200305411 玖、發明說明 (發明說明應敘明：發明所屬之技術領域、先前技術、内容、實施方式及圖式簡單說明） 【發^明所》屬之^控^々頁起^】 本發明涉及一組噻唑衍生物，製備這些化合物的方法 ’和包含一種或多種這些化合物作為活性組分的藥物組合 物。 t先前技術】 上述嘆唾衍生物是有效的大麻素（CBl)受體拮抗劑、 CBi受體同效劑或CBl受體部分同效劑，可用於治療涉·及 大麻素CB!神經傳送的精神和神經疾病及其他疾病。 10 15 20 文獻EP 388909和EP 377457已經描述了 4,5-二芳基噻 坐衍生物作為5-脂肪氧合酶抑制劑用於治療血栓症、高血 壓、過敏症和炎症。兩篇文獻中所有示範性的結構都包含 -個對位被甲氧基、氟、甲硫基或甲基亞硫醯基取代的苯 環。文獻WO 9603392描述了磺醯芳基_芳基噻唑化合物用 於治療炎症以及和炎症有關的疼痛、關節炎或發燒。jp 〇5345772涉及4,5_二芳基㈣化合物作為乙醯膽驗醋酶抑 制劑，和IP 04B4773描述了 4 m㈣化合物具有止 痛、消炎和退熱的作用。 【發明内容1 現在驚奇地發現’式⑴的4,5_二芳基噻唑衍生物，它 們的前體藥物以及它們的鹽200305411 发明 Description of the invention (The description of the invention shall state: the technical field to which the invention belongs, the prior art, the content, the embodiments and the simple description of the drawings. A group of thiazole derivatives, methods of preparing these compounds' and pharmaceutical compositions comprising one or more of these compounds as active ingredients. Previous technology] The above-mentioned derivatives are effective cannabinoid (CBl) receptor antagonists, CBi receptor synergists, or CBl receptor partial synergists, and can be used to treat cannabinoid CB! neurotransmission. Mental and neurological and other diseases. 10 15 20 The documents EP 388909 and EP 377457 have described 4,5-diarylthiazine derivatives as 5-lipoxygenase inhibitors for the treatment of thrombosis, hypertension, allergies and inflammation. All exemplary structures in both documents include a phenyl ring substituted at the para position with a methoxy, fluorine, methylthio or methylsulfinylene group. Document WO 9603392 describes the use of sulfoarylaryl-arylthiazole compounds for the treatment of inflammation and inflammation-related pain, arthritis or fever. jp 05534577 relates to 4,5-diarylfluorene compounds as acetaminophenase inhibitors, and IP 04B4773 describes that 4 mfluorene compounds have analgesic, anti-inflammatory and antipyretic effects. [Summary of the Invention 1] It has now surprisingly been discovered that 4,5-diarylthiazole derivatives of formula VII, their prodrugs and their salts
6 (I) 200305411 玖、發明說明 其中 R表示氫原子或取代基X，所述取代基X選自支化或非 支化的1-3個碳原子的烷基或烷氧基、羥基、鹵素、三氟 甲基、三氟甲基硫基、三氟曱氧基、硝基、氨基、單-或 5二烷基氨基、單-或二-(Ci-2)烷基醯氨基、支化或非 支化的（Cl·3)烷氧基羰基、三氟甲基磺醯基、氨磺醯基、 支化或非支化的（C1_3)烷基磺醯基、羧基、氰基、氨基甲 酿基、支化或非支化的二-(Qy烷基氨基磺醯基、支化或 非支化的單-(Cl_3)烷基氨基磺醯基和乙醯基， 10 Rl是氫原子或1-4個取代基X，其中X具有上述提及的 含義， R2表示苯基、噻吩基、吡啶基或嘧啶基，這些基團可 被1-4個取代基X取代，其中χ具有上述提及的含義，或& 表示萘基， 15 R3表示氫原子、支化或非支化的1-10個碳原子的烷基 或環烷基-烷基基團、苯基、苄基、苯乙基，芳環可被卜5 個取代基Z取代，Z可以相同或不同，選自支化或非支化的 1-3個奴原子的烧基或烧氧基、經基、_素、三氟甲基、 二氟甲基硫基、三氟甲氧基、硝基、氨基、單-或二 2〇烧基氨基、單-或二-(Cl.2m基酿氨基、支化或非支化的 (c^)烷基磺醯基、二甲基磺醯胺基、支化或非支化的π】^ 烧氧基％基、叛基、二氟甲基石黃酿基、氰基、氨基甲醯基 、氨磺醯和乙醯基，或Rs表示吡啶基或嗟吩基， R4表示支化或非支化的i-H)個碳原子的烷基或環烷基_ 200305411 玖、發明說明 烷基基團、支化或非支化的1-10個碳原子的烷氧基、3-8個 石反原子的環烷基、5_1〇個碳原子的二環烷基、6_1〇個碳原 子的二環燒基、支化或非支化的3-10個碳原子的鏈烯基、 5_8個奴原子的環烯基，這些基團可以包含一個或多個選 自氧、氮、硫的雜原子，並且可被羥基、1-3個甲基、乙 基或1-3個氟原子取代，或仏表示苯基、苄基或苯乙基， 這些芳環可被1-5個取代基z取代，z具有上述提及的含義 ，或者R4表示°比啶基或噻吩基，或者R4表示基團NR5R6_， 其中 I和&與它們所連接的氮原子一起形成具有仁丨〇個環 原子的飽和或不飽和的、單環或雙環的雜環基團，該雜環 基團含有一個或多個選自氧、氮、硫的雜原子，並且可被 支化或非支化的1-3個碳原子的烷基、羥基、三氟甲基或 氣原子取代，或 R3和R4與匕們所連接的氮原子一起形成具有個環 原子的飽和或不飽和的、單環或雙環的雜環基團，該雜環 基團含有一個或多個選自氧、氮、硫的雜原子並且可被支 化或非支化的1 _3個碳原子的烧基、經基、三氟甲基或氟 原子取代， 疋大麻素CB〗受體的有效的拮抗劑、同效劑或部分同 效劑。 由於其有效的08】受體活性，本發明的化合物適合用 於治療精神疾病如精神病、焦慮、抑鬱、注意力缺乏症、 記憶障礙、認知障礙、食慾紊亂、肥胖、藥癮、慾望症、 200305411 玖、發明說明 藥物依賴， 、癡呆、張力失常6 (I) 200305411 发明, description of the invention, wherein R represents a hydrogen atom or a substituent X selected from a branched or unbranched alkyl or alkoxy group of 1 to 3 carbon atoms, a hydroxyl group, a halogen , Trifluoromethyl, trifluoromethylthio, trifluorofluorenyloxy, nitro, amino, mono- or 5-dialkylamino, mono- or di- (Ci-2) alkylphosphonium amino, branched Or unbranched (Cl · 3) alkoxycarbonyl, trifluoromethylsulfonyl, sulfamoranyl, branched or unbranched (C1_3) alkylsulfonyl, carboxyl, cyano, amino Methyl alcohol, branched or unbranched di- (Qy alkylaminosulfonyl), branched or unbranched mono- (Cl_3) alkylaminosulfonyl and ethylfluorenyl, 10 Rl is a hydrogen atom Or 1-4 substituents X, where X has the above-mentioned meaning, R2 represents phenyl, thienyl, pyridyl, or pyrimidinyl, these groups may be substituted by 1-4 substituents X, where χ has the above-mentioned The meanings mentioned, or & represents naphthyl, 15 R3 represents a hydrogen atom, a branched or unbranched 1 to 10 carbon atom alkyl or cycloalkyl-alkyl group, phenyl, benzyl, Phenethyl, aromatic ring can be substituted with 5 substituents Z Substitute, Z may be the same or different, and is selected from branched or unbranched 1-3 slave atoms of alkynyl or alkynyl, mesyl, triphenyl, trifluoromethyl, difluoromethylthio, tris Fluoromethoxy, nitro, amino, mono- or di-carbamoylamino, mono- or di- (Cl.2m-based amino, branched or unbranched (c ^) alkylsulfonyl, Dimethyl sulfonamido, branched or unbranched π] ^% oxy group, alkyl, difluoromethyl azinyl, cyano, carbamoyl, sulfamonium and acetamidine Or Rs represents pyridyl or fluorenyl, R4 represents branched or unbranched iH) alkyl or cycloalkyl of carbon atoms_ 200305411 玖, description of the invention alkyl group, branched or unbranched Alkoxy group of 1-10 carbon atoms, cycloalkyl group of 3-8 stone antiatoms, bicycloalkyl group of 5-10 carbon atoms, bicyclic alkyl group of 6-10 carbon atoms, branched or non Branched alkenyl groups of 3-10 carbon atoms, cycloalkenyl groups of 5-8 slave atoms, these groups may contain one or more heteroatoms selected from oxygen, nitrogen, and sulfur, and may be 3 methyl, ethyl or 1-3 fluorine atoms, or Phenyl, benzyl, or phenethyl, these aromatic rings may be substituted by 1-5 substituents z, z has the meaning mentioned above, or R4 represents ° pyridyl or thienyl, or R4 represents the group NR5R6_, Where I and & together with the nitrogen atom to which they are attached, form a saturated or unsaturated, monocyclic or bicyclic heterocyclic group having ren0 ring atoms, the heterocyclic group containing one or more selected from Heteroatoms of oxygen, nitrogen, and sulfur, and can be substituted by branched or unbranched alkyl, hydroxy, trifluoromethyl, or gas atoms of 1-3 carbon atoms, or R3 and R4 are connected to the daggers The nitrogen atoms together form a saturated or unsaturated, monocyclic or bicyclic heterocyclic group having one ring atom. The heterocyclic group contains one or more heteroatoms selected from oxygen, nitrogen, and sulfur and can be branched. Or an unbranched 1-3 carbon atom alkyl group, substituted by a group, trifluoromethyl or fluorine atom, an effective antagonist, synergist or partial synergist of the cannabinoid CB receptor. Due to its effective 08] receptor activity, the compounds of the present invention are suitable for the treatment of mental illnesses such as psychosis, anxiety, depression, attention deficit disorder, memory impairment, cognitive impairment, anorexia, obesity, drug addiction, desire disorder, 200305411发明, invention description drug dependence, dementia, dystonia
有關的疾病，以及治療疼痛，包括神經性疼痛和其他涉及 大麻素神經傳遞的疾病，包括治療腹毒性休克、青光眼、 癌症、糖尿病"區吐…惡心、哮喘、呼吸系統疾病、胃腸 機能紊亂、胃潰瘍、腹瀉和心血管疾病。 藥物依賴，和神經疾病如神經變性疾病 、肌肉強直、顫振、癲癇、多發性硬化 中風、帕金森氏病、早老性癡呆、癲癇 10 本發明化合物對大麻素CB1受體的親合力採用中國倉 鼠卵巢（CHO)細胞的膜製備物進行測定，在該細胞中，人 類大麻素CBi受體連同作為放射性配體的[3H]cp_55,94(^^ 定地被轉染。在培育含有[3H]-配體的新製備的細胞膜製備 物之後’在加入或不加入本發明的化合物的情況下，通過 15用玻璃纖維筛檢程式過遽來分離束縛配體和游離配體。筛 檢程式上的放射性通過液體閃爍計數法進行測量。 本發明化合物的大麻素CBi受體拮抗、同效或部分同 效活性，通過採用人類大麻素(：心受體在其中被穩定地表 達的CHO細胞進行的功能研究進行測定。用毛喉素 20 (forskolin)刺激腺苷酸環化酶，並通過測定累積的環一鱗 酸腺苷（AMP)的量來測定腺苷酸環化酶。在一種依賴濃度 的方式中，通過CBi受體同效劑（如CP-55,940或（R)-WIN-55,212-2)的CB!受體伴隨活性可以減少由毛喉素誘導的環 AMP的累積。CBi受體拮抗劑或部分同效劑，如本發明的 200305411 玖、發明說明 化合物，可以拮抗這種CBi受體介導的反應。 本發明化合物的大麻素受體同效或部分同效活性可以 按照已公開的方法測定，如體内大麻模擬（cannabimimetic) 效果的評價（Wiley，J.L. et al. J. pharmacol. Exp. Ther. 2001， 296, 1013)。 大麻素受體拮抗劑可以表現為反同效劑（Landsman, R. S. et al.，Eur. J. Pharmacol. 1997，334, R1-R2)。 本發明同時涉及式（I)化合物的外消旋體、非對映體的 混合物以及單個立體異構體。 10 15 借助於常規方法，使用輔助物質和/或液體或固體載 體材料，可以將本發明的化合物製成適於給藥的形式。 一種合成本發明化合物的合適方法如下： 合成路線A 路線A的步驟1 式（II)化合物的酯水解反應，其中R7表示支化或非支 化的1-4個碳原子的烷基或苄基。Related diseases, as well as the treatment of pain, including neuropathic pain and other diseases involving cannabinoid neurotransmission, including treatment of abdominal toxic shock, glaucoma, cancer, diabetes " area vomiting ... nausea, asthma, respiratory diseases, gastrointestinal disorders , Stomach ulcers, diarrhea, and cardiovascular disease. Drug dependence, and neurological diseases such as neurodegenerative diseases, muscle rigidity, flutter, epilepsy, multiple sclerosis stroke, Parkinson's disease, Alzheimer's disease, epilepsy 10 Membrane preparations of ovarian (CHO) cells were assayed, in which human cannabinoid CBi receptors were transfected with [3H] cp_55,94 (^^ as radioactive ligands. Incubation contained [3H] -Freshly prepared cell membrane preparation of the ligand 'with or without the addition of a compound of the invention, the bound ligand and free ligand are separated by passing through a glass fiber screening program by 15 steps. Radioactivity is measured by liquid scintillation counting method. The cannabinoid CBi receptor antagonistic, synergistic or partially synergistic activity of the compounds of the present invention is performed by using human cannabinoids: CHO cells in which cardiac receptors are stably expressed. A study was performed in which the adenylate cyclase was stimulated with forskolin 20 and the adenylate cyclase was determined by measuring the amount of accumulated cyclic monoscale adenosine (AMP). In a concentration-dependent manner, the accumulation of cyclic AMP induced by forskolin can be reduced by the CB! Receptor concomitant activity of CBi receptor synergists such as CP-55,940 or (R) -WIN-55,212-2. CBi receptor antagonists or partial synergists, such as the 200305411 (ii) compound of the present invention, can antagonize this CBi receptor-mediated response. The cannabinoid receptor synergistic or partial synergistic activity of the compounds of the present invention can According to published methods, such as evaluation of cannabimimetic effect in vivo (Wiley, JL et al. J. pharmacol. Exp. Ther. 2001, 296, 1013). Cannabinoid receptor antagonists can be expressed as anti Synergists (Landsman, RS et al., Eur. J. Pharmacol. 1997, 334, R1-R2). The present invention also relates to racemates, mixtures of diastereomers and single stereoisomers of compounds of formula (I) Isomers. 10 15 The compounds of the present invention can be made into a form suitable for administration using conventional methods using auxiliary substances and / or liquid or solid carrier materials. A suitable method for synthesizing the compounds of the present invention is as follows: Synthesis route A Route A Step 1 An ester hydrolysis reaction of a compound of formula (II), wherein R7 represents a branched or unbranched alkyl group of 1 to 4 carbon atoms or a benzyl group.
該反應生成式（III)的化合物：This reaction produces a compound of formula (III):
其中，R，RjaR2具有在上文描述的含義。 10 200305411 玖、發明說明 式（II)的本發明化合物，其中R7表示支化或非支化的 1-4個碳原子的烷基或苄基，可以通過公知的方法製備， 如： a) Organic Reactions, Vol.VI, (1951)? p.367-409? Ed. 5 R.Adams，John Wiley and Sons Inc.，New York b) J. S. Carter et al.? Bioorg. Med. Chem. Lett. (1999), 9, 1167-1170 c) T. T. Sakai et al.? Bioorg. Med. Chem. (1999), 75 1559-1566 10 d) A. Tanaka et al.? J. Med. Chem. (1994), 37? 1189-1199 e) J. J. Talley et al.? WO 9603392: Chem. Abstr. 125, 33628 f) V. Cecchetti et al.9 Bioorg. Med. Chem. (1994), 2, 799-806 15 路線A的步驟2 通過活化和偶合方法，如形成活性酯或在所謂的偶合 試劑，例如DCC，HBTU，BOP，CIP(2-氯-1,3-二甲基咪唑 啉鏽六氟磷酸鹽），PyAOP(7-氮雜苯並三唑-1-基氧三（吼咯 烷基）鳞鏽六氟磷酸鹽）等等存在下，式（III)的化合物與式 20 R3R4NH的化合物的反應，其中113和114具有在上文中描述 的含義。活化和偶合方法的更詳細資訊參見a)M. Bodanszky， A. Bodanszky: The Practice of Peptide Synthesis, Springer-Verlag, New York, 1994; ISBN: 0-387-57505-7; b)K. Akaji et al., Tetrahedron Lett. (1994), 359 11 200305411 玖、發明說明 33 15-3318); c)F. Albericio et al.? Tetrahedron Lett. (1997), 38, 4853-4856 。 該反應給出所需的式（I)的噻唑衍生物。 或者，式（III)的化合物與所謂的鹵化劑如亞硫醯氯 5 (S0C12)反應，得到相應的碳醯氯（IV)。Among them, R, RjaR2 has the meaning described above. 10 200305411 发明, Description of the invention The compound of the present invention of formula (II), wherein R7 represents a branched or unbranched alkyl group of 1-4 carbon atoms or benzyl group, which can be prepared by a known method, such as: a) Organic Reactions, Vol. VI, (1951)? P.367-409? Ed. 5 R. Adams, John Wiley and Sons Inc., New York b) JS Carter et al.? Bioorg. Med. Chem. Lett. (1999 ), 9, 1167-1170 c) TT Sakai et al.? Bioorg. Med. Chem. (1999), 75 1559-1566 10 d) A. Tanaka et al.? J. Med. Chem. (1994), 37 1189-1199 e) JJ Talley et al.? WO 9603392: Chem. Abstr. 125, 33628 f) V. Cecchetti et al. 9 Bioorg. Med. Chem. (1994), 2, 799-806 15 Step 2 Through activation and coupling methods, such as the formation of active esters or in the so-called coupling reagents, such as DCC, HBTU, BOP, CIP (2-chloro-1,3-dimethylimidazoline rust hexafluorophosphate), PyAOP ( The reaction of a compound of formula (III) with a compound of formula 20 R3R4NH in the presence of 7-azabenzotriazol-1-yloxytris (allyl) hexafluorophosphate) and the like, wherein 113 and 114 has the meaning described above. For more detailed information on activation and coupling methods, see a) M. Bodanszky, A. Bodanszky: The Practice of Peptide Synthesis, Springer-Verlag, New York, 1994; ISBN: 0-387-57505-7; b) K. Akaji et al., Tetrahedron Lett. (1994), 359 11 200305411 (ii), Invention Description 33 15-3318); c) F. Albericio et al.? Tetrahedron Lett. (1997), 38, 4853-4856. This reaction gives the desired thiazole derivative of formula (I). Alternatively, the compound of formula (III) is reacted with a so-called halogenating agent such as thionyl chloride 5 (SOC12) to give the corresponding carbofluorine (IV).
然後式（IV)的化合物與式R3R4NH的化合物反應得到式（I)的 噻唑衍生物，其中R3和R4具有在上文中描述的含義。該反 應優選在有機域如二異丙基乙基胺（DIPEA)或三乙胺存在 10 下進行。 或者，式（II)的化合物在所謂的氨化反應與式R3R4NH 的化合物進行反應，得到式（I)的°塞σ坐衍生物，其中R3和R4 具有在上文中描述的含義。 或者，式R3R4NH的化合物與強鹼如二異丙基氨化鋰 15 (LDA)、六甲基二石夕氮烧基鋰（LiHMDS)、六甲基二石夕氮烧 基鉀（KHMDS)或六甲基二矽氮烷基納（NaHMDS)等反應， 分別產生式R3R4NLi、R3R4NK或R3R4NNa的化合物，然後 這些化合物與式（II)的化合物反應得到式（I)的噻唑衍生物。 【實施方式】 20 實施例1 A部分：在氮氣氣氛下，將3.04克鎂（0.125摩爾）懸浮 在500毫升無水乙鱗中，然後加入埃晶體。緩慢加入溶解 12 200305411 玫、發明說明 在100¾升無水乙醚中的2〇12克（〇125摩爾）4_氣苄基氯， 以維持溫和的回流。將所得的混合物冷卻至室溫後，向其 中緩k加入2,4-二氯苄腈（17.2克，〇1〇摩爾）溶於1〇〇毫升 曱笨中的溶液。將該混合物升溫至135〇c，通過蒸餾除去 5乙醚，再次向該混合物中加入甲苯，接著將所得混合物再 回μ 2小日守。冷卻至室溫後，在攪拌和冷卻下向其中緩慢 加入400亳升鹽酸溶液（1Ν)。將所得混合物用乙醚萃取兩 次並用硫酸鎂進行乾燥，過濾並在真空下進行濃縮。用快 速色譜（二氣甲烷）得到19 96克（收率67%)2_(4_氣苯基 1〇 (2,4-一氣笨基）乙酮的黃色油狀物。用環己烷對該油狀物 進行結晶，得到純的2-(4-氯苯基）-:1-(2,4-二氣苯基）乙酮。 溶點：65-66°C。kNMR (200 MHz，CDC13) : δ 7.02-7.45 (m，7Η)，4.22 (s，2Η)。 B部分：向2.82克（9.42毫摩爾）2-(4-氣苯基）-ΐ·(2,4-二 15氣苯基）乙酮在25亳升苯中的溶液中，加入0.48亳升（1.49 克，9·3 1毫摩爾）的溴，所得溶液在室溫下攪拌2小時。然 後向其中加入二氣甲烷並將所得溶液用碳酸氫鈉水溶液進 行洗條，有機層用硫酸鎂進行乾燥，過濾並在真空下蒸發 除去溶劑，得到3.55克（收率定量）的2-溴-2-(4-氣苯基）_卜 20 (2,4-二氣苯基）乙酮的黃色油狀物（根據HPLC分析測得純度 〜95%)。^-NMR (200 MHz，CDC13) : δ 7.00-7.50 (m，7H)， 6.16 (s，1H)。 用相似的方法製備：The compound of formula (IV) is then reacted with a compound of formula R3R4NH to give a thiazole derivative of formula (I), wherein R3 and R4 have the meanings described above. This reaction is preferably performed in the presence of an organic domain such as diisopropylethylamine (DIPEA) or triethylamine. Alternatively, a compound of formula (II) is reacted with a compound of formula R3R4NH in a so-called amination reaction to obtain a ° sigma derivative of formula (I), wherein R3 and R4 have the meanings described above. Alternatively, the compound of the formula R3R4NH is combined with a strong base such as lithium diisopropylamide 15 (LDA), lithium hexamethyldiazinolithium lithium (LiHMDS), potassium hexamethyldiasperazoyl (KHMDS), or Hexamethyldisilazyl sodium (NaHMDS) and other reactions generate compounds of formula R3R4NLi, R3R4NK or R3R4NNa, respectively, and then these compounds are reacted with compounds of formula (II) to obtain thiazole derivatives of formula (I). [Embodiment] 20 Example 1 Part A: In a nitrogen atmosphere, 3.04 g of magnesium (0.125 mol) was suspended in 500 ml of anhydrous ethyl scale, and then angstrom crystals were added. Slowly add dissolved 12 200305411 Rose, description of the invention 2012 g (0125 mol) of 4-gas benzyl chloride in 100¾ liters of anhydrous ether to maintain a gentle reflux. After the resulting mixture was cooled to room temperature, a solution of 2,4-dichlorobenzonitrile (17.2 g, 10 mol) in 100 ml of benzene was slowly added thereto. The mixture was warmed to 135 ° C, 5 ether was removed by distillation, toluene was added to the mixture again, and the resulting mixture was then returned to 2 hours. After cooling to room temperature, 400 l of a hydrochloric acid solution (1N) was slowly added thereto with stirring and cooling. The resulting mixture was extracted twice with ether and dried over magnesium sulfate, filtered, and concentrated under vacuum. Flash chromatography (digas methane) was used to obtain 19 96 g (yield 67%) of 2- (4-fluorophenyl 10 (2,4-monobenzyl) ethanone) as a yellow oil. This was treated with cyclohexane. The oil was crystallized to obtain pure 2- (4-chlorophenyl)-: 1- (2,4-difluorophenyl) ethanone. Melting point: 65-66 ° C. KNMR (200 MHz, CDC13 ): δ 7.02-7.45 (m, 7Η), 4.22 (s, 2Η). Part B: To 2.82 g (9.42 mmol) of 2- (4-Gaphenyl) -ΐ · (2,4-Di-15 gas) To a solution of phenyl) ethyl ketone in 25 liters of benzene, 0.48 liters (1.49 g, 9.31 mmol) of bromine was added, and the resulting solution was stirred at room temperature for 2 hours. Then, methane gas was added thereto. The obtained solution was washed with an aqueous solution of sodium bicarbonate, and the organic layer was dried with magnesium sulfate, filtered, and the solvent was removed by evaporation under vacuum to obtain 3.55 g (quantitative yield) of 2-bromo-2- (4-gasbenzene). ) _Bu 20 (2,4-difluorophenyl) ethanone as a yellow oil (purity ~ 95% by HPLC analysis). ^ -NMR (200 MHz, CDC13): δ 7.00-7.50 (m , 7H), 6.16 (s, 1H). Prepared in a similar way:
2-溴-1-(4-氣苯基）-2_(2,4-二氣苯基）乙酮。iH-NMR 13 200305411 玖、發明說明 (200 MHz9 CDCI3) ： δ 7 〇ς ^ τ 〇ττ ， 3’ ό 7.95 (d，J 二 8Hz，2Η)，7.23-7.62 (m5 5Η)，6·77 (s，1Η) 〇 C部分·將9.83克（26·〇毫摩爾）2-漠-2-(4-氯苯基）-1-(2,4-二氯苯基）乙_和5 28克（39 6毫摩爾）硫代草氨酸乙醋 5溶解在50毫升無水乙醇中，將所得的紅色溶液在回流溫度 下加熱4小日守。在真空中蒸發除去溶劑後，將“克紅色粗 產品懸浮在二氣甲燒和甲基叔丁基㈣混合液中，過遽除 去形成的固體’所得的濾液用柱色譜進行純化（洗脫液： 一氯甲烷· Rf〜0.4)，得到521克（收率48%)5_(‘氣苯基 10 4_(2,4-二氯苯基）噻唑·2·羧酸乙酯的黃色油狀物，該黃色 油狀物慢慢地固化。熔點：η7_118^。ih_nmr (2⑼ MHz，CDC13) : δ 7.53，（d，J=2Hz，1H)，7.40 (dt，J=8Hz， J=2Hz，2H)，7.22-7.35 (m，4H)，4.52 (q，J=7Hz，2H)，1.45 (t， J=7Hz，3H) 〇 15 用相似的方法製備： 4-(4-氣苯基）-5-(2,4-二氣苯基）噻唑-2-羧酸乙酯。 D部分：將1.00克（2.42毫摩爾）5-(4-氯苯基）-4-(2,4-二 氣苯基）噻唑-2-羧酸乙酯加入到10毫升的^氨基呱啶中， 然後將所得混合物在50°C加熱攪拌反應4小時。接著加入 20 二氣甲烷並將所得溶液用水洗滌兩次，用硫酸鎂進行乾燥 ’過濾並在真空中通過蒸發除去大部分的二氯甲烷。然後 向其中加入二異丙醚’過濾除去形成的沉澱，將濾液在真 空中進行濃縮，用快速色譜進行提純（乙酸乙酯：石油峻 (40-60)=1:3 (Wv))，得到 330 毫克（收率 29%)5-(4-氣苯基）· 14 200305411 玖、發明說明 4-(2,4-二氣苯基）_n-(i-孤啶基）嗟唑_2_羧醯胺的白色泡沫 體。1H-NMR (4〇〇 MHz，CDC13) : δ 7.92 (s，1H)，7.47 (t， J=2Hz，1H)，7.24-7.32 (m，4H)，7.13 (dt，J=8Hz，J=2Hz， 2H)，2.85-2.93 (m，4H)，1.40-1.82 (m，6H)。 5 用類似的方法製備： 4- (4-氣苯基）-5-(2,4-二氣苯基）-Ν-(1·呱啶基）噻唑-2-羧 醯胺，熔點：190-191。(：。W-NMR (400 MHz，CDC13) : δ 8.03(s，lH)，7.51(d，J=2Hz，lH)，7.22-7.38 (m，6H)，2.90-2.97 (m，4H)，1.75-1.84 (m，4H)，1.44-1.52 (m，2H)。 10 5_(4_氣苯基環庚基-4-(2,4_二氯苯基）噻唑-2-羧醯 胺’熔點：159-161°C。 5- (4-氣苯基）-N_環戊基-4-(2,4-二氯苯基）噻唑-2-羧醯 胺，熔點：111-113°C。 5-(4-氣苯基）-4-(2,4-二氯苯基）-N-(反式-4-羥基環己基 15 )嚷°坐羧醯胺，熔點：i〇9t。 5-(4-氣苯基）-4-(2,4-二氯苯基）以-(2-曱基環己基）噻 唾綾醯胺，熔點：ι34-147^。 5-(4-氣苯基）-4-(2,4-二氯苯基）-Ν-(4-氟苄基）噻唑-2-羧 酉藍胺，溶點：142_144°C。 2〇 . "(4 -氣本基）-4-(2，4-二氯苯基）(反式-4-甲基環己基 )°塞唾-2-羧醯胺，熔點：l65_166aC。 5_(4-氯苯基）-N-(順式-4-甲基環己基）-4-(2,4-二氣苯基 )°塞唑-2-羧醯胺，熔點：72°C。 15 200305411 玖、發明說明 A部分··將4.10克（9.93毫摩爾）5-(4-氣苯基）-4-(2,仁二 氯苯基）噻唑-2-羧酸乙酯懸浮在75亳升甲醇中，向其中加 入氫氧化鉀水溶液（75毫升水中溶解198克（3〇毫摩爾）氫氧 化鉀形成的溶液），將所得混合物在回流溫度加熱2小時。 5然後使所得的黃色溶液達到室溫，將其倒入水中並用丨1^的 鹽酸水溶液進行酸化，得到白色沉澱。過濾收集該沉澱並 用水洗滌兩次，將沉澱在真空中進行乾燥，得到2·59克（收 率68%)5-(4-氣苯基）-4-(2,4-二氣苯基）噻唑-2-羧酸的白色 固體。H-NMR (200 MHz, DMSO-d6) : δ 9.25 (s，1H) 10 7.65-7.72 (m，1Η)，7.28-7.52 (m5 6Η)。 用類似的方法製備： 4-(4-氣苯基）_5-(2,4-二氣苯基）噻唑-2-羧酸 B部分：在氮氣氣氛和室溫下，將ΐ·〇〇克（2·6亳摩爾 )5-(4-氯苯基）-4-(2,4-二氣苯基）噻唑-2-羧酸懸浮在20毫升 15無水乙腈中。向其中先後加入1.36毫升（7.8毫摩爾）二異丙 基乙基胺（DIPEA)、1.08克（2.85毫摩爾）0-苯並三唑小基· N，N，N’，N’-四曱基uroniuin六氟填酸鹽（HBTU)和0.35克 (25.1毫摩爾）〇-叔丁基羥胺鹽酸鹽，在室溫下將所得的混 合物攪拌過夜。將所得混合物在真空中進行濃縮，然後向 20其中加入二氣甲烷，將所得溶液先後用水和鹽水進行洗滌 並用硫酸鎂進行乾燥，過濾並真空蒸發。然後用快速色譜 進行提純（乙酸乙酯··石油鱗（40-60)=1:3 (v/v))，得到〇·6 克（收率51%)Ν-(叔丁氧基）-5-(4-氣苯基）-4-(2,4-二氯苯基） 噻唑-2-羧醯胺的白色泡沫體。iH-NMR (400 MHz，CDC13) 16 200305411 玖、發明說明 :δ 9.20(s，1H)，7.47 (t，J=2Hz，1H)，7.25-7.31 (m，4H)， 7.14 (dt，J=8Hz，J=2Hz，2H)，1.36 (s，9H)。 用類似的方法製備： Ν·(叔丁氧基）-4-(4-氯苯基）-5-(2,4 -二氯苯基）嗟嗤-2· 5 羧醯胺。1H-NMR (400 MHz，CDC13) : δ 9·23 (s，1H)，7.52 (d，J二2Hz，1Η)，7.35 (dt，J=8Hz，J=2Hz，2Η) 7.23-7.31 (m， 4H)，1.40 (s，9H)。 5-(4-氯苯基）-4-(2，4·二氯苯基）-N-(正戊基）嗟σ坐_2 -叛 醯胺。W-NMR (400 MHz, CDC13) : δ 7.46 (s, 1Η)，7·2卜 10 7.32 (m? 5H), 7.14 (dt, J—8Hz? J=2Hz, 2H), 3.42-3.48 (m? 2H)，1.59-1.67 (m，2H)，1.30-1.40 (m，4H)，0.90 (t，J=7Hz， 3H) 〇 5-(4-氣苯基）-N-環己基-4-(2,4-二氣苯基）噻唑-羧醯 月女。H-NMR (400 MHz，CDCI3) : δ7.46 (s，1H)，7 24-7 35 15 (m，4Η)，7.05-7.17 (m，3Η)，3.90-4.00 (m，1Η)，1.98-2.07 (m，2H)5 1.72-1.82 (m，2H)，1.14-1.70 (m，6H)。 實施例3 A部分：向25克（0.135摩爾）4_溴苯甲醛中，先後加入 27.7克（0.135摩爾）2,4-二氣苯乙酸、100亳升乙酸酐和19毫 2〇升（〇_136摩爾）三乙胺，將所得混合物在回流溫度加熱90分 釦。然後將反應混合物冷卻至11〇。(3，將1〇〇亳升水緩慢加 入其中，使所得混合物達到室溫，然後向其中加入乙酸乙 醋，乙酸乙酉旨層用水洗務兩次，用硫酸鎮進行乾燥，過渡 並在真空中進行濃縮，所得的油狀物用二異丙喊進行結晶 17 200305411 玖、發明說明 ，得到26.55克（收率53%)3_(4_溴苯基）_2_(2,4-二氯苯基）丙 烯酸的白色固體。 B部分··將26.55克（71毫摩爾）3-(4-溴苯基）-2_(2,4_二 氯苯基）丙烯酸溶於丨30毫升無水甲苯中，所得的溶液冷卻 5至〇°C。先後向其中加入7.40克（73亳摩爾）三乙胺和198克 (72毫摩爾）二苯基磷醯疊氮化物，所得的混合物在攪拌 2〇分鐘，.然後在室溫下攪拌15〇分鐘。將反應混合物倒入 水中並用乙醚萃取三次，收集有機層並用硫酸鎂進行乾燥 ，在真空中除去乙醚。將所得的甲苯層缓慢地加入到^ % 毫升回/鼠的甲笨中，90分鐘後加入叔丁醇並在回流溫度繼 績加熱1小時，然後緩慢地加入5毫升濃鹽酸。將所得的溶 液在9(TC攪拌過夜後，將其降溫至室溫，用水洗滌兩次並 用硫酸鎂乾燥，過濾並在真空中進行蒸發，得到黃色的油 狀物，用正己烷將該油狀物進行結晶，得到14 72克（收率 I5 6〇/〇)2-(4->臭苯基)小(2,4_二氯苯基）乙酮，炫點：69-70^。 C部分：向5.00克（15毫摩爾）2·(‘溴苯基二氣 苯基）乙酮在50¾升苯中的溶液中，滴加〇·75毫升（15亳摩 爾）的溴，將所得溶液在室溫下攪拌反應4小時，在真空中 進仃濃縮。然後向其中加入二氣甲烧，將所得的溶液用鹽 2〇水進行洗滌並用硫酸鎂進行乾燥，過濾並在真空中進行濃 縮，得到5.96克（收率94%)2|2_(4•漠苯基）小(2,4_二氣笨 基）乙S同油狀物。 D部分·將在30毫升乙醇中含5 96克（14毫摩爾）2冬 2-(4->臭苯基）-1-(2,4-二氣苯基）乙嗣和2.8〇克（21毫摩爾）硫 18 200305411 玖、發明說明 代草氨酸乙醋的溶液在回流溫度下加熱4小時。將其冷卻 至至溫後，過濾除去沉降下來的晶體材料，將濾液在真空 中進行濃縮，得到7·56克燈色油狀材料，將該油狀材料用 快速色碏（乙酸乙酯/石油醚=1/3 (ν/ν))進行純化，接著用二 5異丙醚，谷劑進行結晶，得到2·11克（收率33%)5-(4-溴苯基）_ 4-(2，‘二氣苯基）噻唑-2-羧酸乙酯，熔點：129_13(rc。 E部分：將含1.00克（2·2毫摩爾）5_(4·溴苯基）-4_(2,4_二 氣苯基）噻唑-2-羧酸乙酯和1〇亳升丨_氨基呱啶的混合物在 5〇°C加熱攪拌過夜。然後使所得混合物達到室溫，向其中 10加入二氣甲烷，所得的溶液用水洗滌兩次並用硫酸鎂進行 乾燥，過渡並在真空中進行濃縮，得到一種油狀物，用快 速色譜（乙酸乙酯/石油醚=1/3(v/v))純化該油狀物，得到 870毫克（收率78%)5外漠苯基）_4_(2,心二氣苯基）善(卜瓜 啶基）噻唑-2-羧酸胺，溶點：ι71-173^。 15 用類似的方法製備： 4·(2,4-一氣苯基）-Ν-(1_σ瓜啶基）-5_(4_(三氟甲基）苯基） 噻唑羧酸胺，熔點：181-183°C。 N-環己基-4-(2,4_二氣苯基）_5-(4_(三氟甲基）苯基）噻 唑羧酸胺，熔點：140-142X：。 20 實施例4 A部分··將1.80克（3.94毫摩爾）5-(4-溴苯基）_4_(2,4_二 氯苯基）噻唑-2-羧酸乙酯溶解在20毫升甲醇中，向其中加 入氫氧化鉀的水溶液（將〇.65克（85%)，9 85亳摩目的氫氧 化卸溶解在2G亳升水中形成的溶液），所得混合物在回流 19 200305411 玖、發明說明 溫度下加熱1小時，然後將其倒入水中並用1N的鹽酸溶液 進行酸化。過濾收集生成的沉澱並將其在真空中和室溫下 進行乾燥，得到定量收率的5-(4-溴苯基）-4-(2,4-二氯苯基) 噻唑-2-羧酸，熔點：94_95。(：。 5 B部分··將0.50克（1.17毫摩爾）5_(4_溴苯基）-4_(2,4•二 氣苯基）噻唑-2-羧酸和1.02毫升（5.85亳摩爾）二異丙基乙基 Jk(DIPEA)溶解在5¾升二氣甲烧中，並冷卻至。向其 中加入0·11克（0.81愛：摩爾）7-氮雜-1-經基苯並三唾（H〇At) 和〇·50克（1.76毫摩爾）2-氣-1，3-二甲基咪唑啉鏽六氟磷酸鹽 10 (CIP)，接著加入0.15克（1.%亳摩爾）正戊胺，將所得混合 物在室溫下攪拌過夜。用快速色譜（二氣甲烷）進行純化， 得到〇·28克（收率48%)5-(4-溴苯基）-4-(2 +二氣苯基）-ΙνΚ正 戊基）嗟唑-2-羧醯胺的無定型固體。 用類似的方法製備： 15 5-(4·溴苯基）_4_(2,4·二氣苯基）_Ν·(六氫⑽氮雜環庚 三烯-1-基）噻唑-2-羧醯胺，熔點：2〇6-207°C。 5-(4- /臭笨基）-4·(2,4-二氣苯基(嗎琳_4_基）嗟唑 羧醯胺，無定型固體。 5-(4-氣笨基）·4·(2,4-二氣苯基比咯烷-；1-基）噻唑_ 20 2-羧醯胺，熔點：179-181。(：。 膏施例5 A部分：將〇.5〇克（1·3〇亳摩爾）5<_(4·氣苯基）-4_(2,4_二 氯苯基）噻唑-2-羧酸溶於10毫升二氣甲烷中，向其中先後 加入0.15克（1.30毫摩爾-氨基六氮（1Η)氣雜環庚三烤、 20 200305411 玖、發明說明 〇·18克（1.30¾摩爾）7-氮雜-1-經基苯並三〇坐、心⑽克仏％ 毫摩爾）7-氮雜苯並三唑-1-基氧三（吼咯烷基）鱗鑌六氟磷酸 鹽（PyAOP)和0.34毫升（1.95毫摩爾）二異丙基乙基胺，將所 得溶液在室溫下攪拌1小時。在真空中進行濃縮，得到 5 2·01克的粗品油狀物，用快速色譜（乙酸乙酯/石油醚’ = l/3(v/v))純化該油狀物，得到0.350克（收率56%)5-(4-氯苯 基）-4-(2,4-二氯苯基）->^(六氫（111)氮雜環庚三烯-1_基）噻 唑-2-羧醯胺，熔點：185_186它（用二異丙基醚重結晶後測 得）。 10 用類似的方法製備： 5-(4-氯苯基）-4_(2,4-二氯苯基）·Ν·(六氫環戊烷並[c]吼 口各-2(1H)-基）嗟唑-2-竣醯胺，溶點：i73-174°C。 N-苄基-5-(4-氣苯基）-4-(2,4-二氣苯基）-N·甲基-噻唑-2-竣醯胺，溶點：141-144°C。 15 5-(4-氣苯基）-4-(2,4-二氣苯基）-N-(4-(三氟曱基）苄基） 嗟嗤-2-緩醯胺，炼點：174-176。〇。 5-(4-氯苯基)-4-(2,4-二氯苯基）-N-(外-雙環R.2.1]庚-2- 基）噻唑-2-羧醯胺，熔點：194-195X：。 5-(4·氯笨基）-4-(2,4-二氯苯基）-N-(内-雙環[2.2.1]庚-2- 20 基）噻唑-2-羧醯胺，熔點：181-183X：。 5-(4-氯苯基）-4-(2,5_二氯苯基）-N-(外-雙環[2.2.1]庚-2- 基）嗔唾-2-羧醢胺，炼點：i70°C。 5-(4-氯苯基）·Ν-(環己基）-4-(2,5-二氣苯基）噻唑-2-羧 醯胺，熔點：75°C。 21 200305411 玖、發明說明 5-(4-氯苯基）_4-(2,4-二氯苯基）-N-(四氫-2Ιϋ喃_2_基 氧）噻唑-2-羧醯胺，熔點：85。(：。 實施例6 將1·65克（4.0毫摩爾）5-(4-氯苯基）-4_(2,4_二氣苯基）噻 5唑-2-羧酸乙酯溶解在25毫升的無水四氫呋喃中，向其中加 入0.37毫升（4.0毫摩爾）的苯胺。將所得溶液冷卻至〇它， 向其中加入4.4毫升六甲基二矽氮烷基鈉的四氳呋喃溶液 (1M)。將反應混合物攪拌2小時。然後向其内加入水，混 合物用乙酸乙酯萃取兩次，合併有機層並將其用鹽水洗條 10 ，用硫酸鎂進行乾燥，過濾並在真空中濃縮，殘餘物用二 異丙醚進行結晶，得到1.42克（收率77%)5-(4-氣苯基）-4-(2,4-一氣笨基)善苯基H2-叛醯胺，炫點：i67-168°C。 【圖式簡單說明】 (無） 15 【圖式之主要元件代表符號表】 (無）2-bromo-1- (4-aminophenyl) -2_ (2,4-difluorophenyl) ethanone. iH-NMR 13 200305411 玖, Description of the invention (200 MHz9 CDCI3): δ 7 〇ς ^ τ τττ, 3 'ό 7.95 (d, J 8Hz, 2Η), 7.23-7.62 (m5 5Η), 6.77 ( s, 1Η) 〇C part · 9.83 g (26.0 mmol) 2-mo-2- (4-chlorophenyl) -1- (2,4-dichlorophenyl) ethane and 5 28 g (39 6 mmol) ethyl thiooxamate 5 was dissolved in 50 ml of absolute ethanol, and the resulting red solution was heated at reflux temperature for 4 hours. After removing the solvent by evaporation in a vacuum, "g of red crude product was suspended in a mixed solution of dichloromethane and methyl tert-butyl hydrazone, and the resulting solids were removed by purification. The filtrate obtained was purified by column chromatography (eluent : Monochloromethane · Rf ~ 0.4), 521 g (yield: 48%) of 5 _ ('aerophenyl 10 4_ (2,4-dichlorophenyl) thiazole · 2 · carboxylic acid ethyl ester was obtained as a yellow oil The yellow oil solidified slowly. Melting point: η7_118 ^. Ih_nmr (2⑼ MHz, CDC13): δ 7.53, (d, J = 2Hz, 1H), 7.40 (dt, J = 8Hz, J = 2Hz, 2H ), 7.22-7.35 (m, 4H), 4.52 (q, J = 7Hz, 2H), 1.45 (t, J = 7Hz, 3H) 〇15 Prepared by a similar method: 4- (4-Gaphenyl)- Ethyl 5- (2,4-difluorophenyl) thiazole-2-carboxylic acid. Part D: 1.00 g (2.42 mmol) of 5- (4-chlorophenyl) -4- (2,4-di Phenyl) thiazole-2-carboxylic acid ethyl ester was added to 10 ml of aminopyridine, and the resulting mixture was heated and stirred at 50 ° C. for 4 hours. Then 20 methane gas was added and the resulting solution was washed with water for two hours. Times, dried over magnesium sulfate, filtered and removed in vacuo by evaporation Dichloromethane. Diisopropyl ether was added thereto to remove the formed precipitate by filtration. The filtrate was concentrated in vacuo and purified by flash chromatography (ethyl acetate: petroleum (40-60) = 1: 3). (Wv)) to obtain 330 mg (yield: 29%) 5- (4-aminophenyl) · 14 200305411 玖, description of the invention 4- (2,4-difluorophenyl) _n- (i-isopyridyl ) Oxazole-2-carboxamide. White foam. 1H-NMR (400 MHz, CDC13): δ 7.92 (s, 1H), 7.47 (t, J = 2Hz, 1H), 7.24-7.32 (m , 4H), 7.13 (dt, J = 8Hz, J = 2Hz, 2H), 2.85-2.93 (m, 4H), 1.40-1.82 (m, 6H). 5 Prepared in a similar manner: 4- (4-gas Phenyl) -5- (2,4-difluorophenyl) -N- (1.pyridinyl) thiazole-2-carboxamidine, melting point: 190-191. (: W-NMR (400 MHz, CDC13): δ 8.03 (s, 1H), 7.51 (d, J = 2Hz, 1H), 7.22-7.38 (m, 6H), 2.90-2.97 (m, 4H), 1.75-1.84 (m, 4H), 1.44 -1.52 (m, 2H). 10 5- (4-Gaphenylcycloheptyl-4- (2,4-dichlorophenyl) thiazole-2-carboxamide) 'Melting point: 159-161 ° C. 5- (4-Gaphenyl) -N-cyclopentyl-4- (2,4-dichlorophenyl) thiazole-2-carboxamidine, melting point: 111-113 ° C. 5- (4-Gasphenyl) -4- (2,4-dichlorophenyl) -N- (trans-4-hydroxycyclohexyl 15) 嚷 ° carboxamide, melting point: 109t. 5- (4-Phenyl) -4- (2,4-dichlorophenyl)-(2-fluorenylcyclohexyl) thiasalamine, melting point: ι34-147 ^. 5- (4-Gaphenyl) -4- (2,4-dichlorophenyl) -N- (4-fluorobenzyl) thiazole-2-carboxamidine. Melting point: 142-144 ° C. 2 0. (4- 4-benzyl) -4- (2,4-dichlorophenyl) (trans-4-methylcyclohexyl) ° sialo-2-carboxamide, melting point: 165-166aC. 5_ (4-Chlorophenyl) -N- (cis-4-methylcyclohexyl) -4- (2,4-diphenylphenyl) ° Cetazole-2-carboxamide, melting point: 72 ° C . 15 200305411 发明, Description of the invention Part A ... 4.10 g (9.93 mmol) of 5- (4-phenyl) -4- (2, rendichlorophenyl) thiazole-2-carboxylic acid was suspended in 75 To a liter of methanol, an aqueous potassium hydroxide solution (a solution of 198 g (30 mmol) of potassium hydroxide dissolved in 75 ml of water) was added thereto, and the resulting mixture was heated at reflux temperature for 2 hours. 5 Then the resulting yellow solution was brought to room temperature, poured into water and acidified with a 1% aqueous solution of hydrochloric acid to obtain a white precipitate. The precipitate was collected by filtration and washed twice with water. The precipitate was dried in vacuo to give 2.59 g (yield 68%) of 5- (4-phenyl) -4- (2,4-diphenyl) ) Thiazole-2-carboxylic acid as a white solid. H-NMR (200 MHz, DMSO-d6): δ 9.25 (s, 1H) 10 7.65-7.72 (m, 1Η), 7.28-7.52 (m5 6Η). Prepared in a similar way: 4- (4-Gasphenyl) _5- (2,4-Digasphenyl) thiazole-2-carboxylic acid Part B: In a nitrogen atmosphere and room temperature, 2.6 mol) 5- (4-chlorophenyl) -4- (2,4-diphenylphenyl) thiazole-2-carboxylic acid was suspended in 20 ml of 15 anhydrous acetonitrile. To this was added 1.36 ml (7.8 mmol) of diisopropylethylamine (DIPEA), 1.08 g (2.85 mmol) of 0-benzotriazole small group · N, N, N ', N'-tetrafluorene Based on uroniuin hexafluorofiller (HBTU) and 0.35 g (25.1 mmol) of o-tert-butylhydroxylamine hydrochloride, the resulting mixture was stirred at room temperature overnight. The resulting mixture was concentrated in vacuo, and then digas methane was added thereto, and the resulting solution was washed with water and then brine, dried over magnesium sulfate, filtered, and evaporated in vacuo. It was then purified by flash chromatography (ethyl acetate ·· petroleum scale (40-60) = 1: 3 (v / v)) to obtain 0.6 g (yield 51%) of N- (tert-butoxy)- 5- (4-Gasphenyl) -4- (2,4-dichlorophenyl) thiazole-2-carboxamide white foam. iH-NMR (400 MHz, CDC13) 16 200305411 玖, Description of the invention: δ 9.20 (s, 1H), 7.47 (t, J = 2Hz, 1H), 7.25-7.31 (m, 4H), 7.14 (dt, J = 8Hz, J = 2Hz, 2H), 1.36 (s, 9H). Prepared in a similar manner: N · (tert-butoxy) -4- (4-chlorophenyl) -5- (2,4-dichlorophenyl) fluorene-2. 5 carboxamide. 1H-NMR (400 MHz, CDC13): δ 9 · 23 (s, 1H), 7.52 (d, J = 2Hz, 1Η), 7.35 (dt, J = 8Hz, J = 2Hz, 2Η) 7.23-7.31 (m , 4H), 1.40 (s, 9H). 5- (4-Chlorophenyl) -4- (2,4 · dichlorophenyl) -N- (n-pentyl) 嗟 σ sitting _2-benzamine. W-NMR (400 MHz, CDC13): δ 7.46 (s, 1Η), 7.2b 10 7.32 (m? 5H), 7.14 (dt, J-8Hz? J = 2Hz, 2H), 3.42-3.48 (m 2H), 1.59-1.67 (m, 2H), 1.30-1.40 (m, 4H), 0.90 (t, J = 7Hz, 3H) 〇5- (4-Gaphenyl) -N-cyclohexyl-4- (2,4-Difluorophenyl) thiazole-carbohydrazone. H-NMR (400 MHz, CDCI3): δ 7.46 (s, 1H), 7 24-7 35 15 (m, 4Η), 7.05-7.17 (m, 3Η), 3.90-4.00 (m, 1Η), 1.98 -2.07 (m, 2H) 5 1.72-1.82 (m, 2H), 1.14-1.70 (m, 6H). Example 3 Part A: To 25 grams (0.135 moles) of 4-bromobenzaldehyde, 27.7 grams (0.135 moles) of 2,4-digas phenylacetic acid, 100 milliliters of acetic anhydride, and 19 millimoles (20 milliliters) were added. 136 mol) of triethylamine, and the resulting mixture was heated at reflux temperature for 90 minutes. The reaction mixture was then cooled to 110. (3, 100 liters of water was slowly added to the resulting mixture to reach room temperature, and then ethyl acetate was added thereto, and the ethyl acetate layer was washed twice with water, dried with sulfuric acid, transitioned and performed in vacuum. Concentrated, the resulting oil was crystallized with diisopropanol 17 200305411 054, description of the invention, 26.55 g (53% yield) 3_ (4_bromophenyl) _2_ (2,4-dichlorophenyl) acrylic acid was obtained Part B. · 26.55 g (71 mmol) of 3- (4-bromophenyl) -2- (2,4-dichlorophenyl) acrylic acid was dissolved in 30 ml of anhydrous toluene, and the resulting solution Cool 5 to 0 ° C. 7.40 g (73 mol) of triethylamine and 198 g (72 mmol) of diphenylphosphonium hydrazide were added thereto, and the resulting mixture was stirred for 20 minutes, then at Stir for 15 minutes at room temperature. Pour the reaction mixture into water and extract three times with diethyl ether. Collect the organic layer and dry over magnesium sulfate. Remove the ether in vacuo. The resulting toluene layer is slowly added to ^% ml / rat. In methylbenzyl, add tert-butanol after 90 minutes and continue to increase at reflux temperature. Warm for 1 hour, and then slowly add 5 ml of concentrated hydrochloric acid. After stirring the solution at 9 ° C overnight, it is cooled to room temperature, washed twice with water and dried over magnesium sulfate, filtered and evaporated in vacuo to give A yellow oily substance, which was crystallized from n-hexane to obtain 14 72 g (yield: 1560 / 〇) of 2- (4- > phenyl) small (2,4-dichlorobenzene). Base) ethyl ketone, dazzling point: 69-70 ^. Part C: To a solution of 5.00 g (15 mmol) of 2 · ('bromophenyldiphenylphenyl) ethanone in 50¾ liter of benzene was added dropwise. · 75 ml (15 mol) of bromine, the resulting solution was stirred and reacted at room temperature for 4 hours, and then concentrated in vacuo. Then dichloromethane was added thereto, and the resulting solution was washed with salt 20 water. It was dried with magnesium sulfate, filtered and concentrated in vacuo to obtain 5.96 g (yield 94%) of 2 | 2_ (4 • mophenyl) small (2,4_digasbenzyl) ethane S with oil. Part D · Will contain 5 96 g (14 mmol) of 2-D 2- (4- > styphenyl) -1- (2,4-diphenylphenyl) acetamidine and 2.8 in 30 ml of ethanol. G (21 mmol) sulfur 18 2003 054 11 发明 Description of the invention The solution of oxalamic acid ethyl acetate is heated at reflux temperature for 4 hours. After it is cooled to a temperature, the precipitated crystal material is filtered off, and the filtrate is concentrated in a vacuum to obtain 7.56 g Lamp-colored oily material. The oily material was purified with a fast tincture (ethyl acetate / petroleum ether = 1/3 (ν / ν)), and then crystallized with di 5 isopropyl ether and cereals to obtain 2 11 g (yield 33%) of 5- (4-bromophenyl)-4- (2, 'difluorophenyl) thiazole-2-carboxylic acid ethyl ester, melting point: 129_13 (rc. Part E: 1.00 g (2.2 mmol) of 5_ (4 · bromophenyl) -4_ (2,4_diphenylphenyl) thiazole-2-carboxylic acid ethyl ester and 10 liters of amino group The pyridine mixture was stirred with heating at 50 ° C overnight. The resulting mixture was then allowed to reach room temperature, to which 10 gaseous methane was added, and the resulting solution was washed twice with water and dried over magnesium sulfate, transitioned and concentrated in vacuo to give an oil, which was purified by flash chromatography (ethyl acetate / Petroleum ether = 1/3 (v / v)) The oil was purified to obtain 870 mg (yield 78%) of 5 molyl phenyl) _4_ (2, cardio diphenyl) ) Thiazole-2-carboxylic acid amine, melting point: ι71-173 ^. 15 Prepared by a similar method: 4 · (2,4-Monophenyl) -N- (1_σcitridinyl) -5_ (4_ (trifluoromethyl) phenyl) thiazolecarboxylic acid amine, melting point: 181-383 ° C. N-cyclohexyl-4- (2,4-difluorophenyl) -5- (4- (trifluoromethyl) phenyl) thiazolecarboxylic acid amine, melting point: 140-142X :. 20 Example 4 Part A · 1.80 g (3.94 mmol) of 5- (4-bromophenyl) -4- (2,4-dichlorophenyl) thiazole-2-carboxylic acid ethyl ester was dissolved in 20 ml of methanol To this was added an aqueous solution of potassium hydroxide (a solution formed by dissolving 0.65 g (85%), 9 85 milliliters of hydroxide in 2G liters of water), and the resulting mixture was refluxed 19 200305411 发明, the temperature of the invention After heating for 1 hour, it was poured into water and acidified with a 1N hydrochloric acid solution. The resulting precipitate was collected by filtration and dried under vacuum at room temperature to obtain a quantitative yield of 5- (4-bromophenyl) -4- (2,4-dichlorophenyl) thiazole-2-carboxylic acid. , Melting point: 94_95. (:. 5 Part B. · 0.50 g (1.17 mmol) of 5_ (4-bromophenyl) -4_ (2,4 • difluorophenyl) thiazole-2-carboxylic acid and 1.02 ml (5.85 mol) Diisopropylethyl Jk (DIPEA) was dissolved in 5¾ liters of digas, and cooled to 0. 11 g (0.81 love: mol) of 7-aza-1-acylbenzotrisalcate was added thereto. (HAt) and 0.50 g (1.76 mmol) of 2-gas-1,3-dimethylimidazoline rust hexafluorophosphate 10 (CIP), followed by addition of 0.15 g (1. Amylamine, and the resulting mixture was stirred at room temperature overnight. Purification by flash chromatography (digas methane) gave 0.28 g (yield 48%) of 5- (4-bromophenyl) -4- (2+ Difluorophenyl) -IvK-n-pentyl) oxazole-2-carboxyamidine An amorphous solid. Prepared in a similar manner: 15 5- (4 · Bromophenyl) _4_ (2,4 · Digasphenyl) _N · (Hexahydroazepinetriyl-1-yl) thiazole-2-carboxyfluorene Amine, melting point: 206-207 ° C. 5- (4- / Styrenyl) -4 · (2,4-difluorophenyl (morpholin_4-yl) oxazolecarboxamide, an amorphous solid. 5- (4-styrenyl) · 4. · (2,4-Difluorophenylpyrrolidine-; 1-yl) thiazole-20 2-carboxamide, melting point: 179-181. (:. Paste Example 5 Part A: 0.5. (1 · 30 mol) of 5 < _ (4 · Gaphenyl) -4_ (2,4_dichlorophenyl) thiazole-2-carboxylic acid was dissolved in 10 ml of digas methane, and successively added thereto 0.15 g (1.30 mmol-aminohexaaza (1Η) azacycloheptanine, 20 200305411 玖, description of the invention 0.18 g (1.30 ¾ mole) 7-aza-1-mercaptobenzotriazole, Cardiac dysfunction (% mmol) 7-azabenzotriazol-1-yloxytris (sulrolidyl) squamous hexafluorophosphate (PyAOP) and 0.34 ml (1.95 mmol) diisopropylethyl Amine, and the resulting solution was stirred at room temperature for 1 hour. It was concentrated in vacuo to give 5 2 · 01 g of a crude oil, which was subjected to flash chromatography (ethyl acetate / petroleum ether '= l / 3 (v / v)) The oil was purified to obtain 0.350 g (yield 56%) of 5- (4-chlorophenyl) -4- (2,4-dichlorophenyl)-> ^ (hexahydro (111) Azacycloheptatrien-1_yl ) Thiazole-2-carboxamide, melting point: 185-186 (measured after recrystallization with diisopropyl ether). 10 Prepared in a similar manner: 5- (4-chlorophenyl) -4_ (2,4- Dichlorophenyl) · N · (Hexahydrocyclopentane [[]] Houkou-2 (1H) -yl) oxazole-2-endamidine, melting point: i73-174 ° C. N-benzyl 5--5- (4-Gaphenyl) -4- (2,4-Diphenyl) -N-methyl-thiazole-2-endamidine, melting point: 141-144 ° C. 15 5- (4-Gasphenyl) -4- (2,4-Digasphenyl) -N- (4- (trifluorofluorenyl) benzyl) hydrazone-2-bromofluorene, refining point: 174-176 0. 5- (4-chlorophenyl) -4- (2,4-dichlorophenyl) -N- (exo-bicyclo R.2.1) hept-2-yl) thiazole-2-carboxamide, Melting point: 194-195X: 5- (4 · chlorobenzyl) -4- (2,4-dichlorophenyl) -N- (endo-bicyclo [2.2.1] hept-2-20yl) thiazole- 2-Carboxamide, melting point: 181-183X: 5- (4-chlorophenyl) -4- (2,5-dichlorophenyl) -N- (exo-bicyclo [2.2.1] heptan-2 -Amino) sialyl-2-carboxamide, melting point: i70 ° C. 5- (4-chlorophenyl) · N- (cyclohexyl) -4- (2,5-diphenylphenyl) thiazole- 2-Carboxamide, melting point: 75 ° C. 21 200305411 11, description of the invention 5- (4-chlorophenyl) _4- (2,4-dichlorobenzene Yl) -N- (tetrahydro-2l-pyran-2-yloxy) thiazole-2-carboxamide, melting point: 85. (:. Example 6 1.65 g (4.0 mmol) of 5- (4-chlorophenyl) -4- (2,4-difluorophenyl) thia-5azole-2-carboxylic acid ethyl ester was dissolved in 25 To ml of anhydrous tetrahydrofuran, 0.37 ml (4.0 mmol) of aniline was added. The resulting solution was cooled to zero, and 4.4 ml of a tetramethylfuran solution (1M) of hexamethyldisilazyl sodium was added thereto. The reaction mixture was stirred for 2 hours. Water was then added thereto, the mixture was extracted twice with ethyl acetate, the organic layers were combined and washed with brine 10, dried over magnesium sulfate, filtered and concentrated in vacuo, the residue Crystallization was performed with diisopropyl ether to obtain 1.42 g (yield 77%) of 5- (4-phenyl) -4- (2,4-monobenzyl) phenylphenyl H2-benzylamine. i67-168 ° C. [Simplified description of the drawing] (None) 15 [List of symbols for the main components of the drawing] (None)