曱基-：1，2,4^号二唑士基 甲磺醯基）苯基]甲烷 於4-(甲磺醯基）苯基醋酸（15克，70毫莫耳）在DMF (300毫升) 中之溶液内，於室溫下添加羰基二咪吐（12.5克，77毫莫耳） 。於室溫下0.5小時後，添加乙醯胺肟（5·7克，77毫莫耳）。 在將所形成之混合物於室溫下攪拌過夜後，將混合物加熱 至120 C ’歷經6小時。於冷卻至室溫後，以％ 〇使混合物 淬滅，並以EtOAc萃取。將有機萃液洗滌（η2〇，鹽水），脱 水乾(MgS04) ’過濾及濃縮。藉急驟式層析純化（己垸： EtOAc 1 : 1)，產生(3-甲基_1，2,4』号二唑-5-基）[4-(甲磺醯基）苯基] 甲烷。 步驟2 (圖式4) : (E)-l-(3-溴苯基）-2-(3-甲基-1，2,4』号二嗅-5-基）· 2-[4-(甲續g蠢基）苯基]乙晞 於3-溴基苯甲醛（2.2克，11.9毫莫耳）在甲苯（30毫升）中之 溶液内，添加得自步驟1之產物（OX1)(3 〇克，U 9毫莫耳）與 六氫吡啶（0.4毫升）。過夜回流後，使混合物冷卻至室溫。 在所形成之漿液中，添加MeOH (30毫升）。於進一步回流， 然後冷卻至0°C後，過濾獲得（EH-(3-溴苯基）-2-(3-甲基-1，2,44 二吐-5-基）-2-[4-(甲磺醯基）苯基]乙烯，爲白色固體。 用以製備本發明化合物之漠基峻p林，可根據下文所示之 圖式5製成： -69 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -----------裝--------訂--------- (請先閱讀背面之注意事項再填寫本頁) 1280240 A7 B7 五、發明說明（67 圖式5 溴基4琳之製備XVlIlf (AB6) Referring to Figure 4 above, green acid is used to treat acid XVIIIa with diazomethane in a solvent such as THF to yield methyl ester XVIIId. The ester XVIIId is reduced using DIBAL-H in a solvent such as THF to obtain allyl alcohol XVIIIe. Using reagents such as gasified methanesulfonate and triethylamine, the alcohol group in XVIIIe is converted to a devolatilization group, such as a decanoate, followed by a nucleophile in a solvent such as DMF, in a solvent such as THF. Reagents, such as dimethylamine, are substituted to yield compound XVIIIf. Aryl bromide AB1 (E)-3-(3-bromophenyl)-2-[4-(methylsulfonyl)phenyl]-2-acrylic acid The aryl bromide AB1 was prepared by the following procedure. Add 4-(methylsulfonyl)phenylacetic acid (15 g, 70 mmol) to a solution of 3-bromobenzaldehyde (12.9 g, 70 mmol) in benzene (100 mL) With hexahydropyridine (2 ml).于-67- This paper scale applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) ϋ ϋ ϋ ϋ ϋ ϋ -ϋ II · ϋ ϋ ϋ ·ϋ ϋ II 一 OJI ·ϋ ·ϋ I &gt; 1 ϋ ϋ n I (Please read the notes on the back and fill out this page) Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperatives Ministry of Printing and Economy Ministry Intellectual Property Bureau Staff Consumer Cooperatives Printed 1280240 A7 ---------BT__ V. INSTRUCTIONS (65) After refluxing at night, the mixture was allowed to cool to room temperature. To the slurry thus formed, toluene (10 ml) was added. (E)-3-(3-Bromophenyl)-2-[4-(methylsulfonyl)phenyl]-2-propanoic acid was obtained as a white solid. Aryl bromide AB2 (E)-N-isopropyl-3-(3-bromophenyl)-2-[4-(methylsulfonyl)phenyl]-2-propenylamine aryl bromide AB2 Prepared by the following procedure. In a solution of AB1 (24.9 g, 65 mmol) in toluene (250 ml), add dimethyl sulfoxide (14 3 ml, 196 mmol) and triethylamine (34 ml, 245 mil). Moore). After stirring at room temperature for 0.5 hours, isopropylamine (28 mL, 327 mmol) was added. After a further 2 hours at room temperature, the mixture was allowed to cool to hydrazine. The mixture was neutralized with a saturated aqueous solution of EtOAc and then extracted with EtOAc. The organic extract was washed with EtOAc (EtOAc) (EtOAc) 3-(3-bromophenyl)-2-[4-(methylsulfonyl)phenyl]-2-propanolamine. Aryl bromide AB3 (E)-3-(3-&gt; odor benzene Benzyl-2-(4-(indenyl)phenyl]-2-propanylamine aryl bromide AB3 is prepared according to the procedure described for aryl bromide AB2, but substituted with ammonium hydroxide Isopropylamine as a starting material. Aryl bromide AB4 (E)-N-(T-butyl)-3-(3-bromophenyl)-2_[4-(methylsulfonyl)phenyl] _2_Protonamine aryl bromide AB4 was prepared according to the procedure described for aryl bromide AB2, but isopropylamine was substituted with tri-butylamine as the starting material. Aryl bromide AB5 (Ε )-1_(3·Bromophenyl)-2-(3-methyl-1,2,4′′diazol-5-yl)-2-[4-(methylsulfonyl)benzene-68- The paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -------------------- Order --------- (please Read the notes on the back and fill out this page. Employee Consumption Cooperative Printed 1280240 A7 __B7 _ V. Inventive Note (66) Base] B-Aryl bromide AB5 was prepared by the following procedure: Step 1 (Scheme 3 'oxadiazole Οχι) : 曱--1 , 2,4^ diazol methanesulfonyl)phenyl]methane in a solution of 4-(methylsulfonyl)phenylacetic acid (15 g, 70 mmol) in DMF (300 mL) Add carbonyl dimetrazole (12.5 g, 77 mmol) at room temperature. After 0.5 hours at room temperature, acetaminophen (5. 7 g, 77 mmol) was added. After the resulting mixture was stirred at room temperature overnight, the mixture was heated to 120 C' for 6 hours. After cooling to room temperature, the mixture was quenched with EtOAc and EtOAc. The organic extract was washed (η 2 Torr, brine), dried (MgSO4) and filtered. Purification by flash chromatography (hexane: EtOAc 1 : 1) to give (3-methyl-1,2,4,diazol-5-yl)[4-(methylsulfonyl)phenyl]methane . Step 2 (Scheme 4): (E)-l-(3-Bromophenyl)-2-(3-methyl-1,2,4′′ 2 s--5-yl)· 2-[4- ( Continuation of styrene) phenyl] acetamidine in a solution of 3-bromobenzaldehyde (2.2 g, 11.9 mmol) in toluene (30 mL). 3 g, U 9 mM) with hexahydropyridine (0.4 ml). After refluxing overnight, the mixture was allowed to cool to room temperature. To the resulting slurry was added MeOH (30 mL). After further refluxing, and then cooling to 0 ° C, filtration was carried out to obtain (EH-(3-bromophenyl)-2-(3-methyl-1,2,44 dioxa-5-yl)-2-[4 -(Methanesulfonyl)phenyl]ethene as a white solid. The formula for the preparation of the compound of the present invention can be made according to the following Scheme 5: -69 - The paper scale is applicable to the Chinese country. Standard (CNS) A4 specification (210 X 297 mm) -----------Package--------Book--------- (Please read the back of the note first) Please fill out this page again) 1280240 A7 B7 V. INSTRUCTIONS (67 Figure 5 Preparation of bromo 4 Lin

Br XIX XXaBr XIX XXa

Br XXbBr XXb

XXc 經濟部智慧財產局員工消費合作社邱製 參考上文圖式5及下文圖式5表，在溶劑中，孽如讀或 ’與水之混合物’以親核試劑，譬如甲貌亞績酸納或氰 化钾，處理溴曱基化合物XIX，可用以產生化合物现。化 合物xxb可經由在譬如THF之溶劑中，以鹼譬如第三-丁醇 钟（1.1當量）處理XXa，接著將所形成之混合物°，+—加_至碰 化甲垸在譬如THF溶劑中之溶液内而製成。化合物⑽可在 譬如THF之溶劑中’經由以驗譬如第三_丁醇卸（1]當量）處 理XXb ’接著將所形成之混合物添加至碘化甲烷在譬如· t落劑中之溶液内而製成。化合物XXc (其中尺丨=CN)亦可經 由以鹼譬如第三-丁醇鉀（2.2當量）及碘化甲烷，在駐如tef 之溶劑中，處理XXa而製成。化合物XXc(其中Rl = s〇2Me) 亦可以驗譬如第三-丁醇辞（1 3當量）及換化甲燒Μ當量）， -70- 私紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱 -----------^--------^--------- (請先閱讀背面之注意事項再填寫本頁) [280240XXc Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Qiu refers to the above table 5 and the following table 5, in the solvent, such as reading or 'mixture with water' with nucleophile, such as the appearance of Or potassium cyanide, the bromo-based compound XIX can be treated to produce a compound. Compound xxb can be treated with XXa via a base such as a third-butanol clock (1.1 eq.) in a solvent such as THF, followed by a mixture of the resulting mixture, +-added to a hydrazine-like solvent. Made in solution. Compound (10) can be treated by treating XXb' in a solvent such as THF via a test such as third-butanol (1) equivalent, and then adding the resulting mixture to a solution of methane iodide in a reagent such as LD. production. Compound XXc (wherein 丨 = CN) can also be produced by treating XXa in a solvent such as tef with a base such as potassium butoxide (2.2 equivalents) and methane iodide. Compound XXc (where Rl = s〇2Me) can also be tested for example, such as third-butanol (13 equivalents) and changeable formazan equivalents, -70- private paper scale applies to Chinese National Standard (CNS) A4 specifications ( 210 X 297 公爱-----------^--------^--------- (Please read the notes on the back and fill out this page) [280240

五、發明說明（68 在譬如THF〈溶劑中，處理xxa，接著爲另 燒0.6當量）及另—數量之相同驗(1〇當量〜數量之峨化甲灰成。 圖式5表 溴基4 p林R2.R3 I R1 , XX R1 R2 R3 漠基4：淋〇〇Q S〇2Me H H Q1 S02Me Me H Q2 S〇2Me Me Me Q3 CN H H Q4 CN Me Me Q5 (請先閱讀背面之注意事項再填寫本頁) 裝--------訂---- 經濟部智慧財產局員工消費合作社印製 溴基4：淋Q1 6-(甲磺醯基）甲基各溴基喳啉 溴基4琳Q1係藉下述程序製備。將DMF (500毫升）添加至 6-溴基甲基-8-溴基喹啉（60克，200.毫莫耳）（描述於國際專利 公告WO 94/22852中）與甲烷亞磺酸鈉（27.6克，270毫莫耳）中 。於室溫下攪拌過夜後，以H2 〇 (2〇〇〇毫升）使混合物淬減， 攪拌一小時，藉過濾分離並以Et2 〇洗滌，產生6-(甲磺醯基） 甲基-8-溴基喹啉。 -71 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 1280240 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（69 ) 溴基p奎淋Q2 6-[1-(甲磺醯基）乙基]_8_溴基喳啉 漠基峻琳Q2係藉下述程序製備。於溴基峻淋qj (161克， 54亳莫耳）在THF(500毫升）中，在_78。(：下之溶液内，添加第 三-丁醇鉀（59毫升，1N在THF中）。於-78°C下0.5小時後，將 所形成之混合物在〇°C下攪拌45分鐘，然後藉由套管，逐滴 轉移至Mel (16.7毫升，268.3毫莫耳）在THF (160毫升）中之溶 液内。於室溫下攪;拌過夜後，以飽和nh4 C1溶液，使混合 物中和’並以EtOAc萃取。將有機萃液洗務（h2 〇)(鹽水），脱 水乾燥(MgS〇4) ’過濾及濃縮。在酸中攪；拌，接著藉過攄單 離，獲得6-[1-(甲磺醯基）乙基]溴基喳啉。 溴基喳啉Q3 6-[1-甲基-1-(甲磺醯基）乙基]-8-澳基喳啉 &gt;臭基峻淋Q3係藉下述程序製備。於溴基峻淋Q2 (15.7克， 50毫莫耳）在THF(5〇〇毫升）中，於_78〇c下之溶液内，添加第 三-丁醇鉀（55毫升，1N在THF中）。於-78°C下攪拌〇.5小時後 ’將所形成之混合物在〇°C下攪拌45分鐘，然後逐滴轉移至 Mel (15·6毫升，250毫莫耳）在THF (40毫升）中，於οχ：下之溶 液内。於室溫下搅拌過夜後，將混合物以飽和Nh# ci溶液 中和，並以EtOAc萃取。將有機苹液洗滌（Η2〇，鹽水），脱 水乾燥(MgS〇4)，過濾及濃縮。在醚中攪拌，接著藉過爐單 離，獲得6-[1-甲基-1-(甲磺醯基）乙基]·8·溴基喹啉。 溴基喹啉Q4 6-氰基甲基-8-溴基ρ套琳 -72- 本紙張尺度過用中國國家標準（CNS)A4規格（210 X 297公釐） ----------裝--------訂--------- (請先閱讀背面之注意事項再填寫本頁) 1280240 A7 五、發明說明（70 ) (請先閲讀背面之注意事項再填寫本頁) 溴基喳啉Q4係藉下述程序製備。將DMF (1〇毫升）與H2〇 (5 毫升）添加至6-溴基曱基各溴基喳啉（3克，1〇毫莫耳）（描述 於國際專利公告W094/22852中）與氰化鉀（L6克，乃毫莫邛） 中。於ioo°C下加熱1小時後，以H2〇(1〇〇毫升）使所形成之混 合物淬滅，並以EtOAc萃取。將有機萃液洗滌（Η2〇，鹽水) ，脱水乾燥（MgS〇4)，過濾及濃縮。藉急驟式層析純化（己 燒：EtOAc3: 1)，產生6-氰基曱基冬溴基喹啉。 溴基4：琳Q5 6-[1-甲基-1-氰基乙基]各漠基喳啉 溴基喳啉Q5係藉下述程序製備。於溴基喳啉Q4 (3克， 12.1耄莫耳）在THF (100毫升）中，於-78°c下之溶液内，添加 Mel (1·7耄升，27耄莫耳），接著爲第三_ 丁醇鉀（27亳升，27 耄莫耳）。於_78°C下2小時後，使混合物溫熱至，並以 飽和NH4 C1落液中和，然後以Et〇Ac萃取。將有機萃液洗滌 (ho，鹽水），脱水乾燥（MgS〇4)，過濾及濃縮。藉急驟式 層析純化（己烷：EtOAc 3 ·· 1)，產生6+-甲基小氰基乙基]| 溴基峻琳。 經濟部智慧財產局員工消費合作社印製 用以製備本發明化合物之芊基磷試劑，可根據下文所示 之圖式6製成： 圖式6. 芊基磷試劑之製備 -73- 本紙張尺度適用中國國家標準（CNS)A4規格（210 x 297公爱） ,—- 1280240 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明（715. Description of the invention (68 in the case of THF <solvent, xxa, followed by another 0.6 equivalent) and the same amount of the same test (1 〇 equivalent ~ amount of sputum ash formation. Figure 5 shows bromo group 4 p forest R2.R3 I R1 , XX R1 R2 R3 desert base 4: dripping QS〇2Me HH Q1 S02Me Me H Q2 S〇2Me Me Me Q3 CN HH Q4 CN Me Me Q5 (Please read the notes on the back first Fill in this page) Pack--------Book---- Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed bromo group 4: leaching Q1 6-(methylsulfonyl) methyl bromide porphyrin bromide Base 4 Lin Q1 was prepared by the following procedure: DMF (500 mL) was added to 6-bromomethyl-8-bromoquinoline (60 g, 200 mmol) (described in International Patent Publication WO 94 /22852) with sodium methanesulfinate (27.6 g, 270 mmol). After stirring at room temperature overnight, the mixture was quenched with H.sub.2 (2 mL) and stirred for one hour. Separate and wash with Et2 , to produce 6-(methylsulfonyl)methyl-8-bromoquinoline. -71 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1280240 Economy Wisdom Hui Property Bureau employee consumption cooperative printed A7 B7 V. Description of invention (69) Bromo-based p-quinone Q2 6-[1-(methylsulfonyl)ethyl]_8_bromopyrroline Moji Junlin Q2 Prepared by the following procedure: Add tributyl-butanol potassium (59 ml, in THF (500 ml) in THF (500 mL) in EtOAc. 1N in THF). After 0.5 hrs at -78 °C, the resulting mixture was stirred at 〇 ° C for 45 min and then transferred to Mel (16.7 ml, 268.3 mmol) by means of a cannula. In a solution of THF (160 ml), stir at room temperature; after stirring overnight, the mixture was neutralized with a saturated solution of nh 4 C1, and extracted with EtOAc. The organic extract was washed (h2 〇) (saline) , dehydrated and dried (MgS〇4) 'filtered and concentrated. Stir in acid; mix, then by hydrazine, to obtain 6-[1-(methylsulfonyl)ethyl]bromoporphyrin. The porphyrin Q3 6-[1-methyl-1-(methylsulfonyl)ethyl]-8-auyl porphyrin &gt; odor base is prepared by the following procedure. Gram, 50 millimoles) in THF (5 ml), at _78〇c To the solution, a third potassium butoxide (55 ml, 1 N in THF) was added. After stirring at -78 ° C for 5 hours, the resulting mixture was stirred at 〇 ° C for 45 minutes, then dripped Transfer to Mel (15. 6 mL, 250 mmol) in THF (40 mL) in EtOAc. After stirring at room temperature overnight, the mixture was neutralized with a saturated NaHCI solution and extracted with EtOAc. The organic juice was washed (Η2〇, brine), dehydrated (MgS〇4), filtered and concentrated. Stirring in ether followed by isolation from the furnace gave 6-[1-methyl-1-(methylsulfonyl)ethyl]·8·bromoquinoline. Bromoquinoline Q4 6-cyanomethyl-8-bromo ruthenium-72- This paper scale has been used in China National Standard (CNS) A4 specification (210 X 297 mm) -------- --Install -------- Order --------- (Please read the notes on the back and fill out this page) 1280240 A7 V. Inventions (70) (Please read the back of the note first) Matters fill out this page) Bromoporphyrin Q4 is prepared by the following procedure. Add DMF (1 mL) and H2 (5 mL) to 6-bromodecyl bromopyroline (3 g, 1 mmol) (described in International Patent Publication W094/22852) with cyanide Potassium (L6 grams, is not a mole). The mixture was quenched with H.sub.2 (1 mL). The organic extract was washed (2 mL, brine), dried (MgSO4), filtered and concentrated. Purification by flash chromatography (hexanes: EtOAc 3:1) gave 6- cyano- s- s s s s s s s. Bromo group 4: Lin Q5 6-[1-methyl-1-cyanoethyl] carbyl porphyrins Bromoporphyrin Q5 was prepared by the following procedure. In a solution of bromocarbinphyrin Q4 (3 g, 12.1 mmol) in THF (100 mL) at -78 ° C, Mel (1·7 liter, 27 耄m) was added, followed by Third _ potassium butanol (27 liters, 27 耄 Mo Er). After 2 hours at _78 °C, the mixture was warmed to and neutralized with saturated NH.sub.4 C.sub.1 and then extracted with Et. The organic extract was washed (ho, brine), dried (MgSO.sub.4), filtered and concentrated. Purification by flash chromatography (hexanes: EtOAc 3··1) afforded 6+-methyl-s-cyanoethyl]. The thiophosphorus reagent used to prepare the compound of the present invention is printed by the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs, and can be prepared according to the following formula 6: Figure 6. Preparation of the thiol reagent -73- The paper scale Applicable to China National Standard (CNS) A4 specification (210 x 297 public), -- 1280240 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (71

XXXX

XXII XXIII (X = B〇 XXIV (X = 0S02Me)XXII XXIII (X = B〇 XXIV (X = 0S02Me)

XXV R1 R2 芊基磷試劑（XXV) Η CH2P(Ph)3+Br' P1 Η CH2P(〇)(〇Et)2 P2 CN CH2P(0)(0Et)2 P3 式XXII芳基喹啉可於觸媒譬如Pd(PPh3 )4，及鹼譬如碳酸鈉 (水溶液）存在下，在譬如DME之溶劑中，藉由加熱，使溴 基喳啉XX與硼烷酸XXI偶合而製成。醇XXII可在譬如醋酸 之溶劑中，以HBr (水溶液）處理，而轉化成溴化物XXIII。 醇XXII可於鹼譬如三乙胺存在下，在譬如二氣甲烷之溶劑 中，藉由氣化甲烷磺醯，轉化成磺酸甲酯XXIV。芊基磷試 劑XXV可於PPh3存在下，在譬如乙腈之溶劑中，藉由加熱 XXIII，或經由以亞罐酸二乙酯及驗譬如第三-丁醇钾，在 譬如THF之溶劑中，處理XXIII或XXIV而製成。 -74 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -----------裝--------訂--------- (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 128〇24〇 A7 ' -^_____ 五、發明說明（72 ) 溴化芊基鳞P1 [3-(6-異丙基-8-喹啉基）芊基](三苯基）溴化鳞 溴化苄基鳞P1係藉下述程序製備。 步驟1 : 6-異丙基-8_[3-(羥甲基）苯基]喳啉 將6-異丙基-8-溴基喳啉（1U克，44·4毫莫耳）（描述於國際 專利公告W0 94/22852中）、3-(羥甲基）苯基硼烷酸（8 7〇克， 57.2毫莫耳）、Na2c〇3(2M，71毫升，142毫莫耳）及 Pd(PPh3)4(2.51毫克，2.17毫莫耳）在280毫升DME中之混合物 ，於80°C下攪拌5小時。使所形成之混合物冷卻至室溫，以 EtOAc稀釋，以鹽水洗滌，以SO#脱水乾燥，過濾及濃縮 。急驟式層析（己烷/ EtOAc 1/1)，並在CH2C12 /己烷（1/9)中 攪拌’產生6-異丙基-8-[3-(lk甲基）苯基]p奎p林，爲白色固體。 步驟2 : 6-異丙基各[3-(溴基甲基）苯基]哇啉 將得自本步驟1之羥甲基產物化合物（7·4〇克，26·7毫莫耳） 在AcOH (50毫升）與HBr (50毫升，48%水溶液）中之懸浮液， 於100 C下棍拌12小時。使混合物冷卻至室溫，倒入冰中之 NaOH (2N)内，調整pH値至8，並將混合物以醚稀釋。將有 機相以鹽水洗滌，以MgS04脱水乾燥，過濾及濃縮，產生6_ 異丙基-8-[3-(溴基甲基）苯基]p奎琳，爲黃色固體。 步驟3 : 〇(6-異丙基-8-4琳基）苄基](三苯基）溴化鳞 於仔自本步驟2之 &gt;臭甲基產物化合物（3.807克，11.1毫莫耳） 在40毫升CH3 CN中之溶液内，添加三苯膦（3.22克，12.3毫莫 耳）。將混合物於60°C下攪拌12小時，經冷卻至室溫，以_ 稀釋，過濾，及以醚洗滌，產生[3-(6-異丙基-8-喹啉基）芊基 -75- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ------------裂--------訂--------- (請先閱讀背面之注意事項再填寫本頁) 1280240 A7 B7 五、發明說明（73 ) ](三苯基）溴化鳞。 芊基膦酸酯P2 3-(6-異丙基-8_p奎琳基）爷基鱗酸二乙酉旨 苄基膦酸酯P2係藉下述程序製備。使得自上文P1合成步 驟2之溴甲基化合物（11.34克，1當量）溶於THF (170毫升）中 ’添加亞鱗酸二乙g旨（3.87毫升’ 1.05當量），並使溶液冷卻 至0°C。接著，慢慢添加t-BuOK (3.87毫升，1N，在THF中）。 將反應物攪拌2小時，並藉由添加NH4 C1 (飽和）、水及 EtOAc ’使反應坪滅。分離有機相，並以鹽水洗條，以 MgS〇4脱水乾燥及濃縮。於矽膠上藉急驟式層析純化（己燒 :EtOAc 1/9)獲得3-(6-異丙基-8-喳啉基）辛基膦酸二乙酯，爲 透明油。 苄基膦酸酯P3 3-[6-(1-氣基-1-甲基乙基）-8-ρ奎琳基]爷基膦酸二乙g旨 芊基膦酸酯P3係藉下述程序製備。 步驟1 ·· 6-(1-果基-1-甲基乙基）-8-[3-(經甲基）苯基]p奎p林 按照上述溴化芊基燐P1程序之步驟1，但以溴基喳啉Q5 取代6-異丙基-8-溴基喹啉，作爲起始物質，獲得6-(1-氰基-1-甲基乙基）-8-[3-(羥甲基）苯基]喹啉。 步驟2 :甲續酸3-[6-(1-來基-1-甲基乙基）-8-p套琳基]爷酉旨 於得自本步驟1之醇6-(1-氰基小甲基乙基）各[3-(羥曱基）苯 基]喳啉（5.15克，17毫莫耳）在CH2C12(150毫升）中，於-78。(： 下之溶液内，添加Et3 Ν (3·6毫升，26毫莫耳）與氣化甲烷續 醯（nMsCr)(1.6毫升，21毫莫耳）。於-78°C下〇_5小時後，將混 -76- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閱讀背面之注音？事項再填寫本頁} 裝 丁 &lt;11 I I 1·— ϋ ϋ in ϋ« 1· ί I i=0 經濟部智慧財產局員工消費合作社印製 1280240 A7 _____B7 _ 五、發明說明（74 ) 合物以飽和NiqCl溶液中和，以水稀釋，及以醚萃取。將 有機萃液洗滌（¾ Ο，鹽水），脱水乾燥（MgS〇4)，過濾及濃 縮，產生甲烷磺酸3-[6-(1-氰基-1-甲基乙基）-8-喳啉基]节酯， 爲白色泡沫物。 步驟3 · 3-[6-(1-散基-1-甲基乙基）-8-P奎p林基]爷基膦酸二乙酉旨 於亞磷酸二乙酯（2.5毫升，18毫莫耳）在THF (100毫升）中 ，於-78 C下之溶液内，添加第三-丁醇钟（1M，丁HF，16毫 升’ 16¾旲耳）及仔自本步驟2之甲燒績酸自旨化合物，甲燒 磺酸3-[6·(1-氰基-1-甲基乙基）各喹啉基]节酯（5.1克，13.5毫莫 耳）。於-78°C下0.5小時及於室溫下丨2小時後，將所形成之 混合物以飽和NH4 C1溶液中和，以水稀釋及以醚萃取。將 有機萃液洗滌（H20，鹽水），脱水乾燥（MgS〇4)，過濾及濃 縮。藉急驟式層析純化（己烷：EtOAc 1 : 4至1 : 10)，產生3-[6-(1-氣基-1-曱基乙基）_8·ρ奎p林基]宇基鱗酸二乙g旨，爲油狀物。 (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 -77- ’广tvtc、λ /1 拍故 v 9Q7 八巷、 1280240 Α7 Β7 五、發明說明（75XXV R1 R2 thiol reagent (XXV) Η CH2P(Ph)3+Br' P1 Η CH2P(〇)(〇Et)2 P2 CN CH2P(0)(0Et)2 P3 Formula XXII arylquinoline can be touched A solvent such as Pd(PPh3)4 and an alkali such as sodium carbonate (aqueous solution) are prepared by coupling bromoporphyrin XX with borane acid XXI by heating in a solvent such as DME. The alcohol XXII can be converted to the bromide XXIII by treatment with HBr (aqueous solution) in a solvent such as acetic acid. The alcohol XXII can be converted to the methyl sulfonate XXIV by gasification of methane sulfonium in the presence of a base such as triethylamine in a solvent such as di-methane. The mercaptophosphorus reagent XXV can be treated in the presence of PPh3 in a solvent such as acetonitrile by heating XXIII or by treating the diethyl succinate and a test such as potassium tert-butoxide in a solvent such as THF. Made of XXIII or XXIV. -74 This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) -----------Package--------Set-------- - (Please read the notes on the back and fill out this page.) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 128〇24〇A7 ' -^_____ V. Description of invention (72) Bromine fluorenyl scale P1 [3-( 6-Isopropyl-8-quinolinyl)indolyl](triphenyl)brominated bromobenzyl bromide P1 was prepared by the following procedure. Step 1: 6-Isopropyl-8_[3-(hydroxymethyl)phenyl]porphyrin 6-isopropyl-8-bromoporphyrin (1 U g, 44·4 mmol) (described in International Patent Publication W0 94/22852), 3-(hydroxymethyl)phenylboronic acid (8 7 g, 57.2 mmol), Na2c〇3 (2M, 71 ml, 142 mmol) and Pd A mixture of (PPh3) 4 (2.51 mg, 2.17 mmol) in 280 mL of DME was stirred at 80 ° C for 5 hours. The resulting mixture was cooled to room temperature, diluted with EtOAc EtOAc EtOAc. Flash chromatography (hexane / EtOAc 1/1) and stirring in CH2C12 /hexane (1/9) to yield 6-isopropyl-8-[3-(lkmethyl)phenyl]p p forest, a white solid. Step 2: 6-isopropyl-[3-(bromomethyl)phenyl]morpholine will be obtained from the hydroxymethyl product compound of step 1 (7.4 g, 26.7 mmol) A suspension of AcOH (50 mL) and HBr (50 mL, 48% aq.) was stirred at 100 C for 12 hours. The mixture was allowed to cool to room temperature, poured into NaOH (2N) in ice, pH was adjusted to 8 and mixture was diluted with ether. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated to afford &lt;RTI ID=0.0&gt;&gt; Step 3: 〇(6-isopropyl-8-4 linyl)benzyl](triphenyl) brominated squama from the gt; odor methyl product compound of this step 2 (3.807 g, 11.1 mmol) In a solution of 40 ml of CH3CN, triphenylphosphine (3.22 g, 12.3 mmol) was added. The mixture was stirred at 60 ° C for 12 hours, cooled to room temperature, diluted with EtOAc, filtered and washed with ether to give [3-(6-isopropyl-8-quinolinyl) fluorenyl-75- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) ------------ Crack--------Set--------- (Please read the notes on the back and fill out this page) 1280240 A7 B7 V. Inventive Note (73) ] (Triphenyl) brominated scales. Mercaptophosphonate P2 3-(6-isopropyl-8-p-quinacyl) geranyl sulphate diethyl phthalate P2 was prepared by the following procedure. The bromomethyl compound from the above P1 Synthesis Step 2 (11.34 g, 1 eq.) was dissolved in THF (170 mL) &lt;&quot;&quot;&quot;&quot;&quot; 0 ° C. Next, t-BuOK (3.87 mL, 1 N in THF) was added slowly. The reaction was stirred for 2 h and quenched by EtOAc EtOAc (EtOAc)EtOAc. The organic phase was separated, washed with brine, dried over MgSO 4 and evaporated. Purification by flash chromatography on silica gel (hexanes: EtOAc 1/9) afforded diethyl 3-(6-isopropyl-8-carboyl) octylphosphonic acid as a transparent oil. Benzylphosphonate P3 3-[6-(1-carbyl-1-methylethyl)-8-ρ quinalyl] arylphosphonic acid diethyl glucosylphosphonate P3 Program preparation. Step 1 ···6-(1-Phenyl-1-methylethyl)-8-[3-(methyl)phenyl]p-quine-P-forest according to step 1 of the above-described bromide-based hydrazine P1 procedure, However, 6-isopropyl-8-bromoquinoline was substituted with bromoporphyrin Q5 as a starting material to obtain 6-(1-cyano-1-methylethyl)-8-[3-(hydroxy Methyl)phenyl]quinoline. Step 2: Methyl 3-[6-(1-exyl-1-methylethyl)-8-p-linyl] is derived from the alcohol 6-(1-cyano) obtained in this step 1. Small methyl ethyl) [3-(hydroxyindenyl)phenyl]porphyrin (5.15 g, 17 mmol) in CH2C12 (150 mL) (In the solution below, add Et3 Ν (3·6 ml, 26 mmol) and gasification methane (nMsCr) (1.6 ml, 21 mmol). -5 hours at -78 °C After that, the mixed-76- paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) (please read the phonetic transcription on the back side and then fill out this page). Packing &lt;11 II 1·— ϋ ϋ in ϋ« 1· ί I i=0 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1280240 A7 _____B7 _ V. Invention Description (74) The compound was neutralized with a saturated NiqCl solution, diluted with water, and extracted with ether. The organic extract is washed (3⁄4 Torr, brine), dried (MgS 〇 4), filtered and concentrated to yield 3-[6-(1-cyano-1-methylethyl)-8-啉 ] 节 , , 为 步骤 步骤 步骤 步骤 步骤 步骤 步骤 步骤 步骤 步骤 步骤 步骤 步骤 步骤 步骤 步骤 步骤 步骤 步骤 步骤 步骤 步骤 步骤 步骤 步骤 步骤 步骤 步骤 步骤 步骤 步骤 步骤 步骤 步骤 步骤 步骤 步骤 步骤 步骤Diethyl phosphate (2.5 ml, 18 mmol) in THF (100 mL) in a solution at -78 C, a third-butanol clock (1M, hexanes HF, 16 mL ' 163⁄4 旲) And Aberdeen from this step 2 , 3-sulfonic acid sulfonic acid 3-[6·(1-cyano-1-methylethyl) quinolinyl] benzyl ester (5.1 g, 13.5 mmol), at -78 ° C for 0.5 h and After 2 hours at room temperature, the resulting mixture was neutralized with a saturated NH 4 C1 solution, diluted with water and extracted with ether. The organic extract was washed (H20, brine), dried (MgS 〇 4), filtered and Concentration. Purification by flash chromatography (hexane: EtOAc 1 : 4 to 1: 10) to give 3-[6-(1-carbyl-1-mercaptoethyl)_8·ρ····· The base of bismuth sulphate is an oily substance. (Please read the notes on the back and fill out this page.) Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, Printed -77- 'Guangt tvtc, λ /1 拍故 v 9Q7 Eight Lanes, 1280240 Α7 Β7 V. Invention Description (75

(XXV) 圖式7 卞基蹲試劑-酮偶合(XXV) Figure 7 卞-based reagent-ketone coupling

(請先閱讀背面之注意事項再填寫本頁) --------訂----- 經濟部智慧財產局員工消費合作社印製 相應於式11化合物，可使用上文圖式7概述之反應途徑 製成。化合物XXVI可經由酮VII在溶劑譬如THF中之溶液， 添加至芊基磷試劑XXV與鹼譬如第三-丁醇鉀在溶劑譬如 THF中之混合物内而獲得。然後，相應於式化合物，可 在溶劑混合物，譬如THF/MeOH/水中，經由以〇x〇ne處理 XXVI而製成。或者，式I化合物可於鹼譬如第三-丁醇鉀存 在下，在譬如THF之溶劑中’經由將酮νι_χχ^應而製 成。 參考上文圖式7及下表1，酮類與芊基磷試劑之偶合，會 78 本紙張尺度適用中國國家標準（CNS)A4規格（210 χ 297公釐） 1280240 A7 _ B7 五、發明說明（76 ) 造成表列出之實例。 表1 芊基磷試劑 酮 實例 P2 K3 1 P2 K3 2 P1 K5 3 P1 K2 4 P2 K1 5 P2 K1 6 P2 K6 7 P3 K6 8 P3 K2 9 P2 市售 30 P2 K7 31 P2 K7 32 P2 K8 33 P2 K8 34 P2 K9 35 P3 K8 36 P3 K8 37 P3 K9 38 P3 K10 39 -----------裝--------訂--------- (請先閱讀背面之注意事項再填寫本頁) 圖式8 芳基溴化物-溴基4啉偶合 經濟部智慧財產局員-X消費合作社印製(Please read the note on the back and then fill out this page) --------Book----- Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed corresponding to the compound of formula 11, can use the above Figure 7 The outlined reaction pathway is made. Compound XXVI can be obtained by adding a solution of ketone VII in a solvent such as THF to a mixture of thiophosphorus reagent XXV and a base such as potassium third-butoxide in a solvent such as THF. Then, corresponding to the compound of the formula, it can be prepared by treating XXVI with 〇x〇ne in a solvent mixture such as THF/MeOH/water. Alternatively, a compound of formula I can be prepared in the presence of a base such as potassium butylbutoxide in a solvent such as THF via ketone. Referring to Figure 7 above and Table 1 below, the coupling of ketones with thiophosphorus reagents will apply to the Chinese National Standard (CNS) A4 specification (210 χ 297 mm) on the paper scale. 1280240 A7 _ B7 V. INSTRUCTION (76) Form the examples listed in the table. Table 1 Example of decylphosphorus reagent ketone P2 K3 1 P2 K3 2 P1 K5 3 P1 K2 4 P2 K1 5 P2 K1 6 P2 K6 7 P3 K6 8 P3 K2 9 P2 Commercially available 30 P2 K7 31 P2 K7 32 P2 K8 33 P2 K8 34 P2 K9 35 P3 K8 36 P3 K8 37 P3 K9 38 P3 K10 39 ----------- Packing -------- Order --------- (Please read first Note on the back side of this page) Figure 8 Printed by the Intellectual Property Officer of the Ministry of Economics, the aryl bromide-bromo 4 phenyl coupling

-79- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 1280240 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（77 ) 參考圖式8，相應於式ϊ之化合物，可藉由芳基溴化物 XVIII當場轉化成其相應之石朋义完酸酉旨，其方式是與二石朋W 二甲基丁二醇酯，一種觸媒譬如[l，r-雙（二苯基膦基）_二環戊 二烯鐵]二氯鈀（Π)，及鹼譬如醋酸鉀，在譬如DMF之溶劑中 加熱，接著添加溴基喳啉XX，另一數量之相同觸媒，另— 數量之鹼譬如碳酸鈉（水溶液），及另一段加熱期而製成。 參考上文圖式8，下文表2及表2附綠，芳基溴化物與漠 基喳啉之偶合，舍造成轰列出之督例。 表2 为基 &gt;臭化物 溴基峻琳 實例 AB5 03 14 — AB5 03 15 AB2 05 16 ~ AB2 05 17 AB2 03 20 AB1 05 21 — AB5 Q5 22 ' AB3 Q5 23 ~ AB4 Q5 24 AB1 WO 94/22852 25 ' AB5 WO 94/22852 26 — 表2附錄 芳基溴化物 溴基p奎琳 實例 AB6 Q5 43 本發明化合物可按照下文所示之圖式9製成 -80- •紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ~ ϋ ϋ ^^1 ^11 i^i ϋ —Bi n n · an n ϋ n Βϋ 一 口、t I ·ϋ ϋ n n ϋ I (請先閱讀背面之注音？事項再填寫本頁} 1280240 A7 B7 五、發明說明（78 )-79- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1280240 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 V. Invention Description (77) Reference Figure 8, corresponding to The compound of hydrazine can be converted into its corresponding succinyl acid by the aryl bromide XVIII in the form of a solution with succinyl dimethyl dimethyl butyl glycol ester, a catalyst such as [l, r-double (diphenylphosphino)-dicyclopentadienyl iron]dichloropalladium (ruthenium), and an alkali such as potassium acetate, heated in a solvent such as DMF, followed by the addition of bromoporphyrin XX, another quantity of the same The medium, another amount of alkali, such as sodium carbonate (aqueous solution), and another period of heating. Referring to Figure 8 above, Table 2 and Table 2 below are attached to green, and the coupling of aryl bromide with Moji porphyrin is used to create a list of regulations. Table 2 is a base &gt; stinky bromine base example AB5 03 14 — AB5 03 15 AB2 05 16 ~ AB2 05 17 AB2 03 20 AB1 05 21 — AB5 Q5 22 ' AB3 Q5 23 ~ AB4 Q5 24 AB1 WO 94/22852 25 ' AB5 WO 94/22852 26 — Table 2 Appendix aryl bromide bromo-p-quineline example AB6 Q5 43 The compound of the invention can be made according to the following formula 9 -80- • The paper scale applies to the Chinese national standard (CNS) )A4 size (210 X 297 mm) ~ ϋ ϋ ^^1 ^11 i^i ϋ —Bi nn · an n ϋ n Βϋ One mouth, t I ·ϋ ϋ nn ϋ I (Please read the phonetic notes on the back first? Fill in the page again} 1280240 A7 B7 V. Description of invention (78)

圖式9 XXFigure 9 XX

R2 = Η (實例19)R2 = Η (Example 19)

nr2r3 (請先閱讀背面之注意事項再填寫本頁) ο ΝΗ〇 經濟部智慧財產局員工消費合作社印製 實例27 實例28 CH3 NH~fcH3 實例 29 CH3 圖式9係概述式I化合物之製備，其中醛χχνπ可經由將溴 基喹啉XX、3-甲醯基苯硼烷酸、觸媒譬如pd(pph3 )4及鹼譬 如碳酸鈉（水溶液），在譬如DME之溶劑中加熱而製成。酸 -81 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 1280240 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明（79 XXVII可於驗譬如六氫P比啶存在下，在譬如甲苯之溶劑中 ’經由與XVI加熱，而被轉化成實例18。實例19可經由在 譬如乙腈/水之溶劑混合物中，以硝酸鈽銨（”CAN&quot;)處理實 例18而獲得。或者，醛χχνπ可經由與XV及鹼譬如六氫吡 咬，在譬如甲苯之溶劑中加熱，而被轉化成不飽和酸 XXVIII。然後，可將酸χχνπ@由以偶合系統，譬如EDCI 、HOBT及胺，在譬如DMF之溶劑中處理，使其轉化成醯胺 I (實例 27、28 及 29)。 本發明化合物可根據下文圖式1〇，經由使溴基？奎p林化合 物與硼烷酸化合物偶合而製成。 圖式10 溴基喳啉-硼烷酸酯偶合Nr2r3 (please read the notes on the back and then fill out this page) ο ΝΗ〇 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed Example 27 Example 28 CH3 NH~fcH3 Example 29 CH3 Figure 9 is a summary of the preparation of the compound of formula I, The aldoxime νπ can be produced by heating bromoquinoline XX, 3-methylmercaptobenzeneboronic acid, a catalyst such as pd(pph3)4, and an alkali such as sodium carbonate (aqueous solution) in a solvent such as DME. Acid-81 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1280240 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (79 XXVII can be verified such as hexahydrogen P In the presence of a pyridine, it is converted to Example 18 by heating with XVI in a solvent such as toluene. Example 19 can be treated with cerium ammonium nitrate ("CAN") in a solvent mixture such as acetonitrile/water. Alternatively, the aldoxime can be converted to the unsaturated acid XXVIII by heating with XV and an alkali such as hexahydropyrazole in a solvent such as toluene. Then, the acid χχνπ@ can be coupled to a coupling system such as EDCI. , HOBT and an amine, which are treated in a solvent such as DMF to convert it to guanamine I (Examples 27, 28 and 29). The compounds of the present invention can be obtained by reacting a bromo-quinoline compound according to the following formula 1 The borane compound is coupled to produce. Figure 10 Bromoporphyrin-borane coupling

八八/REight eight / R

Br 溪基峻淋 (XX)Br 溪基峻淋 (XX)

圖式10係説明如何能夠在譬如Pd(〇Ac)2t觸媒，pph3，及 驗譬如碳酸鈉（水溶液）存在下，於譬如正-丙醇之溶劑中， 經由使溴基喳啉XX與硼烷酸酯χΠ偶合，以獲得式[化合物 。參考表3，溴基喳啉與硼烷酸酯之偶合，會造成表列出 -82- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -----------裝--------訂--------- (請先閱讀背面之注意事項再填寫本頁) 1280240 A7 B7 五、發明說明（8〇 ) 之實例。 表3 溴基峻p林 硼烷酸酯 實例 Q2 B2 10 Q3 B2 .11 Q2 B1 12 Q3 B1 13 Q3 B3 40 Q3 B3 41 Q3 B4 42 實例1與2 6-異丙基-8-(3-{(Z/E)_2-[4-(甲磺醯基）苯基]-2-苯基乙烯基}苯基) 峻琳 (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印制衣Figure 10 illustrates how the bromoporphyrin XX and boron can be obtained in the presence of, for example, Pd(〇Ac) 2t catalyst, pph3, and a test such as sodium carbonate (aqueous solution) in a solvent such as n-propanol. The alkanoate oxime is coupled to obtain the formula [compound. Referring to Table 3, the coupling of bromoporphyrins with borane esters will result in a table-82- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ------- ----Install--------Book--------- (Please read the note on the back and then fill out this page) 1280240 A7 B7 V. Examples of inventions (8〇). Table 3 Examples of bromine-based prion borane esterate Q2 B2 10 Q3 B2 .11 Q2 B1 12 Q3 B1 13 Q3 B3 40 Q3 B3 41 Q3 B4 42 Examples 1 and 2 6-isopropyl-8-(3-{ (Z/E)_2-[4-(Methanesulfonyl)phenyl]-2-phenylvinyl}phenyl) Jun Lin (please read the notes on the back and fill out this page) Ministry of Economic Affairs Intellectual Property Bureau Employee consumption cooperative printing clothes

實例1 -83- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 1280240 A7Example 1 -83- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1280240 A7

CH, 實例2 五、發明說明（81 實例1與2係藉下述程戽 Λ ^ 序I備。於+基膦酸酯Ρ2 (330毫克 ’ 0·83毫莫耳）與酉同κι on。古 Α 』Κ3 (200 ^克，〇·77毫莫耳）在THF(6毫升） 中之混5物内，於舍、、w T 4 、/皿下‘加第三-丁醇鉀（1M，THF，0.83 毫升，0.83毫莫耳）。於玄、、四 、 一； '至下1小時後，將混合物以水稀 釋’及以Et20萃取。將有機萃液洗滌(Η〗。)(鹽水），脱水乾 燉（MgS〇4) ’過濾及濃縮。藉急驟式層析純化（己烷： EtOAc 7 · 3)產生貫例1與2，爲白色泡沫物，其中一種產物 係比另一種產物具較低極性。實例丨爲較低極性z_異構物 ，而實例2爲較具極性之E-異構物。 貫例 1 : NMRjHGOOMHz，丙酮-d6)ci 8.79(q，lH)，8.28(q，lH)， 7·94 (d，2H)，7·73 (d，1H)，7.6-7.1 (m，ΜΗ)，3·14 (m，1H)，2·97 (s，3H)，1.34 (d， 6H). 實例 2 : NMRjHGOOMHz，丙酮-d6)d 8/78(q，lH)，8.25(q，lH)， 7.89 (d，2H)，7.71 (d，1H)，7.6 (m，3H)，7.45 (m，3H), 7.39-7.2 (m，8H)，3.11 (m， 4H), 1.34 (d6H). -84- 本紙張尺度適用中國國家標準（CNS)A4規格（210 x 297公爱) -----------{^裝--------訂--------- (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 1280240 A7CH, Example 2 V. Description of the invention (81 Examples 1 and 2 are prepared by the following procedure). The +-phosphonate Ρ2 (330 mg '0·83 mmol) and κ κι on. Α Κ ( 3 (200 ^ g, 〇 · 77 mmol) in a mixture of THF (6 ml), in the room, w T 4 , / dish 'plus third potassium butoxide (1M , THF, 0.83 ml, 0.83 mmol.) Yu Xuan, Si, Yi; 'After 1 hour, dilute the mixture with water' and extract with Et20. Wash the organic extract (Η). ), dehydrated dry stewed (MgS〇4) 'filtered and concentrated. Purified by flash chromatography (hexane: EtOAc 7 · 3) to give a mixture of s. 1 and 2 as a white foam, one product being one product It has a lower polarity. Example 丨 is a lower polarity z-isomer, while Example 2 is a more polar E-isomer. Example 1: NMRjHGOOMHz, acetone-d6)ci 8.79 (q, lH), 8.28 (q,lH), 7·94 (d,2H),7·73 (d,1H),7.6-7.1 (m,ΜΗ),3·14 (m,1H),2·97 (s,3H) , 1.34 (d, 6H). Example 2: NMRjHGOOMHz, acetone-d6)d 8/78 (q, lH), 8.25 (q, lH), 7.89 (d, 2H ), 7.71 (d, 1H), 7.6 (m, 3H), 7.45 (m, 3H), 7.39-7.2 (m, 8H), 3.11 (m, 4H), 1.34 (d6H). -84- Applicable to China National Standard (CNS) A4 specification (210 x 297 public) -----------{^装--------订--------- (please Read the notes on the back and fill out this page.) Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, Printed 1280240 A7

經濟部智慧財產局員工消費合作社印製 實例3 6-異丙基-Η3-[(Ε/Ζ)_2_[4·(甲磺醯基）苯基]·2·(1，3_ρ塞唑_2_基）乙烯 基]丰基}ρ奎啦Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing example 3 6-isopropyl-Η3-[(Ε/Ζ)_2_[4·(methylsulfonyl)phenyl]·2·(1,3_ρ-propazole_2 _基)vinyl]Fengji}ρ奎啦

實例3係藉下述程序製備。於溴化芊基鳞ρι (32〇毫克， 0.531毫莫耳）在2·5毫升THF中，於-78Ό下之懸浮液内，逐滴 添加t-Bu〇K(1.0M，在THF中，〇·55毫升，〇·55毫莫耳），並將 所形成之紅色溶液在〇°C下攪拌30分鐘。然後，於此亞烷基 化合物中，在-78T：下，逐滴添加酮K5 (122毫克，〇·455毫莫 耳）在2耄升THF中之溶液。將混合物溫熱至室溫，然後攪 摔1小時’以NH4 C1 (飽和）使反應淬滅，並以Et〇Ac稀釋。 知有機相以鹽水洗條，以Na2 S04脱水乾燥，過滤及濃縮。 急驟式層析（矽膠藥筒，己烷/ Et〇Ac 10至1〇〇。。，在20分鐘 内）產生實例3 (1.5比1之異構物混合物）。 NMR 1 H (500MHz，在丙酮-d6 中）β 8.79-8.78 (m，1H)，8.26-8.23 (m， 1H)，8.01-7.92 (m，3H)，7.84 (d，0.4H，較少），7.78(d，0.6H，主要），7.73-7.47 (〇1，圆)，7.43(〇1(1，11&quot;1)，7.34(1，0.61-1，主要），7.27(1，0观，較少），7.18(€1， -85- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -----------裝--------訂--------- (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 1280240 A7 ___B7_____ 五、發明說明（83 ) 0·6Η，主要），7.09 (d，0.4H，較少），3.12 (m，1H)，3.11 (s，l:8H，主要），2.99 (s，1·2Η，較少），1.36-1.33 (m，6H). MS (m+l)511. 實例4 6-異丙基-8-(3-{(E)-2-(l-甲基-1H-咪唑-2-基)-2-[4-(甲磺醯基）苯基] 乙少布基}苯基）P套淋 CH^Example 3 was prepared by the following procedure. Add t-Bu〇K (1.0 M in THF) to a suspension of bismuth bromide (32 mg, 0.531 mmol) in 2.5 mL of THF in EtOAc. 55·55 ml, 〇·55 mmoles, and the resulting red solution was stirred at 〇 ° C for 30 minutes. Then, in this alkylene compound, a solution of ketone K5 (122 mg, 〇·455 mmol) in 2 liters of THF was added dropwise at -78T:. The mixture was warmed to room temperature and then stirred for 1 hour. The reaction was quenched with NH4CI (sat) and diluted with Et. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. Flash Chromatography (gelatin cartridge, hexane / Et 〇Ac 10 to 1 Torr., in 20 minutes) gave Example 3 (1.5 to 1 mixture of isomers). NMR 1 H (500 MHz in acetone-d6) β 8.79-8.78 (m, 1H), 8.26-8.23 (m, 1H), 8.01-7.92 (m, 3H), 7.84 (d, 0.4H, less) , 7.78 (d, 0.6H, main), 7.73-7.47 (〇1, circle), 7.43 (〇1 (1,11&quot;1), 7.34 (1,0.61-1, main), 7.27 (1,0 view) , less), 7.18 (€1, -85- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -----------Install ------ --Book --------- (Please read the note on the back and then fill out this page) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1280240 A7 ___B7_____ V. Invention description (83) 0·6Η, mainly ), 7.09 (d, 0.4H, less), 3.12 (m, 1H), 3.11 (s, l: 8H, main), 2.99 (s, 1·2Η, less), 1.36-1.33 (m, 6H) MS (m+l) 511. Example 4 6-Isopropyl-8-(3-{(E)-2-(l-methyl-1H-imidazol-2-yl)-2-[4- (Methanesulfonyl) phenyl] ethyl bromide} phenyl) P set CH ^

實例4係藉下述程序製備。 步驟1 : 6-異丙基-8-(3-{(Ε)-2-(1-甲基-1H-咪唑-2-基）-2-[4-(曱硫 基）苯基]乙烯基}苯基）喳啉 按照實例3之程序，但以酮K2取代K5，作爲起始物質， 獲得6-異丙基-8-(3-{(Ε)-2-(1-甲基-1H-咪唑-2-基）-2-[4-(甲硫基）苯 基]乙晞基}苯基）峻p林。 步驟2 : 6-異丙基-8-(3-{(Ε)-2-(1-甲基-1H-咪唑-2-基）-2-[4-(甲績 醯基）苯基]乙烯基}苯基）峻啉 按照用於製備硼烷酸酯B1之程序（圖式2之步驟2)，但以 -86 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱1 ' &quot; -----------裝--------訂--------- (請先閱讀背面之注意事項再填寫本頁) 1280240 經濟部智慧財產局員工消費合作社印製 A7 __B7___ 五、發明說明（84 ) 本步驟1所獲得之硫化物，取代（E/Z)-2-(3-溴苯基）-1-(1-甲基-ΙΗ-味°坐-2-基）小[4-(甲硫基）苯基]乙晞，作爲起始物質，獲得 實例4。 NMRiHGOOMHz，在丙酮-d6 中8.77(dcUH)，8.24(dd，.lH)， 7.88 (d, 2H)5 7.71 (d3 1H)5 7.59 (d5 1H)5 7.53 (d? 2H)3 7.48 (d5 2H)5 7.41 (dd? 1H) ，7.28 (t，1H)，7.23 (s，1H)，7.15 (d5 1H)，7.07 (d，1H)，6·95 (d，1H)，3.51 (s，3H)， 3.10 (m，1H)，2·99 (s，3H)，1.32 (d，6H)· MS : (m+2) : 509.4 實例5與6 6·異丙基-8-(3-{(Z/E)-2-(4-氟苯基）-2-[4-(甲磺醯基）苯基]乙烯基} 苯基）p奎淋Example 4 was prepared by the following procedure. Step 1: 6-Isopropyl-8-(3-{(Ε)-2-(1-methyl-1H-imidazol-2-yl)-2-[4-(indolyl)phenyl]ethene The base phenyl)porphyrin was subjected to the procedure of Example 3, but substituting K5 with ketone K2 as a starting material to give 6-isopropyl-8-(3-{(Ε)-2-(1-methyl-) 1H-imidazol-2-yl)-2-[4-(methylthio)phenyl]ethenyl}phenyl) phenyl p. Step 2: 6-Isopropyl-8-(3-{(Ε)-2-(1-methyl-1H-imidazol-2-yl)-2-[4-(methylphenyl)phenyl] Vinyl}phenyl)porphyrin according to the procedure used to prepare boranoate B1 (Step 2 of Figure 2), but with -86 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 Love 1 ' &quot; -----------Install--------Book--------- (Please read the note on the back and fill out this page) 1280240 Economy Ministry of Intellectual Property Bureau employee consumption cooperative printed A7 __B7___ V. Description of invention (84) Sulfide obtained in this step 1, replacing (E/Z)-2-(3-bromophenyl)-1-(1-A ΙΗ-ΙΗ-味 ° sit-2-yl)small [4-(methylthio)phenyl]acetamidine as the starting material gave Example 4. NMRiHGOOMHz, 8.77 (dcUH) in acetone-d6, 8.24 ( Dd,.lH), 7.88 (d, 2H)5 7.71 (d3 1H)5 7.59 (d5 1H)5 7.53 (d? 2H)3 7.48 (d5 2H)5 7.41 (dd? 1H) , 7.28 (t, 1H) ), 7.23 (s, 1H), 7.15 (d5 1H), 7.07 (d, 1H), 6.95 (d, 1H), 3.51 (s, 3H), 3.10 (m, 1H), 2·99 (s , 3H), 1.32 (d, 6H)· MS : (m+2) : 509.4 Example 5 and 6 6·isopropyl-8-(3-{(Z/E)-2-(4-fluorobenzene) ) -2- [4- (methanesulfonyl acyl) phenyl] ethenyl} phenyl) p leaching Kui

-87- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -------------------訂--------- (請先閱讀背面之注意事項再填寫本頁) 1280240 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明（85-87- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) ------------------- Order -------- - (Please read the notes on the back and fill out this page) 1280240 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed V. Inventions (85

CKCK

貫例6 實例5與6係藉下述程序製備。按照實例1之程序，但以 酮K1取代K3，作爲起始物質，及藉急驟式層析純化（％。。 EtOAc / 50。。己燒），產生實例5與6。 ch3 NMR 1 H (500MHz，在丙酮-d6中）實例5 :主要（Z)異構物：j 8.78 (dd，1H)，8.25 (dd，1H)，7.93 (d，2H)，7.72 (d，1H)，7,55-7.40 (m，6H)， 7.35 (m，2H)，7.25 (t，1H)，7.23 (s，1H)，7·11 (t，2H)，7.05 (d，1H)，3.12 (m，1H)， 2.96 (s，3H)，1.34 (d，6H). NMR 1 H (500MHz，在丙酮-d6中）實例6 :較少⑹異構物： 8.78 (dd，1H)，8.35 (dd，1H)，7.93 (d，2H)，7.72 (d，1H)，7.65-7.55 (m，3H)， 7.45 (dd, 1H), 7.35-7.15 (m, 9H), 3.12 (m, 4H), 1.34 (d, 6H). 實例7 2-(2-{(E/Z)-2-[3-(6-異丙基-8-喳啉基）苯基]小[4-(甲磺醯基）苯基] 乙％τ基）-1,3-17塞哇-5-基）-2-丙醇 -88- i紙張尺度適A中關家標準（CNS)A4規格（210 x 297公釐） -----------^^褒--------訂--------- (請先閱讀背面之注意事項再填寫本頁) 1280240 A7 B7 五、發明說明（86 )Example 6 Examples 5 and 6 were prepared by the following procedure. Following the procedure of Example 1, but substituting K3 for ketone K1 as a starting material, and purification by flash chromatography (% EtOAc / 50 hexanes). Ch3 NMR 1 H (500 MHz in acetone-d6) Example 5: Primary (Z) isomer: j 8.78 (dd, 1H), 8.25 (dd, 1H), 7.93 (d, 2H), 7.72 (d, 1H),7,55-7.40 (m,6H), 7.35 (m,2H), 7.25 (t,1H), 7.23 (s,1H),7·11 (t,2H),7.05 (d,1H) , 3.12 (m, 1H), 2.96 (s, 3H), 1.34 (d, 6H). NMR 1 H (500 MHz in acetone-d6) Example 6: less (6) isomer: 8.78 (dd, 1H) , 8.35 (dd, 1H), 7.93 (d, 2H), 7.72 (d, 1H), 7.65-7.55 (m, 3H), 7.45 (dd, 1H), 7.35-7.15 (m, 9H), 3.12 (m , 4H), 1.34 (d, 6H). Example 7 2-(2-{(E/Z)-2-[3-(6-isopropyl-8-indolyl)phenyl] small [4- (Methanesulfonyl)phenyl]ethylaminohydrazone-1,3-17-Sev-5-yl)-2-propanol-88- i paper size suitable for the ACN standard (CNS) A4 specification ( 210 x 297 mm) -----------^^褒--------Book--------- (Please read the notes on the back and fill out this page. 1280240 A7 B7 V. Description of invention (86)

實例7係按照實例1之程序製成，但以酮K6取代K3作爲 起始物質。藉急驟式層析純化（100% EtOAc)產生實例7，爲 異構物混合物。 NMR 1 H (400MHz，在丙酮-d6 中）d 8.80 (m，1H)，8.30 (m，1H)，8.05 (d(主要），1.44H)，7·93 (d(較少），0.55H)，7.85 (s(主要），0.72H)，7.77 (s(較 少），0.28H)，7·75-7·45 (m，7H)，7·35 (t(較少），0.28H)，7.28 (t(主要），0.72H)， 7.21 (d(較少），0.28H)，7·10 (d(主要），0.72H)，4.7 (m，1H)，3.15 (m，1H)， 3.15 (s(較少），0.84)，2.99 (s(主要），2.16H)，1_60 (m，6H)，1.35 (m，6H)· MS(m+l) ： 569.6 -----------^----------------- (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 -89- ^紙張尺度適用中國國家標準（CNS)A4規格（210 χ 297公釐） 1280240 A7 B7 五、發明說明（87 ) 實例8 2-[H3-{(E/Z)-2_[5-(1-經基-1-甲基乙基）唑 1 基]·2_[4_(甲磺醯 基）苯基]乙晞基}苯基）-6^奎琳基]_2_甲基丙腈Example 7 was prepared according to the procedure of Example 1, except that K3 was substituted for K3 as a starting material. Purification by flash chromatography (100% EtOAc) gave Example 7 as a mixture. NMR 1 H (400MHz in acetone-d6) d 8.80 (m,1H), 8.30 (m,1H), 8.05 (d (main), 1.44H), 7.93 (d (less), 0.55H ), 7.85 (s (main), 0.72H), 7.77 (s (less), 0.28H), 7.75-7.45 (m, 7H), 7·35 (t (less), 0.28H) ), 7.28 (t (main), 0.72H), 7.21 (d (less), 0.28H), 7·10 (d (main), 0.72H), 4.7 (m, 1H), 3.15 (m, 1H) ), 3.15 (s (less), 0.84), 2.99 (s (main), 2.16H), 1_60 (m, 6H), 1.35 (m, 6H) · MS(m+l): 569.6 ---- -------^----------------- (Please read the notes on the back and fill out this page) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed -89 - ^ Paper scale applies to China National Standard (CNS) A4 specification (210 297 297 mm) 1280240 A7 B7 V. Invention description (87) Example 8 2-[H3-{(E/Z)-2_[5-(1 -transmethyl-1-methylethyl oxazole 1 yl]·2_[4_(methylsulfonyl)phenyl]ethenyl}phenyl)-6^ quinolinyl]_2_methylpropionitrile

貫例8係按照實例1之程序製成，但以酮K6取代K3，及 以爷基膦酸酯Ρ3取代Ρ2，作爲起始物質。藉急驟式層析純 化（20。〇 CH2 Cl2/80。。EtOAc)產生實例8，爲異構物之混合物。 NMR 1 H (400MHz，在丙酮-d6 中）β 8.92 (m, 1H)，8.45 (m, 1H)，8.10 (m，1H)，8·05 (m，1H)，7·93 (m5 1H)，7·85 (m5 2H)，7.77-7.55 (m，XH)，7.40 (t( 較少），0.43H)，7.28 (t(主要），0.57H)，7.21 (d(較少），0.43H)，7.10 (d(主要 )，0.57H)，4.67(s(主要）,〇.57H)，4.63(s(較少），〇.43H)，3.15(s(較少）， 1.3H)，2.99(s(主要），1.7H)，1.90(m，6H)，1.65(s(主要），3·4Η)，1.45(s(較 少），2.6H)· MS(m+l) ： 594.6 實例9 2-甲基-2-[8-(3-{(E)-2-(l-甲基-1H-咪唑-2-基）-2-[4-(甲績醢基）笨基] 乙締基}苯基）-6-峻17休基]丙腈 -90- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ------------裝--- (請先閱讀背面之注意事項再填寫本頁) --訂----- 經濟部智慧財產局員工消費合作社印製 經濟部智慧財產局員工消費合作社印製 1280240 A7 -------- B7 五、發明說明（肪）Example 8 was prepared according to the procedure of Example 1, except that K3 was replaced by ketone K6, and oxime 2 was replaced by yttriumphosphonate 3 as a starting material. Purification by flash chromatography (20. EtOAc / EtOAc /EtOAc) NMR 1 H (400 MHz in acetone-d6) β 8.92 (m, 1H), 8.45 (m, 1H), 8.10 (m,1H),8·05 (m,1H),7·93 (m5 1H) , 7.85 (m5 2H), 7.77-7.55 (m, XH), 7.40 (t (less), 0.43H), 7.28 (t (main), 0.57H), 7.21 (d (less), 0.43 H), 7.10 (d (main), 0.57H), 4.67 (s (main), 〇.57H), 4.63 (s (less), 〇.43H), 3.15 (s (less), 1.3H) , 2.99 (s (main), 1.7H), 1.90 (m, 6H), 1.65 (s (main), 3. 4 Η), 1.45 (s (less), 2.6H) · MS (m + l): 594.6 Example 9 2-Methyl-2-[8-(3-{(E)-2-(l-methyl-1H-imidazol-2-yl)-2-[4-(A) Base] Ethyl}}phenyl)-6-Jun 17 Hike] Propionitrile-90- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) --------- ---装--- (Please read the notes on the back and fill out this page) --Border----- Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Printed Economy Ministry Intellectual Property Bureau Staff Consumer Cooperatives Printed 1280240 A7 -------- B7 V. Invention Description (Fat)

實例9係藉下述程序製備。 步驟1 : 2_甲基-2K3-{(E)-2-(l-甲基-1H-咪唑冬基甲硫 基）苯基]乙烯基}苯基）-6·ρ套啉基]丙腈，係按照實例1之程序 製成，但以酮Κ2取代Κ3，及以芊基膦酸酯Ρ3取代ρ2，作 爲起始物質。 步驟 2 : 2-甲基-2-[8-(3-{(Ε)-2-(1-甲基-1Η-咪唑-2-基）-2-[4-(甲磺 基）苯基]乙烯基}苯基）各峻淋基]丙腈，實例9，係按照用 於製備硼烷酸酯B1之程序（圖式2步驟2)製成，但以本步驟 1中所後得之硫化物取代（E/Z)-2-(3-溴苯基）-1-(1-甲基-1H-咪。坐_ 2-基）小[4-(甲硫基）私基]乙缔，作爲起始物質。在藉急驟式 層析純化（97。。EtOAc/3。。Et3 N)後，獲得實例9。 NMR 1 H (400MHz，在丙酮-d6 中）6 8·92 (dd，1H)，8.45 (dd，1H)， 8.10 (d, 1H), 7.93 (d, 2H), 7.76 (d, 1H), 7.60-7.50 (m5 5H), 7.38 (t, 1H), 7.35 (s, 1H), 7.19 (m, 1H), 7.10 (m, 1H), 6.95 (m, 1H), 3.55 (s, 3H), 3.00 (s, 3H), i.85 (s, 6H). -91 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 x 297公« ) -----------裝--------訂··-------- (請先閱讀背面之注咅？事項再填寫本頁) 1280240 A7Example 9 was prepared by the following procedure. Step 1: 2_Methyl-2K3-{(E)-2-(l-methyl-1H-imidazolylmethylthio)phenyl]vinyl}phenyl)-6·ρ-polyphenyl]propyl The nitrile was prepared according to the procedure of Example 1, except that oxime 3 was replaced by ketone oxime 2, and ρ2 was replaced by fluorenylphosphonate Ρ3 as a starting material. Step 2: 2-Methyl-2-[8-(3-{(Ε)-2-(1-methyl-1Η-imidazol-2-yl)-2-[4-(methylsulfo)phenyl ]] vinyl} phenyl) each thiol] propionitrile, Example 9, prepared according to the procedure used to prepare boranoate B1 (Step 2 of Figure 2), but obtained after this step 1 Sulfide Substituted (E/Z)-2-(3-Bromophenyl)-1-(1-methyl-1H-Mimi. Sodium-2-yl) Small [4-(Methylthio) Private Group] As a starting substance. After purification by flash chromatography (97. EtOAc/3. Et3 N), Example 9 was obtained. NMR 1 H (400 MHz in acetone-d6) 6 8·92 (dd, 1H), 8.45 (dd, 1H), 8.10 (d, 1H), 7.93 (d, 2H), 7.76 (d, 1H), 7.60-7.50 (m5 5H), 7.38 (t, 1H), 7.35 (s, 1H), 7.19 (m, 1H), 7.10 (m, 1H), 6.95 (m, 1H), 3.55 (s, 3H), 3.00 (s, 3H), i.85 (s, 6H). -91 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 public « ) ----------- --------Book··-------- (Please read the note on the back? Please fill out this page again) 1280240 A7

經濟部智慧財產局員工消費合作社印製 五、發明說明（的） MS (m+1) ： 533.3 實例10 6_[H甲續醯基）乙基]各{3-_-2件(甲續gS基）苯基Η-(1，3μι塞唆· 2-基）乙晞基]苯基卜奎琳 〇^-ch3 丨Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Printing, V. Inventions, MS (m+1): 533.3, Example 10, 6_[H, 醯 醯), ethyl], {3-_-2 pieces (continued gS Phenyl hydrazine-(1,3μι唆唆2-yl)ethenyl]phenyl quinoid 〇^-ch3 丨

實例10係藉下述程序製備。 將 &gt;臭基峻啦Q2 (105毫克，〇·33毫莫耳）、硼烷酸酯B2 (236 t 克 ’ 0·51 毫莫耳）、Na2C03(2M，0.65 毫升，1.3 毫莫耳）、 Pd(OAc)2(6.3毫克，0.028毫莫耳）及pph3(28毫克，0.11毫莫耳） 在4耄升正-丙醇中之混合物，於9〇〇c下攪拌2小時。使混合 物冷卻至室溫，以Et0Ac稀釋，以鹽水洗滌，以Na〗s〇4脱水 乾燥’過濾及濃縮。急驟式層析（甲苯/丙酮；4/1)及在己 / EtOAc中攪拌’產生實例1〇 (單一異構物），爲白色固體。 NMR 1 H (400MHz，丙酮-d6) d 8.89 (dd，1H)，8.39 (dd, 1H), 8.07 (d，1H), 8.03 (d5 2H), 7.94 (s, 1H), 7.86 (d? 1H), 7.71-7.68 (m, 3H) 7.62-7.60 (m, 2H), ____ -92- ^紙張尺度適用中國國家標準（CNS)A4規格（210 x 297公釐） ---------—裝·———訂--------- (請先閱讀背面之注咅？事項再填寫本頁) 1280240 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（9〇 ) 7.55 (dd, 1H), 7.45 (s5 1H), 7.34 (t, 1H)5 7.18 (d, 1H), 4.67 (q5 1H)5 3.04 (s, 3H), 2.86 (s，3H)，1.88 (s，3H). MS (M+l) 576. 實例11 6-[l-曱基小(甲磺醯基）乙基]-8-{3-[(E)-2-[4-(甲磺醯基）苯基]_2· (1，3-噻唑-2-基）乙晞基]苯基}喳啉 〇今/〇闩3Example 10 was prepared by the following procedure. Will &gt; stinking base Q2 (105 mg, 〇·33 mmol), boranoate B2 (236 t gram '0·51 mM), Na2C03 (2M, 0.65 cc, 1.3 mM) A mixture of Pd(OAc)2 (6.3 mg, 0.028 mmol) and pph3 (28 mg, 0.11 mmol) in 4 liters of n-propanol was stirred at 9 ° C for 2 hours. The mixture was cooled to room temperature, diluted with EtOAc (EtOAc) and brine. Flash chromatography (toluene/acetone; 4/1) and stirring in hexane / EtOAc afforded Example 1 (single isomer) as a white solid. NMR 1 H (400MHz, acetone-d6) d 8.89 (dd, 1H), 8.39 (dd, 1H), 8.07 (d,1H), 8.03 (d5 2H), 7.94 (s, 1H), 7.86 (d? 1H ), 7.71-7.68 (m, 3H) 7.62-7.60 (m, 2H), ____ -92- ^The paper scale applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) -------- --装··——订--------- (Please read the note on the back? Please fill out this page again) 1280240 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 V. Invention Description ( 9.〇 (1,5), 7.45 (s, 1H), 7.34 (t, 1H) 1.88 (s,3H). MS (M+l) 576. Example 11 6-[l-fluorenyl (methanesulfonyl)ethyl]-8-{3-[(E)-2-[4- (Methanesulfonyl)phenyl]_2·(1,3-thiazol-2-yl)ethenyl]phenyl}porphyrin 〇今/〇 latch 3

h3c 實例11係按照實例10中所述之程序製成，但以溴基峻p林 Q3取代Q2，及使用硼烷酸酯B2。急驟式層析（甲苯/丙酉同 ;9/1)及在EtOAc /己烷中攪拌，產生實例u (單一異構物） ，爲白色固體。 NMR 1 H (400MHz，丙酮-d6) : d 8.90 (dd，lH)，8 41 ⑽，1H)，8 23 (s, 1H)，8.02-7.99 (d，3H)，7·95 (s，1H), 7.86 (d，lH), 7·7〇 (d, 2H), 76〇_7 54 (m, 4H), 7.32 (t, 1H), 7.13 (d, 1H), 3.00 (s, 3H), 2.69 (s, 3H), 1.96 (s? 6H) MS (M+l) 523. -93- 本紙張尺度適用中國國家標準（CNS)A4規格（210 x 297公釐） -----------裝--------訂--------- (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 1280240 A7 ___B7___ 五、發明說明（91 ) 實例12 8-(3-{(Ζ)-2-(1-甲基·1Η-咪唑-2-基）-2-[4-(甲磺醯基）苯基]乙烯基} 苯基)-6-[1-(甲磺醯基）乙基]喳啉 〇屢/CH3H3c Example 11 was prepared according to the procedure described in Example 10, but substituting Q2 with bromo-based P-Q3 and using boranoate B2. Flash chromatography (toluene / hexanes; 9/1). NMR 1 H (400MHz, acetone-d6): d 8.90 (dd,lH),8 41 (10),1H),8 23 (s, 1H), 8.02-7.99 (d,3H),7·95 (s,1H) ), 7.86 (d,lH), 7·7〇(d, 2H), 76〇_7 54 (m, 4H), 7.32 (t, 1H), 7.13 (d, 1H), 3.00 (s, 3H) , 2.69 (s, 3H), 1.96 (s? 6H) MS (M+l) 523. -93- This paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) ------ -----Install--------Book--------- (Please read the notes on the back and fill out this page) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1280240 A7 ___B7___ V. INSTRUCTIONS (91) Example 12 8-(3-{(Ζ)-2-(1-methyl·1Η-imidazol-2-yl)-2-[4-(methylsulfonyl)phenyl] Vinyl} phenyl)-6-[1-(methylsulfonyl)ethyl]porphyrin oxime/CH3

實例12係按照實例10中所述之程序製成，使用溴基喹琳 Q2，但以硼烷酸酯B1取代硼烷酸酯B2。急驟式層析（950。 CH2 Cl2/5。。EtOH)，產生實例12化合物。 NMR 1 H (400MHz，在丙酮-d6 中）β 8.92 (dd，1H)，8·45 (dd，1H)， 8.10 (s，1H)，7.93 (d，2H)，7.76-7.65 (m，4H)，7.59 (dd，1H)，7.39 (t，1H)，7.26 (s，1H)，7.18 (s，1H)，7.05 (m，2H)，4.70 (q，1H)，3.40 (s，3H)，3.13 (s，3H), 2.93 (s, 3H), 1.87 (d, 3H). MS (m+1): 572.4 實例13 8-(3-{(Z)-2-(l-甲基-1H-咪唑-2-基）-2-[4-(甲磺醯基）笨基]乙晞基} 苯基）-6-[l-甲基小(甲磺醯基）乙基 &gt;奎啉 -94- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） I 1&gt; I— i^i in I aemmt mmm-β tm · I team Ban i I n』ον I —al l ·ϋ ϋ «^1 I (請先閱讀背面之注意事項再填寫本頁) 1280240 A7 --- 五、發明說明（92 ) 〇足/CH3Example 12 was prepared according to the procedure described in Example 10 using bromoquineline Q2 but substituting borane B1 with borane B1. Flash chromatography (950. CH2Cl2/5. EtOH) gave the compound of Example 12. NMR 1 H (400 MHz in acetone-d6) β 8.92 (dd, 1H), 8.45 (dd, 1H), 8.10 (s, 1H), 7.93 (d, 2H), 7.76-7.65 (m, 4H) ), 7.59 (dd, 1H), 7.39 (t, 1H), 7.26 (s, 1H), 7.18 (s, 1H), 7.05 (m, 2H), 4.70 (q, 1H), 3.40 (s, 3H) , 3.13 (s, 3H), 2.93 (s, 3H), 1.87 (d, 3H). MS (m+1): 572.4 Example 13 8-(3-{(Z)-2-(l-methyl- 1H-imidazol-2-yl)-2-[4-(methylsulfonyl)phenyl]ethenyl}phenyl)-6-[l-methyl small (methylsulfonyl)ethyl &gt; Porphyrin-94- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) I 1&gt; I—i^i in I aemmt mmm-β tm · I team Ban i I n』ον I —al l ·ϋ ϋ «^1 I (Please read the note on the back and fill out this page) 1280240 A7 --- V. Description of invention (92) 〇足/CH3

-----------裝---- (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 實例13係按照實例10中所述之程序製成，但以溴基喳啉 Q3取代Q2，及以硼烷酸酯B1取代硼烷酸酯B2。急驟式層 析（95% Et〇Ac/5〇/。Et3 N)產生實例13 (單一異構物），爲泡沫物。 NMR1 H (400MHz ^ 在丙酮-d6 中）d 8·92 (dd，1H)，8.45 (dd，1H)， 8.37 (d，1H)，8.05 (d，1H)，7.93 (d，2H)，7.76 (d，1H)，7.69 (d，2H)，7.65 (d，1H)， 7.59 (dd，1H)，7.38 (t，1H)，7.31 (s，1H)，7.18 (s，1H)，7·05 (m，2H)，3.40 (s，3H) ，3.13 (s，3H)，2.70 (s，3H)，1.95 (s，6H). MS (m+l) ： 586.2 實例14與15 6-[l-甲基-1-(甲磺醯基）乙基]-8-(3-{(E/Z)-2-(3-甲基-1，2,4』号二唑-5-基）-2-[4-(甲磺醯基）苯基]乙烯基}苯基 &gt;奎啉 -95- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱） 訂---- 1280240 A7 B7 五、發明說明（93 )-----------Install---- (Please read the note on the back and then fill out this page) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing example 13 is in accordance with the procedure described in Example 10. It was prepared by substituting Q2 with bromoporphyrin Q3 and borane ester B2 with boranoate B1. A flash chromatography (95% Et 〇Ac/5 〇 /. Et3 N) gave Example 13 (single isomer) as a foam. NMR1 H (400MHz ^ in acetone-d6) d 8·92 (dd,1H), 8.45 (dd,1H), 8.37 (d,1H), 8.05 (d,1H), 7.93 (d,2H),7.76 (d,1H), 7.69 (d,2H), 7.65 (d,1H), 7.59 (dd,1H), 7.38 (t,1H),7.31 (s,1H),7.18 (s,1H),7· 05 (m, 2H), 3.40 (s, 3H), 3.13 (s, 3H), 2.70 (s, 3H), 1.95 (s, 6H). MS (m+l): 586.2 Examples 14 and 15 6-[ L-Methyl-1-(methylsulfonyl)ethyl]-8-(3-{(E/Z)-2-(3-methyl-1,2,4′′diazol-5-yl )-2-[4-(methylsulfonyl)phenyl]vinyl}phenyl&gt; quinolin-95- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public) Order -- -- 1280240 A7 B7 V. Description of invention (93)

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

^ch3 經濟部智慧財產局員工消費合作社印製 實例14與15係藉下述程序製備。使芳基溴化物AB5 (249 ί 克，〇·57毫莫耳）、二硼2,3-二甲基丁二醇酯（167毫克，0.6( 毫莫耳）、[1，Γ-雙（二苯基膦基）-二環戊二烯鐵]二氣鈀（Π)(1；; 毫克，0.015毫莫耳）及醋酸鉀（176毫克，1.8毫莫耳）在 -96- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） l28〇240 經濟部智慧財產局員工消費合作社印製 A7 ---------B7____________ 五、發明說明（94 ) DMF (N，N- —曱基甲醯胺）(i〇耄升）中之溶液脱氣，並於 下攪拌3小時。然後，在所形成之混合物中，於25χ：下添加 溴基喳啉Q3 (150晕克，0.46毫莫耳）、⑴广雙（二苯基膦基）_二 裱戊二烯鐵]二氣鈀（11)(12毫克，0.015亳莫耳）及碳酸鈉（〇 6 毫升，2M)。於脱氣後，將混合物在8(rc下加熱過夜。然後 使混合物冷卻至室溫，以馬〇使反應淬滅並以EtOAc萃取。 將有機萃液洗條（¾ 〇，鹽水），脱水乾燥（MgS〇4)，過遽及 濃縮。藉急驟式層析純化（己燒：EtOAc : Et3 N 22 ·· 68 ·· 10， 然後爲己燒：EtOAc 3 : 1)產生異構物（實例14與實例15)。 NMR 1 H (500MHz，丙酮-d6)主要（E)異構物（實例14) : d 8.91 (dd，1H)，8.42 (dd，1H)，8.25 (d，1H)，8.12 (s，1H)，8·02 (d，1H)，8.00 (d， 2H)，7.70 (m，3H)，7.64 (s，1H)，7.55 (dd，1H)，7.38 (t，1H)，7·23 (d，1H)，3.03 (s，3H)，2.69 (s，3H)，2.33 (s，3H)，1·96 (s，6H)· MS (M+l) ： 588.2 較少（Z)異構物（實例 15) : d 8.92 (dd，1H)，8.45 (dd，1H)，8·29 (d， 1H)? 8.07 (d? 1H), 7.99 (d5 2H)5 7.88 (s5 1H), 7.75 (m5 3H), 7.62 (s? 1H), 7.58 (q, 1H)，7.48 (t，1H)，7.24 (d，1H)3.16 (s，3H)，2·70 (s，3H)，2.38 (s，3H)，2.00 (s， 6H). MS (M+l) : 588.2 或者，實例14可藉下述程序製.成： -97- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -----------#裝--------訂---------· (請先閱讀背面之注意事項再填寫本頁) 1280240 A7 B7 五、發明說明（95 )^ch3 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed Examples 14 and 15 were prepared by the following procedures. An aryl bromide AB5 (249 ίg, 〇·57 mmol), diboron 2,3-dimethylbutylene glycol (167 mg, 0.6 (mole), [1, Γ-double ( Diphenylphosphino)-dicyclopentadienyl iron] digas palladium (Π) (1;; mg, 0.015 mmol) and potassium acetate (176 mg, 1.8 mmol) at -96- paper scale Applicable to China National Standard (CNS) A4 specification (210 X 297 mm) l28〇240 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing A7 ---------B7____________ V. Invention description (94 ) DMF (N , N- - mercaptocarbamide) (i liter) solution was degassed and stirred for 3 hours. Then, in the resulting mixture, bromoporphyrin Q3 (150) was added at 25 Torr: Halo, 0.46 mmol, (1) broad bis(diphenylphosphino)-dipentadiene iron] digas palladium (11) (12 mg, 0.015 mmol) and sodium carbonate (〇6 mL, 2M) After degassing, the mixture was heated at 8 (rc) overnight. The mixture was then cooled to room temperature, then quenched with EtOAc and extracted with EtOAc. EtOAc (3⁄4 〇, brine) , dehydration and drying (MgS〇4) After hydration and concentration, purification by flash chromatography (hexane: EtOAc:EtOAc:EtOAc:EtOAc:EtOAc:EtOAc: 1 H (500 MHz, acetone-d6) major (E) isomer (Example 14): d 8.91 (dd, 1H), 8.42 (dd, 1H), 8.25 (d, 1H), 8.12 (s, 1H), 8·02 (d,1H), 8.00 (d, 2H), 7.70 (m, 3H), 7.64 (s, 1H), 7.55 (dd, 1H), 7.38 (t, 1H), 7·23 (d, 1H), 3.03 (s, 3H), 2.69 (s, 3H), 2.33 (s, 3H), 1·96 (s, 6H)· MS (M+l): 588.2 Less (Z) isomer ( Example 15): d 8.92 (dd, 1H), 8.45 (dd, 1H), 8·29 (d, 1H)? 8.07 (d? 1H), 7.99 (d5 2H)5 7.88 (s5 1H), 7.75 (m5 3H), 7.62 (s? 1H), 7.58 (q, 1H), 7.48 (t, 1H), 7.24 (d, 1H) 3.16 (s, 3H), 2·70 (s, 3H), 2.38 (s, 3H), 2.00 (s, 6H). MS (M+l): 588.2 Alternatively, Example 14 can be manufactured by the following procedure: -97- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297)公))--------#装--------订---------· (Please read the notes on the back and fill out this page) 128 0240 A7 B7 V. Description of invention (95)

NH2 甘油NH2 glycerol

ΑΓΒΝ NBS N〇2ΑΓΒΝ NBS N〇2

S02MeS02Me

Mel t-BuONaMel t-BuONa

(請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製(Please read the notes on the back and fill out this page.) Printed by the Consumer Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs.

-98- 本紙張尺度適用中國國家標準（CNS)A4規格（210 x 297公釐） 裝--------訂---------' 1280240 A7 B7 五、發明說明（96 步驟1. Skraup反應 甘油-98- This paper size is applicable to China National Standard (CNS) A4 specification (210 x 297 mm). Packing -------- set---------' 1280240 A7 B7 V. Description of invention ( 96 Step 1. Skraup reaction glycerol

(請先閱讀背面之注意事項再填寫本頁) 於甲烷磺酸（8-10當量）中，在2〇。〇下添加間-硝基笨磺酸 鈉（0.6-0.8當量），接著爲硫酸亞鐵七水合物（〇 〇1-〇 〇5當量）。 在所形成之混合物中添加2-溴基冰甲基苯胺（1當量）。 添加甘油（2-3當量），並將所形成之溶液在12〇_14〇〇c下加熱 ，及熟成直到反應完成爲止。 使混合物冷卻至70-90°C，並以水稀釋。然後，使溶液冷 卻至約20°C，並以NaOH水溶液及碳酸氫鈉中和。添加 MTBE (甲基第三-丁基醚），並將混合物過濾及分離液相（產 物係在MTBE層中）。 步驟2.溴化(Please read the notes on the back and fill out this page) In methanesulfonic acid (8-10 equivalents), at 2〇. Sodium-nitrosulphonate sodium (0.6-0.8 equivalents) was added under the sputum, followed by ferrous sulfate heptahydrate (〇 〇 1-〇 〇 5 equivalents). To the resulting mixture was added 2-bromo-milylmethylaniline (1 equivalent). Glycerol (2-3 equivalents) was added and the resulting solution was heated at 12 Torr to 14 ° C and cooked until the reaction was completed. The mixture was cooled to 70-90 ° C and diluted with water. Then, the solution was cooled to about 20 ° C and neutralized with an aqueous NaOH solution and sodium hydrogencarbonate. MTBE (methyl tert-butyl ether) was added and the mixture was filtered and separated (the product was in the MTBE layer). Step 2. Bromination

經濟部智慧財產局員工消費合作社印製Ministry of Economic Affairs, Intellectual Property Bureau, employee consumption cooperative, printing

AIBN NBS 使得自步驟1之MTBE溶液，經溶劑轉換成氯苯。經過石夕 月’過遽及邵份濃縮後，添加N_溴基琥珀醯亞胺（NBS，〇 6_〇 8 當量）與2,2'-偶氮雙異丁腈(AIBN，0.01-0.1當量）。將已脱氣 之混合物在55-85 C下加熱。將所形成之混合物以環己烷稀 -99- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 1280240 A7 ^-----E___ 玉、發明說明（97 ) (請先閱讀背面之注意事項再填寫本頁) 釋。添加其他NBS (0.3-0.5當量）與AIBN (0.01-0.05當量）。將已 脱氣之混合物在約55-85°C下加熱，直到反應完成爲止。使 混合物在10-40°C下冷卻，並以環己烷稀釋及熟成。藉過濾 分離固體。 步驟3·颯形成AIBN NBS converts the MTBE solution from Step 1 to chlorobenzene via solvent. After Shi Xiyue's over-concentration and concentration of Shao, add N-bromo amber succinimide (NBS, 〇6_〇8 equivalent) and 2,2'-azobisisobutyronitrile (AIBN, 0.01-0.1) equivalent). The degassed mixture was heated at 55-85 C. The resulting mixture is applied to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) on a cyclohexane-99-sheet scale. 1280240 A7 ^-----E___ Jade, invention description (97) (please Read the notes on the back and fill out this page. Add other NBS (0.3-0.5 equivalents) and AIBN (0.01-0.05 equivalents). The degassed mixture is heated at about 55-85 ° C until the reaction is complete. The mixture was allowed to cool at 10-40 ° C and diluted with cyclohexane and cooked. Separate the solids by filtration. Step 3 · Formation

於·/臭甲基-溴峻琳（得自前一步驟之產物，1當量）在DMF 中之溶液内，於10-60°C下添加粉末狀甲：)：完亞續酸鈉（1〇丄5 當量）。將混合物於約50-70°C下加熱30分鐘。將混合物以水 稀釋’同時保持溫度在約50-70χ：下，並激烈攪拌，然後冷 卻至約10-20°C，及熟成。將混合物過濾，並將固體相繼以i :4 DMF /水，然後以水洗滌，並乾燥。 步驟4·甲基化作用Add a powdery form of a powder in the solution of DMF-B-methyl-bromo-jun (product from the previous step, 1 equivalent) in DMF:): sodium sulfoxide (1〇)丄5 equivalents). The mixture was heated at about 50-70 ° C for 30 minutes. The mixture was diluted with water while maintaining the temperature at about 50-70 Torr: and vigorously stirred, then cooled to about 10-20 ° C, and cooked. The mixture was filtered and the solid was washed sequentially with i: 4 DMF / water then water and dried. Step 4·Methylation

經濟部智慧財產局員工消費合作社印製 使颯（前一步驟之產物，丨當量）在]〇1^1：中之溶液冷卻至約 40到（TC。添加第三-丁醇鈉（〜1當量）。慢慢添加碘化甲烷 /DMF溶液（〜1當量^〖），同時保持溫度在約]〇至下。 添加第二部份固體第三-丁醇鈉（〜1當量），接著添加碘化 -100- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 1280240The Ministry of Economic Affairs' Intellectual Property Office employee consumption cooperative printed the solution (the product of the previous step, 丨 equivalent) in the solution of 〇1^1: cooled to about 40 to (TC. Adding third-butyrol sodium (~1) Equivalent). Add methane iodide/DMF solution (~1 equivalent ^ 〖) slowly while keeping the temperature at about 〇. Add the second part of solid sodium tributoxide (~1 equivalent), then add Iodine-100- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1280240

B(OH)2B(OH)2

A7 五、發明說明（98 ) 甲烷/ DMF溶液（〜1當量），同時保持溫度在-5至1〇。〇下（若 ^應未完成，可添加另外之鹼與MeI)。藉由添加水使反應 洋滅，並使產物結晶，將其分離及乾燥。 步驟5· Suzuki偶合A7 V. INSTRUCTIONS (98) Methane/DMF solution (~1 equivalent) while maintaining the temperature at -5 to 1 Torr. Underarm (if ^ should not be completed, additional base and MeI can be added). The reaction was quenched by the addition of water, and the product was crystallized, separated and dried. Step 5 · Suzuki coupling

Pd/C 於得自則一步驟之砜（1當量）之溶液中，添加？(1/(：(5或1〇 重量％，0·005-0·1當量）、碳酸鉀（2_3當量）及3甲醯基苯基 爛fe酸（1-2當量）。將已脱氣之反應混合物在6(M2〇〇C下加熱 ’直到反應完成爲止。將混合物過濾，並將濾液以水稀釋 。使產物結晶，及藉過滤分離並乾、燥。 步驟6.哼二唑 (請先閱讀背面之注意事項再填寫本頁)Pd/C is added to a solution of the sulfone (1 equivalent) obtained in one step. (1/(: (5 or 1% by weight, 0·005-0·1 equivalent), potassium carbonate (2_3 equivalent) and 3-methylphenyl phenolic acid (1-2 equivalents). The reaction mixture is heated at 6 (M 2 〇〇 C until the reaction is completed. The mixture is filtered, and the filtrate is diluted with water. The product is crystallized, separated by filtration and dried and dried. Step 6. Oxadiazole (please Read the notes on the back and fill out this page.)

ΌΗΟ K2C03/DMF 80 CΌΗΟ K2C03/DMF 80 C

Me02SMe02S

OH 1. EDCTHOBt 2. 經濟部智慧財產局員工消費合作社印製 ho、n⑽人OH 1. EDCTHOBt 2. Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed ho, n (10) people

MeOgSMeOgS

H2N 於羥基苯幷三唑（nH〇Btn)水合物（M.5當量）、4-甲磺醯基 苯基醋酸（1當量）在乙腈中之混合物内，添加EDC鹽酸鹽（1-1·5當量）。使此漿液在約20-30°C下熟成30分鐘。 亦可使用其他N-0H化合物，譬如N-羥基鄰苯二甲醯亞胺 -101 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） J28〇24〇 A7 B7 五、 發明說明（99 ) 、2-羥基吡啶N-氧化物、斗羥基琥珀醯亞胺，以替代恥玫 。可使用其他碳化二亞胺，譬如二環己基碳化二亞胺與二 異丙基碳化二亞胺，以替代EDC鹽酸鹽（乙基二甲胺基丙基 碳化二亞胺鹽酸鹽）。 於此漿液中添加乙醯胺肘（1-L5當量）。然後，將所形成之 混合物於回流下加熱，直到反應完成爲止。使所形成之溶 液濃縮，並以醋酸乙酯稀釋。將所形成之混合物，以碳酸 氯鈉水落液洗滌。使此溶液經溶劑轉換成2-丙醇，產物係 在冷卻時結晶，使其分離並乾燥。 步驟7·縮合以形成實例μH2N is added to a mixture of hydroxybenzotriazole (nH〇Btn) hydrate (M. 5 equivalents), 4-methylsulfonylphenylacetic acid (1 equivalent) in acetonitrile, and EDC hydrochloride (1-1) · 5 equivalents). This slurry was aged at about 20-30 ° C for 30 minutes. Other N-0H compounds can also be used, such as N-hydroxyphthalimide-101. This paper scale is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) J28〇24〇A7 B7 V. Invention Description (99), 2-hydroxypyridine N-oxide, hydroxy hydroxy amber imine, in place of shame. Other carbodiimides such as dicyclohexylcarbodiimide and diisopropylcarbodiimide may be used in place of EDC hydrochloride (ethyldimethylaminopropylcarbodiimide hydrochloride). Acetylamine elbow (1-L5 equivalent) was added to the slurry. Then, the resulting mixture was heated under reflux until the reaction was completed. The resulting solution was concentrated and diluted with ethyl acetate. The resulting mixture was washed with aqueous sodium bicarbonate solution. This solution was converted to 2-propanol by a solvent, and the product was crystallized upon cooling, separated and dried. Step 7·Condensation to form an example μ

万；彳于自上文步驟5之醛當量）在孓丙醇中之漿液内，添 加侍自上文步驟6之吟二唑（1丄5當量），接著爲六氫吡啶 (0.2-1.5 當量）。 可以其他落劑替代2_丙醇，例如DMF、乙腈、1·丙醇、 甲苯、S曰類及其他醇類。六氫吡啶係充作鹼性引發劑。可 使用其他月女鹼’尤其是二級胺類，替代六氫吡啶。 ^------—t--------- (請先閱讀背面之注意事項再填寫本頁) 經 濟 部 智 慧 財 產 局 員 工 消 費 合 作 社 印 製In the slurry of propylene glycol, add the oxadiazole (1丄5 equivalent) from step 6 above, followed by the hexahydropyridine (0.2-1.5 equivalents). ). Other sinking agents can be substituted for 2-propanol, such as DMF, acetonitrile, propanol, toluene, sulfonium and other alcohols. Hexahydropyridine is used as a basic initiator. Other months of alkalinium, especially secondary amines, may be used in place of the hexahydropyridine. ^------—t--------- (Please read the notes on the back and fill out this page) Printed by the Ministry of Economic Affairs, Finance and Welfare Bureau

1280240 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（1〇〇 ) 使所形成之混合物，於分子篩上，在回流下加熱，直到 反應完成爲止。於冷卻後，藉過濾分離產物並乾燥。 實例16與17 (Ε/Ζ)-3-{3-[6-(1-氰基小甲基乙基)各峻琳基]苯基卜N-異丙基-2-[4-( 甲磺醯基）苯基]-2-丙晞醯胺1280240 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed A7 B7 V. INSTRUCTIONS (1〇〇) The resulting mixture is heated on a molecular sieve under reflux until the reaction is complete. After cooling, the product was isolated by filtration and dried. Examples 16 and 17 (Ε/Ζ)-3-{3-[6-(1-cyano small methylethyl) 峻 琳 ] ] phenyl phenyl N-isopropyl-2-[4-( A Sulfhydryl)phenyl]-2-propanolamine

實例16Example 16

-3-3

C _-103- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） --------------------訂--------- (請先閱讀背面之注意事項再填寫本頁) 1280240 A7 B7 五、發明說明（101 ) 實例17 實例16與17係按照前述實例14與15之程序製成，但以芳 基溴化物AB2取代AB5，及以溴基喹啉Q5取代Q3，作爲起 始物質。實例16與17係以4 : 1混合物獲得。 NMR 1 H (500MHz，丙酮-d6)主要（E)異構物（實例 16) : d 8.89 (dd，1H)，8.43 (dd，1H)，8.09 (d，1H)，7.90 (d，2H)，7.81 (d，1H)，7.68 (s，1H)， 7.57 (m，4H)，7·45 (s，1H)，7.29 (t，1H)，7.04 (d，1H)，6.71 (bd，1H)，4.13 (m， 1H) 2.92 (s，3H)，1.87 (s，6H)，1· 12 (d，6H). MS (M+l) ： 538.3 較少（Z)異構物（實例 17) : d 8.93 (dd，1H)，8.48 (dd，1H)，8.14 (d， 1H)，7.94 (m，4H)，7.85 (d，2H)，7.70 (dd，2H)，7.59 (q，1H)，7.50 (m，2H)， 7.28 (s，1H)，4.15 (m，1H) 3.13 (s，3H)，1.91 (s，6H)，1.04 (d，6H)· MS (M+l) ： 538.3 實例18 8-(3-{(E)-2-{3-[(4-甲氧基苯氧基）甲基 H，2,4-哼二唑-5-基}-2-[4-(甲 磺醯基）苯基]乙烯基}苯基）-6-[l-曱基-1-(甲磺醯基）乙基]喳啉 -----------裝—.-----訂--------- (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 -104- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 1280240C _-103- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) -------------------- Order----- ---- (Please read the note on the back and then fill out this page) 1280240 A7 B7 V. Description of Invention (101) Example 17 Examples 16 and 17 were prepared according to the procedures of Examples 14 and 15 above, but with aryl bromide Compound AB2 replaces AB5, and Q3 is substituted with bromoquinoline Q5 as a starting material. Examples 16 and 17 were obtained as a 4:1 mixture. NMR 1 H (500MHz, acetone-d6), the main (E) isomer (Example 16): d 8.89 (dd, 1H), 8.43 (dd, 1H), 8.09 (d, 1H), 7.90 (d, 2H) , 7.81 (d,1H), 7.68 (s,1H), 7.57 (m,4H),7·45 (s,1H), 7.29 (t,1H),7.04 (d,1H),6.71 (bd,1H) ), 4.13 (m, 1H) 2.92 (s, 3H), 1.87 (s, 6H), 1· 12 (d, 6H). MS (M+l): 538.3 Less (Z) isomer (Example 17) ) : d 8.93 (dd, 1H), 8.48 (dd, 1H), 8.14 (d, 1H), 7.94 (m, 4H), 7.85 (d, 2H), 7.70 (dd, 2H), 7.59 (q, 1H) ), 7.50 (m, 2H), 7.28 (s, 1H), 4.15 (m, 1H) 3.13 (s, 3H), 1.91 (s, 6H), 1.04 (d, 6H) · MS (M+l): 538.3 Example 18 8-(3-{(E)-2-{3-[(4-Methoxyphenoxy)methyl H,2,4-oxadiazol-5-yl}-2-[4 -(Methanesulfonyl)phenyl]vinyl}phenyl)-6-[l-fluorenyl-1-(methylsulfonyl)ethyl]porphyrin----------- —.-----订--------- (Please read the notes on the back and then fill out this page) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing -104- This paper scale applies to Chinese national standards (CNS) A4 size (210 X 297 mm) 1280240

五、發明說明（1〇2 )V. Description of the invention (1〇2)

(請先閲讀背面之注意事頊存填寫本頁) 裝 ο—ch3 經濟部智慧財產局員工消費合作社印製 實例18係藉下述程序製備。 步驟1 (圖式3) : (4-甲氧基苯氧基）乙腈 將4-甲氧基酚（10克，80毫莫耳）、氣乙腈（7·〇亳升，⑴ 莫耳）及A c〇3 (26克，188毫莫耳）在丙酮（15〇毫升）中之混 物，於室溫下攪拌18小時。將混合物過濾，濃縮，並藉 驟式層析純化（己燒：EtOAc4 : 1)，產生（4-甲氧基苯氧基) 月月，爲透明油。 步驟2 (圖式3) : (4-甲氧基苯氧基）乙醯胺月亏 將得自步驟1之（4-甲氧基苯氧基）乙腈產物（5〇克，31毫 耳）、羥胺鹽酸鹽（4·3克，62毫莫耳）及醋酸納（5 1克，Q 莫耳）在MeOH (1〇〇毫升）中之混合物，於室μ 、至/耻下攪拌2小 。將所形成之混合物於Celite®上過濾，濃哈 、λ 〜 版細，於CHC1，中 105- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） * ϋ n n 言 秦 經濟部智慧財產局員工消費合作社印制衣 !28〇240 A7 $、發明說明（103) 加18小時，及過濾。使所形成之溶液濃縮，產生（4-曱氧基 苯氧基）乙醯胺肟，爲膠質。 步驟3 (圖式3，嘮二唑〇χ2 ) : 3-[(4-甲氧基苯氧基）甲基]-5-[4-(甲續酿基）+基]-1,2,4-17号二峻 3-[(4-甲氧基苯氧基）甲基]-5·[4-(甲磺醯基）爷基]-1，2,4^号二唑 ，係按照圖式3關於ΑΒ5步驟1 (0X1)中所述之程序製成，但 以得自上文步驟2之（4-甲氧基苯氧基）乙醯胺肟取代乙醯胺 肟’並將此反應在90°C下加熱6小時。藉急驟式層析純化（ 己垸：EtOAc 3 : 2至1 ·· 4)產生所要之物質，爲淡褐色固體。 步驟4 : 3-{6-[1-甲基-1-(甲磺醯基）乙基]各喳啉基}苯甲醛 於澳基喹啉Q3 (10.1克，30.9毫莫耳）、3·甲醯基苯硼烷酸 (5.8克，38.7毫莫耳）、肆（三苯膦 &gt;鈀⑼(2丨克，186毫莫耳） 及碳酸鈉（39毫升，2M)中添加DME (330毫升）。於脱氣後， 將混合物在80 C下加熱過夜。於冷卻至室溫後，以％ 〇使 所形成之混合物泮滅，並以EtOAc萃取。將有機萃液洗條 (H2〇，鹽水），脱水乾燥（MgS〇4)，過濾及濃縮。在醚中攪 拌，接著藉過濾單離，獲得3-(6-^甲基·丨_(甲磺醯基）乙基]各 峻p林基}苯甲趁。 步驟5 : 8-(3·{(Ε)-2-{3-[(4-甲氧基苯氧基）甲基pm哼二唑_5_ 基}-2-[4-(甲磺醯基）苯基]乙晞基}苯基）各[丨―甲基小(甲磺醯基） 乙基 &gt;奎p林 將得自本步驟4之產物（150毫克，〇.42毫莫耳）、得自上文 本步驟3之呤二唑ΟΧ2(175毫克，〇·47毫莫耳）及六氫吡啶 (0.1笔升’ 1_0毫莫耳）在甲苯（〇 6毫升）中之混合物，於12〇。〇 -106- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -----------AWI --------^--------- (請先閱讀背面之注意事項再填寫本頁) 1280240 A7 ___B7___ 五、發明說明（1〇4 ) 下加熱3小時。將混合物藉急驟式層析純化（己烷：Et〇Ac 3 :2至1 : 4)，產生實例18，爲泡沐物。 NMR 1 H (400MHz，丙酮-d6) d 8·90 (q，1H)，8.42 (q，1H)，8.24 (d，1H)， 8·20 (s，1H)，8·02 (m5 3H)，7.75-7.66 (m，4H)，7·55 (q，1H)，7.39 (t，1H)，7.25 (d，1H)，7.00 (d，2H)，6·87 (d，2H) 5.17 (s，2H)，3.73 (s，3H)，3.03 (s，3H)，2.80 (s，3H)，1·96 (s，6H)· 實例19 (5-{(Ε)-2-(3-{6-[1-甲基-1-(甲續驢基）乙基]_8^奎琳基）苯基）小[4-( 甲續SS基）苯基]乙晞基卜1，2,4』号二峻-3-基）甲醇 (請先閱讀背面之注意事項再填寫本頁)(Please read the note on the back and fill in this page) Install ο—ch3 Printed by the Intellectual Property Office of the Ministry of Economic Affairs. Employees of the Consumer Cooperatives Example 18 is prepared by the following procedure. Step 1 (Scheme 3): (4-Methoxyphenoxy)acetonitrile 4-methoxyphenol (10 g, 80 mmol), gas acetonitrile (7·m, (1) mol) A mixture of A c 3 (26 g, 188 mmol) in acetone (15 mL) was stirred at room temperature for 18 hours. The mixture was filtered, concentrated and purified by flash chromatography (EtOAc:EtOAc:EtOAc Step 2 (Scheme 3): (4-Methoxyphenoxy)acetamide The monthly loss will be obtained from the (4-methoxyphenoxy)acetonitrile product of Step 1 (5 gram, 31 mils) a mixture of hydroxylamine hydrochloride (4.3 g, 62 mmol) and sodium acetate (51 g, Q Mo) in MeOH (1 mL), stirred at room μ, to/shame 2 small. The resulting mixture is filtered on Celite®, concentrated, λ ~ version fine, in CHC1, medium 105- This paper scale applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) * ϋ nn 言 秦 economy Department of Intellectual Property Bureau employee consumption cooperative printed clothing! 28〇240 A7 $, invention description (103) plus 18 hours, and filtration. The resulting solution was concentrated to give (4-decyloxyphenoxy)acetamidamine as a gum. Step 3 (Formula 3, oxadiazolidine 2): 3-[(4-Methoxyphenoxy)methyl]-5-[4-(methyl aryl)+yl]-1,2, 4-17 Dijun 3-[(4-methoxyphenoxy)methyl]-5·[4-(methylsulfonyl)-yl]-1,2,4^ diazole, according to Scheme 3 is prepared for the procedure described in ΑΒ5, Step 1 (0X1), but with (4-methoxyphenoxy)acetamidamine oxime substituted for acetamidine oxime' and The reaction was heated at 90 ° C for 6 hours. Purification by flash chromatography (hexanes: EtOAc (3:2 to EtOAc) Step 4: 3-{6-[1-Methyl-1-(methylsulfonyl)ethyl]polyporphyrin}benzaldehyde to alkylquinoline Q3 (10.1 g, 30.9 mmol), 3· Add DME (330) to formazan phenylboronic acid (5.8 g, 38.7 mmol), hydrazine (triphenylphosphine) palladium (9) (2 g, 186 mmol) and sodium carbonate (39 ml, 2 M) After the degassing, the mixture was heated at 80 C overnight. After cooling to room temperature, the resulting mixture was quenched with EtOAc and extracted with EtOAc. Brine), dehydrated and dried (MgS〇4), filtered and concentrated. Stirred in ether, followed by filtration to obtain 3-(6-^methyl·丨_(methylsulfonyl)ethyl] Benki} Benzopyrene. Step 5: 8-(3·{(Ε)-2-{3-[(4-Methoxyphenoxy)methyl pm oxadiazole _5_ yl}-2-[ 4-(Methanesulfonyl)phenyl]ethinyl}phenyl) Each [丨-methyl small (methylsulfonyl) ethyl group > quinine will be obtained from the product of step 4 (150 mg, 42.42 millimolar), obtained from the text of step 3 of oxadiazol 2 (175 mg, 〇·47 mmol) and hexahydropyridine (0.1 liters '1_0 mmol) in A Mixture (〇6 ml) at 12〇.〇-106- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) -----------AWI -- ------^--------- (Please read the notes on the back and fill out this page) 1280240 A7 ___B7___ V. Invention instructions (1〇4) Heat for 3 hours. Purification by chromatography (hexane: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc: (q, 1H), 8.24 (d, 1H), 8·20 (s, 1H), 8·02 (m5 3H), 7.75-7.66 (m, 4H), 7·55 (q, 1H), 7.39 ( t,1H), 7.25 (d,1H), 7.00 (d,2H),6·87 (d,2H) 5.17 (s,2H),3.73 (s,3H),3.03 (s,3H),2.80 ( s,3H),1·96 (s,6H)·Example 19 (5-{(Ε)-2-(3-{6-[1-methyl-1-(methyl)methyl)ethyl]_8 ^ 奎琳基)Phenyl) small [4-(methyl-S-benzyl) phenyl] acetyl sulfonyl 1,2,4, yttrium-3-yl)methanol (please read the notes on the back and fill in again) This page)

貫例19係耠下述程序製備。於實例18化合物（25〇毫克， 0.35笔莫耳）在乙腈：水（4 ·· 1，8毫升）中之溶液内，於室溫 下，以兩邵份添加CAN (330毫克，0.62毫莫耳）。於室溫下3 小時後，將混合物以飽和NaHC〇3溶液稀釋，以水稀釋，並 以EtOAc萃取。將有機萃液洗滌〇)(鹽水），脱水乾燥 (MgS〇4) ’過濾、及濃縮。藉急驟式層析純化（己坑：Et〇Ac 3 經濟部智慧財產局員工消費合作社印製 I _；_ -107- 本紙張尺度適用中國國家標準（CNS)A4規格（21G X 297公爱) 經濟部智慧財產局員工消費合作社印製 !28〇240 A7 -^- __B7 五、發明說明（1〇5 ) :7)產生（5-{(Ε)-2-(3-{6-[1-甲基小(甲磺醯基）乙基]-8_喹啉基}苯 基）-1-[4-(甲橫醯基）苯基]乙晞基}-1，2,4-$二唆-3-基）甲醇，爲 淡黃色泡沐物。 NMR 1 H (400MHz，丙酮-d6) β 8.90 (q，1H)，8.42 (q5 1H)，8.25 (d，1H)， 8.15 (s，1H)，8.02 (m，3H)，7.73-7.65 (m，4Η)，7·55 (q，1H)，7.38 (t，1H)，7.23 (d5 1HX 4.67 (m5 3H)5 3.04 (s? 3H)5 2.82 (s5 3H)5 L96 (s, 6H). 實例20 (Ε)-Ν-異丙基-3-(3-{6-[l-甲基小(甲磺醯基）乙基]各喹啉基}苯基）-2-[4-(曱磺醯基）苯基]-2-丙烯醯胺Example 19 was prepared by the following procedure. In a solution of the compound of Example 18 (25 mg, 0.35 mol) in acetonitrile:water (4··1,8 mL), add CAN (330 mg, 0.62 mmol) in two portions at room temperature. ear). After 3 hours at room temperature, the mixture was diluted with EtOAc EtOAc EtOAc. The organic extract was washed (salt), dehydrated (MgS 4) filtered, and concentrated. Purification by flash chromatography (Hit pit: Et〇Ac 3 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing I _; _ -107- This paper scale applies China National Standard (CNS) A4 specification (21G X 297 public) Printed by the Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative! 28〇240 A7 -^- __B7 V. Invention description (1〇5) :7) Generation (5-{(Ε)-2-(3-{6-[1 -Methyl small (methanesulfonyl)ethyl]-8_quinolinyl}phenyl)-1-[4-(methylcyano)phenyl]ethenyl}-1,2,4-$ Di-n--3-yl)methanol is a pale yellow foam. NMR 1 H (400MHz, acetone-d6) β 8.90 (q,1H), 8.42 (q5 1H), 8.25 (d,1H), 8.15 (s,1H), 8.02 (m,3H), 7.73-7.65 (m , 4Η),7·55 (q,1H), 7.38 (t,1H), 7.23 (d5 1HX 4.67 (m5 3H)5 3.04 (s? 3H)5 2.82 (s5 3H)5 L96 (s, 6H). Example 20 (Ε)-Ν-Isopropyl-3-(3-{6-[l-methylsuccinyl)ethyl]quinolinyl}phenyl)-2-[4-( Sulfonyl)phenyl]-2-propenylamine

實例20係按照上文關於實例14與15所述之程序製成，但 以芳基溴化物AB2取代AB5，並使用溴基喹啉Q3作爲起始 物質。 NMR 1 H (300MHz，丙酮-d6) d 8·89 (dd，1H)，8.41 (dd，1H)，8.22 (d，1H) 7.99 (d，1H)，7.88 (d，2H)，7.67 (s，1H)，7.53 (m，4H)，7.43 (s，1H)，7·28 (t，1H) 7.05 (d, 1H)5 6.71 (bd5 1H)? 4.14 (m, 1H), 2.9 (s, 3H), 1.95 (s, 6H), 1.13 (d5 6H) ___ - 108-_ ^ 本紙張尺度適用中國國家標準（CNS)A4規格（210 x 297公釐） ' -----------Φ裝--------訂---------^9 (請先閱讀背面之注音？事項再填寫本頁) 1280240 A7B7 1、發明說明（106 ) MS(M+1)： 591.3 實例21 (Ε)-3-{3-[6-(1-氣基-1-曱基乙基）-8-峻p林基]苯基}-2-[4-(甲續醯基） 苯基]-2-丙烯酸Example 20 was prepared according to the procedures described above for Examples 14 and 15, except that AB5 was substituted with aryl bromide AB2 and bromoquinoline Q3 was used as starting material. NMR 1 H (300MHz, acetone-d6) d 8·89 (dd, 1H), 8.41 (dd, 1H), 8.22 (d, 1H) 7.99 (d, 1H), 7.88 (d, 2H), 7.67 (s ,1H),7.53 (m,4H),7.43 (s,1H),7·28 (t,1H) 7.05 (d, 1H)5 6.71 (bd5 1H)? 4.14 (m, 1H), 2.9 (s, 3H), 1.95 (s, 6H), 1.13 (d5 6H) ___ - 108-_ ^ This paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) ' --------- --Φ装--------Book---------^9 (Please read the phonetic on the back? Please fill out this page again) 1280240 A7B7 1, invention description (106) MS (M +1): 591.3 Example 21 (Ε)-3-{3-[6-(1-carbyl-1-mercaptoethyl)-8-jun p-linyl]phenyl}-2-[4-( A phenyl]-2-acrylic acid

(請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 實例21係按照上文關於實例14與15所述之程序製成，但 以芳基澳化物AB1取代AB5，及以漢基峻淋Q5取代Q3作爲 起始物質。 NMR 1 H (500MHz，甲醇）8.8 (dd，1H)，8.38 (dd，1H)，8.04 (d，2H)， 7.88 (d，2H)，7.66 (d，1H)，7.55 (m，4H)，7.36 (t，1H)，7.29 (s，1H)，7.18 (d，1H)， 2.93 (s, 3H)5 1.88 (s, 6H). MS (M-C02) ·· 451.4 (陰離子）。 實例22 2-甲基-2-[8-(3-{(E)-2-(3-甲基-1,2,4-哼二唑-5-基）-2-[4-(甲磺醯基）苯 基]乙烯基}苯基）-6-4啉基]丙腈 · -109- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱） --------訂-------I 1 AW1 - 128〇24〇(Please read the note on the back and then fill out this page.) Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperative Printed Example 21 is made according to the procedures described above for Examples 14 and 15, but replaces AB5 with aryl ABC AB1. And replace the Q3 with Hanji Junlin Q5 as the starting material. NMR 1 H (500MHz, methanol) 8.8 (dd, 1H), 8.38 (dd, 1H), 8.04 (d, 2H), 7.88 (d, 2H), 7.66 (d, 1H), 7.55 (m, 4H), 7.36 (t, 1H), 7.29 (s, 1H), 7.18 (d, 1H), 2.93 (s, 3H) 5 1.88 (s, 6H). MS (M-C02) · · 451.4 (anion). Example 22 2-Methyl-2-[8-(3-{(E)-2-(3-methyl-1,2,4-oxadiazol-5-yl)-2-[4-(A Sulfhydryl)phenyl]vinyl}phenyl)-6-4olinyl]propanenitrile· -109- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public) ----- ---Order-------I 1 AW1 - 128〇24〇

實例22係按照實例14與15所述之程序製成，使用芳基溴 化物AB5，及以溴基，奎啉q5取代⑺作爲起始物質。 NMR 1 H (500MHz ’ 丙 @同-d6) d 8·90 (dd，1H)，8.43 (dd，1H)，8.1(d，2H)， 8.01 (d，2H)，7.83 (d5 1H)，7·71 (t3H)，7.66 (s，1H)，7.56 (q，1H)，7.55 (dd，1H)， 7.38 (t，1H)，7.22 (d，1H)，3.03 (s，3H)，2.33 (s，3H)，1.87 (s5 6H) MS (M+l) ： 535.2 實例23 (E)-3-{3-[6-(l-氧基-1-甲基乙基奎林基]苯基}_2-[4-(甲確酿基） ^--------訂--------- (請先閱讀背面之注音？事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 苯基]-2-丙晞g蠢胺Example 22 was prepared according to the procedures described in Examples 14 and 15 using aryl bromide AB5 and substituting (7) with bromo and quinolin. NMR 1 H (500 MHz ' 丙 @同-d6) d 8·90 (dd, 1H), 8.43 (dd, 1H), 8.1 (d, 2H), 8.01 (d, 2H), 7.83 (d5 1H), 7 · 71 (t3H), 7.66 (s, 1H), 7.56 (q, 1H), 7.55 (dd, 1H), 7.38 (t, 1H), 7.22 (d, 1H), 3.03 (s, 3H), 2.33 ( s,3H), 1.87 (s5 6H) MS (M+l): 535.2 Example 23 (E)-3-{3-[6-(l-oxy-1-methylethyl quinolinyl)phenyl }_2-[4-(甲确酒) ^--------Book--------- (Please read the phonetic on the back? Please fill out this page again) Ministry of Economic Affairs Intellectual Property Bureau Employee consumption cooperative printed phenyl]-2-propanoid g stupid amine

-110- ^紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 1280240 A7 經濟部智慧財產局員工消費合作社印製 五、發明說明（1〇8 ) 實例23係按照上文關於實例14與I5所述之程序製成，俨 以芳基溴化物AB3取代AB5，及以溴基喳啉q5取代奶作爲 起始物質，獲得標題化合物。 NMR 1 H (500MHz，丙酮-d6) d 8.89 (dd，1H)，8·43 (dd，1H)，8 08 (d 1H)，7·93 (d，2H)，7.8 (d，2H)，7·6 (m，4H)，7·48 (s，1H), 7·31 (t，1H)，7·08 (d 1H)，6·6 (bs，1H)，6.7 (bs，1H)，2·93 (s，3H)，1·87 (s，6H) 實例24 (E)-N-(第三-丁基）-3-{3-[6-(l-氰基-1-甲基乙基）-8-查啉基]笨基卜2-[4-(甲續醯基）苯基]-2-丙烯醯胺-110-^The paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1280240 A7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (1〇8) Example 23 is based on the above The procedure described in Example 14 and I5 was carried out by substituting aryl bromide AB3 for AB5 and bromo porphyrin q5 for the starting material to give the title compound. NMR 1 H (500MHz, acetone-d6) d 8.89 (dd, 1H), 8·43 (dd, 1H), 8 08 (d 1H), 7·93 (d, 2H), 7.8 (d, 2H), 7·6 (m,4H),7·48 (s,1H), 7·31 (t,1H),7·08 (d 1H),6·6 (bs,1H),6.7 (bs,1H) , 2·93 (s, 3H), 1·87 (s, 6H) Example 24 (E)-N-(T-butyl)-3-{3-[6-(l-cyano-1- Methyl ethyl)-8-chaolinyl] stupid 2-[4-(methylsulfonyl)phenyl]-2-propenylamine

YCCHH3 實例24係按照實例14與15所述之程序製成，但以芳基溴 化物AB4取代AB5，及以溴基4啉Q5取代Q3作爲起始物質。 NMR 1 H (500MHz，丙酮-d6) d 8.89 (dd，1H)，8·43 (dd，1H)，8·08 (d， 1H)，7.92 (d，2H)，7.79 (d，1H)，7.58 (m，5H)，7.45 (s，1H)，7.29 (t，1H)，7.04 (d， 1H)，6.4 (bs，1H)，2.93 (s，3H)，1.87 (s，6H)，1.36 (s，9H)· MS (M+l) 553. -111 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ------------裝--------訂--------- (請先閱讀背面之注意事項再填寫本頁) 1280240 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（109 ) 實例25 (EXH3-(6-異丙基-8-喹啉基）苯基]-2-[4-(甲磺醯基）苯基：R-丙烯酸 CH,YCCHH3 Example 24 was prepared according to the procedures described in Examples 14 and 15 except that the aryl bromide AB4 was substituted for AB5 and the bromo 4 phenyl group Q5 was substituted for Q3. NMR 1 H (500MHz, acetone-d6) d 8.89 (dd, 1H), 8·43 (dd, 1H), 8·08 (d, 1H), 7.92 (d, 2H), 7.79 (d, 1H), 7.58 (m, 5H), 7.45 (s, 1H), 7.29 (t, 1H), 7.04 (d, 1H), 6.4 (bs, 1H), 2.93 (s, 3H), 1.87 (s, 6H), 1.36 (s, 9H)· MS (M+l) 553. -111 - This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) ------------ -------Book--------- (Please read the notes on the back and fill out this page) 1280240 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Print A7 B7 V. Inventions (109) Example 25 (EXH3-(6-isopropyl-8-quinolinyl)phenyl]-2-[4-(methylsulfonyl)phenyl: R-acrylic acid CH,

實例25係按照實例14與15所述之程序製成，但以芳基溴 化物AB1取代AB5，及以5-異丙基-8-溴基喹啉（描述於國際專 利公告WO 9422852中）取代Q3作爲起始物質。 NMR 1 H (500MHz，丙酮 Λ) d 8·69 (dd5 1H)，8·26 (dd5 1H)，7·85 (s， 1H)，7.83 (d5 2H)，7.68 (s，1H)，7·51 (d，2H)，7.49 (m，2H)，7.36 (dd，1H)，7.31 (t，1H)，7.20 (s，1H)，7.13 (d，lH)，3.1 (m，1H)，2.93 (s，3H)，1.36 (d，6H). MS (M+l)472. 實例26 6-異丙基-8-(3-{(E)-2-(3-甲基-1，2,4-呤二唑-5·基）-2-[4-(甲磺醯基）苯 基]乙烯基}苯基 &gt;奎啉 -112- 本紙張尺度適用中國國家標準（CNS)A4規格（210 x 297公爱） 裝--------訂--------- (請先閱讀背面之注意事項再填寫本頁) 1280240 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（110 ) CH,Example 25 was prepared according to the procedures described in Examples 14 and 15, but substituting aryl bromide AB1 for AB5 and 5-isopropyl-8-bromoquinoline (described in International Patent Publication WO 9422852). Q3 is used as the starting material. NMR 1 H (500MHz, acetone oxime) d 8·69 (dd5 1H), 8·26 (dd5 1H), 7.85 (s, 1H), 7.83 (d5 2H), 7.68 (s, 1H), 7· 51 (d, 2H), 7.49 (m, 2H), 7.36 (dd, 1H), 7.31 (t, 1H), 7.20 (s, 1H), 7.13 (d, lH), 3.1 (m, 1H), 2.93 (s, 3H), 1.36 (d, 6H). MS (M+l) 472. Example 26 6-isopropyl-8-(3-{(E)-2-(3-methyl-1,2 , 4-oxadiazol-5-yl)-2-[4-(methylsulfonyl)phenyl]vinyl}phenyl&gt; quinolin-112- This paper scale applies to China National Standard (CNS) A4 specification (210 x 297 public) Install--------Book--------- (Please read the notes on the back and fill out this page) 1280240 Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative A7 B7 V. Description of invention (110) CH,

實例26係按照實例14與15所述之程序製成，使用芳基溴 化物AB5，及以5-異丙基-8-溴基喳啉（描述於國際專利公告 WO 9422852中）取代Q3作爲起始物質。 NMR 1 H (500MHz，丙酮-d6) β 8.80 (dd，1H)，8.29 (dd，1H)，8.12 (s， 1H)，8.03 (d，2H)，7.76 (s，1H)，7.73 (m，3H)，7.59 (s，1H)，7·53 (d，1H), 7·47 (q， 1H)，7.36 (t，lH)，7.22 (d，1H)，3.1 (m，1H)，2.93 (s，3H)，2.33 (s5 3H)，1.36 (d， 6H). MS (M+l)510. 實例27 (E)-3-(3-{6-[l-甲基小(甲磺醯基）乙基]各喳啉基}苯基）-2-[4-(甲磺 醯基）苯基]小(1-四氫吡咯基）-2-丙烯小酮 -113- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -----------裝--------訂---------^9« (請先閱讀背面之注意事項再填寫本頁) 1280240 經濟部智慧財產局員工消費合作社印制衣 A7 ___B7 五、發明說明（111 )Example 26 was prepared according to the procedures described in Examples 14 and 15 using aryl bromide AB5 and 5-isopropyl-8-bromoporphyrin (described in International Patent Publication WO 9422852) instead of Q3. Starting material. NMR 1 H (500MHz, acetone-d6) β 8.80 (dd, 1H), 8.29 (dd, 1H), 8.12 (s, 1H), 8.03 (d, 2H), 7.76 (s, 1H), 7.73 (m, 3H), 7.59 (s, 1H), 7·53 (d, 1H), 7·47 (q, 1H), 7.36 (t, lH), 7.22 (d, 1H), 3.1 (m, 1H), 2.93 (s, 3H), 2.33 (s5 3H), 1.36 (d, 6H). MS (M+l) 510. Example 27 (E)-3-(3-{6-[l-methyl small (methane) Mercapto)ethyl]polyporphyrin}phenyl)-2-[4-(methylsulfonyl)phenyl]small (1-tetrahydropyrrolyl)-2-propene ketone-113- paper scale Applicable to China National Standard (CNS) A4 specification (210 X 297 mm) -----------Install--------Set---------^9« ( Please read the notes on the back and fill out this page. 1280240 Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumer Cooperatives, Printed Clothes, A7 ___B7 V. Inventions (111)

實例27係藉下述程序製備。 步驟1 ·· (Ε)-3-(3-{6_[1-甲基-i-(甲磺醯基）乙基]如奎啉基）苯基 )-2-[4-(甲績酿基）苯基]-2-丙晞酸 使得自實例18步驟4之3-{6-[1-曱基小(甲磺醯基）乙基]各喳 啉基}苯甲醛（2.33克，6.60毫莫耳）、4-(甲磺醯基）苯基醋酸 (1.71克，7.98毫莫耳）及六氫吡啶（〇·2〇毫升，ι·98毫莫耳）在 10毫升甲苯中之混合物，回流2天。使混合物冷卻至室溫 ，以CH2C12稀釋，使其接受急驟式層析（CH2Cl2/EtOAc/AcOH 5〇/5〇Π)，及最後與（Et2 0/CH2 Cl2) —起攪拌，並分離而得（E)_3_ (3-{6-[l-甲基-1-(甲績8¾基）乙基]-8-»Ί林基}苯基）-2-[4-(甲績8¾基） 苯基]-2-丙晞酸（單一異構物），爲白色固體。 NMR 1 H (400MHz，丙酮-d6) : d 8·89 (dd，1H)，8.39 (dd，1H)，8.07 (d, 1H), 8.03 (d, 2H), 7.94 (s, 1H), 7.86 (d, 1H), 7.71-7.68 (m, 3H), 7.62-7.60 (m5 2H), 7.55 (dd, 1H)? 7.45 (s, 1H), 7.34 (t, 1H), 7.18 (d, 1H), 4.67 (q, 1H), 3·04 (s，3H)，2.86 (s，3H)，1.88 (s，3H). -114- 本紙張尺度適用中國國家標準（CNS)A4規格（210 x 297公爱） -----------裝--------訂--------- (請先閱讀背面之注意事項再填寫本頁) 1280240 A7Example 27 was prepared by the following procedure. Step 1 ··(Ε)-3-(3-{6_[1-Methyl-i-(methylsulfonyl)ethyl]] quinolyl)phenyl)-2-[4-( Phenyl]-2-propanoic acid afforded 3-{6-[1-mercaptosuccinyl(methylsulfonyl)ethyl]pyridinyl}benzaldehyde (Step 3.30, 6.60). Mixture of millimolar, 4-(methylsulfonyl)phenylacetic acid (1.71 g, 7.98 mmol) and hexahydropyridine (〇·2 mL, ι·98 mmol) in 10 mL of toluene , reflux for 2 days. The mixture was cooled to room temperature, diluted with CH.sub.2Cl.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub. (E)_3_ (3-{6-[l-methyl-1-(methyl)83⁄4yl)ethyl]-8-»Ί林基}phenyl)-2-[4-(甲绩83⁄4基) Phenyl]-2-propanoic acid (single isomer) as a white solid. NMR 1 H (400MHz, acetone-d6): d 8·89 (dd, 1H), 8.39 (dd, 1H), 8.07 (d, 1H), 8.03 (d, 2H), 7.94 (s, 1H), 7.86 (d, 1H), 7.71-7.68 (m, 3H), 7.62-7.60 (m5 2H), 7.55 (dd, 1H)? 7.45 (s, 1H), 7.34 (t, 1H), 7.18 (d, 1H) , 4.67 (q, 1H), 3·04 (s, 3H), 2.86 (s, 3H), 1.88 (s, 3H). -114- This paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297) Public love) -----------Install--------Book--------- (Please read the notes on the back and fill out this page) 1280240 A7

五、發明說明（112) 經濟部智慧財產局員工消費合作社印製 MS (M+1) 576. 步驟2 : (Ε)-3-(3-{6-[1·甲基-1-(甲磺醯基）乙基]各喳啉基）苯基 )-2-[4-(甲磺醯基）苯基]小(1·四氫吡咯基）-2-丙烯+酮 將得自上文本步驟1之(Ε)-3_(3-{6-[1-曱基-1-(甲磺醯基）乙基&gt; 8-口套淋基}苯基）-2·[4-(甲續醯基）苯基]-2-丙烯酸（1〇4毫克，〇 19 毫莫耳）、四氫吡咯（24微升，0.29毫莫耳）、EDCI (1-(3-二甲 胺基丙基）-3-乙基碳化二亞胺鹽酸鹽）(55毫克，〇·29毫莫耳） 及HOBt (1-羥基苯幷三唑水合物）(34毫克，0.25毫莫耳）在1毫 升DMF中之混合物，於室溫下攪拌12小時。將混合物以 EtOAc稀釋，以NH4C1 (飽和）、H20(3x)、鹽水洗滌，以 Na〕SO*脱水乾燥’過濾、及濃縮。於EtOAc /己燒中攪拌，產 生實例27，爲白色固體。 NMR 1 H (400MHz，丙酮-d6) ·· d 8·88 (dd，1H)，8.40 (dd，1H)，8.22 (d， 1H)，8.98 (d，1H)，7.88 (d，2H)，7·67 (d，2Η)，7·60 (d，1H)，7.55-7.52 (m，2H)， 7.34 (t，1H)，7·18 (d，1H)，7.03 (bs，NH)，3.58 (bs，2H)，3.44 (bs，2H)，3.02 (s， 3H)，2.69 (s，3H)，1.95 (s，6H)，1.88 (bs，4H)· MS (M+l) 603. 實例28 (E)-N-環丙基-3-(3-{6-[l-甲基-1-(甲續醯基）乙基]-8-p查淋基}苯基 )2-[4-(甲磺醯基）苯基]-2-丙烯醯胺 -115- -----------裝·-------訂--------- (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 40 02 8 12V. INSTRUCTIONS (112) Ministry of Economic Affairs Intellectual Property Office Staff Consumption Cooperative Print MS (M+1) 576. Step 2: (Ε)-3-(3-{6-[1·Methyl-1-(A) Sulfomethyl)ethyl]pyridolinyl)phenyl)-2-[4-(methylsulfonyl)phenyl]small (1·tetrahydropyrrolyl)-2-propene+one will be obtained from the above text. Step 1 (Ε)-3_(3-{6-[1-mercapto-1-(methylsulfonyl)ethyl&gt; 8-ported lyophile}phenyl)-2·[4-(A Further thiol) phenyl]-2-acrylic acid (1〇4 mg, 〇19 mmol), tetrahydropyrrole (24 μL, 0.29 mmol), EDCI (1-(3-dimethylaminopropyl) Base)-3-ethylcarbodiimide hydrochloride) (55 mg, 〇·29 mmol) and HOBt (1-hydroxybenzotriazole hydrate) (34 mg, 0.25 mmol) in 1 The mixture in ML DMF was stirred at room temperature for 12 hours. The mixture was diluted with EtOAc, EtOAc (EtOAc)EtOAc. Stirring on EtOAc / hexanes gave Example 27 as a white solid. NMR 1 H (400MHz, acetone-d6) ·· d 8·88 (dd,1H), 8.40 (dd,1H), 8.22 (d, 1H), 8.98 (d,1H), 7.88 (d,2H), 7·67 (d, 2Η), 7·60 (d, 1H), 7.55-7.52 (m, 2H), 7.34 (t, 1H), 7.18 (d, 1H), 7.03 (bs, NH), 3.58 (bs, 2H), 3.44 (bs, 2H), 3.02 (s, 3H), 2.69 (s, 3H), 1.95 (s, 6H), 1.88 (bs, 4H)· MS (M+l) 603. Example 28 (E)-N-Cyclopropyl-3-(3-{6-[l-methyl-1-(methylsulfonyl)ethyl]-8-p-chalcyl}phenyl)2- [4-(Methanesulfonyl)phenyl]-2-propenylamine-115- -----------Package·-------Set-------- - (Please read the notes on the back and fill out this page.) This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 40 02 8 12

7 I A I 五、 發明說明（113)7 I A I V. Description of invention (113)

(請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印制衣 實例28係按照實例27步驟2之程序製成，但以環丙胺取代 四氫吡咯，因此產生白色固體。 NMR 1 H (400MHz，丙酮-d6) : d 8.89 (dd，1H)，8.41 (dd，1H)，8.23 (d， 1H)，7·98 (d，1H)，7.87 (d，2H)，7·68 (s，1H)，7.59-7.53 (m，4H)，7.43 (s，1H)， 7.29 (t5 1H)5 7.04 (d5 1H), 6.94 (bs5 1H), 2.89 (s53H)5 2.84-2.80 (m, 1H), 2.69 (s, 3H)，1.96 (s，6H)，0.67-0.63 (m，2H)，0.49-0.45 (m5 2H)· MS (M+l) 589. 實例29 (E)-N-(第三-丁基ΚΗ3-{6-[1-甲基-1-(曱磺醯基）乙基]各峻啉基} 苯基）-2-[4-(甲磺醯基）苯基]-2-丙晞醯胺 -116- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 裝·-------訂--------- 1280240 A7 B7 五、 發明說明（114 )(Please read the notes on the back and fill out this page.) Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed Garment Example 28 is made according to the procedure of Example 27, Step 2, but replaces tetrahydropyrrole with cyclopropylamine, thus producing a white solid. . NMR 1 H (400MHz, acetone-d6): d 8.89 (dd, 1H), 8.41 (dd, 1H), 8.23 (d, 1H), 7·98 (d, 1H), 7.87 (d, 2H), 7 ·68 (s,1H), 7.59-7.53 (m,4H), 7.43 (s,1H), 7.29 (t5 1H)5 7.04 (d5 1H), 6.94 (bs5 1H), 2.89 (s53H)5 2.84-2.80 (m, 1H), 2.69 (s, 3H), 1.96 (s, 6H), 0.67-0.63 (m, 2H), 0.49-0.45 (m5 2H)· MS (M+l) 589. Example 29 (E) -N-(tris-butylphosphonium 3-{6-[1-methyl-1-(indolyl)ethyl]perramyl}phenyl)-2-[4-(methylsulfonyl) )Phenyl]-2-propanolamine-116- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) Packing·-------Set------- -- 1280240 A7 B7 V. Description of invention (114 )

,CH3 Ό N^CH3 丫&quot;CH3 實例29爲白色固體，其係按照實例27步驟2之程序製成， 但以弟二-丁基胺取代四氮P比洛。 NMR 1 H (400MHz，丙酮-d6) : 6 8.89 (dd，1H)，8.41 (dd，1H)，8.23 (d, 1H)，7.98 (d，1H)，7.90 (d，2H)，7.59-7.53 (m，5H)，7.43 (s，1H)，7.30 (t，1H)， 7.0 (d5 1H)，6.43 (bs，1H)，2.94 (s，3H)，2·69 (s，3H)，1.96 (s，6H)，1.36 (s，9H) MS (M+l) 606. 實例30 8-{3-[2,2-雙（4-氯苯基）乙晞基]苯基}-6-異丙基喹啉 ------------•裝 i.------訂---------« (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 CH,, CH3 Ό N^CH3 丫 &quot;CH3 Example 29 is a white solid which was prepared according to the procedure of Step 2 of Example 27, but substituting di-n-butylamine to tetra-nitro-P. NMR 1 H (400MHz, acetone-d6): 6 8.89 (dd, 1H), 8.41 (dd, 1H), 8.23 (d, 1H), 7.98 (d, 1H), 7.90 (d, 2H), 7.59-7.53 (m,5H), 7.43 (s,1H), 7.30 (t,1H), 7.0 (d5 1H), 6.43 (bs,1H), 2.94 (s,3H),2·69 (s,3H),1.96 (s, 6H), 1.36 (s, 9H) MS (M+l) 606. Example 30 8-{3-[2,2-bis(4-chlorophenyl)ethinyl]phenyl}-6- Isopropylquinoline------------•装i.------订---------« (Please read the notes on the back and fill out this page The Ministry of Economic Affairs’ Intellectual Property Office employee consumption cooperative prints CH,

1280240 A71280240 A7

五、發明說明（115 ) 實例30係藉下述程序製備。於芊基膦酸酯p2(i〇〇毫克， 0·25耄莫耳）、4,4’-二氣二苯甲酮（63毫克，〇·25毫莫耳）在 THF (2耄升）中之混合物内，於室溫下添加第三_ 丁醇鉀ο% ’ THF ’ 0.35當升’ 〇·35毫莫耳）。於室溫下1小時後，將混 合物以水/ NH^Cl稀釋，並以Et〇Ac萃取。將有機萃液洗滌 出2〇)(鹽水），脱水乾燥（MgS〇4)，過濾及濃縮。藉急驟式層 析純化（己虎：EtOAc 8 : 2)產生實例30，爲白色泡沫物。 NMR 1 H (300MHz，丙酮-d6) d 8.79 (dd，1H)，8.28 (dd，1H)，7.74 (d，1H)， 7.60 (d，1H)，7.48-7.25 (m，12H)，7.20-7.16 (m，2H), 3.13 (七重線，1H)，1.36 (d5 6H). 實例31與32 6-異丙基-8-(3-{(E/Z)-2-(6-甲基各吡啶基）-2-[4-(甲磺醯基）苯基]乙 烯基}苯基啉 ^3 CH3 (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製V. INSTRUCTIONS (115) Example 30 was prepared by the following procedure.芊 膦phosphonate p2 (i 〇〇 mg, 0·25 耄 Mo), 4,4'-dibenzobenzophenone (63 mg, 〇 25 mmol) in THF (2 liters) In the mixture, add a third potassium butylate ο% 'THF ' 0.35 when liters ' 〇 · 35 millimoles. After 1 hour at room temperature, the mixture was diluted with water / NH^Cl and extracted with EtOAc. The organic extract was washed 2 〇) (brine), dried (MgSO4), filtered and concentrated. Example 30 was obtained as a white foam by flash chromatography (EtOAc:EtOAc:EtOAc). NMR 1 H (300MHz, acetone-d6) d 8.79 (dd, 1H), 8.28 (dd, 1H), 7.74 (d, 1H), 7.60 (d, 1H), 7.48-7.25 (m, 12H), 7.20- 7.16 (m, 2H), 3.13 (seven lines, 1H), 1.36 (d5 6H). Examples 31 and 32 6-isopropyl-8-(3-{(E/Z)-2-(6-methyl) Each pyridyl)-2-[4-(methylsulfonyl)phenyl]vinyl}phenyl phenyl^3 CH3 (please read the note on the back and fill out this page) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative system

s I Ί CH -118- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱） 經濟部智慧財產局員工消費合作社印製 1280240 A7 B7s I Ί CH -118- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public interest) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 1280240 A7 B7

實例32 實例31與32係按照實例30所述之程序製成，但以酮K7取 代4,4’-二氣二苯甲酮，及使用爷基膦酸醋Ρ2作爲起始物質 。NMR 1 H (300MHz，丙酮-d6)(E)異構物（實例 31) : 8.79 (dd, 1H)，8·43 (d，1H)，8.27 (dd，1H)，7.95 (d，2H)，7.73 (d，1H)，7.57-7.43 (m，7H)， 7.32-7.19 (m，3H)，7.10 (d，1H)，3.15 (七重線，1H)，2.98 (s，3H)，1.34 (d，6H)· (Z)異構物（實例 32) : d 8.79 (dd，1Η)，8·35 (d，1HX 8·28 (dd，1H)， 7.92 (d，2H)，7.74 (d，1H)，7.61-7.30 (m，10H)，7.19 (d，1H)，3·13 (s, 3H), 3.11 (七重線，1H)，1.35 (d，6H). 實例33與34 6-異丙基-8-(3-{(E/Z)-2-(5-甲基-2-吡啶基）-2-[4-(甲磺醯基）苯基]乙 烯基丨苯基&gt;1:啉 -119- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -----------裝--------訂--------- (請先閱讀背面之注意事項再填寫本頁) 1280240 A7 _B7 五、發明說明（117 )Example 32 Examples 31 and 32 were prepared according to the procedure described in Example 30 except that 4,4'-dibenzophenone was replaced with ketone K7, and yttrium phosphatidyl 2 was used as the starting material. NMR 1 H (300MHz, acetone-d6) (E) isomer (Example 31): 8.79 (dd, 1H), 8.43 (d, 1H), 8.27 (dd, 1H), 7.95 (d, 2H) , 7.73 (d, 1H), 7.57-7.43 (m, 7H), 7.32-7.19 (m, 3H), 7.10 (d, 1H), 3.15 (seven lines, 1H), 2.98 (s, 3H), 1.34 ( d,6H)· (Z) isomer (Example 32): d 8.79 (dd, 1Η), 8.35 (d, 1HX 8·28 (dd, 1H), 7.92 (d, 2H), 7.74 (d , 1H), 7.61-7.30 (m, 10H), 7.19 (d, 1H), 3·13 (s, 3H), 3.11 (seven lines, 1H), 1.35 (d, 6H). Examples 33 and 34 6- Isopropyl-8-(3-{(E/Z)-2-(5-methyl-2-pyridinyl)-2-[4-(methylsulfonyl)phenyl]ethenylphenyl] ;1: porphyrin-119- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -----------Install--------Set--- ------ (Please read the notes on the back and fill out this page) 1280240 A7 _B7 V. Description of invention (117)

實例34 (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 實例33與34係按照實例30所述之程序製成，但以酮K8取 代4,4’-二氣二苯甲酮，及使用芊基膦酸酯P2作爲起始物質。 NMR I H (300MHz，丙酮-d6 )(E)異構物（實例 33) : d 8.80 (dd， 1H), 8.48 (s, 1H), 8.28 (dd, 1H), 7.99-7.96 (m, 3H), 7.97 (m, 1H), 7.74 (d, 1H), ___-120-_ 本紙張尺度適用中國國家標準（CNS)A4規格（210 x 297公釐） 1280240 A7 B7 五、發明說明（118) 7.61-7.44 (m，6H)，7.27 (t，1H)，7.07 (d，1H)，6.97 (d，1H)，3.15 (七重、線，1H)， 2·96 (s，3H)，1.36 (d，6H). (請先閱讀背面之注意事項再填寫本頁) NMR 1 H (300MHz，丙酮-d6)(Z)異構物（實例 34) : d 8.79 (dd， 1H)，8·52 (s，1H)，8·29 (dd，1H)，7.89 (d，2H)，7.75 (d，1H)，7.65-7.54 (m，4H)， 7.47 (dd，1H)，7.42-7.23 (m，5H)，7.11 (d，1H)，3.12 (s，3H)，3.12 (七重線，1H)， 1.36(d，6H). 實例35 8·(3-{2,2-雙[4-(甲績gg基）苯基]乙晞基}苯基）-6-異丙基峻琳 CH,Example 34 (Please read the note on the back and then fill out this page) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing examples 33 and 34 are made according to the procedure described in Example 30, but replaced by ketone K8 4,4'- Dibenzophenone, and the use of decylphosphonate P2 as a starting material. NMR IH (300MHz, acetone-d6) (E) isomer (Example 33): d 8.80 (dd, 1H), 8.48 (s, 1H), 8.28 (dd, 1H), 7.99-7.96 (m, 3H) , 7.97 (m, 1H), 7.74 (d, 1H), ___-120-_ This paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1280240 A7 B7 V. Description of invention (118) 7.61 -7.44 (m,6H), 7.27 (t,1H),7.07 (d,1H),6.97 (d,1H),3.15 (seventh, line,1H), 2·96 (s,3H),1.36 (d , 6H). (Please read the notes on the back and fill out this page) NMR 1 H (300MHz, acetone-d6) (Z) isomer (Example 34): d 8.79 (dd, 1H), 8.52 ( s,1H),8·29 (dd,1H),7.89 (d,2H),7.75 (d,1H), 7.65-7.54 (m,4H), 7.47 (dd,1H),7.42-7.23 (m, 5H), 7.11 (d, 1H), 3.12 (s, 3H), 3.12 (seventh line, 1H), 1.36(d, 6H). Example 35 8·(3-{2,2-double [4-(A)克基)phenyl]ethinyl}phenyl)-6-isopropyl Junlin CH,

經濟部智慧財產局員工消費合作社印製 實例35係按照實例30所述之程序製成，但以g同K9取代 4,4*-二氣二苯甲酮，及使用芊基膦酸酯P2作爲起始物質。 NMR 1 H (500MHz，丙酮-d6) : d 8.80 (dd，1H)，8.29 (dd，1H)，7.98 (d5 2H), 7.93 (d, 2H), 7.75 (d, 1H), 7.61 (d5 2H), 7.59-7.56 (m, 3H), 7.50 (d, 1H)，7.48-7.44 (m，3H)，7.30 (t，1H)，7.12 (d，1H)，3.14 (七重線，ih)，3.13 (s, 3H), 2.97 (s5 3H)? 1.35 (d, 6H). -121 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 x 297公釐） 1280240 A7 B7 五、發明說明（119 實例36與37 2-甲基-2-[8-(3-{(E/Z)-2-(5-甲基-2-吡啶基）-2-[4-(甲磺醯基）苯基]乙 烯基}苯基）-6-喹啉基]丙腈Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing example 35 was made according to the procedure described in Example 30, but replacing 4,4*-di-benzophenone with g and K9, and using fluorenylphosphonate P2 as Starting material. NMR 1 H (500MHz, acetone-d6): d 8.80 (dd, 1H), 8.29 (dd, 1H), 7.98 (d5 2H), 7.93 (d, 2H), 7.75 (d, 1H), 7.61 (d5 2H ), 7.59-7.56 (m, 3H), 7.50 (d, 1H), 7.48-7.44 (m, 3H), 7.30 (t, 1H), 7.12 (d, 1H), 3.14 (seven lines, ih), 3.13 (s, 3H), 2.97 (s5 3H)? 1.35 (d, 6H). -121 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1280240 A7 B7 V. Description of invention (119 Examples 36 and 37 2-Methyl-2-[8-(3-{(E/Z)-2-(5-methyl-2-pyridyl)-2-[4-(methylsulfonyl)benzene Vinyl}phenyl)-6-quinolinyl]propanenitrile

經濟部智慧財產局員工消費合作社印製Ministry of Economic Affairs, Intellectual Property Bureau, employee consumption cooperative, printing

實例37 實例36與37係按照實例30所述之裎序製成 以g同砧取 -----------裝--------訂--------- (請先閱讀背面之注意事項再填寫本頁) 122- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 經濟部智慧財產局員工消費合作社印製 1280240 A7 __B7_____ 五、發明說明（120 ) 代4，咎二氣二苯甲酮，及以芊基膦酸酯P3取代P2作爲起始 物質。 NMR 1 H (500MHz，丙酮-d6 )(E)異構物（實例 36) : δ 8.90 (dd5 1H)，8·47 (s，1H)，8.43 (dd，1H)，8.08 (d5 1H)，8·00 (s，1H)，7·97 (d，2H)，7·83 (d，1H)，7.57-7.53 (m，5H)，7·50 (s，1H)，7·28 (t，1H)，7·06 (d，1H)，6.96 (d，1H)， 2.96 (s，3H)，2.33 (s，3H)，1.88 (s，6H)· NMR 1 H (300MHz，丙酮-d6)(Z)異構物（實例 37) : d 8.89 (dd， lH)，8.51(s，lH)，8.45(dd，lH)，8.09(d，lH)57.89 (d，2H)，7.72(d，lH)，7.62-7.56 (m，5HX 7.43-7.42 (m，2H)，7.30 (t5 1H)，7.25 (d，1H)，7.10 (d5 1H)，3.11 (s，3H)，2.34(s，3H)，1.87(s6H)· 實例38 2-[8-(3-{2,2-雙[4-(甲磺醯基）苯基]乙烯基}苯基）-6-奎啉基]-2-甲 基丙腈Example 37 Examples 36 and 37 were prepared according to the procedure described in Example 30, taking g with the anvil----------- loaded------ -- (Please read the note on the back and fill out this page) 122- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1280240 A7 __B7_____ DESCRIPTION OF THE INVENTION (120) Generation 4, quinone dibenzophenone, and P2 is substituted with fluorenylphosphonate P3 as a starting material. NMR 1 H (500MHz, acetone-d6) (E) isomer (Example 36): δ 8.90 (dd5 1H), 8.47 (s, 1H), 8.43 (dd, 1H), 8.08 (d5 1H), 8·00 (s,1H),7·97 (d,2H),7·83 (d,1H), 7.57-7.53 (m,5H),7·50 (s,1H),7·28 (t ,1H),7·06 (d,1H),6.96 (d,1H), 2.96 (s,3H), 2.33 (s,3H),1.88 (s,6H)· NMR 1 H (300MHz, acetone-d6 (Z) isomer (Example 37): d 8.89 (dd, lH), 8.51 (s, lH), 8.45 (dd, lH), 8.09 (d, lH) 57.89 (d, 2H), 7.72 (d) , lH), 7.62-7.56 (m, 5HX 7.43-7.42 (m, 2H), 7.30 (t5 1H), 7.25 (d, 1H), 7.10 (d5 1H), 3.11 (s, 3H), 2.34 (s, 3H), 1.87 (s6H)· Example 38 2-[8-(3-{2,2-bis[4-(methylsulfonyl)phenyl]vinyl}phenyl)-6-quinolinyl]- 2-methylpropionitrile

實例38係按照實例30所述之程序製成，但以酮K9取代 4,4·-二氣二苯甲酉同，及以芊基膦酸酯P3取代P2作爲起始物 -123 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） ------------^--------^--------- (請先閱讀背面之注咅？事項再填寫本頁) 經濟部智慧財產局員-J1消費合作社印製 1280240 A7 -^ ___ B7___ 五、發明說明（121 ) 質。 NMR 1 H (500MHz，丙酮-d6) : d 8·90 (dd，1H)，8.44 (dd5 1H)，8.09 (d， 1H)，7.97 (d，2H)，7.92 (d，2H)，7.81 (d，1H)，7.61 (d，2H)，7.58-7.55 (m，3H)， 7.53 (s，1H)，7·44 (s，lH)— 7.32 (t，1H)，7.13 (d，1H)，6·96 (d，1H)，3,13 (s，3H)， 2.97 (s5 3H)5 1.86 (s5 6H). 實例39 2-甲基冬(8-{3-[(E)-2-[4-(甲磺醯基）苯基]-2-(2-吡啶基）乙晞基]苯 基卜奎p林基）丙月倉Example 38 was prepared according to the procedure described in Example 30, except that the ketone K9 was substituted for 4,4·-dioxabenzophenone, and the fluorenylphosphonate P3 was substituted for P2 as the starting material -123 - paper The scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ------------^--------^--------- (please Read the note on the back first? Then fill out this page.) Ministry of Economic Affairs Intellectual Property Officer - J1 Consumer Cooperative Printed 1280240 A7 -^ ___ B7___ V. Invention Description (121) Quality. NMR 1 H (500MHz, acetone-d6): d 8·90 (dd, 1H), 8.44 (dd5 1H), 8.09 (d, 1H), 7.97 (d, 2H), 7.92 (d, 2H), 7.81 ( d,1H), 7.61 (d,2H), 7.58-7.55 (m,3H), 7.53 (s,1H),7·44 (s,lH)— 7.32 (t,1H),7.13 (d,1H) ,6·96 (d,1H),3,13 (s,3H), 2.97 (s5 3H)5 1.86 (s5 6H). Example 39 2-Methyl Winter (8-{3-[(E)-2 -[4-(Methanesulfonyl)phenyl]-2-(2-pyridyl)ethenyl]phenyl buckyinyl)

實例39係按照實例30所述之程序製成，但以酮K10取代 4,4*-二氣二苯甲酮，及以芊基膦酸酯P3取代P2作爲起始物 質。 NMR 1 H (300MHz，丙酮-d6 ) ·· ί 8.90 (dd5 1H), 8.45 (dd, 1H), 8.11， 8.09 (m，2H)，7.84-7.80 (m，3H)，7.72-7.69 (m，1H)，7.63-7.52 (m，5H), 7·43· 7.38 (m, 2H), 7.33 (t, 1H), 7.28 (s, 1H), 7.14 (d, 1H), 2.97 (s, 3H), 1.86 (s, 6H) -124- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） --------------------^--------- i請先閱讀背面之注音心事項再填寫本頁) 1280240 A7 B7 五、發明說明（122)實例40與41 6-[卜甲基·Μ甲磺醯基）乙基]-8-(3-{(E/Z)-2-(5-甲基-2-吡啶基）-2-[4-( 甲磺醯基）苯基]乙晞基}苯基）VT奎琳Example 39 was prepared according to the procedure described in Example 30, except that 4,4*-dibenzobenzophenone was replaced by ketone K10, and P2 was replaced by decylphosphonate P3 as the starting material. NMR 1 H (300MHz, acetone-d6) ·· ί 8.90 (dd5 1H), 8.45 (dd, 1H), 8.11, 8.09 (m,2H), 7.84-7.80 (m,3H), 7.72-7.69 (m, 1H), 7.63-7.52 (m, 5H), 7·43· 7.38 (m, 2H), 7.33 (t, 1H), 7.28 (s, 1H), 7.14 (d, 1H), 2.97 (s, 3H) , 1.86 (s, 6H) -124- The paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) --------------------^ --------- i Please read the notes on the back of the note and then fill out this page.) 1280240 A7 B7 V. INSTRUCTIONS (122) EXAMPLES 40 AND 41 6-[B-Methyl-Methanesulfonyl) Ethyl ]-8-(3-{(E/Z)-2-(5-methyl-2-pyridyl)-2-[4-(methylsulfonyl)phenyl]ethenyl}phenyl)VT Quiline

實例4〇 經濟部智慧財產局員工消費合作社印製Example 4〇 Printed by the Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative

實例41實例41與42係按照實例10中所述之程序製成， 但以溴基 n ϋ. ·1 ϋ »^i Hi ϋ ·1 I n n ϋ ϋ n I ϋ n 0·. a n ϋ ϋ n n in ϋ I (請先閱讀背面之注咅？事項再填寫本頁) -125 木紙張尺度適用中國國家標準（CNS)A4規格（21〇 x 297公釐 1280240 A7 B7 i、發明說明（123 ) 喳啉Q3取代Q2，及以硼烷酸酯B3取代硼烷酸酯B2。 NMR 1 H (400MHz，丙酮-d6)(E)異構物（實例 40) : ^ 8.91 (dd, 1H)，8.45 (s，1H)，8·41 (dd，1H)，8.23 (d，1H)，8.01-8.00 (m，2H)，7.95 (d，2H), 7.57-7.54 (m，4H)，7.51 (d，1H)，7.49 (s，1H)，7.28 (t，1H)，7.07 (d，1H)，6.96 (d，lH)，2.94 (s，3H)，2·69 (s，3H)，2·33 (s，3H)，1.97 (s，6H). NMRiH (400MHz &gt; 丙酮-d6)(Z)異構物（實例 41) : d 8.88 (dd，1H)，8_49 (s，1H)，8.42 (dd，1H), 8.24 (dd，1H)，7·94 (d，1H)，7·88 (d，2H)， 7.61-7.55 (m，5H)，7.47 (s，lH)，7.40 (s，1H)，7.29 (t，1H)，7·24 (d，1H)，7.06 (d，1H)，3.12 (s，3H)，2·68 (s，3H)，2·33 (s，3H)，1.96 (s，6H)· 實例42 2-(6-{(Ε)-2-(3-{6-[1-甲基-1-(甲磺醯基）乙基]-8-喳啉基}苯基）小[4-( 甲磺醯基）苯基]乙烯基}-3-吡啶基）-2-丙醇Example 41 Examples 41 and 42 were prepared according to the procedure described in Example 10, but with bromo groups n. · 1 ϋ »^i Hi ϋ ·1 I nn ϋ I n I ϋ n 0·. an ϋ ϋ nn In ϋ I (Please read the note on the back? Please fill out this page again) -125 Wood paper scale applies to China National Standard (CNS) A4 specification (21〇x 297 mm 1280240 A7 B7 i, invention description (123) 喳The porphyrin Q3 is substituted for Q2, and the boranoate B3 is substituted with boranoate B3. NMR 1 H (400 MHz, acetone-d6) (E) isomer (Example 40): ^ 8.91 (dd, 1H), 8.45 ( s,1H),8·41 (dd,1H), 8.23 (d,1H),8.01-8.00 (m,2H),7.95 (d,2H), 7.57-7.54 (m,4H),7.51 (d, 1H), 7.49 (s, 1H), 7.28 (t, 1H), 7.07 (d, 1H), 6.96 (d, lH), 2.94 (s, 3H), 2·69 (s, 3H), 2·33 (s, 3H), 1.97 (s, 6H). NMRiH (400MHz &gt; Acetone-d6) (Z) isomer (Example 41): d 8.88 (dd, 1H), 8_49 (s, 1H), 8.42 ( Dd,1H), 8.24 (dd,1H),7·94 (d,1H),7·88 (d,2H), 7.61-7.55 (m,5H),7.47 (s,lH),7.40 (s, 1H), 7.29 (t, 1H), 7·24 (d, 1H), 7.06 (d, 1H), 3.12 (s, 3H), 2·6 8 (s, 3H), 2·33 (s, 3H), 1.96 (s, 6H)· Example 42 2-(6-{(Ε)-2-(3-{6-[1-methyl-1 -(Methanesulfonyl)ethyl]-8-carbolinyl}phenyl)sodium [4-(methylsulfonyl)phenyl]vinyl}-3-pyridyl)-2-propanol

實例42係按照實例10中所述之程序製成，但以溴基喹啉 Q3取代Q2，及以硼烷酸酯B4取代硼烷酸酯B2。 NMR 1 H (500MHz，丙酮-d6) : 6 8.91 (dd，1H)，8·80 (d，1H)，8.42 (dd， -126- 本紙張尺度適用中國國家標準（CNS)A4規格（210 x 297公爱） (請先閱讀背面之注意事項再填寫本頁) I I i a^i n 一°J in ϋ ϋ i^i i_i I I . 經濟部智慧財產局員工消費合作社印製 1280240 A7 B7 五、發明說明（124) 1H)，8·23 (d，1H)，8.03-8.01 (m，2H)，7.96 (d，1H)，7.82 (dd，1H)，7.58-7.54 (m， 4H)，7.51 (s，1H)，7.29 (t，1H)，7.08 (d，1H)，7.01 (d，1H)，4.31 (s，1H)，2.96 (s， 3H)，2.70 (s，3H)，1·96 (s，6H)，1.56 (s，6H)· 實例43Example 42 was prepared according to the procedure described in Example 10, substituting Q2 with bromoquinoline Q3 and boranoate B2 with boranoate B4. NMR 1 H (500MHz, acetone-d6) : 6 8.91 (dd,1H),8·80 (d,1H),8.42 (dd, -126- This paper size applies to Chinese National Standard (CNS) A4 specification (210 x 297 public love) (Please read the notes on the back and fill out this page) II ia^in 一°J in ϋ ϋ i^i i_i II . Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1280240 A7 B7 V. Invention Description (124) 1H),8·23 (d,1H),8.03-8.01 (m,2H),7.96 (d,1H),7.82 (dd,1H), 7.58-7.54 (m, 4H),7.51 (s) ,1H), 7.29 (t,1H),7.08 (d,1H),7.01 (d,1H),4.31 (s,1H),2.96 (s,3H),2.70 (s,3H),1·96 ( s,6H),1.56 (s,6H)·Example 43

實例43係按照前述實例i4與i5之程序製成，但以芳基溴 化物AB6取代AB5，及以溴基喳啉Q5取代Q3作爲起始物質。 其他實例如下： -----------裝---------訂---------^9. (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 -127- 本紙張尺度適用中國國家標準（CNS)A4規格（21〇 x 297公釐） 1280240 A7 B7 五、發明說明（ 125Example 43 was prepared according to the procedures of the foregoing Examples i4 and i5, but substituting AB5 with aryl bromide AB6 and Q3 with bromo porphyrin Q5 as starting material. Other examples are as follows: -----------Install---------Book---------^9. (Please read the notes on the back and fill out this page. ) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed -127- This paper scale applies to China National Standard (CNS) A4 specification (21〇x 297 mm) 1280240 A7 B7 V. Invention Description ( 125

.0 -----------裝--------訂--------- (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印制衣 〇4 -128 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 〇 1280240 經濟部智慧財產局員工消費合作社印製 A7.0 -----------Install--------Book--------- (Please read the notes on the back and fill out this page) Ministry of Economic Affairs Intellectual Property Bureau Employee Consumption Cooperatives Printed Clothes 〇 4 -128 This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 〇1280240 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative prints A7

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〇 〇 - 205- -----------裝--------訂--------- (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 1280240 A7 B7 203 五、發明說明（） 經濟部智慧財產局員工消費合作社印製〇〇- 205- -----------Install--------Book--------- (Please read the notes on the back and fill out this page) Paper The scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1280240 A7 B7 203 V. Invention Description () Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

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- 206 - (請先閱讀背面之注意事項再填寫本頁) 訂---------線辦. 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 1280240 A7 B7 204 五、發明說明（）- 206 - (Please read the note on the back and fill out this page) Order---------Line Office. This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1280240 A7 B7 204 V. Invention Description ()

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-209- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -----------裝--------訂--------- (請先閱讀背面之注意事項再填寫本頁) 1280240 A7 B7 五、發明說明（2(37)-209- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) -----------Install ----------- -- (Please read the notes on the back and fill out this page) 1280240 A7 B7 V. Invention Description (2(37)

-----------裝--------訂---------線 (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 -210- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 1280240 A7 B7 五、發明說明（2Q8 經濟部智慧財產局員工消費合作社印製-----------Install--------Book---------Line (please read the notes on the back and fill in this page) Ministry of Economic Affairs Intellectual Property Office staff Consumer Cooperative Printed -210- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1280240 A7 B7 V. Invention Description (2Q8 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

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-221 (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） 經濟部智慧財產局員工消費合作社印製 1280240 A7 _B7 五、發明說明（219 )-221 (Please read the note on the back and fill out this page.) This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm). Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1280240 A7 _B7 V. Invention Description (219)

- 222- (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） [280240 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明（22〇 )- 222- (Please read the note on the back and fill out this page.) This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) [280240 A7 B7 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 5 , invention description (22〇)

- 諸實例之鹽 正如上文所討論者，藥學上可接受之鹽係爲經常需要的 。此種鹽之實例係描述於下文： 鹽製備之一般方法 本發明化合物爲鹼性時之鹽，可以數種方式製備： a) 使化合物溶於可接受之溶劑中，譬如醋酸乙酯。然後添 加可接受之酸，譬如鹽酸，在可接受之溶劑中，譬如 1，4-二氧陸圜。使已沉澱之鹽漿液熟成，然後藉過濾分 離此鹽。 b) 使化合物與可接受之酸，譬如苯橫酸，溶於可接受之溶 劑中，譬如醋酸異丙酯，或溶於溶劑混合物中，譬如醋 -223 - 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） -----------------—訂--------- (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 I280240 A7 -------B7____ 五、發明說明（221 ) 酸異丙醋與甲醇。然後可藉由濃縮，或溶劑轉換，導致 沉澱作用，接著過濾，以分離此鹽。此鹽之更安定結晶 形式，可藉由已沉澱鹽漿液之平衡而獲得，其方式是在 過濾之前，藉由加熱與熟成。亦可在鹽漿液平衡之前， /‘加传自先如批次之種晶’以引發結晶化作用與平衡過 程。 實例Μ化合物之硫酸鹽 實例14化合物之硫酸鹽，係以下述方式製成，使此化合 物（1.00當量）溶於回流醋酸乙酯中。於冷卻至室溫後，慢慢 添加硫酸（1.04當量），同時攪拌。將所形成之懸浮液再攪摔 40分鐘，並藉過濾分離固體，及以醋酸乙酯洗滌，而得實 例14化合物之硫酸鹽。 1 H NMR (500MHz，丙酉同-d6 )·· d 9.45 (d，1Η)，9.23 (d，lH)，8.65 (d，1Η)， 8·25 (d，1H)，8.16 (dd，1H)，8.10 (s，1H)，7.99 (d，2H), 7.80 (d5 2H)，7.60 (d，1H) ，7.49 (s，1H)，7.45 (t，1H)，7.30 (d，1H)，3.09 (s，3H)，2.77 (s，3H)，2.33 (s，3H)， 2.01 (s，6H)。 實例14化合物之甲烷磺酸鹽 實例14化合物之甲烷磺酸鹽，係以下述方式製成，使此 化合物（1.0當量）溶於回流醋酸乙酯中。於冷卻至室溫後， 慢慢添加甲烷磺酸（M當量）同時攪拌。將所形成之懸浮液 攪拌，使其藉蒸發濃縮，及藉過濾分離固體，並以醚洗滌 ，而得實例14化合物之甲烷磺酸鹽。 1 H NMR (500MHz，丙酮-d6) : d 9.45 (d，1H)，9.32 (d，1H)，8.70 (s，1H)， 8·27 (s，1H)，8.22 (t，lH)，8.11 (s，1H)，7.99 (d，2H)，7·78 (d，2H)，7.61 (d，1H)， -224 - —本紙張尺度適用中P國家標準（CNS)A4規格（210 x 297公爱） ------------裝--------訂--------- (請先閱讀背面之注意事項再填寫本頁) l28〇240 A7 B7 i、發明說明（222 ) 7.49 (m5 2HX 7.35 (d5 1H), 3.09 (s? 3H)5 2.78 (s? 3H)5 2.33 (s5 3H), 2.01 (s5 6H). 實例14化合物之對-甲苯磺酸鹽 實例14化合物之對·甲苯磺酸鹽，係以下述方式製成，使 此化合物（1.0當量）溶於回流醋酸乙酯中。於冷卻至室溫後 ，慢慢添加醋酸乙酯中之對-甲苯續酸（1.1當量）。使溶液濃 縮，並使懸浮液熟成及攪拌，且在室溫下週期性地音振3 天。然後藉過濾分離固體，及以醋酸乙酯洗滌，而得實例 14化合物之對-甲苯磺酸鹽。 熔點 184-185°C。 1 H NMR (500MHz，丙酮-d6) : d 9·58 (d，1H)，9.22 (d，1H)，8.63 (s，1H)， 8·23 (d，1H)，8.16 (m，1H)，8.03 (s，1Η)，7·94 (d，2H)，7.73 (d，2H)，7·55 (m，3H)， 7.45 (s，1H)，7.40 (t，lH)，7.27 (d，1H)，7.12 (d，2H)，3.07 (s，3H)，2.75 (s，3H)， 2.33 (s，3H)，2.29 (s，3H)，2.01 (s，6H)。 實例14化合物之2-莕磺酸鹽 實例14化合物之2-萘磺酸鹽，係以下述方式製成，使此 化合物（1.0當量）溶於回流醋酸乙酯中。於冷卻至室溫後， 慢慢添加醋酸乙酯中之2-莕磺酸（1.1當量），接著爲乙醇。 然後添加甲苯至該溶液中，接著濃縮。接著添加更多甲苯 ，並使此懸浮液熟成及攪拌，且在室溫下週期性地音振24 小時。然後，藉過濾分離固體，.及以甲苯洗滌，而得實例 14化合物之2-莕磺酸鹽。 熔點 202-204°C。 1 H NMR (500MHz，丙酮-d6) : d 9.64 (d，1H)，9.30 (d，1H)，8.67 (d，1H)， 8.25 (d，1H)，8.23 (m，1H)，8·16 (s，1H)，7.99 (s，1H)，7.91 (d，2H)，7.87 (m，2H) -225- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閱讀背面之注意事項再填寫本頁) · ϋ n ϋ n tmmg eKmt 一 δ、I ϋ emm§ n ϋ 經濟部智慧財產局員工消費合作社印製 1280240 A7 _____B7______ 五、發明說明（223 ) ，7.82 (d，1H)，7.72 (dd，1H)，7.68 (d，2H)，7·54 (d，1H)，7.52 (m5 2H)，7.43 (brs， 1H)，7.37 (t，1H)，7.22 (d，1H)，3·03 (s，3H)，2.76 (s，3H)，2·33 (s，3H)，2.02 (s， 6H). 實例43化合物之鹽酸鹽 實例43化合物之鹽酸鹽，係以下述方式製成，使此化合 物（1.0當量）溶於醋酸乙酯中，並加熱及音振。在使溶液冷 卻至室溫後，添加1，4-二氧陸圜中之HC1 (4M，1.0當量）同時 攪拌。將此懸浮液再攪拌5分鐘，並藉過濾分離固體，而 得實例43化合物之單鹽酸鹽。 實例14化合物之苯磺酸鹽 實例14化合物之苯磺酸鹽，可以兩種結晶形式取得（，·形 式A”與”形式B”）。此等形式係藉下述程序製成： 鹽形成- Salts of the Examples As discussed above, pharmaceutically acceptable salts are often required. Examples of such salts are described below: General Methods for Salt Preparation The compounds of the present invention are basic when prepared in a number of ways: a) The compound is dissolved in an acceptable solvent, such as ethyl acetate. An acceptable acid, such as hydrochloric acid, is then added, in an acceptable solvent, such as 1,4-dioxane. The precipitated salt slurry is cooked and the salt is separated by filtration. b) The compound and an acceptable acid, such as benzoic acid, are dissolved in an acceptable solvent, such as isopropyl acetate, or dissolved in a solvent mixture, such as vinegar-223 - This paper scale applies to the Chinese National Standard (CNS) A4 size (210 X 297 mm) ------------------book--------- (please read the notes on the back and fill out this page) ) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed I280240 A7 -------B7____ V. Invention Description (221) Acid isopropyl vinegar and methanol. This can then be separated by concentration, or solvent conversion, resulting in precipitation followed by filtration. The more stable crystalline form of the salt can be obtained by equilibration of the precipitated salt slurry by heating and ripening prior to filtration. It is also possible to / / add a seed crystal from the batch before the salt slurry is equilibrated to initiate the crystallization and equilibrium process. Example Sulfate of the Compound Example The sulfate salt of the compound of Example 14 was prepared in such a manner that the compound (1.00 equivalent) was dissolved in ethyl acetate reflux. After cooling to room temperature, sulfuric acid (1.04 equivalent) was slowly added while stirring. The resulting suspension was further stirred for 40 minutes, and the solid was isolated by filtration and washed with ethyl acetate to give the sulfate salt of the compound of Example 14. 1 H NMR (500 MHz, propyl hydrazine - d6 ) · · d 9.45 (d, 1 Η), 9.23 (d, lH), 8.65 (d, 1 Η), 8·25 (d, 1H), 8.16 (dd, 1H) ), 8.10 (s, 1H), 7.99 (d, 2H), 7.80 (d5 2H), 7.60 (d, 1H), 7.49 (s, 1H), 7.45 (t, 1H), 7.30 (d, 1H), 3.09 (s, 3H), 2.77 (s, 3H), 2.33 (s, 3H), 2.01 (s, 6H). Methanesulfonate salt of the compound of Example 14 The methanesulfonate salt of the compound of Example 14 was obtained by dissolving this compound (1.0 eq.) in ethyl acetate. After cooling to room temperature, methanesulfonic acid (M equivalent) was slowly added while stirring. The resulting suspension was stirred, concentrated by evaporation, and the solid isolated by filtration and washed with ether to afford methanesulfonate of the compound of Example 14. 1H NMR (500MHz, acetone-d6): d 9.45 (d,1H), 9.32 (d,1H), 8.70 (s,1H), 8.27 (s,1H), 8.22 (t,lH),8.11 (s, 1H), 7.99 (d, 2H), 7·78 (d, 2H), 7.61 (d, 1H), -224 - — This paper size applies to the P National Standard (CNS) A4 specification (210 x 297 Public love) ------------Installation--------Book--------- (Please read the notes on the back and fill out this page) l28〇240 A7 B7 i, invention description (222) 7.49 (m5 2HX 7.35 (d5 1H), 3.09 (s? 3H)5 2.78 (s? 3H)5 2.33 (s5 3H), 2.01 (s5 6H). -Tosylate salt The p-toluenesulfonate salt of the compound of Example 14 was prepared in such a manner that the compound (1.0 equivalent) was dissolved in ethyl acetate under reflux. After cooling to room temperature, acetic acid B was slowly added. The p-toluene acid in the ester was acidified (1.1 eq.). The solution was concentrated, and the suspension was aged and stirred, and periodically sonicated at room temperature for 3 days. The solid was then separated by filtration and washed with ethyl acetate. The p-toluenesulfonate salt of the compound of Example 14 was obtained. Melting point 184-185 ° C. 1 H NMR (500 MHz, acetone-d6): d 9·58 (d 1H), 9.22 (d,1H), 8.63 (s,1H), 8·23 (d,1H), 8.16 (m,1H),8.03 (s,1Η),7·94 (d,2H),7.73 (d, 2H), 7·55 (m, 3H), 7.45 (s, 1H), 7.40 (t, lH), 7.27 (d, 1H), 7.12 (d, 2H), 3.07 (s, 3H), 2.75 (s, 3H), 2.33 (s, 3H), 2.29 (s, 3H), 2.01 (s, 6H). Example 2 2-anthracenesulfonate salt of the compound of Example 14 2-naphthalenesulfonate This compound (1.0 eq.) was dissolved in ethyl acetate under reflux. After cooling to room temperature, 2-indolesulfonic acid (1.1 eq.) in ethyl acetate was slowly added, followed by ethanol. Toluene was then added to the solution, followed by concentration. Then more toluene was added, and the suspension was cooked and stirred, and periodically sonicated for 24 hours at room temperature. Then, the solid was separated by filtration, and toluene was removed. This was washed to give the 2-indole sulfonate of the compound of Example 14. m.p. 202-204° C. 1 H NMR (500 MHz, acetone-d6): d 9.64 (d, 1H), 9.30 (d, 1H), 8.67 ( d,1H), 8.25 (d,1H), 8.23 (m,1H),8·16 (s,1H),7.99 (s,1H),7.91 (d,2H),7.87 ( m,2H) -225- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page) · ϋ n ϋ n tmmg eKmt-δ, I ϋ emm§ n ϋ Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1280240 A7 _____B7______ V. Invention Description (223), 7.82 (d, 1H), 7.72 (dd, 1H), 7.68 (d, 2H), 7.54 (d,1H), 7.52 (m5 2H), 7.43 (brs, 1H), 7.37 (t,1H), 7.22 (d,1H),3·03 (s,3H),2.76 (s,3H),2 • 33 (s, 3H), 2.02 (s, 6H). The hydrochloride salt of the compound of Example 43. The hydrochloride salt of the compound of Example 43 was prepared in the following manner to dissolve this compound (1.0 eq.) in ethyl acetate. And heat and sound vibration. After allowing the solution to cool to room temperature, HCl (4 M, 1.0 equivalent) in 1,4-dioxane was added while stirring. The suspension was stirred for a further 5 minutes and the solid isolated by filtration afforded the monohydrochloride salt of the compound of Example 43. The besylate salt of the compound of Example 14 The besylate salt of the compound of Example 14 can be obtained in two crystal forms (, Form A" and "Form B"). These forms are prepared by the following procedure: Salt formation

~〇 經濟部智慧財產局員工消費合作社印製 (請先閱讀背面之注意事項再填寫本頁)~〇 Printed by the Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative (please read the notes on the back and fill out this page)

形式A 於實例14化合物（丨當量）在醋酸乙酿中之聚液内，添加苯 磺酸（1-1.2當量）。可像用其他酷類替代醋酸乙醋。添加甲 醇，並將所形成之混合物加熱，直到固體溶解爲止。可使 -226- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 1280240Form A To a solution of the compound of Example 14 (equivalent equivalent) in ethyl acetate, benzenesulfonic acid (1-1.2 equivalents) was added. Can be used to replace ethyl acetate with other cool types. Methanol is added and the resulting mixture is heated until the solids dissolve. The -226- paper size can be applied to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1280240

五、 發明說明（224 ) 用他醇類，譬如乙醇或丙醇，替代甲醇。 將所形成足溶液過濾及濃縮。產物係於濃縮期間結晶析 出。將所形成之混合物以醋酸乙酯稀釋及熟成。藉過濾收 集黃色固體。 时HPLC顯tf 6-[1-甲基(甲磺醯基）乙基]-8 [3-[⑹2 [3-甲基-124· 可一唑-5-基]-2-[4-(甲磺醯基）苯基]乙烯基]苯基]喳啉與苯磺酸 之1 : 1莫耳比。 藉由DSC之熔點：193°C。 形式a之X射線粉末繞射（&quot;m，）光譜圖，係示於圖2中 。確涊用之吸收峰係表列於下，並示於圖5中。 確認形式A多晶 型物之吸收峰 (°2Θ ) 10.0 19.5 21.4 22.4 30.5 經濟部智慧財產局員工消費合作社印製 形式Β 於實例14化合物（1當量）在醋酸異丙酯（i_pr〇Ac)與甲醇·· 1)混合物中之漿液内，添加苯磺酸（Μ·2當量）。可使用其他 酯類替代i-PrOAc，及可使用其他醇類，譬如乙醇或丙醇， 替代甲醇。使此混合物在襲。(：下熟成，直到固體溶解。 將所形成之溶液過濾及蒸餾，同時藉由添加9: i(v/v)i_pi&gt;c)Ae /甲醇混合物，保持其體積。產物係於蒸餾期間結晶析出。 使所形成之混合物在20-7(TC下熟成2-1〇小時，以確保完全 形成形式B。將所形成之灰白色固體藉過濾分離並乾燥。 裝--------訂---------^_^wi (請先閱讀背面之注意事項再填寫本頁) 227- 1280240 A7 B7 五、發明說明（225 ) HPLC顯示6-[1-甲基甲磺醯基）乙基]_8♦[吵2 [3_甲基心，2,4· 哼二唑-5-基]-2-[4-(甲磺醯基）苯基]乙烯基]苯基]峻啉與苯磺酸 之1 : 1莫耳比。 藉由DSC之熔點：21〇t形式B之XRPD光譜圖，係示於圖3中。確認用之吸收峰 係表列於下，且示於圖6中。將此等光譜在圖4中作比較， 其中確認用吸收峰係以箭頭指出。 又 ]雀認形式B多晶 型物之吸收峰 (°2Θ ) 14.4 (請先閱讀背面之注意事項再填寫本頁) 17.7 20.0 20.2 23.7 28.9 熟請此藝者顯而易見之其他變型或修正， 找 範圍與陳述内容中。除了下述申請專利範圍所二月广 本發明並不受到限制。 I外’ .裝----- Φ 經濟部智慧財產局員工消費合作社印製 -228- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公爱）V. INSTRUCTIONS (224) Replace alcohol with other alcohols such as ethanol or propanol. The formed foot solution was filtered and concentrated. The product crystallized during concentration. The resulting mixture was diluted with ethyl acetate and cooked. The yellow solid was collected by filtration. HPLC showed tf 6-[1-methyl(methylsulfonyl)ethyl]-8 [3-[(6)2 [3-methyl-124·coazol-5-yl]-2-[4-( 1 : 1 molar ratio of methanesulfonyl)phenyl]vinyl]phenyl]porphyrin to benzenesulfonic acid. The melting point by DSC: 193 °C. The X-ray powder diffraction (&quot;m,) spectrum of Form a is shown in Figure 2. The absorption peaks used in the table are listed below and shown in Figure 5. Confirmation of the absorption peak of Form A polymorph (°2Θ) 10.0 19.5 21.4 22.4 30.5 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed form 实例 Example 14 compound (1 equivalent) in isopropyl acetate (i_pr〇Ac) Methanol·· 1) To the slurry in the mixture, benzenesulfonic acid (Μ·2 equivalent) was added. Other esters can be used in place of i-PrOAc, and other alcohols, such as ethanol or propanol, can be used instead of methanol. This mixture was attacked. (: aging is completed until the solid dissolves. The resulting solution is filtered and distilled while maintaining its volume by adding 9: i(v/v)i_pi&gt;c) Ae/methanol mixture. The product crystallized during distillation. The resulting mixture was aged at 20-7 (TC for 2-1 hrs to ensure complete formation of Form B. The resulting off-white solid was isolated by filtration and dried. -------^_^wi (Please read the notes on the back and fill out this page) 227- 1280240 A7 B7 V. Description of the invention (225) HPLC shows 6-[1-methylmethylsulfonyl) Ethyl]_8♦[noise 2 [3_methyl heart, 2,4·oxadiazol-5-yl]-2-[4-(methylsulfonyl)phenyl]vinyl]phenyl]porphyrin 1 : 1 molar ratio to benzenesulfonic acid. The XRPD spectrum of Form B by the melting point of DSC: 21 〇t is shown in Figure 3. The absorption peaks used for confirmation are listed below and are shown in Figure 6. These spectra are compared in Figure 4, where it is confirmed that the absorption peak is indicated by an arrow. Also] the absorption peak of Form B polymorph (°2Θ) 14.4 (Please read the note on the back and fill out this page) 17.7 20.0 20.2 23.7 28.9 Other variants or corrections that are familiar to the artist, find the range With the statement content. The present invention is not limited except for the scope of the following patent application. I 外'.装----- Φ Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing -228- This paper scale applies China National Standard (CNS) A4 specification (210 X 297 public)

Claims (1)

12801^09127506號專利申請案 as f文申請專利範圍替換本(95车6月銲 申請專利範圍 一 丨公告本J 一種以式（I)袅示之化合物： S1Patent application No. 12801^09127506 as a replacement for this patent application scope (95 car June welding patent application scope) 丨 Announcement J A compound shown by formula (I): S1 (I) 或其藥學上可接受之鹽，其中： Si，S2及S3係獨立為H或鹵素； h為A_c6烷基、·環C3-C6烷基或-(Ci夂烷基）_s〇n·%· c0烷基），其中任何基團係視情況被M個取代基取代·， 其中各取代基係獨立為_素、-0H、_CN、_c⑼(雜環基 C3-C6烧基）、_c(〇KKCVC6烷基）、&lt;(〇)·芳氧基、烷氧 基、醯基、醯氧基、-環C3-C6烷基、雜環基c3-c6烷基、 芳基、雜芳基、羰基、胺甲醯基或-SOnXq -C6烷基）； A 為 CH ; R2為芳基或雜芳基，視情況被1-5個取代基取代，其中 各取代基係獨立為鹵素、-No〗、-COOH、羰基、-CN、 -CVC6 烧基、-S〇n_(Ci_C6 烷基）、·〇_ 芳基、-〇_ 雜芳 基、-C(O)-雜環基c3-c6烷基、-NH-環C3-C6烷基、胺 基、-OH或C^C6烷基（胺基）取代基，其中各取代基係獨 立視情況被-OH、_〇(CrC6烷基）、-0(芳基）、 68419-950628.DOC 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1280240 si C8 ____D8 六、申請專利範園 -COOH、-COOCCrC^^lO、鹵素、-N02、-CN 或 -c(o)-n(c0-c6 烷基 &gt;(cvc6 烷基）取代； R3係獨立為芳基、雜芳基、-Ci -c6烷基、-Ci -c6烷氧 基、羰基、胺甲醯基、-C(0)0H、-(CrCg烷基ysoyCrCg 烷基）、-C(0)N((VC6烷基）(C0 -C6烷基）或-Ci -c6烷醯基胺 基，其中任何基團係視情況被1-5個取代基取代，其中 各取代基係獨立為鹵素、-N02、-C(0)0H、-CN、羰基、 -C!-C6烷基、-SCVA-C6烷基）、芳氧基、-雜芳基氧基、 -C(O)-雜環基c3 -C6烷基、-NH-環C3 -C6烷基、胺基、_ ο Η 或-C! -C6烷基（胺基）取代基，其中各取代基係獨立視情 況被-OH、q -C6 烷氧基、芳氧基、-C(0)0H、-(:(0)0((^ -C6 烷基）、lS 素、-N02、-CN 或-C(0)-N(C〇 -C6 烷基）(C0 _C6 烷基） 取代； R2與R3之一必須為芳基或雜芳基，視情況經取代； R4為芳基、雜芳基、-CN '羰基、胺甲醯基、-(q -C6烷 基）-SOn-(C「C6 烷基）、-C(0)N(CG-C6 烷基 XC〇-C6 烷基）或 -Ci -C6烧醯基胺基，其中任何基團係視情況被1-5個取代 基取代’其中各取代基係獨立為羰基、-CN、鹵素、 -c(o)(&lt;vc6烷基）、-Cl-C6烷基、-S〇n-(Cl_c6烷基）、胺基、 -0H或-q -C6烷基（胺基）； η係獨立為〇，1或2 ;及 其中芳基係選自苯基及萘基； 雜芳基係選自吼啶基、喹啉基、異喹啉基、嗒畊 基、嘧啶基、吼畊基、喹喏啉基、呋喃基、苯并呋喃 68419-950628.DOC 本紙張尺度適用中國國家標準(CNS) Α4規格(210 X 297公釐) 1280240 A8 B8 C8 ___D8 _ 六、申請專利^ ' ^一~ 美、 — 土、一笨并呋喃基、噻吩基、笨并噻吩基、吡咯基、吲 木基、°比唑基、吲唑基、崎唑基、異噚唑基、噻唑基、 異嘴°坐基、咪唑基、苯并咪唑基、嘮二唑基、噻二唑 基二σ坐基、四嗤基； 雜環基C3 -c6烷基係選自一氮四圜基、四氫吡咯基、 /、氣σ比咬基、六氫σ比畊基、嗎福淋基、四氫吱喃基、二 氮味°坐基、四氫吡咯· 2 -酮、六氫吡啶-2 -酮及硫代嗎福 啉基。 2·根據申請專利範圍第1項之化合物或其藥學上可接受之 鹽，其中 Ri為-q -C6烷基，視情況被1-5個取代基取代。 3·根據申請專利範圍第1項之化合物或其藥學上可接受之 鹽，其中 Ri為-環C3 _C6烷基，視情況被1-5個取代基取代。 4·根據申請專利範圍第1項之化合物或其藥學上可接受之 鹽，其中 R2為芳基，視情況被1_5個取代基取代；及 R3為雜芳基，視情況被丨-5個取代基取代。 5·根據申請專利範圍第1項之化合物或其藥學上可接受&lt; 鹽，其中 h為芳基，視情況被1-5個取代基取代；及 化為芳基，視情況被1-5個取代基取代。 6·根據申請專利範圍第i項之化合物或其藥學上可接受&lt; 鹽，其中 68419-950628.DOC 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公嫠) 1280240 as B8 C8(I) or a pharmaceutically acceptable salt thereof, wherein: Si, S2 and S3 are independently H or halogen; h is A_c6 alkyl, cyclo C3-C6 alkyl or -(Ci夂alkyl)_s〇n %·c0 alkyl), wherein any group is optionally substituted by M substituents, wherein each substituent is independently _, -H, _CN, _c(9) (heterocyclyl C3-C6 alkyl), _c(〇KKCVC6 alkyl), &lt;(〇)·aryloxy, alkoxy, decyl, decyloxy, cyclo-C3-C6 alkyl, heterocyclyl c3-c6 alkyl, aryl, hetero Aryl, carbonyl, aminemethanyl or -SOnXq-C6 alkyl); A is CH; R2 is aryl or heteroaryl, optionally substituted with from 1 to 5 substituents, wherein each substituent is independently halogen , -No, -COOH, carbonyl, -CN, -CVC6 alkyl, -S〇n_(Ci_C6 alkyl), 〇 aryl, -〇_heteroaryl, -C(O)-heterocyclyl a c3-c6 alkyl group, a -NH-cyclo C3-C6 alkyl group, an amine group, an -OH group or a C^C6 alkyl (amino group) substituent, wherein each substituent is independently -OH, _〇 (CrC6) Alkyl), -0(aryl), 68419-950628.DOC This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1280 240 si C8 ____D8 VI. Application for patent garden - COOH, -COOCCrC^^lO, halogen, -N02, -CN or -c(o)-n(c0-c6 alkyl)(cvc6 alkyl) substitution; R3 Is independently aryl, heteroaryl, -Ci-c6 alkyl, -Ci-c6 alkoxy, carbonyl, amine carbaryl, -C(0)0H, -(CrCgalkyl ysoyCrCg alkyl), - C(0)N((VC6 alkyl)(C0-C6 alkyl) or -Ci-c6 alkanoylamino, wherein any group is optionally substituted with from 1 to 5 substituents, wherein each substituent is Independently halogen, -N02, -C(0)0H, -CN, carbonyl, -C!-C6 alkyl, -SCVA-C6 alkyl), aryloxy, -heteroaryloxy, -C(O a heterocyclyl c3 -C6 alkyl, -NH-cyclo C3 -C6 alkyl, an amine group, a _ ο Η or a -C! -C6 alkyl (amino) substituent, wherein each substituent is independently By -OH, q-C6 alkoxy, aryloxy, -C(0)0H, -(:(0)0((^-C6 alkyl), lS, -N02, -CN or -C( 0) -N(C〇-C6 alkyl)(C0_C6 alkyl) substituted; one of R2 and R3 must be aryl or heteroaryl, optionally substituted; R4 is aryl, heteroaryl, -CN 'Carbonyl, amine carbaryl, -(q -C6 alkyl)-SOn-(C"C6 alkane , -C(0)N(CG-C6 alkyl XC〇-C6 alkyl) or -Ci-C6 decylamino group, wherein any group is optionally substituted with 1-5 substituents The substituents are independently carbonyl, -CN, halogen, -c(o) (&lt;vc6 alkyl), -Cl-C6 alkyl, -S〇n-(Cl_c6 alkyl), amine group, -0H or - q-C6 alkyl (amino); η is independently oxime, 1 or 2; and its aryl is selected from phenyl and naphthyl; heteroaryl is selected from acridinyl, quinolinyl, isoquinoline Base, hydrazine, pyrimidinyl, hydrazine, quinoxalinyl, furyl, benzofuran 68419-950628.DOC This paper scale applies to China National Standard (CNS) Α4 specification (210 X 297 mm) 1280240 A8 B8 C8 ___D8 _ Six, apply for patent ^ ' ^ a ~ US, - soil, a stupid and furanyl, thienyl, stupid and thienyl, pyrrolyl, indolinyl, pyrazolyl, carbazolyl, oxazol Base, isoxazolyl, thiazolyl, oxime, imidazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl sigma, tetradecyl; heterocyclic C3 -c6 alkyl Is selected from the group consisting of a nitrogen tetradecyl group, a tetrahydropyrrolyl group, a gas σ ratio bite group , hexahydro σ ratio cultivating base, phorolyl, tetrahydrofuranyl, diazinol, tetrahydropyrrole-2-one, hexahydropyridin-2-one and thiomorpholine. 2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Ri is -q-C6 alkyl, optionally substituted with 1-5 substituents. 3. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Ri is -cycloC3_C6 alkyl, optionally substituted with 1-5 substituents. 4. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R2 is aryl, optionally substituted with 1 to 5 substituents; and R3 is heteroaryl, optionally substituted by 丨-5 Substituted. 5. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein h is an aryl group, optionally substituted with 1 to 5 substituents; and is converted to an aryl group, optionally 1-5 Substituted for substitution. 6. The compound according to the scope of patent application i or its pharmaceutically acceptable salt, 68419-950628.DOC This paper scale applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 1280240 as B8 C8 心為々·^烷基，視情況被M個取代基取代； 化與R3各獨立為芳基或雜芳基，其中每一個係視产 況被1-5個取代基取代0 月 7.根據申請專利範圍第工項之化合物或其藥學上可接 鹽，其中 \，82及83各為H; Ri為-C6烷基，視情況被M個取代基取代； R2與R3各獨立為芳基或雜芳基，其中每一個係 況被1-5個取代基取代。 8·根據申請專利範圍第丨項之化合物或其藥學上可接受之 鹽，其包括The heart is 々·^alkyl, optionally substituted by M substituents; and R3 are each independently aryl or heteroaryl, each of which is replaced by 1-5 substituents depending on the condition of production. A compound of the scope of the patent application or a pharmaceutically acceptable salt thereof, wherein \, 82 and 83 are each H; Ri is a -C6 alkyl group, optionally substituted by M substituents; R2 and R3 are each independently an aryl group Or a heteroaryl group in which each of the conditions is substituted with from 1 to 5 substituents. 8. A compound according to the scope of the patent application, or a pharmaceutically acceptable salt thereof, which comprises 68419-950628.DOC 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 128024068419-950628.DOC This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1280240 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1280240 Ss C8 D8 六、申請專利範圍 CH,This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1280240 Ss C8 D8 VI. Patent application scope CH, 68419-950628.DOC ·6- 本紙張尺度適用中國國家標準(CNS) Α4規格(210 x 297公釐) 1280240 六、申請專利範圍 A8 B8 C8 D868419-950628.DOC ·6- This paper size is applicable to China National Standard (CNS) Α4 specification (210 x 297 mm) 1280240 VI. Patent application scope A8 B8 C8 D8 68419-950628.DOC 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1280240 έβ8 C8 D868419-950628.DOC This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1280240 έβ8 C8 D8 12802401280240 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1280240 bs8 C8 D8This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1280240 bs8 C8 D8 1280240 六、申請專利範圍 68419-950628.DOC1280240 VI. Application for patent scope 68419-950628.DOC 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1280240 申請專利範圍 8 8 8 8 A BCDThis paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1280240 Patent application scope 8 8 8 8 A BCD NN 3 Η • Ν丫CH3 CH -12- 68419-950628.DOC 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 1280240 申請專利範園 A8 B8 C8 D83 Η • Ν丫CH3 CH -12- 68419-950628.DOC This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) 1280240 Patent application Fanyuan A8 B8 C8 D8 Ο CH,Ο CH, 13 68419-950628.DOC 本紙張尺度適用中國國家標準(CNS) Α4規格(210X297公釐) 8 8 8 8 A B c D 1280240 六、申請專利範園 Η313 68419-950628.DOC This paper scale applies to China National Standard (CNS) Α4 specification (210X297 mm) 8 8 8 8 A B c D 1280240 VI. Patent Application Park Η3 2 Η 68419-950628.DOC 本紙張尺度適用中國國家標準(CNS) Α4規格(210 X 297公釐) 4 8 8 8 8 ABCD 1280240 々、申請專利範圍2 Η 68419-950628.DOC This paper scale applies to China National Standard (CNS) Α4 specification (210 X 297 mm) 4 8 8 8 8 ABCD 1280240 々, patent application scope 68419-950628.DOC -15- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1280240 bs8 C8 D868419-950628.DOC -15- This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1280240 bs8 C8 D8 A8 B8 C8 D8 1280240 六、申請專利範圍A8 B8 C8 D8 1280240 VI. Patent application scope 68419-950628.DOC -17- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1280240 C8 D8 六、申請專利範園 ch368419-950628.DOC -17- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1280240 C8 D8 VI. Application for patent garden ch3 68419-950628.DOC -18- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1280240 bs8 C8 D868419-950628.DOC -18- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1280240 bs8 C8 D8 1280240 六、申請專利範園 A8 B8 C8 D81280240 VI. Application for Patent Park A8 B8 C8 D8 -20- 68419-950628.DOC 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1280240 Ββ C8 D8 六、申請專利範圍-20- 68419-950628.DOC This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1280240 Ββ C8 D8 VI. Patent application scope 裝 .訂 線Loading 68419-950628.DOC -21· 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 128024068419-950628.DOC -21· This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1280240 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐) A8 B8 C8 D8 1280240 々、申請專利範圍This paper scale applies to China National Standard (CNS) A4 specification (210 x 297 mm) A8 B8 C8 D8 1280240 々, patent application scope 68419-950628.DOC -23- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1280240 六、申請專利範圍 8 8 8 8 A B c D68419-950628.DOC -23- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1280240 VI. Patent application scope 8 8 8 8 A B c D ,ch3、b,ch3,b -24- 68419-950628.DOC 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) A8 B8 C8 D8 1280240 六、申請專利範圍-24- 68419-950628.DOC This paper size is applicable to China National Standard (CNS) A4 specification (210X 297 mm) A8 B8 C8 D8 1280240 VI. Patent application scope 或其藥學上可接受之鹽。 9·根據申請專利範圍第1項之化合物或其藥學上可接受之 鹽，其包括 6-異丙基-8-(3-{(Z/E)-2-[4-(甲磺醯基）苯基]-2-苯基乙烯基} 苯基 &gt;奎淋； -25- 68419-950628.DOC 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) A8 B8 C8 D8 1280240 六、申請專利範園 6-異丙基-8-{3-[(Z/E)-2-[4-(甲磺醯基）苯基]-2-(1，3·嘍唑-2-基） 乙烯基]笨基}喹啉； 6-異丙基-8-(3-{(Ε)-2-(1-甲基-1Η-咪唑-2-基）·2-[4-(甲磺醯基） 苯基]乙烯基}苯基 &gt;奎啉； 6_異丙基-8-(3-{(Ζ/Ε)-2-(4-氟苯基）-2-[4-(甲磺醯基）苯基]乙 婦基}本基）峻ν林； 2·(2-{(Ε/Ζ)-2-[3_(6-異丙基-8-喹啉基）苯基]小[4-(甲磺醯基） 苯基]乙烯基}-1,3-噻唑-5-基）-2-丙醇； 2-[8_(3-{(Ε/Ζ)-2-[5·(1-羥基-1-甲基乙基)-1，3-噻唑-2-基]-2·[4-(曱磺醯基）苯基]乙烯基}苯基）-6-喹啉基]-2-甲基丙腈； 2-甲基-2-[8-(3-{(Ε)-2-(1-甲基-1H-咪唑-2-基）-2-[4-(甲磺醯基） 苯基]乙烯基}苯基）-6^奎啉基]丙腈； 6-[1-(甲磺醯基）乙基]-8-{3-[(E)-2-[4-(甲磺醯基）苯基]-2_(1，3-ρ塞峻-2-基）乙婦基]苯基奎淋； 6-[1-甲基-1_(甲磺醯基）乙基]-8-{3-[(E)-2-[4-(甲磺醯基）苯 基]-2_(1，3-噻唑-2-基）乙烯基]苯基}喹啉； 8-(3_{(Ζ)_2·(1-甲基_1Η·咪嗤_2·基）_2_[4_(甲石黃醢基）苯基]乙 婦基}本基）-6-[1·(甲石黃酿基）乙基]t?奎淋； 8-(3-{(Ζ)-2-(1-甲基-1H-咪唑-2-基）-2-[4-(甲磺醯基）苯基]乙 婦基}本基）-6-[1-甲基-1_(甲石黃酿基）乙基]ρ奎琳； 6-[1-甲基-1_(甲磺醯基）乙基]各(3y(E/z)冬甲基4,2,4·噚 二嗤-5-基&gt;2-[4-(甲磺醯基）苯基]乙烯基}苯基）P奎啉； (E/Z)-HH6-(1-氰基-1-甲基乙基）-8“奎啉基]苯基}-N-異丙 基-2-[4-(甲磺醯基）苯基]-2-丙烯醯胺； 68419-950628.DOC 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) A8 B8 C8 D8 1280240 六、申請專利範圍 8-(3-{(Ε)-2-{3-[(4·甲氧基笨氧基）甲基]β1，2,4-嘮二唑-5-基}- 2-[4-(甲磺醯基）苯基]乙烯基}苯基•甲基小（甲石黃醯基） 乙基]喹啉； (5-{(Ε)-2-(3-{6-[1-甲基-1-(甲石黃醯基）乙基]奎淋基）苯基）_ 1-[4-(甲石黃醯基）苯基]乙豨基}_1，2,4-β号二嗤-3-基）甲醇； (Ε)-Ν-異丙基-3-(3-{6-[1-甲基-1-(甲磺醯基）乙基]冬喹啉基} 本基）-2-[4-(甲石黃酿基）苯基]-2-丙婦酿胺； (E)-3-{3_[6_(l-氰基-1_甲基乙基）各会琳基]苯基}_2-[4-(甲石黃 醯基）苯基]-2-丙烯酸； 2·甲基-2-[8·(3-{(Ε)-2-(3-甲基-1,2,4-17号二嗤-5-基）-2-[4-(甲續 醯基）苯基]乙烯基}苯基&gt;6-喳啉基]丙腈； (Ε)-3_{3_[6-(1亂基-1-甲基乙基）-8·峻淋基]苯基}-2_[4-(甲石黃 醯基）苯基]-2_丙烯醯胺； (E)-N-(第三-丁基）-3-{3-[6-(1-氰基小甲基乙基）各喹〃株基] 苯基卜2-[4-(甲磺醯基）苯基]-2-丙烯醯胺； (E)-3-[3-(6-異丙基-8-喳啉基）苯基]-2-[4-(甲磺醯基）苯基]-2-丙稀酸， 6-異丙基-8_(3_{(Ε)-2·(3-甲基-1，2,4-嘮二唑-5-基）-2-[4-(甲石黃 醯基）苯基]乙烯基}苯基 &gt;奎啉； (Ε)-3-(3_{6·[&gt;曱基小(甲磺醯基）乙基]各喳啉基}苯基)_2_ [4-(甲石頁酿基）苯基]-1-(1-四氫ρ比洛基）-2-丙稀-1_酉同； (E)-N-環丙基·3-(3-{6-[1-甲基小(甲磺醯基）乙基]各喹啉基} 苯基）-2-[4-(甲磺醯基）苯基]-2-丙烯醯胺； (Ε)-Ν_(第三-丁基）-3-(3-{6-[1-甲基小(甲磺醯基）乙基]各喹 27- 68419-950628.DOC 本紙張尺度適用中國國家標準(CNS) Α4規格(210X297公釐) 1280240 A8 B8 C8 D8_ 六、申請專利範圍 &quot; 一 琳基}苯基）-2-[4-(甲磺醯基）苯基]_2_丙烯醯胺； 8·{3-[2,2·雙（4_氣本基）乙婦基]苯基卜6-異丙基p奎琳； 6·異丙基-8-(3-{(Ε/Ζ)-2-(6_甲基-3-吡啶基）-2-[4-(甲磺醯基） 苯基]乙烯基}苯基）喹啉； 6-異丙基-8-(3_{(Ε/Ζ)-2·(5-甲基-2-ρ比咬基）-2-[4-(甲續醯基） 苯基]乙烯基}苯基）喹啉； 8-(3]2,2·雙[4-(甲磺醯基)苯基]乙烯基}苯基)冬異丙基喳啉； 2_甲基-2-[8·(3_{(Ε/Ζ)_2-(5·甲基·2_ρ比淀基)·2-[4·(甲石夤應基）苯 基]乙烤基}本基）-6-0奎琳基]丙猜； 2-[8-(3-{2,2-雙[4-(甲磺醯基）苯基]乙烯基}苯基）_心喹啉 基]-2·甲基丙腈； 2·曱基_2·(8_{3-[(Ε)-2-[4_(甲石黃醯基）苯基]比咬基）乙稀 基]本基卜6-?奎ρ林基）丙腊； 6-[1-甲基小（甲磺醯基）乙基]_8_(3-{(Ε/Ζ)·2-(5-甲基-2_咄咬 基）-2-[4-(甲磺醯基）苯基]乙烯基}苯基碎啉； 2-(6-{(Ε)-2-(3-{6-[1_甲基-1-(甲石黃醯基）乙基]-8-υ奎琳基}苯 基）-1-[4-(甲磺醯基）苯基]乙烯基}-3-吡啶基）-2-丙醇； 或其藥學上可接受之鹽。 10.根據申請專利範圍第1項之化合物或其藥學上可接受之 鹽，其包括 -28- 68419-950628.DOC 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 1280240 申請專利範圍 A8 B8 C8 D8Or a pharmaceutically acceptable salt thereof. 9. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, which comprises 6-isopropyl-8-(3-{(Z/E)-2-[4-(methylsulfonyl) Phenyl]-2-phenylvinyl}phenyl] quinine; -25- 68419-950628.DOC This paper scale applies to Chinese National Standard (CNS) A4 size (210X 297 mm) A8 B8 C8 D8 1280240 Sixth, apply for patent garden 6-isopropyl-8-{3-[(Z/E)-2-[4-(methylsulfonyl)phenyl]-2-(1,3·carbazole-2 -yl)vinyl]phenyl]quinoline; 6-isopropyl-8-(3-{(Ε)-2-(1-methyl-1Η-imidazol-2-yl)·2-[4- (Methanesulfonyl) phenyl]vinyl}phenyl&gt;quinoline; 6-isopropyl-8-(3-{(Ζ/Ε)-2-(4-fluorophenyl)-2-[ 4-(methylsulfonyl)phenyl]ethenyl}benzin) Junvlin; 2·(2-{(Ε/Ζ)-2-[3_(6-isopropyl-8-quinolinyl) Phenyl] small [4-(methylsulfonyl)phenyl]vinyl}-1,3-thiazol-5-yl)-2-propanol; 2-[8_(3-{(Ε/Ζ) -2-[5·(1-hydroxy-1-methylethyl)-1,3-thiazol-2-yl]-2·[4-(indolyl)phenyl]vinyl}phenyl) -6-quinolinyl]-2-methylpropionitrile; 2-methyl-2-[8-(3-{(Ε)-2-(1-methyl-1H-imidazol-2-yl)- 2-[4-(A Mercapto) phenyl]vinyl}phenyl)-6^ quinolinyl]propanenitrile; 6-[1-(methylsulfonyl)ethyl]-8-{3-[(E)-2-[ 4-(methylsulfonyl)phenyl]-2_(1,3-ρ stopper-2-yl)ethenyl]phenylquinidine; 6-[1-methyl-1_(methylsulfonyl) Ethyl]-8-{3-[(E)-2-[4-(methylsulfonyl)phenyl]-2-(1,3-thiazol-2-yl)vinyl]phenyl}quinoline; 8-(3_{(Ζ)_2·(1-methyl_1Η·米嗤_2·yl)_2_[4_(甲石黄醢基)phenyl]ethoxy}}}))-6-[1·( Ethyroid yellow base) ethyl]t? quino; 8-(3-{(Ζ)-2-(1-methyl-1H-imidazol-2-yl)-2-[4-(methylsulfonate) Phenyl]ethenyl}benzine)-6-[1-methyl-1_(methyl scutellaria)ethyl]ρ奎琳; 6-[1-methyl-1_(methylsulfonyl) Ethyl] each (3y(E/z) winter methyl 4,2,4·indenyl-5-yl&gt;2-[4-(methylsulfonyl)phenyl]vinyl}phenyl) P-quinoline; (E/Z)-HH6-(1-cyano-1-methylethyl)-8"quinolinyl]phenyl}-N-isopropyl-2-[4-(methylsulfonate) Benzo)phenyl]-2-propenylamine; 68419-950628.DOC This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) A8 B8 C8 D8 1280240 VI. Patent application scope 8 -(3-{(Ε)-2-{3-[(4.Methoxyoxy)methyl]β1,2,4-oxadiazol-5-yl}- 2-[4-(A Sulfhydryl)phenyl]vinyl}phenyl•methyl small (methylglycosyl)ethyl]quinoline; (5-{(Ε)-2-(3-{6-[1-methyl-1 -(甲石黄醯)ethyl]quinolyl)phenyl)_ 1-[4-(methioninyl)phenyl]ethenyl}_1,2,4-β-diin-3-yl)methanol ; (Ε)-Ν-isopropyl-3-(3-{6-[1-methyl-1-(methylsulfonyl)ethyl]wynindolinyl} benzyl)-2-[4- (A stone yellow base) phenyl]-2-propanol amine; (E)-3-{3_[6_(l-cyano-1_methylethyl) each liningyl]phenyl}_2 -[4-(methyl sulphate)phenyl]-2-propenoic acid; 2·methyl-2-[8·(3-{(Ε)-2-(3-methyl-1,2,4-17 No. 2 -5-yl)-2-[4-(methyl fluorenyl)phenyl]vinyl}phenyl&gt;6-carbolinyl]propionitrile; (Ε)-3_{3_[6-( 1 disordered-1-methylethyl)-8·Jinglin]phenyl}-2_[4-(methioninyl)phenyl]-2_acrylamide; (E)-N- (third -butyl)-3-{3-[6-(1-cyano small methylethyl) quinolinyl] phenyl b-2-[4-(methylsulfonyl)phenyl]-2- Acrylamide; (E)-3-[3-(6-isopropyl-8-carbolinyl)benzene ]-2-[4-(methylsulfonyl)phenyl]-2-propionic acid, 6-isopropyl-8_(3_{(Ε)-2·(3-methyl-1,2,4 -oxadiazole-5-yl)-2-[4-(methyl sulphate)phenyl]vinyl}phenyl&gt;quinoline;(Ε)-3-(3_{6·[&gt; (Methanesulfonyl)ethyl]polyporphyrin}phenyl)_2_[4-(methyl sulphate)phenyl]-1-(1-tetrahydro-p-l-yl)-2-propene- 1_酉;; (E)-N-cyclopropyl·3-(3-{6-[1-methylsuccinyl)ethyl]quinolinyl}phenyl]-2-[ 4-(methylsulfonyl)phenyl]-2-propenylamine; (Ε)-Ν-(tris-butyl)-3-(3-{6-[1-methyl small (methylsulfonyl) Ethyl] quinolin 27- 68419-950628.DOC This paper scale applies to China National Standard (CNS) Α4 specification (210X297 mm) 1280240 A8 B8 C8 D8_ VI. Patent application scope &quot; 一琳基}phenyl)- 2-[4-(methylsulfonyl)phenyl]_2-propenylamine; 8·{3-[2,2·bis(4-vapine)ethoxyphenyl]phenyl b-6-isopropyl P-quine; 6·isopropyl-8-(3-{(Ε/Ζ)-2-(6-methyl-3-pyridyl)-2-[4-(methylsulfonyl)phenyl] Vinyl}phenyl)quinoline; 6-isopropyl-8-(3_{(Ε/Ζ)-2·(5-methyl-2-ρ ratio) 2-[4-(methyl fluorenyl)phenyl]vinyl}phenyl)quinoline; 8-(3]2,2·bis[4-(methylsulfonyl)phenyl]vinyl}phenyl Winter isopropyl porphyrin; 2_methyl-2-[8·(3_{(Ε/Ζ)_2-(5·methyl·2_ρ ratio aryl)·2-[4·(甲石夤 should Base) phenyl]ethyl bake base} base)-6-0 quinine] Cyan; 2-[8-(3-{2,2-bis[4-(methylsulfonyl)phenyl]ethene }}phenyl)_heart quinolinyl]-2·methylpropionitrile; 2·fluorenyl_2·(8_{3-[(Ε)-2-[4_(甲石醯基)phenyl) than bite Ethyl)benzyl]benzib 6-? 奎ρ林基)propane; 6-[1-methyl succinyl)ethyl]_8_(3-{(Ε/Ζ)·2- (5-methyl-2-indole)-2-[4-(methylsulfonyl)phenyl]vinyl}phenyl porphyrin; 2-(6-{(Ε)-2-(3- {6-[1_Methyl-1-(methyl sulphate)ethyl]-8-fluorenyl}}phenyl)-1-[4-(methylsulfonyl)phenyl]vinyl}-3 -pyridyl)-2-propanol; or a pharmaceutically acceptable salt thereof. 10. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, which comprises -28-68419-950628. DOC. This paper scale applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 1280240 Patent scope A8 B8 C8 D8 11· 一種用於治療磷酸雙酯酶_ 4相關疾病之醫藥組合物，其 包含 治療上有效量之根據申請專利範圍第1項之化合物， 或其藥學上可接受之鹽；及 藥學上可接受之载劑。 12·根據申請專利範圍第丨丨項之醫藥組合物，其係用於治 療或預防氣喘、丨艾性枝氣管炎、慢性阻塞肺病（c〇pD)、 曰伊紅肉芽瘤、牛皮癬，及其他良性或惡性增生性皮膚 病内母*素休克（及有關聯之症狀，譬如在馬中之板層 炎與急性腹痛）、敗血性休克、潰瘍性結腸炎、克隆氏 病、心肌與腦部之再灌注傷害、炎性關節炎、骨質疏鬆 症、慢性絲球體性腎炎、異位性皮炎、專麻疹、成人呼 吸困難徵候簇、幼兒呼吸困難徵候簇、在動物中之慢性 阻塞肺病、尿崩症、過敏性鼻炎、過敏性結合膜炎、春 季結合膜炎、動脈再狹窄、動脈粥瘤硬化、神經性發 炎、疼痛、咳嗽、風濕性關節炎、關節黏連脊椎炎、移 植排斥與移植物對宿主疾病、胃酸過度分泌，細菌、真 菌或病毒所引致之敗血病或敗血性休克、發炎及細胞活 68419-950628.DOC 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1280240 b C/8 D8 六、申請專利範圍 素所媒介慢性組織變性、關節炎、癌症、惡病質、肌肉 消耗、抑鬱、記憶力減弱、單極性抑鬱、具有炎性成份 之急性與慢性神經變性病症、巴金生氏疾病、阿耳滋海 默氏疾病、脊髓外傷、頭部傷害、多發性硬化、腫瘤生 長及正常組織之癌侵入，其包含治療上有效量或預防上 有效量之根據申請專利範圍第1項之化合物或其藥學上 可接受之鹽。 68419-950628.DOC -30- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐)A pharmaceutical composition for treating a phosphodiesterase-4-related disease, comprising a therapeutically effective amount of a compound according to claim 1 of the patent application, or a pharmaceutically acceptable salt thereof; and pharmaceutically acceptable Carrier. 12. The pharmaceutical composition according to the scope of the patent application for the treatment or prevention of asthma, sputum bronchitis, chronic obstructive pulmonary disease (c〇pD), sputum granuloma, psoriasis, and others Benign or malignant proliferative skin disease endogenous sulphate (and related symptoms, such as laminitis and acute abdominal pain in horses), septic shock, ulcerative colitis, Crohn's disease, myocardium and brain Reperfusion injury, inflammatory arthritis, osteoporosis, chronic glomerulonephritis, atopic dermatitis, arthritis, adult dyspnea syndrome, dyspnea syndrome in children, chronic obstructive pulmonary disease in animals, diabetes insipidus , allergic rhinitis, allergic conjunctivitis, spring combined with membranous inflammation, arterial restenosis, atherosclerosis, neurological inflammation, pain, cough, rheumatoid arthritis, joint adhesion spondylitis, transplant rejection and graft pair Host disease, excessive secretion of gastric acid, septicemia or septic shock, inflammation and cell activity caused by bacteria, fungi or viruses 68419-950628.DOC This paper scale applies to China Home Standard (CNS) A4 Specification (210 X 297 mm) 1280240 b C/8 D8 VI. Patent Application: Chronic Tissue Degeneration, Arthritis, Cancer, Cachexia, Muscle Consumption, Depression, Memory Loss, Unipolar Depression Acute and chronic neurodegenerative disorders with inflammatory components, Parkinson's disease, Alzheimer's disease, spinal cord trauma, head injury, multiple sclerosis, tumor growth, and cancer invasion of normal tissues, including therapeutic treatment An effective amount or a prophylactically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof. 68419-950628.DOC -30- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm)
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