TW200843739A - Novel pyrrolinone derivative and composition containing the same - Google Patents

Novel pyrrolinone derivative and composition containing the same Download PDF

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TW200843739A
TW200843739A TW097111332A TW97111332A TW200843739A TW 200843739 A TW200843739 A TW 200843739A TW 097111332 A TW097111332 A TW 097111332A TW 97111332 A TW97111332 A TW 97111332A TW 200843739 A TW200843739 A TW 200843739A
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Hiroyuki Kai
Shunji Shinohara
Takayuki Kameyama
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Shionogi & Co
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    • C07D207/382-Pyrrolones
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Description

200843739 九、發明說明: 【發明所屬之技彳軒領域】 技術領域 本發明關於一種在治療Ρ2χ受體、特別是ρ2χ3&^ 5 P2X2/3受體相關疾病或狀態上有用之化合物以及含有該化 合物之藥學組成物。 【先前技術3 背景技術 已知ATP(二填酸腺苷)係細胞内之能量源及填酸化基 10質,另一方面,亦作為細胞外之資訊傳達物質來發揮作用。 ATP除了因細胞損傷、炎症、侵害刺激、血中氧濃度降低等 各種刺激而被放出至細胞外之外,亦會與其他神經傳導物 貝起攸初級感覺神經(Primary sensory nerve cell)末端放 出到細胞外。已放出至細胞外之ATp將會經由ATp受體而進 15行各種細胞外之資訊傳達(非專利文獻6、非專利文獻7)。 ATP受體可大致區分為離子通道型之ρ2χ家族與G蛋白 質共軛型之P2Y家族。P2X受體家族已有7種亞型(subtype) 被報告,與同貝二聚體或其他Ρ2χ亞型形成雜三聚體,而作 為非選擇性陽離子通道發揮其功能(非專利文獻8)。 20 已知ATP會引起疼痛,使用剔除(knockout)或弱化 (knockdown) P2X3技術之研究更顯示出ρ2χ3受體與慢性疼 痛之傳達相關。P2X3受體專一性地表現在末梢感覺神經, 與同質複合物或P2X2形成雜複合物非專利文獻υ。 其後,亦有一種用作Ρ2Χ3及Ρ2Χ2,3受體之專一性拮抗劑 5 200843739 且稱為Α-3Π491之化合物被報導。A_317491係以下述通式 表不之三取代-N-[(1SH,2,3,4四氫小萘基]苯甲醯胺衍生 物(專利文獻1) ’已有報導指出其對ρ2χ3及ρ2χ2/3受體顯示 出括抗活性’在大鼠之神經障礙性疼痛樣本及炎症性疼痛 5樣本中顯示出鎮痛作用(非專利文獻9)。 【化1】
此一事實顯示出,痛覺係透過Ρ2Χ3或Ρ2Χ2/3受體來傳 達’且Ρ2Χ3或Ρ2Χ2/3受體拮抗劑可用作為鎮痛藥。此外,專 1〇利文獻2〜7亦記載顯示有Ρ2Χ3或Ρ2Χ2/3受體拮抗作用之化 合物。 此外’近年有報告指出,Ρ2Χ3基因剔除小鼠顯示出顯 著之膀胱反射降低(非專利文獻2),暗示了 ρ2χ3拮抗藥在因 膀胱過度活動而引起之疾病治療上亦有用。 非專利文獻3及4記載到,與本發明化合物類似之化合 物頒不出鎮痛活性’但該等均與本發明化合物結構不同。 【專利文獻1】國際申請案WO02/094767號公開公報 【專利文獻2】國際申請案w〇2005/095359號公開公報 【專利文獻3】美國申請案US20070037974公開公報 6 200843739 【專利文獻4】美國申請案US20070049758號公開公報 【專利文獻5】美國申請案US20070049610號公開公報 【專利文獻6】美國申請案US20070049609號公開公報 【專利文獻7】美國申請案US20070049534號公開公報 5 【非專利文獻 1】Neuroscientist 11 (2005) ρρ·345-356 【非專利文獻2】J· Physiol. 567.2 (2005) ρρ·621-639 【非專利文獻 3 】Pharmaceutical Chemistry Journal Vol.39, Νο·9,(2005),pp484-487 【非專利文獻 4 】Pharmaceutical Chemistry Journal 10 Vol.31, No.5, (1997), pp251-254 【非專利文獻5】Expert Opin· Ther· Patens (2006) 16(8) 113-1127. 【非專利文獻6】J· Physiology (2003),554(2),301-308 【非專利文獻7】J· Physiology (2003),553(3), 683-694 15 【非專利文獻8】Pflungers Arch Eur J physiol (2006), 452, 513-537 【非專利文獻9】PNAS (2002),99(26),17179-17184 I:發明内容]J 發明之揭示 20 發明欲解決之課題 本發明提供一種新穎之P2X3及/或P2X2/3受體拮抗劑。 解決課題之手段 本案發明人為了達成上述目的而反覆精心研討,結果 發現與P2X3及/或P2X2/3受體專一性結合而顯示出拮抗作用 7 200843739 之新穎化合物,而完成了下述記載之發明。 (1)一種P2X3及/或P2X2/3受體拮抗劑,含有如下通式(I) 所示之化合物、其製藥上可接受之鹽或是該等之溶劑合物; 通式(I): 【化2】
式中,Z1為可任擇受到保護之羥基、可任擇受到保護 之羥胺基或可任擇具有取代基之胺基,Z2為=0或=N-E(E為 氫、羥基、可任擇具有取代基之低級烷基、可任擇具有取 10 代基之低級烷氧基或是可任擇具有取代基之胺基);或是 【化3】
R4及R5各自獨立為氫或低級烷基,R6為氫、可任擇具 有取代基之低級烷基或醯基,r為0〜2之整數;
Ra&Rb各自獨立為氫或低級烷基; q為0~4之整數; A為環烷基、環烯基、芳基或雜環基; 8 200843739 r1各自獨立為i素、羥基、可任擇具有取代基之低級 烷基、可任擇具有取代基之低級烯基、可任擇具有取代基 之低級炔基、可任擇具有取代基之低級烷氧基、可任擇具 有取代基之低級烷硫基、可任擇具有取代基之醯基、羧基、 5 可任擇具有取代基之低級烷氧羰基、可任擇具有取代基之 胺甲醯基、可任擇具有取代基之低級烷基胺甲醯基、可任 擇具有取代基之胺基、可任擇具有取代基之胺磺醯基、氰 基、硝基、可任擇具有取代基之環烷基、可任擇具有取代 基之環烯基、可任擇具有取代基之芳基或可任擇具有取代 10 基之雜環基; N為0〜3之整數(但, 【化4】
時,Α-(ί^)η亦可為氫); R2為可任擇具有取代基之烧基、可任擇具有取代基之 15低級烧氧基、可任擇具有取代基之低級烧基胺甲醯基、可 任擇具有取代基之環烷基、可任擇具有取代基之環烯基、 可任擇具有取代基之芳基或可任擇具有取代基之雜環基; R3為氫、可任擇具有取代基之烷基、可任擇具有取代 基之環烧基、可任擇具有取代基之環烯基、可任擇具有取 20代基之芳基或可任擇具有取代基之雜環基。 (2)如前述⑴之P2X3及/或P2X2,3受體拮抗劑,其中/為 羥基,Z2為=〇。 9 0 ° 200843739 ⑶如前述⑴之p2X3及/或P2X2/3受體拮抗劑,其中r為 (4)如前述⑴〜(3)中任一項之P2X3及/或P2X2/3受體拮抗 劑,其中環A為笨基、吼啶基或噻唑基。 5 (5)如前述(1)〜(4)中任一項之P2X3及/或P2X2/3受體拮抗 劑’其中R1為可任擇具有取代基之低級烷氧羰基或可任擇 具有取代基之雜環基。 (6) 如前述(1)〜(5)中任一項之P2X3及/或P2X2/3受體拮抗 劑’其中R2為可任擇具有取代基之低級烷基、可任擇具有 10取代基之笨基或可任擇具有取代基之吼啶基。 (7) 如前述(1)〜(6)中任一項之P2X3及/或P2X2/3受體拮抗 劑’其中R3為碳原子數3〜1〇之烷基、環烷基或可任擇具有 取代基之笨基。 (8) 如前述⑴〜(7)中任一項之P2X3及/或P2X2/3受體拮抗 15 劑,其中q為〇。 (9) 如前述⑴〜(7)中任一項之P2X3及/或P2X2/3受體拮抗 劑,其中q為1。 (10) —種如下通式(1,)所示之化合物、其製藥上可接受 之鹽或是該等之溶劑合物,其中通式·· 2〇【化5】 200843739
(R1D)p 式中,z1為可任擇受到保護之羥基、可受任擇保護之 爹工月女基或可任擇具有取代基之胺基,為=〇或=]\^士(e為 氫、羥基、可任擇具有取代基之低級烷基、可任擇具有取 5代基之低級烷氧基或是可任擇具有取代基之胺基;或 【化6】
1 , A ⑶ 5 R及R各自獨立為氫或低級烧基,r6為氫、可任擇具 有取代基之低級烷基或醯基,r為0〜2之整數; 10 環A及環B各自獨立為環烷基、環烯基、芳基或雜環基;
Rla&Rlb各自獨立為_素、羥基、可任擇具有取代基之 低級烷基、可任擇具有取代基之低級烯基、可任擇具有取 代基之低級炔基、可任擇具有取代基之低級烷氧基、可任 擇具有取代基之低級烷硫基、可任擇具有取代基之醯基、 15羧基、可任擇具有取代基之低級烷氧羰基、可任擇具有取 代基之胺甲醯基、可任擇具有取代基之低級烷基胺甲醯 11 200843739 基、可任擇具有取代基之胺基、可任擇具有取代基之胺磺 醯基、氰基或硝基; m及p各自獨立為〇〜2之整數; R2為可任擇具有取代基之烷基、可任擇具有取代基之 5低級烧氧基、可任擇具有取代基之低級烧基胺甲醯基、可 任擇具有取代基之環烷基、可任擇具有取代基之環烯基、 可任擇具有取代基之芳基或可任擇具有取代基之雜環基; R為氫、可任擇具有取代基之低級烧基、可任擇具有 取代基之環烷基、可任擇具有取代基之環烯基、可任擇具 10有取代基之芳基或可任擇具有取代基之雜環基; 但是,環A為吡唑酮且環b為苯基之化合物除外。 (11) 如前述(10)之化合物、其製藥上可接受之鹽或是該 等之溶劑合物,其中Z1為可任擇受到保護之羥基,22為=〇, R2為可任擇具有取代基之烷基、可任擇具有取代基之低級 15烷氧基、可任擇具有取代基之環烷基、可任擇具有取代基 之環烯基、可任擇具有取代基之芳基或可任擇具有取代基 之雜壤基。 (12) 如前述(10)之化合物、其製藥上可接受之鹽或是該 等之溶劑合物,其中r為〇, R2為可任擇具有取代基之烧基, 2〇可任擇具有取代基之低級烧氧基、可任擇具有取代基之環 烷基、可任擇具有取代基之環烯基、可任擇具有取代基之 芳基或可任擇具有取代基之雜環基。 (13) 如前述(1〇)〜(12)中任一項之化合物、其製藥上可接 X之鹽或是該等之溶劑合物,其中環A為苯基、呢啶基或噻 12 200843739 σ坐基。 (14)一種如下述通式(ι,,)所示之化合物、其製藥上可接 受之鹽或是該等之溶劑合物; 【化7】 % Ζ1 R3 乂 Ν〆 、〇 (Γ) y(R1a)m /r1c _1 J R1d 式中,Z1為可任擇受到保護之羥基、可任擇受到保護 之羥胺基或可任擇具有取代基之胺基,Z2為=0或=N-E(E為 氫、羥基、可任擇具有取代基之低級烷基、可任擇具有取 代基之低級烷氧基或可任擇具有取代基之胺基;或者 10 【化8】 ^ ^ 必 i^HCR^r \=/形成 R4及R5各自獨立形成氫或低級院基,r6為氫、可任擇 具有取代基之低級烷基或醯基,r為〇〜2之整數; 環A為環烷基、環烯基、芳基或雜環基; 15 rU各自獨立為A素、羥基、可任擇具有取代基之低級 烧基、可任擇具有取代基之低級烧氧基、可任擇具有取代 基之低級烷硫基、可任擇具有取代基之醯基、羧基、可任 13 200843739 擇具有取代基之低級烧氧幾基、可任擇具有取代基之胺甲 醯基、可任擇具有取代基之低級烷基胺甲醯基、可任擇具 有取代基之胺基、可任擇具有取代基之胺磺醯基、氰基或 硝基; 5 m為0〜2之整數;
Rle及Rld各自獨立為氫或可任擇具有取代基之低級烷 基; R2為可任擇具有取代基之烷基、可任擇具有取代基之 低級烷氧基、可任擇具有取代基之低級烷基胺甲醯基、可 ίο任擇具有取代基之環烷基、可任擇具有取代基之環烯基、 可任擇具有取代基之芳基或可任擇具有取代基之雜環基; R3為氫、可任擇具有取代基之低級烷基、可任擇具有 取代基之環烷基、可任擇具有取代基之環烯基、可任擇具 有取代基之芳基、可任擇具有取代基之雜環基。 15 (15)如前述(14)之化合物、其製藥上可接受之鹽或是該 等之溶劑合物,其中Z1為可任擇受到保護之經基,22為=〇, R2為可任擇具有取代基之烷基、可任擇具有取代基之低級 烷氧基、可任擇具有取代基之環烷基、可任擇具有取代基 之環烯基、可任擇具有取代基之芳基或可任擇具有取代基 20 之雜環基。 (16)如前述(14)之化合物、其製藥上可接受之鹽或是該 等之溶劑合物,其中r為〇, R2為可任擇具有取代基之烷基、 可任擇具有取代基之低級烧氧基、可任擇具有取代基之環 烷基、可任擇具有取代基之環烯基、可任擇具有取代基之 200843739 芳基或可任擇具有取代基之雜環基。 (17)如前述(14)〜(16)中任一項之化合物、其製藥上可接 受之鹽或是該等之溶劑合物,其中環A為苯基、定基或唉 U坐基。 5 (18)—種藥學組成物,含有如前述(1〇)〜(17)中任一項之 化合物、其製藥上可接受之鹽或是該等之溶劑合物。 (19) 一種P2X3及/或P2XW受體拮抗劑,含有如前述 (10)〜(17)中任一項之化合物、其製藥上可接受之鹽或是該 等之溶劑合物。 10 (2〇)—種如前述(10)〜(17)中任一項之化合物、其製藥上 可接受之鹽或是該等之溶劑合物的用途,係將如前述 (10)〜(17)中任一項之化合物、其製藥上可接受之鹽或是該 等之溶劑合物用於治療及/或預防P2X3及/或P2X2/3受體相 關疾病者。 15 (2D 一種P2X3及/或P2XW受體相關疾病之治療及/或預 防方法,係將如前述(10)〜(17)中任一項之化合物、其製藥 上可接受之鹽或是該等之溶劑合物進行投藥者。 此外,更以其他態樣來達成以下記載之發明。 (Γ)一種P2X3或P2X2,3受體拮抗劑,包含如下通式⑴所 2〇 示化合物、其製藥上可接受之鹽或該等之溶劑合物; 通式(I): 【化9】 15 200843739
(CRaRb)q ,,丄' '、A^~(R1)n 式中’ z1為可任擇受到保護之羥基、可任擇受到保護 之爹里胺基或可任擇具有取代基之胺基,z2為〇或NQH;或是 【化10】
R及R各自獨立為氫或低級烧基,R5為氫、低級烧基 或醯基,r為0〜2之整數; A為環烷基、環烯基、芳基或雜環基; R及R各自獨立為氫或低級烧基; q為0或1 ; R1各自獨立為_素、羥基、可任擇具有取代基之低級 烧基、可任擇具有取代基之低級烷氧基、可任擇具有取代 基之低級烧硫基、可任擇具有取代基之醯基、可任擇具有 取代基之羧基、可任擇具有取代基之低級烧氧羰基、可任 15擇具有取代基之胺曱醯基、可任擇具有取代基之低級烷基 胺甲醯基、可任擇具有取代基之胺基、可任擇具有取代基 之胺磺醯基、氰基、硝基、可任擇具有取代基之環烷基、 16 200843739 可任擇具有取代基之環烯基、可任擇具有取代基之芳基或 可任擇具有取代基之雜環基; N為〇〜3之整數;但 【化11】
R2為可任擇具有取代基之低級烷基、可任擇具有取代 基之環烷基、可任擇具有取代基之環烯基、可任擇具有取 代基之芳基或可任擇具有取代基之雜環基; R3為氫、可任擇具有取代基之烷基、可任擇具有取代 10 基之環烷基、可任擇具有取代基之環烯基、可任擇具有取 代基之芳基或可任擇具有取代基之雜環基; (2’)如前述(1,)之Ρ2χ3或ρ2χ2/3受體拮抗劑,其中/為 羥基,Z2為〇。 (3’)如前述(1,)或(2,)之Ρ2χ3或ρ2χ2/3受體拮抗劑,其中 15 A為苯基。 (4’)如前述(Γ)〜(3,)中任一項之P2X3或P2X2/3受體拮抗 劑’其中R為可任擇具有取代基之低級烷氧羰基或可任擇 具有取代基之雜環基。 (5 )如前述(1 ’)〜(4,)中任一項之P2X3或P2X2/3受體拮抗 20劑’其中r2為可任擇具有取代基之苯基或可任擇具有取代 基之σ定基。 (6 )如$述(1,)〜(5,)中任一項之Ρ2Χ3或Ρ2Χ2/3受體拮抗 17 200843739 劑’其中R3為可任擇具有取代基之碳原子數3〜10的烷基、 環烧基或可任擇具有取代基之苯基。 (7’)如前述(1,)〜(6,)中任一項之P2X3或P2X2/3受體拮抗 劑,其中q為0。 (8’)一種如下述通式(1,)所示之化合物、其製藥上可接 受之鹽或該等之溶劑合物;通式(I,)·· 【化12】
式中’ Z1為可任擇受到保護之經基、可任擇受到保護 10之羥胺基或可任擇受到保護之胺基,Z2為0或NOH ;或是 【化13】
R4及R5各自獨立為氫或低級烷基,R6為氫、低級燒基 或醯基,r為0〜2之整數; 15 環A及環B各自獨立為環烷基、環烯基、芳基或雜環基;
Rla及Rlb各自獨立為鹵素、輕基、可任擇具有取代基之 18 200843739 低級烧基、可任擇具有取代基之低級烧氧基、可任擇具有 取代基之低級烷硫基、可任擇具有取代基之醯基、羧基、 可任擇具有取代基之低級烷氧羰基、可任擇具有取代基之 胺甲酸基、可任擇具有取代基之低級烷基胺甲醯基、可任 5擇具有取代基之胺基、可任擇具有取代基之胺磺醯基、氰 基或硝基; m及p各自獨立為〇〜2之整數; R為可任擇具有取代基之低級烧基、可任擇具有取代 基之環烷基、可任擇具有取代基之環烯基、可任擇具有取 1〇代基之芳基可任擇具有取代基之雜環基; R為可任擇具有取代基之低級烧基、可任擇具有取代 基之環烷基、可任擇具有取代基之環烯基、可任擇具有取 代基之芳基或可任擇具有取代基之雜環基; 但,環A為吡唑酮且環B為苯基之化合物除外。 15 (9 )如前述(8’)之化合物、其製藥上可接受之鹽或是該 專之溶劑合物,其中Z1為可任擇受到保護之經基,z2為〇, R為可任擇具有取代基之環烷基、可任擇具有取代基之環 烯基、可任擇具有取代基之芳基或可任擇具有取代基之雜 環基。 20 (10’)一種如下述通式(I,,)所示之化合物、其製藥上可 接受之鹽或是該等之溶劑合物; 式(I”): 【化14】 19 200843739
式中,z1為可任擇受到保護之羥基、可任擇受到保護 之羥胺基或可任擇具有取代基之胺基; Z2為Ο或NOH ;或是 5 【化15】
形成 N-(CR4F^)r NR6 R及R5各自獨立為氫或低級烧基,r6為氫、低級统基 或醯基,r為0〜2之整數; 王衣A為ί衣烧基、ί哀細基、芳基或雜環基; ίο Rla各自獨立為鹵素、羥基、可任擇具有取代基之低級 院基、可任擇具有取代基之低級烧氧基、可任擇具有取代 基之低級烧硫基、可任擇具有取代基之醯基、叛基、可任 擇具有取代基之低級烧氧羰基、可任擇具有取代基之胺甲 醯基、可任擇具有取代基之低級烷基胺甲醯基、可任擇具 15有取代基之胺基、可任擇具有取代基之胺磺醯基、氰基或 硝基; m為〇〜2之整數;Rle及Rld各自獨立為氫或可任擇具有 20 200843739 取代基之低級烷基; R2為可任擇具有取代基之低級烷基、可任擇具有取代 基之環燒基、可任擇具有取代基之環稀基、可任擇具有取 代基之芳基或可任擇具有取代基之雜環基; R3為可任擇具有取代基之低級烷基、可任擇具有取代 基之環烷基、可任擇具有取代基之環婦基、可任擇具有取 代基之芳基、可任擇具有取代基之雜環基。 (1Γ) 一種藥學組成物,含有如前述(8,)〜(1〇,)中任/頊 之化B物其製藥上可接受之鹽或是該等之溶劑合物。 (12’)一種P2&或P2X2,3受體拮抗劑,含有如前述 ⑹〜⑽中任—項之化合物〜其製藥上可接受之鹽或是該 專之溶劑合物。 ⑴,)如前述(1,H7,)中任一項之ρ2χ3或ρ2χ2/3 抗劑,其係一種鎮痛劑 15 20 (14 )種鎮痛劑,含有如前述(8,)〜(1〇,)中任一項之化 合物、其製藥上可接受 , 丧又之鹽或疋该等之溶劑合物。 ()種鎮痛方法,係將如前述(1,)〜(10,)中任-項之 化合物、其製藥上可桩&)甲仕 藥者。 了接又之鹽或是該等之溶劑合物進行投 上可接為一之種骑如前述(1,)〜(1〇,)中任-項之化合物、其製藥 夕-卞,入⑶ 合物、其製藥上可接受之鹽或其等 之洛劑合物以製造鎮痛劑者。 【實施冷式】 21 200843739 本發明之最佳實施形態 本發明之化合物具有下述結構上之特徵: 1)具有吼咯啉-2-酮環作為基本骨架; 2-1)吡咯啉環之3位為烯醇型(enol form)羥基;或 2-2)吡咯啉環3位及4位之取代基共同形成下式所示之 含氮雜環(R4、R5、R6及r與前述者意義相同); 【化16】
N~(CR4R5)r NR6 ίο 3)比各啉嶮丨位之氮被下式所示之基取代(a、r1、Ra Rb、η及q與前述者意義相同); 【化17】 (CRaRb)qV A)-(R1)n 但,前述(2、2)的情況下、灿位之氮亦可不被取 代; 3-1)吼咯啉環丨位之氮被下
Rib 飞所示之基取代(A、B、Rla、 R 、m及p與别述者意義相同); 【化18】
(R1b)p 22 200843739 3-2)鱗琳環!位之氮被下式所示之基取代(a、Ria、 “。、尺^及^與前述者意義相同)。 【化19】
(R1a)m 5 此外’式(1)、(1,)及(I,,)中,n、m及/或p為2以上之整數 時’多數之R1、多數之Rla及/或多數之Rlb各自可相同或不 同。 兹將本說明書中所用之用語說明如下。各用語在未特 別§己載的箣提下具有下述意義。 10 「烷基」係指碳原子數1〜1〇(較佳為碳原子數1〜8,且 更宜為碳原子數1〜6)之直鏈或分枝狀之1價烴基,例如甲 基、乙基、正丙基、異丙基、正丁基、異丁基、第二丁基、 第三丁基、正戊基、異戊基、新戊基、正己基、異己基、 正庚基、異庚基、正辛基、異辛基、正壬基及正癸基等。 15 「低級烷基」係指碳原子數1〜6(較佳為碳原子數丨〜^ 之直鏈或分枝鏈狀1價烴基,可列舉如甲基、乙基、正丙基、 異丙基、正丁基、異丁基、第二丁基、第三丁基、正戊基、 異戊基、新戊基、正己基及異己基等。 「醯基」係指R-CO-所示之基(例如,R為前述「低級燒 20基」或後述之「低級烯基」、「芳基」、「雜環基」、「環烷基」 或「環浠基」)。 23 200843739 碳鏈。原子數3,之單環或多環狀飽和環 奴鏈。早城魏基可崎如環丙基、環丁基、 衣 環己基、職基、環辛基、環壬基 ^ 土、 烧基可列舉如降妓基等。 、“。夕城環 「環烯基」係指含有至少1個碳,雙鍵之碳原子數 3〜10的非芳㈣單環❹環狀基團。單環狀_基可列舉 «戊縣及環己稀基等。多環狀環烯可列舉如降 芳基」係指單環或縮合環之芳麵烴,可列舉如苯 10基、1-萘基、2-萘基、蒽基、菲基及茚基等。 「雜壤基」係指環内具有至少Η@氮原子、氧原子及/ 或硫原子之5〜7員環、縮合有2個以上該等原子之環,或者 是裱内具有至少1個氮原子、氧原子及/或硫原子之5〜7員環 與已縮合有至少1個前述「芳基」、「環烷基」或「環烯基」 15之環衍生出的芳香族或非芳香族單環或縮合環基。可列舉 如:吡咯啉基、吡咯啶并基(pyrr〇lidin〇)、吡咯啶基 (pyrrolidinyl)、咪唑啉基、咪唑啶基、吡唑啉基、吡唾咬基、 N-六氫吡啶基、六氫咄啶基、六氫吡畊并、 六氫°比°井基(piperazinyl)、嗎福琳基(morpholinyl)、嗎福琳 20 并基(morPholin〇)、硫代嗎福啉基、硫代嗎福啉并基、四氫 °底σ南基、二氫吼σ定基、二氫σ荅嘴基、二氫吼。井基、二。夸垸 基、氧硫雜環戊烧基(oxathiolanyl)、硫雜環己烧基 (thianyl)、四氫咬喃基、四氫旅喃基、四氫嗜β坐琳基 (tetrahydrothiazolinyl)及四氫異噻唑啉基等之非芳香族雜 24 200843739 環基;以及 °比略基、°比喷基、咕峻基、四η坐基、吱喃基、嘴吩夷、 吡啶基、咪唑基、三唑基、四唑基、三畊基、嗒啡基、旅 σ定基、吼°井基、異噚峻基、嗟。坐基、異嗟唾基、疏二唾美 5 (thiadiazolyl)、噚唑基及噚二唑基(oxadiaz〇lyl)等之單環芳 香族雜環基;及 吲垛基、異吲哚基、吲唑基、吲啡基、吲哚啉基、異 吲哚啉基、喳啉基、異喳啉基、啐喏啉基、呔畊基、喳唑 啉基、嘹啶、喳噚啉基、嘌呤基、喋啶基、苯并哌喃基、 10苯并咪唑基、苯并異噚唑基、苯并嘮唑基、苯并噚二唑基、 苯并異噻唑基、苯并噻唑基、苯并硫二唑基、苯并呋喃基、 異本弁σ夫喃基、本弁σ塞吩基、苯弁三唾基、味ϋ坐并呢σ定美 三唑并吼啶基、咪唑并噻唑基、吼畊并嗒畊基、苯并咪唑 琳基、苯并二nf烧基、四氫唆琳及四氫苯并。塞吩基等,與 15 其他環縮合而成之雜環基。 「1¾素」係指氣、氣、>臭及峨。 「低級烧氧基」係指R〇-所示之基,可列舉如R與前述 低級烷基意義相同之甲氧基、乙氧基、丙氧基、異丙氧基、 丁氧基、異丁氧基、第二丁氧基、第三丁氧基、戊氧基、 2〇異戊氧基、新戊氧基、己氧基等低級烷氧基。 「低級烧硫基」係指RS-所示之基,可列舉如r與前述 低級烷基意義相同之甲硫基、乙硫基、丙硫基、異丙硫美、 丁硫基、異丁硫基、第二丁硫基、第三丁硫基、戊硫基、 異戊硫基、新戊硫基及己硫基等低級烷硫基。 25 200843739 「低級烧氧魏基」係指ROCO-所示之基,可列舉如R 與前述低級烷基意義相同之甲氧羰基、乙氧羰基、正丙氧 羰基、異丙氧羰基、正丁氧羰基、第三丁氧羰基、正戊氧 羰基等之低級烷氧羰基。 5 「低級烷基胺甲醯基」可列舉如甲基胺曱醯基、乙基 胺甲醯基、正丙基胺甲醯基、異丙基胺曱醯基、正丁基胺 甲醯基、二甲基胺甲醯基、二乙基胺甲醯基、二丙基胺甲 基專之烧基部分碳原子數為1〜6的單或二低級烧基胺甲 醯基。 10 「亦可任擇具有取代基之低級烧基」、「亦可任擇具有 取代基之低級烯基」、「亦可任擇具有取代基之低級炔基」、 「亦可任擇具有取代基之低級烷氧基」、「亦可任擇具有取 代基之低級烷硫基」、「亦可任擇具有取代基之低級烷氧羰 基」、「亦可任擇具有取代基之低級烷基胺甲醯基」之取代 15 基可列舉如選自以下群組中1個或以上之相同或不同的取 代基,但並未僅侷限於此: 羥基、羧基、鹵素(F、a、Bp I)、卤化低級烷氧基(如 CFsO)、環烷基(如環丙基)、環烯基(如環丙烯基)、低級烷 氧基(如甲氧基、乙氧基、丙氧基、丁氧基等”低級烯氧基 20 (如乙烯氧基、烯丙氧基等)、低級烷氧羰基(如甲氧羰基、 乙氧羰基、第三丁氧羰基等)、硝基、亞硝基、胺基、低級 烷基胺基(如甲基胺基、乙基胺基、二甲基胺基等)、醯基胺 基(如乙醯基胺基、苯甲醯胺基等)、芳烷基胺基(如苄基胺 基、三苯甲基胺基)、羥基胺基、亞胺基、羥亞胺基、低級 26 200843739 烷基亞胺基(如甲基亞胺基、乙基亞胺基、二曱基亞胺基 等)、低級烷氧基亞胺基(如曱氧基亞胺基、乙氧基亞胺基 等)、醯基亞胺基(如乙醯基亞胺基、苯甲醯基亞胺基等)、 疊氮基、芳基(如苯基等)、芳烷基(如节基等)、芳烷氧基(如 5苄氧基)、氰基、異氰基、異氰酸基、氰硫基、異氰硫基、 巯基、低級烷硫基(如甲硫基等)、低級烷基磺醯基(如甲磺 醯基、乙磺醯基)、胺甲醯基、低級烷基胺甲醯基(如甲基胺 甲醯基、乙基胺曱醯基、二甲基胺甲醯基等)、胺磺醯基、 低級烷基胺磺醯基、醯基(如甲醯基、乙醯基等)、甲醯氧基、 10硫代甲醯基、硫代羧基、二硫代羧基、硫代胺曱醯基、亞 石黃酸基、磺酸基、肼基、疊氮基、脲基、甲脒基、脈基、 鄰苯二甲醯亞胺基、三低級烷基矽基(三甲矽基等)、酮基及 以下實施例所示取代基。 「可任擇具有取代基之醯基」之取代基係與前述「可 15任擇具有取代基之低級烷基」之取代基相同。醯基(R-C〇_) 之R為「方基」、「雜j哀基」、「環烧基」或「環烯基」時,亦 可令低級烷基(如甲基、乙基、異丙基、第三丁基等)、鹵化 低級烷基(如CF3、CHzCF3、C^CCl3等)、低級烯基、低級 炔基(如乙炔基)等作為取代基。 20 「可任擇具有取代基之胺甲醯基」、「可任擇具有取代 基之胺績醯基」的取代基可列舉如選自下述者所構成群組 中之1個或以上各自相同或不同的取代基’但並不限於此· 羥基、羧基、鹵素(F、Cl、Br、I)、低級烯基(如乙稀基)、 低級炔基(如乙快基)、環烧基(如環丙基)、環稀基(如環丙烯 27 200843739 基)、低級烷氧羰基(如甲氧羰基、乙氧羰基、第三丁氧羰基 荨)、月女基、低級烧胺基(如甲胺基、乙胺基、二甲基胺基等)、 醯基胺基(如乙醯基胺基、苯甲醯胺基等)、芳烷基胺基(如 苄胺基、三苯甲基胺基)、羥胺基、芳基(如苯基等)、氰基、 5異氰基、異氰酸基、氰硫基、異氰硫基、醯基(如甲醯基、 乙酿基等)及以下實施例所示之取代基。 「可任擇具有取代基之胺基」的取代基可列舉如下述 者所構成群組中之1個或以上各自相同或不同的取代基,但 並不限於此:羥基、_素〇?、0:卜;81·、;!)、函化低級烷基(如 cf3、CH2CF3、CH2CC13等)、羥基低級烷基(如羥乙基、 •C(CH3)2CH2〇H等)、鹵化低級烷氧基(如Cf3〇)、低級烷基 (如曱基、乙基、異丙基、第三丁基等)、低級烯基(如乙烯 基)、低級炔基(如乙炔基)、環烷基(如環丙基)、環烯基(如 環丙烯基)、低級烷氧基(如甲氧基、乙氧基、丙氧基、丁氧 15基等)、低級烷氧羰基(第三丁氧羰基等)、低級烯氧基(如乙 烯氧基、烯丙氧基等)、胺基、低級烷胺基(如曱胺基、乙胺 基、一甲基胺基等)、st基胺基(如乙醢基胺基、苯曱酿胺基 等)、芳院基胺基(如苄胺基、三笨甲基胺基羥胺基、亞 胺基、羥亞胺基、低級烷基亞胺基(如甲基亞胺基、乙基亞 20胺基、二曱基亞胺基等)、低級烷氧基亞胺基(如曱氧基亞胺 基、乙氧基亞胺基等)、醯基亞胺基(如乙醯基胺基、苯曱醯 基亞胺基等)、芳基(如苯基等)、芳烷基(如苄基等)、氰基、 醯基(如曱醯基、乙醯基等)及以下實施例所示取代基。 「可任擇具有取代基之環烷基」、「可任擇具有取代基 28 200843739 之環烯基」、「可任擇具有取代基之芳基」、「可任擇具有取 代基之雜環基」、「可任擇具有取代基之苯基」、「可任擇具 有取代基之吼啶基」的取代基可列舉如下述者所構成群組 中之1個或以上各自相同或不同的取代基,但並不限於此: 5羥基、羧基、鹵素(?'〇、61«、1)、_化低級烷基(如〇?3、 CH2CF3、CHfCl3等)、鹵化低級烷氧基(如CF3〇)、低級垸 基(如甲基、乙基、異丙基、第三丁基等)、低級烯基(如乙 烯基)、低級炔基(如乙炔基)、環烷基(如環丙基)、環烯基(如 環丙烯基)、低級烷氧基(如甲氧基、乙氧基、丙氧基、丁氧 10基等)、低級烯氧基(如乙烯氧基、烯丙氧基等)、低級烷氧 羰基(如甲氧羰基、乙氧羰基、第三丁氧羰基等)、硝基、亞 硝基、胺基、低級烷胺基(如甲胺基、乙胺基、二甲基胺基 等)、醯基胺基(如乙醯基胺基、苯甲醯胺基等)、芳烷基胺 基(如苄胺基、三苯甲基胺基)、羥胺基、亞胺基、羥亞胺基、 15低級烷基亞胺基(如甲基亞胺基、乙基亞胺基、二甲基亞胺 基等)、低級烷氧基亞胺基(如甲氧基亞胺基、乙氧基亞胺基 等)、醯基亞胺基(如乙醯基亞胺基、苯甲醯基亞胺基等)、 豐氮基、芳基(如苯基等)、芳烷基(如苄基等)、芳烷氧基(如 节氧基等)、氰基、異氰基、異氰酸基、氰硫基、異氛硫基、 20巯基、低級烷硫基(如甲硫基等)、低級烷基磺醯基(如甲磺 醯基、乙磺醯基)、可任擇具有取代基之胺甲醯基(如胺甲醯 基、N-甲基-N-甲氧基胺甲酸基等)、可任擇具有取代基之 低級烷基胺甲醯基(如甲基胺甲醯基、乙基胺甲醯基、二甲 基胺甲醯基、經乙基胺甲酿基、三氟甲基胺甲酸基、三氟 29 200843739 乙基胺甲醯基等)、胺磺醯基、低級烷基胺磺醯基、醯基(如 甲醯基、乙醯基等)、甲醯氧基、硫代甲醯基、硫代羧基、 二硫代魏基、硫代胺甲酸基、亞橫酸基、續酸基、肼基、 疊氮基、脲基、曱脒基、胍基、鄰苯二甲醯亞胺基、酮基 5 及以下實施例所示之取代基。 於此,鹵化低級烷基、_化低級烷氧基之_素部分與 前述「鹵素」相同。 鹵化低級烧基、低級烧胺基、低級燒基亞胺基、低級 烷基磺醯基、低級烷基胺磺醯基、低級烷基胺甲醯基、芳 10 烷基及芳烷基胺基之烷基或低級烷基部分與前述「低級烷 基」相同。 鹵化低級烷氧基及低級烷氧基亞胺基之低級烷氧基部 分與前述「低級烷氧基」相同。 「低級烯基」包含任意位置上具有1個以上雙鍵之碳原 15子數2〜6(較佳為碳原子數2〜3)之直鏈或分枝狀烯基。具體 來說,包含乙細基、丙細基、異丙烯基、丁浠基、異丁烯 基、異戊二烯基(prenyl)、丁二烯基、戊烯基、異戊烯基、 戍一炸基、己細基、異己細基及己二稀基等。 低級烯氧基之低級烯基部分與前述「低級烯基」相同。 20 「低級炔基」係指碳原子數2〜6(較佳為碳原子數2〜3) 之直鏈狀或分枝狀炔基,具體而言可列舉如乙快基、丙快 基、丁炔基、戊快基及己快基等。該等可於任意位置上具 有1個以上之三鍵,且可更具有雙鍵。 芳烧基胺基及芳烧基之芳基部分與前述「芳基」相同。 30 200843739 隨基、醯基胺基及醯基亞胺基之醯基部分與 「贫 基」相同。 「可任擇受保護之經基」及「可任擇受保護之輕胺基」 中之保護基於所屬技術領域中為習用公知者,舉例來說,」 5 醚及取代醚形成基(如甲基、甲氧基甲基、第三丁氧美甲 基、L乙氧基乙基及苄基等);矽基醚形成基(如三甲矽基、 三乙矽基、第三丁基二甲矽基及甲基-二異丙基矽基等);酯 形成基(如甲酸酯、乙酸酯及三氯乙酸酯等);碳酸酯基(如 甲基奴酸酯、2,2,2-三氯乙基碳酸酯及對硝基苯基碳酸 1〇酯等);磺醯基形成基(甲磺醯基、對甲苯磺醯基)等。 本發明化合物(1)、(1,)或(1,,)中,較佳態様係如下所示: Ζ1為羥基或羥胺基之化合物; 21為羥基之化合物; Ζ2為Ο或ΝΟΗ之化合物; Ζ為Ο之化合物;
之化合物; Α為芳基或雜環基之化合物; Α為苯基之化合物; 2〇 ^ R為可任擇具有取代基之芳基或可任擇具有取代基之 #曰麵雜環基(如嘍吩基、吡啶基、咪唑基、嘧啶基、異噚 X基塞唑基、異噻唑基、硫二唑基、噚唑基、吡唑基及 咢一 σ坐基等)的化合物,· 31 200843739 R2為可任擇具有取代基之苯基的化合物; R3為可任擇具有取代基之烷基、可任擇具有取代基之 環烷基、可任擇具有取代基之芳基或可任擇具有取代基之 雜環基的化合物; 5 r3為烷基、環烷基、可任擇具有取代基之苯基或可任 擇具有取代基之芳香族雜環基(如噻吩基、吡啶基、咪唑 基、嘧啶基、異噚唑基、噻唑基、異噻唑基、硫二唑基、 噚唑基、吡唑基及噚二唑基、喳啉基等)的化合物;及 R3為烷基、環烷基、可任擇具有取代基之苯基的化合 10 物0 本發明化合物(I)中,較佳態樣係如下所示: q為0之化合物; η為1或2,R1為鹵素、可任擇具有取代基之低級烷基、 羧基、可任擇具有取代基之低級烧氧魏基、可任擇具有取 15代基之芳基或可任擇具有取代基之雜環基的化合物; η為1或2 ’ R1為可任擇具有取代基之低級烧氧羰基、可 任擇具有取代基之芳基或可任擇具有取代基之雜環基的化 合物; η為1或2 ’ R1為可任擇具有取代基之低級烧氧羰基、可 20任擇具有取代基之苯基、可任擇具有取代基之非芳香族雜 環基(如間二氧雜環戊烧基(dioxolanyl)、味唾琳基、味峻淀 基、咐唑啉基、異噚唑琳基、噚唑琳基、噻唑啉基、異噻 唑琳基等)、可任擇具有取代基之芳香族雜環基(如嘍吩 基、吼啶基、咪唑基、嘧啶基、異噚唑基、噻唑基、異噻 32 200843739 唑基、硫二唑基、嘮唑基、吡唑基及嘮二唑基等)之化合物。 本發明化合物(I,)中,較佳態樣係如下所示: 襄B為可任擇具有取代基之非芳香族雜環基(如間二氧 /晨戊燒基、味。坐琳基、味嗤σ定基、吼唾琳基、異$唾琳 5基、圬唑啉基、噻唑啉基、異噻唑啉基等)、可任擇具有取 代基之芳香族雜環基(如噻吩基、吡啶基、咪唑基、嘧啶基、 異噚唑基、噻唑基、異噻唑基、硫二唑基、噚唑基、吡唑 基及,二啥基等)的化合物;及 m及p各自獨立為〇或丨之整數,且Rla及Rlb各自獨立為 1〇齒素、羥基、低級烷基或低級烷氧基之化合物。 本發明化合物(I,,)中,較佳態樣係如下所示·· m為0或1之整數,尺^為齒素、羥基、低級烷基或低級 烷氧基之化合物; R C為氫、可任擇具有取代基之低級烷基的化合物; 15 Rld為氫、可任擇具有取代基之低級烷基的化合物;及 R及Rld各自獨立為可任擇具有氫或取代基之低級烷 基的化合物。 紙將本發明化合物之一般合成方法顯示如下。該等合 成所用之起始物質及反應試劑均是可在商業上取得,或是 使用商業上可取得之化合物並依照所屬技術領域中周知之 方法即可製得者。 本發明之化合物(I)(即,通式⑴所示化合物。以下,其 他通式所示之化合物亦有以同樣方式略記者。)舉例來說可 經由以下所示合成路徑而製得。 33 200843739 [路徑1] 【化21】
〇 〇 R2^X^Y〇R7 +(Rl)nT〇\ 〇
Τ AV(CRaRb)q-NH2+ R3~CHO (Π) (in) (IV) (la) (^-(R1)n 式中’ R7為低級烷基,其他記號與前述者意義相同。 5 即,可使化合物(II)、化合物(III)及化合物(IV)在酸存 在下或不存在下、於無溶劑或適當溶劑中進行反應而製得 通式(la)所示之本發明化合物。 本反應中’化合物(111)及化合物(IV)相對於化合物(π) 可使用1當量或以上,且較佳可使用^當量。 10 可使用之酸可列舉如乙酸、對甲苯磺酸及鹽酸等。 可使用之溶劑可列舉如芳香族烴類(例如甲苯、笨、二 甲苯等)、飽和烴類(如環己燒、己烧等)、鍵類(如四氯咬喃、 一乙醚、二噚烷等)及該等之混合溶劑等。 反應溫度為-l〇〜15(rc,較佳為2〇〜⑽。C。反應時間雖 15依化合物而異,但使其反應10分鐘〜80小時即可。 獲知之所而化合物(Ia)可依需要而依照常法(如管柱層 析法、再結晶法等)進行純化。 [路徑2] 【化22】 34 200843739 :A^A^〇R7 + (R )n^^_(CRaRb)q、/TT, O 心 〇R7 (R1)n (II) w (V)
式中之記號與前述者意義相同。 即,使化合物(II)及化合物(V)在酸存在下或不存在 下,於無溶劑或適當溶劑中反應,可製得通式(la)所示本發 5 明化合物。 本反應中,化合物(V)相對於化合物(II)可使用1當量或 以上,且較佳為1〜3當量。 可使用之酸<!:可列舉如乙酸、對甲苯磺酸及鹽酸等。 可使用之溶劑可列舉如芳香族烴類(如甲苯、苯、二甲 10 苯等)、飽和烴類(如環己烧、己烧等)、醚類(如四氫吱喃、 二乙醚、二哼烷等)及該等之混合溶劑等。 反應溫度為-10〜150°C,較佳為20〜100°c。反應時間係 依化合物而異,但使其反應10分鐘〜80小時即可。 獲得之所需化合物(la)可依需要而以常法(如管柱層析 15 法、再結晶法等)加以純化。 [路徑3] 【化23】
Z2 71 Z2 71
0 + R1-Q 丨、 (VII) 35 200843739 式中,L及Q中之一者為二羥基硼、二低級烷基硼或二 低級烷氧基硼,另一者為鹵素或-〇S02(CsF2s+1)(s為1〜4之整 數),其他記號則與前述者意義相同。 即,可使用铃木耦合反應,使化合物(VI)及化合物(VII) 5 於鈀催化劑及鹼存在下,於適當溶劑中反應而製得通式(lb) 所示之本發明化合物。 本反應中,化合物(VII)相對於化合物(VI),可使用1當 量或以上,較佳為1〜3當量。 可使用之鹼可列舉如金屬氫氧化物(如氫氧化鈉、氫氧 10化鉀等)、金屬氫化物(如氫化鈉、氫化鋰等)、金屬碳酸鹽(如 碳酸鈉、碳酸鉀、碳酸铯等)等,相對於化合物(VI)可使用i 當ϊ或以上’且較佳為1〜5當量。 可使用之鈀催化劑可列舉如三(二亞苄基丙酮)二鈀 (〇)、乙酸鈀(II)、一氣雙二苯基膦鈀(π)或四(三苯基膦)鈀(η) 15等,相對於化合物(VI)可使用0·001當量或以上,且較佳為 0.01〜1當量。 可使用之溶劑可列舉如芳香族烴類(如甲苯、苯、二曱 苯等)、飽和烴類(如環己烧、己燒等)、_類(如四氯^南、 二乙醚、H二甲氧基乙燒等)、N,Nc甲基甲酿胺、 20 水及該等之混合溶劑等。 反應溫度為-10〜18(TC,依情況而異可微波照射化,且 宜為20~120°c。反應時間依化合物而異,但使其反應1〇分 鐘〜80小時即可。 獲得之所需化合物(Ib)可依需要而以常法(如管柱層析 36 200843739 法、再結晶法等)來進行純化。 [路徑4] 【化24】 Z2 Z1
Z2 Z1
(CRaRb)q
〇 + R1-M . (νιπ) (lb) 5 式中,L及M中之一者為三烷基錫(如_SnBu3等),另_ 者為鹵素或-〇S〇2(CsF2s+1)(s為1〜4之整數),其他記號與前 述者意義相同。 即,可使用史蒂爾氏耦合(Stillee〇upling)反應,使化合 物(VI)及化合物(VIII)於催化劑存在下於適當溶劑中反應, 10而製得通式(lb)所示之本發明化合物。 本反應中,化合物(VIII)相對於化合物(VI)可使用工當量 或以上,且較佳為1〜3當量。
等)、醚類(如四氫呋喃、 37 200843739 二乙醚、二噚烷、二甲氧基乙烷等)、N,N-二甲基甲醯胺 及該等之混合溶劑等。 反應溫度為-10〜180°C,依情況而異可照射微波,且宜 為20〜120°C。反應時間可依化合物而異,但使其反應10分 5 鐘〜80小時即可。 獲得之所需化合物(I b)可依需要而以常法(如管柱層析 法、再結晶法等)來加以純化。 [路徑5] 【化25】
式中,記號與前述者意義相同。 即,使化合物(IX)於氧化劑存在下,於適當溶劑中反 應即可製得通式(X)所示之本發明化合物。 可使用之氧化劑可列舉如二氧化錳、2-碘氧基苯甲酸 15 等,相對於化合物(IX)可使用1當量或以上,且較佳為1〜1.5 當量。 可使用之溶劑可列舉如芳香族烴類(如甲苯、苯、二曱 苯等)、飽和烴類(如環己烷、己烷等)、i化烴類(如二氯甲 烷、1,2-二氯乙烷等)、醚類(如四氫呋喃、二噚烷等)、酮 20 類(如丙酮、甲基乙基酮等)、腈類(如乙腈等)及該等之混合 溶劑等。 38 200843739 反應溫度為-10〜15(TC,較佳為2〇〜麵。c。反應時間雖 依化合物而異,但使其反應1〇分鐘〜8〇小時即可。 化合物(IX)可以粗製物型態或以常法(如管柱層析法、 再結晶法等)加以純化後用於下一步驟中。 5 [路徑5(續)] 【化26】
(c/2^b)q X1 (Ic) \^)~{ 2 JCH2)t (R1a)m 式中’ t為0〜3之整數,X1及X2各自獨立為NR8、〇或s, R8為氫或低級烷基,其他記號與前述者意義相同。 10 即,可使化合物(x)及化合物(XI)於酸存在下或不存在 下,於無溶劑或適當溶劑中反應,即可製得通式(Ic)所示本 發明化合物。 本反應中,化合物(XI)相對於化合物(X)可使用i當量或 以上,且較佳為1〜3當量。 15 可使用之酸可列舉如對甲苯磺酸、硫酸、對甲苯磺酸 0比ϋ定鐵鹽等。 可使用之溶劑可列舉如芳香族烴類(如曱苯、苯、二曱 苯等)、飽和烴類(如環己烷、己烷等)以及該等之混合溶劑 等。 20 反應溫度為-10〜17〇°C,較佳為20~150°C。反應時間係 39 200843739 依化合物而異’但使其反應10分鐘〜80小時即可。 獲得之所需化合物(1C)可依需要而以常法(如管柱層析 法、再結晶法等)來加以純化。 [路徑6] 5 【化27】
式中,記號與前述者意義相同。 即’可使化合物(X)與化合物(ΧΙΙ)或其鹽於適當溶劑中 反應,來製得通式(Id)所示本發明化合物。化合物(ΧΙΙ)及其 10鹽相對於化合物(X)係使用1〜4當量,且較佳為i〜2.5當量。 化合物(XII)之鹽可列舉如鹽酸鹽、硫酸鹽等礦酸鹽 等。使用該鹽時,係以鹼中和後進行反應。 可使用之鹼可列舉如乙酸鈉、胺類(吡啶等)等,其使用量相 對於化合物(XI)之鹽為U當量,較佳為i〜2當量。 15 可使用之〉谷劑可列舉如烴類(如苯、甲苯、二甲苯等)、 鹵化烴類(如氣仿、1,2-二氣乙烷等)、醚類(如四氫呋喃、 二哼烷等)、醇類(如甲醇、乙醇、正丙醇、異丙醇等)、水 及該等之混合溶劑等。 反應溫度為0~150°C,較佳為2〇〜120°C。 反應日ττ間通S為10分鐘〜24小時程度。 40 20 200843739 獲得之所需化合物(I d)可依需要而以常法(如管柱層析 法、再結晶法等)來加以純化。 [路徑7] 【化28】
式中,Hal為鹵素,R9為羥基之保護基,其他記號與前 述者同義。 即,可使化合物(la)與化合物(XIII)於鹼存在下,於適 當溶劑中進行反應而製得通式(Ie)所示之本發明化合物。化 10 合物(XII)相對於化合物(la)可使用1〜4當量,較佳為1〜2.5當 量。 可使用之鹼可列舉如胺類(三乙胺、吡啶等)等,其使用 量相對於化合物(la)為1〜3當量,較佳為1〜2當量。 可使用之溶劑可列舉如烴類(如苯、曱苯、二甲苯等)、 15 _化烴類(如氯仿、1,2-二氯乙烧等)、醚類(如四氫吱喃、 二噚烷等)、Ν,Ν-二曱基甲醯胺、二曱基亞砜及該等之混 合溶劑等。 反應溫度為-20〜150°C,較佳為0〜120°C。 反應時間通常為10分鐘〜24小時程度。 20 獲得之所需化合物(Ie)可依需要而以常法(如管柱層析 41 200843739 法、再結晶法等)來加以純化。 [路徑8] 【化29】
5 式中,記號與前述者同義。 即,使化合物(la)與胺類或其鹽於適當溶劑中反應,可 製得通式(If)或通式(Ig)所示本發明化合物。胺類及其鹽相 對於化合物(la)係使用1〜4當量,且較佳為1〜2.5當量。 羥基胺之鹽可列舉如鹽酸鹽、硫酸鹽等之礦酸鹽等。 10 使用該鹽時,係以鹼進行中和而使其反應。 可使用之鹼可列舉如乙酸鈉、胺類(吡啶等)等,其使用 量相對於胺類之鹽為1〜3當量,且較佳為1〜2當量。 可使用之溶劑可列舉如烴類(如苯、甲苯、二甲苯等)、 鹵化烴類(如氯仿、1,2-二氯乙烷等)、醚類(如四氫呋喃、 15 二噚烷等)、醇類(如甲醇、乙醇、正丙醇、異丙醇等)、水 及該等之混合溶劑等。 反應溫度為0〜150°C,且較宜為20〜120°C。 反應時間通常為15分鐘〜24小時程度。 獲得之所需化合物(If)或化合物(Ig)可依需要而以常法 20 (如管柱層析法、再結晶法等)來加以純化。 [路徑9] 42 200843739 【化30】
式中,記號與前述者同義。 5 10 15 即,可使化合物(la)與化合物(χιν)於適當溶劑中反 應,而製得通式(ih)所示本發明化合物。化合物(χιν)相對 於化合物(la)係使用1〜4當量,且較佳為^2 5當量。 可使用之溶劑可列舉如乙酸、煙類(如苯、甲苯、二甲 苯等)、醚類(如四氫吱喃、二桃等)、醇類(如甲醇、乙醇、 正丙醇、異丙醇等)及該等之混合溶劑等。 反應溫度為〇〜i5(rc,較佳為5〇〜i3(rc。 反應時間通常為10分鐘〜24小時程度。 獲得之所需化合物⑽可依需要而;常法(如管柱層析 法、再結晶法等)來加以純化。 _ % 可形成製藥學上可接受之其與酸或驗之 鹽酸、硫酸、碩酸、磷酸、氟化氫酸、 酒石酸、乳酸、棒樣;Λ 、號· 三乙基銨;:機 以及,簡㈣、鉀祕金屬之鹽; 本么月化合物或前述製藥上可接受之鹽亦可製 43 20 200843739 成其溶劑合物(較佳為水合物)之溶劑合物。溶劑合物可列舉 如與有機溶劑及/或水之溶劑合物。形成溶劑合物時,可與 任意數量之溶劑分子任擇地配位。 本發明化合物(I)並不限於特定之異構物,而包含所有 5 可能之異構物及消旋體。例如,含有下述之互變異構物。 【化31】
本發明之化合物可為具有特定立體配置且業經離析之 鏡向異構物、或是該等鏡向異構物之混合物。舉例來說, 10 本發明之化合物可以是在吡咯啶并環之5位上具有特定立 44 200843739 體配置且經離析之鏡向異構物或該鏡向異構物之混合物。 舉例來說,當業者可採用結晶化、酶反應、層析法等所屬 技術項域中j貝用之技術而容易地離析出具有特定立體配置 之鏡向異構物。 5 10 15 20 月ίΐ述通式(1)所示本發明化合物具有對於ρ2Χ3及/或 P2X2/3文體之拮抗作用,作為P2X3及/或ρ2χ奶相關疾病之治 療劑甚為有用。P^3及/或似的受體被認為與疼痛及泌尿 系統疾病相 _咖e 撕,26, um_1()15 (2_),Nature,
Vo副,No.26, 1015韻(2_)、非專利文獻卜非專利文 _ ) 頜風濕性關節炎所伴隨之疼痛、變形性關節 炎所伴隨之疼痛、頭痛、偏頭痛、口腔顏面痛、牙痛、舌 痛症、顳f員關節炎所倖左 、/人所机之疼痛、三叉神經痛、肩痛、椎 曰:大扣所伴隨之疼痛、變形性頸椎症所伴隨之疼痛、脊 狹乍所伴隨之疼痛、胸廓出口綜合症⑽ rrzrm腕神《損傷症候群所伴隨之疼 =膽結石所伴隨之疼痛、胰扁 迢結石症、過敏性腸症 、眉尿 骨神經痛、骨折所伴腰肺部痛、坐 S气Μ虑、s 涌、月質疏鬆症所伴隨之疼痛、 二生二風所伴隨m馬尾症候群所伴隨之疼痛 僵直性錄炎所伴隨 得&之疼痛、 症候群、纖維肌痛症候群 手肌㈣ 痛、柏格氏症所伴隨之疼/^"動脈硬化症所伴隨之疼 帶狀癌療所伴隨之料U諾氏現象所伴隨之疼痛、 3熱痛、神經壓迫症候群所伴隨 45 200843739 痛、道症候群所伴隨之疼痛、糖尿病所伴隨之疼 藥物療法:隨ΓΓΓ之疼痛、韓森氏病所伴隨之疼痛、 4- ^ 您、痛、放射線療法所伴隨之瘃痛、ϋ 5 10 15
Xir; r 交感神經維持.二::;=(Dr— 病所伴、、 w候群、夕發性硬化症、皮膚 揀癌性疼痛、術後痛、外傷所伴隨之疼痛、 =、冑之疼痛、心身症所伴隨之疼痛、體化症所伴隨 、痛、«症所伴隨之疼痛、帕金森氏症 =節痛、關節炎所伴隨之疼痛、生理痛、中二 痛專神經障礙性_、t錄賴、錢接受性疼痛、心 因性疼細及駿_胱、尿失禁、縣、尿意緊迫⑽ urgency)、膀胱萎縮、前列腺肥大、前列腺炎、射_、 逼尿肌過度反射(detrusor hyperreflesxia)、排尿障礙、神經 性頻尿、慢性前列腺炎、慢性膀胱炎等,而在治療、緩和 症狀或預防上有效。 本發明之化合物對於ATP受體、特別是现受體具有 高親和性,亞型選擇性及對於其他受體之選擇性亦高了而 可成為副作用(如對運動機能之影響等)降低之藥物。此外, 2〇本發明之化合物亦具有安定性高、經口吸收性佳、顯示出 良好之生體利用率、清除率(ciearance)低、半衰期長、藥效 持續性高及/或肝酶阻礙活性低等優點。 於其他態樣中,本發明提供一種藥學組成物,其含有 有效量之本發明化合物與製藥學上可接受之载體的組合。 46 200843739 將本發明化合物用作藥品時,舉例來說,可使用賦形 刮、結合劑、崩解劑、滑澤劑、著色劑、續味劑、端臭劑、 界面活性劑等所屬技術領域中周知之製藥上可接受之載 體而依常法來製造藥學組成物。 5、=本發明之藥學組成物投料包含人類之哺乳動物以 ^者療日^ ’投藥單位劑形可依治療目的及投藥路徑來加 以適當選擇。具體來說,可列舉如旋劑、膜衣錠、粉劑、 、、/州膠暴劑、液劑、丸劑、懸濁劑、乳劑等經口製劑, ^及及注射劑、栓劑、軟膏、貼劑、噴霧劑等非經口製劑。 10该等投藥單位劑形可以所屬領域巾周知之方法進行製劑 化。 鈾述敁劑中應含之本發明化合物量可依照劑型、投藥 路徑、投藥計畫等來適當變更。 本發明之藥學組成物之投藥方法可依製劑之劑形、患 15者年齡、性別、體重、症狀程度及其他條件等來適當地決 疋,可選擇經口、皮下、經皮、直腸、鼻内、口腔等各種 路梭。 本舍明之樂學組成物所含有之本發明化合物的用量可 依所選擇之投藥路徑、患者年齡、性別、體重、疾病狀態、 20所投藥之本發明化合物種類以及其他條件等加以適當選 擇’但對成人實施經口投藥時,通常為〇.〇5〜i〇〇〇mg/kg/曰, 較佳為0.1〜l〇mg/kg/曰之範圍内。非經口投藥時,將依投藥 路控而大為不同,但通常為0.005〜l〇〇mg/kg/日,且較佳為 〇·〇1〜lmg/kg/曰之範圍内。該等本發明之藥學組成物可1曰i 47 200843739 次或分成數次進行投藥。 本發明化合物之較佳態樣係於下式(a)〜(f)中具有下述 基團者。 【化32】
(4 ⑻ m Pf0*1* 48 200843739 表1
Z1 ZA OH ZB OAc ZC NHOH 表2 R1 R1A COOEt RIB cf3 R1C ocf3 RID scf3 R1E Ac RIF Br RIG 2-或5-呤唑基 R1H 異哼唑-3-基 R1I 3-Me-異噚唑-5-基 R1J 5-Me-異噚唑-3-基 R1K 1,2,4-噚二唑-3-基 R1L 1,3,4-哼二唑-2-基 RIM 5-Me-l,2,4-哼二唑-3-基 R1N 3-Me-l,2,4-哼二唑-5-基 RIO C(Me)=NOMe RIP CH=NOMe R1Q 2-哼唑啉基 R1R 2-嘆唾琳基 R1S 1,3-二噚烷-2-基 表3 R2 R2A iPr R2B nBu R2C tBu R2D cBu R2E cHex R2F Ph R2G 4-C1 或 F-Ph R2H 4-N02-Ph R2I 4-CF3-Ph R2J 4-Me2N-Ph R2K 2-或3-噻吩基 R2L 3-°比°定基 R2M 6-ΜθΟ-3-σΛσ定基 R2N 2 或 3 或 4-MeO-Ph 49 200843739 表4 R3 R3A iPr R3B Et2CH R3C Pr2CH R3D nBu2CH R3E Pr(Me)CH R3F Ph(Me)CH R3G cPent R3H cHex R3I Ph R3J 2-Cl-Ph R3K 2-或 3-或 4-Me-Ph R3L 2-或 3-或 4-MeO-Ph R3M 2-或 3-或 4-F-Ph R3N 3-或 4-Cl-Ph R30 2-σΛσ定基 R3P 4-六氮吼σ定基 R3Q l_Ac-4-六鼠ϋΐί»σ定基 R3R 四氫哌喃-4-基 前述表中,Ac為乙醯基、Me為甲基、Et為乙基、Pr為 丙基、iPr為異丙基、nBu為正丁基、tBu為第三丁基、cBu 為環丁基、cPent為環戊基、cHex為環己基、Ph為苯基。 5 Z1、R1、R2及R3之組合01,111,112,尺3)為下述各化合物。
(Z1,R1,R2,R3)=(ZA,R1A,R2A,R3A),(ZA,R1A,R2A,R3 B),(ZA,R1A,R2A,R3C),(ZA,R1A,R2A,R3D),(ZA,R1A,R2A, R3E),(ZA,R1A,R2A,R3F),(ZA,R1A,R2A,R3G),(ZA,R1A,R2 A,R3H),(ZA,R1A,R2A,R3I),(ZA,R1A,R2A,R3J),(ZA,R1A,R 10 2A,R3K),(ZA,R1A,R2A,R3L),(ZA,R1A,R2A,R3M),(ZA,R1A ,R2A,R3N),(ZA,R1A,R2A,R30),(ZA,R1A,R2A,R3P),(ZA,R1 A,R2A,R3Q),(ZA,R1A,R2A,R3R),(ZA,R1A,R2B,R3A),(ZA, R1A,R2B,R3B),(ZA,R1A,R2B,R3C),(ZA,R1A,R2B,R3D),(Z A,R1A,R2B,R3E),(ZA,R1A,R2B,R3F),(ZA,R1A,R2B,R3G),( 50 200843739 ZA,R1A,R2B,R3H),(ZA,R1A,R2B,R3I),(ZA,R1A,R2B,R3J),( ZA,R1A,R2B,R3K),(ZA,R1A,R2B,R3L),(ZA,R1A,R2B,R3M) ,(ZA,R1A,R2B,R3N),(ZA,R1A,R2B,R30),(ZA,R1A,R2B,R3 P),(ZA,R1A,R2B,R3Q),(ZA,R1A,R2B,R3R),(ZA,R1A,R2C,R 5 3A),(ZA,R1A,R2C,R3B),(ZA,R1A,R2C,R3C),(ZA,R1A,R2C,
R3D),(ZA,R1A,R2C,R3E),(ZA,R1A,R2C,R3F),(ZA,R1A,R2 C,R3G),(ZA,R1A,R2C,R3H),(ZA,R1A,R2C,R3I),(ZA,R1A,R 2C,R3J),(ZA,R1A,R2C,R3K),(ZA,R1A,R2C,R3L),(ZA,R1A, R2C,R3M),(ZA,R1A,R2C,R3N),(ZA,R1A,R2C,R30),(ZA,R1 10 A,R2C,R3P),(ZA,R1A,R2C,R3Q),(ZA,R1A,R2C,R3R),(ZA,R 1A,R2D,R3A),(ZA,R1A,R2D,R3B),(ZA,R1A,R2D,R3C),(ZA, R1A,R2D,R3D),(ZA,R1A,R2D,R3E),(ZA,R1A,R2D,R3F),(Z A,R1A,R2D,R3G),(ZA,R1A,R2D,R3H),(ZA,R1A,R2D,R3I),( ZA,R1A,R2D,R3J),(ZA,R1A,R2D,R3K),(ZA,R1A,R2D,R3L), 15 (ZA,R1A,R2D,R3M),(ZA,R1A,R2D,R3N),(ZA,R1A,R2D,R3 0),(ZA,R1A,R2D,R3P),(ZA,R1A,R2D,R3Q),(ZA,R1A,R2D, R3R),(ZA,R1A,R2E,R3A),(ZA,R1A,R2E,R3B),(ZA,R1A,R2 E,R3C),(ZA,R1A,R2E,R3D),(ZA,R1A,R2E,R3E),(ZA,R1A,R 2E,R3F),(ZA,R1A,R2E,R3G),(ZA,R1A,R2E,R3H),(ZA,R1A, 20 R2E,R3I),(ZA,R1A,R2E,R3J),(ZA,R1A,R2E,R3K),(ZA,R1A, R2E,R3L),(ZA,R1A,R2E,R3M),(ZA,R1A,R2E,R3N),(ZA,R1 A,R2E,R30),(ZA,R1A,R2E,R3P),(ZA,R1A,R2E,R3Q),(ZA,R 1A,R2E,R3R),(ZA,R1A,R2F,R3A),(ZA,R1A,R2F,R3B),(ZA, R1A,R2F,R3C),(ZA,R1A,R2F,R3D),(ZA,R1A,R2F,R3E),(ZA, 51 200843739
R1A,R2F,R3F),(ZA,R1A,R2F,R3G),(ZA,R1A,R2F,R3H),(ZA, R1A,R2F,R3I),(ZA,R1A,R2F,R3J),(ZA,R1A,R2F,R3K),(ZA, R1A,R2F,R3L),(ZA,R1A,R2F,R3M),(ZA,R1A,R2F,R3N),(ZA ,R1A,R2F,R30),(ZA,R1A,R2F,R3P),(ZA,R1A,R2F,R3Q),(ZA 5 ,R1A,R2F,R3R),(ZA,R1A,R2G,R3A),(ZA,R1A,R2G,R3B),(Z A,R1A,R2G,R3C),(ZA,R1A,R2G,R3D),(ZA,R1A,R2G,R3E),( ZA,R1A,R2G,R3F),(ZA,R1A,R2G,R3G),(ZA,R1A,R2G,R3H), (ZA,R1A,R2G,R3I),(ZA,R1A,R2G,R3J),(ZA,R1A,R2G,R3K), (ZA,R1A,R2G,R3L),(ZA,R1A,R2G,R3M),(ZA,R1A,R2G,R3N 10 ),(ZA,R1A,R2G,R30),(ZA,R1A,R2G,R3P),(ZA,R1A,R2G,R3 Q),(ZA,R1A,R2G,R3R),(ZA,R1A,R2H,R3A),(ZA,R1A,R2H, R3B),(ZA,R1A,R2H,R3C),(ZA,R1A,R2H,R3D),(ZA,R1A,R2 H,R3E),(ZA,R1A,R2H,R3F),(ZA,R1A,R2H,R3G),(ZA,R1A,R 2H,R3H),(ZA,R1A,R2H,R3I),(ZA,R1A,R2H,R3J),(ZA,R1A, 15 R2H,R3K),(ZA,R1A,R2H,R3L),(ZA,R1A,R2H,R3M),(ZA,R1 A,R2H,R3N),(ZA,R1A,R2H,R30),(ZA,R1A,R2H,R3P),(ZA, R1A,R2H,R3Q),(ZA,R1A,R2H,R3R),(ZA,R1A,R2I,R3A),(Z A,R1A,R2I,R3B),(ZA,R1A,R2I,R3C),(ZA,R1A,R2I,R3D),(Z A,R1A,R2I,R3E),(ZA,R1A,R2I,R3F),(ZA,R1A,R2I,R3G),(Z 20 A,R1A,R2I,R3H),(ZA,R1A,R2I,R3I),(ZA,R1A,R2I,R3J),(ZA, R1A,R2I,R3K),(ZA,R1A,R2I,R3L),(ZA,R1A,R2I,R3M),(ZA, R1A,R2I,R3N),(ZA,R1A,R2I,R30),(ZA,R1A,R2I,R3P),(ZA, R1A,R2I,R3Q),(ZA,R1A,R2I,R3R),(ZA,R1A,R2J,R3A),(ZA, R1A,R2J,R3B),(ZA,R1A,R2J,R3C),(ZA,R1A,R2J,R3D),(ZA, 52 200843739 R1A,R2J,R3E),(ZA,R1A,R2J,R3F),(ZA,R1A,R2J,R3G),(ZA, R1A,R2J,R3H),(ZA,R1A,R2J,R3I),(ZA,R1A,R2J,R3J),(ZA,R 1A,R2J,R3K),(ZA,R1A,R2J,R3L),(ZA,R1A,R2J,R3M),(ZA,R 1A,R2J,R3N),(ZA,R1A,R2J,R30),(ZA,R1A,R2J,R3P),(ZA,R 5 1A,R2J,R3Q),(ZA,R1A,R2J,R3R),(ZA,R1A,R2K,R3A),(ZA, R1A,R2K,R3B),(ZA,R1A,R2K,R3C),(ZA,R1A,R2K,R3D),(Z A,R1A,R2K,R3E),(ZA,R1A,R2K,R3F),(ZA,R1A,R2K,R3G),( ZA,R1A,R2K,R3H),(ZA,R1A,R2K,R3I),(ZA,R1A,R2K,R3J), (ZA,R1A,R2K,R3K),(ZA,R1A,R2K,R3L),(ZA,R1A,R2K,R3 10 M),(ZA,R1A,R2K,R3N),(ZA,R1A,R2K,R30),(ZA,R1A,R2K,
R3P),(ZA,R1A,R2K,R3Q),(ZA,R1A,R2K,R3R),(ZA,R1A,R2 L,R3A),(ZA,R1A,R2L,R3B),(ZA,R1A,R2L,R3C),(ZA,R1A,R 2L,R3D),(ZA,R1A,R2L,R3E),(ZA,R1A,R2L,R3F),(ZA,R1A, R2L,R3G),(ZA,R1A,R2L,R3H),(ZA,R1A,R2L,R3I),(ZA,R1A 15 ,R2L,R3J),(ZA,R1A,R2L,R3K),(ZA,R1A,R2L,R3L),(ZA,R1A ,R2L,R3M),(ZA,R1A,R2L,R3N),(ZA,R1A,R2L,R30),(ZA,R1 A,R2L,R3P),(ZA,R1A,R2L,R3Q),(ZA,R1A,R2L,R3R),(ZA,R 1A,R2M,R3A),(ZA,R1A,R2M,R3B),(ZA,R1A,R2M,R3C),(Z A,R1A,R2M,R3D),(ZA,R1A,R2M,R3E),(ZA,R1A,R2M,R3F), 20 (ZA,R1A,R2M,R3G),(ZA,R1A,R2M,R3H),(ZA,R1A,R2M,R3 I),(ZA,R1A,R2M,R3J),(ZA,R1A,R2M,R3K),(ZA,R1A,R2M,R 3L),(ZA,R1A,R2M,R3M),(ZA,R1A,R2M,R3N),(ZA,R1A,R2 M,R30),(ZA,R1A,R2M,R3P),(ZA,R1A,R2M,R3Q),(ZA,R1A, R2M,R3R),(ZA,R1A,R2N,R3A),(ZA,R1A,R2N,R3B),(ZA,R1 53 200843739 A,R2N,R3C),(ZA,R1A,R2N,R3D),(ZA,R1A,R2N,R3E),(ZA, R1A,R2N,R3F),(ZA,R1A,R2N,R3G),(ZA,R1A,R2N,R3H),(Z A,R1A,R2N,R3I),(ZA,R1A,R2N,R3J),(ZA,R1A,R2N,R3K),( ZA,R1A,R2N,R3L),(ZA,R1A,R2N,R3M),(ZA,R1A,R2N,R3N 5 ),(ZA,R1A,R2N,R30),(ZA,R1A,R2N,R3P),(ZA,R1A,R2N,R3 Q),(ZA,R1A,R2N,R3R),(ZA,R1B,R2A,R3A),(ZA,R1B,R2A, R3B),(ZA,R1B,R2A,R3C),(ZA,R1B,R2A,R3D),(ZA,R1B,R2 A,R3E),(ZA,R1B,R2A,R3F),(ZA,R1B,R2A,R3G),(ZA,R1B,R 2A,R3H),(ZA,R1B,R2A,R3I),(ZA,R1B,R2A,R3J),(ZA,R1B,R 10 2A,R3K),(ZA,R1B,R2A,R3L),(ZA,R1B,R2A,R3M),(ZA,R1B,
R2A,R3N),(ZA,R1B,R2A,R30),(ZA,R1B,R2A,R3P),(ZA,R1 B,R2A,R3Q),(ZA,R1B,R2A,R3R),(ZA,R1B,R2B,R3A),(ZA,R 1B,R2B,R3B),(ZA,R1B,R2B,R3C),(ZA,R1B,R2B,R3D),(ZA, R1B,R2B,R3E),(ZA,R1B,R2B,R3F),(ZA,R1B,R2B,R3G),(ZA 15 ,R1B,R2B,R3H),(ZA,R1B,R2B,R3I),(ZA,R1B,R2B,R3J),(ZA ,R1B,R2B,R3K),(ZA,R1B,R2B,R3L),(ZA,R1B,R2B,R3M),(Z A,R1B,R2B,R3N),(ZA,R1B,R2B,R30),(ZA,R1B,R2B,R3P),( ZA,R1B,R2B,R3Q),(ZA,R1B,R2B,R3R),(ZA,R1B,R2C,R3A), (ZA,R1B,R2C,R3B),(ZA,R1B,R2C,R3C),(ZA,R1B,R2C,R3D 20 ),(ZA,R1B,R2C,R3E),(ZA,R1B,R2C,R3F),(ZA,R1B,R2C,R3
G),(ZA,R1B,R2C,R3H),(ZA,R1B,R2C,R3I),(ZA,R1B,R2C,R 3J),(ZA,R1B,R2C,R3K),(ZA,R1B,R2C,R3L),(ZA,R1B,R2C,R 3M),(ZA,R1B,R2C,R3N),(ZA,R1B,R2C,R30),(ZA,R1B,R2C, R3P),(ZA,R1B,R2C,R3Q),(ZA,R1B,R2C,R3R),(ZA,R1B,R2D 54 200843739
,R3A),(ZA,R1B,R2D,R3B),(ZA,R1B,R2D,R3C),(ZA,R1B,R2 D,R3D),(ZA,R1B,R2D,R3E),(ZA,R1B,R2D,R3F),(ZA,R1B,R 2D,R3G),(ZA,R1B,R2D,R3H),(ZA,R1B,R2D,R3I),(ZA,R1B, R2D,R3J),(ZA,R1B,R2D,R3K),(ZA,R1B,R2D,R3L),(ZA,R1B 5 ,R2D,R3M),(ZA,R1B,R2D,R3N),(ZA,R1B,R2D,R30),(ZA,R
1B,R2D,R3P),(ZA,R1B,R2D,R3Q),(ZA,R1B,R2D,R3R),(ZA, R1B,R2E,R3A),(ZA,R1B,R2E,R3B),(ZA,R1B,R2E,R3C),(ZA ,R1B,R2E,R3D),(ZA,R1B,R2E,R3E),(ZA,R1B,R2E,R3F),(ZA ,R1B,R2E,R3G),(ZA,R1B,R2E,R3H),(ZA,R1B,R2E,R3I),(ZA 10 ,R1B,R2E,R3J),(ZA,R1B,R2E,R3K),(ZA,R1B,R2E,R3L),(ZA ,R1B,R2E,R3M),(ZA,R1B,R2E,R3N),(ZA,R1B,R2E,R30),(Z A,R1B,R2E,R3P),(ZA,R1B,R2E,R3Q),(ZA,R1B,R2E,R3R),( ZA,R1B,R2F,R3A),(ZA,R1B,R2F,R3B),(ZA,R1B,R2F,R3C),( ZA,R1B,R2F,R3D),(ZA,R1B,R2F,R3E),(ZA,R1B,R2F,R3F),( 15 ZA,R1B,R2F,R3G),(ZA,R1B,R2F,R3H),(ZA,R1B,R2F,R3I),( ZA,R1B,R2F,R3J),(ZA,R1B,R2F,R3K),(ZA,R1B,R2F,R3L),( ZA,R1B,R2F,R3M),(ZA,R1B,R2F,R3N),(ZA,R1B,R2F,R30), (ZA,R1B,R2F,R3P),(ZA,R1B,R2F,R3Q),(ZA,R1B,R2F,R3R), (ZA,R1B,R2G,R3A),(ZA,R1B,R2G,R3B),(ZA,R1B,R2G,R3C) 20 ,(ZA,R1B,R2G,R3D),(ZA,R1B,R2G,R3E),(ZA,R1B,R2G,R3F)
,(ZA,R1B,R2G,R3G),(ZA,R1B,R2G,R3H),(ZA,R1B,R2G,R3I) ,(ZA,R1B,R2G,R3J),(ZA,R1B,R2G,R3K),(ZA,R1B,R2G,R3L) ,(ZA,R1B,R2G,R3M),(ZA,R1B,R2G,R3N),(ZA,R1B,R2G,R3 0),(ZA,R1B,R2G,R3P),(ZA,R1B,R2G,R3Q),(ZA,R1B,R2G,R 55 200843739 3R),(ZA,R1B,R2H,R3A),(ZA,R1B,R2H,R3B),(ZA,R1B,R2H9 R3C),(ZA,R1B,R2H,R3D),(ZA,R1B,R2H,R3E),(ZA,R1B,R2 H,R3F),(ZA,R1B,R2H,R3G),(ZA,R1B,R2H,R3H),(ZA,R1B,R 2H,R3I),(ZA,R1B,R2H,R3J),(ZA,R1B,R2H,R3K),(ZA,R1B,R 5 2H,R3L),(ZA,R1B,R2H,R3M),(ZA,R1B,R2H,R3N),(ZA,R1B, R2H,R30),(ZA,R1B,R2H,R3P),(ZA,R1B,R2H,R3Q),(ZA,R1 B,R2H,R3R),(ZA,R1B,R2I,R3A),(ZA,R1B,R2I,R3B),(ZA,R1 B,R2I,R3C),(ZA,R1B,R2I,R3D),(ZA,R1B,R2I,R3E),(ZA,R1B ,R2I,R3F),(ZA,R1B,R2I,R3G),(ZA,R1B,R2I,R3H),(ZA,R1B, 10 R2I,R3I),(ZA,R1B,R2I,R3J),(ZA,R1B,R2I,R3K),(ZA,R1B,R2 I,R3L),(ZA,R1B,R2I,R3M),(ZA,R1B,R2I,R3N),(ZA,R1B,R2I ,R30),(ZA,R1B,R2I,R3P),(ZA,R1B,R2I,R3Q),(ZA,R1B,R2I, R3R),(ZA,R1B,R2J,R3A),(ZA,R1B,R2J,R3B),(ZA,R1B,R2J, R3C),(ZA,R1B,R2J,R3D),(ZA,R1B,R2J,R3E),(ZA,R1B,R2J, 15 R3F),(ZA,R1B,R2J,R3G),(ZA,R1B,R2J,R3H),(ZA,R1B,R2J, R3I),(ZA,R1B,R2J,R3J),(ZA,R1B,R2J,R3K),(ZA,R1B,R2J,R 3L),(ZA,R1B,R2J,R3M),(ZA,R1B,R2J,R3N),(ZA,R1B,R2J,R 30),(ZA,R1B,R2J,R3P),(ZA,R1B,R2J,R3Q),(ZA,R1B,R2J,R3 R),(ZA,R1B,R2K,R3A),(ZA,R1B,R2K,R3B),(ZA,R1B,R2K,R 20 3C),(ZA,R1B,R2K,R3D),(ZA,R1B,R2K,R3E),(ZA,R1B,R2K, R3F),(ZA,R1B,R2K,R3G),(ZA,R1B,R2K,R3H),(ZA,R1B,R2 K,R3I),(ZA,R1B,R2K,R3J),(ZA,R1B,R2K,R3K),(ZA,R1B,R2 K,R3L),(ZA,R1B,R2K,R3M),(ZA,R1B,R2K,R3N),(ZA,R1B, R2K,R30),(ZA,R1B,R2K,R3P),(ZA,R1B,R2K,R3Q),(ZA,R1 56 200843739
B,R2K,R3R),(ZA,R1B,R2L,R3A),(ZA,R1B,R2L,R3B),(ZA,R 1B,R2L,R3C),(ZA,R1B,R2L,R3D),(ZA,R1B,R2L,R3E),(ZA, R1B,R2L,R3F),(ZA,R1B,R2L,R3G),(ZA,R1B,R2L,R3H),(ZA ,R1B,R2L,R3I),(ZA,R1B,R2L,R3J),(ZA,R1B,R2L,R3K),(ZA, 5 R1B,R2L,R3L),(ZA,R1B,R2L,R3M),(ZA,R1B,R2L,R3N),(Z A,R1B,R2L,R30),(ZA,R1B,R2L,R3P),(ZA,R1B,R2L,R3Q),( ZA,R1B,R2L,R3R),(ZA,R1B,R2M,R3A),(ZA,R1B,R2M,R3B ),(ZA,R1B,R2M,R3C),(ZA,R1B,R2M,R3D),(ZA,R1B,R2M,R 3E),(ZA,R1B,R2M,R3F),(ZA,R1B,R2M,R3G),(ZA,R1B,R2M 10 ,R3H),(ZA,R1B,R2M,R3I),(ZA,R1B,R2M,R3J),(ZA,R1B,R2 M,R3K),(ZA,R1B,R2M,R3L),(ZA,R1B,R2M,R3M),(ZA,R1B, R2M,R3N),(ZA,R1B,R2M,R30),(ZA,R1B,R2M,R3P),(ZA,R1 B,R2M,R3Q),(ZA,R1B,R2M,R3R),(ZA,R1B,R2N,R3A),(ZA, R1B,R2N,R3B),(ZA,R1B,R2N,R3C),(ZA,R1B,R2N,R3D),(Z 15 A,R1B,R2N,R3E),(ZA,R1B,R2N,R3F),(ZA,R1B,R2N,R3G),( ZA,R1B,R2N,R3H),(ZA,R1B,R2N,R3I),(ZA,R1B,R2N,R3J),( ZA,R1B,R2N,R3K),(ZA,R1B,R2N,R3L),(ZA,R1B,R2N,R3M) ,(ZA,R1B,R2N,R3N),(ZA,R1B,R2N,R30),(ZA,R1B,R2N,R3 P),(ZA,R1B,R2N,R3Q),(ZA,R1B,R2N,R3R),(ZA,R1C,R2A,R 20 3A),(ZA,R1C,R2A,R3B),(ZA,R1C,R2A,R3C),(ZA,R1C,R2A, R3D),(ZA,R1C,R2A,R3E),(ZA,R1C,R2A,R3F),(ZA,R1C,R2 A,R3G),(ZA,R1C,R2A,R3H),(ZA,R1C,R2A,R3I),(ZA,R1C,R 2A,R3J),(ZA,R1C,R2A,R3K),(ZA,R1C,R2A,R3L),(ZA,R1C, R2A,R3M),(ZA,R1C,R2A,R3N),(ZA,R1C,R2A,R30),(ZA,R1 57 200843739
C,R2A,R3P),(ZA,R1C,R2A,R3Q),(ZA,R1C,R2A,R3R),(ZA,R 1C,R2B,R3A),(ZA,R1C,R2B,R3B),(ZA,R1C,R2B,R3C),(ZA, R1C,R2B,R3D),(ZA,R1C,R2B,R3E),(ZA,R1C,R2B,R3F),(ZA ,R1C,R2B,R3G),(ZA,R1C,R2B,R3H),(ZA,R1C,R2B,R3I),(Z 5 A,R1C,R2B,R3J),(ZA,R1C,R2B,R3K),(ZA,R1C,R2B,R3L),(Z
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3I),(ZA,R1C,R2C,R3J),(ZA,R1C,R2C,R3K),(ZA,R1C,R2C,R 3L),(ZA,R1C,R2C,R3M),(ZA,R1C,R2C,R3N),(ZA,R1C,R2C, R30),(ZA,R1C,R2C,R3P),(ZA,R1C,R2C,R3Q),(ZA,R1C,R2C ,R3R),(ZA,R1C,R2D,R3A),(ZA,R1C,R2D,R3B),(ZA,R1C,R2 15 D,R3C),(ZA,R1C,R2D,R3D),(ZA,R1C,R2D,R3E),(ZA,R1C,R 2D,R3F),(ZA,R1C,R2D,R3G),(ZA,R1C,R2D,R3H),(ZA,R1C, R2D,R3I),(ZA,R1C,R2D,R3J),(ZA,R1C,R2D,R3K),(ZA,R1C, R2D,R3L),(ZA,R1C,R2D,R3M),(ZA,R1C,R2D,R3N),(ZA,R1 C,R2D,R30),(ZA,R1C,R2D,R3P),(ZA,R1C,R2D,R3Q),(ZA,R 20 1C,R2D,R3R),(ZA,R1C,R2E,R3A),(ZA,R1C,R2E,R3B),(ZA, R1C,R2E,R3C),(ZA,R1C,R2E,R3D),(ZA,R1C,R2E,R3E),(ZA ,R1C,R2E,R3F),(ZA,R1C,R2E,R3G),(ZA,R1C,R2E,R3H),(Z A,R1C,R2E,R3I),(ZA,R1C,R2E,R3J),(ZA,R1C,R2E,R3K),(Z A,R1C,R2E,R3L),(ZA,R1C,R2E,R3M),(ZA,R1C,R2E,R3N),( 58 200843739 ZA,R1C,R2E,R30),(ZA,R1C,R2E,R3P),(ZA,R1C,R2E,R3Q), (ZA,R1C,R2E,R3R),(ZA,R1C,R2F,R3A),(ZA,R1C,R2F,R3B), (ZA,R1C,R2F,R3C),(ZA,R1C,R2F,R3D),(ZA,R1C,R2F,R3E), (ZA,R1C,R2F,R3F),(ZA,R1C,R2F,R3G),(ZA,R1C,R2F,R3H), 5 (ZA,R1C,R2F,R3I),(ZA,R1C,R2F,R3J),(ZA,R1C,R2F,R3K),(
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R3E),(ZA,R1C,R2H,R3F),(ZA,R1C,R2H,R3G),(ZA,R1C,R2 H,R3H),(ZA,R1C,R2H,R3I),(ZA,R1C,R2H,R3J),(ZA,R1C,R2 H,R3K),(ZA,R1C,R2H,R3L),(ZA,R1C,R2H,R3M),(ZA,R1C, R2H,R3N),(ZA,R1C,R2H,R30),(ZA,R1C,R2H,R3P),(ZA,R1 20 C,R2H,R3Q),(ZA,R1C,R2H,R3R),(ZA,R1C,R2I,R3A),(ZA,R
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3Q),(ZA,R1D,R2B,R3R),(ZA,R1D,R2C,R3A),(ZA,R1D,R2C, R3B),(ZA,R1D,R2C,R3C),(ZA,R1D,R2C,R3D),(ZA,R1D,R2 C,R3E),(ZA,R1D,R2C,R3F),(ZA,R1D,R2C,R3G),(ZA,R1D,R 2C,R3H),(ZA,R1D,R2C,R3I),(ZA,R1D,R2C,R3J),(ZA,R1D,R 61 200843739 2C,R3K),(ZA,R1D,R2C,R3L),(ZA,R1D,R2C,R3M),(ZA,R1D, R2C,R3N),(ZA,R1D,R2C,R30),(ZA,R1D,R2C,R3P),(ZA,R1 D,R2C,R3Q),(ZA,R1D,R2C,R3R),(ZA,R1D,R2D,R3A),(ZA, R1D,R2D,R3B),(ZA,R1D,R2D,R3C),(ZA,R1D,R2D,R3D),(Z 5 A,R1D,R2D,R3E),(ZA,R1D,R2D,R3F),(ZA,R1D,R2D,R3G),(
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2E,R3D),(ZA,R1D,R2E,R3E),(ZA,R1D,R2E,R3F),(ZA,R1D, R2E,R3G),(ZA,R1D,R2E,R3H),(ZA,R1D,R2E,R3I),(ZA,R1D ,R2E,R3J),(ZA,R1D,R2E,R3K),(ZA,R1D,R2E,R3L),(ZA,R1D ,R2E,R3M),(ZA,R1D,R2E,R3N),(ZA,R1D,R2E,R30),(ZA,R1 15 D,R2E,R3P),(ZA,R1D,R2E,R3Q),(ZA,R1D,R2E,R3R),(ZA,R 1D,R2F,R3A),(ZA,R1D,R2F,R3B),(ZA,R1D,R2F,R3C),(ZA,R 1D,R2F,R3D),(ZA,R1D,R2F,R3E),(ZA,R1D,R2F,R3F),(ZA,R 1D,R2F,R3G),(ZA,R1D,R2F,R3H),(ZA,R1D,R2F,R3I),(ZA,R 1D,R2F,R3J),(ZA,R1D,R2F,R3K),(ZA,R1D,R2F,R3L),(ZA,R 20 1D,R2F,R3M),(ZA,R1D,R2F,R3N),(ZA,R1D,R2F,R30),(ZA, R1D,R2F,R3P),(ZA,R1D,R2F,R3Q),(ZA,R1D,R2F,R3R),(ZA, R1D,R2G,R3A),(ZA,R1D,R2G,R3B),(ZA,R1D,R2G,R3C),(ZA ,R1D,R2G,R3D),(ZA,R1D,R2G,R3E),(ZA,R1D,R2G,R3F),(Z A,R1D,R2G,R3G),(ZA,R1D,R2G,R3H),(ZA,R1D,R2G,R3I),( 62 200843739 ZA,R1D,R2G,R3J),(ZA,R1D,R2G,R3K),(ZA,R1D,R2G,R3L),( ZA,R1D,R2G,R3M),(ZA,R1D,R2G,R3N),(ZA,R1D,R2G,R30) ,(ZA,R1D,R2G,R3P),(ZA,R1D,R2G,R3Q),(ZA,R1D,R2G,R3R ),(ZA,R1D,R2H,R3A),(ZA,R1D,R2H,R3B),(ZA,R1D,R2H,R3 5 C),(ZA,R1D,R2H,R3D),(ZA,R1D,R2H,R3E),(ZA,R1D,R2H, R3F),(ZA,R1D,R2H,R3G),(ZA,R1D,R2H,R3H),(ZA,R1D,R2 H,R3I),(ZA,R1D,R2H,R3J),(ZA,R1D,R2H,R3K),(ZA,R1D,R 2H,R3L),(ZA,R1D,R2H,R3M),(ZA,R1D,R2H,R3N),(ZA,R1D ,R2H,R30),(ZA,R1D,R2H,R3P),(ZA,R1D,R2H,R3Q),(ZA,R1 10 D,R2H,R3R),(ZA,R1D,R2I,R3A),(ZA,R1D,R2I,R3B),(ZA,R1 D,R2I,R3C),(ZA,R1D,R2I,R3D),(ZA,R1D,R2I,R3E),(ZA,R1 D,R2I,R3F),(ZA,R1D,R2I,R3G),(ZA,R1D,R2I,R3H),(ZA,R1 D,R2I,R3I),(ZA,R1D,R2I,R3J),(ZA,R1D,R2I,R3K),(ZA,R1D, R2I,R3L),(ZA,R1D,R2I,R3M),(ZA,R1D,R2I,R3N),(ZA,R1D, 15 R2I,R30),(ZA,R1D,R2I,R3P),(ZA,R1D,R2I,R3Q),(ZA,R1D,
R2I,R3R),(ZA,R1D,R2J,R3A),(ZA,R1D,R2J,R3B),(ZA,R1D, R2J,R3C),(ZA,R1D,R2J,R3D),(ZA,R1D,R2J,R3E),(ZA,R1D, R2J,R3F),(ZA,R1D,R2J,R3G),(ZA,R1D,R2J,R3H),(ZA,R1D, R2J,R3I),(ZA,R1D,R2J,R3J),(ZA,R1D,R2J,R3K),(ZA,R1D,R 20 2J,R3L),(ZA,R1D,R2J,R3M),(ZA,R1D,R2J,R3N),(ZA,R1D,R 2J,R30),(ZA,R1D,R2J,R3P),(ZA,R1D,R2J,R3Q),(ZA,R1D,R 2J,R3R),(ZA,R1D,R2K,R3A),(ZA,R1D,R2K,R3B),(ZA,R1D, R2K,R3C),(ZA,R1D,R2K,R3D),(ZA,R1D,R2K,R3E),(ZA,R1 D,R2K,R3F),(ZA,R1D,R2K,R3G),(ZA,R1D,R2K,R3H),(ZA, 63 200843739
R1D,R2K,R3I),(ZA,R1D,R2K,R3J),(ZA,R1D,R2K,R3K),(ZA ,R1D,R2K,R3L),(ZA,R1D,R2K,R3M),(ZA,R1D,R2K,R3N),( ZA,R1D,R2K,R30),(ZA,R1D,R2K,R3P),(ZA,R1D,R2K,R3Q) ,(ZA,R1D,R2K,R3R),(ZA,R1D,R2L,R3A),(ZA,R1D,R2L,R3 5 B),(ZA,R1D,R2L,R3C),(ZA,R1D,R2L,R3D),(ZA,R1D,R2L,R 3E),(ZA,R1D,R2L,R3F),(ZA,R1D,R2L,R3G),(ZA,R1D,R2L, R3H),(ZA,R1D,R2L,R3I),(ZA,R1D,R2L,R3J),(ZA,R1D,R2L, R3K),(ZA,R1D,R2L,R3L),(ZA,R1D,R2L,R3M),(ZA,R1D,R2 L,R3N),(ZA,R1D,R2L,R30),(ZA,R1D,R2L,R3P),(ZA,R1D,R 10 2L,R3Q),(ZA,R1D,R2L,R3R),(ZA,R1D,R2M,R3A),(ZA,R1D,
R2M,R3B),(ZA,R1D,R2M,R3C),(ZA,R1D,R2M,R3D),(ZA,R 1D,R2M,R3E),(ZA,R1D,R2M,R3F),(ZA,R1D,R2M,R3G),(ZA ,R1D,R2M,R3H),(ZA,R1D,R2M,R3I),(ZA,R1D,R2M,R3J),(Z A,R1D,R2M,R3K),(ZA,R1D,R2M,R3L),(ZA,R1D,R2M,R3M) 15 ,(ZA,R1D,R2M,R3N),(ZA,R1D,R2M,R30),(ZA,R1D,R2M,R 3P),(ZA,R1D,R2M,R3Q),(ZA,R1D,R2M,R3R),(ZA,R1D,R2N ,R3A),(ZA,R1D,R2N,R3B),(ZA,R1D,R2N,R3C),(ZA,R1D,R2 N,R3D),(ZA,R1D,R2N,R3E),(ZA,R1D,R2N,R3F),(ZA,R1D,R 2N,R3G),(ZA,R1D,R2N,R3H),(ZA,R1D,R2N,R3I),(ZA,R1D, 20 R2N,R3J),(ZA,R1D,R2N,R3K),(ZA,R1D,R2N,R3L),(ZA,R1 D,R2N,R3M),(ZA,R1D,R2N,R3N),(ZA,R1D,R2N,R30),(ZA, R1D,R2N,R3P),(ZA,R1D,R2N,R3Q),(ZA,R1D,R2N,R3R),(Z A,R1E,R2A,R3A),(ZA,R1E,R2A,R3B),(ZA,R1E,R2A,R3C),( ZA,R1E,R2A,R3D),(ZA,R1E,R2A,R3E),(ZA,R1E,R2A,R3F), 64 200843739 (ZA,R1E,R2A,R3G),(ZA,R1E,R2A,R3H),(ZA,R1E,R2A,R3I) ,(ZA,R1E,R2A,R3J),(ZA,R1E,R2A,R3K),(ZA,R1E,R2A,R3L) ,(ZA,R1E,R2A,R3M),(ZA,R1E,R2A,R3N),(ZA,R1E,R2A,R3 0),(ZA,R1E,R2A,R3P),(ZA,R1E,R2A,R3Q),(ZA,R1E,R2A,R 5 3R),(ZA,R1E,R2B,R3A),(ZA,R1E,R2B,R3B),(ZA,R1E,R2B, R3C),(ZA,R1E,R2B,R3D),(ZA,R1E,R2B,R3E),(ZA,R1E,R2B ,R3F),(ZA,R1E,R2B,R3G),(ZA,R1E,R2B,R3H),(ZA,R1E,R2 B,R3I),(ZA,R1E,R2B,R3J),(ZA,R1E,R2B,R3K),(ZA,R1E,R2 B,R3L),(ZA,R1E,R2B,R3M),(ZA,R1E,R2B,R3N),(ZA,R1E,R 10 2B,R30),(ZA,R1E,R2B,R3P),(ZA,R1E,R2B,R3Q),(ZA,R1E, R2B,R3R),(ZA,R1E,R2C,R3A),(ZA,R1E,R2C,R3B),(ZA,R1E ,R2C,R3C),(ZA,R1E,R2C,R3D),(ZA,R1E,R2C,R3E),(ZA,R1 E,R2C,R3F),(ZA,R1E,R2C,R3G),(ZA,R1E,R2C,R3H),(ZA,R 1E,R2C,R3I),(ZA,R1E,R2C,R3J),(ZA,R1E,R2C,R3K),(ZA,R 15 1E,R2C,R3L),(ZA,R1E,R2C,R3M),(ZA,R1E,R2C,R3N),(ZA, R1E,R2C,R30),(ZA,R1E,R2C,R3P),(ZA,R1E,R2C,R3Q),(ZA ,R1E,R2C,R3R),(ZA,R1E,R2D,R3A),(ZA,R1E,R2D,R3B),(Z A,R1E,R2D,R3C),(ZA,R1E,R2D,R3D),(ZA,R1E,R2D,R3E),( ZA,R1E,R2D,R3F),(ZA,R1E,R2D,R3G),(ZA,R1E,R2D,R3H), 20 (ZA,R1E,R2D,R3I),(ZA,R1E,R2D,R3J),(ZA,R1E,R2D,R3K),
(ZA,R1E,R2D,R3L),(ZA,R1E,R2D,R3M),(ZA,R1E,R2D,R3N ),(ZA,R1E,R2D,R30),(ZA,R1E,R2D,R3P),(ZA,R1E,R2D,R3 Q),(ZA,R1E,R2D,R3R),(ZA,R1E,R2E,R3A),(ZA,R1E,R2E,R 3B),(ZA,R1E,R2E,R3C),(ZA,R1E,R2E,R3D),(ZA,R1E,R2E,R 65 200843739
3E),(ZA,R1E,R2E,R3F),(ZA,R1E,R2E,R3G),(ZA,R1E,R2E,R 3H),(ZA,R1E,R2E,R3I),(ZA,R1E,R2E,R3J),(ZA,R1E,R2E,R3 K),(ZA,R1E,R2E,R3L),(ZA,R1E,R2E,R3M),(ZA,R1E,R2E,R 3N),(ZA,R1E,R2E,R30),(ZA,R1E,R2E,R3P),(ZA,R1E,R2E,R 5 3Q),(ZA,R1E,R2E,R3R),(ZA,R1E,R2F,R3A),(ZA,R1E,R2F,R 3B),(ZA,R1E,R2F,R3C),(ZA,R1E,R2F,R3D),(ZA,R1E,R2F,R 3E),(ZA,R1E,R2F,R3F),(ZA,R1E,R2F,R3G),(ZA,R1E,R2F,R3 H),(ZA,R1E,R2F,R3I),(ZA,R1E,R2F,R3J),(ZA,R1E,R2F,R3K ),(ZA,R1E,R2F,R3L),(ZA,R1E,R2F,R3M),(ZA,R1E,R2F,R3N 10 ),(ZA,R1E,R2F,R30),(ZA,R1E,R2F,R3P),(ZA,R1E,R2F,R3Q) ,(ZA,R1E,R2F,R3R),(ZA,R1E,R2G,R3A),(ZA,R1E,R2G,R3B) ,(ZA,R1E,R2G,R3C),(ZA,R1E,R2G,R3D),(ZA,R1E,R2G,R3E) ,(ZA,R1E,R2G,R3F),(ZA,R1E,R2G,R3G),(ZA,R1E,R2G,R3H) ,(ZA,R1E,R2G,R3I),(ZA,R1E,R2G,R3J),(ZA,R1E,R2G,R3K), 15 (ZA,R1E,R2G,R3L),(ZA,R1E,R2G,R3M),(ZA,R1E,R2G,R3N)
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3K),(ZA,R1E,R2H,R3L),(ZA,R1E,R2H,R3M),(ZA,R1E,R2H, R3N),(ZA,R1E,R2H,R30),(ZA,R1E,R2H,R3P),(ZA,R1E,R2H ,R3Q),(ZA,R1E,R2H,R3R),(ZA,R1E,R2I,R3A),(ZA,R1E,R2I, R3B),(ZA,R1E,R2I,R3C),(ZA,R1E,R2I,R3D),(ZA,R1E,R2I,R 66 200843739 3E),(ZA,R1E,R2I,R3F),(ZA,R1E,R2I,R3G),(ZA,R1E,R2I,R3 H),(ZA,R1E,R2I,R3I),(ZA,R1E,R2I,R3J),(ZA,R1E,R2I,R3K) ,(ZA,R1E,R2I,R3L),(ZA,R1E,R2I,R3M),(ZA,R1E,R2I,R3N), (ZA,R1E,R2I,R30),(ZA,R1E,R2I,R3P),(ZA,R1E,R2I,R3Q),(
5 ZA,R1E,R2I,R3R),(ZA,R1E,R2J,R3A),(ZA,R1E,R2J,R3B),(Z
A,R1E,R2J,R3C),(ZA,R1E,R2J,R3D),(ZA,R1E,R2J,R3E),(Z A,R1E,R2J,R3F),(ZA,R1E,R2J,R3G),(ZA,R1E,R2J,R3H),(Z A,R1E,R2J,R3I),(ZA,R1E,R2J,R3J),(ZA,R1E,R2J,R3K),(ZA, R1E,R2J,R3L),(ZA,R1E,R2J,R3M),(ZA,R1E,R2J,R3N),(ZA, 10 R1E,R2J,R30),(ZA,R1E,R2J,R3P),(ZA,R1E,R2J,R3Q),(ZA,R
1E,R2J,R3R),(ZA,R1E,R2K,R3A),(ZA,R1E,R2K,R3B),(ZA,R 1E,R2K,R3C),(ZA,R1E,R2K,R3D),(ZA,R1E,R2K,R3E),(ZA, R1E,R2K,R3F),(ZA,R1E,R2K,R3G),(ZA,R1E,R2K,R3H),(ZA ,R1E,R2K,R3I),(ZA,R1E,R2K,R3J),(ZA,R1E,R2K,R3K),(ZA 15 ,R1E,R2K,R3L),(ZA,R1E,R2K,R3M),(ZA,R1E,R2K,R3N),(Z A,R1E,R2K,R30),(ZA,R1E,R2K,R3P),(ZA,R1E,R2K,R3Q),( ZA,R1E,R2K,R3R),(ZA,R1E,R2L,R3A),(ZA,R1E,R2L,R3B), (ZA,R1E,R2L,R3C),(ZA,R1E,R2L,R3D),(ZA,R1E,R2L,R3E), (ZA,R1E,R2L,R3F),(ZA,R1E,R2L,R3G),(ZA,R1E,R2L,R3H), 20 (ZA,R1E,R2L,R3I),(ZA,R1E,R2L,R3J),(ZA,R1E,R2L,R3K),(
ZA,R1E,R2L,R3L),(ZA,R1E,R2L,R3M),(ZA,R1E,R2L,R3N), (ZA,R1E,R2L,R30),(ZA,R1E,R2L,R3P),(ZA,R1E,R2L,R3Q), (ZA,R1E,R2L,R3R),(ZA,R1E,R2M,R3A),(ZA,R1E,R2M,R3B ),(ZA,R1E,R2M,R3C),(ZA,R1E,R2M,R3D),(ZA,R1E,R2M,R 67 200843739
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(ZA,R1F,R2A,R3N),(ZA,R1F,R2A,R30),(ZA,R1F,R2A,R3P), (ZA,R1F,R2A,R3Q),(ZA,R1F,R2A,R3R),(ZA,R1F,R2B,R3A), (ZA,R1F,R2B,R3B),(ZA,R1F,R2B,R3C),(ZA,R1F,R2B,R3D), (ZA,R1F,R2B,R3E),(ZA,R1F,R2B,R3F),(ZA,R1F,R2B,R3G),( 20 ZA,R1F,R2B,R3H),(ZA,R1F,R2B,R3I),(ZA,R1F,R2B,R3J),(Z
A,R1F,R2B,R3K),(ZA,R1F,R2B,R3L),(ZA,R1F,R2B,R3M),(Z A,R1F,R2B,R3N),(ZA,R1F,R2B,R30),(ZA,R1F,R2B,R3P),(Z A,R1F,R2B,R3Q),(ZA,R1F,R2B,R3R),(ZA,R1F,R2C,R3A),(Z A,R1F,R2C,R3B),(ZA,R1F,R2C,R3C),(ZA,R1F,R2C,R3D),(Z 68 200843739
A,R1F,R2C,R3E),(ZA,R1F,R2C,R3F),(ZA,R1F,R2C,R3G),(Z A,R1F,R2C,R3H),(ZA,R1F,R2C,R3I),(ZA,R1F,R2C,R3J),(ZA ,R1F,R2C,R3K),(ZA,R1F,R2C,R3L),(ZA,R1F,R2C,R3M),(ZA ,R1F,R2C,R3N),(ZA,R1F,R2C,R30),(ZA,R1F,R2C,R3P),(ZA 5 ,R1F,R2C,R3Q),(ZA,R1F,R2C,R3R),(ZA,R1F,R2D,R3A),(ZA
,R1F,R2D,R3B),(ZA,R1F,R2D,R3C),(ZA,R1F,R2D,R3D),(ZA ,R1F,R2D,R3E),(ZA,R1F,R2D,R3F),(ZA,R1F,R2D,R3G),(ZA ,R1F,R2D,R3H),(ZA,R1F,R2D,R3I),(ZA,R1F,R2D,R3J),(ZA, R1F,R2D,R3K),(ZA,R1F,R2D,R3L),(ZA,R1F,R2D,R3M),(ZA 10 ,R1F,R2D,R3N),(ZA,R1F,R2D,R30),(ZA,R1F,R2D,R3P),(ZA
,R1F,R2D,R3Q),(ZA,R1F,R2D,R3R),(ZA,R1F,R2E,R3A),(ZA ,R1F,R2E,R3B),(ZA,R1F,R2E,R3C),(ZA,R1F,R2E,R3D),(ZA, R1F,R2E,R3E),(ZA,R1F,R2E,R3F),(ZA,R1F,R2E,R3G),(ZA, R1F,R2E,R3H),(ZA,R1F,R2E,R3I),(ZA,R1F,R2E,R3J),(ZA,R 15 1F,R2E,R3K),(ZA,R1F,R2E,R3L),(ZA,R1F,R2E,R3M),(ZA,R 1F,R2E,R3N),(ZA,R1F,R2E,R30),(ZA,R1F,R2E,R3P),(ZA,R 1F,R2E,R3Q),(ZA,R1F,R2E,R3R),(ZA,R1F,R2F,R3A),(ZA,R 1F,R2F,R3B),(ZA,R1F,R2F,R3C),(ZA,R1F,R2F,R3D),(ZA,R1 F,R2F,R3E),(ZA,R1F,R2F,R3F),(ZA,R1F,R2F,R3G),(ZA,R1F, 20 R2F,R3H),(ZA,R1F,R2F,R3I),(ZA,R1F,R2F,R3J),(ZA,R1F,R2 F,R3K),(ZA,R1F,R2F,R3L),(ZA,R1F,R2F,R3M),(ZA,R1F,R2F ,R3N),(ZA,R1F,R2F,R30),(ZA,R1F,R2F,R3P),(ZA,R1F,R2F, R3Q),(ZA,R1F,R2F,R3R),(ZA,R1F,R2G,R3A),(ZA,R1F,R2G, R3B),(ZA,R1F,R2G,R3C),(ZA,R1F,R2G,R3D),(ZA,R1F,R2G, 69 200843739
R3E),(ZA,R1F,R2G,R3F),(ZA,R1F,R2G,R3G),(ZA,R1F,R2G, R3H),(ZA,R1F,R2G,R3I),(ZA,R1F,R2G,R3J),(ZA,R1F,R2G,R 3K),(ZA,R1F,R2G,R3L),(ZA,R1F,R2G,R3M),(ZA,R1F,R2G,R 3N),(ZA,R1F,R2G,R30),(ZA,R1F,R2G,R3P),(ZA,R1F,R2G,R 5 3Q),(ZA,R1F,R2G,R3R),(ZA,R1F,R2H,R3A),(ZA,R1F,R2H,R
3B),(ZA,R1F,R2H,R3C),(ZA,R1F,R2H,R3D),(ZA,R1F,R2H,R 3E),(ZA,R1F,R2H,R3F),(ZA,R1F,R2H,R3G),(ZA,R1F,R2H,R 3H),(ZA,R1F,R2H,R3I),(ZA,R1F,R2H,R3J),(ZA,R1F,R2H,R3 K),(ZA,R1F,R2H,R3L),(ZA,R1F,R2H,R3M),(ZA,R1F,R2H,R 10 3N),(ZA,R1F,R2H,R30),(ZA,R1F,R2H,R3P),(ZA,R1F,R2H,R
3Q),(ZA,R1F,R2H,R3R),(ZA,R1F,R2I,R3A),(ZA,R1F,R2I,R3 B),(ZA,R1F,R2I,R3C),(ZA,R1F,R2I,R3D),(ZA,R1F,R2I,R3E) ,(ZA,R1F,R2I,R3F),(ZA,R1F,R2I,R3G),(ZA,R1F,R2I,R3H),( ZA,R1F,R2I,R3I),(ZA,R1F,R2I,R3J),(ZA,R1F,R2I,R3K),(ZA, 15 R1F,R2I,R3L),(ZA,R1F,R2I,R3M),(ZA,R1F,R2I,R3N),(ZA,R 1F,R2I,R30),(ZA,R1F,R2I,R3P),(ZA,R1F,R2I,R3Q),(ZA,R1F ,R2I,R3R),(ZA,R1F,R2J,R3A),(ZA,R1F,R2J,R3B),(ZA,R1F,R 2J,R3C),(ZA,R1F,R2J,R3D),(ZA,R1F,R2J,R3E),(ZA,R1F,R2J ,R3F),(ZA,R1F,R2J,R3G),(ZA,R1F,R2J,R3H),(ZA,R1F,R2J,R 20 3I),(ZA,R1F,R2J,R3J),(ZA,R1F,R2J,R3K),(ZA,R1F,R2J,R3L)
,(ZA,R1F,R2J,R3M),(ZA,R1F,R2J,R3N),(ZA,R1F,R2J,R30),( ZA,R1F,R2J,R3P),(ZA,R1F,R2J,R3Q),(ZA,R1F,R2J,R3R),(Z A,R1F,R2K,R3A),(ZA,R1F,R2K,R3B),(ZA,R1F,R2K,R3C),(Z A,R1F,R2K,R3D),(ZA,R1F,R2K,R3E),(ZA,R1F,R2K,R3F),(Z 70 200843739 A,R1F,R2K,R3G),(ZA,R1F,R2K,R3H),(ZA,R1F,R2K,R3I),(Z A,R1F,R2K,R3J),(ZA,R1F,R2K,R3K),(ZA,R1F,R2K,R3L),(Z A,R1F,R2K,R3M),(ZA,R1F,R2K,R3N),(ZA,R1F,R2K,R30),( ZA,R1F,R2K,R3P),(ZA,R1F,R2K,R3Q),(ZA,R1F,R2K,R3R),( 5 ZA,R1F,R2L,R3A),(ZA,R1F,R2L,R3B),(ZA,R1F,R2L,R3C),(
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L),(ZA,R1F,R2N,R3M),(ZA,R1F,R2N,R3N),(ZA,R1F,R2N,R 30),(ZA,R1F,R2N,R3P),(ZA,R1F,R2N,R3Q),(ZA,R1F,R2N,R 3R),(ZA,R1G,R2A,R3A),(ZA,R1G,R2A,R3B),(ZA,R1G,R2A, R3C),(ZA,R1G,R2A,R3D),(ZA,R1G,R2A,R3E),(ZA,R1G,R2A 71 200843739 ,R3F),(ZA,R1G,R2A,R3G),(ZA,R1G,R2A,R3H),(ZA,R1G,R2 A,R3I),(ZA,R1G,R2A,R3J),(ZA,R1G,R2A,R3K),(ZA,R1G,R2
A,R3L),(ZA,R1G,R2A,R3M),(ZA,R1G,R2A,R3N),(ZA,R1G,R 2A,R30),(ZA,R1G,R2A,R3P),(ZA,R1G,R2A,R3Q),(ZA,R1G,
5 R2A,R3R),(ZA,R1G,R2B,R3A),(ZA,R1G,R2B,R3B),(ZA,R1G
,R2B,R3C),(ZA,R1G,R2B,R3D),(ZA,R1G,R2B,R3E),(ZA,R1 G,R2B,R3F),(ZA,R1G,R2B,R3G),(ZA,R1G,R2B,R3H),(ZA,R 1G,R2B,R3I),(ZA,R1G,R2B,R3J),(ZA,R1G,R2B,R3K),(ZA,R 1G,R2B,R3L),(ZA,R1G,R2B,R3M),(ZA,R1G,R2B,R3N),(ZA, 10 R1G,R2B,R30),(ZA,R1G,R2B,R3P),(ZA,R1G,R2B,R3Q),(ZA ,R1G,R2B,R3R),(ZA,R1G,R2C,R3A),(ZA,R1G,R2C,R3B),(Z A,R1G,R2C,R3C),(ZA,R1G,R2C,R3D),(ZA,R1G,R2C,R3E),( ZA,R1G,R2C,R3F),(ZA,R1G,R2C,R3G),(ZA,R1G,R2C,R3H), (ZA,R1G,R2C,R3I),(ZA,R1G,R2C,R3J),(ZA,R1G,R2C,R3K),( 15 ZA,R1G,R2C,R3L),(ZA,R1G,R2C,R3M),(ZA,R1G,R2C,R3N),
(ZA,R1G,R2C,R30),(ZA,R1G,R2C,R3P),(ZA,R1G,R2C,R3Q) ,(ZA,R1G,R2C,R3R),(ZA,R1G,R2D,R3A),(ZA,R1G,R2D,R3B ),(ZA,R1G,R2D,R3C),(ZA,R1G,R2D,R3D),(ZA,R1G,R2D,R3 E),(ZA,R1G,R2D,R3F),(ZA,R1G,R2D,R3G),(ZA,R1G,R2D,R 20 3H),(ZA,R1G,R2D,R3I),(ZA,R1G,R2D,R3J),(ZA,R1G,R2D,R 3K),(ZA,R1G,R2D,R3L),(ZA,R1G,R2D,R3M),(ZA,R1G,R2D, R3N),(ZA,R1G,R2D,R30),(ZA,R1G,R2D,R3P),(ZA,R1G,R2D ,R3Q),(ZA,R1G,R2D,R3R),(ZA,R1G,R2E,R3A),(ZA,R1G,R2 E,R3B),(ZA,R1G,R2E,R3C),(ZA,R1G,R2E,R3D),(ZA,R1G,R2 72 200843739
E,R3E),(ZA,R1G,R2E,R3F),(ZA,R1G,R2E,R3G),(ZA,R1G,R2 E,R3H),(ZA,R1G,R2E,R3I),(ZA,R1G,R2E,R3J),(ZA,R1G,R2 E,R3K),(ZA,R1G,R2E,R3L),(ZA,R1G,R2E,R3M),(ZA,R1G,R 2E,R3N),(ZA,R1G,R2E,R30),(ZA,R1G,R2E,R3P),(ZA,R1G,R 5 2E,R3Q),(ZA,R1G,R2E,R3R),(ZA,R1G,R2F,R3A),(ZA,R1G,R 2F,R3B),(ZA,R1G,R2F,R3C),(ZA,R1G,R2F,R3D),(ZA,R1G,R 2F,R3E),(ZA,R1G,R2F,R3F),(ZA,R1G,R2F,R3G),(ZA,R1G,R2 F,R3H),(ZA,R1G,R2F,R3I),(ZA,R1G,R2F,R3J),(ZA,R1G,R2F, R3K),(ZA,R1G,R2F,R3L),(ZA,R1G,R2F,R3M),(ZA,R1G,R2F, 10 R3N),(ZA,R1G,R2F,R30),(ZA,R1G,R2F,R3P),(ZA,R1G,R2F,
R3Q),(ZA,R1G,R2F,R3R),(ZA,R1G,R2G,R3A),(ZA,R1G,R2G, R3B),(ZA,R1G,R2G,R3C),(ZA,R1G,R2G,R3D),(ZA,R1G,R2G, R3E),(ZA,R1G,R2G,R3F),(ZA,R1G,R2G,R3G),(ZA,R1G,R2G, R3H),(ZA,R1G,R2G,R3I),(ZA,R1G,R2G,R3J),(ZA,R1G,R2G, 15 R3K),(ZA,R1G,R2G,R3L),(ZA,R1G,R2G,R3M),(ZA,R1G,R2G ,R3N),(ZA,R1G,R2G,R30),(ZA,R1G,R2G,R3P),(ZA,R1G,R2G ,R3Q),(ZA,R1G,R2G,R3R),(ZA,R1G,R2H,R3A),(ZA,R1G,R2 H,R3B),(ZA,R1G,R2H,R3C),(ZA,R1G,R2H,R3D),(ZA,R1G,R 2H,R3E),(ZA,R1G,R2H,R3F),(ZA,R1G,R2H,R3G),(ZA,R1G, 20 R2H,R3H),(ZA,R1G,R2H,R3I),(ZA,R1G,R2H,R3J),(ZA,R1G, R2H,R3K),(ZA,R1G,R2H,R3L),(ZA,R1G,R2H,R3M),(ZA,R1 G,R2H,R3N),(ZA,R1G,R2H,R30),(ZA,R1G,R2H,R3P),(ZA,R 1G,R2H,R3Q),(ZA,R1G,R2H,R3R),(ZA,R1G,R2I,R3A),(ZA,R 1G,R2I,R3B),(ZA,R1G,R2I,R3C),(ZA,R1G,R2I,R3D),(ZA,R1 73 200843739 G,R2I,R3E),(ZA,R1G,R2I,R3F),(ZA,R1G,R2I,R3G),(ZA,R1G, R2I,R3H),(ZA,R1G,R2I,R3I),(ZA,R1G,R2I,R3J),(ZA,R1G,R2 I,R3K),(ZA,R1G,R2I,R3L),(ZA,R1G,R2I,R3M),(ZA,R1G,R2I, R3N),(ZA,R1G,R2I,R30),(ZA,R1G,R2I,R3P),(ZA,R1G,R2I,R 5 3Q),(ZA,R1G,R2I,R3R),(ZA,R1G,R2J,R3A),(ZA,R1G,R2J,R3
B),(ZA,R1G,R2J,R3C),(ZA,R1G,R2J,R3D),(ZA,R1G,R2J,R3E ),(ZA,R1G,R2J,R3F),(ZA,R1G,R2J,R3G),(ZA,R1G,R2J,R3H), (ZA,R1G,R2J,R3I),(ZA,R1G,R2J,R3J),(ZA,R1G,R2J,R3K),(Z A,R1G,R2J,R3L),(ZA,R1G,R2J,R3M),(ZA,R1G,R2J,R3N),(Z 10 A,R1G,R2J,R30),(ZA,R1G,R2J,R3P),(ZA,R1G,R2J,R3Q),(Z
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N),(ZA,R1P,R2A,R30),(ZA,R1P,R2A,R3P),(ZA,R1P,R2A,R3 Q),(ZA,R1P,R2A,R3R),(ZA,R1P,R2B,R3A),(ZA,R1P,R2B,R3 B),(ZA,R1P,R2B,R3C),(ZA,R1P,R2B,R3D),(ZA,R1P,R2B,R3 E),(ZA,R1P,R2B,R3F),(ZA,R1P,R2B,R3G),(ZA,R1P,R2B,R3 5 H),(ZA,R1P,R2B,R3I),(ZA,R1P,R2B,R3J),(ZA,R1P,R2B,R3K ),(ZA,R1P,R2B,R3L),(ZA,R1P,R2B,R3M),(ZA,R1P,R2B,R3N ),(ZA,R1P,R2B,R30),(ZA,R1P,R2B,R3P),(ZA,R1P,R2B,R3Q) ,(ZA,R1P,R2B,R3R),(ZA,R1P,R2C,R3A),(ZA,R1P,R2C,R3B), (ZA,R1P,R2C,R3C),(ZA,R1P,R2C,R3D),(ZA,R1P,R2C,R3E),( 10 ZA,R1P,R2C,R3F),(ZA,R1P,R2C,R3G),(ZA,R1P,R2C,R3H),(
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R1P,R2E,R3C),(ZA,R1P,R2E,R3D),(ZA,R1P,R2E,R3E),(ZA, R1P,R2E,R3F),(ZA,R1P,R2E,R3G),(ZA,R1P,R2E,R3H),(ZA, R1P,R2E,R3I),(ZA,R1P,R2E,R3J),(ZA,R1P,R2E,R3K),(ZA,R 1P,R2E,R3L),(ZA,R1P,R2E,R3M),(ZA,R1P,R2E,R3N),(ZA,R 104 200843739 1P,R2E,R30),(ZA,R1P,R2E,R3P),(ZA,R1P,R2E,R3Q),(ZA,R1 P,R2E,R3R),(ZA,R1P,R2F,R3A),(ZA,R1P,R2F,R3B),(ZA,R1P ,R2F,R3C),(ZA,R1P,R2F,R3D),(ZA,R1P,R2F,R3E),(ZA,R1P, R2F,R3F),(ZA,R1P,R2F,R3G),(ZA,R1P,R2F,R3H),(ZA,R1P,R 5 2F,R3I),(ZA,R1P,R2F,R3J),(ZA,R1P,R2F,R3K),(ZA,R1P,R2F,
R3L),(ZA,R1P,R2F,R3M),(ZA,R1P,R2F,R3N),(ZA,R1P,R2F,R 30),(ZA,R1P,R2F,R3P),(ZA,R1P,R2F,R3Q),(ZA,R1P,R2F,R3 R),(ZA,R1P,R2G,R3A),(ZA,R1P,R2G,R3B),(ZA,R1P,R2G,R3 C),(ZA,R1P,R2G,R3D),(ZA,R1P,R2G,R3E),(ZA,R1P,R2G,R3 10 F),(ZA,R1P,R2G,R3G),(ZA,R1P,R2G,R3H),(ZA,R1P,R2G,R3I ),(ZA,R1P,R2G,R3J),(ZA,R1P,R2G,R3K),(ZA,R1P,R2G,R3L), (ZA,R1P,R2G,R3M),(ZA,R1P,R2G,R3N),(ZA,R1P,R2G,R30), (ZA,R1P,R2G,R3P),(ZA,R1P,R2G,R3Q),(ZA,R1P,R2G,R3R),( ZA,R1P,R2H,R3A),(ZA,R1P,R2H,R3B),(ZA,R1P,R2H,R3C),( 15 ZA,R1P,R2H,R3D),(ZA,R1P,R2H,R3E),(ZA,R1P,R2H,R3F),(
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A,R1P,R2I,R3D),(ZA,R1P,R2I,R3E),(ZA,R1P,R2I,R3F),(ZA, R1P,R2I,R3G),(ZA,R1P,R2I,R3H),(ZA,R1P,R2I,R3I),(ZA,R1 P,R2I,R3J),(ZA,R1P,R2I,R3K),(ZA,R1P,R2I,R3L),(ZA,R1P,R 2I,R3M),(ZA,R1P,R2I,R3N),(ZA,R1P,R2I,R30),(ZA,R1P,R2I 105 200843739
,R3P),(ZA,R1P,R2I,R3Q),(ZA,R1P,R2I,R3R),(ZA,R1P,R2J,R 3A),(ZA,R1P,R2J,R3B),(ZA,R1P,R2J,R3C),(ZA,R1P,R2J,R3 D),(ZA,R1P,R2J,R3E),(ZA,R1P,R2J,R3F),(ZA,R1P,R2J,R3G) ,(ZA,R1P,R2J,R3H),(ZA,R1P,R2J,R3I),(ZA,R1P,R2J,R3J),(Z 5 A,R1P,R2J,R3K),(ZA,R1P,R2J,R3L),(ZA,R1P,R2J,R3M),(ZA
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R2L,R3H),(ZA,R1P,R2L,R3I),(ZA,R1P,R2L,R3J),(ZA,R1P,R 2L,R3K),(ZA,R1P,R2L,R3L),(ZA,R1P,R2L,R3M),(ZA,R1P,R 2L,R3N),(ZA,R1P,R2L,R30),(ZA,R1P,R2L,R3P),(ZA,R1P,R2 L,R3Q),(ZA,R1P,R2L,R3R),(ZA,R1P,R2M,R3A),(ZA,R1P,R2 20 M,R3B),(ZA,R1P,R2M,R3C),(ZA,R1P,R2M,R3D),(ZA,R1P,R
2M,R3E),(ZA,R1P,R2M,R3F),(ZA,R1P,R2M,R3G),(ZA,R1P, R2M,R3H),(ZA,R1P,R2M,R3I),(ZA,R1P,R2M,R3J),(ZA,R1P, R2M,R3K),(ZA,R1P,R2M,R3L),(ZA,R1P,R2M,R3M),(ZA,R1 P,R2M,R3N),(ZA,R1P,R2M,R30),(ZA,R1P,R2M,R3P),(ZA,R 106 200843739
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0),(ZA,R1Q,R2C,R3P),(ZA,R1Q,R2C,R3Q),(ZA,R1Q,R2C,R 3R),(ZA,R1Q,R2D,R3A),(ZA,R1Q,R2D,R3B),(ZA,R1Q,R2D, R3C),(ZA,R1Q,R2D,R3D),(ZA,R1Q,R2D,R3E),(ZA,R1Q,R2 D,R3F),(ZA,R1Q,R2D,R3G),(ZA,R1Q,R2D,R3H),(ZA,R1Q,
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S,R2A,R3P),(ZA,R1S,R2A,R3Q),(ZA,R1S,R2A,R3R),(ZA,R 1S,R2B,R3A),(ZA,R1S,R2B,R3B),(ZA,R1S,R2B,R3C),(ZA,R 1S,R2B,R3D),(ZA,R1S,R2B,R3E),(ZA,R1S,R2B,R3F),(ZA,R 1S,R2B,R3G),(ZA,R1S,R2B,R3H),(ZA,R1S,R2B,IGI),(ZA,R 20 1S,R2B,R3J),(ZA,R1S,R2B,R3K),(ZA,R1S,R2B,R3L),(ZA,R 1S,R2B,R3M),(ZA,R1S,R2B,R3N),(ZA,R1S,R2B,R30),(ZA, R1S,R2B,R3P),(ZA,R1S,R2B,R3Q),(ZA,R1S,R2B,R3R),(ZA, R1S,R2C,R3A),(ZA,R1S,R2C,R3B),(ZA,R1S,R2C,R3C),(ZA, R1S,R2C,R3D),(ZA,R1S,R2C,R3E),(ZA,R1S,R2C,R3F),(ZA, 114 200843739
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R3C),(ZB,R1D,R2B,R3D),(ZB,R1D,R2B,R3E),(ZB,R1D,R2B ,R3F),(ZB,R1D,R2B,R3G),(ZB,R1D,R2B,R3H),(ZB,R1D,R2 B,R3I),(ZB,R1D,R2B,R3J),(ZB,R1D,R2B,R3K),(ZB,R1D,R2 B,R3L),(ZB,R1D,R2B,R3M),(ZB,R1D,R2B,R3N),(ZB,R1D,R 128 200843739 2B,R30),(ZB,R1D,R2B,R3P),(ZB,R1D,R2B,R3Q),(ZB,R1D, R2B,R3R),(ZB,R1D,R2C,R3A),(ZB,R1D,R2C,R3B),(ZB,R1 D,R2C,R3C),(ZB,R1D,R2C,R3D),(ZB,R1D,R2C,R3E),(ZB,R 1D,R2C,R3F),(ZB,R1D,R2C,R3G),(ZB,R1D,R2C,R3H),(ZB, 5 R1D,R2C,R3I),(ZB,R1D,R2C,R3J),(ZB,R1D,R2C,R3K),(ZB,
R1D,R2C,R3L),(ZB,R1D,R2C,R3M),(ZB,R1D,R2C,R3N),(Z B,R1D,R2C,R30),(ZB,R1D,R2C,R3P),(ZB,R1D,R2C,R3Q),( ZB,R1D,R2C,R3R),(ZB,R1D,R2D,R3A),(ZB,R1D,R2D,R3B) ,(ZB,R1D,R2D,R3C),(ZB,R1D,R2D,R3D),(ZB,R1D,R2D,R3 10 E),(ZB,R1D,R2D,R3F),(ZB,R1D,R2D,R3G),(ZB,R1D,R2D,R 3H),(ZB,R1D,R2D,RM),(ZB,R1D,R2D,R3J),(ZB,R1D,R2D,R 3K),(ZB,R1D,R2D,R3L),(ZB,R1D,R2D,R3M),(ZB,R1D,R2D, R3N),(ZB,R1D,R2D,R30),(ZB,R1D,R2D,R3P),(ZB,R1D,R2 D,R3Q),(ZB,R1D,R2D,R3R),(ZB,R1D,R2E,R3A),(ZB,R1D,R 15 2E,R3B),(ZB,R1D,R2E,R3C),(ZB,R1D,R2E,R3D),(ZB,R1D, R2E,R3E),(ZB,R1D,R2E,R3F),(ZB,R1D,R2E,R3G),(ZB,R1D, R2E,R3H),(ZB,R1D,R2E,R3I),(ZB,R1D,R2E,R3J),(ZB,R1D, R2E,R3K),(ZB,R1D,R2E,R3L),(ZB,R1D,R2E,R3M),(ZB,R1 D,R2E,R3N),(ZB,R1D,R2E,R30),(ZB,R1D,R2E,R3P),(ZB,R 20 1D,R2E,R3Q),(ZB,R1D,R2E,R3R),(ZB,R1D,R2F,R3A),(ZB,
R1D,R2F,R3B),(ZB,R1D,R2F,R3C),(ZB,R1D,R2F,R3D),(ZB, R1D,R2F,R3E),(ZB,R1D,R2F,R3F),(ZB,R1D,R2F,R3G),(ZB, R1D,R2F,R3H),(ZB,R1D,R2F,R3I),(ZB,R1D,R2F,R3J),(ZB,R 1D,R2F,R3K),(ZB,R1D,R2F,R3L),(ZB,R1D,R2F,R3M),(ZB,R 129 200843739 1D,R2F,R3N),(ZB,R1D,R2F,R30),(ZB,R1D,R2F,R3P),(ZB,R 1D,R2F,R3Q),(ZB,R1D,R2F,R3R),(ZB,R1D,R2G,R3A),(ZB,R 1D,R2G,R3B),(ZB,R1D,R2G,R3C),(ZB,R1D,R2G,R3D),(ZB, R1D,R2G,R3E),(ZB,R1D,R2G,R3F),(ZB,R1D,R2G,R3G),(ZB, 5 R1D,R2G,R3H),(ZB,R1D,R2G,R3I),(ZB,R1D,R2G,R3J),(ZB,
R1D,R2G,R3K),(ZB,R1D,R2G,R3L),(ZB,R1D,R2G,R3M),(ZB ,R1D,R2G,R3N),(ZB,R1D,R2G,R30),(ZB,R1D,R2G,R3P),(Z B,R1D,R2G,R3Q),(ZB,R1D,R2G,R3R),(ZB,R1D,R2H,R3A),( ZB,R1D,R2H,R3B),(ZB,R1D,R2H,R3C),(ZB,R1D,R2H,R3D) 10 ,(ZB,R1D,R2H,R3E),(ZB,R1D,R2H,R3F),(ZB,R1D,R2H,R3G ),(ZB,R1D,R2H,R3H),(ZB,R1D,R2H,R3I),(ZB,R1D,R2H,R3J ),(ZB,R1D,R2H,R3K),(ZB,R1D,R2H,R3L),(ZB,R1D,R2H,R3 M),(ZB,R1D,R2H,R3N),(ZB,R1D,R2H,R30),(ZB,R1D,R2H, R3P),(ZB,R1D,R2H,R3Q),(ZB,R1D,R2H,R3R),(ZB,R1D,R2I, 15 R3A),(ZB,R1D,R2I,R3B),(ZB,R1D,R2I,R3C),(ZB,R1D,R2I, R3D),(ZB,R1D,R2I,R3E),(ZB,R1D,R2I,R3F),(ZB,R1D,R2I,R 3G),(ZB,R1D,R2I,R3H),(ZB,R1D,R2I,R3I),(ZB,R1D,R2I,R3 J),(ZB,R1D,R2I,R3K),(ZB,R1D,R2I,R3L),(ZB,R1D,R2I,R3M ),(ZB,R1D,R2I,R3N),(ZB,R1D,R2I,R30),(ZB,R1D,R2I,R3P), 20 (ZB,R1D,R2I,R3Q),(ZB,R1D,R2I,R3R),(ZB,R1D,R2J,R3A),( ZB,R1D,R2J,R3B),(ZB,R1D,R2J,R3C),(ZB,R1D,R2J,R3D),( ZB,R1D,R2J,R3E),(ZB,R1D,R2J,R3F),(ZB,R1D,R2J,R3G),(Z B,R1D,R2J,R3H),(ZB,R1D,R2J,R3I),(ZB,R1D,R2J,R3J),(ZB, R1D,R2J,R3K),(ZB,R1D,R2J,R3L),(ZB,R1D,R2J,R3M),(ZB, 130 200843739 R1D,R2J,R3N),(ZB,R1D,R2J,R30),(ZB,R1D,R2J,R3P),(ZB, R1D,R2J,R3Q),(ZB,R1D,R2J,R3R),(ZB,R1D,R2K,R3A),(ZB, R1D,R2K,R3B),(ZB,R1D,R2K,R3C),(ZB,R1D,R2K,R3D),(Z B,R1D,R2K,R3E),(ZB,R1D,R2K,R3F),(ZB,R1D,R2K,R3G),( 5 ZB,R1D,R2K,R3H),(ZB,R1D,R2K,R3I),(ZB,R1D,R2K,R3J),( ZB,R1D,R2K,R3K),(ZB,R1D,R2K,R3L),(ZB,R1D,R2K,R3M) ,(ZB,R1D,R2K,R3N),(ZB,R1D,R2K,R30),(ZB,R1D,R2K,R3 P),(ZB,R1D,R2K,R3Q),(ZB,R1D,R2K,R3R),(ZB,R1D,R2L,R 3A),(ZB,R1D,R2L,R3B),(ZB,R1D,R2L,R3C),(ZB,R1D,R2L, 10 R3D),(ZB,R1D,R2L,R3E),(ZB,R1D,R2L,R3F),(ZB,R1D,R2L,
R3G),(ZB,R1D,R2L,R3H),(ZB,R1D,R2L,R3I),(ZB,R1D,R2L, R3J),(ZB,R1D,R2L,R3K),(ZB,R1D,R2L,R3L),(ZB,R1D,R2L, R3M),(ZB,R1D,R2L,R3N),(ZB,R1D,R2L,R30),(ZB,R1D,R2 L,R3P),(ZB,R1D,R2L,R3Q),(ZB,R1D,R2L,R3R),(ZB,R1D,R 15 2M,R3A),(ZB,R1D,R2M,R3B),(ZB,R1D,R2M,R3C),(ZB,R1D ,R2M,R3D),(ZB,R1D,R2M,R3E),(ZB,R1D,R2M,R3F),(ZB,R 1D,R2M,R3G),(ZB,R1D,R2M,R3H),(ZB,R1D,R2M,R3I),(ZB, R1D,R2M,R3J),(ZB,R1D,R2M,R3K),(ZB,R1D,R2M,R3L),(Z B,R1D,R2M,R3M),(ZB,R1D,R2M,R3N),(ZB,R1D,R2M,R30) 20 ,(ZB,R1D,R2M,R3P),(ZB,R1D,R2M,R3Q),(ZB,R1D,R2M,R3 R),(ZB,R1D,R2N,R3A),(ZB,R1D,R2N,R3B),(ZB,R1D,R2N,R 3C),(ZB,R1D,R2N,R3D),(ZB,R1D,R2N,R3E),(ZB,R1D,R2N, R3F),(ZB,R1D,R2N,R3G),(ZB,R1D,R2N,R3H),(ZB,R1D,R2 N,R3I),(ZB,R1D,R2N,R3J),(ZB,R1D,R2N,R3K),(ZB,R1D,R2 131 200843739 N,R3L),(ZB,R1D,R2N,R3M),(ZB,R1D,R2N,R3N),(ZB,R1D, R2N,R30),(ZB,R1D,R2N,R3P),(ZB,R1D,R2N,R3Q),(ZB,R1
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5 R1E,R2A,R3F),(ZB,R1E,R2A,R3G),(ZB,R1E,R2A,R3H),(ZB ,R1E,R2A,R3I),(ZB,R1E,R2A,R3J),(ZB,R1E,R2A,R3K),(ZB, R1E,R2A,R3L),(ZB,R1E,R2A,R3M),(ZB,R1E,R2A,R3N),(Z B,R1E,R2A,R30),(ZB,R1E,R2A,R3P),(ZB,R1E,R2A,R3Q),( ZB,R1E,R2A,R3R),(ZB,R1E,R2B,R3A),(ZB,R1E,R2B,R3B), 10 (ZB,R1E,R2B,R3C),(ZB,R1E,R2B,R3D),(ZB,R1E,R2B,R3E), (ZB,R1E,R2B,R3F),(ZB,R1E,R2B,R3G),(ZB,R1E,R2B,R3H), (ZB,R1E,R2B,R3I),(ZB,R1E,R2B,R3J),(ZB,R1E,R2B,R3K),( ZB,R1E,R2B,R3L),(ZB,R1E,R2B,R3M),(ZB,R1E,R2B,R3N), (ZB,R1E,R2B,R30),(ZB,R1E,R2B,R3P),(ZB,R1E,R2B,R3Q), 15 (ZB,R1E,R2B,R3R),(ZB,R1E,R2C,R3A),(ZB,R1E,R2C,R3B), (ZB,R1E,R2C,R3C),(ZB,R1E,R2C,R3D),(ZB,R1E,R2C,R3E), (ZB,R1E,R2C,R3F),(ZB,R1E,R2C,R3G),(ZB,R1E,R2C,R3H), (ZB,R1E,R2C,RM),(ZB,R1E,R2C,R3J),(ZB,R1E,R2C,R3K),( ZB,R1E,R2C,R3L),(ZB,R1E,R2C,R3M),(ZB,R1E,R2C,R3N), 20 (ZB,R1E,R2C,R30),(ZB,R1E,R2C,R3P),(ZB,R1E,R2C,R3Q), (ZB,R1E,R2C,R3R),(ZB,R1E,R2D,R3A),(ZB,R1E,R2D,R3B) ,(ZB,R1E,R2D,R3C),(ZB,R1E,R2D,R3D),(ZB,R1E,R2D,R3E ),(ZB,R1E,R2D,R3F),(ZB,R1E,R2D,R3G),(ZB,R1E,R2D,R3 H),(ZB,R1E,R2D,R3I),(ZB,R1E,R2D,R3J),(ZB,R1E,R2D,R3 132 200843739 K),(ZB,R1E,R2D,R3L),(ZB,R1E,R2D,R3M),(ZB,R1E,R2D,R 3N),(ZB,R1E,R2D,R30),(ZB,R1E,R2D,R3P),(ZB,R1E,R2D, R3Q),(ZB,R1E,R2D,R3R),(ZB,R1E,R2E,R3A),(ZB,R1E,R2E, R3B),(ZB,R1E,R2E,R3C),(ZB,R1E,R2E,R3D),(ZB,R1E,R2E, 5 R3E),(ZB,R1E,R2E,R3F),(ZB,R1E,R2E,R3G),(ZB,R1E,R2E, R3H),(ZB,R1E,R2E,R3I),(ZB,R1E,R2E,R3J),(ZB,R1E,R2E,R 3K),(ZB,R1E,R2E,R3L),(ZB,R1E,R2E,R3M),(ZB,R1E,R2E,R 3N),(ZB,R1E,R2E,R30),(ZB,R1E,R2E,R3P),(ZB,R1E,R2E,R 3Q),(ZB,R1E,R2E,R3R),(ZB,R1E,R2F,R3A),(ZB,R1E,R2F,R 10 3B),(ZB,R1E,R2F,R3C),(ZB,R1E,R2F,R3D),(ZB,R1E,R2F,R3 E),(ZB,R1E,R2F,R3F),(ZB,R1E,R2F,R3G),(ZB,R1E,R2F,R3 H),(ZB,R1E,R2F,R3I),(ZB,R1E,R2F,R3J),(ZB,R1E,R2F,R3K) ,(ZB,R1E,R2F,R3L),(ZB,R1E,R2F,R3M),(ZB,R1E,R2F,R3N), (ZB,R1E,R2F,R30),(ZB,R1E,R2F,R3P),(ZB,R1E,R2F,R3Q),( 15 ZB,R1E,R2F,R3R),(ZB,R1E,R2G,R3A),(ZB,R1E,R2G,R3B),(
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R3H),(ZB,R1F,R2C,R3I),(ZB,R1F,R2C,R3J),(ZB,R1F,R2C,R 3K),(ZB,R1F,R2C,R3L),(ZB,R1F,R2C,R3M),(ZB,R1F,R2C,R 3N),(ZB,R1F,R2C,R30),(ZB,R1F,R2C,R3P),(ZB,R1F,R2C,R 3Q),(ZB,R1F,R2C,R3R),(ZB,R1F,R2D,R3A),(ZB,R1F,R2D,R 10 3B),(ZB,R1F,R2D,R3C),(ZB,R1F,R2D,R3D),(ZB,R1F,R2D,R 3E),(ZB,R1F,R2D,R3F),(ZB,R1F,R2D,R3G),(ZB,R1F,R2D,R 3H),(ZB,R1F,R2D,R;3I),(ZB,R1F,R2D,R3J),(ZB,R1F,R2D,R3 K),(ZB,R1F,R2D,R3L),(ZB,R1F,R2D,R3M),(ZB,R1F,R2D,R3 N),(ZB,R1F,R2D,R30),(ZB,R1F,R2D,R3P),(ZB,R1F,R2D,R3 15 Q),(ZB,R1F,R2D,R3R),(ZB,R1F,R2E,R3A),(ZB,R1F,R2E,R3 B),(ZB,R1F,R2E,R3C),(ZB,R1F,R2E,R3D),(ZB,R1F,R2E,R3 E),(ZB,R1F,R2E,R3F),(ZB,R1F,R2E,R3G),(ZB,R1F,R2E,R3 H),(ZB,R1F,R2E,R3I),(ZB,R1F,R2E,R3J),(ZB,R1F,R2E,R3K) ,(ZB,R1F,R2E,R3L),(ZB,R1F,R2E,R3M),(ZB,R1F,R2E,R3N), 20 (ZB,R1F,R2E,R30),(ZB,R1F,R2E,R3P),(ZB,R1F,R2E,R3Q),( ZB,R1F,R2E,R3R),(ZB,R1F,R2F,R3A),(ZB,R1F,R2F,R3B),(Z B,R1F,R2F,R3C),(ZB,R1F,R2F,R3D),(ZB,R1F,R2F,R3E),(ZB, R1F,R2F,R3F),(ZB,R1F,R2F,R3G),(ZB,R1F,R2F,R3H),(ZB,R 1F,R2F,R3I),(ZB,R1F,R2F,R3J),(ZB,R1F,R2F,R3K),(ZB,R1F, 136 200843739
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R3G),(ZB,R1K,R2L,R3H),(ZB,R1K,R2L,R3I),(ZB,R1K,R2L, R3J),(ZB,R1K,R2L,R3K),(ZB,R1K,R2L,R3L),(ZB,R1K,R2L, R3M),(ZB,R1K,R2L,R3N),(ZB,R1K,R2L,R30),(ZB,R1K,R2 L,R3P),(ZB,R1K,R2L,R3Q),(ZB,R1K,R2L,R3R),(ZB,R1K,R 155 200843739 2M,R3A),(ZB,R1K,R2M,R3B),(ZB,R1K,R2M,R3C),(ZB,R1K ,R2M,R3D),(ZB,R1K,R2M,R3E),(ZB,R1K,R2M,R3F),(ZB,R 1K,R2M,R3G),(ZB,R1K,R2M,R3H),(ZB,R1K,R2M,R3I),(ZB, R1K,R2M,R3J),(ZB,R1K,R2M,R3K),(ZB,R1K,R2M,R3L),(Z 5 B,R1K,R2M,R3M),(ZB,R1K,R2M,R3N),(ZB,R1K,R2M,R30) ,(ZB,R1K,R2M,R3P),(ZB,R1K,R2M,R3Q),(ZB,R1K,R2M,R3 R),(ZB,R1K,R2N,R3A),(ZB,R1K,R2N,R3B),(ZB,R1K,R2N,R 3C),(ZB,R1K,R2N,R3D),(ZB,R1K,R2N,R3E),(ZB,R1K,R2N, R3F),(ZB,R1K,R2N,R3G),(ZB,R1K,R2N,R3H),(ZB,R1K,R2 10 N,R3I),(ZB,R1K,R2N,R3J),(ZB,R1K,R2N,R3K),(ZB,R1K,R2 N,R3L),(ZB,R1K,R2N,R3M),(ZB,R1K,R2N,R3N),(ZB,R1K, R2N,R30),(ZB,R1K,R2N,R3P),(ZB,R1K,R2N,R3Q),(ZB,R1 K,R2N,R3R),(ZB,R1L,R2A,R3A),(ZB,R1L,R2A,R3B),(ZB,R 1L,R2A,R3C),(ZB,R1L,R2A,R3D),(ZB,R1L,R2A,R3E),(ZB,
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ZB,R1L,R2F,R3R),(ZB,R1L,R2G,R3A),(ZB,R1L,R2G,R3B),( ZB,R1L,R2G,R3C),(ZB,R1L,R2G,R3D),(ZB,R1L,R2G,R3E),( ZB,R1L,R2G,R3F),(ZB,R1L,R2G,R3G),(ZB,R1L,R2G,R3H),( ZB,R1L,R2G,R3I),(ZB,R1L,R2G,R3J),(ZB,R1L,R2G,R3K),(Z 5 B,R1L,R2G,R3L),(ZB,R1L,R2G,R3M),(ZB,R1L,R2G,R3N),(Z B,R1L,R2G,R30),(ZB,R1L,R2G,R3P),(ZB,R1L,R2G,R3Q),(Z B,R1L,R2G,R3R),(ZB,R1L,R2H,R3A),(ZB,R1L,R2H,R3B),( ZB,R1L,R2H,R3C),(ZB,R1L,R2H,R3D),(ZB,R1L,R2H,R3E), (ZB,R1L,R2H,R3F),(ZB,R1L,R2H,R3G),(ZB,R1L,R2H,R3H) 10 ,(ZB,R1L,R2H,R3I),(ZB,R1L,R2H,R3J),(ZB,R1L,R2H,R3K), (ZB,R1L,R2H,R3L),(ZB,R1L,R2H,R3M),(ZB,R1L,R2H,R3N ),(ZB,R1L,R2H,R30),(ZB,R1L,R2H,R3P),(ZB,R1L,R2H,R3 Q),(ZB,R1L,R2H,R3R),(ZB,R1L,R2I,R3A),(ZB,R1L,R2I,R3 B),(ZB,R1L,R2I,R3C),(ZB,R1L,R2I,R3D),(ZB,R1L,R2I,R3E 15 ),(ZB,R1L,R2I,R3F),(ZB,R1L,R2I,R3G),(ZB,R1L,R2I,R3H),
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R2N,R3K),(ZC,R1D,R2N,R3L),(ZC,R1D,R2N,R3M),(ZC,R1 D,R2N,R3N),(ZC,R1D,R2N,R30),(ZC,R1D,R2N,R3P),(ZC,R 1D,R2N,R3Q),(ZC,R1D,R2N,R3R),(ZC,R1E,R2A,R3A),(ZC, R1E,R2A,R3B),(ZC,R1E,R2A,R3C),(ZC,R1E,R2A,R3D),(ZC 198 200843739
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R1E,R2A,R3K),(ZC,R1E,R2A,R3L),(ZC,R1E,R2A,R3M),(Z C,R1E,R2A,R3N),(ZC,R1E,R2A,R30),(ZC,R1E,R2A,R3P),( 5 ZC,R1E,R2A,R3Q),(ZC,R1E,R2A,R3R),(ZC,R1E,R2B,R3A), (ZC,R1E,R2B,R3B),(ZC,R1E,R2B,R3C),(ZC,R1E,R2B,R3D), (ZC,R1E,R2B,R3E),(ZC,R1E,R2B,R3F),(ZC,R1E,R2B,R3G), (ZC,R1E,R2B,R3H),(ZC,R1E,R2B,R3I),(ZC,R1E,R2B,R3J),( ZC,R1E,R2B,R3K),(ZC,R1E,R2B,R3L),(ZC,R1E,R2B,R3M), 10 (ZC,R1E,R2B,R3N),(ZC,R1E,R2B,R30),(ZC,R1E,R2B,R3P), (ZC,R1E,R2B,R3Q),(ZC,R1E,R2B,R3R),(ZC,R1E,R2C,R3A) ,(ZC,R1E,R2C,R3B),(ZC,R1E,R2C,R3C),(ZC,R1E,R2C,R3D) ,(ZC,R1E,R2C,R3E),(ZC,R1E,R2C,R3F),(ZC,R1E,R2C,R3G) ,(ZC,R1E,R2C,R3H),(ZC,R1E,R2C,R3I),(ZC,R1E,R2C,R3J), 15 (ZC,R1E,R2C,R3K),(ZC,R1E,R2C,R3L),(ZC,R1E,R2C,R3M) ,(ZC,R1E,R2C,R3N),(ZC,R1E,R2C,R30),(ZC,R1E,R2C,R3P) ,(ZC,R1E,R2C,R3Q),(ZC,R1E,R2C,R3R),(ZC,R1E,R2D,R3A ),(ZC,R1E,R2D,R3B),(ZC,R1E,R2D,R3C),(ZC,R1E,R2D,R3 D),(ZC,R1E,R2D,R3E),(ZC,R1E,R2D,R3F),(ZC,R1E,R2D,R3 20 G),(ZC,R1E,R2D,R3H),(ZC,R1E,R2D,R3I),(ZC,R1E,R2D,R3
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3J),(ZC,R1E,R2E,R3K),(ZC,R1E,R2E,R3L),(ZC,R1E,R2E,R 3M),(ZC,R1E,R2E,R3N),(ZC,R1E,R2E,R30),(ZC,R1E,R2E, 5 R3P),(ZC,R1E,R2E,R3Q),(ZC,R1E,R2E,R3R),(ZC,R1E,R2F, R3A),(ZC,R1E,R2F,R3B),(ZC,R1E,R2F,R3C),(ZC,R1E,R2F, R3D),(ZC,R1E,R2F,R3E),(ZC,R1E,R2F,R3F),(ZC,R1E,R2F,R 3G),(ZC,R1E,R2F,R3H),(ZC,R1E,R2F,R3I),(ZC,R1E,R2F,R3 J),(ZC,R1E,R2F,R3K),(ZC,R1E,R2F,R3L),(ZC,R1E,R2F,R3 10 M),(ZC,R1E,R2F,R3N),(ZC,R1E,R2F,R30),(ZC,R1E,R2F,R3
P),(ZC,R1E,R2F,R3Q),(ZC,R1E,R2F,R3R),(ZC,R1E,R2G,R3 A),(ZC,R1E,R2G,R3B),(ZC,R1E,R2G,R3C),(ZC,R1E,R2G,R3 D),(ZC,R1E,R2G,R3E),(ZC,R1E,R2G,R3F),(ZC,R1E,R2G,R3 G),(ZC,R1E,R2G,R3H),(ZC,R1E,R2G,R3I),(ZC,R1E,R2G,R3J 15 ),(ZC,R1E,R2G,R3K),(ZC,R1E,R2G,R3L),(ZC,R1E,R2G,R3M ),(ZC,R1E,R2G,R3N),(ZC,R1E,R2G,R30),(ZC,R1E,R2G,R3P ),(ZC,R1E,R2G,R3Q),(ZC,R1E,R2G,R3R),(ZC,R1E,R2H,R3A ),(ZC,R1E,R2H,R3B),(ZC,R1E,R2H,R3C),(ZC,R1E,R2H,R3 D),(ZC,R1E,R2H,R3E),(ZC,R1E,R2H,R3F),(ZC,R1E,R2H,R3 20 G),(ZC,R1E,R2H,R3H),(ZC,R1E,R2H,R3I),(ZC,R1E,R2H,R3 J),(ZC,R1E,R2H,R3K),(ZC,R1E,R2H,R3L),(ZC,R1E,R2H,R3 M),(ZC,R1E,R2H,R3N),(ZC,R1E,R2H,R30),(ZC,R1E,R2H,R 3P),(ZC,R1E,R2H,R3Q),(ZC,R1E,R2H,R3R),(ZC,R1E,R2I,R 3A),(ZC,R1E,R2I,R3B),(ZC,R1E,R2I,R3C),(ZC,R1E,R2I,R3 200 200843739 D),(ZC,R1E,R2I,R3E),(ZC,R1E,R2I,R3F),(ZC,R1E,R2I,R3G) ,(ZC,R1E,R2I,R3H),(ZC,R1E,R2I,R3I),(ZC,R1E,R2I,R3J),(Z C,R1E,R2I,R3K),(ZC,R1E,R2I,R3L),(ZC,R1E,R2I,R3M),(ZC ,R1E,R2I,R3N),(ZC,R1E,R2I,R30),(ZC,R1E,R2I,R3P),(ZC,R 5 1E,R2I,R3Q),(ZC,R1E,R2I,R3R),(ZC,R1E,R2J,R3A),(ZC,R1 E,R2J,R3B),(ZC,R1E,R2J,R3C),(ZC,R1E,R2J,R3D),(ZC,R1E ,R2J,R3E),(ZC,R1E,R2J,R3F),(ZC,R1E,R2J,R3G),(ZC,R1E, R2J,R3H),(ZC,R1E,R2J,R3I),(ZC,R1E,R2J,R3J),(ZC,R1E,R2 J,R3K),(ZC,R1E,R2J,R3L),(ZC,R1E,R2J,R3M),(ZC,R1E,R2J 10 ,R3N),(ZC,R1E,R2J,R30),(ZC,R1E,R2J,R3P),(ZC,R1E,R2J, R3Q),(ZC,R1E,R2J,R3R),(ZC,R1E,R2K,R3A),(ZC,R1E,R2K, R3B),(ZC,R1E,R2K,R3C),(ZC,R1E,R2K,R3D),(ZC,R1E,R2K ,R3E),(ZC,R1E,R2K,R3F),(ZC,R1E,R2K,R3G),(ZC,R1E,R2K ,R3H),(ZC,R1E,R2K,R3I),(ZC,R1E,R2K,R3J),(ZC,R1E,R2K, 15 R3K),(ZC,R1E,R2K,R3L),(ZC,R1E,R2K,R3M),(ZC,R1E,R2
K,R3N),(ZC,R1E,R2K,R30),(ZC,R1E,R2K,R3P),(ZC,R1E,R 2K,R3Q),(ZC,R1E,R2K,R3R),(ZC,R1E,R2L,R3A),(ZC,R1E, R2L,R3B),(ZC,R1E,R2L,R3C),(ZC,R1E,R2L,R3D),(ZC,R1E, R2L,R3E),(ZC,R1E,R2L,R3F),(ZC,R1E,R2L,R3G),(ZC,R1E, 20 R2L,R3H),(ZC,R1E,R2L,R3I),(ZC,R1E,R2L,R3J),(ZC,R1E,R 2L,R3K),(ZC,R1E,R2L,R3L),(ZC,R1E,R2L,R3M),(ZC,R1E,R 2L,R3N),(ZC,R1E,R2L,R30),(ZC,R1E,R2L,R3P),(ZC,R1E,R 2L,R3Q),(ZC,R1E,R2L,R3R),(ZC,R1E,R2M,R3A),(ZC,R1E, R2M,R3B),(ZC,R1E,R2M,R3C),(ZC,R1E,R2M,R3D),(ZC,R1 201 200843739 E,R2M,R3E),(ZC,R1E,R2M,R3F),(ZC,R1E,R2M,R3G),(ZC,R 1E,R2M,R3H),(ZC,R1E,R2M,R3I),(ZC,R1E,R2M,R3J),(ZC, R1E,R2M,R3K),(ZC,R1E,R2M,R3L),(ZC,R1E,R2M,R3M),(Z C,R1E,R2M,R3N),(ZC,R1E,R2M,R30),(ZC,R1E,R2M,R3P),( 5 ZC,R1E,R2M,R3Q),(ZC,R1E,R2M,R3R),(ZC,R1E,R2N,R3A) ,(ZC,R1E,R2N,R3B),(ZC,R1E,R2N,R3C),(ZC,R1E,R2N,R3D ),(ZC,R1E,R2N,R3E),(ZC,R1E,R2N,R3F),(ZC,R1E,R2N,R3G ),(ZC,R1E,R2N,R3H),(ZC,R1E,R2N,R3I),(ZC,R1E,R2N,R3J) ,(ZC,R1E,R2N,R3K),(ZC,R1E,R2N,R3L),(ZC,R1E,R2N,R3M 10 ),(ZC,R1E,R2N,R3N),(ZC,R1E,R2N,R30),(ZC,R1E,R2N,R3
P),(ZC,R1E,R2N,R3Q),(ZC,R1E,R2N,R3R),(ZC,R1F,R2A,R3 A),(ZC,R1F,R2A,R3B),(ZC,R1F,R2A,R3C),(ZC,R1F,R2A,R3 D),(ZC,R1F,R2A,R3E),(ZC,R1F,R2A,R3F),(ZC,R1F,R2A,R3 G),(ZC,R1F,R2A,R3H),(ZC,R1F,R2A,R3I),(ZC,R1F,R2A,R3J 15 ),(ZC,R1F,R2A,R3K),(ZC,R1F,R2A,R3L),(ZC,R1F,R2A,R3M ),(ZC,R1F,R2A,R3N),(ZC,R1F,R2A,R30),(ZC,R1F,R2A,R3P ),(ZC,R1F,R2A,R3Q),(ZC,R1F,R2A,R3R),(ZC,R1F,R2B,R3A ),(ZC,R1F,R2B,R3B),(ZC,R1F,R2B,R3C),(ZC,R1F,R2B,R3D) ,(ZC,R1F,R2B,R3E),(ZC,R1F,R2B,R3F),(ZC,R1F,R2B,R3G), 20 (ZC,R1F,R2B,R3H),(ZC,R1F,R2B,R3I),(ZC,R1F,R2B,R3J),( ZC,R1F,R2B,R3K),(ZC,R1F,R2B,R3L),(ZC,R1F,R2B,R3M),( ZC,R1F,R2B,R3N),(ZC,R1F,R2B,R30),(ZC,R1F,R2B,R3P),( ZC,R1F,R2B,R3Q),(ZC,R1F,R2B,R3R),(ZC,R1F,R2C,R3A),( ZC,R1F,R2C,R3B),(ZC,R1F,R2C,R3C),(ZC,R1F,R2C,R3D),( 202 200843739
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R2L,R3D),(ZC,R1K,R2L,R3E),(ZC,R1K,R2L,R3F),(ZC,R1K, R2L,R3G),(ZC,R1K,R2L,R3H),(ZC,R1K,R2L,R3I),(ZC,R1K, R2L,R3J),(ZC,R1K,R2L,R3K),(ZC,R1K,R2L,R3L),(ZC,R1K, R2L,R3M),(ZC,R1K,R2L,R3N),(ZC,R1K,R2L,R30),(ZC,R1 20 K,R2L,R3P),(ZC,R1K,R2L,R3Q),(ZC,R1K,R2L,R3R),(ZC,R 1K,R2M,R3A),(ZC,R1K,R2M,R3B),(ZC,R1K,R2M,R3C),(ZC ,R1K,R2M,R3D),(ZC,R1K,R2M,R3E),(ZC,R1K,R2M,R3F),( ZC,R1K,R2M,R3G),(ZC,R1K,R2M,R3H),(ZC,R1K,R2M,R3I ),(ZC,R1K,R2M,R3J),(ZC,R1K,R2M,R3K),(ZC,R1K,R2M,R3 222 200843739
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(ZC,R1L,R2A,R3F),(ZC,R1L,R2A,R3G),(ZC,R1L,R2A,R3H) ,(ZC,R1L,R2A,R3I),(ZC,R1L,R2A,R3J),(ZC,R1L,R2A,R3K), (ZC,R1L,R2A,R3L),(ZC,R1L,R2A,R3M),(ZC,R1L,R2A,R3N ),(ZC,R1L,R2A,R30),(ZC,R1L,R2A,R3P),(ZC,R1L,R2A,R3 15 Q),(ZC,R1L,R2A,R3R),(ZC,R1L,R2B,R3A),(ZC,R1L,R2B,R
3B),(ZC,R1L,R2B,R3C),(ZC,R1L,R2B,R3D),(ZC,R1L,R2B,R 3E),(ZC,R1L,R2B,R3F),(ZC,R1L,R2B,R3G),(ZC,R1L,R2B,R 3H),(ZC,R1L,R2B,R3I),(ZC,R1L,R2B,R3J),(ZC,R1L,R2B,R3 K),(ZC,R1L,R2B,R3L),(ZC,R1L,R2B,R3M),(ZC,R1L,R2B,R 20 3N),(ZC,R1L,R2B,R30),(ZC,R1L,R2B,R3P),(ZC,R1L,R2B,R 3Q),(ZC,R1L,R2B,R3R),(ZC,R1L,R2C,R3A),(ZC,R1L,R2C, R3B),(ZC,R1L,R2C,R3C),(ZC,R1L,R2C,R3D),(ZC,R1L,R2C, R3E),(ZC,R1L,R2C,R3F),(ZC,R1L,R2C,R3G),(ZC,R1L,R2C, R3H),(ZC,R1L,R2C,R3I),(ZC,R1L,R2C,R3J),(ZC,R1L,R2C, 223 200843739
R3K),(ZC,R1L,R2C,R3L),(ZC,R1L,R2C,R3M),(ZC,R1L,R2C ,R3N),(ZC,R1L,R2C,R30),(ZC,R1L,R2C,R3P),(ZC,R1L,R2C ,R3Q),(ZC,R1L,R2C,R3R),(ZC,R1L,R2D,R3A),(ZC,R1L,R2 D,R3B),(ZC,R1L,R2D,R3C),(ZC,R1L,R2D,R3D),(ZC,R1L,R 5 2D,R3E),(ZC,R1L,R2D,R3F),(ZC,R1L,R2D,R3G),(ZC,R1L,R 2D,R3H),(ZC,R1L,R2D,R3I),(ZC,R1L,R2D,R3J),(ZC,R1L,R 2D,R3K),(ZC,R1L,R2D,R3L),(ZC,R1L,R2D,R3M),(ZC,R1L, R2D,R3N),(ZC,R1L,R2D,R30),(ZC,R1L,R2D,R3P),(ZC,R1L ,R2D,R3Q),(ZC,R1L,R2D,R3R),(ZC,R1L,R2E,R3A),(ZC,R1 10 L,R2E,R3B),(ZC,R1L,R2E,R3C),(ZC,R1L,R2E,R3D),(ZC,R1
L,R2E,R3E),(ZC,R1L,R2E,R3F),(ZC,R1L,R2E,R3G),(ZC,R1 L,R2E,R3H),(ZC,R1L,R2E,R3I),(ZC,R1L,R2E,R3J),(ZC,R1L ,R2E,R3K),(ZC,R1L,R2E,R3L),(ZC,R1L,R2E,R3M),(ZC,R1L ,R2E,R3N),(ZC,R1L,R2E,R30),(ZC,R1L,R2E,R3P),(ZC,R1L 15 ,R2E,R3Q),(ZC,R1L,R2E,R3R),(ZC,R1L,R2F,R3A),(ZC,R1L ,R2F,R3B),(ZC,R1L,R2F,R3C),(ZC,R1L,R2F,R3D),(ZC,R1L, R2F,R3E),(ZC,R1L,R2F,R3F),(ZC,R1L,R2F,R3G),(ZC,R1L,R 2F,R3H),(ZC,R1L,R2F,R3I),(ZC,R1L,R2F,R3J),(ZC,R1L,R2F ,R3K),(ZC,R1L,R2F,R3L),(ZC,R1L,R2F,R3M),(ZC,R1L,R2F, 20 R3N),(ZC,R1L,R2F,R30),(ZC,R1L,R2F,R3P),(ZC,R1L,R2F,
R3Q),(ZC,R1L,R2F,R3R),(ZC,R1L,R2G,R3A),(ZC,R1L,R2G, R3B),(ZC,R1L,R2G,R3C),(ZC,R1L,R2G,R3D),(ZC,R1L,R2G, R3E),(ZC,R1L,R2G,R3F),(ZC,R1L,R2G,R3G),(ZC,R1L,R2G, R3H),(ZC,R1L,R2G,R3I),(ZC,R1L,R2G,R3J),(ZC,R1L,R2G,R 224 200843739
3K),(ZC,R1L,R2G,R3L),(ZC,R1L,R2G,R3M),(ZC,R1L,R2G,R 3N),(ZC,R1L,R2G,R30),(ZC,R1L,R2G,R3P),(ZC,R1L,R2G,R 3Q),(ZC,R1L,R2G,R3R),(ZC,R1L,R2H,R3A),(ZC,R1L,R2H, R3B),(ZC,R1L,R2H,R3C),(ZC,R1L,R2H,R3D),(ZC,R1L,R2H 5 ,R3E),(ZC,R1L,R2H,R3F),(ZC,R1L,R2H,R3G),(ZC,R1L,R2H
,R3H),(ZC,R1L,R2H,R3I),(ZC,R1L,R2H,R3J),(ZC,R1L,R2H, R3K),(ZC,R1L,R2H,R3L),(ZC,R1L,R2H,R3M),(ZC,R1L,R2 H,R3N),(ZC,R1L,R2H,R30),(ZC,R1L,R2H,R3P),(ZC,R1L,R 2H,R3Q),(ZC,R1L,R2H,R3R),(ZC,R1L,R2I,R3A),(ZC,R1L,R 10 2I,R3B),(ZC,R1L,R2I,R3C),(ZC,R1L,R2I,R3D),(ZC,R1L,R2I
,R3E),(ZC,R1L,R2I,R3F),(ZC,R1L,R2I,R3G),(ZC,R1L,R2I,R 3H),(ZC,R1L,R2I,R3I),(ZC,R1L,R2I,R3J),(ZC,R1L,R2I,R3K ),(ZC,R1L,R2I,R3L),(ZC,R1L,R2I,R3M),(ZC,R1L,R2I,R3N), (ZC,R1L,R2I,R30),(ZC,R1L,R2I,R3P),(ZC,R1L,R2I,R3Q),(Z 15 C,R1L,R2I,R3R),(ZC,R1L,R2J,R3A),(ZC,R1L,R2J,R3B),(ZC
,R1L,R2J,R3C),(ZC,R1L,R2J,R3D),(ZC,R1L,R2J,R3E),(ZC, R1L,R2J,R3F),(ZC,R1L,R2J,R3G),(ZC,R1L,R2J,R3H),(ZC,R 1L,R2J,R3I),(ZC,R1L,R2J,R3J),(ZC,R1L,R2J,R3K),(ZC,R1L ,R2J,R3L),(ZC,R1L,R2J,R3M),(ZC,R1L,R2J,R3N),(ZC,R1L, 20 R2J,R30),(ZC,R1L,R2J,R3P),(ZC,R1L,R2J,R3Q),(ZC,R1L,R 2J,R3R),(ZC,R1L,R2K,R3A),(ZC,R1L,R2K,R3B),(ZC,R1L,R 2K,R3C),(ZC,R1L,R2K,R3D),(ZC,R1L,R2K,R3E),(ZC,R1L, R2K,R3F),(ZC,R1L,R2K,R3G),(ZC,R1L,R2K,R3H),(ZC,R1L ,R2K,R3I),(ZC,R1L,R2K,R3J),(ZC,R1L,R2K,R3K),(ZC,R1L, 225 200843739
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R1L,R2M,R3F),(ZC,R1L,R2M,R3G),(ZC,R1L,R2M,R3H),(Z C,R1L,R2M,R3I),(ZC,R1L,R2M,R3J),(ZC,R1L,R2M,R3K),( ZC,R1L,R2M,R3L),(ZC,R1L,R2M,R3M),(ZC,R1L,R2M,R3N ),(ZC,R1L,R2M,R30),(ZC,R1L,R2M,R3P),(ZC,R1L,R2M,R3 15 Q),(ZC,R1L,R2M,R3R),(ZC,R1L,R2N,R3A),(ZC,R1L,R2N,R
3B),(ZC,R1L,R2N,R3C),(ZC,R1L,R2N,R3D),(ZC,R1L,R2N, R3E),(ZC,R1L,R2N,R3F),(ZC,R1L,R2N,R3G),(ZC,R1L,R2N, R3H),(ZC,R1L,R2N,R3I),(ZC,R1L,R2N,R3J),(ZC,R1L,R2N, R3K),(ZC,R1L,R2N,R3L),(ZC,R1L,R2N,R3M),(ZC,R1L,R2 20 N,R3N),(ZC,R1L,R2N,R30),(ZC,R1L,R2N,R3P),(ZC,R1L,R
2N,R3Q),(ZC,R1L,R2N,R3R),(ZC,R1M,R2A,R3A),(ZC,R1M ,R2A,R3B),(ZC,R1M,R2A,R3C),(ZC,R1M,R2A,R3D),(ZC,R 1M,R2A,R3E),(ZC,R1M,R2A,R3F),(ZC,R1M,R2A,R3G),(ZC ,R1M,R2A,R3H),(ZC,R1M,R2A,R3I),(ZC,R1M,R2A,R3J),(Z 226 200843739 C,R1M,R2A,R3K),(ZC,R1M,R2A,R3L),(ZC,R1M,R2A,R3M) ,(ZC,R1M,R2A,R3N),(ZC,R1M,R2A,R30),(ZC,R1M,R2A,R3 P),(ZC,R1M,R2A,R3Q),(ZC,R1M,R2A,R3R),(ZC,R1M,R2B, R3A),(ZC,R1M,R2B,R3B),(ZC,R1M,R2B,R3C),(ZC,R1M,R2 5 B,R3D),(ZC,R1M,R2B,R3E),(ZC,R1M,R2B,R3F),(ZC,R1M, R2B,R3G),(ZC,R1M,R2B,R3H),(ZC,R1M,R2B,R3I),(ZC,R1 M,R2B,R3J),(ZC,R1M,R2B,R3K),(ZC,R1M,R2B,R3L),(ZC,R 1M,R2B,R3M),(ZC,R1M,R2B,R3N),(ZC,R1M,R2B,R30),(Z C,R1M,R2B,R3P),(ZC,R1M,R2B,R3Q),(ZC,R1M,R2B,R3R), 10 (ZC,R1M,R2C,R3A),(ZC,R1M,R2C,R3B),(ZC,R1M,R2C,R3 C),(ZC,R1M,R2C,R3D),(ZC,R1M,R2C,R3E),(ZC,R1M,R2C, R3F),(ZC,R1M,R2C,R3G),(ZC,R1M,R2C,R3H),(ZC,R1M,R2 C,R3I),(ZC,R1M,R2C,R3J),(ZC,R1M,R2C,R3K),(ZC,R1M,R 2C,R3L),(ZC,R1M,R2C,R3M),(ZC,R1M,R2C,R3N),(ZC,R1M 15 ,R2C,R30),(ZC,R1M,R2C,R3P),(ZC,R1M,R2C,R3Q),(ZC,R1
M,R2C,R3R),(ZC,R1M,R2D,R3A),(ZC,R1M,R2D,R3B),(ZC, R1M,R2D,R3C),(ZC,R1M,R2D,R3D),(ZC,R1M,R2D,R3E),(Z C,R1M,R2D,R3F),(ZC,R1M,R2D,R3G),(ZC,R1M,R2D,R3H), (ZC,R1M,R2D,R3I),(ZC,R1M,R2D,R3J),(ZC,R1M,R2D,R3K 20 ),(ZC,R1M,R2D,R3L),(ZC,R1M,R2D,R3M),(ZC,R1M,R2D,R 3N),(ZC,R1M,R2D,R30),(ZC,R1M,R2D,R3P),(ZC,R1M,R2D ,R3Q),(ZC,R1M,R2D,R3R),(ZC,R1M,R2E,R3A),(ZC,R1M,R 2E,R3B),(ZC,R1M,R2E,R3C),(ZC,R1M,R2E,R3D),(ZC,R1M, R2E,R3E),(ZC,R1M,R2E,R3F),(ZC,R1M,R2E,R3G),(ZC,R1 227 200843739 M,R2E,R3H),(ZC,R1M,R2E,R3I),(ZC,R1M,R2E,R3J),(ZC,R 1M,R2E,R3K),(ZC,R1M,R2E,R3L),(ZC,R1M,R2E,R3M),(ZC ,R1M,R2E,R3N),(ZC,R1M,R2E,R30),(ZC,R1M,R2E,R3P),(Z C,R1M,R2E,R3Q),(ZC,R1M,R2E,R3R),(ZC,R1M,R2F,R3A),( 5 ZC,R1M,R2F,R3B),(ZC,R1M,R2F,R3C),(ZC,R1M,R2F,R3D),
(ZC,R1M,R2F,R3E),(ZC,R1M,R2F,R3F),(ZC,R1M,R2F,R3G) ,(ZC,R1M,R2F,R3H),(ZC,R1M,R2F,R3I),(ZC,R1M,R2F,R3J), (ZC,R1M,R2F,R3K),(ZC,R1M,R2F,R3L),(ZC,R1M,R2F,R3M ),(ZC,R1M,R2F,R3N),(ZC,R1M,R2F,R30),(ZC,R1M,R2F,R3 10 P),(ZC,R1M,R2F,R3Q),(ZC,R1M,R2F,R3R),(ZC,R1M,R2G,R 3A),(ZC,R1M,R2G,R3B),(ZC,R1M,R2G,R3C),(ZC,R1M,R2G, R3D),(ZC,R1M,R2G,R3E),(ZC,R1M,R2G,R3F),(ZC,R1M,R2 G,R3G),(ZC,R1M,R2G,R3H),(ZC,R1M,R2G,R3I),(ZC,R1M,R 2G,R3J),(ZC,R1M,R2G,R3K),(ZC,R1M,R2G,R3L),(ZC,R1M, 15 R2G,R3M),(ZC,R1M,R2G,R3N),(ZC,R1M,R2G,R30),(ZC,R1 M,R2G,R3P),(ZC,R1M,R2G,R3Q),(ZC,R1M,R2G,R3R),(ZC,R 1M,R2H,R3A),(ZC,R1M,R2H,R3B),(ZC,R1M,R2H,R3C),(ZC ,R1M,R2H,R3D),(ZC,R1M,R2H,R3E),(ZC,R1M,R2H,R3F),( ZC,R1M,R2H,R3G),(ZC,R1M,R2H,R3H),(ZC,R1M,R2H,R3I 20 ),(ZC,R1M,R2H,R3J),(ZC,R1M,R2H,R3K),(ZC,R1M,R2H,R3
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R2L,R3K),(ZC,R1M,R2L,R3L),(ZC,R1M,R2L,R3M),(ZC,R1 M,R2L,R3N),(ZC,R1M,R2L,R30),(ZC,R1M,R2L,R3P),(ZC, R1M,R2L,R3Q),(ZC,R1M,R2L,R3R),(ZC,R1M,R2M,R3A),(Z C,R1M,R2M,R3B),(ZC,R1M,R2M,R3C),(ZC,R1M,R2M,R3D 229 200843739
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K),(ZC,R1R,R2J,R3L),(ZC,R1R,R2J,R3M),(ZC,R1R,R2J,R3 N),(ZC,R1R,R2J,R30),(ZC,R1R,R2J,R3P),(ZC,R1R,R2J,R3 Q),(ZC,R1R,R2J,R3R),(ZC,R1R,R2K,R3A),(ZC,R1R,R2K,R 3B),(ZC,R1R,R2K,R3C),(ZC,R1R,R2K,R3D),(ZC,R1R,R2K, 5 R3E),(ZC,R1R,R2K,R3F),(ZC,R1R,R2K,R3G),(ZC,R1R,R2K ,R3H),(ZC,R1R,R2K,R3I),(ZC,R1R,R2K,R3J),(ZC,R1R,R2K ,R3K),(ZC,R1R,R2K,R3L),(ZC,R1R,R2K,R3M),(ZC,R1R,R2 K,R3N),(ZC,R1R,R2K,R30),(ZC,R1R,R2K,R3P),(ZC,R1R,R 2K,R3Q),(ZC,R1R,R2K,R3R),(ZC,R1R,R2L,R3A),(ZC,R1R, 10 R2L,R3B),(ZC,R1R,R2L,R3C),(ZC,R1R,R2L,R3D),(ZC,R1R, R2L,R3E),(ZC,R1R,R2L,R3F),(ZC,R1R,R2L,R3G),(ZC,R1R, R2L,R3H),(ZC,R1R,R2L,R3I),(ZC,R1R,R2L,R3J),(ZC,R1R, R2L,R3K),(ZC,R1R,R2L,R3L),(ZC,R1R,R2L,R3M),(ZC,R1R ,R2L,R3N),(ZC,R1R,R2L,R30),(ZC,R1R,R2L,R3P),(ZC,R1R 15 ,R2L,R3Q),(ZC,R1R,R2L,R3R),(ZC,R1R,R2M,R3A),(ZC,R1
R,R2M,R3B),(ZC,R1R,R2M,R3C),(ZC,R1R,R2M,R3D),(ZC, R1R,R2M,R3E),(ZC,R1R,R2M,R3F),(ZC,R1R,R2M,R3G),(Z C,R1R,R2M,R3H),(ZC,R1R,R2M,R3I),(ZC,R1R,R2M,R3J),( ZC,R1R,R2M,R3K),(ZC,R1R,R2M,R3L),(ZC,R1R,R2M,R3M 20 ),(ZC,R1R,R2M,R3N),(ZC,R1R,R2M,R30),(ZC,R1R,R2M,R 3P),(ZC,R1R,R2M,R3Q),(ZC,R1R,R2M,R3R),(ZC,R1R,R2N, R3A),(ZC,R1R,R2N,R3B),(ZC,R1R,R2N,R3C),(ZC,R1R,R2 N,R3D),(ZC,R1R,R2N,R3E),(ZC,R1R,R2N,R3F),(ZC,R1R,R 2N,R3G),(ZC,R1R,R2N,R3H),(ZC,R1R,R2N,R3I),(ZC,R1R, 247 200843739
R2N,R3J),(ZC,R1R,R2N,R3K),(ZC,R1R,R2N,R3L),(ZC,R1R, R2N,R3M),(ZC,R1R,R2N,R3N),(ZC,R1R,R2N,R30),(ZC,R1 R,R2N,R3P),(ZC,R1R,R2N,R3Q),(ZC,R1R,R2N,R3R),(ZC,R 1S,R2A,R3A),(ZC,R1S,R2A,R3B),(ZC,R1S,R2A,R3C),(ZC,R 5 1S,R2A,R3D),(ZC,R1S,R2A,R3E),(ZC,R1S,R2A,R3F),(ZC,R 1S,R2A,R3G),(ZC,R1S,R2A,R3H),(ZC,R1S,R2A,R3I),(ZC,R 1S,R2A,R3J),(ZC,R1S,R2A,R3K),(ZC,R1S,R2A,R3L),(ZC,R 1S,R2A,R3M),(ZC,R1S,R2A,R3N),(ZC,R1S,R2A,R30),(ZC, R1S,R2A,R3P),(ZC,R1S,R2A,R3Q),(ZC,R1S,R2A,R3R),(ZC, 10 R1S,R2B,R3A),(ZC,R1S,R2B,R3B),(ZC,R1S,R2B,R3C),(ZC,
R1S,R2B,R3D),(ZC,R1S,R2B,R3E),(ZC,R1S,R2B,R3F),(ZC, R1S,R2B,R3G),(ZC,R1S,R2B,R3H),(ZC,R1S,R2B,R3I),(ZC, R1S,R2B,R3J),(ZC,R1S,R2B,R3K),(ZC,R1S,R2B,R3L),(ZC, R1S,R2B,R3M),(ZC,R1S,R2B,R3N),(ZC,R1S,R2B,R30),(ZC 15 ,R1S,R2B,R3P),(ZC,R1S,R2B,R3Q),(ZC,R1S,R2B,R3R),(ZC
,R1S,R2C,R3A),(ZC,R1S,R2C,R3B),(ZC,R1S,R2C,R3C),(ZC ,R1S,R2C,R3D),(ZC,R1S,R2C,R3E),(ZC,R1S,R2C,R3F),(ZC, R1S,R2C,R3G),(ZC,R1S,R2C,R3H),(ZC,R1S,R2C,R3I),(ZC, R1S,R2C,R3J),(ZC,R1S,R2C,R3K),(ZC,R1S,R2C,R3L),(ZC, 20 R1S,R2C,R3M),(ZC,R1S,R2C,R3N),(ZC,R1S,R2C,R30),(ZC
,R1S,R2C,R3P),(ZC,R1S,R2C,R3Q),(ZC,R1S,R2C,R3R),(ZC ,R1S,R2D,R3A),(ZC,R1S,R2D,R3B),(ZC,R1S,R2D,R3C),(ZC ,R1S,R2D,R3D),(ZC,R1S,R2D,R3E),(ZC,R1S,R2D,R3F),(ZC ,R1S,R2D,R3G),(ZC,R1S,R2D,R3H),(ZC,R1S,R2D,R3I),(ZC 248 200843739 ,R1S,R2D,R3J),(ZC,R1S,R2D,R3K),(ZC,R1S,R2D,R3L),(ZC, R1S,R2D,R3M),(ZC,R1S,R2D,R3N),(ZC,R1S,R2D,R30),(ZC ,R1S,R2D,R3P),(ZC,R1S,R2D,R3Q),(ZC,R1S,R2D,R3R),(ZC ,R1S,R2E,R3A),(ZC,R1S,R2E,R3B),(ZC,R1S,R2E,R3C),(ZC, 5 R1S,R2E,R3D),(ZC,R1S,R2E,R3E),(ZC,R1S,R2E,R3F),(ZC,
R1S,R2E,R3G),(ZC,R1S,R2E,R3H),(ZC,R1S,R2E,R3I),(ZC, R1S,R2E,R3J),(ZC,R1S,R2E,R3K),(ZC,R1S,R2E,R3L),(ZC, R1S,R2E,R3M),(ZC,R1S,R2E,R3N),(ZC,R1S,R2E,R30),(ZC, R1S,R2E,R3P),(ZC,R1S,R2E,R3Q),(ZC,R1S,R2E,R3R),(ZC, 10 R1S,R2F,R3A),(ZC,R1S,R2F,R3B),(ZC,R1S,R2F,R3C),(ZC,R 1S,R2F,R3D),(ZC,R1S,R2F,R3E),(ZC,R1S,R2F,R3F),(ZC,R1 S,R2F,R3G),(ZC,R1S,R2F,R3H),(ZC,R1S,R2F,R3I),(ZC,R1S, R2F,R3J),(ZC,R1S,R2F,R3K),(ZC,R1S,R2F,R3L),(ZC,R1S,R 2F,R3M),(ZC,R1S,R2F,R3N),(ZC,R1S,R2F,R30),(ZC,R1S,R 15 2F,R3P),(ZC,R1S,R2F,R3Q),(ZC,R1S,R2F,R3R),(ZC,R1S,R2
G,R3A),(ZC,R1S,R2G,R3B),(ZC,R1S,R2G,R3C),(ZC,R1S,R2 G,R3D),(ZC,R1S,R2G,R3E),(ZC,R1S,R2G,R3F),(ZC,R1S,R2 G,R3G),(ZC,R1S,R2G,R3H),(ZC,R1S,R2G,R3I),(ZC,R1S,R2 G,R3J),(ZC,R1S,R2G,R3K),(ZC,R1S,R2G,R3L),(ZC,R1S,R2G 20 ,R3M),(ZC,R1S,R2G,R3N),(ZC,R1S,R2G,R30),(ZC,R1S,R2G ,R3P),(ZC,R1S,R2G,R3Q),(ZC,R1S,R2G,R3R),(ZC,R1S,R2H, R3A),(ZC,R1S,R2H,R3B),(ZC,R1S,R2H,R3C),(ZC,R1S,R2H, R3D),(ZC,R1S,R2H,R3E),(ZC,R1S,R2H,R3F),(ZC,R1S,R2H, R3G),(ZC,R1S,R2H,R3H),(ZC,R1S,R2H,R3I),(ZC,R1S,R2H, 249 200843739
R3J),(ZC,R1S,R2H,R3K),(ZC,R1S,R2H,R3L),(ZC,R1S,R2H, R3M),(ZC,R1S,R2H,R3N),(ZC,R1S,R2H,R30),(ZC,R1S,R2H ,R3P),(ZC,R1S,R2H,R3Q),(ZC,R1S,R2H,R3R),(ZC,R1S,R2I, R3A),(ZC,R1S,R2I,R3B),(ZC,R1S,R2I,R3C),(ZC,R1S,R2I,R 5 3D),(ZC,R1S,R2I,R3E),(ZC,R1S,R2I,R3F),(ZC,R1S,R2I,R3G ),(ZC,R1S,R2I,R3H),(ZC,R1S,R2I,R3I),(ZC,R1S,R2I,R3J),(Z C,R1S,R2I,R3K),(ZC,R1S,R2I,R3L),(ZC,R1S,R2I,R3M),(ZC ,R1S,R2I,R3N),(ZC,R1S,R2I,R30),(ZC,R1S,R2I,R3P),(ZC,R 1S,R2I,R3Q),(ZC,R1S,R2I,R3R),(ZC,R1S,R2J,R3A),(ZC,R1 10 S,R2J,R3B),(ZC,R1S,R2J,R3C),(ZC,R1S,R2J,R3D),(ZC,R1S, R2J,R3E),(ZC,R1S,R2J,R3F),(ZC,R1S,R2J,R3G),(ZC,R1S,R 2J,R3H),(ZC,R1S,R2J,R3I),(ZC,R1S,R2J,R3J),(ZC,R1S,R2J, R3K),(ZC,R1S,R2J,R3L),(ZC,R1S,R2J,R3M),(ZC,R1S,R2J,R 3N),(ZC,R1S,R2J,R30),(ZC,R1S,R2J,R3P),(ZC,R1S,R2J,R3 15 Q),(ZC,R1S,R2J,R3R),(ZC,R1S,R2K,R3A),(ZC,R1S,R2K,R3
B),(ZC,R1S,R2K,R3C),(ZC,R1S,R2K,R3D),(ZC,R1S,R2K,R3 E),(ZC,R1S,R2K,R3F),(ZC,R1S,R2K,R3G),(ZC,R1S,R2K,R3 H),(ZC,R1S,R2K,R3I),(ZC,R1S,R2K,R3J),(ZC,R1S,R2K,R3 K),(ZC,R1S,R2K,R3L),(ZC,R1S,R2K,R3M),(ZC,R1S,R2K,R 20 3N),(ZC,R1S,R2K,R30),(ZC,R1S,R2K,R3P),(ZC,R1S,R2K,R 3Q),(ZC,R1S,R2K,R3R),(ZC,R1S,R2L,R3A),(ZC,R1S,R2L,R 3B),(ZC,R1S,R2L,R3C),(ZC,R1S,R2L,R3D),(ZC,R1S,R2L,R 3E),(ZC:,R1S,R2L,R3F),(ZC,R1S,R2L,R3G),(ZC,R1S,R2L,R 3H),(ZC,R1S,R2L,R3I),(ZC,R1S,R2L,R3J),(ZC,R1S,R2L,R3 250 200843739 K),(ZC,R1S,R2L,R3L),(ZC,R1S,R2L,R3M),(ZC,R1S,R2L,R3 N),(ZC,R1S,R2L,R30),(ZC,R1S,R2L,R3P),(ZC,R1S,R2L,R3 Q),(ZC,R1S,R2L,R3R),(ZC,R1S,R2M,R3A),(ZC,R1S,R2M,R 3B),(ZC,R1S,R2M,R3C),(ZC,R1S,R2M,R3D),(ZC,R1S,R2M, 5 R3E),(ZC,R1S,R2M,R3F),(ZC,R1S,R2M,R3G),(ZC,R1S,R2
M,R3H),(ZC,R1S,R2M,R3I),(ZC,R1S,R2M,R3J),(ZC,R1S,R2 M,R3K),(ZC,R1S,R2M,R3L),(ZC,R1S,R2M,R3M),(ZC,R1S, R2M,R3N),(ZC,R1S,R2M,R30),(ZC,R1S,R2M,R3P),(ZC,R1 S,R2M,R3Q),(ZC,R1S,R2M,R3R),(ZC,R1S,R2N,R3A),(ZC,R 10 1S,R2N,R3B),(ZC,R1S,R2N,R3C),(ZC,R1S,R2N,R3D),(ZC,R 1S,R2N,R3E),(ZC,R1S,R2N,R3F),(ZC,R1S,R2N,R3G),(ZC,R 1S,R2N,R3H),(ZC,R1S,R2N,R3I),(ZC,R1S,R2N,R3J),(ZC,R1 S,R2N,R3K),(ZC,R1S,R2N,R3L),(ZC,R1S,R2N,R3M),(ZC,R 1S,R2N,R3N),(ZC,R1S,R2N,R30),(ZC,R1S,R2N,R3P),(ZC,R 15 1S,R2N,R3Q),(ZC,R1S,R2N,R3R)。 其他較佳態樣係於下式(g)〜(n)中具有以下基團者。 251 200843739 【化33】
表5 R2 R20 iPr R2P tBu R2Q cHex R2R Ph R2S 4-OMe-Ph R2T 3-0比°定基 R2U 噻吩基 表6 R3S iPr R3T tBu R3U cHex R3V Ph R3W 2-Cl-Ph R3X 2-吡啶基 252 200843739 表7 A, (僅(h),(i),(j),(k),(m^(n)) A1 2-或 3-或 4-COOEt A2 2-或 3-或 4-CF3 A3 2-或 3-或 4-OCF3 A4 2-或 3-或 4-SCF3 A5 2-或3-或4-異噚唑-3-基 A6 2-或 3-或 4-CH=NOH A7 2-或 3-或 4-CH=NOMe 前述表中,Me為甲基,Et為乙基,iPi:為異丙基,tBu 為第三丁基,cHex為環己基,Ph為苯基。 5 R2、R3及A’之組合(R2, R3, A’)為以下之化合物。
(R2,R3,A,)=(R20,R3S,A1),(R20,R3S,A2),(R20,R3S,A3 ),(R20,R3S,A4),(R20,R3S,A5),(R20,R3S,A6),(R20,R3S,A7 ),(R20,R3T,A1),(R20,R3T,A2),(R20,R3T,A3),(R20,R3T,A4 ),(R20,R3T,A5),(R20,R3T,A6),(R20,R3T,A7),(R20,R3U,A1 10 ),(R20,R3U,A2),(R20,R3U,A3),(R20,R3U,A4),(R20,R3U,A 5),(R20,R3U,A6),(R20,R3U,A7),(R20,R3V,A1),(R20,R3V, A2),(R20,R3V,A3),(R20,R3V,A4),(R20,R3V,A5),(R20,R3V, A6),(R20,R3V,A7),(R20,R3W,A1),(R20,R3W,A2),(R20,R3 W,A3),(R20,R3W,A4),(R20,R3W,A5),(R20,R3W,A6),(R20, 15 R3W,A7),(R20,R3X,A1),(R20,R3X,A2),(R20,R3X,A3),(R2
0,R3X,A4),(R20,R3X,A5),(R20,R3X,A6),(R20,R3X,A7),(R 2P,R3S,A1),(R2P,R3S,A2),(R2P,R3S,A3),(R2P,R3S,A4),(R2P ,R3S,A5),(R2P,R3S,A6),(R2P,R3S,A7),(R2P,R3T,A1),(R2P,R 3T,A2),(R2P,R3T,A3),(R2P,R3T,A4),(R2P,R3T,A5),(R2P,R3T 253 200843739 ,A6),(R2P,R3T,A7),(R2P,R3U,A1),(R2P,R3U,A2),(R2P,R3U, A3),(R2P,R3U,A4),(R2P,R3U,A5),(R2P,R3U,A6),(R2P,R3U,
A7),(R2P,R3V,A1),(R2P,R3V,A2),(R2P,R3V,A3),(R2P,R3V,A 4) ,(R2P,R3V,A5),(R2P,R3V,A6),(R2P,R3V,A7),(R2P,R3W,A1 5 ),(R2P,R3W,A2),(R2P,R3W,A3),(R2P,R3W,A4),(R2P,R3W,A5 ),(R2P,R3W,A6),(R2P,R3W,A7),(R2P,R3X,A1),(R2P,R3X,A2 ),(R2P,R3X,A3),(R2P,R3X,A4),(R2P,R3X,A5),(R2P,R3X,A6) ,(R2P,R3X,A7),(R2Q,R3S,A1),(R2Q,R3S,A2),(R2Q,R3S,A3) ,(R2Q,R3S,A4),(R2Q,R3S,A5),(R2Q,R3S,A6),(R2Q,R3S,A7) 10 ,(R2Q,R3T,A1),(R2Q,R3T,A2),(R2Q,R3T,A3),(R2Q,R3T,A4)
,(R2Q,R3T,A5),(R2Q,R3T,A6),(R2Q,R3T,A7),(R2Q,R3U,A1) ,(R2Q,R3U,A2),(R2Q,R3U,A3),(R2Q,R3U,A4),(R2Q,R3U,A 5) ,(R2Q,R3U,A6),(R2Q,R3U,A7),(R2Q,R3V,A1),(R2Q,R3V, A2),(R2Q,R3V,A3),(R2Q,R3V,A4),(R2Q,R3V,A5),(R2Q,R3V, 15 A6),(R2Q,R3V,A7),(R2Q,R3W,A1),(R2Q,R3W,A2),(R2Q,R3
W,A3),(R2Q,R3W,A4),(R2Q,R3W,A5),(R2Q,R3W,A6),(R2Q, R3W,A7),(R2Q,R3X,A1),(R2Q,R3X,A2),(R2Q,R3X,A3),(R2 Q,R3X,A4),(R2Q,R3X,A5),(R2Q,R3X,A6),(R2Q,R3X,A7),(R 2R,R3S,A1),(R2R,R3S,A2),(R2R,R3S,A3),(R2R,R3S,A4),(R 20 2R,R3S,A5),(R2R,R3S,A6),(R2R,R3S,A7),(R2R,R3T,A1),(R 2R,R3T,A2),(R2R,R3T,A3),(R2R,R3T,A4),(R2R,R3T,A5),(R 2R,R3T,A6),(R2R,R3T,A7),(R2R,R3U,A1),(R2R,R3U,A2),(R 2R,R3U,A3),(R2R,R3U,A4),(R2R,R3U,A5),(R2R,R3U,A6),( R2R,R3U,A7),(R2R,R3V,A1),(R2R,R3V,A2),(R2R,R3V,A3),( 254 200843739
R2R,R3V,A4),(R2R,R3V,A5),(R2R,R3V,A6),(R2R,R3V,A7),( R2R,R3W,A1),(R2R,R3W,A2),(R2R,R3W,A3),(R2R,R3W,A4 ),(R2R,R3W,A5),(R2R,R3W,A6),(R2R,R3W,A7),(R2R,R3X, A1),(R2R,R3X,A2),(R2R,R3X,A3),(R2R,R3X,A4),(R2R,R3X 5 ,A5),(R2R,R3X,A6),(R2R,R3X,A7),(R2S,R3S,A1),(R2S,R3S ,A2),(R2S,R3S,A3),(R2S,R3S,A4),(R2S,R3S,A5),(R2S,R3S, A6),(R2S,R3S,A7),(R2S,R3T,A1),(R2S,R3T,A2),(R2S,R3T,A 3),(R2S,R3T,A4),(R2S,R3T,A5),(R2S,R3T,A6),(R2S,R3T,A7 ),(R2S,R3U,A1),(R2S,R3U,A2),(R2S,R3U,A3),(R2S,R3U,A4 10 ),(R2S,R3U,A5),(R2S,R3U,A6),(R2S,R3U,A7),(R2S,R3V,A1 ),(R2S,R3V,A2),(R2S,R3V,A3),(R2S,R3V,A4),(R2S,R3V,A5), (R2S,R3V,A6),(R2S,R3V,A7),(R2S,R3W,A1),(R2S,R3W,A2), (R2S,R3W,A3),(R2S,R3W,A4),(R2S,R3W,A5),(R2S,R3W,A6 ),(R2S,R3W,A7),(R2S,R3X,A1),(R2S,R3X,A2),(R2S,R3X,A3 15 ),(R2S,R3X,A4),(R2S,R3X,A5),(R2S,R3X,A6),(R2S,R3X,A7 ),(R2T,R3S,A1),(R2T,R3S,A2),(R2T,R3S,A3),(R2T,R3S,A4), (R2T,R3S,A5),(R2T,R3S,A6),(R2T,R3S,A7),(R2T,R3T,A1),( R2T,R3T,A2),(R2T,R3T,A3),(R2T,R3T,A4),(R2T,R3T,A5),(R 2T,R3T,A6),(R2T,R3T,A7),(R2T,R3U,A1),(R2T,R3U,A2),(R2 20 T,R3U,A3),(R2T,R3U,A4),(R2T,R3U,A5),(R2T,R3U,A6),(R2 T,R3U,A7),(R2T,R3V,A1),(R2T,R3V,A2),(R2T,R3V,A3),(R2T ,R3V,A4),(R2T,R3V,A5),(R2T,R3V,A6),(R2T,R3V,A7),(R2T, R3W,A1),(R2T,R3W,A2),(R2T,R3W,A3),(R2T,R3W,A4),(R2T ,R3W,A5),(R2T,R3W,A6),(R2T,R3W,A7),(R2T,R3X,A1),(R2 255 200843739 T,R3X,A2),(R2T,R3X,A3),(R2T,R3X,A4),(R2T,R3X,A5),(R2 T,R3X,A6),(R2T,R3X,A7),(R2U,R3S,A1),(R2U,R3S,A2),(R2 U,R3S,A3),(R2U,R3S,A4),(R2U,R3S,A5),(R2U,R3S,A6),(R2 U,R3S,A7),(R2U,R3T,A1),(R2U,R3T,A2),(R2U,R3T,A3),(R2 5 U,R3T,A4),(R2U,R3T,A5),(R2U,R3T,A6),(R2U,R3T,A7),(R2 U,R3U,A1),(R2U,R3U,A2),(R2U,R3U,A3),(R2U,R3U,A4),(R 2U,R3U,A5),(R2U,R3U,A6),(R2U,R3U,A7),(R2U,R3V,A1),( R2U,R3V,A2),(R2U,R3V,A3),(R2U,R3V,A4),(R2U,R3V,A5),( R2U,R3V,A6),(R2U,R3V,A7),(R2U,R3W,A1),(R2U,R3W,A2) 10 ,(R2U,R3W,A3),(R2U,R3W,A4),(R2U,R3W,A5),(R2U,R3W, A6),(R2U,R3W,A7),(R2U,R3X,A1),(R2U,R3X,A2),(R2U,R3 X,A3),(R2U,R3X,A4),(R2U,R3X,A5),(R2U,R3X,A6),(R2U,R 3X,A7)。 實施例 15 以下顯示實施例俾更具體地說明本發明,但本發明並 不侷限於此等實施例。此外,各略號具有以下所示之意義。 Me :曱基 Et :乙基 Bu : 丁基 20 Ac :乙醯基 TMS :四曱基矽烷 TMS-C1 :三甲矽基氯 DMSO :二甲基亞颯 rt :室溫 256 200843739 實施例1 製造5-環己基_4-(2,2-二曱基丙醯基)-3-羥基-1-(4-異噚唑-3 基本基)-1,5-二氫吼略·2_酮(1-32) 【化34】
於三甲基丙酮酸乙醋(1.00 g,5 mmol)、4-異σ号唾冬基 笨胺(0.80 g,5 mmol)與乙酸(4 mL)之混合液中加入環己院 甲醛(0·61 mL,5 mmol),以95°C攪拌5小時。反應後,冷卻 至室溫,以乙酸乙g旨一邊洗淨一邊滤取已析出之結晶,而 10 獲得呈淡黃色結晶之5-環己基-4-(2,2-二甲基丙醯基)-3_羥 基-1-(4-異嘮唑-3-基苯基)-1,5-二氫吡咯-2-酮(0.60 g,收率: 30%) 〇 熔點:259〜260°C、1H-NMR (δ ppm TMS / DMSO-d6) 〇·62-1·78 (11H,m),1·27 (9H,s),5·28 (1H,d,J=2.4 Hz), 15 7.20 (1H,d,J=1.8 Hz),7.75 (2H,d,J=8.7 Hz),7·98 (2H,d, J=8.7 Hz), 9·03 (1H,d,J=1.8 Hz),11.84 (1H,s) 實施例2 製造5-(3-氟苯基)-3-羥基-H4-異噚唑-3-基苯基)-4-(4-甲氧 基苯曱醯基)-1,5-二氫吼咯-2-酮(1-26) 20【化35】 257 200843739
於(4-甲氧基苯甲醯基)丙酮酸甲酯(0.24 g,1 mmol)、4-異噚唑-3-基苯胺(0.16 g,1 mmol)與二噚烷(1 mL)之混合液 中加入3-氟苯甲酸(0.11 mL, 1 mmol)並於室溫下攪拌2天。 5 反應後,加入二乙醚(3 mL),濾取已析出之結晶,而製得 呈微黃色結晶之5-(3-氟苯基)-3-羥基-1-(4-異噚唑-3-基苯 基)_4-(4-甲氧基苯甲醯基)-1,5-二氫吡咯-2-酮(0.16 g,收率: 34%) 〇 熔點:273 〜274°C (分解)、1H-NMR (δ ppm TMS / 10 DMSO-d6) 3·83 (3H, s),6.43 (1H,s),6.90-7.02 (3H,m), 7.11 (1H,d,J=1.7 Hz),7·23-7·35 (3H,m),7.75-7.87 (6H,m), 8.97 (1H,d,J=1.7 Hz), 11.75 (1H,brs). 實施例3 製造3 -弟二丁基-4-i哀己基-5-(4-異崎σ坐-3-基苯基)-4,5-二氮 15 -1Η-σ 比口各[3,4-c]a 比唾-6-酮(1-96) 【化36】
於5-環己基-4-(2,2-二甲基丙醯基)-3-羥基-1-(4-異噚唑 258 200843739 -3-基苯基)-1,5-二氫吡咯-2-酮(〇.1〇8,〇.25 111111〇1)與乙酸(1 mL)之混合液中加入肼之單水合物(〇·〇36 mL,0.75 mmol), 以85°C攪拌3小時。於反應液中加入水(8〇 mL),再以乙酸 乙酯(100 mL)抽提之。以飽和碳酸氫鈉水(8〇 mLx2)水洗抽 5 取液,再以無水硫酸鎂乾燥後’將減壓濃縮所得殘渣以二 氧化矽凝膠管柱層析法(乙酸乙酯/正己烷)純化,並使所得 結晶進行再結晶(乙酸乙酯),而製得呈無色結晶之3-第三丁 基-4-環己基-5-(4-異°号σ坐-3-基苯基)-4,5-二鼠-1H- 0比洛 [3,4-〇]°比唾-6-酮(0.072 g,收率:71%)。 10 熔點:251 〜252°C、1H-NMR (δ ppm TMS / DMSO-d6) 0.50-2.03 (11H,m), 1·39 (9H,s),5·60 (1H,s),7·20 (1H,d, J=1.8 Hz),7·72 (2H,d,J=8.7 Hz),7·96 (2H,d,J=8.7 Hz), 9.02 (1H, d, J=1.8 Hz), 13.28 (1H, s). 實施例4 15 製造4-(1-乙基丙基)-5-(4-異呤唑-3-基苯基)-3-(6-酮基-1,6- 二氫吡啶-3-基)-4,5-二氫-1H-吡咯[3,4-c]吡唑-6-酮(1-198) 【化37】
於4-(1-乙基丙基)-5-(4-異噚唑-3-基苯基)-3-(6-甲氧基 20 吡啶-3-基)-4,5-二氫-1H-吡咯[3,4-c]吡唑-6-酮(0.067 g,0.15 mmol)、碘化鈉(〇·〇67 g,0.45 mmol)與乙腈(3 mL)之混合液 259 200843739 中添加氯三甲基石夕烧(〇·〇58 mL,〇·45 mmol),回流下攢;拌1 小時。於反應液中加入水(50 mL)與乙酸乙酯(5〇 mL),渡取 析出之結晶,而製得呈微黃色結晶之4-(1-乙基丙基)-5-(4-異噚唑-3-基苯基)-3-(6-酮基-1,6-二氫吼唆-3-基)-4,5-二氫 5 -1Η-σ比洛[3,4-c]°比。坐-6-酮(0.041 g,收率:64%)。 熔點·· >290°C (分解)、1H-NMR (δ ppm TMS / DMSO-d6) 0·50-1·55 (11H,m),6·00 (1H,d,J=2.5 Ηζ),6·49 (1H,d, J=9.4 Hz),7.18 (1H,d,J=1.8 Hz),7.70-7.90 (4H,m),8.01 (2H,d,J=8.4 Hz),9.02 (1H,d,J=1.8 Hz), 12.04 (1H,brs), 10 13.78 (1H, brs). 實施例5 製造3-羥基-4-(4-甲氧基苯甲醯基)-i-(4_甲氧基亞胺基甲基 苯基)-5-苯基-1,5-二氯ϋ比洛-2-嗣(1-199) 【化38】
於3-羥基-1-(4-羥曱基苯基)-4-(4-甲氧基苯曱醯基)-5-本基-1,5-二鐵^比洛-2-酮(0.125 g,0.3 mmol)與丙酮(20 mL) 之混合液中加入氧化錳(IV)(0.625 g,7.18 mmol)並以室溫 攪拌2.5小時後,更加入氧化鐘(1¥)(0.625 §,7.18111111〇1), 20以室溫攪拌4·5小時。反應後,以矽藻土除去不溶之氧化錳 (IV)’濃縮濾液而製得ι·(4_甲酿基苯基)_3__經基_4_(4_甲氧基 260 200843739 苯甲醯基)-5-苯基-1,5-二氫吡咯-2-_之粗製物。於所得粗製 物中加入甲醇,調製成〇·1Μ之曱醇溶液。 於1-(4-曱&&基苯基)-3-經基-4-(4,甲氧基苯甲贐基)-5~ 苯基-1,5-二氫吼咯-2-酮之〇·1Μ甲醇溶液(1 mL,相當於0.1 5 mmo1)加入〇-甲基羥基銨氯化物(0.025 g,0.3 mmol)與乙 酸鈉(0.025 g,0·3 mmol),於回流下授拌3小時。於反應液中 添加水(50 mL)後,以乙酸乙酯(5〇 mL)抽提。以飽和食鹽水 (50 mL)水洗該抽提液,並以無水硫酸鈉乾燥後,於減壓濃 务百所得之殘渣中加入乙酸乙酯,濾取已析出之結晶,而製 10 得呈微黃色結晶之’3-羥基-4-(4-甲氧基苯甲醯基)-1-(4-甲氧 基亞胺基甲基苯基)-5-苯基-1,5-二氫°比嘻-2-酮(1.3 mg,收 率:3%)。 熔點·· 226〜229°C、1H-NMR (δ ppm TMS / DMS0-d6) 3·82 (3H,s),3·85 (3H,s),6·31 (1H,s),6.95-7.75 (13H,m), 15 8.12(1H,s),11.63 (lH,brs). 實施例6 製造1-(1,3-二σ号戍烧-2-基)-3-經基-4-(4_曱氧基苯曱酸 基>5-苯基-1,5-二氫吡咯-2-酮(1-200) 【化39】
將1-(4-甲醯基苯基)-3-羥基-4-(4-甲氧基苯甲醯基)_孓 261 200843739 苯基-1,5-二氫吡咯-2-酮之0.1M甲醇溶液(1 mL,相當於〇」 mmol)濃縮後,力口入甲苯(1 mL)、乙二醇(0.033 mL,〇·6 mm〇i) 與對甲苯磺酸之單水合物(3.8 mg,0·02 mmol),進行共沸脫 水3小時。於反應液中加入水(100 mL),並以乙酸乙醋(wo 5 mL)進行抽提。以飽和食鹽水(1〇〇 mL)水洗抽提液,並以無 水硫酸鈉乾燥後,於減壓濃縮所得殘渣中加入乙酸乙醋, 濾、取析出之結晶,而製得呈淡黃色結晶之二噚戊烧 -2-基)-3-羥基-4-(4-甲氧基苯曱醯基)-5-苯基-1,5-二氫吡咯 -2-酮(3.8mg,收率:8%)。 10 溶點:216〜219°C、1H-NMR (δ ppm TMS / DMSO-d6) 3.81 (3H,s),3.89-4.00 (4H,m),5·63 (1H,s),6.26 (1H,s), 6.94-7.75 (13H,m),11.65 (1H,brs)· 實施例7 製造3-羥基-1-(4-異嘮唑-3-基苯基)-4-(4-甲氧基苯甲醯 15 基)-5-(4-哌啶)-1,5-二氳吡咯-2-酮之鹽酸鹽(1-201) 【化40】
於5-(1-第三丁氧羰基-4-哌啶)-3-羥基-1-(4-異噚唾·3_ 基苯基)-4-(4-甲氧基苯甲酿基)-1,5-二氫°比洛-2-酮(〇.1120 20 0.2 mmol)與甲醇(1 mL)之混合液中加入4 mol/L鹽酸之二 崂烷溶液(0.2 mL,0.8 mmol),以室溫攪拌2·5小時後,更力口 262 200843739 入4 mol/L鹽酸之二噚烧溶液(〇·2 mL,0.8 mmol),於回流下 攪拌0.5小時。反應後,減壓濃縮而製得呈微褐色結晶之3_ 羥基-1-(4-異噚唑-3-基苯基)-4-(4-甲氧基苯甲醯基)-5-(4-哌 啶)-1,5-二氫吡咯-2-酮之鹽酸鹽(0.098 g,收率·· 100%)。 5 1H-NMR (δρριη TMS / DMSO-d6) 1.25-2.09 (5H, m), 2·50-2·74 (2H,m),3.09-3.17 (2H,m),3.90 (3H,s),5.58 (1H, s),7.09 (2H,d,J=8.6 Hz),7·21 (1H,d,J=1.5 Hz),7·82-7·89 (4H,m),8.02 (2H,d,J=8.6 Hz),8·11 (1H,brs),8.58 (1H, brs),9.04 (1H,d,J=1.5 Hz),11.55 (1H,brs)· !〇 實施例8 製造3-(4-甲氧基苯基)-5-(4_噚唑基苯基)_4_苯基-4,5-二 氫-1H』比洛[3,4-c]吼唾-6-酮(1-247) 【化41】
將5-(4-溴苯基甲氧基苯基苯基-4,5-二氫_1Η· 〇比咯[3,4-小比唑4_(〇 138 g,〇 3 mm〇1)與噚唑基三丁基 錫(〇·134 g,0.37 mmol)、三-(2_ 呋喃基)膦(〇〇14 匕 〇 恥 mm〇1)、三(二亞苄基丙酮)二鈀(0)(0.027 g,0.03 mm〇1)、二 可烷(1·5 mL)之混合液於微波照射下以130°C攪拌75分鐘。 使反應液採二氧化石夕凝膠管柱層析法(乙酸乙酉旨/正己燒), I辰縮所得目的物之分液一邊濾取已析出之結晶,而势 263 200843739 得呈無色結晶之3-(4-甲氧基苯基)-5-(4-噚唑-2-基苯基)-4-苯基-4,5-二氫-1H-σ比洛[3,4-c]吼吐-6-酮(12 mg,收率: 10%)。 1H-NMR (δρρπι TMS / DMSO-d6) 3.75 (3H, s), 6.86 5 (1H,s),6.91-7.92 (13H,m),8·17 (1H, s),14.00 (1H,brs)· 實施例9 製造5-環己基-3 -經基-1-(4-異4嗤-3 -基苯基)-4-(4-魏基苯 曱醮基)-1,5-二氫σ比口各-2-酮 【化42】
於5-環己基-3-羥基-1-(4-異噚唑-3-基苯基)-4-(4-甲氧 魏基苯曱醯基)-1,5-二氫吼洛-2-酮(1.98g,4.07mmol)、 THF(20mL)與甲醇(13mL)之混合液中加入2N氫氧化鈉水溶 液(5.09mL),以80°C油浴攪拌2小時。反應後,於冰冷下加 15 入2N鹽酸(5.09mL)後,更加入乙酸乙酯與水,以室溫放置 一夜後濾取析出之結晶,製得呈黃色結晶之5-環己基-3-經 基-1-(4-異噚唑-3-基苯基)-4-(4-羧基苯曱醯基H,5_二氯吼 洛-2-酮(1.70g,收率:88%)。 lH-NMR(6ppmTMS/DMSO-d6)0.73-1.80(HH , m) 20 5.49(1H,d,J=2.4H z ),7·21(1Η,d,j=1.7H z ), 7·80-8·11(8Η,m),9.04(1H,d,J=1.7H z )。 264 200843739 實施例ίο 製造5-環己基-3-羥基-1-(4-異噚唑-3-基苯基)-4-(4-甲基胺 甲醯基苯甲醯基)-1,5-二氫吡咯-2-酮 【化43】
於5-環己基-3-羥基-1-(4-異哼唑-3-基苯基)-4-(4-羧基 苯甲酿基)-1,5-二氫°比口各-2-酉同(0.095g,0.2mmol)與 DMF(2mL)之混合液中加入甲基胺之鹽酸鹽(0.020g, 0.3mmol)、1-經基苯并三。坐(0.041g,0.3mmol)、4-二曱基胺 10 基%b^(0.005g,0.04mmol)、鹽酸 1-乙基-3-(3-二甲基胺基 丙基)羱二亞胺(〇.〇58g ,0.3mmol)及三乙胺 (0.042mL,0.3mmol),並以室溫授拌1小時。反應後,加入乙 酸乙酯與水,濾取已析出之結晶,製得呈淡黃色結晶之5-壞己基-3-經基-1-(4-異σ号峻-3-基苯基)-4-(4-甲基胺甲酿基 15 苯曱醯基)-1,5-二氫吡咯-2-酮(0.062g,收率:64%)。 lH-NMR(5ppmTMS/DMSO-d6)0.72-1.80(1 lH9m) , 2.81(3H,d,J=4.5H z ) , 5.48(lH,d,J=2.5H z ), 7.21(lH,d,J=1.7Hz),7.80-8.03(8H,m),8.64(lH,d,J=4.5H z ),9.04(lH,d,J=1.7H z ),11.73(lH,brs)。 20 實施例11 製造3-第三丁基-5-(4-異噚唑-4-基苯基)-4-(2-甲氧基苯 265 200843739 基)-4,5-二氫-111-°比略[3,4-(:]11比。坐-6-酮 【化44】
將5-(4- >臭苯基)-3-第二丁基-4-(2-甲氧基苯基)-4,5-二 5 氫-1Η-σ比口各[3,4-0]〇比°坐-6-酮(0.10g,0.23mmol)、4-(4,4,5,5- 四甲基-l,3-2-二崎硼烧-2-基)異 _ 吐(0.066g,0.34mmol)、 磷酸三鉀(0· 145g,0.68mmol)、乙二醇二甲醚(3mL)與水 (0.6mL)之混合液作氮取代後,加入[1,1、雙(二苯基膦基)二 茂鐵]二氯鈀(Π)二氯甲烷附加物(0.018g,0.023mmol),回 10 流下攪拌4小時。將反應液以二氧化矽凝膠管柱層析法(乙 酸乙酯/正己烷)純化,製得呈無色結晶之3-第三丁基-5-(4-異噚唑-4-基苯基)-4-(2-甲氧基苯基)-4,5-二氫-1H j比咯 [3,4-c]吡唑-6-酮(0.012g,收率·· 12%)。 lH-NMR0ppmTMS/DMSO-d6)l.O5(9H,s),3·91(3Η, 15 s),6·22-7·61(9Η,m),9·09(1Η,s),9·36(1Η,s),13·34(1Η, s) ° 實施例12 製造3-第三丁基-5-(4-呋喃-3-基苯基)-4-(2-曱氧基苯 基)-4,5-二氫-111-°比洛[3,4-(:]吼哇-6-酮 20 【化45】 266 200843739
將5-(4-溴苯基)-3-第三丁基-4-(2-曱氧基苯基)-4,5-二 氫-111-11比洛[3,4-(:]11比°坐-6-嗣(0.1〇8,0.23111111〇1)、吱喃-3-基 硼酸(0.038g,0.34mmol)、磷酸三鉀(0.096g,0.45mmol)與 5 丁醇(lmL)之混合液作氮取代後,加入(2’,4’,6’-三異丙基聯 苯-2-基)膦(0.009g,0.02mmol)與三(二亞苄基丙酮)二|巴 (0)(0.004g,0.004mmol),於回流下攪拌3小時。使反應液以 二氧化矽凝膠管柱層析法(乙酸乙酯/正己烷)將所得目的物 之分液一邊濃縮一邊析出,濾取結晶而獲得呈無色結晶之 10 3 -弟二丁基-5-(4-咬喃-3 -基苯基)-4-(2-甲氧基苯基)-4,5 -二 氫-1Η-σ比洛[3,4-c]a比唾-6-酮(0.061g,收率:63%)。 lH-NMR(5ppmTMS/DMSO-d6)1.05(9H,s) , 3.90(3H,s),6.37-7.56(10H,m),7.70(lH,s),8.11(lH,s), 13.32(lH,s)。 15 實施例13 製造5-環己基-3-羥基-4-(4-羥基苯曱醯基)-1-(4-異噚唑-3-基本基)-1,5 - ->氮π比1^ - 2 -酉同 【化46】 267 200843739
在冰冷下,於5-環己基-3-羥基-1-(4-異哼唑-3-基苯 基)-4-(4-甲氧基苯甲醯基)-1,5-二氫吡咯-2-酮(0.229g, 0.5mmol)與二氯甲烷(10mL)之混合液中加入1M三溴化硼 5 二氣甲烧溶液(5.0mL,5mmol),並以室溫攪拌溫3天。反應 後,於冰冷下加入少量碳酸鉀分解過剩之三溴化硼,加入 1N氫氧化鈉水溶液後,以乙酸乙酯洗淨。使水層以1N鹽酸 中和,濾取析出之結晶,熱時以乙酸乙酯洗淨,製得呈無 色結晶之5-壤己基-3-控基-4-(4-經基苯甲酸基)-1-(4-異。号13坐 10 -3-基本基)-1,5-*—氮^比咯-2-嗣(0.068g ’ 收率· 31 %)。 lH-NMR(3ppmTMS/DMSO-d6)0.73-1.80(llH,m), 5·41(1Η,d,J=2.5H z ),6·88-6·91(2Η,m),7·20(1Η,d, J=1.7H z ),7·78-8·01(6Η,m),9·03(1Η,d,J=1.7H z ), 10·42(1Η,brs),11.14(lH.brs)。 15 實施例14 製造5-環己基-3-羥基-4-(4-羥甲基苯甲醯基)-1-(4-異噚唑 -3-基苯基)-1,5_二鼠ϋ比略-2-酉同 【化47】 268 200843739
於曱基4-(2-四氫比喃氧基甲基)苯曱醯基丙酮酸 酯(0.178,0.53111111〇1)、4-異噚唑-3-基苯胺(0.0858,0.53111111〇1) 與乙酸(lmL)之混合液中加入環己烷甲醛 5 (0.064mL,0.53mmol),並以95°C攪拌0.5小時。反應後,冷 卻至室溫,一邊以乙酸乙酯洗淨一邊濾取已析出之結晶, 於所得粗製物中加入甲醇(5mL)、THF(5mL)及對甲苯磺酸 吼啶鏽(0.027g,O.llmmol),以60°C攪拌〇·5小時。於反應 液中加入水,以氯仿抽提並以無水硫酸鎂乾燥後,將減壓 10 濃縮所得之殘渣實施再結晶(乙酸乙酯),而製得無色結晶之 5-環己基-3-羥基-4-(4-羥甲基苯甲醯基)-1-(4-異噚唑-3-基 苯基)-1,5-二氫吡咯-2-酮(0.022g,收率:9%)。 lH-NMR(3ppmTMS/DMSO-d6)0.62-1.78(llH,m), 4·61(2Η,d,J=5.6H z ),5·38(1Η,t,J=5.6H z ),5·47(1Η, 15 d,J=2.0H z ),7·21(1Η,d,J=1.7H z ),7·49-8·02(8Η,m), 9.03(1H,d,J=1.7H z ),11·40(1Η,brs) 一般製造法1 製造經離析之鏡向異構物 【化48】 269 200843739
(Γ-1) 式中記號與前述者同義。 使化合物(Γ-l)及光學分割劑(如(S)-曱基2-羥基-2-苯基 乙酸酯)於適當溶劑中與縮合劑(如偶氮二甲酸異丙酯)反 5 應,使所得混合物以常法(如管柱層析法、再結晶法等)純 化,而離析出具有所需立體配置之非鏡向異構物。將所得 非鏡向異構物進行脫保護反應(如加氫反應)即可製造出目 的之鏡向異構物。光學分割劑相對於化合物(Γ-1)係使用 1〜4等量,且較佳為1〜2.5等量。 10 可使用之溶劑可列舉如:芳香族烴類(如甲苯、苯、二 甲苯等)、飽和烴類(如環己烷、己烷等)、醚類(如四氫呋喃、 二乙醚、二哼烷等)醯胺類(如二甲基甲醯胺、二甲基乙醯 胺、Ν-甲基吡咯啶酮)及其等之混合溶劑等。 反應溫度為-10〜150°C,較佳為0〜50°C。反應時間雖依 15 化合物而異,但使其反應10分鐘〜48小時即可。 依照一般製造法1來製造以下化合物。 實施例15 製造( + )-4-(2,2-二甲基丙醯基)-3-羥基-1-(4-異噚唑-3-基苯 基)-5-(2-甲氧基苯基)-1,5-二氫吡咯-2-酮 20 【化49】 270 200843739
於冰冷下,於4-(2,2-二甲基丙醯基)-3-經基-:1-(4-異十坐 -3-基苯基)一5-(2-甲氧基苯基)-1,5-二氫°比嘻-2-酮(〇.43g, lmmol)、(S)-甲基 2-羥基-2-苯基乙酸酯(〇.23g,l.4mmol)、 5三苯基膦(〇.34g,1.3mmol)與THF(lOmL)之混合液中加入偶 氮二甲酸異丙g旨(〇.26mL,1.3mmol),並以室溫授摔〇 5小 時。將反應液減壓濃縮,並使已藉二氧化矽凝膠管柱層析 法(乙酸乙酯/正己烷)純化而獲得之非鏡向異構物混合物再 結晶(乙酸乙酯/正己烷),製得呈無色結晶之非鏡向異構物 10 (0.14g,收率:25%)。 使所得非鏡向異構物(0.058g,O.lmmol)溶解於二。号垸 (3mL)中,加入1〇%鈀碳(〇.〇26g),以室溫進行2小時加氫。 以矽藻土過濾反應液後,將濃縮所得殘渣以二氧化石夕凝膠 管柱層析法(乙酸乙酯/正己烷)純化,製得呈無色結晶之 15 ( + )冰(2,2-二甲基丙酿基)-3-經基-1-(4-異噚tr坐-3-基苯 基)-5-(2-甲氧基苯基)-1,5-二氫吼咯-2-酮(〇.〇43g,收率: 100%,光學純度:100%ee)。 [a]D ·· + 62.5±2.0°.(inCHC13) , lH-NMR0ppmTMS/DMSO-d6)l.lO(9H,s),3·89(3Η,brs), 20 6·39(1Η,brs),6·70-7·82(9Η,m),8·95(1Η,d,J=1.8H z ), 271 200843739 12·08(1Η,brs) 〇 一般製造法2 製造噚唑體 【化50】
式中,X為鹵素,其他記號與前述者同義。 可使化合物(I -2)、輕亞胺基函化物及驗於適當溶劑中 反應而製彳于。獲得之所需化合物可視需要而以常法(如管柱 層析法、再結晶法等)進行純化。羥亞胺基_化物相對於化 10合物(F-2)係使用1〜5等量,較佳為1〜2.5等量。 可使用之溶劑可列舉如:芳香族烴類(如甲苯、苯、二 甲苯等)、飽和烴類(如環己烧、己烧等)、醚類(如四氫呋喃、 二乙醚、二噚烧等)、醯胺類(如二甲基甲醯胺、二甲基乙醯 胺、Ν-甲基吼洛啶酮)及該等之混合溶劑等。 15 可使用之驗可列列舉如金屬氫氧化物(如氫氧化鈉、氫 氧化鉀等)、金屬氫化物(如氫化鈉、氫化鋰等)、金屬碳酸 鹽(如碳酸鈉、碳酸鉀、碳酸鉋等)等,相對於化合物(Γ-2) 可使用2當量或以上,且較佳為2〜10當量。 反應溫度為-40〜150°C,較佳為0〜50°C。反應時間雖依 272 200843739 化合物而異,但使其反應10分鐘〜48小時即可。 依照前述之一般製造法2來製造下述化合物。 實施例16 製造3-第三丁基-5-[4-(3-乙氧羰基異噚唑基)苯基]冬(2_ 5甲氧基本基)-4,5- —鼠比嘻[3,4-c]a比哇-6-酮 【化51】
於冰冷下,於3-第三丁基-5-(4-乙炔基苯基)冰(2-曱氧 基笨基)-4,5- 一氫-1H- σ比洛[3,4-c]吼唾-6-自同(1.51g, 10 3.9mmol)、乙基2-氣-2-羥亞胺基乙酸酯(1.19g,7 8mm〇1) 與THF(4mL)之混合液中緩緩加人三乙胺(! 〇9mL7 8mm〇1) 之THF(3mL)溶液’以〇°c攪拌4小時。於反應液中加入乙基 2-氯-2-經亞胺基乙酸酯(i.i9g,7.8mmol)後,更徐徐加入三 乙胺(0.81mL,5.9mmol)之THF(3mL)溶液,以〇。〇攪拌2小時 15後放置一夜。除去已析出之結晶,將減壓濃縮所得殘渣純 化,而製得呈無色固體之3-第三丁基-5-[4-(3-乙氧魏基-5-異D.坐基)苯基M-(2-曱氧基苯基)-4,5-二氫-lH-t各[3,4-C] °比哇-6-明(1.26g,收率:64%)。 lH-NMR(8ppmTMS/DMSO-d6)1.13(9H,s),1·43(3Η, 20 t,J=7.l),3·50(0·5Η,S),4·01(2·5Η,s),4·45(2Η,q,J=7.3), 6·01(0·3Η,s),6·74-6·88(2·7Η,m),6·91(1Η,d,J=8.6), 273 200843739 7·19(1Η,t,J=7.4),7·70(2Η,d,J=8.6),7·81(2Η,d,J=8.6)。 實施例17 製造3-第三丁基-5-[4-(3-羧基-5-異噚唑基)苯基]_4_(2_甲氧 基苯基)-4,5-二氫-1^1-°比嘻[3,4-〇]°比唾-6-酮 5 【化52】
於3·第三丁基-5-[4-(3-乙氧羰基各異噚唑基)苯 基]冰(2-甲氧基苯基)-4,5-二氫-1H-吡咯[3,4-c]吡唑-6-酮 (1.26g,2.5mmol)、甲醇(4mL)、THF(4mL)及水(3mL)之混 10 合液中加入2N氫乳化納水溶液(1.5mL,3mmol),以50°C撲摔 1小時。反應後,加入水(40mL)與1N鹽酸(2mL),以乙酸乙 酯抽提後再以飽和食鹽水洗淨,並以無水硫酸鈉乾燥之。 乾燥後,使減壓濃縮所得之粗製物懸濁於醚,濾取已析出 之結晶後,製得呈淡黃色結晶之3-第三丁基-5-[4-(3-羧基-5-15 異噚唑基)苯基]-4-(2-甲氧基苯基)-4,5-二氫-1H·-比咯[3,4-c] 吡唑-6-酮(0.84g,收率:71%)。 lH-NMR0ppmTMS/DMSO_d6)l.O5(9H,s),3·96(3Η, s),6·50(0.3Η,s),6·68-6·94(2·7Η,m),7.00-7·25(2Η,m) ’ 7·29(1Η,s),7·77(2Η,d,J=8.6),7.87(2Η,d,J=8.6), 20 13·43(1Η,brs),13·97(1Η,brs)。 實施例18 274 200843739 製造3-第三丁基-5-[4-(3-二甲基胺曱醯基_5-異4 σ坐基)苯 基]-4-(2-曱氧基苯基)-4,5-二氣-1Η-σ比略[3,4-c]0比σ坐-6-嗣 【化53】
於3-第三丁基-5-[4-(3-羧基-5-異噚唑基)苯基]-4-(2-甲 氧基本基)-4,5-二氮-1Η-吼略[3,4-c]吼 坐-6-嗣(0.080g, 0.17mmol)與DMF(2mL·)之混合液中力口人二甲胺鹽酸鹽 (0.021g,〇.25mmol)、1-羥基苯并三唑(〇.〇34g,0.25mmol)、 4- 二甲基胺基吼咬(0.004g,0.03mmol)、鹽酸1-乙基-3-(3-10 二甲基胺基丙基)碳二亞胺(0.048g,0.25mmol)及三乙胺 (0.035mL,0.25mmol),以室溫攪拌2小時。反應後,加入乙 酸乙酯與水,濾取已析出之結晶,而製得呈淡黃色結晶之 5- 環己基-3-每基-1-(4-異$ σ坐-3-基苯基)-4-(4-曱基胺甲酿 基苯甲醯基)-1,5-二氫吡咯-2-酮(0.055g,收率:65%)。 15 lH-NMR(5ppmTMS/DMSO-d6)1.05(9H,s),3·02(3Η, s),3·39(1Η,s),6·50(0·3Η,m),6·65-6·96(2·7Η,m),7·06(1Η, d,J=8.1),7·14(1Η,s),7·19(1Η,t,J=7.6),7·76(2Η,d, J=8.6),7·84(2Η,d,J=8.6),13·32(1Η,brs)。 實施例19 20 製造3-第三丁基-5-[4-(3-羥甲基-5-異噚唑基)苯基]-4-(2-甲 氧基苯基)-4,5-二氫-1士°比嘻[3,4-〇]吼嗤-6-酮 275 200843739 【化54】
於冰冷下,在3-第三丁基-5-[4-(3-羧基-5-異°号峻基)苯 基]-4-(2-曱氧基苯基)-4,5-二氫比 π各[3,4-(:]〇比嗤-6-_ 5 (〇.〇80g,0.17mmol)、三乙胺(〇.〇3imL,0.22mmol)與 THF(2mL)之混合液中加入氯碳酸乙酯 (0.019mL,0.20mmol),並以室溫攪拌2小時。接著,於反應 液中加入氫化硼鈉(0.026g,0.68mmol)與水(〇.3mL)之溶液 後,更加入甲醇(lmL)並以室溫攪拌1〇分鐘。反應後加入 10 水,以乙酸乙酯抽提後,再以1N鹽酸、飽和碳酸鈉水及飽 和食鹽水洗淨,以無水硫酸鈉乾燥之。乾燥後,使減壓濃 縮所獲得之殘渣以二氣甲烷、二乙醚及乙酸乙酯結晶,濾 取已析出之結晶,而製得呈無色結晶之3-第三丁基-5-[4-(3-羥甲基-5-異噚唑基)苯基]-4-(2-甲氧基苯基)-4,5-二氫-1H-15 π比洛[3,4-。]°比唾-6-酮(0.068g,收率:88%)。 1H-NMR(8ppmTMS/DMSO-d6)1.03(9H,s),3·39(1Η, s),3·94(2Η,s),4·51(2Η,d,J=26.9),5·52(5·52(1Η,t, J=5.8),6·47(0·3Η,s),6·65-6·84(2·7Η,m),6·88(1Η,s), 7·05(1Η,d,J=8.1),7·19(1Η,t,J=7.6),7·73(2Η,d,J=8.6), 20 7.78(2H,d,J=8.6),13·13(0·3Η,brs),13·39(0·6Η,brs), 13·58(0·1Η,brs)。 276 200843739 一般製造法3 製造Boc-保護胺體 【化55】
5式中§己號與前述者同義。 將化合物(1’-3)、驗及疊氮化觸(如二苯_酸基疊氮) 於適當溶劑中反應,接著,於反應液中加入第三丁醇與乾 峨如硫酸納、粉末分子篩)即可製得。獲得之所需化合物 可依需要而以常法(如管;^主厚杯_、、表 $ 中g狂層析法、再結晶、抽提等)進行純 10化。疊氮化試劑相對於化合物(1,_3)係使用W等量,且較 佳為1〜2.5等量。 可使用之溶劑可列舉如芳香族烴類(如甲苯、苯、二甲 苯等)、飽和烴類(如環己烷、己烷等)、醚類(如四氫呋喃、 二乙醚、二噚烷等)以及該等之混合溶劑等。 15 可使用之鹼可列舉如金屬氫氧化物(如氫氧化鈉、氫氧 化鉀等)、金屬氫化物(如氫化鈉、氫化鋰等)、金屬碳酸鹽(如 碳酸鈉、碳酸鉀、碳酸鉋等)等,相對於化合物(1,-2)可使用 1當夏或以上’且較佳為1〜5當量。 反應溫度為0~15(TC,較佳為40〜120°C。反應時間係依 20 化合物而異,但使其反應1〇分〜48小時即可。 依照一般製造法3製造以下化合物。 277 200843739 實施例20 製造3-第三丁基-5-[4-(3-第三丁氧羰基胺基-5-異噚唑基)苯 基]-4-(2-甲氧基苯基)-4,5-二氮-111-11比略[3,4-〇]0比嗤-6-酉同 【化56】
於3-第三丁基-5-[4-(3-羧基-5-異噚唑基)苯基]-4-(2-甲 乳基本基)-4,5-二鼠-1H- °比略[3,4-c] °比哇-6- S同(0.948g ’ 2.0mmol)、三乙胺(0.33mL,2.4mmol)與 DMF(15mL)之混合液 中加入二苯基磷酸基疊氮(0.52mL,2.4mmol)並以60°C攪拌2 10 小時。接著,於反應液中加入第三丁醇(15mL)與粉末分子 篩4A(2g)後,更以90°C攪拌3小時。反應後,過濾除去不溶 物,加入水並以乙酸乙S旨抽提後,以氣化銨水溶液及飽和 食鹽水洗淨,並以無水硫酸鈉乾燥之。乾燥後,使減壓濃 縮所得之殘渣以二氯甲烷來結晶化,濾取已析出之結晶, 15 而獲得呈無色結晶之3-第三丁基-5-[4-(3-第三丁氧羰基胺 基-5-異噚唑基)苯基]-4-(2-甲氧基苯基)-4,5-二氫-1H-吼咯 [3,4-c]°比吐-6-酮(0.566g,收率:52%)。 lH-NMR(5ppmTMS/DMSO-d6)1.05(9H,s),1·47(9Η, s),3·95(3Η,s),6·77-6·80(3Η,m),7·00-7·11(2Η,m), 20 7·19(1Η,m),7·72(2Η,d,J=8.6),7·77(2Η,d,J=8.6), 10·34(1Η,s),13.24(1H,brs)。 278 200843739 實施例21 製造3-第三丁基-5-[4-(3-胺基-5-異噚唑基)苯基]-4-(2-甲氧 基苯基)-4,5-二氫-1H-吡咯[3,4-c]吡唑-6-酮 【化57】
於3-第三丁基-5-[4-(3-第三丁氧羰基胺基-5-異哼唑基) 苯基]-4-(2-甲氧基苯基)-4,5-二氫-1H-吡咯[3,4-c]吡唑-6-酮 (0.036g,0.7mmol)與甲醇(2mL)之混合液中加入濃鹽酸 (0.07mL)並以60°C攪拌2小時。反應後濾取析出之結晶,使 10 所得結晶進行再結晶(甲醇/二氯甲烷),而製得呈淡黃色結 晶之3-第三丁基-5-[4-(3-胺基-5-異噚唑基)苯基]-4-(2-甲氧 基苯基)-4,5-二氫-1H-吡咯[3,4-c]吡唑-6-酮(0.02g,收率: 68%) 〇 lH-NMR(SppmTMS/DMSO-d6)1.05(9H,s),3·38(1Η, 15 s),3·94(2Η,s),5·60(2Η,s),6·21(1Η,s),6·44(0·3Η, s),6·65-6·94(2·7Η,m),7·04(1Η,d,J=8.1),7·19(1Η,t, J=7.6),7·67(4Η,s),13·11(0·2Η,brs),13·37(0·7Η,brs), 13·56(0·1Η,brs) 實施例22 20 製造4-(l,2-二酮基丙基)-3-羥基-1-(4-異哼唑-3-基苯 基)-5-(2-甲氧基苯基)-1,5-二氫吼咯-2-酮 279 200843739 【化58】
MeC MeO
;ν°· 於甲基二甲氧基(甲基)乙醯丙酮酸鈉鹽(〇.24g, lmmol)、4-異噚唑-3-基苯胺(〇.16g,lmmol)與乙酸(2mL) 5 之混合液中加入2-曱氧基苯曱駿(〇.14g,lmmol),以室溫攪 拌一夜。反應後加入水濾取已析出之結晶,使所得結晶再 結晶(二氣甲烧/鍵)’而製得呈淡黃色結晶之二_(2,2_二甲氧 基丙醯基)-3-羥基-1 -(4-異呤唑-3-基苯基)-5-(2-甲氧基苯 基)-1,5-二氫°比11 各-2-_(〇.22g,收率:47%)。 10 於4-(2,2-^一甲氧基丙酿基)-3-經基-1-(4-異。号〇坐-3-基苯 基)-5-(2-甲氧基苯基)-1,5-二氫吡咯-2-酮(〇.〇8g,0.17mmol) 中加入乙酸(O.lmL)及水(〇.9mL),以95°C室溫攪拌15分鐘。 反應後加水,以乙酸乙酯抽提後再以無水硫酸鈉乾燥之。 乾燥後,使減壓濃縮所得殘渣以二氣甲烷與醚進行結晶 15化,濾取析出之結晶,而製得呈黃色結晶之4-(1,2-二酮基 丙基)-3-羥基-1-(4-異噚唑基苯基)-5-(2-甲氧基苯基 二氫^比17各-2-酮(0.05g,收率·· 7〇%)。 lH-NMR(3ppmTMS/DMSO-d6)2.24(3H,s),3·80(3Η, s),6·38(1Η,s),6·82(1Η,t,J=7.3),6·93(1Η,d,J=7.3), 20 7·〇8(1Η,d,J=1.6),7·13-7·18(2Η,m),7.70-7·84(4Η,m), 8·96(1Η,d,J=1.6)。 280 200843739 以前述合成路徑、一般製造法及實施例所記載之方法 為準,獲得以下各化合物。茲將構造及物性顯示如下。
281 200843739 化合 物編 號 結構 熔點(°c)或 購入來源及品項 MS m/z [M+] 1-3 Η。。 1 〇 〇 492 1-4 〇^s 〇 ) PHARMEKS 社 PHAR123923 458 1-5 〇 / PHARMEKS 社 PHAR136129 476 282 200843739 化合 物編 號 結構 熔點(°c)或 講入來源及品項 MS m/z [M+] 1-6 1。 ϋ 271-273 459 1-7 Iqn〇2 、 PHARMEKS 社 PHAR135367 503 1-8 Cr1。' 。攀f 0 / PHARMEKS 社 PHAR137229 476 283 200843739
284 200843739 化合 物編 結構 號 熔點(°C)或 購入來源及品項 MS m/z [M+]
PHARMEKS 社 PHAR139255
285 200843739 化合 物編 號 結構 熔點(°c)或 購入來源及品項 MS m/z [M+] 1-15 SPECS AG-690/12867290 476 1-16 〇^ζ)^0^ ψ /° PHARMEKS 社 PHAR146510 492 1-17 ><H f ο人^ 471 286 200843739
熔點(°C)或 購入來源及品項 269-274)d) 221-223 MS m/z [M+] 471 483 424 287 200843739
288 200843739
289 200843739 化合 物編 號 結構 熔點(°c)或 購入來源及品項 MS m/z [M+] 1-27 /°^〇K_/〇h P^o 心 238-240 487 1-28 °ό ο人^ 408 I - 29 \。 〇^( 〇 PHARMEKS 社 PHAR057684 473 290 200843739 化合 物編 結構 號 熔點(°C)或 購入來源及品項 MS m/z [M+] 〇
291 200843739 化合 物編 結構 號 熔點(°C)或 購入來源及品項 MS m/z [M+] 1-33
0^\ PHARMEKS 社 PHAR019403
292 200843739 化合 物編 結構 號 熔點(°C)或 講入來源及品項 MS m/z [M+]
434 卜37
500 〇
PHARMEKS 社 PHAR040562 293 200843739 化合 物編 號 結構 熔點(°c)或 講入來源及品項 MS m/z [M+] 卜39 y。' 。讲 〇 / PHARMEKS 社 PHAR135263 537 1-40 〇 / 254-258(d) 487 1-41 °ψ α PHARMEKS 社 PHAR131877 480 294 200843739 化合 物編 號 結構 熔點(°c)或 購入來源及品項 MS m/z [M+] 1-42 0 ) PHARMEKS 社 PHAR127015 488 1-43 458 1-44 ^yCr1。' ψ 0 / 473 295 200843739
296 200843739
297 200843739 化合 物編 號 結構 熔點(°c)或 iV1; 購入來源及品項 1-51 Ο
〇 〇 483
298 200843739 化合 物編 結構 號 熔點(°C)或 購入來源及品項 MS m/z [M+]
PHARMEKS 社 PHAR027786 〇
299 200843739 化合 物編 號 結構 熔點(°C)或 購入來源及品項 MS m/z [M+] I 一 57 Μ Π
〇 431
300 200843739 %, 化合 物編 號 1-60 卜61 結構
C
C
〇 〇
熔點(°c)或 購入來源及品項 PHARMEKS 社 PHAR142165 PHARMEKS 社 PHAR105869 MS m/z [M+] 488 468 301 200843739 化合 物編 號 結構 熔點(°C)或 購入來源及品項 MS m/z [M+] 1-63
〇 PHARMEKS 社 PHAR026958 1-64 Ο
〇 245-246 471
PHARMEKS 社 PHAR128015 302 200843739
303 200843739
304 200843739 化合 物編 號 結構 熔點(°C)或 購入來源及品項 MS m/z [M+] 1-72 Ο
366 1-73
245-247 434 457 305 200843739
306 200843739 化合 物編 號 結構 熔點(°c)或 購入來源及品項 MS m/z [M+] 1-78 Ο
〇 253-254 453
472
506 307 200843739 化合 物編 號 結構 熔點(°c)或 購入來源及品項 MS m/z [M+] 1-81 分。 〇 / 458 1-83 。十〆 。承 〇 / PHARMEKS 社 PHAR032514 495 1-84 PHARMEKS 社 PHAR137490 416 308 200843739 化合 物編 號 結構 熔點(°c)或 講入來源及品項 MS m/z [M+] 1-85 丫0 6 〇 )SrQr 〇 PHARMEKS 社 PHAR140664 477 1-86 °ψ 〇 / 473 1-87 '畔 0 268-271 430 309 200843739 化合 物編 號 結構 熔點(°c)或 購入來源及品項 MS m/z [M+] 1-88 条, (° PHARMEKS 社 PHAR124071 464 1-89 〇 PHARMEKS 社 PHAR127988 448 1-90 。彳 XT! 。杂 〇 / PHARMEKS 社 PHAR138301 434 310 200843739
熔點rc)或 講入來源及品項 MS m/z [M+] INTERBIOSCREEN 社 STOCK2S-84529 PHARMEKS 社 PHAR068896 PHARMEKS 社 PHAR012733 398 509 416 311 200843739 化合 物編 號 結構 熔點(°c)或 講入來源及品項 MS m/z [M+] 卜94 σ1 °i)Q W/ V二0 〇— PHARMEKS 社 PHAR106162 443 1-95 F-<\ ^y>N IFLAB 社 F0851-0720 414 1-96 u0 h 251-252 405 312 200843739 化合 物編 號 結構 熔點(°c)或 講入來源及品項 MS m/z [M+] 1-97 o~c, 〇 CSC社 D34650002 418 1-98 CHEMDIV 社 C390-0063 491 1-99 Q-(\ /)-N N 0 CHEMDIV 社 C390-0059 416 313 200843739 化合 物編 號 結構 熔點(°C)或 購入來源及品項 MS m/z [M+] 1-100
Br CHEMDIV 社 C390-0113 535 1-101
CHEMDIV 社 C390-0021 525 1-102
Br
CHEMDIV 社 C390-0023 525 314 200843739 化合 物編 結構 號 熔點(°C)或 購入來源及品項 MS m/z [M+] 〇 Br
Br Br
315 200843739 化合 物編 結構 號 熔點(°C)或 講入來源及品項 MS m/z [M+] 1-106 〇
Br CHEMDIV 社 C390-0083 〇
316 200843739 化合 物編 結構 號 熔點(°C)或 講入來源及品項 MS m/z [M+] —〇 Br
CHEMDIV 社 5340-2243 〇
317 200843739 化合 物編 號 結構 熔點(°C)或 購入來源及品項 MS m/z [M+]
318 200843739 化合 物編 結構 號 熔點(°C)或 講入來源及品項 MS m/z [M+] 〇
CSC社 D50050967 438
319 200843739
320 200843739 化合 物編 結構 號 熔點rc)或 講入來源及品項 MS m/z [M+]
321 200843739 化合 物編 結構 號 熔點(°C)或 購入來源及品項 MS m/z [M+]
322 200843739 化合 物編 號 1-127 卜128 1-129
熔點(°C)或 購入來源及品項 MS m/z [M+] CHEMDIV 社 C390-0571 CHEMDIV 社 C390-0605 CHEMDIV 社 C390-0540 324 324 310 323 200843739 化合 物編 號 結構 熔點(°C)或 購入來源及品項 MS m/z [M+] 卜130
CHEMDIV 社 C390-0594 1-131
CHEMDIV 社 C390-0569
CHEMDIV 社 C390-0545 324 200843739 化合 物編 結構 號 熔點rc)或 購入來源及品項 MS m/z [M+]
N 〇 325 200843739 化合 物編 號 結構 熔點(°c)或 購入來源及品項 MS m/z [M+] 1-136 〇 9 〇 CHEMDIV 社 C390-0562 277 1-137 °γνΟ^°\ INTERBIOSCREEN 社 STOCK3S-19371 卜138 r INTERBIOSCREEN 社 STOCK3S-27961 326 200843739 化合 物編 號 構 結 熔點rc)或 購入來源及品項 MS m/z [M+] I 一 139
CHEMICALBLOCK 社 A2826/0119344 1-140
CHEMICALBLOCK 社 A2846/0120094 1-141
CHEMICALBLOCK 社 A2864/0120776 327 200843739 化合 物編 號 結構 熔點(°c)或 購入來源及品項 MS m/z [M+] 卜142 C^Br CHEMICALBLOCK 社 A2921/0123016 1-143 r/ 夂Vv CHEMICALBLOCK 社 A2956/0124459 卜144 0^N-O^° PHARMEKS 社 PHAR020271 328 200843739 化合 物編 結構 號 熔點(°C)或 購入來源及品項 MS m/z [M+]
PHARMEKS 社 PHAR033094 1-146
PHARMEKS 社 PHAR036801 1-147
PHARMEKS 社 PHAR050263 329 200843739 化合 物編 結構 號 熔點(°C)或 購入來源及品項 MS m/z [M+]
1-148
PHARMEKS 社 PHAR062175
PHARMEKS 社 PHAR067480
1-150
PHARMEKS 社 PHAR070697 330 200843739 化合 物編 結構 號 熔點rc)或 講入來源及品項 MS m/z [M+]
PHARMEKS 社 PHAR071219 1-152
PHARMEKS 社 PHAR079682 1-153 〇
PHARMEKS 社 PHAR087561 331 200843739 化合 物編 結構 號 熔點(°C)或 購入來源及品項 MS m/z [M+] 卜154 〇
〇 PHARMEKS 社 PHAR094621 1-155
PHARMEKS 社 PHAR104096
PHARMEKS 社 PHAR107350 332 200843739 化合 物編 號 結構 熔點(°C)或 購入來源及品項 MS m/z [M+] 卜157
PHARMEKS 社 PHAR111534 M58
PHARMEKS 社 PHAR115440
PHARMEKS 社 PHAR117573 333 200843739 化合 物編 號 1-160 1-161 1-162
熔點(°C)或 講入來源及品項 MS m/z [M+] PHARMEKS 社 PHAR118326 PHARMEKS 社 PHAR119097 PHARMEKS 社 PHAR120941 334 200843739 化合 物編 結構 號 熔點(°C)或 購入來源及品項 MS m/z [M+] 1-163
Ο PHARMEKS 社 PHAR127775
PHARMEKS 社 PHAR128943 1-165
PHARMEKS 社 PHAR130612 335 200843739 化合 物編 號 構 結 熔點(°C)或 購入來源及品項 MS m/z [M+] 1-166
PHARMEKS 社 PHAR134114 1-167 ο
0 PHARMEKS 社 PHAR135268 1-168
ό PHARMEKS 社 PHAR137109 336 200843739 化合 物編 號 結構 熔點(°C)或 購入來源及品項 MS m/z [M+] 1-169
〇 PHARMEKS 社 PHAR138274 M70
PHARMEKS 社 PHAR138772 1-171
〇 F PHARMEKS 社 PHAR140674 337 200843739 化合 物編 結構 號 熔點(°C)或 購入來源及品項 MS m/z [M+] 1-172
F PHARMEKS 社 PHAR144655
338 200843739 化合 物編 結構 號 熔點(°C)或 購入來源及品項 MS m/z [M+] 〇
339 200843739 化合 物編 結構 號 熔點(°C)S iV1; 購入來源及品項 1-178
382
340 200843739 化合 物編 結構 號 熔點(°C)或 購入來源及品項 MS m/z [M+] 1-182
〇 498
341 200843739 化合 物編 結構 號 熔點(°C)或 購入來源及品項 MS m/z [M+] 1-185 Ο
193-196 471
377 1-191
416 342 200843739 化合 物編 結構
熔點(°C)或 購入來源及品項 MS m/z [M+] 533 255-256 424 245-246 406 343 200843739 化合 物編 號 結構 熔點(°C)或 講入來源及品項 MS m/z [M+] 1-195 Cnr° s' 〇 479 1-196 o' 449 1-197 〇rr° S^N 〇 479 344 200843739 化合 物編 號 結構 熔點(°c)或 購入來源及品項 MS m/z [M+] 1-198 >290 430 1-199 9 OH OMe 226-229 443 1-200 9 OH 216-219 458 345 200843739
346 200843739 化合物 編號 結構式 熔點(°C)或 購入來源及品項 MS m/z [M+] 1-202
〇 177-178
347 200843739 化合物 編號 結構式 熔點CC)或 購入來源及品項 MS m/z [M+]
348 200843739 化合物 編號 結構式 熔點(°C)或 購入來源及品項 MS m/z [M+] 1-208
〇 >290 434
232-235 461
349 200843739
350 200843739 化合物 編號 結構式 熔點(°C)或 購入來源及品項 MS m/z [M+] 1-215 Ο
〇 〇 207-210 503 1-216 Ο
Ο 229-232 489
351 200843739 化合物 編號 結構式 熔點rc)或 購入來源及品項 MS m/z [M+] 1-218
1-219 Ο
249-252 485
352 200843739 化合物 編號 結構式 熔點(°C)或 講入來源及品項 MS m/z [M+]
〇 241-244 481 247-249 560
353 200843739 化合物 編號 結構式 熔點(°C)或 購入來源及品項 MS m/z [M+] 1-224 Ο
〇 〇 268-272 461
354 200843739 化合物 編號 結構式 熔點rc)或 構入來源及品項 MS m/z [M+] 1-227
221-224 475 1-228
217-218 468 1-229
213-215 355 200843739 化合物 編號 結構式 熔點(°C)或 購入來源及品項 MS m/z [M+] 1-230
229-230 433 1-231
〇 245-248 474 1-232
〇 223-225 462 356 200843739 化合物 編號 結構式 熔點(°C)或 購入來源及品項 MS m/z [M+] 1-233 〇
〇 247-250 477 1-234 Ο
Ο 230-233 465 1-235 Ο
〇 502 357 200843739 化合物 編號 結構式 熔點rc)或 講入來源及品項 MS m/z [M+]
〇 232-234 454
358 200843739 化合物 編號 結構式 熔點(°C)或 購入來源及品項 MS m/z [M+] 1-239 Ο
〇 227-228 433
〇 430 1-241
455 359 200843739 化合物 編號 結構式 熔點(°C)或 購入來源及品項 MS m/z [M+] 1-242
〇 〇- 429 1-243
498 1-244
〇 461 360 200843739 化合物 編號 結構式 熔點(°C)或 購入來源及品項 MS m/z [M+] 1-245 〇
〇 /〇 462 1-246 Ο
〇 435 1-247
449 361 200843739 化合物 編號 結構式 熔點(°C)或 講入來源及品項 MS m/z [M+] 1-248
〇 390 1-249
〇 401 1-250
197-204 362 200843739 化合物 編號 結構式 熔點(°C)或 購入來源及品項 MS m/z [M+] 1-251 Ο Ν
cr 、〇 468 1-252 Ο
〇 434 1-253 Ο
〇 384 363 200843739 化合物 編號 結構式 熔點(°C)或 構入來源及品項 MS m/z [M+] 1-254
〇 430 1-255
〇 380 1-256
482 364 200843739 化合物 編號 結構式 熔點(°C)或 購入來源及品項 MS m/z [M+] 1-257
448 1-258
F 444 1-259
ο 380 365 200843739 化合物 編號 結構式 熔點(°C)或 講入來源及品項 MS m/z [M+] 1-260
378 1-261
382 1-262 η
〇 384 366 200843739 化合物 編號 結構式 熔點(°C)或 購入來源及品項 MS m/z [M+] 1-263
394 1-264
405 1-265 〇
〇 404 367 200843739 化合物 編號 結構式 熔點(°c)或 購入來源及品項 MS m/z [M+] 1-266 Μ 哼。 〇丨 400 1-267 傳 473 1-268 461 368 200843739 化合物 編號 結構式 熔點(°c)或 購入來源及品項 MS m/z [M+] 1-269 373 1-270 448 1-271 7 X) 448 369 200843739 化合物 編號 結構式 熔點rc)或 講入來源及品項 MS m/z [M+] 1-272
434 1-273
462 1-274
468 370 200843739 化合物 編號 結構式 熔點rc)或 購入來源及品項 MS m/z [M+] 1-275
444
371 200843739 化合物 編號 結構式 熔點rc)或 講入來源及品項 MS m/z [M+] 1-278
458 1-279
0 469 1-281 Ο
F F 484 372 200843739 化合物 編號 結構式 熔點(°C)或 購入來源及品項 MS m/z [M+] 1-282
434 1-283
〇 〇 450 1-284
430 373 200843739 化合物 編號 結構式 熔點fC)或 購入來源及品項 MS m/z [M+] 1-285
F F 480 374 200843739 化合物 編號 結構 熔點(°C) MS m/z [M+] II-1
422 II-2
〇 404 ΙΙ-3
〇 418 375 200843739 化合物 編號 結構 熔點(°C) MS m/z [M+] ΙΙ-4
〇 433 ΙΙ-5
〇 418 ΙΙ-6
〇 400 376 200843739 化合物 編號 II-7
377 200843739 化合物 編號 結構 熔點(°c) MS m/z [M+] 11-10
396 11-11 〇
〇 446
411 378 200843739 化合物 編號 結構 熔點rc) MS m/z [M+] 11-13
〇 469 11-14
〇 479 11-15
429 379 200843739 化合物 編號 結構 熔點(°c) MS m/z [M+] 11-16
487
380 200843739
381 200843739
382 200843739 化合物 編號 結構 熔點(°C) MS m/z [M+] 11-25
420
383 200843739 化合物 編號 結構 熔點rc) MS m/z [M+] 11-28
433 11-29 η
451 11-30
429 384 200843739
385 200843739
386 200843739
387 200843739 化合物 編號 結構 熔點(°C) MS m/z [M+] 11-40
Chiral 433 11-41
Chiral 429 11-42
Chiral 429 388 200843739 化合物 編號 構 結 溶點rc) MS m/z [M+] II-43
448 11-44
444 ΙΙ-45 ^ ν/ο ρ 〇
ο
417 389 200843739 化合物 編號 結構 熔點(°C) MS m/z [M+] 11-46
413 11-47 Ο
432 11-48
428 390 200843739 化合物 編號 結構 MS m/z [M+] 11-49
454 11-50
454 11-51
419 391 200843739 化合物 編號 結構 熔點(°C) MS m/z [M+] II-52
450 II-53
487 ΙΙ-54
460 392 200843739 化合物 編號 結構 熔點rc) MS m/z [M+] 11-55
456 11-56
415 11-57
〇 428 393 200843739
394 200843739 化合物 編號 結構 熔點(°C) MS m/z [M+]
11-61
〇 486 11-62
472 11-63
378 395 200843739 化合物 編號 結構 熔點(°C) MS m/z [M+] 11-64
〇 374
396 200843739
397 200843739
398 200843739
399 200843739 化合物 編號 結構 熔點(°C) MS m/z [M+] 11-76
〇 444 11-77
444 11-78
463 400 200843739
401 200843739 化合物 編號 結構 熔點rc) MS m/z [M+] II-82
433 ΙΙ-83
〇 459 ΙΙ-84
434 402 200843739 化合物 編號 結構 熔點(°C) MS m/z [M+]
II-85 ο
Ο 511 11-86
Ο 430 11-87
ο 507 403 200843739 化合物 編號 結構 熔點(°C) MS m/z [M+] 11-88 °0 ό 459 11-89 J V ry^N^o τ Br 477 11-90 /TV^N 九 V Br 417 404 200843739 化合物 編號 結構 熔點(°C) MS m/z [M+] 11-91
413 II-92 ΙΙ-93
469 439 405 200843739 化合物 編號 結構 熔點(°C) MS m/z [M+] 11-94
429 11-95
476 11-96
461 406 200843739 化合物 編號 結構 熔點(°C) MS m/z [M+] 11-97
〇 434
407 200843739 化合物 編號 結構 熔點(°c) MS m/z [M+] II-100
〇 404 II-101
〇 454 II-102
554 408 200843739 化合物 編號 II-103 II-104 II-105
溶點(〇C) MS m/z [M+] 516 516 439 409 200843739 化合物 編號 結構 熔點(°C) MS m/z [M+] 11-106
453 11-107
426 11-108
390 410 200843739 化合物 編號 結構 熔點(°c) MS m/z [M+] 11-109 〇
450
411 200843739 化合物 編號 結構 熔點fC) MS m/z [M+] 11-112
428 11-113
430 11-114
400 412 200843739 化合物 編號 結構 熔點(°c) MS m/z [M+] 11-115
400 11-116
446 11-117
386 413 200843739 化合物 編號 結構 熔點(°c) MS m/z [M+] 11-118 ο 445 11-119 % 472 11-120 Ό^ΝΧΝ 〇^。 472 414 200843739
415 200843739
416 200843739 化合物 編號 結構 熔點rc) MS m/z [M+] II -127
〇 447 11-128
468 11-129 π
449 417 200843739 化合物 編號 結構 熔點(°C) MS m/z [M+] 11-130
〇 444 11-131
471 11-132
445 418 200843739
419 200843739
420 200843739
421 200843739
422 200843739 化合物 編號 結構 熔點rc) MS m/z [M+] 11-145
〇 441 11-146
410 11-147
410 423 200843739 化合物 編號 結構 熔點(°C) MS m/z [M+] 11-148
473 11-149
476 11-150
457 424 200843739
425 200843739
426 200843739
427 200843739 化合物 編號 結構 熔點(°c) MS m/z [M+] 11-160 rV^° 人 Ο 472 11-161 V ο 6 ά 403 11-162 Cr ό ό 413 428 200843739
429 200843739 化合物 編號 結構 熔點(°C) MS m/z [M+] 11-166
399 II-167
〇 N 401 II-168
490 430 200843739 化合物 編號 結構 熔點(°c) MS m/z [M+] 11-169 476 11-170 成。 α 506 11-171 号 〇 459 431 200843739 化合物 編號 II-172 II-173 II-174
溶點rc) MS m/z [M+] 500 467 409 432 200843739
433 200843739
434 200843739 化合物 編號 結構 熔點(°C) MS m/z [M+] 11-181
483 11-182
449 11-183
519 435 200843739
436 200843739 化合物 編號 結構 熔點(°C) MS m/z [M+] 11-187
〇* 516 11-188
404 II-189
451 437 200843739 化合物 編號 結構 熔點(°c) MS m/z [M+] 11-190 今。 ό 465 11-191 471 11-192 〇i? 〇 / 479 438 200843739
439 200843739 化合物 編號 結構 熔點(°C) MS m/z [M+] 11-196
394 11-197
447 11-198
443 440 200843739
441 200843739 化合物 編號 II-202 II-203 II-204
熔點(〇C) MS m/z [M+] 482 434 458 442 200843739
443 200843739
444 200843739 化合物 編號 結構 熔點(°C) MS m/z [M+]
445 200843739 化合物 編號 結構 熔點(°C) MS m/z [M+]
446 200843739 化合物 編號 結構 熔點(°C) MS m/z [M+] 11-217
〇 413 11-218 〇
459
11-219
455 447 200843739 化合物 編號 結構 熔點(°C) MS m/z [M+] 11-220 〇
〇 489 11-221
437 11-222
433 448 200843739 化合物 編號 結構 熔點(°C) MS m/z [M+] 11-223
413 11-224 〇
423
449 200843739 化合物 編號 結構 熔點(°c) MS m/z [M+] 11-226 祜。 443 11-227 \。供 ό 434 11-228 故。 % 〇/ 457 450 200843739 化合物 編號 結構 熔點(°C) MS m/z [M+] II - 229
437 II - 230
419 11-231
437 451 200843739 化合物 編號 結構 熔點(°C) MS m/z [M+] 11-232
433 11-233
454 II-234 〇
485 452 200843739 化合物 編號 結構 熔點(°c) MS m/z [M+] 11-235 Ο
〇 473
453 444 453 200843739
454 200843739 化合物 編號 結構 熔點(°C) MS m/z [M+]
455 200843739 化合物 編號 結構 熔點(°C) MS m/z [M+] 11-244
455 11-245
453
456 200843739 化合物 編號 結構 熔點(°C) MS m/z [M+] II-247
〇- 540 ΙΙ-248
Ο- 542
C ΙΙ-249 Γ\
530 457 200843739
458 200843739 化合物 編號 結構 熔點rc) MS m/z [M+] 11-253
Ο 475
461 447 459 200843739 化合物 編號 結構 熔點(°C) MS m/z [M+] 11-256 Ο
〇 487 11-257
459 11-258
Ο
Ο 455 460 200843739
461 200843739 化合物 編號 結構 熔點rc) MS m/z [M+] 11-262 441 462 200843739 表中: 【化59】
試驗例 5 將導入有人類P2X3受體基因(GenBank註冊序列 Y07683)之C6BU-1細胞的安定表現細胞株播種於塗佈pDL 之96井微滴定盤,使每1井為8〇〇〇個,並於培養基(含有8·3% 牛胎兒血清、8.3%馬血清、1%抗生物質抗真菌劑混合溶液 之DMEM)中以37°C、5%二氧化碳下培養1天。將培養基換 10 為含有 Fluo-3-ΑΜ 4μΜ之添加液(2〇mM HEPES、137mM NaCn、2.7mM KQ、0.9mM MgCl2、5.0mMCaCl2、5.6mM D-葡萄糖、2.5mM 丙磺舒(probenecid)、10%BSA、 0.08%PLURONIC® F-127、ρΗ7·5),以37°C、5%二氧化碳 下培養1小時。以洗淨用缓衝液(20mM HEPES、137mM 15 NaQ、2.7mMKCn、0.9mM MgCl2、5.0mM CaCl2、5.6mM D-葡萄糖、2.5mM丙磺舒、ρΗ7·5)洗淨,以每井4〇μι之洗淨 用緩衝液充滿之。將微滴定盤設於大量快速篩檢系統(High 463 200843739 throughput screening system)FDSS 3000(濱松光子學株式 會社)。開始以FDSS 3000測定螢光強度,並以FDSS 3000 内藏之自動分注裝置,將已藉稀釋用緩衝液(2〇mM HEPES、137mM Nad、2.7mM Κα、0.9mM MgCl2、5.0mM 5 CaCl2、5.6mM D-葡萄糖、2.5mM 丙磺舒、0.1% PLURONIC® F-127、ρΗ7·5)稀釋成不同濃度之被測化合物 DMSO溶液分注為每1井40μ1。5分鐘後,以内藏在FDSS 3000之自動分注裝置分注業已藉稀釋用緩衝液稀釋之 40nM ATP溶液50μ1,持續測定之後3分鐘之螢光強度。從所 10測定之螢光強度值算出微滴定盤每1井之比最大螢光強 度,該比最大螢光強度係將ΑΤΡ溶液添加後之螢光強度最大 值以相對於測定開始時之螢光強度的比表示者。令不含被 測化合物時之比最大螢光強度值為拮抗〇%,且添加稀釋用 緩衝液取代ΑΤΡ時之比最大螢光強度值為拮抗1〇〇%,算出 15拮抗50%之濃度(IC5〇)來評估被測化合物之拮抗活性。比最 大螢光強度之計算係使用FDSS軟體(濱松光子學株式會社) 進行者。ICso之計算係使用微軟ExcEL(Microsoft社)及 XLfit(idbs社)之軟體進行者。 兹將本發明化合物之試驗結果示於下表。 20 464 200843739 化合物編號 P2X3 IC50_) 1-1 0.01 1-2 0.01 1-4 0.02 1-6 0.03 1-20 0.14 1-21 0.16 1-24 0.18 1-25 0.18 1-28 0.26 1-36 0.38 1-44 0.56 1-45 0.58 1-48 0.97 1-49 1.02 1-52 1.27 1-53 1.28 1-57 1.53 1-62 1.96 1-66 3.46 1-69 3.78 1-72 4.79 1-74 5.92 1-76 6.48 1-77 8.01 1-79 8.95 1-88 15.43 1-95 0.56 1-96 0.92 1-118 17.80 1-122 19.30 Μ 24 22.00 1-251 1.40 1-260 5.63 1-273 2.20 1-278 1.40 465 200843739 化合物編號 Ρ2Χ3 IC50_ 1.37 〜 ϊτΤ· 0.86 ' II-13 057 〜 ΪΓΪ4 0.38 ΪΜ6 1.51 〜 ΪΓΠ 0.31 〜 11¾ 2.31 ^ ΪΜ9 0.59 〜 ΙΙ-30 069 〜 ΙΙ-40 0.37 ^^ ΪΜΓ 0.17 ^ ΙΙ-45 1.07 ^ ΙΙ-57 1.68 〜 ΙΙ-64 Γ31 ^ ΙΙ-72 0.66 〜 ΰ^75 0.37 〜 1^85 2.52 〜 1^87 1.32 〜 11-95 0.71 〜 1^98" 1 0.07 ^' II-106 2.08 ΙΙ-123 2.09 〜' II-129 0.74 〜 11-130 0.13 〜 11-171 095 〜 1^72 2.00 ΙΜ81 0.33 〜 II-183 0.03 〜 ΙΙ_193 ττ rCTT---- 一~127 ^ 11-201 0.01 〜' 11-202 1.62 〜 11-217 1.87 〜 本發明之化合物顯示出對P2XS受體之拮抗活性 外,本發明之化合物係對P2X3亞型作用,因此可知,此 對於 έ有P2X2亞型而構成之P2XW受體同樣地亦會顯示出拮抗 5 活性。 〇几 產業上之可利用性 本發明之化合物對於Ρ2Χ3及/或Ρ2Χ2/3受體具有拮抗作 用,而對於Ρ2Χ3及/或Ρ2Χ2/3受體相關疾病或狀態,例如慢 466 200843739 性疼痛、過活動膀胱甚為有用。 L圖式簡單說明3 (無) 【主要元件符號說明】 (無) 467

Claims (1)

  1. 200843739 十、申請專利範圍: 1· 一種P2X3及/或P2X2,3受體拮抗劑,含有如下通式(I)所示 之化合物、其製藥上可接受之鹽或是該等之溶劑合物; 通式(I): 5 【化1】
    式中’ Z1為可任擇受到保護之羥基、可任擇受到保 護之羥胺基或可任擇具有取代基之胺基,z2為=〇或 =N-E(E為氫、羥基、可任擇具有取代基之低級烷基、可 10 任擇具有取代基之低級烷氧基或是可任擇具有取代基 之胺基);或是 【化2】
    形成 R4及R5各自獨立為氫或低級烷基,R6為氫、可任擇 具有取代基之低級烷基或醯基,r為0〜2之整數; Ra及Rb各自獨立為氫或低級烷基; q為0〜4之整數; A為環烷基、環烯基、芳基或雜環基; 468 15 200843739 R1各自獨立為_素、羥基、可任擇具有取代基之低 級烷基、可任擇具有取代基之低級烯基、可任擇具有取 代基之低級炔基、可任擇具有取代基之低級烷氧基、可 任擇具有取代基之低級烷硫基、可任擇具有取代基之醯 基、羧基、可任擇具有取代基之低級烷氧羰基、可任擇 具有取代基之胺甲醯基、可任擇具有取代基之低級烷基 胺曱醯基、可任擇具有取代基之胺基、可任擇具有取代 基之胺磺醯基、氰基、硝基、可任擇具有取代基之環烷 基、可任擇具有取代基之環烯基、可任擇具有取代基之 芳基或可任擇具有取代基之雜環基; N為0〜3之整數(但, 【化3】
    AJR1)!!亦可為氫); 15 r2為可任擇具有取代基之烷基、可任擇具有取代基 之低級烧氧基、可任擇具有取代基之低級烧基胺甲醯 基、可任擇具有取代基之環烷基、可任擇具有取代基之 環烯基、可任擇具有取代基之芳基或可任擇具有取代基 之雜環基; 20 r3為氫、可任擇具有取代基之烷基、可任擇具有取 代基之環烷基、可任擇具有取代基之環烯基、可任擇具 有取代基之芳基或可任擇具有取代基之雜環基。 469 200843739 2·如申請專利範圍第1項之P2X3及/或P2X2/3受體拮抗劑, 其中Z1為羥基,22為=〇。 3·如申請專利範圍第1項之P2X3及/或P2X2/3受體拮抗劑, 其中r為〇。 5 4·如申請專利範圍第1〜3項中任一項之P2X3及/或P2X2/3受 體拮抗劑,其中環A為苯基、吡啶基或噻唑基。 5.如申請專利範圍第1項之P2X3及/或P2X2/3受體拮抗劑, 其中R1為可任擇具有取代基之低級烷氧羰基或可任擇 具有取代基之雜環基。 10 6·如申請專利範圍第丨項之或ρ2χ2/3受體拮抗劑, 其中R2為可任擇具有取代基之低級烷基、可任擇具有取 代基之笨基或可任擇具有取代基之吼啶基。 7·如申請專利範圍第i項之Ρ2χ3及/或Ρ2χ2/3受體拮抗劑, 其中R3為碳原子數3〜10之烷基、環烷基或可任擇具有取 15 代基之苯基。 8·如申請專利範圍第丨項之ρ2Χ3及^ρ2χ2/3受體拮抗劑, 其中q為0。 9·如申請專利範圍第!項之p2Xs及域!^2,3受體拮抗劑, 其中q為1。 20 ι〇· 一種如下通式(I,)所示之化合物、其製藥上可接受之鹽 或是該等之溶劑合物,其中通式(Γ): 【化4】 470 200843739
    (R1D)P 式中,z1為可任擇受到保護之羥基、可受任擇保護 之羥胺基或可任擇具有取代基之胺基,22為:=:〇或 =N-E(E為氫、羥基、可任擇具有取代基之低級烷基、可 任擇具有取代基之低級烷氧基或是可任擇具有取代基 之胺基;或 【化5】
    R及R各自獨立為氫或低級烧基,r6為氫、可任擇 具有取代基之低級烧基或酿基,r為〇〜2之整數; 環A及環B各自獨立為環烷基、環烯基、芳基或雜 環基; Rla&Rlb各自獨立為_素、羥基、可任擇具有取代 基之低級烷基、可任擇具有取代基之低級烯基、可任擇 具有取代基之低級炔基、可任擇具有取代基之低級烷氧 基、可任擇具有取代基之低級烷硫基、可任擇具有取代 基之醯基、羧基、可任擇具有取代基之低級烷氧羰基、 可任擇具有取代基之胺甲醯基、可任擇具有取代基之低 471 200843739 級烷基胺甲醯基、可任擇具有取代基之胺基、可任擇具 有取代基之胺續醯基、氰基或硝基; m及ρ各自獨立為〇〜2之整數; R2為可任擇具有取代基之烷基、可任擇具有取代基 5 之低級烷氧基、可任擇具有取代基之低級烷基胺甲醯 基、可任擇具有取代基之環烷基、可任擇具有取代基之 環烯基、可任擇具有取代基之芳基或可任擇具有取代基 之雜環基; R3為氫、可任擇具有取代基之低級烧基、可任擇具 ίο 有取代基之環烷基、可任擇具有取代基之環烯基、可任 擇具有取代基之芳基或可任擇具有取代基之雜環基; 但是,環A為吡唑酮且環B為苯基之化合物除外。 11 ·如申清專利範圍弟1 〇項之化合物、其製藥上可接受之鹽 或是該等之溶劑合物,其中Z1為可任擇受到保護之羥 15 基’ z為=〇 ’ R2為可任擇具有取代基之烧基、可任擇具 有取代基之低級烷氧基、可任擇具有取代基之環烷基、 可任擇具有取代基之環烯基、可任擇具有取代基之芳基 或可任擇具有取代基之雜環基。 12·如申請專利範圍第10項之化合物、其製藥上可接受之鹽 20 或是該等之溶劑合物,其中r為0,R2為可任擇具有取代 基之烧基,可任擇具有取代基之低級烷氧基、可任擇具 有取代基之環烷基、可任擇具有取代基之環烯基、可任 擇具有取代基之芳基或可任擇具有取代基之雜環基。 13·如申請專利範圍第10〜12項之化合物、其製藥上可接受 472 200843739 之鹽或是該等之溶劑合物,其中環A為苯基、 噻唑基。 °比啶基或 14· -種如下述通式(1,,)所示之化合物、#製藥上可接受 鹽或是該等之溶劑合物: 【化6】 之
    (Γ,) 10 式中’ Z1為可任擇受到保護之羥基、可任擇受到保 護之經胺基或可任擇具有取代基之胺基,Z2為=〇或 =N-E(E為氫、羥基、可任擇具有取代基之低級烷基、可 任擇具有取代基之低級烷氧基或可任擇具有取代基之 胺基;或者 【化7】 Z2 r 21 ^ 形成 N-fCR^r R及R各自獨立形成氯或低級烧基,r6為氯、可任 擇具有取代基之低級烷基或醯基,r為〇〜2之整數; 環A為環烷基、環烯基、芳基或雜環基; R各自獨立為_素、經基、可任擇具有取代基之 473 15 200843739 低級烷基、可任擇具有取代基之低級烷氧基、可任擇具 有取代基之低級烷硫基、可任擇具有取代基之醯基、羧 基、可任擇具有取代基之低級烷氧羰基、可任擇具有取 代基之胺甲醯基、可任擇具有取代基之低級烷基胺曱醯 基、可任擇具有取代基之胺基、可任擇具有取代基之胺 續醯基、氰基或硝基; m為0〜2之整數; Rle及Rld各自獨立為氫或可任擇具有取代基之低 級烷基; R2為可任擇具有取代基之烷基、可任擇具有取代基 之低級烧氧基、可任擇具有取代基之低級烷基胺甲醯 基、可任擇具有取代基之環烷基、可任擇具有取代基之 環烯基、可任擇具有取代基之芳基或可任擇具有取代基 之雜壤基; R3為氫、可任擇具有取代基之低級烷基、可任擇具 有取代基之環烷基、可任擇具有取代基之環烯基、可任 擇具有取代基之芳基、可任擇具有取代基之雜環基。 15·如申請專利範圍第14項之化合物、其製藥上可接受之鹽 或是該等之溶劑合物,其中ζι為可任擇受到保護之羥 基,Z2為=〇,R2為可任擇具有取代基之烷基、可任擇具 有取代基之低級烷氧基、可任擇具有取代基之環烷基、 可任擇具有取代基之環烯基、可任擇具有取代基之芳基 或可任擇具有取代基之雜環基。 16·如申請專利範圍第14項之化合物、其製藥上可接受之鹽 474 200843739 或是該等之溶劑合物,其中r為〇,R2為可任擇具有取代 基之、丨元基、可任擇具有取代基之低級烧氡基、可任擇具 有取代基之環烷基、可任擇具有取代基之環烯基、可任 擇具有取代基之芳基或可任擇具有取代基之雜環基。 5 I7·如申請專利範圍第14〜16項中任一項之化合物、其製藥 上可接受之鹽或是該等之溶劑合物,其中環人為苯基、 。比°定基或嗟唾基。 18. —種藥學組成物,含有如申請專利範圍第1〇〜17項中任 一項之化合物、其製藥上可接受之鹽或是該等之溶劑合 0 物。 19. 一種P2XS及/或P2X2,3受體拮抗劑,含有如申請專利範圍 第10〜17項中任一項之化合物、其製藥上可接受之鹽或 是該等之溶劑合物。 20. 一種如申請專利範圍第10〜17項中任一項之化合物、其 5 製藥上可接受之鹽或是該等之溶劑合物的用途,係將如 申請專利範圍第10〜17項中任一項之化合物、其製藥上 可接受之鹽或是該等之溶劑合物用於治療及/或預防 P2X3及/或Ρ2χ2/3受體相關疾病者。 475 200843739 七、指定代表圖: (一) 本案指定代表圖為:第(無)圖。 (二) 本代表圖之元件符號簡單說明: (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:
    (CRaRb)q 丄 » A^(R1)n ⑴
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US8497263B2 (en) 2013-07-30
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