TW200918507A - Novel HIV reverse transcriptase inhibitors - Google Patents

Novel HIV reverse transcriptase inhibitors Download PDF

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Publication number
TW200918507A
TW200918507A TW097123922A TW97123922A TW200918507A TW 200918507 A TW200918507 A TW 200918507A TW 097123922 A TW097123922 A TW 097123922A TW 97123922 A TW97123922 A TW 97123922A TW 200918507 A TW200918507 A TW 200918507A
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Taiwan
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group
compound
inhibitor
formula
inhibitors
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TW097123922A
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English (en)
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hong-yan Guo
Choung U Kim
Ill-Young Lee
Michael L Mitchell
Gerry Rhodes
Jong-Chan Son
Lianhong Xu
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Gilead Sciences Inc
Korea Res Inst Chem Tech
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Publication of TW200918507A publication Critical patent/TW200918507A/zh

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Description

200918507 九、發明說明 相互參考之相關申請案 本申請案主張美國臨時申請案號60/959,676 (2007年 7月16日提出申請）和美國臨時申請案號60/937,756 (2007 年6月29日提出申請）之權益，該兩件美國臨時申請案爲 所有目的係全部倂入本文作爲參考。 【發明所屬之技術領域】 本發明關於新穎之人免疫缺陷病毒（HIV)反轉錄酶 (RT)抑制劑類、彼之醫藥組成物、製備該新穎HIV反轉錄 酶之方法、及抑制及治療HIV感染之方法。 【先前技術】 近年來，HIV反轉錄酶（RT)抑制劑類已成爲用於抑制 及治療人HIV感染之一類重要治療劑。抑制HIV反轉錄 酶之酶催化功能的化合物能抑制HIV於受感染細胞內之複 製。如習知之RT抑制劑（諸如疊氮胸苷、2’，3’-雙去氧肌 昔、2’，3’-雙去氧胞苷、司他夫定（stavudine)、拉脈優定 (lamivudine)、恩曲他濱（emtricitabine)、阿波卡偉 (abacavir)、泰諾福韋（tenofovir)、奈韋拉平（nevirapine) 、地拉韋定（delavirdine)及依法韋侖（efavirenz)，該等化 合物係迄今已被許可用於治療愛滋病（AIDS)之主要藥物） 所證實者，該等HIV RT抑制劑係用於預防或治療人HIV 感染。 -5- 200918507 如同任何一種抗病毒治療’使用RT抑制劑以治療 AID S最終會導致產生對所給與之藥物較不敏感的病毒。 對該等藥物之抗藥性（降低之敏感性）係發生在pol基因之 反轉錄酶片段上突變的結果。HIV之數個突變株已經特徵 定性且咸信對習知治療劑之抗藥性係基於該RT基因之突 變。因此，爲具有功效，新穎之HIV RT抑制劑必須不僅 能有效地拮抗HIV野生型病毒株’亦必須證實具有拮抗新 出現之突變株（對商品化可購得之RT抑制劑顯現抗藥性者 )的功效。於是，對新穎之HIV RT抑制劑（例如以HIV野 生型病毒株和突變病毒株二者之HIV RT爲標靶者）持續存 有需求。 【發明內容】 發明簡述 於是，於一較佳體系中，本申請案提供新穎之式（I) HIV RT抑制劑化合物：
Y
(I) 或其藥學上可接受之鹽、溶劑化物及/或酯，其中 X和Y係各別爲0或S ; A 係共價鍵、-0-、-S-、-NR5-、-C(0)-、-C(S)-、_ -6- 200918507 C(NR8)-或-C(R6)2-; D係共價鍵、烷撐基、烯撐基或炔撐基； R1係Η、鹵、烷基、鹵烷基、環烷基、經取代之環院 基、雜環基、經取代之雜環基、-ΟΗ、烷氧基、烷硫基、 甲矽烷氧基、烯基、經取代之烯基、炔基、經取代之炔基 、CN、-C(0)-N(R7)2、-0-C(0)-N(R7)2、-N(R7)_c(〇)- N(R7)2、-C(0)-0 烷基、-C(0)-0H、-0-C(0)-〇 焼基、-N(R7)-C(0)-0烷基、甲矽烷氧基、-O-烷撐基-OH、_〇_垸 撐基-0_ 醯基或-S(0)2-N(R7)2 ; R2係鹵、硝基、氰基、烷基、鹵烷基、經取代之院基 、羥基烷基、烷氧基烷基、烯基、經取代之烯基、炔基、 經取代之炔基、烷氧羰基、-N(R7h、烷基胺甲醯基、二院 基胺甲醯基、環烷基、經取代之環烷基、芳基烷基或經取 代之芳基烷基； R3係芳基或雜芳基； R4係Η、烷基、經取代之烷基、環烷基、經取代之環 烷基、羥基烷基、烷氧基烷基、芳基烷基或經取代之芳基 烷基； R5係Η、院基、經取代之烷基、芳基烷基、經取代之 芳基烷基、-ΟΗ、醯基或經取代之醯基； 每個R6係各別爲Η、烷基、環烷基、經取代之環烷 基、羥基、烷氧基、氰基或鹵； 每個R7係各別爲Η、烷基、芳基、經取代之芳基、 芳基烷基、經取代之芳基烷基、環烷基、經取代之環烷基 200918507 、雜芳基或經取代之雜芳基； R8係Η、烷基、芳基、經取代之芳基、（^或烷氧基 » 每個Ζ係各別選自鹵、硝基、羥基、胺基、乙醯胺基 、三氟乙醯胺基、疊氮基、氰基、甲醯基、烷基、經取代 之烷基、烷基胺甲醯基、二烷基胺甲醯基、烯基、經取代 之嫌基块基、經取代之块基、院氧基、經取代之院氧基 、烷氧羰基、環烷基、經取代之環烷基、環烯基、經取代 之環烯基、雜環基、經取代之雜環基、芳基、經取代之芳 基或氧化物；且 η係0至4之整數； 唯其 (a) 當 X 和 Υ 皆爲 〇，R4 係 Η，Α 係 _〇_、、_ C(C>)…_CH(〇H)_或- CH2-，R3 係苯基且 D 係 _CH2·時，Rl 不爲烷氧基； (b) 昌 X 和 Y 皆爲 〇，A 係-s-、-Ο-或- C(〇)-，R3 係 本基，η係2,每個2係烷基，1)係_Ch2_，r2係烷基且 R係H時’ R1不爲未經取代之環烷基、未經取代之雜環 烷基或未經取代之雜芳基； (C) s X 和 Y 皆爲 〇，A 係-C(O)-、-〇-或-NH-，D 係-CH2_ ’ R2係烷基’反3係苯基，〇係2且R4係η時，Ri 不爲Μ取代或未經取代之雜芳基，該雜芳基選自吡啶基、 赌陡基或_曝基. (d)當X和Y皆爲Ο，η係0或2，每個Z係烷基， -8- 200918507 A-R3係苄基、苯甲醯基、苯硫基或苯氧基，R4係η且R2 係乙基或異丙基時，D不爲烯撐基或炔撐基且- D- R1不爲 烷基、羥基烷基或-烷撐基-c(o)-o烷基； (e) 僅R4和-D-R1之一者係Η。 於另一較佳體系中，本申請案提供一種治療HI V感染 之方法’其包含投服至需要該治療之病患體內治療上有效 量之至少一種式（I)化合物或其藥學上可接受之鹽、溶劑化 物及/或酯。 於另一較佳體系中，本申請案提供一種治療HIV感染 之方法’其包含投服至需要該治療之病患體內治療上有效 量之（a)—或多種式（I)化合物和（b)另一治療劑（即一或多種 選自HIV反轉錄酶抑制劑或HIV蛋白酶抑制劑之化合物） 〇 於另一較佳體系中，本發明提供一種治療HIV感染之 方法’其包含投服至需要該治療之病患體內治療上有效量 之（a)式（I)化合物和（b)至少一種選自抑制HIV蛋白酶之化 合物、ΗI V反轉錄酶之非核苷抑制劑、η IV反轉錄酶之核 苷抑制劑、HIV反轉錄酶之核苷酸抑制劑、HIV整合酶抑 制劑、gp4 1抑制劑、CXCR4抑制劑、gpl20抑制劑、 G 6 P D和N A D Η氧化酶抑制劑、c C R 5抑制劑或其他治療 HIV的藥物之化合物或彼等之混合物。 於另一較佳體系中，本發明提供一種套組或容器，其 包含有效量之式（I)化合物以作爲測定潛在之醫藥化合物於 抑制HIV RT及/或HIV生長之能力的測試或分析中之標準 200918507 物或試劑。 發明詳細說明 對本發明之申請專利範圍某些請求項將作詳細之說明 ，且彼等之實例係以附隨之結構和化學式加以闡釋。雖然 係以列舉之申請專利範圍請求項相關連之方式說明本發明 ’但是當能瞭解的是本發明並不欲限於該等申請專利範圍 請求項。相反地’本發明欲含括可包括如於申請專利範圍 所界定者的本發明之範圍內的所有可替代、修飾及等同物 者。 除非另有說明’本文所使用之下述術語和詞彙欲含有 下述之意義： 當本文使用商標名時，申請人欲任意地包括該商標產 物和該商標產物之活性藥學成分。 依據此技藝之使用習慣，用於本文之結構式中的
X 係表示連接核心或骨架結構之部分或取代基的連接點之鍵 結。 本文所使用之“本發明之化合物，，或“式⑴化合物，，係表 示式（I)化合物或其藥學上可接受之鹽、溶劑化物、酯或生 理上功能衍生物。本發明之化合物亦包括該化合物之互變 異構型式’例如本文所描述之互變異構“烯醇，，。同樣地， -10- 200918507 對於可經分離之中間產物（諸如例如式（4)化合物）“式（數 字）化合物”表示該式之化合物及其藥學上可接受之鹽、溶 劑化物、酯及生理上功能衍生物。 “烷基”係含有正鏈、另鏈、特鏈或環狀碳原子之烴基 。例如，院基可含有1至20個碳原子（即Ci-C〗。院基）、1 至1〇個碳原子（即烷基）或1至6個碳原子（即C!-C6烷基）。適當之烷基的實例包括但不限於甲基（Me, -CH3) 、乙基（Et，-CH2CH3)、1-丙基（n-Pr，η-丙基，-CH2CH2CH3) 、2-丙基（i-Pr, i-丙基，-CH(CH3)2)、 1- 丁基（n-Bu, n-丁基，-CH2CH2CH2CH3)、 2- 甲基-1-丙基（i-Bu，i-丁基，-CH2CH(CH3)2)、 2· 丁基（s-Bu，s-丁基，-CH(CH3)CH2CH3)、 2-甲基-2-丙基（t-Bu, t-丁基，-C(CH3)3)、 1- 戊基（n-戊基，-CH2CH2CH2CH2CH3)、 2- 戊基（-CH(CH3)CH2CH2CH3)、3-戊基（-CH(CH2CH3)2)、 2- 甲基_2-丁基（-(：((：}13)2(：112(：113)、 3- 甲基-2-丁基（-CH(CH3)CH(CH3)2)、 3-甲基-ΐ·丁基（_CH2CH2CH(CH3)2)、 2 -甲基-1-丁基（-CH2CH(CH3)CH2CH3)、 1- 己基（-CH2CH2CH2CH2CH2CH3)、 2- 己基（-CH(CH3)CH2CH2CH2CH3)、 3- 己基（-CH(CH2CH3)(CH2CH2CH3))、 2- 甲基-2-戊基（-C(CH3)2CH2CH2CH3)、 3- 甲基-2-戊基（-CH(CH3)CH(CH3)CH2CH3)、 -11 - 200918507 4 -甲基-2-戊基（-CH(CH3)CH2CH(CH3)2)、 3-甲基-3-戊基（-C(CH3)(CH2CH3)2)、 2-甲基-3-戊基（-(：11((：142(：]^3)(：11((：1^)2)、 2.3- 二甲基-2-丁基（-(：(<：113)2(：14((：113)2)、 3.3- 二甲基-2-丁基（-CH(CH3)C(CH3)3 及辛基（-(CH2)7CH3) 〇 “烷氧基”表示具有式-〇-烷基之基，其中上述定義之 烷基係經由氧原子與母分子連接。烷氧基之烷基部分可含 有1至20個碳原子（即C1-C2Q院氧基）、1至12個碳原子（ 即C^-Cu烷氧基）或1至6個碳原子（即C^-Ce烷氧基）。適 當之烷氧基的實例包括但不限於甲氧基（·〇<Η3或-OMe) 、乙氧基（_〇CH2CH3 或-OEt)、特 丁氧基（-0-C(CH3)3 或-OtBu)及類似者。 “鹵烷基”係上述定義之烷基，其中該烷基之一或多個 氫原子係經鹵原子替代。鹵烷基之烷基部分可含有1至20 個碳原子（即Ci-C^鹵烷基）、1至12個碳原子（即Κ12 鹵烷基）或1至6個碳原子（即CrCe鹵烷基）。適當之鹵烷 基的實例包括但不限於-CF3、-CHF2、-CFH2、-CH2CF3及 類似者。 “烯基，，係含有正鏈、另鏈、特鏈或環狀碳原子及至少 一個不飽和部位（即碳碳sp2雙鍵）之烴基。例如，烯基可 含有2至20個碳原子（即C2-C2Q烯基）、2至12個碳原子（ 即C2-C12烯基）或2至6個碳原子（即C2-C6烯基）。適當之 烯基的實例包括但不限於乙烯基（-CH = CH2)、烯丙基卜 -12- 200918507 CH2CH = CH2)、環戊烯基（-C5H7)及 5-己烯基（-CH2CH2CH2CH2CH = CH2)。 “炔基”係含有正鏈、另鏈、特鏈或環狀碳原子及至少 一個不飽和部位（即碳碳sp三鍵）之烴基。例如，炔基可含 有2至20個碳原子（即C2-C2G炔基）、2至12個碳原子（即 C2-C12炔基）或2至6個碳原子（即C2-C6炔基）。適當之炔 基的實例包括但不限於乙炔基（-C = CH)、炔丙基（-CH2C = CH)及類似者。 “烷撐基”係指具有兩個單價基中心之飽和支鏈或直鏈 或環狀烴基，該兩個單價基中心係衍生自除去母烷之相同 或兩個不同碳原子上的兩個氫原子。例如，烷撐基可含有 1至20個碳原子、1至10個碳原子或1至6個碳原子。 典型之烷撐基包括但不限於甲撐基（-CH2-)、1,1-乙基（-CH(CH3)-)、1,2-乙基（-ch2ch2-)、ι，ι-丙基（-ch(ch2ch3)-)、1,2-丙基（-CH2CH(CH3)-)、1，3-丙基（-CH2CH2CH2-)、 1，4-丁基（-CH2CH2CH2CH2-)及類似者。 “烯撐基”係指具有兩個單價基中心之不飽和支鏈或直 鏈或環狀烴基，該兩個單價基中心係衍生自除去母烯之相 同或兩個不同碳原子上的兩個氫原子。例如，烯撐基可含 有2至20個碳原子、2至10個碳原子或2至6個碳原子 。典型之烷撐基包括但不限於1，2-乙烯基（-CH = CH-)。 “炔撐基”係指具有兩個單價基中心之不飽和支鏈或直 鏈或環狀烴基，該兩個單價基中心係衍生自除去母炔之相 同或兩個不同碳原子上的兩個氫原子。例如，炔撐基可含 -13- 200918507 有2至20個碳原子、2至10個碳原子或2至6個碳原子 。典型之炔撐基包括但不限於乙炔撐基（-csc-)、炔丙撐 基（-CH2CeC-)及 4-戊炔撐基（-CH2CH2CH2(^CH-)。 “胺基”係指-NR2，其中每個“R”係各別選自Η、烷基 '經取代之烷基、芳基、經取代之芳基、芳基烷基、經取 代之方基院基等，其中該等院基、經取代之院基、芳基、 經取代之芳基、芳基烷基及經取代之芳基烷基係如本文所 定義及描述者。典型之胺基包括但不限於-νη2、-n(ch3)2 、-NH(CH3)、-N(CH2CH3)2、-NH(CH2CH3)、-NH(經取代 或未經取代之苄基）、-NH(經取代或未經取代之苯基）及類 似者。 “芳基”表示衍生自除去母芳香族環系統之單一碳原子 上的一個氫原子之芳香族烴基。例如，芳基可含有6至20 個碳原子、6至14個碳原子或6至12個碳原子。典型之 芳基包括但不限於衍生自苯、經取代之苯、經取代或未經 取代之萘、經取代或未經取代之蒽、經取代或未經取代之 聯苯及類似者之基（例如衍生自苯之苯基）。 “芳基烷基”係指非環之烷基，其中與碳原子（典型上 係終端或sp3碳原子）鍵結之氫原子之一係經芳基替代。典 型之芳基烷基包括但不限於苄基、2-苯基乙-1-基、萘基甲 基、2 -奈基乙-1-基、蔡並节基、2 -蔡並本基乙-1-基及類 似者（每個該寺基可經取代或未經取代）。該方基院基可包 含7至2G個碳原子’例如烷基部分係1至6個碳原子且 芳基部分係6至14個碳原子。 -14- 200918507 “芳基烯基”係指非環之烯基，其中與碳原子（典型上 係終端或sp3碳原子，但亦可爲sp2碳原子）鍵結之氫原子 之一係經芳基替代。該芳基烯基之芳基部分可包括例如本 文所揭示之任一芳基，且該芳基烯基之烯基部分可包括例 如本文所揭示之任一烯基。該芳基烯基可包含8至20個 碳原子，例如烯基部分係2至6個碳原子且芳基部分係6 至14個碳原子。 “環烷基”係指環僅含有碳原子之飽和單環或多環。環 烷基可爲含有3至7個碳原子之單環、含有7至12個碳 原子之雙環及含有可達約20個碳原子之多環。單環環烷 基含有3至6個（較典型地係5或6個）環原子。雙環環烷 基含有7至12個環原子（例如經排列爲雙環[4,5]、[5,5]、 [5,6]或[6,6]系統）或9或10個環原子（經排列爲雙環[5,6] 或[6，6]系統或螺稠合環）。單環環烷基之非限制性實例包 括環丙基、環丁基、環戊基及環己基（每個該等基可經取 代或未經取代）。 “芳基炔基”係指非環之炔基，其中與碳原子（典型上 係終端或sp3碳原子，但亦可爲sp碳原子）鍵結之氫原子 之一係經芳基替代。該芳基炔基之芳基部分可包括例如本 文所揭示之任一芳基，且該芳基炔基之炔基部分可包括例 如本文所揭示之任一炔基。該芳基炔基可包含8至20個 碳原子，例如炔基部分係2至6個碳原子且芳基部分係6 至14個碳原子。 與烷基、烷撐基、芳基、芳基烷基、雜環基等相關之 -15- 200918507 “經取代”一詞（例如“經取代之烷基”、“經取代之烷撐基，，、 “經取代之芳基，，、“經取代之芳基烷基”、“經取代之雜環 基”及“經取代之碳環基，’（例如經取代之環烷基））分別表示 院基、院撐基、芳基、芳基烷基 '雜環基、碳環基（例如 環院基）’其中一或多個氫原子係各別獨立地經非氫之取 代基替代。典型之取代基包括但不限於_X、-R、-〇·、=〇 、-OR、-SR、-s_、-NR2、_N + R3、=NR、-CX3、 -CN、-OCN、_SCN、-~N = C = 〇、-NCS、-NO > -N02、=N2 、-N3、_NHC( = 〇)R、-C( = 〇)R、-C( = 0)NRR、 -s( = o)2cr、-s( = 〇)2〇h、-s( = o)2r、-〇s( = o)2〇r、 -S( = 0)2NR、-S( = 0)R、_0P( = 0)(0R)2、-N( = 〇)(OR)2、 -N( = 0)(〇-)2、_N( = 0)(0H)2、-N(0)(0R)(0·)、_C( = 〇)R、 烷撐基-C( = 〇)R、-c( = 0)x、烷撐基-c( = o)x、 -C(S)R、-C(0)0R、烷撐基-C(0)0R、-C(〇)〇-、院撐基 _ C(0)0·、-C(S)OR、-C(0)SR、-C(S)SR、 -C(0)NRR、烷撐基-C(0)NRR、-C(S)NRR &_c( = nr)nrr ，其中每個X係各別爲鹵（F、Cl、Br或I)且每個R係各 別爲H、烷基、芳基、芳基烷基、雜環、碳環或保護基或 前藥部分。烷撐基、烯撐基及炔撐基亦可同樣地經取代。 熟習此技藝之人士當能確認當諸如“烷基”、“芳基，，、 “雜環基”等之部分係經一或多個取代基取代時，該等基可 替代地被稱爲“烷撐基”、“芳撐基”、“雜環撐基，，等部分（即 表示該母“烷基”、“芳基”、“雜環基”部分之至少一個氮原 子已經被所指之取代基所替代）。當諸如“烷基”、“芳基”、 -16- 200918507 “雜環基”等之部分係“經取代，，或圖式上顯示經取代（或可選 擇地經取代’例如當取代基之數目係介於0至正整數時） ，則該“烷基，，、“芳基，，、“雜環基，，等可與“烷撐基”、“芳撐 基”、“雜環撐基”等互換。 本文所使用之“前藥，，係指任何化合物，該化合物當被 投服至生物系統時受自發性化學反應、酶催化化學反應、 光分解作用及/或代謝性化學反應之作用能產生藥物（即活 性成分）。因此，前藥係治療活性化合物之共價鍵改質之 類似物或潛伏型式。 熟習此技藝之人士當能明瞭應選擇式（I)化合物之取代 基和其他部分以生成充分安定之化合物，進而提供可經調 製成可接受之安定醫藥組成物的醫藥上有用之化合物。具 有該安定性之式（I)化合物係落入本發明之範疇。 “雜院基”係指烷基’其中一或多個碳原子已經雜原子 (諸如Ο ' N或S)替代。例如，若與母分子連接之烷基的 碳原子係經雜原子（例如〇 ' N或S)替代，則所生成之雜 院基係分別爲烷氧基（例如_ 〇 C η 3等）、烷胺基（例如-NHCH3、-N(CH3)2等）或烷硫基（例如_SCh3)。若非與母分 子連接之烷基的非終端碳原子係經雜原子（例如Ο、N或 S)替代’則所生成之雜烷基係分別爲烷基醚（例如-CH2CH2-〇-CH3 等）' 院胺（例如-ch2NHCH3、-ch2n(ch3)2 等）或院硫基醚（例如-ch2-s-ch3)。若該烷基之終端碳原子 係經雜原子（例如〇 ' N或s)替代，則所生成之雜烷基係 分別爲羥基烷基（例如-CH2CH2-〇H)、胺基烷基（例如- -17- 200918507 CH2NH2)或烷锍基（例如-CH2CH2-SH)。雜烷基可含有例如 1至20個碳原子、1至1〇個碳原子或1至6個碳原子。 Ci-Ce雜烷基表示含有1至6個碳原子之雜烷基。 本文所使用之“雜環”或“雜環基”包括文獻Paquette， Leo A., Principles of Modern Heterocyclic Chemistry (W.A. Benjamin, New York，1968)(特別是第 1、3、4、6、
7 及 9 章）、The Chemistry of Heterocyclic Compounds, A
Series of Monographs (John Wiley & Sons, New York, 1950至迄今）（特別是第13、14、16、19及28卷）及j. Am. Chem· S〇c_ ( 1 960) 82:5 5 66所描述之作爲實例且爲非 限制性的雜環。於本發明之一特定較佳體系中，“雜環，，包 括本文所定義之“碳環”’其中一或多個（例如1、2、3或4 個）碳原子已經雜原子（例如Ο ' N或S)替代。“雜環，，或“雜 環基”包括飽和環、部分未飽和環及芳香族環（即雜芳香族 環）。經取代之雜環基包括例如經本文所揭示之任一取代 基（包括羰基）取代之雜環。 雜環之實例包括作爲實例且爲非限制性之吡啶基 '二 氫吡啶基、四氫吡啶基（脈啶基）、噻唑基、四氫苯硫基、 經硫氧化之四氫苯硫基、嘧啶基 '呋喃基、噻吩基、啦略 基、耻哩基、咪唑基、四唑基、苯並呋喃基、硫萘基、剛 哚基、吲哚吩基、喹啉基、異喹啉基、苯並咪唑基、呢陡 基、4 -哌啶酮基、吡咯啶基、2 _吡咯啶酮基、吡咯啉基、 四氫呋喃基、四氫喹琳基、四氫異喹琳基、十氫喹啉基、 八氫異喹啉基、偶氮啉基、三嗪基、6H-1,2,5 -噻二嗪基、 -18- 200918507 2H，6H-1,5,2-二噻嗪基、噻吩基、噻蒽基、哌喃基、異苯 並呋喃基、色烯基、咕噸基、啡噁噻基、2 Η -吡咯基、異 噻唑基、異噁唑基、吡嗪基、噠嗪基、吲嗪基、異吲哚基 、3 Η -吲哚基、1 Η -吲唑基、嘌呤基、4 Η -喹嗪基、酞嗪基 、萘啶基、喹噁咐基、喹唑啉基、噌啉基、喋啶基、4aH-咔唑基、咔唑基、β -咔啉基、啡啶基、吖啶基、嘧啶基、 鄰啡啉基、啡嗪基、啡噻嗪基、呋咕基、啡噁嗪基、異色 滿基、色滿基、咪唑啶基、咪唑啉基、吡唑啶基、吡唑啉 基、哌嗪基、吲哚啉基 '異吲哚啉基、奎寧環基、嗎啉基 、噁唑啶基、苯並三唑基、苯並異噁唑基、羥吲哚基、苯 並噁唑啉基、靛紅基、雙-四氫呋喃基及類似基（每個該等 基可經取代或未經取代）。 作爲實例且爲非限制性，碳鍵結之雜環係鍵結於吡啶 之第2'3、4、5或6位置上、噠嗪之第3、4、5或6位 置上、嘧啶之第2、4、5或6位置上、吡嗪之第2、3、5 或6位置上、呋喃、四氫呋喃、硫呋喃、噻吩、吡咯或四 氫吡咯之第2、3、4或5位置上、噁唑、咪唑或噻唑之第 2、4或5位置上、異噁唑、吡唑或異噻唑之第3、4或5 位置上、氮丙啶之第2或3位置上、吖丁啶之第2、3或4 位置上、喹啉之第2、3、4、5、6、7或8位置上及異嗤 啉之第1、3、4、5、6、7或8位置上。更爲典型地，碳 鍵結之雜環包括2-吡啶基、3-吡啶基、4-吡啶基、5-吡啶 基、6 ·吡啶基、3 -噠嗪基、4 -噠嗪基、5 -噠嗪基、6 -噠嗪 基、2-嘧啶基、4-嘧啶基' 5·嘧啶基、6-嘧啶基、2-吡嗪 -19- 200918507 基3卩比曉基5耻嗪基、6 -耻嗪基、2 -噻哩基、4 -噻哩 基或5-噻唑基（每個該等基可經取代或未經取代）。 作爲實例且爲非限制性，氮鍵結之雜環係鍵結於氮丙 啶、吖丁啶、吡咯、吡咯啶' 2 -毗咯啉、3 _吡咯啉、咪唑 '咪唑啶、2-咪唑啉、3_咪唑啉、吡唑、吡唑啉、2_吡嗖 啉、3-吡唑咐、哌啶、哌嗪、吲哚、吲哚啉及1H_吲唑之 第1位置上、異吲哚或異吲哚啉之第2位置上、嗎啉之第 4位置上及咔唑或β -咔啉之第9位置上（每個該等基可經取 代或未經取代）°更爲典型地，氮碳鍵結之雜環包括i _氮 丙D定基' 1 -吖丁 D定基、1 -啦略基、丨_咪哩基、丨_ π比哩基及 1 -峨D定基（每個該等基可經取代或未經取代）。 “雜環基院基”係指非環院基’其中與碳原子（典型上 係終端或sp3碳原子）鍵結之一個氫原子係經雜環基替代（ 即雜環基-烷撐基部分）。典型之雜環基烷基包括但不限於 雜環基-CH2-、2-(雜環基）乙-1_基及類似基，其中該“雜環 基’部分包括任一上述之雜環基，其包括文獻Principles of Modern Heterocyclic Chemistry所描述者。熟習此技藝之 人士亦當能瞭解藉由碳-碳鍵或碳-雜原子鍵，該雜環基可 與該雜環基烷基之烷基部分連接，唯其所生成之基係化學 上安定者。該雜環基烷基包含2至20個碳原子，例如該 雜環基烷基之烷基部分係1至6個碳原子且該雜環基部分 係1至14個碳原子。雜環基烷基之實例包括作爲實例且 爲非限制性之含硫、氧及/或氮之5員雜環（諸如噻唑基甲 基、2-噻唑基乙-1-基、咪唑基甲基、噁唑基甲基、噻二唑 -20- 200918507 基甲基等）及含硫、氧及/或氮之6員雜環（諸如喊D定基甲基 、哌嗪基甲基、嗎啉基甲基、吡啶基甲基、噠嗪基甲基、 嘧啶基甲基、吡嗪基甲基等）（每個該等基可經取代或未經 取代）。 “雜環基烯基，，係指非環烯基，其中與碳原子（典型上 係終端或SP3碳原子，但亦可爲sp碳原子）鍵結之一個氫 原子係經雜環基替代（即雜環基-烯撐基部分）°該雜環基燃 基之“雜環基，，部分包括任—本文所述之雜環基’其包括文 獻 Principles of Modern Heterocyclic Chemistry 所描述者 ，且該雜環基烯基之烯基部分包括任一本文所述之烯基。 熟習此技藝之人士亦當能瞭解藉由碳-碳鍵或碳-雜原子鍵 ，該雜環基可與該雜環基烯基之烯基部分連接’唯其所生 成之基係化學上安定者。該雜環基烯基包含3至20個碳 原子，例如該雜環基烯基之烯基部分係2至6個碳原子且 該雜環基部分係1至14個碳原子。 “雜環基炔基”係指非環炔基，其中與碳原子（典型上 係終端或SP3碳原子，但亦可爲SP碳原子）鍵結之一個氫 原子係經雜環基替代（即雜環基-炔撐基部分）。該雜環基炔 基之“雜環基”部分包括任一本文所述之雜環基，其包括文 獻 Principles of Modern Heterocyclic Chemistry 所描述者 ，且該雜環基炔基之炔基部分包括任一本文所述之炔基。 熟習此技藝之人士亦當能瞭解藉由碳-碳鍵或碳-雜原子鍵 ，該雜環基可與該雜環基炔基之炔基部分連接，唯其所生 成之基係化學上安定者。該雜環基炔基包含3至20個碳 -21 - 200918507 原子，例如該雜環基炔基之炔基部分係2至6個碳原子且 該雜環基部分係1至14個碳原子。 “雜芳基”係指芳香族雜ί哀基，其環上含有至少一個雜 原子。可含括於芳香環上之適當雜原子的非限制性實例包 括氧、硫及氮。雜芳環之非限制性實例包括所有列示於“ 雜環基”之定義中的基，其包括吡D定基、吡咯基、噁唑基 、吲哚基、異吲哚基、嘌呤基、呋喃基、噻吩基、苯並咲 喃基、苯並苯硫基、味哩基、咪哩基、噻哩基、異嚼哩基 、姐哩基、異噻哩基、嗤咐基、異喹咐基、曝嗪基、嚼陡 基、吡嗪基等（每個該等基可經取代或未經取代）。 “碳環”或“碳環基”係指飽和、部分未飽和或芳香環， 其係含有3至7個碳原子之單環、含有7至I]個碳原子 之雙環及含有達至約20個碳原子之多環。單環碳環含有3 至6個環原子且更典型地含有5或6個環原子。雙環碳環 含有7至1 2個環原子（例如排列爲雙環[4，5 ]、[ 5 , 5 ]、[ 5，6 ] 或[6,6]系統）或9或1〇個環原子（例如排列爲雙環[5,6]或 [6，6 ]系統）。單環和雙環碳環之實例包括環丙基、環丁基 、環戊基、1-環戊-1-烯基、；!_環戊_2_烯基、卜環戊_3_烯 基、環己基、1-環己-1·烯基、丨_環己_2_烯基' 丨_環己-3_ 烯基、苯基及萘基（每個該等基可經取代或未經取代）。 驢基’係指-C ( 0)-院基、 -C(O)-碳環（經取代或未經取 代）、-c(o)•雜環（經取代或未經取代），其中彼等之烷基、 碳環或雜環部分係如本文所定義者。“醯基，，之非限制性實 例包括-c(o)ch3 -C(0)CH2CH3、-c(0)CH(CH3)2、 -22- 200918507 C(〇)C(CH3)3, -C(〇)-苯基（經取代或未經取代）、_c(〇)_環 丙基（經取代或未經取代）、-C(0).環丁基（經取代或未經取 代）、-C(〇)-環戊基（經取代或未經取代）、_c(〇)_環己基（經 取代或未經取代）、-C(O)-吡啶基（經取代或未經取代）等。 方基雜院基”係指本文定義之雜烷基，其中一個氫原 子（該氫原子可與碳原子或雜原子連接）已經本文所定義之 芳基替代。該芳基可與該雜烷基之碳原子或雜原子鍵結， 唯其所生成之芳基雜烷基係化學安定部分者。例如，芳基 雜烷基可含有通式：-烷撐基-〇-芳基、·烷撐基烷撐基-芳基、-烷撐基-NH-芳基、-烷撐基-NH-烷撐基-芳基、-烷 撐基芳基、·烷撐基-s-烷撐基—芳基等。此外，於上述 通式中之任一烷撐基部分可進一步經本文所定義或例示之 任一取代基取代。 “雜芳基烷基，，係指本文定義之烷基，其中一個氫原子 已經本文所定義之雜芳基替代。雜芳基烷基之非限制性貫 例包括-CH2-吡啶基、_Ch2-吡咯基、-CH2-噁唑基、-CHr 吲哚基、-CH2-異吲哚基、_CH2-嘌呤基、-CH2-呋喃基、_ CH2 -噻吩基、-CH2 -苯並呋喃基、-CH2 -苯並苯硫基、_ CH2-咔唑基、-CH2-咪唑基、-ch2-噻唑基、-CH2-異噁挫 基、-CH2-吡唑基、-CH2_異噻唑基、-CH2-喹啉基、-CH2_ 異喹啉基、-ch2-噠嗪基、-ch2-嘧啶基、-ch2-吡嗪基、_ CH(CH3)-吡啶基、-CH(CH3)·吡咯基、-CH(CH3)-噁哩基 、-CH(CH3)-吲哚基、-ch(CH3)-異吲哚基、-CH(CH3)-嚷 呤基、-ch(ch3)_呋喃基、-CH(CH3)-噻吩基、 -23- 200918507 苯並咲«、韻⑽3)_苯並苯硫基、_ch(CH3m哩基 、-CH(CH3)1D坐基、_CH(CH3)，D坐基、_CH㈣小異噁 唑基' -ch(CH3)_批哩基、_CH(CH3)_異噻哗基、· ch(Ch3)-_基、韻（呢）_異喹啉基、_cH(d)_喔曉基 …CH(CH3)-嗯啶基、-ch(ch3)-d比嗪基等。 “甲砂院氧基’’係指-〇_siR3基，其中R包括院基芳 基（經取代或未經取代）及雜芳基（經取代或未經取代）或彼 等之組合。甲矽烷氧基之非限制性實例包括-〇_Si(CH3h -〇-Si(CH3)2tBu . -0-Si(tBu)2CH3 > -〇-Si(tBu)3 ^ -〇. Si(CH3)2 苯基、_〇_Si(苯基 hCH3 及-〇si(苯基 h。 隣酸酯’和“膦酸醋基，，表示分子內之官能基或部分係 包含至少一個磷-碳鍵和至少—個磷_氧雙鍵。該磷原子係 進一步經氧 '硫及氮取代基取代。如本文所定義者’該“ 膦酸酯’’和“膦酸酯基，，包括含有膦酸、膦酸單酯、膦酸二 酯、膦醯胺、膦二醯胺及膦硫醇酯官能基之分子。 “連接子（基或“連接，，係指包含共價鍵或多個原子之 鏈或基的化學部分，該共價鍵或該鏈或基係共價連接膦酸 醋基或次膦酸醋基至藥物。連接子包括諸如烷氧基（例如 聚乙撐氧基、PEG、聚甲撐氧基）和烷胺基（例如聚乙撐胺 基和Jeffamine™)之重複單元及二酸酯和醯胺（其包括琥珀 酸醋、號拍二酶胺、3，-氧代戊二酸酯、丙二酸酯及己醯胺 )之部分。 “可選擇地經取代”係指該式（1)化合物之特定部分（例 如可選擇地經取代之芳基），其含有0、1、2或多個取代 -24- 200918507 “其酯（彼之酯）”表示化合物之任一酯，其中該分子之-COOH官能基的任一者係經-C(0)0R官能基替代或其中該 分子之-OH官能基的任一者係經-OC(〇)R官能基替代，其 中該酯之R部分係能形成安定酯部分之任何含碳之基，其 包括但不限於烷基、烯基、炔基、環烷基、環烷基烷基、 芳基、芳基烷基、雜環基、雜環基烷基及彼等之經取代的 衍生物。酯亦可包括上述“互變異構烯醇”之酯，例如下述 所示者：
該“其酯（彼之酯）”包括但不限於其藥學上可接受之酯 〇 “其鹽（彼之鹽）”表示本發明之化合物的任何酸及/或鹼 加成鹽，較佳地係其藥學上可接受之鹽。 “藥學上可接受之鹽”表示落入安全藥物判斷之範圍內 '適用於與人和低等動物之組織接觸而不具有過度毒性、 刺激性、過敏反應及類似者、具有相稱合理之受益/風險 比例、通常爲水或油可溶或可分散者及對所欲之用途爲有 -25- 200918507 效者的化合物之鹽。其中能應用該式（I)或（II)之化合物的 化學性質及能與該式（I)或（II)之化合物的化學性質相容者 ，該藥學上可接受之鹽包括藥學上可接受之酸加成鹽及鹽 包括藥學上可接受之鹼加成鹽。適當之鹽係列示於文獻例 如 S. M. Birge et al_，J. Pharm. Sci.，1977，66，pp. 1-19。 “治療”表示投服本發明之化合物或組成物以減輕或除 去HIV疾病之徵狀及/或降低病患體內之病毒量。該“治療 ”亦包含於個體曝露於該病毒之後但於該疾病之徵狀出現 之前及/或於偵測出血液中之該病毒之前投服本發明之化 合物或組成物以防止該疾病徵狀之出現及/或防止血液中 該病毒達到可偵測之量，及投服本發明之化合物或組成物 以防止HIV自母體經圍產期傳輸至嬰兒體內（其係藉由於 母體生產前投服至該母體體內及於嬰兒出生後之最初數日 投遞至該嬰兒體內）。 “手性（chiral)”係指具有鏡像伴之不可重疊性的分子， 而“非手性（achiral)”係指具有鏡像伴之可重疊性的分子。 “立體異構物”係指具有相同之化學組成但於空間之原 子或基團排列呈不同的化合物。 “非鏡像異構物”係指含有2或多個手性中心之立體異 構物且該等手性分子彼此間係非鏡像。非鏡像異構物具有 不同之物理性質（例如熔點、沸點、光譜性質及反應活性） 。藉由筒解析分析方法（諸如電泳和層析）可分離非鏡像異 構物之混合物。 “鏡像異構物”係指化合物之兩個立體異構物，其彼此 -26- 200918507 係不可重疊之鏡像。 本文所使用之立體化學的定義和術語大抵係依循文獻 S. N. Parker，E d. ? McGraw-Hill Dictionary of Chemical Terms ( 1 984) McGraw-Hill Book Company, New York 和 Eliel， E. and Wi 1 en ? S.， Stereochemistry of Organic Compounds ( 1 9 94) John Wiley & Sons，Inc. 5 New York。 許多有機化合物存有光學活性型式，即該等光學活性型式 能旋轉平面偏光之平面。於描述光學活性化合物時，字首 D和L或R和S係用於定義分子之手性中心的絕對組態。 字首d和1或（+ )和（-)係用於表示經該化合物導致之平面 偏光所旋轉的符號，其中（-)或1係表示該化合物係左旋。 字首爲（+ )或d之化合物係右旋。對給定之化學結構，此 等立體異構物係相同（除了該等立體異構物彼此爲鏡像之 外）°特定之立體異構物亦可稱爲鏡像異構物且該等異構 物之混合物通常被稱爲鏡像異構混合物。鏡像異構物之5 〇 :5 0混合物被稱爲消旋混合物或消旋物，且當於化學反應 或製程中未存有立體選擇性或立體專一性時可產生該消旋 混合物或消旋物。該“消旋混合物，，和“消旋物，，係指缺少光 學活性之等莫耳的兩種鏡像異構物之混合物。 保護基 於本發明之內容中，保護基包括前藥部分和化學保護 基。 保護基係可購得、一般習知及慣用者且係可選擇地於 -27 - 200918507 合成過程期間（即製備本發明之化合物的途徑或方法）利用 該保護基以防止發生副反應。最大之部分係關於欲保護何 等基、何時進行保護反應及化學保護基“PG”之本性的決定 將取決於欲拮抗之保護反應的化學性質（例如酸性、鹼性 、氧化、還原或其他條件）及欲進行之合成反應的方向。 若化合物係經多個PG取代，則該等PG無須爲相同且通 常係爲不同。通常，PG將被用於保護官能基（諸如羧基、 羥基、硫基或胺基）且因此係用於防止發生副反應或於另 一方面係用於促進合成功效。用於產生游離、去保護之基 的去保護反應之次序係取決於欲進行之合成反應的方向及 將遭遇之反應條件且熟習此技藝之人士將可決定該等去保 護反應可發生之任何次序。 本發明之化合物的多種不同之官能基可經保護。例如 ，-OH基（無論其是否爲羥基、羧酸、膦酸或其他官能基） 之保護基包括“形成醚或酯之基”。形成醚或酯之基係能作 爲本文所描述之合成示意圖中的化學保護基。然而，如熟 習此技藝之人士將能瞭解者，某些羥基和硫保護基係非形 成醚或酯之基且含括醯胺（如下文所述）。 極爲多數之羥基保護基和形成醯胺之基及對應之化學 斷裂反應係描述於文獻 Protective Groups in Organic Synthesis, Theodora W. Greene and Peter G. M. Wuts (John Wiley & Sons, Inc., New York, 1 999, ISBN 0-471-16019-9) (“Greene ”）中（亦參閱文獻 Kocienski, Philip J.; Protecting Groups (Georg Thieme Verlag Stuttgart, New -28- 200918507
York，1994)，其全部內容係併入本文作爲參考）。特別是 第1章-保護基：回顧，第1至20頁；第2章-羥基保護基 :第21至94頁；第3章-二醇保護基：第95至117頁； 第4章-羧基保護基：第Π8至154頁；第5章-羰基保護 基：第155至184頁。對羧酸、膦酸、膦酸酯及磺酸之保 護基及對酸之其他保護基’參閱下述之Greene文獻。該 等基包括作爲實例且爲非限制性之酯、醯胺、醯肼及類似 者。 形成醚和酯之保護基 形成酯之基包括：（1)形成膦酸酯之基，諸如膦醯胺酯 、硫代磷酸酯、膦酸酯及膦雙醯胺；（2)形成羧酸酯之基， 及（3)形成硫酯之基，諸如磺酸酯、硫酸酯及亞磺酸酯。 本發明之化合物的代謝物 亦屬於本發明之範圍的是本文所描述之化合物的活體 內代謝產物。該等產物可得自於被投服之化合物經例如氧 化、還原、水解、醯胺化、酯化及類似之作用（主要係基 於酶催化反應）。於是，本發明包括藉由包含下述步驟之 方法所產製之化合物：令本發明之化合物與哺乳動物接觸 一段足以產生該化合物之代謝產物的時間。典型地，該等 產物之鑑定係藉由製備經放射性標記（例如C14或H3)的本 發明之化合物’非經腸地投服可偵測劑量（例如大於約〇.5 mg/kg)之該經放射性標記的本發明之化合物至動物（諸如 -29- 200918507 大鼠、小鼠、天竺鼠 '猴或人）體內，令經代謝所需之充 分時間（典型地約3 0秒至30小時）及自尿液、血液或其他 生物樣品分離該經放射性標記的本發明之化合物的轉化產 物。因該等轉化產物係經標記’故可易於分離該等轉化產 物（藉由使用能結合存在於該等代謝物內之抗原決定部位 的抗體以分離其他產物）。利用慣用之方法（例如MS或 NMR分析）以測定代謝物之結構。通常，利用此技藝之人 士所習知的一般藥物代謝硏究之相同方法進行代謝物之分 析。只要未於活體內被發現且即使是本身不具有抗感染活 性’該等轉化產物可用於本發明之化合物的治療性投服劑 量之診斷分析。 式（I)化合物 於一較佳體系中’本申請案提供本文所描述之式（I)化 合物。 於該式（I)化合物之每個較佳體系中，適用下述之但書 (除非另有說明或者除非該但書係明顯地不適用（例如對該 等較佳體系’其中X和γ之一或多者係非爲〇)): (a) 當 X 和 Y 皆爲 0，r4 係 h，A 係- 〇-、-S-、-C(〇) -、-CH(OH)-或- CH2- ’ R3 係苯基且 d 係 _CH2-時，R1 不爲烷氧基； (b) 當 X 和 γ 皆爲 〇，a 係-S-、-0-或-C(O)-，R3 係 苯基’ η係2 ’每個z係烷基，D係-CH2-，R2係烷基且 R4係Η時’ Ri不爲未經取代之環烷基、未經取代之雜環 -30- 200918507 烷基或未經取代之雜芳基；
嘧啶基或噠嗪基；
η係2且R4係Η時，R ，該雜芳基選自吡啶基、 (d)當X和Y皆爲◦，η係0或2，每個Z係烷基， AR係下基 '苯甲醯基、苯硫基或苯氧基，R4係Η且R: 係乙基或異丙基時’ D不爲烯撐基或炔撐基且-D-R1不爲 烷基、 '淫基院基或-烷撐基-C(0)-0烷基； 一者係Η ⑷僅R4和-D-R1之一者係H。 例如’但書（a)排除下式結構之化合物：
其中 A’係-〇-、_s-、-c(0)-、-CH(OH)-或-CH2-且烷基、Z
及n係如本文所定義者。所排除之化合物包括例如US 6911450 、 US 5112835 、 US 5461060 、 US 5318972 ' US 5604209、US 6136815、CN 101016265、WO 03/057677、 JP 2001-114767、 JP 8-3143' FR 2779721 等專利案所揭示 之特定化合物（該等專利案之全部內容基於所有之目的係 倂入本文作爲參考）。 例如，但書（b)排除下式結構之化合物： -31 - 200918507
其中A’係-S-、-〇-或- C(〇)·，“環”係未經取代之環烷基、 未經取代之雜環烷基或未經取代之雜芳基，且烷基係如本 文所定義者。於某些較佳體系中，“環，，可包括經取代之環 烷基、雜環烷基或雜芳基。所排除之化合物包括例如wo 00/6 1 563、WO 00/6 1 564、WO 2007/09 1 8 5 7、US 5 92272 7 等專利案所揭示之特定化合物（該等專利案之全部內容基 於所有之目的係倂入本文作爲參考）。 例如’但書（c)排除下式結構之化合物：
其中 A’係-C(O)-、-〇-或_NH_，z和烷基係如本文所定義 者，且“pyr”係經取代或未經取代之吡啶基、嘧啶基或噠 嗪基。所排除之化合物包括例如 WO 2008/01 6522專利案 所揭示之特定化合物（該專利案之全部內容基於所有之目 的係倂入本文作爲參考）。 例如’但書（d)排除下式結構之化合物： -32- 200918507
其中A’係-CH2-、-〇_、-s·或_C(0)-且D’係烯撐基或炔撐 基，或其中A係-CH2-、-0-、-S -或- C(O)-且D’-R’係垸基 、羥基烷基或-烷撐基-C(〇)-〇烷基；且烷基、烷撐基、烯 撐基及炔撐基係如本文所定義者。所排除之化合物包括例 如US 5747500和KR 1996-014106等專利案所揭示之特定 化合物（該等專利案之全部內容基於所有之目的係倂入本 文作爲參考）。 例如’但書（e)要求僅R4或D-R1 —者可爲η。換言之 ，該式（I)化合物具有下式結構之一：
R 其中R1 、 R: 或描述者。 Υ
R3、 '(Z)n 、Α、Χ、γ、2及n係如本文所定義 於該式⑴化合物之另〜較佳體系中，八係_^(尺6)2-。 於該式（I)化合物之較佳體系中’八係_(^2-。 於該式⑴化合物之力〜較佳體系中’ A係(鹵）2 -。 於該式（I)化合物之另〜較佳體系中，A係_CF2_。 -33- 200918507 於該式（1)化合物之另一較佳體系中’八係_<：(：：12-。 於該式（1)化合物之另一較佳體系中’ A係-C H F -。 於該式（I)化合物之另一較佳體系中’ Α係-CHC1-。 於該式（I)化合物之另—較佳體系中，A係-CHOH-。 於該式（0化合物之另一較佳體系中，A係-CH(〇-烷基 )·，其中烷基包括本文所描述或定義之任何烷基部分。 於該式⑴化合物之另一較佳體系中，A係-C(〇)-。 於該式（I)化合物之另—較佳體系中，A係-〇-。 於該式⑴化合物之另一較佳體系中，A係-S-。 於該式（I)化合物之另一較佳體系中，A係-NR5-。 於該式（I)化合物之另一較佳體系中，A係-NH-。 於該式（I)化合物之另一較佳體系中，A係-N (院基）-， 其中烷基包括本文所描述或定義之任何烷基部分。 於該式⑴化合物之另一較佳體系中，A係_N(芳基院 基）-，其中該芳基烷基部分包括本文所描述或定義之任何 芳基烷基J分，該方基烷基部分可經取代或未經取代。 於該式⑴化合物之另一較佳體系中，A係苄基卜， 其中該苄基部分可經取代或未經取代。 於該式（I)化合物之另一較佳體玄ώ Α 串又1土體系中，Α係-~苯基烷 基）-，其中該苯基烷基部分可經取代或未經取代。 於該式⑴化合物之另〜較佳體系中，Α係_ ，其中該苯乙基部分可經取代或未經取代。 _ 於該式⑴化合物之另—較佳體系 . ~ A係-N (苯某丙 基）-’其中該苯基丙基部分可經取代或未經取代。 -34- 200918507 於該式（I)化合物之另〜較佳體系中，A係-C(NR8)-， 其中R8係如本文所定義者。 於該式（I)化合物之另〜較佳體系中，A係_C(NH)-。 於該式（I)化合物之另〜較佳體系中，a係-C(N烷基）- 〇 於該式（I)化合物之另〜較佳體系中，A係-C(NCH3)- 〇 於該式（I)化合物之另一較佳體系中，A係-C(NCH2CH3)-。 於該式（I)化合物之另一較佳體系中，A係-C(NC(CH3)3)-。 於該式（I)化合物之另、較佳體系中，A係-C(N苯基）- 〇 於該式（I)化合物之另〜較佳體系中，A係-C(N苯基）-，其中該苯基部分係經取代。 於該式（I)化合物之另一較佳體系中，A係-C(NOH)-。 於該式（I)化合物之另一較佳體系中，A係-C(N-0烷 基）-。 於該式（I)化合物之另一較佳體系中，A係-C(N-0烷 基）-，其中該烷基部分包括本文所描述之任何烷基。 於該式（I)化合物之另一較佳體系中，A係共價鍵。 於該式⑴化合物之另一較佳體系中’ A係-CH(CN)-。 於該式（I)化合物之另一較佳體系中，R3係芳基’其 中該芳基可爲本文所描述或定義之任何芳基。 -35- 200918507 於該式（I)化合物之另一較佳體系中，R3係苯基。 於該式（I)化合物之另一較佳體系中，R3係萘基。 於該式（I)化合物之另一較佳體系中，R3係雜芳基， 其中該雜芳基可爲本文所描述或定義之任何雜芳基。 於該式（I)化合物之另一較佳體系中，R3係吡啶基。 於該式（I)化合物之另一較佳體系中，R3係2 -吡啶基 〇 於該式（I)化合物之另一較佳體系中，R3係3-吡啶基 〇 於該式（I)化合物之另一較佳體系中，R3係4-吡啶基 〇 於該式（I)化合物之另一較佳體系中，R3係吡咯甲醯 基。 於該式（I)化合物之另一較佳體系中，R3係1-吡咯甲 醯基。 於該式（I)化合物之另一較佳體系中，R3係2-吡咯甲 醯基。 於該式（I)化合物之另一較佳體系中，R3係3_吡咯甲 醯基。 於該式（I)化合物之另一較佳體系中，R3係呋喃基。 於該式（I)化合物之另一較佳體系中，R3係2 -呋喃基 〇 於該式（I)化合物之另一較佳體系中，R3係3-呋喃基 -36- 200918507 於該式（I)化合物之另一較佳體系中，R3係苯硫基。 於該式（I)化合物之另一較佳體系中，R3係2-苯硫基 〇 於該式（I)化合物之另一'較佳體系中^ R3係3 -苯硫基 0 於該式（I)化合物之另一較佳體系中，R3係吡唑基。 於該式（I)化合物之另一較佳體系中，R3係咪唑基。 於該式（I)化合物之另一較佳體系中，R3係噁唑基。 於該式（I)化合物之另一較佳體系中，R3係異噁唑基 〇 於該式（I)化合物之另一較佳體系中，R3係噻唑基。 於該式（I)化合物之另一較佳體系中，R3係噠嗪基。 於該式（I)化合物之另一較佳體系中，R3係嘧啶基。 於該式（I)化合物之另一較佳體系中，R3係吡嗪基。 於該式（I)化合物之另一較佳體系中，R3係喹啉基。 於該式（I)化合物之另一較佳體系中，R3係苯並咪唑 基。 於該式（I)化合物之另一較佳體系中，R3係吲唑基。 於該式（I)化合物之另一較佳體系中，R3係吲哚基。 於該式（I)化合物之另一較佳體系中，Z係鹵。 於該式（I)化合物之另一較佳體系中，Z係C1。 於該式（I)化合物之另一較佳體系中，Z係F。 於該式（I)化合物之另一較佳體系中，Z係各別爲F或 CM。 -37- 200918507 於該式（I)化合物之另一較佳體系中’ Z係硝基。 於該式（I)化合物之另一較佳體系中’ Z係羥基。 於該式（I)化合物之另一較佳體系中，Z係胺基。 於該式（Ό化合物之另一較佳體系中’ z係乙醯胺基。 於該式（I)化合物之另一較佳體系中’ z係三氟乙醯胺 基。 於該式（I)化合物之另一較佳體系中，z係疊氮基。 於該式（I)化合物之另一較佳體系中，Z係氰基。 於該式（I)化合物之另一較佳體系中’ z係甲醯基。 於該式（I)化合物之另一較佳體系中，Z係院基胺甲醯 基。 於該式（I)化合物之另一較佳體系中，Z係二院基胺甲 醯基。 於該式（I)化合物之另一較佳體系中，Z係垸基。 於該式（I)化合物之另一較佳體系中，Z係_ch3。 於該式（I)化合物之另一較佳體系中，Z係_Ch2ch3。 於該式（I)化合物之另一較佳體系中，Z係異丙基。 於該式（I)化合物之另一較佳體系中，Z係特丁基。 於該式（I)化合物之另一較佳體系中’ Z係烯基。 於該式（I)化合物之另一較佳體系中，Z係嫌丙基。 於該式（I)化合物之另一較佳體系中，Z係經取代之烯 基。 於該式⑴化合物之另一較佳體系中’ Z係= -38- 200918507 於該式（I)化合物之另一較佳體系中， 於該式（I)化合物之另一較佳體系中， 於該式（I)化合物之另一較佳體系中， 於該式（I)化合物之另一較佳體系中， 於該式（I)化合物之另一較佳體系中， 氧基。 於該式（I)化合物之另一較佳體系中， 〇 於該式（I)化合物之另一較佳體系中， 基。 於該式（I)化合物之另一較佳體系中，
基D 於該式（I)化合物之另一較佳體系中， 於該式（I)化合物之另一較佳體系中， 〇 於該式（I)化合物之另一較佳體系 0C(CH3)3。 於該式（I)化合物之另一較佳體系 〇CH2CH3。 於該式⑴化合物之另一較佳體系中， 經取代之環烷基。 於該式（I)化合物之另一較佳體系中， 經取代之環丙基。 於該式（I)化合物之另一較佳體系中， z係炔基。 z係院氧基。 z係甲氧基。 z係乙氧基。 Z係經取代之烷 z係三氟甲氧基 z係甲氧基乙氧 z係乙氧基甲氧 z係烷氧羰基。 Z 係- C(〇)_〇CH3 3，Z 係-C(0)_ ]，z 係(：(0)_ z係經取代或未 乙係經取代或未 乙係經取代或未 -39- 200918507 經取代之丁基。 於該式（I)化合物之另一較佳體系中，z係經取# — Μ代或未 經取代之環戊基。 於該式（I)化合物之另一較佳體系中，Ζ係經|·ν # Μ代或未 經取代之環己基。 於該式（I)化合物之另一較佳體系中，Ζ係經助# Μ代或未 經取代之環烯基。 於該式（I)化合物之另一較佳體系中，Ζ係經助 M tx或未 經取代之環丙烯基。 於該式（I)化合物之另一較佳體系中，Z係經助π _ ^ 或未 經取代之環丁烯基。 於該式（I)化合物之另一較佳體系中，Z係經的 Μ代或未 經取代之環戊烯基。 於該式（I)化合物之另一較佳體系中，ζ係經取代嘴 經取代之環己烯基。 於該式（I)化合物之另一較佳體系中，Ζ係經助# 一 I 丁 Τι似代或未 經取代之雜環基。 於該式（I)化合物之另一較佳體系中，ζ係經助# 、 __ M R或未 經取代之雜芳基。 於該式（I)化合物之另一較佳體系中，Ζ係經取 — Μ τς或未 經取代之芳基。 於該式（I)化合物之另一較佳體系中，當R3係經取、 或未經取代之含Ν雜芳基時，ζ係氧化物，使得ρ 3 丨人κ -2：係 經取代或未經取代之含Ν雜芳基的Ν-氧化物。 ' -40- 200918507 於該式（I)化合物之任一前述較佳體系（其中z係特定 或一般定義者）中，η係至少爲1且R3可選擇地經非特別 定義之Ζ的其他基取代。例如，於—較佳體系（其中ζ係 鹵）中，R3可選擇地包括至少—個非爲鹵之額外基ζ。可 替代地，R3可包括多個（超過1個）該較佳體系中所特定或 一般定義之Ζ基。因此’若Ζ係鹵，該較佳體系包括經鹵 單、二、三取代等之R3。 於該式（I)化合物之另一較佳體系中，η係2。 於該式（I)化合物之另一較佳體系中，η係2且Ζ係選 自鹵、院基、氰基、-CH2-CH2-CN 或-CH = CH-CN。 於該式（I)化合物之另一較佳體系中，η係2且Z係院 基及/或氰基。 於該式（I)化合物之另一較佳體系中，η係2且Ζ係烷 基及/或鹵。 於該式（I)化合物之另一較佳體系中，η係2且Ζ係烷 基及/或CI。 於該式（I)化合物之另一較佳體系中，η係2且Ζ係烷 基及/或 於該式（I)化合物之另一較佳體系中，η係2且Z係鹵 及/或氰基。 於該式（I)化合物之另—較佳體系中，η係2且Ζ係C1 及/或氰基。
於該式（I)化合物之另一較佳體系中，η係2且Ζ係F 及/或氰基。 -41 - 200918507 於該式（I)化合物之另一較佳體系中，η係2且Z係烷 基。 於該式（I)化合物之另一較佳體系中，η係2且Z係鹵 〇 於該式（I)化合物之另一較佳體系中，η係2且Ζ係C1 〇
於該式（I)化合物之另一較佳體系中，η係2且冗係F 〇 於該式⑴化合物之另一較佳體系中，η係2且Ζ係C1 或F。 於該式⑴化合物之另一較佳體系中，D係共價鍵。 於該式⑴化合物之另一較佳體系中，D係烷撐基。 於該式（I)化合物之另一較佳體系中，D係-CH2-。 於該式（I)化合物之另一較佳體系中，D係-CH2CH2-。 於該式（I)化合物之另一較佳體系中，D係-CH2CH2CH2-。 於該式（I)化合物之另一較佳體系中，D係-C H (C Η 3)- ο 於該式（I)化合物之另一較佳體系中，D係-C(CH3)2-。 於該式（I)化合物之另一較佳體系中，D係-CH2-環丙 撐基-CH2-。 於該式（I)化合物之另一較佳體系中，D係烯撐基。 於該式（I)化合物之另一較佳體系中，D係-CH = CH-。 於該式⑴化合物之另一較佳體系中，〇係- -42 - 200918507 CH2CH = CH-。 於該式（I)化合物之另一較佳體系中，D係-CH = CHCH2-。 於該式（I)化合物之另一較佳體系中，D係-CH2CH = CHCH2-。 於該式（I)化合物之另一較佳體系中，D係-CH = CHCH2CH2-。 於該式（I)化合物之另一較佳體系中，D係-CH2CH2CH = CH-。 於該式（I)化合物之另一較佳體系中，D係-CH2CH = CHCH2-。 於該式（I)化合物之另一較佳體系中，D係-(CH3)C = CH-。 於該式（I)化合物之另一較佳體系中，D係-CH2CH = C(CH3)-。 於該式（I)化合物之另一較佳體系中，D係-(CH3)C = CHCH2-。 於該式（I)化合物之另一較佳體系中，D係-CH2C(CH3) = CHCH2-。 於該式（I)化合物之另一較佳體系中，D係-C(CH3) = CHCH2CH2-。 於該式（I)化合物之另一較佳體系中，D係-CH2CH2C(CH3) = CH-。 於該式（I)化合物之另一較佳體系中，〇係- -43- 200918507 CH2C(CH3) = CHCH2 — 於該式（I)化合物之另一較佳體系中，D係-CH = C(CH3)-。 於該式（I)化合物之另一較佳體系中，D係-CH2CH = C(CH3)-。 於該式（I)化合物之另一較佳體系中，〇係-CH = C(CH3)CH2-。 於該式（I)化合物之另一較佳體系中，D係-CH2CH = C(CH3)CH2-。 於該式（I)化合物之另一較佳體系中，D係-CH = C(CH3)CH2CH2-。 於該式（I)化合物之另一較佳體系中，D係-CH2CH2CH = C(CH3)-。 於該式（I)化合物之另一較佳體系中，D係-CH2CH = C(CH3)CH2-。 於該式（I)化合物之另一較佳體系中，D係炔撐基。 於該式（I)化合物之另一較佳體系中，D係-C = C-。 於該式⑴化合物之另一較佳體系中，D係-CH2C^C-。 於該式（I)化合物之另一較佳體系中，D係-CH2CH2C = C-。 於該式（I)化合物之另一較佳體系中，D係-C = CCH2-。 於該式（I)化合物之另一較佳體系中，D係-C = CCH2CH2-。 於該式（I)化合物之另一較佳體系中，0係- -44- 200918507 CH2ChCCH2-。 於該式（I)化合物之另一較佳體系中，0係-CH2CH2CsCCH2-。 於該式（I)化合物之另一較佳體系中，0係-CH2CeCCH2CH2-。 於該式⑴化合物之另一較佳體系中，r1係H ’唯其D 不爲共價鍵。 於該式⑴化合物之另一較佳體系中，R1係烷基，其 中該烷基可包括本文所定義或描述之任何烷基。 於該式⑴化合物之另一較佳體系中’ r1係-CH3。 於該式（I)化合物之另一較佳體系中，Rl係_CH2CH3。 於該式（I)化合物之另一較佳體系中，R1係異丙基。 於該式（I)化合物之另一較佳體系中，R1係特丁基。 於該式⑴化合物之另一較佳體系中，R1係鹵。 於該式⑴化合物之另一較佳體系中，R1係C1。 於該式（I)化合物之另一較佳體系中，R1係F。 於該式（I )化合物之另一較佳體系中，R 1係經取代或 未經取代之環烷基。 於該式（I)化合物之另一較佳體系中，R1係經取代或 未經取代之環丙基。 於該式（I)化合物之另一較佳體系中，R1係經取代或 未經取代之環丁基。 於該式（I)化合物之另一較佳體系中，R1係經取代或 未經取代之環戊基。 -45 - 200918507 R係經取代或 於該式（I)化合物之另一較佳體系中 未經取代之環己基。 於該式（I)化合物之另一較佳體系中，r1 於該式（I)化合物之另一較佳體系中，r1 於該式（I)化合物之另一較佳體系中，Rl 於該式（I)化合物之另一較佳體系中，Rl 係羥基。 係烷氧基。 R1係甲氧基。 係乙氧基。 於該式⑴化合物之另一較佳體系中，Rl係丁氧基。 於該式（I)化合物之另一較佳體系中，Rl係異丙氧基 〇 於該式（I)化合物之另一較佳體系中，Rl係特丁氧基 〇 於該式（I)化合物之另一較佳體系中，R 1係烯基。 於該式（I)化合物之另一較佳體系中，R1係烯丙基。 於該式⑴化合物之另一較佳體系中，R1係炔基。 於該式（I)化合物之另一較佳體系中，Rl係炔丙基。 於該式（I)化合物之另一較佳體系中，R】係氰基。 於該式（I)化合物之另一較佳體系中，Rl係^⑴卜 N(R7)2。 於該式（I)化合物之另一較佳體系中，Rl係_C(〇)_ N(R7)2，其中R7係如本文所定義者。 於該式（I)化合物之另一較佳體系中，Rl係_c(0)_NH2 0 於該式⑴化合物之另一較佳體系中，Rl係_〇_C(〇)_ N(R7)2。 -46 - 200918507 於該式（I)化合物之另一較佳體系中，R1係-0_C(0)-N(R7)2，其中R7係如本文所定義者。 於該式⑴化合物之另一較佳體系中，R1係-〇-C(〇)- NH2。 於該式⑴化合物之另一較佳體系中，R1係雜環基。 於該式（I)化合物之另一較佳體系中，R1係經取代之 雜環基。 於該式⑴化合物之另一較佳體系中’ R1係四氫呋喃 基。 於該式⑴化合物之另一較佳體系中’ R1係環氧丙烷 基。 於該式⑴化合物之另一較佳體系中，Rl係-c(0)-0烷 基。
於該式⑴化合物之另一較佳體系中’ R1係-C (0) -0烷 基，其中該烷基部分包括本文所定義或描述之任何烷基。 於該式⑴化合物之另一較佳體系中，R1係- C(0)_0H 〇 於該式（I)化合物之另一較佳體系中，Rl係甲矽烷氧 基。 於該式⑴化合物之另一較佳體系中’ Rl係- osi(烷基 )3 〇 於該式（I)化合物之另一較佳體系中’ Rl係經取代或 未經取代之-〇Si(烷基）2芳基° 於該式（I)化合物之另一較佳體系中’ R 1係經取代或 -47- 200918507 未經取代之-〇si(芳基）2烷基。 於該式（I)化合物之另一較佳體系中’ R1係經取代或 未經取代之-〇si(芳基）3。 於該式（I)化合物之另一較佳體系中，R1係-〇-烷撐基-oh，其中該烷撐基係本文所定義或描述之任何烷撐基。 於該式（I)化合物之另一較佳體系中’ R1係-〇-烷撐基-〇 -醯基，其中該烷撐基係本文所定義或描述之任何烷撐基 ，且酿基係如本文所定義者。 於該式（I)化合物之另一較佳體系中，R1係-s(〇)2_ N(R7)2，其中R7係如本文所定義者。 於該式（I)化合物之另一較佳體系中’ R2係鹵。 於該式（I)化合物之另一較佳體系中’ R2係ci。 於該式（I)化合物之另一較佳體系中，R2係F。 於該式⑴化合物之另一較佳體系中，R2係硝基。 於該式（I)化合物之另一較佳體系中’ R2係氰基。 於該式（I)化合物之另一較佳體系中，R2係烷基。 於該式⑴化合物之另一較佳體系中’ R2係-ch3。 於該式（I)化合物之另一較佳體系中’ R2係- ch2ch3。 於該式⑴化合物之另一較佳體系中，R2係-ch2ch2ch3 〇 於該式⑴化合物之另一較佳體系中’ R2係異丙基。 於該式（I)化合物之另一較佳體系中，R2係丁基。 於該式（I)化合物之另一較佳體系中，R2係特丁基。 於該式（I)化合物之另一較佳體系中’ R2係經取代之 -48- 200918507 烷基。 於該式（I)化合物之另一較佳體系中，R2係烷氧基烷 基。 於該式（I)化合物之另一較佳體系中，R2係甲氧基乙 基。 於該式（I)化合物之另一較佳體系中，R2係乙氧基乙 基。 於該式（I)化合物之另一較佳體系中，R2係乙氧基甲 基。 於該式（I)化合物之另一較佳體系中，R2係羥基烷基 〇 於該式（I)化合物之另一較佳體系中，R2係烯基。 於該式（I)化合物之另一較佳體系中，R2係烯丙基。 於該式（I)化合物之另一較佳體系中，R2係經取代之 稀基。 於該式（I)化合物之另一較佳體系中，R2係經鹵取代 之稀基。 於該式（I)化合物之另一較佳體系中，R2係炔基。 於該式⑴化合物之另一較佳體系中，R2係炔丙基。 於該式（I)化合物之另一較佳體系中，R2係經取代之 炔基。 於該式（I)化合物之另一較佳體系中，R2係烷氧羰基 〇 於該式（I)化合物之另一'較佳體系中* R2係- C(0)-0- -49- 200918507 CH3。 於該式（I)化合物之另一較佳體系中 CH2CH3。 於該式（I)化合物之另一較佳體系中 C(CH3)3。 於該式⑴化合物之另一較佳體系中 CH(CH3)2。 於該式（I)化合物之另一較佳體系中 其中R7係如本文所定義者。 於該式⑴化合物之另一較佳體系中 醯基。 於該式（I)化合物之另一較佳體系中 NH-CH3。 於該式（I)化合物之另一較佳體系中 甲醯基。 於該式（I)化合物之另一較佳體系中 N(CH3)2。 於該式（I)化合物之另一較佳體系中’ 於該式⑴化合物之另一較佳體系中， 於該式（I)化合物之另一較佳體系中’ 於該式（I)化合物之另一較佳體系中， 於該式（I)化合物之另一較佳體系中’ 於該式（I)化合物之另一較佳體系中 環烷基。 ’ R2 係-c(o)-〇-’ R 係-C(0)-〇· ’ R 係-〇(〇)-〇· ，R2 係-N(R7)2， ’ R2係烷基胺甲 ’ R2 係-O-C(o)- ，R2係二烷基胺 ’ R2 係·〇-(：(〇)- R2係環烷基。 R2係環丙基。 R2係環丁基。 R2係環戊基。 R2係環己基。 ，R2係經取代之 -50- 200918507 於該式（I)化合物之另一較佳體系中，R2係經取代之 環丙基。 於該式（I)化合物之另一較佳體系中，R2係經取代之 環丁基。 於該式（I)化合物之另一較佳體系中，R2係經取代之 環戊基。 於該式（I)化合物之另一較佳體系中，R2係經取代之 環己基。 於該式（I)化合物之另一較佳體系中，R2係芳基烷基 〇 於該式（I)化合物之另一較佳體系中，R2係苄基。 於該式（I)化合物之另一較佳體系中，R2係苯乙基。 於該式（I)化合物之另一較佳體系中，R2係經取代之 芳基烷基。 於該式（I)化合物之另一較佳體系中，R2係經取代之 苄基。 於該式（I)化合物之另一較佳體系中，R2係經取代之 苯乙基。 於該式（I)化合物之另一較佳體系中，R3係芳基。 於該式（I)化合物之另一較佳體系中，R3係苯基。 於該式（I)化合物之另一較佳體系中，R3係雜芳基。 於該式（I)化合物之另一較佳體系中，R3係單環雜芳 基。 於該式（I)化合物之另一較佳體系中，R3係雙環雜芳 -51 - 200918507 基。 於該式（I)化合物之另一較佳體系中，R3係選自
於該式（I)化合物之另一較佳體系中，R3-(Z)n係選自
於該式（I)化合物之另一較佳體系中，R4係Η。 於該式（I)化合物之另一較佳體系中，R4係烷基。 於該式（I)化合物之另一較佳體系中，R4係甲基。 於該式（I)化合物之另一較佳體系中，R4係乙基。 於該式（I)化合物之另一較佳體系中，R4係異丙基。 於該式（I)化合物之另一較佳體系中，R4係丙基。 於該式（I)化合物之另一較佳體系中，R4係丁基。 於該式（I)化合物之另一較佳體系中，R4係另丁基。 於該式（I)化合物之另一較佳體系中，R4係特丁基。 於該式（I)化合物之另一較佳體系中，R4係戊基。 -52- 200918507 於該式（I)化合物之另一較佳體系中，R4係己基。 於該式（I)化合物之另一較佳體系中，R4係經取代之 院基。 於該式（I)化合物之另一較佳體系中，R4係鹵烷基。 於該式（I)化合物之另一較佳體系中，R4係環烷基。 於該式（I)化合物之另一較佳體系中，R4係環丙基。 於該式（I)化合物之另一較佳體系中，R4係環丁基。 於該式（I)化合物之另一較佳體系中，R4係環戊基。 於該式（I)化合物之另一較佳體系中，R4係環己基。 於該式（I)化合物之另一較佳體系中，R4係經取代之 環院基。 於該式（I)化合物之另一較佳體系中，R4係經取代之 環垸基。 於該式（I)化合物之另一較佳體系中，R4係經取代之 環丙基。 於該式（I)化合物之另一較佳體系中，R4係經取代之 環丁基。 於該式（I)化合物之另一較佳體系中，R4係經取代之 環戊基。 於該式（I)化合物之另一較佳體系中，R4係經取代之 環己基。 於該式（I)化合物之另一較佳體系中，R4係羥基烷基 〇 於該式（I)化合物之另一較佳體系中，R4係羥基甲基 -53- 200918507 於該式（I)化合物之另一較佳體系中，R4係羥基乙基 〇 於該式（I)化合物之另一較佳體系中，R4係羥基丙基 〇 於該式（I)化合物之另一較佳體系中，R4係羥基丁基 〇 於該式（I)化合物之另一較佳體系中，R4係烷氧基烷 基。 於該式（I)化合物之另一較佳體系中，R4係甲氧基乙 基。 於該式（I)化合物之另一較佳體系中，R4係乙氧基甲 基。 於該式（I)化合物之另一較佳體系中，R4係乙氧基乙 基。 於該式（I)化合物之另一較佳體系中，R4係特丁氧基 乙基。 於該式（I)化合物之另一較佳體系中，R4係芳基烷基 〇 於該式⑴化合物之另一較佳體系中，R4係苄基。 於該式（I)化合物之另一較佳體系中，R4係苯乙基。 於該式（I)化合物之另一較佳體系中，R4係經取代之 芳基烷基。 於該式（I)化合物之另一較佳體系中，R4係經取代之 -54- 200918507 苄基。 於該式（I)化合物之另一較佳體系中，R4係經取代之 苯乙基。 於該式（I)化合物之另一較佳體系中，A係-C(O)-且R2 係烷基。 於該式（I)化合物之另一較佳體系中，A係-C(O)-且R2 係甲基。 於該式（I)化合物之另一較佳體系中，A係-C(O)-且R2 係乙基。 於該式（I)化合物之另一較佳體系中，A係-C(O)-且R2 係丙基。 於該式（I)化合物之另一較佳體系中，A係-C(O)-且R2 係異丙基。 於該式（I)化合物之另一較佳體系中，A係-C(O)-且R2 係丁基。 於該式（I)化合物之另一較佳體系中，A係-C(O)-且R2 係特丁基。 於該式（I)化合物之另一較佳體系中，A係共價鍵且 R2係烷基。 於該式（I)化合物之另一較佳體系中，A係共價鍵且 R2係甲基。 於該式（I)化合物之另一較佳體系中，A係共價鍵且 R2係乙基。 於該式（I)化合物之另一較佳體系中，A係共價鍵且 -55- 200918507 R2係丙基。 於該式（I)化合物之另一較佳體系中，A係共價鍵且 R2係異丙基。 於該式（I)化合物之另一較佳體系中，A係共價鍵且 R2係丁基。 於該式（I)化合物之另一較佳體系中，A係共價鍵且 R2係特丁基。 於該式（I)化合物之另一較佳體系中，A係-C(O)-且R3 係苯基。 於該式（I)化合物之另一較佳體系中，A係-C(O)-，R3 係苯基且η係2。 於該式⑴化合物之另一較佳體系中，Α係-C(O)-，R3 係苯基，η係2且每個Z係烷基。 於該式⑴化合物之另一較佳體系中，Α係-C(O)-，R3 係苯基，：η係2且每個Z係甲基。 於該式（I)化合物之另一較佳體系中，Α係-C(O)-，R3 係苯基，η係2，一個Z係烷基且另一 Z係氰基。 於該式（I)化合物之另一較佳體系中，Α係-C(O)-，R3 係苯基，η係2，一個Z係甲基且另一 Z係氰基。 於該式⑴化合物之另一較佳體系中，Α係-C(O)-，R3 係苯基，η係2，一個Z係乙基且另一 Z係氰基。 於該式⑴化合物之另一較佳體系中，Α係-C(O)-，R3 係苯基，η係2，一個Z係丙基且另一 Z係氰基。 於該式（I)化合物之另一較佳體系中，Α係- C(O)-且 -56- 200918507 113-2„係3,5-二經取代之苯基。 於該式⑴化合物之另一較佳體系中，A係-C(O)-，R3-Zn係3,5-二經取代之苯基且R2係烷基。 於該式⑴化合物之另一較佳體系中，A係- C(O)-，R3-Zn係3,5-二經取代之苯基且R2係甲基。 於該式⑴化合物之另一較佳體系中，A係- C(O)-，R3-Zn係3,5-二經取代之苯基且R2係乙基。 於該式（I)化合物之另一較佳體系中，A係-C(O)-，R3-Zn係3,5-二經取代之苯基且R2係丙基。 於該式（I)化合物之另一較佳體系中，A係-C(〇)-，R3-Zn係3,5-二經取代之苯基且R2係異丙基。 於該式⑴化合物之另一較佳體系中，A係-C(O)-，R3-Zn係3, 5-二經取代之苯基且R2係丁基。 於該式（I)化合物之另一較佳體系中，A係-C(O)-，R3-Zn係3,5 -二經取代之苯基且R2係特丁基。 於該式（I)化合物之另一較佳體系中，A係共價鍵且 R3係芳基或雜芳基。 於該式（I)化合物之另一較佳體系中，A係共價鍵，R3 係芳基或雜芳基且η係2。 於該式（I)化合物之另一較佳體系中，Α係共價鍵，R3 係芳基或雜芳基，η係2且每個Z係烷基。 於該式（I)化合物之另一較佳體系中，Α係共價鍵，R3 係芳基或雜芳基，η係2且每個Z係甲基。 於該式（I)化合物之另一較佳體系中，Α係共價鍵，R3 -57- 200918507 係芳基或雜芳基’ n係2，一個Z係院基且另一 Z係氰基 〇 於該式（I)化合物之另一較佳體系中’ A係共價鍵’ R3 係芳基或雜芳基’ n係2’ 一個z係甲基且另一 Z係氰基 〇 於該式⑴化合物之另一較佳體系中’ A係共價鍵’ R3 係芳基或雜芳基’η係2’ 一個Z係乙基且另—Z係氰基 〇 於該式⑴化合物之另一較佳體系中’ Α係共價鍵，R3 係芳基或雜芳基，n係2，一個Z係丙基且另一 Z係氰基 σ 於該式⑴化合物之另一較佳體系中，Α係共價鍵且 R3係選自苯基、萘基、吡啶基、吡略甲醯基、咲喃基、苯 硫基、啦B坐基、咪D坐基、嚼哩基、異嚼Π坐基、噻Π坐基、噠 嗪基、嘧啶基、吡嗪基、喹啉基、苯並咪唑基 '吲唑基或 吲哚基。 於該式⑴化合物之另一較佳體系中’ Α係共價鍵’ R 3 係選自苯基、萘基、吡11定基、耻略甲醯基 '肤喃基、苯硫 基、吡唑基、咪唑基、噁唑基、異噁唑基、噻唑基、噠基 、嘧啶基、吡嗪基、喹啉基、苯並咪唑基、吲唑基或吲哚 基，且每個Z係各別爲院基、氰基或鹵。 於該式（I)化合物之另一較佳體系中，A係共價鍵’ R3 係選自苯基、萘基、吡D定基、吡咯甲醯基、呋喃基、苯硫 基、吡唑基、咪唑基、噁唑基、異噁唑基' 噻唑基、噠嗪 -58- 200918507 基、嘧啶基、吡嗪基、喹啉基'苯並咪唑基、吲唑基或吲 哚基，η係2，且每個Z係各別爲烷基、氰基或鹵。 於該式⑴化合物之另一較佳體系中，Α係-C(O)- ’ R3 係選自苯基、萘基、吡啶基、吡咯甲醯基、呋喃基、苯硫 基、吡唑基、咪唑基、噁唑基、異噁唑基、噻唑基、噠嗪 基、嘧啶基、吡嗪基、喹啉基、苯並咪唑基、吲唑基或吲 哚基，且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係-C(O)-，R3 係選自苯基、萘基、吡啶基、吡咯甲醯基、呋喃基、苯硫 基、吡唑基、咪唑基、噁唑基、異噁唑基' 噻唑基、噠嗪 基、嘧啶基、吡嗪基、喹啉基、苯並咪唑基 '吲唑基或吲 哚基，每個Z係各別爲烷基、氰基或鹵，且R4係Η。 於該式⑴化合物之另一較佳體系中，Α係_C(0)-，R3 係選自苯基、萘基、吡啶基、吡咯甲醯基、呋喃基、苯硫 基、吡唑基、咪唑基、噁唑基、異噁唑基、噻唑基、噠曉 基、嘧啶基、吡嗪基、喹咐基、苯並咪唑基、吲唑基或口引 哄基，η係2，毎個Z係各別爲院基、氛基或_ ’且R4係 Η。 於該式（I)化合物之另一較佳體系中，Α係-0- ’ R3係 選自苯基、萘基、吡啶基、吡咯甲醯基、呋喃基、苯硫基 、吡唑基、咪唑基、噁唑基、異噁唑基、噻唑基、噠嗪基 、嘧啶基、吡嗪基、喹啉基、苯並咪唑基、吲唑基或卩引噪 基，且R4係Η。 於該式⑴化合物之另—較佳體系中’ Α係R3係 -59- 200918507 選自苯基、萘基、吡啶基、吡咯甲醯基、呋喃基、苯硫基 、吡唑基、咪唑基、噁唑基、異噁唑基、唾唑基、噠嗪基 、嘧啶基、吡嗪基、喹啉基、苯並咪唑基、吲唑基或吲哚 基，每個z係各別爲烷基、氰基或鹵，且R4係Η。 於該式⑴化合物之另—較佳體系中，Α係-0-，R3係 選自苯基、萘基、吡啶基、吡咯甲醯基、呋喃基、苯硫基 、吡唑基、咪唑基、噁唑基、異噁唑基、噻唑基、噠嗪基 、嘧啶基、吡嗪基、喹啉基、苯並咪唑基、吲唑基或吲哚 基，η係2，每個Z係各別爲烷基、氰基或鹵，且R4係Η 〇 於該式（I)化合物之另一較佳體系中，Α係-NR5-，R3 係選自苯基、萘基、吡啶基、吡咯甲醯基、呋喃基、苯硫 基、吡唑基、咪唑基、噁唑基、異噁唑基' 噻唑基、噠嗪 基、嘧啶基、吡嗪基、喹啉基、苯並咪唑基、吲唑基或Π引 哚基，且R4係η。 於該式⑴化合物之另一較佳體系中，Α係-NR5-，R3 係選自苯基、萘基、吡啶基、吡咯甲醯基、呋喃基、苯硫 基、吡唑基、咪哇基、噁唑基、異噁唑基、噻唑基、噠嗪 基、喃症基、批嗪基、喹啉基、苯並咪哩基、吲唑基或口引 哚基，每個Z係各別爲烷基、氰基或鹵，且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係-NR5-，R3 係選自苯基、萘基、吡啶基 '吡咯甲醯基、呋喃基、苯硫 基、吡唑基、咪唑基、噁唑基、異噁唑基、噻唑基、噠嗪 基、嘧啶基、毗嗪基、喹啉基、苯並咪唑基、吲唑基或Π引 -60- 200918507 哚基，η係2，每個Z係各別爲烷基、氰基或鹵’且以係 Η。 於該式⑴化合物之另一較佳體系中’ A係-S-’ R3係 選自苯基、萘基、毗啶基、吡咯甲醯基、呋喃基、苯硫基 、吡唑基、咪唑基、噁唑基、異噁唑基、噻唑基、噠嗪基 、嘧啶基、吡嗪基、喹啉基、苯並咪唑基、吲唑基或吲哚 基，且R4係Η。 於該式（I)化合物之另一較佳體系中’ Α係-s - ’ r3係 選自苯基、萘基、吡啶基、吡咯甲醯基、呋喃基、苯硫基 、吡唑基、咪唑基、噁唑基、異噁唑基、噻唑基、噠嗪基 、嘧啶基、吡嗪基、喹啉基、苯並咪唑基、吲唑基或吲哚 基，每個Z係各別爲烷基、氰基或鹵，且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係-S-，R3係 選自苯基、萘基、吡啶基、吡咯甲醯基、呋喃基、苯硫基 、吡唑基、咪唑基、噁唑基、異噁唑基、噻唑基、嚏嗪基 、嘧啶基 '吡嗪基' 喹咻基、苯並咪唑基、吲唑基或吲哚 基，η係2，每個Z係各別爲烷基、氰基或鹵，且R4係Η 〇 於該式⑴化合物之另一較佳體系中，Α係- C(〇)-，R2 係烷基且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係- C(〇)-，R2 係甲基且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係-C(〇)-’ R2 係乙基且R4係Η。 -61 - 200918507 於該式（I)化合物之另一較佳體系中，A係-C(0)-，R2 係丙基且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係-C(O)-，R2 係異丙基且R4係Η。 於該式⑴化合物之另一較佳體系中，Α係- C(O)-，R2 係丁基且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係-C(O)-，R2 係特丁基且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係共價鍵，R2 係烷基且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係共價鍵，R2 係甲基且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係共價鍵，R2 係乙基且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係共價鍵，R2 係丙基且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係共價鍵，R2 係異丙基且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係共價鍵，R2 係丁基且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係共價鍵，R2 係特丁基且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係-C(O)-，R3 係苯基且R4係Η。 -62- 200918507 於該式⑴化合物之另一較佳體系中，A係-C(0)-，R3 係苯基，η係2且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係-C(O)-，R3 係苯基，η係2，每個Z係烷基，且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係-C(O)-，R3 係苯基，η係2，每個Z係甲基，且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係-C(O)-，R3 係苯基，η係2，一個Z係烷基，另一個Z係氰基，且R4 係Η。 於該式（I)化合物之另一較佳體系中，Α係-C(O)-，R3 係苯基，η係2，一個Z係甲基，另一個Z係氰基，且R4 係Η。 於該式（I)化合物之另一較佳體系中，Α係-C(O)-，R3 係苯基，η係2，一個Z係乙基，另一個Z係氰基，且R4 係Η。 於該式⑴化合物之另一較佳體系中，Α係-C(O)-，R3 係苯基，η係2，一個Z係丙基，另一個Z係氰基，且R4 係Η。 於該式⑴化合物之另一較佳體系中，Α係-C(O)-，R3-Zn係3,5-二經取代之苯基，且R4係Η。 於該式⑴化合物之另一較佳體系中，Α係-C(O)-，R3-Zn係3,5-二經取代之苯基，R2係烷基，且R4係Η。 於該式⑴化合物之另一較佳體系中，Α係- C(O)-，R3-Zn係3,5-二經取代之苯基，R2係甲基，且R4係Η。 -63- 200918507 於該式（I)化合物之另一較佳體系中’ A係-C(O)-’ R3-Zn係3,5-二經取代之苯基，R2係乙基，且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係-C(0)_，R3-乙11係3,5-二經取代之苯基，112係丙基，且114係11。 於該式⑴化合物之另一較佳體系中，A係-C(O)-，R3-Zn係3,5-二經取代之苯基，R2係異丙基，且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係-C(O)-，R3-Zn係3,5-二經取代之苯基，R2係丁基，且R4係Η。 於該式⑴化合物之另一較佳體系中，Α係-C(O)-，R3-Zn係3,5 -二經取代之苯基，R2係特丁基，且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係共價鍵，R3 係芳基或雜芳基，且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係共價鍵，R3 係芳基或雜芳基，η係2，且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係共價鍵，R3 係芳基或雜芳基，η係2，每個Z係烷基，且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係共價鍵，R3 係芳基或雜芳基，η係2，每個Z係甲基，且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係共價鍵，R3 係芳基或雜芳基，η係2，一個Z係烷基，另一個Z係氰 基，且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係共價鍵，R3 係芳基或雜芳基，η係2，一個Z係甲基，另一個Z係氰 基，且R4係Η。 -64- 200918507 於該式（I)化合物之另一較佳體系中，A係共價鍵，R3 係芳基或雜芳基，η係2，一個Z係乙基，另一個Z係氰 基，且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係共價鍵，R3 係芳基或雜芳基，η係2，一個Z係丙基，另一個Z係氰 基，且R4係Η。 於該式⑴化合物之另一較佳體系中，Α係共價鍵，R3 係選自苯基、萘基、吡啶基、吡咯甲醯基、呋喃基、苯硫 基、吡唑基、咪唑基、噁唑基、異噁嗖基、噻唑基、噠嗪 基、嘧啶基、吡嗪基、喹啉基、苯並咪唑基、吲唑基或吲 哚基，且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係共價鍵，R3 係選自苯基、萘基、吡啶基、吡咯甲醯基、呋喃基、苯硫 基、吡唑基、咪唑基、噁唑基、異噁嗖基、噻唑基、噠嗪 基、嘧啶基、吡嗪基、喹啉基、苯並咪唑基、吲唑基或吲 哚基，每個Z係各別爲烷基、氰基或鹵，且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係共價鍵，R3 係選自苯基、萘基、吡啶基、吡咯甲醯基、呋喃基、苯硫 基、吡唑基、咪唑基、噁唑基、異噁唑基、噻唑基、噠嗪 基、嘧啶基、吡嗪基、喹啉基、苯並咪唑基、吲唑基或吲 噪基’ η係2«每個Z係各別爲院基、氛基或鹵，且R4係 Η。 於該式⑴化合物之另一較佳體系中，Α係-0-且R2係 烷基。 -65- 200918507 於該式（I)化合物之另一較佳體系中，A係-Ο-且R2係 甲基。 於該式（I)化合物之另一較佳體系中，A係-0-且R2係 乙基。 於該式（I)化合物之另一較佳體系中，A係-0-且R2係 丙基。 於該式（I)化合物之另一較佳體系中，A係-0-且R2係 異丙基。 於該式（I)化合物之另一較佳體系中，A係-0-且R2係 丁基。 於該式（I)化合物之另一較佳體系中，A係-0-且R2係 特丁基。 於該式（I)化合物之另一較佳體系中，A係-0-且R3係 苯基。 於該式（I)化合物之另一較佳體系中，A係-0-，R3係 苯基，且η係2。 於該式（I)化合物之另一較佳體系中，Α係-0-，R3係 苯基，η係2，且每個Z係烷基。 於該式（I)化合物之另一較佳體系中，Α係-0-，R3係 苯基，η係2，且每個Z係甲基。 於該式（I)化合物之另一較佳體系中，Α係-0-，R3係 苯基，η係2，一個Z係烷基，且另一個Z係氰基。 於該式（I)化合物之另一較佳體系中，Α係-0-，R3係 苯基，η係2，一個Z係甲基，且另一個Z係氰基。 -66- 200918507 於該式（I)化合物之另一較佳體系中，A係-Ο-，R3係 苯基，η係2，一個Z係乙基，且另一個Z係氰基。 於該式（I)化合物之另一較佳體系中，Α係-0-，R3係 苯基，η係2，一個Z係丙基，且另一個Z係氰基。 於該式（I)化合物之另一較佳體系中，Α係-0-且R3-Zn 係3,5 -二經取代之苯基。 於該式（I)化合物之另一較佳體系中，A係·0-，R3-Zn 係3,5-二經取代之苯基，且R2係烷基。 於該式（I)化合物之另一較佳體系中，A係-0-，R3-Zn 係3，5 -二經取代之苯基，且R2係甲基。 於該式（I)化合物之另一較佳體系中’ A係R3-Zn 係3,5-二經取代之苯基，且R2係乙基。 於該式⑴化合物之另一較佳體系中，A係·0-，R3-Zn 係3,5-二經取代之苯基，且R2係丙基。 於該式（I)化合物之另一較佳體系中，A係-0-，R3-Zn 係3,5-二經取代之苯基，且R2係異丙基。 於該式（I)化合物之另一較佳體系中，A係-0-，R3-Zn 係3,5-二經取代之苯基，且R2係丁基。 於該式（I)化合物之另一較佳體系中，A係-0-，R3-Zn 係3，5-二經取代之苯基，且R2係特丁基。 於該式（I)化合物之另一較佳體系中，A係-0-，R2係 烷基且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係-0-，R2係 甲基且R4係Η。 -67- 200918507 於該式（I)化合物之另一較佳體系中，A係-Ο-，R2係 乙基且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係-0-，R2係 丙基且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係-Ο -，R2係 異丙基且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係-0-，R2係 丁基且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係-0-，R2係 特丁基且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係-0-，R3係 苯基且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係-0-，R3係 苯基，η係2，且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係-0-，R3係 苯基，η係2，每個Z係烷基，且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係-0-，R3係 苯基，η係2，每個Z係甲基，且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係-0-，R3係 苯基，η係2，一個Z係烷基，另一個Z係氰基，且R4係 Η。 於該式（I)化合物之另一較佳體系中，Α係-0-，R3係 苯基，η係2，一個Z係甲基，另一個Z係氰基，且R4係 Η。 -68- 200918507 於該式（I)化合物之另一較佳體系中，A係-Ο-，R3係 苯基，η係2，一個Z係乙基，另一個Z係氰基，且R4係 Η。 於該式（I)化合物之另一較佳體系中，Α係-0-，R3係 苯基，η係2，一個Z係丙基，另一個Z係氰基，且R4係 Η。 於該式（I)化合物之另一較佳體系中，Α係-0-，R3-Zn 係3，5 -二經取代之苯基，且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係-0-，R3-Zn 係3,5 -二經取代之苯基，R2係烷基，且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係-0-，R3-Zn 係3，5-二經取代之苯基，R2係甲基，且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係-0-，R3-Zn 係3,5-二經取代之苯基，R2係乙基，且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係-0-，R3-Zn 係3,5-二經取代之苯基，R2係丙基，且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係-0-，R3-Zn 係3,5-二經取代之苯基，R2係異丙基，且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係-0-，R3-Zn 係3,5-二經取代之苯基，R2係丁基，且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係-0-，R3-Zn 係3，5 -二經取代之苯基，R2係特丁基，且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係-ΝΗ-且R2 係烷基。 -69- 200918507 於該式（I)化合物之另一較佳體系中，A係-NH-且R2 係甲基。 於該式（I)化合物之另一較佳體系中，A係-NH-且R2 係乙基。 於該式（I)化合物之另一較佳體系中，A係-NH-且R2 係丙基。 於該式（I)化合物之另一較佳體系中，A係-NH-且R2 係異丙基。 於該式（I)化合物之另一較佳體系中，A係-NH-且R2 係丁基。 於該式（I)化合物之另一較佳體系中，A係-NH-且R2 係特丁基。 於該式（I)化合物之另一較佳體系中，A係-NH-且R3 係苯基。 於該式（I)化合物之另一較佳體系中，A係-NH-，R3 係苯基且η係2。 於該式⑴化合物之另一較佳體系中，Α係-ΝΗ-，R3 係苯基，η係2，且每個Z係烷基。 於該式（I)化合物之另一較佳體系中，Α係-ΝΗ-，R3 係苯基，η係2，且每個Z係甲基。 於該式（I)化合物之另一較佳體系中，Α係-ΝΗ-，R3 係苯基，η係2，一個Z係烷基，且另一個Z係氰基。 於該式（I)化合物之另一較佳體系中，Α係-ΝΗ-，R3 係苯基，η係2，一個Z係甲基，且另一個Z係氰基。 -70- 200918507 於該式（I)化合物之另一較佳體系中，A係-NH-，R3 係苯基，η係2，一個Z係乙基，且另一個Z係氰基。 於該式（I)化合物之另一較佳體系中，A係-NH-，R3 係苯基，η係2，一個Z係丙基，且另一個Z係氰基。 於該式（I)化合物之另一較佳體系中，Α係-ΝΗ-且R3-Zn係3,5-二經取代之苯基。 於該式（I)化合物之另一較佳體系中，A係-NH-，R3-Zn係3,5-二經取代之苯基，且R2係烷基。 於該式⑴化合物之另一較佳體系中，A係-NH-，R3-Zn係3,5-二經取代之苯基，且R2係甲基。 於該式⑴化合物之另一較佳體系中，A係-NH-，R3-Z n係3，5 -二經取代之苯基，且R2係乙基。 於該式（I)化合物之另一較佳體系中，Α係-NH-，R3-Zn係3,5-二經取代之苯基，且R2係丙基。 於該式⑴化合物之另一較佳體系中，A係-NH-，R3-Zn係3,5-二經取代之苯基，且R2係異丙基。 於該式（I)化合物之另一較佳體系中，A係-NH-，R3-Zn係3,5-二經取代之苯基，且R2係丁基。 於該式（I)化合物之另一較佳體系中，A係-NH-，R3-Zn係3,5-二經取代之苯基，且R2係特丁基。 於該式（I)化合物之另一較佳體系中，A係-NH-，R2 係烷基且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係-NH-，R2 係甲基且R4係Η。 -71 - 200918507 於該式（I)化合物之另一較佳體系中，A係-NH-，R2 係乙基且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係-NH-，R2 係丙基且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係-NH-，R2 係異丙基且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係-NH-，R2 係丁基且R4係Η。 於該式⑴化合物之另一較佳體系中，Α係-NH-，R2 係特丁基且R4係Η。 於該式⑴化合物之另一較佳體系中，Α係-NH-，R3 係苯基且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係-NH-，R3 係苯基，η係2，且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係-NH-，R3 係苯基，η係2，每個Z係烷基，且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係-NH-，R3 係苯基，η係2，每個Z係甲基，且R4係Η。 於該式⑴化合物之另一較佳體系中，Α係-NH-，R3 係苯基，η係2，一個Z係烷基，另一個Z係氰基，且R4 係Η。 於該式⑴化合物之另一較佳體系中，Α係-NH-，R3 係苯基，η係2，一個Z係甲基，另一個Z係氰基，且R4 係Η。 -72 - 200918507 於該式（I)化合物之另一較佳體系中，A係-NH-，R3 係苯基，η係2，一個Z係乙基，另一個Z係氰基，且R4 係Η。 於該式（I)化合物之另一較佳體系中，Α係-NH-，R3 係苯基，η係2，一個Z係丙基，另一個Z係氰基，且R4 係Η。 於該式（I)化合物之另一較佳體系中，Α係-NH-，R3-Zn係3 , 5 -二經取代之苯基，且R4係Η。 於該式⑴化合物之另一較佳體系中，Α係-NH-，R3-Zn係3，5 -二經取代之苯基，R2係烷基，且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係-NH-，R3-工11係3,5-二經取代之苯基，112係甲基，且114係：《。 於該式（I)化合物之另一較佳體系中，A係-NH-，R3-Z n係3，5 -二經取代之苯基，R2係乙基，且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係-NH-，R3_ Zn係3,5-二經取代之苯基，R2係丙基，且R4係Η。 於該式⑴化合物之另一較佳體系中，Α係-NH-，R3-Zn係3,5-二經取代之苯基，R2係異丙基，且R4係Η。 於該式⑴化合物之另一較佳體系中，Α係-NH-，R3-Zn係3,5-二經取代之苯基，R2係丁基，且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係-NH-，R3-Zn係3,5 -二經取代之苯基，R2係特丁基，且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係-CF2-且R2 係烷基。 -73- 200918507 於該式（I)化合物之另一較佳體系中，A係-CF2-且R2 係甲基。 於該式（I)化合物之另一較佳體系中，A係-CF2-且R2 係乙基。 於該式（I)化合物之另一較佳體系中，A係-CF2-且R2 係丙基。 於該式（I)化合物之另一較佳體系中，A係-CF2-且R2 係異丙基。 於該式（I)化合物之另一較佳體系中，A係-CF2-且R2 係丁基。 於該式（I)化合物之另一較佳體系中，A係-CF2-且R2 係特丁基。 於該式（I)化合物之另一較佳體系中，A係-CF2-且R3 係苯基。 於該式（I)化合物之另一較佳體系中，A係-CF2-，R3 係苯基且η係2。 於該式（I)化合物之另一較佳體系中，Α係-CF2-，R3 係苯基，η係2，且每個Z係烷基。 於該式⑴化合物之另一較佳體系中，Α係-CF2-，R3 係苯基，η係2，且每個Z係甲基。 於該式（I)化合物之另一較佳體系中，Α係-CF2-，R3 係苯基，η係2，一個Z係烷基，且另一個Z係氰基。 於該式（I)化合物之另一較佳體系中，Α係-CF2-，R3 係苯基，η係2，一個Z係甲基，且另一個Z係氰基。 -74- 200918507 於該式（I)化合物之另一較佳體系中，A係-CF2-，R3 係苯基，η係2，一個Z係乙基，且另一個Z係氰基。 於該式（I)化合物之另一較佳體系中，A係- CF2-，R3 係苯基，η係2，一個Z係丙基，且另一個Z係氰基。 於該式（I)化合物之另一較佳體系中，Α係- CF2-且R3-Zn係3,5-二經取代之苯基。 於該式（I)化合物之另一較佳體系中，A係-CF2-，R3-Zn係3,5-二經取代之苯基，且R2係烷基。 於該式⑴化合物之另一較佳體系中，A係-CF2-，R3-Zn係3,5-二經取代之苯基，且R2係甲基。 於該式（I)化合物之另一較佳體系中，A係-CF2-，R3-Zn係3,5-二經取代之苯基，且R2係乙基。 於該式（I)化合物之另一較佳體系中，A係-CF2-，R3-Zn係3,5-二經取代之苯基，且R2係丙基。 於該式（I)化合物之另一較佳體系中，A係-CF2-，R3-Zn係3，5-二經取代之苯基，且R2係異丙基。 於該式⑴化合物之另一較佳體系中，A係-CF2-，R3-Ζπ係3,5-二經取代之苯基，且R2係丁基。 於該式（I)化合物之另一較佳體系中，A係-C F 2 -，R3· Zn係3,5 -二經取代之苯基，且R2係特丁基。 於該式（I)化合物之另一較佳體系中，A係-CF2-，R2 係烷基且R4係Η。 於該式⑴化合物之另一較佳體系中，Α係- CF2-，R2 係甲基且R4係Η。 -75- 200918507 於該式（I)化合物之另一較佳體系中，A係-CF2-，R2 係乙基且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係-CF2-，R2 係丙基且R4係Η。 於該式⑴化合物之另一較佳體系中，Α係-CF2-，R2 係異丙基且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係-CF2-，R2 係丁基且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係-CF2-，R2 係特丁基且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係-CF2-，R3 係苯基且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係-CF2-，R3 係苯基，η係2，且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係-CF2-，R3 係苯基，η係2，每個Z係烷基，且R4係Η。 於該式⑴化合物之另一較佳體系中，Α係-CF2-，R3 係苯基，η係2，每個Z係甲基，且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係-CF2-，R3 係苯基，η係2，一個Z係烷基，另一個Z係氰基，且R4 係Η。 於該式⑴化合物之另一較佳體系中，Α係-CF2-，R3 係苯基，η係2，一個Z係甲基，另一個Z係氰基，且R4 係Η。 -76- 200918507 於該式⑴化合物之另一較佳體系中，A係- CF2-，R3 係苯基，η係2，一個Z係乙基，另一個Z係氰基，且R4 係Η。 於該式⑴化合物之另一較佳體系中，Α係-CF2-，R3 係苯基，η係2，一個Z係丙基，另一個Z係氰基，且R4 係Η。 於該式（I)化合物之另一較佳體系中，Α係-CF2-，R3-Zn係3,5-二經取代之苯基，且R4係Η。 於該式⑴化合物之另一較佳體系中，Α係-CF2-，R3-Zn係3，5 -二經取代之苯基，R2係烷基，且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係- CF2-，R3-Zn係3,5-二經取代之苯基，R2係甲基，且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係-CF2-，R3-Zn係3,5-二經取代之苯基，R2係乙基，且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係-CF2-，R3-Zn係3,5-二經取代之苯基，R2係丙基，且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係-CF2-，R3-Zn係3,5-二經取代之苯基，R2係異丙基，且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係-CF2-，R3-Zn係3,5_二經取代之苯基，R2係丁基，且R4係Η。 於該式（I)化合物之另一較佳體系中，Α係- CF2-，R3-Zn係3，5 -二經取代之苯基，R2係特丁基，且R4係Η。
於該式（I)化合物之另一較佳體系中，Α係-C(O)，R3-Zn係3,5-二經取代之苯基，R2係烷基，R4係Η，X和Y -77- 200918507 皆爲Ο，且-D-R1係Η。 於該式（I)化合物之另一較佳體系中，Α係-C(O)，R3-Zn係3,5-二經取代之苯基，R2係烷基，R4係Η，X和Y 皆爲〇，且-D-R1係烷基。 於該式⑴化合物之另一較佳體系中，Α係-C(O)，R3-Zn係3,5 -二經取代之苯基，R2係烷基，R4係Η，X和Y 皆爲0’且-D-R1係鹵院基。 於該式⑴化合物之另一較佳體系中，Α係-C(O)，R3-Zn係3,5-二經取代之苯基，R2係烷基，R4係Η，X和Y 皆爲0，且-D-R1係環烷基烷基。 於該式（I)化合物之另一較佳體系中，Α係-C(0)，R3-Zn係3,5-二經取代之苯基，R2係烷基，R4係Η，X和Y 皆爲Ο，且-D-R1係羥基烷基。 於該式（I)化合物之另一較佳體系中，Α係- C(O)，R3-Zn係3,5-二經取代之苯基，R2係烷基，R4係Η，X和Y 皆爲0，且-D-R1係氰基烷基。 於該式⑴化合物之另一較佳體系中，Α係-C(O)，R3-Zn係3,5-二經取代之苯基，R2係烷基，R4係Η，X和Y 皆爲〇，且-D-R1係-烷撐基- C(0)-N(R7)2。 於該式⑴化合物之另一較佳體系中，A係-C(O)，R3-Zn係3,5-二經取代之苯基，R2係烷基，R4係Η，X和Y 皆爲0，且-D-R1係烷氧基烷基。
於該式⑴化合物之另一較佳體系中，Α係-C(O)，R3-Zn係3，5 -二經取代之苯基，R2係烷基，R4係Η，X和Y -78 - 200918507 皆爲Ο ’且-D-R1係炔基。 於該式（I)化合物之另〜較佳體系中，A係_c(〇)，r3_ Zn係3,5-—經取代之苯基，r2係烷基，r4係H , χ和γ 皆爲Ο，且-D-R1係-炔撐基-環丙基。 於該式⑴化合物之另一較佳體系中，A係_c(〇)，r3_ Zn係3,5_一經取代之苯基，r2係烷基，r4係H，χ和γ 皆爲Ο，且-D-R1係羥基炔基。 於該式（I)化合物之另〜較佳體系中，A係^⑴），r3_ Zn係3,5-—經取代之苯基，R2係烷基，r4係Η，χ和γ 皆爲0，且-D-R1係烯基。 於該式（I)化合物之另〜較佳體系中，Α係-C(O)，R3-Zn係3,5-二經取代之苯基’ R2係烷基，R4係η，χ和γ 皆爲〇，且-D-R1係鹵烯基。 於該式（I)化合物之另一較佳體系中，Α係-C(O)，R3-Zn係3,5-二經取代之苯基’ r2係烷基，r4係η，χ和γ 皆爲〇 ’且-D-R1係經取代或未經取代之雜環基烷基。 於該式（I)化合物之另一較佳體系中，Α係-C(O)，R3-2„係3,5-二經取代之苯基，112係烷基，114係11，\和丫 皆爲 〇，且-D-R1 係-CH2-環丙撐基-CH2-C(0)-0CH3。 於該式（I)化合物之另一較佳體系中’ a係-C(O)，R3-Zn係3,5-二經取代之苯基，R2係烷基，R4係Η，X和Y 皆爲 0,且-D-R1 係-CH2-環丙撐基-CH2-C(0)-0H。
於該式（I)化合物之另一較佳體系中，a係-c(〇)，r3_ Zn係3,5-二經取代之苯基，R2係烷基，R4係Η，X和Y -79- 200918507 皆爲 〇，且-D-R1 係-CH2-環丙撐基-CH2-C(0)-NH(PMB)。 於該式（I)化合物之另一較佳體系中，A係-C(O)，R3-乙11係3,5-二經取代之苯基，112係烷基，114係11，\和丫 皆爲〇，且- D-R1係-烷撐基- C(0)-N(R7)2。 於該式⑴化合物之另一較佳體系中，A係-C(O)，R3-211係3,5-二經取代之苯基，尺2係烷基，114係11，乂和丫 皆爲 〇，且-D-R1 係-CH2-環丙撐基-CH2-C(0)-NH2。 於該式（I)化合物之另一較佳體系中，A係-C(O)，R3-211係3,5-二經取代之苯基，112係烷基，114係11，乂和丫 皆爲 〇，且-D-R1 係-CH2-CH2-0-C(0)-0CH3。 於該式（I)化合物之另一較佳體系中，A係- C(O)，R3-2„係3,5-二經取代之苯基，112係烷基，114係1^，又和丫 皆爲0，且-D-R1係-烷撐基- C(0)-N(R7)2。 於該式（I)化合物之另一較佳體系中，A係-C(O)，R3-Zn係3,5-二經取代之苯基，R2係烷基，R4係Η，X和Y 皆爲0，且-D-R1係-烯撐基- C(0)-0R7。 於該式（I)化合物之另一較佳體系中，A係-C(O)，R3-Zn係3,5-二經取代之苯基，R2係烷基，R4係Η，X和Y 皆爲〇，且-D-R1係-烯撐基- C(0)-N(R7)2。 於該式（I)化合物之另一較佳體系中，A係- C(O)，R3-Zn係3,5-二經取代之苯基，R2係烷基，R4係Η，X和Y 皆爲 〇，且-D-R1 係-CH2-CH = CH-C(0)-NH2。 於該式（I)化合物之另一較佳體系中，A係共價鍵，R3 係芳基或雜芳基，R2係烷基，R4係Η，X和Y皆爲0， -80- 200918507 且-D - R1 係 Η。 於該式（I)化合物之另一較佳體系中，Α係共價鍵，R3 係芳基或雜芳基，Z係烷基、氰基或鹵，R2係烷基，R4係 Η，X和Y皆爲0，且-D-R1係H。 於該式（I)化合物之另一較佳體系中，A係共價鍵，R3 係芳基或雜芳基，Z係烷基、氰基或齒，η係2，R2係烷 基，R4係Η，X和Υ皆爲0，且-D-R1係Η。 於該式（I)化合物之另一較佳體系中，Α係共價鍵，R3 係芳基或雜芳基，R2係烷基，R4係Η，X和Y皆爲Ο， 且-D - R 1係烷基。 於該式（I)化合物之另一較佳體系中，Α係共價鍵，R3 係芳基或雜芳基，R2係烷基，R4係Η，X和Y皆爲Ο， 且-D - R 1係烷基。 於該式（I)化合物之另一較佳體系中，Α係共價鍵，R3 係芳基或雜芳基，Z係烷基、氰基或鹵，R2係烷基，R4係 Η，X和Y皆爲0，且-D-R1係烷基。 於該式（I)化合物之另一較佳體系中，A係共價鍵，R3 係芳基或雜芳基，R2係烷基，R4係Η，X和Y皆爲Ο， 且-D-R1係鹵烷基。 於該式（I)化合物之另一較佳體系中，Α係共價鍵，R3 係芳基或雜芳基，Z係烷基、氰基或鹵，R2係烷基，R4係 Η，X和Y皆爲0，且-D-R1係鹵烷基。 於該式（I)化合物之另一較佳體系中，A係共價鍵，R3 係芳基或雜芳基，Z係烷基、氰基或鹵，η係2，R2係烷 -81 - 200918507 基，R4係Η，X和Y皆爲〇 ’且-D-R1係鹵烷基。 於該式（I)化合物之另一較佳體系中’ D係烷撐基、烯 撐基或炔撐基。 再於另一較佳體系中’該式（I)化合物具有下述式（la) 之結構：
(la) 其中 X、Y、A、D、R2、R3、R4、R5、r6 及 R7 係如上述 式（1)所定義者，且每個Z1係各別選自鹵 '硝基、羥基、 胺基、乙醯胺基、三氟乙醯胺基' 疊氮基、氰基、甲醯基 、燒基、經取代之烷基、烷基胺甲醯基、二烷基胺甲醯基 、燦基、經取代之烯基、炔基、經取代之炔基、烷氧基、 糸二取代之烷氧基、烷氧羰基、環烷基、經取代之環烷基、 環燦基、經取代之環烯基、雜環基、經取代之雜環基、芳 基、經取代之芳基或氧化物·，且Z2係選自鹵 '硝基、羥 基、胺基、乙醯胺基、三氟乙醯胺基、疊氮基、氰基、甲 酸基、i：兀基肢甲酿基、二院基胺甲醯基、稀基、經取代之 烯基、炔基、經取代之炔基、烷氧基、經取代之烷氧基、 烷氧羰基、環烷基、經取代之環烷基、環烯基、經取代之 及少希基、雜環基、經取代之雜環基、芳基、經取代之芳基 -82- 200918507 或氧化物；η係0至3之整數；且R4和-D-R1中僅一者係 Η。 再於另一較佳體系中，該式（I)化合物或其藥學上可接 受之鹽、溶劑化物及/或酯具有選自下述之結構：
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醫藥調製劑 本發明之化合物係經慣用之載體和賦形劑調製，該等 載體和賦形劑之選用係依據一般之實務。藥片將含有賦形 -88- 200918507 劑、滑動劑、塡料、結合劑及類似者°製備無菌狀態之水 溶性調製劑，且當欲經由非口服之方式投遞時’該水溶性 調製劑通常將具有等滲性。所有調製劑將可選擇地含有賦 开多齊ί ，諸如文獻 Handbook of Pharmaceutical Excipients (1986)所揭示者，該文獻之全部內容係倂入本文作爲參考 。賦形劑包括抗壞血酸和其他抗氧化劑、螯合劑（諸如 EDTA)、碳水化合物（諸如糊精）、羥基烷基纖維素、羥基 烷基甲基纖維素、硬脂酸及類似者。該調製劑之pH係介 於約3至約1 1，但一般係約7至1 〇。 雖然可單獨投服該活性成分，但是較佳的是該活性成 分係呈醫藥調製劑之型式。本發明之調製劑（供獸醫用和 人體用兩者）包含至少一種上述定義之活性成分和一或多 種可接受之載體及可選擇地其他治療成分。該等載體必須 是“可接受者”係意謂著與該調製劑之其他成分互溶且對接 受者係生理上無害。 該調製劑包括適用於上述投藥途徑者。該調製劑可方 便地呈單位劑量型式且可藉由藥學技藝所習知之任何方法 加以製備。技術和調製方式通常係見於文獻Remington、 Pharmaceutical Sciences (Mack Publishing Co., Easton， Pa.) ’該文獻之全部內容係倂入本文作爲參考。該等方法 包括致使該活性成分與載體締合之步驟，該載體構成一或 多種輔助成分。通常’製備該調製劑係藉由均勻且緊密地 致使該活性成分與液體載體或微細分開之固體載體或該二 者締合且隨後如有需要係使產物成形。 -89- 200918507 適用於口服投藥的本發明之調製劑可呈分開之單位（ 諸如膠囊、藥包或藥片，每個單位含有預定含量之該活性 成分；粉末或顆粒；於水溶性或非水溶性液體中之溶液或 懸浮液；或水包油液體乳化液或油包水液體乳化液）。該 活性成分亦可以大九藥、舐劑或糊劑之方式投服。 藉由壓縮或模塑且可選擇地與一或多種輔助成分以製 備藥片。製備壓縮藥片可藉由使用適當之機器以壓縮呈自 由流動型式（諸如粉末或顆粒）之活性成分及可選擇地經混 合之結合劑、潤滑劑、惰性稀釋劑、防腐劑、界面活性劑 或分散劑。製備模塑藥片可藉由使用適當之機器以模塑經 惰性液體稀釋劑濕潤之粉末狀活性成分的混合物。該藥片 可選擇地經塗覆或經修整且可選擇地經調製以提供該活性 成分之緩慢或控制釋出。 對眼或其他外部組織（例如口和皮膚）之投藥，該調製 劑較佳地係含有該活性成分之局部用軟膏或乳霜，其中該 活性成分之量係例如0.075至20重量％(其包括該活性成 分之量介於0.1至20重量％且增量爲0.1重量％，諸如〇.6 重量％、0.7重量％等），較佳地係〇 · 2至1 5重量％且最佳 地係〇 . 5至1 0重量％。當調製爲軟膏時，該活性成分可使 用石蠟或與水互溶之軟膏底質。可替代地，該活性成分可 與水包油乳霜底質經調製爲乳霜。 如所欲地，該乳霜底質之水相可包括例如至少3 0重 量％之多元醇（即含有兩個或多個羥基之醇，諸如丙二醇、 丁 -1，3-二醇 '甘露糖醇 '山梨糖醇 '甘油及聚乙二醇（包 -90- 200918507 括PEG 400)及彼等之混合物）。該局部用調製劑可如 地包括能促進該活性成分之吸收或滲透皮膚或其他受 區域的化合物。該皮膚滲透促進劑之實例包括二甲亞 相關類似物。 可以習知之方式自習知之成分構成本發明之乳化 油相。雖然該油相可僅包含乳化劑，但是該油相可如 地包含至少一種乳化劑與脂或油或與脂和油之混合物 佳的係包括親水性乳化劑及作爲安定劑之親油性乳化 亦爲較佳的是包括油和脂。同時，含有安定劑或不含 定劑之乳化劑製造所謂之乳化蠟，且該乳化蠟與該油 一起製造所謂之乳化軟膏底質，該乳化軟膏底質形成 霜調製劑之油分散相。 適用於本發明之調製劑的乳化劑和乳化安定劑 Tween® 6 0、S p an ® 80、鯨蠟芳基醇、苄醇、十四烷 單硬脂酸甘油酯及十二烷基硫酸鈉。 用於調製之適當的油或脂之選擇係基於達到所欲 容性質。該乳霜較佳地應爲非油脂性、非染劑性且爲 洗之產物，該產物具有適當之稠度以避免自管或其他 漏出。可使用直鏈或支鏈之單價或二價烷基酯，諸如 己二酸酯、硬脂酸異十六烷酯、椰子脂肪酸之丙二醇 、十四烷酸異丙酯、油酸癸酯、十六烷酸異丙酯、硬 丁酯、十六院酸2 -乙基己酯或已知爲Crodamol CAP 鏈酯的摻合物，其中最後三者係較佳之酯。取決於所 性質，該等酯可單獨使用或結合使用。可替代地，使 所欲 影響 楓及 液的 所欲 。較 劑。 有安 和脂 該乳 包括 醇、 之美 可沖 容器 二異 二酯 脂酸 之支 需之 用闻 -91 - 200918507 熔點液體，諸如白軟石蠟及/或液體石蠟或其他礦物油。 本發明之醫藥調製劑包含一或多種本發明之化合物和 —或多種藥學上可接受之載體或賦形劑及可選擇地其他治 療劑。含有該活性成分之醫藥調製劑可呈適用於所欲投服 方法之任何型式。當用於口服時，可製備例如藥片、片劑 、錠劑、水溶性或油性懸浮劑、可分散之粉末或顆粒、乳 化液、硬膠囊或軟膠囊、糖漿或酏劑。可依據此技藝所習 知之製備醫藥組成物的任何方法以製備口服組成物且該口 服組成物可含有一或多種包括甜味劑、芳香劑、著色劑及 防腐劑之藥劑以提供可口之製劑。混合該活性成分與適合 藥片製造之非毒性的藥學上可接受之賦形劑的藥片係可接 受的。該等賦形劑可爲例如惰性稀釋劑（諸如碳酸鈣或碳 酸鈉、乳糖、乳糖單水合物、交聯羧甲基纖維素鈉、聚乙 烯吡咯啶酮、磷酸鈣或磷酸鈉）；顆粒劑和崩解劑（諸如玉 米澱粉或藻朊酸）；結合劑（諸如纖維素、微結晶纖維素、 澱粉、明膠或金合歡膠）；及潤滑劑（諸如硬脂酸鎂、硬脂 酸或滑石）。藥片可未經塗覆或可藉由習知技術（包括微膠 囊化技術）加以塗覆以遲延於胃腸道中之崩解和吸收，因 而提供較長時間之持續作用。例如，可使用時間遲延材料 ，諸如單獨之單硬脂酸甘油酯或二硬脂酸甘油酯或彼與蠟 之混合物。 口服調製劑亦可呈硬明膠膠囊（其中該活性成分係與 惰性固體稀釋劑（例如磷酸鈣或高嶺土）混合）或軟明膠膠囊 (其中該活性成分係與水或油性介質（諸如花生油、液體石 -92- 200918507 蠟或橄欖油）混合）之型式。 本發明之水溶性懸浮液混合有該活性成分和適用於製 備水溶性懸浮液之賦形劑。該賦形劑包括懸浮劑（諸如羧 甲基纖維素鈉、甲基纖維素、羥丙基甲基纖維素、藻朊酸 鈉、聚乙烯吡咯啶酮、黃蓍膠及金合歡膠）及分散劑或濕 潤劑（諸如天然存在之磷脂（例如卵磷脂）、烯化氧與脂肪酸 之縮合產物（例如硬脂酸聚氧化乙烯酯）、環氧乙烷與長鏈 脂肪族醇之縮合產物（例如十七乙烯氧十六烷醇）、環氧乙 烷與衍生自脂肪酸和己糖醇酐的部分酯之縮合產物（例如 聚氧乙烯山梨糖醇酐單油酸酯））。該水溶性懸浮液亦可含 有一或多種防腐劑（諸如正羥基苯甲酸乙酯或正羥基苯甲 酸正丙酯）、一或多種著色劑、一或多種芳香劑及一或多 種甜味劑（諸如蔗糖或糖精）。 藉由令該活性成分懸浮於植物油（諸如花生油、橄欖 油、芝麻油或椰子油）或礦物油（諸如液體石蠟）中，可調製 油懸浮劑。該口服懸浮劑可含有增稠劑，諸如蜂蠟、硬石 蠟或十六烷醇。可加入甜味劑（諸如本文所說明者）和芳香 劑以提供可口之口服製劑。可藉由加入抗氧化劑（諸如抗 壞血酸）使該等組成物防腐。 本發明之藉由加入水以適於製備水溶性懸浮劑的可分 散之粉末和顆粒係提供混合該活性成分與分散劑或濕潤劑 、懸浮劑及一或多種防腐劑。適當之分散劑或濕潤劑及懸 浮劑係如前述所例示者。亦可存有額外之賦形劑，例如甜 味劑、芳香劑及著色劑。 -93- 200918507 本發明之醫藥組成物亦可呈水包油乳化液之型式。該 油相可爲植物油（諸如橄欖油或花生油）、礦物油（諸如液體 石蠟）或彼等之混合物。適當之乳化劑包括天然存在之膠（ 諸如金合歡膠和黃蓍膠）、天然存在之磷脂（諸如大豆卵磷 脂）、自脂肪酸和己糖醇酐衍生之酯或部分酯（諸如山梨糖 醇酐單油酸酯）及該部分酯與環氧乙烷之縮合產物（例如聚 氧乙烯山梨糖醇酐單油酸酯）。該乳化液亦可含有甜味劑 和芳香劑。利用甜味劑（諸如甘油、山梨糖醇或蔗糖）可調 製成糖漿和酏劑。該調製劑亦可含有潤藥、防腐劑、芳香 劑或著色劑。 本發明之醫藥組成物可呈無菌可注射製劑之型式，諸 如無菌可注射之水溶性或含油之懸浮液。依據習知技藝並 使用本文已述及之適當分散劑或濕潤劑及懸浮劑可調劑該 懸浮液。該無菌可注射製劑亦可爲非毒性、非經腸之可接 受的稀釋劑或溶劑之無菌可注射溶液或懸浮液（諸如1,3-丁-二醇之溶液）或可經製備爲冷凍乾燥之粉末。可使用之 可接受的載體和溶劑係水、Ringer氏溶液及等滲氯化鈉溶 液。此外，無菌固定油可慣常地作爲溶劑或懸浮基質。爲 此目的，可使用任何無刺激性之固定油，其包括合成之甘 油單酸酯或甘油二酸酯。此外，同樣地可使用脂肪酸（諸 如油酸）以製備可注射製劑。 可與載體物質結合以製備單一劑型之活性成分的量將 會依欲治療之宿主和特定之投藥模式而改變。例如，欲用 於人體之口服投藥的經時釋出調製劑可含有與適當且方便 -94- 200918507 用量之載體物質混合的約1至1000 mg活性物質，其中該 載體物質可占全部組成物（重量）之約5至約9 5重量％。可 製備該醫藥組成物以提供供投藥之可易於測量的用量。例 如，欲供靜脈內輸液之水溶液可含有約3至5 0 0 μ g活性 成分/毫升溶液，致使適當體積之輸液速率可爲約30 ml/ 小時。 適用於對眼投藥之調製劑包括眼滴液，其中活性成分 係溶解或懸浮於適當之載體中，特別是該活性成分之水溶 性溶劑。該調製劑中之該活性成分的濃度較佳地係0.5至 20%，有益地係0.5至10%且特別地係約1.5%重量/重量 (w/w) 〇 適用於經口局部投藥之調製劑包括錠劑（其包含於芳 香性底質（通常爲蔗糖、金合歡膠或黃蓍膠）中之該活性成 分）、片齊彳（其包含於惰性底質（諸如明膠和甘油或蔗糖和金 合歡膠）中之該活性成分）及漱口液（其包含於適當液體載體 中之該活性成分）。 供經直腸投藥之調製劑可爲與適當底質（其包含例如 椰子油或水楊酸酯）之栓劑。 適於肺內或經鼻投藥之調製劑的顆粒大小係例如介於 0.1至500 μπι (其包括顆粒大小介於0.1至500 μιη且該顆 粒大小增量係諸如〇-5 μιη' 1 μιη、30 μπι、35 μιη等）’目. 該調製劑之投服係藉由通過鼻通道之迅速吸入或藉由通過 口之吸入以達到肺泡囊。適當之調製劑包括該活性成分之 水溶液或油溶液。依據慣用之方法可製備適用於氣溶膠或 -95- 200918507 乾粉末投藥之調製劑且該調製劑可與其他治療劑（諸如 今用於治療或預防本文所述之感染的化合物）一起投藥。 適用於陰道投藥之調製劑可爲陰道栓劑、止血墊、 霜、凝膠、糊劑、泡沬或噴霧調製劑，其含有該活性成 及此技藝習知之適當載體。 適用於非經腸投藥之調製劑包括水溶性和非水溶性 無菌注射溶液（該等溶液可含有抗氧化劑、緩衝液、制 劑及使該調製劑與所欲接受者之血液等滲的溶質）及水 性和非水溶性之無菌懸浮液（其可包括懸浮劑和增稠劑 該調製劑係存在於單一劑量或多重劑量之容器（例 密封之安瓿和小瓶）中且可儲存於冷凍乾燥之條件下， 立即使用前僅需添加無菌液體載體（例如注射用水）。自 述型式之無菌粉末、顆粒及藥片製備臨時使用之注射溶 和懸浮液。較佳之單位劑量調製劑係含有該活性成分之 述每日劑量或單位每日次劑量者或彼等之適當部分。 應當瞭解的是，除了前揭特別述及之成分之外，本 明之調製劑可包括關於討論中之調製劑類型的相關技藝 使用之其他藥劑，例如適用於口服投藥之調製劑可包括 香劑。 本發明進一步提供獸醫用組成物，其包含至少一種 述之活性成分及獸醫用載體。 獸醫用載體係用於投服該組成物之物質且可爲固體 液體或氣體物質，該等物質在另一方面係呈惰性或爲獸 技藝所能接受者且能與該活性成分互溶。該等獸醫用組 迄 乳 分 之 菌 溶 如 於 前 液 上 發 所 芳 上 醫 成 -96- 200918507 物可經口服、非經腸或任何其他所欲途徑投藥。 本發明之化合物亦可經調製以提供該活性成分之控制 性釋出，藉以允許較少次數之投藥或改善該活性成分之藥 物動力輪廓或毒性輪廓。於是，本發明亦提供組成物，其 包含經調製以供持續性釋出或控制性釋出的本發明之一或 多種化合物。 活性成分之有效劑量至少取決於將被治療之病症的本 性、毒性、是否該化合物係被用於治療性預防（較低劑量） 或拮抗活性疾病或病症、投藥方法及醫藥調製劑，且將由 臨床醫師利用慣用之劑量漸增硏究加以決定。可預期的是 該有效劑量係約0.000 1至約100 mg/kg體重/天，典型地 係約0.01至約10 mg/kg體重/天，更典型地係約0.01至 約5 mg/kg體重/天且再更典型地係約〇.〇5至約0.5 mg/kg 體重/天。例如，對約70 kg體重之成人的每日候選劑量係 屬1 mg至1000 mg之範圍或介於5 mg至500 mg且可爲 單一或多重劑量之型式。 於另一較佳體系中，本申請案提供一種醫藥組成物， 其包含治療上有效量之式（I)化合物或其藥學上可接受之鹽 、溶劑化物及/或酯及藥學上可接受之載體。 於另一較佳體系中，本申請案提供一種醫藥組成物， 其包含治療上有效量之式（I)化合物或其藥學上可接受之鹽 、溶劑化物及/或酯、至少一種額外之活性治療劑及藥學 上可接受之載體。 -97- 200918507 HIV組合治療 於一較佳體系中’適當組合之非限制性實例包括本發 明之一或多種化合物與一或多種HIV蛋白酶抑制劑、HIV 反轉錄酶之非核苷抑制劑、HIV反轉錄酶之核苷抑制劑、 HIV反轉錄酶之核苷酸抑制劑、HIV整合酶抑制劑、gp41 抑制劑、CXCR4抑制劑、gpl20抑制劑、G6PD和NADH 氧化酶抑制劑、CCR5抑制劑、CCR8抑制劑、進入抑制劑 、RNase Η抑制劑、成熟抑制劑、藥物動力增強劑、治療 HIV之其他藥劑及上述之任何組合的組合。 更特定地，本發明之一或多種化合物可與一或多種選 自下述之化合物組合： 1) HIV蛋白酶抑制劑，例如安潑那韋（amprenavir) (Agenerase)、阿扎那韋（atazanavir)(Reyataz)、福沙普利 那韋(fosamprenavir)(Lexiva )、節地那韋（indinavir) (Crixivan)、洛匹那韋（lopinavir)、利托那韋（ritonavir) (norvir)、奈非那韋（nelfinavir)(Viracept)、沙奎那韋 (saquinavir)(Invirase)、替拉那韋（tipranavir)(Aptivus)、 布卡那韋（brecanavir)、地瑞那韋（darunavir)(Prezista)、 TMC-126、TMC-114、美至那韋（mozenavir)(DMP-450)、 JE-2 147 (AG 1 776)、L - 7 5 6 4 2 3、RO 0 3 3 4 6 4 9、KNI - 2 7 2、 DPC-681、DPC-684、DG17、GS-8 3 74、MK-8122 (PPL-100)、DG35、AG 1 85 9、SPI-25 6、TMC 5 23 90、PL- 3 3 7、 SM-3 223 7 7、SM-3 095 1 5、GRL-0203 1、CRS -074、CRS-075 、 KB-98 及 A-790742 ; -98- 200918507
2) HIV反轉錄酶之非核苷抑制劑，例如卡波韋林 (capravirine)、艾咪韋林（emivirine)、戴拉凡地平 (delaviridine)(Rescriptor)、依法韋侖（efavirenz)(Sustiva) 、奈韋拉平（nevirapine)(Viramune)、（ + )-綿毛胡桐內酯 A (calanolide A)、綿毛胡桐內酯 B (calanolide B)、依曲韋 林（etravirine)(Intelence)、GW5 63 4、DPC-0 8 3、DPC-961 、DPC- 963、MIV-150、MIV-160、MIV-170、大匹韋林 (dapivirine)(TMC-120)、拉皮韋林（rilpivirine)(TMC-278) 、BILR 3 5 5 BS、VRX 84 0773、UK-45 3 0 6 1、RDE A 8 06、 RDEA 427、RDEA 640 ' IDX 8 99 ' ANX-201 (Thiovir) ' R-1 206、LOC-dd、IQP-0410 (SJ-3 3 66)、YM-2 1 5 3 89、YM-22 8 8 5 5、CMX-052 及 CMX- 1 82 ； 3) HIV反轉錄酶之核苷抑制劑，例如疊氮胸苷 (Retrovir)、恩曲他濱（emtricitabine)(Emtriva)、2’，3’ -雙 去氧肌苷（Videx)、司他夫定（stavudine)(Zerit)、2’，3’ -雙 去氧胞苷（Hivid)、拉脈優定（lamivudine)(Epivir)、阿波卡 偉（abacavir)(Ziagen)、安妥嚼苷（amdoxovir)、艾非他濱 (elvucitabine)(ACH 126443)、阿洛夫定（alovudine)(MIV-310)、MIV-210、拉西卡偉（racivir)(消旋 FTC ; PSI-5004) 、D-d4FC、疊氮化磷（phosphazide)、福齊夫定替酯 (fozivudine tidoxil)、阿匹西他濱（apricitibine)(AVX754 ; SPD-754) > GS-73 40、KP-1461、AVX75 6、OBP-601、二 卩惡茂垸胸腺喃症（dioxolane thymine)、TMC-254072、INK-20 、 PPI-801、PPI-802、MIV-410、4’-Ed4T、B-108 及磷 -99- 200918507 夫定醋（fosalvudine tidoxil)(HDP 99.0003 ); 4) HIV反轉錄酶核苷酸抑制劑，例如富馬酸替諾福韋 酯（tenofovir disoproxil fumarate)(Viread)和阿德福韋酯 (adefovir dipivoxil)； 5) HIV整合酶抑制劑，例如薑黃色素、薑黃色素之衍 生物、菊苣酸、菊苣酸之衍生物、3,5 •二咖啡醯奎寧酸、 3，5 -二咖啡醯奎寧酸之衍生物、金黃三羧酸、金黃三羧酸 之衍生物、咖啡酸苯乙酯、咖啡酸苯乙酯之衍生物、酪胺 酸磷酸化抑制劑、酪胺酸磷酸化抑制劑之衍生物、櫟皮酮 、櫟皮酮之衍生物、S- 1 3 60、季特韋（zintevir)(AR-177)、 L-870812、L-870810、帕潘立酮（raltegravir)(Isentress ; MK-0518)、艾咪特拉韋（elvitegravir)(GS-9137)、BMS-5 3 8 1 5 8、GSK3 6473 5 C、BMS-70703 5、MK-2048、GSK-3 495 72 (S-3 4 9 5 72) 、 GSK-265 744 ( S-265 744) 、 G S K- 2473 03 (S-2473 03)、S- 1 3 60 (GW8 1 0 8 7 1 )、1 ,5-DCQA、 INH-001、INT-3 49、V-1 65、RIN-25、BFX-1 001、BFX-1002、BFX- 1 00 3 ' RSC-1838、BCH-33040 及 BA 011 ; 6) gp41 抑制劑，例如恩夫韋地（enfuvirtide)(Fuzeon) 、西夫韋肽（sifuvirtide)、MPI-45 1 93 6、FB 006M、A-3 29029 及 TRI-1 144； 7) CXCR4 抑制齊U ，例如 AMD-070、KRH-3 9 5 5 (CS-3 95 5)、AMD-9370、AMD-345 1、RPI - Μ N、M S X -1 2 2 及 POL-243 8 ； 8) 進入抑制劑，例如 SP01A、PA-1 61、SPC3、TNX- -100- 200918507 3 55、DES6、SP-10、S P - 0 3、C T · 3 1 9 及 CT-3 26 ； 9) gpl20抑制劑，例如 BMS-48 8 043及其前藥、 BlockAide/CR、KPC-2 及 MNLP62 ; 10) G6PD和NADH氧化酶抑制劑，例如免疫素 (immunitin)； 1 1) CCR5抑制劑，例如艾波韋羅（aplaviroc)、尼非韋 羅（nifeviroc)、偉特韋羅（vicriviroc)(sCH-4 1 7690)、馬洛 韋羅(maraviroc)(Selzentry) 、 PRO-140 、 PRO-5 42 、 INCB 1 5 0 5 0、INCB947 1、PF-23 2798、SCH-5 3 2706、GSK-706769、TAK-652、TAK-220、ESN- 196' RO- 1 752、ZM-68 8 5 23 、 AMD-887 、 YM-3 70749 、 NIBR- 1 282、 SCH- 3 5 063 4 ' ZM-6 8 8 5 23 及 CCR5mAb004 ； 12) CCR8 抑制齊ϋ ，例如 ZK-7563 2 6 ; 13) RNase H 抑制齊U，例如 ODN-93 和 ODN-112; 14) 成熟抑制劑，例如貝韋立馬（bevirimat)(PA-457) 、PA-040 、 MPC-90 5 5 (vicecon ; MPI-498 3 9) 、 ACH- 1 0 0703 及 ACH- 1 00706 ; 15) 藥物動力增強劑，例如BAS-100、SPI-452、PF- 4 1 94477、TMC-4 1 629 及紅黴素；及 16) 治療HIV之其他藥劑，例如REP 9、SP-01A、 TNX-3 5 5 ' DES6、ODN-93、ODN-112、VGV-1、阿普林津 (Ampligen)、HRG214、單選殖抗體 Cytolin、VGX-410、 VGX-820 ' KD-247 ' AMZ 0026、CYT 99007、A-221 HIV 、HPH-116、DEBIO-025、BAY 5 0-479 8、MDX010 (單選 -101 - 200918507 殖抗體 ipilimumab)、PBS 119、BIT-225、UBT-8147、 ITI-3 67、AFX-400、BL- 1 05 0、GRN- 1 3 99 5 1、GRN- 1 40665 、AX-3 8 6 79、RGB-34063 8、PPI-3 67 及 ALG 8 89。 於另一較佳體系中，本申請案提供一種組合醫藥劑， 其包含第一醫藥組成物，該第一醫藥組成物包含式（】）化合 物或其藥學上可接受之鹽 '溶劑化物及/或酯；及第二醫 藥組成物’其包含至少一種額外之活性劑，該等額外之活 性劑選自HIV蛋白酶抑制劑、HIV反轉錄酶之非核苷抑制 劑、HIV反轉錄酶之核苷抑制劑、HIV反轉錄酶之核苷酸 抑制劑、ΗIV整合酶抑制劑、g p 4 1抑制劑、C X C R 4抑制 劑、gpl20抑制劑、G6PD和NADH氧化酶抑制劑、CCR5 抑制劑、CCR8抑制劑、進入抑制劑、RNase Η抑制劑、 成熟抑制劑 '藥物動力增強劑、治療HIV之其他藥劑或上 述之任何組合。 投藥途徑 投服本發明之一或多種化合物（本文中稱爲活性成分） 係經對欲被治療之病症爲適當的任何途徑。適當之途徑包 括口服、經直腸、經鼻、局部（其包括經頰和舌下）、經陰 道、非經腸（其包括皮下、肌內、靜脈內、皮內、椎管內 及硬膜外）及類似者。當能瞭解的是’較佳之途徑可依例 如接受者之病症而改變。本發明之化合物的一個優點係爲 口服生物可利用者且可經口服計量。 -102 - 200918507 組合治療 於一較佳體系中，該式（1)化合物可經單獨投服，例如 未與其他活性療成分或治療劑一倂投服。於另一較佳體 系中，該式⑴化合物可與其他活性治療成分或治療劑組合 併用。較佳地，k其他活性治療成分或治療劑係Hiv蛋白 酶抑制劑、其他HIV反轉錄酶抑制劑、HIV進入/融合抑 制劑、ΗIV整合酶抑制劑、η IV出芽/成熟抑制劑或彼等之 組合。 該式（I)化合物之組合係典型地基於欲被治療之病症、 成分間彼此之相互反應性及該組合之藥學性質加以選擇。 例如’當治療感染（例如ΗIV或H C V感染）時，本發明之 組成物係與抗感染劑（諸如本文所描述者）結合。 適於與該式（I)化合物結合之適當抗感染劑的非限制性 實例包括HIV蛋白酶抑制劑、HIV反轉錄酶之非核苷抑制 劑、ΗIV反轉錄酶之核苷抑制劑、η〗ν反轉錄酶之核苷酸 抑制劑、HIV整合酶抑制劑、gp4 1抑制劑、CXCR4抑制 劑、g p 1 2 0抑制劑、G 6 P D和N A D Η氧化酶抑制劑、C C R 5 抑制劑、CCR8抑制劑、進入抑制劑、RNase Η抑制劑、 成熟抑制劑、藥物動力增強劑、治療ΗIV之其他藥劑或彼 等之組合。更特定地，本發明之一或多種化合物可與一或 多種選自下述之化合物組合：1 ) ΗIV蛋白酶抑制劑，例如 安潑那韋 （amprenavir)(Agenerase)、 阿扎那韋 (atazanavir)(Reyataz) ' 福沙普利那韋（fosamprenavir) (Lexiva)、茚地那韋（indinavir)(Crixivan)、洛匹那韋 -103- 200918507 (lopinavir)、利托那韋（ritonavir)(norvir)、奈非那韋 (nelfinavir)(Viracept)、沙奎那韋（saquinavir)(Invirase)、 替拉那韋（tipranavir)(Aptivus)、布卡那韋（brecanavir)、 地瑞那韋（(1&]'11113乂1〇(?“2131&)、丁]^(：-126、丁^4(：-114、美 至那韋（mozenavir)(DMP-450)、JE-2147 (AG1776)、L- 75 6423、RO03 3 4 649、KNI-272、DPC-681、DPC-684、 DG17、GS-8374、MK-8122 (PPL-100)、DG35、AG 1859、 SPI-25 6、TMC 523 90、PL-3 3 7、SM-3 22 3 77、SM-3 095 1 5 、GRL-0203 1、CRS-074、CRS-075、KB-98 及 A-790742 ； 2) HIV反轉錄酶之非核苷抑制劑，例如卡波韋林 (capravirine)、艾咪韋林（emivirine)、戴拉凡地平 (delaviridine)(Rescriptor)、依法韋侖（efavirenz)(Sustiva) 、奈韋拉平（1^¥丨^卩丨1^)(\^^111111^)、（ + )-綿毛胡桐內醋八 (calanolide A)、綿毛胡桐內酯 B (calanolide B)、依曲韋 林（etravirine)(Intelence)、G W 5 6 3 4 ' DPC-083、DPC-961 、DPC-963、MIV-150、MIV-160、MIV-170、大匹韋林 (dapivirine)(TMC-120)、拉皮韋林（rilpivirine)(TMC-278) 、BILR 3 5 5 BS、VRX 840773、UK-45 3 06 1 ' RDEA 806、 RDEA 427、RDEA 640 ' IDX 8 99 ' ANX-201 (Thiovir) ' R-1 206、LOC-dd、IQP-0410 ( S J - 3 3 6 6)、YM - 2 1 5 3 8 9、YM- 22 8 8 5 5、CMX-0 52 及 CMX-1 82 ; 3) HIV 反轉錄酶之核苷 抑制劑，例如疊氮胸苷（Retrovir)、恩曲他濱 (611111^(^1&1^1^)(£1111；1^¥&)、2’，3’-雙去氧肌苷（\^(16\)、司他 夫定（staVUdine)(Zerit)、2’，3’-雙去氧胞苷（Hivid)、拉脈 -104- 200918507 優定（lamivudine)(Epivir)、阿波卡偉（abacavir)(Ziagen)、 安妥嚷苷（amdoxovir)、艾非他濱（elvucitabine)(ACH 1 26443)、阿洛夫定（alovudine)(MIV-310)、MIV-210、拉 西卡偉（racivir)(消旋 FTC ; PSI-5004)、D-d4FC、疊氮化 磷（phosphazide)、福齊夫定替醋（fozivudine tidoxil)、阿 匹西他濱（apricitibine)(AVX754 ; SPD-754)、GS-7340、 KP-1461、AVX756、OBP-601、二噁茂烷胸腺嘧啶 (dioxolane thymine)、TMC-254072、INK-20、PPI-801、 PPI- 802、MIV-410、4’-Ed4T、B-108 及磷夫定酯 (fosalvudine tidoxil)(HDP 99.0003); 4) HIV 反轉錄酶核 苷酸抑制劑，例如富馬酸替諾福韋酯（tenofovir disoproxil fumarate)(Viread)和阿德福韋酯（adefovir dipivoxil) ; 5) HIV整合酶抑制劑，例如薑黃色素、薑黃色素之衍生物、 菊苣酸、菊苣酸之衍生物、3,5 -二咖啡醯奎寧酸、3,5 -二 咖啡醯奎寧酸之衍生物、金黃三羧酸、金黃三羧酸之衍生 物、咖啡酸苯乙酯、咖啡酸苯乙酯之衍生物、酪胺酸磷酸 化抑制劑、酪胺酸磷酸化抑制劑之衍生物、櫟皮酮、櫟皮 酮之衍生物、S- 1 3 60、季特韋（zintevir)(AR-177)、L-870812、L-870810、帕潘立酮（raltegravir)(Isentress ; MK-0518)、艾咪特拉韋（elvitegravir)(GS-9137)、BMS-53 8 1 5 8、GSK3 6473 5C、BMS-70703 5、MK-2048、GSK-349572 (S-349572) ' GSK-265744 (S-265744) > GSK- 2473 03 (S-247303)、S- 1 3 60 (GW8 1 087 1 )、1，5-DCQA、 INH-001 、 INT-3 49、 V-165 、 RIN-25、 BFX-1001 、 BFX- -105 - 200918507 1 002、BFX- 1 003、RSC- 1 8 3 8、BCH-3 3 040 及 BA Oil ； 6) gp41抑制劑，例如恩夫韋地（enfuvirtide)(Fuzeon)、西夫 韋肽（sifuvirtide)、MPI-4 5 1 9 3 6、FB006M、A- 3 29029 及 TRI-1144; 7) CXCR4 抑制劑，例如 AMD-070、KRH-3955 (CS-3 95 5)、AMD-9 3 70、AMD-3 45 1、RPI - MN、M S X -1 2 2 及 P 0 L - 2 4 3 8 ; 8)進入抑制劑，例如 S P 0 1 A、P A -1 6 1、 SPC3、TNX-3 5 5、DES6、SP-10、SP-03、CT-319 及 CT-326; 9) gpl20抑制劑，例如 BMS-488043及其前藥、 BlockAide/CR、K P C - 2 及 Μ N L P 6 2 ; 10) G6PD 和 NADH 氧 化酶抑制劑，例如免疫素（immunitin) ; 1 1) CCR5抑制劑 ，例如艾波韋羅（aplaviroc)、尼非韋羅（nifeviroc)'偉特 韋 羅 （vicriviroc)(SCH-4 1 7690) 、 馬 洛韋羅 (maraviroc)(Selzentry)、PRO-140、PRO-542、INCB 1 5050 ' INCB947 1、PF-23 279 8 ' SCH-532706、GSK-706769、 TAK-6 52、TAK-220、ESN-196、RO- 1 752、ZM-68 8 523、 AMD- 8 8 7、YM-370749、NIBR- 1 282、SCH-3 50634、ZM-6 8 8 5 23 及 CCR5mAb004 ； 12) CCR8 抑芾!J 齊9 ，仿U $D ZK-756326 ； 13) RNase H 抑制劑，例如 ODN-93 和 ODN-1 12 ：14)成熟抑制劑，例如貝韋立馬（bevirimat)(PA-457)、 PA-040、MPC-9055 (vicecon ； MPI-4983 9)、ACH- 1 00703 及 ACH-100706; 15)藥物動力增強劑，例如BAS-100、 SPI-452、PF-4 1 94477、TMC-41 629 及紅黴素；及 16)治 療HIV之其他藥劑，例如REP 9、SP-01A、TNX-3 5 5、 DES6、ODN-93、ODN-1 12、VGV-1 ' 阿普林津（Ampligen) -106- 200918507 、HRG214、單選殖抗體 Cytolin、VGX-410、VGX-820、 KD-247、AMZ 0026、CYT 99007、A-221 HIV、HPH-116 、DEBIO-025、BAY 5 0-479 8、MDX010(單選殖抗體 ipilimumab)、PBS 119、BIT-225、UBT-8147、ITI-3 6 7、 AFX-400、 BL- 1 050、GRN- 1 3 995 1 、GRN- 1 40665、AX-3 8 679、RGB-3 4 0638、PPI-3 67 及 ALG 8 8 9。 亦可令本發明之任一化合物與一或多種其他活性治療 劑結合成供同時或連續投服至人體內之單一劑量型式。該 組合治療可經投服以作爲同時或連續攝食。當連續投服時 ，該組合物可經兩次或多次投服。 共同投服本發明之化合物與一或多種其他活性治療劑 通常係指同時或連續投服本發明之化合物與一或多種其他 活性治療劑，致使本發明之化合物與一或多種其他活性治 療劑之治療上有效量皆存在於病患體內。 共同投服包括在投服一或多種其他活性治療劑之單位 劑量之前或之後投服本發明之化合物之單位劑量，例如在 投服一或多種其他活性治療劑之數秒、數分鐘或數小時內 投服本發明之化合物。例如，可先投服本發明之化合物之 單位劑量，隨後於數秒或數分鐘內投服一或多種其他活性 治療劑之單位劑量。可替代地，可先投服一或多種其他活 性治療劑之單位劑量，隨後於數秒或數分鐘內投服本發明 之化合物之單位劑量。於某些情況下，所欲的是可先投服 本發明之化合物之單位劑量，隨後經數小時（例如1至1 2 小時）之後投服一或多種其他活性治療劑之單位劑量。於 -107 - 200918507 其他情況下，所欲的是可先投服一或多種其他活性治療劑 之單位劑量，隨後經數小時（例如1至1 2小時）之後投服本 發明之化合物之單位劑量。 該組合治療可提供“協同效應”和“協同增效”，即該等 活性成分一起使用所達到之功效係大於分別使用該等化合 物所得到之功效的總合。當該等活性成分係（1)於結合之調 製劑中經共同調劑且經同時投服或投遞；（2)以各別之調製 劑經間隔或平行投遞；或（3)藉由某些其他攝食法可得到協 同增效。若經間隔治療投藥，當該化合物係經連續投服或 投遞時（例如經各別之藥片、九或膠囊或經各別注射器之 不同注射），可得到協同增效。通常，於間隔治療期間， 每個活性成分之有效劑量係經連續（即順序）投服，其中如 同於組合治療般，兩種或多種活性成分之有效劑量係一起 被投服。 於另一較佳體系中，本發明提供一種抑制HIV RT之 方法，其包含投服治療上有效量之式（I)化合物或其藥學上 可接受之鹽、溶劑化物或酯至需要該治療之病患體內。 於另一較佳體系中，本發明提供一種治療或預防HIV 感染之方法，其包含投服治療上有效量之式（I)化合物或其 藥學上可接受之鹽、溶劑化物及/或酯至需要該治療之病 患體內。 於另一較佳體系中，本發明提供一種方法，其進一步 包含共同投服治療用量之至少一種額外之活性劑，該等活 性劑係選自一或多種HIV蛋白酶抑制劑、HIV反轉錄酶之 -108- 200918507 非核苷抑制劑、HIV反轉錄酶之核苷抑制劑、HIV反轉錄 酶之核苷酸抑制劑、HIV整合酶抑制劑、gp41抑制劑、 CXCR4抑制劑、gp 1 20抑制劑、G6PD和NADH氧化酶抑 制劑、CCR5抑制劑、CCR8抑制劑、進入抑制劑、RNase Η抑制劑、成熟抑制劑、藥物動力增強劑、治療HIV之其 他藥劑或彼等之組合。 於另一較佳體系中，本發明提供一種治療 AIDS或 AIDS相關綜合症（ARC)之方法，其包含投服治療上有效量 之式（I)化合物或其藥學上可接受之鹽、溶劑化物及/或酯 至需要該治療之病患體內。 於另一較佳體系中，本發明提供一種共同投服治療用 量之式（I)化合物和至少一種額外之活性劑之方法，該等活 性劑係選自一或多種Η IV蛋白酶抑制劑、Η IV反轉錄酶之 非核苷抑制劑、ΗIV反轉錄酶之核苷抑制劑、η IV反轉錄 酶之核苷酸抑制劑、Η IV整合酶抑制劑、g p 4 1抑制劑、 CXCR4抑帋!j劑、gpl20抑芾[J齊U 、 G6PD和NADH氧化酶抑 制劑、CCR5抑制劑、CCR8抑制劑、進入抑制劑、RNase Η抑制劑、成熟抑制劑、藥物動力增強劑、治療HIV之其 他藥劑或彼等之組合。 於另一較佳體系中，本發明提供一種抑制反轉錄病毒 複製之方法’其包含令該反轉錄病毒與式（I)化合物或其藥 學上可接受之鹽、溶劑化物及/或酯接觸。可於活體外或 活體內（例如於感染反轉錄病毒之病患體內）抑制該反轉錄 病毒之複製。 -109- 200918507 於另一較佳體系中’本發明提供一種抑制反轉錄病毒 複製之方法’其包含令該反轉錄病毒與式（I)化合物和至少 —種額外之活性劑接觸’該等活性劑係選自一或多種HIV 蛋白酶抑制劑、HIV反轉錄酶之非核苷抑制劑、HIV反轉 錄酶之核苷抑制劑、HIV反轉錄酶之核苷酸抑制劑、hiv 整合酶抑制劑、gp4 1抑制劑、CXCR4抑制劑、gp 1 20抑制 劑、G6PD和NADH氧化酶抑制劑、CCR5抑制劑、CCR8 抑制劑、進入抑制劑、R N a s e Η抑制劑、成熟抑制劑、藥 物動力增強劑、治療HIV之其他藥劑或彼等之組合。 於另一較佳體系中’本申請案提供式I或II之化合物 於製備供治療或預防病患之HI V感染的藥物上之用途。 於另一較佳體系中，本申請案提供式〗或Π之化合物 於製備供治療病患之AIDS或AIDS相關綜合症（ARC)的藥 物上之用途。 於另一較佳體系中，本申請案提供式I之化合物於製 備供抑制病患體內之反轉錄病毒複製的藥物上之用途。 再於另一較佳體系中’該式〗化合物係如下述通式U 之化合物般以下述之表列格式（表7)命名：
式II 表 1 至 6 各別顯示該 “ 1，，、“ 2，，、“ 3，，、“ 4，，、“ 5，，及 “ 6，， -110- 200918507 部分之結構。表1至6中每個取代基“ 1 ”、“ 2 ”、“ 3 ”、“ 4 ’ 、“5”及“6”係由包含一個數字和一個字母之“編碼”所表示 。利用構成方式1 .2.3.4.5.6，式II化合物之每個結構可由 表列型式經結合代表每個結構部分之“編碼”而被指定。因 此，例如1 a · 2 a . 3 a . 4 a . 5 a · 6 a表示下式之結構： -111 - 200918507
1”結構 編碼 “1”結構 1 a -ch2ch3 lb -CH2CH2CH2CH3 1 c Id -ch2-o-ch2ch3 . 1 e If 表2 : “2”結構 編碼 “2”結構 2a -ch3 2b -CN 2c Cl 2d -ch2f 2e -nh2 2f -112- 200918507 表3 : “3”結構 編碼 “3”結構 3 a -ch3 3b -CN 3c Cl 3d -ch2f 3e -nh2 3f 表4 : “4”結構
“4”結構 -ch(ch3)2 -CH2CH3 -CH2CH2F -c(ch3)3 -C(CH3)20H -CH(CH3)CH20H “5”結構 Η 編碼 4 a 4b 4 c 4d 4 e 4f 表5 : “5”結構 編碼 5b -CH2NH2
5c -CH2〇H
5d -CH2CH2〇H
5e -CH2CH2CH2OH 5f -O-CH3 -113 - 200918507 表6: “6”結構 編碼 “6”結構 6a -c(o)_ 6b -o- 6c -s- 6d -CHF- 6e -CH2- 6f -CF2- 表7 :式(Π)化合物表列 la.2a.3a.4a.5a.6a, la.2a.3a.4a.5a.6b, la.2a.3a.4a.5a.6c, la.2a.3a.4a.5a.6d, la.2a.3a.4a.5a.6e, la.2a.3a.4a.5a.6f, la.2a.3a.4a.5b.6a, la.2a.3a.4a.5b.6b, la.2a.3a.4a.5b.6c, la.2a.3a.4a.5b.6d, la.2a.3a.4a.5b.6e, la.2a.3a.4a.5b.6f, la.2a.3a.4a.5c.6a, la.2a.3a.4a.5c.6b, la.2a.3a.4a.5c.6c, la.2a.3a.4a.5c.6d, la.2a.3a.4a.5c.6e, la.2a.3a.4a.5c.6f, la.2a.3a.4a.5d.6a, la.2a.3a.4a.5d.6b, la.2a.3a.4a.5d.6c, la.2a.3a.4a.5d.6d, la.2a.3a.4a.5d.6e, la.2a.3a.4a.5d.6f, la.2a.3a.4a.5e.6a, la.2a.3a.4a.5e.6b, la.2a.3a.4a.5e.6c, la.2a.3a.4a.5e.6d, la.2a.3a.4a.5e.6e, la.2a.3a.4a.5e.6f, la.2a.3a.4a.5f.6a, la.2a.3a.4a.5f.6b, la.2a.3a.4a.5f.6c, la.2a.3a.4a.5f.6d, la.2a.3a.4a.5f.6e, la.2a.3a.4a.5f.6f, la.2a.3a.4b.5a.6a, la.2a.3a.4b.5a.6b, la.2a.3a.4b.5a.6c, la.2a.3a.4b.5a.6d, la.2a.3a.4b.5a.6e, la.2a.3a.4b.5a.6f, la.2a.3a.4b.5b.6a, la.2a.3a.4b.5b.6b, la.2a.3a.4b.5b.6c, la.2a.3a.4b.5b.6d, la.2a.3a.4b.5b.6e, la.2a.3a.4b.5b.6f, la.2a.3a.4b.5c.6a, la.2a.3a.4b.5c.6b, la.2a.3a.4b.5c.6c, la.2a.3a.4b.5c.6d, la.2a.3a.4b.5c.6e, la.2a.3a.4b.5c.6f, la.2a.3a.4b.5d.6a, la.2a.3a.4b.5d.6b, la.2a.3a.4b.5d.6c, la.2a.3a.4b.5d.6d, la.2a.3a.4b.5d.6e, la.2a.3a.4b.5d.6f, la.2a.3a.4b.5e.6a, la.2a.3a.4b.5e.6b, la.2a.3a.4b.5e.6c, la.2a.3a.4b.5e.6d, la.2a.3a.4b.5e.6e, la.2a.3a.4b.5e.6f, la.2a.3a.4b.5f.6a, la.2a.3a.4b.5f.6b, la.2a.3a.4b.5f.6c, la.2a.3a.4b.5f.6d, la.2a.3a.4b.5f.6e, la.2a.3a.4b.5f.6f, la.2a.3a.4c.5a.6a, la.2a.3a.4c.5a.6b, la.2a.3a.4c.5a.6c, la.2a.3a.4c.5a.6d, la.2a.3a.4c.5a.6e, la.2a.3a.4c.5a.6f, la.2a.3a.4c.5b.6a, la.2a.3a.4c.5b.6b, la.2a.3a.4c.5b.6c, la.2a.3a.4c.5b.6d, la.2a.3a.4c.5b.6e, la.2a.3a.4c.5b.6f, la.2a.3a.4c.5c.6a, la.2a.3a.4c.5c.6b, la.2a.3a.4c.5c.6c, la.2a.3a.4c.5c.6d, la.2a.3a.4c.5c.6e, la.2a.3a.4c.5c.6f, la.2a.3a.4c.5d.6a, la.2a.3a.4c.5d.6b, la.2a.3a.4c.5d.6c, la.2a.3a.4c.5d.6d, -114- 200918507 la.2a.3a.4c.5d.6e, la.2a.3a.4c.5d.6f, la.2a.3a.4c.5e.6a, la.2a.3a.4c.5e.6b, la.2a.3a.4c.5e.6c, la.2a.3a.4c.5e*6d7 la.2a.3a.4c.5e.6e, la.2a.3a.4c.5e.6f, la.2a.3a.4c.5f.6a, la.2a.3a.4c.5f.6b, la.2a.3a.4c.5f.6c, la.2a.3a.4c.5f.6d, la.2a.3a.4c.5f.6e, la.2a.3a.4c.5f.6f, la.2a.3a.4d.5a.6a, la.2a.3a.4d.5a.6b, la.2a.3a.4d.5a.6c, la.2a.3a.4d.5a.6d, la.2a.3a.4d.5a.6e, la.2a.3a.4d.5a.6f, la.2a.3a.4d.5b.6a, la.2a.3a.4d.5b.6b, la.2a.3a.4d.5b.6c, la.2a.3a.4d.5b.6d, la.2a.3a.4d.5b.6e, la.2a.3a.4d.5b.6f, la.2a.3a.4d.5c.6a, la.2a.3a.4d.5c.6b, la.2a.3a.4d.5c.6c, la.2a.3a.4d.5c.6d, la.2a.3a.4d.5c.6e, la.2a.3a.4d.5c.6f, la.2a.3a.4d.5d.6a, la.2a.3a.4d.5d.6b, la.2a.3a.4d.5d.6c, la.2a.3a.4d.5d.6d, la.2a.3a.4d.5d.6e, la.2a.3a.4d.5d.6f, la.2a.3a.4d.5e.6a, la.2a.3a.4d.5e.6b, la.2a.3a.4d.5e.6c, la.2a.3a.4d.5e.6d, la.2a.3a.4d.5e.6e, la.2a.3a.4d.5e.6f, la.2a.3a.4d.5f.6a, la.2a.3a.4d.5f.6b, la.2a.3a.4d.5f.6c, la.2a.3a.4d.5f.6d, la.2a.3a.4d.5f.6e, la.2a.3a.4d.5f.6f, la.2a.3a.4e.5a.6a, la.2a.3a.4e.5a.6b, la.2a.3a.4e.5a.6c, la.2a.3a.4e.5a.6d, la.2a.3a.4e.5a.6e, la.2a.3a.4e.5a.6f, la.2a.3a.4e.5b.6a, la.2a.3a.4e.5b.6b, la.2a.3a.4e.5b.6c, la.2a.3a.4e.5b.6d, la.2a.3a.4e.5b.6e, la.2a.3a.4e.5b.6f, la.2a.3a.4e.5c.6a, la.2a.3a.4e.5c.6b, la.2a.3a.4e.5c.6c, la.2a.3a.4e.5c.6d, la.2a.3a.4e.5c.6e, la.2a.3a.4e.5c.6f, la.2a.3a.4e.5d.6a, la.2a.3a.4e.5d.6b, la.2a.3a.4e.5d.6c, la.2a.3a.4e.5d.6d, la.2a.3a.4e.5d.6e, la.2a.3a.4e.5d.6f, la.2a.3a.4e.5e.6a, la.2a.3a.4e.5e.6b, la.2a.3a.4e.5e.6c, la.2a.3a.4e.5e.6d, la.2a.3a.4e.5e.6e, la.2a.3a.4e.5e.6f, la.2a.3a.4e.5f.6a, la.2a.3a.4e.5f.6b, la.2a.3a.4e.5f.6c, la.2a.3a.4e.5f.6d, la.2a.3a.4e.5f.6e, la.2a.3a.4e.5f.6f, la.2a.3a.4f.5a.6a, la.2a.3a.4f.5a.6b, la.2a.3a.4f.5a.6c, la.2a.3a.4f.5a.6d, la.2a.3a.4f.5a.6e, la.2a.3a.4f.5a.6f, la.2a.3a.4f.5b.6a, la.2a.3a.4f.5b.6b, la.2a.3a.4f.5b.6c, la.2a.3a.4f.5b.6d, la.2a.3a.4f.5b.6e, la.2a.3a.4f.5b.6f, la.2a.3a.4f.5c.6a, la.2a.3a.4f.5c.6b, la.2a.3a.4f.5c.6c, la.2a.3a.4f.5c.6d, la.2a.3a.4f.5c.6e, la.2a.3a.4f.5c.6f, la.2a.3a.4f.5d.6a, la.2a.3a.4f.5d.6b, la.2a.3a.4f.5d.6c, la.2a.3a.4f.5d.6d, la.2a.3a.4f.5d.6e, la.2a.3a.4f.5d.6f, la.2a.3a.4f.5e.6a, la.2a.3a.4f.5e.6b, la.2a.3a.4f.5e.6c, la.2a.3a.4f.5e.6d, la.2a.3a.4f.5e.6e, la.2a.3a.4f.5e.6f, la.2a.3a.4f.5f.6a, la.2a.3a.4f.5f.6b, la.2a.3a.4f.5f.6c, la.2a.3a.4f.5f.6d, la.2a.3a.4f.5f.6e, la.2a.3a.4f.5f.6f, la.2a.3b.4a.5a.6a, la.2a.3b.4a.5a.6b, la.2a.3b.4a.5a.6c, la.2a.3b.4a.5a.6d, la.2a.3b.4a.5a.6e, la.2a.3b.4a.5a.6f, la.2a.3b.4a.5b.6a, la.2a.3b.4a.5b.6b, la.2a.3b.4a.5b.6c, la.2a.3b.4a.5b.6d, la.2a.3b.4a.5b.6e, la.2a.3b.4a.5b.6f, la.2a.3b.4a.5c.6a, la.2a.3b.4a.5c.6b, la.2a.3b.4a.5c.6c, la.2a.3b.4a.5c.6d, la.2a.3b.4a.5c.6e, la.2a.3b.4a.5c.6f, la.2a.3b.4a.5d.6a, la.2a.3b.4a.5d.6b, la.2a.3b.4a.5d.6c, la.2a.3b.4a.5d.6d, la.2a.3b.4a.5d.6e, la.2a.3b.4a.5d.6f, la.2a.3b.4a.5e.6a, la.2a.3b.4a.5e.6b, la.2a.3b.4a.5e.6c, la.2a.3b.4a.5e.6d, la.2a.3b.4a.5e.6e, la.2a.3b.4a.5e.6f, la.2a.3b.4a.5f.6a, la.2a.3b.4a.5f.6b, la.2a.3b.4a.5f.6c, la.2a.3b.4a.5f.6d, la.2a.3b.4a.5f.6e, la.2a.3b.4a.5f.6f, la.2a.3b.4b.5a.6a, la.2a.3b.4b.5a.6b, la.2a.3b.4b.5a.6c, la.2a.3b.4b.5a.6d, la.2a.3b.4b.5a.6e, la.2a.3b.4b.5a.6f, la.2a.3b.4b.5b.6a, la.2a.3b.4b.5b.6b, la.2a.3b.4b.5b.6c, la.2a.3b.4b.5b.6d, la.2a.3b.4b.5b.6e, la.2a.3b.4b.5b.6f, la.2a.3b.4b.5c.6a, la.2a.3b.4b.5c.6b, la.2a.3b.4b.5c.6c, la.2a.3b.4b.5c.6d, la.2a.3b.4b.5c.6e, la.2a.3b.4b.5c.6f, la.2a.3b.4b.5d.6a, la.2a.3b.4b.5d.6b, 115- 200918507 la.2a.3b.4b.5d.6c, la.2a.3b.4b.5d.6d, la.2a.3b.4b.5d.6e, la.2a.3b.4b.5d.6f, la.2a.3b.4b.5e.6a, la.2a.3b.4b.5e.6b, la.2a.3b.4b.5e.6c, la.2a.3b.4b.5e.6d, la.2a.3b.4b.5e.6e, la.2a.3b.4b.5e.6f, la.2a.3b.4b.5f.6a, la.2a.3b.4b.5f.6b, la.2a.3b.4b.5f.6c, la.2a.3b.4b.5f.6d, la.2a.3b.4b.5f.6e, la.2a.3b.4b.5f.6f, la.2a.3b.4c.5a.6a, la.2a.3b.4c.5a.6b, la.2a.3b.4c.5a.6c, la.2a.3b.4c.5a.6d, la.2a.3b.4c.5a.6e, la.2a.3b.4c.5a.6f, la.2a.3b.4c.5b.6a, la.2a.3b.4c.5b.6br la.2a.3b.4c.5b.6c, la.2a.3b.4c.5b.6d, la.2a.3b.4c.5b.6e, la.2a.3b.4c.5b.6f, la.2a.3b.4c.5c.6a, la.2a.3b.4c.5c.6b, la.2a.3b.4c.5c.6c, la.2a.3b.4c.5c.6d, la.2a.3b.4c.5c.6e, la.2a.3b.4c.5c.6f, la.2a.3b.4c.5d.6a, la.2a.3b.4c.5d.6b, la.2a.3b.4c.5d.6c, la.2a.3b.4c.5d.6d, la.2a.3b.4c.5d.6e, la.2a.3b.4c.5d.6f, la.2a.3b.4c.5e.6a, la.2a.3b.4c.5e.6b, la.2a.3b.4c.5e.6c, la.2a.3b.4c.5e.6d, la.2a.3b.4c.5e.6e, la.2a.3b.4c.5e.6f, la.2a.3b.4c.5f.6a, la.2a.3b.4c.5f.6b, la.2a.3b.4c.5f.6c, la.2a.3b.4c.5f.6d, la.2a.3b.4c.5f.6e, la.2a.3b.4c.5f.6f, la.2a.3b.4d.5a.6a, la.2a.3b.4d.5a.6b, la.2a.3b.4d.5a.6c, la.2a.3b.4d.5a.6d, la.2a.3b.4d.5a.6e, la.2a.3b.4d.5a.6f, la.2a.3b.4d.5b.6a, la.2a.3b.4d.5b.6b, la.2a.3b.4d.5b.6c, la.2a.3b.4d.5b.6d, la.2a.3b.4d.5b.6e, la.2a.3b.4d.5b.6f, la.2a.3b.4d.5c.6a, la.2a.3b.4d.5c.6b, la.2a.3b.4d.5c.6c, la.2a.3b.4d.5c.6d, la.2a.3b.4d.5c.6e, la.2a.3b.4d.5c.6f, la.2a.3b.4d.5d.6a, la.2a.3b.4d.5d.6b, la.2a.3b.4d.5d.6c, la.2a.3b.4d.5d.6d, la.2a.3b.4d.5d.6e, la.2a.3b.4d.5d.6f, la.2a.3b.4d.5e.6a, la.2a.3b.4d.5e.6b, la.2a.3b.4d.5e.6c, la.2a.3b.4d.5e.6d, la.2a.3b.4d.5e.6e, la.2a.3b.4d.5e.6f, la.2a.3b.4d.5f.6a, la.2a.3b.4d.5f.6b, 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la.2d.3a.4f.5c.6a, la.2d.3a.4f.5c.6b, la.2d.3a.4f.5c.6c, la.2d.3a.4f.5c.6d, la.2d.3a.4f.5c.6e, la.2d.3a.4f.5c.6f, la.2d.3a.4f.5d.6a, la.2d.3a.4f.5d.6b, la.2d.3a.4f.5d.6c, la.2d.3a.4f.5d.6d, la.2d.3a.4f.5d.6e, la.2d.3a.4f.5d.6f, la.2d.3a.4f.5e.6a, la.2d.3a.4f.5e.6b, la.2d.3a.4f.5e.6c, la.2d.3a.4f.5e.6d, la.2d.3a.4f.5e.6e, la.2d.3a.4f.5e.6f, la.2d.3a.4f.5f.6a, la.2d.3a.4f.5f.6b, la.2d.3a.4f.5f.6c, la.2d.3a.4f.5f.6d, la.2d.3a.4f.5f.6e, la.2d.3a.4f.5f.6f, la.2d.3b.4a.5a.6a, la.2d.3b.4a.5a.6b, la.2d.3b.4a.5a.6c, la.2d.3b.4a.5a.6d, la.2d.3b.4a.5a.6e, la.2d.3b.4a.5a.6f, la.2d.3b.4a.5b.6a, la.2d.3b.4a.5b.6b, la.2d.3b.4a.5b.6c, la.2d.3b.4a.5b.6d, la.2d.3b.4a.5b.6e, la.2d.3b.4a.5b.6f, la.2d.3b.4a.5c.6a, la.2d.3b.4a.5c.6b, la.2d.3b.4a.5c.6c, la.2d.3b.4a.5c.6d, la.2d.3b.4a.5c.6e, la.2d.3b.4a.5c.6f, la.2d.3b.4a.5d.6a, la.2d.3b.4a.5d.6b, la.2d.3b.4a.5d.6c, la.2d.3b.4a.5d.6d, la.2d.3b.4a.5d.6e, la.2d.3b.4a.5d.6f, la.2d.3b.4a.5e.6a, la.2d.3b.4a.5e.6b, la.2d.3b.4a.5e.6c, la.2d.3b.4a.5e.6d, la.2d.3b.4a.5e.6e, la.2d.3b.4a.5e.6f, la.2d.3b.4a.5f.6a, la.2d.3b.4a.5f.6b, la.2d.3b.4a5f.6c, la.2d.3b.4a.5f.6d, la.2d.3b.4a.5f.6e, la.2d.3b.4a.5f.6f, la.2d.3b.4b.5a.6a, la.2d.3b.4b.5a.6b, la.2d.3b.4b.5a.6Q la.2d.3b.4b.5a.6d, la.2d.3b.4b.5a.6e, la.2d.3b.4b.5a.6f, la.2d.3b.4b.5b.6a, la.2d.3b.4b.5b.6b, la.2d.3b.4b.5b.6c, la.2d.3b.4b.5b.6d, la.2d.3b.4b.5b.6e, la.2d.3b.4b.5b.6f, la.2d.3b.4b.5c.6a, la.2d.3b.4b.5c.6b, la.2d.3b.4b.5c.6c, la.2d.3b.4b.5c.6d, la.2d.3b.4b.5c.6e, la.2d.3b.4b.5c.6f, la.2d.3b.4b.5d.6a, la.2d.3b.4b.5d.6b, la.2d.3b.4b.5d.6c, la.2d.3b.4b.5d.6d, la.2d.3b.4b.5d.6e, la.2d.3b.4b.5d.6f, la.2d.3b.4b.5e.6a, la.2d.3b.4b.5e.6b, la.2d.3b.4b.5e.6c, la.2d.3b.4b.5e.6d, la.2d.3b.4b.5e.6e, la.2d.3b.4b.5e.6f, la.2d.3b.4b.5f.6a, la.2d.3b.4b.5f.6b, la.2d.3b.4b.5f.6c, la.2d.3b.4b.5f.6d, la.2d.3b.4b.5f.6e, la.2d.3b.4b.5f.6f, la.2d.3b.4c.5a.6a, la.2d.3b.4c.5a.6b, la.2d.3b.4c.5a.6c, la.2d.3b.4c.5a.6d, la.2d.3b.4c.5a.6e, la.2d.3b.4c.5a.6f, la.2d.3b.4c.5b.6a, la.2d.3b.4c.5b.6b, la.2d.3b.4c.5b.6c, la.2d.3b.4c.5b.6d, la.2d.3b.4c.5b.6e, la.2d.3b.4c.5b.6f, la.2d.3b.4c.5c.6a, la.2d.3b.4c.5c.6b, la.2d.3b.4c.5c.6c, la.2d.3b.4c.5c.6d, la.2d.3b.4c.5c.6e, la.2d.3b.4c.5c.6f, la.2d.3b.4c.5d.6a, la.2d.3b.4c.5d.6b, la.2d.3b.4c.5d.6c, la.2d.3b.4c.5d.6d, la.2d.3b.4c.5d.6e, la.2d.3b.4c.5d.6f, la.2d.3b.4c.5e.6a, la.2d.3b.4c.5e.6b, la.2d.3b.4c.5e.6c, la.2d.3b.4c.5e.6d, la.2d.3b.4c.5e.6e, la.2d.3b.4c.5e.6f, la.2d.3b.4c.5f.6a, la.2d.3b.4c.5f.6b, la.2d.3b.4c.5f.6c, la.2d.3b.4c.5f.6d, la.2d.3b.4c.5f.6e, la.2d.3b.4c.5f.6f, la.2d.3b.4d.5a.6a, -137- 200918507 la.2d.3b.4d.5a.6b, la.2d.3b.4d.5a.6c, la.2d.3b.4d.5a.6d, la.2d.3b.4d.5a.6e, la.2d.3b*4d.5a.6f, la.2d.3b.4d.5b.6a, la.2d.3b.4d.5b.6b, la.2d.3b.4d.5b.6c, la.2d.3b.4d.5b.6d, la.2d.3b.4d.5b.6e, la.2d.3b.4d.5b.6f, la.2d.3b.4d.5c.6a, la.2d.3b.4d.5c.6b, la.2d3b.4d.5c.6c, la.2d.3b.4d.5c.6d, la.2d.3b.4d.5c.6e, la.2d.3b.4d.5c.6f, la.2d.3b.4d.5d.6a, la.2d.3b.4d.5d.6b, la.2d.3b.4d.5d.6c, la.2d.3b.4d.5d.6d, la.2d.3b.4d.5d.6e, la.2d.3b.4d.5d.6f, la.2d.3b.4d.5e.6a, la.2d.3b.4d.5e.6b, la.2d.3b.4d.5e.6c, la.2d.3b.4d.5e.6d, la.2d.3b.4d.5e.6e, la.2d.3b.4d.5e.6f, la.2d.3b.4d.5f.6a, la.2d.3b.4d.5f.6b, la.2d.3b.4d.5f.6c, la.2d.3b.4d.5f.6d, la.2d.3b.4d.5f.6e, la.2d.3b.4d.5f.6f, la.2d.3b.4e.5a.6a, la.2d.3b.4e.5a.6b, la.2d.3b.4e.5a.6c, la.2d.3b.4e.5a.6d, la.2d.3b.4e.5a.6e, la.2d.3b.4e.5a.6f, la.2d.3b.4e.5b.6a, la.2d.3b.4e.5b.6b, la.2d.3b.4e.5b.6c, la.2d.3b.4e.5b.6d, la.2d.3b.4e.5b.6e, la.2d.3b.4e.5b.6f, la.2d.3b.4e.5c.6a, la.2d.3b.4e.5c.6b, la.2d.3b.4e.5c.6c, la.2d.3b.4e.5c.6d, la.2d.3b.4e.5c.6e, la.2d.3b.4e.5c.6f, la.2d.3b.4e.5d.6a, la.2d.3b.4e.5d.6b, la.2d.3b.4e.5d.6c, la.2d.3b.4e.5d.6d, la.2d.3b.4e.5d.6e, la.2d.3b.4e.5d.6f, la.2d.3b.4e.5e.6a, la.2d.3b.4e.5e.6b, la.2d.3b.4e.5e.6c, la.2d.3b.4e.5e.6d, la.2d.3b.4e.5e.6e, la.2d.3b.4e.5e.6f, la.2d.3b.4e.5f.6a, la.2d.3b.4e.5f.6b, la.2d.3b.4e.5f.6c, la.2d.3b.4e.5f.6d, la.2d.3b.4e.5f.6e, la.2d.3b.4e.5f.6f, la.2d3bAi.5a.6a., la.2d.3b.4f.5a.6b, la.2d.3b.4f.5a.6c, la.2d.3b.4f.5a.6d, la.2d.3b.4f.5a.6e, la.2d.3b.4f.5a.6f, la.2d.3b.4f.5b.6a, la.2d.3b.4f.5b.6b, la.2d.3b.4f.5b.6c, la.2d.3b.4f.5b.6d, la.2d.3b.4f.5b.6e, la.2d.3b.4f.5b.6f, la.2d.3b.4f.5c.6a, la.2d.3b.4f.5c.6b, la.2d.3b.4f.5c.6c, la.2d.3b.4f.5c.6d, la.2d.3b.4f.5c.6e, la.2d.3b.4f.5c.6f, la.2d.3b.4f.5d.6a, la.2d.3b.4f.5d.6b, la.2d.3b.4f.5d.6c, la.2d.3b.4f.5d.6d, la.2d.3b.4f.5d.6e, la.2d.3b.4f.5d.6f, la.2d.3b.4f.5e.6a, la.2d.3b.4f.5e.6b, la.2d.3b.4f.5e.6c, la.2d.3b.4f.5e.6d, la.2d.3b.4f.5e.6e, la.2d.3b.4f.5e.6f, la.2d.3b.4f.5f.6a, la.2d.3b.4f.5f.6b, la.2d.3b.4f.5f.6c, la.2d.3b.4f.5f.6d, la.2d.3b.4f.5f.6e, la.2d.3b.4f.5f.6f, la.2d.3c.4a.5a.6a, la.2d.3c.4a.5a.6b, la.2d.3c.4a.5a.6c, la.2d.3c.4a.5a.6d, la.2d.3c.4a.5a.6e, la.2d.3c.4a.5a.6f, la.2d.3c.4a.5b.6a, la.2d.3c.4a.5b.6b, la.2d.3c.4a.5b.6c, la.2d.3c.4a.5b.6d, la.2d.3c.4a.5b.6e, la.2d.3c.4a.5b.6f, la.2d.3c.4a.5c.6a, la.2d.3c4a.5c.6b, la.2d.3c.4a.5c.6c, la.2d.3c.4a.5c.6d, la.2d.3c.4a.5c6e, la.2d.3c.4a.5c.6f, la.2d.3c.4a.5d.6a, la.2d.3c.4a.5d.6b, la.2d.3c.4a.5d.6c, la.2d.3c.4a.5d.6d, la.2d.3c.4a.5d.6e, la.2d.3c.4a.5d.6f, la.2d.3c.4a,5e.6a, la.2d.3c.4a.5e.6b, la.2d.3c.4a.5e.6c, la.2d.3c.4a.5e.6d, la.2d.3c.4a.5e.6e, la.2d.3c.4a.5e.6f, la.2d.3c.4a.5f.6a, la.2d.3c.4a.5f.6b, la.2d.3c.4a.5f.6c, la.2d.3c.4a.5f.6d, la.2d.3c.4a.5f.6e, la.2d.3c.4a.5f.6f, la.2d.3c.4b.5a.6a, la.2d.3c.4b.5a.6b, la.2d.3c.4b.5a.6c, la.2d.3c.4b.5a.6d, la.2d.3c.4b.5a.6e, la.2d.3c.4b.5a.6f, la.2d.3c.4b.5b.6a, la.2d.3c.4b.5b.6b, la.2d.3c.4b.5b.6c, la.2d.3c.4b.5b.6d, la.2d.3c.4b.5b.6e, la.2d.3c.4b.5b.6f, la.2d.3c.4b.5c.6a, la.2d.3c.4b.5c.6b, la.2d.3c.4b.5c.6c, la.2d.3c.4b.5c.6d, la.2d.3c.4b.5c.6e, la.2d.3c.4b.5c.6f, la.2d.3c.4b.5d.6a, la.2d.3c.4b.5d.6b, la.2d.3c.4b.5d.6c, la.2d.3c.4b.5d.6d, la.2d.3c.4b.5d.6e, la.2d.3c.4b.5d.6f, la.2d.3c.4b.5e.6a, la.2d.3c.4b.5e.6b, -138- 200918507 la.2d.3c.4b.5e.6c, la.2d.3c.4b.5e.6d, la.2d.3c.4b.5e.6e, la.2d.3c.4b.5e.6f, la.2d.3c.4b.5f.6a, la.2d.3c,4b.5f.6b, la.2d.3c.4b.5f.6c, la.2d.3c.4b.5f.6d, la.2d.3c.4b.5f.6e, la.2d.3c.4b.5f.6f, la.2d.3c.4c.5a.6a, la.2d.3c.4c.5a.6b, la.2d.3c.4c.5a.6c, la.2d.3c.4c.5a.6d, la.2d.3c.4c.5a.6e, la.2d.3c.4c.5a.6f, ; la.2d.3c.4c.5b.6a, la.2d*3c.4c.5b.6b, la.2d.3c.4c.5b.6c, la.2d.3c.4c.5b.6d, la.2d.3c.4c.5b.6e, la.2d.3c.4c.5b.6f, la.2d.3c.4c.5c.6a, la.2d.3c.4c.5c.6b, la.2d.3c.4c.5c.6c, la.2d.3c.4c.5c.6d； 13.2(1.30.40.50.60, la.2d.3c.4c.5c.6f, la.2d.3c.4c.5d.6a, la.2d.3c.4c.5d.6b, la.2d.3c.4c.5d.6c, la.2d.3c.4c.5d.6d, la.2d.3c.4c.5d.6e, la.2d.3c.4c.5d.6f, la.2d.3c.4c.5e.6a, la.2d.3c.4c.5e.6b, la.2d.3c.4c.5e.6c, la.2d.3c.4c.5e.6d, la.2d.3c.4c.5e.6e, la.2d.3c.4c.5e.6f, la.2d.3c.4c.5f.6a, la.2d.3c.4c.5f.6b, la.2d.3c.4c.5f.6c, la.2d.3c.4c.5f.6d, la.2d.3c.4c.5f.6e, la.2d.3c.4c,5f.6f7 la.2d.3c.4d.5a.6a, la.2d.3c.4d.5a.6b, la.2d.3c.4d.5a.6c, la.2d.3c.4d.5a.6d, la.2d.3c.4d.5a.6e, la.2d.3c.4d.5a.6f, la.2d.3c.4d.5b.6a, la.2d.3c.4d.5b.6b, la.2d.3c.4d.5b.6c, la.2d.3c.4d.5b.6d, la.2d.3c.4d.5b.6e, la.2d.3c.4d.5b.6f, la.2d.3c.4d.5c.6a, la.2d.3c.4d.5c.6b, 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lb.2d.3b.4e.5e.6d, lb.2d.3b.4e.5e.6e, lb.2d.3b.4e.5e.6f, lb.2d.3b.4e.5f.6a, lb.2d.3b.4e.5f.6b, lb.2d.3b.4e.5f.6c, lb.2d.3b.4e.5f.6d, lb.2d.3b.4e.5f.6e, lb.2d.3b.4e.5f.6f, lb.2d.3b.4f.5a.6a, lb.2d.3b.4f.5a.6b, lb.2d.3b.4f.5a.6c, lb.2d.3b.4f.5a.6d, lb.2d.3b.4f.5a.6e, lb.2d.3b.4f.5a.6f, lb.2d.3b.4f.5b.6a, lb.2d.3b.4f.5b.6b, lb.2d.3b.4f.5b.6c, lb.2d.3b.4f.5b.6d, lb.2d.3b.4f.5b.6e, lb.2d.3b.4f.5b.6f, lb.2d.3b.4f.5c.6a, lb.2d.3b.4f.5c.6b, lb.2d.3b.4f.5c.6c, lb.2d.3b.4f.5c.6d, lb.2d.3b.4f.5c.6e, lb.2d.3b.4f.5c.6f, lb.2d.3b.4f.5d.6a, lb.2d.3b.4f.5d.6b, lb.2d.3b.4f.5d.6c, lb.2d.3b.4f.5d.6d, lb.2d.3b.4f.5d.6e, lb.2d.3b.4f.5d.6f, lb.2d.3b.4f.5e.6a, lb.2d.3b.4f.5e.6b, lb.2d.3b.4f.5e.6c, lb.2d.3b.4f.5e.6d, lb.2d.3b.4f.5e.6e, lb.2d.3b.4f.5e.6f, lb.2d.3b.4f.5f.6a, lb.2d.3b.4f.5f.6b, lb.2d.3b.4f.5f.6c, lb.2d.3b.4f.5f.6d, lb.2d.3b.4f.5f.6e, lb.2d.3b.4f.5f.6f, -181 - 200918507 lb.2d.3c.4a.5a.6a, lb.2d.3c.4a.5a.6b, lb.2d.3c.4a.5a.6c, lb.2d.3c.4a.5a.6d, lb.2d.3c.4a.5a.6e, lb.2d.3c.4a.5a.6f, lb.2d3c.4a.5b.6a, lb.2d.3c.4a.5b.6b, lb.2d.3c.4a.5b.6c, lb.2d.3c.4a.5b.6d, lb.2d.3c.4a.5b.6e, lb.2d.3c.4a.5b.6f, lb.2d.3c.4a.5c.6a, lb.2d.3c.4a.5c.6b, lb.2d.3c.4a.5c.6c, lb.2d.3c.4a.5c.6d, lb.2d.3c.4a.5c.6e, lb.2d.3c.4a.5c.6f, lb.2d.3c.4a.5d.6a, lb.2d.3c.4a.5d.6b, lb.2d.3c.4a.5d.6c, lb.2d.3c.4a.5d.6d, lb.2d.3c.4a.5d.6e, lb.2d.3c.4a.5d.6f, lb.2d.3c.4a.5e.6a, lb.2d.3c.4a.5e.6b, lb.2d.3c.4a.5e.6c, lb.2d.3c.4a.5e.6d, lb.2d.3c.4a.5e.6e, lb.2d.3c.4a.5e.6f, lb.2d.3c.4a.5f.6a, lb.2d.3c.4a.5f.6b, lb.2d.3c.4a.5f.6c, lb.2d.3c.4a.5f.6d, lb.2d.3c.4a.5f.6e, lb.2d.3c.4a.5f.6f, lb.2d.3c.4b.5a.6a, lb.2d.3c.4b.5a.6b, lb.2d.3c.4b.5a.6c, lb.2d.3c.4b.5a.6d, lb.2d.3c.4b.5a.6e, lb.2d.3c.4b.5a.6f, lb.2d.3c.4b.5b.6a, lb.2d.3c.4b.5b.6b, lb.2d.3c.4b.5b.6c, lb.2d.3c.4b.5b.6d, lb.2d.3c.4b.5b.6e, lb.2d.3c.4b.5b.6f, lb.2d.3c.4b.5c.6a, lb.2d.3c.4b.5c.6b, lb.2d.3c.4b.5c.6c, lb.2d.3c.4b.5c.6d, lb.2d.3c.4b.5c.6e, lb.2d.3c.4b.5c.6f, lb.2d.3c.4b.5d.6a, lb.2d.3c.4b.5d.6b, lb.2d.3c.4b.5d.6c, lb.2d.3c.4b.5d.6d, lb.2d.3c.4b.5d.6e, lb.2d.3c.4b.5d.6f, lb.2d.3c.4b.5e.6a, lb.2d.3c.4b.5e.6b, lb.2d.3c.4b.5e.6c, lb.2d.3c.4b.5e.6d, lb.2d.3c.4b.5e.6e, lb.2d.3c.4b.5e.6f, lb.2d.3c.4b.5f.6a, lb.2d.3c.4b.5f.6b, lb.2d.3c.4b.5f.6c, lb.2d.3c.4b.5f.6d, lb.2d.3c.4b.5f.6e, lb.2d.3c.4b.5f.6f, lb.2d.3c.4c.5a.6a, lb.2d.3c.4c.5a.6b, lb.2d.3c.4c.5a.6c, lb.2d.3c.4c.5a.6d, lb.2d.3c.4c.5a.6e, lb.2d.3c.4c.5a.6f, lb.2d.3c.4c.5b.6a, lb.2d.3c.4c.5b.6b, lb.2d.3c.4c.5b.6c, lb.2d.3c.4c.5b.6d, lb.2d.3c.4c.5b.6e, lb.2d.3c.4c.5b.6f, lb.2d.3c.4c.5c.6a, lb.2d.3c.4c.5c.6b, lb.2d.3c.4c.5c.6c, lb.2d.3c.4c.5c.6d, lb.2d.3c.4c.5c.6e, lb.2d.3c.4c.5c.6f, lb.2d.3c.4c.5d.6a, lb.2d.3c.4c.5d.6b, lb.2d.3c.4c.5d.6c, lb.2d.3c.4c.5d.6d, lb.2d.3c.4c.5d.6e, lb.2d.3c.4c.5d.6f, lb.2d.3c.4c.5e.6a, lb.2d.3c.4c.5e.6b, lb.2d.3c.4c.5e.6c, lb.2d.3c.4c.5e.6d, lb.2d.3c.4c.5e.6e, lb.2d.3c.4c.5e.6f, lb.2d.3c.4c.5f.6a, lb.2d.3c.4c.5f.6b, lb.2d.3c.4c.5f.6c, lb.2d.3c.4c.5f.6d, lb.2d.3c.4c.5f.6e, lb.2d.3c.4c.5f.6f, lb.2d.3c.4d.5a.6a, lb.2d.3c.4d.5a.6b, lb.2d.3c.4d.5a.6c, lb.2d.3c.4d.5a.6d, lb.2d.3c.4d.5a.6e, lb.2d.3c.4d.5a.6f, lb.2d.3c.4d.5b.6a, lb.2d.3c.4d.5b.6b, lb.2d.3c.4d.5b.6c, lb.2d.3c.4d.5b.6d, lb.2d.3c.4d.5b.6e, lb.2d.3c.4d.5b.6f, lb.2d.3c.4d.5c.6a, lb.2d.3c.4d.5c.6b, lb.2d.3c.4d.5c.6c, lb.2d.3c.4d.5c.6d, lb.2d.3c.4d.5c.6e, lb.2d.3c.4d.5c.6f, lb.2d.3c.4d.5d.6a, lb.2d.3c.4d.5d.6b, lb.2d.3c.4d.5d.6c, lb.2d.3c.4d.5d.6d, lb.2d.3c.4d.5d.6e, lb.2d.3c.4d.5d.6f, lb.2d.3c.4d.5e.6a, lb.2d.3c.4d.5e.6b, lb.2d.3c.4d.5e.6c, lb.2d.3c.4d.5e.6d, lb.2d.3c.4d.5e.6e, lb.2d.3c.4d.5e.6f, lb.2d.3c.4d.5f.6a, lb.2d.3c.4d.5f.6b, lb.2d.3c.4d.5f.6c, lb.2d.3c.4d.5f.6d, lb.2d.3c.4d.5f.6e, lb.2d.3c.4d.5f.6f, lb.2d.3c.4e.5a.6a, lb.2d.3c.4e.5a.6b, lb.2d.3c.4e.5a.6c, lb.2d.3c.4e.5a.6d, lb.2d.3c.4e.5a.6e, lb.2d.3c.4e.5a.6f, lb.2d.3c.4e.5b.6a, lb.2d.3c.4e.5b.6b, lb.2d.3c.4e.5b.6c, lb.2d.3c.4e.5b.6d, lb.2d.3c.4e.5b.6e, lb.2d.3c.4e.5b.6f, lb.2d.3c.4e.5c.6a, lb.2d.3c.4e.5c.6b, lb.2d.3c.4e.5c.6c, lb.2d.3c.4e.5c.6d, lb.2d.3c.4e.5c.6e, lb.2d.3c.4e.5c.6f, lb.2d.3c.4e.5d.6a, lb.2d.3c.4e.5d.6b, lb.2d.3c.4e.5d.6c, lb.2d.3c.4e.5d.6d, lb.2d.3c.4e.5d.6e, lb.2d.3c.4e.5d.6f, -182- 200918507 lb.2d.3c.4e.5e.6a, lb.2d.3c.4e.5e.6b, lb.2d.3c.4e.5e.6c, lb.2d.3c.4e.5e.6d, lb.2d.3c.4e.5e.6e, lb.2d.3c.4e.5e.6f, lb.2d.3c.4e.5f.6a, lb.2d.3c.4e.5f.6b, lb.2d.3c.4e.5f.6c, lb.2d.3c.4e.5f.6d, lb.2d.3c.4e.5f.6e, lb.2d.3c.4e.5f.6f, lb.2d.3c.4f.5a.6a, lb.2d.3c.4f.5a.6b, lb.2d.3c.4f.5a.6c, lb.2d.3c.4f.5a.6d, ί lb.2d.3c.4f.5a.6e, lb.2d.3c.4f.5a.6f, lb.2d.3c.4f.5b.6a, lb.2d.3c.4f.5b.6b, lb.2d.3c.4f.5b.6c, lb.2d.3c.4f.5b.6d, lb.2d.3c.4f.5b.6e, lb.2d.3c.4f.5b.6f, lb.2d.3c.4f.5c.6a, lb.2d.3c.4f.5c.6b, lb.2d.3c.4f.5c.6c, lb.2d.3c.4f.5c.6d, lb.2d.3c.4f.5c.6e, lb.2d.3c.4f.5c.6f, lb.2d.3c.4f.5d.6a, lb.2d.3c.4f.5d.6b, lb.2d.3c.4f.5d.6c, lb.2d.3c.4f.5d.6d, lb.2d.3c.4f.5d.6e, lb.2d.3c.4f.5d.6f, lb.2d.3c.4f.5e.6a, lb.2d.3c.4f.5e.6b, lb.2d.3c.4f.5e.6c, lb.2d.3c.4f.5e.6d, lb.2d.3c.4f.5e.6e, lb.2d.3c.4f.5e.6f, lb.2d.3c.4f.5f.6a, lb.2d.3c.4f.5f.6b, lb.2d.3c.4f.5f.6c, lb.2d.3c.4f.5f.6d, lb.2d.3c.4f.5f.6e, lb.2d.3c.4f.5f.6f, lb.2d.3d.4a.5a.6a, lb.2d.3d.4a.5a.6b, lb.2d.3d.4a.5a.6c, lb.2d.3d.4a.5a.6d, lb.2d.3d.4a.5a.6e, lb.2d.3d.4a.5a.6f, lb.2d.3d.4a.5b.6a, lb.2d.3d.4a.5b.6b, lb.2d.3d.4a.5b.6c, lb.2d.3d.4a.5b.6d, lb.2d.3d.4a.5b.6e, lb.2d.3d.4a.5b.6f, lb.2d.3d.4a.5c.6a, lb.2d.3d.4a.5c.6b, lb.2d.3d.4a.5c.6c, lb.2d.3d.4a.5c.6d, lb.2d.3d.4a.5c.6e, lb.2d.3d.4a.5c.6f, lb.2d.3d.4a.5d.6a, lb.2d.3d.4a.5d.6b, lb.2d.3d.4a.5d.6c, lb.2d.3d.4a.5d.6d, lb.2d.3d.4a.5d.6e, lb.2d.3d.4a.5d.6f, lb.2d.3d.4a.5e.6a, lb.2d.3d.4a.5e.6b, lb.2d.3d.4a.5e.6c, lb.2d.3d.4a.5e.6d, lb.2d.3d.4a.5e.6e, lb.2d.3d.4a.5e.6f, lb.2d.3d.4a.5f.6a, lb.2d.3d.4a.5f.6b, lb.2d.3d.4a.5f.6c, lb.2d.3d.4a.5f.6d, lb.2d.3d.4a.5f.6e, lb.2d.3d.4a.5f.6f, lb.2d.3d.4b.5a.6a, lb.2d.3d.4b.5a.6b, lb.2d.3d.4b.5a.6c, lb.2d.3d.4b.5a.6d, lb.2d.3d.4b.5a.6e, lb.2d.3d.4b.5a.6f, lb.2d.3d.4b.5b.6a, lb.2d.3d.4b.5b.6b, lb.2d.3d.4b.5b.6c, lb.2d.3d.4b.5b.6d, lb.2d.3d.4b.5b.6e, lb.2d.3d.4b.5b.6f, lb.2d.3d.4b.5c.6a, ;lb.2d.3d.4b.5c.6b, lb.2d.3d.4b.5c.6c, lb.2d.3d.4b.5c.6d, lb.2d.3d.4b.5c.6e, lb.2d.3d.4b.5c.6f, lb.2d.3d.4b.5d.6a, lb.2d.3d.4b.5d.6b, lb.2d.3d.4b.5d.6c, lb.2d.3d.4b.5d.6d, lb.2d.3d.4b.5d.6e, lb.2d.3d.4b.5d.6f, lb.2d.3d.4b.5e.6a, lb.2d.3d.4b.5e.6b, lb.2d.3d.4b.5e.6c, lb.2d.3d.4b.5e.6d, lb.2d.3d.4b.5e.6e, lb.2d.3d.4b.5e.6f, lb.2d.3d.4b.5f.6a, lb.2d.3d.4b.5f.6b, lb.2d.3d.4b.5f.6c, I lb.2d.3d.4b.5f.6d, lb.2d.3d.4b.5f.6e, lb.2d.3d.4b.5f.6f, lb.2d.3d.4c.5a.6a, lb.2d.3d.4c.5a.6b, lb.2d.3d.4c.5a.6c, lb.2d.3d.4c.5a.6d, lb.2d.3d.4c.5a.6e, lb.2d.3d.4c.5a.6f, lb.2d.3d.4c.5b.6a, lb.2d.3d.4c.5b.6b, lb.2d.3d.4c.5b.6c, lb.2d.3d.4c.5b.6d, lb.2d.3d.4c.5b.6e, lb.2d.3d.4c.5b.6f, lb.2d.3d.4c.5c.6a, lb.2d3d.4c.5c.6b, lb.2d.3d.4c.5c.6c, lb.2d.3d.4c.5c6d, lb.2d.3d.4c.5c.6e, ;lb.2d.3d.4c.5c.6f, lb.2d.3d.4c.5d.6a, lb,2d.3d.4c.5d.6b, lb.2d.3d.4c.5d.6c, lb.2d.3d.4c.5d.6d, lb.2d.3d.4c.5d.6e, lb.2d.3d.4c.5d.6f, lb.2d.3d.4c.5e.6a, lb.2d.3d.4c.5e.6b, lb.2d.3d.4c.5e.6c, lb.2d.3d.4c.5e.6d, lb.2d.3d.4c.5e.6e, lb.2d.3d.4c.5e.6f, lb.2d.3d.4c.5f.6a, lb.2d.3d.4c.5f.6b, lb.2d.3d.4c.5f.6c, lb.2d.3d.4c.5f.6d, lb.2d.3d.4c.5f.6e, lb.2d.3d.4c.5f.6f, lb.2d.3d.4d.5a.6a, i lb.2d.3d.4d.5a.6b, lb.2d.3d.4d.5a.6c, lb.2d.3d.4d.5a.6d, lb.2d.3d.4d.5a.6e, lb.2d.3d.4d.5a.6f, lb.2d.3d.4d.5b.6a, lb.2d.3d.4d.5b.6b, lb.2d.3d.4d.5b.6c, lb.2d.3d.4d.5b.6d, lb.2d.3d.4d.5b.6e, lb.2d.3d.4d.5b.6f, lb.2d.3d.4d.5c.6a, -183- 200918507 lb.2d.3d.4d.5c.6b, lb.2d.3d.4d.5c.6c, lb.2d.3d.4d.5c.6d, lb.2d.3d.4d.5c.6e, lb.2d.3d.4d.5c.6f, lb.2d.3d.4d.5d.6a, lb.2d.3d.4d.5d.6b, lb.2d.3d.4d.5d.6c, lb.2d.3d.4d.5d.6d, lb.2d.3d.4d.5d.6e, lb.2d.3d.4d.5d.6f, lb.2d.3d.4d.5e.6a, lb.2d.3d.4d.5e.6b, lb.2d.3d.4d.5e.6c, lb.2d.3d.4d.5e.6d, lb.2d.3d.4d.5e.6e, lb.2d.3d.4d.5e.6f, lb.2d.3d.4d.5f.6a, lb.2d.3d.4d.5f.6b, lb.2d.3d.4d.5f.6c, lb.2d.3d.4d.5f.6d, lb.2d.3d.4d.5f.6e, lb.2d.3d.4d.5f.6f, lb.2d.3d.4e.5a.6a, lb.2d.3d.4e.5a.6b, lb.2d.3d.4e.5a.6c, lb.2d.3d.4e.5a.6d, lb.2d.3d.4e.5a.6e, lb.2d.3d.4e.5a.6f, lb.2d.3d.4e.5b.6a, lb.2d.3d.4e.5b.6b, lb.2d.3d.4e.5b.6c, lb.2d.3d.4e.5b.6d, lb.2d.3d.4e.5b.6e, lb.2d.3d.4e.5b.6f, lb.2d.3d.4e.5c.6a, lb.2d.3d.4e.5c.6b, lb.2d.3d.4e.5c.6c, lb.2d.3d.4e.5c.6d, lb.2d.3d.4e.5c.6e, lb.2d.3d.4e.5c.6f, lb.2d.3d.4e.5d.6a, lb.2d.3d.4e.5d.6b, lb.2d.3d.4e.5d.6c, lb.2d.3d.4e.5d.6d, lb.2d.3d.4e.5d.6e, lb.2d.3d.4e.5d.6f, lb.2d.3d.4e.5e.6a, lb.2d.3d.4e.5e.6b, lb.2d.3d.4e.5e.6c, lb.2d.3d.4e.5e.6d, lb.2d.3d.4e.5e.6e, lb.2d.3d.4e.5e.6f, lb.2d.3d.4e.5f.6a/ lb.2d.3d.4e.5f.6b, lb.2d.3d.4e.5f.6c, lb.2d.3d.4e.5f.6d, lb.2d.3d.4e.5f.6e, lb.2d.3d.4e.5f.6f, lb.2d.3d.4f.5a.6a, lb.2d.3d.4f.5a.6b, lb.2d.3d.4f.5a.6c, lb.2d.3d.4f.5a.6d, lb.2d.3d.4f.5a.6e, lb.2d.3d.4f.5a.6f, lb.2d.3d.4f.5b.6a, lb.2d.3d.4f.5b.6b, lb.2d.3d.4f.5b.6c, lb.2d.3d.4f.5b.6d, lb.2d.3d.4f-5b.6e, lb.2d.3d.4f.5b.6f, lb.2d.3d.4f.5c.6a, lb.2d.3d.4f.5c.6b, lb.2d.3d.4f.5c.6c, lb.2d.3d.4f.5c.6d, lb.2d.3d.4f.5c.6e, lb.2d.3d.4f.5c.6f, lb.2d.3d.4f.5d.6a, lb.2d.3d.4f.5d.6b, lb.2d.3d.4f.5d.6c, lb.2d.3d.4f.5d.6d, lb.2d.3d.4f.5d.6e, lb.2d.3d.4f.5d.6f, lb.2d.3d.4f.5e.6a, lb.2d.3d.4f.5e.6b, lb.2d.3d.4f.5e.6c, lb.2d.3d.4f.5e.6d, lb.2d.3d.4f.5e.6e, lb.2d.3d.4f.5e.6f, lb.2d.3d.4f.5f.6a, lb.2d.3d.4f.5f.6b, lb.2d.3d.4f.5f.6c, lb.2d.3cL4f,5f,6d, lb.2d.3d.4f.5f.6e, lb.2d.3d,4f.5f,6f, lb.2d.3e.4a.5a.6a, lb.2d.3e.4a.5a.6b, lb.2d.3e.4a.5a.6c, lb.2d.3e.4a.5a.6d, lb.2d.3e.4a.5a.6e, lb.2d.3e.4a.5a.6f, lb.2d.3e.4a.5b.6a, lb.2d.3e.4a.5b.6b, lb.2d.3e.4a.5b.6c, lb.2d.3e.4a.5b.6d, lb.2d.3e.4a.5b.6e, lb.2d.3e.4a.5b.6f, lb.2d.3e.4a.5c.6a, lb.2d.3e.4a.5c.6b, lb.2d.3e.4a.5c.6c, lb.2d.3e.4a.5c.6d, lb.2d.3e.4a.5c.6e, lb.2d.3e.4a.5c.6f, lb-2d.3e.4a.5d,6a, lb.2d.3e.4a.5d.6b, lb.2d.3e.4a.5d.6c:, lb.2d.3e.4a.5d.6d, lb.2d.3e.4a.5d.6e, lb.2d.3e.4a.5d.6f, lb.2d.3e.4a.5e.6a, lb.2d.3e.4a.5e.6b, lb.2d.3e.4a.5e.6c, lb.2d.3e.4a.5e.6d, lb.2d.3e.4a.5e.6e, lb.2d.3e.4a.5e.6f, lb.2d.3e.4a.5f.6a, lb.2d.3e.4a.5f.6b, lb.2d.3e.4a.5f.6c, lb.2d.3e.4a.5f.6d, lb.2d.3e.4a.5f.6e, lb.2d.3e.4a.5f.6f, lb.2d.3e.4b.5a.6a, lb.2d.3e.4b.5a.6b, lb.2d,3e.4b,5a.6c, lb.2d.3e.4b,5a.6d, lb.2d3e.4b.5a.6e, lb.2d.3e.4b.5a.6f, lb.2d.3e.4b.5b.6a, lb.2d.3e.4b.5b.6b, lb.2d.3e.4b.5b.6c, lb.2d.3e.4b.5b.6d, lb.2d.3e.4b.5b.6e, lb.2d.3e.4b.5b.6f, lb.2d.3e.4b.5c.6a, lb.2d.3e.4b.5c.6b, lb.2d.3e.4b.5c.6Q lb.2d.3e.4b.5c.6d, lb.2d.3e.4b,5c.6e, lb.2d.3e.4b.5c.6f, lb.2d.3e.4b.5d.6a, lb.2d.3e.4b.5d.6b, lb.2d.3e.4b.5d.6c, lb.2d.3e.4b.5d.6d, lb.2d.3e.4b.5d.6e, lb.2d.3e.4b.5d.6f, lb.2d.3e.4b.5e.6a, lb.2d.3e.4b.5e.6b, lb.2d.3e.4b.5e.6c, lb.2d.3e.4b.5e.6d, lb.2d.3e.4b.5e.6e, lb.2d.3e.4b.5e.6f, lb.2d.3e.4b.5f.6a, lb.2d.3e.4b.5f.6b, lb.2d.3e.4b.5f.6c, lb.2d.3e.4b.5f.6d, lb.2d.3e.4b.5f.6e, lb.2d.3e.4b.5f.6f, lb.2d.3e.4c.5a.6a, -184- 200918507 lb.2d3e.4c.5a.6b； lb.2d.3e.4c.5a.6c, lb.2d.3e.4c.5a.6d, lb.2d.3e.4c.5a.6e, lb.2d.3e.4c.5a.6f, lb.2d.3e.4c.5b.6a, lb.2d.3e.4c.5b.6b, lb.2d.3e.4c.5b.6c, lb.2d.3e.4c.5b.6d, lb.2d.3e.4c.5b.6e, lb.2d.3e.4c.5b.6f, lb.2d.3e.4c.5c.6a, lb.2d.3e.4c.5c.6b, lb.2d.3e.4c.5c.6c, lb.2d.3e.4c.5c.6d, lb.2d.3e.4c.5c.6e, lb.2d.3e.4c.5c.6f, lb.2d.3e.4c.5d.6a, lb.2d.3e.4c.5d.6b, lb.2d.3e.4c.5d.6c, lb.2d.3e.4c.5d.6d, lb.2d.3e.4c.5d.6e, lb.2d.3e.4c.5d.6f, lb.2d.3e.4c.5e.6a, lb.2d.3e.4c.5e.6b, lb.2d.3e.4c.5e.6c, lb.2d.3e.4c.5e.6d, lb.2d.3e.4c.5e.6e, lb.2d.3e.4c.5e.6f, lb.2d.3e.4c.5f.6a, lb.2d.3e.4c.5f.6b, lb.2d.3e.4c.5f.6c, lb.2d.3e.4c.5f.6d, lb.2d.3e.4c.5f.6e, lb.2d.3e.4c.5f.6f, lb.2d.3e.4d.5a.6a, lb.2d.3e.4d.5a.6b, lb.2d.3e.4d.5a.6c, lb.2d.3e.4d.5a.6d, lb.2d.3e.4d.5a.6e, lb.2d.3e.4d.5a.6f, lb.2d.3e.4d.5b.6a, lb.2d.3e.4d.5b.6b, lb.2d.3e.4d.5b.6c, lb.2d.3e.4d.5b.6d, lb.2d.3e.4d.5b.6e, lb.2d.3e.4d.5b.6f, lb.2d.3e.4d.5c.6a, lb.2d.3e.4d.5c.6b, lb.2d.3e.4d.5c.6c, lb.2d.3e.4d.5c.6d, lb.2d.3e.4d.5c.6e, lb.2d.3e.4d.5c.6f, lb.2d.3e.4d.5d.6a, lb.2d.3e.4d.5d.6b, lb.2d.3e.4d.5d.6c, lb.2d.3e.4d.5d.6d, lb.2d.3e.4d.5d.6e, lb.2d.3e.4d.5d.6f, lb.2d.3e.4d.5e.6a, lb.2d.3e.4d.5e.6b, lb.2d.3e.4d.5e.6c, lb.2d.3e.4d.5e.6d, lb.2d.3e.4d.5e.6e, lb.2d.3e.4d.5e.6f, lb.2d.3e.4d.5f.6a, lb.2d.3e.4d.5f.6b, lb.2d.3e.4d.5f.6c, lb.2d.3e.4d.5f.6d, lb.2d.3e.4d.5f.6e, lb.2d.3e.4d.5f.6f, 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lb.2e.3a.4e.5f.6d, lb.2e.3a.4e.5f.6e, lb.2e.3a.4e.5f.6f, lb.2e.3a.4f.5a.6a, lb.2e.3a.4f.5a.6b, lb.2e.3a.4f.5a.6c, lb.2e.3a.4f.5a.6d, lb.2e.3a.4f.5a.6e, lb.2e.3a.4f.5a.6f, lb.2e.3a.4f.5b.6a, lb.2e.3a.4f.5b,6b, lb.2e.3a.4f.5b.6c, lb.2e.3a.4f.5b.6d, lb.2e.3a.4f.5b.6e, lb.2e.3a.4f.5b.6f, lb.2e.3a.4f.5c.6a, lb.2e.3a.4f.5c.6b, lb.2e.3a.4f.5c.6c, lb.2e.3a.4f.5c.6d, lb.2e.3a.4f.5c.6e, lb.2e.3a.4f.5c.6f, lb.2e.3a.4f.5d.6a, lb.2e.3a.4f.5d.6b, lb.2e.3a.4f.5d.6c, lb.2e.3a.4f.5d.6d, lb.2e.3a.4f.5d.6e, lb.2e.3a.4f.5d.6f, lb.2e.3a.4f.5e.6a, lb.2e.3a.4f.5e.6b, lb.2e.3a.4f.5e.6c, lb.2e.3a.4f.5e.6d, lb.2e.3a.4f.5e.6e, lb.2e.3a.4f.5e.6f, lb.2e.3a.4f.5f.6a, lb.2e.3a.4f.5f.6b, lb.2e.3a.4f.5f.6c, lb.2e.3a.4f.5f.6d, lb.2e.3a.4f.5f.6e, lb.2e.3a.4f.5f.6f, lb.2e.3b.4a.5a.6a, lb.2e.3b.4a.5a.6b, lb.2e.3b.4a.5a.6c, lb.2e.3b.4a.5a.6d, lb.2e.3b.4a.5a.6e, lb.2e.3b.4a.5a.6f, lb.2e.3b.4a.5b.6a, lb.2e.3b.4a.5b.6b, lb.2e.3b.4a.5b.6c, lb.2e.3b.4a.5b.6d, lb.2e.3b.4a.5b.6e, lb.2e.3b.4a.5b.6f, lb.2e.3b.4a.5c.6a, lb.2e.3b.4a.5c.6b, lb.2e.3b.4a.5c.6c, lb.2e.3b.4a.5c.6d, lb.2e.3b.4a.5c.6e, lb.2e.3b.4a.5c.6f, lb.2e.3b.4a.5d.6a, lb.2e.3b.4a.5d.6b, lb.2e.3b.4a.5d.6c, lb.2e.3b.4a.5d.6d, lb.2e.3b.4a.5d.6e, lb.2e.3b.4a.5d.6f, lb.2e.3b.4a.5e.6a, lb.2e.3b.4a.5e.6b, lb.2e.3b.4a.5e.6c, lb.2e.3b.4a.5e.6d, lb.2e.3b.4a.5e.6e, lb.2e.3b.4a.5e.6f, lb.2e.3b.4a.5f.6a, lb.2e.3b.4a.5f.6b, lb.2e.3b.4a.5f.6c, lb.2e.3b.4a.5f.6d, lb.2e.3b.4a.5f.6e, lb.2e.3b.4a.5f.6f, lb.2e.3b.4b.5a.6a, lb.2e.3b.4b.5a.6b, lb.2e.3b.4b.5a.6c, lb.2e.3b.4b.5a.6d, lb.2e.3b.4b.5a.6e, lb.2e.3b.4b.5a.6f, lb.2e.3b.4b.5b.6a, lb.2e.3b.4b.5b.6b, lb.2e.3b.4b.5b.6c, lb.2e.3b.4b.5b.6d, lb.2e.3b.4b.5b.6e, lb.2e.3b.4b.5b.6f, lb.2e.3b.4b.5c.6a, lb.2e.3b.4b.5c.6b, lb.2e.3b.4b.5c.6c, lb.2e.3b.4b.5c.6d, lb.2e.3b.4b.5c.6e, lb.2e.3b.4b.5c.6f, lb.2e.3b.4b.5d.6a, lb.2e.3b.4b.5d.6b, lb.2e.3b.4b.5d.6c, lb.2e.3b.4b.5d.6d, lb.2e.3b.4b.5d.6e, lb.2e3b.4b.5d.6f, lb.2e.3b.4b.5e.6a, lb.2e.3b.4b.5e.6b, lb.2e.3b.4b.5e.6c, lb.2e.3b.4b.5e.6d, lb.2e.3b.4b.5e.6e, lb.2e.3b.4b.5e.6f, lb.2e.3b.4b.5f.6a, lb.2e.3b.4b.5f.6b, lb,2e.3b.4b.5f.6c, lb.2e.3b.4b.5f.6d, lb.2e.3b.4b.5f.6e, lb.2e.3b.4b.5f.6f, lb.2e.3b.4c.5a.6a, lb.2e.3b.4c.5a.6b, lb.2e.3b.4c.5a.6c, lb.2e.3b.4c.5a.6d, lb.2e.3b.4c.5a.6e, lb.2e.3b.4c.5a.6f, lb.2e.3b.4c.5b.6a, lb.2e.3b.4c.5b.6b, lb.2e.3b.4c.5b.6c, lb.2e.3b.4c.5b.6d, lb.2e.3b.4c.5b.6e, lb.2e.3b.4c.5b.6f, lb.2e.3b.4c.5c.6a, lb.2e.3b.4c.5c.6b, lb.2e.3b.4c.5c.6c, lb.2e.3b.4c.5c.6d, lb.2e.3b.4c.5c.6e, lb.2e.3b.4c.5c.6f, lb.2e.3b.4c.5d.6a, lb.2e.3b.4c.5d.6b, lb.2e.3b.4c.5d.6c, lb.2e.3b.4c.5d.6d, lb,2e.3b.4c.5d.6e, lb.2e.3b.4c.5d.6f, lb.2e.3b.4c.5e.6a, lb.2e.3b.4c.5e.6b, lb.2e.3b.4c.5e.6c, lb.2e.3b.4c.5e.6d, lb.2e.3b.4c.5e.6e, lb.2e.3b.4c.5e.6f, lb.2e.3b.4c.5f.6a, lb.2e.3b.4c.5f.6b, lb.2e.3b.4c.5f.6c, lb.2e.3b.4c.5f.6d, lb.2e.3b.4c.5f.6e, lb.2e.3b.4c.5f.6f, lb.2e.3b.4d.5a.6a, lb.2e.3b.4d.5a.6b, lb.2e.3b.4d.5a.6c, lb.2e.3b.4d.5a.6d, lb.2e.3b.4d.5a.6e, lb.2e.3b.4d.5a.6f, lb.2e.3b.4d.5b.6a, lb.2e.3b.4d.5b.6b, lb.2e.3b.4d.5b.6c, lb.2e.3b.4d.5b.6d, -188- 200918507 lb.2e.3b.4d.5b.6e, lb.2e.3b.4d.5b.6f, lb.2e.3b.4d.5c.6a, lb.2e.3b.4d.5c.6b, lb.2e.3b.4d.5c.6c, lb.2e.3b.4d.5c.6d, lb.2e.3b.4d.5c.6e, lb.2e.3b.4d.5c.6f, lb.2e.3b.4d.5d.6a, lb.2e.3b.4d.5d.6b, lb.2e.3b.4d.5d.6c, lb.2e.3b.4d.5d.6d, lb.2e.3b.4d.5d.6e, lb.2e.3b.4d.5d.6f, lb.2e.3b.4d.5e.6a, lb.2e.3b.4d.5e.6b, lb.2e.3b.4d.5e.6c, lb.2e.3b.4d.5e.6d, lb.2e.3b.4d.5e.6e, lb.2e.3b.4d.5e.6f, lb.2e.3b.4d.5f.6a, lb.2e.3b.4d.5f.6b, lb.2e.3b.4d.5f.6c, lb.2e.3b.4d.5f.6d, lb.2e.3b.4d.5f.6e, lb.2e.3b.4d.5f.6f, lb.2e.3b.4e.5a.6a, lb.2e.3b.4e.5a.6b, lb.2e.3b.4e.5a.6c, lb.2e.3b.4e.5a.6d, lb.2e.3b.4e.5a.6e, lb.2e.3b.4e.5a.6f, lb.2e.3b.4e.5b.6a, lb.2e.3b.4e.5b.6b, lb.2e.3b.4e.5b.6c, lb-2e.3b.4e.5b.6d, lb.2e.3b.4e.5b.6e, lb.2e.3b*4e.5b.6f, lb.2e.3b.4e.5c.6a, lb.2e.3b.4e.5c.6b, lb.2e.3b.4e.5c.6c, lb.2e.3b.4e.5c.6d, lb.2e.3b.4e.5c.6e, lb.2e.3b.4e.5c.6f, lb.2e.3b.4e.5d.6a, lb.2e.3b.4e.5d.6b, lb.2e.3b.4e.5d.6c, lb.2e.3b.4e.5d.6d, lb.2e.3b.4e.5d.6e, lb.2e.3b.4e.5d.6f, lb.2e.3b.4e.5e.6a, lb.2e.3b.4e.5e.6b, lb.2e.3b.4e.5e.6c, lb.2e.3b.4e.5e.6d, lb.2e.3b.4e.5e.6e, lb.2e.3b.4e.5e.6f, lb.2e.3b.4e.5f.6a, lb.2e.3b.4e.5f.6b, lb.2e.3b.4e.5f.6c, lb.2e.3b.4e.5f.6d, lb.2e.3b.4e.5f.6e, lb.2e.3b.4e.5f.6t lb.2e.3b.4f.5a.6a, lb.2e.3b.4f.5a.6b, lb.2e.3b.4f.5a.6c, lb.2e.3b.4f.5a.6d, lb.2e.3b.4f.5a.6e, lb.2e.3b.4f.5a.6f, lb.2e.3b.4f.5b.6a, lb.2e.3b.4f.5b.6b, lb.2e.3b.4f.5b.6c, lb.2e.3b.4f.5b.6d, lb.2e.3b.4f.5b.6e, lb.2e.3b.4f.5b.6f, lb.2e.3b.4f.5c.6a, lb.2e.3b.4f.5c.6b, lb.2e.3b.4f.5c.6c, lb.2e.3b.4f.5c.6d, lb.2e.3b.4f.5c.6e, lb.2e.3b.4f.5c.6f, lb.2e.3b.4f.5d.6a, lb.2e.3b.4f.5d.6b, lb.2e.3b.4f.5d.6c, lb.2e.3b.4f.5d.6d, lb.2e.3b.4f.5d.6e, lb.2e.3b.4f.5d.6f, lb.2e.3b.4f.5e.6a, lb.2e.3b.4f.5e.6b, lb.2e.3b.4f.5e.6c, lb.2e.3b.4f.5e.6d, lb.2e.3b.4f.5e.6e, lb.2e.3b.4f.5e.6f, lb.2e.3b.4f.5f.6a, lb.2e.3b.4f.5f.6b, lb.2e.3b.4f.5f.6c, lb.2e.3b.4f.5f.6d, lb.2e.3b.4f.5f.6e, lb.2e.3b.4f.5f.6f, lb.2e.3c.4a.5a.6a, lb.2e.3c.4a.5a.6b, lb.2e.3c.4a.5a.6c, lb.2e.3c.4a.5a.6d, lb.2e.3c.4a.5a.6e, lb.2e.3c.4a.5a.6f, lb.2e.3c.4a.5b.6a, lb.2e.3c.4a.5b.6b, lb.2e.3c.4a.5b.6c, lb.2e.3c.4a.5b.6d, lb.2e.3c.4a.5b.6e, lb.2e.3c.4a.5b.6f, lb.2e.3c.4a.5c.6a, lb.2e.3c.4a.5c.6b, lb.2e.3c.4a.5c.6c, lb.2e.3c.4a.5c.6d, lb.2e.3c.4a.5c.6e, lb.2e.3c.4a.5c.6f, lb.2e.3c.4a.5d.6a, lb.2e.3c.4a.5d.6b, lb.2e.3c.4a.5d.6c, lb.2e.3c.4a.5d.6d, lb.2e.3c.4a.5d.6e, lb.2e.3c.4a.5d.6f, lb.2e.3c.4a.5e.6a, lb.2e.3c.4a.5e.6b, lb.2e.3c.4a.5e.6c, lb.2e.3c.4a.5e.6d, lb.2e.3c.4a.5e.6e, lb.2e.3c.4a.5e.6f, lb.2e.3c.4a.5f.6a, lb.2e.3c.4a.5f.6b, lb.2e.3c.4a.5f.6c, lb.2e.3c.4a.5f.6d, lb.2e.3c.4a.5f.6e, lb.2e.3c.4a.5f.6f, lb.2e.3c.4b.5a.6a, lb.2e.3c4b.5a.6b, lb.2e.3c.4b.5a.6c, lb.2e.3c.4b.5a.6d, lb.2e.3c.4b.5a.6e, lb.2e.3c.4b.5a.6f, lb.2e.3c.4b.5b.6a, lb.2e.3c.4b.5b.6b, lb.2e.3c.4b.5b.6c, lb.2e.3c.4b.5b.6d, lb.2e.3c.4b.5b.6e, lb.2e.3c.4b.5b.6f, lb.2e_3c.4b.5c.6a, lb.2e.3c.4b.5c.6b, lb.2e.3c.4b.5c.6c, lb.2e.3c.4b.5c.6d, lb.2e.3c.4b.5c.6e, lb.2e.3c.4b.5c.6f, lb.2e.3c.4b.5d.6a, lb.2e.3c.4b.5d.6b, 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lb.2f.3e.4d.5f.6e, lb.2f.3e.4d.5f.6f, lb.2f.3e.4e.5a.6a, lb.2f.3e.4e.5a.6b, lb.2f.3e.4e.5a.6c, lb.2f.3e.4e.5a.6d, lb.2f.3e.4e.5a.6e, lb.2f.3e.4e.5a.6f, lb.2f.3e.4e.5b.6a, lb.2f.3e.4e.5b.6b, lb.2f.3e.4e.5b.6c, lb.2f.3e.4e.5b.6d, lb.2f.3e.4e.5b.6e, lb.2f.3e.4e.5b.6f, lb.2f.3e.4e.5c.6a, lb.2f.3e.4e.5c.6b, lb.2f.3e.4e.5c.6c, lb.2f.3e.4e.5c6d, lb.2f.3e.4e.5c.6e, lb.2f.3e.4e.5c.6f, lb.2f.3e.4e.5d.6a, lb.2f.3e.4e.5d.6b, lb.2f.3e.4e.5d.6c, lb.2f.3e.4e.5d.6d, lb.2f.3e.4e.5d.6e, lb.2f.3e.4e.5d.6f, lb.2f.3e.4e.5e.6a, lb.2f.3e.4e.5e.6b, lb.2f.3e.4e.5e.6c, lb.2f.3e.4e.5e.6d, lb.2^30.40^50.68, lb.2f.3e.4e.5e.6f, lb.2f.3e.4e.5f.6a, lb.2f.3e.4e.5f.6b, lb.2f.3e.4e.5f.6c, lb.2f.3e.4e.5f.6d, lb.2f.3e.4e.5f.6e, lb.2f.3e.4e.5f.6f, lb.2f.3e.4f.5a.6a, lb.2f.3e.4f.5a.6b, lb.2f.3e.4f.5a.6c, lb.2f.3e.4f.5a.6d, lb.2f.3e.4f.5a.6e, lb.2f.3e.4f.5a.6f, lb.2f.3e.4f.5b.6a, lb.2f.3e.4f.5b.6b, lb.2f.3e.4f.5b.6c, lb.2f.3e.4f.5b.6d, lb.2f.3e.4f.5b.6e, lb.2f.3e.4f.5b.6f, lb.2f3e.4f.5c.6a, lb.2f.3e.4f.5c.6b, lb.2f.3e.4f.5c.6c, lb.2f.3e.4f.5c.6d, lb.2f.3e.4f.5c.6e, -199- 200918507 lb.2f.3e.4f.5c.6f, lb.2f.3e.4f.5d.6a, lb.2f.3e.4f.5d.6b, lb.2f.3e.4f.5d.6c, lb.2f.3e.4f.5d.6d, lb.2f.3e.4f.5d.6e, lb.2f.3e.4f.5d.6f, lb.2f.3e.4f.5e.6a, lb.2f.3e.4f.5e.6b, lb.2f.3e.4f.5e.6c, lb.2f.3e.4f.5e.6d, lb.2f.3e.4f.5e.6e, lb.2f.3e.4f.5e.6f, lb.2f.3e.4f.5f.6a, lb.2f.3e.4f.5f.6b, lb.2f.3e.4f.5f.6c, lb.2f.3e.4f.5f.6d, lb.2f.3e.4f.5f.6e, lb.2f.3e.4f.5f.6f, lb.2f.3f.4a.5a.6a, lb.2f.3f.4a.5a.6b, lb.2f.3f.4a.5a.6c, lb.2f.3f.4a.5a.6d, lb.2f.3f.4a.5a.6e, lb.2f.3f.4a.5a.6f, lb.2f.3£.4a.5b.6a, lb.2f.3f.4a.5b.6b, lb.2f.3f.4a.5b.6c, lb.2f.3f.4a.5b.6d, lb.2f.3f.4a.5b.6e, lb.2f.3f.4a.5b.6f, lb.2f.3f.4a.5c.6a, lb.2f.3f.4a.5c.6b, lb.2f.3f.4a.5c.6c, lb.2f.3f.4a.5c.6d, lb.2f.3f.4a.5c.6e, lb.2f.3f.4a.5c.6f, lb.2f.3f.4a.5d.6a, lb.2f.3f.4a.5d.6b, lb.2f.3f.4a.5d.6c, lb.2f.3f.4a.5d.6d, lb.2f.3f.4a.5d.6e, lb.2f.3f.4a.5d.6f, lb.2f.3f.4a.5e.6a, lb.2f.3f.4a.5e.6b, lb.2f.3f.4a.5e.6c, lb.2f.3f.4a.5e.6d, lb.2f.3f.4a.5e.6e, lb.2f.3f.4a.5e.6f, lb.2f.3f.4a.5f.6a, lb.2f.3f.4a.5f.6b, lb.2f.3f.4a.5f.6c, lb.2f.3f.4a.5f.6d, lb.2f.3f.4a.5f.6e, lb.2f.3f.4a.5f.6f, lb.2f.3f.4b.5a.6a, lb.2f.3f.4b.5a.6b, lb.2f.3f.4b.5a.6c, lb.2f.3f.4b.5a.6d, lb.2f.3f.4b.5a.6e, lb.2f.3f.4b.5a.6f, lb.2f.3f.4b.5b.6a, lb.2f.3f.4b.5b.6b, lb.2f.3f.4b.5b.6c, lb.2f.3f.4b.5b.6d, lb.2f.3f.4b.5b.6e, lb.2f.3f.4b.5b.6f, lb.2f.3f.4b.5c.6a, lb.2f.3f.4b.5c.6b, lb.2f.3f.4b.5c.6c, lb.2f.3f.4b.5c.6d, lb.2f.3f.4b.5c.6e, lb.2f.3f.4b.5c.6f, lb.2f.3f.4b.5d.6a, lb.2f.3f.4b.5d.6b, lb.2f.3f.4b.5d.6c, lb.2f.3f.4b.5d.6d, lb.2f.3f.4b.5d.6e, lb.2f.3f.4b.5d.6f, lb.2f.3f.4b.5e.6a, lb.2f.3f.4b.5e.6b, lb.2f.3f.4b.5e.6c, lb.2f.3f.4b.5e.6d, lb.2f.3f.4b.5e.6e, lb.2f.3f.4b.5e.6f, lb.2f.3f.4b.5f.6a, lb.2f.3f.4b.5f.6b, lb.2f.3f.4b.5f.6c, lb.2f.3f.4b.5f.6d, lb.2f.3f.4b.5f.6e, lb.2f.3f.4b.5f.6f, lb.2f.3f.4c.5a.6a, lb.2f.3f.4c.5a.6b, lb.2f.3f.4c.5a.6c, lb.2f.3f.4c.5a.6d, lb.2f.3f.4c.5a.6e, lb.2f.3f.4c.5a.6f, lb.2f.3f.4c.5b.6a, lb.2f.3f.4c.5b.6b, lb.2f.3f.4c.5b.6c, 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lb.2f.3f.4d.5e.6b, lb.2f.3f.4d.5e.6c, lb.2f.3f.4d.5e.6d, lb.2f.3f.4d.5e.6e, lb.2f.3f.4d.5e.6f, lb.2f.3f.4d.5f.6a, lb.2f.3f.4d.5f.6b, lb.2f.3f.4d.5f.6c, lb.2f.3f.4d.5f.6d, lb.2f.3f.4d.5f.6e, lb.2f.3f.4d.5f.6f, lb.2f.3f.4e.5a.6a, lb.2f.3f.4e.5a.6b, lb.2f.3f.4e.5a.6c, lb.2f.3f.4e.5a.6d, lb.2f.3f.4e.5a.6e, lb.2f.3f.4e.5a.6f, lb.2f.3f.4e.5b.6a, lb.2f.3f.4e.5b.6b, lb.2f.3f.4e.5b.6c, lb.2f.3f.4e.5b.6d, lb.2f.3f.4e.5b.6e, lb.2f.3f.4e.5b.6f, lb.2f.3f.4e.5c.6a, lb.2f.3f.4e.5c.6b, lb.2f.3f.4e.5c.6c, lb.2f.3f.4e.5c.6d, lb.2f.3f.4e.5c.6e, lb.2f.3f.4e.5c.6f, lb.2f.3f.4e.5d.6a, lb.2f.3f.4e.5d.6b, lb.2f.3f.4e.5d.6c, lb.2f.3f.4e.5d.6d, lb.2f.3f.4e.5d.6e, lb.2f.3f.4e.5d.6f, lb.2f.3f.4e.5e.6a, lb.2f.3f.4e.5e.6b, lb.2f.3f.4e.5e.6c, lb.2f.3f.4e.5e.6d, lb.2f.3f.4e.5e.6e, lb.2f.3f.4e.5e.6f, lb.2f.3f.4e.5f.6a, lb.2f.3f.4e.5f.6b, lb.2f.3f.4e.5f.6c, lb.2f.3f.4e.5f.6d, lb.2f.3f.4e.5f.6e, lb.2f.3f.4e.5f.6f, lb.2f.3f.4f.5a.6a, lb.2f.3f.4f.5a.6b, lb.2f.3f.4f.5a.6c, lb.2f.3f.4f.5a.6d, lb.2f.3f.4f.5a.6e, lb.2f.3f.4f.5a.6f, lb.2f.3f.4f.5b.6a, lb.2f.3f.4f.5b.6b, lb.2f.3f.4f.5b.6c, lb.2f.3f.4f.5b.6d7 -200- 200918507 lb.2f.3f.4f.5b.6e, lb.2f.3f.4f.5b.6f, lb.2f.3f.4f.5c.6a, lb.2f.3f.4f.5c.6b, lb.2f.3f.4f.5c.6c, lb.2f.3f.4f.5c.6d, lb.2f.3f.4f.5c.6e, lb.2f.3f.4f.5c.6f, lb.2f.3f.4f.5d.6a, lb.2f.3f.4f.5d.6b, lb.2f.3f.4f.5d.6c, lb.2f.3f.4f.5d.6d, lb.2f.3f.4f.5d.6e, lb.2f.3f.4f.5d.6f, lb.2f.3f.4f.5e.6a, lb.2f.3f.4f.5e.6b, lb.2f.3f.4f.5e.6c, lb.2f.3f.4f.5e.6d, lb.2f.3f.4f.5e.6e, lb.2f.3f.4f.5e.6f, lb.2f.3f.4f.5f.6a, lb.2f.3f.4f.5f.6b, lb.2f.3f.4f.5f.6c, lb.2f.3f.4f.5f.6d, lb.2f.3f.4f.5f.6e, lb. 2f.3f.4f.5f.6f, lc.2a.3a.4a.5a.6a, lc.2a.3a.4a.5a.6b, lc.2a.3a.4a.5a.6c, lc.2a.3a.4a.5a.6d, lc. 2a.3a.4a.5a.6e, lc.2a.3a.4a.5a.6f, lc.2a.3a.4a.5b.6a, lc.2a.3a.4a.5b.6b, lc.2a.3a.4a.5b.6c, lc.2a.3a.4a.5b.6d, lc.2a.3a.4a.5b.6e, lc.2a.3a.4a.5b.6f, lc.2a.3a.4a.5c.6a, lc.2a.3a.4a.5c.6b, lc.2a.3a.4a.5c.6c, lc.2a.3a.4a.5c.6d, lc.2a.3a.4a.5c.6e, lc.2a.3a.4a.5c.6f, lc.2a.3a.4a.5d.6a, lc.2a.3a.4a.5d.6b, 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lc.2b.3b.4e.5d.6e, lc.2b.3b.4e.5d.6f, lc.2b.3b.4e.5e.6a, lc.2b.3b.4e.5e.6b, lc.2b.3b.4e.5e.6c, lc.2b.3b.4e.5e.6d, lc.2b.3b.4e.5e.6e, lc.2b.3b.4e.5e.6f, lc.2b.3b.4e.5f.6a, lc.2b.3b.4e.5f.6b, lc.2b.3b.4e.5f.6c, lc.2b.3b.4e.5f.6d, lc.2b.3b.4e.5f.6e, lc.2b.3b.4e.5f.6f, lc.2b.3b.4f.5a.6a, lc.2b.3b.4f.5a.6b, lc.2b.3b.4f.5a.6c, lc.2b.3b.4f.5a.6d, lc.2b.3b.4f.5a.6e, lc.2b.3b.4f.5a.6f, lc.2b.3b,4f.5b.6a, lc.2b.3b.4f.5b.6b, lc.2b.3b.4f.5b.6c, lc.2b.3b.4f.5b.6d, 1 c.2b.3b.4f.5b.ee, lc.2b.3b.4f.5b.6f, lc.2b.3b.4f.5c.6a, lc.2b.3b.4f.5c.6b, lc.2b.3b.4f.5c.6c, lc.2b.3b.4f.5c.6d, lc.2b.3b.4f.5c.6e, lc.2b.3b.4f.5c.6f, lc.2b.3b.4f.5d.6a, lc.2b.3b.4f.5d.6b, lc.2b.3b.4f.5d.6c, lc.2b.3b.4f.5d.6d, lc.2b.3b.4f.5d.6e, lc.2b.3b.4f.5d.6f, lc.2b.3b.4f.5e.6a, lc.2b.3b.4f.5e.6b, lc.2b.3b.4f.5e.6c, lc.2b.3b.4f.5e.6d, lc.2b.3b.4f.5e.6e, lc.2b.3b.4f.5e.6f, lc.2b.3b.4f.5f.6a, lc.2b.3b.4f.5f.6b, lc2b.3b.4f.5f.6c, lc.2b.3b.4f.5f.6d, lc.2b.3b.4f.5f.6e, lc.2b.3b.4f.5f.6f, lc.2b.3c.4a.5a.6a, lc.2b.3c.4a.5a.6b, lc.2b.3c.4a.5a.6c, lc.2b.3c.4a.5a.6d, lc.2b.3c.4a.5a.6e, lc.2b.3c.4a.5a.6f, lc.2b.3c.4a.5b.6a, lc.2b.3c.4a.5b.6b, lc.2b.3c.4a.5b.6c, lc.2b.3c.4a.5b.6d, lc.2b.3c.4a.5b.6e, lc.2b.3c.4a.5b.6f, lc.2b.3c.4a.5c.6a, lc.2b.3c.4a.5c.6b, lc.2b.3c.4a.5c.6c, lc.2b.3c.4a.5c.6d, lc.2b.3c.4a.5c.6e, lc.2b.3c.4a.5c.6f, lc.2b.3c.4a.5d.6a, lc.2b.3c.4a.5d.6b, lc.2b.3c,4a.5d.6c, lc_2b*3c4a.5d.6d, lc.2b.3c.4a.5d.6e, lc.2b.3c.4a.5d.6f, lc.2b.3c.4a.5e.6a, lc.2b.3c.4a.5e.6b, lc.2b.3c.4a.5e.6c, lc.2b.3c.4a.5e.6d, lc.2b.3c.4a.5e.6e, lc.2b.3c.4a.5e.6f, lc.2b.3c.4a.5f.6a, lc.2b.3c.4a.5f.6b, lc.2b.3c.4a.5f.6c, lc.2b.3c.4a.5f.6d, lc.2b.3c.4a.5f.6e, lc.2b.3c.4a.5f.6f, lc.2b.3c.4b.5a.6a, lc.2b.3c.4b.5a.6b, lc.2b.3c.4b.5a.6c, lc.2b.3c.4b.5a.6d, lc.2b.3c.4b.5a.6e, lc.2b.3c.4b.5a.6f, lc.2b.3c.4b.5b.6a, lc.2b.3c.4b.5b.6b, lc.2b.3c.4b.5b.6c, lc.2b.3c.4b.5b.6d, lc.2b.3c.4b.5b.6e, lc.2b.3c.4b.5b.6f, lc.2b.3c.4b.5c.6a, lc.2b.3c4b.50.6^ lc.2b.3c.4b.5c.6c, lc.2b.3c.4b.5c.6d, lc.2b.3c.4b.5c.6e, lc.2b.3c.4b.5c.6f, lc.2b.3c.4b.5d.6a, lc.2b.3c.4b.5d.6b, lc.2b.3c.4b.5d.6c, lc.2b.3c.4b.5d.6d, lc.2b.3c.4b.5d.6e, lc.2b.3c.4b.5d.6f, lc.2b.3c.4b.5e.6a, lc.2b.3c.4b.5e.6b, lc.2b.3c.4b.5e.6c, lc.2b.3c.4b.5e.6d, lc.2b.3c4b.5e.6e, lc.2b.3c.4b.5e.6f, lc.2b.3c.4b.5f.6a, lc.2b.3c.4b.5f.6b, lc.2b.3c.4b.5f.6c, -210- 200918507 lc.2b.3c.4b.5f.6d, lc.2b.3c.4b.5f.6e, lc.2b.3c.4b.5f.6f, lc.2b.3c.4c.5a.6a, lc.2b.3c.4c.5a.6b, lc.2b.3c.4c.5a,6c, lc.2b.3c.4c.5a.6d, lc.2b.3c.4c.5a.6e, lc.2b.3c.4c.5a.6f, lc.2b.3c.4c.5b.6a, lc.2b.3c.4c.5b.6b, lc.2b.3c.4c.5b.6c, lc.2b.3c.4c.5b.6d, lc.2b.3c.4c.5b.6e, lc.2b.3c.4c.5b.6f, lc.2b.3c.4c.5c.6a, lc.2b.3c.4c.5c.6b, lc.2b.3c.4c.5c.6c, lc.2b.3c.4c.5c.6d, lc.2b.3c.4c*5c.6e, lc.2b.3c.4c.5c.6f, lc.2b.3c.4c.5d.6a, lc.2b.3c.4c.5d.6b, lc.2b.3c.4c.5d.6c, lc.2b.3c.4c.5d.6d, lc.2b.3c.4c.5d.6e, lc.2b.3c4c.5d.6f, lc.2b3c.4c.5e.6a, lc.2b.3c.4c.5e.6b, lc.2b.3c.4c.5e.6c, lc.2b.3c.4c.5e.6d, lc.2b.3c.4c.5e.6e, lc.2b.3c.4c.5e.6f, lc.2b.3c.4c.5f.6a, lc.2b.3c.4c.5f.6b, lc.2b.3c.4c.5f.6c, lc2b3cAc.5L6df 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lc.2f.3f.4b.5b.6e, lc.2f_3f.4b.5b.6f, lc.2f.3f.4b.5c.6a, lc.2f.3f.4b.5c.6b, lc.2f.3f.4b_5c.6c, lc.2f.3f.4b.5c6d, lc.2f.3f_4b.5c.6e, lc.2f.3f.4b.5c.6f, lc.2f.3f.4b.5d.6a, lc.2f.3f.4b.5d.6b, lc.2f.3f_4b.5d.6c, lc.2f.3f.4b.5d.6d, lc.2f.3f.4b.5d.6e, lc.2f.3f.4b.5d.6f, lc.2f.3f.4b.5e.6a, lc.2f.3f.4b.5e.6b, -241 - 200918507 lc.2f.3f.4b.5e.6c, lc2f.3f.4b.5e.6d, lc.2f.3f.4b.5e.6e, lc.2f.3f.4b.5e.6f, lc.2f.3f.4b.5f.6a, lc.2f.3f.4b.5f.6b, lc.2f.3f.4b.5f.6c, lc.2f.3f.4b.5f.6d, lc.2f.3f.4b.5f.6e, lc.2f.3f.4b.5f.6f, lc.2f.3f.4c.5a.6a, lc.2f.3f.4c.5a.6b, lc.2f.3f.4c.5a.6c, lc.2f.3f.4c.5a.6d, lc.2f.3f.4c.5a.6e, lc.2f.3f.4c.5a.6f, lc.2f.3f.4c.5b.6a, lc.2f.3f.4c.5b.6b, lc.2f.3f.4c.5b.6c, lc.2f.3f.4c.5b.6d, lc.2f.3f.4c.5b.6e, lc.2f.3f.4c.5b.6f, lc.2f.3f.4c.5c.6a, lc.2f.3f.4c.5c.6b, lc.2f.3f.4c.5c.6c, lc.2f.3f.4c.5c.6d, lc.2f.3f.4c.5c.6e, lc.2f.3f.4c.5c.6f, lc2f.3f.4c.5d.6a, lc.2f.3f.4c.5d.6b, lc.2f.3f.4c.5d.6c, lc.2f.3f.4c.5d.6d, lc.2f.3f.4c.5d.6e, lc.2f.3f.4c.5d.6f, lc.2f.3f.4c.5e.6a, lc.2f.3f.4c.5e.6b, lc.2f.3f.4c.5e.6c, lc.2f.3f.4c.5e.6d, lc.2f.3f.4c.5e.6e, lc.2f.3f.4c.5e.6f, lc.2f.3f.4c.5f.6a, lc.2f.3f.4c.5f.6b, lc.2f.3f.4c.5f.6c, lc.2f.3f.4c.5f.6d, lc.2f.3f.4c.5f.6e, lc.2f.3f.4c.5f.6f, lc.2f.3f.4d.5a.6a, lc.2f.3f.4d.5a.6b, lc.2f.3f.4d.5a.6c, lc.2f.3f.4d.5a.6d, lc.2f.3f.4d.5a.6e, lc.2f.3f.4d.5a.6f, lc.2f.3f.4d.5b.6a, lc.2f.3f.4d.5b.6b, lc.2f.3f.4d.5b.6c, lc.2f.3f.4d.5b.6d, lc.2f.3f.4d.5b.6e, lc.2f.3f.4d.5b.6f, lc.2f.3f.4d.5c.6a, lc.2f.3f.4d.5c.6b, lc.2f.3f.4d.5c.6c, lc.2f.3f.4d.5c.6d, lc.2f.3f.4d.5c.6e, lc.2f.3f.4d.5c.6f, lc.2f.3f.4d.5d.6a, lc.2f.3f.4d.5d.6b, lc.2f.3f.4d.5d.6c, lc.2f.3f.4d.5d.6d, lc.2f3f.4d.5d.6e, lc.2f.3f.4d.5d.6f, lc.2f.3f.4d.5e.6a, lc.2f.3f.4d.5e.6b, lc.2f.3f.4d.5e.6c, lc.2f.3f.4d.5e.6d, lc.2f.3f.4d.5e.6e, lc.2f.3f.4d.5e.6f, lc.2f.3f.4d.5f.6a, lc.2f.3f.4d.5f.6b, lc.2f.3f.4d.5f.6c, lc.2f.3f.4d.5f.6d, lc.2f.3f.4d.5f.6e, lc.2f.3f.4d.5f.6f, lc.2f.3f.4e.5a.6a, lc.2f.3f.4e.5a.6b, lc.2f.3f.4e.5a.6c, lc.2f.3f.4e.5a.6d, lc.2f.3f.4e.5a.6e, lc.2f.3f.4e.5a.6f, lc.2f.3f.4e.5b.6a, lc.2f.3f.4e.5b.6b, lc.2f.3f.4e.5b.6c, lc.2f.3f.4e.5b.6d, lc.2f.3f.4e.5b.6e, lc.2f.3f.4e.5b.6f, lc.2f.3f.4e.5c.6a, lc.2f.3f.4e.5c.6b, lc.2f.3f.4e.5c.6c, lc.2f.3f.4e.5c.6d, lc.2f.3f.4e.5c.6e, lc.2f.3f.4e.5c.6f, lc.2f.3f.4e.5d.6a, lc.2f.3f.4e.5d.6b, lc.2f.3f.4e.5d.6c, lc.2f.3f.4e.5d.6d, lc.2f.3f.4e.5d.6e, lc_2f.3f_4e.5d.6f, lc.2f.3f.4e.5e.6a, lc.2f.3f.4e.5e.6b, lc.2f.3f.4e.5e.6c, lc.2f.3f.4e.5e.6d, lc.2f.3f.4e.5e.6e, lc.2f.3f.4e.5e.6f, lc.2f.3f.4e.5f.6a, lc.2f.3f.4e.5f.6b, lc.2f.3f.4e.5f.6c, lc.2f.3f.4e.5f.6d, lc.2f.3f.4e.5f.6e, lc.2f.3f.4e.5f.6f, lc.2f.3f.4f.5a.6a, lc.2f.3f.4f.5a.6b, lc.2f.3f.4f.5a.6c, lc.2f.3f.4f.5a.6d, lc.2f.3f.4f_5a.6e, lc_2f_3f.4f.5a.6f, lc.2f.3f.4f.5b.6a, lc.2f.3f.4f.5b.6b, lc.2f.3f.4f.5b.6c, lc.2f.3f.4f.5b.6d, lc.2f.3f.4f.5b.6e, lc.2f.3f.4f.5b.6f, lc.2f.3f.4f.5c.6a, lc.2f.3f.4flc.2f.3f.4f.5c.6c, lc.2f.3f.4f.5c.6d, lc.2f.3f.4f.5c.6e, lc.2f.3f.4f.5c.6f, lc.2f.3f.4f.5d.6a, lc.2f.3f.4f.5d.6b, lc.2f.3f.4f.5d.6c, lc.2f.3f.4f.5d.6d, lc.2f.3f.4f.5d.6e, lc.2f.3f.4f.5d.6f, lc.2f.3f.4f.5e.6a, lc.2f.3f.4f.5e.6b, lc.2f.3f.4f.5e.6c, lc.2f.3f.4f.5e.6d, lc.2f.3f.4f.5e.6e, lc.2f.3f.4f.5e.6f, lc.2f.3f.4f.5f.6a, lc.2f.3f.4f.5f.6b, lc. 2f.3f.4f.5f.6c, lc.2f.3f.4f.5f.6d, lc.2f3f.4f.5f.6e, lc.2f.3f.4f.5f.6f, ld.2a.3a.4a.5a.6a, ld. 2a.3a.4a.5a.6b, ld.2a.3a.4a.5a.6c, ld.2a.3a.4a.5a.6d, ld.2a.3a.4a.5a.6e, ld.2a.3a.4a.5a.6f, ld.2a.3a.4a.5b.6a, ld.2a.3a.4a.5b.6b, ld.2a.3a.4a.5b.6c, ld.2a.3a.4a.5b.6d, ld.2a.3a.4a.5b.6e, ld.2a.3a.4a.5b.6f, ld.2a.3a.4a.5c.6a, ld.2a.3a.4a.5c.6b, ld.2a.3a.4a.5c.6c, ld.2a.3a.4a.5c.6d, ld.2a.3a.4a.5c.6e, ld.2a.3a.4a.5c.6f, ld.2a.3a.4a.5d.6a, ld.2a.3a.4a.5d.6b, ld.2a.3a.4a.5d.6cr ld.2a.3a.4a.5d.6d, ld.2a.3a.4a.5d.6e, ld.2a.3a.4a.5d.6f, ld.2a.3a.4a.5e.6a, ld.2a.3a.4a.5e.6b, ld.2a.3a.4a.5e.6c, ld.2a.3a.4a.5e.6d, ld.2a.3a.4a.5e.6e, ld.2a.3a.4a.5e.6f, ld.2a.3a.4a.5f.6a, ld.2a.3a.4a.5f.6b, ld.2a.3a.4a.5f.6c, ld.2a.3a.4a.5f.6d, ld.2a.3a.4a.5f.6e, ld.2a.3a.4a.5f.6f, ld.2a.3a.4b.5a.6a, ld.2a.3a.4b.5a.6b, ld.2a.3a.4b.5a.6c, ld.2a.3a.4b.5a.6d, ld.2a.3a.4b.5a.6e, ld.2a.3a.4b.5a.6f, ld.2a.3a.4b.5b.6a, ld.2a.3a.4b.5b.6b, ld.2a.3a.4b.5b.6c, -242- 200918507 ld.2a.3a.4b.5b.6d, ld.2a.3a.4b.5b.6e, ld.2a.3a.4b.5b.6f, ld.2a.3a.4b.5c.6a, ld.2a.3a.4b.5c.6b, ld.2a.3a.4b.5c.6c, ld.2a.3a.4b.5c.6d, ld.2a.3a.4b.5c.6e, ld.2a.3a.4b.5c.6f, ld.2a.3a.4b.5d.6a, ld.2a.3a.4b.5d.6b, ld.2a.3a.4b.5d.6c, ld.2a.3a.4b.5d.6d, ld.2a.3a.4b.5d.6e, ld.2a3a.4b.5d.6f, ld.2a.3a.4b.5e.6a, ld.2a.3a.4b.5e.6b, ld.2a.3a.4b.5e.6c, ld.2a.3a.4b.5e.6d, ld.2a.3a.4b.5e.6e, ld.2a.3a.4b.5e.6f, ld.2a.3a.4b.5f.6a, ld.2a.3a.4b.5f.6b, ld.2a.3a.4b.5f.6c, ld.2a.3a.4b.5f.6d, ld.2a.3a.4b.5f.6e, ld.2a.3a.4b.5f.6f, ld.2a.3a.4c.5a.6a, ld.2a.3a.4c.5a.6b, ld.2a.3a.4c.5a.6c, ld.2a.3a.4c.5a.6d, ld.2a.3a.4c.5a.6e, ld.2a.3a.4c.5a.6f, ld.2a.3a.4c.5b.6a, ld.2a.3a.4c.5b.6b, ld.2a.3a.4c.5b.6c, ld.2a.3a.4c.5b.6d, ld.2a.3a.4c.5b.6e, ld.2a.3a.4c.5b.6f, ld.2a.3a.4c.5c.6a, ld.2a.3a.4c.5c.6b, ld.2a.3a.4c.5c.6c, ld.2a.3a.4c.5c.6d, ld.2a.3a.4c.5c.6e, ld.2a.3a.4c.5c.6f, ld.2a.3a.4c.5d.6a, ld.2a.3a.4c.5d.6b, ld.2a.3a.4c.5d.6c, ld.2a.3a.4c.5d.6d, ld.2a.3a.4c.5d.6e, ld.2a.3a.4c.5d.6f, ld.2a.3a.4c.5e.6a, ld.2a.3a.4c.5e.6b, ld.2a.3a.4c.5e.6c, ld.2a.3a.4c.5e.6d, ld.2a.3a.4c.5e.6e, ld.2a.3a.4c.5e.6f, ld.2a.3a.4c.5f.6a, ld.2a.3a.4c.5f.6b, ld.2a.3a.4c.5f.6c, ld.2a.3a.4c.5f.6d, ld.2a.3a.4c.5f.6e, ld.2a.3a.4c.5f.6f, ld.2a.3a.4d.5a.6a, ld.2a.3a.4d.5a.6b, ld.2a.3a.4d.5a.6c, ld.2a.3a.4d.5a.6d, ld.2a.3a.4d.5a.6e, ld.2a.3a.4d.5a.6f, ld.2a.3a.4d.5b.6a, ld.2a.3a.4d.5b.6b, lcL2a.3a.4cL5b.6c, ld.2a.3a.4d.5b.6d, ld.2a.3a.4d.5b.6e, ld.2a.3a.4d.5b.6f, ld.2a.3a.4d.5c.6a, ld.2a.3a.4d.5c.6b, ld.2a.3a.4d.5c.6c, ld.2a.3a.4d.5c.6d, ld.2a.3a.4d.5c.6e, ld.2a.3a.4d.5c.6f, ld.2a.3a.4d.5d.6a, ld.2a.3a.4d.5d.6b, ld.2a.3a.4d.5d.6c, ld.2a.3a.4d.5d.6d, ld.2a.3a.4d.5d.6e, ld.2a.3a.4d.5d.6f, ld.2a.3a.4d.5e.6a, ld.2a.3a.4d.5e.6b, ld.2a.3a.4d.5e.6c, ld.2a.3a.4d.5e.6d, ld.2a.3a.4d.5e.6e, ld.2a.3a.4d.5e.6f, ld.2a.3a.4d.5f.6a, ld.2a.3a.4d.5f.6b, ld.2a.3a.4d.5f.6c, ld.2a.3a.4d.5f.6d, ld.2a.3a.4d.5f.6e, ld.2a.3a.4d.5f.6f, ld.2a.3a.4e.5a.6a, ld.2a.3a.4e.5a.6b, ld.2a.3a.4e.5a.6c, ld.2a.3a.4e.5a.6d, ld.2a.3a.4e.5a.6e, ld.2a.3a.4e.5a.6f, ld.2a.3a.4e.5b.6a, ld.2a.3a.4e.5b.6b, ld.2a.3a.4e.5b.6c, ld.2a.3a.4e.5b.6d, ld.2a.3a.4e.5b.6e, ld.2a.3a.4e.5b.6f, ld.2a.3a.4e.5c.6a, ld.2a.3a.4e.5c.6b, ld.2a.3a.4e.5c.6c, ld.2a.3a.4e.5c.6d, ld.2a.3a.4e.5c.6e, ld.2a.3a.4e.5c.6f, ld.2a.3a.4e.5d.6a, ld.2a.3a.4e.5d.6b, ld.2a.3a.4e.5d.6c, ld.2a.3a.4e.5d.6d, ld.2a.3a.4e.5d.6e, ld.2a.3a.4e.5d.6f, ld.2a.3a.4e.5e.6a, ld.2a.3a.4e.5e.6b, ld.2a.3a.4e.5e.6c, ld.2a.3a.4e.5e.6d, ld.2a.3a.4e.5e.6e, ld.2a.3a.4e.5e.6f, ld.2a.3a.4e.5f.6a, ld.2a.3a.4e.5f.6b, ld.2a.3a.4e.5f.6c, ld.2a.3a.4e.5f.6d, ld.2a.3a.4e.5f.6e, ld.2a.3a.4e.5f.6f, ld.2a.3a.4f.5a.6a, ld.2a.3a.4f.5a.6b, ld.2a.3a.4f.5a.6c, ld.2a.3a.4f.5a.6d, ld.2a.3a.4f.5a.6e, ld.2a.3a.4f.5a.6f, ld.2a.3a.4f.5b.6a, ld.2a.3a.4f.5b.6b, ld.2a.3a.4f.5b.6c, ld.2a.3a.4f.5b.6d, ld.2a.3a.4f.5b.6e, ld.2a.3a.4f.5b.6f, ld.2a.3a.4f.5c.6a, ld.2a.3a.4f.5c.6b, ld.2a.3a.4f.5c.6c, ld.2a.3a.4f.5c.6d, ld.2a.3a.4f.5c.6e, ld.2a.3a.4f.5c.6f, ld.2a.3a.4f.5d.6a, ld.2a.3a.4f.5d.6b, ld.2a.3a.4f.5d.6c, ld.2a.3a.4f.5d.6d, ld.2a.3a.4f.5d.6e, ld.2a.3a.4f.5d.6f, ld.2a.3a.4f.5e.6a, ld.2a.3a.4f.5e.6b, ld.2a.3a.4f.5e.6c, ld.2a.3a.4f.5e.6d, ld.2a.3a.4f.5e.6e, ld.2a.3a.4f.5e.6f, ld.2a.3a.4f.5f.6a, ld.2a.3a.4f.5f.6b, ld.2a.3a.4f.5f.6c, ld.2a.3a.4f.5f.6d, ld.2a.3a.4f.5f.6e, ld.2a.3a.4f.5f.6f, -243- 200918507 ld.2a.3b.4a.5a.6a, ld.2a.3b.4a.5a.6b, ld.2a.3b.4a.5a.6c, ld.2a.3b.4a.5a.6d, ld.2a.3b.4a.5a.6e, ld.2a.3b.4a.5a.6f, ld.2a.3b.4a.5b.6a/ ld.2a.3b.4a.5b.6b, ld.2a.3b.4a.5b.6c, ld.2a.3b.4a.5b.6d, ld.2a.3b.4a.5b.6e, ld.2a.3b.4a.5b.6f, ld.2a.3b.4a.5c.6a, ld.2a.3b.4a.5c.6b, ld.2a.3b.4a.5c.6c, ld.2a.3b.4a.5c.6d, ld.2a.3b.4a.5c.6e, ld.2a.3b.4a.5c.6f, ld.2a.3b.4a.5d.6a, ld.2a.3b.4a.5d.6b, ld.2a.3b.4a.5d.6c, ld.2a.3b.4a.5d.6d, ld.2a.3b.4a.5d.6e, ld.2a.3b.4a.5d.6f, ld.2a.3b.4a.5e.6a, ld.2a.3b.4a.5e.6b, ld.2a.3b.4a.5e.6c, ld.2a.3b.4a.5e.6d, ld.2a.3b.4a.5e.6e, ld.2a.3b.4a.5e.6f, ld.2a.3b.4a.5f.6a, ld.2a.3b.4a.5f.6b, ld.2a.3b.4a.5f.6c, ld.2a.3b.4a.5f.6d, ld.2a.3b.4a.5f.6e, ld.2a.3b.4a.5f.6f, ld.2a.3b.4b.5a.6a, ld.2a.3b.4b.5a.6b, ld.2a.3b.4b.5a.6c, ld.2a.3b.4b.5a.6d, ld.2a.3b.4b.5a.6e, ld.2a.3b.4b.5a.6f, ld.2a.3b.4b.5b.6a, ld.2a.3b.4b.5b.6b, ld.2a.3b.4b.5b.6c, ld.2a.3b.4b.5b.6d, ld.2a.3b.4b.5b.6e, ld.2a.3b.4b.5b.6f, ld.2a.3b.4b.5c.6a, ld.2a.3b.4b.5c.6b, ld.2a.3b.4b.5c.6c, ld.2a.3b.4b.5c.6d, ld.2a.3b.4b.5c.6e, ld.2a.3b.4b.5c.6f, ld.2a.3b.4b.5d.6a, ld.2a.3b.4b.5d.6b, ld.2a.3b.4b.5d.6c, ld.2a.3b.4b.5d.6d, ld.2a.3b.4b.5d.6e, ld.2a.3b.4b.5d.6f, ld.2a.3b.4b.5e.6a, ld.2a.3b.4b.5e.6b, ld.2a.3b.4b.5e.6c, ld.2a.3b.4b.5e.6d, ld.2a.3b.4b.5e.6e, ld.2a.3b.4b.5e.6f, ld.2a.3b.4b.5f.6a, ld.2a.3b.4b.5f.6b, ld.2a.3b.4b.5f.6c, ld.2a.3b.4b.5f.6d, ld.2a.3b.4b.5f.6e, ld.2a.3b.4b.5f.6f, ld.2a.3b.4c.5a.6a, ld.2a.3b.4c.5a.6b, ld.2a.3b.4c.5a.6c, ld.2a.3b.4c.5a.6d, ld.2a.3b.4c.5a.6e, ld.2a.3b.4c.5a.6f, ld.2a.3b.4c.5b.6a, ld.2a.3b.4c.5b.6b, ld.2a.3b.4c.5b.6c, ld.2a.3b.4c.5b.6d, ld.2a.3b.4c.5b.6e, ld.2a.3b.4c.5b.6f, ld.2a.3b.4c.5c.6a, ld.2a.3b.4c.5c.6b, ld.2a.3b.4c.5c.6c, ld.2a.3b.4c.5c.6d, ld.2a.3b.4c.5c.6e, ld.2a.3b.4c.5c.6f, ld.2a.3b.4c.5d.6a, ld.2a.3b.4c.5d.6b, ld.2a.3b.4c.5d.6c, ld.2a.3b.4c.5d.6d, ld.2a.3b.4c.5d.6e, ld.2a.3b.4c.5d.6f, ld.2a.3b.4c.5e.6a, ld.2a.3b.4c.5e.6b, ld.2a.3b.4c.5e.6c, ld.2a.3b.4c.5e.6d, ld.2a.3b.4c.5e.6e, ld.2a.3b.4c.5e.6f, ld.2a.3b.4c.5f.6a, ld.2a.3b.4c.5f.6b, ld.2a.3b.4c.5f.6c, ld.2a.3b.4c.5f.6d, ld.2a.3b.4c.5f.6e, ld.2a.3b.4c.5f.6f, ld.2a.3b.4d.5a.6a, ld.2a.3b.4d.5a.6b, ld.2a.3b.4d.5a.6c, ld.2a.3b.4d.5a.6d, ld.2a.3b.4d.5a.6e, ld.2a.3b.4d.5a.6f, ld.2a.3b.4d.5b.6a, ld.2a.3b.4d.5b.6b, ld.2a.3b.4d.5b.6c, ld.2a.3b.4d.5b.6d, ld.2a.3b.4d.5b.6e, ld.2a.3b.4d.5b.6f, ld.2a.3b.4d.5c.6a, ld.2a.3b.4d.5c.6b, ld.2a.3b.4d.5c.6c, ld.2a.3b.4d.5c.6d, ld.2a.3b.4d.5c.6e, ld.2a.3b.4d.5c.6f, ld.2a.3b.4d.5d.6a, ld.2a.3b.4d.5d.6b, ld.2a.3b.4d.5d.6c, ld.2a.3b.4d.5d.6d, ld.2a.3b.4d.5d.6e, ld.2a.3b.4d.5d.6f, ld.2a.3b.4d.5e.6a, ld.2a.3b.4d.5e.6b, ld.2a.3b.4d.5e.6c, ld.2a.3b.4d.5e.6d, ld.2a.3b.4d.5e.6e, ld.2a.3b.4d.5e.6f, ld.2a.3b.4d.5f.6a, ld.2a.3b.4d.5f.6b, ld.2a.3b.4d.5f.6c, ld.2a.3b.4d.5f.6d, ld.2a.3b.4d.5f.6e, ld.2a.3b.4d.5f.6f, ld.2a.3b.4e.5a.6a, ld.2a.3b.4e.5a.6b, ld.2a.3b.4e.5a.6c, ld.2a.3b.4e.5a.6d, ld.2a.3b.4e.5a.6e, ld.2a.3b.4e.5a.6f, ld.2a.3b.4e.5b.6a, ld.2a.3b.4e.5b.6b, ld.2a.3b.4e.5b.6c, ld.2a.3b.4e.5b.6d, ld.2a.3b.4e.5b.6e, ld.2a.3b.4e.5b.6f, ld.2a.3b.4e.5c.6a, ld.2a.3b.4e.5c.6b, ld.2a.3b.4e.5c.6c, ld.2a.3b.4e.5c.6d, ld.2a.3b.4e.5c.6e, ld.2a.3b.4e.5c.6f, ld.2a.3b.4e.5d.6a, ld.2a.3b.4e.5d.6b, ld.2a.3b.4e.5d.6c, ld.2a.3b.4e.5d.6d, ld.2a.3b.4e.5d.6er ld.2a.3b.4e.5d.6f, -244- 200918507 ld.2a.3b.4e.5e.6a, ld,2a.3b.4e.5e.6b, ld.2a.3b.4e.5e.6c, ld.2a.3b.4e.5e.6d, ld.2a.3b.4e.5e.6e, ld.2a3b.4e.5e.6f, ld.2a.3b.4e.5f.6a, ld.2a.3b.4e.5f.6b, ld.2a.3b.4e.5f.6c, ld.2a.3b.4e.5f.6d, ld.2a.3b.4e.5f.6e, ld.2a.3b.4e.5f.6f, ld.2a.3b.4f.5a.6a, ld.2a.3b.4f.5a.6b, ld.2a.3b.4f.5a.6c, ld.2a.3b.4f.5a.6d, ld.2a.3b.4f.5a.6e, ld.2a.3b.4f.5a.6f, ld.2a.3b.4f.5b.6a, ld.2a.3b.4f.5b.6b, ld.2a.3b.4f.5b.6c, ld.2a.3b.4f.5b.6d, ld.2a.3b.4f.5b.6e, ld.2a.3b.4f.5b.6f, ld.2a.3b.4f.5c.6a, ld.2a.3b.4f.5c.6b, ld.2a.3b.4f.5c.6c, ld.2a.3b.4f.5c.6d, ld.2a.3b.4f.5c.6e, ld.2a.3b.4f.5c.6f, ld.2a.3b.4f.5d.6a, ld.2a.3b.4f.5d.6b, ld.2a.3b.4f.5d.6c, ld.2a.3b.4f.5d.6d, ld.2a.3b.4f.5d.6e, ld.2a.3b.4f.5d.6f, ld.2a.3b.4f.5e.6a, ld.2a.3b.4f.5e.6b, ld.2a.3b.4f.5e.6c, ld.2a.3b.4f.5e.6d, ld.2a.3b.4f.5e.6e, ld.2a.3b.4f.5e.6f, ld.2a.3b.4f.5f.6a, ld.2a.3b.4f.5f.6b, ld.2a.3b.4f.5f.6c, ld.2a.3b.4f.5f.6d, ld.2a.3b.4f.5f.6e, ld.2a.3b.4f.5f.6f, ld.2a.3c.4a.5a.6a, ld.2a.3c.4a.5a.6b, ld.2a.3c.4a.5a.6c, ld.2a.3c.4a.5a.6d, ld.2a.3c.4a.5a.6e, ld.2a.3c.4a.5a.6f, ld.2a.3c.4a.5b.6a, ld.2a.3c.4a.5b.6b, ld.2a.3c.4a.5b.6c, ld.2a.3c.4a.5b.6d, ld.2a.3c.4a.5b.6e, ld.2a.3c.4a.5b.6f, ld.2a.3c.4a.5c.6a, ld.2a.3c.4a.5c.6b, ld.2a.3c.4a.5c.6c, ld.2a.3c.4a.5c.6d, ld.2a.3c.4a.5c.6e, ld.2a.3c.4a.5c.6f, ld.2a.3c.4a.5d.6a, ld.2a.3c.4a.5d.6b, ld.2a.3c.4a.5d.6c, ld.2a.3c.4a.5d.6d, ld.2a.3c.4a.5d.6e, ld.2a.3c.4a.5d.6f, ld.2a.3c.4a.5e.6a, ld.2a.3c.4a.5e.6b, ld.2a.3c.4a.5e.6c, ld.2a.3c.4a.5e.6d7 ld.2a.3c.4a.5e.6e, ld.2a.3c.4a.5e.6f, ld.2a.3c.4a.5f.6a, ld.2a.3c.4a.5f.6b, ld.2a.3c.4a.5f.6c, ld.2a.3c.4a.5f.6d, ld.2a.3c.4a.5f.6e, ld.2a.3c.4a.5f.6f, ld.2a.3c.4b.5a.6a, ld.2a.3c.4b.5a.6b, ld.2a.3c.4b.5a.6c, ld.2a.3c.4b.5a.6d, ld.2a.3c.4b.5a.6e, ld.2a.3c.4b.5a.6f, ld.2a.3c.4b.5b.6a, ld.2a.3c.4b.5b.6b, ld.2a.3c.4b.5b.6c, ld.2a.3c.4b.5b.6d, ld.2a.3c.4b.5b.6e, ld.2a.3c.4b.5b.6f, ld.2a.3c.4b.5c.6a, ld.2a.3c.4b.5c.6b, ld.2a.3c.4b.5c.6c, ld.2a.3c.4b.5c.6d, ld.2a.3c.4b.5c.6e, ld.2a.3c.4b.5c.6f, ld.2a.3c.4b.5d.6a, ld.2a.3c.4b.5d.6b, ld.2a.3c.4b.5d.6c, ld.2a.3c.4b.5d.6d, ld.2a.3c.4b.5d.6e, ld.2a.3c.4b.5d.6f, ld.2a.3c.4b.5e.6a, ld.2a.3c.4b.5e.6b, ld.2a.3c.4b.5e.6c, ld.2a.3c.4b.5e.6d, ld.2a.3c.4b.5e.6e, ld.2a.3c.4b.5e.6f, ld.2a.3c.4b.5f.6a, ld.2a.3c.4b.5f.6b, ld.2a.3c.4b.5f.6c, ld.2a.3c.4b.5f.6d, ld.2a.3c.4b.5f.6e, ld.2a.3c.4b.5f.6f, ld.2a.3c.4c.5a.6a, ld.2a.3c.4c.5a.6b, ld.2a.3c.4c.5a.6c, ld.2a.3c.4c.5a.6d, ld.2a.3c.4c.5a.6e, ld.2a.3c.4c.5a.6f, ld.2a.3c.4c.5b.6a, ld.2a‘3c.4c.5b.6b, ld.2a_3c.4c.5b.6c, ld.2a.3c.4c.5b.6d, ld.2a.3c.4c.5b.6e, ld.2a.3c.4c.5b.6f, ld.2a.3c.4c.5c.6a, ld.2a.3c.4c.5c.6b, ld.2a.3c.4c.5c.6c, ld.2a.3c.4c.5c.6d, ld.2a.3c.4c.5c.6e, ld.2a.3c.4c.5c.6f, ld.2a.3c.4c.5d.6a, ld.2a.3c.4c.5d.6b, ld.2a.3c.4c.5d.6c, ld.2a.3c.4c.5d.6d, ld.2a.3c.4c.5d.6e, ld.2a.3c.4c.5d.6f, ld.2a.3c.4c.5e.6a, ld.2a.3c.4c.5e.6b, ld.2a.3c.4c5e.6c, ld.2a.3c.4c.5e.6d, ld.2a.3c.4c.5e.6e, ld.2a.3c.4c.5e.6f, ld.2a.3c.4c.5f.6a, ld.2a.3c.4c.5f.6b, ld.2a.3c.4c.5f.6c, ld.2a.3c.4c.5f.6d, ld.2a.3c.4c.5f.6e, ld.2a.3c.4c.5f.6f, ld.2a.3c.4d.5a.6a, ld.2a.3c.4d.5a.6b, ld.2a.3c.4d.5a.6c, ld.2a.3c.4d.5a.6d, ld.2a.3c.4d.5a.6e, ld.2a.3c.4d.5a.6f, ld.2a.3c.4d.5b.6a, ld.2a.3c.4d.5b.6b, ld.2a.3c.4d.5b.6c, ld.2a.3c.4d.5b.6d, ld.2a.3c.4d.5b.6e, ld.2a.3c.4d.5b.6f, ld.2a.3c.4d.5c.6a, ld.2a.3c.4d.5c.6b, -245- 200918507 ld.2a.3c.4d.5c.6c, ld.2a.3c.4d.5c.6d, ld.2a.3c.4d.5c.6e, ld.2a.3c.4d.5c.6f, ld.2a.3c.4d.5d.6a, ld.2a.3c.4d.5d.6b, ld.2a.3c.4d.5d.6c, ld.2a.3c.4d.5d.6d, ld.2a.3c.4d.5d.6e, ld.2a.3c.4d.5d.6f, ld.2a.3c.4d.5e.6a, ld.2a.3c.4d.5e.6b, ld.2a.3c.4d.5e.6c, ld.2a.3c.4d.5e.6d, ld.2a.3c.4d.5e.6e, ld.2a.3c.4d.5e.6f, ld.2a.3c.4d.5f.6a, ld.2a.3c.4d.5f.6b, ld.2a.3c.4d.5f.6c, ld.2a.3c.4d.5f.6d, ld.2a.3c.4d.5f.6e, ld.2a.3c.4d.5f.6f, ld.2a.3c.4e.5a.6a, ld.2a.3c.4e.5a.6b, ld.2a.3c.4e.5a.6c, ld.2a.3c.4e.5a.6d, ld.2a.3c.4e.5a.6e, ld.2a.3c.4e.5a.6f, ld.2a.3c.4e.5b.6a, ld.2a.3c.4e.5b.6b, ld.2a.3c.4e.5b.6c, ld.2a.3c.4e.5b.6d, ld.2a.3c.4e.5b.6e, ld.2a.3c.4e.5b.6f, ld.2a.3c.4e.5c.6a, ld.2a.3c.4e.5c.6b, ld.2a.3c.4e.5c.6c, ld.2a.3c.4e.5c.6d, ld.2a.3c.4e.5c.6e, ld.2a.3c.4e.5c.6f, ld.2a.3c.4e.5d.6a, ld.2a.3c.4e.5d.6b, ld.2a.3c.4e.5d.6c, ld.2a.3c.4e.5d.6d, ld.2a.3c.4e.5d.6e, ld.2a.3c.4e.5d.6f, ld.2a.3c.4e.5e.6a, 1ά.23.3ο.4θ.5θ,6^ ld.2a.3c.4e.5e.6c, ld.2a.3c.4e.5e.6d, ld.2a.3c.4e.5e.6e, ld.2a.3c.4e.5e.6f, ld.2a.3c.4e.5f6a, ld.2a.3c.4e.5f.6b, ld.2a.3c.4e.5f.6c, ld.2a.3c.4e.5f.6d, ld.2a.3c.4e.5f.6e, ld.2a.3c.4e.5f.6f, ld.2a.3c.4f.5a.6a, ld.2a.3c.4f.5a.6b, ld.2a.3c.4f.5a.6c, ld.2a.3c.4f.5a.6d, ld.2a.3c.4f.5a.6e, ld.2a.3c.4f.5a.6f, ld.2a.3c.4f.5b.6a, ld.2a.3c.4f.5b.6b, ld.2a.3c.4f.5b.6c, ld.2a.3c.4f.5b.6d, ld.2a.3c.4f.5b.6e, ld.2a.3c.4f.5b.6f, ld.2a.3c.4f.5c.6a, ld.2a.3c.4f.5c.6b, ld.2a.3c.4f.5c.6c, ld.2a.3c.4f.5c.6d, ld.2a.3c.4f.5c.6e, ld.2a.3c.4f.5c.6f, ld.2a.3c.4f.5d.6a, ld.2a.3c.4f.5d.6b, ld.2a.3c.4f.5d.6c, ld.2a.3c.4f.5d.6d, ld.2a.3c.4f.5d.6e, ld.2a.3c.4f.5d.6f, ld.2a.3c.4f.5e.6a, ld.2a.3c.4f.5e.6b, ld.2a.3c.4f.5e.6c, ld.2a.3c.4f.5e.6d, ld.2a.3c.4f.5e.6e, ld.2a.3c.4f.5e.6f, ld.2a.3c.4f.5f.6a, ld.2a.3c.4f.5f.6b, ld.2a.3c.4f.5f.6c, ld.2a.3c.4f.5f.6d, ld.2a.3c.4f.5f.6e, ld.2a.3c.4f.5f.6f, ld.2a.3d.4a.5a.6a, ld.2a.3d.4a.5a.6b, ld.2a.3d.4a.5a.6c, ld.2a.3d.4a.5a.6d, ld.2a.3d.4a.5a.6e, ld.2a.3d.4a.5a.6f, ld.2a.3d.4a.5b.6a, ld.2a.3d.4a.5b.6b, ld.2a.3d.4a.5b.6c, ld.2a.3d.4a.5b.6d, ld.2a.3d.4a.5b.6e, ld.2a.3d.4a.5b.6f, ld.2a.3d.4a.5c.6a, ld.2a.3d.4a.5c.6b, ld.i2a.3d.4a.5c.6c, ld.2a3d.4a.5t.6d, ld.2a.3d.4a.5c.6e, ld.2a.3d.4a.5c.6f, ld.2a.3d.4a.5d.6a, ld.2a.3d.4a.5d.6b, ld.2a.3d.4a.5d.6c, ld.2a.3d.4a.5d.6d, ld.2a.3d.4a.5d.6e, ld.2a.3d.4a.5d.6f, ld.2a.3d.4a.5e.6a, ld.2a.3d.4a.5e.6b, ld.2a.3d.4a.5e.6c, ld.2a.3d.4a.5e.6d, ld.2a.3d.4a.5e.6e, ld.2a.3d.4a.5e.6f, ld.2a.3d.4a.5f.6a, ld.2a.3d.4a.5f.6b, ld.2a.3d.4a.5f.6c, ld.2a.3d.4a.5f.6d, ld.2a.3d.4a.5f.6e, ld.2a.3d.4a.5f.6f, ld.2a.3d.4b.5a.6a, ld.2a.3d.4b.5a.6b, ld.2a.3d.4b.5a.6c, ld.2a.3d.4b.5a.6d, ld.2a.3d.4b.5a.6e, ld.2a.3d.4b.5a.6f, ld.2a.3d.4b.5b.6a, ld.2a.3d.4b.5b.6b, ld.2a.3d.4b.5b.6c, ld.2a.3d.4b.5b.6d, ld.2a.3d.4b.5b.6e, ld.2a.3d.4b.5b.6f, ld.2a.3d.4b.5c.6a, ld.2a.3d.4b.5c.6b, ld.2a.3d.4b.5c.6c, ld.2a.3d.4b.5c.6d, ld.2a.3d.4b.5c.6e, ld.2a.3d.4b.5c.6f, ld.2a.3d.4b.5d.6a, ld.2a.3d.4b.5d.6b, ld.2a.3d.4b.5d.6c, ld.2a.3d.4b.5d.6d, ld.2a.3d.4b.5d.6e, ld.2a.3d.4b.5d.6f, ld.2a.3d.4b.5e.6a, ld.2a.3d.4b.5e.6b, ld.2a.3d.4b.5e.6c, ld.2a.3d.4b.5e.6d, ld.2a.3d.4b.5e.6e, ld.2a.3d.4b.5e.6f, ld.2a.3d.4b.5f.6a, ld.2a.3d.4b.5f.6b, ld.2a.3d.4b.5f.6c, ld.2a.3d.4b.5f.6d, ld.2a.3d.4b.5f.6e, ld.2a.3d.4b.5f.6f, ld.2a.3d.4c.5a.6a, ld.2a.3d.4c.5a.6b, ld.2a.3d.4c.5a.6c, ld.2a.3d.4c.5a.6d, ld.2a.3d.4c.5a.6e, •246- 200918507 ld.2a.3d.4c.5a.6f, ld.2a.3d.4c.5b.6a, ld.2a.3d.4c.5b.6b, ld.2a.3d.4c.5b.6c, ld.2a.3d.4c.5b.6d, ld.2a.3d.4c.5b.6e, ld.2a.3d.4c.5b.6f, ld.2a.3d.4c.5c.6a, ld.2a.3d.4c.5c.6b, ld.2a.3d.4c.5c.6c, ld.2a.3d.4c.5c.6d, ld.2a.3d.4c.5c.6e, ld.2a.3d.4c.5c.6f, ld.2a.3d.4c.5d.6a, ld.2a.3d.4c.5d.6b, ld.2a.3d.4c.5d.6c, ld-2a，3d.4c.5d.6d, ld.2a.3d.4c.5d_6e, ld.2a.3d.4c.5d.6f, ld.2a.3d.4c.5e.6a, ld.2a.3d.4c.5e.6b, ld.2a.3d.4c.5e.6c, ld.2a.3d.4c.5e.6d, ld.2a.3d.4c.5e.6e, ld.2a.3d.4c.5e.6f, ld.2a.3d.4c.5f.6a, ld.2a.3d.4c.5f.6b, ld.2a.3d.4c.5f.6c, ld.2a.3d.4c.5f.6d, ld.2a.3d.4c.5f.6e, ld.2a.3d.4c.5f.6f, ld.2a.3d.4d.5a.6a, ld.2a.3d.4d.5a.6b, ld.2a.3d.4d.5a.6c, ld.2a.3d.4d.5a.6d, ld.2a.3d.4d.5a.6e, ld.2a.3d.4d.5a.6f, ld.2a.3d.4d.5b.6a, ld.2a.3d.4d.5b.6b, ld.2a.3d.4d.5b.6c, ld.2a.3d.4d.5b.6d, ld.2a.3d.4d.5b.6e, ld.2a.3d.4d.5b.6f, ld.2a.3d.4d.5c.6a, ld.2a.3d.4d.5c.6b, ld.2a.3d.4d.5c.6c, ld.2a.3d.4d.5c.6d, ld.2a.3d.4d.5c.6e, ld.2a.3d.4d.5c.6f, ld.2a.3d.4d.5d.6a, ld.2a.3d.4d.5d.6b, ld.2a.3d.4d.5d.6c, ld.2a.3d.4d.5d.6d, ld.2a.3d.4d.5d.6e, ld.2a.3d.4d.5d.6f, ld.2a.3d.4d.5e.6a, ld.2a.3d.4d.5e.6b, ld.2a.3d.4d.5e.6c, ld.2a.3d.4d.5e.6d, ld.2a.3d.4d.5e.6e, ld.2a.3d.4d.5e.6f, ld.2a.3d.4d.5f.6a, ld.2a.3d.4d.5f.6b, ld.2a.3d.4d.5f.6c, ld.2a.3d.4d.5f.6d, ld.2a.3d.4d.5f.6e, ld.2a.3d.4d.5f.6f, ld.2a.3d.4e.5a.6a, ld.2a.3d.4e.5a.6b, ld.2a.3d.4e.5a,6c, ld.2a.3d.4e.5a.6d, ld.2a.3d.4e.5a.6e, ld.2a.3d.4e.5a.6f, ld.2a.3d.4e.5b.6a, ld.2a.3d.4e.5b.6b, ld.2a.3d.4e.5b.6c, ld.2a.3d.4e.5b.6d, ld.2a.3d.4e.5b.6e, ld.2a.3d.4e.5b.6f, ld.2a.3d.4e.5c.6a, ld.2a.3d.4e.5c.6b, ld.2a.3d.4e.5c.6c, ld.2a.3d.4e.5c.6d, ld.2a.3d.4e.5c.6e, ld.2a.3d.4e.5c.6f, ld.2a.3d.4e.5d.6a, ld.2a.3d.4e.5d.6b, ld.2a.3d.4e.5d.6c, ld.2a.3d.4e.5d.6d, ld.2a.3d.4e.5d.6e, ld.2a.3d.4e.5d.6f, ld.2a.3d.4e.5e.6a, ld.2a.3d.4e.5e.6b, ld.2a.3d.4e.5e.6c, ld.2a.3d.4e.5e.6d, ld.2a.3d.4e.5e.6e, ld.2a.3d.4e.5e.6f, ld.2a.3d.4e.5f.6a, ld.2a.3d.4e.5f.6b, ld.2a.3d.4e.5f.6c, ld.2a.3d.4e.5f.6d, ld.2a.3d.4e.5f.6e, ld.2a.3d.4e.5f.6f, ld.2a.3d.4f.5a.6a, ld.2a.3d.4f.5a.6b, ld.2a.3d.4f.5a.6c, ld.2a.3d.4f.5a.6d, ld.2a.3d.4f.5a.6e, ld.2a.3d.4f.5a.6f, ld.2a.3d.4f.5b.6a, ld.2a.3d.4f.5b.6b, ld.2a.3d.4f.5b.6c, ld.2a.3d.4f.5b.6d, ld.2a.3d.4f.5b.6e, ld.2a.3d.4f.5b.6f, ld.2a.3d.4f.5c.6a, ld.2a.3d.4f.5c.6b, ld.2a.3d.4f.5c.6c, ld.2a.3d.4f.5c6d, ld.2a.3d.4f.5c6e, ld.2a.3d.4f.5c.6f, ld.2a.3d.4f.5d.6a, ld.2a.3d.4f.5d.6b, ld.2a.3d.4f.5d.6c, ld.2a.3d.4f.5d.6d, ld.2a.3d.4f.5d.6e, ld.2a.3d.4f.5d.6f, ld.2a.3d.4f.5e.6a, ld.2a.3d.4f.5e.6b, ld.2a.3d.4f.5e.6c, ld.2a.3d.4f.5e.6d, ld.2a.3d.4f.5e.6e, ld.2a.3d.4f.5e.6f, ld.2a.3d.4f.5f.6a, ld.2a.3d.4f.5f.6b, ld.2a.3d.4f.5f.6c, ld.2a.3d.4f.5f.6d, ld.2a.3d.4f.5f.6e, ld.2a.3d.4f.5f.6f, ld.2a3e.4a.5a.6a, ld.2a.3e.4a.5a.6b, ld.2a.3e.4a.5a.6c, ld.2a.3e.4a.5a.6d, ld.2a.3e.4a.5a.6e, ld.2a.3e.4a.5a.6f, ld.2a.3e.4a.5b.6a, ld.2a_3e.4a.5b.6b, ld.2a,3e.4a.5b.6c, ld.2a.3e.4a.5b.6d, ld.2a.3e.4a.5b.6e, ld.2a.3e.4a.5b.6f, ld.2a.3e.4a.5c.6a, ld.2a.3e.4a.5c.6b, ld.2a.3e.4a.5c.6c, ld.2a.3e.4a.5c.6d, ld.2a.3e.4a.5c.6e, ld.2a.3e.4a.5c.6f, ld.2a.3e.4a.5d.6a, ld.2a.3e.4a.5d.6b, ld.2a.3e.4a.5d.6c, ld.2a.3e.4a.5d.6d, ld.2a.3e.4a.5d.6e, ld.2a.3e.4a.5d.6f, ld.2a.3e.4a.5e.6a, ld*2a.3e.4a.5e.6b, ld.2a.3e.4a.5e.6c, ld.2a.3e.4a.5e.6d, ld.2a.3e.4a.5e.6e, -247- 200918507 ld.2a.3e.4a.5e.6f, ld.2a.3e.4a.5f.6a, ld.2a.3e.4a.5f.6b, ld.2a.3e.4a.5f.6c, ld.2a.3e.4a.5f.6d, ld.2a.3e.4a.5f.6e, ld.2a3e.4a.5f.6f, ld.2a.3e.4b.5a.6a, ld.2a.3e.4b.5a.6b, ld.2a.3e.4b.5a.6c, ld.2a.3e.4b.5a.6d, ld.2a.3e.4b.5a.6e, ld.2a.3e.4b.5a.6f, ld.2a.3e.4b.5b.6a, ld.2a.3e.4b.5b.6b, ld.2a.3e.4b.5b.6c, ld.2a.3e.4b.5b.6d, ld.2a*3e.4b.5b.6e, ld.2a.3e.4b.5b.6f, ld.2a.3e.4b.5c.6a, ld.2a.3e.4b.5c.6b, ld.2a.3e.4b.5c.6c, ld.2a.3e.4b.5c.6d, ld.2a.3e.4b.5c.6e, ld.2a.3e.4b.5c.6f, ld.2a.3e.4b.5d.6a, ld.2a.3e.4b.5d.6b, ld.2a.3e.4b.5d.6Q ld.2a.3e.4b.5d.6d, ld.2a.3e.4b,5d.6e, ld.2a.3e.4b.5d_6f, ld.2a,3e.4b.5e.6a, ld.2a.3e.4b.5e.6b, ld.2a.3e.4b.5e.6c, ld.2a.3e.4b.5e.6d, ld.2a.3e.4b.5e.6e, ld.2a.3e.4b.5e.6f, ld.2a.3e.4b.5f.6a, ld.2a.3e.4b.5f.6b, ld.2a.3e.4b.5f.6c, ld.2a.3e.4b.5f.6d, ld.2a.3e.4b.5f.6e, ld.2a.3e.4b.5f.6f, ld.2a.3e.4c.5a.6a, ld.2a.3e.4c.5a.6b, ld.2a.3e.4c.5a.6c, ld.2a.3e.4c.5a.6d, ld.2a.3e.4c.5a.6e, ld.2a.3e.4c.5a.6f, ld.2a.3e.4c.5b.6a, ld.2a.3e.4c.5b.6b, ld.2a.3e.4c.5b.6c, ld.2a.3e.4c.5b.6d, ld.2a.3e.4c.5b.6e, ld.2a.3e.4c.5b.6f, ld.2a.3e.4c.5c.6a, ld.2a.3e.4c.5c.6b, ld.2a.3e.4c.5c.6c, ld.2a.3e.4c.5c.6d, ld.2a.3e.4c.5c.6e, ld.2a.3e.4c.5c.6f, ld.2a.3e.4c.5d.6a, ld.2a.3e.4c.5d.6b, ld.2a.3e.4c.5d.6c, ld.2a.3e.4c.5d.6d, ld.2a.3e.4c.5d.6e, ld.2a.3e.4c.5d.6f, ld.2a.3e.4c.5e.6a, ld.2a.3e.4c.5e.6b, ld.2a.3e.4c.5e.6c, ld.2a.3e.4c.5e.6d, ld.2a.3e.4c.5e.6e, ld.2a.3e.4c.5e.6f, ld.2a.3e.4c.5f.6a, ld.2a.3e.4c.5f.6b, ld.2a.3e.4c.5f.6c, ld.2a.3e.4c.5f.6d, ld.2a.3e.4c.5f.6e, ld.2a.3e.4c.5f.6f, ld.2a.3e.4d.5a.6a, ld.2a.3e.4d.5a.6b, ld.2a.3e.4d.5a.6c, ld.2a.3e.4d.5a.6d, ld.2a.3e.4d.5a.6e, ld.2a.3e.4d.5a.6f, ld.2a.3e.4d.5b.6a, ld.2a.3e.4d.5b.6b, ld.2a.3e.4d.5b.6c, ld.2a.3e.4d.5b.6d, ld.2a.3e.4d.5b.6e, ld.2a.3e.4d.5b.6f, ld.2a.3e.4d.5c.6a, ld.2a.3e.4d.5c.6b, ld.2a.3e.4d.5c.6c, ld.2a.3e.4d.5c.6d, ld.2a.3e.4d.5c.6e, ld.2a.3e.4d.5c.6f, ld.2a.3e.4d.5d.6a, ld.2a.3e.4d.5d.6b, ld.2a.3e.4d.5d.6c, ld.2a.3e.4d.5d.6d, ld.2a.3e.4d.5d.6e, ld.2a.3e.4d.5d.6f, ld.2a.3e.4d.5e.6a, ld.2a.3e.4d.5e.6b, ld.2a.3e.4d.5e.6c, ld.2a.3e.4d.5e.6d, ld.2a.3e.4d.5e.6e, ld.2a.3e.4d.5e.6f, ld.2a.3e.4d.5f.6a, ld.2a.3e.4d.5f.6b, ld.2a.3e.4d.5f.6c, ld.2a.3e.4d.5f.6d, ld.2a.3e.4d.5f.6e, ld.2a.3e.4d.5f.6f, ld.2a.3e.4e.5a.6a, ld.2a.3e.4e.5a.6b, ld.2a.3e.4e.5a.6c, ld.2a.3e.4e.5a.6d, ld.2a.3e.4e.5a.6e, ld.2a.3e.4e.5a.6f, ld.2a.3e.4e.5b.6a, ld.2a.3e.4e.5b.6b, ld.2a.3e.4e.5b.6c, ld.2a.3e.4e.5b.6d, ld.2a.3e.4e.5b.6e, ld.2a.3e.4e.5b.6f, ld.2a.3e.4e.5c.6a, ld.2a.3e.4e.5c.6b, ld.2a.3e.4e.5c.6c, ld.2a.3e.4e.5c.6d, ld.2a.3e.4e.5c.6e, ld.2a.3e.4e.5c.6f, ld.2a.3e.4e.5d.6a, ld.2a.3e.4e.5d.6b, ld.2a.3e.4e.5d.6c, ld.2a.3e.4e.5d.6d, ld.2a.3e.4e.5d.6e, ld.2a.3e.4e.5d.6f, ld.2a.3e.4e.5e.6a, ld.2a.3e.4e.5e.6b, ld.2a.3e.4e.5e.6c, ld.2a.3e.4e.5e.6d, ld.2a.3e.4e.5e.6e, ld.2a.3e.4e,5e.6f, ld.2a.3e.4e.5f，6a, ld.2a.3e.4e.5f.6b, ld.2a.3e.4e.5f*6c, ld.2a.3e.4e.5f.6d, ld.2a.3e.4e.5f.6e, ld.2a.3e.4e.5f.6f, ld.2a.3e.4f.5a.6a, ld.2a.3e.4f.5a.6b, ld.2a.3e.4f.5a.6c, ld.2a.3e.4f.5a.6d, ld.2a.3e.4f.5a.6e, ld.2a.3e.4f.5a.6f, ld.2a.3e.4f.5b.6a, ld.2a.3e.4f.5b.6b, ld.2a.3e.4f.5b.6c7 ld.2a.3e.4f.5b.6d, ld.2a.3e.4f.5b.6e, ld.2a.3e.4f.5b.6f, ld.2a.3e.4f.5c.6a, ld.2a.3e.4f.5c.6b, ld.2a.3e.4f.5c.6c, ld.2a.3e.4f.5c.6d, ld.2a.3e.4f.5c.6e, ld.2a.3e.4f.5c.6f, -248 - 200918507 ld.2a.3e.4f.5d.6a, ld.2a.3e.4f.5d.6b, ld.2a.3e.4f.5d.6c, ld.2a.3e.4f.5d.6d, ld.2a.3e.4f.5d.6e, ld.2a.3e.4f.5d.6f, ld.2a.3e.4f.5e.6a, ld.2a.3e.4f.5e.6b, ld.2a.3e.4f.5e.6c, ld.2a.3e.4f.5e.6d, ld.2a.3e.4f.5e.6e, ld.2a.3e.4f.5e.6f, ld.2a.3e.4f.5f.6a, ld.2a3e.4f.5f.6b, ld.2a.3e.4f.5f.6c, ld.2a.3e.4f.5f.6d, ld.2a.3e.4f.5f.6e, ld.2a.3e.4f.5f.6f, ld.2a.3f.4a.5a.6a, ld.2a.3f.4a.5a.6b, ld.2a.3f.4a.5a.6c, ld.2a.3f.4a.5a.6d, ld.2a.3f.4a.5a.6e, ld.2a.3f.4a.5a.6f, ld.2a.3f.4a.5b.6a, ld.2a.3f.4a.5b.6b, ld.2a.3f.4a.5b.6c, ld.2a.3f.4a.5b.6d, ld.2a.3f.4a.5b.6e, ld.2a.3f.4a.5b.6f, ld.2a.3f.4a.5c.6a, ld.2a.3f.4a.5c.6b, ld.2a.3f.4a.5c.6c, ld.2a.3f.4a.5c.6d, ld.2a.3f.4a.5c.6e, ld.2a.3f.4a.5c.6f, ld.2a.3f.4a.5d.6a, ld.2a.3f.4a.5d.6b, ld.2a.3f.4a.5d.6c, ld.2a.3f.4a.5d.6d, ld.2a.3f.4a.5d.6e, ld.2a.3f.4a.5d.6f, ld.2a.3f.4a.5e.6a, ld.2a.3f.4a.5e.6b, ld.2a.3f.4a.5e.6c, ld.2a.3f.4a.5e.6d, ld.2a.3f.4a.5e.6e, ld.2a.3f.4a.5e.6f, ld.2a.3f.4a.5f.6a, ld.2a.3f.4a.5f.6b, ld.2a.3f.4a.5f.6c, ld.2a.3f.4a.5f.6d, ld.2a.3f.4a.5f.6e, ld.2a.3f.4a.5f.6f, ld.2a.3f.4b.5a.6a7 ld.2a.3f.4b.5a.6b, ld.2a.3f.4b.5a.6c, ld.2a.3f.4b.5a.6d, ld.2a.3f.4b.5a.6e, ld.2a.3f.4b.5a.6f, ld.2a.3f.4b.5b.6a, ld.2a.3f.4b.5b.6b, ld.2a.3f.4b.5b.6c, ld.2a.3f.4b.5b.6d, ld.2a.3f.4b.5b.6e, ld.2a.3f.4b.5b.6f, ld.2a.3f.4b.5c.6a, ld.2a.3f.4b.5c.6b, ld.2a.3f.4b.5c.6c, ld.2a.3f.4b.5c.6d, ld.2a.3f.4b.5c.6e, ld.2a.3f.4b.5c.6f, ld.2a.3f.4b.5d.6a, ld.2a.3f.4b.5d.6b, ld.2a.3f.4b.5d.6c, ld.2a.3f.4b.5d.6d, ld.2a.3f.4b.5d.6e, ld.2a.3f.4b.5d.6f, ld.2a.3f.4b.5e.6a, ld.2a.3f.4b.5e.6b, ld.2a.3f.4b.5e.6c, ld.2a.3f.4b.5e.6d, ld.2a.3f.4b.5e.6e, ld.2a.3f.4b.5e.6f, ld.2a.3f.4b.5f.6a, ld.2a.3f.4b.5f.6b, ld.2a.3f.4b.5f.6c, ld.2a.3f.4b.5f.6d, ld.2a.3f.4b.5f.6e, ld.2a.3f.4b.5f.6f, ld.2a.3f.4c.5a.6a, ld.2a.3f.4c.5a.6b, ld.2a.3f.4c.5a.6c, ld.2a.3f.4c.5a.6d, ld.2a.3f.4c.5a.6e, ld.2a.3f.4c.5a.6f, ld.2a.3f.4c.5b.6a, ld.2a.3f.4c.5b.6b, ld.2a.3f.4c.5b.6c, ld.2a.3f.4c.5b.6d, ld.2a.3f.4c.5b.6e, ld.2a.3f.4c.5b.6f, ld.2a.3f.4c.5c.6a, ld.2a.3f.4c.5c.6b, ld.2a.3f.4c.5c.6c, ld.2a.3f.4c.5c.6d, ld.2a.3f.4c.5c.6e, ld.2a.3f.4c.5c.6f, ld.2a.3f.4c.5d.6a, ld.2a.3f.4c.5d.6b, ld.2a.3f.4c.5d.6c, ld.2a.3f.4c.5d.6d, ld.2a.3f.4c.5d.6e, ld.2a.3f.4c.5d.6f, ld.2a.3f.4c.5e.6a, ld.2a.3f.4c.5e.6b, ld.2a.3f.4c.5e.6c, ld.2a.3f.4c.5e.6d, ld.2a.3f.4c.5e.6e, ld.2a.3f.4c.5e.6f, ld.2a.3f.4c.5f.6a, ld.2a.3f.4c.5f.6b, ld.2a.3f.4c.5f.6c, ld.2a.3f.4c.5f.6d, ld.2a.3f.4c.5f.6e, ld.2a.3f.4c.5f.6f, ld.2a.3f.4d.5a.6a, ld.2a.3f.4d.5a.6b, ld.2a.3f.4d.5a.6c, ld.2a.3f.4d.5a.6d, ld.2a.3f.4d.5a.6e, ld.2a.3f.4d.5a.6f, ld.2a.3f.4d.5b.6a, ld.2a.3f.4d.5b.6b, ld.2a.3f.4d.5b.6c, ld.2a.3f.4d.5b.6d, ld.2a.3f.4d.5b.6e, ld.2a.3f.4d.5b.6f, ld.2a.3f.4d.5c.6a, ld.2a.3f.4d.5c.6b, ld.2a.3f.4d.5c.6c, ld.2a.3f.4d.5c.6d, ld.2a.3f.4d.5c.6e, ld.2a.3f.4d.5c.6f, ld.2a.3f.4d.5d.6a, ld.2a.3f.4d.5d.6b, ld.2a.3f.4d.5d.6c, ld.2a.3f.4d.5d.6d, ld.2a.3f.4d.5d.6e, ld.2a.3f.4d.5d.6f, ld.2a.3f.4d.5e.6a, ld.2a.3f.4d.5e.6b, ld.2a.3f.4d.5e.6c, ld.2a.3f.4d.5e.6d, ld.2a.3f.4d.5e.6e, ld.2a.3f.4d.5e.6f, ld.2a.3f.4d.5f.6a7 ld.2a.3f.4d.5f.6b, ld.2a.3f.4d.5f.6c, ld.2a.3f.4d.5f.6d, ld.2a.3f.4d.5f.6e, ld.2a.3f.4d.5f.6f, ld.2a.3f.4e.5a.6a, ld.2a.3f.4e.5a.6b, ld.2a.3f.4e.5a.6c, ld.2a.3f.4e.5a.6d, ld.2a.3f.4e.5a.6e, ld.2a.3f.4e.5a.6f, ld.2a.3f.4e.5b.6a, ld.2a3f.4e.5b.6b, ld.2a.3f.4e.5b.6c, ld.2a.3f.4e.5b.6d, ld.2a.3f.4e.5b.6e, ld.2a.3f.4e.5b.6f, ld.2a.3f.4e.5c.6a, ld.2a.3f.4e.5c.6b, ld.2a.3f.4e.5c.6c, ld.2a.3f.4e.5c.6d, -249- 200918507 ld.2a.3f.4e.5c.6e, ld.2a.3f.4e.5c.6f, ld.2a.3f.4e.5d.6a, ld.2a.3f.4e.5d.6b, ld.2a.3f.4e.5d.6c, ld.2a.3f.4e.5d.6d, ld.2a.3f.4e.5d.6e, ld.2a.3f.4e.5d.6f, ld.2a.3f.4e.5e.6a, ld.2a.3f.4e.5e.6b, ld.2a.3f.4e.5e.6c, ld.2a.3f.4e.5e.6d, ld.2a.3f.4e.5e.6e, ld.2a.3f.4e.5e.6f, ld.2a.3f.4e.5f.6a, ld.2a.3f.4e.5f.6b, ld.2a.3f.4e.5f.6c, ld.2a.3f.4e.5f.6d, ld.2a.3f.4e.5f.6e, ld.2a.3f.4e.5f.6f, ld.2a.3f.4f.5a.6a, ld.2a.3f.4f.5a.6b, ld.2a.3f.4f.5a.6c, ld.2a.3f.4f.5a.6d, ld.2a.3f.4f.5a.6e7 ld.2a.3f.4f.5a.6f, ld.2a.3f.4f.5b.6a, ld.2a.3f.4f.5b.6b, ld.2a.3f.4f.5b.6c, ld.2a.3f.4f.5b.6d, ld.2a.3f.4f.5b.6e, ld.2a.3f.4f.5b.6f, ld.2a.3f.4f.5c.6a, ld.2a.3f.4f.5c.6b, ld.2a.3f.4f.5c.6c, ld.2a.3f.4f.5c.6d, ld.2a.3f.4f.5c.6e, ld.2a.3f.4f.5c.6f, ld.2a.3f.4f.5d.6a, ld.2a.3f.4f.5d.6b, ld.2a.3f.4f.5d.6c, ld.2a.3f.4f.5d.6d, ld.2a.3f.4f.5d.6e, ld.2a.3f.4f.5d.6f, ld.2a.3f.4f.5e.6a, ld.2a.3f.4f.5e.6b, ld.2a.3f.4f.5e.6c, ld.2a.3f.4f.5e.6d, ld.2a.3f.4f.5e.6e, ld.2a.3f.4f.5e.6f, ld.2a.3f.4f.5f.6a, ld.2a.3f.4f.5f.6b, ld.2a.3f.4f.5f.6c, ld.2a.3f.4f.5f.6d, ld.2a.3f.4f.5f.6e, ld.2a.3f.4f.5f.6f, ld.2b.3a.4a.5a.6a, ld.2b.3a.4a.5a.6b; ld.2b.3a.4a.5a.6c7 ld.2b.3a.4a.5a.6d, ld.2b.3a.4a.5a.6e, ld.2b.3a.4a.5a.6f, ld.2b.3a.4a.5b.6a, ld.2b.3a.4a.5b.6b, ld.2b.3a.4a.5b.6c, ld.2b.3a.4a.5b.6d, ld.2b.3a.4a.5b.6e, ld.2b.3a.4a.5b.6f, ld.2b.3a.4a.5c.6a, ld.2b.3a.4a.5c.6b, ld.2b.3a.4a.5c.6c, ld.2b.3a.4a.5c.6d, ld.2b.3a.4a.5c.6e, ld.2b.3a.4a.5c.6f, ld.2b.3a.4a.5d.6a, ld.2b.3a.4a.5d.6b, ld.2b.3a.4a.5d.6c, ld.2b.3a.4a.5d.6d, ld.2b.3a.4a.5d.6e, ld.2b.3a.4a.5d.6f, ld.2b.3a.4a.5e.6a, ld.2b.3a.4a.5e.6b, ld.2b.3a.4a.5e.6c, ld.2b.3a.4a.5e.6d, ld.2b.3a.4a.5e.6e, ld.2b.3a.4a.5e.6f, ld.2b.3a.4a.5f.6a, ld.2b.3a.4a.5f.6b, ld.2b.3a.4a.5f.6c, ld.2b.3a.4a.5f.6d, ld.2b.3a.4a.5f.6e, ld.2b.3a.4a.5f.6f, ld.2b.3a.4b.5a.6a, ld.2b.3a.4b.5a.6b, ld.2b.3a.4b.5a.6c, ld.2b.3a.4b.5a.6d, ld.2b.3a.4b.5a.6e, ld.2b.3a.4b.5a.6f, ld.2b.3a.4b.5b.6a, ld.2b.3a.4b.5b.6b, ld.2b.3a.4b.5b.6c, ld.2b.3a.4b.5b.6d, ld.2b.3a.4b.5b.6e, ld.2b.3a.4b.5b.6f, ld.2b.3a.4b.5c.6a, ld.2b.3a.4b.5c.6b, ld.2b.3a.4b.5c.6c, ld.2b.3a.4b.5c.6d, ld.2b.3a.4b.5c.6e, ld.2b.3a.4b.5c.6f, ld.2b.3a.4b.5d.6a, ld.2b.3a.4b.5d.6b, ld.2b.3a.4b.5d.6c, ld.2b.3a.4b.5d.6d, ld.2b.3a.4b.5d.6e, ld.2b3a.4b.5d.6f, ld.2b.3a.4b.5e.6a, ld.2b.3a.4b.5e.6b, ld.2b.3a.4b.5e.6c, ld.2b.3a.4b.5e.6d, ld.2b.3a.4b.5e.6e, ld.2b.3a.4b.5e.6f, ld.2b.3a.4b.5f.6a, ld.2b.3a.4b.5f.6b, ld.2b.3a.4b.5f.6c, ld.2b.3a.4b.5f.6d, ld.2b.3a.4b.5f.6e, ld.2b.3a.4b.5f.6f, ld.2b.3a.4c.5a.6a, ld.2b.3a.4c.5a.6b, ld.2b.3a.4c.5a.6c, ld.2b.3a.4c.5a.6d, ld.2b.3a.4c.5a.6e, ld.2b.3a.4c.5a.6f, ld.2b.3a.4c.5b.6a, ld.2b.3a.4c.5b.6b, ld.2b.3a.4c.5b.6c, ld.2b.3a.4c.5b.6d, ld.2b.3a.4c.5b.6e, ld.2b.3a.4c.5b.6f, ld.2b.3a.4c.5c.6a, ld.2b.3a.4c.5c.6b, ld.2b.3a.4c.5c.6c, ld.2b.3a.4c.5c.6d, ld.2b.3a.4c*5c.6e, ld.2b.3a.4c.5c.6f, ld.2b.3a.4c.5d.6a, ld.2b.3a.4c.5d.6b, ld.2b.3a.4c.5d.6c, ld.2b.3a.4c.5d.6d, ld.2b.3a.4c.5d.6e, ld.2b.3a.4c.5d.6f, ld.2b.3a.4c.5e.6a, ld.2b.3a.4c.5e.6b, ld.2b.3a.4c.5e.6c, ld.2b.3a.4c.5e.6d, ld.2b.3a.4c.5e.6e, ld.2b.3a.4c.5e.6f, ld.2b.3a.4c.5f.6a, ld.2b.3a.4c.5f.6b, ld.2b.3a.4c.5f.6c, ld.2b.3a.4c.5f.6d, ld.2b.3a.4c.5f.6e, ld.2b.3a.4c.5f.6f, ld.2b.3a.4d.5a.6a, ld.2b.3a.4d.5a.6b, ld.2b.3a.4d.5a.6c, ld.2b.3a.4d.5a.6d, ld.2b.3a.4d.5a.6e, ld.2b.3a.4d.5a.6f, ld.2b.3a.4d.5b.6a, ld.2b.3a.4d.5b.6b, ld.2b.3a.4d.5b.6c, ld.2b.3a.4d.5b.6d, ld.2b.3a.4d.5b.6e, ld.2b.3a.4d.5b.6f, ld.2b.3a.4d.5c.6a, -250- 200918507 ld.2b.3a.4d.5c.6b, ld.2b.3a.4d.5c.6c, ld.2b.3a.4d.5c.6d, ld.2b.3a.4d.5c.6e, ld.2b.3a.4d.5c.6f, ld.2b.3a.4d.5d.6a, ld.2b.3a.4d.5d.6b, ld.2b.3a.4d.5d.6c, ld.2b.3a.4d.5d.6d, ld.2b.3a.4d.5d.6e, ld.2b.3a.4d.5d.6f, ld.2b.3a.4d.5e.6a, ld.2b.3a.4d.5e.6b, ld.2b.3a.4d.5e.6c, ld.2b.3a.4d.5e.6d, ld.2b.3a.4d.5e.6e, ld.2b.3a.4d.5e.6f, ld.2b.3a.4d.5f.6a, ld.2b.3a.4d.5f.6b, ld.2b.3a.4d.5f.6c, ld.2b.3a.4d.5f.6d, ld.2b.3a.4d.5f.6e, ld.2b.3a.4d.5f.6f, ld.2b.3a.4e.5a.6a, ld.2b.3a.4e.5a.6b, ld.2b.3a.4e.5a.6c, ld.2b.3a.4e.5a.6d, ld.2b.3a.4e.5a.6e, ld.2b.3a.4e.5a.6f, ld.2b.3a.4e.5b.6a, ld.2b.3a.4e.5b.6b, ld.2b.3a.4e.5b.6c, ld.2b.3a.4e.5b.6d, ld.2b.3a.4e.5b.6e, ld.2b.3a.4e.5b.6f, ld.2b.3a.4e.5c.6a, ld.2b.3a.4e.5c.6b, ld.2b.3a.4e.5c.6c, ld.2b.3a.4e.5c.6d, ld.2b.3a.4e.5c.6e, ld.2b.3a.4e.5c.6f, ld.2b.3a.4e.5d.6a, ld.2b.3a.4e.5d.6b, ld.2b.3a.4e.5d.6c, ld.2b.3a.4e.5d.6d, ld.2b.3a.4e.5d.6e, ld.2b.3a.4e.5d.6f, ld.2b.3a.4e.5e.6a, ld.2b.3a.4e.5e.6b, ld.2b.3a.4e.5e.6c, ld.2b.3a.4e.5e.6d, ld.2b.3a.4e.5e.6e, ld.2b.3a.4e.5e.6f, ld.2b.3a.4e.5f.6a, ld.2b.3a.4e.5f.6b, ld.2b.3a.4e.5f.6c, ld.2b.3a.4e.5f.6d, ld.2b.3a.4e.5f.6e, ld.2b.3a.4e.5f.6f, ld.2b.3a.4f.5a.6a, ld.2b.3a.4f.5a.6b, ld.2b.3a.4f.5a.6c, ld.2b.3a.4f.5a.6d, ld.2b.3a.4f.5a.6e, ld.2b.3a.4f.5a.6f, ld.2b.3a.4f.5b.6a, ld.2b.3a.4f.5b.6b, ld.2b.3a.4f.5b.6c, ld.2b.3a.4f.5b.6d, ld.2b.3a.4f.5b.6e, ld.2b.3a.4f.5b.6f, ld.2b.3a.4f.5c.6a, ld.2b.3a.4f.5c.6b, ld.2b.3a.4f.5c.6c, ld.2b.3a.4f.5c.6d, ld.2b.3a.4f.5c.6e, ld.2b.3a.4f.5c.6f, ld.2b.3a.4f.5d.6a, ld.2b.3a.4f.5d.6b, ld.2b.3a.4f.5d.6c, ld.2b.3a.4f.5d.6d, ld.2b.3a.4f.5d.6e, ld.2b.3a.4f.5d.6f, ld.2b.3a.4f.5e.6a, ld.2b.3a.4f.5e.6b, ld.2b.3a.4f.5e.6c, ld.2b.3a.4f.5e.6d, ld.2b.3a.4f.5e.6e, ld.2b.3a.4f.5e.6f, ld.2b.3a.4f.5f.6a, ld.2b.3a.4f.5f.6b, ld.2b.3a.4f.5f.6c, ld.2b.3a.4f.5f.6d, ld.2b.3a.4f.5f.6e, ld.2b.3a.4f.5f.6f, ld.2b.3b.4a.5a.6a, ld.2b.3b.4a.5a.6b, ld.2b.3b.4a.5a.6c, ld.2b.3b.4a.5a.6d, ld.2b.3b.4a.5a.6e, ld.2b.3b.4a.5a.6f, ld.2b.3b.4a.5b.6a, ld.2b.3b.4a.5b.6b, ld.2b.3b.4a.5b.6c, ld.2b.3b.4a.5b.6d, ld.2b.3b.4a.5b.6e, ld.2b.3b.4a.5b.6f, ld,2b.3b,4a.5c.6a, lcL2b.3b.4a.5c.6b, ld.2b.3b.4a.5c.6c, ld.2b.3b.4a.5c.6d, ld.2b.3b.4a.5c.6e, ld.2b.3b.4a.5c.6f, ld.2b.3b.4a.5d.6a, ld.2b.3b.4a.5d.6b, ld.2b.3b.4a.5d.6c, ld.2b.3b.4a.5d.6d, ld.2b.3b.4a.5d.6e, ld.2b.3b.4a.5d.6f, ld.2b.3b.4a.5e.6a, ld.2b.3b.4a.5e.6b, ld.2b.3b.4a.5e.6c, ld.2b.3b.4a.5e.6d, ld.2b.3b.4a.5e.6e, ld.2b.3b.4a.5e.6f, ld.2b.3b.4a.5f.6a, ld.2b.3b.4a.5f.6b, ld.2b.3b.4a.5f.6c, ld.2b.3b.4a.5f.6d, ld.2b.3b.4a.5f.6e, ld.2b.3b.4a.5f.6f, ld.2b.3b.4b.5a.6a, ld.2b.3b.4b.5a.6b, ld.2b.3b.4b.5a.6c, ld.2b.3b.4b.5a.6d, ld.2b.3b.4b.5a.6e, ld.2b.3b.4b.5a.6f, ld.2b.3b.4b.5b.6a, ld.2b.3b.4b.5b.6b, ld.2b.3b.4b.5b.6c, ld.2b.3b.4b.5b.6d, ld.2b.3b.4b.5b.6e, ld.2b.3b.4b.5b.6f, ld.2b,3b,4b.5c.6a, ld.2b.3b.4b.5c.6b, ld.2b.3b.4b.5c.6c, ld.2b.3b.4b.5c.6d, ld.2b.3b.4b.5c.6e, ld.2b.3b.4b.5c.6f, ld.2b.3b.4b.5d.6a, ld.2b.3b.4b.5d.6b, ld.2b.3b.4b.5d.6c, ld.2b.3b.4b.5d.6d, ld.2b.3b.4b.5d.6e, ld.2b.3b.4b.5d.6f, ld.2b.3b.4b.5e.6a, ld.2b.3b.4b.5e.6b, ld.2b.3b.4b.5e.6c, ld.2b.3b.4b.5e.6d, ld.2b.3b.4b.5e.6e, ld.2b.3b.4b.5e.6f, ld.2b.3b.4b.5f.6a, ld.2b.3b.4b.5f.6b, ld.2b.3b.4b.5f.6c, ld.2b.3b.4b.5f.6d, ld.2b.3b.4b.5f.6e, ld.2b.3b.4b.5f.6f, ld.2b.3b.4c.5a.6a, ld.2b.3b.4c.5a.6b, -251 - 200918507 ld.2b.3b.4c.5a.6c, ld.2b.3b.4c.5a.6d, ld.2b.3b.4c.5a.6e, ld.2b.3b.4c.5a.6f, ld.2b.3b.4c.5b.6a, ld.2b.3b.4c.5b.6b, ld.2b.3b.4c.5b.6c, ld.2b.3b.4c.5b.6d, ld.2b.3b.4c.5b.6e, ld.2b.3b.4c.5b.6f, ld.2b.3b.4c.5c.6a, ld.2b.3b.4c.5c.6b, ld.2b.3b.4c.5c.6c, ld.2b.3b.4c.5c.6d, ld.2b.3b.4c.5c.6e, ld.2b.3b.4c.5c.6f, ld.2b.3b.4c.5d.6a, ld.2b.3b.4c.5d.6b, ld.2b.3b.4c.5d.6c, ld.2b.3b.4c.5d.6d, ld.2b.3b.4c.5d.6e, ld.2b.3b.4c.5d.6f, ld.2b.3b.4c.5e.6a, ld.2b.3b.4c.5e.6b, ld.2b.3b.4c.5e.6c, ld.2b.3b.4c.5e.6d, ld.2b.3b.4c.5e.6e, ld.2b.3b.4c.5e.6f, ld.2b.3b.4c.5f.6a, ld.2b.3b.4c.5f.6b, ld.2b.3b.4c.5f.6c, ld.2b.3b.4c.5f.6d, ld.2b.3b.4c.5f.6e, ld.2b.3b.4c.5f.6f, ld.2b.3b.4d.5a.6a, ld.2b.3b.4d.5a.6b, ld.2b.3b.4d.5a.6c, ld.2b.3b.4d.5a.6d, ld.2b.3b.4d.5a.6e, ld.2b.3b.4d.5a.6f, ld.2b.3b.4d.5b.6a, ld.2b.3b.4d.5b.6b, ld.2b.3b.4d.5b.6c, ld.2b.3b.4d.5b.6d, ld.2b.3b.4d.5b.6e, ld.2b.3b.4d.5b.6f, ld.2b.3b.4d.5c.6a, ld.2b.3b.4d.5c.6b, ld.2b.3b.4d.5c.6c, ld.2b.3b.4d.5c.6d, ld-2b.3b.4d.5c.6e, ld.2b.3b.4d.5c.6f, ld.2b.3b.4d.5d.6a, ld.2b.3b.4d.5d.6b, ld.2b.3b.4d.5d.6c, ld.2b.3b.4d.5d.6d, ld.2b.3b.4d.5d.6e, ld.2b.3b.4d.5d.6f, ld.2b.3b.4d.5e.6a, ld.2b.3b.4d.5e.6b, ld.2b.3b.4d.5e.6c, ld.2b.3b.4d.5e.6d, ld.2b.3b.4d.5e.6e, ld.2b.3b.4d.5e.6f, ld.2b.3b.4d.5f.6a, ld.2b.3b.4d.5f.6b, ld.2b.3b.4d.5f.6c, ld.2b.3b.4d.5f.6d, ld.2b.3b.4d.5f.6e, ld.2b.3b.4d.5f.6f, ld.2b.3b.4e.5a.6a, ld.2b.3b.4e.5a.6b, ld.2b.3b.4e.5a.6c, ld.2b.3b.4e.5a.6d, ld.2b.3b.4e.5a.6e, ld.2b.3b.4e.5a.6f, ld.2b.3b.4e.5b.6a, ld.2b.3b.4e.5b.6b, ld.2b.3b.4e.5b.6c, ld.2b.3b.4e.5b.6d, ld.2b.3b.4e.5b.6e, ld.2b.3b.4e.5b.6f7 ld.2b.3b.4e.5c.6a, ld.2b.3b.4e.5c.6b, ld.2b.3b.4e.5c.6c, ld.2b.3b.4e.5c.6d, ld.2b.3b.4e.5c.6e, ld.2b.3b.4e.5c.6f, ld.2b.3b.4e.5d.6a, ld.2b.3b.4e.5d.6b, ld.2b.3b.4e.5d.6c, ld.2b.3b.4e.5d.6d, ld.2b.3b.4e.5d.6e, ld.2b.3b.4e.5d.6f, ld.2b.3b.4e.5e.6a, ld.2b.3b.4e.5e.6b, ld.2b.3b.4e.5e.6c, ld.2b.3b.4e.5e.6d, ld.2b.3b.4e.5e.6e, ld.2b.3b.4e.5e.6f, ld.2b.3b.4e.5f.6a, ld.2b.3b.4e.5f.6b, ld.2b.3b.4e.5f.6c, ld.2b.3b.4e.5f.6d, ld.2b.3b.4e.5f.6e, ld.2b.3b.4e.5f.6f, ld.2b.3b.4f.5a.6a, ld.2b.3b.4f.5a.6b, ld.2b.3b.4f.5a.6c, ld.2b.3b.4f.5a.6d, ld.2b.3b.4f.5a.6e, ld.2b.3b.4f.5a.6f, ld.2b.3b.4f.5b.6a, ld.2b.3b.4f.5b.6b, ld.2b.3b.4f.5b.6c, ld.2b.3b.4f.5b.6d, ld.2b.3b.4f.5b.6e, ld.2b.3b.4f.5b.6f, ld.2b.3b.4f.5c.6a, ld.2b.3b.4f.5c.6b, ld.2b.3b.4f.5c.6c, ld.2b.3b.4f.5c.6d, ld.2b.3b.4f.5c.6e, ld.2b.3b.4f.5c.6f, ld.2b.3b.4f.5d.6a, ld.2b.3b.4f.5d.6b, ld.2b.3b.4f.5d.6c, ld.2b.3b.4f.5d.6d, ld.2b.3b.4f.5d.6e, ld.2b.3b.4f.5d.6f, ld.2b.3b.4f.5e.6a, ld.2b.3b.4f.5e.6b, ld.2b.3b.4f.5e.6c, ld.2b.3b.4f.5e.6d, ld.2b.3b.4f.5e.6e, ld.2b.3b.4f.5e.6f, ld.2b.3b.4f.5f.6a, ld.2b.3b.4f.5f.6b, ld.2b.3b.4f.5f.6c, ld.2b.3b.4f.5f.6d, ld.2b.3b.4f.5f.6e, ld.2b.3b.4f.5f.6f, ld.2b.3c.4a.5a.6a, ld.2b.3c.4a.5a.6b, ld.2b.3c.4a.5a.6c, ld,2b.3c.4a.5a.6d, ld.2b.3c.4a.5a.6e, ld.2b.3c.4a.5a.6t ld.2b.3c.4a.5b.6a, ld.2b.3c.4a.5b.6b, ld.2b.3c.4a.5b.6c, ld.2b.3c.4a.5b.6d, ld.2b.3c.4a.5b.6e, ld.2b.3c.4a.5b.6f, ld.2b.3c.4a.5c.6a, ld.2b.3c.4a.5c.6b, ld.2b.3c.4a.5c.6c, ld.2b.3c.4a.5c.6d, ld.2b.3c.4a.5c.6e, ld.2b.3c.4a.5c.6f, ld.2b.3c.4a.5d.6a, ld.2b.3c.4a.5d.6b, ld.2b.3c.4a.5d.6c, ld.2b.3c.4a.5d.6d, ld.2b.3c.4a.5d.6e, ld.2b.3c.4a.5d.6f, ld.2b.3c.4a.5e.6a, ld.2b.3c.4a.5e.6b, -252 - 200918507 ld.2b.3c.4a.5e.6c, ld.2b.3c.4a.5e.6d, ld.2b.3c.4a.5e.6e, ld.2b.3c.4a.5e.6f, ld.2b.3c.4a.5f.6a, ld.2b.3c.4a.5f.6b, ld.2b3c.4a.5f.6c, ld.2b.3c.4a.5f.6d, ld.2b.3c.4a.5f.6e, ld.2b.3c.4a.5f.6f, ld.2b.3c.4b.5a.6a, ld.2b.3c.4b.5a.6b, ld.2b3c.4b.5a.6c, ld.2b.3c.4b.5a.6d, ld.2b.3c.4b.5a.6e, ld.2b.3c.4b.5a.6f, ld.2b.3c.4b.5b.6a, ld.2b.3c.4b.5b.6b, ld.2b.3c.4b.5b.6c, ld.2b.3c.4b.5b.6d, ld.2b.3c.4b.5b.6e, ld.2b.3c.4b.5b.6f, ld.2b.3c.4b.5c.6a, ld.2b.3c.4b.5c.6b, ld.2b.3c.4b.5c.6c, ld.2b.3c.4b.5c.6d, ld.2b.3c.4b.5c.6e, ld.2b.3c.4b.5c.6f, ld.2b.3c.4b.5d.6a, ld.2b.3c.4b.5d.6b, ld.2b.3c.4b.5d.6c, ld.2b.3c.4b.5d.6d, ld.2b.3c.4b.5d.6e, ld.2b.3c.4b.5d.6f, ld.2b.3c.4b.5e.6a, ld.2b.3c.4b.5e.6b, ld.2b.3c.4b.5e.6c, ld.2b.3c.4b.5e.6d, ld.2b.3c.4b.5e.6e, ld.2b.3c.4b.5e.6f, ld.2b.3c.4b.5f.6a, ld.2b.3c.4b.5f.6b, ld.2b.3c.4b.5f.6c, ld.2b.3c.4b.5f.6d, ld.2b.3c.4b.5f.6e, ld.2b.3c.4b.5f.6f, ld.2b.3c.4c.5a.6a, ld.2b.3c.4c.5a.6b, ld.2b.3c.4c.5a.6c, ld.2b.3c.4c.5a.6d, ld.2b.3c.4c.5a.6e, ld.2b.3c.4c.5a.6f, ld.2b.3c.4c.5b.6a, ld.2b.3c.4c.5b.6b, ld.2b.3c.4c.5b.6c, ld.2b.3c.4c.5b.6d, ld.2b.3c.4c.5b.6e, ld.2b.3c.4c.5b.6f, ld.2b.3c.4c.5c.6a, ld.2b.3c.4c.5c.6b, ld.2b.3c.4c.5c.6c, ld.2b.3c.4c.5c.6d, ld.2b.3c.4c.5c.6e, ld.2b.3c.4c.5c.6f, ld.2b.3c.4c.5d.6a, ld.2b.3c.4c.5d.6b, ld.2b.3c.4c.5d.6c, ld.2b.3c.4c.5d.6d, ld.2b.3c.4c.5d.6e, ld.2b.3c.4c.5d.6f, ld.2b.3c.4c.5e.6a, ld.2b.3c.4c.5e.6b, ld.2b.3c.4c.5e.6c, ld.2b.3c.4c.5e.6d, ld.2b.3c.4c.5e.6e, ld.2b.3c.4c.5e.6f, ld.2b.3c.4c.5f.6a, ld.2b.3c.4c.5f.6b, ld.2b.3c.4c.5f.6c, ld.2b.3c.4c.5f.6d, ld.2b.3c.4c.5f.6e, ld.2b.3c.4c.5f.6f, ld.2b.3c.4d.5a.6a, ld.2b.3c.4d.5a.6b, ld.2b.3c.4d.5a.6c, ld.2b.3c.4d.5a.6d, ld.2b.3c.4d.5a.6e, ld.2b.3c.4d.5a.6f, ld.2b.3c.4d.5b.6a, ld.2b.3c.4d.5b.6b, ld.2b.3c.4d.5b.6c, ld.2b.3c.4d.5b.6d, ld.2b.3c.4d.5b.6e, ld.2b.3c.4d.5b.6f, ld.2b.3c.4d.5c.6a, ld.2b.3c.4d.5c.6b, ld.2b.3c.4d.5c.6c, ld.2b.3c.4d.5c.6d, ld.2b.3c.4d.5c.6e, ld.2b.3c.4d.5c.6f, ld.2b.3c.4d.5d.6a, ld.2b.3c.4d.5d.6b, ld.2b.3c.4d.5d.6c, ld.2b.3c.4d.5d.6d, ld.2b.3c.4d.5d.6e, ld.2b.3c.4d.5d.6f, ld.2b.3c.4d.5e.6a, ld.2b.3c.4d.5e.6b, ld.2b.3c.4d.5e.6c, ld.2b.3c.4d.5e.6d, ld.2b.3c.4d.5e.6e, ld.2b.3c.4d.5e.6f, ld.2b.3c.4d.5f.6a, ld.2b.3c.4d.5f.6b, ld.2b.3c.4d.5f.6c, ld.2b.3c.4d.5f.6d, ld.2b.3c.4d.5f.6e, ld.2b.3c.4d.5f.6f, ld.2b.3c.4e.5a.6a, ld.2b.3c.4e.5a.6b, ld.2b.3c.4e.5a.6c, ld.2b.3c.4e.5a.6d, ld.2b.3c.4e.5a.6e, ld.2b.3c.4e.5a.6f, ld.2b.3c.4e.5b.6a, ld.2b.3c.4e.5b.6b7 ld.2b.3c.4e.5b.6c, ld.2b.3c.4e.5b.6d, ld.2b.3c.4e.5b.6e, ld.2b.3c.4e.5b.6f, ld.2b.3c.4e.5c.6a, ld.2b.3c.4e.5c.6b, ld.2b.3c.4e.5c.6c, ld.2b.3c.4e.5c.6d, ld.2b.3c.4e.5c.6e, ld.2b.3c.4e.5c.6f, ld.2b.3c.4e.5d.6a, ld.2b.3c.4e.5d.6b, ld.2b.3c.4e.5d.6c, ld.2b.3c.4e.5d.6d, ld.2b.3c.4e.5d.6e, ld.2b.3c.4e.5d.6f, ld.2b.3c.4e.5e.6a, ld.2b.3c.4e.5e.6b, ld.2b.3c.4e.5e.6c, ld.2b3c.4e.5e.6d, ld.2b.3c.4e.5e.6e, ld.2b.3c.4e.5e.6f, ld.2b.3c.4e.5f.6a, ld.2b.3c.4e.5f.6b, ld.2b.3c.4e.5f.6c, ld.2b.3c.4e.5f.6d, ld.2b.3c.4e.5f.6e, ld.2b.3c.4e.5f.6f, ld.2b.3c.4f.5a.6a, ld.2b.3c.4f.5a.6b, ld.2b,3c.4f.5a.6c, ld.2b.3c.4f.5a.6d, ld.2b.3c.4f.5a.6e, ld.2b.3c.4f.5a.6f, ld.2b.3c.4f.5b.6a, ld.2b.3c.4f.5b.6b, ld.2b.3c.4f.5b.6c, ld.2b.3c.4f.5b.6d, ld.2b.3c.4f.5b.6e, ld.2b.3c.4f.5b.6f, ld.2b.3c.4f.5c.6a, ld.2b.3c.4f.5c.6b, -253- 200918507 ld.2b.3c.4f.5c.6c, ld.2b.3c4f.5c.6d, ld.2b.3c.4f.5c6e, ld.2b.3c.4f.5c.6f, ld.2b.3c.4f.5d.6a, ld.2b.3c.4f,5d.6b, ld.2b.3c.4f.5d.6c, ld.2b.3c4f.5d.6d, ld.2b.3c.4f.5d.6e, ld.2b.3c.4f.5d.6f, ld.2b.3c.4f.5e.6a, ld.2b.3c.4f.5e.6b, ld.2b.3c.4f.5e.6c, ld.2b.3c.4f.5e.6d, ld.2b.3c.4f.5e.6e, ld.2b.3c.4f.5e.6f, ld.2b.3c.4f.5f.6a, ld.2b.3c.4f.5f.6b, ld.2b3c.4f.5f.6c, ld.2b.3c.4f.5f.6d, ld.2b.3c.4f.5f.6e, ld.2b.3c.4f.5f.6f, ld.2b.3d.4a.5a.6a, ld.2b.3d.4a.5a.6b, ld.2b.3d.4a.5a.6c, ld.2b.3d.4a.5a.6d, ld.2b.3d.4a.5a.6e, ld.2b.3d.4a.5a.6f, ld.2b.3d.4a.5b.6a, ld.2b.3d.4a.5b.6b, ld.2b.3d.4a.5b.6c, ld.2b.3d.4a.5b.6d, ld.2b.3d.4a.5b.6e, ld.2b.3d.4a.5b.6f, ld.2b.3d.4a.5c.6a, ld.2b.3d.4a.5c.6b, ld.2b.3d.4a.5c.6c, ld.2b.3d.4a.5c.6d, ld.2b.3d.4a.5c.6e, ld.2b.3d.4a.5c.6f, ld.2b.3d.4a.5d.6a, ld.2b.3d.4a.5d.6b, ld.2b.3d.4a.5d.6c, ld.2b.3d.4a.5d.6d, ld.2b.3d.4a.5d.6e, ld.2b.3d.4a.5d.6f, ld.2b.3d.4a.5e.6a, ld.2b.3d.4a.5e.6b, ld.2b.3d.4a.5e.6c, ld.2b.3d.4a.5e.6d, ld.2b.3d.4a.5e.6e, ld.2b.3d.4a.5e.6f, ld.2b.3d.4a.5f.6a, ld.2b.3d.4a.5f.6b, ld.2b.3d.4a.5f.6c, ld.2b.3d.4a.5f.6d, ld.2b.3d.4a.5f.6e, ld.2b.3d.4a.5f.6f, ld.2b.3d.4b.5a.6a, ld.2b.3d.4b.5a.6b, ld.2b.3d.4b.5a.6c, ld.2b.3d.4b.5a,6d, ld.2b.3d.4b.5a.6e, ld.2b.3d.4b.5a.6f, ld.2b.3d.4b.5b.6a, ld.2b.3d.4b.5b.6b, ld.2b.3d.4b.5b.6c, ld.2b.3d.4b.5b.6d, ld.2b.3d.4b.5b.6e, ld.2b.3d.4b.5b.6f, ld.2b.3d.4b.5c.6a, ld.2b.3d.4b.5c.6b, ld.2b.3d.4b.5c.6c, ld.2b.3d.4b.5c.6d, ld.2b.3d.4b.5c.6e, ld.2b.3d.4b.5c.6f, ld.2b.3d.4b.5d.6a, ld.2b.3d.4b.5d.6b, ld.2b.3d.4b.5d.6c, ld.2b.3d.4b.5d.6d, ld.2b.3d.4b.5d.6e, ld.2b.3d.4b.5d.6f, ld.2b.3d.4b.5e.6a, ld.2b.3d.4b.5e.6b, ld.2b.3d.4b.5e.6c, ld.2b.3d.4b.5e.6d, ld.2b.3d.4b.5e.6e, ld.2b.3d.4b.5e.6f, ld.2b.3d.4b.5f.6a, ld.2b.3d.4b.5f.6b, ld.2b.3d.4b.5f.6c, ld.2b.3d.4b.5f.6d, ld.2b.3d.4b.5f.6e, ld.2b.3d.4b.5f.6f, ld.2b.3d.4c.5a.6a, ld.2b.3d.4c.5a.6b, ld.2b.3d.4c.5a.6c, ld.2b.3d.4c.5a.6d, ld.2b.3d.4c.5a.6e, ld.2b.3d.4c.5a.6f, ld.2b.3d.4c.5b.6a, ld.2b.3d.4c.5b.6b, ld.2b.3d.4c.5b.6c, ld.2b.3d.4c.5b.6d, ld.2b.3d.4c.5b.6e, ld.2b.3d.4c.5b.6f, ld.2b.3d.4c.5c.6a, ld.2b.3d.4c.5c.6b, ld.2b.3d.4c.5c.6c, ld.2b.3d.4c.5c.6d, ld.2b.3d.4c.5c.6e, ld.2b.3d.4c.5c.6f, ld.2b.3d.4c.5d.6a, ld.2b.3d.4c.5d.6b, ld.2b.3d.4c.5d.6c, ld.2b.3d.4c.5d.6d, ld.2b.3d.4c.5d.6e, ld.2b.3d.4c.5d.6f, ld.2b.3d.4c.5e.6a, ld.2b.3d.4c.5e.6b, ld.2b.3d.4c.5e.6c, ld.2b.3d.4c.5e.6d, ld.2b.3d.4c.5e.6e, ld.2b.3d.4c.5e.6f, ld.2b.3d.4c.5f.6a, ld.2b.3d.4c,5f.6b, ld.2b.3d.4c.5f.6c, ld.2b.3d.4c.5f.6d, ld.2b.3d.4c.5f.6e, ld.2b.3d.4c.5f.6f, ld.2b.3d.4d.5a.6a, ld.2b.3d.4d.5a.6b, ld.2b.3d.4d.5a.6c, ld.2b.3d.4d.5a.6d, ld.2b.3d.4d.5a.6e, ld.2b.3d.4d.5a.6f, ld.2b.3d.4d.5b.6a, ld.2b.3d.4d.5b.6b, ld.2b.3d.4d.5b.6c, ld.2b.3d.4d.5b.6d, ld.2b.3d.4d.5b.6e, ld.2b.3d.4d.5b.6f, ld.2b.3d.4d.5c.6a, ld.2b.3d.4d.5c.6b, ld.2b.3d.4d.5c.6c, ld.2b.3d.4d.5c.6d, ld.2b.3d.4d.5c.6e, ld.2b3d.4d.5c.6f; ld.2b.3d.4d.5d.6a, ld.2b.3d.4d.5d.6b, ld.2b.3d.4d.5d.6c, ld.2b.3d.4d.5d.6d, ld.2b.3d.4d.5d.6e, ld.2b.3d.4d.5d.6f, ld.2b.3d.4d.5e.6a, ld.2b.3d.4d.5e.6b, ld.2b.3d.4d.5e.6c, ld.2b.3d.4d.5e.6d, ld.2b.3d.4d.5e.6e, ld.2b.3d.4d.5e.6f, ld.2b.3d.4d.5f.6a, ld.2b.3d.4d.5f.6b, ld.2b.3d.4d.5f.6c, ld.2b.3d.4d.5f.6d, ld.2b.3d.4d.5f.6e, ld.2b.3d.4d.5f.6f, ld.2b.3d.4e.5a.6a, ld.2b.3d.4e.5a.6b, ld.2b.3d_4e.5a.6c, ld.2b.3d.4e.5a.6d, -254- 200918507 ld.2b.3d.4e.5a.6e, ld.2b.3d.4e.5a.6f； ld.2b.3d.4e.5b.6a, ld.2b.3d.4e.5b.6b, ld.2b.3d.4e.5b.6c, ld.2b.3d.4e.5b.6d, ld.2b.3d.4e.5b.6e, ld.2b.3d.4e.5b.6f, ld.2b.3d.4e.5c.6a, ld.2b.3d.4e.5c.6b, ld.2b.3d.4e.5c.6c, ld.2b.3d.4e.5c.6d, ld.2b.3d.4e.5c.6e, ld,2b.3d.4e.5c.6f, ld.2b.3d.4e.5d.6a, ld.2b.3d.4e.5d.6b, ldL2b.3d.4e.5d.6c, ld.2b.3d.4e.5d.6d, ld_2b.3d.4e.5d.6e, ld.2b.3d.4e.5d.6f, ld.2b.3d.4e.5e.6a, ld.2b.3d.4e.5e.6b, ld.2b.3d.4e.5e.6c, ld.2b.3d.4e.5e.6d, ld.2b.3d.4e.5e.6e, ld.2b.3d.4e.5e.6f, ld.2b.3d.4e.5f.6a, ld.2b.3d.4e.5f.6b, ld.2b.3d.4e.5f.6c, ld.2b.3d.4e.5f.6d, ld.2b.3d.4e.5f.6e, ld.2b.3d.4e.5f.6f, ld.2b.3d.4f.5a.6a, ld.2b.3d.4f.5a.6b, ld.2b.3d.4f.5a.6c, ld.2b.3d.4f.5a.6d, ld.2b.3d.4f.5a.6e, ld.2b.3d.4f.5a.6f, ld.2b.3d.4f.5b.6ar ld.2b.3d.4f.5b.6b, ld.2b.3d.4f.5b.6c, ld.2b.3d.4f.5b.6d, ld.2b.3d.4f.5b.6e, ld.2b.3d.4f.5b.6f, ld.2b.3d.4f.5c.6a, ld.2b.3d.4f.5c.6b, ld.2b.3d.4f.5c.6c, ld.2b.3d.4f.5c.6d, ld.2b.3d.4f.5c.6e, ld.2b.3d.4f.5c.6f, ld.2b.3d.4f.5d.6a, ld.2b.3d.4f.5d.6b, ld.2b.3d.4f.5d.6c, ld.2b.3d.4f.5d.6d, ld.2b.3d.4f.5d.6e, ld.2b.3d.4f.5d.6f, ld.2b.3d.4f.5e.6a, ld.2b.3d.4f.5e.6b, ld.2b.3d.4f.5e.6c, ld.2b.3d.4f.5e.6d, ld.2b.3d.4f.5e.6e, ld.2b.3d.4f.5e.6f, ld.2b.3d.4f.5f.6a, ld.2b.3d.4f.5f.6b, ld.2b.3d.4f.5f.6c, ld.2b.3d.4f.5f.6d, ld.2b.3d.4f.5f.6e, ld.2b.3d.4f.5f.6f, ld.2b.3e.4a.5a.6a, ld.2b.3e.4a.5a.6b, ld.2b.3e.4a.5a.6c, ld.2b.3e.4a.5a.6d, ld.2b.3e.4a.5a.6e, ld.2b.3e.4a.5a.6f, ld.2b.3e.4a.5b.6a, ld.2b.3e.4a.5b.6b, ld.2b.3e.4a.5b.6c, ld.2b.3e.4a.5b.6d, ld.2b.3e.4a.5b.6e, ld.2b.3e.4a.5b.6f, ld.2b.3e.4a.5c.6a, ld.2b.3e.4a.5c.6b, ld.2b.3e.4a.5c.6c, ld.2b.3e.4a.5c.6d, ld.2b.3e.4a.5c.6e, ld.2b.3e.4a.5c.6f, ld.2b.3e.4a.5d.6a, ld.2b.3e.4a.5d.6b, ld.2b.3e.4a.5d.6c, ld.2b.3e.4a.5d.6d, ld.2b.3e.4a.5d.6e, ld.2b.3e.4a.5d.6f, ld,2b.3e.4a.5e.6a7 ld.2b.3e.4a.5e.6b, ld.2b.3e.4a.5e.6c, ld.2b.3e.4a.5e.6d, ld.2b.3e.4a.5e.6e, ld.2b.3e.4a.5e.6f, ld.2b.3e.4a.5f.6a, ld.2b.3e.4a.5f.6b, ld.2b.3e.4a.5f.6c, ld.2b.3e.4a.5f.6d, ld.2b.3e.4a.5f.6e, ld.2b.3e.4a.5f.6f, ld.2b.3e.4b.5a.6a, ld.2b.3e.4b.5a.6b, ld.2b.3e.4b.5a.6c, ld.2b.3e.4b.5a.6d, ld.2b.3e.4b.5a.6e, ld.2b.3e.4b.5a.6f, ld.2b.3e.4b.5b.6a, ld.2b.3e.4b.5b.6b, ld.2b.3e.4b.5b.6c, ld.2b.3e.4b.5b.6d, ld.2b.3e.4b.5b.6e, ld.2b.3e.4b.5b.6f, ld.2b.3e.4b.5c.6a, ld.2b.3e.4b.5c.6b, ld.2b.3e.4b.5c.6c, ld.2b.3e.4b.5c.6d, ld.2b.3e.4b.5c.6e, ld.2b.3e.4b.5c.6f, ld.2b.3e.4b.5d.6a, ld.2b.3e.4b.5d.6b, ld.2b.3e.4b.5d.6c, ld.2b.3e.4b.5d.6d, ld.2b.3e.4b.5d.6e, ld.2b.3e.4b.5d.6f, ld.2b.3e.4b.5e.6a, ld.2b.3e.4b.5e.6b, ld.2b.3e.4b.5e.6c, ld.2b.3e.4b.5e.6d, ld.2b.3e.4b.5e.6e, ld.2b.3e.4b.5e.6f, ld.2b.3e.4b.5f.6a, ld.2b.3e.4b.5f.6b, ld.2b.3e.4b.5f.6c, ld.2b.3e.4b.5f.6d, ld.2b.3e.4b.5f.6e, ld.2b.3e.4b.5f.6f, ld.2b.3e.4c.5a.6a, ld.2b.3e.4c.5a.6b, ld.2b.3e.4c.5a.6c, ld.2b3e.4c.5a.6d, ld.2b.3e.4c.5a.6e, ld.2b.3e.4c.5a.6f, ld.2b.3e.4c.5b.6a, ld.2b.3e.4c.5b.6b, ld.2b.3e.4c.5b.6c, ld.2b.3e.4c.5b.6d, ld.2b.3e.4c.5b.6e, ld.2b.3e.4c.5b.6f, ld.2b.3e.4c.5c.6a, ld.2b.3e.4c.5c.6b, ld.2b.3e.4c.5c.6c, ld.2b.3e.4c.5c.6d, ld.2b.3e.4c.5c.6e, ld.2b.3e.4c.5c.6f, ld.2b.3e.4c.5d.6a, ld.2b.3e.4c.5d.6b, ld.2b.3e.4c.5d.6c, ld.2b.3e.4c.5d.6d, ld.2b.3e.4c.5d.6e, ld.2b.3e.4c.5d.6f, ld.2b.3e.4c.5e.6a, ld.2b.3e.4c.5e.6b, ld.2b.3e.4c.5e.6c, ld.2b.3e.4c.5e.6d, -255 - 200918507 ld.2b.3e.4c.5e.6e, ld.2b.3e.4c.5e.6f, ld.2b.3e.4c.5f.6a, ld.2b.3e.4c.5f.6b, ld.2b.3e.4c.5f.6c, ld.2b.3e.4c.5f.6d, ld,2b.3e.4c.5f.6e, ld.2b.3e.4c.5f.6f, ld.2b.3e.4d.5a.6a, ld.2b.3e.4d.5a.6b, ld.2b.3e.4d.5a.6c7 ld.2b.3e.4d.5a.6d, ld.2b.3e.4d.5a.6e, ld.2b.3e.4d.5a.6f, ld.2b.3e.4d.5b.6a, ld.2b.3e.4d.5b.6b, ld.2b.3e.4d.5b.6c, ld.2b.3e.4d.5b.6d, ld.2b.3e.4d.5b.6e, ld.2b.3e.4d.5b.6f, ld.2b.3e.4d.5c.6a, ld.2b.3e.4d.5c.6b, ld.2b.3e.4d.5c.6c, ld.2b.3e.4d.5c.6d, ld.2b.3e.4d.5c.6e, ld.2b.3e.4d.5c.6f, ld.2b.3e.4d.5d.6a, ld.2b.3e.4d.5d.6b/ ld*2b.3e.4d.5d.6c, ld.2b.3e.4d.5d.6d, ld.2b.3e.4d.5d.6e, ld.2b.3e.4d.5d.6f, ld.2b.3e.4d.5e.6a, ld.2b.3e.4d.5e.6b, ld.2b.3e.4d.5e.6c, ld.2b.3e.4d.5e.6d, ld.2b.3e.4d.5e.6e, ld.2b.3e.4d.5e.6f, ld.2b.3e.4d.5f.6a, ld.2b.3e.4d.5f.6br ld.2b.3e.4d.5f.6c, ld.2b.3e.4d.5f.6d, ld.2b.3e.4d.5f.6e, ld.2b.3e.4d.5f.6f, ld.2b.3e.4e.5a.6a, ld.2b.3e.4e.5a.6b, ld.2b.3e.4e.5a.6c, ld.2b.3e.4e.5a.6d, ld.2b.3e.4e.5a.6e, ld.2b.3e.4e.5a.6f, ld.2b.3e.4e.5b.6a, ld.2b.3e.4e.5b.6b, ld.2b.3e.4e.5b.6c, ld.2b.3e.4e.5b.6d, ld.2b.3e.4e.5b.6e, ld.2b.3e.4e.5b.6f, ld.2b.3e.4e.5c.6a, ld.2b.3e.4e.5c.6b, ld.2b.3e.4e.5c.6c, ld.2b.3e.4e.5c.6d, ld.2b3e.4e.5c.6e, ld.2b.3e.4e.5c.6f, ld.2b.3e.4e.5d.6a, ld.2b.3e.4e.5d.6b, ld.2b.3e.4e.5d.6c, ld.2b.3e.4e.5d.6d, ld.2b.3e.4e.5d.6e, ld.2b.3e.4e.5d.6f, ld.2b.3e.4e.5e.6a, ld.2b.3e.4e.5e.6b, ld.2b.3e.4e.5e.6c, ld.2b.3e.4e.5e.6d, ld.2b3e.4e.5e.6e, ld.2b.3e.4e.5e.6f, ld.2b.3e.4e.5f.6a, ld.2b.3e.4e.5f.6b, ld.2b.3e.4e.5f.6c, ld.2b.3e.4e.5f.6d, ld.2b.3e.4e.5f.6e, ld.2b.3e.4e.5f.6f, ld.2b,3e.4f.5a.6a, ld.2b.3e.4f.5a.6b, ld.2b.3e.4f.5a.6c, ld.2b.3e.4f.5a.6d, ld.2b.3e.4f.5a.6e, ld.2b3e.4f.5a.6f, ld.2b.3e.4f.5b.6a, ld.2b.3e.4f.5b.6b, ld.2b.3e.4f.5b.6c, ld.2b.3e.4f.5b.6d, ld.2b.3e.4f.5b.6e, ld,2b.3e.4f.5b.6f, ld.2b.3e.4f.5c.6a, ld.2b.3e.4f.5c.6b, ld.2b.3e.4f.5c.6c, ld.2b.3e.4f.5c.6d, ld.2b.3e.4f.5c.6e, ld.2b.3e.4f.5c.6f, ld.2b.3e.4f.5d.6a, ld.2b.3e.4f.5d.6b, ld.2b.3e.4f.5d.6c, ld.2b.3e.4f.5d.6d, ld.2b.3e.4f.5d.6e, ld.2b.3e.4f.5d.6f, ld.2b.3e.4f.5e.6a, ld.2b.3e.4f.5e.6b, ld.2b.3e.4f.5e.6c, ld.2b.3e.4f.5e.6d, ld.2b.3e.4f.5e.6e, ld.2b.3e.4f.5e.6f, ld.2b.3e.4f.5f.6a, ld.2b.3e.4f.5f.6b, ld.2b.3e.4f.5f.6c, ld.2b.3e.4f.5f.6d, ld.2b.3e.4f.5f.6e, ld.2b.3e.4f.5f.6f, ld.2b.3f.4a.5a.6a, ld.2b.3f.4a.5a.6b, ld.2b.3f.4a.5a.6c, ld.2b.3f.4a.5a.6d, ld.2b.3f.4a.5a.6e, ld.2b.3f.4a.5a.6f, ld.2b.3f.4a.5b.6a, ld.2b.3f.4a.5b.6b, ld.2b.3f.4a.5b.6c, ld.2b.3f.4a.5b.6d, ld.2b.3f.4a.5b.6e, ld.2b.3f.4a.5b.6f, ld.2b.3f.4a.5c.6a, ld.2b.3f.4a.5c.6b, ld.2b.3f.4a.5c.6c, ld.2b.3f.4a.5c.6d, ld.2b.3f.4a.5c.6e, ld.2b.3f.4a.5c.6f, ld.2b.3f.4a.5d.6a, ld.2b.3f.4a.5d.6b, ld.2b.3f.4a.5d.6c, ld.2b.3f.4a.5(1.6(1, ld.2b.3f.4a.5d.6e, ld.2b.3f.4a.5d.6f, ld.2b.3f.4a.5e.6a, ld.2b.3f.4a.5e.6b, ld.2b.3f.4a.5e.6c, ld.2b.3f.4a.5e.6d, ld.2b.3f.4a.5e.6er ld.2b.3f.4a.5e.6f, ld.2b.3f.4a.5f.6a, ld.2b.3f.4a.5f.6b, ld.2b.3f.4a.5f.6c, ld.2b.3f.4a.5f.6d, ld.2b.3f.4a.5f.6e, ld.2b.3f.4a.5f.6f, ld.2b.3f.4b.5a.6a, ld.2b.3f.4b.5a.6b, ld.2b.3f.4b.5a.6c, ld.2b.3f.4b.5a.6d, ld.2b.3f.4b.5a.ee, ld.2b.3f.4b.5a.6f, ld.2b.3f.4b.5b.6a, ld.2b.3f.4b.5b.6b, ld.2b.3f.4b.5b.6c, ld.2b.3f.4b.5b.6d, ld.2b.3f.4b.5b.6e, ld.2b.3f.4b.5b.6f, ld.2b.3f.4b.5c.6a, ld.2b.3f.4b.5c.6b, ld.2b.3f.4b.5c.6c, ld.2b.3f.4b.5c.6d, ld.2b.3f.4b.5c.6e, ld.2b.3f.4b.5c.6f, -256- 200918507 ld.2b.3f.4b.5d.6a, ld.2b.3f.4b.5d.6b, ld.2b.3f.4b.5d.6c, ld.2b.3f.4b.5d.6d, ld.2b.3f.4b.5d.6e, ld.2b.3f.4b.5d.6f, ld.2b.3f.4b.5e.6a, ld.2b.3f.4b.5e.6b, ld.2b.3f.4b.5e.6c, ld.2b.3f.4b.5e.6d, ld.2b.3f.4b.5e.6e, ld.2b.3f.4b.5e.6f, ld.2b.3f.4b.5f.6a, ld.2b.3f.4b.5f.6b, ld.2b.3f.4b.5f.6c, ld.2b.3f.4b.5f.6d, ld.2b.3f.4b.5f.6e, ld.2b.3f.4b.5f.6f, ld.2b.3f.4c.5a.6a, ld.2b.3f.4c.5a.6b, ld.2b.3f.4c.5a.6c, ld.2b.3f.4c.5a.6d, ld.2b.3f.4c.5a.6e, ld.2b.3f.4c.5a.6f, ld.2b.3f.4c.5b.6a, ld.2b.3f.4c.5b.6b, ld.2b.3f.4c.5b.6c, ld.2b.3f.4c.5b.6d, ld.2b.3f.4c.5b.6e, ld.2b.3f.4c.5b.6f, ld.2b.3f.4c.5c.6a, ld.2b.3f.4c.5c.6b, ld.2b.3f.4c.5c.6c, ld.2b.3f.4c.5c.6d, ld.2b3f.4c.5c.6e, ld.2b.3f.4c.5c.6f, ld.2b.3f.4c.5d.6a, ld.2b.3f.4c.5d.6b, ld.2b.3f.4c.5d.6c, ld.2b.3f.4c.5d.6d, ld.2b.3f.4c.5d.6e, ld.2b.3f.4c.5d.6t ld.2b.3f.4c.5e.6a, ld.2b.3f.4c.5e.6b, ld.2b.3f.4c.5e.6c, ld.2b.3f.4c.5e.6d, ld.2b.3f.4c.5e.6e, ld.2b.3f.4c.5e.6f, ld.2b.3f.4c.5f.6a, ld.2b.3f.4c.5f.6b, ld.2b.3f.4c.5f.6c, ld.2b.3f.4c5f.6d, ld.2b.3f.4c.5f.6e, ld.2b.3f.4c.5f.6f, ld.2b.3f.4d.5a.6a, ld.2b.3f.4d.5a.6b, ld.2b.3f.4d.5a.6c, ld.2b.3f.4d.5a.6d； ld.2b.3f.4d.5a.6e, ld.2b.3f.4d.5a.6f, ld.2b.3f.4d.5b.6a, ld.2b.3f.4d.5b.6b, ld.2b.3f.4d.5b.6c, ld.2b.3f.4d.5b.6d, ld.2b.3f.4d.5b.6e, ld.2b.3f.4d.5b.6f, ld.2b.3f.4d.5c.6a, ld.2b.3f.4d.5c.6b, ld.2b.3f.4d.5c.6c, ld.2b.3f.4d.5c.6d, ld.2b.3f.4d.5c.6e, ld.2b.3f.4d.5c.6f, ld.2b.3f.4d.5d.6a, ld.2b.3f.4d.5d.6b, ld.2b.3f.4d.5d.6c, ld.2b.3f.4d.5d.6d, ld.2b.3f.4d.5d.6e, ld.2b.3f.4d.5d.6f, ld.2b.3f.4d.5e.6a, ld.2b.3f.4d.5e.6b, ld.2b.3f.4d.5e.6c, ld.2b.3f.4d.5e.6d, ld.2b.3f.4d.5e.6e, ld.2b.3f.4d.5e.6f, ld.2b.3f.4d.5f.6a, ld.2b.3f.4d.5f.6b, ld.2b.3f.4d.5f.6c, ld.2b.3f.4d.5f.6d, ld.2b.3f.4d.5f.6e, ld.2b.3f.4d.5f.6f, ld.2b.3f.4e.5a.6a, ld.2b.3f.4e.5a.6b, ld.2b.3f.4e.5a.6c, ld.2b.3f.4e.5a.6d, ld.2b.3f.4e.5a.6e, ld.2b.3f.4e.5a.6f, ld.2b.3f.4e.5b.6a, ld.2b.3f.4e.5b.6b, ld.2b.3f.4e.5b.6c, ld.2b.3f.4e.5b.6d, ld.2b.3f.4e.5b.6e, ld.2b.3f.4e.5b.6f, ld.2b.3f4e.5c.6a, ld.2b.3f.4e.5c.6b, ld.2b.3f.4e.5c.6c, ld.2b.3f.4e.5c.6d, ld.2b.3f.4e.5c.6e, ld.2b.3f.4e.5c.6f, ld.2b.3f.4e.5d.6a, ld.2b.3f.4e.5d.6b, ld.2b.3f.4e.5d.6c, ld.2b.3f.4e.5d.6d, ld.2b.3f.4e.5d.6e, ld.2b.3f.4e.5d.6f, ld.2b.3f,4e.5e.6a, ld.2b.3f.4e.5e.6b, ld.2b.3f.4e.5e.6c, ld.2b.3f.4e.5e.6d, ld.2b.3f.4e.5e.6e, ld.2b.3f.4e.5e.6f, ld.2b.3f.4e.5f.6a, ld.2b.3f.4e.5f.6b, ld.2b.3f.4e.5f.6c, ld.2b.3f.4e.5f.6d, ld.2b.3f.4e.5f.6e, ld.2b.3f.4e.5f.6f, ld.2b.3f.4f.5a.6a, ld.2b.3f.4f.5a.6b, ld.2b.3f.4f.5a.6c, ld.2b.3f.4f.5a.6d, ld.2b.3f.4f.5a.6e, ld.2b.3f.4f.5a.6f, ld.2b.3f.4f.5b.6a, ld.2b.3f.4f.5b.6b, ld.2b.3f.4f.5b.6c, ld.2b.3f.4f.5b.6d, ld.2b.3f.4f.5b.6e, ld.2b.3f.4f.5b.6f, ld.2b.3f.4f.5c.6a, ld.2b.3f.4f.5c.6b, ld.2b.3f.4f.5c.6c, ld.2b.3f.4f.5c.6d, ld.2b.3f.4f.5c.6e, ld.2b.3f.4f.5c.6f, ld.2b.3f.4f.5d.6a, ld.2b.3f.4f.5d.6b, ld.2b.3f.4f.5d.6c, ld.2b.3f.4f.5d.6d, ld.2b.3f.4f.5d.6e, ld.2b.3f.4f.5d.6f, ld.2b.3f.4f.5e.6a, ld.2b.3f.4f.5e.6b, ld.2b.3f.4f.5e.6c, ld.2b.3f.4f.5e.6d, ld.2b.3f.4f.5e.6e, ld.2b.3f.4f.5e.6f, ld.2b.3f.4f.5f.6a, ld.2b3f.4f.5f.6b, ld.2b.3f.4f.5f.6c, ld.2b.3f.4f.5f.6d, ld.2b.3f.4f.5f.6e, ld.2b.3f.4f.5f.6f, ld.2c.3a.4a.5a.6a, ld.2c.3a.4a.5a.6b, ld.2c.3a.4a.5a.6c, ld.2c.3a.4a.5a.6d, ld.2c.3a.4a.5a.6e, ld.2c.3a.4a.5a.6f, ld.2c.3a.4a.5b.6a, ld.2c.3a.4a.5b.6b, ld.2c.3a.4a.5b.6c, ld.2c.3a.4a.5b.6d, ld.2c.3a.4a.5b.6e, ld.2c.3a.4a.5b.6f, ld.2c.3a.4a.5c.6a, ld.2c.3a.4a.5c.6b, ld.2c.3a.4a.5c.6c, -257- 200918507 ld.2c.3a.4a.5c.6d, ld.2c.3a.4a.5c.6e, ld.2c.3a.4a.5c.6f, ld.2c.3a.4a.5d.6a, ld.2c.3a.4a.5d.6b, ld.2c.3a.4a.5d.6c, ld.2c.3a.4a.5d.6d, ld.2c.3a.4a.5d.6e, ld.2c.3a.4a.5d.6f, ld.2c.3a.4a.5e.6a, ld.2c.3a.4a.5e.6b, ld.2c.3a.4a.5e.6c, ld.2c.3a.4a.5e.6d, ld.2c.3a.4a.5e.6e, ld.2c.3a.4a.5e.6f, ld.2c.3a.4a.5f.6a, ld.2c.3a.4a.5f.6b, ld.2c.3a.4a.5f.6c, ld.2c.3a.4a.5f.6d, ld.2c.3a.4a.5f.6e, ld.2c.3a.4a.5f.6f, ld.2c.3a.4b.5a.6a, ld.2c.3a.4b.5a.6b, ld.2c.3a.4b.5a.6c, ld.2c.3a.4b.5a.6d, ld.2c.3a.4b.5a.6e, ld.2c.3a.4b.5a.6f, ld.2c.3a.4b.5b.6a, ld.2c3a.4b.5b.6b, ld.2c3a.4b.5b.6c, ld.2c.3a.4b.5b.6d, ld.2c.3a.4b.5b.6e, ld.2c.3a.4b.5b.6f, ld.2c.3a.4b.5c.6a, ld.2c.3a.4b.5c.6b, ld.2c.3a.4b.5c.6c, ld.2c.3a.4b.5c.6d, ld.2c.3a.4b.5c.6e, ld.2c.3a.4b.5c.6f, ld.2c.3a.4b.5d.6a, ld.2c.3a.4b.5d.6b, ld.2c.3a.4b.5d.6c, ld.2c.3a.4b.5d.6d, ld.2c.3a.4b.5d.6e, ld.2c.3a.4b.5d.6f, ld.2c.3a.4b.5e.6a, ld.2c.3a.4b5e.6b, ld.2c.3a.4b.5e.6c, ld.2c.3a.4b.5e.6d, ld.2c.3a.4b.5e.6e, ld.2c.3a.4b.5e.6f, ld.2c.3a.4b.5f.6a, ld.2c.3a.4b.5f.6b, ld.2c.3a.4b.5f.6c, ld.2c.3a.4b.5f.6d, ld.2c.3a.4b.5f.6e, ld.2c.3a.4b.5f.6f, ld.2c.3a.4c.5a.6a, ld.2c.3a.4c.5a.6b, ld.2c.3a.4c.5a.6c, ld.2c.3a.4c.5a.6d, ld.2c.3a.4c.5a.6e, ld.2c.3a.4c.5a.6f, ld.2c.3a.4c.5b.6a, ld.2c.3a.4c.5b.6b, ld.2c.3a.4c.5b.6c, ld.2c.3a.4c.5b.6d, ld.2c.3a.4c.5b.6e, ld.2c.3a.4c.5b.6f, ld.2c.3a.4c.5c.6a, ld.2c.3a.4c.5c.6b, ld.2c.3a.4c.5c.6c, ld.2c.3a.4c.5c.6d, ld.2c.3a.4c.5c.6e, ld.2c.3a.4c.5c.6f, ld.2c.3a.4c.5d.6a, ld.2c.3a.4c.5d.6b, ld.2c.3a.4c.5d.6c, ld.2c.3a.4c.5d.6d, ld.2c.3a.4c.5d.6e, ld.2c.3a.4c.5d.6f, ld.2c.3a.4c.5e.6a, ld.2c.3a.4c.5e.6b, ld.2c.3a.4c.5e.6c, ld.2c.3a.4c.5e.6d, ld.2c.3a.4c.5e.6e, ld.2c.3a.4c.5e.6f, ld.2c.3a.4c.5f.6a, ld.2c.3a.4c.5f.6b, ld.2c.3a.4c.5f.6c, ld.2c.3a.4c.5f.6d, ld.2c.3a.4c.5f.6e, ld.2c.3a.4c.5f.6f, ld.2c.3a.4d.5a.6a, ld.2c.3a.4d.5a.6b, ld.2c.3a.4d.5a.6c, ld.2c.3a.4d.5a.6d, ld.2c.3a.4d.5a.6e, ld.2c.3a.4d.5a.6f, ld.2c.3a.4d.5b.6a, ld.2c.3a.4d.5b.6b, ld.2c.3a.4d.5b.6c, ld.2c.3a.4d.5b.6d, ld.2c.3a.4d.5b.6e, ld.2c.3a.4d.5b.6f, ld.2c.3a.4d.5c.6a, ld.2c.3a.4d.5c.6b, ld.2c.3a.4d.5c.6c, ld.2c.3a.4d.5c.6d, ld.2c.3a.4d.5c.6e, ld.2c.3a.4d.5c.6f, ld.2c.3a.4d.5d.6a, ld.2c.3a.4d.5d.6b, ld.2c.3a.4d.5d.6c, ld.2c.3a.4d.5d.6d, ld.2c3a.4d.5d.6e, ld.2c.3a.4d.5d.6f, ld.2c.3a.4d.5e.6a, ld.2c.3a.4d.5e.6b, ld.2c.3a.4d.5e.6c, ld.2c.3a.4d.5e.6d, ld.2c3a.4d.5e.6e, ld.2c.3a.4d.5e.6f, ld.2c.3a.4d.5f.6a, ld.2c.3a.4d.5f.6b, ld.2c.3a.4d.5f.6c, ld.2c.3a.4d.5f.6d, ld.2c.3a.4d.5f.6e, ld.2c.3a.4d.5f.6f, ld.2c.3a.4e.5a.6a, ld.2c.3a.4e.5a.6b, ld.2c.3a.4e.5a.6c, ld.2c.3a.4e.5a.6d, ld.2c.3a.4e.5a.6e, ld.2c.3a.4e.5a.6f, ld_2c.3a.4e.5b.6a, ld.2c.3a.4e_5b.6b, ldf2c.3a.4e.5b.6c, ld.2c.3a.4e.5b.6d, ld.2c.3a.4e.5b,6e, ld.2c.3a.4e.5b.6f, ld.2c.3a.4e.5c.6a, ld.2c.3a.4e.5c.6b, ld.2c.3a.4e.5c.6c, ld.2c.3a.4e.5c.6d, ld.2c.3a.4e.5c.6e, ld.2c.3a.4e.5c.6f, ld.2c.3a.4e.5d.6a, ld.2c.3a.4e.5d.6b, ld.2c.3a.4e.5d.6c, ld.2c.3a.4e.5d.6d, ld.2c.3a.4e.5d.6e, ld.2c.3a.4e.5d.6f, ld.2c.3a.4e.5e.6a, ld.2c.3a.4e.5e.6b, ld.2c.3a.4e.5e.6c, ld.2c.3a.4e.5e.6d, ld.2c.3a.4e.5e.6e, ld.Zc.Sa^e.Se^f, ld.2c.3a.4e.5f.6a, ld.2c.3a.4e.5f.6b, ld.2c.3a.4e.5f.6c, ld.2c.3a.4e.5f.6d, ld.2c.3a.4e.5f.6e, ld.2c.3a.4e.5f.6f, ld.2c.3a.4f.5a.6a, ld.2c3a.4f.5a.6b, ld.2c.3a.4f.5a.6c, ld.2c.3a.4f.5a.6d, ld.2c.3a.4f.5a.6e, ld.2c.3a.4f.5a.6f, ld.2c.3a.4f.5b.6a, -258- 200918507 ld.2c.3a.4f.5b.6b, ld.2c.3a.4f.5b.6c, ld.2c.3a.4f.5b.6d, ld.2c.3a.4f.5b.6e, ld.2c.3a.4f.5b.6f, ld.2c.3a.4f.5c.6a, ld.2c.3a.4f.5c.6b, ld.2c.3a.4f.5c,6c； ld.2c.3a.4f.5c.6d, ld.2c.3a.4f.5c.6e, ld.2c.3a.4f.5c.6f, ld.2c.3a.4f.5d.6a, ld.2c.3a.4f.5d.6b, ld.2c.3a.4f.5d.6c, ld.2c.3a.4f.5d.6d, ld.2c.3a.4f.5d.6e, ld.2c.3a.4f.5d.6f, ;ld.2c.3a.4f.5e.6a, ld.2c.3a.4f.5e.6b, ld.2c.3a.4f.5e.6c, ld.2c.3a.4f.5e.6d, ld.2c.3a.4f.5e.6e, ld.2c.3a.4f.5e.6f, ld.2c.3a.4f.5f.6a, ld.2c.3a.4f.5f.6b, ld.2c.3a.4f.5f.6c, ld.2c.3a.4f.5f.6d, ld.2c.3a.4f.5f.6e, ld.2c.3a.4f.5f.6f, ld.2c.3b.4a.5a.6a, ld.2c.3b.4a.5a.6b, ld.2c.3b.4a.5a.6c, ld.2c.3b.4a.5a.6d, ld.2c.3b.4a.5a.6e, ld.2c.3b.4a.5a.6f, ld.2c.3b.4a.5b.6a, ld.2c.3b.4a.5b.6b, ld.2c.3b.4a.5b.6c, ld.2c.3b.4a.5b.6d, ld.2c.3b.4a.5b.6e, ld.2c.3b.4a.5b.6f, ld.2c.3b.4a.5c.6a, ld.2c.3b.4a.5c.6b, ld.2c.3b.4a.5c.6c, ld.2c.3b.4a.5c.6d, ld.2c.3b.4a.5c.6e, ld.2c.3b.4a.5c.6f, ld.2c.3b.4a.5d.6a, ld.2c.3b.4a.5d.6b, ld.2c.3b.4a.5d.6c, ld.2c.3b.4a.5d.6d, ld.2c.3b.4a.5d-6e, ld.2c.3b.4a.5d.6f, ld.2c_3b.4a.5e.6a, lcL2c_3b.4a.5e.6b, ld.2c.3b.4a.5e.6c, ld.2c.3b.4a.5e.6d, ld.2c.3b.4a.5e.6e, ld.2c.3b.4a.5e.6f, ld.2c.3b.4a.5f.6a, ld.2c.3b.4a.5f.6b, ld.2c.3b.4a.5f.6c, ld.2c.3b.4a.5f.6d, ld.2c.3b.4a.5f.6e, ld.2c.3b.4a.5f.6f, ld.2c.3b.4b.5a.6a, ld.2c.3b.4b.5a.6b, ld.2c.3b.4b.5a.6c, ld.2c.3b.4b.5a.6d, ld.2c.3b.4b.5a.6e, ld.2c.3b.4b.5a.6f, ld.2c.3b.4b.5b.6a, ld.2c.3b.4b.5b.6b, ld.2c.3b.4b.5b.6c, ld.2c.3b.4b.5b.6d, ld.2c.3b.4b.5b.6e, ld.2c.3b.4b.5b.6f, ld.2c.3b.4b.5c.6a, ld.2c.3b.4b.5c.6b, ld.2c.3b.4b.5c.6c, ld.2c.3b.4b.5c.6d, ld.2c.3b.4b.5c.6e, ld.2c.3b.4b.5c.6f, ld.2c.3b.4b.5d.6a, ld.2c.3b.4b.5d.6b, ld.2c.3b.4b.5d.6c, ld.2c.3b.4b.5d.6d, ld.2c.3b.4b.5d.6e, ld.2c.3b.4b.5d.6f, ld.2c.3b.4b.5e.6a, ld.2c.3b.4b.5e.6b, ld.2c.3b.4b.5e.6c, ld.2c.3b.4b.5e.6d, ld.2c.3b.4b.5e.6e, ld.2c.3b.4b.5e.6f, ld.2c.3b.4b.5f.6a, ld.2c.3b.4b.5f.6b, ld.2c.3b.4b.5f.6c, ld.2c.3b.4b.5f.6d, ld.2c.3b.4b.5f.6e, ld.2c.3b.4b.5f.6f, ld.2c.3b.4c.5a.6a, ld.2c.3b.4c.5a.6b, ld.2c.3b.4c.5a.6c, ld.2c.3b.4c.5a.6d, ld.2c.3b.4c5a.6e, ld.2c.3b.4c.5a.6f, ld.2c.3b.4c.5b.6a, ld.2c.3b.4c.5b.6b, ld.2c.3b.4c.5b.6Q ld.2c.3b.4c.5b.6d, ld.2c.3b.4c.5b.6e, ld.2c.3b.4c.5b.6f, ld.2c.3b.4c.5c.6a, ld.2c.3b.4c.5c.6b, ld.2c.3b.4c.5c.6c, ld.2c.3b.4c.5c.6d, ld.2c.3b.4c.5c.6e, ld.2c.3b.4c.5c.6f, ld.2c.3b.4c.5d.6a, ld.2c.3b.4c.5d.6b, ld.2c.3b.4c.5d.6c, ld.2c.3b.4c.5d.6d, ld.2c.3b.4c.5d.6e, ld.2c.3b.4c.5d.6f, ld.2c.3b.4c.5e.6a, ld.2c.3b.4c.5e.6b, ld.2c.3b.4c.5e.6c, ld-2c.3b.4c.5e.6d, ld‘2c.3b.4c.5e.6e, ld.2c.3b.4c.5e.6f, ld.2c.3b.4c.5f.6a, ld.2c3bAc.5L6bf ld.2c.3b.4c.5f.6c, ld.2c.3b.4c.5f.6d, ld.2c.3b.4c.5f.6e, ld.2c.3b.4c.5f.6f, ld.2c.3b.4d.5a.6a, ld.2c.3b.4d.5a.6b, ld.2c3b.4d.5a.6c, ld.2c.3b.4d.5a.6d, ld.2c.3b.4d.5a.6e, ld.2c.3b.4d.5a.6f, ld.2c3b.4d.5b.6a, ld.2c.3b.4d.5b.6b, ld.2c.3b.4d.5b.6c, ld.2c.3b.4d.5b.6d, ld.2c.3b.4d.5b.6e, ld.2c.3b.4d.5b.6f, ld.2c.3b.4d.5c.6a, ld.2c.3b.4d.5c.6b, id.2c3bAd3c.6c, ld.2c.3b.4d.5c.6d, ld.2c.3b.4d.5c.6e, ld.2c.3b.4d.5c.6f, ld.2c.3b.4d.5d.6a, ld.2c.3b.4d.5d.6b, ld.2c.3b.4d.5d.6c, ld.2c.3b.4d.5d.6d, ld.2c.3b.4d.5d.6e, ld.2c.3b.4d.5d.6f, ld.2c.3b.4d.5e.6a, ld.2c.3b.4d.5e.6b, ld.2c.3b.4d.5e.6c, ld.2c.3b.4d.5e.6d, ld.2c.3b.4d.5e.6e, ld.2c.3b.4d.5e.6f, ld.2c.3b.4d.5f.6a, ld.2c.3b.4d.5f.6b, ld.2c.3b.4d.5f.6c, ld.2c.3b.4d.5f.6d, -259- 200918507 ld.2c.3b.4d.5f.6e, ld.2c.3b.4d.5f.6f, ld.2c.3b.4e.5a.6a, ld.2c.3b.4e,5a.6b7 ld.2c.3b.4e.5a.6c, ld.2c.3b.4e.5a.6d, ld.2c.3b.4e.5a.6e, ld.2c.3b.4e.5a.6f, ld.2c.3b.4e.5b.6a, ld.2c.3b.4e.5b.6b, ld.2c.3b.4e.5b.6c7 ld.2c.3b.4e.5b.6d, ld.2c.3b.4e.5b.6e, ld.2c.3b.4e.5b.6f, ld.2c.3b.4e.5c.6a, ld.2c.3b.4e.5c.6b, ld.2c.3b.4e.5c.6c, ld.2c.3b.4e.5c.6d, ld.2c.3b.4e.5c.6e, ld.2c.3b.4e.5c.6f, ld.2c.3b.4e.5d.6a, ld.2c.3b.4e.5d.6b, ld.2c.3b.4e.5d.6c, ld.2c.3b.4e.5d.6d, ld.2c.3b.4e.5d.6e, ld.2c.3b.4e.5d.6f, ld.2c.3b.4e.5e.6a, ld.2c.3b.4e.5e.6b, ld.2c.3b.4e.5e.6c, ld.2c.3b.4e.5e.6d, ld.2c.3b.4e.5e.6e, ld.2c.3b.4e.5e.6f, ld.2c.3b.4e.5f.6a, ld.2c.3b.4e.5f.6b7 ld.2c.3b.4e.5f.6c, ld.2c.3b.4e.5f.6d, ld.2c.3b.4e.5f.6e, ld.2c.3b.4e.5f.6f, ld.2c.3b.4f.5a.6a, ld.2c.3b.4f.5a.6b, ld.2c.3b.4f.5a.6c, ld.2c.3b.4f.5a.6d, ld.2c.3b.4f.5a.6e, ld.2c.3b.4f.5a.6f, ld.2c.3b.4f.5b.6a, ld.2c.3b.4f.5b.6b, ld.2c.3b.4f.5b.6c, ld.2c.3b.4f.5b.6d, ld.2c.3b.4f.5b.6e, ld.2c.3b.4f.5b.6f, ld.2c.3b.4f.5c.6a, ld.2c.3b.4f.5c.6b, ld.2c.3b.4f.5c.6c, ld.2c.3b.4f.5c.6d, ld.2c.3b.4f.5c.6e, ld.2c.3b.4f.5c.6f, ld.2c.3b.4f.5d.6a, ld.2c.3b.4f.5d.6b, ld.2c.3b.4f.5d.6c, ld.2c.3b.4f.5d.6d, ld.2c.3b.4f.5d.6e, ld.2c.3b.4f.5d.6f, ld.2c.3b.4f.5e.6a, ld.2c.3b.4f.5e.6b, ld.2c.3b.4f.5e.6c, ld.2c.3b.4f.5e.6d, ld.2c.3b.4f.5e.6e, ld.2c.3b.4f.5e.6f, ld.2c.3b.4f.5f.6a, ld.2c.3b.4f.5f.6b, ld.2c.3b.4f.5f.6c, ld.2c.3b.4f.5f.6d, ld.2c.3b.4f.5f.6e, ld.2c.3b.4f.5f.6f, ld.2c.3c.4a.5a.6a, ld.2c.3c.4a.5a.6b, ld.2c.3c.4a.5a.6c, ld.2c.3c.4a.5a.6d, ld.2c.3c.4a.5a.6e, ld.2c.3c.4a.5a.6f, ld.2c.3c.4a.5b.6a, ld.2c.3c.4a3b.6b, ld.2c.3c.4a.5b.6c, ld.2c.3c.4a.5b.6d, ld.2c.3c.4a.5b.6e, ld.2c.3c.4a.5b.6f, ld.2c.3c.4a.5c.6a, ld.2c.3c.4a.5c.6b, ld.2c.3c.4a.5c.6c, ld.2c.3c.4a.5c.6d, ld.2c.3c.4a.5c.6e, ld.2c.3c.4a.5c.6f, ld.2c.3c.4a.5d.6a, ld.2c.3c.4a.5d.6b, ld.2c.3c.4a.5d.6c, ld.2c.3c.4a.5d.6d, ld.2c.3c.4a.5d.6e, ld.2c.3c.4a.5d.6f, ld.2c.3c.4a.5e.6a, ld.2c.3c.4a.5e.6b, ld.2c.3c.4a.5e.6c, ld.2c.3c.4a.5e.6d, ld.2c.3c.4a.5e.6e, ld.2c.3c.4a.5e.6f, ld.2c.3c.4a.5f.6a, ld.2c3c.4a.5f.6b, ld.2c.3c.4a.5f.6c, ld.2c.3c.4a.5f.6d, ld.2c.3c.4a.5f.6e, ld.2c.3c.4a.5f.6f, ld.2c.3c.4b.5a.6a, ld.2c.3c.4b.5a.6b, ld.2c.3c.4b.5a.6c, ld.2c.3c.4b.5a.6d, ld.2c.3c.4b.5a.6e, ld.2c.3c.4b.5a.6f, ld.2c.3c.4b.5b.6a, ld.2c.3c.4b.5b.6b, ld.2c.3c.4b.5b.6c, ld.2c.3c.4b.5b.6d, ld.2c.3c.4b.5b.6e, ld.2c.3c.4b.5b.6f, ld.2c.3c.4b.5c.6a, ld.2c.3c.4b.5c.6b, ld.2c.3c.4b.5c.6c, ld.2c.3c.4b.5c.6d, ld.2c.3c.4b.5c.6e, ld.2c.3c.4b.5c.6f, ld.2c.3c.4b.5d.6a, ld.2c.3c.4b.5d.6b, ld.2c.3c.4b.5d.6c, ld.2c.3c.4b.5d.6d, ld.2c.3c.4b.5d.6e, ld.2c.3c.4b.5d.6f, ld.2c.3c.4b.5e.6a, ld.2c.3c.4b.5e.6b, ld.2c.3c.4b.5e.6c, ld.2c.3c.4b.5e.6d, ld.2c.3c.4b.5e.6e, ld.2c.3c.4b.5e.6f, ld.2c.3c.4b.5f.6a, ld.2c.3c.4b.5f.6b, ld.2c.3c.4b.5f.6c, ld.2c.3c.4b.5f.6d, ld.2c.3c.4b.5f.6e, ld.2c.3c.4b.5f.6f, ld.2c.3c.4c.5a.6a, ld.2c.3c.4c.5a.6b, ld.2c.3c.4c5a.6c, ld.2c.3c,4c,5a.6d, ld.2c.3c.4c.5a.6e, ld.2c.3c4c,5a.6f, ld.2c-3c.4c.5b,6a, ld.2c.3c.4c.5b.6b, ld.2c,3c.4c.5b.6c, ld.2c.3c.4c.5b.6d, ld.2c.3c.4c.5b.6e, ld.2c.3c.4c.5b.6f, ld.2c.3c.4c.5c.6a, ld.2c.3c.4c.5c.6b, ld.2c.3c.4c.5c.6c, ld.2c.3c.4c.5c.6d, ld.2c.3c.4c.5c.6e, ld.2c.3c.4c.5c.6f, ld.2c.3c.4c.5d.6a, ld.2c.3c.4c.5d.6b, ld.2c.3c.4c.5d.6c, ld.2c.3c.4c.5d.6d, ld.2c.3c.4c.5d.6e, ld.2c.3c.4c.5d.6f, ld.2c.3c.4c.5e.6a, ld.2c.3c.4c.5e.6b, -260- 200918507 ld.2c.3c.4c.5e.6c, ld.2c.3c.4c.5e.6d, ld.2c.3c.4c.5e.6e, ld.2c.3c.4c5e.6f, ld.2c.3c.4c.5f.6a, ld.2c.3c.4c.5f.6b, ld.2c.3c.4c.5f.6c, ld.2c.3c.4c.5f.6d, ld.2c.3c.4c.5f.6e, ld.2c.3c.4c.5f.6f, ld.2c.3c.4d.5a.6a, ld.2c.3c.4d.5a.6b, ld.2c.3c.4d.5a.6c, ld.2c.3c.4d.5a.6d, ld.2c.3c.4d.5a.6e, ld.2c.3c.4d.5a.6f, ld.2c.3c.4d.5b.6a, ld.2c.3c.4d.5b.6b, ld.2c.3c.4d.5b.6c, ld.2c.3c.4d.5b.6d, ld.2c.3c.4d.5b.6e, ld.2c.3c.4d.5b.6f, ld.2c.3c.4d.5c.6a, ld.2c.3c4d.5c.6b, ld.2c.3c.4d.5c.6c, ld.2c.3c.4d.5c.6d, ld.2c.3c.4d.5c.6e, ld.2c.3c.4d.5c.6f, ld.2c.3c.4d.5d.6a, ld.2c.3c.4d.5d.6b, ld.2c.3c.4d.5d.6c, ld.2c.3c.4d.5d.6d, ld.2c.3c.4d.5d.6e, ld.2c.3c.4d.5d.6f, ld.2c.3c.4d.5e.6a, ld.2c.3c.4d.5e.6b, ld.2c.3c.4d.5e.6c, ld.2c.3c.4d.5e.6d, ld.2c.3c.4d.5e.6e, ld.2c.3c.4d.5e.6f, ld.2c.3c.4d.5f.6a, ld.2c.3c.4d.5f.6b, ld.2c.3c.4d.5f.6c, ld.2c.3c.4d.5f.6d, ld.2c.3c.4d.5f.6e, ld.2c.3c.4d.5f.6f, ld.2c.3c.4e.5a.6a, ld.2c.3c.4e.5a.6b, ld.2c.3c.4e.5a.6c, ld.2c.3c.4e.5a.6d, ld.2c.3c.4e.5a.6e, ld.2c.3c.4e.5a.6f, ld.2c.3c.4e.5b.6a, ld.2c.3c.4e.5b.6b, ld.2c.3c.4e.5b.6c, ld.2c.3c.4e.5b.6d, ld,2c.3c.4e.5b.6e, ld.2c.3c.4e.5b.6f, ld.2c.3c.4e.5c.6a, ld.2c.3c.4e.5c.6b, ld.2c.3c.4e.5c.6c, ld.2c.3c.4e.5c.6d, ld.2c.3c.4e.5c.6e, ld.2c.3c.4e.5c.6f, ld.2c.3c.4e.5d.6a, ld.2c.3c.4e.5d.6b, ld.2c.3c.4e.5d.6c, ld.2c.3c.4e.5d.6d, ld.2c.3c.4e.5d.6e, ld.2c.3c.4e.5d.6f, ld.2c.3c.4e.5e.6a, ld.2c.3c.4e.5e.6b, ld.2c.3c.4e.5e.6c, ld.2c.3c.4e.5e.6d, ld.2c.3c.4e.5e.6e, ld.2c.3c.4e.5e.6f, ld.2c.3c.4e.5f.6a, ld.2c.3c.4e.5f.6b, ld.2c.3c.4e.5f.6c, ld.2c.3c.4e.5f.6d, ld.2c.3c.4e.5f.6e, ld.2c.3c.4e.5f.6f, ld.2c.3c.4f.5a.6a, ld.2c.3c.4f.5a.6b, ld.2c.3c.4f.5a.6c, ld.2c.3c.4f.5a.6d, ld.2c.3c.4f.5a.6e, ld.2c.3c.4f.5a.6f, ld.2c.3c.4f.5b.6a, ld.2c.3c.4f.5b.6b, ld.2c.3c.4f.5b.6c, ld.2c.3c.4f.5b.6d, ld.2c.3c.4f.5b.6e, ld.2c.3c.4f.5b.6f, ld.2c.3c.4f.5c.6a, ld.2c.3c.4f.5c.6b, ld.2c.3c.4f.5c.6c, ld.2c.3c.4f.5c.6d, ld.2c.3c.4f.5c.6e, ld.2c.3c.4f.5c.6f, ld.2c.3c.4f.5d.6a, ld.2c.3c.4f.5d.6b, ld.2c.3c.4f.5d.6c, ld.2c.3c.4f.5d.6d, ld.2c.3c.4f.5d.6e, ld.2c.3c.4f.5d.6f, ld.2c.3c.4f.5e.6a, ld2c3cAi3e.6bf ld.2c.3c.4f.5e.6c, ld.2c.3c.4f.5e.6d, ld.2c.3c.4f.5e.6e, ld.2c.3c.4f.5e.6f, ld.2c.3c.4f.5f.6a, ld.2c.3c.4f.5f.6b, ld.2c.3c.4f.5f.6Q ld.2c.3c.4f.5f.6d, ld.2c.3c.4f.5f.6e, ld.2c.3c.4f.5f.6f, ld.2c.3d.4a.5a.6a, ld.2c.3d.4a.5a.6b, ld.2c.3d.4a.5a.6c, ld.2c.3d.4a.5a.6d, ld^c.Sd^a.Sa^e, ld.2c.3d.4a.5a.6f, ld.2c.3d.4a.5b.6a, ld.2c.3d.4a.5b.6b, ld.2c.3d.4a.5b.6c, ld.2c.3d.4a.5b.6d, ld.2c.3d.4a.5b.6e, ld.2c.3d.4a.5b.6f, ld.2c.3d.4a.5c.6a, ld.2c.3d.4a.5c.6b, ld.2c.3d.4a,5c.6c, ld.2c.3d.4a.5c.6d, ld.2c.3d.4a.5c.6e, ld.2c.3d.4a.5c.6f, ld.2c.3d.4a.5d.6a, ld.2c.3d.4a.5d.6b, ld.2c.3d.4a.5d.6c, ld.2c.3d.4a.5d.6d, ld.2c.3d.4a.5d.6e, ld.2c.3d.4a.5d.6f, ld.2c.3d.4a.5e.6a, ld.2c.3d.4a.5e.6b, ld.2c.3d.4a.5e.6c, ld.2c.3d.4a.5e.6d, ld.2c.3d.4a.5e.6e, ld.2c.3d.4a.5e.6f, ld.2c.3d.4a.5f.6a, ld.2c.3d.4a.5f.6b, ld.2c.3d.4a.5f.6c, ld.2c.3d.4a.5f.6d, ld.2c.3d.4a.5f.6e, ld.2c.3d.4a.5f.6f, ld.2c.3d.4b.5a.6a, ld.2c.3d.4b.5a.6b, ld.2c.3d.4b.5a.6c, ld.2c3d.4b.5a.6d, ld.2c.3d.4b.5a.6e, ld.2c3d.4b.5a.6f, ld.2c.3d.4b.5b.6a, ld.2c.3d.4b.5b.6b, ld.2c.3d.4b.5b.6c, ld.2c.3d.4b.5b.6d, ld.2c.3d.4b.5b.6e, ld.2c.3d.4b.5b.6f, ld.2c.3d.4b.5c6a, ld.2c.3d.4b.5c.6b, ld.2c.3d.4b.5c.6c, ld.2c.3d.4b.5c.6d, ld.2c.3d.4b.5c.6er ld.2c.3d.4b.5c.6f, ld.2c.3d.4b.5d.6a, ld.2c.3d.4b.5d.6b, ld.2c.3d.4b.5d.6c, ld.2c.3d.4b.5d.6d, ld.2c.3d.4b.5d.6e, -261 - 200918507 ld.2c.3d.4b.5d.6f, ld.2c3d.4b.5e.6a, ld.2c.3d.4b.5e.6b, ld.2c.3d.4b.5e.6c, ld.2c.3d.4b.5e.6d, ld.2c.3d.4b.5e.6e, ld.2c3d.4b.5e.6f, ld.2c.3d.4b.5f.6a, ld.2c.3d.4b.5f.6b, ld.2c.3d.4b.5f.6c, ld.2c.3d.4b.5f.6d, ld.2c.3d.4b.5f.6e, ld.2c.3d.4b.5f.6f, ld.2c.3d.4c.5a.6a, ld.2c.3d.4c.5a.6b, ld.2c.3d.4c.5a.6c, ld.2c.3d.4c.5a.6d, ld.2c.3d.4c.5a.6e, ld.2c.3d.4c.5a.6f, ld.2c.3d.4c.5b.6a, ld.2c.3d.4c.5b.6b, ld.2c.3d.4c.5b.6c, ld.2c.3d.4c.5b.6d, ld.2c.3d.4c.5b.6e, ld.2c.3d.4c.5b.6f, ld.2c.3d.4c.5c.6a, ld.2c.3d.4c.5c.6b, ld.2c.3d.4c.5c.6c, ld.2c.3d.4c.5c.6d, ld.2c.3d.4c.5c.6e, ld.2c.3d.4c.5c.6f, ld.2c.3d.4c.5d.6a, ld.2c.3d.4c.5d.6b, ld.2c.3d.4c.5d.6c, ld.2c.3d.4c.5d.6d, ld.2c.3d.4c.5d.6e, ld.2c.3d.4c.5d.6f, ld.2c.3d.4c.5e.6a, ld.2c.3d.4c.5e.6b, ld.2c.3d.4c.5e.6c, ld.2c.3d.4c.5e.6d, ld.2c.3d.4c.5e.6e, ld.2c.3d.4c.5e.6f, ld.2c.3d.4c.5f.6a, ld.2c.3d.4c.5f.6b, ld.2c.3d.4c.5f.6c, ld.2c.3d.4c.5f.6d, ld.2c.3d.4c.5f.6e, ld.2c.3d.4c.5f.6f, ld.2c.3d.4d.5a.6a, ld.2c.3d.4d.5a.6b, ld.2c.3d.4d.5a.6c, ld.2c.3d.4d.5a.6d, ld.2c.3d.4d.5a.6e, ld.2c.3d.4d.5a.6f, ld.2c.3d.4d.5b.6a, ld.2c.3d.4d.5b.6b, ld.2c.3d.4d.5b.6c, ld.2c.3d.4d.5b.6d, ld.2c.3d.4d.5b.6e, ld.2c.3d.4d.5b.6f, ld.2c.3d.4d.5c.6a, ld.2c.3d.4d.5c.6b, ld.2c.3d.4d.5c.6c, ld.2c.3d.4d.5c.6d, ld.2c.3d.4d.5c.6e, ld.2c.3d.4d.5c.6f, ld.2c.3d.4d.5d.6a, ld.2c.3d.4d.5d.6b, ld.2c3d.4d.5d.6c, ld.2c.3d.4d.5d.6d, ld-2c.3d.4d.5d.6e, ld.2c.3d.4d.5d.6f, ld.2c.3d.4d.5e.6a, ld.2c.3d.4d.5e.6b, ld.2c.3d.4d.5e.6c, ld.2c.3d.4d.5e.6d, ld.2c.3d.4d.5e.6e, ld.2c.3d,4d.5e.6f, ld.2c.3d.4d.5f.6a, ld.2c.3d.4d.5f.6b, ld.2c.3d.4d.5f.6c, ld.2c.3d.4d.5f.6d, ld.2c.3d.4d.5f.6e, ld.2c.3d.4d.5f.6f, ld.2c.3d.4e.5a.6a, ld.2c.3d.4e.5a.6b, ld.2c.3d.4e.5a.6c, ld.2c.3d.4e.5a.6d, ld.2c.3d.4e.5a.6e, ld.2c.3d.4e.5a.6f, ld.2c.3d.4e.5b.6a, ld.2c.3d.4e.5b.6b, ld.2c.3d.4e.5b.6c, ld.2c.3d.4e.5b.6d, ld.2c.3d.4e.5b.6e, ld.2c.3d.4e.5b.6f, ld.2c.3d.4e.5c.6a, ld.2c.3d.4e.5c.6b, ld.2c.3d.4e.5c.6c, ld.2c.3d.4e.5c.6d, ld.2c.3d.4e.5c.6e, ld.2c.3d.4e.5c.6f, ld.2c.3d.4e.5d.6a, ld.2c.3d.4e.5d.6b, ld.2c.3d.4e.5d.6c, ld.2c.3d.4e.5d.6d, ld.2c.3d.4e.5d.6e, ld.2c.3d.4e.5d.6f, ld.2c.3d.4e.5e.6a, ld.2c.3d.4e.5e.6b, ld.2c.3d.4e.5e.6c, ld.2c.3d.4e.5e.6d, ld.2c.3d.4e.5e.6e, ld.2c.3d.4e.5e.6f, ld.2c.3d.4e.5f.6a, ld.2c.3d.4e.5f.6b, ld.2c.3d.4e.5f.6c, ld.2c.3d.4e.5f.6d, ld.2c.3d.4e.5f.6e, ld.2c.3d.4e.5f.6f, ld.2c.3d.4f.5a.6a, ld.2c.3d.4f.5a.6b, ld.2c.3d.4f.5a.6c, ld,2c.3d.4f.5a.6d, ld.2c.3d.4f.5a.6e, ld.2c,3d.4f.5a.6f, ld.2c,3d.4f.5b.6a, ld.2c.3d.4f.5b.6b, ld.2c.3d.4f.5b.6c, ld.2c.3d.4f.5b.6d, ld.2c.3d.4f.5b.6e, ld.2c.3d.4f.5b.6f, ld.2c.3d.4f.5c.6a, ld.2c.3d.4f.5c.6b, ld.2c,3d.4f.5c.6c, ld.2c.3d.4f.5c.6d, ld.2c.3d.4f.5c.6e, ld.2c.3d.4f.5c.6f, ld.2c.3d.4f.5d.6a, ld.2c.3d.4f.5d.6b, ld.2c.3d.4f.5d.6c, ld.2c.3d.4f.5d.6d, ld.2c.3d.4f.5d.6e, ld.2c.3d.4f.5d.6f, ld.2c.3d.4f.5e.6a, ld.2c.3d.4f.5e.6br ld.2c.3d.4f.5e.6c, ld.2c.3d.4f.5e，6d, ld.2c.3d.4f.5e.6e, ld.2c.3d.4f.5e.6f, ld.2c.3d.4f.5f.6a, ld.2c.3d.4f.5f.6b, ld.2c.3d.4f.5f.6c, ld.2c.3d.4f.5f.6d, ld.2c.3d.4f.5f.6e, ld.2c.3d.4f.5f.6f; ld.2c.3e.4a.5a.6a, ld.2c.3e.4a.5a.6b, ld.2c.3e.4a.5a.6c, ld.2c.3e.4a.5a.6d, ld.2c.3e.4a.5a.6e, ld.2c.3e.4a.5a.6f, ld.2c.3e.4a.5b.6a, ld.2c.3e.4a.5b.6b, ld.2c.3e.4a.5b.6c, ld.2c.3e.4a.5b.6d, ld.2c.3e.4a.5b.6e, ld.2c3e.4a.5b.6f, -262- 200918507 ld.2c.3e.4a.5c.6a, ld.2c.3e.4a.5c.6b, ld.2c.3e.4a.5c.6c, ld.2c.3e.4a.5c.6d, ld.2c.3e.4a.5c.6e, ld.2c.3e.4a.5c.6f, ld.2c.3e.4a.5d.6a, ld.2c.3e.4a.5d.6b, ld.2c.3e.4a.5d.6c, ld.2c.3e.4a.5d.6d, ld.2c.3e.4a.5d.6e, ld.2c.3e.4a.5d.6f, ld.2c.3e.4a.5e.6a, ld.2c.3e.4a.5e.6b7 ld.2c.3e.4a.5e.6c, ld.2c.3e.4a.5e.6d, ld.2c.3e.4a.5e.6e, ld.2c.3e.4a.5e.6f, ld.2c.3e.4a.5f.6a, ld.2c.3e.4a.5f.6b, ld.2c.3e.4a.5f.6c, ld.2c.3e.4a.5f.6d, ld.2c.3e.4a.5f.6e, ld.2c.3e.4a.5f.6f, ld.2c.3e.4b.5a.6a, ld.2c.3e.4b.5a.6b, ld.2c.3e.4b.5a.6c, ld.2c.3e.4b.5a.6d, ld.2c.3e.4b.5a.6e, ld.2c.3e.4b.5a.6f, ld.2c.3e.4b.5b.6a, ld.2c.3e.4b.5b.6b, ld.2c.3e.4b.5b.6c, ld.2c.3e4b.5b.6d, ld.2c_3e.4b.5b.6e, ld.2c.3e.4b_5b.6f, ld.2c.3e.4b.5c.6a, ld.2c.3e.4b.5c.6b, ld.2c.3e.4b.5c.6c, ld.2c.3e.4b.5c.6d, ld.2c.3e.4b.5c.6e, ld.2c.3e.4b.5c.6f, ld.2c.3e.4b.5d.6a, ld.2c.3e.4b.5d.6b, ld.2c.3e.4b.5d.6c, ld.2c.3e.4b.5d.6d, ld.2c.3e.4b.5d.6e, ld.2c.3e.4b.5d.6f, ld.2c.3e.4b.5e.6a, ld.2c.3e.4b.5e.6b, ld.2c.3e.4b.5e.6c, ld.2c.3e.4b.5e.6d, ld.2c.3e.4b.5e.6e, ld.2c.3e.4b.5e.6f, ld.2c.3e.4b.5f.6a, ld.2c.3e.4b.5f.6b, ld.2c.3e.4b.5f.6c, ld.2c.3e.4b.5f.6d, ld.2c.3e.4b.5f.6e, ld.2c.3e.4b.5f.6f, ld.2c.3e.4c.5a.6a, ld.2c.3e.4c.5a.6b, ld.2c.3e.4c.5a.6c, ld.2c.3e.4c.5a.6d, ld.2c.3e.4c.5a.6e, ld.2c.3e.4c.5a.6f, ld.2c.3e.4c.5b.6a, ld.2c.3e.4c.5b.6b, ld.2c.3e.4c.5b.6c, ld.2c.3e.4c.5b.6d, ld.2c.3e.4c.5b.6e, ld.2c.3e.4c.5b.6f, ld.2c.3e.4c.5c.6a, ld.2c.3e.4c.5c.6b, ld.2c.3e.4c.5c.6c, ld.2c.3e.4c.5c.6d, ld.2c.3e.4c.5c.6e, ld.2c.3e.4c.5c.6f, ld.2c.3e.4c.5d.6a, ld.2c.3e.4c.5d.6b, ld.2c.3e.4c.5d.6c, ld.2c.3e.4c.5d.6d, ld.2c.3e.4c.5d.6e, ld.2c.3e.4c.5d.6f, ld.2c.3e.4c.5e.6a, ld.2c.3e.4c.5e.6b, ld.2c.3e.4c.5e.6c, ld.2c.3e.4c.5e.6d, ld.2c.3e.4c.5e.6e, ld.2c.3e.4c.5e.6f, ld.2c.3e.4c.5f.6a, ld.2c.3e.4c.5f.6b, ld.2c.3e.4c.5f.6c, ld.2c.3e.4c.5f.6d, ld.2c.3e.4c.5f.6e, ld.2c.3e.4c.5f.6f, ld.2c.3e.4d.5a.6a, ld.2c.3e.4d.5a.6b, ld.2c.3e.4d.5a.6c, ld.2c.3e.4d.5a.6d, ld.2c.3e.4d.5a.6e, ld.2c.3e.4d.5a.6f, ld.2c.3e.4d.5b.6a, ld.2c.3e.4d.5b.6b, ld.2c.3e.4d.5b.6c, ld.2c.3e.4d.5b.6d, ld.2c.3e.4d.5b,6e, ld.2c.3e.4d.5b.6f, ld.2c.3e.4d.5c.6a, ld.2c.3e.4d.5c.6b, ld.2c.3e.4d.5c.6c, ld.2c.3e.4d.5c.6d, ld.2c.3e.4d.5c.6e, ld.2c.3e.4d.5c.6f, ld.2c.3e.4d.5d.6a, ld.2c.3e.4d.5d.6b, ld.2c.3e.4d.5d.6c, ld.2c.3e.4d.5d.6d, ld.2c.3e.4d.5d.6e, ld.2c.3e.4d.5d.6f, ld.2c.3e.4d.5e.6a, ld.2c.3e.4d.5e.6b, ld.2c.3e.4d.5e.6c, ld.2c.3e.4d.5e.6d, ld.2c.3e.4d.5e.6e, ld.2c.3e.4d.5e.6f, ld.2c.3e.4d.5f.6a, ld.2c.3e.4d.5f.6b, ld.2c.3e.4d.5f.6c, ld.2c.3e.4d.5f.6d, ld.2c.3e.4d.5f.6e, ld.2c.3e.4d.5f.6f, ld.2c.3e.4e.5a.6a, ld.2c.3e.4e.5a.6b, ld.2c.3e.4e.5a.6c, ld.2c.3e.4e.5a.6d, ld.2c.3e.4e.5a.6e, ld.2c.3e.4e.5a.6f, ld.2c.3e.4e.5b.6a, ld.2c.3e.4e.5b.6b, ld.2c.3e.4e.5b.6c, ld.2c.3e.4e.5b.6(1, ld.2c.3e.4e.5b.6e, ld.2c.3e.4e.5b.6f, ld.2c.3e.4e.5c.6a, ld.2c3eAe3c.6b, ld.2c.3e.4e.5c.6c, ld.2c.3e.4e.5c.6d, ld.2c.3e.4e.5c.6e, ld.2c.3e.4e.5c.6f, ld.2c.3e.4e.5d.6a, ld.2c.3e.4e.5d.6b, ld.2c.3e.4e.5d.6c, ld.2c.3e.4e.5d.6d, ld.2c.3e.4e.5d.6e, ld.2c.3e.4e.5d.6f, ld.2c.3e.4e.5e.6a, ld.2c.3e.4e.5e.6b, ld.2c.3e.4e*5e.6c, ld.2c.3e.4e.5e.6d, ld.2c.3e.4e.5e.6e, ld.2c.3e.4e.5e.6f, ld.2c.3e.4e.5f.6a, ld.2c.3e.4e.5f.6b, ld.2c.3e.4e.5f.6Q ld.2c.3e.4e.5f.6d, ld.2c.3e.4e.5f.6e, ld.2c.3e.4e.5f.6f, ld.2c.3e.4f.5a.6a, ld.2c.3e.4f.5a.6b, ld.2c.3e.4f.5a.6c, -263- 200918507 ld.2c.3e.4f.5a.6d, ld.2c.3e.4f.5a.6e, ld.2c.3e.4f.5a.6f, ld.2c.3e.4f.5b.6a, ld.2c.3e.4f.5b.6b, ld.2c.3e.4f.5b.6c, ld.2c.3e.4f.5b.6d, ld.2c.3e.4f.5b.6e, ld.2c.3e.4f.5b.6f, ld.2c.3e.4f.5c.6a, ld.2c.3e.4f.5c.6b, ld.2c.3e.4f.5c.6c, ld.2c.3e.4f.5c.6d, ld.2c.3e.4f.5c.6e, ld.2c.3e.4f.5c.6f, ld.2c.3e.4f.5d.6a, ld.2c.3e.4f.5d.6b, ld.2c.3e.4f.5d.6c, ld.2c.3e.4f.5d.6d, ld.2c.3e.4f.5d.6e7 ld,2c3e.4f.5d.6f, ld.2c.3e.4f.5e.6a, ld.2c.3e.4f.5e.6b, ld.2c.3e.4f.5e.6c, ld.2c.3e.4f.56.6d, ld.2c.3e.4f.5e.6e, ld.2c.3e.4f.5e.6f, ld.2c.3e.4f.5f.6a, ld.2c.3e.4f.5f.6b, ld.2c.3e.4f.5f.6c, ld.2c.3e.4f.5f.6d, ld.2c.3e.4f.5f.6e, ld.2c.3e.4f.5f.6f, ld.2c.3f.4a.5a.6a, ld.2c.3f.4a.5a.6b, ld.2c.3f.4a.5a.6c, ld.2c.3f.4a.5a.6d, ld.2c.3f.4a.5a.6e, ld.2c.3f.4a.5a.6f, ld.2c.3f.4a.5b.6a, ld.2c.3f.4a.5b.6br ld.2c.3f.4a.5b.6c, ld.2c.3f.4a.5b.6d, ld.2c.3f.4a.5b.6e, ld.2c.3f.4a.5b.6f, ld.2c.3f.4a.5c.6a, ld.2c.3f.4a.5c.6b, ld.2c.3f.4a.5c.6c, ld.2c.3f.4a.5c.6d, ld.2c.3f.4a.5c.6e, ld.2c.3f.4a.5c.6f, ld.2c.3f.4a.5d.6a, ld.2c.3f.4a.5d.6b, ld.2c.3f.4a.5d.6c, ld.2c.3f.4a.5d.6d, ld.2c.3f.4a.5d.6e, ld.2c.3f.4a.5d.6f, ld.2c.3f.4a.5e.6a, ld.2c.3f.4a.5e.6b, ld.2c.3f.4a.5e.6c, ld.2c.3f.4a.5e.6d, ld.2c.3f.4a.5e.6e, ld.2c.3f.4a.5e.6f, ld.2c.3f.4a.5f.6a, ld.2c.3f.4a.5f.6b, ld.2c.3f.4a.5f.6c, ld.2c.3f.4a.5f.6d, ld.2c.3f.4a.5f.6e, ld.2c.3f.4a.5f.6f, ld.2c.3f.4b.5a.6a, ld.2c.3f.4b.5a.6b, ld.2c.3f.4b.5a.6c, ld.2c.3f.4b.5a.6d, ld.2c.3f.4b.5a.6e, ld.2c.3f.4b.5a.6f, ld.2c.3f.4b.5b.6a, ld.2c.3f.4b.5b.6b, ld.2c.3f.4b.5b.6c, ld.2c.3f.4b.5b.6d, ld.2c.3f.4b.5b.6e, ld.2c.3f.4b.5b.6f, ld.2c.3f.4b.5c.6a, ld.2c.3f.4b.5c.6b, ld.2c.3f.4b.5c.6c, ld.2c.3f.4b.5c.6d, ld.2c.3f.4b.5c.6e, ld.2c.3f.4b.5c.6f, ld.2c.3f.4b.5d.6a, ld.2c.3f.4b.5d.6b, ld.2c.3f.4b.5d.6c, ld.2c.3f.4b.5d.6d, ld.2c.3f.4b.5d.6e, ld.2c.3f.4b.5d.6f, ld.2c.3f.4b.5e.6a, ld.2c.3f.4b.56.6b, ld.2c.3f.4b.5e.6c, ld.2c.3f.4b.5e.6d, ld.2c.3f.4b.5e.6e, ld.2c.3f.4b.5e.6f, ld.2c.3f.4b.5f.6a, ld.2c.3f.4b.5f.6b, ld.2c.3f.4b.5f.6c, ld.2c.3f.4b.5f.6d, ld.2c.3f.4b.5f.6e, ld.2c.3f.4b.5f.6f, ld.2c.3f.4c.5a.6a, ld.2c.3f.4c.5a.6b, ld.2c.3f.4c.5a.6c, ld.2c.3f.4c.5a.6d, ld.2c.3f.4c.5a.6e, ld.2c.3f.4c.5a.6f, ld.2c.3f.4c.5b.6a, ld.2c.3f.4c.5b.6b, ld.2c.3f.4c.5b.6c, ld.2c.3f.4c.5b.6d, ld.2c.3f.4c.5b.6e, ld.2c.3f.4c.5b.6f, ld.2c.3f.4c.5c.6a, ld.2c.3f.4c.5c.6b, ld.2c.3f.4c.5c.6c, ld.2c.3f.4c.5c.6d, ld.2c.3f.4c.5c.6e, ld.2c.3f.4c.5c.6f, ld.2c.3f.4c.5d.6a, ld.2c.3f.4c.5d.6b, ld.2c.3f.4c.5d.6c, ld.2c.3f.4c.5d.6d, ld.2c.3f.4c.5d.6e, ld.2c.3f.4c.5d.6f, ld.2c.3f.4c.5e.6a, ld.2c.3f.4c.5e.6b, ld.2c.3f.4c.5e.6c, ld.2c.3f.4c.5e.6d, ld.2c.3f.4c.5e.6e, ld.2c.3f.4c.5e.6f, ld.2c.3f.4c.5f.6a, ld.2c.3f.4c.5f.6b, ld.2c.3f.4c.5f.6c, ld.2c.3f.4c.5f.6d, ld.2c.3f.4c.5f.6e, ld.2c.3f.4c.5f.6f, ld.2c.3f.4d.5a.6a, ld.2c.3f.4d.5a.6b, ld.2c.3f.4d.5a.6c, ld.2c.3f.4d.5a.6d, ld.2c.3f.4d.5a.6e, ld.2c.3f.4d.5a.6f, ld.2c.3f.4d.5b.6a, ld.2c.3f.4d.5b.6b, ld.2c.3f.4d.5b.6c, ld.2c.3f.4d.5b.6d, ld.2c.3f.4d.5b.6e, ld.2c.3f.4d.5b.6f, ld.2c.3f.4d.5c.6a, ld.2c.3f.4d.5c.6b, ld.2c.3f.4d.5c.6c, ld.2c.3f.4d.5c.6d, ld.2c.3f,4d.5c.6e, ld.2c.3f.4d.5c.6f, ld.2c.3f.4d.5d.6a, ld.2c.3f.4d.5d.6b, ld.2c.3f.4d.5d.6c, ld.2c.3f.4d.5d.6d, ld.2c.3f.4d.5d.6e, ld.2c.3f.4d.5d.6f, ld.2c.3f.4d.5e.6a, ld.2c.3f.4d.5e.6b, ld.2c.3f.4d.5e.6c, ld.2c.3f.4d.5e.6d, ld.2c.3f.4d.5e.6e, ld.2c.3f.4d.5e.6f, ld.2c.3f.4d.5f.6a, ld.2c3f.4d.5f.6b, ld.2c.3f.4d.5f.6c, ld.2c.3f.4d.5f.6d, ld.2c.3f.4d.5f.6e, ld.2c.3f.4d.5f.6f, ld.2c.3f.4e.5a.6a, ld.2c.3f.4e.5a.6b, ld.2c.3f.4e.5a.6c, ld.2c.3f.4e.5a.6d, ld.2c.3f.4e.5a.6e, ld.2c.3f.4e.5a.6f, ld.2c.3f.4e.5b.6a, ld.2c.3f.4e.5b.6b, ld.2c.3f.4e.5b.6c. -264- 200918507 ld.2c.3f.4e.5b.6d, ld.2c.3f.4e.5b.6e, ld.2c.3f.4e.5b.6f, ld.2c.3f.4e.5c.6a, ld.2c.3f.4e.5c.6b, ld.2c.3f_4e.5c.6c, ld.2c.3f.4e.5c.6d, ld.2c_3f.4e.5c.6e, ld.2c.3f,4e,5c.6f, ld.2c.3f.4e.5d.6a, ld.2c.3f.4e.5d.6b, ld.2c.3f.4e.5d.6c, ld.2c.3f.4e.5d.6d, ld.2c.3f.4e.5d.6e, ld.2c.3f.4e.5d.6f, ld.2c.3f.4e.5e.6a, ld.2c.3f.4e.5e.6b, ld.2c.3f.4e.5e.6c, ld.2c.3f.4e.5e.6d, ld.2c.3f.4e.5e.6e, ld.2c.3f.4e.5e.6f, ld.2c.3f.4e.5f.6a, ld.2c.3f.4e.5f.6b, ld.2c.3f.4e.5f.6c, ld.2c.3f.4e.5f.6d, ld.2c.3f.4e.5f.6e, ld.2c.3f.4e.5f.6f, ld.2c.3f.4f.5a.6a, ld.2c.3f.4f.5a.6b, ld.2c.3f.4f.5a.6c, ld.2c.3f.4f.5a.6d, ld.2c.3f.4f.5a.6e, ld.2c.3f.4f.5a.6f, ld.2c.3f.4f.5b.6a, ld.2c.3f.4f.5b.6b, ld.2c.3f.4f.5b.6c, ld.2c.3f.4f.5b.6d, ld.2c.3f.4f.5b.6e, ld.2c.3f.4f.5b.6f, ld.2c.3f.4f.5c.6a, ld.2c.3f.4f.5c.6b, ld.2c.3f.4f.5c.6c, ld.2c.3f.4f.5c.6d, ld.2c.3f.4f.5c.6e, ld.2c.3f.4f.5c.6f, ld.2c.3f.4f.5d.6a, ld.2c.3f.4f.5d.6b, ld.2c3f.4f.5d.6c, ld.2c.3f.4f.5d.6d, ld.2c.3f.4f.5d.6e, ld.2c.3f.4f.5d.6f, ld.2c.3f.4f.5e.6a, ld.2c.3f.4f.5e.6b, ld.2c.3f.4f.5e.6c, ld.2c.3f.4f.5e.6d, ld.2c.3f.4f.5e.6e, ld.2c.3f.4f.5e.6f, ld.2c.3f.4f.5f.6a, ld.2c.3f.4f.5f.6b, ld.2c.3f.4f.5f.6c, ld.2c.3f.4f.5f.6d, ld.2c.3f.4f.5f.6e, ld.2c.3f.4f.5f.6f, ld.2d.3a.4a.5a.6a, ld.2d.3a.4a.5a.6b, ld.2d.3a.4a.5a.6c, ld.2d.3a.4a.5a.6d, ld.2d.3a.4a.5a.6e, ld.2d.3a.4a.5a,6f, ld.2d.3a.4a.5b.6a, ld.2d.3a.4a.5b.6b, ld.2d.3a.4a.5b.6c, ld.2d.3a.4a.5b.6d, ld.2d.3a.4a.5b.6e, ld.2d.3a.4a.5b.6f, ld.2d.3a.4a.5c.6a, ld.2d.3a.4a.5c.6b, ld.2d.3a.4a.5c.6c, ld.2d.3a.4a.5c.6d, ld.2d.3a.4a.5c.6e, ld.2d.3a.4a.5c.6f, ld.2d.3a.4a.5d.6a, ld.2d.3a.4a.5d.6b, ld.2d.3a.4a.5d.6c, ld.2d.3a.4a.5d.6d, ld.2d.3a.4a.5d.6e, ld.2d.3a.4a.5d.6f, ld.2d.3a.4a.5e.6a, ld.2d.3a.4a.5e.6b, ld.2d.3a.4a.5e.6c, ld.2d.3a.4a.5e.6d, ld.2d.3a.4a.5e.6e, ld.2d.3a.4a.5e.6f, ld.2d.3a.4a.5f.6a, ld.2d.3a.4a.5f.6b, ld.2d.3a.4a.5f.6c, ld.2d.3a.4a.5f.6d, ld.2d.3a.4a.5f.6e, ld.2d.3a.4a.5f.6f, ld.2d.3a.4b.5a.6a, ld.2d.3a.4b.5a.6b, ld.2d.3a.4b.5a.6c, ld.2d.3a.4b.5a.6d, ld.2d.3a.4b.5a.6e, ld.2d.3a.4b.5a.6f, ld.2d.3a.4b.5b.6a, ld.2d.3a.4b.5b.6b, ld.2d.3a.4b.5b.6c, ld.2d.3a.4b.5b.6d, ld.2d.3a.4b.5b.6e, ld.2d.3a.4b.5b.6f, ld.2d.3a.4b.5c.6a, ld.2d.3a.4b.5c,6b, ld.2d.3a.4b.5c.6c, ld_2d.3a.4b.5c.6d, ld.2d.3a.4b.5c.6e, ld.2d.3a.4b.5c.6f, ld.2d.3a.4b.5d.6a, ld.2d.3a.4b.5d.6b, ld.2d.3a.4b.5d.6c, ld.2d.3a.4b.5d.6d, ld.2d.3a.4b.5d.6e, ld.2d.3a.4b.5d.6f, ld.2d.3a.4b.5e.6a, ld.2d.3a.4b.5e.6b, ld.2d.3a.4b.5e.6c, ld.2d.3a.4b.5e.6d, ld.2d.3a.4b.5e.6e, ld.2d.3a.4b.5e.6f, ld.2d.3a.4b.5f.6a, ld.2d.3a.4b.5f.6b, ld.2d.3a.4b.5f.6c, ld.2d.3a.4b.5f.6d, ld.2d.3a.4b.5f.6e, ld.2d.3a.4b.5f.6f, ld.2d.3a.4c.5a.6a, ld.2d.3a.4c.5a.6b, ld.2d.3a.4c.5a.6c, ld.2d.3a.4c.5a.6d, ld.2d.3a.4c.5a.6e, ld.2d.3a.4c.5a.6f, ld.2d.3a.4c.5b.6a, ld.2d.3a.4c.5b.6b, ld.2d.3a.4c.5b.6c, ld.2d.3a.4c.5b.6d, ld.2d.3a.4c.5b.6e, ld.2d.3a.4c.5b.6f, ld.2d.3a.4c.5c.6a, ld.2d.3a.4c.5c.6b, ld.2d.3a.4c.5c.6c, ld.2d.3a.4c.5c.6d, ld.2d.3a.4c.5c.6e, ld.2d.3a.4c.5c.6f, ld.2d.3a.4c.5d.6a, ld.2d.3a.4c.5d.6b, ld.2d.3a.4c.5d.6c, ld.2d.3a.4c.5d.6d, ld.2d.3a.4c.5d.6e, ld.2d.3a.4c.5d.6f, ld.2d.3a.4c.5e.6a, ld.2d.3a.4c.5e.6b, ld.2d.3a.4c.5e.6c, ld.2d.3a.4c.5e.6d, ld.2d.3a.4c.5e.6e, ld.2d.3a.4c.5e.6f, ld.2d.3a.4c.5f.6a, ld.2d.3a.4c.5f.6b, ld.2d.3a.4c.5f.6c, ld.2d.3a.4c.5f.6d, ld.2d.3a.4c.5f.6e, ld.2d.3a.4c.5f.6f, ld.2d.3a.4d.5a.6a, ld.2d.3a.4d.5a.6b, ld.2d.3a.4d.5a.6c, ld.2d.3a.4d.5a.6d, ld.2d.3a.4d.5a.6e, ld.2d.3a.4d.5a.6f, ld.2d3a.4d.5b.6a, ld.2d.3a.4d.5b.6b, ld.2d.3a.4d.5b.6c, -265- 200918507 ld.2d.3a.4d.5b.6d, ld.2d.3a.4d.5b.6e, ld.2d.3a.4d.5b.6f, ld.2d.3a.4d.5c.6a, ld.2d.3a.4d.5c.6b, ld.2d.3a.4d.5c.6c, ld.2d.3a.4d.5c.6d, ld.2d.3a.4d.5c.6e, ld.2d.3a.4d.5c.6f, ld.2d.3a.4d.5d.6a, ld.2d.3a.4d.5d.6b, ld.2d.3a.4d.5d.6c, ld.2d.3a.4d.5d.6d, ld.2d.3a.4d.5d.6e, ld.2d.3a.4d.5d.6f, ld.2d.3a.4d.5e.6a, ld.2d.3a.4d.5e.6b, ld.2d.3a.4d.5e.6c, ld.2d.3a.4d.5e.6d, ld.2d.3a.4d.5e.6e, ld.2d.3a.4d.5e.6f, ld.2d.3a.4d.5f.6a, ld.2d.3a.4d.5f.6b, ld.2d.3a.4d.5f.6c, ld.2d.3a.4d.5f.6d, ld.2d.3a.4d.5f.6e, ld.2d.3a.4d.5f.6f, ld.2d.3a.4e.5a.6a, ld.2d.3a.4e.5a.6b, ld.2d.3a.4e.5a.6c, ld.2d.3a.4e.5a.6d, ld.2d.3a.4e.5a.6e, ld.2d.3a.4e.5a.6f, ld.2d.3a.4e.5b.6a, ld.2d.3a.4e.5b.6b, ld.2d.3a.4e.5b.6c, ld.2d.3a.4e.5b.6d, ld.2d.3a.4e.5b.6e, ld.2d.3a.4e.5b.6f, ld.2d.3a.4e.5c.6a, ld.2d.3a.4e.5c.6b, ld.2d.3a.4e.5c.6c, ld.2d.3a.4e.5c.6d, ld.2d.3a.4e.5c.6e, ld.2d.3a.4e.5c.6f, ld.2d.3a.4e.5d.6a, ld.2d.3a.4e.5d.6b, ld.2d.3a.4e.5d.6c, ld.2d.3a.4e.5d.6d, ld.2d.3a.4e.5d.6e, ld.2d.3a.4e.5d.6f, ld.2d.3a.4e.5e.6a, ld.2d.3a.4e.5e.6b, ld.2d.3a.4e.5e.6c, ld.2d.3a.4e.5e.6d, ld.2d.3a.4e.5e.6e, ld.2d.3a.4e.5e.6f, ld.2d.3a.4e.5f.6a, ld.2d.3a.4e.5f.6b, ld.2d.3a.4e.5f.6c, ld.2d.3a.4e.5f.6d, ld.2d.3a.4e.5f.6e, ld.2d.3a.4e.5f.6f, ld.2d.3a.4f.5a.6a, ld.2d.3a.4f.5a.6b, ld.2d.3a.4f.5a.6c, ld.2d.3a.4f.5a.6d, ld.2d.3a.4f.5a.6e, ld.2d.3a.4f.5a.6f, ld.2d.3a.4f.5b.6a, ld.2d.3a.4f.5b.6b, ld.2d.3a.4f.5b.6c, ld.2d.3a.4f.5b.6d, ld.2d.3a.4f.5b.6e, ld.2d.3a.4f.5b.6f, ld.2d.3a.4f.5c.6a, ld.2d.3a.4f.5c.6b, ld.2d.3a.4f.5c.6c, ld.2d.3a.4f.5c.6d, ld.2d.3a.4f.5c.6e, ld.2d.3a.4f.5c.6f, ld.2d.3a.4f.5d.6a, ld.2d.3a.4f.5d.6b, ld.2d.3a.4f.5d.6c, ld.2d.3a.4f.5d.6d, ld.2d.3a.4f.5d.6e, ld.2d.3a.4f.5d.6f, ld.2d.3a.4f.5e.6a, ld.2d.3a.4f.5e.6b, ld.2d.3a.4f.5e.6c, ld.2d.3a.4f.5e.6d, ld.2d.3a.4f.5e.6e, ld.2d.3a.4f.5e.6f, ld.2d.3a.4f.5f.6a, ld.2d.3a.4f.5f.6b, ld.2d.3a.4f.5f.6c, ld.2d.3a.4f.5f.6d, ld.2d.3a.4f.5f.6e, ld.2d.3a.4f.5f.6f, ld.2d.3b.4a.5a.6a, ld.2d.3b.4a.5a.6b, ld.2d.3b.4a.5a.6c, ld.2d.3b.4a.5a.6d, ld.2d.3b.4a.5a.6e, ld.2d.3b.4a.5a.6f, ld.2d.3b.4a.5b.6a, ld.2d.3b.4a.5b.6b, ld.2d.3b.4a.5b.6c, ld.2d.3b.4a.5b.6d, ld.2d.3b.4a.5b.6e, ld.2d.3b.4a.5b.6f, ld.2d.3b.4a.5c.6a, ld.2d.3b.4a.5c.6b, ld.2d.3b.4a.5c.6c, ld.2d.3b.4a.5c.6d, ld.2d.3b.4a.5c.6e, ld.2d.3b.4a.5c.6f, ld.2d.3b.4a.5d.6a, ld.2d.3b.4a.5d.6b, ld.2d.3b.4a.5d.6c, ld.2d.3b.4a.5d.6d, ld.2d.3b.4a.5d.6e, ld.2d.3b.4a.5d.6f, ld.2d.3b.4a.5e.6a, ld.2d.3b.4a.5e.6b, ld.2d.3b.4a.5e.6c, ld.2d3b.4a.5e.6d, ld.2d.3b.4a.5e.6e, ld.2d.3b.4a.5e.6f, ld.2d.3b.4a.5f.6a, ld.2d.3b.4a.5f.6b, ld.2d.3b.4a.5f.6c, ld.2d.3b.4a.5f.6d, ld.2d.3b.4a.5f.6e, ld.2d.3b.4a.5f.6f, ld.2d.3b.4b.5a.6a, ld.2d.3b.4b.5a.6b, ld.2d.3b.4b.5a.6c, ld.2d.3b.4b.5a.6d, ld.2d.3b.4b.5a.6e, ld.2d.3b.4b.5a.6f, ld.2d.3b.4b.5b.6a, ld.2d.3b.4b.5b.6b, ld.2d.3b.4b.5b.6c, ld.2d.3b.4b.5b.6d, ld.2d.3b.4b.5b.6e, ld.2d.3b.4b.5b.6f, ld.2d.3b.4b.5c.6a, ld.2d.3b.4b.5c.6b, ld.2d.3b.4b.5c.6c, ld.2d.3b.4b.5c.6d, ld.2d.3b.4b.5c.6e, ld.2d.3b.4b.5c.6f, ld.2d.3b.4b.5d.6a, ld.2d.3b.4b.5d.6b, ld.2d.3b.4b.5d.6c, ld.2d.3b.4b.5d.6d, ld.2d.3b.4b.5d.6e, ld.2d.3b.4b.5d.6f, ld.2d.3b.4b.5e.6a, ld.2d.3b.4b.5e.6b, ld.2d.3b.4b.5e.6c, ld.2d.3b.4b.5e.6d, ld.2d.3b.4b.5e.6e, ld.2d.3b.4b.5e.6f, ld.2d.3b.4b.5f.6a, ld.2d.3b.4b.5f.6b, ld.2d.3b.4b.5f.6c, • 266 - 200918507 ld.2d.3b.4b.5f.6d, ld.2d.3b.4b.5f.6e, ld.2d.3b.4b.5f.6f, ld.2d.3b.4c.5a.6a, ld.2d.3b.4c.5a.6b, ld.2d.3b.4c.5a,6c, ld.2d.3b.4c.5a.6d, ld.2d.3b.4c.5a.6e, ld.2d.3b.4c.5a.6f, ld.2d.3b.4c.5b.6a, ld.2d.3b.4c.5b.6b, ld.2d.3b.4c.5b.6c, ld.2d.3b.4c.5b.6d, ld.2d.3b.4c.5b.6e, ld.2d.3b.4c.5b.6f, ld.2d.3b.4c.5c.6a, ld.2d.3b.4c.5c.6b, ld.2d.3b.4c.5c.6c, ld.2d.3b.4c.5c.6d, ld.2d.3b.4c.5c.6e, ld.2d.3b.4c.5c.6f, ld.2d.3b.4c.5d.6a, ld.2d.3b.4c.5d.6b, ld.2d.3b.4c.5d.6c, ld.2d.3b.4c.5d.6d, ld.2d.3b.4c.5d.6e, ld.2d.3b.4c.5d.6f, ld.2d.3b.4c.5e.6a, ld.2d.3b.4c.5e.6b, ld.2d.3b.4c.5e.6c, ld.2d.3b.4c.5e.6d, ld.2d.3b.4c.5e.6e, ld.2d.3b.4c.5e.6f, ld.2d.3b.4c.5f.6a, ld.2d.3b.4c.5f.6b, ld.2d.3b.4c.5f.6c, ld.2d.3b.4c.5f.6d, ld.2d.3b.4c.5f.6e, ld.2d.3b.4c.5f.6f, ld.2d.3b.4d.5a.6a, ld.2d.3b.4d.5a.6b, ld.2d.3b.4d.5a.6c, ld.2d.3b.4d.5a.6d, ld.2d.3b.4d.5a.6e, ld.2d.3b.4d.5a.6f, ld.2d.3b.4d.5b.6a, ld.2d.3b.4d.5b.6b, ld.2d.3b.4d.5b.6c, ld.2d.3b.4d.5b.6d, ld.2d.3b.4d.5b.6e, ld.2d.3b.4d.5b.6f, ld.2d.3b.4d.5c.6a, ld.2d.3b.4d.5c.6b, ld.2d.3b.4d.5c.6c, ld.2d.3b.4d.5c.6d, ld.2d.3b.4d.5c.6e, ld.2d.3b.4d.5c.6f, ld.2d.3b.4d.5d.6a, ld.2d.3b.4d.5d.6b, ld.2d.3b.4d.5d.6c, ld.2d.3b.4d.5d.6d, ld.2d.3b.4d.5d.6e, ld.2d.3b.4d.5d.6f, ld.2d.3b.4d.5e.6a, ld.2d.3b.4d.5e.6b, ld.2d.3b.4d.5e.6c, ld.2d.3b.4d.5e.6d, ld.2d.3b.4d.5e.6e, ld.2d.3b.4d.5e.6f, ld.2d.3b.4d.5f.6a, ld.2d.3b.4d.5f.6b, ld.2d.3b.4d.5f.6c, ld.2d.3b.4d.5f.6d, ld.2d.3b.4d.5f.6e, ld.2d3b.4d.5f.6f, ld.2d.3b.4e.5a.6a, ld.2d.3b.4e.5a.6b, ld.2d.3b.4e.5a.6c, ld.2d.3b.4e.5a.6d, ld.2d.3b.4e.5a.6e, ld.2d.3b.4e.5a.6f, ld.2d.3b.4e.5b.6a, ld.2d.3b.4e.5b.6b, ld.2d.3b.4e.5b.6c, ld.2d.3b.4e.5b.6d, ld.2d.3b.4e.5b.6e, ld.2d.3b.4e.5b.6f, ld.2d.3b.4e.5c.6a, ld.2d.3b.4e.5c.6b, ld.2d.3b.4e.5c.6c, ld.2d.3b.4e.5c.6d, ld.2d.3b.4e.5c.6e, ld.2d.3b.4e.5c.6f, ld.2d.3b.4e.5d.6a, ld.2d.3b.4e.5d.6b, ld.2d.3b.4e.5d.6c, ld.2d.3b.4e.5d.6d, ld.2d.3b.4e.5d.6e, ld.2d.3b.4e.5d.6f, ld.2d.3b.4e.5e.6a, ld.2d.3b.4e.5e.6b, ld.2d.3b.4e.5e.6c, ld.2d.3b.4e.5e.6d, ld.2d.3b.4e.5e.6e, ld.2d.3b.4e.5e.6f, ld.2d.3b.4e.5f.6a, ld.2d.3b.4e.5f.6b, ld.2d.3b.4e.5f.6c, ld.2d.3b.4e.5f.6d, ld.2d3b.4e.5f.6e, ld.2d.3b.4e.5f.6f, ld.2d.3b.4f.5a.6a, ld.2d.3b.4f.5a.6b, ld.2d.3b.4f.5a.6c, ld.2d.3b.4f.5a.6d, ld.2d.3b.4f.5a.6e7 ld.2d.3b.4f.5a.6f, ld.2d.3b.4f,5b.6a, ld.2d.3b.4f.5b.6b, ld.2d.3b.4f.5b.6c, ld.2d.3b.4f.5b.6d, ld.2d.3b.4f.5b.6e, ld.2d.3b.4f.5b.6f, ld.2d.3b.4f.5c.6a, ld.2d.3b.4f.5c.6b, ld.2d.3b.4f.5c.6c, ld.2d.3b.4f.5c.6d, ld.2d.3b.4f.5c.6e, ld.2d.3b.4f.5c.6f, ld.2d.3b.4f.5d.6a, ld.2d.3b.4f.5d.6b, ld.2d.3b.4f.5d.6c, ld.2d.3b.4f.5d.6d, ld.2d.3b.4f.5d.6e, ld.2d.3b.4f.5d.6f, ld.2d.3b.4f.5e.6a, ld.2d.3b.4f.5e.6b, ld.2d.3b.4f.5e.6c, ld.2d.3b.4f.5e.6d, ld.2d.3b.4f.5e.6e, ld.2d.3b.4f.5e.6f, ld.2d.3b.4f.5f.6a, ld.2d.3b.4f.5f.6b, ld.2d.3b.4f.5f.6c, ld.2d.3b.4f.5f.6d, ld.2d.3b.4f.5f.6e, ld.2d3b.4f.5f.6f, ld.2d.3c.4a.5a.6a, ld.2d.3c.4a.5a.6b, ld.2d.3c.4a.5a.6c, ld.2d.3c.4a.5a.6d, ld.2d.3c.4a.5a.6e, ld.2d.3c4a.5a.6f, ld.2d.3c.4a.5b.6a, ld.2d.3c.4a.5b.6b, ld.2d.3c.4a.5b.6c, ld.2d.3c.4a.5b.6d, ld.2d3c.4a.5b.6e, ld.2d.3c.4a.5b.6f, ld.2d.3c.4a.5c.6a, ld.2d.3c.4a.5c.6b, ld.2d.3c.4a.5c.6c, ld.2d.3c.4a.5c.6d, ld.2d.3c.4a.5c.6e, ld.2d.3c.4a.5c.6f, ld.2d.3c.4a.5d.6a, ld.2d.3c.4a.5d.6b, ld.2d.3c.4a.5d.6c, -267- 200918507 ld.2d.3c.4a.5d.6d, ld.2d.3c.4a.5d.6e, ld.2d.3c.4a.5d.6f, ld.2d.3c.4a.5e.6a, ld.2d.3c.4a.5e.6b, ld.2d.3c.4a.5e.6c, ld.2d.3c.4a.5e.6d, ld.2d.3c.4a.5e.6e, ld.2d.3c.4a.5e.6f, ld.2d.3c.4a.5f.6a, ld.2d.3c.4a.5f.6b, ld.2d.3c.4a.5f.6c, ld.2d.3c.4a.5f.6d, ld.2d.3c.4a.5f.6e, ld.2d.3c.4a.5f.6f, ld.2d.3c.4b.5a.6a, ld_2d.3c.4b.5a_6b, ld.2d.3c，4b.5a.6c, ld.2d.3c.4b.5a_6d, ld.2d.3c.4b.5a.6e, ld.2d.3c.4b.5a.6f, ld.2d.3c.4b.5b.6a, ld.2d.3c.4b.5b.6b, ld.2d.3c.4b.5b.6c, ld.2d.3c.4b.5b.6d, ld.2d3c.4b.5b.6e, ld.2d.3c.4b.5b.6f, ld.2d.3c.4b.5c.6a, ld.2d.3c.4b.5c.6b, ld.2d.3c.4b.5c.6c, ld.2d3c.4b.5c.6d, ld.2d.3c.4b.5c.6e, ld.2d.3c.4b.5c.6f, ld.2d.3c.4b.5d.6a, ld.2d.3c.4b.5d.6b, ld.2d.3c.4b.5d.6c, ld.2d.3c.4b.5d.6d, ld.2d.3c.4b.5d.6e, ld.2d.3c.4b.5d.6f, ld.2d.3c.4b.5e.6a, ld.2d.3c.4b.5e.6b, ld.2d.3c.4b.5e.6c, ld.2d.3c.4b.5e.6d, ld.2d.3c.4b.5e.6e, ld.2d.3c.4b.5e.6f, ld.2d.3c.4b.5f.6a, ld.2d.3c.4b.5f.6b, ld.2d.3c.4b.5f.6c, ld.2d.3c.4b.5f.6d, ld.2d.3c.4b.5f.6e, ld.2d.3c.4b.5f.6f, ld.2d.3c.4c.5a.6a, ld.2d.3c.4c.5a.6b, ld.2d.3c.4c.5a.6c, ld.2d.3c.4c.5a.6d, ld.2d.3c.4c.5a.6e, ld.2d.3c.4c.5a.6f, ld.2d.3c.4c.5b.6a, ld.2d.3c.4c.5b.6b, ld.2d.3c.4c.5b.6c, ld.2d.3c.4c.5b.6d, ld.2d.3c.4c.5b.6e, ld.2d.3c.4c.5b.6f, ld.2d.3c.4c.5c.6a, ld.2d.3c.4c.5c.6b, ld.2d.3c.4c.5c.6c, ld.2d.3c.4c.5c.6d, ld.2d.3c.4c.5c.6e, ld.2d.3c.4c.5c.6f, ld.2d.3c.4c.5d.6a, ld.2d.3c.4c.5d.6b, ld.2d.3c.4c.5d.6c, ld.2d.3c.4c.5d.6d, ld.2d.3c.4c.5d.6e, ld.2d.3c.4c.5d.6f, ld.2d.3c.4c.5e.6a, ld.2d.3c.4c.5e.6b, ld.2d.3c.4c.5e.6c, ld.2d.3c.4c.5e.6d, ld.2d.3c.4c.5e.6e, ld.2d.3c.4c.5e.6f, ld.2d.3c.4c.5f.6a, ld.2d.3c.4c.5f.6b, ld.2d.3c.4c.5f.6c, ld.2d.3c.4c.5f.6d, ld.2d.3c.4c.5f.6e, ld.2d.3c.4c.5f.6f, ld.2d.3c.4d.5a.6a, ld.2d.3c.4d.5a.6b, ld.2d.3c.4d.5a.6c, ld.2d3c.4d.5a.6d, ld.2d.3c.4d.5a.6e, ld.2d.3c.4d.5a.6f, ld.2d.3c.4d.5b.6a, ld.2d.3c.4d.5b.6b, ld.2d.3c.4d.5b.6c, ld.2d.3c.4d.5b.6d, ld.2d.3c.4d.5b.6e, ld.2d.3c.4d.5b.6f, ld.2d.3c.4d.5c.6a, ld.2d.3c.4d.5c.6b, ld.2d.3c.4d.5c.6c, ld.2d.3c.4d.5c.6d, ld.2d.3c.4d.5c.6e, ld.2d.3c.4d.5c.6f, ld.2d.3c.4d.5d.6a, ld.2d.3c.4d.5d.6b, ld.2d.3c.4d.5d.6c, ld.2d.3c.4d.5d.6d, ld.2d.3c.4d.5d.6e, ld.2d.3c.4d.5d.6f, ld.2d.3c.4d.5e.6a, ld.2d.3c.4d.5e.6b, ld.2d.3c.4d.5e.6c, ld.2d.3c.4d.5e.6d, ld.2d.3c.4d.5e.6e, ld.2d.3c.4d.5e.6f, ld.2d.3c.4d.5f.6a, ld.2d.3c.4d.5f.6b, ld.2d.3c.4d.5f.6c, ld.2d.3c.4d.5f.6d, ld.2d.3c.4d.5f.6e, ld.2d.3c.4d.5f.6f, ld.2d.3c.4e.5a.6a, ld.2d.3c.4e.5a.6b, ld.2d.3c.4e.5a.6c, ld.2d.3c.4e.5a.6d, ld.2d.3c.4e.5a.6e, ld.2d.3c.4e.5a.6f, ld.2d.3c.4e.5b.6a, ld.2d.3c.4e.5b.6b, ld.2d.3c.4e.5b.6c, ld.2d.3c.4e.5b.6d, ld.2d.3c.4e.5b.6e, ld.2d.3c.4e.5b.6f, ld.2d.3c.4e.5c.6a, ld.2d.3c.4e.5c.6b, ld.2d.3c.4e.5c.6c, ld.2d.3c.4e.5c.6d, ld.2d.3c.4e.5c.6e, ld.2d.3c.4e.5c.6f, ld.2d.3c.4e.5d.6a, ld.2d.3c.4e.5d.6b, ld.2d.3c.4e.5d.6c, ld.2d_3c.4e.5d.6d, ld_2d.3c.4e.5d.6e, ld.2d.3c.4e_5d.6f, ld_2d.3c.4e.5e,6a, ld.2d.3c.4e.5e.6b, ld.2d.3c.4e.5e.6c, ld.2d.3c.4e.5e.6d, ld.2d.3c.4e.5e.6e, ld.2d.3c.4e.5e.6f, ld.2d.3c.4e.5f.6a, ld.2d.3c.4e.5f.6b, ld.2d.3c.4e.5f.6c, ld.2d.3c.4e.5f.6d, ld.2d.3c,4e.5f.6e, ld.2d.3c.4e.5f.6f, ld.2d.3c.4f.5a*6a' ld.2d.3c.4f.5a.6b, ld.2d.3c.4f.5a.6c, ld.2d.3c.4f.5a.6d, ld.2d.3c.4f.5a.6e, ld.2d.3c.4f.5a.6f, ld.2d.3c.4f.5b.6a, ld.2d.3c.4f.5b.6b, ld.2d.3c.4f.5b.6c, -268- 200918507 ld.2d.3c.4f.5b.6d, ld.2d.3c.4f.5b.6e, ld.2d.3c.4f.5b.6f, ld.2d.3c.4f.5c.6a, ld.2d.3c.4f.5c.6b/ Id.2d3c4f.5c.6c, ld.2d.3c.4f.5c.6d, ld.2d.3c.4f.5c.6e, ld.2d.3c.4f.5c.6f, ld.2d.3c.4f.5d.6a, ld.2d.3c.4f.5d.6b, ld.2d.3c.4f.5d.6c, ld.2d.3c.4f.5d.6d, ld.2d.3c.4f.5d.6e, ld.2d.3c.4f.5d.6f, ld.2d.3c.4f.5e.6a, ld.2d.3c.4f.5e.6b, ld.2d.3c.4f.5e.6c, ld.2d.3c.4f.5e.6d, ld.2d.3c.4f.5e.6e, ld.2d.3c.4f.5e.6f, ld.2d.3c.4f.5f.6a, ld.2d.3c.4f.5f.6b, ld.2d.3c.4f.5f.6c, ld.2d.3c.4f.5f.6d, ld.2d.3c.4f.5f.6e, ld.2d.3c.4f.5f.6f, ld.2d.3d.4a.5a.6a, ld.2d.3d.4a.5a.6b, ld.2d.3d.4a.5a.6c, ld.2d.3d.4a.5a.6d, ld.2d.3d.4a.5a.6e, ld.2d.3d.4a.5a.6f, ld.2d.3d.4a.5b.6a, ld.2d.3d.4a.5b.6b, ld.2d.3d.4a.5b.6c, ld.2d.3d.4a.5b.6d, ld.2d.3d.4a.5b.6e, ld.2d.3d.4a.5b.6f, ld.2d.3d.4a.5c.6a, ld.2d.3d.4a.5c.6b, ld.2d.3d.4a.5c.6c, ld.2d.3d.4a.5c.6d, ld.2d.3d.4a.5c.6e, ld.2d.3d.4a.5c.6f, ld.2d.3d.4a.5d.6a, ld.2d.3d.4a.5d.6b, ld.2d.3d.4a.5d.6c, ld.2d.3d.4a.5d.6d, ld.2d.3d.4a.5d.6e, ld.2d.3d.4a.5d.6f, ld.2d.3d.4a.5e.6a, ld.2d.3d.4a.5e.6b, ld.2d.3d.4a.5e.6c, ld.2d.3d.4a.5e.6d, ld.2d.3d.4a.5e.6e, ld.2d.3d.4a.5e.6f, ld.2d.3d.4a.5f.6a, ld.2d.3d.4a.5f.6b, ld.2d.3d.4a.5f.6c, ld.2d.3d.4a.5f.6d, ld.2d.3d.4a.5f.6e, ld.2d.3d.4a.5f.6f, ld.2d.3d.4b.5a.6a, ld.2d.3d.4b.5a.6b, ld.2d.3d.4b.5a.6c, ld.2d.3d.4b.5a.6d, ld.2d.3d.4b.5a.6e, ld.2d.3d.4b.5a.6f, ld.2d.3d.4b.5b.6a, ld.2d.3d.4b.5b.6b, ld.2d.3d.4b.5b.6c, ld.2d.3d.4b.5b.6d, ld.2d.3d.4b.5b.6e, ld.2d.3d.4b.5b.6f, ld.2d.3d.4b.5c.6a, ld.2d.3d.4b.5c.6b, ld.2d.3d.4b.5c.6c, ld.2d.3d.4b.5c.6d, ld.2d.3d.4b.5c.6e, ld.2d.3d.4b.5c.6f, ld.2d.3d.4b.5d.6a, ld.2d.3d.4b.5d.6b, ld.2d.3d.4b.5d.6c, ld.2d.3d.4b.5d.6d, ld.2d.3d.4b.5d.6e, ld.2d.3d.4b.5d.6f, ld.2d.3d.4b.5e.6a, ld.2d.3d.4b.5e.6b, ld.2d.3d.4b.5e.6c, ld.2d.3d.4b.5e.6d, ld.2d.3d.4b.5e.6e, ld.2d.3d.4b.5e.6f, ld.2d.3d.4b.5f.6a, ld.2d.3d.4b.5f.6b, ld.2d.3d.4b.5f.6c, ld.2d.3d.4b.5f.6d, ld.2d.3d.4b.5f.6e, ld.2d.3d.4b.5f.6f, ld.2d.3d.4c.5a.6a, ld.2d.3d.4c.5a.6b, ld.2d.3d.4c.5a.6c, ld.2d.3d.4c.5a.6d, ld.2d.3d.4c.5a.6e, ld.2d.3d.4c.5a.6f, ld.2d.3d.4c.5b.6a, ld.2d.3d.4c.5b.6b, ld.2d.3d.4c.5b.6c, ld.2d.3d.4c.5b.6d, ld.2d.3d.4c.5b.6e, ld.2d.3d.4c.5b.6f, ld.2d.3d.4c.5c.6a, ld.2d.3d.4c.5c.6b, ld.2d.3d.4c.5c.6c, ld.2d.3d.4c.5c.6d, ld.2d.3d.4c.5c.6e, ld.2d.3d.4c.5c.6f, ld.2d.3d.4c.5d.6a, ld.2d.3d.4c.5d.6b, ld.2d.3d.4c.5d.6c, ld.2d.3d.4c.5d.6d, ld.2d.3d.4c.5d.6e, ld.2d.3d.4c.5d.6f, ld.2d.3d.4c.5e.6a, ld.2d.3d.4c.5e.6b, ld.2d.3d.4c.5e.6c, ld.2d.3d.4c.5e.6d, ld.2d.3d.4c.5e.6e, ld.2d.3d.4c.5e.6f, ld.2d.3d.4c.5f.6a, ld.2d.3d.4c.5f.6b, ld.2d.3d.4c.5f.6c, ld.2d.3d.4c.5f.6d, ld.2d.3d.4c.5f.6e, ld.2d.3d.4c.5f.6f, ld.2d.3d.4d.5a.6a, ld.2d.3d.4d.5a.6b, ld.2d.3d.4d.5a.6c, ld.2d.3d.4d.5a.6d, ld.2d.3d.4d.5a.6e, ld.2d.3d.4d.5a.6f, ld.2d.3d.4d.5b.6a, ld.2d.3d.4d.5b.6b, ld.2d.3d.4d.5b.6c, ld.2d.3d.4d.5b.6d, ld.2d.3d.4d.5b.6e, ld.2d3d.4d.5b.6f, ld.2d.3d.4d.5c.6a, ld.2d.3d.4d.5c.6b, ld.2d.3d.4d.5c.6c, ld.2d.3d.4d.5c.6d, ld.2d.3d.4d.5c.6e, ld.2d.3d.4d.5c.6f, ld.2d.3d.4d.5d.6a, ld.2d.3d.4d.5d.6b, ld.2d.3d.4d.5d.6c, ld.2d.3d.4d.5d.6d, ld.2d.3d.4d.5d.6e, ld.2d.3d.4d.5d.6t ld.2d.3d.4d.5e.6a, ld.2d.3d.4d.5e.6b, ld.2d.3d.4d.5e.6c, ld.2d.3d.4d.5e.6d, ld.2d.3d.4d.5e.6e, ld.2d.3d.4d.5e.6f, ld.2d.3d.4d.5f.6a, ld.2d.3d.4d.5f.6b, ld.2d.3d.4d.5f.6c, ld.2d.3d.4d.5f.6d, -269- 200918507 ld.2d.3d.4d.5f.6e, ld.2d.3d.4d.5f.6f, ld.2d.3d.4e.5a.6a, ld.2d.3d.4e.5a.6b, ld.2d.3d.4e.5a.6c, ld.2d.3d.4e.5a.6d, ld.2d.3d.4e.5a.6e, ld.2d.3d.4e.5a.6f, ld.2d.3d.4e.5b.6a, ld.2d.3d.4e.5b.6b, ld.2d.3d.4e.5b.6c, ld.2d.3d.4e.5b.6d, ld.2d.3d.4e.5b.6e, ld.2d.3d.4e.5b.6f, ld.2d.3d.4e.5c.6a, ld.2d.3d.4e.5c.6b, ld.2d.3d.4e.5c.6c, ld.2d.3d.4e.5c.6d, ld.2d.3d.4e.5c.6e, ld.2d.3d.4e.5c.6f, ld.2d.3d.4e.5d.6a, ld.2d.3d.4e.5d.6b, ld.2d.3d.4e.5d.6c, ld.2d.3d.4e.5d.6d, ld.2d.3d.4e.5d.6e, ld.2d.3d.4e.5d.6f, ld.2d.3d.4e.5e.6a, ld.2d.3d.4e.5e.6b, ld.2d.3d.4e.5e.6c, ld.2d.3d.4e.5e.6d, ld.2d.3d.4e.5e.6e, ld.2d.3d.4e.5e.6f, ld.2d3d.4e.5f.6a, ld.2d.3d.4e.5f.6b, ld.2d.3d.4e.5f.6c, ld.2d.3d.4e.5f.6d, ld.2d.3d.4e.5f.6e, ld.2d.3d.4e.5f.6f, ld.2d.3d.4f.5a.6a, ld.2d.3d.4f.5a.6b, ld.2d.3d.4f.5a.6cr ld.2d.3d.4f.5a.6d, ld.2d.3d.4f.5a.6e； ld.2d.3d.4f.5a.6f, ld.2d.3d.4f.5b.6a, ld.2d.3d.4f.5b.6b, ld.2d.3d.4f.5b.6c, ld.2d.3d.4f.5b.6d, ld.2d.3d.4f.5b.6e, ld.2d.3d.4f.5b.6f, ld.2d.3d.4f.5c.6a, ld.2d.3d.4f.5c.6b, ld.2d.3d.4f.5c.6c, ld.2d.3d.4f.5c.6d, ld.2d.3d.4f.5c.6e, ld.2d.3d.4f.5c.6f, ld.2d.3d.4f.5d.6a, ld.2d.3d.4f.5d.6b, ld.2d.3d.4f.5d.6c, ld.2d.3d.4f.5d.6d, ld.2d.3d.4f.5d.6e, ld.2d.3d.4f.5d.6f, ld.2d.3d.4f.5e.6a, ld.2d.3d.4f.5e.6b, ld.2d.3d.4f.5e.6c, ld.2d.3d.4f.5e.6d7 ld.2d.3d.4f.5e.6e, ld.2d.3d.4f.5e.6f, ld.2d.3d.4f.5f.6a, ld.2d.3d.4f.5f.6b, ld.2d.3d.4f.5f.6c, ld.2d.3d.4f.5f.6d, ld.2d.3d.4f.5f.6e, ld.2d.3d.4f.5f.6f, ld.2d.3e.4a.5a.6a, ld.2d.3e.4a.5a.6b, ld.2d.3e.4a.5a.6c, ld.2d.3e.4a.5a.6d, ld.2d.3e.4a.5a.6e, ld.2d.3e.4a.5a.6f, ld.2d.3e.4a.5b.6a, ld.2d.3e.4a.5b.6b, ld.2d.3e.4a.5b.6c, ld.2d.3e.4a.5b.6d, ld.2d.3e.4a.5b.6e, ld.2d.3e.4a.5b.6f, ld.2d.3e.4a.5c.6a, ld.2d.3e.4a.5c.6b, ld.2d.3e.4a.5c.6c, ld.2d.3e.4a.5c.6d, ld.2d.3e.4a.5c.6e, ld.2d.3e.4a.5c.6f, ld.2d.3e.4a.5d.6a, ld.2d.3e.4a.5d.6b, ld.2d.3e.4a.5d.6c, ld.2d.3e.4a.5d.6d, ld.2d.3e.4a.5d.6e, ld.2d.3e.4a.5d.6f, ld.2d.3e.4a.5e.6a, ld.2d.3e.4a.5e.6b, ld.2d.3e.4a.5e.6c, ld.2d.3e.4a.5e.6d, ld.2d.3e.4a.5e.6e, ld.2d.3e.4a.5e.6f, ld.2d.3e.4a.5f.6a, ld.2d.3e.4a.5f.6b, ld.2d.3e.4a.5f.6c, ld.2d.3e.4a.5f.6d, ld.2d.3e.4a.5f.6e, ld.2d.3e.4a.5f.6f, ld.2d.3e.4b.5a.6a, ld.2d.3e.4b.5a.6b, ld.2d.3e.4b.5a.6c, ld.2d.3e.4b.5a.6d, ld.2d.3e.4b.5a.6e, ld.2d.3e.4b.5a.6f, ld.2d.3e.4b.5b.6a, ld.2d.3e.4b.5b.6b, ld.2d.3e.4b.5b.6c, ld.2d.3e.4b.5b.6d, ld.2d.3e.4b.5b.6e, ld.2d.3e.4b.5b.6f, ld.2d.3e.4b.5c.6a, ld.2d.3e.4b.5c.6b, ld.2d.3e.4b.5c.6c, ld.2d.3e.4b.5c.6d, ld.2d.3e.4b.5c.6e, ld.2d.3e.4b.5c.6f, ld.2d.3e.4b.5d.6a, ld.2d.3e.4b.5d.6b, ld.2d.3e.4b.5d.6c, ld.2d.3e.4b.5d.6d, ld.2d.3e.4b.5d.6e, Id^d.Se^b.Sd.ef, ld.2d.3e.4b.5e.6a, ld.2d.3e.4b.5e.6b, ld.2d.3e.4b.5e.6c, ld.2d.3e.4b.5e.6d, ld.2d.3e.4b.5e.6e, ld.2d.3e.4b.5e.6f, ld.2d.3e_4b.5f.6a, ld.2d.3e.4b.5f.6b, ld.2d.3e.4b.5f.6c, ld.2d.3e.4b.5f.6d, ld.2d.3e.4b.5f.6e, ld.2d.3e.4b.5f.6f, ld.2d.3e.4c.5a.6a, ld.2d.3e.4c.5a.6b, ld.2d.3e.4c.5a.6c, ld.2d.3e.4c.5a.6d, ld.2d.3e.4c.5a.6e, ld.2d.3e.4c.5a.6f, ld.2d.3e.4c.5b.6a, ld.2d.3e.4c.5b.6b, ld.2d.3e.4c.5b.6c, ld.2d.3e.4c.5b.6d, ld.2d.3e.4c.5b.6e, ld.2d.3e.4c.5b.6f, ld.2d.3e.4c.5c.6a, ld.2d.3e.4c.5c.6b, ld.2d.3e.4c.5c.6c, ld.2d.3e.4c.5c.6d, ld.2d.3e.4c.5c.6e, ld.2d.3e.4c.5c.6f7 ld.2d.3e.4c.5d.6a, ld.2d.3e.4c.5d.6b, ld.2d.3e.4c.5d.6c, ld.2d.3e.4c.5d.6d, -270- 200918507 ld.2d.3e.4c.5d.6e, ld.2d.3e.4c.5d.6f, ld.2d.3e.4c.5e.6a, ld.2d.3e.4c.5e.6b, ld.2d3e.4c.5e.6c, ld.2d.3e.4c.5e.6d, ld.2d.3e.4c.5e.6e, ld.2d.3e.4c.5e.6f, ld.2d.3e.4c.5f.6a, ld.2d.3e.4c.5f.6b, ld.2d.3e.4c.5f.6c, ld.2d.3e.4c.5f.6d, ld.2d.3e.4c.5f.6e, ld.2d.3e.4c.5f.6f, ld.2d.3e.4d,5a.6a, ld.2d.3e.4d.5a.6b, ld.2d.3e.4d.5a.6c, ld.2d.3e.4d.5a.6d, ld.2d.3e.4d.5a.6e, ld.2d.3e.4d.5a.6f, ld.2d.3e.4d.5b.6a, ld.2d.3e.4d.5b.6b, ld.2d.3e.4d.5b.6c, ld.2d.3e.4d.5b.6d, ld.2d.3e.4d.5b.6e, ld.2d.3e.4d.5b.6f, ld.2d.3e.4d.5c.6a, ld.2d.3e.4d.5c.6b, ld.2d.3e.4d.5c.6c, ld.2d.3e.4d.5c.6d, ld.2d.3e.4d.5c.6e, ld.2d.3e.4d.5c.6f, ld.2d.3e.4d.5d.6a, ld.2d.3e.4d.5d.6b, ld.2d.3e.4d.5d.6c, ld.2d.3e.4d.5d.6d, ld.2d.3e.4d.5d.6e, ld.2d.3e.4d.5d.6f, ld.2d.3e.4d.5e.6a, ld.2d.3e.4d.5e.6b, ld.2d.3e.4d.5e.6c, ld.2d.3e.4d.5e.6d, ld.2d.3e.4d.5e.6e, ld.2d.3e.4d.5e.6f, ld.2d.3e.4d.5f.6a, ld.2d.3e.4d.5f.6b, ld.2d.3e.4d.5f.6c, ld.2d.3e.4d.5f.6d, ld.2d.3e.4d.5f.6e, ld.2d.3e.4d.5f.6f, ld.2d.3e.4e.5a.6a, ld.2d.3e.4e.5a.6b, ld.2d.3e.4e.5a.6c, ld.2d.3e.4e.5a.6d, ld.2d.3e.4e.5a.6e, ld.2d.3e.4e.5a.6f, ld.2d.3e.4e.5b.6a, ld.2d.3e.4e.5b.6b, ld.2d.3e.4e.5b.6c, ld.2d.3e.4e.5b.6d, ld.2d.3e.4e.5b.6e, ld.2d.3e.4e.5b.6f, ld.2d.3e.4e.5c.6a, ld.2d.3e.4e.5c.6b, ld.2d.3e.4e.5c.6c, ld.2d,3e.4e.5c.6d, ld.2d.3e.4e.5c.6e, ld.2d.3e.4e.5c.6f, ld.2d.3e.4e.5d.6a, ld.2d.3e.4e.5d.6b, ld.2d.3e.4e.5d.6c, ld.2d.3e.4e.5d.6d, ld.2d.3e.4e.5d.6e, ld.2d.3e.4e.5d.6f, ld.2d.3e.4e.5e.6a, ld.2d.3e.4e.5e.6b, ld.2d.3e.4e.5e.6c, ld.2d.3e.4e.5e.6d, ld.2d.3e.4e.5e.6e, ld.2d.3e.4e.5e.6f, ld.2d.3e.4e.5f.6a, ld.2d.3e.4e.5f.6b, ld.2d.3e.4e.5f.6c, ld.2d.3e.4e.5f.6d, ld.2d.3e.4e.5f.6e, ld.2d.3e.4e.5f.6f, ld.2d.3e.4f.5a.6a, ld.2d.3e.4f.5a.6b, ld.2d.3e.4f.5a.6c, ld.2d.3e.4f.5a.6d, ld.2d.3e.4f.5a.6e, ld.2d.3e.4f.5a.6f, ld.2d.3e.4f.5b.6a, ld.2d.3e.4f.5b.6b, ld.2d.3e.4f.5b.6c, ld-2d.3e.4f.5b.6d, ld.2d.3e.4f.5b.6e, ld.2d.3e.4f.5b.6f, ld.2d.3e.4f.5c.6a, ld.2d.3e.4f.5c.6b, ld.2d.3e.4f.5c.6c, ld.2d.3e.4f.5c.6d, ld.2d.3e.4f.5c.6e, ld.2d.3e.4f.5c.6f, ld.2d.3e.4f.5d.6a, ld.2d.3e.4f.5d.6b, ld.2d.3e.4f.5d.6c, ld.2d.3e.4f.5d.6d, ld.2d.3e.4f.5d.6e, ld.2d.3e.4f.5d.6f, ld.2d.3e.4f.5e.6a, ld.2d.3e.4f.5e.6b, ld.2d.3e.4f.5e.6c, ld.2d.3e.4f.5e.6d, ld.2d.3e.4f.5e.6e, ld.2d.3e.4f.5e.6f, ld.2d.3e.4f.5f.6a, ld.2d.3e.4f.5f.6b, ld.2d.3e.4f.5f.6c, ld.2d.3e.4f.5f.6d, ld_2d.3e.4f.5f_6e, ld.2d.3e.4f.5f.6f, ld.2d.3f.4a,5a，6a, ld.2d.3f.4a.5a.6b, ld.2d.3f.4a.5a.6c, ld.2d.3f.4a.5a.6d, ld.2d.3f.4a.5a.6e, ld.2d.3f.4a.5a.6f, ld.2d.3f.4a.5b.6a, ld.2d.3f.4a.5b.6b, ld.2d.3f.4a.5b.6c, ld.2d.3f.4a.5b.6d, ld.2d.3f.4a.5b.6e, ld.2d.3f.4a.5b.6f, ld.2d.3f.4a.5c.6a, ld.2d.3f.4a.5c.6b, ld.2d.3f.4a.5c.6c, ld.2d.3f.4a.5c.6d, ld.2d.3f.4a.5c.6e, ld.2d.3f.4a.5c.6f, ld.2d.3f.4a.5d.6a, ld.2d.3f.4a.5d.6b, ld.2d.3f.4a.5d.6c, ld.2d.3f.4a.5d.6d, ld.2d.3f.4a.5d.6e, ld.2d.3f.4a.5d.6f, ld.2d.3f.4a.5e.6a, ld.2d.3f.4a.5e.6b, ld.2d.3f.4a.5e.6c, ld.2d.3f.4a.5e.6d, ld.2d.3f.4a.5e.6e, ld.2d.3f.4a.5e.6f, ld.2d.3f.4a.5f.6a, ld.2d.3f.4a.5f.6b, ld.2d.3f.4a.5f.6c, ld.2d.3f.4a.5f.6d, ld.2d.3f.4a.5f.6e, ld,2d.3f.4a.5f.6f, ld.2d.3f.4b.5a.6a, ld.2d.3f.4b.5a.6b, ld.2d.3f.4b.5a.6c, ld.2d.3f.4b.5a.6d, ld.2d.3f.4b.5a.6e, ld.2d.3f.4b.5a.6f, ld.2d.3f.4b.5b.6a, ld.2d.3f.4b.5b.6b, ld.2d.3f.4b.5b.6c, ld.2d.3f.4b.5b.6d, -271 - 200918507 ld.2d.3f.4b.5b.6e, ld.2d.3f.4b.5b.6f, ld.2d.3f.4b.5c.6a, ld.2d.3f.4b.5c.6b, ld.2d.3f.4b.5c.6c, ld.2d.3f.4b.5c.6d, ld.2d.3f.4b.5c.6e, ld.2d.3f.4b.5c.6f, ld.2d.3f.4b.5d.6a, ld.2d.3f.4b.5d.6b, ld.2d.3f.4b.5d.6c, ld.2d.3f.4b.5d.6d, ld.2d.3f.4b.5d.6e, ld.2d.3f.4b.5d.6f, ld.2d.3f.4b.5e.6a, ld.2d.3f.4b.5e.6b, ld.2d.3f.4b.5e.6c, ld.2d.3f.4b.5e.6d, ld.2d.3f.4b.5e.6e, ld.2d.3f.4b.5e.6f, ld.2d.3f.4b.5f.6a, ld.2d.3f.4b.5f.6b, ld.2d.3f.4b.5f.6c, ld.2d.3f.4b.5f.6d, ld.2d.3f.4b.5f.6e, ld.2d.3f.4b.5f.6f, ld.2d.3f.4c.5a.6a, ld.2d.3f.4c.5a.6b, ld.2d.3f.4c.5a.6c, ld.2d.3f.4c.5a.6d, ld.2d.3f.4c.5a.6e, ld.2d.3f.4c.5a.6f, ld.2d.3f.4c.5b.6a, ld.2d.3f.4c.5b.6b, ld.2d.3f.4c.5b.6c, ld.2d.3f.4c.5b.6d, ld.2d.3f.4c.5b.6e, ld.2d.3f.4c.5b.6f, ld.2d.3f.4c.5c.6a, ld.2d.3f.4c.5c.6b, ld.2d.3f.4c.5c.6c, ld.2d.3f.4c.5c.6d, ld.2d.3f.4c.5c.6e, ld.2d.3f.4c.5c.6f, ld.2d.3f.4c.5d.6a, ld.2d.3f.4c.5d.6b, ld.2d.3f.4c.5d.6C/ ld.2d.3f.4c.5d.6d, ld.2d.3f.4c.5d.6e, ld.2d.3f.4c.5d.6f, ld.2d.3f.4c.5e.6a, ld.2d.3f.4c.5e.6b, ld.2d.3f.4c.5e.6c, ld.2d.3f.4c.5e.6d, ld.2d.3f.4c.5e.6e, ld.2d.3f.4c.5e.6f, ld.2d.3f.4c.5f.6a, ld.2d.3f.4c.5f.6b, ld.2d.3f.4c.5f.6c, ld.2d.3f.4c.5f.6d, ld.2d.3f.4c.5f.6e, ld.2d.3f.4c.5f.6f, ld.2d.3f.4d.5a.6a, ld.2d.3f.4d.5a.6b, ld.2d.3f.4d.5a.6c, ld.2d.3f.4d.5a.6d, ld.2d.3f.4d.5a.6e, ld.2d.3f.4d.5a.6f, ld.2d.3f.4d.5b.6a, ld.2d.3f.4d.5b.6b, ld.2d.3f.4d.5b.6c, ld.2d.3f.4d.5b.6d, ld.2d.3f.4d.5b.6e, ld.2d.3f.4d.5b.6f, ld.2d.3f.4d.5c.6a, ld.2d.3f.4d.5c.6b, ld.2d.3f.4d.5c.6c, ld.2d.3f.4d.5c.6d, ld.2d.3f.4d.5c.6e, ld.2d.3f.4d.5c.6f, ld.2d.3f.4d.5d.6a, ld.2d.3f.4d.5d.6b, ld.2d.3f.4d.5d.6c, ld.2d.3f.4d.5d.6d, ld.2d.3f.4d.5d.6e, ld.2d.3f.4d.5d.6f, ld.2d.3f.4d.5e.6a, ld.2d.3f.4d.5e.6b, ld.2d.3f.4d.5e.6c, ld.2d.3f.4d.5e.6d, ld.2d.3f.4d.5e.6e, ld.2d.3f.4d.5e.6f, ld.2d.3f.4d.5f.6a, ld.2d.3f.4d.5f.6b, ld.2d.3f.4d.5f.6c, ld.2d.3f.4d.5f.6d, ld.2d.3f.4d.5f.6e, ld.2d.3f.4d.5f.6f, ld.2d.3f.4e.5a.6a, ld.2d.3f.4e.5a.6b, ld.2d.3f.4e.5a.6c, ld.2d.3f.4e.5a.6d, ld.2d.3f.4e.5a.6e, ld.2d.3f.4e.5a.6f, ld.2d.3f.4e.5b.6a, ld.2d.3f.4e.5b.6b, ld.2d.3f.4e.5b.6c, ld.2d.3f.4e.5b.6d, ld.2d.3f.4e.5b.6e, ld.2d.3f.4e.5b.6f, ld.2d.3f.4e.5c.6a, ld.2d.3f.4e.5c.6b, ld.2d.3f.4e.5c.6c, ld.2d.3f.4e.5c.6d, ld.2d.3f.4e.5c.6e, ld.2d.3f.4e.5c.6f, ld.2d.3f.4e.5d.6a, ld.2d.3f.4e.5d.6b, ld.2d.3f.4e.5d.6c, ld.2d.3f.4e.5d.6d, ld.2d.3f.4e.5d.6e, ld.2d.3f.4e.5d.6f, ld.2d.3f.4e.5e.6a, ld.2d.3f.4e.5e.6b, ld.2d.3f.4e.5e.6c, ld.2d.3f.4e.5e.6d, ld.2d.3f.4e.5e.6e, ld.2d.3f.4e.5e.6f, ld.2d.3f.4e.5f.6a, ld.2d.3f.4e.5f.6b, ld.2d.3f.4e.5f.6c, ld.2d.3f.4e.5f.6d, ld.2d.3f.4e.5f.6e, ld.2d.3f.4e.5f.6f, ld.2d.3f.4f.5a.6a, ld.2d.3f.4f.5a.6b, ld.2d.3f.4f.5a.6c, ld.2d.3f.4f.5a.6d, ld.2d.3f.4f.5a.6e, ld.2d.3f.4f.5a.6f, ld.2d.3f.4f.5b.6a, ld.2d.3f.4f.5b.6b, ld.2d.3f.4f.5b.6c, ld.2d.3f.4f.5b.6d, ld.2d.3f.4f.5b.6e, ld.2d.3f.4f.5b.6f, ld.2d.3f.4f.5c.6a, ld.2d.3f.4f.5c.6b, ld.2d.3f.4f.5c.6c, ld.2d.3f.4f.5c.6d, ld.2d.3f.4f.5c.6e, ld.2d.3f.4f.5c.6f, ld.2d.3f.4f.5d.6a, ld.2d.3f.4f.5d.6b, ld.2d.3f.4f.5d.6c, ld.2d.3f.4f.5d.6d, ld.2d.3f.4f.5d.6e, ld.2d.3f.4f.5d.6f, ld.2d.3f.4f.5e.6a, ld.2d.3f.4f.5e.6b, ld.2d.3f.4f.5e.6c, ld.2d.3f.4f.5e.6d, ld.2d.3f.4f.5e.6e, ld.2d.3f.4f.5e.6f, ld.2d.3f.4f.5f.6a, ld.2d.3f.4f.5f.6b, ld.2d.3f.4f.5f.6c, ld.2d.3f.4£.5f.6d, ld.2d.3f.4f.5f.6e, ld.2d.3f.4f.5f.6f, ld.2e.3a.4a.5a.6a, ld.2e.3a.4a.5a.6b, ld.2e.3a.4a.5a.6c, -272- 200918507 ld.2e.3a.4a.5a.6d, ld.2e.3a.4a.5a.6e, ld.2e.3a.4a.5a.6f, ld.2e.3a.4a.5b.6a, ld.2e.3a.4a.5b.6b, ld.2e.3a.4a.5b.6c, ld.2e.3a.4a.5b.6d, ld.2e.3a.4a.5b.6e, ld.2e.3a.4a.5b.6f, ld.2e.3a.4a.5c.6a, ld.2e.3a.4a.5c.6b, ld.2e.3a.4a.5c.6c, ld.2e.3a.4a.5c.6d, ld.2e.3a.4a.5c.6e, ld.2e.3a.4a.5c.6f, ld.2e.3a.4a.5d.6a, ld.2e.3a.4a.5d.6b, ld.2e.3a.4a.5d.6c, ld.2e.3a.4a.5d.6d, ld.2e.3a.4a.5d.6e, ld.2e.3a.4a.5d.6f, ld.2e.3a.4a.5e.6a, ld.2e.3a.4a.5e.6b, ld.2e.3a.4a.5e.6c, ld.2e.3a.4a.5e.6d, ld.2e.3a.4a.5e.6e, ld.2e.3a.4a.5e.6f, ld.2e.3a.4a.5f.6a, ld.2e.3a.4a.5f.6b, ld.2e.3a.4a.5f.6c, ld.2e.3a.4a.5f.6d, ld.2e.3a.4a.5f.6e, ld.2e.3a.4a.5f.6f, ld.2e.3a.4b.5a.6a, ld.2e.3a.4b.5a.6b, ld.2e.3a.4b.5a.6c, ld.2e.3a.4b.5a.6d, ld.2e.3a.4b.5a.6e, ld.2e.3a.4b.5a.6f, ld.2e.3a.4b.5b.6a, ld.2e.3a.4b.5b.6b, ld.2e.3a.4b.5b.6c, ld.2e.3a.4b.5b.6d, ld.2e.3a.4b.5b.6e, ld.2e.3a.4b.5b.6f, ld.2e.3a.4b.5c.6a, ld.2e.3a.4b.5c.6b, ld.2e.3a.4b.5c.6c, ld.2e.3a.4b.5c.6d, ld.2e.3a.4b.5c.6e, ld.2e.3a.4b.5c.6f, ld.2e.3a.4b.5d.6a, ld.2e.3a.4b.5d.6b, ld.2e.3a.4b.5d.6c, ld.2e.3a.4b.5d.6d, ld.2e.3a.4b.5d.6e, ld.2e.3a.4b.5d.6f, ld.2e.3a.4b.5e.6a, ld.2e.3a.4b.5e.6b, ld.2e.3a.4b.5e.6c, ld.2e.3a.4b.5e.6d, ld.2e.3a.4b.5e.6e, ld.2e.3a.4b.5e.6f, ld.2e.3a.4b.5f.6a, ld.2e.3a.4b.5f.6b, ld.2e.3a.4b.5f.6c, ld.2e.3a.4b.5f.6d, ld.2e.3a.4b.5f.6e, ld.2e.3a.4b.5f.6f, ld.2e.3a.4c.5a.6a, ld.2e.3a.4c.5a.6b, ld.2e.3a.4c.5a.6c, ld.2e.3a.4c.5a.6d, ld.2e.3a.4c.5a.6e, ld.2e.3a.4c.5a.6f, ld.2e.3a.4c.5b.6a, ld.2e.3a.4c.5b.6b, ld.2e.3a.4c.5b.6c, ld.2e.3a.4c.5b.6d, ld.2e.3a.4c.5b.6e, ld.2e.3a.4c.5b.6f, ld.2e.3a.4c.5c.6a, ld.2e.3a.4c.5c.6b, ld.2e.3a.4c.5c.6c, ld.2e.3a.4c.5c.6d, ld.2e.3a.4c.5c.6e, ld.2e.3a.4c.5c.6f, ld.2e.3a.4c.5d.6a, ld.2e.3a.4c.5d.6b, ld.2e.3a.4c.5d.6c, ld.2e.3a.4c.5d.6d, ld.2e.3a.4c.5d.6e, ld.2e.3a.4c.5d.6f, ld.2e.3a.4c.5e.6a, ld.2e.3a.4c.5e.6b, ld.2e.3a.4c.5e.6c, ld.2e.3a.4c.5e.6d, ld.2e.3a.4c.5e.6e, ld.2e.3a.4c.5e.6f, ld.2e.3a.4c.5f.6a, ld.2e.3a.4c.5f.6b, ld.2e.3a.4c.5f.6c, ld.2e.3a.4c.5f.6d, ld.2e.3a.4c.5f.6e, ld.2e.3a.4c.5f.6f, ld.2e.3a.4d.5a.6a, ld.2e.3a.4d.5a.6b, ld.2e.3a.4d.5a.6c, ld.2e.3a.4d.5a.6d, ld.2e.3a.4d.5a.6e, ld.2e.3a.4d.5a.6f, ld.2e.3a.4d.5b.6a, ld.2e.3a.4d.5b.6b, ld.2e.3a.4d.5b.6c, ld.2e.3a.4d.5b.6d, ld.2e.3a.4d.5b.6e, ld.2e.3a.4d.5b.6f, ld.2e.3a.4d.5c.6a, ld.2e.3a.4d.5c.6b, ld.2e.3a.4d.5c.6c, ld.2e.3a.4d.5c.6d, ld.2e.3a.4d.5c.6e, ld.2e.3a.4d.5c.6f, ld.2e.3a.4d.5d.6a, ld.2e.3a.4d.5d.6b/ ld.2e.3a.4d.5(1.60, ld.2e.3a.4d.5d.6d, ld.2e.3a.4d.5d.6e, ld.2e.3a.4d.5d.6f, ld.2e.3a.4d.5e.6a, ld.2e.3a.4d.5e.6b, ld.2e.3a.4d.5e.6c, ld.2e.3a.4d.5e.6d, ld.2e.3a.4d.5e.6e, ld.2e.3a.4d.5e.6f, ld.2e.3a.4d.5f.6a, ld.2e.3a.4d.5f.6b, ld.2e.3a.4d.5f.6c, ld.2e.3a.4d.5f.6d, ld.2e.3a.4d.5f.6e, ld.2e.3a.4d.5f.6f, ld.2e.3a.4e.5a.6a, ld.2e.3a.4e.5a.6b, ld.2e.3a.4e.5a.6c, ld.2e.3a.4e.5a.6d, ld.2e.3a.4e.5a.6e, ld.2e.3a.4e.5a.6f, ld.2e.3a.4e.5b.6a, ld.2e.3a.4e.5b.6b, ld.2e.3a.4e.5b.6c, ld.2e.3a.4e.5b.6d, ld.2e.3a.4e.5b.6e, ld.2e.3a.4e.5b.6f, ld.2e.3a.4e.5c.6a, ld.2e.3a.4e.5c.6b, ld.2e.3a.4e.5c.6c, ld.2e.3a.4e.5c.6d, ld.2e.3a.4e.5c.6e, ld.2e.3a.4e.5c.6f, ld.2e.3a.4e.5d.6a, ld.2e.3a.4e.5d.6b, ld.2e.3a.4e.5d.6c, ld.2e.3a.4e.5d.6d, ld.2e.3a.4e.5d.6e, ld.2e.3a.4e.5d.6f, ld.2e.3a.4e.5e.6a, ld.2e.3a.4e.5e.6b, ld.2e.3a.4e.5e.6c, ld.2e.3a.4e.5e.6d, -273- 200918507 ld.2e.3a.4e.5e.6e, ld.2e.3a.4e.5e.6f7 ld.2e.3a.4e.5f.6a, ld.2e.3a.4e.5f.6b, ld.2e.3a.4e.5f.6c, ld.2e.3a.4e.5f.6d, ld.2e.3a.4e.5f.6e, ld.2e.3a.4e.5f.6f, ld.2e.3a.4f.5a.6a, ld.2e.3a.4f.5a.6b, ld.2e.3a.4f.5a.6c, ld.2e.3a.4f.5a.6d, ld.2e.3a.4f.5a.6e, ld.2e.3a.4f.5a.6f, ld.2e.3a.4f.5b.6a, ld.2e.3a.4f.5b.6b, ld.2e.3a_4f.5b,6c, ld.2e.3a.4f.5b.6d, ld.2e_3a.4f.5b.6e, ld.2e.3a.4f.5b.6f, ld.2e.3a.4f.5c.6a, ld.2e.3a.4f.5c.6b, ld.2e.3a.4f.5c.6c, ld.2e.3a.4f.5c.6d, ld.2e.3a.4f.5c.6e, ld.2e.3a.4f.5c.6f, ld.2e.3a.4f.5d.6a, ld.2e.3a.4f.5d.6b, ld.2e.3a.4f.5d.6c, ld.2e.3a.4f.5d.6d, ld.2e.3a.4f.5d.6e, ld.2e.3a.4f.5d.6f, ld.2e.3a.4f.5e.6a, ld.2e.3a.4f.5e.6b7 ld.2e.3a.4f.5e.6Q ld.2e.3a.4f.5e.6d, ld.2e.3a.4f.5e.6e, ld.2e.3a.4f.5e.6f, ld.2e.3a.4f.5f.6a, ld.2e.3a.4f.5f.6b, ld.2e.3a.4f.5f.6c, ld.2e.3a.4f.5f.6d, ld.2e.3a.4f.5f.6e, ld.2e.3a.4f.5f.6f, ld.2e.3b.4a.5a.6a, ld.2e.3b.4a.5a.6b, ld.2e.3b.4a.5a.6c, ld.2e.3b.4a.5a.6d, ld.2e.3b.4a.5a.6e, ld.2e.3b.4a.5a.6f, ld.2e.3b.4a.5b.6a, ld.2e.3b.4a.5b.6b, ld.2e.3b.4a.5b.6c, ld.2e.3b.4a.5b.6d, ld.2e.3b.4a.5b.6e, ld.2e.3b.4a.5b.6f, ld.2e.3b.4a.5c.6a, ld.2e.3b.4a.5c.6b, ld.2e.3b.4a.5c.6c, ld.2e.3b.4a.5c.6d, ld.2e.3b.4a.5c.6e, ld.2e.3b.4a.5c.6f, ld.2e.3b.4a.5d.6a, ld.2e.3b.4a.5d.6b, ld.2e.3b.4a.5d.6c, ld.2e.3b.4a.5d.6d, ld.2e.3b.4a.5d.6e, ld.2e.3b.4a.5d.6f, ld.2e.3b.4a.5e.6a, ld.2e.3b.4a.5e.6b, ld.2e.3b.4a.5e.6c, ld.2e.3b.4a.5e.6d, ld.2e.3b.4a.5e.6e, ld.2e.3b.4a.5e.6f, ld.2e.3b.4a.5f.6a, ld.2e.3b.4a.5f.6b, ld.2e.3b.4a.5f.6c, ld.2e.3b.4a.5f.6d, ld.2e.3b.4a.5f.6e, ld.2e.3b.4a.5f.6f, ld.2e.3b.4b.5a.6a, ld.2e.3b.4b.5a.6b, ld.2e.3b.4b.5a.6c, ld.2e.3b.4b.5a.6d, ld.2e.3b.4b.5a.6e, ld.2e.3b.4b.5a.6f, ld.2e.3b.4b.5b.6a, ld.2e.3b.4b.5b.6b, ld.2e.3b.4b.5b.6c, ld.2e.3b.4b.5b.6d, ld.2e.3b.4b.5b.6e, ld.2e.3b.4b.5b.6f, ld.2e.3b.4b.5c.6a, ld.2e.3b.4b.5c.6b, ld.2e.3b.4b.5c.6c, ld.2e.3b.4b.5c.6d, ld.2e.3b.4b.5c.6e, ld.2e.3b.4b.5c.6f, ld.2e.3b.4b.5d.6a, ld.2e.3b.4b.5d.6b, ld.2e.3b.4b.5d.6c, ld.2e.3b.4b.5d.6d, ld.2e.3b.4b.5d.6e, ld.2e.3b.4b.5d.6f, ld.2e.3b.4b.5e.6a, ld.2e.3b.4b.5e.6b, ld.2e.3b.4b.5e.6c, ld.2e.3b.4b.5e.6d, ld.2e.3b.4b.5e.6e, ld.2e.3b.4b.5e.6f, ld.2e.3b.4b.5f.6a, ld.2e.3b.4b.5f.6b, ld.2e.3b.4b.5f.6c, ld.2e.3b.4b.5f.6d, ld.2e.3b.4b.5f.6e, ld.2e.3b.4b.5f.6f, ld.2e.3b.4c.5a.6a, ld.2e.3b.4c.5a.6b, ld.2e.3b.4c.5a.6c, ld.2e.3b.4c.5a.6d, ld.2e.3b.4c.5a.6e, ld.2e.3b.4c.5a.6f, ld.2e.3b.4c.5b.6a, ld.2e.3b.4c.5b.6b, ld.2e.3b.4c.5b.6c, ld.2e.3b.4c.5b.6d, ld.2e.3b.4c.5b.6e, ld.2e.3b.4c.5b.6f, ld.2e.3b.4c.5c.6a, ld.2e.3b.4c.5c.6b, ld.2e.3b.4c.5c.6c, ld.2e.3b.4c.5c.6d, ld.2e.3b.4c.5c.6e, ld.2e.3b.4c.5c.6f, ld.2e.3b.4c.5d.6a, ld.2e.3b.4c.5d.6b, ld.2e.3b.4c.5d.6c, ld.2e.3b.4c.5d.6d, ld.2e.3b.4c.5d.6e, ld.2e.3b.4c.5d.6f, ld.2e.3b.4c.5e.6a, ld.2e.3b.4c.5e.6b, ld.2e.3b.4c.5e.6c, ld.2e.3b.4c.5e.6d, ld.2e.3b.4c.5e.6e, ld.2e.3b.4c.5e.6f, ld.2e.3b.4c.5f.6a, ld.2e.3b.4c.5f.6b, ld.2e.3b.4c.5f.6c, ld.2e.3b.4c.5f.6d, ld.2e.3b.4c.5f.6e, ld.2e.3b.4c.5f.6f, ld.2e.3b.4d.5a.6a, ld.2e.3b.4d.5a.6b, ld.2e.3b.4d.5a.6c, ld.2e.3b.4d.5a.6d, ld.2e.3b.4d.5a.6e, ld.2e.3b.4d.5a.6f, ld.2e.3b.4d.5b.6a, ld.2e.3b.4d.5b.6b, ld.2e.3b.4d.5b.6c, ld.2e.3b.4d.5b.6d, ld.2e.3b.4d.5b.6e, ld.2e.3b.4d.5b.6f, ld.2e.3b.4d.5c.6a, ld.2e.3b.4d.5c.6b, ld.2e.3b.4d.5c.6c, ld.2e.3b.4d.5c.6d, ld.2e.3b.4d.5c.6e, -274- 200918507 ld.2e.3b.4d.5c.6f, ld.2e.3b.4d.5d.6a, ld.2e.3b.4d.5d.6b, ld.2e.3b.4d.5d.6c, ld.2e.3b.4d.5d.6d, ld.2e.3b.4d.5d.6e, ld.2e.3b.4d.5d.6f, ld.2e.3b.4d.5e.6a, ld.2e.3b.4d.5e.6b, ld.2e.3b.4d.5e.6c, ld.2e.3b.4d.5e.6d, ld.2e.3b.4d.5e.6e, ld.2e.3b.4d.5e.6f, ld.2e.3b.4d.5f.6a, ld.2e.3b.4d.5f.6b, ld.2e.3b.4d.5f.6c, ld.2e.3b.4d.5f.6d, ld.2e.3b.4d.5f.6e, ld.2e.3b.4d.5f.6f, ld.2e.3b.4e.5a.6a, ld.2e.3b.4e.5a.6b, ld.2e.3b.4e.5a.6c, ld.2e.3b.4e.5a.6d, ld.2e.3b.4e.5a.6e, ld.2e.3b.4e.5a.6f, ld.2e.3b.4e.5b.6a, ld.2e.3b.4e.5b.6b, ld.2e.3b.4e.5b.6c, ld.2e.3b.4e.5b.6d, ld.2e.3b.4e.5b.6e, ld.2e.3b.4e.5b.6f, ld.2e.3b.4e.5c.6a, ld.2e.3b.4e.5c.6b, ld.2e.3b.4e.5c.6c, ld.2e.3b.4e.5c.6d, ld.2e.3b.4e.5c.6e, ld.2e.3b.4e.5c.6f, ld.2e.3b.4e.5d.6a, ld.2e.3b.4e.5d.6b, ld.2e.3b.4e.5d.6c, ld.2e.3b.4e.5d.6d, ld.2e.3b.4e.5d.6e, ld.2e.3b.4e.5d.6f, ld.2e.3b.4e.5e.6a, ld.2e.3b.4e.5e.6b, ld.2e.3b.4e.5e.6c, ld.2e.3b.4e.5e.6d, ld.2e.3b.4e.5e.6e, ld.2e.3b.4e.5e.6f, ld.2e.3b.4e.5f.6a, ld.2e.3b.4e.5f.6b, ld.2e.3b.4e.5f.6c, ld.2e.3b.4e.5f.6d, ld.2e.3b.4e.5f.6e, ld.2e.3b.4e.5f.6f, ld.2e.3b.4f.5a.6a/ ld.2e.3b.4f.5a.6b, ld.2e.3b.4f.5a.6c, ld.2e.3b.4f.5a.6d, ld.2e.3b.4f.5a.6e, ld.2e.3b.4f.5a.6f, ld.2e.3b.4f.5b.6a, ld.2e.3b.4f.5b.6b, ld.2e.3b.4f.5b.6c, ld.2e.3b.4f.5b.6d, ld.2e.3b.4f.5b.6e, ld.2e.3b.4f.5b.6f, ld.2e.3b.4f.5c.6a, ld.2e.3b.4f.5c.6b, ld.2e.3b.4f.5c.6c, ld.2e.3b.4f.5c.6d, ld.2e.3b.4f.5c.6e, ld.2e.3b.4f.5c.6f, ld.2e.3b.4f.5d.6a, ld.2e.3b.4f.5d.6b, ld.2e.3b.4f.5d.6c, ld.2e.3b.4f.5d.6d, ld.2e.3b.4f.5d.6e, ld.2e.3b.4f.5d.6f, ld.2e.3b.4f.5e.6a, ld.2e.3b.4f.5e.6b, ld.2e.3b.4f.5e.6c, ld.2e.3b.4f.5e.6d, ld.2e.3b.4f.5e.6e, ld.2e.3b.4f.5e.6f, ld.2e.3b.4f.5f.6a, ld.2e.3b.4f.5f.6b, ld.2e.3b.4f.5f.6c, ld.2e.3b.4f.5f.6d, ld.2e.3b.4f.5f.6e, ld.2e.3b.4f.5f.6f, ld.2e.3c.4a.5a.6a, ld.2e.3c.4a.5a.6b, ld.2e.3c.4a.5a.6c, ld.2e.3c.4a.5a.6d, ld.2e.3c.4a.5a.6e, ld.2e.3c.4a.5a.6f, ld.2e.3c.4a.5b.6a, ld.2e.3c.4a.5b.6b, ld.2e.3c.4a.5b.6c, ld.2e.3c.4a.5b.6d, ld.2e.3c.4a.5b.6e, ld.2e.3c.4a.5b.6f, ld.2e.3c.4a.5c.6a, ld.2e.3c.4a.5c.6b, ld.2e.3c.4a.5c.6c, ld.2e.3c.4a.5c.6d, ld.2e.3c.4a.5c.6e, ld.2e.3c.4a.5c.6fr ld.2e.3c.4a.5d.6a, ld.2e.3c.4a.5d.6b, ld.2e.3c.4a.5d.6c, ld.2e.3c.4a.5d.6d, ld.2e.3c.4a.5d.6e, ld.2e.3c.4a,5d.6f, ld.2e.3c.4a.5e.6a, ld.2e.3c.4a.5e.6b, ld.2e.3c.4a.5e.6c, ld.2e.3c.4a.5e.6d, ld.2e.3c.4a.5e.6e, ld.2e.3c.4a.5e.6f, ld.2e.3c.4a.5f.6a, ld.2e.3c.4a.5f.6b, ld.2e.3c.4a.5f.6c, ld.2e.3c.4a.5f.6d, ld.2e.3c.4a.5f.6e, ld.2e.3c.4a.5f.6f, ld.2e.3c.4b.5a.6a, ld.2e.3c.4b.5a.6b, ld.2e.3c.4b.5a.6c, ld.2e.3c.4b.5a.6d, ld.2e.3c.4b.5a.6e, ld.2e.3c.4b.5a.6f, ld.2e.3c.4b.5b.6a, ld.2e.3c.4b.5b.6b, ld.2e.3c.4b.5b.6c, ld.2e.3c.4b5b.6d, ld.2e.3c.4b.5b.6e, ld.2e.3c.4b.5b.6f, ld.2e.3c.4b.5c.6a, ld.2e.3c.4b.5c.6b, ld.2e.3c.4b.5c.6c, ld.2e.3c.4b.5c.6d, ld.2e.3c.4b.5c.6e, ld.2e.3c.4b.5c.6f, ld.2e.3c.4b.5d.6a, ld.2e.3c.4b.5d.6b, ld,2e.3c.4b.5d.6c, ld.2e.3c.4b.5d.6d, ld.2e.3c.4b.5d.6e； ld.2e.3c.4b.5d.6f, ld.2e.3c.4b.5e.6a, ld.2e.3c.4b5e.6b, ld.2e.3c.4b.5e.6c, ld.2e.3c.4b.5e.6d, ld.2e.3c.4b.5e.6e, ld.2e.3c.4b.5e.6f, ld.2e.3c.4b.5f.6a, ld.2e.3c.4b.5f.6b, ld.2e.3c.4b.5f.6c, ld.2e.3c.4b.5f.6d, ld.2e.3c.4b.5f.6e, ld.2e.3c.4b.5f.6f, ld.2e.3c.4c.5a.6a, ld.2e.3c.4c.5a.6b, ld.2e.3c.4c.5a.6c, ld.2e.3c.4c.5a.6d, ld.2e.3c.4c.5a.6e, ld.2e.3c.4c.5a.6f, -275- 200918507 ld.2e.3c.4c.5b.6a, ld.2e.3c.4c.5b.6b, ld.2e.3c.4c.5b.6c, ld.2e.3c.4c.5b.6d, ld.2e.3c.4c.5b.6e, ld.2e.3c.4c.5b.6f, ld.2e.3c.4c.5c.6a, ld.2e.3c.4c.5c.6b, ld.2e.3c.4c.5c.6c, ld.2e.3c.4c.5c.6d, ld.2e.3c.4c.5c.6e, ld.2e.3c.4c.5c.6f, ld.2e.3c.4c.5d.6a, ld.2e.3c.4c.5d.6b, ld.2e.3c.4c.5d.6c, ld.2e.3c.4c.5d.6d, ld.2e.3c.4c.5d.6e, ld.2e.3c.4c.5d.6f, ld.2e.3c.4c.5e.6a, ld.2e.3c.4c.5e.6b, ld.2e.3c.4c.5e.6c, ld.2e.3c.4c.5e.6d, ld.2e.3c.4c.5e.6e, ld.2e.3c.4c.5e.6f, ld.2e.3c.4c.5f.6a, ld.2e.3c.4c.5f.6b, ld.2e.3c.4c.5f.6c, ld.2e.3c.4c.5f.6d, ld.2e.3c.4c.5f.6e, ld.2e.3c.4c.5f.6f, ld.2e.3c.4d.5a.6a, ld.2e.3c.4d.5a.6b, ld.2e.3c.4d.5a.6c, ld.2e.3c.4d.5a.6d, ld.2e.3c.4d.5a.6e, ld.2e.3c.4d.5a.6f, ld.2e.3c.4d.5b.6a, ld.2e.3c.4d.5b.6b, ld.2e.3c.4d.5b.6c, ld.2e.3c.4d.5b.6d, ld.2e.3c.4d.5b.6e, ld.2e.3c.4d.5b.6f, ld.2e.3c.4d.5c.6a, ld.2e.3c.4d.5c.6b, ld.2e.3c.4d.5c.6c, ld.2e.3c.4d.5c.6d, ld.2e.3c.4d.5c.6e, ld.2e.3c.4d.5c.6f, ld.2e.3c.4d.5d.6a, ld.2e.3c.4d.5d.6b, ld.2e.3c.4d.5d.6c, ld.2e.3c.4d.5d.6d, ld.2e.3c.4d.5d.6e, ld.2e.3c.4d.5d.6f, ld.2e.3c.4d.5e.6a, ld.2e.3c.4d.5e.6b, ld.2e.3c.4d.5e.6c, ld.2e.3c.4d.5e.6d, ld.2e.3c.4d.5e.6e, ld.2e.3c.4d.5e.6f, ld.2e.3c.4d.5f.6a, ， ld.2e.3c.4d.5f.6b, ld.2e.3c.4d.5f.6c, ld.2e.3c.4d.5f.6d, ld.2e.3c.4d.5f.6e, ld.2e.3c.4d.5f.6f, ld.2e.3c.4e.5a.6a, ld.2e.3c.4e.5a.6b, ld.2e.3c.4e.5a.6c, ld.2e.3c.4e.5a.6d, ld.2e.3c.4e.5a.6e, ld.2e.3c.4e.5a.6f, ld.2e.3c.4e.5b.6a, ld.2e.3c.4e.5b.6b, ld.2e.3c.4e.5b.6c, ld.2e.3c.4e.5b.6d, ld.2e.3c.4e.5b.6e, ld.2e.3c.4e.5b.6f, ld.2e.3c.4e.5c.6a, ld.2e.3c.4e.5c.6b, ld.2e.3c.4e.5c.6c, ld.2e.3c.4e.5c.6d, ld.2e.3c.4e.5c.6e, ld.2e.3c.4e.5c.6f, ld.2e.3c.4e.5d.6a, ld.2e.3c.4e.5d.6b, ld.2e.3c.4e.5d.6c, ld.2e.3c.4e.5d.6d, ld.2e.3c.4e.5d.6e, ld.2e.3c.4e.5d.6f, ld.2e.3c.4e.5e.6a, ld.2e.3c.4e.5e.6b, ld.2e.3c.4e.5e.6c, ld.2e.3c.4e.5e.6d, ld.2e.3c.4e.5e.6e, ld.2e.3c.4e.5e.6f, ld.2e.3c.4e.5f.6a, ld.2e3c.4e.5f.6b, ld.2e.3c.4e.5f.6c, ld.2e.3c.4e.5f.6d, ld.2e.3c.4e.5f.6e, ld.2e.3c.4e.5f.6f, ld.2e.3c.4f.5a.6a, ld.2e.3c.4f.5a.6b, ld.2e.3c.4f.5a.6c, ld.2e.3c.4f.5a.6d, ld.2e.3c.4f.5a.6e, ld.2e.3c.4f.5a.6f, ld.2e.3c.4f.5b.6a, ld.2e3c.4f.5b.6b, ld.2e.3c.4f.5b.6c, ld.2e.3c.4f.5b.6d, ld.2e.3c.4f.5b.6e, ld.2e.3c.4f.5b.6f, ld.2e.3c.4f.5c.6a, ld.2e.3c.4f.5c.6b, ld.2e.3c.4f.5c.6c, ld.2e.3c.4f.5c.6d, ld.2e.3c.4f.5c.6e, ld.2e.3c.4f.5c.6f, ld.2e.3c.4f.5d.6a, ld.2e.3c.4f.5d.6b, ld.2e.3c.4f.5d.6c, ld.2e.3c.4f.5d.6d, ld.2e.3c.4f.5d.6e, ld.2e.3c.4f.5d.6f, ld.2e.3c.4f.5e.6a, ld.2e.3c.4f.5e.6b, ld.2e.3c.4f.5e.6c, ld.2e.3c.4f.5e*6d, ld.2e.3c.4f.5e.6e, ld.2e.3c.4f.5e.6f, ld.2e.3c.4f.5f.6a, ld.2e.3c.4f.5f.6b, ld.2e.3c.4f.5f.6c, ld.2e.3c.4f.5f.6d, ld.2e.3c.4f.5f.6e, ld.2e.3c.4f.5f.6f, ld.2e.3d.4a.5a.6a, ld.2e.3d.4a.5a.6b, ld.2e.3d.4a.5a.6c, ld.2e.3d.4a.5a.6d, ld.2e.3d.4a.5a.6e, ld.2e.3d.4a.5a.6f, ld.2e.3d.4a.5b.6a, ld.2e.3d.4a.5b.6b, ld.2e.3d.4a.5b.6c, ld.2e.3d.4a.5b.6d, ld.2e.3d.4a.5b.6e, ld.2e.3d.4a.5b.6f, ld.2e.3d.4a.5c.6a, ld.2e.3d.4a.5c.6b, ld.2e.3d.4a.5c.6c, ld.2e.3d.4a.5c.6d, ld.2e.3d.4a.5c.6e, ld.2e.3d.4a.5c.6f, ld.2e.3d.4a.5d.6a, ld.2e.3d.4a.5d.6b, ld.2e.3d.4a.5d.6c, ld.2e.3d.4a.5d.6d, ld.2e.3d.4a.5d.6e, ld.2e.3d.4a.5d.6f, ld.2e.3d.4a.5e.6a, ld.2e.3d.4a.5e.6b, ld.2e.3d.4a.5e.6cr ld.2e.3d.4a.5e.6d, ld.2e.3d.4a.5e.6e, ld.2e.3d.4a.5e.6f, ld.2e.3d.4a.5f.6a, ld.2e.3d.4a.5f.6b, ld.2e.3d.4a.5f.6c, ld.2e.3d.4a.5f.6d, ld.2e.3d.4a.5f.6e, ld.2e.3d.4a.5f.6f, ld.2e.3d.4b.5a.6a, -276- 200918507 ld.2e.3d.4b.5a.6b, ld.2e.3d.4b.5a.6c, ld.2e.3d.4b.5a.6d, ld.2e.3d.4b.5a.6e, ld.2e.3d.4b.5a.6f, ld.2e.3d.4b.5b.6a, ld.2e.3d.4b.5b.6b, ld.2e.3d.4b.5b.6c, ld.2e.3d.4b.5b.6d, ld.2e.3d.4b.5b.6e, ld.2e.3d.4b.5b.6f, ld.2e.3d.4b.5c.6a, ld.2e.3d.4b.5c.6b, ld.2e.3d.4b.5c.6c, ld.2e.3d.4b.5c.6d, ld.2e.3d.4b.5c.6e, ld,2e.3d.4b.5c.6f, ld.2e.3d.4b.5d*6a, ld.2e.3d.4b.5d.6b, ld.2e.3d.4b.5d.6c, ld.2e.3d.4b.5d.6d, ld.2e.3d.4b.5d.6e, ld.2e.3d.4b.5d.6f, ld.2e.3d.4b.5e.6a, ld.2e3d.4b.5e.6b, ld.2e.3d.4b.5e.6c, ld.2e.3d.4b.5e.6d, ld.2e.3d.4b.5e.6e, ld.2e.3d.4b.5e.6f, ld.2e.3d.4b.5f.6a, ld.2e.3d.4b.5f.6b, ld.2e.3d.4b.5f.6c, ld.2e.3d.4b.5f.6d, ld.2e.3d.4b.5f.6e, ld.2e.3d.4b.5f.6f, ld.2e.3d.4c.5a.6a, ld.2e.3d.4c.5a.6b, ld.2e.3d.4c.5a.6c, ld.2e.3d.4c.5a.6d, ld.2e.3d.4c.5a.6e, ld.2e.3d.4c.5a.6f, ld.2e.3d.4c.5b.6a, ld.2e.3d.4c.5b.6b, ld.2e.3d.4c.5b.6c, ld.2e.3d.4c.5b.6d, ld.2e.3d.4c.5b.6e, ld.2e.3d.4c.5b.6f, ld.2e.3d.4c.5c.6a, ld.2e.3d.4c.5c.6b, ld.2e.3d.4c.5c.6c, ld.2e.3d.4c.5c.6d, ld.2e.3d.4c.5c.6e, ld.2e.3d.4c.5c.6f, ld.2e.3d.4c.5d.6a, ld.2e.3d.4c.5d.6b, ld.2e.3d.4c.5d.6c, ld.2e.3d.4c.5d.6d, ld.2e.3d.4c.5d.6e, ld.2e3d.4c.5d.6f, ld.2e.3d.4c.5e.6a, ld.2e.3d.4c.5e.6b, ld.2e.3d.4c.5e.6c, ld.2e.3d.4c.5e.6d, ld.2e.3d.4c.5e.6e, ld.2e.3d.4c.5e.6f, ld.2e.3d.4c.5f.6a, ld.2e.3d.4c.5f.6b, ld.2e.3d.4c.5f.6c, ld.2e.3d.4c.5f.6d, ld.2e.3d.4c.5f.6e, ld.2e.3d.4c.5f.6f, ld.2e.3d.4d.5a.6a, ld.2e.3d.4d.5a.6b, ld.2e.3d.4d.5a.6c, ld.2e.3d.4d.5a.6d, ld.2e.3d.4d.5a.6e, ld.2e.3d.4d.5a.6f, ld.2e.3d.4d.5b.6a, ld.2e.3d.4d.5b.6b, ld.2e.3d.4d.5b.6c, ld.2e.3d.4d.5b.6d, ld.2e.3d.4d.5b.6e, ld.2e.3d.4d.5b.6f, ld.2e.3d.4d.5c.6a, ld.2e.3d.4d.5c.6b, ld.2e.3d.4d.5c.6c, ld.2e.3d.4d.5c.6d, ld.2e.3d.4d.5c.6e, ld.2e.3d.4d.5c.6f, ld.2e.3d.4d.5d.6a, ld.2e.3d.4d.5d.6b, ld.2e.3d.4d.5d.6c, ld.2e.3d.4d.5d.6d, ld.2e.3d.4d.5d.6e, ld.2e.3d.4d.5d.6f, ld.2e.3d.4d.5e.6a, ld.2e.3d.4d.5e.6b, ld.2e.3d.4d.5e.6c, ld.2e.3d.4d.5e.6d, ld.2e.3d.4d.5e.6e, ld.2e.3d.4d.5e.6f, ld.2e.3d.4d.5f.6a, ld.2e.3d.4d.5f.6b, ld.2e.3d.4d.5f.6c, ld.2e.3d.4d.5f.6d, ld.2e.3d.4d.5f.6e, ld.2e.3d.4d.5f.6f, ld.2e.3d.4e.5a.6a, ld.2e.3d.4e.5a.6b, ld.2e.3d.4e.5a.6c, ld.2e.3d.4e.5a.6d, ld.2e.3d.4e.5a.6e, ld.2e.3d.4e.5a.6f, ld.2e.3d.4e.5b.6a, ld.2e.3d.4e.5b.6b, ld.2e.3d.4e.5b.6c, ld.2e.3d.4e.5b.6d, ld.2e.3d.4e.5b.6e, ld.2e.3d.4e.5b.6f, ld.2e.3d.4e.5c.6a, ld.2e.3d.4e.5c.6b, ld.2e.3d.4e.5c.6c, ld.2e.3d.4e.5c.6d, ld.2e.3d.4e.5c.6e, ld.2e.3d.4e.5c.6f, ld.2e.3d.4e.5d.6a, ld.2e.3d.4e.5d.6b, ld.2e.3d.4e.5d.6c, ld.2e.3d.4e.5d.6d, ld,2e.3d.4e.5d.6e, ld.2e.3d.4e.5d.6f, ld.2e.3d.4e.5e.6a, ld.2e.3d.4e.5e.6b, ld.2e.3d.4e.5e.6c, ld.2e.3d.4e.5e.6d, ld.2e.3d.4e.5e.6e, ld.2e.3d.4e.5e.6f, ld.2e.3d.4e.5f.6a, ld.2e.3d.4e.5f.6b, ld.2e.3d.4e.5f.6c, ld.2e.3d.4e.5f.6d, ld.2e.3d.4e.5f.6e, ld.2e.3d.4e.5f.6f, ld.2e.3d.4f.5a.6a, ld.2e.3d.4f.5a.6b, ld.2e.3d.4f.5a.6c, ld.2e.3d.4f.5a.6d, ld.2e3d.4f.5a.6e, ld.2e.3d.4f.5a.6f; ld.2e.3d.4f.5b.6a, ld.2e.3d.4f.5b.6b, ld.2e.3d.4f.5b.6c, ld.2e.3d.4f.5b.6d, ld.2e.3d.4f.5b.6e, ld.2e.3d.4f.5b.6f, ld.2e.3d.4f.5c.6a, ld.2e.3d.4f.5c.6b, ld.2e.3d.4f.5c.6c, ld.2e.3d.4f.5c.6d, ld.2e.3d.4f.5c.6e, ld.2e.3d.4f.5c.6f, ld.2e.3d.4f.5d.6a, ld.2e.3d.4f.5d.6b, ld.2e.3d.4f.5d.6c, ld.2e.3d.4f.5d.6d, ld.2e.3d.4f.5d.6e, ld.2e.3d.4f.5d.6f, ld.2e.3d.4f.5e.6a, -277- 200918507 ld.2e.3d.4f.5e.6b, ld.2e.3d.4f.5e.6c, ld.2e.3d.4f.5e.6d, ld.2e.3d.4f.5e.6e, ld.2e.3d.4f.5e.6f, ld.2e.3d.4f.5f.6a, ld.2e.3d.4f.5f.6b, ld.2e.3d.4f.5f.6c, ld.2e.3d.4f.5f.6d, ld.2e.3d.4f.5f.6e, ld.2e.3d.4f.5f.6f, ld.2e.3e.4a.5a.6a, ld.2e.3e.4a.5a.6b, ld.2e.3e.4a.5a.6c, ld.2e.3e.4a.5a.6d, ld.2e.3e.4a.5a.6e, ld.2e.3e.4a.5a.6f, ld.2e.3e.4a.5b.6a, ld.2e.3e.4a.5b.6b, ld.2e.3e.4a.5b.6c, ld.2e.3e.4a.5b.6d, ld.2e.3e.4a.5b.6e, ld.2e.3e.4a.5b.6f, ld.2e.3e.4a.5c.6a, ld.2e.3e.4a.5c.6b, ld.2e.3e.4a.5c.6c, ld.2e.3e.4a.5c.6d, ld.2e.3e.4a.5c.6e, ld.2e.3e.4a.5c.6f, ld.2e.3e.4a.5d.6a, ld.2e.3e.4a.5d.6b, ld.2e.3e.4a.5d.6c, ld.2e.3e.4a.5d.6d, ld.2e.3e.4a.5d.6e, ld.2e.3e.4a.5d.6f, ld.2e.3e.4a.5e.6a, ld.2e.3e.4a.5e.6b, ld.2e.3e.4a.5e.6c, ld.2e.3e.4a.5e.6d, ld.2e.3e.4a.5e.6e, ld.2e.3e.4a.5e.6f, ld.2e.3e.4a.5f.6a, ld.2e.3e.4a.5f.6b, ld.2e.3e.4a.5f.6c, ld.2e.3e.4a.5f.6d, ld.2e.3e.4a.5f.6e, ld.2e.3e.4a.5f.6f, ld.2e.3e.4b.5a.6a, ld.2e.3e.4b.5a.6b, ld.2e.3e.4b.5a.6c, ld.2e.3e.4b.5a.6d, ld.2e.3e.4b.5a.6e, ld.2e.3e.4b.5a.6f, ld.2e.3e.4b.5b.6a, ld.2e.3e.4b.5b.6b, ld.2e.3e.4b.5b.6c, ld.2e.3e.4b.5b.6d, ld.2e.3e.4b.5b.6e, ld.2e.3e.4b.5b.6f, ld.2e.3e.4b.5c.6a, ld.2e.3e.4b.5c.6b, ld.2e.3e.4b.5c.6c, ld.2e.3e.4b.5c.6d, ld.2e.3e.4b.5c.6e, ld.2e.3e.4b.5c.6f, ld.2e.3e.4b.5d.6a, ld.2e.3e.4b.5d.6b, ld.2e.3e.4b.5d.6c, ld.2e.3e.4b.5d.6d, ld.2e.3e.4b.5d.6e, ld.2e.3e.4b.5d.6f, ld.2e.3e.4b.5e.6a, ld.2e.3e.4b.5e.6b, ld.2e.3e.4b.5e.6c, ld.2e.3e.4b.5e.6d, ld.2e.3e.4b.5e.6e, ld.2e.3e.4b.5e.6f, ld.2e.3e.4b.5f.6a, ld.2e.3e.4b.5f.6b, ld.2e.3e.4b.5f.6c, ld.2e.3e.4b.5f.6d, ld.2e.3e.4b.5f.6e, ld.2e.3e.4b.5f.6f, ld.2e.3e.4c.5a.6a, ld.2e.3e.4c.5a.6b, ld.2e.3e.4c.5a.6c, ld.2e.3e.4c.5a.6d, ld.2e.3e.4c.5a.6e, ld.2e.3e.4c.5a.6f, ld.2e.3e.4c.5b.6a, ld.2e.3e.4c.5b.6b, ld.2e.3e.4c.5b.6c, ld.2e.3e.4c.5b.6d, ld.2e.3e.4c.5b.6e, ld.2e.3e.4c.5b.6f, ld.2e.3e.4c.5c.6a, ld.2e.3e.4c.5c.6b, ld.2e.3e.4c.5c.6c, ld.2e.3e.4c.5c.6d, ld.2e.3e.4c.5c.6e, ld.2e.3e.4c.5c.6f, ld.2e.3e.4c.5d.6a, ld-2e.3e.4c.5d.6b, ld.2e.3e.4c.5d.6c, ld.2e.3e.4c.5d.6d, ld.2e.3e.4c.5d.6e, ld.2e.3e.4c.5d.6f, ld.2e.3e.4c.5e.6a, ld.2e.3e.4c.5e.6b, ld.2e.3e.4c.5e.6c, ld.2e.3e.4c.5e.6d, ld.2e.3e.4c.5e.6e, ld.2e.3e.4c.5e.6f, ld.2e.3e.4c.5f.6a, ld.2e.3e.4c.5f.6b, ld.2e.3e.4c.5f.6c, ld.2e.3e.4c.5f.6d, ld.2e.3e.4c.5f.6e, ld.2e.3e.4c.5f.6f, ld.2e.3e.4d.5a.6a, ld.2e.3e.4d.5a.6b, ld.2e.3e.4d.5a.6c, ld.2e.3e.4d.5a.6d, ld.2e.3e.4d.5a.6e, ld.2e.3e.4d.5a.6f, ld.2e.3e.4d.5b.6a, ld.2e.3e.4d.5b.6b, ld.2e.3e.4d.5b.6c, ld.2e.3e.4d.5b.6d, ld.2e.3e.4d.5b.6e, ld.2e.3e.4d.5b.6f, ld.2e.3e.4d.5c.6a, ld.2e.3e.4d.5c.6b, ld.2e.3e.4d.5c.6c, ld.2e.3e.4d.5c.6d, ld.2e.3e.4d.5c.6e, ld.2e.3e.4d.5c.6f, ld.2e.3e.4d.5d.6a, ld.2e.3e.4d.5d.6b, ld.2e.3e.4d.5d.6c, ld.2e.3e.4d.5d.6d, ld.2e.3e.4d.5d.6e, ld.2e.3e.4d.5d.6f, ld.2e.3e.4d.5e.6a, ld.2e.3e.4d.5e.6b; ld.2e.3e.4d.5e.6c, ld.2e.3e.4d.5e.6d, ld.2e.3e.4d.5e.6er ld.2e.3e.4d.5e.6f, ld.2e.3e.4d.5f.6a, ld.2e.3e.4d.5f.6b, ld.2e.3e.4d.5f.6c, ld.2e.3e.4d.5f.6d, ld.2e.3e.4d.5f.6e, ld.2e.3e.4d.5f.6f, ld.2e.3e.4e.5a.6a, ld.2e.3e.4e.5a.6b, ld.2e.3e.4e.5a.6c, ld.2e.3e.4e.5a.6d, ld*2e.3e.4e.5a.6e, ld.2e.3e.4e.5a.6f, ld.2e.3e.4e.5b.6a, ld.2e.3e.4e.5b.6b, ld.2e.3e.4e.5b.6c, ld.2e.3e.4e.5b.6d, ld.2e.3e.4e.5b.6e, ld.2e.3e.4e.5b.6f, ld.2e.3e.4e.5c.6a, ld.2e.3e.4e.5c.6b, -278- 200918507 ld.2e.3e.4e.5c.6c, ld.2e.3e.4e.5c.6d, ld.2e.3e.4e.5c.6e, ld.2e.3e.4e.5c.6f, ld.2e.3e.4e.5d.6a, ld.2e.3e.4e.5d.6b, ld.2e3e.4e.5d.6c, ld.2e.3e.4e3d.6d, ld^e.Se^e.Sd.ee, ld.2e.3e.4e.5d.6f, ld.2e.3e.4e.5e.6a, ld.2e.3e.4e.5e.6b, ld.2e.3e.4e.5e.6c, ld.2e.3e.4e.5e.6d, ld.2e.3e.4e.5e.6e, ld.2e.3e.4e.5e.6f, ld.2e.3e.4e.5f.6a, ld.2e.3e.4e.5f.6b, ld.2e.3e.4e.5f.6c, ld.2e.3e.4e.5f.6d, ld.2e.3e-4e.5f.6e, ld.2e.3e.4e.5f.6f, ld.2e.3e.4f.5a.6a, ld.2e.3e.4f.5a.6b, ld.2e.3e.4f.5a.6c, ld.2e.3e.4f.5a.6d, ld.2e.3e.4f.5a.6e, ld.2e.3e.4f.5a.6f, ld.2e.3e.4f.5b.6a, ld.2e.3e.4f.5b.6b, ld.2e.3e.4f.5b.6c, ld.2e.3e.4f.5b.6d, ld.2e.3e.4f.5b.6e, ld.2e.3e.4f.5b.6f, ld.2e.3e.4f.5c.6a, ld.2e.3e.4f.5c.6b, ld.2e.3e.4f.5c.6c, ld.2e.3e.4f.5c.6d, ld.2e.3e.4f.5c.6e, ld.2e.3e.4f.5c.6f, ld.2e.3e.4f.5d.6a, ld.2e.3e.4f.5d.6b, ld.2e.3e.4f.5d.6c, ld.2e.3e.4f.5d.6d, ld.2e.3e.4f.5d.6e, ld.2e.3e.4f.5d.6f, ld.2e.3e.4f.5e.6a, ld.2e.3e.4f.5e.6b, ld.2e.3e.4f.5e.6c, ld.2e.3e.4f.5e.6d, ld.2e.3e.4f.5e.6e, ld.2e.3e.4f.5e.6f, ld.2e.3e.4f.5f.6a, ld.2e.3e.4f.5f.6b, ld.2e.3e.4f.5f.6c, ld.2e.3e.4f.5f.6d, ld.2e.3e.4f.5f.6e, ld.2e.3e.4f.5f.6f, ld.2e.3f.4a.5a.6a, ld.2e.3f.4a.5a.6b, ld.2e.3f.4a.5a.6c, ld.2e.3f.4a.5a.6d, ld.2e.3f.4a.5a.6e, ld.2e.3f.4a.5a.6f, ld.2e.3f.4a.5b.6a, ld.2e.3f.4a.5b.6b, ld.2e.3f.4a.5b.6c, ld.2e.3f.4a.5b.6d, ld.2e.3f.4a.5b.6e, ld.2e.3f.4a.5b.6f, ld.2e.3f.4a.5c.6a, ld.2e.3f.4a.5c.6b, ld.2e.3f.4a.5c.6c, ld.2e.3f.4a.5c.6d, ld.2e.3f.4a.5c.6e, ld.2e.3f.4a.5c.6f, ld.2e.3f.4a.5d.6a, ld.2e.3f.4a.5d.6b, ld.2e.3f.4a.5d.6c, ld.2e.3f.4a.5d.6d, ld.2e.3f.4a.5d.6e, ld.2e.3f.4a.5d.6f, ld.2e.3f.4a.5e.6a, ld.2e.3f.4a.5e.6b, ld.2e.3f.4a.5e.6c, ld.2e.3f.4a.5e.6d, ld.2e.3f.4a.5e.6e, ld.2e.3f.4a.5e.6f, ld.2e.3f.4a.5f.6a, ld.2e.3f.4a.5f.6b, ld.2e.3f.4a.5f.6c, ld.2e.3f.4a.5f.6d, ld.2e.3f.4a.5f.6e, ld.2e.3f.4a.5f.6f, ld.2e.3f.4b.5a.6a, ld.2e.3f.4b.5a.6b, ld.2e.3f.4b.5a.6c, ld.2e.3f.4b.5a.6d, ld.2e.3f.4b.5a.6e, ld.2e.3f.4b.5a.6f, ld.2e.3f.4b.5b.6a, ld.2e.3f.4b.5b.6b, ld.2e.3f.4b.5b.6c, ld.2e.3f.4b.5b.6d, ld.2e.3f.4b.5b.6e, ld.2e.3f.4b.5b.6f, ld.2e.3f.4b.5c.6a, ld.2e.3f.4b.5c.6b, ld.2e.3f.4b.5c.6c, ld.2e.3f.4b.5c.6d, ld.2e.3f.4b.5c.6e, ld.2e.3f.4b.5c.6f, ld.2e.3f.4b.5d.6a, ld.2e.3f.4b.5d.6b, ld.2e.3f.4b.5d.6c, ld.2e.3f.4b.5d.6d, ld.2e.3f.4b.5d.6e, ld.2e.3f.4b.5d.6f, ld.2e.3f.4b.5e.6a, ld.2e.3f.4b.5e.6b, ld.2e.3f.4b.5e.6c, ld.2e.3f.4b.5e.6d, ld.2e.3f.4b.5e.6e, ld.2e.3f.4b.5e.6f, ld.2e.3f.4b.5f.6a, ld.2e.3f.4b.5f.6b, ld.2e.3f.4b.5f.6c, ld.2e.3f.4b.5f.6d, ld.2e.3f.4b.5f.6e, ld.2e.3f.4b.5f.6f, ld.2e.3f.4c.5a.6a, ld.2e.3f.4c.5a.6b, ld.2e.3f.4c.5a.6c, ld.2e.3f.4c.5a.6d, ld.2e.3f.4c.5a.6e, ld.2e.3f.4c.5a.6f, ld.2e.3f.4c.5b.6a, ld.2e.3f.4c.5b.6b, ld.2e.3f.4c.5b.6c, ld.2e.3f.4c.5b.6d, ld.2e.3f.4c.5b.6e, ld.2e.3f.4c.5b.6f, ld.2e.3f.4c.5c.6a, ld.2e.3f.4c.5c.6b, ld.2e.3f.4c.5c.6c, ld.2e.3f.4c.5c.6d, ld.2e.3f.4c.5c.6e, ld.2e.3f.4c_5c.6f, ld.2e.3f.4c.5d_6a, ld.2e.3f.4c.5d.6b, ld.2e.3f.4c.5d.6c, ld.2e.3f.4c.5d.6d, ld.2e.3f.4c.5d.6e, ld.2e.3f.4c.5d.6f, ld.2e.3f.4c.5e.6a, ld.2e.3f.4c.5e.6b, ld.2e.3f.4c.5e.6c, ld.2e3f.4c.5e.6d, ld.2e.3f.4c.5e.6e, ld.2e.3f.4c.5e.6f, ld.2e.3f.4c.5f.6a, ld.2e.3f.4c.5f.6b, ld.2e.3f.4c.5f.6c, ld.2e.3f.4c.5f.6d, ld.2e.3f.4c.5f.6e, ld.2e.3f.4c.5f.6f, ld.2e.3f.4d.5a.6a, ld.2e.3f.4d.5a.6b, ld.2e.3f.4d.5a.6c, ld.2e.3f.4d.5a.6d, ld.2e.3f.4d.5a*6e, ld.2e.3f.4d.5a.6f, ld.2e.3f.4d.5b.6a, ld.2e.3f.4d.5b.6b, ld.2e.3f.4d.5b.6c, ld.2e.3f.4d.5b.6d, ld.2e.3f.4d.5b.6e, ld.2e.3f.4d.5b,6f, ld.2e.3f.4d.5c.6a, ld-2e.3f.4d.5c.6b, ld.2e.3f.4d.5c.6c, -279- 200918507 ld.2e.3f.4d.5c.6d, ld.2e.3f.4d.5c.6e, ld.2e.3f.4d.5c.6f, ld.2e.3f.4d.5d.6a, ld.2e.3f.4d.5d.6b, ld.2e3f.4d.5d.6c, ld.2e.3f.4d.5d.6d, ld.2e.3f.4d.5d.6e, ld.2e.3f.4d.5d.6f, ld.2e.3f.4d.5e.6a, ld.2e.3f.4d.5e.6b, ld.2e.3f.4d.5e.6c, ld.2e.3f.4d.5e.6d, ld.2e.3f.4d.5e.6e, ld.2e.3f.4d.5e.6f, ld.2e.3f.4d.5f.6a, ld.2e.3f.4d.5f.6b/ ld.2e.3f.4d.5f.6c, ld.2e.3f.4d.5f.6d, ld.2e.3f.4d.5f.6e, ld.2e.3f.4d.5f.6f, ld.2e.3f.4e.5a.6a, ld.2e.3f.4e.5a.6b, ld.2e.3f.4e.5a.6c, ld.2e.3f.4e.5a.6d, ld.2e.3f.4e.5a.6e, ld.2e.3f.4e.5a.6f/ld.2e.3f.4e.5b.6a, ld.2e.3f.4e.5b.6b, ld.2e.3f.4e.5b.6c, ld.2e.3f.4e.5b.6d, ld.2e.3f.4e.5b.6e, ld.2e.3f.4e.5b.6f, ld.2e.3f.4e.5c.6a, ld.2e.3f.4e.5c.6b, ld.2e.3f.4e.5c.6c, ld.2e.3f.4e.5c.6d, ld.2e.3f.4e.5c.6e, ld.2e.3f.4e.5c.6f, ld.2e.3f.4e.5d.6a, ld.2e.3f.4e.5d.6b, ld.2e.3f.4e.5d.6c, ld.2e.3f.4e.5d.6d, ld.2e.3f.4e.5d.6e, ld.2e.3f.4e.5d.6f, ld.2e.3f.4e.5e.6a, ld.2e.3f.4e.5e.6b, ld.2e.3f.4e.5e.6c, ld.2e.3f.4e.5e.6d, ld.2e.3f.4e.5e.6e, ld.2e.3f.4e.5e.6f, ld.2e.3f.4e.5f.6a, ld.2e.3f.4e.5f.6b, ld.2e.3f.4e.5f.6c, ld.2e.3f.4e.5f.6d, ld.2e.3f.4e.5f.6e, ld.2e.3f.4e.5f.6f, ld.2e.3f.4f.5a.6a, ld.2e.3f.4f.5a.6b, ld.2e.3f.4f.5a.6c, ld.2e.3f.4f.5a.6d, ld.2e.3f.4f.5a.6e, ld.2e.3f.4f.5a.6f, ld.2e.3f.4f.5b.6a, ld.2e.3f.4f.5b.6b, ld.2e.3f.4f.5b.6c, ld.2e.3f.4f.5b.6d, ld.2e.3f.4f.5b.6e, ld.2e.3f.4f.5b.6f, ld.2e.3f.4f.5c.6ar ld.2e.3f.4f.5c.6b, ld.2e.3f.4f.5c.6c, ld.2e.3f.4f.5c.6d, ld.2e.3f.4f.5c.6e, ld.2e.3f.4f.5c.6f, ld.2e.3f.4f.5d.6a, ld.2e.3f.4f.5d.6b, ld.2e.3f.4f.5d.6c, ld.2e.3f.4f.5d.6d, ld.2e.3f.4f.5d.6e, ld.2e.3f.4f.5d.6f, ld.2e.3f.4f.5e.6a, ld.2e.3f.4f.5e.6b, ld.2e.3f.4f.5e.6c, ld.2e.3f.4f.5e.6d, ld.2e.3f.4f.5e.6e,, ld.2e.3f.4f.5e.6f, ld.2e.3f.4f.5f.6a, ld.2e.3f.4f.5f.6b, ld.2e.3f.4f.5f.6c, ld.2e.3f.4f.5f.6d, ld.2e.3f.4f.5f.6e, ld.2e.3f.4f.5f.6f, ld.2f.3a.4a.5a.6a, ld.2f.3a.4a.5a.6b, ld.2f.3a.4a.5a.6c, ld.2f.3a.4a.5a.6d, ld.2f.3a.4a.5a.6e, ld.2f.3a.4a.5a.6f, ld.2f.3a.4a.5b.6a, ld.2f.3a.4a.5b.6b, ld.2f.3a.4a.5b.6c, ld.2f.3a.4a.5b.6d, ld.2f.3a.4a.5b.6e, ld.2f.3a.4a.5b.6f, ld.2f.3a.4a.5c.6a, ld.2f.3a.4a.5c.6b, ld.2f.3a.4a.5c.6c, ld.2f.3a.4a.5c.6d, ld.2f.3a.4a.5c.6e, ld.2f.3a.4a.5c.6f, ld.2f.3a.4a.5d.6a, ld.2f.3a.4a.5d.6b, ld.2f.3a.4a.5d.6c, ld.2f.3a.4a.5d.6d, ld.2f.3a.4a.5d.6e, ld.2f.3a.4a.5d.6f, ld.2f.3a.4a.5e.6a, ld.2f.3a.4a.5e.6b, ld.2f.3a.4a.5e.6c, ld.2f.3a.4a.5e.6d, ld.2f.3a.4a.5e.6e, ld.2f.3a.4a.5e.6f, ld.2f.3a.4a.5f.6a, ld.2f.3a.4a.5f.6b, ld.2f.3a.4a.5f.6c, ld.2f.3a.4a.5f.6d, ld.2f.3a.4a.5f.6e, ld.2f.3a.4a.5f.6f, ld.2f.3a.4b.5a.6a, ld.2f.3a.4b.5a.6b, ld.2f.3a.4b.5a.6c, ld.2f.3a.4b.5a.6d, ld.2f.3a.4b.5a.6e, ld.2f.3a.4b.5a.6f, ld.2f.3a.4b.5b.6a, ld.2f.3a.4b.5b.6b, ld.2f.3a.4b.5b.6c, ld.2f.3a.4b.5b.6d, ld.2f.3a.4b.5b.6e, ld.2f.3a.4b.5b.6f, ld.2f.3a.4b.5c.6a, ld.2f.3a.4b.5c.6b, ld.2f.3a.4b.5c.6c, ld.2f.3a.4b.5c.6d, ld.2f.3a.4b.5c.6e, ld.2f.3a.4b.5c.6f, ld.2f.3a.4b.5d.6a, ld.2f.3a.4b.5d.6b, ld.2f.3a.4b.5d.6c, ld.2f.3a.4b.5d.6d, ld.2f.3a.4b.5d.6e, ld.2f.3a.4b.5d.6f, ld.2f.3a.4b.5e.6a, ld.2f.3a.4b.5e.6b, ld.2f.3a.4b.5e.6c, ld_2f.3a.4b.5e.6d, ld.2f.3a.4b.5e.6e, ld.2f.3a.4b.5e.6f, ld.2f.3a.4b.5f.6a, ld.2f.3a.4b.5f.6b, ld.2f.3a.4b.5f.6c, ld.2f.3a.4b.5f.6d, ld.2f.3a.4b.5f.6e, ld.2f.3a.4b.5f.6f, ld.2f.3a.4c.5a.6a, ld.2f.3a.4c.5a.6b, ld.2f.3a.4c.5a.6c, ld.2f.3a.4c.5a.6d, ld.2f.3a.4c.5a.6e, ld.2f.3a.4c.5a.6f, ld.2f.3a.4c.5b.6a, ld.2f.3a.4c.5b.6b, ld.2f.3a.4c.5b.6c, ld.2f.3a.4c.5b.6d, ld.2f.3a.4c.5b.6e, ld.2f.3a.4c.5b.6f, ld.2f.3a.4c.5c.6a, ld.2f.3a.4c.5c.6b, ld.2f.3a.4c.5c.6c, ld.2f.3a.4c.5c.6d, ld.2f.3a.4c.5c.6e, ld.2f.3a.4c.5c.6f, ld.2f.3a.4c.5d.6a, ld.2f.3a.4c.5d.6b. -280- 200918507 ld.2f.3a.4c.5d.6c, ld.2f.3a.4c.5d.6d, ld.2f.3a.4c.5d.6e, ld.2f.3a.4c.5d.6f, ld.2f.3a.4c.5e.6a, ld.2f.3a.4c5e.6b, ld.2f.3a.4c.5e.6c, ld.2f*3a.4c.5e.6d, ld.2f.3a.4c.5e.6e, ld.2f.3a.4c.5e.6f, ld.2f.3a.4c.5f.6a, ld.2f.3a.4c.5f.6b, ld.2f.3a.4c.5f.6c, ld.2f.3a.4c.5f.6d, ld.2f.3a.4c.5f.6e, ld.2f.3a.4c.5f.6f, ld.2f.3a.4d.5a.6a, ld.2f.3a.4d.5a.6b, ld.2f3a.4d.5a.6c, ld.2f.3a.4d.5a.6d, ld.2f.3a.4d.5a.6e, ld.2f.3a.4d.5a.6f, ld.2f.3a.4d.5b.6a, ld.2f.3a.4d.5b.6b, ld.2f.3a.4d.5b.6c, ld.2f.3a.4d.5b.6d, ld.2f.3a.4d.5b.6e, ld.2f.3a.4d.5b.6f, ld.2f.3a.4d.5c.6a, ld.2f.3a.4d.5c.6b, ld.2f.3a.4d.5c.6c, ld.2f.3a.4d.5c.6d, ld.2f.3a.4d.5c.6e, ld.2f.3a.4d.5c.6f, ld.2f.3a.4d.5d.6a, ld.2f.3a.4d.5d.6b, ld.2f.3a.4d.5d.6c, ld.2f.3a.4d.5d.6d, ld.2f.3a.4d.5d.6e, ld.2f.3a.4d.5d.6f, ld.2f.3a.4d.5e.6a, ld.2f.3a.4d.5e.6b, ld.2f.3a.4d.5e.6c, ld.2f.3a.4d.5e.6d, ld.2f.3a.4d.5e.6e, ld.2f.3a.4d.5e.6f, ld.2f.3a.4d.5f.6a, ld.2f.3a.4d.5f.6b, ld.2f.3a.4d.5f.6c, ld.2f.3a.4d.5f.6d, ld.2f.3a.4d.5f.6e, ld.2f.3a.4d.5f.6f, ld.2f.3a.4e.5a.6a, ld.2f.3a.4e.5a.6b, ld.2f.3a.4e.5a.6c, ld.2f.3a.4e.5a.6d, ld.2f.3a.4e.5a.6e, ld.2f.3a.4e.5a.6f, ld.2f.3a.4e.5b.6a, ld.2f.3a.4e.5b.6b, ld.2f.3a.4e.5b.6c, ld.2f.3a.4e.5b.6d, ld.2f.3a.4e.5b.6e, ld.2f.3a.4e.5b.6f, ld.2f.3a.4e.5c.6a, ld.2f.3a.4e.5c.6b, ld.2f.3a.4e.5c.6c, ld.2f.3a.4e.5c.6d, ld.2f.3a.4e.5c.6e, ld.2f.3a.4e.5c.6f, ld.2f.3a.4e.5d.6a, ld.2f.3a.4e.5d.6b, ld.2f.3a.4e.5d.6c, ld.2f.3a.4e.5d.6d, ld.2f.3a.4e.5d.6e, ld.2f.3a.4e.5d.6f, ld.2f.3a.4e.5e.6a, ld.2f.3a.4e.5e.6b, ld.2f.3a.4e.5e.6c, ld.2f.3a.4e.5e.6d, ld.2f.3a.4e.5e.6e, ld.2f.3a.4e.5e.6f, ld.2f.3a.4e.5f.6a, ld.2f.3a.4e.5f.6b, ld.2f.3a.4e.5f.6c, ld.2f.3a.4e.5f.6d, ld.2f.3a.4e.5f.6e, ld.2f.3a.4e.5f.6f, ld.2f.3a.4f.5a.6ar ld.2f.3a.4f.5a.6b, ld.2f.3a.4f.5a.6c, ld.2f.3a.4f.5a.6d, ld.2f.3a.4f.5a.6e, ld.2f.3a.4f.5a.6f, ld.2f.3a.4f.5b.6a, ld.2f.3a.4f.5b.6b, ld.2f.3a.4f.5b.6c, ld.2f.3a.4f.5b.6d, ld.2f.3a.4f.5b.6e, ld.2f.3a.4f.5b.6f, ld.2f.3a.4f.5c.6a, ld.2f.3a.4f.5c.6b, ld.2f.3a.4f.5c.6c, ld.2f.3a.4f.5c.6d, ld.2f.3a.4f.5c.6e, ld.2f.3a.4f.5c.6f, ld.2f.3a.4f.5d.6a, ld.2f.3a.4f.5d.6b, ld.2f.3a.4f.5d.6c, ld.2f.3a.4f.5d.6d, ld.2f.3a.4f.5d.6e, ld.2f.3a.4f.5d.6f, ld.2f.3a.4f.5e.6a, ld.2f.3a.4f.5e.6b, ld.2f.3a.4f.5e.6c, ld.2f.3a.4f.5e.6d, ld.2f.3a.4f.5e.6e, ld.2f.3a.4f.5e.6f, ld.2f.3a.4f.5f.6a, ld.2f.3a.4f.5f.6b, ld.2f.3a.4f.5f.6c, ld.2f.3a.4f.5f.6d, ld.2f.3a.4f.5f.6e, ld.2f.3a.4f.5f.6f, ld.2f.3b.4a.5a.6a, ld.2f.3b.4a.5a.6b, ld.2f.3b.4a.5a.6c, ld.2f.3b.4a.5a.6d, ld.2f.3b.4a.5a.6e, ld.2f.3b.4a.5a.6f, ld.2f.3b.4a.5b.6a, ld.2f.3b.4a.5b.6b, ld.2f.3b.4a.5b.6c, ld.2f.3b.4a.5b.6d, ld.2f.3b.4a.5b.6e, ld.2f.3b.4a.5b.6f, ld.2f.3b.4a.5c.6a, ld.2f.3b.4a.5c.6b, ld.2f.3b.4a.5c.6c, ld.2f.3b.4a.5c.6d, ld.2f.3b.4a.5c.6e, ld.2f.3b.4a.5c.6f, ld.2f.3b.4a.5d.6a, ld.2f.3b.4a.5d.6b, ld.2f.3b.4a.5d.6c, ld.2f.3b.4a.5d.6d, ld.2f.3b.4a.5d.6e, ld.2f.3b.4a.5d.6f, ld.2f.3b.4a.5e.6a, ld.2f.3b.4a.5e.6b, ld.2f.3b.4a.5e.6c, ld.2f.3b.4a.5e.6d, ld.2f.3b.4a.5e.6e, ld.2f.3b.4a.5e.6f, ld.2f.3b.4a.5f.6a, ld.2f.3b.4a.5f.6b, ld.2f.3b.4a.5f.6c, ld.2f.3b.4a.5f.6d, ld.2f.3b.4a.5f.6e, ld.2f.3b.4a.5f.6f, ld.2f3b.4b.5a.6a, ld.2f.3b.4b.5a.6b, ld.2f.3b.4b.5a.6c, ld.2f.3b.4b.5a.6d, ld.2f.3b.4b.5a.6e, ld.2f.3b.4b.5a.6f, ld.2f.3b.4b.5b.6a, ld.2f.3b.4b.5b.6b, ld.2f.3b.4b.5b.6c, ld.2f.3b*4b.5b.6d, ld.2f.3b.4b.5b.6e, ld.2f.3b.4b.5b.6f, ld.2f.3b.4b.5c.6a, ld.2f.3b.4b.5c.6b, ld.2f.3b.4b.5c.6c, ld.2f.3b.4b.5c.6d, ld.2f.3b.4b.5c.6e, ld.2f.3b.4b.5c.6f, ld.2f.3b.4b.5d.6a, ld.2f.3b.4b.5d.6b, ld.2f.3b.4b.5d.6c, -281 - 200918507 ld.2f.3b.4b.5d.6d, ld.2f.3b.4b.5d.6e, ld.2f.3b.4b.5d.6f, ld.2f.3b.4b.5e.6a, ld.2f.3b.4b.5e.6b, ld.2f.3b.4b.5e.6c, ld.2f.3b.4b.5e.6dr ld.2f.3b.4b.5e.6e, ld.2f.3b.4b.5e.6f, ld.2f.3b.4b.5f.6a, ld.2f.3b.4b.5f.6b, ld.2f.3b.4b.5f.6c, ld.2f.3b.4b.5f.6d, ld.2f.3b.4b.5f.6e, ld.2f.3b.4b.5f.6f, ld.2f.3b.4c.5a.6a, ld.2f.3b.4c.5a.6b, ld.2f.3b.4c.5a.6c, ld.2f.3b.4c.5a.6d, ld.2f.3b.4c.5a.6e, ld.2f.3b.4c.5a.6f, ld.2f.3b.4c.5b.6a, ld.2f.3b.4c.5b.6b, ld.2f.3b.4c.5b.6c, ld.2f.3b.4c.5b.6d, ld.2f.3b.4c.5b.6e, ld.2f.3b.4c.5b.6f, ld.2f.3b.4c.5c.6a, ld.2f.3b.4c.5c.6b, ld.2f.3b.4c.5c.6c, ld.2f.3b.4c.5c.6d, ld.2f.3b.4c.5c.6e, ld.2f.3b.4c.5c.6f, ld.2f.3b.4c.5d.6a, ld.2f.3b.4c.5d.6b, ld.2f.3b.4c.5d.6c, ld.2f.3b.4c.5d.6d, ld.2f.3b.4c.5d.6e, ld.2f.3b.4c.5d.6f, ld.2f.3b.4c.5e.6a, ld.2f.3b.4c.5e.6b, ld.2f.3b.4c.5e.6c, ld.2f.3b.4c.5e.6d, ld.2f.3b.4c.5e.6e, ld.2f.3b.4c.5e.6f, ld.2f.3b.4c.5f.6a, ld.2f.3b.4c.5f.6b, ld.2f.3b.4c.5f.6c, ld.2f.3b.4c.5f.6d, ld.2f.3b.4c.5f.6e, ld.2f.3b.4c.5f.6f, ld.2f.3b.4d.5a.6a, ld.2f.3b.4d.5a.6b, ld.2f.3b.4d.5a.6c, ld.2f.3b.4d.5a.6d, ld.2f.3b.4d.5a.6e, ld.2f.3b.4d.5a.6f, ld.2f.3b.4d.5b.6a, ld.2f.3b.4d.5b.6b, ld.2f.3b.4d.5b.6c, ld.2f.3b.4d.5b.6d, ld.2f.3b.4d.5b.6e, ld.2f.3b.4d.5b.6f, ld.2f.3b.4d.5c.6a, ld.2f.3b.4d.5c.6b, ld.2f.3b.4d.5c.6c, ld.2f.3b.4d.5c.6d, ld.2f.3b.4d.5c.6e, ld.2f.3b.4d.5c.6f, ld.2f.3b.4d.5d.6a, ld.2f.3b.4d.5d.6b, ld.2f.3b.4d.5d.6c, ld.2f.3b.4d.5d.6d, ld.2f.3b.4d.5d.6e, ld.2f.3b.4d.5d.6f, ld.2f.3b.4d.5e.6a, ld.2f.3b.4d.5e.6b, ld.2f.3b.4d.5e.6c, ld.2f.3b.4d.5e.6d, ld.2f.3b.4d.5e.6e, ld.2f.3b.4d.5e.6f, ld.2f.3b.4d.5f.6a, ld.2f.3b.4d.5f.6b, ld.2f.3b.4d.5f.6c, ld.2f.3b.4d.5f.6d, ld.2f.3b.4d.5f.6e, ld.2f.3b.4d.5f.6f, ld.2f.3b.4e.5a.6a, ld.2f.3b.4e.5a.6b, ld.2f.3b.4e.5a.6c, ld.2f.3b.4e.5a.6d, ld.2f.3b.4e.5a.6e, ld.2f.3b.4e.5a.6f, ld.2f.3b.4e.5b.6a, ld.2f.3b.4e.5b.6b, ld.2f.3b.4e.5b.6c, ld.2f.3b.4e.5b.6d, ld.2f.3b.4e.5b.6e, ld.2f.3b.4e.5b.6f, ld.2f.3b.4e.5c.6a, ld.2f.3b.4e.5c.6b, ld.2f.3b.4e.5c.6c, ld.2f.3b.4e.5c.6d, ld.2f.3b.4e.5c.6e, ld.2f.3b.4e.5c.6f, ld.2f.3b.4e.5d.6a, ld.2f.3b.4e.5d.6b, ld.2f.3b.4e.5d.6c, ld.2f.3b.4e.5d.6d, ld.2f.3b.4e.5d.6e, ld.2f.3b.4e.5d.6f, ld.2f.3b.4e.5e.6a, ld.2f.3b.4e.5e.6b, ld.2f.3b.4e.5e.6c, ld.2f.3b.4e.5e.6d, ld.2f.3b.4e.5e.6e, ld.2f.3b.4e.5e.6f, ld.2f.3b.4e.5f.6a, ld.2f.3b.4e.5f.6b, ld.2f.3b.4e.5f.6c, ld.2f.3b.4e.5f.6d, ld.2f.3b.4e.5f.6e, ld.2f.3b.4e.5f.6f, ld.2f.3b.4f.5a.6a, ld.2f.3b.4f.5a.6b, ld.2f.3b.4f.5a.6c, ld.2f.3b.4f.5a.6d, ld.2f.3b.4f.5a.6e, ld.2f.3b.4f.5a.6f, ld.2f.3b.4f.5b.6a, ld.2f.3b.4f.5b.6b, ld.2f.3b.4f.5b.6c, ld.2f.3b.4f.5b.6d, ld.2f.3b.4f.5b.6e, ld.2f.3b.4f.5b.6f, ld.2f.3b.4f.5c.6a, ld.2f.3b.4f.5c.6b, ld.2f.3b.4f.5c.6c, ld.2f.3b.4f.5c.6d, ld.2f.3b.4f.5c.6e, ld.2f.3b.4f.5c.6f, ld.2f.3b.4f.5d.6a, ld.2f.3b.4f.5d.6b, ld.2f.3b.4f.5d.6c, ld.2f.3b.4f.5d.6d, ld.2f.3b.4f.5d.6e, ld.2f.3b.4f.5d.6f, ld.2f.3b.4f.5e.6a, ld.2f.3b.4f.5e.6b, ld.2f.3b.4f.5e.6c, ld.2f.3b.4f.5e.6d, ld.2f.3b.4f.5e.6e, ld.2f.3b.4f.5e.6f, ld.2f.3b.4f.5f.6a, ld.2f.3b.4f.5f.6b, ld.2f.3b.4f.5f.6c, ld.2f.3b.4f.5f.6d, ld.2f.3b.4f.5f.6e, ld.2f.3b.4f.5f.6f, ld.2f.3c.4a.5a.6a, ld.2f.3c.4a.5a.6b, ld.2f.3c.4a.5a.6c, ld.2f.3c.4a.5a.6d, ld.2f.3c.4a.5a.6e, ld.2f.3c.4a.5a.6f, ld.2f.3c.4a.5b.6a, ld.2f.3c.4a.5b.6b, ld.2f.3c.4a.5b.6c, ld.2f.3c.4a.5b.6d, ld.2f.3c.4a.5b.6e, ld.2f.3c.4a.5b.6f, ld.2f.3c.4a.5c.6a, ld.2f.3c.4a.5c.6b, ld.2f.3c.4a.5c.6c, ld.2f.3c.4a.5c.6d, ld.2f.3c.4a.5c.6e, ld.2f.3c.4a.5c.6f, ld.2f.3c.4a.5d.6a, ld.2f.3c.4a.5d.6b, ld.2f.3c.4a.5d.6c, -282- 200918507 ld.2f.3c.4a.5d.6d, ld.2f.3c.4a.5d.6e7 ld.2f.3c.4a.5d.6f, ld.2f.3c.4a.5e.6a, ld.2f.3c.4a.5e.6b, ld.2f.3c.4a.5e.6c, ld.2f.3c.4a.5e.6d, ld.2f.3c.4a.5e.6e, ld.2f.3c.4a.5e.6f, ld.2f.3c.4a.5f.6a, ld.2f.3c.4a.5f.6b, ld.2f.3c.4a.5f.6c, ld.2f.3c.4a.5f.6d, ld.2f.3c.4a.5f.6e, ld.2f.3c.4a.5f.6f, ld.2f.3c.4b.5a.6a, ld.2f.3c.4b.5a.6b, ld.2f.3c.4b.5a.6c, ld.2f.3c.4b.5a.6d, ld.2f.3c.4b.5a.6e, ld.2f.3c.4b.5a.6f, ld.2f.3c.4b.5b.6a, ld.2f.3c.4b.5b.6b, ld.2f.3c.4b.5b.6c, ld.2f.3c.4b.5b.6d, ld.2f.3c.4b.5b.6e, ld.2f.3c.4b.5b.6f, ld.2f.3c.4b.5c.6a, ld.2f.3c.4b.5c.6b, ld.2f.3c.4b.5c.6c, ld.2f.3c.4b.5c.6d, ld.2f.3c.4b.5c.6e, ld.2f.3c.4b.5c.6f, ld.2f.3c.4b.5d.6a, ld.2f.3c.4b.5d.6b, ld.2f.3c.4b.5d.6c, ld.2f.3c.4b.5d.6d, ld.2f.3c.4b.5d.6e, ld,2f.3c.4b.5d.6f, ld.2f.3c.4b.5e.6a, ld.2f.3c.4b.5e.6b, ld.2f.3c.4b.5e.6c, ld.2f.3c.4b.5e.6d, ld.2f.3c4b.5e.6e, ld.2f3c.4b.5e.6f, ld.2f.3c.4b.5f.6a, ld.2f.3c.4b.5f.6b, ld.2f.3c.4b.5f.6c, ld.2f.3c.4b.5f.6d, ld.2f.3c.4b.5f.6e, ld.2f.3c4b.5f.6f, ld.2f.3c.4c.5a.6a, ld.2f.3c.4c.5a.6b, ld.2f.3c.4c.5a.6c, ld.2f.3c.4c.5a.6d, ld.2f.3c.4c.5a.6e, ld.2f.3c.4c.5a.6f, ld.2f.3c.4c.5b.6a, ld.2f.3c.4c.5b.6b, ld.2f.3c.4c.5b.6c, ld.2f.3c.4c.5b.6d, ld.2f.3c.4c.5b.6e, ld.2f.3c.4c.5b.6f, ld.2f.3c.4c.5c.6a, ld.2f3c.4c.5c.6b, ld.2f.3c.4c.5c.6c, ld.2f.3c.4c.5c.6d, ld.2f.3c.4c.5c.6e, ld.2f.3c.4c.5c.6f, ld.2f.3c.4c.5d.6a, ld.2f.3c.4c.5d.6b, ld.2f.3c.4c.5d.6c, ld.2f.3c.4c.5d.6d, ld.2f.3c.4c.5d.6e, ld.2f.3c.4c.5d.6f, ld.2f.3c.4c.5e.6a, ld.2f.3c.4c.5e.6b, ld.2f.3c.4c.5e.6c, ld.2f.3c.4c.5e.6d, ld.2f.3c.4c.5e.6e, ld.2f.3c.4c.5e.6f, ld.2f.3c.4c.5f.6a, ld.2f.3c.4c.5f.6b, ld.2f.3c.4c.5f.6c, ld.2f.3c.4c.5f.6d, ld.2f.3c.4c.5f.6e, ld.2f.3c.4c.5f.6f, ld.2f.3c.4d.5a.6a, ld.2f.3c.4d.5a.6b, ld.2f.3c.4d.5a.6c, ld.2f.3c.4d.5a.6d, ld.2f.3c.4d.5a.6e, ld.2f.3c.4d.5a.6f, ld.2f.3c.4d.5b.6a, ld.2f.3c.4d.5b.6b, ld.2f.3c.4d.5b.6c, ld.2f.3c.4d.5b.6d, ld.2f.3c.4d.5b.6e, ld.2f.3c.4d.5b.6f, ld.2f.3c.4d.5c.6a, ld.2f.3c.4d.5c.6b, ld.2f.3c.4d.5c.6c, ld.2f.3c.4d.5c.6d, ld.2f.3c.4d.5c.6e, ld.2f.3c.4d.5c.6f, ld.2f.3c.4d.5d.6a, ld.2f.3c.4d.5d.6b, ld.2f.3c.4d.5d.6c, ld.2f.3c.4d.5d.6d, ld.2f.3c.4d.5d.6e, ld.2f.3c.4d.5d.6f, ld.2f.3c.4d.5e.6a, ld.2f.3c.4d.5e.6b, ld.2f.3c.4d.5e.6c, ld.2f.3c.4d.5e.6d, ld.2f.3c.4d.5e.6e, ld.2f.3c.4d.5e.6f, ld.2f.3c.4d.5f.6a, ld.2f.3c.4d.5f.6b, ld.2f.3c.4d.5f.6c, ld.2f.3c.4d.5f.6d, ld.2f.3c.4d.5f.6e, ld.2f.3c.4d.5f.6f, ld.2f.3c.4e.5a.6a, ld.2f.3c.4e.5a.6b, ld.2f.3c.4e.5a.6c, ld.2f.3c.4e.5a.6d, ld.2f.3c.4e.5a.6e, ld.2f.3c.4e.5a.6f, ld.2f.3c.4e.5b.6a, ld.2f.3c.4e.5b.6b, ld.2f.3c.4e.5b.6c, ld.2f.3c.4e.5b.6d, ld.2f.3c.4e.5b.6e, ld.2f.3c.4e.5b.6f, ld.2f.3c.4e.5c.6a, ld.2f.3c.4e.5c.6b, ld.2f.3c.4e.5c.6c, ld.2f.3c.4e.5c.6d, ld.2f.3c.4e.5c.6e, ld.2f.3c.4e.5c.6f, ld.2f.3c.4e.5d.6a, ld.2f.3c.4e.5d.6b, ld.2f.3c.4e.5d.6c, ld.2f.3c.4e.5d.6d, ld.2f.3c.4e.5d.6e, ld.2f.3c.4e.5d.6f, ld.2f.3c.4e.5e.6a, ld.2f.3c.4e.5e.6b, ld.2f.3c.4e.5e.6c, ld.2f.3c.4e.5e.6d, ld.2f.3c.4e.5e.6e, ld.2f.3c.4e.5e.6f, ld.2f.3c.4e.5f.6a, ld.2f.3c.4e.5f.6b, ld.2f.3c.4e.5f.6c, ld.2f.3c.4e.5f.6d, ld.2f.3c.4e.5f.6e, ld.2f.3c.4e.5f.6f, ld.2f.3c.4f.5a.6a, ld.2f.3c.4f.5a.6b, ld.2f.3c.4f.5a.6c, ld.2f.3c.4f.5a.6d, ld.2f.3c.4f.5a.6e, ld.2f.3c.4f.5a.6i ld.2f.3c.4f.5b.6a, ld.2f.3c.4f.5b.6b, ld.2f.3c.4f.5b.6c, ld.2f.3c.4f.5b.6d, ld.2f.3c.4f.5b.6e, ld.2f.3c.4f.5b.6f, ld.2f.3c.4f.5c.6a, ld.2f.3c.4f.5c.6b, ld.2f.3c.4f.5c.6c, ld.2f.3c.4f.5c.6d, ld.2f.3c.4f.5c.6e, ld.2f.3c.4f.5c.6f, ld.2f.3c.4f.5d.6a, ld.2f.3c.4f.5d.6b, ld.2f.3c.4f.5d.6c, ld.2f.3c.4f.5d.6d, ld.2f.3c.4f.5d.6e, ld.2f.3c.4f.5d.6f, ld.2f.3c.4f.5e.6a, ld.2f.3c.4f.5e.6b, ld.2f.3c.4f.5e.6c, ld.2f.3c.4f.5e.6d, ld.2f.3c.4f.5e.6e7 ld.2f.3c.4f.5e.6f, ld,2f.3c.4f.5f.6a, ld.2f.3c.4f.5f.6b, -283- 200918507 ld.2f.3c.4f.5f.6c, ld.2f.3c.4f.5f.6d, ld.2f.3c.4f.5f.6e, ld.2f.3c.4f.5f.6f, ld.2f.3d.4a.5a.6a, ld.2f.3d.4a.5a.6b, ld.2f.3d.4a.5a.6c, ld.2f.3d.4a.5a.6d, ld.2f.3d.4a.5a.6e, ld.2f.3d.4a.5a.6f, ld.2f.3d.4a.5b.6a, ld.2f.3d.4a.5b.6b, ld.2f.3d.4a.5b.6c, ld.2f.3d.4a.5b.6d, ld.2f.3d.4a.5b.6e, ld.2f.3d.4a.5b.6f, ld.2f.3d.4a.5c.6a, ld.2f.3d.4a.5c.6b, ld.2f.3d.4a.5c.6c, ld.2f.3d.4a.5c.6d, ld.2f.3d.4a.5c.6e, ld.2f.3d.4a.5c.6f, ld.2f.3d.4a.5d.6a, ld.2f.3d.4a.5d.6b, ld.2f.3d.4a.5d.6c, ld.2f.3d.4a.5d.6d, ld.2f.3d.4a.5d.6e, ld.2f.3d.4a.5d.6f, ld.2f.3d.4a.5e.6a, ld.2f.3d.4a.5e.6b, ld.2f.3d.4a.5e.6c, ld.2f.3d.4a.5e.6d, ld.2f.3d.4a.5e.6e, ld.2f.3d.4a.5e.6f, ld.2f.3d.4a.5f.6a, ld.2f.3d.4a.5f.6b, ld.2f.3d.4a.5f.6c, ld.2f.3d.4a.5f.6d, ld.2f.3d.4a.5f.6e, ld.2f.3d.4a.5f.6f, ld.2f.3d.4b.5a.6a, ld.2f.3d.4b.5a.6b, ld.2f.3d.4b.5a.6c, ld.2f.3d.4b.5a.6d, ld.2f.3d.4b.5a.6e, ld.2f.3d.4b.5a.6f, ld.2f.3d.4b.5b.6a, ld.2f.3d.4b.5b.6b, ld.2f.3d.4b.5b.6c, ld.2f.3d.4b.5b.6d, ld.2f.3d.4b.5b.6e, ld.2f.3d.4b.5b.6f, ld.2f.3d.4b.5c.6a, ld.2f.3d.4b.5c.6b, ld.2f.3d.4b.5c.6c, ld.2f.3d.4b.5c.6d, ld.2f.3d.4b.5c.6e, ld.2f.3d.4b.5c.6f, ld.2f.3d.4b.5d.6a, ld.2f.3d.4b.5d.6b, ld.2f.3d.4b.5d.6c, ld.2f.3d.4b.5d.6d, ld.2f.3d.4b.5d.6e, ld.2f.3d.4b.5d.6f, ld.2f.3d.4b.5e.6a, ld.2f.3d.4b.5e.6b, ld.2f.3d.4b.5e.6c, ld.2f.3d.4b.5e.6d, ld.2f.3d.4b.5e.6e, ld.2f.3d.4b.5e.6f, ld.2f.3d.4b.5f.6a, ld.2f.3d.4b.5f.6b, ld.2f.3d.4b.5f.6c, ld.2f.3d.4b.5f.6d, ld.2f.3d.4b.5f.6e, ld.2f.3d.4b.5f.6f, ld.2f.3d.4c.5a.6a, ld.2f.3d.4c.5a.6b, ld.2f.3d.4c.5a.6c, ld.2f.3d.4c.5a.6d, ld.2f.3d.4c.5a.6e, ld.2f.3d.4c.5a.6f, ld.2f.3d.4c.5b.6a, ld.2f.3d.4c.5b.6b, ld.2f.3d.4c.5b.6c, ld.2f.3d.4c.5b.6d, ld.2f.3d.4c.5b.6e, ld.2f.3d.4c.5b.6f, ld.2f.3d.4c.5c.6a, ld.2f.3d.4c.5c.6b, ld.2f.3d.4c.5c.6c, ld.2f.3d.4c.5c.6d, ld.2f.3d.4c.5c.6e, ld.2f.3d.4c.5c.6f, ld.2f.3d.4c.5d.6a, ld.2f.3d.4c.5d.6b, ld.2f.3d.4c.5d.6c, ld.2f.3d.4c.5d.6d, ld.2f.3d.4c.5d.6e, ld.2f.3d.4c.5d.6f, ld.2f.3d.4c.5e.6a, ld.2f.3d.4c.5e.6b, ld.2f.3d.4c.5e.6c, ld.2f.3d.4c.5e.6d, ld.2f.3d.4c.5e.6e, ld.2f.3d.4c.5e.6f, ld.2f.3d.4c.5f.6a, ld.2f.3d.4c.5f.6b, ld.2f.3d.4c.5f.6c, ld.2f.3d.4c.5f.6d, ld.2f.3d.4c.5f.6e, ld.2f.3d.4c.5f.6f, ld.2f.3d.4d.5a.6a, ld.2f.3d.4d.5a.6b, ld.2f.3d.4d.5a.6c, ld.2f.3d.4d.5a.6d, ld.2f.3d.4d.5a.6e, ld.2f.3d.4d.5a.6f, ld.2f.3d.4d.5b.6a, ld.2f.3d.4d.5b.6b, ld.2f.3d.4d.5b.6c, ld.2f.3d.4d.5b.6d, ld.2f.3d.4d.5b.6e, ld.2f.3d.4d.5b.6f, ld.2f.3d.4d.5c.6a, ld.2f.3d.4d.5c.6b, ld.2f.3d.4d.5c.6c, ld.2f.3d.4d.5c.6d, ld.2f.3d.4d.5c.6e, ld.2f.3d.4d.5c.6f, ld.2f.3d.4d.5d.6a, ld.2f.3d.4d.5d.6b, ld.2f.3d.4d.5d.6c, ld.2f.3d.4d.5d.6d, ld.2f_3d.4d.5d.6e, ld_2f.3d_4d.5d.6f, ld.2f.3d.4d.5e.6a, ld.2f.3d.4d，5e.6b, ld.2f.3d.4d.5e.6c, ld.2f.3d.4d.5e.6d, ld.2f.3d.4d.5e.6e, ld.2f.3d.4d.5e.6f, ld.2f.3d.4d.5f.6a, ld.2f.3d.4d.5f.6b, ld.2f.3d.4d.5f.6c, ld.2f.3d.4d.5f.6d, ld.2f.3d.4d_5f.6e, ld.2f.3d.4d.5f.6f, ld，2f，3d.4e.5a.6a, ld.2f.3d.4e.5a.6b, ld.2f.3d.4e.5a.6c, ld.2f.3d.4e.5a.6d, ld.2f.3d.4e.5a.6e, ld.2f.3d.4e.5a.6f, ld.2f.3d.4e.5b.6a, ld.2f.3d.4e.5b.6b, ld.2f.3d.4e.5b.6c, ld.2f.3d.4e.5b.6d, ld.2f.3d.4e.5b.6e, ld.2f.3d.4e.5b.6f, ld.2f.3d.4e.5c.6a, ld.2f.3d.4e.5c.6b, ld.2f.3d.4e.5c.6c, ld.2f.3d.4e.5c.6d, ld.2f.3d.4e.5c.6e, ld.2f.3d.4e.5c.6f, ld.2f.3d.4e.5d.6a, ld.2f.3d.4e.5d.6b, ld.2f.3d.4e.5d.6c, ld.2f.3d.4e.5d.6d, -284 - 200918507 ld.2f.3d.4e.5d.6e, ld.2f.3d.4e.5d.6f, ld.2f.3d.4e.5e.6a, ld.2f.3d.4e.5e.6b, ld.2f.3d.4e.5e.6c, ld.2f.3d.4e.5e.6d, ld.2f.3d.4e.5e.6e, ld2f.3d.4e.5e.6f, ld.2f.3d.4e.5f.6a, ld.2f.3d.4e.5f.6b, ld.2f.3d.4e.5f.6c, ld.2f.3d.4e.5f.6d, ld.2f.3d.4e.5f.6e, ld.2f.3d.4e.5f.6f, ld.2f.3d.4f.5a.6a, ld.2f.3d.4f.5a.6b, ld.2f.3d.4f.5a.6c, ld.2f.3d.4f.5a.6d, ld.2f.3d.4f.5a.6e, ld.2f.3d.4f.5a.6f, ld.2f.3d.4f.5b.6a, ld.2f.3d.4f.5b.6b, ld.2f.3d.4f.5b.6c, ld.2f.3d.4f.5b.6d, ld.2f.3d.4f.5b.6e, ld.2f.3d.4f.5b.6f, ld.2f.3d.4f.5c.6a, ld.2f.3d.4f.5c.6b, ld.2f.3d.4f.5c.6c, ld.2f.3d.4f.5c.6d, ld.2f.3d.4f.5c.6e, ld.2f.3d.4f.5c.6f, ld.2f.3d.4f.5d.6a, ld.2f.3d.4f.5d.6b, ld.2f.3d.4f.5d.6c, ld.2f.3d.4f.5d.6d, ld.2f.3d.4f.5d.6e, ld.2f.3d.4f.5(1.6^ ld.2f.3d.4f.5e.6a, ld.2f.3d.4f.5e.6b, ld.2f.3d.4f.5e.6c, ld.2f.3d.4f.5e.6d, ld.2f.3d.4f.5e.6e, ld.2f.3d.4f.5e.6f, ld.2f.3d.4f.5f.6a, ld.2f.3d.4f.5f.6b, ld.2f.3d.4f.5f.6c, ld.2f.3d.4f.5f.6d, ld.2f.3d.4f.5f.6e, ld.2f.3d.4f.5f.6f, ld.2f.3e.4a.5a.6a, ld.2f.3e.4a.5a.6b, ld.2f.3e.4a.5a.6c, ld.2f.3e.4a.5a.6d, ld.2f.3e.4a.5a.6e, ld.2f.3e.4a.5a.6f, ld.2f.3e.4a.5b.6a, ld.2f.3e.4a.5b.6b, ld.2f.3e.4a.5b.6c, ld.2f.3e.4a.5b.6d, ld.2f.3e.4a.5b.6e, ld.2f.3e.4a.5b.6f, ld.2f.3e.4a.5c.6a, ld.2f.3e.4a.5c.6b, ld.2f.3e.4a.5c.6c, ld.2f.3e.4a.5c.6d, ld.2f.3e.4a.5c.6e, ld.2f.3e.4a.5c.6f, ld.2f.3e.4a.5d.6a, ld.2f.3e.4a.5d.6b, ld.2f.3e.4a.5d.6c, ld.2f.3e.4a.5d.6d, ld.2f.3e.4a.5d.6e, ld.2f.3e.4a.5d.6f, ld.2f.3e.4a.5e.6a, ld.2f.3e.4a.5e.6b, ld.2f.3e.4a.5e.6c, ld.2f.3e.4a.5e.6d, ld.2f.3e.4a.5e.6e, ld.2f.3e.4a.5e.6f, ld.2f.3e.4a.5f.6a, ld.2f.3e.4a.5f.6b, ld.2f.3e.4a.5f.6c, ld.2f.3e.4a.5f.6d, ld.2f.3e.4a.5f.6e, ld.2f.3e.4a.5f.6f, ld.2f.3e.4b.5a.6a, ld.2f.3e.4b.5a.6b, ld.2f.3e.4b.5a.6c, ld.2f.3e.4b.5a.6d, ld.2f.3e.4b.5a.6e, ld.2f.3e.4b.5a.6f, ld.2f.3e.4b.5b.6a, ld.2f.3e.4b.5b.6b, ld.2f.3e.4b.5b.6c, ld.2f.3e.4b.5b.6d, ld.2f.3e.4b.5b.6e, ld.2f.3e.4b.5b.6f, ld.2f.3e.4b.5c.6a, ld.2f.3e.4b.5c.6b, ld.2f.3e.4b.5c.6c, ld.2f.3e.4b.5c.6d, ld.2f.3e.4b.5c.6e, ld.2f.3e.4b.5c.6f, ld.2f.3e.4b.5d.6a, ld.2f.3e.4b.5d.6b, ld.2f.3e.4b.5d.6c, ld.2f.3e.4b.5d.6d, ld.2f.3e.4b.5d.6e, ld.2f.3e.4b.5d.6f, ld.2f.3e.4b.5e.6a, ld.2f.3e.4b.5e.6b, ld.2f.3e.4b.5e.6c, ld.2f.3e.4b.5e.6d, ld.2f.3e.4b.5e.6e, ld.2f.3e.4b.5e.6f, ld.2f.3e.4b.5f.6a, ld.2f.3e.4b.5f.6b, ld.2f.3e.4b.5f.6c, ld.2f.3e.4b.5f.6d, ld.2f.3e.4b.5f.6e, ld.2f.3e.4b.5f.6f, ld.2f.3e.4c.5a.6a, ld.2f.3e.4c.5a.6b, ld.2f.3e.4c.5a.6c, ld.2f.3e.4c.5a.6d, ld.2f_3e.4c.5a.6e, ld.2f.3e.4c.5a.6t ld.2f.3e.4c.5b.6a, ld.2f.3e.4c.5b.6b, ld.2f.3e.4c.5b.6c, ld.2f.3e.4c.5b.6d, ld.2f.3e.4c.5b.6e, ld.2f.3e.4c.5b.6f, ld.2f.3e.4c.5c.6a, ld.2f.3e.4c.5c.6b, ld.2f.3e.4c.5c.6c, ld.2f.3e.4c.5c.6d, ld.2f.3e.4c.5c.6e, ld.2f.3e.4c.5c.6f, ld.2f.3e.4c.5d.6a, ld.2f.3e.4c.5d.6b, ld.2f.3e.4c.5d.6c, ld.2f.3e.4c.5d.6d, ld.2f.3e.4c.5d.6er ld.2f.3e.4c.5d.6f, ld.2f.3e.4c.5e.6a, ld.2f.3e.4c.5e.6b, ld.2f.3e.4c.5e.6c, ld.2f.3e.4c.5e.6d, ld.2f.3e.4c.5e.6e, ld.2f.3e.4c.5e.6f, ld.2f.3e.4c.5f.6a, ld.2f.3e.4c.5f.6b, ld.2f.3e.4c.5f.6c, ld.2f.3e.4c.5f.6d, ld.2f.3e.4c.5f.6e, ld.2f.3e.4c.5f.6f, ld.2f.3e.4d.5a.6a, ld.2f.3e.4d*5a.6b, ld.2f.3e.4d.5a.6c, ld.2f.3e.4d.5a.6d, ld.2f.3e.4d.5a.6e, ld.2f.3e.4d.5a.6f, ld.2f.3e.4d.5b.6a, ld.2f.3e.4d.5b.6b, ld.2f.3e.4d.5b.6c, ld.2f.3e.4d.5b.6d, ld.2f.3e.4d.5b.6e, ld2f.3e.4d.5b.6f, ld.2f.3e.4d.5c.6a, ld.2f.3e.4d.5c.6b, ld.2f.3e.4d.5c.6c, ld.2f.3e.4d.5c.6d, ld.2f.3e.4d.5c.6e, ld.2f.3e.4d.5c.6f, ld.2f.3e.4d.5d.6a, ld.2f.3e.4d.5d.6b, ld.2f.3e.4d.5d.6c, ld.2f.3e.4d.5d.6d, ld.2f.3e.4d.5d.6e, -285- 200918507 ld.2f.3e.4d.5d.6f, ld.2f.3e.4d.5e.6a, ld.2f.3e.4d.5e.6b, ld.2f.3e.4d.5e.6c, ld.2f.3e.4d.5e.6d, ld.2f.3e.4d.5e.6e, ld.2f.3e.4d.5e.6f, ld.2f.3e.4d.5f.6a, ld.2f.3e.4d.5f.6b, ld.2f.3e.4d.5f.6c, ld.2f.3e.4d.5f.6d, ld.2f.3e.4d.5f.6e, ld.2f.3e.4d.5f.6f, ld.2f.3e.4e.5a.6a, ld.2f.3e.4e.5a.6b, ld.2f.3e.4e.5a.6c, ld.2f.3e.4e.5a.6d, ld.2f*3e.4e.5a.6e, ld.2f.3e.4e.5a.6f, ld.2f.3e.4e.5b.6a, ld.2f.3e.4e.5b.6b, ld.2f.3e.4e.5b.6c, ld.2f.3e.4e.5b.6d, ld.2f.3e.4e.5b.6e, ld.2f.3e.4e.5b.6f, ld.2f.3e.4e.5c.6a, ld.2f.3e.4e.5c.6b, ld.2f.3e.4e.5c.6c, ld.2f.3e.4e.5c.6d, ld.2f.3e.4e.5c.6e, ld.2f.3e.4e.5c.6f, ld.2f.3e.4e.5d.6a, ld.2f.3e.4e.5d.6b, ld.2f.3e.4e.5d.6c, ld.2f.3e.4e.5d.6d, ld.2f.3e.4e.5d.6e, ld.2f.3e.4e.5d.6f, ld.2f.3e.4e.5e.6a, ld.2f.3e.4e.5e.6b, ld.2f.3e.4e.5e.6c, ld.2f.3e.4e.5e.6d, ld.2f.3e.4e.5e.6e, ld.2f.3e.4e.5e.6f, ld.2f.3e.4e.5f.6a, ld.2f.3e.4e.5f.6b, ld.2f.3e.4e.5f.6c, ld.2f.3e.4e.5f.6d, ld.2f.3e.4e.5f.6e, ld.2f.3e.4e.5f.6f, ld.2f.3e.4f.5a.6a, ld.2f.3e.4f.5a.6b, ld.2f.3e.4f.5a.6c, ld.2f.3e.4f.5a.6d, ld.2f.3e.4f.5a.6e, ld.2f.3e.4f.5a.6f, ld.2f.3e.4f.5b.6a, ld.2f.3e.4f.5b.6b, ld.2f3e.4f.5b.6c, ld.2f.3e.4f.5b.6d, ld.2f.3e.4f.5b.6e, ld.2f.3e.4f.5b.6f, ld.2f.3e.4f.5c.6a, ld.2f.3e.4f.5c.6b, ld.2f.3e.4f.5c.6c, ld.2f.3e.4f,5c.6d, ld.2f.3e.4f.5c.6e, ld.2f.3e.4f.5c.6f, ld.2f.3e.4f.5d.6a, ld.2f.3e.4f.5d.6b, ld.2f.3e.4f.5d.6c, ld.2f.3e.4f.5d.6d, ld.2f.3e.4f.5d.6e, ld.2f.3e.4f.5d.6f, ld.2f.3e.4f.5e.6a, ld.2f.3e.4f.5e.6b, ld.2f.3e.4f.5e.6c, ld.2f.3e.4f.5e.6d, ld.2f.3e.4f.5e.6e, ld.2f.3e.4f.5e.6f, ld.2f.3e.4f.5f.6a, ld.2f.3e.4f.5f.6b, ld.2f.3e.4f.5f.6c, ld.2f.3e.4f.5f.6d, ld.2f.3e.4f.5f.6e, ld.2f.3e.4f.5f.6f, ld.2f.3f.4a.5a.6a, ld.2f.3f.4a.5a.6b, ld.2f.3f.4a.5a.6c, ld.2f.3f.4a.5a.6d, ld.2f.3f.4a.5a.6e, ld.2f.3f.4a.5a.6f, ld.2f.3f.4a.5b.6a, ld.2f.3f.4a.5b.6b, ld.2f.3f.4a.5b.6c, ld.2f.3f.4a.5b.6d, ld.2f.3f.4a.5b.6e, ld.2f.3f.4a.5b.6f, ld.2f.3f.4a.5c.6a, ld.2f.3f.4a.5c.6b, ld.2f.3f.4a.5c.6c, ld.2f.3f.4a.5c.6d, ld.2f.3f.4a.5c.6e, ld.2f.3f.4a.5c.6f, ld.2f.3f.4a.5d.6a, ld.2f.3f.4a.5d.6b, ld.2f.3f.4a.5d.6c, ld.2f.3f.4a.5d.6d, ld.2f.3f.4a.5d.6e, ld.2f.3f.4a.5d.6f, ld.2f.3f.4a.5e.6a, ld.2f.3f.4a.5e.6b, ld.2f.3f.4a.5e.6c, ld.2f.3f.4a.5e.6d, ld.2f.3f.4a.5e.6e, ld.2f.3f.4a.5e.6f, ld.2f.3f.4a.5f.6a, ld.2f.3f.4a.5f.6b, ld.2f.3f.4a.5f.6c, ld.2f.3f.4a.5f.6d, ld.2f.3f.4a.5f.6e, ld.2f.3f.4a.5f.6f, ld.2f.3f.4b.5a.6a, ld.2f.3f.4b.5a.6b, ld.2f.3f.4b.5a.6c, ld.2f.3f.4b.5a.6d, ld.2f.3f.4b.5a.6e, ld.2f.3f.4b.5a.6f, ld.2f.3f.4b.5b.6a, ld.2f.3f.4b.5b.6b, ld.2f.3f.4b.5b.6c, ld.2f.3f.4b.5b.6d, ld.2f.3f.4b.5b.6e, ld.2f.3f.4b.5b.6f, ld.2f.3f.4b.5c.6a, ld.2f.3f.4b.5c.6b, ld.2f.3f.4b.5c.6c, ld.2f.3f.4b.5c.6d, ld.2f.3f.4b.5c.6e, ld.2f.3f.4b.5c.6f, ld.2f.3f.4b.5d.6a, ld.2f.3f.4b.5d.6b, ld.2f.3f.4b.5d.6c, ld.2f.3f.4b.5d.6d, ld_2f.3f.4b.5d.6e, ld.2f.3f.4b,5d.6f, ld.2f.3f.4b.5e.6a, ld.2f.3f.4b.5e.6b, ld.2f.3f.4b.5e.6c, ld.2f.3f.4b.5e.6d, ld.2f.3f.4b.5e.6e, ld.2f.3f.4b.5e.6f, ld.2f.3f.4b.5f.6a, ld.2f.3f.4b.5f.6b, ld.2f.3f.4b.5f.6c, ld.2f.3f.4b.5f.6d, ld.2f.3f.4b.5f.6e, ld.2f.3f.4b.5f.6f, ld.2f.3f.4c.5a.6a, ld.2f.3f.4c.5a.6b, ld.2f.3f.4c.5a.6c, ld.2f.3f.4c.5a.6d, ld.2f.3f.4c.5a.6e, ld.2f.3f.4c.5a.6f, ld.2f.3f.4c.5b.6a, ld.2f.3f.4c.5b.6b, ld.2f.3f.4c.5b.6c, ld.2f.3f.4c.5b.6d, ld.2f.3f.4c.5b.6e, ld.2f.3f.4c.5b.6f, ld.2f.3f.4c.5c.6a, ld.2f.3f.4c.5c.6b, ld.2f.3f.4c.5c.6c ld.2f.3f.4c.5c.6d7 ld.2f.3f.4c.5c.6e, ld.2f.3f.4c.5c.6f, ld.2f.3f.4c.5d.6a, ld.2f.3f.4c.5d.6b, ld.2f.3f.4c.5d.6c, ld.2f.3f.4c.5d.6d, ld.2f.3f.4c.5d.6e, ld.2f.3f.4c.5d.6f, ld.2f.3f.4c.5e.6a, ld.2f.3f.4c.5e.6b, ld.2f.3f.4c.5e.6c, ld.2f.3f.4c.5e.6d, ld.2f.3f.4c.5e.6e, ld.2f.3f.4c.5e.6f, ld.2f.3f.4c.5f.6a, ld.2f.3f.4c.5f.6b, ld.2f.3f.4c.5f.6c, ld.2f.3f.4c.5f.6d, ld.2f.3f.4c.5f.6e, ld.2f.3f.4c.5f.6f, ld.2f.3f.4d.5a.6a, ld.2f.3f.4d.5a.6b, ld.2f.3f.4d.5a.6c, ld.2f.3f.4d.5a.6d, ld.2f.3f.4d.5a.6e, ld.2f.3f.4d.5a.6f, ld.2f.3f.4d.5b.6a, -286- 200918507 ld.2f.3f.4d.5b.6b, ld.2f.3f.4d.5b.6c, ld.2f.3f.4d.5b.6d, ld.2f.3f.4d.5b.6e, ld.2f.3f.4d.5b.6f, ld.2f.3f.4d.5c.6a, ld,2£3f.4d.5c.6b, ld.2f.3f.4d.5c.6c, ld.2f.3f.4d.5c.6d, ld.2f.3f.4d.5c.6e, ld.2f.3f.4d.5c.6f, ld.2f.3f.4d.5d.6a, ld.2f.3f.4d.5d.6b, ld.2f.3f.4d.5d.6c, ld.2f.3f.4d.5d.6d, ld.2f.3f.4d.5d.6e, ld.2f.3f.4d.5d.6f, ld.2f.3f.4d.5e.6a, ld.2f.3f.4d.5e.6b, ld.2f.3f.4d.5e.6c, ld.2f.3f.4d.5e.6d, ld.2f.3f.4d.5e.6e, ld.2f.3f.4d.5e.6f, ld.2f.3f.4d.5f.6a, ld.2f.3f.4d.5f.6b, ld.2f.3f.4d.5f.6c, ld.2f.3f.4d.5f.6d, ld.2f.3f.4d.5f.6e, ld.2f.3f.4d.5f.6f, ld.2f.3f.4e.5a.6a, ld.2f.3f.4e.5a.6b, ld.2f.3f.4e.5a.6c, ld.2f.3f.4e.5a.6d, ld.2f.3f.4e.5a.6e, ld.2f.3f.4e.5a.6f, ld.2f.3f.4e.5b.6a, ld.2f.3f.4e.5b.6b, ld.2f.3f.4e.5b.6c, ld.2f.3f.4e.5b.6d, ld.2f.3f.4e.5b.6e, ld.2f.3f.4e.5b.6f, ld.2f.3f.4e.5c.6a, ld.2f.3f.4e.5c.6b, ld.2f.3f.4e.5c.6c, ld.2f.3f.4e.5c.6d, ld.2f.3f.4e.5c.6e, ld.2f.3f.4e.5c.6f, ld,2f.3f.4e.5d_6a, ld.2f.3f.4e.5d.6b, ld-2f.3f.4e.5d.6c, ld.2f.3f.4e_5d.6d, ld.2f.3f.4e.5d.6e, ld.2f.3f.4e.5d.6f, ld.2f.3f.4e.5e.6a, ld.2f.3f.4e.5e.6b, ld.2f.3f.4e.5e.6c, ld.2f.3f.4e.5e.6d, ld.2f.3f.4e.5e.6e, ld.2f.3f.4e.5e.6f, ld.2f.3f.4e.5f.6a, ld.2f.3f.4e.5f.6b, ld.2f.3f.4e.5f.6c, ld.2f.3f.4e.5f.6d, ld.2f.3f.4e.5f.6e, ld.2f.3f.4e.5f.6f, ld.2f.3f.4f.5a.6a, ld.2f.3f.4f.5a.6b, ld.2f.3f.4f.5a.6c, ld.2f.3f.4f.5a.6d, ld.2f.3f.4f.5a.6e, ld.2f.3f.4f.5a.6f, ld.2f.3f.4f.5b.6a, ld.2f.3f.4f.5b.6b, ld.2f.3f.4f.5b.6c, ld.2f.3f.4f.5b.6d, ld.2f.3f.4f.5b.6e, ld.2f.3f.4f.5b.6f, ld.2f.3f.4f.5c.6a, ld.2f.3f.4f.5c.6b, ld.2f.3f.4f.5c.6c, ld.2f.3f.4f.5c.6d, ld.2f.3f.4f.5c.6e, ld.2f.3f.4f.5c.6f, ld.2f.3f.4f.5d.6a, ld.2f.3f.4f.5d.6b, ld.2f.3f.4f.5d.6c, ld.2f.3f.4f.5d.6d, ld.2f.3f.4f.5d.6e, ld.2f.3f.4f.5d.6f, ld.2f.3f.4f.58.6a, ld.2f.3f.4f.5e.6b, ld.2f.3f.4f.5e.6c, ld.2f.3f.4f.5e.6d, ld.2f.3f.4f.5e.6e, ld.2f.3f.4f.5e.6f, ld.2f.3f.4f.5f.6a, ld. 2f.3f.4f.5f.6b, ld.2f.3f.4f.5f.6c, ld.2f.3f.4f.5f.6d, ld.2f.3f.4f.5f.6e, ld.2f.3f.4f.5f.6f, le. 2a.3a.4a.5a.6a, le.2a.3a.4a.5a.6b, le.2a.3a.4a.5a.6c, le.2a.3a.4a.5a.6d, le.2a.3a.4a.5a.6e, le.2a.3a.4a.5a.6f, le.2a.3a.4a.5b.6a, le.2a.3a.4a.5b.6b, le.2a.3a.4a.5b.6c, le.2a.3a.4a.5b.6d, le.2a.3a.4a.5b.6e, le.2a.3a.4a.5b.6f, le.2a.3a.4a.5c.6a, le.2a.3a.4a.5c.6b, le.2a.3a.4a.5c.6c, le.2a.3a.4a.5c.6d, le.2a.3a.4a.5c.6e, le.2a.3a.4a.5c.6f, le.2a.3a.4a.5d.6a, le.2a.3a.4a.5d.6b, le.2a.3a.4a.5d.6c, le.2a.3a.4a.5d.6d, le.2a.3a.4a.5d.6e, le.2a.3a.4a.5d.6f, le.2a.3a.4a.5e.6a, le.2a.3a.4a.5e.6b, le.2a.3a.4a.5e.6c, le.2a.3a.4a.5e.6d, le.2a.3a.4a.5e.6e, le.2a.3a.4a.5e.6f, le.2a.3a.4a.5f.6a, le.2a.3a.4a.5f.6b, le.2a.3a.4a.5f.6c, le.2a.3a.4a.5f.6d, le.2a.3a.4a.5f.6e, le.2a.3a.4a.5f.6f, le.2a.3a.4b.5a.6a, le.2a.3a.4b.5a.6b, le.2a.3a.4b.5a.6c, le.2a.3a.4b.5a.6d, le.2a.3a.4b.5a.6e, le.2a.3a.4b.5a.6f, le.2a.3a.4b.5b.6a, le.2a.3a.4b.5b.6b, le.2a.3a.4b.5b.6c, le.2a.3a.4b.5b.6d, le.2a.3a.4b.5b.6e, le.2a.3a.4b.5b.6f, le.2a.3a.4b.5c.6a, le.2a.3a.4b.5c.6b, le.2a.3a.4b.5c.6c, le.2a.3a.4b.5c.6d, le.2a.3a.4b.5c.6e7 le.2a.3a.4b.5c.6f, le.2a.3a.4b.5d.6a, le.2a.3a.4b.5d.6b, le.2a.3a.4b.5d.6c, le.2a.3a.4b.5d.6d, le.2a.3a.4b.5d.6e, le.2a.3a.4b.5d.6f, le.2a.3a.4b.5e.6a, le.2a,3a.4b.5e.6b, le.2a.3a.4b.5e.6c, le.2a.3a.4b.5e.6d, le.2a.3a.4b.5巳6e, le.2a.3a.4b.5e.6f, le.2a.3a.4b.5f.6a, le.2a.3a.4b.5f.6b, le.2a.3a.4b.5f.6c, le.2a.3a.4b.5f.6d, le.2a.3a.4b.5f.6e, le.2a.3a.4b.5f.6f, le.2a.3a.4c.5a.6a, le.2a.3a.4c.5a.6b, le.2a.3a.4c.5a.6c, le.2a.3a.4c.5a.6d, le.2a.3a.4c.5a.6e, le.2a.3a.4c.5a.6f, le.2a.3a.4c.5b.6a, le.2a.3a.4c.5b.6b, le.2a.3a.4c.5b.6c, le.2a.3a.4c.5b.6d, le.2a.3a.4c.5b.6e, le.2a.3a.4c.5b.6f, le.2a.3a.4c.5c.6a, -287- 200918507 le.2a.3a.4c.5c.6b, le.2a.3a.4c.5c.6c, le.2a.3a.4c.5c.6d, le.2a.3a.4c.5c.6e, le.2a.3a.4c.5c.6f, le.2a.3a.4c.5d.6a, le.2a.3a.4c.5d.6b, le.2a3a.4c.5d.6c, le.2a.3a.4c.5d.6d, le.2a.3a.4c.5d.6e, le.2a.3a.4c.5d.6f, le.2a.3a.4c.5e.6a, le.2a.3a.4c.5e.6b, le.2a.3a.4c.5e.6c, le.2a.3a.4c.5e.6d, le.2a.3a.4c.5e.6e, le.2a.3a.4c.5e.6f, le.2a.3a.4c.5f.6a, le.2a.3a.4c.5f.6b, le.2a.3a.4c.5f.6c, le.2a.3a.4c.5f.6d, le.2a.3a.4c.5f.6e, le.2a.3a.4c.5f.6f, le.2a.3a.4d.5a.6a, le.2a.3a.4d.5a.6b, le.2a.3a.4d.5a.6c, le.2a.3a.4d.5a.6d, le.2a.3a.4d.5a.6e, le.2a.3a.4d.5a.6f, le.2a.3a.4d.5b.6a, le.2a.3a.4d.5b.6b, le.2a.3a.4d.5b.6c, le.2a.3a.4d.5b.6d, le.2a.3a.4d.5b.6e, le.2a.3a.4d.5b.6f, le.2a.3a.4d.5c.6a, le.2a.3a.4d.5c.6b, le.2a.3a.4d.5c.6c, le.2a.3a.4d.5c.6d, le.2a.3a.4d.5c.6e, le.2a.3a.4d.5c.6f, le.2a.3a.4d.5d.6a, le.2a.3a.4d.5d.6b, le.2a.3a.4d.5d.6c, le.2a.3a.4d.5d.6d, le.2a.3a.4d.5d.6e, le.2a.3a.4d.5d.6f, le.2a.3a.4d.5e.6a, le.2a.3a.4d.5e.6b, le.2a.3a.4d.5e.6c, le.2a.3a.4d.5e.6d, le.2a.3a.4d.5e.6e, le.2a.3a.4d.5e.6f, le.2a.3a.4d.5f.6a, le.2a.3a.4d.5f.6b, le.2a.3a.4d.5f.6c, le.2a.3a.4d.5f.6d, le.2a.3a.4d.5f.6e, le.2a.3a.4d.5f.6f, le.2a.3a.4e.5a.6a, le.2a.3a.4e.5a.6b, le.2a.3a.4e.5a.6c, le.2a.3a.4e.5a.6d, le.2a.3a.4e.5a.6e, le.2a.3a.4e.5a.6f, le.2a.3a.4e.5b.6a, le.2a.3a.4e.5b.6b, le.2a.3a.4e.5b.6c, le.2a.3a.4e.5b.6d, le.2a.3a.4e.5b.6e, le.2a.3a.4e.5b.6f, le.2a.3a.4e.5c.6a, le.2a.3a.4e.5c.6b, le.2a.3a.4e.5c.6c, le.2a.3a.4e.5c.6d, le.2a.3a.4e.5c.6e, le.2a.3a.4e.5c.6f, le.2a.3a.4e.5d.6a, le.2a.3a.4e.5d.6b, le.2a.3a.4e.5d.6c, le.2a.3a.4e.5d.6d, le.2a.3a.4e.5d.6e, le.2a.3a.4e.5d.6f, le.2a.3a.4e.5e.6a, le.2a.3a.4e.5e.6b, le.2a.3a.4e.5e.6c, le.2a.3a.4e.5e.6d, le.2a.3a.4e.5e.6e, le.2a.3a.4e.5e.6f, le.2a.3a.4e.5f.6a, le.2a3a.4e.5f.6b, le.2a.3a.4e.5f.6c, le.2a.3a.4e.5f.6d, le.2a.3a.4e.5f.6e, le.2a.3a.4e.5f.6f, le.2a.3a.4f.5a.6a, le.2a.3a.4f.5a.6b, le.2a.3a.4f.5a.6c, le.2a.3a.4f.5a.6d, le.2a.3a.4f.5a.6e, le.2a.3a.4f.5a.6f, le.2a.3a.4f.5b.6a, le.2a.3a.4f.5b.6b, le.2a.3a.4f.5b.6c, le.2a.3a.4f.5b.6d, le.2a.3a.4f.5b.6e, le.2a.3a.4f.5b.6f, le.2a.3a.4f.5c.6a, le.2a.3a.4f.5c.6b, le.2a.3a.4f.5c.6c, le.2a.3a.4f.5c.6d, le.2a.3a.4f.5c.6e, le.2a.3a.4f.5c.6f, le.2a.3a.4f.5d.6a, le.2a.3a.4f.5d.6b, le.2a.3a.4f.5d.6c, le.2a.3a.4f.5d.6d, le.2a.3a.4f.5d.6e, le.2a.3a.4f.5d.6f, le.2a.3a.4f.5e.6a, le.2a.3a.4f.5e.6b, le.2a.3a.4f.5e.6c, le.2a.3a.4f.5e.6d, le.2a.3a.4f.5e.6e, le.2a.3a.4f.5e.6f, le.2a.3a.4f.5f.6a, le.2a.3a.4f.5f.6b, le.2a.3a.4f.5f.6c, le.2a.3a.4f.5f.6d, le.2a.3a.4f.5f.6e, le.2a.3a.4f.5f.6f, le.2a.3b.4a.5a.6a, le.2a.3b.4a.5a.6b, le.2a.3b.4a.5a.6c, le.2a.3b.4a.5a.6d, le.2a.3b.4a.5a.6e, le.2a.3b.4a.5a.6f, le.2a.3b.4a.5b.6a, le.2a.3b.4a.5b.6b, le.2a.3b.4a.5b.6c, le.2a.3b.4a.5b.6d, le.2a.3b.4a.5b.6e, le.2a.3b.4a.5b.6f, le.2a.3b.4a.5c.6a, le.2a.3b.4a.5c.6b, le.2a.3b.4a.5c.6c, le.2a.3b.4a.5c，6d, le.2a.3b.4a.5c.6e, 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' . . · le.2b.3c.4e.5a.6f, le.2b.3c.4e.5b.6a, le.2b.3c.4e.5b.6b, le^b.Sc^e.Sb^c, le^b.Sc^e.Sb^d, le.2b.3c.4e.5b.6e, le.2b.3c.4e.5b.6f, le.2b.3c4e.5c.6a, le.2b.3c.4e.5c.6b, le.2b.3c.4e.5c.6c, le.2b.3c.4e.5c.6d, le.2b.3c.4e.5c.6e, le.2b.3c.4e.5c.6f, le.2b.3c.4e.5d.6a, le.2b.3c.4e.5d.6b, le.2b.3c.4e.5d.6c, le.2b.3c.4e.5d.6d, le.2b.3c.4e.5d.6e, le.2b.3c.4e.5d.6f, le.2b.3c.4e.5e.6a, le.2b.3c.4e.5e.6b, le.2b.3c.4e.5e.6c, le.2b.3c.4e.5e.6d, le.2b.3c.4e.5e.6e, le.2b.3c.4e.5e.6f, le.2b.3c.4e.5f.6a, le.2b.3c.4e.5f.6b, le.2b.3c.4e.5f.6c, le.2b.3c.4e.5f.6d, le.2b.3c.4e.5f.6e, le.2b.3c.4e.5f.6f, le.2b.3c.4L5a.6a, le.2b.3c.4f.5a.6b, le.2b.3c.4f.5a.6c, le.2b.3c.4f.5a.6d, le.2b.3c.4f.5a.6e, le.2b.3c.4f.5a.6f, le.2b.3c.4f.5b.6a, le.2b.3c.4f.5b.6b, le.2b.3c.4f.5b.6c, le.2b.3c.4f.5b.6d, le.2b.3c.4f.5b.6e, le.2b.3c.4f.5b.6f, le.2b.3c.4f.5c.6a, le.2b.3c.4f.5c.6b, le.2b.3c.4f5c.6c, le.2b.3c.4f.5c.6d, le.2b.3c.4f.5c.6e, le.2b.3c.4f.5c.6£; le.2b.3c.4f.5d.6a, le.2b.3c.4f.5d.6b, le.2b.3c.4f.5d.6c, 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lf.2b.3a.4c.5f.6e, lf.2b.3a.4c.5f.6f, lf.2b.3a.4d.5a.6a, lf.2b.3a.4d.5a.6b, lf.2b.3a.4d.5a.6c, lf.2b.3a.4d.5a.6d, lf.2b.3a.4d.5a.6e, lf.2b.3a.4d.5a.6f, lf.2b.3a.4d.5b.6a, lf.2b.3a.4d.5b.6b, lf.2b.3a.4d.5b.6c, lf.2b.3a.4d.5b.6d, lf.2b.3a.4d.5b.6e, lf.2b.3a.4d.5b.6f, lf.2b.3a.4d.5c.6a, lf.2b.3a.4d.5c.6b, lf.2b.3a.4d.5c.6c, lf.2b.3a.4d.5c.6d, lf.2b.3a.4d.5c.6e, lf.2b.3a.4d.5c.6f, lf.2b.3a.4d.5d.6a, lf.2b.3a.4d.5d.6b, lf.2b.3a.4d.5d.6c, lf.2b.3a.4d.5d.6d, lf.2b.3a.4d.5d.6e, lf.2b.3a.4d.5d.6f, lf.2b.3a.4d.5e.6a, lf.2b.3a.4d.5e.6b, lf.2b.3a.4d.5e.6c, lf.2b.3a.4d.5e.6d, lf.2b3a.4d.5e.6e, lf.2b.3a.4d.5e.6f, lf.2b.3a.4d.5f.6a, lf.2b.3a.4d.5f.6b, lf.2b.3a.4d.5f.6c, lf.2b.3a.4d.5f.6d, lf.2b.3a.4d.5f.6e, lf.2b.3a.4d.5f.6f, lf.2b.3a.4e.5a.6a, lf.2b.3a.4e.5a.6b, lf.2b.3a.4e.5a.6c, lf.2b.3a.4e.5a.6d, lf.2b.3a.4e.5a.6e, lf.2b.3a.4e.5a.6f, lf.2b.3a.4e.5b.6a, lf.2b.3a.4e.5b.6b, lf.2b.3a.4e.5b.6c, lf.2b.3a.4e.5b.6d, lf.2b.3a.4e.5b.6e, lf.2b.3a.4e.5b.6f, lf.2b.3a.4e.5c.6a, lf.2b.3a.4e.5c.6b, lf.2b.3a.4e.5c.6c, lf.2b.3a.4e.5c.6d, lf.2b.3a.4e.5c.6e, lf.2b.3a.4e.5c.6f, lf.2b.3a.4e.5d.6a, lf.2b.3a.4e.5d.6b, lf.2b.3a.4e.5d.6c, lf.2b.3a.4e.5d.6d, lf.2b.3a.4e.5d.6e, lf.2b.3a.4e.5d.6f, lf.2b.3a.4e.5e.6a, lf.2b.3a.4e.5e.6b, lf.2b.3a.4e.5e.6c, lf.2b.3a.4e.5e.6d, lf.2b.3a.4e.5e.6e, lf.2b.3a.4e.5e.6f, lf.2b.3a.4e.5f.6a, lf.2b.3a.4e.5f.6b, lf.2b.3a.4e.5f.6c7 lf.2b.3a.4e.5f.6d, lf.2b.3a.4e.5f.6e, lf.2b.3a.4e.5f.6f, lf.2b.3a.4f.5a.6a, lf.2b.3a.4f.5a.6b, lf.2b.3a.4f.5a.6c, lf.2b.3a.4f.5a.6d, lf.2b.3a.4f.5a.6e, lf.2b.3a.4f.5a.6f, lf.2b.3a.4f.5b.6a, lf.2b.3a.4f.5b.6b, lf.2b.3a.4f.5b.6c, lf.2b.3a.4f.5b.6d, lf.2b.3a.4f.5b.6e, lf.2b.3a.4f.5b.6f, lf.2b.3a.4f.5c.6a, lf.2b.3a.4f.5c.6b, lf.2b.3a.4f.5c.6c, lf.2b.3a.4f.5c.6d, lf.2b.3a.4f.5c.6e, lf.2b.3a.4f.5c.6f, lf.2b.3a.4f.5d.6a, lf.2b.3a.4f.5d.6b, lf.2b.3a.4f.5d.6c, lf.2b.3a.4f.5d.6d, lf.2b.3a.4f.5d.6e, lf.2b.3a.4f.5d.6f, lf.2b.3a.4f.5e.6a, lf.2b.3a.4f.5e.6b, lf.2b.3a.4f.5e.6c, lf.2b.3a.4f.5e.6d, lf.2b.3a.4f.5e.6e, lf.2b.3a.4f.5e.6f, 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lf.2b.3b.4e.5a.6f, lf.2b.3b.4e.5b.6a, lf.2b.3b.4e.5b.6b, lf.2b.3b.4e.5b.6c, lf.2b.3b.4e.5b.6d, lf.2b.3b.4e.5b.6e, lf.2b.3b.4e.5b.6f, lf.2b.3b.4e.5c.6a, lf.2b.3b.4e.5c.6b, lf.2b.3b.4e.5c.6c, lf.2b.3b.4e.5c.6d； lf.2b.3b.4e.5c.6e, lf.2b.3b.4e.5c.6f, lf.2b.3b.4e.5d.6a, lf.2b.3b.4e.5d.6b, lf.2b.3b.4e.5d.6c, lf.2b.3b.4e.5d.6d, lf.2b,3b.4e.5d.6e, lf.2b.3b.4e.5d.6f, lf.2b.3b.4e.5e.6a, lf.2b.3b.4e.5e.6b, lf.2b.3b.4e.5e.6c, lf.2b.3b.4e.5e.6d, lf.2b.3b.4e.5e.6e, lf.2b.3b.4e.5e.6f, lf.2b.3b.4e.5f.6a, lf.2b.3b.4e.5f.6b, lf.2b.3b.4e.5f.6c, lf.2b.3b.4e.5f.6d, lf.2b.3b.4e.5f.6e, lf.2b.3b.4e.5f.6f, lf.2b.3b.4f.5a.6a, lf.2b3b.4f.5a.6b, lf.2b.3b.4f.5a.6c, lf.2b.3b.4f.5a.6d, lf.2b.3b.4f.5a.6e, lf.2b.3b.4f.5a.6f, lf.2b.3b.4f.5b.6a, lf.2b.3b.4f.5b.6b, lf.2b.3b.4f.5b.6c, lf.2b.3b.4f.5b.6d, lf.2b.3b.4f.5b.6e, lf.2b.3b.4f.5b.6f, lf.2b.3b.4f.5c.6a, lf.2b.3b.4f.5c.6b, lf.2b.3b.4f.5c.6c, lf2b.3b.4f.5c.6d, lf.2b.3b.4f.5c.6e, lf.2b.3b.4f.5c.6f, lf.2b.3b.4f.5d.6a, lf.2b.3b.4f.5d.6b, lf.2b.3b.4f.5d.6c, lf.2b.3b.4f.5d.6d, lf.2b.3b.4f.5d.6e, lf.2b.3b.4f.5d.6f, lf.2b.3b.4f.5e.6a, lf.2b.3b.4f.5e.6b, lf.2b.3b.4f.5e.6c, lf.2b.3b.4f.5e.6d, lf.2b.3b.4f.5e.6e, lf.2b.3b.4f.5e.6f, lf.2b.3b.4f.5f.6a, lf.2b.3b.4f.5f.6b, lf.2b.3b.4f.5f.6c, lf.2b.3b.4f.5f.6d, lf.2b.3b.4f.5f.6e, lf.2b.3b.4f.5f.6f, lf.2b.3c.4a.5a.6a, lf.2b.3c.4a.5a.6b, lf.2b.3c.4a.5a.6c, lf.2b.3c.4a.5a.6d, lf.2b.3c.4a.5a.6e, lf.2b.3c.4a.5a.6f, lf.2b.3c.4a.5b.6a, lf.2b.3c.4a.5b.6b, lf.2b.3c.4a.5b.6c, lf.2b.3c.4a.5b.6d, lf.2b.3c.4a.5b.6e, lf.2b.3c.4a.5b.6f, lf.2b.3c.4a.5c.6a, lf.2b.3c.4a.5c.6b, lf.2b.3c.4a.5c.6c, lf.2b.3c.4a.5c.6d, lf.2b.3c.4a.5c.6e, lf.2b.3c.4a.5c.6f, lf.2b.3c.4a.5d.6a# If.2b3c4a.5d.6b, lf.2b.3c.4a.5d.6c, lf.2b.3c.4a.5d.6d, lf.2b.3c.4a.5d.6e, lf.2b.3c.4a.5d.6f, lf.2b.3c.4a.5e.6a, lf.2b.3c.4a.5e.6b, lf.2b.3c.4a.5e.6c, lf.2b.3c.4a.5e.6d, lf.2b.3c.4a.5e.6e, lf.2b.3c.4a.5e.6f, lf.2b.3c.4a.5f.6a, lf.2b.3c.4a.5f.6b, lf.2b.3c.4a.5f.6c, lf.2b.3c.4a.5f.6d, lf.2b.3c.4a.5f.6e, lf.2b.3c.4a.5f.6f, lf.2b.3c.4b.5a.6a, lf.2b.3c.4b.5a.6b, lf.2b.3c.4b.5a.6c, -338 - 200918507 lf.2b.3c.4b.5a.6d, lf.2b.3c.4b.5a.6e, lf.2b.3c.4b.5a.6f, lf.2b.3c.4b.5b.6a, lf.2b.3c.4b.5b.6b, lf.2b.3c.4b.5b.6c, lf.2b.3c.4b.5b.6d, lf.2b.3c.4b.5b.6e, lf.2b.3c.4b.5b.6f, lf.2b.3c.4b.5c.6a, lf.2b3c.4b.5c.6b, lf.2b.3c.4b.5c.6c, lf.2b.3c.4b.5c.6d, lf.2b.3c.4b.5c.6e, lf.2b.3c.4b.5c.6f, lf.2b.3c.4b.5d.6a, lf.2b.3c.4b.5d.6b, lf.2b.3c.4b.5d.6c, lf.2b.3c.4b.5d.6d, lf.2b.3c.4b.5d.6e, lf.2b.3c.4b.5d.6f, lf.2b.3c.4b.5e.6a, lf.2b.3c.4b.5e.6b, lf.2b.3c.4b.5e.6c, lf.2b.3c.4b.5e.6d, lf.2b.3c.4b.5e.6e, lf.2b.3c.4b.5e.6f, lf.2b.3c.4b.5f.6a, lf.2b.3c.4b.5f.6b, lf.2b.3c.4b.5f.6c, lf.2b.3c.4b.5f.6d, lf.2b.3c.4b.5f.6e, lf.2b.3c.4b.5f.6f, lf.2b.3c.4c.5a.6a, lf.2b.3c.4c.5a.6b, lf.2b.3c.4c.5a.6c, lf.2b.3c.4c.5a.6d, lf.2b.3c.4c.5a.6e, lf.2b.3c.4c.5a.6f, lf.2b.3c.4c.5b.6ar lf.2b.3c.4c.5b.6b, lf.2b.3c.4c.5b.6c, lf.2b.3c.4c.5b.6d, lf.2b.3c.4c.5b.6e, lf.2b.3c.4c.5b.6f, lf.2b.3c.4c.5c.6a, lf.2b.3c.4c.5c.6b, lf.2b.3c.4c.5c.6c, lf.2b.3c.4c.5c.6d, 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lf.2e.3c4d.5e.6d, lf.2e.3c.4d.5e.6e, lf.2e.3c.4d.5e.6f, lf.2e.3c.4d.5f.6a, lf.2e.3c.4d.5f.6b, lf.2e.3c.4d.5f.6c, lf.2e.3c.4d.5f.6d, lf.2e.3c.4d.5f.6e, lf.2e.3c.4d.5f.6f, lf.2e.3c.4e.5a.6a, lf.2e.3c.4e.5a.6b, lf.2e.3c.4e.5a.6c, lf.2e.3c.4e.5a.6d, lf.2e.3c.4e.5a.6e, lf.2e.3c.4e.5a.6f, lf.2e.3c.4e.5b.6a, lf.2e.3c.4e.5b.6b, lf.2e.3c.4e.5b.6c, lf.2e.3c.4e.5b.6d, lf.2e.3c.4e.5b.6e, lf.2e.3c.4e.5b.6f, lf.2e.3c.4e.5c.6a, lf.2e.3c.4e.5c.6b, lf.2e.3c.4e.5c.6c, lf.2e.3c.4e.5c.6d, lf.2e.3c.4e.5c.6e, lf.2e.3c.4e.5c.6f, lf.2e.3c.4e.5d.6a, lf.2e.3c.4e.5d.6b, lf.2e.3c.4e.5d.6c, lf.2e.3c.4e.5d.6d, lf.2e.3c.4e.5d.6e, lf.2e.3c.4e.5d.6f, lf.2e.3c.4e.5e.6a, lf.2e.3c.4e.5e.6b, lf.2e.3c.4e.5e.6c, lf.2e.3c.4e.5e.6d, lf.2e.3c.4e.5e.6e, lf.2e.3c.4e.5e.6f, lf.2e.3c.4e.5f.6a, lf.2e.3c.4e.5f.6b, lf.2e.3c.4e.5f.6c, lf.2e.3c.4e.5f.6d, lf.2e.3c.4e.5f.6e, lf.2e.3c.4e.5f.6f, lf.2e.3c.4f.5a.6a, lf.2e.3c.4f.5a.6b, lf.2e.3c.4f.5a.6c, lf.2e.3c.4f.5a.6d, lf.2e.3c.4f.5a.6e, lf.2e.3c.4f.5a.6f, lf.2e.3c.4f.5b.6a, lf.2e.3c.4f.5b.6b, lf.2e.3c.4f.5b.6c, lf.2e.3c.4f.5b.6d, lf.2e.3c.4f.5b.6e, lf.2e.3c.4f.5b.6f, lf.2e.3c.4f.5c.6a, lf.2e.3c.4f.5c.6b, lf.2e.3c.4f.5c.6c, lf.2e.3c.4f.5c.6d, lf.2e.3c.4f.5c.6e, lf.2e.3c.4f.5c.6f； lf.2e.3c.4f.5d.6a, lf.2e.3c.4f.5d.6b, lf.2e.3c.4f.5d.6c, lf.2e.3c.4f.5d.6d, lf.2e.3c.4f.5d.6e, lf.2e.3c.4f.5d.6f, lf.2e.3c.4f.5e.6a, lf.2e.3c.4f.5e.6b, lf.2e.3c*4f.5e.6c, lf.2e.3c.4f.5e.6d, lf.2e.3c.4f.5e.6e, lf.2e.3c.4f.5e.6f, lf.2e.3c.4f.5f.6a, lf.2e.3c.4f.5f.6b, lf.2e.3c.4f.5f.6c, lf.2e.3c.4f.5f.6d, lf.2e.3c.4f.5f.6e, lf.2e3c.4f.5f.6f, lf.2e.3d.4a.5a.6a, lf.2e.3d.4a.5a.6b, lf.2e.3d.4a.5a.6c, lf.2e.3d.4a.5a.6d, lf.2e.3d.4a.5a.6e, lf.2e.3d.4a.5a.6f, lf.2e.3d.4a.5b.6a, lf.2e.3d.4a.5b.6b, lf.2e.3d.4a.5b.6c, lf.2e.3d.4a.5b.6d, lf.2e.3d.4a.5b.6e, lf.2e.3d.4a.5b,6f, lf.2e.3d.4a.5c.6a, lf.2e.3d.4a.5c.6b, lf.2e.3d.4a.5c.6c, lf.2e.3d.4a.5c.6d, lf.2e.3d.4a.5c.6e, lf.2e.3d.4a.5c.6f, lf.2e.3d.4a.5d.6a, lf.2e.3d.4a.5d.6b, lf.2e.3d.4a.5d.6c, lf.2e.3d.4a.5d.6d, lf.2e.3d.4a.5d.6e, lf.2e.3d.4a.5d.6f, lf.2e.3d.4a.5e.6a, lf.2e.3d.4a.5e.6b, lf.2e.3d.4a.5e.6c, -359- 200918507 lf.2e.3d.4a.5e.6d, lf.2e.3d.4a.5e.6e, lf.2e.3d.4a.5e.6f, lf.2e.3d.4a.5f.6a, lf.2e.3d.4a.5f.6b, lf.2e.3d.4a.5f.6c, lf.2e.3d.4a.5f.6d, lf.2e.3d.4a.5f.6e, lf.2e3d.4a.5f.6f, lf.2e.3d.4b.5a.6a, lf.2e.3d.4b.5a.6b, lf.2e.3d.4b.5a.6c, lf.2e.3d.4b.5a.6d, lf.2e.3d.4b.5a.6e, lf.2e.3d.4b.5a.6f, lf.2e.3d.4b.5b.6a, lf.2e.3d.4b.5b.6b, lf.2e.3d.4b.5b.6c, lf.2e.3d.4b.5b.6d, lf.2e.3d.4b.5b.6e, lf.2e.3d.4b.5b.6f, lf.2e.3d.4b.5c.6a, lf.2e.3d.4b.5c.6b, lf.2e.3d.4b.5c6c, lf.2e.3d.4b.5c.6d, lf.2e.3d.4b.5c.6e, lf.2e.3d.4b.5c.6f, lf.2e.3d.4b.5d.6a, lf.2e.3d.4b.5d.6b, lf.2e.3d.4b.5d.6c, lf.2e.3d.4b.5d.6d, lf.2e.3d.4b.5d.6e, lf.2e.3d.4b.5d.6f, lf.2e.3d.4b.5e.6a, lf.2e.3d.4b.5e.6b, lf.2e.3d.4b.5e.6c, lf.2e.3d.4b.5e.6d, lf.2e.3d.4b.5e.6e, lf.2e.3d.4b.5e.6f, lf.2e.3d.4b.5f.6a, lf.2e.3d.4b.5f.6b, lf.2e.3d.4b.5f.6c, lf.2e.3d.4b.5f.6d, lf.2e.3d.4b.5f.6e, lf.2e.3d.4b.5f.6f, lf.2e.3d.4c.5a.6a, lf.2e.3d.4c.5a.6b, lf.2e.3d.4c*5a.6c, lf.2e.3d.4c.5a.6d, lf.2e.3d.4c.5a.6e, lf.2e.3d.4c.5a.6f, lf.2e.3d.4c.5b.6a, lf.2e.3d.4c.5b.6b, lf.2e.3d.4c.5b.6c, lf.2e.3d.4c.5b.6d, lf.2e.3d.4c.5b.6e, lf.2e.3d.4c.5b.6f, lf.2e.3d.4c.5c.6a, lf.2e.3d.4c.5c.6b, lf.2e.3d.4c.5c.6c, lf.2e.3d.4c.5c.6d, lf.2e.3d.4c.5c.6e, lf.2e.3d.4c.5c.6f, lf.2e.3d.4c.5d.6a, lf.2e.3d.4c.5d.6b, lf.2e.3d.4c.5d.6c, lf.2e.3d.4c.5d.6d, lf.2e.3d.4c.5d.6e, lf.2e.3d.4c.5d.6f, lf.2e.3d.4c.5e.6a, lf.2e.3d.4c.5e.6b, lf.2e.3d.4c.5e.6c, lf.2e.3d.4c.5e.6d, lf.2e.3d.4c.5e.6e, lf.2e.3d.4c.5e.6f, lf.2e.3d.4c.5f.6a, lf.2e.3d.4c.5f.6b, lf.2e.3d.4c.5f.6c, lf.2e.3d.4c.5f.6d, lf.2e.3d.4c.5f.6e, lf.2e.3d.4c.5f.6f, lf.2e.3d.4d.5a.6a, lf.2e.3d.4d.5a.6b, lf.2e.3d.4d.5a.6c, lf.2e.3d.4d.5a.6d, lf.2e.3d.4d.5a.6e, lf.2e.3d.4d.5a.6f, lf.2e.3d.4d.5b.6a, lf.2e.3d.4d.5b.6b, lf.2e.3d.4d.5b.6c, lf.2e.3d.4d.5b.6d, lf.2e.3d.4d.5b.6e, 、 lf.2e.3d.4d.5b.6f, lf.2e.3d.4d.5c.6a, lf.2e.3d.4d.5c.6b, lf.2e.3d.4d.5c6c, lf.2e.3d.4d.5c.6d, lf.2e.3d.4d.5c.6e, lf.2e.3d.4d.5c.6f, 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lf.2f.3f.4b.5d.6b, lf.2f.3f.4b.5d.6c, lf.2f.3f.4b.5d.6d, lf.2f.3f.4b.5d.6e, lf.2f.3f.4b.5d.6f, lf.2f.3f.4b.5e.6a, lf.2f.3f.4b.5e.6b, lf.2f.3f.4b.5e.6c, lf.2f.3f.4b.5e.6d, lf.2f.3f.4b.5e.6e, lf.2f.3f.4b.5e.6f, lf.2f.3f.4b.5f.6a, lf.2f.3f.4b.5f.6b, lf.2f.3f.4b.5f.6c, lf.2f.3f.4b.5f.6d, lf.2f.3f.4b.5f.6e, lf.2f.3f.4b.5f.6f, lf.2f.3f.4c.5a.6a, lf.2f.3f.4c.5a.6b, lf.2f.3f.4c.5a.6c, lf.2f.3f.4c.5a.6d, lf.2f.3f.4c.5a.6e, lf.2f.3f.4c.5a.6f, lf.2f.3f.4c.5b.6a, lf.2f.3f.4c.5b.6b, lf.2f.3f.4c.5b.6c, lf.2f.3f.4c.5b.6d, lf.2f.3f.4c.5b.6e, lf.2f.3f.4c.5b.6f, lf.2f.3f.4c.5c.6a, lf.2f.3f.4c.5c.6b, lf.2f.3f.4c.5c.6c, lf.2f.3f.4c.5c.6d, lf.2f.3f.4c.5c.6e, lf.2f.3f.4c.5c.6f, lf.2f.3f.4c.5d.6a, lf.2f.3f.4c.5d.6b, lf.2f.3f.4c.5d.6c, lf.2f.3f.4c.5d.6d, lf.2f.3f.4c.5d.6e, lf.2f.3f.4c.5d.6f, lf.2f.3f.4c.5e.6a, lf.2f.3f.4c.5e.6b, lf.2f.3f.4c.5e.6c, lf.2f.3f.4c.5e.6d, lf.2f.3f.4c.5e.6e, lf.2f.3f.4c.5e.6f, lf.2f.3f.4c.5f.6a, lf.2f.3f.4c.5f.6b, lf.2f.3f.4c.5f.6c, lf.2f.3f.4c.5f.6d, lf.2f.3f.4c.5f.6e, lf.2f.3f.4c.5f.6f, lf.2f.3f.4d.5a.6a, lf.2f.3f.4d.5a.6b, lf.2f.3f.4d.5a.6c, lf.2f.3f.4d.5a.6d, lf.2f.3f.4d.5a.6e, lf.2f.3f.4d.5a.6f, lf.2f.3f.4d.5b.6a, lf.2f.3f.4d.5b.6b, lf.2f.3f.4d.5b.6c, lf.2f.3f.4d.5b.6d, lf.2f.3f.4d.5b.6e, lf.2f.3f.4d.5b.6f, lf.2f.3f.4d.5c.6a, lf.2f.3f.4d.5c.6b, lf.2f.3f.4d.5c.6c, lf.2f.3f.4d.5c.6d, lf.2f.3f.4d.5c.6e, lf.2f.3f.4d.5c.6f, lf.2f.3f.4d.5d.6a, lf.2f.3f.4d.5d.6b, lf.2f.3f.4d.5d.6c, lf.2f.3f.4d.5d.6d, lf.2f.3f.4d.5d.6e, lf.2f.3f.4d.5d.6f, lf.2f.3f.4d.5e.6a, lf.2f.3f.4d.5e.6b, lf.2f.3f.4d.5e.6c, lf.2f.3f.4d.5e.6d, lf.2f.3f.4d.5e.6e, lf.2f.3f.4d.5e.6f, lf.2f.3f.4d.5f.6a, lf.2f.3f.4d.5f.6b, lf.2f.3f.4d.5f.6c, lf.2f.3f.4d.5f.6d, lf.2f.3f.4d.5f.6e, lf.2f.3f.4d.5f.6f, lf.2f.3f.4e.5a.6a, lf.2f.3f.4e.5a.6b, lf.2f.3f.4e.5a.6c, lf.2f.3f.4e.5a.6d, lf.2f.3f.4e.5a.6e, lf.2f.3f.4e.5a.6f, lf.2f.3f.4e.5b.6a, -368 - 200918507 lf.2f.3f.4e.5b.6b, lf.2f.3f.4e.5b.6c, lf.2f.3f.4e.5b.6d, lf.2f.3f.4e.5b.6e, lf.2f.3f.4e.5b.6f, lf.2f.3f.4e.5c.6a, lf.2f.3f.4e.5c.6b, lf.2f.3f.4e.5c.6c, lf.2f.3f.4e.5c.6d, lf.2f.3f.4e.5c.6e, lf.2f.3f.4e.5c.6f, lf.2f.3f.4e.5d.6a, lf.2f.3f.4e.5d.6b, lf.2f.3f.4e.5d.6c, lf.2f.3f.4e.5d.6d, lf.2f.3f.4e.5d.6e, lf.2f.3f.4e.5d.6f, lf.2f.3f.4e.5e.6a, lf.2f.3f.4e.5e.6b, lf.2f.3f.4e.5e.6c, lf.2f.3f.4e.5e.6d, lf.2f.3f.4e.5e.6e, lf.2f.3f.4e.5e.6f, lf.2f.3f.4e.5f.6a, lf.2f.3f.4e.5f.6b, lf.2f.3f.4e.5f.6c, lf.2f.3f.4e.5f.6d, lf.2f.3f.4e.5f.6e, lf.2f.3f.4e.5f.6f, lf.2f.3f.4f.5a.6a, lf.2f.3f.4f.5a.6b, lf.2f.3f.4f.5a.6c, lf.2f.3f.4f.5a.6d, lf.2f.3f.4f.5a.6e, lf.2f.3f.4f.5a.6f, lf.2f.3f.4f.5b.6a, lf.2f.3f.4f.5b.6b, lf.2f.3f.4f.5b.6c, lf.2f.3f.4f.5b.6d, lf.2f.3f.4f.5b.6e, lf.2f.3f.4f.5b.6f, lf.2f.3f.4f.5c.6a, lf.2f.3f.4f.5c.6b, lf.2f.3f.4f.5c.6c, lf.2f.3f.4f.5c.6d, lf.2f.3f.4f.5c.6e, lf.2f.3f.4f.5c.6f, lf.2f.3f.4f.5d.6a, lf.2f.3f.4f.5d.6b, lf.2f.3f.4f.5d.6c, lf.2f.3f.4f.5d.6d, lf.2f.3f.4f.5d.6e, lf.2f.3f.4f.5d.6f, lf.2f.3f.4f.5e.6a, lf.2f.3f.4f.5e.6b, lf.2f.3f.4f.5e.6c, lf.2f.3f.4f.5e.6d, lf.2f.3f.4f.5e.6e, lf.2f.3f.4f.5e.6f, lf.2f.3f.4f.5f.6a, lf.2f.3f.4f.5f.6b, lf.2f.3f.4f.5f.6c, lf.2f.3f.4f.5f.6d, lf.2f.3f.4f.5f.6e, lf.2f.3f.4f.5f.6f, -369- 200918507 【實施方式】 反應圖1
化合物1
試劑和條件:i.烷基鹵，K2C〇3, DMF或CH3CH2OCH2CI, SnCU,乙腈 化合物1 :利用下述之一般方法製備化合物1 : 令5-異丙基巴比妥酸（Lancaster)與磷醯氯反應以提供 2,4,6-三氯-5-異丙基嘧啶。隨後令該2,4,6-三氯-5-異丙基 嘧啶與苄基烷醇鹽反應以生咸2,4-雙（苄氧基）-6-氯-5-異丙 基嘧啶。隨後令該2,4-雙（苄氧基）-6-氯-5-異丙基嘧啶與 3-(氰基甲基）-5-甲基苯甲腈反應以生成3-((2，6-雙（苄氧基 )-5 -異丙基唆D疋-4-基）（氨基）甲基）-5 -甲基苯甲膳。令該3_ -370- 200918507 ((2,6-雙（苄氧基）-5-異丙基嘧啶-4-基）（氰基）甲基）-5-甲基 苯甲腈與NaH和02反應以生成酮3-(2,6-雙（苄氧基）-5-異 丙基嘧啶-4-羰基）-5·甲基苯甲腈，其係隨後經催化氫化反 應以生成化合物1。 自3,5-二甲基苯甲酸經多個步驟以製備該3-(氰基甲 基）-5-甲基苯甲腈中間產物，其係藉由利用亞硫醯氯使 3, 5 -二甲基苯甲酸氯化以生成該醯基氯，隨後與氫氧化銨 反應以生成對應之醯胺：3,5-二甲基苯醯胺。藉由於紫外 線（UV)照射下令該3,5-二甲基苯醯胺與NBS和苯甲醯基 過氧化物反應以生成對應之溴甲基腈：3-(溴甲基）-5-甲基 苯甲腈。隨後藉由令該3-(溴甲基）-5-甲基苯甲腈與KCN 反應以生成該3-(氰基甲基）-5-甲基苯甲腈。 化合物2:將碘甲烷（11.1 μΐ, 0.178毫莫耳）加入至碳 酸鋰（13.2 mg，0.178毫莫耳）和3-(5-異丙基-2,6-二側氧-1,2,3,6-四氫-嘧啶-4-羰基）-5-甲基-苯甲腈（化合物1, 52.9 mg，0.178毫莫耳）的混合物之DMF (1.0 ml)溶液中並攪拌 該反應混合物達72小時。令該反應混合物分佈於乙酸乙 酯與飽和氯化銨溶液中。移除有機層，經乾燥（MgS〇4)、 濃縮及逆相 HPLC (Phenomenex Synergi®管柱，5 至 100% 乙腈/H20)純化，再經冷凍乾燥後生成白色粉未（17.4 mg， 31%)。4 NMR (300 MHz, CD3OD): 8.23 (s, 1 Η), 8.14 (s, 1 Η), 7.93 (s, 1 Η), 3.03 (s, 3 Η), 2.47 (s, 3 Η), 2.3-2.1 (m, 1 Η), 1.15 (d, J = 6.6 Hz, 3 H), 1.08 (d, J = 6.6 -371 - 200918507
Hz, 3 Η)。質譜：312.2 (Μ + Η)，31〇·〇 (M_H)。 化合物3:於〇°C下將碘乙烷（0.326 ml, 4.04毫莫耳） 加入至碳酸鉀（0·67 g，4.85毫莫耳）和化合物1 (1.44 g， 4.85毫莫耳，！·〇當量）的混合物之DMF (23 ml)溶液中。 令該反應混合物隔夜回溫至室溫並隨後經濃縮。令殘餘物 分佈於乙酸乙酯與飽和氯化銨溶液中。移除有機層，經乾 燥（MgS04)、濃縮及閃蒸管柱層析（20至50%乙酸乙酯/己 垸）純化以生成3-(3 -乙基-5-異丙基-2,6-一側氧-1，2,3,6 -四 氫-嚼D定-4-簾基）-5 -甲基-苯甲腈（0.900 g，68%); ^ NMR (300 MHz，CDC13) : δ 8.69 (br，1 H)，8_02 (s, 1 h)，7.92 (s，1 H), 7.76 (s，1 H)，3.9-3.8 (m，1 H)，3.2-3.1 (m, i H)， 2.49 (s, 3 H), 2.3-2.1 (m, 1 H), 1.17 (d, J = 6.9 Hz, 3 H) 1.1-1.0 (m, 6 H);質譜：326.2 (M + H)，324.0 (M-H);及 3-(1,3-二乙基-5-異丙基-2,6-二側氧-1，2,3,6-四氮_嚼 啶-4-羰基）-5-甲基-苯甲腈：化合物4 (0.0899 g) ; iH Nmr (3 00 MHz，CD3OD) : δ 8_24 (s，1 H)，8.16 (s，1 η), 7 93 (s, 1 Η), 4.0-3.8 (m, 3 H), 3.3-3.1 (m, 1 H), 2.48 (s> 3 H) 2.3-2.1 (m，i h)，1.3-1.0 (m，12 H)。 化合物5 :於〇〇C下將（溴甲基）環丙烷（22 u1 Λ ^ -ζ HI, 0.224 毫莫耳）加入至碳酸鉀（0.046 g，0.3 3 6毫莫耳）和化合物叉 (〇」〇〇 g，0.336毫莫耳）的混合物之DMF (3.0 ml)溶液中 令該反應混合物隔夜回溫至室溫並分佈於乙酸乙醋與飽和 -372- 200918507 氯化銨溶液中。移除有機層’經乾燥（M gs 0 4)、濃縮及閃 蒸管柱層析（2 0至5 0 %乙酸乙酯/己烷）純化，再經冷凍乾 燥後生成白色粉末（0.03 0 8 g，39%); lfl NMR (300 MHz， CDC13) : δ 9.62 (br，1 H)，8.02 (s，1 H), 7.91 (s, 1 H), 7.74 (s, 1 H), 3.56 (dd, J = 14.7, 8.1 Hz, 1 H), 3.19 (dd, J =14.7, 5.7 Hz, 1 H), 2.47 (s, 3 H), 2.3-2.1 (m, 1 H), 1.18 (d, J - 6.9 Hz, 3 H), 107 (d, J = 6.9 Hz, 3 H), 0.9-0.7 (m, 1 H)，0.4-0.2 (m，4 H);質譜：3 52.1 (M + H)，3 50.0 (M-H) 化合物6:於0°C下攪拌碳酸鉀（2 9 mg，0.212毫莫耳， 1.2當量）、化合物1 (76 mg，0.254毫莫耳，1·0當量）及1-溴-2-氯-丁 - 2-烯（36 mg, 〇_212毫莫耳，1.0當量，依據文 獻 Kuehne et al., /. 01996, 6778 73 -78 0 1 所描述之方法加以製備）的混合物之DMF (2.0 ml)溶液， 隨後經3小時回溫至室溫。令該反應混合物分佈於乙酸乙 酯與飽和氯化銨溶液中。移除有機層’經乾燥（Mgs〇4)、 濃縮及逆相 HPLC (Phenomenex Synergi® 管柱 ’ 5 至 100% 乙腈/Η 20)純化，再經冷凍乾燥後生成白色粉末（20·6 mg, 25%)。】H NMR (300 MHz, CDC13): δ 8.67 (br，1 Η), 8_00 (s, 1 H), 7.87 (s, 1 H), 7.70 (s, 1 H), 5.4-5.35 (m, 1 H), 5.02 (d, J = 14.4 Hz, 1 H), 4.05 (d, J = 16.2 Hz, 1 H), 2.47 (s, 3 Η), 2.2-2.0 (m，1 Η), 1.2-1.0 (m，9 H)。質譜： 3 8 6.1, 3 8 8.1 (M + H) -373- 200918507 化合物7:令化合物1 (95 mg, 0.32毫莫耳，1.2當量） 溶解於DMF (3 ml)中。加入碳酸鉀（37 mg，1當量）並於室 溫下攪拌該反應混合物1〇分鐘。加入1-溴-2-甲氧基-乙 烷（37 mg, 0.266毫莫耳，1當量）和碘化鋰（36 mg, 1當量） 。令該反應混合物於室溫下經隔夜攪拌。將乙酸乙酯加入 至該反應混合物中，隨後經鹽水沖洗。令有機層經濃縮及 純化（矽膠，〇至8 0 % E t Ο A C /己烷），隨後經逆相Η P L C (Phenomenex Synergi®管柱，5 至 100°/。乙腈 /Η20)純化，再 經冷凍乾燥後生成白色粉末（24.8 mg，26%)。LC-MS顯示 3 5 6.1 (M + l)。NMR (300 MHz, CDC13): δ 9.10 (br, 1 Η), 8.10 (s, 1 Η), 8.01 (s, 1 Η), 7.77 (s, 1 Η), 3.78 (m, 2 Η), 3.59 (m, 1 Η), 3.36 (m, 1 Η), 3.03 (s, 3 Η), 2.48 (s, 3 Η), 2.2 (m，1 Η)，1 .20 (dd，6 Η)。 化合物8:令化合物1 (62 mg，0.208毫莫耳，1.2當量 )溶解於DMF (2 ml)中。加入碳酸鉀（24 mg, 1當量）並於室 溫下攪拌該反應混合物10分鐘。加入乙酸2 -溴-乙酯（29 mg, 0.174毫莫耳，1當量）和碘化鋰（23 mg, 1當量）。室溫 下攪拌該反應混合物3天。將乙酸乙酯加入至該反應混合 物中，隨後經鹽水沖洗。令有機層經濃縮及純化（矽膠，〇 至 80% EtOAc/己院），隨後經逆相 HPLC (Phenomenex S y n e r g i ®管柱，5至1 0 0 %乙腈/ Η 2 0)純化，再經冷凍乾燥後 生成白色粉末（15 mg, 22%)。LC-MS 顯示 3 84.0 (Μ+1)。 -374- 200918507 :H NMR (3 00 MHz, CDC13) ： 5 9.06 (br, 1 H), 8.03 H), 7.96 (s, 1 H), 7.81 (s, 1 H), 4.26 (m, 1 H), 4.08 H), 3.40 (m, 1 H), 2.50 (s, 3 H), 2.22 (m, 1 H), 2.03 H), 1.20 (dd，6 H)。 化合物9:於140°C下加熱化合物i (0.0953 g，1 毫莫耳）、氯三甲基矽烷（2.0 μΐ，0.016毫莫耳 1 , 1 , 1 , 3，3,3 -六甲基二矽胺烷（！ . 6 m丨）之混合物4小時 生成褐色溶液。令該反應混合物經冷卻及濃縮。令所 之殘餘物溶解於乙腈（1.6 ml)中並加入氯甲乙醚（3 0.321毫莫耳）和四氯化錫（1M CH2C12溶液，32 μΐ，〇. 毫莫耳）。室溫下令該反應混合物經隔夜攪拌，隨後 和碳酸氫鈉溶液驟冷1小時。令該混合物分佈於乙酸 和水中。移除有機層，經乾燥（Mg S04)、濃縮及閃蒸 層析（1 〇至40 %乙酸乙酯/己烷）純化以生成泡沫。自 甲醇中再結晶析出以生成白色固體（0.06 3 9 g，56%) NMR (3 00 MHz, CD3〇D) ： δ 8.15 (s, 1 Η), 8.08 (s, 7.88 (s, 1 Η), 5.40 (d, J = 10.5 Hz, 1 H), 4.75 (d, J = Hz, 1 H), 3.5-3.2 (m, 2 H), 2.46 (s, 3 H), 2.3-2.1 ( H), 1.13 (d, J = 6.9 Hz, 3 H), 1.06 (d5 J = 6.9 Hz, 0.70 (t，= 6.9 Hz, 3 H);質譜：3 5 6.0 (M + H)，3 5 4.( H)。 (s, 1 (m, 2 (s, 3 0.32 1 :)及 直至 生成 1 μΐ， .03 2 1 經飽 乙酯 管柱 回流 ;Ή 1 Η)， 10.5 :m, 1 3 Η), )(Μ- -375- 200918507 反應圖2
化合物8 化合物1〇 試劑和條件:i. K2C03, MeOH. 化合物10:將碳酸鉀（15 mg，0.108毫旲耳，2.8當量） 加入至化合物8 (15 mg, 0.039毫莫耳）之Me0H (2 ml)溶 液中。室溫下攪拌該反應混合物2小時。令該反應混合物 經濃縮及逆相 HPLC (Phenomenex Synergi®管柱，5至 1 0 0 %乙腈/ Η 2 Ο )純化，再經冷凍乾燥後生成白色粉末（6 _ 1 mg, 46%)。LC-MS 顯示 342.1 (M+l)。lH NMR (300 MHz， CD3OD)顯示大多數係所欲之產物，少數係環狀型式：δ 8.24 (s, 1 Η), 8.19 (s, 1 Η), 7.96 (s, 1 Η), 3.82 (m, 1 Η), 3·60 (m，2 Η)，3·41 (m，1 η)，2.53 (s，3 Η)，2.22 (m，1 Η), 1 . 1 7 (dd, 6 Η)。 -376- 200918507 反應圖3 二 丄 乙炔基-環丙烷 3·環丙基-丙-2-炔-1-醇
試劑和條件：i.n-BuLi, HCHO, THF, -78 0C; ii. MsCI, TEA, DCM, 0 〇C; 化合物 1, K2C03, Lil, DMF. 3-環丙基-丙-2-炔-1-醇：於-78〇C下將正丁基鋰（1.3 Μ己烷溶液，14.3 ml, 18.57毫莫耳，1 . 1當量）加入至乙炔 基-環丙烷（70%甲苯溶液，2 ml，16.88毫莫耳）之TMF (43 ml)溶液中。於〇。(：下攪拌該反應混合物1小時，隨後冷 卻至-78。(：。加入聚甲醛（63 3 mg，21.1毫莫耳，1.25當量） 。於-78°C下攪拌該反應混合物並隨後隔夜回溫至室溫。 令該反應混合物經濃縮，加入乙酸乙酯並利用鹽水沖洗有 機層。令有機層經濃縮及純化（矽膠，〇至20% EtOAc/己烷 )以生成淡黃色油（900 mg, 56%)。4 NMR (3 00 MHz, CDC13) : δ 4.20 (s, 2 Η), 1.62 (s, 1 Η), 1.23 (m, 1 Η), 〇·75 (m，6 H)。 甲磺酸3-環丙基-丙-2·炔基酯：於〇°C下將TEA (140 -377- 200918507 μΐ, 1.0毫莫耳，2.0當量）加入至3-環丙基-丙-2-炔-1-醇之 DCM (2 ml)溶液中，隨後加入MsCl (46 μΐ，0.6毫莫耳， 1.2當量）。於0°C下攪拌該反應混合物30分鐘。濃縮該 反應混合物。加入乙酸乙酯並經飽和NaHC03溶液沖洗。 濃縮有機層，經置於無水硫酸鈉上乾燥後生成淡黃色油 (5 9 mg，6 8%)，其係直接用於下一個步驟中。 化合物11:令化合物1 (121 mg, 0.406毫莫耳，1.2當 量）溶解於DMF (4 ml)中。加入碳酸鉀（59 mg, 0.338毫莫 耳，1當量）並於室溫下攪拌該反應混合物1 〇分鐘。加入 甲磺酸3-環丙基-丙-2-炔基酯（59 mg，0.3 3 8毫莫耳，1當 量）和碘化鋰（45 mg，1當量）。室溫下令該反應混合物經隔 夜攪拌。將乙酸乙酯加入至該反應混合物中，隨後經鹽水 沖洗。令有機層經濃縮和純化（矽膠，〇至80%EtOAC/己烷 )以生成灰色粉末（88 mg，69%)。LC-MS顯示376.1 (M+1) 。NMR (3 00 MHz, CDC13) : δ 8.81 (br，1 H)，8.17 (s, 1 Η), 8.03 (s, l Η), 7.81 (s, 1 Η), 4.91 (d, 1 Η), 3.98 (d, 1 Η), 2.52 (s, 3 Η), 2.22 (m, 1 Η), 1.20 (dd, 6 Η), 0.78 (m, 1 Η), 0.73 (m，2 Η), 0.59 (m, 1 H)，0.38 (m, 1 H)。 -378- 200918507 反應圖4
3-(5-異丙基-2,6-二甲 3-[二氟-(5-異丙基-2,6-二甲 氧基-唆陡·4-碳基氧基-苯φ腈-4-基)-争基]-5-甲 甲基苯甲腈 基-苯甲腈
化合物13 (R=乙基） 化合物14 (R=乙氧基甲基) 試劑和條件:i.去氧氟(Deoxofbuor),催化 EtOH, 110 0C; ii. AcBr, 60 0C; iii. K2C〇3. Etl, DMF; 或氯甲氧基-乙烷，K2C03, Lil, DMF. ' 3-[二氟- (5-異丙基-2,6-二甲氧基-嘧啶-4-基）-甲基】_s 甲基-苯甲腈：將去氧氟（Deox〇fl〇uor)(3 ml,過量）加人g 3-(5-異丙基-2,6-二甲氧基-嘴：]定-4-羯基）-5-甲基-苯甲膳（ 其係藉由用於製備於製備化合物1過程中所生成之3_(2,6_ 雙（苄氧基）-5 -異丙基嘧啶-4 -羰基）-5 -甲基苯甲腈中間產物 的類似方法加以製備，唯其使用甲醇鹽以替代苄基烷醇鹽 )(779 mg，2 _39毫莫耳）中，隨後加入1滴乙醇（約〇」ml) 。於氬氣下加熱該反應混合物至1 1 〇。C達9小時。隨後令 該反應混合物經濃縮，加入乙酸乙酯並令該混合物經鹽水 沖洗。令有機層經濃縮和純化（矽膠，〇至80%EtOAC/己烷 )以生成灰色固體（5〇〇 mg，73%)。LC-MS 顯示 348.1 (M+1) 化合物12:將乙醯溴（2 ml,過量）加入至3-[二氟-(5- 異丙基-2’6-二甲氧基·嘧啶-4-基甲基）-5 -甲基-苯甲腈（500 mg，1_44毫莫耳）中。於氬氣下隔夜加熱該反應混合物至 -379- 200918507 6 0 ° C。隨後令該反應混合物經濃縮和純化（矽膠，〇至 80%EtOAC/己烷）以生成灰色固體（390 mg, 85%)。LC-MS 顯示 3 1 8 . 1 ( Μ - 1)。 化合物13:令化合物12(92mg，0.288毫莫耳，1.2當 量）溶解於DMF (1.4 ml)中。加入碳酸鉀（40 mg，0.288毫 莫耳，1.2當量）並於0°C下攪拌該反應混合物10分鐘。加 入碘乙烷（19_4 μΐ，0.24毫莫耳，1當量）。於0。(：下攪拌該 反應混合物並令其回溫至室溫達2天。將乙酸乙酯加入至 該反應混合物中，隨後經鹽水沖洗。令有機層經濃縮和純 化（矽膠，0至80%EtOAC/己烷）以生成灰色粉末（4.5 mg, 6%)。LC-MS 顯示 3 48.1 (M+1)。NMR (3 00 MHz， CD3〇D) ： δ 7.95 (s, 1 Η), 7.82 (s, 2 Η), 3.58 (m, 2 Η), 2_50 (s, 3 H)，1 .22 (dd，6 H)。 化合物14:令化合物12 (80 mg, 0.25毫莫耳，1.2當 量）溶解於DMF (2 ml)中。加入碳酸鉀（29 mg，0.209毫莫
耳，1當量）並於〇°C下攪拌該反應混合物10分鐘。加入 氯甲氧基乙烷（19.4 μΐ, 0.209毫莫耳，1當量），隨後再加 入碘化鋰（28 mg, 1當量）。於〇°C下攪拌該反應混合物並 令其隔夜回溫至室溫。將乙酸乙酯加入至該反應混含物中 ，隨後經鹽水沖洗。令有機層經濃縮和純化（矽膠，0至 80%EtOAC/己烷）及製備性TLC (2% MeOH/DCM)以生成灰 色粉末（8.3 mg, 11%)。LC-MS 顯示 378.0 (M+l)。WNMR -380- 200918507 (3 00 MHz, CDCI3) ： δ 9.03 (br, 1 Η), 7.76 (s, 1 Η), 7.62 (s, 2 Η), 5.37 (s, 2 Η), 3.40 (m, 2 Η), 2.70 (m, 1 Η), 2.48 (s，3 Η), 1.22 (dd，6 Η), 1.00 (t, 3 η)。F NMR (3 00 MHz, CDC13) : δ -77.43。 亦分離出化合物1 5以作爲該反應之副產物：
CN 化合物15 反應圖5
3,5-二甲基-苯甲腈3_氟甲基_5·甲基_苯甲腈3-氰基甲基-5-議甲基-苯甲腈
3-氟甲基-5-(5-異丙基-2,6-二甲氧基-嘧啶-4-羰基)-苯甲腈
〇 化合物16
試劑和條件：i. a. NBS; CCI4; b. KF, 18-cr-6, ACN; ii. a. NBS; CCI4; b. KCN, Et0H/H20; iii. 4-氯_5-異丙基-2,6-二甲氧基-喷啶，NaH, DMF; b. NaH, 02, DMF; iv. AcBr; v. Etl, K2C03, DMF. 3-氟甲基-5-甲基-苯甲腈：將N-溴琥珀醯亞胺（33.9 g， -381 - 200918507 190毫莫耳）和苯甲醯基過氧化物（2.28 g，9.4毫莫耳）加入 至3,5 -二甲基苯甲腈（25 g，190毫莫耳）之四氯化碳（190 ml)溶液中。於紫外線（UV)燈下令該反應混合物回流3小 時’隨後冷卻至室溫並經過濾。令濾液經濃縮並經矽膠層 析（10%乙醚/己烷）純化以生成不純之產物。令該產物自回 流之乙醚（100 ml)和己烷（400 ml)中析出以生成白色固體 (19.11 g, 4 8 %) 〇 將氟化鉀（2.52 g, 43.41 毫莫耳）、18 -冠-6 (0.76 g, 2.89毫莫耳）及乙腈（20 ml)加入至部分之上述產物（3.04 g， 14.47毫莫耳）中並令所生成之黃色反應混合物回流數天。 藉由過濾以除去所生成之白色沉澱物並令濾液經濃縮和矽 膠層析（〇至20%乙酸乙酯/己烷）純化以生成白色固體（1.27 g, 59%)° *H NMR (300 MHz, CDC13)： δ 7.41 (s, 2 H), 7.37 (s，1 H)，5.33 (d, J = 47 Hz, 2 H)，2.37 (s，3 H)。 3-氰基甲基-5-氟甲基-苯甲腈：將N-溴琥珀醯亞胺 (1.46 g，8.18毫莫耳）和苯甲醯基過氧化物（0.099 g，0.41 毫莫耳）加入至3-氟甲基-5-甲基-苯甲腈（1.22 g，8.18毫莫 耳）之四氯化碳（8 ml)溶液中。於紫外線（UV)燈下令該反應 混合物回流3.5小時，隨後冷卻至室溫並經過濾。令濾液 經濃縮並經矽膠層析（〇至20%乙酸乙酯/己烷）純化以牛成 白色固體（0.3561 g，19%) > 將氰化鉀（0.187 g, 2.87毫莫耳）、乙醇（1.5 ml)及水 (0.5 ml)加入至上述產物（0.3 56 1 g，1.56毫莫耳）中。令該 -382- 200918507 反應混合物回流6小時並冷卻至室溫。令產物經乙酸乙酯 萃取，經水沖洗、乾燥（MgS04)、濃縮及矽膠層析（0至 40%乙酸乙酯/己烷）純化以生成白色固體（0.1 788 g，66%)。 !H NMR (3 00 MHz, CDC13) ： δ 7.55 (s, 3 Η), 5.73 (d, J = 47 Hz，2 H)，3.79 (s, 2 H)。 3-氟甲基- 5-(5-異丙基-2,6-二甲氧基-嘧啶-4-羰基）-苯 甲腈：於〇°C下將60%氫化鈉（0.062 g，1 .5 52毫莫耳）經 30分鐘加入至 3-氰基甲基-5-氟甲基-苯甲腈（0.1351 g, 0.776毫莫耳）和4-氯-5-異丙基-2,6-二甲氧基·嘧啶（0.176 g，0.814毫莫耳）之DMF (5.0 ml)溶液中以生成橙色溶液。 於0°C下攪拌該反應混合物1小時，隨後於室溫下再攪拌 4小時。令該反應混合物經IN HC1溶液驟冷且令其分佈 於乙酸乙酯和飽和NH4C1溶液中。令有機層經飽和NH4C1 溶液沖洗’再經乾燥（M g S Ο 4 )、濃縮及矽膠層析（〇至3 0 % 乙酸乙酯/己烷）純化以生成白色固體（0 . 1 7 1 4 g，6 2 %)。 令上述產物溶解於DMF (5 ml)中並令其冷卻至〇°C。 分批加入60%氫化鈉（0.027 g，〇.686毫莫耳）並於室溫下攪 拌所生成之黃色反應混合物3 0分鐘。於激烈攪拌下令氧 氣經冒泡進入該反應混合物中達4小時。令該反應混合物 經IN HC1溶液驟冷且令其分佈於乙酸乙酯和飽和NH4C1 溶液中。令有機層經水和飽和N Η 4 C 1溶液沖洗，再經乾燥 (MgSCU)、濃縮及矽膠層析（0至50%乙酸乙酯/己烷）純化 以生成白色固體（0.036 g，22%)。NMR (3 00 MHz， -383- 200918507 CDC13) : δ 8.05 (s，1 H)，8.03 (s，1 H)，7.83 (s，1 H)，5.43 (d, J = 47 Hz, 2 H), 4.04 (s, 3 H), 3.88 (s, 3 H), 2.86-2.80 (m，1 H)，1.15 (d，J = 6.9 Hz，6 H);質譜：3 43.2 (M + H) 化合物16:於60。C下攪拌氟甲基- 5_(5 -異丙基_ 2,6-二甲氧基-嘧啶-4-羰基）-苯甲腈（Ο.0% g，〇_l〇5毫莫耳 )之乙醯溴（2.0 m 1)溶液達6小時。令該反應混合物冷卻至 室溫並與乙腈（3 X)經一起蒸發以生成灰白色膜（〇.〇! 6 g， 4 8%) ° 'H NMR (3 00 MHz, CDC13) : δ 1〇·7〇 (br s, 1 H)， 10.30 (br s, 1 H), 8.18 (s, 1 H), 8.09 (s, 1 H), 7.89 (s, 1 H), 5.47 (d, J = 47 Hz, 2 H), 3.41 (s, 3 H), 2.5-2.2 (m, 1 H), 0.95 (d，/ = 6.6 Hz, 6 H);質譜：316.1 (M + H)。 化合物17:於〇。(：下將碘乙烷（4.1 μΐ，0.0507毫莫耳 )和碳酸鉀（7.0 mg，0.05 07毫莫耳）加入至化合物16 (16 mg，0.0507毫莫耳）之DMF (0_5 ml)中。令該反應混合物 經隔夜回溫至室溫，再經乙酸乙酯稀釋、鹽水沖洗、乾燥 (MgS04)及濃縮。令粗產物經矽膠層析（20至50%乙酸乙酯 /己烷）純化，再經冷凍乾燥後生成白色粉末（4.6 mg，26%) 6.9 。NMR (3 00 MHz，CD3OD) : δ 8.44 (s, 1 Η), 8.32 (s，1 Η), 8.14 (s, 1 Η), 5.52 (d, J = 47 Hz, 2 Η), 3.9-3.7 (m, 1 Η), 3.2-3.1 (m, 1 Η), 2.3-2.1 (m, 1 Η), 1.14 (d, J = -384- 200918507
Hz，3 H)，l.l-i.o (m，6 H);質譜：3 44 2 (M + H), 3 42 〇 (Μ-Η)。 反應圖6
丙二酸二苄酯
2-(2,2,2-三氣-乙基)_ 丙二酸二苄酯
2,4,6-三氯-5-(2,2,2-三氟-乙基)-嚼啶 iii
4-氯-2,6-二甲氧基-5-( 2,2,2-三氟-乙基)-嘴啶
3-[2,6-二甲氧基-5-(2,2,2-三氟-乙 基)-嘧啶·4·羰基]-5-甲基-苯甲腈
試劑和條件:i.三氟-甲磺酸2,2,2-三氟-乙酯，NaH，THF;ii a脲7 ，·鱗甲基吡啶;甲醇納，甲醇;iv.a.3-氰基，臆，
NaH, DMF; b. 02; V. AcBr; vi. Etl, U2C〇3, DMF. 2-(2,2,2-三氟-乙基）-丙二酸二苄酯：室溫下將丙二酸 二苄酯（4.825 8，16.97毫莫耳）加入至60%氫化鈉（0.678 §， 16.97毫莫耳）之THF (100 ml)懸浮液中，經30分鐘後生 成澄清溶液。加入三氟甲磺酸2,2,2 -三氟乙酯（3.52 g, 15.43毫莫耳）並於50°C下攪拌該反應混合物48小時。令 該反應混合物經濃縮，分佈於乙醚中，經飽和氯化銨溶液 沖洗且經1 N HC1酸化。令該混合物經乙醚（2 X)萃取、乾 燥（MgS04)及濃縮。令所生成之殘餘物經閃蒸管柱層析（矽 膠，0至0%乙醚/己烷）純化以生成無色油（3.844 g, 68%)。 -385- 200918507 JH NMR (3 00 MHz, CDC13) ： δ 7.4-7.2 (m, 10 H), 5.15 (s, 4 H)，3.75 (t, J = 6.9 Hz, 1 H)，2.9-7.7 (m，2 H)。 2,4,6-三氯-5-(2,2,2-三氟-乙基）-嘧啶：室溫下將脲 (0.558 g, 9.29毫莫耳）和乙醇鈉（21重量％，8.0 ml, 21.4毫 莫耳）加入至2-(2,2,2-三氟-乙基）-丙二酸二苄酯（3.40 g， 9.29毫莫耳）之乙醇（2.0 ml)溶液中。於60°C下攪拌該反 應混合物1 2小時。令該反應混合物冷卻至室溫，經乙醚 (2 0 ml)稀釋並經攪拌1小時。藉由過濾以收集所生成之固 體並經真空乾燥以生成灰白色固體（1.228 g，52%)。令該 固體懸浮於磷醯氯（14 ml)中並小心地加入2,6-二甲基吡啶 (0.7 ml)。於140°C下攪拌該反應混合物1小時並隨後於 1 0 5 ° C下再進行隔夜攪拌。令該反應混合物冷卻至室溫， 經濃縮及與甲苯經一起蒸發以生成褐色油。令殘餘物溶解 於乙醚中並經飽和碳酸氫鈉溶液沖洗。令有機層經乾燥 (MgS04)、濃縮及經閃蒸管柱層析（矽膠，0至10%乙酸乙 酯/己烷）純化以生成白色固體（0.6331 g，49%)。4 NMR (300 MHz, CDC13) ： δ 3.75 (q, J = 9.3 Hz, 2 H)° 4-氯-2，6 -二甲氧基- 5- (2,2,2-三氟-乙基）-嘧啶：於〇°c 下將甲醇鈉（25重量％，1·〇9 ml, 4.77毫莫耳）加入至2,4,6-三氯-5-(2,2,2-三氟-乙基）-嘧啶（0.63 3 g，2.39毫莫耳）之甲 醇（2〇 ml)溶液中。令該反應混合物隔夜回溫至室溫。令該 反應混合物經濃縮，溶解於乙醚中且經水沖洗。令有機層 -386- 200918507 經乾燥（MgS〇4) ’濃縮及經閃蒸管柱層析（矽膠，〇至1〇% 乙酸乙醋/己院）純化以生成無色油（〇 . 5 5 3 1 g, 9 〇 % ρ 1 Η NMR (3 00 MHz, CDC13) : δ 3.87 (s, 3 Η), 3.83 (s, 3 Η), 3.32 (q，J = 10.2 Hz, 2 H);質譜：257·1, 259.1 (M + H)。 3_ [2,6_二甲氧基-5-(2,2,2-三氟-乙基）-嘧啶-4-羰基】- 5 -甲基-苯甲腈··於〇〇c下將6〇%氫化鈉（0170 g，426毫 莫耳）經30分鐘加入至3_氰基甲基_5_氟甲基-苯甲腈 (0.348 g，2·23 毫莫耳）和 4_ 氯-2,6•二甲氧基·5_(2,2,2·三 氟-乙基）-嘧啶（0.546 g, 2.13毫莫耳）之DMF (10.0 ml)溶 液中以生成橙色溶液。於〇。C下攪拌該反應混合物1小時 並隨後於室溫下再攪拌3小時。於激烈攪拌下令氧氣經冒 泡進入該反應混合物中達24小時。令該反應混合物經1 N HC1溶液驟冷且令其分佈於乙酸乙酯和飽和NH4C1溶液中 。令有機層經水和飽和 NH4C1溶液沖洗’再經乾燥 (MgS04)、濃縮及矽膠層析（〇至30%乙酸乙酯/己烷）純化 以生成白色固體（0.476 g, 61%)。4 NMR (3 00 MHz， CDC13) : δ 7.92 (s, 2 Η), 7.63 (s, 1 Η), 4.06 (s, 3 Η), 3.93 (s，3 Η), 3.60 (q，《7 = 10.5 Hz，2 Η), 2.41 (s，3 Η);質譜 ：3 66.2 (M + H)。 化合物18:於60。C下攪拌3-[2,6-二甲氧基- 5-(2,2，2-三氟-乙基）-嘧啶-4-羰基]-5-甲基-苯甲腈（〇_4638 g，1.27毫 莫耳）之乙酸溴（1 3 · 0 m I)溶液3 6小時。令該反應混合物冷 -387- 200918507 卻至室溫並與乙腈（3χ)一起蒸發。令殘餘物經閃蒸管柱層 析（矽膠，〇至5%甲醇/二氯甲烷）純化以生成褐色固體 (0.2179 g, 94%)0 NMR (300 MHz, CD3〇D)： δ 8.12 (s, 1 H), 8.03 (s, 1 H), 7.90 (s, 1 H), 3.15 (q, J = i〇.5 Hz, 2 H)，2.46 (s，3 H);質譜：3 3 6.〇(M-H)。 化合物19:室溫下將碘乙烷（17.6 μΐ，〇_218毫莫耳） 加入至化合物I8 (0·147 g，〇.436毫莫耳）和碳酸鋰（0.016 g，0.218毫莫耳）之DMF (1.0 ml)懸浮液中。室溫下攪拌該 反應混合物72小時’隨後經乙酸乙酯稀釋，經飽和氯化 銨溶液沖洗，經乾燥（M g s 0 4)及濃縮。令殘餘物經逆相 HPLC (Phenomenex Synergi®管柱，5 至 ι〇〇%乙腈 /h2〇)純 化，再經冷凍乾燥後生成白色粉末（3 1 .3 mg，39%)。ιΗ NMR (3 00 MHz，CD3OD) : δ 8.22 (s，1 H)，8_12 (s，1 Η) 7.94 (s，1 Η), 3.9-3.8 (m, 1 Η)，3.3-3.1 (m，2 Η), 2.9-2.7 (m , 1 Η)，2 · 4 7 (s，3 Η)，1.0 8 (t，J = 6.6 Η ζ，3 Η);質譜： 3 66.2 (Μ + Η)，3 63.90 (Μ-Η)。 -388- 200918507 反應圖7
試劑和條件:i.烷基鹵，K2C03, DMF. 化合物20:室溫下將3,3-二甲基烯丙基溴（149111§,1 毫莫耳）加入至化合物1 (297 mg, 1毫莫耳）和無水碳酸鉀 粉末（138 mg，1毫莫耳）之DMF (5 ml)攪拌溶液中。經隔 夜攪拌後，令該混合物經真空下蒸發且令殘餘物經矽膠管 柱層析（溶析液爲乙酸乙酯：己烷（1:2))純化以生成白色固體 (254 mg, 69%)。m.p. 158-159〇C。iH-NMR (200 MHz, CDC13) δ 1.10 (3Η, d, J = 6.8 Hz), 1.20 (3H, d, J = 6.8 Hz), 1.33 (6H, d, J = 4.6 Hz), 2.20 (1H, m), 2.51 (3H, s), 4.11 (1H, m), 4.32 (1H, m), 4.90 (1H, m), 7.76 (1H, s), 7.91 (1H, s)，8.02 (1H，s), 8.96 (1H, s)。 亦分離出副產物化合物2 1 : -389- 200918507
化合物22 :於氮氣下將三乙胺（210 μΐ，1.5毫莫耳）加 入至於冰浴中冷卻的2-丁炔-1-醇（70 mg，1毫莫耳）之氯仿 (1 0 m 1)的攪拌溶液中並逐滴加入甲烷磺醯氯（9 〇 μ i，1 _ 2毫 莫耳）。經攪拌1 .1小時後，令該反應混合物經飽和碳酸氫 鈉水溶液沖洗’再經無水硫酸鎂乾燥，經過濾及真空下蒸 發。令殘餘物再於高真空下經乾燥約20分鐘並與化合物i (297 mg，1毫莫耳）、無水碳酸鉀粉末（138 mg, 1毫莫耳） 及碘化鋰（1 34 mg，丨毫莫耳）混合。隨後於室溫下將DMF (5 ml)加入至該混合物中並進行隔夜攪拌。經蒸發DMF後 ’令殘餘物溶解於甲醇-氯仿（1:9)中並經通過寅氏鹽墊過 爐。真空下蒸發濾液並令殘餘物經矽膠管柱層析（溶析液 爲乙酸乙酯：己院（1 : 2))純化以生成白色固體（1 1 〇 m g，2 6 %) ；m.p. 116-117°C; !H-NMR (200 MHz, CDC13)： δ 1.14 (3H, d, J = 7.〇 Hz), 1.22 (3H, d, J = 7.0 Hz), 1.44 (3H, t, J = 2.4 H z)，2 · 2 6 (1 H，m)，2.5 6 (3 H, s)，4 · 0 0 (1 H，d d, J = 2 · 4
Hz, 17.8 Hz), 4.86 (1H, dd, J = 2.4 Hz, 17.8 Hz), 7.79 (1H, s), 8.09 (1H, s), 8.16 (1H, s), 8.89 (1H, s) ； m/z (El) 349 [M + ]。 -390 - 200918507 化合物23 :室溫下將8 〇重量％炔丙基溴之甲苯（1 1 2 μΐ，1毫莫耳）溶液加入至化合物1 (297 mg，〗毫莫耳）和無 水碳酸鉀粉末（138 mg，1毫莫耳）之DMF (5 ml)的攪拌溶 液中。經隔夜攪拌後’真空下蒸發該混合物並令殘餘物經 矽膠管柱層析（溶析液爲乙酸乙酯：己烷（丨：2))純化以生成白 色固體（167 mg, 50%) ; m.p. 2〇9-210。(： ； iH-NMR (200 MHz，CDC13) : δ 115 (3Η，d，j = 6.8 Hz), 1.23 (3H, d, J = 6.8 Hz), 2.10 (1H，t，J = 2.4 Hz), 2.29 (1H, m), 2.55 (3H， s)，4.16 (1H，d，J=16.0 Hz)，4 74 (1 H，d，J=16 〇 HZ)，7.83 (1H，s)，8.09 (1H，s)，8.17 (1H，s), 1〇 20 (1H, s): m/z (El) 33 5 [M + ]。 化合物24:室溫下將三氟甲磺酸2 22_三氟乙酯（144 μΐ，1毫莫耳）加入至化合物1 (297 mg, 1毫莫耳）和無水碳 酸鉀粉末（138 mg, 1毫莫耳）之DMF (5 ml)的攪拌溶液中 。經隔仪攪拌後’真空下蒸發該混合物並令殘餘物經矽膨 管柱層析（溶析液爲乙酸乙酯：己烷（1 : 9))純化以生成白色固 體（48 mg, 12%); m.p‘ 237-238°C; 'H-NMR (200 MHz, CDCI3) · δ 1.17 (3H, d, J = 5.4 Hz), 1.23 (3H, d, J = 5.4 Hz), 2.23 (1H, m), 2.53 (3H, s), 4.14 (1H, m), 4.62 (1H. m), 7.80 (1H, s), 7.98 (1H, s), 8.07 (1H, s), 9.43 (1H, s) ； m/z (El) 3 79[M + ]。 化合物25:隔夜攪拌油浴（90-11(Γ(：)中之化合物1 -391 - 200918507 (297 mg，1毫莫耳）和無水碳酸鉀粉末（138 mg，！毫莫耳） 的混合物、碘化鋰（134 mg, 1毫莫耳）及3 -溴-1-丙醇（87 μΐ，1毫莫耳）的DM]F (5 ml)溶液。經冷卻至室溫後，真空 下蒸發該混合物並令殘餘物經矽膠管柱層析（溶析液爲乙 酸乙酯：己烷（2:1))純化以生成白色固體（138 mg，39%); m.p. 1 66- 1 67°C； *H-NMR (200 MHz, DMSO-d6)： δ 1.00 (3H, d, J = 7.0 Hz), 1.09 (3H, d, J = 7.0 Hz), 1.5 3 - 1.63 (2H, m), 2.09 (1H, m), 2.47 (3H, s), 3.08 (1H, m), 3.20-3.28 (2H, m), 3.68 (1H, m), 4.38 (1H, t, J = 5.4 Hz), 8.11 (1H, s), 8.24 (1H, s), 8.49 (1H, s), 11.45 (1H, s); m/z (El) 355 [M + ]。 化合物26:室溫下將溴替乙醯胺（3 8 8 mg, 2.81毫莫 耳）加入至化合物1 (836 mg, 2.81毫莫耳）、無水碳酸鉀粉 末（3 88 mg, 2.81毫莫耳）及碘化鋰（377 mg, 2.81毫莫耳）之 DMF (5 ml)攪拌混合物中。經隔夜攪拌後，真空下蒸發該 混合物並令殘餘物經矽膠管柱層析（溶析液爲甲醇：氯仿 (5:95))純化以生成白色固體（37〇1^,37%);111.1).275 -2760C ; W-NMR (200 MHz, DMSO-d6) ; δ 1,05 (3H, d， J = 7.0 Hz), 1.11 (3H, d, J = 7.0 Hz), 2.11 (1H, m), 2.45 (3H, s), 3.87 (1H, d, J=17.0 Hz), 4.02 (1H, d, J=17.0 Hz), 7.09 (1H, s), 7.34 (1H, s), 8.09 (1H, s), 8.19 (1H, s), 8.36 (1H, s) 11.56 (1H, s) ; m/z (El) 3 54[M + ]。 -392- 200918507 化合物27 :於氮氣下將三乙胺（210 μΐ，1·5毫莫耳）加 入至於冰浴中冷卻的4 -甲基-3-丁烯-1-醇（100 mg，1毫莫 耳）之氯仿（10 ml)的攪拌溶液中並逐滴加入甲烷磺醯氯（9〇 μΐ，1.2毫莫耳）。經攪拌1 · 1小時後，令該反應混合物經 飽和碳酸氫鈉水溶液沖洗，再經無水硫酸鎂乾燥，經過濾 及真空下蒸發。令殘餘物再於高真空下經乾燥約20分鐘 並與化合物1 (297 mg, 1毫莫耳）、無水碳酸鉀粉末（138 mg，1毫莫耳）及碘化鋰（134 mg，1毫莫耳）混合。隨後於室 溫下將DMF (5 ml)加入至該混合物中並進行隔夜攪拌。經 蒸發D M F後，令殘餘物溶解於甲醇-氯仿（1 : 9)中並經通過 寅氏鹽墊過濾。真空下蒸發濾液並令殘餘物經矽膠管柱層 析（溶析液爲乙酸乙酯：己烷（1 : 5))純化以生成白色固體（1 18 mg，31%); m.p. 192-194〇C; 】H-NMR (200 MHz，CDC13): δ 1.13 (3H, d, J = 7.0 Hz), 1.22 (3H, d, J = 7.0 Hz), 1.49 (3H, s), 1.62 (3H, s), 2.17-2.27 (4H, m), 2.52 (3H, s), 2.95 (1H, m), 3.75 (1H, m), 4.90 (1H, m), 7.79 (1H, s), 7.94 (1H, s), 8.05 (1H, s), 8.88 (1H, s) ； m/z(EI) 3 79 (M + ) -393- 200918507 反應圖8
2,4,6-三氯-5-乙 基嘧啶
2,4-雙(苄氧基)-6-氯-5-乙基嘧啶 3-((2,6-雙(苄氧基)-5-乙基 嘧啶-4-基)(氰基)甲基)-5-甲基苯甲腈
化合物28 3-(2,6-雙(苄氧基)-5-乙 基嘧啶-4-羰基)-5-甲基 苯甲腈 2,4-雙-苄氧基-6-氯-5-乙基·嘧啶：於氮氣下將金屬鈉 (2.17 g，94_6毫莫耳）加入至於水浴中之苄醇（80 ml)的攪 拌溶液中。經金屬鈉完全反應後，令該混合物於冰浴中冷 卻並分批加入2,4,6 -三氯-5-乙基-嘧啶（10.5 g，49.6毫莫耳 )。經於冰浴中攪拌3 0分鐘後，室溫下隔夜攪拌該反應混 合物。真空下蒸發過量之苄醇，令殘餘物溶解於乙醚中， 經水沖洗’經無水硫酸鎂乾燥，再經過濾及真空下蒸發以 生成灰黃色油。該粗產物經矽膠管柱層析（溶析液爲乙醚： 己烷（4:96))純化以生成白色固體（14§，8 0%);«1.]3.53-54°C ； 'Η NMR (200 MHz, CDC13) δ： 1.14 (3H, t, J = 7.4 Hz), 2.70 (2H, q, 2 = 1 Λ Hz), 5.41 (2H, s), 5.45 (2H, s), 7.34-7.5 3 ( 1 0H, m) ; m/z(EI) : 3 54 (M + )。 3-[(2,6-雙-苄氧基-5-乙基-嘧啶-4·基）-氰基-甲基]-5- 甲基-苯甲腈：於氮氣下將60%氫化鈉（2.34 g, 58.4毫莫耳 -394- 200918507 )分批加入至於冰水浴中的2,4-雙-苄氧基-6-氯-5-乙基-嘧 啶（9.89 g，27.87毫莫耳）和3-氰基甲基-5-甲基-苯甲腈 (4.15 g, 26.5 5毫莫耳）之無水DMF (50 ml)的攪拌混合物 中。經攪拌1小時後，室溫下隔夜攪拌該混合物。令該混 合物經飽和氯化銨水溶液中和。令粗產物經乙醚萃取並自 二氯甲烷-己烷中再結晶析出以生成灰黃色固體（10.3 g， 82%) ； m.p. 139-1410C; NMR (200 MHz，CDC13) δ: 1.00 (3H, t, J = 7.6 Hz), 2.37 (3H, s), 2.5 2-2.5 8 (2H, m), 5.29 (1H, s), 5.49 (4H, s), 7.2 7-7.5 0 ( 1 0H, m)； m/z (El) :474 (M + )。 3-(2,6-雙-苄氧基-5-乙基-嘧啶-4-羰基）-5-甲基-苯甲 腈：於氮氣下將6 0 %氫化鈉（8 6 9 m g，2 1 . 7毫莫耳）分批加 入至於水浴中的3-[(2,6-雙-苄氧基-5-乙基-嘧啶-4-基）·氰 基-甲基]-5 -甲基-苯甲腈（10 g，21.1毫莫耳）之無水DMF (8 0 ml)的攪拌溶液中。經3 0分鐘後’令氧氣經冒泡進入 該反應混合物達5小時。令該混合物經飽和氯化銨水溶液 中和。令粗產物經乙醒萃取並自二氯甲院-己院中再結晶 析出以生成白色固體（8 g，80%) ; m.p. 1 23- 124°C ; 4 NMR (20 0 MHz，CDC13) δ: 1·09 (3H，t, J = 7.4 Hz), 2.43 (3H, s), 2.50 (2H, q, J = 7.4 Hz), 5.35 (2H, s); 5.50 Γ2Η. s)，7.27-7.46 ( 1 0H，m)，7.67 (1H，s), 7.87 (1H, s)，7.92 (1H, s) ; m/z(EI) : 463 (M + )。 -395- 200918507 3-(5 -乙基-2,6-二側氧·1，2,3,6 -四氫-嘧啶-4-羰基）-5-甲基-苯甲腈（化合物28):氫氣下令3-(2,6-雙-苄氧基-5- 乙基-嘧啶-4-羰基）-5 -甲基-苯甲腈（4.5 g，9.7毫莫耳）之無 水乙醇（30 ml)和THF (30 ml)溶液與1〇%碳上鈀（Pd/C; 25〇 mg)攪拌。經1.5小時後，令該混合物經通過寅氏鹽墊 過濾並於真空下蒸發濾液。令殘餘物經矽膠管柱層析（溶 析液爲氯仿：甲醇（95:5))純化以生成白色固體（2.3 g，84%) ;m.p. 253 -254°C ； 1 H NMR ( 2 0 0 Μ Η z，D M S Ο - d 6) δ ： 0.84 (3Η, t, J = 7.0 Hz), 1.96 (2H, q, J = 7.0 Hz), 2.45 (3H, s)5 8.06 (1H, s), 8.11 (1H, s), 8.33 (1H, s), 11.05 (1H, s), 8_28 (1H, s) ; m/z(EI) : 2 8 3 (M + )。 -396- 200918507 反應圖9
,9 J CH3 /χ A Ο化合物28
O I CH
化合物29 O I Cl
〇化合物30
ο化合物31 Ο I Cl
o化合物32
o化合物33
κ 〇 J 乙〒h3 Λ A o化合物34 Ο I / CH,
化合物35 O I Cl
o化合物36 O I Cl
o化合物37 O I Cl
π〇 化合物36
試劑和條件:i.烷基鹵或甲磺酸烷酯，K2C〇3, DMF; ii. (：Η3(：Η20(：Η2(：Ι, SnCI4,乙腈 CH3CH2OCH2CI，SnCI4，乙腈 -397- 200918507 化合物29 :室溫下將碘乙烷（1 6 } μ1，1毫莫耳）加入至 化合物28 (297 mg，1毫莫耳）和無水碳酸鉀粉末（138 mg， 1笔旲耳）之DMF (5 ml)的攪拌溶液中。經隔夜攪拌後， 令該混合物經真空下蒸發並令殘餘物經矽膠管柱層析（溶 析液爲乙酸乙酯：己烷（1:2))純化以生成白色固體（134 mg, 43%) ; m.p. 23 7-23 8°C ； ^-NMR (200 MHz, CDC13) δ ： 0.97 (3H, t, J = 7.4 Hz), 1.16 (3H, t, 3 = 7.2 Hz), 1.95 (1H, m), 2.27 (ih, m), 2.53 (3H, s), 3.22 (1H, m), 3.92 (1H, m), 7.80 (in, S), 7.95 (1H, s), 8.05 (1H, s), 9.06 (1H, s) ;m/z (El) 3 1 1 [M + ]。 化合物31 :室溫下將碘乙烷（161 μΐ, 1毫莫耳）加入至 化合物30 (其係藉由利用類似於美國專利案號6,713,486 所描述之方法加以製備，該美國專利案之全部內容基於所 有目的係倂入本文作爲參考）（3 27 mg，1毫莫耳）和無水碳 酸鉀粉末（138 mg，1毫莫耳）之DMF (5 ml)的攪拌溶液中 。經隔夜攪拌後，令該混合物經真空下蒸發並令殘餘物經 矽膠管柱層析（溶析液爲乙酸乙酯：己烷（1:4))純化以生成白 色固體（149 mg, 42%) ; m.p. 220-22 1 °C ; W-NMR (200 MHz, CDC13): δ 1.12-1.21 (9H，m)，2.24 (1H，m), 3.20 (1H，m)，3.89 (1H，m), 7.71 (1H, t，J=1.8 Hz)，7.81 (2H, d, J = 1.8 Hz)，8.95 (1H，s) ; m/z (El) 3 54 [M + ]。 化合物33 :室溫下將碘乙烷（161 μΐ，1毫莫耳）加入至 -398- 200918507 化合物32 (其係藉由利用類似於美國專利案號6,713,486 所描述之方法加以製備）（3 13 mg，1毫莫耳）和無水碳酸鉀 粉末（138 mg，1毫莫耳）之DMF (5 ml)的攪拌溶液中。經 隔夜攪拌後’令該混合物經真空下蒸發並令殘餘物經矽膠 管柱層析（溶析液爲乙酸乙酯：己烷（1 :4))純化以生成白色固 體（204 mg，59%); m.p. 246-248°C; W-NMR (200 MHz, CDC13) ： δ 0.98 (3H, t, J = 7.4 Hz), 1.17 (3H, t, J = 7.0 Hz), 1.97 (1H, m), 2.28 (1H, m), 3.24 (1H, m), 3.92 (1H, m), 7.11 (1H, t, J = 2.0 Hz), 7.79 (2H, d, J = 2.0 Hz), 9.12 (1H, s) ; m/z (El) 340 [M + ]。 化合物35:室溫下將碘乙烷（161 μ1, 1毫莫耳）加入至 化合物34 (其係藉由利用類似於美國專利案號6,7 13,486 所描述之方法加以製備）（311 mg, 1毫莫耳）和無水碳酸鉀 粉末（138 mg, 1毫莫耳）之DMF (5 ml)的攪拌溶液中。經 隔夜攪拌後，令該混合物經真空下蒸發並令殘餘物經砂膠 管柱層析（溶析液爲乙酸乙酯：己烷（1:2))純化以生成白色固 體（106 mg, 31%); in.p. 28 7-284〇C; W-NMR (200 MHz， CDCI3) ： δ 1.10 (3H, t, J-7.0 Hz), 1.21 (9H, s), 2.53 (3H, s), 3.01 (1H, m), 3.94 (1H, m), 7.98 (1H, s), 8.04 (2H, br. s)，8.97 (1H，s) ; m/z (El) 3 3 9 [M + ]。 化合物37:室溫下將碘乙烷（54 μΐ，0.6 67毫莫耳）加 入至化合物36 (其係藉由利用類似於製備化合物28之方 -399- 200918507 法加以製備，除了使用3-氰基甲基-5-氯-苯甲腈以替代3-氰基甲基-5-甲基·苯甲腈）（212 mg，0.667毫莫耳）和無水碳 酸鉀粉末（92 mg，0.667毫莫耳）之DMF (3.5 ml)的攪拌溶 液中。經隔夜攪拌後，令該混合物經真空下蒸發並令殘餘 物經矽膠管柱層析（溶析液爲乙酸乙酯：己烷（1:2))純化以生 成白色固體（62 mg，27%); m.p. 248-249°C; iH-NMR (200 MHz, CDC13) ： δ 1.12-1.29 (9H, m), 2.20 (1H, m), 3.15 (1H, m), 3.91 (1H, m), 7.97 (1H, t, J = 1.8 Hz), 8.12-8.15 (2H，m), 8.59 (1H，s) ; m/z (El) 3 45 [M + ]。 化合物38:令化合物36 (219 mg, 0.689毫莫耳）、 1，1，1，3,3,3-六甲基二矽胺烷（5 ml)及氯三甲基矽烷（〇 2 ml) 之混合物回流4小時。經冷卻至室溫後，令該混合物經真 空下蒸發並令殘餘物溶解於乙腈（5 m 1)中。於攪拌下加入 氯甲乙醚（64 μΐ，0.689毫莫耳）和iM氯化錫之二氯甲烷 (40 μΐ，0.04毫莫耳）溶液。經隔夜攪拌後，加入過量之碳 酸氫鈉並攪拌1小時。令該混合物經真空下蒸發並令殘餘 物經矽膠管柱層析（溶析液爲乙酸乙酯：己烷（1:3))純化以生
成白色固體（206 mg, 79%); m.p. 162-164。(：； W.NMR (200 MHz, CDCI3) ： δ 0.79 (3Η, t, J = 7.0 Hz), 1.14 (2H, d, J = 7.0 Hz), 1.22 (3H, d, J = 7.〇 Hz), 2.21 (1H, m), 3.21-3.50 (2H, m), 4.68 (1H, d, J = 9.8 Hz), 5.56 (1H, d, J = 9.8 Hz), 7.92 (1H, t, J=1.8 Hz), 8.11 (2H, d, J=1.8 Hz), 8.47 (1H, s) ; m/z (El) 3 75 [M + ]。 -400- 200918507 反應圖ίο
化合物39
。辦N nh2 化合物26
化合物1
化合物40
化合物42 化合物41 試劑和條件:i_亞硫醯氯，苯;ii.乙基-4-溴丁酸酯，Lil, K2C03, DMF; iii.對-甲氧基苄基胺;iv.CAN，乙腈· 化合物39 :將亞硫醯氯（1 ml)和DMF (1滴）加入至化 合物26 (120 mg，0·338毫莫耳）之苯（15 ml)的攪拌溶液中 。令該混合物回流3小時。經冷卻至室溫後，令該混合物 經真空下蒸發並令殘餘物經矽膠管柱層析（溶析液爲乙酸 乙酯：己烷（1 : 1 ))純化以生成白色固體（49 mg，43%) ; m.p_ 270-2 7 1 oC ; ]H-NMR (200 MHz, DMSO-d6) : δ 1.05 (6H， br. s), 2.14 (1H, m), 2.46 (3H, s), 4.48 (2H, br. d), 8.12 (1H, s), 8.27 (1H, s), 8.52 (1H, s), 11.80 (1H, s) ； m/z (El) 3 3 6 [M + ]。 -401 - 200918507 化合物40 :隔夜攪拌油浴（100-115 °C)中之化合物1 (891 mg，3毫莫耳）和無水碳酸鉀粉末（414 mg，3毫莫耳） 的混合物、換化鋰（4〇2 mg，3毫莫耳）及乙基-4-溴丁酸酯 (43 2 μΐ，3毫莫耳）之dmF (15 ml)溶液。經冷卻至室溫後 ’令該混合物經真空下蒸發並令殘餘物經矽膠管柱層析（ 溶析液爲乙酸乙酯：己烷（1:2))純化以生成白色漿液（521 mg, 42%) ； ^-NMR (200 MHz, CDC13) ： δ 1.12 (3H, d, J = 7.0 Hz), 1.17-1.29 (8H, m), 1.85 (1H, m), 2.24 (2H, t, J = 6.8 Hz), 2.51 (3H, s), 3.10 (1H, m), 3.86 (1H, m), 4.12 (2H, q, J = 7.0 Hz), 7.79 (1H, s), 7.96 (1H, s), 8.06 (1H, s), 8.96 (1H, s)。
化合物41:於油浴（170〇c)中攪拌化合物4〇 (411 mg, 1毫莫耳）和對甲氧基苄胺（2 ml)達4小時。經冷卻至室溫 後，令該混合物經矽膠管柱層析（溶析液爲乙酸乙酯：己烷 (1:2))純化以生成灰黃色漿液（218 43%) ; W-NMR (200 MHz, CDC13) ： δ 1.09 (3Η, d, J = 6.8 Hz), 1.20 (3H, d, J = 6.8 Hz), 1.7 7- 1.97 (2H, m), 2.17 (2H, t, J = 6.8 Hz), 2.50 (3H, s), 3.23 (1H, m), 3.75 (3H, s), 3.82 (1H, m), 4.27 (2H, d, 5.4 Hz), 6.50 (1H, t, J = 5.4 Hz), 6.78 (2H, d, J = 7.5
Hz), 7.14 (2H, d, J = 7.5 Hz), 7.72 (1H, s), 7.99 (1H, s), 8.06 (1H, s)。 -402- 200918507 化合物42:室溫下將CAN (咼姉硝酸銨）（475 mg, 〇 86毫莫耳）加入至化合物41 (218 mg，0_43毫莫耳）之乙 腈（4 m 1)的攪拌溶液中’隨後加入蒸飽水（2 m 1)。經4 0分 鐘後，令該混合物經乙酸乙酯稀釋’經水沖洗、無水硫酸 鎂乾燥、過濾及真空下蒸發以生成褐色獎液。令粗產物經 矽膠管柱層析（溶析液爲甲醇：氯仿（3:97))純化以生成白色 固體（125 mg，75%) ; m.P· 261-262〇C ; 1H-NMR (200 MHz, DMSO-dg) : δ 1.00 (3H> d» J = 6.6 Hz), 1.08 (3H, d, J = 6.6 H z)，1 · 5 9 -1 _ 7 5 (2 H，m)，1 · 8 7 · 2.1 2 (3 H，m)，2 · 4 6 (3 H，s)， 3.03 (1H，m)，3·66 (1H，m)，6.66 (1H，s), 7_16 (1H，s)， 8.10 (1H, s)，8.24 (1H, s)，8.47 (1H，s)，11.45 (1H，s); m/z (El) 3 82 [M + ]。 反應圖11
化合物1 化合物43
化合物44 化合物45 試劑和條件:i_甲磺酸扣(特丁基-二苯基-矽烷氧基)-丁-2-炔基酯， Lil，K2C03, DMF; ii. TBAF, THF; iii. H2, Pd/C,乙醇/THF. -403- 200918507 化合物43 :於氮氣下將三乙胺（21〇 μ丨，ι_5毫莫耳）加 入至於冰浴中冷卻的4-特丁基-二苯基甲矽烷氧基-2_丁炔_ 1-醇（324 mg，1晕;莫耳）之氯仿（1〇 ml)的攪拌溶液中並逐滴 加入甲烷磺醯氯（90 μΐ，1.2毫莫耳）。經攪梓小時後， 令該反應混合物經飽和碳酸氫鈉水溶液沖洗，經無水硫酸 鎂乾燥，再經過濾及真空下蒸發。令殘餘物於高真空下再 經乾燥約20分鐘並與化合物1 (297 mg，1毫莫耳）、無水 碳酸鉀粉末（138 mg，1毫莫耳）及碘化鋰（134 mg, 1毫莫耳 )混合。隨後於室溫下將D M F (5 m 1)加入至該混合物中並 經隔夜攪拌。經蒸發D M F後，令殘餘物溶解於甲醇-氯仿 (1:9)中並經通過寅氏鹽墊過濾。真空下蒸發濾液並令殘餘 物經矽膠管柱層析（溶析液爲乙酸乙酯：己烷（1:4))純化以生 成無色漿液（370 mg, 61%) ; W-NMR (200 MHz，CDC13) : δ 0.98 (9Η, s), 1.10 (3Η, d, J = 6.8 Hz), 1.19 (3H, d, J = 6.8 Hz), 2.22 (1H, m), 2.37 (3H, s), 3.87 (2H, s), 4.06 (1H, d, J=18.0 Hz), 4.83 (1H, d, J=18.0 Hz), 7.3 5 -7.60 ( 1 1 H, m), 7.96 (1H，s)，8.06 (1H，s), 8.39 (1H，s)。 化合物44 :令化合物43 (3 70 mg, 0.61毫莫耳）溶解 於THF (5 ml)中並於室溫下與特丁基氟化銨（1M THF溶液 ;0 · 8 ml，0 · 8毫莫耳）攪拌達1小時。令該混合物經真空 下蒸發並令殘餘物經矽膠管柱層析（溶析液爲乙酸乙酯：己 烷（1:1))純化以生成白色固體（168 11^，75%);111.{).181-182°C ； ^-NMR (200 MHz, CDC13) ： δ 1.13 (3H, d, J = 6.8 -404- 200918507
Hz), 1.22 (3H, d, J = 6.8 Hz), 2.03 (1H, br. s), 2.26 (1H, m), 2.54 (3H, s), 3.90 (1H, d, J=16.6 Hz), 4.00 (1H, d, J=16.6 Hz), 4.12 (1H, d, J-18.2 Hz), 4.77 (1H, d, J=18.2 Hz), 7.80 (1H, s), 8.08 (1H, s), 8.19 (1H, s), 9.22 (1H, s) ;m/z(EI) 3 65 (M + )。 化合物45 :於室溫和氫氣下令化合物44 ( 1 00 mg， 0.27毫莫耳）與10% Pd/C (20 mg)之無水乙醇（8 ml)和THF (5 ml)溶液攪拌。經6小時後，令反應混合物經通過寅氏 鹽墊過濾並令該墊經乙醇和氯仿沖洗。令結合之濾液經真 空下蒸發並令殘餘物經矽膠管柱層析（溶析液爲乙酸乙醋： 己烷（1:1))純化以生成無色漿液（57 mg，56%)。自氯仿/乙 醚/己烷中再結晶析出以生成白色固體；m p丨19_12()(3e ; 【H-NMR (200 MHz，CDC13) : δ 1.11 (3h，d，J = 7 〇 Hz) 1.22 (3H, d，J = 7.0 Hz)，1.3 7- 1.5 8 (2H, m)，i 69 (2H m), 2.22 (1H，m), 2.53 (3H, s)，3.20 (1H，m)，3 5 3 _3 59 (2H，m), 3_88 (1H, m)，7.81 (1H，s), 7 98 (1H，s)，8 〇9 (1H，s)，10.02 (1H, s) ; m/z (El) 3 69 [M + ]。 -405- 200918507 反應圖12
化合物23
化合物46
22 化合物47 試劑和條件：i. H2, Pd/C,乙醇/THF. 化合物46 :於室溫和氫氣下令化合物23 (1 00 mg, 0.29 8毫莫耳）與10% Pd/C (20 mg)之無水乙醇（10 ml)和 THF (5 ml)溶液攪拌。經4.5小時後，令反應混合物經通 過寅氏鹽墊過濾並令該墊經乙醇和氯仿沖洗。令結合之濾 液經真空下蒸發並令殘餘物經矽膠管柱層析（溶析液爲乙 酸乙酯：己烷（1··3))純化以生成白色固體（81 mg，80%); m.p. 202-203°C ； 1 Η-N MR (2 0 0 M Hz，C D C13) ; δ 0 · 7 8 ( 3 Η， t, J = 7.4 Hz), 1.13 (3H, d, J = 7.0 Hz), 1.22 (3H, d, J = 7.0
Hz), 1.54-1.64 (2H, m), 2.24 (1H, m), 2.54 (3H, s), 3.02 (1H, m), 3.81 (1H, m), 7.82 (1H, s), 7.97 (1H, s), 8.07 (1H，s)，9.76 (1H, s) ; m/z (El) 3 3 9 [M + ]。 化合物47:於室溫和氫氣下令化合物22 (140 mg, 0.4 毫莫耳）與10% Pd/C (20 mg)之無水乙醇（10 ml)溶液攪拌 -406- 200918507 。經5小時後’令反應混合物經通過寅氏鹽墊過濾並令該 墊經乙醇和氯仿沖洗。令結合之濾液經真空下蒸發並令殘 餘物經矽膠管柱層析（溶析液爲乙酸乙酯：己烷（〗：2))純化以 生成無色漿液（8 8 m g，6 2 %)。自氯仿/乙醚/己烷中再結晶 析出以生成白色固體；m.p_ 1 3 3 - 1 3 4。(： ； A-NMR (200 MHz, DMSO-d6) : δ 0.71 (3H，t，J = 6.6 Hz), 0.99-1.17 (8H, m), 1.3 5 - 1.3 9 (2H, m), 2.09 (1H, m), 2.46 (3H, s), 2.97 (1 H, m)，3 _ 6 5 (1 H，m)，8 . 1 1 (1 H，s)，8.2 4 (1 H , s ), 8.4 9 (1H，s)，11.44 (1H，s) ; m/z (El) 3 53 [M + ]。 反應圖13
化合物42
化合物48 化合物4 8 :將亞硫醯氯（丨m i)和D M F (3滴）加入至化 合物42 (71 mg，〇·185毫莫耳）之苯（24 ml)的攪拌溶液中。 令該 '混合物回流3小時。經冷卻至室溫後，令該混合物經 胃發並令殘餘物經矽膠管柱層析（溶析液爲乙酸乙 己丨完（自1:1至2:1)純化以生成白色固體之化合物48 (54 mg, 8 0%) ; m p 224-225°C ； ]H-NMR (200 MHz, DMSO-d6) : δ 1.14 (3H, d，J = 7 〇 Hz), 1.22 (3H，d，J = 7.0 Hz), 1.84-2.02 (2H, m), 2.21-2.40 (3H, m), 2.54 (3H, s), •19 (1H, m), 4.03 (1H, m), 7.83 (1H, s), 8.03 (1H, s), 8.〇8 (1H，s)，9.58 (1H, s) ; m/z (El) 3 64 (M + )。 -407- 200918507 反應圖14
化合物49 化合物1 3-漠-N-(4-甲 氧基-苄基)-丙醯胺
化合物50 化合物51 化合物49:於油浴（90-110°C)中攪拌化合物1 (297 mg, 1毫莫耳）和無水碳酸鉀粉末（138 mg, 1毫莫耳）之混合 物、碘化鋰（134 mg, 1毫莫耳）及3-溴-N-(4-甲氧基-苄基）-丙醯胺（2 7 2 m g , 1毫莫耳）之D M F ( 5 m 1)溶液1 7小時。經 冷卻至室溫後，令該混合物經真空下蒸發並令殘餘物經矽 膠管柱層析（溶析液爲甲醇：氯仿（3:97))純化；收集 Rf=〇.15之分級液以生成白色漿液（73 mg, 15%)。h-NMR (200 MHz, CDC13) ： δ 1.11 (3Η, d, J = 6.8 HzHz), 1.18 (3H, d, J = 6.8 Hz), 2.22 (1H, m), 2.3 8-2.67 (5 H, m), 3.42 (1H, m), 3.79 (3H, s), 4.17 (1H, m), 4.27 (2H, d, J = 5.6 Hz), 5.96 (1H, t, J = 5.6 Hz), 6.81-6.88 (2H, m), 7.1 4-7.225 (2H, m), 7.80 (1H, s), 8.01 (1H, s), 8.04 (1H, s), 8.83 (1H, s) -408- 200918507 化合物50:將CAN (164 mg, 0.298毫莫耳）加入至室 溫下化合物49 (73 mg, 0.149毫莫耳）之乙腈（2 ml)的攪拌 溶液中，隨後加入蒸餾水（1 m 1)。經1 · 5小時後，令該混 合物經乙酸乙酯稀釋，經水沖洗，經無水硫酸鎂乾燥，再 經過濾及真空下蒸發以生成褐色漿液。令粗產物經矽膠管 柱層析（溶析液爲甲醇：氯仿（5 : 9 5 ))純化以生成白色固體之 化合物 50 (26 mg, 47%) ; m.p. 25 3 -25 4°C ; iH-NMR (200 MHz, CDC13) - δ 1.10 (3H, d, J = 6.6 Hz), 1.17 (3H, d, J = 6.6 Hz), 2.20 (1H, m), 2.40-2.70 (5H, ra), 3.40 (1H, m), 4.13 (1H, m), 6.12 (1H, s), 6.26 (1H, s), 7.80 (1H, s), 8.03 (1H, s), 8.11 (1H, s), 10.26 (1H, s) ； m/z (El) 368 (M + )。 化合物5 1 :將亞硫醯氯（1 m 1)和D M F (3滴）加入至化 合物50 (45 mg，0.122毫莫耳）之苯（10 ml)的攪拌溶液中。 令該混合物回流3小時。經冷卻至室溫後，令該混合物經 真空下蒸發並令殘餘物經矽膠管柱層析（溶析液爲乙酸乙 酯：己烷（2:1)純化以生成白色固體之化合物51 (33 mg， 76%) ； m.p. 195-196°C ； ^-NMR (200 MHz, CDC13) ： δ 1.13 (3H, d, J = 6.6 Hz), 1.20 (3H, d, J = 6.6 Hz), 2.23 (1H, m), 2.55 (3H, s), 2.65-2.86 (2H, m), 3.31 (1H, m), 4.20 (1H, m), 7.85 (1H, s), 8.02 (1H, s), 8.08 (1H, s), 9.14 (1 H, s) ; m/z (El) 3 5 0 (M + )。 -409- 200918507 反應圖15
化合物3 化合物52 化合物52 :藉由氧化化合物3 (例如藉由於大鼠微粒 體（In Vitro Technologies, MD)之磷酸鹽緩衝液（50 mM, pH 7.4)和NADPH (Gentest)之存在下進行培育）可製備化合物 52 °
化合物53 化合物53 :將羥基胺氫氯化物（2 62 mg, 3.77毫莫耳， 20當量）加入至化合物1 (56 mg，0.188毫莫耳）之乙醇（15 ml)溶液中。加熱反應混合物至回流狀態達3天。過濾除 去反應粗產物之沉澱物並令濾液經濃縮及逆相 HPLC (MeCN/水）純化以生成白色固體（19 mg，32%)。LC-MS顯 示 313.1 (M十 1)。'H NMR (300 MHz, CD3OD) : δ 7_81 (s, 1 Η), 7.70 (s, 1 Η), 7.61 (s, 1 Η), 2.44 (s, 3 Η), 2.38 (m, 1 Η)’ 1.71 (d， 6 Η)。 -410- 200918507
化合物54 化合物54:利用美國專利案號6，136,815 (其全部內 容基於所有目的係倂入本文作爲參考）所描述之方法，自 6-(3,5 -二甲基苯甲醯基）-5 -異丙基嘧啶_2,4(1H，3H) -二酮製 備上述之化合物54。
化合物56 令3-[3-(5 -異丙基-2,6-二側氧-1，2,3,6-四氫-嘧啶-4-羰 基）-5 -甲基-苯基]-丙烯腈（化合物55)(323 mg，1毫莫耳）、 HMDS (5 ml)及三甲基甲矽烷基氯（1〇 μΐ)之混合物回流4 小時。經冷卻至室溫後，令該混合物經真空下蒸發。隨後 令殘餘物溶解於乙腈（5 ml)中。將氯甲乙醚（93 μΐ，1毫莫 耳）加入至該攪拌溶液中，隨後加入氯化錫（1 Μ)之二氯甲 烷（1 〇〇 μΐ, 0_ 1毫莫耳）溶液。經隔夜攪拌後’將過量之碳 酸氫鈉加入至該反應混合物中。經攪拌3 0分鐘後’令該 混合物經真空下蒸發並令殘餘物經矽膠管柱層析（溶析液 爲乙酸乙酯：己烷（1:2))純化以生成無色漿液（170 mg，44%) -411 - 200918507 。自乙醚/己烷中再結晶析出以生成白色固體；NMR (200 MHz, CDC13) : δ 0.75 (3H，t，J = 7.0 Hz)，1.10 (3H，d， J = 6.8 Hz), 1.21 (3H, d, J = 6.8 Hz), 2.29 (1H, m), 2.47 (3H, s), 3.20-3.44 (2H, m), 4.77 (1H, d, J=10.0 Hz), 5.48 (1H, d, J = 10.0 Hz), 5.99 (1H, d, J=16.6 Hz), 7.43 (1H, d, J=16.6 Hz), 7.55 (1H, s), 7.77 (1H, s), 7.86 (1H, s), 8.73 (1H, s); m/z (LC/質量，El) 382 (M + H + )。 藉由許多不同之方法，如示於下述之反應圖16，可製 備3-[3-(5-異丙基-2,6-二側氧-1,2,3,6-四氫-嘧啶-4-羰基）-5 -甲基·苯基]-丙嫌腈（化合物55)。 反應圖16
化合物55 1-溴-3-溴甲基-5-甲基-苯：於鎢燈（500 W)光下令3,5-二甲基溴苯（80.25 g，0.43 M)、NBS (77 g，0_43 M)及苯甲 醯基過氧化物（5.2 g, 0.021 M)的混合物之四氯化碳（400 ml)溶液回流3小時。經冷卻至室溫後，過濾該混合物並 於真空下蒸發濾液以生成白色固體，其係經矽膠管柱層析 -412- 200918507 (溶析液爲己烷）純化以生成白色固體（82 g，72%)。m.p. 46-47°C ；NMR(200 MHz，CDC13) : δ 2.32 (3H, s), 4.38 (2H，s)，7.12 (1H，s), 7.25 (1H. s)，7_33 (1H，s)。 (3 _溴-5-甲基-苯基）-乙腈：對配備有額外漏斗之燒瓶 置入氰化鉀（29.6 g, 0.45 M)和蒸餾水（30 ml)。於攪拌下加 熱油浴中之該混合物達至7 0 ° C並經1小時藉由通過該額 外漏斗逐滴加入1-溴-3-溴甲基-5-甲基-苯（80 g，0.3 M)之 乙醇（1 5 0 m 1)溶液。經加入完成後，回流該混合物2小時 。經冷卻至室溫後，令該混合物經真空下蒸發並令殘餘物 分佈於乙醚和水中。取出乙醚層，經水沖洗，經無水硫酸 鎂乾燥，再經過濾及真空下蒸發以生成褐色殘餘物，其係 經矽膠管柱層析（溶析液爲乙醚：己烷（1:3))純化以生成淡褐 色油（47 g，74%)。4 NMR (200 MHz，CDC13) : δ 2.33 (3Η, s), 3.68 (2H, s), 7.08 (1H, s), 7.28 (1H, s), 7.29 (1H, (3-溴-5-甲基·苯基）-(5-異丙基-2,6-二甲氧基-嘧啶-4- 基）-乙腈：於氮氣下將60%氫化鈉（16 g，0.4 M)分批加入 至於冰水浴中之4·氯-5-異丙基-2,6-二甲氧基-嘧啶（47.63 g，0.22 M)和（3-溴-5-甲基-苯基）-乙腈（42 g, 0.2 M)的攪拌 混合物之無水DMF (220 ml)溶液中。經攪拌1小時後，室 溫下隔夜攪拌該混合物。令該混合物經飽和氯化銨水溶液 中和。令該粗產物經乙醚萃取並經矽膠管柱層析（溶析液 -413- 200918507 爲乙醚：己烷（1 :7))純化以生成白色固體（68 g，87%) ; m.p. 1 23 - 1 24°C； ]h NMR (200 MHz, CDC13)： δ 1.11 (3H, d, J = 6.9 Hz), 1.15 (3H, D, 1 = 6.9 Hz), 2.32 (3H, s), 2.97 (1H, m), 4.00 (3H, s), 4.01 (3H,s), 5.34 (1H, s), 7.14 (1H, s), 7.28 (1H, s), 7.31 (1H, s)。 (3-溴-5-甲基-苯基）-(5-異丙基-2,6-二甲氧基-嘧啶-4- 基）-甲酮：於氮氣下將60%氫化鈉（4.92 g, 0.12 M)分批加 入至於水浴中的（3-溴·5-甲基-苯基）-(5-異丙基-2,6-二甲氧 基-嘧啶-4-基）-乙腈（40 g，0.1 M)之無水DMF (300 ml)攪 拌溶液中。經3 0分鐘後，令氧氣經冒泡進入該反應混合 物中達2小時。令該混合物經飽和氯化銨水溶液中和。令 該粗產物經乙醚萃取並經矽膠管柱層析（溶析液爲乙醚：己 烷（1:9))純化以生成白色固體（34.6§,89%);1!1.?.122-123°C ； *H NMR (200 MHz, CDC13) ： δ 1.17 (6H, d, 1 = 1.1 Hz), 2.36 (3H, s), 2.77 (1H, m), 3.92 (3H, s), 4.05 (3H, s), 7 · 5 4 - 7 _ 5 6 (2 H，m)，7.7 5 (1 H，m)。 3-[3-(5-異丙基·2,6-二甲氧基-嘧啶-4-羰基）-5-甲基-苯 基]-丙烯腈：將乙酸鈉（9〇2 mg, 11毫莫耳）、乙酸鈀（224 mg, 1毫莫耳）、四（三苯膦）鈀（〇)(1.049 g，4毫莫耳）及丙 烯腈依此順序加入至（3 -溴-5 -甲基-苯基）-(5 -異丙基-2,6 -二 甲氧基-嘧啶-4-基）-甲酮（3.79 g, 10毫莫耳）之無水DMF (10 ml)的攪伴溶液中。於90-132°C(油浴）下攪泮該混合物 -414- 200918507 約23小時。經冷卻至室溫後，將乙醚和乙酸乙酯（2:1)加 入至該反應混合物中。隨後令該混合物經飽和碳酸氫鈉水 溶液沖洗，經水沖洗2次，經無水硫酸鎂乾燥，再經過濾 及真空下蒸發。令殘餘物經矽膠管柱層析（溶析液爲乙酸 乙酯：己烷（1 : 4 ))純化以生成白色固體（5 9 5 m g，1 7 %)。亦得 到白色固體之Z-異構物（275 mg，8%) ; m.p. 144- 1 45°C ; !H NMR (300 MHz, CDC13) ： δ 1.19 (6H, d, J = 6.9 Hz), 2.42 (3H, s), 2.83 (1H, m), 3.94 (3H, s), 4.08 (3H, s), 5.92 (1H, d, J=16.8 Hz), 7.39 (1H, d, J=16.8 Hz), 7.49 (1 H，s)，7.69 ( 1 H，s)，7.75 (1 H, s)。 Z 異構物：NMR (3 00 MHz, CDC13): δ 1.19 (6H， d, J = 7.2 Hz), 2.45 (3H, s), 2.84 (1H, m), 3.93 (3H, s), 4.06 (3H，s)，5.49 (1H, d，J:12.〇 Hz), 7.11 (1H, d, J=12.0
Hz), 7.75 (1H，s)，7.90 (1H，s)，7·97 (1H，s)。 3-[3-(5-異丙基- 2,6-二側氧-1,2,3,6-四氫·嘧啶-4-羰基 )-5-甲基-苯基]•丙烯腈（化合物55):將草醯氯（25 ml)加入 至3-[3-(5-異丙基-2,6-二甲氧基-嘧啶-4_羰基）-5-甲基-苯 基]-丙烯腈（5.36 g, 15.27毫莫耳）之無水THF (50 ml)攪拌 溶液中。隨後於激烈攪拌下令該混合物隔夜回流。經冷卻 至室溫後，令該混合物經真空下蒸發並令殘餘物經矽膠管 柱層析（溶析液爲乙酸乙酯：己烷（自1:1至4:丨））純化以生 成白色固體（2·7 g, 55%); m.p_ 2 3 3 -2 3 5 °C; 4 NMR (300 MHz, CD3OD/CDCI3) ： δ 1.16 (6H, d, J = 6. 9 Hz), 2.39- -415- 200918507 2.56 (4H, m), 6.12 (1H, d, J=16.6 Hz), 7.49 (1H, d, 3=16.6 Hz)，7.66 (1H，s)，7.83 (1H, s), 7.87 (1H，s) ; m/z (LC/質 量，El) 324 (M + H + )。
化合物57 化合物 57:依循文獻 Tanaka et al. J. Md. Ckw· 1991，3 49-3 5 7所描述之方法，令化合物54與氫硼化 鈉反應並隨後令所生成之中間產物與（二乙基胺基）硫三氟 化物（可購自Aldrich)反應，可得到化合物57。
化合物58 化合物 58:依循文獻 Tanaka et al. Λ Med. C/jem. 1991，3久3 49-3 5 7所描述之方法’令化合物54與氫硼化 鈉反應並隨後令所生成之中間產物與甲烷磺醯氯反應且與 鹼於甲醇中回流，可得到化合物58。 -416- 200918507 Γ\
化合物59 化合物59:利用類似於美國專利案號5,747,5 〇〇 (其 全部內容基於所有目的係倂入本文作爲參考）所描述之方 法’自6·(3,5- —甲基苯甲醯基）_5-異丙基嘧啶_ 2,4(1Η,3Η)-二酮製備化合物59。
化合物60 化合物60 :利用類似於美國專利案號5,747,5〇〇所描 述之方法，自6-(3,5-二甲基苯甲醯基）_5_異丙基嘧啶_ 2,4(1Η，3Η)-二酮製備化合物60。
化合物61 化合物61 :利用類似於美國專利案號6,7 1 3,4 86 (其 全部內容基於所有目的係倂入本文作爲參考）所描述之方 法，自6-(3,5 -二甲基苯基胺基）-5 -乙基嘧啶_2,4(1Η，3Η)- -417- 200918507 二酮製備化合物6 1。
化合物62 化合物62:利用類似於美國專利案號6,713,486所描 述之方法’自6-(3,5-二甲基苯基胺基）_5_乙基嘧啶_ 2,4(1H，3H)-二酮製備化合物62。
化合物63 :利用類似於美國專利案號 机6，7 1 3，4 8 6所描 述之方法’自6-(3,5-二甲基苯基胺基）乙基嘧啶· 2,4(1H，3H)-二酮製備化合物63。 反應圖Π
cr AcO^^i
化合物64
將（2-乙醯氧基乙氧基）甲基溴（I97 mg，丨毫莫耳；其 係藉由文獻丄 所.〜c. rraWi· 1 1 993, ρρ.1109- 1 1 1 1 所描 述之方 法加以 製備）加入至 化合物 1 (297 mg， 1 -418 - ’ 200918507 毫莫耳）和無水碳酸鉀粉末（138 mg, 1毫莫耳）之擾梓混合 物及碘化鋰（134 mg, 1毫莫耳）之DMF (5 ml)溶液中。室 溫下經隔夜攪拌後，令該混合物經真空下蒸發並令殘餘物 經矽膠管柱層析（溶析液爲乙酸乙酯：己烷（1:2))純化以生成 白色固體之化合物 64 (264 mg, 63%); ιη·ρ· 178 - 179。C; 'H-NMR (200 MHz, CDC13) ： δ 1.12 (3Η, d, J = 6.8 Hz), 1.21 (3H, d, J = 6.8 Hz), 2.00 (3H, s), 2.25 (1H, m), 2.51 (3H, s), 3.51-3.58 (2H, m), 3.77-3.83 (2H, m), 4.85 (1H, d, J=10.4 Hz), 5.48 (1H, d, J=10.4 Hz), 7.77 (1H, s), 7.97 (1H, s)，8.04 (1H, s), 8.78 (1H，s)。 室溫下令化合物64 (23 4 mg，0·5 66毫莫耳）與氫氧化 銨（2 ml)之THF (10 ml)和甲醇（1〇 ml)溶液經隔夜攪拌。隨 後令該混合物經真空下蒸發並令殘餘物經矽膠管柱層析（ 溶析液爲乙酸乙酯：己烷（自1 : 1至4 : 1))純化以生成白色泡 沬之化合物6 5 ( 1 8 0 m g，8 5 %) °自氯仿/乙醚/己垸中再結 晶析出以生成白色固體。m.p. 149_150°c; lH_NMR (200 MHz, CDCI3) : δ 1 · Π (3 Η, d，J = 7 · 0 Hz)，1.20 (3Η, d, J = 7.0 Hz), 2.12 (1H, br. s), 2.25 (1H, m), 2.51 (1H, s), 3.44-3.59 (4H, m), 4.93 (1H, d, J=10.6 Hz), 5.42 (1H, d, J-10.6 Hz), 7.76 (1H, s), 8.03 (1H, s), 8.11 (1H, s), 9.31 (1H，s)。 -419- 200918507 反應圖18
化合物66 化合物67 將3-溴丙烷-1-磺酸對甲氧基苄醯胺（322 mg, 1毫莫耳 ，藉由文獻 /. C/iem. 2006, 7 1，65 73 -6578 所描述之 方法製備（m_p. 1〇5-106°C; i-NMR (200 MHz，DMSO-d6) :δ 2.06-2.20 (2H，m)，3.03 (2H，t, J = 7.4 Hz), 3.55 (2H， t, J = 6.6 Hz), 3.74 (3H, s), 4.08 (2H, d, J = 6.2 Hz), 6.91 (2H, d, J = 8.6 Hz), 7.26 (2H, d, J = 8.6 Hz), 7.67 (1H, t, J = Hz); m/Z(EI) 321 (M + )，3 23 (M + 2 + )))加入至化合物 1 (297 mg, }毫莫耳）和無水碳酸鉀粉末（138 mg，1毫莫耳） 的攪拌混合物及碘化鋰（I34 mg，1毫莫耳）之DMF (5 ml) 溶液中。室溫下經隔夜攪拌後，令該混合物經真空下蒸發 並令殘餘物經矽膠管柱層析（溶析液爲甲醇：氯仿（3 :97))純 化以生成白色固體之化合物 66 (210 mg, 39%) ; m.p. 170°C ； 'H-NMR (200 MHz, CDC13)： δ 1.12 (3H, d, J-7.0 Hz), 1.20 (3H, d, J = 7.0 Hz), 1.93 -2.05 (2H, m), 2.22 (1H, m), 2.52 (3H, s), 2.81 (2H, t, J = 6.8 Hz), 3.28 (1H, m), 3.80 (3H, s), 3.96 (1H, m), 4.21 (2H, d, J = 5.8 Hz), 4.90 (1H, t，J = 5.8 Hz)，6·89 (2H，d，J = 7.0 Hz)，7.27 (2H, d， J = 7.0 Hz), 7.79 (1H, s), 7.96 (1H, s), 8.03 (1H, s), 8.82 (1H，s)。 -420- 200918507 室溫下將CAN (427 mg, 0.78毫莫耳）加入至化合物66 (210 mg，0.39毫莫耳）之乙腈（4 ml)攪拌溶液中，隨後加入 蒸餾水（2 m丨）。經2小時後，令該混合物經乙酸乙酯稀釋 ，經水沖洗，經無水硫酸鎂乾燥’再經過瀘及真空下蒸發 以生成褐色漿液。令該粗產物經矽膠管柱層析（溶析液爲 乙酸乙酯：己烷（自1:1至4:1))純化以生成白色固體之化合 物 67 ( 1 20 mg, 7 3%) ； m.p. 24 1 -242°C ； 'H-NMR (200 MHz, DMSO-d6) δ 0.99 (3H, d, J = 6.2 Hz), 1.07 (3H, d, J = 6.2 Hz), 1.80- 1.87 (2H, m), 2.08 (1H, m), 2.45 (3H, s), 2.84-2.8 7 (2H, m), 3.14 (1H, m), 3.81 (1H, m), 6.71 (2H, s), 8.09 (1H, s), 8.24 (1H, s), 8.47 (1H, s), 11.50 (1H, s) ;m/z (El) 4 1 8 (M + )。 反應圖19
化合物68 化合物69 將碘乙烷（〇·8 ml, l〇毫莫耳）加入至5-三氟甲基尿嘧 啶（1.8 g, 10毫莫耳）和無水碳酸鉀粉末（1.38 g, 10毫莫耳） 的攪拌混合物之DMF (50 ml)溶液中。室溫下經隔夜攪拌 後，令該混合物經真空下蒸發並令殘餘物經矽膠管柱層析 (溶析液爲乙酸乙酯：己烷（1:1))純化以生成白色固體之1_ 乙基-5-三氟甲基尿嘧啶（563 mg, 27%); m_p. 259-260°C; W-NMR (2 00 MHz, C D C13 / C D 3 O D) ： δ 1.35 (3H, d, J = 7.2 Hz), 3.87 (2H, q, J = 7.2 Hz), 7.94 (1H, s) ； m/z (El) 208 -421 - 200918507 (M + )。 於氮氣下以使溫度不會超過- 70。C之速率將2M LDA 之庚烷/THF/苯（2.2 ml，4.4毫莫耳）溶液加入至b乙基-5· 三氟甲基尿嘧啶（416 mg，2毫莫耳）之THF (10 ml)溶液中 。經攪拌該混合物1小時後，加入3 -氰基-5 ·甲基苯甲醛 (435 mg, 3毫莫耳）之THF (10 ml)溶液，同時維持溫度低 於-70°C。於-70°C下攪拌該混合物1小時並令其回溫至室 溫。令該溶液經濃鹽酸中和，經水稀釋並經乙酸乙酯萃取 。令有機層經飽和N aH C ◦ 3溶液沖洗，經μ g S Ο 4乾燥，再 經過濾且濃縮至乾燥狀態。令殘餘物經矽膠管柱層析（溶 析液爲甲醇：氯仿（3:97))純化以生成白色固體之化合物68 (552 mg, 78%) ； m.p. 260-262°C ； *H-NMR (200 MHz, DMSO-d6) ： δ 0.81 (3H, t, J = 6.0 Hz), 2.37 (3H, s), 3.58-3.65 (2H, m), 6.10 (1H, d, J = 5.2 Hz), 7.45 (1H, d, J = 5.2 Hz), 7.59 (1H, s), 7.63 (1H, s), 7.66 (1H, s), 11.87 (1H, s) ; m/z (El) 353 (M + )。 室溫下攪拌化合物68 (200 mg，〇.566毫莫耳）與重鉻 酸吡啶鎗（4 2 6 m g，1 · 1 3毫莫耳）之D M F (4 m 1)溶液。經2 4 小時後，令該混合物經真空下蒸發並令殘餘物經矽膠管柱 層析（溶析液爲乙酸乙醋：己院（1 : 2))純化以生成白色固體之 化合物 69 (173 mg, 87%) ; m.p’ 277-278°C ; ^-NMR (200 MHz, DMSO-d6): δ l.00 (3H，d，J = 6·8 Hz)，2.46 (3H，s)， 3.13 (1H，m), 3.80 (lH，m)，8·13 (1H，s)，8.28 (1H，s)， 8.54 (1H，s)，12.17 (1H，s) ·’ m/z (EI) 351 (M + )。 -422- 200918507 反應圖20
M 〇 ''Ν
化合物28 化合物70 將1-碘丁烷（114 μΐ，1毫莫耳）加入至化合物28 (283 mg，1鼋莫耳）和無水碳酸鉀粉末（138 mg, 1毫莫耳）的攪拌 混合物之DMF (5 ml)溶液中。室溫下經隔夜攪拌後，令該 混合物經真空下蒸發並令殘餘物經矽膠管柱層析（溶析液 爲乙酸乙酯：己烷（1:2))純化以生成白色固體之化合物70 (145 mg, 42%) ； m.p. 190-191°C ； Ή-NMR (200 MHz, CDC13) : δ 0.80 (3H，t，J = 7.4 Hz)，0.95 (3H，t，J = 7.4 Hz), 1.08- 1.28 (2H, m), 1.45- 1.60 (2H, m), 1-93 (1H, m), 2.26 (1H，m)，2.52 (3H，s), 3_06 (1H，m), 3.81 (1H, m), 7 79 (1H, s), 7.93 (1H，s), 8.04 (1H，s), 9.56 (1H, s) ; m/z (El) 3 3 9 (M + )。 反應圖21
化合物71 化合物36 將1-碘丁烷（114 μΐ, 1毫莫耳）加入至化合物36 (318 mg，1毫莫耳）和無水碳酸鉀粉末（138 mg，1毫莫耳）的攪拌 混合物之DMF (5 ml)溶液中。室溫下經隔夜攪拌後，令該 -423- 200918507 混合物經真空下蒸發並令殘餘物經矽膠管柱層析（溶析液 爲乙酸乙酯：己烷（1:2))純化以生成灰褐色固體之化合物71 (96 mg, 25%) ； m-P· 183-184°C ； ^-NMR (200 MHz, CDC13) ： δ 0.81 (3H, t, J = 7.4 Hz), 1.07- 1.28 (8H, m), 1.45 - 1.60 (2H, m), 2.20 (1H, m), 3.04 (1H, m), 3.81 (1H, m), 7.98 (1H, s), 8.13 (2H, s), 9.35 (1H, s) ； m/z (El) 373 (M + )。 反應圖22
溴甲基環丙烷 /K2C03/Lil/DMF/ 室溫 (84%)
3-[3-(3-環丙基甲基-5-異丙基-2,6-二側氧-1,2,3,6 -四 氫·嘧啶-4-羰基）-5-甲基-苯基卜丙烯腈（化合物72):室溫 下將溴甲基環丙烷（97 μΐ, 1毫莫耳）加入至3-[3-(5·異丙 基-2,6-二側氧-1,2,3,6-四氫-嘧啶-4-羰基）·5-甲基-苯基]- 丙烯腈（化合物55)(3 23 mg, 1毫莫耳）、無水碳酸鉀粉末 -424- 200918507 (1 65 mg, 1 .2毫莫耳）及碘化鋰（1 34 mg，1毫莫耳）之DMf (5 m 1)擾持溶液中。經隔夜攪拌後，令該混合物經真空γ 蒸發並令殘餘物經矽膠管柱層析（溶析液爲乙酸乙醋 (1:2))純化以生成白色固體之3-[3-(3·環丙基甲基_5_異丙 基-2,6-二側氧-1,2,3,6-四氫-嘧啶-4-羰基）-5-甲基·苯基]_ 丙烯腈（化合物72)(320 mg，84%)。令該產物自氯仿·乙酸 中再結晶析出以生成白色固體；m.p. 225 -226QC ; iH.NMR (3 00 MHz，CDC13) : δ 0.22-0.44 (4H，m)，0.93 (1H，m) 1.12 (3H, d, J = 6.9 Hz), 1.24 (3H, d, J = 6.9 Hz), 2.28 (1H, m), 2.50 (3H, s), 3.2 8 (1H, dd, J = 6.0 Hz, J=1 5.0 Hz), 3.59 (1H, dd, J = 6.0 Hz, J=15.0 Hz), 6.01 (1H, d, J=16.8 Hz), 7.44 (1H, d, J=16.8 Hz), 7.61 (1H, s), 7.77 (1H, s), 7.88 (1H，s)，9.00 (1H, s) ; m/z(EI) 3 77 (M + )。 3-[3-(3 -乙基-5-異丙基-2,6 - —•側氧-1,2,3,6 -四氨·嚼 啶-4-羰基）-5-甲基-苯基】-丙烯腈（化合物73):室溫下將碘 乙烷（97 4丨，1.2毫莫耳）加入至3-[3-(5-異丙基-2,6-二側 氧-1,2,3，6 -四氫-嘧啶-4-羰基）-5 -甲基-苯基]-丙烯腈（化合 物55)(323 mg，1毫莫耳）和無水碳酸鉀粉末（165 mg, 1.2 毫莫耳）之DMF攪拌溶液中。經隔夜攪拌後，令該混合物 經真空下蒸發並令殘餘物經矽膠管柱層析（溶析液爲乙酸 乙酯：己烷（1:2))純化以生成白色固體之3-[3-(3·乙基-5-異 丙基-2,6-二側氧-1,2,3,6-四氫-嘧啶-4-羰基）-5-甲基·苯基 ]-丙烯腈（化合物73)( 1 90 mg，54%)。令該產物自氯仿-乙 -425- 200918507 醚中再結晶析出；m.p. 1 74- 1 76°C; W-NMR (200 MHz, CDC13) ： δ 1.12-1.30 (9H, m), 2.29 (1H, m), 2.51 (3H, s), 3.25 (1H, m), 3.90 (1H, m), 6.06 (1H, d, J=16.8 Hz), 7.47 (1H, d, J=16.8 Hz), 7.64 (1H, s), 7.80 (1H, s), 7.92 (1H. s)，10·08 (1H，s) ; m/z(EI) 351 (M + )。 3-[3-(3-丁基-5-異丙基-2,6-二側氧-1,2,3,6-四氫-嘧 啶-4-羰基）·5-甲基-苯基]-丙烯腈（化合物74):室溫下將碘 丁烷（136 μΐ，1_2毫莫耳）加入至3-[3-(5-異丙基-2,6-二側 氧-1,2,3,6 -四氫-嘧啶-4-羰基）-5 -甲基·苯基]-丙烯腈（化合 物55)(323 mg，1毫莫耳）和無水碳酸鉀粉末（165 mg, 1.2 毫莫耳）之DMF攪拌溶液中。經隔夜攪拌後，令該混合物 經真空下蒸發並令殘餘物經矽膠管柱層析（溶析液爲乙酸 乙酯：己烷（1:2))純化以生成白色漿液之3-[3-(3-丁基-5-異 丙基-2,6-二側氧-1,2,3,6 -四氫-嘧啶-4-羰基）-5 -甲基-苯基 ]-丙嫌膳（化合物74)(170 mg, 44%)。令該產物自乙酸-己 烷中再結晶析出以生成白色固體；111_?.1 64- 1 65°(：;4-NMR (200 MHz, CDC13)： δ 0.79 (3Η, t, J = 7.2 Hz), 1.11- 29 (8H，m)，1.46- 1.5 7 (2H, m), 2.27 (1H，m), 2.50 (3H， s), 3.09 (1H, m), 3.77 (1H, m), 6.00 (1H, d, J=16.8 Hz), 7-44 (1H, d, J=16.8 Hz), 7.61 (1H, s), 7.74 (1H, s), 7.86 (1H, s)，8.75 (1H, s) ; m/z (El) 3 79 (M + )。 -426 - 200918507 反應圖23
3-[3-(3 -乙基-5-異丙基-2,6- —側氧- i，2,3,6 -四氫-喷 陡-4 -鍥基）-5 -甲基-苯基]-丙腈（化合物75):於室溫和氫氣 下攪拌3-[3-(3-乙基-5-異丙基-2,6-二側氧-1，2,3,6-四氫-喃 啶-4-羰基）-5 -甲基-苯基]-丙烯腈（化合物73)(190 mg, 0.54 毫莫耳）與10% Pd/C (20 mg)之無水乙醇（1〇 mi)溶液。經 1 7小時後，令該反應混合物經通過寅氏鹽墊過擴並令該墊 經乙醇和氯仿沖洗。令結合之濾液經真空下蒸發並令殘餘 物經矽膠管柱層析（溶析液爲乙酸乙酯：己院（1:2))純化以生 成白色泡沬之3-[3-(3 -乙基-5-異丙基-2,6-二側氧-l，2,3,6-四氫-I^密陡-4-羰基）-5-甲基-苯基]-丙腈（化合物75)(180mg， 9 4%)。自氯仿-乙醚中再結晶析出以生成白色固體；m.p. 1 73 - 1 74°C ； Ή-NMR (3 00 MHz, CDC13) ： δ 1.13-1.18 (6H, m), 1.23 (3H, d, J = 6.9 Hz), 2.31 (1H, m), 2.4 7 (3H, s), 2.70 (2H, t, J = 6.9 Hz), 3.04 (2H, t, J = 6.9 Hz), 3.25 (1H, m), 3.89 (1H, m), 7.45 (1H, s)5 7.66 (2H5 s), 9.17 (1H, s) ;m/z (El) 3 5 3 (M + )。 -427- 200918507 3-[3-(3-丁基-5-異丙基-2,6-二側氧-1，2,3,6-四氫-嘧 陡-4 -羰基）-5 -甲基-苯基]-丙腈（化合物76):於室溫和氫氣 下攙拌3-[3-(3-丁基-5-異丙基-2,6-二側氧- i,2,3,6-四氫-嘧 陡-4 -簾基）-5 -甲基-苯基]-丙燒腈（化合物74)(180 mg， 0.474毫莫耳）與10% Pd/C (20 mg)之無水乙醇（1〇 mi)溶液 。經1 7小時後，令該反應混合物經通過寅氏鹽墊過濾並 令該塾經乙醇和氣仿沖洗。令結合之據液經真空下蒸發並 令殘餘物經矽膠管柱層析（溶析液爲乙酸乙酯：己烷（1 : 2))純 化以生成白色泡沫之3-[3-(3 -丁基-5-異丙基- 2,6-二側氧_ 1,2,3,6-四氫-嘧啶-4-羰基）-5 -甲基-苯基]-丙腈（化合物 7 6)(1 2 0 m g，6 6 %)。自乙醚-己院中再結晶析出以生成白色 固體；m.p. 1 72- 1 73°C ; j-NMR (3 00 MHz，CDC13) : δ 0.79 (3H, t, J = 7.5 Hz), 1.12-1.24 (8H, m), 1.45- 1.5 9 (2H, m), 2.30 (1H, m), 2.46 (3H, s), 2.68 (2H, t, J = 7.2 Hz), 3.00-3.15 (3H, m), 3.79 (1H, m), 7.44 (1H, s), 7.63 (2H, s), 8.89 (1H，s) ; m/z (El) 381 (M + )。 -428- 200918507 反應圖24
3-(3,5-二異丙基_2,6-二側氧-^，夂。四氫_嘧啶_4羰 基）-5-甲基-苯甲腈（化合物77):將2_碘丙烷（2 ml, 2〇毫 莫耳）加入至3-(5-異丙基-2,6-二側氧- •四氫-嘧啶_ 4-羰基）-5-甲基-苯甲腈（化合物1)(5,94 g，2〇毫莫耳）和無 水碳酸鉀粉末（3.31 g，24毫莫耳）的攪拌混合物之dmf (4〇 ml)溶液中。於油浴（5 0-60°C)中隔夜攪拌該混合物並經真 空下蒸發。令該殘餘物經砂腰管柱層析（溶析液爲乙酸乙 酯：己烷（1:2))純化以生成白色固體之3-(3,5-二異丙基— 2,6-二側氧· 1，2，3，6 -四氫-嘧啶· 4 -羰基）-5 -甲基-苯甲腈（化合物 77)(700 mg, 10%) ; m.p. 27 8 -2 8 0°C ； 'H-NMR (200 MHz, CDC13) : δ 1_11 (3H，d, J = 7.0 Hz), 1_20 (3H，d，J = 7.0 Hz), 1.37 (3H，d, J = 6.6 Hz), 1.47 (3H, d, J = 6.6 Hz)，2.19 (1H, m)，2.5 4 (3 H，s)，3 _ 5 5 (1 H，m), 7 · 8 1 (1 H, s)，7 · 9 8 (1 H, s), -429- 200918507 8.07 (1H, s), 9.09 (1H，s) ; m/z (EI) 33 9 (M + )。 3-(3-異丁基_5-異丙基-2,6-二側氧-1，2,3,6 -四氫-喃陡· 4-羰基）-5-甲基-苯甲腈（化合物78):將2-碘_2_甲基丙烷 (460 μΐ，4毫莫耳）加入至3-(5-異丙基- 2,6-二側氧―丨，2,3,6-四氫-嘧啶-4-羰基）-5-甲基-苯甲腈（化合物1)(1.19 g，4毫 莫耳）和無水碳酸鉀粉末（662 mg，4·8毫莫耳）的攪拌混合 物之DMF (2〇 ml)溶液中。於油浴（5 0-60°C)中隔夜攪拌該 混合物並經真空下蒸發。令該殘餘物經矽膠管柱層析（溶 析液爲乙酸乙酯：己烷（1:2))純化以生成白色固體之3-(3-異 丁基-5-異丙基- 2,6-二側氧-1，2,3,6-四氫-嘧啶-4-羰基）-5-甲基-苯甲腈（化合物 78)(500 mg, 35%); m.p, 200-201 °C; (H-NMR (200 MHz, CDC13) : δ 0.80 (3H, d, J = 3_2 Hz), 0.83 (3H, d, J = 3.2 Hz), 1.12 (3H, d, J = 7.0 Hz), 1.23 (3H, d), J = 7.0 Hz), 1.90 (1H, m), 2.25 (1H, m), 2.53 (3H, s), 2.93 (1H, dd, J=14.2 Hz, J = 7.4 Hz), 3.75 (1H, dd, J=14.2 Hz, J = 7.4 Hz), 7.80 (1H, s)5 7.92 ( 1 H, s), 8.03 (1H, s), 9_〇3 (1H，s) ; m/z (El) 3 5 3 (M + )。
3-(3-丁基-5-異丙基-2,6-二側氧-1,2,3，6 -四氫-嘧啶_4-羰基）-5-甲基-苯甲腈（化合物47广將碘丁烷（1.37 ml，12 毫莫耳）加入至3-(5-異丙基-2,6-二側氧-1，2,3,6-四氫-嘴 啶_4·羰基）-5-甲基-苯甲腈（化合物1)(2.97 g，10毫莫耳）和 無水碳酸鉀粉末（1.66 g, 12毫莫耳）的攪拌混合物之DMF .430 - 200918507 (20 ml)溶液中。於油浴（5〇-60°C)中攪拌該混合物24小時 並經真空下蒸發。令殘餘物經矽膠管柱層析（溶析液爲乙 酸乙酯：己烷（1:2))純化以生成白色泡沫之3-(3-丁基-5·異 丙基-2,6-二側氧-12,3,6-四氫-嘧啶-4-羰基）-5-甲基-苯甲 腈（化合物 47)(1.78 g，50%); h-NMR (200 MHz, CDC13) ：δ 0.80 (3H, d, J = 3.2 Hz), 0.83 (3H, d, J = 3.2 Hz), 1.12 (3H, d, J = 7.〇 Hz), 1.23 (3H, d), J = 7.0 Hz), 1.90 (1H, m), 2.25 (1H, m), 2.53 (3H, s), 2.93 (1H, dd, J=14.2 Hz, J = 7.4 Hz), 3.75 (in, dd, J=14.2 Hz, J = 7.4 Hz), 7.80 (1H, s), 7.92 (1H, s), 8.03 (1H, s), 9.03 (1H, s) ； m/z (El) 353 (M + )。 反應圖25
(」_3·烯基-5-異丙基-2,6-二側氧-1,2,3,6-四氫-嘧 陡-4-鑛基）·5-甲基-苯甲腈（化合物79):於氮氣下將三乙 胺（630 μΐ，4.5毫莫耳）加入至於冰浴中冷卻的3_ 丁烯·丨_醇 (2 16 mg, 毫莫耳）之氯仿（20 ml)攪拌溶液中並逐滴加入 -431 - 200918507 甲烷磺醯氯（270 μΐ，3.6毫莫耳）。經攪拌1.1小時後，令 反應混合物經二氯甲烷稀釋，經飽和碳酸氫鈉水溶液沖洗 ，經無水硫酸鎂乾燥，再經過濾及真空下蒸發。令殘餘物 再經高真空下乾燥約20分鐘並與3-(5-異丙基-2,6-二側 氧-1,2,3，6·四氫-嘧啶-4-羰基）-5-甲基-苯甲腈（化合物 1)(891 mg, 3毫莫耳）、無水碳酸鉀粉末（414 mg, 3.6毫莫 耳）及碘化鋰（4 02 mg，3毫莫耳）混合。隨後將DMF (15 ml) 加入至該混合物中並於油浴（40-5 0°C)中經隔夜攪拌。經蒸 發DMF後，令殘餘物溶解於甲醇-氯仿（1 :9)中並經通過寅 氏鹽墊過濾。令濾液經真空下蒸發並令殘餘物經矽膠管柱 層析（溶析液爲乙酸乙酯：己烷（1:2))純化以生成白色泡沫之 3_(3-丁 - 3-烯基-5-異丙基-2,6-二側氧-1,2,3,6-四氫-嘧啶- 4-羰基）-5-甲基-苯甲腈（化合物79)(320 mg，30°/。）。自乙醚-己烷中再結晶析出以生成白色固體；111·?··^3-：^々。*：;1!!-NMR (3 0 0 MHz, CDC13): δ 1_13 (3H，d, J = 6.9 Hz)，1.22 (3H, d, J = 6.9 Hz), 2.19-2.34 (3H, m), 2.54 (3H, s), 3.15 (1H, m), 3.90 (1H, m), 4.94-5.02 (2H, m), 5.58 (1H, m), 7.82 (1H, s), 7.96 (1H, s), 8.06 (1H, s), 8.99 (1H, s) ； m/z (El) 35 1 (M + )。 3-(3-丁 - 2-烯基-5-異丙基-2，6-二側氧-1,2,3,6 -四氫-嘧 啶-4 -羰基）-5 -甲基·苯甲腈（化合物80):室溫下將巴豆基 氯（97 μΐ, 1毫莫耳）加入至3-(5-異丙基-2,6-二側氧-1,2,3,6 -四氫-嘧啶-4 -羰基）·5 -甲基-苯甲腈（化合物1)(297 -432- 200918507 mg, 1毫莫耳）、無水碳酸鉀粉末（165 mg, 1.2毫莫耳）及碘 化鋰（134 mg, 1毫莫耳）之DMF (5 ml)攪拌溶液中。經隔 夜攪拌後，令該混合物經真空下蒸發並令殘餘物經矽膠管 柱層析（溶析液爲乙酸乙酯：己烷（1:2))純化以生成白色固體 之 3-(3 -丁 - 2-稀基-5-異丙基-2,6 - _•側氧-1,2,3,6 -四氨- II·密 啶·4·羰基）-5-甲基-苯甲腈（化合物80)(3 00 mg，85%)。令 該產物自氯仿-乙醚-己烷中再結晶析出以生成白色固體； m.p. 1 77- 1 7 8°C ； ^-NMR (300 MHz, CDC13) ： δ 1.12 (3H, d, J = 6.6 Hz), 1.21 (3H, d, J = 6.6 Hz), 1.44 (3H, d, J = 5.1 Hz), 2.22 (1H, m), 2.53 (3H, s), 4.02-4.20 (2H, m), 5.19-5.43 (2H, m), 7.78 (1H, s), 7.93 (1H, s), 8.03 (1H, s)5 8.95 (1H, s) ; m/z(EI) 35 1 (M + )。 反應圖26
濃 HCl-MeOH 回流/6小時 (70%)
Etl/K2C03/ DMF/室溫 (63%)
MOMCI/NaH/ DMF (91%) 4-氯-5-異丙基-2,6-二甲氧基-嘧啶
丙基-
6-氯-1-乙基-5-異丙基 3-[氰基-(3-乙基-5-異丙基-1- 化合物81 -3-甲氧基甲基-1H-嘧 甲氧基甲基-2,6-二側氧-1,2,3 陡-2,4-二酮 ，6-四氫-瞎啶-4·基)-甲基]-5-甲 基-苯甲腈 6-氯-5-異丙基-1H-嘧啶-2,4-二酮：令4-氯-5-異丙基- 2,6-二甲氧基-嘧啶（40 g, 18.47毫莫耳）溶解於濃HC1-甲醇 (1 5 0 m 1，1 : 2)中並經回流6小時。令該混合物經真空下蒸 -433- 200918507 發並令殘餘物經矽膠管柱層析（溶析液爲氯仿：甲醇（自95 : 5 至90:10))純化以生成白色固體之6 -氯-5-異丙基-111_嘧啶-2,4-二酮（24.4吕，70 0/〇);111.卩.250-251。(：；1只41411(200 MHz, CDC13) ： δ 1.25 (6Η, d, J = 7.1 Hz), 3.13 (1H, m)； m/z (El) 1 8 8 (M + )。 6 -氯-1-乙基-5-異丙基-1H -嘧陡-2,4 -二酮：室溫下攪 拌6 -氯-5-異丙基-1H -喃陡-2,4 -二酮（18·8 g，100毫莫耳）與 無水碳酸鉀粉末（16.56 g，120毫寞耳）之DMF (200 ml)溶 液。經40分鐘後，加入碘乙院（8 ml，1〇〇毫莫耳）並令該 混合物經隔夜攪拌。令該混合物經真空下蒸發並令殘餘物 經砂膠管柱層析（丨谷析液爲乙酸乙醋：己院（自1 : 4至1:2)) 純化以生成白色固體之6·氯-1-乙基-5_異丙基_1H_喃；D定_ 2,4 -一酮（13_8 g，63%); m.p. i60-161oC; iH-NMR (200 m)，3.22 (1H，m)，4.15 MHz，CDC13) ; δ 1.28- 1.3 5 (9H, m), (2H，q，J = 7.2 Hz) ; m/z (El) 216 (M + )。 6-氯-1-乙基-5-異丙基·3_甲氧基甲基_iH•嘧啶_2,心二 6 %莫耳）加入至於水浴中之 :_2,4_ 二酮（1 1 .5 g, 53 毫莫 酮··將 60% NaH (3.18 g，79.6 臺 。經攪拌40分鐘後，加入
6 -氯-1-乙基-5-異丙基-1H -嚼π定-2 耳）之DMF (100 ml)攪拌溶液中。 工業級氯甲基甲乙醚（7.6 ml，8〇 -434- 200918507 油之6 -氯-1-乙基-5-異丙基-3-甲氧基甲基-1H -嘧啶-2,4 -二 酮（12.6 g，91%) ; 'H-NMR (200 MHz，CDC13) : δ 1.26-1.34 (9Η，m)，3.24 (1Η，m)，3.44 (3Η，s), 4.16 (2Η，q，J = 7.0
Hz)，5.35 (2H，s) ; m/z (El) 260 (M + )。 3-[氰基-(3-乙基·5_異丙基·；!_甲氧基甲基- 2,6-二側氧-1，2,3,6-四氫-嘧啶-仁基卜甲基】-5_甲基-苯甲腈：將60%
NaH (48 3 mg，12毫莫耳）加入至於水浴中的6-氯-1-乙基-5 -異丙基-3-甲氧基甲基-1H_嘧啶_2,4 -二酮（1.43 g，5.48毫 莫耳）和3 -氰基-5-甲基苄基氰化物（857 mg, 5_48毫莫耳） 之DMF (1 2 ml)攪拌溶液中。經1 5分鐘後，令該混合物於 室溫下經隔夜攪拌。將過量之氯化銨加入至該混合物中並 持續攪拌1小時。令該混合物經真空下蒸發並令殘餘物經 矽膠管柱層析（溶析液爲乙酸乙酯：己烷（自1:4至2:3))純 化以生成黃色固體之3-[氰基- (3-乙基-5_異丙基-1-甲氧基 甲基-2,6-二側氧-1,2,3,6 -四氫-嘧啶-4-基）-甲基]-5-甲基-苯甲腈（1.6 g，80%) ; m.p· 2〇2-2050C ; W-NMR (200 MHz， DMSO-d6) ： δ 0.77 (3H, d, J = 6.8 Hz), 1.10 (3H, t, J = 6.8 Hz), 1.20 (3H, d, J = 6.8 Hz), 2.40 (3H, s), 2.55 (1H, m), 3.71 (1H, m), 4.05 (1H, m), 5.21 (2H, dd, J=11.2 Hz, 3 = 9.4 Hz), 6.26 (1H, s), 7.60 (1H, s), 7.69 (1H, s), 7.73 (1 H, s) ; m/z (El) 3 8 0 (M + )。 3-[氰基- (3-乙基_5_異丙基-2,6-二側氧-1,2,3,6-四氫- -435- 200918507 嘧啶-4-基）-甲基】-5-甲基-苯甲腈（化合物85):室溫下將二 甲硫（804 μΐ，1〇毫莫耳）和三氟化硼-二乙醚（300 μΐ，2.37 毫莫耳）加入至3-[氰基- (3-乙基-5-異丙基-1-甲氧基甲基-2,6-二側氧-1，2,3,6 -四氫-嘧啶-4-基）-甲基]-5 -甲基-苯甲腈 U 90 mg, 〇.5毫莫耳）之二氯甲烷（5 ml)攪拌溶液中。經攪 拌3天後，令該混合物經真空下蒸發並令殘餘物經矽膠管 柱層析（溶析液爲乙酸乙酯：己烷（1 : 1))純化以生成白色固體 之3-[氰基- (3-乙基-5-異丙基-2,6-二側氧-1,2,3，6 -四氫-嘧 啶-4-基）-甲基卜5_甲基-苯甲腈（15〇 mg，89。/。）。令該產物自 氯仿-甲醇-乙醚中再結晶析出；m.p. 260-26 TC; h-NMR (200 MHz, DMSO-d6) : δ 0.77 (3H，d, J = 6.6 Hz)，1.07 (3H， t，卜7.0 Hz), 1.19 (3H, d，J = 6.6 Hz), 2.41 (3H, s)，2.49 (1H, m), 3.68 (1H, m), 4.00 (1H, m), 6.22 (1H, s), 7.59 (1H, s), 7.71 (1H, s), 7.73 (1H, s), 11.45 (1H, s)； m/z (El) 3 3 6 (M + )。 反應圖27
NaOMe 5-氧雜-螺[2-4] 庚-6-酮
MeOH OCH, (1-羥基甲基-環 （1-乙烷磺醯氧基甲基 丙基)-乙酸甲酯-環丙S)-乙酸甲_
MsCI/EI3N CH2a2 -60-0°C
OCHj
LiOH THF D> 回流
% OH 化合物83
1) CIC0C0C_F THF/0°C 2) PMBNH2/THF
CAN NHPMB ACN/Ac0H/H20 \X' och3 化合物82 ?h3
nh2 化合物84 化合物85 (1_羥基甲基-環丙基）_乙酸甲酯：將甲醇鈉（ 1.296 g， -436- 200918507 24毫莫耳）加入至於水浴中的粗製5-氧雜-螺[2.4]庚-6-酮 (2.24 g,約20毫莫耳；依據EP 〇 678 515 A1 (其全部內 容基於所有目的係併入本文作爲參考）所描述之方法加以 製備；雜質係N，N -二甲基乙醯胺）之無水甲醇（40 ml)攪拌 溶液中。經15分鐘後，加入氯化銨（2 g)並於室溫下攪拌 該混合物3 0分鐘。令該混合物經真空下蒸發並令殘餘物 經矽膠管柱層析（溶析液爲乙酸乙酯：己烷（1:1))純化以生成 無色油之（卜羥基甲基-環丙基）-乙酸甲酯（5.8§，47%);11 NMR (200 MHz，CDC13) : δ 0.47-0.61 (4 Η，m)，2.4 4 (2 Η , s)，2.55 (1Η，t，J = 5.6 Hz), 3.48 (2Η，d, J = 5.6 Hz), 3.69 (3H，s)。 (1-甲烷磺醯氧基甲基-環丙基）-乙酸甲酯：將甲烷磺 醯氯（483 μΐ，6.24毫莫耳）加入至於乾冰-丙酮浴（_4〇。〇中 冷卻的（1-經基甲基-環丙基）-乙酸甲醋（600 mg，4.16毫莫 耳）之二氯甲烷（10 ml)攪拌溶液中。隨後冷卻該混合物至· 6〇°C並加入三乙胺（928 μΐ, 6.66毫莫耳）。於攪拌下令該 混合物經1小時回溫至0〇C »經冷卻該混合物至-1 5 °C後 ’依序加入冰冷3N HC1溶液（〇.6 ml)、冰冷鹽水（2 ml)及 二氯甲烷（25 ml)。令該混合物經冰冷鹽水（25 ml)沖洗2次 ’經MgS〇4乾燥，再經過濾及真空下蒸發以生成無色油之 粗製（1-甲烷磺醯氧基甲基-環丙基）_乙酸甲酯（962 mg(定量 ))°該粗產物係未經進一步之純化而直接用於下一個反應 中。1H-NMR (200 MHz, CDC13) ： δ 0.62-0.72 (4Η, m), -437- 200918507 2_42 (2H, s)，3.02 (3H，s)，3.70 (3H，s)，4.17 (2H，s)。 {1-[6·(3-氰基-5-甲基-苯甲醯基）_5_異丙基_2,4·二側 氧_3,4-二氫-2H-嘧啶-1-基甲基卜環丙基}_乙酸甲酯（化合 物82):室溫下將DMF (18 ml)加入至3-(5 -異丙基·2,6 -二 側氧-1，2,3,6-四氫-嘧啶-4 -羰基）·5_甲基-苯甲腈（962 mg, 4.16毫莫耳）、無水碳酸鉀粉末（π# mg，4.16毫莫耳）及拂 化鋰（557 mg，4.16晕旲耳）之混合物中。經攪梓3〇分鐘後 ，加入粗製（1-甲烷磺醯氧基甲基-環丙基）_乙酸甲酯（962 mg)之DMF (2 ml)溶液。隨後於油浴（7〇_8〇〇c)中加熱該混 合物並經攪拌約1 9小時。經冷卻至室溫後，令該混合物 經真空下蒸發。令殘餘物溶解於甲醇-二氯甲烷（5:95)中並 經通過寅氏鹽墊過濾。蒸發濾液並令該殘餘物經矽膠管柱 層析（溶析液爲乙酸乙酯：己烷（1 :2))純化以生成白色漿液之 {1-[6-(3 -氰基-5 -甲基-苯甲醯基）_5_異丙基-2,4-二側氧-3,4-二氫-2H-嘧啶-l-基甲基]-環丙基}-乙酸甲酯（化合物 SaWSOmg’Uo/OoiH-NMRpOOMHz’CDClOlOM-0.65 (4H, m), 1.12 (3H, d, J = 7.0 Hz), 1.23 (3H, d, J = 7.0 Hz), 2.17-2.32 (2H, m), 2.44-2.52 (4H, m), 3.58 (1H, d, J=15.2 Hz), 3.69 (3H, s), 3.76 (1H, d, J=15.2 Hz), 7.79 (1H, s), 7.95 (1H, s), B.06 (1H, s), 9.36 (1H, s) ； m/z (El) 423 (M + )。 {l-【6-(3-氰基-5-甲基·苯甲醯基）-5-異丙基-2,4-二側 -438- 200918507 氧-3，4-二氫-2Η·嘧啶-1-基甲基】-環丙基卜乙酸（化合物83) :將氫氧化鋰（20 mg，0_8毫莫耳）和2滴水加入至 (3-氰基-5-甲基-苯甲醯基）-5-異丙基-2,4-二側氧-3,4-二氫_ 2H-嘧啶-卜基甲基]-環丙基}•乙酸甲酯（170 mg，0.4毫莫耳 )之THF (4 ml)攪拌溶液中。令該混合物回流2小時。經 冷卻至室溫後，令該混合物經真空下蒸發並令殘餘物經砂 膠管柱層析（溶析液爲乙酸乙酯至2 0 %甲醇之乙酸乙酯}容 液）純化以生成白色固體之U-[6-(3-氰基-5-甲基-苯甲酿基 )-5-異丙基-2,4-二側氧-3,4 - 一氣- 2H -嚼陡-1-基甲基]-環丙 基}-乙酸（化合物83)(10〇111§，62%)。111.卩.244-245。〇；;11·!-NMR (5 00 MHz, DMSO-d6) : δ 0.21-0.26 (2Η, m), 0.34- 0.36 (1H，m)，0.46-0.48 ( 1 H，m)，0.98 (3H, d，J = 6.8 Hz)， 1.08 (3H，d，J = 6.8 Hz), 2.06-2.12 (2H，m)，2.23 (1H，d， J = 17.0 Hz)，2.44 (3H, s)，3.32 (1H，d，J=15.0 Hz), 3.74 (1H，d，J=15.0 Hz)，8.08 (1H，s)，8.19 (1H，s)，8.43 (1H， s), 11.45 (1H，s)，12.02 (1H，br. s) ; m/z (El) 409 (M + )。 2-{l-[6-(3 -氰基_5_甲基-苯甲酿基）_5_異丙基- 2,4_二側 氧_3,4-二氫- 2Η·嗤陡-1-基甲基]-環丙基}-Ν-(4·甲氧基-节 基）-乙醯胺（化合物84):將草醯氯（38 μΐ，0.44毫莫耳）和1 滴DMF加入至於冰浴中冷卻的Π·[6_(3-氰基-5-甲基-苯甲 醯基）-5-異丙基-2,4·二側氧- 3,4-二氫_2Η_嘧啶-^基甲基]_ 環丙基}-乙酸（90 mg，0.22毫莫耳）之THF (5 ml)攪拌溶液 中。經攪拌1小時後，令該混合物經真空下蒸發。令殘餘 -439- 200918507 物溶解於THF (8 ml)中並加入對甲氧基苄胺（261 μΐ，2毫 莫耳）。經攪拌1小時後，令該混合物經真空下蒸發並令 殘餘物經矽膠管柱層析（溶析液爲乙酸乙酯：己烷（2 : 1):收 集Rf=0.25分級液）純化以生成白色固體之2-{1-[6-(3-氰 基-5-甲基-苯甲醯基）-5 -異丙基-2,4-二側氧-3,4-二氫-2H-嘧啶-卜基甲基]-環丙基}-N-(4_甲氧基-苄基）-乙醯胺（化合 物 84)(97 1^，83%)。】1^河11 (200]^112,〇〇(：13):5 0.40- 0.46 (4H, m), 1.12 (3H, d, J = 6.6 Hz), 1.23 (3H, d, J = 6.6 Hz), 2.00 (1H, d, J-15.4 Hz), 2.25 (1H, m), 2.4 8-2.5 5 (4H, m), 3.45 (1H., d, J = 15.4 Hz), 3.80 (3H, s), 3.90 (1H, d, J=15.4 Hz), 4.3 4-4.3 9 (2H, m), 6.69 (1H, m), 6.83-6.90 (2H, m), 7.22-7.3 0 (2H5 m), 7.81 (1H, s), 8.01 (1H, s), 8.07 (1 H，s), 9_81 (1 H5 s)。 2-{l-[6-(3-氰基-5-甲基-苯甲醯基）-5-異丙基-2,4-二側 氧-3,4 -二氫-2H-嘧啶-1-基甲基]-環丙基}-乙醯胺（化合物 85):室溫下依序將高鈽硝酸銨（201 mg, 0.36毫莫耳）和水 (2 ml)加入至2-{1-[6-(3 -氰基-5-甲基-苯甲醯基）-5 -異丙 基-2,4-二側氧- 3,4-二氫-2H-嘧啶-1-基甲基]-環丙基卜N-(4-甲氧基-苄基）-乙醯胺（97 mg，〇_18毫莫耳）之乙腈（4 ml) 和冰醋酸（1 ml)的攪拌溶液中。經攪拌20分鐘後，令該混 合物經乙酸乙酯稀釋，經水沖洗2次，經MgSCU乾燥’再 經過濾及真空下蒸發。令殘餘物經矽膠管柱層析（溶析液 爲乙酸乙酯至1 〇 %甲醇之乙酸乙酯溶液）純化以生成白色 -440- 200918507 固體之2-{l-[6-(3-氰基-5-甲基-苯甲醯基）-5-異丙基- 2,4-二側氧-3,4-二氫-2H-嘧啶-1-基甲基]-環丙基}-乙醯胺（化 合物 85)(59 mg, 78%)。m.p. 283 -2 85°C ; W-NMR (500 MHz, DMSO-d6) ： δ 0.20-0.27 (2H, m), 0.31-0.36 (1H, m), 0.43-0.47 ( 1 H, m), 0.99 (3H, d, J = 6.8 Hz), 1.08 (3H, d, J = 6.8 Hz), 2.02-2.13 (2H, m), 2.17 (1H, d, J=16.5 Hz), 2.44 (3H, s), 3.32 (1H, d, J=15.1 Hz), 3.39-3.41 (1H, m), 3.46-3.51 (1H, m), 3.79 (1H, d, J=15.1 Hz), 8.08 (1H, s), 8.19 (1H, s), 8.42 (1H, s), 11.45 (1H, s)； m/z (El) 408 (M + )。 反應圖28
化合物8 乙酸2-[6-(3-氰基-5-甲基 苯甲醯基)-5-異丙基-3-(4-甲氧基-苄基)-2,4-二側氧- 3,4-二氫·2Η-嘧啶-1-基]-乙酯
3-[3-(2-羥基-乙基)-5-異丙基 -1-(4-甲氧基-苄基)-2,6-二側 氧-1，2,3,6·四氫-嘧啶-4-羰基 ]-5-甲基-苯甲腈 胺甲酸2-[6-(3-氰基-5-甲基-苯甲醯基化合物86 )-5-異丙基-3-(4-甲氧基-辛基)-2,4-二 側氧-3,4-二氫-2H-嚼啶-1-基]-乙酯 試劑和條件:i.l-漠甲基-4-甲氧基-苯，K2C03, Ul, DMF; ii. K2C03, MeOH; iii.三氯-異氰酸基-甲院,DCM; iv.飽和氨之DCM溶液;CAN,乙酸,MeCN冰. 乙酸2 -【6-(3-氯基-5-甲基-苯甲酿基）_5_異丙基-3-(4- -441 - 200918507 甲氧基-苄基）-2,4-二側氧-3,4-二氫-2H-嘧啶-1-基】-乙酯： 令乙酸2-[6-(3 -氰基-5-甲基-苯甲醯基）-5 -異丙基-2,4 -二側 氧-3,4-二氫-2H-嘧啶-1-基]-乙酯（化合物8)(126 mg, 0.328 毫莫耳，1.0當量）溶解於DMF (1.5 ml)中。加入碳酸鉀（45 mg，1當量）並於室溫下攪拌該反應混合物1〇分鐘。加入 1-溴甲基-4-甲氧基-苯（47 μΐ, 0_328毫莫耳，1當量）和碘化 鋰（44 mg，1當量）。令該反應混合物於室溫下經隔夜攪拌 。將乙酸乙酯加入至該反應混合物中，隨後經鹽水沖洗。 令有機層經濃縮及純化（矽膠，〇-80%EtOAC/己烷）以生成白 色粉末（88 mg，0.175 毫莫耳，53%)。LC-MS 顯示 504.1 (M+1)。 3-[3-(2 -經基-乙基）-5 -異丙基-1-(4-甲氧基-卞基）-2,6-二側氧-1，2,3,6-四氫-嘧啶-4-羰基]-5-甲基-苯甲腈：令乙 酸2-[6-(3-氰基-5-甲基-苯甲醯基）-5-異丙基- 3-(4-甲氧基-苄基）-2,4-二側氧-3,4 -二氫-2H-嘧啶-卜基]-乙酯（88 mg, 0.175毫莫耳，1.2當量）溶解於MeOH (1.5 ml)中。加入碳 酸鉀（48 mg，0.3 49毫莫耳，2當量）並於室溫下攪拌反應混 合物2 0分鐘。令該反應混合物經濃縮及純化（矽膠，〇-1 〇%
MeOH/DCM)以生成白色粉末（76 mg，94%)。LC-MS顯示 462.1 (M+1)。 胺甲酸2-[6-(3-氰基-5-甲基-苯甲醯基）-5-異丙基-3-(4 -甲氧基-苄基）-2,4-二側氧-3,4-二氫-2 H-嘧啶-1-基]乙酯 -442- 200918507 :將三氯-異氰酸基-甲烷（39 ul，0.33毫莫耳，2.0當量）加 入至3-[3-(2-羥基-乙基）-5-異丙基-1-(4 -甲氧基-苄基）-2,6-—側氧_1，2,3,6_四氯-喃b疋-4-羯基]-5 -甲基-苯甲膳（76 mg, 0.165毫莫耳）之DCM (2 ml)溶液中。室溫下攪拌反應混合 物10分鐘。HPLC和LC-MS顯示起始物已完全反應。令 氨氣經冒泡進入測試管之D C Μ (3 m 1)溶液中（維持冒泡5 分鐘）。將該氨溶液加入至上述之反應混合物中。室溫下 攪拌該反應混合物2小時。令該反應混合物經過濾、濃縮 及純化（矽膠，0-80% EtOAC/己烷）以生成白色粉末（42 mg， 51%)。LC-MS 顯示 505.0 (M+1)。 胺甲酸2-[6-(3-氰基-5-甲基-苯甲醯基）-5-異丙基·2,4- 二側氧-3,4-二氫-2Η-嘧啶-卜基]乙酯（化合物86):將高鈽 硝酸銨（156 mg, 0.189毫莫耳，3當量）加入至胺甲酸2-[6-(3-氰基-5-甲基-苯甲醯基）-5-異丙基- 3-(4 -甲氧基·苄基 2,4-二側氧-3,4-二氫-2H-嘧啶-1-基]乙酯（32 mg，0.063 毫 莫耳，1.0 當量）之 MeCN (1 ml)、乙酸（0.4 ml)及水（0.2 ml) 的混合液中。室溫下攪拌反應混合物1 0分鐘。濃縮該反 應混合物。加入乙酸乙酯並令混合物經鹽水沖洗。令有機 層經濃縮和純化（矽膠，20_80% Et0Ac/己烷）以生成白色固 體（13.6 mg, 56%)。NMR (300 MHz, d6 DMSO): δ 11.52 (s，1 H)，8.43 (s，1 Η), 8.22 (s，1 Η), 8.09 (s，1 H)， 3.92 (m, 1 H), 3.81 (m, 2 H), 3.22 (m, 1 H), 2.44 (s, 3 H), 2.08 (m，1 Η), 1.04 (dd，6 H)。 -443- 200918507 反應圖29
試劑和條件:i.4-溴-丁-2-稀酸乙酯，K2C03, Lil, DMF; ii. NH4OH 水溶液，MeOH,微波 120 °C.
4-丨6-(3·氰基-5-甲基-苯甲醯基）-5-異丙基-2,4-二側氧_ 3,4-二氫-2H-嘧啶-1-基]-丁 -2-烯酸乙酯（化合物87):令3-(5·異丙基- 2,6-二側氧-1,2,3,6-四氫-嘧啶-4-羰基）-5-甲基_ 苯甲腈（化合物1)(412 mg, 1.3 8 6毫莫耳，1.0當量）溶解於 DMF (8 ml)中。加入碳酸鉀（191 mg，1當量）並於室溫下攪 拌反應混合物10分鐘。加入4-溴-丁 -2-烯酸乙酯（0.24 ml， 1當量）和碘化鋰（186 mg, 1當量）。室溫下隔夜攪拌該反 應混合物。將乙酸乙酯加入至該反應混合物中，隨後經鹽 水沖洗。令有機層經濃縮和純化（矽膠，0-80% EtOAC/己烷 )以生成淡黃色泡沫（384 mg, 68%)。LC-MS顯示 410.4 (M+1)。 4-[6-(3-氰基-5-甲基-苯甲醯基）-5-異丙基-2,4-二側氧_ 3,4-二氫-2H·嘧啶-1-基】-丁 -2-烯酸醯胺（化合物88):將4. [6-(3-氰基-5-甲基-苯甲醯基）-5-異丙基-2,4-二側氧-3,4、〜 氫- 2H-嘧啶-卜基]-丁 - 2-烯酸乙酯（69 mg，0.168毫莫耳）和 MeOH (0.5 ml)加入至微波反應管（5 ml)中，隨後加入 -444- 200918507 NH4〇H (30%水溶液，0.7 ml,過量）。令反應混合物於 12 0〇C下經微波加熱3〇分鐘。令該反應混合物經濃縮且經 逆相製備性HPLC (MeCN/水）純化以生成白色粉末（4.2 mg， 6.6%)。4 NMR (3 00 MHz, CD3OD) : δ 8.8 (d，1 H)，7.64 (m, 2 Η), 7.4-7.28 (m, 2 Η), 3.19 (dd, 1 Η), 2.52 (m, 1 Η), 0.95 (d, 3 Η)，0.65 (dd，3 H)。LC-MS 顯示 381·〇 (M+l)。 反應圖30
4-氯-5-異丙基-2,6 -二甲氧基-嘧啶
H5-異丙基-2,6-二甲 氧基-嘧啶-4-基)-6-甲 基-1H-吲哚-4-腈
化合物89
試劑和條件±6-甲基-1H-D引《Μ-腈，NaH，DMF，加熱;ii.AcBr，加熱；iii. Etl, K2C03, DMF.
化合物94 化合物95 -喃陡-4-基）-6 -甲基- iij-昭丨 當量）加入至6-甲基_1H_D5| D M F (2 0 m 1)溶液中。經5 1·(5-異丙基-2,6 - 一甲氧基 哚 腈：將 NaH (148 mg, 哚-4-腈（526 mg, 3.37毫莫耳）之 -445- 200918507 分鐘後，將4-氯-5-異丙基-2,6-二甲氧基-嘧啶加入至反應 混合物中。於5 0 ° C下加熱該反應混合物5小時。令該反 應混合物經EtOAc稀釋並經鹽水沖洗。令有機層經濃縮和 純化（矽膠，0-80% EtOAC/己烷）以生成白色固體（470 mg， 42%)。LC-MS 顯示 337.2 (M+1)。 1-(5-異丙基-2,6-二側氧-1,2,3,6-四氫-嘧啶-4-基）-6- 甲基-1H-吲哚-4-腈（化合物89):將AcBr (3 ml)加入至6-甲基-1-(5-異丙基-2,6-二甲氧基·嘧啶-4-基）-1Η-吲哚-4-腈 (470 mg, 1.40毫莫耳）中。於70°C下加熱該反應混合物6 小時。隨後令該反應混合物冷卻至室溫並經濃縮。令反應 粗產物經純化（矽膠，0-80% EtOAc/己烷）以生成白色固體 (280 mg，65%)。LC-MS 顯示 307.1 (M-1)。 1-(3-乙基-5-異丙基·2,6-二側氧-1,2,3,6-四氫-嘧啶-4-基）_6_甲基-1H -吲哚-4-腈（化合物90):令6 -氯-1-(5 -異丙 基-2,6-二側氧-1,2,3,6-四氫-嘧啶-4-基）-1Η-吲哚-4-腈（35 mg，0.113毫莫耳，1.〇當量）溶解於DMF (0.5 ml)中。加入 碳酸鉀（16 mg，1當量）並於室溫下攪拌反應混合物分鐘 。加入EtI (9.1 μ!，1當量）。室溫下攪拌該反應混合物2 小時。將乙酸乙酯加入至該反應混合物中’隨後經鹽水沖 洗。令有機層經濃縮和純化（矽膠，0-80% EtOAC/己烷）以 生成白色粉末（14 mg，37%)。LC-MS 顯示 335.0 (M-1)。4 NMR (3 00 MHz, CDCI3) : δ 9.37 (br, 1 Η), 8.05 (s, 1 Η), -446- 200918507 7.08 (m，2 Η), 6.80 (d，1 H)，3.58 (m，1 H)，3.17(m，1H)， 2_62(s, 3H)，1.88 (m，1H)，1.17 (dd，6 H)，l_〇2 (t，3 H)。 6-苯並咪唑-1-基-1-乙基-5-異丙基-1H-嘧啶-2,4·二酮（ 化合物91):該化合物係藉由類似於用於製備6_氯 乙基-5-異丙基-2,6-二側氧-1，2,3,6-四氫-嘧啶-4-基）_1]9_口引 哚-4-腈（化合物90)之方法（除了使用苯並咪唑以替代6_氯_ 1H-吲哚-4-腈之外）加以製備。LC-MS顯示299.1 (M+1)。 NMR (3 00 MHz，CDC13) : δ 9.32 (br，1 H)，7 97 (m 2 Η), 7.43 (ra, 2 Η), 7.30 (m, 1 Η), 3.60 (m, 1 H), 3 2〇 (m 1H), 1 .98 (m, 1H)，1 .10 (m，9H)。 1-乙基-6-吲唑-1-基-5-異丙基-1H-嘧啶-2,4_二嗣（化合 物92):該化合物係藉由類似於用於製備卜氯-丨-^乙基_ 5-異丙基-2,6-二側氧-1，2,3,6-四氫-嘧啶-4-基）_1H_卩引卩朵_4_ 腈（化合物90)之方法（除了使用1H-吲唑以替代 口朵-4-腈之外）加以製備。LC-MS顯不299.1 (M+i)。4 NMR (3 00 MHz，CDC13) ·· δ 8.97 (br, 1 H)，8.31 (s 丄 H) 7.83 (d, 2 H), 7.54 (m, 1 H), 7.36 (m, 2H), 3.42 (m, i H) 3.20 (m, 1H), 1.90 (m, 1H), 1.15 (dd, 6H), i.〇〇 (t 即。 1-乙基-6-吲哚- ；[_基-5-異丙基-1H-嘧啶·2,4_二嗣（化合 物93):該化合物係藉由類似於用於製備6_氯_u(3_乙基_ 5-異丙基-2,6-二側氧·ι，2,3,6-四氫-嘧啶-4·基），1H•卩引噪·4· -447- 200918507 腈（化合物9 0)之方法（除了使用1 Η -吲哚以替代6 -氯-1 Η -吲 哚-4-腈之外）加以製備。LC-MS顯示2 98.2 (Μ+1)。 NMR (3 00 MHz, CDC13) : δ 8.32 (br，1 Η)，7.72 (d，1 Η)， 7.25 (m, 2 H), 7.19 (m, 1 H), 6.80 (m, 1H), 3.50 (m, 1 H), 3.18 (m，1H)，1.97 (m，1H)，1_17 (dd，6H), 1.03 (t，3H)。 1-乙基-6-咪唑-1-基-5-異丙基-1H-嘧啶-2,4-二酮（化合 物94):該化合物係藉由類似於用於製備6-氯-1-(3-乙基-5-異丙基- 2,6-二側氧·1，2,3,6-四氫-嘧啶-4-基）-1Η-吲哚-4-腈（化合物90)之方法（除了使用咪唑以替代6·氯-1H-吲哚_ 4-腈之外）加以製備。LC-MS顯示249.1 (M+l)。4 NMR (3 0 0 MHz, CDC13) ： δ 9.03 (br, 1 Η), 7.60 (m, 1 Η), 7.32 (m, 1 Η), 7.00 (m, 1 Η), 3.40 (m, 2 Η), 2,08 (m, 1Η), 1.19 (m，9Η)。 1-乙基-5-異丙基-6-吡唑-1·基-1H-嘧啶-2,4-二酮（化合 物95):該化合物係藉由類似於用於製備6-氯-1-(3-乙基-5-異丙基-2,6-二側氧-1，2,3,6-四氫-嘧啶-4-基）-1Η·吲哚-4- 腈（化合物90)之方法（除了使用吡唑以替代6-氯-1Η-吲哚-4-腈之外）加以製備。LC-MS顯示249.1 (M+l)。4 NMR (3 00 MHz, CDCI3) ： δ 9.36 (br, 1 Η), 7.81 (m, 1 Η), 7.58 (m, 1 Η), 6.54 (m, 1 Η), 3.38 (m, 2 Η), 2.04 (m, 1Η), 1.17 (m， 9H)。 -448- 200918507 反應圖31
5-異丙基-2,6-二甲 三氟-甲磺酸5-異丙 氧基-嘧啶-4-醇 基-2,6-二甲氧基-嘧
3-(5-異丙基-2,6-二甲 氧基-嘧啶-4-基)-喹琳 4-氯-5-異丙基 -2,6-二甲氧基-嘧啶 淀-4-基酯
試劑和條件：i. a) BnOH, NaH, DMF; b) H2,10% Pd/C; ii.N-苯基三氟甲院磺醣胺，Cs2C03, DCM. ώ·3-喹啉硼酸,Pd(dpp〇2CI2, 2ΛΛ · Na2C〇3 水溶液，DME,微波; iv. AcBr,加熱；v. Etl, K2C03, DMF. 5-異丙基-2,6-二甲氧基-嘧啶-4-醇：於0°C下將NaH (60%之礦物油液，273 mg，1.05當量）加入至4-氯-5-異丙 基-2,6·二甲氧基-嘧啶（1.4 g, 6.51毫莫耳，1當量）和苄醇 (704 mg, 1.0當量）的混合物之DMF (10 ml)溶液中。於 0°C下攪拌反應混合物，隨後令其回溫至室溫。LC-MS顯 示生成所欲之產物。令該反應混合物經乙酸乙酯稀釋，經 水沖洗2次，經無水硫酸鎂乾燥，再經過濾及真空下蒸發 以生成粗產物。 將10% Pd/C (3 40 mg)加入至上述粗產物（約1.7 g)、 EtOH (9 ml)及EtO Ac (3 6 ml)之混合物中，隨後施加氫氣 球形瓶。室溫下攪拌該反應混合物1小時。令該混合物經 通過寅氏鹽過濾並經濃縮。令粗產物經矽膠管柱層析（溶 析液爲EtO Ac/己烷（20-8 0%))純化以生成白色固體之5-異 -449- 200918507 丙基-2,6 -二甲氧基-嘧啶-4-醇（440 mg，34%經2個步驟）。 'H NMR (3 00 MHz, CDC13)： 1.20 (6H, d), 3.25 (1H, m), 3.95 (6H，d)，12.9 (1H，br)。LC-MS (M+l: 199.1，M-l: 197.0) 〇 三氟甲磺酸5-異丙基-2,6-二甲氧基·嘧啶-4-基酯：將 Cs2C03 (116 mg，1.1當量）加入至5 -異丙基- 2,6 -二甲氧基-嘧啶-4-醇（64 mg, 0.3 22毫莫耳）和N-苯基三氟甲烷磺醯胺 (127 mg，1.1當量）的混合物之DCM (3 ml)溶液中。室溫下 攪拌反應混合物9 0分鐘。令該反應混合物經濃縮及純化（ 矽膠，0-80% EtOAC/己烷）以生成白色固體（74 mg, 69%)。 LC-MS 顯示 3 3 0.9 (M+1)。 3-(5_異丙基-2,6-二甲氧基-嘧啶-4-基）-喹啉：於微波 反應管（5 ml)中，令三氟甲磺酸5_異丙基-2,6 -二甲氧基-嘧 啶-4-基酯（30 mg，0.091毫莫耳）、3-喹啉硼酸（19 mg，1.2 當量）及 Pd(dppf)2Cl2 (7.4 mg，10%)與 DME (2 ml)和 2M Na2C03 7Jc溶液（0.18 ml，4當量）混合。於1 30°C下微波加 熱該反應混合物4 0分鐘。令該反應混合物經濃縮且經逆 相製備性HPLC (MeCN/水）純化以生成白色粉末（14 mg， 50%)。LC-MS 顯示 310.2 (M+1)。 5-異丙基-6 -睦琳-3 -基-1H -喃陡- 2,4 -二嗣（化合物96) :於圓底燒瓶（10 ml)中，將AcBr (1 ml)加入至3-(5 -異丙 -450- 200918507 基-2,6-—甲氧基-嘧啶-4_基）_喹啉（1411^，〇〇45毫莫耳）中 於7 0 下加熱反應混合物2小時。令該反應混合物經 濃縮且經逆相製備性Η P L C (M e C N /水）純化以生成白色粉 末（6 mg，47%)。LC-MS 顯示 28〇 3 (M_1}。 1-乙基-5-異丙基-6-喹啉·3_基·1H•嘧啶-2,4_二酮（化合 物97):令5-異丙基-6-喹啉_3-基-1H-喃卩定-2,4-二酮（6 mg， 0.021毫莫耳，1.0當量）溶解於DMF (0.5 ml)中。加入碳酸 鉀（3 mg，1當量）並於室溫下攪拌反應混合物1〇分鐘。加 入EtI (1 .7 μΐ，1當量）。室溫下隔夜攪拌該反應混合物。 未觀察到反應發生。加入更多量之碳酸鉀（6 mg)。經2小 時後反應完全。令反應粗產物經過濾且經逆相HPLC純化 以生成白色粉末（1.5 mg, 23%)。LC-MS顯示310.2 (M+1) 。W-NMR (3 00 MHz, CDC13) : δ 8.83 (s, 1 H)，8.40 (m，1 Η), 8.22 (m, 1 Η), 7.96 (m, 2H), 7.78 (m, 1 H), 3.58 (m, 2 H), 2.10 (m，1H)，1.90 (dd, 6 H), 1.04 (t，3 H)。 -451 - 200918507 反應圖32
CN
NH2 4-胺基-3,5- 二甲基-苯甲 腈 CN CI 4-氯-3,5-二甲 基-苯甲腈
CN
4-氯-3-氰基甲基 •5-甲基-苯甲腈
4-氯-3-(5-異丙基-2,6-二甲 化合物98 氧基-嘧啶-4-羰基)-5-甲基- 苯甲腈
化合物99 K)§!l?0^： i tBuN02, CuCI2, ACN, 89%; ii. NBS, CCI4, 68%; iii. KCN, Et0H/H20, 39%； iv.a.4-氣-5·異丙基-2,6-二甲氧基-喷陡，NaH, DMF; b. 02, 11% (2 步驟 v. AcBr, 95%; Vi. 碘乙院，K2C03,DMF. 30%. 4-氯-3,5-二甲基-苯甲腈：於〇°C下將亞硝酸特丁酯 (1.35 g，110.26毫莫耳）加入至氯化銅（11)(1.10 g, 8.21毫 莫耳）之乙腈（27 ml)混合物中。將4·胺基-3,5-二甲基-苯甲 腈（1.0 g, 6.84毫莫耳）經5分鐘分批加入至該褐色混合物 中並於室溫下攪拌該反應混合物1 8小時。令該反應混合 物經濃縮，經1N HC1稀釋且經乙醚萃取。令有機層經乾 -452- 200918507 燥（MgS〇4)、經濃縮且經閃蒸管柱層析（矽膠，〇至2〇%乙 酸乙酯/己烷）純化以生成白色固體（1.011 g，89%)。1Η NMR (300 MHz, CDC13) ： 7.30 (s, 2 Η), 2.33 (s, 6 Η) ； 13C NMR (75 MHz, CDC13) ： 1 3 9.9, 1 3 7.8, 1 3 1.5, 1 1 8.3, 1 09.9, 20.6。 4_氯-3-氰基甲基-5-甲基·苯甲腈：加熱4_氯-3, 5_二甲 基-苯甲腈（l.oil g，6.10毫莫耳）、N-溴琥珀醯亞胺（1.087 g，6.10毫莫耳）及苯甲醯基過氧化物（〇·〇74 g, 0.305毫莫 耳）的混合物之四氯化碳（30 ml)溶液至回流狀態達4小時 。令反應混合物冷卻至室溫並經過濾。令濾液經閃蒸管柱 層析（矽膠，0至30%乙酸乙酯/己烷）純化以生成不純之白 色固體的3 -溴甲基-4-氯-5-甲基-苯甲腈（0.9938 g, 66%)， 其係未經進一步之純化而用於下一個步驟中。 於85°C下加熱3-溴甲基-4·氯-5-甲基-苯甲腈（0.993 8 g，4.06毫莫耳）和氰化鉀（0.529 g，8.12毫莫耳）之乙醇（5.0 ml)和水（2.5 ml)溶液3小時。令反應混合物經冷卻，經乙 酸乙酯稀釋’經鹽水沖洗，經乾燥（MgS〇4)，再經濃縮及 閃蒸管柱層析（矽膠，0至3 0 %乙酸乙酯/己烷）純化以生成 白色固體之 4 -氯-3 -氰基甲基-5-甲基-苯甲腈（0.3707 g, 48%)。NMR (3 00 MHz, CDC13) ·· 7.61 (s，1 H)，7.51 (s, 1 H)，3.83 (s，2 H)，2_40 (s，3 H)。 4-氯-3-(5-異丙基-2,6-二甲氧基-嘧啶-4-羰基）-5-甲基- -453- 200918507 苯甲腈：於〇°C下將NaH經15分鐘分批加入至4_氯-5_異 丙基-2,6-二甲氧基-嘧啶（0.442 g，2.04毫莫耳）和4_氯-3_ 氰基甲基-5-甲基-苯甲腈（0_3707 g，1.94毫莫耳）之DMF溶 液中，生成橙紅色反應混合物。經攪拌24小時後，令氧 氣經冒泡進入該反應混合物中達3 6小時。令該反應混合 物經飽和氯化銨溶液和甲醇驟冷並經乙酸乙酯稀釋。令有 機層經飽和氯化銨溶液、H20及飽和氯化銨溶液沖洗，隨 後經乾燥（MgS04)，經濃縮且經閃蒸管柱層析（矽膠，5至 50%乙酸乙酯/己烷）純化以生成標的化合物（0.0767 g，1 1%) ° 'H NMR (3 0 0 MHz, CDC13) : 7.67 (s, 1 Η), 7.59 (s, 1 Η), 4.00 (s, 3 Η), 3.75 (s, 3 Η), 3.3-3.2 (m, 1 Η), 2.37 (s, 3 Η), 1.25 (s, 3 Η), 1.23 (s, 3 H)； 13C NMR (75 MHz, CDCI3) ： 1 92.8, 1 7 1.1, 1 62.2, 1 60.2, 1 3 9.1, 1 3 8.9, 1 3 7.3, 135.9, 132.3, 119.9, 117.4, 110.8, 54.7, 54.2, 26.5, 20.2, 20.2 ;質譜：360.2, 362.1 (M + H)。 4-氯-3-(5-異丙基-2,6-二側氧-1,2,3,6-四氫-嘧啶-4-羰 基）·5-甲基-苯甲腈（化合物98):於65°C下加熱4-氯-3-(5-異丙基-2,6-二甲氧基-嘧啶-4-羰基）-5 -甲基-苯甲腈 (0.0767 g, 0.213毫莫耳）之乙醯溴（3.5 ml)溶液18小時， 隨後冷卻至室溫並經濃縮。令所生成之殘餘物經閃蒸管柱 層析（矽膠，20至100%乙酸乙酯/己烷）純化以生成灰白色 固體之化合物 102 (0_06 7 g，95%)。NMR (3 00 MHz， CD3OD) ： 8.05 (s, 1 Η), 7.96 (s, 1 Η), 2.47 (s, 3 Η), 2.5- -454- 200918507 2.4 (m，1 Η)，ΐ·09 (s，3 h)，[ο? (s，3 H);質譜：3 3 2.2 (Μ + H)。 4-氯-3-(3-乙基-5_異丙基-2,6_二側氧- I】，％。四氫-嘧
啶-4-鑛基）-5-甲基-苯甲腈（化合物99):將碘乙烷（14 μ1, 0.168毫旲耳）加入至化合物98 (〇·〇67 g, 0.202毫莫耳）和 碳酸鉀（0.0279 g，0.202毫莫耳）的混合物之DMF (1.0 ml) 溶液中並令反應混合物於室溫下經隔夜攪拌。令該反應混 合物經飽和氯化銨溶液驟冷，經乙酸乙酯萃取，再經乾燥 (MgS04)及濃縮。令所生成之殘餘物經逆相 HPLC (Phenomenex Synergi®管柱，5 至 100% 乙腈 /水）純化’再 經冷凍乾燥後生成白色粉末（20.5 mg，28%) ° 1H NMR MHz，CD3CN) : 9.15 (s，1 Η)，8.16 (s，1 Η)，7.96 (s，1 H)， 3.52 (br s，2 H)，2.47 (s，3 H)，2.3-2.2 (m, 1 H)，1.1-1.0 (s，9H);質譜：360·2,362·2(Μ + Η)。 -455- 200918507 反應圖33
化合物3
化合物100
化合物101
化合物100 化合物102 試劑和條件:i.NaBH4· EtOH, 44%; ii. DAST, 68%; iii. a. MsCI，Et3N，丁HF; b. KCN， Et0H/H20, 39%. 3-[(3-乙基-5-異丙基-2,6-二側氧-1,2,3,6 -四氫·嘧啶- 4-基）-羥基-甲基】-5-甲基-苯甲腈（化合物100):於〇°C下 將氫硼化鈉（0.081 g, 2.15毫莫耳）加入至3-(3 -乙基-5-異 丙基-2,6-二側氧-1,2,3,6-四氫-嘧啶-4-羰基）-5-甲基-苯甲 腈（化合物3)(0.700 g，2.15毫莫耳）之乙醇（61 ml)溶液中 ，並令反應混合物於〇 ° C下經攪拌2小時，隨後再於室溫 下經隔夜攪拌。加入更多量之氫硼化鈉（0.0 8 1 g，2.1 5毫莫 耳）並令該混合物經攪拌24小時。再次加入更多量之氫砸 化鈉（0.0 81 g，2.15毫莫耳）並持續攪拌6小時。令該反應 混合物經濃縮，經飽和NH4C1溶液驟冷，經IN HC1酸化 ，隨後經乙酸乙酯（2x)萃取。令結合之有機層經乾燥 (Mg SOO，經濃縮且經閃蒸管柱層析（矽膠，30至60%乙酸 乙酯/己院）純化以生成不純之產物。令該不純之產物再次 -456 - 200918507 經閃蒸管柱層析（矽膠，〇至5%甲醇/二氯甲烷）純化，隨後 經閃蒸管柱層析（矽膠，4 0至6 0 %乙酸乙酯/己烷）純化以生 成白色固體（0.31 g, 44%)。4 NMR (300 MHz，CD3OD): 7.55 (s, 1 Η), 7.47 (s, 1 Η), 7.43 (s, 1 Η),6.18 (s, 1 Η), 3.73 (q, J = 6.9 Hz, 2 H), 3.12-3.07 (m, 1 H), 2.37 (s, 3 H), 1.30 (d, J = 7.2 Hz, 3 H), 1.11 (d, J = 6.6 Hz, 3 H), 0.92-0.84 (m，3 H);質譜：328.1 (M + H)。 3-[(3-乙基-5-異丙基-2,6-二側氧-1，2,3,6-四氫-嘧啶- 4-基）-氟-甲基]-5-甲基-苯甲腈（化合物ιοί):於〇°C下將（ 二乙基胺基）三氟化硫（33 μΐ，0.2 5 5毫莫耳）加入至3-[(3-乙基_5_異丙基- 2,6-二側氧-1,2,3,6-四氫-嘧啶-4-基）-羥基-甲基]-5 -甲基-苯甲腈（化合物 100)(55.7 mg, 0.17毫莫耳） 之二氯甲烷（2.〇 ml)溶液中並攪拌反應混合物1小時。令 該反應混合物經飽和NaHC03溶液驟冷並經乙酸乙酯（2x) 萃取。令結合之有機層經乾燥（Mg S 04)，經濃縮且經逆相 HPLC (Phenomenex Synergi®管柱，5 至 100% 乙腈 / H2O)純 化，再經冷凍乾燥後生成白色粉末（45 mg, 80%)。4 NMR (3 00 MHz, CD3OD) ： 7.60 (s, 1 Η), 7.55 (s, 1 Η), 7.46 (s, 1 Η), 7.04 (d, J = 45.9 Hz, 1 H), 3.75 -3.5 7 (m, 2 H), 2.94-2.89 (m, 1 H), 2.40 (s, 3 H), 1.24 (d, J = 6.9 Hz, 3 H); 1.1-1.0 (s，6 H); 19F NMR (CD3OD): -180.5;質譜： 3 3 0. 1 (M + H)。 -457- 200918507 3_【乙氧基-(3·乙基_5_異丙基-2,6-二側氧-1，2,3,6-四 氫_喃陡_4_基）-甲基1-5-甲基-苯甲腈（化合物102):將甲烷 磺醯氯（166 μΐ，2·11毫莫耳）加入至3_[(3·乙基-5-異丙基-2,6-二側氧-1，2,3,6-四氫-喃卩定-4-基）-經基-甲基]-5-甲基-苯甲腈（化合物1 00)(69 mg，〇.211毫莫耳）和三乙胺（353 μΐ，2.53毫莫耳）之THF (4.0 ml)溶液中。於0°C下攪拌該 反應混合物2小時’隨後再於室溫下擾拌4 8小時。令該 反應混合物經乙酸乙酯稀釋，經1 N H C1和飽和N aH C Ο3 溶液沖洗，再經乾燥（Mgs〇4)、濃縮及純化以生成不純之 產物（80 mg)。令所生成之殘餘物溶解於乙醇（1.5 ml)和水 (0.5 ml)中並加入氰化鉀（21 mg，0.32毫莫耳）。令該反應 混合物經回流2小時，經冷卻，經乙酸乙酯稀釋，經飽和 氯化銨溶液沖洗，再經乾燥（MgS〇4)及濃縮。令所生成之 殘餘物經逆相 HPLC (Phenomenex Synergi®管柱，5至 10 0%乙腈/H20)純化，再經冷凍乾燥後生成白色粉末（1 4 mg，22%)。】H NMR (3 00 MHz，CD3OD) : 7.52 (s，1 Η), 7.50 (s, 1 Η), 7.39 (s, 1 Η), 5.98 (s, 1 Η), 3.75-3.5 7 (m, 4 H)， 3.12-3.07 (m, 1 H), 2.37 (s, 3 H), 1.3 7- 1.30 (m, 6 H)，1.15 (d，J = 6.3 Hz，3 H), 0.92-0.8 7 (m，3 H);質譜： 3 5 6.2 (M + H)。 -458- 200918507 反應圖34
4-溴-2-甲氧基-6- 1-溴-3-甲氧基- 3-甲氧基-5-甲基 甲基-苯基胺 5-甲基-苯 -苯甲腈 2-甲氧基各甲基-苯基胺
HO
3-羥基-5-甲基-苯甲腈 3-(2,6-二氯-5-異丙基-嘧啶-4-基氧)-5-甲基-苯 甲腈
化合物103 化合物104 R=Et， 化合物105R=n-Bu 試劑和條件：i. Br, AcOH，MeOH，0 °C -> 室溫；ii. NaN02. AcOH, HC.I，H20. H3P〇2, 0 °C 室溫；《i.
Zn(CN)2, Pd(PPh3)4, DMF, 90 0C; iv. BCI3. Bu4NI, DCM, -78 0C -> 室溫；v. NaH. DMF: vi. BnOH，NaH. DMF; vii. K2C03, DMF, R-l.
4-溴-2-甲氧基-6-甲基-苯基胺：於圓底燒瓶（100 ml) 中，令2-甲氧基-6-甲基-苯基胺（4.54 g，33.16毫莫耳）溶 解於MeOH (15 ml)和乙酸（5 ml)中。令該燒瓶冷卻至0°C 。將溴（1 . 7 m 1, 3 3 · 1 6毫莫耳）之乙酸（5 m 1)溶液逐滴（經3 0 分鐘）加入至該反應物中。於〇°C下攪拌該反應混合物2 小時，隨後經1小時回溫至室溫。濃縮該反應混合物。於 〇°C下加入IN NaOH以中和該反應物。加入乙酸乙酯以萃 取該反應混合物。濃縮有機層並經無水硫酸鈉乾燥後生成 -459- 200918507 暗褐色固體（5·8 g，81%)。LC-MS 顯示 218.0 (M+l)。4 NMR (3 0 0 MHz，CDC13) : δ 6.88(s，1 H)，6.81 (s，1 H)， 3 · 84 (s, 3 H), 2 · 1 1 (s，3 h)。 1-溴-3 -甲氧基-5 -甲基-苯：於圓底燒瓶（250 ml)中， 對4-溴-2-甲氧基-6-甲基-苯基胺（5.8 g, 26.84毫莫耳）載入 乙酸（49 ml)和濃HC1 (5.6 ral)。於0°C下將亞硝酸鈉（2.19 g，31.78毫莫耳）之水（1 2 3 4 5 ml)溶液逐滴加入至該混合物中。 於0°C下攪拌該反應混合物30分鐘。於0°C下加入50% 次磷酸（56.5 ml)。於0°C下攪拌該反應混合物並令其經隔 夜回溫至室溫。加入乙酸乙酯，隨後經飽和NaHC03溶液 沖洗。令有機層經濃縮和純化（矽膠，100%己烷）以生成蒼 白色液體（5.12 g，95%)。NMR (300 MHz, CDC13): δ 6.97(s, 1 Η), 6.87 (s, 1 Η), 6.64 (s, 1 Η), 3.80 (s, 3 Η), 2.36 (s，3 H)。 -460- 1 -甲氧基-5-甲基-苯甲腈：於圓底燒瓶（100 ml)中，對 2 1-溴-3-甲氧基-5-甲基-苯（2.17 g，10.79毫莫耳）、Zn(CN)2 3 (1.9 g，16.19 毫莫耳，當量）及 Pd(PPh3)4 (1.24 g，1.08 毫莫耳，0.1當量）載入DMF (20 ml)。於90°C和氬氣下加 熱反應混合物7小時。加入乙酸乙酯並隨後經鹽水沖洗。 令有機層經濃縮和純化（矽膠，0 - 5 0 % E t0 A c /己烷）以生成 4 白色固體（1.31 g, 83%)。NMR (3 00 MHz，CDC13): δ 5 7.05(s，1 H)，6.97 (s，2 H)，3.81 (s，3 Η), 2.39 (s，3 H)。 200918507 3 -羥基-5-甲基-苯甲腈：於圓底燒瓶（1〇〇 ml)中，令 3 -甲氧基-5 -甲基-苯甲腈（500 mg，3.39毫莫耳）溶解於乾 DCM (15 ml)中並加入特丁基碘化銨（]L38 g，3_73毫莫耳， 3.5當量）。冷卻該燒瓶至-78°C。將BC13 (1M DCM溶液， 11.87 ml，33.16毫莫耳）逐滴加入至該反應物中。於_78〇c 下攪拌該反應混合物並令其經隔夜回溫至室溫。令該反應 混合物經冰驟冷並經飽和NaHC03溶液中和。加入DCM 以萃取該反應混合物。令有機層經濃縮和純化（矽膠，〇 -10% MeOH/DCM)以生成淡黃色固體（408 g, 90%)。LC-MS 顯不 132.0 (M-1)。4 NMR (300 MHz, CDC13): δ 7.20 (s, 1 Η)，6.96 (s，1 Η), 6.91 (s，1 Η), 2.37 (s, 3 Η)。 3-(2,6 - 一氯-5-異丙基-嗯陡-4-基氧）-5 -甲基-苯甲腈： 於0°C下將NaH (60%，125 mg，3.06毫莫耳，1_〇當量）加 入至3 -羥基-5-甲基-苯甲腈（408 mg，3_06毫莫耳）之DMF (10 ml)溶液中。於0°C下攪拌反應混合物5分鐘。隨後加 入2，4,6-三氯-5 -異丙基-嘧啶（691 mg，3.06毫莫耳）。於 〇°C下攪拌該反應混合物30分鐘。將乙酸乙酯加入至該 反應混合物中，隨後經鹽水沖洗。令有機層經濃縮和純化 (矽膠，0-50% EtOAc/己烷）以生成白色固體（86 8 mg，88%) 。LC-MS 顯示 322.1 (M+l)。1HNMR(300 MHz，CDCl3): δ 7.41 (s, 1 Η), 7.26 (s, 1 Η), 7.19 (s, 1 Η), 3.60 (m, 1 Η)，2.42 (s, 3 Η)，1.42 (d, 6 Η)。 -461 - 200918507 3-(2，6-雙-苄氧基·5-異丙基-略旋_4_基氧）_5_甲基-苯 甲腈：於〇°C下將NaH (60%，118 mg，2.88毫莫耳，2.2當 量）加入至苄醇（298 μΐ，2.88毫莫耳）之THF (5 ml)溶液中 。於0 ° C下攪拌反應混合物5分鐘。加入3 _(2,6 -二氯-5 -異丙基-嘧啶-4-基氧）-5 -甲基-苯甲腈（422 mg，1.31毫莫耳） 。於0 ° C下攪拌反應混合物1 5分鐘，隨後經9 0分鐘回溫 至室溫。將乙酸乙酯加入至該反應混合物中，隨後經鹽水 沖洗。令有機層經濃縮和純化（矽膠，0-50% EtOAc/己烷） 以生成白色固體（3 72 mg,純度65% (經HPLC測定），40%) 。LC-MS 顯示 466.1 (M+1)。 3-(5-異丙基-2,6-二側氧-1,2,3,6-四氫-嘧啶-4-基氧）- 5-甲基-苯甲腈（化合物103):令3-(2,6-雙-苄氧基-5-異丙 基-嘧啶-4-基氧）-5-甲基-苯甲腈（3 72 mg，純度65%，0.52 晕莫耳）溶解於EtOAc (20 ml)和EtOH (5 ml)中。加入10%
Pd/C (75 mg)並施加氫氣球形瓶。室溫下攪拌反應混合物 1小時。經通過寅氏鹽過濾以除去該Pd/C並令濾液經濃縮 和純化（矽膠，EtOAc/己烷）以生成白色固體（100 mg，29%) 。LC-MS 顯示 286.0 (M+1 )。 3-(3-乙基-5-異丙基-2,6-二側氧-1,2,3,6-四氫-嘧啶- 4-基氧）-5·甲基-苯甲腈（化合物104):將碳酸鉀（24 mg, 0.172毫莫耳，1.0當量）加入至3-(5 -異丙基-2,6-二側氧- -462 - 200918507 1，2,3,6-四氫-嘧啶-4-基氧）-5-甲基-苯甲腈（化合物103)(59 mg, 0.207毫莫耳，1.2當量）之DMF (2.0 ml)溶液中。室溫 下攪拌反應混合物10分鐘，隨後加入碘乙烷（14 μΐ，0.1 72 毫莫耳）。室溫下令該反應混合物經隔夜攪拌。將乙酸乙 酯加入至該反應混合物中’隨後經鹽水沖洗。令有機層經 濃縮和純化（矽膠，20_80% EtOAc/己烷）’再經純化（逆相 HPLC, MeCN /水）以生成白色粉末（15 mg，28%)。LC-MS顯 示 314.1 (M+l)。NMR (3 0 0 MHz，CDC13): δ 9.17 (br， 1 Η), 7.25 (s, 1 Η), 7.08 (s, 1 Η), 7.00 (s, 1 Η), 3.77(t, 2 Η)，2.69 (m，1 Η)，2.42 (s，3 Η), 1.2 (m，9 Η)。 3-(3-丁基-5-異丙基-2,6-二側氧-1，2,3，6-四氫-嘧啶-4- 基氧）-5 -甲基-苯甲腈（化合物1〇5):將碳酸鉀（9.3 mg， 0.0067毫莫耳，1.0當量）加入至3-(5-異丙基- 2,6-二側氧-1，2,3,6-四氫·嘧啶-4-基氧）-5-甲基-苯甲腈（化合物103)(23 mg，0.0.08毫莫耳，1.2當量）之DMF (1.0 ml)溶液中。室 溫下攪拌反應混合物10分鐘並加入正丁基碘（7.6 Μ， 0.0.067毫莫耳）。令該反應混合物經過濾和純化（逆相 HPLC，MeCN/水）以生成白色粉末（3.8 mg, 1 7%)。LC-MS 顯示 342.1 (M+1)。4 NMR (3 00 MHz，CDC13) : δ 8.37 (br，1 Η)，7.28 (s，1 Η), 7.08 (s，1 Η), 6.9 8 (s, 1 Η), 3.42(t，2 Η)，2.71 (m, 1 Η)，2.42 (s，3 Η)，1_60 (m，2 Η)， 1.28 (m, 2 Η), 1.17 (d，6 Η)，0.88 (t, 3 Η)。 -463- 200918507 反應圖35
N-(3-丁 - 2-烯基-5-異丙基- 2,6-二側氧四氫嘧 啶-4-基）·Ν-(3,5-二甲基-苯基）-乙醯胺（化合物1〇7):將卜 甲院擴釀基-反式-2 -丁稀（269 μ[, 2·28毫莫耳）加入至ν_ (3,5 -—甲基-苯基）-Ν-(5-異丙基- 2,6 - 一側氧- ι，2,3,6-四氫-嚼0定-4-基）-乙酸胺（化合物1〇6)(错由類似於下述反應圖 中製備化合物109之方法加以製備’除了使用2,4,6-三氯-5-異丙基-嘧啶以替代2,4,6-三氯-5-乙基-嘧啶之外）（600 mg，1·9毫莫耳）、無水K2C03粉末（262 mg，19毫莫耳）及 碘化鋰（254 mg，1.9毫莫耳）之DMF (7 ml)攪拌溶液中。經 攪拌1 3小時後，令反應混合物經乙醚稀釋，經水沖洗， 經Mg S04,乾燥，再經過濾及真空下蒸發。令殘餘物經矽 膠管柱層析（溶析液爲乙酸乙酯：己院（1 : 1))純化以生成白色 固體（382 mg，54%)。m.p. l〇3-105°C; m/z (EI) 369 (M + ) 1-丁 -2-烯基- 6-(3,5-二甲基-苯基胺基）-5-異丙基-1H-嚼陡-2,4 -二酮（化合物108):將甲醇鈉（73 mg，1.35毫莫耳 )加入至N-(3-丁 -2-烯基-5-異汽基_2,6-二側氧-1，2,3,6-四 氫-嘧啶-4-基）-N-(3,5-二甲基_苯基）_乙醯胺（化合物 -464- 200918507 107)(100 mg，0_27毫莫耳）之甲醇（3 ml)攪拌溶液中。經4 小時後，令該混合物經過量之N Η 4 C1中和並經真空下蒸發 。令殘餘物經矽膠管柱層析（溶析液爲乙酸乙酯：己烷（1 :2)) 純化以生成白色固體（62 11^，70%；)。111.13.186-187。(：；111-NMR(200 MHz, CDC13)： δ 1.17(6Η, d, J = 6.9 Hz), 1.64-1.67 (3H, m), 2.24 (6H, s), 2.86 (1H. m), 4.25 -4.3 0 (2H, m), 5.33 (1H, s), 5.48-5.54 (2H, m), 6.32 (2H, s), 6.60 (1H，s), 8.42 (1H, s) ; m/z (El) 3 27 (M + )。 反應圖36
Cl ch3 Λ cr ch3
CHO
Me〇'
(3,5-二甲基-苯基)-(5-乙基-2,6-二甲氧基-嘧 啶-4-基)-胺 1)1 …'ch3 coch3 2,4,6-三氯-5- N-(2,6-二氛-5-乙基-嘧啶 乙基-嚼啶 -4-基)-N-(3,5-二甲基-苯 基)-甲醯胺 ?Η3 〇 I CH, 化合物109
tjl ^'ch3 COCH, ch3 化合物109 丫 -、CHS f COCH3 化合物110 7 、ch3 化合物111
COCH3 化合物109 If y'CH3 COCH, 化合物112
化合物113 N-(2,6-二氯-5-乙基-嘧啶-4-基）-N-(3,5-二甲基-苯基）- 甲酿胺：於氮氣下將6u%氫化鈉（2 8 8 g, 72毫莫耳）分批 加入至於冰浴中冷卻的N ·( 3 , 5 -二甲基苯基）甲醯替苯胺 (8·94 g，60毫莫耳）之DMF (60 ml)攪拌溶液中。經1〇分 鐘後’加入2,4,6-三氯-5-乙基-嘧啶（15.2 g，72毫莫耳）。 經攪泮1 0分鐘後，室溫下攪拌該混合物24小時。令該混 -465 - 200918507 合物經乙醚稀釋，經水沖洗3次，經乾燥（MgS〇4)、再經 過濾及真空下蒸發。令殘餘物經矽膠管柱層析（溶析液爲 乙醚：己烷（1:10))純化以生成白色固體（8·6 g’ 44%)°m.P. 1 24- 1 2 50C ; m/z (El) 323 (M + )。 (3，5-二甲基苯基）-(5-乙基-2,6-二甲氧基-嘧啶-4-基）_ 胺：室溫下令金屬鈉（2.3 g, 0.1 M)與甲醇（80 ml)反應。加 入N-(2,6-二氯-5-乙基-嘧啶-4-基）-N-(3,5-二甲基-苯基）-甲醯胺（6 · 4 8 g，2 0毫莫耳）並令該混合物回流4小時。經 冷卻至室溫後，令該反應混合物經過量之N H4 c 1中和。令 該混合物經真空下蒸發並令殘餘物經矽膠管柱層析（溶析 液爲乙酸乙酯：己烷（1:15))純化以生成白色固體（5 g, 88%) 。m.p.ll3-1140C: 'H-NMR (200 MHz, CDC13) δ 1.12 (3H， t, J = 7.5 Hz), 2.31 (6H, s), 2.38 (2H, q, J-7.5 Hz), 3.94 (6H, s), 6.32 (1H, s), 6.70 (1H, s), 7.25 (2H, s) ； m/z (El) 28 7(M + )。 1^-(3,5-二甲基-苯基）-心（5-乙基-2,6-二側氧-1，2,3,6- 四氫-嘧啶-4_基）-乙醯胺（化合物109):令（3,5-二甲基·苯 基）-(5-乙基-2,6-二甲氧基-嘧啶-4-基）-胺（5 g, 17.4毫莫耳 )與乙醯溴（50 ml)回流18小時。經冷卻至室溫後，令該混 合物經真空下蒸發並令殘餘物經矽膠管柱層析（溶析液爲 乙酸乙酯：己烷（2:1))純化以生成白色固體（4.5 g，86%)。 m.p. 23 8-23 9°C ； 1 H-NMR (2 0 0 廳 z，CD C13) : δ 0 · 9 3 (3 Η， -466 - 200918507 t, J-7.5 Hz), 2.05-2.15 (3H, m), 2.24-2.40 (8H, m), 6.94-6.99 (3H，m) ; m/z (El) 301 (M + )。 N-(3-丁 -2-烯基-5·乙基-2，6-二側氧-1,2,3,6 -四氫·嘧 啶-4-基）-N-(3,5-二甲基-苯基）-乙醯胺（化合物110):將卜 甲烷磺醯基-反式-2-丁烯（283 μΐ, 2.4毫莫耳）加入至N-(3,5-二甲基-苯基）-Ν-(5 -乙基-2,6-二側氧-1,2,3，6 -四氫-嘧 啶-4-基）-乙醯胺（化合物 109)(602 mg，2毫莫耳）、無水 K2C03粉末（276 mg，2毫莫耳）及碘化鋰（268 mg，2毫莫耳） 之DMF (6 ml)攪拌溶液中。經攪拌13小時後，令反應混 合物經乙醚稀釋，經水沖洗，經乾燥（Mg SO 4)，再經過濾 及真空下蒸發。令殘餘物經矽膠管柱層析（溶析液爲乙酸 乙酯：己烷（1:1))純化以生成白色固體（291 mg，40%)。m.p. 2 1 8 _ 2 2 0 0 C ; m / z (E I) 3 5 5 (Μ +)。 1-丁 -2-烯基-6-(3,5-二甲基-苯基胺基）-5 -乙基-1H-嘧 啶-2,4 -二酮（化合物ill):將甲醇鈉（73 mg, 1.35毫莫耳） 加入至N-(3-丁 -2-烯基-5-乙基-2,6-二側氧-1,2,3,6-四氫-嘧啶-4-基）-N-(3,5-二甲基-苯基）-乙醯胺（化合物11〇)(9〇 m g，0 · 2 5毫莫耳）之甲醇（3 m 1)攪拌溶液中。經4小時後’ 令該混合物經過量之NH4C1中和並經真空下蒸發。令殘餘 物經矽膠管柱層析（溶析液爲乙酸乙酯：己烷（1 :1))純化以生 成白色固體（57 mg，72%)。m_p. 190-192°c; iH-NMR (200 MHz, CDC13) : δ l.〇〇(3H，t，J = 7.5 Hz), 1.68- 1.70 (3 H, m)， -467- 200918507 2.2 8-2.3 7 (8H, m), 4.31-4.33 (2H, m), 5.44 (1H, s), 5.51-5.58 (2H, m), 6.39 (2H, s), 6.66 (1H, s), 8.72 (1H, s)； m/z (El) 3 1 3 (M + )。 5- (3,5-二甲基-苯基）-]^-(3-乙氧基甲基-5-乙基-2,6-二 側氧-1，2,3,6-四氫-嘧啶-4-基）-乙醯胺（化合物112):令N_ (3,5 -二甲基-苯基）-N-(5 -乙基-2,6-二側氧-1,2,3,6 -四氫-嘧 啶-4-基）-乙醯胺（化合物1 09)(3 0 1 mg, 1毫莫耳）、六甲基 二矽胺烷（5 m 1)及氯三甲基矽烷（5滴）之混合物回流4小時 。經冷卻至室溫後’令該混合物經真空下蒸發。令殘餘物 溶解於乙腈（5 ml)中。加入氯甲乙醚（πο μι，1.2毫莫耳） 和SnCl4(lM二氯甲烷溶液，1〇〇 μ丨，〇」毫莫耳）。室溫下 攪拌該混合物1 6小時。加入過量之碳酸氫鈉並攪拌該混 合物1小時。令該混合物經真空下蒸發並令殘餘物經矽膠 管柱層析（溶析液爲乙酸乙酯：己烷（1 :1))純化以生成白色固 體（162 mg，45%)。m_p. 182-183 °C; HRMS(EI):計算爲 359.184507;結果爲 359.183174。 6- (3,5 -—甲基-苯基胺基）-1-乙氧基甲基-5-乙基- iH-嚼 啶-2,4-二酮（化合物113):將甲醇鈉（73111§，1.35毫莫耳） 加入至N-(3,5- —甲基_苯基）-N-(3 -乙氧基甲基·5 -乙基_2,6_ 二側氧-1，2,3,6-四氫-嘧啶·4-基）-乙醯胺（化合物U2M93 m g，0 · 2 6晕旲耳）之甲醇（5 m 1)擾拌溶中。經4小時後，令 該混合物經過量之NhCl中和並經真空下蒸發β令殘餘物 -468- 200918507 經矽膠管柱層析（溶析液爲乙酸乙酯：己烷（1:2))純化以生成 白色固體（58 mg，70%)°m.p. 175-176°C; iH-NMR (200 MHz, CDC13) ： δ 0.93 (3H, t, J-7.5 Hz), 1.26 (3H, t, J-7.1 Hz), 2.19 (2H, q, J = 7.5 Hz), 2.27 (6H, s), 3.70 (2H, q, J = 7.1 Hz), 5.34 (2H, s), 6.42 (1H, s), 6.46 (2H, s), 6.65 (1H，s)，8.64 (1H, s) ; m/z (El) 317 (M + )。 反應圖37
1-丁 -2-烯基-6-(3,5-二甲基-苯氧基>-5-異丙基-1 H-嘧 啶-2,4-二酮（化合物115):將1-甲烷磺醯基-反式-2-丁烯 (141 μΐ, 1.2毫莫耳）加入至6-(3,5-二甲基-苯氧基）-5-異丙 基-1H-嘧啶-2,4-二酮（化合物114)(其係利用WO 95/18109 所描述之方法加以製備，該專利案之全部內容基於所有目 的係倂入本文作爲參考：274 mg, 1毫莫耳）、無水K2C03 粉末（138 mg, 1毫莫耳）及碘化鋰（134 mg，1毫莫耳）之 DMF (5 ml)攪拌溶液中。經攪拌1 5小時後，令反應混合 物經乙醚稀釋，經水沖洗，經乾燥（Mg S04)，再經過濾及 真空下蒸發。令殘餘物經矽膠管柱層析（溶析液爲乙醚：二 氯甲烷：己烷（1:1:2))純化以生成白色固體（247 mg，75%)。 m.p. 141-143°C ； 'H-NMR (200 MHz, CDC13) : δ 1.13 (6H, d, J = 7.〇 Hz), 1.59 (3H, d, J = 6.0 Hz), 2.29 (6H, s), 2.72 -469 - 200918507 (1H, m)5 4.2 0 (2H, d, J = 5.5 Hz), 5.34-5.61 (2H, m), 6.51 (2H, s), 6.75 (1H，s), 9.00 (1H, s) ; m/z (El) 3 28 (M + )。 反應圖38
化合物117 1-丁 -2-炔基- 6-(3,5-二甲基-苯氧基）-5-異丙基_ih-喷 陡-2,4 -二酮（化合物116):將1-甲院磺酸基-2 -丙炔（247 μΐ，2.1毫莫耳）加入至6-(3,5-二甲基-苯氧基）·5·異丙基_ 1Η-嘧啶-2,4-二酮（化合物1 1 4)(54 8 mg，2毫莫耳）、無水 K2C〇3粉末（276 mg，2毫莫耳）及澳化鋰（268 mg, 2毫莫耳） 之DMF (1 0 ml)攪拌溶液中。經攪拌1 7小時後，令反應混 合物經乙醚稀釋，經水沖洗，經乾燥（M g S 0 4 )，再經過濾 及真空下蒸發。令殘餘物經矽膠管柱層析（溶析液爲乙酸 乙酯：己烷（1:2))純化以生成白色固體（546 mg，84%)。m.p. 1 5 8- 1 60oC; h-NMR (200 MHz，CDC13): δ 1_15 (6H，d， J = 7.0 Hz), 1_69 (3H，t，J = 2.2 Hz), 2,32 (6H，s)，2.80 (1H， m), 4.43 (2H, q, J = 2.2 Hz), 6.60 (2H, s), 6.78 (1H, s), 8_55 (1H, s) ; m/z (El) 3 26 (M + )。 1-丁 -2-烯基-6-(3,5-二甲基-苯氧基）-5-異丙基_111_嘧 陡-2,4-二酮（化合物117):於氫氣下且於？<1/：8&3〇4(15 mg)之存在下攪拌1-丁 - 2-炔基-6-(3,5-二甲基-苯氧基）_5_ -470- 200918507 異丙基-1H -嘧啶- 2,4·二酮（化合物116)(5〇 mg，0.15毫莫耳 )之甲醇（5 ml)溶液。經15分鐘後，令該混合物經通過寅 式鹽管塞過濾並於真空下蒸發濾液。令殘餘物經砂膠管柱 層析（溶析液爲乙酸乙酯：己烷（1:2))純化以生成白色固體 (50 mg, 100%)。m.p· 141-142°C ； ]H-NMR (200 MHz, CDC13) ： δ 1.13 (6H, d, J = 7.0 Hz), 1.61 (3H, dd, J = 6.9 Hz, 1.4 Hz), 2,31 (6H, s), 2.79 (1H, m), 4.35 (2H, d, J = 6.8 Hz), 5.38 (1H, m), 5.60 (1H, m), 6.54 (2H, s), 6.77 (1H, s) ; m/z (El) 3 2 8 (M + )。 MT-2和MT-4細胞之抗病毒和細胞毒性分析 對利用 MT-2細胞之抗病毒分析，將於培養基中經 10% FBS之5倍系列稀釋的2X測試濃度（50 μΐ)之化合物 加入至96個孔槽盤之每個孔槽中（9個濃度；三重複）。令 ΜΤ-2細胞於0.01之多重感染（m.o.i)下感染HIV-IIIb達3 小時。將於含有1 〇% FBS之培養基中的經感染之細胞懸浮 液（5 0 μ 1 ;約1 . 5 X 1 0 4細胞）加入至每個含有經稀釋之化 合物（5 0 μΐ)的孔槽中。令該等盤於37°C下培育5天。對 利用MT-4細胞之抗病毒分析，將於培養基中經10% FBS 之5倍系列稀釋的2 X測試濃度（2 0 μ 1)之化合物加入至 384個孔槽盤之每個孔槽中（7個濃度；三重複）。令ΜΤ-4 細胞於〇 . 0 1之感染（m · 0 · i)下與Η1V_ 111 b混合並立即將病 毒/細胞混合物（2 0 μ 1 ;約2 0 0 0個細胞）加入至每個含有經 稀釋之化合物（20 μΐ)的孔槽中。令該等盤於37°C下培育5 -471 - 200918507 天。經培育5天後，將C e 11T i t e r - G1 ο τ M試劑（1 0 0 μ 1 ;批 號 # G7571，Promega Biosciences, Inc., Madison, WI)力Π 入 至含有MT-2細胞之每個孔槽中且另將該試劑（40 μΐ)加入 至含有ΜΤ-4細胞之每個孔槽中。藉由於室溫下培育1〇分 鐘以進行細胞裂解並讀取化學發光値。 對利用ΜΤ-2細胞之化合物細胞毒性測定，實驗方法 係與利用ΜΤ-2細胞之抗病毒分析者相同，唯其係使用未 受感染之細胞及經3倍系列稀釋之化合物。對利用MT-4 細胞之化合物細胞毒性測定，實驗方法係與利用ΜΤ-4細 胞之抗病毒分析者相同，唯其未加入病毒。 本發明之化合物的抗病毒E C 5 α値（ηΜ)係介於約0.1至 約1000、或約0.1至約500、或約0.1至約300'或約0.1 至約200、或約0.1至約1〇〇、或約〇.1至約50、或低於 約5 0 0、或低於約4 0 0、或低於約3 0 0、或低於約2 0 0、或 低於約1 0 0、或低於約5 0、或低於約2 0、或低於約1 〇。 化合物 3、 5、 6、 9、 13、 14、 17、 25、 38、 46、 47、 54、 56 、 57 、 60 、 70 、 72 、 73 、 74 、 76 、 80 、 86 及 115 之 E C 5 〇値係低於約1 〇。 -472-

Claims (1)

  1. 200918507 十、申請專利範圍 1·—種式（I)化合物
    S Γ ⑴ 或其藥學上可接受之鹽、溶劑化物及/或酯，其中 X和Y係各別爲〇或S ; A 係共價鍵、-0-、-S-、-NR5-' -c(0)_、_c(s)_、 -C(NR8)-或-C(R6)2-; D係共價鍵、烷撐基、烯撐基或炔撐基； R1係Η、鹵、院基、鹵院基、環院基、經取代之環产 基、雜環基、經取代之雜環基、-ΟΗ '烷氧基' 驢基、 烷硫基、甲矽烷氧基、烯基、經取代之烯基、块基、經取 代之炔基、CN、-c(o)-n(r7)2、-0-C(0)-N(R7)2、_n(r7)_ C(0)-N(R7)2、_C(0)-0 院基、-C(〇)-〇H、-〇-C(〇)_〇 院基 、-N(R7)-C(0)-0烷基、甲矽烷氧基、-0-烷撐基-OH、 烷撐基-〇_醯基或- S(0)2-N(R7)2 ; R2係鹵、硝基、氰基 '垸基 '鹵院基、經取代之院基 、羥基烷基、烷氧基烷基、烯基、經取代之烯基、炔基、 經取代之炔基、烷氧羰基、-N(R7)2、烷基胺甲醯基、二烷 基胺甲醯基、環烷基、經取代之環烷基、芳基烷基或經取 代之芳基烷基； -473- 200918507 R3係芳基或雜芳基； R4係Η、烷基、經取代之烷基、環烷基、經取代之環 烷基、羥基烷基、烷氧基烷基、芳基烷基或經取代之芳基 烷基； R5係Η、烷基、經取代之烷基、芳基烷基、經取代之 芳基烷基、-ΟΗ、醯基或經取代之醯基； 每個R6係各別爲Η、院基、環院基、經取代之環院 基、羥基、烷氧基、氰基或鹵； 每個R7係各別爲Η、烷基、芳基、經取代之芳基、 芳基院基、經取代之芳基院基、環院基、經取代之環丨完基 、雜芳基或經取代之雜芳基； R8係Η、烷基、芳基、經取代之芳基、〇Η或烷氧基 每個Ζ係各別選自幽、硝基、羥基、胺基、乙酸胺基 、三氟乙醯胺基、疊氮基、氰基、甲醯基、烷基、經取代 之烷基、烷基胺甲醯基、二烷基胺甲醯基、烯基、經取代 之烯基、炔基、經取代之炔基、烷氧基、經取代之院氧其 、院氧羰基、環烷基、經取代之環烷基、環烯基、經取代 之環烯基、雜環基、經取代之雜環基、芳基、經取代之芳 基或氧化物；且 η係0至4之整數； 唯其 (a)當 X 和 Y 皆爲 Ο，R4 係 Η，A 係 _〇_、_s_、 C(O)-、-CH(OH)-或-Ch2-，R3 係苯基且 D 係_CIi2_ 時，R1 -474- 200918507 不爲烷氧基； (b )當· v X 和 Y 皆爲 0，A 係-S-、-Ο -或-C(〇)-，r3 係 苯基，η 係 3 2 ’母個Ζ係烷基，D係-CH2- ’ R2係烷基且 R4 係 Η 時，·D ! — R不爲未經取代之環烷基、未經取代之雜環 烷基或未經取代之雜芳基； 係-CH2-: 不爲經取 嘧啶基或 由 X 和 Y 皆爲 〇，A 係 _C(0)_、-0-或 _NH_，D R係院基’ R3係苯基’ „係2且R4係η時，R1 #或未經取代之雜芳基，該雜芳基選自耻η定基、 噠嗪基； (d) 由X和Y皆爲〇，n係〇或2，每個Z係基， A-R3係苄甚# 、 鸯、本甲醯基、苯硫基或苯氧基，R4係11且R: 係乙基或驾而宜 基時’ D不爲烯撐基或炔撐基且-不爲 丈兀基匕基院基或-烷撐基_ C ( 〇 ) _ 〇烷基； ()僅R4和-D-R1之—者係H。 2·〜種式（la)化合物 Y
    或其藥學上可接受之鹽、溶劑化物及/或酯，其中 X和Y係各別爲〇或s ; A 係共價鍵、-0-、-S-、-NR5-、-C(O)-、、c(s) C(NR8)~ 或-C(R6)2-; -475- 200918507 D係共價鍵、烷撐基、烯撐基或炔撐基； R1係Η、鹵、烷基、鹵烷基、經取代之環烷基、經取 代之雜環基、-ΟΗ、-0-醯基、烷硫基、甲矽烷氧基、烯基 、經取代之烯基、炔基、經取代之炔基、01^、-(：(0)-N(R7)2 ' -0-C(0)-N(R7)2 ' -N(R7)-C(0)-N(R7)2 ' -C(0)-0 烷基、-C(0)-0H、-0-C(0)-0 烷基、-N(R7)_c(〇)_〇 烷基 、甲矽烷氧基、-0-烷撐基-oh、-O-烷撐基-〇_醯基 或-S(0)2-N(R7)2 ; R2係鹵、硝基、氰基、烷基、鹵烷基' 經取代之烷基 、羥基烷基、烷氧基烷基、烯基、經取代之烯基、炔基、 經取代之炔基、烷氧羰基、-N (R7)2、烷基胺甲醯基、二焼 基胺甲醯基、環烷基、經取代之環烷基、芳基烷基或經取 代之芳基烷基； R3係芳基或雜芳基； R4係Η、烷基、經取代之烷基、環烷基、經取代之環 烷基、羥基烷基、烷氧基烷基、芳基烷基或經取代之芳基 院基， R5係Η ]完基、經取代之烷基、芳基烷基、經取代之 芳基烷基、-ΟΗ、醯基或經取代之醯基； 、經取代之環烷 經取代之芳基、 經取代之環烷基 每個R6係各別爲Η、烷基、環烷基 基、經基、1兀氧基、氰基或_ : 每個R7係各別爲Η、院基、芳基、 芳基烷基、經取代之芳基烷基、環院基、 、雜芳基或經取代之雜芳基； -476- 200918507 R8係Η、烷基、芳基、經取代之芳基、〇 η或烷氧基 j 每個Ζ1係各別選自鹵、硝基、羥基、胺基、乙醯胺 基、三氟乙醯胺基、疊氮基、氰基、甲醯基、烷基、經取 代之烷基、烷基胺甲醯基、二烷基胺甲醯基、烯基、經取 代之烯基、炔基、經取代之炔基、烷氧基' 經取代之烷氧 基、烷氧羰基、環烷基、經取代之環烷基、環烯基 '經取 代之環烯基、雜環基、經取代之雜環基、芳基、經取代之 芳基或氧化物； Ζ2係選自鹵、硝基、羥基、胺基、乙醯胺基' 三氟乙 醯胺基、疊氮基、氰基、甲醯基、烷基胺甲醯基、二院其 胺甲醯基、烯基、經取代之烯基、炔基、經取代之块基、 院氧基、經取代之丨兀氧基、院氧擬基、環院基、終取代之 環烷基、環烯基、經取代之環烯基、雜環基、經取代之雜 環基、芳基、經取代之芳基或氧化物； η係0至3之整數；且 R4和-D-R1中僅一者係Η。 3 · 如申請專利範圍第1項之化合物，其中Α係 -C(R6)2-。 4. 如申請專利範圍第3項之化合物，其中A係 -C(O)-。 5. 如申請專利範圍第1至4項中任〜項之化合物， 其中R2係烷基或鹵烷基。 項之化合物， 6- 如申請專利範圍第1至4項中任 -477- 200918507 其中D係共價鍵或烷撐基。 7. 如申請專利範圍第1至4項中任一項之化合物， 其中R1係Η、烷基、鹵烷基、環烷基或經取代之環烷基 〇 8- 如申請專利範圍第1至4項中任一項之化合物， 其中η係至少爲1且至少一個ζ、Ζ1或Ζ2係-CN。 9 · 如申請專利範圍第1至4項中任一項之化合物， 其中 D係烷撐基、烯撐基或炔撐基；且 R1係Η、鹵、烷基、經取代之烷基、環烷基或經取代 之環烷基、-ΟΗ、烷氧基、-CN、-C(0)-N(R7)2、-0-烷撐 基-OH、-〇-烷撐基-〇-醯基、、-〇_c(〇)_ N(R7)2、-C(0)-0 烷基或- C(0)-〇H。 1 0 如申請專利範圍第1至4項中任一項之化合物， 其中 A 係共價鍵、-C(NR8)-、·〇-或-NR5-: D係共價鍵或烷撐基；且 R2係烷基。 11. 如申請專利範圍第1至4項中任一項之化合物， 其中R1係Η或烷基。 12. 如申請專利範圍第1項之化合物，其中 X和Υ皆爲0 ; R3係苯基； 每個 ζ 係各別選自-CH3、-CN、-CH^CH-CN、-CH2- -478- 200918507 CH2-CN 或 Cl ; n係2 ;
    -CH(OCH3)-、-cH(cN)-、-Ο-或-ΝΗ-;且 D-R1係選自η、烷基、鹵烷基、環烷基烷基、經取代 之環院基烷基、羥基烷基、氰基烷基、-烷撐基_C(0)_ n(r7)2、烷撐基-s(o2)-n(r7)2、-烷撐基-o-c(o)-n(r7)2 、-院撐基-C(0)-0烷基、-烷撐基-C(0)-0H、-烯撐基-C(0)-0院基 ' -烯撐基_C(0)_N(R7)2、烷氧基烷基、烯基 '鹵丨希基、炔基、環烷基炔基、經取代之環烷基炔基、環 院基稀基或經取代之環烷基烯基。 13·如申請專利範圍第1項之化合物，其中r3-(z)2 係選自 ηκ\ r.i CN π
    14.如申請專利範圍第12項之化合物，其中D-R1係 選自 Η、-ch3、-ch2ch3、-ch2ch2ch3、-CH2CH2CH2CH3 、 -CH2CF3 、環 丙基-CH2- 、 -CH2CH2-OH 、-CH2CH2CH2-OH 、 -CH2CH2CH2CH2-OH 、 -ch2cn 、 -CH2CH2CN 、 -CH2CH2CN 、 -ch2c(o)nh2 -479- 200918507 、 -CH2CH2C(0)NH2 、 -CH2CH2CH2C(0)NH2 、 -CH2-0-CH2CH3 、 -CH2CH2-0-CH2CH3 、-CH2CH2CH2-0-CH2CH3 、 -CH2CH2CH2CH2-O-CH2CH3 、-CH2-0-CH3 、 -CH2CH2-0-CH3 、 -CH2CH2CH2-0-CH3 、-CH2CH2CH2CH2-〇-CH3 、 -CH2-C^CH ' -ch2-c = c-ch3 、-CH2-CeC-環丙基、-CH2-CeC-CH2-OH、順式 -CH2CH = CH-CH3 ' Η -CH2CH = CH-CH3 ' -CH2CH = C(CH3)2、-CH2CH2CH = C(CH3)2、 -ch2ch2c(ch3) = ch2、-CH2CC1 = CH(CH3)、-CH(CH3)2、 -CH2CH2CH = CH2、-ch2-環丙撐基-ch2-c(o)-och3、-ch2-環丙撐基-ch2-c(o)-oh ' -ch2-環丙撐基-ch2-c(o)-NH(PMB) ' -CH2-環丙撐基·<：Η2-(：(0)-ΝΗ2、-CH2-CH2-0-C(0)-0CH3、-CH2-CH = CH-C(0)-0CH2CH3 或-ch2-ch = ch-c(o)-nh2。 15.如申請專利範圍第13項之化合物，其中D-R1係 選自 Η、-ch3、-ch2ch3、-ch2ch2ch3、-ch2ch2ch2ch3 、 -CH2CF3 、環 丙基-CH2- 、 -CH2CH2-OH ' -CH2CH2CH2-OH ' -CH2CH2CH2CH2-OH ' -CH2CN ' -CH2CH2CN 、 -ch2c(o)nh2 、 -ch2ch2c(o)nh2 、 -CH2CH2CH2C(0)NH2 、 -CH2-O-CH2CH3 、 -CH2CH2-O-C.H2CH3 、 -ch2ch2ch2-o-ch2ch3 、 -ch2ch2ch2ch2-o-ch2ch3 、 -ch2-o-ch3 、 -ch2ch2-o-ch3 、 -ch2ch2ch2-o-ch3 、-CH2CH2CH2CH2-O-CH3 、 -CH2-C = CH ' -CH2-C = C-CH3 -480 200918507 、-CH2-CeC-環丙基、-CH2-CeC-CH2-OH、順式 -ch2ch = ch-ch3、反式-ch2ch = ch-ch3、 -ch2ch=c(ch3)2、-CH2CH2CH = C(CH3)2、 •CH2CH2C(CH3) = CH2、-CH2CC1 = CH(CH3)、-CH(CH3)2、 -ch2ch2ch = ch2、-ch2-環丙撐基-ch2-c(o)-och3、-ch2-環丙撐基-ch2-c(o)-oh、-ch2-環丙撐基-ch2-c(o)-NH(PMB) ' -CH2-環丙撐基-CH2-C(0)-NH2、-CH2-CH2-0- c(o)-och3、-ch2-ch = ch-c(o)-och2ch3 或-ch2-ch = ch-c(o)-nh2。 16. 如申請專利範圍第1項之化合物，其中 X和Y皆爲〇 ; A係共價鍵； 每個Z係各別選自-CH3、-CN或C1 ; η係2，且 D - R 1係Η或烷基。 17. 如申請專利範圍第1至4項中任一項之化合物， 其中R3係選自
    〇 1 8 .如申請專利範圍第1 7項之化合物’其中D - R 1係 -481 - 200918507 選自 H、-CH3、-CH2CH3、-CH(CH3)2、-CH2CH2CH3 或-CH2CH2CH2CH3。 19.如申請專利範圍第1項之化合物，其係選自
    -482 - 200918507
    -483 - 200918507
    -484 - 200918507
    -485- 200918507
    -486- 200918507
    ;或上述任一之藥學上可接受之鹽、溶劑化物及/或酯。 20.如申請專利範圍第1項之化合物，其係選自 -487- 200918507
    -488- 200918507
    上述任一之藥學上可接受之鹽、溶劑化物及/或醋。 21· 一種醫藥組成物，其包含治療上有效量之申請專 利範圍第1至20項中任一項之化合物及藥學上可接受之 載體。 22·如申請專利範圍第21項之醫藥組成物，其進一 步包含一或多種額外之活性劑。 2 3·如申請專利範圍第2 2項之醫藥組成物，其中該 —或多種額外之活性劑係選自HIV蛋白酶抑制劑、HIV反 轉錄酶之非核苷抑制劑、HIV反轉錄酶之核苷抑制劑、 HIV反轉錄酶之核苷酸抑制劑、HIV整合酶抑制劑、gP4 1 抑制劑、CXCR4抑制劑、gP120抑制劑、G6PD和NADH 氧化酶抑制劑、CCR5抑制劑、CCR8抑制劑、進入抑制劑 、RNase Η抑制劑、成熟抑制劑、藥物動力增強劑、治療 ΗIV之其他藥劑、或彼等之混合物。 24.如申請專利範圍第23項之醫藥組成物，其中 (1)該HIV蛋白酶抑制劑係選自安潑那韋（amprenavir )(Agenerase)、阿扎那韋（atazanavir)(Reyataz)、福沙普利 那 早 （f〇samprenavir)(Lexiva) 、 節 地 那 韋 (indinavii：)(Crixivan)、洛匹那韋（lopinavir)、利托那韋 (ritonavir)(norvir) ' 奈非那韋（nelfinavir)(Viracept)、沙 奎 那 韋 （saquinavir)(Invirase) 、 替 拉 那 韋 -489 - 200918507 (tipranavir)(Aptivus)、布卡那韋（brecanavir)、地瑞那韋 (darunavir)(Prezista)、TMC-126、TMC-114、美至那韋 (mozenavir)(DMP-45 0)、J E - 2 1 4 7 (A G 1 7 7 6 )、L - 7 5 6 4 2 3、 RO033 4649、KNI-272、DPC-681、DPC-684、DG17、GS-8 3 74、MK-8 1 22 (PPL-1 00)、DG3 5、AG 1 8 59、SPI-256、 TMC 523 90、PL- 3 3 7、SM-3 223 77、SM-3 0 95 1 5、GRL-02 03 1、CRS-074、C R S - 0 7 5、K B - 9 8 或 A - 7 9 0 7 4 2 ; (2)該HIV反轉錄酶之非核苷抑制劑係選自卡波韋林 (capravirine)、艾咪韋林（emivirine)、戴拉凡地平 (delaviridine)(Rescriptor)、依法韋命（efavirenz)(Sustiva) 、奈韋拉平〇6乂丨^卩丨1^)(\^1&11111116)、（ + )-綿毛胡桐內醋八 (calanolide A)、綿毛胡桐內酯 B (calanolide B)、依曲韋 林（etravirine)(Intelence)、GW5634、DPC-083、DPC-961 、DPC-963、MIV-150、MIV-160、MIV-170、大匹韋林 (dapivirine)(TMC-120)、拉皮韋林（rilpivirine)(TMC-278) 、BILR 3 5 5 BS、VRX 840773、UK-45 3 06 1、RDEA 806、 RDEA 427、RDEA 640、IDX 8 99、ANX-2 0 1 (Thiovir)、R-1 206、LOC-dd、IQ P - 0 4 1 0 ( S J - 3 3 6 6)、Y M - 2 1 5 3 8 9 ' Y M-22 8 8 5 5、CMX- 0 52 或 CMX-1 82 ； (3 )該HI V反轉錄酶之核苷抑制劑係選自疊氮胸苷 (Retrovir)、恩曲他濱（emtricitabine)(Emtriva)、2’，3’ -雙 去氧肌苷（Videx)、司他夫定（stavudine)(Zerit)、2’，3’ -雙 去氧胞苷（Hivid)、拉脈優定（lamivudine)(Epivir)、阿波卡 偉（abacavir)(Ziagen)、安妥 U惡苷（amdoxovir)、艾非他濱 -490- 200918507 (elvucitabine)(ACH 126443)、阿洛夫定（alovudine)(MlV-310)、MIV-210、拉西卡偉（racivir)(消旋 FTC; PSI-5004) 、D-d4FC、疊氮化磷（phosphazide)、福齊夫定替醋 (fozivudine tidoxil)' 阿匹西他濱（apricitibine)(AVX754; SPD-754)、GS-73 40、KP-1461、AVX75 6、OBP-601、二 嚼茂院胸腺嚼陡（dioxolane thymine)、TMC-254072、INK-20 、 PPI-801、PPI-8 02、ΜIV - 4 1 0、4 ’ - E d 4 T、B - 1 0 8 或磷 夫定酯（fosalvudine tidoxil)(HDP 99.0003 ); (4) 該HIV反轉錄酶核苷酸抑制劑係選自富馬酸替諾 福韋醋（tenofovir disoproxil fumarate)(Viread)或阿德福韋 醋（adefovir dipivoxil)； (5) 該HIV整合酶抑制劑係選自薑黃色素、薑黃色素 之衍生物、菊苣酸、菊苣酸之衍生物、3，5 -二咖啡醯奎寧 酸、3，5 -二咖啡醯奎寧酸之衍生物、金黃三羧酸、金黃三 羧酸之衍生物、咖啡酸苯乙酯、咖啡酸苯乙酯之衍生物、 酪胺酸磷酸化抑制劑、酪胺酸磷酸化抑制劑之衍生物、櫟 皮酮、櫟皮酮之衍生物、S- 1 3 60、季特韋（zintevir)(AR-177) 、 L-870812 、 L-870810 、帕 潘立酮 (raltegravir)(Isentress ； MK-0518) 艾咪特拉韋 (elvitegravir)(GS-9137)、BMS- 5 3 8 1 5 8、GSK3 6473 5C、 BMS-70703 5、MK-204 8、GSK-3495 72 (S-3 49 5 72)、GSK-265744 (S-265744) 、 GSK-247303 (S-247303) 、 S-1360 (GW8 1 08 7 1 )、1,5-DCQA、INH-001、INT-349、V-165、 RIN-25、BFX- 100 1、BFX- 1 002、BFX- 1 003、RSC- 1 8 3 8、 -491 - 200918507 BCH-3 3 040 或 BA 0 1 1 ; (6) 該 gp41抑制劑係選自恩夫韋地（enfuvirtide KFuzeon)、西夫韋肽（sifuvirtide)、MPI-45 1 93 6、FB006M 、A-329029 或 TRI- 1 144 ； (7) 該 CXCR4 抑制劑係選自 AMD-070、KRH-3 95 5 (CS-3 95 5 )、AMD-93 70、AMD-3451、RPI-MN、MSX-122 或 POL-243 8 ; (8) 該進入抑制劑係選自 SP01A、PA-161、SPC3、 TNX-355、DES6、SP-10、SP-03、CT-319 或 CT-326 ； (9) 該gpl20抑制劑係選自BMS-488043及其前藥、 BlockAide/CR、KPC-2 或 MNLP62 ; (10) 該 G6PD和 NADH氧化酶抑制劑係免疫素 (immunitin): (11) 該CCR5抑制劑係選自艾波韋羅（aplaviroc)、尼 非韋羅（nifeviroc)、偉特韋羅（vicriviroc)(SCH-417690)、 馬洛韋羅（maraviroc)(Selzentry)、PRO-140、PRO-542、 INCB 1 5 0 50、INCB947 1、PF-23 2798、SCH-5 32706、GSK-7067 69、TAK-6 52、TAK-220 ' ESN-1 96 ' RO- 1 752、ZM-6 8 8 5 23 、 AMD-8 8 7 、 YM-370749 、 NIBR- 1 282 、 SCH- 3 5 06 3 4、ZM-6 8 8 5 23 或 CCR5mAb004 ； (12) 該 CCR8 抑芾丨J 劑係 ZK-75 6326 ； (13) 該RNase H抑制劑係選自ODN-93或ODN-112 » (14) 該成熟抑制劑係選自貝韋立馬（bevirimatKPA- -492- 200918507 457)、PA-040、MPC-905 5 (vicecon ； MPI-4983 9)、ACH-1 00703 或 ACH- 1 00706 ; (15) 該藥物動力增強劑係選自 BAS-100、SPI-452、 PF-41 94477、TMC-4 1 629 或紅黴素；且 (16) 該治療HIV之其他藥劑係選自REP 9、SP-01A 、TNX-3 5 5、DES6、ODN-93、ODN-1 12、VGV-1、阿普林 津（Ampligen)、HRG214、單選殖抗體 Cytolin、VGX-410 、VGX-820、KD-247 > AMZ 0026、CYT 99007、A-221 HIV ' HPH-116 ' DEBIO-025 ' BAY 5 0-47 98 > MDXO10 (單 選殖抗體 ipilimumab)、PBS 119、BIT-225、UBT-8147、 ITI-3 67、AFX-400、BL- 1 050、GRN- 1 3 99 5 1、GRN- 1 40665 ' AX-38679、RGB-340638、PPI-367 或 ALG 889。 2 5 · —種組合醫藥劑，其包含第一醫藥組成物和第二 醫藥組成物： 該第一醫藥組成物包含申請專利範圍第1至2 0項中 任一項之化合物或其藥學上可接受之鹽、溶劑化物及/或 酯；且 該第二醫藥組成物包含至少一種額外之活性劑，該活 性劑係選自HIV蛋白酶抑制劑、HIV反轉錄酶之非核苷抑 制劑、HIV反轉錄酶之核苷抑制劑、HIV反轉錄酶之核苷 酸抑制劑、HIV整合酶抑制劑、gp41抑制劑、CXCR4抑 制劑、gpl20抑制劑、G6PD和NADH氧化酶抑制劑、 CCR5抑制劑、CCR8抑制劑、進入抑制劑、RNase Η抑制 劑、成熟抑制劑、藥物動力增強劑、治療HIV之其他藥劑 -493- 200918507 、或彼等之混合物。 2 6.如申請專利範圍第2 5項之組合醫藥劑，其中 (1) 該HIV蛋白酶抑制劑係選自安潑那韋（arnprenavir )(Agenerase)、阿扎那韋（atazanavir)(Reyataz)、福沙普利 那韋（fosamprenavir)(LexiVa)、茚地那韋（indinavir) (Crixivan)、洛匹那韋（l〇pinavir)、利托那韋（rit〇navir) (norvir)、奈非那韋（neifinavir)(viracept)、沙奎那韋 (saquinavir)(Invirase)、替拉那韋（tipranavir)(Aptivus)、 布卡那早（brecanavir)、地瑞那韋（darunavir)(Prezista)、 TMC-126、TMC-114、美至那韋（m〇zenavir)(DMP-450)、 JE-2147 (AG 1 7 76)、L-75 6423、RO0334649、KNI-272、 DPC-681、DPC-684、DG17、GS-83 74、MK-8122 (PPL-100)、DG35 ' AG 1 85 9、SPI-2 5 6、TMC 5 23 90 ' PL-3 3 7 ' SM-3223 77、SM-3 095 1 5、GRL-0203 1、CRS-074 ' CRS-075 、 KB-98 或 A-790742 ; (2) 該HIV反轉錄酶之非核苷抑制劑係選自卡波韋林 (capravirine)、艾咪韋林（emivirine)、戴拉凡地平 (delaviridine)(Rescriptor)、依法韋侖（efavirenz)(Sustiva) 、奈韋拉平（nevirapine)(Viramune)、（ + )-綿毛胡桐內酯 A (calanolide A)、綿毛胡桐內醋 B (calanolide B)、依曲韋 林（etravirine)(Intelence)、GW5634、DPC-083、DPC-961 、DPC-963、MIV-150、MIV-160、MIV-170、大匹韋林 (dapivirine)(TMC-120)、拉皮韋林（rilpivirine)(TMC-278 ) 、BILR 3 5 5 BS、VRX 84 0773、UK-4 5 3 06 1 > RDEA 8 06、 -494 - 200918507 RDEA 427、RDEA 640、IDX 899、ANX-201(Thiovir)、R-1 206、LOC-dd、IQP-0410 (SJ-3 3 66)、YM-2 1 53 8 9、YM-228 8 5 5、CMX-052 或 CMX-182 ; (3) 該HIV反轉錄酶之核苷抑制劑係選自疊氮胸苷 (Retrovir)、恩曲他濱（emtricitabine)(Emtriva)、2’，3’ -雙 去氧肌苷（Videx)、司他夫定（stavudine)(Zerit)、2’，3’ -雙 去氧胞苷（Hivid)、_拉脈優定（lamivudine)(Epivir)、阿波卡 偉（abacavir)(Ziagen)、安妥 U惡苷（amdoxovir)、艾非他濱 (elvucitabine)(ACH 126443)、阿洛夫定（alovudine)(MIV-310)、MIV-2 1 0、拉西卡偉（racivir)(消旋 FTC : PSI-5004) 、D-d4FC、疊氮化憐（phosphazide)、福齊夫定替醋 (fozivudine tidoxil)、阿匹西他濱（apricitibine)(AVX754; SPD-754)、GS-7340、KP-1461、AVX75 6 ' OBP-601、二 11惡茂院胸腺喃 Π定（dioxolane thymine)、TMC-254072、INK-20 、 PPI-80 1、PPI-802、ΜIV - 4 1 0、4，- E d 4 T、B 1 0 8 或磷 夫定酯（fosalvudine tidoxil)(HDP 99.0 003 ); (4) 該HIV反轉錄酶核苷酸抑制劑係選自富馬酸替諾 福韋醋（tenofovir disoproxil fumarate)(Viread)或阿德福韋 醋（adefovir dipivoxil); (5) 該HIV整合酶抑制劑係選自薑黃色素、薑黃色素 之衍生物、菊苣酸 '菊苣酸之衍生物、3，5 - 一咖啡醯奎寧 酸、3，5 -二咖啡醯奎寧酸之衍生物、金黃三羧酸、金黃三 殘酸之衍生物、咖啡酸苯乙酯、咖啡酸苯乙酯之衍生物、 酪胺酸磷酸化抑制劑、酪胺酸磷酸化抑制劑之衍生物、櫟 -495- 200918507 皮酮、櫟皮酮之衍生物、S-1360、季特韋（zintevir)(AR-177) 、 L-870812 、 L-870810 、帕 潘立酮 (raltegravir)(Isentress ; MK-0518)、艾味特拉韋 (elvitegravir)(GS-9137) 、 BMS-53 8 1 5 8 、 GSK3 6473 5C 、 BMS-70703 5、MK-2048、GSK-349572 (S-349572)、GSK- 265744 (S-265744) 、 GSK-247303 (S-247303) 、 S-1360 (GW8 1 08 7 1 )、1，5-DCQA、INH-001、INT-349、V-165、 RIN-25 ' BFX-1001、BFX-1 002、BFX- 1 003、RSC- 1 83 8、 BCH-3 3 040 或 BA 01 1 ; (6) 該 gp41抑制劑係選自恩夫韋地（enfuvirtide) (Fuzeon)、西夫韋肽（s i f u v i r t i d e)、Μ PI - 4 5 1 9 3 6、F B 0 0 6 Μ 、A-329029 或 TRI-1 144 ； (7) 該 CXCR4 抑制劑係選自 AMD-070、KRH- 3 9 5 5 (CS-3 95 5 )、AMD-93 70、AMD-3 45 1、RPI-MN、MSX-122 或 POL-243 8 ； (8) 該進入抑制劑係選自SP01A、PA-161、SPC3、 TNX-3 5 5、DES6、SP-1 0、S P - 0 3、C T - 3 1 9 或 C T - 3 2 6 ; (9) 該gpl20抑制劑係選自BMS-488043及其前藥、 BlockAide/CR、KPC-2 或 MNLP62 ; (10) 該 G6PD和NADH氧化酶抑制劑係免疫素 (immunitin); (1 1)該CCR5抑制劑係選自艾波韋羅（apiaviroc)、尼 非韋羅（nifeviroc)、偉特韋羅（vicrivir〇c)(sCH-417690)、 馬洛韋羅（maraviroc)(Selzentry)、PRO-140、PRO-542、 -496- 200918507 INCB 1 5050、INCB947 1、PF-232798、SCH-53 2706、GSK-706769 ' TAK-652、TAK-220、ESN-196、RO- 1 752、ZM-6 8 8 5 23 、 AMD- 8 8 7 、 YM-3 70749 、 NIBR- 1 282 、 SCH- 3 5 06 34、ZM-6 8 8 523 或 CCR5mAb004 ； (12) 該 CCR8 抑制齊!l 係 ZK-756326; (13) 該RNase H抑制劑係選自ODN-93或ODN-112 f (14) 該成熟抑制劑係選自貝韋立馬（bevirimat)(PA-45 7)、PA-040、MPC-905 5 (vicecon ； MPI-49 839)、ACH-1 00703 或 ACH- 1 00706 ； (15) 該藥物動力增強劑係選自 BAS-100、SPI-452、 PF-4 1 94477、TMC-4 1 629 或紅黴素；且 (16) 該治療HIV之其他藥劑係選自 REP 9、SP-01A 、TNX-355、DES6、ODN-93、ODN-112、VGV-1、阿普林 津（Ampligen)、HRG214、單選殖抗體 Cytolin、VGX-410 、VGX-820 ' KD-24 7、AMZ 0026、CYT 99007、A-221 HI V、HPH-1 1 6、DEBIO-025、B A Y 5 0 - 4 7 9 8、M D X 0 1 0 (單 選殖抗體 ipilimumab)、PBS 119、BIT-225、UBT-8147、 ITI-367、AFX-400、B L - 1 0 5 0、G RN - 1 3 9 9 5 1、GRN- 1 40665 、AX-38679、RGB-340638、PPI-367 或 ALG 889。 27 · —種活體外抑制反轉錄病毒複製之方法，其包含 令該反轉錄病毒與申請專利範圍第1至20項中任一項之 化合物或其藥學上可接受之鹽、溶劑化物及/或酯接觸。 28.如申請專利範圍第27項之方法，其進一步包含 -497- 200918507 令該反轉錄病毒與至少一種額外之活性劑接觸，該活性劑 係選自一或多種ΗIV蛋白酶抑制劑、η IV反轉錄酶之非核 苷抑制劑、HIV反轉錄酶之核苷抑制劑、HIV反轉錄酶之 核苷酸抑制劑、HIV整合酶抑制劑、gp41抑制劑、CXCR4 抑制劑、gpl20抑制劑、G6PD和NADH氧化酶抑制劑、 C C R 5抑制劑、C C R 8抑制劑、進入抑制劑、r n a s e Η抑制 劑 '成熟抑制劑、藥物動力增強劑、治療HIV之其他藥劑 、或彼等之混合物。 29.如申請專利範圍第2 8項之方法，其中 (1) 該HIV蛋白酶抑制劑係選自安潑那韋（arnprenavir KAgenerase)、阿扎那韋（atazanavir)(Reyataz) ' 福沙普利 那韋（fosamprenavir)(Lexiva)、茚地那韋（indinavir) (Crixivan)、洛匹那韋（l〇pinavir)、利托那韋（ritonavir) (norvir)、奈非那韋（nelfinavir)(Viracept)、沙奎那韋 (saquinavir)(Invirase)、替拉那韋(tipranavir)(Aptivus)、 布卡那韋（brecanavir)、地瑞那韋（darunavir)(Prezista)、 TMC-126、TMC-114、美至那韋（mozenavir)(DMP-450)、 JE-2147 (AG 1 776)、L-75 6423、RO03 3 4649、KNI-272、 DPC-681 ' DPC-684、DG17 ' GS-8374、MK-8122 (PPL-100)、DG35、AG 1 8 59 ' SPI-2 56、TMC 52390、PL-3 3 7、 SM-322377、SM-3 095 1 5、GRL-0203 1、CRS-074、CRS-0 75、KB-98 或 A-790742 ; (2) 該HIV反轉錄酶之非核苷抑制劑係選自卡波韋林 (capravirine)、艾咪韋林（emivirine)、戴拉凡地平 -498- 200918507 (delaviridine)(Rescriptor)、依法韋侖（efavirenz)(Sustiva) 、奈韋拉平（nevirapine)(Viramune)、（ + )-綿毛胡桐內酯 A (calanolide A)、綿毛胡桐內酯 B (calanolide B)、依曲韋 林（etravirine)(Intelence)、GW5634、DPC-083、DPC-961 、DPC-963、MIV-150、MIV-160、MIV-170、大匹韋林 (dapivirine)(TMC-120)、拉皮韋林（rilpivirine)(TMC-278) 、BILR 3 5 5 BS、VRX 840773、UK-453 06 1 ' RDEA 806 ' RDEA 427、RDEA 640、IDX 8 99、ANX-201 (Thiovir)、R_ 1 206、LOC-dd、IQ P - 0 4 1 0 ( S J - 3 3 6 6)、Y M - 2 1 5 3 8 9、Y M-228 8 55 ' CMX-052 或 CMX-182 ; (3) 該HIV反轉錄酶之核苷抑制劑係選自疊氮胸苷 (Retrovir)、恩曲他濱（emtricitabine)(Emtriva)、2’，3’ -雙 去氧肌苷（Videx)、司他夫定（stavudine)(Zerit)、2’，3’-雙 去氧胞苷（Hivid)、拉脈優定（lamivudine)(Epivir)、阿波卡 偉（abacavir)(Ziagen)、安妥噁苷（amdoxovir)、艾非他濱 (elvucitabine)(ACH 1 2 6 4 4 3 )、阿洛夫定（a 1 〇 v u di ne) (Μ IV-310)、MIV-210、拉西卡偉（racivir)(消旋 FTC; PSI-5004) 、D-d4FC、疊氮化磷（phosphazide)、福齊夫定替酯 (fozivudine tidoxil)、阿匹西他濱（apricitibine)(AVX75 4; SPD-754)、GS-73 40、KP-1461、AVX7 5 6、OBP-601、二 嚷茂院胸腺喃症（d i o x 〇 1 a n e t h y m i n e)、T M C - 2 5 4 0 7 2、IN K -20、PPI-801、PPI- 8 02、MIV-410、4，-Ed4T、B-108 或磷 夫定酯（fosalvudine tidoxil)(HDP 99.0003); (4) 該HIV反轉錄酶核苷酸抑制劑係選自富馬酸替諾 -499- 200918507 福韋酯（tenofovir disoproxil fUmarate)(Viread)或阿德福韋 醋（adefovir dipivoxil)； (5) 該HIV整合酶抑制劑係選自薑黃色素、薑黃色素 之衍生物、菊苣酸、菊苣酸之衍生物、3,5 -二咖啡醯奎寧 酸、3,5 -二咖啡醯奎寧酸之衍生物、金黃三羧酸、金黃三 羧酸之衍生物、咖啡酸苯乙酯、咖啡酸苯乙酯之衍生物、 酪胺酸磷酸化抑制劑、酪胺酸磷酸化抑制劑之衍生物、櫟 皮酮、櫟皮酮之衍生物、S- 1 360、季特韋（zintevir)(AR-177)、L-870812、L-870810、帕潘立嗣（raltegravir) (Isentress ; MK-0518)、艾咪特拉韋（elvitegravir)(GS- 9137)、BMS-5 3 8 1 5 8、GSK3 6473 5 C、BMS-70 7 03 5、MK-2048 、 GSK-349572 (S-349572) 、 GSK-265744 (S-265744) 、GSK-247303 ( S · 2 4 7 3 0 3 )、S - 1 3 6 0 (G W 8 1 0 8 7 1 )、 1，5- DCQA、INH-001、INT-349、V-165、RIN-25、BFX-1001 、BFX-1 002、BFX- 1 003、RSC- 1 8 3 8、BCH-3 3 040 或 BA 011； (6) 該 gp4 1抑制劑係選自恩夫韋地（enfuvirtide) (Fuzeon)、西夫韋肽（sifuvirtide)、MPI-45 1 93 6、FB006M 、A-329029 或 TRI-1 144 ； (7) 該 CXCR4 抑制劑係選自 AMD-070、KRH-3 95 5 (CS-3 9 5 5 )、AMD-93 70、AMD-345 1、RPI-MN、MSX-1 22 或 POL-243 8 ; (8) 該進入抑制劑係選自SP01A、PA-161、SPC3、 TNX-3 5 5、DES6、SP-1 0、SP-03、CT-319 或 CT-3 2 6 ； -500- 200918507 (9) 該gpl20抑制劑係選自BMS-488043及其前藥、 BlockAide/CR、KPC-2 或 MNLP62 ; (10) 該 G6PD和 NADH氧化酶抑制劑係免疫素 (immunitin); (1 1)該CCR5抑制劑係選自艾波韋羅（aplaviroc)、尼 非韋羅（nifeviroc)、偉特韋羅（vicriviroc)(SCH-417690)、 馬洛韋羅（maraviroc)(Selzentry)、PRO-140、PRO-542、 INCB 1 5 0 5 0、INCB947 1、PF-23 2798、SCH-5 3 2706、GSK-70 6769、TAK- 652、TAK-220、ESN-1 96、RO- 1 75 2、ZM-6 8 8 5 23 、 AMD- 8 8 7 、 YM-370749 、 NIBR- 1 2 82 、 SCH- 3 5 063 4、ZM-6 8 8 523 或 CCR5mAb004 ； (1 2)該 C C R 8 抑制劑係 Z K - 7 5 6 3 2 6 ; (13) 該RNase H抑制劑係選自ODN-93或ODN-112 I (14) 該成熟抑制劑係選自貝韋立馬（bevirimat)(PA-45 7)、PA-040 ' MPC-905 5 (vicecon ； MPI-49839)、ACH-1 00703 或 ACH- 1 00706 ； (15) 該藥物動力增強劑係選自 BAS-100、SPI-452、 PF-4 1 94477、TMC-4 1 629 或紅黴素；且 (16) 該治療HIV之其他藥劑係選自 REP 9、SP-01A 、TNX-355、DES6、ODN-93、ODN-112、VGV-1、阿普林 津（Ampligen)、HRG214、單選殖抗體 Cytolin、VGX-410 、VGX- 82 0、KD-247、AMZ 0026、CYT 99007、A-221 HIV、HPH-1 1 6、DEBIO-02 5、BAY 5 0-4 79 8、MDX01 0 (單 -501 - 200918507 選殖抗體 ipilimumab)、PBS 119、BIT·225、UBT-8147、 ITI-3 67、AFX-400、BL- 1 05 0、GRN- 1 3 995 1、GRN- 1 40665 、AX-3 8679、RGB-34063 8、PPI-3 67 或 ALG 8 89。 3 0. —種新穎之化合物，其實質上係如說明書所描述 者。 3 1 · —種如申請專利範圍第1至2 0項中任一項所描 述之化合物，其實質上係如說明書所描述和例示者。 32. —種新穎之醫藥組成物或製備藥物之用途，其實 質上係如說明書所描述者。 3 3 .如申請專利範圍第1至2 0項中任一項之化合物 ，其係作爲治療藥物。 3 4 —種申請專利範圍第1至2 0項中任一項之化合 物於製造供抑制病患體內之Η IV反轉錄酶的藥物上之用途 〇 35 · —種申請專利範圍第1至2 0項中任一項之化合 物於製造供治療或預防病患感染HIV的藥物上之用途。 3 6 · —種申請專利範圍第1至2 0項中任一項之化合 物於製造供治療病患之AIDS或AIDS相關綜合症（ARC)的 藥物上之用途。 3 7.如申g靑專利範圍第3 4項之用途，其中該藥物進 —步包含至少一或多種額外之活性劑。 3 8.如申請專利範圍第3 5項之用途，其中該藥物進 一步包含至少一或多種額外之活性劑。 3 9 _如申s靑專利範圍第3 6項之用途，其中該藥物進 -502 - 200918507 一步包含至少一或多種額外之活性劑。 4 〇 .如申請專利範圍第3 7項之用途，其中 種額外之活性劑係選自HIV蛋白酶抑制劑、HIV 之非核苷抑制劑、HIV反轉錄酶之核苷抑制劑、 錄酶之核苷酸抑制劑、HIV整合酶抑制劑、gp4 1 CXCR4抑制劑、gpl20抑制劑、G6PD和NADH 制劑、CCR5抑制劑、CCR8抑制劑、進入抑制| Η抑制劑、成熟抑制劑、藥物動力增強劑、治療 他藥劑、或彼等之混合物。 4 1.如申請專利範圍第3 8項之用途，其中 種額外之活性劑係選自HIV蛋白酶抑制劑、HIV 之非核苷抑制劑、HIV反轉錄酶之核苷抑制劑、 錄酶之核苷酸抑制劑、HIV整合酶抑制劑、gp4 1 CXCR4 抑制劑、gP120 抑芾！J 劑、G6PD 和 NADH 制劑、CCR5抑制劑、CCR8抑制劑、進入抑制驾 Η抑制劑、成熟抑制劑、藥物動力增強劑、治療 他藥劑、或彼等之混合物。 42.如申請專利範圍第39項之用途，其中 種額外之活性劑係選自HIV蛋白酶抑制劑、HIV 之非核苷抑制劑、HIV反轉錄酶之核苷抑制劑、 錄酶之核苷酸抑制劑、HIV整合酶抑制劑、gp4 1 CXCR4 抑制劑、gpl20 抑制齊[|、G6PD 和 NADH 制劑、CCR5抑制劑、CCR8抑制劑、進入抑制葬 Η抑制劑、成熟抑制劑、藥物動力增強劑、治療 該一或多 反轉錄酶 HIV反轉 抑制劑、 氧化酶抑 )[| ' R N a s e HIV之其 該一或多 反轉錄酶 HIV反轉 抑制劑、 氧化酶抑 [!l ' R N a s e HIV之其 該一或多 反轉錄酶 HIV反轉 抑制劑、 氧化酶抑 F!l、RNase HIV之其 -503- 200918507 他藥劑、或彼等之混合物。 43.如申請專利範圍第40項之用途，其中 (1) 該HIV蛋白酶抑制劑係選自安潑那韋（amprenavir )(Agenerase)、阿扎那韋（atazanavir)(Reyataz)、福沙普利 那韋（fosamprenavir)(Lexiva)、節地那韋（indinavir) (Crixivan)、洛匹那韋（lopinavir)、利托那韋（ritonavir) (norvir)、奈非那韋（nelfinavir)(Viracept)、沙奎那韋 (saquinavir)(Invirase)、替拉那韋（tipranavir)(Aptivus)、 布卡那韋（brecanavir)、地瑞那韋（darunavir)(Prezista)、 TMC-126、TMC-114、美至那韋（mozenavir)(DMP-450)、 JE-2147 (AG 1 776)、L-75 6423、RO03 3 4 649 ' KNI-272、 DPC-68 1、DPC-6 84、DG17、GS-83 74、MK-8122 (PPL-100)、DG35、AG 18 59、SPI-256、TMC 52390、PL- 337、 SM-3223 77、SM-3 095 1 5、GRL-0203 1、CRS-074、CRS-075 、 KB-98 或 A-790742 ； (2) 該HIV反轉錄酶之非核苷抑制劑係選自卡波韋林 (capravirine)、艾咪韋林（emivirine)、戴拉凡地平 (delaviridine)(Rescriptor)、依法韋命（efavirenz)(Sustiva) 、奈韋拉平（nevirapine)(Viramune)、（ + )-綿毛胡桐內酯A (calanolide A)、綿毛胡桐內醋 B (calanolide B)、依曲韋 林（etravirine)(Intelence)、GW5634、DPC-083、DPC-961 、DPC-963、MIV-150、MIV-160、MIV-170、大匹韋林 (dapivirine)(TMC-120)、拉皮韋林（rilpivirine)(TMC-278 ) 、BILR 3 5 5 BS、VRX 840773、UK-45 3 0 6 1 ' RDEA 8 06、 -504- 200918507 RDEA 427 > RDEA 640 > IDX 899 ' ANX-201 (Thiovir) ' R-1 206、LOC-dd、IQP-0410 (SJ-3 3 66)、YM-2 1 5 3 8 9、YM-22 8 8 5 5、CMX-052 或 CMX-182 ; (3) 該HIV反轉錄酶之核苷抑制劑係選自疊氮胸苷 (Retrovir)、恩曲他濱（emtricitabine)(Emtriva)、2’，3’ -雙 去氧肌苷（Videx)、司他夫定（stavudine)(Zerit)、2’，3’-雙 去氧胞苷（Hivid)、拉脈優定（lamivudine)(Epivir)、阿波卡 偉（abacavir)(Ziagen)、安妥 B惡苷（amdoxovir)、艾非他濱 (elvucitabine)(ACH 126443)、阿洛夫定（alovudine)(MIV-310)、MIV-2 1 0、拉西卡偉（racivir)(消旋 FTC ; PSI-5004) 、D-d4FC、疊氮化磷（phosphazide)、福齊夫定替酯 (fozivudine tidoxil)、阿匹西他濱（apricitibine)(AVX754 ; SPD-754)、GS-7340、KP-1461、AVX75 6、OBP-601 ' 二 嚼茂院胸腺喃陡（dioxolane thymine)、TMC-254072、INK-20 、 PPI-801、PPI-802、MI V-4 1 0、4 ’-Ed4T、B-1 08 或磷 夫定酯（fosalvudine tidoxil)(HDP 99.0003); (4) 該HIV反轉錄酶核苷酸抑制劑係選自富馬酸替諾 福韋醋（t e η 〇 f o v i r d i s 〇 p r ο X i 1 f u m a r a t e) (V i r e a d )或阿德福韋 酯（adefovir dipivoxil); (5) 該HIV整合酶抑制劑係選自薑黃色素、薑黃色素 之衍生物、菊苣酸、菊苣酸之衍生物、3，5 -二咖啡醯奎寧 酸、3，5 -二咖啡醯奎寧酸之衍生物、金黃三羧酸、金黃三 羧酸之衍生物、咖啡酸苯乙酯、咖啡酸苯乙酯之衍生物、 酪胺酸磷酸化抑制劑、酪胺酸磷酸化抑制劑之衍生物、櫟 -505- 200918507 皮嗣、櫟皮酮之衍生物、S-1360、季特韋（2丨1^?丨1：)(八11-177)、L-870812、L-870810、帕潘立酮（raltegravir) (Isentress ; MK-0518)、艾咪特拉韋（elvitegravir)(GS- 9137)、BMS- 5 3 8 1 5 8、GSK3 6473 5 C、BMS-70703 5、MK-2048 、 GSK-349572 (S-349572) 、 GSK-265744 (S-265744) 、GSK-24 73 03 (S-247 3 03 )、S- 1 3 60 (GW8 1 087 1 )、1，5- DCQA、INH-001、IN T - 3 4 9、V - 1 6 5、RIN - 2 5、B F X -1 0 0 1 、BFX- 1 002、BFX- 1 003、RSC- 1 8 3 8、BCH-3 3 040 或 BA Oil； (6) 該 g p 4 1抑制劑係選自恩夫韋地（e n f u v i r t i d e ) (Fuzeon)、西夫韋肽（s i f u v i r t i d e)、MPI-45 1 93 6、FB006M 、A-329029 或 TRI- 1 1 44 ; (7) 該 CXCR4 抑制劑係選自 AMD-070、KRH-3955 (CS-3 95 5)、AMD-93 70、AMD-345 1、RPI-MN、MSX-122 或 POL-243 8 ； (8) 該進入抑制劑係選自SP01A、PA-161、SPC3、 TNX-3 5 5、DES6、S P -1 0、S P - 0 3、C T - 3 1 9 或 C T - 3 2 6 ; (9) 該gpl20抑制劑係選自BMS-488043及其前藥、 BlockAide/CR、KPC-2 或 MNLP62 ; (10) 該 G6PD和NADH氧化酶抑制劑係免疫素 (immunitin)； (11) 該CCR5抑制劑係選自艾波韋羅（apiaviroc)、尼 非韋羅（nifeviroc)、偉特韋羅（vicriviroc)(sCH-417690)、 馬洛韋羅（maraviroc)(Selzentry)、PRO-140、PRO-542、 -506- 200918507 INCB 1 5 0 5 0 ' INCB 947 1、PF-232798、SCH-5 3 2706、GSK-7067 69、TAK-652、TAK-220、ESN-1 96 ' RO- 1 752、ZM-68 8 5 23 、 AMD- 8 8 7 、 YM-3 70749 、 NIBR- 1 282 、 SCH- 3 506 34、ZM-6 8 8 523 或 CCR5mAb004 ； (12) 該 CCR8 抑制劑係 ZK-756326; (13) 該RNase H抑制劑係選自ODN-93或ODN-112 » (14) 該成熟抑制劑係選自貝韋立馬（bevirimat)(PA-45 7)、PA-040、MPC-905 5 (vicecon ； MPI-49 83 9)、ACH-100703 或 ACH- 100706 ; (15) 該藥物動力增強劑係選自 BAS-100、SPI-452、 PF-4194477、TMC-41629 或紅黴素；且 (16) 該治療HIV之其他藥劑係選自 REP 9、SP-01A 、TNX-3 5 5、DES6、ODN-93、ODN-112、VGV-1、阿普林 津（Ampligen)、HRG214、單選殖抗體 Cytolin、VGX-410 、VGX- 82 0、KD-247、AMZ 002 6、CYT 99 007、A-221 HIV、HPH-116 ' DEBIO-02 5 ' BAY 5 0 - 4 7 9 8、M D X 0 1 0 (單 選殖抗體 ipilimumab)、PB S 1 1 9、BIT-22 5、UBT-8 1 47、 ITI-3 67、AFX-400、BL- 1 050、GRN- 1 3 995 1、GRN-140665 ' AX-3 8 679 > RGB-3 40 63 8、PPI-3 67 或 ALG 8 8 9。 44.如申請專利範圍第4 1項之用途，其中 (1)該HIV蛋白酶抑制劑係選自安潑那韋（amprenavir )(Agenerase)、阿扎那韋（atazanavir)(Reyataz)、福沙普利 那韋（fosamprenavir)(Lexiva)、茚地那韋（i ndinavir) -507- 200918507 (Crixivan) 洛匹那韋 （lopinavir)、 利托那韋 (ritonavir)(norvir) > 奈非那韋（n e 1 f i n a v i r) (V i r ac e p t)、沙 奎那韋（saquinavir)(Invirase)、替拉那韋（tipranavir) (Aptivus)、布卡那韋（brecanavir)、地瑞那韋（darunavir) (Prezista)、TMC-126、TMC-114、美至那韋（mozenavir) (DMP-4 5 0) ' JE-2147 (AG 1 776)' L-75 642 3、RO03 3 4649、 KNI-272、DPC-68 1、DPC-6 8 4 ' DG1 7、GS-83 74、MK-8122 (PPL-100)、DG35、AG 1 8 5 9、SPI-25 6、TMC 5 23 90 、PL-3 3 7、SM-322377、SM-3 095 1 5、GRL-0203 1、CRS-074 ' CRS-075、K B - 9 8 或 A - 7 9 0 7 4 2 ; (2) 該HIV反轉錄酶之非核苷抑制劑係選自卡波韋林 (capravirine)、艾咪韋林（emivirine)、戴拉凡地平 (delaviridine)(Rescriptor)、依法韋侖（efavirenz)(Sustiva) '奈韋拉平（nevirapine)(Viramune)、（ + )-綿毛胡桐內醋 A (calanolide A)、綿毛胡桐內酯 B (calanolide B)、依曲韋 林（etravirine)(Intelence)、GW5 634、DPC-083、DPC-961 、DPC-963、MIV-150、MIV-160、MIV-170、大匹韋林 (dapivirine)(TMC-120)、拉皮韋林（rilpivirine)(TMC-278) 、BILR 3 5 5 BS、VRX 840773 ' UK-45 3 06 1 ' RDEA 806、 RDEA 427、RDEA 640、IDX 8 99、ANX-201(Thiovir)、R-1 206、LOC-dd、IQP-0410 (SJ-3 3 66)、YM- 2 1 5 3 8 9、YM-22 8 8 5 5、CMX-0 5 2 或 CMX-1 82 ; (3) 該HIV反轉錄酶之核苷抑制劑係選自疊氮胸苷 (Retrovir)、恩曲他濱（emtricitabine)(Emtriva)、2，，3，-雙 -508- 200918507 去氧肌苷（Videx)、司他夫定（stavudine)(Zerit)、2’，3’ -雙 去氧胞苷（Hivid)、拉脈優定（lamivudine)(Epivir)、阿波卡 偉（abacavir)(Ziagen)、安妥嚼苷（amdoxovir)、艾非他濱 (elvucitabine)(ACH 126443)、阿洛夫定（alovudine)(MIV-310)、MIV-210、拉西卡偉（racivir)(消旋 FTC; PSI-5004) 、D-d4FC、疊氮化憐（phosphazide)、福齊夫定替醒 (fozivudine tidoxil)、阿匹西他濱（apricitibine)(AVX754 ; SPD-754)、GS-73 40、KP-1461、AVX7 5 6、OBP-601、二 囉茂院胸腺喷 D定（dioxolane thymine)、TMC-254072、INK-20 、 PPI-801、PPI- 8 02、ΜIV · 4 1 0、4 ’ - E d4 T、B -1 0 8 或磷 夫定酯（fosalvudine tidoxil)(HDP 99.0003); (4) 該HIV反轉錄酶核苷酸抑制劑係選自富馬酸替諾 福韋醋（tenofovir disoproxil fumarate)(Viread)或阿德福韋 醋（adefovir dipivoxil)； (5) 該HIV整合酶抑制劑係選自薑黃色素、薑黃色素 之衍生物、菊苣酸、菊苣酸之衍生物、3，5 -二咖啡醯奎寧 酸、3，5 -二咖啡醯奎寧酸之衍生物、金黃三羧酸、金黃三 羧酸之衍生物、咖啡酸苯乙酯 '咖啡酸苯乙酯之衍生物、 酪胺酸磷酸化抑制劑、酪胺酸磷酸化抑制劑之衍生物、櫟 皮酮、櫟皮酮之衍生物、S- 1 3 60 '季特韋（zintevir)(AR-177)、L-870812、L-870810、帕潘立酬（raltegravir) (Isentress，MK-0518)、艾味特拉韋（61乂^6§犷&乂11_)(03-9137) ' BMS-5 3 8 1 5 8 > GSK3 6473 5 C ' BMS-70703 5 ' MK-2048 > GSK-349572 (S-349572) > GSK-265744 (S-265744) -509- 200918507 、GSK-2473 03 (S-2473 03)、S- 1 3 60 (GW8 1 0 8 7 1 )、1，5- DCQA、INH-001、INT-3 49、V-165、RIN-25、BFX-1001 、BFX- 1 002、BFX- 1 003、RSC- 1 8 3 8、BCH-3 3 040 或 BA Oil； (6) 該 gp41抑制劑係選自恩夫韋地（enfuvirtide) (Fuzeon)、西夫韋肽（sifuvirtide)、MPI-45 1 93 6、FB006M 、A-329029 或 TRI-1 144 ; (7) 該 CXCR4 抑制劑係選自 AMD-070、KRH-3 955 (CS-395 5)、AMD-9370、AMD-3 45 1、RPI-MN ' MSX-122 或 POL-2438 ; (8) 該進入抑制劑係選自SP01A、PA-161、SPC3、 TNX-3 5 5 ' DES6、SP-10、SP-03、CT-319 或 CT-3 26 ； (9) 該gpl20抑制劑係選自BMS-488043及其前藥、 BlockAide/CR、KPC-2 或 MNLP62 ; (10) 該 G6PD和 NADH氧化酶抑制劑係免疫素 (immunitin); (1 1)該CCR5抑制劑係選自艾波韋羅（aplaviroc)、尼 非韋羅（nifeviroc)、偉特韋羅（vicriviroc)(SCH-417690)、 馬洛韋羅（maraviroc)(Selzentry)、PRO-140、PRO-542、 INCB 1 5 0 5 0、INCB947 1、PF-232798、SCH-5 32706、GSK-70 67 69、TAK- 6 52、TAK-220 ' ESN-1 96 ' RO- 1 75 2、ZM-68 8 523 、 AMD-8 8 7 、 YM-3 70749 、 NIBR- 1 282 、 SCH- 3 5 0634、ZM-6 8 8 523 或 CCR5mAb004 ； (12)該 CCR8 抑制劑係 ZK-75 63 26; -510- 200918507 (13) 該RNase Η抑制劑係選自〇DN-93或ODN-112 > (14) 該成熟抑制劑係選自貝韋立馬（bevirimatKPA-457) 、 PA-040 、 MPC-9055 (vicec〇n ; MPI-49839) 、 ACH-100703 或 ACH-100706 ; (15) 該藥物動力增強劑係選自BAS-100、SPI-452、 PF_4 1 94477、TMC-4 1 629 或紅黴素；且 (16) 該治療HIV之其他藥劑係選自 REP 9、SP-01A 、TNX-3 5 5、DES6、ODN-93、ODN-1 12、VGV-1、阿普林 津（Ampligen)、HRG214、單選殖抗體 Cytolin、VGX-410 ' VGX- 820、KD-247、AMZ 0026、CYT 99007、A-221 HIV、HPH-1 1 6、DEBIO-02 5、BAY 50-479 8 ' MDXO1 0 (單 選殖抗體 ipilimumab)、PBS 119、BIT-225、UBT-8147、 ITI-3 67、AFX-400、BL- 1 050、GRN- 1 3 99 5 1、GRN- 1 40665 、AX-3 8679、RGB-34063 8、PPI-3 67 或 ALG 8 89。 45.如申請專利範圍第42項之用途，其中 (1)該HIV蛋白酶抑制劑係選自安潑那韋（amprenavir )(Agenerase)、阿扎那韋（atazanavir)(Reyataz)、福沙普利 那韋(fosamprenavir)(Lexiva)、節地那韋(indinavir) (Crixivan)、洛匹那韋（lopinavir)、利托那韋（ritonavir) (norvir)、奈非那韋（nelfinavir)(Viracept)、沙奎那韋 (saquinavir)(Invirase)、替拉那韋(tipranavir)(Aptivus)、 布卡那韋（brecanavir)、地瑞那韋（darunavir)(Prezista)、 TMC-126、TMC-114、美至那韋（m 0 z e n a v i r) (D Μ P - 4 5 0)、 -511 - 200918507 JE-2147 (AG 1 776)、L-756423、RO0334649、ΚΝΙ-272、 DPC-681、DPC-684、DG17、GS-83 74、MK-8122 (PPL-100)、DG35 ' AG 1 8 5 9、SPI-25 6、TMC 523 90 ' PL-3 3 7 > SM-3 223 77、SM-3 09 5 1 5、GRL-0203 1、CRS-074、CRS-075、KB-98 或 A-790742 ; (2)該ΗIV反轉錄酶之非核苷抑制劑係選自卡波韋林 (capravirine)、艾咪韋林（emivirine)、戴拉凡地平 (delaviridine)(Rescriptor)、依法韋侖（efavirenz)(Sustiva) 、奈韋拉平（1^乂丨^卩丨1^)(乂丨^11111116)、（ + )-綿毛胡桐內酯入 (calanolide A)、綿毛胡桐內酯 B (calanolide B)、依曲韋 林（etravirine)(Intelence) ' GW5634、DPC-083、DPC-961 、DPC-963、MIV-150、MIV-160、MIV-170、大匹韋林 (dapivirine)(TMC-120)、拉皮韋林（rilpivirine)(TMC-27 8 ) 、BILR 3 5 5 BS、VRX 840773、UK-45 3 0 6 1 ' RDEA 806、 RDEA 427、RDEA 640、IDX 8 99、ANX-201(Thiovir)、R-1 206、LOC-dd、IQP-0410 (SJ-3 3 66)、YM-2 1 5 3 8 9、YM-22 8 8 5 5、CMX-0 52 或 CMX-1 82 ; (3 )該HI V反轉錄酶之核苷抑制劑係選自疊氮胸苷 (Retrovir)、恩曲他濱（emtricitabine)(Emtriva)、2’，3’ -雙 去氧肌苷（Videx)、司他夫定（stavudine)(Zerit)、2’，3’ -雙 去氧胞苷（Hivid)、拉脈優定（lamivudine)(Epivir)、阿波卡 偉（abacavir)(Ziagen)、安妥嚼苷（amdoxovir)、艾非他濱 (elvucitabine)(ACH 126443)、阿洛夫定（&1〇¥11(11116)(]^1\^-3 1 0)、MIV-2 1 0、拉西卡偉（racivir)(消旋 F T C ; P S I - 5 0 0 4 ) -512- 200918507 、D-d4FC、疊氮化憐（phosphazide)、福齊夫定替酯 (fozivudine tidoxil)、阿匹西他濱（apricitibine)(AVX754; SPD-754)、GS-7340、KP-1461、AVX75 6、OBP-601、二 嚷茂院胸腺嚼淀（dioxolane thymine)、TMC-254072、INK. 20、PPI-801、PPI-802 ' MIV-410 ' 4’-Ed4T、B-108 或磷 夫定醋（fosalvudine tidoxil)(HDP 99.0003 ); (4) 該ΗIV反轉錄酶核苷酸抑制劑係選自富馬酸替諾 福韋醋（tenofovir disoproxil fumarate)(Viread)或阿德福韋 酯（adefovir dipivoxil); (5) 該HIV整合酶抑制劑係選自薑黃色素、薑黃色素 之衍生物、菊苣酸、菊苣酸之衍生物、3,5 -二咖啡醯奎寧 酸、3,5_二咖啡醯奎寧酸之衍生物、金黃三羧酸、金黃三 羧酸之衍生物、咖啡酸苯乙酯、咖啡酸苯乙酯之衍生物、 酪胺酸磷酸化抑制劑、酪胺酸磷酸化抑制劑之衍生物、櫟 皮酮、櫟皮酮之衍生物、S- 1 3 60、季特韋（2丨1^6^〇(八11-177)、L-870812、L-870810 ' 帕潘立嗣（raltegravir) (Isentress ; MK-0518)、艾咪特拉韋（elvitegravir)(GS-9137)、BMS-5 3 8 1 5 8、GSK3 6473 5 C、BMS-70703 5、MK-2048 、 GSK-349572 (S-349572) ' GSK-265744 (S-265744) 、GSK-2473 03 (S-2473 03 )、S- 1 3 60 (GW8 1 0 87 1 )、 1,5- DCQA、INH-001、INT-3 49、V-165、RIN-25、BFX-1001 、BFX- 1 002、BFX- 1 003、RSC- 1 8 3 8、BCH-3 3 04 0 或 B A 0 11； (6) 該 gp4 1 抑制劑係選自恩夫韋地 -513- 200918507 (enfuvirtide)(Fuzeon)、西夫韋肽（sifuvirtide)、MPI-45 1 93 6 ' FB006M、A-329029 或 TRI-1144 ; (7) 該 CXCR4 抑制劑係選自 AMD-070、KRH-395 5 (CS-3 95 5)、AMD-93 70、AMD-345 1、RPI-MN ' MSX-122 或 POL-243 8 ; (8) 該進入抑制劑係選自 SP01A、PA-161、SPC3、 TNX-35 5、DES6、SP-10、SP-03、CT-319 或 CT-326 ； (9) 該gpl20抑制劑係選自BMS-48 8043及其前藥、 BlockAide/CR、KPC-2 或 MNLP62 ; (10) 該 G6PD和 NADH氧化酶抑制劑係免疫素 (immunitin)； (11) 該CCR5抑制劑係選自艾波韋羅（aplaviroc)、尼 非韋羅（nifeviroc)、偉特韋羅（vicriviroc)(SCH-4 1 7690)、 馬洛韋羅（maraviroc)(Selzentry) ' PRO-140、PRO-542、 INCB 1 5 05 0、INCB947 1、PF-232798、SCH-532706、GSK-706769、TAK-652、TAK-220、ESN-196、RO- 1 752、ZM-68 8 523 、 AMD-8 8 7 、 YM-370749 ' NIBR- 1 282 ' SCH- 350634、ZM-6 8 8523 或 CCR5mAb004 ; (12) 該 CCR8 抑制劑係 ZK-75 6326 ; (13) 該RNase H抑制劑係選自ODN-93或ODN-112 « (14) 該成熟抑制劑係選自貝韋立馬（bevirimat)(PA-457)、PA-040 ' MPC-90 5 5 (vicecon ； MPI-49 8 3 9)、ACH-1 00703 或 ACH- 1 007 06 ； -514- 200918507 (15) 該藥物動力增強劑係選自bAS-100' SPI-452、 PF_4 1 94477、TMC-4 1 629 或紅黴素；且 (16) 該治療HIV之其他藥劑係選自rep 9、SP-01A 、TNX-3 5 5、DES6、0DN-93、0DN-1 1 2、VGV-1、阿普林 津（Ampligen)、HRG214、單選殖抗體 Cytolin、VGX-410 、VGX-820、KD-247、AMZ 002 6、CYT 990 07、A-221 HIV、HPH-1 1 6、DEBIO-025、BAY 5 0 - 4 7 9 8、M D X 0 1 0 (單 選殖抗體 ipilimumab)、PBS 1 1 9、BIT-225、UBT-8 1 47、 ITI- 3 67、AFX-400、BL- 1 05 0、GRN- 1 3 99 5 1、GRN- 1 40665 、AX-38679、RGB-340638、PPI-367 或 ALG 889。 \ 515- 200918507 七 無 明 說 單 簡 號 符 表 為代 圖件 表元 代之 定圖 指表 :案代 圖本本 表' ' 代 \ \ 定一二 ·=曰'^ 無 八、本案若有化學式時，請揭示最能顯示發明特徵的化學 式： Y
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CA2692460A1 (en) 2009-01-08
ZA201000023B (en) 2011-04-28
WO2009005674A2 (en) 2009-01-08
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US20110076276A1 (en) 2011-03-31
EA200971115A1 (ru) 2010-04-30
EP2167476B1 (en) 2015-02-25
CN101784532A (zh) 2010-07-21
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WO2009005674A3 (en) 2009-09-24
AR067181A1 (es) 2009-09-30
KR101551238B1 (ko) 2015-09-09
CN101784532B (zh) 2014-10-22
EP2167476A2 (en) 2010-03-31
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US8334295B2 (en) 2012-12-18
AU2008271114A1 (en) 2009-01-08

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