TW201031662A

TW201031662A - Imidazolylpyrazine derivatives

Info

Publication number: TW201031662A
Application number: TW099102604A
Authority: TW
Inventors: Daiju Hasegawa; Noritaka Kitazawa
Original assignee: Eisai R&D Man Co Ltd
Priority date: 2009-02-26
Filing date: 2010-01-29
Publication date: 2010-09-01
Also published as: AR075605A1; JP2012051806A; WO2010098495A1

Abstract

To provide a novel low-molecular-weight compound that inhibits the production of amyloid- β (A β ). A compound represented by the formula [I]: or a pharmacologically acceptable salt or ester thereof, wherein R1 and R2 are the same or different and each represent a substituent selected from the following Substituent Group a1; m represents an integer of 0 to 3; n represents an integer of 0 to 2; X1 represents a single bond or the like; X2 represents a single bond or the like; Ring A represents a five-membered aromatic heterocyclic group or the like which contains two or more nitrogen atoms and may have 1 to 3 substituents selected from the following Substituent Group b1; and Ring B represents a monocyclic or fused cyclic aromatic ring group such as the formula [2] which may have 1 to 3 substituents selected from the following Substituent Group c1, is effective as a therapeutic agent for a disease such as Alzheimer's disease. Substituent Group al: a C1-6 alkyl group and the like Substituent Group b1: a C1-6 alkyl group and the like Substituent Group c1: an amino group and the like

Description

201031662 六、發明說明：【發明所屬技彳衧領織】 [技術領域] 本發明係有關於-種藥物，更特別地，係有效治療藉由類澱粉_ β (其後稱為Α β)造成之諸如阿兹罕默氏疾病或唐氏症候群之神經退化疾病之咪唑吡畊衍生物，及一藥劑，特別地，係包含作為活性成份之此化合物之用於治療藉由 Αβ造成之疾病之藥劑。 C先前冬好3 [背景技藝] 阿茲罕默氏疾病係一種特徵在於神經元退化及喪失與老化斑塊形成及神經纖維退化之疾病。現今，阿茲罕默氏疾病僅係以一使用一典型上係乙醯膽鹼酯酶抑制劑之症候改善劑之症候治療而治療，且用以抑制疾病發展之基礎療法尚未被發展出。需要發展一種用以控制病理發生之原因之方法，以產生一用於阿茲罕默氏疾病之基礎療法。作為類澱粉先質蛋白質（其後稱為ΑΡΡ)之代謝物之Αβ-蛋白質被認為係高度涉及神經元之退化及喪失及癡呆症症候群之發生（見，例如，非專利文件丨及2)。Ap_蛋白質之主要分子物種係由40個胺基酸組成之Αβ4及具有二於c_端部添加之胺基酸之Αβ42。Αβ40及Αβ42已知具有高凝集性 (見’例如’非專利文件3)且係老化斑塊之主要組份（見，例如’非專利文件3、4及5)。再者，已知Αβ40及Αβ42係藉由於豕族性阿茲罕默氏疾病觀察到之ΑΡΡ及早老素基因之突 201031662 變而增加(見，例如’非專利文件6、7及8)。因此，-降低 Αβ4〇及Αβ42產生之化合物被預期係阿兹罕默氏疾病之發展抑制劑或預防劑。 Αβ係藉由β-分泌酶及其後藉由丫_分泌酶裂解Αρρ而產生。因為此原因’已致力於γ•分泌酶及ρ_分泌酶以降低Αρ 產生。许多已知之此等分泌酶抑制劑係，例如，肽類及肽模仿物，諸如，L-685,458(見，例如，非專利文件9)、 ly_4ii，575(見，例如，非專利文件l〇、n及12)及 LY-450，139(見，非專利文件13、14及丨5)。非肽之化合物係，例如，MRK_560(見非專利文件16及17)及如專利文件丨及之所揭示之具有多數個芳香族環之化合物。但是，以於說明書第17頁揭露之化學式(VI)表示之化合物係不同於本發明之化合物，因為此化合物係限於一具有一2_胺基噻唑基基團作為一主要結構之化合物。201031662 VI. Description of the Invention: [Technical Field] [Technical Field] The present invention relates to a drug, and more particularly, to an effective treatment caused by a starch-like β (hereinafter referred to as Αβ) An imidazole pyridine derivative such as Azheimer's disease or a neurodegenerative disease of Down's syndrome, and a medicament, in particular, an agent for treating a disease caused by Aβ, which is an active ingredient of the compound . C Previous Winter 3 [Background Art] Azheimer's disease is a disease characterized by neuronal degeneration and loss and aging plaque formation and neurofibrosis. Today, Azheimer's disease is treated only with a symptomatic treatment using a symptomatic improvement agent typical of an acetylcholinesterase inhibitor, and the basic treatment for inhibiting the progression of the disease has not yet been developed. There is a need to develop a method for controlling the causes of pathogenesis to produce a basic therapy for Azheimer's disease. The Αβ-protein which is a metabolite of a starch-like precursor protein (hereinafter referred to as sputum) is considered to be highly involved in the degeneration and loss of neurons and the occurrence of dementia syndrome (see, for example, Non-Patent Documents 2). The main molecular species of Ap_ protein is Αβ4 composed of 40 amino acids and Αβ42 having an amino acid added at the end of c_. Αβ40 and Αβ42 are known to have high agglutination (see 'For example, 'Non-Patent Document 3) and are the main components of aged plaques (see, for example, 'Non-Patent Documents 3, 4 and 5'). Further, it is known that Αβ40 and Αβ42 are increased by the observation of 豕Azheimer's disease and the mutation of the presenilin gene 201031662 (see, for example, 'Non-Patent Documents 6, 7 and 8'). Therefore, a compound which reduces the production of Αβ4〇 and Αβ42 is expected to be a developmental inhibitor or preventive agent for Azheimer's disease. The Αβ system is produced by β-secretase and subsequent cleavage of Αρρ by 丫_secretase. For this reason, γ-secretase and ρ_secretase have been devoted to reducing Αρ production. Many such secretase inhibitors are known, for example, peptides and peptide mimetics, such as L-685, 458 (see, for example, Non-Patent Document 9), ly_4ii, 575 (see, for example, Non-Patent Document l, n and 12) and LY-450, 139 (see, Non-Patent Documents 13, 14 and 丨 5). Non-peptide compounds are, for example, MRK_560 (see Non-Patent Documents 16 and 17) and compounds having a plurality of aromatic rings as disclosed in the patent documents. However, the compound represented by the chemical formula (VI) disclosed on page 17 of the specification is different from the compound of the present invention because the compound is limited to a compound having a 2-aminothiazolyl group as a main structure.

且，如專利文件2之說明書第6頁揭示般之以化學表不之化合物係不同於本發明之化合物，因為先者之化入物於以Ah定義之部份結構中不具有吡讲環。 QFurther, the compound which is chemically distinguished as disclosed on page 6 of the specification of Patent Document 2 is different from the compound of the present invention because the precursor of the present invention does not have a pyridyl ring in a part of the structure defined by Ah. Q

[習知技藝文件] [專利文件] [專利文件 1] WO 2004/110350 [專利文件2] WO 2007/102580 [非專利文件] 影響 [非專利文件l]KleinWL及其它七位’阿茲罕默氏疾病之腦部：募聚物Αβ配位體(ADDL)之存在暗示可逆式 5 201031662 失之分子基礎，Proceeding of the National Academy 〇f[Practical Skills Document] [Patent Document] [Patent Document 1] WO 2004/110350 [Patent Document 2] WO 2007/102580 [Non-Patent Document] Affects [Non-Patent Document 1] KleinWL and other seven 'Azham The brain of the disease: the presence of the polymeric Αβ ligand (ADDL) suggests reversible 5 201031662 The molecular basis of loss, Proceeding of the National Academy 〇f

Science USA, 2003, Sep，2; 100 (18)，10417-10422 頁。 [非專利文件2]NitschRM及其它十六位，對抗β-類殺粉之抗體減緩阿兹罕默氏疾病之認知衰退，Neuron, 2003, May 22; 38, 547-554頁。 [非專利文件3 ] Jarrett JT及其它二位，β類澱粉蛋白質之羧基端對於類澱粉形成之播種係重要：阿茲罕默氏疾病發病之推論，Biochemistry, 1993, 32 (18)，4693-4697頁。 [非專利文件4]Glenner GG及其它一位，阿茲罕默氏疾病：一新穎之腦血管類澱粉蛋白質之純化及特性描述之起始報告 ’ Biochemical and Biophysical Research Communications, 1984, May 16, 120 (3)，885-890頁。 [非專利文件5]Masters CL及其它五位，阿茲罕默氏疾病及唐氏症候群之類殿粉斑核心蛋白質，Proceeding of the National Academy of Science USA, 1985, Jun, 82 (12), 4245-4249 頁。 [非專利文件6]Gouras GK及其它十一位，人類腦部之神經元内之 Αβ42細積，American Journal of Pathology, 2000, Jan， 156 (1)，15-20 頁。 [非專利文件7]Scheuner D及其它二十位，與阿茲罕默氏疾病之老化斑塊中相似之分泌之類澱粉β-蛋白質於活體内係藉由與家族性阿茲罕默氏疾病相關連之早老素1及2與ΑΡΡ 突變而增加，Nature Medicine, 1996, Aug，2 (8)，864-870頁。 [非專利文件8]Forman MS及其它四位，瑞典突變類澱粉先 201031662 質蛋白質對神經元及非神經元細胞之β-類澱粉之累積及分泌之不同作用，The Journal of Biological Chemistry，1997, Dec, 19, 272 (51)，32247-32253 頁。 [非專利文件9] Shearman MS及其它九位，L-685, 458，天冬胺酸蛋白酶轉化態模擬，係類澱粉β-蛋白質先質γ-分泌酶活性之有效抑制劑，Biochemistry, 2000, Aug, 1, 39 (30)， 8698-8704頁。 [非專利文件10]ShearmanMS及其它六位，催化位置導引之 γ -分泌酶錯合抑制劑於刻痕S 3及β - A P P裂解間無法藥理學辦別，Biochemistry, 2003, Jun，24, 42 (24)，7580-7586頁。 [非專利文件ll]Lanz ΤΑ及其它三位，使用γ-分泌酶抑制劑 N2-[(2S)-2-(3,5-二氟苯基)-2-羥基乙醯基]-Nl-[(7S)-5·甲基 -6-側氧基·6,7-二氫-5H-二苯并[b，d]氮呼-7-基]-L-丙氨醯胺 (LY-411575)之於年輕（無斑）Tg2576小鼠之腦部、腦脊液及血漿之Αβ藥物動力學研究，The Journal of Pharmacology and Experimental Therapeutics, 2004, Apr，309 (1)，49-55 頁。 [非專利文件12]WongGT及其它十二位，以γ-分泌酶抑制劑 LY- 411，5 7 5之慢性治療抑制β -類澱粉肽產生及改變淋巴細胞生成及腸細胞分化，The Journal of Biological Chemistty 2004, Mar, 26, 279 (13)，12876-12882 頁。 [非專利文件l3]Gitter BD及其它十位，藉由LY450139，一種新穎之功能性γ分泌酶抑制劑，立體選擇性抑制類殺粉p 肽分泌 ’ Neurology of Aging 2004, 25, sup2，第 571 頁。 [非專利文件14] Lanz ΤΑ及其它十八位，於活體内及試管内 7 201031662 之使用γ-分泌酶抑制劑，LY-450139，之類澱粉-β之依濃度而定之調節，The Journal of Pharmacology and Experimantal Therapeutics, 2006, Nov，319 (2) 924-933 頁。 [非專利文件15]Siemers ER及其它十三位，γ-分泌酶抑制劑於具阿茲罕默氏疾病之病患之隨機化研究之作用，Science USA, 2003, Sep, 2; 100 (18), 10417-10422 pages. [Non-Patent Document 2] NitschRM and sixteen other anti-beta-class anti-fungal antibodies slow down cognitive decline in Azheimer's disease, Neuron, 2003, May 22; 38, 547-554. [Non-Patent Document 3] Jarrett JT and two others, the carboxy terminus of beta-starch protein is important for the starch-forming seeding system: a corollary to the onset of Azheimer's disease, Biochemistry, 1993, 32 (18), 4693 4,697 pages. [Non-Patent Document 4] Glenner GG and others, Azheimer's disease: A preliminary report on the purification and characterization of a novel cerebrovascular starch protein' Biochemical and Biophysical Research Communications, 1984, May 16, 120 (3), pages 885-890. [Non-Patent Document 5] Masters CL and five other core proteins, Alzheimer's disease and Down's syndrome, Proceeding of the National Academy of Science USA, 1985, Jun, 82 (12), 4245 -4249 pages. [Non-Patent Document 6] Gouras GK and 11 other Αβ42 fines in neurons of the human brain, American Journal of Pathology, 2000, Jan, 156 (1), 15-20. [Non-Patent Document 7] Scheuner D and the other 20, a secreted starch β-protein similar to that in the aging plaque of Azheimer's disease, in vivo with familial Azheimer's disease Associated with presenilin 1 and 2 and ΑΡΡ mutations increased, Nature Medicine, 1996, Aug, 2 (8), pp. 864-870. [Non-Patent Document 8] Forman MS and four other, Swedish mutant starch first 201031662 plasmonic protein on the accumulation and secretion of β-type starch in neurons and non-neuronal cells, The Journal of Biological Chemistry, 1997, Dec, 19, 272 (51), 32247-32253 pages. [Non-Patent Document 9] Shearman MS and other nine, L-685, 458, aspartic acid protease conversion state simulations, effective inhibitors of beta-protein precursor γ-secretase activity, Biochemistry, 2000, Aug, 1, 39 (30), 8698-8704. [Non-Patent Document 10] ShearmanMS and six other catalytically-guided gamma-secretase mismatch inhibitors are not pharmacologically cleavable between S3 and β-APP cleavage, Biochemistry, 2003, Jun, 24, 42 (24), 7580-7586 pages. [Non-Patent Document 11] Lanz ΤΑ and the other three, using the γ-secretase inhibitor N2-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethenyl]-Nl- [(7S)-5·methyl-6-ophthalyl·6,7-dihydro-5H-dibenzo[b,d]azoh-7-yl]-L-alaninamide (LY- 411575) Αβ pharmacokinetic study of the brain, cerebrospinal fluid and plasma of young (plaque-free) Tg2576 mice, The Journal of Pharmacology and Experimental Therapeutics, 2004, Apr, 309 (1), pp. 49-55. [Non-Patent Document 12] WongGT and 12 other, chronic treatment with γ-secretase inhibitor LY-411, 557 inhibits β-amyloid production and changes lymphocyte production and intestinal cell differentiation, The Journal of Biological Chemistty 2004, Mar, 26, 279 (13), 12876-12882 pages. [Non-Patent Document l3] Gitter BD and the other ten, with LY450139, a novel functional gamma secretase inhibitor, stereoselective inhibition of powdered p-peptide secretion ' Neurology of Aging 2004, 25, sup2, 571 page. [Non-Patent Document 14] Lanz ΤΑ and other 18th place, adjusted in vivo and in vitro 7 201031662 using γ-secretase inhibitor, LY-450139, starch-β-dependent concentration, The Journal of Pharmacology and Experimantal Therapeutics, 2006, Nov, 319 (2) 924-933. [Non-Patent Document 15] Siemers ER and other thirteen, γ-secretase inhibitors in the randomized study of patients with Alzheimer's disease,

Neurology，2〇〇6, 66, 602-604 頁。 [非專利文件16] Best JD及其它九位，於大鼠之使用新穎之 γ-分泌酶抑制劑N-[順-4-[(4-氣苯基)磺醯基]-4-(2,5-二氟苯基）環己基]-1,1，1-三氟曱烷磺醯胺(ΜΚ-560)之於腦部及腦 ® 脊液之Αβ(40)變化之活體内特性化描述，The Journal ofNeurology, 2, 6, 66, 602-604. [Non-Patent Document 16] Best JD and the other nine, the novel γ-secretase inhibitor N-[cis-4-[(4-phenylphenyl)sulfonyl]-4-(2) was used in rats. In vivo characterization of Αβ(40) changes in brain and brain® spinal fluids with 5-difluorophenyl)cyclohexyl]-1,1,1-trifluorodecanesulfonamide (ΜΚ-560) Description, The Journal of

Pharmacology and Experimantal Therapeutics，2006，May 317 (2) 786-790 頁。 [非專利文件17]Best JD及其它十三位，新穎之γ-分泌酶抑制一劑Ν-[順-4-[(4-氣苯基）磺醯基]_4-(2,5-二氟苯基）環己 “ 基]-U，l-三氟曱烷磺醯胺(MK-560)於Tg2576小鼠無明顯之與刻痕相關之病狀地降低類澱粉斑塊沈積，The Journal 一 of Pharmacology and Experimantal Therapeutics, 2007, Feb, 320 (2) 552-558頁。 C 明内3 [發明概要] [欲藉由本發明解決之問題] 如上所述，一種抑制自APP產生Αβ40及Αβ42之化合物已被預期作為藉由Α β造成之疾病（典型上係阿茲罕默氏疾病）之治療或預防之藥劑。但是，具有抑制八04〇及八042產 8 201031662 生之高效率之非肽化合物尚未知。因此，需要一種抑制Αβ40 及Αβ42產生之新穎低分子量化合物。 [解決此問題之手段] 廣泛研究之結果，本案發明人發現一種抑制自ΑΡΡ產生Αβ40及Αβ42之非肽多環化合物，且因此發現一種用於藉由Αβ造成之疾病（典型上係阿茲罕默氏疾病）之治療劑。此發現導致本發明之完成。 • 特別地，本發明係有關於下列1)至20): 1) 一種以化學式[I]表示之化合物： [化學式1]Pharmacology and Experimantal Therapeutics, 2006, May 317 (2) 786-790. [Non-Patent Document 17] Best JD and 13 other, novel γ-secretase inhibits one dose of Ν-[cis-4-[(4-phenylphenyl)sulfonyl]_4-(2,5-di Fluorophenyl)cyclohexyl]-U,l-trifluorodecanesulfonamide (MK-560) reduces the deposition of amyloid plaques in Tg2576 mice without significant scoring-related conditions, The Journal Iof Pharmacology and Experimantal Therapeutics, 2007, Feb, 320 (2) 552-558. C Mingna 3 [Summary of the Invention] [Problems to be solved by the present invention] As described above, one inhibits the production of Αβ40 and Αβ42 from APP. The compound has been expected to be an agent for the treatment or prevention of a disease caused by Αβ (typically Azheimer's disease). However, it has a non-peptide which inhibits the high efficiency of 八04〇 and 八0428 201031662 The compound is not known. Therefore, there is a need for a novel low molecular weight compound which inhibits the production of Αβ40 and Αβ42. [Means for Solving the Problem] As a result of extensive research, the inventors of the present invention have found a non-peptide polycyclic compound which inhibits the production of Αβ40 and Αβ42 from ruthenium, And thus found a disease caused by Αβ Therapeutic agents for the above-mentioned Azheimer's disease. This finding led to the completion of the present invention. • In particular, the present invention relates to the following 1) to 20): 1) A compound represented by the chemical formula [I]: Chemical formula 1]

或其藥理學上可接受之鹽或酯，其中，1^及112係相同或相異，且每一者代表一選自下列取代基族群al之取代基； m代表0至3之整數； η代表0至2之整數； Χι代表i)一單鍵，ii) Η匕學式2] —CeC — 或iii)-CR3=CR4-(其中，R3及R4係相同或相異，且每一者代表（1)一氫原子，（2) — C1-6烷基基團，或(3)—鹵素原子）； X2代表i)一單鍵，ii)一C1-6烷撐基基團，或iii)-X3-(其中， 9 201031662 V /li ± m a 〜八、 ^Or a pharmacologically acceptable salt or ester thereof, wherein 1 and 112 are the same or different, and each represents a substituent selected from the group of substituents a1; m represents an integer from 0 to 3; Represents an integer from 0 to 2; Χι stands for i) a single bond, ii) Η匕2) —CeC — or iii)-CR3=CR4- (where R3 and R4 are the same or different, and each Representing (1) a hydrogen atom, (2) - a C1-6 alkyl group, or (3) - a halogen atom; X2 represents i) a single bond, ii) a C1-6 alkylene group, or Iii)-X3-(where, 9 201031662 V /li ± ma ~ 八, ^

C2-6烷醯基基團，或Cl-6烷基磺醯基基團）；玉衣八代表i)一五員之方香族雜％基團，或…—與一 5-至14_ 員之非芳香族環基團稠合之五員之芳香族雜環基團，其含有二或更多個氮原子且可具有1至3個選自下列取代基族群 bl之取代基(其中’非芳香族環基團具有一經交聯之結構或一螺族環系統）；且環B代表一選自由化學式[2]至[19]所組成族群之單環或铜參合環之芳香族環基團： Η匕學式3]a C2-6 alkanoyl group, or a Cl-6 alkylsulfonyl group); a jade cloth representing i) a five-membered Fangxianghe hetero-group, or...-with a 5- to 14_ member a five-membered aromatic heterocyclic group fused to a non-aromatic ring group, which contains two or more nitrogen atoms and may have 1 to 3 substituents selected from the group bl of the following substituents (where 'non- The aromatic ring group has a crosslinked structure or a spiro ring system); and ring B represents an aromatic ring group selected from a monocyclic or copper ring of the group consisting of the chemical formulas [2] to [19] : Dropout 3]

其每一者可具有1至3個選自下列取代基族群cl之取代基，取代基族群al : — C1-6烷基基團、一C3_8環燒基基團、一 C2-6烯基基團、一C1-6烷氧基基團、一C2-6烯氧基基團、一 C3-8環烷氧基基團、一胺基基團（其中，胺基基團可具有一 C2-6烷醯基基團或C1-6烷基磺醯基基團或1至2個C1-6 烷基基團或C3-8環烷基基團）、一氰基基團、一曱醯基基困、一_素原子、一羥基基團及一硝基基團；取代基基團bl : — C1-6院基基團（其中’垸基基團可以1至3 10 201031662 個鹵素原子取代）、一C2-6烯基基團、一C3-8環烷基基團、一C6-14芳基基團、—C6-14芳基-C1-6烷基基團、一C1-6烷氧基基團、一C2-6烯氧基基團、一C3-8環烷氧基基團、一 C2-6烷醯基基團、一C4-9環烷基羰基基團、一C7-15芳醯基基團、一C1-6烷基磺醯基基團、一C2-6烯基磺醯基基團、一C3-8環烷基磺醯基基團、一C6-14芳基磺醯基基團、一C1-烷硫基基團、一C2-6烯硫基基團、一C3-8環烷硫基基團、一胺基磺醯基基團（其中，胺基磺醯基基團可具有1至2個 C1-6烷基基團、C2-6烯基基團或C3-8環烷基基團）、一胺基基團（其中，胺基基團可具有一C2-6烷醯基基團、C1-6烷基磺醯基基團或C3-8環烷基磺醯基基團，或1至2個C1-6烷基基團或C3-8環烷基基團）、一氰基基團、一甲醯基基團、一鹵素原子、一羥基基團、一硝基基團、一側氧基基團、一 l-n比洛咬基基團、1-σ底咬基基團、一 1-同α底0定基基團、一0引哚啉-1-基基團、一 1，2,3,4-四氫喹啉-1-基基團及一4-嗎啉基基團；取代基基團cl :i)一胺基基團（其中’胺基基團可具有一C2-6 烷醯基基團、C1-6烷基磺醯基基團或C3-8環烷基磺醯基基團，或1至2個C1-6烷基基團或C3-8環烷基基團），ii) 一氰基基，iii)一鹵素原子，iv)—羥基基團及v)v)-i) — C1-6烷基基團，v)-ii) — C2-6烯基基團，v)-iii) — C2-6炔基基團，v)-iv) 一C1-6院氧基基團，v)-v) — C1-6炫硫基基團’ v)-vi) — C1-6 烷基胺基羰基基團，v)-vii) — C1-6烷基磺醯基基團，v)-viii) 一C1-6院基胺基石黃醯基基團，v)-ix) — C2-6院醯基基團，v)-x) 1 1 201031662 一苯基基團，v)-xi)—°比咬基基團，v)-xii)—塔π井基基團， v)-xiii)—嘴。定基基團，v)-xiv) — 1-°比0各咬基基團，ν)-χν) — 1-0底唆基基團，v)-xvi) — 1-同派咬基基團及v)-xvii) — 4-嗎琳基基團，其每一者具有1至3個選自一C1-6烷基基團及一鹵素原子所組成族群之取代基； 2)依據如上之1)之化合物或其藥理學上可接受之鹽或酯，其中，環A係一選自化學式[20]至[26]所組成族群之五員之芳香族雜環基團： [化學式4]Each of them may have 1 to 3 substituents selected from the group of substituents cl, a group of substituents a: - C1-6 alkyl group, a C3-8 cycloalkyl group, a C2-6 alkenyl group a group, a C1-6 alkoxy group, a C2-6 alkenyloxy group, a C3-8 cycloalkoxy group, an amine group (wherein the amine group may have a C2- a 6 alkylalkyl group or a C1-6 alkylsulfonyl group or 1 to 2 C1-6 alkyl groups or a C3-8 cycloalkyl group), a cyano group, a fluorenyl group Base group, a _ atom, a hydroxy group and a nitro group; a substituent group bl: — a C1-6 group group (wherein the 'fluorenyl group can be substituted with 1 to 3 10 201031662 halogen atoms a C2-6 alkenyl group, a C3-8 cycloalkyl group, a C6-14 aryl group, a C6-14 aryl-C1-6 alkyl group, a C1-6 alkane An oxy group, a C2-6 alkenyloxy group, a C3-8 cycloalkoxy group, a C2-6 alkanoalkyl group, a C4-9 cycloalkylcarbonyl group, a C7- 15 arylalkyl group, a C1-6 alkylsulfonyl group, a C2-6 alkenylsulfonyl group, a C3-8 cycloalkylsulfonyl group, a C6-14 aryl group Sulfonyl a group, a C1-alkylthio group, a C2-6-alkenyl group, a C3-8 cycloalkylthio group, an aminosulfonyl group (wherein an aminosulfonyl group) There may be 1 to 2 C1-6 alkyl groups, C2-6 alkenyl groups or C3-8 cycloalkyl groups), an amine group (wherein the amine group may have a C2-6 An alkino group, a C1-6 alkylsulfonyl group or a C3-8 cycloalkylsulfonyl group, or 1 to 2 C1-6 alkyl groups or a C3-8 cycloalkyl group ), a cyano group, a monomethyl group, a halogen atom, a monohydroxy group, a mononitro group, a oneoxy group, an ln carbyl group, a 1-σ bottom a thiol group, a 1-iso-alpha base group, a 0-pyridin-1-yl group, a 1,2,3,4-tetrahydroquinolin-1-yl group, and a 4 a morpholinyl group; a substituent group cl: i) an amino group (wherein the 'amino group' may have a C2-6 alkylalkyl group, a C1-6 alkylsulfonyl group or a C3-8 cycloalkylsulfonyl group, or 1 to 2 C1-6 alkyl groups or a C3-8 cycloalkyl group), ii) a cyano group, iii) a halogen atom, iv) —hydroxyl group and v)v)-i) — C1-6 alkyl a group, v)-ii) - a C2-6 alkenyl group, v) - iii) - a C2-6 alkynyl group, v) - iv) a C1-6 alkoxy group, v) - v) —C1-6 SiO group — v)-vi) — C1-6 alkylaminocarbonyl group, v)-vii) — C1-6 alkylsulfonyl group, v)-viii) C1-6-based amine-based fluorenyl group, v)-ix) - C2-6-indenyl group, v)-x) 1 1 201031662 1-phenyl group, v)-xi)-° ratio Group, v)-xii) - tower π well group, v) - xiii) - mouth. Stationary group, v)-xiv) — 1-° ratio 0 each thiol group, ν)-χν) — 1-0 thiol group, v)-xvi) — 1-isotactic thiol group And v)-xvii) - 4-morphinyl groups each having 1 to 3 substituents selected from the group consisting of a C1-6 alkyl group and a halogen atom; 2) A compound or a pharmacologically acceptable salt or ester thereof, wherein the ring A is an aromatic heterocyclic group selected from the group consisting of five groups of the chemical formulas [20] to [26]: [Chemical Formula 4]

其中，•代表一與化學式[27]之鍵結位置： Η匕學式5]Among them, • represents the bonding position of the chemical formula [27]: Η匕学式5]

(R2)nJ_ Α·代表一與X2之鍵結位置或選自化學式[28]至[39]所組成族群之任一環： [化學式6] 12 201031662(R2)nJ_ Α· represents a bonding position with X2 or a ring selected from the group consisting of chemical formulas [28] to [39]: [Chemical Formula 6] 12 201031662

其中，•及Α·係如上所定義及部份結構： Η匕學式7] 代表一單鍵或一雙鍵，其每一者可具有1至3個選自取代基族群bl之取代基； 3)依據如上之2)之化合物或其藥理學上可接受之鹽或酯，其中，環A係選自化學式[21]、[28]、[29]、[31]、[32] 及[34]至[37]所組成族群之任一環： [化學式8]Wherein, • and Α are as defined above and part of the structure: Η匕 7 7 represents a single bond or a double bond, each of which may have 1 to 3 substituents selected from the group bl of the substituent; 3) A compound according to 2) above, or a pharmacologically acceptable salt or ester thereof, wherein the ring A is selected from the group consisting of the chemical formulas [21], [28], [29], [31], [32] and [ Any of the groups consisting of 34] to [37]: [Chemical Formula 8]

其中，·、A·及部分結構： [化*學式9] 13 201031662 係如上所定義； 4)依據如上之2)之化合物或其藥理學上可接受之鹽或酯，其中’環A係選自化學式[21]、[28-1]、[29-1]、[3^^、 [32-1]及[34-1]至[37-1]所組成族群之任一環： [化學式10]Wherein, ··· and part of the structure: [Chemical Formula 9] 13 201031662 is as defined above; 4) A compound according to 2) above, or a pharmacologically acceptable salt or ester thereof, wherein the 'ring A system Any one selected from the group consisting of the chemical formulas [21], [28-1], [29-1], [3^^, [32-1], and [34-1] to [37-1]: [Chemical formula 10]

其中，·、Α·及部分結構： [化學式11] 係如上所定義； 5)依據如上之2)之化合物或其藥理學上可接受之鹽或酯，其中，環Α係一化學式[28_1；]之環： [化學式12]Wherein, ···· and part of the structure: [Chemical Formula 11] is as defined above; 5) A compound according to 2) above, or a pharmacologically acceptable salt or ester thereof, wherein the cyclic oxime is a chemical formula [28_1; Ring of the ring: [Chemical Formula 12]

28-1 其中，·、A·及部分結構： [化學式13] 係如上所定義； 14 201031662 6) 依據如上之1)之化合物或其藥理學上可接受之鹽或酯，其中，環B係一苯基基團、一》比啶基基團、一噁唑基基團、一咪唑基基團、一噻唑基基團、一二氫苯并呋喃基基團或一噻吩基基團； 7) 依據如上之1)之化合物或其藥理學上可接受之鹽或酯，其中，XHW)— 單鍵或ii)-CR3=CR4-; 8) 依據如上之1)之化合物或其藥理學上可接受之鹽或酯，其中，係一單鍵； 9) 依據如上之1)之化合物或其藥理學上可接受之鹽或酯，其中，X丨係-CR3=CR4-; 10) 依據如上之1)之化合物或其藥理學上可接受之鹽或酯，其中，x2係i)一單鍵或ii)一C1-6烷撐基基團； 11) 依據如上之1)之化合物或其藥理學上可接受之鹽或酯，其中，X2係一單鍵； 12) 依據如上之1)之化合物或其藥理學上可接受之鹽或酯，其中，R!係一C1-6烷基基團或一鹵素原子，且m係1至2; 13) 依據如上之1)之化合物或其藥理學上可接受之鹽或酯，其中，R2係一C1-6烷氧基基團，且η係1 ; 14) 依據如上之9)之化合物或其藥理學上可接受之鹽或酯，其中，R3及R4係相同或相異，且每一者係⑴一氫原子或(2) — ή素原子； 15) 依據如上之9)之化合物或其藥理學上可接受之鹽或酯，其中，R3及R4每一者係一氫原子； 16) 依據如上之1)之化合物或其藥理學上可接受之鹽或 15 201031662 酯，其中，環A之取代基係一選自：一^^烷基基團（其中，烧基基團可以1至3個鹵素原子取代）、—C3—8環烷基基團、一C6-14芳基基團、一C6-14芳基-C1-6烷基基團、一C1-6烷氧基基團、一 C3-8環烷氧基基團、一 C2-6烷醯基基團、一 C7-15芳醯基基團、一C1_6烷基磺醯基基團、一C3_8環烷基磺醯基基團、一C6-14芳基磺醯基基團、一氰基基團、一甲醯基基團、一南素原子、一羥基基團及一側氧基基團所組成族群之取代基； 17) 依據如上之1)之化合物或其藥理學上可接受之鹽或知，其中，環B之取代基係一選自：丨)—胺基基團（其中，胺基基團可具有一C2-6烷醯基基團、C1-6烷基磺酿基基團或 C3-8環烷基磺醯基基團，或1至2個(：1_6烷基基團或〇_8環烷基基團）’ii) 一氰基基團，m) 一函素原子，iv) 一羥基基團，及ν)ν)-ι) — C1-6烷基基團，v)_ii) — C1_6烷氧基基團，力_出) 一C1-6烷硫基基團，及v)_iv)一苯基基團所組成族群之取代基，其每一者可具有1至3個選自一C1_6烷基基團及一 _素原子所組成族群之取代基； 18) —選自下列化學式[Α—η至[A_7]所組成族群之化合物： [化學式14] 16 20103166228-1 wherein: ·, A· and a partial structure: [Chemical formula 13] is as defined above; 14 201031662 6) A compound according to 1) above, or a pharmacologically acceptable salt or ester thereof, wherein ring B is a phenyl group, a pyridyl group, a monooxazolyl group, an imidazolyl group, a thiazolyl group, a dihydrobenzofuranyl group or a thienyl group; A compound according to 1) above, or a pharmacologically acceptable salt or ester thereof, wherein XHW) - a single bond or ii) -CR3 = CR4; 8) a compound according to 1) above or a pharmacologically acceptable thereof An acceptable salt or ester, wherein a single bond; 9) a compound according to 1) above, or a pharmacologically acceptable salt or ester thereof, wherein X 丨-CR3=CR4-; 10) Or a pharmacologically acceptable salt or ester thereof, wherein x2 is i) a single bond or ii) a C1-6 alkylene group; 11) a compound according to 1) above or a pharmaceutically acceptable salt or ester wherein X2 is a single bond; 12) a compound according to 1) above, or a pharmacologically acceptable salt or ester thereof, wherein R! is a C1-6 alkyl group a compound or a halogen atom, and m is 1 to 2; 13) A compound according to the above 1), wherein R 2 is a C 1-6 alkoxy group, and η, or a pharmacologically acceptable salt or ester thereof The compound according to 9) above, or a pharmacologically acceptable salt or ester thereof, wherein R3 and R4 are the same or different, and each is (1) a hydrogen atom or (2) - ή A compound according to 9) above, or a pharmacologically acceptable salt or ester thereof, wherein each of R3 and R4 is a hydrogen atom; 16) a compound according to 1) above or a pharmacological thereof thereof An acceptable salt or 15 201031662 ester wherein the substituent of ring A is selected from the group consisting of: an alkyl group (wherein the alkyl group may be substituted with 1 to 3 halogen atoms), - C3-8 a cycloalkyl group, a C6-14 aryl group, a C6-14 aryl-C1-6 alkyl group, a C1-6 alkoxy group, a C3-8 cycloalkoxy group a C2-6 alkylalkyl group, a C7-15 aryl fluorenyl group, a C1-6 alkyl sulfonyl group, a C3-8 cycloalkyl sulfonyl group, a C6-14 aryl sulfonium group Base group, monocyano group, monomethyl group, one a substituent of a group consisting of a ruthenium atom, a monohydroxy group and a one-side oxy group; 17) a compound according to 1) above, or a pharmacologically acceptable salt thereof, wherein the substituent of ring B is One is selected from the group consisting of: an amine group (wherein the amine group may have a C2-6 alkylalkyl group, a C1-6 alkylsulfonic acid group or a C3-8 cycloalkylsulfonium group) a radical, or 1 to 2 (: 1_6 alkyl or 〇 8 cycloalkyl) 'ii) a cyano group, m) a acyl atom, iv) a hydroxy group, and ν) ν)-ι) — a C1-6 alkyl group, v) _ii) — a C1_6 alkoxy group, a force — a C1-6 alkylthio group, and v) —iv) a phenyl group Substituents of the group consisting of groups, each of which may have 1 to 3 substituents selected from the group consisting of a C1_6 alkyl group and a mono-atom atom; 18) - selected from the following chemical formula [Α-η Compounds of the group consisting of [A_7]: [Chemical Formula 14] 16 201031662

或其藥理學上可接受之鹽或酯；Or a pharmacologically acceptable salt or ester thereof;

=)種包含作為—活性成份之依據如上之收⑻之任一 =之化合物或其藥理學上可接受之鹽或醋之藥劑；及疾，據如上19)之藥劑，其係用於治療一選自阿兹罕默氏 ;癡呆症、唐氏症候群及類殿粉變性症之疾病。【實施方式】 [用以實行本發明之模式] 依據本發明之通式（I)之化合物或其藥理學上可接受之鹽或酯及依據本發明之用於藉由Αβ造成之疾病之治療劑係尚未於任何文件中描述之新穎發明。本發明之化合物可轉化成一用於使〆標靶蛋白質捕捉 17 201031662 於一生物活性低分子化合物内之化學探針。特別地，本發明之化合物可藉由，例如’ j. Mass Spectrum. Soc. Jpn. Vol. 51，No. 5，2003, 492-498 頁或 WO 2007/139149所述之技術，藉由使一標示基團、連接子等引入一不同於一對於表現此化合物活性係重要之結構部份之部份内而轉化成一親和力色譜分析術探針、一光親和力探針等。用於此化學探針之標示基團、連接子等之例子包含於下列之（1)至（5)所組成之族群所示之族群： (1) 蛋白質標示基團，諸如，光親和力標示基團（諸如，苯曱醯基基團、二苯基酮基團、疊氮基基團、羰基疊氮基基團、二吖丙啶基團、烯酮基團、重氮基基團及硝基基團）及化學親和力基團（諸如，於α_碳原子以一鹵素原子取代之酮基團、胺曱醯基基團、酯基團、烧硫基基團、體，諸如，α，β-不飽和之_及酯，及環氧乙烷基團）， (2) 可裂解之連接子，諸如，_s_s_、_〇_Si_〇_、單醣類（諸如，葡萄糖基團及半乳糖基團）及雙醣類（諸如，乳糖），及酶可裂解之寡肽連接子， (3) 魚標（fishing tag)基團，諸如，生物素及3_(4 4_二氟 -5,7·二甲基_4H-3a，4a-二氮雜_4，_s_0引丹婦_3_基）丙酿基， (4) 可檢狀標記物，諸如，放雜標記基團，諸如， I、P、3H及14c ;螢光標記基團，諸如，螢光黃、若丹明、丹黃酿基、傘形花内自旨、7，級e丫基及3_(4,4二氣·5,7_ 一甲基-4H-3a，4a-二氮雜-4，_s_0引丹稀_3_基)丙醯基；化學發光基團，諸如，螢光素及魯総；及重金屬離子，諸如， 18 201031662 鑭系金屬離子及鐳離子；及脂糖:與==、玻璃床、微滴定板，糖珠、瑗相載體結合之基團。、&本乙稀床、•珠及耐論床之固之ωΐΓ針係依據上述文件等所述之方法使-選自如上内而製備Γ組权_之標記基團⑼至本發明化合物=) a medicament comprising, as an active ingredient, a compound according to any one of the above (8) or a pharmacologically acceptable salt or vinegar thereof; and a medicament according to the above 19) for use in the treatment of Selected from Azheimer's disease; dementia, Down syndrome, and disease of the halllet powder degeneration. [Embodiment] [Mode for carrying out the invention] A compound of the formula (I) or a pharmacologically acceptable salt or ester thereof according to the invention and a treatment for a disease caused by Aβ according to the invention The agent is a novel invention that has not been described in any of the documents. The compounds of the invention can be converted into a chemical probe for capturing the target protein into a bioactive low molecular compound. In particular, the compounds of the present invention can be obtained by, for example, the technique described in 'j. Mass Spectrum. Soc. Jpn. Vol. 51, No. 5, 2003, 492-498 or WO 2007/139149 The labeling group, the linker, and the like are introduced into a portion different from the structural portion important for the activity of the compound, and converted into an affinity chromatography probe, a photoaffinity probe, and the like. Examples of the labeling group, the linker and the like used for the chemical probe are included in the group represented by the group consisting of the following (1) to (5): (1) a protein labeling group such as a photoaffinity labeling group a group (such as a benzoinyl group, a diphenylketone group, an azido group, a carbonyl azide group, a diaziridine group, an enone group, a diazo group, and a nitrate a group) and a chemical affinity group (such as a ketone group substituted with a halogen atom at the α-carbon atom, an amine sulfhydryl group, an ester group, a sulfur-burning group, a body such as α, --unsaturated _ and esters, and oxirane groups), (2) cleavable linkers such as _s_s_, _〇_Si_〇_, monosaccharides (such as glucose groups and half) Lactose group) and disaccharide (such as lactose), and enzyme cleavable oligopeptide linker, (3) fishing tag group, such as biotin and 3_(4 4_difluoro-5) , 7· dimethyl _4H-3a, 4a-diaza _4, _s_0 引丹 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ , I, P, 3H and 14c; Labeling groups, such as fluorescein, rhodamine, dansyl, umbellate, 7th, e-mercapto and 3_(4,4 2 gas·5,7_ monomethyl-4H- 3a, 4a-diaza-4, _s_0 sulphate _3_yl) propyl fluorenyl; chemiluminescent groups such as luciferin and reck; and heavy metal ions such as 18 201031662 lanthanide metal ions and Radium ion; and liposaccharide: a group combined with ==, a glass bed, a microtiter plate, a sugar bead, and a ruthenium phase carrier. , <<>><'>><>><>>

發：=:符號、_之一釋，且本特定=:明書:一化合物之結構式可代表-為了方便之 1'疋，本發明包含所有異構物及異構物混合，諸如’可自一化合物之結構產生之幾何異構物、以非對稱碳為基礎之光學異構物、立體異構物及互變異構物。本發明不限於—為了方便之化學式之描述，且可包含此等異構物或—之任—者。因此，本發明之化合物於分子内可具##對稱之碳原子，且以—光學活性化合物或外肩說物存在且本發明不受限地包含此光學活性化合物及外/肖旋物之每·者。雖然化合物之結晶多形艘可能存在，但此化合物亦不限於此，且可以一單—結㈣式或單 -結晶型式之混合物存在。此化合物可為無水物或水合物。本發明亦包含經同位素標定之化合物，其係與化學式 ⑴之化合物相同’但-或多個原子係以—具有與通常於自 '然中發現之原子質量或質4數不同之原子f量或質量數之 19 201031662 原子取代。可併納於本發明化合物内之同位素之例子包含氫、碳、氮、氧、4、氟、峨，及氣之同位素，諸如，2H、 3H、uc、14C、18F、35S、1231 及 1251。含有前述同位素及/或其它原子之其它同位素之本發明化合物及該等化合物之藥學上可接受之衍生物(例如，鹽）係於本發明之範圍内。經同位素標記之本發明化合物，例如’其内併納諸如3H及/或14c之放射性同位素者，可用於藥物及/或基材組織分佈分析。3H及14c由於其易於製備及可檢測而被認為係有用。11及18F同位素被認為可用於PET(正子發射斷層知猫術）’且I同位素被認為可用於SPECT(單質子放射電腦化斷層掃瞄術），所有皆可用於腦部圖像化。以諸如2H之較重同位素取代可提供自較大代謝穩定性產生之某些治療優點，例如，增加活體内之半衰期或降低劑量需求，因此’被認為於某些情況係有用。經同位素標記之本發明之化學式（I)之化合物一般可藉由實行於下之流程及/ 或實施例所揭示之程序，藉由以一可輕易獲得之經同位素標記之試劑取代一非經同位素標記之試劑而製備。 "可歸因於Αβ之疾病"一辭包含廣泛之各種不同狀況，諸如’阿茲罕默氏疾病（例如，參考Klein WL及其它7位，阿茲罕默氏疾病影響之腦部：募聚物Αβ配位體(ADDL)之存在暗示可逆式記憶喪失之分子基礎，Proceeding NationalHair: =: symbol, _ one release, and this specific =: Book: the structural formula of a compound can represent - for convenience 1 '疋, the present invention contains all isomers and isomers, such as 'can Geometric isomers derived from the structure of a compound, optical isomers based on asymmetric carbon, stereoisomers and tautomers. The invention is not limited to the description of the chemical formulas for convenience, and may include such isomers or any of them. Therefore, the compound of the present invention may have a ## symmetrical carbon atom in the molecule, and is present as an optically active compound or an external shoulder and the present invention includes, without limitation, each of the optically active compound and the outer/vertex ·By. Although a crystalline polymorphic vessel of the compound may be present, the compound is not limited thereto and may be present as a mixture of a single-junction (four) formula or a mono-crystalline form. This compound can be an anhydride or a hydrate. The present invention also encompasses an isotope-labeled compound which is the same as the compound of the formula (1) 'but- or a plurality of atomic systems--having an atomic amount of atom different from the atomic mass or mass number 4 usually found in the self or Mass number 19 201031662 Atomic substitution. Examples of isotopes which may be incorporated into the compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, 4, fluorine, ruthenium, and gas isotopes such as 2H, 3H, uc, 14C, 18F, 35S, 1231 and 1251. The compounds of the present invention containing the aforementioned isotopes and/or other isotopes of other atoms and pharmaceutically acceptable derivatives (e.g., salts) of such compounds are within the scope of the invention. Isotopically labeled compounds of the invention, e.g., which incorporate radioisotopes such as 3H and/or 14c, can be used for drug and/or substrate tissue distribution analysis. 3H and 14c are considered useful because of their ease of preparation and detectability. The 11 and 18F isotopes are considered to be useful for PET (positive emission tomography) and the I isotope is considered to be useful for SPECT (single proton radiological computed tomography), all of which can be used for brain imaging. Substitution with heavier isotopes such as 2H may provide certain therapeutic advantages resulting from greater metabolic stability, e.g., increase half-life in vivo or reduce dosage requirements, and are therefore considered useful in certain situations. Isotopically labeled compounds of formula (I) of the present invention can generally be substituted by a readily available isotope-labeled reagent by a procedure as disclosed in the Schemes and/or the Examples below. Prepared by labeled reagents. "The disease attributable to Αβ" encompasses a wide variety of different conditions, such as 'Azham's disease (for example, refer to Klein WL and 7 other, Azheimer's disease-affected brains: The presence of a polymeric Αβ ligand (ADDL) suggests a molecular basis for reversible memory loss, Proceeding National

Academy 〇f Science USA, 2003，Sep 2，100 (18)， 1〇417-1〇422頁；1^3〇1111]^及其它16位，對抗0-類澱粉之抗體減緩阿茲罕默氏疾病之認知衰退，Neuron, 2003，May 22; 20 201031662 38(4)，547-554頁；Jarrett JT及其它2位，β類殿粉蛋白質之羧基端對於類澱粉形成之播種係重要：阿茲罕默氏疾病發病之推論，Biochemistry, 1993, May 11，32 (18)，4693-4697 頁；Glenner GG及其它一位’阿兹罕默氏疾病：一新穎之腦血管類澱粉蛋白質之純化及特性描述之起始報告， Biochemical and biophysical research communications, 1984, May 16, 120 (3), 885-890頁；Masters CL及其它6位，阿茲罕默氏疾病及唐氏症候群之類澱粉斑核心蛋白質，Proceeding National Academy of Science USA, 1985, Jun, 82 (12), 4245-4249頁；Gouras GK及其它11位，人類腦部之神經元内之Αβ42細積，American journal of pathology, 2000，Jan, 156 (1)，15-20頁；Scheuner D及其它20位，與阿茲罕默氏疾病之老化斑塊中相似之分泌之類澱粉β -蛋白質於活體内係藉由與家族性阿茲罕默氏疾病相關連之早老素1及2與ΑΡΡ 突變而增加，Nature Medicine，1996, Aug，2 (8), 864-870 頁；Forman MS及其它4位，瑞典突變類澱粉先質蛋白質對神經元及非神經元細胞之β-類澱粉之累積及分泌之不同作用，The journal of biological chemistry, 1997, Dec, 19，272 (51)，32247-32253頁）、老牛癡呆症（例如，參考Blass JP，腦部代謝及腦部疾病：代謝缺陷是否係阿茲罕默氏癡呆症之近因？ Journal of Neuroscience Research, 2001，Dec 1，66 (5), 851-856頁）、額顳葉癡呆症(例如，參考EvinG及其它11 位，與額顳葉癡呆症有關之早老素-1之替代性轉錄， Neuroreport，2002, Apr 16，13 (5)，719-723頁）、匹克氏疾病 21 201031662 (例如’參考YasuharaO及其它3位，具匹克氏疾病之病患之腦損傷之類殿減質蛋白質之累積，Ne_denee 1994’Apr 25, Π1 (1-2)，63-66頁）、唐氏症候群(例如，參考 Teller JK及其它1 〇位，可溶性類澱粉β_肽之存在係於唐氏症候群之類澱粉斑塊形成之前，Nature Medicine，1996, jan，2 (1)，93-95頁；Tokuda T及其它6位，血漿之類澱粉p蛋白質 Αβ1-40及Αβ1-42(43)之量於唐氏症候群係升高，Annals 〇f Neurology，1997, Feb，41 (2)，271-273 頁）、腦血管病（例如，參考HayashiY及其它9位，早老素_丨涉及阿茲罕默氏疾病影參響之腦部之類殿粉病之證據，Brain Research，1998, Apr 13 789 (2)，307-314頁；Barelli Η及其它15位，對於40及42個胺基酸長之類澱粉β肽具特定性之多株抗體之特性描述：其於檢測早老素之細胞生物學及偶發性阿茲罕默氏疾病及大腦 * 類搬粉病情況之免疫組織化學之用途，Molecular Medicine， · 1997, Oct, 3 (10)，695-707 頁；Calhoun ME及其它 10位，神經元過度表現及突變類澱粉先質蛋白質造成腦血管類澱粉之顯著沈積，Proceeding National Academy of Science USA, 1999, Nov 23, 96 (24)，14088-14093頁；DermautB及其它 l〇位，腦類澱粉病係由於新穎之早老素-1突變之阿茲罕默氏疾病之引起疾病之損傷，Brain, 2001, Dec，124 (12)， 23 83-2392頁）、類澱粉變性症之遺傳性顱内出血(荷蘭型）(例如，參考Cras P及其它9位，特徵在於類澱粉病及APP 692Ala --> Gly突變之大類澱粉核心型老化斑塊之前老年阿茲罕默氏癡呆症，ActaNeuropathologica (Berl)，1998, Sep, 96 (3), 22 201031662 253-260頁；Herzig MC及其它14位，Αβ係標定於具類殿粉變性症之遺傳性顱内出血之小鼠模型之脈管系統，Nature Neuroscience, 2004, Sep, 7 (9)，954-960 頁；van Duinen SG 及其它5位，荷蘭血統之病患之具類澱粉變性症之遺傳性顱内出血係與阿茲罕默氏疾病有關，Proceeding National Academy of Science USA, 1987，Aug, 84 (16)，5991-5994 頁；Levy E及其它8位，遺傳性顱内出血，荷蘭型，之阿茲罕默氏疾病類澱粉基因之突變，Science，1990, Jun 1，248 參 (4959)，1124-1126)、認知障礙(例如，參考Laws SM及其它7 位，早老素-1突變Glu318Gly與記憶缺損疾病間之相關性， Neurobiology of Aging, 2002, Jan-Feb, 23 (1)，55-58頁）、記憶障礙/學習障礙(例如，參考VaucherE及其它5位，表現人 ' 類早老素1轉基因之小鼠之客觀認知記憶及膽鹼能參數， - Experimental Neurology，2002 Jun，175 (2)，398-406 頁；Academy 〇f Science USA, 2003, Sep 2,100 (18), 1〇417-1〇422 pages; 1^3〇1111]^ and 16 other, anti-zero-amyloid antibodies slow down Azheimer's Cognitive decline in disease, Neuron, 2003, May 22; 20 201031662 38(4), pp. 547-554; Jarrett JT and 2 other, the carboxy terminus of the beta-class powder protein is important for the starch-like seeding system: Az Inferences about the onset of Hammer's disease, Biochemistry, 1993, May 11, 32 (18), pages 4693-4697; Glenner GG and one other 'Azham's disease: purification of a novel cerebrovascular starch protein and Initial report on characterization, Biochemical and biophysical research communications, 1984, May 16, 120 (3), 885-890; Masters CL and 6 other, amyloid cores such as Azheimer's disease and Down's syndrome Protein, Proceeding National Academy of Science USA, 1985, Jun, 82 (12), pages 4245-4249; Gouras GK and 11 other, Αβ42 fines in neurons of the human brain, American journal of pathology, 2000, Jan , 156 (1), 15-20 pages; Scheuner D and 20 others, with A similarly secreted starch β-protein in aging plaques of Jammer's disease is increased in vivo by presenilin 1 and 2 and ΑΡΡ mutations associated with familial Azheimer's disease, Nature Medicine, 1996, Aug, 2 (8), 864-870; Forman MS and 4 other, Swedish mutant starch precursor proteins have different effects on the accumulation and secretion of β-starch in neurons and non-neuronal cells, The Journal of biological chemistry, 1997, Dec, 19, 272 (51), 32247-32253), dementia in cattle (for example, reference to Blass JP, brain metabolism and brain diseases: whether metabolic defects are Azheimer's The cause of dementia? Journal of Neuroscience Research, 2001, Dec 1, 66 (5), pp. 851-856), frontotemporal dementia (for example, refer to EvinG and 11 other, related to frontotemporal dementia) Alternative transcription of presenilin-1, Neuroreport, 2002, Apr 16, 13 (5), pp. 719-723), Pico's disease 21 201031662 (eg 'Reference YasuharaO and 3 other patients with Pick's disease Accumulation of reduced protein in brain damage, Ne_den Ee 1994 'Apr 25, Π 1 (1-2), pp. 63-66), Down syndrome (for example, with reference to Teller JK and other 1 〇 position, the presence of soluble starch β-peptide is based on starch such as Down's syndrome Before the formation of plaques, Nature Medicine, 1996, jan, 2 (1), pp. 93-95; Tokuda T and 6 other, plasma-like starch p-proteins Αβ1-40 and Αβ1-42 (43) in the amount of Down Symptoms are elevated, Annals 〇f Neurology, 1997, Feb, 41 (2), pp. 271-273), cerebrovascular disease (eg, reference to HayashiY and other 9, presenilin _ 丨 involves Azheimer's disease Evidence for the disease of the brain, such as Brain Research, Brain Research, 1998, Apr 13 789 (2), pp. 307-314; Barelli and 15 other, for 40 and 42 amino acid long starches Characterization of peptide-specific antibodies: its use in the detection of presenilin cell biology and immunohistochemistry of sporadic Azheimer's disease and brain* powdery mildew, Molecular Medicine, 1997 , Oct, 3 (10), 695-707; Calhoun ME and 10 other, neuronal overexpression and mutant starch precursors White matter causes significant deposition of cerebrovascular starch, Proceeding National Academy of Science USA, 1999, Nov 23, 96 (24), pages 14088-14093; Dermaut B and other l-positions, brain-based starch disease due to novel presenilin - 1 Mutation of disease caused by Azheimer's disease, Brain, 2001, Dec, 124 (12), 23 83-2392), hereditary intracranial hemorrhage of amyloidosis (Dutch type) (for example, reference) Cras P and 9 other, characterized by amyloplast and APP 692Ala --> Gly mutant large starchy aging plaques before Alzheimer's disease, ActaNeuropathologica (Berl), 1998, Sep, 96 ( 3), 22 201031662 253-260; Herzig MC and 14 other, Αβ-system calibrated to the vasculature of a mouse model of hereditary intracranial hemorrhage with nephrotic degeneration, Nature Neuroscience, 2004, Sep, 7 ( 9), pages 954-960; van Duinen SG and 5 other hereditary intracranial hemorrhagic diseases with amyloidosis in Dutch descent are associated with Azheimer's disease, Proceeding National Academy of Science USA, 1987 , Aug, 84 (16), 5991-599 4 pages; Levy E and 8 other, hereditary intracranial hemorrhage, Dutch type, mutation in the Azheimer's disease-like starch gene, Science, 1990, Jun 1, 248 (4959), 1124-1126), Cognition Disorders (for example, reference to Laws SM and other 7 positions, correlation between presenilin-1 mutation Glu318Gly and memory deficit disease, Neurobiology of Aging, 2002, Jan-Feb, 23 (1), pp. 55-58), memory impairment / Learning Disabilities (for example, refer to VaucherE and the other 5, representing the objective cognitive memory and cholinergic parameters of human 'presenilin 1 transgenic mice, - Experimental Neurology, 2002 Jun, 175 (2), pp. 398-406 ;

Morgan D及其它14位，於阿茲罕默氏疾病動物模型之Αβ肽 • 接種預防記憶喪失，Nature, 2000 Dec 21-28, 408 (6815)， 982-985頁；Moran PM及其它3位，於表現751-胺基酸同型體之人類β-類澱粉先質蛋白質之轉基因小鼠之與年齡有關之學習障礙，Proceeding National Academy of Science USA， 1995, June 6, 92 (12)，5341-5345 頁）、類澱粉變性症、腦缺血(例如，參考Laws SM及其它7位，早老素-1突變Glu318Gly 與記憶缺損疾病間之相關性，Neurobiology of Aging, 2002, Jan-Feb，23 (1), 55-58頁；Koistinaho Μ及其它 10位，提供擴散Αβ沈積物但不會形成斑塊之β-類澱粉先質蛋白質轉基因 23 201031662 小鼠顯不增加之缺血性損傷：發炎之角色’ proceeding National Academy of Science USA, 2002, Feb 5, 99 (3), 1610-1615頁；Zhang F及其它4位，過度表現類澱粉先質蛋白質之轉基因小鼠之增加感染缺血性腦部損傷，The j ournal of neuroscience, 1997, Oct 15, 17 (20)，7655-7661 頁）、腦血管型癡呆症（例如，參考Sadowski M及其它6位，阿茲罕默氏疾病之病理與血管型瘋呆症間之關連，NeurochemicalMorgan D and 14 other, Αβ peptides in the animal model of Azheimer's disease • Vaccination against memory loss, Nature, 2000 Dec 21-28, 408 (6815), 982-985; Moran PM and 3 others, Age-related learning disabilities in transgenic mice expressing human beta-beta-proteoproteins of the 751-amino acid isoform, Proceeding National Academy of Science USA, 1995, June 6, 92 (12), 5341-5345 Page), amyloidosis, cerebral ischemia (for example, reference to Laws SM and other 7, presenilin-1 mutation Glu318Gly and memory defect disease, Neurobiology of Aging, 2002, Jan-Feb, 23 (1 ), 55-58; Koistinaho Μ and 10 other, β-starch precursor protein transgenes that provide Αβ sediment but do not form plaques 23 201031662 Mice do not increase ischemic injury: role of inflammation ' proceeding National Academy of Science USA, 2002, Feb 5, 99 (3), 1610-1615; Zhang F and 4 other, transgenic mice overexpressing starch-like precursor protein increased infection with ischemic brain damage , The j ournal of neuroscience, 1997, Oct 15, 17 (20), 7655-7661), cerebrovascular dementia (for example, refer to Sadowski M and 6 other, the relationship between the pathology of Azheimer's disease and vascular dementia, Neurochemical

Research, 2004, Jun，29 (6)，1257-1266頁）、眼肌麻痒（例如，參考O'Riordan S及其它7位，早老素_1突變(E280G)，痙攣性截癱’及頭蓋MRI白質異常，Neurology，2002, Oct 8, 59 (7)，1108-1110頁）、多發性硬化(例如，參考Gehrmann J 及其它4位，多發性硬化症損傷之類澱粉先質蛋白質（APP) 表現，Glia，1995, Oct，15 (2), 141-51 頁；Reynolds WF及其它6位，骨趙過氧化酶多型性係與阿茲罕默氏疾病之性別特定危險性有關 ’ Experimental Neurology, 1999, Jan，155 (1)， 31-41頁）。頭部損傷、顱骨受損（例如，參考Smith DH及其它4位，外傷性腦部損傷之蛋白質累積，NeuroMolecular Medicine，2003，4 (1-2)，59-72頁）、失用症（例如，參考 Matsubara-Tsutsui Μ及其它7位’家族性早發性癡呆症之早老素1突變之分子證據，American journal of Medical Genetics, 2002, Apr 8, 114 (3)，292-298 頁）、普恩蛋白疾病、家族性類澱粉神經病變、三聯體重複疾病（例如，參考 Kirkitadze MD及其它2位，阿茲罕默氏疾病及其它神經退化性異常之典範轉移.养聚物組合物之展現角色，journal of 201031662Research, 2004, Jun, 29 (6), pp. 1257-1266), eye muscle itching (for example, refer to O'Riordan S and other 7 positions, presenilin_1 mutation (E280G), spastic paraplegia' and head cover MRI Abnormal white matter, Neurology, 2002, Oct 8, 59 (7), 1108-1110), multiple sclerosis (for example, reference to Gehrmann J and other 4, starchy precursor protein (APP) expression of multiple sclerosis injury , Glia, 1995, Oct, 15 (2), pp. 141-51; Reynolds WF and 6 other, the bone oxidase polymorphism is associated with the gender-specific risk of Azheimer's disease' Experimental Neurology, 1999, Jan, 155 (1), pp. 31-41). Head injury, skull damage (for example, refer to Smith DH and other 4, protein accumulation in traumatic brain injury, NeuroMolecular Medicine, 2003, 4 (1-2), pages 59-72), apraxia (eg , refer to Matsubara-Tsutsui Μ and other 7 'Molecular Evidences of Presenilin Mutations in Familial Early Dementia, American Journal of Medical Genetics, 2002, Apr 8, 114 (3), pp. 292-298) Enprotein disease, familial amyloid neuropathy, triplet repetitive disease (for example, refer to Kirkitadze MD and other 2, Alzheimer's disease and other neurodegenerative abnormalities. The role of the polymer composition. ,journal of 201031662

Neuroscience Research, 2002, Sep 1，69 (5)，567-577頁； Evert BO及其它8位’炎性基因於擴大之運動失調質_3表現細胞株及脊髓小腦萎縮症3型腦中向上調節，The Journai 〇fNeuroscience Research, 2002, Sep 1, 69 (5), pp. 567-577; Evert BO and other 8 inflammatory genes in the up-regulated dysregulated _3 expression cell line and spinal cerebellar atrophy type 3 brain ,The Journai 〇f

Neuroscience，2001，Aug 1，21 (15)，5389-5396頁；Mann DM 及另一位’具有非阿茲罕默氏疾病及唐氏症候群之癡呆異常者之腦内類澱粉(A4)蛋白質沈積，Neuroscience Letters， 1990, Feb 5, 109 (1-2)，68-75頁）、巴金森氏疾病（例如，參考PrimaveraJ及其它4位，非阿茲罕默氏神經退化之腦部類澱粉-β 累積，Journal of Alzheimer's Disease，1999, Oct，1 (3)， 183-193頁）、具路易氏體之瘋呆症（例如，參考Giasson BI 及其它2位，類澱粉蛋白質之交互作用，NeuroMolecular Medicine，2003, 4 (1-2)，49-58頁；Masliah E及其它6位，β-類澱粉肽於連結阿茲罕默氏疾病及巴金森氏疾病之轉基因小鼠模型促進α-突觸核素累積及神經元欠缺，Proceeding National Academy of Science USA, 2001, Oct 9, 98 (21), 12245-12250頁；8&〇^(^的1^及其它6位，於具有路易氏體之癡呆症之大腦皮質内之類澱粉-β沈積係伴隨相對增加含有Kunitz蛋白酶抑制劑之ΑβΡΡ mRNA同型體， Neurochemistry International, 2005, Feb, 46 (3), 253-260 頁；PrimaveraJ及其它4位，非阿茲罕默氏神經退化之腦部類殿粉-β 累積 ’ Journal of Alzheimer's Disease, 1999, Oct，1 (3)，183-193頁）、巴金森氏症-癡呆症綜合症（例如’參考 Schmidt ML及其它6位，關島型肌萎縮性脊髓侧索硬化症/ 巴金森氏症-癡呆症综合症之類澱粉斑塊含有與於阿兹罕 25 201031662 默氏疾病及病態老化之類澱粉斑塊中發現者相似之Αβ物種，Acta Neuropathologica (Berl)，1998, Feb, 95 (2), 117-122 頁；Ito H及其它3位’關島型巴金森氏症-癡呆症綜合症之含β類澱粉蛋白質之神經纖維糾結之證實，Neuropathology and applied neurobiology，1991，Oct，17 (5)，365-373頁）、與染色體17相關連之額顳葉癡呆症及巴金森氏症（例如，參考 Rosso SM及其它3位，具tau突變之遺傳性額顳葉癡呆症之共存tau及類殿粉病狀，Annals of the New York academy of sciences, 2000, 920，115-119頁）、嗜銀顆粒癡呆症（例如，參考TolnayM及其它4位’低類殿粉(Αβ)斑塊載負量及相對佔優勢之擴散斑塊使嗜銀顆粒疾病與阿茲罕默氏疾病區別， Neuropathology and applied neurobiology, 1999, Aug, 25 (4), 295-305頁）、尼曼匹克氏疾病（例如，參考Jin LW及其它3 位，具尼曼匹克氏C型缺陷之神經元内之類澱粉-β先質蛋白質之類澱粉片斷之細胞内累積係與吞噬小體異常有關， American Journal of Pathology, 2004, Mar, 164 (3), 975-985 頁）、肌萎縮性脊髓側索硬化症（例如，參考Sasaki S及另一位，肌萎縮性脊髓側索硬化症之β-類澱粉先質蛋白質之免疫反應性，Acta Neuropathologica (Berl), 1999, May，97 (5)， 463-468頁；Tamaoka A及其它4位，具肌萎縮性脊髓側索硬化症之病患之皮膚中增加之類厥粉β蛋白質，Journal of neurology，2000, Aug，247 (8)，633-635 頁；Hamilton RL及另一位，肌萎縮性脊髓側索硬化症之阿茲罕默氏疾病病理學，Acta Neuropathologica, 2004, Jun，107 (6), 515-522頁； 26 201031662Neuroscience, 2001, Aug 1, 21 (15), 5389-5396; Mann DM and another protein deposition in the brain of starch-like (A4) with abnormal dementia other than Azheimer's disease and Down's syndrome , Neuroscience Letters, 1990, Feb 5, 109 (1-2), pp. 68-75), Parkinson's disease (for example, refer to Primavera J and other 4, non-Azheimer's neurodegenerative brain starches - β accumulation, Journal of Alzheimer's Disease, 1999, Oct, 1 (3), pp. 183-193), narcotics with Lewy body (for example, reference to Giasson BI and other two, starch-like protein interactions, NeuroMolecular Medicine, 2003, 4 (1-2), pp. 49-58; Masliah E and other 6-position, β-amyloid peptides promote alpha-protrusion in a transgenic mouse model linked to Alzheimer's disease and Parkinson's disease Accelerator accumulation and neuron deficiency, Proceeding National Academy of Science USA, 2001, Oct 9, 98 (21), 12245-12250; 8&〇^(^1^ and other 6 positions, with Louise Starch-β deposits in the cerebral cortex of dementia with a relative increase in Kunitz-containing protease Inhibitors of ΑβΡΡ mRNA isoforms, Neurochemistry International, 2005, Feb, 46 (3), pp. 253-260; PrimaveraJ and other 4, non-Azheimer's neurodegenerative brain-like powder-β accumulation' Journal Of Alzheimer's Disease, 1999, Oct, 1 (3), pp. 183-193), Parkinson's disease-dementia syndrome (eg 'Reference Schmidt ML and 6 other, Guam amyotrophic lateral sclerosis/ Amyloid plaques such as Parkinson's disease-Disease Syndrome contain Αβ species similar to those found in Azhan 25 201031662 Amyloid plaques such as Mohs disease and morbid aging, Acta Neuropathologica (Berl), 1998, Feb , 95 (2), pp. 117-122; Confirmation of neurofibrillary tracts containing beta-starch protein from Ito H and three other Guam-type Parkinson's disease-Dementia syndrome, Neuropathology and applied neurobiology, 1991, Oct , 17 (5), pp. 365-373), frontal dementia and Parkinson's disease associated with chromosome 17 (for example, refer to Rosso SM and the other 3, hereditary frontotemporal dementia with tau mutation) Coexistence of tau and class hall powder symptoms, A Nnals of the New York academy of sciences, 2000, 920, pp. 115-119), argyrophilic granule dementia (for example, refer to TolnayM and other 4 'low class 粉β) plaque load and relative predominance Diffusion plaques distinguish between argyrophilic disease and Azheimer's disease, Neuropathology and applied neurobiology, 1999, Aug, 25 (4), pp. 295-305), Niemann's disease (eg, refer to Jin LW and The other three, intracellular accumulations of starch fragments such as starch-β precursor proteins in neurons with N-type P-type defects are associated with phagosome abnormalities, American Journal of Pathology, 2004, Mar, 164 (3), pp. 975-985), amyotrophic lateral sclerosis (for example, refer to Sasaki S and another, immunoreactive protein of β-starch precursor protein of amyotrophic lateral sclerosis, Acta Neuropathologica (Berl), 1999, May, 97 (5), pp. 463-468; Tamaoka A and four other patients with amyotrophic lateral sclerosis who have increased levels of β powder β protein in the skin, Journal of neurology, 2000, Aug, 247 (8), 633-635 ; Hamilton RL and another, Ezihanmo's disease pathology amyotrophic lateral sclerosis of the, Acta Neuropathologica, 2004, Jun, 107 (6), 515-522 pages; 26 201 031 662

Turner BJ及其它6位，表現突變超氧化物歧化酶丨之轉基因小鼠之腦部β-類澱:粉累積，Neurochemical Research，2004, Dec，29 (12)，2281-2286頁）、水腦症（例如，參考 Weller RO，Turner BJ and 6 other brains in the transgenic mice exhibiting mutant superoxide dismutase 丨: β-type sediment: powder accumulation, Neurochemical Research, 2004, Dec, 29 (12), pp. 2281-2286), water brain Symptom (for example, refer to Weller RO,

CNS之腦脊髓液及間質液之病理學：阿茲罕默氏疾病、普恩蛋白異常及多發性硬化症之重要性，Journal 〇f Neuropathology and Experimental Neurology, 1998, Oct, 57 (10)，885-894頁；Silverberg GD及其它4位，阿茲罕默氏疾病、常壓性水腦，及CSF循環生理學之衰老變化：假說，Pathology of cerebrospinal fluid and interstitial fluid of CNS: importance of Azheimer's disease, Purkinin abnormality and multiple sclerosis, Journal Neurof Neuropathology and Experimental Neurology, 1998, Oct, 57 (10), 885-894; Silverberg GD and 4 other, Azheimer's disease, atmospheric water brain, and aging changes in CSF cycle physiology: hypothesis,

Lancet neurology，2003, Aug, 2 (8), 506-511 頁；Weller RO及其它3位，大腦類澱粉血管病變：阿茲罕默氏疾病之間質液排放通道之Αβ累積，Annals of the New York academy of sciences，2000, Apr, 903, 110-117頁；YowHY及另一位，腦血管疾病於決定阿茲罕默氏疾病之β-類澱粉沈積圖案之角色，Neurology and applied neurobiology，2002, 28，第 149 頁；Weller RO及其它4位，腦血管疾病係Αβ自老人腦部去除失敗之主要因素，Annals of the New York academy of sciences, 2002, Nov, 977，162-168頁）、部份癱疾(例如，參考O'Riordan S及其它7位，早老素-1突變(E280G)、痙攣性麻痒部份癱疾，及頭蓋MRI白質異常，Neurology，2002, Oct 8,59 (7),1108-1110頁；1^181^3以-丁81^1^?^及其它7位，家族性早發性癡呆症之早老素1突變之分子證據，American journal of Medical Genetics, 2002, Apr 8, 114 (3), 292-298 頁；Smith MJ及其它11位，具痙攣性麻痺部份癱瘓之阿茲罕默氏疾病之變化式顯型，Annals of Neurology, 2001, 49 27 201031662 (1), 125-129頁；Crook R及其它17位，由於早老素1之表現子9刪除而具痙攣性截癱及不尋常斑塊之阿茲罕默氏疾病之變型，Nature Medicine，1998, Apr;4 (4)，452-455頁）、進行性上核麻痺(例如，參考BarrachinaM及其它6位，於具有路易氏體之癡呆症之大腦皮質内之類澱粉-β沈積係伴隨相對增加含有Kunitz蛋白酶抑制劑之ΑβΡΡ mRNA同型體， Neurochemistry International, 2005, Feb, 46 (3), 253-260 頁；PrimaveraJ及其它4位，非阿茲罕默氏神經退化之腦部類澱粉-β 累積，Journal of Alzheimer’s Disease, 1999, Oct，1 (3)，183-193頁）、顱内出血(例如，參考Atwood CS及其它3 位，能維持血管完整性及血液供應之密封劑、抗凝血及重塑分子之腦jk管要求，Brain Research Reviews, 2003，Sep, 43 (1)，164-78頁；Lowenson JD及其它2位，蛋白質老化：細胞外類殿粉形成及細胞内修補，Trends in cardiovascular Medicine，1994, 4 (1)，3-8頁）、瘦攣（例如，參考Singleton AB 及其它13位，載負Thrll3-114ins早老素-1突變之早發性阿茲罕默氏病例之病理學，Brain，2000，Dec, 123 (Pt 12)， 2467-2474頁）、輕度認知受損（例如，參考GattazWF及其它 4位，阿茲罕默氏疾病及輕度認知受損之血小板磷脂酶A2 活性，Journal of Neural Transmission, 2004，May, 111 (5)， 591-601頁；Assini A及其它14位，血漿之類殿粉β-蛋白質 42罝於具輕度認知受損之女性係增加，Neurology, 2004, Sep 14, 63 (5), 828-831 頁）、動脈硬化(例如，參考De Meyer GR及其它8位，動脈粥狀硬化之巨噬細胞活化作用之機構 28 201031662 之血小板吞喔及β_類澱粉先質蛋白質之處理，Circulation Reserach, 2002, Jun 14, 9〇 (11), 1197-12041) ° 本說明書中之各種定義將於下說明。心及尺2係相同或相異，且每一者代表一選自下列取代基族群al之取代基。取代基族群al"係指一由一ci-6烷基基團、一C3-8環烷基基團、一C2-6烯基基團、一C1_6烷氧基基團、一C2_6 烯氧基基團、一 C3-8環烷氧基基團、一胺基基團（其中，胺基基團可具有一C2-6醯基基團或C1-6烷基磺醯基基團，或1 至2個C1-6烷基基團或C3_8環烷基基團）、一氰基基團、一甲醯基基團、一鹵素原子、一羥基基團，及一硝基基團所組成之族群。其間，一C1-6烷基基團、一C3-8環烷基基團、一鹵素原子、一Cl_6烷氧基基團，及一C3_8環烷氧基基團係較佳，且一C1-6烷基基團、一鹵素原子及一ci-6烷氧基基團係特別佳。 in代表〇至3之整數’且較佳係〇至2，且特別佳係丨至2。 η代表0至2之整數，且較佳係〇至1，且特別佳係J。 Χι代表i)一單鍵，ii) [化學式15] —c=c—Lancet neurology, 2003, Aug, 2 (8), pp. 506-511; Weller RO and 3 other, brain-type amyloid angiopathy: Αβ accumulation of the effusion channel between Azheimer's disease, Annals of the New York academy of sciences, 2000, Apr, 903, pp. 110-117; YowHY and the other, the role of cerebrovascular disease in determining the beta-type starch deposition pattern of Azheimer's disease, Neurology and applied neurobiology, 2002, 28, p. 149; Weller RO and 4 other, cerebrovascular disease, the main factor in the failure of Αβ from the brain removal of the elderly, Annals of the New York academy of sciences, 2002, Nov, 977, 162-168) Dysentery (for example, refer to O'Riordan S and other 7, presenilin-1 mutation (E280G), pruritus, dysentery, and MRI white matter abnormalities in the skull, Neurology, 2002, Oct 8, 59 (7 Molecular Evidence for Presenilin 1 Mutation in Familial Early-onset Dementia, 1108-1110; 1^181^3 to -Ding 81^1^?^ and 7 Other, American Journal of Medical Genetics, 2002, Apr 8, 114 (3), 292-298 pages; Smith MJ and 11 other, with paralyzed parts Variant phenotype of Azheimer's disease, Annals of Neurology, 2001, 49 27 201031662 (1), pp. 125-129; Crook R and 17 other, sturdy due to the deletion of the predecessor of presenilin 1 A variant of Alzheimer's disease with paraplegia and unusual plaques, Nature Medicine, 1998, Apr; 4 (4), pp. 452-455), progressive supranuclear palsy (for example, reference to Barrachina M and 6 others) A starch-beta deposit in the cerebral cortex with dementia of Louise is associated with a relative increase in the ΑβΡΡ mRNA isoform containing the Kunitz protease inhibitor, Neurochemistry International, 2005, Feb, 46 (3), pp. 253-260; PrimaveraJ And other 4, non-Azheimer's neurodegenerative brain starch-β accumulation, Journal of Alzheimer's Disease, 1999, Oct, 1 (3), pp. 183-193), intracranial hemorrhage (for example, reference to Atwood CS And three other brain, jk tube requirements for sealants, anticoagulation, and remodeling molecules that maintain vascular integrity and blood supply, Brain Research Reviews, 2003, Sep, 43 (1), pp. 164-78; Lowenson JD And 2 other, protein aging: extracellular Temple powder formation and intracellular repair, Trends in cardiovascular Medicine, 1994, 4 (1), 3-8 pages), lean sputum (for example, refer to Singleton AB and other 13 positions, carrying Thrll3-114ins presenilin-1 mutation Pathology of early-onset Azheimer's case, Brain, 2000, Dec, 123 (Pt 12), 2467-2474), mild cognitive impairment (eg, reference to GattazWF and other 4, Azheimer Disease and mild cognitive impairment of platelet phospholipase A2 activity, Journal of Neural Transmission, 2004, May, 111 (5), 591-601; Assini A and 14 other, plasma class peptide β-protein 42 Increased in women with mild cognitive impairment, Neurology, 2004, Sep 14, 63 (5), pp. 828-831), arteriosclerosis (for example, refer to De Meyer GR and other 8 positions, atherosclerosis) Mechanism for macrophage activation 28 Platelet phagocytosis and treatment of β-starch precursor protein in 201031662, Circulation Reserach, 2002, Jun 14, 9〇(11), 1197-12041) ° The various definitions in this specification will As explained below. The heart and the ruler 2 are identical or different, and each represents a substituent selected from the group of substituents a1 below. Substituent group a" refers to a ci-6 alkyl group, a C3-8 cycloalkyl group, a C2-6 alkenyl group, a C1-6 alkoxy group, a C2_6 alkenyloxy group. a group, a C3-8 cycloalkoxy group, an amine group (wherein the amine group may have a C2-6 alkyl group or a C1-6 alkylsulfonyl group, or 1 Up to 2 C1-6 alkyl groups or C3-8 cycloalkyl groups), a cyano group, a monomethyl group, a halogen atom, a hydroxyl group, and a nitro group Ethnic group. Meanwhile, a C1-6 alkyl group, a C3-8 cycloalkyl group, a halogen atom, a Cl-6 alkoxy group, and a C3-8 cycloalkoxy group are preferred, and a C1- A 6-alkyl group, a halogen atom and a ci-6 alkoxy group are particularly preferred. In represents 〇 to an integer of 3' and is preferably from 2 to 2, and particularly preferably to 2 . η represents an integer from 0 to 2, and is preferably from 1 to 1, and particularly preferably J. Χι stands for i) a single key, ii) [Chemical Formula 15] —c=c—

或111)-CR3=CR4_(其中，R3及R_4係相同或相異，且每一者代表（1)一氫原子、（2) — C1-6烷基基團，或(3)一鹵素原子）。 I代表i)一單鍵，Π) — C1-6烷撐基基團，或m)_X3_(其中， χ3 代表-NR5-、-Ο-、-C(O)-、-S-、-S(o)-或 _s(〇)2_，且R 29 201031662 代表一氫原子、—C1娜基基K3娜絲基團、一 C2-6烧醢基基團，或_C1•峨基賴基基團），且較佳係i) 一單鍵或ii)-CR3=CR4-。環A代表…五員之芳香族雜環基團，或ii)-血一5_至 14_員之非芳香族環基團稠合之五員之芳香_環基團，其含有二或更多錢原子且可具有⑴個選自旅軟取代基(其中’非芳香族環基團可具有 = 構或一螺旋環系統）。乂聯之結 "五員之芳香族雜環基團"不被特別限制，含有二或更多個氮原子之五貝芳香族雜環基I其係一佳係指一選自化學式_至[26]所組成族群之土圏較族雜環基團：之芳香Or 111)-CR3=CR4_ (wherein R3 and R_4 are the same or different, and each represents (1) a hydrogen atom, (2) - a C1-6 alkyl group, or (3) a halogen atom ). I represents i) a single bond, Π) — a C1-6 alkylene group, or m) _X3_ (wherein χ3 represents -NR5-, -Ο-, -C(O)-, -S-, -S (o)- or _s(〇)2_, and R 29 201031662 represents a hydrogen atom, a -C1 naphthyl K3 nass group, a C2-6 decyl group, or a _C1•indenyl group a group), and preferably i) a single bond or ii) -CR3=CR4-. Ring A represents a five-membered aromatic heterocyclic group, or ii) - a five-membered aromatic-ring group fused to a non-aromatic cyclic group of 5 to 14 members, which contains two or more More money atoms and may have (1) selected from a soft substituent (wherein a non-aromatic ring group may have a = structure or a helical ring system). The knot of the couple" five-membered aromatic heterocyclic group" is not particularly limited, and the five-shell aromatic heterocyclic group I having two or more nitrogen atoms is preferably selected from the chemical formula _ To the group of [26], the earthworms of the group are more heterocyclic groups: the aroma

[化學式16J A '[Chemical Formula 16J A '

A* A • A，A* A • A,

23 2223 22

21 α· 24 25 26 其中’ •代表一與化學式[27]之鍵結位式： [化學式17]21 α· 24 25 26 where '• represents a bond with the chemical formula [27]: [Chemical Formula 17]

(R2)n 27 且 A·代表一與&之鍵結位置，且更佳地係指—化學 30 201031662 環： [化學式18] A·(R2)n 27 and A· represents a bonding position with & and more preferably - chemistry 30 201031662 Ring: [Chemical Formula 18] A·

21 此基團可具有1至3個選自下列取代基族群bl之取代基。21 This group may have 1 to 3 substituents selected from the group of substituents bl below.

”與一 5-至14-員之非芳香族環基團稠合之五員芳香族雜環基團（其中，非芳香族環基團可具有一經交聯之結構或一螺旋環系統)"不被特別限制，只要其係一含有二或更多個氮原子之與一 5-至14-員之非芳香族環基團稠合之五員芳香族雜環基團（其中，非芳香族環基團可具有一經交聯之結構或一螺旋環系統）。此基團較佳係選自化學式[28]至[39] 所組成族群之任一環： [化學式19]a five-membered aromatic heterocyclic group fused to a 5- to 14-membered non-aromatic ring group (wherein the non-aromatic ring group may have a crosslinked structure or a helical ring system) &quot It is not particularly limited as long as it is a five-membered aromatic heterocyclic group containing two or more nitrogen atoms fused to a 5- to 14-membered non-aromatic ring group (wherein, non-aromatic The group ring group may have a crosslinked structure or a helical ring system. The group is preferably selected from any of the groups consisting of the chemical formulas [28] to [39]: [Chemical Formula 19]

其中，•及A·係如上所定義及部份結構： [化學式20] 31 201031662 代表一單鍵或一雙鍵，更佳地係一選自如下所組成之族群之環： [化學式21]Wherein, • and A· are as defined above and part of the structure: [Chemical Formula 20] 31 201031662 represents a single bond or a double bond, more preferably a ring selected from the group consisting of: [Chemical Formula 21]

其中，·、A·及部份結構： [化學式22] 係如上所定義，且特別佳係一選自化學式R8-1]所組成之族群之環： [化學式23]Wherein, ···· and part of the structure: [Chemical Formula 22] is as defined above, and particularly preferably a ring selected from the group consisting of the chemical formula R8-1]: [Chemical Formula 23]

28-1 其中，·、A·及部份結構： [化學式24] 係如上所定義。此基團可具有1至3個選自下列取代基族群 bl之取代基。”可具有一經交聯之結構或一螺旋環系統”一辭係指非芳香族環基團上之二個碳原子可一起形成一經交聯之結構，或非芳香族環基團上之一個碳原子可形成一螺 32 201031662 旋環系統。 ”取代基族群bl"係指一由一 C1-6烷基基團（其中，烷基基團可以1至3個i素原子取代）、一C2-6烯基基團、一C3-8 環烷基基團、一C6-14芳基基團、一C6-14芳基-C1-6烷基基團、一C1-6烷氧基基團、一C2-6烯氧基基團、一C3-8環烷氧基基團、一C2-6烷醯基基團、一C4-9環烷基羰基基團、一C7-15芳醯基基團、一C1-6烷基磺醯基基團、一C2-6烯基磺醯基基團、一C3-8環烷基磺醯基基團、一C6-14芳基磺酿基基團、一 C1-6烷硫基基團、一 C2-6烯硫基基團、一 C3-8 環烷硫基基困、一胺基磺醯基基團（其中，胺基磺酿基基團可具有1至2個C1-6烷基基團、C2-6烯基基團或C3-8環烷基基團）、一胺基基團（其中，胺基基團可具有一個C2-6烷醯基基團、C1-6烷基磺醯基基團或C3-8環烷基磺醯基基團，或1 至2個C1-6烷基基團或C3-8環烷基基團）、一氰基基團、一曱醯基基團、一ΐ素原子、一經基基團、一确基基團、一氧基基團、一丨-吼!1 各咬基基團、一1-η辰嗓基基團、一 1-同派啶基基團、一吲哚啉-1-基基團、一 12,3,4-四氫喹啉-1-基基團及一4-嗎啉基基團所組成族群之基團。其間較佳係一選自一C1-6烷基基團（其中，烷基基團可以丨至3個鹵素原子取代）、一C3-8環烷基基團、一C6_14芳基基團、一C6_14芳基 -C1-6烷基基團、一 C1_6烷氧基基團、一 C3_8環烷氧基基團、一C2-6烷醯基基團、一C7-15芳醯基基團、一C1-6烷基磺醯基基團、一C3-8環烷基磺酿基基團、一C6-14芳基磺酿基基團、一氰基基團、一曱醯基基團、一鹵素原子、一經 201031662 基基團及一側氧基基團所組成族群之取代基。特別佳係一 C1-6烷基基團（其中，烷基基團可以1至3個鹵素原子取代）、一C3-8環烷基基團、一C6-14芳基基團、一C6-14芳基_ci-6 烷基基團、一C1-6烷氧基基團、一C3-8環烷氧基基團及一鹵素原子。環B代表，例如，一選自化學式[2]至[19]所組成族群之單環或稠合環之芳香族環基團： [化學式25] 兮令w?.-?28-1 wherein, ···· and part of the structure: [Chemical Formula 24] is as defined above. This group may have 1 to 3 substituents selected from the group of substituents bl below. The phrase "having a crosslinked structure or a helical ring system" means that two carbon atoms on a non-aromatic ring group may together form a crosslinked structure or a carbon on a non-aromatic ring group. The atom can form a screw 32 201031662 loop system. "Substituent group bl" means a C1-6 alkyl group (wherein the alkyl group may be substituted with 1 to 3 i atoms), a C2-6 alkenyl group, a C3-8 ring An alkyl group, a C6-14 aryl group, a C6-14 aryl-C1-6 alkyl group, a C1-6 alkoxy group, a C2-6 alkenyloxy group, a a C3-8 cycloalkoxy group, a C2-6 alkylalkyl group, a C4-9 cycloalkylcarbonyl group, a C7-15 arylalkyl group, a C1-6 alkylsulfonyl group a group, a C2-6 alkenylsulfonyl group, a C3-8 cycloalkylsulfonyl group, a C6-14 arylsulfonyl group, a C1-6 alkylthio group, a C2-6 alkenylthio group, a C3-8 cycloalkylthio group, an aminosulfonyl group (wherein the aminesulfonyl group may have 1 to 2 C1-6 alkyl groups) a group, a C2-6 alkenyl group or a C3-8 cycloalkyl group), an amine group (wherein the amine group may have a C2-6 alkylhydrazine group, a C1-6 alkyl group a sulfonyl group or a C3-8 cycloalkylsulfonyl group, or 1 to 2 C1-6 alkyl groups or a C3-8 cycloalkyl group), a cyano group, a fluorene group Base group, monoterpene atom, base group , a thiol group, a oxy group, a 丨-吼!1 each octyl group, a 1-n-n-decyl group, a 1-isopyridyl group, a porphyrin- a group consisting of a 1-group, a 12,3,4-tetrahydroquinolin-1-yl group and a 4-morpholinyl group, preferably selected from a C1-6 group. An alkyl group (wherein the alkyl group may be substituted with 3 halogen atoms), a C3-8 cycloalkyl group, a C6_14 aryl group, a C6_14 aryl-C1-6 alkyl group a C1-6 alkoxy group, a C3-8 cycloalkoxy group, a C2-6 alkylalkyl group, a C7-15 arylalkyl group, a C1-6 alkylsulfonyl group, a C3-8 cycloalkylsulfonic acid group, a C6-14 arylsulfonic acid group, a cyano group, a fluorenyl group, a halogen atom, a 201031662 group and one side a substituent of a group consisting of an oxy group, particularly preferably a C1-6 alkyl group (wherein the alkyl group may be substituted with 1 to 3 halogen atoms), a C3-8 cycloalkyl group, a C6-14 aryl group, a C6-14 aryl-ci-6 alkyl group, a C1-6 alkoxy group, a C3-8 cycloalkoxy group A ring B represents a halogen atom, e.g., one selected from the chemical formulas [2] to [19] the group consisting of an aromatic ring group of monocyclic or fused rings: [Chemical Formula 25] Xi Order w .-??

且較佳係一苯基基團、一°比啶基基團、一噁唑基基團、— 咪唾基基團、/嚷咬基基團、一氫苯并呋喃基基團或—嘴吩基基團，立特別值係一苯基基團或一°比啶基基團。環B 可具有1至3個選自下列取代基族群Cl之取代基。，，取代基基團cl"係指一由i) 一胺基基團（其中’胺基基團可具有一c2_6坑醯基基團、C1-6烷基磺醯基基團或C3_8 環烷基磺醯基基團，或1至2個C1_6烷基基團或C3-8環烷基基團），ii)一氰基基團，m)一鹵素原子，iv)一羥基基圈，及 v) v)…—C1_6炫基基團，v)-ii) — C2-6稀基基團，外出)— C2_6炔基基團，v)_iv)一C1-6烷氧基基團，V)-V)一Cl_6烷硫基基團，v)-vi) — C1-6烧基胺基幾基基團’ v)-vii)—(^乂烷 34 201031662 基磺醯基基團，v)-viii) — C1-6烷基胺基磺醯基基團，v)_ix) 一C2-6烷醯基基團，v)-x)—苯基基團’ v)-xi) — η比啶基基團，v)-xii)—《•荅°丼基基團，v)-xiii)—嘴咬基基團，v)-xiv^ 一 1-吡咯啶基基團，v)-xv) — 1-哌啶基基團，v)-xvi)—丨_同 0底咬基基團及v)-xvii) — 4-嗎琳基基團所組成之族群之基團，其每一者可具有1至3個選自一C1-6烷基基團及一鹵素原子所組成之族群之取代基。其間較佳係一選自i)—胺基基團（其中，胺基基團可具有一個C2-6烷醯基基團、（:^規基磺醯基基團或C3-8環烷基磺醯基基團，或1至2個Cl-6'燒基基團或C3-8環烷基基團），ii) 一氰基基團，iii) 一鹵素原子， iv)—羥基基團，及v)v)-i) — C1-6烷基基團，v)-ii)—C1-6燒氧基基團，v)-iii) — C1-6烷硫基基團及v)-iv)—苯基基團所組成之族群之取代基’其每一者可具有1至3個選自_Cl_6 烷基基團及一 A素原子所組成之族群之取代基。特別較佳係一選自i)一鹵素原子及ii)⑴七一匚^烷基基團及…七)— C1-6烷氧基基團所組成之族群之取代基，其每一者可具有！至3個選自一C1-6烷基基團及一鹵素原子所組成之族群之取代基。 C1-6烷基基團"係指一具有丨至6個碳原子之烷基基團。此基團之較佳例子包含線性或分支之燒基基團，諸如，曱基基團、乙基基團、正丙基基團、異丙基基團、正丁基基團、異丁基基團、第三丁基基團、正戊基基團、異戊基基團、新戊基基團、正己基基團、卜甲基丙基基團、【I 二甲基丙基基團、1·乙基丙基基團、MU乙基丙基基 201031662 團、1-乙基-2-甲基丙基基團、ι，ι，2_三甲基丙基基團、丨_甲基丁基基團、2-甲基丁基基團、丨,丨_二甲基丁基基團、22_ 二甲基丁基基團、2-乙基丁基基團、1,3-二曱基丁基基團、 2-曱基戊基基團，及3_甲基戊基基團。 "鹵素原子"係指氟原子、氣原子、溴原子、碘原子等，且較佳係氟原子、氯原子，或溴原子。 "C1-6烷撐基基團"係指一具有1至6個碳原子之烷撐基基團。此基團之較佳例子包含線性或分支之烷基基團，諸如，甲撐基基團、乙撐基基團、甲基甲撐基基團、丙撐基基團、甲基乙撐基基團、乙基甲撐基基團、二甲基曱撐基基團、丁撐基基團、甲基丙撐基基團、乙基乙撐基基團、二甲基乙撐基基團、丙基甲撐基基團、戊撐基基團及己撐基基團。其間，例如，甲撐基基團、乙撐基基團、曱基甲樓基基團、丙撐基基團、甲基乙撐基基團、乙基甲撐基基團及二甲基甲撐基基團係較佳。 "C3-8環烷基基團"係指一具有3至8個碳原子之環狀烷基基團。此基團之較佳例子包含環丙基基團、環丁基基團、環戊基基團、環己基基團及環庚基基團。 ”C2_6烷醯基基團"係指一其中一氫原子係以一羰基基團取代之具有丨至6個碳原子之烷基基團。此基團之較佳例子包含乙醯基基團、丙醯基基團及丁醯基基團。 ”C1-6烷基磺醯基基團”係指一其中一氫原子係以一續酿基基團取代之具有1至6個碳原子之烧基基團。此基團之較佳例子包含甲烷磺醯基基團及乙烷磺醯基基團。 36 201031662 "C2-6烯基基團"係指一具有2至6個碳原子之烯基基團。此基團之較佳例子包含直鍵或分支之烯基基團，諸如，乙烯基基團、烯丙基基團、卜丙烯基基團、異丙烯基基團、 1-丁烯-1-基基團、1-丁烯-2-基基團、1-丁烯-3-基基團、2-丁烯-1-基基團及2-丁烯-2-基基團。 ” C1-6烷氧基基團”係指一其中一氫原子係以一氧原子取代之具有1至6個碳原子之烷基基團。此基團之較佳例子包含甲氧基基團、乙氧基基團、正丙氧基基團、異丙氧基基團、正丁氧基基團、異丁氧基基團、第二丁氧基基團、第三丁氧基基團、正戊氧基基團、異戊氧基基團、第二戊氧基基團、第三戊氧基基團、正己氧基基團、異己氧基基團、1，2-二甲基丙氧基基團、2-乙基丙氧基基團、丨_甲基_2_ 乙基丙氧基基團、1-乙基-2-甲基丙氧基基團、u，2_三甲基丙氣基基團、1，1，2-三甲基丙氧基基團、1,1-二甲基丁氧基基團、2,2-一甲基丁氧基基團、2-乙基丁氧基基團、ι，3_二甲基丁氧基基團、2-甲基戊氧基基團及3_甲基戊氧基基團。 "C2_6烯氧基基團"係指一其中一氫原子係以一氧原子取代之具有2至6個碳原子之烯基基團。此基團之較佳例子包含線性或分支之烯氧基基團，諸如，乙烯氧基基團、烯丙氧基基團、1-丙烯氧基基團、異丙烯氧基基團、卜丁烯基氧基團、1-丁烯-2-基氧基團、“丁烯_3_基氧基團、2_丁烯-1-基氧基團及2-丁烯-2-基氧基團。 C3-8環烧氧基基團"係指一其中一氫原子係以一氧原子取代之具有3至8個碳原子之環狀烷基基團。此基團之 37 201031662 較佳例子包含環丙氧基基團、環丁氧基基團、環戊氧基基團、環己氧基基團及環庚氧基基團。 "C6-14芳基基團”係指一具有6至14個碳原子之芳香族烴基團。此基團包含苯基基團、萘基基團、蒽基基團及菲基基團。 ”C6-14芳基-C1-6烷基基團”係指一其中一氫原子係以一前述MC6-14芳基基團”取代之具有1至6個碳原子之烷基基團。此基團之較佳例子包含苯曱基基團、苯乙基基團、苯基丙基基團、萘基甲基基團、萘基乙基基團及萘基丙基基團。 "C4-9環烷基羰基基團"係指一以一羰基基團取代之具有3至8個碳原子之環狀烷基基團。此基團之較佳例子包含環丙基羰基基團、環丁基羰基基團、環戊基羰基基團、環己基羰基基團，及環庚基羰基基團。 "C7-15芳醯基基團”係指以一羰基基團取代之前述 "C6-14芳基基團"。此基團之較佳例子包含苯甲醯基基團、萘基羰基基團及蒽基羰基基團。 "C2-6烯基磺醯基基團”係指一其中一氫原子係以一磺醯基基團取代之具有2至6個碳原子之烯基基團。此基團之較佳例子包含線性或分支之烯基磺醯基基團，諸如，乙烯基磺醯基基團、烯丙基磺酿基基團、1-丙烯基磺醯基基團、異丙烯基磺醯基基團、1-丁烯-1-基磺醯基基團、1-丁烯-2-基磺醯基基團、卜丁烯-3-基磺醯基基團、2-丁烯-1-基磺醯基基團，及2-丁烯-2-基磺醯基基團。 38 201031662 ，’C3-8環烷基磺醯基基團"係指一其中一氫原子係以一磺醯基基團取代之具有3至8個碳原子之環狀烷基基團。此基團之較佳例子包含環丙基磺醯基基團、環丁基磺醯基基團、環戊基磺醯基基團、環己基磺醯基基團，及環庚基磺酿基基團。 "C6-14芳基磺醯基基團"係指一其中一氫原子係以一磺醯基基團取代之具有6至14個碳原子之芳香族烴基團。此基團之較佳例子包含笨基磺醯基基團、萘基磺醯基基團，及蒽基績醢基基團。 "C1-6烷硫基基團"係指一其中一氫原子係以一硫原子取代之具有1至6個碳原子之烧基基團。此基團之較佳例子包含甲硫基基團、乙硫基基團、正丙硫基基團、異丙硫基基團、正丁硫基基團、異丁硫基基團、第三丁硫基基團、正戊硫基基團、異戊硫基基團、新戊硫基基團、正己硫基基團，及1-曱基丙硫基基團。 "C2-6烯硫基基團”係指一具有2至6個碳原子之烯硫基基團。此基團之較佳例子包含線性或分支之烯硫基基團，諸如，乙烯硫基基團、烯丙硫基基團、丨_丙烯硫基基團、異丙烯硫基基團、1-丁烯-1-基硫基團、丨_丁烯_2_基硫基團、卜丁烯-3-基硫基團、2-丁烯-i_基硫基團，及2_丁烯_2_基硫基團。 "C3-8環烧硫基基團"係指—其中—氫原子係以一硫原子取代之具有3至8個碳原子之環狀烷基基團。此基團之較佳例子包含環丙硫基、環T硫基基團、環戊硫基基團、環 39 201031662 己硫基基團，及環庚硫基基團。 "可具有1至2個C1-6烷基基團、C2-6烯基基團或C3-8環烷基基團之胺基磺醯基基團”之例子包含胺基磺醯基基團與甲基胺基續酿基基團、乙基胺基績酿基基團、二曱基胺基磺醯基基團、二乙基胺基磺醯基基團、乙烯基胺基磺醯基基團、稀丙基胺基續酿基基團、環丙基胺基確酿基基團、環丁基胺基磺醯基基團，及環己基胺基磺醯基基團。 ”可具有一個C2-6烧酿基基團、C1-6烧基續酿基基團或 C3-8環烷基磺醯基基團或1至2個C1-6烷基基團或C3-8環烷基基團之胺基基團"之例子包含胺基基團與乙醯基胺基基團、丙醯基胺基基團、甲烷磺醯基胺基基團、乙烷磺醯基胺基基困、戊烷磺醯基胺基基團、曱基胺基基團、二甲基胺基基團、乙基胺基基團、二乙基胺基基團、環丙基胺基基團、環丁基胺基基團，及環己基胺基基團。 "C1-6烷基胺基羰基基團π係指一其中一氫原子係以一胺基羰基基團取代之具有1至6個碳原子之烷基基團。此基團之較佳例子包含甲基胺基羰基基團'乙基胺基羰基基團、丙基胺基羰基基團、丁基胺基羰基基團，及己基胺基羰基基團。 "C1-6烷基胺基磺醯基基團"係指一其中一氫原子係以一胺基磺醯基基團取代之具有1至6個碳原子之烷基基團。此基團之較佳例子包含甲基胺基磺醯基基團、乙基胺基績醯基基團、丙基胺基磺醯基基團、丁基胺基磺醯基基團’ 及己基胺基磺醯基基團。 201031662 於本發明，"藥理學上可接受之鹽"並未特別限制，只要其係-藉由Αβ造成之疾狀治療劑之以通式⑴之化合物形成之藥理學上可接受之鹽。此鹽之較佳特別例子包含氫減鹽(諸如，氫氟酸鹽、氫氯酸鹽、氫溴酸鹽，及氫碘酸鹽）、無機酸鹽(諸如，硫酸鹽、硝酸鹽、過氣酸鹽、_ 鹽、碳酸鹽，及碳酸氫鹽）、有機敌酸鹽(諸如，乙酸鹽、草酸鹽、馬來酸鹽、酒石酸鹽、福馬酸鹽，及擰檬酸^And preferably a phenyl group, a pyridyl group, a oxazolyl group, a propyl group, a thiol group, a monohydrofuranyl group or a mouth The pheno group is a mono-phenyl group or a pyridyl group. Ring B may have 1 to 3 substituents selected from the following substituent group C1. , a substituent group cl" means an i-amino group (wherein the 'amino group' may have a c2_6 sulphonyl group, a C1-6 alkyl sulfonyl group or a C3_8 naphthenic group a sulfonyl group, or 1 to 2 C1_6 alkyl groups or a C3-8 cycloalkyl group), ii) a cyano group, m) a halogen atom, iv) a hydroxy group ring, and v) v)...—C1_6 ndyl group, v)-ii) — C2-6 dilute group, exo)—C2_6 alkynyl group, v) _iv) a C1-6 alkoxy group, V -V)-Cl_6 alkylthio group, v)-vi) - C1-6 alkylamino group 'v)-vii) - (^ decane 34 201031662 sulfonyl group, v )-viii) - a C1-6 alkylaminosulfonyl group, v) _ix) a C2-6 alkenyl group, v) - x) - a phenyl group 'v) - xi) - η Bipyridyl group, v)-xii) - "•荅荅 base group, v)-xiii) - mouth biting group, v)-xiv^ a 1-pyrrolidinyl group, v)- Xv) - 1-piperidinyl group, v) - xvi) - 丨 _ with 0 bottom base group and v) - xvii) - 4-morphinyl group consisting of groups of groups, each of which One may have 1 to 3 groups selected from a C1-6 alkyl group and a halogen atom Substituents of the group. Preferably, it is selected from the group consisting of i)-amino groups (wherein the amine group may have a C2-6 alkino group, a sulfonyl group or a C3-8 cycloalkyl group) a sulfonyl group, or 1 to 2 Cl-6'alkyl groups or a C3-8 cycloalkyl group), ii) a cyano group, iii) a halogen atom, iv) a hydroxyl group And v)v)-i) - a C1-6 alkyl group, v) - ii) - a C1-6 alkoxy group, v) - iii) - a C1-6 alkylthio group and v) The substituents of the group consisting of - phenyl) - each of which may have 1 to 3 substituents selected from the group consisting of a _Cl_6 alkyl group and an A atom. Particularly preferred is a substituent selected from the group consisting of i) a halogen atom and ii) (1) a hepta-alkyl group and a seven-) C1-6 alkoxy group, each of which may be have! Up to three substituents selected from the group consisting of a C1-6 alkyl group and a halogen atom. The C1-6 alkyl group " refers to an alkyl group having from 丨 to 6 carbon atoms. Preferred examples of such a group include a linear or branched alkyl group such as a mercapto group, an ethyl group, a n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group. a group, a tributyl group, a n-pentyl group, an isopentyl group, a neopentyl group, a n-hexyl group, a propyl propyl group, a [I dimethyl propyl group, 1 · Ethyl propyl group, MU ethyl propyl group 201031662 group, 1-ethyl-2-methylpropyl group, ι, ι, 2_trimethylpropyl group, 丨_methyl butyl Base group, 2-methylbutyl group, hydrazine, hydrazine-dimethylbutyl group, 22-dimethylbutyl group, 2-ethylbutyl group, 1,3-dioxyl group a butyl group, a 2-decylpentyl group, and a 3-methylpentyl group. "Halogen atom" means a fluorine atom, a gas atom, a bromine atom, an iodine atom, etc., and is preferably a fluorine atom, a chlorine atom, or a bromine atom. "C1-6 alkylene group" means an alkylene group having 1 to 6 carbon atoms. Preferred examples of such a group include a linear or branched alkyl group such as a methylene group, an ethylene group, a methylmethylene group, a propylene group, a methylethylene group. a group, an ethylmerylene group, a dimethyl fluorene group, a butyl group, a methyl propylene group, an ethylethylene group, a dimethylethylene group a propylmethylene group, a pentylene group and a hexylene group. Meanwhile, for example, a methylene group, an ethylene group, a fluorenyl group, a propylene group, a methylethylene group, an ethylmerylene group, and a dimethyl group A phenyl group is preferred. "C3-8 cycloalkyl group" means a cyclic alkyl group having 3 to 8 carbon atoms. Preferred examples of such a group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group. The "C2_6 alkylalkyl group" refers to an alkyl group having from 1 to 6 carbon atoms in which one hydrogen atom is substituted with a carbonyl group. Preferred examples of such a group include an ethyl fluorenyl group. a propylene group and a butyl group. A "C1-6 alkylsulfonyl group" means a group having from 1 to 6 carbon atoms in which one hydrogen atom is substituted by a continuation group. Preferred examples of the group include a methanesulfonyl group and an ethanesulfonyl group. 36 201031662 "C2-6 alkenyl group" means a carbon atom having 2 to 6 carbon atoms Alkenyl group. Preferred examples of such a group include a straight bond or a branched alkenyl group such as a vinyl group, an allyl group, a propenyl group, an isopropenyl group, Buten-1-yl group, 1-buten-2-yl group, 1-buten-3-yl group, 2-buten-1-yl group and 2-buten-2-yl group The "C1-6 alkoxy group" means an alkyl group having 1 to 6 carbon atoms in which one hydrogen atom is substituted by one oxygen atom. A preferred example of such a group includes methoxy group. Base group, ethoxy group, n-propoxy group, a propoxy group, a n-butoxy group, an isobutoxy group, a second butoxy group, a third butoxy group, a n-pentyloxy group, an isopentyloxy group, a second pentyloxy group, a third pentyloxy group, a n-hexyloxy group, an isohexyloxy group, a 1,2-dimethylpropoxy group, a 2-ethylpropoxy group , 丨_methyl_2_ethylpropoxy group, 1-ethyl-2-methylpropoxy group, u, 2_trimethylpropane group, 1,1,2-three Methylpropoxy group, 1,1-dimethylbutoxy group, 2,2-methylbutoxy group, 2-ethylbutoxy group, iota, 3-dimethyl a butyloxy group, a 2-methylpentyloxy group and a 3-methylpentyloxy group. "C2_6 alkenyloxy group" means that one of the hydrogen atoms is replaced by an oxygen atom An alkenyl group having 2 to 6 carbon atoms. Preferred examples of such a group include a linear or branched alkenyloxy group such as a vinyloxy group, an allyloxy group, or a 1-propene group. An oxy group, an isopropenyloxy group, a butenyloxy group, a 1-buten-2-yloxy group, a "butene_3_yloxy group, 2_ En-1-yloxy group and 2-buten-2-yloxy group. The C3-8 cycloalkoxy group" refers to a cyclic alkyl group having 3 to 8 carbon atoms in which one hydrogen atom is substituted with one oxygen atom. Preferred examples of this group 37 201031662 include a cyclopropoxy group, a cyclobutoxy group, a cyclopentyloxy group, a cyclohexyloxy group, and a cycloheptyloxy group. "C6-14 aryl group" means an aromatic hydrocarbon group having 6 to 14 carbon atoms. This group contains a phenyl group, a naphthyl group, a fluorenyl group, and a phenanthryl group. The "C6-14 aryl-C1-6 alkyl group" means an alkyl group having 1 to 6 carbon atoms in which one hydrogen atom is substituted with one of the aforementioned MC6-14 aryl groups. Preferred examples of such a group include a phenylhydrazine group, a phenethyl group, a phenylpropyl group, a naphthylmethyl group, a naphthylethyl group, and a naphthylpropyl group. "C4-9 cycloalkylcarbonyl group" means a cyclic alkyl group having 3 to 8 carbon atoms which is substituted with a carbonyl group. Preferred examples of the group include a cyclopropylcarbonyl group, a cyclobutylcarbonyl group, a cyclopentylcarbonyl group, a cyclohexylcarbonyl group, and a cycloheptylcarbonyl group. "C7-15 arylalkyl group" means the aforementioned "C6-14 aryl group" substituted with a carbonyl group. Preferred examples of this group include a benzyl group and a naphthyl group. a carbonyl group and a mercaptocarbonyl group. "C2-6 alkenylsulfonyl group" means an alkenyl group having 2 to 6 carbon atoms in which one hydrogen atom is substituted with a monosulfonyl group. Group. Preferred examples of such a group include a linear or branched alkenylsulfonyl group such as a vinylsulfonyl group, an allylsulfonyl group, a 1-propenylsulfonyl group, and a different group. Propenylsulfonyl group, 1-buten-1-ylsulfonyl group, 1-buten-2-ylsulfonyl group, buten-3-ylsulfonyl group, 2 a buten-1-ylsulfonyl group, and a 2-buten-2-ylsulfonyl group. 38 201031662, 'C3-8 cycloalkylsulfonyl group" refers to a cyclic alkyl group having 3 to 8 carbon atoms in which one hydrogen atom is substituted with a monosulfonyl group. Preferred examples of the group include a cyclopropylsulfonyl group, a cyclobutylsulfonyl group, a cyclopentylsulfonyl group, a cyclohexylsulfonyl group, and a cycloheptylsulfonyl group. Group. "C6-14 arylsulfonyl group" means an aromatic hydrocarbon group having 6 to 14 carbon atoms in which one hydrogen atom is substituted with a monosulfonyl group. Preferred examples of the group include a sulfhydryl group, a naphthylsulfonyl group, and a fluorenyl group. "C1-6 alkylthio group" means an alkyl group having 1 to 6 carbon atoms in which one hydrogen atom is substituted with a sulfur atom. Preferred examples of the group include a methylthio group, an ethylthio group, a n-propylthio group, an isopropylthio group, an n-butylthio group, an isobutylthio group, and a third. Butylthio group, n-pentylthio group, isopentylthio group, neopentylthio group, n-hexylthio group, and 1-mercaptopropylthio group. "C2-6 olefinylthio group" means an olefinylthio group having 2 to 6 carbon atoms. Preferred examples of such a group include a linear or branched thiol group, such as ethylene sulphide. a group, an allylthio group, a fluorene-propylthio group, an isopropenylthio group, a 1-buten-1-ylthio group, a fluorene-butene-2-ylthio group, a buten-3-ylthio group, a 2-butene-i-ylthio group, and a 2-butene-2-ylthio group. "C3-8 cycloalkylthio group" And wherein the hydrogen atom is a cyclic alkyl group having 3 to 8 carbon atoms, which is substituted by a sulfur atom. Preferred examples of the group include a cyclopropylthio group, a cyclic T-thio group, and a cyclopentane group. a thio group, a ring 39 201031662 hexylthio group, and a cycloheptylthio group. " may have 1 to 2 C 1-6 alkyl groups, C 2-6 alkenyl groups or C 3-8 rings Examples of the aminosulfonyl group of the alkyl group include an aminosulfonyl group and a methylaminohydrogen group, an ethylamino group, a dimercaptoamine group. Thiol group, diethylaminosulfonyl group, vinylaminosulfonyl group, dipropyl propyl group Group, cyclopropyl group determined brewing group, cyclobutyl group Sulfonic group, and cyclohexyl group sulfonylurea group. " may have a C2-6 sinter group, a C1-6 alkyl group or a C3-8 cycloalkylsulfonyl group or 1 to 2 C1-6 alkyl groups or C3- Examples of the amine group of the 8-cycloalkyl group include an amino group and an acetamino group, a propylamino group, a methanesulfonylamino group, and an ethanesulfonate. Amino group, pentanesulfonylamino group, mercaptoamine group, dimethylamino group, ethylamino group, diethylamino group, cyclopropylamine a group, a cyclobutylamino group, and a cyclohexylamino group. "C1-6 alkylaminocarbonyl group π means that one of the hydrogen atoms is substituted with an aminocarbonyl group. An alkyl group having 1 to 6 carbon atoms. Preferred examples of the group include a methylaminocarbonyl group 'ethylaminocarbonyl group, a propylaminocarbonyl group, a butylaminocarbonyl group a group, and a hexylaminocarbonyl group. "C1-6 alkylaminosulfonyl group" means that one of the hydrogen atoms is substituted with an aminosulfonyl group to have 1 to 6 An alkyl group of one carbon atom. A preferred example of this group includes An aminoaminosulfonyl group, an ethylamino fluorenyl group, a propylaminosulfonyl group, a butylaminosulfonyl group, and a hexylaminosulfonyl group. 201031662 In the present invention, the "pharmacologically acceptable salt" is not particularly limited as long as it is a pharmacologically acceptable salt formed by the compound of the formula (1) by a therapeutic agent caused by Αβ. Preferred specific examples of the salt include hydrogen salt reduction (such as hydrofluoride, hydrochloride, hydrobromide, and hydroiodide), inorganic acid salts (such as sulfate, nitrate, and gas). Acid salts, _ salts, carbonates, and bicarbonates), organic acid salt (such as acetate, oxalate, maleate, tartrate, fumarate, and citric acid)

機項酸鹽（諸如，甲燒俩鹽、三氟甲烧猶鹽、乙^酸鹽、苯雜鹽、甲笨確酸鹽，及樟腦雜鹽）、胺基酸^ 如，天冬胺酸鹽及麩胺酸鹽）、季揽(諸鹽及鉀睡H驗金屬-(諸如’鈉 D及驗土金屬鹽(諸如，鎂鹽及妈鹽）。其次，依據本發明之化學式⑴之化合物將被說明。環ΑΓ化學式(1)之化合物或其藥理學上可接受之鹽或嗤， p較佳係-選自化學式[離[26]顺成族群香族雜環基團：貝之方Alkaloids (such as a smoldering salt, a trifluoromethane salt, a sulphate salt, a benzene salt, a succinic acid salt, and a camphor salt), an amino acid, such as aspartic acid Salts and glutamate), seasons (salt and potassium, and metal--such as 'sodium D and soil-measuring metal salts (such as magnesium salts and mom salts). Second, the compounds of formula (1) according to the invention The compound of the formula (1) or its pharmacologically acceptable salt or hydrazine, p is preferably selected from the chemical formula [from the [26] cis group of aromatic heterocyclic groups:

[化學式26][Chemical Formula 26]

其中’ •代表-與化學式网之鍵結位置： [化學式27]Where '• Representative- and the bonding position of the chemical network: [Chemical Formula 27]

23 41 20103166223 41 201031662

且 Α·代表一與X2之鍵結位置，或選自化學式[28]至[39]所組成族群之任一環： [化學式28]And Α· represents a bonding position with X2, or a ring selected from the group consisting of chemical formulas [28] to [39]: [Chemical Formula 28]

其中，•及A·係如上所定義及部份結構： [化學式29]Among them, • and A· are as defined above and part of the structure: [Chemical Formula 29]

代表一單鍵或一雙鍵，其每一者可具有1至3個選自取代基族群bl之取代基。環A更佳係選自化學式[21]、[28]、[29]、 [31]、[32]及[34]至[37]所組成族群之任一環： [化學式30] 42 201031662It represents a single bond or a double bond, each of which may have 1 to 3 substituents selected from the substituent group bl. More preferably, Ring A is selected from any of the groups consisting of the chemical formulas [21], [28], [29], [31], [32], and [34] to [37]: [Chemical Formula 30] 42 201031662

其中，·、Α·及部份結構： [化學式31]Among them, ····· and part of the structure: [Chemical Formula 31]

係如上所定義。環Α特別佳係選自化學式[21]、[28-1]、 [29-1]、[31-1]、[32-1]及[34-1]至[37-1]所組成族群之任一環: [化學式32]Is as defined above. The ringworm is particularly preferably selected from the group consisting of the chemical formulas [21], [28-1], [29-1], [31-1], [32-1], and [34-1] to [37-1]. Any ring: [Chemical Formula 32]

其中，·、A·及部份結構： [化學式33] 係如上所定義。環A最佳係一化學式[28-1]之環： [化學式34]Wherein, ···· and part of the structure: [Chemical Formula 33] is as defined above. Ring A is the ring of the chemical formula [28-1]: [Chemical Formula 34]

28-1 201031662 其中，·、Α·及部份結構： [化學式35] 係如上所定義於化學式(I)之化合物或其藥理學上可接受之鹽或醋，環Β較佳係-苯基基團、—㈣基基團、—料基基團、一咪唾基基團、—料基基g、—二氫料料基基團，或 -嗔吩基基團，且更佳係—苯基基團。28-1 201031662 wherein, ····· and a partial structure: a compound as defined above in the formula (I) or a pharmacologically acceptable salt or vinegar thereof, preferably a phenyl group a group, a -(tetra)yl group, a substituent group, a methantyl group, a material group g, a dihydrogen group group, or a fluorenyl group, and more preferably a group Phenyl group.

於化學式(I)之化合物或其藥理學上可接受之鹽或醋， Χι較佳係i)一單鍵或丨丨）_Cr3=cr4_。於化學式（I)之化合物或其藥理學上可接受之鹽或酯，父2較佳係0—單鍵或ϋ)一C1_6烷撐基基團，且X2更佳係一單鍵。於化學式（I)之化合物或其藥理學上可接受之鹽或醋，較佳地，&係一Cl_6烷基基團或一鹵素原子，且111係1至2。The compound of the formula (I) or a pharmacologically acceptable salt or vinegar thereof is preferably i) a single bond or hydrazine) _Cr3 = cr4_. The compound of the formula (I) or a pharmacologically acceptable salt or ester thereof, the parent 2 is preferably a 0-mono- or oxime-C1_6 alkylene group, and X2 is more preferably a single bond. The compound of the formula (I) or a pharmacologically acceptable salt or vinegar thereof, preferably, is a Cl 6 alkyl group or a halogen atom, and 111 is 1 to 2.

於化學式（I)之化合物或其藥理學上可接受之鹽或醋，較佳地，R2係一C1-6烷氧基基團，且η係1。於化學式（I)之化合物或其藥理學上可接受之鹽或酯，較佳地，尺3及尺4係相同或相異’且每一者係（1)一氫原子或 ⑺一鹵素原子。更佳地，R3及R4皆係氫原子。於化學式（I)或其藥理學上可接受之鹽或酯，對於環A 之取代較佳係一選自一C1-6烷基基團（其中，烷基基團可以 1至3個鹵素原子取代）、一 C3-8環烷基基團、一 C6-14芳基基團、一C6-14芳基-C1-6烷基基團、一C1-6烷氧基基團、 44 201031662 一C3-8環烷氧基基團、一C2-6烷醯基基團、一C7-15芳醯基基團、一C1-6烷基磺醯基基團、一C3-8環烷基磺醯基基團、一C6-14芳基磺醯基基團、一氰基基團、一甲醯基基團、一鹵素原子、一羥基基團及一側氧基基團所組成族群之取代基。於化學式（I)之化合物或其藥理學上可接受之鹽或酯，對於環B之取代較佳係一選自i)一胺基基團（其中，胺基基團可具有一個C2-6烷醯基基團、C1-6烷基磺醯基基團或C3-8 環烷基磺醯基基團，或1至2個C1-6烷基基團或C3-8環烷基基團），ii) 一氰基基團，iii) 一鹵素原子，iv)—羥基基團，及 v) v)-i) — C1-6烷基基團，v)-ii) — C1-6烷氧基基團，v)-iii) 一 C1-6烷硫基基團及v)-iv) —苯基基團所組成族群之取代基，其每一者可具有1至3個選自一C1-6烷基基團及一鹵素原子所組成族群之取代基。至少一選自下列化學式[A-1]至[A-7]所組成族群之化合物： [化學式36] 45 201031662The compound of the formula (I) or a pharmacologically acceptable salt or vinegar thereof, preferably, R2 is a C1-6 alkoxy group, and η is 1. A compound of the formula (I) or a pharmacologically acceptable salt or ester thereof, preferably, the ruler 3 and the ruler 4 are the same or different and each is a (1)-hydrogen atom or a (7)-halogen atom. . More preferably, both R3 and R4 are hydrogen atoms. In the chemical formula (I) or a pharmacologically acceptable salt or ester thereof, the substitution for the ring A is preferably selected from a C1-6 alkyl group (wherein the alkyl group may have 1 to 3 halogen atoms) Substituted), a C3-8 cycloalkyl group, a C6-14 aryl group, a C6-14 aryl-C1-6 alkyl group, a C1-6 alkoxy group, 44 201031662 a C3-8 cycloalkoxy group, a C2-6 alkylalkyl group, a C7-15 arylalkyl group, a C1-6 alkylsulfonyl group, a C3-8 cycloalkyl sulfonate Substitution of a group consisting of a mercapto group, a C6-14 arylsulfonyl group, a cyano group, a monomethyl group, a halogen atom, a monohydroxy group, and a one-sided oxy group base. The compound of the formula (I) or a pharmacologically acceptable salt or ester thereof, preferably substituted for the ring B, is selected from the group consisting of i) an amino group (wherein the amine group may have a C2-6) An alkino group, a C1-6 alkylsulfonyl group or a C3-8 cycloalkylsulfonyl group, or 1 to 2 C1-6 alkyl groups or a C3-8 cycloalkyl group ), ii) a cyano group, iii) a halogen atom, iv) a hydroxyl group, and v) v) -i) - a C1-6 alkyl group, v) - ii) - a C1-6 alkane An oxy group, v)-iii) a C1-6 alkylthio group and a substituent of the group consisting of v)-iv)-phenyl groups, each of which may have from 1 to 3 selected from the group consisting of a substituent of a C1-6 alkyl group and a group consisting of a halogen atom. At least one compound selected from the group consisting of the following chemical formulas [A-1] to [A-7]: [Chemical Formula 36] 45 201031662

或其藥理學上可接受之鹽或酯係特別適合，例如，係作為 —用於藉由類澱粉_β造成之疾病（諸如，阿茲罕默氏疾病、老年癡呆症、唐氏症候群或類澱粉變性症）之治療劑。依據本發明之用於製備通式（I)之化合物之方法將於下說明。以通式[I]表示之化合物： [化學式37]Or a pharmacologically acceptable salt or ester thereof is particularly suitable, for example, as a disease caused by a starch-like granule (such as Azheimer's disease, Alzheimer's disease, Down's syndrome or class) A therapeutic agent for amyloidosis. The process for the preparation of the compound of the formula (I) according to the present invention will be explained below. a compound represented by the general formula [I]: [Chemical Formula 37]

其中，R!、R2、χι、χ2、m、η、環Α及環Β係如上定義，係 46 201031662 依據一諸如下列一般製備方法1及一般製備方法2之方法合成。明顯地’為方便地製備本發明化合物，此方法適當地包含一保護反應步驟及一去保護反應步驟，其使用一對每一步驟適合地選擇之熟習此項技藝者所知之保護基團 (見’ T.Greene等人，"有機合成之㈣基團"，j〇hnWi&& s〇ns，inc.，NewYork，測）。明顯地，為方便地製備本發明化合物，適於每一步驟且係熟習此項技藝者所知之取代基轉化、取代基引人等。亦明顯地，為方便地製備本發明化 &物所有異構物及異構物混合物，諸如，可自此化合物之I。構產生之幾何異構物、以非對稱碳為基礎之光學異構物、立體異構物，及互變異構物，可藉由適於每—步驟之熟習此項技藝者所知之技術(諸如，分段結晶或管柱色譜分析術）以單—化合物製備。 [一般製備方法^ 用於依捸本發明之通式[I]之化合物之典型上使用之一般製備方法將於下說明。 [化學式38]Wherein R!, R2, χι, χ2, m, η, cyclic oxime and cyclic oxime are as defined above, and 46 201031662 is synthesized according to a method such as the following general preparation method 1 and general preparation method 2. Obviously, for the convenience of preparing the compounds of the present invention, the method suitably comprises a protective reaction step and a deprotection reaction step which are suitably selected from a pair of each step to be known to those skilled in the art ( See 'T. Greene et al., " Organic Synthesis (4) Group", j〇hnWi&&s〇ns, inc., NewYork, Measure). Obviously, for the convenience of preparing the compounds of the present invention, it is suitable for each step and is well known to those skilled in the art for substituent conversion, substituent introduction, and the like. It is also apparent that all of the isomers and isomer mixtures of the present invention are conveniently prepared, for example, from this compound. The geometric isomers produced, the optical isomers based on asymmetric carbons, stereoisomers, and tautomers can be obtained by techniques well known to those skilled in the art (for each step). For example, fractional crystallization or column chromatography) is prepared as a single compound. [General Preparation Method ^ One of the typical preparation methods for the compound of the general formula [I] according to the present invention will be described below. [Chemical Formula 38]

於化學式，R]、R2、&、χ2、m、η、環A及環B係如上所疋義，又八代表一鹵素原子(諸如，一氣原子、一溴原子， 47 201031662 或一埃原子）或一確酸鹽基團（諸如’一甲统磺酸鹽基團、一對-甲苯磺酸鹽基團或’一三氟甲烷磺酸鹽基團）；且xB& 表一三烧基錫烧基基團、一领酸基團、一棚酸鹽基團（諸如，一頻哪醇硼酸鹽基團、烷基硼烯基基團、一C2-6烯基基團，或一C2-6快基基團。如上之一般製備方法1係一種藉由使一通式（a~ 1)之化合物及一通式(b-2)之化合物接受步驟1-1之偶合反應製備通式[I]之化合物之方法，或一種藉由使一通式（a-2)之化合物及一通式（b-Ι)之化合物接受步驟1-1之偶合反應製備通式[I]之化合物之方法，其中，取代基XA及Xb係藉由彼此而取代。步驟1-1之偶合反應係依據起始材料改變，且不受特別限制，只要條件相似於此反應者。一熟習此項技藝者所知之方法可用於此反應。此方法之較佳例子包含In the chemical formula, R], R2, &, χ2, m, η, ring A and ring B are as defined above, and eight represent a halogen atom (such as a gas atom, a bromine atom, 47 201031662 or an angstrom atom). Or a acid salt group (such as 'monomethylsulfonate group, a pair of tosylate group or 'trifluoromethanesulfonate group); and xB& a tin group, an acid group, a succinate group (such as a pinacol borate group, an alkylboronyl group, a C2-6 alkenyl group, or a C2) -6 fast group. The general preparation method 1 is a method for preparing a general formula [I] by subjecting a compound of the formula (a-1) and a compound of the formula (b-2) to a coupling reaction of the step 1-1. a method of preparing a compound of the formula [I], or a method of preparing a compound of the formula [I] by subjecting a compound of the formula (a-2) and a compound of the formula (b-indole) to a coupling reaction of the step 1-1, wherein The substituents XA and Xb are substituted by each other. The coupling reaction of the step 1-1 is changed depending on the starting material, and is not particularly limited as long as the conditions are similar to those of the reactant. A method known to those skilled in the art can be used for this reaction. Preferred examples of this method include

Mizoroki-Heck反應（見，例如，R.F. Heck, ”有機反應”，1982, vol. 27,第 345 頁）、Suzuki-Miyaura反應（見，例如，Suzuki, "Chem. Rev.”，1995，vol. 95，第 2457 頁）、Sonogashira反應 (見，例如，K. Sonogashira, ”簡易有機合成’’，1991, vol. 3，第 521 頁）及Stille偶合反應（見’例如，J.K. Stille，"Angew. Chem. Int. Ed. Engl."，1986, vol. 25，第 508 頁）。於Mizoroki-Heck反應，通式（a-1)之一鹵素化合物或三氟甲烧續酸鹽基團化合物較佳係，例如，於相關於通式(a-1) 之化合物係0.01至0.2當量之過渡金屬催化劑存在中，與相關於通式（a-Ι)之化合物係1.0至5.0當量之通式(b-2)之化合 201031662 物(其中’ xB較佳係__C2_6烯基基團）偶合。由處理性及搜拌效率之觀點而言，此反應較佳係於一溶劑存在中實施。使用之4冑,1依細之^始材料及過渡金屬催化咖改變，且並未特別限制，只要料會抑制此反應且使起始材料於其間冷解至某—程度。此溶劑之較佳例子包含乙腈、四氣呋喃、1，4-二噁烷、丨，2_二甲氧基乙烷、苯、甲苯、二甲笨、 1-甲基-2心各烧酮’及N，N_二甲基甲酿胺。反應溫度需為可使偶合反應完全之溫度，且較佳係室溫至l5〇〇c。此反應較佳係於―惰性氣體氛圍中實施，且更佳係於_氮氣或氬氣氛圍。過渡金屬催化劑較佳係，例如，一鈀錯合物，且更佳係一已知之鈀錯合物，諸如，乙酸鈀(H)、二氣雙（三苯基膦)師I)、四(三苯基膦)_)，或三(二苯甲又基丙綱）一纪(〇)亦較佳者係適當添加一膦配位體(較佳係，例如，二苯基膦、三-鄰-甲苯基膦、三_第三丁基膦或2_(二-第三丁基膦基)聯苯），以使此反應有效率地進行。一較佳之結果可於鹼存在中達成。使用之鹼未被特別限制，只要其係用於一與此反應相似之偶合反應。此鹼之較佳例子包含三乙基胺、N，N-二異丙基乙基胺、Ν,Ν-二環己基甲基胺，及氣化四丁基銨。於較佳反應條件下，此反應係於丨至24小時完全，且此反應之進行可藉由一已知之色譜分析術監測。於Suzuki-Miyaura反應，通式（a_i)之一画素化合物或三氟甲烷磺酸鹽化合物較佳係於，例如，相關於通式(a_1}之化合物係0.01至0.5當量之一過渡金屬催化劑存在中，與相關於通式（a-Ι)之化合物係1.〇至5 〇當量之通式（b 2)之化合 49 201031662 物（其中’ χΒ較佳係-餐基團、—硼酸鹽基團（諸如，頻哪醇硼酸鹽基團）、-烧基硼烯基基圏等)偶合。由處理性及攪拌效率之觀點而言，此反應較佳係於一溶劑存在中實施。使用之溶劑依使用之起始材料及過渡金屬催化劑而改變，且並未特別限制，只要其不會抑制此反應且使起始材料於其間溶解至某—程度。此溶劑之較佳例子包含乙猜、四氫呋喃、1,4-二噁烷、ls2_二甲氧基乙烷、苯、甲苯 '二甲苯、1-甲基-2-吼洛炫_、N，N_二甲基甲醢胺、水，及其等之混合溶劑。反應溫度需為一可使偶合反應完全之溫 ❹ 度，且較佳係室溫至·^此反應較佳係於—惰性氣體氛圍中實施’且更佳係於—氮氣或氬氣氛圍。於較佳反應條件下，此反應係於丨至24小時完全，且此反應之進行可藉由 -已知之色譜分析術監測。職金屬催化紐佳係，例如，一已知之㈣合物，且更佳係' —諸如乙酸_1)、二氣雙(三 . 苯基膦)_)、四(三笨基膦卿），或三(二苯甲叉基丙嗣）二鈀(0)之已知鈀錯合物。一膦配位體(較佳係例如三苯基笨基膦、三環己基膦，或三_第三丁基膦)可 ❿ 被適當地添加以使此反應有效率地進行。—季錄鹽（較佳係’例如，氣化四丁基錄或漠化四丁基銨）亦可適當地添加以使此反應有效率地進行。於此反應，一較佳結果可於驗存在中達成。此時使用之驗係依起始材料、使用之溶劑等而改變，且不被特職制。驗之較佳例子包含氫氧化納、氫氧化鋇、mi化绝、破酸納、碳酸鉀、碳酸絶，及磷酸鉀。於較佳反應條件下，此反應係於β24小時完 50 201031662 王，且此反應之進仃可藉由—已知之色譜分析術監測。Mizoroki-Heck reaction (see, for example, RF Heck, "Organic Reactions", 1982, vol. 27, p. 345), Suzuki-Miyaura reaction (see, for example, Suzuki, "Chem. Rev.", 1995, vol 95, p. 2457), Sonogashira reaction (see, for example, K. Sonogashira, "Simple Organic Synthesis", 1991, vol. 3, p. 521) and Stille coupling reaction (see 'for example, JK Stille," Angew. Chem. Int. Ed. Engl.", 1986, vol. 25, p. 508). In the Mizoroki-Heck reaction, a halogen compound or a trifluoromethaneate group compound of the formula (a-1) is preferably, for example, a compound of the formula (a-1), 0.01 to 0.2. In the presence of an equivalent amount of a transition metal catalyst, a compound of the formula (a-Ι) is 1.0 to 5.0 equivalents of the compound of the formula (b-2) 201031662 (wherein the 'xB is preferably a __C2_6 alkenyl group) ) Coupling. From the standpoint of handleability and search efficiency, the reaction is preferably carried out in the presence of a solvent. The use of 4 胄, 1 varies depending on the starting material and the transition metal catalyzed coffee, and is not particularly limited as long as the reaction is inhibited and the starting material is cooled to some extent therebetween. Preferred examples of the solvent include acetonitrile, tetra-furfuran, 1,4-dioxane, anthracene, 2-dimethoxyethane, benzene, toluene, dimethyl benzene, 1-methyl-2 ketone ketone 'and N, N_ dimethyl ketoamine. The reaction temperature is required to be a temperature at which the coupling reaction is completed, and is preferably room temperature to 15 〇〇c. This reaction is preferably carried out in an "inert gas atmosphere" and more preferably in a nitrogen or argon atmosphere. The transition metal catalyst is preferably, for example, a palladium complex, and more preferably a known palladium complex, such as palladium acetate (H), dioxobis(triphenylphosphine) Division I), tetra ( Triphenylphosphine)-), or tris(diphenylmethylpyrimidinyl) is also preferably added with a phosphine ligand (preferably, for example, diphenylphosphine, tri-) O-tolylphosphine, tri-tert-butylphosphine or 2-(di-t-butylphosphino)biphenyl) to allow this reaction to proceed efficiently. A preferred result can be achieved in the presence of a base. The base to be used is not particularly limited as long as it is used in a coupling reaction similar to this reaction. Preferred examples of the base include triethylamine, N,N-diisopropylethylamine, hydrazine, hydrazine-dicyclohexylmethylamine, and tetrabutylammonium vapor. Under the preferred reaction conditions, the reaction is complete for up to 24 hours and the progress of the reaction can be monitored by a known chromatographic analysis. In the Suzuki-Miyaura reaction, a one-pixel compound or a trifluoromethanesulfonate compound of the formula (a-i) is preferably, for example, a compound of the formula (a_1) in the presence of 0.01 to 0.5 equivalent of a transition metal catalyst. Wherein, the compound of the formula (a-Ι) is a compound of the formula (b 2), which is a compound of the formula (a-Ι), and the compound of the formula (b 2) is 49, 201031662 (wherein 'the preferred group is a meal group, a borate group Coupling (such as a pinacol borate group), a pyroboroyl group, etc.. The reaction is preferably carried out in the presence of a solvent from the viewpoint of handleability and stirring efficiency. The solvent is changed depending on the starting material used and the transition metal catalyst, and is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent therebetween. Preferred examples of the solvent include B guess, Tetrahydrofuran, 1,4-dioxane, ls2_dimethoxyethane, benzene, toluene'xylene, 1-methyl-2-indole _, N,N-dimethylformamide, water And its mixed solvent. The reaction temperature needs to be a temperature that makes the coupling reaction complete, and Preferably, the reaction is carried out in an inert gas atmosphere and is preferably carried out in a nitrogen or argon atmosphere. Under the preferred reaction conditions, the reaction is carried out until 24 to 24 hours, and The progress of this reaction can be monitored by - known chromatographic analysis. The metal catalyzed by the metal, for example, a known (tetra) compound, and more preferably '-such as acetic acid_1), two gas double (triphenyl) Known palladium complexes of phosphine)-), tetrakis(triphenylphosphine), or tris(diphenylmethylpyridinium) dipalladium (0). A phosphine ligand (preferably, for example, triphenylphenylphosphine, tricyclohexylphosphine, or tri-t-butylphosphine) can be appropriately added to allow the reaction to proceed efficiently. The quaternary salt (preferably, for example, tetrabutylated gasification or tetrabutylammonium chloride) may be appropriately added to allow the reaction to proceed efficiently. In this reaction, a better result can be achieved in the presence of the test. The test used at this time is changed depending on the starting material, the solvent used, and the like, and is not subject to special functions. Preferred examples of the test include sodium hydroxide, barium hydroxide, mi-acid, sodium chlorate, potassium carbonate, carbonic acid, and potassium phosphate. Under the preferred reaction conditions, the reaction is carried out at 24 hours, 50 201031662 Wang, and the progress of this reaction can be monitored by known chromatographic analysis.

Sonogashim反應依起始材料、溶劑及過渡金屬催化刻而改變J_不又特別限制，只要條件係相似於此反應者。热餐此項技藝者所知之—方法可用於此反應。較佳地，通式（a-Ι)之化合物係’例如於相關於通式卜1)之化合物係0.01至0.2當篁之—過渡金屬催化劑存在中，與相關於通式（a-Ι)之化合物係當量之通式（b_2)之化合物（其中，XB較佳係-C2-6块基基團）偶合。使用溶劑之較佳例子包^乙腈、四氫吱喃、m-hu-二甲氧基乙烧、苯、甲苯、一甲苯、1_曱基_2_„叫烧酮、N，N二甲基甲酿胺，及二曱基亞砜。此溶劑之更佳例子包含四氫呋喃、m-二噁烷、i-甲基-2-鱗烧_，及咖二甲基甲酿胺。反應温度需係-可使偶合反應完全之溫度，且較佳係室溫至i5〇〇c。此反應較佳係於-惰性氣體氛时施，且更佳係於氮氣或氬氣氛圍。於較佳反應條件下，反應係於丨至24小時完全，且反應之進行可藉由-已知之色譜分析術監測。過渡金屬催化劑係，例如，一已知之鈀錯合物，且更佳地係一諸如乙酸把(II)、二氯雙(三苯基膦)鈀(„)、四（三苯基膦)鈀(〇)，或三（二苯甲又基丙酮）二鈀之已知鈀錯合物。一膦配位體（較佳係，例如，三苯基膦、三_鄰_甲笨基膦，或三-第三丁基膦）可被適當地添加以使此反應有效率地進行。於此反應，可添加一金屬鹵化物或一季銨鹽，較佳係，例如，碘化銅⑴、氯化鋰、氟化四丁基銨，或氧化銀⑴。一較佳結果可於鹼存在中達成。此處使用之鹼且不被特別限制，只 51 201031662 要其係用於一與此反應相似之偶合反應。鹼之較佳例子包含鹼性溶劑，諸如，二乙基胺、三乙基胺、n,n•二異丙= 乙基胺、旅咬，及°比咬。於Stille偶合反應，通式(心丨）之一鹵素化合物或三氟甲烷磺酸鹽基團化合物較佳係於，例如，相關於通式之化合物係0.01至0.2當量之一過渡金屬催化劑存在中，與相關於通式（a-Ι)之化合物係1〇至5 〇當量之通式沙幻之化合物（其中，XB較佳係一三烷基錫烷基基團）偶合。較佳地係於此反應適當地使用0.1至5 〇當量之鹵化銅⑴或/及氣化鋰以使此反應有效率地進行。此反應使用之溶劑之較佳例子包含曱笨、二甲苯、N，N-二甲基甲醯胺、N，N_二甲基乙醯胺、1-甲基-2-吡咯烷_，及二甲基亞砜。反應溫度需為一可使偶合反應完全之溫度，且較佳係室溫至15〇<3C。較佳之過渡金屬催化劑係一鈀錯合物，較佳係，例如，一諸如乙酸#巴(11)、二氣雙（三苯基膦）纪(H)、四（三苯基膦)纪(〇)，或三（二苯曱撐基丙酮）二鈀之已知之鈀錯合物，，且更佳係，例如’乙酸把(II)、四（三苯基膦)把(〇)，或三（二苯曱撐基丙酮）二鈀（0)。一膦配位體（較佳係，例如，三苯基膦、三_ 鄰-曱苯基膦、1,3-雙(二苯基膦基）丙烷，或三_第三丁基膦）可被適當地添加以使此反應有效率地進行。此反應較佳係於一惰性氣體氛圍中實施，且更佳係於一氮氣或氬氣氛圍。於較佳反應條件下，此反應係於丨至24小時完全，且此反應之進行可藉由一已知之色譜分析術監測。步驟1-2係一製備通式化學式（a_2)之一化合物及通式 52 201031662 (b_2)之-化合物之方法之例子’其中’取代基XjXb係彼此取代。此步驟係依起始材料改變，且不受特別限制，只要條件係相似於此反應者。與步驟i-丨之相同方法可較佳地被使用，諸如，Mizoroki-Heck反應（見’例如，R.F. Heck，" 有機反應"，1982，vol. 27，第345頁）、Suzuki-Miyaura反應 (見，例如 ’ A. Suzuki, "Chem. Rev."，1995, vol. 95，第2457 頁）、Sonogashira反應（見，例如，κ. Sonogashira，”簡易有機合成"，1991，vol. 3，第521頁）或Stille偶合反應（見，例如，J.K. Stille，"Angew. Chem. Int. Ed. Engl.”，1986, vol. 25, 第508頁）。化學式(a-1)之化合物、化學式（a-2)之化合物、化學式 (b-Ι)之化合物’及化學式(b_2)之化合物係已知或可賭得之化合物，或係可自此等化合物藉由一傳統方法製備之化合物。 [通式(a-1)之化合物之製備]The Sonogashim reaction varies depending on the starting materials, solvent, and transition metal catalysis. J_ is not particularly limited as long as the conditions are similar to those of the reactor. Hot meals are known to those skilled in the art - methods can be used for this reaction. Preferably, the compound of the formula (a-Ι) is, for example, related to the compound of the formula 1 to 0.01 to 0.2 in the presence of a transition metal catalyst, and is related to the formula (a-Ι). The compound is an equivalent compound of the formula (b_2) wherein XB is preferably a -C2-6 block group. Preferred examples of the use of the solvent include acetonitrile, tetrahydrofuran, m-hu-dimethoxyethane, benzene, toluene, monomethylbenzene, 1-hydrazino-2_, ketone, N, N dimethyl Mercaptoamine, and dimercaptosulfoxide. More preferred examples of the solvent include tetrahydrofuran, m-dioxane, i-methyl-2-salt, and glycopyylamine. The reaction temperature is required to be - the temperature at which the coupling reaction is complete, and preferably from room temperature to i5 〇〇 c. The reaction is preferably carried out in an inert gas atmosphere, and more preferably in a nitrogen or argon atmosphere. The reaction is carried out until 24 to 24 hours complete, and the progress of the reaction can be monitored by known-known chromatographic techniques. The transition metal catalyst system, for example, a known palladium complex, and more preferably one such as acetic acid (II) A known palladium complex of dichlorobis(triphenylphosphine)palladium („), tetrakis(triphenylphosphine)palladium (ruthenium), or tris(diphenylmercaptoacetone)dipalladium. A phosphine ligand (preferably, for example, triphenylphosphine, tri-o-phenylphosphonium, or tri-tert-butylphosphine) may be appropriately added to allow the reaction to proceed efficiently. In this reaction, a metal halide or a quaternary ammonium salt may be added, preferably, for example, copper (I) iodide, lithium chloride, tetrabutylammonium fluoride, or silver oxide (1). A preferred result can be achieved in the presence of a base. The base used herein is not particularly limited, and only 51 201031662 is used for a coupling reaction similar to this reaction. Preferred examples of the base include an alkaline solvent such as diethylamine, triethylamine, n, n•diisopropyl=ethylamine, brittle bite, and a specific bite. In the Stille coupling reaction, a halogen compound or a trifluoromethanesulfonate group compound of the formula (cardiac) is preferably, for example, in the presence of a compound of the formula 0.01 to 0.2 equivalent of a transition metal catalyst. And a compound of the formula (a-Ι), which is a compound of the formula (a-Ι), is coupled with a compound of the formula of the formula (wherein XB is preferably a trialkylstannyl group). Preferably, 0.1 to 5 〇 equivalent of copper halide (1) or/and lithium hydride is suitably used in the reaction to effect the reaction efficiently. Preferred examples of the solvent used in the reaction include hydrazine, xylene, N,N-dimethylformamide, N,N-dimethylacetamide, 1-methyl-2-pyrrolidine, and Dimethyl sulfoxide. The reaction temperature is required to be a temperature at which the coupling reaction is completed, and is preferably room temperature to 15 Torr < 3C. A preferred transition metal catalyst is a palladium complex, preferably, for example, one such as acetic acid #巴(11), di- gas bis(triphenylphosphine) (H), tetrakis(triphenylphosphine) ( 〇), or a known palladium complex of tris(diphenylfluorenylacetone)dipalladium, and more preferably, for example, 'acetic acid, (II), tetrakis(triphenylphosphine), (〇), or Tris(diphenylfluorenylacetone)dipalladium (0). a phosphine ligand (preferably, for example, triphenylphosphine, tri-o-nonylphenylphosphine, 1,3-bis(diphenylphosphino)propane, or tri-t-butylphosphine) It is appropriately added to allow this reaction to proceed efficiently. The reaction is preferably carried out in an inert gas atmosphere, and more preferably in a nitrogen or argon atmosphere. Under the preferred reaction conditions, the reaction is complete until 丨 to 24 hours, and the progress of this reaction can be monitored by a known chromatographic analysis. Step 1-2 is an example of a method for preparing a compound of the formula (a_2) and a compound of the formula 52 201031662 (b_2) wherein the substituent XjXb is substituted with each other. This step is changed depending on the starting material, and is not particularly limited as long as the conditions are similar to those of the reaction. The same method as step i-丨 can be preferably used, such as the Mizoroki-Heck reaction (see 'e.g. RF Heck, " Organic Reactions", 1982, vol. 27, page 345), Suzuki-Miyaura Reactions (see, for example, 'A. Suzuki, " Chem. Rev.", 1995, vol. 95, p. 2457), Sonogashira reaction (see, for example, κ. Sonogashira, "Simple Organic Synthesis", 1991, Vol. 3, p. 521) or Stille coupling reaction (see, for example, JK Stille, " Angew. Chem. Int. Ed. Engl., 1986, vol. 25, p. 508). A compound of the formula (a-1), a compound of the formula (a-2), a compound of the formula (b-Ι), and a compound of the formula (b_2) are known or gambling compounds, or may be derived therefrom. A compound prepared by a conventional method. [Preparation of the compound of the formula (a-1)]

[化學式39][Chemical Formula 39]

(c-1)(c-1)

〇入㈣^ ψ NVInto (four) ^ ψ NV

Ra (a-6) > (A 陟赛2- (a-Γ (^2) 於化學式，Ri、R2、m、係如上所定義’ RA及Rb 係如上對於Ri所定義；L〗代表一齒素原子（諸如，一氯原子、〆溴原子，或一块原彳）成一續酸鹽基團（諸如，一甲院續酸發基SI、-對·甲料酸躁基團，或—三氟甲烧績酸鹽 53 201031662 基團广jx2代表-i素原子(諸如，—氣原子—㈣子，或-碟原子）…姐鹽基團（諸如，—甲糾酸鹽基團、一對-曱苯磺酸鹽基團，或一基團。氟甲烷磺酸鹽基團），或一硼酸 _通式㈣之化合物可自-胺化合物㈣作為-起始材料丄由步驟2 1之甲酿基化反應，步驟2_2之偶合反應及於步驟2-3形成-咪唾環而製備，或可自通式㈣之—化合物作為一起始㈣藉由步驟2_4之偶合反應製備。Ra (a-6) > (A 陟赛2- (a-Γ (^2) in the chemical formula, Ri, R2, m, as defined above] 'RA and Rb are as defined above for Ri; L〗 stands for A dentate atom (such as a chlorine atom, a ruthenium bromide atom, or a ruthenium ruthenium) is formed into a sulphonate group (such as a sulfonate group SI, a pair of bismuth phthalate groups, or - three) Fluoromethylated acid salt 53 201031662 The group broadly jx2 represents -i atom (such as - gas atom - (four), or - dish atom) ... sister salt group (such as - methionate group, a pair - an anthracene sulfonate group, or a group. A fluoromethanesulfonate group), or a boronic acid compound of the formula (4) can be used as a starting material from the -amine compound (IV). The styling reaction, the coupling reaction of the step 2-2 and the formation of the imipenyl ring in the step 2-3, or the compound of the formula (4) can be prepared as a starting point (4) by the coupling reaction of the step 2-4.

步驟2 1係依起始材料而改變，且不被特別限制，只要條件係相似於此聽者。熟習此項技藝麵知之-方法可用於此反應。—於許多文件等報導之方法(例如，T_Greene 等人’有機合成之保護基"，iQhn夠& w，心，Step 2 1 varies depending on the starting material, and is not particularly limited as long as the conditions are similar to those of the listener. It is well known in the art that the method can be used for this reaction. - methods reported in many documents (for example, T_Greene et al. 'Protection of organic synthesis', iQhn enough & w, heart,

York，1981)可被使用。York, 1981) can be used.

，驟2-2係依起始材料而改變，且不被特別限制，只條件係相似於此反應者。熟習此項技藝者所知之-方法用於=反應。此方法之較佳例子包含—種於相關於通私之化4係U)至㈣當量之—驗存在中於—溶劑中使狀-化合物及㈣於通式㈣之化合 =之^㈣之—化合_拌之方法。使用之驗依起且不被特舰制。驗之較佳例子包含驗金> 碳酸納s κ仙錢㈣）、驗金心(諸如，碳酸卸 = 鎚)及金屬炫氧化物(諸如，甲氧化納及第」二=吏用之溶劑依起始材料而改變，且不被咖其不會抑似反應且使起始㈣餘解至某一卷 54 201031662 度。溶劑之較佳例子包含鱗溶劑，諸如，四㈣、M_ 一。惡烷’及二乙基喊；幽化溶劑，諸如，二氯甲燒、a 二氣乙烧’及氣仿；極性溶劑，諸如，n，n_二甲基甲醯胺及N-曱基0比洛院酮；非極神杰丨極险溶劑，諸如，甲苯及笨；及其The step 2-2 is changed depending on the starting material, and is not particularly limited, and only the conditions are similar to those of the reaction. As is known to those skilled in the art - the method is used for = reaction. Preferred examples of the method include: - in the presence of the 4th line U) to (4) equivalents in the presence of the drug - in the solvent - the compound - and (d) in the compound of the formula (4) = (4) - Compounding_mixing method. The test of use is based on and is not made by the special ship. A preferred example of the test includes a gold test> sodium carbonate s KS (4), a gold core (such as carbonic acid unloading hammer), and a metal oxide (such as sodium methoxide and the second) solvent. It varies according to the starting material, and is not inhibited by the reaction, and the initial (four) residue is solved to a certain volume 54 201031662 degrees. Preferred examples of the solvent include a scaly solvent, such as four (four), M_ one. Alkane' and diethyl sing; singly-solving solvents such as, for example, methylene chloride, a gas, and gas; polar solvents such as n, n-dimethylformamide and N-mercapto Bilol's ketone; non-extremely dangerous solvents such as toluene and stupid;

等之混合物。反應溫度需係-使反應完全且不會促進-非所欲副產物形成之溫度，且較佳係，例如，㈣至細。c。於較佳反祕件τ，歧财_至24㈣完全，且反應之進行可藉1已知之色譜分析術監測。—賴欲之副產物可藉由此項技藝者所知之技術(諸如，傳統之色譜分析術、萃取，或/及結晶化)移除。步驟2-3驗起始轉岐變，且顿制限制，只要條件係相似於此反應者。_此項技藝者已知之—方式可用於此反應。-於許多文件等報導之方法(諸如，於雜環化合物料及衍生物之化學，第I部份，第33頁，Int⑽.Publish 1953中所述)可被使用。此方法之較佳例子包含-種藉由自通式㈣之-化合物及作為氮來源之氨、織、甲酿胺等形成-料環製備通式⑹)之化合物之方法。使用之溶劑不被特別限制’只要其不會抑制歧應域使起始材料溶解至某-程度。此㈣之較佳例子包含非極性溶劑，諸如，甲苯及苯；醇溶劑，諸如，甲醇及乙醇；有機酸，諸如，乙酸或三氟乙酸’俩，諸如，對_甲笨顧及三氟甲燒續酸；水；及其等之混合物。甲酿胺可選擇性地作為一氣原子源及作為n反應溫度需係_能使反應完全且不會促進一非所欲副產物形成之溫度，且較佳係，例如，室溫 55 201031662 至250°C。產量可於反應係使用一緊密容器實施時改良。於較佳反應條件下，反應係於1至24小時完全，且反應之進行可藉由一已知之色谱分析術監測。一非所欲之副產物可藉由熟習此項技藝者所知之技術(諸如，傳統之色譜分析術、萃取，或/及結晶化)移除。步驟2-4之偶合反應係依起始材料而改變，且不被特別限制，只要條件相似於此反應者。熟習此項技藝者所知之一方法可用於此反應。一於許多文件等報導之方法(諸如， D.D. Davey等人’ "J. Med. Chem."，1991, vol. 34, 2671-2677 頁所述）可被使用。此方法之例子包含一種於相關於通式 (a-4)之化合物係1.〇至5.〇當量之鹼存在或缺乏中，於—溶劑中授拌通式（a-4)之一化合物及相關於通式(a_4)之一化合物係1.0至5.0當量之一咪唾化合物（c_2)之方法。使用之驗之較佳例子包含氫化納、氫氧化納、氫氧化卸、碳酸卸、碳酸鈉、碳酸铯、碳酸鋇、吼啶、二曱吡啶及三乙基胺。使用之溶劑依起始材料而改變，且不被特別限制，只要其不抑制此反應且使起始材料溶解至某一程度。溶劑之較佳例子包含乙腈、四氫呋喃、二甲基亞硬、N，N_:甲基甲酿胺，及N-曱基吡咯烷。鹼可選擇性地作為一溶劑。反應溫度需係一能使反應完全且不會促進一非所欲副產物形成之溫度，且較佳係，例如，室溫至150。〇於較佳反應條件下，反應係於1至24小時完全，且反應之進行可藉由一已知之色谱分析術監測。—非所欲之副產物可藉由熟習此項技藝者所知之技術(諸如，傳統之色譜分析術、萃取，或/及結晶化) 56 201031662 移除。步驟2-4之偶合反應之例子包含一於銅催化劑存在中，於一溶劑中攪拌通式(a_4)之化合物（其中，^較佳係一硼酸基團等）之方法（諸如，J.P_ Collman等人，"Org. Letters.，， 2000’ vol· 2, 1233-1236頁所述）。此方法之較佳例子包含— 種於相關於通式（a_4)之化合物係0 〇1至1 〇當量之一鋼試劑 (諸如，銅、溴化銅，或蛾化銅)存在中，於一溶劑中授拌通式（a_4)之一化合物及相關於通式（a-4)之一化合物係〇· i至 10.0當量之一咪唑化合物（c_2)之方法。使用之銅試劑係依起始材料而改變，且不被特別限制。銅試劑之較佳例子包含鹵化銅（I)、乙酸鋼（11)、硝酸銅（π)，及二羥基-雙 [(Ν’Ν’Ν ,Ν-四甲基乙二胺)銅(η)]氣化物。使用之溶劑依起始材料、試料而改變，且不被特舰制，只要其不抑制此反應且使起始材料溶解至某-程度。；容劑之較佳例子包含謎溶劑’諸如，四氫°夫°南、1，4_二就，及二乙基鍵；_ 化溶劑，諸如，二氣甲烷、12_二氯乙烷，及氣仿；極性溶劑，諸如，乙酸乙酿、Ν，Ν·二曱基甲醯胺祕甲基鱗燒 W ;非極性溶劑，諸如，甲苯、苯及二氣苯；及其等之混合物一驗可依起始材料、試鮮㈣變。驗之較佳肝包含有機鹼，諸如，三乙基胺、吼咬，及四甲基乙二胺；驗金屬鹽’諸如，碳酸鉀、碳酸鈉、乙酸卸、乙酸納，及碳酸铯；及金狀氧化物，諸如，甲氧化納及第三丁氧化钟。，反應溫度需係-使反應完全且不會促進—非所欲副產物形成之溫度’且較佳係，例如，室溫至靡。c 57 201031662 反應時間及改良產量之良好結果可於反應係於氧氣氛圍或空氣流實施時達成。於較佳反應條件下，此反應係於1至24 小時完全’且反應之進行可藉由一已知之色譜分析術監測。一非所欲之副產物可藉由一熟習此項技藝者所知之技術(諸如，傳統之色譜分析術、萃取，或/及結晶化)移除。a mixture of such. The reaction temperature is required to be such that the reaction is complete and does not promote the temperature at which the undesired by-product is formed, and is preferably, for example, (d) to fine. c. For better anti-trick τ, 歧 _ to 24 (4) is complete, and the reaction can be monitored by a known chromatographic analysis. - Byproducts of Lai can be removed by techniques known to those skilled in the art, such as conventional chromatographic analysis, extraction, or/and crystallization. Steps 2-3 test the initial transition, and the limit is imposed as long as the conditions are similar to those of the responder. The method known to the skilled artisan can be used for this reaction. - Methods reported in many documents, such as those described in Chemicals for Heterocyclic Compounds and Derivatives, Part I, page 33, Int (10). Publish 1953 can be used. A preferred example of the method comprises a method for producing a compound of the formula (6) by forming a ring from a compound of the formula (IV) and a nitrogen, a woven, a melamine or the like as a nitrogen source. The solvent to be used is not particularly limited as long as it does not inhibit the domain to dissolve the starting material to a certain extent. Preferred examples of the (4) include non-polar solvents such as toluene and benzene; alcohol solvents such as methanol and ethanol; organic acids such as acetic acid or trifluoroacetic acid, such as, for example, Continued acid; water; and mixtures thereof. The melamine can be selectively used as a source of a gas atom and as a temperature at which the reaction temperature is required to be a temperature which can complete the reaction without promoting the formation of an undesired by-product, and is preferably, for example, room temperature 55 201031662 to 250 °C. The yield can be improved when the reaction system is implemented using a compact container. Under the preferred reaction conditions, the reaction is complete from 1 to 24 hours and the progress of the reaction can be monitored by a known chromatographic analysis. An undesired by-product can be removed by techniques known to those skilled in the art, such as conventional chromatographic analysis, extraction, and/or crystallization. The coupling reaction of the step 2-4 varies depending on the starting material, and is not particularly limited as long as the conditions are similar to those of the reactant. A method known to those skilled in the art can be used for this reaction. A method of reporting such as many documents (such as D.D. Davey et al. " J. Med. Chem.", 1991, vol. 34, pages 2671-2677) can be used. An example of the method comprises: mixing a compound of the formula (a-4) in a solvent in the presence or absence of a base of the compound of the formula (a-4): 〇 to 5. And a method relating to one of the compounds of the formula (a-4), 1.0 to 5.0 equivalents of one of the imazeth compounds (c_2). Preferred examples of use include sodium hydride, sodium hydroxide, hydrogenation, carbonation, sodium carbonate, cesium carbonate, cesium carbonate, acridine, dipyridylpyridine and triethylamine. The solvent to be used varies depending on the starting material, and is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. Preferred examples of the solvent include acetonitrile, tetrahydrofuran, dimethyl-area, N,N-: methylcartoamine, and N-decylpyrrolidine. The base can be optionally used as a solvent. The reaction temperature is such a temperature that the reaction is complete and does not promote the formation of an undesired by-product, and is preferably, for example, room temperature to 150. Under the preferred reaction conditions, the reaction is complete from 1 to 24 hours and the progress of the reaction can be monitored by a known chromatographic analysis. - Undesirable by-products can be removed by techniques known to those skilled in the art, such as conventional chromatographic analysis, extraction, or/and crystallization, 56 201031662. Examples of the coupling reaction of the step 2-4 include a method of stirring a compound of the formula (a-4) (wherein, preferably a boronic acid group, etc.) in a solvent in the presence of a copper catalyst (such as J.P_). Collman et al., "Org. Letters., 2000' vol. 2, pages 1233-1236). Preferred examples of the method include the presence of a compound of the formula (a-4) in the presence of a steel reagent of 0 〇1 to 1 〇 equivalent (such as copper, copper bromide, or copper molybdenum). A method of mixing one of the compounds of the formula (a-4) with a compound of the formula (a-4), 〇·i to 10.0 equivalents of one of the imidazole compounds (c_2), is added to the solvent. The copper reagent to be used varies depending on the starting material, and is not particularly limited. Preferred examples of the copper reagent include copper (I) halide, steel (11) acetate, copper (π) nitrate, and dihydroxy-bis[(Ν'Ν'Ν, Ν-tetramethylethylenediamine) copper (η) )] vapor. The solvent to be used is changed depending on the starting material and the sample, and is not made by a special ship as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. Preferred examples of the solvent include a mystery solvent such as tetrahydrofuran, 1,4-di, and a diethyl bond; a solvent such as di-methane, 12-dichloroethane, And gas-like; polar solvents, such as, acetic acid, sputum, bismuthyl carbamide, methyl sulphate W; non-polar solvents, such as toluene, benzene and di-benzene; and mixtures thereof The test can be changed according to the starting material and the test (four). Preferably, the liver comprises an organic base such as triethylamine, a bite, and tetramethylethylenediamine; a metal salt such as potassium carbonate, sodium carbonate, acetic acid, sodium acetate, and barium carbonate; Gold oxides such as sodium methoxide and third oxidized clocks. The reaction temperature is required to be such that the reaction is complete and does not promote the temperature at which the undesirable by-products are formed and is preferably, for example, room temperature to hydrazine. c 57 201031662 Good results in reaction time and improved yield can be achieved when the reaction is carried out in an oxygen atmosphere or air stream. Under the preferred reaction conditions, the reaction is complete for 1 to 24 hours and the progress of the reaction can be monitored by a known chromatographic assay. An undesired by-product can be removed by techniques known to those skilled in the art, such as conventional chromatographic analysis, extraction, and/or crystallization.

化學式(a-3)之化合物、化學式（a_4)之化合物、化學式 (c-1)之化合物及化學式（c-2)之化合物係已知或可購得之化合物或係可自此等化合物藉由一傳統方法製備之化合物。 [通式(b-Ι)之化合物之製備] [化學式40]A compound of the formula (a-3), a compound of the formula (a-4), a compound of the formula (c-1), and a compound of the formula (c-2), which are known or commercially available, can be borrowed from such compounds. A compound prepared by a conventional method. [Preparation of a compound of the formula (b-Ι)] [Chemical Formula 40]

(M) ϋ)去依蠖反應(M) ϋ) to rely on the reaction

(b-1) I㈣3- 3](b-1) I (four) 3- 3]

於化學式’ X2、XA、環A及環B係如上所定義；l3及U 係如上對於1^所定義；Xc代表一C2-4院揮基基團，或一C2-3 烷撐基基團，其中，一甲撐基基團係以一氧原子或一氮原子替代(其中，氮原子可為一取代基，諸如，一C1_6烷基基團或一苯甲基基團）；P1代表一叛基保護基團，諸如，一甲基基團、一乙基基團、一苯甲基基團、一烯丙基基團、一三苯基甲基基團、一第三丁基基團，或一第三丁基二甲基石夕院基基團，或一鼠原子，且P2代表一氮保護基團，諸如，一第三丁氧基羰基基團或一苯甲氧基羰基基團。 58 201031662 通式(b-l)之—化合物可自作為一起始材料之通式(di) 之一化合物經由步驟3-1之烷基化反應、醯肼化反應及步驟 3-2之去保護反應、步驟3-3之環A之形成，及步驟3-4之The chemical formulas 'X2, XA, Ring A and Ring B are as defined above; l3 and U are as defined above for 1^; Xc represents a C2-4 alkoxy group, or a C2-3 alkylene group Wherein the monomethylene group is replaced by an oxygen atom or a nitrogen atom (wherein the nitrogen atom may be a substituent such as a C1_6 alkyl group or a monobenzyl group); P1 represents a a thiol protecting group such as a monomethyl group, a monoethyl group, a monobenzyl group, an allyl group, a triphenylmethyl group, a tert-butyl group Or a tert-butyldimethylstone group, or a murine atom, and P2 represents a nitrogen protecting group, such as a third butoxycarbonyl group or a benzyloxycarbonyl group. group. 58 201031662 The compound of the formula (bl) - the compound of the formula (di) as a starting material can be subjected to the alkylation reaction of the step 3-1, the deuteration reaction and the deprotection reaction of the step 3-2, Formation of ring A of step 3-3, and steps 3-4

Sandmeyer反應而製備。步驟3-1係依起始材料而改變，且不被特別限制，只要條件相似於此反應者。熟習此項技藝者所知之〆方法可用於此反應。此方法之較佳例子包含—種於相關於通式⑹) 之化〇物係1.0至1〇〇當量之鹼存在中，於一溶劑中授掉通式（d-ι)之一化合物及相關於通式((Μ)之一化合物係1〇至 1〇·〇當量之通式㈣)之一化合物之方法。使用之驗係依起始材料而改變’且不被制㈣。驗之較制子包含驗金屬氫化物(諸如’氫化納及氫化鐘）、驗金屬鹽（諸如，碳酸卸、碳酸納，及碳酸鎚）、金屬院氧化物(諸如，甲氧化納及第三丁氧⑽），及麵金屬鹽(諸如，Τ基Μ、二異丙基酿Prepared by Sandmeyer reaction. Step 3-1 is changed depending on the starting material, and is not particularly limited as long as the conditions are similar to those of the reactants. A method known to those skilled in the art can be used for this reaction. A preferred example of the method comprises the step of administering a compound of the formula (d-ι) in a solvent in the presence of a base of 1.0 to 1 equivalent equivalent of the hydrazine system of the formula (6)). A method of a compound of the formula (() in which one of the compounds of the formula ((Μ) is 1〇 to 1〇·〇 equivalent). The test used is changed according to the starting material' and is not made (4). The tester contains metal hydrides (such as 'hydrogenated sodium and hydrogenation clocks'), metal salts (such as carbonic acid unloading, sodium carbonate, and carbonated hammers), metal oxides (such as sodium methoxide and third). Butoxy (10)), and surface metal salts (such as fluorenyl, diisopropyl)

胺裡及雙-甲基；5規基醯胺鐘）。使用之溶雜起始材料而改變’且不被特職制，只要其不會抑制此反應且使起始材料被溶解至某―程度。_之較佳例子包含娜劑，諸如，四氫吱H4-二姚，及二乙細^化溶劑，諸如，二氣甲烷、U-二氣乙烷，及氣仿；極性溶劑，諸如， Ν，Ν-二甲基甲醯胺及队甲基料細；非極性溶劑，諸如，甲本及本，及其等之混合物。反應溫度需係__使反廣完全且不會促進—非所欲副產物形成之溫度，且較佳係，:如， -HKTC至贈C。於較佳反應條件下，此反應係於_小時完全，且反應之進行可藉由-已知之色譜分析術監測。 59 201031662 一非所欲之副產物可藉由一熟習此項技藝者所知之技術 (諸如’傳統之色譜分析術、萃取，或/及結晶化)移除。步驟3-2之第一階段之醯肼化反應係依起始材料而改變’且不被特別限制，只要條作相似於此反應者。熟習此項技藝者所知之一醯胺化反應可用於此反應。許多文件等報導之方法（绪如’曰本化學協會（編輯），Jikken KagakuAmine and bis-methyl; 5-meryl guanamine clock). The doping starting material used is changed 'and is not subject to special functions as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. Preferred examples of _ include a nucleating agent such as tetrahydrofuran H4-di Yao, and a diethylhydrazine solvent such as di-halogen methane, U-diethane, and gas-like; polar solvent such as hydrazine , Ν-dimethylformamide and a group of methyl materials; non-polar solvents, such as, a, and the present, and mixtures thereof. The reaction temperature is required to be such that the anti-wide is completely and does not promote the temperature at which the undesired by-product is formed, and is preferably, for example, -HKTC to C. Under the preferred reaction conditions, the reaction is complete in _hrs and the progress of the reaction can be monitored by known-known chromatographic techniques. 59 201031662 An undesired by-product can be removed by techniques known to those skilled in the art, such as 'conventional chromatography, extraction, or/and crystallization. The deuteration reaction in the first stage of the step 3-2 is changed depending on the starting material' and is not particularly limited as long as the strip is similar to the one in this reaction. One of the techniques known to those skilled in the art can be used in this reaction. Many documents and other methods of reporting (such as 'Sakamoto Chemical Association (editor), Jikken Kagaku

Koza(Courses in Experimental Chemistry),第 4版（vol. 22)Koza (Courses in Experimental Chemistry), 4th edition (vol. 22)

Yuki Gosei (Organic Synthesis) [IV], Maruzen Co., Ltd., November 1992, 137-144頁所述)可被使用。第二階段之去保護反應係依起始材料而改變’且不被特別限制，只要條件相似於此反應者。熟習此項技藝者所知之一去保護反應可用於此反應。許多文件等報導之方法（見，例如，T. Greene 等人，"有機合成之保護基"，John Wiley & Sons，Inc.，New York, 1981)可被使用。Yuki Gosei (Organic Synthesis) [IV], Maruzen Co., Ltd., November 1992, pages 137-144) can be used. The second stage of the protection reaction varies depending on the starting material' and is not particularly limited as long as the conditions are similar to those of the reactor. One of the techniques known to those skilled in the art to protect the reaction can be used in this reaction. Many methods of reporting such as documents (see, for example, T. Greene et al., "Protective Groups for Organic Synthesis", John Wiley & Sons, Inc., New York, 1981) can be used.

步驟3-3之環A形成反應係依起始材料而改變，且不被特別限制’只要條件相似於此反應者。熟習此項技藝者所知之方法可用於此反應。此方法之較佳例子包含一種於鹼性或酸性糾下於-溶劑中使通式(d_3)之一化合物及相關於通式（d-3)之化合物係^至忉…當量之胺基胍、異硫尿素、氰醯胺等加熱之方法。使狀驗或酸係依起始材^而改變，且不被特別限制。鹼或酸之例子包含諸如鹼金屬氫化物（諸如，氫化鈉及氫化鋰）、鹼金屬鹽（諸如，碳酸鉀轧碳酸鈉及碳酸鉋）、金屬烷氧化物(諸如，甲氧化鈉及第三氧化鉀)及有機驗(諸如’三乙基胺、吡啶及^-二氮雜二I 201031662 ;及諸刚酸、魏、對曱苯續酸The ring A formation reaction of the step 3-3 varies depending on the starting material, and is not particularly limited as long as the conditions are similar to those of the reaction. A method known to those skilled in the art can be used for this reaction. A preferred example of the method comprises a compound in which a compound of the formula (d-3) and a compound related to the formula (d-3) are subjected to basic or acidic correction in a solvent to an equivalent amount of an amine group. , isosulfuric urea, cyanamide and other heating methods. The test or acid is changed depending on the starting material, and is not particularly limited. Examples of the base or acid include, for example, alkali metal hydrides (such as sodium hydride and lithium hydride), alkali metal salts (such as potassium carbonate rolled sodium carbonate and carbonic acid planing), metal alkoxides (such as sodium methoxide and third). Potassium oxide) and organic tests (such as 'triethylamine, pyridine and ^-diaza di-I 201031662; and ruthenium, Wei, p-benzoic acid

被特別限制，㈣係依起崎㈣改變，且不 ?宜-岛*、要八不會抑制此反應且使起始材料被溶解 =二度。溶劑之較佳例子包含醇溶劑，諸如，甲醇、一 —丁醇；喊溶劑，諸如，四氫吱喃、1,4_二魏，及一乙基醚’自化溶劑，諸如’二氯甲烷、1，2-二氣乙烷，及氣仿；極性溶劑，諸如，乙腈、Ν，Ν.二甲基f酸胺及Ν_ 甲基姆非極性溶劑，諸如，二甲苯、甲苯及笨；及其等之混合物。反應溫度需係—使反應完全且不會促進一非所欲财物形紅溫度，且較錢，例如，丨㈣至 1〇〇°C。於較佳反應條件下，此反應係於1至48小時完全，且反應之進行可藉由一已知之色譜分析術監測。一非所欲之田彳產物可藉由一熟習此項技藝者所知之技術(諸如，傳統之色譜分析術、萃取，或/及結晶化)移除。步驟3-4之Sandmeyer反應係依起始材料而改變，且不被特別限制，只要條件相似於此反應者。熟習此項技藝者之一方法可用於此反應。許多文件等報導之方法(諸如，曰本化學協會（編輯），Jikken Kagaku Koza (Courses in Experimental Chemistry),第 4 版（vol. 19) Yuki Gosei (Organic Synthesis) [I], Maruzen Co., Ltd., November 1992, 450-453頁所述)可被使用。 [通式(b-2)之化合物之製備] 下列化學式顯示通式(b_2)之化合物之製備之一例子。 [化學式41] 61 201031662It is particularly limited. (4) It is changed according to Kasaki (4), and it is not suitable for the island, and it will not inhibit the reaction and dissolve the starting material = second degree. Preferable examples of the solvent include an alcohol solvent such as methanol, monobutanol; a solvent such as tetrahydrofuran, 1,4-diwei, and monoethyl ether 'self-solvent such as 'dichloromethane , 1,2-di-ethane, and gas-like; polar solvents such as acetonitrile, hydrazine, hydrazine, dimethyl-f-acid amine and hydrazine-methyl ke non-polar solvent, such as xylene, toluene and stupid; a mixture of such. The reaction temperature is required to be such that the reaction is complete and does not promote the temperature of an undesired property, and is relatively expensive, for example, 丨(iv) to 1 °C. Under the preferred reaction conditions, the reaction is complete from 1 to 48 hours and the progress of the reaction can be monitored by a known chromatographic analysis. An undesired field product can be removed by techniques known to those skilled in the art, such as conventional chromatographic analysis, extraction, and/or crystallization. The Sandmeyer reaction of the step 3-4 varies depending on the starting material, and is not particularly limited as long as the conditions are similar to those of the reactant. One of the methods familiar to those skilled in the art can be used in this reaction. Many documents and other methods of reporting (such as the 曰本化学协会 (editor), Jikken Kagaku Koza (Courses in Experimental Chemistry), 4th edition (vol. 19) Yuki Gosei (Organic Synthesis) [I], Maruzen Co., Ltd , November 1992, pages 450-453) can be used. [Preparation of Compound of the Formula (b-2)] The following chemical formula shows an example of the preparation of the compound of the formula (b_2). [Chemical Formula 41] 61 201031662

於此化學式，X2、XA、Xc、Pi、L3、環A及環B係如上所定義，其中，χΒ代表一C2-6烯基基團，且L5代表一離去基團’諸如，一苯基硫基基團或一對-甲苯基硫烷基基團。通式（b-2)之化合物可如上所述般於步驟1-2自作為一起始材料之通式(b-Ι)之化合物製備。另外，此化合物可自通式（d-2)之一化合物作為一起始材料經由步驟4-1之醯肼化反應、步驟4-2之醯化反應、步驟4-3之環A之形成，及步驟4-4之熱分解反應而製備。步驟4-1可與用如前述步驟3-2之相同醯胺化反應。此方法之較佳例子係於一溶劑攪拌通式(d-2)之一化合物及相關於通式（d-Ι)之化合物係1.〇至10.〇當量之肼之方法。中性反應條件係較佳以使反應方便地進行。使用之溶劑係依起始材料而改變，且不被特別限制，只要其不會抑制此反應且使起始材料被溶解至某一程度。溶劑之較佳例子包含醚溶劑，諸如，四氫呋喃、丨，4_二噁烷，及二乙基醚；幽化溶劑，諸如，二氣甲烷、丨,2_二氯乙烷，及氯仿；極性溶劑，諸如， N，N-二甲基甲醯胺及N_甲基吡咯烷嗣；非極性溶劑，諸如，甲苯及苯；及其等之混合物。反應溫度需係—使反應完全且不會促進-麵欲副產物形成之溫度，且較佳係例如，室溫至H)〇°C。於較佳反應條件下，此反應係於丨至24小時 62 201031662 完全，且反應之進行可藉由一已知之色譜分析術監測。一非所欲之副產物可藉由一熟習此項技藝者所知之技術（諸如’傳統之色譜分析術、萃取，或/及結晶化)移除。步驟4-2可使用與前述步驟3-2般相同之醯胺化反應。許多文件等報導之方法（諸如，曰本化學協會（編輯），Jikken Kagaku Koza (Courses in Experimental Chemistry),第 4版 (vol. 22) Yuki Gosei (Organic Synthesis) [IV], Maruzen Co., Ltd·，November 1992, 137-144頁所述)可被使用。步驟4-3可使用如前述步驟2-3者相同之環化條件。更佳地，通式(b-4)之一化合物可，例如，藉由使通式（d-5)之一化合物及相關於通式（d-5)之一化合物係1.0至10當量之氧氯化磷加熱並攪拌，然後，於乙酸溶劑使形成之化合物及相關於通式（d-5)之一化合物係1.0至10當量之乙酸銨加熱而方便地製備。步驟4-4之熱分解反應係依據起始材料而改變，且不被特別限制’只要條件相似於此反應者。熟習此項技藝者所知之一方法可用於此反應。許多文件等報導之方法(諸如， W. Carrutthers，"某些有機合成之現代方法，第三版" (Cambridge University Press，1986, 120-121 頁）所述)可被使用。更佳地，通式(b-2)之化合物可藉由，例如，使通式(b_4) 之化合物接受熟習此項技藝者所知之一氧化反應及使此化合物加熱而方便地製備。化學式(d-Ι)之化合物、化學式(e-i)之化合物、化學式 (e-2)之化合物及化學式（f-l)之化合物係已知或可購得之化 63 201031662 合物或係可自此等化合物藉由一傳統方法製備之化合物。 [一般製備方法2] 用於依據本發明之通式[η之化合物之典型使用之一般製備方法2將於下說明。 [化學式42]In the formula, X2, XA, Xc, Pi, L3, ring A and ring B are as defined above, wherein χΒ represents a C2-6 alkenyl group and L5 represents a leaving group such as benzene. a thiol group or a pair of -tolylsulfanyl groups. The compound of the formula (b-2) can be produced from the compound of the formula (b-Ι) as a starting material in the above step 1-2. Further, the compound can be formed from a compound of the formula (d-2) as a starting material via the deuteration reaction of the step 4-1, the deuteration reaction of the step 4-2, and the formation of the ring A of the step 4-3. And the thermal decomposition reaction of the step 4-4 is prepared. Step 4-1 can be carried out in the same manner as the amidation reaction as in the above step 3-2. A preferred example of this method is a method in which a compound of the formula (d-2) and a compound of the formula (d-Ι) are stirred in a solvent to a ratio of from 0.1 to 10. Neutral reaction conditions are preferred to facilitate the reaction. The solvent to be used is changed depending on the starting material, and is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. Preferred examples of the solvent include ether solvents such as tetrahydrofuran, hydrazine, 4-dioxane, and diethyl ether; emulsified solvents such as di-methane, hydrazine, 2-dichloroethane, and chloroform; Solvents such as N,N-dimethylformamide and N-methylpyrrolidinium; non-polar solvents such as toluene and benzene; and mixtures thereof. The reaction temperature is required to be such that the reaction is complete and does not promote the temperature at which the by-product is formed, and is preferably, for example, room temperature to H) 〇 °C. Under the preferred reaction conditions, the reaction is complete until 24 hours 62 201031662 and the progress of the reaction can be monitored by a known chromatographic analysis. An undesired by-product can be removed by techniques known to those skilled in the art, such as 'conventional chromatography, extraction, or/and crystallization. Step 4-2 can be carried out using the same amidation reaction as in the previous step 3-2. Many documents and other methods of reporting (such as the 曰本化学协会 (editor), Jikken Kagaku Koza (Courses in Experimental Chemistry), 4th edition (vol. 22) Yuki Gosei (Organic Synthesis) [IV], Maruzen Co., Ltd ·, November 1992, pages 137-144) can be used. Step 4-3 can use the same cyclization conditions as those in the above steps 2-3. More preferably, a compound of the formula (b-4) can be, for example, 1.0 to 10 equivalents of a compound of the formula (d-5) and a compound of the formula (d-5) The phosphorus oxychloride is heated and stirred, and then conveniently prepared by heating the formed compound and the compound of the formula (d-5) in an acetic acid solvent in an amount of 1.0 to 10 equivalents of ammonium acetate. The thermal decomposition reaction of the step 4-4 is changed depending on the starting material, and is not particularly limited as long as the conditions are similar to those of the reactant. One of the methods known to those skilled in the art can be used in this reaction. Many methods of reporting such as documents (such as W. Carrutthers, "Modern Methods of Organic Synthesis, Third Edition" (Cambridge University Press, 1986, pages 120-121) can be used. More preferably, the compound of the formula (b-2) can be conveniently produced, for example, by subjecting the compound of the formula (b-4) to an oxidation reaction known to those skilled in the art and heating the compound. A compound of the formula (d-Ι), a compound of the formula (ei), a compound of the formula (e-2), and a compound of the formula (fl) are known or commercially available. 63 201031662 Compound or system may be used therefrom. A compound prepared by a conventional method. [General Preparation Method 2] The general production method 2 for the typical use of the compound of the general formula [η of the present invention will be described below. [Chemical Formula 42]

0¾ H + (a-7)03⁄4 H + (a-7)

於此化學式 ’ R丨、R2、χ丨、χ2、Xc、Ρι ' L3、m、n、環A及環B係如上所定義。如上之一般製備方法2顯示一說明藉由使通式（a_7)之化合物及通式（d-6)之化合物接受步驟54之環化反應製備通式[I]之化合物之例子。The chemical formula 'R丨, R2, χ丨, χ2, Xc, Ρι ' L3, m, n, ring A and ring B are as defined above. The above general production method 2 shows an example of the preparation of the compound of the general formula [I] by subjecting the compound of the formula (a-7) and the compound of the formula (d-6) to the cyclization reaction of the step 54.

步驟5-1之環A形成反應係依起始材料而改變，且不被特別限制，只要條件相似於此反應者。熟習此項技藝者所知之方法可用於此反應。此方法之較佳例子包含一種於相關於通式（a-7)之化合物係10至10.0當量之鹼存在中，於一溶劑中使通式（a-7)之一化合物及相關於通式(a_7)之化合物係1.0至5.0當量之通式(d_6)之化合物攪拌之方法。此反應由处理14及攪拌效率之觀點較佳係於一溶劑存在中實施。使用之溶劑係依起始材料而改變，且不被特別限制，只要其不會抑制此反應且使起始材料被溶解至某一程度。溶劑之較佳例子包含醇溶劑，諸如，甲醇、乙醇及第三丁醇；醚冷劑’諸如’四氫吱喃、M二魏，及二乙基越；齒化溶 64 201031662 "如，二氯甲燒、α二氯乙炫，及氯仿；極性溶劑，遠如，乙腈、丙腈、Ν，Ν_二甲基甲醯胺迎_甲基料烧嗣，· 非極性溶劑，諸如，甲苯及苯；及其等之混合物。使用之鹼係依起始材料而改變，且不被特別限制。驗之較佳例子包3 ^金屬虱化物（諸如，氫化納及氫化鐘）、驗金屬鹽（諸如，碳酸鉀、破酸納及碳酸鎚）、金屬院氧化物(諸如，〒氧化納及第三丁氧化鉀)及有機驗(諸如，三乙基胺、朗_二異丙基乙基胺、1，8_二氮雜二環[5 4 G]+__7_烯及味嗤）。反應溫度需係—使反應完全且不會促進-非所欲副產物形成之溫度，且較佳係，例如，室溫至·。c。於較佳反應條件下，此反應係於！至7天完全，且反應之進行可藉由一已知之色譜分析術監測。一非所欲之副產物可藉由一熟習此項技藝者所知之技術(諸如，傳統之色譜分析術、萃取，或 /及結晶化)移除。化學式（d-6)之化合物係一已知或可購得之化合物，或係一可自此一化合物藉由一傳統方法製備之化合物。 [通式(a-7)之化合物之製備] 下列化學式顯不通式(a_7)之化合物之製備。 [化學式43] 65 201031662The ring A formation reaction of the step 5-1 varies depending on the starting material, and is not particularly limited as long as the conditions are similar to those of the reactant. A method known to those skilled in the art can be used for this reaction. A preferred example of the method comprises a compound of the formula (a-7) and a related formula in a solvent in the presence of from 10 to 10.0 equivalents of the base of the compound of the formula (a-7) The compound of (a_7) is a method in which 1.0 to 5.0 equivalents of the compound of the formula (d-6) are stirred. This reaction is preferably carried out in the presence of a solvent from the viewpoint of the treatment 14 and the stirring efficiency. The solvent to be used varies depending on the starting material, and is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to a certain extent. Preferable examples of the solvent include alcohol solvents such as methanol, ethanol and tert-butanol; ether refrigerants such as 'tetrahydrofuran, M-di-Wei, and diethyl-over; tooth-soluble solution 64 201031662 " Dichloromethane, α-dichloroethane, and chloroform; polar solvent, as far as acetonitrile, propionitrile, hydrazine, hydrazine dimethyl dimethyl carbamide, methazine, argon, etc., non-polar solvents, such as, Toluene and benzene; and mixtures thereof. The base to be used is changed depending on the starting material, and is not particularly limited. Preferred examples include 3 ^ metal tellurides (such as sodium hydride and hydrogenation clocks), metal salts (such as potassium carbonate, sodium sulphate and carbonated hammers), metal oxides (such as lanthanum oxide and Potassium tributoxide) and organic tests (such as triethylamine, lan-diisopropylethylamine, 1,8-diazabicyclo [5 4 G] + _7-ene and miso). The reaction temperature is required to be such that the reaction is complete and does not promote the temperature at which the undesired by-product is formed, and is preferably, for example, room temperature to. c. Under the preferred reaction conditions, this reaction is based on! It is complete up to 7 days and the progress of the reaction can be monitored by a known chromatographic analysis. An undesired by-product can be removed by techniques known to those skilled in the art, such as conventional chromatographic analysis, extraction, and/or crystallization. The compound of the formula (d-6) is a known or commercially available compound, or a compound which can be prepared from a compound by a conventional method. [Preparation of a compound of the formula (a-7)] The following chemical formula shows the preparation of a compound of the formula (a-7). [Chemical Formula 43] 65 201031662

於此化學式，R,、r2、m、n、乂八及匕係如上所定義；且ΜΑ代表一金屬，諸如，鋅或銅。通式(a_7)之化合物可自作為__起始材料之通式㈤)之一化合物經由步驟6-1之偶合反應、步驟6-2之水解反應及醯肼反應，及步驟6-3之去保護反應而製備。另外，此化合物可自作為一起始材料之通式（a-1)之一化合物經由步驟6_4 之偶合反應及步驟6-3之去保護反應而製備。In the formula, R, r2, m, n, octagonal and anthracene are as defined above; and ΜΑ represents a metal such as zinc or copper. The compound of the formula (a-7) can be subjected to the coupling reaction of the step 6-1, the hydrolysis reaction of the step 6-2 and the hydrazine reaction, and the step 6-3 of the compound of the formula (5) as a starting material. Prepared by deprotecting the reaction. Further, the compound can be produced from a compound of the formula (a-1) which is a starting material via the coupling reaction of the step 6-4 and the deprotection reaction of the step 6-3.

步驟6-1及步驟6-4係依據起始材料而改變，且不被特別限制’只要條件相似於此等反應者。熟習此項技藝者所知之一方法可用於此等反應。Mizoroki-Heck反應（見，例如， R.F· Heck,"有機反應”，1982，vol. 27，第 345 頁）、 Sonogashira反應（見，例如，K. Sonogashira，”簡易有機合成 "，1991，vol. 3,第521頁）等係較佳。於Mizoroki-Heck反應，通式(a-Ι)之一鹵素化合物或三氟曱烷磺酸鹽化合物較佳係，例如，於相關於通式（a“）之化合物係0.01至0.2當量之一過渡金屬催化劑存在中’與相關於通式（a-Ι)之化合物係1.0至5.0當量之通式（f_2)之化合 66 201031662 或L式(f'3)之化合物(其中，X!較佳係-CR3=cr4_)偶合。由處理性及攪拌效率之觀點而言，此反應較佳係於一溶劑存在中實施。使用之溶劑依使用之起始材料及過渡金屬催化劑而改變，且絲制限制，只要其不會抑制此反應且使起始材料於其間溶解至某一程度。此溶劑之較佳例子包含乙腈、四氫呋喃、丨，4_二噁烷、丨，2_二甲氧基乙烷、苯、甲本_甲本、1-甲基各炫嗣，及ν，Ν-二甲基甲醯胺。反應溫度需為一可使偶合反應完全之溫度，且較佳係室溫至150。〇此反應較佳係於一惰性氣體氛圍中實施，且更佳係於一氮氣或氬氣氛圍。過渡金屬催化劑較佳係，例如， —鈀錯合物，且更佳係一已知之鈀錯合物，諸如，乙酸鈀 ⑴）、二氣雙（三苯基膦)鈀(II)、四（三苯基膦)鈀(〇)，或三（二笨甲又基丙酮）二鈀(0)。亦較佳者係適當添加一膦配位體 (較佳係，例如，三苯基膦、三_鄰_曱苯基膦、三_第三丁基膦或2-(二-第三丁基膦基）聯苯），以使此反應有效率地進行。一較佳之結果可於鹼存在中達成。使用之鹼未被特別限制，只要其係用於一與此反應相似之偶合反應。此鹼之較佳例子包含三乙基胺、Ν，Ν-二異丙基乙基胺、Ν，Ν_二環己基甲基胺，及氣化四丁基銨。於較佳反應條件下，此反應係於1至24小時完全，且此反應之進行可藉由一已知之色譜分析術監測。Steps 6-1 and 6-4 are changed depending on the starting materials, and are not particularly limited as long as the conditions are similar to those of the reactants. One of the methods known to those skilled in the art can be used for such reactions. Mizoroki-Heck reaction (see, for example, RF Heck, "Organic Reactions, 1982, vol. 27, p. 345), Sonogashira reaction (see, for example, K. Sonogashira, "Simple Organic Synthesis", 1991, Vol. 3, p. 521) is preferred. In the Mizoroki-Heck reaction, a halogen compound or a trifluorosulfonate compound of the formula (a-Ι) is preferably, for example, one of 0.01 to 0.2 equivalents based on the compound of the formula (a"). In the presence of a transition metal catalyst, a compound of the formula (f_2) wherein the compound of the formula (a-Ι) is 1.0 to 5.0 equivalents, 66 201031662 or L formula (f'3) (wherein X! -CR3=cr4_) coupling. From the viewpoint of handleability and stirring efficiency, the reaction is preferably carried out in the presence of a solvent. The solvent used is changed depending on the starting materials used and the transition metal catalyst, and is made of silk. The limitation is as long as it does not inhibit the reaction and dissolves the starting material to some extent therebetween. Preferred examples of the solvent include acetonitrile, tetrahydrofuran, hydrazine, 4-dioxane, anthracene, 2-dimethoxyB. Alkane, benzene, methanoyl, 1-methyl hydrazine, and ν, Ν-dimethylformamide. The reaction temperature is required to be a temperature at which the coupling reaction is complete, and preferably room temperature is 150. The reaction is preferably carried out in an inert gas atmosphere, and more preferably in a nitrogen or argon atmosphere. The transition metal catalyst is preferably, for example, a palladium complex, and more preferably a known palladium complex such as palladium acetate (1), dioxobis(triphenylphosphine)palladium(II), Tetrakis(triphenylphosphine)palladium (ruthenium) or tris(dibenzoylacetone)dipalladium (0). It is also preferred to add a phosphine ligand as appropriate (preferably, for example, triphenyl) Phosphine, tri-o-phenylphosphine, tri-tert-butylphosphine or 2-(di-t-butylphosphino)biphenyl) to allow this reaction to proceed efficiently. A preferred result is The base to be used is not particularly limited as long as it is used in a coupling reaction similar to the reaction. Preferred examples of the base include triethylamine, hydrazine, hydrazine-diisopropylethylamine. , hydrazine, hydrazine dicyclohexylmethylamine, and tetrabutylammonium hydride. Under the preferred reaction conditions, the reaction is complete for 1 to 24 hours, and the reaction can be carried out by a known chromatographic analysis. Surveillance.

Sonogashira反應係依起始材料、溶劑及過渡金屬催化劑而改變，且不被特別限制，只要條件相似於此反應者。熟習此項技藝者所知之一方法可用於此反應。較佳地，通 67 201031662 式（a-l)之一化合物係，例如，於相關於通式（a-l)之化合物係0.01至0.2當量之一過渡金屬催化劑存在中，與相關於通式（a-l)之化合物係1·0至5.0當量之通式（f-2)之一化合物或通式(f-3)之一化合物偶合，其中，X!較佳係 [化學式44] —c=c— 使用溶劑之較佳例子包含乙腈、四氫呋喃、1,4-二噁烷、1，2-二甲氧基乙烷、苯、甲苯、二甲苯、1-甲基-2-吡咯烷酮、 N，N-二曱基甲醯胺，及二甲基亞颯。此溶劑之更佳例子包含四氫呋喃、1,4-二噁烷、1-曱基-2-吡咯烷酮，及N，N-二甲基甲酿胺。反應溫度需係一可使偶合反應完全之溫度，且較佳係室溫至150°C。此反應較佳係於一惰性氣體氛圍實施，且更佳係於氮氣或氬氣氛圍。於較佳反應條件下，反應係於1至24小時完全，且反應之進行可藉由一已知之色譜分析術監測。過渡金屬催化劑係，例如，一已知之鈀錯合物，且更佳地係一諸如乙酸鈀（II)、二氣雙（三苯基膦）鈀 (Π)、四（三苯基膦)鈀(〇)，或三（二笨甲叉基丙酮）二鈀之已知鈀錯合物。一膦配位體（較佳係，例如，三苯基膦、三 -鄰-甲笨基膦，或三·第三丁基膦）可被適當地添加以使此反應有效率地進行。於此反應，可添加一金屬鹵化物或一李銨鹽，較佳係，例如，碘化銅⑴、氣化鋰、氟化四丁基銨，或氧化銀(I)。一較佳結果可於鹼存在中達成。此處使用之驗且不被特別限制，只要其係用於一與此反應相似之偶合反應。鹼之較佳例子包含有機鹼，諸如，二乙基胺、三乙 68 201031662 基胺、N，N-二異丙基乙基胺、哌啶，及吡啶。步驟6-1之偶合反應亦可使用通式（f-4)之一化合物（其中Xl較佳係一單鍵）。通式(a-Ι)之一鹵素化合物或三氟甲烧/、酸鹽基團化合物較佳係於，例如，相關於通式（a_l)之化合物係0.01至0.2當量之一過渡金屬催化劑存在中，與相關於通式（a])之化合物係1.0至5.0當量之通式（f·4)之化合物（其中，X1較佳係一單鍵)偶合。由處理性及授拌效率之觀點而言，此反應較佳係於一溶劑存在中實施。使用之溶劑依使用之起始材料及過渡金屬催化劑而改變，且並未特別限制，只要其不會抑制此反應且使起始材料於其間溶解至某一程度。此溶劑之較佳例子包含乙腈、四氫呋喃、丨，4_ 二噁烷、丨，2-二甲氧基乙烷、苯、甲苯、二甲苯、1-甲基·2_ 吡咯烷酮，及Ν，Ν-二甲基曱醯胺。反應溫度需為一可使偶合反應完全之溫度，且較佳係室溫至15〇c>c。此反應較佳係於一惰性氣體氛圍中實施，且更佳係於一氮氣或氬氣氛圍。過渡金屬催化劑較佳係，例如，一纪錯合物，且更佳係一已知之鈀錯合物，諸如，乙酸鈀(11)、二氣雙(三苯基膦）把(11)、四（三苯基膦)飽(〇),或三（二苯曱叉基丙酮）二鈀(〇)。亦較佳者係適當添加一膦配位體（較佳係，例如，三苯基膦、三-鄰-曱苯基膦、三-第三丁基膦或2_(二_第三丁基膦基）聯苯）’以使此反應有效率地進行。一較佳之結果可於驗存在中達成。使用之鹼未被特別限制，只要其係用於一與此反應相似之偶合反應。此鹼之較佳例子包含三乙基胺、n,n_ 二異丙基乙基胺、N，N-二環己基甲基胺，及氣化四丁基銨。 69 201031662 於較佳反應條件下，此反應係於1至24小時完全，且此反應之進行可藉由一已知之色譜分析術監測。步驟6-2之第一階段之水解反應係依起始材料而改變，且不被特別限制，只要此等條件相似於此反應者。熟習此項技藝者所知之一方法可用於此反應。許多文件報導之方法（諸如’日本化學協會（編輯），Jikken Kagaku Koza (Courses in Experimental Chemistry),第 4版(vol. 22) YukiThe Sonogashira reaction varies depending on the starting materials, solvent and transition metal catalyst, and is not particularly limited as long as the conditions are similar to those of the reactants. One of the methods known to those skilled in the art can be used in this reaction. Preferably, a compound of the formula (al) is passed, for example, in the presence of a transition metal catalyst of from 0.01 to 0.2 equivalents based on the compound of the formula (al), and is related to the formula (al) The compound is 1 to 0 to 5.0 equivalents of a compound of the formula (f-2) or a compound of the formula (f-3), wherein X! is preferably [Chemical Formula 44] - c = c - using a solvent Preferred examples include acetonitrile, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, xylene, 1-methyl-2-pyrrolidone, and N,N-difluorene. Carbenamide, and dimethyl hydrazine. More preferred examples of the solvent include tetrahydrofuran, 1,4-dioxane, 1-mercapto-2-pyrrolidone, and N,N-dimethylamine. The reaction temperature is required to be a temperature at which the coupling reaction is completed, and is preferably room temperature to 150 °C. The reaction is preferably carried out in an inert gas atmosphere, and more preferably in a nitrogen or argon atmosphere. Under the preferred reaction conditions, the reaction is complete from 1 to 24 hours and the progress of the reaction can be monitored by a known chromatographic analysis. The transition metal catalyst system is, for example, a known palladium complex, and more preferably one such as palladium (II) acetate, dioxobis(triphenylphosphine)palladium (iridium), tetrakis(triphenylphosphine)palladium. (〇), or a known palladium complex of tris(dihydromethaneacetone)dipalladium. A phosphine ligand (preferably, for example, triphenylphosphine, tri-o-methylphenylphosphine, or tri-tert-butylphosphine) may be appropriately added to allow the reaction to proceed efficiently. In this reaction, a metal halide or a lithium ammonium salt may be added, preferably, for example, copper iodide (1), lithium vapor, tetrabutylammonium fluoride, or silver (I) oxide. A preferred result can be achieved in the presence of a base. The test used herein is not particularly limited as long as it is used for a coupling reaction similar to this reaction. Preferred examples of the base include an organic base such as diethylamine, triethyl 68 201031662-amine, N,N-diisopropylethylamine, piperidine, and pyridine. The coupling reaction of the step 6-1 can also be carried out by using a compound of the formula (f-4) (wherein X1 is preferably a single bond). The halogen compound or the trifluoromethane/acid salt group compound of the formula (a-Ι) is preferably, for example, a compound of the formula (a-1) having a transition metal catalyst of 0.01 to 0.2 equivalent. In the above, a compound of the formula (f. 4) wherein 1.0 to 5.0 equivalents of the compound of the formula (a)) (wherein X1 is preferably a single bond) is coupled. From the standpoint of handling and mixing efficiency, the reaction is preferably carried out in the presence of a solvent. The solvent to be used varies depending on the starting material used and the transition metal catalyst, and is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent therebetween. Preferred examples of the solvent include acetonitrile, tetrahydrofuran, hydrazine, 4-dioxane, anthracene, 2-dimethoxyethane, benzene, toluene, xylene, 1-methyl-2-pyrrolidone, and hydrazine, hydrazine-di Methyl decylamine. The reaction temperature is required to be a temperature at which the coupling reaction can be completed, and is preferably room temperature to 15 °c > c. The reaction is preferably carried out in an inert gas atmosphere, and more preferably in a nitrogen or argon atmosphere. The transition metal catalyst is preferably, for example, a complex of a complex, and more preferably a known palladium complex, such as palladium acetate (11), dioxobis(triphenylphosphine), (11), four. (triphenylphosphine) satane (yttrium), or tris(diphenylpyridinylacetone) dipalladium (ruthenium). Also preferably, a phosphine ligand is suitably added (preferably, for example, triphenylphosphine, tri-o-nonylphenylphosphine, tri-tert-butylphosphine or 2-(di-t-butylphosphine) Base) biphenyl)' to allow this reaction to proceed efficiently. A better result can be achieved in the inspection. The base to be used is not particularly limited as long as it is used in a coupling reaction similar to this reaction. Preferred examples of the base include triethylamine, n,n-diisopropylethylamine, N,N-dicyclohexylmethylamine, and vaporized tetrabutylammonium. 69 201031662 Under the preferred reaction conditions, the reaction is complete from 1 to 24 hours and the reaction can be monitored by a known chromatographic analysis. The hydrolysis reaction in the first stage of the step 6-2 is changed depending on the starting materials, and is not particularly limited as long as the conditions are similar to those of the reactants. One of the methods known to those skilled in the art can be used in this reaction. Many methods of document reporting (such as 'Japan Chemical Society (Editor), Jikken Kagaku Koza (Courses in Experimental Chemistry), 4th edition (vol. 22) Yuki

Gosei (Organic Synthesis) [IV], Maruzen Co., Ltd., November 1992, 12-13頁所述)可被使用。第二階段之醯肼化反應係依起始材料而改變，且不被特別限制，只要此等條件相似於此反應者。熟習此項技藝者所知之醯胺化反應可用於此反應。許多文件等報導之方法(諸如，日本化學協會 (編輯），Jikken Kagaku Koza (Courses in Experimental Chemistry)，第 4版(v〇i· 22) Yuki Gosei (Organic Synthesis) [IV]，Maruzen Co” Ltd·，November 1992, 137-144所述)可被使用。步驟6-3之去保護反應係依起始材料而改變，且不被特別限制，只要條件相似於此反應者。熟習此項技藝者所知之一去保護反應可用於此反應。許多文件等報導之方法 (見，例如’ T. Greene等人，”有機合成之保護基”，J〇hn Wiley & Sons, Inc” New York, 1981)可被使用。化學式（f-2)之化合物、化學式（f_3)之化合物及化學式 (f_4)之化合物係已知或可購得之化合物或係可自此等化合物藉由一傳統方法製備之化合物。 70 201031662 [通式(d_6)之化合物之製備] 下列化學式顯示通式(d-6)之化合物之製備之—例子 [化學式45] 'Gosei (Organic Synthesis) [IV], Maruzen Co., Ltd., November 1992, pages 12-13) can be used. The second stage of the deuteration reaction varies depending on the starting materials, and is not particularly limited as long as the conditions are similar to those of the reactants. Amidoxime reaction known to those skilled in the art can be used in this reaction. Many documents and other methods of reporting (such as the Japan Chemical Society (Editor), Jikken Kagaku Koza (Courses in Experimental Chemistry), 4th edition (v〇i· 22) Yuki Gosei (Organic Synthesis) [IV], Maruzen Co" Ltd ·, November 1992, 137-144) can be used. The deprotection reaction of step 6-3 varies depending on the starting material, and is not particularly limited as long as the conditions are similar to those of the reaction. Those skilled in the art are familiar with the art. One known deprotection reaction can be used for this reaction. Many documents and the like are reported (see, for example, 'T. Greene et al., "Protective Groups for Organic Synthesis", J〇hn Wiley & Sons, Inc" New York, 1981) can be used. The compound of the formula (f-2), the compound of the formula (f-3) and the compound of the formula (f-4) are known or commercially available compounds or compounds which can be prepared from such compounds by a conventional method. 70 201031662 [Preparation of a compound of the formula (d-6)] The following chemical formula shows the preparation of a compound of the formula (d-6) - an example [Chemical Formula 45]

(d-6) [少 #3-1] [少嘴 7-1] NC^Xj./ Λ -- Γ __ u—Xc_u NC人χ2~0 (丨7) (e-1) (d-8) 於化學式，x2、xc、環B、Pl、L3及乙4係如上所定義。(d-6) [少#3-1] [少嘴7-1] NC^Xj./ Λ -- Γ __ u—Xc_u NC χ 2~0 (丨7) (e-1) (d-8 In the chemical formula, x2, xc, ring B, Pl, L3 and B are as defined above.

通式（d-6)之化合物可自作為一起始材料之通式乃之一化合物經由步驟3-1之烷基化反應及步驟7_丨之咪唑化反應製備。步驟3-1係藉由如上所述般相同方法實施，且可自通式 (d-7)之一化合物製備通式(d8)之一化合物。步驟7-1係依據起始材料而改變，且不受特別限制，只要條件相似於此反應者。熟習此項技藝者所知之—方法可用於此反應。此方法之較佳例子包含—種於相關於通式_ 之化合物係5.0至_·〇當量之酸存在中，於—醇溶_摔通式(d-8)之化合物之方法。使用之酸係依起始材料而改變，且不被特別限制。酸之較佳例子包含氣化氫及氣乙酿。使用之溶劑依起始材料而改變，且不被特別限制，只要其不會抑制此反應且使起騎胁其間溶職$—程度。溶之較佳例子包含醇溶劑，諸如，甲醇、乙醇及第三丁醇。二，之較佳例子亦包含_化溶劑，諸如，二氣甲烧、H 氯乙烷及氣仿，極性溶劑，諸如，N,N_二甲基甲酿及乂甲基鱗燒酮；非極性_，諸如，甲苯及苯；及其 71 201031662 等之混合物。反應溫度需係一使反應完全且不會促進—非所欲副產物形成之溫度，且較佳係，例如，於較佳反應條件下，此反應係於丨至7天完全，且反應之進行可藉由一已知之色譜分析術監測。一非所欲之副產物可藉由一熟習此項技藝者所知之技術(諸如，傳統之色譜分析術、萃取，或/及結晶化)移除。化學式(d-7)之化合物及化學式(叫之化合物係已知或可購得之化合物或係可自此等化合物藉由—傳統方法製備The compound of the formula (d-6) can be produced from a compound of the formula which is a starting material via the alkylation reaction of the step 3-1 and the imidazole reaction of the step 7_. Step 3-1 is carried out in the same manner as described above, and a compound of the formula (d8) can be produced from a compound of the formula (d-7). Step 7-1 is changed depending on the starting material, and is not particularly limited as long as the conditions are similar to those of the reaction. As is known to those skilled in the art, methods can be used for this reaction. A preferred example of the method comprises a method of reacting a compound of the formula (d-8) with an acid in the range of 5.0 to _ 〇 equivalent of the compound of the formula _. The acid to be used varies depending on the starting material, and is not particularly limited. Preferred examples of the acid include hydrogenated gas and gas. The solvent to be used is changed depending on the starting material, and is not particularly limited as long as it does not inhibit the reaction and causes the degree of mobilization to take place. Preferred examples of the dissolution include alcohol solvents such as methanol, ethanol and tert-butanol. Second, preferred examples also include a _chemical solvent such as a gas-fired gas, H-chloroethane and gas-like, a polar solvent such as N,N-dimethyl ketone and hydrazine methyl ketone; Polarity _, such as toluene and benzene; and a mixture thereof 71 201031662. The reaction temperature is required to be such that the reaction is complete and does not promote the temperature at which the undesired by-product is formed, and preferably, for example, under the preferred reaction conditions, the reaction is carried out until 7 to 7 days, and the reaction proceeds. It can be monitored by a known chromatographic analysis. An undesired by-product can be removed by techniques known to those skilled in the art, such as conventional chromatographic analysis, extraction, and/or crystallization. The compound of the formula (d-7) and the chemical formula (the compound known or commercially available as a compound can be prepared from these compounds by a conventional method)

之化合物。依據本發明之通式(I)之化合物或其藥理學上可接受之鹽有效治療Αβ造成之疾病且以藥物動力學、毒性、穩定性、吸收性等而言係優異。Compound. The compound of the formula (I) or a pharmacologically acceptable salt thereof according to the present invention is effective for the treatment of diseases caused by Aβ and is excellent in terms of pharmacokinetics, toxicity, stability, absorbability and the like.

包含作為一活性成份之依據本發明之化學式⑴之化洽物或其藥理學上可接受之鹽之祕治絲由Α(^成之疾= 之治療劑可藉由-傳統方法製備。藥劑型式之較佳例子自含錠劑、粉末、細微顆粒、顆粒、經塗覆之㈣、膝囊、糖漿、***錠、吸人劑、栓劑、注射劑、軟膏、眼用溶液眼用軟膏、鼻用滴液、耳用滴液、泥敷劑及乳液。此藥齊可使用諸如賦形劑、結合劑、潤滑劑、著色劑⑽味劑之典型使用成份，及諸域'㈣、乳彳㈣、吸㈣、表面泛性劑、PH雜劑、防及抗氧化劑之需要時❹之成份製備，且可藉由摻合-般作為藥物製備之材料之成份而製備。此等成份之例子包含浦及蔬菜油，諸如大豆油、牛脂及合成甘油；Μ ’諸如’液體殘、魚纽及固體石 72 201031662 ，，切酸辛基忙缺十四g_醋；較 ^ ^如，輯硬脂醇及山茶醇；心氧樹脂；聚A therapeutic agent comprising a chemical compound of the formula (1) or a pharmacologically acceptable salt thereof according to the present invention as an active ingredient can be prepared by a conventional method using a therapeutic agent of the compound (1) Preferred examples are self-containing tablets, powders, fine particles, granules, coated (four), knee capsules, syrups, buccal tablets, inhalants, suppositories, injections, ointments, ophthalmic solutions, ophthalmic ointments, nasal sprays Drops, ear drops, poultices and lotions. This medicine can be used with typical ingredients such as excipients, binders, lubricants, colorants (10), and fields '(4), chyle (4), The preparation of the components of the medicinal preparations, which can be prepared by blending - as a component of a pharmaceutical preparation, is prepared by blending (4), a surface-polymerizing agent, a pH-inducing agent, an anti-oxidant, and an antioxidant. Examples of such components include Puhe. Vegetable oils, such as soybean oil, tallow and synthetic glycerin; 诸如 'such as 'liquid residue, fish and solid stone 72 201031662, octyl sulphate is short of 14g_ vinegar; more than ^ ^, stearyl alcohol and camellia Alcohol; cardiooxidic resin;

表面活性劑’諸如，聚氧乙缚脂肪酸醋;去水山 =、：酸醋：油脂肪酸酿、聚氧乙稀去水山梨醇脂肪曰KWiUtE麻油及綠乙烯_聚氧㈣嵌段共聚性聚合物’諸如，羥基乙基纖維素、聚丙烯酸、聚叛基乙稀基聚合物、聚乙二醇、聚乙烯基料烧剩及 :基纖維素；較低等醇，諸如，乙醇及異丙醇；多元醇，諸如’甘油、丙二醇、二丙甘醇及山梨糖醇；糖，諸如，葡萄糖及餘；無機粉末，諸如，料針、㈣馳及石夕酸铭，及經純化之水。冑用之賦形劑之例子包含乳糖、玉米澱粉^糖、葡萄糖、甘露糖醇、山梨糖醇、結晶纖維素及二氧切M吏用之結合.例子包含聚乙稀基醇、聚乙烯基趟、維素、乙基纖維素、***膠、特拉加康斯樹脂膠、明膠、蟲膠、羥基丙基曱基纖維素、羥基丙基纖維素、聚乙烯基料細乙稀嵌段共聚物’及葡甲胺。使用之崩解劑之例子包含澱粉、境脂、明膠粉末、結晶纖維素、碳酸鈣、碳酸氫鈉、檸檬酸鈣、葡聚糖、果膠及羧甲基纖維素鈣。使用之潤滑劑之例子包含硬脂酸鎂、滑石、聚乙二醇、矽石及氫化蔬菜油。使用之著色劑之例子包含允許添加至藥物者。使用之矯味劑包含可可粉、曱醇、安帕斯(empasm)、薄荷油、冰片及肉桂粉。例如口服製備物係藉由添加一活性成份化合物戋 73 201031662 ，、藥或此化。物或鹽之水合物、一賦形劑及若需要時之，例如’ 一結合劑、—崩解劑、一湖滑劑、一著色劑及一矯味劑，然後，藉由-傳統方法使混合物形成，例如，粉末、細微顆粒、顆粒、鍵劑、經塗覆之錠劑或膠囊而製備。明顯地’錠劑或顆粗若需要時可被適當塗覆，例如，以糖塗覆糖聚或'主射製備物係藉由一傳統方法，藉由添加，例如，-pH調_、—助_及特透㈣，及若需要之 Γ助溶劑、一穩定劑等而製備。一外部製備物可不受限地藉=任何傳統方法製備。作為—基本材料通常驗藥物、 ❿ 半藥Π彳t·妝xm等之各種材料之任何者可被使用。驗性材料之例子包含諸如動物及蔬菜油、礦物油、S旨油、壤、較兩等之醇、脂肪酸、聚錢油、表面活性劑、獅 '醇、多兀醇、水溶絲合物、黏土磺物及經純化之水讀料。 - PH調整劑、抗氧化劑、螯合劑、防腐劑及殺黴劑、著色劑、口味劑等右需要可被添加。再者，一具有不同誘發作用之成份(諸如，血流促進劑、殺細菌劑、消炎劑、細胞活化劑、維他命、胺錢、保_或肖質簡難要時可被摻合。 ® 依據本發明之治療劑之劑量可依，例如，症候程度、年齡、性別、體重、投藥模式、鹽之型式及特定疾病型式而改變。典型上，化學式⑴之化合物或其藥理學上可接受之鹽係以每天約30 pg至1〇 g ,較佳係1〇〇叫至5 g，且更佳係100 pg至1〇〇口服投用至成人，或每天約叫至1 g，較佳係100 pg至500 mg，且更佳係1〇〇叩至3〇 mg，個別以單藥劑或數個分開藥劑藉由注射投用至成人。 74 201031662 為治療一藉由類澱粉-β造成之疾病，諸如，阿兹罕默氏疾病、老年癡呆症、唐氏症候群或類凝粉變性症，依據本發明之化學式(I)之化合物或其藥理學上可接受之鹽可與具有下列機構之化合物結合使用。例如，可結合使用之化合物膽驗酯酶抑制劑（例如，多奈旅齊、石杉驗A、他克林、卡巴拉汀、加蘭他敏）；amPA 受體拮抗劑（例如，1，2-二氫°比唆化合物，諸如，3-(2-氰基笨基)-5-(2-°比咬基)-1-苯基-1,2-二氫e比咬-2-酮）；NMDA受體拮抗劑(例如，美曼停）；乙醯膽驗釋放刺激劑（例如，普拉西坦；阿尼西坦）；辦通道激動劑（例如，奈非西坦）；自由基清除劑（例如，EGb 761);血小板活化因子拮抗劑（例如，EGb 761);血小板聚集拮抗劑（例如，EGb 761、三氟柳）；胰島素敏化劑（例如，羅格列酮）；過氧化體增殖活化受體激動劑（例如，羅格列酮）；過氧化體增殖活化受體丫激動劑(例如，羅格列酮）；單胺氧化酶B抑制劑（例如，雷沙吉蘭、司來吉蘭、普魯卡因）；肉鹼乙醯基轉化酶刺激劑（例如，左旋肉鹼）；NSAID(例如，三氟柳、環氧酶·2抑制劑，諸如，塞來昔布）；神經生長因子激動劑（例如，扎利羅登、FPF 1070) ; β-類澱粉抑制劑(例如，塔林弗比、特拉米洛、柳菩林-D);免疫調節劑（例如，塔林弗比、免疫球蛋白、二十五碳五稀酸酯）；NF-kB抑制劑（例如，塔林弗比）；促甲狀腺素釋放荷爾蒙(例如’他替瑞林）；多巴胺D2受體拮抗劑(例如，利螺環酮）；血清素2受體拮抗劑(例如，利螺環酮）；蕈毒鹼Ml受體激動劑（例如，西維美林）；“腎上腺素受體激 75 201031662 動劑(例如’莫待芬寧）；血清素3受體拮抗劑(例如，阿洛司壤）’多巴胺D2乂體激動劑(例如’阿利旅哇）·，多巴胺此典體枯抗劑(例如’阿利艰嗤）；血清素1A受體激動劑(例如^ 阿利派。坐）；企清素2A受體拮抗劑(例如，阿利娘唾）；糖皮質激素拮抗劑(例如，美服培酮）；黃體素拮抗劑(例如，美服培酮）；HMG-CoA還原酶抑制劑(例如，阿伐他汀、辛伐他汀）；腺苦酸吸收抑制劑(例如，丙戊茶驗）；碟二酿酶抑制劑（例如，丙戊茶鹼）；乙醯膽鹼受體激動劑（例如，膽鹼甘磷酸鹽）；膜滲透促進劑（例如，膽鹼甘磷酸鹽）；***素丨參受體拮抗劑(例如，利莫那班）；***素受體激動劑(例如，屈***酚）；血管新生抑制劑(例如，紫杉醇）；免疫抑制劑(例Surfactant 'such as polyoxyethylene bonded fatty acid vinegar; Deshuishan =,: acid vinegar: oil fatty acid brewing, polyoxyethylene sorbitan fat 曰 KWiUtE sesame oil and green ethylene _ polyoxygen (tetra) block copolymerization polymerization '', such as hydroxyethyl cellulose, polyacrylic acid, polyglycidyl polymer, polyethylene glycol, polyethylene base and: cellulose; lower alcohols such as ethanol and isopropyl Alcohol; polyhydric alcohols such as 'glycerin, propylene glycol, dipropylene glycol and sorbitol; sugars such as glucose and coke; inorganic powders such as pin, (iv) and lysine, and purified water. Examples of excipients for use include lactose, corn starch sugar, glucose, mannitol, sorbitol, crystalline cellulose, and dioxo M. The examples include polyethylene glycol, polyvinyl Bismuth, vitamins, ethyl cellulose, gum arabic, Tragacons resin glue, gelatin, shellac, hydroxypropyl decyl cellulose, hydroxypropyl cellulose, polyethylene base ethylene copolymer block copolymerization ' and meglumine. Examples of the disintegrant used include starch, ester, gelatin powder, crystalline cellulose, calcium carbonate, sodium hydrogencarbonate, calcium citrate, dextran, pectin and calcium carboxymethylcellulose. Examples of lubricants used include magnesium stearate, talc, polyethylene glycol, vermiculite and hydrogenated vegetable oil. Examples of the coloring agent used include those which are allowed to be added to a drug. The flavoring agents used include cocoa powder, sterol, empasm, peppermint oil, borneol and cinnamon powder. For example, an oral preparation is prepared by adding an active ingredient compound 戋 73 201031662. a hydrate or a salt hydrate, an excipient and, if desired, such as 'a binder, a disintegrant, a lake slip agent, a colorant and a flavoring agent, and then, by a conventional method It is prepared, for example, as a powder, fine particles, granules, a key, a coated tablet or a capsule. Obviously, the lozenge or granules may be suitably coated if desired, for example, by sugar coating of sugar or 'primary preparations' by a conventional method, by adding, for example, -pH 调, - _ and special permeable (4), and if necessary, a solvent, a stabilizer, etc. are prepared. An external preparation can be prepared without limitation by any conventional method. As a basic material, any of various materials such as a drug, a drug, a drug, a makeup, and the like can be used. Examples of test materials include, for example, animal and vegetable oils, mineral oils, S-oils, soils, alcohols, fatty acids, poly-money oils, surfactants, lion' alcohol, polyterpene alcohols, water-soluble silk compounds, Clay sulphate and purified water reading material. - PH adjusters, antioxidants, chelating agents, preservatives and fungicides, colorants, flavors, etc. can be added to the right. Furthermore, a component with different evoked effects (such as a blood flow promoter, a bactericide, an anti-inflammatory agent, a cell activator, a vitamin, an amine, a _ or a succinct can be blended.) The dose of the therapeutic agent of the present invention may vary depending on, for example, the degree of symptom, age, sex, body weight, mode of administration, type of salt, and specific disease pattern. Typically, the compound of formula (1) or a pharmacologically acceptable salt thereof It is administered from about 30 pg to 1 g per day, preferably from 1 bar to 5 g, and more preferably from 100 pg to 1 bar, or to an adult, or about 1 g per day, preferably 100. Pg to 500 mg, and more preferably 1 to 3 mg, administered to adults by injection or in combination with a single agent or a plurality of separate agents. 74 201031662 To treat a disease caused by a starch-like beta, For example, Azheimer's disease, Alzheimer's disease, Down's syndrome or condensate-like degeneration, the compound of the formula (I) according to the present invention or a pharmacologically acceptable salt thereof can be combined with a compound having the following mechanism For example, a compound that can be used in combination Cholesterol esterase inhibitors (eg, Donai Bieqi, Shishan A, Tacrine, rivastigmine, galantamine); amPA receptor antagonists (eg, 1,2-dihydrogen 唆a compound such as 3-(2-cyanophenyl)-5-(2-° ratio dimethyl)-1-phenyl-1,2-dihydroe ratio ketone-2-one); NMDA receptor antagonism Agents (eg, Meyer); acetaminophen release stimulants (eg, prastamidine; aniracetam); channel agonists (eg, nefiracetam); free radical scavengers (eg, EGb 761); platelet activating factor antagonist (eg, EGb 761); platelet aggregation antagonist (eg, EGb 761, triflumuron); insulin sensitizer (eg, rosiglitazone); peroxisome proliferation activation Body agonists (eg, rosiglitazone); peroxisome proliferator-activated receptor 丫 agonists (eg, rosiglitazone); monoamine oxidase B inhibitors (eg, rasagiline, selegiline, pru Cain); carnitine acetonitrile-converting enzyme stimulating agent (for example, L-carnitine); NSAID (for example, triflumuron, cyclooxygenase-2 inhibitor, such as celecoxib); Growth factor agonists (eg, Zalil Roden, FPF 1070); beta-type starch inhibitors (eg, Tallinnbi, Tramilo, Liupulin-D); immunomodulators (eg, Tallinnby , immunoglobulin, twenty-five carbonic acid esters; NF-kB inhibitors (eg, Tallinnubi); thyrotropin-releasing hormones (eg, statin); dopamine D2 receptor antagonists (eg , spiroxone); serotonin 2 receptor antagonist (eg, lixirocyclone); muscarinic M1 receptor agonist (eg, cevimeline); "adrenal receptor receptor 75 201031662 (eg 'moufenin'); serotonin 3 receptor antagonist (eg, alopros) 'dopamine D2 steroid agonist (eg 'Ali Lv wow) ·, dopamine this canonicide (eg ' Ali hard); serotonin 1A receptor agonist (eg ^ Alipa. Sitting); Qiqing 2A receptor antagonist (for example, Ali Niang saliva); glucocorticoid antagonist (for example, US-based ketone); lutein antagonist (for example, US-based ketone); HMG-CoA reduction Enzyme inhibitors (eg, atorvastatin, simvastatin); adenosine absorption inhibitors (eg, fentanyl tea); dish di-enzyme inhibitors (eg, valproate); acetylcholine a agonist (eg, choline glycolate); a membrane permeation enhancer (eg, choline glycophosphate); a cannabinoid quinone receptor antagonist (eg, rimonabant); a cannabinoid receptor agonist (eg, dronabinol); angiogenesis inhibitors (eg, paclitaxel); immunosuppressants (eg

如，紫杉醇）；微血蛋白拮抗劑（例如，紫杉酵）；血栓烷A 合成酶抑制劑（例如，三氟柳）；抗氧化劑(例如，艾地苯）； - α腎上腺素受體拮抗劑(例如，尼麥角林）；動情激素拮抗劑 (例如，共軛動情激素、曲洛斯坦）；3_β羥基類固醇脫氫酶抑制劑（例如’曲洛斯坦）；訊息傳遞路徑抑制劑（例如，曲洛斯坦）；退黑激素受體激動劑（例如，雷美替胺）；免疫刺激劑(例如’免疫球蛋白、二十五碳五烯酸酯、普魯卡因）； HIV進入抑制劑（例如，普魯卡因）；納通道拮抗劑（例如，普魯卡因）；微細管抑制劑(例如，CPH 82);甘胺酸NMDA 激動劑(例如，環絲胺酸）；腺苷酸Α1受體拮抗劑(例如，KW 3902) ; ATPase刺激劑（例如，三乙醯基尿苷）；粒線體功能促進劑（例如，三乙醯基尿苷）；生長荷爾蒙釋放因子激動劑 (例如，替莫瑞林）；丁基膽鹼酯酶抑制劑（例如，必諾辛絲 76 201031662 胺酸）；α腎上腺素受體拮抗劑（例如，尼麥角林）；NO合成酶II型抑制劑（例如，阿路迪酸）；螯合劑(例如’ PBT2);類澱粉原纖維生成抑制劑（例如，TTP488、PF 4494700);血清素4受體激動劑(例如，PRX 03140);血清素6受體拮抗劑 (例如，SB 742457);苯并二吖呼受體反向激動劑(例如，雷得奎尼）；Ca通道拮抗劑（例如，沙芬醯胺）；菸鹼受體激動劑（例如’依斯洛尼）；及BACE抑制劑（例如，CTS 21166)。再者’如上之化合物包含，例如，多奈旅齊、石杉驗A、他克林、卡巴拉汀、加蘭他敏、普拉西坦、阿尼西坦、奈非西坦、EGb 76卜羅格列酮、雷薩吉蘭、左旋肉鹼、塞來昔布、3-(2-氰基苯基)-5-(2--比啶基)-1-苯基-1，2-二氫°比啶-2-酮、他蘭帕尼、貝坎帕奈、美金胺、扎利羅登、塔林弗比、特拉米洛' 柳菩林-D、他替瑞林、利螺環酮、西維美林、莫待芬寧、阿洛司瓊、阿利哌唑、美服培酮、阿伐他汀、丙戊茶鹼、膽鹼甘磷酸鹽、FPF 1070(CAS編號 143637-01-8)、利莫那班、屈***酚、二十二碳六烯酸、紫杉醇、三氟柳、艾地苯、尼麥角林、共軛動情激素、曲洛斯坦、辛伐他汀、司來吉蘭、雷美替胺、免疫球蛋白、二十碳五烯酸酯、普魯卡因、CPH 82、環絲胺酸、KW 3902(CAS編號136199-〇2-5)、三乙醯基尿苷、動情激素癡呆症治療劑（例如，MIGENIX，vancouver，canada)、替莫瑞林、必諾辛絲胺酸、尼麥角林、阿路迪酸、pBT2、TTp488、 PF 449梢0、PRX 〇314〇、SB 74245?、雷得奎尼、沙芬酿胺、依斯洛尼、CTS 21166、巴平紐瑪、Np 〇3u12、 77 201031662 (2S,3aS,7aS)-l {[(R，R)-2-苯基環丙基]羰基}-2-[(噻唑烷·3-基)羰基]八氫-1Η-吲嵘、西酞普蘭、文拉法辛、柳菩林、普拉雄酮、肽T(CAS編號53-43-0)、貝西吡啶、來昔帕泛、司他可茶鹼、SGS 742(CAS編號 123690-78-8)、T 588(CAS編號142935-03-3)、奈利匹林、地塞米諾、沙可美林、GTS 21(CAS編號 156223-05-1)、CX 516(CAS編號 154235-83-3)、 ABT 089(CAS編號 161417-03-4)、阿那索、替索芬辛、SIB 1553A(即，4-[[2-(1-甲基-2-n比咯啶基）乙基]硫基]酚）、拉多替吉、雷得奎尼、GPI 1485、依斯洛尼、阿路迪酸、MEM 1003(即，3-異丙基5-(2-曱氧基1)4-(2-氣-3_氰基苯基)_2,6-二甲基吡啶-3,5-二羧酸酯）、V 3381(即，2-(2,3-二氫-1H-茚 -3-基胺基）乙醯胺氫氣酸鹽）、法蘭帕托、帕利若汀、普拉雄酮-帕拉汀、尿皮質醇、DP b99(例如，2,2’-(乙撐基二氧）雙(2，1-笨撐基)雙[N-[2-[2-(辛氧基）乙氧基]-2-側氧基乙基] 亞胺基]雙（乙酸)）、凱塞拉、DU 125530、巴平紐瑪、AL 108(即，L-天冬門醯基-L-丙氨醯基-L-脯氨醯基-L-纈氨醯基-L-絲氨醯基-L-異白氨醯基-L-脯氨醢基-L-麵胺醯胺）、 DAS 43卜 DEBIO 9902、DAR 100、米托醌、IPL 455903(即， 5(S)-[3-(環戊氧基)_4_甲氧基苯基]-3(S)-(3-曱基苯曱基）旅啶-2-酮）、E2CDS、PYM 50028、PBT 2、拉可唑坦、SB 742457、CX 717、AVE 1625(即，1-(雙（4-氣苯基）甲基)·3·((3,5-二氟笨基)（曱基磺醯基）甲撐基）四氫吖唉）、LY 450139(即，N2-[2(s)_ 羥基 _3_ 曱基丁醯基]-Nl-[3-甲基-2-側氧基-2,3,4,5-四氫_111-3-苯甲吖呼-1(8)-基]丄-丙氨醯胺）、 201031662For example, paclitaxel); micro-blood protein antagonists (eg, taxol); thromboxane A synthetase inhibitors (eg, triflumuron); antioxidants (eg, idebenone); - alpha adrenergic receptor antagonism Agents (eg, ergoline); estrus hormone antagonists (eg, conjugated estrogen hormone, troxol); 3_beta hydroxysteroid dehydrogenase inhibitors (eg, 'troxan'); message delivery pathway inhibitors (eg , tromethamine); a melatonin receptor agonist (eg, rametamine); an immunostimulatory agent (eg 'immunoglobulin, pentadecapentaenoate, procaine); HIV entry inhibition Agent (eg, procaine); a nanochannel antagonist (eg, procaine); a microtubule inhibitor (eg, CPH 82); a glycine NMDA agonist (eg, cycloserine); gland Α1 receptor antagonist (eg, KW 3902); ATPase stimulant (eg, triethyl uridine); mitochondrial function enhancer (eg, triethyl uridine); growth hormone release factor agonist Agent (eg, temoline); butylcholinesterase inhibition (eg, Binoxin 76 201031662 Amin); alpha adrenergic receptor antagonists (eg, nigeroline); NO synthase type II inhibitors (eg, aludi acid); chelating agents (eg ' PBT2); amyloplasty-like inhibitors (eg, TTP488, PF 4494700); serotonin 4 receptor agonists (eg, PRX 03140); serotonin 6 receptor antagonists (eg, SB 742457); benzodiazepines a snoring receptor inverse agonist (eg, raddini); a Ca channel antagonist (eg, safinamide); a nicotinic receptor agonist (eg, 'islonone); and a BACE inhibitor ( For example, CTS 21166). Furthermore, 'the above compounds include, for example, Donai Bieqi, Shishan A, Tacrine, rivastigmine, galantamine, pravastane, aniracetam, nefiracetam, EGb 76 Brosglitazone, rasagiline, L-carnitine, celecoxib, 3-(2-cyanophenyl)-5-(2--pyridyl)-1-phenyl-1,2 -dihydropyridin-2-one, talanpyr, becamathene, memantine, zali roden, talinforbi, tamilolo 'liuzhuolin-D, tartarelin, li Spiro ketone, cevimeline, vetofenine, alosetron, aripiprazole, meperidine, atorvastatin, valproate, choline glycolate, FPF 1070 (CAS number 143637- 01-8), rimonabant, dronabinol, docosahexaenoic acid, paclitaxel, triflumuron, idebenone, ergoline, conjugated emollient hormone, tromethamine, simvastatin, Selegiline, rametidine, immunoglobulin, eicosapentaenoate, procaine, CPH 82, cycloserine, KW 3902 (CAS number 136199-〇2-5), triethyl Thioglycol uridine, therapeutic agent for estrus hormone dementia (eg, MIGENIX, vancouver, canada), Morrillin, binocine, nigralin, aludyic acid, pBT2, TTp488, PF 449, 0, PRX 〇314〇, SB 74245?, raddini, safflower, amine Slony, CTS 21166, Bapin Newamar, Np 〇3u12, 77 201031662 (2S,3aS,7aS)-l {[(R,R)-2-phenylcyclopropyl]carbonyl}-2-[(thiazole Alkano-3-yl)carbonyl]octahydro-1Η-吲嵘, citalopram, venlafaxine, willow bolin, prasone, peptide T (CAS number 53-43-0), besipirin, Rapafloxacin, statin theophylline, SGS 742 (CAS number 123690-78-8), T 588 (CAS number 142935-03-3), nilipiline, dexamethasone, sabcomeline, GTS 21 (CAS No. 156223-05-1), CX 516 (CAS No. 154235-83-3), ABT 089 (CAS No. 161417-03-4), Anaso, Texofensin, SIB 1553A (ie, 4-[[2-(1-methyl-2-n-pyridyl)ethyl]thio]phenol), Radotiriz, Redknini, GPI 1485, Isolo, Aludi Acid, MEM 1003 (ie, 3-isopropyl 5-(2-decyloxy 1) 4-(2- gas-3-cyanophenyl)_2,6-dimethylpyridine-3,5-di Carboxylate), V 3381 (ie, 2-(2,3-dihydro-1H-indol-3-ylamino)acetamidine Hydrogenate), franpato, parylene, prasone-palatin, urinary cortisol, DP b99 (eg, 2,2'-(ethylenedioxy) double (2,1 - stupid base) bis[N-[2-[2-(octyloxy)ethoxy]-2-oxoethyl]]imino]bis(acetic acid)), Kaysera, DU 125530, Bapin Newma, AL 108 (ie, L-aspartate-L-alaninyl-L-amidoxime-L-amidoxime-L-sermino-yl-L-isoammonium醯-L-ammonium-L- face amine amide, DAS 43 BD DEBIO 9902, DAR 100, mitoxantrone, IPL 455903 (ie, 5(S)-[3-(cyclopentyloxy) _4_Methoxyphenyl]-3(S)-(3-mercaptophenylhydrazinyl) benzidine-2-one), E2CDS, PYM 50028, PBT 2, ractazole, SB 742457, CX 717, AVE 1625 (ie, 1-(bis(4-phenylphenyl)methyl)·3·((3,5-difluorophenyl)(fluorenylsulfonyl)methylene)tetrahydroindole), LY 450139 (ie, N2-[2(s)_hydroxy_3_mercaptobutyl)-Nl-[3-methyl-2-oxo-2,3,4,5-tetrahydro-111-3- Benzopyrene-1(8)-yl]anthracene-alanamine), 201031662

EM 1421(例如，4,4'-[(2R，3S)-2,3-二曱基丁烷-1，4-二基]雙 (1,2-二甲氧基苯）、SRN 001、TTP 488、PRX 03140、地美保林、甘胺酸-脯胺酸-麩胺酸鹽、C105、AL 208、MEM 3454、AC 1202、L 830982、LY 451395(即 ’（R)-N-[2-[4'_(甲基磺醯胺基甲基）聯苯-4-基]丙基]丙烷-2-磺醯胺）、MK 0249、LY2062430、二乙基去甲精胺、尼伯胺、S 18986、 SA 4503(CAS 編號 165377-44-6)、GRI 1、S 17092(即， (2S，3aS，7aS)-l{[(R，R)-2_苯基環丙基]羰基}-2-[(噻唑烷-3-基）羰基]八氫-1H-吲哚）、SL 251188、EUK 189、R 1450、 6,6-二甲基-3-(2-羥基乙基)硫基-1-(噻唑-2-基)-6,7-二氫-2-b 苯并噻吩-4(5H)-酮、CERE 110、右依法克生、CAD 106、 HF 0220、HF 0420、EHT 0202、VP 025、MEM 1414、BGC 201259(即，Ν,Ν-二曱基氨基甲酸、4-[l(S)-(甲基胺基)-3-(4-硝基苯氧基）丙基]苯基酯）、EN 100、ABT 834、ABT239(例如，4-[2-[2-[(2R)-2-曱基吼咯啶基]乙基]-苯并呋喃_5_基]苯曱腈）、SGS 518、R 1500、C 9138、SSR 180711、阿法拉二醇、R 1577、T 817MA(即，1·[3-[2-(1-苯并噻吩-5-基）乙氧基]丙基]四氫吖唉-3-醇馬來酸酯）、CNP 1061(即，4-甲基 -5-(2_硝氧基乙基)噻唑）、KTX 0101(即，β-羥基丁酸鈉）、 GSK 189254(即，6-[3-環丁基-2,3,4,5-四氫-1沁苯并[(1]吖呼 -7-基氧]-N_ 甲基菸鹼醯胺）、AZD 1080、ACC 001、PRX 07034、咪達唑侖、R-苯基絲胺酸、AZD 103(CAS編號 488-59-5)、SN 522、NGX 267(CAS 編號 503431-81-0)、 N-PEP-12、RN 1219、FGLL、AVE 8112、EVT 101、NP 79 201031662 031112、ΜΚ 0752、ΜΚ 0952、LX 6m、PAZ 417、AV 965、 PF 3084014、SYN 114、GSI 953、SAM 315、SAM 531、 D-絲胺酸、來普立寧鉀、BR 16A(CAS編號149175-77-9)、 RPR 107393(CAS 編號 190841-57-7)、NXD 2858、REN 1654、CDD 0102、NC 1900(CAS編號 132925-74-7)、環孢素、 NCX 2216(即，（E)-4-(硝氧基）丁基3-[4-[2-(2-氟聯苯-4-基）丙醯氧基]-3-甲氧基苯基]丙稀酸醋）、NXD 3109、NXD 1191、ZSET 845(即，3,3-二苯基咪唑基[1，2-&]吡啶-2-(31·!)-酮）、ET 002、NT 13、RO 638695(即，[1，6-(1，6-二氧己基)] 二0比洛院-(2R)-羧酸）、必諾辛絲胺酸、BA 1016、XD 4241、 EUK 207(即 ’（SP-5-13)-(乙醯基-κΟ)[13，16，19,22-四氧雜 -3,6-二氮雜三環[21.3.18，12]二十八碳 -1(27),2,6,8,10,12(28),23,25-八稀-27,28-二醇 (2-)-κN3，κN6，κ027,κ028]猛）、LG617抑制劑、zsET 1446、 PAN 811、F 14413(即，2_[5_ 氟-2(S)-甲氧基 _2,3_ 二氫 _M_ 苯并二崎 °井-2-基]-4,5-二氫-1H-咪嗤）、FP 7832(即，Ν-[2-(5· 甲氧基-1-亞硝基-1Η-吲嵘-3-基）乙基]乙醯胺）、ara 014418(即，N-(4-甲氧基苯甲基)-N’-(5-硝基嗟嗤_2_基) 尿素）、AZD 3102、KP 544(即’ 2-胺基_5_(4_氣苯基乙炔基）-4-(4-反-經基環己基胺基）嘴咬）、dp 155 5-氣 -N-[3-[2-(二甲基胺基）乙基]-1H-吲哚·5_基]萘_2_磺醯胺、 ΤΑΚ 〇7〇、石杉驗、N-[2_(3,5_二曱基金剛炫]基）乙基]乙肺氫氣酸鹽、6-[4-[(二甲基胺基）甲基]_5-乙基_2_曱氧基苯基]>>比咬-2-胺、4,6-二苯基^-…(鳴嘴^-基丨派咬+基^荅 80 201031662 口井、N-[(lS，2R)-3-(3,5-二氟苯基)·1·經基_i_[(5S,6R)-5-曱基 -6-(新戊氧基）嗎啉-3-基]丙-2-基]乙醯胺氫氣酸鹽、 N-[(lR，2S)-3-(3,5-二氟苯基)-1-羥基_i_[(2R，4R)-4-苯氧基 °比0各烧-2-基]丙-2-基]-3-[(R)-2-(甲氧基曱基比咯烧-1-幾基]-5-甲基苯甲醯胺、R 1589、米達福泰、苯基絲胺酸、考拉西坦、毒扁豆鹼、西普拉利沙、硝基氟比洛芬、PPI 1019(即，（3α, 5β，7α, 12α)-三羥基膽-24-醯基-L-亮胺醯基 -L-網氨酿基-L-苯基丙氨醯基-L-苯基丙氨酿基-L-丙胺酸）、氨苯砜、MDL100453(CAS編號 129938-34-7)、NS 377、米達茶鹼、丙泊酚磷酸鹽、美曲磷酯、西羅普利、替尼西坦、噻噁畊、司格列肽、依比拉肽、奈拉西坦、米拉醋胺、碘阿霉素、SM 10888(CAS編號 129297-21-8)、U 80816(CAS 編號 138554-11-7)、YM 954(CAS編號 132041-85-1)、SUT 8701(CAS編號 123577-73-1)、阿搏長香胺、FR 121196(CAS 編號 133920-65-7)、LY 274614(CAS編號 136109-04-1)、CL 275838(CAS編號 115931-65-2)、伊格美新、K 7259(CAS編號133667-88-6)、長香考酯、伊地司瓊、CL 287663(CAS編號 125109-98-0)、WAY 100289 (CAS編號 136013-69-9)、SR 46559A(CAS 編號 137733-33-6)、GYKI 46903(CAS 編號 142999-59-5) ' L 670548(CAS 編號 121564-89-4)、Y 29794(CAS 編號 129184-48-1) 、AF125(CAS 編號 7631-86-9)、KFM 19(CAS編號 133058-72-7)、ST 796(即， (S)-3-[3-(三氟甲基）苯甲醯基]胺基）六氫吖呼-2-酮）、RU 33965(CAS編號 122321-05-5)、SDZ 210086(即，㈠-l’，2(S)· 81 201031662 二甲基螺旋[1，3-二噁烷-4,4'-哌啶])、L 689660(CAS編號 144860-79-7)、L 689560(CAS 編號 139051_78-8)、ST 618(即，l-(6,7-二甲氧基-1，2,3,4-四氫-2-萘基)-4-羥基吡咯烷-2-酮）、U 74500A(CAS編號 110101-65-0)、GEA 857(CAS 編號 120493-42-7)、BIBN 99(CAS編號 145301-48-0)、DX 9366、ONO1603(CAS編號 114668-76-7)、MDL102234(CAS 編號 137766-81-5)、P 9939(CAS 編號 157971-37-4)、PD 140532(CAS編號 157971-39-6)、氮替瑞林、MR 16728(CAS 編號 147614-21-9)、達貝洛汀、MDL 102503(即，8-[l(R)-甲基-2_苯基乙基]-1，3-二丙基-7H-黃嘌呤）、PD 141606(即， (±)-(2)-3-(3-苯基-2-丙炔氧基亞胺基)-1-氮雜二環[2.2.1]庚烷）、SNK 882(CAS編號 152221-12-0)、L 696986(CAS編號 141553-45-9)、他唑美林、LY 235959(CAS 編號 137433-06-8)、2-(2-噻噁吡咯烷-1-基）乙醯胺、AK 30 NGF、 ABT 418(CAS編號 147402-53-7)、依他美林、HUP 13、西波吡啶、KST 5452(CAS 編號 157998-88-4)、TJ 54、U 92798(即，7-[4-[雙(4-氟苯基）甲基]全氫-1,4-二吖呼-1-基甲基]-4-異丙基-2-曱氧基-2,4,6-環庚三烯-1-酮）、U 92032(CAS編號 142223-92-5)、3-(氨磺醯氧基)雌-1,3,5(10)-三烯-17-酮、P 11012(CAS編號 164723-36-8)、A 82695(CAS 編號 147388-86-1)、FR 76659(CAS編號 116904-25-7)、阿帕茶鹼、CX 417、7 MEOTA(CAS 編號 5778-80-3)、BU 4514N(CAS編號151013-39-7)、孕烯醇酮、美希醇、ST 857(CAS 編號 154755-63-2)、RU 49041(CAS 編號 201031662 123828-80-8)、RU 35929(CAS編號111711-47-8)、P 878184、 P 128(CAS編號157716-52-4)、優他汀A、優他汀B、LK 12、 NBI 108、NBI 107、NBI 117、L 705106、白花豬母菜武a+B、黃皮醯胺、SM 21(CAS編號155156-22-2)、阿拉泰、rs 17017(即，1-(4-胺基-5-氣-2-曱氧基苯基)-5-(1-哌啶基)-1-戊酮氫氯酸鹽）、AF 150(S)(即，（S)-[l-曱基底咬-4-螺旋-(2·-甲基噻唑烷）])、RO 153505(CAS 編號 78771-13-8)、PV 113(即，1，2,3,4-四氫吡咯-[1,2-a]-吡畊）、阿利蘇加辛、A 98284(即，2(R)-(3-甲基噁唑-5-基)奎寧環）、AP5(CAS編號 136941-85-0)、BD 1054、SDZNDD 094(即，雙-(2-(2-甲基咪唑-1-基）甲基)-吡啶-三（氫-福馬酸酯）、AZ 36041(CAS編號173324-76-0)、奎洛斯的明、A 84543(即，3-[1-甲基吡咯烷-2-(S)-基甲氧基]吡啶福馬酸酯）、BTG 4247(即，（2-[2-氣乙氧基[4-(二曱基胺基）苯基]磷醯基]-乙醯肼）、CGP 50068(CAS編號158647-49-5)、西拉布洛、載斯非利-諾丹噁明、異地衣多糖、MHP 133(即，3-(N，N-二甲基胺甲醯基氧）-1-甲基-2-(4-苯基-半卡腙基甲基）°比啶氣化物）、FR 152558(CAS 編號 151098-08-7)、GVS 111(CAS 編號 157115-85-0)、P 11149(CAS 編號 164724-79-2)、PDC 008004、KST 2818(CAS編號 158623-26-8)、KST 5410(CAS 編號 158623-27-9)、RU 52583(CAS編號 123829-33-4)、PD 151832(CAS編號 149929-39-5)、UCL 1199(即，4-[2-[(5-硝基吡啶-2-基硫烷基）乙基]-1H-咪唑]、異香蘭石杉鹼A、SIB 1765F(CAS 編號 179120-52-6)、JWS USC 751X(即’ 83 201031662 3-[[[2-[[(5-二甲基胺基乙基)-2-呋喃基]甲基]硫基]乙基]胺基]-4-硝基吡啶畊）、GR 175737(即，3-(4-氣苯甲基)-5-[2-(111-咪唑-4_基）乙基]-1,2,4-噁二唑）、〖8 505八(匚入8 編號131774-53-3)、ZTTA 1(即，N-苯甲氧基羰基-硫丙基-硫丙炔醛-二曱基縮醛）、AGN 190837(CAS編號 136527-40-7)、P 10358(188240-59-7)、WAY 131256(CAS編號 174001-71-9)、DBO 83(即，3-(6-氯吡畊-3-基)-二氮雜二環[3.2.1]辛烷二氫氣酸鹽單水合物）、FUB 181(CAS編號 152029-80-6)、RJR 2557、WSU 2088、LVV-血嗎啡樣肽-7、 Μ 40(即，甘丙肽[l-12]-Pro3-(Ala-Leu)2-Ala-NH2)、SIB 1757、SKF 74652(即，[5-氣-2-(4-甲氧基苯基)-3-苯并呋喃基][4-[3-(二曱基胺基)-丙氧基]苯基]甲酮）、CGP 71982、 SCH 57790(即，4·環己基-α-[4·[[4-甲氧基苯基]亞磺醯基] 苯基]-1-哌讲乙腈）、腐胺-D-YiAbetaU、DU 14(即，對-0-(氨磺醯基)-N-十四碳醯基酪胺）、CLZ 4、SL 340026、PPRT 424、西普若西芬、UR 1827(即，2-(1-苯曱基哌啶-4_ 基)_1_[4-(5-甲基嘧啶-4-基胺基）苯基]-1-乙酮）、開普若胺、 TGS 20(即，L-焦谷胺醯-D-丙胺酸醯胺）、PG 9(即，a-托烷基2-[(4-溴）苯基]丙酸酯）、TEI 3356(即，（16S)-15-去氧-16-羥基-16-甲基-9-(0)-亞甲基-DELTA6(9o〇-***素II)、LY 392098(即，噻吩，3-[(2-曱基乙基-2)磺醯基胺基丙基-2]苯基-4-基-)、PG 1000、DM 232、NEPP 11(即，12-異-15-去氧 -18·(4_甲基）苯基-13,14-二氫-δ7-***素A1甲基酯）、VA 100(即’（2,3-二氫-2-[[(4-氟苯甲醯基)胺基]乙基]-1-曱基-5- 201031662 苯基-1H-1，4-苯并二吖呼）、VA 101(即，（2,3-二氫-2-[[(2-嗟吩基羰基）胺基]乙基]-1-甲基-5-苯基-1H-1，4-苯并二„丫呼）、NC 111585(即，（3S)-1，3-雙-[3-[(3-氮雜二環[2.2.2]辛基）-1,2,5-°塞二嗤-4-基氧]-1-丙块-1-基]苯，2L-(+)-酒石酸酯）、IN 201、依莫普若辛芬、卡諾可二醇、胡黃連苷〗，胡黃連苷II、DM 235(即，1-(4-苯甲醯基哌畊_1_基）丙小酮）、單株抗體 10D5、JLK2、JLK 6、JLK 7、DAPT(即，N-[N-(3,5- -—氣苯乙酿基)-L-丙氨酿基]-S-苯基甘胺酸第三丁基醋）、石松生物鹼X、SGS 111(即，（S)-乙基2-[1-(2-苯基乙醯基)吡洛烷-2-曱醯胺基]乙酸酯）、NP 7557、C 9136、C 7617、R 1485、羅非可西保、維吖啶、孟替瑞林、拉扎貝胺、〇RG 2766(CAS 編號50913-82-1)、沙貝魯唑、金剛芬酯、CAS編號 9061-61-4、伊匹達克林、貝美司瓊、咪唑克生、毒扁蟲素、塞福太、舒立托唑、米拉美林、咕諾美林、TJ 960、法索西坦、依斯的明、恩沙素林、扎那派齊、泊替瑞林、扎考必利、RS 86(CAS編號3576-73-6)、ORG 5667(CAS編號 37552-33-3) 、RX 77368(CAS 編號 76820-40-1)、 BMS181168(CAS 編號 123259-91-6)、BY 1949(CAS 編號 90158-59-1)、AWD 5239(CAS 編號 109002-93-9)、YM 796(171252-79-2)、阿洛西坦、Cl 933(CAS 編號 91829-95-7)、ST 793(CAS編號99306-37-3)、西巴西坦、齊羅矽酮、他沙利定、阿伐美林、ΠΤ 2942(148152-77-6) ' OPC 14117(CAS編號 103233-65-4)、依齊維林、AP 521(即， N-(l，3-苯并二唑-5-基甲基）-1，2,3,4-四氫[1]苯并噻吩基 85 201031662EM 1421 (for example, 4,4'-[(2R,3S)-2,3-didecylbutane-1,4-diyl]bis(1,2-dimethoxybenzene), SRN 001, TTP 488, PRX 03140, Dimethoate, Glycine-Proline-Litrate, C105, AL 208, MEM 3454, AC 1202, L 830982, LY 451395 (ie '(R)-N-[2 -[4'_(methylsulfonylaminomethyl)biphenyl-4-yl]propyl]propane-2-sulfonamide), MK 0249, LY2062430, diethylnorseridine, nibamine , S 18986, SA 4503 (CAS No. 165377-44-6), GRI 1, S 17092 (ie, (2S, 3aS, 7aS)-l{[(R,R)-2-phenylcyclopropyl]carbonyl }-2-[(thiazolidine-3-yl)carbonyl]octahydro-1H-indole), SL 251188, EUK 189, R 1450, 6,6-dimethyl-3-(2-hydroxyethyl) Thio-1-(thiazol-2-yl)-6,7-dihydro-2-b benzothiophene-4(5H)-one, CERE 110, right gram, CAD 106, HF 0220, HF 0420 , EHT 0202, VP 025, MEM 1414, BGC 201259 (ie, Ν, Ν-dimercaptocarbamic acid, 4-[l(S)-(methylamino)-3-(4-nitrophenoxy) )propyl]phenyl ester), EN 100, ABT 834, ABT239 (for example, 4-[2-[2-[(2R)-2-mercapto pyridinyl]ethyl]-benzofuran_5 Benzyl Nitrile), SGS 518, R 1500, C 9138, SSR 180711, alfadiol, R 1577, T 817MA (ie, 1·[3-[2-(1-benzothiophen-5-yl)ethoxy) ]propyl]tetrahydroindol-3-ol maleate), CNP 1061 (ie, 4-methyl-5-(2-nitroethyl)thiazole), KTX 0101 (ie, β-hydroxyl) Sodium butyrate), GSK 189254 (ie, 6-[3-cyclobutyl-2,3,4,5-tetrahydro-1 benzo[[1] 吖h-7-yloxy]-N-methyl Nicotinamide, AZD 1080, ACC 001, PRX 07034, Midazolam, R-phenylserine, AZD 103 (CAS No. 488-59-5), SN 522, NGX 267 (CAS No. 503431- 81-0), N-PEP-12, RN 1219, FGLL, AVE 8112, EVT 101, NP 79 201031662 031112, ΜΚ 0752, ΜΚ 0952, LX 6m, PAZ 417, AV 965, PF 3084014, SYN 114, GSI 953 , SAM 315, SAM 531, D-serine, lycopene potassium, BR 16A (CAS number 149175-77-9), RPR 107393 (CAS number 190841-57-7), NXD 2858, REN 1654, CDD 0102, NC 1900 (CAS number 132925-74-7), cyclosporine, NCX 2216 (ie, (E)-4-(nitrooxy)butyl 3-[4-[2-(2-fluorobiphenyl) -4-yl)propenyloxy]-3-methoxyphenyl]propionic acid Vinegar), NXD 3109, NXD 1191, ZSET 845 (ie, 3,3-diphenylimidazolyl [1,2-&]pyridin-2-(31·!)-one), ET 002, NT 13, RO 638695 (ie, [1,6-(1,6-dioxohexyl)] dioxinol-(2R)-carboxylic acid), binooctosine, BA 1016, XD 4241, EUK 207 ( Namely '(SP-5-13)-(ethenyl-κΟ)[13,16,19,22-tetraoxa-3,6-diazatricyclo[21.31,12]28-carbon -1(27),2,6,8,10,12(28),23,25-octa--27,28-diol (2-)-κN3, κN6, κ027, κ028] )), LG617 inhibition Agent, zsET 1446, PAN 811, F 14413 (ie, 2_[5_fluoro-2(S)-methoxy-2,3_dihydro_M_benzodiazepine-2-yl]-4,5- Dihydro-1H-imidazole), FP 7832 (ie, Ν-[2-(5·methoxy-1-nitroso-1Η-indol-3-yl)ethyl]acetamidamine), ara 014418 (ie, N-(4-methoxybenzyl)-N'-(5-nitroindole-2-yl)urea), AZD 3102, KP 544 (ie '2-amino group_5_( 4_gasphenylethynyl)-4-(4-trans-ylcyclohexylamino) mouth bit), dp 155 5-gas-N-[3-[2-(dimethylamino)ethyl ]-1H-吲哚·5_yl]naphthalene_2_sulfonamide, ΤΑΚ 〇7〇, cedar test, N-[2_(3,5_two曱刚 ] ] 基 ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) Bite-2-amine, 4,6-diphenyl^-... (sniffing mouth ^-based 丨丨 + + base ^ 荅 80 201031662 Well, N-[(lS,2R)-3-(3,5- Difluorophenyl)·1·transcarbyl_i_[(5S,6R)-5-mercapto-6-(neopentyloxy)morpholin-3-yl]propan-2-yl]acetamide hydrogen acid Salt, N-[(lR,2S)-3-(3,5-difluorophenyl)-1-hydroxy-i_[(2R,4R)-4-phenoxy ° ° 0 each pyridin-2-yl ]prop-2-yl]-3-[(R)-2-(methoxyindolylpyrrol-1-yl)-5-methylbenzamide, R 1589, Midaforte, Phenyl serine, kuraracetam, physostigmine, sirpril, nitroflurbiprofen, PPI 1019 (ie, (3α, 5β, 7α, 12α)-trihydroxycholin-24-fluorenyl) -L-leucine thiol-L-methyl amide-L-phenylalaninyl-L-phenylalanine-based-L-alanine), dapsone, MDL100453 (CAS number 129938-34 -7), NS 377, micarine, propofol phosphate, melamine, cilostril, tenilacetam, thiophene, sigretin, ibirapeptide, nerazide Tan, Milaamine, Iodine, SM 10888 (CAS number 129297-21-8), U 80816 (CAS number 138554-11-7), YM 954 (CAS number 132041-85-1), SUT 8701 (CAS number 123577-73-1), A Bo long Amine, FR 121196 (CAS No. 133920-65-7), LY 274614 (CAS No. 136109-04-1), CL 275838 (CAS No. 115931-65-2), Igmeixin, K 7259 (CAS No. 133667 -88-6), long cocamdiester, idisetron, CL 287663 (CAS number 125109-98-0), WAY 100289 (CAS number 136013-69-9), SR 46559A (CAS number 137733-33-6 ), GYKI 46903 (CAS No. 142999-59-5) ' L 670548 (CAS No. 121564-89-4), Y 29794 (CAS No. 129184-48-1), AF125 (CAS No. 7631-86-9), KFM 19 (CAS No. 133058-72-7), ST 796 (ie, (S)-3-[3-(trifluoromethyl)benzylidene]amino)hexahydroindole-2-one), RU 33965 (CAS No. 122321-05-5), SDZ 210086 (ie, (a)-l', 2(S)· 81 201031662 dimethyl helix [1,3-dioxane-4,4'-piperidine]) , L 689660 (CAS No. 144860-79-7), L 689560 (CAS No. 139051_78-8), ST 618 (ie, l-(6,7-dimethoxy-1,2,3,4-tetrahydrogen) -2-naphthyl)-4-hydroxypyrrolidin-2-one), U 74500A (CAS series 110101-65-0), GEA 857 (CAS No. 120493-42-7), BIBN 99 (CAS No. 145301-48-0), DX 9366, ONO1603 (CAS No. 114668-76-7), MDL102234 (CAS No. 137766) -81-5), P 9939 (CAS No. 157971-37-4), PD 140532 (CAS No. 157971-39-6), Nitrorelin, MR 16728 (CAS No. 147614-21-9), Dabello T, MDL 102503 (ie, 8-[l(R)-methyl-2-phenylethyl]-1,3-dipropyl-7H-xanthine), PD 141606 (ie, (±)-( 2) -3-(3-phenyl-2-propynyloxyimido)-1-azabicyclo[2.2.1]heptane), SNK 882 (CAS No. 152221-12-0), L 696986 (CAS No. 141553-45-9), tazomelin, LY 235959 (CAS No. 137433-06-8), 2-(2-thiapyrrolidin-1-yl)acetamide, AK 30 NGF, ABT 418 (CAS No. 147402-53-7), Itamiline, HUP 13, West Peptide, KST 5452 (CAS No. 157998-88-4), TJ 54, U 92798 (ie, 7-[4-[ Bis(4-fluorophenyl)methyl]perhydro-1,4-dioxan-1-ylmethyl]-4-isopropyl-2-indolyl-2,4,6-cycloheptane En-1-one), U 92032 (CAS No. 142223-92-5), 3-(Aminosulfonyloxy)Estra-1,3,5(10)-trien-17-one, P 11012 (CAS Number 16 4723-36-8), A 82695 (CAS No. 147388-86-1), FR 76659 (CAS No. 116904-25-7), Apalapine, CX 417, 7 MEOTA (CAS No. 5778-80-3) , BU 4514N (CAS No. 151013-39-7), Pregnenolone, Mexican, ST 857 (CAS No. 154755-63-2), RU 49041 (CAS No. 201031662 123828-80-8), RU 35929 (CAS No. 111711-47-8), P 878184, P 128 (CAS No. 157716-52-4), statin A, statin B, LK 12, NBI 108, NBI 107, NBI 117, L 705106, white flower pig mother武a+B, lycopene, SM 21 (CAS No. 155156-22-2), Aratai, rs 17017 (ie, 1-(4-amino-5-a-2-nonyloxyphenyl) -5-(1-piperidinyl)-1-pentanone hydrochloride), AF 150(S) (ie, (S)-[l-曱 base bite-4-helix-(2·-methyl) Thiazolidine)]), RO 153505 (CAS No. 78871-13-8), PV 113 (ie, 1,2,3,4-tetrahydropyrrole-[1,2-a]-pyrazine), Alisoga Xin, A 98284 (ie, 2(R)-(3-methyloxazol-5-yl)quinuclidine), AP5 (CAS number 136941-85-0), BD 1054, SDZNDD 094 (ie, double- (2-(2-Methylimidazol-1-yl)methyl)-pyridine-tris(hydro-fumarate), AZ 36041 (CAS number 173324- 76-0), Queirox, A 84543 (ie, 3-[1-methylpyrrolidin-2-(S)-ylmethoxy]pyridine fumarate), BTG 4247 (ie, (2- [2-Vethoxyethoxy[4-(didecylamino)phenyl]phosphonium]-acetamidine), CGP 50068 (CAS No. 158647-49-5), Syracuse, Nass Litho-Nandan, Erythramine, MHP 133 (ie, 3-(N,N-dimethylamine-mercapto-oxy)-1-methyl-2-(4-phenyl-semicarbyl) Methyl) ° pyridine vapor), FR 152558 (CAS number 151098-08-7), GVS 111 (CAS number 157115-85-0), P 11149 (CAS number 164724-79-2), PDC 008004, KST 2818 (CAS number 158623-26-8), KST 5410 (CAS number 158623-27-9), RU 52583 (CAS number 123829-33-4), PD 151832 (CAS number 149929-39-5), UCL 1199 ( Namely, 4-[2-[(5-nitropyridin-2-ylsulfanyl)ethyl]-1H-imidazole], isolaline sulphonin A, SIB 1765F (CAS No. 179120-52-6), JWS USC 751X (ie ' 83 201031662 3-[[[2-[[(5-dimethylaminoethyl)-2-furanyl]methyl]thio]ethyl]amino]]-4-nitro Pyridine cultivating), GR 175737 (ie, 3-(4-gasbenzyl)-5-[2-(111-imidazol-4-yl)ethyl]-1 , 2,4-oxadiazole), 8 505 8 (into 8 No. 131774-53-3), ZTTA 1 (ie, N-benzyloxycarbonyl-thiopropyl-thiopropyne aldehyde-dioxin Alkyl acetal), AGN 190837 (CAS number 136527-40-7), P 10358 (188240-59-7), WAY 131256 (CAS number 174001-71-9), DBO 83 (ie, 3-(6-chlorine) Pyridin-3-yl)-diazabicyclo[3.2.1]octane dihydrogenate monohydrate), FUB 181 (CAS number 152029-80-6), RJR 2557, WSU 2088, LVV-blood Morphine-like peptide-7, Μ40 (ie, galanin [l-12]-Pro3-(Ala-Leu)2-Ala-NH2), SIB 1757, SKF 74652 (ie, [5-gas-2-() 4-methoxyphenyl)-3-benzofuranyl][4-[3-(didecylamino)-propoxy]phenyl]methanone), CGP 71982, SCH 57790 (ie, 4 Cyclohexyl-α-[4·[[4-methoxyphenyl]sulfinyl]phenyl]-1-piperidinonitrile, putrescine-D-YiAbetaU, DU 14 (ie, pair-0 -(Aminosulfonyl)-N-tetradecylmercaptoamine), CLZ 4, SL 340026, PPRT 424, Cyproxen, UR 1827 (ie, 2-(1-benzoylpiperidine)- 4_yl)_1_[4-(5-methylpyrimidin-4-ylamino)phenyl]-1-ethanone), caprocycline, TGS 20 (ie, L-pyroglutamine-D-propylamine Acid amide PG 9 (i.e., a- phenylalkyl 2-[(4-bromo)phenyl]propionate), TEI 3356 (ie, (16S)-15-deoxy-16-hydroxy-16-methyl- 9-(0)-methylene-DELTA6 (9o〇-prostaglandin II), LY 392098 (ie, thiophene, 3-[(2-mercaptoethyl-2)sulfonylaminopropyl-2] Phenyl-4-yl-), PG 1000, DM 232, NEPP 11 (ie, 12-iso-15-deoxy-18·(4-methyl)phenyl-13,14-dihydro-δ7-prostate A1 methyl ester), VA 100 (ie '(2,3-dihydro-2-[[(4-fluorobenzylidyl)amino]ethyl]-1-indolyl-5- 201031662 phenyl -1H-1,4-benzodioxan), VA 101 (ie, (2,3-dihydro-2-[[(2-nonylphenyl))amino]ethyl]-1-methyl) -5-phenyl-1H-1,4-benzodioxole, NC 111585 (ie, (3S)-1,3-bis-[3-[(3-azabicyclo[2.2.2] ] octyl)-1,2,5-°-dioxa-4-yloxy]-1-propan-1-yl]benzene, 2L-(+)-tartrate), IN 201, emopro Xinfen, canodiol, berberine, ruthenium II, DM 235 (ie, 1-(4-benzhydrylpiperidine _1-yl) propyl ketone), monoclonal antibody 10D5, JLK2, JLK 6, JLK 7, DAPT (ie, N-[N-(3,5---gas phenylethyl)-L-alanine ]]-S-phenylglycine tributyl vinegar), stone pine alkaloid X, SGS 111 (ie, (S)-ethyl 2-[1-(2-phenylethenyl)pyrrolidine -2-decylamino]acetate), NP 7557, C 9136, C 7617, R 1485, Rofecoxicil, Vegidine, Montesporin, Lazarbeline, 〇RG 2766 (CAS No. 50913-82-1), Sabeluazole, Donkeygyl Ester, CAS No. 9061-61-4, Ipdaline, Bemistron, Imidazoxan, Phytophthora, Sephora, Shu Litazole, milamerin, 咕诺美林, TJ 960, fasocitam, Issamine, Ensasurin, Zanapazi, Bertirin, Zaloparide, RS 86 (CAS No. 3576-73-6), ORG 5667 (CAS No. 37552-33-3), RX 77368 (CAS No. 76820-40-1), BMS181168 (CAS No. 123259-91-6), BY 1949 (CAS No. 90158- 59-1), AWD 5239 (CAS No. 109002-93-9), YM 796 (171252-79-2), azlocamtam, Cl 933 (CAS No. 91829-95-7), ST 793 (CAS No. 99306 -37-3), Sibattam, Zilon, Thaliride, Avalelin, ΠΤ 2942 (148152-77-6) 'OPC 14117 (CAS No. 103233-65-4), Izuvirin, AP 521 (ie, N-(l,3-benzobisazol-5-ylmethyl)-1,2,3,4-tetrahydro[1]benzothiophene 85 201031662

[2,3-c]"比咬-3(R)-曱醯胺氫氣酸鹽）、S 8510(CAS編號 151466-23-8)、JTP4819(CAS編號 162203-65-8)、艾考派齊、 SC 110、FK 960(CAS編號 133920-70-4)、DMP 543(CAS編號 160588-45-4)、更斯的明、Cl 1017(即，（R)-(-)-(Z)-l-氮雜二環[2.2.1]庚-3-酮、0-(3-(3·-甲氧基苯基)-2-丙醯基)-肟馬來酸醋）、T 82(即’ 2-[2-(1-本甲基0辰〇定-4-基）乙基]-2,3-二氫-9-曱氧基-1H-吡咯并[3,4-b]喹啉-1-酮半福馬酸酯）、 NGD 971、天冬胺醯基-丙氨醯基-麩胺醯基-苯基丙氨醯基-精胺醯基-組胺醯基-天冬胺醯基-絲氨醯基-甘胺醯基-酪胺醯基-麩胺醯基-纈氨醯基-組胺醯基-組胺醯基-麩醯胺醯基 -離胺醯基-白胺醯基-绳氨醯基-苯基丙氨醯基-苯基丙氨酿基-丙氨醯基-麩胺醯基-天冬胺醯基-纈氨醯基-甘胺醯基-絲氨醯基-天冬門醯基-離胺醯基-甘胺醯基-丙氨醯基-異白氨醯基-異白氨醯基-甘胺醯基-白胺醯基-甲醯胺醯基-纈氨醯基-甘胺酿基-甘胺酿基_缔氨酿基-绳氨酿基-異白氨酿基-丙胺酸之疫苗、PBT 1(CAS編號 130-26-7)、TCH 346、FK 962(例如，N-(l-乙醯基哌啶基-4-基)-4-氟苯曱醯胺）、伏高利特、KW 6055(CAS編號63233-46-5)、塞匹魯卡品、ZK 93426(CAS 編號 89592-45-0)、SDZ NVI 085(CAS 編號 104195-17-7)、Cl 1002(CAS編號 149028-28-4)、Z 321(CAS 編號130849-58-0)、米立斯瓊、CHF 2060(即，N-庚基氨基甲酸2,4&,9-三甲基-2,3,4,4纹，9,9&-六氫-1,2-噁讲基[6,5-1)]吲嵘-6-基酯-L-酒石酸酯）、吉多卡爾、特貝喹尼、HOE 065(CAS編號 123060-44-6)、SL 650102、GR 253035、ALE 201031662[2,3-c]"Bite-3(R)-guanamine hydrochloride), S 8510 (CAS number 151466-23-8), JTP4819 (CAS number 162203-65-8), Eco Paiqi, SC 110, FK 960 (CAS No. 133920-70-4), DMP 543 (CAS No. 160588-45-4), Gentino, Cl 1017 (ie, (R)-(-)-(Z )-l-azabicyclo[2.2.1]heptan-3-one, 0-(3-(3·-methoxyphenyl)-2-propenyl)-indole maleic acid vinegar, T 82 (ie '2-[2-(1-Benzyl0-chenidine-4-yl)ethyl]-2,3-dihydro-9-decyloxy-1H-pyrrolo[3,4- b]quinolin-1-one semi-fumarate), NGD 971, aspartame-alanine- glutamine-phenylalanine-spermine-mercapto-histamine-based Aspartame-serine-glycidyl-tyramine-glycosyl-amino-mercapto-histamine-histamine-bromide-mercapto-aminoamine Alkyl-alkamine-ylamino-phenylalaninyl-phenylalaninyl-phenylalanine-alkine-alanine-aspartate-aspartate-ammonium-glycine --Les-ammonyl-aspartate-iso-amidino-glycinyl-alanine-iso-ammonium-iso-ammonium-glycinyl-alkamine-based Methionamine-ammonium Glyceryl-glycine-glycine-based aryl-branched-branched-branched-alkaline-alanine-based vaccine, PBT 1 (CAS No. 130-26-7), TCH 346, FK 962 (eg, N-(l-ethylidenepiperidinyl-4-yl)-4-fluorobenzoguanamine), voltahydrate, KW 6055 (CAS number 63233-46-5), spirulina , ZK 93426 (CAS No. 89592-45-0), SDZ NVI 085 (CAS No. 104195-17-7), Cl 1002 (CAS No. 149028-28-4), Z 321 (CAS No. 130849-58-0), Millis Joan, CHF 2060 (ie, N-heptylcarbamic acid 2,4&,9-trimethyl-2,3,4,4,9,9&-hexahydro-1,2- evil [6,5-1)]non-6-yl ester-L-tartaric acid ester), Gigacol, Tebequine, HOE 065 (CAS No. 123060-44-6), SL 650102, GR 253035, ALE 201031662

26015、SB 271046(即，5-氣-N-(4-甲氧基-3-哌畊-1-基-苯基)_3_甲基-2-苯并噻吩磺醯胺）、iAbeta5、SCH 211803(即，哌啶，1-[1-(3-曱基-2-胺基苯基）羰基哌啶-4-基]-4-[(3-氣苯基)磺醯基苯基-4]甲基-)、EVT 301、α-亞麻酸/亞麻油酸、 Kamikihi-To、西高苷、FG 7142(CAS編號78538-74-6)、RU 47067(CAS 編號 111711-92-3)、RU 35963(CAS 編號 139886-03-6)、FG 7080(CAS編號 100332-18-1)、E 2030(CAS 編號 142007-70-3)、變形成長因子β-l、A 72055(即，2·，1-二甲基螺旋[哌啶-4,5'噁唑烷]-3'-曱醛）、NS 626、地來西坦、GT 3001、GT 2501、GT 2342、GT 2016(CAS編號 152241-24-2)、ORG 20091(CAS 編號 141545-50-8)、BCE 001(CAS 編號 95678-81-2)、CGP 35348(CAS 編號 123690-79-9)、WAY 100635(CAS 編號 146714-97-8)、E 4804(CAS 編號 162559-34-4)、LIGA 20(CAS 編號 126586-85-4)、NG 121(即，2-[4,8-二甲基-3(E)，7(E)-單二烯基]-3,5-二羥基-2-甲基-3,4,7,9-四氫-2H-氟[3,4-h]-l-苯并呱喃-7-酮）、MF 247(即，N-[10-(二乙基胺基)癸基]氨基甲酸 (3aS，8aR)-l，3a，8-三甲基-1，2,3,3&，8,8&-六氫吡咯基[2,3-13]吲哚-5-基酯）、JTP 3399(即，N-苯甲基-2(S)_[2(S)-(苯氧基乙醯基)吡咯烷-1-基羰基]吡咯烷-1-甲醯胺）、KF 17329、硫丙咪胺、F 3796(即，1-[2-(1-苯曱基哌啶-4-基）乙基]-3-[3,4-(甲撐基-二氧）苯甲醢基]硫脲）、GT 4001、GT 4002、FPL 14995(CAS 編號 123319-03-9)、RU 34332(CAS 編號 137157-58-5)、SR 96777A(CAS 編號 115767-94-7)、SIB 87 201031662 T1980、NS 649(CAS編號 146828-02-6)、PD 142505(CAS編號 149929-08-8)、GYKI 52466(CAS編號 102771-26-6)、RO 246173(CAS 編號 159723-57-6)、SCH 50911(CAS 編號 160415-07-6)、Z 4105(CAS 編號 119737-52-9)、RS 67333(CAS編號 168986-60-5)、NS 1546、ZM 241385(CAS 編號 139180-30-6)、RO 249975(即，[18,38(2,8)，5尺]_3_(1-苯甲基-5-氧基吡咯烷-2-基甲基）-5-(lH-咪唑-5-基甲基）環己烷-1-乙醯胺）、AF 185(即，8-曱基-3-(2-丙炔基)-1,3,8-三氮雜螺旋[4,5]癸烷-2,4-二酮）、CEP 427、CX 423、CX 438、 CX 480、CDP-乙醇胺 ' GT4003、GT40H、GT501 卜 MS 430(CAS編號 122113-44-4)、MBF 379(即，[3,3-雙（羥基甲基）-8-羥基-3,4-二氫-2H-1,4-苯噁畊-5-基][3，,5'-二羥基 _4’·(2-側氧基-2-苯基乙氧基）苯基]甲酮）、NGD 187(CAS編號 163565-48-8)、DUP 856、MR 3066、MF 8615(即，5-胺基-6-氯-4-羥基-3,4-二氫-1H-噻呱喃基-[3,4-b]喹啉酮）、喜巴辛、ABS 300、RJR 2403(CAS編號538-79-4)、MF 268(CAS 編號 174721-00-7)、RO 465934(即，N，N-二曱基氨基曱酸 3-(2-環己基)-2,3,33,4,5,91>六氫-11^苯并|>]吲哚-6-基酯）、 NS 393、RGH 2716(CAS 編號 134069-68-4)、WW 678702(12,12-雙(3-呋喃基)-6,11-二氫-6，11-乙醇苯并[b]喹畊氣）、RS 66252(即，1-丁基-2-[(2，-(2H-四唑-5-基)-聯苯-4-基）甲基]-1H-吲哚-3-羧酸）、AIT 034(CAS編號 138117-48-3)、NG 012(CAS 編號 131774-53-3)、PD 142012(CAS編號5778-84-7)、GT 4054、GT 4077、GT 4035、 201031662 P 26(CAS 編號 152191-74-7) 、RGH 5279(即， (-)-(13aR，13bS)-13a-乙基-2,3,5,6，13a，13b-六氫-1H-吲哚基 [3,2，1-去]吡啶基[3,2，l-ij][l，5]萘啶-12-羧酸2-乙醯氧基乙基酯）、AIT 083、CeNeS、***（即，1,3,5(10)-雌三烯-3，17β-二醇）、WAY132983((3R，4R)-3-(3-六硫烷基吡讲-2-基氧)-l-氮雜二環[2.2.1]庚烷氯氫酸鹽）、ABS 205、ABS 401、SX 3507(即 ’ 3-(3-丙基_1,2,4_噁二唑-5-糧）喹噁啉-2(1H)-酮）、 ARR 17779(即，（-)-螺旋[1-氮雜二環[2.2.2]辛烯-3,5-噁唑烷]酮）、XE "1(即，1〇,1〇_雙(4-吼咬基甲基）蒽·1〇(9Η)-酮）、苯乙基諾西斯林、RO 657199、RJR 1781(即，R(+)-2-(3-吡啶基)-1-氮雜二環[2.2.2.]辛烷）、RJR 1782(即，S(-)-2-(3-吡啶基)-1-氮雜二環[2.2.2·]辛烷）、吉拉替、托西林、TC 2559(即，（E)-N-甲基·4-[3-(5-乙氧基吡啶）基]-3-丁烯-1-胺）、ER 127528(即，1-(3-氟苯甲基)-4-[(2-氟-5,6·二甲氧基 -1-節酿1-2-基）甲基]旅β定氫氯酸鹽）、IF塞托西林、塔加西、阿克斯尼、辛西林、噻辛西林、單株抗體266、Apan-CH、DP 103、SPI 339(即，4-[3-(4-側氧基·4,5,6,7-四氫吲哚-1-基）丙醯基胺基]苯甲酸乙基酯）、S 37245(即，4-(1,4-苯并二噁烷 -5-基)-l-[3(S)-羥基-5-硝基-吲滿-2-基]-哌畊）、LLG 88、AZD 2858、緩血酸胺、AN 240、NG 002(即，5-羥基-5-(2-羥基 -1-甲基乙基)-4-甲氧基呋喃-2(5H)-酮）、UCB 29427(即，2-環丙基-4-(環丙基胺基)-6-(嗎啉基)-1,3,5-三畊）、TRH-SR、 RO 401641(CAS編號 122199-02-4)、MPV 1743AIII(CAS編號 150586-64-4)、IDRA 21(CAS編號22503-72-6)、CEP 431、 89 201031662 ACPD(CAS 編號 67684-64-4)、CT 3577(即，3,7-二曱基 -1-[11-(3,4,5-三甲氧基苯甲基胺基)_11_氧基十一烷基]黃嘌呤）、CT 2583、NXD 9062、去鐵諾丹噁烷、DP b99、PBT 1、 T 817MA、阿法拉二醇（CAS編號57-91-0)、AL 108、SL 650102、RS 67333(CAS編號 168986-60-5)、RS 17017、SGS 518、SYN 114、SB 271046、R〇 657199、PRX 07034、舒立托唑（CAS編號110623-33-19)、特貝喹尼（CAS編號 113079-82-6)、FG 7142(CAS 編號 78538-74-6)、RU 34332(CAS編號 137157-58-5)、SX 3507、RO 153505(CAS 編號 78771-13-8)、RU 33965(CAS 編號 122321-05-5)、S 8510(CAS 編號 l5l466_23-8)、沙貝魯唑（CAS 編號 104383-17-7)、沙立布洛(CAS編號 118790-71-9)、NS 626、 NS 649(CAS 編號 146828-02-6)、U 92032(CAS 編號 142223-92-5)、MEM 1003、U 92798、RGH 2716(CAS編號 134069-68-4)、沙芬醯胺（CAS 編號 133865-89-1)、AZD 0328、MEM 63908、ABT 418(CAS編號 147402-53-7)、ARR 17779、RJR 2403(CAS 編號 538-79-4)、TC 2559、A 82695(CAS編號 147388-86-1)、A 84543、A 98284、DBO 83、 RJR 2557、SIB 1765F(CAS編號 179120-52-6)、GTS 21(CAS 編號 156223-05-1)、MEM 3454、SIB 1553A、EVP 6124、 SSR 180711、ABT 089(CAS編號 161417-03-4)、ABT 107、 ABT 560、TC 5619、TAK 070、N-[(lS，2R)-3-(3,5-二氟苯基>1-羥基-l-[(5S，6R)-5-甲基-6-(新戊氧基)嗎啉-3-基]丙-2-基]乙醯胺氫氣酸鹽、6·氟-5-(2-氟-5-甲基苯基)-3,4-二氫"比 201031662 啶、2-胺基-6-[2-(3’-甲氧基聯苯-3-基）乙基]-3,6-二甲基-5,6-26015, SB 271046 (ie, 5-gas-N-(4-methoxy-3-pipedino-1-yl-phenyl)_3_methyl-2-benzothiophenesulfonamide), iAbeta5, SCH 211803 (ie, piperidine, 1-[1-(3-indolyl-2-aminophenyl)carbonylpiperidin-4-yl]-4-[(3-phenylphenyl)sulfonylphenyl- 4] methyl-), EVT 301, α-linolenic acid/linolenic acid, Kamikihi-To, cisplatin, FG 7142 (CAS number 78538-74-6), RU 47067 (CAS number 111711-92-3), RU 35963 (CAS No. 139886-03-6), FG 7080 (CAS No. 100332-18-1), E 2030 (CAS No. 142007-70-3), deformation growth factor β-l, A 72055 (ie, 2· , 1-dimethyl helical [piperidine-4,5'oxazolidine]-3'-furfural), NS 626, diracetam, GT 3001, GT 2501, GT 2342, GT 2016 (CAS number 152241) -24-2), ORG 20091 (CAS No. 141545-50-8), BCE 001 (CAS No. 95678-81-2), CGP 35348 (CAS No. 123690-79-9), WAY 100635 (CAS No. 146714-97 -8), E 4804 (CAS No. 162559-34-4), LIGA 20 (CAS No. 126586-85-4), NG 121 (ie, 2-[4,8-dimethyl-3(E),7 (E)-monodienyl]-3,5-dihydroxy-2-methyl-3,4,7,9-tetrahydro-2H-fluoro[3,4-h]-l-benzopyran -7- ), MF 247 (ie, N-[10-(diethylamino)indolyl]carbamic acid (3aS,8aR)-l,3a,8-trimethyl-1,2,3,3&,8 , 8 &-hexahydropyrrolyl [2,3-13]non-5-yl ester), JTP 3399 (ie, N-benzyl-2(S)_[2(S)-(phenoxy) Ethyl)pyrrolidin-1-ylcarbonyl]pyrrolidine-1-carboxamide), KF 17329, thiomethamine, F 3796 (ie, 1-[2-(1-phenylhydrinopiperidin-4) -yl)ethyl]-3-[3,4-(methylene-dioxy)benzylidene]thiourea), GT 4001, GT 4002, FPL 14995 (CAS number 123319-03-9), RU 34332 (CAS No. 137157-58-5), SR 96777A (CAS No. 115767-94-7), SIB 87 201031662 T1980, NS 649 (CAS No. 146828-02-6), PD 142505 (CAS No. 149929-08-8) ), GYKI 52466 (CAS number 102771-26-6), RO 246173 (CAS number 159723-57-6), SCH 50911 (CAS number 160415-07-6), Z 4105 (CAS number 119737-52-9), RS 67333 (CAS No. 168986-60-5), NS 1546, ZM 241385 (CAS No. 139180-30-6), RO 249975 (ie, [18,38(2,8),5 ft]_3_(1-Benzene Methyl-5-oxypyrrolidin-2-ylmethyl)-5-(lH-imidazol-5-ylmethyl)cyclohexane-1-ethylamine), AF 185 (ie 8-mercapto-3-(2-propynyl)-1,3,8-triazadicyclo[4,5]nonane-2,4-dione), CEP 427, CX 423, CX 438, CX 480, CDP-ethanolamine 'GT4003, GT40H, GT501 Bu MS 430 (CAS No. 122113-44-4), MBF 379 (ie, [3,3-bis(hydroxymethyl)-8-hydroxy-3,4- Dihydro-2H-1,4-benzoin-5-yl][3,5'-dihydroxy-4'·(2-o-oxy-2-phenylethoxy)phenyl]methanone ), NGD 187 (CAS No. 163565-48-8), DUP 856, MR 3066, MF 8615 (ie, 5-amino-6-chloro-4-hydroxy-3,4-dihydro-1H-thiopyran) --[3,4-b]quinolinone), xibabin, ABS 300, RJR 2403 (CAS number 538-79-4), MF 268 (CAS number 174721-00-7), RO 465934 (ie, N,N-dimercaptoaminoamic acid 3-(2-cyclohexyl)-2,3,33,4,5,91>hexahydro-11^benzo|>]吲哚-6-yl ester) , NS 393, RGH 2716 (CAS No. 134069-68-4), WW 678702 (12,12-bis(3-furyl)-6,11-dihydro-6,11-ethanol benzo[b]quind Gas), RS 66252 (ie, 1-butyl-2-[(2,-(2H-tetrazol-5-yl)-biphenyl-4-yl)methyl]-1H-indole-3-carboxylate Acid), AIT 034 (CAS No. 138117-48-3), NG 012 (CAS No. 131774-53-3), PD 1420 12 (CAS No. 5778-84-7), GT 4054, GT 4077, GT 4035, 201031662 P 26 (CAS No. 152191-74-7), RGH 5279 (ie, (-)-(13aR, 13bS)-13a- Ethyl-2,3,5,6,13a,13b-hexahydro-1H-indolyl[3,2,1-de]pyridyl[3,2,l-ij][l,5]naphthyridine -12-carboxylic acid 2-acetoxyethyl ester), AIT 083, CeNeS, estradiol (ie, 1,3,5(10)-estratriene-3,17β-diol), WAY132983 ( (3R,4R)-3-(3-hexasulfanylpyran-2-yloxy)-l-azabicyclo[2.2.1]heptane hydrochloride), ABS 205, ABS 401, SX 3507 (ie ' 3-(3-propyl_1,2,4-oxadiazole-5-food) quinoxaline-2(1H)-one), ARR 17779 (ie, (-)-helix [1] -azabicyclo[2.2.2]octene-3,5-oxazolidine]one, XE "1 (ie, 1 〇, 1 〇 _ bis (4-吼基 methyl) 蒽 · 1 〇(9Η)-ketone), phenethylnosine, RO 657199, RJR 1781 (ie, R(+)-2-(3-pyridyl)-1-azabicyclo[2.2.2.]octane ), RJR 1782 (ie, S(-)-2-(3-pyridyl)-1-azabicyclo[2.2.2.]octane), Girardine, Tocillin, TC 2559 (ie, ( E)-N-methyl·4-[3-(5-ethoxypyridyl)]-3-buten-1-amine), ER 127528 (ie, 1- (3-Fluorobenzyl)-4-[(2-fluoro-5,6.dimethoxy-1-toluene 1-2-yl)methyl]Budget beta-hydrochloride), IF plug Tosicillin, taigaxi, axniline, xincillin, thicillin, monoclonal antibody 266, Apan-CH, DP 103, SPI 339 (ie, 4-[3-(4-lateral oxy-4,5) , 6,7-tetrahydroindol-1-yl)propanylamino]benzoic acid ethyl ester), S 37245 (ie, 4-(1,4-benzodioxan-5-yl)- L-[3(S)-hydroxy-5-nitro-indan-2-yl]-piped), LLG 88, AZD 2858, tromethamine, AN 240, NG 002 (ie, 5-hydroxy- 5-(2-hydroxy-1-methylethyl)-4-methoxyfuran-2(5H)-one), UCB 29427 (ie, 2-cyclopropyl-4-(cyclopropylamino) -6-(morpholinyl)-1,3,5-three tillage), TRH-SR, RO 401641 (CAS number 122199-02-4), MPV 1743AIII (CAS number 150586-64-4), IDRA 21 ( CAS No. 22503-72-6), CEP 431, 89 201031662 ACPD (CAS No. 67684-64-4), CT 3577 (ie, 3,7-dimercapto-1-[11-(3,4,5-) Trimethoxybenzylamino))11-oxyundecyl]xanthine), CT 2583, NXD 9062, desferrolane, DP b99, PBT 1, T 817MA, alfadiol (CAS) No. 57-91-0), AL 108, SL 650102, RS 67333 (CAS number 168986-60-5), RS 17017, SGS 518, SYN 114, SB 271046, R〇657199, PRX 07034, stiletto (CAS number 110623-33-19), Tebequine (CAS No. 113079-82-6), FG 7142 (CAS No. 78538-74-6), RU 34332 (CAS No. 137157-58-5), SX 3507, RO 153505 (CAS No. 78871-13- 8), RU 33965 (CAS No. 122321-05-5), S 8510 (CAS No. l5l466_23-8), Sabeluzole (CAS No. 104383-17-7), Shalibo (CAS No. 118790-71- 9), NS 626, NS 649 (CAS No. 146828-02-6), U 92032 (CAS No. 142223-92-5), MEM 1003, U 92798, RGH 2716 (CAS No. 134069-68-4), Safin Indoleamine (CAS No. 133865-89-1), AZD 0328, MEM 63908, ABT 418 (CAS No. 147402-53-7), ARR 17779, RJR 2403 (CAS No. 538-79-4), TC 2559, A 82695 (CAS No. 147388-86-1), A 84543, A 98284, DBO 83, RJR 2557, SIB 1765F (CAS No. 179120-52-6), GTS 21 (CAS No. 156223-05-1), MEM 3454, SIB 1553A, EVP 6124, SSR 180711, ABT 089 (CAS No. 161417-03-4), ABT 107, ABT 560, TC 5619, T AK 070, N-[(lS,2R)-3-(3,5-difluorophenyl>1-hydroxy-l-[(5S,6R)-5-methyl-6-(pivalooxy) )morpholin-3-yl]propan-2-yl]acetamide hydrochloric acid, 6·fluoro-5-(2-fluoro-5-methylphenyl)-3,4-dihydro " ratio 201031662 Pyridine, 2-amino-6-[2-(3'-methoxybiphenyl-3-yl)ethyl]-3,6-dimethyl-5,6-

羥嘧啶-4(3H)-酮、AZD 1080、ARA 014418、XD 4241、Z 321(CAS 編號 130849-58-0)、ONO 1603(CAS 編號 114668-76-7)、JTP 3399、優利他汀 A(CAS 編號Hydroxypyrimidine-4(3H)-one, AZD 1080, ARA 014418, XD 4241, Z 321 (CAS number 130849-58-0), ONO 1603 (CAS number 114668-76-7), JTP 3399, eustatin A ( CAS number

137563-63-4)、優利他汀 B(CAS 編號 137563-64-5)、P 128(CAS 編號 157716-52-4) 、Y 29794(CAS 編號 129184-48-1)、ZTTA 1、JTP 4819(CAS編號 162203-65-8)、赢單株抗體266、度洛西汀、依他普侖草酸鹽、氟西汀、三氟137563-63-4), eustatin B (CAS No. 137563-64-5), P 128 (CAS No. 157716-52-4), Y 29794 (CAS No. 129184-48-1), ZTTA 1, JTP 4819 ( CAS number 162203-65-8), win single antibody 266, duloxetine, escitalopram oxalate, fluoxetine, trifluoro

W 戊肟胺馬來酸鹽、帕羅西汀、舍曲林、達泊西汀、去甲文拉法辛、***、法β坐酮、米那普命、去甲丙米β井、度洛西丁，及比西法咬。本發明現將參考實施例作詳細說明；但是，此等實施例僅提供作為例示目的。依據本發明之用於藉由Αβ造成之 - 疾病之治療劑不於任何情況被限於下列特別實施例。熟習此項技藝者可藉由對下列參考例及實施例與本說明書之申 φ 清專利範圍作種改變而完全實施本發明，且此等改變係於本說明書之申請專利範圍之範圍内。虽例示化合物具有立體異構物時，若絕對結構未被決疋時，具光學旋轉之化合物之名稱無需依序地對應於其後於下列實施例中之結構式。下列縮寫被用於下列實施例。 DMF: Ν，Ν-二甲基曱醯胺 THF:四氫呋喃 EDC: 1-乙基_3_(3_二甲基胺基丙基)碳二醯亞胺氫氣酸 91 201031662 HOBT: 1-羥基苯并*** IPEA:二異丙基乙基胺 TEA:三乙恭胺 BOPC1:雙(2-側氧基-3ϋ院基)磷醯氣除非其它特別指示外，色譜分析術係使用Fuji Silysia Chemical Ltd.製造之BW-300作為載劑貫知*。 [實施例] 實施例1及2 (+)-8-(4-氟-2-三氟甲基苯基)-2-{(E)_2_[6_甲氧基-5-(4-甲基米°坐-1-基）ff比讲基]乙稀基}-5,6,7,8-四氫-[1，2,4]三唾基[l，5-a]ni^D定及(-)-8-(4-氟-2-二氟曱基苯基)-2-{(E)-2-[6-曱氧基-5-(4-甲基-1H-咪唑-卜基）°比畊-2-基]乙烯基}_5,6,7,8-四氫-[1，2,4]***基[l，5-a]n比咬 [化學式46]W pentamidine maleate, paroxetine, sertraline, dapoxetine, desvenlafaxine, sibutramine, beta beta ketone, milnacipate, norpropanol beta well, Duloxetine, and bitafa. The invention will now be described in detail with reference to the embodiments; however, these embodiments are provided by way of illustration only. The therapeutic agent for disease caused by Αβ according to the present invention is not limited to the following specific examples in any case. The present invention can be fully implemented by a person skilled in the art from the following reference examples and examples, and the scope of the invention is to be construed as being within the scope of the claims. Although the exemplified compound has a stereoisomer, the name of the compound having optical rotation does not need to sequentially correspond to the structural formula in the following examples, if the absolute structure is not determined. The following abbreviations are used in the following examples. DMF: Ν, Ν-dimethyl decylamine THF: tetrahydrofuran EDC: 1-ethyl_3_(3-dimethylaminopropyl) carbodiimide hydrogen acid 91 201031662 HOBT: 1-hydroxybenzone Triazole IPEA: Diisopropylethylamine TEA: Triethylamine BOPC1: Bis(2-Sideoxy-3 oxime-based) Phosphorus Helium Gas Chromatography is performed using Fuji Silysia Chemical Ltd. unless otherwise specified. The manufactured BW-300 is known as a carrier*. [Examples] Examples 1 and 2 (+)-8-(4-fluoro-2-trifluoromethylphenyl)-2-{(E)_2_[6-methoxy-5-(4-A Kimi ° sit-1-base) ff than the base] ethyl group}-5,6,7,8-tetrahydro-[1,2,4]trisyl [l,5-a]ni^D And (-)-8-(4-fluoro-2-difluoroindolylphenyl)-2-{(E)-2-[6-decyloxy-5-(4-methyl-1H-imidazole -Buji) ° Tractor-2-yl]vinyl}_5,6,7,8-tetrahydro-[1,2,4]triazolyl [l,5-a]n ratio bite [Chemical Formula 46]

參考例2獲得之(E)-3-[6-甲氧基-5-(4-甲基-1H-味β坐_ι_ 基)-"比讲-2-基]丙酸酯醯肼三氫氯酸鹽(4.7克）及咪唑（1〇克）添加至於甲醇(228毫升）内之參考例4獲得之乙基5_氣_2_(4_ 氟-2-三氟甲基苯基）戊醯亞胺氫氣酸鹽（5.2克)之溶液’其後於室溫攪拌7天。然後’反應溶液於50°C攪拌28小時。乙酸乙酯(2〇〇毫升）、食鹽水（100毫升）、5 N氫氯酸(20毫 92 201031662 升)及水(300毫升)依序添加至反應溶液，然後，有機層被分離。水性層以乙酸乙酯再淬取。混合之有機層於無水硫酸鎮乾無’且於減壓下濃縮，獲得5.7克之標題化合物之外消旋物。形成之外消旋物藉由Daicel Chemical Industries，Ltd. 製造之CHIRALPAK™ IC(2公分x25公分，移動相：乙腈：甲醇-3.7’流速.15毫升/分鐘）分離獲得具有藉由Daicel(E)-3-[6-Methoxy-5-(4-methyl-1H-flavor β sitting_ι_yl)-"bi-2-yl]propionate oxime obtained in Reference Example 2 Trihydrochloride (4.7 g) and imidazole (1 g) were added to methanol (228 ml) in Reference Example 4 to obtain ethyl 5-nitrox-2-(4-fluoro-2-trifluoromethylphenyl) A solution of pentamidine imine hydrochloride (5.2 g) was then stirred at room temperature for 7 days. Then, the reaction solution was stirred at 50 ° C for 28 hours. Ethyl acetate (2 ml), brine (100 ml), 5 N hydrochloric acid (20 m 92 201031662 liters) and water (300 ml) were sequentially added to the reaction solution, and then the organic layer was separated. The aqueous layer was extracted again with ethyl acetate. The combined organic layers were dried over anhydrous sulphuric acid and concentrated under reduced pressure to yield 5.7 g of the title compound. The racemate formed was isolated by CHIRALPAKTM IC (2 cm x 25 cm, mobile phase: acetonitrile: methanol-3.7' flow rate: 15 ml/min) manufactured by Daicel Chemical Industries, Ltd. with Daicel

Chemical Industries, Ltd.製造之CHIRALPAKTM ib(4.6 mm x 150 mm，移動相：己烷：乙醇=85:15，流速：i.o毫升/ 分鐘，40°C)分析而產生之ι〇·ι分鐘之滯留時間及正光學旋轉之標題光學活性化合物（1.21克，94% ee) ’及具有自相同分析產生之9.25分鐘之滞留時間及負光學旋轉之標題光學活性化合物（1.09克，>99% ee)。具正光學旋轉之標題光學活性化合物之性質數值係如下。 ESI-MS; m/z 500 [M++H]。 1 H-NMR (CDC13) δ (ppm): 1.87-1.96 (m, 1H), 2.13-2.29 (m, 2H), 2.29 (s, 3H), 2.42-2.48 (m, 1H), 4.14 (s, 3H), 4.27-4.41 (m, 2H), 4.64 (dd, J = 5.6, 8.8 Hz, 1H), 7.03 (dd, J = 5.2, 8.8 Hz, 1H), 7.17-7.22 (m, 1H), 7.44 (dd, J = 2.8, 9.2 Hz, 1H), 7.45 (d, J = 15.6 Hz, 1H), 7.58 (m, 1H), 7.61 (d, J = 15.6 Hz, 1H)，7.93 (s, 1H), 8.44 (d，J = 1.6 Hz, 1H)。具負光學旋轉之標題光學活性化合物之性質數值係如下。ESI-MS; m/z 500 [M++H]。 !H-NMR (CDC13) δ (pprn): 1.87-1.96 (m, 1H), 2.12-2.31 (m, 93 201031662 2H)，2.29 (s，3H)，2.42-2.48 (m, 1H)，4.14 (s, 3H), 4.27-4.41 (m, 2H), 4.64 (dd, J = 5.6, 8.8 Hz, 1H), 7.03 (dd, J = 5.2, 8.8 Hz, 1H), 7.17-7.22 (m, 1H), 7.44 (dd, J = 2.8, 9.2 Hz, 1H), 7.45 (d, J - 15.6 Hz, 1H), 7.58 (m, 1H), 7.61 (d, J = 15.6 Hz, 1H)，7.93 (s，1H)，8.44 (d，J = 1.6 Hz，1H)。實施例3及4 (+)-8-(2,4-二氟苯基)-2-{(E)_2_[6_ 甲氧基_5 (4 曱基_1H 咪唑-1-基）吡畊-2-基]乙烯基}_5,6,7,8_四氫***基 [l，5-a]0比0定及(-)-8-(2,4-二鼠苯基)_2](e)_2-[6-甲氧基-5-(4_ 甲基-1H-味唾-1-基户比口井-2-基]乙稀基}_5 6 7 8_四氫々,2 4] 三吐基[1,5-a]。比咬 [化學式47]The retention of ι〇·ι minutes by CHIRALPAKTM ib (4.6 mm x 150 mm, mobile phase: hexane:ethanol = 85:15, flow rate: io ml/min, 40 °C) manufactured by Chemical Industries, Ltd. Time and positive optical rotation of the title optically active compound (1.21 g, 94% ee) ' and title optically active compound (1.09 g, > 99% ee) having a residence time of 9.25 minutes and negative optical rotation from the same analysis . The numerical values of the title optically active compound having positive optical rotation are as follows. ESI-MS; m/z 500 [M++H]. 1 H-NMR (CDC13) δ (ppm): 1.87-1.96 (m, 1H), 2.13-2.29 (m, 2H), 2.29 (s, 3H), 2.42-2.48 (m, 1H), 4.14 (s, 3H), 4.27-4.41 (m, 2H), 4.64 (dd, J = 5.6, 8.8 Hz, 1H), 7.03 (dd, J = 5.2, 8.8 Hz, 1H), 7.17-7.22 (m, 1H), 7.44 (dd, J = 2.8, 9.2 Hz, 1H), 7.45 (d, J = 15.6 Hz, 1H), 7.58 (m, 1H), 7.61 (d, J = 15.6 Hz, 1H), 7.93 (s, 1H) , 8.44 (d, J = 1.6 Hz, 1H). The numerical values of the title optically active compound having a negative optical rotation are as follows. ESI-MS; m/z 500 [M++H]. !H-NMR (CDC13) δ (pprn): 1.87-1.96 (m, 1H), 2.12-2.31 (m, 93 201031662 2H), 2.29 (s, 3H), 2.42-2.48 (m, 1H), 4.14 ( s, 3H), 4.27-4.41 (m, 2H), 4.64 (dd, J = 5.6, 8.8 Hz, 1H), 7.03 (dd, J = 5.2, 8.8 Hz, 1H), 7.17-7.22 (m, 1H) , 7.44 (dd, J = 2.8, 9.2 Hz, 1H), 7.45 (d, J - 15.6 Hz, 1H), 7.58 (m, 1H), 7.61 (d, J = 15.6 Hz, 1H), 7.93 (s, 1H), 8.44 (d, J = 1.6 Hz, 1H). Example 3 and 4 (+)-8-(2,4-difluorophenyl)-2-{(E)_2_[6_methoxy_5(4 decyl_1H imidazol-1-yl)pyrazine -2-yl]vinyl}_5,6,7,8-tetrahydrotriazolyl [l,5-a]0 to 0 and (-)-8-(2,4-di-r-phenyl)_2 ](e)_2-[6-Methoxy-5-(4-methyl-1H-flavor-1-one-base-butan-2-yl]ethenyl}_5 6 7 8_tetrahydroanthracene, 2 4] Three sputum [1,5-a]. Specific bite [Chemical Formula 47]

三（二笨甲叉基丙酮）二鈀（140毫克）、三（鄰甲苯基)膦 (93·1毫克）及TEA(358 uL)添加至於甲苯（133毫升）内之參考例5獲得之8-(2,4-二氟-苯基)-2-乙烯基_5,6,7,8_四氫二唑基[l，5_a]°比啶（200毫克）及參考例丨獲得之5溴_3甲氧基-2-(4-甲基-1H-咪唑-1-基）吡畊(226毫克）之懸浮液，其後於110 ° C攪拌18小時。反應溶液内之固體藉由過濾經塞里塑料移除，且濾、液於減壓下濃縮。形成之殘質藉由矽石凝膠管柱色譜分析術（載劑：Fuji Silysia Chemical Ltd.製造之 ChromatorexTM(其後縮寫為“Nh矽石凝膠，，))純化獲得124毫 94 201031662 克之標題化合物之外消旋物。形成之外消旋物藉由Daicel Chemical Industries, Ltd.製造之CHIRALPAK™ 1C (2公分 x25公分；移動相··乙腈··曱醇=3··7，流速：13毫升/分鐘) 分離獲得具有藉由Daicel Chemical Industries, Ltd.製造之 CHIRALPAK™ IB(4.6 mm x 150 mm，移動相：乙猜：甲烧 =3:7，流速：1.0毫升/分鐘，40。〇分析而產生之45分鐘之滯留時間之標題光學活性化合物(36.3毫克，>99% ee)，及具有自相同分析產生之8_9分鐘之滯留時間之標題光學活性化合物(49.4毫克，>99% ee)。具4.5分鐘之滞留時間之標題光學活性化合物之性質數值係如下。 ESI-MS; m/z 450 [M++H]。 'H-NMR (CDC13) δ (ppm): 2.00-2.20 (m, 3H), 2.29 (s, 3H), 2.35-2.38 (m, 1H), 4.16 (s, 3H), 4.31 (m, 2H), 4.54 (m, 1H), 6.85-6.88 (m, 2H), 6.96 (m, 1H)，7.48 (d, J = 15 6 Hz 1H) 7.69-7.65 (m，2H)，7.94 (s, 1H)，8.45 (s, 1H)。具8.9分鐘之滯留時間之標題光學活性化合物之性質數值係如下。 ESI-MS; m/z 450 [M++H]。 !H-NMR (CDCI3) δ (ppm): 2.00-2.26 (m, 3H), 2.29 (s, 3H), 2.33-2.40 (m, 1H), 4.16 (s，3H)，4.30-4.32 (m, 2H), 4.54 (m， 1H), 6.82-6.89 (m, 2H), 6.96 (m, 1H), 7.48 (d, J = 15 6 Hz 1H)，7.59-7.65 (m, 2H)，7.94 (s, 1H)，8.45 (s，ih) 〇實施例5至12之化合物係藉由與實施例3及4相同之方 95 201031662 法獲得（第1及2)表。 [第1表] 第1表結搆式Reference Example 5 obtained by adding tris(dibromomethylideneacetone) dipalladium (140 mg), tris(o-tolyl)phosphine (93·1 mg) and TEA (358 uL) to toluene (133 ml) -(2,4-difluoro-phenyl)-2-vinyl-5,6,7,8-tetrahydrodiazolyl [l,5_a]° pyridine (200 mg) and reference example 5 A suspension of bromo-3-methoxy-2-(4-methyl-1H-imidazol-1-yl)pyrazine (226 mg) was stirred at 110 ° C for 18 hours. The solid in the reaction solution was removed by filtration through a plug of plastic, and the filtrate was concentrated under reduced pressure. The residue formed was purified by a vermiculite gel column chromatography (carrier: ChromatorexTM manufactured by Fuji Silysia Chemical Ltd. (hereinafter abbreviated as "Nh vermiculite gel,") to obtain a title of 124 mil 2010 31 662 gram. Compound racemate. Formation of racemate by CHIRALPAKTM 1C manufactured by Daicel Chemical Industries, Ltd. (2 cm x 25 cm; mobile phase · acetonitrile · decyl alcohol = 3 · · 7, flow rate: 13 ML/min) was obtained by CHIRALPAKTM IB manufactured by Daicel Chemical Industries, Ltd. (4.6 mm x 150 mm, mobile phase: B guess: methyl burn = 3:7, flow rate: 1.0 ml/min, 40. 〇 The title optically active compound (36.3 mg, > 99% ee), which was analyzed for 45 minutes of residence time, and the title optically active compound (49.4 mg, > 99%) having a residence time of 8-9 minutes from the same analysis. Ee). The property of the title optically active compound having a residence time of 4.5 minutes is as follows. ESI-MS; m/z 450 [M++H]. 'H-NMR (CDC13) δ (ppm): 2.00-2.20 (m, 3H), 2.29 (s, 3H), 2.35-2.38 (m, 1H), 4.16 (s, 3H), 4.31 (m, 2 H), 4.54 (m, 1H), 6.85-6.88 (m, 2H), 6.96 (m, 1H), 7.48 (d, J = 15 6 Hz 1H) 7.69-7.65 (m, 2H), 7.94 (s, 1H), 8.45 (s, 1H). The property of the title optically active compound with a retention time of 8.9 minutes is as follows. ESI-MS; m/z 450 [M++H].H-NMR (CDCI3) δ (ppm): 2.00-2.26 (m, 3H), 2.29 (s, 3H), 2.33-2.40 (m, 1H), 4.16 (s, 3H), 4.30-4.32 (m, 2H), 4.54 (m, 1H) ), 6.82-6.89 (m, 2H), 6.96 (m, 1H), 7.48 (d, J = 15 6 Hz 1H), 7.59-7.65 (m, 2H), 7.94 (s, 1H), 8.45 (s, Ih) The compounds of Examples 5 to 12 were obtained by the same methods as Examples 3 and 4, 95 201031662 (Forms 1 and 2). [Table 1] Table 1 Structure

lH-NMRlH-NMR

c 19 » »J »73 D，2>m，m，9 c m k(d<). <(219<1H7c 19 » »J »73 D,2>m,m,9 c m k(d<). <(219<1H7

9 » »3252 » 9) ^ · o · Hi VSHh 12 9 - 7 - c1H I ,49 ,84^ 2(1η?;2υ3 6z>’ 9 2 H · H s -9 - 417 -o( 125 " .704 · »4 \y M - 8 4 >2 k(H8 g| 23015=8· P7 - V » -J PI)s ·Ζ7^ (k(4H(dH c〇 2 3 4 ，6 L )3 )> » 1 ) · 4- -r 3) s -H7^7 1H(42 = 3 V9 » »3252 » 9) ^ · o · Hi VSHh 12 9 - 7 - c1H I ,49 ,84^ 2(1η?;2υ3 6z>' 9 2 H · H s -9 - 417 -o( 125 " .704 · »4 \y M - 8 4 >2 k(H8 g| 23015=8· P7 - V » -J PI)s ·Ζ7^ (k(4H(dH c〇2 3 4 ,6 L ) 3 )> » 1 ) · 4- -r 3) s -H7^7 1H (42 = 3 V

'4 ，3 ? 5234，H -9 I 4ddl，3 12 4 »d(5)9 • · · 4 )/v 2 Η· ;2 .ηοο7·27 s - 2370 P3 , , 7B-S> PI)s · » (Hi h><4>,3 41hh) 7.6 ]^ · T _H，，7H s 1 H (4 2 2) ~ cl 9，，HH8 .4 D » 2) m 815 8 4 cm.H< , . II 2178 Z7J8 9 4-1. 9 7 Cm, 2 Η), 2. 4 9 <m, .3 3-4. 3 J = 6. Ο, ,J=7. 6H Cm, 3H>， 7. 73 (d, (s , 1 H),'4,3 ? 5234,H -9 I 4ddl,3 12 4 »d(5)9 • · · 4 )/v 2 Η· ;2 .ηοο7·27 s - 2370 P3 , , 7B-S> PI) s · » (Hi h><4>,3 41hh) 7.6 ]^ · T _H,,7H s 1 H (4 2 2) ~ cl 9,,HH8 .4 D » 2) m 815 8 4 cm. H< , . II 2178 Z7J8 9 4-1. 9 7 Cm, 2 Η), 2. 4 9 <m, .3 3-4. 3 J = 6. Ο, , J=7. 6H Cm, 3H&gt ;, 7. 73 (d, (s , 1 H),

c 1 9 ,，H D »2)m494m1-> . cm.H< :< -HI (2108 4 78 2 j .H .HdH '4 2 z 6 • H' 6 2 3 5c 1 9 ,, H D »2)m494m1-> . cm.H<:< -HI (2108 4 78 2 j .H .HdH '4 2 z 6 • H' 6 2 3 5

P3 PI V > 2 (1}7h H ，6 • 4t 9 )4>-7-74<<sh)P3 PI V > 2 (1}7h H ,6 • 4t 9 )4>-7-74<<sh)

• 4、 2 .H 9• 4, 2 .H 9

o s - Ny. δ23 4 »H1-7 <H > :5、-l、-3>S1>H，J> .9， 1 H( -H 1 2 »H7 -2 C1942，Hdl，7h D ，2，，1<，>，6 c S .>mH vmH> 2h(494(1h- 8 :4 : *5H 9> m ·42> .6 z , • H(4 -= H7 -Hd 12 2 I 6J1 ,5-8{ 85 4 9S.3广d-H)v 8(2Os - Ny. δ23 4 »H1-7 <H > :5, -l, -3>S1>H,J> .9, 1 H( -H 1 2 »H7 -2 C1942, Hdl, 7h D , 2,, 1 <, >, 6 c S .>mH vmH> 2h(494(1h- 8 :4 : *5H 9> m ·42> .6 z , • H(4 -= H7 -Hd 12 2 I 6J1 , 5-8{ 85 4 9S.3 wide dH) v 8 (2

4d<95-8 -35，d30 ? /(T '7 ，d • Hs 1 >02 -H 2 ,n » -5dl4d<95-8 -35,d30 ? /(T '7 ,d • Hs 1 >02 -H 2 ,n » -5dl

I 6 m. p. 2 ^ 6 d 6 ，6 d w6 ，，d J _4>d<9 z’-2rIH(d30H(di 2(/-4 2)76Hd 1,509-1- H， g 2 6 Jl)^<2·4·一-.¾ o- 4Jd ml -I 6 mp 2 ^ 6 d 6 , 6 d w6 ,, d J _4 > d < 9 z'-2rIH (d30H(di 2(/-4 2)76Hd 1,509-1-H, g 2 6 Jl)^&lt ;2·4·一-.3⁄4 o- 4Jd ml -

J8·L 9) p 8 475 z , • Hs1·，，，· Η m V4 96 201031662 [第2表] 第2表例祐貲J8·L 9) p 8 475 z , • Hs1·,,,· Η m V4 96 201031662 [Table 2] Table 2 Example 佑

7 1 « *31031 2 4L. * ΓΟ * 3 Η /1 7 Ϊ» 6 · 2 2 ·3δ « flsH -2 5)d = 2 3.S,H/J'· 0)1-4 3 4 »H1 « rr 0 *· f 4- *0 1 ^ 2 31) m »( J :r h{7 4s'， )s 8 »5(d Dn4 ,m-,H>7675 P2D(?1 '64 (· .^4 ™ »} ♦ *〇 2i3 1m'H.78 f 3 Jc. 1 I Di>m4-,6 o K{ - 73 2HH 3307 * *H11 D »4.2)7 6 * » cnl·，H f ‘ 2 s、 (<241X5H(H7 1 « *31031 2 4L. * ΓΟ * 3 Η /1 7 Ϊ» 6 · 2 2 ·3δ « flsH -2 5)d = 2 3.S,H/J'· 0)1-4 3 4 » H1 « rr 0 *· f 4- *0 1 ^ 2 31) m »( J :rh{7 4s', )s 8 »5(d Dn4 ,m-,H>7675 P2D(?1 '64 (· .^4 TM »} ♦ *〇2i3 1m'H.78 f 3 Jc. 1 I Di>m4-,6 o K{ - 73 2HH 3307 * *H11 D »4.2)7 6 * » cnl·,H f ' 2 s, (<241X5H(H

(CD3〇D) δ (ppm) :2. 0 3-2. 27 (m, 3Hj a 2. 2 4 (s, 3H) , 2, 3 4 2, 4 0 (m, iH) , 4. I 9 (s. 3H) 4. 2 7-4, 34 im, 2H) ( 4. S 5 (m 1 H)，7, 1 卜 7, ] 8 (m, 3ii) , ?, 1-7. 3 6 Cm, IH) . 44 (d, J- 5- βΗζ, ΪΗ) . T. 54 (d, J = 1 6, 0 Hz，1H> ,7.67 (s, 1H>，8, 0 3 (s，II!) · 8. 4 5 (d，J = 2iU, HK 货铱例ii(CD3〇D) δ (ppm): 2. 0 3-2. 27 (m, 3Hj a 2. 2 4 (s, 3H) , 2, 3 4 2, 4 0 (m, iH) , 4. I 9 (s. 3H) 4. 2 7-4, 34 im, 2H) ( 4. S 5 (m 1 H), 7, 1 Bu 7, 8 (m, 3ii), ?, 1-7. 3 6 Cm, IH) . 44 (d, J- 5-βΗζ, ΪΗ) . T. 54 (d, J = 1 6, 0 Hz, 1H>, 7.67 (s, 1H>, 8, 0 3 (s, II!) · 8. 4 5 (d, J = 2iU, HK goods example ii

<CD3OD) 6 (ppm) : 2, 0 0-2. 2 1 (m, 3H)，2, 2 5 (s，3H) , 2. 3 4-'1、4 0 (m. iH) » 4. 2 0 ($, 3H), 4, 29 — 4, 3 6 (mt 3H)，1. 06-7, 11 (τη, 2H) , 7, 2 0 -7. 2 3 (m, 2 H) f ?. 4 6 {d, J«1 δ, QHz, IH), 7. 56 (d, J-l 5. 6Hz, 1H) , 7. 6 8 im, IH) , 8, 0 5 <s5 1H) t ϋ. 4$ (d, J 6Hz, IH). 實铱例<CD3OD) 6 (ppm) : 2, 0 0-2. 2 1 (m, 3H), 2, 2 5 (s, 3H) , 2. 3 4-'1, 4 0 (m. iH) » 4. 2 0 ($, 3H), 4, 29 — 4, 3 6 (mt 3H), 1. 06-7, 11 (τη, 2H) , 7, 2 0 -7. 2 3 (m, 2 H ) f ?. 4 6 {d, J«1 δ, QHz, IH), 7. 56 (d, Jl 5. 6Hz, 1H) , 7. 6 8 im, IH) , 8, 0 5 <s5 1H ) t ϋ. 4$ (d, J 6Hz, IH). Example

<CD3OD) a (ρρπι) :2. 0.1-2. 23 〈取 3H〕，2. 2 S (s, 3H) , 2. 3 3-2. 38 <m, IH) , 4, 20 (s, 3H), 4. 2 9 — 4, 3 8 (m, 3H) , 7. 06-7. 11 (m* 2H) . 7, 2 0 -T. 2 3 (m. 2 H) , 7. 4$ (dt J^l S. 6Hz, IH), 7- S6 (d, J^IS. 6Hz, IH) , 7. 6 8 Cm» IH) » S, OS (s, IH) , 8, 4S (d, J = 1, 6Hz, IH) 實施例13及14 (+)及㈠-8-(5-異丙基-4-甲氧基-2-甲基苯基）-2-[6-甲氧基 -5-(4-甲基-1H-咪唑-1-基吡。丼-2-基）-5,6,7,8-四氫[1,2,4]三。坐基[l,5-a]°比咬之合成 [化學式48]<CD3OD) a (ρρπι) : 2. 0.1-2. 23 <take 3H], 2. 2 S (s, 3H) , 2. 3 3-2. 38 <m, IH) , 4, 20 ( s, 3H), 4. 2 9 — 4, 3 8 (m, 3H) , 7. 06-7. 11 (m* 2H) . 7, 2 0 -T. 2 3 (m. 2 H) , 7 . 4$ (dt J^l S. 6Hz, IH), 7- S6 (d, J^IS. 6Hz, IH) , 7. 6 8 Cm» IH) » S, OS (s, IH) , 8, 4S (d, J = 1, 6 Hz, IH) Examples 13 and 14 (+) and (i)-8-(5-isopropyl-4-methoxy-2-methylphenyl)-2-[6 -Methoxy-5-(4-methyl-1H-imidazol-1-ylpyridin-2-yl-2-yl)-5,6,7,8-tetrahydro[1,2,4]tri. Synthesis of sitting base [l,5-a]° bite [Chemical Formula 48]

參考例6獲得之2-溴-8-(5-異丙基-4-曱氧基-2-甲基苯 97 201031662 基)-5,6,7,8_四氫[⑶]三絲[15⑽毫克）、參考例 3獲得之3_甲氧基邻.甲基_m•抓丨基)5三丁基錫烧基㈣(270毫克）、乙酸_(14 8毫克）、u-雙(二苯基鱗基)丙炫(54.3毫克）、氧化亞銅(1)(94 2毫克如甲基_2鱗烧_(4毫升)於氮氛圍於咖❻熱並獅二小時。反應混合物回到室溫’以乙酸乙δ旨稀釋，缝，經塞里塑料過渡。水及鹽水添加轉液，且有制被分離。有機層於無水硫酸鎂乾燥乾燥，然後，於減壓下濃縮。殘質藉由凝膠管柱色5普分析術(載劑：Chromatorex™ NH)純化獲得外消旋標題化合物。外消旋標題化合物藉由Daicel Chemicai Industries， Ltd.製造之CHIRALPAKTMIC(2公分x 25公分；移動相：乙腈：曱醇=20:80，流速：12毫升/分鐘）分離獲得具有9.8分鐘之滯留時間及正光學旋轉之標題光學活性化合物（13.9毫克’ >99°/。ee)及具有1 〇.8分鐘之滞留時間及負光學旋轉之標題光學活性化合物（12.7毫克，>99% ee)。具正光學旋轉之標題光學活性化合物之性質數值係如下。 ESI-MS; m/z 474 [M++H]。 1H_NMR (CDC13) δ (ppm): 1.06 (d，J = 6.8 Hz, 3H)，1.10 (d， J = 6.8 Hz, 3H), 1.95-2.03 (m, 1H), 2.05-2.15 (m, 1H), 2.20-2.38 (m, 2H), 2.30 (d, J = 0.8 Hz, 3H), 2.35 (s, 3H), 3.19 (qq, J = 6.8, 6.8 Hz, 1H), 3.82 (s, 3H), 4.26 (s, 3H), 4.39-4.44 (m, 2H), 4.49-4.51 (m, 1H), 6.58 (s, 1H), 6.69 (s, 1H), 7.64 (dd, J = 1.2, 0.8 Hz, 1H), 8.49 (d, J = 1.2 Hz, 1H), 98 201031662 8.73 (s, 1H)。具負光學旋轉之標題光學活性化合物之性質數值係與 (+)-異構物者相同。實施例15至18之化合物係藉由與實施例13及14相同之方法獲得（第3表）。 [第3表] 第3表2-Bromo-8-(5-isopropyl-4-indolyl-2-methylbenzene 97 201031662)-5,6,7,8-tetrahydro[(3)]trifilament obtained in Reference Example 6 15(10) mg), 3_methoxy-o-methyl-m-methane, which is obtained in Reference Example 3, 5, tributyltin alkyl (4) (270 mg), acetic acid _ (14 8 mg), u-bis (diphenyl) Base squama) propyl (54.3 mg), cuprous oxide (1) (94 2 mg such as methyl 1-2 scallops _ (4 ml) in a nitrogen atmosphere in a hot pot and lion for two hours. The reaction mixture returned to the room The temperature was diluted with acetic acid, and it was sewed and transferred through a plug of plastic. The water and brine were added to the liquid and separated, and the organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. Purification of the racemic title compound by gel column chromatography (carrier: ChromatorexTM NH). The racemic title compound by CHIRALPAKTM IC (2 cm x 25 cm; manufactured by Daicel Chemicai Industries, Ltd.; Phase: acetonitrile: decyl alcohol = 20:80, flow rate: 12 ml/min) Separate to obtain the title optically active compound with a residence time of 9.8 minutes and positive optical rotation (13.9 mg ' > 99 ° / .ee) The title optically active compound (12.7 mg, > 99% ee) having a residence time of 1 〇.8 min and negative optical rotation. The property of the title optically active compound having positive optical rotation is as follows. ESI-MS; m/ z 474 [M++H] 1H_NMR (CDC13) δ (ppm): 1.06 (d, J = 6.8 Hz, 3H), 1.10 (d, J = 6.8 Hz, 3H), 1.95-2.03 (m, 1H) , 2.05-2.15 (m, 1H), 2.20-2.38 (m, 2H), 2.30 (d, J = 0.8 Hz, 3H), 2.35 (s, 3H), 3.19 (qq, J = 6.8, 6.8 Hz, 1H ), 3.82 (s, 3H), 4.26 (s, 3H), 4.39-4.44 (m, 2H), 4.49-4.51 (m, 1H), 6.58 (s, 1H), 6.69 (s, 1H), 7.64 ( Dd, J = 1.2, 0.8 Hz, 1H), 8.49 (d, J = 1.2 Hz, 1H), 98 201031662 8.73 (s, 1H). Properties of the title optically active compound with negative optical rotation and (+) - The isomers were the same. The compounds of Examples 15 to 18 were obtained by the same methods as in Examples 13 and 14 (Table 3). [Table 3] Table 3

貲祐洌編號蛣楫式實祐例 ^^入〆 \=/ 實铱例16 實铱例17 實铱例18 參考例1 5-溴-3-甲氧基-2-(4-甲基-1H-咪唑-1-基)吡讲之合成 [化學式49]赀佑洌 No. 蛣楫式实佑例^^入〆\=/ Example 16 Example 17 Example 18 Reference Example 1 5-Bromo-3-methoxy-2-(4-methyl- Synthesis of 1H-imidazol-1-yl)pyrazine [Chemical Formula 49]

Br 99 201031662 N-(5-溴-3-甲氧基吡啡_2_基）甲醯胺之合成 [化學式50]Br 99 201031662 Synthesis of N-(5-bromo-3-methoxypyridin-2-yl)carbenamide [Chemical Formula 50]

乙酸Sf (150毫升）以滴液方式添加至於冰冷卻下之甲酸 (150毫升）’其後’於相同溫度攪拌25分鐘。於THF(2〇〇毫升）内之5-溴-3-甲氧基吡斗_2_基胺（CAS #5900-13-0，38.7 克）之溶液於10分鐘期間以滴液方式添加至反應混合物，然後’反應溶液於室溫授拌一小時。冰水添加至反應溶液，且沈殿粉末藉由過濾收集。形成之粉末以水清洗，然後，空氣乾燥隔夜獲得41.2克之標題化合物。標題化合物之性質數值係如下。 1 H-NMR (CDCI3) δ (ppm)： 4.06 (s, 3H), 7.87 (s, 1H), 7·87 (brd, J = ll.o Hz, 1H), 9.37 (d，J = l10 Hz, 1H)。 N-(5-溴-3-甲氧基吡讲_2-基)-N-(2-側氧基丙基）甲醯胺之貪成 [化學式51] v 氣丙酮(21.2毫升）以滴液方式添加至於dmf(412毫升）内之N-(5-溴-3-甲氧基吡啫-2_基）甲醯胺(41·2克）、碳酸铯 (92.7克）及碘化鉀(3·〇9克）之加熱至50°C之懸汙液。然後，反應溶液授拌1.5小時。反應溶液引至擾拌之冰水(3公升） 100 201031662 内，且沈澱之粉末藉由過濾收集。形成之粉末以水清洗，然後，空氣乾燥三小時。其後，41.3克之標題化合物藉由於室溫之減壓下乾燥而獲得。化合物之性質數值係如下。 'H-NMR (CDC13) δ (ppm): 2.23 (s, 3H), 4.06 (s, 3H), 4.75 (s, 2H)，8.00 (s, 1H), 9.18 (s，1H)。 5-溴-3-曱氧基-2-(4-曱基-1H-咪唑-1-基)吼畊之合成 [化學式52]Acetic acid Sf (150 ml) was added dropwise to the formic acid (150 ml) under ice-cooling and then stirred at the same temperature for 25 min. A solution of 5-bromo-3-methoxypyridin-2-ylamine (CAS #5900-13-0, 38.7 g) in THF (2 mL) was added dropwise over 10 min to The reaction mixture was then allowed to react for one hour at room temperature. Ice water was added to the reaction solution, and the sediment powder was collected by filtration. The resulting powder was washed with water and then air dried overnight to give 41.2 g of the title compound. The qualitative values of the title compounds are as follows. 1 H-NMR (CDCI3) δ (ppm): 4.06 (s, 3H), 7.87 (s, 1H), 7·87 (brd, J = ll.o Hz, 1H), 9.37 (d, J = l10 Hz , 1H). The greed of N-(5-bromo-3-methoxypyridin-2-yl)-N-(2-oxopropyl)carbamamine [Chemical Formula 51] v Air acetone (21.2 ml) N-(5-bromo-3-methoxypyridin-2-yl)carbenamide (41·2 g), cesium carbonate (92.7 g) and potassium iodide (3) in dmf (412 ml) · 〇 9 g) of the suspension heated to 50 ° C. Then, the reaction solution was stirred for 1.5 hours. The reaction solution was introduced into a stirred ice water (3 liter) 100 201031662, and the precipitated powder was collected by filtration. The formed powder was washed with water and then air dried for three hours. Thereafter, 41.3 g of the title compound was obtained by drying under reduced pressure at room temperature. The properties of the compounds are as follows. 'H-NMR (CDC13) δ (ppm): 2.23 (s, 3H), 4.06 (s, 3H), 4.75 (s, 2H), 8.00 (s, 1H), 9.18 (s, 1H). Synthesis of 5-bromo-3-indolyl-2-(4-indolyl-1H-imidazol-1-yl) hydrazine [Chemical Formula 52]

乙酸銨（16.6克）、Ν-(5-溴-3-甲氧基吡_-2-基)-Ν-(2-側氧基丙基）甲醯胺(41.3克）、三氟乙酸（16.6毫升）及甲苯(268 毫升）之混合物於迴流下加熱二小時，同時使用Dean-Stark 裝置移除水分。反應溶液回到室溫。乙酸乙酯及冰水添加至反應溶液，且混合物以冰冷卻。然後，反應溶液以濃的含水胺呈鹼性，然後，有機層被分離。形成之有機層以鹽水清洗，且於減壓下濃縮。殘質藉由矽石凝膠管柱色譜分析術純化，且洗提之分級物於減壓下濃縮。形成之殘質以第三丁基曱基醚固化，且固體藉由過濾收集。固體以醚第三丁基曱基醚-庚烷(2:1)清洗，及以空氣乾燥獲得20.4克之標題化合物。化合物之性質數值係如下。 (CDC13) δ (ppm)·· 2.29 (d，J = 1.2 Hz，3H)， 4.15 (s, 3H), 7.55 (dd, J = 1.2, 1.2 Hz, 1H), 8.09 (s, 1H), 8.40 (d, J = 1.2 Hz, 1H)。 101 201031662 參考例2 (E)-3-[6-曱氧基·5-(4-甲基-1H-咪唑-1-基户比啫_2_基]兩醯肼三氫氯酸鹽之合成 [化學式53]Ammonium acetate (16.6 g), Ν-(5-bromo-3-methoxypyridin-2-yl)-indole-(2-o-oxypropyl)formamide (41.3 g), trifluoroacetic acid ( A mixture of 16.6 ml) and toluene (268 ml) was heated under reflux for two hours while removing water using a Dean-Stark apparatus. The reaction solution was returned to room temperature. Ethyl acetate and ice water were added to the reaction solution, and the mixture was cooled with ice. Then, the reaction solution was made basic with a concentrated aqueous amine, and then the organic layer was separated. The resulting organic layer was washed with brine and concentrated under reduced pressure. The residue was purified by a silica gel column chromatography, and the eluted fraction was concentrated under reduced pressure. The resulting residue was solidified with tert-butyl mercapto ether and the solid was collected by filtration. The solid was washed with ether tributyl decyl ether-heptane (2:1). The properties of the compounds are as follows. (CDC13) δ (ppm)·· 2.29 (d, J = 1.2 Hz, 3H), 4.15 (s, 3H), 7.55 (dd, J = 1.2, 1.2 Hz, 1H), 8.09 (s, 1H), 8.40 (d, J = 1.2 Hz, 1H). 101 201031662 Reference Example 2 (E)-3-[6-decyloxy-5-(4-methyl-1H-imidazol-1-yl to 啫_2_yl] bisphosphonium trihydrochloride Synthesis [Chemical Formula 53]

第三丁基2-{(Ε)-3-[6-甲氧基_5-(4·曱基·1Η-咪唑-1-基）吡讲 -2-基]丙醯基}肼羧酸酯之合成 [化學式54]Third butyl 2-{(Ε)-3-[6-methoxy-5-(4-indenyl-1Η-imidazol-1-yl)pyr-2-yl]propenyl}indole carboxylic acid Synthesis of esters [Chemical Formula 54]

參考例1獲得之5-溴-3-甲氧基-2-(4-甲基-1Η-咪唑-1-基) 吡，并（15克）、第三丁基2-丙烯醯肼羧酸酯（CAS #28689-14-7，11.5克）、三-鄰-曱苯基膦(3.4克）、三(二苯甲又基兩酮）二鈀（0)(5.14克）、^^八(14.4毫升）及〇1^(90.9毫升）之混合物於ioo°c攪拌二小時。反應溶液冷卻至室溫。然後，乙酸乙酯（50毫升）及第三丁基甲基醚(5〇毫升）添加至反應溶液，其後，以冰冷卻。沈澱之固體藉由過濾收集。形成之粉末以第三丁基甲基醚乙酸乙酯（1:1)清洗，然後，以空氣乾燥隔夜，獲得22,8克之標題化合物。此化合物之性質數值係如下。 H-NMR (CDC13) δ (ppm): 1.51 (s, 9H), 2.30 (s, 3H) 102 201031662 4.17 (s, 3H), 6.96 (d, J = 15.2 Hz, 1H), 7.62 (brs, 1H), 7.67 (d, J = 15.2 Hz，1H), 8.03 (s，1H)，8.50 (brs，1H)。 (E)-3-[6-甲氧基-5-(4-甲基-1H-咪唑-1-基）吼畊-2-基]丙烯醯肼三氫氯酸鹽之合成 [化學式55]5-Bromo-3-methoxy-2-(4-methyl-1Η-imidazol-1-yl)pyridyl, obtained in Reference Example 1, and (15 g), tert-butyl 2-propene carboxylic acid Ester (CAS #28689-14-7, 11.5 g), tri-o-p-phenylphosphine (3.4 g), tris(diphenylmethyl ketone) dipalladium (0) (5.14 g), ^^8 A mixture of (14.4 ml) and 〇1^ (90.9 ml) was stirred at io °c for two hours. The reaction solution was cooled to room temperature. Then, ethyl acetate (50 ml) and a third butyl methyl ether (5 ml) were added to the reaction solution, followed by cooling with ice. The precipitated solid was collected by filtration. The resulting powder was washed with ethyl bromoethyl ether (1:1), and then dried in vacuo to afford 22,8 g of the title compound. The property values of this compound are as follows. H-NMR (CDC13) δ (ppm): 1.51 (s, 9H), 2.30 (s, 3H) 102 201031662 4.17 (s, 3H), 6.96 (d, J = 15.2 Hz, 1H), 7.62 (brs, 1H) ), 7.67 (d, J = 15.2 Hz, 1H), 8.03 (s, 1H), 8.50 (brs, 1H). Synthesis of (E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)indole-2-yl]acrylonitrile hydrazine trihydrochloride [Chemical Formula 55]

濃氫氯酸（110毫升）添加至於甲醇（110毫升）内之第三丁基2-{(E)-3-[6-甲氧基-5-(4-甲基-1H-咪唑-1-基)吡畊-2-基] 丙烯醯基}肼羧酸酯（22.8克）之懸浮液，其後，於室溫攪拌 4.5小時。反應溶液經塞里塑料過濾。濾液於減壓下濃縮。殘質以甲苯稀釋，然徵，於減壓下濃縮。再次地，殘質以甲苯稀釋，然後，於減壓下濃縮。殘質以THF稀釋，然後，沈澱之固體藉由過濾收集。固體以THF清洗，然後，於減壓下於室溫乾燥，獲得16.1克之標題化合物。此化合物之性質數值係如下。 ^-NMR (CD3OD) δ (ppm): 2.46 (d, J = 1.2 Hz, 3H), 4.28 (s, 3H), 7.27 (d, J = 15.2 Hz, 1H), 7.84 (d, J = 15.2 Hz, 1H), 8.17 (dd, J = 1.6, 1.2 Hz, 1H), 8.38 (s, 1H), 9.72 (d, J = 1.6 Hz, 1H)。參考例3 3-曱氧基-2-(4-曱基-1H-咪唑-1-基)-5-三丁基錫烷基吡啡之合成 103 201031662 [化學式56]Concentrated hydrochloric acid (110 ml) added to the third butyl 2-{(E)-3-[6-methoxy-5-(4-methyl-1H-imidazole-1) in methanol (110 mL) A suspension of pyridin-2-yl]propenyl}hydrazinecarboxylate (22.8 g) was stirred at room temperature for 4.5 hours. The reaction solution was filtered through a plug of plastic. The filtrate was concentrated under reduced pressure. The residue was diluted with toluene, then concentrated and concentrated under reduced pressure. Again, the residue was diluted with toluene and then concentrated under reduced pressure. The residue was diluted with THF, and then the precipitated solid was collected by filtration. The solid was washed with THF and then dried at room temperature under reduced pressure to afford 16.1 g of the title compound. The property values of this compound are as follows. ^-NMR (CD3OD) δ (ppm): 2.46 (d, J = 1.2 Hz, 3H), 4.28 (s, 3H), 7.27 (d, J = 15.2 Hz, 1H), 7.84 (d, J = 15.2 Hz , 1H), 8.17 (dd, J = 1.6, 1.2 Hz, 1H), 8.38 (s, 1H), 9.72 (d, J = 1.6 Hz, 1H). Reference Example 3 Synthesis of 3-decyloxy-2-(4-mercapto-1H-imidazol-1-yl)-5-tributylstannylpyramide 103 201031662 [Chemical Formula 56]

鲁參考例1獲得之5-溴-3-曱氧基_2_(4-曱基-1H-咪唑_;ι_基) "比畊(500毫克）、六正丁基二錫（1 48毫升）、四（三笨基膦）二鈀(0)(215毫克）及二甲苯(2〇毫升）之混合物於迴流下加熱— 小時。反應溶液冷卻至室溫，然後，於減壓下濃縮。殘質藉由矽石凝膠管柱色譜分析術純化獲得270毫克之標題化合物，呈油狀物。此化合物之性質數值係如下。 ^-NMR (CDC13) δ (ppm): 0.90-0.94 (m, 9H), 1.31-1.56 (m, 12H), 1.62-1.66 (m, 6H), 2.30 (d, J = 0.8 Hz, 3H), 4.12 (s, 3H), 7.60 (dd, J = 1.2, 0.8 Hz, 1H), 7.98 (s, 1H), 8.45 (d, J = 1.2 Hz, 1H)。參考例4 乙基5-氣-2-(4-氧-2-三氟甲基苯基）戍醢亞胺氫氣酸鹽之合成 [化學式57]Reference Example 1 obtained 5-bromo-3-indolyl_2_(4-mercapto-1H-imidazole_; i-based) " specific tillage (500 mg), hexa-n-butyltin (1 48) A mixture of cc), tetrakis(triphenylphosphine)dipalladium (0) (215 mg) and xylene (2 mL) was heated under reflux for an hour. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. Residues were purified by silica gel column chromatography to give 270 mg of the title compound as an oil. The properties of this compound are as follows. ^-NMR (CDC13) δ (ppm): 0.90-0.94 (m, 9H), 1.31-1.56 (m, 12H), 1.62-1.66 (m, 6H), 2.30 (d, J = 0.8 Hz, 3H), 4.12 (s, 3H), 7.60 (dd, J = 1.2, 0.8 Hz, 1H), 7.98 (s, 1H), 8.45 (d, J = 1.2 Hz, 1H). Reference Example 4 Synthesis of ethyl 5-gas-2-(4-oxo-2-trifluoromethylphenyl) quinone imine hydrogen salt [Chemical Formula 57]

第三丁氧化鉀（9.58克）添加至於氮氛圍中於冰冷卻下之於THF(400毫升）之4-氟-2-(三氟甲基）苯基乙腈（15.08克）之溶液，且混合物於相同溫度攪拌20分鐘。1-溴-3-氯丙烷 104 201031662 (8.07毫升)添加至反應溶液，其後，攪拌三小時。飽和氣化銨溶液添加至反應溶液，其後以乙酸乙酯萃取。有機層於無水硫酸鎂乾燥，然後’於減壓下濃縮獲得粗製之5-氯-2-(4-氟-2-三氟甲基苯基)戊腈。於乙醇（800毫升）内之此粗製之5-氯-2-(4-氟-2-三氟甲基苯基）戊腈之溶液於冰冷卻下以氯化氫起泡一小時。然後，反應溶液於室溫攪拌16小時。反應溶液於減壓下濃縮。 φ 於乙醇(800毫升）内之此殘質之溶液再次於於冰冷卻下以氣化氫起泡一小時。然後，反應溶液於室溫攪拌16小時。反應溶液於減壓下濃縮。第三丁基甲基醚添加至形成之殘質。研製產生13.4克之標題化合物。此化合物之性質數值係如下。 ESI-MS; m/z 326 [M++H]。 'H-NMR (CDC13) δ (ppm): 1.41 (t, J = 7.2 Hz, 3H), 1.69-1.94 (m, 2H), 2.37 (m, 1H), 2.58 (m, 1H), 3.55-3.62 (m, ❿ 2H), 4.46 (dd, J = 7.2, 8.4 Hz, 1H), 4.64 (q, J = 7.2 Hz, 2H), 7.38 (m, 1H), 7.43 (dd, J = 2.8, 8.8 Hz, 1H), 7.90 (dd, J = 4.8, 13_6 Hz, 1H)。參考例5 8-(2,4-二氟苯基)-2-乙烯基·5,6,7,8-四氫[i，2,4]***基[l，5-a] 吡啶之合成 [化學式58] 105 201031662Potassium tert-butoxide (9.58 g) was added to a solution of 4-fluoro-2-(trifluoromethyl)phenylacetonitrile (15.08 g) in THF (400 mL). Stir at the same temperature for 20 minutes. 1-Bromo-3-chloropropane 104 201031662 (8.07 ml) was added to the reaction solution, followed by stirring for three hours. A saturated vaporized ammonium solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then evaporated. A solution of this crude 5-chloro-2-(4-fluoro-2-trifluoromethylphenyl)pentanenitrile in ethanol (800 ml) was bubbled with hydrogen chloride for one hour under ice cooling. Then, the reaction solution was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure. A solution of this residue in EtOAc (800 mL) was again bubbled with hydrogenated hydrogen for one hour under ice cooling. Then, the reaction solution was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure. The third butyl methyl ether is added to the formed residue. Development of 13.4 g of the title compound was obtained. The properties of this compound are as follows. ESI-MS; m/z 326 [M++H]. 'H-NMR (CDC13) δ (ppm): 1.41 (t, J = 7.2 Hz, 3H), 1.69-1.94 (m, 2H), 2.37 (m, 1H), 2.58 (m, 1H), 3.55-3.62 (m, ❿ 2H), 4.46 (dd, J = 7.2, 8.4 Hz, 1H), 4.64 (q, J = 7.2 Hz, 2H), 7.38 (m, 1H), 7.43 (dd, J = 2.8, 8.8 Hz , 1H), 7.90 (dd, J = 4.8, 13_6 Hz, 1H). Reference Example 5 8-(2,4-Difluorophenyl)-2-vinyl·5,6,7,8-tetrahydro[i,2,4]triazolyl[l,5-a]pyridine Synthesis [Chemical Formula 58] 105 201031662

1-胺基-3-(2,4-二氟苯基)哌啶-2-酮之合成 [化學式59]Synthesis of 1-amino-3-(2,4-difluorophenyl)piperidin-2-one [Chemical Formula 59]

亞硫酿氣(7毫升）以滴液方式添加至於冰冷卻下之甲酵 (80毫升）内之2,4-二氟苯基乙酸(4克）之溶液，然後，反應溶液於室溫授拌二小時。反應溶液於減壓下濃縮。形成之殘質通過一短管柱，獲得粗製之曱基(2,4-二氟苯基）乙酸酯產物。The sulfurous gas (7 ml) was added dropwise to a solution of 2,4-difluorophenylacetic acid (4 g) in a solution (80 ml) under ice cooling, and then the reaction solution was applied at room temperature. Mix for two hours. The reaction solution was concentrated under reduced pressure. The resulting residue is passed through a short column to obtain a crude mercapto (2,4-difluorophenyl) acetate product.

氫化鈉（含有60%礦物油’ 976毫克)添加至於冰冷卻下之DMF(60毫升）内之粗製甲基(2,4-二氟苯基）乙酸酯之溶液，其後，於室溫授拌1·5小時。反應溶液以冰冷卻，且1-氣-3-碘丙烷(2.57毫升）以滴液方式添加。然後，反應溶液於室溫攪拌三小時。飽和氣化銨溶液及乙酸乙酯添加至反應溶液，且有機層被分離。形成之有機層依序以水及鹽水清洗，於無水硫酸鎂乾燥，然後，於減壓下濃縮。形成之殘質通過一短管柱，獲得粗製之甲基5-氯-2-(2,4-二氟苯基)戊酸酯產物。肼單水合物（11·3毫升）添加至於乙醇(60毫升）内之粗製甲基5-氣-2-(2,4-二氟苯基)戊酸酯之溶液。混合物於室溫攪拌14小時，然後，於迴流下加熱11小時。反應溶液於減壓 106 201031662 下濃縮。乙酸乙酯及飽和碳酸氫鈉溶液添加至形成之殘質，且有機層被分離。形成之有機層於無水硫酸鎂乾燥，且於減壓下濃縮。殘質藉由矽石凝膠管柱色譜分析術（載劑：Chromatorex™ NH)純化，獲得2.97克之標題化合物。此化合物之性質數值係如下。 1H-NMR (CDC13) δ (ppm): 1.89-2.16 (m, 4H)， 3.56-1.89-2.16 (m, 2H)，3.83 (m，1H), 4，58 (brs，2H), 6.78-6.86 (m，2H), 7.11 (m, 1H)。 N-[3-(2,4-二氟苯基辰咬-1-基]-3-對-甲苯基硫燒基丙醯胺之合成 [化學式60]Sodium hydride (containing 60% mineral oil '976 mg) was added to a solution of the crude methyl (2,4-difluorophenyl) acetate in DMF (60 mL) under ice cooling, then at room temperature Mix for 1.5 hours. The reaction solution was ice-cooled, and 1-nitro-3-iodopropane (2.57 ml) was added dropwise. Then, the reaction solution was stirred at room temperature for three hours. A saturated ammonium carbonate solution and ethyl acetate were added to the reaction solution, and the organic layer was separated. The organic layer formed was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The resulting residue is passed through a short column to give the crude methyl 5-chloro-2-(2,4-difluorophenyl)pentanoate product. A solution of crude methyl 5- gas-2-(2,4-difluorophenyl)pentanoate was added to hydrazine monohydrate (11.3 ml) in ethanol (60 mL). The mixture was stirred at room temperature for 14 hours and then heated under reflux for 11 hours. The reaction solution was concentrated under reduced pressure 106 201031662. Ethyl acetate and a saturated sodium hydrogencarbonate solution were added to the formed residue, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (c: ChromatorexTM NH) to give 2.97 g of the title compound. The properties of this compound are as follows. 1H-NMR (CDC13) δ (ppm): 1.89-2.16 (m, 4H), 3.56-1.89-2.16 (m, 2H), 3.83 (m, 1H), 4,58 (brs, 2H), 6.78-6.86 (m, 2H), 7.11 (m, 1H). Synthesis of N-[3-(2,4-difluorophenylheptan-1-yl]-3-p-tolylsulfanylpropionamide [Chemical Formula 60]

EDC(3.77克）、ΗΟΒΤ(2_66克)及ΙΡΕΑ(9.13毫升)依序添加至於DMF(90毫升）内之1 -胺基-3-(2,4-二氟笨基）哌啶-2-酮（2.97克）及3-[(4-甲基苯基）硫基]丙酸(2.7克）之溶液，其後，於室溫攪拌27小時。乙酸乙酯及水添加至反應溶液，且有機層被分離。形成之有機層於無水硫酸鎂乾燥，經由一矽墊過濾，然後，於減壓下濃縮。形成之殘質藉由矽石凝膠管柱色譜分析術純化，獲得3.66克之標題化合物。此化合物之性質數值係如下。 !H-NMR (CDC13) δ (ppm): 1.96-2.03 (m, 3H), 2.14 (m, 1H), 2.32 (s, 3H), 2.52 (m, 2H), 3.18 (m, 2H) 3.60-3.78 (m, 2H), 3.93 (m，1H), 6.77-6.87 (m，2H)，7.U (山 J = 8·〇 Hz，2H)， 107 201031662 7.22-7.30 (m，4H), 7.84 (brs, 1H)。 8-(2,4-二氟苯基)-2-(2-對-甲苯基硫烷基乙基)-5,6,7,8-四氫 -[1,2,4]***基[1，5^]«比啶之合成 [化學式61]EDC (3.77 g), hydrazine (2_66 g) and hydrazine (9.13 ml) were added sequentially to 1-amino-3-(2,4-difluorophenyl)piperidin-2- in DMF (90 mL) A solution of the ketone (2.97 g) and 3-[(4-methylphenyl)thio]propanoic acid (2.7 g) was stirred at room temperature for 27 hours. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated. The residue formed was purified by a silica gel column chromatography to give 3.66 g of the title compound. The properties of this compound are as follows. !H-NMR (CDC13) δ (ppm): 1.96-2.03 (m, 3H), 2.14 (m, 1H), 2.32 (s, 3H), 2.52 (m, 2H), 3.18 (m, 2H) 3.60- 3.78 (m, 2H), 3.93 (m, 1H), 6.77-6.87 (m, 2H), 7.U (Mountain J = 8·〇Hz, 2H), 107 201031662 7.22-7.30 (m, 4H), 7.84 (brs, 1H). 8-(2,4-Difluorophenyl)-2-(2-p-tolylsulfanylethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolyl [1,5^]« Synthesis of pyridine [Chemical Formula 61]

氧氣化磷(75.6毫升)添加至N-[3-(2,4-二氟苯基)-2-噁哌啶-1-基]-3-對-甲苯基硫烷基丙醯胺(3.66克），其後，於120°C 攪拌一小時。然後，反應溶液於減壓下濃縮。乙酸銨(6.66 克）及乙酸(90毫升)依序添加至形成之殘質，且反應混合物於150°C攪拌2.5小時。反應溶液於減壓下濃縮。乙酸乙酯及含水之氨添加至形成之殘質，且有機層被分離。形成之有機層於無水硫酸鎂乾燥，且於減壓下濃縮。形成之殘質藉由石夕石凝膠管柱色譜分析術（載劑：Chromatorex™ NH) 純化，獲得1.4克之標題化合物。此化合物之性質數值係如下。 ESI-MS; m/z 386 [M++H]。 8-(2,4-二氟苯基)-2-乙烯基-5,6,7,8-四氫[1,2,4]***基[l，5-a] °比咬之合成 [化學式62]Oxygenated phosphorus (75.6 ml) was added to N-[3-(2,4-difluorophenyl)-2-oxipridin-1-yl]-3-p-tolylsulfanylpropanamine (3.66). (g), after which it was stirred at 120 ° C for one hour. Then, the reaction solution was concentrated under reduced pressure. Ammonium acetate (6.66 g) and acetic acid (90 ml) were added sequentially to the formed residue, and the reaction mixture was stirred at 150 ° C for 2.5 hours. The reaction solution was concentrated under reduced pressure. Ethyl acetate and aqueous ammonia were added to the formed residue, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The residue formed was purified by Shihashi gel column chromatography (carrier: ChromatorexTM NH) to give 1.4 g of the title compound. The properties of this compound are as follows. ESI-MS; m/z 386 [M++H]. Synthesis of 8-(2,4-difluorophenyl)-2-vinyl-5,6,7,8-tetrahydro[1,2,4]triazolyl [l,5-a] ° ratio bite [Chemical Formula 62]

108 201031662 過換酸鈉（1.16克）添加至於曱醇（135毫升）及水(67 4毫升）内之8-(2,4-二氟笨基）_2_(2_對-甲苯基硫烷基乙基）-5,6,7,8-四氫[1，2,4]***基冲比唆（1_4克）之混合溶液，其後，於室溫攪拌19小時。反應溶液於減壓下濃縮。然後，乙酸乙酯及水添加至殘質，且有機層被分離。形成之有機層於無水硫酸鎂乾燥，且於減壓下濃縮。於甲苯内之形成殘質之溶液於迴流下加熱三天。反應溶液於減壓下濃縮’且形成之殘質藉由石夕石凝膠管柱色譜分析術純化。然後，形成之產物通過一NH矽石墊，獲得744毫克之標題化合物。此化合物之性質數值係如下。 ESI-MS; m/z 262 [M++H]。 !H-NMR (CDC13) δ (ppm): 1.96-2.19 (m, 3H), 2.32 (m, 1H), 4.25 (m, 2H), 4.52 (dd, J = 6.0, 7.22 Hz, 1H), 5.45 (dd, J = 1.6, 10.8 Hz, 1H), 6.15 (dd, J = 1.6, 17.6 Hz, 1H), 6.67 (dd, J =10.8, 17.6 Hz，1H)，6.79-6.92 (m, 3H)。參考例6 2-》臭-8-(5-異丙基-4-甲氧基_2-甲基本基)-5,6,7,8-四氣[1，2,4] 三0坐基[l,5-a]e比淀之合成 [化學式63] —/ 0— 甲基(5-異丙基-4-曱氧基-2-甲基苯基）乙酸酯之合成 [化學式64] 109 201031662108 201031662 Sodium percarbonate (1.16 g) added to 8-(2,4-difluorophenyl)_2_(2_p-tolylsulfanyl) in methanol (135 ml) and water (67 4 ml) A mixed solution of ethyl)-5,6,7,8-tetrahydro[1,2,4]triazole-based oxime (1 - 4 g) was stirred at room temperature for 19 hours. The reaction solution was concentrated under reduced pressure. Then, ethyl acetate and water were added to the residue, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The residue forming solution in toluene was heated under reflux for three days. The reaction solution was concentrated under reduced pressure and the residue formed was purified by silica gel column chromatography. The resulting product was then passed through an NH vermiculite pad to afford 744 mg of the title compound. The properties of this compound are as follows. ESI-MS; m/z 262 [M++H]. !H-NMR (CDC13) δ (ppm): 1.96-2.19 (m, 3H), 2.32 (m, 1H), 4.25 (m, 2H), 4.52 (dd, J = 6.0, 7.22 Hz, 1H), 5.45 (dd, J = 1.6, 10.8 Hz, 1H), 6.15 (dd, J = 1.6, 17.6 Hz, 1H), 6.67 (dd, J = 10.8, 17.6 Hz, 1H), 6.79-6.92 (m, 3H). Reference Example 6 2-"Oxo-8-(5-isopropyl-4-methoxy-2-methylphenyl)-5,6,7,8-tetraki [1,2,4] Synthesis of the base [l,5-a]e ratio synthesis [Chemical formula 63] - / 0 - methyl (5-isopropyl-4-decyloxy-2-methylphenyl) acetate synthesis [chemical formula 64] 109 201031662

❹ 亞硫醯氣(3.5毫升）以滴液方式添加至於冰冷卻下之甲醇(5〇毫升）内之(5-異丙基-4-甲氧基·2_甲基苯基）乙酸(CAS 編號，81354-65-6, 5.5克）之溶液。然後，反應溶液回到室溫，且攪拌二小時。反應溶液於減壓下濃縮。飽和碳酸氩鈉溶液及第三丁基甲基醚添加至殘質，且有機層被分離。形成之有機層以鹽水清洗，然後，於無水硫酸納乾燥。此乾燥劑藉由過濾分離，然後，有機層於減壓下濃縮。殘質藉由矽石凝膠管柱色譜分析術純化，獲得標題化合物(5〇克）。此化合物之性質數值係如下。 !H-NMR (CDC13) δ (ppm): 1.19 (d, J = 7.2 Hz, 3H), 1.19 (d? J = 7.2 Hz, 3H), 2.28 (s, 3H), 3.25 (qq, j = 7.2, 7.2 Hz, 1H), 3.58 (s, 2H), 3.68 (s, 3H), 3.80 (s, 3H), 6.66 (s, 1H), 7.00 (s, 1H)。甲基5-氣-2-(5-異丙基-4-曱氧基-2-甲基苯基)戊酸酯之合成 [化學式65]❹ Thionite (3.5 ml) was added dropwise to (5-isopropyl-4-methoxy-2-methylphenyl)acetic acid (CAS) in methanol (5 mL) under ice cooling. No., 81354-65-6, 5.5 g). Then, the reaction solution was returned to room temperature and stirred for two hours. The reaction solution was concentrated under reduced pressure. A saturated sodium argon carbonate solution and a third butyl methyl ether were added to the residue, and the organic layer was separated. The resulting organic layer was washed with brine and dried over anhydrous sodium sulfate. This desiccant was separated by filtration, and then the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (5 g). The properties of this compound are as follows. !H-NMR (CDC13) δ (ppm): 1.19 (d, J = 7.2 Hz, 3H), 1.19 (d? J = 7.2 Hz, 3H), 2.28 (s, 3H), 3.25 (qq, j = 7.2 , 7.2 Hz, 1H), 3.58 (s, 2H), 3.68 (s, 3H), 3.80 (s, 3H), 6.66 (s, 1H), 7.00 (s, 1H). Synthesis of methyl 5-gas-2-(5-isopropyl-4-oxooxy-2-methylphenyl)valerate [Chemical Formula 65]

於無水DMF(30毫升）内之甲基（5_異丙基_4_甲氧基_2_ 甲基苯基）乙酸酯（5克）之溶液添加至於氮^氛圍中之於4至 6°C之内部溫度之無水DMF(5〇t升）内之6〇0/。氫化鈉（928毫 110 201031662Add a solution of methyl (5-isopropyl_4_methoxy-2-methylphenyl) acetate (5 g) in anhydrous DMF (30 ml) to a nitrogen atmosphere at 4 to 6 The internal temperature of °C is 6〇0/ in anhydrous DMF (5〇t liter). Sodium hydride (928 mM 110 201031662

克）之懸浮液，其後，於相同溫度攪拌五分鐘。然後，1-氯 -3-碘丙烷（4·5毫升）添加至於4至6°C之内部溫度之反應溶液。其後，反應溶液回到室温，且攪拌四小時。乙酸乙酯添加至反應溶液，其後，以水清洗。形成之有機層以鹽水清洗，然後，於無水硫酸鈉乾燥。此乾燥劑藉由過遽分離，然後，有機層於減壓下濃縮。殘質藉由矽石凝膠管柱色譜分析術純化，獲得標題化合物(7.7克）。此化合物之性質數值係如下。 1 H-NMR (CDC13) δ (ppm): 1.17 (d, J = 7.2 Hz, 3H), 1.19 (d, J = 7.2 Hz, 3H), 1.64-1.97 (m, 3H), 2.14-2.25 (m, 1H), 2.35 (s, 3H), 3.24 (qq, J = 7.2, 7.2 Hz, 1H), 3.48-3.56 (m, 2H), 3.64 (s, 3H), 3.77 (t, 7.6 Hz, 1H), 3.08 (s, 3H), 6.64 (s, 1H), 7.08 (s, 1H)。第三丁基N’-[5-氣-2-(5-異丙基-4-曱氧基-2-甲基苯基）戊醯基]肼羧酸酯之合成The suspension was then stirred at the same temperature for five minutes. Then, 1-chloro-3-iodopropane (4.5 ml) was added to the reaction solution at an internal temperature of 4 to 6 °C. Thereafter, the reaction solution was returned to room temperature and stirred for four hours. Ethyl acetate was added to the reaction solution, followed by washing with water. The resulting organic layer was washed with brine and dried over anhydrous sodium sulfate. The desiccant was separated by hydrazine, and then the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound ( 7.7 g). The nature of the properties of this compound is as follows. 1 H-NMR (CDC13) δ (ppm): 1.17 (d, J = 7.2 Hz, 3H), 1.19 (d, J = 7.2 Hz, 3H), 1.64-1.97 (m, 3H), 2.14-2.25 (m , 1H), 2.35 (s, 3H), 3.24 (qq, J = 7.2, 7.2 Hz, 1H), 3.48-3.56 (m, 2H), 3.64 (s, 3H), 3.77 (t, 7.6 Hz, 1H) , 3.08 (s, 3H), 6.64 (s, 1H), 7.08 (s, 1H). Synthesis of tert-butyl N'-[5-gas-2-(5-isopropyl-4-indolyl-2-methylphenyl)pentanyl]indole carboxylate

[化學式66][Chemical Formula 66]

5N氫氧化鈉溶液（22毫升）添加至於曱醇（25毫升)-THF(25毫升）内之甲基5-氣-2-(5-異丙基-4-甲氧基-2-甲基苯基）戊酸酯（7.7克)之混合溶液，其後，於室溫攪拌四小時。反應溶液於減壓下濃縮。水添加至殘質，其後，以庚烷清洗。水性層以5 N氫氯酸呈酸性，其後，以第三丁基甲 111 201031662 基醚萃取。形成之有機層以鹽水清洗，然後，於無水硫酸鈉乾燥。此乾燥劑藉由過濾分離，且有機層於減壓下濃縮，獲得5-氣-2-(5-異丙基-4-甲氧基_2·甲基苯基)戊酸(6 2克）。 B0PC1(7.9克）添加至於冰冷卻下之於二氣曱烷（12〇毫升）内之5-氣-2-(5-異丙基-4-甲氧基_2_甲基苯基）戊酸(6 2 克）、肼基甲酸第三丁酯（4.1克）&IPEA(1〇 8毫升）之溶液。然後，反應溶液於室溫攪拌隔夜。反應溶液於減壓下濃縮。碳酸氫鈉溶液及第三丁基甲基醚添加至殘質，且有機層被分離。形紅有制以鹽水清洗，織，於無水硫酸納乾燥。此乾燥劑藉由過濾分離，然後，有機層於減壓下濃縮。殘質藉由矽石凝膠管柱色譜分析術純化，獲得標題化合物 (6.1克）。此化合物之性質數值係如下。 ESI_MS; m/z 435 [M++Na]。 5-氯-2-(5-異丙基·4-甲氧基_2-甲基苯基)戊酸醯肼之合成 [化學式67]5N NaOH solution (22 ml) was added to benzyl alcohol (25 mL) in THF (25 mL). A mixed solution of phenyl)pentanoate (7.7 g) was stirred at room temperature for four hours. The reaction solution was concentrated under reduced pressure. Water was added to the residue, after which it was washed with heptane. The aqueous layer was acidic with 5 N hydrochloric acid, after which it was extracted with a tributylmethyl 111 201031662 ether. The resulting organic layer was washed with brine and dried over anhydrous sodium sulfate. The desiccant was separated by filtration, and the organic layer was concentrated under reduced pressure to give 5-dichloro-2-(5-isopropyl-4-methoxy-2-methylphenyl)pentanoic acid (6 2 g) ). B0PC1 (7.9 g) was added to 5-Gas-2-(5-isopropyl-4-methoxy-2-methylphenyl)pentane in dioxane (12 mL) under ice-cooling A solution of acid (62 g), tert-butyl carbazate (4.1 g) & IPEA (1 mL). Then, the reaction solution was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure. A sodium hydrogencarbonate solution and a third butyl methyl ether were added to the residue, and the organic layer was separated. The red form is washed with salt water, woven, and dried in anhydrous sodium sulfate. The desiccant was separated by filtration, and then the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (6.1 g). The properties of this compound are as follows. ESI_MS; m/z 435 [M++Na]. Synthesis of 5-chloro-2-(5-isopropyl-4-methoxy-2-methylphenyl)pentanoic acid oxime [Chemical Formula 67]

4Ν氯化氫-乙酸乙酯溶液(5〇毫升）添加至溶於乙酸乙酯 (50毫升）内之第三丁基冲_[5_氣_2_(5異丙基_4甲氧基甲基苯基)戊醯基]肼羧酸酯(61克)之溶液，其後，於室溫攪拌 3.5小時。反應麟以於冰冷卻下之5Ν氫氧灿溶液呈驗性，且有機層被分離。形成之有機層以鹽水清洗，然後，於無水硫義乾燥。此細雜㈣濾分離然後，有機 112 201031662 層於減壓下濃縮。殘質藉由矽石凝膠管柱色譜分析術純化，獲得標題化合物(4.4克）。此化合物之性質數值係如下。 ESI-MS; m/z 313 [M++H]。4 Νhydrogen chloride-ethyl acetate solution (5 liters) was added to the third butyl _[5_gas_2_(5 isopropyl-4 methoxymethylbenzene) dissolved in ethyl acetate (50 ml) A solution of the pentyl hydrazide] carboxylic acid ester (61 g) was stirred at room temperature for 3.5 hours. The reaction lining was tested for 5 Ν oxyhydrogen solution under ice cooling, and the organic layer was separated. The resulting organic layer was washed with brine and dried over anhydrous sulphur. This fine (4) filter was separated and then the organic 112 201031662 layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound ( 4.4 g). The properties of this compound are as follows. ESI-MS; m/z 313 [M++H].

h-NMR (CDC13) δ (PPm): 1-186 (d, J = 6.8 Hz, 3H)，1.190 (d, J = 7.2 Hz, 3H), 1.61-1.85 (m, 2H), 1.93-2.04 (m, 1H), 2.26-2.88 (m, 1H), 2.27 (s, 3H), 3.25 (qq, J = 7.2, 6.8 Hz, 1H), 3.48-3.59 (m, 3H), 3.75-3.89 (m, 5H), 6.49 (br s, 1H), 6.65 (s，1H)，7.08 (s, 1H)。 8-(5-異丙基-4-曱氧基-2-曱基苯基)-5,6,7,8-四氫[1,2,4]三0圭基[l，5-a]吡啶-2-基胺之合成 [化學式68]h-NMR (CDC13) δ (PPm): 1-186 (d, J = 6.8 Hz, 3H), 1.190 (d, J = 7.2 Hz, 3H), 1.61-1.85 (m, 2H), 1.93-2.04 ( m, 1H), 2.26-2.88 (m, 1H), 2.27 (s, 3H), 3.25 (qq, J = 7.2, 6.8 Hz, 1H), 3.48-3.59 (m, 3H), 3.75-3.89 (m, 5H), 6.49 (br s, 1H), 6.65 (s, 1H), 7.08 (s, 1H). 8-(5-Isopropyl-4-decyloxy-2-mercaptophenyl)-5,6,7,8-tetrahydro[1,2,4]trimethyl group [l,5-a Synthesis of pyridin-2-ylamine [Chemical Formula 68]

對-甲笨磺酸單水合物(4克）添加至於乙醇（150毫升）内之5-氣-2-(5-異丙基-4-甲氧基-2-曱基苯基)戊酸醯肼(4.4克) 及氰胺(3.6克）之溶液，且混合物於80。(：之迴流下加熱二小時。冷卻至室溫後，ΤΕΑ(9·8毫升）添加至反應溶液，且混合物於80。(：迴流下進一步加熱三天。反應溶液於減壓下濃縮。碳酸氫鈉溶液及乙酸乙酯添加至殘質，且有機層被分離。形成之有機層以鹽水清洗，然後，於無水硫酸鈉乾燥。此乾燥劑藉由過濾分離，然後，有機層於減壓下濃縮。殘質藉由石夕石凝膠管柱色譜分析術純化，獲得標題化合物(2 4 克）。此化合物之性質數值係如下。 113 201031662 ESI-MS; m/z 301 [M++H]。 1H-NMR (CDC13) δ (ppm): 1.12 (d，J = 6.8 Hz, 3H)，1.14 (d， J = 6.8 Hz, 3H), 1.86-2.26 (m, 4H), 2.27 (s, 3H), 3.19 (qq, J =6.8, 6.8 Hz 1H), 3.79 (s, 3H), 4.02 (br s, 2H), 4.06-4.12 (m, 2H), 4.19-4.24 (m, 1H), 6.64 (s，1H)，6.69 (s, 1H)。 2-溴-8-(5-異丙基-4-甲氧基-2-曱基苯基)-5,6,7,8-四氫[1,2,4] 三0坐基之合成5-Gas-2-(5-isopropyl-4-methoxy-2-indolylphenyl)pentanoic acid added to ethanol (150 ml) A solution of hydrazine (4.4 g) and cyanamide (3.6 g), and the mixture was at 80. (: The mixture was heated under reflux for two hours. After cooling to room temperature, hydrazine (9·8 ml) was added to the reaction solution, and the mixture was stirred at 80. (: further heated under reflux for three days. The reaction solution was concentrated under reduced pressure. The sodium hydrogen solution and ethyl acetate were added to the residue, and the organic layer was separated. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The desiccant was separated by filtration and then the organic layer was evaporated. The residue was purified by silica gel column chromatography to give the title compound (24 g). The property of this compound is as follows. 113 201031662 ESI-MS; m/z 301 [M++H 1H-NMR (CDC13) δ (ppm): 1.12 (d, J = 6.8 Hz, 3H), 1.14 (d, J = 6.8 Hz, 3H), 1.86-2.26 (m, 4H), 2.27 (s, 3H), 3.19 (qq, J = 6.8, 6.8 Hz 1H), 3.79 (s, 3H), 4.02 (br s, 2H), 4.06-4.12 (m, 2H), 4.19-4.24 (m, 1H), 6.64 (s, 1H), 6.69 (s, 1H). 2-bromo-8-(5-isopropyl-4-methoxy-2-indolylphenyl)-5,6,7,8-tetrahydro [1,2,4] Synthesis of three zero bases

[化學式69][Chemical Formula 69]

亞硝酸異戊鹽（1毫升）添加至於乙腈（50毫升）内之8-(5-異丙基-4-甲氧基-2-甲基苯基）-5,6,7,8-四氫[1，2,4]***基 [1,5-a]。比啶-2-基胺（1.5克）及溴化銅（11)(1.7克）之溶液，且混合物於70°C加熱並攪拌45分鐘。乙酸乙酯添加至反應溶液，其後，以含水之氨清洗。形成之有機層以鹽水清洗，然後，於無水硫酸鈉乾燥。此乾燥劑藉由過渡分離，然後，有機層於減壓下濃縮。殘質藉由矽石凝膠管柱色譜分析術純化，獲得標題化合物（1.4克）。此化合物之性質數值係如下。 ESI-MS; m/z 364 [M++H]。 1 H-NMR (CDC13) δ (ppm): 1.11 (d, J = 7.2 Hz, 3H), 1.12 (d, J = 7.2 Hz, 3H), 1.90-2.30 (m, 4H), 2.26 (s, 3H), 3.19 (qq, J =7.2, 7.2 Hz, 1H), 3.80 (s, 3H), 4.24-4.29 (m, 2H), 4.30-4.36 114 201031662 (m，1H)，6.59 (s，1H)，6.65 (s，1H)。測試例1 於來自大执胎兒腦部之神經元培養物内之Ap肽之量化本發明實施下列測試以展現依據本發明之通式⑴之化合物之實用性。 (1)大鼠初代神經元培養物初代神經元培養物係自胚胎期第18天Wistar大鼠 φ (Charles Rlver JaPan，Yokohama, Japan)之大腦皮質層製備。特別地，胚胎係自於***麻醉下之懷孕大鼠無菌式移除。腦部自胚胎隔離且浸潰於以冰冷卻之L_15培養基（例如，Invitrogen Corp. Cat #11415-064, Carlsbad, CA，USA，或SIGMA L1518)。大腦皮質層於立體顯微鏡下自隔離之腦部收集。收集之大腦皮質層片斷物於一於37°C之含有0.25〇/〇 " 胰蛋白酶（Invitrogen Corp. Cat #15050-065, Carlsbad，CA， USA)及0.01%DNase(Sigma D5025，St. Louis, MO, USA)之 φ 酶溶液以酶處理30分鐘以使細胞分散。在此，酶反應係藉由添加經鈍化之馬血清至此溶液而停止。經酶處理之溶液以1，500 rpm離心處理五分鐘以移除上澄液。5至10毫升之培養基添加至形成之細胞團。以2% B27補充物（Invitrogen Corp. Cat #17504-044, Carlsbad, CA, USA)、25 μΜ 2-M基乙醇(2-ME, WAKO Cat #139-06861, Osaka, Japan)、0.5 mM L-楚胺酿胺（Invitrogen Corp. Cat #25030-081，Carlsbad, CA， USA)，及抗生素-抗真菌素(Invitrogen Corp. Cat #15240-062, Carlsbad，C A, US A)補充之神經細胞（Neurobasal)培養基 115 201031662 (Invitrogen Corp. Cat #21103-049, Carlsbad, CA，USA)作為培養基(神經細胞/B27/2-ME)。但是，未以2-ME (神經細胞 /B27)補充之如上之神經細胞培養基被用於此分析。細胞係藉由使添加此培養基之細胞團溫和移液而再次分散。細胞分散液經由一40-μιη之耐綸篩網（Cell Strainer，Cat #35-2340, Becton Dickinson Labware，Franklin Lakes, NJ, USA)過滤以移除剩餘之細胞團，因此，獲得一神經元細胞懸浮液。神經元細胞懸浮液以培養基稀釋，然後，於以聚_L或D-離胺酸預先塗覆之96-孔聚苯乙烯培養板(Falcon Cat #35-3075, Becton Dickinson Labware，Franklin Lakes, NJ，USA，使用如下所示方法以聚-L-離胺酸塗覆，或BIOCOATtn^w胞環境聚-D-離胺酸細胞培養器皿96-孔板，Cat #35-6461，Becton Dickinson Labware，Franklin Lakes, NJ, USA)以 5 x 1〇5 個細胞/公分2之起始細胞密度以1〇〇μ1/孔之體積被覆。聚_L•離胺酸塗覆係如下實行。100 pg/毫升之聚-L-離胺酸(SIGMA P2636, St. Louis, MO, USA)溶液係以0.15 Μ硼酸鹽緩衝液 (pH 8.5)以無菌式製備。100吨/孔之溶液添加至96_孔之聚本乙稀培養板’且於室溫培養一或多個小時，或於4〇c隔夜或更久。其後，經塗覆之96·孔聚苯乙烯培養板以無菌水清洗四次或更多次’然後’乾燥或以無菌PBS或培養基沖洗，且用於細胞被覆。被覆之細胞於37°C之培養板於5% C〇2-95%空氣培養一天。然後，全部量之培養基以新的神經細胞/B27/2-ME培養基替換，然後，此等孔另外培養三天。添加化合物 116 201031662 藥物係如下般於第4天添加至培養板。全部量之培養基自此等孔移除，且添加180 μΐ/孔之不含有2-ME且含有2% Β-27(神經細胞/Β27)之神經細胞培養基。於二甲基亞礙（其後縮寫為DMSO)内之測試化合物之溶液以神經細胞/Β27稀釋至高於最終濃度10倍之濃度。添加20 μΐ/孔之稀釋液，且與培養基充份混合。最終D M S Ο濃度係1 %或更少。僅d μ S Ο 添加至對照組。取樣細胞舫添加化合物後培養三天，且全部量之培養基被收集。形成之培養基作為ELISA樣品。細胞生存評估細胞生存係藉由MTT分析依據下列程序評估。收集培養基後，100 μΐ/孔之預先加溫之培養基添加至此等孔。再者’ 8 μΐ/孔之於D-PBS(-)(Dulbecco蛾酸鹽緩衝之食鹽水， SIGMA D8537，St· Louis, MO, USA)内之8 毫克/毫升之 MTT(SIGMA M2128, St. Louis, MO, USA)之溶液添加至此等孔。96-孔聚苯乙烯培養板於37〇c之培養器於5〇/〇 C〇2-95%空氣培養20分鐘。添加1〇〇 μι孔之MTT溶解緩衝液’且MTT代謝產物結晶充份溶解於37〇(^5% c〇2_95% 空氣之培養器内之緩衝液。然後，每一孔之於55〇 nm之吸收率被測量。MTT溶解緩衝液係如下般製備。1〇〇克SDS(十二烷基硫酸鈉（月桂基硫酸鈉），WAK〇 191_〇7145, 〇saka,Addition of isoamyl nitrite (1 ml) to 8-(5-isopropyl-4-methoxy-2-methylphenyl)-5,6,7,8-tetra in acetonitrile (50 mL) Hydrogen [1,2,4]triazolyl [1,5-a]. A solution of pyridin-2-ylamine (1.5 g) and copper bromide (11) (1.7 g) was added, and the mixture was heated at 70 ° C and stirred for 45 minutes. Ethyl acetate was added to the reaction solution, followed by washing with aqueous ammonia. The resulting organic layer was washed with brine and dried over anhydrous sodium sulfate. This desiccant was separated by a transition, and then the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (l. The properties of this compound are as follows. ESI-MS; m/z 364 [M++H]. 1 H-NMR (CDC13) δ (ppm): 1.11 (d, J = 7.2 Hz, 3H), 1.12 (d, J = 7.2 Hz, 3H), 1.90-2.30 (m, 4H), 2.26 (s, 3H ), 3.19 (qq, J = 7.2, 7.2 Hz, 1H), 3.80 (s, 3H), 4.24-4.29 (m, 2H), 4.30-4.36 114 201031662 (m, 1H), 6.59 (s, 1H), 6.65 (s, 1H). Test Example 1 Quantification of Ap peptides in neuronal cultures from the brain of a large fetus The following tests were carried out to demonstrate the utility of the compounds of the formula (1) according to the present invention. (1) Rat primary neuron culture The primary neuronal culture system was prepared from the cerebral cortex of Wistar rat φ (Charles Rlver JaPan, Yokohama, Japan) on the 18th day of embryonic stage. In particular, the embryonic line is aseptically removed from pregnant rats under ether anesthesia. The brain is isolated from the embryo and immersed in ice-cold L_15 medium (e.g., Invitrogen Corp. Cat #11415-064, Carlsbad, CA, USA, or SIGMA L1518). The cerebral cortex is collected from the isolated brain under a stereomicroscope. The collected cerebral cortex fragments contained 0.25 〇/〇" trypsin (Invitrogen Corp. Cat #15050-065, Carlsbad, CA, USA) and 0.01% DNase (Sigma D5025, St. Louis) at 37 °C. The φ enzyme solution of MO, USA) was treated with enzyme for 30 minutes to disperse the cells. Here, the enzymatic reaction is stopped by adding passivated horse serum to the solution. The enzyme-treated solution was centrifuged at 1,500 rpm for five minutes to remove the supernatant. 5 to 10 ml of the medium is added to the formed cell mass. 2% B27 supplement (Invitrogen Corp. Cat #17504-044, Carlsbad, CA, USA), 25 μΜ 2-M-based ethanol (2-ME, WAKO Cat #139-06861, Osaka, Japan), 0.5 mM L - Invitrogen Corp. Cat #25030-081, Carlsbad, CA, USA, and anti-antibiotics (Invitrogen Corp. Cat #15240-062, Carlsbad, CA, US A) supplemented nerve cells (Neurobasal) medium 115 201031662 (Invitrogen Corp. Cat #21103-049, Carlsbad, CA, USA) was used as the medium (neural cells/B27/2-ME). However, the above neuronal medium not supplemented with 2-ME (neural cells/B27) was used for this analysis. The cell line was again dispersed by gentle pipetting of the cell mass to which this medium was added. The cell dispersion was filtered through a 40-μηη nylon screen (Cell Strainer, Cat #35-2340, Becton Dickinson Labware, Franklin Lakes, NJ, USA) to remove the remaining cell mass, thus obtaining a neuron cell suspension. The neuronal cell suspension is diluted in medium and then plated in 96-well polystyrene plates pre-coated with poly-L or D-isoamine (Falcon Cat #35-3075, Becton Dickinson Labware, Franklin Lakes, NJ , USA, coated with poly-L-lysine using the method shown below, or BIOCOATtn^ cell environment poly-D-lysine cell culture vessel 96-well plate, Cat #35-6461, Becton Dickinson Labware, Franklin Lakes, NJ, USA) was coated with a volume of 1 μμl/well at a starting cell density of 5 x 1 〇 5 cells/cm 2 . The poly-L•isoleic acid coating system was carried out as follows. A solution of 100 pg/ml of poly-L-isoamine acid (SIGMA P2636, St. Louis, MO, USA) was prepared aseptically in 0.15 Torr borate buffer (pH 8.5). A 100 ton/well solution was added to the 96-well polyethyl acetate plate' and incubated at room temperature for one or more hours, or overnight at 4 〇c or longer. Thereafter, the coated 96-well polystyrene culture plate was washed four times or more with sterile water 'then' dry or rinsed with sterile PBS or medium, and used for cell coating. The coated cells were cultured at 37 ° C for one day in 5% C 〇 2-95% air. Then, the entire amount of the medium was replaced with a new nerve cell/B27/2-ME medium, and then these wells were cultured for another three days. Addition of Compound 116 201031662 The drug was added to the culture plate on the fourth day as follows. The entire amount of the medium was removed from the wells, and 180 μM/well of a nerve cell medium containing no 2-ME and containing 2% Β-27 (neural cells/Β27) was added. A solution of the test compound in dimethyl sulfoxide (hereinafter abbreviated as DMSO) was diluted with nerve cells/Β27 to a concentration 10 times higher than the final concentration. Add 20 μΐ/well of the dilution and mix well with the medium. The final D M S concentration is 1% or less. Only d μ S Ο was added to the control group. Sampling The cells were cultured for three days after the addition of the compound, and the entire amount of the medium was collected. The medium formed was used as an ELISA sample. Cell Survival Assessment Cell survival was assessed by MTT assay according to the following procedure. After the medium was collected, 100 μΐ/well of pre-warmed medium was added to the wells. Further, 8 μM/well of DMT (-) (Dulbecco moth buffered saline, SIGMA D8537, St. Louis, MO, USA) 8 mg/ml of MTT (SIGMA M2128, St. A solution of Louis, MO, USA) is added to these wells. 96-well polystyrene plates were incubated in a 37 °C incubator at 5 〇 / 〇 C 〇 2-95% air for 20 minutes. Add 1 μM well of MTT Lysis Buffer' and the MTT metabolite crystals were fully dissolved in 37 〇 (^5% c〇2_95% air in the buffer of the incubator. Then, each well was at 55 〇nm The absorption rate was measured. The MTT lysis buffer was prepared as follows: 1 gram SDS (sodium lauryl sulfate (sodium lauryl sulfate), WAK 〇 191_〇 7145, 〇saka,

Japan)溶於 250 毫升 N，N-二甲基甲醯（WAK〇 045-02916,Japan) is soluble in 250 ml of N,N-dimethylformamidine (WAK〇 045-02916,

Osaka，Japan)與250毫升蒸餾水之混合溶液。每一者35〇 μ1 il7 201031662 之濃氫氣酸及乙酸進一步添加至此溶液，使此溶液具有約 4.7之最終pH。測量時，無被覆細胞且僅含有培養*&MTT溶液之孔被設疋為背景（bkg)。測得之數值個別應用於下列方程式，包含自其減去bkg值。因此，相對於對照組（未以藥物處理之組’ CTRL)之比率（CTRL之際)被計算以比較及評估細胞生存活性。 CTRL 之 %=((八550_樣品-八550—bkg)/(A550—CTRL-bkg))x 1 〇〇 (八550_樣品：樣品孔之於55〇 nm之吸收率，A550_bkg :背景孔之於550 nm之吸收率，A550_CTRL :對照組孔之於550 nm之吸收率）A mixed solution of Osaka, Japan) and 250 ml of distilled water. Each of the 35 〇 μ1 il7 201031662 concentrated hydrogen acid and acetic acid was further added to the solution to give a final pH of about 4.7. At the time of measurement, the wells without the coated cells and containing only the culture *&MTT solution were set as the background (bkg). The measured values are individually applied to the following equations, including subtracting the bkg value therefrom. Therefore, the ratio (CTRL) of the control group (not in the group of drug treatments (CTRL) was calculated to compare and evaluate the cell survival activity. CTRL%=((eight 550_sample-eight 550-bkg)/(A550-CTRL-bkg))x 1 〇〇(eight 550_sample: sample hole at 55 〇nm absorption, A550_bkg: background hole Absorption rate at 550 nm, A550_CTRL: absorbance at 550 nm in the control wells)

Αβ ELISA 對於Αβ ELISA，Wako Pure Chemical Industries, Ltd.之人類/大鼠 β類澱粉(42)ELISA Kit Wako(#290-62601)或IBL Co.，Ltd之人類類澱粉β(1-42) Assay Kit (#27711)被使用。 Αβ ELISA係依據製造商推薦之方案（於所附文件中所述之方法)實行。但是，Αβ校正曲線係使用β-類澱粉肽1-42，大鼠(Calbiochem，#171596 [Αβ42])產生。結果係於第1表以相對於對照組之培養基中之Αβ濃度之百分率顯示（CTRL之 %)。由Αβ濃度之結果，以對照組之50%減少Αβ濃度之每一化合物之濃度(IC50)被計算。此等數據係顯示於第4表。 [第4表] 第4表 118 201031662 實施例1 〇實施例12 實施例14Αβ ELISA For Αβ ELISA, human/rat beta-starch (42) ELISA Kit Wako (#290-62601) from Wako Pure Chemical Industries, Ltd. or human-based starch β(1-42) Assay from IBL Co., Ltd. Kit (#27711) is used. The Αβ ELISA was carried out according to the manufacturer's recommended protocol (described in the attached document). However, the Αβ calibration curve was produced using a β-amyloid peptide 1-42, a rat (Calbiochem, #171596 [Αβ42]). The results are shown in Table 1 as a percentage of the concentration of Aβ in the medium relative to the control group (% of CTRL). As a result of the Αβ concentration, the concentration (IC50) of each compound which reduced the Αβ concentration by 50% of the control group was calculated. These data are shown in Table 4. [Table 4] Table 4 118 201031662 Embodiment 1 实施 Example 12 Example 14

測試化合物實施例2 實施例Test compound Example 2 Example

Αβ42產生之功效因此，依據本發明之通式⑴之化合物或其藥理學上可接受之鹽具⑽低學2產生之魏。叫本發明可特別地提供用於藉由Αρ造成之神經退化疾病（諸如，阿兹罕默氏疾病或唐氏症候群)之治療劑。 [產業應用性] 依據本發明之通式⑴之化合物具有降低八^產生之功效，且因此係特別地作為用於藉由Αρ造成之神經退化疾病 (諸如，阿兹罕默氏疾病或唐氏症候群)之治療劑。【圖式簡單說明】 (無）【主要元件符號說明】 (無） 119Efficacy of the production of Αβ42 Therefore, the compound of the formula (1) or the pharmacologically acceptable salt thereof according to the present invention (10) is produced by the lower learning. The present invention is particularly useful as a therapeutic agent for a neurodegenerative disease caused by Αρ, such as Azheimer's disease or Down's syndrome. [Industrial Applicability] The compound of the formula (1) according to the present invention has an effect of reducing the production of sputum, and thus is particularly useful as a neurodegenerative disease caused by Αρ (such as Azheimer's disease or Down's disease). Therapeutic agent for syndromes). [Simple description of the diagram] (none) [Description of main component symbols] (none) 119

Claims

201031662 七、申請專利範圍： 1. 一種以化學式[I]表示之化合物， [化學式1]201031662 VII. Patent application scope: 1. A compound represented by chemical formula [I], [Chemical Formula 1]

或其藥理學上可接受之鹽或酯，其中，心及尺2係相同或相異，且每一者代表—選自下列取代基族群al之取代基； m代表0至3之整數； η代表0至2之整數； X】代表i)一單鍵，ii) [化學式2] —c=c— αχ, ιιΐ)Or a pharmacologically acceptable salt or ester thereof, wherein the heart and the ruler 2 are the same or different, and each represents a substituent selected from the group of substituents a1; m represents an integer from 0 to 3; Represents an integer from 0 to 2; X] represents i) a single bond, ii) [Chemical Formula 2] —c=c—αχ, ιιΐ)

*ν j久八4 W仲PJ 3兄；f目吳，且每*ν j long eight 4 W Zhong PJ 3 brother; f eyes Wu, and each

代表⑴-氫原子，（2)-C1姚基基團，或(3)—齒子）；入2代表i) 一單鍵，⑴一⑽烧樓基基圏或叫X 中，x、3代表_NHcm(0)|S(c 且R5代表-氫原子、K絲·、—C尸 ::舰基基團，或⑽输基基圏;; 裒代表〇-五貝之芳香族雜環基團，或ii} 一虚 ===;合之五㈣香_環基團多個亂原子且可具有1至3個選自下列取> 120 201031662 族群bi之取代基(其中，該#芳香族環基團可具有—經交聯之結構或一螺族環系統），且環B代表一選自由化學式[2]至[19]所組成族群之單環或稠合環之芳香族環基圑： [化學式3] 2 9 2 * a > ^ ' 6 1Represents (1)-hydrogen atom, (2)-C1 yaki group, or (3)-dentate); 2 represents i) a single bond, (1) one (10) burns the base 圏 or X, x, 3 represents _ NHcm(0)|S(c and R5 represents -hydrogen atom, K-silk, -C corpse:: ship-based group, or (10)-transporting hydrazine; 裒 represents 〇-five aromatic aromatic heterocyclic group , or ii} a virtual ===; a five (four) fragrant ring group of a plurality of chaotic atoms and may have from 1 to 3 substituents selected from the following: 120 201031662 group bi (where the # aromatic The cyclic group may have a crosslinked structure or a spiro ring system, and ring B represents an aromatic ring group selected from a monocyclic or fused ring of the group consisting of the chemical formulas [2] to [19]. : [Chemical Formula 3] 2 9 2 * a > ^ ' 6 1

其每一者可具有1至3個選自下列取代基族群。之取代基，取代基族群al : — C1-6烧基基團、一C3-8環烧基基團、一C2-6稀基基團、一C1-6烧氧基基團、一C2-6稀氧基基團、一C3-8環烷氧基基團、一胺基基團（其中，該胺基基團可具有一C2-6烷醯基基團或C1-6烷基磺醯基基團或i 至2個C1-6烷基基團或C3-8環烷基基團）、一氰基基團、一甲醯基基團、一鹵素原子、一羥基基團及一硝基基團；取代基基團bl : — C1-6烷基基團（其中，該烷基基團可以 1至3個鹵素原子取代）、一 C2-6烯基基團、一 C3-8環烷基基團、一C6-14芳基基團、一C6-14芳基-C1-6烷基基團、一C1-6烷氧基基團、一C2_6烯氧基基團、一C3-8環烷氧基基團、一C2-6烷酿基基團、一C4-9環烷基羰基基團、一C7-15芳酿基基團、一C1_6烷基磺醯基基團、一C2-6 121 201031662 烯基磺醯基基團、一C3-8環烷基磺醯基基團、一C6-14 芳基磺醯基基團、一C1-6烷硫基基團、一C2-6烯硫基基團、一C3-8環烷硫基基團、一胺基磺醯基基團（其中，該胺基磺醯基基團可具有1至2個C1-6烷基基團、C2-6烯基基團或C3-8環烷基基團）、一胺基基團（其中，該胺基基團可具有一 C2-6烷醯基基團、C1-6烷基磺醯基基團或 C3-8環烷基磺醯基基團，或1至2個C1-6烷基基團或C3-8 環院基基團）、一氰基基團、一曱醯基基團、一函素原子、一羥基基團、一硝基基團、一側氧基基團、一 1-β比咯啶基基團、1-娘咬基基團、一 1-同略咬基基團、一β弓卜朶琳 -1-基基團、一 1,2,3,4-四氫啥琳-1-基基團及一4-嗎1#基基團；取代基基團cl : i) 一胺基基團（其中，該胺基基團可具有一C2-6烷醯基基團、C1-6烷基磺醯基基團或C3-8環烷基磺醯基基團，或1至2個C1-6烷基基團或C3_8環烷基基團），ii)一氣基基，iii)一鹵素原子，iv)—羧基基團及v) v)-i) 一C1-6烷基基團，v)-ii) — C2-6烯基基團，v)-iii) — C2-6 炔基基團，v)-iv) — C1-6烷氧基基團，v)-v) — C1-6烷硫基基團，v)-vi) — C1-6烷基胺基羰基基團，v)-vii) — C1-6烷基磺醯基基團，v)-viii) — C1-6烷基胺基磺醯基基團，v)-ix) 一C2-6烷醯基基團，v)-x)—苯基基團，v)-xi)—吡啶基基團，v)-xii)— α荅0丼基基團，v)-xiii)—鳴咬基基團，v)-xiv) 一 1-°比咯咬基基團，v)-xv) — 1-旅咬基基團，v)_xvi) — 1-同哌啶基基團及v)-xvii) — 4-嗎啉基基團，其每一者具有1 201031662 至3個選自一C1-6烷基基團及一鹵素原子所組成族群之取代基。 2.如申請專利範圍第1項之化合物或其藥理學上可接受之鹽或酯，其中，該環A係一選自化學式[20]至[26]所組成族群之五員之芳香族雜環基團： [化學式4]Each of them may have 1 to 3 substituent groups selected from the group consisting of the following. Substituents, a substituent group a: a C1-6 alkyl group, a C3-8 cycloalkyl group, a C2-6 dilute group, a C1-6 alkoxy group, a C2- a 6-oxyl group, a C3-8 cycloalkoxy group, or an amine group (wherein the amine group may have a C2-6 alkylalkyl group or a C1-6 alkylsulfonate group) a radical or i to 2 C 1-6 alkyl groups or a C 3-8 cycloalkyl group), a cyano group, a methionyl group, a halogen atom, a hydroxy group, and a nitro group a substituent group bl : — a C 1-6 alkyl group (wherein the alkyl group may be substituted with 1 to 3 halogen atoms), a C 2-6 alkenyl group, a C 3-8 ring An alkyl group, a C6-14 aryl group, a C6-14 aryl-C1-6 alkyl group, a C1-6 alkoxy group, a C2_6 alkenyloxy group, a C3- 8-cycloalkoxy group, a C2-6 alkyl aryl group, a C4-9 cycloalkylcarbonyl group, a C7-15 aryl group, a C1-6 alkyl sulfonyl group, C2-6 121 201031662 Alkenylsulfonyl group, a C3-8 cycloalkylsulfonyl group, a C6-14 arylsulfonyl group, a C1-6 alkylthio group, a C2 -6 olefin a group, a C3-8 cycloalkylthio group, an aminosulfonyl group (wherein the aminosulfonyl group may have 1 to 2 C1-6 alkyl groups, C2- a 6 alkenyl group or a C3-8 cycloalkyl group), an amine group (wherein the amine group may have a C2-6 alkylalkyl group, a C1-6 alkylsulfonyl group a C3-8 cycloalkylsulfonyl group, or 1 to 2 C1-6 alkyl groups or a C3-8 ring-based group), a cyano group, a fluorenyl group, a genomic atom, a hydroxy group, a nitro group, a oxy group, a 1-β-pyridyl group, a 1-n-butyl group, a 1-octyl group a group, a β-bendolin-1-yl group, a 1,2,3,4-tetrahydroinden-1-yl group and a 4-?1# group; a substituent group cl: i An amino group (wherein the amine group may have a C2-6 alkylalkyl group, a C1-6 alkylsulfonyl group or a C3-8 cycloalkylsulfonyl group, or 1 to 2 C1-6 alkyl groups or C3_8 cycloalkyl groups), ii) monohydric group, iii) a halogen atom, iv)-carboxy group and v) v)-i) a C1-6 Alkyl group, v)-ii) - C2-6 alkenyl团,v)-iii) — C2-6 alkynyl group, v)-iv) — C1-6 alkoxy group, v)-v) — C1-6 alkylthio group, v)-vi ) — C1-6 alkylaminocarbonyl group, v)-vii) — C1-6 alkylsulfonyl group, v)-viii) — C1-6 alkylaminosulfonyl group, v )-ix) a C2-6 alkino group, v)-x)-phenyl group, v)-xi)-pyridyl group, v)-xii)-α荅0丼 group, v)-xiii) - gnabdenyl group, v)-xiv) a 1-° ratio of a thiol group, v)-xv) — 1-bend bite group, v)_xvi) — 1- a piperidinyl group and a v)-xvii)-4-morpholinyl group each having 1 201031662 to 3 substituents selected from the group consisting of a C1-6 alkyl group and a halogen atom . 2. The compound of claim 1 or a pharmacologically acceptable salt or ester thereof, wherein the ring A is one selected from the group consisting of aromatics of the group consisting of the chemical formulas [20] to [26] Ring group: [Chemical Formula 4]

24 25 26 其中，•代表一與該化學式[27]之鍵結位置： [化學式5] . 0 (Rl且 A·代表一與X2之鍵結位置或選自化學式[28]至[39]所組成族群之任一環： [化學式6] 20103166224 25 26 where: • represents the bonding position of the chemical formula [27]: [Chemical Formula 5] . 0 (Rl and A· represent the bonding position of X and X2 or selected from the chemical formulas [28] to [39] Any ring that constitutes a group: [Chemical Formula 6] 201031662

其中，•及Α·係如上所定義及部份結構： [化學式7] 代表一單鍵或一雙鍵，其每一者可具有1至3個選自取代基族群Μ之取代基。 3.如申請專利範圍第2項之化合物或其藥理學上可接受之鹽或酯，其中，該環Α係選自化學式[21]、[28]、[29]、 [31]、P2]及[34]至[37]所組成族群之任一環：Wherein, • and Α are as defined above and a partial structure: [Chemical Formula 7] represents a single bond or a double bond, each of which may have 1 to 3 substituents selected from the group of substituents. 3. The compound of claim 2 or a pharmacologically acceptable salt or ester thereof, wherein the cyclic oxime is selected from the group consisting of the chemical formulas [21], [28], [29], [31], P2] And any ring of the group consisting of [34] to [37]:

[化學式8][Chemical Formula 8]

其中，·、A·及部分結構： [化學式9] 124 201031662 係如上所定義。 4.如申請專利範圍第2項之化合物或其藥理學上可接受之鹽或酯，其中，該環A係選自化學式[21]、[28-1]、[29-1]、 [31-1]、[32-1]及P4-1]至[37-1]所組成族群之任一環： [化學式10]Wherein, ···· and part of the structure: [Chemical Formula 9] 124 201031662 is as defined above. 4. The compound of claim 2 or a pharmacologically acceptable salt or ester thereof, wherein the ring A is selected from the group consisting of the chemical formulas [21], [28-1], [29-1], [31] -1], [32-1], and any ring of the group consisting of P4-1] to [37-1]: [Chemical Formula 10]

其中，·、A·及部分結構： [化學式11] 係如上所定義。 5.如申請專利範圍第2項之化合物或其藥理學上可接受之鹽或酯，其中，該環A係一化學式[28-1]之環： [化學式12]Wherein, ···· and part of the structure: [Chemical Formula 11] is as defined above. 5. The compound of claim 2 or a pharmacologically acceptable salt or ester thereof, wherein the ring A is a ring of the formula [28-1]: [Chemical Formula 12]

其中，·、A·及部分結構： [化學式13] 係如上所定義。 125 201031662 6. 如申請專利範圍第1項之化合物或其藥理學上可接受之鹽或酯，其中，該環B係一苯基基團、一吼啶基基團、一 °惡。坐基基團、一 β米β坐基基團、一嘆β坐基基團、一二氫苯并呋喃基基團或一噻吩基基團。 7. 如申請專利範圍第1項之化合物或其藥理學上可接受之鹽或酯，其中，Χι係i)一單鍵或ii)-CR3=CR4-。 8. 如申請專利範圍第1項之化合物或其藥理學上可接受之鹽或酯，其中，Χι係一單鍵。 9. 如申請專利範圍第1項之化合物或其藥理學上可接受之鹽或酯，其中，XH^、-CR3=CR4-。 10. 如申請專利範圍第1項之化合物或其藥理學上可接受之鹽或酯，其中，x2係i)一單鍵或ii)一C1-6烷撐基基團。 11. 如申請專利範圍第1項之化合物或其藥理學上可接受之鹽或酯，其中，X2係一單鍵。 12. 如申請專利範圍第1項之化合物或其藥理學上可接受之鹽或酯，其中，Ri係一C1-6烷基基團或一鹵素原子，且 m係1至2。 13. 如申請專利範圍第1項之化合物或其藥理學上可接受之鹽或酯，其中，R2係一C1-6烷氧基基團，且η係1。 14. 如申請專利範圍第9項之化合物或其藥理學上可接受之鹽或酯，其中，R3及尺4係相同或相異，且每一者係（1)一氫原子或(2) — i素原子。 15. 如申請專利範圍第9項之化合物或其藥理學上可接受之鹽或S旨，其中，R3及R4每一者係一氫原子。 201031662 16. 如申請專利範圍第1項之化合物或其藥理學上可接受之鹽或酯，其中，該環A之該取代基係一選自：一C1-6烷基基團（其中，該烷基基團可以1至3個鹵素原子取代）、一 C3-8環烷基基團、一 C6-14芳基基團、一 C6-14芳基 -C1-6烷基基團、一C1-6烷氧基基團、一C3-8環烷氧基基團、一C2-6烷醯基基團、一C7-15芳醯基基團、一C1-6 烷基磺醯基基團、一 C3-8環烷基磺醯基基團、一 C6-14 方基確酿基基團、'鼠基基團、一曱酿基基團、·—鹵素原子、一羥基基團及一側氧基基團所組成族群之取代基。 17. 如申請專利範圍第1項之化合物或其藥理學上可接受之鹽或酯，其中，該環B之該取代基係一選自：i)一胺基基團（其中，該胺基基團可具有一 C2-6烧醯基基團、C1-6 f 烷基磺醯基基團或C3·8環烷基磺醯基基團，或1至2個 * C1-6烷基基團或C3·8環烧基基團），丨丨)一氰基基團，iii) 一鹵素原子’ iv)一經基基團’及v) V)_i)-"C1·6烷基基 • 團，v)-ii)'c卜6烷氧基基團’v)_iii)一C1_6烷硫基基團，及v)-iv)—苯基基團所組成族群之取代基’其每一者可具有1至3個選自一C卜6烧基基團及一鹵素原子所組成族群之取代基。 18. —種化合物，其係選自化學式[A_1]至[A-7]所組成之族群： 127 201031662Wherein, ···· and partial structure: [Chemical Formula 13] is as defined above. The compound of claim 1 or a pharmacologically acceptable salt or ester thereof, wherein the ring B is a monophenyl group, an acridinyl group, and a decant. A sitting group, a β-m β-sitting group, a singly β-sodium group, a dihydrobenzofuranyl group or a thienyl group. 7. The compound of claim 1 or a pharmacologically acceptable salt or ester thereof, wherein Χι is i) a single bond or ii)-CR3=CR4-. 8. The compound of claim 1 or a pharmacologically acceptable salt or ester thereof, wherein Χι is a single bond. 9. The compound of claim 1 or a pharmacologically acceptable salt or ester thereof, wherein XH^, -CR3 = CR4-. 10. The compound of claim 1 or a pharmacologically acceptable salt or ester thereof, wherein x2 is i) a single bond or ii) a C1-6 alkylene group. 11. The compound of claim 1 or a pharmacologically acceptable salt or ester thereof, wherein X2 is a single bond. 12. The compound of claim 1 or a pharmacologically acceptable salt or ester thereof, wherein Ri is a C1-6 alkyl group or a halogen atom, and m is 1 to 2. 13. The compound of claim 1 or a pharmacologically acceptable salt or ester thereof, wherein R2 is a C1-6 alkoxy group and η is 1. 14. The compound of claim 9 or a pharmacologically acceptable salt or ester thereof, wherein R3 and 4 are the same or different and each is (1) a hydrogen atom or (2) — i atom. 15. A compound according to claim 9 or a pharmacologically acceptable salt thereof, wherein each of R3 and R4 is a hydrogen atom. The compound of claim 1 or a pharmacologically acceptable salt or ester thereof, wherein the substituent of the ring A is selected from the group consisting of: a C1-6 alkyl group (wherein An alkyl group may be substituted with 1 to 3 halogen atoms), a C3-8 cycloalkyl group, a C6-14 aryl group, a C6-14 aryl-C1-6 alkyl group, a C1 a -6 alkoxy group, a C3-8 cycloalkoxy group, a C2-6 alkyl fluorenyl group, a C7-15 aryl fluorenyl group, a C1-6 alkyl sulfonyl group a C3-8 cycloalkylsulfonyl group, a C6-14 aryl group, a 'murine group, a broth group, a halogen atom, a hydroxyl group, and a Substituents of the group consisting of pendant oxy groups. 17. The compound of claim 1 or a pharmacologically acceptable salt or ester thereof, wherein the substituent of the ring B is selected from the group consisting of: i) an amino group (wherein the amine group) The group may have a C2-6 decyl group, a C1-6f alkylsulfonyl group or a C3.8 cycloalkylsulfonyl group, or 1 to 2*C1-6 alkyl groups. a group or a C3·8 cycloalkyl group, 丨丨) a cyano group, iii) a halogen atom 'iv) through a group ' and v) V) _i)-"C1·6 alkyl group • a group, v)-ii) a 'c 6 alkoxy group 'v) _iii) a C1_6 alkylthio group, and a substituent of the group consisting of v)-iv)-phenyl groups One may have 1 to 3 substituents selected from the group consisting of a C-hexyl group and a halogen atom. 18. A compound selected from the group consisting of chemical formulas [A_1] to [A-7]: 127 201031662

或其藥理學上可接受之鹽或酯。 · 19. 20. —種藥劑’包含作為-活性成份之如申請專利範圍扪至18項中任-項之化合物或其藥理學上可接受之鹽酯。 —⑩ 如申請專利範圍第19項之藥劑，係用於治療一選自阿茲罕默氏疾病、癡呆症、唐氏症候群及類澱粉變性症之疾病0 128 v 201031662 四、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：Or a pharmacologically acceptable salt or ester thereof. 19. 20. A pharmaceutical agent' comprises, as an active ingredient, a compound of any one of the claims -18 to 18 or a pharmacologically acceptable salt thereof. —10 The pharmaceutical agent of claim 19 is for the treatment of a disease selected from the group consisting of Azheimer's disease, dementia, Down's syndrome and amyloidosis. 0 128 v 201031662 IV. Designated representative map: ( a) The representative representative of the case is: ( ). (none) (2) A brief description of the symbol of the representative figure:

五、本案若有化學式時，請揭示最能顯示發明特徵的化學式：5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention:

(R丄(R丄

ι-〇-χ2-〇Ι-〇-χ2-〇