TWI327470B - Substituted pyrrolo-pyrazole derivatives as kinase inhibitors - Google Patents
Substituted pyrrolo-pyrazole derivatives as kinase inhibitors Download PDFInfo
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- TWI327470B TWI327470B TW092135527A TW92135527A TWI327470B TW I327470 B TWI327470 B TW I327470B TW 092135527 A TW092135527 A TW 092135527A TW 92135527 A TW92135527 A TW 92135527A TW I327470 B TWI327470 B TW I327470B
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Classifications
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Description
1327470 玖、發明說明:· 【發明所屬之技術領域】 本發明係有關吡咯吡唑衍生物,其製備方法, 化合物之醫藥組成物,及其用作為治療劑特別用 症及細胞增殖病症之用途。 【先前技術】 若干胞毒藥物例如氟尿嘧啶(5 - F U )、阿黴素 (d ο X 〇 r u b i c i η )及喜樹驗類,破壞D N A或影響細胞 結果於許多病例造成細胞週期的間接阻斷。因此 劑對正常細胞及腫瘤細胞造成不可逆損傷,結果 毒性及副作用。 就此方面而言,需要有可經由選擇性導致腫瘤 停止及細胞凋亡,而作為高度特異性抗腫瘤劑, 前使用藥物具有可相媲美的效果但毒性較低。 眾所周知通過細胞週期的進行係受到一系列檢 制(也稱作為約束點),檢查點係藉一族稱作為週 (Cyclin)依賴型激酵素(Cdk)酵素調節。Cdks本. 個層面調節,例如結合至週期素。 不同C d k /週期素複合物等協調活化及去活化乃 期正常進行所需。關鍵性G卜S及G 2 - Μ之變遷係 C d k /週期素活性活化所控制。於G 1 , C d k 4 /週期素] 週期素E媒介S-期的起點。前進通過S期,需要 期素A活性,而Cdc2/週期素A(Cdkl)及Cdc2/週 活化為有絲分裂的起點所需。有關為週期素及週 型激酵素之一般參考文獻例如Kevin R. Webste 312/發明說明書(補件)/93-03/92135527 包含該等 於治療癌 代謝路徑 ,此等藥 導致顯著 細胞增殖 且比較目 查點控 期素 身又於多 細胞週 由不同 )及 C d k 2 / C d k 2 / 週 期素B之 期素依賴 e t a 1 , 6 1327470 in Exp. Op in. Invest. Drugs,1998,V o1. 7(6), 8 8 7 ° 腫瘤細胞的檢查點控制部分由於c d k活性的調節失 而有缺陷。例如於腫瘤細胞觀察得週期素E及c d k s表 改變,小鼠cdk抑制劑p27 KIP基因的刪失,結果導 症發生率增高。 有更多證據證實cdks為細胞週期進行的速率限制症 構想,如此c d k s構成治療性介入的分子標把。特別, 抑制cdk/週期素激酵素活性將有助於限制腫瘤細胞之 調增殖。 【發明内容】 本發明之目的係提供可用於治療經由細胞週期依賴 激酵素活性變更所引起及/或關聯的細胞增殖病症。本 之另一目的係提供具有c d k /週期素激酵素抑制活性之 合物。 本發明人發現若干吡唑化合物具有c d k /週期素激酵 抑制活性,如此可用作為抗腫瘤劑之治療,以及就毒 副作用兩方面而言,沒有前述目前使用之抗腫瘤藥物 關缺點。 特別,本發明°比唑衍生物可用於治療多種癌症包括 非限制性):癌瘤例如膀胱癌、乳癌、結腸癌、腎癌、肝 肺癌包括小細胞肺癌、食道癌、膽囊癌、卵巢癌、胰 胃癌、子宮頸癌、甲狀腺癌、攝護腺癌、及皮膚癌包 狀細胞癌;造血細胞淋巴細胞系腫瘤包括血癌、急性 細胞性血癌、急性淋巴母細胞性血癌、B細胞淋巴瘤 3丨2/發明說明書(補件)/93-03/92丨35527
8 6 5 - 調因 現的 致癌 r素 直接 失 型 發明 化 素 性及 的相 (但 癌、 癌、 括鱗 淋巴 、T 7 1327470 細胞淋巴瘤、何杰_金氏淋巴瘤、非何杰金氏淋 、髮狀細胞淋巴瘤及波奇氏淋巴瘤(B u r k e 11 ’ s 1 y in p h o m a );造血系統骨髓細胞系腫瘤包括急性 性白血病、骨髓發育不全症候群以及前骨髓細 病;間質細胞來源腫瘤包括纖維肉瘤及橫紋肌 經系統及周邊神經系統腫瘤,包括星狀細胞瘤 胞瘤、神經膠瘤及許旺氏瘤;其它腫瘤包括黑 胞瘤、睪丸癌、骨肉瘤、著色性乾皮病、角化 狀腺濾泡癌及卡波西氏肉瘤。 由於cdks於細胞增殖之調節扮演的關鍵角| 。坐衍生物也可用於治療多種細胞增殖病症,例 腺增生、家族性腺腫息肉、神經纖維瘤、乾癣 硬化相關之血管平滑肌細胞增生、肺纖維硬變 腎小球性腎炎及術後血管狹窄及再狹窄。 本發明化合物可用於治療阿茲海默氏病,如 tau蛋白質之罐酸化所提示(J. Biochem. 117 1 9 9 5 ) ° 本發明化合物作為細胞凋亡調節劑,也可用 症、病毒感染、預防Η I V感染個體出現愛滋病 病及神經退化病症。
本發明化合物可用於抑制腫瘤血管新生及腫 及治療器官移植排斥及宿主抗移植物(h 〇 s t ν e I 病。 本發明化合物也可作為其它蛋白質激酵素抑 蛋白質激酵素例如不同同質異形體之蛋白質激 312/發明說明書(補件)/93-03/92135527 巴瘤 及慢性骨髓 胞性白血 瘤;中柩神 、神經母細 素瘤、精細 性黃瘤、曱 L ,此等0比 如良性攝護 、動脈粥狀 、關節炎、 c d k 5涉及 ,741-749, 於治療癌 、自體免疫 瘤轉移,以 'sus graft) 制劑,該等 酵素C、 8 1327470
Met ' PAK-4、 PAK-5、 ZC-1、 STLK-2、 DDR-2、 Aurora 1、 Aurora 2、 Bub-1、 PLK' Chkl ' Chk2、 HER2、 rail' MEK1 、MAPK、 EGF-R、 PDGF-R、 FGF-R、 IGF-R、 P13K、威爾(Weel) 激酵素、Src、 Abl 、 Akt' MAPK、 ILK、 MK-2、 IKK-2、Cdc 7、Nek,因此本發明化合物可用於治療與其它蛋白 質激酵素相關疾病。 本發明化合物也可用於治療及預防放射性治療誘生之 禿髮或化學治療誘生之禿髮。 如此,本發明提供一種治療細胞增殖病症之方法,該細 胞增殖病症係由於細胞週期依賴型激酵素活性變更所引起 及/或關聯,該方法係經由對有需要的哺乳類投予有效量式 (I a )或(I b )表示之nt。坐衍生物
其中 R為基團-C0Ra、-C0NHRa或- C0NRaRh其中1^及Rh各自分別 為氮或選自直鍵或分支Ci-Ce炫基、C3_C6環炫•基 '芳基 、芳基烷基、雜環基或雜環基烷基之選擇性經取代之基图 或;Ra及Rh連同其鍵結之氮原子形成一個選擇性含有另一 個選自N、N Η、0或S之雜原子或雜原子基團之選擇性經取 代之5員或6員雜環; h係選自下列基團組成的群組: a)直鍵或分支C3-C<烧基; 9 3丨2/發明說明書(補件)/93-03/92丨35527 1327470 b )環烷基、環烷基-烷基或烷基-環烷基,其中該環烷基部 分包含C3-C 6環烷基,以及其中該烷基部分包含任何直鏈 或分支Cl_C·!烧基; c) 3-曱基噻吩-2-基;2-噻吩基;苯基;2 ,6 -二氟苯基;4-(胺 基磺醯基)苯基;4-(二曱基胺基曱基)苯基;4-(4 -曱基 °底°井基)甲基-苯基; d) 式(Ila)或(lib)基團:
其中式(I I a ),環表示一個5員至7員雜環系環,其中直接 鍵聯至分子其餘部分之X表示碳原子或氮原子;Y為碳原 子、氮原子、氧原子或硫原子或為NH基,但X及Y中之至 少一者非為碳原子;Re於式(I I a)雜環系環的自由位置之 任一位置,各自分別為鹵原子或羥基,或ΙΓ為選自直鏈或 分支C I - C 6烷基、C 3 - C s環烷基、芳基、芳基烷基、雜環基、 雜環基烷基、胺基、胺基羰基、羧基、酮基(=0 )、烷氧羰 基、烷基羰基或芳基羰基之選擇性經取代之基團;以及η 為0或1至4之整數; e)式(lie)或(lid)基團: 其中1^、1^"及ΙΓ為相同或相異且各自分別表示氫原子或 選擇性經以一或多個選自羥基(-0 Η )、胺基羰基(-C 0 N Η 2) 10 312/發明說明書(補件)/93-03/92丨35527 1327470 或曱基胺基羰基(-CONHCHO之基團取代之直鏈或分 C I _ C 6坑基; 但式(la)中,當R,為式(lie)基團以及Rd或R’d2 氫原子,而!^或R’di另一者為乙基或正丁基時, -C 0 Ra,而Ra係作為3 -溴苯基、苄基、4 -第三丁基 4-第三丁基苯基曱基、4 -氟苯基甲基、環丙基或2· 基; 或其醫藥上可接受之鹽。 前述方法之較佳具體實施例中,細胞增殖病症係 癌症、阿茲海默氏病、病毒感染、自體免疫病及神 病症組成之群組。 可治療之特定類型癌症包括癌瘤、鱗狀細胞癌、 胞系或淋巴細胞系之造血系統腫瘤、間質細胞來源 瘤、中樞神經系統及周邊神經系統腫瘤、黑素瘤、 瘤、睪丸癌、骨肉瘤、著色性乾皮病、角化性黃瘤 腺濾泡癌及卡波西氏肉瘤。 於前述方法之另一具體實施例中,細胞增殖病症 由良性攝護腺肥大、家族性腺腫息肉、神經纖維瘤 癬、動脈粥狀硬化相關之血管平滑肌細胞增生、肺 變、關節炎、腎小球性腎炎及術後血管狹窄及再狹 外,本發明方法提供腫瘤血管新生及腫瘤轉移抑制 官移植排斥及宿主抗移植物病之治療。本發明方法 細胞週期抑制或c d k /週期素依賴型抑制。 除前述外,本發明方法目的提供放射性治療誘生 化學治療誘生禿髮之治療及預防。 312/發明說明書(補件)/93-03/92135527 支 一者為 R非為 苯基、 -萘基甲 選自由 經退化 骨髓細 之腫 精細胞 、曱狀 係選自 病、乾 纖維硬 窄。此 以及器 也提供 禿髮或 11 1327470 本發明也提供一種式(I a )或(I b )表示之吡唑衍生物
R為基團-C0Ra、 -C0NHRa或-C0NRaRb,其中Ra及Rh各自分 別為氫或選自直鍵或分支Cl-Cs院基、C3-C6環院基、芳基 、芳基烷基、雜環基或雜環基烷基之選擇性經取代之基團 或;RB及Rb連同其鍵結之氮原子形成一個選擇性含有另一 個選自N、N Η、0或S之雜原子或雜原子基團之選擇性經取 代之5員或6員雜環;. . R!係選自下列基團組成的群組: a)直鍵或分支C3-C4院基; b )環烷基、環烷基-烷基或烷基-環烷基,其中該環烷基部 分包含Cn-Ce環烷基,以及其中該烷基部分包含任何直鏈 或分支Cl_C4烧基; c) 3-曱基噻吩-2 -基;2_噻吩基;苯基;2’6 -二氟苯基;4-(胺 基磺醯基)苯基;4-(二曱基胺基甲基)苯基;4-(4 -甲基 。底。井基)曱基-苯基; d) 式(Ila)或(lib)基團:
其中式(I I a ),環表示一個5員至7員雜環系環,其中直接 鍵聯至分子其餘部分之X表示碳原子或氮原子;Y為碳原 子、氮原子、氧原子或硫原子或為NH基,但X及Y中之至 12 312/發明說明書(補件)/93-03/92135527 1327470 少一者非為碳原子;Re於式(I I a )雜環系環自1 一位置,各自分別為鹵原子或羥基,或IT為選 支Cl- C6坑基、C3-C1;環烧基、芳基、芳基院基 雜環基烷基、胺基、胺基羰基、羧基、酮基(= 基、烷基羰基或芳基羰基之選擇性經取代之基 為0或1至4之整數; e)式(lie)或(lid)基團: r r —' —Ο R'd (He) did) 其中…、尺^及Re為相同或相異且各自分別表 選擇性經以一或多個選自羥基(-0 Η )、胺基羰2 或曱基胺基羰基(-C0NHCHO之基團取代之直鏈 C I - C ϋ坑基; 但式(la)中,當R,為式(lie)基團以及Rd* R 氫原子,而1^或Rd之另一者為乙基或正丁基 -C 0 R a,而R a係作為3 -溴苯基、苄基、4 -第三 4 -第三丁基苯基曱基、4 -氟苯基曱基、環丙基 基; 或其醫藥上可接受之鹽。 本發明也包括式(I a )或(I b )表示之。比。坐衍生 成,除非另行規定,否則可方便地如式(I )化合 義。包含式(I )。比°坐衍生物之醫藥組成物也含括 經由參照後文詳細說明將更了解本發明及其 項優點。 【貫施方式】 3丨2/發明說明書(補件)/93-03/92135527 3位置之任 自直鍵或分 、雜環基、 0)、烷氧羰 團;以及η 示氫原子或 t (-CONHz) 或分支 之一者為 時,R非為 丁基笨基、 或2 -萘基甲 物之合 物分組及定 •於本發明。 伴隨之多 13 1327470 若干雜環化合物為業界已知作為蛋白質激酵素抑制 劑。舉例言之,2 -羧醯胺基吡唑類及2 -脲基-吡唑類及其 衍生物曾經於國際專利申請案W 0 0 1 / 1 2 1 8 9、W 0 01/12188' WO 02/48114 及 WO 02/70515(全部皆由本案申 請人提出申請)揭示作為蛋白質激酵素抑制劑。 包含吡唑部分及具有激酵素抑制活性之稠環雙環化合 物也揭示於 WO 00/69846 及 WO 02/12242 以及 WO 03/ 028720(PCT/EP02/10534 請求 2001 年 9 月 26 日美國專利 申請案第09/962162號之優先權)以及共同審查之 PCT/EP03/04862C請求2002年5月17日美國專利中請案 6 0 / 3 8 1 0 9 2之優先權)各案申請人皆為本案申請人。 本發明之化合物目的係落入前述W 0 0 2 / 1 2 2 4 2之通式之 範圍,該案以引用方式併入此處,該案4匕合物並未特別於 此處舉例說明。 除非另行規定,當參照式(I )化合物本身以及任一種醫 藥組成物或任一種包含該等醫藥組成物之治療處理時,本 發明包括本發明化合物之全部水合物、溶劑合物、錯合物、 代謝產物及前驅藥。前驅藥為任一種共價鍵結化合物,其 於活體内根據式(I )而釋放出活性親代藥物。 式(I )化合物之代謝產物為任一種於活體内例如投予有 需要之哺乳動物體内可轉成本式(I )化合物之任一種化合 物。 典型地,但非表示限制例,當投予式(I )化合物時,該 衍生物可被轉成多種化合物,例如包括容易排泄之較為可 溶性衍生物例如羥化衍生物。如此,依據代謝途徑而定, 14 312/發明說明書(補件)/93-03/92丨35527 1327470 任一種經化衍生物皆可視為式(i)化合物之代謝產物。 若對掌中心或另一種異構中心形式存在於本發明化合 物,則全部此等異構物形式或異構物包括對映異構物及非 對映異構物意圖皆涵蓋於本發明。含有一個對掌中心之化 合物可呈外消旋混合物使用,對映異構豐富混合物或外消 旋混合物可使用眾所周知之技術分離,而可單獨使用個別 對映異構物。當化合物具有不飽和碳-碳雙鍵時,順(z)異 構物及反(E)異構物係屬於本發明之範圍。其中化合物可呈 互變異構形式例如酮基-烯醇互變異構物存在,各別互變異 構形式無論是否平衡存在或主要呈一種形式存在預期皆含 括於本發明之範圍。 此處說明中,除非另行陳明,否則直鏈或分支C i - C 6烷 基(因而涵蓋C! - C 4烷基一詞),意圖表示例如曱基、乙基、 正丙基、異丙基、正丁基、異丁基、第三丁基、第二丁基、 正戊基、正己基等基團。 C3-CB環烷基一詞除非另行規定,否則意圖表示環脂族環 例如環丙基、環丁基、環戊基及環己基。 芳基一詞包括帶有1或2個環部分彼此稠合或藉單鍵鍵 聯之碳環系烴或雜環系烴,其中至少一個環為芳香族;於 存在時,任何芳香族雜環系烴也稱作為雜芳基,包含一個 具有1至3個選自Ν、ΝΗ、0或S之雜原子或雜原子基之5 員或6員環。 根據本發明之芳基例如為苯基、聯苯基、α或点-萘基、 二氫萘基、噻吩基 '苯并噻吩基、呋喃基、苯并呋喃基、 。比°各基、σ米吐基、。比。坐基、°塞。坐基、異。塞。坐基、。琴。坐基、 15 312/發明說明書(補件)/93-03/92135527 1327470 異0笔。坐基、°比。定基、。比。丼基、。密。定基、。荅D片基、。5丨0朵基、 異吲哚基、嘌呤基、喳啉基、異喳啉基、二氫喳啉基、喳D驾啉 基、苯并二氧一烯戊環基、四氫薛基、茚基、三唑基等。 除非另行陳明,否則雜環或雜環基一詞包括含1至3個 選自Ν、ΝΗ、0或S之雜原子或雜原子基之5或6員飽和、 部分不飽和或完全不飽和雜環。 除了完全不飽和雜環外,先前稱作為芳香族雜環且由芳 基一詞所涵蓋之根據本發明之飽和或部分不飽和雜環例如 。比喃、0比°各D定、0比〇各琳、0米0坐琳、哺0坐。定、0比。坐0ί、°比吐 啉、噻唑啉、噻唑啶、二氫呋喃、四氫呋喃、1,3 -二氧一 稀戊環、°底。定、°底°井、嗎琳等。 當述及本發明化合物其t h屬於(b)組時,1^本身可表 示指定環烷基例如環丙基;指定環烷基-烷基例如環丙基曱 基;或甚至指定烷基-環烷基例如曱基環丙基;全部皆具有 下式:
環坑基 環烧基_炫基 烧基-¾烧基 當述及本發明化合物其中Ri為式(Ila)基團時,5員至7 員雜環系環直接透過X原子鍵聯至分子其餘部分如後:
例如此等5員至7員雜環包括任一個前文已經報告之5 16 312/發明說明書(補件)/93-03/92135527 1327470 環。任 雜等時 員 -在 β 雜存 至 氮 若 員 氧 外 此 雜 II 如 例 環 雜 員
雜 II 式 於 位 而 子 原 氫 個 1 換 置 由 經 C R 個 式 為 〇 R 置 中 位其 由物 自 合 個化 一 明 任發 之本 環及 系 述 環 當 ίι 或 圑 基 亞 下 如 有 具 物 生 酯 酸 基 胺r\ 或 物 生 " 基 脲7) 為r\ 別 -*--0 可 時式
N 人 ο R, C丄
e R 明 發 本 據 根 於 團 基 C R 及 h R · a R 述 前 否 定 規 行 另 ^ d 非 N—R 除 其任一個自由位置可經以一或多個例如1至6個分別選自 下列群組之基團選擇性取代:齒原子、硝基、酮基(=0)、 氰基、烷基、多氟化烷基、多氟化烷氧基、烯基、炔基' 羥基烷基、芳基、芳基烷基、雜環基、環烷基、羥基、烧 氧基、芳氧基、雜環基氧基、亞曱基二氧基、烷基羰基氧 基、芳基羰基氧基、環烯基氧基、亞烷基胺基氧基、羧基、 烷氧羰基、芳氧羰基、環烷氧羰基、胺基、脲基、烷基胺 基、二烷基胺基、芳基胺基、二芳基胺基、甲醯胺基、烷 基羰基胺基、芳基羰基胺基、雜環羰基胺基、烷氧羰基胺 基、烷氧基亞胺基、烷基磺醯胺基、芳基磺醯胺基、曱醯 基、烷基羰基、芳基羰基、環烷基羰基、雜環基羰基、胺 基羰基、烷基胺基羰基、二烷基胺基羰基、烷基磺醯基、 芳基磺醯基、胺基磺醯基、烷基胺基磺醯基、二烷基胺基 續醯基、芳硫基及烧硫基。 . 就此方面而言,有關鹵原子一詞表示氤、氣、漠或峨原 17 3丨2/發明說明書(補件)/93-03/92135527 1327470 子。 至於烯基或炔基等詞,表示前述任一種直鏈或分支(:2-(:〇 烷基進一步帶有一個雙鍵或參鍵。本發明之烯基或炔基之 非限制例例如乙烯基、丙烯基、1 -丙烯基、異丙烯基、1 -丁烯基、2 -丁烯基、3 -丁烯基、2 -戊烯基、1-己烯基、乙 炔基、2-丙炔基、4-戊炔基等。 全氟化烷基或烷氧基等詞,意圖表示前述直鏈或分支 C, - C G烷基或烷氧基,其經以多於一個氟原子取代例如三氟 曱基、三氟乙基、1,1,1,3,3,3 -六氟丙基、三氟曱氧基等。 烷氧基、芳氧基、雜環氧基及其衍生物等詞,意圖表示 前述任一個烧基、芳基或雜環基透過一個氧原子(-〇-)而鍵 聯至分子其餘部分。 由前文說明,熟諳技藝人士顯然易知複合名稱基團例如 環烷基烷基、芳基烷基、雜環基烷基、烷氧基、烷硫基 、芳氧基、芳基烷氧基、烷基羰基氧基、芳基烷基、雜環 基烷基等係表示其衍生之各部分之習知定義。例如雜環基 烷氧基之基團為烷氧基例如烷基氧基,其中該烷基部分進 一步經以一個雜環基取代,以及其中該烷基及雜環基定義 如前。 式(I )化合物之醫藥上可接受之鹽包括與無機酸或有機 酸生成之酸加成鹽,該等酸例如硝酸、氫氣酸、氫溴酸、 硫酸、過氣酸、磷酸、乙酸、三氟乙酸、丙酸、乙醇酸、 乳酸、草酸、丙二酸、蘋果酸、順丁烯二酸、酒石酸、檸 檬酸、苯甲酸、桂皮酸、扁桃酸、甲烷磺酸、羥基乙基磺 酸及水楊酸。較佳本發明化合物之酸加成鹽係選自鹽酸鹽 18 312/發明說明書(補件)/93-03/92135527 1327470 或甲坑$黃酸鹽。 式(I )化合物之醫藥上可接受之鹽也包括與無機鹼或有 機鹼生成之鹽,使用之鹼例如為鹼金屬或鹼土金屬特別為 鈉、鉀、鈣或鎂氫氧化物、碳酸鹽或碳酸氫鹽、無環胺類 或環狀胺類,較佳為甲基胺、乙基胺、二乙基胺、三乙基 胺、哌啶等。 第一類較佳式(I a )或(I b)化合物係以下述衍生物表 示,其中R為基團-C0Ra,Ra定義如前以及R,為第三丁基。 另一類較佳式(I a )或(I b )化合物係以下述衍生物表 示,其中R為基團-C0NHRa,Ra定義如前以及!^為第三丁 基。 另一類較佳式(I a )或(I b )化合物係以下述衍生物表 示,其中R為基團-C0NRHRb,厂及Rb定義如前以及R,為第 三丁基。 另一類較佳式(I a )或(I b )化合物係以下述衍生物表 示,其中R定義如前,R!為式(Ila)基團選自:
其中ΙΓ具有前文報告之定義。 另一類較佳式(I a )或(I b )化合物係以下述衍生物表 示,其中R定義如前,R,為式(Ila)基團選自:
其中ΙΓ具有前文報告之定義。 19 3丨2/發明說明書(補件)/93-03/9213^27 1327470 前述各類別中,特佳為式(I a )化合物其中R為基團 -C0Ra > 1^為4 -氟苯基或環丁基,以及R!定義如通式。 也特佳為式(la)化合物,其中R定義如通式,以及Ri 為選自第三丁基、1-曱基-哌啶-4-基、1-曱基-哌喷-4-基、 2-(R,S)_ra氫°夫喃-2-基、2-(R) -四氫°夫喃-2-基或2-(S)-四氫σ夫喃-2-基之基團。 概略參照本發明之任一種特定式(I )化合物,選擇性呈 醫藥可接受之鹽形式,參考實驗乙節。 如前文指示,本發明之又一目的為製備式(I )化合物之 方法。 因此,式(I)化合物及其醫藥上可接受之鹽可經由一種 方法獲得,該方法包含: a )式(I I I a )或(I I I b )化合物: 乂 (ma) h2n cooh h2n
(mb) COOH 與丙稀猜反應,獲得對應式(I V a )或(I V b )衍生物 又 COOH (tVb) y NC-^-n COOH . NC (IVa) b )保護式(I V a )或(I V b )化合物之胺基,獲得對應式(V a )或 (V b )衍生物
'N COOH y cooh nc Q (Va) Q (Vb) 其中Q為適當胺基保護基; c )式(V a )或(V b )化合物與適當烷化劑反應,獲得式(V I a ) 或(V I b )對應酯衍生物 20 3丨2/發明說明書(補件)/93-03/92丨35527 1327470 乂_
COOAIk (Vlb) NC、/ 、ν· COOAIk \ Q (Via) 其中Aik表示適當Ci-Ca烷基; 獲得對應式 d)式(Via)或(Vlb)化合物與氫化鈉(NaH)反應 (V I I a )或(V I I b )衍生物
e)式(Vila)或(Vllb)化合物與肼水合物反應而獲得式 (V I I I a )或(V I I I b )化合物
f )式(V I I I a)或(V I I I b )化合物與氣曱酸乙酯反應而獲得式 (I X a )或(I X b )衍生物,各自係呈兩種幾何異構形式之任一 種
以及式(I X a )或(I X b )化合物根據(g · 1 )、( g _ 2 )或(g . 3 )之任 一步驟反應 g. 1)與式(X)化合物反應 RaC0-Z (X) 其中IT定義如前以及Z為鹵原子,獲得式(XIa)或(Xlb) 化合物 21 3 12/發明說明書(補件)/93-03/92135527 1327470
HN\ R
HN\ R 其中R為基團-COR g · 2 )與式(X I I )化合物 (XII) 其中Ra定義如前,獲得式(XIa)或(Xlb)化合物其中R為基 團-C0NHRa ;或 g. 3)與式(XIII)適當胺,於三光氣或適當氣甲酸酯存在下 反應
HNRaR (XIII) 其中R a及R h定義如前,獲得式(X I a )或(X I b )化合物,其 中R為基團-C0NRaRh ; h )根據(g . 1 )至(g · 3 )任一步驟製備之式(X I a )或(X I b )化合 物之胺基脫去保護,因而獲得對應式(X I V a )或(X I V b )衍生
其中R定義如前;以及式(XlVa)或(XlVb)化合物根據其它 步驟(i.l)、(i.2)、(i.3)或(i.4)之任一步驟反應 i . 1 )與式(X V )醯基鹵衍生物反應 R 丨-C0Z (XV) 其中Ri係如式(la)或(lb)於(a)、(b)、(c)群組所述、式 (I I a ),X為碳原子以及式(I I b)所述,以及Z為鹵原子因 22 312/發明說明書(補件)/93-03/92丨35527 1327470 而獲得式(X V I a )或(X V I b )化合物
i · 2 )與5員至7員式(X V I I )雜環化合物或式(X V I I I 於三光氣存在下反應 適當胺
HN(R〇)R'd (XVIII) 其中X為NH及Y、Rc、n、Rd& R’d定義如前,獲得 (XVIa)或(XVIb)化合物,其中R定義如前,以及Ri為 基團,而X為氮原子,以及R、Y、R。及η定義如前 (lie)基圑其中1^及R’d定義如前; i . 3 )與式(X I X )羧酸於適當縮合劑存在下反應 對應式 式(I la) ,或式 R. -COOH (XIX) 獲得式(X V I a )或(X V I b )化合物,其中R ,係如式(I a ) 之(a)、(b)、(c)群組所述,或Ri為式(Ila)基團而 原子,或式(lib)基團,以及R、Y、Rc及η定義如 i . 4 )與式(X X )化合物反應 R. -C0Z (XX) 其中R !為式(I I d )基團,以及Z為氣原子或溴原子 獲得式(XVIa)或(XVIb)化合物,其中R定義如前以 為式(lid)基團;以及 j )根據(i · 1 )至(i . 4 )之任一步驟製備之式(X V I a )或 化合物於鹼性條件下反應,獲得對應式(I a )或(I b) 或(I b ) X為碳 前; ,因而 及R, (XVIb) 衍生 3丨2/發明說明書(補件)/93-03/92135527 23 1327470 物,其中.R及RI定義如前,以及選擇性地, k )將其分別轉成其它式(I a )或(I b )化合物,及/或轉 藥上可接受之鹽。 前述方法為根據業界眾所周知可進行之類似方法 首先,業界人士顯然易知,根據前述方法製備之 或(I b)化合物呈異構物混合物獲得時,其根據任一 技術分離成單一式(I a )或(I b )異構物仍然屬於本發 圍。 同理,根據眾所周知方法,其對應鹽轉成自由態 (I a )或(I b )亦屬於本發明之範圍。 根據該方法步驟(a ),式(I I I a )或(I I I b )化合物I 月青於適當鹼如氫氧化鈉存在下反應。反應較佳係於 -1 0 °C至室溫之溫度進行。 根據該方法步驟(b ),式(I V a )或(I V b )胺基根據-1 法例如使用第三丁氧羰基酐(B 〇 c 2 0 ),以及於適當溶 月青或二氣曱烷存在下接受保護,獲得對應式(V a )或 生物,其中胺基保護基Q只表示第三丁氧羰基(b 〇 c 根據該方法步驟(c ),式(V a )或(V b )化合物羧基岛 適當烷基ii如曱基碘存在下操作而被轉成對應烷基 物。 反應係於適當溶劑如二甲基曱醯胺存在下及於鹼 件下例如使用碳酸氫鈉或碳酸氫鉀進行。 根據該方法步驟(d ),式(V I a )或(V I b )化合物經d 化鈉反應而被轉成對應式(V I I a )或(V I I b )環狀衍生 應係於適當溶劑如二氧己環或四氫呋喃存在下,於 3丨2/發明說明書(補件)/93-03/92丨35527 成其醫 〇 式(I a ) 種習知 明之範 化合物 冬丙烯 水於約 ?知方 劑如乙 (V b )衍 )° 色由於 酯衍生 性條 ί與氫 物。反 回流溫 24 1327470 度進行。 根據該方法步驟(e ),式(V I I a )或(V I I b )化合物經與肼 水合物且較佳與過量肼一水合物例如高達1 0當量,於適當 溶劑如鹵化烴類、低碳醇類或其混合物存在下進行。反應 較佳係於乙醇存在下經由添加肼至式(V I I a )或(V I I b )化合 物溶液且於約2 0 °C至約7 0 °C溫度攪拌一段適當時間例如 約48小時進行。較佳前述反應也係於冰醋酸存在下進行。 根據該方法步驟(f ),式(V I I I a )或(V I I I b )化合物與氣 曱酸乙酯反應,獲得對應式(I X a )或(I X b )衍生物。該反應 係根據眾所周知之操作條件,於適當鹼如二異丙基乙基胺 存在下及於適當溶劑如四氫呋喃進行。 顯然乙氧幾基可鍵結至式(V I I I a )及(V I I I b )化合物之 任一個呲唑氮原子,因而獲得如下式(I X a )或(I X b )幾何異
就此方面而言,任一對式(I X a )或(I X b )幾何異構物皆可 根據眾所周知之方法例如於層析條件下分離,如此分離之 各別幾何異構物隨後接受後續處理。另外,幾何異構物混 合物可就此於隨後方法步驟處理而未提供任何分離。 實際上,獲得兩種分開幾何異構物之乙氧羰基,最終於 25 3丨2/發明說明書(補件V93-03/92丨35527 1327470 處理結束時被去除,熟諸技藝人士顯然易知前述兩種方法 皆可用於製備本發明式(I a )或(I b )化合物。 但較佳如實施例之報告,該方法首先係經由分離及隔離 (I X a )或(I X b )幾何異構物,以及隨後讓異構物反應成為所 需化合物而進行。 根據該方法步驟(g · 1 ),式(I X a )或(I X b )化合物與適當 式(X )衍生.物其中Z表示鹵原子,較佳與氣或溴反應。 典型地,式(I X a )或(I X b )化合物溶解於適當溶劑如二氣 曱烷、二甲基甲醯胺、四氫呋喃、二氧己環等,添加適當 鹼如三乙基胺、二異丙基乙基胺、碳酸鈉等。然後加入式 (X )化合物,混合物於約2 0 °C至約8 0 °C溫度攪拌約2小時 至約1 5小時。 可選擇性使用適當催化劑如二甲基胺基-吡啶。 根據方法步驟(g . 2 ),式(I X a )或(I X b )化合物經由實質 如方法步驟(g. 1 )所述,但無需使用鹼,而與式(X I I )異氱 酸S旨衍生物反應。 根據方法步驟(g . 3 ),式(I X a )或(I X b )化合物與式(X I II ) 胺,於三光氣或適當氯曱酸酯如氣曱酸4 -硝基苯酯存在下 反應,因而獲得對應脲基衍生物。反應係於四氫呋喃(T H F ) 或於適當鹵化烴,較佳為二氣甲烷(D C Μ ),或於適當胺如二 異丙基乙基胺或三乙基胺存在下,於約-70 °C至室溫範圍之 溫度進行。 根據方法步驟(h ),式(X I a )或(X I b )經保護之胺基於眾 所周知之操作條件下,例如酸性條件下,於三氟乙酸或鹽 酸存在下脫去保護。 26 3丨2/發明說明書(補件)/93-03/92135527 1327470 式(X I a )或(X I b )化合物如此懸浮於適當溶劑如二氣甲 烷或二氧己環,使用選用酸之濃溶液處理。另外,較佳使 用市售氣態氣化氫溶解於二氧己環溶液(4 Μ H C 1 )。然後混 合物於約2 0 t至約4 0 °C溫度範圍攪拌約2小時至約1 5小 時時間。 根據任一方法步驟(i . 1 )、( i · 2 )、( i · 3 )或(i . 4 ),式 (X I V a )或(X I V b )化合物進一步與適當衍生物反應,獲得對 應式(X V I a )或(X V I b )羧醯胺基、脲基或胺基曱酸酯衍生物。 步驟(i . 1 )係使用式(X V )醯鹵較佳為醯氣於適當溶劑如 二氣甲烷及鹼性條件例如於適當胺如二異丙基乙基胺存在 下進行。 反應獲得式(X V I a )或(X V I b )羧醯胺基衍生物,其中R, 定義如式(I ) ( a )至(c )群組、式(I I a )而X為碳原子以及式 (I I b);由前文說明,熟諳技藝人士顯然易知R!基團直接 鍵聯至式(X V I a )或(X V I b )羰基部分之原子為碳原子。 步驟(i . 2 )之進行方式係使用式(X V I I )雜環衍生物或式 (X V I I I )胺,於三光氣存在下,且實質如方法步驟(g · 3 )所 述進行。 就此方面而言,步驟(i.2)允許獲得式(XVIa)或(XVIb) 脲基衍生物,其中R !為式(I I a )基團,X為氮原子,或式 (lie)基團,其中Y、IT、η、1^及Rd’定義如前。 同理,步驟(i · 3 )之縮合係與式(X I X )羧酸衍生物,於適 當縮合劑例如二環己基甲二酿亞胺(D C C )、1 -乙基-3 - ( 3 ’ -二曱基胺基丙基)曱二醯亞胺(E DC)或0 -苯并三唑基四甲 基四氟硼酸異脲錄(T B T U )存在下進行,以及根據眾所周知 27 312/發明說明書(補件)/93-03/92135527 1327470 之羧醯胺衍生物之製法操作。 根據方法步驟(i · 4 ),式(X I V a )或(X I V b )化合物與適當 式(XX)衍生物(此處R,為式(lid)基團以及Re如式(la)或 (I b )所述)反應而獲得對應式(X V I a )或(X V I b )胺基曱酸酯 衍生物。 就此方面而言,式(XlVa)或(XlVb)化合物溶解於適當溶 劑如二氣曱坑、二曱基曱醯胺、四氫。夫喃、二氧己環等, 添加適當鹼如三乙基胺、二異丙基胺、碳酸鈉等至其中。 然後加入通式(X X )化合物,混合物於約2 0 °C至約8 0 °C範圍 之溫度攪拌約2小時至約1 5小時時間。根據較佳具體實施 例,可選擇性使用適當催化劑如二甲基胺基吼啶。 根據方法步驟(j ),步驟(i . 1 )至(i · 4 )之任一步驟所得 式(XlVa)或(XlVb)化合物與適當鹼如三乙基胺,於適當溶 劑如曱醇或乙醇存在下反應,獲得所需式(I a )或(I b)化合 物。 最後,依據方法步驟(k ),後述化合物(I a )或(I b )可如 前文報告選擇性轉成醫藥上可接受之鹽,或根據習知方法 後續處理,或另外,可轉成其它式(I a )或(I b )化合物。 至於非限制性範例,帶有羧基酯官能基之式(I a )或(I b) 化合物可根據業界眾所周知之方法轉成多種衍生物,而將 羧基酯基轉成羧醯胺類、N -經取代之羧醯胺類、N , N -二取 代之羧醯胺類、羧酸類等。 操作條件為業界已知的條件,包含例如將羧基酯基轉成 羧醯胺基,於氨或氫氧化銨於適當溶劑如低碳烷醇、二甲 基曱醯胺或其混合物存在下反應;較佳反應係使用氫氧化 28 3 i 2/發明說明書(補件)/93-03/92135527 1327470 銨於甲醇/二曱基甲醯胺混合物,於約5 0 °C至約1 0 0 °C範圍 之溫度進行。 類似之操作條件也適用於製備N -經取代之羧醯胺類或 N,N -二取代之羧醯胺類,該反應中使用適當第一級胺或第 二級胺取代氨或氫氧化銨。 同理,羧基酯基可使用業界眾所周知之鹼性或酸性水解 條件而轉成對應羧酸衍生物。 至於另一例,帶有胺基官能基之式(I a )或(I b )化合物容 易轉成對應羧醯胺衍生物或脲基衍生物。 由前文說明,業界人士顯然易知,根據方法步驟(k ), 任一種式(I a )或(I b )化合物具有官能基,該官能基可進一 步衍生成為另一種官能基,根據業界眾所周知之方法後續 處理,獲得其它式(I a )或(I b )化合物,意圖也涵蓋於本發 明之範圍。 根據式(I )化合物之製備方法之任一種變化方法,起始 物料及任何其它反應物為已知為容易根據已知方法製備。 舉例言之,雖然式(I I I a )或(I I I b )起始物料為市面上可 得,但式⑴、(XII) > (XIII)、(XV)、(XVII) ' (XVIII)、 (X I X )及(X X )化合物為已知或容易根據已知方法製備。 該方法之式(V I I a )或(V I I b )中間化合物為新穎,如此構 成本發明之又一目的
其中Q表示適當氮保護基,例如第三丁氧羰基(b 〇 c )。 為方便了解,若根據前述方法製備之式(I )化合物係呈 29 3丨2/發明說明書(補件)/93-03/92丨35527 1327470 異構物混合獲得,則其根據習知技術分離成為單一式(i) 異構物係屬於本發明之範圍。習知外消旋混合物之光學分 割技術包括例如非對映異構物鹽衍生物之分溶結晶或製備 性對掌HPLC 。 此外,由前文說明顯然易知指定式(I a )或(I b )化合物可 經由始於式(I X a )或(I X b )幾何異構物混合而製備,或另外 ,始於兩種幾何異構物之各別異構物而製備。 當根據前述任一種變化方法製備式(I )化合物時,屬於_ 起始物料或其中間物範圍内之選擇性官能基且可能產生非 期望副反應之官能基需根據習知技術適當保護。同理,後 者轉成自由態脫保護化合物也可根據已知程序進行。 此外,本發明式(I )化合物也可根據業界已知組合化學 技術,經由以串列方式完成前述數種中間物間之反應,以 及經由於固相合成(S P S )條件下加工處理而進行。 舉例言之,根據步驟(g · 1 )、( g · 2 )或(g. 3 )之任一步驟 製備之式(X I a )或(X I b )化合物可被支載於適當聚合物樹 脂。特別,式(X I a )或(X I b )之乙氧羰基可於鹼性條件下, 例如於三乙基胺或二異丙基胺去除,所得化合物係經由吼 。坐氛原子本身而固定至前述支樓樹脂
如此所得經支載之中間物隨後根據方法步驟(h )以及步 驟(i · 1 )、( i . 2 )、( i . 3 )或(i . 4 )之任一步驟反應,獲得對 應本發明式(1 a )或(I b )化合物,仍然支載於聚合物樹脂。 30 312/發明說明書(補件)/93-03/92135527 1327470 隨後,根據已知方法例如於鹼性或酸性條件下裂解樹脂, 獲得所需式(I a )或(I b)化合物。 顯然經由以串列方式進行前述方法反應,換言之,遵照 例如前述組合辦法進行反應,可製備及收集數種式(I a )及 (I b )化合物。
因此,本發明之又一目的為一種包含兩種或兩種以上式 (la)化合物之存庫 其中 R為基團-C0Ra、-C0NHRa或-C0NRaRb其中Ra及Rb各自分別 為氮或選自直鏈或分支C^-Ce烷基、(:3-(:6環烷基、芳基 、芳基烷基、雜環基或雜環基烷基之選擇性經取代之基團 或;Ra及Rh連同其鍵結之氮原子形成一個選擇性含有另一 個選自N、N Η、0或S之雜原子或雜原子基團之選擇性經取 代之5員或6員雜環;
Ri係選自下列基團組成的群組: a) 直鍵或分支C3-C<i炫基; b) 環烷基、環烷基-烷基或烷基-環烷基其中該環烷基部分 包含C3-C6環烧基,以及其中該坑基部分包含任何直i連或 分支C I - C 4烧基; c) 3_甲基°塞吩_2 -基;2_°塞吩基;笨基;2,6_二氟^笨基; 4-(胺基石黃醒基)苯基,4-(二甲基胺基曱基)苯基;4-(4-甲基哌畊基)甲基-笨基; 31 312/發明說明書(補件)/93-03/92135527 1327470 d)式(Ila)或(lib)基團:
rVR" X Y
N (Ha) (Hb) 其中式(I I a ),環表示一個5員至7員雜環系環,其中直接 鍵聯至分子其餘部分之X表示碳原子或氮原子;Y為碳原 子、氮原子、氧原子或硫原子或為NH基,但X及Y中之至 少一者非為碳原子;R ε於式(I I a )雜環系環自由位置之任 一位置,各自分別為鹵原子或羥基,或Re為選自直鏈或分 支Ci-Ce烷基、C3-C6環烷基、芳基、芳基烷基、雜環基、 雜環基烷基、胺基、胺基羰基、羧基、酮基(=0)'烷氧羰 基、烷基羰基或芳基羰基之選擇性經取代之基團;以及η 為0或1至4之整數; e)式(lie)或(lid)基團: / r -N -〇 R.d (He) (Hd) 其中Rd、R’d及Re為相同或相異且各自分別表示氫原子或 選擇性經以一或多個選自羥基(-0 Η )、胺基羰基(-C 0 N Η 2) 或曱基胺基羰基(-CONHCHO之基團取代之直鏈或分支 C I _ C 6院基; 但式(la)中,當Ri為式(lie)基團以及1^或Rdi —者為 氫原子,而1^或Rd之另一者為乙基或正丁基時,R非為 -C 0 Ra,而Ra係作為3 -溴笨基、苄基、4 -第三丁基苯基、 4 -第三丁基苯基曱基、4 -氟苯基甲基、環丙基或2 -萘基曱 基: 或其醫藥上可接受之鹽。 32 312/發明說明書(補件)/93-03/92丨35527 1327470
同理,本發明之又一目的為一種包含兩種或兩種以上式 (I b )化合物之存庫 其中 R為基團-C0Ra、-C0NHRH或- C0NRaRb其中Ra及Rh各自分別 為氫或選自直鍵或分支Cl_C6炫基、C3~Cli環坑基、芳基、 芳基烷基、雜環基或雜環基烷基之選擇性經取代之基團 或;Ra及Rh連同其鍵結之氮原子形成一個選擇性含有另一 個選自Ν、ΝΗ、0或S之雜原子或雜原子基團之選擇性經取 代之5員或6員雜環; R!係選自下列基團組成的群組: a)直键或分支C3-C4烧基; b )環烷基、環烷基-烷基或烷基-環烷基其中該環烷基部分 包含C3-Cg環烷基,以及其中該烷基部分包含任何直鏈或 分支C I - C Ί烧基; c) 3_曱基°塞吩_2_基;2-。塞吩基;苯基;2,6 —二亂苯基;4_(胺 基磺醯基)苯基;4-(二曱基胺基曱基)苯基;4-(4 -曱基 哌畊基)甲基-笨基; d) 式(Ila)或(lib)基團:
其中式(I I a ),環表示一個5員至7員雜環系環,其中直接 鍵聯至分子其餘部分之X表示碳原子或氮原子;Y為碳原 33 312/發明說明書(補件)/93-03/92丨35527 1327470 子、氮原子、氧原子或硫原子或為Ν Η基,但X及Y中之至 少一者非為碳原子;Rε於式(I I a )雜環系環自由位置之任 一位置,各自分別為鹵原子或羥基,或Re為選自直鏈或分 支Ct-Cfi烷基、C3-C<i環烷基、芳基、芳基烷基、雜環基、 雜環基烷基、胺基、胺基羰基、羧基、酮基(=0 )、烷氧羰 基、烷基羰基或芳基羰基之選擇性經取代之基團;以及η 為0或1至4之整數; e)式(lie)或(lid)基團: 广 尸 —' —〇 R.d (He) (lid) 其中Rd、尺^及1Γ為相同或相異且各自分別表示氫原子或 選擇性經以一或多個選自羥基(-0 Η )、胺基羰基(-C 0 Ν Η 2) 或曱基胺基羰基(-C0NHCHO之基團取代之直鏈或分支 C I _ C G烧基; 或其醫藥上可接受之鹽。 有關前述式(I)化合物之存庫之一般參文獻,且參考實 驗乙節。 由前文,熟諳技藝人士顯然易知一旦如此製備吡咯°比唑 衍生物存庫,例如由數百種或甚至數千種式(I a )或(I b )化 合物組成,則該存庫如前文報告可極為有利地用於篩檢特 定激酵素。 有關化合物存庫及其用作為生物活性篩檢工具之用法 之概略參考文獻可參考J. Med. Che m'· 1999,42,2373- 2382;及 B i ο o r g. Med. C h e m . Lett 10 ( 2 0 0 0 ) > 223-226 ° 藥理學 34 312/發明說明書(補件)/93-03/92135527 1327470 式(i)化合物具有作為蛋白質激酵素抑制劑活性,因此 可用於例如限制腫瘤細胞之失調增殖。 於治療中,式(I )化合物可用於治療多種腫瘤,例如前 文報告之腫瘤,以及用於治療其它細胞增殖病症例如乾癖 、動脈粥狀硬化相關血管平滑肌細胞增殖、及術後血管狹 窄及再狹窄,以及用於治療阿茲海默氏病。 推定Cdk/週期素抑制劑之抑制活性以及選定化合物之 強度係經由基於使用S P A技術(A in e r s h a m P h a r m a c i a B i o t e c h )之檢定分析方法測定。 檢定分析係經由經過放射標記之磷酸根部分藉激酵素 移轉至生物素化酶基質組成。結果所得33P標記之生物素 化產物結合至經鏈絲抗生物素塗覆S P A珠粒(生物素容量 1 3 0微微莫耳/毫克),及於閃爍計數器測量發光。 C d k 2 /週期素A活性之抑制檢定分析 激酵素反應:4 # Μ於罩著生物素化組織蛋白腺Η 1 (Sigma # Η-5505)酶基質,10# Μ ΑΤΡ(0.Ι" Ci P33 γ - ATP) ,4 . 2奈克C d k 2 /週期素A錯合物抑制劑於終容積3 0微升 緩衝液(TRIS HC1 10 niM pH 7.5,MgC 12 10 ηιΜ - DTT 7.5 mM + 0.2毫克/毫升BSA)添加至96孑L U字形底的各孔。於室 溫培養3 0分鐘後,藉1 0 〇微升P B S + 3 2 m Μ E D T A + 0 . 1 % 崔頓(Triton) X-100 + 500# M ATP 含 1 毫克 SPA 珠粒終 止反應。然後1 1 0微升容積移至光學孔板(0 p t i p 1 a t e )。 經2 0分鐘後,酶基質之捕捉培養後,1 〇 〇微升5 M C s C 1 添加至其中讓珠粒分層至板頂部,讓其放置4小時,隨後 於桌面計數裝置進行放射性計數。 35 3 12/發明說明書(補件)/93-03/92135527 1327470 I C 5 0之測定:抑制劑係於0 . 0 0 1 5 # Μ至1 0 # Μ之不等濃 度測試。使用四參數邏輯方程式,藉電腦程式G r a ρ h Ρ a d P r i z m分析實驗資料: y =底 + (頂-底 V(l + l(T((logIC50-x)* 斜率)) 此處x為抑制劑濃度對數值,y為反應;y始於底,而以彎 曲形狀走到頂。
Ki計算: 實驗方法:反應係於含3 . 7 η Μ酶' 組織蛋白脒及A T P (冷/經標記A T P之常數比1 / 3 0 0 0 )之缓衝液(1 0 in Μ T r 1 s, pH 7.5,10 mM MgCl2 0.2 毫克 / 毫升 BSA ,7. 5 mM DTT) 進行。藉E D T A終止反應,酶基質被捕捉於磷膜(得自 M i 1 1 i ρ 〇 r e公司之M u 1 t i s c r e e η 9 6孔平板)。經徹底洗蘇 後,多重篩檢孔板於桌面計數器讀取。測定各ATP濃度及 組織蛋白腺濃度之對照(時間零)。 實驗設計:反應速度係於四種不同A T P '酶基質(組織蛋 白腺)及抑制劑濃度測定。8 0點濃度矩陣環繞個別A T P值 及酶基質K m值設計,及環繞I C 5 0值(0 . 3、1、3、9倍K m 或I C 5 0值)設計。於無抑制劑存在下且於不同A T P濃度及 酶基質濃度下之初步時程實驗,允許於K i測定實驗之線性 反應範圍選用單一終點時間(1 0分鐘)。 動態參數估值:動態參數係使用完整資料集合(8 0點) ,使用[方程式1 ](競爭抑制劑相對於A T P,隨機機轉)藉同 時非線性最小平方迴歸分析估計: v = ( V in · A. B ) / [ α . Κ a · Κ b + α . Κ a · B + a. Kb. A + A · B + a . Ka/Ki. I. ( Kb + B/ ^ )] [方程式 1] 36 3丨2/發明說明書(補件)/93-03/92丨35527 1327470 此處A = [ A Τ P ],B =[酶基質],I =[抑制劑], K a、K b、K i分別為A T P、酶基質及抑制劑 及yS分別為酶基質與ATP結合、以及酶基 之協力因數。 此外,選用化合物之對一組與細胞週期 E,Cdkl/週期素 Bl,Cdk5/p25,Cdk4/週期 之絲/蘇激酵素具有特徵特性,也對M A P K I G F 1 - R ' Aurora-2 及 Akt 具有特異性。 Cdk2/週期素E活性之抑制檢定分析 激酵素反應:1 0 /z Μ經罩住之生物素化 (Sigma # Η-5505)酶基質,3〇v M ATPC0.3 ,4奈克G S Τ - C d k 2 /週期素Ε錯合物抑制ΐ 升緩衝液(TRIS HC1 10 mM pH 7.5,MgCl2 in M + 0 . 2毫克/毫升B S A )添加至9 6孔U字 室溫培育6 0分鐘後,藉1 0 0微升P B S + 3 崔頓 X-100 + 500//M ATP 含 1 毫克 SPA 珠 後1 1 0微升容積移至光學孔板。 於2 0分鐘培養進行酶基質捕捉後,添加 讓珠粒分層至板頂端,讓其放置4小時, 裝置進行放射性計數。 I C 5 0之測定:參見上文 C d k 1 /週期素B 1活性之抑制檢定分析 激酵素反應:4 # Μ經罩住之生物素化組 (Sigma # H-5505)S每基質,20y Μ ΑΤΡ(0. 2 ,3奈克C d k 1 /週期素Β錯合物抑制劑於约 3丨2/發明說明書(補件)/93-03/92135527 V πι =[最大速度], 之解離常數。α 質與抑制劑結合 (C d k 2 /週期素 素D 1 )嚴格相關 、PKA ' EGFR ' 组織蛋白腺H1 β Ci P 3 3 7 -ATP) H於終容積3 0微 1 0 mM,DTT 7.5 形底之各iL。於 2 in M ED ΤΑ +0.1% 粒終止反應。然 1 0 0 微升 5 M C s C 1 隨後於桌面計數 織蛋白竦Η 1 μ Ci P33 r -ATP) 容積3 0微升緩 37 1327470 衝液(TRIS HCl 10 mM pH 7.5,MgCl2 10 mM,DTT 7.5 ιηΜ + 0.2毫克/毫升BSA)添力〇至96孔U字形底之各孔。於室 溫培育2 0分鐘後,藉10 0微升P B S + 3 2 m Μ E D T A + 0 . 1% 崔頓X - 1 0 0 + 5 0 0 # Μ A Τ Ρ含1毫克S Ρ Α珠粒終止反應。然 後Π 0微升容積移至光學孔板。 於2 0分鐘培養進行酶基質捕捉後,添加1 0 0微升5 M C s C 1 讓珠粒分層至板頂端,讓其放置4小時,隨後於桌面計數 裝置進行放射性計數。 I C 5 0之測定:參見上文 C d k 5 / ρ 2 5 活性之抑制檢定分析 C d k 5 / p 2 5活性之抑制檢定分析係根據如下方案進行。 激酵素反應·· 1 0 μ Μ生物素化組織蛋白腺Η 1 (Sigma # H-5505)酶基質,30/z M ATPC0.3# Ci P33r -ATP),15 奈克 C D K 5 / ρ 2 5錯合物抑制劑於終容積3 0微升緩衝液(T R I S H C 1 10 mM pH 7.5,MgCl2 10 mM,DTT 7.5 mM + 0.2 毫克 / 毫 升B S A )添加至9 6孔U字形底之各孔。於室溫培育3 0分鐘 後,藉100微升?88+'32 11^£0丁八+0.1%崔頓乂-100 + 500 # M A T P含1毫克S Ρ A珠粒終止反應。然後1 1 0微升容積 移至光學孔板。 於2 0分鐘培養進行酶基質捕捉後,添加1 0 0微升5 M C s C 1 讓珠粒分層至板頂端,讓其放置4小時,隨後於桌面計數 裝置進行放射性計數。 I C 5 0之測定:參見上文 C d k 4 /週期素 D 1 活性之抑制檢定分析 激酵素反應:0 · 4 " Μ 小 a GST-Rb ( 7 6 9 - 9 2 1 )(# sc-41 12 38 3丨2/發明說明書(補件)/93-03/92丨35527 1327470 得自 Santa Cruz)梅基質,ΙΟμΜ ΑΤΡ( 0. 5 // Ci Ρ33 γ -ΑΤΡ),100奈克經桿病毒表現之GST-Cdk4/週期素D1,適 當濃度之抑制劑於終容積5 0微升緩衝液(T R I S H C 1 1 0 in Μ pH 7.5,MgC12 10 mM,7. 5 mM DTT + 0.2 毫克 / 毫升 BSA) 添加至9 6孔U字形底礼板的各礼。於3 7 °C培養4 0分鐘後, 藉2 0微升E D T A 1 2 0 m Μ終止反應。 捕捉:6 0微升由各孔移至M u 1 t i S c r e e η孔板,讓酶基質 結合至磷酸纖維素過濾器膜。然後孔板以1 5 0微升/孔不含 C a…/ M g_ ‘之P B S洗3次,藉Μ υ 1 t i S c r e e η過遽系統過渡。 偵測:讓過濾器於3 7 °C乾燥,然後加入1 0 0微升/孔閃 爍劑,於桌面計數儀器藉放射性計數偵測經過33P標記之 Rb片段。 I C 5 0測定:參見上文 M A Ρ K活性之抑制檢定分析 激酵素反應:1 0 // Μ經罩住之生物素化Μ B P ( S i g m a # M-1891)酶基質,15// M ATP(0.15仁 Ci Ρ33 γ -ATP) > 30 奈 克G S T - M A K ( U p s t a t e生技公司# 1 4 - 1 7 3 ),抑制劑於終容 積 3 0 微升缓衝液(T R I S H C 1 1 0 m Μ ρ Η 7 · 5,M g C 1 2 1 0 m 1Λ, DTT 7.5 in Μ + 0.2毫克/毫升BSA)添加至96孔U字形底之 各孔。於室溫培育3 0分鐘後,藉1 0 0微升Ρ B S + 3 2 m Μ E D T A + 0.1 %崔頓X-100 + 500am ATP含1毫克SPA珠粒終止反 應。然後1 1 0微升容積移至光學孔板。 於2 0分鐘培養進行酶基質捕捉後,添加1 〇 〇微升5 M C s C 1 讓珠粒分層至板頂端,讓其放置4小時,隨後於桌面計數 裝置進行放射性計數。 39 3丨2/發明說明書(補件)/93-03/92丨35527 1327470 I C 5 0之測定:參見上文 Ρ Κ Α活丨生之扣卩制檢:定分析 激酵素反應:1 0 " Μ經罩住之生物素化組織蛋白腺Η 1 (Sigma # Η-5505)酶基質,10" Μ ΑΤΡ(0·2μ Ci P33r -ATP) ,0 · 4 5單位P K A ( S i g m a # 2 6 4 5 ),抑制劑於終容積3 0微 升緩衝液(TRIS HC1 10 mM pH 7.5, MgClz 10 mM, DTT 7.5 in M + 0 . 2毫克/毫升B S A )添加至9 6孔U字形底之各孔。於 室溫培育9 0分鐘後,藉1 0 0微升P B S + 3 2 m Μ E D T A + 0 . 1 % 崔頓X - 1 0 0 + 5 0 0 // M A T P含1毫克S P A珠粒终止反應。然 後1 1 0微升容積移至光學孔板。 於2 0分鐘培養進行酶基質捕捉後,添加1 0 0微升5 M C s C 1 讓珠粒分層至板頂端,讓其放置4小時,隨後於桌面計數 裝置進行放射性計數。 I C 5 0之測定:參見上文 EGFR活性之抑制檢定分析 激酵素反應:1 0 # Μ經罩住之生物素化Μ B P ( S i g m a # M-1891)酶基質,2/zM ATP (0.04# Ci P33 γ -ATP) - 36 奈 克經昆蟲細胞表現之GST-EGFR,抑制劑於終容積30微升 緩衝液(Hepes 50 mM pH 7.5,MgCl2 3 mM,MnCl2 3 ιηΜ, DTT 1 mM,NaV〇3 3#M + 0.2 毫克 / 毫升 BSA)添加至 96 孔 U 字形底之各孔。於室溫培育2 0分鐘後,藉1 0 0微升P B S + 3 2 m Μ E D T A + 0 · 1 % 崔頓 X - 1 0 0 + 5 0 0 y M A T P 含 1 毫克 S P A 珠粒終止反應。然後1 1 0微升容積移至光學孔板。 於2 0分鐘培養進行酶基質捕捉後,添加1 〇 〇微升5 M C s C 1 讓珠粒分層至板頂端,讓其放置4小時,隨後於桌面計數 40 3丨2/發明說明書(補件)/93-03/92丨35527 1327470 裝置進行放射性計數。 I C 5 0之測定:參見上文 I G F 1 - R活,ϋ之扣p制檢:定分析 I G F 1 - R活性之抑制檢定分析係根據如下方 激酵素反應:1 0 // Μ生物素化Μ B P ( S i g m a 1 8 9 1 )酶基質,0 - 2 0仁M抑制劑,6 # M ATP, ATP,及22.5奈克GST-IGF1-R(於室溫與冷 前培養3 0分鐘)於終容積3 0微升緩衝液(5 0 7.9,3 mM Μ n C 1 2 > 1 mM DTT,3#M N a V 0 3 ) 字形底孔板之各孔。於室溫培養35分鐘後, 微升PBS緩衝液終止反應,PBS緩衝液含有 500//M 冷 ATP,0.U崔頓 X-100 及 10 毫克 / 抗生物素塗覆S P A珠粒。培養2 0分鐘後,取 浮液,移至9 6孔含1 0 0微升5 M C s C 1光學孔 後,於P a c k a r d桌上型放射性讀取器讀取孔 間。
Aurora-2 活性之才卬制才衾定分析 激酵素反應:8 μ Μ生物素化胜肽(4次重41 ,10" Μ ATP ( 0 . 5// C i 33 r -ATP) - 15 奈克 A 劑於終容積3 0微升緩衝液(Η E P E S 5 0 m Μ p H mM - 1 mM DTT,0.2 毫克 / 毫升 BSA,3//M 正 至96孔U字形底孔板之各孔。於室溫培養:: 止反應,藉加入1 0 0微升珠粒懸浮液捕捉生 分層:1 0 0微升C s C 1 2 5 Μ添加至各孔,讓其 隨後於桌上型儀器計數放射性。 3丨2/發明說明書(補件)/93-03/92135527 案進行。 型錄# Μ-ΐ # C i 33P-6 0 # Μ 冷 ‘ATP mM HEPES pH 私加至96孔U 藉加入1 0 0 3 2· mM EDTA, 毫升經鏈絲菌 出1 1 0微升懸 板。經4小時 板經2分鐘時 L LRRWSLG) u r 〇 r a - 2 抑制 7.0, MgCl2 10 饥酸鹽)添加 ! 0分鐘後,終 物素胜肽。 放置4小時’ 41 1327470 1 C 5 0測定:參見上文 Cdc7/dbf4活[生之抑制檢:定分析 C d c 7 / d b f 4活性之抑制檢定分析係根據如下方案進行。 生物素-MCM2酶基質於使用t33-ATP追蹤的ATP存在 下,藉C d c 7 / D b f 4錯合物轉移磷酸化。然後經磷酸化之生 物素-M C Μ 2酶基質藉經鏈絲菌抗生物素塗覆之S P A珠粒捕 捉,藉/3計數評估磷酸化程度。 C d c 7 / d b f 4活性之抑制檢定分析係於9 6孔孔板根據下述 方案進行。 於孔板之各孔内加入: -1 0微升酶基質(生物素化M C Μ 2,6 # Μ終濃度) -10微升酵素(Cdc7/Dbf4,12.5 nM終濃度) -1 0微升試驗化合物(η Μ至# Μ範圍之1 2種遞增濃度而 產生劑量-反應曲線) -然後1 0微升冷A Τ Ρ ( 1 0 # Μ終濃度)及放射性 A Τ Ρ ( 1 / 2 5 0 0莫耳比含冷A T P )之混合物用於開始反應,讓反 應於37°C進行 酶基質、酵素及ATP稀釋於50 niM HEPES pH 7.9,其中 含有 15 ιιιΜ MgCl2,2 mM DTT,3/zM NaVCh,2 niM 璃酸甘 油能及0 . 2毫克/毫升B S A。試驗化合物溶劑也含有1 0 % DMSO ° 培養2 0分鐘後,藉各孔内添加1 0 0微升P B S ρ Η 7 . 4而 終止反應,P B S含有5 0 in Μ E D T A,1 m Μ冷A Τ Ρ,0 . 1 %崔頓 X 1 0 0及1 0毫克/毫升經鏈絲諸抗生物素塗覆之S Ρ A珠粒。 於室溫培養1 5分鐘後,發生生物素化M C Μ 2 -鏈絲菌抗生 42 312/發明說明書(補件)/93-03/92丨35527 1327470 物素SPA珠粒交互作用後,使用Packard細胞收穫機 (F i 1 t e r m a t e )將珠粒捕捉於9 6孔過渡板(U n i f i 1 t e r G F / B ),以蒸餾水洗滌,然後使用桌上型計數器(P a c k a r d ) 計數。 數目扣掉空白組,然後實驗資料(各點重複試驗三次)使 用非線性迴歸分析(S i g m a作圖)分析進行I C 5 0測定。 經由前述抑制檢定分析,本發明式(I )化合物具有顯著 c d k抑制活性。例如參考以下式(I a )及(I b )兩種代表性本 發明化合物對C d k 2 /週期素A進行實驗資料(I C 5»): 化合物1: N-[5-(2,2 -二曱基丙醯基)-6,6 -二甲基 -1,4,5,6 -四氫0比0各[3,4-c]°比。坐-3-基]二4一氟苄醯胺(ICs〇 0 . 0 3 0 # Μ );及 化合物2: Ν-[5-(2,2-二曱基丙醯基)-1,4,5, 6-四氫吡 略[3,4 - c ] °比。坐-6 -螺環丙院-3 -基]-4 _氟罕酿胺(I C 5 〇 0· 0 2 5 /z M)。 出乎意外地,抑制活性顯然優於先前技術W 0 0 2 / 1 2 2 4 2之極為接近的化合物之抑制活性,後述化合物於此 處稱作為參考化合物(參考W0 02/12242化合物1143,第 7 6頁底;及實施例1 9跨第2 4 2 - 2 4 3頁之化合物),用作為 比較用途,且如前文報告係對C d k 2 /週期素A進行試驗: 參考化合物:N-[5 -乙酿基-6 ,6-二曱基- 4,6 -二氫吡略 [3 , 4 - c ]。比唑-3 -基]-(3 -溴)¥ 醯胺(I C 5。1 · 7 // Μ )
43 3丨2/發明說明書(補件)/93-03/92丨35527 1327470 至目前為止,本發明新穎化合物出乎意外地具有比wo 0 2 / 1 2 2 4 2結構式最接近的先前化合物顯著更高的C d k抑制 活性,因此用於治療特別可有效對抗與細胞週期依賴型激 酵素活性變更相關的增殖病症。 本發明化合物可呈單一藥劑投藥,或另外,可組合已知 抗癌治療投藥,例如放射性治療或化學治療方案組合細胞 抑制劑或細胞毒劑、抗生素類藥劑、烷化劑、抗代謝劑 、激素劑、免疫劑、干擾素類藥劑、環氧合酶抑制劑(例如 C 0 X - 2抑制劑)、基質金屬蛋白酶抑制劑、端粒酶抑制劑、 酪胺酸激酵素抑制劑、抗生長因子受體劑、抗HER劑 、抗E G F R劑、抗血管生成劑(例如血’管生成抑制劑)、法尼 基轉移 抑制劑、r a s - r a f信號轉導路徑抑制劑、細胞週 期抑制劑、其它c d k s抑制劑、管蛋白結合劑、拓樸異構 I抑制劑、拓樸異構酶I I抑制劑等。 若調配成固定劑量,則此等組合產物採用於後述劑量範 圍之本發明化合物、及於核准劑量範圍之其它醫藥活性劑。 當不適合使用組合調配物時,式(I )化合物可與已知抗 癌藥劑接續使用。 本發明式(I )化合物適合投予哺乳類例如投予人類,依 據病人年齡、體重、情況及投藥途徑而定,可藉尋常途徑 及劑量投藥。 例如口服投予式(I )化合物之適當劑量係於每劑約1 0毫 克至約5 0 0毫克之範圍,每日1至5次。本發明化合物可 以多種劑型投藥,例如經口投藥呈錠劑、膠囊劑、糖衣錠 或膜衣錠、液態溶液劑或懸浮液劑劑型;經直腸投藥係呈 44 3丨2/發明說明書(補件)/93-03/92丨35527 1327470 栓劑劑型;經腸道外投藥例如肌肉注射或經靜脈及/或鞘内 及/或脊柱内注射或輸注投藥。 本發明也包括醫藥組成物,其包含一種式(I )化合物或 其醫藥上可接受之鹽組合一種醫藥上可接受之賦形劑,其 可為載劑或稀釋劑。 含本發明化合物之醫藥組成物通常係遵照習知方法製 備,可以適當醫藥劑型投藥。例如固體口服劑型連同活性 化合物,含有稀釋劑如乳糖、葡萄糖、蔗糖、蔗糖、纖維 素、玉米澱粉或馬鈐薯澱粉;潤滑劑如矽氧、滑石、硬脂 酸、硬脂酸鎂或硬脂酸鈣及/或聚乙二醇類;黏結劑例如澱 粉類、阿拉伯膠、明膠、曱基纖維素、羧曱基纖維素或聚 乙烯基吡咯啶酮;崩散劑如澱粉、藻蛋白酸、藻蛋白酸鹽 或乙醇酸澱粉鈉;發泡劑;染料;甜味劑;濕潤劑如卵磷 脂、聚山梨酸鹽、硫酸月桂酯鹽類;以及一般用於醫藥調 配物之無毒且無藥理活性物質。此等醫藥製劑可以已知方 式製造,例如利用混合、造粒、打錠、加糖衣或加膜衣方 法製造。 口服投藥用之液體分散液可為糖漿劑、乳液劑及懸浮液 劑。舉例言之,糖漿劑含有蔗糖劑或蔗糖與甘油及/或甘露 糖醇及山梨糖醇作為載劑。 懸浮液劑及乳液劑可含有天然樹膠 '瓊脂、藻蛋白酸 鈉、果膠、曱基纖維素、羧曱基纖維素、或聚乙烯醇例如 作為載劑。肌肉注射用懸浮液劑或溶液劑連同活性化合物 可含有醫藥可接受性之載劑如無菌水、橄禮油、油酸乙醋 、二醇類如丙二醇,以及若有所需,含有適量利度卡因 45 312/發明說明書(補件)/93-03/92135527 1327470 (lidocaine)鹽酸鹽。 靜脈注射或靜脈輸注用之溶液劑可含有無菌水作為載 劑;或較佳可呈無菌水性等張食鹽水溶液形式,或可含有 丙二醇作為載劑。 栓劑可有含醫藥上可接受之載劑如可可脂、聚乙二醇 、聚氧伸乙基、聚山梨糖醇脂肪酸酯界面活性劑或卵磷脂 連同活性化合物。 為求更明白了解本發明,但非限制性,現在舉出下列實 施例。 概略方法 .於考慮特定本發明式(I )化合物之合成製備之前,例如 後文實施例之報告,須注意若干化合物係根據其化學名列 舉及指示於此處,而大部分其它化合物係方便且明確地藉 編碼系統連同其1 Η - N M R資料(參考如下表I I I、I V及V )以 及HPLC/質譜資料(參考下表VI )識別。 特別各代碼識別單一特定式(I a )或(I b )化合物且係由 三個單元A-M-B組成。 A表示任何取代基R[參考式(la)或(lb)],經由-NH -基 附接於分子之其餘部分;各特定A基係於下表I以連續編 號表示。 同理,B表示任何取代基R,[參考式(la)或(lb)],經由 羰基(C 0 )基附接於分子之其餘部分;各特定B基係於下表 I I以連續編號表示。 Μ表示經A基及B基取代之二價部分中央核心;特別Μ 係依據下式由Μ 1或Μ 2改變,個別表示具有式(I a )或(I b) 46 312/發明說明書(補件)/93-03/92丨35527 1327470
為了方便參照,表I及I I之全部A基及B基皆以適當 化学式標示,也指示與分子Μ其餘部分之附接點。 因此,舉例言之,表III化合物Α06-Μ1-Β01表示式(la) 化合物有個中央Μ 1核心,於箭頭指示位置經以A 0 6基及 B01基取代;同理,表V化合物A04-M2-B08表示式(lb)化 合物有個中央Μ 2核心,於箭頭指示位置經以A 0 4基及B 0 8 基取代: 47 3 12/發明說明書(補件)/93-03/92135527 1327470
表1 Α01 Α02 Α03 Α04 Α05 FVM F Α06 Α07 Α08 Α09 0 Α10 48 312/發明說明書(補件)/93-03/9213 5527 1327470
All Ο Α12 从 A13 Α14 A15 ΑΙ6 A17 α0^ Α18 asx/M A19 Α20 ΗΝ^ A21 ο Α22 A23 co1m Α24 人 Μ U Η A25 又Μ Α26 1又Μ
312/發明說明書(補件)/93-03/92135527 49 1327470
A27 众又M Η A28 人M A29 A30 〇^Μ A31 A32 A33 'OjD^ A34 o ΓΤ^Μ A35 0 A36 A37 A38 /0 A39 〇yj〇1m nh2 A40 A41 A42 CN 0 (YM
3丨2/發明說明書(補件)/93-〇3/92丨35527 50 1327470 A43 Α44 A45 Α46 0 A47 Ο^Μ Α48 〇〇Λ A49 0 cA Α50 A51 Α52 ο A53 0 〇τ〇Λμ Α54 A55
表II 51 312/發明說明書(補件)/93-03/92丨35527 1327470 B01 B02 B03 B04 B05 B06 k/NH B07 M S B08 ^Ν、 B09 '0 BIO M、o B11 %a B12 OH BI3 Λ OH B14 BI5 M;o BI6 'C\ nh2
312/發明說明書(補件)/93-03/92135527. 52 1327470 B17 BIS 以〇 B19 Μι> B20 M〇〇 B21 k/N、 B22 % B23 s OH B24 m'n^toh V OH B25 m、n^^〇h 1 B26 m、n^^OH H B27 H B28 M、N^ H B29 0 人 nh2 B30 %、 lv^'〇H B31 M、〇 k/N\ 、OH B32 OH M、人 u 53 3丨2/發明說明書(補件)/93-03/92丨35527 1327470 B33 Ν ΟΗ Β34 μ、〇Λη2 B35 Μ、〇 9 Β36 ^"νη2 B37 'α Β38 k^NH B39 μ、〇 、νη2 Β40 B41 k^Y〇H φ F Β42 μ'ν^ k^N^N^OH B43 Β44 B45 Μν^ Β46 Μ Ο η/ 1 54 3 12/發明說明書(補件)/93-03/92135527 1327470 B47 人 Β48 0 1 B49 BSO \ B5I Μτ> B52 BS3 Ιώ BS4 BSS Ί 0 (實施例1 ) N-(2 -氰基乙基)-2 -甲基丙胺酸 50克(0.48莫耳)2 -曱基丙胺酸添加至氫氧化鈉(19.6克) 於水(1 0 0毫升)之冷溶液(水/冰)。一旦溶液變澄清’於冷 卻時逐滴加入3 4毫升(0 · 5 0莫耳)丙烯腈。讓混合物放置 隔夜。1 8小時後,藉冷卻(水/冰)加入2 8毫升乙酸;生成 白色固體沉澱;2 0 0毫升9 5 %乙醇逐滴力π入燒瓶,連續攪拌 1小時,然後讓混合物於冰箱放置2 - 3小時。過濾後,收 集固體,於8 0 °C烤箱乾燥。濾液經蒸發及以乙醇(1 6 0毫升) 攝取。於冷卻下獲得額外量產物,經過濾及脫水。由第一 次過濾獲得7 2克標題化合物。總產率:9 5 %。 ESI MS : ιη/ζ 157 (MH+); Ή NMR (400 MHz, DMSO-de): ό 7.47 (s, 1 H ) , 2.70 ( t, 2H), 2.48 (t, 2H), 1.18 (s, 6H)。 經由以類似方式操作,製備下述化合物: 1 - [ 2 -(氰基乙基)胺基]環己烷羧酸
El MS: m/z 154 (Μ), 136 (M-HaO), 114 (M-CH2CN), 68 55 312/發明說明書(補件)/93-03/92丨35527 1327470 (100%, cyclopr=C=0); Ή NMR (400 MHz, DMSO-d〇):(5 7.47 (s, 1H), 2.86 (t, 2H, J = 6. 6 Hz), 2.48 ( t, 2H, J = 6 . 6 Hz), 1.09 (dd, 2H, J = 6. 9 Hz, J = 4. 1 Hz), 0.86 (dd, 2H, J = 6. 9 Hz, J = 4. 1 Hz) ° (實施例2 ) N-(第三丁氧截基)-N-(2 -氰·基乙基)-2_曱基丙胺酸 44.5克(0.285莫耳)N-(2 -氰基乙基)-2 -曱基丙胺酸及 5 1 · 7克四曱基氫氧化銨五水合物於4 0 °C溶解於乙腈(2升) ,且當獲得澄清溶液時加入1 1 2克B 〇 c 2 0。混合物於4 0 °C 放置2 4小時。次日,又加入2 0克B 〇 c 2 0同時維持溫度於 4 0 °C 。每8 - 1 2小時,加入2 0克B 〇 c 2 0至總量1 9 2克。4 曰後蒸發去除溶劑,殘餘物攝取於水U 〇 〇 〇毫升),且以乙 醚(5 0 0毫升)洗兩次。水性部分以檸檬酸調整至p Η 3 - 4, 且以乙酸乙S旨萃取,以水(2 0 0毫升)洗;條及遭縮。獲得5 2 克標題化合物。(產率:7 2 %)。 ESI MS: m/z 274 (M+NH4); Ή NMR ( 4 0 0 MHz, D M S Ο - d 〇) : (5 3 . 5 2 (t, 2H, J = 6.8 Hz), 2.68 (t, 2H, J=6. 8 Hz), 1.18-1.38 (m, 15H)。 經由以類似方式處理製備下述化合物: 卜[(第三丁氧羰基)(2-氰基乙基)胺基]環丙烷羧酸 El MS: m/z 272 (M+NH4), 255 (MH+); Ή NMR (400 MHz, DMS〇-de):(5 12.55 (bs, 1H), 3.33 (m, 2H), 2.7 1 (m, 2H), 0.97-1.63 (m, 13H卜 (實施例3 ) N-(第三丁氧羰基)-N-(2 -氰基乙基)-2 -曱基丙胺酸甲酯 56 3丨2/發明說明書(補件)/93-03/92135527 1327470 62克(0.23莫耳)N-(第三丁氧羰基)-N-(2 -氰基乙 基)-2 -曱基丙胺酸溶解於350毫升DMF,且加入50克碳酸 氫鉀。數分鐘後,滴入3 0毫升曱基碘(M e I ),且該混合物 於室溫授拌6小時。然後又加入1 5毫升M e I。混合物於室 溫放置隔夜。以1 . 5升水稀釋後,溶液以乙酸乙酯萃取(3 次)。有機相以小量水洗蘇,以硫酸鈉脫水,蒸發及於機械 幫浦乾燥。如此獲得6 0 . 5克(9 7 % ) N -(第三丁氧羰 基)-N-(2 -氰基乙基)-2 -甲基丙胺酸曱酯。 ESI MS: m/z 288 (M+NH4); Ή NMR ( 4 0 0 MHz, DMSO-dc) : <5 3.5 5 ( m, 5H), 2.70 ( t, 2H, J=6. 7 Hz), 1.40 (s, 6H), 1.36 (s, 9H) ° 經由以類似方式處理製備下述化合物: 1-[(第三丁氧羰基)(2 -氰基乙基)胺基]環丙烷羧酸曱酯 EI MS: m/z 286 (M+NH4); Ή NMR ( 4 0 0 MHz, DMSO-de): <5 3. 61 (s, 3H), 3.42 (t, 2H, J=6.7 Hz), 2.71 (m, 2H), 1.07-1.62 (m, 13H)° (實施例4 ) 4 -氰基-3-羥基-2 ,2-二曱基- 2,5-二氫-1H-吼咯-1-羧酸第 三丁錯 45克N-(第三丁氧羰基)-N-(2 -氰基乙基)-2 -甲基丙胺 酸曱酯於氮下溶解於二氧己環(2 4 0毫升),加入7, 9克氫 化鈉。混合物回流6小時(1 2 0 °C内溫),然後讓其於室溫放 置隔夜(T L C : C Η 2 C 1 2 / E t 0 Η 9 0 / 1 0 )。蒸發去除溶劑,加水 (1 0 0 0毫升)及混合物以檸檬酸調整至ρ Η 3 - 4。水層以乙酸 乙酯萃取4次,萃取物以有限量水洗滌及蒸發。然後殘餘 57 312/發明說明書(補件)/93-03/92135527 1327470 物以己烷攝取,蒸發及由己烷結晶。如此獲得3 3. 1克4 -氰基-3-羥基-2, 2-二曱基- 2,5-二氫-1H-。比咯-1-羧酸第三 丁 (產率:8 5 % )。 ESI MS: m/z 237 (M-H-); 'H NMR (400 MHz, DMS0-d(〇:(5 4.06-4.10 (2s, 2H,隨形 體),1 . 48 (s, 6H), 1 _ 47 (s, 9H)。 經由以類似方式處理製備下述化合物: 6 -氰基-7-酮基-4-氮雜螺[2. 4]庚烷-4-羧酸第三丁酯 E I MS: m/z 235 (M-H-); Ή NMR (400 MHz, DMS〇-d〇) : ά 4. 63 (t, 1 H, J = 9. 8 Hz), 4.24 (t, 1 H, J = 1 0 . 2 Hz ), 3.74 ( t , 1 H, J = 1 0. 2 Hz ), 1 . 67-2. 16 ( in, 2H ) , 1 . 34- 1 . 4 1 ( s, 9H ) , 0. 9 3 - 1 . 2 0 ( m, 2H)。 (實施例5 ) 3-胺基-6, 6-二甲基-2,6 -二氫0比0各[3,4-c]° 比0坐- 5(4H)-羧 酸第三丁酯 32克4 -氰基-3-羥基-2, 2-二曱基- 2,5-二氫-1H-吡咯 -1 -羧酸第三丁酯(0 . 1 3 4莫耳)添加至4 3 0毫升絕對乙醇。 於此溶液内,加入9毫升(0 . 1 8莫耳)肼水合物,接著加入 1 2毫升冰醋酸(1 . 5當量);混合物於6 0 °C攪拌4 8小時, 去除乙醇,殘餘物以4 0 0毫升碳酸氫鈉溶液攝取,以乙酸 乙酯萃取數次,至完整萃取所需產物。有機相經脫水及蒸 發。藉急速層析術(洗提劑:C H C 13 / E t Ο Η 9 7 / 3 )純化以及與 己烷/乙酸乙酯9 / 1濕磨之後,獲得2 5克標題化合物。總 產量30.5克(產率:88%)。 58 312/發明說明書(補件)/93-03/92135527 1327470 ESI MS: m/z 253 (MH+); Ή NMR (400 MHz, DMS0-dG):5 4.06-4.10 (2s 體),1..48 (2s, 6H,隨形體),1.47 (2s, 9H, 經由以類似方式處理製備下述化合物: 3 _胺基-2 , 6 -二氫σ比D各[3,4 - c ] °比0坐-6 -螺環丙为 酸第三丁酯
El MS : m/z 251 (MH + ); Ή NMR ( 4 0 0 MHz, DMSΟ-d〇) : 5 1 1 . 1 2 ( bs , Π (bs,2H), 4.16-4.33 (m, 2H), 1.57-1.91 (m, (s, 9H), 0.6 5 - 0.8 3 (m, 2H) ° (實施例6 ) 3 -胺基- 6,6-二曱基。比略[3,4-c]°比唑- 2,5(4H, 5 -第三丁酯2-乙酯及3-胺基-6, 6-二甲基-4, 6 并[3,4-c]吡唑-1,5 -二羧酸5-第三丁酯1-乙 15克3_胺基_6,6_二甲基_2,6_二氮0比°各[3, -5(4H)-羧酸第三丁酯(59. 4毫莫耳)溶解於無; 毫升),於0°C於氬氣氣氛下首先使用N,N -二異 (5 0毫升)處理,然後使用C 1 C 0 2 E t ( 4 . 6 5毫升, 滴處理。9 0分鐘後,溶劑以乙酸乙酯(1升)稀 滌然後以鹽水洗滌,以硫酸鈉脫水及蒸發。粗 層析術(己烷/乙酸乙酯2 / 8 )純化,獲得7 . 3克3 二曱基。比略[3,4 - c ]。比唑-2,5 ( 4 Η,6 Η )-二竣酸Ε 2 -乙酯作為主要化合物,3 8 %產率連同5 . 7克3 二甲基-4,6 -二氫。比0各[3,4 - c ] °比。坐-1,5 -二叛 S! S旨1-乙醋,30%產率。 3 i 2/發明說明書(補件)/93-03/92135527 ,2Η, 隨形 隨形體)。 t -5(4Η)-羧 1), 5.13 2Η), 1.38 6 Η )-二羧酸 -二氫吡咯 4 - c ] σ比0坐 ^ T H F ( 1 5 0 丙基乙基胺 '1當量)逐 釋,以水洗 產物藉急速 -胺基_ 6,6 -;-第三丁酯 -胺基-6,6 -L 5 -第三丁 59 1327470 3 -胺基-6, 6-二甲基吡咯[3,4-c]°比唑-2, 5(4H,6H)-二 羧酸5 -第三丁 1旨2 -乙醋 ESI MS: m/z 3 2 5 ( Μ Η + ); Ή NMR (400 MHz, DMSO-dc):54.35 (q, 2H), 4.10 (2s, 2H,隨形體),1.50-1.51 (m, 6H) , 1.41-1.43 (2s, 9H,隨 形體),1 _ 2 9 ( t, 3 H )。 3 -胺基-6,6-二甲基-4,6 -二氫0 比 〇各[3,4-c]。比。坐-1,5-二羧酸5 -第三丁 S旨1-乙醋 ESI MS: m/z 325 (MH+); Ή NMR (400 MHz ,DMSO-d 6 ) : (5 4.28 (q, 2H, J = 7. 1 Hz 4.09-4.14 ( 2 s , 2H, 隨形 體), 1.66-1. 6 7 ( m, 6H ), 1.41-1.44 ( 2 s , 9H, 隨形 體), 1.27 (t, 3H, J=7.1 Hz) 經由以類似方式處理製備下述化合物: 3 -胺基-吡咯[3,4 - c ]。比唑-6 -螺環丙烷-2,5 ( 4 Η,6 Η )-二羧 酸5 -第三丁酯2 -乙酉旨 Ε I MS: in / z 3 2 3 ( Μ Η + ); Ή NMR (400 MHz, DMSO-dc) :5 4.30 (q, 2H, J = 7. 1 Hz), 4.27 (bs, 2H), 1.65-2.01 (in, 2H), 1.38 (s, 9H), 1.27 (t, 3H, J = 7.1 Hz ) , 0.82-0.96 (m, 2H)= 3 -胺基-4,6 -二氫0比0各[3 , 4 - c ] 0比0坐-6 -螺環丙坑-1 , 5 -二羧酸5 -第三丁酯1-乙酷 E S I M S : ni / z 3 2 3 ( Μ Η + ); Ή NMR (400 MHz, DMSO-d〇):54.26 (bs, 2H), 4.21 (q, 2H, J=7.0 Hz), 1.36-1.97 (m, 13H), 1.23 (t, 3H, J-7.0 Hz) ° 60 312/發明說明書⑽件)/93-03/92 Π5527 1327470 (實施例7 ) 3 - [ ( 4 -氟苯曱醯基)胺基]-6,6 -二甲基-4,6 -二 [3,4-c]°比唑-1,5 -二羧酸5-第三丁酯1-乙酯 3 -胺基-6, 6-二曱基-4, 6-二氫吼咯并[3, 4-c -1,5 -二羧酸5 -第三丁酯2 -乙酯(2.0克’ 6.1( 解於THF(40毫升),首先使用Ν,Ν -二異丙基乙 毫升,3 0 . 8毫莫耳)處理,然後於0 °C以4 -氟苯 微升,6 _ 7 7毫莫耳)溶解於T H F ( 8毫升)逐滴處 合物於室溫攪拌5小時,濃縮及溶解於二氣甲 碳酸氫鈉水溶液洗滌及以鹽水洗滌。有機相以 水,蒸發及藉急速層析術(洗提劑:己烷/乙酸, 純化,獲得2 . 5克標題化合物,9 0 %產率。 ESI MS: m/z 447 (MH+); 'H NMR ( 4 0 0 MHz, DMSO-de) :5 11.47 (s, 1H), (in, 2H ) , 7.2 5 - 7.3 7 ( m , 2H ) , 4 . 4 4 - 4. 4 7 ( 2 s 體),4. 43 (q,2H,J = 7. 1 Hz), 1 . 73-1 75 ( 形體),1 . 4 3 - 1 · 4 6 ( 2 s,9 H,隨形體),1 · 3 3 ( t Hz) ° 經由以類似方式處理製備下述化合物: 3-[(4-氟苯甲醯基)胺基]-6 ,6-二甲基吡咯[3, -2,5(4H,6H) -二羧酸5-第三丁酯2 -乙酯 ESI MS: m/z 447 (MH+); Ή NMR ( 4 0 0 MHz, DMS0-d6):<5 10.78 (s, 1H), (m, 2 H), 7.40-7.47 (m, 2H), 4.51-4.49 (2s 體),4.43 (q, 2H, J = 7.1 Hz), 1.59-1.60 ( 3丨2/發明說明書(補件)/93-03/92135527 氫。比0各 ]nt。坐 丨毫莫耳)溶 基胺(5 . 4 曱醯氯(8 0 0 理。反應混 炫,以餘和 硫酸鈉脫 L SI 8 0 / 2 0 ) 8. 04-8. 1 7 ,2H, 隨形 2 s , 6 Η,隨 ,3Η, J = 7. 1 4 — c ] °比。坐 7. 95-7. 99 ,2H, 隨形 2s, 6H), 61 1327470 1.43-1.46 (2s, 9H,隨形體),1.34 (t, 3H, J=7.1 Hz)。 3-[( 4 -氟 苯曱 醯基)胺基]-° 比咯[3, 4- c ] 口比 口坐-6 - 螺環丙烧 -2,5 (4H, 6Η )- 二羧酸5 -第三丁 酯2 -乙il ESI MS : Π1 / Ζ 4 4 5 ( Μ Η + ); Ή N M R (- 4 0 0 MHz, DMSO-de) ;δ 10.; 8 1 (S, 1 Η), 7.95- 8. 06 (in, 2H), 7 . 3 9-7.49 (in , 2 Η ), 4.( 37 (bs, 2Η), 4.41 (Q. 2H, J = 7 . 1 Hz ),1 . 80-2. 10 (m ,2Η ), 1.41 (s , 9H), 1 . 32 (t, 3H, J = 7 . 1 Ηζ ), 0.93- 1 . 0 6 ( m, 2H)° (實施例 8) 3-( { [(3- •氟苯 基)胺基]幾基 }鹿 f基- 6, 6-二〒 r基- 4, 6-二 二氣 口比'口各 [3, ^ :-c ]。比 °坐-1,5 -二叛 酸 5-第 三 丁酯 1 -乙 酯 3- 胺基 -6,6 -二曱基-2, 6- 二 氫°比 咯 [3, 4- c ] 0比 口坐-1, 5- 二羧 酸5 -第三 .丁酷 1 -乙酯( 3. 0克’ 9. 24毫 莫耳 )溶解 於 無 水 T H F ( 5 0毫升),於室溫以 3- •氟苯 基 -異氰 酸酯 (1.4 克 10.2 1毫 莫耳 ,:1 · 1當量)處 理 及攪 拌 隔仪。 次6 丨反應 混 合 物經 蒸發 , 以 二氣甲烷攝取 及 以鹽 水 洗蘇。 有機相以 硫 酸 鈉脫 水及 蒸發 至乾。藉毒速 層 析術 (CH2Cl"MeOH :90/1 0) 純 化, 獲得 3.0! 5克(產率7 1 % )標 題化 合 物。 ESI MS : m / ζ 4 6 2 ( MH+ ); Ή NMR (4 00 ΜΗ 1 z , D M S 0 - d ο): δ 9 • 74 (s ,1H), 9.0 5 ( s , 1 Η )’ 7.44 (111 , 1 Η), 7 . 3 3 (in, 1 Η ) ,7 .16 (m, 1H), 6.84 (ηι, 1Η), 4.43 (111 , 4Η) ,1.76 (2s,( 3Η) ,1 · 48 (2s, 9H, 隨形 體 ), 1.36 (t, 3Η , J=7.1 Hz) ° (實袖 ί例 9) 3-[( °泉。定 - 1_截基)胺基]_6, 6 - 二曱 基 -4,6- 二 iL π比d各 62 3 12/發明說明書(補件)/93-03/92135527 1327470 [3,4-c]°比唑-1,5 -二羧酸5 -第三丁酯1-乙酯 於三光氣(550毫克,1.85毫莫耳,0.4當量)於四氫呋 喃(50毫升)之溶液内,於-40 °C加入3 -胺基-6, 6 -二甲基 -4,6-二氫〇比0各[3,4-(:]〇比°坐-1,5-二敌酸5-第三丁酯1-乙 酯(1.5克,4. 62毫莫耳)於四氫呋喃(50毫升)之溶液及 Ν,Ν -二異丙基乙基胺(1.8毫升,2.2當量)。3小時後,加 入哌啶(6 9 0微升,1 · 5當量)及Ν,Ν -二異丙基乙基胺(1 · 2 毫升,1.5當量)於四氫°夫喃(25毫升)之溶液。讓反應以2 小時時間達到室溫(T L C :乙酸乙酯/己烷9 0 / 1 0 )。蒸發去 除溶劑後,固體溶解於二氣甲烷,溶液以鹽水洗滌,有機 相以硫酸鈉脫水及濃縮。固體藉急速層析術(洗提劑:乙酸 乙酯/己烷5 0 / 5 0 )純化。固體以二異丙基醚處理及過濾, 獲得1 . 4 5克標題化合物,7 2 %產率。 ESI MS: m/z 436 (MH+); Ή NMR ( 4 0 0 MHz, DMSO-de) : 5 9.36 (s, 1 H ) , 4.46 ( m, 4H), 3.40 (in, 4 H ), 1.76 (2s, 6H), 1.54 ( m, 6H ) , 1.44 (2s, 9H,隨形體),1.36 (t, 3H, J=7.1 Hz)。 (實施例1 0 ) 3-[(4_敦苯曱酿基)胺基]_6, 6_二曱基_5, 6_二氣0比0各 [3,4 - c ] σ比唑一1 ( 4 Η )-幾酸乙酯鹽酸鹽 3-[(4_氟笨甲醯基)胺基]-6 ,6-二甲基- 4,6-二氫°比咯 [3,4-c]°比唑-1,5 -二羧酸5 -第三丁酯卜乙酯(2. 5克,5.59 毫莫耳)溶解於二氧己環(5 0毫升),以4 Μ鹽酸於二氧己環 (2 8毫升,2 0當量)處理。於4 0 °C經2小時(T L C : C Η 2 C 1 2 / M e 0 Η. 9 0 / 1 0 )後,反應混合物經濃縮,殘餘物以乙醚處理,過濾 63 3! 2/發明說明書(補件)/93-03/92 ] 35527 1327470 獲 得 標題 化 合 物 !. 09 克 ), 呈 固體, 9 8%產率 〇 ES I MS : m / Z 347 (MH + ); , 丨Η NMR ( 4 00 MHz, D M S 0 - d 6 ) :δ 11.28 (S, 1 H) ,8 .06-8.11 (in 1 2H), 7 .28- 7 · 34 (m, 2H), 4.40 (Q, 2H, J = 7.1 Hz), 3. 92 (s, 2H), ,1 .- 42 (2s, 6H), 1.33 (t, 3H, J = 7.1 Hz ) ° 經 由以 類 似 方 式 處理製 備 下 述化合 物: 3- [( 4 - H 苯 甲 酿 基 )胺基] -6 ,6 -二甲基-5 , 6-二 氫 0比〇各 [3,4 - c ]。比唑-2 ( 4 Η )-羧酸乙酯鹽酸鹽 ESI MS: m/z 347 (MH+); 丨Η NMR (400 MHz, DMSO -d< 0 : :δ 10.92 (s, 1Η), 9.89 ( s, 1 Η ), 8 .02 (m, 2H), 7. 49 (m, 2Η), 4. 6 1 (s, 2H ) , 4.5 1 (q > 2H ,J = 7. 1 Hz), 1 · 69 ( S, 6Η), 1.39 (t, 3H, J = 7. 1 Hz )= ) 3- [( 4- 氟苯曱醯基)胺 基 ]_ 5, 6- 二氫°比洛[3 ,4 - c ]〇比口坐_ 6 - 螺 環 丙 烷-2 ( 4 Η )-羧酸 乙 酯 鹽 酸 鹽 ESI MS : m/z 345 (MH+); Ή NMR ( 4 0 0 MHz, DM SO - de) : δ 10.87 ( bs, 1 H ), 10.00 ( bs, 2H), 7.9 3 - 8.0 4 (m, 2H), 7. 3 9 - 7. 5 3 (m, 2H), 4.6 9 ( bs, 2H), 4.41 (q, 2H, J=7.1 Hz), 1.68 (dd, 2H, J=8.6 Hz, J = 6. 1 Hz), 1.41 (dd, 2H, J = 8. 6 Hz, J = 6.1 Hz), 1.33 (t, 3H, J=7.1 Hz) » (實施例1 1 ) 5-(2, 2-二曱基丙醯基)-3-[(4 -氟苯甲醯基)胺基]-6, 6-二 曱基-5 , 6 -二氫°比0各[3,4 - c ] °比。坐-1 ( 4 Η )-缓酸乙酯 3 - [( 4 -氟苯甲醯基)胺基]-6,6 -二甲基-5 , 6 -二氫吡咯 64 3丨2/發明說明書(補件)/93-03/92135527 1327470 [3 , 4 - c ]。比唑-](4 Η )-羧酸乙酯鹽酸鹽(2 · 0克,! 於二氣甲烷(7 0毫升),於0 °C以Ν,Ν -二異丙基 毫升,9.2毫莫耳,1.6當量)處理,及以特戊i 升,6 . 3毫莫耳,1 . 1當量)處理。徐缓將反應 及攪拌隔夜(T L C : C Η 2 C 12 / E t 0 A c 9 0 / 1 0 )。溶液 氫鈉水溶液及鹽水洗滌。有機相以硫酸鈉脫水 急速層析術(洗提劑:C Η 2 C 1 2 / Ε ΐ 0 A c 9 0 / 1 0 )純化 克標題化合物,82%產率。 ESI MS: πι/ζ 431 (MH+); Ή NMR ( 4 0 0 MHz, DMSO-de) :511.51 ( s, 1 H ), (in, 2H),7. 2 3 - 7. 3 7 (m, 2H), 4. 90 ( s, 2H), 4 1 = 1. 1 Hz), 1.80 (s, 6H), 1.33 ( t, 3H, J = 7.: (s, 9H)。 經由以類似方式處理製備下述化合物: 5_(2, 2_二甲基丙酿基)-3—[(4_氟苯甲S盘基)月安 氫。比。各[3 , 4 - c ] σ比。坐-6 -螺環丙坑-2 ( 4 Η )-級酸乙 ESI MS: m/z 429 (MH+); 1 H NMR ( 4 0 0 MHz, DMSO-da) : <5 10.81 ( bs , 1 H ), (in, 2H ), 7.38-7.48 (m, 2H), 5.10 ( bs, 2H) 2H, J = 7. 1 Hz), 2.33 (dd, 2H, J = 6. 8 Hz, J = 4. (t, 3H, J = 7. 1 Hz), 1.22 (s, 9H), 0. 90 (dd,
Hz, J = 4. 2 Hz)。 (實施例1 2 ) 1^-[5-(2,2-二甲基丙醯基)-6,6-二曱基-1,4,5 略[3,4_c]°比。坐-3_基]氟¥酿胺 3丨2/發明說明書(補件)/93-03/92丨35527 77毫莫耳) 乙基胺(1 . 6 癒氣(7 8 0微 調整至室溫 以飽和碳酸 ,蒸發及藉 ,獲得2. 03 8. 05-8.14 .42 (q, 2H, :Hz ),1· 22 基]-5,6 _ 二 * m 7. 96-8. 04 ,4.42 ( q , 2 Hz ), 1.32 2H, J=6.8 ,6 -四氫。比 65 1327470 5-(2,2-二曱基丙醯基)-3-[(4-氟苯甲醯基)胺基]-6,6-二曱基-5,6-二氫吡咯[3,4-(:]0比唑-1(41〇-羧酸乙酯 (2.0克,4.64毫莫耳)溶解於曱醇(60毫升),以TEA(6. 45 毫升,46.4毫莫耳,10當量)處理,於室溫攪拌(TLC: CH2Cl2/MeOH 95/5)。蒸發後,固體以乙醚/己烷處理及過 濾,獲得1 . 4 3克標題化合物,8 6 %產率。 ESI MS: iii/z 359 (MH + ); Ή NMR ( 4 0 0 MHz, DMSO-de) :512.41 ( bs, 1 H ), 10.91 (bs, 1H), 7.98-8.11 (m, 2H), 7.20-7.44 (m, 2H), 4.66-4.92 (bs, 2H ) , 1.64 ( s, 6H) , 1.21 (s, 9H) ° 經由以類似方式處理製備下述化合物: 1^-[5-(2,2-二曱基丙醯基)-2,4,5,6-四氫0比0各[3,4-(:]11比 唑-6 -螺環丙烷-3 -基]-4 -氟苄醯胺 ESI MS: m/z 357 (MH+); Ή NMR ( 4 0 0 MHz, D M S 0 - d e) : <5 1 1 . 5 9 - 1 2 . 4 7 (bs, 1H), 10 .9 4 (b s, 1H), 8 . 0 2 - 8 . 11(丨 η , 2H ), 7. 27 -7 .37 (m, 2H), 4. 9 9 (s, 2H ), 2 .25 (dd, 2H, J = :6. 5 Hz, J=4 .4 Hz ), 1.20 (s ) 9H), 0.79 (dd ,2H, J = 6 .5 Η z , J = 4. 4 Hz) ° N- { 6 ,6-- 二甲基- 5-[ (2R)- 四氫 呋 喃 -2 -基羰 基 1-1,4,5,6- 四 氫 〇比〇各 [3 , 4 - c ]〇比 〇坐- 3 _ 基} _ 4- 氟 ¥ 醯胺 ESI MS: m/z 373 (MH+); Ή NMR ( 4 0 0 MHz, DMS〇-d〇) : (5 12.49 ( bs, 1H), 10.96 (bs, 1H), 8.09 (m, 2H),7.34 (m, 2H), 4.86 (m, 2H), 4.56 (t, 1 H ), 3.83 ( m, 2H), 2.02 ( m , 2H), 1.86 ( m, 2H ), 1.68 (s, 6 H )。 66 312/發明說明書(補件)/93-03/92丨35527 1327470 α,, + 27.7 (c = 0.50, MeOH) N -丨6,6-二曱基- 5- [(2R) -四氬呋喃-2-基羰基]-1,4,5,6-四氫0Λ。各[3,4 - c ] 0比口坐-3 -基} - 4 -氟苄酿胺 ESI MS: m/z 373 (MH+); Ή NMR ( 4 0 0 MHz, DMSO-do) : 5 12.49 ( bs, 1 H ) , 10.96 ( bs, 1H), 8.09 (m, 2H ), 7.34 (m, 2H), 4.86 (m, 2H), 4.56 (t, 1 H), 3.83 (m, 2H), 2.02 (m, 2H), 1.86 (m, 2H), 1.68 (s, 6H)。 a d-25. 9 (c=0. 76, MeOH) (實施例1 3 ) 4-(1-甲基-11 底口定-4-基氧基)-苯甲酸甲酯 於1-曱基-°底°定-4 -醇(6.8克,59毫莫耳),PPh3(三苯 基膦,15.5克,59毫莫耳)及4 -羥基-苯曱酸曱酯(6克, 3 9毫莫耳)於T H F ( 1 5 0毫升)之溶液内,於0 °C緩慢加入偶 氮二羧酸二乙酯(9.5毫升,59毫莫耳)於1'}^(30毫升)。 讓反應混合物以24小時時間溫熱至室溫。然後經蒸發,殘 餘物再度溶解於5 %水性檸檬酸(7 0 0毫升)。溶液以乙酸乙 酯(3 X 2 5 0毫升)洗滌,以濃氫氧化銨(p Η約8 )調整為鹼性, 然後以二氣曱烷(3 X 2 5 0毫升)萃取。合併二氣曱烷萃取物 以鹽水洗滌,脫水及蒸發獲得油,油於矽膠,使用二氯甲 烷-甲醇(9 0 : 1 0 )作為洗提劑,藉急速層析術純化,獲得標 題化合物,呈黃色油(7·4克,75%)。 ESI MS: m/z 250 (MH+); Ή NMR ( 4 0 0 MHz, DMSO-De) <5 ppm 1. 7 (in, 2H), 2.0 (m,2H), 2.2 (in, 5H), 2.7 (m, 2H), 3.8 (s, 3H), 4.5 (m, 1H), 67 312/發明說明書(補件)/93-03/92135527 1327470 7.1 (d, J=9.0 Hz, 2H), 7.9 (d, J=9.0 Hz, 2H)。 (實施例1 4 ) 4-(1-曱基-哌啶-4-基氧基)-苯甲酸,鹽酸鹽 4-(1-曱基-哌啶-4-基氧基)-苯甲酸曱酯(7.3克,29毫 莫耳)溶解於6 N水性鹽酸(2 2 0毫升)。於8 5 °C加熱6小時 後,真空去除溶劑。殘餘物以水攝取及蒸發兩次,然後又 以丙酮攝取兩次。所得固體最終於丙酮濕磨,獲得鹽酸鹽, 呈白色粉末(6 . 4克,8 0 %產率)。 Ή NMR ( 4 0 0 MHz, DMSO-Dg)(5 ppm 2.0 (in, 4H ) , 2.8 ( m , 3 H ), 3.3 (in, 4H), 4.7 (m, 1H), 7.1 (m, 2H), 7.9 (m, 2H), 9.9 ( d, J = 2 0 . 4 Hz, 1 H ) , 12.6 ( s, 1 H)。 (實施例1 5 ) 4 -( 4 -羥基-哌啶-1 -基)笨曱酸乙酯 4- 氟 -苯甲酸乙 酯(1 · 6 8克, 1 0毫 莫耳 ), 哌啶-4 -1 醇( 1 . 12 克 » 11 毫莫 耳)及 無水碳酸鉀 ( 1 · 38 克 ,1 0毫莫 耳 )於 D M S 0 ( 1 0毫升)之混合物於1 2 0 °C加 熱6 小 時 0冷 卻 後 ) 混 合 物 倒 入水 及冰( 5 0 0毫升)内 j 以 乙酸 乙i i旨萃取 〇 有; 機. 層 以 水 及 鹽水 洗滌, 脫水及蒸發 。殘 餘物 於 矽膠使 用 己 烧 / 乙 酸 乙 酯(1 0 / 3 0 )作為洗提劑 藉 急速層析術純 化, 獲 得 標 題 化 合 物 呈 白色固體(1 . 6克 j 6 4%)。 ES I MS :m / ζ 2 5 0 (MH+ ); 1 Η NMR (400 MHz, DMS〇-D〇) (5 ppm 1 .3 ( t , J = 7 . 1 Η ζ , 3H ), 1 · 4 (in, t 2H), 1 . 8 (m, 2H), 3. 0 (m , 2H): ,3 .7 (m, 2Η), 4 .2 (Q J = ’ 7. 1 Η ζ, 2H ),4.7 (d,, J = 4.3 Η ζ , 1 Η ), 6.9 ( m, 2H ), 7.7 ( in, 2H) 〇 68 3 12/發明說明書(補件)/93-03/92丨35527 1327470 (實施例1 6 ) 4 - ( 4 -氟-哌啶-1 -基)苯曱酸乙酯 於4 - ( 4 -羥基-哌啶-1 -基)苯甲酸乙酯(1 · 2 5 β 耳)於無水二氣曱烷(30毫升)之溶液内,於室溫 氛下緩慢加入D A S Τ ( 0 . 9 7克,6毫莫耳)於二氯 升)。反應混合物於室溫攪拌1小時,然後以水 浮熄、(q u e n c h )。有機層以鹽水洗游:,脫水及蒸名 於矽膠,使用己烷/乙酸乙酯(7 0 / 3 0 )作為洗提脅 析術純化,獲得標題化合物,呈白色固體(0 . 7 . ESI MS: m/z 2 5 2 (MH+ ); Ή NMR ( 4 0 0 MHz, DMS〇-D6)(5 ppm 1.3 (t, J = 7.] 1.8 ( m , 2 H ) , 2.0 (m, 2H), 3. 3 (m, 2H), 3. 6 ( m (s , 2H ) , 4.8 (s, 1H ) , 7.0 ( s, 2H ) , 7.8 ( s (實施例1 7 ) 4 - ( 4 -氟-哌啶-1 -基)笨曱酸 於4 - ( 4 -氟-哌啶-1 -基)苯曱酸乙酯(0 . 7克,2 · 於乙醇(5 0毫升)及2 N氫氧化鈉(2 0毫升)之混名 攪拌24小時。然後乙醇經蒸發去除,溶液以水 稀釋及以2N鹽酸中和。酸呈白色固體分離,固楚 及真空脫水(0.52克,82%)。 ESI MS: ιη/ζ 224 (MH+); Ή NMR (400 MHz, DMSO-De) (5 ppm 1.8 ( m, 2H ), 2. 3.3 ( m, 2H), 3.5 ( m, 2H ) , 5.0 (s, 1H), 7.0 7.8 ( s, 2H ) , 12.2 (s, 1H) ° 如先前任一實例所述處理,換言之,經由使用 3丨2/發明說明書(補件)/93-03/92135527 ,5毫莫 於惰性氣 曱烷(5毫 t碳酸氫鈉 卜。殘餘物 J藉急速層 免,56%)° [Hz, 3H), ,2H), 4.2 ,2H) ° 7毫莫耳) 、物於室溫 (20毫升) ί以水洗滌 0 (m, 2H ), (s, 2H), I任一種適 69 1327470
當起始物料以及任一種適當反應物,根據先前揭示之方法 處理,也製備其它式(I a )及(I b)化合物報告如下表I I I。 有關識別各個特定式(I a )及(I b)化合物之編碼系統之說明 註解,參考實驗乙節起點之「概略方法」。 表I I I A02M1B01 'H NMR (400 MHz, DMSO-d6): δ 12.45 (bs, 1H), 10.99 (s, 1H), 7.84 (m, 2H), 7.52 (m, 1H), 7.40 (m, 1H), 4.86 (s, 2H), 1.65 (s, 6H), 1.21 (s, 9H). A03M1B01 'H NMR (400 MHz, DMSO-d6): δ 12.46 (bs, 1H), 11.01 (s, 1H), 8.05 (m, 1H), 7.88 (m, 1H), 7.54 (m, 1H), 4.86 (s, 2H), 1.65 (s, 6H), 1.21 (s, 9H). 70 312/發明說明書(補件)/93-〇別2丨35527 1327470 A04M1BO1 'H NMR (400 MHz, DMSO-d6): δ 12.45 (bs, 1H), 10.89 (s, 1H), 7.7 (m, 1H), 7.38 (m, 1H), 7.20 (s, 1H), 4.89 (s, 2H), 1.68 (s, 6H), 1.24 (s, 9H). A05M1B01 ’H NMR (400 MHz, DMSO-d(〇: δ 12.54 (bs,1H), 11.07 (s, 1H), 7.76 (s, 2H), 7.51 (s, 1H), 4.89 (s, 2H), 1.68 (s, 6H), 1.25 (s, 9H). A06M1B01 'H NMR (400 MHz, DMSO-d6): δ 12.43 (bs, 1H), 10.98 (s, 1H), 7.98 (d, 2H, J = 8.0 Hz), 7.54 (d, 2H, J = 8.0 Hz), 4.86 (s, 2H), 1.65 (s, 6H), 1.21 (s, 9H). A07M1B01 *H NMR (400 MHz, DMSO-d6): δ 12.47 (bs, 1H), 11.16 (s, 1H), 8.16 (d, 2H, J = 7.9 Hz), 7.85 (d, 2H, J = 7.9 Hz), 4.88 (s, 2H), 1.65 (s, 6H), 1.21 (s, 9H). A08M1B01 'H NMR (400 MHz, DMSO-d6): δ 12.50 (bs, 1H), 11.17 (s, 1H), 9.13 (s, 1H,), 8.76 (m, 1H), 8.33 (m, 1H) 7.51 (m, 1H), 4.91 (s, 2H), 1.69 (s, 6H), 1.25 (s, 9H). A09M1B01 'H NMR (400 MHz, DMSO-d6): δ 12.54 (bs, 1H), 11.25 (s, 1H), 8.75 (d, 2H), 7.91 (d, 2H), 4.92 (s, 2H), 1.69 (s, 6H), 1.25 (s, 9H). A10M1B01 *H NMR (400 MHz, DMSO-d6): 5 12.47 (bs, 1H), 11.00 (s, 1H), 8.12 (m, 1H), 7.86 (m, 1H), 7.12 (m, 1H), 4.86 (s, 2H), 1.68 (s, 6H), 1.25 (s, 9H). A11M1B01 lH NMR (400 MHz, DMSO-d6): δ 12.11 (bs, 1H), 10.77 (s, 1H), 8.45 (s, 1H), 7.69 (m, 2H), 4_89 (s, 2H), 1.68 (s, 6H),1_25 (s,9H). A12M1B01 'HNMR (400 MHz, DMSO-d6): δ 12.22 (bs, 1H), 10.31 (s, 1H), 4.76 (s, 2H), 2.12 (m, 3H), 1.61 (s, 6H), 1.19 (s, 9H), 0.87 (d, 6H, J -6.5 Hz). A13M1B01 'HNMR(400 MHz, DMSO-dfi): δ 12.21 (bs, 1H), 10.19 (bs, 1H), 4.80 (s, 2H), 3.28 (m, 1H), 2.25-1.70 (m, 6H), 1.60 (s, 6H), 1.20 (s, 9H). A14M1B01 'HNMR(400 MHz, DMSO-d6): δ 12.35 (bs, 1H), 10.38 (bs, 1H), 4.75 (s, 2H), 1.82 (m, 1H), 1.60 (s, 6H), 1.20 (s, 9H), 0.78 (m, 4H). 71 312/發明說明書(補件)/93-03/92135527 1327470 A15M1B01 'H NMR (400 MHz, DMSO-d6): δ 12.3 (bs, 1H), 9.89 (s, 1H), 4.80 (s, 2H), 1.64 (s, 6H), 1.23 (s, 9H), 1.21 (s, 9H). A16M1B01 'H NMR (400 MHz, DMSO-d6): δ 12.35 (bs, 1H), 11.02 (s, 1H), 8.09 (d, 2H, J = 8.2 Hz), 7.47 (d, 2H, J = 8.2 Hz), 4.85 (s, 2H), 1.64 (s, 6H), 1.21 (s, 9H). A19M1B01 'H NMR (400 MHz, DMSO-d6): δ 12.48 (bs, 1H), 10.82 (s, 1H), 8.43 (m, 1H), 7.45 (m, 1H), 6.70 (m, 1H), 4.85 (s, 2H), 1.67 (s, 6H), 1.25 (s, 9H). A20M1B01 lH NMR (400 MHz, DMSO-d6): δ 12.26 (bs, 1H), 10.38 (s, 1H), 4.80 (s, 2H), 3.04 (m, 2H), 2.52 (m, 3H), 1.64 (m, 10H), 1.23 (s, 9H). A22M1B01 'H NMR (400 MHz, DMSO-d6): δ 12.43 (bs, 1H), 11.06 (s, 1H), 8.3-7.6 (m, 7H), 4.99 (s, 2H), 1.71 (m, 6H), 1.26 (s, 9H). A23M1B01 'H NMR (400 MHz, DMSO-do): δ 12.48 (bs, 1H), 11.07 (s, 1H), 8.68 (s, 1H), 8.08 (m, 4H), 7.66 (m, 2H), 4.95 (s, 2H), 1.70 (m, 6H), 1.27 (s, 9H). A24M1B01 'H NMR (400 MHz, DMSO-d6): δ 12.05 (bs, 1H), 8.87 (s, 1H), 7.19 (m, 4H), 6.91(bs, 1H), 4.73 (s, 2H), 4.32 (d, 2H, J = 5.85 Hz), 2.30 (s,3H), 1.63 (s, 6H), 1.22 (s, 9H). A25M1B01 'H NMR (400 MHz, DMSO-d6): δ 12.31-12.05 (2bs, 1H), 8.48 (s, 1H), 7.30 (m, 5H), 7.00 (bs, 1H), 4.73 (s, 2H), 4.33 (d, 2H, J = 5.85 Hz), 1.63 (s, 6H), 1.22 (s, 9H). A28M1B01 'H NMR (400 MHz, DMSO-d6): δ 12.07 (bs, 1H), 8.99 (s, 1H), 4.72 (s,2H), 3.40 (m, 4H), 1_63 (s, 6H), 1_5 (m, 6H),1_22 (s, 9H). A29M1B01 lH NMR (400 MHz, DMSO-d6): δ 12.36 (bs, 1H), 10.08 (s, 1H), 4.82 (s, 2H), 3.15 (bs, 2H), 2.32 (s, 6H), 1.65 (s, 6H), 1.23 (s, 9H). A02M2B01 'H NMR (400 MHz, DMSO-d6): δ 12.29 (bs, 1H), 11.05 (s, 1H), 7.9-7.35 (m, 3H), 5.03 (s, 2H), 2.29 (m, 2H), 1.24 (s, 9H), 0.84 (m, 2H). 72 312/發明說明書(補件)/93-03/92丨35527 1327470 A04M2B01 'H NMR (400 MHz, DMSO-d6): δ 12.21 (bs, 1H), 10.90 (s, 1H), 7.79 (m, 1H), 7.40 (m, 1H), 7.21 (m, 1H), 5.03 (s, 2H), 2.29 (m, 2H), 1.24 (s, 9H), 0.83 (m, 2H). A05M2B01 •H NMR (400 MHz, DMSO-d6): δ 12.30 (bs, 1H), 11.17 (s, 1H), 7.77 (s, 2H), 7.51 (s, 1H), 5.04 (s, 2H), 2.29 (m, 2H), 1.24 (s, 9H), 0.84 (m, 2H). A06M2B01 屮 NMR (400 MHz, DMSO-d6): δ 12.28 (bs,1H), 11.04 (s, 1H), 8.03 (d, 2H, J = 8.0 Hz), 7.61 (d, 2H, J = 8.0 Hz), 5.03 (s, 2H), 2.29 (m, 2H), 1.24 (s, 9H), 0.83 (m, 2H). A07M2B01 'H NMR (400 MHz, DMSO-d6): δ 12.32 (bs, 1H), 11.22 (s, 1H), 8.21 (d, 2H, J = 7.9 Hz), 7.91 (d, 2H, J = 7.9 Hz), 5.05 (s, 2H), 2.29 (m, 2H), 1.24 (s, 9H), 0.84 (m, 2H). A10M2B01 'H NMR (400 MHz, DMSO-de): 5 12.23 (bs, 1H), 11.02 (s, 1H), 8.10 (m, 1H), 7.87 (m, 1H), 7.22 (m, 1H), 5.01 (s, 2H), 2.29 (m, 2H), 1.24 (s, 9H), 0.84 (m, 2H). A12M2B01 H NMR (400 MHz, DMSO-d6)·· δ 12.03 (bs, 1H), 10.36 (bs, 1H), 4.95 (s, 2H), 2.26 (m, 2H), 2.17 (m, 2H), 2.09 (m, 1H), 1.22 (s, 9H), 0.93 (m, 6H), 0.80 (m, 2H). A13M2B01 'H NMR (400 MHz, DMSO-d6): δ 12.05 (bs, 1H), 10.28 (bs, 1H), 4.96 (s, 2H), 3.32 (m, 1H), 2.25 (m, 8H), 1.23 (s, 9H), 0.78 (m, 2H). A14M2B01 'H NMR (400 MHz, DMSO-d6): δ 12.03 (bs, 1H), 10.72 (bs, 1H), 4.91 (s, 2H), 2.25 (m, 2H), 1.82 (m, 1H), 1.20 (s, 9H), 0.80 (m, 6H). A15M2B01 'H NMR (400 MHz, DMSO-d6): δ 12.01 (bs, 1H), 9.92 (s, 1H), 4.94 (s, 2H), 2.25 (m, 2H), 1.22 (s, 18H), 0.78 (m, 2H). A19M2B01 lH NMR (400 MHz, DMSO-d6): 8 12.21 (bs, 1H), 10.82 (s, 1H), 7.92 (m, 1H), 7.49(m, 1H), 6.69 (m, 1H), 5.01 (s, 2H), 2.29 (m, 2H), 1.24 (s, 9H), 0.83 (m, 2H). A27M2B01 'H NMR (400 MHz, DMSO-d5): δ 11.98 (bs, 1H), 9.02 (s, 2H), 7.45 (m, 1H), 7.33 (m, 1H), 7.13 (m, IH), 6.81 (m5 1H), 4.96 (s, 2H), 73 3 12/發明說明書(補件)/93-03/92135527 1327470 2.27 (m, 2H), 1.23 (s, 9H), 0.81 (m, 2H). A28M2B01 'H NMR (400 MHz, DMSO-d6): δ 11.83 (bs, 1H), 9.03 (s, 1H), 4.87 (s, 2H), 3.41 (m, 4H), 2.23 (m, 2H), 1.58 (m, 2H), 1.49 (m, 4H), 1.22 (s, 9H),0.76 (m, 2H). A30M1B01 'H NMR (400 MHz, DMSO-d6): 5 ppm 1.2 (s, 9 H) 1.7 (s, 6 H) 4.9 (s, 2 H) 7.4-8.1 (m, 5 Η) 11.2 (s, 1 H) 12.5 (s, 1 H) A31M1B01 'H NMR (400 MHz, DMSO-d6): 5 ppm 1.2 (s, 9 H) 1.7 (s, 6 H) 1.7 (m, 2 H) 2.0 (m, 2 H) 2.2 (s, 3 H) 2.3 (m, 2 H) 2.7 (m, 2 H) 4.5 (m, 1 H) 4.9 (s, 2 H) 7.0 (d, >7.9 Hz, 2 H) 8.0 (d, J=7.9 Hz, 2 H) 10.7 (s, 1 H) 12.4 (s, 1 H) A32M1B01.HCI NMR (400 MHz, DMSO-de):(兩種隨形體洗合物)δ ppm 1.25 (s, 18 H) 1.68 (s, 12 H) 1.84 (m, 2 H) 2.07 (m, 4 H) 2.29 (d, 7=14.0 Hz, 2 H) 2.80 (d, >5.0 Hz, 3 H) 2.82 (d? J=5.0 Hz, 3 H) 3.11 (m, 2 H) 3.20 (m, 2 H) 3.40 (m, 2 H) 3.52 (d, J=14.0 Hz, 2 H) 4.67 (m, 1 H) 4.87 (m, 1 H) 4.89 (s, 4 H) 7.21 (dd, y=8.8, 2.3 Hz, 1H) 7.25 (dd,/=8.8, 2.3 Hz, 1H) 7.45 (m, 2 H) 7.5-7.7 (m, 4 H) 9.90 (bs, 1 H) 9.97 (bs, 1 H) 10.93 (s, 2 H) 12-13 (bs, 2 H). A33M1B01.2HC1 'H NMR (400 MHz, DMSO-d6): δ ppm 1.3 (s, 9 H) 1.7 (s, 6 H) 2.8 (s, 3 H) 3.4 (m, 10 H) 4.9 (s, 2 H) 7.6 (s, 2 H) 8.1 (d, 7=7.9 Hz, 2 H) 10.4 (s, 1 H) 11.0 (s, 1 H) A34M1B01.HC1 'H NMR (400 MHz, DMSO-d6): δ ppm 1.3 (s, 9 H) 1.7 (s, 6 H) 1.9 (m, 4 H) 3.4 (ms 4 H) 4.9 (m, 1 H) 4.9 (s, 2 H) 7.0 (d, /=9.1 Hz, 2 H) 7.9 (d, /=9.0 Hz, 2 H) 10.6 (s, 1 H) A35M1B01 'H NMR (400 MHz, DMSO-d6): δ ppm 1.2 (s, 9 H) 1.6 (s, 6 H) 2.3 (s, 3 H) 2.5 (m, 4 H) 3.1 (m, 2 H) 3.3 (m, 2 H) 4.8 (s, 2 H) 6.9 (d, 7=8.2 Hz, 2 H) 7.9 (d, 7=8.4 Hz, 2 H) 10.5 (s, 1 H) 12.3 (s, 1 H) A36M1B01 'H NMR (400 MHz, DMSO-d6): δ ppm 1.2 (s, 9 H) 1.6 (s, 6 H) 2.1 (m, 2 H) 2.5 (t, J=8.0 Hz, 2 H) 3.9 (t, >7.0 Hz, 2 H) 4.8 (s, 2 H) 7.8 74 312八發明說明書(補件)/93-03/92135527 1327470 (d, /=8.9 Hz, 2 Η) 8.0 (d, J^8.8 Hz, 2 H) 10.8 (s, 1 H) 12.4 (s, 1 H) A37M1B01 'H NMR (400 MHz, DMSO-d6): δ ppm 1.3 (s, 9 H) 1.7 (s, 6 H) 4.1 (m, 2 H) 4.5 (m, 2 H) 4.9 (s, 2 H) 7.7 (d, /=8.2 Hz, 2 H) 8.1 (d, /=7.8 Hz, 2 H) 10.9 (s, 1 H) 12.4 (s, 1 H) A38M1B01 *H NMR (400 MHz, DMSO-d6): δ ppm 1.3 (s, 9 H) 1.7 (s, 6 H) 3.8 (s, 3 H) 3.9 (s, 3 H) 4.9 (s, 2 H) 7.1 (d, >8.5 Hz, 1 H) 7.6 (d, 7=1.2 Hz, 1 H) 7.7 (dd, 7=8.5,2.0 Hz, 1 H) 10.8 (s, 1 H) 12.4 (s, 1 H) A38M2B01 'H NMR (400 MHz, DMSO-d6): δ ppm 0.8 (m, 2 H) 1.2 (s, 9 H) 2.3 (m, 2 H) 3.8 (s, 3 H) 3.9 (s, 3 H) 5.0 (s, 2 H) 7.1 (m, 1 H) 7.6 (m, 1 H) 7.7 (m, 1 H) 10.8 (s, 1 H) 12.2 (s, 1 H) A39M1B01 'HNMR (400 MHz, DMSO-de): δ ppm 1.3 (s, 9 H) 1.7 (s, 6 H) 4.9 (s, 2 H) 7.5 (s, 1 H) 8.0 (d, 7=7.3 Hz, 2 H) 8.05 (d, 7=7.3 Hz, 2 H) 8.11 (s, 1 Η) 11.0 (s, 1 H) 12.5 (s, 1 H) A40M1B01 'H NMR (400 MHz, DMSO-d6): δ ppm 1.2 (s, 9 H) 1.6 (s, 3 K) 4.9 (s, 2 H) 8.0 (d, /=8.4 Hz, 2 H) 8.1 (d, /=8.5 Hz, 2 Η) 11.2 (s, 1 H) 12.5 (s, 1 H) A41M1B01 *H NMR (400 MHz, DMSO-d6): δ ppm 1.2 (s, 9 H) 1.7 (s, 6 H) 4.9 (s, 2 H) 7.7 (t, /=7.6 Hz, 1 H) 8.1 (d, >7.6 Hz, 1 H) 8.3 (d, 7=7.9 Hz, 1 H) 8.4 (s, 1 Η) 11.2 (s, 1 H) 12.5 (s, 1 H) A43M1B01 lH NMR (400 MHz, DMSO-d6): δ ppm 1.2 (s, 9 H) 1.7 (s, 6 H) 4.9 (s, 2 H) 7.3 (m, 2 H) 7.6 (m, 1 H) 7.7 (m, 1 H) 10.9 (s, 1 H) 12.4 (s, 1H) A44M1B01 'H NMR (400 MHz, DMSO-d6): δ ppm 1.25 (s, 9 H) 1.68 (s, 6 H) 3.85 (s, 3 H) 4.88 (s, 2 H) 7.03 (m, 2 H) 8.01 (d, /=8.29 Hz, 2 H) 10.74 (s, 1 H) 12.40 (s, 1 H) A45M1B01 'H NMR (400 MHz, DMSO-d6): 6 ppm 1.3 (s, 9 H) 1.7 (s, 6 H) 3.8 (s, 3 H) 4.9 (s, 2 H) 7.2 (m, 1 H) 7.4 (m, 1 H) 7.6 (m, 2 H) 10.9 (s, 1 H) 12.5 (s, 1 H) A46M1B01 'H NMR (400 MHz, DMSO-d6): δ ppm 1.3 (s, 9 H) 1.7 (s, 6 H) 4.0 75 312/發明說明書(補件)/93-03/92135527 1327470 (s, 3 H) 4.9 (s, 2 H) 7.1 (t, /=7.4 Hz, 1 Η) 7.2 (d, 7=8.3 Hz, 1 H) 7.6 (1,/=7.8 Hz, 1 H) 7.8 (dd,J=7_7, 1_7 Hz, 1 H) 10.3 (s,1 H) 12.4 (s, 1H) A47M1B01 'H NMR (400 MHz, DMSO-d6): δ ppm 1.2 (s, 9 H) 1.6 (s, 6 H) 3.6 (s, 2 H) 4.8 (s, 2 H) 7.25 (m, 1 H) 7.32 (m, 4 H) 10.7 (s, 1 H) 12.3 (s,1 H) A48M1B01 'H NMR (400 MHz, DMSO-d6): δ ppm 1.16 (s, 9 H) 1.60 (s, 6 H) 3.78 (s, 2 H) 4.75 (s, 2 H) 7.47 (m, 3 H) 7.80 (s, 1 H) 7.86 (m, 3 H) 10.74 (s, 1 H) 12.30 (s, 1 H) A49M1B01 'H NMR (400 MHz, DMSO-d6): δ ppm 1.23 (s, 9 H) 1.67 (m, 14 H) 2.79 (m, 1 H) 4.80 (s, 2 H) 10.37 (s, 1 H) 12.23 (s, 1 H) A50M1B01 'H NMR (400 MHz, DMSO-de): δ ppm 1.32 (m, 6 H) 1.23 (s, 9 H) 1.74 (m, 4 H) 1.64 (s, 6 H) 2.36 (m, 1 H) 4.79 (s, 2 H) 10.30 (s, 1;H) 12.21 (s, 1 H) A51M1B01 'H NMR (400 MHz, DMSO-d6): δ ppm 1.2 (s, 9 H) 1.6 (s, 6 H) 2.0 (m, 4 H) 3.9 (m, 2 H) 4.4 (dd, /=8.2, 5.6 Hz, 1 H) 4.8 (s, 2 H) 10.1 (s, 1 H) 12.3 (s, 1 H) A52M1B01.HC1 'H NMR (400 MHz, DMSO-d6): δ ppm 1.2 (s, 9 H) 1.6 (s, 6 H) 1.9 (m, 4 H) 2.6 (m, 1 H) 2.8 (m, 3 H) 3.0 (m, 2 H) 3.4 (m, 2 H) 4.8 (s, 2 H) 9.6 (s, 1 H) 10.6 (s, 1 H) 12.4 (s, 1 H) A53M1B01 'H NMR (400 MHz, DMSO-de): δ ppm 1.2 (s, 9 H) 1.4 (m, 1 H) 1.5 (m, 1 H) 1.6 (s, 6 H) 1.7 (m, 2 H) 2.0 (s, 3 H) 2.6 (m, 2 H) 3.0 (t, >13.0 Hz, 1 H) 3.8 (d, >13.7 Hz, 1 H) 4.4 (d, 7=12.9 Hz, 1 H) 4.8 (s, 2 H) 10.4 (s, 1 H) 12.3 (s, 1 H) A54M1B01 'H NMR (400 MHz, DMSO-d6): δ 12.52 (bs, 1H), 11.23 (s, 1H), 8.30 (m, 2H), 7.96 (m, 1H), 7.76 (m, 1H), 4.91 (bs, 2H), 1.69 (s, 6H), 1.25 (s, 9H). A01M1B02 'H NMR (400 MHz, DMSO-d6): δ ppm 1.65 (s, 6 H), 2.0 (m, 4 H) 3.79 (m, 2 H), 4.53 (t, 1 H), 4.83 (m, 2 H), 7.3 (m, 2 H), 8.05 (m, 2 312/發明說明書(補件)/93-03/92135527 1327470 H), 10.92 (s, 1 H), 12.45 (s, 1 Η). A48M1B02 'H NMR (400 MHz, DMSO-de): δ ppm 1.59 (s, 3 H) 1.60 (s, 3 H) 1.86 (m, 4 H) 3.70 (m, 2 H) 3.76 (s, 2 H) 4.44 (t, 7=6.52 Hz, 1 H) 4.55 (d, 7=12.44 Hz, 1 H) 4.72 (d, >12.56 Hz, 1 H) 7.46 (m, 3 H) 7.78 (s, 1 H) 7.86 (m, 3 H) 10.74 (s, 1 H) 12.32 (s, 1 H) A03M1B14 lH NMR (400 MHz, DMSO-d6): δ ppm 1.7 (s, 6 H) 2.0 (m, 4 H) 3.8 (m, 2 H) 4.6 (t, >6.6 Hz, 1 H) 4.7 (d, 7=12.4 Hz, 1 H) 4.9 (d, >12.4 Hz, 1 H) 7.6 (ddd, 7=10.5, 8.5, 8.4 Hz, 1 H) 7.9 (m, 1 H) 8.1 (m, 1 H) 11.1 (s, 1 H) 12.5 (s, 1 H) a〇 +24.5 (c=1.08s MeOH) A12M1B14 'H NMR (400 MHz, DMSO-d6): δ ppm 0.92 (d, 7=6.58 Hz, 6 H) 1.65 (d,y=2.44 Hz, 6 H) 1.96 (m, 5 H) 2.16 (d, J=6.95 Hz, 2 H) · 3.80 (m, 2 H) 4.53 (dd, 7=6.95, 6.10 Kz, 1 H) 4.68 (m, 2 H) 10.37 (s, 1 H) 12.30 (s, 1 H) ccD+24.0 (c= 1.00, MeOH) A13M1B14 lH NMR (400 MHz, DMSO-d6): δ ppm 1.64 (s, 6 H) 1.97 (m, 10 H) 3.25 (m, 1 H) 3.80 (m, 2 H) 4.55 (t, 7=6.58 Hz, 1 H) 4.70 (m, 2 H) 10.26 (s, 1 H) 12.28 (s, 1 H) aD +24.7 (c=1.09, MeOH) A32M1B14.HCI 4 NMR (400 MHz, DMSO-de):(兩種隨形體 iS·合物)δ ppm 1.68 (s, 12 H) 1.8-2.1 (m, 10 H) 2.30 (d, 7=14.0 Hz, 2 H) 2.80 (d, 7=5.0 Hz, 3 H) 2.83 (d, 7=5.0 Hz, 3 H) 3.1-3.3 (m, 4 H) 3.45 (m, 2 H) 3.52 (d, 7=14.0 Hz, 2 H) 3.7-3.8 (m, 4 H) 4.56 (dd, •7=7.0, 6.0 Hz, 2 H) 4_66 (m, 1 H) 4.71,4.88 (2 d, J=13 Hz, 4 H) 4.87 (m, 1H) 7.21 (dd, J=8.0,2.3 Hz, 1H) 7.26 (dd, 7=8.8, 2.3 Hz, 1H) 7.46 (m, 2 H) 7.5-7.7 (m, 4 H) 9.89 (bs, 2 H) 10.94 (s, 2 H) 12-13 (bs, 2 H). a〇+17.4(c=1.02, MeOH) A33M1B14.2HC1 'H NMR (400 MHz, DMSO-d6): δ ppm 1.7 (s, 3 H) 1.7 (s, 3 H) 2.0 77 312/發明說明書(補件)/93-03/92丨35527 1327470 (m, 4 Η) 2.8 (s, 3 Η) 3.7 (m, 10 Η) 3.8 (m, 2 Η) 4.6 (dd, /=7.3, 5.9 Hz, 1 H) 4.7 (d, /=12.4 Hz, 1 H) 4.9 (d, 7=12.4 Hz, 1 H) 7.6 (d, J=7.3 Hz, 2 H) 8.0 (d, 7=8.2 Hz, 2 H) 10.3 (s, 1 Η) 11.0 (s, 1 H) a〇+14.7 (c=1.09, MeOH) A31M1B14 lH NMR (400 MHz, DMSO-d6): δ ppm 1.7 (s, 6 H) 2.1 (m, 8 H) 2.8 (m, 3 H) 3.3 (m, 4 H) 3.8 (m, 2 H) 4.6 (dd, >7.2, 6.1 Hz, 1 H) 4.7 (m, 1 H) 4.7 (d, 7=12.6 Hz, 1 H) 4.9 (d, 7=12.6 Hz, 1 H) 7.1 (m, 2 H) 8.0 (m, 2 H) 9.9 (m, 1 H) 10.8 (s, 1 H) 12.2 (s, 1 H) a〇(呈鹽故鹽 )+17.0 (c=1.08, MeOH) A01M2B14 'HNMR (400 MHz, DMSO-de): δ 12.25 (bs, 1H), 10.98 (bs, 1H), 8.11 (m, 2H), 7.34 (m, 2H), 4.96 (m, 2H), 4.56 (t, 1H), 3.77 (m, 2H) 2.24 (m, 2H), 2.03 (m, 2H), 1.87 (m, 2H), 0.93 (s, 2H). a〇+15.9 (c=l .06, MeOH) A12M1B21.HC02H lH NMR (400 MHz, DMSO-d6): δ ppm 0.9 (d, J=6.6 Hz, 6 H) 1.2 (s, 3 H) 1.5 (m, 2 H) 1.7 (s; 6 H) 2.2 (m, 12 H) 4.7 (s, 2 H) 8.2 (s, 1 H) 10.4 (s, 1 H) 12.3 (s, 1 H) A01M1B21.HC1 4 NMR (400 MHz, DMSO-de):(兩種隨形體谋•合物)δ ppm 1.29 (s, 3 Η) 1.38 (s, 3 Η) 1.65 (m, 2 Η) 1.70 (s, 3 Η) 1.73 (s, 3 H) 1.95 (d, 7=14.0 Hz, 2 H) 2.08 (m, 2 H) 2.46 (d, J=14.0 Hz, 2 H) 2.74 (d,*7=5.0 Hz, 3 H) 2.79 (d,*/=5.0 Hz, 3 H) 2.87 (m, 2 H) 3.13 (m, 2 H) 3.3-3.5 (m, 4 H) 4.86 (s, 4 H) 7.35 (t, 7=8.9 Hz, 4 H) 8.09 (dd, /=8.9, 5.5 Hz, 4H) 9.5 (bs, 1 H) 9.7 (bs, 1 H) 11.01 (s, 1 Η) 11.03 (s, 1 H) 12-13 (bs, 2 H). A01M1B22.HC1 'H NMR (400 MHz, DMSO-d6): δ ppm 1.69 (s, 6 H) 2.16 (m, 6 H) 3.32 (m, 6 H) 4.89 (s, 2 H) 7.36 (t, J=8.66 Hz, 2 H) 8.08 (dd, 7=9.02, 5.49 Hz, 2 H) 9.58 (s, 1 H) 11.01 (s, 1 H) 12.55 (s, 1 H) A48M1B43 'H NMR (400 MHz, DMSO-d6): δ ppm 1.16 (t, 7=7.13 Hz, 3 H) 1.57 (s, 6 H) 3.76 (s, 2 H) 4.00 (q, 7=7.07 Hz, 2 H) 4.38 (s, 2 H) 7.48 (m, 3 H) 7.79 (s, 1 H) 7.87 (m, 3 H) 10.73 (s, 1 H) 12.32 (s, 1 H) 3丨2/發明說明書(補件)/93-03/92】35527 78 1327470 (實施例1 8 ) |\|-{6,6-二甲基-5-[(1-甲基哌啶-4-基)羰基]-2,4,5,6-四 氫。比0各[3 , 4 - c ] °tt。坐-3 -基} - 4 -氟苄SI胺 3-[(4 -敗苯甲酿基)胺基]-6,6 -二甲基- 5,6 -二氫吼0各 [3 , 4 - c ]吡唑-6 -螺環丙烷-2 ( 4 Η )-羧酸乙酯鹽酸鹽(0 . 5 克,1.3毫莫耳)於二氣甲烷(25毫升)於室溫以Ν,Ν -二異 丙基乙基胺(1.13毫升,6.5毫莫耳,5當量)及1^丁1](0.542 克,1 . 6 9毫莫耳,1 . 3當量)處理1小時,然後加入1 -甲 基-。底。定-4-叛酸鹽酸鹽(0.29克,1.61毫莫耳,1.2當量)。 反應攪拌隔夜(T L C : C H 2 C 12 / M e 0 Η 9 0 / 1 0 )。溶液以飽和碳 酸氫鈉水溶液及鹽水洗滌,有機相以·硫酸鈉脫水及濃縮。 殘餘物溶解於曱醇(16毫升),以ΤΕΑ(2毫升,14. 3毫莫耳, 11當量)處理’於室溫攪拌隔夜。(TLC: CH2Cl2/MeOH/NH4〇H' 9 0 / 1 0 / 1 )。蒸發後,固體藉急速層析術純化(洗提劑: CH2Cl2/MeOH/NH4〇H 90/10/2)。固體以二異丙基醚處理及 過濾,獲得0 . 3 6克標題化合物,6 9 %產率。 ESI MS: m/z 400 (MH+); Ή NMR ( 4 0 0 MHz, DMS〇-d〇) : 5 1 2. 48 ( bs, 1 H ), 10.97 (bs, 1 H ),8 . 0 9 ( m,2 H ),7 . 3 5 ( m,2 H ),4 . 7 5 ( b s,2 H ),2 . 8 7 (ηι, 2H ) , 2.40 (m, 1 H ) , 2.24 ( s, 3H ) , 2.05 ( m, 2H ) , 1.67 (ni, 1 0 H )。 經由以類似方式處理製備下述化合物: !\1-[5-[(1-甲基哌啶-4-基)羰基]-2,4,5,6-四氫。比咯 [3 , 4 - c ]吡唑-6 -螺環丙烷一 3 -基]-4 -氟苄S莲胺 ESI MS: m/z 398 (MH+); 79 3丨2/發明說明書(補件)/93-03/92丨35527 1327470 Ή NMR (400 MHz, DMSO-d6):(5 12.20 (bs, 1H), 11.00 (s, 1 H), 8.10 (m, 2H) , 7.36 (m, 2H), 4.9 1 ( s, 2H), 2.84 (in, 2H), 2.40 (m, 1H), 2.23 (m, 5H), 2.0 (m, 2H), 1.65 (m, 4H), 0.89 (m, 2H) ° 經由以類似方式處理以及經由使用適當起始物料以及 任一種適當反應物,遵照前述方法,也製備額外式(I a )及 (I b )化合物,報告如下表I V。 80 3 12/發明說明書(補件)/93-03/92135527 1327470
表IV A01M1B03.HC1 ’H NMR (400 MHz,DMSO-d6): δ 11.02 (s,1H), 9.56 (bs,1H),8.11 (m, 2H), 7.36 (m, 2H), 4.80 (bs, 2H), 3.43 (m, 2H), 3.07 (m, 2H) 2.75 (d, 3H), 2.69 (m, 1H), 1.94 (m, 4H), 1.67 (m, 6H). A02M1B03.HC1 'H NMR (400 MHz, DMSO-d6) δ ppm 1.68 (m, 6 H) 1.93 (m, 4 H) 2.74 (m, 4 H) 3.07 (m, 2 H) 3.42 (m, 2 H) 4.81 (s, 2 H) 7.46 (m, 1 H) 7.59 (td, 7=7.96, 5.91 Hz, l H) 7.82 (ddd, 7=10.00, 2.32, 1.59 Hz, 1 H) 7.87 (dt,y=7.90, 1.11 Hz, 1 H) 9.49 (s, 1 H) 11.09 (s, 1 H) A03M1B03.HC1 lH NMR (400 MHz, DMSO-d6) δ ppm 1.69 (m, 6 H) 1.93 (m, 4 H) 2.74 (m, 4 H) 3.02 (m, 2 H) 3.34 (m, 2 H) 4.79 (s, 2 H) 7.40 (m, 1 H) 7.53 (m, 1 H) 7.60 (m, 1 H) 9.48 (s, 1 H) 11.11 (s, 1 H) A04MIB03 * 'H NMR (400 MHz, DMSO-d6): δ 12.48 (bs, 1H), 10.93 (s, iH): 7.75 (m, IH), 7.40 (m, 1H), 7.22 (m, 1H), 4.75 (bs, 2H), 2.S5 (m, 2H), 2.38 (m, 1H), 2.21 (bs, 3H), 2.01 (m, 2H), 1.67 (m, 10H). A05M1B03.HC1 'H NMR (400 MHz, DMSO-d6): δ 12.6 (bs, 1H), 11.19 (s, 1H), 9.49 (bs, IH), 7.72 (m, 2H), 7.51 (m, 1H), 4.80 (bs, 2H), 3.46 (m, 2H), 3.06 (m, 2H), 2.76 (bd, 3H), 2.71 (m, 1H), 1.97 (m, 2H), 1.81 (m, 2H), 1.67 (s, 6H). A06M1B03.HC1 NMR (400 MHz, DMSO-d6): δ 12.55 (bs, 1H),11.06 (s, 1H), 9.66 (bs, 1H), 8.02 (m, 2H), 7.63 (m, 2H), 4.81 (s, 2H), 3.4 (m, 2H), 3.01 (m, 2H), 2.75 (bs, 3H), 2.68 (m, 1H), 1.95 (m, 2H), 1.84 (m, 2H), 1.67 (s, 6H). A07M1B03.HC1 'H NMR (400 MHz, DMSO-d6): δ 12.60 (bs, 1H), 11.25 (s, 1H), 9.50 (bs, 1H), 8.19 (d, 2H, J = 7.9 Hz), 7.92 (d, 2H, J = 7.9 Hz), 4.83 (s, 2H), 3.4 (m, 2H), 3.01 (m, 2H), 2.78 (bd, 3H), 2.75 (m, 1H), 1.9 (m, 2H), 1.8 (m,2H), 1.67 (s, 6H). A09M1B03.2HC1 1H NMR (400 MHz, DMS0-d6) 5 ppm 11.38 (s, 1H), 9.68 (s, 1H), 8.83 (d, 7=6.22 Hz, 2H), 7.98 (d, >6.22 Hz, 2H), 4.82 (s, 2H), 3.4
3丨2/發明說明書(補件)/^3-03/92135527 81 (m, 2H), 3.07 (m, 2H), 2.75 (bd, 3H), 2.69 (m, 1H), 1.90 (m, 4H), 1.69 (s,6H) A10M1B03.HC1 lH NMR (400 MHz, DMSO-d6): δ 12.52 (bs, 1H), 11.07 (s, 1H), 9.50 (bs, 1H), 8.12 (m, 1H), 7.86 (m, 1H), 7.22 (m, 1H), 4.79 (bs, 2H), 3.42 (m, 2H), 3.08 (m, 2H), 2.76 (m, 4H), 1.94 (m, 2H), 1.82 (m, 2H), 1.67 (s, 6H). A11M1B03.HC1 'H NMR (400 MHz, DMSO-d6): δ 12.41 (bs, 1H), 10.83 (s, 1H), 9.55 (s, 1H), 8.43 (dd, 7=2.80, 1.46 Hz, 1H), 7.67 (dd,/=5.12, 1.46 Hz, 1H), 7.65 (dd,J=5· 12, 2.80 Hz, 1H),4.79 (s, 2H), 3.47 (m, 2H), 3.06 (m, 2H), 2.74 (m, 4H), 1.88 (m, 4H), 1.68 (s, 6H). A12MIB03 'H NMR (400 MHz, DMSO-d6): δ 12.29 (bs, 1H), 10.40 (s, 1H), 4.65 (s, 2H), 2.86 (m, 2H), 2.35 (m, 1H), 2.22 (bs, 3H), 2.17 (d, 2H, J = 7.07 Hz), 2.02 (m, 3H), 1.64 (m, 10H), 0.92 (d, 6H, J = 6.6 H-i). 1 A12M1B03.HCI 'H NMR (400 MHz, DMSO-d6): 8 12.29 (s, 1H), 10.41 (bs, 1H), 9.57 | (s, 1H), 4.71 (s, 2H), 3.46 (m, 2H), 3.07 (m, 2H), 2.75 (bd, 3H), 2.69 (m, lH),2.17(d, 2H,J = 6.95 Hz), 2.04 (m, 1H), 1.92 (m,4H), 1.67 (s, 6H), 0.92 (d, 6H, J = 6.7 Hz). A13M1B03 'H NMR (400 MHz, DMSO-d6): 5 12.29 (bs, 1H), 10.27 (s, 1H), 4.69 (s, 2H), 3.35 (m, 1H), 2.87 (m, 2H), 2.38 (m, 1H), 2.24 (bs, 3H), 2.20 (m, 6H), 2.07 (m, 2H), 1.63 (m, 10H). A13M1B03.HC1 'H NMR (400 MHz, DMSO-d6): δ 12.34 (bs, 1H), 10.30 (s, 1H), 9.48 (bs, IH), 4.75 (s, 2H), 3.47 (m, 2H), 3.31 (m, 1H), 3.09 (m, 2H), 2.75 (bd, 3H), 2.70 (m, 1H), 2.23-1.76 (m, 10H), 1.64 (s, 6H). A13M1B03.CH3S03H 'HNMR(400MHz,DMSO-d6):6 12.33 (bs, 1H), 10.31 (s, 1H), 9.21 (bs, 1H), 4.75 (s, 2H), 3.44 (m, 2H), 3.24 (m, 1H), 3.09 (m, 2H), 2.78 (bd, 3H), 2.72 (m, 1H), 2.35 (s, 3H), 2.23-1.72 (m, 10H), 1.64 (s, 6H). A14M1B03 'H NMR (400 MHz, DMSO-d6): δ 12.30 (bs, 1H), 10.72 (s, 1H), 4.63 (s, 2H), 2.86 (m, 2H), 2.34 (m, 1H), 2.23 (bs, 3H), 2.04 (m, 2H), 1.83 (m, 1H), 1.63 (m, 10H), 0.79 (m, 4H). 3丨2/發明說明書(補件)/93-03/92丨35527 82 1327470 A16M1B03 'H NMR (400 MHz, DMSO-d6): δ 12.30 (bs, 1H), 11.10 (s, 1H), 8.13 (d, 2H, J = 7.9 Hz), 7.51 (d, 2H, J = 7.9 Hz), 4.75 (s, 2H), 2.86 (m, 2H), 2.39 (m, 1H), 2.22 (s, 3H), 2.03 (m, 2H), 1.69 (m, 10H). A17M1B03 'HNMR (400 MHz, DMSO-d6): 6 12.48 (bs, 1H), 10.98 (s, 1H), 7.79 (m, 1H), 7.61 (m, 1H), 7.54 (m, 1H), 7.45 (m, 2H), 7.25 (m, 2H), 7.10 (m, 2H), 4.72 (s, 2H), 2.82 (m, 2H), 2.34 (m, 1H), 2.19 (s, 3H), 1.96 (m,2H), 1.66 (m, 10H). A19M1B03.HC1 'HNMR (400 MHz, DMSO-d6): δ 10.87 (s, 1H), 9.55 (bs, 1H), 7.93 (dd,/=1.71,0.85 Hz, 1H), 7.44 (dd, 7=3.48, 0.79 Hz, 1H), 6.70 (dd, 7=3.48, 1.77 Hz, 1H), 4.77 (bs, 2H), 3.30 (m, 2H), 3.05 (m, 2H), 2.74 (m, 4H), 1.93 (m, 2H), 1.84 (m, 2H), 1.67 (s, 6H). A21M1B03 lH NMR (400 MHz, DMSO-d6): δ 12.40 (bs, 1H), 11.00 (s, 1H), 8.65 (d, 1H, J = 2.5 Hz), 8.16 (d, 2.H, J = 8.3 Hz), 8.01 (d, 2H, J = 8.3 H?), 7.83 (d, 1H, J = 1.6 H?.), 6.62 (dd, 1H, J = 2.5 Hz), 4.47 (s, 2H), 2.86 (m, 2H), 2.38 (m, 1H), 2.22 (s, 3H), 2.03 (m, 2H), 1.69 (m, 10H). A22M1B03 'H NMR (400 MHz, DMSO-d6): δ 12.44 (bs, 1H), 11.12 (s, 1H), 8.25 (m, 1H), 8.09 (m, 1H), 8.03 (m, 1H), 7.75 (m, 1H), 7.60 (m, 3H), 4.82 (bs, 2H), 2.84 (m, 2H), 2.38 (m, 1H), 2.19 (s, 3H), 1.98 (m, 2H), 1.70 (m, 10H). A23M1B03 'HNMR (400 MHz, DMSO-d6): δ 12.51 (bs, 1H), 11.11 (s, 1H), 8.67 (bs, 1H), 8.07 (m, 4H), 7.66 (m, 2H), 4.80 (bs, 2H), 2.86 (m, 2H), 2.38 (m, 1H), 2.22 (s, 3H), 2.02 (m, 2H), 1.69 (m, 10H). A24M1B03 'H NMR (400 MHz, DMSO-d6): δ 12.11 (bs, 1H), 8.82 (s, 1H), 7.19 (m, 4H), 6.81 (m, 1H), 4.61 (s, 2H), 4.29 (d, 2H, J = 5.80 Hz), 2.85 (m, 2H), 2.33 (m, 1H), 2.30 (s, 3H), 2.21 (s, 3H), 2.03 (m, 2H), 1.63 (m, 10H). A25M1B03 'H NMR (400 MHz, DMSO-d6): 6 12.08 (bs, 1H), 8.85 (s, 1H), 7.30 (m, 5H), 6.91 (bs, 1H), 4.61 (s, 2H), 4.32 (d, 2H, J = 5.90 Hz), 2.86 (m, 2H), 2.35 (m, 1H), 2.30 (s, 3H), 2.05 (m, 2H), 1.63 (m, 10H). 312/發明說明書(補件)/93-03/92丨35527 1327470 A26M1B03 *H NMR (400 MHz, DMSO-d6): 8 12.00 (bs, 1H), 8.67 (s, 1H), 6.45 (bs, 1H), 4.59 (s, 2H), 3.06 (m, 2H), 2.83 (m, 2H), 2.34 (m, 1H), 2.19 (s, 3H), 1.96 (m, 2H), 1.65 (m, 4H), 1.62 (s, 6H), 1.43 (m, 2H), 0.88 (t, 3H). A27M1B03 *H NMR (400 MHz, DMSO-d6): δ 12.25 (bs, 1H), 9.05 (s, 1H), 7.45 (m, 1H), 7.33 (m, 1H), 7.13 (m, iH), 6.81 (m, 1H), 4.68 (s, 2H), 2.89 (m, 2H), 2.40 (m, 1H), 2.26 (s, 3H), 2.1 (m, 2H), 1.65 (m, 10H). A28M1B03.HC1 'H NMR (400 MHz, DMSO-d6): δ 12.13 (bs, 1H), 9.05 (bs, 1H), 4.64 (s, 2H), 3.5-3.2 (m, 8H), 2.75 (m, 4H), 1.94 (m, 2H), 1.82 (m, 2H), 1.63 (m, 12H). A30M01B03 4 NMR (400 MHz, DMSO-d6): δ 12.48 (bs, 1H), 10.93 (bs, 1H), 8.0 (m, 2H), 7.61 (m, 1H), 7.51 (m, 2H), 4.76 (bs, 2H), 2.86 (m, 2H), 2.38 (m, 1H), 2.23 (bs, 3H), 2.03 (m, 2H), 1.67 (m, 10H). A01M1B04.HC1 'H WMR (400 MHz, DMSO-d6): δ 1.24 (t, 7=7.32 Hz, 3 H) i .69 (s;-6 H) 1.98 (m, 4 H) 2.78 (m, 1 H) 3.09 (dd, 7=7.32, 5.00 Hz, 4 H) 3.50 (d, J=11.71 Hz, 2 H) 4.80 (s, 2 H) 736 (t, /=8.78 Hz, 2 H) 8.09 (m, 2 H) 9.30 (s, 1 H) 11.01 (s, 1 H) 12.56 (s, 1 H). A03M1B04.HC1 lH NMR (400 MHz, DMSO-d6): δ 1.24 (t, J=7.32 Hz, 3 H) 1.69 (s, 6 H) 1.91 (m, 4 H) 2.77 (m, 1 H) 3.31 (m, 6 H) 4.80 (s, 2 H) 7.61 (m, 1 H) 7.91 (m, 1 H) 8.07 (m, 1 H) 9.24 (s, 1 Η) 11.11 (s, 1 H) 12.59 (s, 1 H). AI2M01B04.HC1 'H NMR (400 MHz, DMSO-d6): δ 0.92 (d, /=6.58 Hz, 6 H) 1.24 (t, J=7.26 Hz, 3 H) 1.65 (s, 6 H) 1.88 (m, 4 H) 2.06 (m, 1 H) 2.17 (d, J=7.07 Hz, 2 H) 2.70 (m, I H) 3.23 (m, 6 H) 4.72 (s, 2 H) 9.32 (s, 1 H) 10.41 (s, 1 H) 12.34 (s, 1 H). A13M01B04.HC1 lH NMR (400 MHz, DMSO-ds): δ 1.25 (t, 7=7.32 Hz, 3 H) 1.65 (s, 6 H) 2.03 (m, 10 H) 2.77 (m, 1 H) 3.28 (m, 7 H) 4.75 (s, 2 H) 9.31 (s, 1 H) 10.30 (s, 1 H) 12.35 (s, 1 H). A27M01B04.HC1 'H NMR (400 MHz, DMSO-d6): δ 1.24 (t, /=7.32 H2, 3 H) 1.66 (s, 6 84 312/發明說明書(補件)/93-03/92丨35527 1327470 H) 1.89 (m, 4 Η) 2.75 (s, 1 Η) 3.18 (m, 6 Η) 4.73 (s, 2 Η) 6.80 (m, 1 Η) 7.08 (ddd, J=8.17, 1.95,0.73 Hz, 1 H) 7.32 (td, 7=8.17, 6.95 Hz, 1 H) 7.52 (dt,J=l 1.89, 2.35 Hz, 1 H) 9.10 (s, 1 H) 9.22 (s, 1 H) 9.27 (s, 1 H) 12.24 (s, 1 H) A01MIB05 'H NMR (400 MHz, DMSO-de): δ 12.48 (bs, 1H), 10.97 (s, 1H), 8.09 (m, 2H), 7.35 (m, 2H), 4.75 (s, 2H), 3.00 (m, 2H), 2.44 (m, 1H), 2.24 (m, 2H), 1.8-1.5 (m, 5H), 1.67 (s, 6H), 0.38 (m, 4H). A03M1B05.HC1 'H NMR (400 MHz, DMSO-d6): δ 0.82 (m, 2 H) 0.99 (s, 2 H) 1.68 (s, 6 H) 1.91 (m, 4 H) 2.79 (m, 1 H) 3.38 (m, 5 H) 4.81 (s, 2 H) 7.62 (m, 1 H) 7.92 (ddd, J=8.72,4.27,1.40 Hz, 1 H) 8.08 (ddd, J=l 1.52,7.80, 2.13 Hz, 1 H) 9.14 (s, 1 H) 11.12 (s, 1 H) 12.57 (s, 1 H) AI2M1B05.HC1 'H NMR (400 MHz, DMSO-d6): δ 0.82 (m, 2 H) 0.93 (d, 7=6.58 Hz, 6 H) 1.00 (s, 2 H) 1.65 (s, 6 Η) 1.90 (m, 4 H) 2.06 (m, 1 H) 2.17 (d, /=7.07 Hz, 2 H) 2.76 (m, 1 H) 3.36 (m, 5 H) 4.73 (s, 2 H) 9.20 (s;-l H) 10.41 (s, 1 H) 12.35 (s, 1 H) A13M1B05.HC1 'H NMR (400 MHz, DMSO-d6): δ 0.82 (m, 2 H) 1.01 (s, 2 H) 1.65 (s, 6 H) 2.01 (m, 10 H) 2.78 (m, 1 H) 3.33 (m, 6 H) 4.77 (s, 2 H) 9.23 (s, 1 H) 10.30 (s, 1 H) 12.25 (s, 1 H) A27M1B05.HC1 'H NMR (400 MHz, DMSO-d6): δ 0.82 (q, 7=6.87 Hz, 2 H) 1.00 (m, 2 H) 1.66 (s, 6 H) 1.88 (m, 4 H) 2.77 (m, 1 H) 3.40 (m, 5 H) 4.75 (s, 2 H) 6.81 (m, 1 H) 7.09 (ddd, J=8.11,1.95, 0.79 Hz, 1 H) 7.32 (td, >8.20, 7.01 Hz, 1 H) 7.52 (dt, 7=11.77,2.23 Hz, 1 H)9.10 (s, 1 H) 9.17 (m, 1 H) 9.21 (s, 1 H) 12.99 (s, 1 H) A01M1B06.HCI 'H NMR (400 MHz, DMSO-d6): δ 1.68 (s, 6 H) 1.80 (m, 4 H) 2.81 (m, 1 H) 3.01 (m, 2 H) 3.38 (m, 2 H) 4.78 (s, 2 H) 7.36 (t, 7=8.84 Hz, 2 H) 8.09 (dd, /=8.96, 5.43 Hz, 2 H) 8.35 (m, 1 H) 8.62 (d, >9.88 Hz, 1 Η) 11.00 (s, 1 H) 12.52 (s, I H) A03M1B06.HC1 'H NMR (400 MHz, DMSO-d6): δ 1.68 (s, 6 H) 1.83 (m, 4 H) 2.80 (m, 1 H) 3.00 (m, 2 H) 3.37 (m, 2 H) 4.78 (s, 2 H) 7.61 (m, 1 H) 7.92 85 3丨2/發明說明書(補件)/93-03/92丨35527 1327470 (m, 1 Η) 8.07 (ddd, 7=11.49, 7.83, 2.13 Hz, 1 H) 8.45 (m, 2 H) 11.11 (s, 1 H) 12.57 (s, 1 H) A04M1B07 H NMR (400 MHz, DMSO-d6): δ ppm 1.81 (s, 6 H) 2.21 (s, 3 H) 4.51 (s, 2 H) 6.96 (d, 7=4.88 Hz, 1 H) 7.16 (t, /=7.68 Hz, 1 H) 7.35 (t, 7=10.97 Hz, 1 H) 7.54 (d, 7=5.00 Hz, 1 H) 7.69 (m, 1 H) 10.88 (s, 1 H) 12.56 (s, 1 H) A12M1B07 'H NMR (400 MHz, DMSO-d6): δ 12.37 (bs, 1H), 10.35 (s, 1H), 7.54 (d,1H, J = 5.0 Hz), 6.96 (d, 1H, J = 5.0 Hz), 4.42 (s, 2H),2.20 (s, 3H), 2.10 (d, 2H, J = 7.19 Hz), 1.98 (m, 1H), 1.77 (s, 3H), 0.87 (d, 6H, J = 6.47Hz). A13M1B07 'H NMR (400 MHz, DMSO-d6): δ ppm 1.74 (m, 1 H) 1.77 (s, 6 H) 1.88 (m, 1 H) 2.02 (m, 2 H) 2.14 (m, 2 H) 2.20 (s, 3 H) 3.18 (m, 1 H) 4.44 (s, 2 H) 6.97 (d, >5.00 Hz, 1 H) 7.55 (d, 7=4.88 Hz: l H) 10.25 (s, 1 H) 12.36 (s, 1 H) A14M1B07 *H NMR (400 MHz, DMSO-d6): 6 ppm 0.72 (m, 4 H) 1.77 (s, 7 H) 2.18 (s, 3 H) 4.39 (s, 2 H) 6.95 (d, 7=5.00 Hz, 1 H) 7.54 (d, 7=5.00 Hz, 1 H) 10.69 (s, 1 H) 12.37 (s, 1 H) A21M1B07 'H NMR (400 MHz, DMSO-d6): δ ppm 1.82 (s, 6 H) 2.23 (s, 3 H) 4.53 (s, 2 H) 6.61 (s, 1 H) 6.98 (d, 7=5.00 Hz, 1 H) 7.56 (d, 7=4.88 Hz, 1 H) 7.82 (s, 1 H) 7.96 (m, 2 H) 8.10 (d, 7=7.44 Hz, 2 H) 8.64 (d, /=2.44 Hz, 1 H) 10.98 (s, 1 H) 12.57 (s, 1 H) A23M1B07 'H NMR (400 MHz, DMSO-d6): δ ppm 1.83 (s, 6 H) 2.23 (s, 3 H) 4.57 (s, 2 H) 6.98 (d, >5.00 Hz, 1 H) 7.56 (d, >4.88 Hz, 1 H) 7.63 (m, 2 H) 8.01 (m, 4 H) 8.63 (m, 1 H) 11.07 (s, 1 H) 12.58 (s, 1 H) A25M1B07 'H NMR (400 MHz, DMSO-d6): δ ppm 1.76 (s, 6 H) 2.19 (s, 3 H) 4.26 (d, 7=5.85 Hz, 2 H) 4.36 (s, 2 H) 6.86 (s, 1 H) 6.95 (d, 7=4.88 Hz, 1 H) 7.22 (s, 3 H) 7.32 (m, 2 H) 7.53 (d, J=4.88 Hz, 1 H) 8.82 (s, 1 H) 12.14 (s, 1 H) A27M1B07 'H NMR (400 MHz, DMSO-d6): 5 ppm 1.79 (s, 6 H) 2.21 (s, 3 H) 86 312/發明說明書(補件)/93-03/92135527 1327470 4.44 (s, 2 H) 6.78 (m, 1 Η) 6.97 (d, 7=4.88 Hz, 1 Η) 7.07 (m, 1 Η) 7.29 (m, 1 Η) 7.35 (m, 1 Η) 7.55 (d, ^=5.00 Hz, 1 H) 9.04 (s, 1 H) 12.32 (s, 1 H) A30M1B07 'H NMR (400 MHz, DMSO-d6): δ ppm 1.81 (s, 6 H) 2.22 (s, 3 H) 4.52 (s, 2 H) 6.97 (d, /=5.00 Hz, 1 H) 7.48 (m, 2 H) 7.56 (m, 1 H) 7.56 (d, 7=5.00 Hz, 1 H) 7.95 (d, 7=7.32 Hz, 2 H) 10.92 (s, 1 H) 12.55 (s,lH) A48M1B07 W NMR (400 MHz, DMSO-d6): δ ppm 1.73 (s, 6 H) 2.13 (s, 3 H) 3.71 (s, 2 H) 4.35 (s, 2 H) 6.89 (d, 7=4.88 Hz, 1 H) 7.40 (dd, J=8.47, 1.65 Hz, I H) 7.47 (m, 3 H) 7.74 (s, 1 H) 7.84 (m, 3 H) 10.74 (s, 1 H) 12.40 (s, 1 H) A53M1B07 'H NMR (400 MHz, DMSO-d6): 8 ppm 1.34 (m, 1 H) 1.50 (m, .l H) 1.72 (m, 2 H) 1.77 (s, ό H) 1.98 (s, 3 H) 2.19 (s, 3 H) 2.55 (m, 2 H) t 3.00 (m, 1 H) 3.81 (d, /=12.56 Hz, 1 H) 4.35 (d, /=12.07 Hz, l^H) 4.42 (s, 2 H) 6.96 (d, >5.00 Hz, 1 H) 7.54 (d, J=4.88 Hz, 1 H) 10.45 (s, 1 H) 12.40 (s, 1 H) A54M1B07 *H NMR (400 MHz, DMSO-d6): δ ppm 1.82 (s, 6 H) 2.22 (s, 3 H) 4.53 (s, 2 H) 6.97 (d, >5.00 Hz, 1 H) 7.56 (d, 7=5.00 Hz, 1 H) 7.72 (m, 1 H) 7.91 (m, 1 H) 8.24 (m, 2 Η) 11.24 (s, 1 H) 12.62 (s, 1 H) A31M01B19.HC1 lH NMR (400 MHz, DMSO-d6): δ 1.80 (s, 6 H) 2.07 (m, 4 H) 2.81 (m, 3 H) 3.14 (m, 4 H) 4.75 (m, 1 H) 4.99 (s, 2 H) 7.13 (m, 2 H) 7.20 (dd, >4.94, 3.84 Hz, 1 H) 7.63 (dd, /=3.72, 0.79 Hz, 1 H) 7.80 (d, 7=5.00 Hz, 1 H) 8.02 (m, 2 H) 10.07 (m, 1 Η) 10.86 (s, 1 Η) 11.99 (s, 1H) A31M1B20.HC1 4 NMR (400 MHz, DMSO-de):(兩種隨形體混合物)δ ppm 1.63 (m, 8 Η) 1.67 (s, 12 Η) 1.86 (m, 2 Η) 2.10 (m, 4 Η) 2.28 (d, J=14.0 Hz, 2 Η) 2.68 (m, 2 Η) 2.79 (d, 7=5.0 Hz, 3 H) 2.81(d, 7=5.0 Hz, 3 H) ) 3.1-3.3 (m, 4 H) 3.46 (m, 2 H) 3.52 (d, 7=14.0 Hz, 2 H) 3.90 (m, 8 H) 4.68 (m, 1 H) 4.76 (m, 4 H) 4.89 (m, 1 H) 3丨2/發明說明書(補件)/93-03/92丨35527 1327470 7.11 (d, J=8.9 Hz, 2 Η) 7.14 (d, J=8.9 Hz, 2 H) 8.01 (d, J=8.9 Hz, 2H) 8.03 (d, J=8.9 Hz, 2 H) 10.02 (bs, 2 H) 10.81 (bs, 2 H) A33M1B20.HC1 'H NMR (400 MHz, DMSO-d6):5 ppm 1.65 (m, 4 H) 1.68 (s, 6 H) 2.70 (m, 1 H) 2.81 (s, 3 H) 2.9-3-8 (bs, 8 H) 3.90 (m, 4 H) 4.06 (bs, 2 H) 4.77 (s, 2 H) 7.62 (bs, 2 H) 8.07 (d, J=7.8 Hz, 2 H) 10.60 (bs, 1 H) 11.01 (s, 1 H) A12M1B44 'H NMR (400 MHz, DMSO-d6): δ ppm 0.14 (m, 2 H) 0.46 (m, 2 H) 0.91 (d, ^=6.58 Hz, 6 H) 1.01 (m, 1 H) 1.66 (s, 6 H) 2.05 (m, 1 H) 2.16 (d, 7=7.07 Hz, 2 H) 2.24 (d, /=6.58 Hz, 2 H) 4.54 (s, 2 H) 10.35 (s, 1 H) 12.27 (s, 1 H) A13M1B44 'H NMR (400 MHz, DMSO-d6): δ ppm 0.15 (m, 2 H) 0.47 (m, 2 H) 1.01 (m, 1 H) 1.66 (s, 6 H) 1.80 (m, 1 H) 1.92 (m, 1 H) 2.08 (m, 2 H) 2.17 (in, 2 H) 2.26 (d, /=6.46 Hz, 2 H) 3.25 (m, 1 H) 4.5S (s, 2\H) 10.25 (s, 1 H) 12.26 (s, 1 H) AI4M1B44 'H NMR (400 MHz, DMSO-d6): δ ppm 0.13 (m, 2 H) 0.44 (m. 2 H) 0.76 (m, 4 H) 0.98 (m, 1 H) 1.65 (s, 6 H) 1.81 (m, 1 H) 2.22 (d, 7=6.58 Hz, 2 H) 4.51 (s, 2 H) 10.69 (s, 1 H) 12.27 (s, 1 H) A25M1B44 lH NMR (400 MHz, DMSO-d6): δ ppm 0.13 (m, 2 H) 0.45 (m, 2 H) 0.99 (m, 1 H) 1.65 (s, 6 H) 2.23 (d, >6.46 Hz, 2 H) 4.31 (d, 7=5.85 Hz, 2 H) 4.49 (s, 2 H) 6.89 (s, 1 H) 7.25 (m, 1 H) 7.28 (d, 7=7.07 Hz, 2 H) 7.34 (m, 2 H) 8.83 (s, 1 H) 12.04 (s, 1 H) A26M1B44 *H NMR (400 MHz, DMSO-d6): δ ppm 0.14 (m, 2 H) 0.47 (m, 2 H) 0.87 (t, /=7.44 Hz, 3 H) 1.00 (m, 1 H) 1.43 (m, 2 H) 1.64 (s, 6 H) 2.23 (d, J=6.58 Hz, 2 H) 3.04 (m, 2 H) 4.48 (s, 2 H) 6.43 (s, 1 H) 8.65 (s, 1 H) 12.00 (s, 1 H) A30M1B44 'H NMR (400 MHz, DMSO-d6): δ ppm 0.16 (m, 2 H) 0.47 (m, 2 H) 1.02 (m, 1 H) 1.70 (s, 6 H) 2.28 (d, >6.58 Hz, 2 H) 4.65 (s, 2 H) 7.51 (m, 2 H) 7.59 (m, 1 H) 8.01 (d, 7=7.44 Hz, 2 H) 10.91 (s, 1 H) 12.46 (s, 1 H) 312/發明說明書(補件V93-03/92135527 1327470 A54M1B44 'η NMR (400 MHz, DMSO-d6): δ ppm 0.16 (m, 2 H) 0.47 (m, 2 H) 1.02 (m, 1 H) 1.70 (s, 6 H) 2.28 (d, 7=6.58 Hz, 2 H) 4.65 (s, 2 H) 7.78 (m, 1 H) 7.98 (m, 1 H) 8.35 (m, 2 Η) 11.25 (s, 1 H) 12.53 (s, 1 H) A04M1B45 'H NMR (400 MHz, DMSO-d6): δ ppm 0.60 (m, 1 H) 0.97 (m, 1 H) 1.12 (d, *7=5.97 Hz, 3 H) 1.19 (m, 1 H) 1.51 (m, 1 H) 1.66 (s, 6 H) 4.86 (s, 2 H) 7.20 (m, 1 H) 7.40 (m, 1 H) 7.76 (m, 1 H) 10.89 (s, 1 H) 12.48 (s, 1 H) A30M1B45 'H NMR (400 MHz, DMSO-d6): δ ppm 0.61 (m, 1 H) 0.96 (m, 1 H) 1.13 (d, J=5.85 Hz, 3 H) 1.20 (m, 1 H) 1.53 (m, 1 H) 1.67 (s, 6 H) 4.87 (s, 2 H) 7.51 (m, 2 H) 7.60 (m, 1 H) 8.02 (d, 7=7.07 Hz, 2 H) 10.92 (s, 1 H) 12.47 (s, 1 H) A54M1B45 'H NMR (400 MHz, DMSO-d6): δ ppm 0.61 (m, 1 H) 0.96 (m, 1 H) I. !3 (d, 7=5.85 Hz, 3 H) 1.20 (m, 1 H) 1.53 (tn, 1 H) 1.67 (s, 6::H) 4.88 (s, 2 H) 7.77 (m, 1 H) 7.96 (m, 1 H) 8.31 (d, 1 H) 8.39 1 H) II. 26 (s, 1 H) 12.54 (s,l H). A01M1B47 lH NMR (400 MHz, DMSO-d6): δ ppm 1.79 (s, 6 H) 2.23 (s, 6 H) 3.52 (s, 2 H) 4.43 (s, 2 H) 7.26 (t, 7=8.78 Hz, 2 H) 7.38 (m, 4 H) 7.95 (dd, 7=8.84, 5.55 Hz, 2 H) 10.90 (s, 1 H) 12.50 (s, 1 H) A48M1B47 'H NMR (400 MHz, DMSO-d6): 6 ppm 1.79 (s, 6 H) 2.14 (s, 6 H) 3.41 (s, 2 H) 3.67 (s, 2H), 4.33 (s, 2 H) 7.30 (m, 5 H) 7.45 (m, 2 H) 7.70 (m, 1 H) 7.80 (m, 3 H) 10.70 (s, 1 H) 12.37 (s, 1 H) A48M1B48 'H NMR (400 MHz, DMSO-d6): δ ppm 1.76 (s, 6 H) 2.18 (s, 3 H) 2.35 (m, 8H), 3.45 (s, 2 H) 3.68 (s, 2H), 4.34 (s, 2 H) 7.30 (m, 5 H) 7.47 (m, 2 H) 7.70 (m, 1 H) 7.81 (m, 3 H) 10.70 (s, 1 H) 12.37 (s, 1 H) A01M1B50 'H NMR (400 MHz, DMSO-d6): δ ppm 0.87 (t, ^7.44 Hz, 3 H) 1.49 (m, 2 H) 1.68 (s, 6 H) 2.27 (t, 7=7.38 Hz, 2 H) 4.64 (s, 2 H) 7.30 (m, 2 H) 8.04 (m, 2 H) 10.92 (s, 1 H) 12.43 (s, 1 H) A04M1B50 'H NMR (400 MHz, DMSO-d6): δ ppm 0.93 (t, J=7.44 Hz, 3 H) 1.56 312/發明說明書(補件)/93-03/92135527 1327470 (m, 2 Η) 1.68 (s, 6 Η) 2.28 (t, 7=7.38 Hz, 2 Η) 4.68 (s, 2 Η) 7.22 (m, 1 Η) 7.40 (m, 1 Η) 7.75 (m, 1 Η) 10.88 (s, 1 Η) 12.47 (s, 1 Η) A13M1B50 'H NMR (400 MHz, DMSO-d6): 6 ppm 0.93 (t, 7=7.38 Hz, 3 H) 1.55 (m, 2 H) 1.64 (s, 6 H) 1.80 (m, 1 H) 1.93 (m, 1 H) 2.07 (m, 2 H) 2.18 (m, 2 H) 2.27 (t, /=7.38 Hz, 2 H) 3.23 (m, 1 H) 4.61 (s, 2 H) 10.24 (s, 1 H) 12.27 (s, 1 H) A14M1B50 'H NMR (400 MHz, DMSO-d6): δ ppm 0.78 (d, 7=1.95 Hz, 4 H) 0.91 (t, 7=7.38 Hz, 3 H) 1.52 (m, 2 H) 1.64 (s, 6 H) 1.82 (m, 1 H) 2.24 (t, 7=7.38 Hz, 2 H) 4.55 (s, 2 H) 10.70 (s, 1 H) 12.27 (s, 1 H) A30M1B50 lH NMR (400 MHz, DMSO-d6): δ ppm 0.94 (t >7.44 Hz,3 H) 1.57 (m, 2 H) 1.69 (s, 6 H) 2.30 (t, /=7.38 Hz, 2 H) 4.68 (s, 2 H) 7.52 (m, 2 H) 7.60 (m, 1 H) 8.01 (d, >7.80 Hz, 2 H) 10.92 (s, 1 H) 12.46 (s, 1 H) A54M1B50. 'H NMR (400 MHz, DMSO-d6): 6 ppm 0.94 (t, 7=7.44 Hz, 3 H) 1.57 (m, 2 H) 1.69 (s, 6 H) 2.29 (t, >7.38 Hz, 2 H) 4.70 (s, 2 H) 8.31 (m, 4 H) 11.25 (s, 1 H) 12.53 (s, 1 H) A04M1B51 'H NMR (400 MHz, DMSO-d6): δ ppm 1.68 (s, 6 H) 2.03 (m, 2 H) 3.27 (m, 1 H) 3.73 (m, 3 H) 3.93 (t, 7=8.11 Hz, 1 H) 4.76 (m, 2 H) 7.21 (m, 1 H) 7.39 (m, 1 H) 7.74 (m, 1 H) 10.90 (s, 1 H) 12.49 (s, 1 H) A12M1B51 *H NMR (400 MHz, DMSO-d6): δ ppm 0.92 (d, /=6.58 Hz, 6 H) 1.65 (s, 6 H) 2.03 (m, 3 H) 2.17 (d, /=7.07 Hz, 2 H) 3.21 (m, 1 H) 3.73 (m, 3 H) 3.91 (t, 7=8.11 Hz, 1 H) 4.66 (m, 2 H) 10.38 (s, 1 H) 12.30 (s, 1 H) A13M1B51 *H NMR (400 MHz, DMSO-d6): δ ppm 1.65 (s, 6 H) 1.80 (m, 1 H) 1.96 (m, 3 H) 2.07 (m, 2 H) 2.19 (m, 2 H) 3.26 (m, 2 H) 3.74 (m, 3 H) 3.92 (t, 7=8.11 Hz, 1 H) 4.70 (m, 2 H) 10.27 (s, 1 H) 12.29 (s, 1 H) A14M1B51 lH NMR (400 MHz, DMSO-d^): δ ppm 0.78 (m,4 H) 1.64 (s,6 H) 1.83 (m, 1 H) 2.01 (m, 2 H) 3.20 (m, 1 H) 3.72 (m, 3 H) 3.90 (t, 312/發明說明書(補件)/93-03/92135527 1327470 J=8.05 Hz, 1 Η) 4.64 (m, 2 Η) 10.71 (s, 1 Η) 12.29 (s, 1 Η) A01M1B52 'H NMR (400 MHz, DMSO-dfi): δ ppm 1.79 (s, 6 H) 4.43 (s, 2 H) 7.2-7.95 (m, 9 H) 10.90 (s, 1 H) 12.50 (s, 1 H) A01M1B53 lH NMR (400 MHz, DMSO-d6): δ ppm 1.82 (s, 6 H) 4.43 (s, 2 H) 7.15 (m, H) 7.27 (m, H) 7.34 (m, H) 7.58 (m, H) 7.68 (m, H) 10.93 (s, 1 H) 12.62 (s, 1 H) A04M1B53 'H NMR (400 MHz, DMSO-d6): δ ppm 1.82 (s, 6 H) 4.43 (s, 2 H) 7.15 (m, 1 H) 7.27 (m, 2 H) 7.34 (m, 1 H) 7.58 (m, 1 H) 7.68 (m, 1 H) 10.93 (s, 1 H) 12.62 (s, 1 H) A48M1B53 'H NMR (400 MHz, DMSO-d5): δ ppm 1.73 (s, 6 H) 3.69 (s, 2 H) 4.27 (s,2 H) 7.18 (m, 2 H) 7.38 (m, 1 H) 7.45 (m, 3 H) 7.71 (m, 1 H) 7.80 (m, 3 H) 10.76 (s, 1 H) 12.45 (s, 1 H) A54M1B53 *H NMR (400 MHz, DMSO-d6): δ ppm 1.83 (s, 6 H) 4.46 (s, 2\H) 7.28 (m, 2 H) 7.59 (m, 1 H) 7.71 (m, 1 H) 7.92 (m, 1 H) 8.21 (in,1 H) 8.29 (m, 1 H) 11.26 (s, 1 H) 12.68 (s, 1 H) A01M1B54 'H NMR (400 MHz, DMSO-d6): δ ppm 1.81 (s, 6 H) 4.43 (s, 2 H) 7.24 (m, 2 H) 7.42 (m, 2 H) 7.63 (d, /=8.26 Hz, 2 H) 7.87 (d, 7=8.26 Hz, 2 H) 7.95 (m, 2 H) 10.93 (s, 1 H) 12.62 (s, 1 H) A48M1B54 'H NMR (400 MHz, DMSO-d6): δ ppm 1.77 (s, 6 H) 3.69 (s, 2 H) 4.33 (s, 2 H) 7.32-7.89 (m, 13 H) 10.75 (s, 1 H) 12.41 (s, 1 H) A01M2B03 'H NMR (400 MHz, DMSO-d6): δ 12.20 (bs,1H),11.00 (s,1H), 8.10 (m, 2H), 7.36 (m, 2H), 4.91 (s, 2H), 2.84 (m, 2H), 2.4 (m, 1H), 2.23 (m, 5H), 2.0 (m, 2H), 1.65 (m, 4H), 0.89 (m, 2H). A02M2B03 *H NMR (400 MHz, DMSO-d6): δ 12.28 (bs, 1H), 11.08 (s, 1H), 7.88 (m, 2H), 7.51 (m, 2H), 4.92 (s, 2H), 2.84 (m, 2H), 2.41 (m, 1H), 2.25 (m, 5H), 2.05 (m, 2H), 1.68 (m, 4H), 0.91 (m, 2H). A04M2B03 'H NMR (400 MHz, DMSO-d6): δ 12.24 (bs, 1H), 10.91(s, 1H), 7.75 (m, 1H), 7.41 (m, 1H), 7.22 (m, 1H), 4.91 (s, 2H), 2.79 (m, 2H), 2.34 (m, 1H),2.24 (m, 2H), 2.16 (s,3H), 1.91 (m, 2H), 1.65 (m, 4H), 0.89 91 3丨2/發明說明書(補件)/93-03/92丨35527 1327470 (m, 2H). A05M2B03 4 NMR (400 MHz, DMSO-d6): δ 12.31 (bs, 1H),11.16(s,1H), 7.75 (m, 2H), 7.51 (m, 1H), 4.91 (s, 2H), 2.79 (m, 2H), 2.35 (m, 1H), 2.25 (m, 2H), 2.17 (s, 3H), 1.90 (m, 2H), 1.65 (m, 4H), 0.90 (m, 2H). A06M2B03 'H NMR (400 MHz, DMSO-d6): 6 12.45 (bs, 1H), 11.06 (s, 1H), 8.03 (m, 2H), 7.61 (m, 2H), 4.91 (s, 2H), 2.84 (m, 2H), 2.41 (m, 1H), 2.21 (m, 5H), 2.0 (m, 2H), 1.65 (m, 4H), 0.89 (m, 2H). A07M2B03 'H NMR (400 MHz, DMSO-d6): 6 12.30 (bs, 1H), 11.25 (s, 1H), 8.20 (m, 2H), 7.92 (m, 2H), 4.94 (s, 2H), 2.95 (m, 2H), 2.45 (m, 1H), 2.27 (m, 5H), 2.2 (m, 2H), 1.73 (m, 4H), 0.91 (m, 2H). A10M2B03 'H NMR (400 MHz, DMSO-d6): δ 12.25 (bs, 1H), 11.04 (s, 1H), 8.15 (m, 1H), 7.87 (m, 1H), 7.22 (m, 1H), 4.89 (s, 2H), 2.82 (m, 2H), 2.37 (m, 1H), 2.22 (m, 5H), 1.9 (m, 2H), 1.65 (m, 4H), 0.91 (m, 2H). A11M2B03 'HNMR (400 MHz, DMSO-d6): δ 12.22 (bs, 1H), 10.81 (s, 1H), 8.45 (m, 1H), 7.69 (m, 2H), 4.90 (s, 2H), 2.82 (m, 2H), 2.37 (m, 1H), 2.24 (m, 2H), 2.18 (m, 3H), 1.93 (m, 2H), 1.66 (m, 4H), 0.89 (m, 2H). A12M2B03 'H NMR (400 MHz, DMSO-d6): δ 12.06 (bs, 1H), 10.04 (s, 1H), 4.82 (s, 2H), 2.85 (m, 2H), 2.34 (m, 1H), 2.22 (m, 7H), 2.05 (m, 3H), 1.65 (τη, 4H), 0.93 (d, 6H, J = 6.58Hz), 0.85 (m, 2H). A13M2B03 lH NMR (400 MHz, DMSO-d6): δ 12.04 (bs, 1H), 10.08 (s, 1H), 4.85 (s, 2H), 3.25 (m, 1H), 2.85 (m, 2H), 2.39 (m, 1H), 2.25-1.75 (m, 13H), 1.67 (m, 4H), 0.85 (m, 2H). A19M2B03 ^ NMR (400 MHz,DMSO-d6): δ 12.24 (bs, 1H), 10.84 (s, 1H), 7.94 (m, 1H), 7.51 (m, 1H), 6.70 (m, 1H), 4.88 (s, 2H), 2.85 (m, 2H), 2.40 (m, IH), 2.22 (m, 5H), 2.01 (m, 2H), 1.67 (m, 4H), 0.89 (m, 2H). A38M2B03 *H NMR (400 MHz, DMSO-d6): δ 12.21 (bs, 1H), 10.81(s, 1H), 7.66 (m, 2H), 7.08 (m, 1H), 4.92 (s, 2H), 3.86 (s, 6H), 2.81 (m, 2H), 2.38 (m,1H), 2.25 (m,2H),2.18 (s,3H), 1.94 (m,2H), 1.66 (m,4H), 0.90 (m, 2H). 92 312/發明說明書(補件)/93-03/92丨35527 1327470 A01M2B04 'H NMR (400 MHz, DMSO-d6): δ 12.45 (bs, 1H), 11.00 (s, 1H), 8.10 (m, 2H), 7.36 (m, 2H), 4.91 (s, 2H), 2.95 (m, 2H), 2.42 (m, 3H), 2.24 (m, 2H), 1.95 (m, 2H), 1.7 (m, 4H), 1.02 (t, 3H), 0.89 (m, 2H). A02M2B04 'H NMR (400 MHz, DMSO-d6): δ 12.27 (bs, 1H), 11.07 (s, 1H), 7.85 (m, 2H), 7.68 (m, 1H), 7.45 (m, 1H), 4.91 (s, 2H), 2.90 (m, 2H), 2.34 (m, 3H), 2.25 (m, 2H), 1.92 (m, 2H), 1.65 (m, 4H), 1.0 (t, 3H), 0.90 (m, 2H). A04M2B04 'H NMR (400 MHz, DMSO-d6): δ 12.23 (bs, 1H), 10.91(s, 1H), 7.78 (m, 1H), 7.41 (m, 1H), 7.22 (m, 1H), 4.91 (s, 2H), 2.91 (m, 2H), 2.35 (m, 3H), 2.24 (m, 2H), 1.91 (m, 2H), 1.65 (m, 4H), 1.00 (t, 3H), 0.89 (m, 2H). A05M2B04 'H NMR (400 MHz, DMSO-d6): δ 12.31 (bs, 1H), 11.16(s, 1H), 7.75 (m,2H), 7.54 (m, 1H), 4 〇2 (s,2H),2.92 (m,2H),2.35 (m, 3H),2.25 (m, 2H), 1.92 (m, 2H), 1.65 (m, 4H), 1.01 (t, 3H), 0.90 (m, 2H). A06M2B04 'H NMR (400 MHz, DMSO-d6): δ 12.25 (bs, 1H), 11.05 (s, 1H), 8.03 (m, 2H), 7.6 (m, 2H), 4.91 (s, 2H), 2.90 (m, 2H), 2.45-2.20 (m, 5H), 1.85 (m, 2H), 1.67 (m, 4H), 1.02 (t, 3H), 0.89 (m, 2H). A07M2B04 *H NMR (400 MHz, DMSO-d6): δ 12.31 (bs, 1H), 11.34 (s, 1H), 8.20 (m, 2H), 7.91 (m, 2H), 4.95 (s, 2H), 3.15-1.5 (m, 13H), 1.06 (t, 3H), 0.91 (m, 2H). A10M2B04 'H NMR (400 MHz, DMSO-d6): δ 12.25 (bs, 1H), 11.04 (s, 1H), 8.15 (m, 1H), 7.88 (m, 1H), 7.22 (m, 1H), 4.89 (s, 2H), 2.92 (m, 2H), 2.45-2.20 (m, 5H), 1.9 (m, 2H), 1.65 (m, 4H), 1.01 (t, 3H), 0.89 (m, 2H). A11M2B04 *H NMR (400 MHz, DMSO-d6): δ 12.22 (bs, 1H), 10.81 (s, 1H), 8.46 (m, 1H), 7.69 (m, 2H), 4.90 (s, 2H), 2.92 (m, 2H), 2.34 (m, 3H), 2.25 (m, 2H), 1.92 (m, 2H), 1.65 (m, 4H), 1.01 (t, 3H), 0.89 (m, 2H). A13M2B04 'H NMR (400 MHz, DMSO-d6): δ 12.04 (bs, 1H), 10.27 (s, 1H), 4.86 (s, 2H), 2.89 (m, 2H), 2.45-1.75 (m, 14H), 1.65 (m, 4H), 1.00 (t, 3H), 0.85 (m, 2H). 93 312/發明說明書(補件)/93-03/92丨35527 1327470 A14M2B04 H NMR (400 MHz, DMSO-dc): δ 12.05 (bs,1H), 10.71 (s, 1H),4.79 (s, 2H), 2.88 (m, 2H), 2.31 (m, 3H), 2.21 (m, 2H), 1.89 (m, 3H), 1.62 (m, 4H), 0.99 (t, 3H), 0.82 (m, 6H). A19M2B04 *H NMR (400 MHz, DMSO-ds): 5 12.24 (bs, 1H), 10.84 (s, 1H), 7.94 (m, 1H), 7.51 (m, 1H), 6.71 (m, 1H), 4.88 (s, 2H), 2.97 (m, 2H), 2.40 (m, 3H), 2.24 (m, 2H), 2.01 (m, 2H), 1.68 (m, 4H), 1.02 (t, 3H), 0.89 (m, 2H). A38M2B04 *H NMR (400 MHz, DMSO-d6): δ 12.20 (bs, 1H), 10.81(s, 1H), 7.66 (m, 2H), 7.08 (m, 1H), 4.92 (s, 2H), 3.86 (s, 6H), 2.92 (m, 2H), 2.45-2.20 (m, 5H), 1.84 (m, 2H), 1.66 (m, 4H), 1.01 (t, 3H), 0.89 (m, 2H). A01M2B05 'H NMR (400 MHz, DMSO-d6): δ 12.25 (bs, 1H), 11.00 (s, 1H), 8.11 (m, 2H), 7.36 (m, 2H), 4.92 (s, 2H), 3.00 (m, 2H), 2.44 (m, 1H), 2.24 (m, 4H), 1.6 (m, 5H), 0.89 (m, 2H), 0.38 (m, 4H). t: A06M2B05 ’H NMR (400 MHz, DMSO:d6): δ 12.3 (bs, 1H): 11.06 (s, 1H), 8.05 " · · . (m, 2H), 7.6 (m, 2H), 4.92 (s, 2H), 3.00 (m, 2H), 2.44 (m, 1H), 2.24 (m, 4H), 1.62 (m, 5H), 0.89 (m, 2H), 0.39 (m, 4H). A07M2B05 'H NMR (400 MHz, DMSO-d6): δ 12.3 (bs, 1H), 11.24 (s, 1H), 8.21 (m, 2H), 7.9 (m, 2H), 4.94 (s, 2H), 2.99 (m, 2H), 2.44 (m, 1H), 2.25 (m, 4H), 1.59 (m, 5H), 0.89 (m, 2H), 0.37 (m, 4H). A01M2B06.HCI *H NMR (400 MHz, DMSO-d6): δ 0.92 (m, 2H), 1.78 (m, 4 H) 2.24 (m, 2H), 2.81 (m, 1 H) 3.01 (m, 2 H) 3.38 (m, 2 H) 4.95 (s, 2 H) 7.37 (t, >8.84 Hz, 2 H) 8.10 (dd, /=8.96, 5.43 Hz, 2 H) 8.35 (m, 1 H) 8.65 (d, >9.88 Hz, 1 Η) 11.00 (s, 1 H) 12.52 (s, 1 H) A01M2B47 'H NMR (400 MHz, DMSO-d6): δ ppm 1.01 (m, 2 H) 2.18 (s, 6 H) 2.36 (m, 2 H) 3.46 (s, 2 H) 4.62 (s, 2 H) 7.28 (m, 2 H) 7.36 (m, 2 H) 7.41 (m, 2 H) 7.98 (m, 2 H) 10.93 (s, 1 H) 12.27 (s, 1 H) A48M2B53 'H NMR (400 MHz, DMSO-d6): δ ppm 1.13 (m, 2 H) 2.29 (m, 2 H) 3.72 (s, 2 H) 4.43 (s, 2 H) 7.18 (m, 2 H) 7.38 (m, 1 H) 7.45 (m, 3 H) 7.71 (m, 1 H) 7.80 (m, 3 H) 10.79 (s, 1 H) 12.23 (s, 1 H) 94 312/發明說明書(補件)/93-03/92135527 1327470 (實施例1 9 ) |^-{6,6-二甲基-5-[(4-曱基哌啩-1-基)羰基]-2,4,5,6-四 氫。比。各[3,4 - c ] °坐-3 -基} - 4 -氟苄Sf胺 於三光氣(195毫克,0.65毫莫耳,0.56當量)於二氯甲 烷(15毫升)之溶液内加入3-[(4 -氟苯f醯基)胺基]-6,6-二曱基-5,6-二氫〇比0各[3,4-(:]〇比唑-2(41〇-叛酸乙酯鹽酸 鹽(442毫克,1.15毫莫耳)於二氣曱烷(30毫升)之溶液, 接著加入N,N -二異丙基乙基胺(760微升,4.31毫莫耳,
3 . 7 5當量)。3小時後,加入N -甲基哌畊(1 9 5微升,1 7 2 毫莫耳,1.5當量)及二異丙基乙基胺(300微升,1.72毫 莫耳,1.5當量)於二氣曱烷(8毫升)之溶液。反應於室溫 攪拌隔夜(T L C : C Η 2 C 1 2 / M e Ο Η 9 0 / 1 0 )。溶液以鹽水洗滌, 有機相以硫酸鈉脫水及濃縮。殘餘物溶解於曱醇(1 6毫 升),以TEAC1. 6毫升,11.5毫莫耳,10當量)處理,於室 溫攪拌隔夜。(T L C : C Η 2 C 12 / M e Ο Η 9 0 / 1 0 )。蒸發後,固體 藉急速層析術純化(洗提劑:C H 2 C 1 2 / M e Ο Η 9 0 / 1 0 )。固體以 二異丙基醚處理及過濾,獲得0 . 2 9 4克標題化合物,6 4 % 產率。I ESI MS : m/z 401 (MH+); Ή NMR ( 4 0 0 MHz, DMS0-dc):5 12.39 (bs, 1H), 10.39 (s, 1H), 8.04 (m, 2H, Ar), 7.31 (m, 2H), 4.53 (bs, 2H), 3.04 (ηκ 4H), 2.40 (m, 4H), 2.22 (bs, 3H), 1.60 (bs, 6H )° 經由以類似方式處理製備下述化合物: 1^-[5-[(4-甲基0底0井-1-基)幾基]-2,4,5,6-四氫°比〇各 95 312/發明說明書(補件)/93-03/92135527 1327470 [3 , 4 - c ]吡唑-6 -螺環丙烷-3 -基]-4 -氟¥醯胺 ESI MS: πι/ζ 399 (MH + ); Ή NMR (400 MHz, DMS〇-de):5 12.19 (bs, 1 H ), 1 0 . 9 5 ( s, 1H) , 8.09 (m, 2H), 7.35 (m, 2H), 4.70 (bs, 2H), 3.18 (m, 4H), 2.34 (m, 7H) , 1.92 (m, 2H), 0.97 (m,2H)。 (實施例2 0 ) 4 -氣-N - [ 6 , 6 -二曱基-5 - ( 4 -吡咯啶-1 -基甲基-哌啶-1 -羰 基)-1,4,5,6 -四氫。比咯[3,4 - c ]吡唑-3 -基]-τ醯胺,鹽酸 鹽 N-[5-(4 -胺基曱基-哌啶-1-羰基)-6,6-二曱基 -2, 4, 5,6 -四氫比咯并[3, 4-c]咄唑-3-基]-4-氣-苄醯胺 (3 1 0毫克,0 . 7毫莫耳),1 , 4 -二溴丁烷(9 2微升,0 · 7毫 莫耳)及碳酸氫鈉(600毫克,7毫莫耳)於絕對乙醇(15毫 升)之混合物於微波爐於1 5 0 °C加熱1 5分鐘。冷卻後,溶 液經蒸發。殘餘物以二氣甲烷/甲醇(9 0 : 1 0 )及水攝取,所 得懸浮液經過濾,有機層經蒸發至乾。殘餘物藉急速層析 術以二氣曱烷/甲醇/ 3 0 %氫氧化銨水溶液(9 5 / 5 / 0 . 5 )純 化。獲得產物,2 0 %產率(7 1毫克)。 化合物溶解於甲醇(3毫升),加入4 N鹽酸於二氧己環溶 液(4 0微升,0 . 1 6毫莫耳),然後溶液經蒸發。所得固體於 醚濕磨,獲得標題鹽酸鹽,呈白色粉末。 ESI MS: m/z 485 (MH+); Ή NMR (400 MHz, DMS〇-De)(5 ppm 1.24 (m, 2H), 1.63 (s, 6H), 1.92 (m, 7H), 2.67 (t, J = 11.83 Hz, 2H), 3.01 (m, 2H ), 3.09 ( t, J = 6. 46 Hz, 2H), 3. 4 7 ( m, 4H), 4. 56 (s, 96 312/發明說明書(補件)/93-03/92 i 35527 1327470 2H), 7.59 (d, J 二 8. 54 Hz, 2H), 8.0 1 (d, J = 8.66Hz, 2H), 9.49 (s, 1H), 11.02 (s, 1H), 12.50 (s, 1H)。 經由以類似方式處理以及經由使用適當起始物料以及 任一種適當反應物,遵照前述方法,也製備額外式(I a)及 (I b )化合物,報告如下表V。
表V A03M1B08.HC1 'H NMR (400 MHz, DMSO-d6): δ 1.65 (d, >9.15 Hz, 6 Η) 2.84 (d, 7=3.17 Hz, 3 H) 3.06 (s, 4 H) 3.58 (s, 4 H) 4.62 (s, 2 H) 7.61 (m, 1 H) 7.91 (m, 1 H) 8.07 (m, I H) 9.98 (s, 1 Η) 11.08 (s, 1 H) 12.61 (s, 1 H) A04M1B08 'H NMR (400 MHz, DMSO-d6): δ 12.44 (bs, 1H), 10.85 (s, 1H), 7.74 (m, 1H), 7.18 (m, 1H), 7.20 (s, 1H), 4.59 (bs, 2H), 3.06 (m, 4H), 2.38 (m, 4H), 2.22 (bs,3H), 1.64 (bs, 6H). 97 3 12/發明說明書(補件)/93-03/92丨35527 1327470 A06M1B08 'Η NMR (400 MHz, DMSO-d6): δ 12.46 (bs, 1H), 10.99 (s, 1H), 8.01 (m, 2H), 7.59 (m, 2H), 4.59 (bs, 2H), 3.07 (m, 4H), 2.40 (m, 4H), 2.25 (bs, 3H), 1.64 (bs, 6H). A07M1B08 'H NMR (400 MHz, DMSO-d6): δ 12.49 (bs, 1H), 11.16 (s, 1H), 8.19 (d, 2H, J = 7.80 Hz), 7.88 (d, 2H, J = 7.80 Hz), 4.60 (s, 2H), 3.06 (m, 4H), 2.38 (m, 4H), 2.22 (s,'3H), 1.64 (bs, 6H). · A12M1B08 'H NMR (400 MHz, DMSO-d,;): δ 12.24 (bs, 1H), 10.32 (s, 1H), 4.47 (s, 2H), 3.03 (m, 4H), 2.34 (m, 4H), 2.20 (s, 3H), 2.15 (d, 2H, J = 7.20 Hz), 2.05 (m, 1H), 1.59 (s, 6H), 0.92 (d, 6H, J = 6.59 Hz). A13M1B08 'H NMR (400 MHz, DMSO-d6): δ 12.23 (bs, 1H), 10.22 (s, 1H), 4.50 (bs, 2H), 3.32 (m, 1H), 3.04 (m, 4H), 2.35 (m, 4H), 2.21 (s, 3H), 1.91-1.8 (m, 6H), 1.59 (bs, 6H). A14MIB08 'H NMR (400 MKz, DMSO-d6): δ 12.23 (bs, 1H), 10.66 (s, 1H), 4.44 (bs, 2H), 3.02 (m, 4H), 2.33 (m, 4H), 2.19 (s, 3H), 1.82 (m, 1H), 1*59 (bs, 6H), 0.78 (m, 4H). A16M1B08 *H NMR (400 MHz, DMSO-d^): δ 12.46 (bs, 1H), 11.04 (s, 1H), 8.12 (m, 2H), 7.51 (m, 2H), 4.57 (bs, 2H), 3.06 (m, 4H), 2.36 (m, 4H), 2.20 (s, 3H), 1.64 (bs, 6H). A17M1B08 'H NMR (400 MHz, DMSO-d6): δ 12.44 (bs, 1H), 10.94 (s, 1H), 7.78 (m, 1H), 7.61 (bs, 1H), 7.51 (m, 1H), 7.45 (m, 2H), 7.20 (m, 2H), 7.09 (m, 2H), 4.55 (bs, 2H), 3.06 (m, 4H), 2.40 (m, 4H), 2.24 (bs, 3H), 1.63 (bs, 6H). A18M1B08 'H NMR (400 MHz, DMSO-d6): δ 12.44 (bs, 1H), 10.99 (s, IH), 7.96 (m, 2H), 7.47-7.33 (m, 7H), 4.55 (bs, 2H), 3.03 (m, 4H), 2.52 (m, 4H), 2.28 (bs, 3H), 1.63 (bs, 6H). Α21Μ1β〇8 'H NMR (400 MHz, DMSO-d6): δ 12.44 (bs, 1H), 10.95 (bs, 2H), 8.66 (m, 1H)„ 8.14 (m, 2H), 8.00 (m, 2H), 7.83 (m, 1H), 6.82 (m, 1H), 4.59 (s, 2H), 3.06 (m, 4H), 2.36 (m, 4H), 2.21 (s, 3H), 1.64 (bs, 6H). Α22Μ1Β08 'H NMR (400 MHz, DMSO-d6): δ 12.41 (bs, 1H), 11.06 (bs, 1H), 8.50-7.60 (m, 7H), 4.64 (s, 2H), 3.07 (m, 4H), 2.35 (m, 4H), 2.18 (s, 3H), 1.66 (bs, 98 3丨2/發明說明書(補件)/93-03/92丨35527 1327470 6H). A23M1B08 'H NMR (400 MHz, DMSO-d6): δ 12.45 (bs, 1H), 11.05 (bs, 1H), 8.66 (bs, 1H), 7.07 (m, 4H), 7.65 (m, 2H), 4.62 (s, 2H), 3.07 (m, 4H), 2.37 (m, 4H), 2.21 (s,3H), 1.65 (bs, 6H). A24M1B08 lH NMR (400 MHz, DMSO-d6): δ 12.02 (bs, 1H), 8.80 (s, 1H), 7.19 (m, 4H), 6.90 (bs, 1H), 4.42 (s, 2H), 4.31 (d, 2H J = 5.73 Hz), 3.02 (m, 4H), 2.34 (m, 4H), 2.30 (s, 3H), 2.20 (s, 3H), 1.59 (s, 6H). A25M1B08 'H NMR (400 MHz, DMSO-d6): δ 12.02 (bs, 1H), 8.83 (s, 1H), 7.31 (m, 5H), 6.99 (bs, 1H), 4.42 (s, 2H), 4.33 (d, 2H J = 5.85 Hz), 3.02 (m, 4H), 2.34 (m, 4H), 2.19 (s, 3H), 1.59 (s, 6H). A26M1B08 'H NMR (400 MHz, DMSO-d6): δ 12.00 (bs, 1H), 8.65 (s, 1H), 6.54 (m, 1H), 4.41 (s, 2H), 3.02 (m, 6H), 2.34 (m, 4H), 2.20 (s, 3H), 1.5S (s, 6H), 1.43 (m, 2H), 0.88 (t, 3H). A27M1B08 . 'H NMR (400 MHz, DMSO-d6): δ 12.22 (bs, 1H), 9.16 (s, 2H), 7.46 (m, 1H), 7.33 (m, 1H), 7.13 (m, 1H), 6.80 (m, 1H), 6.99 (bs, 1H), 4.48 (s, 2H), 3.05 (m, 4H), 2.35 (m, 4H), 2.20 (s, 3H), 1.61 (s, 6H). A01M1B09 'H NMR (400 MHz, DMSO-d6): δ 12.37 (bs, 1H), 10.88 (s, 1H), 8.04 (m, 2H), 7.31 (m, 2H), 4.51 (bs, 2H), 2.97 (m, 4H), 1.59 (bs, 6H), 1.50 (m, 6H). A06M1B09 'H NMR (400 MHz, DMSO-d6): δ 12.44 (bs, 1H), 10.98 (s, 1H), 8.01 (d, 2H, J = 8.3 Hz), 7.58 (d, 2H, J = 8.3 Hz), 4.57 (bs, 2H), 3.00 (m, 4H), 1.63 (bs, 6H), 1.54 (m, 6H). A01M1B10 lH NMR (400 MHz, DMSO-d6): δ 12.41 (bs, 1H), 10.89 (s, 1H), 8.04 (m, 2H), 7.30 (m, 2H), 4.56 (bs, 2H), 3.59 (m, 4H), 3.01 (m, 4H), 1.61 (bs, 6H). A01M1B11 'H NMR (400 MHz, DMSO-d6): δ 12.52 (bs, 1H), 10.91 (s, 1H), 8.07 (m, 2H), 7.35 (m, 2H), 4.54 (bs, 2H), 3.33 (m, 2H), 2.63 (m, 2H), 1.63 (m, 8H), 1.49 (m, 1H), 1.15 (m, 2H), 0.94 (d,3H, J = 6.5 Hz). A13M1B11 'H NMR (400 MHz, DMSO-d6): δ 12.23 (bs, 1H), 10.19 (s, 1H), 4.50 (s, 2H), 3.33 (m, 3H), 2.62 (m, 2H), 2.4-I.4 (m, 15H), 1.15 (m, 2H), 0.95 (d, 3H,J = 6.58Hz). 312/發明說明書(補件)/93-03/92丨35527 1327470 Α14Μ1ΒΠ 'H NMR (400 MHz, DMSO-d6): δ 12.23 (bs, 1H), 10.63 (s, 1H), 4.43 (s, 2H), 3.33 (m, 2H), 2.61 (m, 2H), 1.9-1.4 (m, 10H), 1.11 (m, 2H), 0.95 (d, 3H, J = 6.58 Hz), 0.77 (m, 4H). A14M1B12 'H NMR (400 MHz, DMSO-d6): δ 12.23 (bs, 1H), 10.64 (s, 1H), 4.43 (s, 3H), 3.33 (m, 4H), 2.60 (m, 2H), 1.59 (m, 10H), 1.11 (m, 2H), 0.78 (m, 4H). A01MIB13 'H NMR (400 MHz, DMSO-d6): δ 12.42 (bs, 1H), 10.91 (s, 1H), 8.08 (m, 2H), 7.33 (m, 2H), 4.56 (bs, 2H), 4.35 (bs, 1H), 3.46 (m, 4H), 2.65 (m, 2H), 1.75-1.05 (m, 13H). A02M2B08 lH NMR (400 MHz, DMSO-d6): δ 12.00 (bs, 1H), 11.02 (s, 1H), 7.86 (m, 2H), 7.57 (m, 2H), 4.70 (bs, 2H), 3.14 (m, 4H), 2.40 (m, 4H), 2.25 (bs, 3H), 1.91 (m, 2H),0.97(m, 2H). A04M2B08 'H NMR (400 MHz, DMSO-d6): δ 12.16 (bs, 1H), 10.84 (s, 1H), 7.76 (m, 3H), 4.69 (bs, 2H), 3;12.(m, 4H), 2.35 (m, 4H), 2.21 (bs, 3H), 1.90 (m, 2H), ·· 0:97 (m, 2H). A06M2B08 * •H NMR (400 MHz, DMSO-d6): δ 12.20 (bs, 1H), 11.00 (s, 1H), 8.02 (m, 2H), 7.59 (m, 2H), 4.70 (bs, 2H), 3.15 (m, 4H), 2.51 (m, 4H), 2.29 (bs, 3H), 1.92 (m, 2H), 0.89 (m, 2H). A07M2B08 'HNMR (400 MHz, DMSO-d6): δ 12.24 (bs, 1H), 11.17 (s, 1H), 8.19 (m, 2H), 7.89 (m, 2H), 4.72 (bs, 2H), 3.14 (m, 4H), 2.41 (m, 4H), 2.26 (bs, 3H), 1.92 (m, 2H), 0.98 (m, 2H). A10M2B08 'HNMR(400 MHz, DMSO-d6): δ 12.18 (bs, 1H), 10.98 (s, 1H), 8.11 (m, 1H), 7.87 (m, 1H), 7.21 (m, 1H), 4.66 (bs, 2H), 3.13 (m, 4H), 2.37 (m, 4H), 2.23 (bs, 3H), 1.91 (m, 2H), 0.97 (m, 2H). A14M2B08 'H NMR (400 MHz, DMSO-d6): δ 11.98 (bs, 1H), 10.66 (s, 1H), 4.56 (bs, 2H), 3.10 (m, 4H), 2.34 (m, 4H), 2.21 (bs, 3H), 1.87 (m, 2H), 1.86 (m, 1H), 0.92 (m, 2H), 0.82 (m, 4H). A17M2B08 'H NMR (400 MHz, DMSO-d6): δ 12.17 (bs, IH), 10.95 (s, 1H), 7.79 (m, 1H), 7.62 (bs, 1H), 7.51 (m, 1H), 7.45 (m, 2H), 7.27 (m, 1H), 7.20 (m, 1H), 7.09 (m, 2H), 4.66 (bs, 2H), 3.12 (m, 4H), 2.35 (m, 4H), 2.21 (s, 3H), 1.90 100 3 1W發明說明書(補件)/93-03/92丨35527 1327470 (m, 2H), 0.98 (m, 2H). A18M2B08 'H NMR (400 MHz, DMSO-dfi): δ 12.17 (bs, 1H), 11.00 (s, 1H), 7.97 (bs, 1H), 7.94 (m, 1H), 7.42 (m, 7H), 4.67 (bs, 2H), 3.11 (m, 4H), 2.32 (m, 4H), 2.20 (s, 3H), 1.90 (m, 2H), 0.98 (m, 2H). A19M2B08 'H NMR (400 MHz, DMSO-d6): 5 12.17 (bs, 1H), 10.77 (s, 1H), 7.92 (bs, 1H), 7.49 (m, 1H), 6.69 (m, 1H), 4.66 (bs, 2H), 3.12 (m, 4H), 2.37 (m, 4H), 2.23 (s, 3H), 1.90 (m, 2H), 0.96 (m, 2H). A01M2B09 *H NMR (400 MHz, DMSO-d6): δ 12.13 (bs, 1H), 10.93 (s, 1H), 8.09 (m, 2H), 7.36 (m, 2H), 4.65 (bs, 2H), 3.08 (m, 4H), 1.87 (m, 2H), 1.53 (m, 6H), 0.96 (m, 2H). A01M2B10 'H NMR (400 MHz, DMSO-d6): δ 12.10 (bs, 1H), 10.95 (s, 1H), 8.09 (m, 2H), 7.34 (m, 2H), 4.70 (bs, 2H), 3.62 (m, 4H), 3.12 (m, 4H), 1.93 (m, 2H), 0.96 (tn, 2H). A01M2BI1 'H NMR (400 MHz, DMSO-d6): δ 12.15 (bs, IH), 10.93 (s, IH), 8.09 (m, 2H); 7.36 (m, 2H), 4.65 (bs, 2H), 3.54 (m, 2H), 2.65 (m, 2H), 1.87 (m, 2H), 1.61 (m, 2H), 1.50 (m, 1H), 1.12 (m, 2H), 0.94 (m, 5H). A01M2B12 'H NMR (400 MHz, DMSO-d6): δ 11.88 (bs, 1H), 10.93 (s, 1H), 8.08 (m, 2H), 7.36 (m, 2H), 4.66 (bs, 2H), 3.54 (m, 2H), 3.45 (m, 3H), 2.65 (m, 2H), 1.87 (m, 2H), 1.66 (in, 2H), 1.50 (m, 1H), 1.12 (m, 2H), 0.94 (m, 2H). A01M2B13 'H NMR (400 MHz, DMSO-d6): δ 11.33 (bs, 1H), 10.93 (s, 1H), 8.08 (m, 2H), 7.36 (m, 2H), 4.65 (bs, 2H), 3.54 (m, 2H), 3.45 (m, 3H), 2.65 (m, 2H), 1.87 (m, 2H), 1.66 (m, 2H), 1.50 (m, 1H), 1.40 (m, 2H), 1.12 (m, 2H), 0.95 (m, 2H). A48M1B08 'H NMR (400 MHz, DMSO-d6): δ 1.55 (s, 6H), 2.19 (s, 3H), 2.35 (m, 4H), 2.98 (m, 4H), 3.75 (s, 2H), 4.44 (s, 2H), 7.5 (m, 3H), 7.75 (s, 1H), .7.85 (m, 3H), 10.7 (bs, 1H), 12.5 (bs, 1H). A30M1B08 'H NMR (400 MHz, DMSO-d6): 8 1.63 (s, 6H), 2.20 (s, 3H), 2.36 (m, 4H), 3.06 (m, 4H), 4.57 (s, 2H), 7.51 (m, 2H), 7.60 (m, 1H), 7.99 (m, 2H), 10.89 (bs, 1H), 12.42 (bs, 1H). 312/發明說明書(補件)/93-03/92135527 101 1327470 A38M2B08 'H NMR (400 MHz, DMSO-d6): δ 0.96 (m, 2H), 1.91 (bs, 2H), 2.23 (bs, 3H), 2.37 (bs, 4H), 3.13 (bs, 4H), 3.86 (s, 6H), 4.69 (s, 2H), 7.07 (s, 1H), 7.66 (bs, 2H), 10.76 (s, 1H), 12.14 (bs, 1H). A54M1B08 4 NMR (400 MHz, DMSO-d6): δ 1.64 (s, 6H), 2.20 (s, 3H), 2.36 (m, 4H), 3.06 (m, 4H), 4.59 (bs, 2H), 7.77 (m, 1H), 7.96 (m, 1H), 8.3 (m, 1H), 8.36 (s, 1H), 11.23 (s, 1H), 12.50 (bs, 1H). A04M1B12 'H NMR (400 MHz, DMSO-d6): δ 1.16 (m, 2H), 1.4-1.75 (m, 9H), 2.62 (m, 2H), 3.33 (m, 4H), 4.46 (t, 1H), 4.56 (bs, 2H), 7.2 (m, 2H), 7.75 (m, 1H), 10.84 (s, 1H), 12.43 (s, 1H). A01M1B12 'H NMR (400 MHz, DMSO-d6): δ 1.17 (m, 2H), 1.51 (m, 1H), 1.63 (s, 6H), 1.66 (m, 2H), 2.62 (m, 2H), 3.32 (m, 4H), 4.54 (bs, 2H), 7.35 (m, 2H), 8.07 (m, 2H), 10.92 (s, 1H), 12.4 (bs, 1H). A43M1B13 4 NMR (400 MHz,DMSO-d6): δ 12.25 (bs,1H),10.7 (s; 1H), 7.85 (m, 3H), 7.8 (s, 1H), 7.45 (m, 3H): 4.4 (bs, 2H), 4.3 (i, 1H), 3.75 (s, 2H)i 3.44 (m, 4H), 2.65 (m, 2H), 1.70 (m, 2H), 1.67 (s, 6H), 1.52 (m, 1H), 1.39 (m, 2H), 1.15 (m,2H). A30M1B13 lH NMR (400 MHz, DMSO-d6): δ 7.99 (m, 2H),7.59 (m, 1H),7.51 (m,2H), 4.56 (bs, 2H), 4.35 (t, 1H), 3.46 (m, 4H), 2.97 (m, 2H), 1.45-1.95 (m, 11H), 1.17 (m, 2H). A23M1B13 'H NMR (400 MHz, DMSO-d6): δ 12.45 (bs, 1H), 11.02 (s, 1H), 8.67 (s, 1H), 8.07 (m, 4H), 7.65 (m, 2H), 4.61 (bs, 2H), 4.35 (t, 1H), 3.46 (m, 4H), 2.63 (m, 2H), 1.45-1.85 (m, 8H), 1.52 (m, 1H), 1.42 (m, 2H), 1.18 (m, 2H). A14M1B13 'H NMR (400 MHz, DMSO-d6): δ 12.23 (bs, 1H), 10.64 (s, 1H), 4.42 (bs, 2H), 4.35 (t, 1H), 3.47 (m, 2H), 3.33 (m, 2H), 2.56 (m, 2H), 1.82 (m, 1H), 1.65 (m, 2H), 1.59 (s, 6H), 1.52 (m, 1H),1.4 (m, 2H), 1.12 (m, 2H), 0.78 (m, 4H). A04M1B13 'H NMR (400 MHz, DMSO-d6): δ 12.43 (bs, 1H), 10.84 (s, 1H),7.76 (m, 1H), 7.38 (m, 1H), 7.2 (m, 1H), 4.56 (bs, 2H), 4.34 (t, 1H), 3.45 (m, 2H), 3.33 (m, 2H), 2.56 (m, 2H), 1.75-1.55 (m, 8H), 1.53 (m, 1H), 1.40 (m, 2H), 312/發明說明書(補件)/93-03/92135527 1327470 1.15 (m, 2H). A16M1B13 lH NMR (400 MHz, DMSO-d6): δ 12.45 (bs, 1H), 11.02 (s, 1H), 8.12 (m, 2H), 7.51 (m, 2H), 4.56 (bs, 2H), 4.35 (t, 1H), 3.48-3.20 (m, 4H), 2.61 (m, 2H), 1.72-1.09 (m, 13H). A22M1BI3 'H NMR (400 MHz, DMSO-d6): 5 12.40 (bs, 1H), 11.02 (s, 1H), 7.3-8.4 (m, 7H), 4.65 (bs, 2H), 4.33 (t, 1H), 3.44 (m, 4H), 2.65 (m, 2H), 1.70 (m, 2H), 1.67 (s, 6H), 1.52 (m, 1H), 1.39 (m, 2H), 1.15 (m, 2H). A13M1B13 'H NMR (400 MHz, DMSO-d6): δ 1.15 (m, 2 H) 1.40 (q, /=6.54 Hz, 2 H) 1.51 (m, 1 H) 1.59 (s, 6 H) 1.68 (m, 2 H) 1.79 (m, 1 H) 1.91 (m, 1 H) 2.07 (m, 2 H) 2.17 (m, 2 H) 2.61 (t, 7=12.13 Hz, 2 H) 3.24 (m, 1 H) 3.39 (d, 7=14.75 Hz, 2 H) 3.47 (m, 2 H) 4.35 (m, 1 H) 4.49 (s, 2 H) 10.19 (s, 1 H) 12.22 (s, 1 H) A21M1B13 'H NMR (400 MHz, DMSO-d6): δ 1.16 (m, 2 H) 1.40 (q, /=6.71 Hz,4 2 H) 1.55 (m, 1 H) 1.64 (s, 6 H) 1.69 (d, /-12.80 Hz, 2 H) 2.62 (m, 2 Η) ΪΑ2 (d, 7=11.83 Hz, 2 H) 3.47 (m, 2 H) 4.35 (t, 7=5.12 Hz, 1 H) 4.58 (s, 2 H) 6.62 (m, 1 H) 7.83 (d, J=1.46 Hz, 1 H) 7.99 (d, >9.39 Hz, 2 H) 8.15 (d, 7=8.17 Hz, 2 H) 8.65 (d, 7=2.44 Hz, 1 H) 10.94 (s, 1 H) 12.43 (s, 1 H) A25M1B13 lH NMR (400 MHz, DMSO-d6): δ 12.02 (bs, 1H), 8.82 (bs, 1H), 7.3 (m, 5H), 7.0 (bs, 1H), 4.40 (s, 2H), 4.33 (m, 3H), 3.45 (m, 2H), 3.33 (m, 2H), 2.59 (m, 2H), 1.66 (m, 2H), 1.57 (m, 7H), 1.40 (m, 2H), 1.13 (m, 2H). A27M1B13 'H NMR (400 MHz, DMSO-d6): δ 12.20 (bs, 1H), 9.02 (bs, 1H), 7.45 (m, 1H),7.31 (m, 1H), 7.12 (m, 1H), 6.81 (m, 1H), 4.47 (bs, 2H), 4.34 (t, 1H), 3.46 (m, 2H), 3.32 (m, 2H), 2.62 (m, 2H), 1.66 (m, 2H), 1.58 (m, 7H), 1.40 (m, 2H), 1.15 (m, 2H). A24M1B13 'H NMR (400 MHz, DMSO-d6): δ 12.03 (bs, 1H), 8.79 (bs, 1H), 7.24 (m, 1H), 7.18 (m, 3H), 6.92 (bs, 1H), 4.39 (bs, 2H), 4.35 (t, 1H), 4.31 (m, 2H), 3.46 (m, 2H), 3.33 (m, 2H), 2.56 (m, 2H), 2.3 (s, 3H), 1.65 (m, 2H), 1.58 (m, 7H), 1.40 (m, 2H), 1.13 (m, 2H). A26M1B13 'HNMR (400 MHz, DMSO-d6):5 11.99 (bs, 1H);8.66 (bs, 1H), 6.56 (bs, 312/發明說明書(補件)/93-03/92] 35527 103 1327470 1H), 4.38 (bs, 2H), 4.35 (t, 1H), 3.46 (m, 2H), 3.32 (m, 2H), 3.05 (m, 2H), 2.56 (m, 2H), 1.66 (m, 2H), 1.57 (m, 7H), 1.46 (m, 4H), 1.14 (m, 2H), 0.88 (t, 3H). A12M1B13 'H NMR (400 MHz, DMSO-d6): δ ppm 0.92 (d, 7=6.46 Hz, 6 H) 1.12 (m, 2 H) 1.39 (q, 7=6.58 Hz, 2 H) 1.54 (m, 1 H) 1.59 (s, 6 H) 1.67 (d, 7=14.51 Hz, 2 H) 2.06 (m, 1 H) 2.16 (d, /=6.95 Hz, 2 H) 2.60 (m, 2 H) 3.38 (m, 2 H) 3.46 (m, 2 H) 4.35 (t, 7=5.12 Hz, 1 H) 4.46 (s, 2 H) 10.30 (s, 1 H) 12.23 (s, 1 H) A54M1B13 'H NMR (400 MHz, DMSO-d6): δ ppm 1.15 (m, 2 H) 1.40 (q, 7=6.63 Hz, 2 H) 1.53 (m, 1 H) 1.64 (s, 6 H) 1.68 (d, 7=12.93 Hz, 2 H) 2.62 (t, J=11.89 Hz, 2 H) 3.42 (d, 7=11.22 Hz, 2 H) 3.46 (m, 2 H) 4.35 (t, 7=4.88 Hz, 1 H) 4.57 (s, 2 H) 7.77 (t, 7=8.72 Hz, 1 H) 7.97 (d, 7=6.10 Hz, 1 H) 8.30 (d, 7=7.68 Hz, 1 H) 8.36 (s, 1 Η) 11.21 (s, 1 H) 12.49 (s, 1 H) A01M.IB27 'H NMR (400 MHz, DMSO-d6): δ ppm 0.86 (t, 3 Η), l .27 (m, 2 H),n ,3S (m; 2 H), 1.61 (s, 6H), 3.0 (m, 2 H), 4.41 (m, 2 H), 5.98 (bs, HI), 7.33 (ni, 2 H), 8.06 (m, 2 H), 10.86 (s, 1 H) 12.39 (s, 1 H).. A01M2B27 'H NMR (400 MHz, DMSO-d6): δ ppm 0.78 (m, 2 H), 0.86 (t, 3 H), 1.27 (m, 2 H), 1.38 (m, 2 H), 2.06 (m, 2 H), 3.0 (m, 2 H), 4.41 (m, 2 H), 5.98 (bs, I H), 7.31 (m, 2 H), 8.05 (m, 2 H), 10.86 (s, 1 H) 12.38 (s, 1 H). A01M1B28 'H NMR (400 MHz, DMSO-d6): 6 ppm 1.00 (t, 3 H), 1.62 (s, 6H), 3.04 (m, 2 H), 4.42 (m, 2 H), 6.01 (bs, 1H), 7.30 (m, 2 H), 8.07 (m, 2 H), 10.85 (s, 1 H) 12.38 (s, 1 H). A55M1B28 'H NMR (400 MHz, DMSO-d6): δ ppm 1.00 (t, 3 H), 1.49 (d, 7=7.50 Hz, 3 H), 1.55 (s, 3 H), 1.58 (s, 3 H), 3.01 (m, 2 H), 4.04 (q, 1 H), 4.34 (m, 2 H), 5.99 (bs, 1H), 7.48 (m, 3 H), 7.87 (m, 4 H), 10.61 (s, 1 H) 12.23 (s, 1 H). A01M2B28 'H NMR (400 MHz, DMSO-d6): δ ppm 0.78 (m, 2 H), 0.99 (m, 3 H), 2.06 (m, 2 H), 2.98 (m, 2 H), 4.56 (m, 2 H), 6.14 (bs, 1 H), 7.33 (m, 2 H), 8.07 (m, 2 H), 10.88 (s, 1 H) 12.09 (s, 1 H). A48M2B28 'H NMR (400 MHz, DMSO-d6): δ ppm 0.74 (m, 2 H), 0.96 (m, 3 H), 2.03 (m, 2 H), 2.96 (m, 2 H), 3.80 (s, 2 H), 4.45 (s, 2 H), 5.68 (bs, 1 H), 6.06 (bs, 3丨2/發明說明書(補件)/93-03/92丨35527 104 1327470 1 Η), 7.4-8.0 (m, 7 Η), 10.70 (s, 1 Η). A0IMIB49 'Η NMR (400 MHz, DMSO-d6): δ ppm 1.06 (d, /=6.55 Hz, 6 H), 1.61 (s, 6 H), 3.78 (m, 1 H), 4.41 (m, 2 H), 5.66 (m, 1 H), 7.31 (m, 2 H), 8.06 (m, 2 H), 10.85 (s, 1 H) 12.39 (s, 1 H). A48M1B49 'H NMR (400 MHz, DMSO-d6): 5 ppm 1.01 (d, 7=6.5 Hz, 6 H), 1.56 (s, 6 H), 3.76 (m, 1 H), 4.29 (m, 2 H), 5.66 (m, 1H), 7.47 (m, 3 H), 7.78 (m, 1 H), 7.85 (m, 3 H), 10.67 (s, 1 H) 12.24 (s, 1 H). A01M2B49 lH NMR (400 MHz, DMS0-d6): δ ppm 0.81 (m, 2 H), 1.09 (d, 7=6.64 Hz, 6 H), 2.09 (m, 2 H), 3.74 (m, 1 H), 4.60 (m, 2 H), 5.85 (m, 1 H), 7.36 (m, 2 H), 8.10 (m, 2 H), 10.92 (s, 1 H) 11.76 (s, 1 H). A01M1B55 •. 'H NMR (400 MHz, DMSO-d6): δ ppm 1.57 (m, 2 H), 1.63 (s, 6 H), 1.73 (m, 2 H), 2.25 (m, 1 H), 2.64 (m, 2 H), 3.43 (m, 2 H), 4.56 (m, 2 H), 6.75 (s, 1 H), 7.27 (s, 1 H), 7.34 (m, 2 H), 8.09 (m, 2 H), 10.92 (s, 1 H) 12.45. {s, 1 H). A01M2B55 'H NMR (400 MHz, DMSO-d6): δ ppm 0.96 (m, 2H), 1.55 (m, 2 H), 1.71 (m, 2 H), 1.82 (m, 2 H), 2.34 (m, 1 H), 2.75 (m, 2 H), 3.48 (m, 2 H), 4.67 (m, 2 H),6.75 (s, 1 H), 7.28 (s, 1 H),7.35 (m,2 H), 8.10 (m, 2 H), 10.98 (s, 1 H) 12.19 (s, 1 H). (實施例2 1 ) 如前文報告製備之若干式(I a )及(I b)本發明化合物也 可利用Η P L C /質譜技術,因而經由滯留時間(r . t.)及質量 [Μ + Η Γ特徵化。 操作條件報告如後: HPLC/MS 方法 1 HPLC設備係由Waters 2790 HPLC系統裝配有996 Waters PDA偵測器及Micromass mod. ZQ單一四極質谱儀裝配有 電灑(E S I )離子源組成。儀器之控制、資料之獲得及資料之 處理係由Millennium 4.0及MassLynx 3.5軟體提供。
Η P L C係於2 5 t於1毫升/分鐘流速,使用R P 1 8 \V a t e r s X 105 31刀發明說明書(補件)/93-03/92丨35527 1327470
Terra (4. 6Χ50毫米,3.5微米)管柱進行。動相A為乙酸 敍5 in Μ緩衝液(ρ Η 5 . 5含乙酸/乙月奢9 5 : 5 ),動相B為水/ 乙腈(5 : 9 5 );梯度為8分鐘内自1 0至9 0 % Β,然後維持9 0 % Β 2分鐘。注入容積為1 0微升。 質譜儀係於正離子模式及負離子模式操作,毛細電壓設 定於2. 5千伏特;源溫度為1 2 0 °C ;錐為1 0伏特;全掃描 ,設定100至800 a mu質量範圍。 HPLC/MS 方法 2 HPLC設備係由Waters 2790 HPLC系統裝配有996 Waters P D A 4貞測器及M i c r 〇 m a s s m 〇 d . Z Q單一四極質譜儀裝配有 電灑(E S I )離子源組成。儀器之控制、資料之獲得及資料之 處理係由Millennium 4.0及MassLynx 3.5軟體提供° Η P L C係於2 5 °C於1毫升/分鐘流速,使用R P 1 8 W a t e r s X Terra (4. 6X5◦毫米,3. 5微米)管柱進行。動相A為乙酸 敍5 in Μ緩衝液(p Η 5 · 5含乙酸/乙腈9 5 : 5 ),動相B為水/ 乙腈(5 : 9 5 );梯度為4分鐘内自1 0至9 0 % Β,然後維持9 0 % Β 1分鐘。注入容積為1 0微升。 質譜儀係於正離子模式及負離子模式操作,毛細電壓設 定於2. 5千伏特;來源溫度為1 2 0 °C ;錐為1 0伏特;全掃 描,設定1 0 0至8 0 0 a m u質量範圍。 HPLC/MS 方法 3 質譜係使用電灑(E S I )游離技術以正離子偵測及負離子 偵測記錄於F i η n i g a n L C Q離子捕捉質譜儀。質譜儀直接連 結至 SSP4000 HPLC 系統(Thermo Separation),裝配有 L c P a 1自動取樣機(C T C分析公司)及U V 6 0 0 0 L P P D A偵測器 106 3 12/發明說明書(補件)/93-03/92丨35527 1327470 (T h e r m 〇 S e p a r a t i ο η )。儀器之控制' 資料之獲得及處理係 使用X c a 1 i b u r 1 . 2軟體進行。Η P L C分析係於室溫以1毫 升/分鐘流速,使用RP C18 Waters X-Terra管柱(4.6Χ50 毫米;3 . 5微米)進行。 動相A為乙酸銨5 m Μ緩衝液(p Η 5 · 5含乙酸):乙腈 9 0:10,及動相Β為乙酸銨5 m Μ緩衝液(ρ Η 5. 5含乙酸): 乙腈1 0 : 9 0 ;梯度為7分鐘内自0至1 0 0 % Β,然後維持1 0 0 % Β 2分鐘,隨後再度平衡。總L C時間為1 2分鐘。注入容 積為1 0微升。紫外光偵測係於2 1 5奈米至4 0 0奈米進行。 離子係於下述條件下產生:E S I喷灑器電壓4 . 0千伏特 ,加熱毛細溫度2 5 5 °C ,鞘套氣態氮壓力5. 0巴。全掃描 偵測模式(5 0至1 0 0 0 a m u )用於最密集離子之M S / M S分析 (規度化碰接能:3 5 % )。 紫外光偵測:2 1 5 - 4 0 0奈米。 HPLC/MS 方法 4 使用之Η P L C系統(A 1 1 i a n c e 2 7 9 0,有熱穩自動取樣機 及分歧閥L a b P r 〇,紫外光偵測器2 4 8 7及s a t i η界面,Z Q 質譜儀具有Ε S I界面)為W a t e r s公司(美國,麻省,密德弗) 產品。化學發光氮偵測器(C L N D ) m 〇 d . 8 0 6 0為A N T E K儀器 公司(美國德州,休士頓)產品。液體操縱器M i n i p r e ρ 7 5 為Tecan集團公司(瑞士,Maennedorf公司)產品。 使用之層析術條件如後:流速設定於1毫升/分鐘。採 用二動相(動相A : 0 . 1 °/〇曱酸,動相B : 0 . 1 %甲酸於曱醇) 以5 % B至9 5 % B之線性梯度於1 0分鐘操作,維持2分鐘, 接著再度平衡於5 % B又經3分鐘。操作時間1 5分鐘。注 107 3丨2/發明說明書(補件)/93-03/92丨35527 1327470 入容積1 0微升,自動取樣器溫度2 5 °C ,偵測波長2 2 0奈 米。 如 下 表 V I報告, 製備若干其它 式(I a)及(I b )化合物, 各 白 係 經 由 前 述 A - M- Β編碼系統識別,進一步根據前文報 告 之 實 驗 條 件 透過 Η P L C /質譜特徵 化。 表 V I 化 合 物 HPLC 方法 r _ t ·(分鐘) [Μ + Η Γ 108 312/發明說明書(補件)/93-03/92135527 1327470 A01M1B09 3 4.60 386.0 A01M1B10 3 3.52 388.0 A01M1B11 1 5.55 400.5 A01M1B16 1 2.82 415.5 A01M1B18 1 3.06 455.5 A01M1B23 3 2.71 406.0 A01M1B24 3 5.05 434.0 A01M1B25 3 . 3.10 376.0 A01M1B26 3 2.80 362.1 A01M1B29 1 4.00 431.5 A01M1B30 1 3.39 402.4 A01M1B31 1 2.60 431.5 A01M1B32 3 6.07 430.0 A01M1B33 3 3.67 416.0 A01M1B35 1 3.66 402.4 A01M1B36 1 2.70 401.5 A01M1B37 1 4.75 404.4 A01M1B38 1 2.76 401.5 A01M1B40 1 2.74 475.5 A01M1B41 3 4.75 510.1 A01M1B42 1 3.79 480.5 A01M1B46 3 2.68 419.0 A01M1B49 3 3.87 360.0 A02M1B11 2 2.35 400.5 A02M1B16 2 1.09 415.5 A02M1B18 2 1.16 455.5 A02M1B29 2 1.64 431.5 A02M1B30 2 1.36 402.4 A02M1B31 2 0.96 431.5 A02M1B35 2 1.48 402.4 A02M1B36 2 1.01 401.5 A02M1B37 2 1.96 404.4 A02M1B38 2 1.03 401.5 A02M1B40 2 1.01 475.5 A02M1B42 2 1.59 480.5 A04M1B09 1 5.02 404.4 A04M1B10 1 3.77 406.4 A04M1B11 1 5.57 418.5 A04M1B25 1 3.25 394.4 A04M1B27 1 4.72 392.4 A04M1B28 1 3.68 364.4 A04M1B30 1 3.34 420.4 A04M1B33 1 3.88 434.5 109 3丨2/發明說明書(補件)/93-03/92 ] 35527 1327470 A04M1B34 1 3.40 447.5 A04M1B41 1 5.25 528.5 A04M1B49 1 4.18 378.4 A05M1B11 1 6.03 418.5 A05M1B18 1 3.08 473.5 A05M1B29 1 4.30 449.5 A05M1B30 1 0.72 420.4 A05M1B31 1 2.66 449.5 A05M1B35 1 4.00 420.4 A05M1B36 1 2.83 419.4 A05M1B37 1 5.17 422.4 A05M1B38 1 2.79 419.4 A05M1B40 1 2.82 493.5 A05M1B42 1 4.07 498.5 A06M1B11 1 6.09 416.9 A06M1B16 1 3.17 431.9 A06M1B18 1 3.39 472.0 A06M1B29 1 4.42 447.9 A06M1B31 1 2.99 447.9 A06M1B36 1 3.04 417.9 A06M1B39 1 3.15 447.0 A06M1B40 1 3.08 492.0 A06M1B42 1 4.17 497.0 A07M1B11 2 3.07 450.5 A07M1B16 2 1.78 465.5 A07M1B18 2 1.86 505.6 A07M1B29 2 2.36 481.5 A07M1B30 2 2.11 452.4 A07M1B31 2 1.69 481.5 A07M1B35 2 2.24 452.4 A07M1B36 2 1.72 451.5 A07M1B37 2 2.73 454.4 A07M1B38 2 1.71 451.5 A07M1B40 2 1.73 525.5 A07M1B42 2 2.25 530.5 A10M1B11 1 3.83 388.5 A10M1B16 1 2.56 403.5 A10M1B18 1 2.58 443.6 A10M1B29 1 3.76 419.5 A10M1B30 1 3.13 390.5 A10M1B31 1 2.24 419.5 A10M1B37 1 4.45 392.5 A10M1B38 1 2.35 389.5 110 312/發明說明書(補件)/93-03/92135527 1327470 A10M1B40 1 2.34 463.6 A10M1B42 1 3.54 468.6 A12M1B09 1 4.43 348.5 A12M1B10 1 3.18 350.4 A12M1B25 1 2.71 338.4 A12M1B28 1 3.08 308.4 A12M1B31 1 1.89 393.5 A12M1B33 1 3.40 378.5 A12M1B41 1 4.80 472.6 A12M1B49 1 3.56 322.4 A13M1B09 1 4.24 346.4 A13M1B10 1 2.98 348.4 A13M1B11 1 4.82 360.5 A13M1B25 1 2.52 336.4 A13M1B28 1 2.86 306.4 A13M1B30 1 2.66 362.4 A13M1B31 1 1.86 391.5 A13M1B33 1 3.22 376.5 A13M1B41 1 4.67 470.6 A13M1B49 1 3.37 • 320.4 ! A14M1B09 1 3.80 332.4 A14M1B10 1 2.57 334.4 A14M1B11 4 8.32 346.2 A14M1B30 1 2.28 348.4 A14M1B31 1 1.39 377.5 A14M1B33 1 2.87 362.4 A14M1B34 1 2.41 375.4 A14M1B35 1 2.52 348.4 A14M1B41 1 4.30 456.5 A14M1B49 1 2.94 306.4 A16M1B09 1 5.93 452.4 A16M1B10 1 4.78 454.4 A16M1B11 1 6.43 466.5 A16M1B25 1 4.27 442.4 A16M1B28 1 4.73 412.4 A16M1B30 1 4.32 468.4 A16M1B31 1 3.37 497.5 A16M1B32 1 5.20 496.5 ,A16M1B33 1 4.82 482.5 A16M1B34 1 4.34 495.5 A16M1B35 1 4.60 468.4 A16M1B49 1 5.15 426.4 A17M1B11 2 3.37 474.6 312/發明說明書(補件)/93-03/9213 5527 1327470 A17M1B16 2 2.29 489.6 A17M1B18 2 2.33 529.7 A17M1B29 2 2.60 505.6 A17M1B30 2 2.39 476.5 A17M1B31 2 2.08 505.6 A17M1B35 2 2.53 476.5 A17M1B36 2 2.08 475.6 A17M1B37 2 3.01 478.5 A21M1B09 1 4.92 434.5 A21M1B10 1 3.78 436.5 A21M1B25 1 3.33 424.5 A21M1B28 1 3.71 394.4 A21M1B31 1 2.66 479.6 A21M1B33 1 3.90 464.5 A21M1B49 1 4.13 408.5 A22M1B09 1 5.54 418.5 A22M1B10 1 4.65 420.5 A22M1B11 1 6.05 432.5 A22M1B25 1 3.81 408.5 A22M1B27 1 5.27 .406.5 A22M1B28 1 4.33 378.4 A22M1B30 1 3.86 434.5 A22M1B31 1 2.92 463.6 A22M1B32 1 4.81 462.6 A22M1B33 1 4.40 448.5 A22M1B34 1 3.90 461.5 A22M1B35 1 4.46 434.5 A22M1B41 1 4.11 542.6 A22M1B49 1 4.77 392.5 A23M1B09 1 5.91 418.5 A23M1B10 1 4.67 420.5 A23M1B11 1 6.45 432.5 A23M1B25 1 4.16 408.5 A23M1B27 1 5.56 406.5 A23M1B28 1 4.62 378.4 A23M1B30 1 4.20 434.5 A23M1B31 1 3.21 463.6 A23M1B32 1 5.13 462.6 A23M1B33 1 4.72 448.5 A23M1B34 1 4.24 461.5 A23M1B35 1 4.49 434.5 A23M1B41 1 5.98 542.6 A23M1B49 1 5.05 392.5 112 312/發明說明書(補件)/93-03/92135527 1327470 A24M1B09 1 5.02 411.5 A24M1B10 1 3.91 413.5 A24M1B28 1 3.87 371.5 A24M1B31 1 2.73 456.6 A24M1B33 1 4.05 441.5 A24M1B49 1 4.28 385.5 A25M1B09 1 4.65 397.5 A25M1B10 1 3.53 399.5 A25M1B25 1 3.13 387.5 A25M1B28 1 3.48 357.4 A25M1B30 1 3.20 413.5 A25M1B31 1 2.26 442.5 A25M1B33 1 3.47 427.5 A25M1B41 1 4.94 521.6 A25M1B49 1 3.91 371.5 A26M1B09 1 3.87 349.4 A26M1B10 1 2.72 351.4 A26M1B28 1 2.62 309.4 A26M1B33 1 3.00 379.5 A26M1349 1 3.06 323.4 A27M1B09 1 5.34 401.5 A27M1B10 1 4.13 403.4 A27M1B25 1 3.65 391.4 A27M1B31 1 2.85 446.5 A27M1B33 1 4.22 431.5 A27M1B49 1 4.52 375.4 A30M1B09 1 4.78 368.5 A30M1B10 1 3.53 370.4 A30M1B11 1 5.33 382.5 A30M1B25 1 3.04 358.4 A30M1B27 1 4.45 356.4 A30M1B28 1 3.43 328.4 A30M1B30 1 3.13 384.4 A30M1B31 1 2.27 413.5 A30M1B33 1 3.69 398.5 A30M1B34 1 3.21 411.5 A30M1B35 1 3.38 384.4 A30M1B41 1 5.06 492.6 A30M1B49 1 3.91 342.4 A48M1B09 3 5.30 432.1 A48M1B10 3 4.18 434.1 A48M1B23 3 3.38 452.1 A48M1B24 3 3.78 480.1 113 312/發明說明書(補件)/93-03/92〗35527 1327470 A48M1B25 3 3.83 422.1 A48M1B26 3 3.48 408.2 A48M1B30 3 4.00 448.2 A48M1B31 3 3.22 477.1 A48M1B32 3 4.28 476.3 A48M1B33 3 4.23 462.1 A48M1B40 3 3.33 521.3 A48M1B41 3 4.72 556.2 A48M1B46 3 3.43 465.1 A48M1B49 3 4.77 406.1 A53M1B09 1 3.10 417.5 A53M1B28 1 2.02 377.5 A53M1B49 1 2.37 391.5 A54M1B09 1 5.87 436.4 • A54M1B10 1 4.65 438.4 A54M1B11 4 9.71 450.1 A54M1B25 1 4.14 426.4 A54M1B28 .1 4.60 396.4 A54M1B31 1 3.22 481.5 • A54M1B33 1 4.70 466.5 A54M1B34 1 4.20 479.5 A54M1B35 1 4.46 452.4 A54M1B41 1 5.93 560.6 A54M1B49 1 5.05 410.4 A01M2B11 2 2.75 398.5 A01M2B16 2 1.40 413.5 A01M2B18 2 1.50 453.5 A01M2B29 2 2.08 429.5 A01M2B30 2 1.71 400.4 A01M2B31 2 1.27 429.5 A01M2B35 2 1.84 400.4 A01M2B36 2 1.31 399.2 A01M2B37 2 2.33 402.4 A01M2B38 2 1.34 399.4 A01M2B40 2 1.34 473.5 A01M2B42 2 1.93 478.5 A06M2B09 1 5.52 400.9 A06M2B11 1 6.04 414.9 A06M2B16 1 2.95 429.9 A06M2B18 1 3.16 470.0 A06M2B29 1 4.57 445.9 A06M2B30 1 3.82 416.9 A06M2B31 1 2.90 445.9 114 312/發明說明書(補件)/93-03/92丨35527 1327470 A06M2B35 1 4.08 416.9 A06M2B36 1 2.94 415.9 A06M2B37 1 5.20 418.9 A06M2B38 1 3.00 415.9 A06M2B40 1 3.03 490.0 A07M2B11 2 3.10 448.5 A07M2B16 2 1.80 463.5 A07M2B18 2 1.90 503.5 A07M2B29 2 2.46 479.5 A07M2B30 2 2.13 450.4 A07M2B31 2 1.71 479.5 A07M2B35 2 2.26 450.4 A07M2B36 2 1.74 449.4 A07M2B37 2 2.75 452.4 A07M2B38 2 1.78 449.4 A07M2B40 2 1.76 523.5 A07M2B42 2 2.29 528.5 A17M2B16 2 2.10 487.6 A17M2B18 2 2.17 527.6 A17M2B2S 2 2.73 503.6 A17M2B30 2 2.40 474.5 A17M2B31 2 2.01 503.6 A17M2B35 2 2.55 474.5 A17M2B36 2 2.03 473.5 A17M2B37 2 3.05 476.5 A17M2B38 2 2.07 473.5 A17M2B40 2 2.04 547.6 A17M2B42 2 2.55 552.6 115 3丨2/發明說明書(補件)/93-03/92135527
Claims (1)
1327470 公告本 拾、申 1 · 一種 1年么月4日修(更)正本 請專利範圍: 式(I a )化合物 FHB 2 4 2Θ10 r 皆擬务
N 3 其中 r 為-cor C 3 - C 6 環 擇性經取 R 1為式(I 人 (la) O’ R, 基團,其中Ra為氫或選自直鏈或分支〇-(:6烷基、 ,基、芳基、芳基烷基、雜環基或雜環基烷基之選 代之基團; la)基團: -CT (Ha) 示一個5員至7員雜環系環,其中直接鍵聯至分 分之X表示碳原子或氮原子;Y為碳原子、氮原 ί1或硫原子或為NH基,但X及Y中之至少一者非 ;Re於式(I I a )雜環系環自由位置之任一位置, 為選自直鍵或分支Cl-C6烧基、C3-C6環院基、芳 烷基、雜環基、雜環基烷基、胺基、胺基羰基、 基( = 0)、烷氧羰基、烷基羰基或芳基羰基之選擇 之基團;以及η為0或1至4之整數; Re係選擇性地於其一或多個自由位置進一步經 自下列基團組成之群組之基團取代:鹵原子、硝
其中環表 子其餘部 子、氧原-為碳原子 各自分別 基、芳基 羧基、酮 性經取代 其中Ra及 由分別選
92135527 116 1327470 基、嗣基( = 〇)、氛基、燒基、多氟化烧基、多氟化烧氧基、 烯基、炔基、羥基烷基、芳基、芳基烷基、雜環基、環烷 基、羥基、烷氧基、芳氧基、雜環基氧基、亞甲基二氧基、 烷基羰基氧基、芳基羰基氧基、環烯基氧基、亞烷基胺基 氧基、羧基、烷氧羰基、芳氧羰基、環烷氧羰基、胺基、 腺基、炫基胺基、二烧基胺基、芳基胺基、二芳基胺基、 甲醯胺基、烷基羰基胺基、芳基羰基胺基、雜環羰基胺基、 烷氧羰基胺基、烷氧基亞胺基、烷基磺醯胺基、芳基磺醯 胺基、曱醯基、烷基羰基、芳基羰基、環烷基羰基、雜環 基羰基、胺基羰基、烷基胺基羰基、二烷基胺基羰基、烷 基磺醯基、芳基磺醯基、胺基磺醯基、烷基胺基磺醯基、 二烷基胺基磺醯基、芳硫基及烷硫基; 或其醫藥上可接受之鹽。 2 .如申請專利範圍第1項之式(I a )化合物,其中,R ^為 式(I la)基團選自:
其中,R、n及1?£定義如申請專利範圍第1項。 3.如申請專利範圍第1項之式(la)化合物,其中,1為 式(I la)基團選自:
117 92135527 1327470 其中,R、η及Re定義如申請專利範圍第1項。 4. 一種化合物,選擇性地呈醫藥上可接受之鹽形式,該 化合物係選自由下列化合物組成之群組: Ν-{6,6-二曱基- 5- K2R)-四氫呋喃-2-基羰基]-l,4,5,6-四氫°比洛[3,4-c]°比°坐-3-基}-4-氟苄酿胺, Ν-{6,6-二曱基- 5- K2S)-四氫呋喃-2-基羰基]-1,4,5,6-四氫°比洛[3,4-c]0比0坐-3-基}-4 -氟苄酿胺, N-{6, 6-二甲基-5-[(l-甲基哌啶-4 -基)羰基]-2, 4, 5, 6 -四 氫吡咯[3, 4-c]吡唑-3-基}-環丁烷苄醯胺; N-{6,6-二甲基- 5- [(l-甲基哌啶-4 -基)羰基]-2,4,5,6-四· 氫吡咯[3,4-c]吡唑-3-基}-4-氟苄醯胺, 卜{6,6-二曱基-5-[(4-曱基哌畊-1-基)羰基]-2,4,5,6-四 氫0比洛[3, 4-〇]°比〇坐-3-基}-4-氟苄酿胺, 3-曱基1-[1,4,5,6-四氫-6,6-二甲基-5-[(1-甲基-4-哌 啶基)羰基]吡咯[3, 4-c]吡唑-3-基]-丁醯胺,及 4_氯- N- [6,6-二曱基- 5- (4-0比洛咬-1_基-甲基-π底咬-1_幾 基)-1,4,5,6 -四氫η比嘻[3,4-(:]11比°坐-3_基]_节酿胺; 或其醫藥上可接受之鹽。 5. —種醫藥組成物,包含治療有效量之如申請專利範圍 第1項定義之化合物或其醫藥上可接受之鹽,以及至少一 種醫藥上可接受之賦形劑、載劑及/或稀釋劑。 118 92135527
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TW092135527A TWI327470B (en) | 2002-12-19 | 2003-12-16 | Substituted pyrrolo-pyrazole derivatives as kinase inhibitors |
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US (5) | US7407971B2 (zh) |
EP (2) | EP2266987B1 (zh) |
JP (2) | JP4739761B2 (zh) |
KR (2) | KR20120038465A (zh) |
CN (1) | CN1726217B (zh) |
AP (1) | AP2005003343A0 (zh) |
AR (1) | AR042525A1 (zh) |
AU (1) | AU2003300255B9 (zh) |
BR (1) | BR0317455A (zh) |
CA (1) | CA2508069C (zh) |
CR (2) | CR7880A (zh) |
CU (1) | CU23550B7 (zh) |
EA (1) | EA010596B1 (zh) |
EC (1) | ECSP055864A (zh) |
ES (2) | ES2605848T3 (zh) |
GE (1) | GEP20084435B (zh) |
HK (1) | HK1086256A1 (zh) |
HR (1) | HRP20050562A2 (zh) |
IL (2) | IL169019A (zh) |
IS (1) | IS7857A (zh) |
MA (1) | MA27569A1 (zh) |
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MX (1) | MXPA05006791A (zh) |
MY (1) | MY141196A (zh) |
NO (1) | NO333178B1 (zh) |
NZ (1) | NZ540644A (zh) |
OA (1) | OA13015A (zh) |
PL (1) | PL377285A1 (zh) |
RS (1) | RS20050462A (zh) |
TN (1) | TNSN05163A1 (zh) |
TW (1) | TWI327470B (zh) |
UA (1) | UA81790C2 (zh) |
WO (1) | WO2004056827A2 (zh) |
ZA (1) | ZA200504298B (zh) |
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AU2014337122B2 (en) | 2013-10-18 | 2019-01-03 | Dana-Farber Cancer Institute, Inc. | Heteroaromatic compounds useful for the treatment of proliferative diseases |
US9862688B2 (en) | 2014-04-23 | 2018-01-09 | Dana-Farber Cancer Institute, Inc. | Hydrophobically tagged janus kinase inhibitors and uses thereof |
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AU2015263884B2 (en) * | 2014-05-23 | 2019-11-14 | Mingsight Pharmaceuticals, Inc. | Treatment of autoimmune disease |
KR102575327B1 (ko) * | 2014-10-31 | 2023-09-07 | 유비이 가부시키가이샤 | 치환 디히드로피롤로피라졸 화합물 |
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JP6861166B2 (ja) | 2015-03-27 | 2021-04-21 | ダナ−ファーバー キャンサー インスティテュート, インコーポレイテッド | サイクリン依存性キナーゼの阻害剤 |
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JP2019112306A (ja) * | 2016-04-28 | 2019-07-11 | 宇部興産株式会社 | 慢性閉塞性肺疾患の治療または予防のための医薬組成物 |
JP2019112305A (ja) * | 2016-04-28 | 2019-07-11 | 宇部興産株式会社 | アトピー性皮膚炎の治療または予防のための医薬組成物 |
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