TW200825054A - Quinoline compounds - Google Patents

Quinoline compounds Download PDF

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TW200825054A
TW200825054A TW096138869A TW96138869A TW200825054A TW 200825054 A TW200825054 A TW 200825054A TW 096138869 A TW096138869 A TW 096138869A TW 96138869 A TW96138869 A TW 96138869A TW 200825054 A TW200825054 A TW 200825054A
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atoms
optionally substituted
substituted
compound
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Ronald Charles Bernotas
Robert Ray Singhaus
John William Ullrich
David Harry Kaufman
Robert Lester Morris
Jay E Wrobel
Baihua Hu
James Winfield Jetter
Michael David Collini
Jeremy Mark Travins
Ronald Louis Magolda
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Wyeth Corp
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract

This invention relates generally to quinoline-based modulators of Liver X receptors (LXRs) and related methods.

Description

200825054 九、發明說明： 【發明所屬之技術領域】 相關申請案之交又參考 本發明請求2006年1〇月18曰申請之美國專利臨時申請 5案第60/852,588號的優先權，該案也將在此併人文中當作 參考。 發明領域 本發明概括而言係關於以喹啉為主之肝異受體（LXRs) 的調節物以及相關的方法。 10 發明背景 在已開發國家中，動脈粥狀硬化已列為主要死亡原因 之中。一些與動脈粥狀硬化相關的獨立危險因子包括存在 15有相對高值之血清LDL膽固醇和相對低值之血清HDL膽固 醇在罹患病患中。因此，一些抗粥狀動脈硬化治療法包括 投予用以降低高血清LDL膽固醇值的藥劑（例如斯他汀）。 增加病患HDL膽固醇值之藥劑也可能有用於抗粥狀動 脈硬化療法中。HDL膽固醇被相信在從周邊組織將膽固醇運 20送至肝臟來代謝與排泄中扮演一主要的角色（此過程有時 稱之為“逆轉式膽固醇運輸”）。ABCA1係一運輸基因，涉 及HDL的製造以及逆轉式膽固醇運輸。向上調節aBCA1因 此能夠造成增加的逆轉式膽固醇運輸並抑制腸内膽固醇的 吸收。除此之外，也相信HDL可抑制LDL膽固醇的氧化、 200825054 減少内皮細胞的發炎反應、抑制凝血途徑、以及促進—氧 化氮的可利用性。 肝X受體（LXRs)，原本在肝臟中發現當成孤生受體， 為細胞核核内賀爾蒙受體族群的一員並且相信涉及了膽固 5 醇和脂肪代謝的調節。LXRs係配體活化轉錄因子並且鍵社 至DNA與視黃醇X受體作為專門的雜二聚體。雖然LXRa通 常在例如肝、腎、脂肪組織、小腸和巨嗟細胞組織中被發 現，但是LXRP顯示出一普遍存在的組織分佈型態。在巨嗟 細胞中藉由氧化類固醇（内生性配體）活化LXRs造成許多涉 10 及脂肪代謝和逆轉式膽固醇運輸的基因（包括先前提及的 ABCA1、ABCG1、和 ApoE)表現。 研究已經進行，以LXRa基因剔除（k/〇)、LXRp基因 剔除（k/o)和雙基因剔除（k/o)小鼠來測定LXRs在脂質恆定 狀態以及動脈粥狀硬化中所扮演的生理學角色。這些研究 15 所得之數據暗示在正常給予飼料的雙基因剔除（k/o)小鼠 中，觀察到有增加膽固醇的堆積在脾臟、肺臟和動脈壁的 巨噬細胞（泡沫細胞）。該增加的膽固醇堆積相信與存在著 減少的血清HDL膽固醇和增加的LDL膽固醇有關，即使小 鼠中的總膽固醇值大約正常。雖然LXRa k/o小鼠在肝基因 20表現上並沒有顯示出顯著的變異，但是ϋΟφ k/o小鼠顯示 出減少58%的肝ABCA1表現以及增加208%的SREBPlc表現， 此暗示著LXRP可能涉及肝SREBPlc表現的調節。 從採用兩種不同粥狀動脈硬化小鼠模組（Ap〇E k/o和 LDLR k/o)所獲得的數據暗示LXRa或β的激化物可能在巨 7 200825054 嗟細胞中向上調節ABCA1的表現上相當有。例如，當以LXRa 或β激化物處理ApoE k/o和LDLR k/o小鼠12星期，可 觀察到粥狀動脈硬化病灶被抑制。該試驗的激化物被發現 對血清膽固醇和脂蛋白值具有多變的影響，且顯示出相對 的造成血清HDL膽固醇和三酸甘油酯值顯著的增加。這些 活體内數據被發現與使用㈣激化物於巨仙胞中所獲得 的試管内數據一致。 10 除了上述對脂質和三酸甘油酯的影響之外，也相信 LXRs的活化會抑炎和前發炎反應基因的表現。這種假 說係基於從採用三财同發炎模組之研究所獲得的數據 (LPS誘導的敗血症、耳的急性接難皮膚炎以及動脈壁的 慢性粥狀《社«)。料輯WLxR㈣物能調解 膽固醇從巨伽胞的移除和血管發炎的抑制。 C發明内容:J 發明概要 本發明係普遍關於以喹嗷氣士 ^ 狄γ 土％為主之肝異受體（LXRs)的調 郎物以及相關方法和組成物。 一態樣中，本發明的特徵在於— 種式（I)的化合物： R4 R3 R2200825054 IX. Description of the invention: [Technical field to which the invention pertains] The present application also refers to the priority of the US Patent Provisional Application No. 5, No. 60/852,588, filed on Jan. 18, 2006. It will be used as a reference here and in the humanities. FIELD OF THE INVENTION The present invention is generally directed to modulators of quinoline-based liver heterotopes (LXRs) and related methods. 10 BACKGROUND OF THE INVENTION In developed countries, atherosclerosis has been listed as the leading cause of death. Some of the independent risk factors associated with atherosclerosis include the presence of 15 relatively high levels of serum LDL cholesterol and relatively low levels of serum HDL cholesterol in patients with comorbidities. Therefore, some anti-atherosclerotic treatments include administration of agents (e.g., statins) to lower high serum LDL cholesterol levels. Agents that increase the HDL cholesterol level of patients may also be used in anti-atherosclerotic sclerotherapy. HDL cholesterol is believed to play a major role in the metabolism and excretion of cholesterol from peripheral tissues to the liver (this process is sometimes referred to as "reversed cholesterol transport"). ABCA1 is a transport gene involved in the manufacture of HDL and reversed cholesterol transport. Up-regulation of aBCA1 can therefore result in increased reverse cholesterol transport and inhibition of intestinal cholesterol absorption. In addition, it is believed that HDL inhibits the oxidation of LDL cholesterol, 200825054 reduces the inflammatory response of endothelial cells, inhibits the coagulation pathway, and promotes the availability of nitrogen oxides. Liver X receptors (LXRs), originally found in the liver as orphan receptors, are members of the hormonal receptor population within the nucleus and are believed to be involved in the regulation of cholesterol and fat metabolism. The LXRs ligand activates transcription factors and binds to DNA and retinol X receptors as specialized heterodimers. Although LXRa is commonly found in, for example, liver, kidney, adipose tissue, small intestine, and giant scorpion cell tissues, LXRP shows a ubiquitous tissue profile. Activation of LXRs by oxidative steroids (endogenous ligands) in mega-cells results in a number of genes involved in fat metabolism and reversed cholesterol transport, including the previously mentioned ABCA1, ABCG1, and ApoE. Studies have been conducted to determine the physiology of LXRs in lipid homeostasis and atherosclerosis using LXRa knockout (k/〇), LXRp knockout (k/o) and double knockout (k/o) mice. Learning role. The data obtained in these studies 15 suggest that in double-knockout (k/o) mice that are normally given feed, macrophages (foam cells) that accumulate cholesterol in the spleen, lungs, and arterial walls are observed. This increased cholesterol accumulation is believed to be associated with the presence of reduced serum HDL cholesterol and increased LDL cholesterol, even though the total cholesterol value in the mice is approximately normal. Although LXRa k/o mice did not show significant variation in liver gene 20 expression, ϋΟφ k/o mice showed a 58% reduction in liver ABCA1 performance and a 208% increase in SREBPlc expression, suggesting that LXRP may It involves the regulation of liver SREBPlc expression. Data obtained from two different atherosclerotic mouse modules (Ap〇E k/o and LDLR k/o) suggest that LXRa or β-exciting may up-regulate ABCA1 in giant 7 200825054 sputum cells. There is quite a lot. For example, when ApoE k/o and LDLR k/o mice were treated with LXRa or β-excimer for 12 weeks, atherosclerotic lesions were observed to be inhibited. The initiator of this test was found to have a variable effect on serum cholesterol and lipoprotein values and showed a relative increase in serum HDL cholesterol and triglyceride values. These in vivo data were found to be consistent with the in vitro data obtained using (iv) the excitons in the giant cells. 10 In addition to the above effects on lipids and triglycerides, it is also believed that activation of LXRs will be manifested by anti-inflammatory and pro-inflammatory genes. This hypothesis is based on data obtained from a study using the Sankyo Inflammation Module (LPS-induced sepsis, acute dermatitis of the ear, and chronic porridge of the arterial wall). The WLxR (4) material can mediate the removal of cholesterol from the giant cells and the inhibition of vascular inflammation. C SUMMARY OF THE INVENTION: J SUMMARY OF THE INVENTION The present invention relates generally to the modulating of liver heterologous receptors (LXRs), which are mainly quinoxaline di-gamma soil %, and related methods and compositions. In one aspect, the invention features a compound of formula (I): R4 R3 R2

(I) 20 200825054 其中： R 係氫、CrC6 烧基、NHHCCrCe 烷基）、或 NCCrc6 院基）2 ; R2係： (i) 氯、氰基、或鹵基；或 (ii) Ci-Cu烧基或Ci-Ci2鹵烧基，其之每一可任意 地以1-5 Ra取代；或(I) 20 200825054 where: R is hydrogen, CrC6 alkyl, NHHCCrCe alkyl), or NCCrc6 (2); R2 is: (i) chlorine, cyano, or halo; or (ii) Ci-Cu a base or a Ci-Ci2 halogen group, each of which may be optionally substituted with 1-5 Ra; or

10 1510 15

20 (ui) Ct-Go芳烷基或含有6_2〇原子之雜芳烷基， 其之每一可任意地以1-10 Rb取代；或 (iv) G-L烯基或匕2炔基，其之每一可任意地 以1-10 取代； (v) C3-C1G環烷基、含有3—1〇原子之雜環基、或含 有3-10原子之雜環烯基，其之每一可任意地以i 5 Rb 取代；或 (vi) C6-C18芳基或含有5—16原子之雜芳基其之每 一可任意地以1-10 Rd取代；或 (vii) —XR8，其中： X係—⑽―’· U⑼「’其中t係〇-2 ;-呢 -C(0)NR9- ； -C(NH)NR9- ; -C(〇)〇- ; -CH2〇- ; -ΝΚ^〇2. 或-s〇2’-，其中R9係氫或Ci_C6烷基；且 R8係： (i)氫；或 (11) CrC12烷基或Cl—Ci2鹵烧基，其之每一可任意 地以1-5 Ra取代；或 心 9 200825054 (iii)C7-G。芳録或含有6_2()原子之雜芳炫基， 其之每一可任意地以卜】〇Rb取代；或 (iv) C2-C12 烯基或 c2〜r, ^ π土尺u U炔基，其之每一可任意地 以1-10 Rc取代； —環減或含有3_1()原子之雜環基，其之 每一可任意地以1-5 Rb取代，·或 (vi) Ce-Ci8芳基或含右ς — 有16原子之雜芳基，其之 母一可任意地以1-10俨取代； 10 15 20 R3係ocu芳基或含有5_14原子之 每一可·· ，又 (Ο任意地以1-2 R1G取代，且 (ii)任意地以1—4 IT取代；其中： R1Q係WA，其中： W於各次出現時係獨立地為_鍵；—m，盆 中 t 係 〇—2 ; -NR9— · —rvrrnmg '、 伸烧基；或c 炔基；-WkG-Ce伸烷美、.々π 狎 1 甲况基）一，或—（C!-C6伸烷基; w1於各次出現時係獨立地為m， 係 0-2 ; -NR9- ; —C((nNR9— ·十 Γ 、 )，或CM伸炔基；且 Α於各次出現時係獨立地為： (i) Ce-Cio 芳基，其： (a) 係以1—2 Rf取代；且 (b) 可任意地以丨―4 Re取代； 10 200825054 或 ⑴）含有5-1G原子之雜芳基，其： (a) 係以卜2 f+ a 、 ^ % m 或3有一經取代的環肩 亥原子係選自_和孙所組成之群；且 (b) 可任意地以〗-4 r取代； 二^提是該含有原子之雜芳基並相，Ο尸惡 或 (iii) 含有 8-12 屌；^ > 10 15 20 .τ ，、子之芳基氮環基 (arylazacyclyl)，其： (a) 係以1-2 Rf取代，且 (b) 任意地以1—4 f取代· 或 (iv) 絲亞伽基縣、雜芳基亞伽基環基、芳 土石尹、醯基環基或雜芳基確醯基環基，其之每—包含㈣ 原子且可任意地以丨―4 Re取代； 或 (V) [1’2’4]—°惡二唾基’可任意地以1 Re取代； R、R、R、和R7之每一者係獨立地為： (0氫；或 (ii) Rc ;或 立（出）CA。烷基或c广“鹵烷基，其之每一可任 意地以1-10 Ra取代；或 11 200825054 ’其之每一可任意地 其之每一可任意地 (iv) G-C2。烯基或C2〜c2〇炔基 以^10 Re取代，·或 (v) G-Go芳烷基或雜芳烷基， 以^10 Rb取代； 5 V於各次出現時係獨立地為： (i)NRgRh;硝基；疊氮基；羥基；側氧基；硫酮基； 一_ ; Go烷氧基或C⑼鹵基烷氧基，其之每一係 任意地以1_10 Ra’取代；含有5-16原子之Ce—Ci8芳氧 10 基或雜芳氧基，其之每一係任意地以1-10 Rd取代； CK：2。芳烷氧基、含有6-20原子之雜芳烷氧基、C3—Cl6環 烧氧基、Cs-C2。環烯氧基、含有3-20原子之雜環氧基、 或含有3-20原子之雜環稀基，其之每一係任意地以 1 一 10 Rb取代；氫硫基；C2。硫基烷氧基；G-C2。硫基 15 鹵基烷氧基；含有5-16原子之C6-C18硫基芳氧基或硫 基雜芳氧基，其之每一係任意地以1-10 Ρ取代；C7-C20 硫基芳烷氧基、含有6-20原子之硫基雜芳烷氧基、G-C!6 硫基環烷氧基、C3-C2。硫基環烯氧基、含有3-20原子之 硫基雜環氧基、或含有3-20原子之硫基雜環烯氧基， 20 其之每一係任意地以MO Rb取代；氰基；-C(0)Rj ; -C(0)0Rj ； -0C(0)RJ ； -C(0)SRJ ； -SC(0)RJ ; -C(S)SRJ ； -SC(S)Rj ; -C(〇)NRgRh ; -NRkC(0)Rj ; -CXNlORj ; -0C(0)NRgRh ; _NRkC(0)NRgRh ; -NRkC(0)0Rj ; -S(0)nRra， 其中 n 係 1 或 2 ; -NRkS(0)nRra ;或-P(0)(0Rg)(0Rh); 12 200825054 或 (ii) G-G。環烷基、CH：2。環烯基、含有3_2〇原 子之雜環基、含有3-20原子之雜環烯基、含有8_2〇原 子之芳基雜環基、或含有8-20原子之雜芳基雜環基， 5 其之每一係任意地以1-10 Rb取代；20 (ui) Ct-Go aralkyl or heteroaralkyl containing 6 2 〇 atoms, each of which may be optionally substituted with 1-10 Rb; or (iv) GL alkenyl or 匕 2 alkynyl, Each may be optionally substituted with 1-10; (v) a C3-C1G cycloalkyl group, a heterocyclic group having 3 to 1 atom, or a heterocyclic alkenyl group having 3 to 10 atoms, each of which may be optionally Substituted with i 5 Rb; or (vi) C6-C18 aryl or heteroaryl containing 5-16 atoms each of which may be optionally substituted with 1-10 Rd; or (vii) - XR8, wherein: X Department—(10)―'· U(9)“'where t is 〇-2;-呢-C(0)NR9- ; -C(NH)NR9- ; -C(〇)〇- ; -CH2〇- ; -ΝΚ^ 〇2. or -s〇2'-, wherein R9 is hydrogen or Ci_C6 alkyl; and R8 is: (i) hydrogen; or (11) CrC12 alkyl or Cl-Ci2 haloalkyl, each of which may be optionally Substituted with 1-5 Ra; or heart 9 200825054 (iii) C7-G. Azure or a heteroaryl group containing 6 2 () atoms, each of which may be optionally substituted with 〇Rb; or (iv a C2-C12 alkenyl group or a c2~r, ^ π soil size u U alkynyl group, each of which may be optionally substituted with 1-10 Rc; - a ring-reduced or heterocyclic group having a 3_1 () atom, Each Optionally substituted with 1-5 Rb, or (vi) Ce-Ci8 aryl or containing fluorene-heteroaryl having 16 atoms, the parent of which may be optionally substituted with 1-10 ;; 10 15 20 R3 Ocu aryl or containing each of 5 to 14 atoms, and (optionally substituted with 1-2 R1G, and (ii) arbitrarily substituted with 1-4 IT; where: R1Q is WA, where: W Each occurrence is independently _ bond; -m, t-system 〇-2 in the pot; -NR9---rvrrnmg ', extended alkyl; or c alkynyl; -WkG-Ce alkylene, 々π狎1 A condition base), or -(C!-C6 alkylene; w1 is independently m in each occurrence, is 0-2; -NR9-; -C((nNR9- · 十Γ, , or CM an alkynyl group; and each occurrence is independently: (i) a Ce-Cio aryl group, which: (a) is substituted with 1-2 Rf; and (b) is optionally丨—4 Re substituted; 10 200825054 or (1)) A heteroaryl group containing a 5-1 G atom, which: (a) is a group of 2 2 + a, ^ % m or 3 having a substituted ring shoulder atomic atom selected from _ And the group consisting of grandchildren; and (b) may be arbitrarily substituted with 〖-4 r; the second is the phase of the heteroaryl containing atoms, Ο 恶 or (iii) contains 8-12 屌; ^ > 10 15 20 .τ , aryllazacyclyl, which: (a) is substituted with 1-2 Rf, and (b Arbitrarily substituted with 1-4 f or (iv) silk gamma county, heteroaryl gamma cyclyl, aryl earth fluorenyl, fluorenyl cyclyl or heteroaryl fluorenyl cyclyl, each of which - containing (iv) atoms and optionally substituted with 丨-4 Re; or (V) [1'2'4] - oxadiazolyl can be optionally substituted with 1 Re; R, R, R, and R7 Each is independently: (0 hydrogen; or (ii) Rc; or standing (out) CA. Alkyl or c-wide "haloalkyl, each of which may be optionally substituted with 1-10 Ra; or 11 200825054 'each of which may optionally be (iv) G-C2. Or a C2~c2 decynyl group substituted with ^10 Re, or (v) a G-Go aralkyl or heteroaralkyl group, substituted with ^10 Rb; 5 V is independently present at each occurrence: i) NRgRh; nitro; azide; hydroxy; pendant oxy; thioketo; _; Go alkoxy or C(9) haloalkoxy, each of which is optionally substituted with 1_10 Ra'; 5-16 atoms of Ce-Ci8 aryloxy 10 or heteroaryloxy, each of which is optionally substituted with 1-10 Rd; CK: 2. Aralkyloxy, heteroaryl having 6-20 atoms An oxy group, a C3-Cl6 cycloalkoxy group, a Cs-C2 group, a cycloalkenyloxy group, a heterocyclic oxy group having 3 to 20 atoms, or a heterocyclic group having 3 to 20 atoms, each of which is optionally Substituted with 1 to 10 Rb; thiol group; C2. thioalkoxy; G-C2. thiol 15 haloalkoxy; C6-C18 thioaryloxy or sulfhydryl containing 5-16 atoms An aryloxy group, each of which is optionally substituted with 1-10 ;; a C7-C20 thioaralkyloxy group, containing 6-20 Thio-heteroaralkyloxy, GC!6 thiocycloalkoxy, C3-C2, thiocycloalkenyloxy, thioheterocyclyloxy having 3-20 atoms, or containing 3-20 atoms a thioheterocyclenyloxy group, 20 each of which is optionally substituted with MO Rb; a cyano group; -C(0)Rj; -C(0)0Rj; -0C(0)RJ; -C(0 SRJ; -SC(0)RJ ; -C(S)SRJ ; -SC(S)Rj ; -C(〇)NRgRh ; -NRkC(0)Rj ; -CXNlORj ; -0C(0)NRgRh ; _NRkC( 0) NRgRh ; -NRkC(0)0Rj ; -S(0)nRra, where n is 1 or 2; -NRkS(0)nRra ; or -P(0)(0Rg)(0Rh); 12 200825054 or (ii GG. cycloalkyl, CH: 2. cycloalkenyl, heterocyclic group containing 3 2 fluorene atom, heterocyclic alkenyl group having 3-20 atoms, aryl heterocyclic group containing 8 2 fluorene atom, or containing 8- a hetero atom heterocyclic group of 20 atoms, 5 each of which is optionally substituted with 1-10 Rb;

Ra’於各次出現時係獨立地為NRgRh;硝基；疊氮基； 羥基；側氧基；氰基；-C(〇)Rj ; —c(〇)ORj ; —〇c(〇)Rj ; -C(0)SR\ -sc(0)t 卜C(S)SR。—sc(s)Rj; —c(〇)NRgRh’; 10 —NRkC(0)Rj ; —; -〇C(0)NRf ; —NRkc(〇)NRgRh ; -NRkC(0)0Rj ; -S(0)nRffi，其中 n 係 j 或 2 ;〜NRks(〇)nR、 -P(0)(0Rg)(0Rh) ; C3-C2Q 環院基；c3-C2Q 環烯基；含有 3-20原子之雜環基；或含有3—2Q原子之雜環烤基； 15 R於各次出現時係獨立地為： ⑴函基；NIW;硝基；疊氮基；經基；側氧基； 硫酮基；I ·，（V·c2。烧氧基或Ci—C2。祕烧氧基，其 之每-係任意地以卜lGRa取代；C6—^芳氧基或含有 5-16原子之雜芳氧基，其之每—係任意地以卜ι〇作 20代；Cr⑶芳烧氧基、含有6〜20原子之雜芳烧氧基、C3—Ci6 環烧氧基、C3-C2〇環埽氧基、含有3—2〇原子之雜環氧 基、或含有3-2G原子之雜環烯氧基，其之每一係任意 地以1-10 Rb’取代；氫硫基；Ci_C2q硫基錄基；C!—& 硫基鹵基烷氧基；含有5-16原子之C6—Cl8硫基芳氧基 13 200825054 或硫基雜芳氧基，其之每一係任意地以1-10 Rd取代； C7-C20硫基芳烷氧基、含有6-20原子之硫基雜芳烷氧 基、C3-Cl6硫基環烧氧基、C3-C20硫基環稀氧基、含有 3-20原子之硫基雜環氧基、或含有3-20原子之硫基雜 5 環烯氧基，其之每一係任意地以1-10 Rb取代；氰基； -C(0)RJ ； -C(0)0RJ ； -0C(0)RJ ； -C(0)SRJ ； -SC(0)RJ ； -C(S)SRJ； -SC(S)RJ； -C(0)NRgRh； -NRkC(0)RJ； -C(NR1)RJ ； -0C(0)NRgRh ; -NRkC(0)NRgRh ; -NRkC(0)0Rj ; -S(0)nRffl， 其中 n係 1 或 2; -NRkS(0)nRm;或-P(0)(0Rg)(0Rh);或 i〇 者 (i i ) Cl - C2Q烧基或Cl_C2G鹵院基，其之每'一係任意 地以1-10 Ra取代；或 (iii) C2-C20稀基或C2-C2G快基，其之每一係任意 地以1-10 Re取代；或 15 (iv) C6-Ci8芳基或含有5-16原子之雜芳基，其之 每一係任意地以1-10 Rd取代；或 (v) C3-C2。環烧基、C3-C2。環稀基、含有3-20原子 之雜環基、或含有3-20原子之雜環烯基，其之每一係 任意地以1-10 Rb’取代； 20Ra' is in each occurrence independently NRgRh; nitro; azide; hydroxy; pendant oxy; cyano; -C(〇)Rj; -c(〇)ORj ; —〇c(〇)Rj ; -C(0)SR\ -sc(0)t Bu C(S)SR. —sc(s)Rj; —c(〇)NRgRh′; 10 —NRkC(0)Rj ; —; —〇C(0)NRf ; —NRkc(〇)NRgRh ; —NRkC(0)0Rj ; -S( 0) nRffi, where n is j or 2; ~NRks(〇)nR, -P(0)(0Rg)(0Rh); C3-C2Q ring-based; c3-C2Q cycloalkenyl; containing 3-20 atoms a heterocyclic group; or a heterocyclic base containing 3 to 2 Q atoms; 15 R is independently present in each occurrence: (1) a functional group; NIW; a nitro group; an azide group; a transaluminum; a pendant oxy group; a group; I ·, (V·c2. alkoxy or Ci-C2. alkoxy groups, each of which is optionally substituted with PFRA; C6-^ aryloxy or heteroaryl containing 5-16 atoms Oxyl, each of which is optionally used as a 20th generation; Cr(3) aryloxy group, heteroaryl alkoxy group having 6 to 20 atoms, C3—Ci6 cycloalkoxy group, C3-C2 anthracene ring An oxy group, a heterocyclic oxy group having 3 to 2 atomic atoms, or a heterocyclic oxy group having 3 to 2 carbon atoms, each of which is optionally substituted with 1-10 Rb'; a thiol group; a Ci_C2q thio group Recording group; C!-&thiohaloalkoxy; C6-Cl8 thioaryloxy group containing 5-16 atoms; 200825054 or thioheteroaryloxy, each of which is optionally 1 -10 Rd substituted; C7-C20 thioaralkyloxy, 6-20 atom thioheteroaryloxy, C3-Cl6 thiocycloalkoxy, C3-C20 thiocyclophosphoxy, containing a thioheterocyclooxy group of 3 to 20 atoms, or a thiohetero5-cycloalkenyloxy group having 3 to 20 atoms, each of which is optionally substituted with 1-10 Rb; a cyano group; -C(0) RJ ; -C(0)0RJ ; -0C(0)RJ ; -C(0)SRJ ; -SC(0)RJ ; -C(S)SRJ; -SC(S)RJ; -C(0)NRgRh ; -NRkC(0)RJ; -C(NR1)RJ ; -0C(0)NRgRh ; -NRkC(0)NRgRh ; -NRkC(0)0Rj ; -S(0)nRffl, where n is 1 or 2; -NRkS(0)nRm; or -P(0)(0Rg)(0Rh); or i(i) Cl - C2Q alkyl or Cl_C2G halogen hospital base, each of which is optionally 1-10 Ra substituted; or (iii) C2-C20 dilute or C2-C2G fast radical, each of which is optionally substituted with 1-10 Re; or 15 (iv) C6-Ci8 aryl or containing 5-16 atoms Heteroaryl, each of which is optionally substituted with 1-10 Rd; or (v) C3-C2. Cyclic base, C3-C2. a cycloaliphatic group, a heterocyclic group having 3 to 20 atoms, or a heterocyclic alkenyl group having 3 to 20 atoms, each of which is optionally substituted with 1-10 Rb';

Rb於各次出現時係獨立地為Ra’ ；鹵基；G-C2。烷氧 基或Ci-GG鹵基烷氧基，其之每一係任意地以1-10 Ra 取代；C6-C18芳氧基或含有5-16原子之雜芳氧基，其之 每一係任意地以1_10 Rd取代；Ci-C2G烧基或C1-C2G _ 14 200825054 烧基’其之每一係任音 Γ_Γ .、 〜地以PiORa取代；C2-C2。烯基； 2 20炔基，或C6-CI8芳基< j 土 As有5-1Θ原子之雜芳基， 八之母一係任意地以M〇 Rd取代； R於各次出現時係獨立地為： (1) _ 基；NRgRh ;硝基 · 一 ^ ^ ^ ^ ^ ®虱基，羥基，側氧基； 10 15 20 ^每一係任意地以卜1”取代；芳氧基或含; 6原子之雜芳氧基，其之每—係任意地以卜^取 2 'C2°芳烷氧基、含有1 2 3 4-20原子之雜芳烷氧基、C16 環院氧基、環烯氧基、含有3—2()原子之雜環氧 基、或含有3-2G原子之雜環烯氧基，其之每一係任意 也以1 10 R取代，氫硫基；Ci_C2〇硫基烧氧基；C —^ 石度基_基烷氧基；含有5—16原子之匕―硫基芳氧基 或硫基雜芳氧基，其之每一係任意地以 1 -10 Rd 取代；Rb is independently Ra'; halo; G-C2 in each occurrence. An alkoxy group or a Ci-GG haloalkoxy group, each of which is optionally substituted with 1-10 Ra; a C6-C18 aryloxy group or a heteroaryloxy group having 5-16 atoms, each of which is Optionally substituted with 1_10 Rd; Ci-C2G alkyl or C1-C2G _ 14 200825054 burnt base 'each of which is Γ Γ 、 、 、 〜 〜 〜 〜 、 、 、 、 、 、 、 、 、 、 、 〜 〜 〜 〜 〜 ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; Alkenyl; 2 20 alkynyl, or C6-CI8 aryl < j The soil As has a heteroaryl group of 5-1 fluorene, and the parent of VIII is optionally substituted with M 〇 Rd; R is independent in each occurrence The ground is: (1) _ group; NRgRh; nitro · a ^ ^ ^ ^ ^ ® fluorenyl, hydroxy, pendant oxy; 10 15 20 ^ each line is optionally substituted with 1"; aryloxy or 6 atomic heteroaryloxy group, each of which is optionally taken as 2 'C2 ° aralkyloxy group, heteroaryl alkoxy group having 1 2 3 4-20 atom, C16 ring alkoxy group, a cycloalkenyloxy group, a heterocyclic oxy group having 3 to 2 () atoms, or a heterocyclic alkenyloxy group having 3 to 2 G atoms, each of which is optionally substituted with 1 10 R, a thiol group; Ci_C2 〇 Thioalkyloxy; C—^ 度 _  yl alkoxy; 匕-thioaryloxy or thioheteroaryloxy having 5-16 atoms, each of which is optionally 1 - 10 Rd replaced;

Cr_C2°硫基芳烷氧基、含有Θ-20原子之硫基雜芳烷氧 基、CH^硫基環烷氧基、硫基環烯氧基、含有 15 1 一20原子之硫基雜環氧基、或含有3-20原子之硫基雜 2 壤烯氧基，其之每一係任意地以U0 Rb取代；氰基； 3 -C(0)RJ ; -C(〇)〇Rj ； -0C(0)RJ ； -C(0)SRj ； -SC(0)Rj ; -C(S)SRj; -SC(S)RJ ； -C(0)NRgRh ； -NRkC(0)RJ ； -C(NRi)Rj; 4 一0C(0)NiW ; -NRkC(0)NRgRh ; -NRkC(0)0Rj ; -S(0)nRffi， 其中 n 係 1 或 2 ; -NRkS(0)nRm ;或-P(0)(0Rg)(0Rh);或 (ii) C3-C20環烧基、C3-C20環稀基、含有3-20原 200825054 子之雜％<基、或含有3_2G原子之雜環烯基，其之每一 係任意地以M〇 Rb’取代；或 卜(111) Cl8芳基或含有5-16原子之雜芳基，其之 每一係任意地以1-10 Rd取代； 5Cr_C2°thioarylalkoxy, thioheteroaralkyloxy having Θ-20 atom, CH^thiocycloalkoxy, thiocycloalkenyloxy, thioheterocyclic ring containing 15 1 to 20 atoms An oxy group, or a thio-heteropolyeneoxy group having 3 to 20 atoms, each of which is optionally substituted with U0 Rb; a cyano group; 3 - C(0)RJ; -C(〇)〇Rj; -0C(0)RJ ; -C(0)SRj ; -SC(0)Rj ; -C(S)SRj; -SC(S)RJ ; -C(0)NRgRh ; -NRkC(0)RJ ; C(NRi)Rj; 4 - 0C(0)NiW ; -NRkC(0)NRgRh ; -NRkC(0)0Rj ; -S(0)nRffi, where n is 1 or 2; -NRkS(0)nRm ; -P(0)(0Rg)(0Rh); or (ii) a C3-C20 cycloalkyl group, a C3-C20 ring-dilute group, a 3-20 original 200825054 miscellaneous % base, or a 3_2G atom-containing hetero a cycloalkenyl group, each of which is optionally substituted with M〇Rb'; or a (111) Cl8 aryl group or a heteroaryl group having 5-16 atoms, each of which is optionally substituted with 1-10 Rd ; 5

Rd於各次出現時係獨立地為： ，⑴鹵基，· NIW ;確基；疊氮基；經基；Ci—C2。烷 氧基或g C2。由基院氧基，其之每一係任意地卩卜i〇 Ra 取代；C6—Cl8彡氧基或含有5-16原子之雜芳氧基，其 10之每—係任意地以HG Rd取代；以。芳錄基、含 有6-20原子之雜芳烷氧基、Cie環烷氧基、環 烯虱基、含有3-20原子之雜環氧基、或含有3-2〇原子 之雜環浠氧基，其之每一係任意地以1-10 Rb，取代；氫 硫基；C!-C2。硫基烷氧基；硫基_基烷氧基；含 有5-16原子之C6-Ci8硫基芳氧基或硫基雜芳氧基，其 之母一係任意地以1-1〇 Rd取代；G-C2。硫基芳烧氧基、 含有6-20原子之硫基雜芳烷氧基、C3-Ci6硫基環烷氧 基、CrC2。硫基環烯氧基、含有3-20原子之硫基雜環氧 基、或含有3-20原子之硫基雜環烯氧基，其之每一係 任意地以 1-1〇 Rb 取代；氰基；-c(o)tr ; —C(0)〇rj ; -0C(0)RJ ; -C(0)SRJ ； -SC(0)RJ ； -C(S)SRJ ; -SC(S)RJ ； -C(0)NRgRh ; -NRkC(0)RJ ； -C(NR1)RJ ； -〇C(〇)NRgRh ； -NRkC(〇)NRgRh; -NRkC(0)0Rj; -S(0)nRn，其中 n 係 i 或 2 ; -NRkS(〇)nRm ;或—p(〇)(〇r)(〇Rh); 16 200825054 (11) Cl-C2。烷基或Ci-C2〇 _烷基，其之每一係任意 地以1-10 Ra取代；或 (iii) 烯基或a—炔基，其之每一係任意 地以1-10 Re取代；或 5 (iv) C?—C2°芳烷基、含有6-20原子之雜芳烷基、 C3-^環烷基、Ο。環烯基、含有3—2〇原子之雜環基、 或含有3-20原子之雜環烯基，其之每一係任意地以 1 -10 Rb取代；或 (V) C6-Cl8芳基或含有5_16原子之雜芳基，其之每 10 —係任意地以1-10 Rd取代； 15 20 R於各次出現時係獨立地為幽基；NRgRh;確基； 疊氮基；祕；㈣絲；以。㈣基；C2—C2。稀 基；c2-c2。快基；C3_C2o環絲；C3_C2。環稀基；含有 3-20原子之雜環基；含有3_2Q原子之雜輯基心―心 芳烧基；含有6-2G原子之雜芳院基；以道氧基；Cl_C2。 鹵基烧氧基；ou芳氧基；雜芳氧基；“芳烧氧 基’ 3有6 2G原子之雜奸氧基；g 氧基；^匕。 環稀氧基；含# 3,軒之雜環氧基；含有3-20原子 之雜環烯氧基：氫硫基；Gi_G2。硫纽氧基；硫 基函基烧氧基；Ce-C18硫基芳氧基；含有㈣原子之硫 基雜芳氧基；O-Go硫基純氧基；含有6 2()原子之硫 基雜芳錄基；G3-Gn魏氧基；G3_G2()硫基環稀 氧基、含有3-20原子之硫基雜環氧、或含有3 2〇原子 17 200825054 之硫基雜環烯氧基；氰基；-C(0)R。-C(0)0R。-0C(0)Rj; -C(0)SRj ; -SC(0)Rj ; -C(S)SRj ; -SC(S)Rj; -C(0)NRgRh ; -NRkC(0)Rj ; -C(NRi)Rj ; -〇c(〇)NRgRh ; -NRkC(0)NRgRh ; -NRkC(0)0Rj ; -S(0)nRm，其中 n 係 i 或 2 ; -NRkS(0)nr ; 或-P(0)(0Rg)(0Rh);Rd appears independently at each occurrence: , (1) halo, NIW; exact; azide; merid; Ci-C2. Alkoxy or g C2. Each of the 10 ketones, optionally substituted by HG Rd, is substituted by a ketone oxy group, each of which is optionally substituted with i〇Ra; C6-Cl8 decyloxy or a heteroaryloxy group having 5-16 atoms; ; Aromatic group, a heteroaralkyloxy group having 6 to 20 atoms, a Cie cycloalkoxy group, a cycloalkenylene group, a heterocyclic oxy group having 3 to 20 atoms, or a heterocyclic oxime having 3 to 2 atomic atoms Each of which is optionally substituted with 1-10 Rb; a thiol group; C!-C2. Thioalkoxy; thio-ylalkoxy; C6-Ci8 thioaryloxy or thioheteroaryloxy having 5-16 atoms, the parent of which is optionally substituted by 1-1〇Rd ;G-C2. A thioarylalkoxy group, a thioheteroaralkyloxy group having 6 to 20 atoms, a C3-Ci6 thiocycloalkoxy group, and CrC2. a thiocycloalkenyloxy group, a thioheterocyclooxy group having 3 to 20 atoms, or a thioheterocycloalkenyloxy group having 3 to 20 atoms, each of which is optionally substituted with 1-1〇Rb; Cyano; -c(o)tr ; -C(0)〇rj ; -0C(0)RJ ; -C(0)SRJ ; -SC(0)RJ ; -C(S)SRJ ; -SC(S RJ ; -C(0)NRgRh ; -NRkC(0)RJ ; -C(NR1)RJ ; -〇C(〇)NRgRh ; -NRkC(〇)NRgRh; -NRkC(0)0Rj; -S(0 nRn, where n is i or 2; -NRkS(〇)nRm; or -p(〇)(〇r)(〇Rh); 16 200825054 (11) Cl-C2. An alkyl group or a Ci-C2 〇-alkyl group, each of which is optionally substituted with 1-10 Ra; or (iii) an alkenyl group or an a-alkynyl group, each of which is optionally substituted with 1-10 Re Or 5 (iv) C?-C2° aralkyl, heteroaralkyl containing 6-20 atoms, C3-^cycloalkyl, hydrazine. a cycloalkenyl group, a heterocyclic group having 3 to 2 atomic atoms, or a heterocyclic alkenyl group having 3 to 20 atoms, each of which is optionally substituted with 1 to 10 Rb; or (V) a C6-Cl8 aryl group Or a heteroaryl group having 5-16 atoms, each of which is optionally substituted with 1-10 Rd; 15 20 R is independently a cleavage group in each occurrence; NRgRh; a deterministic group; an azide group; (four) silk; to. (four) base; C2 - C2. Dilute base; c2-c2. Fast base; C3_C2o loop wire; C3_C2. a ring-like group; a heterocyclic group having 3 to 20 atoms; a heterocyclic group containing a core of 3 to 2 Q atoms; a heteroaryl group containing 6 to 2 G atoms; a oxo group; and a Cl_C2 group. Halo alkoxy; ou aryloxy; heteroaryloxy; "arylalkoxy" 3 has 6 2G atom of oxytetracycline; g oxy; ^ 匕. cycloaliphatic; containing # 3, Xuan a heterocyclic oxy group; a heterocyclic alkenyloxy group having 3 to 20 atoms: a thiol group; a Gi-G2 thioneoxy group; a thiol group alkoxy group; a Ce-C18 thioaryloxy group; Thioheteroaryloxy; O-Go thiopurity oxy; thio-heteroaryl group containing 6 2 () atom; G3-Gn-propoxy group; G3_G2() thio-cycloaliphaticoxy group, 3- a 20-atom thio-heteroepoxy, or a sulfhydrylheterocycloalkenyloxy group having a 32 atomic atom 17 200825054; a cyano group; -C(0)R.-C(0)0R.-0C(0)Rj; -C(0)SRj ; -SC(0)Rj ; -C(S)SRj ; -SC(S)Rj; -C(0)NRgRh ; -NRkC(0)Rj ; -C(NRi)Rj ; 〇c(〇)NRgRh ; -NRkC(0)NRgRh ; -NRkC(0)0Rj ; -S(0)nRm, where n is i or 2; -NRkS(0)nr ; or -P(0)(0Rg )(0Rh);

Re於各次出現時係獨立地為c6烷基，可任意地 以1-3 Ra取代；Ci-Ce鹵烷基；苯基；4一氟苯基；鹵基； 沒基，NRgR，硝基；（V·a烯基；C2-C6炔基；Ci-C6烷 1〇 氧基；Cl—&鹵基烷氧基；氰基；或—c(〇)Rj ;Re is independently c6 alkyl at each occurrence, optionally substituted with 1-3 Ra; Ci-Ce haloalkyl; phenyl; 4-fluorophenyl; halo; ruthenium, NRgR, nitro (V.a alkenyl; C2-C6 alkynyl; Ci-C6 alkane 1 methoxy; Cl-&haloalkoxy;cyano; or -c(〇)Rj;

Rf於各次出現時係獨立地為： (Ο -S⑻nR' —(CH2)i 6S⑻，、—NRks⑻，、或 0S(0)nR、其中n於各次出現時係獨立地為工或2 ;或 15 (⑴-商咖心―NRk⑽.i_RgRh、或 -0C(0)0RJ ;或 1 -2側氧基 U1U 3有5-10原子之雜環基 取代或任思地以1—3 取代·戈 20 (iv)含有 5-1〇 其之每一係任意地以 (v)-YRf，其中γ於各次出 烷基、-0-、或-NR9-; 原子之雜環烯基或1H-苯并咪唑， 1-3 Re取代；或 現時係獨立地為。—(；6伸 R於各次出現時係獨立地為： 18 200825054 (i) 含有5-10原子之雜環基，可以1-2側氧基取 代且可任意地以1-3 Re取代；或 (ii) 含有5-10原子之雜環烯基或1H-苯并咪唑， 其之每一係任意地以1-3 Re取代； 5Rf appears independently at each occurrence: (Ο -S(8)nR' - (CH2)i 6S(8), -NRks(8), or 0S(0)nR, where n is independently work or 2 in each occurrence; Or 15 ((1)-commercial heart-NRk(10).i_RgRh, or -0C(0)0RJ; or 1-2 side-oxyl U1U 3 substituted with a heterocyclic group of 5-10 atoms or optionally substituted with 1-3 Ge 20 (iv) contains 5-1 each of which is optionally (v)-YRf, wherein γ is in each alkyl group, -0-, or -NR9-; heterocycloalkenyl or 1H of the atom -benzimidazole, 1-3 Re substituted; or presently independently - (6 extension R in each occurrence is independently: 18 200825054 (i) a heterocyclic group containing 5-10 atoms, 1-2 side oxy substituted and optionally substituted with 1-3 Re; or (ii) 5-10 atom heterocycloalkenyl or 1H-benzimidazole, each of which is optionally 1-3 Re substituted; 5

Rg、Rh、R1、和Rk之每一，在每一可能情況下係獨立 地為： (i) 氫；或 (ii) Ci-Go烷基或G-Go鹵基烷基，其之每一係任 10 意地以1-10 Ra取代；或 (iii) C2-C2。稀基或C2-C2。快基’其之每一係任意地 以1-10 Re取代；或 (iv) C3-C2。環烧基、C3-C2。環稀基、含有3-20原 子之雜環基、含有3-20原子之雜環烯基、O-C2。芳烷基、 15 或含有6-20原子之雜芳烷基，其之每一係任意地以 1-10 Rb取代；或 (v) C6-Ci8芳基或含有5-16原子之雜芳基^其之每 一係任意地以1 -10 Rd取代；或 (vi) -0Rj ; -C(0)Rj ; -C(0)0Rj ; -C(0)NRgRh ;或 20 -S(0)nRffl ；Each of Rg, Rh, R1, and Rk, wherever possible, is independently: (i) hydrogen; or (ii) Ci-Go alkyl or G-Go haloalkyl, each of which Is optionally substituted with 1-10 Ra; or (iii) C2-C2. Dilute or C2-C2. Each of the fast bases is optionally substituted with 1-10 Re; or (iv) C3-C2. Cyclic base, C3-C2. A cycloaliphatic group, a heterocyclic group having 3 to 20 atoms, a heterocycloalkenyl group having 3 to 20 atoms, and O-C2. An aralkyl group, 15 or a heteroarylalkyl group having 6 to 20 atoms, each of which is optionally substituted with 1-10 Rb; or (v) a C6-Ci8 aryl group or a heteroaryl group having 5 to 16 atoms ^ Each of them is arbitrarily replaced by 1 -10 Rd; or (vi) -0Rj ; -C(0)Rj ; -C(0)0Rj ; -C(0)NRgRh ; or 20 -S(0) nRffl ;

Rj於各次出現時係獨立地為： (i)氫；或 (i i) Ci-C2。烧基或C1-C2。_基烧基’其之每'係任 意地以1-10 Ra取代；或 19 200825054 (ii〇 C2~C2。烯基或C2—^炔基，其之每—係任意地 以1-10 Re取代；或 (IV) C3-C2。環烷基、c3-c2G環烯基、含有3—2〇原 子之雜環基、含有3_2〇原子之雜環稀基、C7_C2❶芳院基、 5或含有6一2〇原子之雜芳烧基，其之每一係任意地以 1 -10 Rb取代；或 (v) C6-Cu芳基或含有5—16原子之雜芳基，其之每 一係任意地以1-10 Rd取代；或 Γ於各次出現時係獨立地為Rj、〇Rj、或NRgRh ; R於各次出現時係獨立地為Rj或NRgRh ; 或其之一 N-氧化物和/或其之一醫藥上可接受的鹽類。 於-態樣巾，本發明之特徵在式⑴的化合物，其中： R1係氫或Cl-C6烧基； 15 X 係-C(0)- ; ; -S⑼t_ ’ 其中 t 係 〇—2 ; _服9 ~C(0)NR9- ; -C(NH)NR9- ； -C(〇)〇- ; -CH2〇- ; ,t_S〇2NR9 其中R9係氫或Ci-G烷基；Each occurrence of Rj is independently: (i) hydrogen; or (i i) Ci-C2. Burning base or C1-C2. Each of the 'base groups' is optionally substituted with 1-10 Ra; or 19 200825054 (ii〇C2~C2. alkenyl or C2-alkynyl, each of which is optionally 1-10 Re Substituted; or (IV) C3-C2. cycloalkyl, c3-c2G cycloalkenyl, heterocyclic group containing 2-3 atom, heterocyclic group containing 3_2 fluorene atom, C7_C2 fluorene, 5 or a heterocyclic group of 6 to 2 atoms, each of which is optionally substituted with 1 to 10 Rb; or (v) a C6-Cu aryl group or a heteroaryl group having 5 to 16 atoms, each of which is a Optionally substituted with 1-10 Rd; or each occurrence is independently Rj, 〇Rj, or NRgRh; R is independently Rj or NRgRh at each occurrence; or one of its N-oxides And/or one of its pharmaceutically acceptable salts. The invention is characterized by a compound of formula (1) wherein: R1 is hydrogen or Cl-C6 alkyl; 15 X-C(0) - ; ; -S(9)t_ ' where t is 〇-2; _服9 ~C(0)NR9- ; -C(NH)NR9- ; -C(〇)〇- ; -CH2〇- ; ,t_S〇2NR9 R9 is hydrogen or Ci-G alkyl;

Rg、Rh、R1、和Rk之每一者於各次出現時係獨立地為·· (i) 氯；或 (ii) Ci-C2。烷基或Ci-Go鹵基烧基，其之每一係任音 地以1-10 Ra取代；或 〜 (in) G-G。烯基或G-C2。炔基，其之每一係任意地以 Mo r取代；或 (iv) (：3-(：2〇環烷基、G-Gg環烯基、含有3_2〇原子之 20 200825054 ^ 5 雜環基、含有3-20原子之雜環烯基、芳絲、或含 有6-2◦原子之雜芳烧基，其之每—係任意地以卜ι〇作 代；或 (V) a-cls芳基或含有5—16原子之雜芳基，其之每一 係任意地以1-10 Rd取代；或 (vi) -〇R^ ; -C(0)r ； -C(0)0R^ ; -C(0)NRr ;或 -S(0)nRffl ； n係1或2 ;且 f \ 10 R2、R3、R4、R5、R6、r' R8、R9、rig、γ、w、r、A、Ra、 m、R'r、Rn、和t可如 上述疋義，或其之一 N-氧化物和/或其之一醫藥上可接受的 鹽類。 15 / 另一態樣中，本發明之特徵在於此中劃出輪廓範圍之 任一特定的喹啉化合物（例如如同範例中所示）。在某些實 施例中，該化合物可選自範例43-190、192-198、201、202、 204-210 、 212-217 、 220-223 、 226 、 229-257 、 259-267 、 269-272 、 274-365 、 367-370 、 372 、 374-39卜 394-396 、 398、400、402-593、和595-597之標題化合物所組成之群， 20 以及範例397、399、40卜和598-600中之每一標題化合物。 如此中所使用，該術語“標題化合物”指的是（〇該化合 物的名稱為一特定範例的標題或（ii)範例397、399、401、 和598-600中所描述之每一化合物名稱。說的更清楚的是， 當該範例提出一多步驟之合成法時，該標題化合物係多步 21 200825054Each of Rg, Rh, R1, and Rk is independently (i) chlorine; or (ii) Ci-C2. An alkyl or Ci-Go haloalkyl group, each of which is substituted with 1-10 Ra; or ~ (in) G-G. Alkenyl or G-C2. An alkynyl group, each of which is optionally substituted with Mo; or (iv) (: 3-(: 2〇cycloalkyl, G-Ggcycloalkenyl, 20-2〇 atom containing 20 200825054 ^ 5 heterocyclic group) a heterocyclic alkenyl group having 3 to 20 atoms, an aromatic silk, or a heteroaromatic group having 6 to 2 atomic atoms, each of which is optionally substituted with a bucking group; or (V) a-cls aromatic a group or a heteroaryl group having 5 to 16 atoms, each of which is optionally substituted with 1-10 Rd; or (vi) - 〇R^; -C(0)r; -C(0)0R^; -C(0)NRr ; or -S(0)nRffl ; n is 1 or 2; and f \ 10 R2, R3, R4, R5, R6, r' R8, R9, rig, γ, w, r, A And Ra, m, R'r, Rn, and t may be as defined above, or one of the N-oxides and/or one of its pharmaceutically acceptable salts. 15 / In another aspect, The features of the invention are hereby delineated to any particular quinoline compound of the range (for example as shown in the examples). In certain embodiments, the compound may be selected from the examples 43-190, 192-198, 201, 202, 204-210, 212-217, 220-223, 226, 229-257, 259-267, 269-272, 274-365, 367-370, 372, 374-39b 3 a group of the title compounds of 94-396, 398, 400, 402-593, and 595-597, 20 and each of the title compounds of Examples 397, 399, 40, and 598-600. As used herein, The term "title compound" refers to (the name of the compound is the title of a specific example or (ii) the name of each compound described in the examples 397, 399, 401, and 598-600. It is more clear that When the example proposes a multi-step synthesis method, the title compound is multi-step 21 200825054

“4-[3’ -(乙基石黃醯基）—4,— 十、平、签」本I丨-d- ψ基三 397之一種該標題化合物係 -甲基聯苯-3-基]甲基 5 -8-(三氟甲基）喧琳”。 -態樣中，本發明之特徵在於_醫藥組成物，其包括 式⑴之化合物[包括其之任何次類（subgenera)或特定的 化合物）或其之鹽類（例如，一醫藥可接受的鹽類）或其之前 10驅藥以及一醫藥上可接受的佐劑、載體或稀釋劑。在一些 實施例中，该組成物可包括一有效量之該化合物或其之鹽 類。在一些實施例中，該組成物可另包括一額外的治療劑。 本發明亦普遍關於以此中所述之喹啉化合物來調節（例如， 15活化）LXRS。在一些實施例中，該方法包括，例如，在一檢體中 (例如，不含組織、細胞之试驗培養基、細胞為基料之試驗纟立養 基)將LXR與式⑴之化合物（包括其之任何次類或特定的化合物） 接觸。在其他實施例中，該方法可包括將式（1)之化合物（包括其 之任何次類或特定的化合物)投藥至一個體(例如，哺乳類動物、 20人類、具有或有機率得到此中所述之一種或多種疾病或失調）。 一態樣中，本發明亦普遍關於在一個體中（例如，需要 其之個體）預防或治療（例如，控制、改善、減輕、減緩進 程，延遲開始，或減少發展的機率）一種或多種LXR_媒介之 疾病或失調的方法。該方法包括投藥一有效量之式（I)化合 22 200825054 物（包括其之任何次類或特定的化合物）或其之一醫藥 接受的鹽誠前驅藥至—個體。LXR_媒介之疾病或失調可 包括，例如，心血管疾病（例如，急性冠心症、再狹窄症）、 5 10 15 20 動脈粥狀魏、·_硬化錄、第丨型糖尿病、第π 型糖尿病、χ症候群、肥胖症、脂質失調（例如，血脂显常、 高血脂症、高三酸甘油脂血症、高膽固醇血症、低祖和 南LDL)、§忍知失調（例如’阿茲罕默症、失智症）、發炎疾 病（彳夕111硬化症、類風濕性關節炎、發炎腸道疾病、 克隆氏症子S㈣異位症、LPS-料的敗血症、耳之急 性接觸性皮膚炎、動脈壁之慢性粥狀動脈硬化發炎）、乳^ 濱症、曱狀腺炎、皮膚老化或結締組織疾病。 、 另'態才篆Φ 心，甲，本發明關於在一個體中（例如， 個體）調節（例如，描i^ 八— 9加）血清HDL膽固醇值的方法，其包括 - 文里之式（I)化合物（包括其之任何次類或特定的 化合物）或其之—較— 〜一西樂上可接受的鹽類或前驅藥至一個體。 =發卿於在—個财（例如，需要其之 凡r 減少）血清LDL膽固醇值的方法，其包括"4-[3'-(ethyl sulphate)- 4, -10, ping, hexa", one of the I 丨-d- fluorenyl 397, the title compound is -methylbiphenyl-3-yl]methyl 5 -8-(trifluoromethyl) 喧琳. In the aspect, the invention is characterized by a pharmaceutical composition comprising a compound of the formula (1) [including any subgenera or specific compound thereof) Or a salt thereof (for example, a pharmaceutically acceptable salt) or a precursor thereof, and a pharmaceutically acceptable adjuvant, carrier or diluent. In some embodiments, the composition may comprise an effective The compound or a salt thereof. In some embodiments, the composition may additionally comprise an additional therapeutic agent. The invention is also generally regulated with respect to the quinoline compound described herein (e.g., 15 activation). LXRS. In some embodiments, the method comprises, for example, a compound of formula (1) in a sample (eg, a test medium containing no tissue, cells, or a cell-based test). Contact (including any subclass or specific compound thereof). In other embodiments, the party May include administering a compound of formula (1), including any subclass or specific compound thereof, to a body (eg, a mammal, 20 human, having or having an organic rate of one or more of the diseases or disorders described herein) In one aspect, the invention is also generally directed to preventing or treating (eg, controlling, ameliorating, mitigating, slowing down, slowing the onset, or reducing the chance of development) in one body (eg, an individual in need thereof). A method of diagnosing a disease or disorder of a plurality of LXR-medias, the method comprising administering an effective amount of the formula (I) compound 22 200825054 (including any subclass or specific compound thereof) or one of the medicinal salt precursors To - individual. LXR_media diseases or disorders may include, for example, cardiovascular disease (eg, acute coronary heart disease, restenosis), 5 10 15 20 atherosclerotic Wei, · _ hardening, type III diabetes , type π diabetes, snoring syndrome, obesity, lipid disorders (eg, blood lipids, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low ancestors and southern LDL), § Tolerance (eg 'Azhheimer's disease, dementia'), inflammatory disease (彳夕111 sclerosis, rheumatoid arthritis, inflammatory bowel disease, Crohn's disease S (four) ectopic disease, LPS-material Sepsis, acute contact dermatitis of the ear, chronic atherosclerotic inflammation of the arterial wall), breast cancer, verrucous, skin aging or connective tissue disease. The invention relates to a method for modulating (e.g., expressing) serum HDL cholesterol values in a body (e.g., an individual), comprising - a compound of formula (I) (including any subclass or specific thereof) a compound) or a ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- It includes

>里之式（I)化合物（包括其之任何次類或特定 化合物）或复之— J /、—谱藥上可接受的鹽類或前驅藥至一個體。 另 雜;1¾ 、，中，本發明關於在一個體中（例如，需要Α 個體）調節（例‘ 而戈/、炙> Compounds of formula (I) (including any subclass or specific compound thereof) or complexes - J /, - pharmaceutically acceptable salts or prodrugs to one body. In addition, in the present invention, the present invention relates to regulation in a body (for example, requiring an individual) (for example, ‘戈和,炙

J如’增加）逆轉式膽固醇運輸的方法，1包 括投藥一有效旦 、 /、L 里之式（I)化合物（包括其之任何次類或特定 的化合物）或装+ 寸疋 /、之一醤藥上可接受的鹽類或前驅藥至一個 體。 23 200825054 另一態樣中，本發明關於在一個體中（例如，需要其之 個體）調節（例如，減少或抑制）膽固醇吸收的方法，其包 括投藥一有效量之式（I)化合物（包括其之任何次類或特定 的化合物）或其之一醫藥上可接受的鹽類或前驅藥至一個 5 體。 再另一態樣中，本發明關於預防或治療心血管疾病（例 如，急性冠心症、再狹窄症）的方法，其包括投藥一有效量 之式（I)化合物（包括其之任何次類或特定的化合物）或其 之一醫藥上可接受的鹽類或前驅藥至一個體。 10 一態樣中，本發明關於預防或治療動脈粥狀硬化和/ 或粥狀動脈硬化病灶的方法，其包括投藥一有效量之式（I) 化合物（包括其之任何次類或特定的化合物）或其之一醫藥 上可接受的鹽類或前驅藥至一個體。 另一態樣中，本發明關於預防或治療糖尿病（例如，第 15 I型或第II型糖尿病）的方法，其包括投藥一有效量之式（I) 化合物（包括其之任何次類或特定的化合物）或其之一醫藥 上可接受的鹽類或前驅藥至一個體。 再另一態樣中，本發明關於預防或治療X症候群的方 法，其包括投藥一有效量之式（I)化合物（包括其之任何次 20 類或特定的化合物）或其之一醫藥上可接受的鹽類或前驅 藥至一個體。 一態樣中，本發明關於預防或治療肥胖症的方法，其 包括投藥一有效量之式（I)化合物（包括其之任何次類或特 定的化合物）或其之一醫藥上可接受的鹽類或前驅藥至一 24 200825054 個體。 另一態樣中，本發明關於預防或治療脂質失調（例如， 血脂異常、高血脂症、高三酸甘油脂血症、高膽固醇血症、 - 低HDL和高LDL)的方法，其包括投藥一有效量之式（I)化合 . 5 物（包括其之任何次類或特定的化合物）或其之一醫藥上可 接受的鹽類或前驅藥至一個體。 再另一態樣中，本發明關於預防或治療認知失調（例 如，阿茲罕默症或失智症）的方法，其包括投藥一有效量之 ί 式（I)化合物（包括其之任何次類或特定的化合物）或其之 10 一醫藥上可接受的鹽類或前驅藥至一個體。 一態樣中，本發明關於預防或治療失智症的方法，其 包括投藥一有效量之式（I)化合物（包括其之任何次類或特 定的化合物）或其之一醫藥上可接受的鹽類或前驅藥至一 個體。 15 另一態樣中，本發明關於預防或治療阿茲罕默症的方 法，其包括投藥一有效量之式（I)化合物（包括其之任何次 % 類或特定的化合物）或其之一醫藥上可接受的鹽類或前驅 - 藥至一個體。 _ 再另一態樣中，本發明關於預防或治療發炎疾病（例 20 如，多發性硬化症、類風濕性關節炎、發炎性腸道疾病、 克隆氏症、子宮内膜異位症、LPS-誘導的敗血症、耳朵的 急性接觸性皮膚炎、或動脈壁的慢性粥狀動脈硬化發炎） 的方法，其包括投藥一有效量之式（I)化合物（包括其之任 何次類或特定的化合物）或其之一醫藥上可接受的鹽類或 25 200825054 前驅藥至一個體。 另一態樣中，本發明關於預防或治療類風濕性關節炎 的方法，其包括投藥一有效量之式（I)化合物（包括其之任 何次類或特定的化合物）或其之一醫藥上可接受的鹽類或 5 前驅藥至一個體。 再另一態樣中，本發明關於預防或治療乳麋瀉症的方 法，其包括投藥一有效量之式（I)化合物（包括其之任何次 類或特定的化合物）或其之一醫藥上可接受的鹽類或前驅 藥至一個體。 10 再另一態樣中，本發明關於預防或治療甲狀腺炎的方 法，其包括投藥一有效量之式（I)化合物（包括其之任何次 類或特定的化合物）或其之一醫藥上可接受的鹽類或前驅 藥至一個體。 一態樣中，本發明關於預防或治療結締組織疾病（例 15 如，骨關節炎或肌腱炎）的方法，其包括投藥一有效量之式 (I)化合物（包括其之任何次類或特定的化合物）或其之一 醫藥上可接受的鹽類或前驅藥至一個體（例如，哺乳類動物 諸如人類）。在實施例中，該式（I)化合物抑制（例如，減少 或降低）軟骨分解。在實施例中，該式（I)化合物誘導（例 20 如，增加或增大）軟骨再生。在實施例中，該式（I)化合物 抑制（例如，減少或降低）軟骨分解並誘導（例如，增加或增 大）軟骨再生。在實施例中，該式（I)化合物抑制（例如，減 少或降低）聚蛋白多醣酶的活性。在實施例中，該式（I)化 合物抑制（例如，減少或降低）骨關節炎病灶中發炎細胞激 26 200825054 素的產生。 另一態樣中，本發明關於預防或治療皮膚老化的方 法，其包括投藥（例如，局部投藥）至一個體（例如，哺乳類 動物諸如人類）所需之有效量之式（I)化合物（包括其之任 5 何次類或特定的化合物）或其之一醫藥上可接受的鹽類或 前驅藥。在實施例中，該皮膚老化可源自年代老化、光老 化、類固醇-誘導的皮膚變薄、或其之組合。 該術語“皮膚老化”包括源自内因性年代老化（例 如，變深的表情線、皮膚厚度降低、無彈性、和/或減少無 10 瑕的光滑表面）、源自光老化（例如，深皺紋、黃且似皮革 般表面、皮膚硬化、彈性纖維變性、粗糙、色素沉殿（老人 斑）和/或有疤的皮膚）、和源自類固醇-誘導之皮膚變薄的 皮膚狀況。於是，本發明之另一態樣中係對抗紫外（UV)光 傷害作用的方法，其包括以一有效量之式（I)化合物來與曝 15 露於紫外光之皮膚細胞接觸。 在一些實施例中，該式（I)化合物（包括其之任何次類 或特定的化合物）並不會顯著地增加個體中血清和/或肝的 三酸甘油醋值。 在一些實施例中，該投予的式（I)化合物（包括其之任 20 何次類或特定的化合物）為一 LXR致效劑（例如，一 LXR致 效劑或一 LXR致效劑，例如，一 LXR致效劑）。 於若干實施例中，個體為有需要之個體（例如被識別為 需要此種處理之個體）。識別需要此種處理之個體可由個體 或醫療照護專業人員判定，可能為主觀（例如意見）或客觀 27 200825054 (例如藉試驗或診斷方法測定）。於若干實施例中，個體為 哺乳動物。於若干實施例中，個體為人類。 於又一態樣中，本發明亦係關於製造本文所述化合物 之方法。另外，該方法包括取本文所述之中間化合物中之 5 任一者，讓其與一種或多種化學劑以一個步驟或多個步驟 反應來製造本文所述化合物。 於一個態樣中，本文係關於包裝產品。包裝產品包括 一容器、於容器内之前述化合物之一、以及圖說（例如標籤 或仿單）與該容器結合，且指示投予該化合物用於治療及控 10 制由可體醇用於治療及控制此中所述之疾病或失調。 實施例可包含一種或多種下列特徵。 接附於式（I)中該喹啉環第4位置之取代基可如下定 義： 15 (I) R3係C6-Ch芳基，其：（〇係以卜2 R1G取代，和（ii) 任意地以1-4 Re取代；且 A於各次出現時係獨立地為G-Go芳基，其：（a)係 以1-2 Rf取代；且（b)可任意地以1-4 Re取代；並 20 Rf於各次出現時係獨立地為： (i) -S(0)nRn、-（CHOhSCOXR11、-NRkS(0)nRn、或 -0S(0)nRn、其中η於各次出現時係獨立地為0、：l、或2 (例 如，1或2);或 (ii) -NRkC(0)NRgRh、-NRkC(0)0Rj、-0C(0)NRgRh、或 28 200825054 -0C(0)0Rj ;或J. For example, 'increased' a method for reversing cholesterol transport, 1 comprising administering a compound of formula (I) (including any subclass or specific compound thereof) or one of + 疋/, in a valid denier, /, L A pharmaceutically acceptable salt or prodrug to a body. 23 200825054 In another aspect, the invention relates to a method of modulating (eg, reducing or inhibiting) cholesterol absorption in a body (eg, an individual in need thereof) comprising administering an effective amount of a compound of formula (I) (including Any of its subclasses or specific compounds) or a pharmaceutically acceptable salt or prodrug thereof to a 5-body. In still another aspect, the invention relates to a method of preventing or treating a cardiovascular disease (eg, acute coronary heart disease, restenosis) comprising administering an effective amount of a compound of formula (I), including any of its subclasses Or a specific compound) or one of its pharmaceutically acceptable salts or prodrugs to a body. In one aspect, the invention relates to a method of preventing or treating atherosclerosis and/or atherosclerotic lesions comprising administering an effective amount of a compound of formula (I) (including any subclass or specific compound thereof) Or one of its pharmaceutically acceptable salts or prodrugs to a body. In another aspect, the invention relates to a method of preventing or treating diabetes (eg, Type 15 I or Type II diabetes) comprising administering an effective amount of a compound of formula (I) (including any subclass or specific thereof) a compound or a pharmaceutically acceptable salt or prodrug thereof to a body. In still another aspect, the present invention relates to a method of preventing or treating X syndrome comprising administering an effective amount of a compound of formula (I), including any of its 20 classes or specific compounds, or one of them pharmaceutically Accept the salt or precursor to one. In one aspect, the invention relates to a method of preventing or treating obesity comprising administering an effective amount of a compound of formula (I), including any subclass or specific compound thereof, or a pharmaceutically acceptable salt thereof Class or prodrug to a 24 200825054 individual. In another aspect, the invention relates to a method of preventing or treating a lipid disorder (eg, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, - low HDL, and high LDL), comprising administering a drug An effective amount of a compound of formula (I). 5 (including any subclass or specific compound thereof) or a pharmaceutically acceptable salt or prodrug thereof to a body. In still another aspect, the invention relates to a method of preventing or treating a cognitive disorder (eg, Azheimer's disease or dementia) comprising administering an effective amount of a compound of formula (I), including any of its a class or a specific compound) or a pharmaceutically acceptable salt or prodrug thereof to a body. In one aspect, the invention relates to a method of preventing or treating dementia comprising administering an effective amount of a compound of formula (I), including any subclass or specific compound thereof, or one of them pharmaceutically acceptable Salt or prodrug to one body. In another aspect, the invention relates to a method of preventing or treating Alzheimer's disease comprising administering an effective amount of a compound of formula (I), including any sub-class or specific compound thereof, or one of A pharmaceutically acceptable salt or a precursor-drug to a body. _ In yet another aspect, the present invention relates to the prevention or treatment of inflammatory diseases (eg, 20, such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, Crohn's disease, endometriosis, LPS) a method of inducing sepsis, acute contact dermatitis of the ear, or chronic atherosclerotic inflammation of the arterial wall, comprising administering an effective amount of a compound of formula (I), including any subclass or specific compound thereof Or one of its pharmaceutically acceptable salts or 25 200825054 prodrugs to a body. In another aspect, the invention relates to a method of preventing or treating rheumatoid arthritis comprising administering an effective amount of a compound of formula (I), including any subclass or specific compound thereof, or a pharmaceutical thereof Acceptable salts or 5 precursors to one body. In still another aspect, the invention relates to a method of preventing or treating diarrhea, comprising administering an effective amount of a compound of formula (I), including any subclass or specific compound thereof, or a pharmaceutical thereof Acceptable salts or prodrugs to one body. In still another aspect, the invention relates to a method of preventing or treating thyroiditis comprising administering an effective amount of a compound of formula (I), including any subclass or specific compound thereof, or a pharmaceutically acceptable Accept the salt or precursor to one. In one aspect, the invention relates to a method of preventing or treating a connective tissue disease (eg, 15 such as osteoarthritis or tendinitis) comprising administering an effective amount of a compound of formula (I), including any subclass or specific thereof a compound or a pharmaceutically acceptable salt or prodrug thereof to a body (eg, a mammal such as a human). In an embodiment, the compound of formula (I) inhibits (e. g., reduces or reduces) cartilage breakdown. In an embodiment, the compound of formula (I) induces (e.g., increases or increases) cartilage regeneration. In an embodiment, the compound of formula (I) inhibits (e. g., reduces or reduces) cartilage breakdown and induces (e. g., increases or increases) cartilage regeneration. In an embodiment, the compound of formula (I) inhibits (e. g., reduces or decreases) the activity of aggrecanase. In an embodiment, the compound of formula (I) inhibits (e. g., reduces or reduces) the production of inflammatory cells in osteoarthritic lesions. In another aspect, the invention relates to a method of preventing or treating skin aging comprising administering an effective amount of a compound of formula (I) to a body (eg, a mammal, such as a human) for administration (eg, topical administration) (including Any of its 5 or a specific compound) or one of its pharmaceutically acceptable salts or precursors. In embodiments, the skin aging may be derived from ageing, photoaging, steroid-induced skin thinning, or a combination thereof. The term "skin aging" includes endogenous aging (eg, deeper expression lines, reduced skin thickness, inelasticity, and/or reduced smooth surface without 10 )), derived from photoaging (eg, deep wrinkles) , yellow and leathery surfaces, skin hardening, elastic fiber denaturation, roughness, pigmentation (old age spots) and/or sputum skin), and skin conditions derived from steroid-induced skin thinning. Thus, another aspect of the invention is a method of combating ultraviolet (UV) light damage comprising contacting an effective amount of a compound of formula (I) with skin cells exposed to ultraviolet light. In some embodiments, the compound of formula (I), including any subclass or specific compound thereof, does not significantly increase the triglyceride value of serum and/or liver in an individual. In some embodiments, the administered compound of formula (I), including any of its 20 or specific compounds, is an LXR agonist (eg, an LXR agonist or an LXR agonist, For example, an LXR agonist). In several embodiments, the individual is an individual in need thereof (e.g., an individual identified as needing such treatment). Identifying individuals in need of such treatment may be determined by the individual or medical care professional, possibly subjective (eg, opinion) or objective 27 200825054 (eg, by test or diagnostic method). In several embodiments, the individual is a mammal. In several embodiments, the individual is a human. In yet another aspect, the invention is also directed to a method of making a compound described herein. Additionally, the method comprises taking any one of the intermediate compounds described herein and reacting it with one or more chemicals in one or more steps to produce a compound described herein. In one aspect, this article is about packaging products. The packaged product comprises a container, one of the aforementioned compounds in the container, and a graphic representation (such as a label or a copy) in combination with the container, and indicating that the compound is administered for treatment and control by a steroid alcohol for treatment and Control the disease or disorder described herein. Embodiments may include one or more of the following features. The substituent attached to the 4th position of the quinoline ring in the formula (I) can be defined as follows: 15 (I) R3 is a C6-Ch aryl group, which is: (the lanthanide is substituted with ib 2 R1G, and (ii) arbitrarily Substituted with 1-4 Re; and A in each occurrence is independently a G-Go aryl group, which: (a) is substituted with 1-2 Rf; and (b) can optionally be 1-4 Re Substituting; and 20 Rf is independently in each occurrence: (i) -S(0)nRn, -(CHOhSCOXR11, -NRkS(0)nRn, or -0S(0)nRn, where η appears in each occurrence The time is independently 0, :1, or 2 (for example, 1 or 2); or (ii) -NRkC(0)NRgRh, -NRkC(0)0Rj, -0C(0)NRgRh, or 28 200825054 -0C (0)0Rj; or

(ID _ R3係含有5-14原子之雜芳基，其係：（i)任意地以1-2 . 5 R1G取代，和（ii)任意地以1-4 Re取代；且 A於各次出現時係獨立地為C6-C1()芳基，其：（a)係 以1-2 Rf取代；且（b)可任意地以1-4 Re取代；並 Rf於各次出現時係獨立地為： ' (i) -S(0)nRn、-(CHOhSCOXR11、-NRkS(0)nRn、或 ίο -0S(0)nRn、其中n於各次出現時係獨立地為1、或2 ;或 (ii) -NRkC(0)NRgRh、-NRkC(0)0Rj、-0C(0)NRgRh、或 -0C(0)0R、或 (III) 15 R3係C6-Ch芳基，其係：（i)以1-2 R1G取代，和（ii)任 意地以1-4 Re取代；且 / ' v A於各次出現時係獨立地為含有5-10原子之雜芳基， - 其： (a) 係以1-2 Rf取代或含有一經取代的環原子，該原 20 子係選自S(0)和S〇2所組成之群；且 (b) 可任意地以1_4 Re取代； 前提是該含有5-10原子之雜芳基並非[1，2,4]-噁二 σ坐基；且(ID _ R3 is a heteroaryl group having 5 to 14 atoms, which is: (i) arbitrarily substituted with 12.5. 5 R1G, and (ii) optionally substituted with 1-4 Re; and A at each time When present, is independently a C6-C1() aryl group: (a) is substituted with 1-2 Rf; and (b) is optionally substituted with 1-4 Re; and Rf is independently present at each occurrence The ground is: '(i) -S(0)nRn, -(CHOhSCOXR11, -NRkS(0)nRn, or ίο -0S(0)nRn, where n is independently 1, or 2 at each occurrence; Or (ii) -NRkC(0)NRgRh, -NRkC(0)0Rj, -0C(0)NRgRh, or -0C(0)0R, or (III) 15 R3 based C6-Ch aryl, which is: i) substituted with 1-2 R1G, and (ii) optionally substituted with 1-4 Re; and / ' v A is independently a heteroaryl group containing 5-10 atoms in each occurrence, - a) substituted with 1-2 Rf or containing a substituted ring atom selected from the group consisting of S(0) and S〇2; and (b) optionally substituted with 1_4 Re; Is that the heteroaryl group having 5-10 atoms is not a [1,2,4]-caustic sigma; and

Rf於各次出現時係獨立地為： 29 200825054 (i) -S(0)nRn、-(ChUCOLR11、-NRkS(0)nRn、或 - 0S(0)nRn、其中n於各次出現時係獨立地為1或2 ;或 (ii) -NRkC(0)NRgRh、—NRkC(0)0RJ、-0C(0)NRgRh、或 -0C(0)0Rj ;或 5 (IV) R3係C6-Ch芳基，其係：（i)以1-2R1G取代，和（ii)任 意地以1-4 Re取代；且 A於各次出現時係獨立地為C6-C1Q芳基，其：（a)係 10 以1-2 Rf取代；且（b)可任意地以1-4 Re取代；並Rf appears independently at each occurrence: 29 200825054 (i) -S(0)nRn, -(ChUCOLR11, -NRkS(0)nRn, or - 0S(0)nRn, where n is present at each occurrence Independently 1 or 2; or (ii) -NRkC(0)NRgRh, -NRkC(0)0RJ, -0C(0)NRgRh, or -0C(0)0Rj; or 5 (IV) R3 C6-Ch An aryl group, wherein: (i) is substituted with 1-2R1G, and (ii) is optionally substituted with 1-4 Re; and A is independently a C6-C1Q aryl group in each occurrence, which: (a) Line 10 is substituted with 1-2 Rf; and (b) can be optionally substituted with 1-4 Re;

Rf於各次出現時係獨立地為： (iii) 含有5-10原子之雜環基，可以1-2側氧基取 代或任意地以1-3 Re取代；或 (iv) 含有5-10原子之雜環烯基或1H-苯并咪唑，其 15 之每一^系任意地以1 - 3 Re取代；或 (v) -YRf，其中Y於各次出現時係獨立地為CrCe伸烷 基、-〇-、或-NR9-;或 (V) R3係C6-Ch芳基，其係：（i)以1-2R1Q取代，和（ii)任 20 意地以1-4 Re取代；且 A於各次出現時係獨立地為含有8-12原子之芳基氮環 基，其：（a)係以1-2 Rf取代，和 (b)任意地以1-4 Re取代；且Rf is independently present at each occurrence: (iii) a heterocyclic group containing 5-10 atoms, which may be substituted with 1-2 oxy groups or optionally substituted with 1-3 Re; or (iv) contains 5-10 a heterocyclenyl group of an atom or 1H-benzimidazole, each of which is optionally substituted with 1 - 3 Re; or (v) -YRf, wherein Y is independently a CrCe alkane in each occurrence a group, -〇-, or -NR9-; or (V) R3 is a C6-Ch aryl group, wherein: (i) is substituted with 1-2R1Q, and (ii) is optionally substituted with 1-4 Re; A, in each occurrence, is independently an aryl nitrogen ring group containing 8-12 atoms, which: (a) is substituted with 1-2 Rf, and (b) is optionally substituted with 1-4 Re;

Rf於各次出現時係獨立地為： 30 200825054 (I) -S(0)nRn、-(CI^uSCCOx、—NRkS(〇)nRn、或 -0S(0)nR'其巾n於各次出現時係獨立地為】或2 ;或者 (II) -NRkC(0)NRgRh、-NRkC(〇)〇Rj、_〇c(〇)NRgRh、或 -0C(0)0Rj ;或 5 (VI) R3係c6-Cu芳基，其：（i)以卜2 RlQ取代，並（ii)任 意地以1-4 Re取代；而且 A於各次出現時係獨立地為芳基亞磺醯基環基、雜芳 10基亞磺醯基環基、芳基磺醯基環基或雜芳基磺醯基環基， 其之每一包含8-10原子且可任意地以卜4 Re取代；或 (VII) R係C6-Ci4芳基，其：⑴以卜2 R1。取代，和（ii)任 15 意地以1-4 Re取代；且 A於各次出現時係獨立地為[1，2, 4]—。惡二嗤基，可任 思地以1 -2 Re取代。 R1為氫。 2〇 R2為氫。 R2為：（ii) C6烷基，可任意地以1—2Ra取代；或（iii) C7 —ClD芳烧基’可任意地以1—3 Rb取代；或（vii) -XR8 〇 R2為C1-C6烷基，可任意地以i_2 Ra(例如，R2為CH3 ; 或ClCH3或CH(CH3)2)取代。為NRgRh或羥基。例如， 31 200825054 R2 為 CH2NRgRh。 R2為㈣。芳烧基，可任意地以卜3 Rb (例如，铲為 节基）取代。r2為氰基。a XR^m、e(Q)i C(0)0H、或 C(0)〇Et)。 5 R3為Ce—Cl。芳基，其⑷以卜2 (例如υ Ru>取代.# ⑹任意地以卜2r取代。R3為苯基，其（咖丨^取代: 和⑹任意地以卜2 Re取代。r3為苯基，其以丨R1。取代。 R3可具有如此中所述之式A，其中W和A為此中所 1〇定義之任一（同類的、次類的、或特定的）：Rf appears independently at each occurrence: 30 200825054 (I) -S(0)nRn, -(CI^uSCCOx, -NRkS(〇)nRn, or -0S(0)nR' When appearing independently, or 2; or (II) -NRkC(0)NRgRh, -NRkC(〇)〇Rj, _〇c(〇)NRgRh, or -0C(0)0Rj; or 5 (VI) R3 is a c6-Cu aryl group which is (i) substituted with br 2 RlQ and (ii) optionally substituted with 1-4 Re; and A is independently an arylsulfinyl ring at each occurrence. a heteroaryl 10 sulfinyl cyclyl, an aryl sulfonyl cyclyl or a heteroaryl sulfonyl cyclyl, each of which contains 8 to 10 atoms and optionally substituted with 4 Re; (VII) R-based C6-Ci4 aryl, which: (1) is substituted with br 2 R1. and (ii) is optionally substituted with 1-4 Re; and A is independently [1, 2 in each occurrence) , 4] - oxadiyl, can be optionally substituted with 1-2 Re. R1 is hydrogen. 2 〇 R2 is hydrogen. R2 is: (ii) C6 alkyl, optionally substituted with 1-2Ra; Or (iii) a C7-ClD aryl group may be optionally substituted with 1-3 Rb; or (vii) -XR8 〇R2 is a C1-C6 alkyl group, optionally i_2 Ra (for example, R2 is CH3; or ClCH3 or CH ( CH3) 2) Substituted as NRgRh or hydroxy. For example, 31 200825054 R2 is CH2NRgRh. R2 is (IV). The aryl group can be optionally substituted with br 3 Rb (for example, shovel as a base). r2 is a cyano group. XR^m, e(Q)i C(0)0H, or C(0)〇Et). 5 R3 is Ce-Cl. An aryl group, wherein (4) is substituted with ib 2 (for example, υ Ru>, .# (6) is optionally substituted with br 2r. R 3 is a phenyl group, which is substituted with (2) arbitrarily. , which is substituted by 丨R1. R3 may have the formula A as described herein, where W and A are either one of the definitions (same, subclass, or specific):

(A). 15 R3可具有式（A-4):(A). 15 R3 may have the formula (A-4):

r^V^WAr^V^WA

(A_4) 其中W和A為此中所定義 之任一，且r為氫或Re如此 32 25 200825054 中所定義（例如，鹵基，如氯或氟）。 R3為含有5-10原子之雜芳基，其⑴以1 r取代，和 ⑻任意地幻-2 IT取代。例如，R3為㈣基”塞吩基、 嘆唾基、或財基，其⑴以π取代，和（⑴任意地以 1 -2 Re取代。 W為I。為一鍵。评為Ci_C3伸炫基（例如，_CH2—)。(A_4) wherein W and A are any of those defined herein, and r is hydrogen or Re as defined in 32 25 200825054 (for example, a halogen group such as chlorine or fluorine). R3 is a heteroaryl group having 5 to 10 atoms, which is substituted by (1) with 1 r and (8) by arbitrary illusion-2 IT. For example, R3 is a (tetra)yl-based thiophene group, a sinyl group, or a fluorenyl group, wherein (1) is substituted with π, and ((1) is optionally substituted with 1-2 Re. W is I. It is a bond. It is rated as Ci_C3 Base (for example, _CH2—).

w為CK：4伸炔基（例如，-㈣-)。W為-0(Cl-c3伸烧基）_ 或-(C】-C3伸院基）〇一（例如，_〇CH2或_CH2〇_)。张為如 一鍵’-〇(c】-c3伸烧基）—，和_(Ci—G伸烧基）〇_。 A為：⑴苯基，其⑷以i Rf取代，和⑹任意地以 卜2 Re取代；或（ii)含有5_8原子之雜絲其⑷以iRf 取代，和（b)任意地以1-3 Γ取代，前提是該含有5-8原子 Μ之雜芳基並非[lu]—嚼二唾基；或（iH)四氣喧琳基或 四氫異啥琳基，其（a)以i Rf取代，和⑻任意地以卜2 Re 取代。 R^-S(0)nRn (例如，Rf 為—s〇2Rn) ◦w is CK: 4 an alkynyl group (for example, -(tetra)-). W is -0 (Cl-c3 extended alkyl)_ or -(C)-C3 extended base) (for example, _〇CH2 or _CH2〇_). Zhang Weiru One button '-〇(c)-c3 extension base)—, and _(Ci—G extension base)〇_. A is: (1) a phenyl group, which (4) is substituted with i Rf, and (6) is optionally substituted with 2 2 Re; or (ii) a heterofilament containing 5-8 atoms (4) is substituted with iRf, and (b) is optionally 1-3 ΓSubstitution, provided that the heteroaryl group containing 5-8 atomic fluorene is not [lu]-chew-saltyl; or (iH) tetra-gas sulfhydryl or tetrahydroisoindolinyl, (a) as i Rf Instead, and (8) are optionally substituted with Bu 2 Re. R^-S(0)nRn (for example, Rf is -s〇2Rn) ◦

『為Q-ClO烷基，可任意地以卜2 Ra取代。Rn為未經 取代的Ci-C3烷基（例如，『為⑶3)。Rn為經卜2 (例如， 1) Ra取代之C2-C8烷基或C3-C8烷基。Ra為羥基；Ci—C3烷 氧基；NRgRh ;含有8-1〇任意地以卜3 Rb (例如，側氧基） 取代之原子的务基雜J辰基；或;或Ra為經基；Ci—G 33 200825054 烧氧基；NRSRh;鹵基；含有8,原子之芳基雜環基，可任 意地以1-3 Rb取代；氰基；或c(〇)〇Rj。 5 10 15 20 『為N㈣。在-些實施例中，R、Rh可各自獨立地 為氫；ca。絲，可任意地以卜2 Ra取代；c心芳燒 基，可任意地a i抑取代；或—⑽Rj。在某些實施例中^ RMW可各自獨立地為氫；Cl—C6未經取代之烧基；以經 基或CrC3烧氧基取代之C2-C8絲；节基；或一c(〇)CH3。"It is a Q-ClO alkyl group and can be optionally substituted with Bu 2 Ra. Rn is an unsubstituted Ci-C3 alkyl group (e.g., "(3)3). Rn is a C2-C8 alkyl group or a C3-C8 alkyl group substituted by Ra (for example, 1) Ra. Ra is a hydroxy group; a Ci-C3 alkoxy group; NRgRh; a ruthenium group containing 8-1 Å of an atom optionally substituted with a b 3 Rb (for example, a pendant oxy group); or; Ci-G 33 200825054 alkoxy; NRSRh; halo; aryl heterocyclyl containing 8, atom, optionally substituted with 1-3 Rb; cyano; or c(〇)〇Rj. 5 10 15 20 "For N (four). In some embodiments, R, Rh may each independently be hydrogen; ca. The silk may be optionally substituted with b 2 Ra; the c-aryl group may be optionally substituted with a i; or - (10) Rj. In certain embodiments, the RMW may each independently be hydrogen; a C1-C6 unsubstituted alkyl group; a C2-C8 filament substituted with a base or a CrC3 alkoxy group; a benzyl group; or a c(〇)CH3 .

Rn為含有5-1G原子之雜環基，可任意地以卜5以取 代。例如，Rn為嗎琳-4-基、1♦定基、旅嘻^—基、或处 咯啶-1-基，其之每一者係任意地以丨―3 Rb取代。Rn is a heterocyclic group having a 5-1 G atom, and may be optionally substituted with a ruthenium. For example, Rn is a morphin-4-yl group, a 1♦ group, a ruthenium group, or a arsenyl-1-yl group, each of which is optionally substituted with 丨-3 Rb.

Rn為C^-Ci。芳烷基或G-C8環烷基，其之每一者係任 意地以卜5 Rb取代。R1 C2—ClQ烯基，可任意地以卜2 rc 取代。Rn為C6-C1Q芳基，可任意地以丨―2 Rd取代。Rn is C^-Ci. An aralkyl group or a G-C8 cycloalkyl group, each of which is optionally substituted with a b 5 Rb. R1 C2-ClQ alkenyl group may be optionally substituted with b 2 rc . Rn is a C6-C1Q aryl group and can be optionally substituted with 丨-2 Rd.

Rf為-__!»、—败⑻舭；或―嫩⑼nRn。Rk 為氫。Rg、Rh、和K可各自獨立地為氫；θ α烷基，可任 思地以1-2 Ra取代；或〇C!。芳基，可任意地以卜2 Rd取 代。Rn為Ci-C6烷基，可任意地以丨―2 Ra取代；或Ce—^ 芳基，可任意地以1-2 Rd取代。Rf is -__!», -failed (8)舭; or "nen (9)nRn. Rk is hydrogen. Rg, Rh, and K may each independently be hydrogen; θ α alkyl, optionally substituted with 1-2 Ra; or 〇C!. The aryl group can be optionally substituted with Bu 2 Rd. Rn is a Ci-C6 alkyl group which may be optionally substituted with 丨-2 Ra; or a Ce-^ aryl group which may be optionally substituted with 1-2 Rd.

Rf為含有5-7原子之雜環基，其中該些原子可以i側 氧基取代並可任意地以1—2 Re取代。 R為含有5-7原子之雜環烯基或1H—苯并咪唑，其之 每一可任意地以1-2 Re取代。 R為4,5-二氫噁唑基，2-側氧基-咪唑啶基，4,5-二氫-1H-咪唑基，1，2,5,6-四氫-嘧啶基，5,6-二氫 34 200825054 -2H-[1，3]噁嗪基，或2-側氧基-唑啶yl.Rf is a heterocyclic group having 5 to 7 atoms, wherein the atoms may be substituted with an i-oxy group and may be optionally substituted with 1-2 Re. R is a heterocyclic alkenyl group having 5-7 atoms or 1H-benzimidazole, each of which may be optionally substituted with 1-2 Re. R is 4,5-dihydrooxazolyl, 2-sided oxy-imidazolidinyl, 4,5-dihydro-1H-imidazolyl, 1,2,5,6-tetrahydro-pyrimidinyl, 5, 6-Dihydro 34 200825054 -2H-[1,3]oxazinyl, or 2-sided oxy-oxazolidinyl.

Rfg 1H-苯并咪唑.Rfg 1H-benzimidazole.

Re於各次出現時係獨立地為鹵基、Cl_C3烧基、Cl-C3 _ 基烷基、Ci-G烷氧基、NRgRh、苯基、或4-氟苯基。 5 R3可具有式D:Re is independently a halogen group, a Cl_C3 alkyl group, a Cl-C3 alkyl group, a Ci-G alkoxy group, an NRgRh group, a phenyl group, or a 4-fluorophenyl group. 5 R3 can have the formula D:

Rf1Rf1

其中： W係一鍵；-0- ; Ci-3伸烷基；C2 — 4伸炔基；-0(0-3伸 10 烧基）-；_(Ci-3伸烧基）0-;Wherein: W is a bond; -0-; Ci-3 alkyl; C2-4 alkynyl; -0 (0-3 extended 10 alkyl)-; _ (Ci-3 extended alkyl) 0-;

Rfl、Rf2、Rf3、Rf4、和 Rf5 之一者係： (i) -S(0)nRn、-(CHOhSCOXR11、-NRkS(0)nRn、或 -0S(0)nRn、其中n於各次出現時係獨立地為1或2 ;或 (ii) -NRkC(0)NRgRh、-NRkC(0)0Rj、-0C(0)NRgRh、或 15 -0C(0)0Rj ;或 (iii) 含有5-10原子之雜環基，可以1-2側氧基取 代或任意地以1-3 Re取代；或 (iv) 含有5-10原子之雜環烯基或1H-苯并咪唑，其 之每一係任意地以1-3 Re取代；或 35 200825054 (v)-YRf，其中γ於各次出現時係獨立地為c〗—&伸烷 基、-0-、或-NR9-;以及其他者之每一係獨立地 、和r之一者為：⑽(〇上或 -NRkS(0)nRn;或（Π) —NRkC(〇)NRf 或—NRkc(〇)〇Rj ;或（iii) 5含有5-7原子之雜環基，可以！側氧基取代或任意地以卜2 f取代；或（iv)含有5-7原子之雜環烯基或1H—苯并咪 唑，其之每一係任意地以1-2 Re取代；且其他四者可各自 獨立地為氫、鹵基、Cl-G烷基、G-G鹵基烷基、Cl—C3烷氧 基、或 NRgRh。 10 R 、Rf2、Rf3、Rf4、和 Rf5 之四者為氫。One of Rfl, Rf2, Rf3, Rf4, and Rf5 is: (i) -S(0)nRn, -(CHOhSCOXR11, -NRkS(0)nRn, or -0S(0)nRn, where n appears in each occurrence The time is independently 1 or 2; or (ii) -NRkC(0)NRgRh, -NRkC(0)0Rj, -0C(0)NRgRh, or 15-0C(0)0Rj; or (iii) contains 5- a heterocyclic group of 10 atoms which may be substituted with a 1-2 oxy group or optionally substituted with 1-3 Re; or (iv) a heterocycloalkenyl group having 5 to 10 atoms or 1H-benzimidazole, each of which Or arbitrarily substituted with 1-3 Re; or 35 200825054 (v)-YRf, wherein γ is independently c--& alkyl,-0-, or -NR9-; Each of the systems is independent, and one of the r is: (10) (〇 or -NRkS(0)nRn; or (Π) - NRkC(〇)NRf or -NRkc(〇)〇Rj; or (iii) 5 a heterocyclic group having 5 to 7 atoms, which may be substituted with a pendant oxy group or optionally substituted with a b 2 f; or (iv) a heterocyclic alkenyl group having 5 to 7 atoms or 1H-benzimidazole, each of which One is optionally substituted with 1-2 Re; and the other four may each independently be hydrogen, halo, Cl-G alkyl, GG haloalkyl, Cl-C3 alkoxy, or NRgRh. 10 R , Rf2, R Four of f3, Rf4, and Rf5 are hydrogen.

Rf2 為：⑴-S(0)nRn 或—NRkS(〇)nRn ;或⑴） ~NRkC(0)NRf 或-NRkC(0)0K ;或（iii)含有 5—7 原子之雜 環基，可以1側氧基取代或任意地以UK取代；或（iv)含 有5-7原子之雜環烯基或1H—苯并咪唑，其之每一係任意 15地以卜2 Re取代；且imRf4、和Rf5可各自獨立地為 氳、鹵基、OC3烷基、Ci-C3鹵基烷基、Ci-C3烷氧基、或 NRgRh。Rfl、F、Rf4、和 Rf5 之每一者為氫。Rf2 為—s⑽n。 R為：（i)含有5-7原子之雜環基，可以丨側氧基取 代或任意地以1-2 Re取代；或（ϋ)含有5_7原子之雜環 2〇烯基或1H—苯并咪唑，其之每一係任意地以1-2 Re取代。 例如，Rf2為4, 5-二氫噁唑基、2-侧氧基—哮唑啶基、4, 5-一氫-1H-咪唑基、1，2, 5, 6-四氫—嘧啶基、5, 6_二氫 -2H-[1，3]噁嗪基、或2-侧氧基—唑啶基。如其他範例，R2f 為1 Η-苯并咪。坐基。 36 25 200825054 R3可具有式D-l: RA22Rf2 is: (1)-S(0)nRn or -NRkS(〇)nRn; or (1)) ~NRkC(0)NRf or -NRkC(0)0K; or (iii) a heterocyclic group containing 5-7 atoms, a 1-sided oxy group substituted or arbitrarily substituted with UK; or (iv) a heterocyclic alkenyl group having 5-7 atoms or 1H-benzimidazole, each of which is substituted with any of the 15 substituents; and imRf4, And Rf5 may each independently be an anthracene, a halo group, an OC3 alkyl group, a Ci-C3 haloalkyl group, a Ci-C3 alkoxy group, or an NRgRh. Each of Rfl, F, Rf4, and Rf5 is hydrogen. Rf2 is -s(10)n. R is: (i) a heterocyclic group having 5 to 7 atoms, which may be substituted with a fluorenyloxy group or optionally substituted with 1-2 Re; or (a) a heterocyclic 2 decyl group having 1 to 7 atoms or 1H-benzene. And imidazole, each of which is optionally substituted with 1-2 Re. For example, Rf2 is 4,5-dihydrooxazolyl, 2-oxo-oxazolidine, 4,5-monohydro-1H-imidazolyl, 1,2,5,6-tetrahydro-pyrimidinyl , 5,6-Dihydro-2H-[1,3]oxazinyl, or 2-sided oxy-oxazolidinyl. As another example, R2f is 1 Η-benzopyrimidine. Sitting on the base. 36 25 200825054 R3 can have the formula D-l: RA22

其中： 15 R32係氫或Re (例如，鹵基，如，氟或氯）； W為此中所定義之任一^例如，或一鍵）； RA22和RA23之每一者係獨立地為氫或Re ;且 RA24和RA25之一係Rf (例如，-S〇2Rn)，且另一者係氫或Wherein: 15 R32 is hydrogen or Re (for example, a halogen group such as fluorine or chlorine); W is any one defined for this purpose, for example, or a bond; each of RA22 and RA23 is independently hydrogen. Or Re; and one of RA24 and RA25 is Rf (for example, -S〇2Rn), and the other is hydrogen or

Re。 2〇 在某些實施例中，其之前提是僅有RA22、RA23、RA24、* RA25中之一者係Re。 R3為含有5-10(例如，5-6)原子之雜芳基，其（i)以1 R1Q 取代，並（ii)任意地以1-2 Re取代；且 W係一鍵；並且 25 A具有式（B-9): RA22Re. 2〇 In some embodiments, it is previously mentioned that only one of RA22, RA23, RA24, * RA25 is Re. R3 is a heteroaryl group having 5-10 (e.g., 5-6) atoms, which (i) is substituted with 1 R1Q, and (ii) is optionally substituted with 1-2 Re; and W is a bond; and 25 A With formula (B-9): RA22

rA25 (B-9) 37 35 200825054 其中： RA22和RA23之每一者係獨立地為氫或Re ;且 R和RA25之一係Rf(例如，—S〇2Rn)，且另一者係氫或 Re ； 在某些實施例中，其之前提是僅有RA22、RAM、、和 RA25中之一者係Re。 R3可具有式（A-4);並 W為一鍵；且 A為含有5-8原子之雜芳基，其（a)以1 例如，„) 取代，並（b)任意地以1-3 Re取代，前提是該含有δ-g原子 之雜芳基並非[1，2, 4]-噁二唑基。 R3可具有式（A-4);且 15 W為一鍵；和 A為四氫喹啉基或四氫異喹啉基，其（3)以丨例如， -S〇2Rn)取代，並（b)任意地以1—2 Re取代。 R3可具有式（A-4);和 20 W為一鍵；且 A為苯并[b]11 塞吩基-1，1-二氧化物、3, 4-二氫-2H-硫 基吼喃[2, 3-b>比啶基-1，1-二氧化物、或2, 3-二氫苯并[b] 噻吩基-1，1-二氧化物，其之每一係任意地以1-3 Re取代。 38 200825054 R可具有式D—1 ; R32為氫或Re (例如，鹵基，如，氟 或氯）；且 W為此中所疋義之任一（例如，-0-或一鍵）；RA22和RA23 之每一者係獨立地為氫或Re;且 5 RA2、RA25之-係 Rf，例如： (I) 含有5-7原子之雜環基，可以丨側氧基取代或任 意地以1-2 Re取代；或 (II) 含有5-7原子之雜環烯基或1H_苯并咪唑，其之 每-係任意地以卜2 Re取代；且另一為氯或Re。 〇 在某些實施例中，其之前提是僅RA22、RA23、RA24、和^25 中之一者係。 R可具有如此中所定義之式（E)或（F)。 R為氫。R32為鹵基（例如，氣或氟）。 氧化物、3, 4-二氳-2H-硫 20 Λ句丰开Lb」噻吩基-1，1-基吼喃[2, 3-b>比咬基-u—二氧化物、或2, 3一二氣苯并㈨ 嗟吩基-1，1-二氧化物，其之每_係任意地以卜3 Re取代。 R於各次出現時係獨立地為鹵基；Ci_G烷基，可任意地以 1 2 R取代，G-C3鹵基烧基；（^一(]3烧氧基；經基；硝其· 氰基；NRgRh;苯基；或4一氟苯基。 土，rA25 (B-9) 37 35 200825054 wherein: each of RA22 and RA23 is independently hydrogen or Re; and one of R and RA25 is Rf (eg, -S〇2Rn) and the other is hydrogen or Re; In some embodiments, it is previously mentioned that only one of RA22, RAM, and RA25 is Re. R3 may have the formula (A-4); and W is a bond; and A is a heteroaryl group having 5-8 atoms, which is (a) substituted with 1, for example, „), and (b) optionally 1- 3 Re substituted, provided that the heteroaryl group containing a δ-g atom is not a [1,2,4]-oxadiazolyl group. R3 may have the formula (A-4); and 15 W is a bond; a tetrahydroquinolyl group or a tetrahydroisoquinolyl group, which (3) is substituted with hydrazine, for example, -S〇2Rn), and (b) is optionally substituted with 1-2 Re. R3 may have formula (A-4) And 20 W are a bond; and A is benzo[b]11-septenyl-1,1-dioxide, 3,4-dihydro-2H-thiopyrano[2, 3-b> ratio Pyridyl-1,1-dioxide, or 2,3-dihydrobenzo[b]thienyl-1,1-dioxide, each of which is optionally substituted with 1-3 Re. 38 200825054 R may have the formula D-1; R32 is hydrogen or Re (for example, a halogen group such as fluorine or chlorine); and W is any of the meanings (for example, -0- or one-bond); RA22 and RA23 Each of them is independently hydrogen or Re; and 5 RA2, R25-Rf, for example: (I) a heterocyclic group having 5-7 atoms, which may be substituted with a fluorenyloxy group or arbitrarily at 1-2 Re substituted; or (II) contains 5-7 a heterocycloalkenyl group or a 1H-benzimidazole, each of which is optionally substituted with 2 Re; and the other is chlorine or Re. In some embodiments, it is previously only RA22, RA23 And one of RA24, and ^25. R may have the formula (E) or (F) as defined herein. R is hydrogen. R32 is halo (e.g., gas or fluorine). 4-diindole-2H-sulfur 20 haiku broad open Lb"thienyl-1,1-ylfuran [2, 3-b> than bite-u-dioxide, or 2, 3-dibenzene And (9) fluorenyl-1,1-dioxide, each of which is optionally substituted with a Bu 3 Re. R is independently a halogen group in each occurrence; a Ci_G alkyl group may be optionally substituted with 1 2 R, a G-C3 halo group; (^3) alkoxy group; a base group; Cyano; NRgRh; phenyl; or 4-fluorophenyl.

為氫。 R5和R6之每一者為氫或氟。R4、矿和R6之每一者 R4、R5和R6之每一者為氫，j^為氣除外之基。 39 200825054 R7為氯、氰基、Ci-C6烷基、C〗-C3鹵基烷基、G-Ce烷氧 基、C(0)0Rj、C(0)NRgRh、或 S〇2Rm。 尺7為c〗-α (例如，Ci-c3)鹵基烷基（例如，cf3)。r7為 鹵基（例如，氯或溴，較佳的為氯）。R7為S〇2Rm。Γ為CH3。 5 R7為氫或氰基。在一些實施例中，其之前提是當1^係S〇2Rn 且Rn係Ci-α烷基時，則R7係為氟基除外之基。 該化合物可具有如此中所定義之任一種式（I11)或 (V)。 10 該術語“哺乳類動物”包括涵蓋小氣、大鼠、牛、綿 羊、豬、兔、山羊、馬、猴、狗、I苗、和人類等之生物。 “有效量”係指一化合物之量可造成受治療之個體產 生一治療效果（例如，疾病、失調、或其之症狀的治療、控 制、改善、預防、延遲開始、和減少發展機率）。治療效果 15 為客觀（藉若干試驗或標記測定）、或主觀（亦即個體提供有 效指示或個體感覺有效）。上述該化合物之有效量的範圍可 從大約0· 01 mg/Kg至大約1000 mg/Kg(例如，從大約0· 1 mg/Kg至大約100 mg/Kg，從大約1 mg/Kg至大約100 mg/Kg)。有效劑量也將依據投藥途徑，以及可能共同使用 20 之其它藥劑而改變。 該術語“鹵基”或“鹵素”係指氟、氯、溴或碘基團 之任一者。 大致上且除非另行指示，否則取代基（基團）字首名稱 係藉下列方式而衍生自親代氫化物：（i)以字尾「基」、「二 25 基」、「三基」、「四基」等置換「烷」；或（ii)以字尾「基」、 40 200825054 「二基」、「三基」、「四基」等置換親代氫化物中之「e」（此 處當規定時’有自由價之原子被給予符合親代氫化物已經 建立的任何編號之儘可能低的數字）。公認的簡化名稱，例 如’金剛烷基、萘基、蒽基、菲基、咬喃基、n比啶基、異 5喧淋基、啥琳基、和。辰。定基，以及普通名稱，例如，乙稀 基、烯丙基、苯基、和喧吩基也在此通篇中廣泛使用。常 見的編號/編字系統也用於取代基的編號和稠合之雙環、三 環和多環的命名中。 4術居係指一為直鏈或分枝狀鏈之飽和的烴 1〇鏈，該鏈含有指定數之碳原子。例如，Cl-C2。烷基指的是該 基内含有從1至20(内含）的碳原子。任一原子可被取代。 烧基之範例’包括但非限於甲基、乙基、Λ—丙基、異丙基、 和第三丁基。 、雙環、三環、或 ’一種或多種取代 該術語“環烧基”係指飽和的單環 15其他多環的烴基。任一原子可被，例如It is hydrogen. Each of R5 and R6 is hydrogen or fluorine. Each of R4, ore, and R6 is each hydrogen, and each of R4, R5, and R6 is hydrogen, and j^ is a group other than gas. 39 200825054 R7 is chloro, cyano, Ci-C6 alkyl, C-C3 haloalkyl, G-Ce alkoxy, C(0)0Rj, C(0)NRgRh, or S〇2Rm. Ruler 7 is c-alpha (e.g., Ci-c3) haloalkyl (e.g., cf3). R7 is a halo group (e.g., chlorine or bromine, preferably chlorine). R7 is S〇2Rm. Γ is CH3. 5 R7 is hydrogen or cyano. In some embodiments, it is previously mentioned that when S^2Rn and Rn are Ci-α alkyl, R7 is a group other than a fluorine group. The compound may have any one of formula (I11) or (V) as defined herein. 10 The term "mammal" includes organisms that include petty, rat, cow, sheep, pig, rabbit, goat, horse, monkey, dog, seedling, and human. By "effective amount" is meant an amount of a compound that results in a therapeutic effect (e.g., treatment, control, amelioration, prevention, delay onset, and reduced developmental chance) of the subject being treated. Therapeutic effect 15 is objective (by several tests or markers), or subjective (ie, the individual provides an effective indication or the individual feels effective). An effective amount of the above compound may range from about 0.01 mg/kg to about 1000 mg/kg (e.g., from about 0.1 mg/kg to about 100 mg/kg, from about 1 mg/kg to about 100). Mg/Kg). The effective dose will also vary depending on the route of administration and other agents that may be used together. The term "halo" or "halogen" refers to any of a fluorine, chlorine, bromine or iodine group. Substantially and unless otherwise indicated, the substituent (group) prefix is derived from the parent hydride by: (i) suffix "base", "two 25 base", "three base", Replacement of "alkane" with "four bases"; or (ii) replacement of "e" in parental hydrides by suffix "base", 40 200825054 "two bases", "three bases", "four bases", etc. At the time of the stipulation, 'the atom with a free price is given the lowest possible number that matches any number already established by the parent hydride. Recognized simplified names such as 'adamantyl, naphthyl, anthryl, phenanthryl, cumyl, n-pyridyl, heteroquinone, fluorene, and. Chen. Base groups, as well as common names such as ethylene, allyl, phenyl, and porphin are also widely used throughout this text. A common numbering/typing system is also used for the numbering of the substituents and the naming of the fused bicyclic, tricyclic and polycyclic rings. The term "system" refers to a saturated hydrocarbon chain of one chain, which is a linear or branched chain, and which contains a specified number of carbon atoms. For example, Cl-C2. The alkyl group means that the group contains from 1 to 20 (inclusive) of carbon atoms. Any atom can be substituted. Examples of alkyl groups include, but are not limited to, methyl, ethyl, hydrazine-propyl, isopropyl, and tert-butyl. , bicyclic, tricyclic, or 'one or more substitutions The term "cycloalkyl" refers to a saturated monocyclic 15 other polycyclic hydrocarbon group. Any atom can be, for example

基取代。-環之碳當成-魏基與其他部份的接點。環烧 基可包括稠合的環。龄的環係指享有共同碳原子的環。 環烧基部份可包括，例如，_基、環丁基、環戊基、環 己基、環庚基、金剛烷基、和降莰基（雙環[2·21]庚基）。 20 該術語“伸烧基”、“伸烯基，，、和“伸炔基，，係個 別指二價的烷基（例如，—CH2_)、烯基（例如，—ch=ch_)、 和炔基（例如，-Ce〇)部份。 該術語“鹵烧基”係指一烧基，其中至少-個氫原子 被鹵基置換。在一些實施例中，多於一個在一烷基上之氫 41 200825054 原子（2、3、4、5、6、7、8、9、10、U、12、13、14、15、 16、17、18、19、20、21、22、23、24、25、26 等個氫原 子）可被多於一個鹵素（例如，2、3、4、5、6、7、8、9、 10、U、12、13、14、15、16、17、18、19、20、2卜 22、 5 23、24、25、26等個鹵原子）置換。在這些實施例中，該些 氫原子之每一者可被相同的鹵素（例如，氟）置換或者該些 氫原子可被鹵素之組合（例如，氟和氣）置換。“鹵烧基” 亦包括烷基部份，其中所有的氫已經被i基（例如，全鹵 基烷基，如，全氟基烷基，諸如三氟甲基）置換。 ίο 該術語“芳烷基”係指其中一個烷基氫原子由芳基 置換之烷基部分。烷基部分之碳中之一者係用作為芳烷基 附接至另一個部分之附接點。芳烷基包括其中於烷基部分 上之多於一個氫原子已經由芳基置換之基團。任一個環原 子或鏈原子可例如經以一或多個取代基取代。“芳烷基” 15 之實例包括但非限於苄基、2-苯乙基、3-苯丙基、二苯甲 基（聯苯甲基）、三苯甲基（三苯基甲基）。 該術語“雜芳烷基”係指其中烷基之氫原子係經以 雜芳基置換之烷基部分。烷基部分之碳原子之一係用作為 芳烷基附接至另一個部分之附接點。雜芳烷基包括其中烷 20 基部分上之多於一個氫原子已經經以雜芳基置換之基團。 任一個環原子或鏈原子皆可經例如一個或多個取代基取 代。雜芳烧基例如包括比唆基乙基。 該術語“烯基”係指一含有2-20碳原子且具有一或 多個雙鍵之直線狀或分枝狀的烴鏈。任一原子可，例如， 42 200825054 一或多個取代基取代。烯基可包括中間或終端雙鍵，包含， 例如，稀丙基、1-丁烯基、2-己稀基和3-辛浠基。該雙鍵 碳之一者可任意地為該烯基取代基的接點。該術語“炔 基”係指一含有2-20碳原子且具有一或多個三鍵之直線狀 5 或分枝狀的碳氫鏈。炔基可包括中間或終端三鍵，包含部 份，例如，乙炔基、丙快基、和3-己炔基。該三鍵碳之一 者可任意地為該炔基取代基的接點。 該術語“烷氧基”係指-0-烷基基團。該術語“氫硫 基”係指一 SH基團。該術語“硫基烷氧基”係指-S-烷基 ίο 基團。該術語“芳氧基”和“雜芳氧基”係個別指-0-芳基 基團和-0-雜芳基基團。該術語“硫基芳氧基”和“硫基雜 芳氧基”係個別指-S-芳基基團和-S-雜芳基基團。 該術語“芳烷氧基”和“雜芳烷氧基”係個別指-0-芳烷基基團和-0-雜芳烷基基團。該術語“硫基芳烷氧基” 15 和“硫基雜芳烧氧基”係個別指-S-芳烧基基團和-S-雜芳 烷基基團。該術語“環烷氧基”係指-〇-環烷基基團。該術 語“環烯氧基”和“雜環烯氧基”係個別指-0-環烯基基 團和-0-雜環烯基基團。該術語“雜環氧基”係指-0-雜環 基基團。該術語“硫基環烷氧基”係指-S-環烷基基團。 20 該術語“硫基環烯氧基”和“硫基雜環烯氧基”係個別指 -S-環烯基基團和-S-雜環烯基基團。該術語“硫基雜環氧 基”係指-S-雜環基基團。 該術語“雜環基”係指一飽和的單環、雙環、三環或 其他多環系統，其中若為單環則具有1-4雜原子、若為雙 43 200825054 環則具有1-8雜原子、或若為三環則具有ι — 1〇雜原子， 該雜原子係選自0、N、或S(以及其之一氧化物和二氧化物， 例如，N—(T、S(0)、S〇2)。因此，—雜環基的環包含碳原 子，和1-4、1-8、或1-10(若分別為單環、雙環、或三環） 5選自N、0、或S之雜原子。-環之雜原子或環之碳係該雜 環基取代基與其他部份的接點。任一原子可被，例如，一 或多個取代基取代。該雜環基可包含稠合的環。稠合的環 係享有共同碳或氮原子的環。該雜環基可包括，例如，四 氫呋喃基〜四氫哌喃基〜哌啶基^“打丨办卜“卯以^⑽）、 10哌嗪基、嗎啉基（morpholiny卜morph〇lin〇)、吡咯啉基、 和〇比ϋ各σ定基。 該術語環稀基係指部份未飽和的單環、雙環、三 環、或其他多環的烴基。-環之碳（例如，飽和的或未飽和 的）係該環烯基取代基的接點。任一原子可被，例如，一或 15多個取代基取代。該環烯基可包含稠合的環。稠合的環係 享有共同奴原子之環。環烯基部份可包括，例如，環己稀 基、環己二烯基、或降冰片烯基（n〇rb〇rnenyl)。 該術語“雜環烯基”係指部份未飽和的單環、雙環、 三環、或其他多環的烴基，其中若為單環則該烴基具有卜4 2〇雜原子、若為雙環則該烴基具有卜8雜原子、或若為三環 則該烴基具有HG雜原子，該雜原子係選自Q、N、或§(以 及其之-氧化物和二氧化物，例如，n_q_、s⑻、s〇2)[例 如，碳原子和Η、1-8、或h〇(若分別為單環、雙環、 或三環）選自N、0、或S之雜原子]。一環之碳（例如，飽和 44 200825054 或未飽和的）或雜原子係該雜環取代基的接點。任一原 子可被例如—或多個取代基取代。該雜環稀基可包二 稍合的壞。稠合的環係享有共同碳或氮原子之環。雜 基可包括’例如，四氫对基、二氫㈣基、4,5二= 唾基、4,5-二氣|米蜂U’5 6—四氯—錢基、和 二氫-2H-[1，3]噁嗪基。 ’ 該術語“芳基”係指一完全未飽和，芳香之單環、雔 環、或三環的煙環系統，其中任一環原子可被，例如，: 或夕個取代基取代。芳基可包含稠合的環。稍合的環係享 有共同碳原子之環。芳基部份可包括 ’例如，苯基、笑其 蒽基、和芘基。 * &、 15Substituted. - The carbon of the ring acts as a contact between Wei-Ki and other parts. The cycloalkyl group may include a fused ring. Rings of the age refers to rings that share a common carbon atom. The cycloalkyl moiety may include, for example, a benzyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, an adamantyl group, and a norbornyl group (bicyclo[2·21]heptyl group). The terms "extension group", "alkenyl group," and "alkenyl group", each refers to a divalent alkyl group (eg, -CH2_), an alkenyl group (eg, -ch=ch_), and An alkynyl group (eg, -Ce〇) moiety. The term "haloalkyl" refers to a alkyl group in which at least one hydrogen atom is replaced by a halogen group. In some embodiments, more than one hydrogen on an alkyl group is 41 200825054 atoms (2, 3, 4, 5, 6, 7, 8, 9, 10, U, 12, 13, 14, 15, 16 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, etc. hydrogen atoms can be more than one halogen (for example, 2, 3, 4, 5, 6, 7, 8, 9, 10 Substituting halogen atoms such as U, 12, 13, 14, 15, 16, 17, 18, 19, 20, 2, 22, 5, 23, 24, 25, and 26). In these embodiments, each of the hydrogen atoms may be replaced by the same halogen (e.g., fluorine) or the hydrogen atoms may be replaced by a combination of halogens (e.g., fluorine and gas). "Haloalkyl" also includes alkyl moieties in which all of the hydrogen has been replaced by an i group (e.g., a perhaloalkyl group such as a perfluoroalkyl group such as a trifluoromethyl group). The term "aralkyl" refers to an alkyl moiety in which one alkyl hydrogen atom is replaced by an aryl group. One of the carbons of the alkyl moiety is used as an attachment point for attachment of the aralkyl group to another moiety. The aralkyl group includes a group in which more than one hydrogen atom on the alkyl moiety has been replaced by an aryl group. Any one of a ring atom or a chain atom may be substituted, for example, with one or more substituents. Examples of "aralkyl" 15 include, but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, diphenylmethyl (biphenylmethyl), trityl (triphenylmethyl). The term "heteroaralkyl" refers to an alkyl moiety wherein the hydrogen atom of the alkyl group is replaced by a heteroaryl group. One of the carbon atoms of the alkyl moiety is used as an attachment point for attachment of the aralkyl group to another moiety. The heteroarylalkyl group includes a group in which more than one hydrogen atom on the alkane group moiety has been replaced with a heteroaryl group. Any one of a ring atom or a chain atom may be substituted by, for example, one or more substituents. The heteroaryl group includes, for example, a decylethyl group. The term "alkenyl" refers to a straight or branched hydrocarbon chain containing from 2 to 20 carbon atoms and having one or more double bonds. Any atom may be, for example, 42 200825054 substituted with one or more substituents. The alkenyl group may include an intermediate or terminal double bond, and includes, for example, a propyl group, a 1-butenyl group, a 2-hexyl group, and a 3-octyl group. One of the double bond carbons may be arbitrarily the junction of the alkenyl substituent. The term "alkynyl" refers to a linear or branched hydrocarbon chain containing from 2 to 20 carbon atoms and having one or more triple bonds. The alkynyl group may include an intermediate or terminal triple bond, and includes a moiety such as an ethynyl group, a propionyl group, and a 3-hexynyl group. One of the three bond carbons may be arbitrarily the junction of the alkynyl substituent. The term "alkoxy" refers to a -alkyl group. The term "hydrogenthio" refers to an SH group. The term "thioalkoxy" refers to a -S-alkyl ίο group. The terms "aryloxy" and "heteroaryloxy" refer to each of the -O-aryl group and the -0-heteroaryl group. The terms "thioaryloxy" and "thioheteroaryloxy" are used individually to refer to the -S-aryl group and the -S-heteroaryl group. The terms "aralkyloxy" and "heteroaralkyloxy" each refer to an -O-aralkyl group and an -O-heteroarylalkyl group. The term "thioarylalkoxy" 15 and "thioheteroaryl alkoxy" are used individually to refer to the -S-arylalkyl group and the -S-heteroarylalkyl group. The term "cycloalkoxy" refers to a -〇-cycloalkyl group. The terms "cycloalkenyloxy" and "heterocycloalkenyloxy" refer individually to the-0-cycloalkenyl group and the -0-heterocycloalkenyl group. The term "heterocyclicoxy" refers to a -heterocyclyl group. The term "thiocyclocycloalkoxy" refers to a -S-cycloalkyl group. The term "thiocycloalkenyloxy" and "thioheterocycloalkenyloxy" are used individually to refer to a -S-cycloalkenyl group and a -S-heterocycloalkenyl group. The term "thioheterocycloalkyl" refers to a -S-heterocyclyl group. The term "heterocyclyl" refers to a saturated monocyclic, bicyclic, tricyclic or other polycyclic ring system wherein, if it is a single ring, it has from 1 to 4 heteroatoms, if it is a double of 43, the 200825054 ring has a 1 to 8 An atom, or a tricyclic ring, has a ι - 1 〇 heteroatom selected from 0, N, or S (and one of its oxides and dioxides, for example, N-(T, S(0) ), S〇2). Therefore, the ring of the heterocyclic group contains a carbon atom, and 1-4, 1-8, or 1-10 (if monocyclic, bicyclic, or tricyclic, respectively) 5 is selected from N, a hetero atom of 0 or S. A hetero atom of a ring or a carbon of a ring is a point of attachment of the substituent of the heterocyclic group to other moieties. Any atom may be substituted by, for example, one or more substituents. The cyclic group may comprise a fused ring. The fused ring system may have a ring of a common carbon or nitrogen atom. The heterocyclic group may include, for example, tetrahydrofuranyl~tetrahydropyranyl-piperidinyl^" "卯^^(10)), 10 piperazinyl, morpholiny (morpholiny), pyrrolinyl, and fluorene are each sigma. The term cycloaliphatic refers to a partially unsaturated monocyclic, bicyclic, tricyclic, or other polycyclic hydrocarbon radical. The carbon of the ring (e.g., saturated or unsaturated) is the junction of the cycloalkenyl substituent. Any atom may be substituted by, for example, one or more than 15 substituents. The cycloalkenyl group can comprise a fused ring. The fused ring system has a ring of common slave atoms. The cycloalkenyl moiety can include, for example, cyclohexyl, cyclohexadienyl, or norbornyl (n〇rb〇rnenyl). The term "heterocyclenyl" refers to a partially unsaturated monocyclic, bicyclic, tricyclic, or other polycyclic hydrocarbon radical wherein, in the case of a monocyclic ring, the hydrocarbyl group has a tetra-doped heteroatom, if a double ring The hydrocarbon group has a heteroatom, or if it is a tricyclic, the hydrocarbon group has an HG hetero atom selected from Q, N, or § (and its oxides and dioxides, for example, n_q_, s(8) , s〇 2) [for example, a carbon atom and a ruthenium, 1-8, or h〇 (if a monocyclic, bicyclic, or tricyclic ring, respectively) is selected from a hetero atom of N, 0, or S]. A ring of carbon (e.g., saturated 44 200825054 or unsaturated) or a hetero atom is the junction of the heterocyclic substituent. Any atom may be substituted by, for example, - or a plurality of substituents. The heterocyclic dilute group may be slightly miscellaneous. A fused ring system has a ring of common carbon or nitrogen atoms. The hetero group may include, for example, a tetrahydro-p-yl group, a dihydro(tetra)yl group, a 4,5-di-salt group, a 4,5-digas, a rice bee U'5 6-tetrachloro-keh group, and a dihydro-2H group. -[1,3]oxazinyl. The term "aryl" refers to a completely unsaturated, aromatic monocyclic, anthracene, or tricyclic ring system wherein any of the ring atoms may be substituted, for example, with: or a substituent. The aryl group can comprise a fused ring. The slightly ringed ring has a ring of common carbon atoms. The aryl moiety may include, for example, a phenyl group, a decyl group, and a fluorenyl group. * &, 15

V 20 /亥麟“_基”係指-完全未飽和，料之單環、 雙¥、二、或其他多環的烴基，其中若為單環則該烴基 二有4雜原子、若為雙環則該烴基具有1-8雜原子、或 若為二環則軸基具有1，雜原子，該雜原子係獨立地選 自〇、N、或S(以及其之一氧化物和二氧化物,例如， S(0)、S〇2)[例如，石山搭 反原子和1—4、1-8、或1-1〇(若分別 ”、、早衣、、雙％、或三環）選自NHS之雜原子]。任一 原子γ被，例如，一或多個取代基取代。雜芳基可包含稠 口的稠口的每係享有共同碳或氮原子之環。雜芳基可 包括例如，η比吩A # 土、噻％基、呋喃基、咪唑基、吲^朵基、 異啥琳基、料基和料基。 勺人亥口芳基雜環基”和“雜芳基雜環基”係指分別 匕a方基％或雜芳基環之雙環、三環、或其他多環的環 45 200825054 糸統，其中該芳基環或雜芳基環係與含有 °、N、或❿及其之-氧化物和二氧化物，例如= s(〇)、s〇2)之雜原子的雜環基環稠合 的環原子係碳。任一^ 衣基壤之剩餘 5 10 15 20V 20 /海麟 "_基" means a monocyclic, double, double, or other polycyclic hydrocarbon group which is completely unsaturated, wherein if it is a single ring, the hydrocarbon group has 4 heteroatoms, if it is a double ring Then the hydrocarbyl group has 1-8 heteroatoms, or if bicyclic, the axial group has 1, heteroatoms independently selected from ruthenium, N, or S (and one of its oxides and dioxides, For example, S(0), S〇2) [for example, Shishan anti-atomic and 1-4, 1-8, or 1-1 〇 (if respectively), early clothing, double%, or tricyclic) From a hetero atom of NHS]. Any atom γ is substituted, for example, by one or more substituents. A heteroaryl group may comprise a fused, condensed ring each having a common carbon or nitrogen atom. The heteroaryl group may include For example, η ratio pheno A #土, thiophene, furyl, imidazolyl, fluorenyl, isoindolyl, base and base. Spooned aryl heterocyclyl" and "heteroaryl" "Heterocyclyl" means a bicyclic, tricyclic, or other polycyclic ring of 匕a aryl or heteroaryl ring, respectively, in which the aryl or heteroaryl ring system contains °, N Or ❿ and its oxide A ring atomic carbon fused to a heterocyclic ring of a hetero atom such as = s(〇), s〇2). Any remaining of the clothing base 5 10 15 20

代卢― 可被，例如，一或多個取取代A Η在〜方基部或該雜環基部上的環原子可作土 娘基與其他部份的接點〜方土雜 芳其額J G括但非限定於，基於 基二醯二:，_基環基’雜芳基亞續酿基環基，芳 環系統的範圍土，。芳基續酿基環基定義下所緣出之該 芳基芳基氮環基，’係指含有-與雜環之環稠合的 之環含或其他多環的環系統，其中該雜環 1子了4 雜環之環_餘環原子係碳）。任 原子可被，例如，-或多個幻任 該雜環基部上的環 二°在该芳基部或 接吨。㈣ 乍為和基輯基與其他部份的 二列如，芳基氮環基可包括U， 的 i’m四氧異料基、和異, h 甲醯亞胺基）。 /、 土 ，3——酮（鄰苯二 该術語“芳基亞磺醯基環美” 基，，係指分別包含一芳基产和亲隹芳基亞石黃醯基環 其他多環的環系統，Α中；美:基%之雙環、三環、或 個、咖-(亞伽基㈣基環軸含有一 硫原子形成#r- 、雜％基的環稠合（即，其之 y于形成糸統的部份， 子係碳）。任1子可被 ”雜％基之環的剩餘環原 該芳基例如，—或多個取代基取代。在 雜衣基部上的碳環原子可作為該芳基亞績酿基環 46 200825054 基和該雜芳基亞磺醯基環基與其他部份的接點。例如，該 環系統可包括：代卢- can be, for example, one or more of the ring atoms of the substituted A Η at the base of the square or the base of the heterocyclic ring can be used as a joint between the soil and other parts. However, it is not limited to, based on the base bismuth: _ yl ring group 'heteroaryl arylene ring base group, the range of the aromatic ring system soil. The arylaryl nitrogen ring group derived from the definition of an aryl cyclyl ring group, 'means a ring system containing a ring or a polycyclic ring fused to a heterocyclic ring, wherein the heterocyclic ring 1 sub- 4 heterocyclic ring _ residual ring atomic carbon). Any atom may be, for example, - or a plurality of rings on the heterocyclic ring moiety at the aryl moiety or ton. (d) 乍 and base groups and other parts of the two columns, for example, the aryl nitrogen ring group may include U, i'm tetraoxane, and iso, h-mercaptoimine). /, soil, 3 - ketone (o-phenylene) the term "arylsulfinylcyclomethine", which refers to a ring system comprising an aryl group and a polycyclic ring of a nucleophilic aryl sulfite ring, respectively. Α中;美:Based on the bicyclic, tricyclic, or mono-, gamma-(a gamma (tetra)-based ring axis containing a sulfur atom to form a #r-, hetero-memberyl ring fused (ie, its y is formed Part of the genus, the daughter carbon. Any one may be substituted by the remaining ring of the ring of the heteropoly group, for example, or a plurality of substituents. The carbon ring atom at the base of the coat can be used as The aryl aryl ring 46 200825054 and the heteroaryl sulfinyl ring group are bonded to other moieties. For example, the ring system can include:

1 〇 5 該術語“芳基磺醯基環基”和“雜芳基磺醯基環基” 係指分別包含一芳基環或雜芳基環之雙環、三環、或其他 多環的環系統，其中該芳基環或雜芳基環係與含有一個 -S〇2-(磺醯基）環原子之雜環基的環稠合（即，其之硫原子 形成該環系統的部份，且該雜環基之環的剩餘環原子係 10 碳）。任一原子可被，例如，一或多個取代基取代。在該芳 基/雜環基部或該雜環基部上的碳環原子可作為該芳基磺 醯基環基和該雜芳基磺醯基環基與其他部份的接點。例 如，該環系統可包括：1 〇 5 The terms "arylsulfonylcyclyl" and "heteroarylsulfonylcyclyl" refer to a bicyclic, tricyclic, or other polycyclic ring containing an aryl or heteroaryl ring, respectively. a system wherein the aryl or heteroaryl ring system is fused to a ring containing a heterocyclic group of a -S〇2-(sulfonyl) ring atom (ie, a sulfur atom thereof forms part of the ring system) And the remaining ring atom of the ring of the heterocyclic group is 10 carbons). Any atom may be substituted, for example, by one or more substituents. A carbon ring atom on the aryl/heterocyclic base or the heterocyclic base may serve as a junction of the arylsulfonylcyclyl group and the heteroarylsulfonylcyclyl group with other moieties. For example, the ring system can include:

W ；S： //、 〇 該術語“側氧基”係指一氧原子，當接附至碳時則形 成一羰基（00)、或當接附至一硫原子時則形成一亞磺醯 47 15 200825054 基或磺縣的部份、或當接附至氮時則形成N—氧化物的部 份。該術語“仙基，，係指一硫原子，當接附至碳時則形 成一硫基羰基(⑽。所描述之符號如⑽.）、和c(nri) 係分別指雙㈣結至氧、硫、和氮原子之礙原子。 5 10 该術語“取代基”係指一基“取代”，例如，烷基、 _烧基、《基、烯基、炔基、芳縣、雜芳烧基、雜環 基、雜環烯基、環烯基、芳基、或雜芳基上之任一原子。 一態樣中一個基團上之取代基（例如Rd)可獨立為對該取代 基所說明之可許可之原子或原子團中之單一者，或任二者 或任多者之組合。另一態樣中，一取代基本身可能被任一 上述取代基（例如，Rd，）取代。 大致上，當對一特定變數的定義包括氫機率及非氫機 ^南原子、絲、芳基等）時，「非為氫之取代基」等術語 集合表示該特定變數之非氫機率。 在一些實施例中，該化合物具有用於與製造和膽 口醇排出相關的基因（例如，Αβαί)之致效劑的活性以及用 於與三酸甘油酯合成相關的基因（例如，SREBP-lc)之拮抗 劑活性。 —或更多本發明實施例的詳細說明在下列提出。本發 2〇明的其他特徵和優點將從說明書與申請專利範圍中輕易得 知。 【貪施冷式】 較佳實施例之詳細說明 本毛月係普遍關於以喧琳為主之肝異受體（lx糾的調 48 200825054 節物以及相關的方法和組成物。 該以喹啉為主之LXR調節物具有通式（1):W ; S: //, 〇 The term "sideoxy" means an oxygen atom which, when attached to carbon, forms a carbonyl group (00) or forms a sulfinium oxime when attached to a sulfur atom. 47 15 200825054 Part of the base or sulfonate, or part of the N-oxide when attached to nitrogen. The term "xianki," refers to a sulfur atom which, when attached to carbon, forms a thiocarbonyl group ((10). The symbols described are (10).), and c(nri) are respectively referred to as a double (tetra) knot to oxygen. The sulphur, and the nitrogen atom hinder the atom. 5 10 The term "substituent" refers to a group "substituted", for example, alkyl, _alkyl, "yl, alkenyl, alkynyl, aryl, miscellaneous Any one of a group, a heterocyclic group, a heterocycloalkenyl group, a cycloalkenyl group, an aryl group, or a heteroaryl group. A substituent on a group in one aspect (for example, Rd) may independently be the substituent A single or any combination of any of the permissible atoms or groups of atoms is illustrated. In another aspect, a monosubstituent may be substituted with any of the above substituents (e.g., Rd,). In general, when the definition of a particular variable includes a hydrogen probability and a non-hydrogen atom, a filament, an aryl group, etc., a set of terms such as "non-hydrogen substituent" means a non-hydrogen probability of the particular variable. In some embodiments, the compound has activity for an agonist associated with the manufacture of a gene associated with bicarbonol excretion (eg, Αβαί) and for use in genes associated with triglyceride synthesis (eg, SREBP-lc Antagonist activity. - or more Detailed descriptions of embodiments of the invention are set forth below. Other features and advantages of the present invention will be readily apparent from the description and claims. [Greed cold application] Detailed description of the preferred embodiment The present Maoyue is generally related to the heterogeneous liver receptors based on 喧琳 (1x rectification 48 200825054 and related methods and compositions. The main LXR regulator has the general formula (1):

(I) / 其"m、R5、R6、R7、R8、R9、rx、Y、(I) / its "m, R5, R6, R7, R8, R9, rx, Y,

Rh、R:、Rj、Rk、R'Rn、n、，”M_m·。 為解說方便，須明瞭用於r1、r2、r3、r4、r5、r6、r7、 R8、R9、r、X、γ、w、r、A、Ra、Ra， 10 、二:之 任一者中所列舉的任何範圍(例如，c,-c12，卜5)或一特定 範圍之次範圍（例如，以、以，卜2)係表示其包括落在 此列舉範圍中之每一個數，且包括該列舉範圍之最高與最 低值。例如，Cl—C4範圍之烧基被明瞭成意指C】、C2、C3、 、C】-C4、Cl-C3、Cl_C2、C2_C4、C2_C3、或 ca 烧基，以 15及1-3範圍之Ra被明瞭成意指卜2、3、卜3、卜2、或^Rh, R:, Rj, Rk, R'Rn, n,, "M_m·. For the convenience of explanation, it must be understood that it is used for r1, r2, r3, r4, r5, r6, r7, R8, R9, r, X, Any range recited in any of γ, w, r, A, Ra, Ra, 10, 2: (eg, c, -c12, Bu 5) or a range of a specific range (eg, by , 2) indicates that it includes each number falling within the scope of this list, and includes the highest and lowest values of the enumerated range. For example, the alkyl group in the range of Cl-C4 is understood to mean C], C2, C3. , C, -C4, Cl-C3, Cl_C2, C2_C4, C2_C3, or ca burnt base, Ra in the range of 15 and 1-3 is clearly defined as meaning 2, 3, Bu 3, Bu 2, or ^

Ra 〇 為求容易揭露，須了解於本說明書中（包括申請專 圍），基團係以、、如本文之任—處之定義1及其類）來定義， X特定基團之定義包括第—次出現的最廣義的通俗定義， 49 200825054 以及於本說明書之任 義0 一處所闡釋之任何次類和特定的定 在一些實施例中，R1為氫。 在一些實施例中，R2為： 10 15 20 (1)氫、氰基、或鹵基；或(例如，Cl—或㈣)烧基或【Μ例如， 1-⑵岐基，其之每—可任意地以卜5 (例如， 、1-3 ' 1-2、1) Ra取代；或 (i i i) C7-C2〇(例如，η η γλ Cl6、Ct—&、Cr~Cio)芳烷基或含 有 6-20(例如，6—14、6—12、R 1n、卜 12 6—10)原子之雜芳烷基，复之母-可任意地以卜糊如，卜5、"、"、；取代；或 C3 Cu)(例如，c3-c7)環烧基，可任意地以卜5 (例 σ ’ 卜4、1-3、1—2、1) Rb取代；或 u (Vi) Cl8(例如H C6-ClG、苯基）芳基或含有 6(例如’ 5-14、5—10、5—6)原子之雜芳基，其之每一W意地以HG(例如，卜5、卜4、卜3、卜2、i)Rd取代； 或 (vi XR8 50 200825054 在一些實施例中，^為： (i)氫或氰基；或 (11) Ci C12 (例如，Cl—Ce或c广⑴烷基或ο—& (例 如Ci C6S Ci C4)函烧基，其之每一可任意地以卜5 (例 5如，卜4、卜3、1—2、1) Ra取代；或 (iii) CrC2。（例如，c7_Ci6、C7_Ci2、C7_Cie)芳烷基或含 有6-20(例如，6-14、6—12、6_1〇)原子之雜芳烧基其之 每-可任意地以1-10 (例如，卜5、Η、卜3、卜2、i)Rb 取代。 10 在一些實施例中，R2為：（ii)Ci_C6烧基，可任意地 以卜2 Ra取代；或（iii) c7—Ci。芳烧基，可任意地以13 Rb 取代；或（vii) -XR8。 在某些實施例中，R2為氫。 在某些實施例中，R2為Cl_C6 (例如，Ci_C4)燒基，其 可任意地以1或2 Ra (例如，NRgRh、羥基、氰基、或 〜C(0)0Rj)取代。 例如，R為CHs(曱基）、乙基、Λ—丙基、或異丙基。一 示範性的R2取代基為CH3。 在某些實施例中，R2為經一個Ra取代之Cl—Ce(例如， C!或G)烷基。在實施例中，『為羥基或NRgRh。例如，R2 為 CH2NRgRh。 51 200825054 g在實施例中，Rg和P可皆為氫。在某些實施例中， R牙R之一者為氫，且另一為C —C2。（例如，c _C6、 CK：3)齒烧基（例如，氟甲基、三氟甲基、或氣乙基）； 5 或Cl—C2°烧基（例如甲基、乙基、或異丙基），其可任意 地，c!-C,烧氧基（例如，Ci_u、Ci—C6、㈣、例如， 甲氧基）、氰基、C2-C2〇 (例如，C2—(^心C6、C2_⑺烯基（例 如’烯丙基）、或c3-c2。環燒基（例如，環丙基或環戊基） 取代。 10 在某些實蘭巾，R2為芳絲，可任意地以卜3 (例如，1-2、1)R、例如，Ci—C3烷基；&—罐基， 如，Cl—G全氟燒基；_素；或CN)取代。-示範性的r2 芳烷基取代基為节基。 在某些實施例中，R2為氰基。 15 在某些實施例中，R2為鹵基。 在某iL實她例中，^2為院基（例如，全 鹵院基，如，CF3)。 20 在系些實施例中，R、C6—C1。芳基，其可任意地以 卜3 (例如’卜2、1) Rd (例如，Ci—C3烷基；Ci—鹵烷 基，例如，Cl_C3全氟燒基；錢；或CN)取代。例如， R2為任意地經1-3 Rd取代之苯基。 在某些實施射，R2為含有5-1G原子之雜芳基，可 任意地以卜3 (例如，1-2、υ Rd (例如，Ci_C3烧基；μ 鹵炫基，如，全氟烷基；鹵素；CN ; NRgRh ;或匕〜匕 52 200825054 烧氧基）取代。例如，R2為吼σ定基、嘧咬基、嗟吩基、苯并 異噁唑基、苯并噻吩基、噁二唑基、吡咯基、吡唑基、咪 唑基、四唑基、或呋喃基，其之每一可任意地以13 ^取 代。一示範性的R2雜芳基取代基為四唑基。 5 在某些實施例中，R2為C3-C7環烷基或含有3-7原 子之雜環基，其之每一可任意地以丨_5 (例如，丨_4、丨一3、 1-2、1) R取代。在實施例中，當存在有Rb時，Rb可被接 附至連接該環烷基或雜環基環到該喹啉基中心之第3位置 的相同碳原子上。 10 在某些實施例中，R2為-XR8。 例如，X為-C(0)0-，從而形成該式—c⑺）〇R8的酯類 部份。在某些實施例中，R8為氯或c广&(例如，Ci—C4)烧 基（例如，甲基或乙基）。 如同另一範例，X為—C(0)NR9—，從而形成該式 15 C(〇)NR R的醯胺部份。在這些實施例中，R8和R9可各自 獨立地為氫或Ci-CK例如，Cl-C4)烷基。在某些實施例中， R8和R9兩者可皆為氫；或R8*R9之一者為氫，且另一者 為Crc6 (例如，Cl-C4)烷基（例如，CH3或乙基）。 如一範例，X為_S(0)t—，從而形成該式_s(〇)tR8的颯 20部份。在某些實施例中，R8為氫或Ci—Ce(例如，Ci_C4)烧基 (例如，乙基），且t為〇、1、或2(例如，2)。 如另一範例，X為-NR9-，從而形成該式_NR8R9的胺基 邛伤。在某些實施例中，R9為氫或匕―匕（例如，Ci—C4)烷基， 且R8可如此中任一處之定義者。在某些實施例中，R8*R9 53 200825054 可皆為氫。 變數R3 在一些實施例中，以C6—Cl8 (例如，C6—Ci4、c^。、 苯基）芳基，其係⑴以卜5 (例如，1-4、1-3、1-2、1) Rl。 取代且（ii)任意地以丨―4(例如，丨―3、丨―2、丨）Re取代。在 實施例中，當R3經『取代時，每―Μ互相無關： 烧基；c3 _烷基，例如，Ci_C3全就基烧基；齒素；或 10 15 在-些實施例中’ R、芳基，其係⑴以卜5 (例如’卜4、"、卜2、υ Rl。取代且⑼任意地以Η (例如，1-3、1-2、1) Re取代。 在些實施例中，Ce—Ci。芳基，其係⑴以1或 2 R1G取代且（ii)任意地以丨或2 Re取代。 、在二實^例中，R為萘基，其係（丨）以1或2 R1◦取 代且（ii)任意地以1或2 取代。 在一些實施例中，R3為苯基，其係（i)以i或2 riq取 代且（⑴任意地以1或2『（例如，1 Re，其為，例如， 鹵基，如，氟或氯）取代。· 在些貫她例中，R3為C6_Ci。芳基，其係⑴以1 ^ 20取代且（ii)任意地以1或2 Re取代。 在某些實施例中，R3為苯基，其係⑴以1 R1。取代且 (11)任思地以1或2 Re (例如’鹵基）取代。在這些實施 例：：R3可具有式(A) ’其中R1。(即，該部份，)可被接附 -壞碳，該環碳相對於連接鮮基環至财料之第4位 54 200825054 置的環碳為鄰位、間位或對位（較佳為間位），且當存在有 Re時，其可被連接至沒有被WA佔據的環碳。例如，R3可具 有式（A-1)或（A-1’ ），其中R1G (WA)在式（I)中被接附至相 對於連接該苯基環至該喹啉環之第4位置的環碳為間位的 該環碳。Ra 〇 容易 容易 容易 容易 , , 须 须 须 须 须 须 须 须 须 须 须 须 须 须 Ra Ra Ra Ra Ra Ra Ra Ra Ra Ra Ra Ra Ra Ra Ra Ra Ra Ra Ra Ra Ra Ra Ra Ra Ra Ra Ra Ra Ra - The most general definition of the second occurrence, 49 200825054 and any subclass and specific explanations set forth in the teachings of this specification. In some embodiments, R1 is hydrogen. In some embodiments, R 2 is: 10 15 20 (1) hydrogen, cyano, or halo; or (eg, Cl— or (d)) alkyl or [Μ, eg, 1-(2) fluorenyl, each of which— Optionally substituted with 5 (eg, 1-3 '1-2, 1) Ra; or (iii) C7-C2〇 (eg, η η γλ Cl6, Ct-&, Cr~Cio) aralkyl a base or a heteroaralkyl group containing 6-20 (e.g., 6-14, 6-12, R 1n, and 12 6-10) atoms, a complex mother - optionally arbitrarily, b, " , ",;substituted; or C3 Cu) (eg, c3-c7) cycloalkyl, optionally substituted with 5 (eg, σ ' 4, 1-3, 1-2, 1) Rb; or u (Vi) Cl8 (eg H C6-ClG, phenyl) aryl or heteroaryl containing 6 (eg '5-14, 5-10, 5-6) atoms, each of which is intentionally HG (eg , Bu 5, Bu 4, Bu 3, Bu 2, i) Rd substituted; or (vi XR8 50 200825054 In some embodiments, ^ is: (i) hydrogen or cyano; or (11) Ci C12 (for example, Cl-Ce or c-poly (1) alkyl or ο-& (for example, Ci C6S Ci C4) functional group, each of which can be arbitrarily 5 (Example 5, for example, Bu 4, Bu 3, 1-2 1) Ra substitution; or (iii) C rC2 (for example, c7_Ci6, C7_Ci2, C7_Cie) an aralkyl group or a heteroaryl group containing 6-20 (e.g., 6-14, 6-12, 6_1 〇) atoms, each of which may optionally be 1-10 (for example, 卜5, Η, 卜3, 卜2, i) Rb is substituted. 10 In some embodiments, R2 is: (ii) Ci_C6 alkyl, optionally substituted with 2 Ra; or (iii) c7 —Ci. An aryl group, optionally substituted with 13 Rb; or (vii) —XR 8. In certain embodiments, R 2 is hydrogen. In certain embodiments, R 2 is Cl —C 6 (eg, Ci—C 4 )alkyl. It may be optionally substituted with 1 or 2 Ra (for example, NRgRh, hydroxy, cyano, or ~C(0)0Rj). For example, R is CHs (fluorenyl), ethyl, hydrazine-propyl, or iso A exemplified R2 substituent is CH3. In certain embodiments, R2 is a Cl-Ce (eg, C! or G) alkyl group substituted with one Ra. In an embodiment, "is hydroxy or NRgRh. For example, R2 is CH2NRgRh. 51 200825054 g In an embodiment, both Rg and P may be hydrogen. In certain embodiments, one of R teeth R is hydrogen and the other is C-C2. , c _C6, CK: 3) tooth-burning base (for example, fluoromethyl, three Methyl or gas ethyl); 5 or Cl-C2 ° alkyl (eg methyl, ethyl, or isopropyl), optionally, c!-C, alkoxy (eg, Ci_u, Ci) —C6, (IV), for example, methoxy), cyano, C2-C2〇 (for example, C2-(C6, C2_(7) alkenyl (eg 'allyl), or c3-c2. A cycloalkyl group (for example, cyclopropyl or cyclopentyl) is substituted. 10 In some solid blue towels, R2 is an aromatic filament, optionally arbitrarily 3 (for example, 1-2, 1) R, for example, Ci-C3 alkyl; &-can base, such as Cl-G Fluoroalkyl; _; or CN) substitution. - An exemplary r2 aralkyl substituent is a benzyl group. In certain embodiments, R 2 is cyano. In certain embodiments, R2 is halo. In an example of iL, ^2 is a hospital base (for example, a full halogen base, such as CF3). 20 In some embodiments, R, C6-C1. An aryl group which may be optionally substituted with 3 (e.g., '2, 1) Rd (e.g., Ci-C3 alkyl; Ci-haloalkyl, for example, Cl_C3 perfluoroalkyl; money; or CN). For example, R2 is a phenyl group optionally substituted with 1-3 Rd. In some embodiments, R2 is a heteroaryl group containing 5-1G atoms, optionally arbitrarily 3 (for example, 1-2, υ Rd (for example, Ci_C3 alkyl; μ halo-based, such as perfluoroalkane) Halogen; CN; NRgRh; or 匕~匕52 200825054 alkoxy substituted). For example, R2 is 吼σ-based, pyrimidine, porphinyl, benzoisoxazolyl, benzothienyl, dioxin An azolyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, or furyl group, each of which may be optionally substituted with 13^. An exemplary R2 heteroaryl substituent is a tetrazolyl group. In certain embodiments, R 2 is C 3 -C 7 cycloalkyl or heterocyclyl containing 3-7 atoms, each of which may optionally be 丨 5 (eg, 丨 4, 丨 3, 1-2 1) R. In the examples, when Rb is present, Rb may be attached to the same carbon atom to which the cycloalkyl or heterocyclyl ring is attached to the third position of the quinolyl group. In certain embodiments, R2 is -XR8. For example, X is -C(0)0-, thereby forming an ester moiety of the formula -c(7))〇R8. In certain embodiments, R8 is chloro or c-ampl & (e.g., Ci-C4) alkyl (e.g., methyl or ethyl). As another example, X is -C(0)NR9-, thereby forming the guanamine moiety of the formula 15 C(〇)NR R . In these embodiments, R8 and R9 may each independently be hydrogen or Ci-CK, for example, Cl-C4)alkyl. In certain embodiments, both R8 and R9 may be hydrogen; or one of R8*R9 is hydrogen and the other is Crc6 (eg, Cl-C4) alkyl (eg, CH3 or ethyl) . As an example, X is _S(0)t-, thereby forming the 飒20 portion of the _s(〇)tR8. In certain embodiments, R8 is hydrogen or Ci-Ce (e.g., Ci_C4) alkyl (e.g., ethyl), and t is deuterium, 1, or 2 (e.g., 2). As another example, X is -NR9-, thereby forming an amine group of the formula _NR8R9. In certain embodiments, R9 is hydrogen or 匕-匕 (eg, Ci-C4)alkyl, and R8 can be as defined anywhere in this. In certain embodiments, R8*R9 53 200825054 can be both hydrogen. The variable R3 is, in some embodiments, a C6-Cl8 (e.g., C6-Ci4, c^., phenyl) aryl group, the system (1) of which is 5 (e.g., 1-4, 1-3, 1-2, 1) Rl. Instead, (ii) arbitrarily substituted with 丨-4 (for example, 丨-3, 丨-2, 丨) Re. In the examples, when R3 is "substituted, each Μ is independent of each other: alkyl; c3 - alkyl, for example, Ci_C3 all-based alkyl; dentate; or 10 15 in some embodiments 'R, An aryl group, wherein the system (1) is substituted with bl (e.g., 'Bu 4, ", Bu 2, υ Rl. and (9) is optionally substituted with Η (for example, 1-3, 1-2, 1) Re. In the example, Ce-Ci. aryl, which is (1) substituted with 1 or 2 R1G and (ii) optionally substituted with hydrazine or 2 Re. In the two examples, R is a naphthyl group, which is (丨) Substituted with 1 or 2 R1◦ and (ii) optionally substituted with 1 or 2. In some embodiments, R3 is phenyl which is (i) substituted with i or 2 riq and ((1) optionally 1 or 2 "(for example, 1 Re, which is, for example, a halogen group such as fluorine or chlorine) is substituted. · In some examples, R3 is C6_Ci. An aryl group, the system (1) is substituted by 1^20 and (ii) Optionally substituted with 1 or 2 Re. In certain embodiments, R3 is phenyl, which is substituted by 1 R1. and (11) is optionally substituted with 1 or 2 Re (eg, 'halo). These embodiments: R3 can have the formula (A) 'where R1. (ie, the part,) can be connected Attached - bad carbon, the ring carbon is ortho, meta or para (preferably meta) relative to the 4th position of the connection of the fresh base ring to the fourth position 54 200825054, and when there is Re , which may be attached to a ring carbon that is not occupied by WA. For example, R3 may have formula (A-1) or (A-1'), wherein R1G (WA) is attached in formula (I) to The ring carbon connecting the phenyl ring to the 4th position of the quinoline ring is a meta carbon.

在某些實施例中，R3為苯基，其被1 R1()取代，且R3 可具有式（A-2)，例如，式（A-3):In certain embodiments, R3 is phenyl, which is substituted by 1 R1(), and R3 can have formula (A-2), for example, formula (A-3):

WAWA

(A-2)(A-2)

(A-3) 10 仍在其他實施例中，R3可具有式（A-4): 20(A-3) 10 In still other embodiments, R3 may have the formula (A-4): 20

(A-4) 55 200825054 其中W和A可如此中任一卢 〇e r，( , ^ ^ 處所定義者；且R32為氫；戍 R (例如，鹵基，如，氯或氟）。 旦戈 任一些貫施例中，R3為含有 负 b 16(例如，5-14、5-10、 Η)原子之雜芳基，其係 nl0 1 b C例如，；l-4、1-3、1-2、 )R取代且（ii)任意地以丨 (例如，卜3、卜2、1)『 代。在實施例中，當R^Re取代時，每—㈣互相益 2.CK：道基例如，^全氟烧基 素；或CN。 10 15 在一些實施例中，R3為含冑5_1〇原子之雜芳基，其係 ω以1-5⑽如’ η、卜3、卜2、，取代且（⑴任意 地以W(例如，1—3、1-2、1) Re取代。 在一些實施例中，R3為含有5-10原子之雜芳基，其係 ⑴以1-4 (例如，卜3、卜2、υ R1。取代且⑴）任意地以】 或2 Re取代。 在一些貫施例中，r3為含有5-6原子之雜芳基，其係 (i)以卜4 (例如，1—3、1-2、l)Rie取代且（ii)任意地以i 或2 Re(例如，Ci_C3鹵烷基，如，Ci_c3全氟烷基如， Ci C2王氣燒基；或_素）取代。 在某些實施例中，R3為ϋ比咬基、喷σ定基、嗟吩基、或 吱喃基（例如，σ比咬基或哺σ定基），其係（i)以14 (例如， 1一3、1-2、1)R1G取代且（ii)任意地以1或2Re(例如，Cl_C3 函烧基’例如，Ci-C3全氟烷基，如，Ci-C2全氟烷基；或 鹵素）取代。 56 200825054 在一些實施例中，R3為含有5~10(例如，5-6)原子之 雜芳基，其係（i)以1 R1()取代，且（ii)任意地以卜2 Re取 在某些實施例中，R3為吡啶基、嘧啶基、噻吩基、噻 5唑基、吡唑基、或呋喃基（例如，吡啶基、噻吩基、噻唑基、 或。比唑基），其係（i)以1 R1。取代且（ii)任意地以i或2^e (例如，匕七鹵烷基，例如，Cl—G全氟烷基，例如，Ci—g 全鼠烧基；或_素）取代。 在某些實施例中，R3為吡啶基、噻吩基、吡唑基、或 10噻唑基（例如，噻吩基或噻唑基）。 在—些實施例中，w為-0-。 在一些實施例中，w為一鍵。 w為C1-C3伸烧基（例如，ch2) 〇(A-4) 55 200825054 wherein W and A may be as defined by any of the 〇, ( , ^ ^; and R32 is hydrogen; 戍R (eg, halo, eg, chloro or fluoro). In any of the examples, R3 is a heteroaryl group containing a negative b 16 (e.g., 5-14, 5-10, fluorene) atom, which is nl0 1 b C, for example,; l-4, 1-3, 1 -2, ) R is substituted and (ii) arbitrarily 丨 (for example, Bu 3, Bu 2, 1). In the examples, when R^Re is substituted, each (4) is mutually beneficial. 2.CK: a cyclyl group, for example, a perfluoroalkyl group; or CN. 10 15 In some embodiments, R 3 is a heteroaryl group containing a 胄 5 1 〇 atom, which is ω 1-5 (10) such as ' η, 卜 3, 卜 2, and ((1) arbitrarily in W (eg, 1 —3, 1-2, 1) Re. In some embodiments, R 3 is a heteroaryl group having 5-10 atoms, and the system (1) is substituted with 1-4 (for example, Bu 3, Bu 2, υ R 1 . And (1)) is optionally substituted with or 2 Re. In some embodiments, r3 is a heteroaryl group having 5-6 atoms, and the system (i) is ib4 (for example, 1-3, 1-2, l) Rie substituted and (ii) optionally substituted with i or 2 Re (for example, Ci_C3 haloalkyl, such as Ci_c3 perfluoroalkyl such as Ci C2 sulphur; or _). Wherein R3 is a thiol base, a sigma group, a porphyrin group, or a fluorenyl group (for example, σ is a bite base or a sigma group), and the system (i) is 14 (for example, 1 to 3, 1 2, 1) R1G is substituted and (ii) optionally substituted with 1 or 2Re (for example, a Cl_C3 functional group 'for example, a Ci-C3 perfluoroalkyl group such as a Ci-C2 perfluoroalkyl group; or a halogen). 200825054 In some embodiments, R3 is a heteroaryl containing 5-10 (eg, 5-6) atoms, which is (i) is 1 R1() And (ii) optionally taken as 2 Re. In certain embodiments, R3 is pyridyl, pyrimidinyl, thienyl, thiazolyl, pyrazolyl, or furanyl (eg, pyridyl, thiophene) a group, a thiazolyl group, or a oxazolyl group, which is (i) substituted with 1 R1. and (ii) optionally i or 2^e (for example, anthracene haloalkyl, for example, Cl-G perfluoro An alkyl group, for example, a Ci-g whole mouse alkyl group; or a _ mer). In certain embodiments, R3 is pyridyl, thienyl, pyrazolyl, or 10 thiazolyl (eg, thienyl or thiazolyl) In some embodiments, w is -0-. In some embodiments, w is a bond. w is a C1-C3 stretching group (eg, ch2) 〇

卜C3伸烷基）〇-。 在一些實施例中， 在~^些實 在一些實施例中， 伸烷基）W1-(例如， 基）0-，例如，—0CH2〜或 伸燒基>、和—（Cl〜G >卜C3 alkyl)〇-. In some embodiments, in some embodiments, an alkyl group, W1 - (e.g., a group) 0-, for example, -0CH2~ or a stretching group>, and - (Cl~G >

Rf取代； 些實施例中，A , E (b)住意地以1 為一環基，其係（a)以一或多個 1-4 Re取代。 57 200825054 在一些實施例中，A為· (i-A) C6-C,。（例如，苯基）芳基，其係⑷以卜5 (例如， 1 4 1 3 1 2卜如’ j)Rf取代；且（b)任意地以卜4(例 5如，1-3、1-2、卜如，卜2) Re取代； 和/或 (ii-A)含有5-1()(例如，5_8)原子之雜芳基，其係 ⑷以1-5 (例如’h、"、卜2、卜如，i)Rf取代；且 (b)任意地以1-4 (例如，卜3、卜2、i，如，l 3) Re取代. H)前提是該含有5-1Q原子之雜芳基並和，2 4]U坐基； 和/或 ㈤—A)含有8-12原子之芳基氮縣（例如，四氯嗜 淋基或四氫異喧琳基），其係⑷以卜5 (例如，卜4、㈠、 1例如，1) R取代，且（b)任意地以卜4 (例如，U、 5卜2、1，如，卜2) IT取代。 只轭例中，下列組合之任一者可用於定義A·· • (i-A) 、 （ii-A)、或（iii—A);或 20 • (i-A)和（ii-A)、或（i—A)和（Hi—A)、或 (ii-A)和（iii—a);或 • (i-A)、（ii一A)、和⑴卜A)。 如，f—-些實施例中’ A為C6-ClD芳基，其係⑴以13 (例 1) R取代且（ii)任意地以！或2『取代。 58 200825054 在-些實，中，A為萘基，其係⑴以 卜2、1)R>代且⑴）任意地以取代。（例如’ 在-些實施例中，A為笨基，其係⑴ 卜2、Π R取代且（ii)任意地以1或2 Re取代。例如’ 在某些實施例中，A為苯基，其係⑴以卜 ⑷^取代且⑹任意地幻或”取代/例如’ 例如，A可具有式 r. 专： 可被接附讀’該環碳相對於連接至w之環碳八R 位、間位或對位（較佳為間位）： “別為鄰 10 Λ (Β-1) (Β-2) (B-3) 如其他範例，A可具有式（b-4)、（B-5)、（B—6)、或 (Β-Ό ’其中該苯基環以（a)l Rf*(b)l Re取代： 59 15 200825054Rf is substituted; in some embodiments, A, E(b) is desirably substituted with 1 as a ring group, wherein (a) is substituted with one or more 1-4 Re. 57 200825054 In some embodiments, A is (i-A) C6-C,. (e.g., phenyl)aryl, which is substituted by (i) 5 (e.g., 1 4 1 3 1 2 as 'j) Rf; and (b) arbitrarily as 4 (example 5, 1-3, 1-2, 卜如, 卜 2) Re substituted; and/or (ii-A) a heteroaryl group containing a 5-1 () (for example, 5-8) atom, the system (4) being 1-5 (for example, 'h, ", Bu2, Buru, i) Rf substitution; and (b) arbitrarily substituted with 1-4 (for example, Bu 3, Bu 2, i, such as l 3) Re. H) premise that the content contains 5 a heteroaryl group of -1Q atom and a 2,4 U group; and/or (5)-A) an aryl nitrogen county having 8-12 atoms (for example, tetrachloroisolinyl or tetrahydroisoindolyl) , the system (4) is replaced by Bu 5 (for example, Bu 4, (1), 1 for example, 1) R, and (b) is arbitrarily replaced by Bu 4 (for example, U, 5 Bu 2, 1, etc.) . In the yoke example, any of the following combinations may be used to define A·· • (iA), (ii-A), or (iii-A); or 20 • (iA) and (ii-A), or ( i-A) and (Hi-A), or (ii-A) and (iii-a); or • (iA), (ii-A), and (1) Bu A). For example, f—in some embodiments, 'A is a C6-ClD aryl group, which is substituted with 13 (Example 1) R and (ii) arbitrarily! Or 2 "replace. 58 200825054 In some embodiments, A is a naphthyl group, and the system (1) is optionally substituted with 2, 1) R > and (1)). (For example, in some embodiments, A is a stupid group, which is substituted by (1) 2, Π R and (ii) arbitrarily substituted with 1 or 2 Re. For example, 'in certain embodiments, A is phenyl. , the system (1) is replaced by 卜 (4) ^ and (6) arbitrarily or "substituted / for example" For example, A may have the formula r. Specific: Can be attached to read 'the ring carbon relative to the ring carbon connected to w , meta or para (preferably meta): "Do not be adjacent 10 Λ (Β-1) (Β-2) (B-3) As other examples, A may have the formula (b-4), ( B-5), (B-6), or (Β-Ό ' where the phenyl ring is replaced by (a) l Rf*(b)l Re: 59 15 200825054

RfRf

Re (B-4)Re (B-4)

Rf or(Re) (Β·5)Rf or(Re) (Β·5)

Re or (Rf)Re or (Rf)

Re or(Rf) or (Rf) ΛRe or(Rf) or (Rf) Λ

Rf or(Re) (B-6)Rf or(Re) (B-6)

Rf or (Re) (B-7) 如其他範例，A可具有式（B-8)，其中該苯基環以（a)l RXb)2 Re取代： ΛRf or (Re) (B-7) As another example, A may have the formula (B-8) in which the phenyl ring is substituted with (a)l RXb)2 Re: Λ

Rf or (Re)Rf or (Re)

Reor(Rf) (B-8) 如另一範例，Α可具有式（Β-9): RA22 >A23 、RA24 RA25 (B-9) 60 15 200825054 其中： RA22和RA23之每一者可獨立地為氳或Re，•且 R和R之一者為Rf (例如，—s〇2Rn)，且另一者為氫 或Re 〇 5 在某些實施例中，限定僅RA22、RA23、rA24、和rA25之一 者為IT。 在某些實施例中，RA25為Rf(例如，—s〇2Rn)，且rA22、rA23、 f i i. 和RA24之每-者為氫。在某些實施例中，广為Rf (例如， 一鮮），RA22、RA23、和C之一者（例如，〇為『，且 10 另二者可個別為氫。 在其他實施例中，RA24為Rf (例如，—s〇D，且RA22、 R、和R25之每-者為氫。在某些實施例中，rA24為八例 如，-S〇2r)，d、和 c 之—者（例如，rA22)為 Re， 且另二者可個別為氫。 15 在其他實施例中，A為含有5-10原子之雜芳基，其係 (a)以卜3 (例如’ 1-2、1) r取代；且⑹任意地以13 (例 如’卜2、1) R取代；前提為該含有51()原子之雜芳基並 非[1，2, 4]-°惡二唾基。 20 在一些實施射，A為含有5—1G原子之雜芳基，其係 ⑷以1 Rf取代；且⑹任意地以卜3 (例如，卜 取代；前提為該含有5-10原子之雜芳基並非[i 2，d σ坐基。 在-些實施例中，Α為含有5_8原子之雜芳基，其係 61 200825054 (a)以1 Rf取代；且（b)任意地以ι—3 (例如，1-2、1) Re 取代；前提為該含有5-10原子之雜芳基並非[1，2, 4]-噁二 ϋ坐基。 在某些實施例中，Α為吡咯基、吡啶基、吡啶基-Ν-氧 5化物、嘧啶基、吡唑基、噻吩基、呋喃基、喹啉基、噁唑 基、噻唑基、咪唑基、異噁唑基、或吲哚基，其之每一係 (a)以1 Rf取代；且（b)任意地以卜3 (例如，卜2、1) Re 取代。 在某些實施例中，A為吡咯基、吡啶基、嘧啶基、吡 1〇唑基、噻吩基、呋喃基、喹啉基、噁唑基、噻唑基、咪唑 基、或異噁唑基，其之每一係（a)以丨浐取代；且（b)任意 地以1-3 (例如，1-2、1) Re取代。 在某些實施例中，A為吡啶基、嘧啶基、噻吩基、呋 喃基、噁唑基、噻唑基、咪唑基、或異噁唑基，其之每一 15係（a)以1 Rf取代；且（b)任意地以1—3 (例如，丨―2、υ IT取代。 在某些實施例中，A為吼啶基，其中w係接附至該0比 啶基之第2或第3位置。 在實施例中，A V比咬基，其+ W係接附至該吼咬基 0之第2位置’ 係接附至該吼絲環的第4或第6位 置。該環更可以卜2或3Γ (例如，_基，如，氯；或NRgRh， 如’腦）取代。例如，A為㈣基，其中接附至該吼咬 基衰之第2位置，以及r係、接附至該。比咬基環的第6位 置，且1 Γ係接附至該㈣基環之第4位置。如其他範例， 62 200825054 A為吡啶基，其中W係接附至該吡啶基環之第2位置，以 及Rf係接附至該吡啶基環的第6位置，且一 Re取代基係接 附至該吡啶基環的第3、第4、和第5位置。 在其他實施例中，A為吡啶基，其中W係接附至該吡 5 啶基環之第3位置，以及Rf係接附至該吡啶基環的第5 位置。該環更可以1、2或3 Re (例如，鹵基，如，氯； 或NRgRh，如，NH2)取代。 在某些實施例中，A為噻吩基，其中W係接附至該噻 10 吩基環之第2位置，以及Rf係接附至該噻吩基環的第5 位置。該環更可以1、2或3 Re (例如，鹵基，如，氯； 或NRgRh，如，NH2)取代。 在一些實施例中，A為四氫喹啉基或四氫異喹啉基， 15 其係（a)以1-3 (例如，1-2、l)Rf取代；且（b)任意地以 1_3(例如 ’ 1_2、1) Re取代。 在一些實施例中，A為四氫喹琳基或四氫異喹琳基， 其係（a)以1 Rf取代；且（b)任意地以1或2 Re取代。 在一些實施例中，A為四氫喹啉基或四氫異喹啉基， 20 其係以1 Rf取代。在某些實施例中，W可被接附至該四氫 口奎琳基或四氫異喧琳基之芳香環部份（例如，第5位置）。 在某些實施例中，Rf可被接附至該四氫喹啉基或四氫異喹 啉基的氮環原子（例如，當Rf係S〇2Rn時）。在某些實施例 中，W可被接附至該四氫喹琳基或四氫異喹琳基的第5位 63 200825054 置，^係SO,，且該SO,基團被接附至該四氫喹啉基或 四氫異喹啉基的氮環原子。· 在一些實施例中，當A係（a)以一個或多個Rf取代； 5且（b)以1-4 Re取代時，則Re於各次出現時可獨立地為_ 基（例如，氟或氣）、Cl-C3烧基（例如，CH3)、Ci-C3 _燒 基（例如，CF3)、Ci-C3烧氧基（例如，OCH3)、NRgRh (例如， NH2)、笨基、或4-氟苯基。在某些實施例中，Re於各次出 現時可獨立地鹵基（例如，氟或氣）、G-C3烷基（例如， 10 CH3)、Ci-Cs 鹵烷基（例如，CFs)、G-C3 烷氧基（例如，〇CH3)、 NRgRh (例如，NH2)。 在一些實施例中，A為一環基，其（幻包括一經取代的 環原子，係選自S(0)和S〇2，例如，s〇2，所組成之群；且 15 (b)任意地以1-4 Re取代。 20 在一些實施例中，A為含有5-1〇(例如，5-8)原子之 雜芳基，其（a)包括一經取代的環原子，係選自s(〇)和s〇2 所組成之群；且（b)任意地以ι、4(例如，13、丨_2、丨，如， 1 -3) Re取代。 在某些實施例中，A為含冑5、1〇(例如，5_8)原子之雜 芳基，其⑷包括-經取代的環原子，係選自⑽和肌， 例如，S〇2,所組成之群。例如1絲并[b]嘆吩基Ul_ 二氧化物（齡，其中w係接附㉔科[b]㈣基環系統 64 200825054 之該苯基環部份，如，其之第4位置；或W係接附至該苯 并[b]噻吩基環系統之該噻吩基環部份，如，其之第3位置）。 在一些實施例中，A為芳基績酿基環基或雜芳基績酸 5 基環基，其之每一包括8-10個原子並任意地以1-4(例如， 1-3、1-2、1，如，l-3)Re取代。 在某些實施例中，A為雜芳基磺醯基環基，其包括8-10 個原子並任意地以1-4(例如’ 1-3、1-2、1 ’如’ l_3)Re 取代。例如’ A為3，4-二氯-2H-硫°比喃[2，3-b]。比。定基1，1 -10 二氧化物（例如，其中W係接附至該硫吡喃[2, 3-b]吡啶基 環系統之該苯基環部份，如，其之第4位置；或W係接附 至該苯并[b]噻吩基環系統之該吡啶基環部份，如，其之第 2或第4位置）。 在某些實施例中，A為芳基磺醯基環基，其包括8-10 15 個原子並任意地以1-4(例如，1-3、1-2、1，如，l-3)Re 取代。例如，A為2，3_二氮-苯弁[b ]σ塞吩基1，1_二氧化物 (例如，其中W係接附至該苯并[b]噻吩基環系統之該苯基 環部份，如，其之第4位置）。 20 在一些實施例中，當A係一環基，其（a)包括一經取代 的環原子，係選自S(0)和S〇2，例如，S〇2，所組成之群； 且（b)任意地以1-4 Re取代時，則Re於各次出現時可獨立 地為1¾基；Ci-C3烧基，任意地以1-2 Ra取代；C1-C3 ή 烷基；G-C3烷氧基；羥基；氰基；硝基；NRgRh ;苯基；或 65 200825054 4-氟苯基。在某些實施例中’ R於各次出現時可獨立地為 鹵基；CrC3烷基，任意地以1 -2 Ra (例如，P為c⑼肥 取代；羥基；氰基；或硝基。 5 在一些實施例中，A為[1，2, 4]-噁二唑基，可任音地 以1 Re取代。在某些實施例中，A具有式（〇:Reor(Rf) (B-8) As another example, Α can have the formula (Β-9): RA22 > A23, RA24 RA25 (B-9) 60 15 200825054 where: each of RA22 and RA23 can be independent The ground is 氲 or Re, and one of R and R is Rf (eg, —s〇2Rn), and the other is hydrogen or Re 〇5. In certain embodiments, only RA22, RA23, rA24, One of the rA25 is IT. In certain embodiments, RA25 is Rf (eg, -s〇2Rn), and each of rA22, rA23, f i i., and RA24 is hydrogen. In some embodiments, Rf (eg, a fresh), one of RA22, RA23, and C (eg, 〇 is, and 10 may be hydrogen separately. In other embodiments, RA24 Rf (for example, -s〇D, and each of RA22, R, and R25 is hydrogen. In some embodiments, rA24 is eight, for example, -S〇2r), d, and c ( For example, rA22) is Re, and the other two may be hydrogen independently. 15 In other embodiments, A is a heteroaryl group containing 5-10 atoms, which is (a) is 卜3 (eg '1-2, 1) r is substituted; and (6) is optionally substituted with 13 (for example, 'Bu 2, 1) R; provided that the heteroaryl group containing 51 () atoms is not [1, 2, 4]-° di-saltyl. In some embodiments, A is a heteroaryl group containing 5 to 1 G atom, and the system (4) is substituted with 1 Rf; and (6) is optionally substituted with a 3 (for example, a silane; provided that the heteroaryl group contains 5 to 10 atoms) Not [i 2,d σ sitting. In some embodiments, Α is a heteroaryl containing 5-8 atoms, which is 61 200825054 (a) is replaced by 1 Rf; and (b) is optionally ι-3 ( For example, 1-2, 1) Re is substituted; the premise is that it contains 5-10 atoms of hetero It is not [1,2,4]-oxadipine. In certain embodiments, hydrazine is pyrrolyl, pyridyl, pyridyl-hydrazine-oxy-5, pyrimidinyl, pyrazolyl, thienyl, furan. a group, a quinolyl group, an oxazolyl group, a thiazolyl group, an imidazolyl group, an isoxazolyl group, or a fluorenyl group, each of which is substituted with 1 Rf; and (b) optionally exemplified by 3 (for example , 2, 1) Re is substituted. In certain embodiments, A is pyrrolyl, pyridyl, pyrimidinyl, pyridazolyl, thienyl, furyl, quinolyl, oxazolyl, thiazolyl, Imidazolyl or isoxazolyl, each of which is substituted with deuterium (a); and (b) optionally substituted with 1-3 (eg, 1-2, 1) Re. In certain embodiments , A is pyridinyl, pyrimidinyl, thienyl, furyl, oxazolyl, thiazolyl, imidazolyl, or isoxazolyl, each of which is substituted with 1 Rf; and (b) optionally The ground is replaced by 1-3 (eg, 丨-2, υ IT. In certain embodiments, A is an acridinyl group, wherein w is attached to the second or third position of the 0-pyridine group. In the example, the AV is attached to the bite base 0 than the bite base. The 2 position' is attached to the 4th or 6th position of the silk loop. The ring may be replaced by 2 or 3 (for example, a base such as chlorine; or NRgRh, such as 'brain'. For example, A is (4) a base attached to the second position of the bite base, and the r system attached thereto. The sixth position of the bite base ring and the 1 tether attached to the 4th position of the (4) base ring As another example, 62 200825054 A is a pyridyl group in which the W system is attached to the second position of the pyridyl ring, and the Rf is attached to the sixth position of the pyridyl ring, and a Re substituent is attached. To the 3rd, 4th, and 5th positions of the pyridyl ring. In other embodiments, A is pyridinyl, wherein the W is attached to the 3rd position of the pyridinyl ring, and the Rf is attached to the 5th position of the pyridyl ring. The ring may be substituted with 1, 2 or 3 Re (for example, a halogen group such as chlorine; or NRgRh such as NH2). In certain embodiments, A is a thienyl group, wherein the W is attached to the second position of the thiophene ring, and the Rf is attached to the 5th position of the thienyl ring. The ring may be substituted with 1, 2 or 3 Re (for example, a halogen group such as chlorine; or NRgRh such as NH2). In some embodiments, A is tetrahydroquinolyl or tetrahydroisoquinolinyl, 15 is (a) substituted with 1-3 (eg, 1-2, 1) Rf; and (b) optionally 1_3 (eg '1_2, 1) Re substitution. In some embodiments, A is tetrahydroquinolinyl or tetrahydroisoquinolinyl, which is (a) substituted with 1 Rf; and (b) optionally substituted with 1 or 2 Re. In some embodiments, A is tetrahydroquinolyl or tetrahydroisoquinolinyl, and 20 is substituted with 1 Rf. In certain embodiments, W may be attached to the aromatic ring moiety of the tetrahydroquinone or tetrahydroisoindolyl (e.g., position 5). In certain embodiments, Rf can be attached to the nitrogen ring atom of the tetrahydroquinolyl or tetrahydroisoquinolinyl group (e.g., when Rf is S〇2Rn). In certain embodiments, W may be attached to the 5th position of the tetrahydroquinolinyl or tetrahydroisoquinolinyl group, 2008 2008054, and the SO, the group is attached thereto. A nitrogen ring atom of a tetrahydroquinolyl group or a tetrahydroisoquinolyl group. · In some embodiments, when A (a) is substituted with one or more Rf; 5 and (b) is substituted with 1-4 Re, then Re may independently be a _ group at each occurrence (eg, Fluorine or gas), Cl-C3 alkyl (eg, CH3), Ci-C3-alkyl (eg, CF3), Ci-C3 alkoxy (eg, OCH3), NRgRh (eg, NH2), stupid, Or 4-fluorophenyl. In certain embodiments, Re may independently be a halo group (eg, fluoro or a gas), a G-C3 alkyl group (eg, 10 CH3), a Ci-Cs haloalkyl group (eg, CFs), G-C3 alkoxy (eg, 〇CH3), NRgRh (eg, NH2). In some embodiments, A is a cyclic group, which (including a substituted ring atom, is selected from the group consisting of S(0) and S〇2, eg, s〇2, and is composed of; Substituted with 1-4 Re. 20 In some embodiments, A is a heteroaryl containing 5-1 〇 (eg, 5-8) atoms, (a) including a substituted ring atom, selected from s a group of (〇) and s〇2; and (b) optionally substituted with ι, 4 (eg, 13, 丨_2, 丨, eg, 1-3) Re. In some embodiments, A a heteroaryl group containing a ruthenium 5, 1 〇 (for example, 5-8) atom, wherein (4) includes a -substituted ring atom selected from the group consisting of (10) and a muscle, for example, S〇2, for example, a filament. [b] singular base Ul_ dioxide (age, where w is attached to 24 families [b] (iv) base ring system 64 200825054 of the phenyl ring portion, such as its 4th position; or W system attached To the thiophene ring moiety of the benzo[b]thienyl ring system, eg, the third position thereof. In some embodiments, A is an aryl cyclyl or heteroaryl acid 5 A base group, each of which includes 8-10 atoms and optionally 1-4 (for example, 1-3, 1-2 1, for example, l-3) Re. In certain embodiments, A is a heteroarylsulfonylcyclyl group comprising 8-10 atoms and optionally 1-4 (eg, '1-3, 1-2, 1 'such as 'l_3) Re is substituted. For example, 'A is 3,4-dichloro-2H-sulfur ratio butyl [2,3-b]. Ratio. 1,1 -10 dioxide ( For example, wherein the W is attached to the phenyl ring moiety of the thiopyran [2,3-b]pyridyl ring system, such as its 4th position; or the W is attached to the benzo[b] a pyridyl ring moiety of the thienyl ring system, such as the second or fourth position thereof. In certain embodiments, A is an arylsulfonyl ring group comprising 8-10 15 atoms And optionally substituted with 1-4 (for example, 1-3, 1-2, 1, such as, l-3) Re. For example, A is 2,3-diazo-benzoquinone [b]σ-septenyl 1 , a monooxide (eg, wherein the W is attached to the phenyl ring moiety of the benzo[b]thienyl ring system, eg, its fourth position). 20 In some embodiments, A is a cyclic group comprising (a) a substituted ring atom selected from the group consisting of S(0) and S〇2, for example, S〇2, and (b) optionally 1-4 Re When replaced Then Re may independently be a 13⁄4 group at each occurrence; a Ci-C3 alkyl group, optionally substituted with 1-2 Ra; a C1-C3 ή alkyl group; a G-C3 alkoxy group; a hydroxyl group; a cyano group; ; NRgRh ; phenyl; or 65 200825054 4-fluorophenyl. In certain embodiments 'R may independently be halo when present; CrC3 alkyl, optionally 1-2 Ra (eg, P Substituted for c(9) fertilizer; hydroxyl; cyano; or nitro. 5 In some embodiments, A is [1,2,4]-oxadiazolyl, which may be substituted with 1 Re. In some embodiments, A has the formula (〇:

1〇 其中R為歲i;鹵基；Ci-C3烧基，任意地以i_2 Ra取 代，Ci-C3鹵烧基；Ci-C3烧氧基；經基；氰基；石肖基；NRgRh ; 苯基；或4-氟苯基。在某些實施例中，f為氫；_基； 烧基’任意地以1-2 Ra(例如，Ra為C(0)NRgRh)取代；Ci-C3 鹵烷基；0-C3烷氧基；NRgRh;苯基；或4—氟苯基。在某些 15實施例中’『為氫；鹵基；C1-C3烧基，任意地以1—2 Ra (例 如’ Ra為C(0)NRgRh)取代；羥基；氰基；或硝基。 變數Rf 在一些實施例中，RfK各次出現時為·· (i_F) -S(0)nRn 或-NRkS(0)nRn，其中 n 係 〇、i 或 2(例 如，1或2); 66 200825054 (ii-F) -_kc(〇)NRgRh或-NRkC(〇)〇RJ ; 和/或 (⑴―F)含有5-10(例如，5_7)原子之雜環基， 以1側乳基取代並任意地以卜3 (例如，卜2、^取;； —(,1V F) 3有5—1G(例如，5-7)原子之雜環烯基或1H_ 本开咪唾，其之每_係任意地以13(例如，卜2、⑽取代。 10 15 20 在一些實施例中，下列組合之任一者可用於定義Ri: • (i-F)和（ii-F)、或（i-F)和（iiiF)、或 (i-F)和（iv-F)、或（iii_F)和（iv_F);或/ • (i-F)、、和（iii_F);或 • (i-F) 、 （ii-F) 、 （iii-F)、和(ivF), 在一些實施例中’ Rf為一s⑻nRn(例如，__η)。在實 施例中’ t Rn係Rj時’則R,不為氫。在實施例中，η為㈧ 或η為1或2。 在一些實施例中，『為Cl_Cio(例如，Cl_C5或CK：4 (VC8)烷基或例如，（^或Ci—⑴齒烷基，任意地 以1-2 Ra取代。 在某些實施例中，R、Ci—G。（例如,Cl-Ca^ C^Cs,ic C3 Cs)烧基，任意地以1〜2(例如，l)Ra取代。 67 200825054 在某些實施例中，Rn為未經取代之分枝狀或非分枝狀 的 Cl-Cl。（例如 ’ Cl_C5、Cl_C3、C2-C8、或 C3-C8)烧基。在實 施例中，Rn為未經取代的G-Cs烷基。例如，Rn為甲基（CH3)。 如其他範例，Rn為乙基（CH2CH3)。如另一範例，Rn為異丙 5 基（CH(CH3)2)。在另一範例中，1^為 CH2CH2CH3、CH(CH3)2、 或 CH(CH3)CH2CH3。 在某些實施例中’ Rn為Cl_ClO(例如’ C1-C5或Cl_C3)鹵 烷基。例如，Rn為 CF3 或 CH2CH2CH2C1。 在某些實施例中，Rn為經1-2(例如，l)Ra取代的C2-C8 10 烷基或C3-C8烷基。Ra為羥基；Ci-Cs烷氧基；NRgRh ;含有 8-10原子之芳基雜環基，可任意地以1-3 Rb (例如，側 氧基）取代；或C(0)0t;或Ra為羥基；G-Cs烷氧基；NRgRh ; 鹵基；含有8-10原子之芳基雜環基，可任意地以1-3 Rb 取代；氰基；或c(0)0f。例如，舉例來說，Rn為分枝狀或 15 非分枝狀的C3-C8烷基，其係以1-2(例如，1) Ra取代。在 某些實施例中，Ra為： (i) 羥基；或 (ii) Ci-G烷氧基（例如，0CH3);或 (iii) NRgRh (例如，Rg和Rh可相互獨立地為氫；Ci-C6 20 烧基’任意地以1 _2 Ra取代；C7-C1G芳烧基’任意地以1 -2Wherein R is the year i; a halogen group; a Ci-C3 alkyl group, optionally substituted with i_2 Ra, a Ci-C3 halogen group; a Ci-C3 alkoxy group; a thiol group; a cyano group; a stone succinyl group; NRgRh; Or 4-fluorophenyl. And R. ; NRgRh; phenyl; or 4-fluorophenyl. In some 15 examples, "hydrogen;halo; C1-C3 alkyl, optionally substituted with 1-2 Ra (e.g., 'Ra is C(0)NRgRh); hydroxy; cyano; or nitro. Variable Rf In some embodiments, each occurrence of RfK is (i_F) -S(0)nRn or -NRkS(0)nRn, where n is 〇, i or 2 (eg, 1 or 2); 200825054 (ii-F) -_kc(〇)NRgRh or -NRkC(〇)〇RJ ; and/or ((1)-F) a heterocyclic group containing 5-10 (for example, 5-7) atoms, substituted with a 1-sided lactide group And optionally arbitrarily 3 (for example, 卜2, ^;; - (, 1V F) 3 has a heterocyclic alkenyl group of 5 - 1G (for example, 5-7) atoms or 1H_ _ is optionally substituted by 13 (eg, Bu 2, (10). 10 15 20 In some embodiments, any of the following combinations may be used to define Ri: • (iF) and (ii-F), or (iF) And (iiiF), or (iF) and (iv-F), or (iii_F) and (iv_F); or / (iF), , and (iii_F); or • (iF), (ii-F), (iii-F), and (ivF), in some embodiments 'Rf is a s(8)nRn (eg, __η). In the embodiment 't Rn is Rj' then R, not hydrogen. In an embodiment, η is (8) or η is 1 or 2. In some embodiments, "is Cl_Cio (eg, Cl_C5 or CK: 4 (VC8) alkyl or, for example, (^ or Ci-(1) dentate alkyl, optionally 1- 2 Ra replacement In certain embodiments, R, Ci-G. (eg, Cl-Ca^C^Cs, ic C3 Cs) is optionally substituted with 1 to 2 (eg, 1) Ra. 67 200825054 In some embodiments, Rn is unsubstituted branched or non-branched Cl-Cl (eg, 'Cl_C5, Cl_C3, C2-C8, or C3-C8) alkyl. In an embodiment, Rn is Unsubstituted G-Cs alkyl. For example, Rn is methyl (CH3). As another example, Rn is ethyl (CH2CH3). As another example, Rn is isopropyl 5 (CH(CH3)2) In another example, 1 is CH2CH2CH3, CH(CH3)2, or CH(CH3)CH2CH3. In certain embodiments 'Rn is Cl_ClO (eg, 'C1-C5 or Cl_C3) haloalkyl. For example, Rn is CF3 or CH2CH2CH2C1. In certain embodiments, Rn is C2-C810 alkyl or C3-C8 alkyl substituted with 1-2 (eg, 1) Ra. Ra is hydroxy; Ci-Cs alkoxy NRgRh; an arylheterocyclic group having 8 to 10 atoms, optionally substituted with 1-3 Rb (for example, a pendant oxy group); or C(0)0t; or Ra is a hydroxyl group; G-Cs alkoxy group; ; NRgRh ; a halogen group; an arylheterocyclic group having 8 to 10 atoms, optionally substituted with 1-3 Rb; a cyano group; or a c(0)0fFor example, Rn is a branched or 15 non-branched C3-C8 alkyl group substituted with 1-2 (e.g., 1) Ra. And R&lt -C6 20 alkyl group 'optionally substituted with 1 _2 Ra; C7-C1G aryl group' arbitrarily 1 - 2

Ra取代；-C(0)Rj;或-S(0)nRm;例如，Ra 為 NH2、NHCH3、NH(Et)、 或NH(y-丙基））；或 (iv) 氰基；或 (v) 含有8-20，例如8-10，原子之芳基雜環基，可任 68 200825054 意地以1-4，例如1-2 Rb(例如，側氧基，例如，Ra為為鄰 苯二甲醯亞胺基）取代；或 (vi) C(0)0Rj (例如，（：（0)0013或（：（0)01〇。 在某些實施例中，Ra可被接附至該烷基的二級或三級 5 碳原子。 在一些實施例中，Rn為分枝狀或非分枝狀的Ci_Cs (例 如，Ci，C2,或c3)烷基，其係以1 Ra取代。在某些實施例 中，Ra為： 10 (i)經基；或 (iii) NRgRh ;或 (iv) 氰基；或 (v) 含有8-20 ’例如8-10 ’原子之芳基雜環基’可任 意地以1-4，例如1-2 Rb(例如，側氧基，例如，Ra為為鄰 15 苯二甲醯亞胺基）取代。 在某些實施例中，當Rn係經一個或多個1^取代之烷 基，且Ra係NRgRh時，則Rg和Rh可各自獨立地為， (i)氫；或 20 (ii) CrG 烷基（例如，CH3、CH2CH3、或 CH(CH3)CH2CH3) 或鹵烧基（例如’ CH2CH2F或CH2CH2CI) ’其之每一係任意地 以氰基取代；或 (iii) C2-ClD婦基或C2-C20快基（例如’ C3稀基或快 基）；或 69 200825054 (IV) C7 C2〇芳烷基（例如，苄基），其係任意地以鹵基 (例如，氟或氯）取代；或 (v) C(〇W(例如，f為CH3或經-C00H取代的苯基）或 S〇2lT (例如，為 CH3)。 例如R和R之一者為氫或Ci-G烧基；且另一者為·· (11) 〇C8(例如，Cl —C5)烧基（例如，CH3、CH2CH3、或 CH(CH3)CH2CH3)4 , CH2CH2p 5il CH2CH2C1), 每一係任意地以氰基取代；或 (ill) c2-Cn)(例如，c2—c6)烯基或 C2_Ci。（例如，C2-Ce) 10炔基（例如，C3烯基或炔基）；或 (iv) Oc2。（如’ c7—ClQ)芳烷基（例如，节基），其係任 意地以鹵基（例如，氟或氯）取代；或 (V) C(0)w (例如，Rj為CH3或經_c〇〇H取代的苯基） 或S〇2Rra (例如，『為CJ}3)。 15 在一些實施例中，Rn為—NRgRh。 在某些實施例中，俨和Rh可各自獨立地為·· (Ο氫；或 (ii) CrCn)(例如，〇C7、C「C6、C6、匕、c2-C8、C2、 20 C3-C8)烷基（分枝狀或非分枝狀，視情況而定），任意地以 1-2(例如，1) Ra取代；或 (iii) C6-Cn)芳基（例如，苯基），任意地以卜％例如， 1 2、1) R (例如，Ci至C3烧基，任意地以I ? Ra取代· 鹵素；-CN或-C〇2R〇取代； 70 200825054 (iv) O-Ci。芳烷基（例如苄基），任意地以1-3(例如， 1-2、l)Rb (例如，Ci至C3院基，任意地以1-2 Ra取代； 鹵素；-CN或-C〇2Rj)取代；或 (v) C?-Cio環烷基，任意地以1—3(例如，卜2、l)Rb 5 取代；或 (vi) -C(0)RJ 。 在某些實施例中，Rg* Rh可各自獨立地為氫；G-Ci。烷 基，任意地以1-2(例如，1) Ra取代；c7-Cw芳烷基，任意 1〇 地以 1-3(例如，1-2、1) Rb取代；或—c(〇)RJ。 在某些實施例中，Rg和Rh可各自獨立地為氫；未經 取代之Ci-C6烷基；經羥基或Ci-C3烷氧基取代之c2-C8烷 基；苄基；或-C(0)CH3。 15 在某些實施例中，Rg和Rh之一者為氫或Cl—C3烷基； 且另一者為： (ii) Cl~~ClO(例如 ’ C1-C7、Cl-C6、Cl_C3、Cl、C2-Cs、C2、 C3-C8)烧基或鹵烧基（例如，烧基，如，分枝狀或非分枝狀 20的），其之每一係任意地以1-3(例如，1) Ra取代；或 (iii) C6-Cig芳基（例如，苯基），任意地以u(例如， 1 -2、1) Rd取代；或 (iv) Cr·G。芳烷基（例如苄基），任意地以卜3(例如， 1-2、l)Rb取代；或 71 200825054 (v) CrU環烷基，任意地以1-3(例如，1-2、1) Rb 取代；或 (vi) -C(0)Rj 。 5 在某些實施例中，Rg和Rh可皆為： (i)氫；或 (iv) C7-Ci〇芳烧基（例如节基），任意地以1-3(例如， 1-2、l)Rb取代。在實施例中，1^為OCW例如，CrU'CrO C1-C3)烧氧基（例如，OCH3)。 10 在某些實施例中，Rn為-N(H)(Rh)、-N(CH3)(Rh)、或 -N(CH2CH3)(Rh)。 在某些實施例中，Rh為未經取代的Ci-C6烧基（例如， CH3、CH2CH3、分枝狀或非分枝狀的C3-C6烧基）；C2-C8烧基（例 15 如，分枝狀或非分枝狀的C3-C8烷基），其係以1 Ra取代。 在某些實施例中，Ra為羥基、CrCs烷氧基（例如，0CH3)、 NRgRh(例如，NH2)、或氰基，較佳為羥基。 在某些實施例中，Rh為C7-C1Q芳烷基（例如苄基），可任 意地以1 Rb(例如，鹵基，例如，氟；或CrC6烷氧基，如， 20 OCHs)取代。 在某些實施例中，Rh為-C(0)Rj(例如，-C(0)CH3)。 在一些實施例中，Rn為含有5-10(例如，5-8、5-6)原 子之雜環基，可任意地以1-5(例如，1-4、1-3、1-2、1， 72 200825054 例如，1) Rb取代。 在某些實施例中，Rn為嗎琳-4-基、1-派唆基、4-旅咬 基、略嗪-1-基、或吡咯啶-；[_基，其之每一係任意地以 1-3(例如’ 1-2、1) Rb取代。在某些實施例中，矿為Cl—c3 5烷基或-c(〇)〇Rj[例如，r為οc4烷基，例如，第三丁基， 或R為Cl-C4烧基、C7-C20(例如’ C7-C1。）芳院基，例如， 苄基]。 在一些實施例中，]^為Ct_Ci。芳烷基（例如，苄基），任 10 意地以1-3(例如，1—2、1) Rb取代。在某些實施例中，Rb 為G-C3烷基，其係任意地以丨_2(例如，1) Ra取代；鹵基； 氰基；或C(0)0Rj。在某些實施例中，P為Ci_C3烷基（例 如，ch3)，其係任意地以i Ra(例如，c(0)0Rj，如，c(〇)〇CH3) 取代；或鹵基（例如，氟）。 15 在一些實施例中，Rn為C3-C8環烷基（例如，環戊基）， 任意地以1-3(例如，1-2、i)Rb取代。 在些實施例中’ R為C2-Ce稀基（例如，浠丙基、1 一 丙稀基），任意地以1-2 Rc取代。 20 在一些貫施例中，R係Ce-ClG芳基，任意地以1—2 Rd 取代。在某些實施例中，1^為Cl_C3烷基，其係任意地以 1 -2(例如，l)Ra取代；鹵基；氰基；或c(0)0f。 73 200825054 在一些實施例中，^為-NRkS(0)nRn。在某些實施例中， Rk為氫。在某些實施例中，^為Cl—C6烷基（CH3、CH2ch3)， 任思地以卜2 Ra取代；或Cg-Cig芳基（例如，苯基），任意 地以1-2 Rd (例如，ch3)取代。 5 在一些實施例中，Rf g—NRkC(〇)〇Rj 或—NRkc(〇)NRgRh。 在某些實施例中，Rk為氫。在某些實施例中，Rg、Rh、和Rj 可各自獨立地為氫；Ci-Ce娱:基，係任意地以1_2 Ra (例如， 氯）取代或C6-Go芳基，係任意地以卜2 Rd (例如，CH3)取 1〇代。在某些貫施例中，K為Ci-C6烧基，係任意地以1—2 Ra(例 如，氯）取代。在某些實施例中，P和Rh之一者為氫。 在一些實施例中，Rf為： (i) 含有5-7原子之雜環基，係以丨側氧基取代並任 15 意地以1-2 Re取代；或 (ii) 含有5-7原子之雜環烯基或1H-苯并咪唑，其之 每一係任意地以1-2 Re取代。 在某些實施例中，^為4, 5-二氫噁唑基、2—側氧基— 咪唑啶基、4, 5-二氫-1H-咪唑基、丨，2, 5, 6-四氫-嘧啶基、 20 5, 6—二氫·~2Η—[丨，3]噁嗪基、或2-側氧基—唑啶基，其之每 一係任意地以1-2 Re取代。 在某些實施例中，1^為111-苯并咪唑。 在某些實施例中，Re於各次出現時係獨立地為G至 G烷基（例如，CH3)或鹵烷基，其之每一係任意地以 74 200825054 R (例如’ C(0)0Rj，如C(0)0H)取代；或苯基。Ra substituted; -C(0)Rj; or -S(0)nRm; for example, Ra is NH2, NHCH3, NH(Et), or NH(y-propyl)); or (iv) cyano; or v) an arylheterocyclyl group containing 8-20, for example 8-10, atoms, may be 68 200825054 intended to be 1-4, such as 1-2 Rb (for example, a pendant oxy group, for example, Ra is phthalic acid) Mercapto imine) substitution; or (vi) C(0)0Rj (eg, (:(0)0013 or (:(0)01〇. In certain embodiments, Ra may be attached to the alkane Secondary or tertiary 5 carbon atoms of the radical. In some embodiments, Rn is a branched or non-branched Ci_Cs (eg, Ci, C2, or c3) alkyl group, which is substituted with 1 Ra. And R. 'Alternatively substituted with 1-4, such as 1-2 Rb (eg, pendant oxy group, for example, Ra is an ortho 15 phthalimido). In certain embodiments, when Rn is passed through a Or a plurality of substituted alkyl groups, and when Ra is NRgRh, then Rg and Rh may each independently be (i) hydrogen; or 20 (ii) CrG alkyl (eg, CH3, CH) 2CH3, or CH(CH3)CH2CH3) or a halogenated group (eg 'CH2CH2F or CH2CH2CI)' each of which is optionally substituted with a cyano group; or (iii) a C2-ClD base or a C2-C20 fast radical (eg 'C3 dilute or fast radical; or 69 200825054 (IV) C7 C2 aralkylene (eg, benzyl), optionally substituted with a halo group (eg, fluoro or chloro); or (v) C ( 〇W (for example, f is CH3 or a phenyl substituted by -C00H) or S〇2lT (for example, CH3). For example, one of R and R is hydrogen or a Ci-G alkyl group; and the other is (11) 〇C8 (eg, Cl—C5) alkyl (eg, CH3, CH2CH3, or CH(CH3)CH2CH3)4, CH2CH2p5ilCH2CH2C1), each of which is optionally substituted with a cyano group; or (ill) C2-Cn) (eg, c2-c6) alkenyl or C2_Ci. (eg, C2-Ce) 10 alkynyl (eg, C3 alkenyl or alkynyl); or (iv) Oc2 (eg 'c7-ClQ) An aralkyl group (eg, a benzyl group) optionally substituted with a halo group (eg, fluoro or chloro); or (V) C(0)w (eg, Rj is CH3 or substituted with _c〇〇H) Phenyl) or S〇2Rra (for example, "CJ}3). 15 In some embodiments, Rn is -NRgRh. In certain embodiments, ruthenium and Rh may each independently be (·hydrogen; or (ii) CrCn) (eg, 〇C7, C “C6, C6, 匕, c2-C8, C2, 20 C3- C8) alkyl (branched or non-branched, as the case may be), optionally substituted with 1-2 (eg, 1) Ra; or (iii) C6-Cn) aryl (eg, phenyl) , optionally, in the form of, for example, 1, 2, 1) R (for example, Ci to C3 alkyl, optionally substituted by I? Ra, halogen; -CN or -C〇2R〇; 70 200825054 (iv) O- Ci. Aralkyl (e.g., benzyl), optionally 1-3 (e.g., 1-2, l) Rb (e.g., Ci to C3, optionally substituted with 1-2 Ra; halogen; -CN or -C〇2Rj) substituted; or (v) C?-Ciocycloalkyl, optionally substituted with 1-3 (eg, 2, 1) Rb 5; or (vi) -C(0)RJ. In some embodiments, Rg*R may each independently be hydrogen; G-Ci. alkyl, optionally substituted with 1-2 (eg, 1) Ra; c7-Cw aralkyl, optionally 1 - 1 3 (eg, 1-2, 1) Rb substitution; or -c(〇)RJ. In certain embodiments, Rg and Rh may each independently be hydrogen; unsubstituted Ci-C6 alkyl; Or Ci-C3 alkoxy Substituted c2-C8 alkyl; benzyl; or -C(0)CH3. 15 In certain embodiments, one of Rg and Rh is hydrogen or Cl-C3 alkyl; and the other is: (ii Cl~~ClO (eg 'C1-C7, Cl-C6, Cl_C3, Cl, C2-Cs, C2, C3-C8) alkyl or haloalkyl (eg, alkyl, eg, branched or non-fractional) Each of the dendrimers 20) is optionally substituted with 1-3 (eg, 1) Ra; or (iii) a C6-Cig aryl group (eg, phenyl), optionally with u (eg, 1 - 2, 1) Rd substituted; or (iv) Cr·G. aralkyl (for example benzyl), optionally substituted with 3 (for example, 1-2, 1) Rb; or 71 200825054 (v) CrU naphthenic a radical, optionally substituted with 1-3 (eg, 1-2, 1) Rb; or (vi) -C(0)Rj. 5 In certain embodiments, both Rg and Rh may be: (i) hydrogen Or (iv) a C7-Ci aryl group (eg, a benzyl group), optionally substituted with 1-3 (eg, 1-2, 1) Rb. In an embodiment, 1^ is OCW, for example, CrU'CrO C1-C3) alkoxy (eg, OCH3). 10 In certain embodiments, Rn is -N(H)(Rh), -N(CH3)(Rh), or -N(CH2CH3)(Rh) In certain embodiments, Rh is an unsubstituted Ci-C6 alkyl group (eg, For example, CH3, CH2CH3, branched or non-branched C3-C6 alkyl); C2-C8 alkyl (Example 15, eg, branched or non-branched C3-C8 alkyl), Replaced with 1 Ra. In certain embodiments, Ra is hydroxy, CrCs alkoxy (eg, 0CH3), NRgRh (eg, NH2), or cyano, preferably hydroxy. In certain embodiments, Rh is a C7-C1Q aralkyl group (e.g., benzyl), which may be optionally substituted with 1 Rb (e.g., halo, e.g., fluoro; or CrC6 alkoxy, e.g., 20 OCHs). In certain embodiments, Rh is -C(0)Rj (eg, -C(0)CH3). In some embodiments, Rn is a heterocyclic group containing 5-10 (eg, 5-8, 5-6) atoms, optionally 1-5 (eg, 1-4, 1-3, 1-2 , 1, 72 200825054 For example, 1) Rb replacement. In certain embodiments, Rn is morphin-4-yl, 1-hydrazino, 4-Benbityl, oxazin-1-yl, or pyrrolidine-; [-based, each of which is optional The ground is substituted with 1-3 (for example, '1-2, 1) Rb. In certain embodiments, the ore is Cl-c3 5 alkyl or -c(〇)〇Rj [eg, r is οc4 alkyl, for example, a third butyl group, or R is a Cl-C4 alkyl group, C7- C20 (e.g., 'C7-C1.) aryl base, for example, benzyl]. In some embodiments, ^^ is Ct_Ci. An aralkyl group (e.g., benzyl) is optionally substituted with 1-3 (e.g., 1-2, 1) Rb. In certain embodiments, Rb is G-C3 alkyl optionally substituted with 丨_2 (eg, 1) Ra; halo; cyano; or C(0)0Rj. In certain embodiments, P is Ci_C3 alkyl (eg, ch3), which is optionally substituted with i Ra (eg, c(0)0Rj, eg, c(〇)〇CH3); or halo (eg, ,fluorine). In some embodiments, Rn is C3-C8 cycloalkyl (eg, cyclopentyl), optionally substituted with 1-3 (eg, 1-2, i) Rb. In some embodiments, 'R is a C2-Ce dilute group (e.g., fluorenyl, 1-propyl), optionally substituted with 1-2 Rc. 20 In some embodiments, the R-based Ce-ClG aryl group is optionally substituted with 1-2 Rd. In certain embodiments, 1 is a Cl_C3 alkyl group, optionally substituted with 1-2 (e.g., 1) Ra; halo; cyano; or c(0)0f. 73 200825054 In some embodiments, ^ is -NRkS(0)nRn. In certain embodiments, Rk is hydrogen. In certain embodiments, ^ is Cl-C6 alkyl (CH3, CH2ch3), optionally substituted with 2 Ra; or Cg-Cig aryl (eg, phenyl), optionally 1-2 Rd ( For example, ch3) is substituted. 5 In some embodiments, Rf g—NRkC(〇)〇Rj or —NRkc(〇)NRgRh. In certain embodiments, Rk is hydrogen. In certain embodiments, Rg, Rh, and Rj may each independently be hydrogen; Ci-Ce: radical, optionally substituted with 1_2 Ra (eg, chloro) or C6-Go aryl, optionally Bu 2 Rd (for example, CH3) takes 1 generation. In some embodiments, K is a Ci-C6 alkyl group and is optionally substituted with 1-2 Ra (e.g., chlorine). In certain embodiments, one of P and Rh is hydrogen. In some embodiments, Rf is: (i) a heterocyclic group containing 5-7 atoms, substituted with a fluorenyloxy group and optionally substituted with 1-2 Re; or (ii) containing 5-7 atoms Heterocyclenyl or 1H-benzimidazole, each of which is optionally substituted with 1-2 Re. And X. Hydrogen-pyrimidinyl, 20 5 , 6-dihydro·~2Η-[丨,3]oxazinyl, or 2-oxooxy-oxazolidinyl, each of which is optionally substituted with 1-2 Re. In certain embodiments, 1 is 111-benzimidazole. In certain embodiments, Re, in each occurrence, is independently G to G alkyl (eg, CH3) or haloalkyl, each of which is optionally at 74 200825054 R (eg, 'C(0) 0Rj, such as C(0)0H) substituted; or phenyl.

在一些實施例中，R4、R5和R6之每一者係互相獨立地 5為氮或_基（例如，IO。在某些實施例中，R4、R5和R6 之每一者為氫。在某些實施例中，R4、R5和R6之每一者為 氯’且R7為非氫者（例如，Ci_C3鹵烷基，如Cf3)。 在一些實施例中，R7為氫、鹵基、氰基、Ci_Ci()(例如， CrCe 或 c3)烧基、或 Cl_Cl。（例如，Ci_C6 或 Ci_C3)鹵烷 ίο 基、c2〇 烧氧基（例如，甲氧基）、c(〇)〇Rj、c(〇)NRgRh、 或 S〇2Rm。 在一些實施例中，R7為氫、鹵基、氰基、Ci_Ciq(例如， C!-C6或G-C3)烷基、或ο-匕〇(例如，CrC6或CrCs)鹵烷 基、或 S〇2Rra。 15 在一些實施例中，R7為氫、氟、氯、氰基七-Cn)(例 如，CrCe 或 G-Cs)烧基、或 Cl—Cl。（例如，Ci_C6 或 Ci_c〇 鹵烧基、Cl-C2Q烧氧基（例如，甲氧基）、c(〇)〇Rj、 C(0)NRgRh、或 S〇2Rra。 在一些實施例中，R為氫；氯或溴（例如，氯）、氰基、 20 Ci-Cn)(例如，Ci-OCrCs)烧基、或 Ci—Ci。（例如，OCrC3) 鹵烷基、或S〇2Rm。 在一些實施例中，R7為鹵基、氰基、Ci—Ci〆例如，Ci—Ce 或CrCs)烧基、或CrCH)(例如，Cl-C6或Ci_C3)齒烧基、 C1-C20 烧氧基（甲氧基）、C(0)〇Rj、c(〇)NRgRh、戋 s〇2Rm 〇 75 200825054 在一些實施例中’ R7為鹵基、氰基、Ci—G。（例如，Ci —C6、 CrC3)炫基、或 C!-Ci。（例如，Cl_c6、Cl—c3)函烧基、或 s〇2Rm。 在一些實施例中，R7為氟、氣、氰基、Ci—Ciq(例如， 匕-匕或Ci-c3)燒基、或Ci—CiQ(例如，Ci-C4 Ci_c3)鹵烷 5 基、Cl一C20 烧氧基（例如，甲氧基）、c(〇)〇Rj、（X〇)NRgRh、 或 S〇2Rffl。 在一些實施例中，R7為氯或溴（例如，氣）、氰基、 CrCu)(例如 ’ CrCrCi-c3)烷基、G-C1Q(例如，CrCrCrCs) 鹵烷基、或S〇2Rm。 0 在一些實施例中，R7為氯、氰基、G-Ce烷基、OCs鹵 烧基、Cl—Ce 烷氧基、C(0)0Rj、C(0)NRgRh、或 S〇2Rm。 在 t貫細*例中’ R為_基、Cl-ClG(例如，Cl-C6或Cl_C3) 烧基、Ci-Cu)(例如，〇-c6或C厂c3)鹵烷基'CrG。烷氧基（例 如’甲氧基）、C(0)〇Rj、c(〇)NRgRh、或 S〇2Rffl。 5 在一些實施例中，R7為鹵基七-Ch)(例如七-OOCs) 烷基、Cui(例如，〇C6、CrCs)鹵烷基、或S〇2Rm。 在一些實施例中，R7為氟、氯、〇C1Q(例如，CrC6或 C广C3)烧基、匕-C1()(例如，Ci-C6或CrC3)鹵烧基、（：广。2〇烧 氧基（例如’甲氧基）、c(0)0Rj、C⑹NRf、或s〇2tr。 〇 在一些實施例中，R7為氯或溴（例如，氯）；C!。（例 如 ’ Ci-C6、Crc3)烷基、CrCh)(例如，CrCe、OC3)鹵烷基、 或 S〇2Rm。 在一些實施例中，R7為氟、C(0)0Rj、或C(0)NRgRh。 在一些實施例中，R7為C(〇)〇t或C(0)NRgRh。 76 200825054 在某些實施例中，R7為氫；氟、氣基；氰基；CH3;CF3; 或SO2CH3。在某些實施例中，R7為氟；氯；氰基；CH3; CF3 ; S〇2CH3 ; S〇2CH2CH3 ;或 S〇2CH(CH3)2。在某些實施例中，R7 為 5 非氟者’例如’ R7為氯；CH3 ; CF3 ;或SO2CH3。 在某些實施例中，1?7為Ci-Ce (例如，G-C3)鹵烷基（例 如，CF3) 〇 · 在某些實施例中，R7為鹵基（例如，氟或氯，例如，氯）。 在某些實施例中，R7為S〇2Rra(例如，Γ為CH3、CH2CH3、 10 或 CH(CH3)2)。 在某些實施例中，R7為氫或氰基。 在某些實施例中，R7為G-Go烷氧基（例如，0CH3)。 在某些實施例中，R7為C(0)0Rj (例如，（：（0)011或（：（0)0(：113) 或 C(0)NRgRh (例如，C(0)NH2)。· 15 在一些實施例中，當Rf為S〇2Rn且Rn為C〗-C6烷基（例 如，CHs)時，則R7為非氟者。 在一些實施例中，落於上述定義中之R7為非ii基者（例 如，氟）。 20 一化合物之子集包括其中R3為式（D)者： 77 200825054In some embodiments, each of R4, R5, and R6, independently of each other, 5 is a nitrogen or a yl group (eg, IO. In certain embodiments, each of R4, R5, and R6 is hydrogen. In certain embodiments, each of R4, R5, and R6 is chloro' and R7 is non-hydrogen (eg, Ci_C3 haloalkyl, such as Cf3). In some embodiments, R7 is hydrogen, halo, cyanide. a group, a Ci_Ci() (for example, CrCe or c3) alkyl group, or a Cl_Cl. (for example, Ci_C6 or Ci_C3) a halogen alkane, a c2 alkoxy group (for example, a methoxy group), a c(〇)〇Rj, c(〇)NRgRh, or S〇2Rm. In some embodiments, R7 is hydrogen, halo, cyano, Ci_Ciq (eg, C!-C6 or G-C3) alkyl, or ο-匕〇 (eg, , CrC6 or CrCs) haloalkyl, or S〇2Rra. 15 In some embodiments, R7 is hydrogen, fluoro, chloro, cyano-7-Cn) (eg, CrCe or G-Cs), or Cl- Cl. (For example, Ci_C6 or Ci_c〇 halogen, Cl-C2Q alkoxy (eg, methoxy), c(〇)〇Rj, C(0)NRgRh, or S〇2Rra. In some embodiments, R It is hydrogen; chlorine or bromine (for example, chlorine), cyano, 20 Ci-Cn) (for example, Ci-OCrCs), or Ci-Ci. (for example, OCrC3) haloalkyl, or S〇2Rm. In some embodiments, R7 is halo, cyano, Ci-Ci, for example, Ci-Ce or CrCs), or CrCH) (eg, Cl-C6 or Ci_C3) dentate, C1-C20 oxygenated (Methoxy), C(0)〇Rj, c(〇)NRgRh, 戋s〇2Rm 〇75 200825054 In some embodiments 'R7 is halo, cyano, Ci-G. (for example, Ci - C6, CrC3) dazzle, or C!-Ci. (for example, Cl_c6, Cl-c3), or s〇2Rm. In some embodiments, R7 is fluoro, gas, cyano, Ci-Ciq (eg, 匕-匕 or Ci-c3) alkyl, or Ci-CiQ (eg, Ci-C4 Ci_c3) halo-5, Cl A C20 alkoxy group (e.g., methoxy), c(〇)〇Rj, (X〇)NRgRh, or S〇2Rffl. In some embodiments, R7 is chloro or bromo (e.g., gas), cyano, CrCu) (e.g., 'CrCrCi-c3) alkyl, G-C1Q (e.g., CrCrCrCs) haloalkyl, or S〇2Rm. In some embodiments, R7 is chloro, cyano, G-Ce alkyl, OCs halo, Cl-Ce alkoxy, C(0)0Rj, C(0)NRgRh, or S〇2Rm. In the case of t-thin, 'R is a _ group, a Cl-ClG (e.g., Cl-C6 or Cl_C3) alkyl group, a Ci-Cu) (e.g., 〇-c6 or C plant c3) haloalkyl 'CrG. Alkoxy (e.g., 'methoxy), C(0), Rj, c(〇)NRgRh, or S〇2Rffl. 5 In some embodiments, R7 is halo-7-Ch) (eg, seven-OOCs) alkyl, Cui (eg, 〇C6, CrCs) haloalkyl, or S〇2Rm. In some embodiments, R7 is fluoro, chloro, hydrazine C1Q (eg, CrC6 or C-C3) alkyl, hydrazine-C1 () (eg, Ci-C6 or CrC3) halogen, (: 2 〇 2 〇 Alkoxy (eg 'methoxy'), c(0)0Rj, C(6)NRf, or s〇2tr. In some embodiments, R7 is chlorine or bromine (eg, chlorine); C! (eg 'Ci- C6, Crc3) alkyl, CrCh) (eg, CrCe, OC3) haloalkyl, or S〇2Rm. In some embodiments, R7 is fluoro, C(0)0Rj, or C(0)NRgRh. In some embodiments, R7 is C(〇)〇t or C(0)NRgRh. 76 200825054 In certain embodiments, R7 is hydrogen; fluoro, carbyl; cyano; CH3; CF3; or SO2CH3. In certain embodiments, R7 is fluoro; chloro; cyano; CH3; CF3; S〇2CH3; S〇2CH2CH3; or S〇2CH(CH3)2. In certain embodiments, R7 is 5 non-fluorinated', e.g., R7 is chloro; CH3; CF3; or SO2CH3. In certain embodiments, 1-7 is Ci-Ce (eg, G-C3) haloalkyl (eg, CF3). In certain embodiments, R7 is halo (eg, fluoro or chloro, eg, ,chlorine). In certain embodiments, R7 is S〇2Rra (eg, Γ is CH3, CH2CH3, 10 or CH(CH3)2). In certain embodiments, R7 is hydrogen or cyano. In certain embodiments, R7 is G-Go alkoxy (eg, 0CH3). In certain embodiments, R7 is C(0)0Rj (eg, (:(0)011 or (:(0)0(:113) or C(0)NRgRh (eg, C(0)NH2). · 15 In some embodiments, when Rf is S〇2Rn and Rn is C-C6 alkyl (eg, CHs), then R7 is non-fluorinated. In some embodiments, R7 falls within the above definition. A non-ii base (eg, fluorine). 20 A subset of compounds including those in which R3 is of formula (D): 77 200825054

Rf1Rf1

其中： W係一鍵；-0- ; Ch伸烷基（例如，-CH2-) ; C2-4伸炔基 5 (例如’ -C三C-) ; -0(C卜3伸烧基）-(例如，-OCH2-);或-(C卜3 伸烷基）0-(例如，-CH2〇-);Wherein: W is a bond; -0-; Ch alkyl (for example, -CH2-); C2-4 alkynyl 5 (for example, -C three C-); -0 (Cb3) - (for example, -OCH2-); or -(CBu3 alkyl)0-(for example, -CH2〇-);

Rfl、Rf2、Rf3、Rf4、和 Rf5 之一者（例如，Rfl、Rf2、或 Rf3 ; 如，1^2或 Rf3 ;如，Rf2)為： (i) -S(0)nRn、-(CHzUCOXR11、-NRkS(0)nRn、或 ίο -0S(0)nRn ;其中n於各次出現時係獨立地為1或2 ;或 (ii) -NRkC(0)NRgRh、-NRkC(0)0Rj、-0C(0)NRgRh、或 -0C(0)0f ;或 (iii) 含有5-10原子之雜環基，係以1-2側氧基取 代並任意地以1 - 3 Re取代；或 15 (iv)含有5-10原子之雜環烯基或1H-苯并咪唑，其 之每一係任意地以1-3 Re取代；或 (v) -YRf’，其中Y於各次出現時係獨立地為Ci-Ce伸 烧基、-0-、或-NR9-;且其他者之每一係獨立地為氮或Re ’ 其中1^、11、1^、1^、1^、1^、1^、和1^於各次出現時係各 78 200825054 自互相獨立地如此中任一處所定義者。 、Rf3、Rf4、和 Rf5之一者（例One of Rfl, Rf2, Rf3, Rf4, and Rf5 (for example, Rfl, Rf2, or Rf3; eg, 1^2 or Rf3; eg, Rf2) is: (i) -S(0)nRn, -(CHzUCOXR11) , -NRkS(0)nRn, or ίο -0S(0)nRn; where n is independently 1 or 2 at each occurrence; or (ii) -NRkC(0)NRgRh, -NRkC(0)0Rj, -0C(0)NRgRh, or -0C(0)0f; or (iii) a heterocyclic group containing 5-10 atoms, substituted with a 1-2 side oxy group and optionally substituted with 1-3 Re; or 15 (iv) a heterocycloalkenyl group having 5-10 atoms or 1H-benzimidazole, each of which is optionally substituted with 1-3 Re; or (v) -YRf', wherein Y is present at each occurrence Independently Ci-Ce extended alkyl, -0-, or -NR9-; and each of the other independently is nitrogen or Re' where 1^, 11, 1^, 1^, 1^, 1^ , 1^, and 1^ in each occurrence of each of the 78 200825054 from each other independently defined by one of the places, Rf3, Rf4, and Rf5 (example

在一些實施例中，Rfl、γ Rfl、Rf2、或 Rf3 ;例如，γ 側氧基取代並任意地以1—3(例如，丨―2、1)Re取代；或 (iv-F)含有5-10(例如，5-7)原子之雜環烯基或1H〜 1 -3(例如，1-2、1 )Re 10苯并咪唑，其之每一者係任意地以 取代。 在某些實施例中’ Rf]、Rf2、、R“、和f5中之四者為 氫。 在某些實施例中，Rfl、Rf2、Rf3、R“、和f5中之三者為In some embodiments, Rfl, γ Rfl, Rf2, or Rf3; for example, γ-side oxy is substituted and optionally substituted with 1-3 (eg, 丨-2, 1) Re; or (iv-F) contains 5 a heterocyclenyl group of -10 (e.g., 5-7) atoms or 1H~1 -3 (e.g., 1-2, 1) Re 10 benzimidazole, each of which is optionally substituted. In some embodiments, four of 'Rf', Rf2, R', and f5 are hydrogen. In certain embodiments, three of Rfl, Rf2, Rf3, R", and f5 are

式（B-4)、（B-5)、（B-6)、或（B-7)中所示]。 在某些實施例中，Rfl、Rf2、Ri3、Rf4、和γ中之一者（例 如，Rn、Ri2、或 Rf3;例如，Rf24 Rf3:例如，R为為—s(〇)nRn(例 20如’ n為2 ;例如，Rn為Ci-Cio烧基，係任意地以1—2 取 代；或 NRgRh)。 其他實施例可包括此中所述之更多其他特徵中的一 79 200825054 化合物之另一子集包括其中R3為式〇1者. RA22It is shown in formula (B-4), (B-5), (B-6), or (B-7). And R. For example, 'n is 2; for example, Rn is a Ci-Cio alkyl group, optionally substituted with 1-2; or NRgRh.) Other embodiments may include one of the other features described herein. 79 200825054 Compound Another subset includes those in which R3 is of the formula RA1. RA22

其中： 15 R32為氫；或，如此中任一處所定義為Re (例如，齒基， 例如，氟或氯）； W如此中任一處所定義者（例如，—〇一或一鍵）； RA22和RA23之每一者係獨立地為氫或Re ;和 RA24和RA25之一者係Rf(例如，—s〇2Rn)，且另一者係氫 20 或 Re。 在某些實施例中，其限定僅RA22、RA23、RA24、和V25中 之一者為IT。RA22、RA23、R似、和係如此中任一處所定義。 其他實施例可包括此中所述之更多其他特徵中的—者。 25 化合物之另一子集包括其中： R3係含有5-10(例如，5-6)原子之雜芳基，其係（i)以 1 RlG取代，並（ii)任意地以1-2 Re取代；且 W係一鍵；以及 A具有式（B-9): 80 30 200825054 RA22Wherein: 15 R32 is hydrogen; or, any of these is defined as Re (for example, a dentate group, for example, fluorine or chlorine); W is defined in any of the places (for example, 〇 one or one bond); RA22 Each of RA and 23 is independently hydrogen or Re; and one of RA24 and RA25 is Rf (eg, -s〇2Rn), and the other is hydrogen 20 or Re. In some embodiments, it defines that only one of RA22, RA23, RA24, and V25 is IT. RA22, RA23, R, and the system are defined in any of these places. Other embodiments may include one of the many other features described herein. Another subset of 25 compounds includes wherein: R3 is a heteroaryl containing 5-10 (eg, 5-6) atoms, which is (i) substituted with 1 R1G, and (ii) optionally 1-2 Re Substituted; and W is a bond; and A has the formula (B-9): 80 30 200825054 RA22

RA25 10 (B-9) 其中： RA22和RA23之每一者係獨立地為氫或Re ;和 RA24和RA25之一者係Rf(例如，-S〇2Rn)，且另一者係氫 15 或 Re ; 在某些實施例中，其限定僅RA22、RA23、RA24、和RA25中 之一者為1^。1^22、{^23、1^24、和1^25係如此中任一處所定義。 其他實施例可包括此中所述之更多其他特徵中的一者。 2〇 化合物之另一子集包括其中： R3具有式（A-4);和 W係一鍵；且 A係含有5-8原子之雜芳基，其係（a)以1 Rf(例如， -S〇2Rn)取代，並（b)任意地以1-3 Γ取代，前提是該含有 25 5-8原子之雜芳基並非[1，2, 4]-噁二唑基。其他實施例可 包括此中所述之更多其他特徵中的一者。 化合物之另一子集包括其中： R3具有式（A-4);且 81 200825054 w係一鍵；以及 A係四氫啥琳基或四氫異啥琳基，其係（a)以1 ^(例 如，-S〇2Rn)取代，並（b)任意地以1-2 Re取代。其他實施例 可包括此中所述之更多其他特徵中的一者。 5 化合物之另一子集包括其中： R3具有式（A-4);且 W係一鍵；以及 A係苯并[b]噻吩基-1，1-二氧化物、3,4-二氫-2H-硫 ίο 基吡喃[2, 3-b]吡啶基-1，1-二氧化物、或2, 3-二氫苯并[b] 噻吩基-1，1-二氧化物，其之每一者係任意地以1-3 Re取 代。其他實施例可包括此中所述之更多其他特徵中的一者。 化合物之另一子集包括其中： 15 R3具有式D-l ; R32為氫或Re(例如，鹵基，如氟或氯）； W係如此中任一處所定義（例如，-0-或一鍵）；RA22和RA23之 每一者係獨立地為氫或Re;且 RA24和RA25之一者係Rf，例如： (i) 含有5-7原子之雜環基，係以1側氧基取代並任 20 意地以1-2 Re取代；或 (ii) 含有5-7原子之雜環烯基或1H-苯并咪唑，其之 每一者係任意地以1-2 Re取代；且另一者係氫或Re。 在某些實施例中，其限定僅RA22、RA23、RA24、和RA25中 之一者為1^。1^22、{^23、1^24、和1^25係如此中任一處所定義。 82 200825054 其他實施例可包括此中所述之更多其他特徵中的一者。 在這些實施例中，R32為氫；或R32為鹵基（例如，氯或 氟）。 化合物之另一子集包括其中R3具有式（E):RA25 10 (B-9) where: each of RA22 and RA23 is independently hydrogen or Re; and one of RA24 and RA25 is Rf (eg, -S〇2Rn), and the other is hydrogen 15 or Re; In some embodiments, it defines that only one of RA22, RA23, RA24, and RA25 is 1^. 1^22, {^23, 1^24, and 1^25 are defined in any of these places. Other embodiments may include one of the many other features described herein. Another subset of the 2-oxime compound includes: wherein R3 has the formula (A-4); and the W-link is a bond; and the A-line contains a heteroaryl group of 5-8 atoms, which is (a) is 1 Rf (for example, -S〇2Rn) is substituted, and (b) is optionally substituted with 1-3 ,, provided that the heteroaryl group containing 25 5-8 atoms is not [1,2,4]-oxadiazolyl. Other embodiments may include one of the many other features described herein. Another subset of compounds includes wherein: R3 has the formula (A-4); and 81 200825054 w is a bond; and the A-line tetrahydroindenyl or tetrahydroisoindolinyl, the system (a) is 1 ^ (for example, -S〇2Rn) is substituted, and (b) is optionally substituted with 1-2 Re. Other embodiments may include one of the many other features described herein. 5 another subset of compounds includes wherein: R3 has the formula (A-4); and W is a bond; and the A-line benzo[b]thienyl-1,1-dioxide, 3,4-dihydrogen -2H-sulfuro[pyridylpyrano[2,3-b]pyridinyl-1,1-dioxide, or 2,3-dihydrobenzo[b]thienyl-1,1-dioxide, Each of them is arbitrarily substituted with 1-3 Re. Other embodiments may include one of the many other features described herein. Another subset of compounds includes wherein: 15 R3 has the formula D1; R32 is hydrogen or Re (eg, halo, such as fluoro or chloro); W is as defined anywhere (eg, -0- or one-bond) Each of RA22 and RA23 is independently hydrogen or Re; and one of RA24 and RA25 is Rf, for example: (i) a heterocyclic group having 5-7 atoms, which is substituted with a 1-sided oxy group. 20 is optionally substituted with 1-2 Re; or (ii) a heterocyclic alkenyl group having 5-7 atoms or 1H-benzimidazole, each of which is optionally substituted with 1-2 Re; and the other is Hydrogen or Re. In some embodiments, it defines that only one of RA22, RA23, RA24, and RA25 is 1^. 1^22, {^23, 1^24, and 1^25 are defined in any of these places. 82 200825054 Other embodiments may include one of the other features described herein. In these embodiments, R32 is hydrogen; or R32 is halo (e.g., chlorine or fluorine). Another subset of compounds includes wherein R3 has the formula (E):

(E) 其中： ίο W係一鍵；-0_ ; Ci-3伸烧基（例如，-CH2-) ; C2-4伸快基 (例如，-C = C-) ; -0(C卜3伸烧基）-(例如，-OCH2-);或-(C卜3 伸烧基）0-(例如’ _CH2〇-); 以： (i) -S(0)nRn、-(CI^hSCOXR11、-NRkS(0)nRn、或 15 -0S(0)nRn ;或 (ii) -NRkC(0)NRgRh、-NRkC(0)0Rj、-0C(0)NRgRh、或 -0C(0)0Rj ;或 (iii) 含有5-10原子之雜環基，係以1-2侧氧基取 代並任意地以1-3 Re取代；或 20 (iv)含有5-10原子之雜環烯基或1H-苯并咪唑，其 83 200825054 之每一者係任意地以1_ 3 Re取代；或 (v) -YRf’，其中Y於各次出現時係獨立地為CrCe伸 烧基、-0-、或-NR9-;且其他者係各自獨立地為氫或Re ; 以及 5 Re於各次出現時係獨立地為鹵基；Ci-Ce烷基，任意地 以1-2Ra取代；CrCs鹵基烷基；C〗-c3烷氧基；NRgRh;苯基； 或4-氟苯基；其中Rn、η、Rk、Rf’、Rg、Rh、Rj、和Re於各 次出現時係互相獨立地如此中任一處所定義。 10 在一些實施例中，Rf為： (i-F) -S(0)nRn4-NRkS(0)nRn，其中 η係 1 或 2 ;或 (ii-F) -NRkC(0)NRgRh 或-NRkC(0)0Rj;或 (iii-F)含有5-10(例如，5-7)原子之雜環基，其係 以1側氧基取代並任意地以1-3(例如，1-2、1) Re取代； 15 或 (iv-F)含有5-10(例如，5-7)原子之雜環烯基或1H-苯并咪唑，其之每一者係任意地以1-3(例如，1-2、l)Re 取代。 20 在某些實施例中，Rf為^^⑴）^例如，η為2 ;例如， {^為CrU烷基，任意地以1-2 Ra取代；或NRgRh)。(E) where: ίο W is a bond; -0_; Ci-3 is extended (for example, -CH2-); C2-4 is extended (for example, -C = C-); -0 (CBu 3) Stretching base)-(for example, -OCH2-); or -(CBu3 stretching base) 0-(for example, ' _CH2〇-); to: (i) -S(0)nRn, -(CI^hSCOXR11 , -NRkS(0)nRn, or 15 -0S(0)nRn; or (ii) -NRkC(0)NRgRh, -NRkC(0)0Rj, -0C(0)NRgRh, or -0C(0)0Rj; Or (iii) a heterocyclic group having 5 to 10 atoms, which is substituted with a 1-2 oxy group and optionally substituted with 1-3 Re; or 20 (iv) a heterocycloalkenyl group having 5 to 10 atoms or 1H -benzimidazole, each of 83 200825054 is optionally substituted with 1-3 Re; or (v) -YRf', wherein Y is independently CrCe, -0-, or -NR9-; and the others are each independently hydrogen or Re; and 5 Re is independently a halogen group in each occurrence; Ci-Ce alkyl, optionally substituted with 1-2Ra; CrCs haloalkyl ; C - a c3 alkoxy; NRgRh; phenyl; or 4-fluorophenyl; wherein Rn, η, Rk, Rf', Rg, Rh, Rj, and Re are mutually independent in each occurrence Defined anywhere. 10 In some embodiments, Rf is (iF) -S(0)nRn4-NRkS(0)nRn, wherein η is 1 or 2; or (ii-F) -NRkC(0)NRgRh or -NRkC(0)0Rj; or (iii-F) contains a heterocyclic group of 5-10 (e.g., 5-7) atom, which is substituted with a 1-sided oxy group and optionally substituted with 1-3 (e.g., 1-2, 1) Re; 15 or (iv-F) A heterocycloalkenyl group or a 1H-benzimidazole having 5-10 (e.g., 5-7) atoms, each of which is optionally substituted with 1-3 (e.g., 1-2, l) Re. In certain embodiments, Rf is ^^(1))^, for example, η is 2; for example, {^ is a CrU alkyl group, optionally substituted with 1-2 Ra; or NRgRh).

Re可存在或不存在（即，所有沒有被…和Rf所佔據之位 置可接附至氫或Re ;或其之組合）。 在某些實施例中，W可被接附至吡啶基環的第2位置， 84 200825054 且Rf可被接附至吡啶基環的第4或第6位置。這些環更可 以1、2或3 Re (例如，鹵基，如氯；或NRgRh，如NH2)取 代。例如，W可被接附至吡啶基環的第2位置，1^可被接附 至吡啶基環的第6位置，且1 Re可被接附至吡啶基環的第 5 4位置。如其他範例，W可被接附至°比σ定基環的第2位置，Re may or may not be present (i.e., all positions not occupied by ... and Rf may be attached to hydrogen or Re; or a combination thereof). In certain embodiments, W can be attached to the second position of the pyridyl ring, 84 200825054 and Rf can be attached to the 4th or 6th position of the pyridyl ring. These rings may be substituted by 1, 2 or 3 Re (e.g., a halogen group such as chlorine; or NRgRh such as NH2). For example, W may be attached to the 2nd position of the pyridyl ring, 1^ may be attached to the 6th position of the pyridyl ring, and 1 Re may be attached to the 5th position of the pyridyl ring. As another example, W can be attached to the second position of the σ base ring.

Rf可被接附至吡啶基環的第6位置，且Re取代基可被接附 至吡啶基環的第3、第4、和第5位置。 在其他實施例中，W可被接附至吡啶基環的第3位置， 且Rf可被接附至吡啶基環的第5位置。該環更可以1、2 10 或3 Re(例如，鹵基，如氯；或NRgRh，如NIL·)取代。 其他實施例可包括此中所述之更多其他特徵中的一 者。 化合物之再另一子集包括其中R3具有式F: 15Rf may be attached to the 6th position of the pyridyl ring, and the Re substituent may be attached to the 3rd, 4th, and 5th positions of the pyridyl ring. In other embodiments, W can be attached to the 3rd position of the pyridyl ring, and Rf can be attached to the 5th position of the pyridyl ring. The ring may be substituted with 1, 2 10 or 3 Re (for example, a halogen group such as chlorine; or NRgRh such as NIL.). Other embodiments may include one of the many other features described herein. Yet another subset of compounds includes wherein R3 has the formula F: 15

85 200825054 其中Re為氫；鹵基；Ci-G烧基，任意地以i-2『取 代，Ci-C3鹵烧基；C1-C3烧氧基；經基；氰基；石肖基；NRf ; 苯基；或4-氟苯基。在某些實施例中，為氫；鹵基；Ci—C6 烧基’任意地以1-2 Ra(例如，c(0)NRgRh)取代；CrCs 5 _烷基；G-C3烷氧基，· NRgRh ,·苯基；或4-氟苯基。在某 些實施例中’ R為氮，鹵基；Ci-C3烧基，任意地以1 —2 Ra (例如，Ra為C(0)NRgRh)取代；羥基；氰基；或硝基。 其他實施例可包括此中所述之更多其他特徵中的一 者。 10 在一些實施例中，化合物可具有式（π): R4 R385 200825054 wherein Re is hydrogen; halo; Ci-G alkyl, optionally substituted by i-2, Ci-C3 halo; C1-C3 alkoxy; meridin; cyano; schiffki; NRf; Base; or 4-fluorophenyl. In certain embodiments, is hydrogen; halo; Ci-C6 alkyl is optionally substituted with 1-2 Ra (eg, c(0)NRgRh); CrCs5-alkyl; G-C3 alkoxy, · NRgRh, · phenyl; or 4-fluorophenyl. In certain embodiments, 'R is nitrogen, halo; Ci-C3 alkyl, optionally substituted with 1-2 Ra (e.g., Ra is C(0)NRgRh); hydroxy; cyano; or nitro. Other embodiments may include one of the many other features described herein. In some embodiments, the compound can have the formula (π): R4 R3

(II) 其中R2、R3、P、r5、r6、和r7係如此中任一處所定義 (同類、次類、或特定）。 在一些實施例中，該化合物可具有式（III): 86 200825054 H R3 ,R2 (ΠΙ) 其中R2、R3、和R7係如此中所定義（同類、次類、或 特定）。 在一些實施例中，該化合物可具有式（IV)或（IV-1).·(II) wherein R2, R3, P, r5, r6, and r7 are as defined in any of these places (same, subclass, or specific). In some embodiments, the compound can have the formula (III): 86 200825054 H R3 , R2 (ΠΙ) wherein R2, R3, and R7 are as defined herein (same, subclass, or specific). In some embodiments, the compound can have formula (IV) or (IV-1).

其中R2、W、A、R4、R5、R6、R7、和R32係如此中所定義 (同類、次類、或特定）。 在一些實施例中，該化合物可具有式（V):Wherein R2, W, A, R4, R5, R6, R7, and R32 are as defined herein (same, sub-class, or specific). In some embodiments, the compound can have the formula (V):

WAWA

R2 ΗR2 Η

或 ff-OOr ff-O

Η m 87 10 200825054 其中R2、W、A、R7、和R32係如此中所定義（同類、次 類、或特定）。 式（II)、（III)、（IV)、（IV-1)、（v)、和（V-1)化合物之 5 其他實施例包括此中所述之任一種或更多種特徵。 須了解此種化學實體之實際電子結構無法只以一個標 準形式（亦即路易士結構）充分表示。雖然不欲受理論所 限，但實際結構為兩種或多種標準形式之混成或加權平 均，合稱為共振形式或共振結構。共振結構並非分開的化 10 15 學實體，只可存在於紙上。其彼此間的差異只在於特定化 學實體之鍵結電子或非鍵結電子之所在位置或Γ所在」。可 能一種共振結構比另一種共振結構對混成體有更大貢獻。 a〜 π π π、貝他例面說明及圖形說明係就技藝界 已知對一特定物種為主要共振形式來作說明。 此處所述化合物可根據此處所述方法及/或習知有機 化學合成方法，而由市售起始物料及反應劑合成。此處所 述化㈣可由反應混合物中分離，進—步藉諸如管柱層析 術、高壓液相層析術或再結晶等方法純化。如熟諳技藏人 士了解’其它合成本文所示化學式之化合物之方法為^ 技藝人士顯然易知。此外，可以適當順序進行各 ^ 驟來獲得《之化合物。可料合成本文所親合物^ 成化學轉糾保餘枝（賴及㈣賴 。 知’例如包括說明於下列參考文獻之該等合成;:所已 Ur〇Ck ’综合有機轉換，VCH出版社⑽9) ; T w. “此 20 200825054 及P. G. M. Wuts，有機合成保護基，第2版，約翰威利父子 公司（1991);L. Fieser 及 Μ· Feiser，Fieser and Fieser’ s 有機合成反應劑，約翰威利父子公司（1994);及L. Paquette編輯，有機合成試劑百科，約翰威利父子公司 5 (1995)，及其隨後之各個版本。 喹啉-聯芳醚-颯和磺醯胺的合成 一般而言，其中W為氧（0)之化合物可如下面流程圖1 所示製備。 流程圖1Η m 87 10 200825054 where R2, W, A, R7, and R32 are as defined (same, subclass, or specific). Other embodiments of the compounds of formula (II), (III), (IV), (IV-1), (v), and (V-1) include any one or more of the features described herein. It is important to understand that the actual electronic structure of such a chemical entity cannot be fully represented in only one standard form (ie, the Lewis structure). Although not wishing to be bound by theory, the actual structure is a mixture or weighted average of two or more standard forms, collectively referred to as a resonant form or a resonant structure. The resonant structure is not separate. It can only exist on paper. The only difference between them is the location or location of the bonding electrons or non-bonded electrons of a particular chemical entity. It is possible that one resonant structure contributes more to the hybrid than the other resonant structure. A~ π π π, beta histological description and graphical description are described in the art world as a major resonance form for a particular species. The compounds described herein can be synthesized from commercially available starting materials and reactants according to the methods described herein and/or conventional organic chemical synthesis methods. The (4) described herein can be isolated from the reaction mixture and purified by methods such as column chromatography, high pressure liquid chromatography or recrystallization. For example, skilled artisans understand that other methods of synthesizing the compounds of the formula shown herein are apparent to those skilled in the art. In addition, each of the compounds can be obtained in an appropriate order to obtain the compound. It is possible to synthesize the conjugates of the present invention into chemical rectification (respectively). The knowledge includes, for example, the synthesis described in the following references;:Ur〇Ck 'comprehensive organic conversion, VCH Press (10)9) ; T w. "This 20 200825054 and PGM Wuts, Organic Synthetic Protection Group, 2nd Edition, John Wiley & Sons (1991); L. Fieser and Μ Feiser, Fieser and Fieser's Organic Synthesis Reagents, John Wiley & Sons (1994); and L. Paquette, ed., Organic Synthetic Reagents, John Wiley & Sons, Inc. 5 (1995), and subsequent editions. Quinoline-biarylether-hydrazine and sulfonamide Synthesis In general, a compound wherein W is oxygen (0) can be prepared as shown in Scheme 1 below.

喹啉-酚（其之非限定範例係流程圖1上方所示之化合 物 100)可依，例如，Collini 等人於 US 2005/0131014(被 併入此中當作參考）中所述製備，並與鹵化之芳基砜（例 89 200825054 如，102)或鹵化之芳基磺醯胺（例如，1〇1)反應。當該鹵 為氟或氯時一般會進行芳香族的置換，這通常是在—“ 性、非質子溶劑諸如DMF、DSM0、和其之類似物中，並存= 著驗基（例如碳酸鉀或碳酸铯），在高溫（通常從衾、 100-150 C)下數小時至數天而完成。當位於該鹵化之芳美 砜或鹵化之芳基磺醯胺上_素係溴或碘時，可使用—相: 步‘驟’其為使用一銅鹽，例如，Cu I，並存在著一配體諸 N，N-二甲基甘胺酸或L-脯氨酸’在一溶劑諸如1 4__吳广 10 中進行。該耦合反應可使用所屬領域所熟知之常見方、去來 進行。該鹵化之芳基颯和鹵化之芳基磺醯胺的製備範^列、 及形成該聯芳醚（其中W =氧）的步驟係於下面描述。 齒化之芳基砜的合成 可使用一些常見的合成方法來製備鹵化之芳基石風。 15 在一些實施例中，該合成可包括將市售的_化芳基碏 酿基氣化物不完全還原’係使用硫化納和碳酸氣納於水 中，通常在95-100。(：進行〇· 5至1小時以產生該芳基亞石备 酸鈉。該反應被冷卻，以烷化試劑諸如R-LG (其中LG係 一離基諸如漠、礙、或甲苯續酸鹽）來處理。該燒化f式挪1包 20括但不限於碘乙烷、3-溴基_1-丙醇、和其之類似物。一相 轉移催化劑（通常為溴化四丁基銨）被加入並將該二相混合 物在40-100 °C加熱數小時以產生該函化之芳基碾（流程圖 2)。 90 200825054Quinoline-phenol, which is a non-limiting example of the compound 100 shown above in Scheme 1, can be prepared as described in, for example, Collini et al., US 2005/0131014, which is incorporated herein by reference. Reaction with a halogenated aryl sulfone (Example 89 200825054, eg 102) or a halogenated aryl sulfonamide (eg, 1〇1). When the halogen is fluorine or chlorine, aromatic substitution is generally carried out, usually in "sexual, aprotic solvents such as DMF, DSM0, and the like, and coexisting with a test group (such as potassium carbonate or carbonic acid).铯), completed at high temperature (usually from 衾, 100-150 C) for hours to days. When located on the halogenated aryl sulfone or halogenated aryl sulfonamide _ bromo or iodine, can be used - phase: step "step" which is the use of a copper salt, for example, Cu I, and the presence of a ligand of N, N-dimethylglycine or L-valine in a solvent such as 1 4__ This is carried out in Wu Guang 10. The coupling reaction can be carried out using a common method well known in the art. The preparation of the halogenated aryl fluorene and the halogenated aryl sulfonamide, and the formation of the biaryl ether ( The step wherein W = oxygen) is described below. Synthesis of Toothed Aryl Sulfone The halogenated aryl stone can be prepared using some common synthetic methods. 15 In some embodiments, the synthesis can include commercially available _ aryl aryl brewing base gas incomplete reduction 'series using sodium sulfide and carbonic acid in water, through At 95-100. (: 〇·5 to 1 hour to produce the aryl sulfite sodium. The reaction is cooled to an alkylating agent such as R-LG (where LG is a ruthenium such as Or a toluene hydrochloride. The burn-in formula 1 includes, but is not limited to, iodoethane, 3-bromo-1-propanol, and the like. A phase transfer catalyst (usually bromine) Tetrabutylammonium) is added and the biphasic mixture is heated at 40-100 °C for several hours to produce the functional aryl mill (Scheme 2). 90 200825054

應复圖2 so_ 柳細 —% 碰分缝 的随3•儀_&/城/18树Should be repeated Figure 2 so_ 柳细 —% 缝分缝的三•仪_&/城/18树

HalHal

SOJ^SOJ^

W 在其他實施例中，可以―燒化試劑並當存在著一驗基 (通常為碳酸卸）、在—適當的溶劑（諸如丙酮）中將齒化之 硫基盼進彳了統。該反應通f在4Q至航加熱Η小時， 7 Ρ ,、、、後以職氫鈉水溶液和⑽㈣（過硫酸氫複合物） 處理。在18-48小時夕銘·«八私 τ之後Τ刀離出所欲之^化的芳基砜（流 程圖3)。 10 琉程圈3In other embodiments, the sulphur-based sulphur group can be expected to be "burned" and in the presence of a test (usually carbonic acid), in a suitable solvent such as acetone. The reaction f is treated by heating at 4Q to nautical hours, 7 Ρ, , , and then with aqueous sodium hydrogenate solution and (10) (iv) (hydropersulfate complex). In the 18-48 hour eve, «eight private τ, the sickle leaves the desired aryl sulfone (flow chart 3). 10 laps 3

XX

Ha,-Cr s) K^CO^WhLG/ ^ ^ :65-70: $忍3小時 b) NaHCO,水溶渙/丙鲷/0Χ0ΜΕ 室溫/1S至48小時 在其他實施例中，芳基溴化物和碘化物可被轉換成為 15鹵化之芳基砜，特別是甲基砜，其係使用一銅催化的耦合 反應進行在甲基亞續酸鈉上（流程圖4)。 流程圖4Ha,-Cr s) K^CO^WhLG/ ^ ^ :65-70: $3 hours b) NaHCO, water soluble 鲷/鲷/0Χ0ΜΕ room temperature / 1S to 48 hours In other examples, aryl bromide The compound and iodide can be converted to a 15 halogenated aryl sulfone, particularly methyl sulfone, which is carried out on sodium methyl sulfite using a copper catalyzed coupling reaction (Scheme 4). Flow chart 4

MeS02NaMeS02Na

_ L· -遞氨續aOH/DM犯 95 %/18小時_ L· - Delivering ammonia to aOH/DM commit 95%/18 hours

91 200825054 鹵化之芳基磺醯胺的合成 一般而言，i化之芳基磺醯胺可藉由將鹵化的芳基磺 醯基氣化物與胺反應來製備（流程圖5)。 流程圖591 200825054 Synthesis of Halogenated Arylsulfonamide In general, an arylsulfonamide can be prepared by reacting a halogenated arylsulfonyl vapor with an amine (Scheme 5). Flow chart 5

藉由酚類進行芳基鹵化物置換反應來製備聯芳醚礙 在一些實施例中，可藉由4-(3-經基苯基）-啥琳和鹵 10 化之芳基砜（其中鹵素較佳為氟或氯）之間的置換反應來製 備聯芳醚。該反應通常在100至150 °C在一極性溶劑（諸 如DMF、DMS0、和N-甲基吡咯啶）中加熱數小時至數天（流 程圖6)。 流程圖6Preparation of biaryl ethers by aryl halide displacement reaction of phenols In some embodiments, aryl sulfones can be obtained by 4-(3-pyridylphenyl)-fluorene and halogenated 10 (halogen A dissociation reaction between fluorine or chlorine is preferred to prepare the biaryl ether. The reaction is usually carried out at 100 to 150 ° C for several hours to several days in a polar solvent such as DMF, DMS0, and N-methylpyrrolidine (Scheme 6). Flow chart 6

藉由酚類進行芳基鹵化物耦合反應來製備聯芳醚颯 在一些實施例中，可藉由4-(3-經基苯基）-喧琳和鹵 化之芳基砜（其中鹵素較佳為溴或碘）之間的耦合反應來製 92 200825054 備聯芳醚。該反應通常在100至150 °C在一極性溶劑（諸 如DMS0)中並伴隨著一銅溶解化劑（諸如L-脯氨酸）加熱數 天（流程圖7)。Preparation of biaryl ether oxime by aryl halide coupling reaction in some embodiments, by 4-(3-pyridylphenyl)-fluorene and halogenated aryl sulfone (wherein halogen is preferred) For the coupling reaction between bromine or iodine) 92 200825054 aryl ether. The reaction is usually carried out in a polar solvent (such as DMS0) at 100 to 150 °C with a copper dissolving agent such as L-valine for several days (Scheme 7).

流程圖7Flow chart 7

藉由甲基砜之烷化反應來製備聯芳醚颯 在一些實施例中，此中所述之該喹啉-聯芳醚-甲基颯 可藉由形成甲基颯陰離子而進一步被處理，其通常使用一 強鹼（諸如正丁基鋰或第二丁基鋰於一溶劑，如醚或THF， ίο 中），通常在0°C至室溫，隨後添加環氧以形成如下面流程 圖8中所示之3-羥基丙基砜。 流程圖8Preparation of Diaryl Ethers by Methylation of Methyl Sulfone In some embodiments, the quinoline-biaryl ether-methyl oxime described herein can be further processed by formation of a methyl hydrazine anion, It usually uses a strong base (such as n-butyllithium or a second butyllithium in a solvent such as ether or THF, ίο), usually at 0 ° C to room temperature, followed by the addition of epoxy to form the following flow chart 3-hydroxypropyl sulfone shown in 8. Flow chart 8

QHQH

93 15 200825054 藉由酚類進行芳基鹵化物置換反應來製備聯芳醚磺醢 胺 在一些實施例中，可藉由4-(3-經基苯基）-喧琳和鹵 化之芳基磺醯胺（其中鹵素較佳為氟）之間的置換反應來製 5 備具有磺醯胺基的聯芳醚。該反應通常在100至150 °C在 一極性溶劑（諸如DMF、DMS0、和N-甲基11比洛咬）中加熱2 小時至2天（流程圖9) 流程圖993 15 200825054 Preparation of biaryl ether sulfonamide by aryl halide displacement reaction In some embodiments, 4-(3-pyridylphenyl)-fluorene and halogenated aryl sulfonate A dissociative reaction between decylamine (wherein the halogen is preferably fluorine) is prepared to prepare a biaryl ether having a sulfonamide group. The reaction is usually heated in a polar solvent (such as DMF, DMS0, and N-methyl 11 pirin) at 100 to 150 °C for 2 hours to 2 days (Scheme 9).

10 藉由酚類進行芳基S化物耦合反應來製備聯芳醚磺醯 胺 在其他實施例中，可藉由4-(3-經基苯基）-啥琳和鹵 15 化之芳基磺醯胺（其中i素較佳為溴或碘）之間的耦合反應 來製備具有磺醯胺取代基之聯芳醚。該反應通常在100至 150 °C在一極性溶劑（諸如1，4-二°惡烧）中並伴隨著一銅溶 解化劑（諸如L-脯氨酸或N，N-二甲基甘胺酸）和一驗基（諸 如碳酸铯）加熱數小時至數天（流程圖10) 94 20 20082505410 Preparation of biaryl ether sulfonamide by aryl group S coupling reaction with phenols In other embodiments, aryl sulfonate can be obtained by 4-(3-phenylphenyl)-fluorene and halogen 15 A biaryl ether having a sulfonamide substituent is prepared by a coupling reaction between guanamine (wherein i is preferably bromine or iodine). The reaction is usually carried out at 100 to 150 ° C in a polar solvent such as 1,4-dioxacin followed by a copper dissolving agent such as L-valine or N,N-dimethylglycolamine. Acid) and a test (such as cesium carbonate) heated for hours to days (flowchart 10) 94 20 200825054

Ar-〇CH2-Ar’化合物的製備 透過紛之烧化作用Preparation of Ar-〇CH2-Ar' compound through burning

在一些實施例中，以芳基烷基i化物（芳烷基鹵化物） 將4-(3-經基苯基）-啥淋在一溶劑（諸如乙腈或DMF)中，同 時存在著一驗基（通常為碳酸铯或碳酸钟），一般在迴流加 熱6至24小時，進行烷化反應，能產生如流程圖11中所 示之节基颯取代物。 10 流程圖11In some embodiments, 4-(3-pyridylphenyl)-indole is eluted with a arylalkyl i-oxide (aralkyl halide) in a solvent such as acetonitrile or DMF. The base (usually cesium carbonate or carbonic acid), typically heated at reflux for 6 to 24 hours, is subjected to an alkylation reaction to produce a hydrazine hydrazine substituent as shown in Scheme 11. 10 Flowchart 11

口f琳-Ar-CH2〇-Ar’ 化合物的製備 15 透過將啥琳-Ar-CIhBr與Ar’ OH反應 啥琳-芳基-CH2O-芳基諷或啥琳-芳基-CH2O-芳基績酿 胺之製備可藉由常見的方法將4-(3-羥基甲基苯基）喹啉轉 95 200825054 換成對應的漠化物來完成，例如，與一漠化劑（諸如三填化 鱗於-溶劑如二氯甲烧或其之類似物中）反應。紛（或雜紛) 可被烧化’其Μ基齡常見眺化條件（如上述流程圖工1 中所示）下進行或使用其他條件諸如氫化鈉或其他驗基並 5存在著一溶劑如DMF或THF(流程圖12)來進行。 流程圖12Preparation of a compound of aryl-Ar-CH2〇-Ar' 15 by reacting 啥-Ar-CIhBr with Ar' OH 啥 --aryl-CH2O-aryl aryl or 啥-aryl-CH2O-aryl The preparation of the amine can be accomplished by replacing the 4-(3-hydroxymethylphenyl)quinoline to 95 200825054 with a corresponding desertification by a common method, for example, with a desertification agent (such as three-filled scales). It is reacted in a solvent such as methylene chloride or the like. Any (or heterogeneous) can be burned 'the common ageing conditions of the base age (as shown in Figure 1 above) or using other conditions such as sodium hydride or other tests and 5 a solvent such as DMF Or THF (flowchart 12). Flow chart 12

数芳基伸甲某之製備 透過芳基環戍硼统進行苄基齒化物之耦合反應 在一些實施例中，聯芳基伸甲基可透過使用 4-（3-[(Η0)2Β]-苯基-喹啉，藉由耦合方法來製備，該方法 使用戊醯硼與一適當的催化劑（例如，一鈀催化劑，如鈀肆 三苯膦（Pd(PPh)3)4與一鹼基，通常為碳酸鉋、碳酸鈉或碳 酸鉀）。該形成的環戊硼烷經過與一苄基鹵化物（通常為苄 基溴）反應後，形成該喹啉聯芳基伸甲基（流程圖13)。 流程圖13 96Preparation of a number of aryl groups to form a benzyl dentate coupling reaction through an aryl ring oxime system. In some embodiments, a biaryl group methyl group can be permeable to 4-(3-[(Η0)2Β]-phenyl. - Quinoline, prepared by a coupling method using pentambor boron with a suitable catalyst (for example, a palladium catalyst such as palladium triphenylphosphine (Pd(PPh)3) 4 and a base, usually Carbonate planer, sodium carbonate or potassium carbonate. The formed cyclopentane borane is reacted with a monobenzyl halide (usually benzyl bromide) to form the quinoline biaryl methyl group (Scheme 13). Figure 13 96

X 200825054X 200825054

Hel = Br,Cl 透過㈣-芳基f基鹵化物進料基職佩之輕合Hel = Br,Cl through the (tetra)-aryl f-halide halide feed base

AM 在其他實施例中，聯芳基伸甲基可藉由應用如流程圖 12中所述之料基i化物、並使用—絲硼酸或雜芳制 酸以及與流程圖财所述之相似條件（流程圖⑷來㈣。 迹:释夏AM In other embodiments, the biarylmethyl group can be obtained by applying a base group as described in Scheme 12, and using a boric acid or a heteroaryl acid and similar conditions as described in the scheme ( Flow chart (4) to (4). Trace: Summer

10 透過㈣-絲ψ Λ化物進行芳基環戊職之耦合反 應（例如，具有磺醯胺取代基之聯芳基-伸甲基) 在一些實施例中，具有磺醯胺取代基之聯芳基伸f 基，可藉由將環戊碱與节基演相合，以如同流程圖13中 97 200825054 使用之類似條件來製備。該苄基漠包含一續酸s旨，具有一 離基諸如五氟紛，可藉由在一溶劑（諸如THF與其之類似物） 中並存在著三級胺鹼基（諸如DBU與其之類似物）下加熱而 被胺（HNRgRh)置換。如此產生該喹啉-聯芳基伸甲基磺醯胺 5 (流程圖15)。 流程圖1510 coupling reaction of an aryl ring group through a (iv)-silk telluride (for example, a biaryl-methyl group having a sulfonamide substituent). In some embodiments, a sulfonamide substituent The base extension can be prepared by similar conditions as used in 97 200825054 in Scheme 13 by combining the cyclopentyl base with the nodal base. The benzyl group contains a repeating acid, having an isolated group such as pentafluoro, which may be present in a solvent such as THF and the like, and a tertiary amine base such as DBU and the like Under heating, it is replaced by an amine (HNRgRh). The quinoline-biarylmethylsulfonamide 5 is thus produced (Scheme 15). Flow chart 15

聯芳基之製備 10 透過Suzuki與·酸之耦合反應 在一些實施例中，聯芳基或芳基-雜芳基化合物可藉由 將4-苯基喹啉上之溴化物、碘化物、或三氟甲磺酸鹽與具 有適當取代基之硼酸耦合來製備，其使用常見的Suzuki條 件，包括一把催化劑如Pd(PPh3)4與其之類似物，伴隨著 15 一鹼基，通常在高溫下（50 - 110 °C)。（流程圖16) 98 200825054 流程圈16Preparation of a biaryl group 10 by coupling reaction of Suzuki with an acid In some embodiments, a biaryl or aryl-heteroaryl compound can be obtained by bromide, iodide, or The triflate is prepared by coupling with a boronic acid having an appropriate substituent using common Suzuki conditions, including a catalyst such as Pd(PPh3)4 and its analogs, accompanied by 15 bases, usually at elevated temperatures. (50 - 110 °C). (Flowchart 16) 98 200825054 Flow circle 16

透過Suzuki與環戊硼烷之耦合反應 5 在其他實施例中，聯芳基或芳基-雜芳基化合物可藉由 將含有4-苯基喹啉之環戊硼烷，與芳基溴化物或芳基碘化 與具有適當取代基之料錢化物或雜芳基峨化物輛 一 A I備$使用之Suzuki條件，例如，如流程圖w中 1〇⑺不，包括一鈀催化劑如Pd(PPh3)4與一鹼基，通常在高 现下(5〇 - 110 °c)。(流程圖17) 流程圖17Coupling reaction via Suzuki with cyclopentane. In other embodiments, a biaryl or aryl-heteroaryl compound can be obtained by reacting cyclopentane with 4-phenylquinoline with an aryl bromide. Or an aryl iodide with a suitable substituent or a heteroaryl telluride. The Suzuki condition used, for example, as in Scheme w, 1〇(7) does not include a palladium catalyst such as Pd (PPh3). ) 4 and one base, usually at a high rate (5〇-110 °c). (Flowchart 17) Flowchart 17

與喹啉-Ar-CH2CH2-Ar’ 之製備 在鈀催化劑的存在下將一適當的芳基溴與三甲基—三 土錫燒基乙炔基—石夕燒輕合，隨後去石夕院化，可產生該芳 99 200825054 基乙炔。該乙炔可在存有一鈀催化劑下與一適當的芳基一 函化物（漠或峨）耦合，以產生該聯苯基經取代的乙炔。改 變乙炔基鏈接體可透過使用氫化反應與異相催化來輕易完 成為（流程圖18)。 5Preparation of Quinoline-Ar-CH2CH2-Ar' In the presence of a palladium catalyst, a suitable aryl bromide is lightly combined with trimethyl-tris-s-s- ethynyl--Xi Xi-sing, followed by Shi Xiyuan The aromatic 99 200825054 acetylene can be produced. The acetylene can be coupled to a suitable aryl compound (molybdenum or hydrazine) in the presence of a palladium catalyst to produce the biphenyl substituted acetylene. Changing the ethynyl linker can be easily accomplished by using a hydrogenation reaction and heterogeneous catalysis (Scheme 18). 5

2 (1) 流程圖18 1) ©yfeSn-CEC-aCO-lsh 甲笨，逋流2 (1) Flowchart 18 1) ©yfeSn-CEC-aCO-lsh

C2) ZC2) Z

XX

之製備 在聯芳醚砜含有一雜芳基（如吡啶）之實施例中，4-(3-10搜基本基）喹琳可在一極性溶劑（如MF)中、存在一驗基（例 如碳酸鉀)下與2, 6—二氟吡啶反應，以產生2氟吡啶中間 產物，其可在—極性溶劑（諸如DMF)中與烷基亞磺酸鈉反應 以產生该目標°比°定-石風產物（流程圖19)。 100 200825054 流程圖19In the example in which the biaryl ether sulfone contains a heteroaryl group (such as pyridine), 4-(3-10-base) quinoline can be present in a polar solvent (such as MF) (for example, Reaction with 2,6-difluoropyridine under potassium carbonate) to produce a 2fluoropyridine intermediate which can be reacted with sodium alkyl sulfinate in a polar solvent such as DMF to produce the target. Stone wind product (flowchart 19). 100 200825054 Flowchart 19

在其他實施例中，吡啶砜之製備，可藉由將2-氣-4-5 氟吡啶與硫醇之鈉在一極性溶劑（諸如DMF)中反應產生4- 烷基硫基-2-氯吡啶，隨後在上述相似條件下與4-(3-羥基 苯基）喹啉反應，所產生的硫化物，若需要的話，可使用側 氧基NE® (2HK〇5S. HK〇4S. K2〇4S之品牌）或其他氧化物將其氧 化成對應的砜（流程圖20)。In other embodiments, the pyridine sulfone can be prepared by reacting 2-ox-4-5 fluoropyridine with sodium thiol in a polar solvent such as DMF to yield 4-alkylthio-2-chloro. Pyridine, followed by reaction with 4-(3-hydroxyphenyl)quinoline under similar conditions as described above, the resulting sulfide, if desired, can be used as a side-oxyne NE® (2HK〇5S. HK〇4S. K2〇 It is oxidized to the corresponding sulfone by the brand of 4S or other oxides (Scheme 20).

101 200825054 在其他實施例中，可藉由銅-誘導之3-溴基-5-(甲基 磺醯基）吡啶與4-(3-羥基苯基）喹啉的耦合反應來製備吡 啶-砜，其通常使用Cul，在N，N-二甲基甘胺酸鹽酸鹽和一 驗基如碳酸铯的存在下，在1，4-二°惡烧中，在高溫（通常在 5 迴流）下（流程圖21)。 流程圖21101 200825054 In other embodiments, the pyridine-sulfone can be prepared by a coupling reaction of copper-induced 3-bromo-5-(methylsulfonyl)pyridine with 4-(3-hydroxyphenyl)quinoline. , which usually uses Cul, in the presence of N,N-dimethylglycine hydrochloride and a test group such as cesium carbonate, in 1,4-two-degree methane, at high temperature (usually at 5 reflux) Next (flowchart 21). Flow chart 21

在其他實施例中，吡啶颯之製備，可藉由將4-溴基Ι-ΐΟ 烷基硫基-吡啶與4-(3-羥基苯基）喹啉，在流程圖21中之 相似耦合條件下耦合，隨後以側氧基NE®氧化成如流程圖 20中之砜（流程圖22)。 流程圖22In other embodiments, the pyridinium is prepared by the similar coupling conditions in Scheme 21 by 4-bromoindole-indenylthio-pyridine and 4-(3-hydroxyphenyl)quinoline. The lower coupling is followed by oxidation of the pendant oxygen NE® to the sulfone as in Scheme 20 (Scheme 22). Flow chart 22

102 200825054 在一些實施例中，可使用三氣吡啶依據流程圖23中 之概要來製備經取代的吡啶基颯。 流程圖23102 200825054 In some embodiments, substituted pyridylpurines can be prepared using tris-pyridine according to the scheme in Scheme 23. Flowchart 23

30% H2D2 TFM巡流30% H2D2 TFM Cruise

RSQ2Na DMF ~80DC α. of ΖRSQ2Na DMF ~80DC α. of Ζ

ο α aο α a

PBf,PBf,

5 在其他實施例中，可依據流程圖24製備其他的經鹵化 之。比σ定基石風。流程圖245 In other embodiments, other halogenated ones can be prepared in accordance with Scheme 24. Set the windshield than σ. Flowchart 24

Ο, 丫 GI _2Ο, 丫 GI _2

DHDH

R.S02Nial〇yF 120¾ K2CO^CH3CN 50R.S02Nial〇yF 1203⁄4 K2CO^CH3CN 50

ClCl

10% Pd/C10% Pd/C

NC〇iNH4/MeDH 60 °CNC〇iNH4/MeDH 60 °C

'70% HIF-哒嚏 60'70% HIF-哒嚏 60

^ K, SO2R^ K, SO2R

103 200825054 在一些實施例中，可依流程圖25中所示之已知中間產 物製備雙環的吼啶基砜（受到限制）。 流程圖25103 200825054 In some embodiments, a bicyclic acridinyl sulfone can be prepared according to known intermediates shown in Scheme 25 (restricted). Flow chart 25

具有小雜環取代基之喹啉-聯芳醚的製備 在一些實施例中，具有小雜環且含聯芳基伸甲基的喧 琳（諸如2-味嗤琳酮和2-唾烧酮）之製備，可藉由使用銅-10 誘導的耦合將咪唑啉酮或唑烷酮耦合至一溴苄基醇或碘 苄基醇，產生該經2-咪唑啉酮或2-唑烷酮取代之苄基醇。 該些醇類可被轉換成溴化物，通常使用PBn，如流程圖12 中所示。這些被耦合至含有環戊硼烷之喹啉係在如同流程 圖13中所示之相似條件下進行（流程圖26)。 104 15 200825054Preparation of Quinoline-Diaryl Ethers with Small Heterocyclic Substituents In some embodiments, a quinone having a small heterocyclic ring and containing a biarylmethyl group (such as 2-mistinone and 2-propyrone) For the preparation, the imidazolinone or oxazolone can be coupled to the monobromobenzyl alcohol or iodobenzyl alcohol by copper-10 induced coupling to produce the 2-imidazolidinone or the 2-oxazolidinone. Benzyl alcohol. These alcohols can be converted to bromides, typically using PBn, as shown in Scheme 12. These were coupled to a quinoline system containing cyclopentane in a similar condition as shown in Scheme 13 (Scheme 26). 104 15 200825054

流程圖 ΟFlow chart

αιΐΜ2(ΧΜ'二囔烷 反-1，2-二S基環己貌 mmΐΜιΐΜ2(ΧΜ'dioxane anti-1,2-di-S-cyclohexene mm

120 °C120 °C

IMFIMF

I? = Η或舍鼗掰 -ό 關 θ.2:〇Μ ΟI? = Η or 鼗掰 - ό off θ.2: 〇Μ Ο

基直,.NHS〇2Rn、NHC(0)0Rj、和·^(Q)NHRh之喹啉-聯若 5 醚的gi 含有取代基 NHSCbR11、NHC(0)0Rj、和 NHC(0)NHRh 之唾 琳聯芳_的製備，可藉由將氟硝基苯與喹琳_紛在一極性溶 劑中（諸如DMF或DMA)、並存在有一鹼基（通常為碳酸鉀）、 在高溫（通常為80 - 150T)下反應一般為4至24小時。 1〇該硝基在產物中被還原，通常以錫金屬在氫氯酸中伴隨著 共〉谷劑諸如甲醇或乙醇，或藉由把催化劑（如果可實施的 話）進行氫化反應。該所產生的胺可與異氰酸酯反應以產生 脲’可與烷基氣曱酸酯反應以產生胺基甲酸酯，並可與烷 基石黃醯基氣化物或芳基磺醯基氣化物反應以產生磺醯胺， 105 200825054 如流程圖27中所示。更可藉由環化作用形成2-味嗤琳酮 (來自脲）和2-唑烷酮（來自胺基甲酸酯）來進一步精製許多 產物，如流程圖27中所示： 流程圖27 5The gi containing the substituents NHSCbR11, NHC(0)0Rj, and NHC(0)NHRh are contained in the gi of the NHS〇2Rn, NHC(0)0Rj, and ^(Q)NHRh. Linlianfang_ can be prepared by using fluoronitrobenzene and quinoline in a polar solvent (such as DMF or DMA), and there is one base (usually potassium carbonate) at high temperature (usually 80 - 150T) The reaction is generally 4 to 24 hours. The nitro group is reduced in the product, usually by hydrogenation of tin metal in hydrochloric acid with a co-solvent such as methanol or ethanol, or by subjecting the catalyst, if practicable, to hydrogenation. The resulting amine can be reacted with an isocyanate to produce a urea' which can be reacted with an alkyl gas phthalate to produce a carbamate, and which can be reacted with an alkylphosphonium or a sulfonyl vapor to produce a sulfonate. Guanamine, 105 200825054 is as shown in flow chart 27. Further, a number of products can be further refined by cyclization to form 2-mistinone (from urea) and 2-oxazolidinone (from urethane), as shown in Scheme 27: Scheme 27 5

2 106 200825054 噁唑啉和相關取代基之一般製備 在一些實施例中，可使用三氟甲磺酸酐將醯胺取代基 (其中驢胺為二級結構且包含一經基丙基或羥基乙基）環 化，以產生如流程圖28中之相似的噁唑啉。 5 流程圖282 106 200825054 General Preparation of Oxazolines and Related Substituents In some embodiments, a guanamine substituent can be used using trifluoromethanesulfonic anhydride (wherein the guanamine is a secondary structure and comprises a propyl or hydroxyethyl group) Cyclization to produce a similar oxazoline as in Scheme 28. 5 Flowchart 28

在一些實施例中，可藉由將酯類與一胺基-肟反應來製 備°惡二唾，如流程圖29所示。 10 流程圖29In some embodiments, the dimorphism can be prepared by reacting an ester with an amine-oxime, as shown in Scheme 29. 10 Flowchart 29

在一些實施例中，可藉由將酯類與二胺反應來製備咪 嗤琳，如流程圖30所示。 107 15 200825054In some embodiments, the imide can be prepared by reacting an ester with a diamine, as shown in Scheme 30. 107 15 200825054

具有8-H或8-S〇2R之喹啉的製備 5 在一些實施例中，可根據流程圖31製備化合物（其中 R7係氫或S〇2Rn)。 流程圖31Preparation of Quinoline with 8-H or 8-S〇2R 5 In some embodiments, a compound (wherein R7 is hydrogen or S〇2Rn) can be prepared according to Scheme 31. Flowchart 31

10 本發明化合物可含有一個或多個非對稱中心，如此可 呈外消旋化合物及外消旋混合物、單一對映異構物、個別 非對映異構物及非對映異構物混合物等形式。全部此等化 108 200825054 合物之此種異構形式皆明示含括於本發明。本發明化合物 也含有鍵聯（例如碳-碳鍵、碳—氮鍵諸如醯胺鍵），其中鍵 旋轉係受到該特定鍵聯所限，例如由於存在有環或雙鍵所 限。如此，全部順/反異構物及E/z異構物及旋轉異構物皆 5明示含括於本發明。本發明化合物也可以多種互變異構形 式表示，於此種情況下，本發明明示包括此處所述化合物 之全部互變異構形式，即使只表示單一互變異構形（例如環 系之烷基化可能導致多個位置之烷基化，本發明明示包括 全部此等反應產物）。全部此等化合物之異構型皆明示含括 10於本發明。全部此處所述化合物之結晶型皆明示含括於本 發明。 本發明化合物包括化合物本身，以及若適用時包括其 鹽及其前藥。例如鹽可於此處所述化合物之陰離子與本文 所述化合物上之帶正電之取代基（例如胺基）間形成。適當 15陰離子包括氯陰離子、溴陰離子、碘陰離子、硫酸根、硝 酸根、磷酸根、擰檬酸根、甲磺酸根、三氟乙酸根及乙酸 根。同理，鹽也可於陽離子與本文所述化合物上之帶負電 之取代基（例如羧酸根）間形成。適當陽離子包括鈉離子、 鉀離子、鎂離子、鈣離子、及銨陽離子如四曱基銨離子。 20前藥之實例包括酯類及其它藥學上可接受之衍生物，其當 投予個體時可提供活性化合物。 本發明化合物之藥學上可接受之鹽包括衍生自藥學上 可接受之無機及有機酸類及驗類之該等鹽類。適當酸鹽類 之實例包括乙酸鹽、己二酸鹽、褐藻酸鹽、天冬酸鹽、苯 109 200825054 甲酉欠鹽、苯績酸鹽、硫酸氫鹽、丁酸鹽、檸檬酸鹽、樟腦 酉文鹽、樟腦石黃酸鹽、二葡萄糖酸鹽、十二燒基琉酸鹽、乙 石K酸鹽、甲酸鹽、反丁烯二酸鹽、葡萄糖庚酸鹽、乙醇酸 鹽、半硫酸鹽、庚酸鹽、己酸鹽、氫氯酸鹽、氫溴酸鹽、 氫碟S曼鹽、2-經基乙績酸鹽、乳酸鹽、順丁稀二酸鹽、丙 二酸鹽、甲磺酸鹽、2-烷磺酸鹽、菸鹼酸鹽、硝酸鹽、巴 姆酸鹽（palmoate)、果膠酸鹽、過硫酸鹽、3_苯基丙酸鹽、 磷酸鹽、苦味酸鹽、特戊酸鹽、丙酸鹽、水楊酸鹽、丁二 酸鹽、硫酸鹽、酒石酸鹽、硫氰酸鹽、甲苯續酸鹽及十一 1〇 烷酸鹽。其它酸諸如草酸，本身雖然並非藥學上可接受之 酸，但可用於製備鹽類，該鹽類可用於作為中間物，用來 獲得本發明之化合物及其藥學上可接受之酸加成鹽。衍生 自適當鹼之鹽類包括鹼金屬鹽（例如鈉鹽）、鹼土金屬鹽（例 如鎂鹽）、銨鹽及N-(烷基）4+鹽。本發明也包含此處揭系化 15 合物之任何鹼性含氮基團之第四化。水或油溶性戒分散性 產物可經由此種第四化獲得。此處所述任一種化學式化技 物之鹽形式為窥基之胺基酸鹽（例如L-精胺酸鹽、L-離版紅 鹽、L-組胺酸鹽）。 “藥學上可接受的載體或佐劑，，一詞係指矸連同本發 2〇明化合物投予個體（例如病人）之載劑或輔劑，其不會破瓌 本發明化合物之藥理活性，且當以足夠輸送治療用f之牝 合物之劑量投藥時該載劑或輔劑為無毒。 可用於本發明之組成物之藥學上可接受之載劑、佐Μ 及載媒劑包括但非限於離子交換劑、鋁氧、硬脂酸鋁、印 110 200825054 磷脂、自行乳化藥物輸送系統（SEDDS)諸如d-α-生育鹼聚 乙二醇1000 丁二酸酯、用於藥學劑型之界面活性劑諸如务 恩（Tween)或其它類似之聚合物輸送基體、血清蛋白諸如人 血清白蛋白、緩衝物質諸如磷酸鹽類、甘胺酸、山梨酸、 5 山梨酸鉀、飽和植物脂肪酸之部分甘油酯混合物、水、赞 類或電解質，諸如硫酸精胺、構酸氫二鈉、構酸氫鉀、氯 化鈉、辞鹽類、膠體矽氧、三矽酸鎂、聚乙烯基吡咯啶_、 基於纖維素之物質、聚乙二醇、羧基甲基纖雉素鈉、聚兩 烯酸酯、蠟類、聚乙烯—聚氧伸丙基—嵌段聚合物、聚乙二 10 醇及羊毛脂。環糊精類諸如α-環糊精、環糊精及γ-環糊 精’或化學改性衍生物如羥基烷基環糊精類包括2-及3-羥 基丙基-万-環糊精或其它增溶衍生物也可有利地用於提升 本文所述化學式化合物之輸送。 通常，本文所述化合物可用於治療（例如控制、改善、 15預防、延遲發作或降低發展的風險）經由LXRs所媒介之一 種或多種疾病、失調、病況或症狀（例如心血管疾病（如急 性对心症、血官再度狹窄）、動脈粥狀硬化、動脈粥樣硬化 之損害、第一型糖尿病、第二型糖尿病、χ症候群、肥胖症、 脂質失調（例如血脂異常、高血脂、高三酸甘油酯血症、高 2〇膽固醇血症、低HDL濃度、高LDL濃度）、認知失調（例如 阿茲罕默症、失智症）、發炎疾病（例如，多發性硬化症、 類風濕性關節炎、發炎腸道疾病、克隆氏症、子宮内膜異 位症、LPS-誘導的敗血症、耳之急性接觸性皮膚炎、動脈 壁之慢性粥狀動脈硬化發炎）、乳麋瀉症或甲狀腺炎）。 25 一由UR媒介之失調或生理學的病況，係指一失調或 111 200825054 病況其中LXR可引起該病況的發作，或當抑制—特定的 可影響訊息傳遞，如此可用於治療、控制、改盖、 10 延遲發作或降低該失調或病況發展的風險。這此失，的# 例包括，但非限於，心血管疾病（如急性冠心症、血二再， 狹窄）、動脈粥狀硬化、動脈粥樣硬化之損害、第一 i，又 病、第二型糖尿病、X症候群、肥胖症、脂質失,（例女血 脂異常、南血脂、而三酸甘油醋血症、高膽固醇血，广 HDL濃度、南LDL濃度）、認知失調（例如阿兹罕默广失/ 症）、發炎疾病（例如’多發性硬化症、類風濕性關節炎: 發炎腸道疾病、克隆氏症、子宮内膜異位症、Lps—誘導的 敗血症、耳之急性接觸性皮膚炎、動脈壁之慢性粥狀二脈 硬化發炎）、乳麋瀉症或甲狀腺炎。 雖然不希望被理論所侷限，一般相信會活化膽固醇的 排出（例如，向上調節ABCA1)，但並不會實質上增加肝中 15 SREBP-1 c表現和三酸甘油酯合成的LXR調節物既可減少粥 狀動脈硬化的機率又可降低所伴隨增加血清和肝三酸甘油 酯值的可能性。可藉由使用常見的藥理學試驗方法來評估 具有分化調節ABCA1 (ABCGl)vs· SREBP-lc能力之候選化 合物，該方法測量候選化合物鍵結上LXR與向上調節ABCM 20 基因的傾向。 在一些實施例中，一開始LXR配體可在無細胞之LXR万 和LXRa鍵結競爭法中被鑑別出來。可進一步藉由用於組 織選擇性基因調節之基因表現藍圖來特徵化LXR配體。 在一些實施例中，此中所述之化合物對ABCA1轉錄活 25 化具有致效劑活性，但並不實質上影響（例如，抑制）已分 112 200825054 化之THP-l巨噬細胞中SREBP-lc基因的表現。以拮抗劑模 式之基因表現分析法可被用來進一步描緣出ABCA1和 SREBP-lc基因表現的分化調控。在某些實施例中，此中所 述之化合物傾向優先拮抗SREBP-lc之活化（一種基因涉及 5 膽固醇和脂肪酸恆定狀態的指標），但並不實質上影響（例 如，具有相對最小或附加的影響）ABCA1基因表現或已知會 有助於HDL生物合成之基因（根據以已知有效能合成的LXR 激化物進行之競爭法）。細胞形態或組織種類可進一步以另 外的細胞株’腸的、CaCo2或肝的、HepG2和Huh-7細胞來 10 被評估，其中這些細胞之ABCA1活性被相信會影響淨膽固 醇的吸收和逆轉式膽固醇的運輸。所進行之試驗步驟以及 從此中所獲得的結果被記載於範例一節中。 在一些實施例中，此中所述之化合物對ABCA1具有致效劑活 性且對SREBP-lc具有拮抗劑活性(例如，以細胞為主試驗分析法 15中之基因種調節來測定）。在某些實施例中，此中所述之化合物 (在致效劑模式中）具有至少約20%之效力在透過LXR之ABCA1的 活化，且並不實質上致效SREBP-lc(關於一參考化合物N-(2, 2, 2-二亂-乙基）-N-[4_(2, 2, 2-二氟^-1-經基-1-三氣甲基-乙基）-苯 基]-苯績醯胺（Schultz, Joshua R.，Genes & Development 2〇 (2000)，14(22)， 2831-2838)最多約 25% 效力）。在某些實施 例中，此中所述之化合物（在拮抗劑模式中）並不會實質上拮抗 ABCA1基因的表現。雖然不希望被理論所侷限，一般相信會有一 附加的影響在關於該參考化合物之EC50濃度時之ABCA1基因的 表現。在某些實施例中，此中所述之化合物(在拮抗劑模式中）在 113 200825054 一藥劑依賴型方式中抑制了致效劑-媒介之SREBP-lc基因的表 現0 在一些實施例中，為研究式（I)化合物對皮膚老化之影 響，例如，在臨床試驗中，細胞被分離並製備與分析rna 5 以評估 TIMP1、ABCA12、核心蛋白聚糖（decorin)、TNF α、 ΜΜΡ1、ΜΜΡ3、和/或IL-8之表現值。該基因表現值（即一基 因表現的模式）被量化，例如，藉由北方墨點分析法或 RT-PCR，透過測量所產生之蛋白質的量，或透過測量 TIMP1、ABCA12、核心蛋白聚糖、TNFa、MMP卜 MMP3、和/ 1〇或IL-8的活性值，所有憑藉之方法皆為已知或熟習此藝者 所熟知。如此一來，該基因表現的模式可用來當成一指標， 指示出細胞對該式（I)化合物之生理學反應。因此，該反應 狀悲可在以式（I)化合物處理個體之前或期間之多點來被 測定。 15 在一實施例中，此中所述之細胞激素和金屬蛋白酵素 的表現，可被用來幫助透過一 LXR—為主之機制治療皮膚老 化之化合物的設計和/或鑑定。因此，本發明提供方法（在 此中也稱作“篩選法，’）於鑑定調節物，即，LXR調節物， 具有對’例如，TIMP1、ABCA12、核心蛋白聚糖、tnfα、 2〇 ΜΜΡ1、ΜΜΡ3、和/或il-8表現之刺激或抑制效果。 一示範性的篩選法係一細胞-為主之試驗分析法，其中表現 LXR之細胞係與一試驗化合物接觸，並測定出該試驗化合物透過 LXR—為主之機制調節ΤΙΜΡ1、ABCA12、核心蛋白聚糖、TNFa、 MMP1、MMP3、和/或il-8的表現。測定該試驗化合物調節TIMP卜 114 200825054 ABCA12、核心蛋白聚糖、TNFa、MMP卜MMP3、和/或IL—8表現 的能力可透過監控，例如，DNA、mRNA、或蛋白質值來完成，或 藉由測量TIMP卜ABCA12、核心蛋白聚糖、TNFa、ΜΜρι、關兕、 和/或IL-8之活性值來完成，所有憑藉之方法皆為已知或熟習此 5藝者所熟知。該細胞，例如，可為哺乳動物源，例如，人類。 在-些實施例中，為研究式⑴化合物對骨關節炎之影 響，例如，在臨床試驗中，細胞被分離並製備與分析RM 以評估ApoD與其他暗示與骨關節炎相關之基因（例如， TNFa)的表現值。該基因表現值（即一基因表現的模式）可 1〇藉由北方墨點分析法或RT-PCR被量化，透過測量所產生之 蛋白質的量，或透過測量Ap〇D與其他基因之活性值，所有 憑藉之方法皆為已知或熟習此藝者所熟知。如此一來，該 基口表現的核式可用來當成一指標，指示出細胞對該⑽ 調控劑之生理學反應。因此，該反應狀態可在以uR調控 15劑處理個體之前或期間之多點來被測定。 一不範性的篩選法係一細胞-為主之試驗分析法，其中表現 LXR之細胞係與—試驗化合物接觸，並測定出該試驗化合物透過 - LXR-為主之機制調節Ap〇D祕和/或聚蛋白多_活性和/或 細胞激素的製造。測定該試驗化合物調節ApoD表現和/或聚蛋白 2〇多糖酶活性和/或細胞激素的製造可透過監控，例如，DNA、_A、 或蛋白貝值來元成，或藉由測量Ap〇D、聚蛋白多糖酶、和/或tnf Q 之活性值來完成，所有憑藉之方法皆為已知或熟習此藝者所熟 知。該細胞，例如，可為哺乳動物源，例如，人類。 於若干實施例中，本文所述化合物可與一種或多種其 115 200825054 它治療劑一起投予。於若千實施例中，額外藥劑可與本發 明化合物分開投予，作為多劑治療計畫之一部分（例如與一 種或多種式（I)化合物之投予以不同的重疊排程來循序投 予）。另外，此等藥劑可與本發明化合物混合於單一組成物 5 構成單一劑型之一部分。於又另一個實施例中，此等藥劑 可呈分開藥劑而與一種或多種式（I)化合物於約略相同時 間投予（例如於一種或多種式（I)化合物之投予同時投 予）。當本發明之組成物包含此處所示化學式之化合物於一 種或多種額外治療劑或預防劑之組合投予時，該化合物及 10額外藥劑須以正常於單一治療計畫中通常投予之劑量之約 1%至約100%，更佳約5%至95%間之劑量百分比存在。 本文所述化合物及組成物例如可經口、經腸道外（例如 皮下、皮内、靜脈、肌肉、關節内、動脈内、滑囊内、胸 内、鞘内、病灶内及藉顱内注射或輸注技術）投藥、藉吸入 15喷務、局部、經直腸、經鼻、經頰、經陰道投藥，透過楂 入貯裔投藥，藉注射、經皮、經腹内、經黏膜、或呈眼用 製劑技藥，劑里係於母4小時至12〇小時約〇· 〇 1毫克/千 克至1000毫克/千克之範圍（例如由約〇· 至約毫克/ 千克，由約0· 1至約100毫克/千克，由約i至約丄⑽毫克 2〇 /千克，由約1至約10毫克/千克），或根據特定藥物的要 求決定。動物及人類使用劑量（以每平方米體表面積之毫克 數為基準）間之交互關係· Freireich等人，癌症化學治 療Rep. 50，219 (1966)說明，體表面積可由病人升高及體 重約略測定。例如參考科學表，蓋吉藥品公司（g e 土灯 116 20082505410 The compounds of the invention may contain one or more asymmetric centers, such that they may be racemic and racemic mixtures, single enantiomers, individual diastereomers and mixtures of diastereomers, etc. form. All such equivalents 108 200825054 All such isomeric forms of the compounds are expressly included in the present invention. The compounds of the invention also contain linkages (e.g., carbon-carbon bonds, carbon-nitrogen bonds such as guanamine linkages) wherein the bond rotation is limited by the particular linkage, e.g., due to the presence of a ring or double bond. Thus, all cis/trans isomers, E/z isomers, and rotamers are explicitly included in the present invention. The compounds of the invention may also be represented in a variety of tautomeric forms, in which case the invention expressly encompasses all tautomeric forms of the compounds described herein, even if only a single tautomeric form (e.g., ring alkylation) It may result in alkylation of a plurality of positions, and the invention expressly includes all such reaction products). All isomeric forms of these compounds are expressly included in the present invention. All of the crystalline forms of the compounds described herein are expressly included in the present invention. The compounds of the invention include the compound itself, and if applicable, salts thereof and prodrugs thereof. For example, a salt can be formed between an anion of a compound described herein and a positively charged substituent (e.g., an amine group) on a compound described herein. Suitable 15 anions include chloride anions, bromine anions, iodine anions, sulfates, nitrates, phosphates, citrate, mesylate, trifluoroacetate and acetate. Similarly, a salt can also be formed between a cation and a negatively charged substituent (e.g., a carboxylate) on a compound described herein. Suitable cations include sodium ions, potassium ions, magnesium ions, calcium ions, and ammonium cations such as tetradecylammonium ions. Examples of 20 prodrugs include esters and other pharmaceutically acceptable derivatives which, when administered to an individual, provide the active compound. The pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and assays. Examples of suitable acid salts include acetate, adipate, alginate, aspartate, benzene 109 200825054 formazan, phthalate, hydrogen sulfate, butyrate, citrate, camphor酉文盐, camphor maye, digluconate, dodecyl phthalate, ethyl sulphate, formate, fumarate, glucose heptanoate, glycolate, half Sulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydrogen Sman salt, 2-alkyl acid salt, lactate, cis-succinate, malonate , mesylate, 2-alkanesulfonate, nicotinic acid salt, nitrate, palmate (palmoate), pectate, persulfate, 3-phenylpropionate, phosphate, bitter Acid salts, pivalates, propionates, salicylates, succinates, sulfates, tartrates, thiocyanates, toluates, and undecanoic acid salts. Other acids such as oxalic acid, although not themselves a pharmaceutically acceptable acid, can be used in the preparation of salts which are useful as intermediates for obtaining the compounds of the present invention and their pharmaceutically acceptable acid addition salts. Salts derived from appropriate bases include alkali metal salts (e.g., sodium salts), alkaline earth metal salts (e.g., magnesium salts), ammonium salts, and N-(alkyl) 4+ salts. The invention also encompasses the characterization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil soluble or dispersible products can be obtained via such fourthization. The salt form of any of the chemical formulating techniques described herein is an amino acid salt of a scouring base (e.g., L-arginine, L-ionic red salt, L-histamine). "Pharmaceutically acceptable carrier or adjuvant," the term "carrier" or an adjuvant that is administered to an individual (eg, a patient) in combination with a compound of the invention, which does not interfere with the pharmacological activity of the compound of the invention, And the carrier or adjuvant is non-toxic when administered at a dose sufficient to deliver the therapeutic composition of the therapeutic agent. The pharmaceutically acceptable carrier, adjuvant and vehicle which can be used in the compositions of the present invention include but not Limited to ion exchangers, aluminum oxide, aluminum stearate, India 110 200825054 phospholipids, self-emulsified drug delivery system (SEDDS) such as d-α-tocopheryl polyethylene glycol 1000 succinate, interface activity for pharmaceutical formulations Agents such as Tween or other similar polymer delivery matrix, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glycerides of saturated vegetable fatty acids Mixture, water, like or electrolyte, such as spermine sulfate, disodium hydrogen hydride, potassium hydrogen hydride, sodium chloride, salt, colloidal oxygen, magnesium tris-citrate, polyvinylpyrrolidine _, based on Cellulose substance Polyethylene glycol, sodium carboxymethyl cellulose, polyalkenoates, waxes, polyethylene-polyoxypropyl-block polymers, polyethylene glycols and lanolin. Cyclodextrins such as Α-cyclodextrin, cyclodextrin and γ-cyclodextrin' or chemically modified derivatives such as hydroxyalkyl cyclodextrins include 2- and 3-hydroxypropyl-wan-cyclodextrin or other solubilized derivatives The agents may also be advantageously used to enhance the delivery of the chemical formula compounds described herein. In general, the compounds described herein may be used to treat (eg, control, ameliorate, prevent, delay, or reduce the risk of development) one or more of the mediators via LXRs. Disease, disorder, condition or symptom (eg cardiovascular disease (eg acute heart disease, re-stenosis of blood), atherosclerosis, damage to atherosclerosis, type 1 diabetes, type 2 diabetes, snoring syndrome, Obesity, lipid disorders (eg dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL concentrations, high LDL concentrations), cognitive disorders (eg Azheimer's disease, dementia) Inflammatory disease (for example, Sclerosis, rheumatoid arthritis, inflammatory bowel disease, Crohn's disease, endometriosis, LPS-induced sepsis, acute contact dermatitis of the ear, chronic atherosclerotic inflammation of the arterial wall ), celiac disease or thyroiditis. 25 A condition of dysregulation or physiology of UR, refers to a disorder or 111 200825054 condition in which LXR can cause the onset of the condition, or when inhibition - specific affectable messages Delivery, so can be used to treat, control, change, 10 delay the onset or reduce the risk of the development of the disorder or condition. This case includes, but is not limited to, cardiovascular disease (such as acute coronary heart disease, blood two Further, stenosis), atherosclerosis, atherosclerosis, first i, disease, type 2 diabetes, X syndrome, obesity, lipid loss, (women's dyslipidemia, southern blood lipids, and tris Glycerolemia, hypercholesterolemia, broad HDL concentration, southern LDL concentration), cognitive disorders (eg, Azheimer's disease), inflammatory diseases (eg 'multiple sclerosis, rheumatoid arthritis: hair Bowel disease, Crohn's disease, endometriosis, LPS- induced sepsis, acute contact dermatitis of the ear inflammation, chronic arterial walls of two gruel arteriosclerosis inflammation), breast disease diarrhea elk or thyroiditis. Although not wishing to be bound by theory, it is generally believed that it will activate the excretion of cholesterol (eg, up-regulating ABCA1), but does not substantially increase the LSR modulator of 15 SREBP-1 c expression and triglyceride synthesis in the liver. Reducing the chance of atherosclerosis can also reduce the likelihood of increased serum and hepatic triglyceride values. Candidate compounds having the ability to differentiate and modulate ABCA1 (ABCG1) vs. SREBP-lc can be assessed by using common pharmacological assays, which measure the propensity of LXR on the candidate compound linkage and up-regulate the ABCM 20 gene. In some embodiments, the initial LXR ligand can be identified in cell-free LXR and LXRa binding competitions. The LXR ligand can be further characterized by a blueprint of the gene expression for tissue selective gene regulation. In some embodiments, the compounds described herein have potent agent activity against ABCA1 transcriptional transcription, but do not substantially affect (eg, inhibit) SREBP- in THP-I macrophages that have been isolated 112 200825054. The performance of the lc gene. Gene expression profiling in an antagonist format can be used to further characterize the differentiation regulation of ABCA1 and SREBP-lc gene expression. In certain embodiments, the compounds described herein tend to preferentially antagonize the activation of SREBP-lc (a gene that is involved in the index of 5 cholesterol and fatty acid constant state), but does not substantially affect (eg, has a relatively minimal or additional Affects) ABCA1 gene expression or a gene known to contribute to HDL biosynthesis (based on competition methods performed with LXR excimers synthesized with known potency). Cell morphology or tissue types can be further evaluated in additional cell lines 'intestinal, CaCo2 or liver, HepG2 and Huh-7 cells, where ABCA1 activity is believed to affect net cholesterol absorption and reversal cholesterol Transportation. The experimental procedures performed and the results obtained therefrom are described in the Examples section. In some embodiments, the compounds described herein have potent agent activity on ABCA1 and antagonist activity on SREBP-lc (e.g., as determined by gene regulation in cell-based assay 15). In certain embodiments, the compounds described herein (in the agonist mode) have an efficacy of at least about 20% of the activation of ABCA1 through the LXR and are not substantially effective for SREBP-lc (for a reference) Compound N-(2, 2, 2-disorder-ethyl)-N-[4_(2, 2, 2-difluoro(-1-yl)-1-trimethyl-ethyl-ethyl)-phenyl - Benzene (Schultz, Joshua R., Genes & Development 2 (2000), 14 (22), 2831-2838) up to about 25% potency). In certain embodiments, the compounds described herein (in the antagonist mode) do not substantially antagonize the expression of the ABCA1 gene. While not wishing to be bound by theory, it is generally believed that there will be an additional effect on the performance of the ABCA1 gene at the EC50 concentration of the reference compound. In certain embodiments, the compounds described herein (in the antagonist mode) inhibit the performance of the agonist-mediated SREBP-lc gene in a drug-dependent manner in 113 200825054. In some embodiments, To investigate the effect of a compound of formula (I) on skin aging, for example, in clinical trials, cells are isolated and prepared and analyzed for rna 5 to assess TIMP1, ABCA12, decorin, TNFα, ΜΜΡ1, ΜΜΡ3, And/or the performance value of IL-8. The gene expression value (ie, the pattern of expression of a gene) is quantified, for example, by measuring the amount of protein produced by Northern blot analysis or RT-PCR, or by measuring TIMP1, ABCA12, decorin, The activity values of TNFa, MMP, MMP3, and /1〇 or IL-8, all of which are known or known to those skilled in the art. In this way, the pattern of expression of the gene can be used as an indicator to indicate the physiological response of the cell to the compound of formula (I). Thus, the responsiveness can be determined at a multipoint before or during the treatment of the individual with a compound of formula (I). In one embodiment, the performance of the cytokines and metalloproteinases described herein can be used to aid in the design and/or identification of compounds for skin aging through an LXR-based mechanism. Thus, the invention provides methods (also referred to herein as "screening methods,") for identifying modulators, ie, LXR modulators, having pairs of 'eg, TIMP1, ABCA12, decorin, tnfα, 〇ΜΜΡ1, An stimulatory or inhibitory effect of ΜΜΡ3, and/or il-8. An exemplary screening method is a cell-based assay in which a cell line expressing LXR is contacted with a test compound and the test compound is determined The performance of ΤΙΜΡ1, ABCA12, decorin, TNFa, MMP1, MMP3, and/or il-8 was regulated by LXR-based mechanism. The test compound was assayed to regulate TIMP 114, 200825054 ABCA12, decorin, TNFa, The ability of MMPs to express MMP3, and/or IL-8 can be accomplished by monitoring, for example, DNA, mRNA, or protein values, or by measuring TIMP, ABCA12, decorin, TNFa, ΜΜρι, Guan, and / or IL-8 activity values are accomplished, all of which are well known or familiar to those skilled in the art. The cells, for example, may be of mammalian origin, for example, humans. In some embodiments, Research The effect of the compound of formula (1) on osteoarthritis, for example, in clinical trials, cells are isolated and prepared and analyzed for RM to assess the performance of ApoD and other genes implicated in osteoarthritis (eg, TNFa). The value (ie, the pattern of a gene expression) can be quantified by Northern blot analysis or RT-PCR, by measuring the amount of protein produced, or by measuring the activity of Ap〇D and other genes, The method is known or familiar to those skilled in the art. Thus, the nucleus of the base can be used as an indicator to indicate the physiological response of the cell to the (10) modulator. Therefore, the reaction state can be It is determined at a multipoint before or during the treatment of 15 agents with uR. A non-standard screening method is a cell-based assay, in which a cell line expressing LXR is contacted with a test compound and measured. The test compound modulates the production of Ap〇D secret and/or polyprotein poly-activity and/or cytokine via a -LXR-based mechanism. The test compound is assayed to modulate ApoD expression and/or polyprotein 2 The production of polysaccharidase activity and/or cytokine can be achieved by monitoring, for example, DNA, _A, or protein shellfish, or by measuring the activity values of Ap〇D, aggrecanase, and/or tnf Q. This is accomplished by all methods known or known to those skilled in the art. The cells, for example, can be of mammalian origin, for example, humans. In several embodiments, the compounds described herein can be combined with one or more of them 115. 200825054 Its therapeutic agent is administered together. In the embodiment, the additional agent can be administered separately from the compound of the invention as part of a multi-dose treatment plan (e.g., different from the administration of one or more compounds of formula (I). Overlapping schedules for sequential injection). Additionally, such agents may be combined with a compound of the invention in a single composition 5 to form part of a single dosage form. In yet another embodiment, the agents can be administered as separate pharmaceutical agents at about the same time as one or more compounds of formula (I) (e.g., administered simultaneously with administration of one or more compounds of formula (I)). When a composition of the invention comprises a compound of the formula shown herein in a combination of one or more additional therapeutic or prophylactic agents, the compound and the 10 additional agent are administered in a dosage normally normal to a single treatment regimen. A dosage percentage of between about 1% and about 100%, more preferably between about 5% and 95%, is present. The compounds and compositions described herein can be administered, for example, orally or parenterally (eg, subcutaneously, intradermally, intravenously, intramuscularly, intraarticularly, intraarterially, intrasaccularly, intrathoracically, intrathecally, intralesionally, and by intracranial injection or Infusion technique) administration, inhalation, 15 spray, partial, transrectal, nasal, buccal, transvaginal administration, administration by infusion into the sputum, by injection, percutaneous, intra-abdominal, transmucosal, or ophthalmic The preparation technique is in the range of from about 4 hours to about 12 hours in the mother, from about 1 mg/kg to about 1000 mg/kg (for example, from about 〇· to about mg/kg, from about 0.1 to about 100). Mg/kg, from about i to about 丄 (10) mg 2 〇 / kg, from about 1 to about 10 mg / kg), or according to the requirements of specific drugs. The interaction between animal and human doses (based on milligrams per square meter of body surface area) Freireich et al., Cancer Chemotherapy Rep. 50, 219 (1966) states that body surface area can be measured by patient and body weight . For example, reference scientific table, Geji Pharmaceuticals Co., Ltd. (g e earth lamp 116 200825054

Pharmaceuticals)，紐約州阿茲里，537 (197〇)。於若干 實施例中，組成物係經口投藥或藉注射投藥。本文方法預 期涵盍投予有效量之化合物或化合物組成物來達成期望效 果或所述效果。典型地，本發明之藥學組成物可每日投藥 5約1次至約6次，或另外，呈連續輸注投藥。此種投藥可 用作為k性治療或急性治療。可與載劑材料組合來製造單 一劑型之活性成分用量將依據所處理的宿主及特定投藥模 式而改變。典型製劑含有約5%至約95%活性化合物（w/w)。 另外’此等製劑含有約2〇%至約80%活性化合物。 1〇 可能需要比前文引述劑量更低劑量或更高劑量。任何 特定病人之特定劑量計晝及治療計畫將依據多項因素決 定’該等因素包括所使用之特定化合物之活性、年齡、體 重、一般健康狀況、性別、飲食、投藥時間、排泄速率、 藥物組合、疾病嚴重度及病程、病情或症狀、病人是否好 15發该疾病、病情或症狀，以及治療醫師的判定。 當病人的病情改善時，若有所需可投予維持劑量之本 發明化合物、組成物或組合物。隨後當症狀已經改善至期 望程度時，投予劑量或投予頻率或二者可依據症狀之函數 降至可維持改善的病情的程度。但長期當疾病症狀復發 20 時，病人可能需要間歇治療。 本發明組成物可含有任何習知無毒藥學上可接受之載 劑、輔劑或載媒劑。於某種情況下，調配物之油可使用藥 學上可接受之酸、鹼、或緩衝劑調整，來增進所調配之化 合物或其輸送形式之安定性。 117 200825054 、、且成物可呈無菌注射製劑劑型 性懸浮液劑十、， 王，…囷压射用水 已知技術 懸浮液劑。此㈣浮液劑可依據技藝界 浮劑調酉L使用讀劑或濕潤劑（例如吞恩（Tween)80)及懸 5 10 15 20 劑或溶劑之=注射製劑也為於無毒腸道外可接受之稀釋 “、、菌 >主射用溶液劑或懸浮液劑，例如呈 丁二醇之溶馀 9 糖醇 /。可使用之可接受之㈣劑及溶劑包括甘露 / _ 林袼氏溶液及等張氣化鈉溶 用無菌固定油Μη — 又，由作為浴劑或懸浮介質。用於此 用任何品牌之』便 ^ ^ 口疋油，包括合成一酸甘油酯或二酸甘油 馱諸如油酸及其甘油酯衍生物可用於製備注射 劑’如同天然藥學上可接受之油類諸如撖欖油或t麻油可 二作為^射製劑之油類，特別其聚氧基伸乙基化版本。此 等油[生岭液劑和懸浮液劑也含有常用於調配藥學上可接受 之聖諸如礼液及/或懸浮液之劑型配方之長鏈醇稀釋劑 或分散劑、或絲甲基纖維素等分散劑。其它常用之界面 活性劑諸如呑恩類或史班類（Span)及/或其它類似乳化劑 或生物利用率提升劑等常用於藥學上可接受之固體劑型、 液體劑型或其它劑型之製造者也可用於配方目的。 本發明之組成物可呈任一種口服可接受之劑型經口投 予，口服可接受之劑型包括但非限於膠囊劑、錠劑、乳液 劑及水性懸浮液劑、分散劑及溶液劑。以供口服使用之錠 劑為例，常用之載劑包括乳糖及玉米澱粉。也典型添加潤 滑劑諸如硬脂酸鎂。供呈膠囊劑型經口投藥，有用之稀釋 劑包括乳糠及乾玉米澱粉。當水性懸浮液劑及/或乳液劑經 118 200825054 浮於或溶解於油相且與乳化劑及/ ，可添加若干甜味劑及/或矯味劑 口投藥時，活性成分可懸 或懸浮劑組合。若有所需 及/或著色劑。 5 10 15 此算ίΓΓ之組成物也可呈供直腸投藥之栓_型投予。 ,θ人而/ 了經由將本發明化合物於適當非刺激性賦形劑 Π”’該賦形劑於室溫時為固體，但於肛溫時為液 括’ Ρ將於直腸_解轉放出活性成分。 括但非限於可可脂、蜂觀聚乙二_。 局，投予本發明組成物可用於期望之治療涉及方便藉 局部用藥之區域戋芎官卑 以、商… …供局部施用於皮膚，組成物須 配，含有活性成分懸浮於或溶解於載劑。 本發明化合物之局部投藥用載劑包括但非限於礦油、液體 石蠛、白軟石蠘、丙二醇、聚氧伸乙基聚氧伸丙基化合物、 乳化蠘及水。另外，組絲可麻成適當洗料乳膏劑， 含有活性化合物以適當乳化劑懸浮於或溶解於栽劑。適當 載劑包括但非限於礦油、山梨聚糖一油酸酯、玻利索貝 (polysorbate) 60、鯨蠟酯蠟、鯨蠟硬脂醇、2—辛某十二 垸醇、平醇及水。本發明組成物也可藉直腸拾劑調配物或 呈適當之沒腸調配物局部施用於下腸道。 局部經皮貼片也含括於本發明。本發明也包括貼片來 輪送本文之活性化學治療組合物。貼片包括如此處所示之 材料層（例如聚合物、布、紗布、繃帶）及此處所示化學式 化合物。材料層之一邊黏著有保護層來阻擋化合物戋組成 物的通過。貼片可額外包括黏著劑來將貼片於個體身體定 119 200825054 位 物 組成物之組成 可耐水。 。黏著劑為包括天然、 ，且當與個體皮声拯、…3 δ成來源之俎 黏著劑可置於貼/上=7可暫_著於皮膚 間。黏著劑可製作成具有沾接觸—段長時 觸時可將裳置固定定 Ί者強度，因此蓄意接 其它蓄意移除）時，_ ^有積極動作（例如扯、剥、或 外在壓力，切破糾謂置錄著劑本身的 言之，黏著劑允，由：黏著劑為感壓黏著劑，換 10 向皮膚定位 身’來將點著劑（以及欲黏著於皮膚之裝置）背 本發明組成物可藉鼻喷霧劑或吸入投予。 絲據製_配技藝界眾知之技術製備，且可製^ 於食鹽水之溶液劑’採用节醇或其它適當保藏劑、吸收促 15 進劑來提升生物率，且使用氟化碳類及/或其它技藝界 已知之增溶劑或分散劑。 具有本文之化學式化合物及額外藥劑（例如治療劑） 之組成物可使用本文所述投藥途徑投予。於若干實施例 中八有此處所示化子式化合物及額外藥劑（例如治療劑） 之組成物可使用可植入裝置投予。可植入裝置及相關技術 20為技藝界所已知，當需要連續釋放或定時釋放輸送本文所 述化合物或組成物時可用作為輸送系統。此外，可植入裝 置輸送系統可用作為化合物或組成物輸送之乾定特定點 (例如局部位置、器官）。―等人，生物材料，22⑹： 563(2_。涉及交替輪送法之定時輸送技術也可用於本發 120 200825054 明。舉例言之，基於聚合物技術、持續釋放技術及包膠技 術（例如聚合物、微脂粒）之定時釋放調配物也可用於輸送 本文所述化合物及組成物。 將於下列實施例進一步說明本發明。但須了解此等實 5 例僅供舉例說明之用而絕非視為囿限本發明。 範例 範例1 1-(乙基磺醢基）-3-氟苯Pharmaceuticals), 537 (197 〇), Azri, NY. In some embodiments, the composition is administered orally or by injection. The methods herein are contemplated to administer an effective amount of a compound or composition of the compound to achieve the desired effect or effect. Typically, the pharmaceutical compositions of this invention may be administered from about 1 to about 6 times daily, or alternatively, administered as a continuous infusion. Such administration can be used as a k-therapy or an acute treatment. The amount of active ingredient which can be combined with the carrier materials to produce a single dosage form will vary depending upon the host being treated and the particular mode of administration. A typical preparation will contain from about 5% to about 95% active compound (w/w). Further, such formulations contain from about 2% to about 80% active compound. 1〇 It may be necessary to administer lower doses or higher doses than previously mentioned. The specific dosing and treatment plan for any particular patient will be determined by a number of factors' such factors as the activity, age, weight, general health, sex, diet, time of administration, rate of excretion, drug combination of the particular compound used. , the severity of the disease and the course of the disease, the condition or symptoms, whether the patient is good or not, the disease, the condition or the symptoms, and the judgment of the treating physician. When the condition of the patient is improved, a maintenance dose of the compound, composition or composition of the present invention can be administered if desired. Then, when the symptoms have improved to a desired level, the dose or frequency of administration or both can be reduced to a level that maintains an improved condition as a function of the symptoms. However, when the symptoms of the disease recur 20 for a long time, the patient may need intermittent treatment. The compositions of the present invention may contain any conventional non-toxic pharmaceutically acceptable carrier, adjuvant or vehicle. In some cases, the oil of the formulation may be adjusted with a pharmaceutically acceptable acid, base, or buffer to enhance the stability of the formulated compound or its delivery form. 117 200825054, and the composition can be aseptic injection preparations. Suspension preparations, 10,, ..., 囷 injection water known technology suspension. The (iv) floatant can be used in accordance with the skill of the float agent, using a reading or wetting agent (such as Tween 80) and suspension 5 10 15 20 or solvent = injection preparation is also non-toxic and enterally acceptable Dilute ",, bacteria", a primary spray solution or suspension, such as a solution of butanediol, 9 sugar alcohols. The acceptable (four) agents and solvents include mannose / _ Lin's solution and Isotonic sodium dissolving with sterile fixed oil Μ — again, used as a bath or suspending medium. Used in any brand of 便 ^ ^ ^ mouth oil, including synthetic monoglycerides or diglycerides such as oil The acid and its glyceride derivative can be used in the preparation of an injection, such as a natural pharmaceutically acceptable oil such as eucalyptus oil or t sesame oil, which can be used as an oil for injection preparation, in particular, a polyoxylated ethylated version. Oil [Chengling Liquid and Suspension Agents also contain long-chain alcohol diluents or dispersants, or silk methyl cellulose, which are commonly used in the formulation of pharmaceutically acceptable formulations such as liquids and/or suspensions. Other commonly used surfactants such as 呑恩 or 史班(Span) and/or other similar emulsifiers or bioavailability enhancers, and the like, which are commonly used in pharmaceutically acceptable solid dosage forms, liquid dosage forms or other dosage forms, may also be used for formulation purposes. The composition of the present invention may be in any form. Orally acceptable dosage forms for oral administration include, but are not limited to, capsules, troches, emulsions, and aqueous suspensions, dispersions, and solutions. For tablets for oral use, for example, commonly used Carriers include lactose and corn starch. Lubricants such as magnesium stearate are also typically added. For oral administration in capsule form, useful diluents include cradle and dry corn starch. When aqueous suspensions and/or lotions When 118 200825054 floats or dissolves in the oil phase and is added to the emulsifier and/or may be added with several sweeteners and/or flavoring agents, the active ingredient may be suspended or suspended in combination. If necessary and/or colorant 5 10 15 The composition of this 也 也 can also be administered as a suppository for rectal administration. θ human / by using the compound of the present invention in a suitable non-irritating excipient Π" Room temperature As a solid in a liquid including but 'Ρ _ Solutions will rectal rpm at rectal temperature evolution of the active ingredient. Including but not limited to cocoa butter, bee poly. The composition of the present invention can be used for the desired treatment, which is convenient for the topical administration of the drug, for the topical application to the skin, the composition must be formulated, and the active ingredient is suspended or dissolved in the carrier. . Topical pharmaceutical carriers for the compounds of this invention include, but are not limited to, mineral oil, liquid sarcophagus, balsa sulphur, propylene glycol, polyoxyethylidene propyl propyl compound, emulsified hydrazine, and water. Alternatively, the filaments may be in the form of a suitable rinse cream containing the active compound suspended or dissolved in a suitable emulsifier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monooleate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, decyl alcohol and water. . The compositions of the present invention may also be topically applied to the lower intestinal tract by a rectal mass formulation or in a suitable enteric formulation. Topical transdermal patches are also included in the present invention. The invention also includes patches for the active chemotherapeutic compositions herein. The patch comprises a layer of material (e.g., polymer, cloth, gauze, bandage) as shown herein and a compound of the formula shown herein. A protective layer is adhered to one of the material layers to block the passage of the compound ruthenium composition. The patch may additionally include an adhesive to fix the patch to the individual body. 119 200825054 The composition of the composition is water resistant. . Adhesives include natural, and when it comes to individual skin, ... 3 δ into the source of the adhesive can be placed on the paste / top = 7 can be temporarily placed between the skin. The adhesive can be made to have a dip contact - the length of the segment can be fixed when the touch is fixed, so that when the deliberate connection is deliberately removed, the _ ^ has a positive action (such as pulling, peeling, or external pressure, Cut and confuse the words of the agent itself, the adhesive agent, by: adhesive as a pressure-sensitive adhesive, change the body to the skin 10 to place the agent (and the device to adhere to the skin) back The composition of the invention can be administered by nasal spray or by inhalation. It is prepared according to the technology known to the art, and can be used in the solution of saline solution, using alcohol or other suitable preservatives, and promoting absorption. Agents to increase biological rate, and use fluorinated carbons and/or other solubilizing or dispersing agents known to the art. Compositions having the chemical formulas herein and additional agents (e.g., therapeutic agents) can be administered using the routes of administration described herein. In some embodiments, a composition of a compound of the formula shown herein and an additional agent (e.g., a therapeutic agent) can be administered using an implantable device. The implantable device and related art 20 are within the skill of the art. Know when needed Continued or timed release can be used as a delivery system when delivering a compound or composition as described herein. In addition, an implantable device delivery system can be used as a specific point (eg, local location, organ) for delivery of a compound or composition. , Biomaterials, 22(6): 563 (2_. Timing transport technology involving alternating rounds can also be used in this issue 120 200825054. For example, based on polymer technology, sustained release technology and encapsulation technology (eg polymer, micro) The timed release formulation of the lipid granules can also be used to deliver the compounds and compositions described herein. The invention will be further illustrated by the following examples, but it should be understood that these 5 examples are for illustrative purposes only and are not considered as 囿The invention is limited to the following. Example 1 1-(ethylsulfonyl)-3-fluorobenzene

在氮氣下，將3-氟苯磺醯基氯化物（〇. 973 g，5. 00 10 _〇1)、碳酸氫鈉（〇· 84 g，10· 0 mmol)、和硫化鈉（1. 16 g， _〇1)之一經攪拌混合物在95-100 X的水（7 mL)中加熱1 小時。該反應冷卻至約50 °C，然後加入（nBu)4NBr (100 mg) 和乙基碘化物（2· 5 mL)，並在70 °C加熱18小時。冷卻該 反應，加入水（10 mL)並以二氣甲烷（3 X 15 mL)萃取。以 15 MgS〇4乾燥該萃取物並減壓濃縮。在矽膠上進行色層分析， 以10/90至40/60之乙酸乙酯/己烷梯度洗提以產生如一無 色油狀物之該標題化合物（878 mg)。 範例2-34 203-Fluorobenzenesulfonyl chloride (〇. 973 g, 5. 00 10 _〇1), sodium hydrogencarbonate (〇·84 g, 10·0 mmol), and sodium sulfide (1. One of 16 g, _〇1) was heated in 95-100 X water (7 mL) for 1 hour with stirring. The reaction was cooled to about 50 ° C, then (nBu) 4NBr (100 mg) and ethyl iodide (2.5 mL) were added and heated at 70 °C for 18 hours. The reaction was cooled, water (10 mL) was added andEtOAc was evaporated. The extract was dried with 15 MgS 〇 4 and concentrated under reduced pressure. Chromatography on silica gel eluting with a gradient of 10/90 to 40/60 ethyl acetate / hexanes to give the title compound (878 mg) as a colourless oil. Example 2-34 20

Hal w 辦 NaHCCXWa漭0#fe0 95-1W €#45 -€0分鐘Hal w Office NaHCCXWa漭0#fe0 95-1W €#45 - €0 minutes

HalHal

RiG_-8u|4N&/加熟/18 小時RiG_-8u|4N&/plus cooked/18 hours

以類似於上述範例1之方法，使用所對應之經鹵化的 200825054 適當的洗提液洗 芳基績醯基氣化物和烧化基藥劑，並以一 提來製備該下述的化合物。 範例2 5 3-[(2-氟苯基)磺醢基>1-丙酵 基氣化物以 備該標題化 使用2-氟苯磺醯基氣化物當成該芳基續醜 及使用3-溴基-1-丙醇當成該烧化基藥劑來製 合物。 MS (ES) m/z 219.0 ；The following compound was prepared by a method similar to that of the above Example 1, using the corresponding halogenated 200825054 appropriate eluent to wash the aryl sulfhydryl group and the burn-in-based agent. Example 2 5 3-[(2-Fluorophenyl)sulfonyl> 1-propanyl carbide for use in the title formation using 2-fluorobenzenesulfonyl sulphate as the aryl group continues to be ugly and uses 3- Bromo-1-propanol is prepared as the burn-in agent. MS (ES) m/z 219.0;

ίο HRMS:計算值 C9HuF〇3S + H+，219. 04857;實測值（ESIΊο HRMS: Calculated value C9HuF〇3S + H+, 219. 04857; measured value (ESI

[Μ+ΗΓ)，219.0489。 範例3 15 1-氟基-3-(甲基磺醢基）苯 使用3-氟苯石黃醯基氣化物當成該芳基俩基氯化物以 及使用碘甲烷當成該烷化基藥劑來製備該標題化合物。 MS (ES) /Z7/Z 175. 0。 20 範例4 3-[(3-氟苯基)磺醢基]-2,2-二甲基_1_丙酵 使用3-氟苯雜基氣化物當成該芳基俩基氣化物以 及使用4-溴基-2-曱基-2-丁醇當成該烧化基藥劑來製備該 標題化合物。 122 200825054 MS (ES) /z//z 246· 9。 範例5 5-[ (3-氟苯基)續酿基]-1-戊酵 5 使用3-氟苯磧醢基氯化物當成該芳基續醯基氯化物以 及使用5-溴基-1-戊醇當成該烷化基藥劑來製備該標題化 合物。 MS (ES) yz//z 246· 9。 ίο 範例6 1，3-二氟-5-（甲基確酿基）苯 使用3, 5-二氟苯磺醯基氯化物當成該芳基磺醯基氯化 物以及使用碘甲烷當成該烷化基藥劑來製備該標題化合 物。 15 MS (El) /Z7/Z 192。 範例7 4-氟基-1_甲基-2 -（甲基確酿基）苯 使用5-氟基-2-甲基苯-1-磺醯基氯化物當成該芳基磺 20 醯基氯化物以及使用碘曱烷當成該烷化基藥劑來製備該標 題化合物。 mp 77 °C ; MS (ES) /Z//Z 188· 9。 範例8 123 200825054 4-溴基-1-甲基-2-(甲基續醢基）苯 使用5-溴基-2-甲基苯-1-磺醯基氯化物當成該芳義# 醯基氣化物以及使用碘甲烷當成該烷化基藥劑來製備兮授 題化合物。 mp 121 °C 〇 範例9 4-溴基-2-（乙基磺醢基）一1 一甲基苯 10 使用5-溴基-2-甲基苯-1-石黃醯基氯化物當成該芳美石里 醯基氯化物以及使用碘乙烷當成該烷化基藥劑來製備該^ 題化合物。 mp 49 °C ； MS (ES) m/z 262. 7 ° 範例10 卜氟基-3-[(3-甲基丁基)磺醢基]苯 使用3-氟苯磺醯基氣化物當成該芳基磺醯基氣化物以 及使用1-溴基-3-甲基丁烷當成該烷化基藥劑來製備該標 題化合物。 MS (ES)231.0。 範例 11 卜氟基-3-(異丁基磺醢基）苯 使用3_氣本~酿基氣化物當成該芳基績酿基氯化物以 及使用1-溴基-2-甲基丙烷當成該烷化基藥劑來製備該標 124 200825054 題化合物。 MS (ES)仞/z 217. 0。 範例12 5 1-氟基-3-(丙基確酿基）苯 使用3-氟苯磺醯基氯化物當成該芳基磺醯基氯化物以 及使用1-碘丙烷當成該烷化基藥劑來製備該標題化合物。 MS (ES) Λ//Ζ 203. 0。 ίο 範例13 3-[(3-氟苯基）續酸基]-1-丙酵 使用3-氟苯磺醯基氯化物當成該芳基磺醯基氯化物以 及使用3-溴基-1-丙醇當成該烷化基藥劑來製備該標題化 合物。。 15 MS (ES) y/7/z 218_ 9 ; HRMS:計算值 CeHuFOsS + H+， 219.04857;實測值（ESI，[Μ+ΗΓ)，219.0475。 範例14 1-氟基-3-(異丙基碟酿基）苯 20 使用3-氟苯磺醯基氯化物當成該芳基磺醯基氯化物以 及使用2-碘丙烷當成該烷化基藥劑來製備該標題化合物。 MS (ES) Λ//Ζ 203· 0。 範例15 125 200825054 1-（苄基磺醯基）-3-氟苯 使用3-氟苯磺醯基氣化物當成該芳基磺醯基氯化物以 及使用苄基溴化物當成該烷化基藥劑來製備該標題化合 物。 mp 134-135 沱；HRMS:計算值 Cl3HllF〇2S， 250.04638 ;實測值（El, M+·)，250.0469。 ’ 範例 16 1，3-二氣基-5-(丙基磺醢基）苯 10 使用3, 5—二氯苯磺醯基氯化物當成該芳基磺醯基氣化 物以及使用1-碘丙烷當成該烷化基藥劑來製備該標題化人 物。 mp 59-61 °C ; MS (ES) 252_9 ; HRMS:計算值 C9Hi〇Cl2〇2S，251· 97785 ;實測值（ΕΙ，Μ+· )，251 9776。 15 範例17 3-[(3, 5-二氣苯基）磺醢基]-1-丙酵 使用3, 5-二氯苯磺醯基氣化物當成該芳基續醯基氯化 物以及使用3-溴基-1-丙醇當成該烷化基藥劑來製備該標 20 題化合物。 mp 80-82 °C ; MS (ES) 268·9 。 範例18 1-氟基-3 - [(3-甲氧基丙基)磺醢基]苯 126 200825054 使用3-氟苯績醯基氯化物當成該芳基磺醯基氯化物工乂 及使用1-溴基-3-甲氧基丙烷當成該烷化基藥劑來製備該 標題化合物。 MS(ES)/z//z 233. 0 ; HRMS:計算值 C1GH13F〇3S + H+ 5 233.06422 ;實測值（ESI，[M+H]+)，233.0643。 範例19 1, 3-二氯基-5_[(3-甲基丁基）磺醢基]苯 使用3, 5-二氯苯磺醯基氯化物當成該芳基磺醯基氯化 ίο物以及使用1-漠基-3-甲基丁烧當成該烧化基藥劑來製備 該標題化合物。 mp 64-65 °C ; MS (ESI) 280 ; HRMS:計算值 C11H14CI2O2S，280.00915;實測值（EI，M+·)，280 〇〇78。 15 範例20 1-(環戊基磺醢基）-3-氟苯 使用3-氟苯磺醯基氯化物當成該芳基磺醯基氣化物以 及使用環戊基碘化物當成該烷化基藥劑來製備該標題化合 物。 20 MS (ES) λ//ζ 229· 0。 範例21 4-[ (3-氟苯基）磺醢基]一 2一甲基一 2-丁酵 使用3-氟苯績醯基氣化物當成該芳基伽基氯化物以 127 200825054 及使用4-溴基-2-甲基-2-丁醇當成該烷化基藥劑來製備該 標題化合物。 MS (ES) m/z 229. 1 [M+H-H20] + l 5 範例22 1，4-二溴基-2-（甲基磺醢基）苯 使用2, 5-二溴苯磺醯基氯化物當成該芳基磺醯基氯化 物以及使用甲基碘當成該烷化基藥劑來製備該標題化合 物。 10 MS (ES) ZZ//Z 312· 6。 範例23 4-溴基-1 -甲氧基-2-(甲基磺醢基）苯 使用5-溴基-1-甲氧基-苯磺醯基氯化物當成該芳基磺 15 醯基氯化物以及使用甲基碘當成該烷化基藥劑來製備該標 題化合物。 MS (ES) m/z 264. 8 〇 . 範例24 20 1_氟基-4-(丙基續酿基）苯 使用4-氟苯磺醯基氯化物當成該芳基磺醯基氣化物以 及使用碘丙烷當成該烷化基藥劑來製備該標題化合物。 MS (ES) /ff/z 203· ：1。 128 200825054 範例25 1 - (稀丙基續醢基）-4-氟基苯 使用4-就苯磺酸基氯化物當成該芳基磺醯基氯化物以 及使用烯丙基溴化物當成該烷化基藥劑來製備該標題化人 5物。 。 MS (ES) 201. 0。 範例2 6 1-氯基-3-{[(4-氟基苯基)磺醢基]甲基}苯 10 使用4—氟苯磺醯基氯化物當成該芳基磺醯基氣化物以 及使用1-(溴甲基）-3-氯苯當成該烷化基藥劑來製備該桿 題化合物。 MS (ES) 282_ 9。 15 範例27 卜氟基-4-(異丁基磺醢基）苯 使用4-氟本^頁酿基氣化物當成該芳基續酿基氣化物以 及使用1-溴基-3-甲基丁烷當成該烷化基藥劑來製備該標 題化合物。 20 MS (ES) 217. 0。 範例28 (4-{[(4-氟苯基）磺醢基]甲基}苯基）乙酸乙酯 使用4-氟苯磺醯基氯化物當成該芳基磺醯基氯化物以 129 200825054 及使用2-(4-(溴甲基）苯基）乙酸乙酯當成該烷化基藥劑來 製備該標題化合物。 MS (ES) /z//z 337_ 0。 5 範例29 1-氟基-4 - [(3-甲基丁基)磺醢基]苯 使用4-氟苯石黃醯基氣化物當成該芳基續酿基氣化物以 及使用卜漠基-3-甲基丁烧當成該院化基藥劑來製備該標 題化合物。 1〇 MS (ES) π/ζ 231·0 。 範例30 1-(環戊基磺醢基）-4-氟苯 使用4-氟苯磺醯基氣化物當成該芳基磺醯基氯化物以 15及使用磁環戊烧當成該烷化基藥劑來製備該標題化合物。 MS (ES) 229· 0。 範例31 3-[ (4-氣苯基)續殖基]-1-丙酵 2〇 使用4-氟苯磺醯基氣化物當成該芳基磺醯基氯化物、 及使用3-溴基-1-丙醇當成該烷化基藥劑來製備哕枳曰、 合物 MS (ES)你// 219.0 ; HRMS:計算值 c9HuF〇3S + 219.04857 ;實測值（ESI，[Μ+ΗΓ)，219.048。 + 130 200825054 範例32 1_( 丁基殘酿基）-4-氣苯 使用4-氟苯磺醯基氯化物當成該芳基磺醯基氣化物以 5 及使用碘丁烷當成該烷化基藥劑來製備該標題化合物。 MS (ES) y/7/z 217. 0。 範例33 1-氟基-2-{[(4-氟苯基)磺醯基]甲基}苯 10 使用4-氟苯磺醯基氯化物當成該芳基磺醯基氣化物以 及使用1-(溴甲基）-2-氟苯當成該烷化基藥劑來製備該標 題化合物。 MS (El) zzz/z 268。 15 範例34 2, 5-二甲基苄基-4-氣苯基填 使用4-氟苯磺醯基氣化物當成該芳基磺醯基氣化物以 及使用2-(溴甲基）-1，4-二甲基苯當成該烷化基藥劑來製 備該標題化合物。 20 MS (ESI)瓜/z 278。 範例35 1-氟基-3-(異丙基續酿基）苯 在氮氣下，將3-氟苯硫醇（3. 38 mL，40. 0 mmol)、碳 131 200825054 酸鉀（11_ 04 g，80· 0 mmol)、和 2-峨丙烧（6· 00 mL，60· 0 mmol) 之—經攪拌混合物在65-70 °C的丙酮（120 mL)中加熱2. 5 小時。冷卻該反應後，加入〇· 3 Μ之含碳酸氫鈉的水（240 mL)，然後逐部份的加入0Χ0ΝΕ® (61. 6 g)並在室溫攪拌18 5小時。加入水（100 mL)至該反應中並以二氯甲烷（2 X 150 mL) 卒取。以MgS〇4乾燦该卒取物並減壓濃縮。在碎膠上進行色 層分析，以25/75至50/50之乙酸乙酯/己烷梯度洗提以產 生如一淡橘色溶液之該標題化合物（6· 21 計算 值 CgHuFOzS，202.04638;實測值（ΕΙ，Μ+·)，202.0469。 10[Μ+ΗΓ), 219.0489. EXAMPLE 3 15 1-Fluoro-3-(methylsulfonyl)benzene The following title compound was prepared using 3-fluorophenylphosphonium sulphate as the aryl yl chloride and using methyl iodide as the alkylating agent. . MS (ES) / Z7/Z 175. 0. 20 Example 4 3-[(3-Fluorophenyl)sulfonyl]-2,2-dimethyl-1-propanyl-propionate using 3-fluorobenzene-based gasification as the aryl-based gasification and use of 4 - bromo-2-mercapto-2-butanol as the alkylating agent to prepare the title compound. 122 200825054 MS (ES) /z//z 246· 9. EXAMPLE 5 5-[(3-Fluorophenyl) continuation]-1-pentyl 5 The use of 3-fluorophenylhydrazine chloride as the aryl hydrazino chloride and the use of 5-bromo-1- Pentanol is used as the alkylating agent to prepare the title compound. MS (ES) yz//z 246· 9. Οο Example 6 1,3-Difluoro-5-(methyl aryl) benzene using 3,5-difluorobenzenesulfonyl chloride as the arylsulfonyl chloride and using methyl iodide as the alkylation The title compound is prepared by a base agent. 15 MS (El) / Z7/Z 192. Example 7 4-Fluoro-1 -methyl-2 -(methyl aryl) benzene using 5-fluoro-2-methylphenyl-1-sulfonyl chloride as the aryl sulfonyl 20 decyl chloride The title compound is prepared by the use of the iodide as the alkylating agent. Mp 77 °C; MS (ES) /Z//Z 188· 9. Example 8 123 200825054 4-bromo-1-methyl-2-(methyl decyl) benzene using 5-bromo-2-methylphenyl-1-sulfonyl chloride as the aryl group The vaporized compound is prepared using the methyl iodide as the alkylating agent. Mp 121 °C 〇Example 9 4-Bromo-2-(ethylsulfonyl)-1-methylbenzene 10 Using 5-bromo-2-methylphenyl-1-stone as the aragonite The compound is prepared by using ruthenium chloride and using iodoethane as the alkylating agent. Mp 49 °C; MS (ES) m/z 262. 7 ° Example 10 fluoroamino-3-[(3-methylbutyl)sulfonyl]benzene using 3-fluorobenzenesulfonyl carboxide as the The title compound is prepared from an arylsulfonyl vapor and using 1-bromo-3-methylbutane as the alkylating agent. MS (ES) 231.0. Example 11 fluoroamino-3-(isobutylsulfonyl)benzene is used as the aryl base chloride and 1-bromo-2-methylpropane is used as the The alkylating agent is used to prepare the compound of claim 124 200825054. MS (ES) 仞/z 217. 0. Example 12 5 1-Fluoro-3-(propyl-propyl) benzene using 3-fluorobenzenesulfonyl chloride as the arylsulfonyl chloride and using 1-iodopropane as the alkylating agent The title compound was prepared. MS (ES) Λ//Ζ 203. 0. Οο Example 13 3-[(3-Fluorophenyl)sutra]-1-propanyl-propanyl 3-fluorobenzenesulfonyl chloride as the arylsulfonyl chloride and 3-bromo-1- The title compound is prepared as propanol as the alkylating agent. . </RTI> <RTI ID=0.0></RTI> </ RTI> <RTI ID=0.0></RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Example 14 1-Fluoro-3-(isopropyl broth) benzene 20 Using 3-fluorobenzenesulfonyl chloride as the arylsulfonyl chloride and using 2-iodopropane as the alkylating agent To prepare the title compound. MS (ES) Λ//Ζ 203· 0. Example 15 125 200825054 1-(Benzylsulfonyl)-3-fluorobenzene uses 3-fluorobenzenesulfonyl vapor as the arylsulfonyl chloride and benzyl bromide as the alkylating agent The title compound was prepared. Mp 134-135 沱; HRMS: calculated Cl3HllF 〇 2S, 250.04638; found (El, M+·), 250.0469. 'Example 16 1,3-Dimethyl-5-(propylsulfonyl)benzene 10 Using 3,5-dichlorobenzenesulfonyl chloride as the arylsulfonyl vapor and using 1-iodopropane The titled person is prepared as the alkylating agent. Mp 59-61 ° C; MS (ES) 252 </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 15 Example 17 3-[(3, 5-Diphenyl)sulfonyl]-1-propanyl using 3,5-dichlorobenzenesulfonyl sulphate as the aryl hydrazino chloride and using 3 - bromo-1-propanol as the alkylating agent to prepare the title compound. Mp 80-82 °C; MS (ES) 268·9. Example 18 1-Fluoro-3 -[(3-methoxypropyl)sulfonyl]benzene 126 200825054 Using 3-fluorobenzene fluorenyl chloride as the arylsulfonyl chloride plant and using 1 - bromo-3-methoxypropane as the alkylating agent to prepare the title compound. MS (ES) / z / /z </RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; Example 19 1, 3-Dichloro-5-[(3-methylbutyl)sulfonyl]benzene using 3,5-dichlorobenzenesulfonyl chloride as the arylsulfonyl chloride The title compound was prepared using 1-carbyl-3-methylbutane as the burn-in base. Mp 64-65 ° C; MS (ESI) 280; HRMS: calcd. C </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 15 Example 20 1-(cyclopentylsulfonyl)-3-fluorobenzene using 3-fluorobenzenesulfonyl chloride as the arylsulfonyl vapor and using cyclopentyl iodide as the alkylating agent To prepare the title compound. 20 MS (ES) λ//ζ 229· 0. Example 21 4-[(3-Fluorophenyl)sulfonyl]-2-methyl- 2-butyrin using 3-fluorobenzene as the sulfhydryl hydride as the aryl galactyl chloride as 127 200825054 and use 4 - bromo-2-methyl-2-butanol as the alkylating agent to prepare the title compound. MS (ES) m/z 229. 1 [M+H-H20] + l 5 Example 22 1,4-Dibromo-2-(methylsulfonyl)benzene using 2,5-dibromobenzenesulfonate The title compound is prepared as the arylsulfonyl chloride and using methyl iodide as the alkylating agent. 10 MS (ES) ZZ//Z 312· 6. Example 23 4-Bromo-1-methoxy-2-(methylsulfonyl)benzene using 5-bromo-1-methoxy-benzenesulfonyl chloride as the arylsulfonyl 15 fluorenyl chloride The title compound is prepared by the use of methyl iodide as the alkylating agent. MS (ES) m/z 264. 8 〇. Example 24 20 1_Fluoro-4-(propyl continuation) benzene using 4-fluorobenzenesulfonyl chloride as the arylsulfonyl vapor and The title compound was prepared using iodopropane as the alkylating agent. MS (ES) / ff / z 203 · : 1. 128 200825054 Example 25 1 - (Dilylpropyl fluorenyl)-4-fluorobenzene using 4- benzenesulfonate chloride as the arylsulfonyl chloride and using allyl bromide as the alkylation The title agent was used to prepare the titled human 5 material. . MS (ES) 201. 0. Example 2 6 1-Chloro-3-{[(4-fluorophenyl)sulfonyl]methyl}benzene 10 Using 4-fluorobenzenesulfonyl chloride as the arylsulfonyl vapor and use 1-(Bromomethyl)-3-chlorobenzene is used as the alkylating agent to prepare the compound. MS (ES) 282_ 9. 15 Example 27 fluoroyl-4-(isobutylsulfonyl)benzene using 4-fluorobenzyl sulphate as the aryl sulphonate and 1-bromo-3-methylbutene The title compound is prepared as the alkylating agent. 20 MS (ES) 217. 0. Example 28 (4-{[(4-Fluorophenyl)sulfonyl)methyl}phenyl)acetate using 4-fluorobenzenesulfonyl chloride as the arylsulfonyl chloride to 129 200825054 and The title compound was prepared using 2-(4-(bromomethyl)phenyl)acetate as the alkylating agent. MS (ES) /z//z 337_ 0. 5 Example 29 1-Fluoro-4 - [(3-methylbutyl)sulfonyl] benzene using 4-fluorophenyl fluorenyl valence as the aryl hydride and the use of chlorin-3-methyl Ding was used as the base compound to prepare the title compound. 1〇 MS (ES) π/ζ 231·0. Example 30 1-(cyclopentylsulfonyl)-4-fluorobenzene using 4-fluorobenzenesulfonyl sulfoxide as the arylsulfonyl chloride as 15 and using magnetic cyclopentane as the alkylating agent To prepare the title compound. MS (ES) 229· 0. Example 31 3-[(4-Phenylphenyl)propanyl]-1-propanyl 2 〇 using 4-fluorobenzenesulfonyl sulfoxide as the arylsulfonyl chloride, and using 3-bromo- 1-propanol is used as the alkylating agent to prepare the oxime compound MS (ES). You / 219.0; HRMS: Calculated C9HuF 〇 3S + 219.04857; found (ESI, [Μ+ΗΓ), 219.048. + 130 200825054 Example 32 1_(butyl residual)-4- benzene using 4-fluorobenzenesulfonyl chloride as the arylsulfonyl vapor as 5 and using iodine butane as the alkylating agent To prepare the title compound. MS (ES) y/7/z 217. 0. Example 33 1-Fluoro-2-{[(4-fluorophenyl)sulfonyl]methyl}benzene 10 Using 4-fluorobenzenesulfonyl chloride as the arylsulfonyl vapor and using 1- The title compound is prepared as (bromomethyl)-2-fluorobenzene as the alkylating agent. MS (El) zzz/z 268. 15 Example 34 2, 5-Dimethylbenzyl-4- phenyl phenyl hydride using 4-fluorobenzenesulfonyl sulphate as the aryl sulfonyl sulphate and using 2-(bromomethyl)-1, The title compound was prepared as 4-alkylbenzene as the alkylating agent. 20 MS (ESI) melon / z 278. Example 35 1-Fluoro-3-(isopropyl)-Benzene Benzene 3-Fluorobenzenethiol (3.38 mL, 40.0 mmol), Carbon 131 200825054 Potassium Acid (11_04 g) under nitrogen 5小时。 Heated in an acetone (120 mL) at 65-70 ° C for 2.5 hours. After cooling the reaction, 〇·3 Μ························ Water (100 mL) was added to the reaction and was taken in dichloromethane (2 X 150 mL). The residue was dried with MgS 4 and concentrated under reduced pressure. The chromatographic analysis was carried out on a granule, eluting with a 25/75 to 50/50 ethyl acetate/hexane gradient to give the title compound as a pale orange solution (6·21 calculated value CgHuFOzS, 202.04638; (ΕΙ,Μ+·), 202.0469. 10

範例36 $训 -K2C0觀關 SH 齡7〇沱落3小時 feiaqNaHCO^ JOIONE 窒溫/18至48小時Example 36 $ training - K2C0 Guan SH age 7 fallen 3 hours feiaqNaHCO^ JOIONE 窒 temperature / 18 to 48 hours

以類似於上述範例35之方法，使用所對應之經齒化的 硫盼和烧化基_ R—LG，並[適㈣洗提液洗提來製備 讜下述的化合物。 範例36 1-氟基-3-（甲基磺醢基）苯 以及使用碘甲烷當成該烷 使用3-氟苯硫醇當成該硫紛 化基藥劑來製備該標題化合物。 132 20 200825054 MS (ES) m/z 175. 1 範例37 1-(乙基續酿基）-3-氣苯 5 使用3-氟苯硫醇當成該硫酚以及使用碘乙烷當成該烷 化基藥劑來製備該標題化合物。 MS (ES) m/z 189. 0 範例38 ίο 3-[ (3-氟苯基）項酿基]-1-丙酵 使用3-氟苯硫醇當成該硫紛以及使用3-漠基-1-丙醇 當成該烷化基藥劑來製備該標題化合物。 MS (ES) m/z 218. 9 15 範例39 4-[(3-氟苯基)確酿基]-2-甲基-2-丁酵 使用3-氟苯硫醇當成該硫酚以及使用4-甲基苯磺酸 3-羥基-3-甲基丁酯當成該烷化基藥劑來製備該標題化合 物。 20 MS (ES) m/z 229. 1 [M+H-H20] + l 範例40 1-氟基-3-(甲基續酿基）苯 133 200825054 將1-&gt;臭基-3-氟苯（ΐ〇· 〇 g，57· 1 mmol)、甲烧亞石黃酸 鈉（7· 〇〇 g ’ 68· 6 mmol)、CuK1· 〇8 g，5· 71 _〇1)、L—捕 氨酸（1.31 g, 11· 4 mmol)和氫氧化鈉（0.456 g，114_〇1) 之一經攪拌混合物在95 的DMS〇(135 mL)中加熱一整夜 (大約18小時）。冷卻該反應後，以水稀釋，然後以乙酸乙 酯（2 X 150 mL)萃取。以MgS〇4乾燥該萃取物並減壓濃縮。 在矽膠上進行色層分析，以25/75之乙酸乙酯/己烷洗提以 生如無色固狀物之该標題化合物（6. 21 g)。MS (ES) /7/^ 175.卜 範例41至42The compound described below was prepared by a method similar to that of the above Example 35, using the corresponding dentate thiophenanthrene and sinter _ R-LG, and [equivalent (4) eluent elution. Example 36 1-Fluoro-3-(methylsulfonyl)benzene and the use of methyl iodide as the alkane The title compound was prepared using 3-fluorobenzenethiol as the sulfur sulfonating agent. 132 20 200825054 MS (ES) m/z 175. 1 Example 37 1-(ethyl continuation)-3- benzene benzene 5 using 3-fluorobenzenethiol as the thiophenol and using ethyl iodide as the alkylation The title compound is prepared by a base agent. MS (ES) m/z 189. 0 Example 38 ίο 3-[(3-Fluorophenyl) aryl]-1-propanyl using 3-fluorobenzenethiol as the sulphur and using 3-climate- The title compound is prepared as 1-propanol as the alkylating agent. MS (ES) m/z 218. 9 15 Example 39 4-[(3-Fluorophenyl)-yield]-2-methyl-2-butyrin using 3-fluorobenzenethiol as the thiophenol and The title compound was prepared as the alkylating agent as 3-hydroxy-3-methylbutyl 4-methylbenzenesulfonate. 20 MS (ES) m/z 229. 1 [M+H-H20] + l Example 40 1-Fluoro-3-(methyl styrene) benzene 133 200825054 1-&gt; Benzene (ΐ〇·〇g, 57·1 mmol), sodium sulphate (7· 〇〇g '68·6 mmol), CuK1·〇8 g, 5·71 _〇1), L- One of the amino acid (1.31 g, 11. 4 mmol) and sodium hydroxide (0.456 g, 114_〇1) was heated in a mixture of 95 mL of DMS (135 mL) overnight (about 18 hours). After cooling the reaction, it was diluted with water and then extracted with ethyl acetate (2×150 mL). The extract was dried with MgS 4 and concentrated under reduced pressure. The title compound (6. 21 g) was obtained as a colorless solid. MS (ES) /7/^ 175. Bu Examples 41 to 42

CulL 氨酸綱 簡气：/18小時CulL is a simple gas: /18 hours

以類似於上述範例40之方法，使用適當的芳基溴化 15 物’並以一適當的洗提液洗提來製備該下述的化合物。 範例41 1-氣基-3-氟基-5-（甲基續酿基）苯 使用1-溴基-3-氣基-5-氟苯當成該芳基溴化物來製備 〇 為標題化合物。 MS (El) m/z 208 134 200825054 範例42 1, 3-二氟基-5-(甲基磺醢基）苯 使用1 -&gt;臭基_3, 5-—氟本當成該芳基溴化物來製備兮 標題化合物。 5 MS (ΕΙ) Λ//Ζ 192。 範例43 4 - {3-[3-(乙基磺醢基）苯氧基]苯基卜3—甲基—8—(三 氟甲基）喹啉 1〇 在氮氣下，將3-（3-甲基-8-（三氟甲基）一4一喹啉基）酚 (91 mg，0· 30 mmol)、1-(乙基磺醯基）—3_氟苯（85 呃，〇.奶 mmol)、和碳酸鉀（58 mg，〇· 60 mmol)之一經攪拌混合物 在150 °C的DMF(1.5 mL)中加熱18小時。冷卻該反應後， 加入水（5 mL)，然後以二氣甲烷（3 χ 5 mL)萃取。以_〇4 15乾燥該萃取物並減壓濃縮。在矽膠上進行色層分析，以 10/90至40/60梯度之乙酸乙酯/己烷洗提以產生如一暗灰 色固狀物之該標題化合物（136 mg)。MS (ES) m/z 4718。 HRMS:計算值 C25H2〇F3N〇3S + H+，472.11887;實測值（ESI， [M+H] + )，472.1194。 範例44 1狀The following compounds were prepared in a manner similar to that of Example 40 above, using the appropriate aryl bromide&apos; and eluting with a suitable eluent. Example 41 1-Actyl-3-fluoro-5-(methyl aryl) benzene The title compound was prepared using 1-bromo-3-yl-5-fluorobenzene as the aryl bromide. MS (El) m/z 208 134 200825054 Example 42 1, 3-difluoro-5-(methylsulfonyl)benzene using 1 -&gt; odorant_3, 5-fluoro is present as the aryl bromide The compound was prepared to give the title compound. 5 MS (ΕΙ) Λ//Ζ 192. Example 43 4 - {3-[3-(ethylsulfonyl)phenoxy]phenyldi-3-methyl-8-(trifluoromethyl)quinoline 1〇 3-(3) under nitrogen -Methyl-8-(trifluoromethyl)- 4-quinolinyl)phenol (91 mg, 0·30 mmol), 1-(ethylsulfonyl)-3-fluorobenzene (85 呃, 〇. Milk (mmol) and one of potassium carbonate (58 mg, 〇 60 mmol) were heated in a stirred mixture at 150 ° C in DMF (1.5 mL) for 18 h. After cooling the reaction, water (5 mL) was added and then extracted with di-methane (3 EtOAc). The extract was dried with _ 〇 4 15 and concentrated under reduced pressure. Chromatography on silica gel eluting with a gradient of 10/90 to 40/60 ethyl acetate/hexanes to afford the title compound (136 mg) as a dark solid. MS (ES) m/z 4718. HRMS: calcd for C.sub.2, s, s, s, s, s, s, s, s, s, s, s. Example 44 1 shape

135 200825054 以類似於上述範例43之方法，使用所對應之經_化的 芳基颯和嗤淋齡芳基溴化物，並以一適當的洗提液洗提來 製備該下述的化合物。當在矽膠上正相純化不會產生純化 合物時，使用逆相色層分析之額外的純化過程來進一步純 5 化該化合物。在一些實例中，使用乙酸乙酯代替在萃取步 驟中之二氯甲烷。 範例44 3-甲基-4-{3 - [3-（丙基磺醸基）苯氧基]苯基卜8—(三 1〇 氟甲基）喹啉 MS(ES) m/z 485.8 ; HRMS:計算值 C26H22F3N〇3S + 486· 13452;實測值（ESI，[M+H] + )，486. 1326。 範例 45 15 4-{3-[3-（異丙基續酸基）苯氧基]苯基}-3-甲基 -8-(三氟甲基）啥琳 MS(ES)m/z 485.8 ; HRMS:計算值 C26H22F3N〇3S + H+， 486.13452;實測值（ESI, [M+H] + )，486.1349。 20 範例46 4-{3-[3-(苄基磺醢基）苯氧基]苯基}-3-甲基-8〜（三 氟甲基）喹啉 MS(ES) m/z 533·8 ; HRMS:計算值 C3〇H22F3N〇3S + H+， 534.13452;實測值（ESI，[M+H] + )，534.1346。 136 25 200825054 範例47 3-甲基-4-{3-[2-(甲基磺醢基）苯氧基]苯基卜8-(三 氟甲基）考琳 mp 203-205 °C ; MS(ES) m/z 457.8 ; HRMS:計算值 5 C24H18F3N〇3S + H+，458. 10322 ;實測值（ESI，[M+H] + )， 458·1016 。 範例48 4 - {3 - [3-(異丁基磺醢基）苯氧基]苯基}-3-甲基 ίο -8-(三氟甲基）喹啉 MS(ES) m/z 499.8 ; HRMS:計算值 C27H24F3N〇3S + H+， 500.15017 ;實測值（ESI, [M+H] + )，500. 1494。 範例49 15 3一甲基-4-(3-{3-[(3_甲基丁基）磺醢基]苯氧基}苯 基)-8 - (三氟甲基)喹啉 MS (ES) m/z 513.8 ; HRMS:計算值 C28H26F3N〇3S + H+， 514· 16582;實測值（ESI, [M+H] + )，514 1642。 20 範例51 3 - [(2 - {3 - [3 -甲基-8- (三氟甲基)一4-舍淋基]苯氧基}苯基) 磺酸基]-1-丙酵 mp 73-75 °C (圖形並不非常陡）；MS (ES) m/z 501. 8 ; HRMS:計算值 C26H22F3N〇4S + H+，502.12944;實測值（ESI, 137 200825054 [M+H]+)， 502·1281 。 範例51 4-{3-[3-氯基-5-(丙基磺醢基）苯氧基]苯基卜3-甲基 5 - 8-(三氟甲基)喹琳 MS (ES) m/z 519. 7 ; HRMS:計算值 C26H21ClF3N〇3S + H+， 520.09555;實測值（ESI，[M+H]+)，520.0947。 範例52 ι〇 3-[(3-{3-[3-甲基-8 - (三氟甲基)- 4-喹啉基]苯氧基}苯基) 續班基]-1-丙酵 MS (ES) m/z 501.8 ； HRMS:計算值 C26H22F3N〇4S + H+， 502_ 12944;實測值（ESI，[M+H]+)，502.1304。 15 範例53 4-(3-{3_[(3-甲氧基丙基)磺醢基]苯氧基}苯基)-3-甲基 -8-(三氟甲基)啥琳 MS (ES) m/z 515· 9 ; HRMS:計算值 C27H24F3N〇4S + H+, 516.14509;實測值（ESI, [M+H]+), 516.1458。 20 範例54 4-(3-{3-氣基-5-[(3-甲基丁基)確斑基]苯氧基}苯基)-3_ 甲基-8-(三氟甲基)喹啉 MS(ES)m/z 548.0; HRMS:計算值 C28H25ClF3N〇3S + H+， 138 200825054 548.12685;實測值（ESI，[M+H] + )，548. 1264。 範例55 3 - [(4 - {3 - [3-甲基-8-(三氟甲基)-4-喹啉基]苯氧基}苯基) 5 確斑基]-1-丙醇 MS (ES) m/z 502. 0 ; HRMS:計算值 C26H22F3N〇4S + H+， 502.12944;實測值（ESI，[M+H] + )，502.1301。 範例56 10 3-甲基-4 - {3-[4-（甲基磺醢基）苯氧基]苯基}-8-（三 氟甲基）喹啉 MS (ES) m/z 458.0 ; HRMS:計算值 C24H18F3N〇3S + H+， 458.10322;實測值（ESI，[M+H] + )，458.1037。 15 範例 57 2- 甲基-4-[ (3-{3- [3-甲基-8-(三氟甲基)-4-喹啉基]苯氧 基}苯基)磺醢基]-2-丁酵 MS (ES) m/z 529. 8 ; HRMS:計算值 C28H26F3N〇4S + H+， 530.16074;實測值（ESI，[M+H] + )，530· 159。 20 範例58 3- 苄基-8-氣基-4-{3-[3-(甲基磺醢基）苯氧基]苯基} 喹啉 MS (ES) m/z 499. 9 ； HRMS:計算值 C29H22ClN〇3S + H+, 139 200825054 500.10817;實測值（ESI，[M+H] + )，500.1083。 範例59 3-甲基-4-{3-[3-（甲基磺醢基）苯氧基]苯基卜8-(三 5氟甲基）喹啉 MS (ES) m/z 457. 8 ； HRMS:計算值 C24H18F3NO3S + H+， 458.10322;實測值（ESI，[M+H] + )，458.1017。 範例 60 ίο 4-{3-[3-氟基-5-（甲基磺醢基）苯氧基]苯基}-3_甲基 -8-（三氟甲基）考琳 MS (ES) m/z 475.8 。 範例61 15 8-氯基-3-甲基-4-{3-[3-（甲基磺醢基）苯氧基]苯基} 喹啉 MS (ES) m/z ML 1 ； HRMS:計算值 C23H18ClN〇3S + H+， 424.07687;實測值（ESI, [M+H]+)，424.0781。 20 範例62 4-{3-[3-氣基-5-(甲基續斑基）苯氧基]苯基}-3-甲基 -8-(三氟甲基）告琳 MS (ES) π/ζ 491. 7。 140 200825054 範例63 2, 2-二甲基-3-[(3-{3-[3-甲基-8-(三氟甲基）-4-喹 啉基]苯氧基}苯基）磺醢基]-1-丙酵 MS (ES) /Z7/Z 529. 9。 5 範例64 4-[(3-{3 - [3 -甲基-8-（三氟甲基）-4-喹啉基]苯氧基} 苯基）續酿基]-1_丁酵 MS (ES) /z//z515.9 ； HRMS:計算值 C27H24F3N〇4S + H+， ίο 516· 14509 ;實測值（ESI，[Μ+ΗΓ)，516· 1459 ; 範例 65 5-[(3-{3-[3-甲基-8-（三氣甲基）-4-啥琳基]苯氧基} 苯基)磺醢基]-1-戊酵 15 MS (ES) /Z//Z 529.9 ； HRMS:計算值 C28H26F3N〇4S + H+， 530.16074;實測值（ESI, [Μ+ΗΓ)，530.1598; 範例66 3-节基-4-{3-[3-(甲基確酿基）苯氧基]苯基}-8-（三 20 氟甲基）喹啉 MS (ES) 7Ζ//Ζ 533. 8。 範例67 3-节基-4-{3-[4-（甲基續酸基）苯氧基]苯基卜8-（三 141 200825054 氟甲基）喹啉 MS (ES) 533· 8。 範例68 5 3-节基-4-{3-[3-(異丁基碟酿基）苯氧基]苯 基}-8-（三氟甲基）喹啉 MS (ES) 575.8。 範例 69 ίο 3-节基-4-(3-{3-[ (3-甲基丁基）碟斑基]苯氧基}苯 基）-8-(三氟甲基）啥琳 MS (ES) /σ/ζ 589· 8。 範例70 15 4-{3-[3-(甲基磺醢基）苯氧基]苯基}-8-（三氟甲基） 喹啉 mp 147-148 °C ; MS (ES) /ff/z 443.9 。 範例71 2〇 3-[(3-{3-[3-节基-8-（三氣甲基）-4-啥琳基]苯氧基} 苯基）磺醢基]-1-丙酵 MS (ES) /Z7/Z 577_ 8。 範例72 142 200825054 3-节基_4-{3-[4-(乙基續酸基）苯氧基]苯基}-8-（三 氟甲基）喹啉 MS (ES) /z//z 548· 0。 範例73 3-苄基_4-{3-[4-(丙基項酿基）苯氧基]苯基}-8-(三 氟甲基）喹啉 MS (ES) /Z7/Z 562· 0。 ίο 範例74 4-{3-[4-（乙基續酸基）苯氧基]苯基}-8_(三氟甲基） 喹啉 MS (ES) /Z//Z 458. 0。 15 範例 75 4-{3-[4-(丙基磺醯基）苯氧基]苯基}-8-(三氟甲基） 喹啉 MS (ES)瓜/z 474·0。 20 範例76 4-{3-[4-(異丙基磺醢基）苯氧基]苯基}-8-(三氟甲基) 喹啉 MS (ES) π// 472. 0。 143 200825054 範例77 4-{3-[4-(異丁基磺醢基）苯氧基]苯基}-8-(三氟甲基) 喹啉 MS (ES) Λ7/Ζ 486· 0。 範例78 4-（3-{4-[(3-甲基丁基）磺醢基]苯氧基}苯基）-8-（三 氟甲基）喹啉 MS (ES) 7Z//Z 500· 0。 範例79 4 -（3-{4-[(2-氟苄基）磺醢基]苯氧基}苯基）-8-(三氟 甲基）喹啉 MS (ES)瓜/z 537·9 。 範例80 3-[(4-{3-[8-(三氟甲基）-4-啥琳基]苯乳基}苯基）橫 酿基]-1_丙酵 MS (ES) m/z 488.0 〇 範例81 4-{3-[4-(丁基磺醢基）苯氧基]苯基}-8-(三氟甲基） 喹啉 MS (ES) π// 486·0 。 144 200825054 範例82 2-[(4-{3-[8-（三氟甲基）-4-啥琳基]苯氧基}苯基）續 醯基]乙酵 5 MS (ES) /Z7/Z 472· 0。 範例83 4-{3-[4-(烯丙基磺醢基）苯氧基]苯基}-8-(三氟甲基) 喹啉 ίο MS (ES) 470. 2。 範例 84 4-{3-[3-(乙基磺醢基）苯氧基]苯基}-8-(三氟甲基） 喹啉 15 mp 147 °C ; MS (ES) 457· 9 ; HRMS:計算值 C24H18F3N〇3S + H+，458.10322;實測值（ESI, [M+H]+)， 458·1019 。 範例85 2〇 4-{3-[3-(丙基確酿基）苯氧基]苯基}-8-(三氟甲基） 喹啉 mp 133 °C ; MS (ESI) y/7/z 472. 1199 ; HRMS:計算值 C25H2GF3N〇3S + H+，472.11887;實測值（ESI，[Μ+ΗΓ)， 472.1199 。 145 200825054 範例86 4-{3-[3-(異丙基磺醯基）苯氧基]苯基}-8-(三氟甲基） 喹啉 5 MS (ES) y/7/z 472. 0。 範例87 4-{3-[3-(異丁基磺醢基）苯氧基]苯基}-8-(三氟甲基） 喹啉 10 MS (ES) 486. 0。 範例88 4-（3-{3-[(3-甲基丁基）磺醢基]苯氧基}苯基）-8-（三 氟甲基）喹啉 15 MS (ES) — 500_ 0。 範例89 4-{3-[3-(環戊基磺醢基）苯氧基]苯基卜8-(三氟甲基） 喹啉 20 MS (ES) 497. 9。 範例90 4-{3-[3-(苄基磺醢基）苯氧基]苯基}-8-(三氟甲基） 喹啉 146 200825054 MS (ES) /z//z 519. 9。 範例91 3- [(3-{3-[8-(三氟甲基）-4-喹啉基]苯氧基}苯基)磺 5 酿基]-1-丙酵 MS (ES) //?/&gt; 488. 0。 範例92 (4-{[(4-{3-[8-（三氟甲基）-4-喹啉基]苯氧基}苯基） ίο 磺醢基]甲基}苯基）乙酸乙酯 MS (ES) Λ7/Ζ 606· 0。 範例93 4- （3-{4- [(2, 5-二甲基苄基）確酿基]苯氧基}苯 15 基）-8-(三氟甲基）啥琳 mp 94-96 °C ; MS (ES) /z//z 548. 0。 範例94 4-{3-[4-（甲基續斑基）苯氧基]苯基}-8-（三氟甲基） 20 啥琳 mp 88-90 °C ; MS (ES) /»// 444. 0。 範例95 3-苄基-4-{3-[4-(異丙基確酸基）苯氧基]苯 147 200825054 基}-8-(三氣甲基）啥琳 mp 64-66 °C ； MS (ES) m/z 562. 0 ° 範例 96 3-苄基-4-{3-[4-(異丁基磺醯基）苯氧基]苯 基}-8-（三氟甲基）養琳 mp 77-79 °C ； MS (ES) m/z 576. 1 ° 範例97 i〇 3-节基-4-(3-{4-[(3-甲基丁基）確酸基]苯氧基}苯 基）-8 -（三氟甲基）喹啉 MS (ES) m/z 590.0. 範例98 15 3-苄基-4-(3-{4-[ (2-氟苄基）磺醢基]苯氧基}苯 基）-8-(三氟甲基）啥琳 mp 99-101 °C ; MS (ES) Λ//Ζ 628· 0。 範例99 2〇 3-[(4-{3-[3-节基-8-（三氟甲基）-4-啥琳基]苯氧基} 苯基）續酸基]_1_丙酵 MS (ES) 7Z//Z 578· 0。 範例100 148 200825054 4 - {3_[4-(烯丙基磺醢基）苯氧基]苯基}-3-苄基 - 8-（三氟甲基）喹啉 MS (ES) Λ//Ζ 560· 2。 . 5 範例101 3-苄基-4-{3-[4-( 丁基磺醯基）苯氧基]苯基}-8-(三 氟甲基）喹啉 MS (ES) y/7/z 576· 0。 ί 10 範例102 3-苄基-4-{3-[3-（乙基確酿基）苯氧基]苯基}-8-（三 氟甲基）喹啉 MS (ES) 7Z//Z 548· 0。 15 ./ \ 範例103 3-苄基-4-{3-[3-(丙基續酸基）苯氧基]苯基}-8-(三 氟甲基）喹啉 MS (ES) /Z7/Z 562. 0。 20 範例104 3-苄基-4-{3-[3-(異丙基磺醯基）苯氧基]苯 基}-8_(三氟甲基）啥琳 MS (ES) /Z7/Z 562· 0。 149 200825054 jpJ^J 105 3-苄基-4-{3-[3-(苄基確醢基）苯氧基]苯基}_8_(三 氟甲基）喹啉 MS (ES) π/ζ 610· 0 〇 劍106 3-苄基-4-(3-{3-[(3-甲氧基丙基）磺醢基]苯氧基}苯 基）一8 -（三氟甲基）喹啉 MS (ES) /z//z 592. 0。 鱼例107 3- 苄基-4-{3-[3-(環戊基碟斑基）苯氧基]苯 基}-8-(三氟甲基）喹啉 MS (ES) 588_ 0 〇 jg▲例 108 4- [(3-{3-[3-苄基-8-(三氟甲基）-4-唉琳基]苯氧基} 苯基）讀斑基]-2-甲基-2-丁酵 MS (ES) yz//z 606. 0 〇 範例 109 4 - {3-[4-甲基-2-（甲基磺醢基）苯氧基]苯基}一8一（三 氟甲基）喹啉 mp 83-84 °C ; MS (ES) ζσ/ζ 457· 9。 150 200825054 範例110 4-{3-[4_甲基-3-(甲基磺醯基）苯氧基]苯基}-8-(三 氟甲基）喹啉 5 mp 147-149 °C ; MS (ES) 457.8。 範例111 4-{3_[2-氟基-5-（甲基續酿基）苯氧基]苯基}-8-（三 氟甲基）喹啉 10 MS (ES) zzz/z 461.8。 範例112 4-{3-[3-氟基-5-（曱基項酸基）苯氧基]苯基}-8-（三 氟曱基）喹啉-3-甲腈 15 MS (ES) /Z//Z 486. 8。 範例113 4-（3-{3-[(3-幾基-3-甲基丁基）碟酿基]苯氧基}苯 基）-8-(三氟甲基）考琳-3-甲腈 20 MS (ES) Λ//Ζ 540· 8。 範例114 4-{3-[3-(丙基磺醢基）苯氧基]苯基}-8-(三氟甲基） 啥琳-3-甲腈 151 200825054 MS (ES) /z7/z 496. 8。 範例115 4-{3-[3-(乙基確酿基）苯氧基]苯基}-8-(三氟甲基） 5 啥琳-3-甲腈 MS (ES) /Z7/Z 482· 8。 範例116 4-{3-[4-（甲基確酿基）苯氧基]苯基}-8-（三氟甲基） ίο 啥琳_3-甲腈 MS (ES) /z//z 468· 7。 範例117 4-{3-[3-（甲基確酿基）苯氧基]苯基}-8-(三氟甲基） 15 啥琳-3-甲腈 MS (ESI) Λ//Ζ 469。 範例118 [(4_{3-[3-节基-8-(三氟甲基）-4-啥琳基]苯氧基}苯 20 基）磺醢基]乙酸 MS (ES) m/z 577. 9 ； HRMS:計算值 C31H22F3N〇5S + H+， 578. 12435;實測值（ESI，[M+H]+)，578.1264。 範例119 152 200825054 於{2-[ (4-{3-[3-节基-8-（三氟甲基啥琳基]苯氧 基}苯基）磺醢基]乙基卜2-丙胺 MS (ES) 605. 0 ; HRMS:計算值 C34H31F3N2〇3S + H+， 605.20802;實測值（ESI，[Μ+ΗΓ)，605.2053。 蓺例120 4-[3-(4_{[2-(異丙基胺基）乙基]磺醢基}苯氧基）苯 基]-8-（三氟甲基）喹啉_3-甲腈 MS (ES) 540· 0。 蓺例121 4-{3-[3-（甲基磺醢基）苯氧基]苯基卜8一（三氟甲基） 喹啉-3-羧酸乙酯 MS (ES) m/z 515.8 〇 览例122 4-{3-[3-（甲基續斑基）苯氧基]苯基}—8一（三氟甲基） 喹啉-3-羧酸 MS (ES) m/z 487_ 7。 範例123 4-{3-[2-氟基-4-（甲基磺醢基）苯氧基]苯基卜8一（三 氟甲基）喹啉-3-甲腈 MS (ES) m/z 486_ 9。 153 200825054 範例124 4-{3-[4-甲氧基-3-（曱基磺醢基）苯氧基]寒基卜3-甲基 -8-(三氟甲基)唉琳 5 該一般步驟係基本上與Dawei Ma和Qian Cai於 厂s 2003，5，3799-3802 中所述之步驟雷同。 在氮氣下，將3-(3-曱基-8-(三氟甲基）-4一喹啉基）酚 (151 mg，0.50 mmol)、4-溴基-1-甲氧基-2-（甲基磺醯基） 苯（199 mg，0.75 mmol)、n，N-二甲基甘胺酸氫氯酸鹽（28 ίο mg，〇· 020 mmol)、Cul (20 mg，0_ 10 mmol)和 CS2CO3 (326 mg，1·00 mmol)之一經攪拌混合物在105-110 〇c的u— 二嗔烧（3· 0 mL)中加熱44小時。冷卻該反應後，加入水， 然後以二氯甲烷萃取。以MgS〇4乾燥該萃取物並減壓濃縮。 在矽膠上進行色層分析，以10/90至20/80梯度之乙酸乙 15酯/己烷洗提，並以逆相色層分析進一步純化以產生如一白 色泡沫固狀物之該標題化合物（49 mg)。MS (ES) m/z 487. 7。 #例 125 至 126135 200825054 The following compounds were prepared in a manner similar to that of Example 43 above, using the corresponding arylated aryl hydrazine and hydrazine aryl bromide, and eluted with a suitable eluent. When normal phase purification on tannin does not result in a purification, an additional purification process using reverse phase chromatography is used to further purify the compound. In some instances, ethyl acetate is used in place of the dichloromethane in the extraction step. Example 44 3-methyl-4-{3-[3-(propylsulfonyl)phenoxy]phenyl b-8-(tris- 1 fluoromethyl)quinoline MS (ES) m/z 485.8; HRMS: calcd for C26H22F3N </RTI> &lt;RTI ID=0.0&gt; Example 45 15 4-{3-[3-(Isopropenyl)phenoxy]phenyl}-3-methyl-8-(trifluoromethyl)anion MS (ES) m/z 485.8 HRMS: calcd for C26H22F3N </RTI> &lt;RTI ID=0.0&gt;&gt; 20 Example 46 4-{3-[3-(Benzylsulfonyl)phenoxy]phenyl}-3-methyl-8~(trifluoromethyl)quinoline MS(ES) m/z 533· HRMS: calcd for C3 </RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; 136 25 200825054 Example 47 3-Methyl-4-{3-[2-(methylsulfonyl)phenoxy]phenyl b-(trifluoromethyl)Cauline mp 203-205 °C; MS (ES) m/z </RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; Example 48 4 - {3 - [3-(Isobutylsulfonyl)phenoxy]phenyl}-3-methyl ίο -8-(trifluoromethyl)quinoline MS (ES) m/z 499.8 HRMS: calcd for C27H24F3N 〇3S + H+, 500.15017; found (ESI, [M+H]+), 500. Example 49 15 3-Methyl-4-(3-{3-[(3-methylbutyl)sulfonyl]phenoxy}phenyl)-8-(trifluoromethyl)quinoline MS (ES m/z </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 20 Example 51 3 - [(2 - {3 - [3 -Methyl-8-(trifluoromethyl)- 4-isolinyl]phenoxy}phenyl)sulfonate]-1-propanol mp 73-75 °C (Graphics is not very steep); MS (ES) m/z 501. 8 ; HRMS: calculated C26H22F3N 〇 4S + H+, 502.12944; measured value (ESI, 137 200825054 [M+H]+) , 502·1281. Example 51 4-{3-[3-Chloro-5-(propylsulfonyl)phenoxy]phenyl-3-methyl-5-8-(trifluoromethyl)quinoline MS (ES) m </ RTI> </ RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; Example 52 ι〇3-[(3-{3-[3-methyl-8 -(trifluoromethyl)-4-quinolinyl]phenoxy}phenyl) Continuum]-1-propanyl MS (ES) m/z </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; 15 Example 53 4-(3-{3_[(3-Methoxypropyl)sulfonyl]phenoxy}phenyl)-3-methyl-8-(trifluoromethyl)anion MS (ES m/z 515·9; HRMS: calcd for C27H24F3N, s, s, s, s, s, s, s, s, s, s. 20 Example 54 4-(3-{3-Gasyl-5-[(3-methylbutyl)-decyl]phenoxy}phenyl)-3-methyl-8-(trifluoromethyl)quina </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Example 55 3 - [(4 - {3 - [3-Methyl-8-(trifluoromethyl)-4-quinolinyl]phenoxy}phenyl) 5 decyl]-1-propanol MS (ES) m/z </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> </RTI> <RTIgt; </RTI> <RTIgt; Example 56 10 3-Methyl-4 - {3-[4-(methylsulfonyl)phenoxy]phenyl}-8-(trifluoromethyl)quinoline MS (ES) m/z 458.0; HRMS: calcd for C24H18F3N </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; 15 Example 57 2-Methyl-4-[(3-{3-[3-methyl-8-(trifluoromethyl)-4-quinolinyl]phenoxy}phenyl)sulfonyl]- 2-butanyl MS (ES) m/z </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> </RTI> </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 20 Example 58 3-Benzyl-8-carbyl-4-{3-[3-(methylsulfonyl)phenoxy]phenyl}quinoline MS (ES) m/z 499. 9 ; HRMS: For C29H22ClN 〇3S + H+, 139 200825054 500.10817; found (ESI, [M+H] + ), 500.1083. Example 59 3-Methyl-4-{3-[3-(methylsulfonyl)phenoxy]phenyl b-8-(tris-5fluoromethyl)quinoline MS (ES) m/z 457. HRMS: calcd for C24H18F3NO3S + H+, 458.10322; found (ESI, [M+H]+), 458.1017. Example 60 ίο 4-{3-[3-Fluoro-5-(methylsulfonyl)phenoxy]phenyl}-3-methyl-8-(trifluoromethyl)colin MS (ES) m/z 475.8. Example 61 15 8-Chloro-3-methyl-4-{3-[3-(methylsulfonyl)phenoxy]phenyl}quinoline MS (ES) m/z ML 1 ; HRMS: C23H18ClN 〇 3S + H+, 424.07687; found (ESI, [M+H]+), 424.078. 20 Example 62 4-{3-[3-Gas-5-(methyl leucoyl)phenoxy]phenyl}-3-methyl-8-(trifluoromethyl) 琳琳 MS (ES) π/ζ 491. 7. 140 200825054 Example 63 2,2-Dimethyl-3-[(3-{3-[3-methyl-8-(trifluoromethyl)-4-quinolinyl]phenoxy}phenyl)sulfonate醢基]-1-propanyl MS (ES) / Z7/Z 529. 9. 5 Example 64 4-[(3-{3 - [3 -Methyl-8-(trifluoromethyl)-4-quinolinyl]phenoxy}phenyl) Continuation]]-1_丁酵MS (ES) /z//z515.9 ; HRMS: Calculated C27H24F3N〇4S + H+, ίο 516· 14509 ; Measured value (ESI, [Μ+ΗΓ), 516· 1459 ; Example 65 5-[(3-{ 3-[3-Methyl-8-(trimethylmethyl)-4-indolyl]phenoxy}phenyl)sulfonyl]-1-pentyl 15 MS (ES) /Z//Z 529.9 HRMS: Calculated C28H26F3N 〇 4S + H+, 530.16074; found (ESI, [Μ+ΗΓ), 530.1598; Example 66 3-mercapto-4-{3-[3-(methyl-branched) phenoxy Base]phenyl}-8-(tris20-fluoromethyl)quinoline MS (ES) 7Ζ//Ζ 533. 8. Example 67 3-Piecle-4-{3-[4-(methylsudanyl)phenoxy]phenyl b-8-(tri 141 200825054 fluoromethyl)quinoline MS (ES) 533·8. Example 68 5 3-Piece-4-{3-[3-(Isobutyl-bromo)phenoxy]phenyl}-8-(trifluoromethyl)quinoline MS (ES) 575.8. Example 69 ίο 3-Pieceyl-4-(3-{3-[(3-methylbutyl)discyl]phenoxy}phenyl)-8-(trifluoromethyl)anion MS (ES ) /σ/ζ 589· 8. Example 70 15 4-{3-[3-(Methylsulfonyl)phenoxy]phenyl}-8-(trifluoromethyl)quinoline mp 147-148 °C; MS (ES) /ff/ z 443.9. Example 71 2〇3-[(3-{3-[3-Pheptyl-8-(trimethyl)-4-indolyl]phenoxy}phenyl)sulfonyl]-1-propanyl MS (ES) / Z7 / Z 577_ 8. Example 72 142 200825054 3-Blockyl_4-{3-[4-(ethylhexanoic acid)phenoxy]phenyl}-8-(trifluoromethyl)quinoline MS (ES) /z// z 548· 0. Example 73 3-Benzyl_4-{3-[4-(propyl-anisyl)phenoxy]phenyl}-8-(trifluoromethyl)quinoline MS (ES) /Z7/Z 562· 0. Οο Example 74 4-{3-[4-(ethylhexanoic acid)phenoxy]phenyl}-8-(trifluoromethyl)quinoline MS (ES) /Z//Z 458. 15 Example 75 4-{3-[4-(propylsulfonyl)phenoxy]phenyl}-8-(trifluoromethyl)quinoline MS (ES) melon/z 474·0. 20 Example 76 4-{3-[4-(Isopropylsulfonyl)phenoxy]phenyl}-8-(trifluoromethyl)quinoline MS (ES) π / / 472. 143 200825054 Example 77 4-{3-[4-(Isobutylsulfonyl)phenoxy]phenyl}-8-(trifluoromethyl)quinoline MS (ES) Λ7/Ζ 486·0. Example 78 4-(3-{4-[(3-Methylbutyl)sulfonyl]phenoxy}phenyl)-8-(trifluoromethyl)quinoline MS (ES) 7Z//Z 500 · 0. Example 79 4 -(3-{4-[(2-Fluorobenzyl)sulfonyl]phenoxy}phenyl)-8-(trifluoromethyl)quinoline MS (ES) melon / z 537·9 . Example 80 3-[(4-{3-[8-(Trifluoromethyl)-4-indolyl]phenyl rylate}phenyl) porch]-1_propanyl MS (ES) m/z 488.0 〇Example 81 4-{3-[4-(Butylsulfonyl)phenoxy]phenyl}-8-(trifluoromethyl)quinoline MS (ES) π// 486·0. 144 200825054 Example 82 2-[(4-{3-[8-(Trifluoromethyl)-4-indolyl]phenoxy}phenyl) hydrazinyl] ethyl acetate 5 MS (ES) /Z7/ Z 472· 0. Example 83 4-{3-[4-(Allylsulfonyl)phenoxy]phenyl}-8-(trifluoromethyl)quinoline ίο MS (ES) 470. 2. Example 84 4-{3-[3-(ethylsulfonyl)phenoxy]phenyl}-8-(trifluoromethyl)quinoline 15 mp 147 ° C; MS (ES) 457·9; HRMS Calcd for C24H18F3N 〇3S + H+, 458.10322; found (ESI, [M+H]+), 458·1019. Example 85 2〇4-{3-[3-(Provyl)phenyloxy]phenyl}-8-(trifluoromethyl)quinoline mp 133 ° C; MS (ESI) y/7/ </ RTI> </ RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; 145 200825054 Example 86 4-{3-[3-(Isopropylsulfonyl)phenoxy]phenyl}-8-(trifluoromethyl)quinoline 5 MS (ES) y/7/z 472. 0. Example 87 4-{3-[3-(Isobutylsulfonyl)phenoxy]phenyl}-8-(trifluoromethyl)quinoline 10 MS (ES) 486. Example 88 4-(3-{3-[(3-Methylbutyl)sulfonyl]phenoxy}phenyl)-8-(trifluoromethyl)quinoline 15 MS (ES) - 500_0. Example 89 4-{3-[3-(Cyclopentylsulfonyl)phenoxy]phenyl b- 8-(trifluoromethyl)quinoline 20 MS (ES) 497. Example 90 4-{3-[3-(Benzylsulfonyl)phenoxy]phenyl}-8-(trifluoromethyl)quinoline 146 200825054 MS (ES) /z//z 519. Example 91 3- [(3-{3-[8-(Trifluoromethyl)-4-quinolinyl]phenoxy}phenyl)sulfonate 5]]-propanyl MS (ES) // ?/&gt; 488. 0. Example 92 (4-{[(4-{3-[8-(Trifluoromethyl)-4-quinolinyl]phenoxy}phenyl) ίο sulfonyl]methyl}phenyl)acetate MS (ES) Λ 7/Ζ 606· 0. Example 93 4- (3-{4- [(2, 5-Dimethylbenzyl)]] phenyloxy}phenyl 15 yl)-8-(trifluoromethyl) 啥 mp 94-96 ° C ; MS (ES) /z//z 548. 0. Example 94 4-{3-[4-(methyl contigyl)phenoxy]phenyl}-8-(trifluoromethyl) 20 啥 mp 88-90 ° C ; MS (ES) /»/ / 444. 0. Example 95 3-benzyl-4-{3-[4-(isopropyl acid)phenoxy]benzene 147 200825054 base}-8-(trimethylmethyl) 啥 mp 64-66 °C; MS (ES) m/z 562. 0 ° Example 96 3-benzyl-4-{3-[4-(isobutylsulfonyl)phenoxy]phenyl}-8-(trifluoromethyl) Yanglin mp 77-79 °C ; MS (ES) m/z 576. 1 ° Example 97 i〇3-pyryl-4-(3-{4-[(3-methylbutyl)-acidic acid group] Phenoxy}phenyl)-8-(trifluoromethyl)quinoline MS (ES) m/z 590.0. Example 98 15 3-benzyl-4-(3-{4-[ (2-fluorobenzyl) Sulfhydryl]phenoxy}phenyl)-8-(trifluoromethyl)anthracene mp 99-101 °C; MS (ES) Λ//Ζ 628·0. Example 99 2〇3-[(4-{3-[3-Pheptyl-8-(trifluoromethyl)-4-indolyl]phenoxy}phenyl)-reductive acid]_1_-propanyl MS (ES) 7Z//Z 578· 0. Example 100 148 200825054 4 - {3_[4-(allylsulfonyl)phenoxy]phenyl}-3-benzyl- 8-(trifluoromethyl)quinoline MS (ES) Λ//Ζ 560· 2. . 5 Example 101 3-Benzyl-4-{3-[4-(butylsulfonyl)phenoxy]phenyl}-8-(trifluoromethyl)quinoline MS (ES) y/7/ z 576· 0. 10 10 Example 102 3-Benzyl-4-{3-[3-(ethyl aryl)phenoxy]phenyl}-8-(trifluoromethyl)quinoline MS (ES) 7Z//Z 548· 0. 15 ./ \ Example 103 3-Benzyl-4-{3-[3-(propylsulfonyl)phenoxy]phenyl}-8-(trifluoromethyl)quinoline MS (ES) /Z7 /Z 562. 0. 20 Example 104 3-Benzyl-4-{3-[3-(isopropylsulfonyl)phenoxy]phenyl}-8-(trifluoromethyl)fluorene MS (ES) /Z7/Z 562 · 0. 149 200825054 jpJ^J 105 3-Benzyl-4-{3-[3-(benzyl decyl)phenoxy]phenyl}_8-(trifluoromethyl)quinoline MS (ES) π/ζ 610 · 0 〇剑106 3-benzyl-4-(3-{3-[(3-methoxypropyl)sulfonyl]phenoxy}phenyl)-8-(trifluoromethyl)quinoline MS (ES) /z//z 592. 0. Fish Example 107 3-Benzyl-4-{3-[3-(cyclopentylbenzophenoxy)phenoxy]phenyl}-8-(trifluoromethyl)quinoline MS (ES) 588_ 0 〇jg ▲Example 108 4- [(3-{3-[3-benzyl-8-(trifluoromethyl)-4-indolyl]phenoxy}phenyl)-reading yl]-2-methyl- 2-butyrate MS (ES) yz//z 606. 0 〇Example 109 4 - {3-[4-Methyl-2-(methylsulfonyl)phenoxy]phenyl}-81 (three Fluoromethyl)quinoline mp 83-84 °C; MS (ES) ζσ/ζ 457·9. 150 200825054 Example 110 4-{3-[4-Methyl-3-(methylsulfonyl)phenoxy]phenyl}-8-(trifluoromethyl)quinoline 5 mp 147-149 ° C ; MS (ES) 457.8. Example 111 4-{3_[2-Fluoro-5-(methyl succinyl)phenoxy]phenyl}-8-(trifluoromethyl)quinoline 10 MS (ES) zzz / z 461.8. Example 112 4-{3-[3-Fluoro-5-(indolyl)phenoxy]phenyl}-8-(trifluoromethyl)quinoline-3-carbonitrile 15 MS (ES) /Z//Z 486. 8. Example 113 4-(3-{3-[(3-Mercapto-3-methylbutyl)-dishyl]phenoxy}phenyl)-8-(trifluoromethyl)Cauline-3-A Nitrile 20 MS (ES) Λ//Ζ 540· 8. Example 114 4-{3-[3-(propylsulfonyl)phenoxy]phenyl}-8-(trifluoromethyl)fluorene-3-carbonitrile 151 200825054 MS (ES) /z7/z 496. 8. Example 115 4-{3-[3-(Ethyl styrene)phenoxy]phenyl}-8-(trifluoromethyl) 5 啥-line-3-carbonitrile MS (ES) /Z7/Z 482 · 8. Example 116 4-{3-[4-(Methyl-glycosyl)phenoxy]phenyl}-8-(trifluoromethyl) ίο 啥琳_3-carbonitrile MS (ES) /z//z 468· 7. Example 117 4-{3-[3-(Methyl-glycolyl)phenoxy]phenyl}-8-(trifluoromethyl) 15 啥-lin-3-carbonitrile MS (ESI) Λ//Ζ 469 . Example 118 [(4_{3-[3-Pheptyl-8-(trifluoromethyl)-4-indolyl]phenoxy}benzene 20-yl)sulfonyl]acetic acid MS (ES) m/z 577 HRMS: calcd for C31H22F3N s5S + H+, 578. 12435; Example 119 152 200825054 on {2-[ (4-{3-[3-]-based-8-(trifluoromethyl啥-linyl)phenoxy}phenyl)sulfonyl]ethyl 2-ethylamine MS (ES) 605. 0 ; HRMS: calcd for C3, H,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, Amino)ethyl]sulfonyl}phenoxy)phenyl]-8-(trifluoromethyl)quinoline-3-carbonitrile MS (ES) 540·0. Example 121 4-{3-[ Ethyl 3-(methylsulfonyl)phenoxy]phenyl b-(trifluoromethyl)quinoline-3-carboxylate MS (ES) m/z 515.8 〇 122 122 122 122 [3-(methyl contigyl)phenoxy]phenyl}-8-(trifluoromethyl)quinoline-3-carboxylic acid MS (ES) m/z 487_ 7. Example 123 4-{3- [2-Fluoro-4-(methylsulfonyl)phenoxy]phenyl b-(trifluoromethyl)quinoline-3-carbonitrile MS (ES) m/z 486_ 9. 153 200825054 Examples 124 4-{3-[4-Methoxy-3-(indolylsulfonyl)phenoxy] chillyl 3-methyl-8-(trifluoromethyl)anthracene 5 This general procedure is basic The procedure is the same as that described in Dawei Ma and Qian Cai in Plants 2003, 5, 3799-3802. Under nitrogen, 3-(3-mercapto-8-(three) Fluoromethyl)-4-quinolinyl)phenol (151 mg, 0.50 mmol), 4-bromo-1-methoxy-2-(methylsulfonyl)benzene (199 mg, 0.75 mmol), n , N-dimethylglycine hydrochloride (28 ίο mg, 〇·020 mmol), Cul (20 mg, 0-10 mmol) and CS2CO3 (326 mg, 1·00 mmol) -110 〇c u-dithizone (3.0 mL) was heated for 44 hours. After cooling the reaction, water was added and then extracted with dichloromethane. The extract was dried with MgSO 4 and concentrated under reduced pressure. The chromatographic analysis was carried out on silica gel eluting with a gradient of 10/90 to 20/80 of ethyl acetate/hexane and further purified by reverse phase chromatography to give the title compound as a white foam solid. Mg). MS (ES) m/z 487. 7. #例125 to 126

以類似於上述範例124之方法，或使用碳酸铯當成鹼 154 20 200825054 基、N，N-二甲基甘胺酸取代L-脯氨酸、以及1，4-二噁烷當 成溶劑，使用適當之經鹵化的芳基砜和喹啉酚來製備該下 述的化合物： 5 範例125 4-{3-[4-甲基-3-（甲基磺醢基）苯氧基]苯基}-8-(三 氟甲基）喹啉 與範例110係為相同之化合物但使用範例124中所述 之方法。mp 147-149 °C ; MS (ES) y/7/z 457. 8。 ίο 範例126 3-甲基-4-(3-{3-[(甲基磺醯基）甲基]苯氧基}苯 基）-8-(三氟甲基）喹啉 MS (ES) /Z7/Z 471. 8。 15 範例127 8-氯基-4-{3-[4-(嗎啉-4-基磺醢基）苯氧基]苯 基卜3-丙基啥琳 在氮氣下’將3-(8-氯基-3-丙基-4-啥琳基）紛（108 20 mg，0· 40 mmol)、4-[(氟苯基）磺醯基]嗎琳（102 mg，0· 50 mmol)、和碳酸卸（70 mg，0· 50 mmol)之一經攪拌混合物在 100 °C的DMF(1. 0 mL)中加熱20小時。冷卻該反應後，加 入水（4 mL)，然後以二氯甲烧（2 X 5 mL)萃取。以MgS〇4 乾燥該萃取物並減壓濃縮。在矽膠上進行色層分析，以 155 200825054 35/65之乙酸乙酯/己烷洗提以產生如一油狀物之該標題化 合物（113 mg)。mp 137-138 °C; MS (ES)m/z 523.1 ; HRMS: 計算值 C28H27ClN2〇4S + H+，523· 14528 ;實測值（ESI， [M+H] + )，523.1444。 簸例128至173In a manner similar to the above Example 124, or using cesium carbonate as the base 154 20 200825054, N,N-dimethylglycine instead of L-valine, and 1,4-dioxane as a solvent, suitably used The halogenated aryl sulfone and quinolinol are used to prepare the following compounds: 5 Example 125 4-{3-[4-Methyl-3-(methylsulfonyl)phenoxy]phenyl}- 8-(Trifluoromethyl)quinoline is the same compound as Example 110 but using the method described in Example 124. Mp 147-149 °C; MS (ES) y/7/z 457. 8. Οο Example 126 3-Methyl-4-(3-{3-[(methylsulfonyl)methyl]phenoxy}phenyl)-8-(trifluoromethyl)quinoline MS (ES) / Z7/Z 471. 8. 15 Example 127 8-Chloro-4-{3-[4-(morpholin-4-ylsulfonyl)phenoxy]phenyl-3-propylindene under nitrogen <3-(8- Chloro-3-propyl-4-indolyl) (108 20 mg, 0·40 mmol), 4-[(fluorophenyl)sulfonyl]lin (102 mg, 0·50 mmol), And one of the carbonated (70 mg, 0. 50 mmol) was stirred and heated in DMF (1. 0 mL) at 100 °C for 20 hours. After cooling the reaction, water (4 mL) was added and then extracted with methylene chloride (2×5 mL). The extract was dried with MgS 〇 4 and concentrated under reduced pressure. Chromatography on silica gel eluting with EtOAc EtOAc EtOAc EtOAc (EtOAc) Mp 137-138 ° C; MH (MH): s. Examples 128 to 173

以類似於上述範例127之方法，使用所對應之經鹵化的 芳基磺醯胺和喹啉酚，並以一適當的洗提液洗提來製備該 10 下述的化合物（依據取代作用變更溫度）。一般而言，間位一 鹵基芳基磺醯胺受限於高溫，通常為150 X，然而鄰位-和對位-i基芳基磺醯胺可在較低的溫度，通常為1〇〇 °C 至150 °C，反應。在若干範例中，當R非Η時，可獲得較 高的產率。 15 範例128 3-节基-4-{3-[3_(嗎琳-4-基續殖基）苯氧基]苯 基}-8-（三氟甲基）喹啉 MS (ES) ζβ/ζ 605· 2。 範例129 156 20 200825054 4-{3-[3-(嗎淋-4-基確酿基）苯氧基]苯基}-3-苯基 -8-（三氟曱基）啥琳 mp 88 °C ; MS (ES) /z//z 591· 2。 5 範例130 4-{3-[3-苄基-8-(三氟甲基）-4-喹啉基]苯氧基}-舲 甲基苯磺醢胺 mp 77-79 °C ; MS (ES) Tff/z 549· ：1。 ίο 範例131 4-{3-[3-苄基-8-(三氟甲基）-4-喹啉基]苯氧基}-舲 乙基苯橫酸胺 MS (ES) /Z//Z 563·卜 15 範例132 4-{3-[3-苄基-8-（三氟甲基）-4-喹啉基]苯氧 基}-术舲二甲基苯磺醢胺 MS (ES) τζζ/ζ 563. ：1。 20 範例133 4-{3-[3-苄基-8-(三氟甲基）-4-喹啉基]苯氧基}-舲 乙基甲基苯續醢胺 mp 66 °C ; MS (ES) /b/z 577.2。 157 200825054 134 4-{3-[3-节基-8-(三氟甲基）-4-嘆琳基]苯氧 基卜爪於二乙基苯磺醢胺 mp 80 °C ; MS (ES) yzz/z 591.2。 135 3-苄基_4-{3_[4_(啦洛咬-1-基續雄基）苯氧基]苯 基卜8-（三氟甲基）喹啉 mp 101 °C ; MS (ES) /»// 589.2。 砂136 3-苄基-4-{3-[4-(哌啶-1-基磺醢基）苯氧基]苯 基}-8-（三氟甲基）喹啉 MS (ES) τζ//ζ 603· 2。 私例 137 3- 苄基-4-(3-{4-[(4-甲基哌嗪-1-基）磺醢基]苯氧基} 苯基）- 8-（三氟甲基）啥琳 mp 77 °C ; MS (ES) 618·2。 gM 138 4- {3-[3-苄基-8-(三氟甲基）-4-喹啉基]苯氧基}-於 丙基苯磺醢胺 MS (ES) /z7/z 577. 2。 158 200825054 範例139 4-{3-[3-苄基-8-(三氟甲基）-4-喹啉基]苯氧基}-舲 異丙基苯磺醢胺 5 MS (ES) /Z7/Z 577. 2。 範例140 舲苄基-4-{3-[3-苄基-8-(三氟甲基）-4-喹啉基]苯氧 基}苯磺醯胺 10 mp 98 °C ; MS (ES) 7Z//Z 625. 2。 範例141 3-苄基-4-{3 - [4-（嗎琳-4-基續斑基）苯氧基]苯 基}-8-(三氟甲基）喹啉 15 mp 118 °C ; MS (ES) zh/z 605· 2。 範例142 3-{3-[3-节基-8-(三氟甲基）-4-啥琳基]苯氧基}-於 甲基苯磺醯胺 20 MS (ES) /Z7/Z 548. 8。 範例143 3-{3-[3-苄基-8-（三氟甲基）-4-啥琳基]苯氧 基}-术舲二甲基苯磺醢胺 159 200825054 MS (ES) m/z 562.7 〇 範例144 3-{3-[3-节基-8-（三氟甲基）-4-考琳基]苯氧基}-於 5 乙基-舲甲基苯磺醢胺 MS (ES) /Z7/Z 576. 8。 範例145 3-{3-[3-苄基-8-(三氟甲基）-4-喹啉基]苯氧 ίο 基}_况舲二乙基苯磺醯胺 MS (ES) Λ//Ζ 590. 8。 範例 146 3-苄基-4-{3-[3-(«比咯啶-1-基磺醯基）苯氧基]苯 15 基}-8-（三氟甲基）啥琳 MS (ES) /Z7/Z 588· 8。 範例147 3-苄基-4-{3-[3-(哌啶-1-基磺醢基）苯氧基]苯 20 基}-8-（三氟甲基）啥琳 MS (ES) 7Z//Z 602· 8。 範例148 3-苄基-4-(3-{3-[(4-甲基哌嗪-1-基）磺醢基]苯氧基} 160 200825054 苯基）- 8-(三氟甲基）喹啉 MS (ES) ζζζ/ζ 617. 9。 , 蓺例149 5 3-{3-[3-苄基-8-（三氟甲基）-4-啥琳基]苯氧基}-於 丙基苯磺醢胺 - MS (ES) 576. 8。 ' 範例150 ίο 3-{3-[3-苄基-8-(三氟甲基）-4-啥琳基]苯氧基}-iV· 異丙基苯磺醢胺 MS (ES) Λ//Ζ 574· 6。 範例151 15 於苄基-{3-[3-苄基-8-（三氟甲基）-4-啥琳基]苯氧 基}苯確斑胺 I MS (ES) 622· 6。 範例152 2〇 3-甲基-4-{3-[4-(嗎啉-4-基磺醢基）苯氧基]苯基}-8-(三 氟甲基)喹琳 mp 86-88 °C ; MS (ES) m/z 529.2 ; HRMS:計算值 C27H23F3N2〇4S + H+，529.14034;實測值（ESI, [M+H] + )， 529·1417 。 161 200825054 範例153 8-氯基-3-甲基-4-{3_[4-(嗎啉-4-基磺醢基）苯氧基] 苯基}喹啉 5 MS (ES) m/z 495. 1 ; HRMS:計算值 C26H23ClN2〇4S + H+， 495.11398;實測值（ESI, [M+H] + )，495.1144。 窺例154 8-氯基-3-異丙基-4-{3-[4-(嗎啉-4-基磺醢基）苯氧 ίο 基]苯基}喹啉 mp 93-95 °C ; MS (ES) m/z 523.1 ; HRMS:計算值 C28H27ClN2〇4S + H+，523.14528;實測值（ESI，[M+H] + )， 523.1434 。 15 範例155 4-[3-(8-氯基-3-甲基-4-喹啉基）苯氧基]-N, N-二甲 基苯磺醢胺 MS (ES) m/z 453. 1 ; HRMS:計算值 C24HyClN2〇3S + H+， 453. 10342;實測值（ESI, [M+H] + )，453.1022。 #例 156 4-[3-(8-氣基-3-甲基-4-喹啉基）苯氧基]-N-乙基-N-甲基 苯讀醢胺 MS (ES) m/z 467. 1 ; HRMS:計算值 C25H23ClN2〇3S + H+， 162 200825054 467.11907;實測值（ESI, [M+H] + )，467. 1195。 範例157 8-氣基-3-甲基-4-{3-[4-（e比洛咬-1-基續斑基）苯氣 5 基]苯基}喹啉 MS (ES) m/z 479· 1 ; HRMS:計算值 C26H23ClN2〇3S + Η+， 479.11907;實測值（ESI，[M+H] + )，479.1171。 f 範例 158 10 4-[3-(8-氣基-3-甲基-4-喹啉基）苯氧基]-N-甲基苯 磺醯胺 MS (ES) m/z 437· 1 ; HRMS··計算值 C23H19ClN2〇3S + H+， 439.08777;實測值（ESI, [M+H]+)，439· 086。 15 範例159 8-氯基-4-{3-[3-氟基-5-(嗎啉-4-基磺醢基）苯氧基]苯 ( 基}-3_甲基喹啉 - HRMS:計算值 C26H22ClFN2〇4S + H+，513. 10456 ;實測 . 值（ESI, [Μ+Η]+)， 513.1044 。 20 i 例 160 4 - [3-(8-氣基-3-甲基-4-喹啉基）苯氧基]-N-丙基苯 磺醯胺 MS (ES) m/z 467. 1 ; HRMS:計算值 C25H23ClN2〇3S + H+， 163 200825054 467.11907;實測值（ESI, [M+H] + )，467.1181。 範例161 N-苄基-4-[3-(8-氣基-3-甲基_4-喹啉基）苯氧基]苯 5 續醢胺 MS (ES) m/z 515. 1 ; HRMS:計算值 C29H23ClN2〇3S + H+， 515.11907;實測值（ESI，[M+H] + )，515.1211。 範例162 ίο 3-[3-(8-氯基-3-甲基-4-喹啉基）苯氧基]-#-甲基苯 磺醢胺 MS (ES) π// 439· 1 ; HRMS:計算值 C23H19ClN2〇3S + H+， 439.08777;實測值（ESI, [Μ+ΗΓ)，439_ 0868。 15 範例163 3-[3-(8-氣基-3-甲基_4-啥琳基）苯氧基]-iV-乙基苯 磺醢胺 MS (ES) 7Z//Z 453. 1 ; HRMS:計算值 C24H21ClN2〇3S + H+， 453.10342;實測值（ESI, [M+H] + )，453.1044。 20 輯例164 3-[3-(8-氯基-3-甲基啥琳基）苯氧基]丙基苯 磺醢胺 MS (ES) /»// 467. 1 ; HRMS:計算值 C25H23ClN2〇3S + H+， 164 200825054 467.11907;實測值（ESI, [Μ+ΗΓ)，467_ 1195。 j备例165 3-[3-(8-氣基-3-甲基-4-喹啉基）苯氧基]異丙基 5 苯磺醯胺 MS (ES) /ff/z 467_ 1 ; HRMS:計算值 C25H23ClN2〇3S + H+， 467. 11907;實測值（ESI, [M+H]+)，467.1173。 j备例166 ίο 於苄基-3-[3-(8-氯基-3-甲基-4-喹啉基）苯氧基]苯 續酿胺 MS (ES) 515. 1 ; HRMS:計算值 C29H23ClN2〇3S + H+， 515.11907;實測值（ESI，[Μ+ΗΓ)，515· 117卜 15 範例 167 3-[3-(8-氯基-3-甲基-4-喧琳基）苯氧基]-术Y-二甲 基苯磺醢胺 MS (ES)历/z 453. 1 ; HRMS:計算值 C24H21ClN2〇3S + H+， 453.10342;實測值（ESI, [Μ+ΗΓ)，453.1017。 20 望▲例168 3-[3-(8-氯基-3-甲基-4-啥琳基）笨氧基]-乙基-於 甲基苯磺醢胺 MS (ES) /ff/z 467. 1 ; HRMS:計算值 C25H23ClN2〇3S + H+， 165 200825054 467.11907;實測值（ESI, [M+H]+)，467.1183。 範例169 8-氯基-3-甲基-4-{3-[3-(比洛咬-1-基續越l基）苯氣 5 基]苯基}喹啉 MS (ES) π/ζ 479· 1 ; HRMS:計算值 C26H23ClN2〇3S + H+， 479.11907;實測值（ESI，[M+H]+)，479.1186。 範例170 10 3-[3 -（8-氣基-3-甲基-4-喹啉基）苯氧基]-术#·二乙 基苯磺醮胺 MS (ES) zb/z 481. 1 ; HRMS:計算值 C26H25ClN2〇3S + H+， 481.13472;實測值（ESI，[M+H]+)，481.1336。 15 範例171 8-氯基-3-甲基-4 - {3-[3-（旅咬-1-基績斑基）苯氧基] 苯基}喹啉 MS (ES) 493_ 1 ; HRMS:計算值 C27H25ClN2〇3S + H+， 493.13472;實測值（ESI，[M+H]1)，493. 1348。 20 範例172 8-氣基-3-甲基-4-（3-{3-[(4-甲基旅唤-1-基）確隨基] 苯氧基}苯基）喹啉 MS (ES) 7Z//Z 508. 1 ; HRMS:計算值 C27H26ClN3〇3S + H+， 166 200825054 508.14561;實測值（ESI，[M+H]+)，508.1456。 範例173 8-氯基-3-甲基-4 - {3-[3-(哌嗪一 1 一基磺醢基）苯氧基] 5 苯基}喹啉 HRMS:計算值 C26H24CIN3O3S + H+，494.12996;實測 值（ESI，[Μ+ΗΓ)，494_ 1311。 範例174 10 8-氣基-3-甲基-4 - {3-[3_(嗎琳-4-基確酸基）苯氧基] 苯基}喹啉 在氮氣下，將3-(8-氯基-3-甲基-4-啥琳基）紛（100 mg，〇· 37 mmol)、4-(3-漠苯基績醯基）嗎琳（170 mg，〇· 56 mmol)、Cul (11 mg，0· 056 _〇1)、Me2NCH2C〇2H 氫氯酸鹽 15 (23 mg，0_ 167 mmol)和石炭酸铯（70 mg, 0. 50 mmol)之一經 攪拌混合物在100 °C的1，4-二噁烷（3.0 mL)中加熱18小 時。冷卻該反應後，加入水，然後以乙酸乙酯萃取。以MgS〇4 乾燥該萃取物並減壓濃縮。在矽膠上進行色層分析，以 30/70之乙酸乙酯/己烷洗提以產生如一棕褐色固狀物之該 20 標題化合物（120 mg)。 HRMS:計算值 C26H23ClN2〇4S + H+，495.11398;實測 值（ESI，[Μ+ΗΓ)，495· 1146· _例 175 至 188 167 200825054The compound of the following 10 was prepared by a method similar to the above Example 127, using the corresponding halogenated arylsulfonamide and quinolinol, and eluted with a suitable eluent (change temperature according to substitution) ). In general, the meta-haloarylsulfonamide is limited to high temperatures, typically 150 X, whereas the ortho- and para-i-arylsulfonamides can be at lower temperatures, typically 1 Torr. 〇 ° C to 150 ° C, the reaction. In several examples, a higher yield can be obtained when R is not ruthenium. 15 Example 128 3-benzyl-4-{3-[3_(morphin-4-yl-propionyl)phenoxy]phenyl}-8-(trifluoromethyl)quinoline MS (ES) ζβ/ ζ 605· 2. Example 129 156 20 200825054 4-{3-[3-(N-Phenyl-4-yl)-phenoxy]phenyl}-3-phenyl-8-(trifluoromethyl) 啥 mp 88 ° C ; MS (ES) /z//z 591· 2. 5 Example 130 4-{3-[3-Benzyl-8-(trifluoromethyl)-4-quinolinyl]phenoxy}-indolemethylbenzenesulfonamide mp 77-79 ° C ; MS ( ES) Tff/z 549· :1. Οο Example 131 4-{3-[3-Benzyl-8-(trifluoromethyl)-4-quinolinyl]phenoxy}-indolyl benzene amide acid MS (ES) /Z//Z 563·卜15 Example 132 4-{3-[3-Benzyl-8-(trifluoromethyl)-4-quinolinyl]phenoxy}- succinyl dimethyl sulfonamide MS (ES) Τζζ/ζ 563. :1. 20 Example 133 4-{3-[3-Benzyl-8-(trifluoromethyl)-4-quinolinyl]phenoxy}-indolylethylbenzene benzoic acid mp 66 ° C ; MS ( ES) /b/z 577.2. 157 200825054 134 4-{3-[3-Pheptyl-8-(trifluoromethyl)-4-indolyl]phenoxypeptone in diethylbenzenesulfonamide mp 80 °C; MS (ES ) yzz/z 591.2. 135 3-Benzyl_4-{3_[4_(Lilodi-1-yl-androstyl)phenoxy]phenyl b- 8-(trifluoromethyl)quinoline mp 101 °C; MS (ES) / »// 589.2. Sand 136 3-benzyl-4-{3-[4-(piperidin-1-ylsulfonyl)phenoxy]phenyl}-8-(trifluoromethyl)quinoline MS (ES) τζ/ /ζ 603· 2. Private example 137 3-benzyl-4-(3-{4-[(4-methylpiperazin-1-yl)sulfonyl]phenoxy}phenyl)- 8-(trifluoromethyl)anthracene Lynn mp 77 ° C; MS (ES) 618·2. gM 138 4- {3-[3-Benzyl-8-(trifluoromethyl)-4-quinolinyl]phenoxy}-propylsulfonamide MS (ES) /z7/z 577. 2. 158 200825054 Example 139 4-{3-[3-Benzyl-8-(trifluoromethyl)-4-quinolinyl]phenoxy}-indolylbenzenesulfonamide 5 MS (ES) /Z7 /Z 577. 2. Example 140 Benzylbenzyl-4-{3-[3-benzyl-8-(trifluoromethyl)-4-quinolinyl]phenoxy}benzenesulfonamide 10 mp 98 ° C; MS (ES) 7Z//Z 625. 2. Example 141 3-benzyl-4-{3-[4-(morphin-4-yl contigyl)phenoxy]phenyl}-8-(trifluoromethyl)quinoline 15 mp 118 ° C ; MS (ES) zh/z 605· 2. Example 142 3-{3-[3-Pheptyl-8-(trifluoromethyl)-4-indolyl]phenoxy}-methylbenzenesulfonamide 20 MS (ES) /Z7/Z 548 . 8. Example 143 3-{3-[3-Benzyl-8-(trifluoromethyl)-4-indolyl]phenoxy}-indole dimethyl sulfonamide 159 200825054 MS (ES) m/ z 562.7 〇Example 144 3-{3-[3-Pheptyl-8-(trifluoromethyl)-4-carbinyl]phenoxy}- in 5-ethyl-nonylmethyl sulfonamide MS ( ES) /Z7/Z 576. 8. Example 145 3-{3-[3-Benzyl-8-(trifluoromethyl)-4-quinolinyl]phenoxy ε]} 舲 diethyl acetophenamide MS (ES) Λ// Ζ 590. 8. Example 146 3-Benzyl-4-{3-[3-(«pyrrolidin-1-ylsulfonyl)phenoxy]benzene 15 yl}-8-(trifluoromethyl)anion MS (ES ) /Z7/Z 588· 8. Example 147 3-Benzyl-4-{3-[3-(piperidin-1-ylsulfonyl)phenoxy]benzene 20-yl}-8-(trifluoromethyl)fluorene MS (ES) 7Z //Z 602· 8. Example 148 3-Benzyl-4-(3-{3-[(4-methylpiperazin-1-yl)sulfonyl]phenoxy} 160 200825054 Phenyl)- 8-(trifluoromethyl) Quinoline MS (ES) ζζζ/ζ 617. 9. , Example 149 5 3-{3-[3-Benzyl-8-(trifluoromethyl)-4-indolyl]phenoxy}-p-propylbenzenesulfonamide-MS (ES) 576. 8. ' Example 150 ίο 3-{3-[3-Benzyl-8-(trifluoromethyl)-4-indolyl]phenoxy}-iV·isopropyl sulfonamide MS (ES) Λ/ /Ζ 574· 6. Example 151 15 Benzyl-{3-[3-benzyl-8-(trifluoromethyl)-4-indolyl]phenoxy}benzidine plaque I MS (ES) 622·6. Example 152 2〇3-Methyl-4-{3-[4-(morpholin-4-ylsulfonyl)phenoxy]phenyl}-8-(trifluoromethyl)quinolin mp 86-88 </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; 161 200825054 Example 153 8-Chloro-3-methyl-4-{3_[4-(morpholin-4-ylsulfonyl)phenoxy]phenyl}quinoline 5 MS (ES) m/z 495 HRMS: calcd for C26H23ClN2 </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; Spectrophotograph 154 8-chloro-3-isopropyl-4-{3-[4-(morpholin-4-ylsulfonyl)phenoxy ε]phenyl}quinoline mp 93-95 °C; MS (ES) m/z </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> </RTI> <RTIgt; 15 Example 155 4-[3-(8-Chloro-3-methyl-4-quinolinyl)phenoxy]-N, N-dimethylbenzenesulfonamide MS (ES) m/z 453. HRMS: Calculated C24HyClN2 〇3S + H+, 453. 10342; found (ESI, [M+H]+), 453.102. #例156 4-[3-(8-Alkyl-3-methyl-4-quinolinyl)phenoxy]-N-ethyl-N-methylbenzene decylamine MS (ES) m/z </RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; Example 157 8-Alkyl-3-methyl-4-{3-[4-(e-Butyl-1-yl contigyl)benzene 5 yl]phenyl}quinoline MS (ES) m/z </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; f Example 158 10 4-[3-(8-Alkyl-3-methyl-4-quinolinyl)phenoxy]-N-methylbenzenesulfonamide MS (ES) m/z 437· 1 ; HRMS··································· 15 Example 159 8-Chloro-4-{3-[3-fluoro-5-(morpholin-4-ylsulfonyl)phenoxy]benzene (yl}-3-methylquinoline-HRMS: Calculated value C26H22ClFN2 〇4S + H+, 513. 10456 ; Measured. Value (ESI, [Μ+Η]+), 513.1044. 20 i Example 160 4 - [3-(8-Alkyl-3-methyl-4- </RTI> quinolyl)phenoxy]-N-propylbenzenesulfonamide MS (ES) m/z 467. 1 ; HRMS: Calculated C25H23ClN2 〇3S + H+, 163 200825054 467.11907; Measured (ESI, [M+ H] + ), 467.1181. Example 161 N-Benzyl-4-[3-(8-methyl-3-methyl-4-cycloquinolyl)phenoxy]benzene 5 Continuum oxime MS (ES) m /z 515. 1 ; HRMS: Calculated C29H23ClN2 〇3S + H+, 515.11907; found (ESI, [M+H] + ), 515.1211. Example 162 ίο 3-[3-(8-Chloro-3-yl) Benzene-4-quinolinyl)phenoxy]-#-methylbenzenesulfonamide MS (ES) π// 439· 1 ; HRMS: calcd for C23H19ClN2 〇3S + H+, 439.08777; Μ+ΗΓ), 439_ 0868. 15 Example 163 3-[3-(8-Alkyl-3-methyl- 4-indolyl)phenoxy]-iV-ethylbenzenesulfonamide MS (ES) 7Z//Z 453. 1 ; HRMS: calculated C24H21ClN2 〇3S + H+, 453.10342; found (ESI, [M+H] + ), 453.1044 20 Example 164 3-[3-(8-Chloro-3-methylindolyl)phenoxy]propylbenzenesulfonamide MS (ES) /»// 467. 1 ; HRMS: Calculated C25H23ClN2 〇3S + H+, 164 200825054 467.11907; found (ESI, [Μ+ΗΓ), 467_ 1195. j Preparation 165 3-[3-(8-Alkyl-3-methyl-4-quinolinyl)benzene OH] isopropyl 5-benzenesulfonamide MS (ES) / ff / z 467 </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; j备例166 ί 于 benzyl-3-[3-(8-chloro-3-methyl-4-quinolinyl)phenoxy]benzene continuine MS (ES) 515. 1 ; HRMS: Calculated value C29H23ClN2 〇3S + H+, 515.11907; found (ESI, [Μ+ΗΓ), 515·117b 15 Example 167 3-[3-(8-Chloro-3-methyl-4-indolyl) Phenoxy]-y-Y-dimethylbenzenesulfonamide MS (ES) calendar /z 453. 1 ; HRMS: calculated C24H21ClN2 〇3S + H+, 453.10342; found (ESI, [Μ+ΗΓ), 453.1017 . 20 ▲ Example 168 3-[3-(8-Chloro-3-methyl-4-indolyl) phenyloxy]-ethyl-methylbenzenesulfonamide MS (ES) /ff/z </RTI> </RTI> <RTIgt; </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; Example 169 8-Chloro-3-methyl-4-{3-[3-(Bilobit-1-one continued 1-yl)benzene gas 5-yl]phenyl}quinoline MS (ES) π/ζ </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; Example 170 10 3-[3 -(8-Alkyl-3-methyl-4-quinolinyl)phenoxy]-surgery #·diethylbenzenesulfonamide MS (ES) zb/z 481. 1 HRMS: calcd for C26H25ClN2 </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 15 Example 171 8-Chloro-3-methyl-4 - {3-[3-(Bigbit-1-one phenyl) phenoxy]phenyl}quinoline MS (ES) 493_ 1 ; HRMS: For C27H25ClN2 〇3S + H+, 493.13472; found (ESI, [M+H]1), 493. 20 Example 172 8-Alkyl-3-methyl-4-(3-{3-[(4-methyl-tele-l-yl)-according to benzyl]phenoxy}phenyl)quinoline MS (ES 7Z//Z 508. 1 ; HRMS: calcd for C27H26ClN3 〇3S + H+, 166 </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> ESI, [M+H]+, 508.1456. Example 173 8-Chloro-3-methyl-4 - {3-[3-(piperazine-l-ylsulfonyl)phenoxy] 5 phenyl}quinoline HRMS: Calculated C26H24CIN3O3S + H+, 494.12996 ;Measured value (ESI, [Μ+ΗΓ), 494_ 1311. Example 174 10 8-Alkyl-3-methyl-4 - {3-[3_(morphin-4-yl-acidic)phenoxy]phenyl}quinoline 3-(8- under nitrogen) Chloro-3-methyl-4-indolyl) (100 mg, 〇·37 mmol), 4-(3-carbophenyl) hydrazine (170 mg, 〇· 56 mmol), Cul (11 mg, 0· 056 _〇1), Me2NCH2C〇2H Hydrochloric acid 15 (23 mg, 0_ 167 mmol) and bismuth carbate (70 mg, 0.50 mmol) one of the stirred mixture at 100 °C , 4-dioxane (3.0 mL) was heated for 18 hours. After cooling the reaction, water was added, followed by extraction with ethyl acetate. The extract was dried with MgS 〇 4 and concentrated under reduced pressure. Chromatography on silica gel eluting with 30/70 ethyl acetate / hexanes to give the title compound (120 mg) as a tan solid. HRMS: calculated C26H23ClN2 〇 4S + H+, 495.11398; found (ESI, [Μ+ΗΓ), 495·1146· _ 175 to 188 167 200825054

以類似於上述範例174之方法，使用所對應之經溴化的 芳基磺醯胺和喹啉酚，並以一適當的洗提液洗提來製備該 下述的化合物。 5 範例175 8-氣基-3-甲基-4-{3-[3-（嗎啉-4-基磺醢基）苯氧基] 苯基}喹啉 HRMS:計算值 C26H23ClN2〇4S + H+，495.11398 ;實測值 1〇 (ESI，[Μ+ΗΓ)，495.1146。 範例176 4-（{3-[3-(8-氣基-3-甲基-4-啥琳基）苯氧基]苯基} 磺醢基）哌嗪-1-羧酸第三丁酯 15 HRMS:計算值 C31H32ClN3〇5S + H+，594. 18240 ;實測 值（ESI，[Μ+ΗΓ)，594· 179卜· 蘇▲例177 3-[3-(8-氯基-3-甲基-4-啥琳基）苯氧基]-於(2-幾基 20 乙基）苯磺醢胺 HRMS:計算值 C24H21CIN2O4S + H+，469.09833 ;實測 168 200825054 值（ESI, [Μ+ΗΓ)，469. 0962。 範例178 3-[3-(8-氯基-3-甲基-4-喹啉基）苯氧基]-ΛΚ2-羥基 5 乙基）-於甲基苯磺醯胺 ' HRMS:計算值 C25H23ClN2〇4S + H+，483. 11398 ;實測 • 值（ESI, [Μ+ΗΓ)，483· 1148。 《 範例179 10 3-{3-[3-甲基-8-(三氟甲基）-4-喹啉基]苯氧基}-炉 丙基苯磺醯胺 HRMS:計算值 C26H23F3M)3S + H+，501. 14542 ;實測值 (ESI，[Μ+ΗΓ)，501_ 1465。 15 範例180 舲乙基-舲甲基-3-{3-[3_甲基-8-(三氟甲基）-4-喹啉 &quot; 基]苯氧基}苯磺醢胺 - HRMS:計算值 C26H23F3N2〇3S + H+，501. 14542 ;實測值 (ESI，[M+H]+)，501_144。 20 範例181 ΛΚ2-羥基乙基）-舲甲基-3-{3-[3-甲基-8-（三氟甲 基）-4-喹啉基]苯氧基}苯磺醢胺 MS (ES) τζ//ζ516.8 ； HRMS:計算值 C26H23F3N2〇4S + H+， 169 200825054 517.14034;實測值（ESI, [Μ+ΗΓ)，517. 14卜 範例182 ΛΚ2-羥基乙基）_3-{3-[3-甲基-8-(三氟甲基）-4-喹 5 啉基]苯氧基}苯磺醯胺 HRMS:計算值 C25H21F3N2〇4S + H+，503. 12469 ;實測值 (ESI，[M+H]+)，503.123b 範例183 ίο iV-(2-幾基丙基）-3-{3-[3-甲基-8-(三氟甲基）-4-考 啉基]苯氧基}苯磺醢胺 HRMS:計算值 C26H23F3N2〇4S + H+，517. 14034 ;實測值 (ESI，[Μ+ΗΓ)，517.1384。 15 範例184 ΛΚ2-羥基-2-甲基丙基）-3-{3-[3-甲基-8-（三氟甲 基）-4-喹啉基]苯氧基}苯磺醢胺 HRMS:計算值 C27H25F3N2〇4S + H+，531. 15599 ;實測值 (ESI，[Μ+ΗΓ)，531_ 1558。 20 範例185 ΛΚ2-羥基-2-甲基丙基）-|一甲基一3-{3-[3-甲基 -8-（三氟甲基）-4-喹啉基]苯氧基}苯磺醢胺 MS (ES) Λ//Ζ 544· 9 ; HRMS:計算值 C28H27F3N2〇4S + H+， 170 200825054 545.17164;實測值（ESI, [M+H]+)，545.1719。 範例186 ΛΚ2-甲氧基-2-甲基丙基）_3-{3-[3-甲基-8-（三氟甲 5 基）-4-喹啉基]苯氧基}苯磺醢胺 MS (ES) m/z 542. 8 ； HRMS:計算值 C28H27F3N2〇4S + H+， 545.17164;實測值（ESI, [Μ+ΗΓ)，545.1698。 範例187 ίο ΛΚ2-甲氧基-2-甲基丙基）-舲甲基-3_{3-[3-甲基 -8-(三氟甲基）-4-喹啉基]苯氧基}苯磺醢胺 MS (ES) Λ//Ζ 558. 9 ; HRMS:計算值 C29H29F3N2〇4S + H+， 559.18729;實測值（ESI, [M+H]+)，559.1882。 15 範例188 於（2-經基-1,1-二甲基乙基）-3-{3-[3-甲基-8-（三氟 甲基）-4-喹啉基]苯氧基}苯磺醢胺 MS (ES) m/z h28.S ； HRMS:計算值 C27H25F3N2〇4S + H+, 531.15599;實測值（ESI, [M+H]+), 531.154卜 20 範例189 4-[ 3-(6-氟基-11比咬-2-基氧基）-苯基]-3-甲基-8-三 氟甲基-喹啉 171 200825054 將3-[3-甲基-8-(三氟甲基)—4-喹啉基]酚(〇·2〇〇 g，〇.658 mmol)、2, 6-二氟基吡啶(〇· 〇98 g，〇· 856 腿〇1)和 K2C〇3 (〇. 181 g’ 1_32 mmol)加入DMF(5 mL)中並於氮大氣下在60 °C加熱一整 夜。冷卻該反應，以水稀釋並以乙酸乙酯萃取。該經化合的有機 5物以一半飽和的食鹽水溶液沖洗並透過MgS〇4乾燥。該乙酸乙酯 被移除然後透過管柱色層分析純化該產出物質以產生如一油狀 物之該標題化合物（0· 242 g，92%)。 範例190 1〇 3-甲基一4—(3_{[6-（甲基磺醢基）吡啶-2-基]氧基}苯 基)-8-(三氟甲基)啥琳 將4-[3-(6-氟基-吡啶-2-基氧基)-苯基]—3-甲基—8-三氟甲 基-喹啉（0· 236 g，0· 59 mmol)和 NaS〇2Me (90 mg，0. 89 mmol) 於DMF(5 mL)中在60 °C加熱3小時。另外加入NaS〇2Me並將該反 I5 應在150 C加熱一整仪。另外加入NaS〇2Me並繼續加熱一整夜。 冷卻該反應，以水稀釋，並以乙酸乙酯萃取。該經化合的有機物 以一半飽和的食鹽水溶液沖洗並透過MgS〇4乾燥。該乙酸乙酯被 移除然後透過色層分析純化該產出物質以產生如一白色固狀物 之該標題化合物（0.199 8,74%)。111^8:計算值（：231^^2〇$ + 11+， 20 459.09847 ;實測值（ESI, [M+H]1)，459.0972。 範例191 2-氣基-4-(甲基硫基）吼咬 172 200825054 將 2-氯基-4-氟基吡啶（1· 〇〇 g，7· 60 mmol)和 MeSNa (〇· 639 g，9· 12 mmol)於DMF(8 mL)中在環境溫度下攪拌一整夜。將水加 入該反應並以乙酸乙酯萃取。該經化合的有機物以一半飽和的食 鹽水溶液沖洗，透過MgS〇4乾燥，並減壓濃縮。經色層分析後產 5 生如一無色油狀物之該標題化合物（〇. 976 g，81%)。 範例192 3-甲基-4-[3-(4-甲基硫烷基-吡啶-2-基氧基)-苯基]- 8-三 氟甲基-喹啉 10 將 2-氯基-4-(甲基硫基)β比咬（〇. 170 g，1. 07 mmol)、3-[3- 甲基-8-(三氟甲基)-4-喹啉基]酚（〇· 250 g，0.822 mmol)和K2CO3The following compounds were prepared in a manner similar to that of Example 174 above, using the corresponding brominated arylsulfonamide and quinolinol, and eluted with a suitable eluent. 5 Example 175 8-Alkyl-3-methyl-4-{3-[3-(morpholin-4-ylsulfonyl)phenoxy]phenyl}quinoline HRMS: Calculated C26H23ClN2 〇4S + H+ , 495.11398; measured value 1 〇 (ESI, [Μ + ΗΓ), 495.1146. Example 176 4-({3-[3-(8-Alkyl-3-methyl-4-indolyl)phenoxy]phenyl}sulfonyl)piperazine-1-carboxylic acid tert-butyl ester 15 HRMS: Calculated C31H32ClN3 〇5S + H+, 594. 18240; found (ESI, [Μ+ΗΓ), 594· 179·············啥 啥 ) ) ) 苯 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 469 469 469 469 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 469 469 469 469 469 469 469 469 469 469 469 469 469 469 0962. Example 178 3-[3-(8-Chloro-3-methyl-4-quinolinyl)phenoxy]-indole 2-hydroxy-5 ethyl)-methylbenzenesulfonamide 'HRMS: Calculated C25H23ClN2 〇4S + H+, 483. 11398 ; measured value (ESI, [Μ+ΗΓ), 483·1148. Example 179 10 3-{3-[3-Methyl-8-(trifluoromethyl)-4-quinolinyl]phenoxy}-furyl sulfonamide HRMS: Calculated C26H23F3M)3S + H+, 501. 14542; found (ESI, [Μ+ΗΓ), 501_ 1465. 15 Example 180 Ethylethyl-fluorenylmethyl-3-{3-[3_methyl-8-(trifluoromethyl)-4-quinoline&quot; phenyloxy}benzenesulfonamide-HRMS: For C26H23F3N2 〇3S + H+, 501. 14542; found (ESI, [M+H]+), 501 144. 20 Example 181 ΛΚ2-Hydroxyethyl)-indolemethyl-3-{3-[3-methyl-8-(trifluoromethyl)-4-quinolinyl]phenoxy}benzenesulfonamide MS ( ES) τ ζ / / ζ 516.8; HRMS: calculated C26H23F3N2 〇 4S + H+, 169 200825054 517.14034; measured value (ESI, [Μ + ΗΓ), 517. 14 卜 Example 182 ΛΚ 2-hydroxyethyl) _3-{3 -[3-Methyl-8-(trifluoromethyl)-4-quinoxalinyl]phenoxy}benzenesulfonamide HRMS: calcd for C25H21F3N2 〇4S + H+, 503. 12469; [M+H]+), 503.123b Example 183 ίο iV-(2-monopropyl)-3-{3-[3-methyl-8-(trifluoromethyl)-4-carbolinyl] Benzene} benzenesulfonamide HRMS: calcd for C26H23F3N2 s s s s s s s s s s s s s s s s s s s. 15 Example 184 ΛΚ2-Hydroxy-2-methylpropyl)-3-{3-[3-methyl-8-(trifluoromethyl)-4-quinolinyl]phenoxy}benzenesulfonamide HRMS : calcd for C27H25F3N2 〇 4S + H+, 531. 15599; found (ESI, [Μ+ΗΓ), 531_ 1558. 20 Example 185 ΛΚ2-Hydroxy-2-methylpropyl)-|monomethyl-3-{3-[3-methyl-8-(trifluoromethyl)-4-quinolinyl]phenoxy} Benzene sulfonamide MS (ES) Λ / / Ζ 544· 9 ; HRMS: calcd for C28H27F3N2 〇4S + H+, 170 200825054 545.17164; found (ESI, [M+H]+), 545.1719. Example 186 ΛΚ2-methoxy-2-methylpropyl)_3-{3-[3-methyl-8-(trifluoromethyl5-yl)-4-quinolinyl]phenoxy}benzenesulfonamide MS (ES) m/z </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; Example 187 ίο ΛΚ2-methoxy-2-methylpropyl)-fluorenylmethyl-3_{3-[3-methyl-8-(trifluoromethyl)-4-quinolinyl]phenoxy} Benzene sulfonamide MS (ES) Λ / / Ζ 558. 9 ; HRMS: calcd for C29H29F3N2 〇4S + H+, 559.18729; </RTI> (ESI, [M+H]+), 559.1882. 15 Example 188 (2-Hydroxy-1,1-dimethylethyl)-3-{3-[3-methyl-8-(trifluoromethyl)-4-quinolinyl]phenoxy Benzene sulfonamide MS (ES) m/z h28.S; HRMS: calcd for C27H25F3N2 〇4S + H+, 531.15599; found (ESI, [M+H]+), 531.154 -(6-fluoro-11-buty-2-yloxy)-phenyl]-3-methyl-8-trifluoromethyl-quinoline 171 200825054 3-[3-methyl-8-( Trifluoromethyl)-4-quinolinyl]phenol (〇·2〇〇g, 〇.658 mmol), 2,6-difluoropyridine (〇·〇98 g, 〇·856 leg 〇1) and K2C 〇 3 (〇. 181 g' 1_32 mmol) was added to DMF (5 mL) and heated at 60 ° C overnight under nitrogen atmosphere. The reaction was cooled, diluted with water and extracted with EtOAc. The combined organic 5 was washed with a half-saturated aqueous solution of saline and dried over MgS 4 . The ethyl acetate was removed and the product was purified by column chromatography to give the title compound (0·242 g, 92%) as an oil. Example 190 1〇3-methyl-4-(3_{[6-(methylsulfonyl)pyridin-2-yl]oxy}phenyl)-8-(trifluoromethyl)anionine 4- [3-(6-Fluoro-pyridin-2-yloxy)-phenyl]-3-methyl-8-trifluoromethyl-quinoline (0·236 g, 0·59 mmol) and NaS〇 2Me (90 mg, 0.89 mmol) was heated in DMF (5 mL) at 60 °C for 3 h. In addition, NaS〇2Me was added and the counter I5 was heated at 150 C. Also add NaS〇2Me and continue to heat overnight. The reaction was cooled, diluted with water and extracted with EtOAc. The combined organics were washed with a half-saturated aqueous solution of saline and dried over MgS 4 . The ethyl acetate was removed and the material was purified by chromatography to give the title compound (0.199 8.74%) as a white solid. 111^8: Calculated value (: 231^^2〇$ + 11+, 20 459.09847; measured value (ESI, [M+H]1), 459.0972. Example 191 2-Alkyl-4-(methylthio) ) bite 172 200825054 2-Chloro-4-fluoropyridine (1·〇〇g, 7.60 mmol) and MeSNa (〇·639 g, 9.12 mmol) in DMF (8 mL) in the environment The mixture was stirred at room temperature overnight. Water was added to the reaction and extracted with ethyl acetate. The combined organics were washed with a half-saturated aqueous salt solution, dried over MgSO 4 and concentrated under reduced pressure. The title compound (〇. 976 g, 81%) was obtained as a colorless oil. Example 192 3-methyl-4-[3-(4-methylsulfanyl-pyridin-2-yloxy)- Phenyl]- 8-trifluoromethyl-quinoline 10 2-Chloro-4-(methylthio)β ratio bite (〇 170 g, 1. 07 mmol), 3-[3-methyl 8-(-trifluoromethyl)-4-quinolinyl]phenol (〇·250 g, 0.822 mmol) and K2CO3

(0· 227 g，1. 64 mmol)於 DMF(5 mL)中在 80 °C 加熱一整夜。TLC 顯示無反應。另外加入吡啶化合物和Κ£〇3並將該反應在150 °C 加熱一整夜。冷卻該反應，以水稀釋，並以乙酸乙酯萃取。該經 15化合的有機物以一半飽和的食鹽水溶液沖洗，透過MgS〇4乾燥， 並減壓濃縮。透過色層分析純化該殘餘物以產生混有些許紛之該 才示遞化合物（0· 310 g)。该物負無經進一步純化被接續使用。 範例Lig 20 3一甲基甲基磺酸基）吡啶-2-基]氧基}苯 基)-8-(三氟甲基)喹啉 將含有3-甲基-4-[3-(4-甲基硫烷基—D比啶_2_基氧基)—苯 基]-8-三氟甲基-喧琳之丙酮/水(20虬之1:1混合物）與NaHC〇3 173 200825054 (0· 207 g，2· 46 mmol)和 〇xone® (ΐ· 26 g，2· 06 mmol)-起在室 溫攪拌一整夜。在減壓下移除該丙酮並以乙酸乙酯萃取該產生的 浴液。違經化合的有機物以一半飽和的食鹽水溶液沖洗，透過 MgS〇4乾燥，並減壓濃縮。透過色層分析純化該殘餘物以產生如一 5白色泡沫之該標題化合物（231 mg)。MS (ES) /ζ7/ζ458· 8 ; HRMS: 計算值 C23H17F3N2O3S + H+，459.09847 ;實測值（ESI, [M+H]+) 459.0988 。 範例194至195 10 以類似於上述範例190至範例193之方法，但在起始步驟中 以以2, 6-一氟基吼11 定取代2-氯基-4-氟基σ比ϋ定，使用適當之硫醇 鈉來製備該下述的2, 6-吡啶化合物。 15 範例194 2-甲基-4-[ (6-{3-[3-甲基-8-(三氟甲基)-4-喹啉基]苯氧 基卜比淀-2-基)磺醢基]-2-丁酵 HRMS:計算值 C27H25F3N2〇4S + H+，531.15599 ;實測值（ESI， [M+HD，531.1547。 20 範例195 4-[3-({6-[(3-甲氧基-3-甲基丁基)續斑基]批咬-2-基}氧 基)苯基]-3-甲基-8-(三氟甲基)啥琳 174 200825054 HRMS:計算值 C28H27F3N2〇4S + H+，545.17164 ;實測值（ESI， [M+H]〇，545.1656。 範例196 5 3-甲基-4-(3-{ [5-(甲基磺醢基）吼啶-3-基]氧基}苯 基)-8-(三氟甲基)啥琳 將3-漠基-5-（甲石夤醯基)°比°定（233mg，0· 989mmol，參閱， 例如，W0 2002/060438之合成敘述)加入3-[3-甲基-8-(三氟甲 基)-4-喧琳基]紛（150 mg，0.494 mmol)、Cul (9 mg，0.0494 i〇 mmol)、N-N-二甲基甘胺酸氯酸鹽（25mg，0.185mmol)、Cs2C〇3 (482 mg，1.47 mmol)於1，4-二噁烷（5 mL)中之一混合物中。將該反 應在迴流加熱一整夜，然後冷卻並加入水。以乙酸乙酯萃取該混 合物並透過MgS〇4乾燥該化合的有機物，然後減壓濃縮。將該殘 餘物色層分析以產生如一白色固狀物之該標題化合物（140 mg， 15 62%)。 MS (ESI) /ff/z 459 ; HRMS:計算值 C23HnF3N2〇3S + H+， 459.09847;實測值（ESI，[M+H]+)，459· 1004。 範例197 3-甲基-4- [ 3-(2-甲基硫烷基-吡咬-4 -基氧基)-苯基]-8-三 2〇 氟甲基-啥琳 將4-漠基-2-(甲基硫基)σ比咬(201 mg，0.989 mmol)加入含 有3-[3-甲基-8-(三氟甲基）-4-喧琳基]紛（200 mg，0.659 mmol)、Cul (13 mg，0. 066 mmol)、N-N-二甲基甘胺酸氫氣酸鹽 (35 mg，0· 24 mmol)、CS2CO3 (644 mg，1· 98 mmol)於 1，4-二口惡 175 200825054 烷(5 mL)中之混合物中。在迴流加熱整夜之後，將該反應冷卻、 加入水、並以乙酸乙酯萃取。該經化合的萃取物透過MgS〇4乾燥 並減壓濃縮。將該殘餘物色層分析以產生如一白色黏態固狀物之 該標題化合物（279 mg)。MS (ES+): 458.9。 5 範例198 3-甲基-4-(3-{[2-(甲基磺醢基）”比啶-4-基]氧基}苯 基)-8-(三氟甲基)考琳 在含有3-甲基-4-[3-(2-甲基硫燒基-吼咬-4-基氧基)-苯 10 基]-8-三氟甲基-啥琳（226 mg，0· 529 mmol)之以1:1混合的丙 蒙1/水混合物（10 mL)中加入 NaHC〇3(132 mg，1. 58 mmol)和 0x〇ne@ (325 mg，1· 32 mmol)並在環境溫度下攪拌整夜。在減壓下移除 丙酮並以乙酸乙酯萃取該所產生的水狀混合物。透過MgS〇4乾燥 經化合的萃取物、減壓濃縮、並透過管柱色層分析純化該殘餘物 15 以產生如一白色固狀物之該標題化合物（169 mg)。MS (ES) /b/z 427· 0。 範例199 3,4-二氩-簾硫基nb喃[2,3 -b]吡咬1,1,8-三氧化物 20 在〇 °C將30% H2O2 (40· 0 mL, 352 mmol)緩緩加入三氟乙酸 (225 mL)中。冰浴被移除並加入該雙環吡啶基—硫化物（6.1〇 g， 40· 4 mmol，製備請參閱，例如，Taylor和Macor所著之/. 0/瓦 0?挪· 1987，52，4280-4287)，將該反應於45 °C加熱整夜。濃 縮該反應並以熱MeOH將改殘餘物磨碎。冷卻與過濾該混合物以 176 200825054 產生如一白色固狀物之該標題化合物（7. 〇〇 g，87%)。MS (es〇 m/z 200 ° 範例200 5 7-溴基-3,4-二氩-怨硫基吡喃[2,3-b]11*咬1，卜二氡化物 (八）和5-溴基-3,4-二氩-^硫基吡喃[2,3-1)]吡啶1，1〜二氣化 物(B) 將3, 4-二氫-2H-硫基吡喃[2, 3-b]吡啶1，1，8-三氣化 物（1.00 g，5_02 mmol)和Ρ(0)Βη (10.0 g)在65 °C加熱 ίο 0· 5小時。冷卻該反應並小心地加入飽和的NaHC〇3與些許 乙酸乙s旨以減少泡沫形成。然後加入固態K2C〇3直到該反鹿 變成鹼性。以乙酸乙酯萃取該混合物然後透過MgS〇4乾燥該 經化合的萃取物並減壓濃縮。該殘餘物經色層分析以分另,j 產生用於下一步驟之標題化合物A (0.245 g)和B (〇.156 15 g) 0 範例201 7- {3- [3-甲基_8-(三氟甲基)-4-喹啉基]苯氧基}-3,4-二 氫-2ZF·硫基吼味[2, 3-b]吼咬1,1_二氧化物 20 將3-[3-甲基-8-(三氟甲基)-4-喹琳基]酚（172 mg，0· 57 mmol)加入含有7-演基-3, 4-二氫-2H-硫基0比喃[2, 3-b]σ比唆 1，1-二氧化物（l〇〇mg，〇· 38mmol)、Cul (11 mg，0· 057 mmol)、 N-N-二甲基甘胺酸鹽酸鹽（30 mg，0· 213 mmol)、Cs2C〇3 (557 mg， 177 200825054 1· 71 mmol)於1，4-二噁烧(5 mL)中之一混合物中並在迴流加熱整 夜。以乙酸乙酯萃取該經冷卻的混合物然後透過MgS〇4乾燥該經 化合的萃取物並減壓濃縮。該殘餘物經色層分析以產生如一白色 固狀物之不同的標題化合物（16811^)。^{3邙8)/»/7 484.9;111^8: 5 計算值 C25H19F3N2〇3S + H+，485.11412 ;實測值（ESI, [M+H]〇， 485.114。 範例202 5-{3-[3_甲基-8-(三氟甲基)-4-啥琳基]苯氧基}-3,4-二 ίο 氩-2昃硫基吡喃[2,3-b]吡啶1,1-二氧化物 將3_[3_甲基-8-（三氟甲基）-4-啥琳基]紛（269 mg， 0.89 mmol)加入含有5-漠基-3, 4-二氫-2H-硫基°比喃 [2, 3-1)]°比°定 1，1-二氧化物（156 mg，0· 595 mmol)、CuI (17 mg，0· 089 mmol)、N-N-二甲基甘胺酸鹽酸鹽（46 mg，0· 333 15 mmol)、CS2CO3 (869 mg，2_ 67 mmol)於 1，4-二噁烷（5 mL) 中之一溶液中並在迴流加熱整夜。以乙酸乙酯萃取該經冷 卻的混合物然後透過MgSCU乾燥該經化合的萃取物並減壓 濃縮。該殘餘物經色層分析以產生如一白色固狀物之不同 的標題化合物（127 1^)。仏5(^5)/»/^ 485.0;11{^3:計 20 算值 C25H19F3N2〇3S + H+，485· 11412;實測值（ESI，[Μ+ΗΓ)， 485·115卜 範例203 178 200825054 2,4,6_三氯基-|1比咬1-氧化物 將2, 4, 6-三氣吼°定（4· 26 g，23. 4 mmol)溶於三氟乙酸（25 mL)中並加入30% ΗΛ2 (5· 9 mL)。該混合物在100 °C加熱4小時， 然後冷卻並倒入水中（150 mL)。以二氯甲烷萃取該混合物並以飽 5 和的NaHC〇3水溶液沖洗該經化合的萃取物，透過MgS〇4乾燥以 及減壓濃縮。該殘餘物經色層分析以產生該標題化合物，其無經 進一步分析而被使用。 範例204 10 4-[3-(4,6-二氣基-1-氧基-吼咬-2-基氧基)-苯基]-3-甲 基-三氟甲基-啥琳 將2, 4, 6-三氯基-吡啶1-氧化物（0· 244 g，1. 23 mmol)、 3-[3-甲基-8-(三氟甲基)-4-口奎琳基]盼(0.250 g，0.822 mmol) 和 K2CO3 (0· 227 g，1· 64 mmol)加入 DMF (5 mL)中並在 80 °C 加 15 熱整夜。冷卻該反應，以水稀釋並以乙酸乙酯萃取。以半飽和的 食鹽水水溶液沖洗該經化合的有機物，透過MgS〇4乾燥並減壓濃 縮。該殘餘物經色層分析以產生如一白色固狀物之該標題化合物 (0-330 g，86%)，其無經進一步分析即被使用。 範例205 4-(3-{[4-氯基-6-（甲基續酸基)-1-氧離子基〇比咬一 2-基] 氧基}苯基)-3-甲基-8-(三氟甲基)啥琳 179 20 200825054 將含有4-[3-(4,6-二氣-1-氧基-吼啶-2-基氧基）-苯 基]-3-甲基-8-三氟甲基-唾琳（330 mg，0.709 mmol)和甲烧亞 績酸鈉（72 mg，0_ 709 mmol)之 DMF(5 mL)於 80 °C 加熱整夜。 冷卻該反應，以水稀釋並以乙酸乙酯萃取。以半飽和的食鹽水水 5 溶液沖洗該經化合的有機物，透過MgS〇4乾燥並減壓濃縮。該殘 餘物經色層分析以產生如一白色固狀物之該標題化合物（190 mg，53%)。MS (ES) /»//508. 9 ; HRMS:計算值 C23H16ClF3N2〇4S + H+, 509· 05442;實測值（ESI, [M+H]1)，509.0532。 10 範例206 4-[3-(4-氣基-6-甲磺醢基-吼啶-2-基氧基)-苯基]-3-甲 基-8-三氟甲基-啥淋 將4-[3-(4-氯基-6-甲磺醯基-1-氧基-η比啶-2-基氧基)-苯 基]-3-甲基-8-三氟甲基-啥琳（0.122 g，0.239 mmol)溶於二氣 15 甲烷(5mL)中並加入ΡΒη (0.3581^之1.0肘溶液於二氣甲烷中， 0.358 mmol)，然後攪拌整夜。該反應以飽和的NaHC〇3水溶液進 行水淬’以乙酸乙S旨萃取，並透過MgS〇4乾燥與減壓濃縮。該殘 餘物經色層分析以產生如一白色固狀物之該標題化合物（75 mg， 64%)。 HRMS··計算值 C23H16ClF3N2〇3S + H+，493.05950 ;實測 20值阳1，此盯)，493.059卜 範例207 3,5-二氣基-2-氟基-6-{3-[3-甲基-8-(三氟甲基)-4-啥琳 基]苯氧基} *比咬-4-胺 180 200825054 將 4-胺基-3, 5-二氯-2, 6-二氟基吡啶（0_ 850 g，4. 28 mmol) 加入含有3-[3-甲基-8-(三氟曱基)-4-喹啉基]酚（1.00 g，3· 29 mmol)、Κ£〇3 (0. 909 g，6. 58 mmol)於乙腈（10 mL)中之溶液中 並將該反應於50 °C加熱整夜。LC-MS顯示些許之起始酚仍然存 5 在。一另外加入0. 5 g之^比^定並持續加熱2小時。加入水於該經 冷卻之反應並以乙酸乙酯萃取。透過MgS〇4乾燥該經化合之萃取 物，減壓遭縮，且該殘餘物透過色層分析純化以產生如一白色泡 沫之該標題化合物（1. 09 g，69%)。MS (ES) Λ7/Ζ 481. 7。 10 範例208 3,5-二氣-2-(甲基磺醢基）-6-{3-[3-甲基-8-（三氟甲 基)-4-喹啉基]苯氧基}吡啶-4-胺 將3, 5-二氯-2-氟基-6-{3-[3-甲基-8-(三氟甲基)-4-喧琳 基]本氧基}σ比唆-4-胺（1.068 g ’ 2.21 mmol)加入含有甲烧亞石黃 15 酸鈉（〇· 399 g，3· 32 mmol)於 DMF (15 mL)中之一溶液中並在 100 °C加熱60小時。另外加入甲烷亞磺酸鈉以及DMF並將該反應於 120 °C加熱整夜。將水加入該經冷卻之反應中，以乙酸乙酯萃取， 並以半飽和的食鹽水水溶液沖洗該經化合的有機物。透過MgS〇4 乾燥之萃取物進行減壓濃縮且該殘餘物經色層分析以產生如一 20白色泡沫之該標題化合物（〇· 828 g，70%)。MS (ES)瓜令541. 7。 範例209 181 200825054 2-甲續醢基；〜[3一(3一甲基-8-三氟甲基--4-喹琳基)一苯氧 基]-吡啶-4-基胺 將3, 5-一氯-2-甲績醯基-6-[3-(3-甲基-8-三氟甲基-4-口奎 淋基)-苯氧基]-吼啶—4—基胺（0·692 g，127刪〇1)加入含有蟻 5 酸銨（3· 50 g ’ 55· 5 咖〇1)和 10% 碳上鈀（〇· 139 g)於 MeOH (5 mL) 中之一/谷液中然後在60 °C加熱整夜。將另外1· β g之犧酸銨以 及另一份之10% Pd/c加入該反應中，然後持續加熱數小時。伴 隨著2· 5 g之蟻酸銨與〇· 050 g之1〇% Pd/C加入更多的Me〇H。 加熱該反應另整夜期間。該反應被冷卻並透過助濾器（Celite)過 1〇渡。濃縮該母液並透過管柱色層分析純化該所產生的物質以產生 該標題化合物，其進一步被用於下一步驟（0.400 g，67%)。 範例210 4-(3-{[4-氟基-6-（甲基磺醢基）吼啶-2-基]氧基}苯 15基)-3-甲基-8-(三氟甲基)考琳(0·227 g, 1.64 mmol) was heated in DMF (5 mL) at 80 °C overnight. TLC showed no response. Further, a pyridine compound and 〇3 were added and the reaction was heated at 150 ° C overnight. The reaction was cooled, diluted with water and extracted with EtOAc. The 15 organic compound was washed with a half-saturated aqueous salt solution, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by chromatography to give a mixture of the compound (0.33 g). This material was used in succession without further purification. An example of Lig 20 3 -monomethylsulfonyl pyridin-2-yl]oxy}phenyl)-8-(trifluoromethyl)quinoline will contain 3-methyl-4-[3-(4 -Methylsulfanyl-D-pyridyl-2-yloxy)-phenyl]-8-trifluoromethyl-indene-acetone/water (1:1 mixture of 20 )) and NaHC〇3 173 200825054 (0· 207 g, 2·46 mmol) and 〇xone® (ΐ· 26 g, 2·06 mmol) - stirred at room temperature overnight. The acetone was removed under reduced pressure and the resulting mixture was extracted with ethyl acetate. The compound which was neutralized was washed with a half-saturated aqueous solution of saline, dried over Mg??, and concentrated under reduced pressure. The residue was purified by chromatography to give the title compound (231 mg). MS (ES) / ζ 7 / ζ 458. 8; HRMS: calcd., calcd, calcd. Examples 194 to 195 10 are similar to the methods of the above Examples 190 to 193, but in the initial step, the 2-chloro-4-fluoro σ ratio is substituted by 2,6-monofluoro fluorene, The following 2,6-pyridine compound was prepared using a suitable sodium thiolate. 15 Example 194 2-Methyl-4-[(6-{3-[3-methyl-8-(trifluoromethyl)-4-quinolinyl]phenoxybubbi-2-yl)sulfonate醢基]-2-butyric acid HRMS: calculated value C27H25F3N2 〇4S + H+, 531.15599; measured value (ESI, [M+HD, 531.1547. 20 Example 195 4-[3-({6-[(3-methoxy) Benzyl-3-methylbutyl) contiguous group] Bite-2-yl}oxy)phenyl]-3-methyl-8-(trifluoromethyl)fluorene 174 200825054 HRMS: Calculated value C28H27F3N2〇 4S + H+, 545.17164; found (ESI, [M+H] 〇, 545.1656. Example 196 5 3-methyl-4-(3-{ [5-(methylsulfonyl)acridin-3-yl) ]oxy}phenyl)-8-(trifluoromethyl)anthene will be 3-mercapto-5-(methylphosphonium) ° ratio (233 mg, 0·989 mmol, see, for example, W0 2002 Synthesis of /060438) Add 3-[3-methyl-8-(trifluoromethyl)-4-indolyl] (150 mg, 0.494 mmol), Cul (9 mg, 0.0494 i〇mmol), NN-dimethylglycine chlorate (25 mg, 0.185 mmol), Cs2C 3 (482 mg, 1.47 mmol) in a mixture of 1,4-dioxane (5 mL). Heated under reflux overnight, then cooled and added water. The mixture was extracted with ethyl acetate. The combined organics were dried <RTI ID=0.0>(M </RTI> <RTI ID=0.0> HRMS: Calculated C23HnF3N2 〇3S + H+, 459.09847; found (ESI, [M+H]+), 459 · 1004. Example 197 3-Methyl-4-[3-(2-methylsulfanyl) -Pyridin-4-yloxy)-phenyl]-8-tris(2)fluoromethyl-phthalocyanine 4-meryl-2-(methylthio)σ ratio bite (201 mg, 0.989 mmol) Add 3-[3-methyl-8-(trifluoromethyl)-4-indolyl] (200 mg, 0.659 mmol), Cul (13 mg, 0.066 mmol), NN-dimethyl A solution of glycine hydrogenate (35 mg, 0. 24 mmol), CS2CO3 (644 mg, 1. 98 mmol) in 1,4-dioxan 175 200825054 hexane (5 mL). After heating under reflux overnight, the reaction was cooled, water was added and ethyl acetate was evaporated. The combined extract was dried over MgS 4 and concentrated under reduced pressure. The residue was analyzed to give the title compound (279 mg) as a white solid. MS (ES+): 458.9. 5 Example 198 3-Methyl-4-(3-{[2-(methylsulfonyl)"pyridin-4-yl]oxy}phenyl)-8-(trifluoromethyl)Colin Contains 3-methyl-4-[3-(2-methylthioalkyl-indole-4-yloxy)-benzene-10-yl]-8-trifluoromethyl-indole (226 mg, 0· 529 mmol) of a 1:1 mixture of Cinnam 1/water (10 mL) was added with NaHC〇3 (132 mg, 1.58 mmol) and 0x〇ne@ (325 mg, 1.32 mmol) and Stir at ambient temperature overnight. The acetone was removed under reduced pressure and the resulting aqueous mixture was extracted with ethyl acetate. The combined extracts were dried with &lt;RTI ID=0.0&gt; The residue 15 was purified to give the title compound ( 169 mg) as a white solid. MS (ES) / b/z 427 · 0. Example 199 3,4-di- ar- s- syl 3 -b] pyridine bit 1,1,8-trioxide 20 30% H2O2 (40·0 mL, 352 mmol) was slowly added to trifluoroacetic acid (225 mL) at 〇 ° C. The ice bath was removed. And adding the bicyclopyridyl-sulfide (6.1 〇g, 40·4 mmol, see preparation, for example, by Taylor and Macor /. 0 / watt 0? Norwegian 1987, 52, 4280-4287), will The reaction The mixture was heated at 45 ° C. The title compound was obtained (jjjjjjjjjjj MS (es〇m/z 200 ° Example 200 5 7-bromo-3,4-diargon-sulphurylpyran [2,3-b]11* bite 1, dimide (eight) and 5-bromo-3,4-diar-(sulfanylpyrano[2,3-1)]pyridine 1,1~di-vapor (B) 3,4-dihydro-2H-thiopyran [2,3-b]pyridine 1,1,8-trivapor (1.00 g, 5_02 mmol) and Ρ(0)Βη (10.0 g) were heated at 65 ° C for ίο 0. 5 hours. Cool the reaction and be careful Saturated NaHC〇3 and a little acetic acid were added to reduce foam formation. Solid K2C〇3 was then added until the anti-deer became alkaline. The mixture was extracted with ethyl acetate and then dried by MgS〇4. The residue was concentrated under reduced pressure. The residue was chromatographed to give the title compound A (0.245 g) and B (〇.156 15 g) for the next step. Example 201 7- {3- [ 3-methyl-8-(trifluoromethyl)-4-quinolinyl]phenoxy}-3,4-dihydro-2ZF·thio-based astringent [2, 3-b] bite 1,1_Dioxide 20 3-[3-Methyl-8-(trifluoromethyl)-4-quinolinyl]phenol (172 mg, 0·57 mmol) was added to contain 7-acting-3 , 4-dihydro-2H-thiol 0-pyrano[2,3-b]σ 唆1,1-dioxide (10 mg, 〇·38 mmol), Cul (11 mg, 0·057 mmol) ), NN-dimethylglycine hydrochloride (30 mg, 0·213 mmol), Cs2C〇3 (557 mg, 177 200825054 1.71 mmol) in 1,4-dioxin (5 mL) One of the mixtures was heated under reflux overnight. The cooled mixture was extracted with ethyl acetate and the combined extract was dried over MgSO 4 and concentrated under reduced pressure. The residue was chromatographed to give the title compound (16811) as a white solid. 。^^^^^^^^^^^ _Methyl-8-(trifluoromethyl)-4-indolyl]phenoxy}-3,4-diίο argon-2-indolethiopyrano[2,3-b]pyridine 1,1- Dioxide added 3_[3_methyl-8-(trifluoromethyl)-4-indolyl] (269 mg, 0.89 mmol) to 5-amino-3,4-dihydro-2H- 1,2-dioxide (156 mg, 0·595 mmol), CuI (17 mg, 0·089 mmol), NN-dimethyl, thio-pyrano ratio [2, 3-1)]° A solution of glycine hydrochloride (46 mg, 0·333 15 mmol), CS2CO3 (869 mg, 2_67 mmol) in 1,4-dioxane (5 mL) was warmed to reflux overnight. The cooled mixture was extracted with ethyl acetate and the combined extract was dried over MgSCU and concentrated under reduced pressure. The residue was chromatographed to give the title compound (127 1 ) as a white solid.仏5(^5)/»/^ 485.0;11{^3: Calculated 20 Calculated value C25H19F3N2〇3S + H+, 485·11412; measured value (ESI, [Μ+ΗΓ), 485·115 卜 203 178 200825054 2,4,6-trichloro--1 is more soluble in 2,4,6-trioxane (4·26 g, 23. 4 mmol) in trifluoroacetic acid (25 mL) Add 30% ΗΛ2 (5·9 mL). The mixture was heated at 100 °C for 4 hours, then cooled and poured into water (150 mL). The mixture was extracted with dichloromethane and the combined extract was washed with a saturated aqueous solution of NaHC.sub.3, dried over MgSO.sub.4 and concentrated under reduced pressure. The residue was chromatographed to give the title compound which was used without further analysis. Example 204 10 4-[3-(4,6-Dioxa-1-one-oxime-2-yloxy)-phenyl]-3-methyl-trifluoromethyl-啥琳2 , 4,6-trichloro-pyridine 1-oxide (0·244 g, 1.23 mmol), 3-[3-methyl-8-(trifluoromethyl)-4-hydroxypheninyl] Hope (0.250 g, 0.822 mmol) and K2CO3 (0·227 g, 1.66 mmol) were added to DMF (5 mL) and 15 hot overnight at 80 °C. The reaction was cooled, diluted with water and extracted with EtOAc. The combined organic material was washed with a half-saturated aqueous solution of brine, dried over MgSO 4 and concentrated under reduced pressure. The residue was chromatographed to give the title compound (0-330 g, 86%) as a white solid, which was used without further analysis. Example 205 4-(3-{[4-Chloro-6-(methylsulfanyl)-1-oxo-indenyl quinone than 2-yl]oxy}phenyl)-3-methyl-8 -(Trifluoromethyl)啥琳179 20 200825054 will contain 4-[3-(4,6-di-n-l-oxy-acridin-2-yloxy)-phenyl]-3-methyl -8-Trifluoromethyl-salin (330 mg, 0.709 mmol) and sodium sulphate (72 mg, 0- 709 mmol) in DMF (5 mL) were warmed overnight at 80 °C. The reaction was cooled, diluted with water and extracted with EtOAc. The combined organics were washed with a half-saturated aqueous solution of brine, dried over MgSO 4 and evaporated. The residue was chromatographed to give the title compound (190 mg, <RTIgt; MS (ES) /» / / 508. 9 ; HRMS: calcd., calcd., calcd, s, s, s, s, s, s, s, s, s, s, s, s, s, s. 10 Example 206 4-[3-(4-Gas-6-methylsulfonyl-acridin-2-yloxy)-phenyl]-3-methyl-8-trifluoromethyl-phosphonium will 4-[3-(4-Chloro-6-methylsulfonyl-1-oxy-η-pyridin-2-yloxy)-phenyl]-3-methyl-8-trifluoromethyl-啥 Lin (0.122 g, 0.239 mmol) was dissolved in hexanes (5 mL) and EtOAc (. The reaction was subjected to water quenching with a saturated aqueous solution of NaHC 〇 3 to extract with ethyl acetate and dried over MgSO 4 and concentrated under reduced pressure. The residue was chromatographed to give the title compound (75 mg, 64%) as a white solid. HRMS··calculated value C23H16ClF3N2〇3S + H+, 493.05950; measured 20 value yang 1, this stare), 493.059 exe 207 3,5-dioxa-2-fluoro-6-{3-[3-methyl -8-(Trifluoromethyl)-4-indolyl]phenoxy} *Bist-4-amine 180 200825054 4-Amino-3,5-dichloro-2,6-difluoropyridine (0_ 850 g, 4. 28 mmol) Addition of 3-[3-methyl-8-(trifluoromethyl)-4-quinolinyl]phenol (1.00 g, 3.29 mmol), Κ£〇3 (0. 909 g, 6.58 mmol) in EtOAc (10 mL). LC-MS showed that some of the starting phenol remained. An additional 0.5 g was added and the heating was continued for 2 hours. Water was added to the cooled reaction and extracted with ethyl acetate. The compound was dried (MgSO.sub.4). MS (ES) Λ 7/Ζ 481. 7. 10 Example 208 3,5-dioxa-2-(methylsulfonyl)-6-{3-[3-methyl-8-(trifluoromethyl)-4-quinolinyl]phenoxy} Pyridyl-4-amine 3, 5-dichloro-2-fluoro-6-{3-[3-methyl-8-(trifluoromethyl)-4-indolyl] oxy}σ ratio唆-4-amine (1.068 g ' 2.21 mmol) was added to a solution containing sodium sulphate 15 (sodium 399 g, 3.32 mmol) in DMF (15 mL) and heated at 100 °C. 60 hours. Further, sodium methanesulfinate and DMF were added and the reaction was heated at 120 °C overnight. Water was added to the cooled reaction, extracted with ethyl acetate, and the combined organics were washed with a half-saturated aqueous brine solution. The title compound (〇·828 g, 70%) was obtained as a white foam. MS (ES) melon order 541.7. Example 209 181 200825054 2-methyl sulfhydryl; ~[3-(3-methyl-8-trifluoromethyl--4-quinolinyl)-phenoxy]-pyridin-4-ylamine 3 5-monochloro-2-methylindole-6-[3-(3-methyl-8-trifluoromethyl-4-hydroxyl-yl)-phenoxy]-acridin-4-ylamine (0·692 g, 127 〇 1) Adding ammonium ant 5 (5·50 g '55·5 curry 1) and 10% palladium on carbon (〇·139 g) in MeOH (5 mL) The heat was then heated overnight at 60 °C. An additional 1·β g of ammonium sulphate and another 10% of Pd/c were added to the reaction and heating was continued for several hours. Accompanied by 2.5 g of ammonium formate and 〇· 050 g of 1% Pd/C added more Me〇H. The reaction was heated overnight during the night. The reaction was cooled and passed through a filter aid (Celite). The mother liquor was concentrated and purified by column chromatography to give the title compound, which was further used in the next step (0.400 g, 67%). Example 210 4-(3-{[4-Fluoro-6-(methylsulfonyl)acridin-2-yl]oxy}phenyl-15-yl)-3-methyl-8-(trifluoromethyl Kaolin

將2-甲磺醯基-6-[3-(3-甲基-8-三氟甲基--4-喹啉 基）-苯氧基]-°比咬-4-基胺（〇_ 300 g，0· 633 mmol)加入含 有70% HF-吡啶（5 mL)之Teflon圓底燒瓶並冷卻至0 °C。 逐部份加入亞硝酸鈉（0· 262 g，3. 80 mmol)。在20 °C攪 20 拌該反應達2小時，然後在60 °C攪拌1小時。將該反應 冷卻至20 °C，加入冰，隨後以固狀NaHC〇3中和。以乙酸乙 酯萃取該混合物並以水沖洗該經化合的萃取物，然後透過 MgS〇4乾燥。該萃取物經減壓濃縮且該殘餘物經色層分析以 產生如一白色泡洙之該標題化合物（〇. 159 g，53%)。 MS 182 200825054 (ES) m/z 477. 1 ° 範例211 1-（淡基甲基）-4-（甲基續酿基）苯 5 將 1-甲磺醯基-4-甲基-苯（1· 30 g，7. 5 mmol)、n- 溴丁二醯亞胺（1· 30 g，7_ 10 mmol)、和過氧化苯（70 mg， 0.30 mmol)於CCh (70 mL)中之一經檀拌的混合物在迴流 加熱4小時。冷卻、過濾、並減壓濃縮該反應。濃縮該經 化合的有機相並將該殘餘物經色層分析，以1:9乙酸乙醋： ίο 己烷洗提以產生如一白色固狀物之該標題化合物（0. 700 g ， 38%) 。 mp 99-101 °C ; MS (ES) m/z 248·9 。 範例212 4-(3-{[3-(甲基磺醢基）苄基]氧基}苯基）_8-(三氟 15 甲基）喹啉 將3-(8-三氟甲基--4-喹啉基）-酚（0_100g，0_35 mmol)、1-(溴甲基）-3-(甲基磺醯基）苯（0. 130 g，0.52 mmol)，和碳酸铯（676 mg，2. 10 mmol)於乙腈（5 mL)中之 一混合物在室溫攪拌3小時。過濾和減壓濃縮該反應，且 20 該殘餘物經色層分析，以1:1乙酸乙酯：己烷洗提以產生如 一白色固狀泡沫知該標題化合物（0. 147 g，93°/〇)。mp 63-65 X. C24H18F3N〇3S之計算質量為457.47 ;實測值（ES， [M+H] + )，458.2。 183 200825054 範例213至2152-Methanesulfonyl-6-[3-(3-methyl-8-trifluoromethyl--4-quinolinyl)-phenoxy]-° ratio -4-aminoamine (〇_ 300 g, 0·633 mmol) was added to a Teflon round bottom flask containing 70% HF-pyridine (5 mL) and cooled to 0 °C. Sodium nitrite (0·262 g, 3.80 mmol) was added portion by portion. The reaction was stirred at 20 ° C for 2 hours and then at 60 ° C for 1 hour. The reaction was cooled to 20 ° C, ice was added, and then neutralized with solid NaHC. The mixture was extracted with ethyl acetate and the combined extract was washed with water and then dried through MgS 4 . The extract was concentrated under reduced pressure and the residue was applied tojjjjjjjjjjjjj MS 182 200825054 (ES) m/z 477. 1 ° Example 211 1-(Letylmethyl)-4-(methyl aryl) benzene 5 1-Methylsulfonyl-4-methyl-benzene ( 1·30 g, 7.5 mmol, n-bromobutaneimine (1·30 g, 7-10 mmol), and benzene peroxide (70 mg, 0.30 mmol) in CCh (70 mL) The mixture of sandalwood was heated at reflux for 4 hours. The reaction was cooled, filtered, and concentrated under reduced pressure. The combined organic phase was concentrated and the residue was purified eluting elut elut elut elut elut elut elut elut elut . Mp 99-101 °C; MS (ES) m/z 248·9. Example 212 4-(3-{[3-(Methylsulfonyl)benzyl]oxy}phenyl)_8-(trifluoro15methyl)quinoline 3-(8-trifluoromethyl-- 4-quinolinyl)-phenol (0-100 g, 0-35 mmol), 1-(bromomethyl)-3-(methylsulfonyl)benzene (0.130 g, 0.52 mmol), and cesium carbonate (676 mg, 2. A mixture of 10 mmol) in acetonitrile (5 mL) was stirred at room temperature for 3 h. Filtration and concentration of the reaction under reduced pressure, and EtOAc (EtOAc): 〇). The calculated mass of mp 63-65 X. C24H18F3N〇3S is 457.47; measured value (ES, [M+H] + ), 458.2. 183 200825054 Examples 213 to 215

下列化合物以上面範例212所述之相似方法製備，取 5 代該適當的啥琳-盼和节基1¾化物。 範例213 4-（3-{[4-(甲基磺醢基）苄基]氧基}苯基）-8-(三氟 甲基）喹啉 10 mp 75-77 °C ; MS (ES) 7Z//Z 458.2。 範例214 3-苄基-4-(3 - {[4-(甲基磺醢基）苄基]氧基}苯 基）-8-（三氟甲基）喹啉 15 mp 94-95 °C ; MS (ES) /Z//Z 548· 0。 範例215 3-苄基-4-(3-{ [3-(甲基磺醢基）苄基]氧基}苯 基）-8-(三氟甲基）喹啉 20 mp 77-79 °C ; MS (ES) zw/z 548· 0。 184 200825054 範例216 3-甲基-4-{3-[3-(甲基續酿基）节基]苯基}-8-（三氟 甲基）喹琳 5 將3-甲基-4-[3-(4,4,5,5-四甲基-1，3,2-二雜氧戊 硼烷-2-基）苯基]-8_(三氟甲基）喹啉（0. 150 g，0· 363 mmol) 加入含有1-(溴甲基）-3-(甲磺醯基）苯（0.181 g，0.726 mmol)、Pd(PPh3)4 (0. 021 g，0· 0181 mmol)、曱苯（5 mL) 和 EtOH (1 mL)於 2M Na2C〇3 (0· 55 mL，1· 10 mmol)中之一 10 溶液中並迴流2. 5小時。冷卻該反應，以水稀釋，並以乙 酸乙醋萃取。以水和食鹽水沖洗該經化合的有機物，透過 MgS〇4乾燥，並減壓濃縮。該殘餘物經色層分析以產生如一 黃色固狀物之該標題化合物（0. 149 g，90%)。HRMS:計算 值 C25H2〇F3N〇2S + H+，456· 12396 ;實測值（HRMS，[M+H]+)， 15 456.1224 。 範例217 3-苄基-4-{3-[3-(乙基磺醯基）苄基]苯基}-8-(三氟 甲基）喹啉 20 將 Pd(PPh3)4 (0. 023 g，0· 020 mmol)加入含有 3-苄 基-4-[3-（溴基甲基）苯基]-8-(三氟甲基）喹啉（182 mg， 0· 40 mmol)和3-乙基績醯基-苯基侧酸（129 mg，0· 60 mmol) 之 DME (4· 0 mL)與 2M Na2C〇3水溶液（0· 60 mL，1· 20 mmol) 之一經攪拌的混合物中。將該混合物在80 °C加熱18小時， 185 200825054 冷卻，加入水（15 mL)，並以二氣甲烷（2 x 15 mL)萃取。 該萃取物被乾燥（MgS〇4)以及減壓濃縮。該殘餘物在石夕膠上 經色層分析，以30:70至50:50之梯度的乙酸乙酿：己院洗 提’且該所產生的物質被進一步以逆相純化（在後者溶劑系 5統中〜〇·5)，使用〇:1〇〇至100:0梯度之乙猜：水以 產生如一白色泡沫固狀物之該標題化合物（81 mg)。 Ms (ES) m/z 545.8 ； HRMS:計算值 c32H26F3N〇2S + Ιί+ 546. 17091;實測值（ESI, [Μ+ΗΓ)，546. 1702。 範例218 3-甲基苯確酸五氟苯酯 將鄰甲苯磺醯氣（2.83 g，14.8咖〇1)加入五氟酚 (3.27 g，17_0 mmol)和三乙基胺（3·1〇 mL，22·3 職〇1)於 二氯甲烷（50 mL)中之一溶液中並在2〇 χ攪拌整夜。濃 15縮該反應且該殘餘物進入乙酸乙酯中，依序以水、1N HC1 水溶液、2N NaOH水溶液和食鹽水沖洗。透過MgS〇4乾燥該 有機層，減壓濃縮，並經色層分析以產生如一無色液態之 該標題化合物（4. 82 g，96%)。 範例219 3-(溴甲基)苯磺酸五氟苯酯 將五氟苯基3-甲基苯磺酸酯（4· 76 g，14. J咖〇1)、 N-溴丁二醯亞胺（2.79 g，15.5 mmol)和删（〇. 115 g， 0. 70 mmol)於CCh (75 mL)中之一溶液在迴流加熱2小時。 186 200825054 加入催化的過氧化苯并持續加熱整夜。透過助濾器咖心) 過濾該經冷卻之反應並減壓濃縮。殘餘物經色層分析以產 生該標題化合物。 3 範例220 3 - [3 - (3-甲基-8-三氟甲基一4-喹啉基)一苄基]一苯續酸五 氟基苯酯 將3-甲基-4-[3-（4, 4, 5, 5-四甲基— 1,3, 2-二雜氧戊 硼烷-2-基）苯基]-8-(三氟甲基）喹啉（〇. 575g，181 _q1) 10加入含有五氟苯基3-(溴基甲基）苯磺酸酯（1β50 g，362 mmol)和 Pd(pph3)4 (〇· 1〇5 g，0· 091 mmol)於 2M Na2C〇3 水 &gt;谷液（2· 7 mL，5· 4 mmol)、甲苯（15 mL)和 EtOH (3 mL) 中之一攪拌溶液中並在迴流加熱3小時。冷卻該反應，以 水稀釋，並以乙酸乙酯萃取。以水然後食鹽水沖洗該經化 15合之有機物，並透過MgS〇4乾燥。濃縮得來之殘餘物經色層 分析以產生純度足夠用於下一步驟之該標題化合物（〇. 9〇 §) 〇 範例221 3 - {3-[3-甲基-8-（三氟甲基）_4-喹啉基]苄基}—肸丙 基苯磺醯胺 將含有3-[3-(3-曱基-8-三氟甲基一4-喹啉基）—节 基]—笨績酸五氟苯基酯（0· 150 g，0· 253 mmol)、1 —丙基 胺（〇· 044 g，〇· 759 mmol)和 DBU (0· 056 mL，〇· 38 mmol) 187 200825054 於THF中之一溶液在65 °C加熱3小時。冷卻該反應並加 入2N HC1水溶液。以乙酸乙酯萃取該反應混合物並透過 MgS〇4乾燥。該物質經色層分析以產生如一白色固狀物之該 標題化合物（0· 154 g)。MS (ES) /ff/z 497· 0 ; HRMS:計 5 算值 C27H25F3N2〇2S + H+，499. 16616;實測值（ESI, [Μ+ΗΓ)， 499.1689 。 範例222至223The following compounds were prepared in a similar manner as described in Example 212 above, taking 5 generations of the appropriate hydrazine- and hydrazine groups. Example 213 4-(3-{[4-(Methylsulfonyl)benzyl]oxy}phenyl)-8-(trifluoromethyl)quinoline 10 mp 75-77 ° C; MS (ES) 7Z//Z 458.2. Example 214 3-Benzyl-4-(3 - {[4-(methylsulfonyl)benzyl]oxy}phenyl)-8-(trifluoromethyl)quinoline 15 mp 94-95 °C ; MS (ES) /Z//Z 548· 0. Example 215 3-Benzyl-4-(3-{[3-(methylsulfonyl)benzyl]oxy}phenyl)-8-(trifluoromethyl)quinoline 20 mp 77-79 °C ; MS (ES) zw/z 548· 0. 184 200825054 Example 216 3-Methyl-4-{3-[3-(methyl aryl)phenyl]phenyl}-8-(trifluoromethyl)quinolin 5 3-methyl-4- [3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-8-(trifluoromethyl)quinoline (0. 150 g,0· 363 mmol) Add 1-(bromomethyl)-3-(methylsulfonyl)benzene (0.181 g, 0.726 mmol), Pd(PPh3)4 (0. 021 g, 0·0181 mmol) 5小时。 The benzene (5 mL) and EtOH (1 mL) in a solution of 2M Na2C 〇 3 (0. 55 mL, 1 · 10 mmol) 10 and reflux for 2.5 hours. The reaction was cooled, diluted with water and extracted with EtOAc. The combined organic material was washed with water and brine, dried over MgSO 4 and evaporated. The residue was chromatographed to give the title compound (0. 149 g, 90%). HRMS: Calculated C25H2 〇F3N 〇2S + H+, 456· 12396; found (HRMS, [M+H]+), 15 456.1224. Example 217 3-Benzyl-4-{3-[3-(ethylsulfonyl)benzyl]phenyl}-8-(trifluoromethyl)quinoline 20 Pd(PPh3)4 (0. 023 g,0· 020 mmol) added 3-benzyl-4-[3-(bromomethyl)phenyl]-8-(trifluoromethyl)quinoline (182 mg, 0·40 mmol) and 3 - a mixture of DME (4.0 mL) of ethyl thiol-phenyl-acid (129 mg, 0·60 mmol) and 2M Na2C〇3 (0·60 mL, 1·20 mmol) in. The mixture was heated at 80 °C for 18 hours, 185 200825054 cooled, water (15 mL) was added and extracted with di-methane (2 x 15 mL). The extract was dried (MgS 4) and concentrated under reduced pressure. The residue was chromatographed on a Shijiao gel, and was subjected to a gradient of 30:70 to 50:50 in acetic acid: hexanes elution and the resulting material was further purified by reverse phase (in the latter solvent system) 5 中 〇 5 5), using 〇: 1 〇〇 to 100:0 gradient B guess: water to give the title compound (81 mg) as a white foam solid. Ms (ES) m/z 545.8; HRMS: calcd., calcd, s, s, s, s, s, s, s, s, s, s, s. Example 218 3-Phenylbenzate pentafluorophenyl ester o-toluenesulfonate (2.83 g, 14.8 curry 1) was added to pentafluorophenol (3.27 g, 17_0 mmol) and triethylamine (3.11 mL) , 22·3 Job 1) In one of dichloromethane (50 mL) and stirred at 2 Torr overnight. The reaction was concentrated and the residue was taken into ethyl acetate and washed sequentially with water, 1N aqueous HCl, 2N aqueous NaOH and brine. The organic layer was dried <RTI ID=0.0>(M </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; Example 219 3-Fluorophenylbenzenesulfonate pentafluorophenyl ester pentafluorophenyl 3-methylbenzenesulfonate (4·76 g, 14. J Curry 1), N-bromobutadiene A solution of the amine (2.79 g, 15.5 mmol) and EtOAc (EtOAc: EtOAc) 186 200825054 Add catalyzed benzene peroxide and continue to heat overnight. The cooled reaction was filtered through a filter aid and concentrated under reduced pressure. The residue was chromatographed to give the title compound. 3 Example 220 3 - [3-(3-Methyl-8-trifluoromethyl- 4-quinolinyl)-benzyl]-benzoic acid pentafluorophenyl ester 3-methyl-4-[3 -(4, 4, 5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-8-(trifluoromethyl)quinoline (〇. 575g, 181 _q1) 10 added with pentafluorophenyl 3-(bromomethyl)benzenesulfonate (1β50 g, 362 mmol) and Pd(pph3)4 (〇·1〇5 g, 0·091 mmol) in 2M One of Na2C〇3 water &gt; trough solution (2.7 mL, 5.4 mmol), toluene (15 mL) and EtOH (3 mL) was stirred and heated at reflux for 3 hr. The reaction was cooled, diluted with water and extracted with EtOAc. The chlorinated organic matter was washed with water and then with brine, and dried through MgS 4 . The residue obtained by concentration was chromatographed to give the title compound (p. 9 〇 §) of sufficient purity for the next step. Example 221 3 - {3-[3-methyl-8-(trifluoromethyl) ))- 4-quinolinyl]benzyl}- propyl propyl sulfonamide will contain 3-[3-(3-mercapto-8-trifluoromethyl- 4-quinolinyl)-] Stupid acid pentafluorophenyl ester (0·150 g, 0·253 mmol), 1-propylamine (〇·044 g, 〇·759 mmol) and DBU (0·056 mL, 〇·38 mmol) 187 200825054 One of the solutions in THF was heated at 65 °C for 3 hours. The reaction was cooled and a 2N aqueous HCl solution was added. The reaction mixture was extracted with ethyl acetate and dried over Mg?? The material was chromatographed to give the title compound (0· 154 g) as a white solid. MS (ES) / ff / z 497 · 0 ; HRMS: calcd. calcd. C27H25F3N2 〇2S + H+, 499. 16616; found (ESI, [Μ+ΗΓ), 499.1689. Examples 222 to 223

ίο 以上述相似方法製備下列化合物，使用適當的胺取代 1-丙基胺。 範例222 於乙基-於甲基_3-{3-[3-甲基-8-（三氟甲基）-4-啥 15 啉基]节基}苯磺醢胺 MS (ES) m/z 499. 0 &gt; HRMS:計鼻值 C27H25F3N2O2S + H+， 499.16616;實測值（ESI, [M+H]+)，499· 165卜 範例223 2〇 ΛΚ2-羥基乙基）-舲甲基-3-{3-[3-甲基-8-(三氟甲 188 200825054 基）-4-喹啉基]苄基}苯磺醯胺 MS(ES)/»/z515.0 ; HRMS:計算值 c27H25F3N2〇3S + H+， 515.16107;實測值（ESI，[M+H]+)，515. 1599。 224 5 1-(3-羥基甲基-苯基）-咪唑啶〜2-酮 將3-碘苄基醇（ΐ·84 g，7.9 _〇ι)和2-咪唑啉酮 (10. 15 g，118 mmol)加入含有 CuI(〇· 149 g，〇· 79 mmol)、 K3PO4 (3.33g’ 15.7 mmol )、和 N，N，〜二甲乙稀二胺（〇 I? inL ’ 1 · 5 7 πππο 1)於DMF (3 0 inL)中之一混合物中，並將該混 10合物在120 °C加熱整夜。冷卻該反應，以乙酸乙酯稀釋， 並透過助濾器Celite過濾。加入水和NaC1，然後層間分 離。水層萃取數次並透過MgS〇4乾燥該經化合之有機物，然 後濃縮。所產生之物質經色層分析以產生該標題化合物 (0.22 g)。 15 &amp;feL225 1-(3-淡基甲基-苯基）一味峻咬一 2 一網 在含有1_(3_羥基甲基-苯基）-咪唑啶-2-酮（0.220 g，1.14咖〇1)於THF(7 mL)中加入〇 M含有PBn之二 2〇氯甲烧（2.28mL ’ 2.28_〇1)。i小時之後，反應經減壓濃 縮然後加人乙酸乙i旨以及轉的Μα)3水賴。層分離然 後以更多的NaHC〇3溶液沖洗該有機層。透過MgS〇4乾燥該 有機物，然後濃縮，該殘餘物經色層分析以產生該標題化 合物（0. 180 g)。 189 200825054 範例226 1-(3-{3-[3-甲基-8-（三氟甲基）-4-嗓琳基]苄基}苯 基）味嗅咬-2 -8¾ 5 將3-甲基-4-[3-(4,4,5,5-四甲基-1，3,2-二雜氧戊 硼烷-2-基）苯基]-8-(三氟甲基）喹啉（0_ 150 g，0. 363 mmol) 加入含有1-(3-溴甲基-苯基）-味唾°定-2-酮（0.185 g， 0· 73 mmol)、Pd(PPh3)4 (0· 021 g，0· 018 mmol)、甲苯（5 mL)和 EtOH (1 mL)於 2M Na2C〇3水溶液（0· 55 mL，1· 09 mmol) i〇 中之溶液中並迴流2小時。冷卻該反應，以水稀釋，並以 乙酸乙酯萃取。以水和食鹽水沖洗該經化合的有機物，然 後透過MgS〇4乾燥。濃縮後，該殘餘物經色層分析以產生如 一白色固狀物之該標題化合物（0. 137 g)。HRMS:計算值 C27H22F3N3O + H+, 462. 17877 ；實測值（ESI，[M+H]+)， 15 462.1799 。 範例227 3 -（3-羥基甲基-苯基）-唑啶-2-酮 將3-溴基苄基醇（1. 56 g，8. 34 mmol)和2-°惡峻烧酮 20 (0.871 g，10.00 mmol)加入含有反-1，2-二胺基環己烧 (0· 10 mL，0· 83 mmol)、Cul (0· 079 g，0· 417 mmol)、和 K2CO3 (2. 30 g，16. 7 mmol)之二°惡烧（40 mL)中並迴流整夜。 加入額外的2-噁唑烷酮（1· 0 g)、Cul和反-1，2-二胺基環 己烧（0. 3 mL)並持續加熱7小時。濃縮該反應混合物且該 190 200825054 殘餘物經色層分析以產生純度足_於下—步驟之該標題 化合物（1. 94 g)。 範例228 3-（3-淡基甲基-苯基）一嗤咬一2一綱 -5 在含有3_(3-羥基甲基-苯基）-唑啶-2-酮（1.61 g，Ίο The following compounds were prepared in a similar manner as above, substituting the appropriate amine for the 1-propylamine. Example 222 Ethyl-methyl-methyl 3-(3-[3-methyl-8-(trifluoromethyl)-4-indole 15 phenyl]] benzyl sulfonamide MS (ES) m/ z 499. 0 &gt; HRMS: counter-value C27H25F3N2O2S + H+, 499.16616; found (ESI, [M+H]+), 499· 165. Example 223 2〇ΛΚ2-hydroxyethyl)-舲methyl-3 -{3-[3-Methyl-8-(trifluoromethyl 188 200825054 benzyl)-4-quinolinyl]benzyl}benzenesulfonamide MS (ES) /»/z 515.0 ; HRMS: Calculated C27H25F3N2 〇3S + H+, 515.16107; found (ESI, [M+H]+), 515. 1599. 224 5 1-(3-Hydroxymethyl-phenyl)-imidazole pyridine~2-one 3-iodobenzyl alcohol (ΐ·84 g, 7.9 _〇ι) and 2-imidazolidinone (10. 15 g , 118 mmol) added with CuI (〇·149 g, 〇·79 mmol), K3PO4 (3.33g' 15.7 mmol), and N,N,~dimethylethylenediamine (〇I?inL ' 1 · 5 7 πππο 1) In a mixture of DMF (30 inL), the mixed mixture was heated at 120 °C overnight. The reaction was cooled, diluted with ethyl acetate and filtered thru EtOAc EtOAc. Water and NaC1 were added and the layers were separated. The aqueous layer was extracted several times and the combined organic matter was dried through MgS 4 and then concentrated. The resulting material was chromatographed to give the title compound (0.22 g). 15 &amp;feL225 1-(3-Lipylmethyl-phenyl) one-spotted bite one 2 one net containing 1_(3-hydroxymethyl-phenyl)-imidazolidin-2-one (0.220 g, 1.14 coffee) 〇1) To a solution of 〇M containing PBn in THF (7 mL) (2.28 mL ' 2.28 〇 1). After 1 hour, the reaction was concentrated under reduced pressure and then added with acetic acid and Μα)3 water. The layers were separated and the organic layer was rinsed with more NaHC 3 solution. The title compound (0. 180 g) was obtained by chromatography. 189 200825054 Example 226 1-(3-{3-[3-Methyl-8-(trifluoromethyl)-4-indolyl]benzyl}phenyl)-scented bite-2 -83⁄4 5 Methyl-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-8-(trifluoromethyl) Quinoline (0-150 g, 0. 363 mmol) was added to contain 1-(3-bromomethyl-phenyl)-propargin-2-one (0.185 g, 0·73 mmol), Pd(PPh3)4 (0· 021 g, 0· 018 mmol), toluene (5 mL) and EtOH (1 mL) in a solution of 2M Na 2 C 3 aqueous solution (0·55 mL, 1·09 mmol) in hydrazine and reflux for 2 hours . The reaction was cooled, diluted with water and extracted with EtOAc. The combined organic matter was washed with water and brine, and then dried through MgS 4 . After concentrating, the residue was subjected to EtOAc (m.) HRMS: calcd for C^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Example 227 3 -(3-Hydroxymethyl-phenyl)-oxazolidin-2-one 3-bromobenzyl alcohol (1.56 g, 8.34 mmol) and 2-° caeonione 20 ( 0.871 g, 10.00 mmol) was added with trans-1,2-diaminocyclohexane (0·10 mL, 0·83 mmol), Cul (0·079 g, 0·417 mmol), and K2CO3 (2. 30 g, 16. 7 mmol) in a low-temperature (40 mL) solution and refluxed overnight. Additional 2-oxazolidinone (1.0 g), Cul and trans-1,2-diaminocyclohexane (0.3 mL) were added and heating was continued for 7 hours. The reaction mixture was concentrated and the residue was purified by chromatography. Example 228 3-(3-Leptylmethyl-phenyl)-anthraquinone-2-yl--5-containing 3-(3-hydroxymethyl-phenyl)-oxazolidin-2-one (1.61 g,

， 8.34咖卜得自先前步驟)之THF (50 mL)中加入1〇 M :有PBn之二氣甲烷（16.7mL’16 7_〇1)並攪拌η、 f 時。濃_反應生錢餘物，其經乙酸乙自旨和_的NaHC〇3 丨水溶液處理。層分離然後以更多的稀釋·〇3水溶液沖洗 '亥有機層。透過MgS〇4乾燥該有機層並減壓濃縮。該殘餘物 經色層分析以產生該標題化合物（1 〇3 g)。 範例229 3-（3-{3-[3-甲基-8-（三氟甲基）一4一喹啉基]苄基}苯 基）-1，3-嗤咬-2-鋼 15 將3—甲基-4一[3—(4,4,5,5-四甲基-1,3,2-二雜氧戊 ( 硼烷-2-基）苯基]-8-（三氟曱基）喹啉（〇· 15〇g，〇 363inm〇1) 力口入含有3-(3-溴曱基-苯基）一唑啶一2_酮（〇· 185 g，〇. 726 咖〇1)和 Pd(PPh3)4 (0.021 g，0 018 _〇1)之甲苯（5 mL) 、 以及含有 Et0H (1 mL)之 2M Na2C〇3 水溶液（〇· 55 mL，1. 098.34 Add the 1 〇 M from the previous step) in THF (50 mL): dioxane with PBn (16.7 mL '16 7_〇1) and stir η, f. Concentrated _ reaction to the residue of the money, which was treated with an aqueous solution of acetic acid and NaHC 3 hydrazine. The layers were separated and then the organic layer was rinsed with more diluted 〇3 aqueous solution. The organic layer was dried through MgSO 4 and concentrated under reduced pressure. The residue was chromatographed to give the title compound (1 〇3 g). Example 229 3-(3-{3-[3-Methyl-8-(trifluoromethyl)-4 quinolinyl]benzyl}phenyl)-1,3-bite-2-steel 15 3-methyl-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaoxypentane(boran-2-yl)phenyl]-8-(trifluoro曱 )) quinoline (〇·15〇g, 〇363inm〇1) containing 3-(3-bromoindolyl-phenyl)-oxazolidine-2-one (〇·185 g, 〇. 726 咖〇1) and Pd(PPh3)4 (0.021 g, 0 018 _〇1) toluene (5 mL), and 2M Na2C〇3 aqueous solution containing Et0H (1 mL) (〇·55 mL, 1. 09

、2〇 mm〇1)中並迴流2小時。以水稀釋該經冷卻之反應並以乙酸 乙醋萃取。以水和食鹽水沖洗該經化合的有機物，然後透 過MgS〇4乾燥。減壓》辰縮後，該殘餘物經色層分析以產生如 一暗白色固狀物之該標題化合物（〇. 163 g)。MS (ES) 7Z7/Z 463.1 ; HRMS:計算值 〇27Η21ρ3Ν2〇2 + H+，463.16279 ;實 191 200825054 測值（ESI, [M+H]+)，463. 1626。 範例230 8-氣基-3 -甲基-4 - [3 - (3-硝基-苯氧基）-苯基]-喹啉 將a有3-(8-氟基—3-甲基-一4-喧琳基）-紛（2. 50 g， 5 9· 26 mmol)、卜氟基〜3-確基苯（1· 97 mL，18· 5 mmol)、和 K2C〇3 (2.56 g，18·53 mmol)於 DMF (30 mL)中之一經攪拌 的混合物在迴流加熱4小時。冷卻該反應，以水稀釋，並 以乙fee乙自旨萃取。以一半飽和的食鹽水沖洗該經化合的有 機物並透過MgS〇4乾燥。該物質經色層分析，以15:85乙 10酸乙醋：己燒洗提，產生如一暗白色固狀物之該標題化合物 (2. 71 g，75%)。 MS (ES) /ζ7/π 391. 1 範例231 3 - [3 - (8-氣基-3-甲基--4-喹啉基)-苯氧基]-苯胺 在含有8-氯基-3-甲基-4-[3-(3-硝基-苯氧基）-苯 15 基]—喹啉（2.49 g，6· 37 mmol)於濃鹽酸（20 mL)和甲醇（20 mL)之一混合物中加入錫金屬（3· 〇2 g，25. 5 _〇1)並在5〇 X 加熱2.5小時。冷卻該反應並倒進含有NaHC〇3(50 g)、水 (1〇〇 mL)以及些許乙酸乙酯之大錐形燒瓶。攪拌該混合物 一小時然後以乙酸乙酯萃取。以水和食鹽水沖洗該經化合 20 的有機物並透過MgSCU乾燥。該產物經色層分析，以30:70 乙酸乙酯：己烷洗提，產生如一黃色固狀物之該標題化合物 (1. 19 g)。MS (ES) 361· 1。 範例232 ^{3 - [3-(8 -氣基-3-甲基-4-喹啉基）苯氧基]苯基} 192 200825054 苯磺醢胺 在含有3-[3-(8_氣基-3-甲基_4_喧琳基）_笨氧基]、 苯胺（0. 100 g，0. 277 _1)和三乙基胺（〇 〇8〇 mL，〇 55 _〇1)於THF (3 raL)中之-溶液中加入苯磺醯氯(ο· mL ’0_ 33 mmol)並在20 X攪拌整夜。過慮並濃縮該反應。 透過逆相HPLC (10至100%之乙腈於水中）純化該殘餘物以 產生如一白色固狀物之該標題化合物（〇. 027 g)。Ms /Z//Z499· 1 ; HRMS:計算值 + H+，501. 10342 ; 實測值（ESI, [M+H]+)，501· 1042。 範例233至237, 2〇 mm〇1) and reflux for 2 hours. The cooled reaction was diluted with water and extracted with ethyl acetate. The combined organic matter was washed with water and brine, and then dried through MgS 4 . After decompression, the residue was chromatographed to give the title compound ( s. 163 g) as a dark white solid. MS (ES) 7Z7/Z 463.1 ; HRMS: calcd. 〇 Η Η ρ ρ ρ ρ 〇 〇 〇 + + + + + + 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 2008 463 463 463 463 463 463 Example 230 8-Alkyl-3-methyl-4-[3-(3-nitro-phenoxy)-phenyl]-quinoline will have a 3-(8-fluoro-3-methyl-喧4-喧琳基)- 纷(2. 50 g, 5 9·26 mmol), fluoroamino~3- sure benzene (1.97 mL, 18·5 mmol), and K2C〇3 (2.56 g) The stirred mixture of one of DMF (30 mL) was heated at reflux for 4 h. The reaction was cooled, diluted with water and extracted with EtOAc. The combined organic matter was washed with half saturated saline and dried through MgS〇4. The title compound (2. 71 g, 75%) was obtained eluted elute elute MS (ES) / ζ 7 / π 391. 1 Example 231 3 - [3 - (8-Alkyl-3-methyl--4-quinolinyl)-phenoxy]-phenylamine in the presence of 8-chloro- 3-Methyl-4-[3-(3-nitro-phenoxy)-phenyl-15-yl]-quinoline (2.49 g, 6.37 mmol) in concentrated hydrochloric acid (20 mL) To one of the mixtures was added tin metal (3·〇2 g, 25.5 _〇1) and heated at 5 〇X for 2.5 hours. The reaction was cooled and poured into a large conical flask containing NaHC(R) 3 (50 g), water (1 mL) and a little ethyl acetate. The mixture was stirred for one hour and then extracted with ethyl acetate. The compound of the compound 20 was washed with water and brine and dried through a MgSCU. The product was chromatographed eluting with EtOAc (EtOAc:EtOAc) MS (ES) 361·1. Example 232 ^{3 - [3-(8-Gasyl-3-methyl-4-quinolinyl)phenoxy]phenyl} 192 200825054 Benzene sulfonamide contains 3-[3-(8_气Benzyl-3-methyl-4(indolyl)_phenyloxy], aniline (0. 100 g, 0. 277 _1) and triethylamine (〇〇8〇mL, 〇55 _〇1) To the solution in THF (3 raL) was added benzenesulfonium chloride (ο· mL '0_ 33 mmol) and stirred at 20 X overnight. The reaction is considered and concentrated. The residue was purified by mp EtOAc (EtOAc:EtOAc) Ms /Z//Z499· 1 ; HRMS: Calculated value + H+, 501. 10342; found (ESI, [M+H]+), 501· 1042. Examples 233 to 237

193 200825054 以上述範例232之相似方法製備下列化合物，應用適 當的啥琳-盼、氟硝基苯、和RS〇2Cl或氣甲酸酯r〇c(〇)C1。 簸例233 5 於{3-[3-(8-氣基-3-甲基-4-喹啉基）苯氧基]苯基} 甲烷磺醢胺 步驟基本上與上述相似除了以甲磺醯氯取代苯磺醯 氣。仏5(^5)/»々437.0;1^8:計算值（：231119(：1仏〇33 + 11+， 439.08777;實測值（ESI, [M+H].)，439· 087卜 10 範例234 於{3-[3-(8-氣基-3-甲基-4-喹啉基）苯氧基]苯基} 乙烷磺醢胺 步驟基本上與上述相似除了以乙烷磺醯氯取代苯磺 15 醯氯。MS (ES) Λ7//451· 0 ; HRMS··計算值 C24H2X1N203S + Η+，453.10342;實測值（ESI, [Μ+ΗΓ)，453.1033。 範例235 {3-[3-(8-氣基-3-甲基-4-喹啉基）苯氧基]苯基}氨 20 基甲酸甲酯 步驟基本上與上述相似除了以氣甲酸甲酯取代苯磺 醯氣。MS(ES)/z//z419.1; HRMS:計算值 C24H19ClN2〇3 + H+， 419.11570;實測值（ESI，[M+H]+)，419.1154。 194 200825054 多‘例2 3 6 {3 - [3-(8-氣基-3-甲基-4-喹啉基）苯氧基]苯基}氣 基甲酸乙酯 步驟基本上與上述相似除了以氯曱酸乙酯取代苯磺 5 醯氣。MS (ES) Λ7/ζ431· 1 ; HRMS:計算值 C25H21CIN2O3 + H+， 433.13135;實測值（ESI, [Μ+ΗΓ)，433.1322。 里例237 {3-[3 - (8-氣基-3-甲基-4-喹啉基）苯氧基]苯基}氨 10 基甲酸異丁酯 步驟基本上與上述相似除了以氣甲酸異丁酯取代苯 石黃醯氣。MS (ES) Λ7/ζ 459·1 ; HRMS:計算值 C27H25CIN2O3 + Η+，461.16265;實測值（ESI，[Μ+Η]+)，461.1628。 15 範例238 於{3-[3-(8-氯基-3-甲基-4-喹啉基）苯氧基]苯 基}-，-乙脲 在含有3-[3-(8-氣基-3-曱基一4-喹啉基）-苯氧基]-苯胺（0.100 g，0· 277 mmol)之THF (3 mL)中加入異氰酸 20 乙酯（0· 024 mL，0· 31 mmol)並在20 °C攪拌整夜。過濾並 濃縮該反應。該殘餘物透過逆相HPLC (10至1〇〇%之乙腈 於水中）純化以產生如一白色固狀物之該標題化合物 (0.037 g)。MS(ES)/z?/z430.1; HRMS:計算值 C25H22CIN3O2 + H+，432. 14733;實測值（ESI, [Μ+ΗΓ)，432.1456。 195 200825054 jfe例 239 至 242 以相似方法製備下列化合物，應用適當的喹啉二芳基 醚苯胺以及異氰酸酯。 5 ψ, #J 239 於{3-[3-(8-氣基一3-甲基-4-喹啉基）苯氧基]苯 基}_^ -異丙腺 步驟基本上與上述相似除了以異氰酸異丙酯取代異 10 氰酸乙酯。MS (ES) Λ7/Ζ444. 1 ; HRMS:計算值 C26H24ClN3〇2 + H+，446. 16298;實測值（ESI, [Μ+ΗΓ)，446.1638。 j反例240 於{3-[3-(8-氣基-3-甲基-4-喹啉基）苯氧基]苯 15 基}-^-苯脲 步驟基本上與上述相似除了以異氰酸苯酯取代異氰 酸乙酯。MS (ES) y»/z 478. 1 ; HRMS:計算值 C29H22ClN3〇2 + H+，480. 14733;實測值（ESI，[M+H]+)，480.1473。 2〇 赛例241 iV-（2-氣基乙基）-Υ -{3-[3-(8-氣基-3-甲基-4-考琳 基）苯氧基]苯基}脲 以上述相似方法製備，但一開始在加溫至20 X前的 0 °C時添加異氰酸氯乙酯。分離出如同棕色泡沫之該標題 196 200825054 化合物。HRMS:計算值 G^HnChM)2 + H+，466_ 10836 ;實 測值（ESI，[M+H]+)，466. 1083。 範例242 5 {3-[3-(8-氯基-3-甲基-4-啥琳基）苯氧基]苯基}氣 基甲酸2-氣乙酯 在含有3-[3-(8-氯基-3-甲基一4-喹啉基）-苯氧基]一 苯胺（0_ 265 g，0.734 mmol)和三乙基胺（0.107 mL，0.77 mmol)於甲苯（5 mL)中加入氣甲酸2-氯乙酯（0.075 mL， 1〇 〇· 734 mmol)達1小時。以水水淬該反應並以乙酸乙酯萃 取。以水沖洗該經化合的有機物，透過MgS〇4乾燥與濃縮。 該殘餘物經色層分析，以30:70乙酸乙酯：己烷洗提，產生 如白色泡沫之該標題化合物（0· 245 g，72%)。HRMS:計算 值 C25H2〇Cl2N2〇3 + H+，467.09237;實測值（ESI, [Μ+ΗΓ)， 15 467.0942。 範例243 8-氣基-3-甲基-4-{3-[3-(5-甲基-4, 5-二氩-1，3-嚼 唑-2-基）苯氧基]苯基}喹啉 2〇 在冷卻至-40 °C之含有3-[3-(8-氣基-3-曱基--4-口奎 琳基）-苯氧基]-N-(2-羧基-丙基）-苯甲醯胺（0.096 g， 〇· 214 mmol)和 DMAP (0· 078 g，0. 642 mmol)於二氯甲烧 (5 mL)中之一溶液中加入三氟甲磺酸酐（〇. 054 mL，0. 322 mmol)並將該反應在20 °C攪拌1· 5小時。添加額外的三氟 197 200825054 甲磺酸酐並將該反應攪拌整夜。將該反應通過一短碎膠加 上以20:80甲醇：二氯甲烷洗提。移除該溶劑並將該殘餘物 透過逆相色層分析純化以產生如一白色固狀物之該標題化 合物（17 mg)。 MS (ES) yff/z 429. 1 ; HRMS:計算值 5 C26H21CIN2O2 + H+，429· 13643 ;實測值（ESI, [M+H]+) 429·1356 。 範例244 1-{3-[3-(8-氣基-3-甲基-4-喹啉基）苯氧基]苯 10 基}-3-甲基咪唑啶-2-酮 將含有1-{3-[3-（8-氣基-3-甲基-4-喹啉基）-苯氧 基]-苯基卜咪唑啶-2-酮（〇. 1〇〇 g，〇. 232 mmol)之 DMF (3 mL)與 60%含有 NaH 之礦物油（o.oii g，0.279 mmol)— 起攪 拌15分鐘。加入碘甲烷（〇· 017 ‘，0. 28 mmol)並使得該 15反應攪拌整夜。該反應以1NHC1水淬，然後層分離。以乙 酸乙醋萃取該水層。以半飽和的食鹽水沖洗該經化合的有 機物並透過MgS〇4乾燥。該產物經色層分析以產生如一白色 固狀物之該標題化合物（〇〇87§，85%)。111^3:計算值 C26H22ClN3〇2 + H+，444. 14733;實測值（ESI，[Μ+ΗΓ)， 20 444·1457 。 範例245 1 -{3-[3-(8-氣基一3-甲基一4-喹啉基）苯氧基]苯 基}-3-乙基味唾咬-2-_ 198 200825054 步驟基本上與上述（範例244)相似除了以碘乙烷取 代碘甲烷。MS (ES)/Z//Z458. 3. HRMS:計算值 C27H24ClN3〇2 + H+，458.16298;實測值（ESI, [Μ+ΗΓ)，458.1599。 5 範例246 8-氯基-4-{3-[3-(4-異丙基-4, 5-二氩-1，3-兔嗅-2-基）苯氧基]苯基}-3-甲基喹啉 將3-[3-（8-氣基-3-甲基--4-喹啉基）-苯氧 基]-N-（1-羥基甲基-2-甲基-丙基）-苯甲醯胺（0.059 g， 1〇 〇· 127 mmol)和 DAST (0· 020 mL，0_ 153 mmol)於二氯甲烷 (3mL)中在20°C攪拌整夜。在該反應中加入飽和的NaHCOs 水溶液達0. 5小時。層分離並透過MgS〇4乾燥該有機層。該 粗產物經色層分析以產生如一黃色油狀物之該標題化合 物。HRMS:計算值 C28H25ClN2〇2 + H+，457. 16773 ;實測 15 值（ESI，[Μ+ΗΓ)，457. 1683。 範例247 8-氯基-3-甲基-4_{3-[3-(4_ 丙基-4, 5-二氩-1，3-兔 唑-2-基）苯氧基]苯基}喹啉 20 步驟基本上與上述（範例246)相似除了以3-[3-(8- 氣基-3-甲基一4-喹啉基）-苯氧基]-N-(l-羥基甲基-丁 基）-苯甲醯胺取代3-[3-(8-氣基-3-甲基一4-喹啉基）-苯 氧基]-N-(1-羥基甲基-2-甲基-丙基苯甲醯胺。HRMS:計 算值 C28H25ClN2〇2 + H+，457.16773;實測值（ESI，[Μ+ΗΓ)， 199 200825054 457.1681 〇 範例248 8-氣基-4-{3-[3-(4, 4-二甲基-4, 5-二氩-1, 3-噁唑 5 -2-基）苯氧基]苯基}-3-甲基喹啉 步驟基本上與範例246相似除了以3-[3-(8-氣基-3-甲基一4_唾琳基）-苯氧基]-Ν-(2-經基_1，1-二甲基-乙 基）-苯甲醯胺取代3-[3-(8-氯基-3-甲基--4-啥琳基）-笨 氧基]-N-(l-羥基曱基-2-曱基-丙基）-苯甲醯胺。HRMS:計 1〇 算值 C27H23ClN2〇2 + H+，443.15208;實測值（ESI，[Μ+ΗΓ)， 443.1497 〇 範例249 3 - {3 - [3 - (8-氯基-3-甲基一4-喹啉基)-苯氧基]-苯基}-2 -側氧基-咪唑咬-1-基)-乙酸甲酯 15 在1-{3-[3-(8-氯基-3-甲基一4-喹啉基）-苯氧基]- 苯基卜咪唑啶-2-酮（0. 100 g，0. 232 mmol)於 THF (3 mL) 中加入1·0Μ含有叔丁醇鉀之THF (0· 255 mL，0. 255 mmol) 達15分鐘。然後加入漠乙酸甲醋（0· 044 mL，0. 46 mmol) 並將該反應攪拌整夜。該反應以IN HC1水淬，然後以乙酸 20乙酯萃取。透過MgS〇4乾燥該經化合的萃取物並濃縮。該殘 餘物經色層分析以產生繼續成為酸之如一黃色油狀物的該 標題化合物（0. 055 g)。 §M 250 200 200825054 -(8-氯基-3-甲基一4-喹啉基）苯氧基]苯 基卜2-側氧基咪唑啶―丨一基）乙酸193 200825054 The following compounds were prepared in a similar manner to Example 232 above, using the appropriate phthalocyanine, fluoronitrobenzene, and RS〇2Cl or carbative r〇c(〇)C1. Example 233 5 The step of {3-[3-(8-methyl-3-methyl-4-quinolinyl)phenoxy]phenyl}methanesulfonamide is substantially similar to the above except that methanesulfonate is used. Chlorine-substituted benzenesulfonate.仏5(^5)/»々437.0;1^8: Calculated value (: 231119(:1仏〇33 + 11+, 439.08777; measured value (ESI, [M+H].), 439· 087) Example 234 in the step of {3-[3-(8-methyl-3-methyl-4-quinolinyl)phenoxy]phenyl}ethanesulfonamide is substantially similar to the above except that ethanesulfonate is used. Chloro-substituted benzene sulfonate 15 醯 。. MS (ES) Λ7//451· 0 ; HRMS··calculated value C24H2X1N203S + Η+, 453.10342; measured value (ESI, [Μ+ΗΓ), 453.1033. Example 235 {3-[ The methyl 3-(8-methyl-3-methyl-4-quinolinyl)phenoxy]phenyl}aminolcarbamate step is substantially similar to the above except that the benzenesulfonate is replaced by methyl metformate. MS (ES) / z / / z 419.1; HRMS: calcd for C24H19ClN2 〇3 + H+, 419.11570; found (ESI, [M+H]+), 419.1154. 194 200825054 Multiple 'Example 2 3 6 {3 - The step of [3-(8-methyl-3-methyl-4-quinolinyl)phenoxy]phenyl}carboformate is substantially similar to the above except that ethyl chlorosulfonate is substituted for benzenesulfonate 5 醯MS (ES) Λ7/ζ431· 1 ; HRMS: Calculated C25H21CIN2O3 + H+, 433.13135; found (ESI, [Μ+ΗΓ), 433.1322. Example 237 {3-[3 - (8-Gas-based - 3-A The step of isobutyl ester of -4-quinolinyl)phenoxy]phenyl}aminolcarboxylic acid is substantially similar to the above except that the benzathine is substituted with isobutyl carbazate. MS (ES) Λ7/ζ 459· HRMS: Calculated C27H25CIN2O3 + Η+, 461.16265; found (ESI, [Μ+Η]+), 461.1628. 15 Example 238 in {3-[3-(8-chloro-3-methyl-4) -quinolinyl)phenoxy]phenyl}-,-ethylurea containing 3-[3-(8-carbyl-3-indolyl-4-quinolinyl)-phenoxy]-aniline (0.100 To a solution of EtOAc (3 mL), EtOAc (EtOAc (EtOAc,EtOAc. Purification by reverse phase HPLC (10 to 1% acetonitrile in water) to give the title compound (0.037 g) as a white solid. MS (ES)/z?/z430.1; HRMS: Calculated C25H22CIN3O2 + H+, 432. 14733; found (ESI, [Μ+ΗΓ), 432.1456. 195 200825054 jfe Examples 239 to 242 The following compounds were prepared in a similar manner using the appropriate quinoline diaryl ether aniline and isocyanate. 5 ψ, #J 239 The step of {3-[3-(8-alkyl-3-methyl-4-quinolinyl)phenoxy]phenyl}_^-isopropyl gland is basically similar to the above except The iso-cyanate ethyl ester was replaced with isopropyl isocyanate. MS (ES) Λ 7 / Ζ 444. 1 ; HRMS: calcd., calcd. j counterexample 240 in the step of {3-[3-(8-methyl-3-methyl-4-quinolinyl)phenoxy]benzene 15 yl}- phenylurea is substantially similar to the above except that isocyanate The phenyl ester is substituted for ethyl isocyanate. MS (ES) </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 2〇赛例241 iV-(2-carboethyl)-fluorene-{3-[3-(8-methyl-3-methyl-4-colinyl)phenoxy]phenyl}urea Prepared in a similar manner as described above, but initially adding chloroethyl isocyanate at 0 °C before heating to 20 X. The title 196 200825054 compound was isolated as a brown foam. HRMS: calcd. </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; Example 242 5 2-Ethyl ethyl ester of {3-[3-(8-chloro-3-methyl-4-indolyl)phenoxy]phenyl}carbazate in 3-[3-(8 -Chloro-3-methyl-4-quinolinyl)-phenoxy]monophenylamine (0_265 g, 0.734 mmol) and triethylamine (0.107 mL, 0.77 mmol) in toluene (5 mL) 2-Chloroethylformate (0.075 mL, 1 〇〇·734 mmol) was allowed to stand for 1 hour. The reaction was quenched with water and extracted with ethyl acetate. The combined organics were rinsed with water and dried and concentrated through MgS 4 . The residue was chromatographed eluting EtOAc (EtOAc:EtOAc) HRMS: Calculated C25H2 〇Cl2N2 〇3 + H+, 46. 092.37; found (ESI, [Μ+ΗΓ), 15 467.0942. Example 243 8-Alkyl-3-methyl-4-{3-[3-(5-methyl-4,5-diar-1,3-1,3-oxazol-2-yl)phenoxy]phenyl }Quinoline 2〇 contains 3-[3-(8-alkyl-3-indolyl--4-hydroxyl-yl)-phenoxy]-N-(2-carboxyl group) cooled to -40 °C -propyl)-benzamide (0.096 g, 〇· 214 mmol) and DMAP (0·078 g, 0.642 mmol) in a solution of trichloromethane (5 mL) The anhydride (〇. 054 mL, 0. 322 mmol) was stirred and stirred at 20 ° C for 1.5 hours. Additional trifluoro 197 200825054 methanesulfonic anhydride was added and the reaction was stirred overnight. The reaction was stripped through a short gum and eluted with 20: 80 methanol: dichloromethane. The solvent was removed and the residue was purified by EtOAc EtOAc (EtOAc) MS (ES) yff/z </RTI> </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; Example 244 1-{3-[3-(8-Alkyl-3-methyl-4-quinolinyl)phenoxy]benzene-10-yl}-3-methylimidazolidin-2-one will contain 1- {3-[3-(8-Alkyl-3-methyl-4-quinolinyl)-phenoxy]-phenyl-imidazolidin-2-one (〇. 1〇〇g, 〇. 232 mmol DMF (3 mL) was stirred with 60% NaH-containing mineral oil (o.oii g, 0.279 mmol) for 15 minutes. Methyl iodide (〇·017 ‘, 0.28 mmol) was added and the 15 reaction was stirred overnight. The reaction was quenched with 1 NHC1 and then separated. The aqueous layer was extracted with ethyl acetate. The compounded organic matter was washed with a half-saturated saline solution and dried through MgS〇4. The product was chromatographed to give the title compound ( </ RTI> </ RTI> <RTIgt; 111^3: Calculated value C26H22ClN3 〇2 + H+, 444. 14733; found (ESI, [Μ+ΗΓ), 20 444·1457. Example 245 1 -{3-[3-(8-Gasyl-3-methyl-1,4-quinolinyl)phenoxy]phenyl}-3-ethyl-salt bite-2-_ 198 200825054 Step basic The above is similar to the above (Example 244) except that methyl iodide is substituted with methyl iodide. MS (ES) / Z / / Z 458. 3. HRMS: calcd for C27H24ClN3 〇2 + H+, 458.16298; found (ESI, [Μ+ΗΓ), 458.1599. 5 Example 246 8-Chloro-4-{3-[3-(4-isopropyl-4, 5-diar-1,3-1,3- ol-2-yl)phenoxy]phenyl}-3 -methylquinoline 3-(3-(8-carbyl-3-methyl--4-quinolinyl)-phenoxy]-N-(1-hydroxymethyl-2-methyl-propyl Benzoguanamine (0.059 g, 1 〇〇 127 mmol) and DAST (0· 020 mL, 0- 153 mmol) were stirred in dichloromethane (3 mL) at 20 ° C overnight. 5小时。 The saturated NaHCOs aqueous solution was added for 0.5 hours. The layers were separated and the organic layer was dried through MgS〇4. The crude product was chromatographed to give the title compound as a yellow oil. HRMS: Calculated C28H25ClN2 〇2 + H+, 457. 16773; found 15 (ESI, [Μ+ΗΓ), 457. 1683. Example 247 8-Chloro-3-methyl-4_{3-[3-(4-propyl-4-, 5-diar-1,3-1,3-oxazol-2-yl)phenoxy]phenyl}quin The porphyrin 20 step is substantially similar to the above (Example 246) except that 3-[3-(8-methyl-3-methyl-4-quinolinyl)-phenoxy]-N-(l-hydroxymethyl) -butyl)-benzamide to 3-[3-(8-yl-3-methyl-4-quinolinyl)-phenoxy]-N-(1-hydroxymethyl-2-methyl --propyl benzamide. HRMS: calculated C28H25ClN2 〇2 + H+, 457.16773; found (ESI, [Μ+ΗΓ), 199 200825054 457.1681 〇 Example 248 8-Gasyl-4-{3-[3 The step of -(4,4-dimethyl-4,5-diar ar-1,3-oxazol-5-2-yl)phenoxy]phenyl}-3-methylquinoline is substantially similar to Example 246 In addition to 3-[3-(8-a)-3-methyl-1,4-disindolyl-phenoxy]-indole-(2-yl-1,1-dimethyl-ethyl)- Benzylamine substituted 3-[3-(8-chloro-3-methyl--4-indolyl)-indolyl]-N-(l-hydroxyindol-2-yl-propyl-propyl - Benzalamine. HRMS: Calculated as 1 〇C27H23ClN2 〇2 + H+, 443.15208; found (ESI, [Μ+ΗΓ), 443.1497 〇 Example 249 3 - {3 - [3 - (8-chloro) -3-methyl-4-quinolinyl)-phenoxy]- Phenyl}-2-oxo-imidazolium-1-yl)-methyl acetate 15 in 1-{3-[3-(8-chloro-3-methyl-4-quinolinyl)-benzene Oxy]-phenylimidazolidin-2-one (0. 100 g, 0.223 mmol) was added THF (3 mL) to THF (0· 255 mL, 0. 255 mmol) for 15 minutes. Then methyl acetate (0. 044 mL, 0.446 mmol) was added and the reaction was stirred overnight. The reaction was quenched with IN HCl and then extracted with ethyl acetate. The combined extract was dried through MgS 4 and concentrated. The residue was chromatographed to give the title compound (0. 055 g). §M 250 200 200825054 -(8-Chloro-3-methyl-4-quinolinyl)phenoxy]phenyl 2-dioxyimidazolidinium-indenyl)acetic acid

將（3-{3-[3-(8-氯基-3-甲基--4-喹啉基）-苯氧基]-笨基}一2—側氧基-咪唾°定-1-基）-乙酸甲酯（0. 055 g，〇. 109 5 mmol)和 1肩 Li〇H 水溶液（1 mL)於 THF (3 mL)中在 20 X 授掉整夜。在減壓下移除該THF並以2 N HC1水溶液酸化 該殘餘物然後以乙酸乙酯萃取。該萃取物透過MgS〇4乾燥並 濃縮。該殘餘物經色層分析以產生如黃色固狀物之該標題 化合物。HRMS:計算值 c27H22C1N3〇4 + H+，488· 13716 ;實 10 測值（ESI, [Μ+ΗΓ)，488. 1361。 範例251 4 - [(3-{3 - [3-甲基-8-（三氟甲基）-4-喹啉基]苯氧基} 苯基）確斑基]-2-丁酵 I5 在4-[3-（3-甲石黃酿基-苯氧基）-苯基]_3-甲基-三 氟甲基-喹琳（〇· 150 g，〇. 328 mmol)於醚（2 mL)中加入1. 4 Μ含有s-BuLi之環己烷（0.35 mL，0.49 mmol)，然後攪 拌15分鐘。加入環氧丙烷（〇· 23 mL，3. 28 mmol)和THF (1 mL)並將該反應攪拌整夜。以飽和的氣化銨水淬該反應並以 2〇 乙酸乙酯萃取。透過MgS〇4乾燥該經化合的有機物然後濃 縮。該產生的物質經色層分析以產生如一棕褐色固狀物之 該標題化合物。MS (ES)瓜/z 515. HRMS:計算值 C27H24F3N〇4S + H+，516.14509;實測值（ESI, [Μ+ΗΓ)， 516.1465 。 201 200825054 範例252 1-[(3-{3-[3-甲基-8-(三氟甲基）-4-啥琳基]苯氧基} 苯基）磺醢基]戊-3-酵 5 步驟基本上與範例251相同除了以1，2-環氧丁烷取 代環氧丙烷。MS (ES) z/7/z 529.8. HRMS:計算值 C28H26F3N〇4S + H+，530.16074;實測值（ESI, [M+H]—)， 530.1555 。 10 範例253 1 -[(3-{3-[3-甲基-8-(三氟甲基）-4-喹啉基]苯氧基} 苯基）確酸基]己—3_酵 步驟基本上與範例251相同除了以1，2-環氧戊烷取 代環氧丙烷。MS (ES) Λ7/Ζ 543· 8· HRMS:計算值 15 C29H28F3N〇4S + H+，544· 17639 ;實測值（ESI，[Μ+ΗΓ)， 544·1757 。 範例254 4-U3 - [3 - (8-氣基-3-甲基一4-喹啉基）苯氧基]苯基} 20 確斑基）-2-丁醇 將 δ 有 DMSO (〇· 073 g，0· 940 mmol)之 THF (1· 5 mL) 冷卻至 〇 Τ。加人 WuLi (0.19 niL，〇·47 _卜 2.5 Μ 之溶液於己貌中）並攪拌5分鐘。快速地加入含有8—氣基 -4-[3-(3-甲確醯基—笨氧基）_苯基]—3—甲基—喧琳（〇·⑽ 202 200825054 g，〇· 235 mmol)之 THF (1 mL)。在 20 °C 攪拌 30 分鐘之 後，加入環氧丙烷（〇· 050 mL，〇· 71 mmol)。經過攪拌整夜 後，將該反應以1 N HC1水溶液水淬並以乙酸乙酯萃取。 該些萃取物經MgS〇4乾燥並濃縮。殘餘物經色層分析以產生 5 如一暗白泡沫-固狀之該標題化合物（0· 048 g)。MS (ES) ζζ?/ζ 482· 1 ; HRMS:計算值 C26H24ClN〇4S + H+，482. 11873 ; 實測值（ESI, [Μ+ΗΓ)，482.1169。 範例255 10 4 -（{3-[3 - (8-氣基-3-甲基-4-喹啉基）苯氧基]苯基} 續醢基）- 2-甲基-2-丁酵 步驟基本上與上述相同除了以1，2-環氧-2-甲基丙烷 取代環氧丙烷並以飽和的氣化銨取代1 NHC1。MS (ES) /z7/z 495. 7 ; HRMS:計算值 c27H26C1N〇4S + H+，496. 13438 ;實 15 測值（ESI, [Μ+ΗΓ)，496.1336。 範例256 4 -(3-{3 - [3- (第三丁基-二甲基-矽烷基氧基)-丙烷-1-磺 酸基]-苯氧基卜苯基)-8-氣基-3H啥淋 步驟基本上與上述相同除了以（2-溴乙氧基）-第三丁 基二甲基矽烷取代環氧丙烷並以飽和的氯化銨取代1 N HC1。該化合物無經純化即接續用於下一步驟。 範例257 203 200825054 3-({3-[3-(8-氯基-3-甲基-4-喹啉基）苯氧基]苯基} 磺醢基）-1-丙酵 在含有4-(3-{3-[3-（第三丁基-二甲基-矽烷基氧 基）-丙烷-1-磺醯基]-苯氧基}-苯基）-8-氣基-3-甲基-喹 5 啉之THF(5 mL)溶液中加入四丁基氟化銨（3當量）並在20 °C攪拌1小時。將飽和的氯化銨和水加入該反應中，然後 以乙酸乙酯萃取。以食鹽水沖洗該萃取物，透過MgS〇4乾燥 與濃縮。該殘餘物經色層分析以產生如一黃色固狀物之該 標題化合物。MS (ES) y»/z 467· 7 ; HRMS:計算值 ίο C25H22CINO4S + H+，468.10308;實測值（ESI, [Μ+ΗΓ)， 468.1026 。 範例258 3-[3-氰基-8-（三氟甲基）-4-喹啉基]苯基三氟甲烷 15 磺酸酯 將含有4-(3-羥基-苯基）-8-三氟甲基-喹啉一3-甲腈 (260 mg，0.828 mmol)和Ν-苯基雙（三氟甲烷磺酸亞胺） (414 mg，1_ 16 mmol)於THF (20 mL)中之一經擾拌的混合 物冷卻至0 °C，然後一次加入第三丁氧基鉀（120 mg，丨.〇8 20 mmol)。所產生的橘色混合物在0 °C攪拌1小時，然後以 水水淬並以乙酸乙酯萃取。該有機萃取物透過MgS〇4乾燥並 減壓濃縮。該殘餘物經色層分析，以梯度之乙酸乙酯：己烷 洗提，產生如一棕色粉末狀之該標題化合物（136mg，產率 37%) 。 MS (ESI) m/z 447·8 。 204 200825054 範例259 H[3—11基（三氟甲基）-4·料基]聯苯-3-基} 甲烷磺醢胺 5 冑含有3_[3_氛基、8、（三氟甲基）-4-喧琳基]苯基三 氣甲烧續義 基硼酸（44^0.20,1)^04(64^0.30 0^) 和 Pd(PPh3)4 (15 mg ’ 〇. 13 _〇1)於二噁烷（5 …中之一 混合物在迴流加熱2小時。過遽該反應並將該濾液減壓濃 10縮。透過HPIX純化該殘餘物以獲得如—白色固狀物之該標 題化合物（25 mg)。MS (ES) m/z 467_8 ; HRMS:計算值 C24H16F3N3〇2S + H+，468.09881 ;實測值（ESI, [M+H].)， 468·098卜 15 #例 260 至 266(3-{3-[3-(8-Chloro-3-methyl--4-quinolinyl)-phenoxy]-phenyl]- 2-oxy-mi-propion-1 Methyl-acetate (0.055 g, 109. 109 5 mmol) and a 1 liter aqueous solution of Li 〇H (1 mL) were applied in THF (3 mL) at 20 X overnight. The THF was removed under reduced pressure and the residue was crystallised eluted with 2 N EtOAc. The extract was dried over MgS 4 and concentrated. The residue was chromatographed to give the title compound as a yellow solid. HRMS: Calculated c27H22C1N3 〇4 + H+, 488· 13716; Measured (ESI, [Μ+ΗΓ), 488. 1361. Example 251 4 - [(3-{3 - [3-Methyl-8-(trifluoromethyl)-4-quinolinyl]phenoxy}phenyl)-de-spotted]-2-butyric acid I5 4-[3-(3-Mercapto-phenoxy)-phenyl]-3-methyl-trifluoromethyl-quinoline (〇· 150 g, 〇. 328 mmol) in ether (2 mL 1. 4 环 Cyclohexane (0.35 mL, 0.49 mmol) containing s-BuLi was added, followed by stirring for 15 minutes. Propylene oxide (〇 23 mL, 3.28 mmol) and THF (1 mL) were added and the mixture was stirred overnight. The reaction was quenched with saturated aqueous ammonium sulfate and extracted with ethyl acetate. The combined organic matter was dried through MgS 4 and then concentrated. The resulting material was chromatographed to give the title compound as a tan solid. MS (ES) melon / z 515. HRMS: calcd for C27H24F3N </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 201 200825054 Example 252 1-[(3-{3-[3-Methyl-8-(trifluoromethyl)-4-indolyl]phenoxy}phenyl)sulfonyl]pent-3-yl The procedure of 5 is essentially the same as in Example 251 except that propylene oxide is replaced by 1,2-butylene oxide. MS (ES) </ RTI> </ RTI> <RTI ID=0.0></RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 10 Example 253 1 -[(3-{3-[3-Methyl-8-(trifluoromethyl)-4-quinolinyl]phenoxy}phenyl)-acidic acid]3-3-fermentation step Substantially the same as in the example 251 except that the propylene oxide was replaced by 1,2-epoxypentane. MS (ES) Λ 7/Ζ 543·8· HRMS: Calculated for 15 C29H28F3N 〇 4S + H+, 544· 17639; Measured (ESI, [Μ+ΗΓ), 544·1757. Example 254 4-U3 - [3 - (8-Alkyl-3-methyl- 4-quinolinyl)phenoxy]phenyl} 20 decyl)-2-butanol δ DMSO (〇· 073 g, 0·940 mmol) of THF (1.5 mL) was cooled to 〇Τ. Add WuLi (0.19 niL, 〇·47 _b 2.5 Μ solution in the appearance) and stir for 5 minutes. Quickly add 8-oxo-4-[3-(3-methyl-decyl-phenyloxy)-phenyl]-3-methyl-indole (〇·(10) 202 200825054 g, 〇· 235 mmol ) THF (1 mL). After stirring at 20 ° C for 30 minutes, propylene oxide (〇·050 mL, 〇·71 mmol) was added. After stirring overnight, the reaction was quenched with 1N aqueous HCI andEtOAc. The extracts were dried over MgS 4 and concentrated. The residue was chromatographed to give the title compound (0·048 g) as a white solid. MS (ES) ζζ?/ζ 482·1; HRMS: calcd for C26H24ClN 〇 4S + H+, 482. 11873; Found (ESI, [Μ+ΗΓ), 482.1169. Example 255 10 4 -({3-[3 - (8-Alkyl-3-methyl-4-quinolinyl)phenoxy]phenyl} hydrazino)- 2-methyl-2-butyrate The procedure is essentially the same as above except that propylene oxide is replaced by 1,2-epoxy-2-methylpropane and 1 NHC1 is replaced by saturated ammonium hydride. MS (ES) /z7/z 495. 7; HRMS: calcd., calcd, s, s, s, s, s, s, s, s, s, s, s. Example 256 4 -(3-{3 - [3-(Terbutyl-dimethyl-decyloxy)-propane-1-sulfonyl]-phenoxyphenyl)-8-yl The -3H rinse step is essentially the same as above except that (2-bromoethoxy)-tert-butyldimethylsilane is substituted for propylene oxide and 1 N HCl is replaced with saturated ammonium chloride. This compound was used in the next step without purification. Example 257 203 200825054 3-({3-[3-(8-Chloro-3-methyl-4-quinolinyl)phenoxy]phenyl}sulfonyl)-1-propanyl in 4- (3-{3-[3-(Third butyl-dimethyl-decyloxy)-propane-1-sulfonyl]-phenoxy}-phenyl)-8-yl-3- Tetrabutylammonium fluoride (3 equivalents) was added to a solution of methyl-quinoline in THF (5 mL) and stirred at 20 ° C for 1 hour. Saturated ammonium chloride and water were added to the reaction, followed by extraction with ethyl acetate. The extract was washed with saline and dried and concentrated through MgS 4 . The residue was chromatographed to give the title compound as a yellow solid. MS (ES) y»/z 467·7; HRMS: calc. calc. C25H22CINO4S + H+, 468.10308; found (ESI, [Μ+ΗΓ), 468.1026. Example 258 3-[3-Cyano-8-(trifluoromethyl)-4-quinolinyl]phenyltrifluoromethane 15 sulfonate will contain 4-(3-hydroxy-phenyl)-8-tri One of fluoromethyl-quinoline-3-carbonitrile (260 mg, 0.828 mmol) and fluorenyl-phenylbis(trifluoromethanesulfonimide) (414 mg, 1-16 mmol) in THF (20 mL) The scrambled mixture was cooled to 0 ° C and then potassium tert-butoxide (120 mg, 丨. 〇 8 20 mmol) was added in one portion. The resulting orange mixture was stirred at 0 ° C for 1 hour, then quenched with water and extracted with ethyl acetate. The organic extract was dried over MgSO 4 and concentrated under reduced pressure. The residue was chromatographed eluting EtOAc (EtOAc:EtOAc MS (ESI) m/z 447·8. 204 200825054 Example 259 H[3-11-(trifluoromethyl)-4-yl]biphenyl-3-yl}methanesulfonamide 5 胄 contains 3_[3_yl group, 8, (trifluoromethyl) )-4-喧琳基]Phenyl trisole trimethylsulfonate (44^0.20,1)^04(64^0.30 0^) and Pd(PPh3)4 (15 mg ' 〇. 13 _〇1) The mixture was heated under reflux for 2 hours in a mixture of dioxane (5). The reaction was concentrated and the filtrate was concentrated under reduced pressure. 25 mg). MS (ES) m/z 467_8; HRMS: Calculated C24H16F3N3 〇2S + H+, 468.09881; Measured (ESI, [M+H].), 468·098b 15 #例260至266

以範例259之相似方法製備下列化合物，應用適當的 芳基硼酸和喹淋-芳基三氟甲續酸鹽。 260 205 20 200825054 4-[3’ -（甲基磺醢基）聯苯-3-基]-8-（三氟甲基）喹啉 - 3-甲腈 MS(ES)/z//z452.8 ； HRMS:計算值 C24H15F3N2〇2S + H+， 453.08791;實測值（ESI, [Μ+ΗΓ)，453· 087卜 範例261 4-[3’-(乙基磺醯基）聯苯-3-基]-8-(三氟甲基）喹啉 -3-甲腈 MS (ES) 466. 8。 10 15 20 範例262 iV-{3’ -[3-II基-8-（三氟甲基）-4-啥琳基]聯苯-4-基} 甲烷磺醢胺 MS (ES) Λ7/Ζ 467. 8。 範例263 iV-{3’ -[3-氰基-8-（三氣甲基）-4-啥琳基]聯苯-3-基}-4-甲基苯磺醢胺 MS (ES) y/7/z 543· 9。 範例264 4-[4’-(甲基磺醢基）聯苯-3-基]-8-(三氟甲基）喹啉 -3-甲腈 MS (ES) /Z7/Z 452. 8。 206 200825054 範例265 4-{3-[1-(苯基磺醯基）-1及-吲哚-3-基]苯基}-8-(三 氟甲基）喹啉-3-甲腈 5 MS (ES) m/z 553.8 。 範例266 3’ -[3-氰基-8-（三氟甲基）-4-喹啉基]-沪甲基聯苯 - 3-磺醯胺 10 MS (ES) m/z 468 。The following compounds were prepared in a similar manner to Example 259 using the appropriate aryl boronic acid and quinone-aryl trifluoromethane hydrochloride. 260 205 20 200825054 4-[3'-(Methylsulfonyl)biphenyl-3-yl]-8-(trifluoromethyl)quinoline-3-carbonitrile MS(ES)/z//z452. 8 ; HRMS: Calculated C24H15F3N2 〇 2S + H+, 453.08791; Measured (ESI, [Μ+ΗΓ), 453· 087. Example 261 4-[3'-(ethylsulfonyl)biphenyl-3-yl ]-8-(Trifluoromethyl)quinoline-3-carbonitrile MS (ES) 466. 8. 10 15 20 Example 262 iV-{3' -[3-IIyl-8-(trifluoromethyl)-4-indolyl]biphenyl-4-yl} methanesulfonamide MS (ES) Λ7/Ζ 467. 8. Example 263 iV-{3'-[3-Cyano-8-(trimethylmethyl)-4-indolyl]biphenyl-3-yl}-4-methylbenzenesulfonamide MS (ES) y /7/z 543. 9. Example 264 4-[4'-(Methylsulfonyl)biphenyl-3-yl]-8-(trifluoromethyl)quinoline-3-carbonitrile MS (ES) /Z7/Z 452. 206 200825054 Example 265 4-{3-[1-(phenylsulfonyl)-1 and -indol-3-yl]phenyl}-8-(trifluoromethyl)quinoline-3-carbonitrile 5 MS (ES) m/z 553.8. Example 266 3'-[3-Cyano-8-(trifluoromethyl)-4-quinolinyl]-h-methylbiphenyl-3-sulfonamide 10 MS (ES) m/z 468.

15 4-{3-[3-(甲基磺醢基）苯氧基]苯基卜3-(1沪四唑 -5-基）-8-（三氟甲基）喹啉 將含有4-{3-[3-(曱基磺醯基）苯氧基]苯基}-8-(三 氟甲基）喧淋-3-甲腈（30 mg，0· 06 mmol)、NaNs (100 mg， 1· 54 mmol)、三乙基胺鹽酸鹽（200 mg，1.45 mmol)於 DMF 20 (5 mL)中之一混合物在95 QC加熱整夜。移除該固狀物並 207 200825054 將該液體經色層分析，以梯度之乙酸乙酯：己烷洗提以產生 如一白色固狀物之該標題化合物（25 mg，80%)。MS (ES) m/z 512」。 5 範例268 4 -（3-溴甲基-苯基）-3-甲基-8-三氟甲基-喹啉 將含有[3-（3-甲基-8-三氟甲基—4-喹啉基苯基]-曱醇（150 mg，0.471 mmol)於乾甲苯（5 mL)中之一經攪拌 的混合物在0°C時加入1·〇Μ含有三溴化磷之CH2CI2,（2.9 1〇 mL，2· 9 mmol)。15分鐘之後，使該反應加溫至20 T。3 小時之後，以水水淬該反應並以乙酸乙酯萃取。透過MgS〇4 乾燥該經化合之有機物並減壓濃縮。該殘餘物經色層分 析，以乙酸乙酯：己烷洗提以產生如一淡棕色粉末之該標題 化合物（178 mg，84%)。 MS (ESI) m/z 380_ 02。 15 範例269 3-甲基-4-[3-({[1-（甲基磺醢基)-1,2, 3,4-四氫喹啉-5-基]氧基}甲基)苯基]-8-(三氟甲基)啥琳 將含有卜甲磺醯基-1，2,3, 4-四氫-喹啉-5-基（59 mg，0· 26 mmol)之乾DMF(4 mL)與含有60%氫化鈉之油（12 2〇 mg ’0· 31 mmol)—起在20 T攪拌15分鐘，然後加入4-(3-溴基甲基-苯基）-3-甲基-8-三氟甲基-喹啉（90 mg，0.237 mmol)。3小時之後，以水水淬該反應並減壓濃縮以產生一 棕色粉末，其透過HPLC純化（梯度之水：乙腈）以產生如一 暗白色粉末之該標題化合物（49 mg，39%)。MS (ESI) m/z 208 200825054 526.8。 範例270至27215 4-{3-[3-(Methylsulfonyl)phenoxy]phenyl b 3-(1 Shanghai tetrazol-5-yl)-8-(trifluoromethyl)quinoline will contain 4- {3-[3-(indolylsulfonyl)phenoxy]phenyl}-8-(trifluoromethyl)phosphonium-3-carbonitrile (30 mg, 0.06 mmol), NaNs (100 mg , 1. 54 mmol), a mixture of triethylamine hydrochloride (200 mg, 1.45 mmol) in DMF 20 (5 mL) was warmed overnight at 95 Q. The solid was removed and 207 EtOAc (EtOAc): EtOAc (EtOAc) MS (ES) m/z 512". 5 Example 268 4 -(3-Bromomethyl-phenyl)-3-methyl-8-trifluoromethyl-quinoline will contain [3-(3-methyl-8-trifluoromethyl- 4- One of the stirred mixtures of quinolinylphenyl]-nonanol (150 mg, 0.471 mmol) in dry toluene (5 mL) was added at 0&lt;0&gt;C to give CH2CI2 containing phosphorus tribromide, (2.9 1 〇mL, 2·9 mmol). After 15 minutes, the reaction was allowed to warm to 20 T. After 3 h, the reaction was quenched with water and extracted with ethyl acetate. The organic compound was dried over Mgs. The residue was concentrated with EtOAc EtOAc (EtOAc). Example 269 3-Methyl-4-[3-({[1-(methylsulfonyl)-1,2,3,4-tetrahydroquinolin-5-yl]oxy}methyl)phenyl) ]-8-(Trifluoromethyl) sulfonate will contain dry DMF containing methanesulfonyl-1,2,3,4-tetrahydro-quinolin-5-yl (59 mg, 0.26 mmol) 4 mL) with an oil containing 60% sodium hydride (12 2 mg [0· 31 mmol) - stirred at 20 T for 15 minutes, then added 4-(3-bromomethyl-phenyl)-3-methyl -8-trifluoromethyl-quinoline 90 mg, 0.237 mmol). After 3 hours, the title compound was obtained from EtOAc (EtOAc) Mg, 39%). MS (ESI) m/z 208 200825054 526.8. Examples 270 to 272

以範例269之相似方法製備下列化合物，除了改用適 當的苄基溴化物-啥淋和紛： / 範例270 ίο 3-节基-4-[3-({[1-(甲基續酿基)_1,2, 3,4-四氩啥琳-5- 基]氧基}甲基)苯基]-8-(三氟甲基)喹啉 MS (ESI) m/z 602.9 。 範例271 15 3-苄基-4-[3-({[2-（甲基磺醢基)-l,2,3,4-四氩異喹啉 - 5-基]氧基}甲基)苯基]-8-(三氟甲基)喹啉 MS (ESI) m/z 602.8 。 範例272 20 3-甲基-4-[3-({[2-(甲基磺醯基)-1，2, 3,4-四氩異喹啉 - 5-基]氧基}甲基)苯基]- 8-(三氟甲基)啥琳 209 200825054 MS (ESI) m/z 526.8 。 範例273 3-(2-甲氧基-2-側氧基乙硫基）苯基硼酸 5 將含有3-氫硫基苯基删酸（0. 50 g，3. 2 mmol)、溴 乙酸甲酯（1· 5 g，10 mmol)、和碳酸鉀（5· 0 g，37 mmol) 於15 mL之DMF中之一混合物在45 °C加熱整夜。將該反 應倒進水中並以乙酸乙酯萃取。透過MgS〇4乾燥該萃取物並 濃縮。該粗產物無經進一步純化而被用於下一步驟。 10 範例274 2-(3’ -(3-氰基-8-(三氟甲基)-4_啥琳基)聯苯-3-基硫基） 乙酸甲酯 使用3-(2-甲氧基-2-側氧基乙硫基）苯基硼酸和 15 3-[3-氰基-8_(三氟甲基）-4-啥琳基]苯基三敦甲院石黃酸 酯，以範例259中所述之方法製備該標題化合物。 範例275 ({3’ - [3-氰基-8-（三氟甲基）-4-啥琳基]聯苯-3-基} 20 磺醢基）乙酸 將含有2-(3’-（3-氰基-8-(三氟甲基）-4-喧琳基）聯 苯-3-基硫基）乙酸甲酯（25 mg，0· 05 mmol)、乙酸（5 mL)、 30% H202之一混合物在50 °C加熱3小時。將該混合物倒 進水中並以n-BuOH萃取。移除該溶劑以產生如一白色固狀 210 200825054 物之該標題化合物（10 mg，37%)。MS (ES) m/z 497. 0。 範例276 4-{3-[3-（甲基磺醯基）苯氧基]苯基}-8-（三氟甲基） 5 喹啉-3 -甲醢胺 將含有4-{3-[3-(甲基石黃醯基）苯氧基]苯基}-8-（三 氟甲基）喹琳-3-緩酸（100 mg，0· 205 mmol)和U-羰基二 咪峻（85 mg，0· 053 mmol)於DMF(5 mL)中之一混合物在 60 °C加熱1小時。冷卻該混合物，然後加入THF (1〇 mL) 10和濃NH4〇H (15 mL)。將該反應在室溫攪拌整夜並藉由HPLC 純化以產生如一白色固狀物之該標題化合物（64 mg)。MS (ES) m/z 486.9 。The following compounds were prepared in a similar manner as in Example 269, except that the appropriate benzyl bromide-supplement was used instead: / 270 ίο 3-pyryl-4-[3-({[1-(methyl)) 1 , 2, 3,4-tetrahydroquinone-5-yl]oxy}methyl)phenyl]-8-(trifluoromethyl)quinoline MS (ESI) m/z 602.9. Example 271 15 3-Benzyl-4-[3-({[2-(methylsulfonyl)-l,2,3,4-tetrafluoroisoquinoline-5-yl]oxy}methyl) Phenyl]-8-(trifluoromethyl)quinoline MS (ESI) m/z 602.8. Example 272 20 3-Methyl-4-[3-({[2-(methylsulfonyl)-1,2,3,4-tetrafluoroisoquinoline-5-yl]oxy}methyl) Phenyl]- 8-(trifluoromethyl)anion 209 200825054 MS (ESI) m/z 526.8. Example 273 3-(2-Methoxy-2-oxoethoxyethylthio)phenylboronic acid 5 will contain 3-hydrothiophenyl-decanoate (0.50 g, 3.2 mmol), bromoacetate A mixture of ester (1.5 g, 10 mmol) and potassium carbonate (5.0 g, 37 mmol) in 15 mL of DMF was heated at 45 °C overnight. The reaction was poured into water and extracted with ethyl acetate. The extract was dried through MgS 4 and concentrated. This crude product was used in the next step without further purification. 10 Example 274 2-(3'-(3-Cyano-8-(trifluoromethyl)-4_indolyl)biphenyl-3-ylthio)acetic acid methyl ester using 3-(2-methoxy Benzyl-2-oxoethylthio)phenylboronic acid and 15 3-[3-cyano-8-(trifluoromethyl)-4-indolyl]phenyl sultanate The title compound was prepared by the method described in Example 259. Example 275 ({3'-[3-Cyano-8-(trifluoromethyl)-4-indolyl]biphenyl-3-yl} 20 sulfonyl)acetic acid will contain 2-(3'-( Methyl 3-cyano-8-(trifluoromethyl)-4-indolyl)biphenyl-3-ylthio)acetate (25 mg, 0.05 mmol), acetic acid (5 mL), 30% One of the H202 mixtures was heated at 50 °C for 3 hours. The mixture was poured into water and extracted with n-BuOH. The solvent was removed to give the title compound (10 mg, 37%) as a white solid. MS (ES) m/z 497. 0. Example 276 4-{3-[3-(Methylsulfonyl)phenoxy]phenyl}-8-(trifluoromethyl) 5 quinolin-3-carbamide will contain 4-{3-[ 3-(methylglycosinyl)phenoxy]phenyl}-8-(trifluoromethyl)quinolin-3-acid (100 mg, 0·205 mmol) and U-carbonyl dimizone (85 mg , 0. 053 mmol) One of the mixtures in DMF (5 mL) was heated at 60 ° C for 1 hour. The mixture was cooled, then THF (1 mL) 10 and concentrated NH.sub.4H (15 mL). The reaction was stirred at rt EtOAc (m.) MS (ES) m/z 486.9.

以範例276所述之相似方法製備下列化合物。 範例277 ’甲基-4-{3- [3-（甲基磺醢基）苯氧基]苯基卜8一（三 211 200825054 氟甲基）喹啉-3-甲醯胺 MS (ES) m/z 501.1 。 範例278 5 舲乙基-4 - {3-[3-（甲基磺醯基）苯氧基]苯基}-8-(三 氟甲基）喹啉-3-甲醯胺 MS (ES) m/z 515. 2。· 範例279 ίο 3-甲基-4-[3’-(甲基續醢基)聯苯-3-基]-8- (三氟甲基)喹 啉 在含有4-(3-漠基-苯基)-3-甲基-三氟甲基-啥琳(0. 050 g，0· 14 mmol)於甲苯(3 mL)和乙醇(0· 5 mL)中加入3-(甲石黃醯基） 苯棚酸（0_ 30 mmol)、2 M Na2C〇3水溶液（0· 25 mL，0· 50 mmol)、 15 和 Pd(PPh3)4 (9 mg，0· 0075 mmol)。將該反應在 90 °C 加熱 8 小 時。移除該溶劑並將該殘餘物經色層分析，使用10:90乙酸乙酯： 己烷，以獲得0. 051 g之該標題化合物。 MS(ES) /»// 441.8。 2〇 範例280至288The following compounds were prepared in a similar manner as described in Example 276. Example 277 'Methyl-4-{3-[3-(methylsulfonyl)phenoxy]phenyl b-8 (III 211 200825054 fluoromethyl)quinoline-3-carboxamide MS (ES) m/z 501.1. Example 278 5 舲ethyl-4 - {3-[3-(methylsulfonyl)phenoxy]phenyl}-8-(trifluoromethyl)quinoline-3-carboxamide MS (ES) m/z 515. 2. · Example 279 ίο 3-methyl-4-[3'-(methyl hydrazinyl)biphenyl-3-yl]-8-(trifluoromethyl)quinoline in the presence of 4-(3-Molyl- Phenyl)-3-methyl-trifluoromethyl-indole (0. 050 g, 0·14 mmol) in 3-toluene (3 mL) and ethanol (0.5 mL) Benzolic acid (0-30 mmol), 2 M Na2C〇3 aqueous solution (0.25 mL, 0·50 mmol), 15 and Pd(PPh3)4 (9 mg, 0. 0075 mmol). The reaction was heated at 90 °C for 8 hours. The solvent was removed and the residue was purified EtOAcjjjjjjjj MS(ES) /»// 441.8. 2〇 Example 280 to 288

212 200825054 以範例279所述之相似方法，使用適當的函化芳基砜 和喹啉芳基溴化物或環戊硼烷並使用一適當選自Na2C〇3、 K2CO3、或CS2CO3的驗基以及一適當包括甲苯：乙醇混合物 5 和DMF之溶劑，來製備下列化合物。 範例280 3- 节基-4-[3’ -(甲基項斑基）聯苯-3-基]-8-（三氟甲 基）喹啉 10 MS (ESI) Λ//Ζ 518。 範例281 4- [3’ -（甲基續酿基）聯苯-3-基]-8_(三氟甲基）啥琳 MS (ES) 7Z//Z 427. 8。 15 範例282 3-乙基-4-[3’ -(甲基續酿基）聯苯-3-基]-8_(三氟甲 基）喹啉 MS (ES)你/z 455· 8。 20 範例283 3’ -[3-甲基-8-(三氟甲基）-4-喹啉基]聯苯-3-磺醢 胺 MS (ES) τζζ/ζ 442· 8。 213 200825054 範例284 4-[3’ -（甲基績酸基）聯苯-3-基]-3-丙基-8-（三氟甲 基）喹啉 5 範例285 3-異丙基-4-[3, -（甲基續酿基）聯苯-3-基]-8-(三氟 甲基）喹啉 ίο 範例286 3-氣基-4-[3’ -(甲基磺醯基）聯苯-3-基]-8-(三氟甲 基）喹啉 範例287 15 4-[3-（2-氯基-鳴咬-4-基）-苯基]-3-甲基-8-三氟甲 基-喹啉 MS (ES) m/z 400.0. 範例288 2〇 4-[3-（6-氣基-喊咬-4-基）-苯基]-3-甲基-8-三氟甲 基-喹啉 MS (ES) /Z7/Z 400. 0。 或者，可藉由將芳基溴化物轉換成環戊硼烷，隨後與 214 200825054 一合適的i基取代的芳基或雜芳基單元耦合來製備式I化 合物。 範例289212 200825054 In a similar manner as described in Example 279, using the appropriate functional aryl sulfone and quinoline aryl bromide or cyclopentane borane and using a suitable base selected from Na2C〇3, K2CO3, or CS2CO3, and The following compounds were prepared by appropriately including a solvent of toluene: ethanol mixture 5 and DMF. Example 280 3-Cellyl-4-[3'-(methyl-based phenyl)biphenyl-3-yl]-8-(trifluoromethyl)quinoline 10 MS (ESI) Λ//Ζ 518. Example 281 4- [3'-(Methyl aryl)biphenyl-3-yl]-8-(trifluoromethyl)anion MS (ES) 7Z//Z 427. 8. 15 Example 282 3-Ethyl-4-[3'-(methyl aryl)biphenyl-3-yl]-8-(trifluoromethyl)quinoline MS (ES) you /z 455· 8. 20 Example 283 3'-[3-Methyl-8-(trifluoromethyl)-4-quinolinyl]biphenyl-3-sulfonamide MS (ES) τζζ/ζ 442·8. 213 200825054 Example 284 4-[3'-(Methylic acid)biphenyl-3-yl]-3-propyl-8-(trifluoromethyl)quinoline 5 Example 285 3-isopropyl-4 -[3, -(methyl aryl)biphenyl-3-yl]-8-(trifluoromethyl)quinoline ί 例 Example 286 3-Alkyl-4-[3'-(methylsulfonyl) Biphenyl-3-yl]-8-(trifluoromethyl)quinoline Example 287 15 4-[3-(2-Chloro-Naxito-4-yl)-phenyl]-3-methyl- 8-Trifluoromethyl-quinoline MS (ES) m/z 400.0. Example 288 2〇4-[3-(6-Alkyl-Crypt-4-yl)-phenyl]-3-methyl- 8-trifluoromethyl-quinoline MS (ES) / Z7/Z 400. 0. Alternatively, a compound of formula I can be prepared by converting an aryl bromide to a cyclopentane borane followed by coupling with a suitable i-substituted aryl or heteroaryl unit of 214 200825054. Example 289

3-甲基-4-[3-(4,4, 5, 5-四甲基-1, 3, 2-二雜氧戊硼烷-2-基)苯基]-8-（三氟甲基)喹啉 10 ί &quot; 15 在氮大氣下，將4-(3-溴基苯基）-甲基-8-（三氟甲 基）喹啉（3.45 g，9. 40 mmol)、雙（戊醯）二硼（2.87 g，11.3 mmol)和醋酸鉀（2. 9 g，30 mmol)於甲苯（70 mL)中授拌。 加入Pd(PPh3)4並將該反應在90 °C加熱8小時。該反應混 合物分佈於乙酸乙酯與水之間。以食鹽水沖洗該有機層， 然後乾燥與減壓濃縮，並將該殘餘物經色層分析以產生如 一白色固狀物之該標題化合物（2. 30 g，58%)。MS (ESI) m/z 414。 範例290 3’ - [3-苄基-8-(三氟甲基)-4-啥琳基]-於(2-經基-2-甲基 丙基)聯苯-3-續酿胺 215 200825054 將3-甲基-4-[3-(4, 4, 5, 5-四甲基-1，3, 2-二雜氧戊硼烧 -2-基）苯基]-8_ (三氟甲基）啥淋(0.10g，0· 20mmolh#KDMF(3 mL)中並加入3-澳基-N_(2-經基-2-甲基丙基)-苯磺醯胺（0.25 mmol)、CS2CO3 (0· 20 g，0· 60 mmol)和 Pd(PPh3)4 (0· 012 g，0. 01 5 mmol)。將該反應在100 °C加熱12小時。移除該溶劑並將該殘餘 物藉由色層分析純化，以20:80乙酸乙酯：己烷洗提，以產生如 一棕褐色固狀物之該標題化合物（0.017 g)。MS (ES) /ff/z 590· 8。 0 範例291至3653-methyl-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-8-(trifluoromethyl) ))quinoline 10 ί &quot; 15 4-(3-bromophenyl)-methyl-8-(trifluoromethyl)quinoline (3.45 g, 9.40 mmol), double under nitrogen atmosphere (Hengthene) diboron (2.87 g, 11.3 mmol) and potassium acetate (2.9 g, 30 mmol) were mixed in toluene (70 mL). Pd(PPh3)4 was added and the reaction was heated at 90 °C for 8 hours. The reaction mixture was distributed between ethyl acetate and water. The organic layer was washed with EtOAc (EtOAc m.) MS (ESI) m/z 414. Example 290 3' - [3-Benzyl-8-(trifluoromethyl)-4-indolyl]-(2-carbo-2-methylpropyl)biphenyl-3-continued 215 200825054 3-methyl-4-[3-(4, 4, 5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-8_ (trifluoro Methyl) guanidine (0.10 g, 0·20 mmolh #KDMF (3 mL) and 3-3-amino-N-(2-carbo-2-methylpropyl)-benzenesulfonamide (0.25 mmol), CS2CO3 (0·20 g, 0·60 mmol) and Pd(PPh3)4 (0·012 g, 0.015 mmol). The reaction was heated at 100 ° C for 12 hours. The solvent was removed and the residue was removed. The title compound (0.017 g), m. 0 Examples 291 to 365

以上述之相似方法，使用適當的i化芳基砜和喹啉芳基硼 15酸或硼酯來製備下列化合物。 3 —[3〜苄基-8-（三氟甲基）-4-喹啉基]-ΛΚ2-羥基乙 基）聯苯-3-項魏胺 216 200825054 MS (ES)瓜/z 562.8。 範例292 3-节基_4-[3’ -(嗎琳-4-基續酿基）聯苯-3-5 基]-8-(三氟甲基）喹啉 MS (ES)你/z 588.8。 範例293 3’ - [3-节基-8-（三氟甲基）-4-啥琳基]-於（2_幾基乙 10 基）-舲甲基聯苯-3-磺醢胺 MS (ES) Λ//Ζ 576. 8。 範例294 3-苄基-4-[3’ -氣基-4’ -(丙基磺醢基）聯苯-3-15 基]-8-（三氟甲基）啥琳 MS (ES) 7Z//Z 579. 9。 範例295 3-苄基-4-[ 3’ -氯基_4’ -（異丙基磺醢基）聯苯-3-20 基]-8-（三氟甲基）啥琳 MS (ES)瓜/z 579·9。 範例296 3-苄基-4-[3’-氯基-4’-（異丁基磺醢基）聯苯-3 - 217 200825054 基]-8-（三氟甲基）啥琳 MS (ES) τζζ/ζ 593_ 9。 範例297 5 3-节基-4-{3’ -氯基-4’ -[(3-甲基丁基）續酿基]聯苯 - 3-基}-8_(三氟甲基）啥琳 MS (ES) 608. 0。 範例298 ίο 3-节基-4-[3’ -氯基-4’ -（乙基碟酸基）聯苯-3- 基]_8-（三氟甲基）啥琳 MS (ES) /Z//Z 565· 9。 範例299 15 4-[4’-(稀丙基確酸基）-3’ -氣聯苯-3-基]-3-节基 - 8-（三氟甲基）喹啉 MS (ES) Λ//Ζ 578. 0。 範例300 2〇 3-({3’ -[3-节基-8-（三氟甲基）-4-啥琳基]-3-氯聯 苯-4-基}確酸基）-1-丙酵 MS (ES) /Z//Z 595. 9。 範例301 218 200825054 3-节基-4-[3’ -（丙基項酿基）聯苯-3-基]-8-（三氟甲 基）喹啉 MS (ES) Λ//ζ 546· 0。 . 5 範例302 3-苄基-4-[3’ -(異丙基確酿基）聯苯-3-基]-8-(三氟 甲基）喹啉 MS (ES) zff/z 546·0 。 / 10 範例303 3-节基-4-[3’ -（異丁基確酿基）聯苯-3-基]-8-(三氟 甲基）喹啉 MS (ES) yzz/z 560· ：1。 15 範例304 3-节基-4- {3’ -[(3_甲基丁基）項酿基]聯苯-3- / i 基}-8-(三氟甲基）喧淋 MS (ES) /z//z 574. 1。 20 範例305 3-节基-4-[3’ -（乙基續酿基）聯苯-3-基]-8-（三氟甲 基）喹琳 MS (ES) 7Z//Z 532· 0。 範例306 219 200825054 4-[3’ -(稀丙基確酿基）聯苯-3-基]-3-节基-8-(三氟 甲基）喹啉 MS (ES) 7Z//Z 544· 0。 5 範例307 3-（{3, - [3-节基-8-（三氟甲基）-4-啥琳基]聯苯-3-基}續酿基）-1-丙酵 MS (ES) yzz/z 562. 0。 ίο 範例308 3-节基-4-{3-[5-(甲基續酿基）ϋ比咬_3-基]苯 基}-8-（三氟甲基）喹啉 MS (ES) /ζ//ζ 518. 9。 15 範例309 3-节基-4-[4’ -( 11比洛咬-1-基項酿基）聯苯-3-基]-8-(三氟甲基）啥琳 MS (ES) Λ//Ζ 572· 9。 20 範例310 3-苄基-4-[3’ -〇比咯啶-1-基磺醢基）-5’ -(三氟甲基） 聯苯-3-基]-8-（三氟甲基）喹啉 MS (ES) Λ//Ζ 641· 0。 220 200825054 範例311 4-[3’ -(稀丙基續酿基）-5’ -（三氟甲基）聯苯-3-基]-3-节基_8-（三氟甲基）啥琳 MS (ES) /Z7/Z 611· 9。 5 範例312 3-苄基-4-[3’ -（異丁基續酿基）-5’ -（三氟甲基）聯苯 _3-基]-8-(三氟甲基）哮琳 MS (ES) /Z7/Z 627. 9。 10 範例313 3-苄基-4-[3’ -(丙基續酿基）-5’ -（三氟甲基）聯苯 - 3-基]-8-（三氟甲基）喹啉 MS (ES) /Z//Z 613. 9。 15 範例314 3-节基-4-[3’ - [(3-甲基丁基）確酿基]-5’ -（三氟甲 基）聯苯-3-基]-8-(三氟甲基）喹啉 MS (ES) /»// 641· 9。 20 範例315 3-{ [3’ - [3-苄基-8-（三氟甲基）-4-啥琳基]-5-（三氟 甲基）聯苯-3-基]續酿基}-1-丙酵 MS (ES) Λ//Ζ 629. 9。 221 200825054 範例316 3- 苄基-4-[3’-（異丙基磺醢基）-5’-（三氟甲基）聯苯 - 3-基]-8-（三氟甲基）啥琳 5 MS (ES) Λ7/Ζ 613· 9。 範例317 4- [3’ -（乙基磺醢基）聯苯-3-基]-3-甲基-8-(三氟甲 基）喹啉 10 MS (ES) Λ//Ζ 455_ 8。 範例318 3-甲基-4-[3’ -（丙基磺醢基）聯苯-3-基]-8-（三氟甲 基）喹啉 15 MS (ES) τζζ/ζ 469· 8。 範例319 3- （{3’ -[3-甲基-8-（三氟甲基）-4-啥淋基]聯苯-3-基}續酸基）-1-丙酵 20 MS (ES) /Z//Z 485_ 8。 範例320 4- [3’ -氯基-4’ -（甲基續酸基）聯苯-3-基]-3-甲基 -8-(三氟甲基）喹啉 222 200825054 MS (ES) τζζ/ζ 475· 7。 範例321 4-[3’ -氯基-4’ -（乙基碟酿基）聯苯-3-基]-3-甲基 5 -8-（三氣甲基）啥琳 MS (ES)瓜/z 489·7 。 範例322 4-[3’ -氯基-4’ -（丙基續酿基）聯苯-3-基]-3-甲基 ίο - 8-（三氟甲基）喹啉 MS (ES)瓜/z 503·7 。 範例323 3-（{3-氯基-3’ -[3-甲基-8-（三氟甲基）-4-喹啉基] 15 聯苯-4-基}磺醢基）-1-丙酵 MS (ES) /Z7/Z 519· 7。 範例324 3-甲基-4-{3-[5-(甲基碟酿基）β比咬-3-基]苯 20 基}-8-（三氟甲基）啥琳 MS (ES) 442· 8。 範例325 3-甲基-4-[4’ -(甲基確酸基）聯苯-3-基]-8-（三氟甲 223 200825054 基）喹啉 MS (ES) /z?/z 441.8。 範例326 5 4-{3-[5-(乙基磺醯基）nb啶-3-基]苯基}-3-甲基 - 8-（三氟甲基）喹啉 MS (ES) zff/z 456. 8。 範例327 10 4-[4’-（稀丙基續酸基）-3’ -氣基聯苯-3-基]_3-甲基 _8-（三氟甲基）啥淋 MS (ES) yz//z 501. 7。 範例328 15 3-节基-4-[4’ -(甲基讀酿基）聯苯-3-基]-8-（三氟曱 基）喹啉 MS (ES) /ff/z 517·7 。 範例329 2〇 3-节基-4-{3-[5-(乙基續酸基）11比咬-3-基]苯 基}-8-（三氟甲基）養琳 MS (ES) /»// 532· 7。 範例330 224 200825054 3-节基-4-[3’ -氯基-4’ -(甲基續酿基）聯苯-3-基]-8-(三氟甲基）啥琳 MS (ES) 7ζ//ζ 551· 7。 5 範例331 3- 甲基-4-{3’ -[(1幻-丙-1-稀-1-基續酿基]聯苯-3-基}-8-(三氟甲基）啥琳 MS (ES) 7Z//Z 465. 7。 ίο 範例332 4- [3’ -（乙基確酿基）聯苯-3-基]-8-(三氟甲基）啥琳 MS (ES) m/z 441. 7 〇 . 範例333 15 4-[3’ -(丙基確酸基）聯苯-3-基]-8-（三氟甲基）啥琳 MS (ES) Λζ/ζ 455· 7。 範例334 4-{3’ -[(1幻-丙-1-稀_1_基確酿基]聯苯_3-2〇 基卜8-(三氟甲基）啥琳 MS (ES) /b/z 453. 7。 範例335 3-（{3’ -[8-(三氟甲基）-4-喹啉基]聯苯-3-基}磺醢 225 200825054 基）-l-丙酵 MS (ES) m/z 471. 7 ° 範例336 基]-8-(三氟 4 - [3’-氣基-4’-（甲基磺醯基）聯苯 甲基）喹啉 MS (ES) Λ//ζ 461· 6。 範例337 ίο 4-[3’ -氣基-4’ -（乙基磺醢基）聯苯-3-基]-8-(三氟 甲基）喹啉 MS (ES) /Z//Z 475. 6。 範例338 15 4-[3’ -氣基_4’ -（丙基項酿基）聯苯-3-基]-8-(三氟 甲基）喹啉 MS (ES) λ//ζ 489. 6。 範例339 2〇 4-{3’ -氣基-4’ - [(1幻-丙_1-稀-1-基項酸基]聯苯 _3-基卜8-（三氟甲基）啥琳 MS (ES) π// 487. 6。 範例340 226 200825054 3-({3-氣基-3’ - [8-（三氣甲基）-4-啥琳基]聯苯-4-基}確酸基）-1-丙醇 MS (ES) 505. 6。 5 範例341 4-{3-[5-（甲基磺醢基）咕啶-3-基]苯基}-8-(三氟甲 基）喹啉 MS (ES) 428. 7。 10 範例342 4-[4’-(甲基磺醢基）聯苯-3-基]-8-（三氟甲基）喹啉 MS (ES) 427· 7。 範例343 15 4-{3-[5-(乙基罐酿基）-1-氧離子基11比咬-3-基]苯 基}-8-（三氟甲基）喹啉 MS (ESI) 7Z//Z 459。 範例344 2〇 4-{3-[5-(乙基磺醯基）吼啶-3-基]苯基}-8-(三氟甲 基）喹啉 MS (ES)仍/z 442.9 。 範例345 227 200825054 舲甲基-3’ -[3-甲基-8-（三氟甲基）-4-喹啉基]聯苯 -3-磺醢胺 MS (ES) /Z//Z 456· 9。 5 範例346 於乙基-3’ -[3-甲基-8-（三氟甲基）-4-啥琳基]聯苯 -3-磺醯胺 MS (ES) zzz/z 470· 9。 ίο 範例347 3’-[3-甲基-8-（三氟甲基）-4-喹啉基]-Y-丙基聯苯 - 3-確酸胺 MS (ES) /z7/z 484_ 9。 15 範例348 於異丙基-3’ - [3-甲基-8-（三氟甲基）-4-啥琳基]聯 苯-3-續醯胺 20 範例349 3-甲基-4-[3’ 吡咯啶-1-基磺醯基）聯苯-3- 基]-8 -（三氟甲基）喹啉 MS (ES)瓜/z 496.8 。 228 200825054 範例350 舲甲基-3’ -[8-（三氟甲基）-4-喹啉基]聯苯-3-磺醢 胺 MS (ES) /ff/z 442.8 。 範例351 於乙基-3’ - [8-（三氟甲基）-4-啥琳基]聯苯-3-續酿 胺 f MS (ES) 456. 8。 ίο 範例352 iV-丙基-3’ - [8-(三氣甲基）-4_啥琳基]聯苯-3-續酿 胺 MS (ES)瓜/z 470.8。 15 範例353 於異丙基-3’ -[8-（三氟甲基）-4-啥琳基]聯苯-3-續 醢胺 MS (ES)瓜/z 470· 9。 20 範例354 4-[3’ -(11比洛咬-1-基續酸基）聯苯-3-基]-8-（三氟甲 基）喹啉 MS (ES) m/z 482.8 ° 229 200825054 範例355 4-[4’ -甲基-3’ -（甲基磺醯基）聯苯-3-基]-8-（三氟 甲基）喹啉 5 MS (ES) /z//z 442. 1。 範例356 4-[3’ -（乙基磺醯基）-4’ -甲基聯苯-3-基]-8-(三氟 甲基）喹啉 10 MS (ES) /Z7/Z 456· ；1。 範例357 4-[4’ -（甲基磺醢基）-2’ -(三氟甲基）聯苯-3-基]-8_(三氟甲基）啥琳 15 MS (ES) 7Z//Z 496· 1。 範例358 4-[4’ -（乙基磺醢基）-2’ -(三氟甲基）聯苯_3-基]-8-（三氟甲基）喹啉 20 MS (ES) ys/z 510· 2。 範例359 3-甲基-4-[4’ -甲基-3’ -（甲基磺醢基）聯苯-3-基]-8-（三氟甲基）喹啉 230 200825054 MS (ES)仍/z 456.1 。 例 3 6 0 3- 甲基-4-[4’ -（甲基磺醢基）-2’ -（三氟甲基）聯苯 5〜3-基]-8-（三氟甲基）喹啉 MS (ES)你/z 510· 1。 361 4- [4’ -(乙基續酸基）-2’ -(三氟甲基）确苯-3-基]-3-1〇甲基-8-（三·象*甲基）啥琳 MS (ES)瓜/z 524. 2。 琉化物之氧化（Oxone®方法） 15 上述該喹啉具有一硫化物，其中可依照文獻中所述之 方法jt可依照先前範例35中所述之自硫基酚來製備鹵化芳 基颯所使用之Oxone®將硫氧化成砜。 @例 362 2〇 3-苄基-4-[3-(1,1-二氧離子基-1-苯并噻吩—4—基） 輩基]一 三氟甲基）考琳 MS (ES) y/7/z 528. 0。 第例363 231 200825054 3- 甲基-4-{3-[2-(甲基磺醢基）嘧啶-4-基]苯基}-8 (三氟甲基）-喹啉 MS (ES) zzz/z 444. 1。 5 範例 364 4- [3-(1，1-二氧離子基-1-苯并噻吩-3-基）苯基]- 3-甲基-8-（三氟甲基）喹啉 MS (ES) /»/ζ 451.8。 ίο 範例365 4-[3-（6-甲確酿基-鳴咬-4-基）-苯基]-3-甲基-8-三 氟甲基-喹啉 MS (ES) /Z7/Z 444. 1。 15 範例366 3-节基-4-（3-乙炔基苯基）-8-(三氟甲基）-嗟琳 在含有3-苄基-4-(3-溴基-苯基）-8-三氟甲基-喹啉 (1. 02 g，2. 3 _〇1)和三甲基-三丁基錫烧基乙快基-碎烧 (1· 30 g，3. 4 _〇1)於甲苯（25 mL)中之一溶液中加入 20 Pd(PPh3)4 (270 mg)並在120 °C加熱3小時。之後冷卻該 反應並減壓濃縮。該殘餘物經色層分析，以10:90乙酸乙 酯：己烷洗提，以產生如一油狀物之3-苄基-8-三氟甲基 -4-(3-三甲基矽烷基乙炔基-苯基）-喹啉。MS (ESI) m/z 460· 0。 232 200825054 一種該油狀物之溶液，即含有3-苄基-8-三氟曱基 -4-(3-三甲基矽烷基乙炔基-苯基）-喹啉（730 mg，1.6 mmol)和碳酸钟（220 mg，1· 6 mmol)於甲醇（30 mL)中，在 環境溫度下被攪拌3小時。該反應混合物被濃縮至乾燥並 5 將該殘餘物置入乙酸乙酯中，然後以30 mL (IN HC1)沖洗。 乾燥與減壓濃縮該有機層，色層分析後產生該標題化合物 (870 mg ， 80%) 。 MS (ESI) m/z 388 。 範例367 ίο 3-节基-4-(3-{[5-(甲基續酿基）11比咬-3-基]乙快基}苯 基)-8-(三氟甲基)啥琳 在含有3-苄基-4-(3-乙炔基-苯基）-8-三氟甲基-喹 琳（80 mg，0· 20 mmol)、3-溴基口比咬甲基颯（93 mg，0· 40 mmol)、口底口定（80 mg，0· 90 mmol)於甲苯（2· 0 mL)中之一 15 溶液中加入Pd(Cl)2(PPh3)2 (8. 0 mg)並在90 °C加熱3小 時。冷卻並減壓濃縮該反應。將該殘餘物置入乙酸乙S旨中， 然後以IN HC1水溶液（10 mL)沖洗。乾燥與減壓濃縮該有 機層，色層分析後產生該標題化合物（75 mg，70%)。 MS (ES) m/z 542.9 〇 20 範例368至370 以範例366和367所述之相似方法，使用適當的ή化芳基 或雜芳基以及喹啉乙炔製備下列化合物。 233 200825054The following compounds were prepared in a similar manner as described above using the appropriate i-arylsulfone and quinoline aryl boron 15 acid or boron ester. 3-[3~Benzyl-8-(trifluoromethyl)-4-quinolinyl]-indole 2-hydroxyethyl)biphenyl-3-yl-propanamine 216 200825054 MS (ES) melon/z 562.8. Example 292 3-block base _4-[3'-(Nallin-4-yl continuation) biphenyl-3-5 yl]-8-(trifluoromethyl)quinoline MS (ES) you /z 588.8. Example 293 3' - [3-Pheptyl-8-(trifluoromethyl)-4-indolyl]-(2-methylhexyl-10-yl)-indolemethylbiphenyl-3-sulfonamide MS (ES) Λ//Ζ 576. 8. Example 294 3-Benzyl-4-[3'-carbyl-4'-(propylsulfonyl)biphenyl-3-15-yl]-8-(trifluoromethyl)fluorene MS (ES) 7Z //Z 579. 9. Example 295 3-Benzyl-4-[ 3'-chloro- 4'-(isopropylsulfonyl)biphenyl-3-20-yl]-8-(trifluoromethyl)fluorene MS (ES) Melon / z 579·9. Example 296 3-Benzyl-4-[3'-chloro-4'-(isobutylsulfonyl)biphenyl-3 - 217 200825054 base]-8-(trifluoromethyl)anion MS (ES ) τζζ/ζ 593_ 9. Example 297 5 3-benzyl-4-{3'-chloro-4'-[(3-methylbutyl) continuation]biphenyl-3-yl}-8-(trifluoromethyl)啥琳MS (ES) 608. 0. Example 298 ίο 3-Pieceyl-4-[3'-Chloro-4'-(ethyl-discyl)biphenyl-3-yl]_8-(trifluoromethyl)fluorene MS (ES) /Z //Z 565· 9. Example 299 15 4-[4'-(Ltypropyl-Acidyl)-3'-azepine-3-yl]-3-pyringyl-8-(trifluoromethyl)quinoline MS (ES) Λ //Ζ 578. 0. Example 300 2〇3-({3' -[3-Pheptyl-8-(trifluoromethyl)-4-indolyl]-3-chlorobiphenyl-4-yl}-acidic acid)-1- Propylene MS (ES) / Z / / Z 595. 9. Example 301 218 200825054 3-benzyl-4-[3'-(propyl-branched)biphenyl-3-yl]-8-(trifluoromethyl)quinoline MS (ES) Λ//ζ 546· 0. 5 Example 302 3-Benzyl-4-[3'-(isopropyl aryl)biphenyl-3-yl]-8-(trifluoromethyl)quinoline MS (ES) zff/z 546· 0. / 10 Example 303 3-benzyl-4-[3'-(isobutyl-anhydride)biphenyl-3-yl]-8-(trifluoromethyl)quinoline MS (ES) yzz/z 560· :1. 15 Example 304 3-blockyl-4-{3'-[(3_methylbutyl)-glycol]biphenyl-3- /i-based}-8-(trifluoromethyl)phosphonium MS (ES ) /z//z 574. 1. 20 Example 305 3-mercapto-4-[3'-(ethyl succinyl)biphenyl-3-yl]-8-(trifluoromethyl)quinene MS (ES) 7Z//Z 532· 0 . Example 306 219 200825054 4-[3'-(Ltypropyl propyl)biphenyl-3-yl]-3-pyringo-8-(trifluoromethyl)quinoline MS (ES) 7Z//Z 544 · 0. 5 Example 307 3-({3, -[3-]-based-8-(trifluoromethyl)-4-indolyl]biphenyl-3-yl}continuary)-1-propanyl MS (ES ) yzz/z 562. 0. Οο Example 308 3-Piece-4-{3-[5-(Methyl) ϋ 咬 _3-yl]phenyl}-8-(trifluoromethyl)quinoline MS (ES) / ζ//ζ 518. 9. 15 Example 309 3-Phase-4-[4'-(11-Button-1-one base)biphenyl-3-yl]-8-(trifluoromethyl)啥琳 MS (ES) Λ //Ζ 572· 9. 20 Example 310 3-Benzyl-4-[3'-indolylpyridin-1-ylsulfonyl)-5'-(trifluoromethyl)biphenyl-3-yl]-8-(trifluoromethyl) Base) Quinoline MS (ES) Λ//Ζ 641· 0. 220 200825054 Example 311 4-[3'-(Lipyl propyl)-5'-(trifluoromethyl)biphenyl-3-yl]-3-pyrimidyl-8-(trifluoromethyl)anthracene Lynn MS (ES) / Z7 / Z 611 · 9. 5 Example 312 3-Benzyl-4-[3'-(isobutyl aryl)-5'-(trifluoromethyl)biphenyl-3-yl]-8-(trifluoromethyl) roaring MS (ES) / Z7/Z 627. 9. 10 Example 313 3-Benzyl-4-[3'-(propyl aryl)-5'-(trifluoromethyl)biphenyl-3-yl]-8-(trifluoromethyl)quinoline MS (ES) /Z//Z 613. 9. 15 Example 314 3-benzyl-4-[3'-[(3-methylbutyl)]-5'-(trifluoromethyl)biphenyl-3-yl]-8-(trifluoro Methyl)quinoline MS (ES) /»// 641· 9. 20 Example 315 3-{ [3' - [3-Benzyl-8-(trifluoromethyl)-4-indolyl]-5-(trifluoromethyl)biphenyl-3-yl] }-1-Protease MS (ES) Λ//Ζ 629. 9. 221 200825054 Example 316 3-Benzyl-4-[3'-(isopropylsulfonyl)-5'-(trifluoromethyl)biphenyl-3-yl]-8-(trifluoromethyl)anthracene Lynn 5 MS (ES) Λ 7/Ζ 613· 9. Example 317 4-[3'-(ethylsulfonyl)biphenyl-3-yl]-3-methyl-8-(trifluoromethyl)quinoline 10 MS (ES) Λ//Ζ 455_8. Example 318 3-Methyl-4-[3'-(propylsulfonyl)biphenyl-3-yl]-8-(trifluoromethyl)quinoline 15 MS (ES) τ ζζ / ζ 469. Example 319 3-({3'-[3-Methyl-8-(trifluoromethyl)-4-indolyl]biphenyl-3-yl}sutrabasin)-1-propanyl 20 MS (ES ) /Z//Z 485_ 8. Example 320 4-[3'-Chloro-4'-(methylsudanyl)biphenyl-3-yl]-3-methyl-8-(trifluoromethyl)quinoline 222 200825054 MS (ES) Τζζ/ζ 475· 7. Example 321 4-[3'-Chloro-4'-(ethyl-branol)biphenyl-3-yl]-3-methyl-5-8-(trimethylmethyl)啥琳 MS (ES) melon /z 489·7. Example 322 4-[3'-Chloro-4'-(propyl continuation)biphenyl-3-yl]-3-methyl ίο - 8-(trifluoromethyl)quinoline MS (ES) melon /z 503·7. Example 323 3-({3-Chloro-3'-[3-methyl-8-(trifluoromethyl)-4-quinolinyl] 15 biphenyl-4-yl}sulfonyl)-1- Propylene MS (ES) / Z7 / Z 519 · 7. Example 324 3-Methyl-4-{3-[5-(methyl broth) β butyl-3-yl]benzene 20 yl}-8-(trifluoromethyl) 啥 MS MS (ES) 442 · 8. Example 325 3-Methyl-4-[4'-(methyl-acid-acid)biphenyl-3-yl]-8-(trifluoromethyl 223 200825054-based) quinoline MS (ES) /z?/z 441.8 . Example 326 5 4-{3-[5-(ethylsulfonyl)nb)-3-yl]phenyl}-3-methyl- 8-(trifluoromethyl)quinoline MS (ES) zff/ z 456. 8. Example 327 10 4-[4'-(Dilylpropyl-acid)-3'-azabiphenyl-3-yl]-3-methyl-8-(trifluoromethyl)phosphonium MS (ES) yz //z 501. 7. Example 328 15 3-mercapto-4-[4'-(methyl-read-branched)biphenyl-3-yl]-8-(trifluoromethyl)quinoline MS (ES) /ff/z 517·7 . Example 329 2〇3-pyringyl-4-{3-[5-(ethylhexanoic acid) 11 butyl-3-yl]phenyl}-8-(trifluoromethyl)line MS (ES) /»// 532· 7. Example 330 224 200825054 3-Cellyl-4-[3'-Chloro-4'-(methyl hollenyl)biphenyl-3-yl]-8-(trifluoromethyl)anion MS (ES) 7ζ//ζ 551· 7. 5 Example 331 3-methyl-4-{3'-[(1 phantom-prop-1-en-1-yl aryl)biphenyl-3-yl}-8-(trifluoromethyl)啥琳MS (ES) 7Z//Z 465. 7. ίο Example 332 4- [3'-(Ethyl-Acryl)biphenyl-3-yl]-8-(trifluoromethyl)anion MS (ES) m/z 441. 7 〇. Example 333 15 4-[3'-(Pro-Acidyl)biphenyl-3-yl]-8-(trifluoromethyl)fluorene MS (ES) Λζ/ζ 455 · 7. Example 334 4-{3' -[(1 phantom-propan-1- </ RTI> 1-1) phenyl _3-2 decyl b 8-(trifluoromethyl) 啥 MS MS ES) /b/z 453. 7. Example 335 3-({3'-[8-(Trifluoromethyl)-4-quinolinyl]biphenyl-3-yl}sulfonium 225 200825054 base)-l -Protease MS (ES) m/z 471. 7 ° Example 336 base]-8-(trifluoro 4 -[3'-carbyl-4'-(methylsulfonyl)biphenylmethyl)quinoline MS (ES) Λ//ζ 461· 6. Example 337 ίο 4-[3'-Gasyl-4'-(ethylsulfonyl)biphenyl-3-yl]-8-(trifluoromethyl) Quinoline MS (ES) /Z//Z 475. 6. Example 338 15 4-[3'-Gasyl_4'-(propyl-glycolyl)biphenyl-3-yl]-8-(trifluoro Methyl)quinoline MS (ES) λ//ζ 489. 6. Example 339 2〇4-{3' - gas base-4' - [(1 phantom-propion_1 - dilute-1-yl acid group]biphenyl_3-kib-8-(trifluoromethyl)anthene MS (ES) π// 487. 6. Example 340 226 200825054 3-({3-gas base -3' - [8-(trimethylmethyl)-4-indolyl]biphenyl-4-yl}acid acid)-1-propanol MS (ES) 505. 6. 5 Example 341 4-{ 3-[5-(Methylsulfonyl)acridin-3-yl]phenyl}-8-(trifluoromethyl)quinoline MS (ES) 428. 7. 10 Example 342 4-[4'- (Methylsulfonyl)biphenyl-3-yl]-8-(trifluoromethyl)quinoline MS (ES) 427· 7. Example 343 15 4-{3-[5-(ethyl cans )-1-Oxygenyl 11 is more than -3-yl]phenyl}-8-(trifluoromethyl)quinoline MS (ESI) 7Z//Z 459. Example 344 2〇4-{3-[5 -(Ethylsulfonyl)acridin-3-yl]phenyl}-8-(trifluoromethyl)quinoline MS (ES) still /z 442.9. Example 345 227 200825054 舲Methyl-3'-[ 3-Methyl-8-(trifluoromethyl)-4-quinolinyl]biphenyl-3-sulfonamide MS (ES) /Z//Z 456·9. 5 Example 346 in Ethyl-3'-[3-methyl-8-(trifluoromethyl)-4-indolyl]biphenyl-3-sulfonamide MS (ES) zzz/z 470·9. Ίο Example 347, 3'-[3-Methyl-8-(trifluoromethyl)-4-quinolinyl]-Y-propylbiphenyl-3-acid acid MS (ES) /z7/z 484_ 9 . 15 Example 348 in isopropyl-3'-[3-methyl-8-(trifluoromethyl)-4-indolyl]biphenyl-3- continued decylamine 20 Example 349 3-Methyl-4- [3' Pyrrolidin-1-ylsulfonyl)biphenyl-3-yl]-8-(trifluoromethyl)quinoline MS (ES) melon/z 496.8. 228 200825054 Example 350 舲Methyl-3'-[8-(trifluoromethyl)-4-quinolinyl]biphenyl-3-sulfonamide MS (ES) /ff/z 442.8. Example 351 to ethyl-3'-[8-(trifluoromethyl)-4-indolyl]biphenyl-3-continuous amine f MS (ES) 456. Ίο Example 352 iV-propyl-3' - [8-(trimethylmethyl)-4_indolyl]biphenyl-3-continuous amine MS (ES) melon/z 470.8. 15 Example 353 in isopropyl-3'-[8-(trifluoromethyl)-4-indolyl]biphenyl-3- continued decylamine MS (ES) melon/z 470·9. 20 Example 354 4-[3' -(11 pirate-1-one-butylic acid)biphenyl-3-yl]-8-(trifluoromethyl)quinoline MS (ES) m/z 482.8 ° 229 200825054 Example 355 4-[4'-Methyl-3'-(methylsulfonyl)biphenyl-3-yl]-8-(trifluoromethyl)quinoline 5 MS (ES) /z//z 442. 1. Example 356 4-[3'-(ethylsulfonyl)-4'-methylbiphenyl-3-yl]-8-(trifluoromethyl)quinoline 10 MS (ES) /Z7/Z 456· ;1. Example 357 4-[4'-(Methylsulfonyl)-2'-(trifluoromethyl)biphenyl-3-yl]-8-(trifluoromethyl)fluorene 15 MS (ES) 7Z// Z 496· 1. Example 358 4-[4'-(ethylsulfonyl)-2'-(trifluoromethyl)biphenyl-3-yl]-8-(trifluoromethyl)quinoline 20 MS (ES) ys/ z 510· 2. Example 359 3-Methyl-4-[4'-methyl-3'-(methylsulfonyl)biphenyl-3-yl]-8-(trifluoromethyl)quinoline 230 200825054 MS (ES) Still /z 456.1. Example 3 6 0 3-methyl-4-[4'-(methylsulfonyl)-2'-(trifluoromethyl)biphenyl 5~3-yl]-8-(trifluoromethyl)quina Porphyrin MS (ES) you /z 510· 1. 361 4- [4'-(ethylhexanoic acid)-2'-(trifluoromethyl)-phenyl-3-yl]-3-1〇methyl-8-(trisyl-methyl) Lynn MS (ES) melon / z 524. 2. Oxidation of Telluride (Oxone® Process) 15 The quinoline described above has a sulfide which can be prepared according to the method described in the literature by preparing a halogenated aryl fluorene from a thiophenol as described in the previous Example 35. Oxone® oxidizes sulfur to sulfone. @例362 2〇3-Benzyl-4-[3-(1,1-dioxalyl-1-benzothiophen-4-yl) thiol]-trifluoromethyl) Corin MS (ES) Y/7/z 528. 0. Example 363 231 200825054 3-Methyl-4-{3-[2-(methylsulfonyl)pyrimidin-4-yl]phenyl}-8 (trifluoromethyl)-quinoline MS (ES) zzz /z 444. 1. 5 Example 364 4- [3-(1,1-Dioxal-1-benzothiophen-3-yl)phenyl]-3-methyl-8-(trifluoromethyl)quinoline MS (ES ) /»/ζ 451.8. Οο Example 365 4-[3-(6-Methoxy-Bitter-4-yl)-phenyl]-3-methyl-8-trifluoromethyl-quinoline MS (ES) /Z7/Z 444. 1. 15 Example 366 3-benzyl-4-(3-ethynylphenyl)-8-(trifluoromethyl)-indole containing 3-benzyl-4-(3-bromo-phenyl)-8 -Trifluoromethyl-quinoline (1. 02 g, 2. 3 _〇1) and trimethyl-tributyltin-based ketone-fragmentation (1·30 g, 3. 4 _〇1) To one of the toluene (25 mL) was added 20 Pd(PPh3)4 (270 mg) and heated at 120 °C for 3 hours. The reaction was then cooled and concentrated under reduced pressure. The residue was chromatographed eluting with 10:90 ethyl acetate:hexane to afford 3-benzyl-8-trifluoromethyl-4-(3-trimethyldecanealkyl) as an oil. Ethynyl-phenyl)-quinoline. MS (ESI) m/z 460. 232 200825054 A solution of the oil containing 3-benzyl-8-trifluorodecyl-4-(3-trimethyldecylethynyl-phenyl)-quinoline (730 mg, 1.6 mmol) And a solution of carbonic acid (220 mg, 1.6 mmol) in methanol (30 mL) was stirred at ambient temperature for 3 h. The reaction mixture was concentrated to dryness and the residue was taken in ethyl acetate then rinsed with 30 <RTIgt; The title compound (870 mg, 80%) was obtained. MS (ESI) m/z 388. Example 367 ίο 3-pyringyl-4-(3-{[5-(methyl aryl) 11 butyl-3-yl]ethyl yl)}phenyl)-8-(trifluoromethyl) 啥 啥In the presence of 3-benzyl-4-(3-ethynyl-phenyl)-8-trifluoromethyl-quinolin (80 mg, 0·20 mmol), 3-bromo-based ratio methyl guanidine (93) Pd(Cl)2(PPh3)2 (8. 0 mg) was added to one of 15 solutions of toluene (2.0 mL) in a solution of 100 mg, 0.40 mmol). ) and heated at 90 °C for 3 hours. The reaction was cooled and concentrated under reduced pressure. The residue was taken up in ethyl acetate (EtOAc) and then rinsed with &lt The title compound (75 mg, 70%) was obtained after chromatography. MS (ES) m/z 542.9 〇 20 Examples 368 to 370 The following compounds were prepared in a similar manner as described in Examples 366 and 367 using the appropriate deuterated aryl or heteroaryl and quinoline acetylene. 233 200825054

範例368 3-苄基-4-(3-{[4-〇比咯啶-1-基磺醢基）苯基]乙炔 5 基}苯基）-8_(三氣甲基）啥琳 MS (ES) /Z7/Z 597. 0。 範例369 3-节基-4-(3-{[3-(比洛咬_1_基續酿基）苯基]乙快 ίο 基}苯基）-8-(三氣曱基）啥琳 MS (ES) 597. 0。 範例370 3-节基-4-(3-{[3-(咐*咯咬-1-基確斑基）-5-（三氟甲 15 基）苯基]乙炔基}苯基）-8-(三氟甲基）喹啉 234 200825054 MS (ES) m/z 665.0 ° 範例371 6-氟基-2, 3-二氩-苯并[b]噻吩1，1-二氧化物 將含有1-(溴曱基）-4-氟基-2-（甲磺醯基）苯（〇· 25G 5 g，0· 94 mmol)和氫化鈉（0· 042 g，1. 1 mmol)於 DMF (1〇 mL) 中之一混合物在20 °C攪拌6小時。將該反應倒進水中並 以乙酸乙酯萃取。該萃取物先以食鹽水然後MgS〇4乾燥’過 濾，並減壓濃縮。濃縮該經化合的有機相並將該殘餘物經 1:9乙酸乙酯：己烷之色層分析以產生如一白色固狀物之該 1〇 標題化合物（0. 090 g，52%)。mp 119-121 X。C8H?F〇2S 之 計算質量為186.21;實測值&lt;^8，[肘+11] + )，186.9° 範例372 4-{3-[(1，1-二氧離子基-2, 3-二氫-1-苯并嘆吩-6-基) 15氧基]苯基}-8-(三氟甲基）喹啉 將3-[8-（三氟甲基4-喹啉基]-酚（0.070 g，0.244 mmol)、6-氟基-2, 3-二氫-苯并[b]噻吩1，1-二氧化物（0.091 g，〇· 488 mmol)和 K2CO3 (0· 070 g，〇· 488 mmol)於 DMF(5 mL) 中化合並在150 °C加熱2天。冷卻該反應，過濾並透過HPLC純 20 化以產生如一白色泡沫固狀物之該標題化合物（0.040 g，36%)。 即161 -163 °C ; CmHWNOsS之計算質量為455. 47 ;實測值（ES， [M+HJ+), 455.7. 235 200825054 範例373 3-[3-苄基-8-(三氟甲基）-4-喹啉基]-N-(2-羥基丙 基）苯甲醢胺 將含有3-(3-苄基-8-三氟甲基--4-喹啉基）-苯甲酸 5 (0· 102 g，0· 249 mmol)、2-胺基-1-丙醇（0.093 g，1.2 mmol)、EDC 1(0. 238 g，1. 23 mmol)、和 4-二甲基胺基σ比口定 (0. 083 g，0· 49 mmol)之一經攪拌的混合物於乙腈（70 mL) 中迴流下加熱3小時。冷卻該反應，過濾並減壓濃縮。濃 縮該經化合的有機相，並將該殘餘物經1:8乙酸乙酯：己烷 10 之色層分析以產生如一清澈黏狀固狀物之該標題化合物 (0.021 g，18%)。C27H23F3〇2N2 之計算質量為 464. 49 ;實測 值（ES，[M+H] + )，465.2。 範例374至375Example 368 3-Benzyl-4-(3-{[4-p-pyrrolidin-1-ylsulfonyl)phenyl]acetylene-5-yl}phenyl)-8-(trimethylmethyl)indene MS ( ES) /Z7/Z 597. 0. Example 369 3-block base-4-(3-{[3-(Bilo bit _1_ yl) phenyl] 乙快 ίο }}phenyl)-8-(三气曱基)啥琳MS (ES) 597. 0. Example 370 3-mercapto-4-(3-{[3-(咐*-bito-1-yl-behenyl)-5-(trifluoromethyl15-yl)phenyl]ethynyl}phenyl)-8 -(trifluoromethyl)quinoline 234 200825054 MS (ES) m/z 665.0 ° Example 371 6-Fluoro-2, 3-diar-benzo[b]thiophene 1,1-dioxide will contain 1 -(Bromofluorenyl)-4-fluoro-2-(methylsulfonyl)benzene (〇·25G 5 g, 0·94 mmol) and sodium hydride (0.42 g, 1.1 mmol) in DMF ( One of the mixtures of 1 〇 mL) was stirred at 20 ° C for 6 hours. The reaction was poured into water and extracted with ethyl acetate. The extract was first filtered through brine and then dried over MgSO 4 and concentrated under reduced pressure. The combined organic phase was concentrated and the residue was crystalljjjjjjjjjjjjj Mp 119-121 X. The calculated mass of C8H?F〇2S is 186.21; the measured value is &lt;^8, [elbow+11] + ), 186.9° Example 372 4-{3-[(1,1-dioxoisyl-2, 3- Dihydro-1-benzoindole-6-yl)15-oxy]phenyl}-8-(trifluoromethyl)quinoline 3-[8-(trifluoromethyl-4-quinolinyl)- Phenol (0.070 g, 0.244 mmol), 6-fluoro-2,3-dihydro-benzo[b]thiophene 1,1-dioxide (0.091 g, 〇·488 mmol) and K2CO3 (0· 070 g) The title compound (0.040 g, </RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 36%), ie 161 - 163 °C; calculated mass of CmHWNOsS is 455. 47; measured value (ES, [M+HJ+), 455.7. 235 200825054 Example 373 3-[3-benzyl-8-(trifluoro Methyl)-4-quinolinyl]-N-(2-hydroxypropyl)benzamide will contain 3-(3-benzyl-8-trifluoromethyl--4-quinolinyl)-benzene Formic acid 5 (0·102 g, 0·249 mmol), 2-amino-1-propanol (0.093 g, 1.2 mmol), EDC 1 (0. 238 g, 1.23 mmol), and 4-dimethyl One of the amino group σ ratio (0. 083 g, 0·49 mmol) of the stirred mixture in B (70 mL) was heated under reflux for 3 hours. The reaction was cooled, filtered and concentrated under reduced vacuum. The organic phase was concentrated and the residue was purified The title compound (0.021 g, 18%) was obtained as a viscous solid. The calculated mass of C27H23F3 〇2N2 was 464.49; found (ES, [M+H] + ), 465.2. Examples 374 to 375

以範例373所述之相似方法，使用適當的胺基醇和喹 啉製備下列化合物。 範例374 3-[3-节基-8-（三氟甲基）-4-啥琳基卜N-(2-幾基-2- 236 200825054 苯基乙基）苯甲醢胺 mp 95-97 ； MS (ES) m/z 525.2 ° 範例375 3-{3-[3-苄基-8_(三氟甲基）-4-喹啉基]苯氧 基丨-N -（3-羥基丙基）苯甲醢胺 mp 122-1247 ; MS (ES) Λ//Ζ 556.8。 範例376 3-节基-4-{3-[3-(5- 甲基-4, 5-二氩-1, 3-嗔峻-2-基） 10 苯氧基]苯基}-8-(三氟甲基）喹啉 將3-(3-节基-8-(三氟甲基)-4-喹啉基)-N-(2-羥基乙基） 苯甲醯胺（0.100 g，〇· 179 mmol)和柏傑士試劑（Burgess Reagent)(0. 086 g，〇· 359 mmol)置入 THF(5 mL)中並在 75 °C 加 熱2小時。冷卻該反應，過濾並在減壓下移除該溶劑。該殘餘物 15 經以1:9乙酸乙酯：己烷之色層分析純化，以產生如一清澈黏性 固狀物之該標題化合物（0· 070 g，71%)。C33H27F3N2〇3之計算質量為 538.56;實測值（ES，[M+H]〇，539.2。 範例377至381The following compounds were prepared in a similar manner as described in Example 373 using the appropriate amino alcohol and quinoline. Example 374 3-[3-Phenyl-8-(trifluoromethyl)-4-indolyl N-(2-yl-2-yl-2-250 200825054 phenylethyl)benzamide mp 95-97 MS (ES) m/z 525.2 ° Example 375 3-{3-[3-Benzyl-8-(trifluoromethyl)-4-quinolinyl]phenoxyindole-N-(3-hydroxypropyl) Benzoamide mp 122-1247; MS (ES) Λ//Ζ 556.8. Example 376 3-mercapto-4-{3-[3-(5-methyl-4,5-diar-ar-, 3-indolyl-2-yl) 10 phenoxy]phenyl}-8- (Trifluoromethyl)quinoline 3-(3-pyryl-8-(trifluoromethyl)-4-quinolinyl)-N-(2-hydroxyethyl)benzamide (0.100 g, 〇· 179 mmol) and Burgess Reagent (0.086 g, 359·359 mmol) were placed in THF (5 mL) and heated at 75 °C for 2 h. The reaction was cooled, filtered and the solvent was removed under reduced pressure. The residue 15 was purified by EtOAc EtOAc (EtOAc:EtOAc) The calculated mass of C33H27F3N2〇3 is 538.56; measured value (ES, [M+H]〇, 539.2. Examples 377 to 381

237 200825054 以範例376所述之相似方法，使用適當的哇琳製備下 列化合物。 範例377 5 3-苄基-4-{3-[3-(4, 5-二氩-1，3-噁唑-2-基）苯氧基]苯 基}-8-（三氟甲基)考琳 棕褐色漿液；MS (ES) λ//ζ 525. 2。 範例 378 1〇 3-苄基-4-{3-[3-(5-苯基-4, 5-二氩-1，3-嚼嗤-2-基） 苯氧基]苯基}-8-(三氟甲基）喹啉 mp 98-100 °C ; MS (ES) 601· 2 〇 範例379 15 3-苄基-4-{3-[3-(4-甲基-4, 5-二氫-1，3-嚼嗤一2-基） 苯氧基]苯基三氟f基）啥琳 黃色黏性固狀物；MS (ES) Λ/// 539.2。 範例380 2〇 3-苄基-4-{3-[3-(4, 4-二甲基-4, 5-二氫-1，3-鳴唾 -2-基）苯氧基]苯基}-8-(三氟甲基）考琳 mp 65-67 °C ; MS (ES) /z//z 553.2。 範例381 238 200825054 3-苄基-4-{3-[3-(5, 6-二氩-4H-1, 3-噁嗪-2-基）苯 氧基]苯基}-8-(三氟甲基）喹淋 棕褐色漿液；MS (ES) 539。 ) 範例382 3-苄基-4-{3-[3-(4,5-二氩-1H-咪唑_2-基）苯氧基] 苯基卜8-（三氟甲基）喹啉 將含有3-(3-(3-苄基-8-(三氟曱基)-4-喹啉基)苯氧基)苯 甲酸甲醋（G. IGOg，〇· 179_〇、乙二胺(〇._g，〇·97_ι)、 1〇和2·0 Μ三甲基鋁之甲苯(〇·49 ml，.97 mmol)置入甲苯(3 mL) 中，並在迴流加熱1· 5小時。冷卻該反應，將其倒進2 N HC1中 並以二氯甲烧萃取。以食鹽水沖洗該有機層，以MgS〇4乾燥，過 慮，並在減壓下移除該溶劑。該殘餘物經以U乙酸乙酯：己烧 之色層分析純化，以產生如一白色固狀物之該標題化合物（〇· 〇81 15 g，81%)。mp 110—112 °c ; C32H24F3N3〇 之計算質量為 523. 56 ;實 測值（ES，[M+H]+)，524_2。 383 5 387237 200825054 In a similar manner as described in Example 376, the following compounds were prepared using the appropriate wahlin. Example 377 5 3-Benzyl-4-{3-[3-(4,5-diar-1,3-oxazol-2-yl)phenoxy]phenyl}-8-(trifluoromethyl ) Colin Brown's slurry; MS (ES) λ//ζ 525. 2. Example 378 1〇3-Benzyl-4-{3-[3-(5-phenyl-4,5-di-argon-1,3-chin-2-yl)phenoxy]phenyl}-8 -(trifluoromethyl)quinoline mp 98-100 °C; MS (ES) 601· 2 〇 Example 379 15 3-benzyl-4-{3-[3-(4-methyl-4, 5- Dihydro-1,3-glycidyl-2-yl)phenoxy]phenyltrifluorof-yl)anthracene yellow viscous solid; MS (ES) Λ/// 539.2. Example 380 2〇3-Benzyl-4-{3-[3-(4,4-dimethyl-4,5-dihydro-1,3-octanth-2-yl)phenoxy]phenyl }-8-(Trifluoromethyl)Cauline mp 65-67 °C; MS (ES) /z//z 553.2. Example 381 238 200825054 3-Benzyl-4-{3-[3-(5, 6-diarth-4H-1, 3-oxazin-2-yl)phenoxy]phenyl}-8-(III Fluoromethyl) quinine tan slurry; MS (ES) 539. Example 382 3-Benzyl-4-{3-[3-(4,5-diar-argon-1H-imidazol-2-yl)phenoxy]phenyl b- 8-(trifluoromethyl)quinoline Contains 3-(3-(3-benzyl-8-(trifluoromethyl)-4-quinolinyl)phenoxy)benzoic acid methyl vinegar (G. IGOg, 〇·179_〇, ethylenediamine ( 〇._g, 〇·97_ι), 1 〇 and 2·0 Μ trimethylaluminum toluene (〇·49 ml, .97 mmol) were placed in toluene (3 mL) and heated at reflux for 1.5 hours. The reaction was cooled, poured into 2 N HCl and extracted with methylene chloride. The organic layer was washed with brine, dried over MgSO.sub. The title compound ( 〇· 〇 81 15 g, 81%) was obtained as a white solid. mp 110-112 ° C; C32H24F3N3 〇 523. 56 ; measured value (ES, [M+H]+), 524_2. 383 5 387

r2R2

239 200825054 以範例382所述之相似方法，使用適當的喹啉和二胺製備 下列化合物。 範例383 5 4-{3-[3-(1Η-苯并味嗅-2-基）苯氧基]苯基}-3-节基 - 8-(三氟曱基）喹啉 mp 65-67 °C ; MS (ES) 7Z//Z 572.2。 範例384 ίο 3-苄基-4-{3-[3-(4-甲基-4,5-二氩-111-咪唑-2-基） 苯氧基]苯基}-8-(三氟甲基）喹啉 黃色黏稠固狀物；MS (ES) zzz/z 537. 9。 範例385 15 3-苄基-4 - {3-[3-（1-甲基-4,5-二氫-111-咪唑-2-基） 苯氧基]苯基}-8-（三氟甲基）啥琳 淡黃色黏稠固狀物；MS (ES) y/7/z 537. 9。 範例386 2〇 3-苄基-4-{3-[3-(1, 4, 5, 6-四氩嘧啶-2-基）苯氧基] 苯基}-8-（三氟甲基）啥琳 淡黃色黏稠固狀物；MS (ES) 7Z7/Z 537. 8。 範例387 240 200825054 3一苄基-4-{3-[3-(1-甲基-1，4, 5, 6-四氩鳴咬-2-基） 苯氧基]苯基}-8-（三氟甲基）啥琳 mp 137-139 0C ; MS (ES) y»/z 552。 5 範例388 3-苄基-4-[3-(3-甲基-1，2,4-噁二唑-5-基）苯基]-8-(三 氟甲基)啥琳 將含有3-(3-苄基-8-三氟甲基—一4-喹啉基)一苯甲酸甲酯 (0.100 g ’ 0· 237 mmol)、Ν’ -經基乙亞二醯胺(〇· 〇〇9〇 g，〇. 119 10 mm〇1)、和 60% 氫化鈉之油（7· 〇 呢，〇· 131 mmol)置入 THF(3 mL) 中並在迴流城整夜。冷卻該反應，將其倒進水中独乙酸乙醋 萃取。以食鹽水和Mgsa麵财顧，赠，並在減壓下移除 该溶劑。將該殘餘物放入石夕膠磁盤，以Bi〇tage H〇riz〇n在己烧 s:乙酸乙自旨（9:1)中經色層分析，以產生如—棕褐色黏性固狀物 15之0· 038 g (71%)的嚼二唾心说刪之計算質量為秘·化實 測值（ES，[M+H]+)，445. 8。 範例 389-391239 200825054 The following compounds were prepared in a similar manner as described in Example 382 using the appropriate quinoline and diamine. Example 383 5 4-{3-[3-(1Η-Benzo- ol-2-yl)phenoxy]phenyl}-3-pyringyl-8-(trifluoromethyl)quinoline mp 65-67 °C; MS (ES) 7Z//Z 572.2. Example 384 ίο 3-Benzyl-4-{3-[3-(4-methyl-4,5-di-argon-111-imidazol-2-yl)phenoxy]phenyl}-8-(trifluoro Methyl)quinoline yellow viscous solid; MS (ES) zzz/z 537. 9. Example 385 15 3-Benzyl-4 - {3-[3-(1-methyl-4,5-dihydro-111-imidazol-2-yl)phenoxy]phenyl}-8-(trifluoro Methyl) 啥 淡 pale yellow viscous solid; MS (ES) y/7/z 537. 9. Example 386 2〇3-Benzyl-4-{3-[3-(1, 4, 5, 6-tetrahydropyrimidin-2-yl)phenoxy]phenyl}-8-(trifluoromethyl)啥琳 pale yellow viscous solid; MS (ES) 7Z7/Z 537. 8. Example 387 240 200825054 3-Benzyl-4-{3-[3-(1-methyl-1,4,5,6-tetraarthrene-2-yl)phenoxy]phenyl}-8- (Trifluoromethyl) 啥 mp mp 137-139 0C ; MS (ES) y»/z 552. 5 Example 388 3-Benzyl-4-[3-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]-8-(trifluoromethyl)indole will contain 3 -(3-Benzyl-8-trifluoromethyl-mono-4-quinolinyl)-benzoic acid methyl ester (0.100 g '0·237 mmol), Ν'- thioglyoxime (〇·〇 〇9〇g, 〇 119 10 mm 〇 1), and 60% sodium hydride oil (7·〇, 〇·131 mmol) were placed in THF (3 mL) and refluxed overnight. The reaction was cooled and poured into water to separate ethyl acetate. Take the salt water and Mgsa face, donate, and remove the solvent under reduced pressure. The residue was placed in a Shishijiao disk and chromatographed with Bi〇tage H〇riz〇n in hexane: acetic acid B (9:1) to produce, for example, a tan-colored viscous solid. 0. 038 g (71%) of the material 15 is chewed and said that the calculated quality is the secret measured value (ES, [M+H]+), 44. 8. Example 389-391

241 200825054 以範例388中所述之相似方法，使用適當的喹啉和胺基-肟 製備下列化合物。 [例 389 5 3-苄基-4-{3-[3-(4-氟苯基）-1，2, 4-嗔二嗅-5-基] 苯基}-8-（三氟甲基）喹啉 mp 111-113 °C ; MS (ES) /»// 525. 8。 1 例 390 10 2-(5-{3-[3-苄基-8-(三氟甲基）-4-喹啉基]苯 基}-1,2,4-噁二唑-3-基）乙醢胺 mp 91-93 °C ; MS (ES) /Z7/Z 489。 範例391 15 3-节基-4_[3-(3-苯基-1，2, 4-嚼二攻-5-基）苯 基]-8-（三氟甲基）喹啉 清澈黏狀漿液；MS (ES) zb/z 508· 0。 蔽例392 (2-胺基淡基苯基)(3-輕基苯基）甲8¾ 氮氣下將冷卻至〇°C之含有1 M BCL·於對-二甲苯中（39· 〇 虬，39· 0 mmol)之1-氯苯(50 mL)的攪拌溶液中加入含有2-溴苯 胺（10· 32 g，60_ 0 mmol)之氯苯(50 mL)超過5分鐘。添加入額 外的氯苯(50 mL)，10分鐘之後，加入3-曱氧基苯甲腈(3. 66 mL， 242 200825054 30· 0 mmol)和 AlCh (5_ 21 g，39· 0 mmol)，然後將該反應在 90 °C加熱3小時，在130 °C加熱20小時。冷卻該反應，加入冰(50 g)和2M鹽酸(50 mL)並將該反應在70-8〇 X加熱〇_ 5至1小時。 冷卻後，以水(50 mL)稀釋該反應並以二氣甲烷（1〇〇虬，5〇 mL) • 5萃取。透過MSS〇4乾燥該經化合的萃取物並減壓濃縮。使用梯度 10/90至50/50之乙酸乙酯/己烷將該殘餘物經色層分析，以產生 如一黃色固狀物之該標題化合物（3.1〇 g)。 範例393 1〇 3-(8-溴基-3-甲基-4-喹啉基）酚 在含有（2-胺基-3-溴基苯基）（3-羥基苯基）曱酮 (3.06 g，1〇·〇 mm〇l)和丙醛二乙基乙縮醛（4.9〇 ^，3〇 mmol)於乙酸（30 mL)中之一經攪拌的溶液中加入濃硫酸（2〇 滴移液管量，約〇· 5 mL)並在11〇 X加熱24小時。冷卻該 15反應’減壓濃縮以移除大部分的乙酸。加入飽和的 NaHOMlOO mL)至該殘餘物並以二氣甲烷（2 χ 1〇〇 mL)萃 取。透過MgS〇4乾燥該萃取物並減壓濃縮。經梯度1〇:9〇 至30:70之乙酸乙酯：己烷洗提之色層分析後產生如一黃色 固狀物之該標題化合物（1· 90 g)。 MS (ES) 7Z//Z 314. 0 ; 20 HRMS:計算值 C16Hi2BrN0 + H+，314. 01750 ;實測值（ESI， [Μ+ΗΓ)，314. 0174。 範例394 8-溴基-3 -甲基-4 - {3 - [3-（甲基磺醢基）苯氧基]苯基} 喹啉 243 200825054 基本上使用與範例43中所述之相同方法製備該化合 物，但起始物質為3-(8-溴基-3-甲基-4-喹啉基）酚。MS (ES) λ//ζ 468· 0 ; HRMS:計算值 C23H18BrN〇3S + H+，468. 02635 ; 實測值（ESI, [M+H]+)，468· 025。 5 範例395 3-甲基-8-（甲基磺醢基）-4-{3-[3-(甲基磺醢基）苯 氧基]苯基}喹啉 基本上使用與範例43中所述之相同方法製備該化合 物’但起始物質為臭基-甲基_4-{3_[3_(甲基石黃酿基） 1〇 苯氧基]苯基}喹啉。HRMS··計算值C24H21N〇5S2 + H+， 468.09339;實測值（ESI, [M+H]+)，468.0928。 範例396 3-甲基-4-{3 - [3-（甲基磺醢基）苯氧基]苯基}喹啉 將含有8-溴基-3-曱基-4-{3-[3-(甲基磺醯基）苯氧 15 基]苯基}哇琳（230 mg，0· 50 mmol)、蟻酸銨（252 mg，2. 00 ramol)、和10%碳上鈀（5〇呃）於甲醇（1〇111〇中之一混合物 在60 °C加熱3小時。冷卻該反應，過濾，然後減壓濃縮 成一固體。加入飽和的NaHCOs水溶液（10 mL)至該殘餘物， 以二氯甲烷（2 X 10 mL)萃取，並將該萃取物減壓濃縮。該 20 殘餘物經色層分析，以一梯度50/50至100/0之乙酸乙酯/ 己烷洗提，以產生如一淡黃色固狀物之該標題化合物（152 mg，80%)。HRMS:計算值 C23H19N〇3S + H+，390.11584;實 測值（ESI，[Μ+ΗΓ)，390· 1176。 244 397 397200825054 以範例1-396中之一例或多例所述的相似方法製備下 列化合物。 5 A. 4- [3，-(乙基磺醯基）-甲基聯苯-3-基]-3-甲 基三氟甲基）啥琳 MS (ES) m/z 470.2 ； ίο Β· 4 - {3-[3-氣基-5-(甲基磺醢基）苯氧基]苯 基}-8_(三氟甲基）喹啉-3-甲腈 MS (ES) m/z 503.1 ； C. 8-氣基-4-{3-[3-(甲基續斑基）苯氧基]苯基}考 15 琳-3-甲猜 MS(ES)m/z 435. 1; HRMS:計算值 C23H15ClN2〇3S + H+， 435.05647;實測值（ESI，[M+H] + )，435.0553; D1. 4-{3-[3-（甲基續酸基）苯氧基]苯基}啥琳-3- 20 甲醢胺 MS (ES) m/z 419. 1 ; HRMS:計算值 C23H18N2〇4S + H+， 419.10600;實測值（ESI，[M+H] + )，419.1044; D2· 4-[4’ -溴基-3’ -（甲基磺醢基）聯苯-3- 245 200825054 基]-8-(三氟甲基）喹啉 MS (ES) m/z 506.0 ； Ε· 4-[4,-溴基-3’ -(乙基磺醢基）聯苯-3-5 基]-8-(三氟甲基）啥琳 MS (ES) m/z 520.0 ； F. 4-[2’，5’ -二氟基-4’ -(甲基磺醯基）聯苯-3- 基]-8-（三氟甲基）啥琳 10 MS (ES) m/z 464.1 ； G. 4-[4,-(乙基續醯基）-2’，5’ -二氟基聯苯-3-基]-8_(三氟甲基）喹啉 MS (ES) m/z 478.1 ； 15 Η· 4-[2’，4’ -二氟基-5’ -(甲基磺醢基）聯苯一3一 基]-8-(三氣甲基）啥琳 MS (ES) ra/z 464.1 ； 20 I · 4-[ 5’ -(乙基磺酿基）-2,，4, -二氟基聯苯一3一 基]_8-（三氟甲基）啥琳 MS (ES) m/z 478. 1 ； J_ 2-甲基-4-[(3-{3-[8-（三氟甲基）一4一唉琳基]苯 246 200825054 氧基}苯基）磺醢基]-2-丁酵 mp 77-79 °C ； MS (ES) m/z 516.2 ； K. 4-{3-[4-(甲基磺醯基）苯氧基]苯基}_8-（三氟 5 甲基）喹啉-3-甲醢胺 MS (ES) m/z 487.1 ； L. 4_{3_[2-氟基-4-(甲基續斑基）苯氧基]苯 基}-8-（三氟甲基）喹啉-3-甲醢胺 ίο MS (ES) m/z 505.0 ； Μ. 4-{3 - [4-氣基-3-(甲基續酸基）苯氧基]苯 基}-8_(三氟甲基）啥琳 mp 100-102 °C ; MS (ES) m/z 478.0 ; HRMS:計算 15 值 C23H15ClF3N〇3S + H+，478.04860;實測值（ESI, [M+H] + )， 478.0479 ； N. 4-[4’ -淡基-3’ -（乙基確斑基）聯苯-3-基]-3-甲 基_8_(三氟甲基）啥琳 20 MS (ES) m/z 533.9 ； 0· 4- [ 2’，5’ -二氟基-4’ -(甲基磺醢基）聯苯-3- 基]-3-甲基-8-(三氟甲基）啥琳 MS (ES) m/z 478.0 ； 247 200825054 Ρ· 4- [ 4’ -(乙基磺醢基）-2’，5’ -二氟基聯苯-3- 基]-3-甲基-8-(三氟甲基）喹啉 MS (ES) m/z 492.0 ； 5 Q· 4 - [2’，4’-二氟基-5’-(甲基磺醢基）聯苯-3- 基]-3-甲基-8-(三氟甲基）啥琳 MS (ES) m/z 478. 0 ； i〇 R. 4-[5’ -（乙基磺醢基）-2’，4’ -二氟基聯苯-3- 基]-3-甲基-8-（三氟甲基）喧琳 MS (ES) m/z 492.0 ； S· 4-{3_[3-氟基-5-（甲基確酸基）苯氧基]苯 15 基}-8-(三氟甲基）嗟琳-3 -甲斑胺 MS (ES) m/z 505.0 ； Τ· 4-{3-[ 3-氣基-5-(甲基確斑基）苯氧基]苯 基}-8-（三氟甲基）喹啉-3-甲醢胺 2〇 MS (ES) m/z 521.0 ； U· 3-甲基-4-{3-[3-（甲基確斑基）苯氧基]苯基}啥 啉-8-甲腈 MS (ES) m/z 415. 1 ; HRMS:計算值 C24H18N2〇3S + H+， 248 200825054 415.11109;實測值（ESI，[M+H] + )，415.1110; V. 4-{3-[3-(異丙基磺醯基）苯氧基]苯基}-8-(三 氟甲基）喹啉-3-甲醢胺 . 5 MS (ES) m/z 515.1 ； W. 4-[3’ -（甲基確斑基）聯苯-3-基]-8-(三氟甲基） 邊琳-3-幾酸 ： MS (ES) m/z 472.0 ； ίο X. 4-[3’ -（曱基續酸基）聯苯-3-基]-8-(三氟甲基） 喹啉-3-羧酸乙酯 MS (ES) m/z 500.0 ； 15 Y. 4-[3’ -(甲基確酿基）聯苯-3-基]-8-（三氟甲基） 喹啉-3-甲醯胺 / v MS (ES) m/z 471.0 ； Z. 4-{3-[3-(丙基磺醢基）苯氧基]苯基}-8-(三氟 20 甲基）喹啉-3-甲醢胺 MS (ES) m/z 515.0 ； AA. 4-[4’ -溴基-3’ -(甲基磺醯基）聯苯-3-基]-3-甲基-8 -（三氟甲基）喹啉 249 200825054 MS (ES) m/z 520.0 ; AB. 4-[3’-（異丙基磺醯基）聯苯-3-基]-8-(三氟甲 基）喹啉-3-甲腈 5 MS (ES) m/z 481. 1 ； HRMS:計算值 C26H19F3N2〇2S + H+， 481.11921;實測值（ESI-FTMS，[M+H]l + )，481.12001; AC. 8-氟基-4- {3 - [3-（甲基磺醢基）苯氧基]苯基} 喹啉-3-羧酸乙酯 10 MS (ES) m/z 466. 1 ； HRMS:計算值 C25H2〇FN〇5S + H+, 466.11190;實測值（ESI-FTMS，[M+H]l + )，466.11303; AD. 8_氟基-4-{3-[3-(甲基磺醢基）苯氧基]苯基} 啥琳-3-甲雄膝 15 MS (ES) m/z 437. 0 ； HRMS:計算值 C23HnFN2〇4S + H+， 437.09658;實測值（ESI-FTMS，[M+H]l + )，437; AE. 8-氣基-4-{3-[3-(甲基磺醢基）苯氧基]苯基} 喹啉 20 mp 117-119 °C ； MS (ES) m/z 410.0 ； AF. 4-[4’ -甲氧基-3’ -（甲基磺醢基）聯苯-3-基]-3-甲基-8-(三氟甲基）唉琳 MS (ES) m/z 472.1 ； 250 200825054 AG. 4-[4’ -甲氧基-3’ -（甲基續酿基）聯苯-3-基]-8-（三氟甲基）喹啉 MS (ES) ra/z 458.1 ； 5 AH. 3-（{4-甲基-3’ -[3-甲基-8-(三氟甲基）-4-喹 琳基]聯苯-3-基}續酿基）-1-丙酵 MS (ES) ra/z 500.2 ； ίο AI. 3-（{4_甲基-3’-[8-（三氟甲基）-4-喹啉基]聯 苯-3-基}磺醢基）-1-丙酵 MS (ES) ra/z 486.1 ； AJ. 8-氯基-4-{3-[3-（甲基碟酸基）苯氧基]苯基} 15 喹啉-3-甲醯胺 MS(ES)m/z 453.0; HRMS:計算值 C23HnClN2〇4S-H+， 451.05248;實測值（ESI, [M-H]-)，451.0526; AK. 8-氯基-4-{3-[3-(甲基磺醯基）苯氧基]苯基} 20 喹啉-3-羧酸 MS (ES) m/z 454. 1 ； HRMS:計算值 C23H16ClN〇5S + H+， 454.05105;實測值（ESI, [M+H] + )，454.0517; AL. 3-({4-氱基-3’ -[3-甲基-8-(三氟甲基）-4-喹 251 200825054 啉基]聯苯-3-基}磺醢基Μ-丙酵 MS (ES) ra/z 520.1 ； AM. 4-{3-[3-(已基續酸基）苯氧基]苯基}-8-（三氟 5 甲基）喹啉-3-甲醢胺 MS (ES) m/z 501.1 ； AN. 4-[3’ -（乙基續酿基）聯苯-3-基]_8_(三氟甲基） 考琳-3-甲酿胺 10 MS (ES) m/z 484.9 ； AO. 3-（{4-淡基-3’ -[8-(三象甲基）-4-唉琳基]聯 苯-3-基}碟斑基）-1-丙酵 MS (ES) m/z 550.0 ； 15 AP. 4-{3’ -[(二甲基胺基）磺醢基]聯苯一3-基}-8-(三氟甲基）喹啉-3-甲醢胺 MS (ES) m/z 499.9 ； 2〇 AQ· 8-氯基-4-{3-[3-(乙基磺醢基）苯氧基]苯基} 喹啉 MS (ES) m/z 423. 9 ； HRMS:計算值 C23H18ClN〇3S + H+， 424.07687;實測值（ESI，[M+H] + )，424.0772; 252 200825054 AR. 8-氣基-4-{3-[3-(丙基磺醢基）苯氧基]笨基} 喹啉 MS (ES) m/z 437· 9 ; HRMS:計算值 C24H2QClN〇3S + H+， ， 438. 09252 ;實測值（ESI, [M+H] + )，438· 0933 ; ， 5 AS. 3-({4-氣基-3’ -[8-(三氟甲基）-4-喹啉基]聯 苯-3-基}磺醯基）-1-丙酵 MS (ES) m/z 505.8 ； r \ i〇 AT. 4-[3’ -(異丙基續酸基）聯苯-3-基]-8-(三氟甲 基）喹啉 MS (ES) m/z 455.9 ； AU. 8-氣基-4-{3-[3-(異丙基磺醢基）苯氧基]苯基} 15 喹啉 MS (ES) m/z 437.9 ； / 、 HRMS:計算值 C24H2QClN〇3S + H+，438. 09252 ;實測 • 值（ESI, [M+H]+)， 438.0935 ; 20 AV. 4-[3’ -（胺基續酸基）聯苯-3-基]-8-(三氟甲基） 喹啉-3-甲醢胺 MS (ES) m/z 471.9 ； AW. 2-甲基-4-（{3’ -[8-（三氟甲基）一4-喹啉基]聯 253 200825054 苯-3-基}確酸基）-2-丁醇 MS (ES) m/z 499.9 ； ΑΧ. 2-甲基-4-（{3, -[3-甲基-8-（三氟甲基）-4-喹 5 琳基]聯苯-3-基}續酸基）-2-丁酵 MS (ES) m/z 513.9 ； AY. 8-II基-4-{3-[3-(甲基橫酿基）苯氧基]苯基} 喹啉-3-甲醢胺 10 HRMS··計算值 C24HnN3〇4S + H+，444. 10125 ;實測值 (ESI, [M+H] + ), 444.101； ΑΖ· 4-(3-{3-[(二甲基胺基）磺醢基]苯氧基}苯 基）-8-（三氟甲基）喹啉-3-甲醢胺 15 MS (ES) m/z 515. 9 ;以及 AAA. 4-{2-氯基-5-[3-(甲基碟酸基）苯氧基]苯 基}-8-(三氟甲基）考琳 MS (ES) m/z 478· 0。 20 範例398 流程圖32 254 200825054241 200825054 The following compounds were prepared in a similar manner as described in Example 388 using the appropriate quinoline and amine-oxime. [Example 389 5 3-benzyl-4-{3-[3-(4-fluorophenyl)-1,2,4-fluoren-5-yl]phenyl}-8-(trifluoromethyl Quinoline mp 111-113 ° C; MS (ES) /»// 525. 8. 1 390 10 2-(5-{3-[3-benzyl-8-(trifluoromethyl)-4-quinolinyl]phenyl}-1,2,4-oxadiazol-3-yl Ethylamine mp 91-93 ° C; MS (ES) / Z7/Z 489. Example 391 15 3-Block-4_[3-(3-Phenyl-1,2,4-Chesin-5-yl)phenyl]-8-(trifluoromethyl)quinoline clear viscous slurry ;MS (ES) zb/z 508· 0. Example 392 (2-Amino-p-phenyl) (3-light-phenyl)methyl 83⁄4 under nitrogen to be cooled to 〇 ° C containing 1 M BCL · in p-xylene (39 · 〇虬, 39 · 0 mmol) of 1-chlorobenzene (50 mL) was added to a stirred solution of 2-bromoaniline (10·32 g, 60_0 mmol) in chlorobenzene (50 mL) over 5 min. Additional chlorobenzene (50 mL) was added and after 10 minutes, 3-methoxybenzonitrile (3. 66 mL, 242 200825054 30·0 mmol) and AlCh (5_21 g, 39·0 mmol) were added. The reaction was then heated at 90 °C for 3 hours and at 130 °C for 20 hours. The reaction was cooled, ice (50 g) and 2M hydrochloric acid (50 mL) were then weighed and the reaction was heated at 70-8 Torr for 5 to 1 hour. After cooling, the reaction was diluted with water (50 mL) and extracted with di-methane (1 EtOAc, EtOAc). The combined extract was dried by MSS(R) 4 and concentrated under reduced pressure. The residue was chromatographed using EtOAc (EtOAc:EtOAc) Example 393 1〇3-(8-Bromo-3-methyl-4-quinolinyl)phenol containing (2-amino-3-bromophenyl)(3-hydroxyphenyl)fluorenone (3.06 G,1〇·〇mm〇l) and propionaldehyde diethyl acetal (4.9〇^, 3〇mmol) in a solution of one of acetic acid (30 mL), concentrated sulfuric acid (2〇 pipetting solution) Tube volume, approx. 5 mL) and heated at 11 〇X for 24 hours. The 15 reaction was cooled to concentration under reduced pressure to remove most of the acetic acid. Saturated NaHOM 100 mL) was added to the residue and extracted with di-methane (2 χ 1 〇〇 mL). The extract was dried through MgS 4 and concentrated under reduced pressure. The title compound (1·90 g) was obtained as a yellow solid from EtOAc: EtOAc: EtOAc: MS (ES) 7Z//Z 314. 0; 20 HRMS: calcd., calcd. Example 394 8-bromo-3-methyl-4 - {3- [3-(methylsulfonyl)phenoxy]phenyl}quinoline 243 200825054 Basically the same procedure as described in Example 43 was used. This compound was prepared, but the starting material was 3-(8-bromo-3-methyl-4-quinolinyl)phenol. MS (ES) λ / / ζ 468·0; HRMS: calcd. calcd., calcd, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s. 5 Example 395 3-Methyl-8-(methylsulfonyl)-4-{3-[3-(methylsulfonyl)phenoxy]phenyl}quinoline was used essentially as in Example 43. The compound was prepared in the same manner as described above but the starting material was a odor-methyl-4-{3_[3_(methyl scutane) 1 phenoxy]phenyl}quinoline. HRMS··························· Example 396 3-Methyl-4-{3-[3-(methylsulfonyl)phenoxy]phenyl}quinoline will contain 8-bromo-3-indenyl-4-{3-[3 -(methylsulfonyl)phenoxy 15 yl]phenyl}wowlin (230 mg, 0·50 mmol), ammonium formate (252 mg, 2. 00 ramol), and 10% palladium on carbon (5 〇呃The mixture was heated in a mixture of methanol (1 〇 111 3 at 60 ° C for 3 hours. The reaction was cooled, filtered, and then concentrated under reduced pressure to a solid. A saturated aqueous NaHCOs solution (10 mL) was added to the residue to dichloro The methane (2 X 10 mL) was extracted, and the extract was concentrated under reduced pressure. The residue was purified by chromatography, eluting with a gradient of 50/50 to 100/0 ethyl acetate / hexane to yield The title compound (152 mg, 80%), mp.: calcd, calcd, calcd, calcd, calcd, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, The following compounds were prepared in a similar manner as described in one or more of -396. 5 A. 4- [3,-(ethylsulfonyl)-methylbiphenyl-3-yl]-3-methyltrifluoro Methyl)啥琳 MS (ES) m/z 470.2 ; ίο Β· 4 - {3-[3-气基-5-(甲Sulfhydryl)phenoxy]phenyl}-8-(trifluoromethyl)quinoline-3-carbonitrile MS (ES) m/z 503.1 ; C. 8-carbyl-4-{3-[3- (methyl succinyl) phenoxy] phenyl} test 15 lin-3-a guess MS (ES) m / z 435. 1; HRMS: calculated C23H15ClN2 〇 3S + H +, 435.05647; measured value (ESI, [M+H] + ), 435.0553; D1. 4-{3-[3-(Methylsulfonyl)phenoxy]phenyl}indole-3- 20 formamide MS (ES) m/z 419. 1 ; HRMS: calculated C23H18N2 〇 4S + H+, 419.10600; found (ESI, [M+H] + ), 419.1044; D2· 4-[4'-bromo-3'-(methylsulfonate Biphenyl-3- 245 200825054 benzyl]-8-(trifluoromethyl)quinoline MS (ES) m/z 506.0; Ε·4-[4,-bromo-3'-(ethylsulfonate) Biphenyl-3-5-yl]-8-(trifluoromethyl)fluorene MS (ES) m/z 520.0 ; F. 4-[2',5'-difluoro-4'-(A Benzene sulfhydryl)biphenyl-3-yl]-8-(trifluoromethyl)anthracene 10 MS (ES) m/z 464.1 ; G. 4-[4,-(ethylthenyl)-2 ',5'-Difluorobiphenyl-3-yl]-8-(trifluoromethyl)quinoline MS (ES) m/z 478.1 ; 15 Η· 4-[2',4'-difluoro- 5'-(methylsulfonyl)biphenyl-3-yl]-8-(three Methyl) 啥琳 MS (ES) ra/z 464.1 ; 20 I · 4-[ 5' -(ethylsulfonic acid)-2,4,-difluorobiphenyl-3-yl]_8-( Trifluoromethyl) 啥 MS MS (ES) m/z 478. 1 ; J_ 2-methyl-4-[(3-{3-[8-(trifluoromethyl)- 4-indolyl]benzene 246 200825054 oxy}phenyl)sulfonyl]-2-butyric acid mp 77-79 °C; MS (ES) m/z 516.2; K. 4-{3-[4-(methylsulfonyl) Phenoxy]phenyl}_8-(trifluoro-5methyl)quinoline-3-carboxamide MS (ES) m/z 487.1 ; L. 4_{3_[2-fluoro-4-(methyl continued Phenyl)phenoxy]phenyl}-8-(trifluoromethyl)quinoline-3-carboxamide ίο MS (ES) m/z 505.0 ; Μ. 4-{3 - [4-carbyl- 3-(methylsudanyl)phenoxy]phenyl}-8-(trifluoromethyl)anthracene mp 100-102 °C; MS (ES) m/z 478.0; HRMS: Calculated 15 C23H15ClF3N〇3S + H+, 478.04860; found (ESI, [M+H]+), 478.0479; N. 4-[4' - succinyl-3'-(ethyl-decyl)biphenyl-3-yl]-3 -methyl_8_(trifluoromethyl)啥琳 20 MS (ES) m/z 533.9 ; 0· 4- [ 2',5'-difluoro-4'-(methylsulfonyl)biphenyl -3-yl]-3-methyl-8-(trifluoromethyl)啥琳 M S (ES) m/z 478.0 ; 247 200825054 Ρ· 4- [ 4' -(ethylsulfonyl)-2',5'-difluorobiphenyl-3-yl]-3-methyl-8 -(trifluoromethyl)quinoline MS (ES) m/z 492.0 ; 5 Q· 4 - [2',4'-difluoro-5'-(methylsulfonyl)biphenyl-3-yl ]-3-methyl-8-(trifluoromethyl)啥琳 MS (ES) m/z 478. 0 ; i〇R. 4-[5' -(ethylsulfonyl)-2',4 '-Difluorobiphenyl-3-yl]-3-methyl-8-(trifluoromethyl)fluorene MS (ES) m/z 492.0 ; S· 4-{3_[3-fluoro--5 -(Methyl-acidic acid)phenoxy]phenyl-15-yl}-8-(trifluoromethyl)indole-3-melamine MS (ES) m/z 505.0 ; Τ· 4-{3-[ 3-Alkyl-5-(methyl-behenyl)phenoxy]phenyl}-8-(trifluoromethyl)quinoline-3-carboxamide 2〇MS (ES) m/z 521.0 ; · 3-Methyl-4-{3-[3-(methyl- phenoxy)phenoxy]phenyl} porphyrin-8-carbonitrile MS (ES) m/z 415. 1 ; HRMS: Calculated C24H18N2〇3S + H+, 248 200825054 415.11109; found (ESI, [M+H] + ), 415.1110; V. 4-{3-[3-(isopropylsulfonyl)phenoxy]phenyl} 8-(-trifluoromethyl)quinoline-3-carboxamide. 5 MS (ES) m/z 515.1 ; W. 4-[3 -(Methyl-decyl)biphenyl-3-yl]-8-(trifluoromethyl) acenaphthyl-3-acid: MS (ES) m/z 472.0 ; ίο X. 4-[3' - Ethyl (biphenyl-3-yl)-8-(trifluoromethyl)quinoline-3-carboxylate MS (ES) m/z 500.0 ; 15 Y. 4-[3' - (Methyl-furanyl)biphenyl-3-yl]-8-(trifluoromethyl)quinoline-3-carboxamide / v MS (ES) m/z 471.0 ; Z. 4-{3-[ 3-(propylsulfonyl)phenoxy]phenyl}-8-(trifluoro20methyl)quinoline-3-carboxamide MS (ES) m/z 515.0 ; AA. 4-[4' -bromo-3'-(methylsulfonyl)biphenyl-3-yl]-3-methyl-8-(trifluoromethyl)quinoline 249 200825054 MS (ES) m/z 520.0 ; 4-[3'-(Isopropylsulfonyl)biphenyl-3-yl]-8-(trifluoromethyl)quinoline-3-carbonitrile 5 MS (ES) m/z 481. 1 ; : Calculated C26H19F3N2 〇2S + H+, 481.11921; found (ESI-FTMS, [M+H]l + ), 481.12001; AC. 8-fluoroyl-4-{3 - [3-(methylsulfonyl) Ethyl phenoxy]phenyl}quinoline-3-carboxylate 10 MS (ES) m/z 466. 1 ; HRMS: calcd for C25H2 〇FN 〇5S + H+, 466.11190; [M+H]l + ), 466.11303; AD. 8_Fluoro-4-{3-[3 -(methylsulfonyl)phenoxy]phenyl} 啥琳-3-甲雄 knee 15 MS (ES) m/z 437. 0 ; HRMS: Calculated C23HnFN2 〇4S + H+, 437.09658; ESI-FTMS, [M+H]l + ), 437; AE. 8-Alkyl-4-{3-[3-(methylsulfonyl)phenoxy]phenyl}quinoline 20 mp 117- 119 °C; MS (ES) m/z 410.0; AF. 4-[4'-methoxy-3'-(methylsulfonyl)biphenyl-3-yl]-3-methyl-8- (Trifluoromethyl) 唉 MS MS (ES) m/z 472.1 ; 250 200825054 AG. 4-[4'-Methoxy-3'-(methyl styrene)biphenyl-3-yl]-8 -(trifluoromethyl)quinoline MS (ES) ra/z 458.1 ; 5 AH. 3-({4-methyl-3'-[3-methyl-8-(trifluoromethyl)-4- Quinolinyl]biphenyl-3-yl}continuation)-1-propanyl MS (ES) ra/z 500.2 ; ίο AI. 3-({4_methyl-3'-[8-(trifluoro Methyl)-4-quinolinyl]biphenyl-3-yl}sulfonyl)-1-propanyl MS (ES) ra/z 486.1 ; AJ. 8-Chloro-4-{3-[3- (Methyl benzoate) phenoxy] phenyl} 15 quinolin-3-carboxamide MS (ES) m/z 453.0; HRMS: calcd for C.sup. MH]-), 451.0526; AK. 8-Chloro-4-{3-[3-(methylsulfonyl) Oxy]phenyl} 20 quinolin-3-carboxylic acid MS (ES) m/z 454. 1 ; HRMS: calcd. AL. 3-({4-mercapto-3'-[3-methyl-8-(trifluoromethyl)-4-quino 251 200825054 phenyl]]biphenyl-3-yl}sulfonyl hydrazine -Protease MS (ES) ra/z 520.1 ; AM. 4-{3-[3-(hexyl) phenoxy]phenyl}-8-(trifluoro-5methyl)quinoline-3 -Metformamide MS (ES) m/z 501.1 ; AN. 4-[3' -(ethyl succinyl)biphenyl-3-yl]_8_(trifluoromethyl)Calline-3-cartoamine 10 MS (ES) m/z 484.9 ; AO. 3-({4-Phenyl-3'-[8-(trimethylene)-4-indolyl]biphenyl-3-yl}disc )-1-propanyl MS (ES) m/z 550.0 ; 15 AP. 4-{3' -[(dimethylamino)sulfonyl]biphenyl-3-yl}-8-(trifluoromethyl) ))quinoline-3-carboxamide MS (ES) m/z 499.9 ; 2〇AQ· 8-chloro-4-{3-[3-(ethylsulfonyl)phenoxy]phenyl} Quinoline MS (ES) m/z 423. 9; HRMS: calcd for C.sup..sup.sup.sup.sup. -{3-[3-(propylsulfonyl)phenoxy]phenyl}quinoline MS (ES) m/z 437·9; HRMS: calcd for C24H2QClN 〇3S + H+, , 438. 09252; Measured (ESI, [M+H] + ), 438 · 0933 ; , 5 AS. 3-( {4-Alkyl-3'-[8-(trifluoromethyl)-4-quinolinyl]biphenyl-3-yl}sulfonyl)-1-propanyl MS (ES) m/z 505.8; r \ i〇AT. 4-[3'-(isopropyl hexanoic acid)biphenyl-3-yl]-8-(trifluoromethyl)quinoline MS (ES) m/z 455.9 ; AU. 8 - gas-based 4-{3-[3-(isopropylsulfonyl)phenoxy]phenyl} 15 quinoline MS (ES) m/z 437.9; /, HRMS: Calculated C24H2QClN〇3S + H+ , 438. 09252 ; Measured value (ESI, [M+H]+), 438.0935; 20 AV. 4-[3'-(Amino-reperyl)biphenyl-3-yl]-8-(trifluoro Methyl)quinoline-3-carboxamide MS (ES) m/z 471.9 ; AW. 2-methyl-4-({3'-[8-(trifluoromethyl)- 4-quinolinyl]联 253 200825054 Benz-3-yl}acid acid)-2-butanol MS (ES) m/z 499.9 ; ΑΧ. 2-methyl-4-({3, -[3-methyl-8-( Trifluoromethyl)-4-quino-5-aryl]biphenyl-3-yl}sutra-acid)-2-butyric acid MS (ES) m/z 513.9 ; AY. 8-IIyl-4-{3- [3-(Methyltra-yl)phenoxy]phenyl}quinoline-3-carboxamide 10 HRMS·· Value C24HnN3 〇4S + H+, 444. 10125; found (ESI, [M+H] + ), 444.101; ΑΖ· 4-(3-{3-[(dimethylamino)sulfonyl]phenoxy Benzyl)-8-(trifluoromethyl)quinoline-3-carboxamide 15 MS (ES) m/z 515. 9 ; and AAA. 4-{2-chloro-5-[3- (Methyl benzoate) phenoxy]phenyl}-8-(trifluoromethyl)Korline MS (ES) m/z 478·0. 20 Example 398 Flowchart 32 254 200825054

R1, R2 = H? le, Et, i；Pr A· 3-[(3 - {3-[8-(三氟甲基）一4一喹啉基]苯氧基}苯 基）磺醯基]丙-1-胺 步驟1:將含有3—氟硫酚（1_ 28 g，10 mmol)、N-(3-5溴基丙基）本一甲.亞胺（2· 68 g，i〇 mm〇i) '和碳酸铯 (6· 52 g，20 mmol)於DMF(20 mL)中之一混合物在室溫攪拌 2小時。以水水泮该反應並以乙酸乙g旨萃取。乾燥並濃縮該 經化合的有機層以產生如一白色固狀物之2-{3—[(3_氟苯 基）硫基]丙基}-1Η-異吲哚 e-1，3(2H)—二酮（3· 〇 g，95%)。 10 MS (ES) m/z 316. 0。 步驟2:室溫下將祕（3〇mL，50%於水中）加入含 有2-{3-[(3-氟苯基）硫基]丙基} — 1H—異㈣—二 酮（2.9g，9.2_〇1)之乙酸（3〇mL)中。將該混合物在⑼ %加熱2小時並倒進水巾。㈣與鶴該固狀物以產生如 15 一白色固狀物之21[(3-氟基苯基）確醯基]丙基}-1H-異 口弓卜朵-1，3(2H)-二_ (2· 5 g，78 %)。奶（ES) m/z 348· 0。 步驟3:將含有2-{3_[(3-氟苯基）磺醯基]丙 基卜1H_異°引味—丨，3(2H)-二酮（〇_ 69 g，2 mmol)、3-(8-(三 氟甲基）-4-喧琳基）酚（〇 29g，J _〇1)、碳酸鉋（3.29g， 20 23.8 mmol)於1〇mLDMF中之一混合物在140 2C加熱整夜。 255 200825054 將該混合物倒進水中並以乙酸乙酯萃取。透過矽膠色層分 析（乙酸乙酯/己烷）純化該經化合的有機物以產生如一白 色固狀物之2-{3-[(3-{3-[8-（三氟甲基）-4-口奎琳基]苯氧 基}苯基）磺醯基]丙基卜If異吲哚-1,3(2奶-二酮（〇· 31 5 g，50%)。MS (ES) zz//z616_ 9 ; HRMS:計算值 C33H23F3N2〇5S + H+，617.13525;實測值（ESI, [M+H]+)，617.1353。 步驟4:將2-{3-[(3-{3-[8-(三氟甲基）-4-喹啉基] 苯氧基}苯基）磺醯基]丙基}-1及-異吲哚-1，3(2^)-二酮 (〇· 1 g，0· 16 mmol)溶於乙醇（15 mL)中然後加入2 mL之 1〇 聯胺。迴流該溶液達2小時然後移除該溶劑。該殘餘物經 逆相HPLC(AcCN/水）純化，洗提出25 mg (32%)之如一黏稠 固狀物的該標題化合物。MS(ES)/»/z 487.0; HRMS:計 算值 C25H21F3N2〇3S + H+，487.12977;實測值（ESI，[Μ+ΗΓ)， 487· 1299。 15 Β· N-甲基-3-(3-（3-（8-（三氟甲基）-4-啥琳基）苯 氧基）苯基項酸基）丙-1-胺 步驟1:室溫氮大氣下，將甲磺醯氣（46 mg，0.399 mmol)加入含有3-[(3-{3-[8-(三氟甲基）-4-喹啉基]苯 20 氧基}苯基）石黃醢基]-1-丙醇（162 mg，0· 333 mmol )和π匕口定 (34mg，0· 432 mmol)於 CH2Cl2(2. 5mL)中之一攪拌溶液中。 30分鐘後，以水（〇· 5 ml)水淬該反應混合物，萃取，在減 壓下分離及濃縮成一棕色聚液。透過RP-HPLC (乙腈：水） 純化該相同的楽：液以產生如一淡棕色粉末之 256 200825054 3-（3-(3-(8-(三氟甲基）-4-喹啉基）苯氧基）苯基磺醯基） 丙基甲烷磺酸酯（13811^，產率73°/〇。^^(£3)////^566.0。 步驟2:將含有3-(3-(3-(8-(三氟甲基）-4-喹啉基） 本氧基）苯基石黃醯基）丙基甲烧石黃酸S旨（55 mg，0. 11 mmol) 5 和甲基胺7N之EtOH (5 ml)和THF (5 ml)置入一含有磁攪 拌棒的小玻璃瓶中。該小玻璃瓶加蓋並在45°C加熱15小 時。所產生的黃色溶液晶減壓濃縮成一黃色漿液。該相同 漿液經RP-HPLC純化產生如一淡棕色粉末之該標題化合物 27· 7 mg (產率 47%)。MS (ES)瓜/z 501· 0。 10 範例399 以範例398B所述之相似方法製備下列化合物。 A. 3_[(3-{3-[3-甲基-8-(三氟甲基）-4-喹啉基]苯 15 氧基}苯基）磺醢基]丙-1-胺 MS (ES) /h/z500. 9 ； HRMS:計算值 C26H23F3N2〇3S + H+， 501.14542;實測值（ESI，[M+H]+)，501.1456; Β. 於甲基-3-[(3-{3-[3-甲基-8-(三氟甲基）-4-啥 20 啉基]苯氧基}苯基)磺醢基]丙-I-胺 MS (ES) w/zbU. 9 ； HRMS:計算值 C27H25F3N2〇3S + H+， 515.16107;實測值（ESI, [Μ+ΗΓ)，515.1611; C. 乙基-3-[(3-{3-[3-甲基-8-(三氟甲基）-4-養 257 200825054 淋基]苯氧基}苯基)確斑基]丙—1 一胺 MS (ES) yz//z528. 9 ； HRMS:計算值 C28H27F3N2〇3S + H+， 529.17672;實測值（ESI, [Μ+ΗΓ)，529.1771; 5 D· A異丙基-3-[(3-{3-[3-甲基-8-（三氟甲基）-4- 喹啉基]苯氧基}苯基）磺醢基]丙-1-胺 MS(ES)/»/z542.9 ； HRMS:計算值 C29H29F3N2〇3S + H+， 543.19237;實測值（ESI, [M+H]+)，543.1925; ίο E. 於乙基-3-[(3-{3-[8-(三氟甲基）-4-唉琳基]苯 氧基}苯基)磺醢基]丙-1-胺 MS (ES) zff/z 515_ 1 ;以及 F. N-異丙基-3-（3-(3-(8-（三氟甲基）-4-喹啉基） 15 苯氧基）苯基磺醢基）丙-1-胺 MS (ES) 528. 9。 範例400 4-{2-氣基-5-[3-(甲基磺斑基）苯氧基]苯基卜8-（三 2〇 氟甲基）喹啉 步麻1: 4-(2-氣基-5-甲氧基苯基）-8-（三氟甲基） 喹啉 將氮氣泡通過含有4-氣基-8-(三氟甲基）喧琳（347 mg，1. 5 mmol)、2-氯基-5-甲氧基苯基硼酸（355 mg ’ 1· 88 258 200825054 mmol)、2M Na2C〇3水溶液（3 mL，6 mmol)之二甲氧基乙烧 (6 mL)的一混合物達10分鐘。加入四-三苯基膦鈀（ns mg， 0· 15 mmol)並將該混合物在85 °C授拌3小時。冷卻該懸 浮液並倒進含有乙酸乙酯（60 mL)和NaHC〇3水溶液之一混合 5物中。層分離並以NaHC〇3水溶液（1〇 mL)、水（1〇 mL)、和 食鹽水（20 mL)進一部沖洗該有機層。透過Na2S〇4乾燥該有 機層並減壓濃縮。使用梯度0:100至20:80之E:H將該殘 餘物經Si〇2色層分析純化以產生如一暗白色黏稠固狀物。 HRMS:計算值 CnHuCmNO + lT，338.05540;實測值（ESI， 1〇 [Μ+ΗΓ Obs’d)，338.0562。 步称2: 4-氣基-3-[8-(三氟甲基）-4-唉琳基]紛R1, R2 = H? le, Et, i; Pr A· 3-[(3 - {3-[8-(trifluoromethyl)-4 quinolinyl]phenoxy}phenyl)sulfonyl ] Propan-1-amine Step 1: Will contain 3-fluorothiophenol (1-28 g, 10 mmol), N-(3-5 bromopropyl) Ben-methylimine (2·68 g, i〇) Mm〇i) ' and a mixture of cesium carbonate (6·52 g, 20 mmol) in DMF (20 mL) was stirred at room temperature for 2 h. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layer is dried and concentrated to give 2-{3-[(3-fluorophenyl)thio]propyl}-1Η-isoindole e-1,3(2H) as a white solid. —Dione (3·〇g, 95%). 10 MS (ES) m/z 316. 0. Step 2: Add Mi(3〇mL, 50% in water) to 2-{3-[(3-fluorophenyl)thio]propyl}-1H-iso(tetra)-dione (2.9g) at room temperature , 9.2_〇1) in acetic acid (3〇mL). The mixture was heated at (9)% for 2 hours and poured into a water towel. (d) with the solids of the crane to produce, as a white solid, 21 [(3-fluorophenyl) decyl] propyl}-1H-iso-orbyl-1,3(2H)- Two _ (2·5 g, 78%). Milk (ES) m/z 348·0. Step 3: Will contain 2-{3_[(3-fluorophenyl)sulfonyl]propyl b. 1H-iso-flavor, 3, 3(2H)-dione (〇_69 g, 2 mmol), a mixture of 3-(8-(trifluoromethyl)-4-indolyl)phenol (〇29g, J_〇1), carbonated (3.29g, 20 23.8 mmol) in 1〇mL DMF at 140 2C Heat all night. 255 200825054 The mixture was poured into water and extracted with ethyl acetate. The compounded organic material was purified by silica gel chromatography (ethyl acetate/hexane) to yield 2-{3-[(3-{3-[8-(trifluoromethyl)-4) as a white solid. - 口奎琳基]phenoxy}phenyl)sulfonyl]propylbu Ifiso-1,3 (2 milk-diketone (〇· 31 5 g, 50%). MS (ES) zz //z616_ 9 ; HRMS: calculated value C33H23F3N2 〇 5S + H+, 617.1350; measured value (ESI, [M+H]+), 617.1353. Step 4: 2-{3-[(3-{3-[8 -(Trifluoromethyl)-4-quinolinyl]phenoxy}phenyl)sulfonyl]propyl}-1 and -isoindole-1,3(2^)-dione (〇·1 g, 0·16 mmol) was dissolved in ethanol (15 mL) and then 2 mL of 1 hydrazine was added. The solution was refluxed for 2 hours and then the solvent was removed. The residue was purified by reverse phase HPLC (AcCN/water). , 25 mg (32%) of the title compound as a viscous solid. MS(ES) /»/z 487.0; HRMS: Calculated C25H21F3N2 〇3S + H+, 487.12977; measured value (ESI, [Μ+ ΗΓ), 487· 1299. 15 N·N-methyl-3-(3-(3-(8-(trifluoromethyl)-4-indolyl)phenoxy)phenyl-acid)) -1-amine Step 1: Methanesulfonate at room temperature under nitrogen atmosphere 46 mg, 0.399 mmol) was added to contain 3-[(3-{3-[8-(trifluoromethyl)-4-quinolinyl]benzene 20-oxy}phenyl)-carsonyl]-1-propanol ( 162 mg, 0·333 mmol) and π匕口定 (34 mg, 0·432 mmol) in one of CH2Cl2 (2.5 mL). After 30 minutes, water (5 ml) was quenched with water. The reaction mixture, extracted, separated under reduced pressure and concentrated to a brown liquid. The same hydrazine was purified by RP-HPLC (acetonitrile: water) to give 256 as a light brown powder. 200825054 3-(3-(3- (8-(Trifluoromethyl)-4-quinolinyl)phenoxy)phenylsulfonyl)propylsulfonate (13811^, yield 73°/〇.^^(£3)/ ///^566.0. Step 2: Will contain 3-(3-(3-(8-(trifluoromethyl)-4-quinolinyl) oxy)phenyl fluorinyl) propyl sulphate S (55 mg, 0.11 mmol) 5 and methylamine 7N in EtOH (5 ml) and THF (5 ml) were placed in a small glass bottle containing a magnetic stir bar. The mixture was heated at 45 ° C for 15 hours, and the resulting yellow solution was concentrated under reduced pressure to a yellow syrup. The same syrup was purified by RP-HPLC to give the title compound (yield: 47%) as a pale brown powder. MS (ES) melon / z 501 · 0. 10 Example 399 The following compounds were prepared in a similar manner as described in Example 398B. A. 3_[(3-{3-[3-Methyl-8-(trifluoromethyl)-4-quinolinyl]benzene 15 oxy}phenyl)sulfonyl]propan-1-amine MS ( </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; -[3-Methyl-8-(trifluoromethyl)-4-indole 20 phenyl]phenoxy}phenyl)sulfonyl]propyl-I-amine MS (ES) w/zb. : calculated C27H25F3N2 〇3S + H+, 515.16107; found (ESI, [Μ+ΗΓ), 515.1611; C. ethyl-3-[(3-{3-[3-methyl-8-(trifluoromethyl)乙)-4-养257 200825054 lyophile] phenoxy}phenyl) decyl] propyl-1 monoamine MS (ES) yz//z528. 9 ; HRMS: calculated C28H27F3N2 〇3S + H+, 529.17672; Found (ESI, [Μ+ΗΓ), 529.1771; 5 D·Aisopropyl-3-[(3-{3-[3-methyl-8-(trifluoromethyl)-4- quinolyl) Phenoxy}phenyl)sulfonyl]propan-1-amine MS(ES)/»/z 542.9 ; HRMS: calcd for C29H29F3N2 〇3S + H+, 543.19237; found (ESI, [M+H] +), 543.1925; ίο E. Ethyl-3-[(3-{3-[8-(trifluoromethyl)-4-indolyl]phenoxy}phenyl)sulfonyl]propyl- 1-amine MS (ES) zff/z 515_ 1 ; and F. N- different 3- (3- (3- (8- (trifluoromethyl) -4-quinolyl) 15) phenyl sulfo Dukes yl) propan-1-amine MS (ES) 528. 9. Example 400 4-{2-Gasyl-5-[3-(methylsulfonyl)phenoxy]phenyl b-(tris-2-fluoromethyl)quinoline Step 1: 4-(2- The gas-based 5-methoxyphenyl)-8-(trifluoromethyl)quinoline was bubbled through a nitrogen-containing solution containing 4-methyl-8-(trifluoromethyl)anthracene (347 mg, 1.5 mmol) , 2-Chloro-5-methoxyphenylboronic acid (355 mg '1·88 258 200825054 mmol), 2M Na2C〇3 aqueous solution (3 mL, 6 mmol) of dimethoxyethane (6 mL) A mixture of up to 10 minutes. Tetra-triphenylphosphine palladium (ns mg, 0.15 mmol) was added and the mixture was stirred at 85 °C for 3 hours. The suspension was cooled and poured into a mixture 5 containing one of ethyl acetate (60 mL) and aqueous NaHC. The layers were separated and the organic layer was washed with aq. NaHCI 3 (1 mL), water (1 mL), and brine (20 mL). The organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by Si 〇 2 chromatography using E:H gradient from 0:100 to 20:80 to yield as a dark white viscous solid. HRMS: Calculated Cn HuCmNO + lT, 338.05540; found (ESI, 1 〇 [Μ+ΗΓ Obs'd), 338.0562. Step 2: 4-Alkyl-3-[8-(trifluoromethyl)-4-indolyl]

在步驟1所獲得之4-(2-氯基-5-甲氧基苯 基）-8-(三氟甲基）喧琳中加入°比咬鹽酸鹽（4 g)，並將該混 15 合物加熱至200 °C，期間該混合物變成一均質溶液。1. 5 小時之後，將水（40 mL)和乙酸乙酯（60 mL)倒進該反應 中，形成層分離。該有機層更進一步以5%檸檬酸水溶液（3 X 10 mL)、飽和的NaHC〇3水溶液（10 mL)、和食鹽水（20 mL) 沖洗。透過NaAO4乾燥該有機層並減壓濃縮。使用梯度 2〇 〇:1〇〇至30:70之E:H將該殘餘物經Si〇2色層分析純化 以產生如一白色泡泳固狀物之4-氯基-3-[8-(三氟甲 基）-4-喹啉基]酚。MS (ES) m/z 324· 1 ; HRMS:計算值 CieHgCIFsNO + H+, 324.03975 ；實測值（ESI, [M+H]+)， 324·0406 。 259 200825054 步称3: 4-{2-氣基〜5〜[3〜（甲基姐基)苯氧基]苯基卜8 (三氟甲基)喹啉 將含有4-氣基-3-[8、（三敦曱基）—4—啥淋基]齡⑽ 5 呃，〇· 25 _〇1)、Km (69 吨，〇· 5 _〇1)、w—氟基-3—(甲 基石黃醯基）苯（64 mg，〇·37 _)於朦（3此）中之一混合 物在150 C加熱24小時。冷卻該反應並峨QAe(5Q ‘）和 水（10 mL)稀釋。分離該些層並以水（4 χ 1〇⑹和食鹽水 (20 mL)沖洗财機層。透偷孤乾_有機層並減壓濃 H)縮。使用梯度0:100至25··75之E:H將該殘餘物經色 層分析純化。更進一步透過使用梯度5:95至1〇〇:()之乙 腈：H2〇的C18逆相色層分析純化該殘餘物質以產生如一白 色泡泳固狀物之4-{2-氯基-5-[3-(甲基石黃醯基）苯氧基]苯 基}-8-(三氟甲基）啥琳。MS (ES) 478· 0. HRMS·計 15 算值 C23H15CIF3NO3S + H+，478· 04860 ;實測值（ESI, [Μ+ΗΓ)，478.0488。 401 以範例400，步驟3所述之相似方法製備下列化合 20 物。 Α. 3-[(3-{4-氯基-3-[8-(三氟甲基）-4-喹啉基]苯 氧基}苯基)磺醢基]-1-丙酵 如同範例400中步驟3之製備，除了使用4-氣基 260 200825054 -3-[8-(三氟甲基）-4-啥琳基]齡和3-[(3-氟苯基）石黃醯 基]-1-丙醇當成反應物來產生如一白色固狀物之該標題化 合物。MS (ES) m/z 522. 0 ; HRMS:計算值 C25H19ClF3N〇4S + H+，522.07482;實測值（ESI, [Μ+ΗΓ)，522. 0748。 5 Β. 4-{2-氣基-5-[3-(異丙基磺醢基）苯氧基]苯 基}-8-(三氟甲基）喹啉 如同範例400中步驟3之製備，除了使用4-氯基 -3-[8-(三氟甲基）-4-喹啉基]酚和3-氟基-1-(異丙基磺醯 10基）苯當成反應物以產生如一白色泡沫之該標題化合物。 MS (ES) ra/z 506.0 ; HRMS:計算值 C25H19ClF3N〇3S + H+， 506.07990;實測值（ESI, [M+H]+)，506.0802。 C. 4—{2-氯基-5-[3-（乙基磺醢基）苯氧基]苯 15 基}-8-(三氟甲基）考琳 如同範例400中步驟3之製備，除了使用4-氯基 -3-[8-(三氟甲基)-4-喹啉基]酚和丨―（乙基磺醯基)—3_氟苯當成 反應物以產生如一白色泡沫之該標題化合物。MS (ES) m/z 492· 0 ; HRMS:計算值 C24HnClF3N〇3S + H+，492. 06425 ;實測值 2〇 (ESI，[M+HD，492.0645。 D· 4—(2-氣基-5-[4-（甲基磺醢基）苯氧基]苯 基}-8-（三氟甲基）喹啉 如同範例400中步驟3之製備，除了使用4-氯基 261 200825054 -3-[8-(三氟甲基）-4-喹啉基]酚和4-氟基-1-(甲基磺醯基） 苯當成反應物以產生如一白色泡沫之該標題化合物。Ms (ES) m/z 478.0 ; HRMS:計算值 C23H15ClF3N〇3S + H+， 478.04860;實測值（ESI, [Μ+ΗΓ)，478.0487。 範例402 4-{2-氯基-5-[4-(乙基磺醢基）苯氧基]苯基}-8-(三 氟甲基）喹啉 將含有4-氣基-3-[8-（三氟甲基）-4-喹啉基]酚（1〇7 1〇 mg，〇· 33 mmol)、Cs2C〇3 (215 mg，0· 66 mmol)、和 4-（乙 基石黃醯基）-1-氟笨（94 mg，0.5 mmol)之二甲基乙醯胺（3 mL)在120 C加熱16小時。冷卻該反應並以EtOAc(50 mL) 和水（10 mL)稀釋。層分離並將該有機層以水（4 χ i〇 和食鹽水（20 mL)沖洗。以Na2S〇4乾燥該有機層並減壓濃 15 縮。透過以梯度0:100至25:75之E:H洗提的Si〇2色層 分析純化該殘餘物。該殘餘物質更進一步透過使用梯度 5:95至100:0之乙腈：h2〇的C18逆相色層分析純化，以產 生如一白色泡沫之該標題化合物。MS (ES) m/z 491. 6 ; HRMS··計算值 C24HnClF3N〇3S + H+，492. 06425;實測值 20 (ESI，[M+H]+)，492. 0644。 辑例403 4-{2-氣基-5-[4-(異丙基磺醢基）苯氧基]苯 基}-8-(三氟甲基）考琳 262 200825054 比照範例402製備，除了使用4-氯基-3-[8-（三氟甲 基)-4-喹啉基]酚和4-氟基-i-(異丙基磺醯基)-苯作為反應物以 產生如一白色泡沫之該標題化合物。MS (ES) m/z 505. 6 ; HRMS: 計算值 C25H19ClF3N〇3S + H+，506.07990;實測值（ESI，[M+H]+)， 5 506·0797 。 筑例404 4-{5-[4-(乙基磺醯基）苯氧基]-2-氟苯基}—8_(三氟 甲基）喹啉 步驟1: 4-（2-氟基-5-甲氧基苯基）-8-(三氟甲基）啥 10 淋 比照範例400中步驟1製備，除了使用4-氣基-8-(三 氟甲基）喹啉和2-氟基-5-甲氧基苯基硼酸作為反應物以產 生如一白色泡沫之該標題化合物。MS (ES) m/z 322.6; HRMS:計算值 CnHuF4N0 + H+，322.08495 ;實測值（ESI， 15 [Μ+ΗΓ)，322. 0852。 步驟2: 4-氟基-3-[8-（三氟甲基）-4-喹啉基]酚In the 4-(2-chloro-5-methoxyphenyl)-8-(trifluoromethyl) sulfonium obtained in the step 1, a specific ratio of biting hydrochloride (4 g) is added, and the mixture is mixed. The mixture was heated to 200 ° C during which time the mixture became a homogeneous solution. 1. After 5 hours, water (40 mL) and ethyl acetate (60 mL) were poured into the reaction to form a layer. The organic layer was further washed with a 5% aqueous citric acid solution (3×10 mL), a saturated aqueous solution of NaHC 3 (10 mL), and brine (20 mL). The organic layer was dried over NaAO4 and concentrated under reduced pressure. The residue was purified by Si2 color chromatography using gradient 2 〇〇: 1 〇〇 to 30: 70 EtOAc to yield 4-chloro -3-[8-( Trifluoromethyl)-4-quinolinyl]phenol. MS (ES) m/z 324·1; HRMS: calcd. </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 259 200825054 Step 3: 4-{2- gas-based ~5~[3~(methyl-s-yl)phenoxy]phenyl b-8 (trifluoromethyl)quinoline will contain 4-alkyl-3- [8, (三敦曱基)—4—啥淋基] Age (10) 5 呃, 〇· 25 _〇1), Km (69 tons, 〇·5 _〇1), w-Fluoryl-3—( A mixture of methyl sulfonium) benzene (64 mg, 〇·37 _) in hydrazine (3) was heated at 150 C for 24 hours. The reaction was cooled and diluted with QAe (5Q ') and water (10 mL). The layers were separated and the reservoir was rinsed with water (4 χ 1 〇 (6) and brine (20 mL). The organic layer was smashed and dried and concentrated under reduced pressure. The residue was purified by chromatography using E:H gradient from 0:100 to 25··75. Further, the residue was purified by C18 reverse phase chromatography using a gradient of 5:95 to 1 :() in acetonitrile:H.sub.2 to afford 4-{2-chloro--5 as a white blister solid. -[3-(Methylglycosyl)phenoxy]phenyl}-8-(trifluoromethyl)anthracene. MS (ES) 478. 0. HRMS calc. calcd. for C.sub.sup.sssssssssssssssssssssssssssssss 401 The following compound 20 was prepared in a similar manner as described in Example 400, Step 3. [. 3-[(3-{4-Chloro-3-[8-(trifluoromethyl)-4-quinolinyl]phenoxy}phenyl)sulfonyl]-1-propanyl as an example Preparation of step 3 in 400, except that 4-gasyl 260 200825054 -3-[8-(trifluoromethyl)-4-indolyl] age and 3-[(3-fluorophenyl) sulphate]- 1-propanol is used as the reactant to give the title compound as a white solid. MS (ES) m/z 522. 0; HRMS: calcd., calcd, s, s, s, s, s, s, s, s, s, s, s, s, s, s. 5 Β. 4-{2-Alkyl-5-[3-(isopropylsulfonyl)phenoxy]phenyl}-8-(trifluoromethyl)quinoline as prepared in Step 3 of Example 400 In addition to using 4-chloro-3-[8-(trifluoromethyl)-4-quinolinyl]phenol and 3-fluoro-1-(isopropylsulfonyl-10-yl)benzene as a reactant to produce The title compound is a white foam. MS (ES) </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; C. 4-{2-Chloro-5-[3-(ethylsulfonyl)phenoxy]benzene 15 yl}-8-(trifluoromethyl)colin is prepared as in Step 3 of Example 400, In addition to using 4-chloro-3-[8-(trifluoromethyl)-4-quinolinyl]phenol and hydrazine-(ethylsulfonyl)-3-fluorobenzene as a reactant to produce a white foam The title compound. MS (ES) m/z 492·0; HRMS: calcd for C24HnClF3N 〇3S + H+, 492. 06425; Measured value 2 〇 (ESI, [M+HD, 492.0645. D. 4 - (2-carbyl-5) -[4-(Methylsulfonyl)phenoxy]phenyl}-8-(trifluoromethyl)quinoline was prepared as in Step 3 of Example 400, except that 4-chloroyl 261 200825054 -3-[ 8-(Trifluoromethyl)-4-quinolinyl]phenol and 4-fluoro-1-(methylsulfonyl)benzene are reacted to give the title compound as a white foam. Ms (ES) m /z 478.0 ; HRMS: calcd for C,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, Phenoxy]phenyl}-8-(trifluoromethyl)quinoline will contain 4-alkyl-3-[8-(trifluoromethyl)-4-quinolinyl]phenol (1〇7 1 〇mg, 〇·33 mmol), Cs2C〇3 (215 mg, 0·66 mmol), and 4-(ethyl sulphate)-1-fluorobenzidine (94 mg, 0.5 mmol) of dimethylacetamide (94 mg, 0.5 mmol) 3 mL) was heated for 16 hours at 120 C. The reaction was cooled and diluted with EtOAc (50 mL) and water (10 mL), and the organic layer was rinsed with water (4 χ i〇 and brine (20 mL). With Na2S The organic layer was dried and concentrated under reduced pressure. The residue was purified by chromatography eluting with E:H eluting from 0:100 to 25:75. The residue was further passed through a gradient. Purification by C18 reverse phase chromatography of 95 to 100:0 acetonitrile:h.sub.2 to afford the title compound as a white foam. MS (ES) m/z 491. 6; HRMS··calc. C24HnClF3N〇3S + H+, 492. 06425; found 20 (ESI, [M+H]+), 492. 0644. Example 403 4-{2- gas--5-[4-(isopropylsulfonyl)phenoxy Benzyl}-8-(trifluoromethyl)Cauline 262 200825054 Prepared according to Example 402 except that 4-chloro-3-[8-(trifluoromethyl)-4-quinolinyl]phenol was used and 4-fluoro-i-(isopropylsulfonyl)-benzene as the reactant to give the title compound as a white foam. MS (ES) m/z 505. 6; HRMS: Calculated C25H19ClF3N〇3S + H+ , 506.779090; measured value (ESI, [M+H]+), 5 506·0797. Building Example 404 4-{5-[4-(ethylsulfonyl)phenoxy]-2-fluorophenyl}-8-(trifluoromethyl)quinoline Step 1: 4-(2-Fluoro- 5-methoxyphenyl)-8-(trifluoromethyl)indole 10 was prepared as described in Step 1 of Example 400 except that 4-methyl-8-(trifluoromethyl)quinoline and 2-fluoro group were used. -5-Methoxyphenylboronic acid as a reactant to give the title compound as a white foam. MS (ES) m/z </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; Step 2: 4-Fluoro-3-[8-(trifluoromethyl)-4-quinolinyl]phenol

比照範例400中步驟2製備，除了使用4-(2-氟基-5-甲 氧基苯基)-8-(三氟甲基）喧琳作為反應物以產生如一白色泡沐 2〇 之該標題化合物。MS (ES) m/z 308_ 0 ; HRMS:計算值CwHANO + H+, 308.06930;實測值（ESI，[M+H]+Obs，d)，308.0696。 步驟3: 4-{5-[4-(乙基磺醢基）苯氧基]-2-氟苯 基}-8-(三氟甲基)崎琳 263 25 200825054 比照範例402製備，除了使用4-氟基-3-[8-(三氟甲 基)-4-喹啉基]酚和1〜（乙基磧醯基)-4-氟苯作為反應物以產生 如一白色泡沫之該標題化合物。MS (ES) m/z 475· 7 ; HRMS:計 算值 C24H17F4NO3S + H+，476.09380 ;實測值（ESI, [M+HD， 5 476. 0938。 範例405 4 - {2-氟基-5-[4-(異丙基磺醢基）苯氧基]苯基卜8-(三 氟甲基)喹啉 比照範例402製備，除了使用4-氟基-3-[8-(三氟甲基)-4-1〇啥琳基]驗和4-氟基-i-(異丙基磺醯基)—苯作為反應物以產生 如一白色泡沫之該標題化合物。MS (ES) m/z 489· 7 ; HRMS:計 算值 C25H19F4N〇3S + H+，490.10945 ;實測值（ESI, [M+HD， 490.1094。 範例406 15 4气2—氣基—5- [ 2-氟基-4-(甲基磺醢基）苯氧基]苯 基}-8-(三氟甲基)唉琳 比照範例402製備，除了使用4-氯基-3-[8-(三氟甲基)-4-啥琳基]酴和1，2-二氟基-4-(甲基磺醯基）苯作為反應物以產生 如一白色泡沫之該標題化合物。MS (ES) m/z 495· 6 ; HRMS:計 20 算值 C23H14ClF4N〇3S + H+, 496.03918 ;實測值（ESI，[M+H]+ Obs’ d)，496. 0395。 範例407 264 200825054 4 - {5-[3-(乙基磺醢基）苯氧基]-2-氟基苯基}-8-(三氟 甲基)喹啉 比照範例402製備，除了使用4-氟基-3-[8-(三氟甲基)-4-喧琳基]紛和1-(乙基磺醯基)_3—氟苯作為反應物以產生如一白 5色泡洙之該標題化合物。MS (ES) m/z 475.7 ; HRMS:計算值 C24HnF4N〇3S + H+, 476.09380 ;實測值（ESI, [M+H]+ Obs’d)， 476. 0943。 範例408 4 - {2-氟基-5-[3-(甲基磺醢基）苯氧基]苯基卜8-(三氟 1〇甲基)喹啉 比照範例402製備，除了使用4-氟基-3-[8-(三氟甲基)-4-喧琳基]紛和3-氟基-1-(甲基磺醯基)-苯作為反應物以產生如一 白色泡沫之該標題化合物。MS (ES) m/z 461.6 ; HRMS:計算 值 C23H15F4N〇3S + H+，462.07815 ;實測值（ESI, [M+H]〇, 15 462.0779。Prepared according to step 2 of Example 400, except that 4-(2-fluoro-5-methoxyphenyl)-8-(trifluoromethyl)anthracene was used as the reactant to give a white foam. Title compound. MS (ES) m/z </RTI> 308 <RTI ID=0.0>; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Step 3: 4-{5-[4-(ethylsulfonyl)phenoxy]-2-fluorophenyl}-8-(trifluoromethyl)-salphin 263 25 200825054 Prepared according to Example 402, except 4-fluoro-3-[8-(trifluoromethyl)-4-quinolinyl]phenol and 1-(ethylamido)-4-fluorobenzene as reactants to give the title as a white foam Compound. MS (ES) m/z 475·7; HRMS: calcd for C24H17F4NO3S + H+, 476.09380; found (ESI, [M+HD, 5 476. 0938. Example 405 4 - {2-Fluoro-5-[4 -(isopropylsulfonyl)phenoxy]phenyl b-(trifluoromethyl)quinoline was prepared as in Example 402 except that 4-fluoro-3-[8-(trifluoromethyl)- 4-1 〇啥 基 ] and 4-fluoro-i-(isopropylsulfonyl)-benzene as the reactant to give the title compound as a white foam. MS (ES) m/z 489. HRMS: Calculated C25H19F4N 〇3S + H+, 490.10945; found (ESI, [M+HD, 490.1094. Example 406 15 4 gas 2 - gas base - 5 - [ 2-fluoro-4-(methylsulfonate) Phenyloxy]phenyl}-8-(trifluoromethyl)anion was prepared analogously to Example 402 except that 4-chloro-3-[8-(trifluoromethyl)-4-indolyl] was used. Hydrazine and 1,2-difluoro-4-(methylsulfonyl)benzene as the reactant to give the title compound as a white foam. MS (ES) m/z 495 · 6; HRMS: C23H14ClF4N〇3S + H+, 496.03918; found (ESI, [M+H] + Obs' d), 496. 0395. Example 407 264 200825054 4 - {5-[3-(ethylsulfonyl)phenoxy ]-2-fluoro group The base}-8-(trifluoromethyl)quinoline was prepared as in Example 402 except that 4-fluoro-3-[8-(trifluoromethyl)-4-indolyl] and 1-(ethyl) were used. Sulfhydryl)-3-fluorobenzene as a reaction product to give the title compound as a white color, m.p., s., s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, [M+H]+ Obs'd), 476. 0943. Example 408 4 - {2-Fluoro-5-[3-(methylsulfonyl)phenoxy]phenyl b-8-(trifluoro-1 〇Methyl)quinoline was prepared according to Example 402 except that 4-fluoro-3-[8-(trifluoromethyl)-4-indolyl] and 3-fluoro-1-(methylsulfonate) were used. The title compound was obtained as a white foam. MS (ESI) m/z 461.6; 15 462.0779.

範例40Q 4- {2-氟基-5- [ 3-氟基-5-(甲基磺醢基）苯氧基]苯 基}-8-(三氟甲基)啥琳 比照範例402製備，除了使用4-氟基-3-[8-(三氟曱基)-4-20喹啉基]酚和丨，3-二氟基_5-(甲基磺醯基）苯作為反應物以產生 如一白色泡沫之該標題化合物。MS (ES) m/z 479· 6 ; HRMS:計 异值 C23H14F5NO3S + H+，480.06873 ;實測值（ESI，[M+H]〇, 480. 0685。 265 200825054 輯例410 4 - {2-氣基-5-[3-氟基_5-(甲基磺醢基）苯氧基]苯 基}-8-(三氟甲基)唉琳 比照範例402製備，除了使用4-氯基—3-[8-(三氟甲基)_4一 5喹啉基]酚和丨，3—二氟基-5-(甲基磺醯基）苯作為反應物以產生 如一白色泡沫之該標題化合物。MS (ES) m/z 495· 6 ; HRMS:計 算值 C23HHC1F4N03S + H+，496.03918;實測值（ESI，[M+HD， 496. 0389。 範例411 ίο 3 一[(4-{4-氣基-3 - [8-(三氟甲基)-4-皆林基]苯氣基}苯 基)磺醢基]-1-丙酵 比照範例402製備，除了使用4-氣基—3-[8-(三氟甲基)一4一 喹啉基]酚和3-[(4-氟基苯基)磺醯基卜卜丙醇作為反應物以產 生如一白色泡沐之該標題化合物。MS (ES) m/z 521· 6 ; HRMS:計 15 算值 C25H19ClF3N〇4S + Η.，522.07482 ;實測值（ESI，[M+H]〇, 522.0748 。 範例412 4-{2_氟基-5〜[4-(甲基磺醢基）苯氧基]苯基}-8_(三氟 甲基)喹啉 比照範例402製備，除了使用4-氟基-3-[8-(三氟甲基)一4-喹啉基]酚和4-氟基（甲基磺醯基)_苯作為反應物以產生如一 白色泡沫之該標題化合物。MS (ES) m/z 461·6 ; HRMS··計算 266 200825054 值 C23H15F4N〇3S + H+，462.07815;實測值（ESI，[M+H]+〇bs，d)， 462. 0783。 範例413 4- {2-氯基-5- [ 2-氯基-4-(甲基磺醢基）苯氧基]苯 5 基}-8-(三氟甲基)嗓琳 比照範例400中步驟3製備，除了使用4-氣基-3-[8-(三氟 甲基)-4-喹啉基]酚和1, 2-二氣-4-（甲基磺醯基）苯作為二甲基 乙醯胺中之反應物以產生如一白色泡沫之該標題化合物。MS (ES) m/z 511· 9 ; HRMS:計算值 C23HuC12F3N〇3S + H+, 512· 00963 ;實 i〇 測值（ESI, [M+H]+ Obs’d), 512.0099。 範例414 [(4-{4-氣基-3 - [8-(三氟甲基)-4-会林基]苯氣基}苯基） 確酸基]乙猜 比照範例400中步驟3製備，除了使用4-氣基-3-[8-(三 15 氟甲基)-4-喹啉基]酚和1，2-二氯-4-(甲基磺醯基）苯作為二甲 基乙醯胺中之反應物以產生如一白色泡沫之該標題化合物。MS (ES) m/z 503.0 ; HRMS:計算值 CziHmCIFIOsS + H+， 503.04385;實測值（ESI, [M+H]+0bs，d)，503.0443。 267 200825054 X〇Example 40Q 4-{2-Fluoro-5-[3-fluoro-5-(methylsulfonyl)phenoxy]phenyl}-8-(trifluoromethyl)phosphonium is prepared according to Example 402, In addition to using 4-fluoro-3-[8-(trifluoromethyl)-4-20 quinolyl]phenol and hydrazine, 3-difluoro-5-(methylsulfonyl)benzene as a reactant The title compound is produced as a white foam. MS (ES) m/z 479·6; HRMS: Calculated value C23H14F5NO3S + H+, 480.06873; Measured (ESI, [M+H] 〇, 480. 0685. 265 200825054 例 410 4 - {2- -5-[3-Fluoro-5-(methylsulfonyl)phenoxy]phenyl}-8-(trifluoromethyl)phosphonium was prepared according to Example 402 except that 4-chloro- 3- was used. [8-(Trifluoromethyl)_4-5 quinolinyl]phenol and hydrazine, 3-difluoro-5-(methylsulfonyl)benzene as the reactant to give the title compound as a white foam. (ES) m/z 495·6; HRMS: Calculated C23HHC1F4N03S + H+, 496.03918; found (ESI, [M+HD, 496. 0389. Example 411 ίο 3 -[(4-{4-) - [8-(Trifluoromethyl)-4-allyl] phenylyl}phenyl)sulfonyl]-1-propanyl was prepared according to Example 402 except that 4-gasyl-3-[8- (Trifluoromethyl)- 4-quinolinyl]phenol and 3-[(4-fluorophenyl)sulfonylbupropanol as reactants to give the title compound as a white foam. MS (ES m/z 521· 6 ; HRMS: Calculated for 15 C25H19ClF3N 〇 4S + Η., 527.07482; Measured value (ESI, [M+H] 〇, 522.0748. Example 412 4-{2_Fluoro-5~[ 4-(methylsulfonyl) Phenoxy]phenyl}-8-(trifluoromethyl)quinoline was prepared as in Example 402 except that 4-fluoro-3-[8-(trifluoromethyl)-4-quinolinyl]phenol was used and 4 - fluoro (methylsulfonyl)-benzene as the reactant to give the title compound as a white foam. MS (ES) m / z 461 · 6; HRMS · · Calculation 266 200825054 Value C23H15F4N 〇 3S + H+, 462.07815 Found (ESI, [M+H] + 〇bs, d), 462. 0783. Example 413 4- {2-Chloro-5-[2-chloro-4-(methylsulfonyl)benzene Oxy]phenyl-5-}-8-(trifluoromethyl)phosphonium is prepared as in Step 3 of Example 400 except that 4-methyl-3-[8-(trifluoromethyl)-4-quinolinyl is used. And phenol and 1,2-dioxa-4-(methylsulfonyl)benzene as the reactant in dimethylacetamide to give the title compound as a white foam. MS (ES) m/z 511. 9 ; HRMS: Calculated value C23HuC12F3N 〇 3S + H+, 512· 00963 ; Real 〇 measured value (ESI, [M+H]+ Obs'd), 512.0099. Example 414 [(4-{4-Gasyl-3 - [8-(trifluoromethyl)-4-memberinyl]benzene)}phenyl) acyl] B. Measured according to Step 3 of Example 400 In addition to 4-methyl-3-[8-(tri15-fluoromethyl)-4-quinolinyl]phenol and 1,2-dichloro-4-(methylsulfonyl)benzene as dimethyl The reactant in acetamide to give the title compound as a white foam. MS (ES) m/z </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 267 200825054 X〇

415 4-{3-[3-氟基-5-(甲基磺醢基）苯氧基]苯基卜8一（甲 基磺酿基）喹啉 5 步驟1: 2,2一二甲基-5一[(E)-{[2-（甲基續醢基)苯基]亞 胺}甲基]-1，3-二嚼烧-4,6-二酮 將含有 2, 2-二甲基-1，3-二σ惡烧一4,6-二酮（1· 59 g, Π 〇 mmol)和原甲酸三甲酯（10 mL)之一混合物在1〇5 γ加熱2小時。 10將該混合物冷卻至90 °C，然後加入含有2-(甲基續醯基）苯胺 (1· 71 g，10· 0 mmol)之 DMF(10 mL)。將該混合物在丨25 X 加 熱3小時，然後緩慢地倒進冰水(200 mL)中。收集該沉澱物，以 水沖洗’並高真空下乾燥，以產生如一暗白色粉末之該標題化合 物。MS (ES) m/z 323.7，HRMS:計算值 CuHisNOeS + NH/， 15 343.09583 ;實測值（ESI, [M+NH4]+ Obs’d), 343.0960。 步驟2: 4-氣基-8-(甲基確躔基)喹啉 268 200825054 將2, 2-二甲基-5-[(E)-{[2-（甲基磺醯基）苯基]亞胺}甲 基]-1，3-二噁烷-4, 6-二酮（1. 20 g，3_ 7 mmol)在 Dowtherm A (5 mL)中260 °C加熱4小時（氣體放出）。將該混合物冷卻至室溫， 形成沉澱物。以二乙醚(50mL)稀釋該反應。收集該棕色固狀物， 5 以醚沖洗，並在真空下乾燥。將該固狀物在氧氯化磷(5 mL)中在 90 °C加熱2小時。小心地將該混合物倒進含有冰水（1〇〇 mL)和 EtOAc(75 mL)之一經攪拌的混合物。仔細地以固態碳酸鉀中合該 混合物並將層分離。以2M Na2C〇3水溶液、水(50 mL)、和食鹽水 (50mL)沖洗該有機層。透過Na2S〇4乾燥後，揮發該溶劑，將該產 1〇 生的物質透過使用梯度2:98至30:70之E:H的Si〇2色層分析 純化，以產生如一暗白色固狀物之該標題化合物。MS (ES) m/z 241.7 ; HRMS:計算值 C1QH8ClN〇2S + H+，242.00370 ;實測值 (ESI, [M+H]+0bs’d)，242.0040。 15 步驟3: 3-[8-(甲基磺醢基）-4-喹啉基]酚 比照範例400中步驟1製備，除了使用4-氣基-8-（甲 基石黃醯基）啥琳和3-經基苯基棚酸作為反應物以產生如一 白色泡沫之該標題化合物。MS (ES) m/z 299· 9 ; HRMS:計 算值 C16H13N〇3S + H+，300.06889;實測值（ESI, [M+H] + 2〇 〇bs’d)，300. 0695。 步驟4: 4-{3-[3-敗基-5-（甲基確殖基）苯氧基]苯 基}-8-（甲基確酸基)考琳 比照範例402製備，除了使用3-[8-(甲基磺醯基)一4-喧 25啉基]酚和1，3-二氟基-5-(甲基磺醯基)苯作為二甲基乙醯胺中 269 200825054 之反應物以產生如一白色泡沫之該標題化合物。MS (ES) m/z 471.6 ; HRMS:計算值 C23H18FN〇5S2 + H+，472.06832 ;實測值 (ESI, [M+H]+0bs’d)，472.0684。 範例416 5 4-{3-[3-(乙基磺醢基）苯氧基]苯基}-8-(甲基磺醢基） 喹啉 比照範例402製備，除了使用3-[8-(甲基磺醯基）-4-喹啉基]酚和1-(乙基磺醯基）-3-氟基苯作為二甲基乙醯 胺中之反應物以產生如一白色泡沫之該標題化合物。MS (ES) ίο m/z 467.9; HRMS:計算值 C24H2A05S2 + H+，468. 09339; 實測值（ESI，[M+H]+0bs’d)，468.0938; 範例417 4 - {3-[3-(異丙基確醢基)苯氧基]苯基}-8-(甲基續醢基) 喹啉 15 比照範例402製備，除了使用3-[8-（甲基磺醯基）- 4- 喧琳基]酚和3-氟基-l-(異丙基磺醯基）-苯作為二甲基乙 醯胺中之反應物以產生如一白色泡沫之該標題化合物。MS (ES) m/z 481.9 ； HRMS:計算值 C25H23N〇5S2 + H+， 482.10904;實測值（ESI，[M+H]+〇bs，d)，482 1〇91。 2〇 範例@ 34(：Μ3-[8 -（甲基確醢基)-4-喹啉基]苯氧基}苯基)磺 斑基]-1-丙酵 比照範例402製備，除了使用3-[8-(甲基磺醯基）-4-啥淋基]盼和3-[(3-氟基苯基）磺醯基]-1-丙醇作為二甲 270 200825054 基乙醯胺中之反應物以產生如一白色泡沫之該標題化合 物。MS (ES) m/z 497.9 ; HRMS:計算值 C25H23N〇6S2 + H+， 498.10396;實測值（ESI，[M+H]+0bs’d)，498.1045。 範例419 5 4-{3-[4-(乙基磺醢基）苯氧基]苯基}-8-(甲基磺醢基） 喹琳 比照範例402製備，除了使用3-[8-(甲基磺醯基）-4-喹啉基]酚和1-(乙基磺醯基）-4-氟苯作為二甲基乙醯胺 中之反應物以產生如一白色泡沫之該標題化合物。MS (ES) 10 m/z 467.9; HRMS:計算值 C24H21N〇5S2 + H+，468.09339; 實測值（ESI，[M+H]+Obs’d)，468.0933。 範例420 8-(甲基磺醢基）-4-{3-[4-(丙基磺醢基）苯氧基]苯基} 啥琳 15 比照範例402製備，除了使用3-[8-(甲基磺醯基）-4- 喹啉基]酚和4-氟基-1-(丙基磺醯基）-苯作為二甲基乙醯 胺中之反應物以產生如一白色泡沫之該標題化合物MS (ES) m/z 481.9; HRMS:計算值 C25H23NO5S2 + H+，482. 10904; 實測值（ESI, [M+H]+Obs’d), 482. 1093。 20 範例421 4 - {3-[4-(異丙基磺醢基）苯氧基]苯基卜8_(甲基磺醢 基）喹啉415 4-{3-[3-Fluoro-5-(methylsulfonyl)phenoxy]phenyl b-8-(methylsulfonic acid)quinoline 5 Step 1: 2,2-dimethylene -5-[(E)-{[2-(methyl sulfonyl)phenyl]imine}methyl]-1,3-di-c-butyl-4,6-dione will contain 2, 2- A mixture of methyl-1,3-dioxazole- 4,6-dione (1·59 g, Π 〇 mmol) and trimethyl orthoformate (10 mL) was heated at 1 〇 5 γ for 2 hours. 10 The mixture was cooled to 90 ° C, then DMF (10 mL) containing 2-(methyl decyl) phenylamine (1·71 g, 10.0 mmol) was added. The mixture was heated at 丨25 X for 3 hours and then slowly poured into ice water (200 mL). The precipitate was collected, rinsed with water and dried under high vacuum to give the title compound as a dark white powder. MS (ES) m/z </RTI> </RTI> </RTI> <RTI ID=0.0></RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Step 2: 4-Alkyl-8-(methyl-decyl)quinoline 268 200825054 2,2-Dimethyl-5-[(E)-{[2-(methylsulfonyl)phenyl Imino}methyl]-1,3-dioxane-4,6-dione (1. 20 g, 3-7 mmol) heated in Dowtherm A (5 mL) at 260 °C for 4 hours (gas evolution) . The mixture was cooled to room temperature to form a precipitate. The reaction was diluted with diethyl ether (50 mL). The brown solid was collected, 5 rinsed with ether and dried under vacuum. The solid was heated in a solution of phosphorus oxychloride (5 mL) at 90 °C for 2 hours. The mixture was poured carefully into a stirred mixture containing one of ice water (1 mL) and EtOAc (75 mL). The mixture was carefully combined with solid potassium carbonate and the layers were separated. The organic layer was washed with 2M aqueous Na.sub.2 C.sub.3, water (50 mL), and brine (50 mL). After drying through Na2S〇4, the solvent is volatilized, and the produced material is purified by Si〇2 color layer chromatography using a gradient of 2:98 to 30:70 to yield a dark white solid. The title compound. MS (ES) m/z </RTI> </RTI> <RTI ID=0.0></RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 15 Step 3: 3-[8-(Methylsulfonyl)-4-quinolinyl]phenol was prepared in accordance with Step 1 of Example 400, except that 4-methyl-8-(methyl sulphate) was used. 3-Phenylphenyl benzene acid is used as the reactant to give the title compound as a white foam. MS (ES) m/z 299·9; HRMS: Calculated C16H13N 〇3S + H+, 300.06889; found (ESI, [M+H] + 2〇 〇bs'd), 300. 0695. Step 4: 4-{3-[3-Arsyl-5-(methyl-decyl)phenoxy]phenyl}-8-(methyl-acidic acid)Kolin was prepared according to Example 402 except that 3 was used. -[8-(methylsulfonyl)- 4-indolyl] phenol and 1,3-difluoro-5-(methylsulfonyl)benzene as dimethylacetamide 269 200825054 The reactants are used to give the title compound as a white foam. MS (ES) m/z </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; Example 416 5 4-{3-[3-(ethylsulfonyl)phenoxy]phenyl}-8-(methylsulfonyl)quinoline was prepared as in Example 402 except that 3-[8-( Methylsulfonyl)-4-quinolinyl]phenol and 1-(ethylsulfonyl)-3-fluorobenzene as the reactant in dimethylacetamide to give the title compound as a white foam . MS (ES) ίο m/z 467.9; HRMS: Calculated C24H2A05S2 + H+, 468. 09339; Found (ESI, [M+H]+0bs'd), 468.0938; Example 417 4 - {3-[3- (Isopropyl thiol)phenoxy]phenyl}-8-(methyl sulfonyl)quinoline 15 was prepared as in Example 402 except that 3-[8-(methylsulfonyl)-4- The phenol and 3-fluoro-l-(isopropylsulfonyl)-benzene are used as the reactants in dimethylacetamide to give the title compound as a white foam. MS (ES) m/z </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 2〇Example @34(:Μ3-[8-(methyl-decyl)-4-quinolinyl]phenoxy}phenyl)sulfonyl]-1-propanyl was prepared according to Example 402 except that 3 was used. -[8-(methylsulfonyl)-4-indole] and 3-[(3-fluorophenyl)sulfonyl]-1-propanol as dimethyl 270 200825054 The reactants are used to produce the title compound as a white foam. MS (ES) m/z 497.9: </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Example 419 5 4-{3-[4-(ethylsulfonyl)phenoxy]phenyl}-8-(methylsulfonyl)quinolin was prepared according to Example 402 except that 3-[8-( Methylsulfonyl)-4-quinolinyl]phenol and 1-(ethylsulfonyl)-4-fluorobenzene are used as the reactants in dimethylacetamide to give the title compound as a white foam. MS (ES) <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; Example 420 8-(Methylsulfonyl)-4-{3-[4-(propylsulfonyl)phenoxy]phenyl}indan 15 was prepared as in Example 402 except that 3-[8-( Methylsulfonyl)-4-quinolinyl]phenol and 4-fluoro-1-(propylsulfonyl)-benzene as the reactant in dimethylacetamide to give the title as a white foam </RTI> </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 20 Example 421 4 - {3-[4-(Isopropylsulfonyl)phenoxy]phenyl b-8-(methylsulfonyl)quinoline

比照範例402製備，除了使用3-[8-(甲基績醯基）-4-啥琳基]齡和4-氟基-1-(異丙基石黃酿基）—苯作為二甲基乙 25醯胺中之反應物以產生如一白色泡沫之該標題化合物。MS (ES) m/z 481.9 ； HRMS:計算值 c25H23N〇5S2 + H+， 271 200825054 482.10904;實測值（ESI, [M+H]+0bs，d)，482. 109卜 範例422 8-（甲基磺醢基）-4- {3-[3-（甲基磺醢基）苯氧基]苯基} 喹琳 5 比照範例402製備，除了使用3-[8-（甲基磺醯基）-4- 喹啉基]酚和3-氟基-1-(甲基磺醯基）-苯作為二甲基乙醯 胺中之反應物以產生如一白色泡沫之該標題化合物。MS (ES) m/z 453. 6; HRMS:計算值 C23H19N〇5S2 + H+，454.07774; 實測值（ESI, [Μ+ΗΓ)，454.0781。 10 範例423 8-（甲基磺斑基）-4 - {3-[4-（甲基磺醢基）苯氧基]苯基} 喹琳 比照範例402製備，除了使用3-[8-(甲基磺醯基）-4-喧琳基]紛和4-氟基-1-(甲基磺醯基）-苯作為二甲基乙酸 15胺中之反應物以產生如一白色泡沫之該標題化合物。MS (ES) m/z 453.6 ; HRMS··計算值 c23H19N〇5S2 + H+，454. 07774 ; 實測值（ESI, [Μ+ΗΓ)，454.0782。 範例424 4-{3-[2-氟基-4-(甲基磺醢基）苯氧基]苯基}一8一（甲 2〇 基磺醢基）喹啉 比照範例402製備，除了使用3一[8-(甲基磺醯基）一4一 喹啉基]酚和1，2-二氟基一 4-(甲基磺醯基）苯作為二甲基 乙醯胺中之反應物以產生如一白色泡沫之該標題化合物。 MS (ES) m/z 471.6 ; HRMS:計算值 c23H18FN〇5S2 + ΙΓ， 25 472.06832 ;實測值（ESI, [Μ+ΗΓ)，472.0682。 272 200825054Prepared in accordance with Example 402 except that 3-[8-(methylglycosyl)-4-indolyl]-age and 4-fluoro-1-(isopropylstone)-benzene were used as the dimethyl group. The reactant in 25 decylamine to give the title compound as a white foam. MS (ES) m/z 481.9; HRMS: calcd., calcd,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, Sulfomethyl)-4-{3-[3-(methylsulfonyl)phenoxy]phenyl}quinolin 5 was prepared according to Example 402 except that 3-[8-(methylsulfonyl)- 4-Quinolinyl]phenol and 3-fluoro-1-(methylsulfonyl)-benzene as the reactant in dimethylacetamide to give the title compound as a white foam. MS (ES) m/z 453. Found: </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; 10 Example 423 8-(Methylsulfonyl)-4 - {3-[4-(methylsulfonyl)phenoxy]phenyl}quinoline was prepared according to Example 402 except that 3-[8-( Methylsulfonyl)-4-indolyl] and 4-fluoro-1-(methylsulfonyl)-benzene as the reactant in dimethylacetic acid 15 amine to give the title as a white foam Compound. MS (ES) m/z 453.6; HRMS································ Example 424 4-{3-[2-Fluoro-4-(methylsulfonyl)phenoxy]phenyl}-8-(methyl-2-ylsulfonyl)quinoline was prepared according to Example 402 except 3-I[8-(methylsulfonyl)-4-ylquinolinyl]phenol and 1,2-difluoro-4-(methylsulfonyl)benzene as reactants in dimethylacetamide To produce the title compound as a white foam. MS (ES) m/z 471.6; HRMS: calcd., s, s, s, s, s, s, s, s, s, s, s, s, s, s. 272 200825054

敷J 425 5 3一（甲基確酸基）一4一(3、1&gt;(甲基續酸基）苯氧基]苯 基}-8-(三氟甲基）喹啉 步驟1: 4一(3一甲氧基苯基)-3-(甲基確雄基)-8-(三氟 甲基）喹啉 在含有[2-胺基-3-(三氟甲基）苯基](3_甲氧基苯基） 10甲酮（147rag，0.50_〇1)和1，1-二乙氧基-2-(甲基績酿 基）乙烧（98 mg，〇·5〇 _〇1)於冰醋酸⑽此）中之一經 攪拌的混合物中加入-滴移液管之濃硫酸並在uq ^㈣ 20小時。在該經冷卻之反應中加入含有Μ· (5 之水 (20 mL)亚以二氯甲院萃取。透過錢該萃取物並減 15壓濃縮。該殘餘物透過以梯度35:65至100:0之E:H洗提 的色層分析純化以產生如—白色固狀物之該標題化合物 (122 mg，於初始溶劑系統中Rf〜〇15)。ms (es) 382· 1，HRMS:計算值（；18h14f3n〇3S + H+，382· 07192 ;實 測值（ESI, [M+H]+)，382· 0719。 273 200825054 步驟2: 3-[3-（甲基碟斑基）-8-(三氟甲基）-4-啥琳 基]酚 將含有4 -（3-甲氧基苯基）-3-(甲基磺醯基）-8 -（三氟 5甲基）喹啉（1.18 g，3.10 mmol)於吡啶鹽酸鹽（4.6 g)之 一混合物在200 °C加熱2小時，然後倒進冰中。使冰融化 然後以二氣曱烷（30mL，20mL)萃取該混合物。透過MgS〇4 乾燥該萃取物並減壓濃縮。經色層分析，以梯度20:80至 50:50之E: Η洗提，以產生如一白色固狀物之該標題化合物 10 (1· 13 §，於 50:50 Ε:Η 中 Rf 〜〇· 35)。MS (ES) /Ζ//Ζ 368. 1 ; HRMS:計算值 CnH12F3N〇3S + H+, 368.05627;實測值（ESI, [Μ+ΗΓ), 368.0567。 步驟3: 3-（甲基磺醢基）一4-{3-[3 -（甲基磺醢基）苯 15氧基]苯基}-8-（三氟甲基）喹啉 將含有3-[3-(甲基磺醯基）—8_(三氟甲基）—4-喹啉基] 齡（183 mg，〇· 50 mmol)、3-MeS〇2PhB(OH)2 (150 g，〇· 75 mmol)、Cu(0Ac)2 (91 mg)、n比唆（〇· 12 mL，1· 5 mmol)、 和粉狀之4A分子篩（〇·5〇 g)於二氯曱烧（i〇 mL)中之一混 20合物在室溫攪拌64小時（部份接觸空氣）。該反應透過助渡 器（Celite)過濾，加入水（15mL)，並以二氣甲烷萃取。該 萃取物透過MgS〇4乾燥並減壓濃縮。該殘餘物經過以梯度 50:50至1〇〇:〇之E:Η洗提的色層分析，更進一步藉由逆相 色層分析純化以產生如一白色固狀物之該標題化合物（188 274 200825054 mg)。MS (ES) /z//z 521.8 ; HRMS:計算值 C24H18F3N〇5S2 + H+，522.06512;實測值（ESI, [M+H]+)，522.0652。Apply J 425 5 3 -(methyl-acidic acid)- 4-(3,1&gt;(methylphosphoryl)phenoxy]phenyl}-8-(trifluoromethyl)quinoline Step 1: 4 Mono(3-methoxyphenyl)-3-(methyl-androstyl)-8-(trifluoromethyl)quinoline in the presence of [2-amino-3-(trifluoromethyl)phenyl]( 3_Methoxyphenyl) 10-ketone (147rag, 0.50_〇1) and 1,1-diethoxy-2-(methyl-flavored) Ethylene (98 mg, 〇·5〇_〇 1) Add one-drip pipette of concentrated sulfuric acid to one of the glacial acetic acid (10) in this mixture and add it to uq ^ (d) for 20 hours. In the cooled reaction, a solution containing hydrazine (5 mL of water (20 mL) was added to the solution of dichloromethane. The extract was passed through the weight and concentrated under reduced pressure. The residue was passed through a gradient of 35:65 to 100: Chromatography of 0:H eluted to afford the title compound as a white solid (122 mg, Rf~ 〇15 in the initial solvent system).ms (es) 382 · 1, HRMS: Value (;18h14f3n〇3S + H+, 382· 07192 ; measured value (ESI, [M+H]+), 382· 0719. 273 200825054 Step 2: 3-[3-(methyl-ray plaque)-8- (Trifluoromethyl)-4-indolyl]phenol will contain 4-(3-methoxyphenyl)-3-(methylsulfonyl)-8-(trifluoro-5methyl)quinoline ( 1.18 g, 3.10 mmol) of a mixture of one of pyridine hydrochloride (4.6 g) was heated at 200 ° C for 2 hours, then poured into ice. The ice was thawed and the mixture was extracted with dioxane (30 mL, 20 mL). The extract was dried over MgSO.sub.4 and concentrated under reduced pressure. EtOAc (EtOAc) elute §, at 50:50 Ε: Η in Rf ~ 〇 · 35). MS (ES) / Ζ / / 368 368. 1 ; HRMS: Calculated CnH12F3N 〇3S + H+, 368.05627; found (ESI, [Μ+ΗΓ), 368.0567. Step 3: 3-(methylsulfonyl)- 4-{3-[3 -(Methylsulfonyl)benzene 15oxy]phenyl}-8-(trifluoromethyl)quinoline will contain 3-[3-(methylsulfonyl)-8-(trifluoromethyl)- 4-quinolinyl] age (183 mg, 〇· 50 mmol), 3-MeS〇2PhB(OH)2 (150 g, 〇·75 mmol), Cu(0Ac)2 (91 mg), n 唆 ( 〇· 12 mL, 1·5 mmol), and powdered 4A molecular sieve (〇·5〇g) in a mixture of dichloropyrene (i〇mL) and stirred at room temperature for 64 hours (partial The reaction was filtered through a Celite filter, water (15 mL) was added and extracted with di-methane. The extract was dried over MgSO 4 and concentrated under reduced pressure. To the title: 色 E: 色 的 的 的 的 , , , 188 188 188 188 188 188 188 188 188 188 188 188 188 188 188 188 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( </ RTI> </ RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt;

篪例426至45Q 5 以相似於範例43流程之方法製備下列範例426至459 中之化合物，除了使用適當對應的函化芳基砜和喹啉酚用 來進行所欲之取代作用。 範例426 3-(甲基確醯基）-4-{3-[3-(丙基續醢基）苯氧基]苳 ίο 基}-8-（三敗甲基）啥淋 比照範例43製備，除了使用3-[3-(甲基續醢 基）-8-(三氟甲基）-4-啥琳基]盼和3-氟基-i-(丙基石黃鱗 基）-苯作為反應物以產生如一暗白色固狀物之該標題化含 物48(^+)//7/^549.8 [丛+11] + ;111^:計算值〇26112而她32 15 + H+, 550. 09642 ；實測值（ESI, [M+H]+ Obs，d)， 550·0955 。 範例427 4-{3-[3-(異丙基磺醢基）苯氧基]苯基}_3-(甲基磺雖 20 基）-8-（三氟甲基）喹啉 比照範例43製備，除了使用3一[3_(甲基磺醢 基）-8-(三氟甲基）-4-喧琳基]盼和1-(異丙基續醯基）-3-氟苯作為反應物以產生如一白色固狀物之該標題化合物。 MS (ES+) π/ζ 549.8 [M+H]+; HRMS:計算值 C26H22F3N〇5S2 275 200825054 + H+, 550.09642 ；實測值（ESI, [M+H]+ Obs’d), 550·0959 。 範例428 5 4-{3-[3-氟基-5-（甲基磺醢基）苯氧基]苯基卜3-(甲 基磺醢基）- 8-(三氟甲基）喹啉 比照範例43製備，除了使用3-[3-（曱基磺醯 基）-8-（三氟甲基）-4-喹琳基]盼和3, 5-二敦基-1-（甲基石黃 醯基）苯作為反應物以產生如一白色固狀物之該標題化合 10 物。MS (ES+)/Z7//539· 8 [M+H] + ; HRMS:計算值 C24HnF4N〇5S2 + H+, 540.05570 ；實測值（ESI， [M+H]+ Obs，d)， 540.0552 。 範例429 15 4 - {3-[3-氣基-5-（甲基確醢基)苯氧基]苯基}-3-（甲基續醢 基)-8-(三氟甲基)啥琳 比照範例43製備，除了使用3-[3-（甲基磺醯 基）-8-(三氟甲基）-4-喹啉基]酚和3-氯基-5-氟基-1-（甲 基石黃醯基）苯作為反應物以產生如一白色固狀物之該標題 20 化合物。MS (ES+) /ff/z 555. 8 [M+H]+ ; HRMS:計算值 C24HnClF3N〇5S2 + H+，556·02615;實測值（ESI，[M+H] + Obs’d)，556.0256。 範例430 276 200825054 4- {3-[ 3-(乙基讀斑基）-5-氟基苯氧基]苯基}-3-甲基 - 8-（三氟甲基）啥琳 比照範例43製備，除了使用3-甲基-8-(三氟甲 基）-4-啥琳基]紛和3, 5-二氟基_1_(乙基績醯基）苯作為反 5 應物以產生如一白色固狀物之該標題化合物。MS (ES) /ff/z 489.8 ; HRMS:計算值 C25H19F4N〇3S + H+，490· 10945 ;實 測值（ESI，[M+H]+0bs’d)，490.1094。 範例431 10 8-氯基-3-異丙基-4-{3-[3-(甲基磺醢基）苯氧基]苯 基}喹啉 比照範例43製備，除了使用3-異丙基-8-氣基--4-σ奎琳基]紛和3-氟基-1 -(甲基項醯基）苯作為反應物以產 生如一白色固狀物之該標題化合物。MS (ES) y/7/z 451. 9 ; 15 HRMS:計算值 C25H22ClN〇3S + H+，452· 1082 ;實測值（ESI， [M+H]+ Obs’d)，452· 1085。 範例432 3-甲基-8-(三氟甲基）-4-(3-{3-[(三氟甲基）磺醢基] 20 苯氧基}苯基）喹啉Examples 426 to 45Q 5 The compounds of the following Examples 426 to 459 were prepared in a similar manner to the procedure of Example 43 except that the corresponding corresponding functional aryl sulfone and quinolinol were used to carry out the desired substitution. Example 426 3-(Methyl-decyl)-4-{3-[3-(propyl sulfhydryl)phenoxy] 苳ίο yl}-8-(tri-m-methyl) oxime was prepared according to Example 43 In addition to using 3-[3-(methyl fluorenyl)-8-(trifluoromethyl)-4-indolyl] and 3-fluoro-i-(propyl stellate)-benzene as reactants To produce a titled material such as a dark white solid 48(^+)//7/^549.8 [cluster +11] + ; 111^: calculated value 〇26112 and her 32 15 + H+, 550. 09642; Found (ESI, [M+H]+ Obs,d), 550·0955. Example 427 4-{3-[3-(Isopropylsulfonyl)phenoxy]phenyl}_3-(methylsulfonyl 20-yl)-8-(trifluoromethyl)quinoline prepared according to Example 43 In addition to using 3-mono[3_(methylsulfonyl)-8-(trifluoromethyl)-4-indolyl] and 1-(isopropyl sulfonyl)-3-fluorobenzene as reactants To give the title compound as a white solid. MS (ES+) π / ζ 549.8 [M+H]+; HRMS: calcd., calcd, calcd, calcd, calcd, calcd. Example 428 5 4-{3-[3-Fluoro-5-(methylsulfonyl)phenoxy]phenyl 3-(methylsulfonyl)-8-(trifluoromethyl)quinoline Prepared according to Example 43, except that 3-[3-(indolylsulfonyl)-8-(trifluoromethyl)-4-quinolinyl] and 3,5-diyl-l-(methyl) Acetin is used as a reactant to give the title compound as a white solid. MS (ES+) / Z7 / / 539. 8 [M+H] + </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Example 429 15 4 - {3-[3-Gasyl-5-(methyl-decyl)phenoxy]phenyl}-3-(methyl decyl)-8-(trifluoromethyl)anthracene Lin was prepared according to Example 43, except that 3-[3-(methylsulfonyl)-8-(trifluoromethyl)-4-quinolinyl]phenol and 3-chloro-5-fluoro-1- (Methylglycosyl)benzene is used as the reactant to give the title compound as a white solid. MS (ES+) / ff / z 555. 8 [M+H]+; HRMS: calcd. calcd. </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Example 430 276 200825054 4- {3-[ 3-(ethyl-plaque)-5-fluorophenoxy]phenyl}-3-methyl- 8-(trifluoromethyl)anion Prepared, except that 3-methyl-8-(trifluoromethyl)-4-indolyl] and 3,5-difluoroyl_1-(ethylhistyl)benzene were used as anti-5 reagents to produce The title compound is as a white solid. MS (ES) / ff / z 489.8; HRMS: calcd. (md: s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s. Example 431 10 8-Chloro-3-isopropyl-4-{3-[3-(methylsulfonyl)phenoxy]phenyl}quinoline was prepared as in Example 43, except that 3-isopropyl was used. -8-Gasyl--4- syl- cylinyl] and 3-fluoro-l-(methyl-indenyl)benzene are used as the reactants to give the title compound as a white solid. MS (ES) y/7/z 451. 9; 15 HRMS: calcd for C25H22ClN 〇3S + H+, 452 · 1082; found (ESI, [M+H]+ Obs'd), 452·1085. Example 432 3-Methyl-8-(trifluoromethyl)-4-(3-{3-[(trifluoromethyl)sulfonyl] 20 phenoxy}phenyl)quinoline

277 200825054 步驟1: 1 -氟基-3-三兔基甲續酸基-苯 將含有3 -氣本-1 -石頁酿氣（5.0 g，25.7 mmol)、18-冠 -6 醚（〇· Π0 g，0· 642 mmol)、和氟化鉀（7· 46 g，128 mmol) 於乙腈（51 mL)中之一混合物搜拌4小時。加入飽和的 5 NaHC〇3水溶液（200 mL)並以乙酸乙酯萃取該混合物。以飽 和的NaHCCb水溶液（200 mL)沖洗該經化合的有機物，透過 MgS〇4乾燥，並濃縮以產生如一黃色油狀物之該中間產物3-氟苯確醯氟（4· 20 g，92%)，其無經進一步純化即被用於下 一步驟。N2大氣下，在含有3-氟苯-1-磺醯氟（4.20 g，23. 6 1〇則ιοί)和二氟化三（二甲胺基）硫（三甲基矽烷基）（〇 649 g， 2· 36 mmol)之THF (24 mL)中逐滴加入含有（三氟甲基）三甲 基石夕烧（7. 06 ml，47· 1 mmol)之 THF(24 mL)透過 〇· 25 小 時，並將該反應在室溫攪拌整夜。加入水並以乙酸乙酯萃 取該反應。以水沖洗該經化合的有機萃取物數次，然後以 15半飽和的食鹽水沖洗，透過MgS〇4乾燥並濃縮。藉由以梯度 〇· 100至20:80之E:H洗提的色層分析純化，以產生如一 黃色液狀物之該標題化合物（3. 32 g，62%)。 步驟2: 3-甲基-8-(三氟甲基）一4一（3-{3-[(三氟甲基） 20磺醯基]苯氧基}苯基）喹啉 比照範例43製備，除了使用3一甲基—8—(三氟甲 基）-4-喧琳基]盼和3—氟基_卜（三氟曱基石黃醯基）笨作為反 應物，在100 T加熱，以產生如-白色固狀物之該標題化 278 200825054 合物。MS (ES+) /z//z 511· 7 [M+H]+ ; HRMS:計算值 C24H15F6NO3S + H+, 512.07496 ；實測值（ESI，[M+H] + 〇bs’d)，512.0750。277 200825054 Step 1: 1 -Fluoro-3-trisylcarbamate-Benzene will contain 3-gaso-1 - stellite (5.0 g, 25.7 mmol), 18-crown-6 ether (〇 · Π0 g, 0·642 mmol), and a mixture of potassium fluoride (7·46 g, 128 mmol) in acetonitrile (51 mL) for 4 hours. A saturated aqueous solution of 5 NaHC 3 (200 mL) was added and the mixture was extracted with ethyl acetate. The combined organics were washed with a saturated aqueous solution of NaHCCb (200 mL), dried over &lt;RTI ID=0.0&gt;&gt; ), which was used in the next step without further purification. In the atmosphere of N2, it contains 3-fluorobenzene-1-sulfonium fluoride (4.20 g, 23.61 〇 ιοί) and tris(dimethylamino) sulphide (trimethyl decyl) (〇649 g, 2·36 mmol) of THF (24 mL) was added dropwise with THF (24 mL) containing (trifluoromethyl)trimethyl sulphur (7. 06 ml, 47·1 mmol). The reaction was stirred at room temperature overnight. Water was added and the reaction was extracted with ethyl acetate. The combined organic extract was washed with water several times, then rinsed with 15 half-saturated brine, dried over MgSO 4 and concentrated. The title compound (3. 32 g, 62%) was obtained as a yellow liquid. Step 2: 3-Methyl-8-(trifluoromethyl)-tetra-(3-{3-[(trifluoromethyl) 20sulfonyl]phenoxy}phenyl)quinoline prepared according to Example 43 In addition to using 3-methyl-8-(trifluoromethyl)-4-indolyl] and 3-fluoro-based (trifluoromethane fluorenyl) as a reactant, heating at 100 T to produce For example, the white solidified title 278 200825054. MS (ES+) /z//z </RTI> </RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </ RTI> </ RTI> </ RTI> <RTIgt;

BdH 433 4-{3-[3-(甲基磺醢基）苯氧基]苯基}一8-（三氟甲基） 喹啉-3-胺 步驟1: 2-(4-(3-甲氧基苯基）-8-(三氟甲基）喹啉 -3-基）異吲哚啉-；[，3—二酮 比照範例24中步驟1製備，除了使用（2-胺基-3-(三 氟甲基）苯基）（3-甲氧基苯基）甲酮和2-(2, 2-二乙氧基乙 基）異吲哚琳-1，3-二酮作為反應物以產生如一白色固狀物 之邊標題化合物。MS (ES+) zs/z 449· 1 [M+H]+。 步驟2: 4_(3-甲氧基苯基）-8-(三氟甲基）喹啉-3一胺 比照範例398之步驟4製備，除了使用2-(4-(3-甲 氧基苯基）-8-(三氟甲基）喹啉-3-基）異吲哚啉—1，3—二酮 作為反應物以產生如一黃色固狀物之該標題化合物。MS (es) /z//z 319. 1 0 步驟3: 4-{3-[3-（甲基磺醢基）苯氧基]苯基}一8一（三 氟甲基）啥琳_3-胺 自上述之5亥甲氧基的去甲基化之後，以範例43中所述 之相似方法自2-(4-(3-羥基苯基）-8-(三氟甲基）喹啉一3— 279 200825054 基）異吲哚啉-1，3-二酮製備該標題化合物。MS (ES) m/z 458. 7 ; HRMS:計算值 C23HnF3N2〇3S + H+，459· 09847 ;實 測值（ESI，[Μ+ΗΓ)，459.0985。 5 j在例434 4-{2-氯基-5-[3-（甲基讀醯基）苯氧基]苯基}一8-氟喹 啉 以範例43中所述之相似方法製備該標題化合物。MS (ES) m/z 427.6 ； HRMS:計算值 C22H15ClFN〇3S + H+， ίο 428_ 05179 ;實測值（ESI, [M+H]+ Obs’d)，428. 0521。 簸例435 4-{2-氣基-5-[3-(甲基磺醢基）苯氧基]苯基}喹啉 以範例43中所述之相似方法製備該標題化合物。MS 15 (ES) m/z 409.7 ； HRMS:計算值 C22H16ClN〇3S + H+， 410.06122;實測值（ESI, [Μ+ΗΓ), 410.0618。 範例436 4-{2_氣基-5-[3-(甲基碟醢基)苯氧基]苯基卜8-氟喹啉-3- 20 羧酸 以範例43中所述之相似方法製備該標題化合物。MS (ES) m/z 471.6 ； HRMS··計算值 C23H15ClFN〇5S + H+， 472.04163;實測值（ESI, [Μ+ΗΓ)，472.0419。 280 200825054 範例437 3-甲基-4-{1 -[3-(甲基磺醢基）苯基]-ih-«比唑-4-基}-8-（三氟甲基）喹琳 步驟1: 3-甲基-4-（1H-吡唑-4-基）-8-(三氟甲基）喹 5 琳 以範例259中所述之相似方法製備該標題化合物。MS (ES) m/z 277.6 ； HRMS:計算值+ 278.08996;實測值（ESI, [M+H]+0bs，d)，278.0903。 ίο 步驟2: 3-甲基一4-{卜[3-(甲基確醢基)苯基]-iH-吡唑-4- 基}-8-(三氟甲基)啥琳 以範例43中所述之相似方法製備該標題化合物。MS (ES) m/z 432. 0 ； HRMS:計算值 + H+， 432.09881;實測值（ESI，[M+H]+0bs’d)，432.0992。 15 範例438 8-甲基-4 - {3-[3-（甲基磺醢基）苯氧基]苯基}喹啉-3- 羧酸 以範例43中所述之相似方法製備該標題化合物。MS 20 (ES) m/z 434. 1 ； HRMS:計算值 C24H19N〇5S + H+， 434. 10567;實測值（ESI，[M+H]+0bs，d)，434.1065。 439 8-氯基-4_{3-[3-(乙基磺醢基）苯氧基]苯基}喹啉-3- 281 200825054 甲醢胺 步驟1: 8-氣基-4-(3-羥基苯基）喹啉羧酸乙酯 將含有4-溴基-8-氯喹啉-3-羧酸乙酯（5· 2〇 g，16· 6 mmol)、3-.基本糊@文（4· 53 g，33· 1 mmol)、碳酸納（6· 85 5 g，49· 7 mmol)、四（三苯基膦）鈀（〇) (5· 73 g，4· 97 咖〇1)、 甲苯（160 mL)、H2O (80 mL)、和乙醇（4〇 mL)之一攪拌均 勻的混合物在迴流加熱4小時。在該經冷卻的反應中加入 水（75 mL)並以乙酸乙醋萃取數次。以食鹽水沖洗 该經化合的萃取物’以MgS〇4乾燥，過濾，並減壓濃縮成一 10 棕色漿液。透過色層分析純化以產生如一黃色粉末之該標 題化合物（4. 19 g，77%)。MS (ES) m/z 328· 1 ; HRMS:計 算值 Ci8HuClN〇3 + H+，328.07350;實測值（ESI，[Μ+ΗΓ)， 328.0748 。 步驟2: 8-氯基-4-{3-[3-(乙基確酸基）苯氧基]苯基} 啥琳-3-甲雄L胺 根據範例43之步驟，自8-氣基-4-(3-經基苯基）喧琳 -3-羧酸乙酯和1-(乙基績醯基）-3-氟苯製備該標題化合 物。MS (ES) m/z 466.8 。 20 範例440 8-氣基-4 - {3-[3-氱基-5-（甲基確酸基）苯氧基]苯基} 喹啉-3-甲醢胺 根據範例43之步驟，自8-氣基-4-(3-羥基苯基）喹啉 282 200825054 -3-羧酸乙酯和1，3-二氣-5-(曱基磺醯基）苯製備該標題化 合物。MS (ES) m/z 486. 6。 範例441 8-氟基-4-{3-[3-(甲基續酸基）苯氧基]苯基}啥琳 步驟1: 3-(8-氟基-4-考琳基）紛 以範例259中所述之相似方法製備該標題化合物。MS (ES) ra/z 237.8 ； HRMS:計算值 C15H1QFN0 + H+， 240.08192;實測值（ESI, [Μ+ΗΓ)，240.0818。 步驟2: 8-氟基-4-{3-[3-(甲基磺醢基）苯氧基]苯基} 喹啉 以範例43中所述之相似方法製備該標題化合物。MS (ES) m/z 393.6 ； HRMS:計算值 C22H16FN〇3S + H+， 15 394.09077 ;實測值（ESI，[M+H]+ Obs’d)，394.0912。 範例442 4-{3-[3_(甲基讀酸基）苯氧基]苯基}-3-苯基-8-(三 氟甲基）喹啉 ~ 20 比照範例43製備，除了使用3-[3-苯基-8-(三敗甲 .基）-4-喹啉基]酚和3-氟基-1-(甲基磺醯基）_苯作為反應 物以產生如一清澈漿液之該標題化合物。MS (ES) m/z 520· 0 ; HRMS:計算值 C29H2QF3N〇3S + H+，520.11887;實 測值（ESI, [M+H]+〇bs’d)，520.1190。 283 25 200825054 範例442 4 - {3 - [3-(甲基磺醯基）苯氧基]苯基}喹啉-8-甲腈 步驟1: 4-羥基喹啉-8-甲腈 第一部份，比照範例415中步驟2製備，除了使用 5 2-{ [(2, 2-一甲基-4, 6-二氧-1，3-二σ惡烧-5-亞甲基）甲基] 胺基}苯甲腈作為反應物以產生如一棕褐色固狀物之該標 題化合物。MS (ES) m/z 171.3。 步驟2: 4-淡基喧琳-8-甲腈 10 第二部份，比照範例415中步驟2製備，除了使用4- 羥基喹啉-8-甲腈和含有ρ(〇)βΓ3之DMF作為反應物以產生 如一棕褐色固狀物之該標題化合物。MS (ES) m/z 232. 8。 步驟3: 4-（3-羥基苯基）喹啉-8-甲腈 15 將含有4-溴喹啉-8-甲腈（700 mg，3. 1 mmol)、3-羥 基苯基硼酸（832 mg，6· 10 mmol)、Pd(PPh3)4 (488 mg，0· 42 mmol)、和 K3P〇4 (1· 60 g，7. 5 mmol)於 1，4 二噁烷（50 mL) 中之一混合物在迴流攪拌3小時。冷卻該反應，於含有loo mL水之分液漏斗中過濾，並以乙酸乙酯萃取。透過MgS〇4 20 乾燥該萃取物並減壓濃縮。該殘餘物經過梯度10:90至 50:50之E··Η的色層分析，以產生如一黃色固狀物之該標題 化合物（600 mg)。MS (ES) m/z 246· 8。 步驟4: 4-{3-[3-(甲基磺醢基）苯氧基]苯基}喹啉 25 _8-甲腈 284 200825054 比照範例43製備，除了使用4-(3-羥基苯基）喹啉-8-甲腈和卜氟基一（甲基績醯基）苯作為反應物以產生如一 暗白色固狀物之該標題化合物。MS (ES) m/z 400· 7。 5 gJLMi 4- {3- [3-（乙基續酸基）苯氧基]苯基}啥琳一 8一甲腈 比照範例43製備，除了使用4-(3-羥基苯基）喹啉-8-甲腈和1—(乙基續酿基）—3_氟苯作為反應物以產生如一暗 白色固狀物之該標題化合物。MS (ES) m/z 414. 7。 10 J 445 4 - {3-[3-(丙基磺醢基）苯氧基]苯基}喹啉-8-甲腈 比照範例43製備，除了使用4-(3-羥基苯基）喹啉-8-甲腈和1-氟基-3-(丙基磺醯基）苯作為反應物以產生如一 15 栋褐色固狀物之該標題化合物。MS (ES) m/z 428. 8。 辑例446 4-{3-[3-(異丙基磺醢基）苯氧基]苯基}喹啉-8-甲腈 比照範例43製備，除了使用4-(3-羥基苯基）喹啉-8-2〇 甲腈和氟基—3-(異丙基續醯基）苯作為反應物以產生如 一暗白色固狀物之該標題化合物。MS (ES) m/z 428. 8。 範例447 4-{3-[3-(苄基磺醢基）苯氧基]苯基}喹啉-8-甲腈 285 200825054 比照範例43製備，除了使用4-(3-羥基苯基）喹啉-8-甲腈和1_(节基項醯基）-3-氟苯作為反應物以產生如一紅 色固狀物之該標題化合物° MS (Es) m/z 476. 8。 5 gji 448 4 -（3-{3-[(3-羥基丙基）磺醢基]苯氧基}苯基）喹啉 -8-甲腈 比照範例43製備，除了使用4-(3-羥基苯基）喹啉-8-甲腈和3-[(3-氟苯基）磺醯基]-1-丙醇作為反應物以產生 1〇 如一暗白色固狀物之該標題化合物。MS (ES) m/z 444· 7。 輯例449 4 - {3-[3-氟基-5-(甲基磺醢基）苯氧基]苯基}喹啉-8- 甲腈 15 比照範例43製備，除了使用4-(3-羥基苯基）喹啉-8- 甲腈和1，3-二氟基-5-（甲基磺醯基）苯作為反應物以產生 如一暗白色固狀物之該標題化合物。MS (ES) m/z 418. 7。 範例450 20 4-{3-[3-(乙基磺醢基）-5-氟基苯氧基]苯基}喹啉-8 - 甲腈 比照範例43製備，除了使用4-(3-羥基苯基）喹啉-8-甲腈和1，3-二氟基-5-(乙基磺醯基）苯作為反應物以產生 如一淡黃色固狀物之該標題化合物。MS (ES) m/z 432. 7。 286 200825054 範例451 4- {3-[4-（甲基磺醢基）苯氧基]苯基}喹啉-8-甲腈 比照範例43製備，除了使用4-(3-羥基苯基）喹啉-8-5 甲猜和1-氣基-4-（甲基績酿基）苯作為反應物以產生如一 暗白色固狀物之該標題化合物。MS (ES) m/z 400. 7。 範例452 4- {3-[4-（乙基續酿基）苯氧基]苯基}啥琳-甲腈 10 比照範例43製備，除了使用4-(3-羥基苯基）喹啉-8- 曱腈和4-(乙基磺醯基）-1-氟苯作為反應物以產生如一暗 白色固狀物之該標題化合物。MS (ES) m/z 414. 7。 範例453 15 步驟1: 4-(2-氣基-5-甲氧基苯基）喹啉-8-甲腈 比照範例400中步驟2製備，除了使用4-溴基喹啉-8-甲腈和2-氯基-5-(甲氧基苯基）硼酸作為反應物以產生如 一暗白色固狀物之該標題化合物。 2〇 步驟2: 4-（2_氣基-5-經基苯基）啥琳-8-甲腈 比照範例400中步驟2製備，除了使用4-(2-氯基-5-甲氧基苯基）喹啉-8-甲腈作為反應物以產生如一暗白色固 狀物之該標題化合物。MS (ES) m/z 281.0 ; HRMS:計算 值 C16H9ClN2〇 + H+，281.04762;實測值（ESI，[Μ+ΗΓ 287 200825054BdH 433 4-{3-[3-(Methylsulfonyl)phenoxy]phenyl}-8-(trifluoromethyl)quinoline-3-amine Step 1: 2-(4-(3- Methoxyphenyl)-8-(trifluoromethyl)quinolin-3-yl)isoindoline-;[,3-dione is prepared according to step 1 of Example 24, except that (2-amino group- 3-(Trifluoromethyl)phenyl)(3-methoxyphenyl)methanone and 2-(2,2-diethoxyethyl)isoindolin-1,3-dione as reaction The title compound is produced as a white solid. MS (ES+) zs/z 449· 1 [M+H]+. Step 2: 4_(3-Methoxyphenyl)-8-(trifluoromethyl)quinolin-3-amine was prepared as in Step 4 of Example 398 except that 2-(4-(3-methoxybenzene) was used. The title compound is obtained as a yellow solid as a yellow solid. MS (es) /z//z 319. 1 0 Step 3: 4-{3-[3-(Methylsulfonyl)phenoxy]phenyl}-8-(trifluoromethyl)indole_ After demethylation of the 3-amine from the above 5 methoxy group, from 2-(4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinaline in a similar manner as described in Example 43 The title compound was prepared from the porphyrin- 3 - 279 200825054 base iso-oxaline-1,3-dione. MS (ES) m/z </RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; 5 j in Example 434 4-{2-Chloro-5-[3-(methyl-decyl)phenoxy]phenyl}- 8-fluoroquinoline was prepared in a similar manner as described in Example 43 Compound. MS (ES) m/z 422. Found. Example 435 4-{2-Vinyl-5-[3-(methylsulfonyl)phenoxy]phenyl}quinoline The title compound was obtained in a similar procedure as described in Example 43. MS 15 (ES) m/z 409.7: </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; Example 436 4-{2_Gasyl-5-[3-(methyldoximino)phenoxy]phenyl b- 8-fluoroquinoline-3- 20 carboxylic acid was prepared in a similar manner as described in Example 43 The title compound. MS (ES) m/z </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 280 200825054 Example 437 3-Methyl-4-{1 -[3-(methylsulfonyl)phenyl]-ih-«pyrazol-4-yl}-8-(trifluoromethyl)quinidine 1: 3-Methyl-4-(1H-pyrazol-4-yl)-8-(trifluoromethyl)quinoline 5 The title compound was prepared in a similar manner as described in Example 259. MS (ES) m/z </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; Οο Step 2: 3-methyl-4-{Bu[3-(methyl-decyl)phenyl]-iH-pyrazol-4-yl}-8-(trifluoromethyl)anionine as Example 43 The title compound was prepared in a similar manner as described above. MS (ES) m/z 422. Found: &lt;RTI ID=0.0&gt;&gt; 15 Example 438 8-Methyl-4 - {3-[3-(methylsulfonyl)phenoxy]phenyl}quinoline-3-carboxylic acid The title compound was prepared in a similar manner as described in Example 43 . MS 20 (ES) m/z 434. Found: s., s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s. 439 8-Chloro-4_{3-[3-(ethylsulfonyl)phenoxy]phenyl}quinoline-3- 281 200825054 Formamide Step 1: 8-Alkyl-4-(3- Ethyl hydroxyphenyl)quinolinecarboxylate will contain ethyl 4-bromo-8-chloroquinoline-3-carboxylate (5·2〇g, 16.6 mmol), 3-.basic paste@文(4 · 53 g, 33·1 mmol), sodium carbonate (6·85 5 g, 49·7 mmol), tetrakis(triphenylphosphine)palladium (〇) (5·73 g, 4·97 curry 1), A stirred mixture of one of toluene (160 mL), H.sub.2 (80 mL), and ethanol (4 mL) was heated at reflux for 4 hours. Water (75 mL) was added to the cooled reaction and extracted several times with ethyl acetate. The combined extract was washed with brine to dryness with MgS 4, filtered, and concentrated under reduced pressure to a 10 brown slurry. Purification by chromatography to give the title compound (4. 19 g, 77%) as a yellow powder. MS (ES) m/z </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Step 2: 8-Chloro-4-{3-[3-(ethyl-Acidyl)phenoxy]phenyl}-indolyl-3-methyl-l-amine. According to the procedure of Example 43, from 8-gas The title compound was prepared from ethyl 4-(3-phenylphenyl)-indole-3-carboxylate and 1-(ethyldido)-3-fluorobenzene. MS (ES) m/z 466.8. 20 Example 440 8-Alkyl-4 - {3-[3-indolyl-5-(methyl-acid)phenoxy]phenyl}quinoline-3-carboxamide According to the procedure of Example 43, 8-Vethyl-4-(3-hydroxyphenyl)quinoline 282 200825054 Ethyl-3-carboxylate and 1,3-di-5-(indolylsulfonyl)benzene The title compound was prepared. MS (ES) m/z 486. 6. Example 441 8-Fluoro-4-{3-[3-(methylsudanyl)phenoxy]phenyl}anthracene Step 1: 3-(8-fluoro-4-caolinyl) The title compound was prepared in a similar manner as described in Example 259. MS (ES) </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Step 2: 8-Fluoro-4-{3-[3-(methylsulfonyl)phenoxy]phenyl}quinoline The title compound was obtained in a similar procedure as described in Example 43. MS (ES) m/z 393.6; </RTI> </RTI> </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </RTI> <RTIgt; Example 442 4-{3-[3_(Methyl-Phenyl)phenoxy]phenyl}-3-phenyl-8-(trifluoromethyl)quinoline~20 Prepared according to Example 43, except 3- [3-Phenyl-8-(tris-methyl)-4-quinolinyl]phenol and 3-fluoro-1-(methylsulfonyl)-benzene as reactants to produce a clear slurry Title compound. MS (ES) m/z 520····································· 283 25 200825054 Example 442 4 - {3 - [3-(Methylsulfonyl)phenoxy]phenyl}quinoline-8-carbonitrile Step 1: 4-Hydroxyquinolin-8-carbonitrile Part 1 Part, prepared according to step 2 of Example 415, except that 5 2-{[(2,2-monomethyl-4,6-dioxo-1,3-dioxazolidine-5-methylene)methyl was used. Amino}benzonitrile as a reactant to give the title compound as a tan solid. MS (ES) m/z 171.3. Step 2: 4-Petylpyrimidine-8-carbonitrile 10 The second part, prepared in accordance with Step 2 of Example 415, except that 4-hydroxyquinoline-8-carbonitrile and DMF containing ρ(〇)βΓ3 were used as The reactants are taken to give the title compound as a brown solid. MS (ES) m/z 232. 8. Step 3: 4-(3-Hydroxyphenyl)quinoline-8-carbonitrile 15 will contain 4-bromoquinoline-8-carbonitrile (700 mg, 3. 1 mmol), 3-hydroxyphenylboronic acid (832) Mg, 6·10 mmol), Pd(PPh3)4 (488 mg, 0.42 mmol), and K3P〇4 (1·60 g, 7.5 mmol) in 1,4 dioxane (50 mL) One of the mixtures was stirred at reflux for 3 hours. The reaction was cooled, filtered in a sep. The extract was dried through MgS(R) 4 20 and concentrated under reduced pressure. The residue was chromatographed on a gradient of 10:90 to 50:50 to afford the title compound (600 mg) as a yellow solid. MS (ES) m/z 246·8. Step 4: 4-{3-[3-(Methylsulfonyl)phenoxy]phenyl}quinoline 25 -8-carbonitrile 284 200825054 Prepared according to Example 43, except that 4-(3-hydroxyphenyl) was used. Quinoline-8-carbonitrile and fluoro-mono(methylindolyl)benzene are used as the reactants to give the title compound as a dark white solid. MS (ES) m/z 400·7. 5 gJLMi 4- {3- [3-(ethylsutonyl)phenoxy]phenyl}indene-8-carbonitrile was prepared as in Example 43, except that 4-(3-hydroxyphenyl)quinoline- 8-carbonitrile and 1-(ethyl aryl)-3-fluorobenzene are used as the reactants to give the title compound as a dark white solid. MS (ES) m/z 414. 7. 10 J 445 4 - {3-[3-(Propylsulfonyl)phenoxy]phenyl}quinoline-8-carbonitrile was prepared as in Example 43, except that 4-(3-hydroxyphenyl)quinoline was used. -8-carbonitrile and 1-fluoro-3-(propylsulfonyl)benzene were used as the reactants to give the title compound as a brown solid. MS (ES) m/z 428. 8. Example 446 4-{3-[3-(Isopropylsulfonyl)phenoxy]phenyl}quinoline-8-carbonitrile was prepared as in Example 43, except that 4-(3-hydroxyphenyl)quine was used. The title compound was obtained as a dark white solid as mp mp </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; MS (ES) m/z 428. 8. Example 447 4-{3-[3-(Benzylsulfonyl)phenoxy]phenyl}quinoline-8-carbonitrile 285 200825054 Prepared according to Example 43, except for the use of 4-(3-hydroxyphenyl)quine And the title compound ( MS (Es) m/z 476. 8 is obtained as a red solid. 5 gji 448 4 -(3-{3-[(3-hydroxypropyl)sulfonyl]phenoxy}phenyl)quinoline-8-carbonitrile was prepared as in Example 43, except that 4-(3-hydroxyl) was used. Phenyl)quinoline-8-carbonitrile and 3-[(3-fluorophenyl)sulfonyl]-1-propanol are used as the reactants to give the title compound as a dark white solid. MS (ES) m/z 444· 7. EXAMPLE 449 4 - {3-[3-Fluoro-5-(methylsulfonyl)phenoxy]phenyl}quinoline-8-carbonitrile 15 Prepared as in Example 43, except that 4-(3- Hydroxyphenyl)quinoline-8-carbonitrile and 1,3-difluoro-5-(methylsulfonyl)benzene are used as the reactants to give the title compound as a dark white solid. MS (ES) m/z 418. 7. Example 450 20 4-{3-[3-(ethylsulfonyl)-5-fluorophenoxy]phenyl}quinoline-8 -carbonitrile Prepared as in Example 43, except that 4-(3-hydroxyl) was used Phenyl)quinoline-8-carbonitrile and 1,3-difluoro-5-(ethylsulfonyl)benzene are used as the reactants to give the title compound as a pale yellow solid. MS (ES) m/z 432. 7. 286 200825054 Example 451 4- {3-[4-(Methylsulfonyl)phenoxy]phenyl}quinoline-8-carbonitrile Prepared as in Example 43, except that 4-(3-hydroxyphenyl)quine was used The title compound was obtained as a dark white solid as mp mp. MS (ES) m/z 400. 7. Example 452 4-{3-[4-(ethyl succinyl)phenoxy]phenyl}indole-carbonitrile 10 was prepared as in Example 43, except that 4-(3-hydroxyphenyl)quinoline-8 was used. - phthalonitrile and 4-(ethylsulfonyl)-1-fluorobenzene as the reactant to give the title compound as a dark white solid. MS (ES) m/z 414. 7. Example 453 15 Step 1: 4-(2-Vinyl-5-methoxyphenyl)quinolin-8-carbonitrile was prepared as in Step 2 of Example 400 except that 4-bromoquinoline-8-carbonitrile was used. And 2-chloro-5-(methoxyphenyl)boronic acid as the reactant to give the title compound as a dark white solid. 2〇Step 2: 4-(2-Hydroxy-5-phenylphenyl)fluorene-8-carbonitrile was prepared as in Step 2 of Example 400 except that 4-(2-chloro-5-methoxy) was used. Phenyl)quinoline-8-carbonitrile is used as the reactant to give the title compound as a dark white solid. MS (ES) m/z 281.0; HRMS: Calculated C16H9ClN2 〇 + H+,281.04762; found (ESI, [Μ+ΗΓ 287 200825054

Obs’d)，281.0482。 步驟3: 4-{2-氣基-5-[3-(甲基磺醢基）苯氧基]苯基} 考琳-8-甲猜 5 比照範例43製備，除了使用4-(2-氣基-5-羥基苯基） 喹啉-8-甲腈和1-氟基-3-(甲基磺醯基）苯作為反應物以產 生如一暗白色固狀物之該標題化合物。MS (ES)m/z 434. 9 ; HRMS:計算值+ 435.05647;實測值（ESI， [M+H]+ Obs’d)，435.0568。 ίο 範例454 8-氯基-4-{3-[3-(甲基磺醮基）苯氧基]苯基}喹啉 比照範例43製備，除了使用3-(8-氣基-4-喹啉基） 紛和1-氟基-3-(甲基續醯基）苯作為反應物以產生如一暗 15 白色固狀物之該標題化合物。MS (ES) m/z 410. 0 ; HRMS: 計算值 C22H16ClN〇3S + H+，410.06122 ;實測值（ESI， [M+H]+ Obs’d)，410.0615。 範例455 20 8-氯基-4-{3-[3-(乙基磺醢基）苯氧基]苯基}喹啉 比照範例43製備，除了使用3-(8-氯基-4-喹啉基） 紛和 1_(乙基績醯基）-3-氟苯作為反應物以產 生如一白色固狀物之該標題化合物。MS (ES) m/z 423. 9 ; HRMS:計算值 C23H18ClN〇3S + H+，424.07687;實測值（ESI， 288 200825054 [Μ+ΗΓ)，424.0772。 範例456 8-氯基_4-{2-氣基-5-[3-(甲基磺醢基）苯氧基]苯基} 5 喹啉 步驟1: 4-溴基-8-氯喹啉 比照範例415中步驟2製備，除了使用8-氣基-喹啉 -4-酴作為反應物與含有ρ(〇)Βη之DMF以產生如一棕褐色 固狀物之該標題化合物。MS (ES) m/z 241.9 ; HRMS:計 ίο 算值 C9H5BrClN + H+，241. 93666 ;實測值（ESI, [Μ+ΗΓ Obs’d)，241.9372。 步驟2: 8-氯基-4-(2-氣基-5-甲氧基苯基）喹啉 比照上面範例415中步驟3製備，除了使用4-溴基-8-15 氣喹啉和（2-氣基-5-甲氧基苯基）硼酸作為反應物以產生 如一暗白色固狀物之該標題化合物。MS (ES) m/z 304. 0 ; HRMS:計算值 C16HnC12N0 + H+，304.02904;實測值（ESI, [Μ+ΗΓ Obs’d)，304. 0294。 2〇 步驟3: 4-氯基-3-(8-氣基-4-啥琳基）紛 比照上面範例415中步驟4製備，除了使用8-氯基 -4-(2-氣基-5-甲氧基苯基）喧琳作為反應物以產生如一暗 白色固狀物之該標題化合物。HRMS:計算值Ci^C^NO + ir， 290.01339;實測值（ESI, [M+H]+0bs’d)，290. 014卜 289 25 200825054 步驟4: 8-氯基-4-{2-氣基-5-[3-(甲基磺醢基）苯氧 基]苯基}喹啉 比照範例43製備，除了使用4一氣基_3_(8_氣基—4一 喹啉基）酚和3-氟基-1-(甲基磺醯基）苯作為反應物以產 5生如一暗白色固狀物之該標題化合物。MS (ES)m/z 443. 9 ; HRMS:計算值 C22H15CM〇3S + H+，444.02224;實測值（ESI， [Μ+ΗΓ Obs’ d)，444· 0226。 輯例457 ίο 8-氣基-4-{2-氣基-5-[3-(乙基磺醢基）苯氧基]苯基} 喹啉 比照範例43製備，除了使用4-氣基-3-(8-氣基-4-喹啉基）酚和1-(乙基磺醯基）-3-氟苯作為反應物以產生 如一暗白色固狀物之該標題化合物。MS (ES) m/z 458. 1 ; 15 HRMS:計算值 C23H17CI2NO3S + H+，458· 03789;實測值（ESI， [M+H]+ Obs’d)，458.0386。 範例458 8-甲基-4-{3-[3-(甲基續酸基）苯氧基]苯基}啥琳 2〇 步驟1: 3-（8-甲基-4-嗟琳基）紛 比照範例415中步驟3製備，除了使用4-溴基-8-甲 基喹啉作為反應物以產生如一黃色固狀物之該標題化合 物。MS (ES) m/z 236.2 ; HRMS:計算值 UHwNO + H+， 236.10699;實測值（ESI, [Μ+ΗΓ Obs’d)，236.1074。 290 200825054 步驟2·· 8-甲基-4-{3-[3-（甲基磺斑基）苯氧基]苯基} 喹啉 比照範例43製備，除了使用3_(8—甲基—4_喹啉基） 5酚和3—氟基―1^甲基磺醯基）苯作為反應物以產生如一暗 白色固狀物之該標題化合物。MS (ES) m/z 390. 1 ; HRMS: 計算值 CssHnNOsS + r，390.11584;實測值（ESI，[M+H] + Obs’d)，390.1165。 ίο 範例459 8-甲氧基-4-{3-[3-(f基磺醢基）苯氧基]苯基}喹啉 步驟1: 3-(8-甲氧基-4-嗓琳基）紛 比照範例415中步驟3製備，除了使用4-溴基-8-甲 氧基喹啉作為反應物以產生如一黃色固狀物之該標題化合 15 物。MS (ES) m/z 252· 0 ; HRMS:計算值 C16H13N〇2 + H+， 252.10190;實測值（ESI, [M+H]+0bs，d)，252· 1029。 步驟2: 8-甲氧基-4-{3-[3-（甲基磺醢基）苯氧基]苯 基}喹啉 2〇 比照範例43製備，除了使用3-(8-曱氧基-4-喹啉基） 酴和3-氟基-1-(甲基續醢基）苯作為反應物以產生如一暗 白色固狀物之該標題化合物。MS (ES) m/z 405. 9 ; HRMS: 計算值 C23Hi9N〇4S + H+，406· 11076;實測值（ESI，[M+H] + Obs’ d), 406.1110。 291 200825054 在一級和二級磺醯胺（Rf = s〇2Rn，且Rn = NRgRh)的製 備中’該«胺可作為4-甲氧基$基所保護之化合物來被 製備。以二氟乙酸（TFA)處理以移除該4_甲氧基苄基，留下 範例4fiflObs’d), 281.0482. Step 3: 4-{2-Gasyl-5-[3-(methylsulfonyl)phenoxy]phenyl} Corin-8-A-guess 5 Prepared according to Example 43, except that 4-(2- Gaso-5-hydroxyphenyl)quinoline-8-carbonitrile and 1-fluoro-3-(methylsulfonyl)benzene are used as the reactants to give the title compound as a dark white solid. MS (ES) m/z 434. Found: &lt;RTI ID=0.0&gt;&gt; Ίο Example 454 8-Chloro-4-{3-[3-(methylsulfonyl)phenoxy]phenyl}quinoline was prepared as in Example 43, except that 3-(8-methyl-4-quinoline was used The morphyl) and 1-fluoro-3-(methyl decyl) benzene are used as the reactants to give the title compound as a dark white solid. MS (ES) m/z </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; Example 455 20 8-Chloro-4-{3-[3-(ethylsulfonyl)phenoxy]phenyl}quinoline was prepared as in Example 43, except that 3-(8-chloro-4-quinoline was used And the title compound is obtained as a white solid. MS (ES) m/z </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Example 456 8-Chloro-4-{2-carbyl-5-[3-(methylsulfonyl)phenoxy]phenyl} 5 quinoline Step 1: 4-Bromo-8-chloroquinoline Prepared in Step 2 of Example 415, except that 8-oxo-quinoline-4-indole was used as the reactant and DMF containing ρ(〇)Βη to give the title compound as a tan solid. MS (ES) m/z </RTI> </RTI> </RTI> <RTI ID=0.0></RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Step 2: 8-Chloro-4-(2-carbyl-5-methoxyphenyl)quinoline was prepared as in Step 3 of Example 415 above, except that 4-bromo-8-15 oxaquinoline and 2-Vethyl-5-methoxyphenyl)boronic acid was used as the reactant to give the title compound as a dark white solid. MS (ES) m/z </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; 2〇Step 3: 4-Chloro-3-(8-methyl-4-indolyl) was prepared in accordance with Step 4 of Example 415 above except that 8-chloro-4-(2-carbyl-5) was used. -Methoxyphenyl) as a reactant to give the title compound as a dark white solid. HRMS: Calculated value Ci^C^NO + ir, 290.01339; found (ESI, [M+H]+0bs'd), 290. 014 289 25 200825054 Step 4: 8-Chloro-4-{2- Gas-based 5-[3-(methylsulfonyl)phenoxy]phenyl}quinoline was prepared as in Example 43, except that 4-monosyl_3_(8-methyl-4-tetraquinolinyl)phenol was used. 3-fluoro-1-(methylsulfonyl)benzene is used as the reactant to give the title compound as a dark white solid. MS (ES) m/z 443. Found: </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; EXAMPLE 457 ίο 8-Alkyl-4-{2-carbyl-5-[3-(ethylsulfonyl)phenoxy]phenyl}quinoline was prepared as in Example 43, except that 4-alkyl- 3-(8-Alkyl-4-quinolinyl)phenol and 1-(ethylsulfonyl)-3-fluorobenzene were used as the title compound to give the title compound as a dark white solid. MS (ES) m/z </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; Example 458 8-Methyl-4-{3-[3-(methylsudanyl)phenoxy]phenyl}anthracene 2〇 Step 1: 3-(8-methyl-4-indolyl) Prepared as described in Step 3 of Example 415 except that 4-bromo-8-methylquinoline was used as the residue to afford the title compound as a yellow solid. MS (ES) m/z 236.2; HRMS: calcd. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 290 200825054 Step 2·· 8-Methyl-4-{3-[3-(methylsulfonyl)phenoxy]phenyl}quinoline was prepared according to Example 43, except that 3-(8-methyl-4) was used. _Quinolinyl) 5 phenol and 3-fluoro-l^methylsulfonyl)benzene as the reactant to give the title compound as a dark white solid. MS (ES) m/z </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Ίο Example 459 8-Methoxy-4-{3-[3-(f-sulfonyl)phenoxy]phenyl}quinoline Step 1: 3-(8-Methoxy-4-indolyl) Prepared according to Step 3 of Example 415 except that 4-bromo-8-methoxyquinoline was used as the reactant to give the title compound as a yellow solid. MS (ES) m/z </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Step 2: 8-Methoxy-4-{3-[3-(methylsulfonyl)phenoxy]phenyl}quinoline 2 oxime prepared according to Example 43, except that 3-(8-decyloxy) was used. -4-Quinolinyl)indole and 3-fluoro-1-(methyl-decyl)benzene are used as the reactants to give the title compound as a dark white solid. MS (ES) m/z </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 291 200825054 In the preparation of primary and secondary sulfonamides (Rf = s〇2Rn, and Rn = NRgRh), the amine can be prepared as a compound protected by a 4-methoxyl group. Treated with difluoroacetic acid (TFA) to remove the 4-methoxybenzyl group, leaving the sample 4fifl

HCI e%c：cv 二巍 水心雙(4_甲氧基苄基)一3一 {3一 [3 一甲基_8一(三氟甲基)-4一喹 10 啉基]苯氧基}苯確醢胺 步驟1: 3-溴基-N-(4-甲氧基苄基)苯項醢胺 以4-曱氧基苄基胺(2· 85 mL，22. 0 mmol)處理含有3-溴基 苯磺醯氣(5· 11 g，20. 0 mmol)和三乙基胺（3. 〇7 mL，22. 0 mmol) 於二氯甲烷(100 mL)中之一經攪拌的混合物超過5分鐘。在室溫 15 2小時後，以飽和的NaHC〇3水溶液（1〇〇 mL)處理該反應並以二氣 甲烷(2 X 50 mL)萃取。該經化合的萃取物被(MgS〇4)乾燥並被減 壓濃縮成一固狀物。經過以梯度3〇:7〇至50:50之E:U洗提的色 292 200825054 層分析後產生如一白色固狀物之該標題化合物（6.18g，於5〇:50 E:H 中 Rf 〜〇· 4)。MS (ES-) 353· 6 。 步驟2: 3-溴基-Ν,Ν-雙（4-甲氧基苄基）苯確醢胺 5 以含有60% NaH之油（440 mg，11· 0 mmol)處理含有3-溴基 -N-(4-甲氧基苄基）苯石黃醯胺（3.56 g，10·0 mmol)於DMF(20 mL) 中之一溶液。氣體散出。20分鐘之後，加入4-甲氧基苄基氯(1.63 mL，12· 0 mmol)並在室溫攪拌該反應達5小時。將該反應倒進水 (60 mL)中，產生一白色沉澱物。把沉澱物過濾掉，以水沖洗， 10並透過減壓乾燥以產生如一白色固狀物之該標題化合物（4. 92 g，於 E:H 中 Rf 〜0· 5)。MS (ES+) yzz/z 475 [M+H]+。 步驟3:术舲雙（4-甲氧基苄基）-3-{3-[3-甲基 -8 -（三氟甲基）-4-喹啉基]苯氧基}苯磺醢胺 15 將含有3-甲基-8-三氟甲基-4-(3-羥基苯基）喹啉（303 mg，1· 00 mmol)、3-溴基-N，N-雙（4-甲氧基苄基）苯磺醯胺 (714 mg，1. 50 mmol)、埃化亞銅（40 mg，0· 20 mmol)、N，N-二甲基甘胺酸鹽酸鹽（53 mg，0.38 mmol)、碳酸鉋（977 mg， 3· 00 mmol)於二噁院（20 mL)中之一經攪拌的混合物在100 20 °C加熱18小時。以水（50 mL)處理該經冷卻之反應並以乙 酸乙酯（3 X 30 mL)萃取。該萃取物透過MgS〇4乾燥，減壓 濃縮，並經過以梯度15:85至50:50之E:Η洗提的色層分 析，以產生如一白色固狀物之該標題化合物（352 mg)。MS (ES) m/z 699.0 ； HRMS:計算值 C39H33F3N2〇5S + H+， 293 200825054 699.2135;實測值（ESI，[M+H]+0bs’d)，699.2128。 篪例461 况舲雙（4-甲氧基苄基）-3-{3-[8-（三氟甲基）-4-喹啉 5 基]苯氧基}苯磺醢胺 以如範例460之相似方法，但使用4-(3-經基苯基）-8-三氟甲基-喹啉和3-溴基-N，N-雙（4-甲氧基苄基）苯磺醯 胺，來製備如一白色固狀物之該標題化合物。MS (ESI) Λ7/Ζ 685 ; HRMS:計算值 “IkFIOsS + H+，685. 1979 ;實測 ίο 值（ESI，[M+H]+ Obs’d)，685. 1984。 範例462 术舲雙（4-甲氧基苄基）-4 - {3-[3-甲基-8-（三氟甲 基）-4-啥琳基]苯氧基}苯續斑胺HCI e%c:cv 巍水心双(4_methoxybenzyl)-3-{3-[3 monomethyl-8-(trifluoromethyl)-4-quinoline 10 phenyl]phenoxy Benzene amide amide step 1: 3-bromo-N-(4-methoxybenzyl)benzamide is treated with 4-decyloxybenzylamine (2·85 mL, 22.0 mmol) Stirring with 3-bromobenzenesulfonium oxime (5·11 g, 20.0 mmol) and triethylamine (3. mL7 mL, 22.0 mmol) in dichloromethane (100 mL) The mixture is more than 5 minutes. After a period of 15 hours at room temperature, the reaction was treated with aq. sat. NaHC.sub.3 (1 mL) and extracted with di-methane (2 X 50 mL). The combined extract was dried (MgS〇4) and concentrated under reduced pressure to a solid. The color of the title compound (6.18 g, Rf ~ 〇· 4). MS (ES-) 353· 6 . Step 2: 3-Bromo-indenyl, hydrazine-bis(4-methoxybenzyl)benzamide 5 was treated with an oil containing 60% NaH (440 mg, 11.0 mmol) containing 3-bromo- A solution of N-(4-methoxybenzyl)benzamine (3.56 g, 10·0 mmol) in DMF (20 mL). The gas is released. After 20 minutes, 4-methoxybenzyl chloride (1.63 mL, 1 .0 mmol) was added and the mixture was stirred at room temperature for 5 hr. The reaction was poured into water (60 mL) to give a white solid. The precipitate was filtered, washed with water, and dried with EtOAc EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj MS (ES+) yzz/z 475 [M+H]+. Step 3: Succinic bis(4-methoxybenzyl)-3-{3-[3-methyl-8-(trifluoromethyl)-4-quinolinyl]phenoxy}benzenesulfonamide 15 will contain 3-methyl-8-trifluoromethyl-4-(3-hydroxyphenyl)quinoline (303 mg, 1.00 mmol), 3-bromo-N,N-bis (4-A Oxybenzyl) benzenesulfonamide (714 mg, 1.50 mmol), cuprous copper (40 mg, 0·20 mmol), N,N-dimethylglycine hydrochloride (53 mg, 0.38 mmol), a mixture of carbonated (977 mg, 3.0 mmol) in a dioxic (20 mL) mixture was heated at 100 20 °C for 18 hours. The cooled reaction was treated with water (50 mL) and ethyl acetate (3×30 mL). The extract was dried over MgSO.sub.4, EtOAc (EtOAc m.) . MS (ES) m/z </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Example 461 bis(4-methoxybenzyl)-3-{3-[8-(trifluoromethyl)-4-quinoline-5yl]phenoxy}benzenesulfonamide as in Example 460 A similar method, but using 4-(3-phenylphenyl)-8-trifluoromethyl-quinoline and 3-bromo-N,N-bis(4-methoxybenzyl)benzenesulfonamide To prepare the title compound as a white solid. MS (ESI) Λ 7/Ζ 685 ; HRMS: Calculated value "IkFIOsS + H+, 685. 1979; measured ίο value (ESI, [M+H] + Obs'd), 685. 1984. Example 462 舲 double (4 -Methoxybenzyl)-4 - {3-[3-methyl-8-(trifluoromethyl)-4-indolyl]phenoxy}benzene serotonin

步驟1: 4-氟基-IK4-甲氧基苄基)苯續醢胺 294 200825054 基本上以範例460中步驟1之相同方法製備該標題化合 物，除了起始物質以4-氟苯磺醯氯來取代3_溴苯磺醯氣，分離 出一白色固狀物。肘8(^1)/»// 293.9 [1^11]-。 5 步驟2: 4一氟基-N，N一雙(4-甲氧基苄基)苯續醢胺 以以含有60% NaH之油（440 mg，Π· 〇 _ι)處理含有4_ 氟基-N-(4-甲氧基苄基）苯磺醯胺（2· 95 g，ΐ〇· 〇 mm〇i)於DMF(2〇 mL)中之一溶液。氣體散出。20分鐘之後，加入4-甲氧基苄基氯 (1· 63 mL，12· 0 mmol)並在室溫攪拌該反應達5小時。以水(6〇 10處理該反應，產生一白色沉澱物。該物質經過使用梯度2〇:8〇至 40:60之E:H的色層分析以產生如一白色固狀物之該標題化合物 (3.08 g&gt;MS (ES) λ?/ζ415。 步驟3:术舲雙（4-甲氧基苄基）-4 - {3 - [3-甲基 15 -8-(三氟甲基）-4-喹啉基]苯氧基}苯磺醢胺 將含有3-甲基-8-三氟甲基-4-(3-經基苯基）嗤琳（3〇3 mg，1· 00 mmol)、4-氟基-N，N-雙（4-甲氧基苄基）苯磺醯胺 (499 mg，1· 20 mmol)、K2C〇3(276 mg，2· 00 mmol)於 DMF(5. 0 mL)中之一經攪拌的混合物在130 °C加熱18小時。以水（2〇 20 mL)和食鹽水（2 mL)處理該經冷卻的反應。以乙酸乙醋（3 χ 10 mL)萃取該混合物。該萃取物透過MgS04乾燥，減壓濃 縮，並經過以梯度15:85至40:60之E:Η洗提的色層分析 以產生如一白色固狀物之該標題化合物（582 mg)。MS (ES) ζ»/ζ 699·1 ; HRMS:計算值 C39H33F3N2O5S + H+，699.21350 ; 295 200825054 實測值（ESI，[M+H]+0bs’d)，699.2129。 範例463 术於雙（4-甲氧基苄基）-4-{ 3-[8-（三氟甲基）-4-啥琳 5 基]苯氧基}苯磺醢胺 以如同範例462中步驟3的相同方法，但使用8-三氟 甲基-4-（3-羥基苯基）喹啉和4-氟基-N，N-雙（4-甲氧基苄 基）苯磺醯胺作為基質來製備如一暗白色固狀物之該標題 化合物。MS (ESI) zs/z 685 ; HRMS:計算值 C38H31F3N2〇5S + ίο H+, 685.19785 ；實測值（ESI, [M+H]+ Obs’d)， 685·1978 。 464Step 1: 4-Fluoro-IK4-methoxybenzyl)benzene decylamine 294 200825054 The title compound was prepared essentially in the same manner as in Step 1 Instead of 3-bromobenzenesulfonate, a white solid was isolated. Elbow 8 (^1)/»// 293.9 [1^11]-. 5 Step 2: 4-Fluoro-N,N-bis(4-methoxybenzyl)benzene decylamine to treat 4_fluoro group with oil containing 60% NaH (440 mg, Π·〇_ι) a solution of -N-(4-methoxybenzyl)benzenesulfonamide (2·95 g, ΐ〇·〇mm〇i) in DMF (2 mL). The gas is released. After 20 minutes, 4-methoxybenzyl chloride (1·63 mL, 1 .0 mmol) was added and the mixture was stirred at room temperature for 5 hr. The reaction was treated with water (6 〇 10) to give a white precipitate. The material was chromatographed using a gradient of 2 〇: 8 〇 to 40:60 EtOAc to yield the title compound as a white solid ( 3.08 g&gt;MS (ES) λ?/ζ415. Step 3: Sputum bis(4-methoxybenzyl)-4 - {3 - [3-methyl 15 -8-(trifluoromethyl)-4 -quinolinyl]phenoxy}benzenesulfonamide will contain 3-methyl-8-trifluoromethyl-4-(3-pyridylphenyl) fluorene (3〇3 mg, 1.00 mmol) 4-fluoro-N,N-bis(4-methoxybenzyl)benzenesulfonamide (499 mg, 1·20 mmol), K2C〇3 (276 mg, 1.00 mmol) in DMF (5) One of the stirred mixtures was heated at 130 ° C for 18 hours. The cooled reaction was treated with water (2 〇 20 mL) and brine (2 mL) and extracted with ethyl acetate (3 χ 10 mL) The mixture was dried over MgSO4, concentrated under reduced pressure and purified eluting with EtOAc EtOAc EtOAc MS (ES) ζ»/ζ 699·1 ; HRMS: Calculated value C39H33F3N2O5S + H+, 699.21350 ; 295 200825054 Measured value (ESI, [M+H]+0 Bs'd), 699.2129. Example 463 is a technique of bis(4-methoxybenzyl)-4-{3-[8-(trifluoromethyl)-4-indolyl-5-yl]phenoxy}benzenesulfonate The guanamine was treated in the same manner as in Step 3 of Example 462, but using 8-trifluoromethyl-4-(3-hydroxyphenyl)quinoline and 4-fluoro-N,N-bis(4-methoxy). Benzyl) benzenesulfonamide as a substrate to give the title compound as a dark white solid. MS (ESI) s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s M+H]+ Obs'd), 685·1978. 464

3-{3-[3-甲基-8-(三氟甲基）-4-喹啉基]苯氧基}苯磺 醢胺 將含有水菸雙（4-甲氧基苄基）-3-{3-[3-曱基-8-(三氟 20 甲基）-4-喹琳基]苯氧基}苯石黃醢胺（302 mg，0· 43 mmol) 296 200825054 於三氟乙酸（4 mL)和CH2CI2 (4 mL)中之一混合物在室溫氮 氣下攪拌18小時。減壓濃縮該反應，以飽和的NaHC〇3水溶 液（10 mL)處理並以CH2CM2 X 5 mL)萃取。該經乾燥（MgS〇4) 的萃取物透過以梯度20:80至50:50之E:Η洗提的色層分 5 析，以產生如一白色固狀物之該標題化合物（199 mg)。MS (ES) m/z 458. 9 ； HRMS:計算值 C23H17F3N2O3S + H+， 459.09847;實測值（ESI，[M+H]+0bs’d)，459. 0987。 465 10 4-{3-[8-(三氟甲基）-4-啥琳基]苯氧基}苯確斑胺 以如同範例464的相同方法，但使用水，雙（4-甲氧 基节基）-3-{3-[8_(三氟曱基）-4-喧琳基]苯氧基}苯績醯 胺作為基質來製備如一暗白色固狀物之該標題化合物。MS (ES) m/z 444.9 ； HRMS:計算值 C22H15F3N2〇3S + H+， 15 445.0828 ;實測值（ESI, [M+H]+ Obs’d)，445.0835。 範例466 4-{3-[3-甲基-8-（三氟甲基）-4-啥琳基]苯氧基}苯續 醢胺 2〇 基本上以如同範例464的相同方法，但使用术舲雙（4- 甲氧基苄基）-4-{3-[3-甲基-8-（三氟甲基）-4-喹啉基]苯 氧基}苯磺醯胺作為基質來製備如一白色固狀物之該標題 化合物。MS (ES) 458· 9 ; HRMS:計算值 C23HnF3N2〇3S + H+，459. 09847 ;實測值（ESI, [M+H]+ Obs，d)， 297 200825054 459.0988 ° 範例467 4-{3-[8-(三氟甲基）-4-喹啉基]苯氧基}苯磺醯胺 5 基本上以如同範例464的相同方法，但使用水雙（4- 甲氧基苄基）-4-{3-[8-（三氟甲基）-4-喹啉基]苯氧基}苯 磺醯胺作為基質來製備如一暗白色固狀物之該標題化合 物。MS (ES) /Z//Z444. 6 ; HRMS:計算值 C22H15F3N2〇3S + H+， 445· 08282;實測值（ESI，[M+H]+0bs，d)，445.0833。 ίο 範例468 3_異丙基-4-{3 - [3_(甲基磺班基）苯氧基]苯 基}-8-(三氟甲基）考琳 步驟1: 3-異丙基-4-(3-甲氧基苯基）-8-(三氟甲基） 15 喹啉 以如同範例425中步驟1的相同方法，但使用[2-胺 基一3一（三氟甲基）苯基](3-甲氧基苯基）甲酮和3-曱基丁醛 作為基質來製備如一淡黃色固狀物之該標題化合物。MS (ES) ////&gt; 346.0;111^3:計算值（：2()1118?3腸 + 11+，346.1413;實 2〇 測值（esi，[_μ obs，d)，346· 1422。 步驟2: 3-[3-異丙基-8-(三氟甲基）-4-喹啉基]酚 以如同範例425中步驟2的相同方法，但使用3-異丙 基-4-(3-甲氧基苯基）—8_(三氟甲基）喹啉作為基質來製備 298 200825054 如一暗白色固狀物之該標題化合物。MS (ES) m/z 332. 1 ; HRMS:計算值 C19H16F3NO + H+，332.1257;實測值（ESI, [M+H]+ 〇bs’ d)，332·1266。 5 步驟3: 3-異丙基-4-{3〜[3-(甲基磺醢基）苯氧基]苯 基}-8 -（二氣甲基）啥琳 以如同範例43的相同方法，但使用3—[3_異丙基 -8-(三氟甲基）-4-喹啉基]酚和i一氟基_3一（甲基磺醯基）苯 作為基質來製備該標題化合物。MS (ES) m/z 485. 9。 10 j备例469 3-甲基-4 - (3-{[3-（甲基磺醢基）苄基]氧基}苯 基）-8-（三氟甲基）嗓琳 以如同範例212的相同方法，但使用3-甲基-4-(3-羥 15基苯基）_8-(三氟甲基）喹啉和1-(溴基甲基）-3-(甲基磺醯 基）苯作為基質來製備如一白色固狀物之該標題化合物。MS (ES) ra/z 472.0 ； HRMS:計算值 C25H2〇F3N〇3S + H+， 472· 1189;實測值（ESI, [M+H]+0bs’d)，472.1191。 2〇 範例470 3-甲基-4-(3-{[4 -（甲基磺醢基）苄基]氧基}苯 基）-8-(三氟甲基）喹啉 以如同範例212的相同方法，但使用3-甲基-4-(3-羥 基苯基）-8-（三氟曱基）喹啉和i-(氣基甲基）一4-(甲基磺醯 299 200825054 基）苯作為基質來製備如一白色固狀物之該標題化合物。MS (ES) m/z 472. 0 ; HRMS:計算值 C25h2()F3N〇3S + H+， 472.1189;實測值（ESI，[M+H]+0bs，d)，472· 1192。 5 範例471至482 下列範例471至482中之化合物基本上根據範例259 的方法製備，除了使用適當的反應物來取代。 範例471 4-{5-[3-（乙基續酸基）苯基]一2-喧吩基}_3-甲基 10 _8-（三氟甲基）喹啉3-{3-[3-Methyl-8-(trifluoromethyl)-4-quinolinyl]phenoxy}benzenesulfonamide will contain shisha bis(4-methoxybenzyl)-3- {3-[3-Mercapto-8-(trifluoro 20methyl)-4-quinolinyl]phenoxy}benzamine (302 mg, 0·43 mmol) 296 200825054 in trifluoroacetic acid ( A mixture of 4 mL) and CH 2 CI 2 (4 mL) was stirred at room temperature under nitrogen for 18 hours. The reaction was concentrated under reduced EtOAc (EtOAc)EtOAc. The dried (MgS 4 ) extract was passed through a color layer eluted with a gradient of 20:80 to 50:50 to afford the title compound (199 mg) as a white solid. MS (ES) m/z </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; 465 10 4-{3-[8-(Trifluoromethyl)-4-indolyl]phenoxy}benzidine in the same manner as in Example 464, but using water, bis(4-methoxy) The title compound is prepared as a dark white solid as a base. -3-{3-[8-(trifluoromethyl)-4-indolyl]phenoxy}benzamine. MS (ES) m/z 444.9: </RTI> <RTI ID=0.0></RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; Example 466 4-{3-[3-Methyl-8-(trifluoromethyl)-4-indolyl]phenoxy}benzene continued amine 2〇 essentially in the same manner as in Example 464, but using Bis(4-methoxybenzyl)-4-{3-[3-methyl-8-(trifluoromethyl)-4-quinolinyl]phenoxy}benzenesulfonamide as a substrate The title compound was prepared as a white solid. MS (ES) 458·9; HRMS: Calculated C23HnF3N2 〇3S + H+, 459. 09847; found (ESI, [M+H]+ Obs,d), 297 200825054 459.0988 ° Example 467 4-{3-[ 8-(Trifluoromethyl)-4-quinolinyl]phenoxy}benzenesulfonamide 5 was essentially the same procedure as in Example 464, but using water bis(4-methoxybenzyl)-4- {3-[8-(Trifluoromethyl)-4-quinolinyl]phenoxy}benzenesulfonamide was used as a substrate to give the title compound as a dark white solid. MS (ES) / Z / / Z 444. 6; HRMS: calcd for C.sup.ssssssssssssssssssssssssssssssssssss Οο Example 468 3_Isopropyl-4-{3 -[3_(methylsulfanyl)phenoxy]phenyl}-8-(trifluoromethyl)colin Step 1: 3-isopropyl- 4-(3-Methoxyphenyl)-8-(trifluoromethyl) 15 quinoline in the same manner as in Step 1 of Example 425, but using [2-amino-l-(trifluoromethyl) Phenyl](3-methoxyphenyl)methanone and 3-mercaptobutyraldehyde were used as a base to prepare the title compound as a pale yellow solid. MS (ES) ////&gt;346.0; 111^3: Calculated value (: 2 () 1118? 3 intestine + 11 +, 346.1413; real 2 〇 measured value (esi, [_μ obs, d), 346· 1422. Step 2: 3-[3-Isopropyl-8-(trifluoromethyl)-4-quinolinyl]phenol in the same manner as in Step 2 of Example 425, but using 3-isopropyl-4 -(3-Methoxyphenyl)-8-(trifluoromethyl)quinoline as a substrate. 298. The title compound was obtained as a dark white solid. MS (ES) m/z 332. 1 ; Calculated C19H16F3NO + H+, 332.1257; found (ESI, [M+H] + 〇bs' d), 332·1266. 5 Step 3: 3-isopropyl-4-{3~[3-(methyl Sulfomethyl)phenoxy]phenyl}-8-(dimethylmethyl)indole in the same manner as in Example 43, but using 3-[3_isopropyl-8-(trifluoromethyl)- The title compound was prepared as a substrate using 4- quinolinyl]phenol and i-fluoro-l-(methylsulfonyl)benzene as a substrate. MS (ES) m/z 485. 9. 10 j. Base-4 - (3-{[3-(methylsulfonyl)benzyl)oxy}phenyl)-8-(trifluoromethyl)anthracene in the same manner as in Example 212, but using 3- Methyl-4-(3-hydroxyl-ylphenyl)-8-(trifluoro The title compound was prepared as a white solid. mp EtOAc (EtOAc): Value C25H2〇F3N〇3S + H+, 472· 1189; found (ESI, [M+H]+0bs'd), 472.1191. 2〇Example 470 3-Methyl-4-(3-{[4 -( Methylsulfonyl)benzyl]oxy}phenyl)-8-(trifluoromethyl)quinoline in the same manner as in Example 212, but using 3-methyl-4-(3-hydroxyphenyl) -8-(Trifluoromethyl)quinoline and i-(methylmethyl)- 4-(methylsulfonyl 299 200825054) benzene were used as a substrate to prepare the title compound as a white solid. MS (ES m/z 472. 0 ; HRMS: calculated C25h2()F3N〇3S + H+, 472.1189; found (ESI, [M+H]+0bs,d), 472·1192. 5 Examples 471 to 482 The compounds of 471 to 482 were prepared essentially according to the procedure of Example 259 except that the appropriate reactants were used. Example 471 4-{5-[3-(ethylhexanoic acid)phenyl]- 2-nonyl }_3-Methyl 10 _8-(trifluoromethyl)quinoline

以範例259中所述之相似方法製備該標題化合物。MS (ES) m/z 461.7 ； HRMS:計算值 c23H18F3N〇2S2 + H+， 462.08038;實測值（ESI，[M+H]+)，462.0800。 15 範例472 4-{5-[3-（乙基磺醯基）苯基]一2一噻吩基}_8一（三氟甲 基）喹琳 以範例259中所述之相似方法製備該標題化合物。MS (ES) m/z 447.7 ； HRMS:計算值 C22H16F3N〇2S2 + 11+， 20 448.06473 ;實測值（ESI，[m+h]+ 0bs，d)，448. 0653。 範例 473 3-甲基-4-{5-[3-（甲基磺醢基）苯基hi 3_噻唑_2_ 基}-8- (三氟甲基)養琳 300 200825054 以範例259中所述之相似方法製備該標題化合物。MS (ES) m/z 448.9 ; HRMS:計算值 C21H15F3N2O2S2 + H+， 449.05998;實測值（ESI, [M+H]+0bs，d)，449.0603。 5 範例474 乙基4-{5-[3-(甲基續醢基）苯基]-2-嘍吩基}-8-(三氟甲 基)啥琳-3-叛酸乙酶 以範例259中所述之相似方法製備該標題化合物。 1〇 範例475 4 - {5-[3-（甲基磺醢基)苯基]一2-噻吩基}-8-(三氟甲基)喹 琳-3-甲醢胺 以範例276中所述之相似方法製備該標題化合物。MS (ES) m/z 477·0 。 15 範例476 4-{5’ -[3-(甲基續醢基)苯基]一2,2, -bi噻吩-5-基}-8-(三 氟甲基)哈琳-3-鼓酸乙酿The title compound was prepared in a similar manner as described in Example 259. MS (ES) m/z 46 </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; </ RTI> </ RTI> </ RTI> <RTIgt; 15 Example 472 4-{5-[3-(ethylsulfonyl)phenyl]-2-ylthiophenyl}_8-(trifluoromethyl)quinolin The title compound was prepared in a similar manner as described in Example 259. . MS (ES) m/z 447.7; </RTI> </RTI> <RTI ID=0.0></RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; Example 473 3-Methyl-4-{5-[3-(methylsulfonyl)phenylhi 3_thiazol-2-yl}-8-(trifluoromethyl)line 300 200825054 The title compound was prepared in a similar manner. MS (ES) m/z 448.9; </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; 5 Example 474 Ethyl 4-{5-[3-(methylthenyl)phenyl]-2-indolyl}-8-(trifluoromethyl)indole-3-derivative B-zyme The title compound was prepared in a similar manner as described in 259. 1〇Example 475 4 - {5-[3-(Methylsulfonyl)phenyl]- 2-thienyl}-8-(trifluoromethyl)quinolin-3-carboxamide as shown in Example 276 The title compound was prepared in a similar manner. MS (ES) m/z 477·0. 15 Example 476 4-{5'-[3-(Methyl hydrazino)phenyl]- 2,2,-bithiophen-5-yl}-8-(trifluoromethyl) Harlem-3-drum Acid

以範例259中所述之相似方法製備該標題化合物。MS 20 (ES) m/z 587.9 ； HRMS:計算值 C28H2〇F3N〇4S3 + H+, 588.05793;實測值（ESI, [M+H]+0bs，d)，588.0582。 範例477 8-氟基-4-[3’ -（甲基磺醢基）聯苯一3一基]喹啉 301 200825054 步驟1: 3-(8-氟基-4-喹啉基）苯基三氟甲烷磺酸酯 以範例258中所述之相似方法製備該標題化合物。ms (ES) m/z 371.7 。 5 步驟2: 8-氟基-4-[3, -（甲基磺醢基）聯苯-3-基]喹 琳 以範例259中所述之相似方法製備該標題化合物。ms (ES) m/z 378.3 ； HRMS:計算值 C22H16FN〇2S + H+， 378.09585;實測值（ESI，[M+H]+0bs，d)，378.0963。 ίο 範例478 3-甲基-4-{5-[3-（甲基磺醢基）苯基]-2-噻吩 基}_8-（三氟甲基）喹啉 步驟1: 4-（5-氣基-2-噻吩基）-3-甲基-8-(三氟甲基） 15 喹啉 以範例259中所述之相似方法製備該標題化合物。MS (ES) m/z 327.6 ； HRMS:計算值 C15H9C1F3NS + H+, 328.01691;實測值（ESI, [M+H]+0bs，d), 328.0175。 2〇 步驟2: 3-甲基_4-{5-[3-(甲基磺醢基）苯基]-2-噻 吩基}-8-（三氟甲基）喹啉 以範例259中所述之相似方法製備該標題化合物。MS (ES) m/z 447.6 ； HRMS:計算值 C22H16F3N〇2S2 + H+， 448.06473;實測值（ESI, [M+H]+Obs，d)，448.0650。 302 200825054 範例479 4- [3-（甲基磺醢基）苯基]-8-(三氟甲基）喹啉 以範例259中所述之相似方法製備該標題化合物。MS 5 (ES) m/z 351·9 。 範例480 4-{5-[3-(甲基磺醢基）苯基]-2-噻吩基}-8-（三氟甲 基）喹啉 ίο 步驟1: 4-(5-氣基-2-噻吩基）-8-(三氟甲基）喹啉 以範例259中所述之相似方法製備該標題化合物。MS (ES) m/z 313_ 6。 步驟2: 4-{5 - [3-（甲基磺醢基）苯基]-2-噻吩 15 基}-8-（三氟甲基）喹啉 以範例259中所述之相似方法製備該標題化合物。MS (ES) m/z 433.6 。 範例481 2〇 队恥二甲基-3-{5-[3-甲基-8-（三氟甲基）-4-喹啉 基]-2-噻吩基}苯磺醢胺 以範例259中所述之相似方法製備該標題化合物。MS (ES) ra/z 476.6 ； HRMS:計算值 C23H19F3N2〇2S2 + H+， 477.09128;實測值（ESI，[M+H]+0bs’d)，477. 091 卜 303 200825054 範例482 3-甲基-4-{5-[4-（甲基磺醢基）苯基]一2一噻吩 基}-8-（三氟甲基）啥琳 以範例259中所述之相似方法製備該標題化合物。MS (ES) m/z 447.6 ； HRMS:計算值 C22H16F3N〇2S2 + H+， 448.06473;實測值（ESI, [M+H]+0bs，d)，448.0648。 範例483至506 下列範例483至506中之化合物基本上根據範例279 的方法製備，除了使用適當的反應物來取代。The title compound was prepared in a similar manner as described in Example 259. MS 20 (ES) m/z </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Example 477 8-Fluoro-4-[3'-(methylsulfonyl)biphenyl-3-yl]quinoline 301 200825054 Step 1: 3-(8-Fluoro-4-quinolinyl)phenyl Trifluoromethanesulfonate The title compound was prepared in a similar manner as described in Example 258. Ms (ES) m/z 371.7. 5 Step 2: 8-Fluoro-4-[3,-(methylsulfonyl)biphenyl-3-yl]quinolin The title compound was prepared in a similar manner as described in Example 259. </ RTI> <RTI ID=0.0></RTI> </ RTI> <RTI ID=0.0></RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Οο Example 478 3-Methyl-4-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}_8-(trifluoromethyl)quinoline Step 1: 4-(5- The title compound was prepared in a similar manner as described in Example 259. m.p. MS (ES) m/z </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; 2〇Step 2: 3-Methyl_4-{5-[3-(methylsulfonyl)phenyl]-2-thienyl}-8-(trifluoromethyl)quinoline as shown in Example 259 The title compound was prepared in a similar manner. MS (ES) m/z 436. 302 200825054 Example 479 4-[3-(Methylsulfonyl)phenyl]-8-(trifluoromethyl)quinoline The title compound was obtained in a similar procedure as described in Example 259. MS 5 (ES) m/z 351·9. Example 480 4-{5-[3-(Methylsulfonyl)phenyl]-2-thienyl}-8-(trifluoromethyl)quinoline ίο Step 1: 4-(5-Gas-2 -Thienyl)-8-(trifluoromethyl)quinoline The title compound was prepared in a similar manner as described in Example 259. MS (ES) m/z 313_ 6. Step 2: 4-{5-[3-(Methylsulfonyl)phenyl]-2-thiophene 15yl}-8-(trifluoromethyl)quinoline Prepared in a similar manner as described in Example 259 Title compound. MS (ES) m/z 433.6. Example 481 2〇 Team shame dimethyl-3-{5-[3-methyl-8-(trifluoromethyl)-4-quinolinyl]-2-thienyl}benzenesulfonamide as Example 259 The title compound was prepared in a similar manner as described. MS (ES) </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 4-{5-[4-(Methylsulfonyl)phenyl]-2-ylthiophenyl}-8-(trifluoromethyl)indole was prepared in a similar manner as described in Example 259. MS (ES) m/z 447.6: </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; Examples 483 to 506 The compounds of the following Examples 483 to 506 were prepared essentially according to the procedure of Example 279, except that the appropriate reactants were used.

SiLi83 4一[3’ -（甲基磺醢基）聯苯一3-基]一8_(三氟甲基）喹啉 比照範例279製備，除了使用4-(3-溴苯基）—8—(三氟 甲基）喹啉和3-(甲基磺醯基）苯基硼酸作為反應物，以產 生如一白色固狀物之該標題化合物。MS (ES) 427. 8。 |ε^1__484. 4-[4’ -甲基-3’ -（甲基磺醢基）聯苯一3—基]—8一（三氟甲 基）喹啉 比照範例279製備，除了使用4—(3-溴基苯基）—8_(三 氟甲基）喹啉和4-甲基-3-(甲基磺醯基）苯基硼酸作為反應 物’以產生如一白色固狀物之該標題化合物。Ms (ES)仍么 304 200825054 442. 1 ° 範例485 4-[3’ -(甲基磺醢基）聯苯一3—基]一3一苯基(三氟甲 5 基）喹啉 比照範例279製備，除了使用(3一溴苯基）_3_苯基 -8-(三氟甲基）喹啉酮和3-（甲基磺醯基）苯基硼酸作為反 應物，以產生如一暗白色固狀物之該標題化合物。MS(ES) 7Ζ7/ζ 503. 7 〇 10 範例486 3’-[8-（三氟甲基）-4-喹啉基]聯苯一3一磺醢胺 比照範例279製備，除了使用4—(3—溴苯基）_8_(三氟 甲基）喹啉和3-胺磺醯基苯基硼酸作為反應物，以產生如 15 一棕褐色固狀物之該標題化合物。MS (ES) 7!7/z d 1。 範例487 私（3’-(3-(1，3-二氧異吲哚啉—2_基）丙基硫基）聯苯 -3-基）-8-(三氟甲基）喹啉一3一羧酸乙酯 zo 比照範例279製備，除了使用8-(三氟甲基）-4-(3-(三 氟甲基石兴醯基氧基）苯基）啥琳_3—羧酸乙醋和(3_(ι，3— 二氧異吲哚啉-2-基）丙基硫基）苯基硼酸作為反應物，以產 生如一棕褐色固狀物之該標題化合物。Ms (ES) 仍/zMO. 1。 305 200825054 範例488SiLi83 4-[3'-(methylsulfonyl)biphenyl-3-yl]-8-(trifluoromethyl)quinoline was prepared according to Example 279 except that 4-(3-bromophenyl)-8- (Trifluoromethyl)quinoline and 3-(methylsulfonyl)phenylboronic acid are used as the reactants to give the title compound as a white solid. MS (ES) 427. 8. |ε^1__484. 4-[4'-Methyl-3'-(methylsulfonyl)biphenyl-3-yl]-8-(trifluoromethyl)quinoline was prepared according to Example 279 except that 4 was used. -(3-Bromophenyl)-8-(trifluoromethyl)quinoline and 4-methyl-3-(methylsulfonyl)phenylboronic acid as reactants to give a white solid Title compound. Ms (ES) still 304 200825054 442. 1 ° Example 485 4-[3'-(methylsulfonyl)biphenyl-3-yl]-3-phenylphenyl(trifluoromethyl-5-yl)quinoline analogy Prepared in 279, except using (3-bromophenyl)_3_phenyl-8-(trifluoromethyl)quinolinone and 3-(methylsulfonyl)phenylboronic acid as the reactants to give a dark white The title compound of the solid. MS(ES) 7Ζ7/ζ 503. 7 〇10 Example 486 3'-[8-(Trifluoromethyl)-4-quinolinyl]biphenyl-3-sulfonamide was prepared according to Example 279 except that 4- (3-Bromophenyl)-8-(trifluoromethyl)quinoline and 3-aminesulfonylphenylboronic acid are used as the reactants to give the title compound as a brown solid. MS (ES) 7!7/z d 1. Example 487: Private (3'-(3-(1,3-dioxoisoindol-2-yl)propylthio)biphenyl-3-yl)-8-(trifluoromethyl)quinoline 3-Carboxylic acid ethyl ester zo was prepared as in Example 279 except that 8-(trifluoromethyl)-4-(3-(trifluoromethylstone) phenyl) phthalocyanine-3-carboxylic acid was used. Ethyl vinegar and (3_(ι,3-dioxaisoindolin-2-yl)propylthio)phenylboronic acid were used as the reaction to give the title compound as a brown solid. Ms (ES) is still /zMO. 1. 305 200825054 Example 488

2-胺基-4-[3’ -（甲基續酿基）聯苯-3-基]-8-（三氟甲 基）喹啉-3 -甲醢胺 5 步驟1: 2-胺基-4-（3-淡基苯基）-8-（三氟甲基）啥琳 -3 -甲醢胺 以NaH(348 mg，8. 7 mmol，60%分散液於油中）處理 含有（2-胺基-3-(三氟甲基）苯基）（3-溴苯基）甲酮（1.0 g， 2. 9 mmol)和 2-氰基乙醯胺（366 mg，4. 4 mmol)於 DMS0 (5· 0 10 mL)中之一經攪拌的混合物。在氣體散出後，將該反應管加 蓋並在110 °C加熱20小時。將該經冷卻的反應倒進水（80 mL)中並以乙酸乙酯萃取。該萃取物透過MgS〇4乾燥並減壓 濃縮。該殘餘物透過以梯度20:80至100:0之E:H洗提的 色層分析純化，以產生如一白色固狀物之該標題化合物 15 (713 mg ， 60%)。 MS (ES) m/zm. 6 ； HRMS:計算值 CnHuBrFlO + H+， 410.01103;實測值（ESI，[M+H]+0bs’d)，410.0114。 步驟2: 2-胺基-4-[3’ -(甲基確酿基）聯苯-3-20 基]-8-(三氟甲基）喹啉-3-甲醢胺 比照範例279製備，除了使用2-胺基-4-(3-溴苯 基）-8-（三氣甲基）喧琳-3-甲酿胺和3-（甲基石黃酿基）苯基 306 200825054 硼酸作為反應物，以產生如一白色固狀物之該標題化合 物。MS (ES) 7Z7/Z 486. 0 ; HRMS··計算值 C24H18F3N3〇3S + H+， 486.10937;實測值（ESI，[M+H]+ Calc，d)，486. 1094。 5 蓺例489 4-[4’ -氟基-3’ -(甲基磺醯基）聯苯一3一基]-8一（三氟甲 基）喹啉 比照範例279製備，除了使用4-(3-(4, 4, 5, 5-四甲基 _1，3，2 -二雜乳戍侧烧_2-基）苯基）-8-(三氣甲基）啥琳和 ίο 4-氣基-1-氟基-2_(甲基績醯基）苯，填酸二氫鉀和醋酸|巴 (11)作為反應物，以產生如一白色固狀物之該標題化合 物。MS (ES) π/ζ 445. 8。 蓺例490 15 4-[4’ -氟基-3’ -(甲基續酸基）聯苯-3-基]一3-甲基 _8-（三氟甲基）啥琳 比照範例279製備，除了使用3-曱基-4-（3-（4, 4, 5, 5-四甲基-1，3, 2-二雜氧戊硼烷-2-基）苯基）-8-(三氟甲基） 啥琳酮和4-氣基-1-氟基-2-(甲基績醯基）苯，磷酸二氫钾 20 和醋酸鈀（II)作為反應物，以產生如一白色固狀物之該標 題化合物。MS (ES) zzz/z 459· 8。 蓺例491 2-[3-({3’-[8-(三氟甲基）-4-喹啉基]聯苯-3_基}硫 307 200825054 基）丙基]-1於異吲哚-1, 3(2i9)-二酮 比照範例279製備，除了使用4-(3-溴基苯基）-8-(三 氟甲基）-喹啉和2-(3-(3-（4, 4, 5, 5-四甲基-1，3, 2-二雜氧 戊硼烷-2-基）苯基硫基）-丙基）異吲哚啉-1，3-二酮作為反 5 應物，以產生如一白色固狀物之該標題化合物。MS (ES) /ff/z 568_ 7。 範例492 Y-乙基-3-（{3’-[3-甲基-8-（三氟甲基）-4_喹啉基] 10 聯苯-3-基}續酸基）丙-1-胺 比照範例279製備，除了使用3-曱基-4-(3-（4, 4, 5, 5-四甲基-1，3, 2-二雜氧戊硼烷-2-基）苯基）-8-(三氟甲基） 喹啉酮和3-(3-溴苯基磺醯基）—N-乙基丙-1 -胺作為反應 物，以產生如一白色固狀物之該標題化合物。 15 MS (ES) /»/ζ 513· 1。 範例493 #-甲基-3_({3’ -[3-甲基-8-(三氟甲基）-4-喹啉基] 嫌苯-3-基}確酸基）丙-1-胺 2〇 比照範例279製備，除了使用3-甲基-4-(3-(4, 4, 5, 5- 四甲基-1，3, 2-^ —雜氧戊侧院-2-基）苯基）-8-(三氟甲基） 喹啉酮和3-(3-溴基苯基磺醯基甲基丙-1-胺作為反應 物，以產生如一白色固狀物之該標題化合物。 MS (ES) Λ//Ζ 499. 1。 範例494 308 25 200825054 己基-3-({3、[8_(三氟甲基)_4_料基]聯苯_3基} 續酿基）丙-1-胺 比照範例279製備，除了使用4-(3-溴笨基）_8—(三氟 甲基# 3-(3,苯基績醯基）—N_乙基叫胺作為 反應物，以產生如-白色固狀物之該標題化合物。ms(es) /27/z 499. 0 〇 範例495 甲基-3-U3,、[8_(三氟甲基)_4_料基]聯苯_3基} ίο 續酿基）丙-1-胺 比照範例279製備，除了使用4—(3_溴笨基）_8—(三氟 曱基）-啥琳和3-(3,苯基石黃醯基）—N—曱基兩小胺作為反 應物，以產生如一白色固狀物之該標題化合物 484. ：1。 範例496 8-氣基-4-[3’ -（甲基磺醢基）聯苯一3一基]喹啉 步驟1: 4-(3-溴基苯基)-8-氣基喹啉 以3-溴苯基硼酸(〇· 15 mmol)、磷酸二氫鉀(〇·沈gl 2 20 咖〇1)、和 Pd(pPh3)4 (20 mg，0· 017 mmol)處理含有 4_溴基一8一 氯基噎啉（〇· 200 g，〇. 82 mmol)之）惡烷（3 mL)。該反應在90 °C加熱8小時。移除該溶劑並將該殘餘物使用10:90 E：:H之色層 分析以獲得〇· 085 g之該標題化合物。做（ES) /z//z 317. 8。 309 200825054 步驟2: 8-氣基-4-[3, -（甲基磺醢基）聯苯-3-基]喹 啉 比照範例279製備，除了使用4-(3-溴苯基）-8-氯喹啉 和3-(甲基磺醯基）苯基硼酸作為反應物，以產生如一白色 5固狀物之該標題化合物。MS (ES) Λ//Ζ 393. 9。 範例4Q7 5一{3-[3-甲基-8-（三氟甲基）-4-喹啉基]苯基}噻吩 -2-磺醢胺 10 比照範例279製備，除了使用3-甲基-4-(3-(4,4, 5, 5- 四甲基-1,3, 2-二雜氧戊硼烷—2-基）苯基）-8-(三氟甲基） 啥琳_和5-溴噻吩-2-磺醯胺作為反應物，以產生如一白色 固狀物之該標題化合物。MS (ES) yz//z 449. 1。 15 範例498 5-{3-[8-(三氟甲基）-4-喹啉基]苯基}噻吩-2-磺醢胺 比照範例279製備，除了使用4-(3-溴苯基）-8-(三氟 甲基）-喹啉和5-溴噻吩—2-磺醯胺作為反應物，以產生如 一白色固狀物之該標題化合物。MS (ES) 434. 9。 20 1 例 499 3-甲基-4-{3-[5-（甲基磺釀基）-2-噻吩基]苯 基卜8-（三氟甲基）喹啉 比照範例279製備，除了使用3-甲基-4-(3-(4, 4, 5, 5- 25四甲基一丨，3, 2_二雜氧戊硼烷-2-基）苯基）-8-(三氟甲基） 4淋0¾和2-溴基-5-(甲基-績醯基）嗟吩作為反應物，以產 310 200825054 生如一白色固狀物之該標題化合物。MS (ES) z/7/z 447. 9。 範例500 4-{3-[5-（乙基磺醢基）一2-噻吩基]苯基}-3-甲基 5 - 8-（三氟甲基）啥淋 步驟1: 2-溴基-5-(乙基磺醢基）噻吩 比照範例1，使用5-溴噻吩-2-磺醯氯作為該芳基磺醯 氯且碘乙烷作為該烷化劑，來製備該標題化合物。 MS (ES) Λ//Ζ 253. 9。 10 步驟2: 4-{3-[5-(乙基確斑基）-2-嗅吩基]苯基}-3_ 甲基-8-（三氟甲基）喹啉 比照範例279製備，除了使用3-曱基-4-(3-(4, 4, 5, 5-四甲基-1，3, 2-二雜氧戊硼烷-2-基）苯基）-8-（三氟甲基） 15啥琳_和2-溴基-5-(乙基磺醯基）-噻吩作為反應物，以產 生如一白色固狀物之該標題化合物。MS (ES) /ff/z 462. 0。 3一甲基-4-{3-[5-（丙基續斑基）-2-嗟吩基]苯 20基卜8〜（三氟甲基）喹啉酮 步驟1: 2_溴基-5-(丙基磺醢基）噻吩 比照範例1製備該標題化合物，除了使用5-溴噻吩-2-~酿氣作為該芳基磺醯氯並以1-碘丙烷作為該烷化劑。2-Amino-4-[3'-(methyl aryl)biphenyl-3-yl]-8-(trifluoromethyl)quinolin-3-carbamide 5 Step 1: 2-Amino -4-(3-Leptylphenyl)-8-(trifluoromethyl) phthalocyanine-3-carboxamide was treated with NaH (348 mg, 8.7 mmol, 60% dispersion in oil). 2-Amino-3-(trifluoromethyl)phenyl)(3-bromophenyl)methanone (1.0 g, 2. 9 mmol) and 2-cyanoacetamide (366 mg, 4. 4 mmol ) a stirred mixture of one of DMS0 (5.00 mL). After the gas was released, the reaction tube was capped and heated at 110 ° C for 20 hours. The cooled reaction was poured into water (80 mL) andEtOAc. The extract was dried over MgS 4 and concentrated under reduced pressure. The residue was purified by chromatography eluting with EtOAc (EtOAc:EtOAc) MS (ES) m/z m. Found: </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; Step 2: 2-Amino-4-[3'-(methyl-mercapto)biphenyl-3-20-yl]-8-(trifluoromethyl)quinoline-3-carboxamide was prepared as in Example 279. In addition to the use of 2-amino-4-(3-bromophenyl)-8-(trimethylmethyl) sulfonium-3-cartoamine and 3-(methyl stellate) phenyl 306 200825054 boric acid As a reactant, the title compound was obtained as a white solid. MS (ES) 7Z7/Z 486. 0; HRMS······································ 5 Example 489 4-[4'-Fluoro-3'-(methylsulfonyl)biphenyl-3-yl]-8-(trifluoromethyl)quinoline was prepared according to Example 279 except that 4- (3-(4, 4, 5, 5-tetramethyl-1,3,2-dioxalate side-burning 2-yl)phenyl)-8-(trimethylmethyl)啥琳 and ίο 4 - a gas-based 1-fluoro-2-yl (methyl fluorenyl) benzene, potassium dihydrogenate and acetic acid, bat (11) as a reaction to give the title compound as a white solid. MS (ES) π/ζ 445. 8. Example 490 15 4-[4'-Fluoro-3'-(methylsudanyl)biphenyl-3-yl]-3-methyl-8-(trifluoromethyl)indole prepared according to Example 279 In addition to using 3-mercapto-4-(3-(4, 4, 5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-8-( Trifluoromethyl) linalone and 4-oxyl-1-fluoro-2-(methylindolyl)benzene, potassium dihydrogen phosphate 20 and palladium(II) acetate as reactants to give a white solid The title compound. MS (ES) zzz/z 459· 8. Example 491 2-[3-({3'-[8-(Trifluoromethyl)-4-quinolinyl]biphenyl-3_yl}sulfur 307 200825054 propyl)propyl]-1 in isoindole -1,3(2i9)-dione was prepared as in Example 279 except using 4-(3-bromophenyl)-8-(trifluoromethyl)-quinoline and 2-(3-(3-(4) , 4, 5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylthio)-propyl)isoindoline-1,3-dione as an anti 5 Reagents to give the title compound as a white solid. MS (ES) / ff / z 568_ 7. Example 492 Y-Ethyl-3-({3'-[3-methyl-8-(trifluoromethyl)-4_quinolinyl]10-biphenyl-3-yl}-supply))-1 -Amine was prepared as in Example 279 except that 3-mercapto-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene was used. And the 3-(3-bromophenylsulfonyl)-N-ethylpropan-1-amine is used as a reactant to produce a white solid Title compound. 15 MS (ES) /»/ζ 513· 1. Example 493 #-Methyl-3_({3'-[3-methyl-8-(trifluoromethyl)-4-quinolinyl] phenyl-3-yl} acyl) propan-1-amine 2〇 Prepared according to Example 279, except that 3-methyl-4-(3-(4, 4, 5, 5-tetramethyl-1,3,2-^-hypoxanthene-2-yl) was used. Phenyl)-8-(trifluoromethyl)quinolinone and 3-(3-bromophenylsulfonylmethylpropan-1-amine as reactants to give the title compound as a white solid MS (ES) Λ//Ζ 499. 1. Example 494 308 25 200825054 Hexyl-3-({3,[8_(trifluoromethyl)_4_)]biphenyl_3yl} continuation base) 1-amine was prepared as in Example 279 except that 4-(3-bromophenyl)-8-(trifluoromethyl# 3-(3,phenylphenyl)-N-ethylamine was used as the reactant. To give the title compound as a white solid. ms(es) /27/z 499. 0 〇Example 495 methyl-3-U3,,[8_(trifluoromethyl)_4_yl]biphenyl _3 base} ίο continuation base) propan-1-amine was prepared according to Example 279, except that 4-(3-bromophenyl)-8-(trifluoromethyl)-indenyl and 3-(3, phenyl sulphate were used. - N-fluorenyl two small amines as reactants to produce a white solid Compound 484.: 1. Example 496 8-Alkyl-4-[3'-(methylsulfonyl)biphenyl-3-yl]quinoline Step 1: 4-(3-Bromophenyl)- 8-oxoquinoline with 3-bromophenylboronic acid (〇·15 mmol), potassium dihydrogen phosphate (〇·沈 gl 2 20 咖〇1), and Pd(pPh3)4 (20 mg, 0·017 mmol) The methane (3 mL) containing 4-bromo-mono-monochloroporphyrin (〇·200 g, 〇. 82 mmol) was treated. The reaction was heated at 90 °C for 8 hours. The solvent was removed and the residue was analyzed using a 10:90 E::H color layer to afford </ RTI> 085 g of the title compound. Do (ES) /z//z 317. 8. 309 200825054 Step 2: 8-Alkyl-4-[3,-(methylsulfonyl)biphenyl-3-yl]quinoline was prepared as in Example 279 except using 4-(3-bromophenyl)-8 -Chloroquinoline and 3-(methylsulfonyl)phenylboronic acid are used as the reactants to give the title compound as a white solid. MS (ES) Λ//Ζ 393. 9. Example 4Q7 5-{3-[3-Methyl-8-(trifluoromethyl)-4-quinolinyl]phenyl}thiophene-2-sulfonamide 10 was prepared according to Example 279 except that 3-methyl was used. -4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-8-(trifluoromethyl) _ and 5-bromothiophene-2-sulfonamide are used as the reactants to give the title compound as a white solid. MS (ES) yz//z 449. 1. 15 Example 498 5-{3-[8-(Trifluoromethyl)-4-quinolinyl]phenyl}thiophene-2-sulfonylamine was prepared as in Example 279 except using 4-(3-bromophenyl) -8-(Trifluoromethyl)-quinoline and 5-bromothiophene-2-sulfonamide are used as the reactants to give the title compound as a white solid. MS (ES) 434. 9. 20 1 Example 499 3-Methyl-4-{3-[5-(methylsulfanyl)-2-thienyl]phenyl b- 8-(trifluoromethyl)quinoline prepared according to Example 279, except 3-methyl-4-(3-(4, 4, 5, 5- 25 tetramethyl-indenyl, 3,2-dioxaborolan-2-yl)phenyl)-8-(trifluoro Methyl) 4 hydrazine and 2-bromo-5-(methyl-d-decyl) porphin are used as the reactants to give the title compound as a white solid. MS (ES) z/7/z 447. 9. Example 500 4-{3-[5-(Ethylsulfonyl)- 2-thienyl]phenyl}-3-methyl-5-8-(trifluoromethyl)phosphonium Step 1: 2-Bromo -5-(ethylsulfonyl)thiophene The title compound was prepared by the same procedure as Example 1, using 5-bromothiophene-2-sulfonium chloride as the arylsulfonyl chloride and ethyl iodide as the alkylating agent. MS (ES) Λ//Ζ 253. 9. 10 Step 2: 4-{3-[5-(Ethyl aryl)-2- olenophenyl]phenyl}-3_methyl-8-(trifluoromethyl)quinoline was prepared as in Example 279 except Using 3-mercapto-4-(3-(4, 4, 5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-8-(trifluoro Methyl) 15啥琳_ and 2-bromo-5-(ethylsulfonyl)-thiophene are used as the reactants to give the title compound as a white solid. MS (ES) / ff/z 462. 0. 3-monomethyl-4-{3-[5-(propyl contigyl)-2-nonyl]benzene 20 phenyl 8~(trifluoromethyl)quinolinone Step 1: 2 bromo- 5-(Propylsulfonyl)thiophene The title compound was prepared in the same manner as in Example 1 except that 5-bromothiophene-2-~ as the arylsulfonyl chloride and 1-iodopropane as the alkylating agent.

Ms (ES) y»/z 268. 9。 步驟2: 3-甲基-4-{3-[5-（丙基磺醢基）-2-噻吩基] 311 200825054 苯基}-8-（三氟甲基）喹啉酮 比照範例279製備，除了使用3-甲基-4-(3-(4, 4, 5, 5-四甲基_1，3, 2-二雜氧戊侧院-2-基）苯基）-8-(三就甲基） 啥琳酮和2-溴基-5-(丙基磺醯基）嗟吩作為反應物，以產生 5 如一白色固狀物之該標題化合物。 MS (ES) λζ/ζ 476. 0。 範例502 4-{3-[5-（異丙基續斑基）-2-嘆吩基]苯基}-3-甲基 1〇 -8-（三氟甲基）喹啉 步驟1: 2-淡基-5-(異丙基續酿基）售吩 比照範例1製備該標題化合物，除了使用5-溴噻吩-2-石黃酿氯作為該芳基續酿氣並以1_峨-2 -曱基丙烧作為該烧 化劑。MS (ES) 268. 9。 15 步驟2: 4-{3-[5-(異丙基續酸基）-2-嘆吩基]苯 基}-3-甲基-8-(三氟甲基）啥琳 比照範例279製備，除了使用3-曱基-4-(3-(4, 4, 5, 5-四甲基_1，3, 2-二雜氧戊石朋烧-2-基）苯基）-8-（三就甲基） 20 喹啉酮和2-溴基-5-(異丙基-磺醯基）噻吩作為反應物，以 產生如一白色固狀物之該標題化合物。MS (ES) π/ζ476. 0。 範例503 3-[(5-{3-[3-甲基-8-（三氟甲基）-4_喹啉基]苯 25 基}-2-噻吩基）磺醢基]1-丙酵 比照範例279製備，除了使用3-甲基-4-(3-(4, 4, 5, 5- 312 200825054 四甲基-1，3, 2-二雜氧戊硼烷—2-基）苯基）-8〜（三氟甲基） 喹啉酮和3-(5-溴噻吩-2-基磺醯基）-1-丙醇作為反應物， 以產生如一白色固狀物之該標題化合物。 . MS (ES) m/z 492.0 ° 5 ； 範例504 4-{3-[5-（甲基磺醢基）一2-噻吩基]苯基}一8-（三氟甲 基）喹啉 步驟1: 2-淡基-5-(甲基確斑基）嘆吩 ί 10 使用5—溴噻吩-2-磺醯氯當作該芳基磺醯氯並以碘甲 烷當作該烷化劑以製備該標題化合物。 MS (ES) /β/ζ 240. 9。 步驟2: 4 - {3 - [5-(甲基磺醢基）- 2-噻吩基]苯 15 基卜8-(三氟甲基）喹啉 比照範例279製備，除了使用4-(3-溴苯基）-8-(三氟 甲基）-喹啉和2-溴基-5-(甲基磺醯基）噻吩作為反應物， v 以產生如一白色固狀物之該標題化合物。MS (ES) _ 433· 9。 20 ’ 範例505 4-{3-[5-(乙基磺醢基）_2-噻吩基]苯基}-8-(三氟甲 基）喹啉 比照範例279製備，除了使用4-(3-溴苯基）-8-(三氟 25甲基）-喹啉和2-溴基-5-(乙基磺醯基）-噻吩作為反應 物，以產生如一白色固狀物之該標題化合物。MS (ES)瓜/z 313 200825054 447.9 ° 4 - {3-[5-(異丙基磺醢基）-2-噻吩基]苯基}-8-(三氟 5甲基）喹啉 比照範例279製備，除了使用4_(3_溴苯基）_8_(三氟 甲基喹啉和2—溴基-5-(異丙基磺醯基）噻吩作為反應 物，以產生如一白色固狀物之該標題化合物。MS (ES) /ff/z 462· 0 0 ίο j|例5虹 該下列範例507之化合物基本上係根據範例233的方 法製備。 N-(4-(3-(3-(甲基磺醢基）苯氧基）苯基）_8_(三氟 甲基）喹啉-3-基）甲烷磺醢胺 15 以範例233所述之相似方法製備該標題化合物。 MS (ES) TZ///536· 9 ; HRMS:計算值 C24H19F3N2〇5S2 + H+， 537.07602;實測值（ESI, [M+H]+0bs，d), 537. 0757。 範例508至526 20 下列範例至526中之化合物基本上根據範例276 的方法製備，除了使用適當的反應物來取代。 範例508 8-氣基-4-{3-[3-(甲基磺醢基）苯氣基]苯基}養琳一3一 314 200825054 甲醢胺 MS(ES)m/z 453.0; HRMS:計算值 C23HnClN2〇4S-H+， 451.05248;實測值（ESI，[Μ-ΗΓ)，451.0526。 5 範例509 Ν-苄基-3 - [(3-{3 - [8-(三氟甲基)- 4-喹啉基]苯氧基}苯基) 磺醢基]丙-1-胺 MS (ES) m/z 576. 9 ； HRMS:計算值 C32H27F3N2〇3S + H+， 577.17672;實測值（ESI，[M+H]+Obs’d)，577.1766。 ο 範例510 Ν - (4-氟基苄基)-3-[(3-{3-[8-(三氟甲基)-4-喹啉基]苯氧 基}苯基)續斑基]丙-1-胺 MS (ES) m/z 594_ 8 ; HRMS:計算值 C32H26F4N2〇3S + Η+， 15 595. 16730 ;實測值（ESI，[M+H]+ Obs’d)，595. 1685。 範例511 N-{3-[(3-{3-[8-(三氟甲基)- 4-啥啉基]苯氧基}苯基)磺醢 基]丙基}丙-2_浠基-1-胺 20 MS (ES) m/z 526.8 。 範例512 3 - ({3-[(3-{3-[8-(三氟甲基)-4-喹啉基]苯氧基}苯基)磺 醢基]丙基}胺基)丙腈 315 200825054 MS (ES) m/z 539. 8 ； HRMS:計算值 C28H24F3N3〇3S + H+， 540.15632;實測值（ESI, [M+H]+0bs’d)，540.1561。 範例513 5 N-{3-[(3-{3-[8-(三氟甲基)-4-喹啉基]苯氧基}苯基)磺醢 基]丙基}丙-2-快-1-胺 MS (ES) m/z 524. 8 ; HRMS:計算值 C28H23F3N2〇3S + H+， 525.14542;實測值（ESI, [M+H]+0bs’d)，525. 1456。 ίο 範例514 IH2-氟乙基)-3-[(3-{3 - [8 - (三氟甲基)_4-舍林基]苯氧基} 苯基)磺醢基]丙-1-胺 MS (ES) m/z 532·8 。 15 範例515 N-甲氧基-3-[ (3-{3_[8-(三氟甲基)-4-啥琳基]苯氧基}苯 基)磺醢基]丙-1-胺 MS (ES) m/z 516. 8 ； HRMS:計算值 C26H23F3N2〇4S + H+， 517.14034;實測值（ESI, [Μ+ΗΓ)，517.1399。 20 辑例516 4 -（3-{3-[(3-氯基丙基）磺醢基]苯氧基}苯基）-8-(三 氟甲基）喹啉 使用N-甲基羥基胺鹽酸鹽當作起始物質，自上述反應 316 200825054 (範例515)分離出該產物。MS (ES) m/z 505. 7 ; HRMS··計 算值 C25H19ClF3N〇3S + H+，506.07990 ;實測值（ESI, [M+H]+ Obs’d)，506· 0796。 5 範例517 N-甲基-N-{3-[(3-{3-[8-(三氟甲基)-4_喹啉基]苯氧基}苯 基)續斑基]丙基}丙-2-炔-1-胺 MS (ES) m/z 538. 8 ; HRMS:計算值 C29H25F3N2〇3S + H+， f % 539_ 16107 ;實測值（ESI，[M+H]+ Obs’d)，539. 1608。 ίο 範例518 (2RHH3-[(3-{3-[8-(三氟甲基)-4-喹啉基]苯氧基}苯基) 續斑基]丙基} 丁_2-胺 MS (ESI) m/z 543 ； HRMS:計算值 C29H29F3N2〇3S + H+， 15 543. 19237 ;實測值（ESI，[M+H]+ Obs，d)，543. 1935。 v 簸例519 (2S) - N-{3-[(3 - {3 - [8 - (三氟甲基)-4-啥啉基]苯氧基}苯基) 磺醢基]丙基}丁-2-胺 - 2〇 MS (ES) m/z 542. 9 ; HRMS:計算值 C29H29F3N2〇3S + H+， 543.19237;實測值（ESI，[M+H]+0bs’d)，543.1922。 典例520 317 200825054 N-(3-氯基苄基)- 3-[(3 - {3 - [8 - (三氟甲基)-4-啥琳基]苯氧 基}苯基)項雄基]丙-1-胺 MS (ES) m/z 610. 8 ； HRMS:計算值 C32H26ClF3N2〇3S + H+， 611.13775 ；實測值（ESI, [M+H]+ Obs’d)， 5 611·1386 。 範例521 (4-(3-(3-（甲基磺醯基）苯氧基）苯基）一8_(三氟甲基） 喹啉-3-基）甲胺 10 MS (ES) m/z 473· 0 ; HRMS:計算值 C24H19F3N2〇3S + H+， 473.11412;實測值（ESI, [M+H]+0bs’d)，473.1143。 範例522 4-{2-氯基-5-[3-(甲基磺醢基）苯氧基]苯基卜8-氟基 15 啥琳-3 -甲酸胺 以範例276中所述之相似方法製備該標題化合物。MS (ES) m/z 470. 6 ； HRMS:計算值 C23H16ClFN2〇4S + H+， 471.05761;實測值（ESI, [Μ+ΗΓ)，471.0578。 20 範例523 4-{2-氣基-5-[3-(甲基磺醯基）苯氧基]苯基}-8-氰基 喹啉-3-甲醢胺 以範例276中所述之相似方法製備該標題化合物。MS (ES) m/z 478·0 。 318 200825054 辦例524 8-甲基-4-{3-[3-（甲基磺醯基）苯氧基]苯基}喹啉-3- 甲醢胺Ms (ES) y»/z 268. 9. Step 2: 3-Methyl-4-{3-[5-(propylsulfonyl)-2-thienyl] 311 200825054 Phenyl}-8-(trifluoromethyl)quinolinone Prepared according to Example 279 In addition to using 3-methyl-4-(3-(4, 4, 5, 5-tetramethyl-1,3,2-dioxaoxylan-2-yl)phenyl)-8-( And the 2-bromo-5-(propylsulfonyl) porphin as a reaction product to give the title compound as a white solid. MS (ES) λζ/ζ 476. 0. Example 502 4-{3-[5-(Isopropyl leucine)-2-thinyl]phenyl}-3-methyl 1 〇-8-(trifluoromethyl)quinoline Step 1: 2 - lyophile-5-(isopropyl continuation) sold the title compound according to Example 1 except that 5-bromothiophene-2-yellow-brown chlorine was used as the aryl continuous gas and 1_峨- 2 - mercaptopropene was used as the burning agent. MS (ES) 268. 9. 15 Step 2: 4-{3-[5-(Isopropylethano)-2-thinyl]phenyl}-3-methyl-8-(trifluoromethyl)anionine prepared according to Example 279 In addition to using 3-mercapto-4-(3-(4, 4, 5, 5-tetramethyl-1,3,2-dioxapentazol-2-yl)phenyl)-8- (Trimethyl) 20 quinolinone and 2-bromo-5-(isopropyl-sulfonyl)thiophene as the reactants to give the title compound as a white solid. MS (ES) π/ζ476. 0. Example 503 3-[(5-{3-[3-Methyl-8-(trifluoromethyl)-4_quinolinyl]benzene 25-yl}-2-thienyl)sulfonyl] 1-propanyl Prepared according to Example 279 except that 3-methyl-4-(3-(4, 4, 5, 5-312 200825054 tetramethyl-1,3,2-dioxaborolan-2-yl)benzene was used. a base compound of -8-(trifluoromethyl)quinolinone and 3-(5-bromothien-2-ylsulfonyl)-1-propanol as a reactant to give the title compound as a white solid. . MS (ES) m/z 492.0 ° 5 ; Example 504 4-{3-[5-(Methylsulfonyl)- 2-thienyl]phenyl}-8-(trifluoromethyl)quinoline 1: 2-Pentyl-5-(methyl-decyl) sin. 10 Use 5-bromothiophene-2-sulfonyl chloride as the arylsulfonyl chloride and use methyl iodide as the alkylating agent. The title compound was prepared. MS (ES) / β / ζ 240. 9. Step 2: 4 - {3 - [5-(Methylsulfonyl)-2-thienyl]benzene 15 benzyl 8-(trifluoromethyl)quinoline was prepared as in Example 279 except using 4-(3- Bromophenyl)-8-(trifluoromethyl)-quinoline and 2-bromo-5-(methylsulfonyl)thiophene are used as the reactants to give the title compound as a white solid. MS (ES) _ 433· 9. 20' Example 505 4-{3-[5-(ethylsulfonyl)_2-thienyl]phenyl}-8-(trifluoromethyl)quinoline was prepared as in Example 279 except using 4-(3- Bromophenyl)-8-(trifluoro25methyl)-quinoline and 2-bromo-5-(ethylsulfonyl)-thiophene are used as the reaction to give the title compound as a white solid. MS (ES) melon / z 313 200825054 447.9 ° 4 - {3-[5-(isopropylsulfonyl)-2-thienyl]phenyl}-8-(trifluoro-5methyl)quinoline analogy Preparation 279, except that 4-(3-bromophenyl)-8-(trifluoromethylquinoline and 2-bromo-5-(isopropylsulfonyl)thiophene were used as the reactants to give a white solid. The title compound. MS (ES) / ff / z 462 · 0 0 ίο j | Example 5 The following compounds of Example 507 were prepared essentially according to the procedure of Example 233. N-(4-(3-(3-( Methylsulfonyl)phenoxy)phenyl)-8-(trifluoromethyl)quinolin-3-yl)methanesulfonamide 15 The title compound was prepared in a similar manner as described in Example 233. MS (ES) TZ ///··················· The compound was prepared essentially according to the procedure of Example 276, except that the appropriate reactants were used. Example 508 8-Alkyl-4-{3-[3-(methylsulfonyl)benzeneyl]phenyl} A 3-31 314 200825054 methotrexate MS (ES) m / z 453.0; HRMS: calculated value C23HnClN2 〇 4S-H + 451.05248; found (ESI, [Μ-ΗΓ), 451.0526. 5 Example 509 Ν-benzyl-3 - [(3-{3 - [8-(trifluoromethyl)-4-quinolinyl]phenoxy) </ RTI> </ RTI> <RTI ID=0.0></RTI> </RTI> <RTI d), 577.1766. ο Example 510 - (4-Fluorobenzyl)-3-[(3-{3-[8-(trifluoromethyl)-4-quinolinyl]phenoxy}phenyl Continuation of plaques] propan-1-amine MS (ES) m/z 594_ 8 ; HRMS: calculated C32H26F4N2 〇3S + Η+, 15 595. 16730 ; measured value (ESI, [M+H]+ Obs'd ), 595. 1685. Example 511 N-{3-[(3-{3-[8-(Trifluoromethyl)-4-phenylindolyl)phenoxy}phenyl)sulfonyl]propyl} Propan-2-ylmercapto-1-amine 20 MS (ES) m/z 526.8. Example 512 3 - ({3-[(3-{3-[8-(trifluoromethyl)-4-quinolinyl) Phenyloxy}phenyl)sulfonyl]propyl}amino)propanenitrile 315 </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; [M+H]+0bs'd), 540.1561. Example 513 5 N-{3-[(3-{3-[8-(Trifluoromethyl)-4-quinolinyl]phenoxy}phenyl)sulfonyl]propyl}propan-2- fast </RTI> </ RTI> </ RTI> </ RTI> <RTI ID=0.0></RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Οο Example 514 IH2-Fluoroethyl)-3-[(3-{3 - [8-(trifluoromethyl)_4-sherinyl]phenoxy}phenyl)sulfonyl]propan-1-amine MS (ES) m/z 532·8. 15 Example 515 N-Methoxy-3-[(3-{3_[8-(Trifluoromethyl)-4-indolyl]phenoxy}phenyl)sulfonyl]propan-1-amine MS (ES) m/z 516. 8; HRMS: calcd for C26H23F3N2 〇4S + H+, 517.14034; Measured value (ESI, [Μ+ΗΓ), 517.1399. 20 Example 516 4 -(3-{3-[(3-Chloropropyl)sulfonyl]phenoxy}phenyl)-8-(trifluoromethyl)quinoline using N-methylhydroxylamine The hydrochloride salt was used as the starting material and the product was isolated from the above reaction 316 200825054 (Example 515). MS (ES) m/z 505. 7; HRMS·································· 5 Example 517 N-Methyl-N-{3-[(3-{3-[8-(trifluoromethyl)-4_quinolinyl]phenoxy}phenyl) contigyl]propyl} Prop-2-yn-1-amine MS (ES) m/z 538. 8 ; HRMS: calcd for C29H25F3N2 〇3S + H+, f % 539 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ , 539. 1608. Οο Example 518 (2RHH3-[(3-{3-[8-(Trifluoromethyl)-4-quinolinyl]phenoxy}phenyl) contigyl]propyl}but-2-amine MS ( ESI) m/z 543 ; HRMS: calcd for C,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, N-{3-[(3 - {3 - [8-(Trifluoromethyl)-4-indolyl]phenoxy}phenyl)sulfonyl]propyl}butan-2-amine - 2〇 MS (ES) m/z 542. 9; HRMS: calcd for C,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, -Chlorobenzyl)- 3-[(3 - {3 - [8-(trifluoromethyl)-4-indolyl]phenoxy}phenyl)-androstyl]propan-1-amine MS (ES m/z 610. 8 ; HRMS: calculated C32H26ClF3N2 〇3S + H+, 611.13775; found (ESI, [M+H]+ Obs'd), 5 611·1386. Example 521 (4-(3-( 3-(methylsulfonyl)phenoxy)phenyl)-8-(trifluoromethyl) quinolin-3-yl)methylamine 10 MS (ES) m/z 473·0; HRMS: Calculated C24H19F3N2 〇3S + H+, 473.11412; found (ESI, [M+H]+0bs'd), 473.1143. Example 522 4-{2-Chloro-5-[3-(methylsulfonyl)phenoxy The title compound was prepared in a similar manner as described in Example 276. MS (ES) m/z 470. 6; HRMS: Calculated C23H16ClFN2 〇4S + H+ , 471.05761; found (ESI, [Μ+ΗΓ), 471.078. 20 Example 523 4-{2-carbyl-5-[3-(methylsulfonyl)phenoxy]phenyl}-8-cyanide The title compound was prepared in a similar manner as described in Example 276. MS (ES) m/z 478·0. 318 200825054 Example 524 8-Methyl-4-{3-[ 3-(methylsulfonyl)phenoxy]phenyl}quinoline-3-carbamide

5 以範例276中所述之相似方法製備該標題化合物。MS (ES) m/z 433.0 ； HRMS:計算值 C24H2〇N2〇4S + H+， 433. 12165;實測值（ESI，[M+H]+0bs’d)，433.1225。 範例525 ι〇 4-{3- [ 3-氣基-5-（甲基續斑基）苯氧基]苯基}_8-（三 氟甲基）喹啉-3-甲醢胺 根據範例276之方法，自8-三氟曱基-4-(3-羥基苯基） 喹啉-3-羧酸乙酯和1，3-二氯-5-(甲基磺醯基）苯製備該標 題化合物。MS (ES) m/z 521. 0。 15 範例526 4-{3-[3-(乙基磺醢基）苯氧基]苯基}-8-(三氟甲基） 喹啉-3-甲醢胺 根據範例276之方法，自8-三氟甲基-4-(3-羥基苯基） 20 喹啉-3-羧酸乙酯和1-(乙基磺醯基）-3-氟苯製備該標題化 合物。MS (ES) m/z 501. 1。 在實施例中，其中^為-8(0)21^之化合物的硫化物 前驅物可在一般條件下使用〇xone®將其氧化成對應的 25 砜，並根據上述範例35自硫基酚製備_化芳基砜。 319 200825054The title compound was prepared in a similar manner as described in Example 276. MS (ES) m/z 436. Found. Example 525 ι〇4-{3-[3-Gasyl-5-(methyl contigyl)phenoxy]phenyl}_8-(trifluoromethyl)quinoline-3-carboxamide according to Example 276 Method for preparing the title from ethyl 8-trifluorodecyl-4-(3-hydroxyphenyl)quinoline-3-carboxylate and 1,3-dichloro-5-(methylsulfonyl)benzene Compound. MS (ES) m/z 521. 0. 15 Example 526 4-{3-[3-(ethylsulfonyl)phenoxy]phenyl}-8-(trifluoromethyl)quinoline-3-carboxamide According to the method of Example 276, from 8 The title compound was prepared from ethyl trifluoromethyl-4-(3-hydroxyphenyl) 20 quinolin-3-carboxylate and 1-(ethylsulfonyl)-3-fluorobenzene. MS (ES) m/z 501. 1. In an embodiment, a sulfide precursor of a compound of -8(0)21^ can be oxidized to the corresponding 25 sulfone using 〇xone® under normal conditions and prepared from thiophenol according to Example 35 above. _ aryl sulfone. 319 200825054

範例527 4-(3’ -{[3-(1, 3-二氧-1, 3-二氩-2及-異吲哚-2-基）丙 5 基]磺醯基}聯苯-3-基）-8-(三氟甲基）喹啉-3-羧酸乙酯 比照範例35製備，除了使用4-(3’-(3-(1,3-二氧異 ^引σ朵琳-2-基丙基硫基）聯苯-3-基）-8-(三氟甲基）啥琳 -3-魏酸乙酯作為反應物，以產生如一白色固狀物之該標題 化合物。MS (ES) /ff/z 672. 7。 10 範例528 2-[3-（{3’ -[3-甲基-8-（三氟甲基）-4-啥琳基]聯苯 -3-基}磺醢基）丙基]-If異吲哚-1, 3(2扔-二酮 比照範例35製備，除了使用2-(3-(3’ -(3-甲基-8-(三 氟甲基）_4-啥琳基）聯苯-3-基硫基）丙基）異π引0朵淋-1，3-15 二酮作為反應物，以產生如一白色固狀物之該標題化合 物。MS (ES) /ff/z 614.7 。 範例529 2-[3-({3’ -[8-(三氟甲基）-4-啥琳基]聯苯-3-基}續 醢基）丙基]-1及-異吲哚-1，3(2^)-二酮 320 200825054 比照範例35製備，除了使用2-[3-({3’-[8-(三氟甲 基）_4—喧琳基]聯苯—3-基}硫基）丙基]—1及-異a弓| u朵 -1，3(2奶-二酮作為反應物，以產生如一白色固狀物之該標 題化合物。MS (ES) /ζ7/ζ 600. 6。 在一些實施例中，Rn可為經酜醯基取代之烧基。在這 些實施例中，可藉由以S太醯基經取代之化合物，例如，以 含有聯胺之溶劑，通常在迴流加熱數小時，處理來獲得該 對應的一級胺為。 0Example 527 4-(3' -{[3-(1, 3-Dioxy-1,3-diargon-2 and -isoindol-2-yl)propan-5yl]sulfonyl}biphenyl-3 -ethyl)-8-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester was prepared as in Example 35 except that 4-(3'-(3-(1,3-dioxoiso)] Ethyl 2-ylpropylthio)biphenyl-3-yl)-8-(trifluoromethyl)indole-3-teroic acid was used as the residue to give the title compound as a white solid. MS (ES) / ff / z 672. 7. 10 Example 528 2-[3-({3' -[3-methyl-8-(trifluoromethyl)-4-indolyl]biphenyl-3 -yl}sulfonyl)propyl]-If isoindole-1, 3 (2 throw-dione is prepared according to Example 35 except that 2-(3-(3'-(3-methyl-8-())) Trifluoromethyl)- 4-indolyl)biphenyl-3-ylthio)propyl)isoπ-indole-1,3-ldione as a reactant to give a white solid Title compound. MS (ES) / ff / z 614.7. Example 529 2-[3-({3' -[8-(Trifluoromethyl)-4-indolyl]biphenyl-3-yl} continued Propyl]-1 and -isoindole-1,3(2^)-dione 320 200825054 Prepared according to Example 35 except that 2-[3-({3'-[8-(trifluoromethyl)) )_4—喧琳基]Biphenyl -3-yl}thio)propyl]-1 and -iso-a-bone|u-l,3 (2 milk-dione as a reactant to give the title compound as a white solid. MS (ES /ζ7/ζ 600. 6. In some embodiments, Rn may be a mercapto-substituted alkyl group. In these embodiments, a compound substituted with a S-terpenyl group, for example, may be included. The solvent of the hydrazine is usually heated under reflux for several hours to obtain the corresponding primary amine.

範例530 3-({3’ -[8-（三氟甲基）-4-啥琳基]聯苯-3-基}續酿基） 15 丙-1-胺 將2-(3-(3’ -(8-(三氟甲基）-4-喹啉基）聯苯-3-基磺 醯基）丙基）異°弓卜朵琳-1，3-二酮（0· 050 g，0· 083 mmol)溶 於乙醇（15 mL)中並加入聯胺（1. 0 mL)。將該溶液迴流3小 時，然後移除該溶劑。透過逆相HPLC(乙腈/水）純化該殘餘 20 物以獲得如一黏狀固狀物之該標題化合物（25 mg)。MS (ES) 321 200825054 /z//z 470. 7 〇 範例531 3 -（{3’-[3-甲基-8-（三氟甲基）-4-喹啉基]聯苯-3-基} 磺醢基）丙-1-胺 比照範例398中步驟4製備，除了使用2-(3-(3’-(3- 甲基-8-(三氟甲基）-4-喹啉基）聯苯-3-基磺醯基）丙基）異 吲哚啉-1，3-二酮作為反應物，以產生如一半固狀之該標題 化合物。MS (ES) zz7/z 484· 7。 範例532 ίο 4-{3’ -[(3-胺基丙基）碟酿基]聯苯-3-基}-8_(三氟甲 基）啥淋-3-叛酸乙S旨 比照範例398中步驟4製備，除了使用 4-(3’ -{[3-(1，3-二氧-1，3-二氫-2及-異吲哚-2-基）丙基] 石黃酿基}聯苯_3-基）-8_(三氣甲基）喧琳-3_叛酸乙S旨作為 15 反應物，以產生如一半固狀之該標題化合物。MS (ES) /ff/z 542. 7。 範例533Example 530 3-({3'-[8-(Trifluoromethyl)-4-indolyl]biphenyl-3-yl} continuation) 15 propan-1-amine 2-(3-(3) '-(8-(Trifluoromethyl)-4-quinolinyl)biphenyl-3-ylsulfonyl)propyl)iso-bendolin-1,3-dione (0·050 g, 0· 083 mmol) was dissolved in ethanol (15 mL) and hydrazine (1.0 mL) was added. The solution was refluxed for 3 hours and then the solvent was removed. The residue was purified by reverse phase HPLC (EtOAc/EtOAc) to afford the title compound (25 mg). MS (ES) 321 200825054 /z//z 470. 7 〇Example 531 3 -({3'-[3-Methyl-8-(trifluoromethyl)-4-quinolinyl]biphenyl-3- The base sulfonyl)propan-1-amine was prepared as described in Step 4 of Example 398 except that 2-(3-(3'-(3-methyl-8-(trifluoromethyl)-4-quinolinyl) was used. Biphenyl-3-ylsulfonyl)propyl)isoindoline-1,3-dione as a reactant to give the title compound as a half solid. MS (ES) zz7/z 484· 7. Example 532 ίο 4-{3'-[(3-Aminopropyl) dish-branched]biphenyl-3-yl}-8-(trifluoromethyl)phosphonium-3-decarboxylate B. Prepared in step 4 except using 4-(3'-{[3-(1,3-dioxo-1,3-dihydro-2 and-isoindol-2-yl)propyl] anthraquinone }Biphenyl-3-yl)-8-(trimethylmethyl)喧琳-3_Resin B is intended as the 15 reactant to give the title compound as a half solid. MS (ES) / ff / z 542. 7. Example 533

322 200825054 3-(4,5-二氫-111-咪唑-2-基)-4-{3-[3-（甲基續醢基）苯氧 基]苯基}-8-(三氟甲基)啥琳 將含有4-{3-[3_(甲基績醯基）苯氧基]苯基}-8-(三氟 甲基）口奎琳-3-甲腈（50 mg，0· 10 mmol)、乙二胺（10 mL)、 5 和P2S5 (5 mg)之一混合物在70 °C加熱4小時。將該混合 物倒進水中，以乙酸乙酯萃取，並濃縮。該殘餘物經過以 梯度之E:H洗提的色層分析以產生如一黃色固狀物之該標 題化合物（15 mg)。MS (ES) m/z 511.8 ; HRMS:計算值 C26H20F3N3O3S + H+, 512. 12502 ；實測值（ESI，[M+H] + 10 Obs，d)，512· 1247。 範例534至536322 200825054 3-(4,5-Dihydro-111-imidazol-2-yl)-4-{3-[3-(methylthenyl)phenoxy]phenyl}-8-(trifluoromethyl)啥)啥琳 will contain 4-{3-[3_(methylglycosyl)phenoxy]phenyl}-8-(trifluoromethyl)-hydroxypyrimidine-3-carbonitrile (50 mg, 0· A mixture of 10 mmol), ethylenediamine (10 mL), 5 and P2S5 (5 mg) was heated at 70 °C for 4 hours. The mixture was poured into water, extracted with ethyl acetate and concentrated. The residue was chromatographed eluting with a gradient of E:H to give the title compound (15 mg) as a yellow solid. MS (ES) m/z </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; Examples 534 to 536

cf3 Z = -C02CH2Ph cf3 Z = -C02CH2Ph 範例534 15 4- [ (3- {3- [ 8-(三氟甲基)-4-啥琳基]苯氧基}苯基)硫基]派 咬-1-羧酸苄酯 323 200825054 步驟1: 3-(1-(苄基氧基羰基）哌啶-4-基硫基）苯基 硼酸 將含有3-氫硫基苯基硼酸（〇· 77 g，5. 00 mmol)、4-溴口辰唆-1-魏酸苄酯（1· 49 g，5· 00 mmol)、和碳酸铯（5. 〇〇 5 g，15· 2 mmol)於DMF (15 mL)中之一混合物在室溫擾拌2 小時。將該反應倒進水中並以乙酸乙酯萃取。該萃取物透 過MgS〇4乾燥並濃縮，以產生3-(1-(苄基氧基羰基）哌啶一4一 基硫基）苯基棚酸。該粗產物無經任何進一步純化即用於下 一反應。 10 步驟2: 4-[(3-{3-[8-（三氟甲基）-4-啥琳基]苯氧基} 苯基）硫基]旅咬-1-叛酸节酿 將含有3-(1-(苄基氧基幾基）旅淀-4-基硫基）苯基侧 酸（0· 190 g，0· 50 mmol)、3-(8-(三氟甲基）一4-喹啉基）酚 15 (〇_ 15 g，0· 5 mmol)、醋酸銅（ΙΙ)(〇· 18 g，1· 〇 mm〇i)、 三乙基胺（0· 25 g，3· 5 mmol)、和4A分子篩於二氣甲烷（15 mL)中之一混合物，在室溫攪拌整夜。將該固狀物過濾掉並 將該液體倒進水中，然後以乙酸乙酯萃取。該些萃取物透 過MgS〇4乾燥並濃縮。該殘餘物經過以梯度之e:η洗提的色 20層分析以產生如一白色固狀物之該標題化合物（130 mg)。 MS (ES) m/z 615.0 ; HRMS:計算值 C35H29F3n2〇3s + H+， 615.19237;實測值（ESI，[M+H]+〇bs，d)，615.1923。 範例535 324 200825054 4-[(3- {3- [8-(三氟甲基)-4-啥琳基]苯氧基}苯基)確醢基] 哌咬-1-叛酸苄酯 將含有4-[(3-{3-[8-(三氟甲基）-4-喹啉基]苯氧基} 本基）硫基]旅°定-1-羧酸苄自旨（100 mg，0· 16 mmol)和50% 5 Η2〇2(3· 0 mL)於乙酸（3. 0 mL)中之一混合物在60 °C加熱1 小時。將該混合物倒進水中，以乙酸乙酯萃取，並濃縮。 該殘餘物經過以梯度之e:h洗提的色層分析以產生如一固 狀物之該標題化合物（45 mg)。（ES) m/z 647· 0 ; HRMS:計 算值 C35H29F3N2〇5S + H+，647.18220;實測值（ESI，[Μ+ΗΓ)， 10 647. 182 卜 範例536 4-{3-[3-(痕唆-4-基讀醢基）苯氧基]苯基}-8-(三氟 甲基）喹啉 15 將含有48% HBr(1.0 mL)於乙酸(45%體積）中之一溶液逐滴 加入含有4-[(3-{3-[8-(三氟甲基)-4-喹啉基]苯氧基}苯基)磺 醯基]娘咬-1-魏酸苄酯（30 mg，〇· 〇5〇 mmol)於乙酸（lmL)之一混 合物中。將該混合物在室溫攪拌〇· 5小時。加入二乙醚並收集該 固狀物以產生如一暗白色固狀物之該標題化合物（21 mg)。MS (ES) 20 m/z 513.0 ; HRMS:計算值 C27H23F3N2〇3S + H+，513.14542 ;實 測值（ESI, [M+H]+0bs’d)，513.1454。 範例537至539 325 200825054Cf3 Z = -C02CH2Ph cf3 Z = -C02CH2Ph Example 534 15 4- [(3- {3- [ 8-(Trifluoromethyl)-4-indolyl]phenoxy}phenyl)thio] Benzyl 1-carboxylate 323 200825054 Step 1: 3-(1-(Benzyloxycarbonyl)piperidin-4-ylthio)phenylboronic acid will contain 3-hydrothiophenylboronic acid (〇· 77 g, 5. 00 mmol), 4-bromo-tertyl-1-propionate benzyl ester (1·49 g, 5.00 mmol), and cesium carbonate (5. 〇〇5 g, 15. 2 mmol) One of the mixtures in DMF (15 mL) was scrambled for 2 hours at room temperature. The reaction was poured into water and extracted with ethyl acetate. The extract was dried over MgS 4 and concentrated to give 3-(1-(benzyloxycarbonyl)piperidine-4-ylthio)phenyl phthalic acid. This crude product was used in the next reaction without any further purification. 10 Step 2: 4-[(3-{3-[8-(Trifluoromethyl)-4-indolyl]phenoxy}phenyl)thio]Break bite-1-Resin tasting will contain 3-(1-(Benzyloxymethyl) lyophilic-4-ylthio)phenyl-acid (0·190 g, 0·50 mmol), 3-(8-(trifluoromethyl)- 4-quinolinyl)phenol 15 (〇_ 15 g, 0·5 mmol), copper acetate (ΙΙ) (〇· 18 g, 1·〇mm〇i), triethylamine (0·25 g, 3 · 5 mmol), and a mixture of 4A molecular sieves in di-methane (15 mL), stirred at room temperature overnight. The solid was filtered off and the liquid was poured into water and then extracted with ethyl acetate. The extracts were dried over MgS 4 and concentrated. The residue was subjected to EtOAc (EtOAc) eluted eluted eluted elute MS (ES) m/z </RTI> <RTI ID=0.0></RTI> </RTI> </RTI> <RTIgt; </RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Example 535 324 200825054 4-[(3- {3- [8-(Trifluoromethyl)-4-indolyl]phenoxy}phenyl) decyl] piperidine-1-benzylate benzyl ester Contains 4-[(3-{3-[8-(trifluoromethyl)-4-quinolinyl]phenoxy} benzyl)thio] °定定-1-carboxylic acid benzylic (100 mg , 0. 16 mmol) and 50% 5 Η 2 〇 2 (3.0 mL) in a mixture of acetic acid (3.0 mL) was heated at 60 ° C for 1 hour. The mixture was poured into water, extracted with ethyl acetate and concentrated. The residue was chromatographed eluting with a gradient of e:h to give the title compound (45 mg) as a solid. (ES) m/z 647· 0 ; HRMS: Calculated C35H29F3N2 〇5S + H+, 647.18220; Measured (ESI, [Μ+ΗΓ), 10 647. 182 Examples 536 4-{3-[3-(marks唆-4-yl read decyl)phenoxy]phenyl}-8-(trifluoromethyl)quinoline 15 A solution containing 48% HBr (1.0 mL) in acetic acid (45% by volume) Add 4-[(3-{3-[8-(trifluoromethyl)-4-quinolinyl]phenoxy}phenyl)sulfonyl] Nitrient 1-Benzyl Benzate (30 mg) , 〇· 〇 5 〇 mmol) in a mixture of acetic acid (1 mL). The mixture was stirred at room temperature for 5 hours. The title compound (21 mg) was obtained as a dark white solid. MS (ES) 20 m/z (m/z): </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; Example 537 to 539 325 200825054

弟例537 4-({3’-[8-(三氟甲基)-4-喹啉基]聯苯—3-基}硫基)哌啶 叛酸节S旨 5 以範例259中所述之相似方法製備該標題化合物。 MS (ES) m/z 598. 7 ; HRMS:計算值 C35H29F3N2〇2S + H+， 599.19746;實測值（ESI，[M+H]+0bs，d)，599.1967。 j反例538 10 4- ({3’-[8-(三氟甲基)-4-啥琳基]聯苯一3-基}磺斑基)旅啶 -1-羧酸苄酯 以範例535中所述之相似方法製備該標題化合物。MS (ES) m/z 631.0 ； HRMS:計算值 C35H29F3N2〇4S + H+, 631· 18729;實測值（ESI, [M+H]+0bs，d), 631.1862。 範例539 326 15 200825054 4-[3’ -(哌啶-4-基磺醢基）聯苯-3-基]-8-（三氟甲基） 喹啉 以範例536中所述之相似方法製備該標題化合物。MS (ES) m/z 496.7 ； HRMS:計算值 C27H23F3N2〇2S + H+， 497.15051;實測值（ESI, [M+H]+0bs，d)，497_1502。Example 537 4-({3'-[8-(Trifluoromethyl)-4-quinolinyl]biphenyl-3-yl}thio)piperidinic acid sulphate S. 5 as described in Example 259 The title compound was prepared in a similar manner. MS (ES) m/z </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; j counterexample 538 10 4-({3'-[8-(trifluoromethyl)-4-indolyl]biphenyl-3-yl}sulfonyl) benzyl-1-carboxylic acid benzyl ester as an example 535 The title compound was prepared in a similar manner as described above. MS (ES) m/z </RTI> <RTI ID=0.0></RTI> <RTI ID=0.0></RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Example 539 326 15 200825054 4-[3'-(piperidin-4-ylsulfonyl)biphenyl-3-yl]-8-(trifluoromethyl)quinoline Prepared in a similar manner as described in Example 536 The title compound. MS (ES) m/z 495. Found.

r、 ίο ί \ ! 15 20 範例540 4-{3-[3-（甲基磺醢基）苯氧基]苯基卜8_(三氟甲基） 喹啉-3-羧酸甲酯 將含有4-(3-(3-(甲基磺醯基）苯氧基）苯基）_8—(三氟 甲基）喹啉-3-綾酸（5· 〇〇 g，1〇· 3 _〇1)、碘化甲烷（3· 〇 ， 42 mmol)、和 K2C〇3 (5_ 0 g，36 mmol)於丙酮（50 mL)中之 一溶液加熱至迴流。2小時後，冷卻、過濾、並濃縮該反應。 該產物透過以梯度25:75之E:H洗提的管柱色層分析純 化’以產生一黃色泡沫（3· 50 g，68%)。MS (ES) m/z 502· 0。 範例541 - 甲基磺醢基）苯氧基]苯基} 一8一（三氟甲基) 喹啉-3-基]甲酵 在含有4〜丨3〜[3-(甲基磺醯基）苯氧基]苯基}-8-(三氟 327 200825054 甲基）啥琳-3-叛酸甲酯（0. 10 g，0· 20 mmol)於 THF(5. 0 mL) 中之一經冷卻（0 °C)的溶液中，加入含有1.0 M LiAlH4於 THF(0. 25 mL)中之一溶液。1小時後，將該反應倒進2N HC1 水溶液中並以乙酸乙酯萃取。乾燥（MgS〇4)該有機層，濃 5 縮，並藉由以50:50 E:H洗提之管柱色層分析純化，以產 生一白色泡沫（35 mg，37%)。MS (ES) m/z 474.0。r, ίο ί \ ! 15 20 Example 540 4-{3-[3-(Methylsulfonyl)phenoxy]phenyl b-8-(trifluoromethyl)quinoline-3-carboxylic acid methyl ester will contain 4-(3-(3-(methylsulfonyl)phenoxy)phenyl)_8-(trifluoromethyl)quinoline-3-furoic acid (5· 〇〇g, 1〇· 3 _〇 1) A solution of methane iodide (3·〇, 42 mmol) and K2C〇3 (5_0 g, 36 mmol) in acetone (50 mL) was heated to reflux. After 2 hours, the reaction was cooled, filtered and concentrated. The product was purified by column chromatography on a gradient of 25:75 E:H to afford a yellow foam (3·50 g, 68%). MS (ES) m/z 502·0. Example 541 - Methylsulfonyl)phenoxy]phenyl}-8-(trifluoromethyl)quinolin-3-yl]methyl leaver containing 4~丨3~[3-(methylsulfonyl) a phenoxy]phenyl}-8-(trifluoro 327 200825054 methyl) sulfonium-3-deoxymethyl ester (0.10 g, 0·20 mmol) in THF (5.0 mL) A solution containing 1.0 M LiAlH4 in THF (0.25 mL) was added to the cooled (0 °C) solution. After 1 hour, the reaction was poured into aq. The organic layer was dried (MgSO.sub.4), concentrated and purified by column chromatography eluting with 50:50 E:H to yield a white foam (35 mg, 37%). MS (ES) m/z 474.0.

、80C 範例542 4-[3-（3-{[3-（甲基胺基）丙基]罐斑基}苯氧基）苯 ίο 基]-8-（三氟甲基）啥琳-3-甲酸胺 步驟1: 4-(3-(3-(3_(甲基磺醢基氧基）丙基磺醯基） 苯氧基）苯基）-8_(三氟甲基）嗟琳-3-鼓酸甲S旨 在含有4-(3-(3-(3-羥基丙基磺醯基）苯氧基）苯 基）-8-(三氟曱基）口奎琳-3-叛酸甲酯（1.20 g，2.2 mmol)於 15 CH2Cl2(20 mL)和 NEts (1. 00 mL，7. 2 mmol)中之一經冷卻 (0 °C)的溶液中，加入甲石黃醯氣（0· 30 mL，4· 0 mmol)。在 328 200825054 1小時後，將該反應倒進2N HC1水溶液中並以CH2CI2萃取。 乾燥（MgSCh)该有機層並濃縮以產生如一油狀物之該標題 化合物（1· 20 g’ 88%)，其無經進一步純化即被使用。奶（es) m/z 623·8 0 5 步驟2: 4-(3-(3-(3-(第三丁氧基羰基（甲基）胺基） 丙基續疏基）苯氧基）苯基）-8-(三氟甲基）唉琳一3—幾酸甲 酯 將含有4-(3-(3-(3-(甲基績醯基氧基）丙基石黃醯基）苯 ίο氧基）苯基）-8-(三氟甲基）喹啉-3-羧酸甲酯（〇. 8〇 g，i mmol)和2. 0 Μ甲基胺於甲醇（20 mL)中之一溶液在室溫攪 拌。40小時後，濃縮該反應並加進入乙酸乙酯。以飽和的 NaHC〇3水溶液沖洗該有機層，乾燥，並濃縮。將所產生的 油狀物溶於CHsCMlO mL)中，然後加入二碳酸二第三丁酯 15 (1· 〇〇 g，4· 6 mmol)。將該反應在室溫攪拌24小時，然後 濃縮。透過以30:70之E:H洗提的管柱色層分析純化該粗 產物以產生如一油狀物之該標題化合物（〇 15 g，18%)。Ms (ES) m/z 658·9 0 20 步驟3: 4—(3—(3-(3-(第三-丁氧基羰基（甲基）胺基） 丙基續醢基）苯氧基）苯基）-8-(三氟甲基）啥琳-3-叛酸 將含有4-(3-(3-(第三-丁氧基羰基（甲基）胺基）丙基 績醯基）本氧基）苯基）-8-(三I甲基）口奎琳—3一魏酸甲酉旨 (0_15 g，0.23 mmol)和 2·0 M NaOH 水溶液（1 mL)於 329 200825054 THF/MeOH (5 mL)中之一溶液加熱至迴流。3小時之後，將 該反應倒進含有IN HC1水溶液（3 mL)之水（1〇〇 mL)中，然 後以乙酸乙酯萃取。乾燥並濃縮該有機物以產生如一泡沫 之該標題化合物（0· 12 g，81%)。MS (ES) m/z 645· 0。 5 步驟4: 2-（3-(3-（3-胺甲醢基_8-（三氟甲基）-4-喹 琳基）苯氧基）苯基確醢基）丙基（甲基）氨基甲酸第三丁酯 將含有4-(3-(3-(3-(第三—丁氧基羰基（甲基）胺基）丙 基磺醯基）苯氧基）苯基）—8—(三氟甲基）喹啉_3_羧酸 1〇 (〇· 12 g，0· 19 mmol)和羰基二咪唑（〇· 15 g，〇· 95 丽〇1) 於DMF(5.0 mL)中之一溶液加熱至6〇 χ。i小時之後，將 該反應冷卻至室溫，然後加入濃氫氧化銨溶液（2 mL)。在j 小時之後，將該反應倒進水中並以Et〇Ac萃取。乾燥 EtOAc，然後濃縮成一油狀物（〇·丨〇 g，82%)。MS (ES) m/z 15 643.9。 步驟5: 4-[3-(3_{[3_(甲基胺基）丙基]磺醢基}苯氧 基）苯基]-8-（三氟甲基）啥琳一3一甲酸胺 將含有3-(3-(3-(3-胺甲醯基-8-(三氟甲基）一4一喹啉 20基）苯氧基）苯基磺醯基）丙基（甲基）氨基甲酸第三丁酯 g，〇·16 mmol)和三氟乙酸（0·5 mL)於 CH2Ch(5 mL) 中之-溶液在室溫攪拌。2小時之後，以飽和的Na·水 /谷液冲洗4反應，乾燥，並濃縮成如一泡泳之該標題化合 物（0· 050 g，57%)。MS (ES) m/z 543·9。 330 200825054 ψΜ 543, 80C Example 542 4-[3-(3-{[3-(Methylamino)propyl]cansyl}phenoxy)phenyl)]-8-(trifluoromethyl)anthene-3 - formic acid amine step 1: 4-(3-(3-(3-(methylsulfonyloxy)propylsulfonyl)phenoxy)phenyl)-8-(trifluoromethyl)anthene-3 - Sodium benzoate is intended to contain 4-(3-(3-(3-hydroxypropyl)sulfonyl)phenoxy)phenyl)-8-(trifluoromethyl) phenoxy-3 retinoic acid The methyl ester (1.20 g, 2.2 mmol) was added to a solution of one of 15 CH2Cl2 (20 mL) and NEts (1.0 mL, 7.2 mmol) in a cooled (0 ° C) solution. · 30 mL, 4·0 mmol). After 1 hour at 328 200825054, the reaction was poured into a 2N aqueous HCl solution and extracted with CH2CI2. The organic layer was dried (M.sub.2). Milk (es) m/z 623·8 0 5 Step 2: 4-(3-(3-(3-(t-butoxycarbonyl(methyl)amino)propyl) phenoxy)phenoxy) Phenyl)-8-(trifluoromethyl) fluorene-3-methyl acid will contain 4-(3-(3-(3-(methyl(hydroxymethyl)propyl))) Methyl)phenyl)-8-(trifluoromethyl)quinoline-3-carboxylate (〇. 8〇g, i mmol) and 2.0 of methylamine in methanol (20 mL) The solution was stirred at room temperature. After 40 hours, the reaction was concentrated and added to ethyl acetate. The organic layer was washed with a saturated aqueous NaHC solution, dried and concentrated. The oil thus obtained was dissolved in CHsCMlO mL), then dibutyl succinate 15 (1·〇〇 g, 4·6 mmol) was added. The reaction was stirred at room temperature for 24 hours and then concentrated. The crude product was purified by column chromatography eluting with EtOAc: EtOAc (EtOAc) Ms (ES) m/z 658·9 0 20 Step 3: 4-(3-(3-(3-(T-Butoxycarbonyl)(methyl)amino)propyl) phenoxy) Phenyl)-8-(trifluoromethyl)indol-3-reaction acid will contain 4-(3-(3-(tris-butoxycarbonyl(methyl))amino)propyl) ) oxy)phenyl)-8-(tri-Imethyl)-hydroxypyrazine-3-propionic acid formazan (0-15 g, 0.23 mmol) and aqueous 2.0 M NaOH (1 mL) at 329 200825054 THF One of the solutions in /MeOH (5 mL) was heated to reflux. After 3 hours, the reaction was poured into water (1 mL) of aqueous EtOAc (3 mL). The title compound (0·12 g, 81%) was obtained as a foam. MS (ES) m/z 645·0. 5 Step 4: 2-(3-(3-(3-Aminomethyl)-8-(trifluoromethyl)-4-quinolinyl)phenoxy)phenyl-decyl)propyl (methyl) The third butyl carbamate will contain 4-(3-(3-(3-(t-butoxycarbonyl(methyl)amino)propylsulfonyl)phenoxy)phenyl)-8 —(trifluoromethyl)quinoline_3_carboxylic acid 1〇(〇·12 g, 0·19 mmol) and carbonyldiimidazole (〇·15 g, 〇·95 〇1) in DMF (5.0 mL) One of the solutions was heated to 6 Torr. After 1 hour, the reaction was cooled to room temperature then concentrated aqueous ammonium hydroxide (2 mL). After j hours, the reaction was poured into water and extracted with EtOAc. The EtOAc was dried <RTI ID=0.0> MS (ES) m/z 15 643.9. Step 5: 4-[3-(3_{[3_(Methylamino)propyl]sulfonyl}phenoxy)phenyl]-8-(trifluoromethyl)phosphonium-tricarboxylate Containing 3-(3-(3-(3-aminocarbamimido-8-(trifluoromethyl)-4-tetraquinoline 20yl)phenoxy)phenylsulfonyl)propyl(methyl)amino The solution of tert-butyl formate g, 〇·16 mmol) and trifluoroacetic acid (0.5 mL) in CH.sub.2 (5 mL) was stirred at room temperature. After 2 hours, the reaction was washed with aq. EtOAc EtOAc (EtOAc)EtOAc. MS (ES) m/z 543·9. 330 200825054 ψΜ 543

CFS Ν - -{3-[8一（三氟甲基）_4_喹啉基]苯氧基}苯基) 5 續斑基]丙基丨甲燒確斑胺 將3-(3-(3〜（8—(三氟甲基）-4_喹啉基）苯氧基）苯基磺 酿基）丙—卜胺（50呢，〇· 103 mmol)、甲石黃醯氯（41 mg， 〇· 124 mmol)、和叹^定（12 mg，〇· 14 咖⑷於 CH2Cl《5 … 中之10物_ 15小時’然後減壓濃縮成一掠色粉末。 10透過以梯度乙腈：水洗提之逆相HPLC純化該粗產物以產生 如一暗白色粉末之該標題化合物（42mg, 72%)。做（ES) m/z 564_ 8。 範例544 15 卜乙基一3 一一[(3_{3 - [8-（三氟甲基）-4-喹啉基]苯氧 基}苯基)續疏基]丙基}膝 將含有3-(3-(3-(8-(三氟甲基）-4-喹啉基）苯氧基）苯 基磺醯基）丙-1-胺（50 mg，〇. 103 mmol)、異氰酸乙酯（9. 0 mg，0· 124 mmol)於 CH2C12 (5 mL)中之一混合物攪拌 1. 5 2〇小時，然後經減壓濃縮成一棕色粉末。藉由以梯度乙腈：水 洗提之逆相HPLC純化該粗產物，以產生如一暗白色粉末之 331 200825054 MS (ES) m/z 557. 該標題化合物（52 mg， 辦例545 N-{3 [(3-{3-[8-(三氟甲基)4-啥琳基]苯氧基}苯基） 續釀基]丙基}乙敢胺 將含有3-r — u 二氟甲基）-4-喹啉基）苯氧基）苯 基石黃醢基）丙-1〜胺（5f) mrr Λ ’ 〇· 103 mmol)、乙醯氣（11 mg， 0. 124 mmol)、吡啶 m 9 心 mg，〇· 14 丽〇1)於 CH2Ch(5 mL) 中之一混合物攪拌1 c; f # • ΰ小時，然後經減壓濃縮成衣粉末。 10 藉由以梯度乙猜：水洗提之逆相HPLC純化該粗產物，以產 生如暗白色$末之該標題化合物⑽呢，68%)。(es) m/z 528.8。CFS Ν - -{3-[8-(trifluoromethyl)_4_quinolinyl]phenoxy}phenyl) 5 contiguous] propyl hydrazine acetophene 3-(3-(3 ～(8-(Trifluoromethyl)-4_quinolinyl)phenoxy)phenylsulfonyl)propyl-p-amine (50, 〇·103 mmol), scutellarin (41 mg, 〇· 124 mmol), and sighing (12 mg, 〇· 14 coffee (4) in CH2Cl “10 of 10 _ 15 hours” and then concentrated under reduced pressure into a fading powder. 10 by washing with gradient acetonitrile: water The crude product was purified by reverse phase EtOAc to afford titled compound (42mg, <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; -(Trifluoromethyl)-4-quinolinyl]phenoxy}phenyl) continuation] propyl} knee will contain 3-(3-(3-(8-(trifluoromethyl)-4) - quinolinyl)phenoxy)phenylsulfonyl)propan-1-amine (50 mg, 〇. 103 mmol), ethyl isocyanate (9.0 mg, 0· 124 mmol) in CH2C12 (5 One of the mixture was stirred for 1.52 hours, then concentrated under reduced pressure to a brown powder. The crude product was purified by reverse phase HPLC eluting with gradient acetonitrile: water. Such as a dark white powder 331 200825054 MS (ES) m / z 557. The title compound (52 mg, case 545 N-{3 [(3-{3-[8-(trifluoromethyl)4-啥琳Benzyloxy}phenyl) styrene] propyl} ethaneamine will contain 3-r- u difluoromethyl)-4-quinolinyl)phenoxy)phenyl fluorinyl) propyl-1~ Amine (5f) mrr Λ ' 〇 · 103 mmol), acetamidine (11 mg, 0. 124 mmol), pyridine m 9 heart mg, 〇· 14 〇 1) Mixture of one of CH2Ch (5 mL) 1 c; f # • ΰ hours, then concentrate the powder into a garment under reduced pressure. The crude product was purified by reverse phase HPLC eluting with a gradient eluted with water to give the title compound (10) (68%) as dark white. (es) m/z 528.8.

1) Αγ-F, k2co3 DMF, 210 °C 2) N2H4&gt; 60 °C1) Αγ-F, k2co3 DMF, 210 °C 2) N2H4&gt; 60 °C

o co2ho co2h

15 例546 2-（{3-[(3-{3-[8_(三氟甲基）喹啉一4一基]苯氧基}苯 基）磺醢基]丙基}胺甲醢基）苯甲酸 將含有3-(8-(三氟甲基）-4-喹啉基）酚（2〇〇 mg，0. 69 20 mmol)、1-氟基-3_(甲基石黃醯基）苯（212 mg，1· 04 mmol)、 和碳酸鉀（286 mg，2· 08 mmol)於DMA(5 mL)中之一混合物 332 200825054 密封於一玻璃小瓶中，並在210 T加熱1小時。冷卻至室 溫並過濾，以產生如一棕色漿液之濾出物。藉由以梯度乙 腈：水洗提之逆相HPLC純化該粗產物，以產生如一棕色粉 末之2-(3-(3-(3-(8-(三氟甲基）-4-喹啉基）苯氧基）苯基 5磺醯基）丙基）異吲哚啉—1,3-二酮（310 mg，73%)。在該棕 色粉末中加入含有無水聯胺（1· 〇 mL)之乙醇（5 mL)，然後 將该反應在60 °C加熱3小時。冷卻至室溫、減壓濃縮成 ^ 一标色粉末。藉由以梯度乙腈：水洗提之逆相HPLC純化該 &quot; 粗產物，以產生如一黃色漿液之該標題化合物（9 mg，6%)。 10 MS (ES) m/z 634·8 。15 cases 546 2-({3-[(3-{3-[8-(trifluoromethyl)quinoline-4-yl]phenoxy}phenyl)sulfonyl]propyl}amine-methyl) Benzoic acid will contain 3-(8-(trifluoromethyl)-4-quinolinyl)phenol (2 〇〇 mg, 0.62 20 mmol), 1-fluoro-3-(methyl sulphate) benzene ( 212 mg, 1.004 mmol), and a mixture of potassium carbonate (286 mg, 2.08 mmol) in DMA (5 mL) 332 200825054 were sealed in a glass vial and heated at 210 T for 1 hour. Cool to room temperature and filter to produce a filtrate such as a brown slurry. The crude product was purified by reverse phase HPLC eluting with gradient acetonitrile: water to give 2-(3-(3-(3-(8-(trifluoromethyl)-4- quinolinyl)) as a brown powder. Phenoxy)phenyl 5sulfonyl)propyl)isoindoline-1,3-dione (310 mg, 73%). Ethanol (5 mL) containing anhydrous hydrazine (1·〇 mL) was added to the brown powder, and the reaction was heated at 60 ° C for 3 hours. Cool to room temperature and concentrate under reduced pressure to a color-coded powder. The &quot;crude product was purified by reverse phase HPLC eluting with gradient acetonitrile: water to give the title compound (9 mg, 6%) as a yellow powder. 10 MS (ES) m/z 634·8.

範例547 15 4一{3-[3-(甲基磺醢基）苯氧基]苯基卜8一（三氟甲基） 哮琳-3-甲亞斑胺（carboximidamide) 步驟1:在含有氯化銨（1. 07 g，20 mmol)於甲苯（20 mL) 之一懸浮液中，於〇至5 2C下緩慢地加入2 Μ含三甲基I呂 之甲苯（10 mL)。添加完畢後，將該反應靜置回溫至室溫， 2〇 然後攪拌1小時。 步驟2:在含有4-（3-（3-(甲基石黃驢基）苯氧基）苯 333 200825054 基）（三氟曱基）喹啉-3-甲腈（15 mg)於甲苯（2 mL)中之 /合液中加入2 Μ含三曱基鋁之甲苯（3 mL)。將該溶液加 考^ 2 4： ] η 士 守至80 Qc。冷卻該反應混合物，並藉由小心地將 ^容液倒進含矽膠於氯仿中之一泥漿中來將該鋁複合物分 解。將該混合物攪拌5分鐘並將該矽膠過濾。以甲醇沖洗 慮餅。減壓濃縮該溶液。透過色層分析純化以產生該標 題化合物。MS (ES) m/z 486.0。Example 547 15 4 -{3-[3-(Methylsulfonyl)phenoxy]phenyl b-8-(trifluoromethyl) carboximidamide Step 1: Inclusion Ammonium chloride (1. 07 g, 20 mmol) in a suspension of toluene (20 mL) was slowly added to a solution of toluene (10 mL) containing trimethyl I. After the addition was completed, the reaction was allowed to stand to warm to room temperature, and then stirred for 1 hour. Step 2: Containing 4-(3-(3-(3-(methyl-xaphthyl)phenoxy)benzene 333 200825054) (trifluoromethyl) quinoline-3-carbonitrile (15 mg) in toluene (15 mg) 2 Μ of the toluene (3 mL) containing tridecyl aluminum was added to 2 mL). Add this solution to ^ 2 4: ] η 士 守 to 80 Qc. The reaction mixture was cooled, and the aluminum composite was decomposed by carefully pouring the solution into a slurry containing cerium in chloroform. The mixture was stirred for 5 minutes and the mash was filtered. Rinse the cake with methanol. The solution was concentrated under reduced pressure. Purification by chromatography analysis to produce the title compound. MS (ES) m/z 486.0.

10 範例548 4 - {3-[3-(甲基磺醢基）苯氧基]苯基}喹啉-8-羧酸 將4-{3-[3-（甲基磺醯基）苯氧基]苯基}喹啉-8-曱腈 (300 mg，〇· 75 mmol)在 120 X 於 Ac0H(5 mL)和濃硫酸中 加熱20小時。冷卻該反應並將其倒進冰水（1〇〇 mL)中。劇 15 烈攪拌後，過濾所形成之沉澱物，以水沖洗，並於減壓中 乾燥，以產生如一暗白色固狀物之該標題化合物（256 mg)。 MS (ESI) ra/z 420 ； HRMS··計算值 C23HnN〇5S + H+’ 420.09002;實測值（ESI，[M+H]+0bs’d)，420.0905。10 Example 548 4 - {3-[3-(Methylsulfonyl)phenoxy]phenyl}quinoline-8-carboxylic acid 4-{3-[3-(methylsulfonyl)phenoxy The phenyl]quinoline-8-indolecarbonitrile (300 mg, 〇·75 mmol) was heated in 120× in Ac0H (5 mL) and concentrated sulfuric acid for 20 h. The reaction was cooled and poured into ice water (1 mL). After vigorous stirring, the precipitate formed was filtered, washed with water and dried under reduced pressure to give the title compound (256 mg) as a dark white solid. MS (ESI) ?? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ?

334 200825054 範例549 4-{3-[3-(甲基磺醢基）苯氧基]苯基}喹啉-8-羧酸甲 酯 5 將4-{3-[3-(甲基磺醯基）苯氧基]苯基}喹啉-8-羧酸 (200 mg，0.47 mmol)在 80 °C 於 MeOH(40 mL)和濃硫酸（2 mL)中加熱12小時。冷卻該反應，以水（50 mL)處理，並以 乙酸乙酯（3 X 50 mL)萃取。該萃取物以MgS〇4乾燥並減壓 濃縮，以產生如一白色固狀物之該標題化合物（189 mg)。 10 MS (ES) m/z 433. 9 ； HRMS:計算值 C24H19N〇5S + H+， 434.10567;實測值（ESI, [M+H]+0bs，d)，434· 1059。334 200825054 Example 549 4-{3-[3-(Methylsulfonyl)phenoxy]phenyl}quinoline-8-carboxylic acid methyl ester 5 4-{3-[3-(methylsulfonate) The phenoxy]phenyl}quinoline-8-carboxylic acid (200 mg, 0.47 mmol) was heated in MeOH (40 mL) The reaction was cooled with EtOAc (EtOAc)EtOAc. The extract was dried with EtOAc (EtOAc) (EtOAc) </ RTI> </ RTI> <RTI ID=0.0></RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt;

範例550 15 4-{3-[3-(甲基磺醢基）苯氧基]苯基}喹啉邛一甲醢胺 將4-{3-[3-(甲基磺醯基）苯氧基]苯基丨喹啉-8-羧酸 (70 mg，0· 17 mm〇i)和羰基二咪唑（76 mg，〇. 47 咖〇1)在 60 °C於DMF(10 mL)中加熱1小時。冷卻該反應，以ΝΗ4〇Η(4· 〇 mL，64 mmol)處理並在室溫攪拌1〇小時。以水（5〇虬）處 20理該反應混合物，並以乙酸乙酯（3 X 50 mL)萃取。該萃取 物以MgSCh乾燥並減壓濃縮。於矽膠上進行以梯度1〇:9〇 335 200825054 至100:0之E:H洗提的色層分析，以產生如一暗白色固狀 物之該標題化合物（36 mg)。MS (ES) m/z 418.8 ; HRMS: 計算值 C23H18N2〇4S + H+，419.10600;實測值（ESI, [M+H] + 〇bs’d)，419.1064。Example 550 15 4-{3-[3-(Methylsulfonyl)phenoxy]phenyl}quinolinium monomethylamine 4-{3-[3-(methylsulfonyl)phenoxy Phenyl]quinoxaline-8-carboxylic acid (70 mg, 0·17 mm〇i) and carbonyldiimidazole (76 mg, 〇. 47 ca 〇 1) heated at 60 ° C in DMF (10 mL) 1 hour. The reaction was cooled, treated with EtOAc (4 mL, EtOAc) The reaction mixture was taken up in water (5 EtOAc) andEtOAcEtOAc The extract was dried over MgSCh and concentrated under reduced pressure. Chromatographic analysis of E:H elution with a gradient of 1 〇:9 〇 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 MS (ES) m/z 422.

範例5 51 CIExample 5 51 CI

4-{3-[4-氯基-3-(甲基磺醢基）苯氧基]苯基卜8-(三 10氟甲基）喹啉 步驟1: 5-溴基-2-氯苯磺醢氯 將5-漠基-2-氯苯胺（2.6 g’9.7 mm〇i)與含有乙酸 (8 mL)和濃鹽酸（4 mL)之乙腈化合。逐滴加入含有NaN〇2 (802 mg，11· 6 mmol)之水（3 mL)超過10分鐘，並將該反 15 應於冰浴中冷卻。20分鐘之後，將二氧化硫氣體打氣通過 該反應達1小時。加入含有CuCl2(l. 62 g，12. 1 mm〇i)於 水（3 mL)之一溶液，並將該反應在室溫攪拌整夜。將該反 應倒進冰水（100 mL)中。劇烈擾拌之後，形成沉澱物。過 據該沉澱物，以水沖洗，並在減壓中乾燥，以產生如一白 色固狀物之該標題化合物（3· 1 g)，其無經進一步純化即被 336 20 200825054 使用。 步驟2: 4-溴基-1 —氣基一2一（甲基磺醢基）苯 以範例1中所述之相似方法，使用5-溴基_2一氯基苯 5磺醯氯和碘甲烷製備該標題化合物。MS (ES) m/z 268. 7。 步驟3: 4-{3-[4-氯基-3-(甲基磺醢基）苯氧基]苯 基}-8-（三氟甲基）喹啉 f 比照範例124製備，除了使用3-[8-(三氟甲基）-4-喹 10啉基]酚和4-溴基-1-氯基-2-(甲基磺醯基）苯作為反應 物’以產生如一暗白色固狀物之該標題化合物。MS (ES) m/z 478. 0 ; HRMS:計算值 C23H15ClF3N〇3S + H+，478· 0486 ;實 測值（ESI，[M+H]+ Obs’d)，478.0479。 15 範例552 4-{4-[3-（甲基磺醢基）苯基]吼啶—2-基}-8-(三氟甲 I 基）喹啉 步驟1: 2-氣基-4-[3-(甲基磺醢基）苯基]吡啶 將氮氣通過一含有2-氣基-4-峨定（478 mg，2 ' 20 mmo1)、3-(甲基磺醯基）苯基硼酸（400 mg，2·00 mmol)、2 • M Na2C〇3水溶液（2. 0 inL，4. 0 mmol)、和二甲氧基乙烷（6.0 mL)之劇烈攪拌的混合物達ι〇分鐘。加入四-三苯基膦I巴 (119 mg，〇· 10〇 _〇1)並將該混合物在8〇。(：劇烈攪拌6 小時。該混合物經冷卻並在乙酸乙酯（40 mL)和水（30 mL) 2 5 之間區分開來。層被分離，並以水（2 X 10 mL)和食鹽水（20 337 200825054 mL)沖洗該有機層。以Na2S〇4乾燥該有機層並減壓濃縮。透 過以梯度5:95至50:50之E:H洗提的Si〇2色層分析純化 該殘餘物’以產生如一暗白色固狀物之該標題化合物。MS (ES) m/z 267.8 ; HRMS··計算值 C12HuC1N〇2S + Η+, 5 268· 01935 ;實測值（ESI，[Μ+ΗΓ Obs’d), 268.0196。 步驟2: 4-{4-[3-（甲基磺醢基）苯基]吼啶-2-基}-8-（三氟甲基）唉琳 將含有4-氣基-8-(三敦甲基）口奎琳（462 mg，2 mmol)、 ι〇 雙（戊隨）一侧（560 mg，2· 2 mmol)、Pd2(dba)3 (50 mg， 0· 055 mmol)、2-(二環己基膦）聯苯（loo mg，〇·29 mmol)、 和KOAc (300 mg，3 mmol)之一混合物在90 °C於二噁烷 (12 mL)中加熱16小時。該混合物經冷卻並在乙酸乙酯（4〇 mL)和水（20 mL)之間區分開來。層被分離，並以水（2 x 1〇 15 mL)和食鹽水（20 mL)沖洗該有機層。以Na2S〇4乾燥該有機 層並減壓濃縮。透過以梯度〇:1〇〇至15:85之E:h洗提的 Si〇2色層分析純化該殘餘物，以產生混有8_三氟甲基喹啉 (比率約1:1)之4-(4, 4, 5, 5-四甲基-1，3,2-二雜氧戊硼烧 -2-基）-8-(三氟甲基）喹啉。將該粗產物（31〇 mg)放進含有 20 2-氯基-4-[3-(甲基磺醯基）苯基]〇比啶（14〇 mg，〇_52 mmol)、Na2C〇3 水溶液（2. 0 Μ，2· 0 mL，4. 0 mmol)、和二 甲氧基乙烷（5 mL)之一玻璃小瓶中。將氮氣通過該混合物 10分4里’然後加入四-二苯基膦I巴（120 mg，0. 100 mmol)。 將該混合物在85 °C加熱4小時，然後將該混合物冷卻並 25在乙酸乙酯（40 mL)和水（20 mL)之間區分開來。層被分離， 並以水（2 X 10 mL)和食鹽水（20 mL)沖洗該有機層。以Na2S〇4 338 200825054 機層並減壓濃縮。透過以梯度2:98至5(^之[Η /㈣Sl()2色層分析純化該殘餘物。該殘餘物質更進一步 透過以梯度5:95至_:〇之乙腈：H2〇的⑽逆相色層分析 來純化以產生如-白色泡沫之該標題化合物。ms (es) _ 428.7 ; HRMS:計算值 C22H15F3N2〇2s + 矿，429 〇8791 ;實 測值（ESI, [Μ+ΗΓ)，429.0882。4-{3-[4-Chloro-3-(methylsulfonyl)phenoxy]phenyl b-8-(tris10fluoromethyl)quinoline Step 1: 5-bromo-2-chlorobenzene Sulfoonyl chloride 5-glycosyl-2-chloroaniline (2.6 g '9.7 mm 〇i) was combined with acetonitrile containing acetic acid (8 mL) and concentrated hydrochloric acid (4 mL). Water (3 mL) containing NaN〇2 (802 mg, 11.6 mmol) was added dropwise over 10 minutes, and the reaction was cooled in an ice bath. After 20 minutes, the sulfur dioxide gas was purged through the reaction for 1 hour. A solution containing one of CuCl2 (1.62 g, 12.1 mm〇i) in water (3 mL) was added and the mixture was stirred at room temperature overnight. The reaction was poured into ice water (100 mL). After vigorous scrambling, a precipitate formed. The precipitate was washed with water and dried under reduced pressure to give the title compound (3·1 g) as a white solid, which was used in 336 20 200825054 without further purification. Step 2: 4-Bromo-1 -oxyl-2-methyl(methylsulfonyl)benzene In a similar manner as described in Example 1, 5-bromo-2-chlorobenzene 5 sulfonium chloride and iodine were used. The title compound was prepared as methane. MS (ES) m/z 268. 7. Step 3: 4-{3-[4-Chloro-3-(methylsulfonyl)phenoxy]phenyl}-8-(trifluoromethyl)quinoline f Prepared according to Example 124 except 3 -[8-(Trifluoromethyl)-4-quinolinol]phenol and 4-bromo-1-chloro-2-(methylsulfonyl)benzene as reactants to give a dark white solid The title compound. MS (ES) m/z </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; 15 Example 552 4-{4-[3-(Methylsulfonyl)phenyl]acridin-2-yl}-8-(trifluoromethyl I)quinoline Step 1: 2-Alkyl-4- [3-(Methylsulfonyl)phenyl]pyridine is passed through a gas containing 2-oxyl-4-indole (478 mg, 2' 20 mmo1), 3-(methylsulfonyl)phenylboronic acid (400 mg, 2·00 mmol), 2 • M Na 2 C 3 aqueous solution (2.0 inL, 4.0 mmol), and dimethoxyethane (6.0 mL). Tetra-triphenylphosphine I bar (119 mg, 〇·10〇 _〇1) was added and the mixture was at 8 Torr. (: Stir vigorously for 6 hours. The mixture was cooled and separated between ethyl acetate (40 mL) and water (30 mL). The layers were separated and taken with water (2 X 10 mL) and brine ( 20 337 200825054 mL) The organic layer was rinsed. The organic layer was dried over Na.sub.2.sub.4 and concentrated under reduced pressure. The residue was purified by chromatography eluting with E:H gradient from 5:95 to 50:50. 'To produce the title compound as a dark white solid. MS (ES) m/z 267.8; HRMS························ 'd), 268.0196. Step 2: 4-{4-[3-(Methylsulfonyl)phenyl]acridin-2-yl}-8-(trifluoromethyl)fluorene will contain 4-gas -8-(Sandun methyl) hydroxy quinine (462 mg, 2 mmol), 〇 bis (pentose) side (560 mg, 2.2 mmol), Pd2 (dba) 3 (50 mg, 0 · Mixture of 055 mmol), 2-(dicyclohexylphosphine)biphenyl (loo mg, 〇·29 mmol), and KOAc (300 mg, 3 mmol) at 90 ° C in dioxane (12 mL) Heating for 16 hours. The mixture was cooled and separated between ethyl acetate (4 mL) and water (20 mL). The organic layer was washed with water (2 x 1 〇 15 mL) and brine (20 mL). The organic layer was dried over Na 2 EtOAc EtOAc. The residue was purified by E:h eluting Si〇2 chromatography to give 4-(4, 4, 5, 5-tetramethyl) mixed with 8-trifluoromethylquinoline (ratio 1:1). Base-1,3,2-dioxaborolan-2-yl)-8-(trifluoromethyl)quinoline. The crude product (31 mg) was placed in 20 2-chloro-4 -[3-(methylsulfonyl)phenyl]pyridinium (14 〇 mg, 〇_52 mmol), Na2C〇3 aqueous solution (2.0 Μ, 2.0 mL, 4.0 mmol), and In a glass vial of dimethoxyethane (5 mL), nitrogen was passed through the mixture for 10 minutes 4' then tetra-diphenylphosphine I bar (120 mg, 0. 100 mmol) was added. Heat at 85 °C for 4 hours, then cool the mixture and separate between ethyl acetate (40 mL) and water (20 mL). The layers were separated and taken with water (2 X 10 mL) and brine ( 20 mL) rinse the organic layer. Concentrate with Na2S〇4 338 200825054 and under reduced pressure. Pass through a gradient of 2:98 to 5 (^[Η /(四)Sl()2 color layer The residue was purified. The residue was further purified by (10) reverse phase chromatography eluting with a gradient of 5:95 to EtOAc:H.sub.2 to afford the title compound as a white foam. Ms (es) _ 428.7 ; HRMS: calculated C22H15F3N2 〇 2s + ore, 429 〇 8791; measured value (ESI, [Μ+ΗΓ), 429.0882.

範例553 ίο 3_甲基一 4-H 一 [3-（甲基續醢基）苯基]- 2-噻吩基}-8_(三氟 甲基)喹啉 步驟1: 3-甲基-4-（噻吩-2-基）-8-(三氟甲基）喹啉 以範例279所述之相似方法製備該化合物。MS (ES) m/z 293·3 〇 15 步驟2: 4-(4-溴噻吩-2-基）-3-甲基_8-（三氟甲基） 喹啉 在含有3-甲基-4-(噻吩-2-基）-8-(三氟甲基）喹啉 (250 mg，0· 896 mmol)和醋酸鈉（294 mg，2. 69 mmol)於水 20 (10 mL)中之一混合物中逐滴加入含溴（429 mg，2. 69 mmol) 339 200825054 之水（5 mL)超過30分鐘。加入鋅（I” mg，2· 69 mmol)並 將所產生的棕色混合物在5〇 X加熱15小時。以乙酸乙酯 (20raL)萃取該經冷卻的棕色混合物，過濾，以MgS〇4乾燥， 並在減壓中濃縮成一杈產棕色粉末之4_(4_溴噻吩一2一 5基）-3-甲基-8-(三敦甲基）喹啉（360呢）。MS (ES) m/z 372· 0。該產物無經純化即用於下一步驟。 步驟3: 3一甲基〜4〜{4-[3-(甲基磺醢基）苯基]-2-噻 吩基}-8-(三氟甲基）啥琳Example 553 ίο 3_Methyl 4-H-[3-(methyl decyl)phenyl]-2-thienyl}-8-(trifluoromethyl)quinoline Step 1: 3-Methyl-4 -(Thien-2-yl)-8-(trifluoromethyl)quinoline The compound was prepared in a similar manner as described in Example 279. MS (ES) m/z 293·3 〇 15 Step 2: 4-(4-bromothiophen-2-yl)-3-methyl-8-(trifluoromethyl)quinoline in 3-methyl- 4-(Thien-2-yl)-8-(trifluoromethyl)quinoline (250 mg, 0·896 mmol) and sodium acetate (294 mg, 2.69 mmol) in water 20 (10 mL) A mixture containing bromine (429 mg, 2.69 mmol) 339 200825054 in water (5 mL) was added dropwise over 30 minutes. Zinc (I" mg, 2.69 mmol) was added and the resulting brown mixture was heated at 5 Torr for 15 h. The cooled brown mixture was extracted with ethyl acetate (20 EtOAc), filtered and dried with EtOAc. And concentrated under reduced pressure to give a brown powder of 4-(4-bromothiophene-2-yl-5)-3-methyl-8-(Tritonmethyl)quinoline (360). MS (ES) m /z 372·0. The product was used in the next step without purification. Step 3: 3-Methyl~4~{4-[3-(methylsulfonyl)phenyl]-2-thienyl} -8-(trifluoromethyl)啥琳

〇 以範例279所述之相似方法製備該標題化合物。MS (ES) m/z 447·9 。The title compound was prepared in a similar manner as described in Example 279. MS (ES) m/z 447·9.

範例554 3-甲基-4-{5-[3-（甲基磺醢基）苯基]一3一噻吩基卜8一(三氟 甲基)喹啉 步驟1: 4-溴基-2-（3-(甲基磺醢基）苯基）噻吩 以範例279所述之相似方法製備該標題化合物。MS (ES) m/z 317.2。 340 20 200825054 步驟2: 3-甲基-4-{5-[3-（甲基靖酿基）苯基]-3-嗟 吩基}-8-（三氟甲基）喹啉 在室溫，於一反應玻璃小管中置入含有4-溴基 -2-(3-(甲基磺醯基）苯基）噻吩（88 mg，0· 276 mmol)、4-5 溴基-6-甲基-8-(三氟甲基）啥琳酸（80 mg，0· 276 mmol)、 4, 4, 4’，4’，5, 5, 5’，5’ -八甲基-2, 2’ -雙（1，3, 2-二雜氧戊 侧烧）（77 mg，0· 304 mmol)、碳酸钟（81 mg，0· 828 mmol)、 二氣雙（三苯膦）鈀（11)(49 mg，0. 276 mmol)之 DMSO (2. 0 mL)。將該玻璃小瓶加蓋並在90 °C加熱3小時。冷卻與過 1〇 濾之後，該濾出物進一步透過RP-HPLC(乙腈：水）純化以產 生如一黃色粉末之該標題化合物（17 mg，28%)。MS (ES) m/z 447. 9。 範例555 15 N-(4-甲氧基苄基）-N-甲基-3-{3- [3-甲基-8-（三氟甲 基）-4-喹啉基]苯氧基}苯磺醢胺 比照範例460中步驟3製備，除了使用3-[3-(曱基 磺醯基）-8-(三氟甲基）-4-喹啉基]酚和3-溴基-N-(4-甲氧 基节基）-N_甲基苯石黃醯胺作為反應物，以產生如一白色固 20 狀物之該標題化合物。MS (ES) m/z 593. 0。 範例556 N-(4-甲氧基节基）-N-甲基-4-{3-[3-甲基-8-(三氟甲 基）-4-啥琳基]苯氧基}苯續酸胺 341 200825054 比照範例462中步驟3製備，除了使用3-[3-(甲基石黃 醯基）-8-（二氟甲基4-喹啉基]酚和溴基_N_(4_甲氧基 苄基）-N-甲基苯磺醯胺作為反應物，以產生如一白色固狀 物之該標題化合物。MS (ES) m/z 591 0。 5 範例557 N-甲基-3 - {3-[3-甲基+(三氟甲基）-4-嗟琳基]苯氧 基}苯磺醢胺 比照範例464製備，除了使用N-(4-甲氧基苄基）-N-10甲基-3-{3-[3-甲基-8〜（三氟甲基）-4-喹啉基]苯氧基}苯 磺醯胺作為反應物，以產生如一白色固狀物之該標題化合 物。MS (ES) m/z 472.8 。 558 15 N-甲基-4-{3-[3-甲基-8-（三氟甲基）-4-喹啉基]苯氧 基}苯磺醢胺 比照範例464製備，除了使用N-(4-甲氧基苄基）-N-甲基-4-{3-[3-甲基-8〜（三氟甲基）-4-喹啉基]苯氧基}苯 石頁胺作為反應物’以產生如一白色固狀物之該標題化合 20 物。MS (ES) m/z 472.8 。 範划559 4-{3-[3-(乙基續酸基）苯氧基]苯基}-3-異丙基 342 200825054 -8-（三氟甲基）喧琳 比照範例43製備，除了使用3-[3-異丙基-8-(三氟甲 基）—4-α查琳基]酴和3-(乙基石黃醯基）-1-氟苯作為基質，以 產生該標題化合物。MS (ES) m/z 499. 8。 範例560 3-異丙基-4-{3-[3-(丙基確殖基）苯氧基]苯 基}-8-(三氟甲基）啥琳 比照範例43製備，除了使用3-[3-異丙基-8-(三氟甲 ίο 基）-4-唾淋基]紛和3-氟基-1-(丙基績醯基）-苯作為基 質，以產生該標題化合物。MS (ES) m/z 513.9。 範例561 3-異丙基-4_{3-[3-(異丙基磺醢基）苯氧基]苯 15 基}-8-(三氟甲基）喹啉 比照範例43製備，除了使用3-[3-異丙基-8-(三氟甲 基）_4_啥琳基]齡和3-氟基-1-(異丙基績醯基）—苯作為基 質，以產生該標題化合物。MS (ES) m/z 513.8。 20 範例562 4-{3-[3-氟基-5-(甲基磺醢基）苯氧基]苯基}-3-異丙 基-8-(三氟甲基）啥琳 比照範例43製備，除了使用3-[3-異丙基-8-(三氟甲 343 200825054 基）-4-喹啉基]酚和3, 5-二氟基-1-(甲基磺醯基）苯作為基 質，以產生該標題化合物。MS (ES) m/z 503. 8。 範例563 5 4_{3-[3-(乙基磺醯基）-5-氟基苯氧基]苯基}-3-異丙 基_8-（三氟甲基）喧琳 比照範例43製備，除了使用3-[3-異丙基-8-(三氟甲 基）-4-啥淋基]紛和3，5-二氣基-1-(乙基績S篮基）苯作為基 質，以產生該標題化合物。MS (ES) m/z 517. 8。 10 範例564 4-{3_[3-氣基-5-(甲基磺醢基）苯氧基]苯基}-3-異丙 基_8-（三氟甲基）啥琳 比照範例43製備，除了使用3-[3-異丙基-8-(三氟甲 15 基）-4_啥琳基]盼和3，5-二氣-1_(甲基績酿基）苯作為基 質，以產生該標題化合物。MS (ES) m/z 519. 8。 範例565 3-異丙基-4-{3-[2 -（甲基磺醢基）苯氧基]苯 20 基}-8_(三氟甲基）啥琳 比照範例43製備，除了使用3-[3-異丙基-8-(三氟甲 基）-4-喧淋基]紛和2-氣基-1_(甲基續酿基）-苯作為基 質，以產生該標題化合物。MS (ES) m/z 485. 8。 344 200825054 ψΜ 566 3-異丙基-4 - {3 - [4-(甲基磺醢基）苯氧基]苯 基}-8-(三氟甲基）啥琳 比照範例43製備，除了使用3-[3-異丙基-8-(三氟甲 5 基）-4-喹啉基]酚和4-氟基-1-(甲基磺醯基）-苯作為基 質’以產生該標題化合物。MS (ES) m/z 485· 8。 567 4-{3-[4-(乙基磺醢基）苯氧基]苯基}-3-異丙基 ίο -8-（三氟甲基）養琳 比照範例43製備，除了使用3-[3-異丙基-8-(三氟甲 基）-4-喹啉基]酚和1 —(乙基磺醯基）-4-氟苯作為基質，以 產生該標題化合物。MS (ES) m/z 499. 8。 範例568 15 8 -甲氧基-4 - {3-[3-（甲基磺醢基）苯氧基]苯基}喹啉 比照範例43製備，除了在一微波反應器中205-210 °C 加熱1小時，並使用3-(8-甲氧基-4-喹啉基）酚和3-氟基 -1 -（甲基磺醯基）笨作為基質，以產生該標題化合物。MS (ES) m/z 405.9; HRMS:計算值 C23H19N〇4S + H.，406. 11076;實 20 測值（ESI，[M+H]+ 〇bs，d)，406. 1110。 範例569 4 - {3-[3-（乙基磺醢基）苯氧基]苯基8一甲氧基喹啉Example 554 3-Methyl-4-{5-[3-(methylsulfonyl)phenyl]-3-monothiophene b-(trifluoromethyl)quinoline Step 1: 4-bromo-2 -(3-(Methylsulfonyl)phenyl)thiophene The title compound was prepared in a similar manner as described in Example 279. MS (ES) m/z 317.2. 340 20 200825054 Step 2: 3-Methyl-4-{5-[3-(methyl succinyl)phenyl]-3-indolyl}-8-(trifluoromethyl)quinoline at room temperature , 4-bromo-2-(3-(methylsulfonyl)phenyl)thiophene (88 mg, 0·276 mmol), 4-5 bromo-6-methyl was placed in a reaction glass vial. -8-(trifluoromethyl) phthalic acid (80 mg, 0·276 mmol), 4, 4, 4', 4', 5, 5, 5', 5'-octamethyl-2, 2 '-Bis(1,3,2-dioxaoxyl side) (77 mg, 0·304 mmol), carbonic acid clock (81 mg, 0·828 mmol), dioxobis(triphenylphosphine)palladium (11 (49 mg, 0. 276 mmol) in DMSO (2.0 mL). The glass vial was capped and heated at 90 °C for 3 hours. The title compound (17 mg, 28%) was obtained as a yellow powder (yield: EtOAc). MS (ES) m/z 447. 9. Example 555 15 N-(4-Methoxybenzyl)-N-methyl-3-{3-[3-methyl-8-(trifluoromethyl)-4-quinolinyl]phenoxy} Phenylsulfonamide was prepared as in step 3 of Example 460 except that 3-[3-(indolylsulfonyl)-8-(trifluoromethyl)-4-quinolinyl]phenol and 3-bromo-N were used. -(4-Methoxy-hydroxyl)-N-methylphenidinamine as a reactant to give the title compound as a white solid. MS (ES) m/z 593. 0. Example 556 N-(4-Methoxy-based)-N-methyl-4-{3-[3-methyl-8-(trifluoromethyl)-4-indolyl]phenoxy}benzene Acid amide 341 200825054 Prepared according to step 3 of Example 462 except that 3-[3-(methyl sulphate)-8-(difluoromethyl-4-quinolinyl)phenol and bromo-N_(4_A) were used. The oxybenzyl)-N-methylbenzenesulfonamide is used as the reactant to give the title compound as a white solid. MS (ES) m/z 591 0. 5 Example 557 N-Methyl-3 {3-[3-Methyl+(trifluoromethyl)-4-indolyl]phenoxy}benzenesulfonamide was prepared as in Example 464 except that N-(4-methoxybenzyl)-N was used. -10 methyl-3-{3-[3-methyl-8~(trifluoromethyl)-4-quinolinyl]phenoxy}benzenesulfonamide as a reactant to give a white solid The title compound. MS (ES) m/z 472.8. 558 15 N-methyl-4-{3-[3-methyl-8-(trifluoromethyl)-4-quinolinyl]phenoxy Benzene sulfonamide was prepared as in Example 464 except that N-(4-methoxybenzyl)-N-methyl-4-{3-[3-methyl-8~(trifluoromethyl)-4 was used. -Quinolinyl]phenoxy}benzamide as a reactant' to produce such a label as a white solid 20 compound. MS (ES) m/z 472.8. s 559 4-{3-[3-(ethylhexanoic acid)phenoxy]phenyl}-3-isopropyl 342 200825054 -8- (Trifluoromethyl) 喧 Lin was prepared according to Example 43, except that 3-[3-isopropyl-8-(trifluoromethyl)-4-α-chalinyl] oxime and 3-(ethyl sulphate)- 1-fluorobenzene as a substrate to give the title compound. MS (ES) m/z 499. 8. Example 560 3-isopropyl-4-{3-[3-(propyl-propionyl)phenoxy Phenyl}-8-(trifluoromethyl)indole was prepared according to Example 43, except that 3-[3-isopropyl-8-(trifluoromethyl)methylpyranyl] and 3 were used. -Fluoro-1-(propyl-decyl)-benzene as a substrate to give the title compound. MS (ES) m/z 513.9. Example 561 3-isopropyl-4_{3-[3-(iso Propylsulfonyl)phenoxy]benzene 15yl}-8-(trifluoromethyl)quinoline was prepared as in Example 43, except that 3-[3-isopropyl-8-(trifluoromethyl)-4 was used. _啥琳基] aging and 3-fluoro-1-(isopropyl decyl)-benzene as a substrate to give the title compound. MS (ES) m/z 513.8. 20 Example 562 4-{3- [3-Fluoro-5-(methylsulfonyl)phenoxy]phenyl}-3-isopropyl -8-(Trifluoromethyl)indole was prepared according to Example 43, except that 3-[3-isopropyl-8-(trifluoromethyl 343 200825054 benzyl)-4- quinolinyl]phenol and 3, 5- were used. Difluoro-1-(methylsulfonyl)benzene was used as a substrate to give the title compound. MS (ES) m/z 503. 8. Example 563 5 4_{3-[3-(ethylsulfonyl)-5-fluorophenoxy]phenyl}-3-isopropyl-8-(trifluoromethyl)anthracene was prepared according to Example 43 In addition to using 3-[3-isopropyl-8-(trifluoromethyl)-4-indolyl] and 3,5-dioxa-1-(ethyl) S basket as benzene To produce the title compound. MS (ES) m/z 517. 8. 10 Example 564 4-{3_[3-Vinyl-5-(methylsulfonyl)phenoxy]phenyl}-3-isopropyl-8-(trifluoromethyl)anionine prepared according to Example 43 In addition to using 3-[3-isopropyl-8-(trifluoromethyl15-yl)-4-indolyl] and 3,5-diqi-1_(methyl-flavoryl)benzene as a substrate, The title compound is produced. MS (ES) m/z 519. 8. Example 565 3-Isopropyl-4-{3-[2-(methylsulfonyl)phenoxy]benzene 20-yl}-8-(trifluoromethyl)phosphonium was prepared according to Example 43, except that 3- [3-Isopropyl-8-(trifluoromethyl)-4-indole] and 2-carbyl-1_(methyl aryl)-benzene were used as a substrate to give the title compound. MS (ES) m/z 485. 8. 344 200825054 ψΜ 566 3-isopropyl-4 - {3-[4-(methylsulfonyl)phenoxy]phenyl}-8-(trifluoromethyl)anthracene was prepared according to Example 43, except 3-[3-isopropyl-8-(trifluoromethyl5-yl)-4-quinolinyl]phenol and 4-fluoro-1-(methylsulfonyl)-benzene as the matrix ' to produce the title Compound. MS (ES) m/z 485·8. 567 4-{3-[4-(ethylsulfonyl)phenoxy]phenyl}-3-isopropyl ίο -8-(trifluoromethyl) lin is prepared according to Example 43, except that 3- [3-Isopropyl-8-(trifluoromethyl)-4-quinolinyl]phenol and 1-(ethylsulfonyl)-4-fluorobenzene were used as a substrate to give the title compound. MS (ES) m/z 499. 8. Example 568 15 8 -Methoxy-4 - {3-[3-(methylsulfonyl)phenoxy]phenyl}quinoline was prepared as in Example 43, except 205-210 ° C in a microwave reactor Heating for 1 hour and using 3-(8-methoxy-4-quinolinyl)phenol and 3-fluoro-1-(methylsulfonyl) as a substrate to give the title compound. MS (ES) m/z 495. Example 569 4 - {3-[3-(ethylsulfonyl)phenoxy]phenyl 8-methoxyquinoline

比照範例43製備，除了在一微波反應器中205-210 °C 345 200825054 加熱1小時，並使用3-(8-甲氧基-4-喹啉基）酚和1-(乙基 磺醯基）-3-氟苯作為基質，以產生該標題化合物。MS (ES) m/z 420. 0 ; HRMS:計算值 CuhNi^S + H+，420· 12641 ;實 測值（ESI，[M+H]+0bs’d)，420.1268。 5 範例570 4-{3-[3-(異丙基磺醢基）苯氧基]苯基}-8-甲氧基喹 啉 比照範例43製備，除了在一微波反應器中205-210 X 加熱1小時，並使用3-(8-甲氧基-4-喹啉基）酚和3-氟基 1〇 -1-(異丙基磺醯基）苯作為基質，以產生該標題化合物。MS (ES) m/z 434. 1 ； HRMS:計算值 C25H23N〇4S + H+， 434.14206;實測值（ESI，[M+H]+Obs’d)，434. 1426。 範例571 4-{3 - [3-氟基-5-（甲基磺醢基）苯氧基]苯基}-8-甲氧 15 基喹啉 比照範例43製備，除了在一微波反應器中205-210 °C 加熱1小時，並使用3-(8-甲氧基-4-喹啉基）酚和3, 5-二 氟基_1_(甲基橫醯基）苯作為基質，以產生該標題化合物。 MS (ES) m/z 423. 9 ； HRMS:計算值 C23H18FN〇4S + H+， 20 424. 10133 ;實測值（ESI, [M+H]+ Obs’d)，424· 1015。 範例572 4-{3-[3-(乙基磺醢基）-5-氟基苯氧基]苯基}-8-甲氧 基喹啉Prepared according to Example 43, except that in a microwave reactor, 205-210 ° C 345 200825054 was heated for 1 hour, and 3-(8-methoxy-4-quinolinyl)phenol and 1-(ethylsulfonyl) were used. -3-fluorobenzene as a substrate to give the title compound. MS (ES) m/z 420. </RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> </ RTI> <RTIgt; 5 Example 570 4-{3-[3-(Isopropylsulfonyl)phenoxy]phenyl}-8-methoxyquinoline prepared as in Example 43, except in a microwave reactor 205-210 X It was heated for 1 hour, and 3-(8-methoxy-4-quinolinyl)phenol and 3-fluoro-1-indol-1-(isopropylsulfonyl)benzene were used as a substrate to give the title compound. MS (ES) m/z 434. Found: </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; Example 571 4-{3 - [3-Fluoro-5-(methylsulfonyl)phenoxy]phenyl}-8-methoxy-15-quinoline was prepared as in Example 43, except in a microwave reactor Heating at 205-210 ° C for 1 hour, and using 3-(8-methoxy-4-quinolinyl)phenol and 3,5-difluoro-l-(methylcylinyl)benzene as a substrate to produce The title compound. MS (ES) m/z </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> </RTI> <RTIgt; </RTI> <RTIgt; Example 572 4-{3-[3-(ethylsulfonyl)-5-fluorophenoxy]phenyl}-8-methoxyquinoline

比照範例43製備，除了在一微波反應器中205-210 T 346 200825054 加熱1小時，並使用3-(8-甲氧基-4-喹啉基）酚和3, 5一二 氟基-1-(乙基磺醯基）苯作為基質，以產生該標題化合物。 MS (ES) m/z 438.0 ; HRMS:計算值 C24H2〇FN〇4S + H+， 438.11698;實測值（ESI，[M+H]+0bs，d)，438. 1176。 5 範例573 4 {3 [3 (乙基確酿基）苯氧基]苯基}一8一甲基啥琳 ’ 比照範例43製備，除了在一微波反應器中2〇5_21〇χ 加熱1小時，並使用3-(8-甲基-4-喹啉基）酚和1 —(乙基磺 〔 醯基）_3~·氟基苯作為基質，以產生該標題化合物。MS (ES) 10 m/z 404· 0 ; HRMS:計算值 CuIkNOsS + H+，404· 13149 ;實 測值（ESI, [M+H]+〇bs’d), 404. 1319。 範例574 4-{3-[3-(異丙基磺醢基）苯氧基]苯基卜8_甲基喹啉 比照範例43製備，除了在一微波反應器中205-210 X 15 加熱1小時，並使用3-(8-甲基-4-喹啉基）酚和3-氟基 -1-(異丙基磺醯基）苯作為基質，以產生該標題化合物。MS % (ES) ra/z 418.1 ; HRMS:計算值 C25H23N〇3S + H+， 418· 14714;實測值（ESI, [M+H]+0bs’d)，418_ 1473。 範例575 2〇 4 - {3-[3-氟基-5-（甲基磺醢基）苯氧基]苯基卜8-甲基 喹啉Prepared according to Example 43, except that in a microwave reactor, 205-210 T 346 200825054 was heated for 1 hour, and 3-(8-methoxy-4-quinolinyl)phenol and 3,5-difluoroyl-1 were used. -(Ethylsulfonyl)benzene as a substrate to give the title compound. MS (ES) m/z </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 5 Example 573 4 {3 [3 (Ethyl aryl) phenoxy]phenyl}- -8-methyl fluorene' Prepared according to Example 43, except that in a microwave reactor 2 〇 5 _ 21 〇χ heating for 1 hour And using 3-(8-methyl-4-quinolinyl)phenol and 1-(ethylsulfonyl)- 3~-fluorobenzene as a substrate to give the title compound. MS (ES) 10 m/z 404·0; HRMS: calcd., calc., calcd. (ESI, [M+H] + 〇bs'd), 404. 1319. Example 574 4-{3-[3-(Isopropylsulfonyl)phenoxy]phenyl b-8-methylquinoline was prepared as in Example 43, except that in a microwave reactor 205-210 X 15 was heated 1 The title compound was obtained using 3-(8-methyl-4-quinolinyl)phenol and 3-fluoro-1-(isopropylsulfonyl)benzene as a substrate. MS </ RTI> <RTI ID=0.0></RTI> </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0> Example 575 2〇 4 - {3-[3-Fluoro-5-(methylsulfonyl)phenoxy]phenyl b- 8-methylquinoline

比照範例43製備，除了在一微波反應器中205-210 °C 加熱1小時，並使用3-（8-甲基-4-喹啉基）酚和3, 5-二氟 基-1-(甲基磺醯基）苯作為基質，以產生該標題化合物。MS 347 200825054 (ES) m/z 407.9 ； HRMS:計算值 C23H18FN〇3S + H+， 408.10642;實測值（ESI，[M+H]+0bs’d)，408. 1066。 範例576 4-{3-[3-(乙基磺醢基）-5-氟基苯氧基]苯基}-8-甲基 5 喹啉 比照範例43製備，除了在一微波反應器中205-210 °C 加熱1小時，並使用3-(8-甲基-4-喹琳基）盼和3, 5-二氟 基-1-(乙基磺醯基）苯作為基質，以產生該標題化合物。MS (ES) m/z 422. 1 ; HRMS:計算值 C24H2〇FN〇3S + H+， ίο 422. 12207 ;實測值（ESI, [M+H]+Obs，d), 422. 1225。 範例577 3-（{3-[3-(8-甲基-4-喹啉基）苯氧基]苯基}磺醮 基）-1-丙酵 比照範例43製備，除了在一微波反應器中205-210 °C 15 加熱1小時，並使用3-(8-甲基-4-喹啉基）酚和3-[(3-氟 苯基）磺醯基]-1-丙醇作為基質，以產生該標題化合物。MS (ES) m/z 433.8 ; HRMS··計算值 C25H23N〇4S + H+， 434. 14206;實測值（ESI, [M+H]+Obs，d)，434.1420。 範例578 20 4一(3一[3一氣基-5-(甲基磺醢基）苯氧基]苯基卜8-甲基 喹啉 比照範例43製備，除了在一微波反應器中205-210 T 加熱1小時，並使用3-（8-甲基-4-喹啉基）酚和3, 5-二氯 -1-（甲基磺醯基）笨作為基質，以產生該標題化合物。MS (ES) 348 200825054 m/z 423· 7 ; HRMS:計算值 C23H18ClN〇3S + H+，424. 07687 ; 實測值（ESI，[M+H]+0bs’d)，424. 0766。 範例579 4 - {4-[3-(甲基磺醢基)苯基]-2-噻吩基}-8-(三氟甲基)喹 5 啉 以範例259所述之相似方法製備該標題化合物。MS (ES) 433·8 ; HRMS:計算值 C2晶4FWO2S2 + H+，434. 04908 ;實 測值（ESI, [M+H]+Obs’d)，434.0486。 範例580 1〇 4 - {4 - [2-(甲基確醢基）苯基]-2-噻吩基}-8-(三氟甲基)喹 啉 以範例259所述之相似方法製備該標題化合物。MS (ES) 433.8 ; HRMS:計算值 C2晶4F3N〇2S2 + H+，434.04908 ;實 測值（ESI，[M+H]+ Obs’d)，434·0491。. 15 範例581 4-{4-[4-（甲基確醢基）苯基]- 2-噻吩基卜8-(三氟甲基）喹 啉 以範例259所述之相似方法製備該標題化合物。MS (ES) 7z//z 433·8 ; HRMS:計算值 CuHmFsNO^ + H+，434.04908 ;實 20 測值（ESI, [M+H]+ Obs’d)，434· 0484。 範例582 349 200825054 4- {5- [ 3-(甲基續殖基)苯基]嘆吩基卜8-(三氟甲基)啥 琳 以範例259所述之相似方法製備該標題化合物。MS (ES) 瓜/z 433_ 8 ; HRMS:計算值 C21H14F3NO2S2 + H+，434.04908 ;實 5 測值（ESI, [M+H]+ Obs’d)，434.0484。 範例583至593 以範例276所述之相似方法製備範例583-593中之下 列化合物。 1〇 範例 583 ({[4-{3 - [3-(甲基續醢基)苯氧基]苯基卜8-(三氟甲 喹啉-3-基]甲基}胺基）乙腈 MS (ES) m/z 511·9 。 15 範例584 2-甲氧基-N-{ [4 - {3 - [3 -（甲基磺醢基）苯氧基 基卜8-(三氟甲基)唉琳-3-基]甲基}乙胺 MS (ES) m/z 531.0 。 2〇 範例585 N - {[4 - {3-[3-(甲基續醢基)苯氧基]苯基卜8-(三氟甲 喹啉-3-基]甲基卜2-丙胺 MS (ES) m/z 515.0 。 350 200825054 5 範例586 N-{[4-{3-[3-(甲基續醯基)苯氧基]苯基}-8-(三氟甲基) 喹啉-3-基]甲基}丙-2-烯基-1-胺 MS (ES) m/z 513.0 。 / 1 範例587 1-環丙基-N-{[4-{3-[3-（甲基碟酿基）苯氧基]苯 基}-8-(三氟甲基)啥琳-3-基]甲基}甲胺 10 MS (ES) m/z 527.0 。 15 / 範例588 N-{ [4 - {3-[3-(甲基確醯基)苯氧基]苯基}-8-(三氟甲基) 者淋-3-基]甲基}乙胺 MS (ES) m/z 500.9 。 1 \ ~ 20 範例589 N-甲基-1-[4 - {3-[3-（甲基續酿基)苯氧基]苯基卜8-(三 氟甲基)喹啉-3-基]甲胺 MS (ES) m/z 486.9 。 範例590 351 200825054 3-({[4-{3-[3 -（甲基磺醢基）苯氧基]苯基}-8-(三氟甲 基)喹啉-3-基]甲基}胺基)丙腈 MS (ES) m/z 525·9 。 5 範例591 2-氟基-N-{[4 - {3-[3-（甲基續醯基）苯氧基]苯 基}-8 - (三氟甲基)喹琳-3-基]甲基}乙胺 MS (ES) m/z 519.0 〇 ίο 範例592 N-{ [4 - {3-[3-（甲基確醢基)苯氧基]苯基}_8-(三氟甲基) 喹琳-3-基]甲基}丙-卜胺 MS (ES) m/z 515.0 。 15 藝例593 N-{[4-{3- [3-(甲基項酿基)苯氧基]苯基卜8一 (三氟甲基） 喹啉-3-基]甲基}環戊胺 MS (ES) m/z 541.0 。 20 範例594 2-胺基-4-（3-甲氧基苯基）_8一（三氟甲基）喹啉_3一甲 醢胺 比照範例488製備，除了使用（2-胺基-3-(三氟甲基） 352 200825054 苯基）（3-甲氧基苯基）甲酮和2-氰基乙醯胺作為反應物，以 產生如一白色固狀物之該標題化合物。MS (ES) zzz/z362. 0 ; HRMS:計算值 C18H14F3N3〇2 + H+，362.11109;實測值（ESI， [M+H]+ Calc’d)， 362.1111 。 範例595 2-胺基-4-[3’ -（甲基磺醯基）聯苯一3一基]一8-（三氟甲 基）喹啉-3-甲腈 步驟1: 2-胺基-4-(3-溴基苯基）-8-(三氟甲基）喹啉 -3-甲腈 比照範例488製備，除了使用（2—胺基—3_(三氟甲基） 笨基）（3-溴基苯基）甲顚I和丙二腈作為反應物，以產生如一 白色固狀物之該標題化合物。MS (ES) yz//z 391. 8。 步驟2: 2-胺基一4-[3, -（甲基磺醢基）聨苯-3-基]-8-（三氟甲基）啥琳一 3-甲猜 比照範例279製備，除了使用2一胺基-4-(3-溴基苯 基）-8-（三氟甲基）喹啉一3一甲腈和3一（甲基磺醯基）苯基硼 酸作為反應物，以產生如一白色固狀物之該標題化合物。 MS (ES) yzz/z 467. 9。 範例596 2 一胺基一4_[3’ —（甲基磺醢基）聯苯-3-基]-8-(三氟甲 基0喹啉-3-羧酸 步驟1: 2-胺基-4-(3-溴基苯基）-8-(三氟甲基）喹啉 〜3-羧酸 353 200825054 將含有2-胺基-4-(3-溴基苯基）-8-(三氟甲基）喹啉 -3-甲腈（1.0 g，2.5 mmol)和 AcOH:H2S〇4(濃）（1:1)之一 溶液加熱至迴流。48小時之後，將該反應倒進水（100 mL) 中並以乙酸乙酯萃取。乾燥並濃縮該有機層以產生如一白 5 色固狀物之該標題化合物（0. 89 g，85%)。MS (ES) 410· 8。 步驟2: 2-胺基-4-[3’ -(甲基續班基）聯苯-3 -基]-8-（三氟甲基）喹啉-3-羧酸 10 比照範例279製備，除了使用2-胺基-4-(3-溴苯 基）-8-(三氟甲基）喹啉-3-羧酸和3-（甲基磺醯基）苯基硼 酸作為反應物，以產生如一白色固狀物之該標題化合物。 MS (ES) /Z//Z 486· 9。 範例597 15 4-[3’ -（甲基確酸基）聯苯-3-基]-8-（三氟甲基）喧琳 - 2-胺 步驟1: 4-（3-淡基苯基）-8-（三氟甲基）啥琳-2-胺 將含有胺基-4-(3-漠基苯基）-8-(三I甲基）喧琳 -3-魏酸（0. 1 g，0. 24 mmol)於極少量之陶氏熱媒 20 (Dowtherm)(5 mL)中之一溶液加熱至250 °C。1小時之後， 將N2(g)通過該反應，移除該陶氏熱媒，並將該殘餘物透過 以梯度15:85至40:60之E:H洗提的色層分析，以產生如 一白色固狀物之該標題化合物（80 mg)。MS (ES) ζζζ/ζ 366.8。 354 200825054 步驟2: 4-[3’-（甲基續酿基）聯苯-3-基]-8-（三氟甲 基）喹啉-2-胺 比照範例279製備，除了使用4-(3-溴苯基）-8-(三氟 5 甲基）-喹啉-2-胺和3-(甲基磺醯基）苯基硼酸作為反應 物，以產生如一白色固狀物之該標題化合物。MS (ES) τζζ/ζ 443. 0。 範例598 ίο 以範例43中所述之相似反應條件，使用適當的起始物 質，製備下列化合物。 A. 4-{2-氣基-5 - [3-（甲基磺醢基）苯氧基]苯 基}-8-甲氧基喹啉 15 Β· 4-{2-氯基-5-[3-(乙基磺醯基）苯氧基]苯 基}-8-甲氧基喹啉 C. 4-{2-氯基-5_[3-(異丙基磺醢基）苯氧基]苯 基}-8-甲氧基喹啉 D. 4-{2-氣基-5 - [3-氟基-5-(甲基續酿基）苯氧 20 基]苯基}-8-甲氧基喹啉 E. 4-{2-氯基-5-[3-(乙基續酸基）-5-氟苯氧基] 苯基}-8-甲氧基喹啉 F. 4 - {2-氣基-5-[3-氣基-5-（甲基磺醢基）苯氧 基]苯基}-8-甲氧基喹啉 355 200825054 G· 4 - {5 - [3-氯基-5-(甲基磺醯基）苯氧基]2-氟 基苯基}-8-甲氧基喹啉 丨4-{2-氟基-5-[3-氟基_5-（甲基續酸基）苯氧 基]苯基卜8-甲氧基喹啉 5 I. 4-{5-[3-(乙基續斑基）-5-氟苯氧基]2-氟苯 基}-8-甲氧基考琳 J· 4-{2 -氟基-5-[3-（甲基磺醢基）苯氧基]苯 基}-8_甲氧基喹琳 K· 4-{5-[3-(乙基磺醢基）苯氧基]-2-氟苯 1〇 基}_8-甲氧基喹啉 L· 4-{2-氟基-5-[3-(異丙基磺醢基）苯氧基]苯 基}-8-甲氧基嗓琳 M· 4-{2-氣基-5-[3-(甲基磺醢基）苯氧基]苯 基}-8-（甲基確斑基）啥琳 15 N· 4-{2-氣基-5-[3-(乙基磺醢基）苯氧基]苯 基}-8 -（甲基磺醢基）喹啉 〇· 4_{2-氣基_5-[3-(異丙基磺醢基）苯氧基]苯 基}-8-（甲基磺醢基）喹啉 P· 4 - {2-氣基-5-[3-氟基-5-（甲基磺醢基）苯氧 20 基]苯基}-8-(甲基磺醢基）喹啉 Q. 4 - {2-氣基-5-[3-（乙基磺醢基）-5-氟苯氧基] 苯基}-8-(甲基確酸基）喧琳 R· 4-{2-氣基-5-[3-氯基-5-（甲基磺醢基）苯氧 基]苯基}-8-（甲基磺醢基）喹啉 356 200825054 S. 4-{5-[3-氣基-5 -（甲基磺醢基）苯氧基]2-氟 苯基}-8-（甲基磺醯基）喹啉 T. 4-{2-氣基-5-[3-氟基-5-（甲基續酿基）苯氧 基]苯基}-8-（甲基磺醯基）喹啉 5 U. 4-{5-[3-(乙基磺醢基）-5-氟苯氧基]2-氟苯 基}-8 -（甲基磺醯基）喹啉 V. 4-{2-氟基-5-[3-（甲基續酿基）苯氧基]苯 基}-8-（甲基磺醢基）喹啉 W. 4-{5-[3-(乙基磺醯基）苯氧基]-2-氟苯 1〇 基}_8-（甲基續酿基）啥琳 X. 4-{2-氟基-5-[3-(異丙基磺醢基）苯氧基]苯 基}-8-（甲基續酿基）嘆琳 Y. 2-甲基-4-{3 - [3-(甲基磺醢基）苯氧基]苯 基}-8-（三氟甲基）考琳 15 Z. 4-{3-[3-（乙基磺醯基）苯氧基]苯基}-2-甲 基-8-(三氟甲基）啥琳 AA. 4-{3_[3-(異丙基磺醢基）苯氧基]苯基}-2-甲基-8-(三氟甲基）喹啉 BB. 4-{3-[3-氟基-5-(甲基磺醢基）苯氧基]苯 2〇 基}-2-甲基-8-(三氟甲基）啥琳 CC. 4-{3-[3-(乙基磺醢基）-5_氟苯氧基]苯 基}-2-甲基-8-（三氟甲基）啥琳 DD. 2-甲基-4-[3’ -（甲基磺醢基）聯苯-3-基]-8-(三氟甲基）啥琳 357 200825054 ΕΕ· 4-{2 -氟基-5 - [3-（甲基磺醢基）苯氧基]苯 基}-2-甲基-8-（三氟甲基）啥琳 FF. 4-{5-[3-(乙基磺醯基）苯氧基]2-氟基-苯 基}-2-甲基-8 -（三氟甲基）喹啉 5 GG. 4-{2-氟基-5-[3-(異丙基磺醢基）苯氧基]苯 基}-2-甲基_8-（三氟甲基）啥琳 ΗΗ. 4-{2-氟基-5-[3-氟基-5-（甲基磺醯基）苯氧 基]苯基}-2-甲基-8-（三氟甲基）喹啉 II. 4-{5-[3-(乙基磺醯基)-5-氟基苯氧基]2-氟基-ίο 苯基}-2-甲基-8-(三氟甲基)啥琳 JJ· 4-{2-氣基-5-[3-(甲基磺醯基）苯氧基]苯 基}-2_甲基-8 -（三氟甲基）喹啉 KL 4-{2-氯基-5-[3-（乙基磺醢基）苯氧基]苯 基}-2-甲基-8-（三氟甲基）啥琳 15 LL. 4-{2-氣基-5-[3-(異丙基磺醯基）苯氧基]苯 基}-2-甲基-8 -（三氟甲基）喹啉 MM. 4-{2_氯基-5-[3_氟基-5-（甲基磺醢基）苯氧 基]苯基}-2-甲基-8-（三氟甲基）喹啉 NN. 4-{2-氯基-5-[3-(乙基磺醢基）-5-氟苯氧基] 2〇 苯基}-2_甲基-8-（三氟甲基）啥琳 00. 4 - {2-甲基-5-[4-（甲基磺醢基）苯氧基]苯 基}-8-（三氟甲基）啥琳 PP. 4-{5-[4-（乙基磺醢基）苯氧基]2-甲基苯 基}-8-（三氟甲基）啥琳 358 200825054 QQ· 4-{5_[4-(異丙基磺醯基）苯氧基]2-甲基苯 基}-8-（三氟甲基）喹啉 RR· [(4-{4-甲基-3-[8-（三氟甲基）-4-喹啉基] 苯氧基}苯基)磺醢基]乙腈 5 SS. 8-氣基-4-{2-氣基-5-[3-(甲基確酿基）苯氧 基]苯基}-2-甲基啥琳 TT. 8-氯基-4-{2-氣基-5-[3-(乙基磺醢基）苯氧 基]苯基}-2_甲基喹啉 UU. 8-氣基-4-{2-氣基-5-[3-(異丙基磺醢基）苯 氧基]苯基}-2-甲基喹啉 VV. 8-氣基-4-{2-氣基-5-[3-氟基-5-（甲基磺醢 基）苯氧基]苯基}-2-甲基喹啉 WW. 8-氯基-4-{2-氯基-5-[3-（乙基磺醢基）-5-氟苯氧基]苯基}-2-甲基喹啉 15 XX· 8-氯基-4-{2-氟基-5-[3-（甲基磺醯基）笨氧 基]苯基}-2-甲基喹啉 YY. 8-氯基-4-{2_氟基-5-[3-(乙基磺醢基）苯氧 基]苯基}-2-甲基邊琳 ZZ. 8-氯基-4-{2-氟基-5-[3-（異丙基磺釀基）苯 20 氧基]苯基}-2-甲基喹啉 AAA· 8-氯基-4-{2-氟基-5-[3-氟基-5-(甲基 磺醢基）苯氧基]苯基}-2-甲基喹啉 BBB. 8-氱基-4-{2-氟基-5-[3-(乙基磺醢 基）-5-氟苯氧基]苯基}-2-甲基喹啉 359 200825054 ccc. 8-氣基_4-{5-[3-(甲基磺醢基）苯氧基] 苯基}-2-甲基喹啉 DDD· 8-氣基-4-{5-[3-(乙基磺醢基）苯氧基] 苯基}-2-甲基考琳 EEE· 8-氣基-4-{5-[3-(異丙基磺醢基）苯氧 基]苯基}-2-甲基啥琳 FFF. 8一氣基-4-{5-[3-氟基-5-（甲基磺醢基） 苯氣基]苯基}-2-甲基峻琳 GGG. 8_氣基-4-{5-[ 3-(乙基磺醢基）一5-氟基 苯氧基]苯基}-2-甲基啥琳 範例599 以範例212中所述之相似反應條件，使用適當的起始 物貝’製備下列化合物。 Α· 2-甲基-4_(3-{[3-（甲基磺醢基）苄基]氧基} 苯基）-8_(三氟甲基）啥琳 Β· 4-(2-氟基-5- {[3-（甲基磺斑基）节基]氧基}苯 基)-2-甲基-8-(三氟甲基)啥琳 C· 4-(2-氣基-5-{[3-（甲基磺醢基）苄基]氧基} 苯基）-2 -甲基-8-（三氟甲基）啥琳 D. 4-(2-氟基-5-{[3-(甲基磺醢基）苄基]氧基} 苯基）-8-甲氧基啥淋 360 200825054 Ε· 4 -（2-氣基-5-{[3 -（甲基磺醢基）苄基]氧基} 苯基）-8-甲氧基喹啉 F· 4 - (2-氟基-5-{ [3-（甲基績斑基）苄基]氧基} 苯基）-8-（甲磺醢基）喹啉 G· 4 -（2-氣基-5-{[3-(甲基磺醢基）苄基]氧基} 苯基）-8 -（甲磺醢基）喹啉 H· 8-氣基-4-(2-氟基-5-{[3-(甲基續酸基）苄 基]氧基}苯基）-2-甲基啥琳 I· 8-氣基-4-(2-氯基-5-{[3-（甲基續酿基）苄 基]氧基}苯基）-2-甲基啥琳 範例600 以範例259中所述之相似反應條件，使用適當的起始 物質，製備下列化合物。 A· 2-曱基-4-[3’ -(甲基磺醢基）聯苯-3-基]-8-（三氟甲基）啥琳 B· 4-[4-氣基-3’-（甲基磺醢基）聯苯_5_基]一2_ 甲基-8-（三氟甲基）喹啉 C. 4-[4-氟基-3’ -（甲基磺釀基）聯苯_5_基]—2一 甲基-8-（三氟甲基）喹啉 D· 4 - [4-氣基-3’-（甲基磺醢基）聯苯一基]一8-甲氧基喹啉 361 200825054 E. 4-[4-氟基-3’ -（甲基磺醢基）聯苯-5-基]-8-甲氧基喹啉 F. 4-[4-氣基-3’ -(甲基續酿基）聯苯-5-基]-8-（甲續斑基）啥琳 5 G. 4-[4-氟基-3’ -（甲基磺醢基）聯苯-5- 基]-8-（甲確酸基）啥琳 H. 8-甲氧基-4-[3’-（甲基磺醢基）聯苯-3-基] 喹啉 I. 8-(甲磺醢基）-4-[3’-(甲基磺醢基）聯苯-3- 10 基]啥啉 範例601 以範例258中所述之相似反應條件，使用適當的起始 物質，製備下列中間產物。 15 A. 4-氯基-3 - [2-甲基-8-（三氟甲基）-4-喹啉基] 苯基三氟甲烷磺酸酯 B. 4-氟基-3-[2-甲基_8-（三氟甲基）-4-啥琳基] 苯基三氟甲烷磺酸酯 20 C. 3_(8-甲氧基-4-啥琳基）苯基三氟甲烧續酸 酯 D. 4-氯基-3-（8-甲氧基-4-啥琳基）苯基三氟甲 烷磺酸酯 362 200825054 Ε· 4-氟基+(8-甲氧基_4_啥琳基）苯基三氣甲 烷磺酸酯 F· 4-氣基+(8-(甲續酸基啥琳基）苯基三 氟甲烷磺酸酯 5 G· 4—氟基—3—(8_(甲磺醢基）-4-喹啉基）苯基三 氟甲烷磺酸酯 H· 3 - (8-氣基-2-甲基-4-喹啉基）苯基三氟甲烷 磺酸酯 f I · 4-氯基-3 - (8-氣基-4-喹啉基）苯基三氟甲烷 10 磺酸酯 J· 8-氣基-(4_氟基-3--4-喹啉基）苯基三氟甲 烷磺酸酯 κ· 8-氣基-(4-氣基—3-一 4-喹啉基）苯基三氟甲 烷磺酸酯 範例602 例400中步驟2所述之相似反應條件，使用適當 的起始物質，製備下财間產物。 Α· 3 - [2 -甲基-8一（三氟甲基）-4-喹啉基]酚 Β· 4-氣基一 3-[2-甲基_8一（三氟甲基）-4-喹啉基] 酚 c· 4-氟基一 3 一[2一甲基_8一（三氟甲基）一4 一喹啉基] 酚 363 200825054 D. 4-氱基-3-[8 -甲氧基-4-喹啉基]酚 E. 4-氟基-3-[8-甲氧基-4-喹啉基]酚 F. 4-甲基-3-[8-（三氣甲基）-4-啥琳基]紛 G. 4-氯基-3-[8-(甲磺醢基）- 4-喹啉基]酚 H. 4-氟基-3-[8-(甲確斑基）- 4-啥琳基]盼 I. 3 -（8-氯基-2-甲基-4-啥琳基）盼 J. 3-（8-氣基-2-甲基-4-唉琳基）4-氣基紛 K. 4-氯基-3-(8-氣基-2-甲基-4-喹啉基）酚 ίο 範例603 以範例400中步驟1所述之相似反應條件，使用適當 的起始物質，製備下列中間產物。 15 20 A. 4-（2-氟基-5-甲氧基苯基）- 2-甲基-8-(三氟 甲基）喹啉 B. 4 -（2-氯基-5-甲氧基苯基）-2-甲基-8-(三氟 甲基）喹啉 C. 4-（3-甲氧基苯基）-2-甲基-8-（三氟甲基）啥 啉 D. 4-（3-甲氧基-6-甲基苯基）-8-（三氟甲基）啥 啉 E. 4-（2-氟基-5-甲氧基苯基）-8-甲氧基喹啉 F. 4-（2-氣基-5-甲氧基苯基）-8-甲氧基喹啉 364 200825054 G. 4-(2-氟基-5-甲氧基苯基)_8_(甲確殖基）啥 啉 H· 4_^基+甲氧基苯基)_8_(甲確離基）唉 啉 5 L 8 一氣基Μ 一 (2-氣基-5-甲氧基苯基)一 2一甲基 喹啉 J· 8-氣基-4 - (2-氟基一 5 一甲氧基苯基)—2 一甲基 喹啉 1〇 範例604 生物試驗 曰本發明之代表化合物以常見的藥理學試驗方法評估， 測量=對於LXR之結合親和力以及其對於ΑΒαι基因之向 上調節的旎力，其中ABCA1基因可引起膽固醇從與動脈粥 15樣硬化有關之細胞，如巨噬細胞，的排流。 LXR之活性在維持膽固醇之恆定狀態上是非常重要的，但其 同時調節脂肪酸代謝可導致血清中與肝中三酸甘油酯數值的增 加。活化膽固醇排流但對肝中SREBP_lc表現和三酸甘油酯合成 造成最少影響的選擇性UR調節物，可被期盼去減少粥狀動脈硬 20 化機率與改善治療指數並盡量減少對代謝平衡上有害影響的可 能性。 因此，LXR配體一開始在無細胞之LXR /5和LXR 競爭結合試驗中被發現。LXR配體之特徵更進一步透過用 於組織選擇性基因調節之基因表現資料來被鑑明。選擇性 365 200825054 LXR調節物展現出對於ABCA1轉錄活化之致效劑活性。 所進行之試驗方法和所獲得之結果係概括地敘述於下 列各項中： I.人類LXRP之配體-結合試驗方法 5 II.人類LXRa之配體-結合試驗方法 III. 於THP-1細胞中之ABCA1基因調節的定量分析 IV. 結果 I. 人類LXRP之配體-結合試驗方法 ίο 藉由下列流程展示代表之式（I)化合物的人類LXRP配 體結合試驗。 材料和方法： 緩衝液：lOOmM ΚΠ，100mM TRIS (在 +4°C pH 7.4)， 15 8· 6%甘油，0· ImM PMSF*，2mM MTG*，0· 2% CHAPS (* 非 用於沖洗緩衝液） 顯跡同位素：3H T0901317 受體來源:來自表現生物素化hLXRp之細胞的 E. coli萃取物。萃取物於如上面相似緩衝液中製備，但使 20 用 50mM 之 TRIS。 第1天 沖洗鏈黴抗生物素蛋白並將沖洗緩衝液覆蓋於光盤。 稀釋受體萃取物以產生Bmax〜4000 cpm，然後加進 位孔中。 366 200825054 以鋁箔紙包覆該些盤，然後儲存於+4°C整夜。 第2天 將該些試驗配體在DMS0中進行序列稀釋。 製造5nM之含有放射線活性顯跡同位素於緩衝液中的 5 溶液。 將250μ1稀釋的顯跡同位素與自每一序列稀釋濃度中 得來之5μ1試驗配體混合。 沖洗該覆蓋有受體之光盤。 於該覆蓋有受體之光盤中，每一位孔添加200μ1之配 ίο 體/放射線標諸混合物。 以鋁箔紙包覆該些盤，然後培養於+4°C整夜。 第3天 吸出該些位孔，並沖洗該些光盤。密封該盤。 量測盤中剩餘之放射線活性。 15 II.人類LXR α之配體-結合試驗方法 藉由下列流程展示代表之式（I)化合物的人類LXRa 配體結合試驗。 20 材料和方法： 緩衝液：100mM KC卜 lOOmM TRIS(在 +4°C pH 7.4)， 8. 6%甘油，0· ImM PMSF*，2mM MTG*，0· 2% CHAPS (* 非 用於沖洗緩衝液） 顯跡同位素：3H T0901317 367 200825054 受體來源：來自表現生物素化hLXR α之細胞的 E.coli萃取物。萃取物於如上面相似緩衝液中製備，但使 用 50mM 之 TRIS。 第1天 5 沖洗鏈黴抗生物素蛋白並將沖洗緩衝液覆蓋於光盤。 稀釋受體萃取物以產生Bmax〜4000 cpm，然後加進 位孔中。 以鋁箔紙包覆該些盤，然後儲存於+4°C整夜。 第2天 ίο 將該些試驗配體在DMS0中進行序列稀釋。 製造5nM之含有放射線活性顯跡同位素於緩衝液中的 溶液。 將250μ1稀釋的顯跡同位素與自每一序列稀釋濃度中 得來之5μ1試驗配體混合。 15 沖洗該覆蓋有受體之光盤。 於該覆蓋有受體之光盤中，每一位孔添加200μ1之配 體/放射線標誌混合物。 以鋁箔紙包覆該些盤，然後培養於+4°C整夜。 第3天 20 吸出該些位孔，並沖洗該些光盤。密封該盤。 量測盤中剩餘之放射線活性。 III. THP-1細胞中之ABCA1基因調節的定量分析 368 200825054 使用下列方法評估該式（I)化合物於ABCA1基因調節 上的影響。 材料和方法： 5 細胞培_養：自 American Type Culture Collection (Manassas，VA)取得該THP-i單核細胞的細胞株（ATCC # TIB-202) ’並培養於含有10% j?BS、2 mM L-麩胺醯胺 '和 55 uM /3-氫硫基乙醇（BME)的RPMI 1640培養基（Gibco,Prepared according to Example 43, except that it was heated at 205-210 °C for 1 hour in a microwave reactor using 3-(8-methyl-4-quinolinyl)phenol and 3,5-difluoro-1-( Methylsulfonyl)benzene is used as a substrate to give the title compound. MS 347 </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Example 576 4-{3-[3-(ethylsulfonyl)-5-fluorophenoxy]phenyl}-8-methyl-5 quinoline was prepared as in Example 43, except in a microwave reactor 205 Heating at -210 °C for 1 hour, and using 3-(8-methyl-4-quinolinyl) and 3,5-difluoro-1-(ethylsulfonyl)benzene as a substrate to produce Title compound. MS (ES) m/z 422. 1; HRMS: calcd for C24H2 〇FN 〇 3S + H+, ίο 422. 12207; Measured (ESI, [M+H]+Obs,d), 422. 1225. Example 577 3-({3-[3-(8-Methyl-4-quinolinyl)phenoxy]phenyl}sulfonyl)-1-propanyl was prepared as in Example 43, except in a microwave reactor Heating at 205-210 °C for 1 hour and using 3-(8-methyl-4-quinolinyl)phenol and 3-[(3-fluorophenyl)sulfonyl]-1-propanol as matrix To produce the title compound. MS (ES) m/z 436. Found: </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Example 578 20 4 -(3 -[3 - gas-5-(methylsulfonyl)phenoxy]phenyl b-8-methylquinoline prepared as in Example 43, except in a microwave reactor 205-210 T was heated for 1 hour, and 3-(8-methyl-4-quinolinyl)phenol and 3,5-dichloro-1-(methylsulfonyl) was used as a substrate to give the title compound. (ES) 348 200825054 m/z 423· 7 ; HRMS: calcd for C23H18ClN 〇3S + H+, 424. 07687; found (ESI, [M+H]+0bs'd), 424. 0766. Example 579 4 - {4-[3-(Methylsulfonyl)phenyl]-2-thienyl}-8-(trifluoromethyl)quinoline 5 The title compound was prepared in a similar manner as described in Example 259. MS (ES 433·8 ; HRMS: Calculated value C2 crystal 4FWO2S2 + H+, 434. 04908; measured value (ESI, [M+H]+Obs'd), 434.0486. Example 580 1〇4 - {4 - [2-( The title compound was prepared in a similar manner to that described in Example 259. MS (ES) 433.8; HRMS: Calculated C2 Crystal 4F3N〇2S2 + H+, 434.04908; found (ESI, [M+H]+ Obs'd), 434·0491. 15 Example 581 4-{4-[4-(methyl-decyl)phenyl The title compound was prepared in a similar manner to that described in Example 259. MS (ES) 7z//z 433·8; HRMS: Calculated value CuHmFsNO^ + H+ , 434.04908; real 20 measured value (ESI, [M+H] + Obs'd), 434·0484. Example 582 349 200825054 4- {5- [ 3-(methyl phenyl)phenyl] sinyl The title compound was prepared in a similar manner to that described in Example 259. MS (ES) melon/z 433 _ 8 ; HRMS: Calculated C21H14F3NO2S2 + H+, 434.04908; [M+H]+ Obs'd), 434.0484. Examples 583 to 593 The following compounds of Examples 583-593 were prepared in a similar manner as described in Example 276. 1 〇 Example 583 ({[4-{3 - [3 -(Methyl fluorenyl)phenoxy]phenyl b-(trifluoromethyl quinolin-3-yl)methyl}amino)acetonitrile MS (ES) m/z 511·9. 15 Example 584 2-methoxy-N-{ [4 - {3 - [3 - (methylsulfonyl) phenoxy) 8-(trifluoromethyl)indol-3-yl]methyl }ethylamine MS (ES) m/z 531.0. 2〇Example 585 N - {[4 - {3-[3-(methyl hydrazinyl)phenoxy]phenyl b- 8-trifluoromethyl quinolin-3-yl]methyl 2-propanamine MS (ES) m/z 515.0. 350 200825054 5 Example 586 N-{[4-{3-[3-(Methyl-decyl)phenoxy]phenyl}-8-(trifluoromethyl)quinoline -3-yl]methyl}prop-2-enyl-1-amine MS (ES) m/z 513.0 / 1 Example 587 1-cyclopropyl-N-{[4-{3-[3-( Methyl phenyl) phenoxy]phenyl}-8-(trifluoromethyl)indol-3-yl]methyl}methylamine 10 MS (ES) m/z 527.0. 15 / EXAMPLE 588 N- { [4 - {3-[3-(methyl-decyl)phenoxy]phenyl}-8-(trifluoromethyl)-indol-3-yl]methyl}ethylamine MS (ES) m /z 500.9 . 1 \ ~ 20 Example 589 N-Methyl-1-[4- <{3-[3-(methyl aryl)phenoxy]phenyl b- 8-(trifluoromethyl)quinoline -3-yl]methylamine MS (ES) m/z 486.9. Example 590 351 200825054 3-({[4-{3-[3 -(Methylsulfonyl)phenoxy)phenyl}-8- (Trifluoromethyl)quinolin-3-yl]methyl}amino)propanenitrile MS (ES) m/z 525·9. 5 Example 591 2-Fluoro-N-{[4 - {3-[ 3-(methyl decyl)phenoxy]phenyl}-8 -(trifluoromethyl)quinolin-3-yl]methyl}ethylamine MS (ES) m/z 519.0 〇ίο Example 592 N-{ [4 - {3-[3-(Methyl-decyl)phenoxy]phenyl}_8-(trifluoromethyl)quinolin-3-yl]methyl}propanamine MS (ES) m/z 515.0. 15 Example 593 N-{[4-{3-[3-(Methyl-glycolyl)phenoxy]phenyl b-8-(trifluoromethyl)quinoline- 3-yl]methyl}cyclopentylamine MS (ES) m/z 541.0. 20 Example 594 2-Amino-4-(3-methoxyphenyl)_8-(trifluoromethyl)quinoline_3 Monomethylamine was prepared as in Example 488 except using (2-amino-3-(trifluoromethyl) 352 200825054 phenyl)(3-methoxyphenyl)methanone and 2-cyanoacetamide as The title compound was obtained as a white solid. MS (ESI) &lt;RTI ID=0.0&gt;&gt; d), 362.1111. Example 595 2-Amino-4-[3'-(methylsulfonyl)biphenyl-3-yl]-8-(trifluoromethyl)quinoline-3-carbonitrile Step 1: 2-Amino 4-(3-Bromophenyl)-8-(trifluoromethyl)quinoline-3-carbonitrile was prepared as in Example 488 except using (2-amino-3-(trifluoromethyl)phenyl) (3-Bromophenyl)formamidine I and malononitrile as the reactants to give the title compound as a white solid. MS (ES) yz//z 391. 8. Step 2: 2-Amino-4-[3,-(methylsulfonyl)indol-3-yl]-8-(trifluoromethyl)fluorene-3-method was prepared according to Example 279, except Using 2-amino-4-(3-bromophenyl)-8-(trifluoromethyl)quinoline-1,3-carbonitrile and 3-(methylsulfonyl)phenylboronic acid as reactants, The title compound is produced as a white solid. MS (ES) yzz/z 467. 9. Example 596 2 monoamino- 4_[3'-(methylsulfonyl)biphenyl-3-yl]-8-(trifluoromethyl 0-quinoline-3-carboxylic acid Step 1: 2-Amino- 4-(3-Bromophenyl)-8-(trifluoromethyl)quinoline~3-carboxylic acid 353 200825054 will contain 2-amino-4-(3-bromophenyl)-8-(III A solution of fluoromethyl)quinoline-3-carbonitrile (1.0 g, 2.5 mmol) and AcOH:H 2 S 4 (concentrated) (1:1) was heated to reflux. After 48 hours, the reaction was poured into water ( The title compound (0. 89 g, 85%) was obtained as a white solid, mp. : 2-Amino-4-[3'-(methylhydrocarbyl)biphenyl-3-yl]-8-(trifluoromethyl)quinoline-3-carboxylic acid 10 Prepared according to Example 279, except 2-Amino-4-(3-bromophenyl)-8-(trifluoromethyl)quinoline-3-carboxylic acid and 3-(methylsulfonyl)phenylboronic acid as reactants to produce as one The title compound is obtained as a white solid. MS (ES) /Z//Z 486. 9. Example 597 15 4-[3'-(Methyl-Acidyl)biphenyl-3-yl]-8-(III Fluoromethyl) 喧 - 2-amine Step 1: 4-(3-Pemylphenyl -8-(Trifluoromethyl) fluorene-2-amine will contain amino-4-(3-lylphenyl)-8-(tri-Imethyl)indole-3-weilic acid (0. 1 g, 0. 24 mmol) was heated to 250 ° C in one of a very small amount of Dowtherm (5 mL). After 1 hour, N2 (g) was passed through the reaction to remove the The Dow heat medium was analyzed by chromatography on a gradient of 15:85 to 40:60 E:H eluted to give the title compound (80 mg) as a white solid. Ζζζ/ζ 366.8. 354 200825054 Step 2: 4-[3'-(Methyl aryl)biphenyl-3-yl]-8-(trifluoromethyl)quinolin-2-amine prepared according to Example 279 In addition to using 4-(3-bromophenyl)-8-(trifluoro-5methyl)-quinolin-2-amine and 3-(methylsulfonyl)phenylboronic acid as a reactant to give a white The title compound of the solid. MS (ES) τ ζζ / ζ 443. 0. Example 598 ίο The following compounds were prepared using the appropriate starting materials under the similar reaction conditions as described in Example 43. A. 4-{2 - gas-based 5-[3-(methylsulfonyl)phenoxy]phenyl}-8-methoxyquinoline 15 Β· 4-{2-chloro-5-[3-(ethyl Sulfur Benzo)phenoxy]phenyl}-8-methoxyquinoline C. 4-{2-chloro-5-[3-(isopropylsulfonyl)phenoxy]phenyl}-8- Methoxyquinoline D. 4-{2-carbyl-5-[3-fluoro-5-(methyl aryl)phenoxy 20 yl]phenyl}-8-methoxyquinoline E. 4-{2-Chloro-5-[3-(ethylsutonyl)-5-fluorophenoxy]phenyl}-8-methoxyquinoline F. 4 - {2-carbyl-5 -[3-carbyl-5-(methylsulfonyl)phenoxy]phenyl}-8-methoxyquinoline 355 200825054 G· 4 - {5 - [3-Chloro-5-(A Alkylsulfonyl)phenoxy]2-fluorophenyl}-8-methoxyquinolinium 4-{2-fluoro-5-[3-fluoro-based 5-(methylsulfonate) Phenoxy]phenyl b- 8-methoxyquinoline 5 I. 4-{5-[3-(ethyl contigyl)-5-fluorophenoxy]2-fluorophenyl}-8- Oxycholin J· 4-{2-Fluoro-5-[3-(methylsulfonyl)phenoxy]phenyl}-8_methoxyquinine K· 4-{5-[3 -(ethylsulfonyl)phenoxy]-2-fluorobenzene 1 fluorenyl}_8-methoxyquinoline L· 4-{2-fluoro-5-[3-(isopropylsulfonyl) Phenoxy]phenyl}-8-methoxyindole M· 4-{2-carbyl-5-[3-(methylsulfonyl)phenoxy]phenyl}-8-(A)基定斑基)啥琳15 N· 4-{2-气5-[3-(ethylsulfonyl)phenoxy]phenyl}-8-(methylsulfonyl)quinolinium·4_{2-carbyl_5-[3-(isopropyl Alkylsulfonyl)phenoxy]phenyl}-8-(methylsulfonyl)quinoline P· 4 - {2-carbyl-5-[3-fluoro-5-(methylsulfonyl) Benzene oxide 20-yl]phenyl}-8-(methylsulfonyl)quinoline Q. 4 - {2-carbyl-5-[3-(ethylsulfonyl)-5-fluorophenoxy Phenyl}-8-(methyl-acidic acid) 喧琳 R· 4-{2-carbyl-5-[3-chloro-5-(methylsulfonyl)phenoxy]phenyl} 8-(-methylsulfonyl)quinoline 356 200825054 S. 4-{5-[3-Acety-5-(methylsulfonyl)phenoxy]2-fluorophenyl}-8-( Methylsulfonyl)quinoline T. 4-{2-carbyl-5-[3-fluoro-5-(methyl aryl)phenoxy]phenyl}-8-(methylsulfonate Quinoline 5 U. 4-{5-[3-(ethylsulfonyl)-5-fluorophenoxy]2-fluorophenyl}-8-(methylsulfonyl)quinoline V. 4-{2-Fluoro-5-[3-(methyl aryl)phenoxy]phenyl}-8-(methylsulfonyl)quinoline W. 4-{5-[3-( Ethylsulfonyl)phenoxy]-2-fluorobenzene 1 fluorenyl}_8-(methyl continuation) 啥琳 X. 4-{2-Fluoro-5-[3-(isopropylsulfonate) Benzo)benzene ]]phenyl}-8-(methyl continuation) 叹琳 Y. 2-methyl-4-{3 - [3-(methylsulfonyl)phenoxy]phenyl}-8-( Trifluoromethyl)Cauline 15 Z. 4-{3-[3-(ethylsulfonyl)phenoxy]phenyl}-2-methyl-8-(trifluoromethyl)anion AA. 4-{3_[3-(isopropylsulfonyl)phenoxy]phenyl}-2-methyl-8-(trifluoromethyl)quinoline BB. 4-{3-[3-fluoro -5-(methylsulfonyl)phenoxy]phenyl-2-meryl}-2-methyl-8-(trifluoromethyl)anthracene CC. 4-{3-[3-(ethylsulfonate) -5-fluorophenoxy]phenyl}-2-methyl-8-(trifluoromethyl)anthracene DD. 2-methyl-4-[3'-(methylsulfonyl)-linked Benz-3-yl]-8-(trifluoromethyl)anthracene 357 200825054 ΕΕ·4-{2-Fluoro-5-[3-(methylsulfonyl)phenoxy]phenyl}-2 -methyl-8-(trifluoromethyl)anthracene FF. 4-{5-[3-(ethylsulfonyl)phenoxy]2-fluoro-phenyl}-2-methyl-8 -(trifluoromethyl)quinoline 5 GG. 4-{2-fluoro-5-[3-(isopropylsulfonyl)phenoxy]phenyl}-2-methyl_8-(three Fluoromethyl) 啥琳ΗΗ. 4-{2-Fluoro-5-[3-fluoro-5-(methylsulfonyl)phenoxy]phenyl}-2-methyl-8-(three Fluoromethyl)quinoline II 4-{5-[3-(ethylsulfonyl)-5-fluorophenoxy]2-fluoro-yl phenyl}-2-methyl-8-(trifluoromethyl)啥琳JJ·4-{2-carbyl-5-[3-(methylsulfonyl)phenoxy]phenyl}-2-methyl-8-(trifluoromethyl)quinoline KL 4-{2 -Chloro-5-[3-(ethylsulfonyl)phenoxy]phenyl}-2-methyl-8-(trifluoromethyl)fluorene 15 LL. 4-{2- gas-based- 5-[3-(Isopropylsulfonyl)phenoxy]phenyl}-2-methyl-8-(trifluoromethyl)quinoline MM. 4-{2_Chloro-5-[3 _Fluoro-5-(methylsulfonyl)phenoxy]phenyl}-2-methyl-8-(trifluoromethyl)quinoline NN. 4-{2-Chloro-5-[3 -(ethylsulfonyl)-5-fluorophenoxy] 2〇phenyl}-2_methyl-8-(trifluoromethyl)anion 00. 4 - {2-methyl-5-[ 4-(methylsulfonyl)phenoxy]phenyl}-8-(trifluoromethyl)fluorene PP. 4-{5-[4-(ethylsulfonyl)phenoxy]2- Methylphenyl}-8-(trifluoromethyl)anthracene 358 200825054 QQ·4-{5_[4-(isopropylsulfonyl)phenoxy]2-methylphenyl}-8-( Trifluoromethyl)quinoline RR·[(4-{4-methyl-3-[8-(trifluoromethyl)-4-quinolinyl]phenoxy}phenyl)sulfonyl]acetonitrile 5 SS. 8-gas base-4-{2-gas Benzyl-5-[3-(methyl-decyl)phenoxy]phenyl}-2-methylindene TT. 8-chloro-4-{2-carbyl-5-[3-(B Sulfosyl)phenoxy]phenyl}-2_methylquinoline UU. 8-Alkyl-4-{2-carbyl-5-[3-(isopropylsulfonyl)phenoxy Phenyl}-2-methylquinoline VV. 8-Alkyl-4-{2-carbyl-5-[3-fluoro-5-(methylsulfonyl)phenoxy]phenyl} -2-methylquinoline WW. 8-chloro-4-{2-chloro-5-[3-(ethylsulfonyl)-5-fluorophenoxy]phenyl}-2-methyl Quinoline 15 XX· 8-chloro-4-{2-fluoro-5-[3-(methylsulfonyl)phenyloxy]phenyl}-2-methylquinoline YY. 8-Chloro -4-{2_Fluoro-5-[3-(ethylsulfonyl)phenoxy]phenyl}-2-methylbendene ZZ. 8-Chloro-4-{2-fluoro- 5-[3-(isopropylsulfonyl)benzene 20 oxy]phenyl}-2-methylquinoline AAA· 8-chloro-4-{2-fluoro-5-[3-fluoro -5-(methylsulfonyl)phenoxy]phenyl}-2-methylquinoline BBB. 8-mercapto-4-{2-fluoro-5-[3-(ethylsulfonyl) )-5-fluorophenoxy]phenyl}-2-methylquinoline 359 200825054 ccc. 8-gas group_4-{5-[3-(methylsulfonyl)phenoxy]phenyl} -2-methylquinoline DDD· 8-gasyl-4-{5-[3-(ethylsulfonyl)phenoxy ]phenyl}-2-methylcoolin EEE· 8-carbyl-4-{5-[3-(isopropylsulfonyl)phenoxy]phenyl}-2-methylfluorene FFF. 8-monomethyl-4-{5-[3-fluoro-5-(methylsulfonyl)benzene-based]phenyl}-2-methyljunlin GGG. 8_gas--4-{5- [3-(Ethylsulfonyl)-5-fluorophenoxy]phenyl}-2-methylindole Example 599 Using the similar reaction conditions as described in Example 212, using the appropriate starting material The following compounds were prepared. Α· 2-Methyl-4_(3-{[3-(methylsulfonyl)benzyl]oxy}phenyl)-8-(trifluoromethyl)anthracene 4-(2-fluoroyl) -5- {[3-(Methylsulfonyl)] benzyl]oxy}phenyl)-2-methyl-8-(trifluoromethyl) oxime C· 4-(2-carbyl-5 -{[3-(methylsulfonyl)benzyl]oxy}phenyl)-2-methyl-8-(trifluoromethyl)anthracene D. 4-(2-fluoro-5-{ [3-(Methylsulfonyl)benzyl]oxy} phenyl)-8-methoxyindole 360 200825054 Ε· 4 -(2-Alkyl-5-{[3 -(methylsulfonate) Benzyl]oxy} phenyl)-8-methoxyquinoline F· 4 - (2-fluoro-5-{[3-(methylbendrobyl)benzyl)oxy} phenyl -8-(Methanesulfonyl)quinoline G·4-(2-carbyl-5-{[3-(methylsulfonyl)benzyl)oxy}phenyl)-8-(methylsulfonate) Hydrazino)quinoline H· 8-carbyl-4-(2-fluoro-5-{[3-(methylsulfonyl)benzyl]oxy}phenyl)-2-methylindene I · 8-Alkyl-4-(2-chloro-5-{[3-(methyl aryl)benzyl)oxy}phenyl)-2-methylindene Example 600, as shown in Example 259 The following compounds were prepared using similar starting materials, using similar starting conditions. A· 2-mercapto-4-[3'-(methylsulfonyl)biphenyl-3-yl]-8-(trifluoromethyl)anthene B· 4-[4-carbyl-3' -(methylsulfonyl)biphenyl-5-yl]-2-methyl-8-(trifluoromethyl)quinoline C. 4-[4-Fluoro-3'-(methylsulfonic acid) Biphenyl_5_yl]-2-methyl-8-(trifluoromethyl)quinoline D·4 - [4-carbyl-3'-(methylsulfonyl)biphenyl-yl]-8 -methoxyquinoline 361 200825054 E. 4-[4-Fluoro-3'-(methylsulfonyl)biphenyl-5-yl]-8-methoxyquinoline F. 4-[4- Gas-based-3'-(methyl aryl)biphenyl-5-yl]-8-(methyl leucine) 啥琳 5 G. 4-[4-Fluoro-3'-(methylsulfonate) Biphenyl-5-yl]-8-(methanoate) 啥琳 H. 8-methoxy-4-[3'-(methylsulfonyl)biphenyl-3-yl]quinoline I. 8-(Methanesulfonyl)-4-[3'-(methylsulfonyl)biphenyl-3-yl]porphyrin Example 601 Using the appropriate reaction conditions as described in Example 258, using the appropriate Starting materials, the following intermediates were prepared. 15 A. 4-Chloro-3-[2-methyl-8-(trifluoromethyl)-4-quinolinyl]phenyltrifluoromethanesulfonate B. 4-fluoro-3-[2 -methyl_8-(trifluoromethyl)-4-indolyl]phenyl trifluoromethanesulfonate 20 C. 3_(8-methoxy-4-indolyl)phenyl trifluoromethane R. D. 4-Chloro-3-(8-methoxy-4-indolyl)phenyltrifluoromethanesulfonate 362 200825054 Ε· 4-Fluoro+(8-methoxy-4) _啥琳基)Phenyl tri-gas methane sulfonate F · 4-gas base + (8-(methyl acid sulfonyl) phenyl trifluoromethane sulfonate 5 G · 4-fluoro group — 3 — (8-(Methanesulfonyl)-4-quinolinyl)phenyltrifluoromethanesulfonate H·3-(8-methyl-2-methyl-4-quinolinyl)phenyltrifluoromethanesulfonate Acid ester f I · 4-chloro-3-(8-methyl-4-quinolinyl)phenyltrifluoromethane 10 sulfonate J· 8-carbyl-(4-fluoro-3--4 -quinolinyl)phenyltrifluoromethanesulfonate κ·8-yl-(4-carbyl-3-tris-2-quinolinyl)phenyltrifluoromethanesulfonate Example 602 Example 400 Step 400 For the similar reaction conditions, the following product was prepared using the appropriate starting material. Α· 3 - [2-Methyl-8-(trifluoromethyl)-4-喹 啉 ] Β 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- 4- _8-(Trifluoromethyl)- 4-quinolinyl]phenol 363 200825054 D. 4-Mercapto-3-[8-methoxy-4-quinolinyl]phenol E. 4-fluoro-3 -[8-methoxy-4-quinolinyl]phenol F. 4-methyl-3-[8-(trimethylmethyl)-4-indolyl] G. 4-chloro-3- [8-(Methanesulfonyl)- 4-quinolinyl]phenol H. 4-Fluoro-3-[8-(methyl-decyl)- 4-indolyl] Pan I. 3 -(8- Chloro-2-methyl-4-indolyl) is expected to be J. 3-(8-methyl-2-methyl-4-indolyl) 4-carbyl K. 4-chloro-3- (8-Alkyl-2-methyl-4-quinolinyl)phenol ίο Example 603 The following intermediate product was prepared using the appropriate starting materials in the similar reaction conditions as described in Step 1 of Example 400. 15 20 A. 4-(2-Fluoro-5-methoxyphenyl)-2-methyl-8-(trifluoromethyl)quinoline B. 4-(2-chloro-5-methoxyphenyl) -2-methyl-8-(trifluoromethyl)quinoline C. 4-(3-methoxyphenyl)-2-methyl-8-(trifluoromethyl)porphyrin D. 4-( 3-methoxy-6-methylphenyl)-8-(trifluoromethyl)porphyrin E. 4-(2-fluoro-5-- Phenyl)-8-methoxyquinoline F. 4-(2-carbyl-5-methoxyphenyl)-8-methoxyquinoline 364 200825054 G. 4-(2-Fluoro- 5-methoxyphenyl)_8_(methyl-decyl)porphyrin H. 4_^yl+methoxyphenyl)_8_(methyl-iso-yl)porphyrin 5 L 8-gas-based hydrazine -5-Methoxyphenyl)-2-methylhydroxyquinoline J. 8-carbyl-4(2-fluoroyl-5-methoxyphenyl)-2 monomethylquinoline 1 〇 Example 604 Biological Tests The representative compounds of the present invention are evaluated by common pharmacological test methods, measuring = binding affinity for LXR and its upward regulation of ΑΒαι gene, which causes cholesterol to be associated with atherosclerosis 15 The drainage of cells, such as macrophages. The activity of LXR is very important in maintaining a constant state of cholesterol, but simultaneous regulation of fatty acid metabolism leads to an increase in the value of triglyceride in the serum and in the liver. Selective UR modulators that activate cholesterol drainage but have minimal effects on SREBP_lc expression and triglyceride synthesis in the liver can be expected to reduce atherosclerotic hardening and improve therapeutic index and minimize metabolic balance. The possibility of harmful effects. Therefore, LXR ligands were first discovered in cell-free LXR/5 and LXR competitive binding assays. The characteristics of the LXR ligand are further identified by gene expression data for tissue selective gene regulation. Selectivity 365 200825054 LXR modulators exhibit agonist activity for ABCA1 transcriptional activation. The test methods performed and the results obtained are generally described in the following: I. Ligand-binding assay method for human LXRP 5 II. Ligand-binding assay method for human LXRa III. THP-1 cells Quantitative analysis of ABCA1 gene regulation in IV. Results I. Ligand-binding assay method for human LXRP ίο The human LXRP ligand binding assay representing the compound of formula (I) is shown by the following scheme. Materials and Methods: Buffer: 100 mM 100, 100 mM TRIS (pH 7.4 at +4 ° C), 15 8 · 6% glycerol, 0·1 mM PMSF*, 2 mM MTG*, 0·2% CHAPS (* not used for rinsing Buffer) Trace Isotope: 3H T0901317 Receptor Source: E. coli extract from cells expressing biotinylated hLXRp. The extract was prepared in a similar buffer as above except that 20 mM TRIS was used. Day 1 Flush streptavidin and cover the wash buffer on the disc. The receptor extract was diluted to produce Bmax ~ 4000 cpm and then added to the well. 366 200825054 The plates were covered with aluminum foil and stored at +4 ° C overnight. On day 2, the test ligands were serially diluted in DMS0. A 5 nM solution containing a radioactively visible isotope in a buffer was prepared. A 250 μl diluted trace isotope was mixed with 5 μl of the test ligand from each sequence dilution. Rinse the disc covered with the receptor. In the disc covered with the receptor, 200 μl of the body/radiation standard mixture was added to each well. The trays were covered with aluminum foil and then incubated at +4 ° C overnight. On the third day, the holes are sucked out and the discs are washed. Seal the disc. The remaining radiation activity in the disk is measured. 15 II. Ligand-Binding Test Method for Human LXR α The human LXRa ligand binding assay representing the compound of formula (I) is shown by the following scheme. 20 Materials and Methods: Buffer: 100 mM KC Bu lOOmM TRIS (at +4 ° C pH 7.4), 8. 6% glycerol, 0·1 mM PMSF*, 2 mM MTG*, 0·2% CHAPS (* not used for rinsing Buffer) Trace Isotope: 3H T0901317 367 200825054 Receptor Source: E. coli extract from cells expressing biotinylated hLXR alpha. The extract was prepared in a similar buffer as above, but using 50 mM TRIS. Day 1 5 Flush streptavidin and cover the wash buffer on the disc. The receptor extract was diluted to produce Bmax ~ 4000 cpm and then added to the well. The trays were covered with aluminum foil and stored at +4 ° C overnight. Day 2 ίο The test ligands were serially diluted in DMS0. A 5 nM solution containing a radioactively visible isotope in a buffer was produced. A 250 μl diluted trace isotope was mixed with 5 μl of the test ligand from each sequence dilution. 15 Rinse the disc covered with the receptor. In the disk covered with the receptor, 200 μl of the ligand/radiation marker mixture was added to each well. The trays were covered with aluminum foil and then incubated at +4 ° C overnight. Day 3 20 Aspirate the holes and rinse the discs. Seal the disc. The remaining radiation activity in the disk is measured. III. Quantitative analysis of ABCA1 gene regulation in THP-1 cells 368 200825054 The effect of the compound of formula (I) on the regulation of the ABCA1 gene was evaluated using the following method. Materials and Methods: 5 Cell culture: The cell line of THP-i mononuclear cells (ATCC # TIB-202) was obtained from American Type Culture Collection (Manassas, VA) and cultured in 10% j?BS, 2 mM L-glutamine indole and 55 uM /3-hydrogenthioethanol (BME) in RPMI 1640 medium (Gibco,

Carlsbad，Ca)中。細胞以密度7·5 χ ι〇4於含有5〇一 1〇〇 1〇 ng/ml 佛波 12, 13-二丁酸酯（Sigma，St. Louis，Mo)之完全 培養基中的形式被置入96位孔盤中，並培養三天以誘導分 化成黏附的巨噬細胞。經分化的THP—丨細胞以含有溶於 MS0(Sigma，D-8779)之試驗化合物或配體的缺乏佛波酯培 養基處理。最終DMS0濃度不可超過培養基體積的〇· 3%。測 15量兩次藥劑反應所造成的影響，濃度範圍為0.001至30之 微莫耳濃度，並將經處理的細胞在分離之前培養另外 的18小時。以載劑處理之未經激活的細胞在每一盤中當成 陰性對照組。一種LXR致效劑的參考，n-(2, 2, 2-三氟基一 乙基）-N-[4-(2, 2, 2-三氟基-1-羥基-1 —三氟甲基—乙基）_ 2〇 苯基]-苯磺醯胺（Schultz, Joshua R·，Genes &amp; Development (2000), 14(22), 2831-2838)，劑量為 h 〇 uM並當成陽性對照組。在拮抗劑模組中，受研究之化合物 在150nM GW3965，三氟甲基-苄基—（2,2-二苯基-乙基）一胺 基]-丙氧基]-苯基）-乙酸（C〇llins，LL·，乂处4 369 200825054 (2000)，45:1963-1966.)，的存在下被分析。抗劑分析的 結果以反致效作用％和IC50 (以單位μΜ)表示。 RNA之分離與定量:根據製造者建議，使用PrepStation 5 6100 (Applied Biosystems, Foster City，Ca)將所有細胞中 RNA自培養於96位孔盤中經處理之細胞中分離出來。RNA 在分析前重新懸浮於無核醣核酸酶存存在的水中並儲存 於-70°C。以 RiboGreen 試驗步驟 #R-11490 (Molecular Probes，Eugene，OR)定量 RNA 的濃度。 ίο 基因表現分析：根據製造者指示，藉由以Perkin Elmer Corp·化學品在ABI Prism 7700序列偵測系統（Applied Biosystems, Foster City，CA)上進行即時（rea卜time) PCR，來定量基因特異的mRNA。將全部RNA中取部分檢體 15 (50-100 ng)於50 ul反應物中進行重覆二次或三次試驗， 其使用單一-步驟RT-PCR以及標準曲線法來預測特定mRNA 的濃度。基因特異性引子和探針組之序列係以引子快捷軟 體（Applied Biosystems，Foster City，CA)設計。該人類 ABCA1引子和探針序列係：正向， 20 CAACATGAATGCCATTTTCCAA ， 肖 ， ATAATCCCCTGAACCCAAGGA ，以及 # 名十 ， 6FAM-TAAAGCCATGCCCTCTGCAGGAACA-TAMRA°RT 以及 PCR 反應係 根據用於 Taqman Gold RT-PCR 之 pe Applied Biosystems 私或用於Quantitect彳朱針之Qiagen氏流程。 370 200825054 ABCA1 mRNA之相對值係使用購於市面之GAPDH mRNA或 rRNA 棟針/弓I 子組（Appl ied Biosystems，Foster Ci ty， CA)來標準化。 統計： 5 使用AN0VA，依SAS分析之變異的單向分析，來進行 RNA檢體之平均值、標準差以及統計上有意義的重複評估。 試劑：Carlsbad, Ca). The cells were plated at a density of 7·5 χ ι〇4 in complete medium containing 5〇1〇〇1〇ng/ml phorbol 12, 13-dibutyrate (Sigma, St. Louis, Mo). The cells were placed in a 96-well plate and cultured for three days to induce differentiation into adherent macrophages. The differentiated THP-sputum cells were treated with a phorbol ester-free medium containing a test compound or ligand dissolved in MS0 (Sigma, D-8779). The final DMS0 concentration should not exceed 培养基·3% of the medium volume. The effect of the two doses of the drug was measured at a concentration ranging from 0.001 to 30 micromolar concentrations, and the treated cells were cultured for an additional 18 hours prior to isolation. Unactivated cells treated with vehicle were used as negative control in each dish. A reference for LXR agonist, n-(2, 2, 2-trifluoro-ethyl)-N-[4-(2, 2, 2-trifluoro-1-hydroxy-1-trifluoromethyl) —-ethyl)_ 2〇phenyl]-benzenesulfonamide (Schultz, Joshua R., Genes &amp; Development (2000), 14(22), 2831-2838) at a dose of h 〇uM and used as a positive control group. In the antagonist module, the compound under study is at 150 nM GW3965, trifluoromethyl-benzyl-(2,2-diphenyl-ethyl)monoamido]-propoxy]-phenyl)-acetic acid (C〇llins, LL., 4 4 369 200825054 (2000), 45: 1963-1966.), was analyzed in the presence. The results of the anti-agent analysis are expressed as % anti-effect and IC50 (in μ). Isolation and quantification of RNA: RNA from all cells was isolated from treated cells cultured in 96 well plates using PrepStation 5 6100 (Applied Biosystems, Foster City, Ca) according to the manufacturer's recommendations. RNA was resuspended in water in the presence of ribonuclease prior to analysis and stored at -70 °C. The RNA concentration was quantified by RiboGreen test procedure #R-11490 (Molecular Probes, Eugene, OR). Ίο Gene performance analysis: Quantitative gene specificity was performed by Perkin Elmer Corp. Chemicals on ABI Prism 7700 Sequence Detection System (Applied Biosystems, Foster City, CA) according to manufacturer's instructions. mRNA. A portion of the sample 15 (50-100 ng) of all RNA was subjected to repeated two or three experiments in 50 ul of the reaction, which used single-step RT-PCR and standard curve methods to predict the concentration of a particular mRNA. Sequences of gene-specific primers and probe sets were designed using the primer software (Applied Biosystems, Foster City, CA). The human ABCA1 primer and probe sequence: forward, 20 CAACATGAATGCCATTTTCCAA, XI, ATAATCCCCTGAACCCAAGGA, and #名十, 6FAM-TAAAGCCATGCCCTCTGCAGGAACA-TAMRA°RT and the PCR reaction according to pe Applied Biosystems for Taqman Gold RT-PCR Qiagen's process for Quantitect. 370 200825054 The relative values of ABCA1 mRNA were normalized using the commercially available GAPDH mRNA or rRNA PIN/A subgroup (Appl ied Biosystems, Foster Ci ty, CA). Statistics: 5 Using AN0VA, the one-way analysis of the variation of the SAS analysis was performed to obtain the mean, standard deviation, and statistically significant repeated evaluation of the RNA samples. Reagents:

-GAPDH探針與引子-鐵克曼（Taqman)GAPDH品管 10 試劑 402869 或 4310884E 18S核糖體RNA -鐵克曼18S品管試劑4308329 10包鐵克曼PCR核心試劑組402930 快安（Qiagen)即時定量探針RT-PCR 204443。 15 IV.結果 hLXRb 結合試 驗 hLXRa 結合試 驗 — 憑藉LXR配體之 基因調控 (THP-1細胞株） 範例 1〇50 UM) ICso UM) EC50 ABCA1 (uM) 致效作 用百分 比 ABCA1 (%) 43 0.0016 0.0061 44 0.0026 0.0227 45 0.0018 0. 0079 46 0.0249 0. 138 371 200825054 47 0. 559 7. 1 48 0.0081 0. 061 49 0. 0130 0. 118 50 0. 105 0.451 51 0. 073 4· 1 52 0.0014 0.0047 53 0.0032 0.0186 54 &gt;1 &gt;1 55 0.0132 0.0409 56 0.0416 0. 153 1. 25 72 57 0.0082 0. 121 58 0.0012 0.0033 59 0-0010 0.0024 60 0.0019 0.0066 61 0.0011 0.0034 62 0.0029 0.0276 63 0.0062 0.0400 64 0.0020 0.0100 65 0.0019 0.0122 66 0.0009 0.0020 67 0.0103 0.0343 68 0.0037 0.0217 69 0.0042 0. 051 70 0.0028 0.0397 0. 53 86 71 0.0017 0.0035 72 0. 0174 0-081 73 0.0302 0. 121 74 0. 144 1. 19 75 &gt;1 &gt;1 76 0. 108 0.819 77 &gt;1 &gt;1 78 &gt;1 &gt;1 79 &gt;1 &gt;1 80 0.377 1.40 81 &gt;1 &gt;1 82 0. 252 1. 36 84 0.0028 0.0417 0. 82 103 85 0.0250 0. 252 2. 83 91 372 200825054 86 0.0024 0.0397 87 0. 081 0.419 88 0. 102 0. 705 89 0.0273 0. 189 90 0. 1593 &gt;1 91 0.0078 0. 106 0. 61 93 92 &gt;1 &gt;1 94 0.221 1. 19 95 0.0109 0. 060 96 0. 063 0. 603 97 0. 101 0. 788 98 &gt;1 &gt;1 99 0.0115 0.0589 100 &gt;1 &gt;1 101 0.0277 0. 336 102 0.0017 0.0040 103 0.0017 0.0083 104 0.0017 0.0034 105 0.0092 0. 080 106 0.0020 0.0069 107 0.0030 0.0146 108 0.0028 0.0171 109 &gt;1 &gt; 1 110 0.0041 0. 085 111 0. 198 1. 07 112 0.0050 0. 060 113 0. 046 0. 710 114 0.0106 0. 118 115 0.0025 0.0249 116 0. 255 0. 972 117 0.0022 0-0135 118 0. 099 0. 190 119 0.0149 0. 046 120 0. 650 2. 10 121 0.0020 0.0067 122 1. 08 6.35 123 0. 314 &gt; 1 124 0.0082 0. 056 373 200825054 126 0.0032 0.0297 127 0.0362 0. 124 128 0.0019 0.0045 129 0.0054 0.0120 130 0.0071 0. 048 131 0.0121 0. 074 132 0.0050 0.0285 133 0.0212 0. 155 134 0. 056 0. 678 135 0. 038 0. 164 136 0. 056 &gt;1 137 0.0165 0. 093 138 0.0154 0. 066 139 0.0131 0. 048 140 0. 049 0. 156 141 0.0269 0. 128 142 0.0019 0.0030 143 0.0024 0.0042 144 0.0022 0.0049 145 0.0049 0.0215 146 0.0022 0.0049 147 0.0039 0.0090 148 0.0018 0.0038 149 0.0036 0.0149 150 0.0045 0.0153 151 0.0051 0.0247 152 0. 263 0. 541 153 0.454 1. 51 154 0. 091 0.346 155 0.0246 0. 114 156 0. 175 0. 617 157 0.551 1.41 158 0.0398 0. 189 159 0.0323 0. 176 160 0. 074 0. 181 161 &gt; 1 &gt; 1 162 0.0016 0.0055 163 0.0035 0.0220 374 200825054 164 0.0081 0. 056 165 0.0089 0. 057 166 0. 0179 0. 061 167 0. 0012 0.0044 168 0. 0015 0.0113 169 0. 0039 0.0213 170 0.0073 0. 064 171 0. 0194 0. 092 172 0.0050 0.0298 173 0.0023 0.0134 174 0.0036 0.0178 176 0.0045 0.0139 177 0.0023 0.0113 178 0.0011 0.0040 179 0.0063 0.0298 180 0. 0018 0.0091 181 0.0009 0.0023 182 0. 0017 0.0049 183 0.0046 0. 035 184 0.0125 0. 146 185 0.0051 0. 048 186 0. 056 0. 383 187 0. 077 0. 389 188 0.0056 0.0233 190 0-0041 0. 049 193 0.0057 0. 035 194 3. 19 12.4 195 &gt; 1 &gt; 1 196 0.0031 0.0217 198 0.0012 0.0045 201 0. 184 1. 07 202 0.0387 0. 263 205 6.23 25. 3 206 0. 094 1. 07 1.80 16 210 0.0261 0. 294 212 0.0108 0. 167 213 0. 322 &gt; 1 214 0.0395 0. 178 375 200825054 215 0.0043 0.0224 216 0.0018 0.0118 217 0.0018 0.0035 221 0.0155 0.0546 222 0.0020 0.0145 223 0.0009 0.0023 226 0.0473 0. 181 229 0.0187 0. 093 232 0. 356 0. 602 233 0.0042 0.0197 234 0.0175 0.0604 235 0. 157 0. 382 236 0. 346 0. 652 237 &gt; 1 &gt;1 238 0. 105 0. 525 239 0. 177 0. 634 240 0.0428 0. 097 241 0.0917 0. 198 242 0. 154 0. 380 243 0.338 0. 532 244 0. 100 0. 565 245 0.0556 0. 251 246 1. 04 1. 63 247 0. 911 2. 05 248 1.86 3. 37 250 0.0373 0. 191 251 0.0024 0.0231 252 0.0040 0.0329 253 0.0041 0.0260 254 0.0026 0.0394 255 0.0072 0. 149 257 0.0009 0.0047 259 0.0905 0. 386 260 0.0030 0.0165 261 0.0117 0. 096 262 &gt;1 &gt;1 263 &gt; 1 &gt;1 264 &gt;1 &gt;1 376 200825054 265 1. 27 1.40 266 0. 0091 0.0745 267 5. 29 26.6 269 0. 175 &gt; 1 270 0.0045 0.0450 271 0.0545 0. 293 272 0. 165 1. 27 275 0. 082 1. 06 276 0. 0185 0. 602 0. 113 104 277 0. 367 3. 67 278 0.7306 6.8641 279 0.0018 0.0094 280 0.0015 0.0067 281 0.0044 0.0679 0. 11 88 282 0.0024 0-0054 283 0.0083 0.0344 284 0.0038 0.0066 285 0.0041 0.0085 286 0.0038 0.0141 287 0. 335 1. 74 288 0. 681 1. 67 290 0.380 1. 01 291 0.0240 0. 228 292 &gt;1 &gt;1 293 0.0073 0. 081 294 0. 083 &gt;1 295 0. 071 &gt; 1 296 0. 187 &gt;1 297 &gt; 1 298 0.0288 0. 615 299 0. 065 0.835 300 0. 0213 0. 159 301 0.0345 0.2024 302 0-0430 0. 158 303 0. 253 &gt; 1 304 &gt; 1 &gt; 1 305 0.0054 0. 050 306 0.0069 0. 068 377 200825054 307 0.0085 0. 131 308 0.0111 0. 09 309 &gt; 1 311 1. 61 6. 66 312 &gt; 1 313 &gt; 1 &gt; 1 314 5. 00 &gt;1 315 0.4127 &gt;1 316 &gt;1 317 0.0052 0. 073 318 0.083 0.401 319 0.0192 0.2510 320 0.0528 0. 208 321 0. 137 0. 331 322 0. 375 &gt; 1 323 0.0767 0. 289 324 0. 096 0. 536 325 0. 355 &gt;1 326 0. 277 1. 71 327 0.586 &gt;1 328 0. 109 0. 686 329 0. 094 0.422 330 0.0263 0. 123 331 0.0138 0. 116 332 0.0328 0.362 333 0.249 1. 70 334 0.0516 0.449 335 0. 094 1. 31 336 0. 138 &gt;1 337 &gt; 1 &gt; 1 ' 338 &gt; 1 &gt;1 339 &gt;1 &gt;1 340 0. 330 0. 989 341 0. 698 3. 53 342 &gt;1 &gt;1 343 &gt;1 &gt;1 344 &gt;1 &gt;1 345 0.0068 0.0527 378 200825054 346 0. 148 0.493 347 0.292 1.26 348 0.808 1. 09 349 0. 239 &gt; 1 350 0.0152 0. 195 351 0. 232 1. 36 352 0.850 &gt;1 353 &gt;1 &gt;1 354 0. 364 &gt;1 355 0.0031 0.0382 0. 065 80 356 0.0405 0.422 357 &gt;1 &gt; 1 359 0.0032 0.0124 360 &gt; 1 362 0. 070 0. 124 363 0.0544 0. 650 364 0.211 0.712 365 1. 76 5. 53 367 0.0077 0. 074 369 &gt;1 372 0.0661 0-574 373 1. 39 3.66 374 0. 739 0.824 375 0. 0113 0. 175 376 0.0275 0. 086 377 0.0207 0. 099 378 0. 190 1. 10 379 0-0287 0. 108 380 0.0474 0.200 381 0.0216 0. 095 382 0.0467 0. 181 383 0. 074 0. 109 384 0.0391 0. 149 385 0.0167 0. 051 386 0. 134 0.419 387 0.0545 0. 130 388 0. 093 0.467 389 &gt;1 &gt; 1 379 200825054 390 0. 379 &gt;1 391 &gt;1 &gt; 1 394 0.0023 0.0046 395 0.0068 0. 098 396 0. 0148 0. 217 397A 0.0258 0. 249 397B 0.0333 0. 199 397C 0.0029 0.0247 0.41 100 397D1 2.86 397D2 0.0031 0.0450 0. 04 90 397E 0.0460 0.321 1. 36 77 397F 0.251 &gt;1 397G 0. 676 &gt; 1 397H 0.0049 0.0246 0. 08 81 3971 0.0128 0. Ill 0.44 73 397J 0. 146 1. 72 397K 15. 0 &gt; 1 397L 2. 92 &gt;1 397M 0.0033 0. 067 0. 61 103 397N 0.0404 0. 280 3970 0. 076 0. 251 397P 0. 097 0. 369 397Q 0.0033 0.0103 397R 0.0063 0. 043 397S 0.0231 0. 745 0. 717 96 397T 0. 061 1. 77 1.89 87 397U 0.0019 0.0144 397V 0.0053 0. 286 397W 13.8 &gt;10 397X 0.0026 0.0131 397Y 0.0424 0. 616 0. 115 71 397Z 0. 056 1. 36 397AA 0.0027 0-0109 397AB 0. 082 0. 301 397AC 0.0166 0. 126 397AD 0. 610 12. 7 397AE 0-0072 0. 129 0. 58 82 397AF 0. 629 &gt;1 380 200825054 397AG 1. 01 &gt;1 397AH 0.0392 0.764 397AI 0. 07 1. 12 397AJ 0.0157 0.542 0.437 107 397AK 0. 738 3. 05 397AL 0.0315 0.463 397AM 0.0108 0.409 0.54 104 397AN 0. 150 2. 93 397A0 0. 108 1. 10 397AP 0. 128 2.31 397AQ 0.0058 0·123 0. 645 100 397AR 0.0314 0. 389 397AS 0.0306 0. 592 397AT 0. 161 1. 13 397AU 0.0051 0. 244 397AV 0.394 3. 54 397AW 1.38 2. 99 397AX 0.451 3. 34 397AY 0. 300 6.85 397AZ 0.0073 0. 215 397AAA 0.0013 0.0085 0.035 103 398A 0.0183 0.456 398B 0.0334 0. 753 3. 58 130 399A 0.0015 0.0095 2.23 78 399B 0.0012 0.0362 399C 0.0029 0. 118 399D 0.0131 0. 093 399E 0. 103 1.34 399F 0. 140 0.848 1. 33 94 401A 0.0011 0.0100 401B 0.0012 0.0197 401C 0.0012 0.0141 0.010 110 401D 0. 089 0. 249 0. 55 64 402 0. 090 0. 500 3. 11 98 403 0. 130 0. 568 404 0. 146 0. 640 405 0. 114 0. 983 406 0. 117 0. 700 381 200825054 407 0.0015 0.0250 0. 113 110 408 0.0009 0.0120 0. 056 115 409 0.0017 0. 057 0. 274 113 410 0.0018 0.0312 0. 202 130 411 0.0387 0. 220 412 0. 109 1.43 413 &gt; 1 &gt;1 414 0. 073 0. 319 415 0.479 &gt;1 416 0.221 5.6120 417 0. 143 6.84 418 0.848 13.7 419 14.2 &gt; 1 420 &gt;1 421 &gt; 1 &gt;1 422 0. 217 2.29 423 &gt; 1 424 &gt;1 425 0.0018 0.0167 0. 043 113 426 0.0034 0.0474 0. 654 100 427 0.0010 0.0133 0. 397 109 428 0.0032 0.0322 0. 25 100 429 0.0047 0. 062 1. 24 100 430 0.0016 0.0207 0. 088 87 431 0.0026 0.0035 432 0.0179 0. 089 0.405 93 433 0.0024 0.0437 0. 39 116 434 0.0181 0. 389 3· 6 79 435 0.0606 0.869 436 4. 97 21.8 437 0. 686 7. 20 439 0.0091 0. 785 0. 355 117 440 0. 077 2. 83 0. 69 138 441 0. 067 1. 75 442 0.0049 0-0100 443 0-0268 0. 697 1. 84 106 444 0.0172 0. 723 1. 11 117 445 0. 092 1. 06 382 200825054 446 0.0172 0. 644 1.38 127 447 &gt; 1 &gt;1 448 0. 195 3. 09 449 0.0712 &gt;1 4.34 100 450 0. 108 &gt;1 5. 75 100 451 &gt;1 &gt;1 452 &gt; 1 &gt;1 453 0.0040 0. 067 1.44 171 456 0.0024 0.0219 1. 00 186 457 0.0034 0.0378 0. 37 162 458 0.0135 0. 155 1. 06 94 459 0.233 4. 76 464 0.0019 0.0102 0. 18 78 465 0.0180 0. 192 1. 19 79 466 0.0548 0. 192 1. 06 105 467 0.484 1.38 468 0.0029 0.0036 469 0.0030 0.0220 0. 345 116 470 0. 078 0. 375 1. 26 106 471 0. 107 0. 765 472 0. 060 1. 73 473 0.475 4. 84 475 1. 00 11.8 476 &gt;1 &gt;1 477 0.223 4. 78 478 0.0273 0.291 0.235 96 479 &gt;1 &gt;1 480 0.0090 0. 192 0. 355 189 481 0. 231 &gt; 1 482 &gt; 1 &gt; 1 485 0. 0013 0.0041 486 0.0310 0.324 0.403 107 488 0. 094 1. 06 1. 1 74 489 0.0026 0.0315 0. 14 103 490 0. 0017 0.0102 491 &gt; 1 &gt; 1 492 0. 097 1. 26 493 0. 054 0. 746 383 200825054 494 0. 553 7. 29 495 0.238 3. 12 496 0. 0122 0. 148 0. 29 129 497 0.440 1. 17 498 2. 32 5. 64 499 0. 056 0. 334 1. 32 57 500 0. 109 0.435 501 0.457 0. 813 502 0. 134 0.446 503 0.427 1. 02 504 0. 175 1. 07 505 0. 134 0. 535 506 0. 194 0. 887 507 0.0028 0.0159 509 0.0072 0. 115 3. 21 125 510 0.0075 0. 120 511 0.0444 0.493 1. 75 84 512 0-0130 0. 393 2. 03 90 513 0.0112 0. 364 1.43 90 514 0.0656 1. 04 2.47 109 515 0.0275 0.230 3. 35 129 516 0.0285 0. 212 0. 96 92 517 0.0211 0. 311 1.87 97 518 0.0356 0. 192 0. 93 77 519 0. 129 1.42 520 0.0062 0. 074 2. 01 98 521 0. 116 2. 60 522 0. 147 11. 1 1. 17 109 523 0. 054 1. 93 0-695 77 524 0.0282 0. 756 0. 355 125 527 0.0053 0.0272 528 0.0159 0. 101 0.495 99 529 0.0223 0. 561 530 0.242 5. 25 531 0.0284 1.22 3. 75 57 532 0.0363 0.437 533 0. 367 4.44 534 &gt;1 384 200825054 535 0.0198 0. 271 0. 325 80 536 0.0222 0. 277 537 &gt;1 &gt; 1 539 5. 71 12. 3 540 0.0015 0.0047 0. 23 238 541 0.0043 0. 046 0. 185 111 542 0.243 4.86 543 0.0133 0. 242 544 0.0009 0.0024 0. 335 102 547 5. 13 29.8 548 10.2 &gt;1 549 0. 083 1.45 550 2.84 &gt; 1 552 0.0129 0. 355 0. 130 139 553 0.0087 0. 068 0. 23 130 554 0.0073 0. 061 1.31 105 555 0.0114 0. 0141 0. 030 136 556 0. 074 0. 333 557 0.0018 0.0039 0. 020 117 558 0.0360 0. 180 0. 745 86 559 0.0033 0.0039 560 0.0038 0.0073 0. 110 167 561 0.0042 0.0050 0. 015 146 562 0.0036 0.0045 563 0.0052 0.0072 564 0.0052 0.0087 565 0.0149 0. 170 0.86 83 566 0.0106 0. 052 0. 215 81 567 0.0268 0·107 0. 28 82 569 0. 141 10.2 4.42 52 570 0. 113 7. 34 2.54 47 571 0-565 27. 2 572 1. 28 18. 1 573 0.0186 0. 280 1. 73 132 574 0.0096 0. 250 3. 33 89 575 0.0261 0.398 1.86 126 576 0. 043 0. 633 2. 95 101 578 0. 218 1. 12 385 200825054 579 0.0093 0. 095 0. 100 75 580 &gt;1 &gt;1 581 &gt;1 &gt; 1 582 0.0112 0. 138 583 0.0140 0. 121 584 0.0134 0. 361 585 0. 096 1. 20 586 0. 0019 0.0091 0. 38 137 587 0. 0227 0.423 0. 33 109 588 0.0323 0.411 0. 105 125 589 0. 0152 0. 085 0. 235 189 590 0.0067 0. 055 591 0.0023 0.0144 0. 080 113 592 0.0128 0. 167 593 0.0304 0. 604 595 0. 045 0. 201 0. 66 89 596 &gt;1 &gt; 1 597 0. 364 4. 13 根據標準藥理學試驗步驟中所獲得之結果，本發明之 化合物可有用於治療或抑制LXR媒介之疾病。尤其是，本 發明之化合物可有用於治療或抑制動脈粥狀硬化以及粥 5 狀動脈硬化的病灶、降低LDL膽固醇值、增高HDL膽固醇 值、增加逆轉式膽固醇的運輸、抑制膽固醇的吸收、治療 或抑制阿茲罕默氏症、第I型糖尿病、第II型糖尿病、多 發性硬化症、類風濕性關節炎、急性冠心症、血管再狹窄 症、發炎腸道疾病（IBD)、克隆氏症、子宮内膜異位症、 10 乳麋瀉症、以及甲狀腺炎。 一些本發明之實施例已經被描述。然而，需知道可在 不背離本發明之精神與範圍進行各種修改。因此，其它實 施例係於申請專利範圍中。 386 200825054 L圖式簡單說明3 無 【主要元件符號說明】 無 387-GAPDH probe and primer-Takman GAPDH quality tube 10 reagent 402869 or 4310884E 18S ribosomal RNA-Tiekeman 18S quality control reagent 4308329 10 pack Tektronix PCR core reagent group 402930 Quicken (Qiagen) Instant Quantitative probe RT-PCR 204443. 15 IV. Results hLXRb Binding Assay hLXRa Binding Assay - Gene Regulation by LXR Ligand (THP-1 Cell Line) Example 1〇50 UM) ICso UM) EC50 ABCA1 (uM) Percentage of Effect ABCA1 (%) 43 0.0016 0.0061 44 0.0026 0.0227 45 0.0018 0. 0079 46 0.0249 0. 138 371 200825054 47 0. 559 7. 1 48 0.0081 0. 061 49 0. 0130 0. 118 50 0. 105 0.451 51 0. 073 4· 1 52 0.0014 0.0047 53 0.0032 0.0186 54 &gt;1 &gt;1 55 0.0132 0.0409 56 0.0416 0. 153 1. 25 72 57 0.0082 0. 121 58 0.0012 0.0033 59 0-0010 0.0024 60 0.0019 0.0066 61 0.0011 0.0034 62 0.0029 0.0276 63 0.0062 0.0400 64 0.0020 0.0100 65 0.0019 0.0122 66 0.0009 0.0020 67 0.0103 0.0343 68 0.0037 0.0217 69 0.0042 0. 051 70 0.0028 0.0397 0. 53 86 71 0.0017 0.0035 72 0. 0174 0-081 73 0.0302 0. 121 74 0. 144 1. 19 75 &gt;1 &gt ;1 76 0. 108 0.819 77 &gt;1 &gt;1 78 &gt;1 &gt;1 79 &gt;1 &gt;1 80 0.377 1.40 81 &gt;1 &gt;1 82 0. 252 1. 36 84 0.002 8 0.0417 0. 82 103 85 0.0250 0. 252 2. 83 91 372 200825054 86 0.0024 0.0397 87 0. 081 0.419 88 0. 102 0. 705 89 0.0273 0. 189 90 0. 1593 &gt;1 91 0.0078 0. 106 0 61 93 92 &gt;1 &gt;1 94 0.221 1. 19 95 0.0109 0. 060 96 0. 063 0. 603 97 0. 101 0. 788 98 &gt;1 &gt;1 99 0.0115 0.0589 100 &gt;1 &gt; 1 101 0.0277 0. 336 102 0.0017 0.0040 103 0.0017 0.0083 104 0.0017 0.0034 105 0.0092 0. 080 106 0.0020 0.0069 107 0.0030 0.0146 108 0.0028 0.0171 109 &gt;1 &gt; 1 110 0.0041 0. 085 111 0. 198 1. 07 112 0.0050 0. 060 113 0. 046 0. 710 114 0.0106 0. 118 115 0.0025 0.0249 116 0. 255 0. 972 117 0.0022 0-0135 118 0. 099 0. 190 119 0.0149 0. 046 120 0. 650 2. 10 121 0.0020 0.0067 122 1. 08 6.35 123 0. 314 &gt; 1 124 0.0082 0. 056 373 200825054 126 0.0032 0.0297 127 0.0362 0. 124 128 0.0019 0.0045 129 0.0054 0.0120 130 0.0071 0. 048 131 0.0121 0. 074 132 0.0050 0.0285 133 0 .0212 0. 155 134 0. 056 0. 678 135 0. 038 0. 164 136 0. 056 &gt;1 137 0.0165 0. 093 138 0.0154 0. 066 139 0.0131 0. 048 140 0. 049 0. 156 141 0.0269 0. 128 142 0.0019 0.0030 143 0.0024 0.0042 144 0.0022 0.0049 145 0.0049 0.0215 146 0.0022 0.0049 147 0.0039 0.0090 148 0.0018 0.0038 149 0.0036 0.0149 150 0.0045 0.0153 151 0.0051 0.0247 152 0. 263 0. 541 153 0.454 1. 51 154 0. 091 0.346 155 0.0246 0. 114 156 0. 175 0. 617 157 0.551 1.41 158 0.0398 0. 189 159 0.0323 0. 176 160 0. 074 0. 181 161 &gt; 1 &gt; 1 162 0.0016 0.0055 163 0.0035 0.0220 374 200825054 164 0.0081 0 056 165 0.0089 0. 057 166 0. 0179 0. 061 167 0. 0012 0.0044 168 0. 0015 0.0113 169 0. 0039 0.0213 170 0.0073 0. 064 171 0. 0194 0. 092 172 0.0050 0.0298 173 0.0023 0.0134 174 0.0036 0.0178 176 0.0045 0.0139 177 0.0023 0.0113 178 0.0011 0.0040 179 0.0063 0.0298 180 0. 0018 0.0091 181 0.00 09 0.0023 182 0. 0017 0.0049 183 0.0046 0. 035 184 0.0125 0. 146 185 0.0051 0. 048 186 0. 056 0. 383 187 0. 077 0. 389 188 0.0056 0.0233 190 0-0041 0. 049 193 0.0057 0. 035 194 3. 19 12.4 195 &gt; 1 &gt; 1 196 0.0031 0.0217 198 0.0012 0.0045 201 0. 184 1. 07 202 0.0387 0. 263 205 6.23 25. 3 206 0. 094 1. 07 1.80 16 210 0.0261 0. 294 212 0.0108 0. 167 213 0. 322 &gt; 1 214 0.0395 0. 178 375 200825054 215 0.0043 0.0224 216 0.0018 0.0118 217 0.0018 0.0035 221 0.0155 0.0546 222 0.0020 0.0145 223 0.0009 0.0023 226 0.0473 0. 181 229 0.0187 0. 093 232 0. 356 0. 602 233 0.0042 0.0197 234 0.0175 0.0604 235 0. 157 0. 382 236 0. 346 0. 652 237 &gt; 1 &gt;1 238 0. 105 0. 525 239 0. 177 0. 634 240 0.0428 0. 097 241 0.0917 0. 198 242 0. 154 0. 380 243 0.338 0. 532 244 0. 100 0. 565 245 0.0556 0. 251 246 1. 04 1. 63 247 0. 911 2. 05 248 1.86 3. 37 250 0.0373 0. 191 251 0.0024 0.0231 252 0.0040 0.0329 253 0.0041 0.0260 254 0.0026 0.0394 255 0.0072 0. 149 257 0.0009 0.0047 259 0.0905 0. 386 260 0.0030 0.0165 261 0.0117 0. 096 262 &gt;1 &gt;1 263 &gt; 1 &gt;1 264 &gt; 1 &gt;1 376 200825054 265 1. 27 1.40 266 0. 0091 0.0745 267 5. 29 26.6 269 0. 175 &gt; 1 270 0.0045 0.0450 271 0.0545 0. 293 272 0. 165 1. 27 275 0. 082 1. 06 276 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0.0141 287 0. 335 1. 74 288 0. 681 1. 67 290 0.380 1. 01 291 0.0240 0. 228 292 &gt;1 &gt;1 293 0.0073 0. 081 294 0. 083 &gt;1 295 0. 071 &gt; 1 296 0. 187 &gt;1 297 &gt; 1 298 0.0288 0. 615 299 0. 065 0.835 300 0. 0213 0. 159 301 0.0345 0.2024 302 0-0430 0. 158 303 0. 253 &gt; 1 304 &gt; 1 &gt; 1 305 0.0054 0. 050 306 0.0069 0. 068 377 200825054 307 0.0085 0. 131 308 0.0111 0. 09 309 &gt; 1 311 1. 61 6. 66 312 &gt; 1 313 &gt; 1 &gt; 1 314 5. 00 &gt;1 315 0.4127 &gt;1 316 &gt;1 317 0.0052 0. 073 318 0.083 0.401 319 0.0192 0.2510 320 0.0528 0. 208 321 0. 137 0. 331 322 0. 375 &gt; 1 323 0.0767 0. 289 324 0 0 0 0 0 0 0 0 0 0 0 0 0 0.249 1. 70 334 0.0516 0.449 335 0. 094 1. 31 336 0. 138 &gt;1 337 &gt; 1 &gt; 1 ' 338 &gt; 1 &gt;1 339 &gt;1 &gt;1 340 0. 330 0. 989 341 0. 698 3. 53 342 &gt;1 &gt;1 343 &gt;1 &gt;1 344 &gt;1 &gt;1 345 0.0068 0.0527 378 200825054 346 0. 148 0.493 347 0.292 1.26 348 0.808 1. 09 349 0. 239 &gt; 1 350 0.0152 0. 195 351 0. 232 1. 36 352 0.850 &gt;1 353 &gt;1 &gt;1 354 0. 364 &gt;1 355 0.0031 0.0382 0. 065 80 356 0.0405 0.422 357 &gt;1 &gt; 1 359 0.0032 0.0124 360 &gt; 1 362 0. 070 0. 124 363 0.0544 0. 650 364 0.211 0.712 365 1. 76 5. 53 367 0.0077 0. 074 369 &gt;1 372 0.0661 0-574 373 1. 39 3.66 374 0. 739 0.824 375 0. 0113 0. 175 376 0.0275 0. 086 377 0.0207 0. 099 378 0. 190 1. 10 379 0-0287 0. 108 380 0.0474 0.200 381 0.0216 0. 095 382 0.0467 0. 181 383 0. 074 0. 109 384 0.0391 0. 149 385 0.0167 0. 051 386 0. 134 0.419 387 0.0545 0. 130 388 0. 093 0.467 389 &gt;1 &gt; 1 379 200825054 390 0. 379 &gt;1 391 &gt;1 &gt; 1 394 0.0023 0.0046 395 0.0068 0. 098 396 0. 0148 0. 217 397A 0.0258 0. 249 397B 0.0333 0. 199 397C 0.0029 0.0247 0.41 100 397D1 2.86 397D2 0.0031 0.0450 0. 04 90 397E 0.0460 0.321 1. 36 77 397F 0.251 &gt;1 397G 0. 676 &gt; 1 397H 0.0049 0.0246 0. 08 81 3971 0.0128 0. Ill 0.44 73 397J 0. 146 1. 72 397K 15 . 0 &gt; 1 397L 2 92 &gt;1 397M 0.0033 0. 067 0. 61 103 397N 0.0404 0. 280 3970 0. 076 0. 251 397P 0. 097 0. 369 397Q 0.0033 0.0103 397R 0.0063 0. 043 397S 0.0231 0. 745 0. 717 96 397T 0. 061 1. 77 1.89 87 397U 0.0019 0.0144 397V 0.0053 0. 286 397W 13.8 &gt;10 397X 0.0026 0.0131 397Y 0.0424 0. 616 0. 115 71 397Z 0. 056 1. 36 397AA 0.0027 0-0109 397AB 0. 082 0 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 12 397AJ 0.0157 0.542 0.437 107 397AK 0. 738 3. 05 397AL 0.0315 0.463 397AM 0.0108 0.409 0.54 104 397AN 0. 150 2. 93 397A0 0. 108 1. 10 397AP 0. 128 2.31 397AQ 0.0058 0·123 0. 645 100 397AR 0.0314 0. 389 397AS 0.0306 0. 592 397AT 0. 161 1. 13 397AU 0.0051 0. 244 397AV 0.394 3. 54 397AW 1.38 2. 99 397AX 0.451 3. 34 397AY 0. 300 6.85 397AZ 0.0073 0. 215 397AAA 0.0013 0.0085 0.035 103 398A 0.0183 0.456 398B 0.0334 0. 753 3. 58 130 399A 0.0015 0.0095 2.23 78 399B 0.0012 0.0362 399C 0.0029 0. 118 399D 0.0131 0. 093 399E 0. 103 1.34 399F 0. 140 0.848 1. 33 94 401A 0.0011 0.0100 401B 0.0012 0.0197 401C 0.0012 0.0141 0.010 110 401D 0. 089 0. 249 0. 55 64 402 0. 090 0. 500 3. 11 98 403 0. 130 0. 568 404 0. 146 0. 640 405 0. 114 0. 983 406 0. 117 0. 700 381 200825054 407 0.0015 0.0250 0. 113 110 408 0.0009 0.0120 0. 056 115 409 0.0017 0. 057 0. 274 113 410 0.0018 0.0312 0. 202 130 411 0.0387 0. 220 412 0. 109 1.43 413 &gt; 1 &gt;1 414 0. 073 0. 319 415 0.479 &gt;1 416 0.221 5.6120 417 0. 143 6.84 418 0.848 13.7 419 14.2 &gt; 1 420 &gt;1 421 &gt; 1 &gt;1 422 0. 217 2.29 423 &gt; 1 424 &gt;1 425 0.0018 0.0167 0. 043 113 426 0.0034 0.0474 0. 654 100 427 0.0010 0.0133 0. 397 109 428 0.0032 0.0322 0. 25 100 429 0.0047 0. 062 1. 24 100 430 0.0016 0.0207 0. 088 87 431 0.0026 0.0035 432 0.0179 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 83 0. 69 138 441 0. 067 1. 75 442 0.0049 0-0100 443 0-0268 0. 697 1. 84 106 444 0.0172 0. 723 1. 11 117 445 0. 092 1. 06 382 200825054 446 0.0172 0 644 1.38 127 447 &gt; 1 &gt;1 448 0. 195 3. 09 449 0.0712 &gt;1 4.34 100 450 0. 108 &gt;1 5. 75 100 451 &gt;1 &gt;1 452 &gt; 1 &gt;1 453 0.0040 0. 067 1.44 171 456 0.0024 0.0219 1. 00 186 457 0.0034 0.0378 0. 37 162 458 0.0135 0. 155 1. 06 94 459 0.233 4. 76 464 0.0019 0.0102 0. 18 78 465 0.0180 0. 192 1. 19 79 466 0.0548 0. 192 1. 06 105 467 0.484 1.38 468 0.0029 0.0036 469 0.0030 0.0220 0. 345 116 470 0. 078 0. 375 1. 26 106 471 0. 107 0. 765 472 0. 060 1. 73 473 0.475 4. 84 475 1. 00 11.8 476 &gt;1 &gt;1 477 0.223 4. 78 478 0.0273 0.291 0.235 96 479 &gt;1 &gt;1 480 0.0090 0. 192 0. 355 189 481 0. 23 1 &gt; 1 482 &gt; 1 &gt; 1 485 0. 0013 0.0041 486 0.0310 0.324 0.403 107 488 0. 094 1. 06 1. 1 74 489 0.0026 0.0315 0. 14 103 490 0. 0017 0.0102 491 &gt; 1 &gt; 1 492 0. 097 1. 26 493 0. 054 0. 746 383 200825054 494 0. 553 7. 29 495 0.238 3. 12 496 0. 0122 0. 148 0. 29 129 497 0.440 1. 17 498 2. 32 5 64 499 0. 056 0. 334 1. 32 57 500 0. 109 0.435 501 0.457 0. 813 502 0. 134 0.446 503 0.427 1. 02 504 0. 175 1. 07 505 0. 134 0. 535 506 0. 194 0. 887 507 0.0028 0.0159 509 0.0072 0. 115 3. 21 125 510 0.0075 0. 120 511 0.0444 0.493 1. 75 84 512 0-0130 0. 393 2. 03 90 513 0.0112 0. 364 1.43 90 514 0.0656 1. 04 2.47 109 515 0.0275 0.230 3. 35 129 516 0.0285 0. 212 0. 96 92 517 0.0211 0. 311 1.87 97 518 0.0356 0. 192 0. 93 77 519 0. 129 1.42 520 0.0062 0. 074 2. 01 98 521 0. 116 2. 60 522 0. 147 11. 1 1. 17 109 523 0. 054 1. 93 0-695 77 524 0.0282 0. 756 0. 355 125 527 0.0053 0.0272 528 0.0159 0. 101 0.495 99 529 0.0223 0. 561 530 0.242 5. 25 531 0.0284 1.22 3. 75 57 532 0.0363 0.437 533 0. 367 4.44 534 &gt;1 384 200825054 535 0.0198 0. 271 0. 325 80 536 0.0222 0. 277 537 &gt;1 &gt 1 539 5. 71 12. 3 540 0.0015 0.0047 0. 23 238 541 0.0043 0. 046 0. 185 111 542 0.243 4.86 543 0.0133 0. 242 544 0.0009 0.0024 0. 335 102 547 5. 13 29.8 548 10.2 &gt;1 549 0. 083 1.45 550 2.84 &gt; 1 552 0.0129 0. 355 0. 130 139 553 0.0087 0. 068 0. 23 130 554 0.0073 0. 061 1.31 105 555 0.0114 0. 0141 0. 030 136 556 0. 074 0. 333 557 0.0018 0.0039 0. 020 117 558 0.0360 0. 180 0. 745 86 559 0.0033 0.0039 560 0.0038 0.0073 0. 110 167 561 0.0042 0.0050 0. 015 146 562 0.0036 0.0045 563 0.0052 0.0072 564 0.0052 0.0087 565 0.0149 0. 170 0.86 83 566 0.0106 0. 052 0. 215 81 567 0.0268 0·107 0. 28 82 569 0. 141 10.2 4.42 52 570 0. 113 7. 34 2.54 47 571 0-565 27. 2 572 1. 28 18. 1 573 0.0186 0. 280 1. 73 132 574 0.0096 0. 250 3. 33 89 575 0.0 261 0.398 1.86 126 576 0. 043 0. 633 2. 95 101 578 0. 218 1. 12 385 200825054 579 0.0093 0. 095 0. 100 75 580 &gt;1 &gt;1 581 &gt;1 &gt; 1 582 0.0112 0 138 583 0.0140 0. 121 584 0.0134 0. 361 585 0. 096 1. 20 586 0. 0019 0.0091 0. 38 137 587 0. 0227 0.423 0. 33 109 588 0.0323 0.411 0. 105 125 589 0. 0152 0. 085 0. 235 189 590 0.0067 0. 055 591 0.0023 0.0144 0. 080 113 592 0.0128 0. 167 593 0.0304 0. 604 595 0. 045 0. 201 0. 66 89 596 &gt;1 &gt; 1 597 0. 364 4 13 The compound of the present invention may have a disease for treating or inhibiting the LXR vector according to the results obtained in the standard pharmacological test procedure. In particular, the compounds of the present invention may be useful for treating or inhibiting atherosclerosis and atherosclerotic arteriosclerosis, lowering LDL cholesterol, increasing HDL cholesterol, increasing reversal cholesterol transport, inhibiting cholesterol absorption, treating or Inhibition of Azheimer's disease, Type I diabetes, Type II diabetes, Multiple Sclerosis, Rheumatoid Arthritis, Acute Coronary Heart Disease, Vascular Restenosis, Inflammatory Bowel Disease (IBD), Crohn's Disease , endometriosis, 10 celiac disease, and thyroiditis. Some embodiments of the invention have been described. However, it is to be understood that various modifications may be made without departing from the spirit and scope of the invention. Therefore, other embodiments are within the scope of the patent application. 386 200825054 L graphic simple description 3 None [Main component symbol description] None 387

Claims (1)

200825054 十、申請專利範圍： 1. 一種式（I)的化合物: R4 R3200825054 X. Patent application scope: 1. A compound of formula (I): R4 R3 其中： R1係氫、CrCe 烷基、NHz'NIKG-α 烷基）、或 n(c!-c6 烧基）2 ; R2係： (i) 氫、氰基、或鹵基；或 (ii) Ci-Ci2烧基或Ci-Ci2鹵烧基，其之每一可任意 地以1-5 Ra取代；或 (iii) C?-C2。芳院基或含有6-20原子之雜芳烧基， 其之每一可任意地以1-10 Rb取代；或 (iv) C2-Ci2稀基或C2-Ci2炔基，其之每一可任音地 以1-10 Rc取代； (v) C3-Go環烷基、含有3-10原子之雜環基、或含 有3-10原子之雜環浠基，其之每一可任意地以卜5 p 取代；或 (Vi) C6—Cl8芳基或含有5-16原子之雜芳基，其之每 388 200825054 一可任意地以1-10 Rd取代；或 (vii) -XR8，其中： X 係-C(0)- ; ; -S(0)t-，其中 t 係 0-2 ; -NR9-; -C(0)NR9- ; -C(NH)NR9- ; -C(0)0- ; -CH2〇- ; -NR9S〇2-; 或-SChNR9-，其中R9係氫或〇(：6烧基；且 R8係： (i) 氫；或 (ii) Ci-Ci2烷基或Ci-Ci2鹵烷基，其之每一可任意 地以1-5 Ra取代；或 (in) C7-C“芳烷基或含有6-20原子之雜芳烷基， 其之每一可任意地以MO Rb取代；或 (iv) Cr·C”烯基或C2—Cl2炔基，其之每一可任意地 以1-10 Rc取代； (V) Cs-Go環烷基或含有3—10原子之雜環基，其之 母可任思地以1-5 Rb取代；或 —(vi) C6-C18芳基或含有5—16原子之雜芳基，其之 每一可任意地以1 — 1〇 Rd取代； R3係OCu芳基或含有5_14原子之雜芳基，其之 每一可： (i) 任思地以1—2 R1G取代，且 (ii) 任意地以卜4 Re取代；其中· R係WA，其中· 389 200825054 W於各次出現時係獨立地為一鍵；-〇-; _S(0)t- ’其 中 t 係 0-2 ; -NR9- ; -C(0)NR9- ; Ch 伸烷基；或 C2-6 伸 炔基；-WXCi-Ce伸烷基;或-（Ci-Ce伸烷基Μ1-; W1於各次出現時係獨立地為-0_ ; -S(0)t-，其中t 5 係 0-2 ; -NR9- ; -C(0)NR9-;或 C2-6 伸炔基；且 A於各次出現時係獨立地為： (i) C6-C1Q 芳基，其： (a) 係以1-2 Rf取代；且 (b) 可任意地以1-4 Re取代； 10 或 (ii) 含有5-10原子之雜芳基，其： (a) 係以1-2 Rf取代或含有一經取代的環原 子，該原子係選自S(0)和S〇2所組成之群；且 (b) 可任意地以1-4 Re取代； 15 前提是該含有5-10原子之雜芳基並非[1，2,4]_噁 二峻基； 或 (iii) 含有 8-12原子之芳基氮環基 (arylazacyclyl)，其： 20 (a)係以1-2 Rf取代，且 (b)任意地以1_4 Re取代； 或 (iv) 芳基亞磺醯基環基、雜芳基亞磺醯基環基、芳 基磺醯基環基或雜芳基磺醯基環基，其之每一包含8-10 390 200825054 原子且可任意地以1—4 Re取代； 或 (V) [1，2, 4]-噁二哇基，可任意地以1 Re取代； R4、R5、R6、和R7之每一者係獨立地為： (i) 氫；或 (ii) Rc ;或 (iii) Ci-C2〇烧基或Ci-C2〇鹵烧基，其之每一可任 意地以1-1〇 Ra取代；或 (iv) G-Cm烯基或C2-C2〇炔基，其之每一可任意地 以mo r取代；或 一 (V) C7-C2〇芳烷基或雜芳烷基，其之每一可任意地 以1-10 Rb取代； “ Ra於各次出現時係獨立地為： (1) NRgRh;硝基；疊氮基；羥基；侧氧基；硫酮基； 4R1 ; Cl-C2。烷氧基或ο—。。鹵基烷氧基，其之每一係 任意地以1-10 取代；含有5_16原子之Ce—Ci8芳氧 基或雜芳氧基，其之每一係任意地以1-10 Rd取代； C?—C2°芳貌氧基、含有6—2〇原子之雜芳烧氧基、C3-Cl6環 烷氧基、G-Gg環烯氧基、含有3—2〇原子之雜環氧基、 或含有3-2G原子之雜環稀基，其之每—係任意地以 卜10 Rb取代，·氫硫基’1“硫基烧氧基；Cl—C2Q硫基 齒基炫氧基；含有5—16原子之^硫基芳氧基或硫 391 200825054 基雜芳氧基’其之每一係任意地以1-10 Rd取代；C7-C2〇 硫基芳烷氧基、含有6-20原子之硫基雜芳烷氧基、C3-C16 硫基環烷氧基、C3-C2〇硫基環烯氧基、含有3-20原子之 硫基雜環氧基、或含有3-20原子之硫基雜環烯氧基， 其之每一係任意地以1-1〇 Rb取代；氰基；_C(〇)Rj ; -C(0)〇Rj ; -0C(0)Rj ； -C(0)SRj ； -SC(0)RJ ; -C(S)SRj ； -SC(S)Rj ; -C(0)NRgRh ; -NRkC(0)Rj ; -CXNIORJ ; -〇C(0)NRgRh ; -NRkC(〇)NRgRh ; -NRkC(0)0Rj ; -S(0)nRra， 10 其中 n 係 1 或 2 ; -NRkS⑼JT ;或-P(〇)(〇Rg)(〇Rh); 或 (ii) C3-C2〇環烷基、c3-C2〇環烯基、含有3—20原 子之雜環基、含有3-20原子之雜環烯基、含有8-20原 子之芳基雜環基、或含有8-20原子之雜芳基雜環基， 其之每一係任意地以1-1〇 Rb取代； 15 Ra於各次出現時係獨立地為NRgRh;硝基；疊氮基； 羥基；側氧基；氰基；—C(0)R。__c(〇)〇Rj ; —〇c(〇)Rj; 20 -C(〇)SR] ; -SCWRj ; -C(S)SRj ; —SC⑻Rj ; —C⑼NRgRh ; NR C(0)R , C(NR )RJ ； -〇C(〇)NRgRh ; -NRkC(0)NRgRh ； -NRkC(0)0R】;-S(0)nr ’ 其中 n 係 i 或 2 ; _NRks⑻nR„ ; -_w)w);C3_C2〇環烧基；c3_c2。環稀基；含有 3_20原子之雜環基；或含有&quot;原子之雜環烯基； R於各次出現時係獨立地為： 392 200825054 1 i基，NRgR ;硝基；疊氮基；羥基；側氧基； ”，基，=NR，（VC2〇烷氧基或Ci—C2Q鹵基烷氧基，其 之每-係任意地以取代；C6—。芳氧基或含有 原子之雜芳氧基，其之每—係任意地以卜1〇 Rd取 方烷氧基、含有6 —2〇原子之雜芳烷氧基、k «氧基、c3-c2。環埽氧基、含有3_2〇原子之雜環氧 基、或含有3-2G原子之雜環烯氧基，其之每一係任意 地以HO Rb取代；氫硫基；Ci—a。硫基烧氧基；“ 〇 硫基_基烷氧基；含有5-16原子之C6—Cl8硫基芳氧基 或石，IL基雜芳氧基，其之每一係任意地以^0 Rd取代； C7-C2〇硫基芳烷氧基、含有6-2〇原子之硫基雜芳烷氧 基、C3-Cl6硫基環烷氧基、C3~C2〇硫基環烯氧基、含有 3-20原子之硫基雜環氧基、或含有3—2〇原子之硫基雜 環烯氧基，其之每一係任意地以1 — 1〇 ρ取代；氰基； 5 -C(0)RJ ； -C(0)0RJ ； -0C(0)Rj ; -C(0)SRJ ； -SC(0)Rj ; -C(S)SRj; -SC(S)Rj; -C(0)NRgRh; -NRkC(0)Rj; -CCNIORJ; -0C(0)NRgRh ; -NRkC(0)NRgRh ; -NRkC(0)0Rj ; -S(0)nRm， 其中 n係 1 或 2; -NRkS(0)nRm;或-p(〇)(〇Rg)(〇Rh);或 者 0 (ii) Cl-C20炫基或Cl-C20齒烧基，其之每一係任意 地以1-10 Ra取代；或 (iii) G-Go稀基或C2-C2。块基，其之每一係任意 地以1-10 Re取代；或 (iv) Ce-C!8芳基或含有5-16原子之雜芳基，其之 393 200825054 每一係任意地以1—10 Rd取代；或 (V) C3-C2« 魏基、C3_C2。環縣、含有 3—2〇 之雜環基、或含有3-2〇原子之雜環縣，其之每 任意地以1-10 Rb’取代； ” 5 10 “各次出現時係獨立地；鹵基；G_C2()境氧 基或㈣。i纽氧基，其之每—係任意地以 械|C6-G18芳氧基或含有5_16原子之㈣氧基，其之 每一係任意地以卜10 Rd取代；Ci_c2。院基或Ci C2。南 烷基其之每一係任意地以卜1〇『取代；C2_C2e烯義. 炔基；或Ce_Ci8芳基或含有516原子之雜芳^，’ 其之每一係任意地以1-10 Rd取代； RC於各次出現時係獨立地為： ⑴自基；NRgRh ;確基；疊氮基；;側氧基； 瓜_基，=NR，Cl—G。烷氧基或Ci—c^基烷氧基，其 之每-係任意地以卜lor取代；G6—u芳氧基或含^ 6原子之雜芳氧基，其之每一係任意地以HQ ”取 代’Cr“芳烷氧基、含有6—2〇原子之雜芳烷氧基^ &amp;烷氧基、Cs-Go環烯氧基、含有3—2〇原子之雜環氧 基' 或含有3-20原子之雜環烯氧基，其之每一係任意 地以1-10 Rb取代；氫硫基；Cl—匕。硫基烷氧基；c 一匕。 &amp;基i基烷氧基；含有5_16原子之Ce—C 8硫基芳氧基 或敬基雜芳氧基，其之每一係任意地以1-10 Rd取代； 394 200825054 C7-G〇硫基芳烷氧基、含有6-20原子之硫基雜芳烷氧 基、Cs-Cie硫基環烧氧基、C3-C2〇硫基環稀氧基、含有 3-20原子之硫基雜環氧基、或含有3-20原子之硫基雜 環烯氧基，其之每一係任意地以1-1〇 Rb取代，·氰基，· -C(0)RJ ； -C(0)0RJ ； -0C(0)Rj ; -C(0)SRJ ； -SC(0)Rj ; -C(S)SRJ ； -SC(S)RJ ； -C(0)NRgRh; -NRkC(0)Rj ； -C(NRi)Rj ; -0C(0)NRgRh ; -NRkC(0)NRgRh ; -NRkC(0)0Rj ; -S(0)nRm， 其中 n 係 1 或 2 ; -NRkS(0)nRm;或—p(〇)(〇Rg)(〇Rh);或 (ii) C3-C2。環烧基、c3-C2〇環烯基、含有3_2〇原 子之雜環基、或含有3-20原子之雜環烯基，其之每一 係任意地以1 -1 〇 Rb取代；或 (iii) α-Cu芳基或含有5—16原子之雜芳基，其之 每一係任意地以1 — 10 Rd取代； 15Wherein: R1 is hydrogen, CrCe alkyl, NHz 'NIKG-α alkyl), or n(c!-c6 alkyl) 2; R2 is: (i) hydrogen, cyano, or halo; or (ii) Ci-Ci2 alkyl or Ci-Ci2 halogenated groups, each of which may be optionally substituted with 1-5 Ra; or (iii) C?-C2. a aryl group or a heteroaryl group containing 6-20 atoms, each of which may be optionally substituted with 1-10 Rb; or (iv) a C2-Ci2 dilute group or a C2-Ci2 alkynyl group, each of which may be Anyally substituted with 1-10 Rc; (v) a C3-Go cycloalkyl group, a heterocyclic group having 3 to 10 atoms, or a heterocyclic fluorenyl group having 3 to 10 atoms, each of which may optionally be a 5P-substituted; or a (Vi) C6-Cl8 aryl group or a heteroaryl group having 5-16 atoms, each of which may be optionally substituted with 1-10 Rd per 388 200825054; or (vii) -XR8, wherein: X-C(0)-; ; -S(0)t-, where t is 0-2; -NR9-; -C(0)NR9- ; -C(NH)NR9- ; -C(0) 0-; -CH2〇-; -NR9S〇2-; or -SChNR9-, wherein R9 is hydrogen or deuterium (:6 alkyl; and R8 is: (i) hydrogen; or (ii) Ci-Ci2 alkyl or a Ci-Ci2 haloalkyl group, each of which may be optionally substituted with 1-5 Ra; or (in) a C7-C "aralkyl group or a heteroarylalkyl group having 6 to 20 atoms, each of which may be optionally Substituted with MO Rb; or (iv) Cr·C” alkenyl or C2-Cl 2 alkynyl, each of which may be optionally substituted with 1-10 Rc; (V) Cs-Go cycloalkyl or containing 3- a hetero atom of 10 atoms, the mother of which can be thought of 1-5 Rb substituted; or —(vi) a C6-C18 aryl group or a heteroaryl group having 5-16 atoms, each of which may be optionally substituted with 1-1 〇Rd; R3 is an OCu aryl group or contains 5-14 Each of the heteroaryl groups of the atom may be: (i) replaced by 1-2 R1G, and (ii) arbitrarily substituted with b 4 Re; wherein · R is WA, wherein · 389 200825054 W The second occurrence is independently a bond; -〇-; _S(0)t- 'where t is 0-2; -NR9- ; -C(0)NR9- ; Ch alkyl; or C2-6 Alkynyl; -WXCi-Ce alkyl; or -(Ci-Ce alkyl Μ1-; W1 is independently -0_; -S(0)t-, where t 5 is 0- 2; -NR9-; -C(0)NR9-; or C2-6 an alkynyl group; and A in each occurrence is independently: (i) C6-C1Q aryl, which: (a) 1-2 Rf substituted; and (b) optionally substituted with 1-4 Re; 10 or (ii) a heteroaryl group having 5-10 atoms, which: (a) is substituted with 1-2 Rf or contains one a substituted ring atom selected from the group consisting of S(0) and S〇2; and (b) optionally substituted with 1-4 Re; 15 provided that the heteroaryl group contains 5-10 atoms Not [1, 2,4]- oxadicarbyl; or (iii) an aryllazacyclyl group having 8-12 atoms, wherein: 20 (a) is substituted with 1-2 Rf, and (b) is optionally 1_4 Re substituted; or (iv) an arylsulfinyl ring group, a heteroaryl sulfinyl ring group, an arylsulfonyl ring group or a heteroarylsulfonyl ring group, each of which contains 8 -10 390 200825054 Atoms and optionally substituted with 1-4 Re; or (V) [1,2,4]-oxadiazolyl, optionally substituted with 1 Re; R4, R5, R6, and R7 Each is independently: (i) hydrogen; or (ii) Rc; or (iii) Ci-C2 calcined or Ci-C2 hydrazine, each of which may optionally be 1-1. Ra substituted; or (iv) G-Cm alkenyl or C2-C2 decynyl, each of which may be optionally substituted with mo; or a (V) C7-C2 aralkyl or heteroarylalkyl group, Each of them may be optionally substituted with 1-10 Rb; "Ra is independently present in each occurrence: (1) NRgRh; nitro; azide; hydroxy; pendant oxy; thioketo; 4R1; Cl-C2. Alkoxy or ο-. . a haloalkoxy group, each of which is optionally substituted by 1-10; a Ce-Ci8 aryloxy or heteroaryloxy group having 5 to 16 atoms, each of which is optionally substituted with 1-10 Rd; - C2 ° aromatic oxygen, heteroaryl alkoxy containing 6-2 atom, C3-Cl6 cycloalkoxy, G-Gg cycloalkenyloxy, heterocyclic oxy group containing 2-3 atom, Or a heterocyclic ring containing 3-2G atoms, each of which is optionally substituted with 10 Rb, a thiol group '1' thioalkyl alkoxy group; a C1-C2Q thioheptyl methoxy group; 5-16 atomic thioaryloxy or sulfur 391 200825054 Heteroaryloxy' each of which is optionally substituted with 1-10 Rd; C7-C2 thiol aralkyloxy, containing 6-20 Atomic thioheteroaralkyloxy, C3-C16 thiocycloalkoxy, C3-C2 decylthiocycloalkenyloxy, thioheterocyclooxy containing 3-20 atoms, or containing 3-20 atoms a thioheterocyclenyloxy group, each of which is optionally substituted with 1-1〇Rb; cyano; _C(〇)Rj; -C(0)〇Rj; -0C(0)Rj; -C (0)SRj ; -SC(0)RJ ; -C(S)SRj ; -SC(S)Rj ; -C(0)NRgRh ; -NRkC(0)Rj ; -CXNIORJ ; -〇C(0)NRgRh ; -NRkC(〇)N RgRh ; -NRkC(0)0Rj ; -S(0)nRra, 10 where n is 1 or 2; -NRkS(9)JT; or -P(〇)(〇Rg)(〇Rh); or (ii) C3-C2〇 a cycloalkyl group, a c3-C2 anthracenyl group, a heterocyclic group having 3 to 20 atoms, a heterocycloalkenyl group having 3 to 20 atoms, an arylheterocyclic group having 8 to 20 atoms, or 8-20 a heteroarylheterocyclyl group of an atom, each of which is optionally substituted with 1-1〇Rb; 15 Ra is independently NRgRh in each occurrence; a nitro group; an azide group; a hydroxyl group; a pendant oxy group; Cyano; -C(0)R.__c(〇)〇Rj ; —〇c(〇)Rj; 20 -C(〇)SR] ; -SCWRj ; -C(S)SRj ; —SC(8)Rj ; —C(9)NRgRh ; NR C(0)R , C(NR )RJ ; -〇C(〇)NRgRh ; -NRkC(0)NRgRh ; -NRkC(0)0R]; -S(0)nr ' where n is i or 2; _NRks(8)nR„ ; -_w)w); C3_C2〇 〇 烧; c3_c2. a heterocyclic group; a heterocyclic group having 3 to 20 atoms; or a heterocycloalkenyl group containing an atom; R is independently present in each occurrence: 392 200825054 1 i group, NRgR; nitro group; azide group; ; pendant oxy; ", aryl, NR, (VC2 decyloxy or Ci-C2Q haloalkoxy, each of which is optionally substituted; C6-. aryloxy or heteroaryl containing atom An oxy group, each of which is optionally a ruthenium alkoxy group, a heteroaralkyloxy group having 6 to 2 atomic atoms, a k-oxy group, a c3-c2 group, a cyclodecyloxy group, and a 3_2 a heterocyclic oxy group of a halogen atom, or a heterocyclic alkenyloxy group having 3 to 2 G atoms, each of which is optionally substituted with HO Rb; a thiol group; a Ci-a. a thiol alkoxy group; a cyclyloxy group; a C6-Cl8 thioaryloxy group having 5-16 atoms or a stone, an IL-heteroaryloxy group, each of which is optionally substituted with ^0 Rd; C7-C2 thiol group Aralkyloxy, thioheteroaryloxy group having 6-2 fluorene atom, C3-Cl6 thiocycloalkoxy group, C3~C2 sulfonylcycloalkenyloxy group, sulfur group containing 3-20 atom Epoxy group or thioheterocyclic ring containing 2-3 fluorene atoms An oxy group, each of which is optionally substituted with 1 - 1 〇 ρ; cyano; 5 - C(0)RJ; -C(0)0RJ; -0C(0)Rj; -C(0)SRJ; -SC(0)Rj ; -C(S)SRj; -SC(S)Rj; -C(0)NRgRh; -NRkC(0)Rj; -CCNIORJ; -0C(0)NRgRh ; -NRkC(0) NRgRh ; -NRkC(0)0Rj ; -S(0)nRm, where n is 1 or 2; -NRkS(0)nRm; or -p(〇)(〇Rg)(〇Rh); or 0 (ii) a Cl-C20 leukoyl group or a Cl-C20 dentate group, each of which is optionally substituted with 1-10 Ra; or (iii) a G-Go dilute group or a C2-C2 group, each of which is optional Substituted with 1-10 Re; or (iv) Ce-C!8 aryl or heteroaryl containing 5-16 atoms, 393 200825054 each of which is optionally substituted with 1-10 Rd; or (V) C3-C2« Weiji, C3_C2. Ring County, heterocyclic group containing 2-3 fluorene, or heterocyclic county containing 3-2 〇 atoms, each of which is optionally substituted with 1-10 Rb'; ” 5 10 "Even occurrences are independently; halo; G_C2() oxo or (d). i neooxy, each of which is optionally a mechanical |C6-G18 aryloxy group or a (4) oxy group containing 5-16 atoms Each of them is arbitrarily replaced by Bu 10 Rd; Ci_c2. Dean or Ci C2. Each of the south alkyl groups is optionally substituted with a "C2_C2e alkenyl group; or a Ce_Ci8 aryl group or a hetero atom containing 516 atoms", each of which is optionally 1-10 Rd Substituting; RC is independently in each occurrence: (1) self-based; NRgRh; exact; azide; side oxygen; melon-based, =NR, Cl-G. Alkoxy or Ci-cylalkoxy, each of which is optionally substituted with lor; G6-u aryloxy or heteroaryloxy containing 6 atom, each of which is optionally HQ" replaces 'Cr" aralkyloxy, heteroaralkyloxy group having 6-2 atomic atom, &amp; alkoxy group, Cs-Go cycloalkenyloxy group, heterocyclic oxy group containing 2-3 atom Or a heterocyclic alkenyloxy group having 3 to 20 atoms, each of which is optionally substituted with 1-10 Rb; a thiol group; Thioalkoxy; c a hydrazine. &amp;yl i-alkoxy; C-C8 thioaryloxy or cyclyl heteroaryloxy having 5-16 atoms, each of which is optionally substituted with 1-10 Rd; 394 200825054 C7-G〇 Thioarylalkoxy, thioheteroaryloxy group having 6 to 20 atoms, Cs-Cie thiocycloalkoxy group, C3-C2 sulfonylcyclopentyloxy group, sulfur group having 3 to 20 atoms a heterocyclic oxy group or a thioheterocycloalkenyloxy group having 3 to 20 atoms, each of which is optionally substituted with 1-1 〇Rb, cyano, · -C(0)RJ; -C( 0) 0RJ ; -0C(0)Rj ; -C(0)SRJ ; -SC(0)Rj ; -C(S)SRJ ; -SC(S)RJ ; -C(0)NRgRh; -NRkC(0 Rj ; -C(NRi)Rj ; -0C(0)NRgRh ; -NRkC(0)NRgRh ; -NRkC(0)0Rj ; -S(0)nRm, where n is 1 or 2; -NRkS(0) nRm; or -p(〇)(〇Rg)(〇Rh); or (ii) C3-C2. a cycloalkyl group, a c3-C2 anthracenyl group, a heterocyclic group having a 3 2 fluorene atom, or a heterocyclic alkenyl group having 3 to 20 atoms, each of which is optionally substituted with 1 -1 〇Rb; or Iii) an α-Cu aryl group or a heteroaryl group having 5 to 16 atoms, each of which is optionally substituted with 1 - 10 Rd; 20 R於各次出現時係獨立地為： 产⑴函基；NIW;石肖基；疊氮基；經基；Ci C2〇烷 氧基或ο-〇。_基烷氧基，其之每一係任意地以i i〇Ra 取，；c6-c18芳氧基或含有5_16原子之雜芳氧基其 之每一係任意地以卜1G Rd取代；㈣。芳絲基、含 有6—20原子之雜純氧基、㈤6環院氧基、C3-C2。環 稀氧基、含有3-20原子之雜環氧基、或含有3 2〇原子 ^雜％烯減’其之每—係任意地以卜㈣b.取代；氮 Cl C2。^基烷氧基；Ci_C2。硫基鹵基烷氧基；含 有5 16原子之Ge_Gi8硫基芳氧基或硫基雜芳氧基，其 395 200825054 之每一係任意地以1-10 Rd取代；Ct_C2°硫基芳烷氧基、 含有6-20原子之硫基雜芳院氧基、C3—Cl6硫基環烷氧 基、C3-C2〇硫基環烯氧基、含有3-2〇原子之硫基雜環氧 基、或含有3-20原子之硫基雜環烯氧基，其之每一係 任意地以1-10 Rb取代；氰基；_C(0)Rj ;—以⑴; -〇C(〇)Rj ; —c(〇)SRj ; -SC(0)Rj ; -C(S)SRj ;〜sc(S)Rj ; ^C(〇)NRgRh ; -NRkC(0)RJ ； -C(NR1)RJ ； -〇C(〇)NR8Rh ; 一NRkC(0)NRgRh; -NRkC(0)0Rj; -S(0)nR' 其中 n 係丨或 2 ; 一NRkS(0)nRm ;或-P(0)(0Rg)(0Rh); (ii) Ci-C2〇烧基或Ci-C2。鹵烧基，其之每一係任音 地以1-10 Ra取代；或 (iii) C2-C2。烯基或C2-C2。炔基，其之每一係任意 地以1-10 R。取代；或 (iv) OGo芳烷基、含有6—20原子之雜芳烷基、 C3-C2。環烷基、C3_C2。環烯基、含有3_20原子之雜環基、 或含有3-20原子之雜環魅，其之每—係任意地土以 1-10 Rb取代；或 (v) C6-C18芳基或含有5_16原子之雜芳基，其之每 係任思地以1 -10 取代； 、分认rq現呀係獨立地為囹丞；硝j 疊氮基；祕^-“燒基：以㈣基；c^ 基’ C2-C2°炔基；以。環烧基;㈣。環烯基卜 3-2〇原子之雜環基；含有㈣原子之雜環稀基^ 396 200825054 芳烷基；含有6-20原子之雜芳烷基；Ci—C2q烷氧基；Ci C2〇 鹵基烷氧基；a-Cu芳氧基；雜芳氧基；C7_C2()芳烷氧 基；含有6-20原子之雜芳烷氧基；C3-Ci6環烷氧基；C3-C2〇 壤烯氧基；含有3-20原子之雜環氧基；含有3_2〇原子 5 之雜環烯氧基；氫硫基；C2〇硫基烷氧基；匕-C20硫 基函基烧乳基’ C6-Cm硫基芳氧基；含有5-16原子之硫 基雜芳氧基；C7-C2〇硫基芳烷氧基；含有6-20原子之硫 基雜芳烷氧基；G-G6硫基環烷氧基；c3-C2〇硫基環烯 氧基、含有3-20原子之硫基雜環氧、或含有3-20原子 10 之硫基雜環烯氧基；氰基；-C(0)K ; -C(0)0Rj; -0C(0)Rj; -C(0)SRj ; -SC(0)Rj ; -C(S)SRj ; -SC(S)Rj ; -C(0)NRgRh ; -NRkC(0)RJ ； -C(NRi)Rj ； -0C(0)NRgRh ； -NRkC(0)NRgRh ; -NRkC(0)0Rj ; -S(0)nRm，其中 n 係 1 或 2 ; -NRkS(0)nRm ; 或-P(0)(0Rg)(0Rh); 15 Re於各次出現時係獨立地為Ci-C6烷基，可任意地 以1-3 Ra取代；Ci~~C6鹵烧基；苯基；4-氟苯基；鹵基； 罗里基；NRgRh ;石肖基；C2-C6稀基；C2-C6快基；Ci-C6燒 氧基；Ci-C6鹵基烧氧基；氰基；或-C(0)Rj ; 20 Rf於各次出現時係獨立地為： (i) -S(0)nRn、-（CH2)HS(0)nRn、-NRkS(0)nRn、或 -〇S(0)nRn、其中n於各次出現時係獨立地為1或2 ;或 (ii) -NRkC(0)NRgRh、-NRkC(0)0Rj、-0C(0)NRgRh、或 397 200825054 -0C(0)0R。或 (iii) 含有5-10原子之雜環基，可以1-2側氧基 取代或任意地以1-3 Re取代；或 (iv) 含有5-10原子之雜環烯基或1H-苯并咪唑， 5 其之每一係任意地以1-3 Re取代；或 (v) -YRf，其中Y於各次出現時係獨立地為Ci-Ce伸 烷基、-0-、或-NR9-; Rf’於各次出現時係獨立地為： 10 (i)含有5-10原子之雜環基，可以1-2側氧基取 代且可任意地以1-3 Re取代；或 (ii)含有5-10原子之雜環烯基或1H-苯并咪唑， 其之每一係任意地以1-3 Re取代； 15 Rg、Rh、R1、和Rk之每一，在每一可能情況下係獨立 地為： (i)氫；或 (i i ) Cl_C20烧基或Cl-C20 _基烧基，其之每'^系任 意地以1-10 Ra取代；或 20 (i i i) C2-C2〇稀基或C2-C2G快基，其之每一係任意地 以1-10 Re取代；或 (iv) C3-C2。環烧基、C3-C2。環稀基、含有3-20原 子之雜環基、含有3-20原子之雜環烯基、C7-C2〇芳烷基、 或含有6-20原子之雜芳烷基，其之每一係任意地以 398 200825054 1-10 Rb取代；或 (V) C6—Cl8芳基或含有5-16原子之雜芳基，其之每 一係任意地以1〜10 Rd取代；或 520 R is independently present in each occurrence: (1) functional group; NIW; schlossyl; azide; meridine; Ci C2 decyloxy or ο-〇. Or alkoxy groups, each of which is optionally taken as i i 〇 Ra; a c6-c18 aryloxy group or a heteroaryloxy group having 5 to 16 atoms each of which is optionally substituted with 1G Rd; (d). An aromatic group, a hetero-oxy group containing 6-20 atoms, (5) a 6-ring alkoxy group, C3-C2. Each of the cyclooxyloxy group, the heterocyclic oxy group having 3 to 20 atoms, or the atomic olefin having 3 2 Å atoms is arbitrarily substituted with b (d) b.; nitrogen Cl C2. ^-alkoxy; Ci_C2. Thiohaloalkoxy; a Ge_Gi8 thioaryloxy or thioheteroaryloxy group having 5 16 atoms, each of 395 200825054 optionally substituted with 1-10 Rd; Ct_C2° thioarylalkoxy a thio-heteroaryloxy group having 6-20 atoms, a C3-Cl6 thiocycloalkoxy group, a C3-C2 sulfonylcycloalkenyloxy group, a thioheterocyclooxy group having a 3-2 fluorene atom Or a thioheterocyclenyloxy group having 3 to 20 atoms, each of which is optionally substituted with 1-10 Rb; cyano; _C(0)Rj; - (1); - 〇C(〇)Rj ; -c(〇)SRj ; -SC(0)Rj ; -C(S)SRj ;~sc(S)Rj ; ^C(〇)NRgRh ; -NRkC(0)RJ ; -C(NR1)RJ ; - 〇C(〇)NR8Rh ; an NRkC(0)NRgRh; -NRkC(0)0Rj; -S(0)nR' where n is 丨 or 2; an NRkS(0)nRm ; or -P(0)( 0Rg) (0Rh); (ii) Ci-C2 calcined or Ci-C2. A halogen group, each of which is substituted with 1-10 Ra; or (iii) C2-C2. Alkenyl or C2-C2. Alkynyl groups, each of which is optionally 1-10 R. Substituted; or (iv) OGo aralkyl, heteroarylalkyl group having 6-20 atoms, C3-C2. Cycloalkyl, C3_C2. a cycloalkenyl group, a heterocyclic group having 3 to 20 atoms, or a heterocyclic ring containing 3 to 20 atoms, each of which is substituted with 1-10 Rb; or (v) a C6-C18 aryl group or containing 5-16 The heteroaryl group of the atom, each of which is replaced by 1 -10; the recognition of rq is independent of 囹丞; the nitrate j azide; the secret ^-"burning base: (4) base; ^基' C2-C2° alkynyl; Cycloalkyl; (d): a heterocyclic group of a cycloalkenyl 3-2 fluorene atom; a heterocyclic group containing a (iv) atom; 396 200825054 aralkyl; 20 atom heteroarylalkyl; Ci-C2q alkoxy; Ci C2 〇 haloalkoxy; a-Cu aryloxy; heteroaryloxy; C7_C2() aralkyloxy; 6-20 atom a heteroaralkyloxy group; a C3-Ci6 cycloalkoxy group; a C3-C2 decyloxy group; a heterocyclic oxy group having 3 to 20 atoms; a heterocyclic oxy group having a 3 〇 atom: 5; a thiol group; C2 thiol alkoxy; 匕-C20 thiol succinyl-C6-Cm thioaryloxy; thio-heteroaryloxy group containing 5-16 atoms; C7-C2 thiol arylalkoxide a thioheteroaryloxy group having 6 to 20 atoms; a G-G6 thiocycloalkoxy group; a c3-C2 thiol group Alkenyloxy, thio-heteroepoxy having 3-20 atoms, or thioheterocycloalkenyloxy having 3-20 atoms; cyano; -C(0)K; -C(0)0Rj; 0C(0)Rj; -C(0)SRj ; -SC(0)Rj ; -C(S)SRj ; -SC(S)Rj ; -C(0)NRgRh ; -NRkC(0)RJ ; -C (NRi)Rj ; -0C(0)NRgRh ; -NRkC(0)NRgRh ; -NRkC(0)0Rj ; -S(0)nRm, where n is 1 or 2; -NRkS(0)nRm ; or -P (0) (0Rg) (0Rh); 15 Re is independently Ci-C6 alkyl at each occurrence, optionally substituted with 1-3 Ra; Ci~~C6 halogenated group; phenyl; 4- Fluorophenyl; halo; Rorykyl; NRgRh; schlossyl; C2-C6 dilute; C2-C6 fast radical; Ci-C6 alkoxy; Ci-C6 halo alkoxy; cyano; or -C ( 0) Rj ; 20 Rf is independently of each occurrence: (i) -S(0)nRn, -(CH2)HS(0)nRn, -NRkS(0)nRn, or -〇S(0) nRn, wherein n is independently 1 or 2 in each occurrence; or (ii) -NRkC(0)NRgRh, -NRkC(0)0Rj, -0C(0)NRgRh, or 397 200825054 -0C(0) 0R. Or (iii) a heterocyclic group having 5 to 10 atoms, which may be substituted with a 1-2 oxy group or optionally substituted with 1-3 Re; or (iv) a heterocycloalkenyl group having 5 to 10 atoms or 1H-benzene And imidazole, 5 each of which is optionally substituted with 1-3 Re; or (v) -YRf, wherein Y is independently Ci-Ce alkyl,-0-, or -NR9 in each occurrence - Rf' is, at each occurrence, independently: 10 (i) a heterocyclic group containing 5-10 atoms, which may be substituted with 1-2 side oxy groups and optionally substituted with 1-3 Re; or (ii a heterocycloalkenyl group having 5-10 atoms or 1H-benzimidazole, each of which is optionally substituted with 1-3 Re; each of 15 Rg, Rh, R1, and Rk, in every possible case The lower system is independently: (i) hydrogen; or (ii) Cl_C20 alkyl or Cl-C20-based alkyl, each of which is optionally substituted with 1-10 Ra; or 20 (iii) C2-C2 A sulfhydryl group or a C2-C2G fast group, each of which is optionally substituted with 1-10 Re; or (iv) C3-C2. Cyclic base, C3-C2. a cycloaliphatic group, a heterocyclic group having 3 to 20 atoms, a heterocycloalkenyl group having 3 to 20 atoms, a C7-C2 aralkylene group, or a heteroarylalkyl group having 6 to 20 atoms, each of which is a system Optionally substituted with 398 200825054 1-10 Rb; or (V) C6-Cl8 aryl or heteroaryl containing 5-16 atoms, each of which is optionally substituted with 1~10 Rd; or 5 10 15 20 (Vi) —0Rj ;〜C(〇)矿；一c(0)0Rj ; -C(0)NRgRh ;或 -S(0)nRm ; R於各次出現時係獨立地為： (i)氫；或 ()Cl C2D燒基或_基烧基，其之每一係任 意地以1-10 Ra取代；或 (iii) C2 C2。締基或ο—心炔基，其之每一係任意地 以1-10 R。取代；或 展院基、G-C2。環烯基、含有3—2〇 子之雜％基、含有3,原子之雜環·心^芳烧基、 或含有W原子之雜芳院基，其之每—係 1 -10 Rb取代；或 (v) C6-U芳基或含有516原子之 4任意地以卜1〇R、代;或 方…、之母 r於各次出現時係獨立地為R]、QR)、或職“ R於各次出現時係獨立地為Ri或峨h. 類 或其之一 N-氧化物和/或其之—醫藥上可接受的鹽 項之化合物，其中： ’其： 2·如申請專利範圍第1 R3係C6-Cl4芳基 取代，並 ⑴以1-2 R1 399 200825054 (ii)任意地以1-4 Re取代；而且 A於各次出現時係獨立地為C6-Ci〇芳基，其： (a) 以1-2 Rf取代；並 5 (b)任意地以1-4 Re取代；而且 Rf於各次出現時係獨立地為： (i) -S(0)nRn、-(CH2)HS(0)nRn、-NRkS(0)nRn、或 -0S(0)nRn，其中n於各次出現時係獨立地為1或2 ;或 10 者 (ii) -NRkC(0)NRgRh、-NRkC(0)0Rj、-0C(0)NRgRh、 或-0C(0)0Rj。 3.如申請專利範圍第1項之化合物，其中： 15 R3係含有5-14原子之雜芳基，其·. (i) 以1-2 R1G取代，並 (ii) 任意地以1-4 Re取代；而且 A於各次出現時係獨立地為Ce-Ci。芳基，其： 20 (a)以1-2 Rf取代；並 (b) 任意地以1-4 Re取代；而且 Rf於各次出現時係獨立地為： (i) -S(0)nRn、-(CHOhSCOXR11、-NRkS(0)nRn、或 400 200825054 -0S(0)nRn，其中η於各次出現時係獨立地為1或2 ;或 者 (ii) -NRkC(0)NRgRh、-NRkC(0)0Rj、-0C(0)NRgRh、 或-0C(0)0Rj。 5 4.如申請專利範圍第1項之化合物，其中： R3係C6-Ch芳基，其： (0以1-2 R1G取代，並 (ii)任意地以1-4 Re取代；而且 ίο A於各次出現時係獨立地為含有5-10原子之雜芳 基，其： (a) 係以1-2 1^取代或含有一經取代的環原子，該 環原子係選自S(0)和S〇2所組成之群；且 (b) 可任意地以1-4 Re取代； 15 前提是該含有5-10原子之雜芳基並非任意經取代 地[1，2,4]-σ惡二唾基；以及 Rf於各次出現時係獨立地為： (i) -S(0)nRn、-(CHOhSCOXR11、-NRkS(0)nRn、或 20 -0S(0)nRn、其中η於各次出現時係獨立地為1或2 ;或 (ii) -NRkC(0)NRgRh、-NRkC(0)0Rj、-0C(0)NRgRh、 或-0C(0)0RJ。 5.如申請專利範圍第1項之化合物，其中： R3係C6-Ch芳基，其： 401 200825054 (i) 以1-2 R1G取代，並 (ii) 任意地以1-4 Re取代；而且 A於各次出現時係獨立地為C6-Cl0芳基’其： 5 (a)以1-2 Rf取代；並 (b)任意地以1-4 Re取代；而且 Rf於各次出現時係獨立地為： (iii) 含有5-10原子之雜環基，可以1-2側氧基 10 取代並可或任意地以1-3 Re取代；或 (iv) 含有5-10原子之雜環烯基或1H-苯并咪唑， 其之每一係任意地以1_3 Re取代；或 (v) -YRf，其中Y於各次出現時係獨立地為G-Ce伸 烧基、-〇-、或-NR9-;以及 15 Rf’於各次出現時係獨立地為： (i) 含有5-10原子之雜環基，可以1-2側氧基取 代並可或任意地以1-3 Re取代；或 (ii) 含有5-10原子之雜環烯基或1H-苯并咪唑， 20 其之每一係任意地以1-3 Re取代。 6.如申請專利範圍第1項之化合物，其中： R3係C6-Ch芳基，其： (i)以1-2 R1G取代，並 402 200825054 (ii)任意地以1-4 Re取代；而且 A於各次出現時係獨立地為含有8-12原子之芳基 氮壤基’其： (a) 係以1-2 Rf取代，且 (b) 任意地以1—4 Re取代；以及 Rf於各次出現時係獨立地為： (i) -S(0)nRn、—(CH2)1_6S(〇)nRn、—NRks(〇)x、或 —〇S(〇)nRn、其中n於各次出現時係獨立地為1或2 ;或 (Π) -NRkC(0)NRgRh、_NRkC(0)〇Rj、—0C(0)NRgRh、 或一〇C(0)〇Rj。 如申請專利範圍第1項之化合物，其中： R係C6~Cl4芳基，其： (0以1-2 R1Q取代，並 (Π)任意地以1-4 Re取代；而且 A於各次出現時係獨立地為芳基亞磺醯基環基、雜 芳基亞磺醯基環基、芳基磺醯基環基或雜芳基磺醯基環 基’其之每一包含8-10原子且可任意地以1-4 Re取代。 如申請專利範圍第1項之化合物，其中： R係Ce-Ci4芳基，其： (i) 以1 R1Q取代，並 (ii) 任意地以1-4 Re取代；而且 403 200825054 A於各次出現時係獨立地為[1，2, 4]-σ惡二唾基，可 任意地以1〜2 Re取代。 9.如申晴專利範圍第i項之化合物，其*尺3係Wio芳 基’其（丨）以1 R1G取代；並（ii)任意地以1-2 Re取代。 1〇·如申凊專利範圍第1項之化合物，其中R3具有式（A-4):10 15 20 (Vi) — 0Rj ; ~C(〇) ore; a c(0)0Rj ; -C(0)NRgRh ; or -S(0)nRm ; R is independently of each occurrence: ( i) hydrogen; or () Cl C2D alkyl or yl group, each of which is optionally substituted with 1-10 Ra; or (iii) C2 C2. An alkene or an octyl alkynyl group, each of which is optionally 1-10 R. Replace; or show the base, G-C2. a cycloalkenyl group, a hetero-based group containing 3 to 2 fluorenes, a heterocyclic ring containing 3, an atom, or a hetero-aromatic group containing a W atom, each of which is substituted with 1 -10 Rb; Or (v) a C6-U aryl group or a 516 atom containing 4 arbitrarily arbitrarily; or a parent ..., the parent r is independently R], QR), or " R, in each occurrence, is independently a compound of the Ri or 峨h. class or one of its N-oxides and/or a pharmaceutically acceptable salt thereof, wherein: 'its: 2 · as claimed Range 1 R3 is a C6-Cl4 aryl group substituted, and (1) is arbitrarily substituted with 1-4 Re at 1-2 R1 399 200825054 (ii); and A is independently C6-Ci aryl at each occurrence. , (a) substituted with 1-2 Rf; and 5 (b) arbitrarily substituted with 1-4 Re; and Rf is independently of each occurrence: (i) -S(0)nRn, - (CH2)HS(0)nRn, -NRkS(0)nRn, or -0S(0)nRn, where n is independently 1 or 2 at each occurrence; or 10 (ii) -NRkC(0) NRgRh, -NRkC(0)0Rj, -0C(0)NRgRh, or -0C(0)0Rj. 3. A compound according to claim 1, wherein: 15 R3 is a heteroaryl group having 5 to 14 atoms, which is (i) substituted with 1-2 R1G, and (ii) optionally substituted with 1-4 Re; and A is independently present at each occurrence Ce-Ci. aryl, which: 20 (a) is substituted with 1-2 Rf; and (b) is optionally substituted with 1-4 Re; and Rf is independently present at each occurrence: (i) -S (0) nRn, -(CHOhSCOXR11, -NRkS(0)nRn, or 400 200825054 -0S(0)nRn, where η is independently 1 or 2 at each occurrence; or (ii) -NRkC(0) NRgRh, -NRkC(0)0Rj, -0C(0)NRgRh, or -0C(0)0Rj. 5. The compound of claim 1, wherein: R3 is a C6-Ch aryl group, which: 0 is substituted with 1-2 R1G, and (ii) is optionally substituted with 1-4 Re; and ίο A is independently a heteroaryl group having 5-10 atoms in each occurrence, wherein: (a) 1-2 1^substituted or containing a substituted ring atom selected from the group consisting of S(0) and S〇2; and (b) optionally substituted with 1-4 Re; The heteroaryl group having 5-10 atoms is not optionally substituted [1,2,4]-σ oxadiazide; and Rf is independent in each occurrence (i) -S(0)nRn, -(CHOhSCOXR11, -NRkS(0)nRn, or 20 -0S(0)nRn, where η is independently 1 or 2 at each occurrence; or (ii -NRkC(0)NRgRh, -NRkC(0)0Rj, -0C(0)NRgRh, or -0C(0)0RJ. 5. The compound of claim 1, wherein: R3 is a C6-Ch aryl group, which: 401 200825054 (i) is substituted with 1-2 R1G, and (ii) is optionally substituted with 1-4 Re; A, in each occurrence, is independently C6-Cl0 aryl': 5 (a) is substituted with 1-2 Rf; and (b) is optionally substituted with 1-4 Re; and Rf is present at each occurrence Independently: (iii) a heterocyclic group containing 5-10 atoms, which may be substituted with 1-2 pendant oxy group 10 and may be optionally substituted with 1-3 Re; or (iv) a heterocyclic ring having 5-10 atoms. Alkenyl or 1H-benzimidazole, each of which is optionally substituted with 1_3 Re; or (v) -YRf, wherein Y is independently a G-Ce stretching group, -〇-, in each occurrence Or -NR9-; and 15 Rf' are independently present in each occurrence: (i) a heterocyclic group containing 5-10 atoms, which may be substituted with 1-2 side oxy groups and optionally 1-3 Re Substituting; or (ii) a heterocycloalkenyl group having 5-10 atoms or 1H-benzimidazole, each of which is optionally substituted with 1-3 Re. 6. The compound of claim 1, wherein: R3 is a C6-Ch aryl group, wherein: (i) is substituted with 1-2 R1G, and 402 200825054 (ii) optionally substituted with 1-4 Re; A, in each occurrence, is independently an aryl nitrogen-based soil having 8-12 atoms ': (a) is substituted with 1-2 Rf, and (b) is optionally substituted with 1-4 Re; and Rf In each occurrence, it is independently: (i) -S(0)nRn, -(CH2)1_6S(〇)nRn, -NRks(〇)x, or -〇S(〇)nRn, where n is in each The second occurrence is independently 1 or 2; or (Π) -NRkC(0)NRgRh, _NRkC(0)〇Rj, -0C(0)NRgRh, or a 〇C(0)〇Rj. The compound of claim 1, wherein: R is a C6~Cl4 aryl group, wherein: (0 is substituted with 1-2 R1Q, and (Π) is optionally substituted with 1-4 Re; and A appears in each occurrence When independently arylsulfinylcyclyl, heteroarylsulfinylcyclyl, arylsulfonylcyclyl or heteroarylsulfonylcyclyl, each of which contains 8-10 atoms And optionally substituted with 1-4 Re. The compound of claim 1, wherein: R is a Ce-Ci4 aryl group, which: (i) is substituted with 1 R1Q, and (ii) is optionally 1- 4 Re is substituted; and 403 200825054 A is independently [1,2,4]-σ dioxin in each occurrence, and can be optionally substituted with 1~2 Re. 9. For example, Shen Qing patent scope i a compound of the formula 3, wherein the genus of the genus is substituted with 1 R1G; and (ii) is optionally substituted with 1-2 Re. R3 has the formula (A-4): (A_4) 其中R32係氫或R6。 U.如申請專利範圍第1項之化合物，其中R3係含有5-1〇 原子之雜芳基，其（0以1R1。取代，並（ii)任意地以1-2 Re取代。 12.如申請專利範圍第丨項之化合物，其中R3係吡啶基、 噻吩基、噻唑基、或吡唑基，其（i)以1 IT取代，並（ii) 任意地以1-2 Re取代。 13·如申請專利範圍第i項之化合物，其中w係選自_〇—、 鍵、-0(Ci-G伸烷基）-、和-(〇C3伸烷基）〇-所組成 之群。 14·如申請專利範圍第1項之化合物，其中A係苯基，其（a) 以1 Rf取代，並（b)任意地以1-2 Re取代。 15·如申請專利範圍第1項之化合物，其中A係含有5-8原 404 200825054 子之雜芳基，其（a)以1 V取代，並（b)任意地以1-3 Re 取代，前提是該含有5-8原子之雜芳基並非[1，2, 4]-噁 二唑基。 16·如申請專利範圍第丨項之化合物，其中A係四氫喹啉基 或四氫異喹啉基，其（a)以1 Rf取代，並（b)任意地以 1-2 Re取代。 17·如申請專利範圍第丨項之化合物，其中A係苯并[匕]噻 为基-1，1-一氧化物、3, 4-二氫-2H-硫基口比喃[2, 3-b]外匕 啶基-1，1-二氧化物、或2,3_二氫苯并[b]噻吩基—Μ一 二氧化物，其之每一係任意地以1—3 f取代。 18·如申請專利範圍第！項之化合物，其中^係―s〇2Rn。 19·如申請專利範圍第ι8項之化合物，其中『係匕-匕。产 基，可任意地以1—2 Ra取代。 20·如申請專利範圍第19項之化合物，其中Rn係非經取代 之Ci-C3烷基。 21·如申請專利範圍第19項之化合物，其中係ch3。 22.如申請專利範圍第μ項之化合物，其中Rn係匕〜匕产 基，其任意地以1-2 Ra取代，其中ρ於各次出現時: 獨立地為羥基；Cl-C3烷氧基；NRsRh ;鹵基；含有8一1〇 原子之芳基雜環基，可任意地以l—3Rb取代；氰基或 C(0)0Rj 。 土 ’ 3 23·如申請專利範圍第18項之化合物，其中Ry^、NRgRh。 24·如申請專利範圍第23項之化合物，其中Rg*Rh係各自 獨立地為氫Cw烷基，可任意地以1—2Ra取代；c?—c 405 200825054 芳烧基’可任意地以1_3 Rb取代；或-C(0)Rj。 25.如申請專利範圍第18項之化合物，其中Rn係含有5-10 原子之雜環基、C7-Cl。芳烧基、或C3-C8環烧基’其之 每一者可任意地以1-5 Rb取代。 5 26.如申請專利範圍第1項之化合物，其中Rf係： (i) 含有5-7原子之雜環基，可以1側氧基取代或 任意地以1-2 Re取代；或 (ii) 含有5-7原子之雜環烯基，其可任意地以1-2 Re取代。 10 27.如申請專利範圍第26項之化合物，其中1^係4,5-二氫 噁唑基、2-側氧基-咪唑啶基、4, 5-二氫-1H-咪唑基、 1，2, 5, 6-四氫-嘧啶基、5, 6-二氫-2H-[1，3]噁嗪基、或 2-側氧基-唑啶基。 28. 如申請專利範圍第1項之化合物，其中^係1H-苯并咪 15 σ坐基。 29. 如申請專利範圍第1項之化合物，其中R3具有式D-1: RA22(A_4) wherein R32 is hydrogen or R6. U. The compound of claim 1, wherein R3 is a heteroaryl group having a 5-1 fluorene atom, wherein (0 is substituted with 1R1. and (ii) is optionally substituted with 1-2 Re. A compound of the invention of claim 3, wherein R3 is pyridinyl, thienyl, thiazolyl, or pyrazolyl, which (i) is substituted with 1 IT and (ii) is optionally substituted with 1-2 Re. A compound of claim i, wherein w is selected from the group consisting of 〇—, bond, —(Ci-G alkylene)-, and —(〇C3alkyl)-. A compound according to claim 1, wherein A is a phenyl group, (a) is substituted with 1 Rf, and (b) is optionally substituted with 1-2 Re. 15. A compound as claimed in claim 1 Wherein A is a heteroaryl group of 5-8 precursor 404 200825054, which (a) is substituted with 1 V and (b) is optionally substituted with 1-3 Re, provided that the heteroaryl contains 5-8 atoms The base is not a [1,2,4]-oxadiazolyl group. The compound of claim 3, wherein the A is a tetrahydroquinolyl group or a tetrahydroisoquinolyl group, and (a) is 1 Rf. Replace, and (b) arbitrarily take 1-2 Re 17. A compound of the scope of the patent application, wherein A is a benzo[匕]thiol-1,1-monooxide, 3,4-dihydro-2H-sulfanylpyranyl group [2] , 3-b]exetidinyl-1,1-dioxide, or 2,3-dihydrobenzo[b]thienyl-fluorene-dioxide, each of which is optionally 1-3 Substituting f. 18. A compound of the scope of the patent application, wherein the system is -s〇2Rn. 19. The compound of claim </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> — 2 Ra. 20. A compound according to claim 19, wherein Rn is a non-substituted Ci-C3 alkyl group. 21. A compound according to claim 19, wherein ch3. The compound of the invention, wherein the Rn is a hydrazine-hydrazine-based group, which is optionally substituted with 1-2 Ra, wherein ρ is present at each occurrence: independently a hydroxyl group; a Cl-C3 alkoxy group; NRsRh; a aryl group having 8 to 1 atom, optionally substituted by 1-3Rb; a cyano group or C(0)0Rj. A compound of claim 18, wherein Ry ^, NRgRh. 24 The compound of claim 23, wherein Rg*Rh is each independently hydrogen Cw alkyl, optionally substituted by 1-2Ra; c?-c 405 200825054 arylalkyl group can be optionally substituted with 1-3 Rb Or -C(0)Rj. 25. A compound according to claim 18, wherein Rn contains a heterocyclic group of 5-10 atoms, C7-Cl. Each of the aryl group or the C3-C8 cycloalkyl group can be optionally substituted with 1-5 Rb. 5. 26. The compound of claim 1, wherein the Rf is: (i) a heterocyclic group containing 5-7 atoms, which may be substituted with a 1-oxy group or optionally substituted with 1-2 Re; or (ii) A heterocycloalkenyl group having 5 to 7 atoms, which may be optionally substituted with 1-2 Re. 10 27. A compound according to claim 26, wherein the compound is 4,5-dihydrooxazolyl, 2-sided oxy-imidazolidinyl, 4,5-dihydro-1H-imidazolyl, 1 , 2, 5, 6-tetrahydro-pyrimidinyl, 5,6-dihydro-2H-[1,3]oxazinyl, or 2-sided oxy-oxazolidinyl. 28. The compound of claim 1, wherein the compound is 1H-benzopyrene. 29. A compound as claimed in claim 1 wherein R3 has the formula D-1: RA22 W係-〇-或一鍵； 3〇 RA22和RA23之每一者係獨立地為氫或Re ;且 406 200825054 RA24和RA25之一係-S〇2『，另一者係氫或Re; 前提是僅有RA22、RA23、RA24、和RA25中之一者係Re Ο 30·如申請專利範圍第29項之化合物，其中R32係氫、氟、 或氣。 5 31·如申請專利範圍第1項之化合物，其中： R3係含有5-1〇原子之雜芳基，其（i)以1 R1G取代， 並（ii)任意地以1-2 Re取代；且 W係一鍵；並且 A具有式（B-9): RA22W-〇- or one-key; 3〇RA22 and RA23 are each independently hydrogen or Re; and 406 200825054 one of RA24 and RA25 is -S〇2", the other is hydrogen or Re; It is a compound of only one of RA22, RA23, RA24, and RA25, which is a compound of claim 29, wherein R32 is hydrogen, fluorine, or gas. 5: The compound of claim 1, wherein: R3 is a heteroaryl group having a 5-1 fluorene atom, wherein (i) is substituted with 1 R1G, and (ii) is optionally substituted with 1-2 Re; And W is a key; and A has the formula (B-9): RA22 (B-9) 其中： RA22和RA23之每一者係獨立地為氫或Re ;且 RA24和RA25之一係-S〇2Rn，另一者係氫或Re ; 前提是僅有IT、RA23、RA24、和中之一者係Re。 2 ·如申睛專利範圍第1項之化合物，其中：(B-9) where: each of RA22 and RA23 is independently hydrogen or Re; and one of RA24 and RA25 is -S〇2Rn, the other is hydrogen or Re; provided that only IT, RA23, One of RA24, and one is Re. 2 · For example, the compound of claim 1 of the scope of the patent, wherein: R3具有式（A-4): 407 200825054 其中R係氯或;和 W係一鍵；且 A係含有5-8原子之雜芳基，其（3)以丨Rf取代， 並（b)任意地以丨-3 Re取代，前提是該含有5 8原子之 雜芳基並非[1，2, 4]-噁二唾基。 33·如申請專利範圍第1項之化合物，其中· R具有式（A-4):R3 has the formula (A-4): 407 200825054 wherein R is chlorine or; and W is a bond; and A contains a heteroaryl group of 5-8 atoms, (3) is substituted with 丨Rf, and (b) is optionally The ground is substituted with 丨-3 Re, provided that the heteroaryl group having 5 8 atoms is not [1,2,4]-oxadisinyl. 33. For the compound of claim 1, wherein R has the formula (A-4): (A-4) 其中R32係氫或Re ;和 W係一鍵；且 A係四氫喧琳基或四氫異啥琳基，其（&amp;)以1 ^取 代，並（b)任意地以1—2 Re取代。 4 _如申凊專利範圍第1項之化合物，其中· R3具有式（A-4):(A-4) wherein R32 is hydrogen or Re; and W is a bond; and A is tetrahydroindenyl or tetrahydroisoindolinyl, which is substituted with 1^, and (b) optionally Replace with 1-2 Re. 4 _ For example, the compound of claim 1 of the patent scope, wherein R3 has the formula (A-4): I (A-4) 其中R32係氫或Re ;和 408 200825054 w係一鍵；且 A係苯并[b]噻吩基-1，1-二氧化物、3, 4-二氫-2H-硫基吡喃[2, 3-b]吡啶基-1，1-二氧化物、或2, 3-二氫苯 并[b]噻吩基-1,1-二氧化物，其之每一係任意地以1-3 5 Re取代。 35.如申請專利範圍第1項之化合物，其中R3具有式D-1: RA22I (A-4) wherein R32 is hydrogen or Re; and 408 200825054 w is a bond; and A is benzo[b]thienyl-1,1-dioxide, 3,4-dihydro-2H-sulfur Pyridyl [2, 3-b]pyridinyl-1,1-dioxide, or 2,3-dihydrobenzo[b]thienyl-1,1-dioxide, each of which is optional The ground is replaced by 1-3 5 Re. 35. A compound according to claim 1 wherein R3 has the formula D-1: RA22 其中： 20 R32係氫或Re ; W係-〇-或一鍵； RA22和RA23之每一者係獨立地為氫或Re ;且 RA24 和 RA25 之一係： (i) 含有5-7原子之雜環基，可以1側氧基取代並 25 可任意地以1-2 Re取代；或 (ii) 含有5-7原子之雜環烯基或1H-苯并咪唑， 其之每一係任意地以1-2 Re取代；且另一為氫或Re ; 前提為僅RA22、RA23、RA24、和RA25中之一者係Re。 36.如申請專利範圍第1項之化合物，其中R3具有式F: 409 200825054 10Wherein: 20 R32 is hydrogen or Re; W is -〇- or one bond; each of RA22 and RA23 is independently hydrogen or Re; and one of RA24 and RA25 is: (i) contains 5-7 atoms a heterocyclic group which may be substituted with a 1-oxy group and 25 may be optionally substituted with 1-2 Re; or (ii) a heterocyclic alkenyl group having 5-7 atoms or 1H-benzimidazole, each of which is optionally Substituted with 1-2 Re; and the other is hydrogen or Re; provided that only one of RA22, RA23, RA24, and RA25 is Re. 36. The compound of claim 1, wherein R3 has the formula F: 409 200825054 10 15 、吋你獨立地為氫；鹵基，烷 暴’可任意地以1-2 Ra取苻· Γ Γ上* ^ 取代’ Cl一C3南基烧基；C「C3烷 乳基；NRgRh;苯基；或4-氟苯基。 20 37·如申請專利範圍第！項之化合物，其中ri係氯。 38.如申請專利範圍第1項之化合物，其中γ係氫。 39·如申請專利範圍第丨項之化合物，其中R2係： (11) c!-C6烷基，可任意地以i—2 Ra取代；或 (Hi) Cr~Cu)芳烷基，可任意地以卜3 Rb取代；或 (vii) —xR80 25 4〇·如申请專利範圍第1項之化合物，其中r4、r5和π之 每一者係氫。 41·如申請專利範圍第1項之化合物，其中R7係氯、氰基、 ci〜c6烷基、c广c3鹵基烷基、c广α烷氧基、c(o)〇Rj、 C(0)NRgRh、或 S〇2Rm。 42.如申請專利範圍第1項之化合物，其中R7係Ci_C3鹵 烷基。 43·如申請專利範圍第42項之化合物，其中R7係CF3。 410 200825054 44如申請專利範圍第l項之化合物，其中該化合物係選自 範例 43-190、192-198、201、202、204-210、212-217、 220-223、226、229-257、259-267、269-272、274-365、 367-370、372、374-391、394-396、398、400、402-593、 和595-597之標題化合物所組成之群，以及範例洲7、 399、401、和598-600中之每一標題化合物。 45· —種醫藥組成物或其之醫藥上可接受的鹽類，包含申請 專利範圍第1項化合物以及一醫藥上可接受的載體。 10 15 20 f 46· —種預防或治療肝X受體媒介之疾病或失調的方法， 該方法包括投予一個體治療上所需有效劑量之如申請 專利範圍第1項的化合物或其之醫藥上可接受的鹽類。 47_ —種預防或治療心血管疾病的方法，該方法包括投予一 個體治療上所需有效劑量之如申請專利範圍第丨項的化 合物或其之醫藥上可接受的鹽類。 48·如申請專利範圍第47項之方法，其中該心血管疾病係 急性冠心症或血管再狹窄症。 49· 一種預防或治療阿茲罕默症或失智症的方法，該方、去包 括投予-個體治療上所需有效劑量之如申請專利範= 第1項的化合物或其之醫藥上可接受的鹽類。 50. —種預防或治療第I型或第丨丨型糖尿病的方法，哼方 法包括投予-個體治療上所需有效劑量之如申請= 範圍第1項的化合物或其之醫藥上可接受的鹽類。1 51. -種預防d絲脈雜硬化和/或·動脈硬化病灶 的方法，該方法包括投卜個體治療上所需有效劑= 411 200825054 如申請專利範圍第1項的化合物或其之醫藥上可接受的 鹽類。 52. —種預防或治療X症候群的方法，該方法包括投予一個 體治療上所需有效劑量之如申請專利範圍第1項的化合 5 物或其之醫藥上可接受的鹽類。 53. —種預防或治療肥胖症的方法，該方法包括投予一個體 治療上所需有效劑量之如申請專利範圍第1項的化合物 或其之醫藥上可接受的鹽類。 54. —種預防或治療一或多種選自血脂異常、高血脂症、高 ίο 三酸甘油脂血症、高膽固醇血症、低HDL和高LDL所組 成之群之脂質失調的方法，該方法包括投予一個體治療 上所需有效劑量之如申請專利範圍第1項的化合物或其 之醫藥上可接受的鹽類。 55. —種預防或治療一發炎疾病的方法，該方法包括投予一 15 個體治療上所需有效劑量之如申請專利範圍第1項的化 合物或其之醫藥上可接受的鹽類。 56. 如申請專利範圍第55項之方法，其中該發炎疾病係多 發性硬化症、類風濕性關節炎、發炎性腸道疾病、克隆 氏症（Crohn’s disease)、子宮内膜異位症、LPS-誘導 20 的敗血症、耳朵的急性接觸性皮膚炎、或動脈壁的慢 性粥狀動脈硬化發炎。 57. 如申請專利範圍第55項之方法，其中該發炎疾病係類 風濕性關節炎。 58. —種預防或治療乳麋瀉症的方法，該方法包括投予一個 412 所需有效劑量之如中請專利範圍第 物或其之醫藥上可接受的鹽類。 項的化合 59. 體=防或治療甲狀腺炎的方法，該方 物或其_上可接專利範_〜 60. —種治療結締組織疾病的方法， 所需有效劑量之如;請專:二:乳 化合物或其之醫藥上可接受的鹽類。 弟1項的 61. 如申請專利範圍第6〇項之 10 骨分解並誘發軟骨再生。$化合物抑制軟 62·如申請專利範圍第6〇項之方法 蛋白多醣酶的活性。 、&quot;化口物抑制聚 63·如申請專利範圍第6〇項之 15 關節炎病灶中發炎細胞激素的產生化口物抑制骨 料·如申請專利範圍第6〇項 係骨關節炎或肌腱炎。、…、中該結締組織疾病 6=請專利範圍第6〇項之方法，其中該哺乳類動物係 20 66.2治療皮膚老化的方法，該方法包括投予一哺乳類動 ⑺療上所需有效劑量之如巾請專利第1項的化合 物或其之醫藥上可接受的鹽類。 6?.如申請專利範圍第66項之方法，其中該哺乳類動物係 人類。 68·如申請專利範圍第66項之方法，其中該化合物係被局 413 200825054 部投藥。 69.如申請專利範圍第66項之方法，其中該皮膚老化係源 自年代老化、光老化、類固醇—誘導的皮膚變薄、或其 之組合。 5 70. —種增加一個體中血清HDL膽固醇值的方法，該方法包 括投予一個體治療上所需有效劑量之如申請專利範圍 弟1項的化合物或其之醫藥上可接受的鹽類。 71. —種減少一個體中血清LDL膽固醇值的方法，該方法包 括投予該個體治療上所需有效劑量之如申請專利範圍 10 第1項的化合物或其之醫藥上可接受的鹽類。 72· —種增加一個體中逆轉式膽固醇運輸的方法，該方法包 括投予該個體治療上所需有效劑量之如申請專利範圍 第1項的化合物或其之醫藥上可接受的鹽類。 73·-種減少-個體中膽固醇吸收的方法，ς方法包括投予 15 該個體治療上所需有效劑量之如申請專利範圍第i項的 化合物或其之醫藥上可接受的鹽類。 414 200825054 七、指定代表圖： (一） 本案指定代表圖為：第（）圖。（無) (二) 本代表圖之元件符號簡單說明：15 , 吋 you are independently hydrogen; halogen, alkane storm 'optional 1-2 Ra 苻 · Γ Γ ^ ^ ^ ^ Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl Phenyl; or 4-fluorophenyl. 20 37. A compound according to the scope of claim 2, wherein ri is chlorine. 38. A compound according to claim 1 wherein γ is hydrogen. The compound of the above formula, wherein R2 is: (11) c!-C6 alkyl, optionally substituted with i-2 Ra; or (Hi) Cr~Cu) aralkyl, optionally arb 3 Rb Or a compound of claim 1, wherein each of r4, r5 and π is hydrogen. 41. A compound according to claim 1 wherein R7 is a compound of claim 1 Chlorine, cyano, ci~c6 alkyl, c-c3 haloalkyl, c-a wide alkoxy, c(o)〇Rj, C(0)NRgRh, or S〇2Rm. The compound of claim 1, wherein R7 is a Ci_C3 haloalkyl group. 43. The compound of claim 42 wherein R7 is CF3. 410 200825054 44. The compound of claim 1 wherein the compound is selected from the group consisting ofExamples 43-190, 192-198, 201, 202, 204-210, 212-217, 220-223, 226, 229-257, 259-267, 269-272, 274-365, 367-370, 372, 374 a group consisting of the title compounds of -391, 394-396, 398, 400, 402-593, and 595-597, and each of the title compounds of Examples 7, 399, 401, and 598-600. A pharmaceutical composition or a pharmaceutically acceptable salt thereof, comprising a compound of claim 1 and a pharmaceutically acceptable carrier. 10 15 20 f 46· A disease for preventing or treating liver X receptor vectors Or a method of dysregulation, which comprises administering a therapeutically effective amount of a compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof. 47_A method for preventing or treating cardiovascular diseases The method comprises administering to a body a therapeutically effective amount of a compound as claimed in the scope of the patent application or a pharmaceutically acceptable salt thereof. 48. The method of claim 47, wherein the heart Vascular disease is acute coronary heart disease or vascular restenosis. Or a method of treating Alzheimer's disease or dementia, the party comprising, including the administration of a therapeutically effective amount of the compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof 50. A method for preventing or treating type I or type 2 diabetes, the method comprising administering a compound that is effective for a therapeutically effective amount of the compound as claimed in claim 1 or a pharmaceutically acceptable compound thereof Salt. 1 51. A method for preventing d-filament atherosclerosis and/or atherosclerotic lesions, the method comprising: administering an effective agent to a subject for treatment = 411 200825054, for example, the compound of claim 1 or a medicinal thereof Acceptable salts. 52. A method of preventing or treating X syndrome, the method comprising administering to a body a therapeutically effective amount of a compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof. 53. A method of preventing or treating obesity, the method comprising administering to a body a therapeutically effective amount of a compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof. 54. A method for preventing or treating one or more lipid disorders selected from the group consisting of dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL, and high LDL. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, which comprises administering a therapeutically effective amount to a body treatment. 55. A method of preventing or treating an inflammatory disease, the method comprising administering to a subject an therapeutically effective amount of a compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof. 56. The method of claim 55, wherein the inflammatory disease is multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, Crohn's disease, endometriosis, LPS - Inducing 20 sepsis, acute contact dermatitis of the ear, or chronic atherosclerotic inflammation of the arterial wall. 57. The method of claim 55, wherein the inflammatory condition is rheumatoid arthritis. 58. A method of preventing or treating diarrhea, the method comprising administering a 412 desired effective dose of a pharmaceutically acceptable salt, or a pharmaceutically acceptable salt thereof. Combination of 59. Body = method of preventing or treating thyroiditis, the prescription or its _ can be attached to the patent _~ 60. A method for treating connective tissue diseases, such as the required effective dose; please: two A milk compound or a pharmaceutically acceptable salt thereof. 61 of the younger brother 61. If the bone of the sixth paragraph of the patent application is decomposed and induces cartilage regeneration. The compound inhibits softness. 62. The method of claim 6 is the activity of the proteoglycan. , &quot;Chemical substances inhibit poly63. As in the scope of the patent application, the inflammatory cytokines in the arthritis lesions inhibit the aggregates. inflammation. The method of claim 6, wherein the mammalian method 20 66.2 treats skin aging, the method comprising administering a mammalian (7) therapeutically effective dose as The compound of claim 1 or a pharmaceutically acceptable salt thereof. 6. The method of claim 66, wherein the mammal is a human. 68. The method of claim 66, wherein the compound is administered by the Department of 413 200825054. 69. The method of claim 66, wherein the skin aging is derived from ageing, photoaging, steroid-induced skin thinning, or a combination thereof. 5 70. A method of increasing serum HDL cholesterol levels in a body, the method comprising administering to a body a therapeutically effective amount of a compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof. 71. A method of reducing serum LDL cholesterol levels in a subject, the method comprising administering to the individual a therapeutically effective amount of a compound as claimed in claim 1 of claim 1 or a pharmaceutically acceptable salt thereof. A method of increasing the transport of reversing cholesterol in a body, the method comprising administering to the individual a therapeutically effective amount of a compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof. 73. A method of reducing cholesterol absorption in an individual, the method comprising administering a therapeutically effective amount of the compound of claim i, or a pharmaceutically acceptable salt thereof, as claimed in claim i. 414 200825054 VII. Designated representative map: (1) The representative representative of the case is: (). (none) (2) A brief description of the symbol of the representative figure: 八、本案若有化學式時，請揭示最能顯示發明特徵的化學式：8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention:
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