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TWI376367B - An amine derivative as a npy y5 receptor antagonist - Google Patents

An amine derivative as a npy y5 receptor antagonist Download PDF

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Publication number
TWI376367B
TWI376367B TW096114901A TW96114901A TWI376367B TW I376367 B TWI376367 B TW I376367B TW 096114901 A TW096114901 A TW 096114901A TW 96114901 A TW96114901 A TW 96114901A TW I376367 B TWI376367 B TW I376367B
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Taiwan
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substituent
compound
nmr
dmso
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TW096114901A
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TW200811091A (en
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Takayuki Okuno
Naoki Kouyama
Masahiro Sakagami
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Shionogi & Co
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    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/03—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C311/05—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms to acyclic carbon atoms of hydrocarbon radicals substituted by nitrogen atoms, not being part of nitro or nitroso groups
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    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
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    • C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
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Description

1376367 九、發明說明： 【發明所屬之技術領域】 本發明爲有關具有ΝΡΥ Y5受體拮抗作用而作爲醫藥， 尤其抗肥胖藥有用之新穎化合物。 【先前技術】 神經胜肽Y(以下稱NPY)爲由36個胺基酸殘基而成之胜 肽，於1982年由猪腦分離。ΝΡΥ於人及動物之中樞神經 系及末梢組織廣泛分布。
於以往之報告，得知ΝΡΥ於中樞神經系中具有攝食促進 作用、抗痙攣作用、學習促進作用、抗焦慮作用、抗壓力 作用等，更有與憂鬱病、阿滋海黙型痴呆、巴金森病等中 樞神經系疾病深深關連之可能性。又於末梢組織中，ΝΡΥ 因引起血管等平滑肌或心肌之收縮，故認爲與循環器系障 礙也有關連。更知與肥胖症、糖尿病、激素異常等代謝性 疾病也有關連（參照非專利文獻1)。故ΝΡΥ受體拮抗劑對 如上述ΝΡΥ受體關連之種種疾病有成爲預防或治療藥之可 能性。 ΝΡΥ受體至今發現Υ1、Υ2、Υ3、Υ4、Υ5及Υ6之亞型（ 參照非專利文獻2)。Υ5受體至少與攝食機能關連，其拮 抗劑暗示成爲抗肥胖藥（參照非專利文獻3)。 與本發明化合物類似之構造而具有ΝΡΥ Υ5受體拮抗作 用之具有磺醯基之胺衍生物記載於專利文獻1、專利文獻 2 '專利文獻3、專利文獻4等。此外，於專利文獻5、專 利文獻8、專利文獻9、專利文獻1 〇及專利文獻1 1記載 1376367 【專利文獻13】美國專利申請公開第2007/060598 冊 【專利文獻14】國際公開第2005/1 2 1 1 07號小冊 【發明內容】 發明欲解泱夕課題 本發明之目的爲提供具有優異NPY Y5受體拮抗作 新穎化合物。令專利文獻1、2記載之化合物試驗之 ，確認藥物代謝酵素之強力誘導》試驗專利文獻10 之一部分化合物之結果，有貧血誘發作用等毒性。 解決課顆：> 丰跺 本發明者致力硏究之結果，成功合成如下具有優異 Y5受體拮抗作用之新穎化合物。具有磺醯基之醯胺 物於專利文獻5公知爲具有NPY Y5受體拮抗作用之 物。但本發明者令醯胺衍生物作成胺衍生物之化合物 現與取代前之化合物相較其腦移行性大爲改善。又確 發明之化合物與專利文獻1、2之化合物相較，爲不 起藥物代謝酵素之誘導之化合物，終於完成本發明。 也即本發明爲有關： (1)如下式（I)化合物、其製藥容許鹽或這些之溶劑合物 【化1】 R1—Y—N-X-N—Z (I) I / R2 R7 [式中R1爲可有取代基之低烷基， Y 爲-s(0)n-(n 爲 1 或 2)或-CO-， 號小
用之 結果 記載 NP Y 衍生 化合 ，發 認本 易引 1376367 R2爲氫或可有取代基之低烷基， R1及R2可一起形成低伸烷基， R7爲氫或可有取代基之低烷基， X爲 可有取代基之低伸烷基， 可有取代基之低伸烯基， 可有取代基之-C0-低伸烷基， 可有取代基之- C0-低伸烯基或 【化2】
(CR3R4)p— (式中R3、R4、R5及R6各自獨立爲氫或可有取代基之低烷 基， 【化3】
爲可有取代基之環伸烷基、可有取代基之環伸烯基、可有 取代基之雙環伸烷基、可有取代基之伸芳基或可有取代基 之雜環二基’P及q各自獨立爲〇〜2之整數，p及q之任 一方不爲〇， 但 【化4】
不爲 -9- 1376367
[式中R14爲可有取代基之苯基])， -nr2-x-爲 【化6】
(式中 【化
-N
可爲哌啶二基、哌畊二基、吡啶二基、吡阱 二基或吡咯二基，U爲低伸烷基或低伸烯基） Z爲可有取代基之低烷基 '可有取代基之低 代基之胺基、可有取代基之低烷氧基、可有 式基、可有取代基之雜環式基， (但Z不爲3環之稠合雜環式基、可有取代 可有取代基之喹唑啉基）] (但X爲 【化8】 一 (CR3R4)p—(CR5R6)q— 【化9】 -0- 爲可有取代基之環伸烷基，q爲1，q爲0, 二基、吡咯啶 > 嫌基、可有取 取代基之烴環 基之噻唑基或 且Z爲可有取 -10- 1376367 【化1 7】 R1—Y—Ν-Χ-Ν—Ζ (I) R2 R7 [式中R1爲可有取代基之低烷基， Υ 爲-S(0)2-， R2爲氫或可有取代基之低烷基， R7爲氫或可有取代基之低烷基， X爲
【化1 8】 —(CR3R4)p—(^}—(CR5R6)q- (式中R3及R4各自獨立爲氫， 【化1 9】 -0- 爲可有取代基之環伸烷基，P爲1或2，q爲0, 但
【化20】 "Θ' 不爲 【化2 1】
[式中R14爲可有取代基之苯基])， Z爲可有取代基之烴環式基或可有取代基之雜環式基] (但Z爲3環之稠合雜環式基、可有取代基之噻唑基或可 -14- 1376367 有取代基之喹唑啉基之化合物除外）， (16) Z爲可有取代基之苯基、可有取代基之吡啶基、可有 取代基之嗒阱基、可有取代基之吡阱基、可有取代基之嘧 啶基、可有取代基之喹啉基、可有取代基之異喹啉基、可 有取代基之苯并噻唑基、可有取代基之苯并咪唑基、可有 取代基之苯并噚唑基、可有取代基之噻唑并吡啶基或可有 取代基之噚唑并吡啶基之（15)記載之化合物、其製藥容許 鹽或這些之溶劑合物，
(17) 如下式（I)化合物、其鹽或這些之溶劑合物， 【化22】 R1—Y—N-X-N—Z (I) I / R2 R7 [式中R1爲可有取代基之低烷基， Y 爲-S(0)2_， R2爲氫或可有取代基之低烷基， R7爲氫或可有取代基之低烷基，
X爲 【化23】 —(CR3R4)p—(CR5R6)q- (式中R3及R4各自獨立爲氫， 【化24】 -0- 爲可有取代基之環伸烷基，P爲1或2，q爲0)， Z爲可有取代基之苯基、可有取代基之吡啶基 '可有％# -15- 1376367 基之嗒阱基、可有取代基之吡畊基、可有取代基之嘧啶基 、可有取代基之喹啉基、可有取代基之異喹啉基、可有取 代基之苯并噻唑基、可有取代基之苯并咪唑基、可有取代 基之苯并噚唑基、可有取代基之噻唑并吡啶基或可有取代 基之噚唑并吡啶基]， (18) 如（1)〜（17)中任一項之化合物、其製藥容許鹽或這 些之溶劑合物爲有效成分之醫藥組成物，
(19) 如（1)〜（I7)中任一項之化合物、其製藥容許鹽或這 些之溶劑合物爲有效成分之NPY Y5受體拮抗劑， (2 0)如下式化合物、其鹽或這些之溶劑合物， 【化25】 V^^T)-NH2 U2 (式中R1爲乙基或第三丁基）， (21)如下式化合物、其鹽或這些之溶劑合物，
【化26】 0
ΝΗ 0——tert-Bu (式中R1爲乙基、異丙基或第三丁基）， (22)如下式化合物、其鹽或這些之溶劑合物， 1376367 【實施方式】 實施發明之最佳形態 以下說明本說明書中使用之各用語。本說明書中，各用 語於單獨使用之場合，或與其他用語一起使用之場合也爲 同一意義。 「鹵素」爲氟、氯、溴及碘。尤以氟及氯較佳。
「可被保護之羥基」、「可被保護之羥低烷基」之保護 基包含所有通常使用之羥基保護基。例如醢基（乙醯基、 三氯乙醯基、苄醯基等）、低烷氧羰基（第三丁氧羰基等）、 低烷磺醯基（甲磺醯基等）、低烷氧基低烷基（甲氧甲基等） 、三烷基矽烷基（第三丁基二甲基矽烷基等）等。
「低烷基」包含碳數1〜10之直鏈或分枝狀之烷基，例 如甲基、乙基、正丙基、異丙基、正丁基、異丁基、第二 丁基、第三丁基、正戊基、異戊基、新戊基、己基、異己 基、正庚基、異庚基、正辛基、異辛基、正壬基及正癸基 等。 R1中「低烷基」宜碳數2〜10，尤宜碳數2〜6,最好爲 乙基、異丙基或第三丁基。 其他場合中「低烷基」宜碳數1〜6,尤宜碳數1〜4。 Z中「可有取代基之低烷基」之取代基可爲例如（1)鹵素 ;(2)氰基；（3)可有由各如下定義之取代基群β選擇之1 以上取代可能之基取代之（i)羥基、（Π)低烷氧基、（iii)氫 硫基、（iv)低院硫基、（v)醯基、（vi)醯氧基、（vii)羧基、 -18- 1376367 (νίΠ)低烷氧羰基、（ix)亞胺基、（x)胺甲醯基、（xi)硫胺甲 醯基、（xii)低烷胺甲醯基' (xiii)低烷硫胺甲醯基、（xiv) 胺基、（xv)低烷胺基或（xvi)雜環羰基；或 (4)如下式基： 【化2 9】 —W—(CR10R11)s -(J) (式中R1C)及R11各自獨立爲氫或低烷基，若有2以上之 R1()及/或R11存在時，各Rl()及R11可相異，
W爲單鍵、〇、S或NR12， R12爲氫、低烷基或苯基， 【化30】 爲各如下定義之取代基群α選擇之1以上取代可能之基取 代之環烷基、雙環烷基、環烯基、芳基或雜環式基， s爲0〜4之整數）等。
於此取代基群α爲（1)鹵素；（2)氧基；（3)氰基；（4)硝基 ;(5)可有低烷基或羥基取代之亞胺基； (6)各可有由取代基群β選擇之1以上取代可能之基取代之 (i)羥基、（ii)低烷基、（iii)低烯基、（iv)低烷氧基、（ν)羧基 、（vi)低烷氧羰基、（vii)醯基、（viii)醯氧基、（ix)亞胺基 、（X)氫硫基、（xi)低烷硫基、（xii)胺甲醯基、（xiii)低烷胺 甲醯基、（xiv)環烷胺甲醯基、（xv)硫胺甲醯基、（xvi)低烷 硫胺甲醯基、（xvii)低烷亞磺醯基、（xviii)低烷磺醯基、 (xix)胺磺醯基、（XX)低烷胺磺醯基及（xxi)環烷胺磺醯基； -19- 1376367 (7) 各可有取代基群β、低烷基、低烷氧基低烷基、可被保 護之羥低烷基、鹵低烷基、低烷磺醯基及/或芳磺醯取代之 ⑴環烷基、（ii)環烯基、（iii)環烷氧基、（iv)胺基及（V)伸烷 二氧基：及
(8) 各可有取代基群β、低烷基、鹵低烷基及/或氧基取代之 (i)苯基、（ii)萘基、（iii)苯氧基、（iv)苯低烷氧基、（ν)苯硫 基、（vi)苯低烷硫基、（vii)苯偶氮基、（viii)雜環式基、 (ix)雜環氧基、（X)雜環硫基、（xi)雜環羰基及（xii)雜環磺 醯而成群。 作爲B環中取代基之取代基群α之適例爲鹵素；硝基； 羥基； 可有取代基之低烷基（於此取代基爲鹵素、氰基、苯基、 羧基及/或低烷氧羰基）； 低烯基：低烷氧羰低烯基： 可有取代基之低烷氧基（於此取代基爲鹵素、羥基、低烷 氧基、羧基、低烷氧羰基、低烷胺基及/或氰基）；
醯基；羥亞胺基；低烷硫基；低烷亞磺醯基；胺磺醯基； 可有取代基之胺基（於此取代基爲低烷基、可被保護之羥 低烷基、苯基及/或醯基）； 伸烷二氧基；氰苯基；雜環取代苯基；聯苯基；苯氧基； 可有低烷基取代之苯偶氮基； 可有取代基之雜環式基（於此取代基爲可被保護之羥基； 氫硫基；鹵素；低烷基：環烷基；低烷氧羰基；胺基；低 烷氧羰胺基：胺甲醯基：氧基：苯基：低烷氧苯基；或雜 -20· 1376367 環式基）、尤宜鹵素；可有鹵素取代之低烷基：可有鹵素 取代之低烷氧基。 取代基群β爲鹵素、可被保護之羥基、氫硫基、低烷氧 基、低烯基、胺基、低烷胺基、低烷氧羰胺基、低烷硫基 、醯基、羧基、低烷氧羰基、胺甲醯基、氰基、環烷基、 苯基、苯氧基、低烷苯基、低烷氧苯基、鹵苯基、萘基及 雜環式基而成群。
Ζ以外中「可有取代基之低烷基」（例如於R1中場合等） 之取代基可爲由取代基群β選擇之1以上之基而任意之位 置可有這些取代基取代。 「低烷氧基」、「低烷氧羰基」、「低烷氧羰低烷基」
、「低烷苯基」、「低烷氧苯基」、「低烷胺甲醯基」、 「低烷硫胺甲醯基」、「低烷胺基」、「鹵低烷基」、「 羥低烷基」、「苯低烷氧基」、「低烷硫基」、「苯低烷 硫基」、「低烷氧羰胺基」、「低烷氧羰低烯基」、「低 烷亞磺醯基」、「低烷磺醯基」、「芳低烷氧羰基」、「 低烷苄醯基」及「低烷氧苄醯基」之低烷基部分與上述「 低烷基」同樣》 「可有取代基之低烷氧基」之取代基爲由取代基群Ρ選 擇之1以上之基，宜苯基、低烷苯基、低烷氧苯基、萘基 或雜環式基。 「環烷基」包含碳數3〜8、宜5或6之環狀之烷基。具 體而言，爲環丙基、環丁基、環戊基、環己基、環庚基及 環辛基等》 -21 - 1376367 「可有取代基之環烷基」之取代基爲由取代基群α選擇 之1以上之基等而可於任意之位置取代。 「雙環烷基」包含由2環共有2個或其以上之原子之碳 數5〜8之脂肪族環去除1個氫之基。具體而言，爲雙環 [2.1_0]戊基、雙環[2_2.1]庚基、雙環[2·2.2]辛基及雙環 [3.2.1]辛基等。
「低稀基」爲於任意位置有1以上雙鍵之碳數2〜10， 宜碳數2〜8’尤宜碳數3〜6之直鏈或分枝狀之烯基。具 體而言’包含乙烯基、丙烯基、異丙烯基、丁烯基、異丁 烯基、異戊二烯基、丁二烯基、戊烯基、異戊烯基、戊二 烯基、己烯基、異己烯基、己二烯基、庚烯基、辛烯基、 壬烯基及癸烯基等。 「低烷氧羰低烯基」中「低烯基」部分與上述「低烯基 」同樣。
「可有取代基之低烯基」之取代基可爲鹵素、低烷氧基 、低烯基、胺基、低烷胺基、低烷氧羰胺基、低烷硫基、 醯基、羧基、低烷氧羰基、胺甲醯基、氰基、環烷基、苯 基、低烷苯基、低烷氧苯基、萘基及/或雜環式基等。 「醯基」包含（1)碳數1〜10,尤宜碳數1〜6,最好碳數 1〜4之直鏈或分枝狀之烷羰基或烯羰基，（2)碳數4〜9， 宜碳數4〜7之環烷羰基及（3)碳數7〜11之芳羰基。具體 而言’包含甲醯基、乙醯基、丙醯基、丁醯基、異丁醯基 、戊醯基、特戊醯基、己醯基、丙烯醯基、丙炔醯基、甲 基丙烯醯基、巴豆醯基、環丙羰基、環己羰基、環辛羰基 -22- 1376367 及节酿基等。 F醯氧基」之醯基部分與上述同樣。 「環烯基」包含於上述環烷基之環中任意位置有1以上 之雙鍵者，具體而言，可爲環丙烯基、環丁烯基、環戊烯 基、環己烯基及環己二烯基等。 「可有取代基之環烯基」之取代基爲由取代基群β選擇 之1以上之基。
「可有取代基之胺基」之取代基爲取代基群卩、可有取 代基之苄醯基及/或可有取代基之雜環羰基（於此取代基爲 羥基、低烷基、低烷氧基及/或低烷硫基）。 「芳基」爲單環或多環之芳香族碳環式基，包含苯基、 萘基、蒽基及菲基等》又包含與其他非芳香族烴環式基稠 合之芳基，具體而言，氫茚基、茚基、聯苯基、苊基、四 氫萘基及莽基等。尤以苯基較佳。 「芳低烷氧羰基」之芳基部分也同樣。
Ζ中「可有取代基之芳基」及「可有取代基之苯基」包 含可有取代基群α、由取代基群α選擇之取代可能之1以 上之基取代之低烷基等取代之「芳基」、「苯基」。 Ζ以外之「可有取代基之芳基」及「可有取代基之苯基 」之取代基爲由取代基群Ρ選擇之1以上之基。 「烴環式基」包含上述「環烷基J 、「環烯基」、「雙 環烷基」及「芳基J 。 「非芳香族烴環式基」包含上述「環烷基」、「環烯基 」及「雙環烷基」。 -23 - 1376367 唑啉基、哌啶基、哌阱基、嗎啉基、嗎啉基、硫嗎啉基、 硫嗎啉基、二硫氫吡啶基、四氫呋喃基、四氫吡喃基、四 氫噻唑基、四氫異噻唑基等非芳香族雜環式基。 與雜環以外之環稠合之稠合雜環式基（例如苯并噻唑基等 )爲可於任一環有鍵結。 「可有取代基之雜環式基」及「可有取代基之2環之稠 合雜環式基」之取代基與上述「可有取代基之芳基」同樣
「雜環羰基」、「雜環氧基」、「雜環硫基」及「雜環 取代苯基」之雜環式基部分與上述「雜環式基」同樣。 「低伸烷基」包含亞甲基1〜6個，宜2〜6個，尤宜3 〜6個連續之2價基，具體而言，亞甲基、伸乙基、三亞 甲基、四亞甲基、五亞甲基及六亞甲基等。尤宜四亞甲基 R1及R2 —起形成低伸烷基之場合包含
。宜 【化3 2】
「低伸烷二氧基」之低伸烷基部分與上述「低伸院基」 同樣，宜亞甲基二氧基或伸乙基二氧基》
-25- 1376367 群β選擇之1以上取代可能之基，宜鹵素、羥基、低烷基 、鹵低烷基、低烷氧基、胺基、低烷胺基、醯基、羧基或 低烷氧羰基等。任意之位置可有這些基取代。 -NR2-X-爲 【化3 3】
之場合，宜U爲亞甲基、伸乙基，尤宜 【化34】
H2
本發明化合物包含各化合物之生成可能之製藥容許鹽。
「其製藥容許鹽」可爲例如鹽酸、硫酸、硝酸或磷酸等無 機酸之鹽；對甲苯磺酸、甲磺酸、草酸或檸檬酸等有機酸 之鹽；銨、三甲胺或三乙胺等有機鹼之鹽；鈉或鉀等鹼金 屬之鹽；及鈣或錶等鹼土金屬之鹽等。 本發明化合物包含對化合物（I)之溶劑合物，宜水合物。 本發明化合物1分子可與任意數之水分子配位。 本發明化合物（I)若有不對稱碳原子時，包括消旋體、兩 對掌體及所有立體異構物（幾何異構物、表異構物、鏡像 異構物等）。又本發明化合物⑴若有雙鍵之場合可有E體 及Z體存在時，包括其任一方。又X爲環伸烷基時，包括 順體及反體之任一方。 本發明之化合物（I)可例如依如下方法合成。以下以X爲-
-27- 1376367 CH2-G-或-G-CH2-說明。 [Y = S(0)n之場合] 【化35.】
R ^02^81 2 HN _ ,C02R13 -- 工锃A
;02R13
工锃D R2
^^ο2η 6
(式中Hal爲鹵素，-G-CH2-與式（I)之-X-同義，R13爲低烷 基，其他與前述同義）
工程A 化合物1和具有對應目的化合物之取代基R1之磺醯鹵2 於適當溶劑中，於0 °C〜5 (TC反應數分〜數小時，則得η 爲2之化合物3。溶劑可使用四氫呋喃、二甲基甲醯胺、 乙醚、二氯甲烷、甲苯、苯、二甲苯、環己烷、己烷、氯 仿、乙酸乙酯、乙酸丁酯、戊烷、庚烷、二噚烷、丙酮、 乙腈、水及這些之混合溶劑等。 -28- 1376367
工程B 化合物1和具有取代基R1之亞磺醯鹵4反應，得n=i之 化合物5。反應條件與上述工程A同樣。
工程C
工程B所得化合物5依常法來氧化反應，則得n = 2之化 合物3。氧化劑可用間氯苯甲酸、過乙酸、過氧化氫、過 三氟乙酸、過碘酸鈉 '次亞氯酸鈉、過錳酸鉀等，反應可 於0°C〜50°C施行。溶劑可用四氫呋喃、二甲基甲醯胺、 乙醚、二氯甲烷、甲苯 '苯、二甲苯、環己烷、己烷、氯 仿、乙酸乙酯、乙酸丁酯、戊烷、庚烷、二曙烷、丙酮、 乙腈、水、甲醇、乙醇、異丙醇及這些之混合溶劑等。
工程D
工程A或C所得化合物3於適當溶劑中以鹼處理，得化 合物6。鹼可用氫氧化鈀、氫氧化鈉、氫氧化鉀、肼、丙 烷硫醇鋰鹽等，溶劑可用四氫呋喃、二甲基甲醯胺、二噚 院、丙酮、乙腈、甲醇、乙醇、丙醇、水及這些之混合溶 劑等。可於0°c〜100°c反應數分〜數十小時。
工程E 工程D所得化合物6和具有對應目的化合物之取代基z 及R7之胺基化合物7於適當溶劑中，於〇它〜5〇。(：反應數 分〜數小時而得化合物8。溶劑可用四氫呋喃、二甲基甲 醯胺、乙醚、二氯甲烷、甲苯、苯、二甲苯、環己烷、己 烷、氯仿、乙酸乙酯、乙酸丁酯、戊烷、庚烷、二噚烷、 丙酮、乙腈、水及這些之混合溶劑等，必要時也可用亞磺 -29- 1376367 醯氯、醯鹵、酸酐、活性化酯等活性化劑。
工程F 所得化合物8於適當溶劑中，以適當還原劑處理，得化 合物（Ι-A)。還原劑可用硼氫化鈉、硼氫化鋰、氫化鋰鋁等 、溶劑可用四氫呋喃、二甲基甲醯胺、二噚烷、乙腈、甲 醇、乙醇、丙醇、乙酸及這些之混合溶劑等。可於0-c〜 l〇〇C反應數分〜數十小時。
工程G
工程D所得化合物6於適當溶劑中，以還原劑處理而得 化合物9。還原劑可用硼氫化鈉、硼氫化鋰、氫化鋰鋁、 二硼烷等，溶劑可用四氫呋喃 '二甲基甲醯胺、二噚烷、 乙腈、甲醇 '乙醇 '丙醇及這些之混合溶劑等。可於〇°C 〜1 0 0 °c反應數分〜數十小時，必要時也可經由醯齒、酸 酐、活性化酯等中間體。 工程Η
工程G所得化合物9可依常法氧化反應，則得化合物1 0 。氧化劑可用間氯苯甲酸、過乙酸、過氧化氫、過三氟乙 酸、過碘酸鈉、次亞氯酸鈉、過錳酸鉀、Dess-Martin過 碘酸、二甲亞颯/草醯氯（Swern氧化）、釕觸媒等，反應於-8 0°C〜5 0°C施行。溶劑可用四氫呋喃、二甲基甲醯胺、乙 醚、二氯甲烷、甲苯、苯、二甲苯、環己烷、己烷、氯仿 、乙酸乙酯'乙酸丁酯、戊烷、庚烷、二噚烷、丙酮、乙 腈、水、甲醇、乙醇、異丙醇及這些之混合溶劑等。
工程J
-30- 1376367 所得化合物10與具有對應目的化合物之取代基Z及R7 之胺基化合物7依常法還原地施行胺基化反應，得化合物 (Ι-A)。還原劑可用硼氫化鈉、三乙醯氧基硼氫化鈉、氰基 硼氫化鈉等，反應在〇°C〜50°C施行》溶劑可用四氫呋喃 、二甲基甲醯胺、二噚烷、乙腈、甲醇、乙醇、丙醇、乙 酸、鹽酸及這些之混合溶劑等。 [Y = CO之場合]
【化36】 R2 HN, ^COjR R'-CO-Hal 11
工程K R2 R1. .N^^COsR1
Ύ O
工程D 12 R2 R^N^^COjH ° 13
工程G
RJ
RYN
工程H RVN o
,CHO R7HN-Z 7
工程J 15
R2
R7 (l-B) (式中各符號與前述同義，-G-CHy與式（I)之-X-同義）
工程K
化合物1和具有對應目的化合物之取代基R1之醯鹵11 於適當溶劑，-2(TC〜50 °C反應數分〜數小時而得化合物 12。溶劑可用四氫呋喃、二甲基甲醯胺、乙醚、二氯甲烷 、甲苯、苯、二甲苯、環己烷、己烷、氯仿、乙酸乙酯' 乙酸丁酯、戊烷、庚烷、二噚烷、丙酮、乙腈、水及這些 之混合溶劑等。 工程D、工程〇、工程Η及工程J 所得化合物12依上述工程D、工程G、工程Η及工程j 同樣方法可得本發明之化合物（Ι_Β)。
-31 - 1376367 【化37】 ο
Η
工程L
0 H RO
工裎M 〇
11 ’rq/^g
16 17 i, 工程N I 工程o z 工程p ^ HO’^G’N'R7 N3/^G，N、R7 19
z 21
工程Q 20z R1 人
22
工程R ---► r〆丫、r R2 Z I 、G 、R7 (I-C) (式中各符號與前述同義，-CH2_G-與式⑴之-x-同義，R爲 院基）
工程L
於化合物16導入取代基R7之工程。例如r7Xi(x1爲鹵 素）於鹼之存在下反應，得化合物17。溶劑可用四気咲喃 、二甲基甲酿胺。反應可於室溫施行。鹼可用三乙胺、p比 啶、二甲胺基吡啶等。式（Ι-C)中，R7爲氫之化合物不施行 本工程。 工程Μ 於化合物17導入取代基Ζ之工程。可例如ΖΧ'Χ1爲鹵 素）於鹼之存在下反應，而得化合物18。溶劑可用甲醇、 乙醇' 異丙醇、二甲基甲醯胺等。反應於室溫下或加溫下 -32- 1376367 施行。可例如封管而用微波爐反應裝置施行。鹼可用Ν,Ν· 二異丙基乙胺等。 工程Ν 令化合物18還原而得化合物19之工程。還原劑可用氫 化鋰鋁。溶劑可用四氫呋喃等。反應於室溫施行。 工程〇
令化合物19疊氮化而誘導爲化合物20之工程。例如於 化合物19以三乙胺爲鹼，與甲磺醯氯反應，使化合物19 誘導爲甲磺酸酯。予以甲磺醯基化時之溶劑可用氯仿。所 得化合物與疊氮化鈉反應，於二甲基甲醯胺中等，室溫下 或加溫下施行疊氮化，得化合物20。 工程Ρ 令化合物20還原而得化合物21之工程。以接觸還原施 行。觸媒可用10%鈀碳等。溶劑可用乙醇等》
工程Q
化合物21與式：F^-Y-X'X1爲鹵素等，γ爲s、SO、so2 或CO)化合物反應而得化合物22之工程。式：R^-Y-X1所 示化合物可爲各種之磺醯氯、醯氯等。溶劑可用四氫呋喃 、二甲基醯胺等。反應可於室溫下或加溫下施行。以鹼之 存在下施行較佳，鹼可用吡啶、三乙胺等。式（Ι-C)中，R2 爲氫之化合物不施行以下之工程R，化合物22成爲最終目 的化合物。也可用Y=S或SO之式：Ri-Y-X1所示化合物來 反應而得化合物22，其後氧化而變換成γ爲S〇2之化合 物，而供其次之工程。 -33- 1376367
工程R 於化合物22導入取代基R2之工程。令R2xi(xi爲鹵素 等）於鹼之存在下與化合物22反應而得化合*(I_C)。鹼可 用氫化鈉等。溶劑可用二甲基甲醯胺等。 上述之工程中，可用以下之中間體❶· 化38 O Z R0
Z
N 、R7 、R7
18
Z
19 Z N3/^tG/N、R7 H2n/^G’N、R7 21 20 (式中R爲可有取代基之低烷基，r7爲氫或可有取代基之 低烷基’ G爲1，4·環伸烷基，Z爲可有取代基之烴環式基 或可有取代基之雜環式基）
R尤其可用低烷基，更以甲基、乙基較佳。尤以乙基較 佳。 R以氮較佳。 Z以可有取代基之雜環式基較佳。 尤其以下之化合物較佳。 式： 【化3 9】
N—Z
{ C -34- 1376367 (式中各符號與前述同義，-CH2-G-與式（I)之-X-同義，r爲 烷基，Pro爲胺基保護基）
工程S 於化合物17導入保護基之工程。保護基可廣泛用 Protective Groups in Organic Synthesis(Theodra W. Greene
著）等記載之保護基。以可於酸性條件下去除之胺基保護 基較佳。可爲苄氧羰基、第三丁氧羰基等。例如令 ProX'X1爲鹵素等，Pro爲苄氧羰基、第三丁氧羰基等）， pr〇-〇-pr〇(pro爲苄氧羰基、第三丁氧羰基等）於鹼之存在 下反應而得化合物23。溶劑可用四氫呋喃、二甲基甲醯胺 。反應於室溫施行》鹼可用三乙胺、吡啶、二甲胺基吡啶 等。R7爲氫之化合物也可同樣反應。
工程T 令化合物23還原而得化合物24之工程。還原劑可用氫 化鋰鋁。溶劑可用四氫呋喃等。反應於室溫施行。
工程U
令化合物2 4疊氮化來誘導爲化合物2 5之工程》例如於 化合物24以三乙胺爲鹼，與甲磺醯氯反應，使化合物24 誘導爲甲磺酸酯。甲磺醯基化時之溶劑可用氯仿。所得化 合物與疊氮化鈉反應，於二甲基甲醯胺中等，室溫下或加 溫下施行疊氮化，也可得化合物2 5。
工程V 令化合物25還原而得化合物26之工程。化合物25用三 苯滕及水來還原而得化合物26。反應於加溫下施行。溶劑
-36- 1376367 可用四氫呋喃。除用三苯膦之還原法以外，可施行接觸還 原。接觸還原之場合，觸媒可用10%鈀碳等。溶劑可用乙 醇等。使用何種還原法，可依使用保護基而適宜選擇。 工程w
化合物26與式：Ι^-Υ-Χ'Χ1爲鹵素等，Y爲S、SO、S02 或CO)所示化合物反應而得化合物27而工程。式：W-Y-χ^χ1爲鹵素等）所示化合物可爲各種之磺醯氯、醯氯等。 溶劑可用四氫呋喃、二甲基醯胺等。反應在室溫下或加溫 下施行。以鹼之存在下施行較佳，鹼可用吡啶、三乙胺等 。又也可用Y = S或SO之式：W-Y-X1所示化合物來反應而 得化合物27後，氧化而變換成Y爲S02之化合物而供其 次之工程。
工程X 爲去除化合物27之保護基之工程。保護基之去除可依保 護基而選用各種條件。例如第三丁氧羰基可以酸去除。苄 氧羰基可以接觸還原等去除。
工程Y 爲於化合物28導入取代基Z之工程。可例如ZX^X1爲 鹵素）於鹼之存在下反應而得化合物（I-D) »溶劑可用甲醇 、乙醇、異丙醇、二甲基甲醯胺等。反應可於室溫下或加 溫下施行。例如封管而用微波爐反應裝置來施行。鹼可用 N，N-二異丙基乙胺等。 上述之工程中，可用以下之中間體。 -37- 1376367 化 /GΠΟΛ 4 〇
ProIN、
7 R
Ho ΡΓΟΙΝ R7
PrIN
R 23 fj>ro h2n^^g/N、r7 R1 人[| 26 24 25
ProI ,N 27 R7 R1/Y、N〆 I R2 HI ,N. 'R/ 28 (式中R爲可有取代基之低烷基，Pro爲保護基，R7爲氫或 可有取代基之低烷基，G爲1，4-環伸烷基，Y爲S02或SO ，R1爲可有取代基之低烷基，R2爲氫或可有取代基之低 烷基） R尤以低烷基，更以甲基、乙基較佳。尤以乙基較佳。 Pro以可於酸性條件下去除之胺基保護基較佳。例如Pro 以式：-(C = 0)-O-R(R爲可有取代基之低烷基、可有取代基 之低烯基）所示基較佳。尤其第三丁氧羰基較佳β R7以氫較佳。 Υ以S02較佳。 R1以尤其低烷基 更爲異丙基、乙基較佳。尤以乙基較 佳 R2以氫較佳。 尤其以下之化合物較佳 式： -38- 1376367 【化42】
NH2 (式中R1爲乙基或第三丁基）所示化合物。 式：
(式中R1爲乙基、異丙基或第三丁基）所示化合物。 式： 【化44】
(式中Z爲可有取代基之烴環式基或可有取代基之雜 基）所示化合物。 本發明之化合物皆具有NPY Y5受體拮抗作用’尤 合物爲以下之化合物。 式（I)中 R1爲可有取代基之低烷基（以下稱R1爲R1-1)化合物， R1爲各可有鹵素取代之碳數1〜10之烷基（以下稱] R1 -2)化合物， R1爲可有鹵素取代之碳數1〜10之烷基（以下稱R1爲 3)化合物， R1爲異丙基或第三丁基（以下稱R1爲R1-4)化合物， 環式 宜化 ^爲 R1- -39- 1376367
(以下稱Z爲Ζ·2)化合物， ζ 爲-(CH2)r-W-(CH2)s-V
[式中W爲單鍵、0、S或NR12，R12爲氫或低烷基，V爲 各可有取代基之芳基或雜環式基（於此取代基爲鹵素、羥 基、低烷基、鹵低烷基、低烷氧基、低烯基、胺基、低烷 胺基、醯基、羧基、低烷氧羰基、苯基或單環之雜芳基） ，r爲1〜4之整數，s爲0〜4之整數] (以下稱Z爲Z-3)化合物，
Z 爲-(CH2)r-W-(CH2)s-V
[式中W爲單鍵、0、S、NH或NMe，V爲各可有取代基 之苯基或雜芳基（於此取代基爲鹵素、低烷基、鹵低烷基 、低烷氧基、胺基或低烷胺基），r爲1〜3之整數，s爲〇 或1] (以下稱Z爲Z-4)化合物， Z爲可有取代基之烴環式基 [於此取代基爲鹵素；羥基；
可有取代基之低烷基（於此取代基爲鹵素、羥基、羧基、 低烷氧羰基、氰基及/或苯基）； 可有低烷氧羰基取代之低烯基； 可有取代基之低烷氧基（於此取代基爲鹵素、羥基、低院 氧基、羧基、低烷氧羰基、低烷胺基、環烷基、氰基及/或 雜環式基）； 環烷基：環烷氧基；醯基；低烷硫基；胺甲醯基；低烷胺 甲醯基；環烷胺甲醯基；羥亞胺基： -42- 1376367 可有取代基之胺基（於此取代基爲低烷基、可被保護之羥 低烷基、低烷氧基低烷基、醯基、低烷磺醯基、芳磺醯及/ 或苯基）； 可有鹵素、氰基、苯基及/或雜環式基取代之苯基； 低烷亞磺醯基；低烷胺磺醯基：環烷胺磺醯基； 硝基；氰基；伸烷二氧基；可有低烷基取代之苯偶氮基： 苯氧基；氧基；
可有取代基之雜環式基（於此取代基爲可被保護之羥基； 氫硫基；鹵素；低烷基；環烷基；低烷氧羰基：醯基；胺 基；低烷氧羰胺基：胺甲醯基：氧基：苯基：低烷氧苯基 :鹵苯基；雜環式基及/或氧基）； 可有低烷基取代之雜環磺醯基；雜環氧基；可有低烷基取 代之雜環羰基] (以下稱z爲Z-5)化合物， Z爲可有取代基之苯基
(於此取代基爲鹵素；羥基；可有鹵素、羥基、低烷氧羰 基、氰基及/或苯基取代之低烷基；低烷氧羰低烯基；可有 鹵素、低烷氧基、低烷氧羰基、環烷基及/或雜環式基取代 之低烷氧基；環烷基；環烷氧基；醯基；低烷硫基；胺甲 醯基；低烷胺甲醯基：可有低烷基、羥低烷基、醯基、低 院擴酸基及/或苯基取代之胺基；可有_素、氰基、苯基及 /或雜環式基取代之苯基； 低烷胺磺醯基；環烷胺磺醯基；硝基；伸烷二氧基；可有 低烷基取代之苯偶氮基；苯氧基；氧基；可有羥基、鹵素
{ C -43- 1376367 、低烷基、低烷氧羰基、胺基、胺甲醯基、苯基、鹵苯基 、雜環式基及/或氧基取代之雜環式基；雜環氧基：及/或 可有低烷基取代之雜環磺醯基）（以下稱Z爲Z-6)化合物， Z爲可有取代基之苯基
(於此取代基爲鹵素；可有鹵素、羥基、低烷氧羰基及/或 苯基取代之低烷基；可有鹵素及/或環烷基取代之低烷氧基 :環烷基；環烷氧基；醯基；低烷硫基；低烷胺甲醯基； 可有低烷基、羥低烷基、醯基及/或苯基取代之胺基；可有 哌啶基取代之苯基；環烷胺磺醯基；伸烷二氧基；苯氧基
可有低烷基取代之嗎啉基或嗎啉基；羥基、可有低烷基、 低烷氧羰基、苯基、鹵苯基及/或氧基取代之哌啶基；可有 羥基、胺甲醯基及/或氧基取代之吡咯啶基；可有苯基或嘧 啶基取代之哌畊基；二硫氫吡啶基；吡咯基；吡咯啉基； 可有鹵素及/或低烷基取代之咪唑基；吡唑基；噻吩基；噻 二唑基；呋喃基；噚唑基；異噚唑基；可有低烷基及/或苯 基取代之四唑基；吲哚啉基；吲哚基；四氫唾啉基；可有 低烷基取代之苯并噻唑基；可有氧基取代之四氫異噻唑基 :可有氧基取代之苯并吡喃基；四氫吡喃氧基；四氫呋喃 氧基；可有低院基取代之嗎啉基擴酿基；及/或可有低院基 取代之哌啶基磺醯基）（以下稱z爲Z-7)化合物， Z爲可有取代基之苯基（於此取代基爲鹵素、低烷基、鹵低 烷基、低烷氧基、環烷氧基、低烷胺甲醯基、苯基、低烷 基嗎啉基及/或四氫吡喃氧基）（以下稱Z爲Z-8)化合物， -44- 1376367 z爲可有取代基之雜環式基（於此取代基爲鹵素、羥基、低 烷基、鹵低烷基、低烷氧基、氫硫基、低烷硫基、醯基、 羧基、低烷氧羰基、胺基、低烷胺基、苯基、萘基、可有 鹵素取代之苯硫基、可有鹵素取代之苯氧基、可有氧基及/ 或低烷基取代之雜環式基）（以下稱z爲Z-9)化合物，
Z爲各可有取代基之噻吩基、吡唑基、唾唑基、噻二唑基 、吡啶基、嘧啶基、吡畊基、嗒阱基、三畊基、吲哚基、 異吲哚基、吲哚啉基、異吲哚啉基、吲唑基、苯并吡喃基 、苯并噚唑基、苯并噻吩基、苯并唾唑基、苯并噻唑啉基 、苯并噻二唑基、苯并咪唑基、喹啉基、異唾啉基、二硫 氫苯并呋喃基、咔唑基、吖啶基、二苯并呋喃基或噻唑并 吡啶基（於此取代基爲低烷基；鹵低烷基；低烷氧基：低 烷氧羰基；醯基；低烷氧羰低烷基；氫硫基；各可有鹵素 取代之苯基、萘基、苯硫基或苯氧基；呋喃基；硝基；氧. 基；及/或可有低烷基取代之嗎啉基）（以下稱Z爲Z-10)化 合物，
Z爲各可有取代基之噻吩基、噻唑基、噻二唑基、吡啶基 、吡阱基、吲哚基、異吲哚啉基、苯并吡喃基、唾啉基、 咔唑基、二苯并呋喃基、苯并吡喃基、苯并噻吩基或苯并 噻唑基（於此取代基爲低烷基、鹵低烷基、低烷氧基、低 烷氧羰基、醯基、苯基、萘基、苯硫基、低烷基嗎啉基及 氧基而成群選擇之1以上之基） (以下稱Z爲Z-1 1)化合物， R1 爲 R1-2，R2 爲 R2-2，η 爲 2，X、Y 及 z 之組合（X，Y，Z) -45- 1376367 爲以下之組合之化合物， (Χ，Υ，Ζ) = (Χ-3，Υ-2，Ζ-1)，（Χ-3，Υ-2，Ζ-2)，（Χ-3，Υ-2，Ζ-3)，（Χ- 3，Υ-2，Ζ-4)，（Χ-3，Υ-2，Ζ-5)，（Χ·3，Υ-2，Ζ-6)，（Χ-3，Υ-2，Ζ-7)，（Χ- 3，Υ-2，Ζ-8)，（Χ-3，Υ-2，Ζ·9)，（Χ-3，Υ-2，Ζ-10)，（Χ-3，Υ-2,Ζ-11)， (Χ-3，Υ-3，Ζ-1)，（Χ·3，Υ-3，Ζ-2)，（Χ-3，Υ-3，Ζ-3)，（Χ-3，Υ-3，Ζ- 4)，（Χ-3，Υ-3，Ζ-5)，（Χ-3，Υ-3，Ζ-6)，（Χ-3，Υ-3，Ζ-7)，（Χ-3，Υ-3，Ζ- 8)，（Χ-3，Υ-3，Ζ-9)，（Χ-3，Υ-3，Ζ-10)，（Χ-3，Υ-3，Ζ-11)， (Χ-4，Υ-2，Ζ-1)，（Χ-4，Υ-2，Ζ-2)，（Χ-4，Υ-2，Ζ-3)，（Χ·4，Υ-2，Ζ-
4)，（Χ-4，Υ-2，Ζ-5)，（Χ-4，Υ-2，Ζ-6)，（Χ-4，Υ-2，Ζ-7)，（Χ-4，Υ-2，Ζ- 8)，（Χ-4，Υ-2，Ζ-9)，（Χ-4，Υ-2，Ζ-10)，（Χ-4，Υ-2，Ζ-1 1)， (Χ-4，Υ-3，Ζ-1)，（Χ-4，Υ-3，Ζ-2)，（Χ-4，Υ-3，Ζ-3)，（Χ-4，Υ-3，Ζ- 4)，（Χ-4，Υ·3，Ζ-5)，（Χ-4，Υ-3，Ζ-6)，（Χ-4，Υ-3，Ζ-7)，（Χ-4，Υ-3，Ζ- 8)，（Χ-4，Υ-3，Ζ-9)，（Χ-4，Υ-3，Ζ·10)，（Χ-4，Υ-3，Ζ-1 1)， (Χ-5，Υ-2，Ζ-1)，（Χ-5，Υ-2，Ζ-2)，（Χ-5，Υ-2，Ζ-3)，（Χ-5，Υ-2，Ζ- 4)，（Χ-5，Υ-2，Ζ-5)，（Χ-5，Υ-2，Ζ-6)，（Χ-5，Υ-2，Ζ-7),(Χ-5，Υ-2，Ζ- 8)，（Χ-5，Υ-2，Ζ-9)，（Χ-5，Υ-2，Ζ_10)，（Χ-5，Υ-2，Ζ-1 1)，
(Χ-5，Υ-3，Ζ-1)，（Χ-5，Υ·3，Ζ-2)，（Χ-5，Υ-3，Ζ-3)，（Χ-5，Υ-3，Ζ- 4)，（Χ-5，Υ-3，Ζ-5)，（Χ-5，Υ-3，Ζ-6)，（Χ-5，Υ-3，Ζ-7)，（Χ-5，Υ-3，Ζ- 8)，（又-5，丫-3，乙-9)，（又-5，丫-3，乙-10)或（又-5，丫-3,2-11) 或其製藥容許鹽、或這些之溶劑合物。 本發明之ΝΡΥ Υ5受體拮抗劑對ΝΡΥ Υ5關連疾病全般有 效地作用，尤其對肥胖之預防及/或治療及攝食抑制有用。 又對肥胖成爲危險因子之疾病，例如糖尿病、高血壓、高 脂血症、動脈硬化、急性冠狀動脈症候群等預防/及或治療
-46- 1376367 也有效。 更本發明化合物不僅有ΝΡΥ Y5受體拮抗作用，且具備 醫藥之有用性，具有下述任一或所有優異特徵。 a) CYP酵素抑制弱。 b) 不易引起藥物代謝酵素之誘導。 c) 呈高生物利用性等良好之藥物動態。 d) 貧血誘發作用等毒性低。 e) 代謝安定性高。
f) 具有高Y5受體選擇性。 g) 水溶性高。 h) 腦移行性高。 且本發明之ΝΡΥ Y5受體拮抗劑對ΝΡΥ Y1及Y2受體之 親和性低，具有高Y5受體選擇性。NPY於末梢惹起持續 性之缺陷收縮作用，但此作用主要仲介Y1受體。Y5受！| 與如此作用完全無關連，故基於末梢血管收縮而誘發副作 用之可能性低，可視爲安全之醫藥而適合使用。
ΝΡΥ Y5受體拮抗劑抑制攝食而呈抗肥胖效果。故無見諸 抑制消化吸收而呈抗肥胖效果之藥劑之消化不良等副作用 ’和呈抗肥胖效果之如血清素轉運蛋白抑制劑之抗鬱作用 等中樞性副作用爲本藥劑之特色之一。 本發明之化合物作爲抗肥胖藥或攝食抑制劑來投與時， 經口或非經口之任一方法皆可投與。經口投與可依常法調 製成錠劑、顆粒劑、散劑、膠囊劑、九劑、液劑、糖漿劑 、口含劑或舌下劑等通常使用之劑型來投與。非經口投與 -47- 1376367 可以例如肌肉內投與、靜脈內投與等注射劑、坐劑、經皮 吸收劑 '吸入劑等通常使用之任一劑型皆可適宜投與。本 發明之化合物因經口吸收性高，適合以經口劑使用。 於本發明之化合物之有效量令適合其劑型之賦形劑、結 合劑、濕潤劑、崩壞劑、滑澤劑、稀釋劑等各種醫藥用添 加劑依必要而混合作爲醫藥製劑。注射劑時與適當載體一 起滅菌處理作成製劑。
具體而言，賦形劑可用乳糖、白糖、葡萄糖、澱粉、碳 酸鈣或結晶纖維素等、結合劑可用甲基纖維素、羧甲基纖 維素、羥丙基纖維素、明膠或聚乙烯基吡咯啶酮等、崩壞 劑可用羧甲基纖維素、羧甲基纖維素鈉、澱粉、藻酸鈉、 洋菜末或十二基硫酸鈉等、滑澤劑可用滑石、硬脂酸鎂或 聚乙二醇等。坐劑之基劑可用可可脂、聚乙二醇或甲基纖 維素等。又作爲液劑或乳濁性、懸浮性之注射劑可令調製 時通常使用之助溶劑、懸浮化劑、乳化劑、安定化劑、保 存劑、等張劑等適宜添加，經口投與時也可加矯味劑、芳 香劑等。 作爲本發明化合物之抗肥胖藥或攝食抑制劑之投與量宜 考慮患者之年齡、體重、疾病之種類和程度、投與經路等 而設定，成人經口投與時，通常爲0.05〜100mg/kg/曰， 宜0.1〜10m g/kg/日之範圍內。非經口投與之時，依投與 經路而大爲相異，通常爲0.005〜10mg/kg/日，宜0.01〜 lmg/kg/日之範圍內。可分1日1回〜數回投與。 以下舉實施例更詳細說明本發明，但發明不受此限定。
-48- 1376367 又本說明書中所用縮寫如下。 M e :甲基 Et:乙基 i-Pr:異丙基 DMSO:二甲亞碾 Pd-C:鈀碳 THF:四氫呋喃
DMF:N，N·二甲基甲醯胺 mCPBA:間氯苯甲酸 【實施例】 實施例1化合物（Ii-Ι)之合成 第1工程
〇2N^j-
o2n
C6H4FN〇2 Mol. Wt. : 141.1
C13H18N202 Mol. Wt. ： 234.29 3-氟硝苯（2.00 g，14.2 mmol)溶解於二甲亞颯15 ml’加 3,5-二甲基哌啶（3.21 g，28.4 mmol)和碳酸鉀（3.92 g，28·4 mmol)於15 (TC攪拌3小時。反應液注入水而以乙酸乙醋萃 取》令有機層水洗而以無水硫酸鈉乾燥。減壓蒸除溶劑 殘渣加乙酸乙酯及己烷，濾取析出之結晶而得目的物取代 硝苯2.05 g，産率62%。 'H-NMR (CDCI3) δρριη: 0.76 (q，1H，J = 12.0 Hz), 0 96 (d, 6H, J = 6.3 Hz), 1.70-1.91 (m, 3H), 2.32 (t, 2H, j ^ -49- 1376367 12.0 Hz), 3.62-3.72 (m, 2H), 7.17-7.25 (m, 1H), 7.34 (t, 1H, J = 8.1 Hz), 7.59 (d, 1H, J = 8.1 Hz), 7.71 (s, 1H). 第2工程 【化52】
c13h18n2o2 MoL Wt.: 234.29
M〇.C^°2N024.31
第1工程所得化合物（2.05 g，8.75 mmol)溶解於乙醇25 ml，加入10°/。Pd-C( 0.20g )來氫添加反應12小時。以矽 藻土濾除Pd-C，令濾液減壓濃縮。殘渣以矽膠柱層析精製 而得目的物苯胺1.62 g，産率90%。 ^-NMR (CDC13) δρριη: 0.69 (q, 1H, J = 12.0 Hz), 0.92 (d, 6H, J = 6.3 Hz), 1.75 - 1.9 8 (m, 3H), 2.22 (t, 2H, J = 12.0 Hz), 3.5 3 -3.62 (m, 2H), 6.21 (d, 1H, J = 7.5 Hz), 6.38 (s, 1H)., 6.42 (d, 1H, J = 8.1 Hz), 7.04 (t, 1H, J = 8.1 Hz). 第3工程
【化53】 co2h L1AIH4
THF
C11H23NO3S Mol. Wt :249.37 C11H21NO4S Mol. Wt :263.35 原料羧酸（合成法記載於國際公開第01/037826號小冊 )(5.04 g，19.1 mmol)懸浮於四氫呋喃50 ml，於冰冷下加 氫化鋰鋁 （0.726 g，1 9.1 mmol)，於室溫攪拌1小時。反 應液再冰冷攪泮，小心滴下水（1 . 5 m L )。滴下後，於室溫 攪拌5分，濾除生成之沈澱，令濾液減壓濃縮。殘渣加乙 -50- 1376367 酸乙酯及己烷，濾取析出之結晶而得目的物醇3.15 g，産 率 66% » ^-NMR (DMS0-d6) Sppm: Ο· 8 8 (q，2Η，J = 1 1 ·6 Ηz)， 1.25 (s, 9H), 1.15-1.30 (m, 3H), 1.67- 1.76 (m, 2H), 1.83-1.92 (m, 2H), 2.97 (m, 1H), 3.13-3.20 (m, 2H), 4.35 (t5 1H, J = 5.2 Hz), 6.71 (d, 1H, J = 8.8 Hz). 第4工程 【化54】
C11H23NO3S Mol.Wt.: 249.37 Μ ΧΗΟ C11H21N03S Mol. Wt. :247.35 第3工程所得化合物（5 00 mg, 2.01 mmol)溶解於氯仿5 ml，力Π Dess-Martin 過澳酸（893 mg，2.11 mmol)，於室溫 攪拌1小時。濾除沈澱，令濾液減壓濃縮。殘渣以矽膠柱 層析精製而得目的物醛385 mg，産率77%。 'H-NMR (DMSO-d6) δ p p m : 1.2 6 (s，9 Η)，1.1 3 -1 . 3 8 (m，
4H), 1.8 5 - 1.9 8 (m, 4H), 2.16 (m, 1H), 3.01 (m, 1H), 6.80 (d, 1H, J = 8.0 Hz), 9.54 (s, 1H). 第5工程 【化5 5】
Mol.Wl.: 247.35
第2工程所得苯胺（107 mg，0.523 mmol)溶解於四氫呋喃 -51 - 1376367 3 ml ’加第4工程所得醛（130 mg，0.523 mmol)、於室溫攪 拌1小時。反應液加硼氫化鈉（23.7mg，0.628 mmol)，更於 室溫攪拌3小時。反應液以乙酸乙酯萃取。令有機層水洗 、以無水硫酸鈉乾燥。減壓蒸除溶劑，殘渣以矽膠柱層析 精製而得目的物99.3 mg，産率43%。 iH-NMR (DMSO-d6) δρριη: 0.64 (q, 1H, J = 11.6 Hz), 0 87 (d, 6H, J = 6.0 Hz), 0.92- 1.08 (m, 2H), 1.25 (s, 9H), 1.15-1.32 (m5 2H), 1.41 (m, 1H), 1.5 8- 1.95 (m, 7H), 2.08
(t, 2H, J = 11.6 Hz), 2.75-2.82 (m, 2H), 3.00 (m, 1H), 3.48-3.5 5 (m, 2H), 5.31 (m, 1H), 5.94 (d, 1H, J = 8.5 Hz),
6.08-6.13 (m, 2H), 6.71 (d, 1H, J = 8.5 Hz), 6.85 (t, 1H, J = 8.5 Hz)·熔點：161-162°C 實施例2化合物（I j -1)之合成 第1工程 【化5 6】
Me02C
C11H21NO4S M〇丨.Wt. :263.35
TsOH ：,i?CF： (^Pr)2NEt
i-PrOH
〇F3 C14H17F3N2〇2 Mol. Wt. ： 302.29 原料胺（1_20 g，3.64 mmol)和2-氯-5-三氟甲基吡啶 (727 mg，4.0 1 mmol)懸浮於異丙醇4 ml，加N，N-二異丙 基乙胺（1.87 ml, 10.9 mmol)來封管後，用微波爐反應裝置 以1 6(TC之條件反應1小時。反應液注入水而以乙酸乙酯 萃取。令有機層水洗而以無水硫酸鈉乾燥。減壓蒸除溶劑 ’殘渣以矽膠柱層析精製而得目的物酯222 mg，産率20% -52- 1376367 第2工程 【化57】 Me 0 2〇 C F 3 CuHnF3N2〇2 Mol. Wt : 302.29
H
CF3i)MsCI. Et3N CHCl·, iD NaN3/DMF
C13H17F3N20 C|3H16F3Ns Mol. Wt :274.28 WoLWt. :299.29
第1工程所得酯（207 mg，0.68 5 mmol)溶解於四氫呋喃3 ml，冰冷下加入氫化鋰鋁 （31.1 mg，0.822 mmol)，於室溫 攪拌0.5小時。反應液注入冰水而以乙酸乙酯萃取後，令 有機層水洗而以無水硫酸鈉乾燥，減壓蒸除溶劑而得醇。 所得醇溶解於氯仿3ml，加三乙胺（0.28 ml，2.04 mmol)， 於冰冷下滴下甲磺醯氯 （〇·12 ml，1.64 mmol)，於室溫攪 拌1小時。反應液注入水而以乙酸乙酯萃取後，令有機層 水洗而以無水硫酸鈉乾燥，減壓蒸除溶劑而得甲磺酸酯。 所得甲磺酸酯溶解於二甲基甲醯胺3ml，加入疊氮化鈉 (2 21 mg，3.40 mmol)，於100°C攪拌3小時。反應液注入 水而以乙酸乙酯萃取。令有機層水洗而以無水硫酸鈉乾燥 。減壓蒸除溶劑，殘渣以矽膠柱層析精製而得目的物疊氮 化物178 mg，産率87%。 第3工程 【化58】
i)Hi, Pd-C EtOH
HaN
ii) J^rSOjCI Et3N THF
H ciBH2iFaN302S Mol.Wl. :379.44
Cia^ ib^jNs
Mol.Wl.: 299.29 第2工程所得疊氮化物（178 mg, 0.595 mmol)溶解於乙 •53- 1376367 醇3 ml，力〇 10% Pd-C( 30 mg )而氫添加反應4小時。令 Pd-C以矽藻土濾除，令濾液減壓濃縮而得胺。 所得胺溶解於四氫呋喃3ml，加三乙胺（0.28 ml，0.714 mmol)，於冰冷下滴下異丙磺醯氯 （0.10 ml, 1.64 mmol)而 攪拌1小時。反應液注入水而以乙酸乙酯萃取後，令有機 層水洗而以無水硫酸鈉乾燥。減壓蒸除溶劑，殘渣以矽膠 柱層析精製而得目的物64.8 mg，産率29%。
*H-NMR (DMSO-d6) δ: 0.92- 1.06 (m, 2 Η), 1.10-1.25 (m, 2H,), 1.22 (d, 6H, J = 6.4 Hz), 1.38 (m, 1H), 1.76- 1.84 (m, 2H), 1.93 -2.02 (m, 2H), 2.81 (t, 2H, J = 6.0 H z), 3.0 8 - 3 .1 9 (m, 1H), 3.69 (m, 1H), 6.53 (d, 1H, J = 8.8 Hz), 6.95 (t, 1H, J = 5.6 Hz), 7.16 (d, 1H, J = 7.6 Hz), 7.58 (d, 1H, J = 8.8 Hz), 8.26 (s, 1H)熔點：1 5 5- 1 5 6°C 實施例3化合物（Ij_l)之合成 第1工程 【化5 9】
Me02C
C15H23NO5S M ol.Wt. :329.41
(B〇C)2〇 EtsN
TsOH
ChbCb
Mol. Wt.: 257.33 原料胺（132 g，401 mmol)冰冷下懸浮於二氯甲烷1000 ml，依序加三乙胺（123 ml, 882 mmol)、（Boc)2〇(l〇l ml, 44 0 mmol)而反應1 0分。其後更於室溫反應2小時，蒸除 溶劑。於檸檬酸水（檸檬酸一水合物50g，水400 ml)注入 殘渣而作成pH4，以乙酸乙酯萃取。令有機層水洗，以無 水硫酸鎂乾燥，減壓蒸除溶劑而得目的物，定量》 -54- 1376367 'H-NMR (DMS0-d6) 5ppm: 1 .06- 1.25 (m, 2H), 1.25-1.43 (m, 2H), 1.37 (s, 9H), 1.75- 1.94 (m, 4H), 2.19 (tt, 1H, J = 11.7, 3.9 Hz), 3.07-3.24 (m, 1H), 3.58 (s, 3H), 6.74 (d, 1H, J = 6.6 Hz). 第2工程 【化60】
L1AIH4 THF
C13H23NO4 C12H23NO3
Mol. Wt. :257.33 Mol. Wt.: 229.32
氫化鋰銘 （18.3 g, 483 mmol)懸浮於四氫呋喃800 ml’ 於冰冷攪拌下以1小時徐徐加第l工程所得酯之四氫呋喃 (3 00 ml)溶液。於冰冷下反應10分後，更於室溫反應2.5 小時。令反應液再冰冷，依序加水和四氫呋喃之混合液 (1:1，36 ml)、2N氫氧化鈉水溶液（18 ml)、水（18 ml)而攪 拌20分。其後更於室溫攪拌1.5小時，濾除析出物，令濾 液減壓濃縮》於殘渣加乙酸乙酯及己烷，濾取析出之結晶 而得目的物醇79.5 g，産率87%(第1〜2工程合計）。 iH-NMR (DMSO-d6) δρριη: 0.78-1.00 (m, 2H), 1.00-1.32 (m, 3H), 1.37 (s, 9H), 1.65- 1.84 (m, 4H), 3.04-3.24 (m, 3H), 4.32-4.42 (m, 1H), 6.66 (d, 1H, J = 7.8 Hz). 第3工程 【化6 1】
C12H23NO3 Mol. Wt :229.32
i) MSCI/THF ii) NaN3/DMF
.Boc C12H22N4O2 Mol Wt. ： 254.33 -55- 1376367
原料醇 （79.5 g，347 mmol)溶解於四氫呋喃800 ml，冰 冷攪拌下依序加三乙胺（72.5 ml，520 mmol)、甲磺醯氯 (32.2 ml，416 mmol)而反應1.5小時。反應液注入檸檬酸 水（檸檬酸一水合物30g，水500 ml)作成pH4，以乙酸乙 酯萃取後，令有機層水洗而以無水硫酸鎂乾燥。令減壓蒸 除溶劑之途中濾取析出之結晶，以己烷洗淨而得甲磺酸酯 100 g。所得甲磺酸酯溶解於二甲基甲醯胺100 ml，加疊 氮化鈉（63.7 g，980 mmol)，於80°C反應2小時。反應液 注入水而以乙酸乙酯萃取。令有機層水洗，以無水硫酸鎂 乾燥，減壓蒸除溶劑而得目的物疊氮化物，定量（粗重量 8 5.4 g)。 'H-NMR (DMSO-d6) 5ppm: 0.90-1.21 (m, 4H), 1.32-1.50 (m, 1H)S 1.37 (s, 9H), 1.65- 1.84 (m, 4H), 3.06-3.24 (m, 3H), 6.71 (d, 1H, J = 8.1 Hz). 第4工程 【化62】
ΆΒί ^12^2^4〇2 Mol. Wt. :254.33 PPh3 H20
THF
Boc ^12^24^2^2 Mol. Wt. ： 228.33 第3工程所得疊氮化物室溫溶解於四氫呋喃900 ml，依 序加三苯膦（103 g，392 mmol)、水（90卩1)，於80 °C反應 1.5小時》蒸除溶劑770 ml，依序加水300ml、乙酸乙酯 400 ml、2N鹽酸150 ml作成pH2.5，施行分液萃取。有機 層以2N鹽酸萃取，合倂水層而以乙酸乙酯洗淨後，以2N 氫氧化鈉作成鹼性，以乙酸乙酯及氯仿反復萃取。合倂有 -56- 1376367 機層，以無水硫酸鎂乾燥。減壓蒸除溶劑，殘渣加己烷， 濾取析出之結晶，以己烷洗淨而得目的物胺41.7 g，産率 5 3 %(第3〜4工程合計）。 •H-NMR (DMS0-d6) 5ppm: 0.77-0.96 (m, 2H), 1.00-1.18 (m, 3H), 1.37 (s, 9H), 1.67-1.82 (m, 4H), 2.30-2.38 (m, 2H), 2.90-3.60 (m, 2H), 3.05-3.22 (m, 1H), 6.66 (d, 1H, J =7.2 Hz).
第5工程 【化63】 Ο ο
C12H24N202 C15H30N2O4S Μol.wt :228.33 Mol. Wt.: 334.47
原料胺（37.5 g，164 mmol)懸浮於四氫呋喃400 m卜於-55 〜-40°C攪拌下徐徐依序加三乙胺（91.7 ml，656 mmol)、異 丙磺醯氯（32.2 ml, 416 mmol)，徐徐昇溫至0°C並反應6 小時。反應液注入冰冷之‘稀酸水溶液，以乙酸乙酯萃取。 令有機層水洗，以無水硫酸鎂乾燥。減壓蒸除溶劑，殘渣 加異丙醚，濾取析出之結晶，以異丙醚洗淨而得目的物磺 酿胺43.1 g，産率79%。 'H-NMR (DMSO-d6) δρριη: 0.79-0.98 (m, 2H), 1.00-1.36 (m, 3H), 1.20 (d, 6H, J = 6.6 Hz), 1.37 (s, 9H), 1.70-1.84 (m, 4H), 2.72-2.80 (m, 2H), 3.04-3.22 (m, 2H), 6.68 (d, 1H, J = 8.1 Hz), 6.94 (t, 1H, J = 6.0 Hz). 第6工程 -57- 1376367 溶劑，殘渣以矽膠柱層析精製而得目的物化合物（Ij-1)158 mg，産率 60% β 又第5工程中異丙磺醯氯代之以乙磺醯氯來反應，得Ri 爲乙基之如下化合物》 【化66】
Cl4H28N2〇4S Mol. Wl. :320.45
^-NMR (DMSO-d6) 6ppm: 0.80-0.98 (m, 2H), 1.02-1.18 (m, 2H), 1.17 (t, 3H, J = 7.2 Hz), 1.22-1.34 (m, 1H), 1.37 (s, 9H), 1.68- 1.82 (m, 4H), 2.68-2.78 (m, 2H), 2.96 (q, 2H, J = 7.2 Hz), 3.04-3.22 (m, 1H), 6.68 (d, 1H, J = 8.1 Hz), 6.94 (t, 1H, J = 6.0 Hz). 第5工程中異丙磺醯氯代之以第三丁亞磺醯氯來反應， 其後用mCPBA來氧化，得R1爲第三丁基之如下化合物（ 參照 W02001037826，實施例 3)。
【化67】
CieH32tS|2〇4S Mol. Wt. : 348.5 h-NMR (DMSO-d6) δρριη: 0.79- 1.00 (m，2H)，1.01-1.20 (m，2H)，1.22-1.34 (m，1H)，1.25 (s，9H)，1.37 (s，9H)， 1.70-1.86 (m，4H)，2.81-2.90 (m，2H)，3.04-3.22 (m，1H)， 6.68 (d, 1H, J = 8.1 Hz), 6.83 (t, 1H, J = 6.0 Hz). -59- 1376367 利用上述化合物，得第6工程中R1爲乙基或第三丁基之 如下化合物。 R 1爲乙基之場合 【化68】
C^H21CIN2〇2S Mol.Wt. ： 256.79
H-NMR (DMSO-d6) 5ppm: 0.84- 1.02 (m, 2H), 1.18 (t, 3H, J = 7.5 Hz), 1.20- 1.40 (m, 3H), 1.74- 1.82 (m, 2H), 1.90-2.00 (m, 2H), 2.72-2.80 (m, 2H), 2.8 3 -2.96 (m, 1H), 2.97 (q, 2H, J = 7.5 Hz), 7.04 (t, 1H, J = 6.0 Hz), 8.03 (s, 3H). R1爲第三丁基之場合 【化69】
C11H25CIN2O2S Mol. Wt.： 284.85 ίμη2
HCI «
H-NMR (DMSO-d6) 5ppm: 0.84- 1.04 (m, 2H), 1.16-1.38 (m, 3H), 1.26 (s, 9H), 1.74- 1.84 (m, 2H), 1.92-2.02 (m, 2H), 2.82-2.9 8 (m, 3H), 6.90 (d, 1H, J - 6.0 Hz), 8.01 (s, 3H). 同樣合成之以下化合物也包括於本發明。 { e -60- 1376367 【化7 0】
1-1 1-2 1-3 ΙΑ 1-5 1-6 1-7 1-8 1-9 1-10 1-11
1-12 1-13 1-14 1-15 1-16 1-17 1-18 1-19 1-20 1-21 1-22
H
伽
-61 - 1376367 【化7 1】 0 1-23 a Ml 1-24
1-25 y〇.j l~35 ysNj〇^H^XX^ 〇 x-36 xkx^to^ 0 0 1-26
.Ν. 〇。〇 1-27 00 Η 1-38 βχχ a 1-28 OMe 1-39 1-29 鲁 1-30 Η Η ο >· N N 00 U^c, 1-40 Ον- Ο 气|
Ml N0〇 x> N〇〇 1-31 ^08¾ 1-42
H 1-32 0¾ °ΉΧΙ_ 143 〇""t) CLn -Cl 1-33 144
^XX -62- 1376367
1-47 1-48
1-49 1-50
1-61 1-51 1-52 1-53 1-54 1-55
〇MJ〇 〇. Ό
O a Ό
1-56 1-57 1-58 1-59 1-60 1-62 1-63 1-64 1-65 1-66
-63- 1376367 【化7 3】 J-67 1-68 1-69 1-70 1-71 1-72 1-73 1-74 1-75 1-76 1-77 1-78 ^δ〇.^ ^bO.^ OJ ^6〇..s Χ>Λ 1-79 1-80 1-81 h2 1-82 O, nh2
XX >〇 〇 Λ-
〇.2HCI N〇-NH2
O 8 CLg Oy^ NH2 1-83 1-84 1-85 1-86 1-87 1-88 1-89 1-90
^6〇J ^b〇J ^sb〇J ^b〇J Λ ^6〇J
XXN X»
OTBS OTBS a,
XX
〜。H
Ou, 〇2Me
X02H
On- -64- 1376367 【化7 4】 1-91 ^
!.92 C^S^H Η 1-93 1-105 、Ke 1-94 CI^S*^ Η 1-106 ° ^ Cu^ 1-95
XX^ 1-96
t ^i〇N N J^H 0¾ N 人N 1-97 1-98
々iiOJJ 1-99 1-100 1-101 1-102
H do
Cu. 1-103 1-104 1-107 1-108 1-109 1-110 1-111 1-112 1-113
Λ -65- 1376367 【化7 5】 Ι-】]5 "ΐ、 I**l 16 Η 1-127 〇〇/ 1-128 Η ,Ν 1-117 1-118 Η Η °'"〇 ^13° 1-119 ν/ tl Η 1-120 乂兵 1-131 Η …1 1-132 〇-'〇 U，..N^S>^Q.f _ u 1-121 1-122
^s.nn^| H 〇5 认1-133 ¢5¾ 1-134 1-123 CU. 1-135 1-124
H nNX) 1-136 J-125 O：h 1-137 1-126 '耳 丫、h 0 0 ^v.N^.〇cf2chf2 1-138 1376367 【化7 6】 Ι-Ϊ39 1-151
Cl 1-140 〇〇Ό·』 I H CF3 χ-152 ^
j-141 ^£όλ
m3 ms
1-142 OMe
1-154 00 Ά$) 1-143 1-144
H C〇2Me 0。kA-N^cc^MeH ；XrF 1-155 1-156
Hsnvn H s'N^b〇.J
CQ 0 1-145
OJ
1-157 I H 乂 SN 60 1-146 fo. H 0-¾ N-NH 1-158 1-147 ^£oj 以OMe 1-159 Hoy 1-148 Wa, H 广0 1-160 ^b〇.,S0〇^ 1-149 ^o. 』，NJ〇 1-161 0¾ 1-150 h ci 00 1-162 { c <· -67- 1376367 【化7 7]1-163 ^fo. OH 1-173 Η
OJ 1-164
1 XX^CC^Me 1-174 a 〇τ〇〇2η 1-165 06
1-175 Η
1-166
荔OJ ΙΊ76 1-167
A 1-177 O' 〇s^C〇2(V(0
fQ^C〇zH 1-168
^〇OJ 1-178 1-169 1-170 ΝΛα Meφ〇Ό Me 1-179 ΐΊ8〇 混 0 Jqt。〜_e2 ^〇Ό, -N, 1-171 Μη
6%n〇j 1-172 1-182 -N、
)1D -68- 1376367 [化7 8] 1-183 1-193 1-184 1-194 1-185
ΟΌ
Ό-J
N 1-195 ^OJH0〇Me^OJNU H ^^OMi 乂cfoj 4' C02Me 1-186
XO-jS 1-196
Ns^wOEt XX OEt 1-187 I H OMe 1-188 H " OMe 1-198 I- 189 OMe NMe2 i_i99 n_n 1-200 1-191 '0
Xr1 1-201
0¾Woj切 ^N—OH^b〇J^〇.J x> c〇 1-192 1-202
-69- 1376367 【化7 9】 1-203 X?' conh2 1-204 xx> 1-205 CONH^( 1-206
OuGN 1-207 1-208 1-209 1-210 S02NH2
CQ 1-211 1-212 1-213 1-214 1-215 1-216 1-217 1-218 1-219 1-220 1376367 【化8 0】 1-227
Op 1-228
Ο 1-229
Ό0Ο
1-230
1-231
1-232 1-233 1-234 1-235 1-236 1-237
-71 - 1376367 【化8 1】
-72. 1376367 [化8 2] 1-260 1-271 I Η Λ〇νσο"
Me 1-261
XV
OTBS k,〇TBS 1-272 1-262 1-273 1-263 1-264 。’ m 1-274 ,Η Η Ν Ν 1-275 1-265 1-266 1-267
、ΎΜ£ ώ χχ^ C02Me 、n〜oh
A χο2η 1-276 4Sf 00^Κ 1-277 〇〇 1-278 Ο, OMe νλν Η o' OCFoCHFo
1-268
Nu>〇?if 1-279
Η N〇y 1-269 1-280
^ΟΗ 0 SMe 1-270
,Me >SN -73- 1376367 【化8 3】 1-282 1-283 1-284 1-285
1-293 1-294 1-295 1-296 1-297
1-287 1-288 1-289
1-290 1-291 1-292
1-298 1-299
1-300 1-301
1-303 Cl >-sN 〇〇Ή -74- 1376367 【化8 4】 、l Η 1-304 〇〇
1-315
I H >SN cf3 H 一 N -N^S 1-305 00
H 1-316 1-306
A 1-317 1-307 μ 00
1-318
1-308 1-309 ^SN 00 Ή、 ^SN 〇〇 Ί 1-319
0 1-320
1-310 1-311 1-312 1-313 1-314
1-321 1-322 1-323 1-324 1-325
Me
-75- 1376367 【化85】
1-326 1-327 1-328 1-329
1-337
1-338 1-340
1-339 .
OMe 1-330
1-341
ja ΝΜθ2 'Q-0'^NMe2 1-331 1-332
1-342 1-343
1-333
1-344 1-334
1-335
1-336 1-345 1-346 1-347
-76- 1376367
1-351 1-352 1-353 ® 1-354 1-355 1-356 [化8 6] 1-348 1-349 1-350
1-357
CONH-( 1-358 1-359
1-360 1-361 1-362 1-363
1-364
/ C、 v - -77- 1376367 【化8 7】 1-366 1-377
Χ-367 I-37S X-36S 1-379 «χ^ςΡ ； 1-369 ^^ΝηΧ)^ 1-380 剛 1-381 1 Η Η 么 w、Nx> 1-371 Λ8ν^ ^χχ' 1-382 1-372 z^'Q-N^^^S ο'_、δ Η 、〇 1-383 如 1-373 0¾ 〜1Vi ο ν^ΝΛ_ 〇^Q,〇| 1-384 An. 0¾ 〜、K〇^j〇 1-374 y^-β N^s. 1-385 Ag-l· H 1-375 ✓^g-N Ν/ν H 、Ni〇 1-386 七卜K〇。一 1-376 〜Ntl 1-387 H 以OMe -78- 1376367 【化8 8] - 1-388 kNVS 1-399 〜H〇^r。 - 1-389 ^Ny^OMe ^OMe 1-400 V八 〜㈡"QrV 1-390 々B 1-401 H 0 H • 1-391 XX、 、no 1-402 1-392 Λ3ν^ H 以Ό 1'403 1-393 ^N〇〇 1-404 d'b Νγ%. ^NHz I-3S4 d'b 1-405 °'° H • 1-395 Ί On、 c^c, 1-406 (ft* 〜bon、 1-396 1-407 〜Νγ^ 2HCI 1-397 cTb 1-408 〇"° 〜Κχχ8 1-398 N^n H 1-409 0¾ -79- 1376367
Η 1-426 .Η Η ό.0 1-427
【化8 9】 1-410 H 〜 1-421 XX^COiH 1-411 〜h 0^ nh2 1-422 H 〜NsD , ^N〇-〇K 1-412 J'l 〜HtV n’ns 1-423 _^β 一 〜ho 1-413 H 1-424 Me 0 1-414 1-425 Me
Μ17 々'ί 一 I-41S 1-419 1-420 W—R〇l，h
OH 〆 ΝΝ 〇〇 LA^s^C02Me -80- 1376367 【化9 0] 1-432 M33 ,Η Ηit 1434 I H ΛΝ' 00
CO 1-435 I H ΛΝ' 00
H
1-436 1-437 1438 1-439 I H x^sN' 00 y—NoSMe
,H ^sN、 00 K〇C〇
H 1-440 ^Lsn CN Me Nn,
H OM _N I
1-441 <：S H N, 1442 〇〇 H 」N、 00 日r
0 0 M43 oso 〇0X3 1444 1-445 1-446 n^q,〇cf2chf2 1-447 1448 1449 1450 1-451 1-452 1-453 1454 1455
-81 - 1376367 【化9 1】
1-456 1-457 1-458 1-459 1-460 1-461 1-462 1-463 1-464 1-465 1-466
ΙΑ6Ί IA62 1469 1470 1471 1-472 1-473 1474 1475 1476 W77
-82 1376367 【化9 2】 1-478 M79 1-480 Μ ^0S0 Η •N/LO Ν Me
0^c〇2M Η 1-481
1-482 1-483 Μ84 4?·
H N0°"C〇2Me M95
1-485
XO2H H 1-486
Λ 0°' 1-487 -^0°
,CN 1-488 1489 1490 1-491 e M92 l〇pC02H 1-493 I-A94 1-496 NMe〇 1-497 1498 1-499
-83- 1376367 [化9 3] 1-500 1-501 1-502 it 1-503 1-504 1-505 ^.ί3. 〇0Me 1-510 〜Mc〇 1 0 H U〇Me 1-511 ^ν^Ν^^ΧΌΝΗ— BrS K^C02Me 1-512 〜βΌυ〇Ν 已 1-513 ^"€csm> HO Nx^ 1-514 1-515 so2imh2 1-516 -Ν 1-506 Ν w〇c° ο^ό
1-517 eft) 1-507 Ο 1-518 .n^.och3 OCH, )CH, H N.
CN I Η Η欠―N〇c f3 1-508 ^S-N, XX〕 1-519 1-509 .R^q^C0NH2 1-520
S 84 1376367
【化9 4】 1-521 1-522 1-523 1-524 1-525 1-526 1-527
1-528
1-529 1-530 1-531
〇L N〇〇 1-532 1-533 1-534 1-535 1-536 1-537 1-538 1-539 1-540 O〇 T〇七
r q ^ ， -85-
1376367 【化9 5】 1-543 1-544 1-545 1-546 1-547 1-548 1-549 1-550 1-551 1-552 I-切欠〇^ 1-554 1-555 1-556 1-557 1-558 1-559 1-560 1-561 1-562 1-563 1-564
1376367 【化9 6]
1-565 1-566 1-567 1-568 1-569 1-570 1-571 1-572
1-576 1-577 1-578 1-579 1-580 1-581 1-582 1-583
co2h
Nu>〇K
Mi N
SOJ
I H γ^Ι Me
I H 1-573 1-574 1-575
OH
C02Me 1-584 H 〇〇 LXn 〇0' 1-585
0〇Me -87- 1376367 【化9 7】 1-587 1-589 1-590 ^SNr^i Η00 kA,N 』SN^i Η 00乂sV、Η 〇〇
x-592 1-593 1-594 1-595 Η 00 kXN ;SNr^ H 00 k^LN4M〇j
Η N^CI 1-599 如0¾ νά A^nNjQ H 1-600 1-601 H 1-602 °°C .n^ocf2chf2 〇 1-603 ^N〇L SMe 1-604 1-605 Jc〇o CN 1-606 ^OMe 1-607 N" 1-596
Me H Nn,
1-597 1-608 IT Br OMe〜
1-598 h C02Me 〇〇 kxLN 备C02Me u 0 0 U^njCn f C Λ ·* -88- 1376367 【化98】 1-611 1-610
N-NH
1-612 1-613
1-614 1-615 1-616 1-617 1-618 1-619 1-620
1-623 1-624 1-625 1-626 1-627 1-628 1-629 1-630 1-631
89- 1376367 【化9 9】 1-632 1-633 1-634 七ciOJ ^〇s〇tXii Η 1-635 1-636 1-644 〇S〇X^n^〇^CN VoO ⑽七cfcu^j Ns^ Me I-⑽ \>°X) Me H N〇2 I補々cfojji3 1-637 1-638 1-639 1-640 1-641 1-642 1-643 乂。S(?〇J々c?〇J^-c〇2Me Λ〇5〇ΧΧην〇〇 ^C02Me 1-653 1-654 J：sf ^Qf°^NMG2
1-649 1-650 ^oCLRji? 00 cu
N !-651 ^〇ν〇^Μ^Χ) 1-652
4R1CXR A
OMe A〇s〇〇LRXrNMe2
OJ
-90- 1376367
【化100】 1-656 OJ Η 0 Χτ〔 1-668 '〇^R_^rC0NH2 Ο v
丨OJf Λ〇5〇ΤΧΕ]νΟ〇Μ8 Η Η ^OMe 1-660 〇Ό XXnyS Ν 心C02Me ^SclR^ob ^ΟΒA0Si〇J 1-657 〇b〇 1-658 1-659 00 1-661 1-662 0 05 [Sj^vvOl-^664 ^TX^C0 1-663 1-665 1-666 1-667 (iJbN〇Jr、 ^'CN,Η VAOJ 戊〕 1-669 tx> 1-670 ^bO^Wv^/C〇NH^々i〇J3. 1-671 1-672 1-673 1-674 1-675 1-676
^XX 1-677 〇% 1-678 1-679 so2nh2 H n^-^och3
OJ1 0CH3CH： x>, cf3
g〇J cf、、〇
NH -91 - 1376367
【化101】 1-680 ^JA OO
1-690 ,OAc 00 1-681 00 L〇Pr 1-691 1-682 1-683
C〇〇H 1-692 1-693 1-684
1-694 乂J〇J』E Cl Σ-685 ^Ol! 1-695 1-686 1-696
>WNT^ H OMe 4 CX^N s^^0-CN 1-687 1-697 1-688 1-698 W〇J. 'N-N ^NHMe
OEt 1-689 C00B 1-699 0_0 ζΧΝ
^pD r c :】 > -w f -92- 1376367 【化102】 q Η ^〇s〇 A^h x-711 ^Srx^sSm2 l-102 Ab1·712
1-703 >1』
COOH 白 1-713
SMe 1-704
2 1-714 NH. ★icu X)rs' 1-705 1-706
1-707 1-708 1-716 1-717 1-718
^?OJW〇J
Et °X)
H
JyJ^CH20H osnh2 1-709
NHAc 1-719
-93- 1376367 【化103】 1-720 1-730 00 Ο0'
Et 1-721 α〇δ〇ΗΧΧ^ 1-731 ^〇NXXn 1-722 ，Η 1-723 Η 1-733 0 0 O^C0NMe2
a〇s〇xxs c O^C〇2Me
X-724 ^-CXB 1-734 i H Jsn
O Ό 0 0 Ov^N^jO^CONHMe 1-725 1-735 I H ^SN 00
tXHN
Na〇：
1-726 H 0 0 IA.N
1-736 〇〇 Ox^cnO 1-727
Usi 00
i〇J 1-737
0
^〇s〇XXK
1-728 1J XXKjOl, 1-738 I H λ〇Ν 0¾ 〇r 1-729 1-739 ^XXK, ,0Me 、0Me -94- 1376367 【化104】 1-740
H Me , 1-750 "COO Me 1-741
^XXW 1-751
H H OMe k>^V，N'0^C〇NMe2 1-742 1-743 參 Η 1-752 〇〇 00
1-753
NH
aP
1-744 u H
1-754 o
No 0 1-745 1-755
On〇 ,OJ. KCOOMe 1-746 eg. 1-756 〇L(
H .Rj\L〇〆 1-747 Ό^ΝΟΗ 1-757 1-748 1-758 H <Jui〇J· ^c,
TO OMe OMe 1-749 °^〇ji〇O〇' 1-759 -95-
1376367 【化106】 la-23 la-24 la-25 la-26
la-27 la.-2 8 la-29
la-30 la-31 la-32 la-33 〇 H *^F 0〇SbO-..N^L,F,H FVNcr 七〇.崎^o.
tX Ό： OMe OMe la-35 la-36 la-37 la-38 la-39 Ia40 Ia41 Ia42 Ia43 Ia44
-97- 1376367 【化10 7】 I“5 o^o
07、W獅〜¥
No
Ia^7 Ο Ν0) la-58
Ia^8 ,.n 'Μ
la-49 ^00 13-,. Ο la-60 la-50
51 增
Wxxt
la-61 Η
la-62 ★〇sfc,」W〇,,..
0 1¾.
Me -埝〇..、- 0^0
"Nt> NHS02Me la-53 W〇,_
Hn
la-64
H la-54 說〇·,
H Λ la-65 W〇.,JWtx
N
On la-55
la-66
NHS〇2Ph OH
-98- 1376367 【化108]
la-67 la-68 la-69 la-70 la-71
la-72 la-73 la-74 la-75
la-83 la-84 la-79 la-80 la-81 la-82
la-76 la-77
-99- 1376367 【化109] la-89 la-90 la-91
la-104 la-105 la-106 la-107 la-108 la-109 la-110 la-111
la-123 Ia-124 , H la-125 , H Ia-126 H H 〇〇 Uk^N la-127 la-130 la-131 la-122
〇、n R
H 丨丨W VCO 〇〇 o： c〇 o, O' cf3 CF,
Woj
Ia-132 O H °'〇 O^n^q^conh-C -100- 1376367 【化1 1 0】 la-133 la-134
Ia-135
；Op la-136 Ϋ la-137 cu
F la-138 !αρ
la-139 0¾ XXJ '0
Ia_14。為 J
Ia-141 \S〇N<Q la-142 〇〇 o CF,
Ι&—143 W 'xx> ^-〇cf3 la-144 la-145 la-146 la-147 la-148 la-149 la-150 la-151 la-152 la-153 la-154 1376367 【化1 1 1】 Ia-155 忍 Ia_166 CF,
H la-156 Η3〇^Ό h la_l67u.』€〇 H3C^ H Ia_157 〇〇 ia-168 ，b la-169
\ η少H 〇〇 U：,M fl la-158 oo
H 00 '〇J、 cf3 00
H 00
'〇J la-159 cu. ^〇sS° la-171 la-160 o
la-161
Op cp3 la-172 la-173 la-162 o la-163 la-164 la-165 ^os6"
NTYCOOoO la-174 la-175 la-176
00 a』 O〇
H 。〇 00
o〇o〇0O -102- ΒΊ636Ί 1^1121 ia-\n la-m 爲- M^CF3 la-\SO Η Ia493
Ia-\90 ^os〇S〇, Ο
Ia-\19 la-\Sl
5
Ia-\94 v ^00 Ό·<.^^ομη^Ό-J^o'
la-脱
Xa-lS3 %St),
Ia-\84
t7a
Ia-\95
Ia-\96 ^O, 、
N 'Oo
la-197
U5 广cf(3U
Ia-19S
〇s〇OJ t>0〇
滿 W〇.,J
Ia-187 la-188 la-189 o'b H op
la-199 h, Ό·Ά 八 Ia-2〇〇 Τ'δ-Ν,χ^. h ΤΙ Ψ 〇〇〇-w. ,H h OcP〇_〇,0，-"Nt>co^ Ia·201 v切OUD 1咖
-103- 0 1376367 【化1 口】 la-203 la-204
Ad la-216 la-219 la-220 xIo, la-205 s
Asn O'b^aiX)· cf3
o O〇x5
Xa-221 Ό〇-^ la-222_十v?…“I瑪少 X,20B i&.224 VhO η 06 ㈣智 〇J 々3 Ia_225 Ia-21〇 ^α«
Xa-2〇^ /cjt) ，
la-226
ia-2nw M〇Jv' b H la-228 Ή, la-213 〇 la-229 la-214 ia23〇 Ia-215 贫 O'少
〇〇H
la-227
H CH3
CONH
-104- 1376367 【化1 1 4】 la-231 la-232 la-233 la-234 la-235 la-236 la-237 la-238 la-239 la-240 la-241 la-242 la-243 la-244
-105- ;v 如9
Ib-14 lb-15 lb-16 lb-17 lb-18
^19 ^0-¾ 负-'0 一如』tv
Ib-^
Ib-20 lb-21 lb-22
-106- 1376367 【化1 1 6】 lb-23 秦4f
Ib-24 lb-25 lb-26 lb-27 lb-28 lb-29 lb-30 lb-31 lb-32 lb-33
lb-35 lb-36 lb-31 lb-38 lb-39 lb-40 Ib^l lbA2 lb-43 lb-44
-107- 1376367 【化1 1 7】 lb-45 lb-46 lb-47 lb-48 lb-49
So』 々〇 〇L』-
H
lb-57 ^〇Jj lb-56 'Q^h
Ib-58 lb-59
H XX^OH^NS)<
H lb-50 h
lb-60 h
0
H
H
lb-51 H lb-61 lb-62 lb-52
H σο η o H V H 〇 00
XXB x>
lb-63 H lb-53 〇〇 lb-64 lb-54
H
N^V 00 lb-65 o
JHS02Me Y1 hXX \ H >IHS02Ph μ 00 n
H lb-55
So』 lb-66
H
OH
00 < c -108- 1376367 【化1 1 8】 lb-68 ^
OJ ύα lb-78 Η
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Ib-108 lb-109
lb-110 0^1H2
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lb-133 lb-134 lb-135 lb-136 Ib-137 lb-138 lb-139 lb-140 lb-141 lb-142 lb-143
lb-148 lb-149 lb-151 lb-152 lb-' lb-154 lb-146 Η^χ lb-147
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Q 112- 1376367 【化122】
lb-155 lb-156 lb-157 lb-158 lb-159 lb-160 lb-161 lb-162 lb-163 lb-164 lb-165
lb-166 lb-167 lb-168 lb-169 lb-171 lb-172 lb-173 lb-174 lb-175 lb-176
re、 -113 - 1376367 【化1 2 3】 lb-177 lb-178 lb-179 lb-180
N
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lb-181 lb-182 τα so2nh lb-188 lb-189 lb-190 lb-191 lb-192
lb-183
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【化124] lb-199 lb-200 lb-201 lb-202 lb-203 lb-204 lb-205 lb-206 lb-207 lb-208 lb-209
lb-210 lb-211 lb-212 lb-213 lb-214 lb-215 lb-216 lb-219 lb-220 lb-221 lb-222 lb-223 lb-224 lb-225 lb-226
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Ic-35 Ic-36 Ic-37 Ic-38 Ic-39Ic， Ic41 Ic-42 Ic43 Ic44
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Ic-45 Ic-46 Ic-47
Ic-48 Ic-49 Ic-50 Ic-51 Ic-52 Ic-53
Ic-54 Ic-55
Ic-56 Ic-57 Ic-58 Ic-59 Ic-60 Ic-61 Ic-62 Ic-63 Ic-64 Ic-65 Ic-66
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Ic-100 Ic-101 Ic-102 Ic-103 Ic-104 Ic-105 Ic-106 Ic-107 Ic-108 Ic-109 Ic-110
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Ic-123
Ic-124
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Ic-126
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Ic-163 Ic-164 Ic-165
Ic-166 Ic-167 Ic-168 Ic-169 Ic-171 Ic-172 Ic-173 Ic-174 Ic-175 Ic-176
* -123- 1376367 【化1 3 3]
Ic-177 Ic-178 Ic-179 Ic-180 Ic-181 Ic-182 Ic-183 Ic-184 Ic-185 Ic-186 Ic-187
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Ic-188 Ic-189 Ic-190 Ic-191 Ic-192 Ic-193 Ic-194 Ic-195 Ic-196 Ic-197 Ic-198
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Ic-201 Ic-202 Ic-203 Ic-204 Ic-205
Ic-206 Ic-207 Ic-208 Ic-209
Ic-210 Ic-211
Ic-212 Ic-213 Ic-214 Ic-215 Ic-216 Ic-219 Ic-220 Ic-221 Ic-222 Ic-223 Ic-224 Ic-225 Ic-226
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Id-81
Id-82
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Id-86
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Id-91 Id-92 Id-93 Id-94 Id-95 Id-96 Id-97 Id-98 Id-99
Id-100 Id-101 Id-102 Id-103
Id-105 Id-106 Id-107 Id-108 Id-109 Id-110
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Id-121
Id-122 Id-123 Id-124 Id-125 Id-126 Id-127 Id-128 Id-129 Id-130 Id-131
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Id-133 Id-134 Id-135 Id-136 Id-137 Id-138 Id-139 Id-140 Id-141 Id-142 Id-143
Id-144 Id-145 Id-146 Id-147
Id-148 0¾ H Id-149 八k Id-150 Id-151 H Id-152 ch3
Id-153 Id-154
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Id-222 Id-223 Id-224 Id-225
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Ih-160
Ih-161
Ih-162 • Ih-163
Ih-164
Ih-165
Ih-166 Ih-167 Ih-168 Ih-169 Ih-171
Ih-172 Ih-173 Ih-174 Ih-175 Ih-176
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XX onh Ih-198 -154- 1376367 【化16 4】 Ih-199
Ih-200
Ih-201
Ih-202
Ih-203
Ih-204
Ih-205
Ih-206
Ih-207
Ih-208
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Ih-212
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Ih-222 η V 0¾ Ih-223 h F' ^224 滅 o〇^F XXy Ih-225 H ^ 〇6^XXn^kf3 -155 - 1376367 化合物1-72 [化 165]
*H-NMR (DMSO-d ) δ : 0.90-1.05 (m, 2 Η), 1.05-1.15 (m, 6Η), 1.25 (s, 9H,), 1.15 c
-1.32 (m, 3H), 1.41 (m, !H), 1.75-1.98 (m, 4H), 2.11 (m, 1H), 2.58-3.38 (m, 5H), 3 • 58-3.76 (m，2H), 5. Π (m, 1H), 6.25-6.92 (m, 5H)融點：147-149cC 化合物〖a-140 [化 166]
'H-NMR (CDC.1) δ : 1.02-1.20 (m, 2 H), 1.17-1.32 (m, 2 H), 1.37 (d, 6H, J = 6.9 Hz), 1.46-1.70 (in, 4H), 1.86-1.95 (m, 2H), 2.08-2.18 (m, 2H), 3.01 (d, 2H, J = 6. 9 Hz), 3.13 (m, 1H), 3.25 (m, 1H), 3.87 (d, 1H, J = 8.4 Hz) , 6.61(d, 2H, J = 8.7 Hz ),7.39 (d, 2H, J = 8.7 Hz)
化合物la-141 [化 167]
H-NMR (CDCI) δ : 1.00-1.30 (m, 4 H), 1.37 (d, 6H, J = 6.9 Hz), 1.59 (m, 1H), 1. 3 87-1.98 (m, 2H), 1.99-2.18 (m, 5H), 2.85 (q, 3H, J = 7.5 Hz), 2.97 (d, 2H, J = 6.9 Hz), 3.12 (m, 1H), 3.23 (m, 1H), 3.88 (d, 1H, J = 8.1 Hz), 6.53 (d, iH, J = 7.8 Hz) ,6.63 (brs, 1H), 7.04 (d, 1H, j = 7.8 Hz) Mass: 35l[M+H] 化合物la-178 -156- 1376367 [化 168]
'H-NMR (CDC1) δ : 1.08-1.36 (m, 4 Η), 1.39 (s, 9H), 1.59 (m, 1H), 1.90-1.99 (m, 3 2H), 2.16-2.26 (m, 2H), 3.17-3.34 (m,3H), 3.69 (d, 1H, J = 9.3 Hz), 6.68 (d, 1H, J =9.3 Hz), 7.77 (dd, 1H, J = 2.1 Hz and 9.3 Hz)； 8.49 (brs, 1H) Mass: 394[M+H]+ 化合物lb-138 [化 169]
YOj δ : 1.02-1.34 (m, 4 Η), 1.37 (d, 6H, J = 6.6 Hz), 1.57 (m, 1H), 1. 丨H_NMR (CDC13) 87-1.97 (m, 2H), 2.07-2.18 (m, 2H), 2.93 (d, 2H, J = 6.6 Hz), 3.13 (m, 1H), 3.25 ( m,lH),3.99(cUH，J = 8.4Hz),6.38(m，lH),6.49(brs，lH)，6.97(q,m,J=9· 3 Hz) Mass:347[M+H] 化合物Ii-2 [化 170]
'H-NMR (DMSO-d ) 5 : 0.91-1.06 (m, 2H), 1.12-1.28 (m, 11H), 1.31-1.47 (m, 1H) 6 ,1.75-1.94 (m, 4H), 2.19 (t, 2H, J = 11.3 Hz), 2.79 (t, 2H, J = 6.0 Hz), 2.93-3.08 ( m, 1H), 2.97 (q, 2H, J = 7.42 Hz), 3.46 (m, 2H), 3.57-3.69 (m, 2H), 5.71 (t, 1H, J = 5.2 Hz), 5.77 (d, 1H, J = 11.5 Hz), 5.88-5.96 (m, 2H), 7.01 (d, 1H, J = 7,4 Hz). 化合物Π-3 [化 171] -157- 1376367
lH-NMR (DMSO-d ) δ : 0.90-1.07 (m, 2 H), 1.15-1.21 (m, 1H), 1.27 (s, 9H), 1.40-6
1.49 (m, 2H), 1.82 (d, 2H, J = 11.6 Hz), 1.92 (d, 2H, J = 11.6 Hz), 2.79-2.84 (m, 2 H), 2.97-3.10 (m, 1H), 3.24 (s, 3H), 3.55-3.62 (m, 2H), 3.84-3.91 (m, 2H), 5.50-5. 59 (m, 1H), 6.40 (d, 1H, J = 8.0 Hz), 6.56 (s, 1H), 6.72 (d, 1H, J = 8.4 Hz), 6.97 (d, 1H, J = 8.4 Hz).融點：166-168°C 化合物[i-4 [化 17¾
'H-NMR (DMSO-d ) δ : 0.87 (t, 3H, J = 7.2 Hz), 0.93-1.06 (m, 2H), 1.13-1.21 (m, 6
1H), 1.26 (s, 9H), 1.37-1.49 (m, 2H), 1.61-1.72 (m, 2H), 1.82 (d, 2H, J = 12.0 Hz) ,1.91 (d, 2H, J = 12.0 Hz), 2.78-2.84 (m, 2H), 2.97-3.08 (m, 1H), 3.61-3.71 (m, 2 H), 5.52-5.60 (m, 1H), 6.40 (d, 1H, J = 8.4 Hz), 6.56 (s, 1H), 6.73 (d, 1H, J = 8.8 Hz), 6.97 (d, 1H, J = 8.8 Hz).融點：185-186°C 化合物Ii-5 [化 173]
'H-NMR (DMSO-d ) 5 : 0.90-1.05 (m, 2H), 1.26 (s, 9H), 1.28-1.31 (m, 1H), 1.35-6 1.47 (m, 8H), 1.81 (d, 2H, J = 12.4 Hz), 1.91 (d, 2H, J = 12.4 Hz), 2.77-2.84 (m, 2 -158- 1376367
Η), 2.96-3.07 (m, 1Η), 4.30-4.42 (m, 1H), 5.51-5.64 (m, 1H), 6.39 (d, 1H, J = 8.0 Hz), 6.55 (s, 1H), 6.72 (d, 1H, J = 8.8 Hz), 7.07 (d, 1H, J = 8.8 Hz).融點：156-15 7°C 化合物丨卜6 [化 174]
'H-NMR (DMSO-d ) δ : 0.91-1.07 (in, 2H), 1.19-1.25 (m, 4H), 1.26 (s, 9H), 1.38-6 1.49 (m, 2H), 1.82 (d, 2H, J = 8.8 Hz), 1.91 (d, 2H, J = 8.8 Hz), 2.79-2.84 (m, 2H). 2.97-3.07 (m, 1H)( 3.69-3.80 (m, 2H), 5.51-5.63 (ra, 1H), 6.41 (d, 1H, J = 8.0 Hz) ,6.56 (s, 1H), 6.72 (d, 1H, J = 8.8 Hz), 6.97 (d, 1H, J = 8.8 Hz〉·融點：178-179°C 化合物Ii-7 [化 175]
'H-NMR (DMSO-d ) δ : 0.92-1.07 (m, 2H), 1.19-1.22 (m, 1H), 1.26 (s, 9H), 1.38-6 1.48 (m，2H), 1.8έ (d, 2H, J = 11.6 Hz), 1.91 (d, 2H, J = 11.6 Hz), 2.79-2.84 (m, 2 H), 2.95-3.09 (m, 1H), 3.25 (s, 3H), 5.52-5.60 (m, 1H), 6.41 (d, 1H, J = 8.4 Hz), 6. 56 (s, 1H). 6.72 (d, 1H, J = 8.4 Hz), 6_92 (d, 1H, J = 8.4 Hz).融點：206-2071 化合物li-8 [化 176]
-159- 1376367 5H-NMR (DMSO-d ) 5 : 0.91-1.05 (m, 2H), 1.16-1.24 (m, 1H), 1.26 (s, 9H), 1.37-6 1.47 (m, 2H), 1.81 (d, 2H, J = 12.8 Hz), 1.90 (d, 2H, J = 12.8 Hz), 2.75-2.81 (m. 2 H), 2.96-3.08 (m, 1H), 5.45-5.52 (m, 1H), 6.33 (d, 1H. J = 8.4 Hz), 6.50 (s, 1H), 6. 68-6.80 (m, 2H), 11.02 (brs, 1H).融點：213-214^: 化合物li-9 [化 177]
lH-NMR (DMSO-d ) δ : 0.91-1.08 (m, 2 H), 1.17-1.30 (m, 8H), 1.44 (brs, 1H), 1.8 6 2.(d, 2H, J = 12.4 Hz), 1.89 (d, 2H, J = 12.4 Hz), 2.78-2.82 (m, 2H), 2.97-3.15 (m, 2H), 3.23 (s, 3H), 3.55-3.62 (m, 2H), 3.83-3.90 (m, 2H), 5.52-5.59 (m, 1H), 6.40 ( d, 1H, J = 8.0 Hz), 6.55 (s, 1H), 6.92 (d, 1H, J = 8.0 Hz), 6.97 (d, 1H, J = 8.4 Hz). 融點：：120-121°C 化合物丨i-10 [化 178]
lH-NMR (DMSO-d ) 8 : 0.88 (t, 3H, J = 7.2 Hz), 0.93-1.08 (m, 2H), 1.17-1.30 (m, 6 8H), 1.44 (brs, 1H), 1.52-1.61 (m, 2H), 1.83 (d, 2H, J = 12.0 Hz), 1.90 (d, 2H, J = 12.0 Hz), 2.78-2.84 (m, 2H), 2.98-3.15 (ra, 2H), 3.62-3.71 (m, 2H), 5.52-5.60 (m, 1H), 6.41 (d, 1H, J = 8.4 Hz), 6.57 (s, 1H), 6.92 (d, 1H, J = 8.0 Hz), 6.97 (d, 1H, J = 8.4 Hz).融點：144-145。。 化合物li-11 [化 179] -160- 1376367
'H-NMR (DMSO-dJ δ : 0.90-1.08 (m, 2H), 1.15-1.30 (m, 8H), 1.33-1.50 (m, 7H), 6 l. 82 (d. 2H, J = 12.0 Hz), 1.89 (d, 2H, J = 12.0 Hz), 2.78-2.86 (m, 2H), 2.96-3.14 ( m, 2H), 4.30-4.45 (m, 1H), 5.50-5.61 (m, 1H), 6.40 (d, 1H, J = 7.6 Hz), 6.55 (s, 1 H), 6.92 (d，1H, J = 7.2 Hz), 7.07 (d, 1H，J = 7.6 Hz).融點：137-138T： 化合物H-12
[化 180]
'H-NMR (DMSO-d ) δ : 0.92-1.07 (m, 2H), 1.14-1.30 (m, 11H), 1.36-1.50 (m, 1H) 6
,1.82 (d, 2H, J = 12.0 Hz), 1.89 (d, 2H, J = 12.0 Hz), 2.78-2.85 (m, 2H), 2.97-3.15 (m, 2H), 3.69-3.79 (m, 2H), 5.52-5.60 (m, 1H), 6.41 (d, 1H, J = 8.4 Hz), 6.56 (s, 1 H), 6.92 (d, 1H, J = 7.2 Hz〉，6.98 (d, 1H. J = 8.4 Hz).融點：158-159°C 化合物Ii-13 [化 181]
'H-NMR (DMSO-d ) δ : 0.90-1.06 (m, 2H), 1.12-1.30 (m, 8H), 1.34-1.51 (m, 1H), 6 l. 82 (d, 2H, J = 12.0 Hz), 1.88 (d, 2H, J = 12.0 Hz), 2.77-2.83 (m, 2H), 2.95-3.12 ( m, 2H), 3.25 (s, 3H), 5.51-5.59 (m, 1H), 6.41 (d, 1H, J = 8.8 Hz), 6.56 (s, 1H), 6.8 6-6.97 (m, 2H).融點.：157-1581 化合物Ii-14 1376367 [化 182]
'H-NMR (DMSO-d ) 5 : 0.91-1.08 (m, 2 Η), 1.12-1.30 (m, 5H), 1.38-1.50 (m, 1H), 6 l. 82 (d, 2H, J = 12.0 Hz), 1.88 (d, 2H, J = 12.0 Hz), 2.77-2.85 (m, 2H), 2.90-3.09 (m, 3H), 3.23 (s, 3H), 3.55-3.61 (m, 2H), 3.84-3.91 (m, 2H), 5.52-5.60 (m, 1H), 6. 40 (d, 1H, J = 8.4 Hz), 6_55 (s, 1H), 6.89-7.00 (m, 2H).融點：150-151°C 化合物U-15
[化 L83] H
XXl^0 'H-NMR (DMSO-d ) δ : 0.88 (s, 3H), 0.90 (s, 3H), 0.92-1.08 (m, 2H), 1.12-1.30 ( 6
m, 5H), 1.35-1.51 (m, 1H), 1.83 (d, 2H, J = 12.4 Hz), 1.89 (d, 2H, J = 12.4 Hz), 2. 00-2.16 (m, 1H), 2.77-2.84 (m, 2H), 2.90-3.10 (m, 3H), 3.42-3.55 (m, 2H), 5.50-5. 65 (m, 1H), 6.40 (d, 1H, J = 8.4 Hz), 6.56 (s, 1H)，6.88-7.01 (m, 2H)融點：132-13 3°C
化合物Ii-16 [化 184]
lH-NMR (DMSO-d ) δ : 0.87 (t, 3H, J = 6.8 Hz), 0.90-1.08 (m,' 2H), 1.10-1.28 (m, 6 5H), 1.35-1.50 (m, 1H), 1.59-1.72 (m, 2H), 1.82 (d, 2H, J = 12.0 Hz), 1.89 (d, 2H, J = 12.0 Hz), 2.77-2.85 (m, 2H), 2.90-3.09 (m, 3H), 3.61-3.71 (m, 2H), 5.52-5.61 (m, 1H), 6.40 (d, 1H, J = 8.0 Hz), 6.56 (s, 1H), 6.97 (d, 2H, j = 8.0 Hz).融點：136 ' V·» «· -162- 1376367 -137t： 化合物li-Π [化 185] Η
'H-NMR (DMSO-d) 5 : 0.92-1.06 (m. 2H), 1.12-1.28 (m, 5H), 1.33-1.50 (m, 7H), 6 l. 81 (d, 2H, J = 12.0 Hz), 1.88 (d, 2H, J = 12.0 Hz), 2.78-2.84 (m, 2H), 2.90-3.08 (
m, 3H), 4.28-4.44 (m, 1H), 5.49-5.79 (m, 1H), 6.39 (d, 1H, J - 8.0 Hz), 6.55 (s, 1 H), 6.97 (d, 1H, J = 7.6 Hz), 7.07 (d, 1H, J = 8.0 Hz). :124-125°C 化合物I卜18 [化 186]
'H-NMR (DMSO-d ) 5 : 0.90-1.07 (m, 2H), 1.12-1.29 (ra, 8H), 1.36-1.51 (m, 1H), l. 82 (d, 2H, J = 12.0 Hz), 1.89 (d, 2H, J = 12.0 Hz), 2.78-2.86 (m, 2H), 2.90-3.09 (
m, 3H), 3.68-3.80 (m, 2H), 5.51-5.61 (m, 1H), 6.41 (d, 1H, J = 8.4 Hz), 6.57 (s, 1 H), 6.97 (d, 2H, J = 8.4 Hz).融點：163-164T 化合物Ii-19 [化 187]
\ 'h-NMR (DMSO-d ) 6 : 0.89-1.08 (m, 2H), 1.11-1.30 (m, 5H), 1.35-1.51 (m, 1H), l. 82 (d, 2H, J = 10.8 Hz), 1.89 (d, 2H, J = 10.8 Hz), 2.75-2.88 (m, 2H), 2.89-3.10 ( m, 3H), 3.25 (s, 3H), 5.48-5.60 (m, 1H), 6.42 (d, 1H, J = 7.6 Hz), 6.56 (s, 1H), 6.9 -163- 1376367 2 (d, 1H, J = 7.6 Hz), 6.98 (d, 1H, J = 5.6 Hz).融點.：189-190°C 化合物Ii-20 [化 188]
'H-NMR (DMSO-d ) δ : 0.95-1.13 (m, 2H), 1.31-1.59 (m, 10H), 1.73-1.92 (m, 4H) 6
,2.12-2.26 (m, 2H), 2.84 (d, 2H, J = 6.0 Hz), 3.07-3.30 (m, 4H), 4.30-4.46 (m, 1H ),5.64 (brs, 1H), 6.41 (d, 1H, J = 8.4 Hz), 6.57 (s, 1H), 7..08 (d, 1H. J = 8.4 Hz). 融點：165-1661 化合物丨卜21 [化 189]
'H-NMR (DMSO-d ) δ ： 0.86-1.25 (m, 10H), 1.40 (d, 3H, J = 6.9Hz), 1.52 (m, 1H), 6
1.82-1.93 (m, 4H), 2.95-3.00 (m, 5H), 3.63-3.91 (m, 2H), 4.61-4.68 (m, 1H), 6：73 (brs, 2H), 7.01 (d, 2H, J = 7.8Hz), 7.11 (d, 1H, J = 8.1Hz,). 化合物Π-22 [化 190]
'H-NMR (DMSO-d ) δ : 0.98-1.10 (m, 2 H), 1.15-1.34 (m, 5H), 1.36-1.43 (m, 9H), 6 1.53 (m, 1H), 1.82.1-93 (m, 4H), 2.94-3.01 (m, 6H), 4.52 (m, 1H), 4.63 (m, 1H), 6 -164- 1376367 .73 (brs, 2H), 7.02 (d, 1H, J = 7.5Hz), 7.21-7.25 (m, 1H). 化合物li-23 [化 191]
'κ-NMR (DMSO-d ) 6 : 0.86-1.04 (m, 4 H), 1,25 (s, 10H), 1.30 (s, 6H), 1.38 (s, 3 6
H), 1.40 (s, 3H), 178-1.92 (m 4H), 2.76-2.80 (m, 2H), 3.03 (m, 1H), 4.54-4.63 (m, 1H), 5.57 (m, 1H), 6.16 (s, 1H), 6.22 (d, 1H, J = 8.4Hz), 6.76 (d, 1H, J = 8.4Hz), 6. 98 (d, 1H, J = 8.4Hz). 化合物Ii-24 [化 192]
iH-NMR (DMS〇-d ) δ : 0.98-U1 (m, 5 H), 1.15-1.31 (m, 20H), 1.57 (m, 1H), 1.8 6
2.1-93 (m, 4H), 2.74-2.81 (m, 1H), 3.01-3.06 (m, 2H), 3.35 (m, 1H), 3.40 (m, 1H), 4.04-4.17 (m, 3H), 6.77 (d, 1H, J = 9.0Hz), 化合物Ii-25 [化 193]
'H-NMR (DMSO-d ) δ : 0.98-1.20 (m, 13 H), 1.30 (d, 3H, J = 3H), 1.59 (m, 1H), 1 6 .81-1.91 (m, 4H), 2.73-2.83 (m, 1H), 2.94-3.04 (m, 4H), 3.35-3.45 (m, 2H), 4.08-4
-165- 1376367 .19 (m, 3H), 6.88 (brs, 3H), 7.03 (d, 1H, J = 8.4Hz). 化合物U-26 [化 194]
2 HCI H 、，、 'H-NMR (DMSO-d ) δ : 1.02-1.10 (m, 2H), 1.19-1.32 (m, 2H), 1.26 (s, 9H), 1.55 ( 6
m, 1H), 1.86-1.93 (m, 4H), 3.01-3.04 (m, 3H), 6.76 (d, 1H, J = 8.7 Hz), 7.03 (m, 1 H), 7.37-7.43 (m, 3H), 7,76-7.80 (m, 1H), 8.20-8.23 (m, 1H). 8.34-8.40 (m, 1H), 8 .78-8.79 (m, 1H) 化合物li-27 [化 195]
'H-NMR (DMSO-d ) 5 : 1.03-1.10 (m, 2H), 1.20-1.30 (m. 2H), 1.21 (d. 6H, J = 6.9 6
Hz), 1.53 (m, 1H), 1.88 (m, 4H), 2.99-3.15 (m, 3H), 7.33-7.35 (m, 3H), 7.71-7.75 (m, 1H), 8.16-8.18 (m, 1H), 829-8.32 (m, IK), 8.76-8.78 (m, 1H)
化合物Ii-28 [化 196]
'H-NMR (DMSO-d ) 6 : 1.04-1.11 (m, 2H), 1.15-1.28 (m, 2H), 1.19 (t, 3H, J =7.2 6
Hz), 1.59 (m, 1H), 1.87-1.91 (m, 4H), 2.93-3.08 (m, 2H), 2.97 (q, 2H, J =7.2 Hz), 3.06-3.08 (m, 2H), 7.01 (m, 1H), 7.17 (d, 1H, J =7.5Hz), 7.43 (d, 1H, J =7.5Hz), 7. 50-7.57 (m, 2H). 7.80-7.84 (m, 1H), 8.25-8.27 (m, 1H), 8.39-8.44 (m. 1H), 8.80-8. -166- 1376367 82 (m, 1H) 化合物li-29 [化 197]
'H-NMR (DMSO-d) δ : 0.99-1.10 (m, 2H), 1.15-1.28 (m, 2H), 1.19 (t, 3H, J =7.5 6 .
Hz), 1.52 (m, 1H), 1.84-1.91 (m, 4H), 2.94-3.01 (m, 5H), 6.88 (m, 1H), 7.00 (d, 1H ,J =7.8 Hz), 7.26-7.28 (m, 2H), 7.38 (m, 1H), 7.76 (d, 1H, J = 3.3. Hz), 7.90 (d, 1 H, J =3.3 Hz) 化合物Ii-30 [化 198] 2Ησ ^ 'h-NMR (DMSO-d) 6 : 0.93-1.08 (m, 2 H), 1.18-1.33 (m, 2H), 1.26 (s, 9H), 1.45 6
(m, 1H), 1.78-1.97 (m, 4 H), 2.86-2.94 (m, 2H), 2.95-3.10 (m, 1H), 5.91 (m, 1H), 6.55 (d, 1H, J = 7.6 Hz), 6.63-6.71 (m, 2H), 6.73 (d, 1H, J = 8.0 Hz), 7.06 (s, 1H), 7.15 (t, 1H, J = 8.0 Hz), 7.60 (s, 1H), 8.11 (s, 1H), 8.31 (s, 1H) 化合物Ii-31 [化 199]
'H-NMR (DMSO-d) δ : 0.93-1.08 (m, 2 H), 1.13-1.28 (m, 2H), 1.26 (s, 9H), 1.43 6 (m, 1H), 1.76-1.97 (m, 4 H), 2.83-3.18 (m, 3H), 5.79 (m, 1H), 6.21 (s, 2H), 6.44 ( d, 1H, J = 6.8 Hz), 6.58-6.67 (m, 2H), 6.73 (d, 1H, J = 8.0 Hz), 7.10 (t, 1H. J = 8.0 -167- 1376367
Hz), 7_2i (s, 2H)融點.:205-206t： 化合物U-32 [化200] cr 'H-NMR (DMSO-d ) 6 : 0.90-1.05 (m, 2 H), 1.05-1.28 (m, 11H), 1.41 (m, 1H), 1. 6
75-1.92 (m, 4 H), 2.11 (t, 2H, J = 10.0 Hz), 2.73-2.82 (m, 2H), 2.91-3.08 (m, 3H), 3.24 (d, 2H, J = 11.2 Hz), 3.62-3.72 (m, 2H), 5.07 (m, 1H), 6.47 (d, 2H, J = 7.2 Hz ),6.72 (d, 2H, J = 7.2 Hz), 6.97 (d, 1H, J = 7.6 Hz)融點：165-166t： 化合物Ii-33 [化 201]
^-NMR (DMSO-d ) 6 : 0.91-1.06 (m, 2H), 1.15-1.26 (m, 8H), 1.33-1.48 (m, 1H), 6
1.71-1.93 (m, 4H), 2.88 (d, 2H, J = 6.5 Hz), 2.93-3.15 (m, 2H), 5.70 (brs, 2H), 6.6 3 (d, 2H, J = 9.1 Hz), 6.93-6.96 (m, 1H), 7.38-7.42 (m, 2H), 7.57 (d, 2H, J = 9.1 H z), 7.88-7.93 (m, 2H) 化合物[卜34 [化202] Ή » HC,
U^tV〇rF Q% 'H-NMR (DMSO-d ) δ : 0.98-1.02 (m, 2H), 1.16-1.18 (m, 5H), 1.42 (s, 1H), 1.75-1.91 (m, 4H), 2.88 (d, 2H, J = 6.6 Hz), 2.96 (q, 3H, J = 7.3 Hz), 6.63 (d, 2H, j = 8. c -168- 1376367 9 Hz), 6.99-7.02 (m, 1H), 7.38-7.41 (m, 2H), 7.57 (d, 2H, J = 8.9 Hz), 7.89-7.92 ( m, 2H). 化合物Ii-35 [化203]
'H-NMR (DMSO-d ) δ : 0.90-1.52 (m, 5H), 1.L9 (t, 3H, J = 7.2 Hz), 1.75-1.96 (m, 8
4H), 2.50-3.10 (m, 3H), 2.62 (q, 2H, J = 7.2 Hz), 5.55-5.70 (m, 1H ), 6.57 (d, 2H, J = 8.7 Hz), 6.80-7.04 (m, 4H), 7.01 (d, 1H, J = 7.8 Hz), 7.34 (d, 2H, J = 8.7 Hz) 化合物Ii-36 [化204]
lH-NMR (DMSO-d) δ : 0.90-1.50 (m, 5H)，1.19 (t, 3H, J = 7.2 Hz), 1.75-1.95 (m, 6 4H), 2.70-3.10 (m, 3H), 2.97 (q, 2H, J = 7.2 Hz), 3.70 (s, 3H), 5.40-5.50 (m, 1H ), 6.53 (d, 2H, J = 8.7 Hz), 6.74 (d, 2H, J = 8.7 Hz), 6.78-6.90 (m, 4H), 6.99 (d, 1H, J = 7.8 Hz)
化合物li-37 [化205]
Ή-NMR (CDC1) 6 : 1.02-1.32 (m, 4 H), 139 (s, 9H,), 1.58 (m, 1H), 1.86-1.96 (m, 3 2H), 2.12-2.22 (m, 2H), 3.02 (d, 2H, J = 6.6 Hz), 3.25 (m, 1H), 3.67 (d, 1H, J = 9.3 Hz) , 6.67(d, 2H, J = 8.7 Hz), 7.41 (d, 2H, J = 8.7 Hz) Mass:393[M+H] 化合物Ii-38 -169- 1376367 tXc, 'H-NMR (DMSO-d ) 5 : 0.93-1.07 (m, 2H), 1.17-1.26 (m, 2H), 1.19 (t, 3H, J = 7.1 6
Hz), 1.43 (s, 1H), 1.77-1.85 (m, 2H), 1.85-1.94 (m, 2H), 2.82 (t, 1H, J = 5.8 Hz), 2.98 (m, 1H), 2.97 (q, 2H, J = 7.1 Hz), 5.87 (m, 1H), 6.56 (d, 2H, J = 8.6 Hz), 6.98 (d, 1H, J = 7.6 Hz), 7.02 (d, 2H, J = 8.6 Hz).
[化206]
化合物Ii-39 [化207]
JH-NMR (DMSO-d ) δ : 0.98-1.10 (m, 2H), 1.19-1.35 (m, 2H), 1.29 (s, 9H), 1.46 ( 6 s, 1H), 1.73-1.98 (m, 4H), 2.93 (m, 1H), 3.04 (m, 1H), 6.60-6.69 (m, 2H), 6.75 (d, 1H, J = 8.8 Hz), 6.97 (d, 1H, J = 7.6 Hz), 7.49 (d, 1H, J = 8.8 Hz), 8.05 (s, 1H). 化合物Ii-40 [化208]
'H-NMR (DMSO-d ) 6 : 0.96-1.09 (in, 2H), 1.16-1.29 (m, 2H), 1.19 (t, 3H, J = 7.3
Hz), 1.45 (s, 1H), 1.76-1.94 (m, 4H), 1.76 (s, 2H), 2.93 (t, 2H, J = 5.8 Hz), 2.97 ( q, 2H, J = 7.3 Hz), 6.66 (s, 1H), 6.94-7.01 (m, 2H), 7..49 (d, 1H, J = 8.6 Hz), 8.04 ( s, 1H). 化合物Ii_41 [化209] -170- 1376367
JH-NMR (DMSO-d ) δ : 0.91-1.05 (m, 2H), 1.17-1.33 (m, 2H), 1.26 (s, 9H), 1.35-6 1.48 (m, 1H), 1.76-1.86 (m, 2H), 1.86-1.95 (m, 2H), 2.76-2.82 (m, 1H), 2.96-3.08 (m, 1H), 3.71 (s, 3H), 5.21-5.30 (m, 1H), 6.57 (d, 1H, J = 8.6 Hz), 6.73 (d, 1H, J = 8.6 Hz), 7.02 (dd, 1H, J = 8.6, 2.3 Hz), 7.44 (d, 1H, J = 2.3 Hz). 化合物Ii-42 [化 210]
'H-NMR (DMS〇-d〉δ : 0.98-1.01 (m, 2H), 1.18-1.28 (m, 2H), 1.19 (t, 3H, J = 7.1 6
Hz), 1.42 (s, 1H), 1.76-1.85 (m, 2H), 1.85-1.93 (m, 2H), 2.79 (t, 2H, J = 5.9 Hz), 2.97 (q, 2H, J = 7.1 Hz), 3.02 (m, 1H), 3.71 (s, 3H), 5.26 (m, 1H), 6.58 (d, 1H, J = 8.6 Hz), 6.98 (d, 2H, J = 7.8 Hz), 7.02 (d, 2H, J = 8.6 Hz), 7.44 (br s, 1H). 化合物丨i-4'3 [化 211]
'H-NMR (DMSO-d ) 5 : 0.98-1.06 (m, 2H), 1.16-1.25 (m, 2H), 1.18 (t, 3H, J =7.5 6
Hz), 1.51 (m, 1H), 1.83-1.91 (m, 4H), 2.85 (t, 2H, J = 6.3 Hz),. 2.97 (q, 2H, J = 7.5 Hz), 3.04(m, 1H), 3.56 (s, 3H), 5.46 (t, 1H, J = 6.3 Hz). 5.76 (s, 1H), 6.49 (d, 1H，J =7.8 Hz), 7.21 (t, 1H, J = 7.5Hz), 7.32 (t, 2H, J = 7.5 Hz), 7.68 (d, 2H, J = 7.5 Hz ) 化合物Ii-44 -171 - 1376367 [化 212]
'H-NMR (DMSO-d ) 6 : 0.96-1.05 (m, 2H), 1.18 (t, 3H, J = 7.2 Hz), 1.24 (m, 2H), 1.48 (m, 1H), 1.76-1.91 (m, 4H), 2.91 (d, 2H, J = 6.6 Hz), 2.97 (q, 2H, J = 7.2 Hz), 6.35 (s, 1H), 6.99 (d, 1H, J = 7.8 Hz), 7.46-7.49 (m, 3H), 7.73-7.76 (m, 2H) 化合物Π-45 [化213]
lH-NMR (DMSO-d ) δ : 0.92-1.08 (m, 2H), 1.15-1.22 (m, 1H), 1.26 (s, 9H), 1.37-6 1.51 (m, 2H), 1.81 (d, 2H, J = 11.6 Hz), 1.91 (d, 2H, J = 11.6 Hz), 2.76-2.86 (m, 2 H), 2.97-3.08 (m, 1H), 3.35 (s, 3H), 5.82-5.91 (m, 1H), 6.26 (d, 1H, J = 13.6 Hz), 6.39 (s, 1H), 6.73 (brs, 1H).融點.:215-216¾ 化合物U-46 [化 214]
'H-NMR (CDC1) δ : 1.02-1.32 (m, 4H), 1.24 (d, 6H, J = 6.0 Hz), 1.39 (s, 9H), 1.5 3 4 (m, 1H), 1.84-1.94 (m, 2H), 2.12-2.22 (m, 2H), 2.39 (t, 2H, J = 10.5 Hz), 2.94 (d ,2H, J = 6.9 Hz), 3.24 (m, 1H), 3.38 (d, 1H, J = 9.6 Hz), 3.61 (d, lH, J = 9.6 Hz), 3.72-4.00 (m, 2H), 5.83-5.94 (m, 1H), 5.96-6.10 (m, 2H). 化合物Π-47 [化 215] -172- 1376367
'H-NMR (DMSO-d ) δ : 0.91-1.07 (m, 2H), 1.16-1.34 (m, 11H), 1.40 〇η, 1H), 1.79 (d, 2H, J = 12.5 Hz), 1.90 (d, 2H, J = 11.9 Hz), 2.82 (t, 2H, J = 5.5 Hz), 3.01 (m. 1 H), 6.12-6.18 (m, 3H), 6.30 (t, 1H, J = 5.5 Hz), 6.76 (d, 1H, J = 8.7 Hz). 化合物li-48 [化 216]
!H-NMR (CDC13) 6 : 1.00-1.28 (m, 4H), 1.39 (s, 9H), 1.56 (m, 1H), 1.91 (d, 2H, J =12.4 Hz), 2.08-2.21 (m, 4H), 2.58 (t, 2H, J = 8.1 Hz), 2.97 (d, 2H, J = 6.0 Hz), 3. 23 (m, 1H), 3.70 (d, 1H, J = 9.4 Hz), 3.80 (t, 2H, J = 7.1 Kz), 6.66 (d, 2H, J = 8.7 Hz), 7.36 (d, 2H, J = 8.7 Hz).
化合物ii-49 [化 217]
'H-NMR (DMS〇-dB) δ : 0.92-1.06 (m, 2H), 1.17-1.33 (m, 11H), 1.41 (m, 1H), 1.80 (d, 2H, J = 12.9 Hz), 1.90 (dj 2H, J = 11.4 Hz), 2.82 (t, 2H, J = 6.1 Hz), 3.01 (m, 1 H), 6.07 (t, 1H, J = 5.3 Hz), 6.34-6.43 (m, 2H), 6.51 (dd, 1H, J1 = 8.2 Hz, J2 = 1.8 Hz), 6.75 (d, 1H, J = 8.5 Hz), 7.11 (t, 1H, 8.2 Hz). 化合物li-50 -173 - 1376367 [化218] 'H-NMR (DMSO-d ) δ : 0.92-1.08 (m, 2H), 1.14-1.31 (m, 8H), 1.43 (m, 1H), 1.76-6 1.94 (m, 4H), 2,82 (t, 2H, J = 6.0 Hz), 2.95-3Λ6 (m, 2H), 5.90 (t, 1H, J = 5.5 Hz), 6.56 (d, 2H, J = 8.7 Hz), 6.95 (d, 1H, J = 7.9 Hz), 7.03 (d, 2H, J = 8.6 Hz).
化合物Ii-51 [化 219].
'H-NMR (DMSO-d ) δ ： 0.90-1.08 (m, 2H), 1.13Ί.31 (m, 8H), 1.42 (m, 1H), 1.76- 6 1.94 (m, 4H), 2.83 (t, 2H, J = 6.0 Hz), 2.95-3.16 (m, 2H), 6.07 (t, 1H, J = 5.4 Hz), 6.36-6.46 (m, 2H), 6.53 (dd, 1H, J1 = 8.1 Hz, J2 = 1.9 Hz), 6.95 (d, 1H, J = 7.9 Hz ),7.12 (d, 1H,J=8.1 Hz).
化合物Ii-52 [化220]
'H-NMR (DMSO-d ) δ ·. 0.91-1.10 (m, 2H), 1.19-1.37 (m, llH), 1.45 (m, 1H), 1.78 6 -1.90 (m, 4H), 2.84 (t, 2H, J = 6.0 Hz), 3.04 (m, 1H), 4.64 (q, 2H, J = 9.0 Hz), 5.73 (t, 1H, J = 5.4 Hz), 6.13-6.21 (m, 2H), 6.26 (d, 1H, J = 7.2 Hz), 6.78 (d, 1H, J = 8. 4 Hz), 6.99 (t, 1H, 8.0 Hz). -174- 1376367 化合物Π-53 [化 221]
'H-NMR (DMSO-d ) δ : 0.90-1.06 (m, 2H), 1.13-1.30 (m, 8H), 1.42 (m, 1H), 1.75- 6 1.93 (m, 4H), 2.80 (t, 2H, J = 6.2 Hz), 2.93-3.16 (m, 2H), 5.66 (t, 1H, J = 5.5 Hz). 6.53 (d, 2H, J = 9.1 Hz), 6.89 (d, 2H, J = 8.8 Hz), 6.92 (t, 1H, J = 75 Hz), 6.94 (
H~F
d, 1H, J = 8.0 Hz). 化合物Ii-54 [化222]
]H-NMR (DMSO-d ) δ : 0.88-1.05 (m, 2H), 1.14-1.32 (m, 11H), 1.41 (m, 1H), 1.75 6
-1.94 (m, 4H), 2.77 (t, 2H, J = 6.0 Hz), 3.01 (m, 1H), 4.54 (q, 2H, J = 9.0 Hz), 5.33 (t, 1H, J = 5.8 Hz), 6.49 (d, 2H, J = 8.8 Hz), 6.75 (d, 1H, J = 8.8 Hz), 6.80 (d, 2H, J = 8.8 Hz). 化合物Ii-55 [化 223]
'H-NMR (DMSO-d ) δ : 0.90-1.06 (m, 2H), 1.14-1.31 (m, 8H), 1.40 (m, 1H), 1.74- β 1.93 (m, 4H), 2.79 (t, 2H, J = 5.9 Hz), 2.94-3.15 (m, 6H), 3.69 (t, 4H, J = 4.8 Hz), -175 - 1376367 5.70-5.94 (m, 4H), 6.94 (d, 1H, J = 8.0 Hz). 化合物1ί-56 [化224] €〇 'H-NMR (DMSO-d ) δ : 0.98-1.14 (m. 2H), 1.15Ί.32 (m, 5H), 1.54 (m, 1H), 1.83-6
1.96 (m, 4H), 2.89-3.10 (m, 5H), 6.17 (t, 1H, J = 5.2 Hz), 6.63 (d, 1H, J = 2.2 Hz), 7.02 (d, 1H, J = 7.7 Hz), 7.21 (dd, 1H, J1 = 9.1 Hz, J2 = 2.5 Hz), 7.27 (dd, 1H, J1 =8.2 Hz, J2 = 4.4 Hz), 7.67 (d, 1H, J = 9.1 Hz), 7.97 (d, 1H, J = 8.2 Hz), 8.45 (dd, 1H, J1 =4.3 Hz,J2 = 1.5 Hz). 化合物Ii-57 [化225]
'H-NMR (DMSO-d ) 8 : 0.97-1.14 (m, 2H), 1.17-1.34 (m, 8H), 1.54 (m, 1H), 1.83-6 1.96 (m, 4H), 2.94 (t, 2H, J = 6.0 Hz), 2.99-3.18 (m, 2H), 6.17 (t, 1H, J = 5.4 Hz), 6.63 (d, 1H, J = 2.5 Hz), 6.96 (d, 1H, J = 7.7 Hz), 7.21 (dd. 1H, J1 = 9.1 Hz, J2 = 2 .5 Hz), 7.27 (dd, 1H, J1 = 8.2 Hz, J2 = 4.1 Hz), 7.67 (d, 1H, J = 9.1 Hz), 7.97 (d, 1 H, J = 8.0 Hz), 8.45 (dd, 1H, J1 = 4.3 Hz, J2 = 1.5 Hz). 化合物H-58 [化226] -176- 1376367
Ο 'H-NMR (DMSO-d ) δ ： 0.90-1.07 (m, 2H), 1.12-1.29 (m, 5H), 1.40 (m, 1H), 1.74-1.93 (m, 4H), 2.80 (t, 2H, J = 5.9 Hz), 2.92-3.07 (m, 7H), 3.69 (t, 4H, J = 4.8 Hz), 5.69-5.95 Cm, 4H), 6.99 (d, 1H, J = 7.7 Hz). 化合物Π-59 [化227]
lH-NMR (DMSO-d ) δ : 0.94-1.11 (tn, 2H), 1.14-1.30 (m, 5H), 1.47 (m, 1H), 1.78-6 l. 95 (m, 4H), 2.88-3.09 (m, 5H), 3.80 (s, 3H), 6.09 (t, 1H, J = 5.6 Hz), 6.81-6.86 ( m, 1H), 6.96 (dd, 1H, J1 = 8.8 Hz, J2 = 2.8 Hz), 7.01 (d, 1H, J = 7.4 Hz), 7.29 (t, 1 H, J = 8.0 Hz), 7.45-7.51 (m, 2H), 7.66 (d, 1H, J = 8.5 Hz), 8.04 (d, 1H, J = 2.8 Hz )_ 化合物Ii-60 [化228]
'H-NMR (DMSO-d ) 6 : 1.03 (m, 2H), 1.19 (t, 2H, J = 7.8 Hz), 1.21 (m, 2H), 1.46 6 (m, 1H), 1.76-1.95 (m, 4H), 2.90 (t, 2H, J = 5.8 Hz), 2.97 (q, 2H, J = 7.3 Hz), 3.03 (m, 1H), 3.80 (s, 3H), 5.95 (m, 1H), 6.90 (m. 1H), 6.98 (d, 1H, J = 7.8 Hz), 6.98 (d d, 1H, J = 7.8, 7.8 Hz), 7.06 (d, 1H, J = 8.6 Hz), 7.26 (dd, 1H, J = 7.8, 7.8 Hz), 7.6 -177- 1376367 1 (d, 1H, J = 8.6 Hz), 7.69 (d, 1H, J = 7.8 Hz), 8.03 (s, 1H). 化合物Ii-61 [化229] 為.J、 'h-NMR (DMSO-d ) δ : 0.96-1.09 (m, 2H), 1.18-1.29 (ra,2H), 1.19 (t, 3H, J = 7.6 6
Hz), 1.47 (m, 1H), 1.87 (m, 5H), 2.90 (t, 2H, J = 6.3 Hz), 2.97 (q, 2H, J = 7.6 Hz), 3.02 (m, 1H), 5.98 (m, 1H), 6.63 (d, 2H, J = 8.3 Hz), 6.98 (d,. 1H, J = 7.3 Hz), 7.14 (m, 1H), 7.73 (s, 2H), 7.83 (d, 2H, J = 8.3 Hz), 8.52 (d, 1H, J = 4.0 Hz). 化合物Ii-62 [化 230]
'H-NMR (DMSO-d) δ : 0.98-1.01 (m, 2H), 1.20 (s, 9H), 1.20-1.37 (m, 2H), 1.42 ( 6
m, 1H), 1.76-1.96 (m, 4H), 2.28-2.37 (m, 2H), 2.75-2.85 (m, 2H), 3.02 (m, 1H), 3. 36 (t, 2H, J = 7.8 Hz), 3.57 (t, 2H( J = 6.3 Hz), 5.66 (m, 1H), 6.54 (d, 2H, J = 8.0 Hz), 6.73 (d, 1H, J = 8.6 Hz), 7.00 (d, 1H, J = 8.0 Hz). 化合物Ii-63 [化 231]
'H-NMR (DMSO-d； δ : 0.96-1.14 (m, 2H), 1.14-1.32 (m, 2H), 1.19 (t, 3H, J = 7.2 -178 1376367
Hz), 1.50 (m, 1H), 1.76-1.96 (m, 4H), 2.91-3.10 (m, 3H), 2.97 (q, 2H, J = 7.2 Hz), 6.28 (m, 1H), 7.02 (d, 1H, J = 7.8 Hz), 7.32-7.46 (m, 3H), 8.20 (d, 1H, J = 6.9 Hz ),8.22 (s, 2H). 化合物丨i-64 [化232]
'H-NMR (DMSO-d ) δ : 1.03-1.15 (m, 2H), 1.18-1.29 (m, 2H), 1.24 (d, 6H, J = 6.3
Hz), 1.52 (m, 1H), 1.86-1.94 (m, 2H), 2.10-2.19 (m, 2H), 2.40 (t, 2H, J = 6.0 Hz), 2.95 (d, 2H, J = 6.0 Hz), 3.23 (m, 1H), 3.40 (d, 2H, J = 11.4 Hz), 3.75-3.85 (m, 2H ),3.86 (d, 1H, J = 9.3 Hz), 6.14 (d, 1H, J = 8.5 Hz), 6.15 (s, 1H), 6.29 (d, 1H, J = 8 .5 Hz), 7.06 (d. 1H, J = 8.5 Hz). 化合物Π-65 [化233]
'H-NMR (CDC1) δ :1.08-1.16 (m, 2H), 1.14 (d, 6H, J = 6.8 Hz), 1.21-1.30 (m, 2H ),1.29 (s, 9H), 1.78 (t, 2H, J = 10.6 Hz), 1.83-1.92 (m, 2H), 2.11-2.19 (m, 2H), 2. 78 (d, 2H, J = 10.6 Hz), 3.06 (s, 2H), 3.23 (m, 1H), 3.38 (s, 2H), 3.70-3.80 (m, 2H) ,4,02 (d, 1H, J = 9.9 Hz), 5.37 (s, 1H), 6.30 (s, 1H). 化合物Ii-66 [化234]
179- 1376367 'H-NMR (DMSO-d ) δ : 1.01-1.12 (m, 2H), 1.20-1.34 (m, 2H), 1.27 (s, 9H), i.54 ( 6 m, 1H), 1.82-1.99 (m, 4H), 2.91-2.98 (m, 2H), 3.06 (m ,1H), 6.17 (s, 1H), 6.63 (s, 1H), 6.78 (d, 1H, J = 9.0 Hz), 7.20 (m, IH), 7.27 (m, 1H), 7.77 (d, 1H, J = 9.0 Hz), 7.98 (d, 1H, J = 9.0 Hz), 8.54 (s, 1H). 化合物Ii-67 [化2 35]
H-NMR (DMSO-d) 5 : 0.92-1.06 (m, 2H). 1.20-1.32 (m, 2H), 1.26 (s, 9H), 1.42 ( e m, 1H), 1.78-1.88 (m, 2H), 1.88-1.96 (m, 2H), 2.78-2.86 (m, 2H), 3.02 (m ,1H), 5. 89 (s, 1H), 6.56 (d, 1H, J = 8.4 Hz), 6.76 (d, 1H, J = 8.4 Hz), 7.02 (d, 1H, J = 8.4 Hz). 化合物Ii-68 [化236]
H-NMR (DMSO-d) δ : 0.92-1.05 (m, 2H), 1.19 (s, 9H), 1.20-1.32 (m, 2H), 1.26 ( 6 s, 9H), 1.42 (m, 1H), 1.80-1.96 (m, 4H), 2.77 (s, 2H), 3.04 (m, 1H), 5.29 (s, 1H), 6.44 (d, 1H, J = 7.2 Hz), 6.68 (d, 1H, J = 7.2 Hz), 6.75 (d, 1H, J = 8.4 Hz). 化合物Π-69 [化 237]
lH-NMR (DMSO-d ) δ : 0.95-1.10 (m, 2H), 1.20-1.32 (m, 2H), 1.26 (s, 9H), 1.47 ( 6 -180- 1376367 m, lJ-ί), 1.80-1.88 (m, 2H), 1.88-1.95 (m, 2H), 2.88-2.95 (m, 2H), 3.02 (s, 1H), 6. 07 (m, 1H), 6.77 (d, 1H, J = 8.4 Hz), 6.97 (d, 1H, J = 7.6 Hz), 7.26 (t, 1H, J = 7.6 Hz), 7.35-7.42 (m, 2H), 7.46 (d, 1H, J = 8.4 Hz), 7.91 (d, 1H, J = 7.6 Hz), 8.04 (s, 1H). 化合物Ii-70 [化238]
'H-NMR (DMSO-d) δ : 0.93-1.05 (m, 2H), 1.10-1.32 (m, 2H), 1.26 (s, 9H), 1.42 ( m, 1HX 1.78-1.86 (m, 2H), 1.86-1.95 (m, 2H), 2.78-2.83 (m, 2H), 3.03 (m, 1H), 4. 80 (q, 2H, J = 9.2 Hz), 5.48 (t, 1H, J = 5.6 Hz), 6.69：6.76 (m, 2H), 7.08 (dd, 1H, J =8.8, 2.4 Hz), 7.45 (d, 1H, J = 2.4 Hz). 化合物Ii-71 [化239]
'H-NMR (DMSO-d ) δ : 0.96-1.10 (m, 2H), 1.20-1.32 (m, 2H), 1.27 (s, 9H), 1.82-6 1.88 (m, 2H), 1.88-1.97 (m, 2H), 2.83-2.88 (m, 2H), 3.04 (m, 1H), 5.82 (s, 1H), 6.6 9 (m, 1H), 6.76 (d, 1H, J = 8.8 Hz), 7.12 (dd, 1H, J = 9.2, 8.8 Hz), 7.37 (m, 1H). 7. 87 (d, 1H, J = 2.8 Hz), 7.99 (s, 1H). 化合物Ii-72 [化240]
181 - 1376367
[化244]
化合物li-73 [化 241] 化合物[i-74 [化242] 化合物Ii-75 [化243] 化合物Π-77 [化245] 化合物〗卜78 [化246] -182- 1376367
化合物Ii-79 [化247]
7¾ 化合物1卜80 [化248]
化合物Ii-81 [化249]
化合物Ii-82 [化250]
化合物li-83 ，c、 183 - 1376367
[化 251] 1XD..，j 化合物Ii-84 [化252]
'H-NMR (DMSO-d ) 6 : 0.91-1.08 (m, 2H), 1.14-1.30 (t, 3H, J = 7.5 Hz ), 1.41 (m 6 ,1H), 1.73-1.94 (m, 4H), 2.34-2.46 (m, 2H), 2.85 (t, 2H, J = 6.6 Hz), 2.97 (q, 2H, J = 7.5 Hz), 3.00 (m, 1H), 3.25 (t, 2H, J = 7.5 Hz), 3.53 (t, 2K, J = 6.6 Hz), 6.27 (d ,2H, J = 11.7 Hz), 6.52 (t, 1H, J = 5.1 Hz), 7.00 (d, 1H, J = 7.2 Hz). 化合物丨i-85 [化 253]
化合物Ii-86 [化 254]
化合物Π-87 [化255] -184- 1376367
化合物Π-88 [化256]
化合物Π-89 [化 257]
化合物U-90 [化 258]
0¾ U,J
HCI 化合物Ii-91 [化259]
'H-NMR (DMS〇-d ) δ : 0.92-1.05 (m, 2H), 1.13 (d, 6H, J = 6.0 Hz), 1.18-1.30 (m, 1376367 2H), 1.21 (d, 6H, I = 6.4 Hz), 1.40 (m, 1H), 1.76-1.83 (m, 2H), 1.83-1.93 (m, 2H), 2.19 (dd, 1H, J = 11.2, 11.2 Hz), 2.76-2.82 (m, 2H), 3.01.(m, 1H), 3.09 (m, 1H), 3. 45 (d, 2H, J = 11.2 Hz), 3.58-3.69 (m, 2H), 5.67 (m, 1H), 5.77 (d, 1H, J = 12.0 Hz) ,5.90 (s, 1H), 5.91 (m, 1H), 6.91 (d. 1H, J = 7.6 Hz). 化合物li-92 [化260]
'H-NMR (DMSO-d ) δ : 0.90-1.07 (m, 2H), 1.14-1.30 (m, 2H), 1.21 (d, 6H, J = 6.6 6
Hz), 1.32-1.46 (tn, 1H), 1.75-1.92 (m, 4H), 2.78-2.83 (m, 2H), 2.95-3.18 (m, 6H), 3.66-3.72 (m, 4H), 5.75 (brs, 1H), 6.00 (s, 1H), 6.04 (s, 1H), 6.11 (s, 1H), 6.95 (d, 1H, J = 9.0 Hz). 化合物Ii-93 [化 261]
'H-NMR (DMSO-d ) δ : 0.90-1.08 (m, 2H), 1.13-1.27 (m, 5H), 1.42 (m, 1H), 1.74- 1.93 (m, 4H), 2.30-2.40 (m, 2H), 2.81 (d, 2H, J = 6.6 Hz), 2.97 (q, 2H, J = 7.5 Hz), 3.00 (m, 1H), 3.49 (t, 2H, J = 7.5 Hz), 3.66 (t, 2H, J = 6.6 Hz), 5.00-5.50 (brs, 2H ),6.07-6.15 (m, 2H), 6.25(s, 1H), 7.00 (d, 1H, J = 6.6Hz). 化合物Ii-94 [化262]
i c -186 - 1376367 'H-NMR (DMSO-d) δ : 0.92-1.07 (m, 2H), 1.15-1.32 (m, 5H), 1.21 (d, 6H, J = 6.9 6
Hz), 1.42 (m, 1H), 1.74-1.93 (m, 4H), 2.30-2.42 (m, 2H), 2.81 (d, 2H, J = 6.6 Hz), 2.92-3.18 (m, 2H), 3.49 (t, 2H, J = 7.5 Hz), 3.66 (t, 2H, J = 6.6 Hz), 4.70-5.30 (br s, 2H), 6.05-6.16 (m, 2H), 6.25 (s, 1H), 6.95 (d, 1H, J = 8.1Hz). 化合物丨i-95 [化263]
'H-NMR (DMSO-d) δ : 0.90-1.06 (m, 2H), 1.16-1.31 (d, 6H, J = 6.9 Hz), 1.40 (m, 6 1H), 1.73-1.94 (m, 4H), 2.34-2.46 (m, 2H), 2.84 (t, 2H, J = 6.0 Hz), 2.94-3.16 (m, 2H), 3.28 (t, 2H, J = 7.5 Hz), 3.53 (t, 2H, J = 6.6 Hz), 6.27 (d, 2H, J = 11.7 Hz), 6 .52 (t, 1H, J = 5.4 Hz), 6.94 (d, 1H, J = 7.8 Hz). 化合物Ii-96 [化264]
'H-NMR (DMSO-d) δ : 0.91-1.04 (m, 2H), 1.20-1.32 (m, 2H), 1.26 (s, 9H), 1.40 ( 6 tn, 1H), 1.76-1.95 (m, 4H), 2.77-2.83 (m, 2H), 2.99-3.04 (m, 5H), 3.67-3.72 (m, 4 H), 5.71 (m, 1H), 5.79 (d, 1H, J = 11.7 Hz), 5.89 (s, 1H), 5.90 (m, 1H), 6.72 (d, 1H ,J = 8.4 Hz). 化合物Ii-97 [化265]
187- 1376367 'H-NMR (DMSO-d ) S : 0.92-1.03 (m, 2H), 1.20-1.32 (m, 2H), 1.26 (s, 9H), 1.41 ( 6 m, 1H), 1.77-1,93 (m, 4H), 2.78-2.83 (m, 2H), 2.97-3.05 (m, 5H), 3.68-3.72 (m, 4 H), 5.36 (m, 1H), 6.04 (d, 1H, J = 8.0 Hz), 6.10 (s, 1H). 6.11 (d, 1H, J = 8.0 Hz), 6. 72 (d, 1H, J = 8.0 Hz), 6.89 (dd, 1H, J = 8.0, 8.0 Hz). 化合物Ii-98 [化266]
lH-NMR (DMSO-d ) δ : 0.92-1.04 (m, 2H), 1.17-1.29 (m, 2H), 1.21 (d, 6H, J = 6.4
Hz), 1.41 (m, 1H), 1.75-1.92 (m, 4H), 2.77-2.83 (m, 2H), 2.95-3.05 (m, 5H), 3.09 (m, 1H), 3.67-3.72 (m, 4H), 5.36 (m, 1H), 6.04 (d, 1H, J = 8.0 Hz), 6.10 (s, 1H), 6. 11 (d, 1H, J = 8.0 Hz), 6.89 (dd, 1H, J = 8.0, 8.0 Hz), 6.92 (d, 1H, J = 8.0 Hz). 化合物Ii-99 [化267]
'H-NMR (DMSO-d ) δ : 0.90-1.06 (m, 2H), 1.15-1.31 (m, 2H), 1.21 (d, 6H, J = 6.9 6
Hz), 1.39 (m, 1H), 1.47-1.62 (m, 6H), 1.74-1.94 (m, 4H), 2.78 (t, 2H, J = 6.0 Hz), 2.93-3.16 (m, 6H), 5.64-5.76 (m, 2H), 5.83-5.92 (m, 2H), 6.94 (d, 1H, J = 7.8 Hz). 化合物Π-100 [化268]
'H-NMR (DMSO-d ) δ : 0.90-1.06 (m, 2H), 1.15-1.30 (m, 2H), 1.21 (d, 6H, J = 6.9 6 -188- 1376367
Hz), 1.40 (m, 1H), i.74-1.96 (m, 8H), 2.79 (t, 2H, J = 6.0 Hz), 2.93-3.18 (m, 6H), 5.48-5.67 (m, 4H), 6.94 (d, 1H, J = 8.1 Hz). 化合物[i-101 [化269]
'H-NMR (DMSO-d) δ : 0.90-1.06 (m, 2H), 1.13-1.29 (m, 2H), 1.18 (t, 3H, J = 7.5 6
Hz), 1.39 (m, 1H), 1.47-1.62 (m, 6H), 1.75-1.94 (m, 4H), 2.79 (t, 2H, J = 6.0 Hz), 2.97 (q, 2H, J = 7.5 Hz), 3.03-3.10 (m, 4H), 5.64-5.75 (m, 2H), 5.83-5.91 (m, 2H), 7.00 (d, 1H, J = 7.8 Hz). 化合物li-102 [化270]
Ό
o
'H-NMR (DMSO-d ) δ : 0.90-1.07 (m, 2H), 1.13-1.29 (m, 2H), 1.18 (t, 3H, J = 7.5 Hz), 1.41 (m, 1H), 1.74-1.96 (m, 8H), 2.79 (t, 2H, J = 6.0 Hz), 2.97 (q, 2H, J = 7.5 Hz), 3.00 (m, 1H), 3.09-3.19 (m, 4H), 5.46-5.66 (m, 4H), 6.99 (d, 1H, J = 7.2 Hz). 化合物Ii-103 [化 271]
'H-NMR (DMSO-d ) δ : 0.91-1.03 (m, 2H), 1.16-1.29 (m, 2H), 1.21 (d, 6H, J = 6.8 6
Hz), 1.40 (m, 1H), 1.75-1.92 (m, 4H), 2.20 (s, 3H), 2.35-2.43 (m, 4H), 2.75-2.82 ( -189- 1376367 m, 2H), 2.88-3.13 (m, 6H), 5.67 (m, 1H), 5.76 (d, 1H, J = 11.2 Hz), 5.82-5.92 (m, 2H), 6.91 (d, 1H, J = 8.0Hz). 化合物li-104 [化272]
'H-NMR (DMSO-d) δ : 0.92-1.02 (m, 2H), 1.19-1.32 (m, 2H), 1.26 (s, 9H), 1.39( 6
m, 1H), 1.75-1.95 (m, 4H), 2.19 (s, 3H), 2.38-2.42 (m, 4H), 2.77-2.83 (m, 5H), 2.9 8-3.09 (m, 5H), 5.67 (m, 1H), 5.76 (d, 1H, J = 11.2 Hz), 5.88 (m, 1H), 5.88 (s, 1H), 6.72 (d, 1H, J = 8.8Hz). 化合物li-105 [化273]
lH-NMR (DMSO-d ) 8 : 0.95-1.09 (m, 2H), U8-1.31 (m, 2H), 1.22 (d, 6H, J = 6.8 6
Hz), 1.44 (m, 1H), 1.78-1.93 (m, 4H), 2.87-2.92 (m, 2H), 3.03 (m, 1H), 3.10 (m, 1 H), 6.13 (m, 1H), 6.21 (m, 1H), 6.22 (s, 2H)( 6.51 (s, 1H), 6.52 (d, 1H, J = 8.0 Hz), 6.92 (d, 1H, J = 8.0 Hz), 7.26 (s, 2H). 化合物Ii-106 [化274]
'H-NMR (DMSO-d) δ : 0.97-1.08 (m, 2H), 1.17-1.29 (m, 5H), 1.40-1.68 (m, 3H), 6 190- 1376367 1.80-1.92 (m, 2H), 2.90 (t, 2H, J = 6.0 Hz), 2.94-3.06 (m, 3H), 6.12-6.22 (m, 4H), 6.50-6.54 (m, 2H), 6.94-7.00 (m, 1H), 7.26-7.27 (m, 2H). 化合物[卜107 [化275] 'H-NMR (DMSO-d ) δ : 0.91-1.03 (m, 2H), 1.16-1.29 (m, 2H), 1.21 (d, 6H, J = 6.4 6
Hz), 1.40 (m, 1H), 1.74-1.92 (m, 4H), 2.75-2.81 (m, 2H), 2.84 (s, 3H), 3.00 (m, 1 H), 3.09 (m, 1H), 3.25 (s, 3H), 3.35-3.47 (m, 4H), 5.59-5.67 (m, 4H), 6.91 (d, 1H, J = 8.0 Hz). 化合物li-108 [化276]
^-NMR (DMSO-d ) δ : 0.92-1.03 (m, 2H), 1.18-1.32 (m, 2H), 1.26 (s, 9H), 1.40 ( 6
m, 1H), 1.75-1.94 (m, 4H), 2.75-2.81 (m, 2H), 2.83 (s, 3H), 3.01 (m, 1H), 3.25 (s, 3H), 3.34-3.47 (m, 4H), 5.58-5.70 (m, 4H), 6.72 (d, 1H, J = 8.4 Hz). 化合物丨i-109 [化277]
'H-NMR (DMSO-d.) δ : 0.90-1.51 (m, 10H), 1.21 (d, 6H, J = 6.9 Hz), 1.56-1.67 ( m, 3H), 1.71-1.93 (m, 6H), 2.64 (s, 3H), 2.78 (t, 2H, J = 6.0 Hz), 2.93-3.17 (m, 2H -191 - 1376367 ),3.44 (m, 1H), 5.56-5.77 (tn, 4H), 6.94 (d, IH, J = 7.8 Hz). 化合物Π-110 [化278]
'H-NMR (DMSO-d) 6 : 0.83-1.01 (m, 2H), 1.00-1.40 (m, 3H), 1.21 (d, 6H, J = 6.9 6
Hz), 1.68-1.91 (m, 4H), 2.73 (t, 2H, J = 6.0 Hz), 2.90-3.15 (m, 2H), 2.95 (s, 3H), 4,48 (s, 2H), 5.60-5.72 (m, 4H), 6.94 (d, 1H, J = 7.8 Hz), 7.15-7.35 (m, 5H). 化合物Ii-111 [化279]
*H-NMR (DMSO-d) 6 : 0.97-1.14 (m, 2H), 1.14-1.33 (m, 5H), 1.45-1.61 (m, 1H), 6
1.81-1.96 (m, 4H), 2.90-3.10 (m, 5H), 6.34 (t, 1H, J = 5.2 Hz), 6.51 (d, 1H, J = 2.2 Hz), 6.99-7.07 (m, 2H), 7.36 (dd, 1H, J = 8.2, 4.1 Hz), 8.02 (d, 1H, J = 8.5 Hz), 8. 48 (dd, 1H, J = 4.1,1.4Hz). 化合物U-L12 [化280]
βχΧκ lH-_R (DMSO-d > δ _· 0.97-1.13 (m, 2H), 1.17-1.34 (m, 8H), 1.45-1.59 (m, 1H), 6 1.81-1.99 (m, 4H), 2.94 (t, 2H, J = 5.9 Hz), 2.99-3.21 (m, 2H), 6.33 (t, 1H, J = 5.4 Hz), 6.51 (d, 1H, J = 2.2 Hz), 6.96 (d, 1H, J = 7.7 Hz), 7.02 (dd, 1H, J = 13.5, 2.2 -192- 1376367
Hz), 7.36 (dd, 1H, J = 8.2, 4.1 Hz), 8.02 (d, 1H, J = 8.5 Hz), 8.48 (dd, 1H, J = 4.1, 1.4 Hz). 化合物I卜113 [化 281] 'H-NMR (DMSO-d ) δ : 0.93-1.13 (m, 2H), 1.15-1.34 (m, 8H), 1.39-1.57 (m, 1H),
1.79- 1.95 (m, 4H), 2.87 (t, 2H, J = 6.2 Hz), 2.94-3.16 (m, 2H), 3.54 (s, 3H), 5.66 ( t, 1H, J = 5.5 Hz), 6.49 (d, 1H, J = 9.6 Hz), 6.73 (d, 1H, J = 2.8 Hz), 6.91-7.02 (m, 2H), 7.29 (d, 1H, J = 9.3 Hz), 7.72 (d, 1H, J = 9.3 Hz). 化合物丨卜114 [化282]
'H-NMR (DMSO-d ) δ : 0.93-1.10 (m, 2H), 1.14-1.33 (m, 8H), 1.41-1.56 (m, 1H), 6
1.79- 1.94 (m, 4H), 2.89 (t, 2H, J = 6.0 Hz), 2.95-3.16 (m, 2H), 6.00 (t, 1H, J = 5.4 Hz), 6.84 (dd, 1H, J = 8.8, 2.2 Hz), 6.95 (d, 1H, J = 8.0 Hz), 7.07 (d, 1H, J = 2.2 Hz), 7.72 (d, 1H, J = 8.8 Hz), 8.86 (s, 1H). 化合物Ii-115 [化283]
lH-NMR (DMSO-d ) δ : 0.94-1.06 (m, 4H), 1.26 (s, 9H), 1.40-1.51 (m, 1H), 1.84 ( 6 d, 2H, J = 12.4 Hz). 1.91 (d, 2H, J = 12.4 Hz), 2.85-2.90 (m, 2H), 2.97-3.06 (m, 1 H), 5.93-5.99 (m, 1H), 6.63-6.79 (m, 3H), 7.40 (d, 1H, J = 8.8 Hz), 8.32 (s, 1H). -193 1376367 化合物Π-116 [化284] XQ- Ο *H-NMR (DMSG'd ) δ : 0.95-1.07 (m, 4H), 1.26 (s, 9H), 1.39-1.47 (m, 1H), 1.80 ( 6
d, 2H, J = 12.4 Hz), 1.91 (d, 2H, J = 12.4 Hz), 2.87-2.93 (m, 2H), 2.98-3.06 (m, 1 H), 3.37 (s, 3H), 6.27 (s, 1H), 6.55 (d, 1H, J = 8.8 Hz), 6.73 (d, 1H, J = 8.8 Hz), 6. 80 (t, 1H, J = 5.2 Hz), 7.32 (d, 1H, J = 8.8 Hz). 化合物丨i-117 [化285]
*H-NMR (DMSO-d ) § ： 0.94-1.08 (m, 4H), 1.20 (s, 3H), 1.22 (s, 3H), 1.39-1.51 ( 6
m, 1H), 1.80 (d, 2H, J = 12.4 Hz), 1.88 (d, 2H, J = 12.4 Hz), 2.87-2.94 (m, 2H), 2. 97-3.07 (m, 1H), 3.08-3.14 (m, 1H), 3.37 (s, 3H), 6.27 (s, 1H), 6.55 (d, 1H, J = 8.4 Hz), 6.82 (t, 1H, J = 5.6 Hz), 6.94 (d, 1H, J = 8.0 Hz), 7.32 (d, 1H, J = 8.4 Hz). 化合物U-U8 [化286]
>〇 *H-NMR (DMSO-d ) δ : 0.92-1.06 (m, 4H), 1.26 (s, 9H), 1.38-1.50 (m, 1H), 1.83 ( 6 d, 2H, J = 12.4 Hz), 1.90 (d, 2H, J = 12.4 Hz), 2.80-2.86 (m. 2H), 2.96-3.06 (m, 1 H), 3.26 (s, 3H), 5.58-5.65 (m, 1H), 6.27 (d, 1H, J = 8.4 Hz), 6.38 ($, 1H). 6.75 (d ,1H, J = 8.4 Hz), 6.99 (d, 1H, J = 8.4 Hz). -194- 1376367 化合物Ii-119 [化287]
'H-NMR (DMSO-d ) δ : 0.94-1.06 (m, 4H), 1.26 (s, 9H), 1.39-1.50 (m, 1H), 1.84 ( 6 d, 2H, J = 12.4 Hz), 1.90 (d, 2H, J = 12.4 Hz), 2.81-2.89 (m, 2H), 2.96-3.07 (m, 1 H). 3.51 (s, 3H), 5.79-5.84 (m, 1H), 6.60 (s, 1H), 6.75 (d, 1H, J = 8.8 Hz), 7.03 (d ,1H, J = 8.8 Hz), 7.19 (d, 1H, J = 8.8 Hz).
化合物Π-120 [化288]
'H-NMR (DMSO-d ) δ ： 0.93-1.10 (m, 4H), 1.26 (s, 9H), 1.37-1.40 (m, 1H), 1.42 ( 6 s, 3H), 1.44 (s, 3H), 1.83 (d, 2H, J = 12.4 Hz), 1.91 (d, 2H, J = 12.4 Hz), 2.79-2.96 (m, 2H), 2.97-3.07 (m, 1H), 4.33-4.46 (m, 1H), 5.50-5.59 (m, 1H), 6.25 (d, 1H, J =8.8 Hz), 6.57 (s, 1H), 6.75 (d, 1H, J = 8.4 Hz), 7.00 (d, 1H, J = 8.4 Hz).
化合物Ii-121 [化289]
'H-NMR (DMSO-d ) 6 : 0.90-1.06 (m, 4H), 1.26 (s, 9H), 1.36-1.49 (m, 1H), 1.82 ( c d, 2H, J = 12.4 Hz), 1.90 (d, 2H, J = 12.4 Hz), 2.80-2.87 (m, 2H), 2.95-3.97 (m, 1 H), 3.27 (s, 3H), 5.85-5.92 (m, 1H), 6.33 (s, 1H), 6.36 (s, 1H), 6.75 (d, 1H, J = 8.8 Hz). 化合物U-122 -195- 1376367 [化290]
'H-NMR (DMSO-d ) δ : 0.92-1.08 (m, 4H), 1.26 (s, 9H), 1.38-1.41 (m, 1H), 1.42 ( 6 s, 3H), 1.43 (s, 3H), 1.82 (d, 2H, J = 11.8 Hz), 1.90 (d, 2H, J = 11.8 Hz), 2.83-2.88 (m, 2H), 2.98-3.06 (m, 1H), 4.33-4.47 (m, 1H), 6.35 (s, 1H), 6.54 (s, 1H), 6.76 (d, 1H, J = 8.4 Hz), 8.32 (s, 1H).
化合物U-123 [化 291]
'H-NMR (DMSO-d ) δ : 0.93-1.06 (m, 4H), 1.22 (s, 3H), 1.24 (s, 3H), 1.26 (s, 9H) 6
,1.39-1.50 (m. 1H), 1.81 (d, 2H, J = 12.4 Hz), 1.90 (d, 2H, J = 12.4 Hz), 2.87-2.93 (m, 2H), 2.96-3.07 (m, 1H), 4.39-4.47 (m, 1H), 6.30 (s, 1H), 6.54 (d, 1H, J = 8.8 Hz), 6.77 (d, 1H, J = 8.8 Hz), 6.86 (t, iH, J = 5.2 Hz), 7.32 (d, 1H, J = 8.4 Hz). 化合物Ii-124 [化292]
^-NMR (DMSO-d ) δ : 0.90-1.05 (m, 4H), 1.26 (s, 9H), 1.36-1.51 (m, 1H), 1.79 ( 6
d, 2H, J = 12.4 Hz), 1.90 (d, 2H, J = 12.4 Hz), 2.80-2.86 (m, 2H), 3.01 (s, 3H), 3.0 2-3.05 (m, 1H), 3.49 (t, 2H, J = 4.8 Hz), 4.26 (t, 2H, J = 4.8 Hz), 6.02 (s, 1H), 6.2 0 (t, 1H, J = 5.6 Hz), 6.31 (d, 1H, J = 8.8 Hz), 6.74 (d, 1H, J = 8.8 Hz), 7.43 (d, 1H -196- 1376367 ,J = 8.4 Hz). 化合物Π-125 [化293]
'H-NMR (DMSO-d ) δ : 0.92-1.02 (m, 4H), 1.08 (t, 3H, J = 7.2 Hz), 1.25 (s, 9H), 6 l. 35-1.42 (m, 1H), 1.79 (d, 2H, J = 12.0 Hz), 1.90 (d，2H, J = 12.0 Hz), 2.80-2.86 (
m, 2H), 2.96-3.05 (m, 1H), 3.42-3.51 (m, 4H), 4.20-4.26 (m, 2H), 6.03 (s, 1H), 6.2 0 (s, 1H), 6.31 (d, 1H, J = 8.8 Hz), 6.75 (d, 1H, J = 8.8 Hz), 7.42 (d, 1H, J = 8.8 H z). 化合物Ii-126 [化294]
'H-NMR (DMSO-d ) δ : 0.92-1.02 (m, 4H), 1.09 (s, 3H), 1.11 (s, 3H), 1.25 (s, 9H) 6
,1.43-1.55 (m, 1H), 1.80 (d, 2H, J = 12.4 Hz), 1.91 (d, 2H, J = 12.0 Hz), 2.84 (m, 2H), 2.97-3.08 (m, 1H), 3.37 (t, 2H, J = 5.2 Hz), 4.18 (t, 2H, J = 5.2 Hz), 4.71-4. 80 (m, 1H), 6.05 (s, 1H), 6.19 (t, 1H, J = 5.2 Hz), 6.32 (d, 1H, J = 8.8 Hz), 6.74 (d, 1H, J = 8.4 Hz), 7.18 (d, 1H, J = 8.4 Hz). 化合物Ii-127 [化295]
-197- 1376367 *H-NMR (DMSO-d ) δ : 0.94-1.12 (m, 2H), 1.14-1.39 (m, 5H), 1.34-1.56 (m, 1H), 6 1.70-1.97 (m, 4H), 2.87-3.10 (ra, 5H), 6.17 (t, 1H, J = 5.2 Hz), 6.94-7.06 (m, 2H), 7.35-7.47 (m, 4H), 7.75-7.80 (m, 1H), 8.07 (d, 1H, J = 3.0 Hz). 化合物Ii-128 [化296]
*H-NMR (DMSO-d ) δ : 0.96-1.12 (m, 2H), 1.14-1.31 (m, 5H), 1.31-1.55 (m, 1H), 6 1.70-1.96 (m, 4H), 2.89-3.09 (m, 5H), 6.24 (t, 1H, J = 5.4 Hz), 6.94-7.05 (m, 2H), 7.24 (d, 1H, J = 6.9 Hz), 7.52 (t, 1H, J = 8.0 Hz), 7.75 (d, 1H, J = 8.8 Hz), 7.88-7. 97 (m, 2H), 8.07 (d, 1H, J = 2.5 Hz). 化合物Π-129 [化297]
'H-NMR (DMSO-d,) 5 : 0.98-1.12 (m, 2H), 1.18-1.30 (m, 2H), 1.19 (t, 3H, J = 6.8 b
Hz), 1.48 (m, 1H), 1.79-1.95 (m, 4H), 2.92-3.09 (m, 3H), 2.97 (q, 2H, J = 6.8 Hz), 6.27 (m, ΙΗλ 7.01 (d, 1H, J = 8.0 Hz), 7.39-7.47 (m, 2H), 7.56 (m, 1H), 8.18-8.25 (m, 2H), 8.23 (s, 2H). 化合物Ii-130 [化298]
-198- 1376367 'H-NMR (DMSO-d) 6 : 0.96-1.12 (m, 2H), 1.15-1.30 (m, 2H), 1.18 (t, 3H, J = 7.2 6
Hz), 1.45-1.64 (m, 1H)； 1.78-1.96 (m, 4H), 2.97 (q, 2H, J = 7.2 Hz), 2.95-3.15 (m ,1H), 3.22-3.28 (m, 2H), 6.89 (d, 1H, J = 9.0 Hz), 6.94-7.02 (m, 2H), 7.38 (t, 1H, J = 6.0 Hz), 7.46 (t, 2H, J = 7.5 Hz), 7.78 (d, 1H, J = 9.0 Hz), 7.96 (d, 2H, j = 9.0 Hz). 化合物[i-131 [化 299]
*H-NMR (DMSO-d ) δ : 0.96-1.12 (ra, 2H), 1.15-1.30 (m, 2H), 1.18 (t, 3H, J = 7.2 6
Hz), 1.48-1.62 (m, 1H), 1.78-1.96 (m, 4H), 2.98 (q, 2H, J = 7.2 Hz), 2.94-3.10 (m ,1H), 3.22-3,28 (m, 2H), 6.89 (d, 1H, J = 9.0 Hz), 7.02 (d, 1H, J = 9.0 Hz), 7.10 (t ,1H, J = 5.4 Hz), 7.22 (td, 1H, J = 9.0, 3.0 Hz), 7.47-7.56 (m, 1H), 7.77-7.88 (m, 3H). 化合物Ii-132 [化300]
^-NMR (DMSO-d) δ : 0.96-1.13 (m, 2H), 1.15-1.32 (m, 2H), 1.19 (t, 3H, J = 7.5 6
Hz), 1.48-1.65 (m, 1H), 1.78-1.96 (m, 4H), 2.98 (q, 2H, J = 7.2 Hz), 2.94-3.12 (m ,1H), 3.22-3.28 (m, 2H), 6.89 (d, 1H, J = 9.0 Hz), 7.01 (d, 1H, J = 6.0 Hz), 7.09 (t ,1H, J = 5.4 Hz), 7.27-7.35 (m, 2H), 7.42-7.50 (m, 1H), 7.57 (dd, 1H, J = 9.0, 3.0 Hz), 7.86 (td, 1H, J = 7.5, 3.0 Hz). 化合物Π-133 -199- 1376367 [化 301]
'H-NMR (DMSO-d ) δ : 0.92-1.08 (m, 2H), 1.15-1.30 (m, 2H), 1.21 (d. 6H, J = 6.6 6
Hz), 1.42-1.58 (m, 1H), 1.72-1.94 (m, 4H), 2.95-3.20 (m, 4H), 4.89-4.98 (m, 2H), 6.65 (brs, 1H), 6.92 (d, 1H, J = 9.0 Hz), 6.91-6.98 (m, 1H), 7.03 (d, 1H, J = 9.0 H z).
化合物li-134 [化302] 七l w 'H-NMR (DMSO-d ) δ : 0.90-1.08 (m, 2H), 1.15-1.30 (m, 2H), 1.21 (d, 6H, J = 6.6 6
Hz), 1.42-1.58 (m, 1H), 1.72-1.94 (m, 4H), 2.92-3.20 (m, 4H), 6.74 (t, 1H, J = 6.0 Hz), 6.94 (t, 1H, J = 6.0 Hz), 6.97 (s, 1H), 7.08-7.24 (m, 5H). 化合物Ii-135 [化303]
lH-NMR (DMSO-d ) δ : 0.95-1.10 (m, 2H), 1.12-1.30 (m, 2H), 1.19 (t, 3H, J = 7.2 6
Hz), 1.48-1.60 (m, 1H), 1.76-1.94 (m, 4H), 2.92-3.10 (m, 1H), 2.97 (q, 2H, J = 7. 2 Hz), 3.18-3.30 (m, 2H), 6.89 (d, 1H, J = 9.6 Hz), 7.02 (brs, 1H), 7.11 (t, 1H, J = 5.4 Hz), 7.42-7.56 (m, 2H), 7.85 (d, 1H, J = 9.6 Hz), 7.93 (d, 1H, J = 7.5 Hz), 8.03 (s, 1H). 化合物Ii-136
-200- 1376367 [化 304]
7¾ 'H-NMR (DMSO-d ) δ ： 0.98-1.12 (m, 2H). 1.13-1.30 (m, 2H), 1.18 (t, 3H, J = 7.2 6
Hz), 1.48-1.62 (m, 1H), 1.78-1.96 (m, 4H), 2.92-3.12 (m, 1H), 2.97 (q, 2H, J = 7. 2 Hz), 3.22-3.32 (m, 2H), 6.89 (d, 1H, J = 9.0 Hz), 7.01 (d, 1H, J = 7.5 Hz), 7.20 (t ,1H, J = 6.0 Hz), 7.62 (s, 1H), 7.91 (d, 1H, J = 9.0 Hz), 8.02 (s, 2H). 化合物Ii-137 [化305]
Ή-NMR (DMSO-d) δ ： 0.95Ί.12 (m, 2H), 1.13-1.30 (m, 2H), 1.18 (t, 3H, J = 7.2 6
Hz), 1.65-1.95 (m, 5H), 2.93-3.12 (m, 1H), 2.97 (q, 2H, J = 7.2 Hz), 3.25-3.40 (m ,2H), 5.07-5.16 (m, 2H), 7.01 (d, 1H. J = 7.5 Hz), 7.25 (t, 1H, J = 6.0 Hz), 7.92-8. 03 (m, 3H), 8.33 (d, 1H, J = 6.0 Hz). 化合物li-138 [化306]
^-NMR (DMSO-d ) δ ： 0.91Ί.26 (m, 4H), 1.19 (t, 3H, J = 7.5 Hz), 1.36-1.43 (m, 6 1H), 1.78-1.90 (m, 4H), 2.90-3.07 (m, 3H), 2.96 (q, 2H, J = 7.5 Hz), 5.69 (t, 1H, J =5.7 Hz), 5.81 (d, 1H, J = 2.4 Hz), 7.00 (d, 1H, J = 7.8 Hz), 7.16-7.39 (m, 3H), 7. 73-7.79 (m, 1H), 7.86-7.88 (m, 1H). -201 - 1376367 化合物Π-139 [化307]
'H-NMR (DMSO-d) δ : 0.90-1.06 (m, 4H), 1.20 (s, 3H), 1.22 (s, 3H), 1.40-1.52 (m, 1H), 1.81 (d, 2H, J = 12.4 Hz), 1.88 (d, 2H, J = 12.4 Hz), 2.90-2.98 (m, 2H), 2. 99-3.13 (m, 2H), 5.68 (t, 1H, J = 5.6 Hz), 5.81 (s, 1H), 6.93 (d, 1H, J = 8.8 Hz). 7. 16-7.40 (m, 3H), 7.76 (t, 1H, J = 8.0 Hz), 7.87 (s, 1H).
化合物丨i-140 [化308]
lH-NMR (DMSO-d ) δ : 0.90-1.06 (m, 4H), 1.26 (s, 9H), 1.40-1.49 (m, 1H), 1.82 (d, 2H, J = 12.4 Hz), 1.91 (d, 2H, J = 12.4 Hz), 2.90-2.99 (m, 2H), 3.01-3.06 (m, 1 H), 5.67 (t, 1H, J = 6.0 Hz), 5.81 (s, 1H), 6.74 (d, 1H, J = 8.4 Hz), 7.14-7.40 (m, 3 H), 7.76 (t, 1H, J = 8.4 Hz), 7.87 (s, 1H).
化合物Π-141 [化 309]
H-NMR (DMSO-d ) δ : 0.97-1.06 (m, 2H), 1.18-1.27 (m, 2H), 1.21 (d, 6H, J = 6.9
Hz), 1.45-1.59 (m, 1H), 1.76-1.81 (m, 2H), 1.87-1.91 (m, 2H), 2.97-3.09 (m, 1H), 3.10-3.13 (m, 1H), 3.17-3.22 (m, 2H), 6.94-7.02 (m, 2H), 6.98 (td, 1H, J = 7.8, 1. 2 Hz), 7.36 (dd, 1H, J = 7.8, 0.6 Hz), 7.65 (dd, 1H, J = 7.8, 0.6 Hz), 8.00-8.05 (m, 1H). -202- 1376367 化合物Ii-142 [化 310]
'H-NMR (DMSO-d ) δ ： 0.96-1.04 (m, 2H), 1.18-1.28 (m, 2H), 1.20 (d, 6H, J = 6.9 6
Hz), 1.43-1.59 (m, 1H), 1.74-1.79 (m, 2H), 1.85-1.90 (m, 2H), 2.92-3.07 (m, 1H), 3.09-3.18 (m, 3K), 6.92-6.99 (m, 2H), 7.10 (td, 1H, J = 7.8, 1.2 Hz), 7.21 (dd, 1H ,J = 7.8, 0.6 Hz), 7:31 (dd, 1H, J = 7.8, 0.6 Hz), 7.89-7.97 (m, 1H).
化合物[ί-143 [化 311]
'H-NMR (DMSO-d ) δ : 0.97-1.07 (m, 2H), 1.17-1.23 (m, 2H), 1.18 (t, 3H, J = 7.2 6
Hz), 1.42-1.57 (m, 1H), 1.73-1.78 (m, 2H), 1.86-1.90 (m, 2H), 2.93-3.02 (m, 1H), 2.97 (q, 2H, J = 7.2 Hz), 3.11 (t, 2H, J = 6.3 Hz), 6.91-7.02 (m, 2H), 7.19 (dd, 1H, J = 8.4, 4.8 Hz), 7.34 (dd, 1H, J = 9.3, 2.4 Hz), 8.00 (t, 1H, J = 6.0 Hz).
化合物li-144 [化 312]
Vl-NMR (DMSO-d ) δ : 0.97-1.08 (m, 2H), 1.16-1.24 (m, 2H), 1.18 (t. 3H, J = 7.2 6
Hz), 1.42-1.59 (m, 1H), 1.74-1.80 (m, 2H), 1.85-1.90 (m, 2H), 2.92-3.03 (m, 1H), 2.97 (q, 2H, J = 7.5 Hz), 3.18 (t, 2H, J = 6.3 Hz), 6.99-7.07 (m, 2H), 7.33 (dd, 1H, J = 9.0, 4.8 Hz), 7.58 (dd, 1H, J = 8.7, 2.7 Hz). 8.00 (t, 1H, J = 5.4 Hz). 1376367 化合物Ii-145 [化 313]
'H-NMR (DMSO-d ) δ : 0.97-1.09 (m, 2H), 1.17-1.23 (m, 2H), 1.18 (t, 3H, J = 7.2 6
Hz), 1.43-1.59 (m, 1H), 1.72-1.81 (m, 2H), 1.85-1.92 (m, 2H), 2.95-3.06 (m, 1H), 2.97 (q, 2H, J = 7.5 Hz), 3.19 (t, 2H, J = 6.0 Hz), 7.01 (d, 1H, J = 8.1 Hz), 7.20-7. 23 (m, 1H), 7.33 (dd, 1H, J = 8.7, 0.6 Hz), 7.58 (dd, 1H, J = 2.1, 0.9 Hz), 8.11-8.1 8 (m, 1H). 化合物Π-146 [化 314]
*H-NMR (DMSO-d ) 5 : 0.98-1.06 (m, 2H), 1.15-1.21 (m, 2H), 1.18 (t, 3H, J = 7.2 ti
Hz), 1.42-1.58 (m, 1H), 1.70-1.81 (m, 2H), 1.82-1.96 (m, 2H), 2.93-3.00 (m, 3H), 3.13-3.19 (m, 2H), 6.98-7.02 (m, 2H), 7.26-7.27 (m, 1H), 7.32-7.35 (m, 1H), 8.18 -8.21 (m, 1H). 化合物Ii-147 [化 315]
lH-NMR (DMSO-d ) δ : 0.98-1.04 (m, 2H), 1.16-1.23 (m, 2H), 1.18 (t, 3H, J = 7.2 6
Hz), 1.43-1.59 (m, 1H), 1.73-1.78 (m, 2H), 1.86-1.89 (m, 2H), 2.93-3.00 (m, 3H), -204- 1376367 3.11-3.15 (m, 2H), 6.72-6.79 (m, 1H), 7.00-7.08 (m, 2H), 7.29-7.34 (m, 1H), 8.13 -8.16 (m, 1H). 化合物H-148 [化 316]
'H-NMR (DMSO-d ) δ : 0.94-1.06 (m, 2H), U5-1.26 (m, 2H), 1.18 (t, 3H, J = 7.2 6
Hz), 1.45-1.58 (m, 1H), 1.72-1.80 (m, 2H), 1.84-1.92 (m, 2H), 2.96 (q, 2H, J = 7. 2 Hz), 2.96-3.05 (m, 1H), 3.09-3.16 (m, 2H), 6.99 (d, 1H, J = 8.0 Hz), 7.13 (dd, 1 H, J = 8.0, 2.0 Hz), 7.20 (d, 1H, J = 8.4 Hz), 7.49 (d, 1H, J = 2.0 Hz), 8.11 (t, 1H, J = 6.0 Hz). 化合物Ii-149 [化 317]
]H-NMR (DMSO-d ) δ : 0.96-1.08 (m, 2H), 1.12-1.24 (m, 2H), 1.18 (t, 3H, J = 7.2 6
Hz), 1.43-1.59 (m, 1H), 1.74-1.80 (m，2H), 1.86-1.91 (m, 2H), 2.93-3.01 (m, 3H), 3.17-3.22 (m，2H), 7.00-7.05 (m, 2H), 7.37-7,39 (m, 1H), 7,65-7.68 (m，1H), 8.22 -8.26 (m, 1H). 化合物li-150 [化 318]
F 'H-NMR (DMSO-d ) 5 : 0.98-1.08 (m, 2H), 1.15-1.29 (m, 2H), 1.21 (d, 6H, J = 6.9 6 -205 - 1376367
Hz), 1.44-1.60 (m, 1H), 1.74-1.80 (m, 2H), 1.86-1.91 (m, 2H), 2.95-3.17 (m, 2H), 3.21-3.27 (m, 2H), 6.95-6.98 (m, 1H), 8.10 (dd, 1H, J = 8.4, 2.7 Hz), 8.19 (dd, 1H ,J = 3.0, 1.5 Hz), 8.44-8.47 (m, 1H). 化合物Ii-151 [化 319]
Cl *H-NMR (DMSO-d ) δ : 0.99-1.04 (m, 2H), 1.15-1.23 (m, 2H), 1.21 (d, 6H, J = 6.3
5
Hz), 1.43-1.59 (m, 1H), 1.73-1.81 (m, 2H), 1.85-1.91 (m, 2H), 2.97-3.18 (m, 2H), 3.21-3.29 (m, 2H), 6.95-6.98 (m, 1H), 8.20-8.23 (m, 2H), 8.58-8.61 (m, 1H). 化合物Ii-152 [化320]
^-NMR (DMSO-d) δ·: 0.96-1.04 (m, 2H), 1.15-1.26 (m, 2H), 1.25 (s, 9H), 1.56-6
1.62 (m, 1H), 1.78-1.83 (m, 2H)( 1.87-1.93 (m, 2H), 2.98-3.08 (m, 1H), 3.17 (t, 2H ,J = 6.3 Hz), 3.48 (s, 3H), 6.47 (d, 2H, J = 8.7 Hz), 6.89-6.96 (m, 2H), 7.11-7.19 ( m, 2H). 化合物Ii-153 [化 321]
'H-NMR (DMSO-d) δ : 0.95-1.04 (m, 2H), 1.13-1.30 (m, 2H), 1.18 (t, 3H, J = 7.5 6 -206- 1376367
Hz), 1.41 (m, 1H), 1.7L-1.94 (m, 4H), 2.80-2.89 (m, 2H), 2.92-3.10 (m, 2H), 2.97 (q, 2H, J = 7.5 Hz), 3.21-3.30 (m, 2H), 6.25-6.35 (m, 2H), 6.39 (dd, 1H, J = 8.4, 2. 1 Hz), 7.01 (d, 1H, J = 7.5 Hz), 7.01 (dd, 1H, J = 8.4, 8.4 Hz). 化合物Ii-154 [化322]
'H-NMR (DMSO-d ) δ : 0.91-1.09 (m, 2H), 1.16-1.28 <m, 2H), 1.18 (t, 3H, J = 7.5 6
Hz), 1.42 (m, 1H), 1.74-1.95 (m, 4H), 2.80-3.16 (m, 9H), 2.97 (q, 2H, J = 7.5 Hz), 6.24-6.36 (m, 2H), 6.30 (dd, 1H, J = 8.4, 2.1 Hz), 7.10 (dd, 1H, J = 8.4, 2.1 Hz), 7 .05 (d, 1H, J = 8.4 Hz). 化合物Π-155 [化323]
化合物Π-156 [化 324]
F D 化合物Ii-157 [化325] -207- 1376367
化合物li-158 [化326]
'H-NMR (DMSO-d ) 6 : 0.91-1.07 (m, 2H), 1.10-1.30 (m, 5H), 1.41 (m, 1H), 1.76-6 1.94 (m, 4H), 2.74-2.83 (m, 2H), 2.83 (s, 3H), 2.90-3.08 (m, 3H), 2.96 (s, 3H), 5.6 8 (m, 1H), 6.39 (m, 1H), 6.58 (m, 1H), 6.95 (dd, 1H, J = 8.4, 8.4 Hz), 7.00 (d, 1H, J =7.8 Hz). 化合物U-159 [化 327]
化合物li-160 [化 328]
化合物Ιί-161 [化329] -208- 1376367
化合物Ii-162 [化 330]
化合物[i-163 [化 331]
化合物Ii-164 [化332]
□ 化合物Π-165 [化333]
-209- 1376367 化合物I卜166 [化334]
F 0 化合物丨卜167 [化335]
化合物Π-168 [化336]
化合伽卜169
[化337]
化合物Ii-170 [化338] -210- 1376367
化合物Ii-171 [化339]
化合物Π-172 [化340]
化合物Ii-173 [化 341]
'H-NMR (DMSO-d ) δ : 0.95-1.08 (rn, 2H), 1.15-1.28 (m, 2H), 1.19 (t, 3H, J = 7.2 6
Hz),1.43 (m, 1H), 1.76-1.85 (m, 2H), 1.85-1.93 (m, 2H), 2.76-2.82 (m, 2H), 2.88 ( t, 2H, J = 6.0 Hz), 2.97 (t, 2H, J = 7.2 Hz), 3.00 (m, 1H), 3.64-3.70 (m, 4H), 6.33 ( m, 1H)( 6.37 (d, 1H, J = 8.4 Hz), 6.56 ($, 1H), 7.00 (d, 1H, J = 7.8 Hz), 7.28 (d, 1H ,J = 8.4 Hz). 化合物Ii-174 -211 - 1376367 [化342]
ο cf3 化合物[i-175 [化343]
化合物丨i-176 [化344]
化合物Ii-177 [化345]
化合物Ii-178 [化 346]
-212- 1376367 化合物Π-179 [化347]
化合物1卜180 [化348]
化合物Η-181 [化 349]
化合物Ii-182 [化350]
化合物Ii-183 [化 351]
-213 - 1376367 化合物li-184 [化352]
化合物li-185 [化 353]
化合物丨i-186 [化354] Η NV-WCp3 1¾
化合物[i-187 [化 355]
化合物丨i-188 [化 356] -214- 1376367
化合物li-189 [化357]
化合物Ii-190 [化 358]
化合物Ii-191 [化359]
化合物Π-192 [化360]
-215 1376367 化合物Ii-193 [化 361]
化合物[i-194 [化362]
化合物Ii-195 [化 363]
化合物Ii-196 [化364]
化合物Ii-197 [化365] r £ -216- 1376367
化合物I卜198 [化366]
化合物Ii-199 [化367]
化合物Π-200 [化368]
化合物Ii-20i [化 369]
化合物Π-202
-217- 1376367 [化 370] Vo、 JUCF3 化合物丨i-203 [化 371] 化合物Ii-204 ' [化372] 化合物Ii-206 [化374]
化合物Π-205 [化373]
-218 - 1376367
化合物Ij-2 [化375] 〜馬 'H-NMR (DMSO-d ) 5 : 0.98-1.24 (m, 4H), 1.19 (t, 3H, J = 7.5 Hz), 1.40 (m, 1H), 6 1.78-1.88 (m, 2H), 2.02-2.14 (m, 2H), 2.80 (t, 2H, J = 6.0 Hz), 2.86 (q, 2H, J = 7.2 Hz), 3.64-3.82 (m. 1H), 6.40 (d, 2H, J = 8.1 Hz), 7.01 (d, 2H, J = 7.2 Hz), 7.32-7. 50 (m, 4H), 7.99 (d, 2H, J = 6.9 Hz) 化合物Ij-3 [化376]
1.78-1.88 (ra, 2H), 2.02-2.14 (m, 2H), 2.78 (t, 2H, J = 6.0 Hz), 2.98 (q, 2H, J = 7.5 Hz), 3.60-3.78 (rn, 1H), 6.40-6.50 (m,2H), 6.85-6.92 (m, IH), 6.97-7.03 (m, 1H), 7.22-7.35 (m, 2H), 7.36-7.46 (m, 2H). 7.88-7.96 (m, 1H) 化合物lh4 [化377]
-219- 1376367 'h-NMR (DMSO-d ) δ : 0.92-1.24 (m, 4H), 1.19 (t, 3H, J = 7.2 Hz), 1.38 (m, 1H), 6 1.78- 1.88 (m, 2H), 1.96-2.06 (m, 2H), 2.78 (t, 2H, J = 6.0 Hz), 2.98 (q, 2H, J = 7.5 Hz), 3.60-3.78 (m, 1H), 6.50 (t, 1H, J = 3.9 Hz), 6.53 (s, 1H), 7.00 (t, 1H, J = 5.7 Hz), 7.25 (t, 1H, J = 7.2 Hz), 7.34-7.45 (m, 2H), 7.55 (d, 2H, j = 7.2 Hz), 7.67 (dd, 1H, J = 8.7, 2.7 Hz), 8.29 (d, 1H, J = 2.7 Hz) 化合物Ij-5 [化378] Q. 0
'H-NMR (DMSO-d ) δ : 0.92-1.24 (m, 4H), 1.19 (t, 3H, J = 7.2 Hz), 1.38 (m, 1H), 6 1.78- 1.88 (m, 2H), 1.96-2.06 (m, 2H), 2.78 (t, 2H, J = 6.0 Hz), 2.98 (q, 2H, J = 7.5 Hz), 3.60-3.78 (m, 1H), 6.52 (d, 1H, J = 8.4 Hz), 6.60 (d, 1H, J = 7.8 Hz), 7.01 (t, 1H, J = 5.7 Hz), 7.20-7.36 (m, 3H), 7.46 (t, 1H, J = 8.1 Hz), 7.55 (d, 1H, J = 8.7 Hz), 8.15 (s, 1H) 化合物Ij-6 Wk379]
H !H-NMR (DMSO-d ) 6 : 0.92-1.24 (m, 4H), 1.19 (t, 3H, J = 7.2 Hz), i.40 (m, 1H), 6 1.78- 1.88 (m, 2H), 1.96-2.06 (m, 2H), 2.78 (t, 2H, J = 6.0 Hz), 2.98 (q, 2H, J = 7.5 Hz), 3.60-3.78 (m, 1H), 6.51 (d, 1H, J = 8.7 Hz), 6.60 (d, 1H, J = 7.5 Hz), 7.01 (t, 1H, J = 5.7 Hz), 7.02-7.12 (m, 1H), 7.36-7.48 (m, 3H), 7.71 (dd, 1H, J = 8.7, 2.1 Hz), 8.33 (d, 1H, J = 2.1 Hz) 化合物Ij-7 [化380] -220 1376367
'h-NMR (DMSO-d ) δ : 0.92-1.24 (m, 4H), 1.19 (t, 3H, J = 7.2 Hz), 1.40 (m, 1H), 6 1.78-1.88 (m, 2H), 1.96-2.06 (m, 2H), 2.78 (ΐ, 2H, J = 6.0 Hz), 2.98 (q, 2H, J = 7.5 Hz), 3.60-3.78 (m, 1H), 6.50 (d, 2H, J = 8.7 Hz), 6.99 (t, 1H, J = 6.0 Hz), 7.16-7. 26 (m, 2H), 7.52-7.68 (m, 3H), 8.25 (s, 1H) 化合物丨j-8 [化 381]
^-NMR (CDC1) 5 : 1.15-1.26 (m, 4H), 1.40 (t, 3H, J = 7.5 Hz), 1.55-1.58 (m, 1H 3 ),1.93 (d, 2H, J = 9.7 Hz), 2.23 (d, 2H, J = 9.7 Hz), 3.01-3.11 (m, 4H), 3.56-3.61 ( m, 1H), 3.84 (s, 3H), 4.34 (t, 1H, J = 6.1 Hz), 4.83-4.86 (m, 1H), 6.46 (d, 1H, J = 8 .6 Hz), 6.99 (d, 1H, J = 8.5 Hz), 7.05 (d, 1H, J = 8.5 Hz), 7.29 (s, 1H), 7.30-7.34 ( m, 1H), 7.69 (dd, 1H, J = 8.7, 2.4 Hz), 8.25 (s, 1H). 化合物Ij-9 [化382]
JH-NMR (CDC1) δ : 1.16-1.24 (m, 4H), 1.40 (t, 3H, J = 6.2 Hz), 1.55-1.59 (m, 1H ),1.94 (d, 2F-I, J = Π.8 Hz), 2.23 (d, 2H, J = 11.8 Hz), 3.03-3.09 (in, 4H), 3.58-3.6 2 (m, 1H), 3.88 (s, 3H), 4.29 (t, 1H, J = 6.4 Hz), 4.85-4.89 (m, 1H), 6.49 (d, 1H, J =8.7 Hz), 6.88 (dd, 1H, J = 8.7, 2.2 Hz), 7.04-7.06 (m, 1H), 7.10 (d, 1H, J = 8.7 H z), 7.36 (t, 1H, J = 7.9 Hz), 7.70 (dd, 1H, J = 8.7, 2.2 Hz), 8.32 (s, 1H). 化合物Ij-l〇 -221 - 1376367 [化383]
'H-NMR (CDC1) 6 : 1.19-1.30 (m, 4H), 1.41 (t, 3H, J = 6.3 Hz), 1.56-1.59 (m, 1H 3 ),1.94 (d. 2H, J = 11.1 Hz), 2.23 (d, 2H, J = 11.1 Hz), 3.01-3.11 (m, 4H), 3.57-3.6 1 (m, 1H), 3.87 (s, 3H), 4.27 (t, 1H, J = 6.4 Hz), 4.98 (s, 1H), 6.50 (dd, 1H, J = 8.7 ,2.2 Hz), 6.99 (d, 2H, J = 8.9 Hz), 7.43 (d, 2H, J = 8.7 Hz), 7.68 (dd, 1H, J = 8.7, 2.2 Hz), 8.25 (s, 1H).
化合物lj-11 [化384]
'H-NMR (DMSO-d) δ : 0.93-1.08 (m, 2H), 1.09-1.25 (m, 5H), 1.39 (m, 1H), 1.75- 6
1.86 (m, 2H), 1.95-2.07 (m, 2H), 2.34 (s, 3H), 2.78 (t, 2H, J = 6.2 Hz), 2.98 (q, 2H ,J = 7.3 Hz), 3.65 (tn, 1H), 6.45-6.53 (m, 2H), 7.01 (t, 1H, J = 5.6 Hz), 7.07 (d, 1H ,J = 7.1 Hz), 7.23-7.38 (m, 3H), 7.64 (dd, 1H, J1 = 8.8 Hz, J2 = 2.5 Hz), 8.26 (d, 1 H, J = 2.5 Hz). 化合物Ij-12 [化385]
'H-NMR (DMSO-d) δ : 0.93-1.08 (ra, 2H), 1.09-1.27 (m, 11H), 1.39 (m, 1H), 1.76 Θ -1.87 (m, 2H), 1.96-2.06 (m, 2H), 2.78 (t, 2H, J = 6.2 Hz), 2.84-3.03 (m, 3H), 3.66 (m, 1H), 6.45-6.54 (m, 2H), 7.01 (t, 1H, J = 5.8 Hz), 7.13 (d, 1H, J = 6.9 Hz), 7.27 -7.41 (m, 3H), 7.66 (dd, 1H, J1 = 8.8 Hz, J2 = 2.5 Hz), 8.27 (d, 1H, J = 2.2 Hz).
-222- 1376367 化合物lj-13 [化386] 'H-NMR (DMSO-d ) 6 : 0.92-1.09 (m, 2H), 1.09-1.25 (ra, 5H), 1.39 (m, 1H), 1.76- fi
1.85 (m, 2H), 1.95-2.06 (m, 2H), 2.78 (t, 2H, J = 6.2 Hz), 2.98 (q, 2H, J = 7.3 Hz), 3.68 (m, 1H), 6.52 (d, 1H, J = 8.8 Hz), 6.66 (d, 1H, J = 8.0 Hz), 7.02 (t, 1H, J = 5.5 Hz), 7.23 (d, 1H, J = 8.1 Hz), 7.49-7.55 (m, 2H), 7.62 (d, 1H, J1 = 8.5 Hz), 7.72 ( dd, 1H, J1 = 8.8 Hz, J2 = 2.5 Hz), 8.35 (d, 1H, J = 2.5 Hz). 化合物Ihl4 [化387]
'H-NMR (DMSO-d) δ :· 0.92-1.22 (m, 4H), 1.22 (d, 6H, J = 6.4 Hz), 1.39 (m, 1H), 6
1.76-1.86 (m, 2H), 1.95-2.03 (m, 2H), 2.81 (t, 2H, J = 6.4 Hz), 3.10-3.20 (m, 1H), 3.60-3.75 (m, 1H), 6.65 (d, 1H, J = 4.8 Hz), 6.70 (s, 1H), 6.88-6.98 (m, 2H)( 8.16 (d, 1H, J = 5.2 Hz). 化合物Ij-15 [化388]
'H-NMR (CDC1) 5 : 1.02-1.28 (m, 4H), 1.38 (d, 6H, J = 6.9 Hz), 1.52 (m, 1H), 1.8 3 5-1.94 (m, 2H), 2.11-2.21 (m, 2H), 3.01 (t, 2H, J = 6.6 Hz), 3.10-3.25 (m, 1H), 3.3 8-3.54 (m, 1H), 4.22 (ΐ, 1H, J = 6.3 Hz). 4.58 (d, 1H, J = 7.8 Hz), 6.34 (d, 1H, J = -223 1.8 Hz), 6.53 (dd, 1H, J = 5.4, 1.8 Hz), 7.93 (d, 1H, J = 5.4 Hz). 化合物丨hl6 [化389] 'H-NMR (CDCI) δ : 1.03-1.28 (m, 4H), 1.37 (d, 6H, J = 6.9 Hz), 1.52 (m, 1H), 1.8 3 4-1.93 (m, 2H), 2.11-2.21 (ra, 2H), 3.01 (t, 2H, J = 6.6 Hz), 3.09-3.24 (m, 1H), 3.4 0-3.54 (m, IH), 4.26 (t, 1H, J = 6.6 Hz), 4.44 (d, 1H, J = 8.1 Hz), 6.29 (d, 1H, J = 8.7 Hz), 7.33 (dd, 1H, J = 8.7, 2_7 Hz>, 7.99 (d, 1H, J = 2.7 Hz). 化合物Ihl7 [化390]
'H-NMR (DMSO-d) δ : 0.92-1.22 (m, 4H), 1.21 (d, 6H, J = 6.8 Hz), 1.36 (m, 1H), 6 1.76-1.84 (m, 2H), 1.92-2.00 (m, 2H), 2.80 (t, 2H, J = 6.4 Hz), 3.08-3.18 (m, 1H), 3.45-3.56 (m, 1H), 6.36 (d, 1H, J = 8.4 Hz), 6.43 (d, 1H, J = 7.2 Hz), 6.75 (d, 1H, J = 7.6 Hz), 6.94 (t, 1H, J = 6.0 Hz), 7.33 (t, 1H, J = 7.6 Hz). 化合物!j-18 [化 391]
'H-NMR (DMSO-d ) 5 : 0.98-1.24 (m, 4H), 1.22 (d, 6H, J = 6.9 Hz), 1.40 (m, 1H), 6 1.78-1.88 (m, 2H), 2.04-2.14 (m, 2H), 2.83 (t, 2H, J = 6.0 Hz), 3.10-3.22 (m, 1H), 3.64-3.82 (m, 1H), 6.40 (d, 2H, J = 8.4 Hz), 6.95-7.05 (m, 2H), 7.35-7.50 (m, 4H) ,7.99 (d, 2H, J = 7.2 Hz) -224- 1376367 化合物丨j-19 [化392]
'H-NMR (CDC1) δ : 1.22-1.38 (m, 4Η), 1.38 (d, 6H, J = 8.0 Hz), 1.54 (m, 1H), 1.8 3
6-1.95 (ra, 2H), 2.18-2.26 (m, 2H), 3.03 (t, 2H, J = 6.0 Hz), 3.12-3.22 (m, 1H), 3.5 2-3.64 (m, 1H), 4.16 (t, 1H, J = 6.4 Hz), 4.82-4.92 (m, 1H), 6.46 (d, 1H, J = 8.0 H z), 7.10-7.20 (m, 2H), 7.23-7.33 (m, 1H), 7.37 (t, 1H, J = 8.0 Hz), 7.65 (d, 1H, J = 8.7 Hz), 8.24 (s, 1H). 化合物lj-20 [化393]
'H-NMR (CDC1) δ : 1.22-1.38 (m. 4H), 1.39 (d, 6H, J = 8.0 Hz), 1.54 (m, 1H), 1.8 3
6-1.95 (m, 2H), 2.18-2.26 (m, 2H), 3.03 (t, 2H, J = 6.0 Hz), 3.12-3.22 (m, 1H), 3.5 2-3.64 (m, 1H), 4.16 (t, 1H, J = 6.4 Hz), 4.78-4.88 (m, 1H), 6.46 (d, 1H, J = 8.0 H z), 6.98(t, 1H, J = 5.7 Hz), 7.18 (d, 1H, J = 8.0 Hz), 7.23-7.29 (m, 1H). 7.33-7.40 ( m, 1H), 7.65 (d, 1H, J = 8.7 Hz), 8.29 (s, 1H). 化合物Ij-21 [化394]
CrF 'H-NMR (CDC1) 6 : 1.10-1.30 (m, 4H), 1.38 (d, 6H, J = 8.0 Hz), 1.54 (m, 1H), 1.8 3
6-1.95 (m, 2H). 2.18-2.26 (m, 2H), 3.03 (t/2H, J = 6.0 Hz), 3.13-3.22 (m, 1H), 3.5 2-3.64 (m, 1H), 4.15 (t, 1H, J = 6.4 Hz), 4.78-4.88 (m, 1H), 6.46 (d, 1H, J = 8.0 H -225- 1376367 z), 7.07-7.14 (m, 2H), 7.40-7.46 (m, 2H), 7.62 (d, 1H, J = 8.7 Hz), 8.23 (s, IH). 化合物Ij-22 [化395]
QMe 'H-NMR (DMSO-d ) δ : 0.95-1.25 (m, 4H), 1.22 (d, 6H, J = 6.6 Hz), 1.25-1.50 (br 6
,1H), 1.81 (d, 2H, J = 11.4 Hz), 2.00 (d, 2H, J = 10.5 Hz), 2.81 (t, 2H, J = 6.6 Hz), 3.05-3.22 (m, IK), 3.58-3.80 (m, 1H), 3.76 (s, 3H), 6.49 (d, 2H, J = 8.7 Hz), 6.50 -6.70 (br, 1H), 6.95-7.10 (m, 3H), 7.20-7.32 (m, 2H), 7.51 (d, 1H, J = 7.2Hz), 8.05 (br, 1H). ESI(positive) 418.3 [M+H]+ 化合物丨j-23 [化396]
'H-NMR (DMSO-d ) δ : 0.95-1.32 (m, 4H), 1.22 (d, 6H, J = 6.6 Hz), 1.25-1.55 (br 6
,1H), 1.82 (d, 2H, J = 11.4 Hz), 2.01 (d, 2H, J = 10.2 Hz), 2.81 (t, 2H, J = 6.6 Hz), 3.05-3.22 (m, 1H), 3.58-3.78 (m, 1H), 3.80 (s, 3H), 6.59 (d, 2H, J = 9.6 Hz), 6.85 (dd, 1H, J = 8.4 Hz, 2.4 Hz), 6.99 (t, 3H, J = 5.7Hz), 7.05-7.18 (m, 2H), 7.32 (d, 1 H, J = 7.8Hz), 7.76 (d, 1H, J = 8.4Hz), 8.27 (d, 1H, J = 2.1 Hz). ESI(positive) 418. 3 CM+H3+ 化合物Ij-24 [化397]
'H-NMR (DMSO-d ) δ : 0.92-1.25 (m, 4H), 1.22 (d, 6H, J = 6.6 Hz), 1.28-1.48 (m, 6
-226- 1376367 1H), 1.81 (d, 2H, J = 10.8 Hz), 2.00 (d, 2H, J = 9.6 Hz). 2.81 (t, 2H, J = 6.6 Hz), 3 .08-3.22 (m, 1H), 3.58-3.74 (m, 1H), 3.77 (s, 3H), 6.51 (d, 2H, J = 8.7 Hz), 6.97 (d ,2H, J = 8.7 Hz), 6.98 (brs. 1H), 7.48 (d, 2H, J = 8.7 Hz), 7.63 (dd, 1H, J = 11.4Hz ,2.4Hz), 8.21 (d, 1H, J = 2.4 Hz). ESI(positive) 418.3[M+H]+ 化合物l〗-25 [化398]
lH-NMR (DMSO-d ) 6 : 0.92-1.22 (m, 4H), 1.27 (s, 9H), 1.38 (m, 1H), 1.78-1.88 ( 6 m, 2H), 1.95-2.05 (m, 2H), 2.88 (t, 2H, J = 6.0 Hz), 3.60-3.80 (m, 1H), 6.65 (d, 1H ,J = 5.4 Hz), 6.70 (s, 1H), 6.87 (t, 1H, J = 6.0 Hz), 6.94 (d, 1H, J = 7.8 Hz), 8.16 ( d, 1H, J = 5.4 Hz) 化合物Ij-26 [化 399]
'H-NMR (DMSO-d ) δ : 0.92-1.22 (m, 4H), 1.27 (s, 9H), 1.38 (m, 1H), 1.78-1.88 (
m, 2H), 1.94-2.04 (m, 2H), 2.88 (t, 2H, J = 6.0 Hz). 3.60-3.80 (m, 1H), 6.53 (d, 1H ,J = 8.7 Hz), 6.87 (t, 1H, J = 5.7 Hz), 7.19 (d, 1H, J = 7.5 Hz), 7.59 (dd, 1H, J = 9. 0, 2.4 Hz), 8.26 (d, 1H, J = 2.4 Hz) 化合物Ij-27 [化400]
'H-NMR (DMSO-d) δ : 0.92-1.22 (m, 4H)； 1.26 (s, 9H), 1.38 (m, 1H), 1.76-1.86 ( -227- 1376367 m, 2H), 1.92-2.02 (m, 2H), 2.88 (t, 2H, J = 6.0 Hz), 3.40-3.60 (m, 1H), 6.36. (d, 1H ,J = 8.1 Hz), 6.43 (d, 1H, J = 6.9 Hz), 6.80 (d, 1H, J = 7.5 Hz), 6.86 (t, 1H, J = 5.4 Hz), 7.34 (t, 1H, J = 8.4 Hz) 化合物Ij-28 [化 401] 0 0
'H-NMR ((DMSO-d ) δ : 0.93-1.18 (m, 4H), 1.21 (d, 6H, J = 6.9 Hz), 1.39 (m, 1H) 6
,1.75-1.86 (m, 2H), 1.94-2.05 (m, 2H), 2.80 (t, 2H, J = 6.0 Hz), 3.09-3.27 (m, 2H ),6.19 (d, 1H, J = 8.1 Hz), 6.64 (d, 2H, J = 8.7 Hz), 6.98 (t, 1H, J = 6.0 Hz), 7.33 ( d, 2H, J = 8.7 Hz) Mass:379[M+Hr 化合物ij-29 [化402]
lH-NMR (DMSO-d ) δ : 0.93-1.18 (m, 4H), 1.22 (s, 3H), 1.24 (s, 3H), 1.32-1.49 ( 6
m, 2H), 1.82 (d, 2H, J = 11.2 Hz), 2.04 (d, 2H, J = 11.2 Hz), 2.75-2.87 (m, 2H), 3. 07-3.28 (m, 2H), 6.64 (s, 1H), 6.96 (s, 1H), 7.10-7.22 (m, 2H), 7.25-7.39 (m, 2H), 7.77-7.90 (m，2H), 8.63 (s, 1H).融點：161-162°C 化合物Ih30 [化403] Η 'H-NMR (DMSO-d ) δ : 0.92-1.22 (m, 4H), 1.27 (s, 9H), 1.37 (m, 1H), 1.76-1.86 ( 6 m, 2H), 1.94-2.05 (m, 2H)( 2.88 (t, 2H, J = 6.3 Hz), 3.19 (m, 1H), 6.19 (d, 1H, J = -228- 1376367 7.5 Hz), 6.64 (d, 2H, J = 8.7 Hz), 6.88 (d, 1H, J = 6.0Hz), 7.33 (d, 2H, J = 8.7 Hz )Mass:392M+ 化合物[j-31 [化404]
F 'H-NMR (DMSO-d) δ : 0.92-1.16 (m, 4H), 1.26 (s, 9H), 1,36 (m, 1H), 1.72-1.83 ( 6
m, 2H), 1.92-2.02 (m, 2H), 2.87 (t, 2H, J = 6.3 Hz), 3.12 (m, 1H), 6.09-6.23 (m, 4 H), 6.87 (t, 1H, J = 6.0 Hz) Mass:361[M+H]+ 化合物Ij-32 [化405]
F F H 'H-NMR (CDCI) δ : 1.00-1.20 (tn, 4H), 1.40 (s, 9H), 1.42-1.64 (m, 2H), 1.84-1.9 3 5 (m, 2H), 2.09-2.20 (m, 2H), 3.07 (m, 1H), 3.07 (t, 2H, J = 6.3 Hz), 3.90 (m, 1H), 6.10 (dd, 2H, J = 9.6, 5.4 Hz).
化合物丨j-33 [化406]
'H-NMR (DMSO-d) δ : 0.93-1.21 (m, 5H), 1.28 (s, 9H), 1.33-1.46 (m, 1H), 1.82 ( 6 d, 2H, J = 11.6 Hz), 2.04 (d, 2H, J = 11.6 Hz), 2.86-2.95 (m, 2H), 3.03-3.29 (m, 1 H), 6.59-6.71 (m, 1H), 6.80-6.92 (m, 1H), 7.09-7.21 (m, 2H), 7.27-7.37 (m, 2H), 7 .77-7.88 (m, 2H), 8.58-8.67 (s, 1H).融点:172-173°C 化合物丨j-34 -229- 1376367 N八Cl 'H-NMR (DMSO-d ) δ : 0.96-1.08 (m, 2H), 1.12-1.24(m, 2H), 1.21 (d, 6H, J = 6.4 6
Hz), 1.38 (m, 1H), 1.76-1.86 (m, 2H), 1.92-2.00 (m, 2H), 2.80 (t, 2H, J = 6.4 Hz), 3.10-3.20 (m, 1H), 3.48-3.60 (m, 1H), 6.95 (t, 1H, J = 5.6 Hz), 7.41 (d, 1H, J = 7.6 Hz), 7.63 (s, 1H), 7.82 (s, 1H).
[化407]
化合物Ij-35 [化408]
'H-NMR (DMSO-d ) 6 : 0.96-1.26 (m, 4H), 1.27 (s, 9H),. 1.38 (m, 1H). 1.78-1.88 ( m, 2H). 1.92-2.02 (m, 2H), 2.88 (t, 2H, J = 6.0 Hz), 3.48-3.62 (m. 1H), 6.87 (t, 1H ,J = 6.0 Hz), 7.45 (d, 1H, J = 7.5 Hz), 7.63 (s, 1H), 7.82 (s, 1H) 化合物U-36 [化409]
lH-NMR (DMSO-d ) 8 : 0.96-1.06 (m, 2H), 1.12-1.20 (m, 2H), 1.21 (d, 6H, J = 6.6 6
Hz), 1.39 (m, 1H), 1.78-1.84 (m, 2H), 1.95-1.99 (m, 2H), 2.81 (t, 2H, J = 6.0 Hz), 3.10-3.20 (m, 1H), 3.74-3.88 (m, 1H), 6.80 (s, 1H), 6.98 (t, 1H, J = 6.0 Hz), 7.93 ( d, 2H, J = 7.2 Hz), 8.53 (s, 1H). 化合物U-37 [化 410] -230- 1376367
'H-NMR (DMSO-d ) δ : 0.96-1.30 (m, 4H), 1.19 (t, 3H, J = 7.2 Hz), 1.42 (m, 1H), 1.78-1.88 (m, 2H), 2.04-2.16 (m, 2H), 2.80 (t, 2H, J = 6.0 Hz), 2.99 (q, 2H, J = 7.5 Hz), 3.72-3.90 (m, 1H), 6.85 (d, 1H, J = 9.6 Hz), 6.93 (d, 1H, J = 7.5 Hz), 7.04 (t, 1H, J = 5.7 Hz), 7.26-7.38 (m, 2H), 7.40-7.52 (m, 1H), 7.57 (d, 1H, J = 9.0 Hz), 7 .85 (t, 1H, J =7.8 Hz)
化合物丨j-38 [化411]
'H-NMR (DMSO-d ) 6 : 0.96-1.30 (m, 4H), 1.19 (t. 3H, J = 7.2 Hz), 1.42 (m, 1H), 6 1.78-1.88 (rn, 2H), 2.04-2.16 (m, 2H), 2.80 (t, 2H, J = 6.0 Hz), 2.99 (q, 2H, J = 7.5 Hz), 3.72-3.90 (m, 1H), 3.80 (s, 3H), 6.72 (d, 1H, J = 7.8 Hz), 6.77 (d, 1H, J = 9.0 Hz), 6.98-7.10 (m, 2H), 7.12 (d, 1H, J = 8.4 Hz), 7.38 (t, 1H, J = 8.1 Hz), 7.56 (d, 1H, J = 9.3 Hz), 7.61 (d, 1H, J = 7.8 Hz) 化合物lj-39'
[化 412]
'H-NMR (DMSO-d ) 5 : 0.96-1.30 (m, 4H), 1.19 (t, 3H, J = 7.2 Hz), 1.42 (m, 1H), 6 1.78-1.88 (m, 2H), 2.04-2.16 (m, 2H), 2.80 (t, 2H, J = 6.3 Hz), 2.99 (q, 2H, J = 7.5 Hz), 3.72-3.90 (m, 1H), 6.85 (d, 1H, J = 9.6 Hz), 6.92 (d, 1H, J = 7.5 Hz), 7.04 (t, 1H, J = 5.7 Hz), 7.21 (t, 1H, J = 8.7 Hz), 7.46-7.56 (m, 1H), 7.75-7.88 (m, 3H) 化合物U-40 -231 - 1376367 [化 413]
'H-NMR (DMSO-d ) δ : 0.96-1.10 (m, 2H), 1.19 (t, 3H, J = 7.2 Hz), 1.15-1.26 (m, 6 2H), 1.42 (m, 1H), 1.78-1.88 (m, 2H), 2.04-2.14 (m, 2H), 2.80 (t, 2H, J = 6.3 Hz), 2.99 (q, 2H, J = 7.5 Hz), 3.76-3.87 (m, IK), 6.85 (d, 1H, J = 9.6 Hz), 6.91 (d, 1H, J = 7.5 Hz), 7.01 (t, 1H, J = 5.7 Hz), 7.42-7.52 (m, 2H), 7.83 (d, 1H, J = 8.0 Hz), 7 .93 (d, 1H, J = 8.0 Hz), 8.02 (s, 1H).
化合物Ij-41 [化 414]
]H-NMR (DMSO-d ) δ : 0.96-1.30 (m, 4H), 1.20 (t, 3H, J = 7.5 Hz), 1.42 (m, 1H), 6 1.78-1.88 (m, 2H), 2.04-2.16 (m, 2H), 2.80 (t, 2H, J = 6.3 Hz), 2.99 (q, 2H, J = 7.5 Hz), 3.76-3.90 (m, 1H), 6.88 (d, 1H, J = 9.3 Hz), 6.97 (d, 1H, J = 7.5 Hz), 7.03 (t, 1H, J = 5.7 Hz), 7.67-7.77 (m, 2H), 7.92 (d, 1H, J = 9.6 Hz), 8.26 (d, 1H, J = 6.9 Hz), 8.33(s, 1H)
化合物Ij-42 [化 415]
'H-NMR (DMSO-d ) 6 ： 0.93-1.10 (m, 2H), 1.20 (t, 3H, J= 7.2 Hz), 1.22-1.28 (m, 6 1H), 1.35-1.50 (m, 2H), 1.84 (d, 2H, J = 12.0 Hz), 2.08 (d, 2H, J = 12.0 Hz), 2.63-2.76 (m, 2H), 2.91-3.03 (m, 2H), 3.75-3.90 (m, 1H), 6.86 (d, 1H, J = 9.2 Hz), 6.93 (d, 1H, J = 7.2 Hz), 6.98-7.07 (in, 1H), 7.36 (d, 1H, J = 7.2 Hz), 7.59 (t, 1H, J = 8. -232- 1376367
0 Hz), 7.85 (d, 1H, J = 9.2 Hz), 7·9卜8.02 (m, 2H).融点：i44-l45〇C 化合物Ij-43 [化 416]
'H-NMR (DMSO-d ) δ : 0.94-1.06 (m, 2H), 1.10-1.24 (m, 2H), 1.21 (d, 6H, J = 6.8 6
Hz), 1.39 (m, 1H), 1.76-1.86 (m, 2H), 1.98-2.06 (m, 2H), 2.81 (t, 2H, J = 6.4 Hz), 3.10-3.20 (m, 1H), 3.62-3.74 (m, 1H), 6.84 (d. 1H, J =9.2 Hz), 6.88-6.98 (m, 2H), 7.31 (d, 1H, J = 9.6 Hz). 化合物丨j-44 [化 417]
'H-NMR (DMSO-d ) 5 : 0.94-1.26 (m, 4H), 1.20 (d, 6H, J = 6.6 Hz), 1.40 (m, 1H), 6 1.78-1.88 (m, 2H), 2.04-2.16 (m, 2H), 2.81 (t, 2H, J = 6.3 Hz), 3.06-3.20 (m, 1H), 3.72-3.90 (m, 1H), 6.75-6.88 (m, 2H), 6.97 (t, 1H, J = 6.0 Hz), 7.30-7.48 (m, 3H), 7.76 (d, 1H, J = 9.3 Hz), 7.94 (d, 2H, J =8.4 Hz)
化合物U-45 [化 418]
lH-NMR (DMSO-d ) δ : 0.96-1.28 (m, 4H), 1.22 (d, 6H, J = 6.9 Hz), 1.42 (m, 1H), 6 1.78-1.88 (m, 2H), 2.04-2.16 (m, 2H), 2.83 (t, 2H, J = 6.3 Hz), 3.10-3.22 (m, 1H), 3.74-3.92 (m, 1H), 6.85 (d, 1H, J = 9.0 Hz), 6.91 (d, 1H, J = 7.5 Hz), 6.98 (t, 1H, J = 6.0 Hz), 7.25-7.36 (m, 2H), 7.40-7.50 (m, 1H), 7.57 (d, 1H, J = 6.9 Hz), 7.85 (t -233 - 1376367 ,1H, J=8.1 Hz) 化合物Ij-46 [化 419]
'H-NMR (DMSO-d ) 6 : 0.96-1.28 (m, 4H), 1.22 (d, 6H, J = 6.6 Hz), 1.42 (m, 1H), 6 1.78-1.88 (m, 2H), 2.04-2.16 (m, 2H), 2.83 (t, 2H, J = 6.3 Hz), 3.10-3.22 (m, 1H), 3.74-3.92 (m, 1H), 6.85 (d, 1H, J = 9.3 Hz), 6.90 (d, 1H, J = 7.5 Hz), 6.98 (t，1H,
J = 6.0 Hz), 7.21 (t, IH, J = 7.8 Hz), 7.46-7.56 (m, 1H), 7.75-7.86 (m, 3H) 化合物[卜47 [化420]
丫 Ά 'H-NMR (DMSO-d ) δ : 0.96-1.28 (m, 4H), 1.22 (d, 6H, J = 6.9 Hz), 1.42 (m, 1H), 6 L78-L88 (m, 2H), 2.04-2.16 (m, 2H), 2.83 (t, 2H, J = 6.0 Hz), 3.10-3.22 (m( 1H), 3.74-3.92 (m, 1H), 6.81 (d, 1H, J = 7.5 Hz), 6.84 (d, 1H, J = 9.3 Hz), 6.98 (t, 1H, J = 6.3 Hz), 7.25-7.35 (m, 2H), 7.77 (d, 1H, J = 9.3 Hz), 7.96-8.06 (m, 2H)
化合物Ij-48 [化 421]
'H-NMR (DMSO-d ) δ : 0.96-1.28 (m, 4H), 1.22 (d, 6H, J = 6.9 Hz), 1.42 (m, 1H), 6 1.78-1.88 (m, 2H), 2.04-2.16 (m, 2H), 2.83 (t, 2H, J = 6.3 Hz), 3.10-3.22 (m, IH), 3.74-3.92 (m, 1H), 3.80 (s, 3H), 6.71 (d, 1H, J = 7.8 Hz), 6.76 (d, 1H, J = 9.3 Hz), 6.98 (t, 1H, J = 5.7 Hz), 7.05 (d, 1H, J = 7.2 Hz), 7.12 (d, 1H, J = 7.8 Hz), 7.38 (t,
-234- 1376367 1H, J = 8.4 Hz), 7.56 (d, 1H, J = 9.3 Hz), 7.62 (d, 1H, J = 6.9 Hz) 化合物丨h49 [化 42¾ OMe 'H-NMR (DMSO-d) δ : 0.96-1.28 (ra, 4H), 1.22 (d, 6H, J = 6.6 Hz), 1.42 (m, 1H), 6
1.78-1.88 (m, 2H), 2.04-2.16 (m, 2H), 2.83 (t, 2H, J = 6.0 Hz), 3.10-3.22 (m, 1H), 3.74-3.92 (m, 1H), 3.82 (s, 3H), 6.78-6.88 (m, 2H), 6.92-7.04 (m, 2H), 7.37 (t, 1H ,J = 7.5 Hz), 7.46-7.58 (m, 2H), 7.79 (d, 1H. J = 9.3 Hz) 化合物丨j-50 [化423]
'H-NMR (DMSO-d ) 5 : 0.96-1.28 (m, 4H), 1.22 (d, 6H, J = 6.9 Hz), 1.42 (m, 1H), 6 1.78-1.88 (m, 2H), 2.04-2.16 (m, 2H), 2.83 (t, 2H, J = 6.0 Hz), 3.10-3.22 (m, 1H), 3.74-3.92 (m, 1H), 3.80 (s, 3H), 6.70 (d, 1H, J = 7.8 Hz), 6.82 (d, 1H, J = 9.3 Hz), 6.95-7.05 (m, 3H), 7.72 (d, 1H, J = 9.3 Hz), 7.90 (d, 2H, J = 9.0 Hz).
化合物[j-51 [化424]
〇vCF3 'H-NMR (DMSO-d ) δ : 0.92-1.05 (m, 2H), 1.07-1.20 (m, 2H), 1.22 (d, 6H, J = 6.9 Hz), 1.39 (m, 1H), 1.76-1.85 (m, 2H), 2.02-2.10 (m, 2H), 2.81 (t, 2H, J = 6.3 Hz), 3.09-3.20 (m, 1H), 3.57-3.68 (m, 1H), 4.89-4.98 (m, 2H), 6.47 (d, 1H, J = 8.0 Hz), 6.88 (d, 1H, J = 7.5 Hz), 6.96 (t, 1H, J = 6.0 Hz), 7.02 (d, 1H, J = 7.5 Hz). 1376367 化合物[j-52 [化425]
AxijjjXo 'H-NMR (DMSO-d) δ :.0.92-1.05 (m, 2H), 1.07-1.20 (m, 2H), 1.22 (d, 6H, J = 6.9 6
Hz), 1.39 (m, 1H), 1.52-1.74 (m, 6H), 1.77-1.85 (m, 2H), 1.87-1.97 (m, 2H), 2.02 -2.09 Cm, 2H), 2.81 (t, 2H, J = 6.3 Hz), 3.09-3.20 (m, 1H), 3.55-3.65 (m, 1H), 5.25 -5.32 (m, 1H), 6.19 (d, 1H, J = 8.0 Hz), 6.77 (s, 2H), 6.95 (t, 1H, J = 6.0 Hz). 化合物〖j-53 [化426]
*H-NMR (DMSO-d) 6 : 0.92-1.15 (m, 4H), 1.21 (d, 6H, J = 6.9 Hz), 1.38 (m, 1H), 1.77-1.85 (m, 2H), 1.88-1.95 (m, 4H), 2.02-2.09 (m, 2H), 2.80 (t, 2H, J = 6.3 Hz), 3.09-3.20 (m, 1H), 3.25-3.35 (m, 4H), 3.55-3.65 (m, 1H), 5.80-5.85 (m, 1H), 6.72 (d, 1H, J = 8.0 Hz), 6.80 (d, 1H, J = 8.0 Hz), 6.96 (t, 1H, J = 6.0 Hz).
化合物丨j-54 [化427]
Η lH-NMR (DMSO-d) δ : 0.92-1.20 (m, 4H), 1.21 (d, 6H, J = 6.9 Hz), 1.38 (m, 1H), e 1.77-1.85 (m, 2H), 2.02-2.09 (m, 2H), 2.80 (t, 2H, J = 6.3 Hz), 3.09-3.20 (m, 1H). 3.58-3.65 (m, 1H), 6.56 (d, 1H, J = 8.0 Hz), 6.90-6.98 (m, 2H), 7.03-7.10 (m, 3H) ,7.15 (t, 1H, J = 8.0 Hz), 6.38 (t, 2H, J = 8.0 Hz). 化合物[j-55
-236- 1376367 [化428]
'H-NMR (DMSO-d ) 8 : 0.92-1.20 (m, 4H), 1.21 (d, 6H, J = 6.9 Hz), 1.38 (m, 1H), 1.77-1.85 (m, 2H), 2.02-2.09 (m, 2H), 2.80 (t, 2H, J = 6.3 Hz), 3.09-3.20 (m, 1H), 3.58-3.65 (m, 1H), 6.55 (d, 1H, J = 8.0 Hz), 6.90-6.98 (m, 2H), 7.05-7.15 (m, 3H) ,7.21 (t, 2H, J = 8.0 Hz).
化合物Ih56 [化429]
i-NMR (DMS〇-d ) δ : 0.92—1.20 (m, 4H), 1.21 (d, 6H, J = 6·9 Hz), 1‘38 (m, 1H). 1.77-1.85 (m, 2H), 2.02-2.09 (m, 2H), 2.80 (t, 2H, J = 6.3 Hz), 3.09-3.20 (m, 1H), 3.58-3.65 (m, 1H), 3.75 (s, 3H), 6.49 (d, 1H, J = 8.0 Hz), 6.87-6.98 (m, 4H), 7.00 -7.07 (m, 3H). 化合物Ij-57 [化430]
'H-NMR (DMSO-d ) 6 : 0.96-1.28 (m, 4H), 1.27 (s, 9H), 1.40 (m, 1H), 1.78-1.88 ( m, 2H), 2.00-2.10 (m, 2H), 2.88 (t, 2H, J = 6.0 Hz), 3.60-3.76 (m, 1H), 6.82-6.92 ( m, 2H), 6.96 (d, 1H, J = 7.8 Hz), 7.32 (d, 1H, J = 9.6 Hz). 化合物U-58 [化 431] -237- 1376367
'h-NMR (DMSO-d ) δ : 0.99-1.28 (m, 4H), 1.21 (d, 6H, J = 6.9 Hz). 1.39 (m, 1H), 6 1.78-1.86 (m, 2H), 2.04-2.10 (m, 2H), 2.82 (t, 2H, J = 6.1 Hz), 3.06-3.20 (m, 1H), 3.80-3.96 (m, 1H), 6.71 (d, 1H, J = 9.0 Hz), 6.76-6.86 (m, 1H), 6.90-6.98 (m, 1H) ,7.10 (t, 1H, J =8.1 Hz), 7.39-7.50 (ra, 2H), 7.56 (d, 1H, J = 7.5 Hz), 7.78 (d, 1H, J = 7.5 Hz). 化合物Ij-59 .
[化432]
lH-NMR (DMSO-d ) δ : 0.99-1.28 (m, 4H). 1.27 (s, 9H), 1.40 (m, 1H), 1.80-1.85 ( 6 m, 2H), 2.04-2.09 (m, 2H), 2.91 (t, 2H, J = 6.1 Hz), 3.80-3.96 (m, 1H), 6.70 (d, 1H ,J = 9.0 Hz), 6.81-6.87 (m, 2H), 7.10 (t, 1H, J = 8.1 Hz), 7.39-7.44 (m, 2H), 7.56 ( d, 1H, J = 7.5 Hz), 7.79 (d, 1H, J = 7.5 Hz). 化合物Ij-60 [化433]
'H-NMR (DMSO-d ) δ : 0.97-1.09 (m, 2H), 1.23 (d, 6H, J = 6.9 Hz), 1.31-1.50 (m, 6 2H), 1.82-1.87 (m, 2H), 2.01-2.05 (m, 2H), 2.83 (t, 2H, J = 6.0 Hz), 3.11-3.20 (m, 1H), 4.00-4.18 (m, 1H), 6.83 (d, 1H, J = 5.7 Hz), 6.90-7.06 (m, 2H), 7.45 (t, 1H, J =6.9 Hz), 7.59 (t, 1H, J = 8.1 Hz), 7.67 (d, 1H, J = 8.4 Hz), 7.83 (d, 1H, J = 5.7 H z), 8.27 (d, 1H, J= 7.5 Hz). 化合物Ij-61 -238 - 1376367 [化434]
'H-NMR (DMSO-d ) δ : 0.96-1.09 (m, 2H). 1.28 (s, 9H), 1.29-1.50 (m, 2H), 1.82-1.87 (m, 2H), 2.01-2.05 (m, 2H), 2.91 (t, 2H, J = 7.8 Hz), 4.00-4.18 (m, 1H), 6.82-6.89 (m, 2H), 6.97 (d, 1H, J = 7.5 Hz ), 7.45 (t, 1H, J = 7.2 Hz), 7.59 (t, 1H, J = 8. 1 Hz), 7.67 (d, 1H, J = 7.8 Hz), 7.84 (d, 1H, J = 6.0 Hz), 8.27 (d, 1H, J = 8.4 Hz). 化合物Ij-62
[化435]
'H-NMR (DMSO-d ) δ : 0.96-1.14 (m, 2H), 1.18-1.30 (m, 2H), 1.22 (d, 6H, J = 6.6 6
Hz), 1.40 (m, 1H), 1.78-1.88 (m, 2H), 2.04-2.14 (m, 2H)( 2.81 (t, 2H, J = 6.3 Hz), 3.10-3.20 (m, 1H), 3.58-3.70 (m, 1H), 6.95-7.03 (m, 2H), 7.20 (t, 1H, J = 7.5 Hz ), 7.37 (d, 1H, J = 8.1 Hz), 7.64 (d, 1H, J = 7.5 Hz), 7.92 (d, 1H, J = 7.8 Hz).
化合物Ij-63 [化436]
lH-NMR (DMSO-d ) δ : 1.00 (dd, 2H, J = 24.8, 10.6 Hz), 1.15-1.22 (m, 2H), 1.18 6 (t, 3H, J = 7.6 Hz), 1.27 (s, 9H), 1.34-1.40 (m, 1H), 1.81 (d, 2H, J = 11.6 Hz), 2.07 (d, 2H, J = 11.6 Hz), 2.60 (q, 2H, J = 7.6 Hz), 2.89 (t, 2H, J = 6.3 Hz), 3.52-3.63 ( m, 1H), 6.87 (t, 1H, J = 5.8 Hz), 7.04 (d, 1H, J = 7.9 Hz), 7.27 (d, 1H, J = 8.2 Hz), 7.47 ($, 1H), 7.80 (d, 1H, j = 7.6 Hz). 化合物丨j-64 -239- 1376367 [化437] 〇〇 >r^X) 'H-NMR (DMS〇-d) δ : 0.92:i.l0 (m, 2H), 1.12-1.25 (m, 2H), 1.27 (s, 9H), 1.37 ( 6 m, 1H), 1.76-1.84 (m, 2H), 2.02-2.12 (m, 2H), 2.89 (t, 2H, J = 6.0 Hz), 3.50-3.66 ( m, 1H), 6.87 (t, 1H, J = 5.7 Hz), 7.03 (dd, 1H, J = 8.7, 2.7 Hz), 7.32-7.37 (m, 1H), 7.58 (dd, 1H, J = 8.7, 2.7 Hz), 7.92 (d, 1H, J = 7.2 Hz).
化合物lj-65 [化438]
'H-NMR (DMSO-d ) δ : 1.01 (dd, 2H, J = 24.6, 10.2 Hz), 1.21 (dd, 2H, J = 24.6, 1 6 0.2 Hz), 1.27 (s, 9H), 1.34-1.40 (m, 1H), 1.82 (d, 2H, J = 11.2 Hz), 2.08 (d, 2H, J = 11.2 Hz), 2.89 (t, 2H, J = 6.2 Hz), 3.59-3.65 (m, 1H), 6.87 (t, 1H, J = 5.8 Hz), 7. 21 (dd, 1H, J = 8.6, 2.4 Hz), 7.34 (d, 1H, J = 8.6 Hz), 7.77 (d, 1H, J = 1.8 Hz), 8.0 6 (d, 1H, J = 7.6 Hz).
化合物Ij-66 [化439]
*H-NMR (CDCl) δ : 1.09-1.46 (m, 4H), 1.41 (s, 9H), 1.54 (m, 1H), 1.90-2.00 (m, 3 2H), 2.24-2.34 (m, 2H), 3.09 (t, 2H, J = 6.6 Hz),'3.46-3.60 (m, 1H), 3.99 (t, 1H, J =6.6 Hz), 6.58 (brs, 1H), 7.58(s, 2H), 7.85 (s, 1H). 化合物Ih67 -240- 1376367 [化440]
'H-NMR (DMSO-d ) δ : 0.90-1.30 (m, 4H), 1.27 (s, 9H), 1.30-1.48 (m, 1H), 1.82 ( 6 d, 2H, J = 11.1 Hz), 2.08 (d, 2H, J = 9.6 Hz), 2.89 (t, 2H, J = 6.3 Hz), 3.55-3.70 ( m, 1H), 6.87 (t, 1H, J = 5.7 Hz), 7.17 (m, 1H), 7.41 (d, 1H, J = 8.7 Hz), 7.77 (d, 1 H, J = 1.5 Hz), 8.10 (d, 1H, j = 7.5 Hz). ESI(positive)m/z 466.2 [M+H]+
化合物Ij-68 [化 441]
'H-NMR (DMSO-d ) 5 : 0.90-1.28 (m, 4H), 1.25 (s, 9H), 1.32 (m, 1H), 1.76-1.82 ( 6 m, 2H), 2.00-2.10 (m, 2H), 2.87 (t, 2H, J = 6.6 Hz), 3.50-3.62 (m, 1H), 3.71 (s, 3H ),6.77 (dd, 1H, J = 8.7, 2.7 Hz), 6.84 (t, 1H, J = 5.7 Hz), 7.22-7.28 (m, 2H), 7.66 ( d, 1H, J = 7.2 Hz). 化合物丨j-69 [化442]
'H-NMR (DMSO-d ) δ : 0.94-1.10 (m, 2H), 1.12-1.25 (m, 2H), 1.27 (s, 9H), 1.37 ( m, 1H), 1.76-1.84 (m, 2H), 2.02-2.12 (m, 2H), 2.90 (t, 2K, J = 6.0 Hz), 3.52-3.68 ( m, 1H), 3.84 (s, 3H), 6.82 (d, 1H, J = 8.1 Hz), 6.88 (t, 1H, J = 5.4 Hz), 6.95 (t, 1H, J = 7.8 Hz), 7.23 (d, 1H, J = 7.8 Hz), 7.83 (d, 1H, J = 7.8 Hz). 化合物丨j-70 [化443] -241 - 1376367
!H-NMR _S〇-d ) δ : 0.98-1.10 (m, 2H), 1.19 (t, 3H, J = 7.2 Hz), U7-1.32 (m, 6 2H). 1.40 (m, 1H), 1.76-1.88 (m, 2H), 2.04-2.14 (m, 2H), 2.79 (t, 2H, J = 6.0 Hz), 2.98 (q, 2H, J = 7.2 Hz), 3.60-3.78 (m, 1H), 7.03 (t, LH, J = 6.3 Hz), 7.45-7.54 (m ,2H), 8.10 (s, 1H), 8.34 (d, 1H, J = 7.2 Hz). 化合物Ij-71 [化444]
'H-NMR (DMSO-d ) δ ： 1.01 (dd, 2H, J = 26.1, 12.3 Hz), 1.16-1.22 (m, 2H), 1.22 6 (d, 6H, J = 6.6 Hz), 1.35-1.41 (m, 1H), 1.70-1.77 (rn, 1H), 1.82 (d, 2H, J = 11.6 Hz ),2.08 (d, 2H, J = 11.6 Hz), 2.81 (t, 2H, J = 6.3 Hz), 3.66-3.72 (m, 1H), 6.99 (t, 1 H, J = 6.3 Hz), 7.23 (dd, 1H, J = 8.1, 4.7 Hz), 7.66 (d, 1H, J = 8.1 Hz), 8.07 (d, 1H ,J = 4.7 Hz), 8.26 (d, 1H, J = 6.3 Hz). 化合物U-72 [化445]
JH-NMR (DMSO-d ) δ ： 1.01 (dd, 2H, J = 24.8, 11.3 Hz), 1.18-1.23 (m, 2H), 1.27 6 (s, 9H), 1.36-1.39 (m, 1H), 1.82 (d, 2H, J = 11.5 Hz), 2.08 (d, 2H, J = 11.5 Hz), 2. 89 (t, 2H, J = 6.1 Hz), 3.65-3.73 (m, 1H), 6.87 (t, 1H, J = 5.7 Hz), 7.23 (dd, 1H, J =8.1, 4.8 Hz), 7.66 (d, 1H, J = 7.9 Hz), 8.07 (d, 1H, J = 4.7 Hz), 8.26 (d, 1H, J = 7 .6 Hz). -242- 1376367 化合物Ij-73 [化446]
'H-NMR (CDC1) δ : 1.09-1.46 (m, 4H), 1.41 (s, 9H), 1.55 (m, 1H), 1.92-2.02 (m, 2 3 H), 2.24-2.34 (m, 2H), 3.09 (t, 2H, J = 6.3 Hz), 3.58-3.72 (m, 1H), 3.98 (t, 1H, J = 6.0 Hz), 6.30 (brs，1H), 7.62(d, 1H, J = 8.1 Hz), 7.77 (d, 1H, J = 8.4 Hz).
化合物lj-74 [化447]
H ^-NMR (DMSO-d ) δ : 0.90-1.08 (m, 2H), 1.12-1.40 (m, 3H), 1.25 (s, 9H), 1.76-6 1.86 (m, 2H), 1.98-2.10 (m, 2H), 2.87 (d, 2H, J = 6.3 Hz), 3.40-3.56 (m, 1H), 6.85 (brs, 1H), 6.93 (t, 1H, J = 7.5 Hz), 7.07 (t, 1H, J = 7.5 Hz), 7.20 (d, 1H, J = 7.5 Hz ),7.29 (d, 1H, J = 7.8 Hz), 7.79 (brs, 1H). 化合物Ij-75 [化448]
Cl 'H-NMR (CDCU δ : 1.08-1.26 (m, 2H), 1.36-1.60 (m, 3H), 1.40 (s, 9H), 1.92-2.0 2 (m, 2H), 2.22-2.32 (m, 2H). 3.08 (t, 2H, J = 6.6 Hz), 3.68-3.80 (m, 1H), 4.03 (t, 1H, J = 6.0 Hz). 7.06 (brs, 1H), 7.20-7.36(m, 3H). 化合物lh76 i 化 449] -243 - 1376367
'H-NMR (DMSO-d ) 6 : 1.02 (dd, 2H, J = 25.2, 12.4 Hz), 1.17 (t, 3H, J = 7.1 Hz), 6 1.20 (t, 3H, J = 7.3 Hz), 1.26-1.35 (m, 2H), 1.37-1.42 (m, 1H), 1.83 (d, 2H, J = 11. 6 Hz), 2.05 (d, 2H, J = 11.6 Hz), 2.80 (t, 2H, J = 6.4 Hz), 2.99 (q, 2H, j = 7.3 Hz), 3.65-3.72 (m, 1H), 4.01 (q, 2H, J = 7.1 Hz), 6.32 (d, 1H, J = 7.9 Hz), 6.86-6.94 (m ,2H), 7.01 (t, 1H, J = 6.0 Hz), 7.12 (d, 1H, J = 6.9 Hz), 7.17 (d, 1H, J = 6.8 Hz). 化合物[j-77
[化450]
'H-NMR (DMSO-d ) δ : 1.02 (dd, 2H, J = 24.8, 10.8 Hz), 1.19-1.21 (m, 2H), 1.30 6 (s, 9H), 1.37-1.41 (m, 1H), 1.84 (d, 2H, J = 10.6 Hz), 2.06 (d, 2H, J = 10.6 Hz), 2. 92 (t, 2H, J = 6.3 Hz), 3.50-3.52 (m, 1H), 6.42 (d, 1H, J = 8.1 Hz), 6.83 (d, 1H, J = 7.9 Hz), 6.88-6.92 (m, 2H), 7.11-7.14 (m, 2H), 10.58 (s, 1H). 化合物Ij-78 [化 451]
'H-NMR (DMSO-d ) 5 : 0.97-1.05 (m, 2H), 1.20-1.26 (m, 2H), 1.28 (s, 9H), 1.34- 6 1.38 (m, 1H), 1.84 (d, 2H, J = 11.5 Hz), 2.07 (d, 2H, J = 11.5 Hz), 2.90 (t, 2H, J = 6.1 Hz), 3.47 (s, 3H), 3.63-3.69 (m, 1H), 6.34 (d, 1H, J = 7.6. Hz), 6.87-6.93 (m, 3 H), 7.11 (d, 1H, J = 8.4 Hz), 7.17 (d, 1H, J = 8.4 Hz). 化合物Ij-79 [化452] -244- 1376367
'H-NMR (DMSO-d ) δ : 1.03 (dd, 2H, J = 23.6, 10.8 Hz), 1.18 (t, 3H, J = 7.5 Hz), 1.25-1.34 (m, 2H), 1.29 (s, 9H), 1.37-1.40 (m, 1H), 1.86 (d, 2H, J = 11.7 Hz), 2.07 (d, 2H, J = 11.7 Hz), 2.92 (t, 2H, J = 6.2 Hz), 3.67-3.73 (m, 1H), 4.03 (q, 2H, J = 7.1 Hz), 6.34 (d, 1H, J = 7.9 Hz), 6.87-6.96 (m, 3H), 7.14 (dd, 1H, J = 8.1, 1.2 Hz) ,7.l9(dd, 1H, ] = 8.1, 1.2 Hz).
化合物Ij-80 [化453]
'H-NMR (DMSO-d ) δ : 1.00 (dd, 2H, J = 23.2, 11.9 Hz), 1.19-1.25 (m, 2H), 1.28 6 (s, 9H), 1.33-1.38 (m, 1H), 1.45 (s, 3H), 1.47 (s, 3H). 1.83 (d, 2H, J = 11.1 Hz), 2. 07 (d, 2H, J = 11.1 Hz), 2.90 (t, 2H, J = 6.1 Hz), 3.62-3.70 (m, 1H), 4.57-4.66 (m, 1H), 6.21 (d, 1H, J = 7.9 Hz), 6.82-6.94 (m, 3H), 7.18 (d, 1H, J = 7.6 Hz), 7.31 (d, 1H, J = 7.6 Hz).
化合物U-81 [化454]
化合物丨j-82 [化455]
-245 - 1376367 'H-NMR (DMSO-d ) 8 : 0.90-1.19 (m, 4H), 1.28 (s, 9H), 1.32-1.45 (m, 1H), 1.80 ( 6 d, 2H, J = 11.2 Hz), 1.98 (d, 2H, J = 11.2 Hz), 2.84-2.93 (m, 2H), 3.26 (s, 3H), 3.4 0-3.53 (m, 1H), 6.29 (d, 1H, J = 8.0 Hz), 6.38 (d, 1H. J = 7.2 Hz), 6.86 (s, 1H), 7.3 3 (d, 1H, J = 8.4 Hz). 化合物丨h83 [化456]
化合物丨j-84 [化457]
'H-NMR (DMSO-d ) δ : 0.92-1.20 (m, 4H), 1.18 (t, 3H, J = 7.2 Hz), 1.40 (m, 1H), 6
1.75-1.85 (m, 2H), 1.96-2.06 (m, 2H), 2.78 (t, 2H, J = 6.0 Hz), 2.98 (q, 2H, J = 7.2 Hz), 3.60-3.78 (m, 1H), 6.38 (d, 1H, J = 8.1 Hz), 6.67 (s, 1H), 6.72 (d, 1H, J = 5.4 Hz). 7.00 (t, 1H, J = 6.0 Hz), 7.36-7.54 (m, 3H), 7.62 (d, 2H, J = 6.9 Hz), 8.00 (d, 1H, J = 5.4 Hz) 化合物Ij-85 [化458]
'H-NMR (DMSO-d ) δ : 1.00-1.20 (m, 4H), 1.20 (t, 3H, J = 7.2 Hz), 1.43 (m, 1H), 6 1.80-1.88 (m, 2H), 2.03-2.13 (m, 2H), 2.81 (t, 3H, J = 6.0 Hz), 3.00 (q, 2H, J = 7.2 Hz), 3.26 (m, 1H), 6.17 (d, 1H, J = 7.6 Hz), 6.57 (s, 1H), 6.96-7.07 (m, 2H), 7.35 ( dd, 1H, J = 8.4, 4.0 Hz), 8.02 (d, 1H, J = 8.4 Hz), 8.47 (d, 1H, J = 4.0 Hz). -246- 1376367 化合物Ij-86 [化459] 'h-NMR (DMSO-d ) δ : 1.00-1.24 (m, 4H), 1.23 (d, 6H, J = 6.4 Hz), 1.42 (m, 1H), 6
1.80-1.88 (m, 2H), 2.03-2.12 (m, 2H), 2.79-2.87 (m, 2H), 3.16 (m, 1H), 3.27 (m, 1 H), 6.17 (d, 1H, J = 8.0 Hz), 6.57 (s, 1H), 6.99 (d, 1H, J = 8.0 Hz), 7.01 (s, 1H), 7. 35 (dd, 1H, J = 8.0, 4.0 Hz), 8.02 (d, 1H, J = 8.0 Hz), 8.47 (d, 1H, J = 2.8 Hz). 化合物Ij-87 [化460] 0 0 Η
'h-NMR (DMSO-d) δ : 0.95-1.08 (m, 2H)» Γ.11-1.25 (m, 2H), 1.20 (t, 3H, J = 7.2 6
Hz), 1.40 (m, 1H), 1.76-1.86 (m, 2H), 1.97-2.04 (rn, 2H), 2.73-2.82 (m, 2H), 2.99 (q, 2H, J = 7.2 Hz), 3.70 (m, 1H), 6.53 (d, 1H, J = 8.8 Hz), 6.53 (d, 1H, J = 8.8 Hz) ,7.01 (t, 1H, J = 6.0 Hz), 7.58 (d, 1H, J = 3.2 Hz), 7.79 (d, 1H, J = 3.2 Hz), 7.86 ( d, 1H, J = 8.8 Hz), 8.55 (s, 1H).
化合物Ij-88 [化 461]
^-NMR (DMSO-d) δ : 0.92-1.07 (m, 2H), 1.09-1.20 (m, 2H), 1.19 (t, 6H, J = 7.2 6
Hz), 1.39 (m, 1H), 1.75-1.83 (m, 2H), 1.95-2.03 (m, 2H), 2.74-2.81 (m, 2H), 2.98 (q, 2H, J = 7.2 Hz), 3.66 (m, 1H), 6.48 (d, 1H, J = 8.4 Hz), 6.60 (d, 1H, J = 7.6 Hz) ,7.00 (t, 1H, J = 5.6 Hz), 7.06 (dd, 1H, J = 4.8, 2.4 Hz), 7.25 (d, 1H, J = 2.4 Hz), 7.37 (d, 1H, J = 4.8 Hz), 7.60 (dd, 1H, J = 8.4, 2.0 Hz), 8.26 (s, 1H). -247- 1376367 化合物Ij-89 [化462]
Hz), 1.39 (m, 1H), 1.76-1.84 (m, 2H), 1.96-2.04 (m, 2H), 2.73-2.81 (m, 2H), 2.98 (q, 2H, J = 7.2 Hz), 3.65 (m, 1H), 6.41-6.50 (m, 2H), 7.01 (t, 1H, J = 6.0 Hz). 7.44 (d, 1H, J = 4.0 Hz), 7.58 (m, 1H), 7.59 (s, 1H), 7.68 (d, 1H, J = 8.0 Hz), 8.34 (s, 1 H). 化合物Ij-90 [化 463]
'H-NMRiDMSO-d) δ :0.95-1.08 (m,2H), 1.12-1.25 (m，2H), 1.19 (t>3H，J = 7.2 6
Hz), 1.39 (m, 1H), 1.76-1.86 (m, 2H), 1.94-2.03 (m, 2H), 2.75-2.82 (m, 2H), 2.98 (q, 2H, J = 7.2 Hz), 3.71 (m, 1H), 6.54 (d, 1H, J = 8.8 Hz), 6.98-7.07 (m, 2H), 7.25 (s, 1H), 7.85 (dd, 1H, J = 8.8, 2.0 Hz), 8.07 (s, 1H), 8.56 (d, 1H, J = 2.0 Hz). 化合物Ij-91 [化464]
'H-NMR (DMSO-d) δ : 0.93-1.07 (m, 2H), 1.11-1.22 (m, 2H), 1.21 (d, 6H, J = 6.8 6
Hz), 1.38 (m, 1H), 1.77-1.85 (m, 2H), 1.95-2.03 (m, 2H), 2.77-2.83 (m, 2H), 3.14 (m. 1H), 3.72 (m, 1H), 6.53 (d, 1H, J = 8.8 Hz), 6.97 (t, 1H, J = 6.0 Hz), 7.02 (d, 1 H, J = 7.6 Hz), 7.25 (s, 1H), 7.84 (dd, 1H, J = 8.8, 2,0 Hz), 8.06 (s, 1H), 8.56 (d, 1 H, J = 2.0 Hz). S ) -248- 1376367 化合物lj-92 [化465]
!H-NMR (DMSO-d ) 8 : 0.92-1.03 (m, 2H), 1.11-1.23 (m, 2H), 1.21 (d, 6H, j = 6.8 6
Hz), 1.37 (m, 1H), 1.75-1.83 (m, 2H), 1.91-1.99 (m, 2H), 2.36-2.42 (m, 2H), 3.12 (m, 1H), 3.70 (m, 1H), 6.49 (d, 1H, J = 9.2 Hz), 6.97 (t, 1H, J = 6.0 Hz), 7.47 (d, 1 H, J = 8.0 Hz), 7.62 (d, 1H, J = 8.0 Hz), 8.36 (s, 1H).
化合物Ij-93 [化466]
'H-NMR (DMSO-d ) 6 : 0.95-1.13 (m, 4H), 1.23 (d, 6H, J = 6.9 Hz), 1.31-1.44 (m, 6 1H), 1.78-1.82 (m, 2H), 2.03-2.06 (m, 2H), 2.76-2.82 (m, 2H), 3.10-3.19 (m, 1H), 3.20-3.25 (m, 4H), 3.58-3.65 (m, 1H), 3.69-3.74 (m, 4H), 6.04 (d, 1H, J = 7.5 Hz) ,6.72 (d, 1H, J = 9.6 Hz), 6.95-6.99 (m, 1H), 7.10 (d, 1H, J = 9.6 Hz).
化合物Ij-94 [化467]
lH-NMR (DMSO-d ) 8 : 0.96-1.42 (m, 5H), 1.22 (d, 6H, J = 6.9 Hz), 1.79-1.83 (m, 2H), 2.03-2.07 (m, 2H), 2.80 (d, 2H, J = 6.3 Hz), 3.10-3.19 (m, 1H), 3.54-3.70 (m ,1H), 3.74 (s, 3H), 6.57-6.64 (m, 3H), 6.72-6.75 (m, 1H), 6.90-7.09 (m, 3H). 7.24 -7.30 (m, 1H). 化合物Ij-95 [化 468] -249- 1376367
'H-NMR (DMSO-d ) δ : 0.93-1.04 (m, 2H), 1.10-1.18 (m, 2H), 1.21 (d, 6H, J = 6.6
Hz), 1.34-1.44 (m, 1H), 1.78-1.87 (m, 2H), 2.02-2.12 (m, 2H), 2.77-2.84 (m, 2H), 3.10-3.20 (m, 1H), 3.52-3.70 (mf 1H), 6.64 (d, 1H, J = 8.0 Hz), 6.88-7.06 (m, 5H) ,7.12 (d, 1H, J = 8.0 Hz), 7.37-7.46 (m, 1H). 化合物lj-96 [化469]
'H-NMR (DMSO-d) δ : 0.90-1.04 (m, 2H), 1.05-1.18 (m, 2H), 1.21 (d, 6H, J = 6.6 6
Hz), 1.33-1.43 (m, 1H), 1.75-1.84 (tn, 2H), 1.98-2.08 (m, 2H), 2.76-2.84 (m, 2H), 3.08-3.18 (m, 1H), 3.52-3.64 (m, 1H), 6.55 (d, 1H, J = 8.0 Hz), 6.91-7.00 (m, 2H) ,7.15-7.38 (m, 5H). 化合物IJ-97 [化 470]
'H-NMR (DMSO-d ) 6 : 0.96-1.08 (m, 2H), 1.12-1.25 (m, 2H), 1.19 (t, 3H, J = 7.2 6
Hz), 1.35-1.47 (m, 1H), 1.78-1.87 (m, 2H), 2.02-2.10 (m, 2H), 2.78-2.83 (m, 2H), 2.98 (q, 2H, J = 7.2 Hz), 3.70-3.82 (m, 1H), 6.82 (d, 1H, J = 8.0 Hz), 6.93 (d, 1H, J = 8.0 Hz), 7.01 (t, 1H, J = 4.5 Hz), 7.13 (d, 1H, J = 4.0 Hz), 7.43 (d, 1H, J = 4.0 Hz), 7.76 (d, 1H, J = 8.0 Hz). 化合物Ij-98 [化 471] -250- 1376367
'H-NMR (DMSO-d ) 5 : 0.97-1.10 (m, 2H), 1.17-1.28 (m, 2H), 1.19 (t, 3H, J = 7.2 6
Hz), 1.37-1.49 (m, 1H), 1.80-1.88 (m, 2H), 2.04-2.12 (in, 2H), 2.77-2.83 (m, 2H), 2.99 (q, 2H, J = 7.2 Hz), 3.76-3.88 (m, 1H), 6.85 (d, 1H, J = 8.0 Hz), 6.99-7.05 ( m, 2H), 7.61 (s, 1H), 7.90 (d, 1H, J = 8.0 Hz), 8.02 (s, 2H).
化合物Ij-99 [化472]
'H-NMR (DMSO-d ) 5 : 0.98-1.10 (m, 2H), 1.14-1.26 (m, 2H), 1.19 (t, 3H, J = 7.2 6
Hz), 1.37-1.48 (m, 1H), 1.80-1.88 (m, 2H), 2.04-2.13 (m, 2H), 2.77-2.83 (m, 2H), 2.96 (s, 6H), 2.99 (q, 2H, J = 7.2 Hz), 3.76-3.86 (m, 1H), 6.72-6.78 (m, 2H), 6.82 (d, 1H, J = 8.0 Hz), 7.02 (t, 1H, J = 4.5 Hz), 7.18 (d, 1H, J = 8.0 Hz), 7.26 (t, 1H, J =8.0 Hz), 7.34 (s, 1H), 7.74 (d, 1H, J = 8.0 Hz).
化合物I j-100 [化473]
^-NMR (DMSO-d ) δ : 0.98-1.10 (m, 2H), 1.16-1.27 (m, 2H), 1.19 (t, 3H, J = 7.2 6
Hz), 1.37-1.48 (m, 1H), 1.80-1.88 (m, 2H), 2.04-2.13 (m, 2H), 2.77-2.83 (m, 2H), 2.99 (q, 2H, J = 7.2 Hz), 3.76-3.86 (m, 1H), 6.83 (d, 1H, J = 8.0 Hz), 6.89 (d, 1H, J = 8.0 Hz), 7.02 (t„ 1H, J = 4.5 Hz), 7.42-7.50 (m, 3H), 7.53-7.59 (m, 2H). 化合物Ij-l〇l [化474] 1376367
'H-NMR (DMSO-d ) δ : 0.92-1.05 (m, 2H), 1.08-1.20 (m, 2H), 1.21 (d, 6H, J = 6.6 6
Hz), 1.36-1.43 (m, 1H), 1.76-1.84 (m, 2H), 2.02-2.09 (m, 2H), 2.77-2.83 (m, 2H), 3.10-3.20 (m, 1H), 3.56-3.68 (m, 1H), 6.62 (d, 1H, J = 8.0 Hz), 6.93 (d, 1H, J = 8. 0 Hz), 6.98 (t, 1H, J = 4.5 Hz), 7.10-7.15 (m, 3H). 7.43 (d, 2H, J = 8.0 Hz). 化合物Ihl〇2 [化475]
'H-NMR (DMSO-d ) δ : 0.92-1.05 (m, 2H), 1.08-1.20 (m, 2H), 1.21 (d, 6H, J = 6.6 6
Hz〉，1.36-1.43 (m, 1H), 1.76-1.84 (m, 2H), 2.02-2.09 (m, 2H), 2.77-2.83 (m, 2H), 3.10-3.20 (m, 1H), 3.57-3.68 (m, 1H), 6.65 (d, 1H, J = 8.0 Hz), 6.94 (d, 1H, J = 8. 0 Hz), 6.97 (t, 1H, J = 4.5 Hz), 7.06 (d, 1H, J = 8.0 Hz), 7.13 (d, 1H, J = 8.0 Hz), 7 .18-7.26 (m, 2H), 7.41 (t, 1H, J = 8.0 Hz). 化合物Ij-103 [化476]
'H-NMR (DMSO-d ) 6 : 0.88-1.04 (m, 2H), 1.05-1.20 (m, 2H), 1.21 (d, 6H, J = 6.6 6
Hz), 1.33-1.43 (m, 1H), 1.77-1.82 (m, 2H), 2.00-2.07 (m, 2H), 2.76-2.82 (m, 2H), 3.08-3.20 (m, 1H), 3.52-3.64 (m, 1H), 6.57 (d, 1H, J = 8.0 Hz), 6.92-7.00 (m, 2H) ,7.17 (d, 1H, J = 8.0 Hz), 7.23-7.28 (m, 2H), 7.38 (t, 1H, J = 8.0 Hz). 7.56 (d, 1H, J = 8.0 Hz). 化合物lj-104 、[化477] -252- 1376367 'H-NMR (DMSO-d ) δ : 0.96-1.08 (m, 2H), 1.12-1.24 (m, 2H), 1.19 (t, 3H, J = 7.6 6
Hz), 1.35-1.46 (m, 1H), 1.78-1.86 (m, 2H), 2.04-2.12 (m, 2H), 2.76-2.82 (m, 2H), 2.98 (q, 2H, J = 7.6 Hz), 3.67-3.78 (m, 1H), 6.27 (s, 2H), 6.71 (d, 1H, J = 8.0 Hz), 6.93 (d, 1H, J = 8.0 Hz), 7.02 (brs, 1H), 7.52 (s, 2H), 7.67 (d, 1H, J = 8.0 Hz). 化合物Ij-105 [化478]
'H-NMR (DMSO-d ) 3 : 0.96-1.08 {m, 2H), 1.13-1.25 (m, 2H), 1.19 (t, 3H, J = 7.6 6
Hz), 1.35-1.46 (m, 1H), 1.78-1.87 (m, 2H), 2.04-2.12 (m, 2H), 2,76-2.83 (m, 2H), 2.99 (q, 2H, J = 7.6 Hz), 3.72-3.82 (m, 1H), 6.82 (d, 1H, J = 8.0 Hz), 6.85 (d, 1H, J = 8.0 Hz), 7.03 (t, 1H, J = 4.5 Hz), 7.12 (t, 1H, J = 4.0 Hz), 7.51 (d, 1H, J = 4.0 Hz), 7.56 (d, 1H, J = 4.0 Hz), 7.76 (d, 1H, J = 8.0 Hz). 化合物lj-106 [化479]
'H-NMR (DMSO-d ) δ : 0.88-1.02 (m, 2H), 1.07-1.20 (m, 2H), 1.21 (d, 6H, J = 6.6 6
Hz), 1.33-1.45 (m, 1H), 1.76-1.85 (m, 2H), 2.02-2.08 (m, 2H), 2.76-2.83 (m, 2H), 3.10-3.20 (m, 1H), 3.57-3.67 (m, 1H), 6.63 (d, IH, J = 8.0 Hz), 6.92-7.00 (m, 3H) ,7.13 (d, 1H, J = 8.0 Hz), 7.29-7.36 (m, 1H), 7.42-7.50 (m, 1H). 化合物Ij-107 [化480]
-253 - 1376367
'H-NMR (DMSO-d ) δ : 0.88-1.02 (m, 2H), 1.07-1.20 (m, 2H), 1.21 (d, 6H, J = 6.6 6
Hz), 1.33-1.43 (m, 1H), 1.75-1.83 (m, 2H), 1.98-2.06 (τη, 2H), 2.76-2.83 (m, 2H), 3.08-3.18 (m, 1H), 3.52-3.63 (m, 1H), 6.57 (d, 1H. J = 8.0 Hz), 6.93 (d, 1H, J = 8. 0 Hz), 6.97 (t, 1H, J = 4.5 Hz), 7.12 (t, LH, J = 4.0 Hz), 7.19 (d, 1H, J = 8.0 Hz), 7 .33-7.47 (m, 2H).
化合物 [化 481]
'H-NMR (DMSO-d ) δ : 0.88-1.02 (m, 2H), 1.07-1,20 (m, 2H), 1.21 (d, 6H, J = 6.6 6
Hz), 1.33-1.43 (m, 1H), 1.75-1.83 (m, 2H), 1.98-2.07 (m, 2H), 2.76-2.83 (m, 2H), 3.08-3.18 (m, 1H), 3.54-3.63 (m, 1H), 6.63 (d, 1H, J = 8.0 Hz), 6.93-7.00 (m, 2H) ,7.14 (t, 1H, J = 8.0 Hz), 7.20-7.37 (m, 3H). 化合物丨j-109 [化482]
'H-NMR (DMSO-d ) 8 : 0.82-1.05 (m, 2H), 1.05-1.20 (m, 2H), 1.21 (d, 6H, J = 6.6 6
Hz), 1.32-1.43 (m, 1H), 1.76-1.83 (m, 2H), 2.00-2.08 (m, 2H), 2.29 (s, 3H), 2.76-2.83 (m, 2H), 3.08-3.18 (m, 1H), 3.56-3.66 (m, 1H), 6.55 (d, 1H, J = 8.0 Hz), 6.90 (d, 1H, J = 8.0 Hz), 6.93-7.00 (m, 3H), 7.05 (d, 1H, J = 8.0 Hz), 7.17 (d, 2H, J = 8. 0 Hz). 化合物[j-110 [化483] -254- 1376367
'H-NMR (DMSO-d) δ : 0.91-1.19 (m, 4H), 1.28 (s, 9H), 1.32-1.43 (m, 1H), 1.80 ( 6 d, 2H, J = 12.0 Hz), 2.07 (d, 2H, J = 12.0 Hz), 2.88 (t, 2H, J = 6.4 Hz), 3.16-3.27 ( m. 1H), 5.47 (d, 1H, J = 7.6 Hz), 5.80 (s, 1H), 6.S3 (d, 1H, J = 6.0 Hz), 7.15-7.40 ( m, 3H)f 7.75 (t, 1H, J = 8.4 Hz), 7.86 (s, 1H). 化合物丨j-111 [化 484]
!H-NMR (DMSO-d ) δ : 0.91-1.19 (m, 4H), 1.21 (d, 6H. J = 6.9 Hz), 1.32-1.43 (m, 1H), 1.76-1.82 (m, 2H), 2.02-2.12 (m, 2H), 2.77-2.83 (m, 2H), 3.08-3.27 (m, 2H), 5.48 (d, 1H, J = 8.1 Hz), 5.80 (d, 1H, J = 2.7 Hz), 6.95 (t, 1H, J = 6.0 Hz), 7.15-7. 39 (m, 3H), 7.75 (td, 1H, J = 8.4, 1.8 Hz), 7.86 (t, 1H, J = 2.7 Hz). 化合物Ij-112 [化 485]
'H-NMR (DMSO-d) δ : 0.91-1.19 (m, 4H), 1.18 (t, 3H, J = 7.2 Hz), 1.30-1.45 (m, 6 1H>, 1.76-1.82 (m, 2H), 2.02-2.12 (m, 2H), 2.77-2.83 (m, 2H), 2.98 (q, 2H, J = 7. 2 Hz) 3.10-3.30 (in, 1H), 5.48 (d, 1H, J = 7.8 Hz), 5.80 (d, 1H, J = 2.7 H2), 6.99 (t, 1H, J = 6.0 Hz), 7.15-7.40 (m, 3H), 7.75 (td, 1H, J = 8.4, 1.8 Hz), 7.86 (t, 1H, J = 2.7 Hz). 化合物Ij~113 [化486] -255 - 1376367
化合物Ij-114 [化487]
化合物lj-115 [化488]
'H-NMR (DMSO-d ) δ : 0.92-1.19 (m, 4Η), 1.19 (t, 3H, J = 7.2 Hz), 1.30-1.45 (m, 6 1H), 1.76-1.84 (m, 2H), 2.02-2.12 (m, 2H), 2.74-2.82 (m, 2H), 2.98 (q, 2H, J = 7. 2 Hz) 3.15-3.30 (m, 1H), 5.53 (d, 1H, J = 8.1 Hz), 5.80 (d, 1H, J = 2.4 Hz), 6.92 (t, 1H, J = 8.4 Hz), 7.01 (t, 1H, J = 6.0 Hz), 7.37-7.43 (m, 3H), 8.21 (d, 1H, J = 2.4 Hz). 化合物Ij-116 [化489]
化合物Ij-117 [化 490]
化合物Ij-118 [化 491] -256- 1376367
'H-NMR (DMSO-d ) δ : 0.92-1.19 (m, 4H), 1.19 (t, 3H, J = 7.5 Hz), 1.30-1.45 (ra, 6 1H), 1.75-1.86 (m, 2H), 2.02-2.12 (m, 2H), 2.74-2.83 (m, 2H), 2.97 (q, 2H, J = 7.5 Hz) 3.13-3.30 (m, 1H), 5.38 (d, 1H, J = 8.4 Hz), 5.75 (d, 1H, J = 2.7 Hz), 6.99 (t, 1H, J = 6.3 Hz), 7.18-7.28 (m, 2H), 7.63-7.70 (m. 2H), 8.11 (d, 1H, J = 2.7 Hz). 化合物Ij-119
[化492]
lH-NMR (DMSO-d ) δ : 0.88-1.19 (m, 4H), 1.18 (t, 3H, J = 7.5 Hz), 1.28-1.45 (m, 6 1H), 1.73-1.83 (m, 2H), 2.02-2.13 (m, 2H), 2.73-2.81 (m, 2H), 2.95 (q, 2H, J = 7. 5 Hz) 3.12-3.30 (m, 1H), 5.36 (d, 1H, J = 7.5 Hz), 5.76 (d, 1H, J = 2.4 Hz), 6.98 (t, 1H, J = 6.0 Hz), 7.30 (td, 1H, J = 7.5, 1.8 Hz), 7.42 (td, 1H, J = 7.8, 1.5 Hz), 7.53 -7.60 (m, 2H), 7.84 (d, 1H, J = 2.7 Hz). 化合物Ij-120 [化493]
'H-NMR (DMSO-d) 6 : 0.92-1.19 (m, 4H), 1.19 (t, 3H, J = 7.5 Hz), 1.30-1.45 (m, 6 1H), 1.74-1.84 (m, 2H), 2.02-2.10 (m, 2H), 2.75-2.82 (m, 2H), 2.97 (q, 2H, J = 7. 5 Hz) 3.20-3.30 (m, 1H), 5.52 (d, 1H, J = 7.8 Hz), 5.80 (d, 1H, J = 2.4 Hz), 6.99 (t, 1H, J = 6.0 Hz), 7.13 (d, 1H, J = 8.1 Hz), 7.40 (t, 1H, J = 8.1 Hz), 7.62 (d, 1H, J = 8.4 Hz), 7.72 (s, 1H), 8.22 (d, 1H, J = 2.4 Hz). 化合物Ij-121 [化494] -257- 1376367
'H-NMR (DMSO-d ) 8 : 0.92-1.19 (m, 4H), 1.19 (t, 3H, J = 7.5 Hz), 1.30-1.45 (m, 6 1H), 1.74-1.84 (m, 2H), 2.02-2.12 (m, 2H), 2.75-2.82 (m, 2H), 2.98 (q, 2H, J = 7. 5 Hz) 3.15-3.30 (m, 1H), 5.47 (d, 1H, J = 8.1 Hz), 5.78 (d, 1H, J = 2.4 Hz), 7.00 (t, 1H, J = 6.0 Hz), 7.43 (d, 2H, J = 7.8 Hz), 7.67 (d, 2H, J = 9.0 Hz), 8.17 (d, 1H, J = 2.4 Hz). 化合物Ij-122 [化495]
'H-NMR (DMS〇-d ) δ : 0.94-1.07 (m, 4H), 1,19 (t, 3H, j = 7.2 Hz), 1.32-1.50 (m, 6 1H), 1.81-1.84 (m, 2H), 1.99-2.07 (m, 2H), 2.77-2.81 (m, 2H), 2.98 (q, 2H, J = 7. 2 Hz), 3.60-3.77 (m, 1H), 7.01-7.05 (m, 1H), 7.22-7.40 (m, 4H), 7.81-7.87 (m, 1H) ,8.02 (s, 1H), 8.36 (s, 1H). 化合物Ij-123 [化496]
'H-NMR (DMSO-d ) δ : 0.95-1.12 (m, 4H), 1.18 (t, 3H, J = 7.2 Hz), 1.32-1.50 (m, 6 1H), 1.77-1.81 (m, 2H), 1.96-1.99 (m, 2H), 2.74-2.78 (m, 2H), 2.97 (q, 2H, J = 7. 2 Hz), 3.54-3.70 (m, 1H), 4.81 (q, 2H, J = 9.0 Hz), 6.50-6.53 (m, 1H), 6.99-7.03 ( m, 1H), 7.50 (d, 1H, J =0.9 Hz) 7.83 (cl, 1H, J = 0.9 Hz). 化合物lj-124 [化497] { c - -258 - 1376367 0 0
H-NMR (DMSO-d ) δ : 0.95-1.23 (m, 4H)，1.19 (t, 3H，J = 7.2 Hz), 1.32-1.50 (m, 1H), 1.77-1.81 (m, 2H), 2.03-2.07 (m, 2H), 2.74-2.80 (m, 2H), 2.97 (q, 2H, J = 7. 2 Hz), 3.61-3.73 (m, 1H), 7.00-7.04 (m, 1H), 7.09-7.12 (m, 1H), 7.29-7.37 (m, 2H) ,7.45-7.52 (m, 1H), 7.88-7.94 (m, 2H), 8.04-8.05 (m, 1H). 化合物lj-125 [化498]
'H-NMR (DMSO-d ) δ : 0.94-1.14 (m, 4H), 1.19 (t, 3H, J = 7.2 Hz), 1.32-1.50 (m,
B 1H), 1.79-1.83 (m, 2H), 1.97-2.03 (m, 2H), 2.76-2.81 (m, 2H), 2.98 (q, 2H, J = 7. 2 Hz), 3.50-3.63 (m, 1H), 4.43 (q, 2H, J = 9.0 Hz), 7.00-7.04 (m, 1H), 7.13-7.15 ( m, 1H), 7.35 (s, 1H) 7.55 (s, 1H). 化合物【j-126 [化499]
'H-NMR (DMSO-d ) δ : 1.02-1.08 (tn, 2H). 1.17-1.29 (m, 2H), 1.19 (t, 3H, J = 7.5 6
Hz), 1.36-1.43 (m, 1H), 1.79-1.85 (m, 2H), 2.05-2.11 (m, 2H), 2.79 (t, 2H, J = 6.0 Hz), 2.99 (q, 2H, J = 7.5 Hz), 3.53-3.62 (m, 1H), 6.98 (t, 1H, J = 7.8 Hz), 7.03 (t, 1H, J = 6.3 Hz), 7.28 (dd, 1H, J = 7.5, 1.2 Hz), 7.63 (dd, 1H, J = 7.5, 1.2 Hz), 8.28 (d, 1H, J = 7.5 Hz). 化合物Ij-127 [化500] -259- 1376367
‘H-NMR (DMSO-d) δ : 0.97-1.05 (m, 2H), 1.18-1.24 (m, 2H)，1.16 (t, 3H, J = 7_5 $
Hz), 1.34-1.41 (m, 1H), 1.77-1.81 (m, 2H), 2.02-2.08 (m, 2H), 2.76 (t, 2H, J = 6.0 Hz), 2.96 (q, 2H, J = 7.5 Hz), 3.55-3.64 (m, 1H), 7.00 (t, 1H, J = 7.8 Hz), 7.18 (dd ,1H, J = 8.4, 1.8 Hz), 7.32 (dd, 1H, J = 8.4, 0.6 Hz), 7.74 (d, 1H, J = 1.8 Hz), 8.04 (d, 1H, J = 7.8 Hz). 化合物【j-128
[化 501]
*H-NMR (DMSO-d ) δ : 0.98-1.07 (m, 2H), 1.15-1.26 (m, 8H), 1.32-1.43 (m, 1H), a 1.78-1.84 (m, 2H), 1.98-2.09 (m, 2H), 2.60 (q, 2H, J = 7.5 Hz), 2.78 (t, 2H, J = 6.3 Hz), 2.96 (q, 2H, J = 7.5 Hz), 3.55-3.64 (m, 1H), 6.98-7.05 (m, 2H), 7.27 (dd, 1H, J = 7.8, 1.8 Hz), 7.47 (m, 1H), 7.84 (d, 1H, J =7.5 Hz). 化合物Ij-129 [化502]
'H-NMR (DMSO-d) δ : 0.92-1.15 (m, 2H), 1.15-1.35 (m, 2H), 1.19 (t, 3H, J = 7.2 Hz), 1.33-1.48 (m, 1H), 1.78-1.88 (m, 2H), 2.04-2.16 (m, 2H), 2.78-2.84 (m, 2H), 2.97 (q, 2H, J = 7.2 Hz), 3.62-3.80 (m, 1H), 7.02 (t, 1H, J = 6.0 Hz), 7.45 (d, 1H, J = 9.0 Hz), 8.09 (dd, 1H, J = 9.0, 2.4 Hz), 8.68 (d, 1H, J = 2.4 Hz), 8.70 (brs, 1H). 化合物Ij-130 [化503] -260- ' * 1376367 'h-NMR (DMSO-d ) 6 : 0.88-1.10 (m, 2H), 1.15-1.46 (m, 3H), 1.21 (d. 6H, J = 6.6 6
Hz), 1.78-1.88 (m, 2H), 1.98-2.08 (m, 2H), 2.76-2.86 (m, 2H), 3.10-3.20 (m, 1H), 3.46-3.62 (m, 1H), 6.91-6.96 (m, 1H), 7.01 (brs, 1H), 7.64 (d, 1H, J = 7.8 Hz), 8.0 7 (d, 1H, J = 5.1 Hz), 8.35 (d, 1H, J = 7.8 Hz). 化合物丨j-131 [化504]
'H-NMR (DMSO-d ) 5 : 0.92-1.05 (m. 2H), 1.15-1.30 (m, 2H), 1.27 Cs, 9H), 1.30-6 1.43 (m, 1H), 1.77-1.86 (m, 2H), 1.98-2.08 (m, 2H), 2.86-2.92 (m, 2H), 3.35-3.50 (m, 1H)( 3.73 (s, 3H), 6.69 (dd, IH, J = 8.4, 2.0 Hz), 6.86 (t, 1H, J = 6.0 Hz), 7.01 (d, 1H, J = 2.0 Hz), 7.10 (d, 1H, J = 8.4 Hz), 7.62 (d, 1H, J = 7.6 Hz). 化合物Ij-132 [化505]
'H-NMR (DMSO-d ) 8 : 0.92-1.08 (m, 2H), 1.15-1.33 (m, 2H), 1.19 (t, 3H( J = 7.2 6
Hz), 1.33-1.42 (m, 1H), 1.76-1.86 (m, 2H), 1.98-2.08 (m, 2H), 2.76-2.82 (m, 2H), 2.97 (q, 2H, J = 7.2 Hz), 3.40-3.58 (rn, 1H), 7.01 (t, 1H, J = 6.0 Hz), 7.13 (d, 1H, J =8.4 Hz), 7.20 (d, 1H, J = 8.4 Hz), 7.49 (s. 1H), 8.01 (d, 1H, J = 7.6 Hz). 化合物lj-133 [化506] -261 - 1376367 'h-NMR (DMSO-d ) δ : 0.96-1.10 (m, 2H), 1.16-1.28 (m, 2H), 1.19 (t, 3H, J = 7.2 6
Hz), 1.33-1.46 (m, 1H), 1.78-1.85 (m, 2H), 2.04-2.12 (m, 2H), 2.76-2.82 (m, 2H), 2.98 (q, 2H, J = 7.2 Hz), 3.55-3.70 (m, 1H), 7.01 (t, 1H, J = 6.0 Hz), 7.12 (t, 1H, J = 9.6 Hz), 7.48 (d, 1H, J = 7.6 Hz), 8.13 (d, 1H, J = 7.6 Hz). 化合物Ij-134 [化507]
'H-NMR (DMSO-d ) δ : 0.98-1.08 (m, 2H), 1.15-1.26 (m, 2H), 1.21 (d, 6H, J = 6.9 6
Hz), 1.33-1.42 (m, 1H), 1.39-1.84 (m, 2H). 2.05-2.09 (m, 2H), 2.81 (t, 2H, J = 6.3 Hz), 3.10-3.20 (m, 1H), 3.61-3.75 (m, 1H), 6.98 (t, 1H, J = 6.0 Hz), 7.45 (dd, 1H, J = 7.5, 0.6 Hz), 7.60 (dd, 1H, J = 8.4, 1.5 Hz), 8.17 (d, 1H, J = 1.5 Hz), 8.50 (d, 1 H, J = 7.5 Hz). 化合物U-i35 [化508]
'H-NMR (DMSO-d ) δ : 0.98-1.08 (m, 2H), 1.15-1.25 (m, 2H), 1.21 (d, 6H, J = 6.6 6
Hz), 1.35-1.44 (m, 1H), 1.80-1.84 (m, 2H), 2.05-2.08 (m, 2H), 2.81 (t, 2H, J = 6.3 Hz), 3.10-3.19 (m, 1H), 3.62-3.78 (m, 1H), 6.98 (t, 1H, J = 6.0 Hz), 7.79 (d, 1H, J =2.1 Hz), 8.10 (d, 1H, J = 2.1, 1.5 Hz), 8.52 (d, 1H, J = 6.9 Hz). 化合物Ij-136 [化509] -262- 1376367
'H-NMR (DMSO-d ) a : 0.97-1.08 (m, 2H), 1.17-1.24 (m, 2H), 1.19 (t, 3H, J = 7.5 6
Hz), 1.33-1.41 (m, 1H), 1.78-1.83 (m, 2H), 2.04-2.08 (m, 2H), 2.78 (t, 2H, J = 6.3 Hz), 2.98 (q, 2H, J = 7.2 Hz), 3.56-3.67 (m, 1H), 7.00-7.04 (m, 2H), 7.39 (d, 1H, J = 2.1 Hz), 7.66 (dd, 1H, J = 8.4, 1.8 Hz), 8.14 (d, 1H, J = 7.5 Hz). 化合物丨hi 37 [化 510]
^-NMR (DMS〇-d6) δ : 0.96-1.10 (m, 2H), 1.12-1.28 (m. 2H), 1.21 (d, 6H, J = 6.9 Hz), 1.31 (t, 3H, J = 6.9 Hz), 1.33-1.46 (m, 1H), 1.76-1.85 Cm, 2H), 2.02-2.16 (m, 2H), 2.78-2.84 (m, 2H), 3.10-3.22 (m, 1H), 3.50-3.64 (m, 1H), 3.98 (q, 2H, J = 6. 9 Hz), 6.78 (dd, 1H, J = 8.7, 2.7 Hz), 6.98 (t, 1H, J = 6.0 Hz), 7.23-7.27 (m, 2H), 7 .68 (d, 1H,J = 7.2 Hz). 化合物【j-138 [化 511]
'H-NMR (DMSO-d ) 6 : 0.94-1.08 (m, 2H), 1.14-1.26 (m, 2H), 1.19 (t, 3H, J = 7.2 6
Hz), 1.33-1.45 (m, 1H), 1.77-1.86 (m, 2H), 2.03-2.12 (m, 2H), 2.76-2.82 (m, 2H), 2.98 (q, 2H, J = 7.2 Hz), 3.52-3.68 (m, 1H), 6.97-7.06 (m, 2H), 7.34 (dd, 1H, J = 8.4, 4.8 Hz), 7.56 (dd, 1H, J = 8.4, 2.4 Hz), 7.91 (d, 1H, J = 7.6 Hz). 化合物lj-139 [化 512] -263- 1376367
!H-NMR (DMSO-d ) δ : 0.96-1.12 (m, 2H), 1.16-1.32 (m, 2H), 1.21 (d, 6H, J = 6.6 6
Hz), 1.32-1.46 (m, 1H), 1.78-1.86 (m, 2H), 2.02-2.16 (m, 2H), 2.78-2.84 (m, 2H), 3.10-3.21 (m, 1H), 3.58-3.76 (m, 1H). 7.00 (t, 1H, J = 6.0 Hz), 8.19-8.23 (m, 2H), 8.52 (d, 1H, J = 6.9 Hz). 化合物Ij-140 [化 513]
'H-NMR (DMSO-d) δ : 0.96-1.12 (m, 2H), 1.12-1.30 (m, 2H), 1.21 (d, 6H, J = 6.6
Hz), 1,32-1.46 (m, 1H), 1.78-1.86 (m, 2H), 2.02-2.16 (m, 2H), 2.78-2.84 (m, 2H), 3.10-3.20 (m, 1H), 3.58-3.78 (m, 1H), 7.01 (t, 1H, J = 6.0 Hz), 8.08 (dd, 1H, J = 8 .4, 2.7 Hz), 8.19 (d, 1H, J = 2.7 Hz), 8.38 (d, 1H, J = 7.2 Hz). 化合物Ij-141 [化 514]
*H-NMR (DMSO-d) 5 : 0.97-1.08 (m, 2H), 1.15-1.22 (m, 5H), 1.34-1.42 (m, 1H), 1.78-1.83 (m, 2H), 2.04-2.08 (m, 2H), 2.78 (t, 2H, J = 6.0 Hz), 2.98 (q, 2H, J = 7.2 Hz), 3.53-3.62 (m, 1H), 3.81 (s, 1H), 7.02 (t, 1H, J = 6.3 Hz), 7.41 (s, 1H), 7.53 (s ,1H), 7.88 (d, 1H,J = 7.5 Hz). 化合物丨j-142 [化 515] -264- 1376367
'H-NMR (DMSO-d ) δ : 0.94-1.06 (m, 2H), 1.17-1.30 (m, 2H), 1.18 (t, 3H, J = 7.5 6
Hz), 1.32-1.41 (m, 1H), 1.79-1.84 (m, 2H), 2.01-2.05 (m, 2H), 2.77 (t, 2H, J = 6.0 Hz), 2.98 (q, 2H, J = 7.2 Hz),.3.41-3.58 (m, 1H), 6.97 (dd, 1H, J = 8.4, 2.4 Hz), 6. 99-7.03 (m, 1H), 7.27 (d, 1H. J = 2.4 Hz), 7.34 (dd, 1H, J = 8.4, 0.3 Hz), 8.07-8.14 (m, 1H).
化合物Ij-143 [化 516]
'H-NMR (DMSO-d ) 5 : 0.94-1.08 (m, 2H), 1.16-1.33 (m, 2H), 1.19 (t, 3H, J = 7.2 6
Hz), 1.33-1.45 (m, 1H), 1.77-1.86 (m, 2H), 2.00-2.08 (m, 2H), 2.74-2.82 (m, 2H), 2_98 (q, 2H, J = 7.2 Hz), 3.38-3.54 (m, 1H), 6.90-7.00 (m, 1H), 7.02 (t, 1H, J = 4. 5 Hz), 7.19 (dd, 1H, J = 8.4, 5.1 Hz), 7.33 (dd, 1H, J. = 8.4, 2.7 Hz), 7.88 (d, 1H, J =7.8 Hz).
化合物I卜144 [化 517]
JH-NMR (DMSO-d ) δ : 0.94-1.06 (m, 2H), 1.19-1.29 (m, 2H), 1.18 (t, 3H, J = 7.2
G
Hz), 1.31-1.41 (m, 1H), 1.79-1.84 (m, 2H), 2.01-2.05 (m, 2H), 2.77 (t, 2H, J = 6.0 Hz), 2.98 (q, 2H, J = 6.9 Hz), 3.41-3.57 (m, 1H), 6.71-6.79 (m, 1H), 7.06-7.08 (m ,2H), 7.31 (dd, 1H, J = 8.7, 4.8 Hz), 8.03 (d, 1H, J = 7.8 Hz). 化合物Ij-145 [化 518] -265 - 1376367
'H-NMR (DMSO-d ) δ : 0.95-1.16 (m, 2H), 1.18-1.44 (m, 3H), 1.21 (d, 6H, J = 6.6 6
Hz), 1.78-1.86 (m, 2H), 2.02-2.12 (m, 2H). 2.78-2.84 (m, 2H), 3.10-3.20 (m, 1H), 3.40-3.58 (m, 1H), 6.95 (t, 1H, J = 7.8 Hz), 7.01 (brs, 1H), 7.09 (t, 1H, J = 6.9 Hz X 7.22 (d, 1H, J = 6.6 Hz), 7.31 (d, 1H, J = 7.8 Hz), 7.83 (d, 1H, J = 7.8 Hz). 化合物Ij-146 [化 519]
化合物Ij-147 [化520]
化合物Ij-148 [化 521]
試驗例1腦移行性和仲介P-gp之藥物間相互作用 就腦移行性（腦/血漿分配係數；Kp)，由小白鼠（Jcl ; C57BL/6J小白鼠，$，7週齡）靜脈內投與（0.5 mg/2 mL/kg)後之血续及腦內濃度來評價。結果，化合物（I-?〗) 之腦 Kp値（Kp C()nt.)爲1.29，呈高腦移行性。 -266- 1376367 GF/C濾過。以50 mM Tris-HCl緩衝液，pH 7.4洗淨後， 以γ計數器求出玻璃濾器上之放射活性。非專一性結合乃 於20 0 ηΜ胜肽ΥΥ之存在下測定，求出對專一性胜肽ΥΥ 結合之被檢化合物之50%抑制濃度（IC5〇値）[參照Inui，a. et al. Endocrinology 131，2090-2096 (1992)] 〇 結果如下表 本發明之化合物抑制對NPY Y5受體之胜肽ΥΥ(與NPY 同屬物質）之結合。也即本化合物對NPY Y5受體呈親和性 .【表1】 化合物編號 結合 IC5〇(nM) Ii-1 0.10 Ii-16 2.5 Ii-34 11 Ii-44 3.4 Ij-1 0.70 Ij-52 0.27 Ij-59 2.5 Ij-66 0.39
試驗例3 CHO細胞中cAMP生成抑制作用 表現人NPY Y5受體之CHO細胞於2.5mM異丁基甲基黄 嘌呤（SIGMA公司）之存在下於37°C培養20分後，添加本 發明化合物而培養5分，其後加50 nMNPY及10 μΜ富科 素（forskolin，Sigma公司）而培養30分.。添加IN HC1而
-268 - 1376367 停止反應後，上清中之 cAMP量用 EIA套組（Amersham LIFE SIENCE公司製）來測定。以對由富科素（forskolin)刺 激之cAMP生成之NPY抑制作用爲10 0%，求出對此NPY 作用之本發明化合物之50%抑制濃度（IC5〇値）。 試驗例4
使用 Y1表現細胞（人神經母細胞瘤，SK-N-MC)膜標品及 Y2表現細胞（人神經母細胞瘤，SMS-ΚΑΝ)膜標品，以與試 驗例2同樣之方法試驗，測定本發明之化合物對NPY Y1 受體及NPY Y2受體之親和性。由其結果確認本發明之化 合物具有NPY Y5受體選擇性。 試驗例5
乙醚麻醉下，由雄性C57BL/6J小白鼠（12-14週齡，25-3 〇g)之外後頭稜至鼻背部沿正中切開皮膚，而露出頭蓋骨 上部。由露出部前頂（bregma)向λ約1 mm後方，由正中 線於左側約1mm之位置用電鑽打開直徑約1mm之穴。於 麻醉覺醒後之小白鼠強制經口投與懸浮於0.5%羥丙基甲基 纖維（信越化學公司製）水溶液或其水溶液之被檢物質，投 與1小時後，由預先開設之頭部開口部用導管注入NPY Y5 受體專一性激動劑（[cPph'NPYU’Ala'Aib32, Gln34]-hPancreatic Polypeptide:Tocris 公司製）0.1nmol。注 入2小時後及4小時後測定小白鼠之攝食量，調査0.5 %羥 甲基纖維溶液投與群與被檢物質投與群之間之攝餌量之差 。結果，本發明化合物以6mg/kg之用量投與之場合，與 投與0.5 %羥丙基甲基纖維之場合比較，攝食量顯著地抑制
-269- 1376367 製劑例 如下示製劑例僅爲例示，無任何限定發明之範圍之意圖 製劑例1錠劑 化合物（1-1) 1 5mg 澱粉 1 5mg 乳糖 1 5mg 結晶性纖維 1 9mg 聚乙烯基醇 3mg 蒸飽水 30ml 硬脂酸鈣 3 mg
硬脂酸鈣以外之成分均勻混合，破碎造粒而乾燥，作成 適當大小之顆粒劑。次添加硬脂酸鈣而壓縮成形爲錠劑。 製劑例2膠囊劑 化合物（1-2) 1 0 m g 硬脂酸鎂 1 Omg 乳糖 8 0 m g
均勻混合爲粉末或細粒狀而作成散劑》令其充塡於膠囊 容器而作成膠囊劑。 製劑例3顆粒劑 化合物（1-3) 30g 乳糖 265 g 硬脂酸鎂 5g -270- f ti 、-ta» 1376367 充分混合而壓縮成型後，粉碎、整粒、篩別爲適當大小 之顆粒劑。 【産業上之利用可能性】 由以上之試驗例得知，本發明之化合物呈ΝΡΥ Y5受體 拮抗作用。故本發明之化合物作爲抗肥胖藥及攝食抑制劑 非常有用。 【圖式簡單說明】 無0
C -271

Claims (1)

1376367 I修 修正本 第0961 14901號1具有NPY Y5受體拮抗作用之胺衍生物」 專利案 (2012年7月26曰修正） 十、申請專利範圍： 1.一種如下式⑴化合物、其製藥容許鹽或這些之.溶劑合物， Ri—Y—N—X—N—Z (I) I / R2 R7
[式中R1爲C1-C10烷基， Y 爲-S(0)n-(n 爲 1 或 2)， R2爲氫， R7爲氫， X爲 -(CR3R4)p—(^)—(CR5R6)q- (式中R3、R4、R5及R6各自獨立爲氫，
爲C3-C6伸環烷基，ρ及q各自獨立爲0〜2之整數，且ρ 及q不同時爲〇， 但 -0- 不爲
[式中R 14爲可有取代基之苯基])， -nr2-x-可爲 1376367 修正本
爲哌啶二基、哌哜二基、吡啶二基、吡啡二基、吡咯啶二 基或吡咯二基，u爲C1-C10伸烷基或C2-C10伸烯基）， Z爲可有取代基之烴環式基或可有取代基之雜環式基（其中 取代基爲選自側氧基、硝基、氰基、鹵素、Cl-CIO烷基、 鹵C1-C10烷基、C1-C10烷氧基C1-C10烷基、C1-C10烷 基雜環cn-cio烷基、芳基、鹵芳基、C1-C10烷基芳基、 鹵C1-C10烷基芳基、C1-C10烷氧基芳基、鹵C1-C10烷 氧基芳基、Cl-C10烷基胺基芳基、雜環基、鹵雜環基、 C1-C10烷基雜環基、經側氧基取代之雜環基、C1-C10烷 氧基、鹵C1-C10烷氧基、芳氧基、鹵芳氧基、C1-C10烷 基芳氧基、C1-C10烷氧基芳氧基、C3-C6環烷氧基、C1-C10烷基胺基、芳基C1-C10烷基胺基、C1-C10烷氧基 C1-C10烷基胺基、C3-C6環烷基胺基 '芳基C1-C10烷基 胺基、雜環羰基、Cl-C10烷基胺甲醯基、及鹵芳基磺醯基 組成之群組中之1個以上的取代基）， (但Z不爲3環之稠合雜環式基、可有取代基之噻唑基或可 有取代基之喹唑啉基）] (但X爲 - (CR3R4)p—(^)—(CR5RS)q-其中 -2- 1376367 修正本
爲可有取代基之C3-C6伸環烷基，p爲0，q爲1，且Z爲 可有取代基之嘧啶基之化合物除外）。 2. 如申請專利範圍第1項之化合物、其製藥容許鹽或這些之 溶劑合物，其中Y爲-S(0)2-。 3. 如申請專利範圍第1項之化合物、其製藥容許鹽或這些之 溶劑合物，其中X爲 —(CR3R4)p—(CR5R6)q-
，R1爲碳數2〜10之烷基。 4·如申請專利範圍第3項之化合物、其製藥容許鹽或這些之 I 溶劑合物，其中z爲可有取代基之雜環式基（其中取代基與 申請專利範圍第1項相同）。 5.如申請專利範圍第3項之化合物、其製藥容許鹽或這些之 溶劑合物，其中 -Θ-
爲伸環己基， P及q各自獨立爲0或1，p及q不同時爲0。 6.如申請專利範圍第5項之化合物、其製藥容許鹽或這些之 溶劑合物，其中Z爲可有取代基之苯基、可有取代基之吡 啶基、可有取代基之吡唑基、可有取代基之異噚唑基、可 有取代基之嘮二唑基、可有取代基之嗒啩基、可有取代基 之吡畊基 '可有取代基之嘧啶基或可有取代基之2環之稠 合雜環（其中取代基與申請專利範圍第丨項相同）。 1376367 修正本 7-$D申請專利範圍第1項之化合物、其製藥容許鹽或這些之 溶劑合物，其中X爲 〜(CR3R4)p~~(^)-(CR5R6)q— ’ P + q 爲 1 或 2。 8.如申請專利範圍第7項之化合物、其製藥容許·鹽或這些之 溶劑合物’其中p + q爲1。 9·〜種如下式（I)化合物 '其製藥容許鹽或這些之溶劑合物， R1—Y—N-X—N—Z (I) R2 R7 [式中R1爲Cl -C1 0烷基， Y 爲-s(o)2-， R2爲氫， R7爲氫， X爲 -(CR3R4)p—(^}—(CR5R6)q-(式中R5及R6各自獨立爲氫，其中 爲C3-C6伸環烷基，ρ爲0，q爲1或2)， Z爲可有取代基之烴環式基或可有取代基之雜環式基（其中 取代基與申請專利範圍第1項相同）] (但Z爲3環之稠合雜環式基、可有取代基之嘧啶基或可有 取代基之噻唑基之化合物-除外）。 10.如申請專利範圍第9項之化合物、其製藥容許鹽或這些之 溶劑合物，其中Z爲可有取代基之苯基、可有取代基之氫 1376367 修正本 茚基、可有取代基之吡啶基、可有取代基之嗒哜基、可有 取代基之吡唑基、可有取代基之異0f唑基、可有取代基之 噚二唑基或可有取代基之2環之稠合雜環（其中取代基與申 請專利範圍第1項相同）。
11.如申請專利範圍第9項之化合物、其製藥容許鹽或這些之 溶劑合物，其中Z爲可有取代基之異喹啉基、可有取代基 之苯并噻唑基、可有取代基之苯并噚唑基、可有取代基之 苯并吡啶基、可有取代基之苯并嗒哜基、可有取代基之苯 并咪唑基、可有取代基之噻唑并吡啶基、可有取代基之苯 并異嘮唑啉基、可有取代基之苯并噚唑啉基、可有取代基 之苯并噚哜基或可有取代基之苯醯氧基吖庚因基（其中取代 基與申請專利範圍第1項相同）。 12.—種如下式（I)化合物、其製藥容許鹽或這些之溶劑合物 R1 —Y——N-X-N—Z (I) I / R2 R7 [式中R1爲C1-C10烷基， Y 爲-s(o)2-， R2爲氫， R7爲氫， X爲 —(CR3R4)p
(CR5R6)q- (式中R3及R4各自獨立爲氫，其中 -Θ-爲C3-C6伸環烷基，p爲1或2，q爲〇， 1376367 修正本 但 —Qr 不爲
[式中R14爲可有取代基之苯基])， Z爲可有取代基之烴環式基或可有取代基之雜環式基] (但Z爲3環之稠合雜環式基、可有取代基之噻唑基或可有 取代基之喹唑啉基之化合物除外）》 13.如申請專利範圍第12項之化合物、其製藥容許鹽或這些之 溶劑合物，其中Z爲可有取代基之苯基、可有取代基之吡 啶基、可有取代基之嗒哜基、可有取代基之吡哜基、可有 取代基之嘧啶基、可有取代基之喹啉基、可有取代基之異 喹啉基、可有取代基之苯并噻唑基、可有取代基之苯并咪 唑基、可有取代基之苯并噚唑基、可有取代基之噻唑并吡 啶基、可有取代基之嘮唑并吡啶基或可有取代基之吡唑基（ 其中取代基與申請專利範圍第1項相同）。 14·~種如下式⑴化合物、其製藥容許鹽或這些之溶劑合物， R1—Υ——Ν-Χ—Ν—Ζ (I) I / R2 R7 [式中R1爲Cl -C1 0烷基， Υ 爲-s(o)2-， 1376367 修正本 - (CR3R4)p-(^}—(CR5R6)q- (式中R3及R4各自獨立爲氫，其中
爲C 3 - C 6伸環烷基.，.p爲1 ·或2，q爲0-)， Z爲可有取代基之苯基、可有取代基之吡啶基、可有取代 基之嗒畊基、可有取代基之吡畊基、可有取代基之嘧啶基 、可有取代基之喹啉基、可有取代基之異喹啉基、可有取 φ 代基之苯并噻唑基、可有取代基之苯并咪唑基、可有取代 基之苯并噚唑基、可有取代基之噻唑并吡啶基、可有取代 基之嘮唑并吡啶基或可有取代基之吡唑基（其中取代基與申 請專利範圍第1項相同）]» — 15.如申請專利範圍第14項之化合物、其製藥容許鹽或這些之 溶劑化物，其中Z爲可有取代基之吡啶基、可有取代基之 苯并唾唑基、可有取代基之苯并噚唑基、或可有取代基之 噻唑并吡啶基（其中取代基與申請專利範圍第1項相同）。 φ 16.如申請專利範圍第14項之化合物、其製藥容許鹽或這些之 溶劑化物，其中P爲1。 1 7.如申請專利範圍第1 5或1 6項之化合物、其製藥容許鹽或 這些之溶劑化物，其中Z爲可有取代基之苯并噻唑基或可 有取代基之苯并噚唑基（其中取代基爲（1)鹵素；（3)氰基； (4)硝基；或（6)各自可經鹵素敢代之（i)羥基、（ii)Cl-CIO烷 基或（iv)Cl-ClO烷氧基）。 18.—種醫藥組成物，其係以如申請專利範圍第1至17項中任 一項之化合物、其製藥容許鹽或這些之溶劑合物爲有效成 修正本 &376367 分。 19. 一種ΝΡΥ Y5受體拮抗劑，其係以如申請專利範圍第1至 17項中任一項之化合物、其製藥容許鹽或這些之溶劑合物 爲有效成分。 2 0.—種如下式化合物、其鹽或這些之溶劑合物，
—NH? (式中R1爲乙基或第三丁基）。
21.—種如下式化合物、其鹽或這些之溶劑合物
(式中R1爲乙基、異丙基或第三丁基）。
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