TW201035076A - Aryl imidazole compound - Google Patents

Abstract

A compound represented by the formula (I): or a pharmacologically acceptable salt or ester thereof, wherein Ring A represents a triazolyl group or the like which may be substituted, Ring B represents a phenyl group or the like which may be substituted, X1 represents a single bond or the like, R1 and R2 each represent a C1-6 alkyl group or the like, m represents an integer of 0 to 3, and n represents an integer of 0 to 2, is effective as a therapeutic agent for a disease caused by Aβ.

Description

201035076 VI. Description of the invention: [Technical field to which the invention pertains] FIELD OF THE INVENTION The present invention relates to a drug, and more particularly to a therapeutically useful class; I and each _β (hereinafter referred to as Ap) A neurodegenerative disease such as an arrhythmia disease or a polycyclic aryl group of Down's syndrome. The rice saliva derivative and a drug are more particularly concerned with a drug comprising the compound as an active ingredient for the treatment of a disease caused by Aβ. D [Prior Art] Background of the Invention - Alzheimer's disease is a disease characterized by neuronal degeneration and loss, and formation of senile plaques and neurofibrillation. At present, Alzheimer's disease is treated with symptomatic treatment using a symptom-improving agent typified by an acetylcholinesterase inhibitor, and no basic treatment for inhibiting the disease has been developed. There is a need to develop a method of controlling the onset of pathology to form the underlying treatment for Alzheimer's disease. It is presumed that Αβ-protein which is a metabolite of a starch-like precursor protein (hereinafter referred to as ΑΡΡ) is highly involved in the degeneration and loss of neurons and the onset of symptoms of dysthymia (for example, refer to Non-Patent Documents 1 and 2). The main molecular class of Αβ-protein is Αβ40 and Αβ42 containing 40 amino acids, and two amino acids are added to the C-terminus. Αβ40 and Αβ42 are known to be highly accumulating (e.g., Non-Patent Document 3) and are the main components of senile plaques (e.g., refer to Non-Patent Documents 3, 4, and 5). Further, it is known that Αβ40 and Αβ42 are increased by the mutation observed in the familial Alzheimer's disease and the presenilin gene 3 201035076 (see, for example, Non-Patent Documents 6, 7 and 8). Thus, the compound which can be reduced is expected to be used as an inhibitor or preventive agent for AlH. The Αβ system is produced by cleavage of App by a secretase and subsequent cleavage by p secretase. For this reason, attempts have been made to form γ-secretase inhibitors and β-secretase to reduce the production of Aβ. A variety of such secretase inhibitors are known 'for example, peptides and peptide mimetics such as L_685, 458 (for example, refer to Non-Patent Document 9), LY_4U, 575 (for example, reference non-articles 1G, 11 and 12) and LY -450, 139 (refer to Non-Patent Documents 13, 14 and 15). Non-peptide compounds such as MRK-560 (see Non-Patent Documents 16 and 17) and compounds having a plurality of aromatic rings are disclosed in Patent Documents 1 and 2. However, the compound represented by the formula (VI) which is not disclosed on page I7 of the specification differs from the compound of the present invention in that the compound is limited to a compound having a 2-aminothiazolyl group as a main structural formula. And the compound represented by the formula (1) disclosed on page 6 of the specification of Patent Document 2 differs from the compound of the present invention in that the former is limited to a compound having an ethynyl group, an extended ethylene group or a low methyl linking group described as Χ. First Month 1 Technical Document Patent Document Patent Document 1: WO 2004/110350 Patent Document 2 : WO 2007/102580 Non-Patent Document Non-Patent Document 1: Klein WL and Seven Others, Alzheimer's Disease Brain: Recruitment The presence of Αβ ligand (ADDL) suggests a molecular basis for reversible memory loss, Proceedings of the National Academy of Sciences, September 2, 2003; 201035076 100(18), 10417-10422. Non-Patent Document 2: Nitsch RM and another sixteen, anti-beta-type amyloid antibodies slow cognitive decline in Alzheimer's disease, Neuron, 2003, May 22; 38' 547-554. Non-Patent Document 3: Jarrett JT and two others, the carboxyl terminal of beta-amyloid protein is critical for the sowing of starch-like formation: the suggestion of the cause of Alzheimer's disease, 'Biochemistry, 1993, 32(18), Page 4693-4697. Non-Patent Document 4: Glenner GG and another, Alzheimer's disease: Preliminary report on the purification and characterization of novel cerebrovascular amyloid proteins, Biochemistry and Biophysical Research Newsletter, 1984, May 16, 120 ( 3), pages 885-890. Non-Patent Document 5: Masters CL and five others, Alzheimer's disease and core protein of amyloid plaques such as Down's syndrome, Proceedings of the National Academy of Sciences' 1985, June, 82(12), 4245-4249 page. Non-Patent Document 6: Gouras GK and seven others, Αβ42 accumulation in neurons of the human brain, American Journal of Pathology, January 2000, 156(1), 15_2 〇. Non-Patent Document 7: Scheuner D and 20 others, a starch-like protein secreted in age-related plaques similar to Alzheimer's disease, in vivo due to presenilin associated with familial Alzheimer's disease Increased 'natural medicines' with presenilin 2 and ΑΡΡ mutations, August 2, 1996, (8), pp. 864-870. Non-Patent Document 8: Forman MS and four others, the differential effect of Swedish mutant starch precursor protein on β-type starch accumulation and secretion in neurons and non-neuronal cells, Journal of Biochemistry, 1997, December 19曰, 272(51) '32247-32253. 5 201035076 Non-Patent Document 9: Shearman MS and nine others, L-685, 458, a transient state mimetic of aspartic thiol protease, a potent inhibitor of γ-secretase activity of the starch-like β-protein precursor, organism Chemistry, August 1, 2000, 39 (30), 8698-8704. Non-Patent Document 9: Shearman MS and six others, catalytic position-directed gamma-secretase complex inhibitors have no pharmacological differences between notched S3 and β-ΑΡΡ cleavage' biochemistry, 2003, June 24 , 42(24), 7580-7586 pages. Non-Patent Document 11: LanzTA and three others, using the γ-secretase inhibitor N2-[(2S)-2-(3,5-difluorophenyl)_2-hydroxyethylidene]-Nl-[(7S) )-5-mercapto-6-one-6,7-dihydro-5H-dibenzo[b,d]indole-7-yl]-L-alanamine indole (LY-411575) in childhood (none Plaque) Tg2576 mouse brain, cerebrospinal fluid and blood sputum β pharmacodynamic study, Journal of Pharmacology and Experimental Therapeutics, April 4, 309(1), 49-55. Non-Patent Document 12: Wong GT and 12 others, long-term treatment with γ-secretase inhibitor LY-411,575 inhibits the production of β-amyloid peptides and changes lymphoid production and intestinal cell differentiation, Journal of Biochemistry, March 26, 2004, 279(13), 12879-12882. Non-Patent Document 13: Gitter BD and 10 others, using LY450139, a novel functional gamma secretase inhibitor to selectively inhibit the secretion of starch-like peptides, aging neurology, 2004, 25, SUp 2, 571 pp. Non-Patent Document 14: Lanz TA and another 18 people, using the γ-secretase inhibitor LY-4 5 013 9 in vivo and in vitro to regulate the concentration dependence of starch-like β-Pharmacology and Experimental Therapeutics , November 2006, 319(2), 201035076 924-933. Non-Patent Document 15: Effects of γ-secretase inhibitors in the random assignment study of Siemers ER and another 12 people in patients with Alzheimer's disease, Neurology, 2006, 66, 602-604. Non-Patent Document 16: Best JD and the other nine people' use of the novel broad-secretase inhibitor Ν-[cis-4-[(4-chlorophenyl)sulfonyl]-4-(2,5-di) in rats Fluorophenyl)cyclohexyl]-1,1,1-trifluoromethanesulfonamide (ΜΚ_560) is characterized in vivo by changes in Αβ(40) in the brain and cerebrospinal fluid, Journal of Pharmacology and Clinical Therapeutics, May 2006, 317(2), 786-790. Non-patent document Π ·· Best JD and 13 others, novel γ_secretase inhibitor Ν-[cis-4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluoro Phenyl)cyclohexyl]-U,1-trifluoromethanesulfonamide (ΜΚ-560) reduces the deposition of amyloid plaques in Tg2576 mice without gap-related pathological evidence, Journal of Pharmacology and Clinical Therapeutics February 2007, 320 (2), 552-558. t韵^明内溶1 SUMMARY OF THE INVENTION The problem to be solved by the present invention is as described above, and the compound which inhibits the manufacture of APP is expected to be used as a remedy or agent caused by Αβ, and the surface is Alzheimer's The disease is a typical representative. However, it has not been known to inhibit the highly potent non-peptide compounds manufactured by the eight. There is a need for a novel low molecular weight compound that can be made. Means for Solving the Problem Through thorough thorough research results, the inventors have found that a novel non-7 201035076 peptide polycyclic compound can inhibit the production of Αβ from APP, thus finding a therapeutic agent for a disease caused by Αβ, which is Alzheimer's disease is a typical representative. The findings of this finding led to the completion of the present invention. SUMMARY OF THE INVENTION In particular, the present invention relates to the following 1) to 12): 1) A compound represented by the formula [I]:

Or a pharmacologically acceptable salt or ester thereof, wherein the centers thereof 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; η represents 0 to 2 An integer: W represents a nitrogen atom or a carbon atom; a ring Α represents a ring selected from the group consisting of formulas [2] to [8]:

6 7 8 5 8 201035076 each of which may have from one to three substituents selected from the group of substituents below, wherein · represents a bond to the position of the formula [9]: 0 9 and A· represents a bond Junction to XI position; ❹ X 〗 indicates i) single bond, ii) C1-6 alkylene, iH) extended vinyl which may have j to 2 C2-6 炫 or ιν)-Χ2- (where Χ2 means _Nr3_, _〇_, -c(o)_, -NR3C(0)-, -C(0)NR3-, _s-, -S(O)- or -s(0)2- and r3 Represents a hydrogen atom, a Cl-6 alkyl group, a C3-6 cycloalkyl group, a C2-6 alkanoyl group or a C1-6 alkylsulfonyl group; and a ring B is selected from the formulas [10] to [27] a monocyclic or fused ring aromatic ring group in the group consisting of:

0 〇 Ο Ό ’ 11 ’ 12 ’ 13 ’ 14 » 15

Each of them may have one to three substituents selected from the group of substituents below [Substituent group a: C1-6 alkyl 'C3-8 cycloalkyl, C2-6 alkenyl, C1- 6 alkoxy, (: 2_6 alkenyloxy, C3-8 cycloalkyloxy, amine group (wherein the 9 201035076 amine group may have a C2-6 alkyl fluorenyl group or a Cl-6 alkyl sulfonyl alcohol group or 1 Up to 2 C1-6 alkyl or C3-8 cycloalkyl), cyano, decyl, halogen, hydroxy and nitro; substituent group bl: C1-6 alkyl (wherein the alkyl group can be Substituted with 1 to 3 halogen atoms), C2-6 alkenyl, C3-8 cycloalkyl, C6-14 aryl, C6-14 aryl-C1-6 alkyl, C1-6 alkoxy, C2- 6 alkenyloxy, C3-8 cycloalkyloxy, C2-6 alkyl fluorenyl, C4-9 cycloalkylcarbonyl, C7-15 aryl fluorenyl, C1-6 alkylsulfonyl, C2-6 alkenyl Sulfonyl, C3-8 cycloalkylsulfonyl, C6-14 arylsulfonyl, C1-6 alkylthio, C2-6 alkenyl, C3-8 cycloalkylthio, aminesulfonyl (wherein the amine sulfonyl group may have 1 to 2 C 1-6 alkyl groups, C 2-6 alkenyl groups or C 3-8 cycloalkyl groups), an amine group (wherein the amine group may have a C 2-6 alkyl fluorenyl group, C1-6 alkylsulfonyl or C3-8 cycloalkylsulfonyl or 1 2 C1-6 alkyl or C3-8 cycloalkyl), cyano, decyl, halogen, hydroxy, nitro, oxy, 1-pyrrolidinyl, 1-piperidinyl, 1-highper Pyridyl, porphyrin-1-yl, 1,2,3,4-tetrahydroinden-1-yl and 4-indolyl; substituent group cl): i) amine group (wherein the amine group) May have a C2-6 alkyl fluorenyl group, a C1-6 alkyl sulfonyl group or a C3-8 cycloalkyl sulfonyl group or 1 to 2 C1-6 alkyl or C3-8 cycloalkyl), ii) cyanide a group, (1)) a halogen atom, iv) a radical, and v) vi) a C1-6 alkyl 'v-ii) a C2-6 alkenyl group, a v_iii) a C2-6 alkynyl group, a v-iv) C1-6 alkoxy group Base, vv) C1-6 thiol group, v-vi) C1-homoamine group, v-vii) C1-6 alkylsulfonyl, v-viii) C1-6 alkylamine sulfonyl, V-ix) C2-6 alkanoyl, vx)phenyl, v-xi)eltD, v-xii), v-xiii) mouth bite, v-xiv) 1-pyrrolidinyl, v -xv) 1-piperidinyl, v_xvi) 1-homopiperidinyl and v-xvii) 4-carbolinyl, each of which may have been selected from the group consisting of C1-6 alkyl and halogen atoms 10 201035076 1 to 3 substituents in the group]; 2) The compound of the above item 1) or a pharmacologically acceptable salt or ester thereof, wherein the ring A is selected from the group consisting of [3] to [8] in the group consisting of one of the ring:

And a pharmacologically acceptable salt or ester thereof, wherein the ring A is represented by the formula [3]: 〆·3; 4) the compound of the above item 1) or a pharmacologically acceptable salt thereof Or an ester wherein ring B is a phenyl group, an acridine group, a carbazolyl group, an imidazolyl group, a thiazolyl group, a dibenzobenzofuranyl group or a thienyl group; 5) a compound of the above item 1) or a pharmacologically acceptable thereof a salt or ester wherein Χ is i) a single bond, ii) a C1-6 alkyl group or iii) -X2- (wherein X2 represents -NR3- or -C(O)- and R3 represents a hydrogen atom, C1-6 alkane a compound of the above item 1) or a pharmacologically acceptable salt or ester thereof, wherein 1^ is (wherein, C3-6 cycloalkyl, C2-6 alkanoyl or C1-6 alkylsulfonyl); Or a pharmaceutically acceptable salt or ester of the compound of the above item 1), wherein 11 201035076 R2 is a C1-6 alkoxy group and η is 1 And a pharmacologically acceptable salt or ester thereof, wherein the substituent of the cyclic oxime is selected from the group consisting of C1-6 alkyl (wherein the alkyl group Substituted with 1 to 3 halogen atoms), C3-8 cycloalkyl, C6-14 aryl, C6-14 -C1-6 alkyl, C1-6 alkoxy, C3-8 cycloalkyloxy, C2-6 alkyl fluorenyl, C7-15 aryl fluorenyl, C1-6 alkylsulfonyl, C3-8 a cycloalkylsulfonyl group, a C6-14 arylsulfonyl group, a cyano group, a decyl group, a halogen atom, a hydroxyl group, and an oxy group;

And a pharmacologically acceptable salt or ester thereof, wherein the substituent of the ring B is selected from the group consisting of: i) an amine group (wherein the amine group may have one C2-6 alkanoyl, C1-6 alkylsulfonyl or C3-8 cycloalkylsulfonyl or 1 to 2 C1-6 alkyl or C3-8 cycloalkyl), ii) cyano, iii iS atom, iv) thiol, and v) vi) C1-6 da "yl, v-ii" C1-6 alkoxy, v-iii) C1-6 alkylthio, and v-iv) phenyl Each of them may have 1 to 3 substituents selected from the group consisting of a C1-6 alkyl group and a halogen atom;

10) A compound selected from the group consisting of the following formulas [A-1] to [A-6]:

12 201035076

Or a pharmaceutically acceptable salt or ester thereof;

n) a medicament comprising the compound of any one of the above items 1) to 1 or a pharmacologically acceptable salt or ester thereof as an active ingredient; and 12) the medicament of the above item 11) for use in Alzheimer's Treatment of illness, dementia, Down syndrome, or mild powder degenerative disease. [Embodiment] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The therapeutic agent of the compound of the general formula [I] or a pharmacologically acceptable salt or ester thereof according to the present invention and the disease caused by Aβ according to the present invention has not been described in any A novel invention of the document. The compounds of the invention can be converted into chemical probes for capturing the target proteins in biologically active low molecular weight compounds. In particular, the labeling group, the linking group, and the like are introduced into the structural components necessary for the activity of the compound by the technique of the Japanese Society of Scientific and Technical Journal, Vol. 51, No. 5, 2003, 492-498, or WO 2007/139149 (for example). In part, the compounds of the invention can be converted into affinity chromatography probes, photoaffinity probes, and the like. 13 201035076 Examples of the labeling group, the linking group and the like for the chemical probe include the groups shown in the group consisting of the following (1) to (5): 0) a protein labeling group such as a photoaffinity labeling group (such as a benzindenyl group, a benzophenone group, an azide group, a carbonyl azide group, a dimethyl group, an enone group, a diazo group, and a nitro group) and a chemical affinity group (such as an α-carbon atom substituted with a halogen atom) a keto group, an amine sulfhydryl group, an ester group, an alkylthio group, a Michael acceptor such as an α,β-unsaturated ketone and an ester, and an oxirane group, and (2) a cleavable link group such as -ss, -O-Si-O-, monosaccharides (such as glucosyl and galactosyl) and disaccharides (such as lactose), and enzyme-catalyzed cleavable nutrient-bonding groups, (3) bait-labeling groups such as Biotin and 3-(4,4-di- _5,7-dimethyl 4H-3a,4a-di-sigma-4-a-s-indol-3-yl)propyl, (4) Detectable labels such as radioactive labeling groups such as I25, 32ρ, soil and -14c; fluorescent labeling groups such as luciferin, rhodamine, diammonium naphthalene sulfonyl, ketone, 7-stone xiao And 3-(4,4-di-l-5,7-dimethyl-4H-3a,4a-丫丫•4-boron-s_茚莘_3_yl)propanyl; chemically cold-based groups such as luciferin and luminol; and heavy metal ions such as lanthanide metal ions and radium y, (5) A group bonded to a solid phase carrier such as a glass bead, a glass bed, a micro force plate, an agarose bead, an agarose bed, a polystyrene bead, a polystyrene bed, a nylon bead, and a nylon bed. When a label selected from a group consisting of (丨) to (5) is introduced into a probe of the present invention according to the method described in the aforementioned document or the like, the probe can be used as an identifier for searching for a novel drug. Target (for example) standard 14 201035076 Chemical probe for protein. The definitions of the symbols, terms, and the like used in the present specification and the details of the present invention will be further explained below. In the present specification, a certain isomer can be represented for the structural formula of the compound. However, the present invention encompasses the construction of compounds from which the isomers and isomer mixtures such as geometric isomers, optical isomers based on asymmetric carbon atoms, stereoisomers and tautomers can be produced. For convenience, the invention may include any of its isomers or mixtures without being limited to the chemical description. Thus, the compounds of the present invention may have asymmetric atoms in the molecule and be present as optically active compounds or racemates, and the present invention includes - optically active compounds and racemates without limitation. Although a crystalline polymorph of the compound may be present, the compound is not limited thereto and may be present in a single crystal form or a mixture of mono-crystal forms. The compound can be a dehydrate or a hydrate. The present invention also encompasses isotopically-labeled compounds which are identical to the compounds of formula (1), but one or more of the atomic systems are replaced by atoms having atomic or mass numbers different from those found in nature. Examples of the isotopes which may be incorporated in the compound of the present invention include isotopes of gas, carbon, nitrogen, oxygen, phosphorus, fluorine, iodine and chlorine such as 2H, $, %, %, 18F, 35S, 1231 and 1251. Compounds of the invention containing the foregoing isotopes and/or other isotopes of other atoms and the orally acceptable derivatives (e.g., salts) of such compounds are within the scope of the invention. The isotopically labeled compounds of the present invention, e.g., compounds in which a radioisotope such as 3H and/or 14c is incorporated, can be used in pharmaceutical and/or enzyme matrix tissue distribution assays. 3h&I4c is considered useful because it is easy to prepare and easy to detect. nC and isotopic considerations for PET (positive emission tomography) and 1251 isotope are considered to be available for SPECT (single positron emission computed tomography), all of which can be used for brain imaging. The use of heavier isotopes such as 2H substitutions provides therapeutic advantages with higher metabolic stability, such as prolonged half-life in vivo or reduced dose requirements, which is considered useful in some cases. Isotopically labeled compounds of formula (I) of the present invention can generally be prepared by performing the procedures shown in the following reaction schemes and/or examples by preparing a readily available isotopically labeled reagent for the replacement of a non-isotopically labeled reagent. . The term "disease attributable to Aβ" includes a wide variety of conditions such as Alzheimer's disease (for example, refer to Klein WL and seven others, the brain of Alzheimer's disease: recruiting polymer Αβ ligands ( The presence of ADDL) suggests the molecular basis of reversible memory loss, Proceedings of the National Academy of Sciences, 2nd, 3rd, September 2nd; 100(18), 1〇4ΐ7_ι〇 422 pages; Nitsch RM and another 16 people, anti-β Amyloid-like antibodies slow cognitive decline in Alzheimer's disease, neurons 2 to 3 years, May 22, 38 '547-554; Jarrett JT and two others, beta-type amyloid The key importance of the seeding of the temple powder formation: the suggestion of the cause of Alzheimer's disease, biochemistry '1993, 32 (18), 4693-4697; Glenner GG and another 'Alzheimer's disease: novel brain Preliminary report on the purification and characterization of vascular amyloid, Biochemistry and Biophysical Research Newsletter, 1984, May 16, 120 (3), 885-890; Masters CL and five others, Alzheimer Starch plaque core protein such as disease and Down syndrome, Proceedings of the National Academy of Sciences, 1 present 85 , June, 82 (12), 4245_4249 16 201035076, Gouras GK and seven others, the accumulation of Αβ42 in the brain of the human brain, American Journal of Pathology January 2000, 156 〇), 15_2 ; page; ScheunerD and the other two Ten people's starch-like protein secreted in senile plaques similar to Alzheimer's disease is increased in vivo due to presenilin 1 and 2 and sputum mutations associated with familial Alzheimer's disease, natural medicine , August 2, 1996, (8), 864-870; Forman MS and four others, the difference in the accumulation and secretion of β-type starch in neuronal and non-neuronal cells of Swedish mutant starch precursor protein Effects, Journal of Biochemistry, 1997, December 19, 272 (51), 32247-32253), elderly dementia (eg reference to Blass Jp, brain metabolism and encephalopathy: metabolic defects are Alzheimer's dementia The cause of the disease? Journal of Neuroscience Research, December 1, 2001, 66 (5), pp. 851_856), forehead dementia (for example, refer to Evin G and eleven others, presenilin _ 丨 associated amount An alternative to dementia, NeuroReport, April 16, 2002, 13(5), 719-723 Pico's disease (for example, reference to Yasuhara Ο and three others, starch-like precursor protein accumulation in brain lesions of patients with Pick's disease, neuroscience letter, 1994, April 25, Π 1 (1_2) ' 63 -66 pages), Down syndrome (for example, referring to Teller JK and 10 others, the presence of soluble starch 0_peptide is the precursor of the formation of starch plaques such as Down's syndrome, Nature Medicine, 1996, 2, 2 1) '93-95 pages; TokudaT and another six people's syndromes such as Down's syndrome p protein Αβ1-40 and Αβ1-42 (43) increased plasma concentrations, neurological annual report 'February 1997, 41 ( 2) 'Page 271-273), vascular lesions of the cerebrovascular (for example, with reference to Hayashi Υ and nine other people, Presenilin-1 is involved in Alzheimer's disease, such as amyloplasty in the brain, brain research, 1998 4 13th, 789(2), pp. 307-314; Barelli and 15 others, 40 and 42 amino acid powders p 17 201035076 Peptide specificity novel multi-strain antibody characterization: it is used Immunohistochemistry for examining cell biology of presenilin and occasional cases of Alzheimer's disease and brain amyloplasty , Molecular Medicine, October 1997, 3 (1〇), 695-707; Calhoun ME and the other ten people's mutant starch-precursor protein neuronal over-expression results in significant deposition of cerebrovascular Proceedings of the National Academy of Sciences 'November 23, 1999, 96 (24), 14088-14093; Dermaut B and 10 others, brain amyloplasty due to novel presenilin-1 mutation caused by Alzheimer's Pathogenic lesions of the disease, brain, December 2001, 124(12) '2383-2392), hereditary cerebral hemorrhage with a class of powdery degeneration (Dutch type) (for example, reference to Cras P and nine others, Alzheimer's disease dementia characterized by amyloplasty and senile plaques in the large genus of the 692Ala-Gly mutation, Acta Neuropathologica (Berl), 1998 September, 96(3) '253-260; Herzig MC and 14 others, Αβ targets the vascular bed in a mouse model of hereditary intracerebral hemorrhage with amyloidosis.

Natural Neuroscience 'September 2004, 7 (9), pp. 954-960; van Duinen SG and five other people with Dutch-derived patients with hereditary cerebral hemorrhage with amyloidosis are associated with Alzheimer's disease 'Proceedings of the National Academy of Sciences, August 1987, 84 (16) ' 5991-5994; Levy E and eight others, hereditary cerebral hemorrhage Dutch type Alzheimer's disease starch gene mutation, science, 199 June 1 曰 '248 (4959), 1124-1126), cognitive impairment (for example, reference to Laws SM and seven others, presenilin) mutation Giu318Gly and memory impaired complaints, neurobiology of aging , 2002, January-February, 23(1), 55-58), § I have recalled I1 predisposition/learning disorder (for example, refer to Vaucher E and another five 18 201035076 people, in the performance of human presenilin-ι gene Objective Cognitive Memory and Cholinergic Parameters in Transgenic Mice, Experimental Neurology, June 2002, 175(2), pp. 398-406; Morgan D and Fourteen, Alzheimer's Disease Animals Immunization with Αβ-peptide in the study model prevents memory loss, Nature, December 21-28, 2000, 408 (6815), pp. 982-985 Moran ΡΜ and three others, the learning deficit associated with the aging of 751 amino acid homologous gene-transforming mice expressing human beta-starch precursor protein, Proceedings of the National Academy of Sciences, June 6, 1995, 92 ( 12), 5341-5345), amyloidosis, cerebral ischemia (for example, reference to Laws SM and seven others, presenilin-1 mutation Glu318Gly and memory impaired complaints, neurobiology of aging, 2002 , January-February, 23(1), 55-58 pages; Koistinaho Μ and 10 others, β-type starch precursor protein gene-transferred mice with diffused Αβ sediment but no plaque formation Increased blood tendency: Inflammatory role, Proceedings of the National Academy of Sciences, February 5, 2002, 99(3), 1610-1615 pages; Zhang F and four others, excessive expression of starch-like precursor protein gene-transgenic mice Increased sensitivity to bloody brain injury, Journal of Neuroscience, 1997, October 15曰, 17(20), 7655-7661), cerebrovascular dementia (eg, reference to Sadowski 另 and six others, Az Association between pathology of Hammer's disease and vascular dementia, neurochemical study , June 2004, 29 (6), pages 1257-1266), eye muscle itching (for example, refer to O'Riordan S and seven others, presenilin-1 mutation (E280G), spastic paralysis, and intracranial MRI Abnormal white matter, neurology, October 8, 2002, 59(7), 11〇8_1110), multiple sclerosis (eg, reference GehrmannJ and four others, starch-like precursor protein (APP) in multiple sclerosis lesions Performance, Glia, October 1995, 15(2), 141-51 19 201035076; Reynolds WF and six others, myeloperoxidase polymorphism is associated with gender-specific Alzheimer's disease risk, experiment Neurology, January 1999, 155(1), pp. 31-41), head injury, skull injury (eg reference DH, and four others, protein accumulation of k-type double injury, neuronal drug, 2003, 4 ( 1-2), pages 59-72), apraxia (for example, reference to Matsubara-Tsutsui Μ and seven others, molecular evidence of presenilin-1 mutation in familial early-onset dementia, American Journal of Internal Medicine Genetics 2 〇〇April 8 曰' 114(3) '292-298 pages), Pri〇n disease, familial amyloid neuropathy, three Repetitive disease (for example, reference to Kirkitadze MD and two others, typical migration of Alzheimer's disease and other neurodegenerative disorders: the role of a polymeric assembly emerges, Journal of Neuroscience Research, September 1, 2002, 69 ( 5), 567-577; Evert BO and eight others, upregulated inflammatory genes in the amplified ataxin-3-expressing cell line and spinocerebellar ataxia type 3 brain , Journal of Neuroscience, August 1, 2001, 21 (15), 5389-5396; Mann DM and another, inside the brain of individuals with dementia other than Alzheimer's disease and Down's syndrome Precipitation of starch (A4), neuroscience, February 5, 1990, 109 (1-2), pp. 68-75), Parkinson's disease (for example, refer to Primavera J and four others, Yu Fei Brain accumulation of starch beta in Alzheimer's neurodegeneration, Alzheimer's Disease Journal, 1 month, 1999, 1 (3), pp. 183-193), dementia with Luwei (For example, refer to Giasson ΒΙ and the other two, the interaction of the protein-producing proteins. Neuromolecular drugs, 2003, 4 (1-2), 49-58; Masliah E and six others, β-classes in a model of genetically transgenic mice associated with Alzheimer's disease and Parkinson's disease Amyloid peptide enhances α_synthetic nuclides 20 201035076 (synuclein) accumulation and neuronal defects, Proceedings of the National Academy of Sciences, October 9, 2001 '98(21), 12245-1225G; Barrachina 另 and six others, Starch-like starch in the cerebral cortex containing dementia _@ deposited with the relative increase of ΑβΡρ mRNA isoforms containing Kumtz protease inhibitors, International Neurochemistry, February 2, 5, 46(3), pp. 253-260; Primavera J and four others, accumulating in the brain of non-Alzheimer's neurodegeneration, Alzheimer's disease, 1 month, 1999丨(3), pp. 183-193, Parkinson's-mental syndrome (eg reference to SchmidtML and six other people's Guam amyotrophic lateral sclerosis/Bakinson _ dementia complexes, etc. Amyloid plaques contain what is seen in starch plaques similar to Alzheimer's disease and pathological aging' February 1998, 95(2), 117-122 ;Ito Η and three others, verification of β-like amyloid neurofibrillary tangles in Guankins-Batkinson-mental syndrome, Neuropathology and Applied Neurobiology, October 1991, 17(5) , pp. 365-373), frontotemporal dementia and Parkinson's disease associated with chromosome 17 (eg, reference to rosso SM and three others, coexisting with hereditary frontotemporal dementia with a tau mutation!; and Starch-like pathology, New York Academy of Sciences Annual Report, 2000, 920, pp. 115-119), dementia with silver-stained granules (eg reference to Tolnay Μ and four others, low starch-like (Αβ) plaque loading and relative Mainly containing diffuse plaques to distinguish between silvery granule disease and Alzheimer's disease, Neuropathology and Applied Neurobiology, August 1999, 25(4), pp. 295-305), Niemann-Pick Niemann-Pick disease (for example, refer to Jin LW and three others, in the intracellular accumulation of starch-producing fragments such as starch-β precursor proteins in neurons with Niemann Pick's type C deficiency Abnormalities in endosomes, American Journal of Pathology, March 2004, 164(3), 975-985 21 201035076) Amyotrophic lateral sclerosis (eg, reference to Sasaki S and another, immunoreactivity of β-starch precursor protein in amyotrophic lateral sclerosis, Acta Neuropathologica (Berl), May 1999, 97(5), pp. 463-468; Tamaoka A and four others have an increase in β-proteins in the skin of patients with amyotrophic lateral sclerosis, Journal of Neurology, August 2, 247 (8 ), 633-635; Hamilton RL and another, pathology of Alzheimer's disease in amyotrophic lateral sclerosis, Acta

Neuropathologica, June 2004, 107(6), pp. 515-522; Turner BJ and six others, showing beta-starch accumulation in the brain of mutant mice with superoxide dismutase 丨 gene, neurochemistry Study December 2004, 29 (12), pp. 2281-2286), water brain (eg, reference to 6 丨 to 11 〇, pathology of cerebrospinal fluid and interstitial fluid of 〇 milk: Alzheimer's disease' Significance of Puri Disease and Multiple Sclerosis, Journal of Neuropathology and Experimental Neurology, October 1998 '57(10), pp. 885-894; Silverberg GD and four others, Alzheimer's disease, normal brain pressure Changes in aging of water brain and CSF cycle physiology: hypothesis, lancet, August 2003, 2(8), pp. 506-511; Weller RO and three others' brain starch vascular disease: Alzheimer The accumulation of Αβ in the interstitial fluid discharge pathway, New York Academy of Sciences Annual Report, April 2000, 903, 110-117; Yow ΗΥ and another person, cerebrovascular disease in determining Alzheimer's disease β_ class powder The role of sedimentary patterns 'Nervology and Applied Neurobiology, 2002, 28 ' 149 pages; Weller RO and four others, cerebral blood Tube disease is the main cause of the failure of Αβ from the aging human brain 'New York Academy of Sciences Annual Report, November 2002, 977, 162_168), light paraplegia (for example, refer to 〇 'Ri〇rdan S and seven others, Presenilin-1 mutation ( E280G), spastic paralysis, and intracranial MRI white matter abnormalities, 22 201035076 God! It, October 8, 2002 曰, 59(7), ll〇8_iii〇); Matsubara-Tsutsui Μ and seven others, family Molecular evidence for presenilin-1 mutations in early-onset dementia, American Journal of Internal Medicine Genetics, April 8, 曰 '114(3), pp. 292-298); Smith MJ and eleven others, with 痉挛The variable phenotype of Alzheimer's disease, the annual report of neurology, 2〇〇1, 49(1) '125-129 pages; Crook R and 17 others, due to the sequence of presenilin Variation of Alzheimer's disease with spastic sputum and unusual plaque caused by censoring, natural medicine, April 1998; 4(4), 452_455), progressive nuclear paralysis (eg reference Barrachina 另 and the other six, with starch-like degeneration in the cerebral cortex of the dementia with deposition of sinensis The relative increase in the ApPP mRNA isoforms of the agent, International Neurochemistry '2〇〇5, February, 46(3)' 253-260; Primavera j and four others, non-Alzheimer's neurodegenerative starch _{3 Brain Accumulation, Alzheimer's Disease Journal, October 1999, 1 (3), pp. 183-193), cerebral hemorrhage (for example, reference to Atwood CS and three others, allowing maintenance of blood vessels and blood supply) Cerebrovascular requirements for sealants, anticoagulants and remodeling of model molecules, Brain Research Review, September 2003, 43(1), pp. 164-78; Lowenson JD and two others, protein aging: extracellular Starch-like formation and intracellular repair, cerebrovascular drug trends, 1994, 4(1), 3-8 pages), 痉挛 (for example, see Singlet〇n AB and another 12 people, with Thrll3-114ins presenilin-1 Mutation of the pathology of early-onset Alzheimer's disease 'brain' in December, i23 (Ptl2), 2467-2474), mild cognitive impairment (eg with reference to Gattaz wf and four others) Platelet phospholipase A2 activity in humans, Alzheimer's disease and mild cognitive impairment, Journal of Neurotransmission, May 2004, 111(5), 591_6〇1; A Ssini 23 201035076 A and another 14 people, increased plasma concentrations of starch-like protein β-protein 42 in women with mild cognitive impairment 'neurology' September 14, 2004 '63(5), pp. 828-831) Atherosclerosis (for example, with reference to De Meyer GR and eight others, treatment of platelet phagocytosis and beta-type starch precursor protein as macrophage activation in atherosclerosis, cycle study, June 14, 2002, 90(11), pp. 1197-1204). "Substituent group a", "substituent group" and "substituent group c 1" mean a compound represented by formula (I) which can be effectively used for the treatment of a disease caused by Aβ according to the present invention. The following groups. "Substituent group a1" means C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl, C1-6 alkoxy, C2-6 alkenyloxy, C3-8 cycloalkyloxy , an amine group (wherein the amine group may have a C2-6 alkyl fluorenyl group or a C1-6 alkyl sulfonyl group or 1 to 2 C 1-6 alkyl groups or a C 3-8 cycloalkyl group), a cyano group, a formazan group Base, halogen atom, hydroxyl group and nitro group. "Substituent group bl" means a C1-6 alkyl group (wherein the alkyl group may be substituted with 1 to 3 halogen atoms), a C2-6 alkenyl group, a C3-8 cycloalkyl group, a C6-14 aryl group, C6-14 aryl-C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyloxy, C3-8 cycloalkyloxy, C2-6 alkanoyl, C4-9 cycloalkylcarbonyl, C7-15 aryl fluorenyl, C1-6 alkylsulfonyl, C2-6 alkenylsulfonyl, C3-8 cycloalkylsulfonyl, C6-14 arylsulfonyl 'C1-6 alkylthio a C2-6 alkenylthio group, a C3-8 cycloalkylthio group, an aminesulfonyl group (wherein the aminesulfonyl group may have 1 to 2 C1-6 alkyl groups, a C2-6 alkenyl group or a C3-8 ring) An alkyl group, an amine group (wherein the amine group may have a C2-6 alkyl fluorenyl group, a C1-6 alkyl sulfonyl group or a C3-8 cycloalkyl sulfonyl group or 1 to 2 C 1-6 alkyl groups or C3-8 cycloalkyl), cyano, carbhydryl, halogen atom, hydroxy, 24 201035076 schlossyl, oxy, 1-alpha pyrryl, 1-branched, 1-tob.丨 朵 琳 lin-1-yl, 1,2,3,4-tetrahydroquinolin-1-yl and 4-tyrosinyl. "Substituent group cl" means an amine group (wherein the amine group may have a C2-6 alkyl fluorenyl group, a C1-6 alkyl sulfonyl group or a C3-8 cycloalkyl sulfonyl group or 1 to 2 C1 groups) -6 alkyl or C3-8 cycloalkyl), ii) cyano, iii) halogen, iv) hydroxy, and v) vi) C1-6 alkyl, v-ii) C2-6, v- Iii) C2-6 alkynyl, v-iv) C1-6 alkoxy, vv) C1-6 alkylthio, v-vi) Cl-alkylaminecarbonyl, v-vii) C1-6 alkylsulfonate Base, v-viii) C1-6 alkylamine sulfonyl, v-ix) C2-6 alkyl fluorenyl, vx) phenyl, v-xi) Dltn, ν-xii)·1 荅D well base , v-xiii)^a base, v-xiv) 1-° ratio 11 each 0 base, v-xv) 1-Brigade base, v-xvi) 1-high slightly bite base and v-xvii) 4-flavor The linke group may each have 1 to 3 substituents selected from the group consisting of a C1-6 alkyl group and a halogen atom. The "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom or the like and is preferably a fluorine atom, a chlorine atom or a desert atom. "C1-6 alkyl" means an alkyl group having 1 to 6 carbon atoms. Preferred examples of the group include linear or branched alkyl groups such as methyl, ethyl, n-propyl, isopropylidene, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, Neopentyl, n-hexyl, 1-mercaptopropyl, 1,2-dimethylpropyl, 1-ethylpropyl, 1-methyl-2-ethylpropyl, 1-ethyl-2- Mercaptopropyl, 1,1,2-dimercaptopropyl, 1-mercaptobutyl, 2-methylbutyl, 1,1-didecylbutyl, 2,2-dimethylbutyl 2-ethylbutyl, 1,3-dimercaptobutyl, 2-methylpentyl and 3-decylpentyl. "C1-6 alkylene" means an alkylene group having 1 to 6 carbon atoms. Preferable examples of the group include a linear or branched alkyl group such as an anthracenylene group, an exoethyl 25 201035076 group, a methylmethylene group, a propyl group, a methyl group ethyl group, and an ethyl group of a methyl group. Methyl, butyl, methyl propyl, ethyl ethyl, methyl: ethyl, propylmethylene, pentyl and hexyl. Among them, for example, a subunit, an ethyl group, a mercaptomethyl group, a propyl group, a methyl group ethyl group, an ethyl group and a dimethyl fluorenylene group are preferred. The preferred embodiment of the "C3-8 cycloalkyl group" means a cycloalkane group having 3 to 8 carbon atoms, including a cyclopropyl group, a cyclobutyl group, a cyclopentyl group = a cycloheptyl group. The hexyl group and "C2-6 alkenyl" mean an alkenyl group having 2 to 6 carbon atoms. Preferred examples include linear or branched alkenyl groups such as vinyl, allyl 'propenyl, isopropenyl, 1-butenyl, buten-2-yl, κ丁稀冬美, 2·丁埽-1- Base and 2-butene-2-yl. The "C2-6 alkynyl group" means an alkynyl group having 2 to 6 carbon atoms. Examples of the ruthenium of the group include linear or branched alkynyl groups such as ethynyl group, i, block group, propyl block group, butynyl group, pentynyl group and hexynyl group. The C3-8% alkyloxy group means a ring system alkyl group having 3 to 8 carbon atoms which is replaced by an oxygen atom. Preferred examples of the group include % propoxy 'cyclo Toxy 'cyclopentyloxy, cyclohexyloxy and cyclooctyloxy. "C3-8 cycloalkylthio group" means a ring system alkyl group having 3 to 8 carbon atoms wherein one hydrogen atom is replaced by a sulfur atom. Preferred examples of the group include a cyclopropylthio group, a cyclobutylthio group, a cyclopentylthio group, a cyclohexylthio group, a cycloheptylthio group and a cyclooctylthio group. "C1-6 alkoxy" means one of the alkyl groups containing from 丨 to 6 carbon atoms. 26 201035076 The hydrogen atom is replaced by an oxygen atom. Preferred examples of the group include a methoxy group, an ethoxy group, a n-propenyl group, an isopropoxy group, a n-butoxy group, an isobutoxy group, a second butoxy group, a third butoxy group, and a n-pentyl group. Oxyl, isopentyloxy, second pentyloxy, third pentyloxy, n-hexyloxy, isohexyloxy, hydrazine, 2-dimethylpropoxy, 2-ethylpropoxy, 丨_曱Base 2_ethylpropoxy, puethyl-2-methylpropoxy, 1,1,2-trimethylpropoxy, hi-trimethylpropoxy, fluorenyl dibutoxy 2,2-Dimethylbutoxy, 2-ethylbutoxy, anthracene, 3-dimethoxybutoxy, 2-methylpentyloxy and 3-decylpentyloxy. The "C1-6 alkylthio group" means an alkyl group having one carbon atom, and one of the hydrogen atoms is replaced by a sulfur atom. Preferred examples of the group include anthracenylthio group, ethylthio group, n-propylthio group, isopropylthio group, n-butylthio group, isobutylthio group, tert-butylthio group, n-pentylthio group, isopentyl sulfide Base, neopentylthio, n-hexylthio and propylmethylthio. Mercapto and butyl ketone - "C2-6 alkyl fluorenyl" means an alkyl group containing (f) carbon atoms which is substituted by one hydrogen atom. Preferred examples of the group include ethyl acetate, C

"Alkyl group" means that one of the atomic atoms containing (1) carbon atoms is replaced by a sulfonyl group. The group ~ sulfonyl and ethanesulfonyl. Examples include A. The olefinic atomic system of a carbon atom is replaced by an oxygen atom. In the preferred embodiment 2 of the group, a branch of a dilute oxy group such as a B-group, an oxy group, • Include linear or dilute: yl, yloxy oxime oxydiyl, 2-butenyloxy and 2-butan-2-yloxy.丁¥3-基 27 201035076 "C2-6 olefinyl group" The hydrogen atom is replaced by a sulfur atom. The group refers to an alkenyl group having 2 to 6 carbon atoms, and preferred examples thereof include a linear <branched dilute sulfur group such as an ethylene sulfhydryl group, a propyl propyl thio group, a 2- propyl thio group, and a butyl group. 1-ylthio, 1-butyl-2-ylthio '1-butylene-3-ylthio, 2-butanylthio and 2-but-2-ylthio. The "C2-6 dilute thiol group" means an alkenyl group having 2 to 6 carbon atoms, and one of the hydrogen atoms is replaced by a sulfonyl group. Preferred examples of the group include an ethyl group-enhanced S basket base, a dilute propyl group, a 2-propylene base group, an i-butyl group, a 1-butene-2-yl group. Sulfhydryl and 1-butene_3_ylsulfonyl. "C3-8 环炫基基" means a ring system p group having 3 to 8 carbon atoms, wherein one hydrogen atom is replaced by a sulfonyl group. Preferred examples of the group include a cyclopropylsulfonyl group, a cyclobutylsulfonyl group, a cyclopentylsulfonyl group, a cyclohexyl fluorenyl group, and a cycloheptyl fluorenyl group. The "C6-14 aryl group" means a monocyclic, bicyclic or tricyclic aromatic hydrocarbon ring having 6 to 14 carbon atoms. Preferred examples of the group include 6 to 14 membered monocyclic, bicyclic or tricyclic aromatic hydrocarbon ring groups such as stupid, fluorenyl, aryl, base, heptalaenyl group, and hydrazine. Phenyl, fluorenyl, benzoic, fluorenyl and phenanthryl. The "C7-15 aryl fluorenyl group" means that one of the above-mentioned C6-14 aryl groups is replaced by a carbonyl group. Preferred examples of the group include a benzindenyl group, a benzyloxy group, a naphthoquinone group, a biphenylcarbonyl group, a fluorenylcarbonyl group, a phenanthrylcarbonyl group and a fluorenylcarbonyl group. The "C6-14 aryl-C1-6 building group" means that one of the above-mentioned C1-6 alkyl groups is replaced by the aforementioned C 6 -14 aryl group. Preferable examples of the group include a benzyl group, a phenethyl group, a phenylpropyl group, a naphthylmethyl group, and a biphenylmethyl group. 28 201035076 "C6-14 arylsulfonyl" means that one of the aforementioned C644 aryl groups is replaced by a sulfonyl group. Preferred examples of the group include a phenylsulfonyl phthalocyanine group and a biphenyl continuation base. The "C4-9 cyclic carbonyl group" means a ring-based alkyl group having 3 to 8 carbon atoms which is substituted by a carbonyl group. Preferable examples of the group include a cyclopropylcarbonyl group, a cyclobutylcarbonyl group, a cyclopentylcarbonyl group, a cyclohexylcarbonyl group and a cycloheptylcarbonyl group. The "C1-6 alkylamine carbonyl group" means an alkyl group having from 丨 to 6 carbon atoms, and one of the hydrogen atoms is replaced by an amine carbonyl group. Preferable examples of the group include a methylaminocarbonyl group, an ethylaminecarbonyl group, a propylaminecarbonyl group, a butylaminecarbonyl group, and a hexylaminecarbonyl group. The "C1-6 alkylamine thiol group" means a group having from 1 to 6 carbon atoms, wherein one hydrogen atom is replaced by an amine sulfonyl group. Preferred examples of the group include a methylamine continuation group, an ethyl amide group, a propylamine group, a butylamine sulfonyl group and a hexylamine sulfonyl group. When W is a nitrogen atom and R2 is a hydroxyl group, the compound includes, for example, a tautomer represented by the following formula:

One of the substituents in the ring B definition selected from one of the substituent groups cl to three substituents may be present at any substitutable position on the ring. Ring B can be linked to Xj at any alternative location on the ring. For example, when the ring B is represented by the formula 19: 29 201035076

Ring B may be linked to Χί in an alternative position indicated by any of the following formulas 19-1 to 19-7:

In the present invention, the "pharmaceutically acceptable salt" is not particularly limited as long as it is a pharmacologically acceptable salt of the compound of the above formula [I] which is a therapeutic agent for a disease caused by Αβ. Preferred examples of salts include hydrogen oximes (such as hydrofluorides, hydrides, hydrogen deserts, and hydrogen moths), inorganic acid salts (such as sulfates, acid salts, perchlorates, phosphates). Classes, carbonates and bicarbonates), organic carboxylates (such as acetates, oxalates, maleates, tartrates, fumarates and citrates) Class), organic sulfonates (such as methanesulfonates, triflate, ethanesulfonates, benzenesulfonates, tosylates, and camphorsulfonates), amines Base salts (such as aspartates and glutamates), fourth amine salts, alkali metal salts (such as sodium salts and potassium salts) and alkaline earth metal salts (such as magnesium salts and Calcium salt

30 201035076 Next, a compound of the formula [i] according to the present invention will be explained. In the compound of the formula [I] or a pharmacologically acceptable salt thereof, preferably a C1-6 alkyl group or a halogen atom and η is an integer of 1 to 2; and a particularly good core is (: 1-6 alkyl group and η An integer of 1 to 2; and an optimal core is a methyl group and η is 1. In the compound of the formula [I] or a pharmacologically acceptable salt thereof, preferably R2 is a halogen atom, a hydroxyl group or a C1-6 alkoxy group. And η is an integer of 1 to 2; more preferably R2 is a C1-6 alkoxy group and η is an integer of 1 to 2; and particularly preferably R2 is a methoxy group and η is 1.

In the compound of the formula [I] or a pharmacologically acceptable salt thereof, X! is preferably i) a single bond, ii) a Cl-6 alkylene group which may have 1 to 2 C1-6 alkyl groups or iii)- X2- (wherein X2 represents -NR3- or -CO- and R3 represents a hydrogen atom, a C1-6 alkyl group, a C3-6 cycloalkyl group, a C2-6 alkanoyl group or a C1-6 alkylsulfonyl group). In the compound of the formula [I] or a pharmacologically acceptable salt thereof, the ring A is preferably represented by any one of the following formulas 3 to 8:

7 and particularly preferably represented by Formula 3 In the compound of the formula [I] or a pharmacologically acceptable salt thereof, the ring B is preferably represented by any one of the following formulas: 31 201035076

Each of them may be substituted with 1 to 3 substituents selected from the group of substituents. The substituent group bl is preferably composed of (1) Cl_6 alkyl (wherein the substituent may be substituted with 1 to 3 i atoms) '(2) C3-8 cycloalkyl, (3) C6-14 aryl, (4) C6-14 aryl-C1-6 alkyl, (5) C1-6 alkoxy, (6) (^^cycloalkyloxy, (7) C2-6 alkanoyl '(8) C7- I5 aryl fluorenyl, (9) C1_6 alkylsulfonyl, (10) C3-8 cycloalkylsulfonyl, (u) C6_14 arylsulfonyl, (12) cyano, (13) formazan And (14) a substituent composed of a halogen atom, a (15) hydroxyl group and a (16)oxy group. The substituent group cl is preferably an (1) amine group (wherein the amine group may have a C2-6 alkane group) , C1-6 alkylsulfonyl or C3-8 cycloalkylsulfonyl or 1 to 2 C1-6 alkyl or C3-8 cycloalkyl), (2) cyano, (3) atom , (4) thiol and (5) (5M) Cl-6 alkyl '(5)-2) Cl-6 methoxy, (5)-3) Cl-6 sulphur and (5)-4 The phenyl group each may have 1 to 3 substituents selected from the group consisting of a substituent consisting of a C1_6 alkyl group and a halogen atom. At least one compound is selected from the group consisting of the following formulas [A-1] to [A-6]:

32 201035076

Or a pharmaceutically acceptable salt thereof is particularly suitable (for example) and can be used as a therapeutic agent for a disease caused by a starch-like β-like such as Alzheimer's disease, elderly dementia, Down syndrome or a starch-like degenerative disease. . The method for preparing the compound of the general formula [I] according to the present invention will be explained below. a compound represented by the compound of the general formula [I]:

Wherein Ri, R2, m, η, W, ring A, X! and the ring oxime are as defined above, and are synthesized according to a method such as the following General Process 1 to General Process 7 (for example). It is apparent that in order to facilitate the preparation of the compounds of the present invention, the method comprises the use of a suitable protective reaction step and a deprotection reaction step using a protecting group known to those skilled in the art which are suitably selected for each step (refer to T Greene et al., "Organic Synthesis Protecting Group", John Wiley & Sons, New York, 1981). It is apparent that for convenience 33 201035076, the compounds of the present invention are prepared which comprise substituent substitutions, substituent introductions and the like which are suitable for the respective steps and are known to those skilled in the art. It is also apparent that for ease of preparation of the compounds of the invention, all isomers and mixtures of isomers such as geometric isomers which may be derived from the structural formulas of the invention, optical isomers based on asymmetric carbon, stereoisomers and tautomers The preparation can be prepared as a single compound, such as sorting crystallization or column chromatography, by techniques known to those skilled in the art and known to those skilled in the art. General Preparation Method 1 The general production method 1 which is typically used for the compound of the formula [I] according to the present invention will be explained below.

(a-2) (b-1) wherein R!, R2, m, η, W, ring A, X丨 and ring B are as defined above; XA represents a halogen atom such as a chlorine atom, a bromine atom or an iodine atom. Or a sulfonic acid group such as a fluorinated acid group, a p-toluene acid group or a trifluoromethanesulfonate group; and XB represents a trialkylstannyl group, a dihydroxyboronic acid group or a dihydroxyborate such as a pinacol. Butterroot. The above general process 1 is a process for preparing a compound of the general formula [I], which is subjected to a coupling reaction with a compound of the formula (b-2) in a step 1-1 via a compound of the formula (a-Ι); or a A process for the preparation of a compound of the general formula [I] is carried out by a reaction of a compound of the formula (a-2) with a compound of the formula (bl) in a step wherein the substituents XA and XB are substituted with each other. The coupling reaction of the step 1-1 varies depending on the starting materials, and is not particularly limited as long as the conditions are similar to the reaction conditions. A method known to those skilled in the art can be used for the reaction. Preferred examples of the method include the Suzuki-Miyaura reaction (for example, reference to Α·Suzuki, "Chem Rev", I995, vol. S> 5, p. 2457) and Stille coupling reaction. (for example, reference

JK Stille, "Angew. Chem. Im. Ed. Engl.,,, 1986, ν〇1· 25, P 〇508) 〇' In the eucalyptus-Miyaura reaction, a generic compound or trifluorosulfonate Preferably, the compound is, for example, in the presence of from 1 to 0.5 equivalent of a transition metal catalyst relative to the compound of the formula (a-Ι), and the coupling is from 1 to _0 to 5 _0 equivalent to the compound of the formula ay) (b-2) a compound (wherein XB is preferably a dihydroxyboronic acid group or a dihydroxyborate such as pinar dihydroborate). In view of handling property and stirring efficiency, the reaction is preferably carried out in the presence of a solvent. The solvent of Q varies depending on the starting materials used and the transition metal catalyst, and is not particularly limited as long as the reaction is not inhibited and the starting materials are allowed to dissolve therein to some extent. Preferred examples of the solvent include acetonitrile. , tetrahydrofuran, 1,4-dioxene beta, anthracene, 2-2-dioxane, benzene, toluene, dimethyl strepone, "methyl-2-pyrrolidone, hydrazine, hydrazine dimethyl dimethyl decylamine , water and its mixed solvent. The reaction temperature should be the temperature at which the coupling reaction can be completed and is preferably room temperature to 2 〇 (TC. It should preferably be carried out in an inert atmosphere and more preferably in a nitrogen or argon atmosphere. Under the preferred reaction conditions, the reaction is carried out in a period of up to 24 hours, and the reaction can be monitored by known shore analysis techniques. The medium is preferably known as palladium mismatch 35 201035076. It is better to have gone! Bar complex such as acetic acid (π), gas (triphenyl lin), (II) '肆 (a stupid base (〇) or ginseng (dipyridyl propyl hydrazine) two (〇). The ligand may be appropriately added (preferably triphenylphosphine, tris-tolyltris-tricyclohexylphosphine or tri-n-3) The phosphine, for example, is used to make the reaction work efficiently. It is also possible to appropriately add the fourth material, such as chlorination, to make the reaction costly. In the presence of the reaction towel, (4), better results can be achieved. At this time, the test system is different depending on the starting material, the solvent to be used, and the like, and is not particularly limited. Preferred examples include sodium hydroxide, barium hydroxide, potassium fluoride, fluorinated planer, sodium carbonate, and potassium carbonate. , cesium carbonate and potassium phosphate. Under the preferred reaction conditions, the reaction is completed in 丨 to 24 hours, and the reaction can be monitored by known chromatographic techniques. The halogen compound or the triflate compound of the formula (a-Ι) is preferably linked to a compound of the formula (a _ 丨), for example, from 0.01 to 0.2 equivalent in the Stirling coupling reaction. In the presence of a metal catalyst, it is coupled with 1.0 to 5.0 equivalents of the compound of the formula (b_2) (wherein Xb is preferably a trialkylstannyl group) with respect to the compound of the formula (p), preferably in the reaction. 0.1 to 50 equivalents of copper halide (1) or/and lithium halide to allow the reaction to proceed efficiently. Preferred examples of the solvent used in the reaction include toluene, diphenylbenzene, hydrazine, hydrazine-dimethylformamide, hydrazine, hydrazine. - dimethylacetamide, 1-methyl-2-pyrrolidone and dimethyl sulfoxide. The reaction temperature must be a temperature at which the coupling reaction can be carried out, preferably from room temperature to 150 °C. Preferably, the transition metal catalyst is a complex compound, and a complex compound such as acetic acid (II), dichloroanthracene (triphenylphosphine) palladium (II), ruthenium (triphenylphosphine) palladium (preferably known) is preferred. 0) or ginseng (dibenzylideneacetone) dipalladium (0), and more preferably, for example, palladium acetate (ruthenium), ruthenium (triphenylphosphine) palladium (0) or ginseng (dibenzylideneacetone) dipalladium (0). Phosphorus ligands may be appropriately added (compared with 36 201035076 o-p-phenylphosphine, 1,3-anthracenyl (diphenylphosphino)propane). The reaction is preferably carried out in the case of yttrium as diphenylphosphine, three - or di-tertiary-tert-butylphosphine) to make the ruthenium and better than the gas or the ^ c ^ rolling mill. Preferred reaction conditions

Next, the reaction is completed in 1 to 24 hours, and the reaction can be monitored by a known chromatographic technique.

Step 1 2 is an example of a method for preparing a compound of the formula (a-2) and a compound of the formula (b-2) wherein the substituent XA and the substituent are substituted with each other. This step differs depending on the starting material' and is not particularly limited as long as the conditions are similar to the present reaction conditions. Methods known to those skilled in the art can be used in the present reaction. A method similar to the following can be used, such as Suzuki_Miyaura reaction (for example, reference A)

Suzuki, "Chem. Rev.", 1995, vol. 95, p. 2457) and Stirling coupling reactions (for example, see JK Stille, "Angew. Chem. Int. Ed. Engl.,, 1986, vol. 25 , p. 508) Preparation of the compound of the formula (a-1) The following formula shows an example of the preparation of the compound of the formula (a-1).

[Step 2-2]

In the formula, R!, R2, m, η, W, and Xa are as defined above; ra and Rb are as defined above for & and 1^ represents a halogen atom such as a chlorine atom, a desert atom or a helium atom or indeed An acid group such as a fluorite group, a p-benzoic acid group or a tri-37 201035076 atom such as a fluorine atom, a chlorine atom H-acid group, a p-carbamic acid group or a tri-afluoromethanesulfonate group; &l2 represents _ or an iodine atom, a sulfonic acid group such as a methanesulfonate group or a dihydroxyboronic acid group. The formula (from the amine compound (4) as the starting material w step 2 - 曱, the step 2 as the reaction and the step 2: to prepare; or can be used from the compound of the formula (a-4) _ 2-4 The coupling is reversed. ^ Step_ varies according to the starting material and has no special restrictions

It can be similar to the reaction conditions. A method known to those skilled in the art can = the reaction. It is possible to use a method such as multiple documents (T. Greene et al. | "Organic Synthesis (Four) Base"" about Wheeled Wiley & Sons, New York (four) years, ^ example).

/Step 2-2 differs depending on the starting material and is not particularly limited as long as the conditions are similar to the present anti-myster. A method known to those skilled in the art can be used for the reaction. Preferred examples of the method include a solvent, and a compound of the formula (IV) and a compound of the formula (IV) relative to the compound of the formula (IV) in the presence of a compound of the formula (IV) of 1.G to 1 G.G. (d) methods of compounds. The test used varies depending on the starting material and is not subject to any special restrictions. Preferred examples of the base include metal hydrides (such as sodium hydride and hydrogen), metal salts (such as potassium carbonate, sodium carbonate and carbonic acid (6), and metalloids (such as sodium methoxide and third potassium oxide). The solvent used is different according to the starting material and is not limited to the limit and allows the starting material to be dissolved in the towel to a certain county. The preferred example of the solution #1 includes the solvent J. Such as tetrahydrogen bite ' 1,4_20 mountain and B shout; _ solvent such as dichloromethyl 38 201035076 alkane, 1,2-dichloroethane and gas; polar solvent such as N, N dimethyl Methionine and N-methylpyrrolidone; non-polar solvents such as toluene and benzene; and mixtures thereof. The reaction temperature must be a temperature at which the reaction can be completed without causing undesired by-product formation, for example, preferably (TC). Under the preferred reaction conditions, the reaction is completed in ~24 hours, and the reaction can be monitored by known chromatographic techniques. Undesired by-products 18 can be removed by techniques known to those skilled in the art, Such as conventional chromatography, extraction and / or crystallization. Step 2-3 varies depending on the starting material There is no particular limitation as long as the conditions are similar to the reaction conditions. A method known to those skilled in the art can be used for the reaction. A plurality of documents and the like can be used (such as the description of the chemical of the heterocyclic compound). Correction points, % page, book publishing company, 1953.) Preferred examples of the method include preparing a general formula by forming a light ring via a compound of the formula (IV) and ammonia, a salt, a formamide, or the like as a nitrogen source. The (a-Ι) compound side & the dissolution to be used is not particularly limited as long as the reaction is not inhibited and the starting material is allowed to dissolve therein to some extent. Preferred examples of the solvent include a non-polar solvent such as toluene. And a benzoquinone solvent such as methanol and ethanol; an organic acid such as acetic acid or trifluoroacetic acid such as p-toluene and trifluoromethane; water; and a mixture thereof. If desired, mesamine can be used as a slit atom source and as _, The reaction temperature must be a temperature at which the reaction can be completed without causing the formation of undesired by-products, for example, preferably from room temperature to 25 (TC. The yield can be improved when the reaction system (4) is carried out in a tight vessel. Under good reaction conditions, the reaction is in the range of 丨hours to %hours, and the progress of the reaction can be monitored by known tomography. Non-= «谙 艺 艺 已知 _ _ _ _ _ _ _ _ 习 习 习39 201035076 Removal. The coupling reaction of Step 2-4 is different depending on the starting materials and there is no special limitation 'as long as the conditions are similar to the reaction conditions. The method known to those skilled in the art can be used for the reaction. A method of reporting a plurality of documents, etc. (such as described in D_D. Davey et al., "J. Med. Chem.,, 1991, vol. 34 p 2671-2677). Examples of methods include solvents, relative to the formula (a_4) The compound is 1.0 to 5.0, and in the presence or absence of the test, the compound of the formula (a-4) (wherein L2 is preferably a halogen atom or the like) and the compound of the formula (a-4) are disturbed. A method of 1.0 to 5.0 equivalents of the imidazole compound (c-2). Preferred examples of the test used include sodium hydride, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, carbonic acid, cesium carbonate, pyridine, dimethyl pyridine and triethylamine. The solvent to be used varies depending on the starting materials and is not particularly limited as long as the reaction is not inhibited and the starting materials are allowed to dissolve therein to some extent. Preferred examples of the solvent include acetonitrile, tetrahydrofuran 'dioxin, N,N_: methylformamide, and N-decylpyrrolidone. A base can be used as a / granule as needed. The reaction temperature must be a temperature at which the reaction can be completed without causing formation of undesired by-products, and is preferably, for example, room temperature to 15 (TC. Under the preferred reaction conditions, the reaction is completed in 1 to 24 hours, and the reaction can be carried out. Chromatography is monitored to monitor the progress of the reaction. Undesirable by-products can be removed by techniques known to those skilled in the art such as conventional chromatography or/and crystallization. Examples of coupling reactions of Steps 2-4 include solvent in copper. In the presence of a catalyst, a method of mixing a compound of the formula (a-4) (wherein L2 is preferably a ruthenium group, etc.) (such as described in J.P_C〇llman et al., "Organic Letter", 2〇 〇〇, ν〇ι 2, 1233-1236). A preferred example of the method is included in the solvent, in the relative 40 201035076 Formula 4 4) The compound is 〇Q1 to 1 () equivalent steel reaction such as copper, desertification In the presence of 5 or /, in the presence of steel, the compound of the formula (a 4) is 0.1 to 10.0 equivalents of the compound relative to the compound of the formula. Take the method of compound (4). The copper used in the agent is based on the initial (four) and is not subject to any special restrictions. Preferred examples of copper reactants include agglomerated copper (1), copper (II) acetate, copper (II) nitrate, and chlorinated chlorin-[[ν,ν,ν,,ν,·四基伸乙Diamine) copper (10). The solvent to be used varies depending on the starting materials, the reactants, and the like, and is not particularly limited as long as the reaction is not inhibited and the starting materials are allowed to dissolve in the towels to some extent. Preferred examples of the solvent include a solvent such as tetrahydrofuran' 1,4 - 20 mountain and an acetylating solvent such as dichlorocarbyl, u-diethylene and gas-like; polar solvent such as b-n N, N-II Methylformamide and N-methyl phase; non-polar solvents such as toluene, benzene and dichlorobenzene, and mixtures thereof. A base can be used depending on the starting materials, reactants, and the like. Preferable examples of the base include organic bases such as triethylamine, pyridine, and tetradecylethylidene; alkali metal salts such as potassium carbonate, sodium carbonate, potassium acetate, sodium acetate, and carbonic acid planing; and metal alkoxides such as Sodium methoxide and potassium butoxide. The reaction temperature must be a temperature at which the reaction can be completed without causing formation of an undesirable by-product, and is preferably, for example, room temperature to 200 °C. Good results are obtained when the reaction is carried out under an oxygen atmosphere or a gas stream, such as a reduction in reaction time and an improvement in yield. Under the preferred reaction conditions, the reaction is completed in 丨 to 24 hours, and the reaction can be monitored by known tomography. Undesirable by-products can be removed by methods known to those skilled in the art such as conventional chromatographic extraction and/or crystallization. The compound of the formula (a-3), the compound of the formula (a-4), the compound of the formula (c-1) and the compound of the formula (c 2) are known or commercially available compounds or can be converted therefrom by a conventional method. 201035076 Compound prepared by the compound. Preparation of the compound of the formula (b-1) The following formula shows an example of the preparation of the compound of the formula (b-indole). O2n

(d-2)

[Step %3, 21

(b-3)

a sulfonate such as a hydroxyboron, or a diatom, 'X, XA, ring A and ring B are as described above for a stator such as a fluorine atom, a gas atom, a bromine atom or an iodine atom, and a sulfonate. Acid or triflate sulfonate or azide. The compound of the formula (b-indole) can be used as a starting material from the compound of the formula (dl); the condensation reaction of the step 3-1, the reduction of the step 3-2 and the Sandmeyer reaction of the step 3-1. preparation. The coupling reaction of the step 3-1 varies depending on the starting materials and is not particularly limited as long as the conditions are similar to the reaction conditions. The reaction is known by methods known to those skilled in the art. Examples of the method include a solvent, and a rhodium (d 1) δ complex with respect to the formula (d_i) in the presence or absence of a base of from 1 Torr to 5 Torr with respect to the compound of the formula (d-Ι) The compound is a method of 1. 〇 to 5. 〇 equivalent of the compound of the formula (d-2). Preferred examples of the test used include sodium hydride, sodium hydroxide, potassium hydroxide, potassium carbonate, linna, cesium carbonate, chlorpyrifos, pyridine, lutidine and triethylamine. The solvent to be used varies depending on the starting materials, and is not particularly limited, and it is only possible to suppress the reaction and allow the starting material to be mixed into a certain degree. Preferable examples of the solvent include acetonitrile tetrahydrofuran, disulfoxide, hydrazine, hydrazine-dimethylformamide and N-mercaptopurine. A base can be used as a solvent as needed. The reaction temperature must be a temperature at which the reaction can be completed without causing formation of an undesired by-product, and is, for example, preferably from room temperature to 150 °C. Under the preferred reaction conditions, the reaction is carried out for up to 24 hours to monitor the progress of the reaction by known chromatographic techniques. Undesirable by-products can be removed by methods known to those skilled in the art, such as conventional chromatographic techniques or/and crystallization.硝基 The nitro reduction reaction of the step 3-2 is different depending on the starting materials and is not particularly limited as long as the conditions are similar to the reaction conditions. Skilled people - known reduction reactions can be used for this reaction. You can use multiple files, etc., as reported (such as in the Japanese Chemical Society (editor), Jikken Kagaku Koza (Experimental Chemistry Program), 4th Edition (20th issue) Yuki Gosei (Organic Synthesis) [Iv], Maruzen Company (MaruzenC〇Ltd), ^ Magic Year ^ Month, Page).桑 The Sandermeier reaction of Step 3 - 3 varies depending on the starting materials and is not specific as long as the conditions are similar to the present reaction conditions. A method known to those skilled in the art can be used for this reaction. You can use a method such as 'Reporting at the Japan Chemical Society (Editor's), Pulse enKagakuK (4) (Experiment = Learning Program)' 4th Edition (2nd issue) YukiG〇sei (Organic Synthesis) (1), Maruzen , November 1992, pages 450-453). The compound of the formula ((M) and the compound of the formula (d_2) is a known or commercially available compound or a compound which can be prepared from such a compound by a conventional method. General Preparation Method 2 43 201035076 Method: = According to the invention Preparation of yN~(^rNH2 + (Rl)m (RjJn (a-7) by the compound of formula [1]

NH (β-1) Ή» [Step 4-1]

(R' Ring A and Ring B are as defined above; and P1 is a dilute propyl group. The urethane protecting group such as methyl, ethyl, alkalyl group or the above-mentioned general material is secretly reduced by the formula (IV). The compound of the formula is subjected to the method of preparing a compound of the general formula [η] in the step 4]. The ring-forming reaction of the step 4-1 is different depending on the starting material and is not limited as long as the conditions are similar to the reaction conditions. A method known in the art can be used for the reaction. Preferred examples of the method include the solvent in the presence of the compound (4) and the equivalent of the compound of the formula (a-7) and the compound of the formula (a-7). The method of 〇 equivalent of the heart-shaped compound. In view of the efficiency of the processing and mixing, the ❹ is compared with the agent T. The prepared __ starting material and the special limit of t, such as leaf-to-different and no r heart-cutting begins with a detailed explanation of B = 。. Examples of preferred solvents include alcohol solvents such as methanol, ethylene and a second alcohol; lining agents such as tetrahydrofuran, i 4 bis. 2 gas A... gas and gas 7 = agent such as 7 昧 1 々 'polar solution = — base, ketone The present invention and its present compound. The alkali root used 44 201035076 varies depending on the starting materials and is not particularly limited. Examples of preferred tests include hydrides (such as sodium hydride and hydrogenation clocks) and metal salts ( Such as carbonic acid known as sodium carbonate and carbonic acid planing, metal alkoxides (such as sodium methoxide and first, potassium oxide) and organic bases (such as triethylamine, N, N-diisopropyl) ^ D, 1,8-dioxinbicyclo [5.4.0] undecene _7-ene and imidazole). The earth amine, the reaction temperature must be a temperature that can complete the reaction without causing undesired formation, such as room temperature To 20 (rc. in the preferred reaction strip r, anti-deer

Completed from 1st to 7th, the reaction can be monitored by known chromatographic techniques. Undesirable W彳 products can be removed by methods known to those skilled in the art such as conventional techniques, extraction or/and crystallization. Preparation of the compound of the formula (a-7) The following formula shows an example of the preparation of the compound of the formula (a-7).

[Step 5-1] w [Step 5-2] Xa-^ N^n-L vJ_cn

Ma~CN \=|=/ (h>m (Ft2)n (h_1) (R〇m (R2), (a·1) H (a-8) h2n-n-p2 (M) - NyN~^ (Rl)m (R2), NV<KV01 [Step 5-3] )n- (a-10) (a-9)

Wherein 'Ri, R2, m, n, Xa and W are as defined above. 'The nitrogen protecting group such as the third butoxycarbonyl or benzyloxycarbonyl group; and -VI, such as rhenium or copper, means that the gold is of the general formula ( A-7) The compound can be obtained from the compound of the formula (a-Ι) as a starting reaction by the coupling of the step 5-1, the hydrolysis of the step 5-2, the deuteration of the step 5 3 and the deprotection of the step 5-4. And prepared. The coupling reaction of the step 5-1 differs depending on the starting materials and is not 彳 殊 殊 45 201035076 The conditions are similar to the reaction conditions. A method known to those skilled in the art can be used for this reaction. The souther compound or the trifluoromethanesulfonate compound of the formula (^) is preferably linked to the compound of the formula (a_1), for example, from 〇〇1 to 〇.2, in the presence of a transition metal catalyst, relative to The compound of the formula is coupled with 1 〇 of metal cyanide such as cyanide (II) represented by the formula (h-Ι). In view of handling and mixing efficiency, the ketone is preferably in the presence of a solvent. The solvent to be used varies depending on the starting material and the transition metal catalyst used, and is not particularly limited as long as the reaction is not inhibited and the starting material is allowed to dissolve in the towel to some extent. Including acetonitrile, tetrahydrogen chelate, 1,4·20 mountain, u-dimethoxyethane, benzene, toluene, xylene, 1-methyl-2_, and dimethyl carbamide. The reaction temperature is required to be a temperature at which the coupling reaction can be completed and preferably & room temperature to 15 Torr. The reaction is preferably carried out under an inert gas atmosphere and more preferably under a gas atmosphere of I or argon. For example, a palladium complex is preferred, and a known palladium complex such as palladium (II) acetate or dichlorophosphonium (triphenylphosphine) is preferred. Palladium (11), hydrazine (triphenylphosphine) ruthenium (〇) or ginseng (diphenylidene propyl) 二 (〇). It is also preferred to add a linolenic ligand (preferably diphenylphosphine) , tri-o-tolylphosphine, tri-tertiary-butylphosphino 2-(di-t-butylphosphino), stupid 'exemplary' to make the reaction more efficient. As a result, the test is not particularly limited as long as it can be used for the coupling reaction similar to the present reaction, and preferred examples thereof include: ethylamine, N,N-diisopropylethylamine, hydrazine, hydrazine _: cyclohexyl Methylamine, and gasified tetrabutylammonium. Under the preferred reaction conditions, the reaction is completed in 丨 to 24 hours, and the reaction can be carried out by known chromatographic techniques. The nitrile hydrolysis reaction system of step 5-2 It varies according to the starting material and has no special limit of 46 201035076, as long as the conditions are similar to the reaction conditions. The method known to those skilled in the art can be used for the reaction. The methods reported in various documents, etc. can be used (such as the description in Japan). Society (editor) 'Jikken Kagaku Koza (Experimental Chemistry Program), 4th Edition (No. 22) Yuki Gosei (Organic Synthesis) [IV], Pills The company, in November 1992, pages 12-13).

The deuteration reaction in the step 5-3 may be carried out depending on the starting materials, and is not particularly limited as long as the conditions are similar to the reaction conditions. The amidation reaction known to those skilled in the art is useful for this reaction. You can use multiple documents and other reported methods (53⁄4 as described in the Japanese Chemical Society (editor), Jikken Kagalcu Koza (Experimental Chemistry Program), 4th edition (22nd issue) Yuki Gosei (Organic Synthesis) [W] , Maruzen Corporation, November 1992, pp. 137-144). The deprotection reaction of the step 5-4 may be carried out depending on the starting materials, and is not particularly limited as long as the conditions are similar to the reaction conditions. Deprotection reactions known to those skilled in the art are useful for this reaction. The method reported by a plurality of documents or the like can be used (for example, refer to T_Greene et al., "Organic Synthesis Protecting Group", John Wiley & Sons, New York, 1981, for example). The compound of the formula (f-1) and the compound of the formula (h-indole) are known compounds or commercially available compounds or compounds which can be synthesized from such compounds by a known method. Preparation of the compound of the formula (e-indole) The following formula shows an example of the preparation of the compound of the formula (e-1).

Where X!, Ring B and 卩 are as defined above. 47 201035076 Starting material The compound of the formula 0-1) can be prepared from the compound of the formula (e-2) from the imidization of the hydrazine of the step 6-1. Step 6-1 differs depending on the starting materials and is not particularly limited as long as the conditions are similar to the reaction conditions. Methods known to those skilled in the art can be used to react. Preferred examples of the method include a method of stirring a compound of the formula (e_2) in an alcohol solvent in the presence of 5.0 to 100.0 equivalents of an acid of the compound. The acid used varies depending on the starting material. There are no particular limitations, and preferred examples thereof include hydrogen chloride and ethyl chlorochloride. The solvent to be used varies depending on the starting materials and is not particularly limited as long as the reaction is not inhibited and the starting materials are allowed to dissolve therein to some extent. Preferable examples of the solvent include alcohol-based solvents such as methanol, ethanol, and tert-butanol. Preferred examples of the solvent include a mixed solvent of a deuterated solvent such as dichalcethane, 1,2_diethylene b-fibrate, and Chloroform; polar solvents such as hydrazine, hydrazine-dimethylformamide and N-methylpyrrolidone; non-polar solvents such as toluene and stupid; and mixtures thereof with alcoholic solvents. The reaction temperature is required to complete the reaction. The temperature which does not contribute to the formation of undesired by-products, for example, preferably 〇 ° C to 10 ° C. Under the preferred reaction conditions, the reaction system is completed from 1 to 7 days. Monitor the progress of the reaction. Unexpected By-products may be removed by techniques known to those skilled in the art such as conventional chromatographic techniques for extraction and/or crystallization. The compound of formula (e-2) is a known compound or a commercially available compound or may be a customary method. Compounds prepared by the like, etc. General Preparation Method 3 The general method 3 for the compound of the formula (Ia) and the compound of the formula (lb) which are typically used according to the present invention will be explained below. 48 201035076

[ib] where Ri, R2, m, η, W, X! and ring B are as defined above. The foregoing General Process 3 shows an example of a process for preparing a compound of the formula (Ia) from the carboxylic acid compound (a-9) as a starting material via the amidation of Step 7-1 and the dehydration reaction of Step 7-2; A method for producing a compound of the formula (Chemical) having a ring A having the formula [3] is carried out by the ring recombination of the step 7-3. The amidation of step 7-1 is carried out by the same method as the above step 5-1 and the compound of the formula (a) can be prepared from the compound of the formula (a-9). The dehydration reaction of the step 7-2 varies depending on the starting materials. There is no particular limitation as long as the conditions are similar to the present reaction conditions. Known methods described in a number of documents can be used (for example, Eur. J. Med. Chem. vol. 42, p. 934, 200. For example, The compound of the formula (a-11) is a solvent which is stirred in the presence of from about 〇〇〇 to 1 〇〇〇 equivalent of a dehydration reagent relative to the compound of the formula (a-ΙΙ). The dehydration reactant used is based on the starting material. There is no particular limitation on the difference. Preferred examples of the dehydration reagent include glass bismuth chloride, bismuth pentoxide, pentachloride, tetrahydrochloride, tripolyphosphoric acid, triphenylphosphine carbon tetrachloride and triphenyl. Phosphine-four desertification carbon. The solvent to be used is not particularly limited as long as it does not inhibit the reaction and allows the starting material to be dissolved therein to some extent. A preferred example of the solvent (10) solvent such as tetrahydroanion,丨, 4_20山和乙越; Halogenated solvents such as dioxin, H chloroform Imitation; polar solvent 49 201035076 such as N,N-dimercaptocaramine, N-decylpyrrolidone and acetonitrile; non-polar, six agents such as stupid, stupid and dioxane; and mixtures thereof. The agent can be used as a solvent. The reaction temperature must be a temperature at which the reaction can be completed without causing formation of an undesired by-product, and is preferably, for example, 〇 to 2 。. Under the reaction conditions, the reaction is carried out at 1 to 24 The hour is completed, and the progress of the reaction can be monitored by known chromatographic techniques. Undesirable by-products can be removed by techniques known to those skilled in the art such as conventional chromatographic techniques or/and crystallization. Step 7-3, The conversion of the carbazole ring to the triazole ring system varies depending on the starting material and is not particularly limited as long as the conditions are similar to the reaction conditions. A method known to those skilled in the art can be used for the reaction. Preferably, the compound of the formula (10) and the relative The compound of the formula (la) is a nitrogen source of 5 to 50 equivalents such as ammonia, an ammonium salt or formamide, for example, stirred in a solvent. The solvent to be used is not particularly limited as long as the reaction is not inhibited and the starting material is allowed to dissolve. To some extent Preferable examples of the solvent include organic acids such as acetic acid and trifluoroacetic acid. Nonpolar solvents such as toluene and benzene; alcohol solvents such as methanol and ethanol; sulfonic acids such as p-toluene and trifluoromethane; water; and mixtures thereof. = It is necessary to use A. "The reaction temperature must be a temperature response which can be reacted without causing the formation of undesired by-products, and for example, preferably from room temperature to 25 () 1 when the reaction system When the dense container is introduced: the yield is good. Under the preferred reaction conditions, the reaction is completed in the hour to the hour, and the reaction can be monitored by known chromatographic techniques. Undesired sub = object It is known by techniques known to those skilled in the art, such as conventional chromatographic extraction or/and crystallization removal. In step 7.3, the oxime-amine is used as a source to transfer 50 201035076 algebras [1, 2 , 4] 4_ position of triazole. Preparation of the compound of the formula (f-2) The following formula shows a preparation example of the compound of the formula (f-2): HO 2 Ν 2Ν-Ν-Ρ 2 [Step 8-2] . [Step 8-1] 0 ΪΧ, Ό (f -2) [Step 8-3] In the formula, X, P2 and Ring B are as defined above.

G The compound of the formula (f-2) can be produced from the carboxylic acid compound (f-3) as a starting material by the deuteration reaction of the step 8-1 and the deprotection reaction of the step 8-2. The compound (f-2) can also be directly derived from the ester compound (f-5) as shown in the step 8-3. The amidation of the step 8-1 is carried out by the same method as the above step 5-3 and can be carried out from the compound of the formula 5-3. A compound of the formula (f-4) is prepared. The deprotection of the step 8-2 is carried out in the same manner as in the above step 5-4, and the compound of the formula (f-2) can be obtained from the compound of the formula (f-4). The deuteration reaction of the formula 8-3 varies depending on the starting materials and is not particularly limited as long as the conditions are similar to those of the reaction. A known amidation reaction known to those skilled in the art can be used in this reaction. The method reported by a plurality of documents or the like can be used (for example, in the Japanese Chemical Society (editor), Jikken Kagaku Koza (Experimental Chemistry Program), 4th edition (22nd issue) Yuki G〇sei (Organic Synthesis) [IV], Maruzen Corporation' November 1992, pp. 265-267). A derivative of the compound of the formula (f_2) having a substituent on the gas atom may be a substituted carbamic acid salt (such as N,-mercaptopurine carboxylic acid benzyl ester hydrochloride, CAS No. 880-21-7). Substituting the general formula (f_u compound). The method of using the present compound in step 7 to reductively introduce a substituent into a compound [i, 2, 4] 51 201035076 a sitting % in addition to the aforementioned general methods 1 to 3 Further, the compound of the general formula [1] according to the present invention, wherein χι is a marriage, can also be produced according to the general methods 4 to 7. The general method 4 is generally used in the general formula (Ic) of the present invention. The method 4 is described below.

The formulas Φ, P, R2, m, η, W and ring B are as defined above. The method of the above-mentioned method 4 shows that the compound of the formula (Ic) having the ring 12 having [12,4] oxadiazole is prepared by the cyclization reaction of the step 9-1, using the tickic acid compound (a-9) as a starting material. An example of a method. The cyclization reaction of the step 9-1 varies depending on the starting materials and is not particularly limited as long as the conditions are similar to the reaction conditions. A known method described in a plurality of documents (for example, refer to Patent Publication No. DE-102004061750) can be used for the reaction. The hydroxy-compound compound (g-1) is easily prepared by reacting a cyanamide compound with hydroxylamine by a method known to those skilled in the art (for example, as described in j. Chem. Soc) Chem. Commun., p. 806, 1970). Process 5 is generally described below for the general process 5 of the compound of the formula (Id), the compound of the formula (Ie) and the compound of the formula (If) according to the invention. 52 201035076

In the formula, Ri, R·2, m, η, W and ring B are as defined above. BRIEF DESCRIPTION OF THE PREFERRED EMBODIMENT 5 shows that the ring A is prepared from the ruthenium compound (a-7) as a starting material via the carbonase amination of the step 10-1 and the cyclization reaction of the step -2 10-2 [1, 3, 4 An example of a method of the compound of the formula (Id) of oxadiazole; and also showing that the ring A is prepared from the sulfonamide compound (a-1) via the cyclization reaction of the step 10-3, having [1,3,4]thiadiene An example of a method of azole compound of the formula (ie). General Process 5 further shows a process for preparing a compound of the formula (If) wherein ring a has [^, 4] triterpene from the ruthenium compound (a-7) as a starting material via the cyclization reaction of step 1〇_4. Example. (4) The secret amine of 1()_1 (4) The ring deficiency of 1Q_2 is different depending on the starting material and is not subject to any special restrictions, as long as the conditions are similar to those of such reactions. A number of documents (such as those described in j. 〇rg. Chem, v〇1 71, p 9548, 2006) can be used for such reactions. The isothiocyanate compound (g_2) may be a material or may be readily prepared by a reaction known to those skilled in the art, such as the reaction of a commercially available aniline compound with a thiol disaccharide or thiophosgene. The cyclization reaction of the step H)-3 varies depending on the starting materials and is not particularly limited as long as the conditions are similar to the reaction conditions. As stated in several documents 53 201035076

It is easy to know the method by heat (for example, Rev. Roum. Chim., vol. 50, p. l9 can be used for the reaction. The cyclization reaction of step 10-4 is based on The starting materials vary and are not prepared as long as the conditions are similar to the present reaction conditions. Methods known in the literature (for example, as described in Eur. J. Med. Chem., vol. t 2007) can be used for the reaction. The thioisourea compound (g-3) may be commercially available or may be prepared by methods known to those skilled in the art such as commercially available thiourea compounds and mercapto iodide anti-deer. General Process 6: Process 6 Typical use according to this The compound of the general formula (Ig) of the invention - will be explained as follows. .w. N- 'Ν-^Λ-Χα [Step 11-1] (Rl)m (R2)n

(a-1) wherein R丨, R2, m, η, W, XA and ring B are as defined above. The above general process 6 is shown as starting material from compound (a-1), step 11-1. An example of a method of preparing a compound of the general formula [Ig] having an imidazole ring by bromination and the cyclization reaction of the step 11-2. The bromoacetylation of the step 11-1 varies depending on the starting materials and is not particularly limited as long as the conditions are similar to the reaction conditions. Known methods described in a number of documents (for example, described in Bioorg. Med. Chem. Lett., vol. 13, ρ. 2059, 2003) can be used in the reaction. 54 201035076 The cyclization reaction of the step 11-2 varies depending on the starting materials and has no special cation, as long as the conditions are similar to the reaction conditions. The methods described in the various documents (for example, as described in Eur. J. Med. Chem., v.l. 41 2006) can be used in the reaction. The compound of the formula (g-4) is a known or commercially available compound or a compound which can be prepared from such a compound by a known method. General method 7

A general production method 7 which is typically used in the compound of the general formula (Ih) and the general formula (1) according to the present invention will be explained below. mouth

Wherein R!, R2, m, η, W and the ring system are as defined above. The above general process 7 is shown from the compound (a-8) as a starting material, the furnace is formed by the step (4) of the step 12-1 and the cyclization reaction of the step 12.2 is used for the preparation of the ring: having the general formula of [1, 2, 4] An example of the method of the ruthenium complex; also: from the oxonium compound (a-14) as a starting material via the cyclization reaction of the step 12-3 for the preparation of the ring A having the [1,2,4] thiadiazole An example of a method of a compound of formula (Ii). The reaction for forming oxindole in the step 12-1 varies depending on the starting materials and is not particularly limited as long as the conditions are similar to the reaction conditions. Known methods as described in the various documents (for example, as described in Synth. c〇mmun, v〇1. 26, p 4351, 55 201035076 1996) can be used for this reaction. The cyclization reaction of the step 12-2 is carried out by heating the oxindole compound (a-14) and the 2-mercaptoisothiourea compound (g-3) in the presence of a solvent in the presence of a base. The cyclization reaction in the step 12-3 is carried out by heating the oxindole compound (a-14) and the isothiocyanate compound (g-2) in a solvent. As described in detail above, the compound of the general formula [I] can be produced according to the general methods 1 to 7 used in the compound of the present invention, or can be produced by other methods known to those skilled in the art. The examples described hereinafter will provide for the preparation of such methods, and the compounds of the general formula [I] can be readily prepared by methods known to those skilled in the art based on such examples. The compound of the general formula [I] or a pharmacologically acceptable salt or ester thereof according to the present invention can be effectively used for the treatment of a disease caused by Aβ and is excellent in terms of pharmacodynamics, toxicology, stability, absorption and the like. A therapeutic agent for a disease caused by Aβ caused by the compound of the general formula [I] or a pharmacologically acceptable salt or ester thereof according to the present invention can be produced by a known method. Preferred examples of the dosage form include lozenges, powders, fine granules, granules, coated tablets, capsules, syrups, throat tablets, inhalants, suppositories, injections, ointments, ophthalmic solutions, ophthalmic ointments Agents, nasal drops, ear drops, lozenges and lotions. The medicament can be prepared by using typically used ingredients such as excipients, binders, lubricants, coloring and flavoring agents, and ingredients such as stabilizers, emulsifiers, absorption enhancers, surfactants, Prepared by a pH adjusting agent, a preservative, and an antioxidant; and can be prepared by blending ingredients commonly used as a pharmaceutical preparation. These ingredients include animal oils and vegetable oils such as soybean oil, bovine 56 201035076 oil and synthetic triglycerides, esters, and "$beiyuan such as liquid stone, decane and solid esters; Acid octyl 12 vinegar and meat ring isopropyl alcohol stearyl alcohol and succinyl alcohol, · polyester, · sugar fat · V such as polyoxyethylene ethyl vinegar, polysorbate, polyoxygen , polyoxyethylene ethyl polysorbate fatty acid; water "gas (four) block copolymer polymer, flat, ... soil eutropha, poly-di-acid, a few ethylene

侗石山卢醇 polyvinylpyrrolidone and 甲甲雄雄· Low transalkanols such as ethanol and isomethyl fibers, auxins, diols, dipropylene glycol and sorbose:: Portuguese: such as glycerin, The powder of the machine is such as donation liver, Ming and two: such as (4) sugar and curtain sugar; examples of the excipients include lactose, U, and alcohol water. Examples of the use of the sugar alcohol, the sugar, the sugar starch, the corn starch, the sucrose, the glucose, the sorbitan, and the crystalline fiber 1 include polyethylene glycol alcohol, polyethyl emulsifier. Used mucocellulose, gum arabic, western her, gelatin: cellulose, ethyl cellulose, propyl cellulose, poly /, shellac, propyl methyl oxyethylene block copolymer and Base grape ^ ° each set _, polypropylene glycol - poly case including the use of powdered gelatin powder used in the hydrogen ^ sodium, lemon _, dextrin, fruit • shoutin, carbon _ 'carbonated lubricant examples include hard Wax _, ^ base fiber, fine. It is used in Shixi and hydrogenated vegetable oil. A coloring agent for ethylene glycol and a dioxive drug is used. Examples used include allowing addition to the brain, Apexon (-(four), thin two: her ^ 7', borneol and cinnamon powder. For example, the taste of oral preparations / 糸 per addition by the addition of active ingredients 57 201035076 or a salt or ester or compound hydrate thereof or a salt or ester thereof, an excipient, and if necessary, a binder, a disintegrating agent, a lubricant, a coloring agent, and a flavoring agent, and then, for example, by conventional methods The mixture is formed into a powder, a fine granule, a granule 'storage' coating (four), or a capsule. It is apparent that the key or granules may be coated, for example, by a suitable coating, such as a sugar coating, if desired. The main injection preparation can be prepared by adding a pH adjuster, a solubilizing agent, an isotonic agent (for example), and if necessary, adding a solubilizing agent, a stabilizer, etc., and the external preparation can be borrowed - a conventional method The preparation is not particularly limited. As for the test material, it can be prepared by using four kinds of materials, such as drugs, quasi drugs, cosmetics, etc. As for the base material, it can be used for drugs, quasi drugs, Among various materials such as cosmetics Examples of base materials include animal oils and plants, mineral oils, vinegar oils, soils, high carbon alcohols, fatty acids, oxygenated oils, surfactants, phospholipids, alcohols , polyols, water-soluble polymers, clay minerals and pure water, etc. If necessary, add a positive regulator, antioxidant, chelating agent, preservative and fungicide, coloring agent 'flavoring agent. Further, if necessary, a component having a differential induction effect such as a blood flow promoter, a bactericide, an anti-inflammatory agent, a cell activator, a vitamin, an amino acid, a moisturizer or a keratolytic agent may be blended. The dosage of the agent varies depending, for example, on the degree of symptoms, age, sex, body weight, administration mode, salt type, and specific disease type. Typically, the compound of the formula [I] or a pharmacologically acceptable salt thereof is in a single dose or The knife is divided into several doses, about 3 gram to 10 grams per ounce, preferably 1 〇〇 microgram to 5 gram, and more preferably just gram to gram, orally administered to an adult, and the heart is about 30 micro 58 per day. G to 1 gram, preferably 100 micrograms 500 mg, and more preferably 100 micrograms to 3 milligrams, is administered to adults for treatment of diseases caused by starch-like beta such as Alzheimer's disease, elderly dementia 'Down' syndrome or amyloidosis The compound of the formula [I] or a pharmacologically acceptable salt or ester thereof according to the present invention may be used in combination with a compound having the following mechanism. For example, these compounds include a cholinesterase inhibitor (for example, Donepezil) ), huperzine A, tacrine, rivastigmine, galantamine; AMPA receptor antagonists (eg 1,2-dihydropyridine compounds such as 3) -(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydroacridin-2-one); NMDA receptor antagonist (eg memantine) ; 醯 醯 验 test release stimulator (such as pramiracetam; aniracetam); mother channel agonist (such as nefiracetam); free radical scavenger ( For example, EGb 761), platelet activating factor antagonist (eg EGb 761); platelet aggregation antagonist (eg EGb 76 triflusal) )); insulin sensitizer (such as rosiglitazone); peroxisome proliferator-activated receptor agonist (such as Rosieta Tazon); peroxisome proliferator _ activation a gamma agonist (eg, Rosieta Tazon); a monoamine oxidase inhibitor (eg, rasagiline, selegiline, procaine); carnitine acetyltransferase stimulation Agents (eg, levacecarnine); NSAIDs (eg, trifluorosilane, cyclooxygenase-2 inhibitors such as celecoxib); nerve growth factor agonists (eg, salibonden (xaliproden) ), FPF 1070); β-class starch inhibitors (eg Tarrenflurbil 59, 201035076 (tarenflurbil), Tramiprosate, leuprorelin-D); immunomodulatory agents (eg Tarrenfjord) , immunoglobulin, heptaylethyl ester); NF-kB inhibitors (eg, Tarrenfu); thyrotropin-releasing hormones (eg, taltirelin); dopamine D2 receptor antagonists ( For example, risperidone; serotonin 2 receptor antagonists (eg, Rui Pei Li Dong); Alkaline M1 receptor agonist (eg ceviline); α-adrenergic receptor agonist (eg modafinil); serotonin 3 receptor antagonist (eg arosetron) )); dopamine D2 receptor agonist (eg aripiprazole); dopamine D2 receptor antagonist (eg Aripiprazo); serotonin 1A receptor agonist (eg Alibaba serotonin 2A) Receptor antagonists (eg, Aripiprazol); glucocorticoid antagonists (eg, mifepristone); progesterone antagonists (eg, milphimone); hmG-C〇A reductase inhibitors ( For example, atorvastatin, simvastatin, adenosine absorption inhibitors (such as propentofylline); diacetate inhibitors (such as wave plate tofinin) An acetylcholine receptor agonist (eg, choline (alf〇scerate); a membrane permeability enhancer (eg, choline Ephex); a cannabinoid receptor antagonist (eg, rimonabant); cannabinoid receptor agonists (eg, dronabinol; blood vessels) Neonatal inhibitors (eg, paclitaxel); immunosuppressive agents (eg, paclitaxel); tubulin antagonists (eg, paclitaxel); thromboxane A synthetase inhibitors (eg, trifluorosilane); antioxidants (eg, Idebenone); alpha adrenergic receptor antagonists (eg, nicergoline); estrogen antagonists (eg, light 201035076 estrogen, tripartane) 3_0 hydroxysteroid dehydrogenase inhibitor (eg, tripotam); signal transduction pathway inhibitor (eg, tripotam); melatonin paternal agonist (eg, ramelteon); immunization Stimulants (eg, immunoglobulins, heptapentaethyl ester, procaine HIV entry inhibitors (eg, procaine); sodium channel antagonists (eg, procaine); microtubule inhibitors (eg, CPH 82); Glycine NMDA agonist (eg, cycloserine); adenine A1 receptor antagonist (eg KW 3902); ATPase stimulant (eg triethyl uridine); mitochondrial function enhancer (eg triethyl hydrazine) Uridine); growth hormone releasing factor agonist Tesalmorelin; butyl gallstones _ inhibitors (eg, benoxine (1^11〇1^11^1'丨1^)); 〇1 adrenergic receptor Body antagonists (eg, nisagulin); NO synthetase type II inhibitors (eg, arundic acid); chelating agents (eg, PBT 2); starch-like fibrillogenesis inhibitors (eg, TTP488, PF) 4494700); serotonin 4 receptor agonist (eg PRX 03140); serotonin 6 receptor antagonist (eg SB 742457); benzodioxin receptor inverse agonist (eg radequinil), Bow channel antagonists (eg, Shafenama (4) such as curry)); final acid receptor agonists (eg, ispr〇nicline); and BACE inhibitors (eg, CTS2丨i 66). Further, the aforementioned compounds include, for example, Dona Paige, Hu Paijin A, Taklin, Dihuati, Jialantamin, Pamirashitan, Anilahitan, Neferahitan, EGb 76 Brosig Gattazon, Rasha Gelin, Leihua Sakanin, Selecom, 3-(2-cyanophenyl)-5-(2-°-pyridyl)_丨_phenyl 1, 2-Dihydro"bipyridine, talampanel, becampanel, mermaid, sariboden, taurfubi, cuemipo, berlin _D, tower 61 201035076 Terrylin, Rui Pei Lidong, Sevier Merlin, Modafini, Arosse Chong, Alipipazzo, Miffin Pidong, Attohua Statin, Boto Tofilin, Choline Fosserie, FPF 1070 (CAS number 143637-01-8), Ramoban, Doñabino, hexadecenoic acid, Pacific paclitaxel, trifluorofloxacin, Idebeon, Nisere, 辍Estrogen, tripatan, xinhuastatin, sirrin, lammet, immunoglobulin, heptaethyl ester, procaine, CPH 82, cycloserine, KW 3902 (CAS No. 136199-02-5), Sanyi brewing urine, estrogen dementia Therapeutic agents (eg MIGENIX, Vancouver, Canada), tasmarinus, pirosin, nisergic, arudic acid, PBT 2, TTP488, PF 4494700, PRX 03140, SB 742457, Radhani, Shafinamai, Iponikin, CTS 21166, Bapineuzumab, NP 031112, (2S, 3aS, 7aS)-1 {[(R,R)_2-benzene Cyclopropyl]carbonyl}-2-[(thiazolidin-3-yl)yl]octahydro-1H-indole, citalopram, venlafaxine, reporin (levprorelin), prasterone, peptide T (CAS number 53-43-0), besipiridine, lexipafant, stacofylline, SGS 742 (CAS number 123690-78-8), T 588 (CAS number 142935-03-3), nerisipiridine, dexanabinol, sabcomeline, GTS 21 (CAS number 156223-05-1), CX 516 (CAS number 154235-83-3), ABT 089 (C AS number 161417-03-4), Anasos (anasos), Tesofensine (tesofensine) , SIB 1553A (that is, 4-[[2-(1-曱基-2-〇0) bite Ethyl] sulfur] discretion 0, ladostigil, radniki 'GPI 1485, 62 201035076 Iponikin, arudic acid, MEM 1003 (ie 4-(2-chloro-3-) Cyanophenyl)-2,6-diamidinopyridine-3,5-dicarboxylic acid) 3-isopropyl vinegar 5-(2-decyloxy) vinegar, V 3381 (also known as 2-(2,3- Dihydro-1H-indol-3-ylamine)acetic acid amine hydrochloride), farampator, paliroden, pastron, paladin, yuleco Urocortin, DP b99 (ie 2.2,-(extended ethyldioxy)C(2,l-phenylene)[N-[2-[2-(octyloxy)ethoxy]-2 -ketoethyl]imine]indole (acetic acid)), capserod, DU 125530, bapyrian, AL 108 (ie L-aspartate-L-alaninyl-L - amidoxime-L- guanamine aryl-L-serine aryl-L-iso-alkamine aryl-L-amine aryl-L-Chuamine), DAS 431, DEBIO 9902, DAR 100, Mitoquinone, IPL 455903 (ie 5(S)-[3-(cyclopentyloxy)-4-indolyloxyphenyl]-3(S)-(3-methylbenzyl)piperidin Pyridin-2-one), E2CDS, PYM 50028, PBT2, lecozotan, SB 742457, CX 717, AVE 1625 (ie 1-(贰) (4-chlorophenyl)methyl)-3-((3,5-difluorophenyl)(methylsulfonyl)arylene) LY450139 (also known as N2-[2(s) -hydroxy-3-methylbutanyl]-Nl-[3-methyl-2-keto-2,3,4,5-tetrahydro-1H-3-benzoindole-1(S)-yl]- L-alanamine), £1421 (ie 4,4'-[(211,35)-2,3-dimethylbutane-1,4-diyl]indole (1,2-dimethoxy) Benzene), SRN 001, TTP 488, PRX 03140, dimebolin, glycine acid valine-glycolate, C105, AL 208, MEM 3454, AC 1202, L 830982, LY 451395 ( That is, (R)-N-[2-[4'_(methylsulfonamidemethyl)biphenyl-4-yl]propyl]propane-2-sulfonamide), MK 0249, LY 2062430, two Ethyl spermidine, neboglamine, S 18986, SA 4503 (CAS number 165377-44-6), GRI 1, S 17092 (ie (28, 3 & 8, 7 & 8)-1 {[(尺, !1)-2-phenylcyclopropyl] 63 201035076 carbonyl}-2-[(thiazolidin-3-yl)carbonyl]octahydro-1H-indole), SL 251188, EUK 189, R 1450,6,6-diamidino-3-(2-hydroxyethyl)sulfan-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophene-4(5H)- Ketone, CERE 110, dexefaroxan 'CAD 106 ' HF 0220, HF 0420, EHT 0202, VP 025, MEM 1414, BGC 201259 (ie N,N-dimethylaminecarboxylic acid, 4-[l(S)-(methylamine)-3-(4-nitrogen) Phenoxy)propyl]phenyl), hydrazine 100, ABT 834, ΑΒΤ239 (ie 4-[2-[2-[(2R)-2-methylpyrrolidinyl]ethyl]-benzofuran- 5-yl]benzonitrile, SGS 518, R 1500, C 9138, SSR 180711, afatradiol, R 1577, T 817MA (ie 1-[3-[2-(1-benzo) Nitrate-5-yl)ethoxy]propyl] °丫. Dan-3-ol cis-butane diester), CNP 1061 (ie 4-mercapto-5-(2-nitroxyethyl)thiazole), KTX 0101 (also known as β-hydroxybutyrate), GSK 189254 (ie 6-[3-cyclobutyl-2,3,4,5-tetrahydro-111-benzo[(1] 吖h-7-yloxy]-> 1-methylnicotine 醯Amine, AZD 1080, ACC 001, PRX 07034, midazolam, R-Fenselin, AZD 103 (CAS number 488-59-5), SN 522, NGX 267 (CAS number 503431) -81-0), N-PEP-12, RN 1219, FGLL, AVE 8112, EVT 1 (H, NP 031112, MK 0752, MK 0952, LX 6171, PAZ 417, AV 965, PF 3084014, SYN 114, GSI 953, SAM 315, SAM 531, D-serine, leteprinim 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), ciclosporin, NCX 2216 (ie 3-[4-[2-(2-fluorobiphenyl-4-yl)) (E)-4-(indolylphenyl)acrylic acid) (E)-4-(nitroxyl)butyl ester), NXD 3109, 201035076 NXD 1191, ZSET 845 (ie 3,3-diphenylimidazo[12a] Pyridine-2(3H)-one), ET 002, NT 13 , RO 638695 (ie [1,6-(1,6-diketohexyl)]dipyrrolidine-(2R)-carboxylic acid), bisnorcymserine, BA 1016, XD 4241, EUK 207 (ie (SP-5-13)-(acetate-κΟ)[13,16,19,22-tetraindole-3,6-dioxatricyclol 21.3.18,12]octadecene-1 ( 27), 2,6,8,1012(28),23,25-octadecene-27,28-diolate (2-)-κN3,κN6,κ027,κ028) manganese, LG617 inhibitor, ZSET 1446, ΡΑΝ8Η, F 14413 (also known as 2-[5-fluoro-2(S)-methoxy-2,3-dihydro-1,4-benzodi"-)-2-yl]-4,5-di Hydrogen-1H-imidazole), FP 7832 (ie N-[2-(5-methoxy-1-nitros-1H-indol-3-yl)ethyl]acetamide), ARA 014418 (ie N-(4-methoxybenzyl)-N,-(5-nitro-1,3-thiazol-2-yl)urea), AZD 3102, KP 544 (ie 2-amine-5-(4-chloro) Phenylethylidene)-4-(4-trans-hydroxycyclohexylamine)pyrimidine), DP 155, 5-chloro-N-[3-[2-(dimethylamine)ethyl]-1H-indole哚-5-yl]naphthalene-2-sulfonamide, TAK 070, Hupaijin, N-[2-(3,5-dimethyladamantan-1-yl)ethyl]acetamidine hydrochloride, 6-[4-[(Dimethylamino)methyl]-5-ethyl-2-indoleoxyphenyl]pyridin-2-amine, 4,6-diphenyl-3-(4-(cyclohexane) - 2-Based), N-[(lS,2R)-3-(3,5-difluorophenyl)-small-1-[(5S,6R)_5-methyl -6-(synyloxy)porphyrin-3-yl]propan-2-yl]acetamide hydrochloride, N-[(lR,2S)-3-(3,5-difluorophenyl) 1-hydroxy-1 -[(2R,4R)-4-phenoxypyrrolidin-2-yl]propan-2-yl]-3-[(R)-2-(methoxymethyl)° ratio Pyridin-1-carbonyl]-5-methylbenzylamine, R 1589, midafotel, veselin, clurastatin, lentils, sip risan Cipalisant), nitroflurbiprofen, PPI 1019 (ie (3α,5β, 7α, 12α)-trihydroxycholethane-24-mercaptoamine sulfhydryl 65 201035076 -L- amidoxime -L-Amphetamine-L-Amphetamine-L-alanine), dapsone, MDL 100453 (CAS number 129938-34-7), NS 377, midaxifylline, wave Propofol scallate, merifonate, ceronapril, tenilsetam, sufoxazine, seglitide, ebitarate (ebiratide), nebacetam, milacemide, edodosso Isoodoxorubicin, SM10888 (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), apovincamine, FR121196 (CAS number 133920-65-7), LY 274614 (CAS number 136109-04-1), CL 275838 (CAS number 115931-65-2), imemesine ), K 7259 (CAS No. 133667-88-6), Vinconate, Itasetron, CL 287663 (CAS number 125109-98-0), WAY 100289 (CAS number 136013-69- 9), SR 46559A (CAS number 137733-33-6), GYKI 46903 (CAS number 142999-59-5), L 670548 (CAS number 121564-89-4), Y 29794 (CAS number 129184-48-1) , AF 125 (CAS number 7631-86-9), KFM 19 (CAS number 133058-72-7), ST 796 (ie (S)-3-[3-(trifluoromethyl)benzyl) amine ) hexahydropurin-2-one), RU 33965 (CAS number 122321-05-5), SDZ 210086 (ie (-)-l', 2(S)-dimethyl snail [1,3-two . No. "Mountain-4,4'-piperidine]), L 689660 (CAS number 144860-79-7), L 689560 (CAS number 13905 Bu 78-8), ST 618 (ie 1-(6,7-) Dimethoxy 12,4-tetrahydro-2-naphthyl)-4-hydroxypyrrolidin-2-one), U 74500A (CAS number 110101-65-0), 66 201035076 GEA 857 (CAS number 120493-42-7 ), BIBN 99 (CAS number 145301-48-0), DX 9366, ΟΝΟ 1603 (CAS number 114668-76-7), MDL 102234 (CAS number 137766-81-5), P 9939 (CAS number 157971-37- 4), PD 140532 (CAS number 157971-39-6), Azettilin (azetirelin), MR 16728 (CAS number 147614-21-9), Dabelotine, MDL 102503 (ie 8 -[l(R)-methyl-2-phenylethyl]-1,3-dipropyl-7H-xanthine), PD 141606 (ie (±)-(B)-3-(3-stupid) Benzyl-2-propynyloxyimine)-1-indenylbicyclo[2.2.1]heptane), SNK 882 (CAS number 152221-12-0), L 696986 (CAS number 141553-45-9), Tazomeline, LY235959 (CAS number 137433-06-8), 2-(2-thioketopyrrolidin-1-yl)acetamide, AK 30 NGT, ABT 418 (CAS number 147402-53-7 ), Itameline, HUP 13, Hibolite (s Ibopirdine), KST 5452 (CAS number 157998-88-4), TJ 54, U 92798 (also known as 7-[4-[贰(4-fluorophenyl)fluorenyl]perhydro-1,4-dioxime -1-ylmethyl]-4-isopropyl-2-oxo-2,4,6-cycloheptatrien-1-one), U 92032 (CAS number 142223-92-5), 3-( Acesulfonyloxy)estr-1,3,5(10)-trien-17-one, P 11012 (CAS number 164723-36-8), A 82695 (CAS number 147388-86-1), FR 76659 (CAS number 116904-25-7), apaxifylline, CX 417, 7 MEOTA (CAS number 5778-80-3), BU 4514N (CAS number 151013-39-7), gestic alcohol ketone ( Pregnenolone), mexidol, ST 857 (CAS number 154755-63-2), RU 49041 (CAS number 123828-80-8), RU 35929 (CAS number 111711-47-8), P 878184, P 128 (CAS number 157716-52-4), Jura Statin 67 201035076

(eurystatin) A, Jurastar; D, B, LK 12, NBI 108, NBI 107, NBI 117, L 705106, bacoside A+B, clausenamide, SM 21 (CAS No. 155156-22-2), alatide, RS Π017 (ie 1-(4-amine-5-Ga-2-oxophenyl)_5_(ι_piperidinyl)-1-pentanone Hydrochloride), AF 150(S) (ie (S)-[l-mercapto-piperidin-4-spiro-(2'-mercaptothiazoline)]), RO 153505 (CAS number 78871-13 -8), PV 113 (ie 1,2,3,4-tetrahydropyrrole-[l,2-a]-pyrazine), arisugacin, A 98284 (ie 2 (R) )-(3-methyl.salt-5-yl quinidine), AP 5 (CAS number 136941-85-0) 'BD 1054, SDZNDD 094 (ie 贰-(2-(2-methylimidazole) -1-yl)methyl)-° than pyridine-gin (hydrogen-fumarate), AZ 36041 (CAS number 173324-76-0), quilostigmine, A 84543 (ie 3-[1-methyl 0 ratio" bite-2-(S)-ylmethoxy]pyridine fumarate), BTG 4247 (ie 2-[2- gas ethoxy[4-(two) Methylamine)phenyl]phosphonium]-acetamidine), CGP 50068 (CAS number 158647-49-5), cerebrocrast, de-ironing Nordanoxamine, isolichenan, MHP 133 (ie 3-(N,N-dimethylaminodecyloxy)-1-mercapto-2-(4-benzene) Base-semicarbazone fluorinated pyridine rust), 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 (ie 4-[2-[(5-nitropyridin-2-ylsulfanyl)ethyl]-1H-0 mw), Isohuhuperzine A, SIB 68 201035076 1765F (CAS number 179120-52-6), JWS USC 751X (ie 3-[[[2-[[(5-dimethylaminoethyl)-2- fluorenyl]methyl]thio]hexyl]amine ]-4-石肖嗒耕), GR 175737 (also known as 3-(4-chlorobenzyl)-5-[2-(1Η-imidazol-4-yl)ethyl]-1,2,4_哼Diazole), KS 505A (CAS number 131774-53-3), ZTTA 1 (ie N-benzyloxycarbonyl-thiopropyl-thiopropargylaldehyde-dimethylacetal), AGN 190837 (CAS number 136527- 40-7), P 10358 (188240-597), WAY 131256 ((CAS number 174001- 71-9), DBO 83 (ie 3-(6-chloropyridin-3-yl)-dioxabicyclo[3.2.1]octane dihydrochloride monohydrate), FUB 181 (CAS number 152029 -80-6), RJR 2557, WSU 2088, LVV-haemorphin-7, M40 (ie, galanin [1-12]-Pro3-(Ala-Leu)2-Ala-NH2), SIB 1757, SKF 74652 (ie [5-gas-2-(4-methoxyphenyl)-3-benzofuranyl][4-[3-(dimethylamine)-propoxy]phenyl] Anthrone), CGP71982, SCH 57790 (ie 4-cyclohexyl_α_[4-[[4-methoxyphenyl]sulfinyl]phenyl]-1-piperidinonitrile), Putriscine )-D-Yebebe, l 14 (ie, p-〇-(Amidino)-N-tetradecylidene tyrosine), CLZ 4, SL 340026, PPRT 424, Ciproxifan, UR 1827 (also known as 2-(1-benzyl brigade. D--4-yl)_1_[4-(5-methylpyrimidin-4-ylamine)phenyl]-1-ethanone), carbotamin, TGS 20 (ie L-pyramine) --D_alanine decylamine), PG 9 (also known as decyl 2-[(4.bromo)phenyl]propionate), TEI 3356 (ie (16S)-15-deoxy-16 -hydroxy-16-methyl-9-(0)-low oxime-δ6(9ο〇-prostaglandin I1), LY392098 (ie thiophene, 3-[(2-methylethyl-2)sulfonylamine) Propyl-2]phenyl-4-yl-), PG 1000, DM 232, NEPP 11 (ie 12-iso-15-deoxy-18-(4-methyl)phenyl-13,14-di Mouse-87-prostaglandin into 1A 69 201035076 ester), VA 100 (ie (2,3-dihydro-2-[[(4-fluorobenzyl))]]]]] 5-phenyl-1H-1,4-indolizine), VA 101 (ie (2,3-dihydro-2-[[(2-thienylcarbonyl))]]] Methyl-5-phenyl-1H-M-benzodioxan), NC 111585 (ie (3S)-1,3-贰-[3-[(3-吖二环[2.2.2] 辛Base)-1,2,5-π-supplemented syl-O-oxy]-1-propan-1-yl]benzene, 2L-(+)-tartrate), IN 201, Immerbo Xifang Imoproxifan), kanokodiol, picroside I, picoside II, DM 235 (ie 1-(4-benzylindolylpipen-1-yl)propan-1-one), monoclonal antibody 10D5, JLK 2, JLK6, JLK7, DAPT (ie N-[N_(3,5) -difluorophenyridinyl)-L-propylaminoindenyl]-S-phenylglycine tributyl ester), huperine X, SGS 111 (ie 2-[l-(2- Phenylethyl pyrrolidine-2-carboxamide] (S)-ethyl acetate), NP 7557, C 9136, C 7617, R 1485, rofecoxib, velnacrine , montirelin, lazabemide, ORG 2766 (CAS number 50913-82-1), sabeluzole, adafenoxate, CAS stone horse 9061 -61-4, ipidacrine, bemesetron, idazoxan, linopirdine, selfotel, suritozole , milameline, xanomeline, TJ 960, fasoracetam, eptastigmine, ensaculin, zanapezil ), Posatirelin, zacopride, RS 86 (CAS number 3576-73-6) , ORG 5667 (CAS number 37552-33-3), RX 77368 (CAS number 76820-40-l), BMS 181168 (CAS number 123259-91-6), BY 1949 (CAS number 90158-59-1), 201035076 AWD 5239 (CAS number 109002-93-9), YM 796 (171252-79-2), aloracetam (aloracetam), Cl 933 (CAS number 91829-95-7), ST 793 (CAS number 99306- 37-3), cebaracetam, zifrosilone, talsaclidine, alvameline, JTP 2942 (148152-77_6), OPC 14117 (CAS No. 103233-65-4), elziverine, AP 521 (ie N-(l,3-benzodioxin-5-ylmethyl)-1,2,3,4- Tetrahydro[1]benzothieno[2,3-c]pyridine-3(R)-carboxamide hydrochloride), S8510 (CAS number 151466-23-8), JTP 4819 (CAS number 162203-65) -8), icopezil, SC 110, FK 960 (CAS number 133920-70-4), DMP 543 (CAS number 160588-45-4), Ganstin (叾 &1181^111丨1^), (:11017 (also known as (11)-(-)-(2)-1-indenyl ring [2.2.1] hept-3-one, 0-(3-(3'-methoxy) Phenyl)-2-propenyl)-indole maleate), T 82 ( 2-[2-(1-Benzylpiperidin-4-yl)ethyl]-2,3-dihydro-9-methoxy-1H-pyrrolo[3,4-b]quinoline-1- Ketone hemifumarate), NGD 971, aspartate-alanamine-glycosyl- amphetamine-spermine-indenyl-histamine-yl-aspartate-serine-based -Glycidyl-tyrosine-yl- glutaminyl- amidino-ylamine-histamine-histamine-mercapto glutamine-iso-amino-ylamine-ylamine-hydrazinyl- Amphetamine-aldolyl-alkalyl-alaninyl-glutaminyl-aspartate-ammonium-glycosyl-seramine-aspartate-aspartate-aminoamine-glycine Aminyl-alanamine-iso-amylamine-iso-amylamine-glycine-ylamine-aminoglycolyl-carbamide-glycine-glycine-glycine Amidoxime-amidino-iso-amylamine-alanine vaccine, PBT 1 (CAS number 130-26-7), TCH 346, FK 962 (also known as N-(l-Ethyl) Pyridin-4·yl)-4-71 201035076 flubenzamide, voxergolide, KW 6055 (CAS number 63233-46-5), sulphur pilocarpine, ZK 93426 (CAS number 89592-45-0 ), SDZNVI 085 (CAS number 104195-17-7), CI 1002 (CAS number 149028-28-4), Z 321 (CAS number 130849-58-0), mirisetron, CHF 2060 (ie N-heptylcarbamic acid 2,4a,9-trimethyl-2, 3,4,4a,9,9a-hexahydro-1,2-indole and [6,5-b]non-6-yl ester-L-tartrate), gedocarnil, special Terbequinil, HOE 065 (CAS number 123060-44-6), SL 650102, GR253035, ALE 26015, SB 271046 (ie 5-gas-N-(4-methoxy-3-piper-1) -yl-phenyl)-3-methyl-2-benzothiophenesulfonamide), ibeta (iAbeta) 5, SCH 211803 (ie piperidine, 1-[1-(3-methyl-2-) Amine phenyl)carbonylpiperidin-4-yl]-4-[(3-phenylphenyl)sulfonylphenyl-4]methyl-), EVT 301, alpha-linolenic acid/linoleic acid, kami Kamikihi-To, siagoside, FG 7142 (CAS number 78538-74-6), RU 47067 (CAS number 111711-92-3), RU 35963 (CAS number 139886-03 -6), FG 7080 (CAS number 100332-18-1), E 2030 (CAS number 142007-70-3), transforming growth factor β-l, A 72055 (also known as 2',1-dimethyl snail [piperidin-4,5'-oxazolidine]-3'-carboxyaldehyde), NS 626, dimirracetam, GT 30 (H, GT 25 (H, GT 2342, GT 2016 (CAS number 152241-24-2), ORG 20091 (CAS number 141545-50-8), BCE 001 (CAS number 95678-81-2), CGP 35348 (CAS number 123690-79-9), WAY 100635 (CAS number 146714-97-8), E 4804 (CAS number 162559-34-4), LIGA 20 (CAS number 126586-85-4), NG 121 (also That is, 2-[4,8-dimercapto 72, 201035076 -3(E), 7(E)--adenosyl]-3,5-dihydroxy-2-indolyl-3,4,7,9 -tetrahydro-2H-fluoro[3,4-h]-l-benzopiperan-7-one), MF 247 (ie N-[10-(diethylamine) fluorenyl]aminecarboxylic acid (3aS) ,8aR)-l,3a,8-trimethyl-l,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole-5-yl ester), JTP 3399 (also Namely N-benzyl-2(S)-[2(S)-(phenoxyethyl)pyrrolidin-1-ylcarbonyl]pyrrolidin-1-carboxamide), KF 17329, sipram ( Thioperamide), F 3796 (ie 1-[2-(1-benzylpiperidin-4-yl)ethyl]-3-[3,4-(methylene-dioxy)benzylidene]thiourea ), GT 4001, GT 4002, FPL 14995 (CAS number 123319-03-9), RU 34332 (CAS number 137157-58-5), SR 96777A (CAS number 115767-94-7), SIB T1980, NS 649 ( CAS number 146828-02-6), PD 1425 05 (CAS number 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 number 168986-60-5), NS 1546, ZM 241385 (CAS number 139180-30-6), RO 249975 (ie [IS, 3S (2, S) ,5R]-3-(l-benzyl-5-ketopyrrolidin-2-ylmethyl)-5-(lH-imidazol-5-ylmethyl)cyclohexane-1-ethylamine), AF 185 (ie 8-decyl-3-(2-propynyl)-1,3,8-trisuro[4,5]indole-2,4-dione), CEP 427, CX423, CX 438 , CX 480, CDP-ethanolamine, GT 4003, GT 4〇n, GT 5011, MS 430 (CAS number 122113-44-4), MBF 379 (ie [3,3-贰(hydroxyindole)-8- Hydroxy-3,4-dihydro-2H-1,4-benzo. No.5-based][3',5'-dihydroxy-4'-(2-keto-2-phenylethoxy)phenyl]anthone), NGD 187 (CAS number 163565-48-8) , DUP 856, MR 3066, MF 8615 (ie 5-amine-6-chloro-4-hydroxy-3,4-dihydro-1H-thiophene 73 201035076 0Nan-[3,4-b]°t : Lin Ketone), himbacine, ABS 300, RJR 2403 (CAS number 538-79-4), MF 268 (CAS number 174721-00-7), RO 465934 (ie N, N-dimethyl 3-(2-cyclohexyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indol-6-yl) amide, NS 393, RGH 2716 (CAS No. 134069-68-4), WIN 678702 (12,12-贰(3-furyl)-6,11-dihydro-6,11-ethylenebenzo[b]gasified quinoline till), RS 66252 (ie 1-butyl-2-[(2,-(2H-tetrazol-5-yl)-biphenyl-4-yl)indolyl]_1H-indole-3-carboxylic acid), AIT 034 (CAS number 138117-48-3), NG 012 (CAS number 131774-53-3), PD 142012 (CAS number 5778-84-7), GT 4054, GT 4077, GT 4035, P26 (CAS number 152191-74 -7), RGH 5279 (ie (-)-(13aR,13bS)-13a-ethyl-2,3,5,6,13&,131>hexahydro-1沁吲哚[3,2, 1-(16)pyrido[3,2,1- out [1,5]°nidine-12-carboxylate 2-Ethyloxyethyl ester), Octa-1, 083, CeNeS, estradiol (also known as 1,3,5(10)-estratriene-3,17β-diol), WAY 132983 ((3R, 4R) )-3-(3-hexylsulfanylpyrrol-2-yloxy)-1-indenylbicyclo[2.2.1]heptane hydrochloride), ABS 205, ABS 401, SX 3507 (ie 3- (3-propyl-1,2,4-°diazol-5-yl)quinoline oxalyl-2(1H)-one), ARR 17779 (ie (-)-spiro[l-fluorene ring [2.2.2] Octene-3,5-oxazolidine]-2-one), XE991 (ie 10,10-indole (4-pyridylmethyl)indole-10(9H)-one), phenanthrene Phenylnorcymserine, RO 657199, RJR 1781 (ie R(+)-2-(3-pyridyl)-1-indenyl ring [2.2.2] octane, RJR 1782 (ie 8(-)-2-(3-° ratio bite base)-1-〇丫2 ring [2.2.2] Xin Xuan>) 'Gilatai (8 such as 1; 丨 (^), tossing ( Tolserine), TC 2559 (ie (E)-N-methyl-4-[3-(5-ethoxyacridinyl)-3-buten-1-amine), ER 127528 (ie 1- (3-fluorobenzyl)_4-[(2- 74 201035076

Fluor-5,6-dimethoxy-1-tetrahydroindole-2-yl)methyl]. Hydrochloride), thiatolserine, targacept, axonyx, sisin, thiacymserine, 266 antibodies, Apan )-CH, DP 103, SPI 339 (ie 4·[3-(4-keto-4,5,6,7-tetrahydroindol-1-yl)propanylamine]ethyl benzoate), S 37245 (ie 4-(1,4-benzodio[2] y-5_yl)-l-[3(S)--5-nitro-tetrahydroindole_2_yl]-π bottom σ Well), [LG 88, AZD 2858, trometamol, AN 240, NG 002 (also known as 5-hydroxy-5-(2-pyridylethyl)-4-methoxy oxime) Nor-2(5H)-one), UCB 29427 (ie 2-cyclopropyl-4-(cyclopropylamine)-6-(porphyrin)-1,3,5-tricycle), TRH-SR , RO 401641 (CAS number 122199-02-4), MPV 1743AIII (CAS number 150586-64-4) ' IDRA 21 (CAS number 22503-72-6), CEP 431, ACPD (CAS number 67684-64-4) , CT 3577 (ie 3,7-dimercapto-1-[11-(3,4,5-trimethoxybenzylamine)-11-one undecyl]xanthine), CT 2583, NXD 9062 , de-iron-Nodanozamin, DPb99, PBT, T 817MA, Afford, Europe (CAS No. 57-91-0), AL 108, SL 650102, RS 67333 (CAS No. 168986-60-5), RS-17017, SGS 518, SYN 114, SB 271046, R0657199, PRX 07034, Suritoto (CAS No. 110623-33-19), Tebini (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. 78771-13-8), RU 33965 ( CAS No. 122321-05-5), S 8510 (CAS No. 151466-23-8), Sabeluzzo (CAS No. 104383-17-7), Seri Becky (CAS No. 118790-71- 9), NS 626, NS 649 (CAS No. 146828-02-6), U 92032 (CAS No. 75 201035076 142223-92-5), MEM 1003, U 92798, RGH 2716 (CAS No. 134069-68- 4), Safina Mai (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 1807Π, ABT 089 (CAS No. 161417-03-4), ABT 107, ABT 560, TC 5619, TAK 070, N-[(lS, 2R)-3-(3,5-difluorophenyl)-l-hydroxy-l-[(5S,6R)-5-A -6-(neopentyloxy)porphyrin-3-yl]propan-2-yl]acetamide hydrochloride, 6-fluoro-5-(2-fluoro-5-methylphenyl)-3, 4-dihydropyridine, 2-amine-6-[2-(3'-methoxybiphenyl-3-yl)ethyl]-3,6-dimercapto-5,6-not ticking-4 ( 3H) ketone, AZD 1080, ARA 014418, XD 424, Z 321 (CAS No. 130849-58-0), ΟΝΟ 1603 (CAS No. 114668-76-7), JTP 3399, Jura Statin A (CAS No 137563-63-4), Jura Statin B (CAS No. 137563-64-5) ' P128 (CAS No. 157716-52-4) > Y 29794 (CAS No. 129184-48-1)' ZTTA 1 ' JTP 4819 (CAS No. 162203-65-8), monoclonal antibody 266, duloxetine, escitalopram oxalate, fluoxetine, fufosamine Fluvoxamine, paroxetine, sertraline, dapoxetine, desvenlafaxine, sibutramine, nafa Nefazodone, milnacipran, desipramine, duloxitin, and bichifadine. 201035076 EXAMPLES The details of the present invention will now be described with reference to examples, but these examples are for illustrative purposes only. The therapeutic agent for the disease caused by Aβ according to the present invention is by no means limited to the following specific examples. A person skilled in the art can fully implement the present invention by making various modifications to the following reference examples and examples, as well as the scope of the patent application of the specification, and such modifications are within the scope of the invention. When the example compound has a stereoisomer, if the absolute configuration is not determined, the name of the compound having optical rotation does not necessarily correspond to the structural formula of the following examples. The following abbreviations are used in the following examples. DMF : Ν, Ν-dimethylformamide THF: tetrahydro α-furan EDC: 1-ethyl-3-(3-dimercaptopropylpropyl)methylenediamine hydrochloride ΗΟΒΤ : 1- Hydroxybenzotriazol: Diisopropylethylamine TEA: Triethylamine Unless otherwise stated, the chromatography was carried out using BW-300 manufactured by Fuji Silysia Chemical Ltd. . Preparation 1 Synthesis of 6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridine-2-carbonitrile

77 201035076 N-(6-  -2-methoxypyrene 唆 _3 _ base) the content of methotrexate 0

0r was added dropwise to acetic acid (204 ml) under ice cooling with acetic anhydride (2·3 ml), and the mixture was stirred at room temperature for 25 minutes. 6_Bromopyridin-3-amine powder (CAS #89466-18_2'丨46g) was placed in the reaction mixture in 1 minute, and then the reaction &gt; solution was allowed to stand at the same temperature for 3 minutes. Remove the water bath. The second butyl group (tetra) (300 ml) and n-geptane _ml were sequentially added dropwise to the reaction solution' and then the reaction solution was minute. The precipitated powder was collected by filtration. The obtained powder was crushed using a mortar, washed with a third butyl broth methyl ether and dried under reduced pressure to give 137.4 g of the title compound. Then the combination of the sputum and the lotion is concentrated under the reduced-^ and koji. The residue was triturated with tributylmethyl ether and dried under reduced pressure to give 21.9 g of the title compound. The properties of the compounds are as follows. </ RTI> </ RTI> <RTIgt; Preparation of 'N-(6-moly-2-methoxyt-3-yl)-N-(2'propyl)indole

I

Acetone _ (82 ml) was added dropwise to N (6 bis 2-methoxypyridin-3-yl) decylamine (159.3 g), carbonic acid (359 g) and potassium iodide (11.4 g) over 7 minutes. ) a suspension in DMF (8 ml). The reaction solution was then stirred at room temperature 78 201035076 for 1 hour and 20 minutes. The reaction solution was concentrated under reduced pressure. Ethyl acetate and water were added to the residue, and the organic layer was separated. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate The properties of the compounds are as follows. 'H-NMR (CDC13) δ (ppm): 2.17 (s, 3H), 4.00 (s, 3H), 4.47 (s, 2H), 7.13 (d, J = 7.6 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), 8.22 (s, 1H) Synthesis of 〇6-bromo-2-methoxy-3-(4-methyl-1H-imidazol-1-yl)pyridine

Ammonium acetate (267 g) and N-(6-bromo-; 2-methoxyindole. _3_yl)_n-(2-ketopropyl)decylamine (199 g) in glacial acetic acid (400 ml) The suspension was stirred for 1 hour and 10 minutes. The reaction solution was adjusted back to room temperature. Ethyl acetate and ice water were added to the reaction solution and the mixture was cooled with ice. Then, concentrated aqueous ammonia (5 mL) was added dropwise and then the organic layer was separated. The obtained organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. The organic layer was then purified by short-chotane dioxide gel column chromatography (carrier: Wakogel C-200, and Wako Pure Chemical Industries, Ltd.): eluting solvent: Ethyl acetate). The elution fraction is concentrated. The residue was dried with ethyl acetate and EtOAc (EtOAc)EtOAc. The wet milling mother liquor is then concentrated. The residue obtained was purified by cerium oxide gel column chromatography (carrier: and gelatin C 2 〇〇; eluting solvent: toluene-acetic acid 79 201035076 ethyl ester). The target elution fraction is concentrated. The obtained residue was triturated with EtOAc (EtOAc)EtOAc. The properties of the compound are as follows. 1 H-NMR (CDC13) δ (ppm): 2.29 (d, J = 0.8 Hz, 3H), 4.03 (s, 3H), 6.92 (dd, J = 1.2, 0.8 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.73 (d, J = 1.2 Hz, 1H). ESI-MS; m/z 268 [M++H]. Synthesis of 6-methoxy-5-(4-mercapto-1H-imidazol-1-yl)pyridine-2-carbonitrile

Trit(triphenylphosphine)palladium(0) (8.5 g) was added to 6-bromo-2-methoxy-3-(4-indolyl-1H-imidazol-1-yl). A suspension of pyridine (50 g) and zinc cyanide (11) (35 g) in N-methylpyrrolidone (400 ml), and the mixture was stirred at 100 ° C for 1 hour and 10 minutes. The reaction solution was added dropwise to ice water (1.5 liters) and concentrated aqueous ammonia (150 ml) by stirring the mixed solution. The precipitated powder was filtered. The resulting powder was washed with water and then air dried overnight to give 56.5 g of the title compound. The properties of the compounds are as follows. 'H-NMR (CDC13) δ (ppm): 2.30 (s, 3H), 4.09 (s, 3H), 7.02 (brs, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.90 (brs, 1H). Preparation 2 Synthesis of 6-oxime-5-(4-methyl-1H-imidazol-1-yl)pyridine-2-carboxylic acid 80 201035076

Lithium hydroxide powder (13 g) was added to 6-methoxy-5·(4, decyl-1Η-imidazol-1-yl)-pyridin-2-indenecarbonitrile (52.4 g) obtained in Preparation Example 1 in water ( A suspension of 464 ml) and the mixture was heated under reflux for 3 hours. The reaction solution was allowed to cool to room temperature. The reaction solution was filtered through celite, and the celite was washed with water (1 mL). The pH was adjusted to 4 to 5 by adding concentrated hydrochloric acid to the filtrate under ice cooling.收集 Collect the precipitated powder by filtration. The obtained powder was washed with water and then air-dried to give 51.9 g of the title compound. The properties of the compound are as follows. *H-NMR (DMSO-D6) δ (ppm): 2.17 (s, 3H), 4.01 (s, 3H), 7.33 (brs, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.99 (d , J = 7.6 Hz, 1H), 8.02 (brs, 1H). Preparation Example 3 Synthesis of N'-[6-oxime-5-(4-methyl-1H-imidazol-1-yl)pyridine-2-carbonyl]ruthenium carboxylic acid

〇ΪΡΕΑ (2 ml), HOBT (632 mg) and EDC (896 mg) were added to the 6-methoxy-5-(4-methyl-1Η-imidazol-1-yl)pyridine-2-carboxylate obtained in Preparation 2. A solution of the acid (546 mg) and tert-butyl phthalate (371 mg) in DMF (10 ml) and the reaction mixture was stirred at room temperature for 20 hr. Brine was added to the reaction solution, followed by extraction three times with ethyl acetate. The obtained organic layer was dried over anhydrous sulfuric acid 81 &lt;RTI ID=0.0&gt;&gt; The residue was purified by cerium oxide gel camp # chromatography (carrier: chr〇matorex NH, manufactured by Fuji Aseli Chemical Co., Ltd. (hereinafter referred to as "NH cerium dioxide gel") Eluent solvent: ethyl acetate-heptane afforded 740.7 mg of the title compound. Title The nature of the compound is as follows. ES-MS ; m/z 348 [M++H] ° Preparation Example 4 6-anthoxy-5-(4-mercapto-1H-imidazol-1-yl)pyridine-2-carboxylic acid hydrazine and 6- Synthesis of methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridinecarboxylic acid hydrazine hydrochloride

N'-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridinium. Synthesis of Benzyl-2-carbonyl]hydrazinecarboxylate

Benzyl phthalate (27.8 g), HOBT (24.8 g) and EDC (35.4 g) were sequentially added to the oxime-5-(4-methyl-1H-imidazol-1-yl)pyridine-2 obtained in Preparation 2. - Carboxylic acid (51.9 g) and IPEA (44 ml) in DMF (184 mL). Ethyl acetate, ice water, and a sodium hydrogencarbonate solution were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dehydrated with anhydrous magnesium sulfate and then filtered through a NH: cerium oxide condensate lining 82 201035076. The resulting filtrate was concentrated under reduced pressure. Ethyl acetate was added to the obtained residue, and the powder was collected by filtration. The obtained powder was air-dried to obtain 28.4 g of the title compound. Further, the extracted aqueous layer was re-extracted with ethyl acetate. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate and then filtered th The resulting filtrate was concentrated under reduced pressure. Ethyl acetate was added to the obtained residue and the powder was collected by filtration. The obtained powder was air-dried to obtain 9.15 g of the title compound. The properties of the compounds are as follows. 'H-NMR (CDC13) δ (ppm): 2.31 (d, J = 1.2 Hz, 3H), 4.08 (s, 3H), 5.23 (s, 2H), 6.87 (brs, 1H), 7.01 (t, J = 1.2 Hz, 1H), 7.32-7.45 (m, 5H), 7.71 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 1.2 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H ), 9.17 (brs, 1H). 6-methoxy-5-(4-methyl-1H-imidazole-l-yl) "pyridinium-2-carboxylic acid oxime and 6-methoxy-5-(4-mercapto-1H-imidazole_ι Synthesis of _-)pyridine-2-carboxylic acid hydrazine hydrochloride

10%-carbon (50% wet '2.84 g) added to N,-[6-oxime-5-(4-methyl-1H-imidazol-1-yl)pyridine-2-carbonyl]indole carboxylic acid A solution of the ester (28.4 g) in methanol (300 mL). The mixture was hydrogenated at medium pressure (2 atm to 3 atm) for 5 hours. Gas imitation (6 〇 0 ml) was added to the reaction solution, followed by filtration through diatomaceous earth to remove palladium-carbon. The filtrate was concentrated under reduced pressure to give &lt;1&gt; The properties of the compounds are as follows. ^-NMR (CDC13) δ (ppm): 2.30 (d, J = 1.2 Hz, 3H), 4.06 (s, 83 201035076 3H), 4.10 (s, 1H), 4_11 (s, 1H), 7.01 (t, J = 1.2 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.86 (d, J = 1-2 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 8.69 (brs, 1H). The hydrochloride salt of the title compound was obtained by the same procedure, but the hydrogenation reaction was carried out in a mixed solvent of chloroform-decanol. The properties of the compounds are as follows. ^-NMR (CDC13) δ (ppm): 2.31 (d, J = 1.2 Hz, 3H), 4.06 (s, 3H), 7.01 (t, J = 1.2 Hz, 1H), 7.71 (d, J = 7.6 Hz , 1H), 7.88 (d, J = 1.2 Hz, 1H), 7.89 (Mountain J = 7·6 Hz, 1H), 8.69 (brs, 1H). Preparation 5 Synthesis of 2-bromo-l-[6-indoleoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]ethanone dihydrochloride

Synthesis of 6-(1-ethoxyvinyl)-2-methoxy-3-(4-methyl-1H-imidazol-1-yl)pyridine

1-Ethoxyvinyltri-n-butyltin (3.7 ml) was added to 6-methoxy-5-(4-methyl-1H-i-pyran-1-yl)acridine obtained in Preparation Example 1 (2·66 g) And a suspension of ruthenium chloride (diphenylphosphine) (Π) (35 mg) in Twenty Mountain (25 ml), and the mixture was stirred at 100 ° C for 5 hours and 45 minutes. It was then concentrated under reduced pressure. The reaction solution was cooled to room temperature and the residue obtained was purified by cerium oxide gel column chromatography 84 201035076 (carrier: and gelatin C-200, heptane: ethyl acetate = 1: 0 —^9:1 —&gt;3:1 —1:1). The target elution fraction is concentrated. The obtained powder was wet-milled with EtOAc-EtOAc (EtOAc). The mother liquor was then concentrated to give 858 mg of the title compound. The properties of the compounds are as follows. 'H-NMR (CDC13) δ (ppm): 1.45 (t, J = 7.2 Hz, 3H), 2.30 (s, 3H), 3.98 (q, J = 7.2 Hz, 2H), 4.04 (s, 3H), 4.38 (d, J = 1.6 Hz, 1H), 5.48 (d, J = 1.6 Hz, 1H), 6.97 (s, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.78 (s, 1H). Synthesis of 2-bromo-l-[6-methoxy-5-(4-mercapto-1H-imidazol-1-yl)pyridin-2-yl]ethanone dihydrochloride

N-bromobutaneimine (543 mg) was added to 6-(1-ethoxyvinyl)-2-methoxy-3-(4-methyl-1H-imidazol-1-yl)pyridine at room temperature (791 mg) in THF (15 mL) - water (2 mL). Saturated sodium hydrogen carbonate solution and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine and dried over anhydrous magnesium sulfate. The anhydrous sulfuric acid is filtered by the oil and removed from the organic layer. A solution of 4 N hydrogen chloride in ethyl acetate was added to the obtained filtrate. The filtrate was then concentrated under reduced pressure to give the title compound. The properties of the compounds are as follows. ES-MS ; m/z 310 [M++H-2HC1]. Preparation 6 85 201035076 Synthesis of N-(2,5-dimethylphenyl)-N'-oxindole

Nh2

V N-cyano-2,5-dimethylaniline (CAS #10533-09-2, 468 mg), hydroxylamine monohydrochloride (334 mg) and potassium carbonate (885 mg) were refluxed for 30 minutes in ethanol. The reaction solution was adjusted back to room temperature. Water and ethyl acetate were then added to the reaction solution, and the organic layer was separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate sulfate The residue was purified by EtOAc EtOAc (EtOAc:EtOAc:EtOAc The properties of the compounds are as follows. ES-MS ; m/z 180 [M++H]. Preparation 7 Synthesis of N-hydroxy-6-methoxy-5-(4-mercapto-1H-imidazol-1-yl)pyridine-2-carboxyindole

The title compound (46 mg) was obtained according to the method of the preparation of the preparation of the compound of the formula 6 of 6-oxime-5-(4-mercapto-1H-imidazol-1-yl). Obtained with pyridine-2-carbonitrile (50.0 mg). The properties of the compounds are as follows. 'H-NMR (CDC13) δ (ppm): 2.31 (s, 3H), 4.07 (s, 3H), 5.51 (brs, 2H), 6.98 (s, 1H), 7.57 (d, J = 7.6 Hz, 1H ), 7.63 (d, J = 86 201035076 7·6 Hz, 1H), 7.82 (S, 1H). Preparation 8 Synthesis of 2-oxo-3-(4-mercapto-1H-imidazol-1-yl)-6-tributylstannylpyridine

6-Bromo-2-indolyl-3-(4-methyl-1H-imidazol-1-yl)pyridinium (10 g) obtained in Preparation Example 1 and hexa-n-butyltin (31.8 ml) were dissolved in toluene (300 ml) ). Niobium (triphenylphosphine)palladium (2.2 g) was added and the mixture was heated under reflux for four hours under a nitrogen atmosphere. After allowing it to cool, the insoluble matter was removed from the reaction solution by filtration through diatomaceous earth. The filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc (EtOAc) elute The properties of the compounds are as follows. 'H-NMR (CDC13) δ (ppm): 0.90 (t, J = 7.2 Hz, 9H), 1.03-1.22 (m, 6H), 1.30-1.40 (m, 6H), 1.49-1.70 (m, 6H) ,

Q 2.29 (s, 3H), 4.01 (s, 3H), 6.96 (s, 1H), 7.10 (d, J = 7.2 Hz, 1H), 7.63 (d, J = 7.2 Hz, 1H), 7.75-7.77 ( m, 1H). Preparation 9 N-(2,5·Dimethylphenyl)-2-{[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)acridin-2-yl]carbonyl } Synthesis of thiolamine

87 201035076 Preparation of 6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridine-2-reoxasy (119 mg), tea (100 μL) and isothiocyanate obtained in Preparation 4. A mixed solution of 2,5-dimethylphenyl ester (54.5 mg) in ethanol (3 ml)_dMF (600 μl) was refluxed for 10 minutes. Ethyl acetate was added to the reaction solution, and the resulting precipitate was collected by filtration to give 100 mg of the title compound. Preparation 10 Synthesis of 1-(5-diethylamine-2-methylphenyl)_2-methylisothiourea hydroiodide

Methyl iodide (0-197 ml) was added to a solution of (5-diethylamine-2-nonylphenyl) thiourea (CAS #810662-71-6 '0.5 g) in methanol (7 mL). The reaction solution was stirred with heating under reflux for 22 hours. Subsequent concentration under reduced pressure gave 0.7773 g of compound. The properties of the compounds are as follows. ES-MS ; m/z 252 [M++H-HI]. Preparation 11 Synthesis of 1-(5-isopropyl-4-oxo-2-methylphenyl)_2-methylisothiourea hydroiodide

The title compound (0.222 g) was obtained from (5-isopropyl-4-methoxy-2-methylphenyl)thiourea (Cas #1056049-53-6' 0.139 g) 201035076 according to the procedure of Preparation 10. The properties of the compounds are as follows. ES-MS ; m/z 253 [M++H-HI]. Preparation 12 6-Methoxy-5-(4-methyl-1H-imidazolyl)pyridine-2-carboxylic acid hydrazine, -[2-(5-isopropyl-4-methoxy-2- Synthesis of methylphenyl)ethinyl]anthracene

Synthesis of (5-isopropyl-4-methoxy-2-nonylphenyl) acetate

Ammonia (3.5 ml) was added dropwise to (5-isopropyl-4-methoxy-2-methylphenyl;) acetic acid (CAS #81354_65_6, 5 5 g) in methanol under ice cooling ( 5 〇 ml) of the trough. The reaction solution was then adjusted back to room temperature and stirred for 2 hours. The reaction solution was concentrated under reduced pressure. Add pure and carbonated (10) solution and third butyl. The obtained organic layer was washed with brine and then the desiccant was separated by filtration, and then the organic layer was purified by chromatography on the residue by chromatography.

(S, old), 7.00 (s, methyl ether and organic layer were separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. NMR (CE J = 7.2 Hz, 3) 3.58 (s, 2H), 1H). 201035076 Synthesis of 5-(isopropyl-4-oxooxy-2-indenylphenyl)acetate

a solution of methyl 5-(isopropyl-4-oxo-2-phenylphenyl)acetate (780 mg) in ethanol (1 mL), and a mixture of hydrazine monohydrate (0.8 mL) Heat at 80 C for 1 hour. Subsequently, hydrazine monohydrate (〇 8 ml) was added and the mixture was further heated at 80 ° C for 3.5 hours under reflux. The reaction solution was concentrated under reduced pressure. The properties of the compounds are as follows. ESI-MS; m/z 237 [M++H]. 1 H-NMR (CDC13) δ (ppm): 1.19 (d, J = 6.8 Hz, 3H), 1.19 (d, J = 6.8 Hz, 3H), 2.24 (s, 3H), 3.25 (qq, J = 6.8 , 6.8 Hz, 1H), 3.54 (s, 2H), 3.80-3.86 (m, 5H), 6.52 (br s, 1H), 6.68 (s, 1H), 6.95 (s, 1H). 6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridine-2-carboxylic acid N'-[2-(5-isopropyl-4-methoxy-2-methylbenzene Synthesis of bismuth

IPEA (996 μl) was added to (5-isopropyl-4-f-oxy-2-methylphenyl)acetic acid hydrazine (338 mg) under ice-cooling. 6-methoxy-5 obtained in Preparation 2. -(4-mercapto-purine-mouth-m2 sitting on a small base) 咐*° toluene (476 mg) and HOBT (290 ml 201035076 g) in DMF (10 ml). Then, EDC (411 mg) was added at the same temperature. The reaction solution was then adjusted back to room temperature and stirred overnight. Ethyl acetate and sodium hydrogencarbonate solution were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine and then dried over anhydrous sodium sulfate. The desiccant was separated by filtration and then the organic layer was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc. The properties of the compounds are as follows. ESI-MS; m/z 452 [M++H]. *H-NMR (CDC13) δ (ppm): 1.22 (d, J = 6.8 Hz, 3H), 1.22 (d, J - 6.8 Hz, 3H), 2.30 (s, 3H), 2.37 (s, 3H), 3.28 (qq, J = 6.8, 6.8 Hz, 1H), 3.70 (s, 2H), 3.84 (s, 3H), 4.08 (s, 3H), 6.73 (s, 1H), 7.00 (d, J = 1.6 Hz , 1H), 7.06 (s, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.86 (d, J = 1.6 Hz, 1H), 8.0-8.05 (br, 1H), 9.88-9.82 (br, 1H). Preparation 13 6-Methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridine-2-carboxylic acid N'-[2-(5-isopropyl-4-methoxy-2- Synthesis of nonylphenyl)ethyl hydrazide]-Ν'-methyl hydrazine

Synthesis of Ν'-[2-(5-isopropyl-4-methoxy-2-methylphenyl)ethenyl]-oxime-methylhydrazinecarboxylate 91 201035076

IPEA (3.1 ml) was added to (5-isopropyl-4-tetramethoxy-2-methylphenyl)acetic acid (CAS #81354-65-6, 1 g), N,-indole A solution of benzyl hydrazide hydrochloride (CAS #880-21-7, 1.2 g) and HOBT (909 mg) in DMF (20 mL). EDC (1.3 g) was then added at the same temperature. The reaction solution was adjusted back to room temperature and stirred overnight. Ethyl acetate and sodium hydrogencarbonate solution were added to the reaction solution, and the organic layer was separated. The obtained organic layer was washed with brine and then dried over anhydrous sodium sulfate. The desiccant was removed by filtration and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (1 g). The properties of the compounds are as follows. ES-MS ; m/z 385 [M++H]. Synthesis of (5-isopropyl-4-methoxy-2-indolyl)acetic acid N-methylhydrazine

N'-[2-(5-Isopropyl-4-methoxy-2-methylphenyl)ethinyl]-N,-mercaptopurine carboxylic acid benzyl ester (1 g) dissolved in ethanol (30 ml And in H-Cube (manufactured by THALES Nanotechnology Inc.; continuous flow hydrogenation reactor), catalytic hydrogenation using 1% palladium-carbon ruthenium for 5 hours . The organic layer was concentrated under reduced pressure toiel The properties of the compounds are as follows. ES-MS ; m/z 251 [M++H]. 92 201035076 6-Methoxy-5-(4-methyl-1H-mip-1-yl)°Bite-2-butyric acid n,-[2_(5-isopropyl-4-methoxy-2 Synthesis of -methylphenyl)ethinyl]-Ν'-mercapto

ΙΡΕΑ (444 μl) and EDC (183 mg) were sequentially added to (5-isopropyl_4-methoxy-2-nonylphenyl)acetic acid hydrazine-methylhydrazine (160 mg). - a solution of oxime-5-(4-methyl-oxime-11 m. sm.) s. The reaction solution was stirred at room temperature for 5 hours. Ethyl acetate and sodium hydrogencarbonate solution were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine and then dried over anhydrous sodium sulfate. The desiccant was separated by filtration and the organic layer was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) The properties of the compounds are as follows. 'H-NMR (CDC13) δ (ppm): 1.09 (d, J = 6.8 Hz, 3H), 1.09 (d, J = 6.8 Hz, 3H), 2.17 (s, 3H), 2.31 (s, 3H), 3.18 (qq, J = 6.8, 6.8 Hz, 1H), 3.30 (s, 3H), 3.64 (s, 2H), 3.79 (s, 3H), 3.92 (s, 3H), 6.62 (s, 1H), 6.87 (s, 1H), 7.02 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 9-14 (s, 1H). Preparation 14 2-(5-Tertiary-2-methoxyphenyl)-5-oxopentenyl imidate hydrochloride and 2-(5-t-butyl-2-methoxyphenyl) Synthesis of ethyl acetimidate, g g hydrochloride salt 93 201035076

Synthesis of 4-t-butyl-1-methoxy-2-methylbenzene

Potassium carbonate (8.4 g) and methyl iodide (2.9 ml) were added to a solution of 4-tert-butyl-2-methylphenol (CAS #98-27-1, 5.0 g) in DMF (25 ml), and The mixture was stirred at room temperature for three days. Ice water and hexane were added to the reaction solution, and the organic layer was separated. The obtained organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate and then evaporated The properties of the compounds are as follows. • H-NMR (CDC13) δ (ppm): 1.30 (s, 9H), 2.22 (s, 3H), 3.81 (s, 3H), 6.76 (d, J = 9.2 Hz, 1H), 7.15-7.19 (m , 2H). Synthesis of 2-bromodecyl-4-t-butyl-1-methoxybenzene

N-bromobutaneimine (5.66 g) and 2,2'-arsenazo (isobutyronitrile) (71 mg) were added to 4-t-butyl-1-methoxy-2-methylbenzene ( 5.16 g) of a solution of four gasified carbon 94 201035076 (25 ml) and the mixture was heated under reflux for 1.5 hours. The reaction solution was cooled by ice and then insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure to give 7.78 g of the title compound. The properties of the compounds are as follows. !H-NMR (CDC13) δ (ppm): 1.30 (s, 9H), 3.88 (s, 3H), 4.58 (s, 2H), 6.81 (d, J = 8.4 Hz, 1H), 7.31 (dd, J = 8.4, 2.4 Hz, 1H), 7_34 (d, J = 2.4Hz, 1H). Synthesis of (5-t-butyl-2-methoxyphenyl)acetonitrile

- a solution of potassium methoxide (2.96 g) added to 2-di- thiol-4-t-butyl-1-methoxyox (7-78 g) in dimethyl sulfoxide (50 ml), and a mixture Stir at room temperature for 16 hours. Ice and tert-butyl mercaptoether were added to the reaction solution, and the organic layer was separated. The aqueous layer was again extracted with a third butyl methyl ether. The combined organic layers were sequentially washed with water (twice) and brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue obtained was purified by cerium dioxide gel column chromatography (carrier: kematidine NH; eluting solvent: heptane-ethyl acetate: Gengyuan = 1:49). The target elution fraction is concentrated. The residue obtained was wet-milled in a home to obtain 1.9 g of the title compound. The wet milling mother liquor is concentrated. The residue thus obtained was wet-milled in a house to obtain 0.47 g of the title compound. The properties of the compounds are as follows. H-NMR (CDCI3) δ (ppm): 1.31 (s, 9H), 3.68 (s, 2H), 3.85 (s, 3H), 6.82 (d, J = 8·4 Hz, 1H), 7.32 (dd , J = 8·4, 2 4 Hz, 1H), 7-36 (d, J = 2.4 Hz, 1H). 95 201035076 Synthesis of 2-(5-tri-butyl-2-methoxyphenyl)_5_gas valeronitrile

A solution of n-butyllithium in hexane (2.69 Μ, 3.0 mL) was added to a solution of hydrazine, hydrazine-diisopropylamine (1 - 2 mL) in THF (15 mL). 1 minute. The solution was cooled to _78 ° Cj and a solution of (5-t-butyl-2-methoxyphenyl)acetonitrile (15 g) in THF (6 5 liters) was added dropwise. The solution was stirred at -30 ° C for 25 minutes and then cooled again to -^^. i gas-3-iodopropane (1.2 ml) was added dropwise to the solution, and then the reaction solution was slowly heated to room temperature. After cooling the reaction solution with ice, a solution of lithium hexamethyldiamine amine in tetrahydrofuran (1.0 Torr, 4.4 ml) was added to the reaction solution. Then, a solution of hydrazine-diisopropylamine (0-6 ml) and n-butyllithium in hexane (2·69 Μ, 1.5 ml) was added to the reaction solution. A saturated vaporized ammonium solution is added to the reaction solution. Then ethyl acetate and water were added and the organic layer was separated. The organic layer was washed with EtOAc EtOAc (EtOAc m. The obtained residue was purified by cerium oxide gel column chromatography (carrier: Merck - cerium oxide gel 60 (230_4 〇 0 mesh); eluting solvent: heptane: acetic acid B = 1 :49) A 1:7 mixture of 864 mg (5-t-butyl-2-methoxyphenyl)acetonitrile and the title compound was obtained. The properties of the compounds are as follows. H-NMR (CDC13) δ (ppm): 1.31 (s, 9H), 1.86-2.12 (m, 4H), 3·54·3.60 (m, 2H), 3.84 (s, 3H), 4.18-4.24 (m , 1H), 6.83 (d, J ~ 8·4 Hz, 1H), 7.31 (dd, J = 8.4, 2.4 Hz, 1H), 7.40 (d, J = 2.4 96 201035076

Hz, 1H). 2-(5-Tertibutyl-2-methoxyphenyl)-5-pivalyl imidate ethyl ester hydrochloride and 2-(5-t-butyl-2-methoxyphenyl) Synthesis of ethyl imidate hydrochloride

a 1:7 mixture of (5-t-butyl-2-methoxyphenyl)acetonitrile and 2-(5-tri-butyl-2-methoxyphenyl)-5-chlorovaleronitrile (864 mg) A solution of ethanol (8 ml) was passed through the vaporized hydrogen under ice cooling for 15 minutes. The reaction solution was stirred at room temperature for 1 day. The reaction solution was concentrated under reduced pressure to give the title compound. The property values of ethyl 2-(5-t-butyl-2-methoxyphenyl)-5-chloropentainimidate hydrochloride are as follows. ES-MS; m/z 326 [M++H-HC1]. The property values of ethyl 2-(5-t-butyl-2-methoxyphenyl)ethyl imidate hydrochloride are as follows. ES-MS ; m/z 250 [M++H-HC1] ° Preparation 15 3-bromo-1-methyl-5-(2-trifluoromethylphenoxy)-1Η-[1,2,4 Synthesis of triazole

Br

F F 97 201035076 1-methyl-3-stone Xiao-5-(2-trifluoroanthracene basic oxygen)-1Η-[1,2,4] three-synthesis synthesis

F • F 2-hydroxybenzyltrifluoride (157 mg) and potassium carbonate (134 mg) were added to μmethyl-3-nitro-5-bromo-1Η_[1,2,4]triazole (CAS #31123-19 -0, 100 mg) in DMF (3 mL), and the mixture was stirred at 95 ° C for 6 hours and 30 minutes. After allowing to cool, diethyl ether and water were added to the reaction solution, and the organic layer was separated. 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. The residue was purified by EtOAc EtOAc (EtOAc) The properties of the compounds are as follows. ^-NMR (CDC13) δ (ppm): 3.97 (s, 3H), 7.44 (t, J = 7.6 Hz, 1H), 7.68-7.77 (m, 3H). Synthesis of 1-methyl-5-(2-trifluoromethylphenoxy)&gt;ih-[1,2,4]triazol-3-ylamine

10%-carbon (20 mg) was added to 丨_曱基_3_nitro-5-(2-trifluorodecylphenoxy)-1Η-[1,2,4]triazole (35 g) A solution of methanol (5 well). The mixture was stirred at room temperature under a hydrogen atmosphere of 1 atm for 3 hours and 3 minutes. The carbon was removed by filtration through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) The properties of the compounds are as follows. 'H-NMR (CDCI3) δ (ppm): 3.63 (s, 3H), 3.96 (s, 2H), 7.33 (brs, 1H), 7.62 (brs, 2H), 7.69 (d, J = 7.6 Hz, 1H ). Synthesis of 3-bromo-1-methyl-5-(2-trifluorodecylphenoxy)-1H-[1,2,4]triazole

Ο 1-Methyl-5-(2-trifluorodecylphenoxy)_ih-[1,2,4]triazol-3-ylamine (45 gm) was dissolved in acetonitrile (23⁄4 L). Copper bromide (i.e. (94 mg) and isoamyl nitrite (61.2 mg)' and a mixture of 70 were added. (: Stir for 1 hour and 30 minutes.

After it was cooled, the reaction solution was concentrated under reduced pressure. Ethyl acetate and a saturated ammonium sulfate solution were added to the residue and the organic layer was separated. The resulting organic layer was washed with brine and dehydrated with anhydrous sulfur. The dried organic layer was concentrated under reduced pressure. Residual _NH diterpene (four) material chromatography was purified to obtain the title compound _. The compound (IV) values of the compounds are as follows. H_NMR (CDCl3) δ (ppm): 3.80 (s, 3H), 7.37 (t, J = 7 6 Hz 1H)' 7_64 (U = λ6 Hz, 1H), 7.70 (d, J = 7.6 Hz, 2H). Example 1 (2,5-dimethylphenyl Hh6_methoxy_5 case base. M). Synthesis of biti-2-yl H1,2,4K dis- _3_yl}amine 99 201035076

HOBT (63. 2 mg) was added to N_(2,5-dimethylphenyl)-indole-hydroxyindole (56.0 mg) obtained in Preparation Example 6, and 6-methoxy_5_(4_A obtained in Preparation Example 2) A solution of the base 1H_imidazole-1_yl)pyridine-2-carboxylic acid (72·8 mg), EDC (89.7 mg) and TEA (87 μL) in DMF (3 mL). The reaction solution was stirred overnight at room temperature and then stirred at 8 for 8 hours. Water and ethyl acetate were added to the reaction solution and the organic layer was separated. The obtained organic layer was washed with brine, dehydrated with anhydrous magnesium sulfate and then reduced. The residue was purified by column chromatography on a dioxo gel column (eluent solvent: cum-methane-hexane: methanol = 9 〇: 1 〇). Subsequently, the concentrated residue was purified to afford 16 mg of the title compound. The properties of the compounds are as follows. 'H-NMR (CDC13) δ (ΡΡ^1 2·32 (s, 6H), 2.39 (s, 3H), 4.19 (s, 3H), 6.60 (s, 1H), 6·82 (d,] = 7.6 Hz, m), 7 grab 7 (seven) continent 7.72 (d, J = 7.6 Hz, _, 7.82 (s, 1H), 7 89 (d, ; = 7 6 Hz, ' 1H), 7.93 (s, 1H). Example 2 (2,5-Dimethylphenyl)_{3 Makeup A gas _Methyl scent _Mini saliva small base than bite_2_ base]-[1,2,4] 嗟二冰-5 -基}'Amine synthesis

100 201035076 2,5-dimethylbenzoquinone isothiocyanate (CAS (4) 4...-7, π 7 mg) and N|6^_5_(4_f base·m_imidinyl (4) obtained in Preparation Example 7 - continuous lung (4) The money of the kiss (2 ml) is lion for three hours and then at room temperature (four) overnight. Water and acetic acid are added to the reaction solution and the organic layer is recorded. The organic layer is obtained and then concentrated. Separation of the oxidized rubber column (eluent solvent: heptane, ethyl acetate, ethyl acetate: methanol = 80:20). Subsequently, the concentrated residual bell

The residue was taken as a compound of 10 mg of the title compound. The properties of the compounds are as follows. 1 H-NMR (CD3 OD) δ (ppm): 2 2 τ

· 25 ^J = 〇-8 Hz, 3H), 2.31 (s 3H), 2.36 (s, 3H), 4.15 (s, 3H) 7 〇WH T λ7·°1 (d, J = 7.6Hz, 1H) , 7 19 (d, J = 7.6 Hz, 1H), 7.22-7.25 (m , tj 1U, (iv) 2H), 7·56 (s, 1H), 7.90 (d,

J = 8.0 Hz, 1H), 7.96 (d, J = 8 〇pt 1T 8 0H^ 1H), 8.00 (d, J = 〇.8Hz, 1H) 0 The compound of Example 3 was obtained by the method of Example 2 ( Table 1. Example number - - - Example 3 ci ——.........................~ Example 4 (2,5-II Methylphenyl)]3_[6_曱氧.7 Α1 π 2 41^ fluorenyl-1H-imidazole·1_yl)·pyridyl-2-yl]-[l'2'4h 嗤_5_yl Ba Yicheng's Bacheng 101 201035076 N-

/〇

1-(2,5-Dimethylphenyl)_2·methyl-isothiourea monohydrochloride (CAS #91147-36-3, 65_1 mg), N-hydroxy-6-methoxy obtained in Preparation Example 7 · 5_(4_Methyl-1Η-.Mizozol-1-yl)0 is refluxed with a solution of bite-2-carboxyindole (5〇·0 mg) and tea (56.3 μl) in ethanol (2 ml) and Then at 75. (: Stirring the mixture. Water and ethyl acetate were added until the reaction solution and the organic layer were separated. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. Column chromatography purification (eluent solvent: heptane-ethyl acetate-ethyl acetate: methanol = 80:20) and subsequent purification by preparative thin layer of cerium oxide gel chromatography (developing solvent · heptane The title compound was obtained as follows: ESI-MS; m/z 377 [M++H]. 1 H-NMR (CDC13) δ (ppm): 2.32 ( s, 6H), 2.39 (s, 3H), 4.19 (s, 3H), 6.60 (s, 1H), 6.82 (d, J = 7.6 Hz, 1H), 7.05-7.10 (m, 2H), 7.73 (d , J = 8.0 Hz, 1H), 7·82 (s, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.94 (s, 1H). Example 5 (2,5-Dimethylphenyl) -{5_[6_曱氧·5_(4_methyl_1H-imidazol-1-yl)_.pyridin-2-yl]-[1,3,4]oxadiazol-2-yl}- Amine synthesis

102 201035076 Preparation Example 9 obtained N_(2,5_-thenyl group) terminal 2 _ base group)·2·thoracic oxygen from methylbenzene chlorinated chlorine (41.8 mg) and Dtb 肼methylthioguanamine ( 3G mg) 'The armor is in the machine for four hours. Add a solution of THF (2 ml) to ethyl acetate to the reaction solution and the organic layer. The obtained organic layer was washed with a slight air, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. Residual bias "... ‘U(4), sulphur-purine sputum gel column chromatography purification (extraction solvent: heptane I acetic acid ethyl acetate acetonitrile: methanol 20).

The residue after the IW was washed with diethyl ether to give a 5 gram title compound. The properties of the compounds are as follows. ESI-MS; m/z 377 [M++H]. H-NMR (CDC13) δ (ppm); 2.32 (s, 3H), 2.34 (s, 3H), 2.38 (s, 3H), 4.15 (s, 3H), 6.84 (brs, 1H), 6.89 (d, J = 7.6 Hz, 1H), 7.03 (s, 1H), 7.11 (d, j = 7 6 Hz, 1H), 7 67 (d, 】 = 7 6 Hz, 1H), 7.84 (d, J = 7· 6 Hz, iH), 7 89 (brs, 2H). Example 6 (2,5-diindolyl)-{5-[6-oxime_5_(4-methyl-1H-imidazol-1-yl)-pyridin-2-yl]-[1 Synthesis of 3,4]嗟二唾·2_ylbumin

Preparation of ruthenium-(2,5-dimethylphenyl)_2-{[6-oxime-5-(4-methyl-1Η-imidazol-1-yl) D-pyridin-2-yl] A solution of carbonyl}mercaptopurine (10. 0 mg) in a dish of acid (300 μL) was mixed at 90 ° C for 1 hour. The reverse solution was neutralized by adding ethyl acetate and 2 N sodium hydroxide solution to the reaction solution under ice cooling, and then the organic layer was separated. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate and then evaporated. The residue &amp; was purified by gel column chromatography (eluent solvent · heptane - acetonitrile G g 曰 one acetic acid ethyl acetate: methanol = 8). Subsequently, the concentrated residue was washed with 3.03⁄4 g of the title compound. The properties of the compounds are as follows. ESI-MS; m/z 393 [M++H]. 1 H-NMR (CDC13) δ (ppm): 2.30 (s, 3H), 2 32 r 〇τ .UH), 2.38 (s 3H), 4.03 (s, 3H), 6.98-7.00 (m, 2H), 7.17 (a T _ _ , , u, = 7.6 Hz, 1H), 7.35-7.37 (m, 1H), 7.65 (d, J = 7.6 Hz, lm 7 〇〇^ ' (d, J = i 2

Hz, 1H), 7.92 (d, J = 7.6 Hz, 1H). 'Example 7 diethyl-N*3, {H6_methoxy-5 private methyl] (tetra) saliva)-n-pyridin-2-yl]-2H-[1,2,4]triazole_3 -yl}-4·methylbenzene 13-amine synthesis

4 N hydrochloric acid in ethyl acetate (2 liters) was added to the oxime obtained in Preparation Example 3, [6-methoxy-H4-methyl-m-stalk-%. The reaction was carried out for four hours at room temperature than biting _2_carbyl] lysine tributyl vinegar (30 mg). The reaction solution was concentrated under reduced pressure. Add "(3 ml), TEA (G.l2 ml) and Preparation 1 (5-diethylamine-2. fluorenyl) 2-methylisothiocyanate hydrochloride 104 201035076 ( From the 39 to 4 gram of the crude product, 6-methoxy-5-(4-mercapto-ih-i-pyran-1-yl)0-pyridine-2-carboxylic acid hydrazine hydrochloride, and the mixture was stirred and stirred under reflux for 18 hours. The reaction solution was cooled to room temperature and then a saturated sodium hydrogencarbonate solution was added, followed by extraction three times with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by cerium dioxide gel column chromatography (carrier: kematidine NH; eluting solvent: ethyl acetate ~ ethyl acetate _ methanol) and then further by cerium oxide gel column layer The purification was carried out (eluent solvent: ethyl acetate-methanol) to give the title compound. The properties of the compounds are as follows. ESI-MS; m/z 433 [Μ++Η]. !H-NMR (CDC13) δ (ppm): 1.20 (t, J = 6.8 Hz, 6H), 2.24 (s, 3H), 2.31 (s, 3H), 3.38 (q, J = 6.8 Hz, 4H), 4.12 (s, 3H), 6.34 (d, J = 7.2 Hz, 1H), 6.55 (s, 1H), 6.96-7.10 (m, 2H), 7.62 (bs, 1H), 7.69 (d, J = 7.6 Hz , 1H), 7.79 (d, J = 7.6 Hz, 1H), 7.86 (bs, 1H). Example 8 (5-Isopropyl 4-methoxy-2-methylphenyl)-{5-[6-methoxy-5-(4-methyl-1H-imidazolyl)-acridine-2 Synthesis of -yl]-2H-[1,2,4]triazol-3-yl}amine

The title compound (47.9 mg) was obtained according to the method of Example 7 from N-[6-methoxy-5-(4-methyl-1H-13 m. - succinyl] decanoic acid tert-butyl ester (406 mg) and Preparation Example 11 obtained 1-(5-isopropyl-4-methoxy-2-105 201035076 methylphenyl)-2-mercaptoisothiourea hydrogen Iodate (669 mg) was obtained. The properties of the compounds are as follows. ESI-MS; m/z 434 [M++H]. H-NMR (CDC13) δ (ppm): 1.23 (d, J = 6.8 Hz, 6H), 2.26-2.36 (m, 6H), 3.24-3.38 (m, 1H), 3.82 (s, 3H), 4.1 〇(s? 3H), 6.26 (bs, 1H), 6.72 (s, 1H), 6.96-7.06 (m, 1H) 7.60-7.90 (m, 4H). The compounds of Examples 9 to 11 were prepared by the same procedure as in Example 7 (Table 2). Table 2 Example number structure type ~~ ] Example 9 ~~----- 1 N-NH P 1 N-NH Example 10 Example 11 ----- 1 N-NH Γ -0 Example 12 6=Xi Knee 4 • Synthesis of methoxy-2-methyl(tetra)yl Hu,4k: salivation-3-(4_fluorenyl-1H-imidazolyl)pyridine 106 201035076 r

6-Methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridine-2-carboxylic acid N'-[2-(5-isopropyl-4-oxime) obtained in Preparation Example 12. A solution of 2-nonylphenyl)ethinyl]indole (515 mg) in phosphonium chloride (8 ml) was heated with stirring at 120 ° C for 30 min. The reaction solution was concentrated under reduced pressure. Tributyl decyl ether and saturated sodium hydrogen carbonate solution were added and the organic layer was separated. The resulting organic layer was washed with brine and then dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and then the organic layer was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc. The properties of the compounds are as follows. ESI-MS; m/z 434 [M++H]. !H-NMR (CDC13) δ (ppm): 1.19 (d, J = 7.2 Hz, 3H), 1.19 (d, J = 7.2 Hz, 3H), 2.30 (s, 3H), 2.43 (s, 3H), 3.26 (qq, J = 7.2, 7.2 Hz, 1H), 3.81 (s, 3H), 7.12 (s, 3H), 4.24 (s, 2H), 6.69 (s, 1H), 7.02 (d, J = 1.2 Hz , 1H), 7.17 (s, 1H), 7.66 (d, J - 8.0 Hz, 1H), 7·83 (d, J = 8.0 Hz, 1H), 7.88 (d, J = 1.2 Hz, 1H). Example 13 6-[5-(5-Isopropyl-4-oxo-2-methylf-yl)-1H-[1,2,4]triazol-3-yl]-2-methoxy-3 Synthesis of -(4_methyl-1H-imidazol-1-yl) ° pyridine

107 201035076 6-[5-(5-isopropyl-4-oxo-2-methylbenzyl)-[1,3 obtained by the addition of sodium acetate (961 mg) dried under reduced pressure to Example 12. , 4]. No. Diazol-2-yl]-2-indoleoxy-3-(4-methyl-1H-imidazol-1-yl). A solution of pyridine (180 mg) in acetic acid (10 ml), and the mixture was stirred and stirred at 150 ° C for three days. After allowing to cool, the reaction solution was concentrated under reduced pressure. Ethyl acetate and a saturated sodium hydrogencarbonate solution were added and the organic layer was separated. The resulting organic layer was washed with brine and then dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and then the organic layer was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc. The properties of the compounds are as follows. ESI-MS; m/z 433 [M++H]. H-NMR (CDC13) δ (ppm): 1.19 (d, J = 7.2 Hz, 3H), 1.19 (d, J = 7.2 Hz, 3H), 2.30 (s, 3H), 2.33 (s, 3H), 3.26 (qq, J = 7.2, 7.2 Hz, 1H), 3.82 (s, 3H), 4.11 (s, 3H), 4.14 (s, 2H), 6.69 (s, 1H), 7.00-7.04 (m, 1H) , 7.12 (s, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.82-7.88 (m, 2H). Example 14 6-[5-(5-Isopropyl-4-methoxy-2-indolylfyl)-2-methyl-2H-[1,2,4]triazol-3-yl]-2 Synthesis of methoxy-3-(4-methyl-1H-imidazol-1-yl)pyridine

60% sodium hydride (19 mg) was added to Example 13 to give 6-[5-(5-isopropyl-4-oxo-2-methylbenzyl)-1 Η-[1,2 , 4] triazole-3-108 201035076 yl]-2-methoxy-3-(4-methyl-1H-imidazol-1-yl). A solution of pyridine (100 mg) and mercapto iodine (29 μL) in DMF (3 mL). The reaction solution was adjusted to room temperature and stirred under a nitrogen atmosphere for 1 hour. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resulting organic layer was washed with brine and then dehydrated with anhydrous sodium sulfate. The desiccant was removed by filtration, and then the organic layer was concentrated under reduced pressure. The residue was purified by NH.sub.2 silica gel column chromatography to give the title compound (74 mg). The properties of the compounds are as follows. ESI-MS; m/z 447 [M++H].

*H-NMR (CDC13) δ (ppm): 1.20 (d, J = 6.8 Hz, 3H), 1.20 (d, J = 6.8 Hz, 3H), 2.31 (s, 3H), 2.41 (s, 3H), 3.25 (qq, J = 6.8, 6.8 Hz, 1H), 3.80 (s, 3H), 4.03 (s, 2H), 4.08 (s, 3H), 4.32 (s, 3H), 6.67 (s, 1H), 7.01 (d, J = 1.2 Hz, 1H), 7.19 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 1.2 Hz, 1H), 7.92 (d, J = 8.0 Hz , 1H). Example 15 6-[5-(5-Isopropyl-4-methoxy-2-indolylbenzyl)-1-indolyl-1H-[1,2,4]trika-3-yl]-2 Synthesis of -oxo-3-(4-methyl-1H-imidazol-1-yl)pyridine

Preparation of 6-oxime-5-(4-mercapto-1H-imidazol-1-yl)pyridine-2-carboxylic acid N'-[2-(5-isopropyl-4-oxo-2) A solution of -methylphenyl)ethinyl]-indole-methylsulfonate (150 mg) in phosphonium chloride (4 ml) was heated at 120 ° C with stirring at 109 201035076 for 1.5 hours. The reaction solution was concentrated under reduced pressure. Ethyl (5 ml) and acetic acid (249 mg) dried under reduced pressure were added to the residue (iv) and the reaction mixture was stirred at 150 C for 2.5 hours. After allowing to cool, the reaction solution was reduced under reduced pressure. Ethyl acetate and a saturated sodium hydrogencarbonate solution were added to the residue, and the organic layer was separated. The resulting organic layer was rehydrated and then dehydrated with anhydrous sodium sulphate. It is removed by dryness and then concentrated under reduced pressure. The residue was purified by aq. The properties of the compounds are as follows. ° ESI ESI-MS; m/z 447 pvj++H]. lH_NMR (CDC1W (PPm): 1.13 (cU = 6.8 Hz, 3H), 1.13 (d J = 6.8 HZ, 3H), 2.61 (s, 3H), 2.33 (s, 3H), 3.23 (qq, j). 6 8' 6.8 HZ, 1H), 3.76 (S, 3H), 3.81 (s, 3H), 4.165 (S, 2H), 41 is (S, 3H), 6 68 (S, 1J1), M4 (s, 1H), 7.01 (s, 1H), 7.62 (d, j. 7.6 Hz, 1H), 7·81-7·85 (m, 2H). The compounds of Examples 16 to 20 are the same as in Examples 12 and 13. method

110 201035076

Table 3 Example Number Structure Example 16 Example 17 [N-NH Example 18 1 rT Vp Example 19 1 Ν - ΝΗ ^ fV Example 20 1 Ν-ΝΗ Νρ:^ Examples 21 and 22 2-Methoxy-3-(4- Mercapto-1H-imidazol-1-yl)-6-[1-mercapto-5-(2-trifluorodecylbenzyl)-1Η-[1,2,4]triazol-3-yl]- Acridine and 2-oxo-3-(4-mercapto-1H-imidazol-1-yl)-6-{1-methyl-5-[l-(2-trifluoromethylphenyl)ethyl ]-1H-[1,2,4] Tris-7-yl}D is a synthesis of bite 111 201035076

Methyl iodide (144 μl) was added to the 2-methoxy-3-(4-methyl-1H-methane.sodium-1-yl)-6-[5-(2-trifluorodecylbenzyl) obtained in Example 18. A mixed solution of _iH_[i,2,4]triazol-3-yl]pyridinium (400 mg) and sodium hydride (1 mg) in dmF (6 ml), followed by stirring for 2 hr. Add water to the reaction mixture. Then ethyl acetate and the organic layer were added and separated. The organic layer was washed with brine, dehydrated with anhydrous magnesium sulfate and then transferred. The filtrate was concentrated under reduced pressure. The residue obtained was purified by thin layer of cerium oxide gel to afford 127.7 mg of 2-methoxy-3-(4-methyl-1H-imidazol-1-yl)-6-[1-indolyl-5- (2-Trifluoromethylbenzyl)-1Η-[1,2,4]triazol-3-yl]-pyridine and 35.7 mg of 2-methoxy-3-(4-mercapto-1H-imidazole-1 -yl)-6-{1-mercapto-5-[l-(2-trifluoromethylphenyl)ethyl]-1H-[1,2,4]triazol-3-yl}° ratio. set. 2-oxo-3-(4-methyl-1H-imidazol-1-yl)-6-[1-methyl-5-(2-trifluoromethylbenzyl)-1Η-[1,2, 4] The properties of triazol-3-yl]-pyridine are as follows. ESI-MS; m/z 429 [M++H]. 'H-NMR (CDC13) δ (ppm): 2.31 (s, 3H), 4.10 (s, 3H), 4.32 (s, 2H), 4.36 (s, 3H), 7.00-7.03 (m, 1H), 7.31 -7.37 (m, 1H), 7.41-7.50 (m, 2H), 7.65-7.53 (m, 2H), 7.86 (d, J = 1.2 Hz, 1H), 7.93 (d, J = 7.6 Hz, 1H). 2-methoxy-3-(4-methyl-1H-imidazol-1-yl)-6-{l-methyltrifluoromethylphenyl)ethyl]-1H-[1,2,4] The oxazol-3-yl}° ratio of the nature of the pyridine is as shown in 112 201035076. ESI-MS; m/z 444 [M++H]. 1 H-NMR (CDC13) δ (ppm): 1.72 (d, J = 7.2 Hz, 3H), 2.31 (s, 3H), 4.08 (s, 3H), 4.35 (s, 3H), 4.74 (q, J = 7.2 Hz, 1H), 7.01 (br s, 1H), 7.27-7.33 (m, 1H), 7.45-7.51 (m, 1H), 7.63-7.72 (m, 3H), 7.88 (br s,1H), 7.96 (d, J = 8·0 Hz, 1H). Example 23 (2,5-Dimercaptophenyl)-{4-[6-methoxy-5-(4-methyl-old-imidazol-1-yl)-11 ratio. Synthesis of quinol-2-yl]-1H-imidin-2-yl}amine

IPEA (0.0394 ml) was added to the 2-bromo[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]ethanone dihydrochloride salt obtained in Preparation Example 5 ( 17.3 mg) and N-(2,5-dimethylphenyl)-indole (CAS #46049-94-9, 7_38 mg) in DMF (1 mL) in 1 〇〇. Stir for 4.5 hours. The reaction solution was cooled to room temperature and then a saturated sodium hydrogen carbonate solution was added, followed by extraction twice with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate and evaporated. The residue was purified by EtOAc EtOAc (EtOAc:EtOAc) The properties of the compounds are as follows. ESI-MS; m/z 375 [M++H]. H-NMR (CD3〇D) δ (ppm): 2.16 (s, 3H), 2.24 (s, 3H), 2.38 (s, 3H), 3.63 (s, 3H), 7.00-7.58 (m, 6H), 7.66-7.98 (m, 2H). 113 201035076 The compound of Example 24 was obtained by the same procedure as in Example 23 (Table 4). Table 4 Example Number Structure Example 24 ο Example 25 6-[5-(5-Tert-butyl-2-oxobenzyl)_ih-[1,2,4]tris-3-yl]-2- Methoxy-3-(4-methyl-1H-0m0 sitting-1-yl). ratio. Fixed synthesis

Preparation of 2-(5-t-butyl-2-methoxyphenyl)-5-pivalyl imidate ethyl ester hydrochloride and 2-(5-t-butyl-2-methoxyl) obtained in Preparation 14. A solution of a mixture of phenyl)ethylenimine oxime ethyl ester hydrochloride (192 mg) in ethanol (2 ml) was added to the 6-methoxy-5-(4-methyl-1H-imidazole obtained in Preparation 4. A suspension of 1-yl)pyridine-2-carboxylic acid hydrochloride (135 mg) and imidazole (194 mg) in DMF (2 mL). The reaction solution was then stirred at 1 Torr for 3 hours and 40 minutes. The reaction solution was allowed to cool to room temperature. Then, ethyl acetate, water and 1 N hydrochloric acid (1 ml) were added to the reaction solution and the organic layer was separated. The obtained organic layer was washed sequentially with brine and brine, dried over anhydrous magnesium sulfate and evaporated. The residue obtained was purified by cerium oxide gel column chromatography 114 201035076 (carrier: kematidine NH; eluting solvent: ethyl acetate: heptane = 1:2-> 2:1-0: 1) and subsequently purified by CHIRALPAK® (2 cm χ 25 cm; mobile phase: 15% ethanol-hexane) manufactured by Daicel Chemical Industries, Ltd. to obtain 7.2 mg of the title compound. The properties of the compounds are as follows. ESI-MS; m/z 433 [Μ++Η]. H-NMR (CDC13) δ (ppm): 1.29 (s, 9H), 2.30 (s, 3H), 3.90 (s, 3H), 4.13 (s, 3H), 4.22 (s, 2H), 6.89 (d , J = 8.4 Hz, 1H), 7.01 (brs, 1H), 7.30 (dd, J - 8.4, 2.4 Hz, 1H), 7.34 (d, J = 2.4 Hz, 1H), 7.65 (d, J = 7.6 Hz , 1H), 7.76-7.90 (m, 2H), 11.05 (brs, 1H). Example 26 6-[5-(3-Tertibutyl-4-methoxybenzyl)-1Η-[1,2,4]triazol-3-yl]-2-methoxy-3-(4- Synthesis of methyl-1H-imidazol-1-yl)pyridine

The title compound (25.7 mg) was obtained from 2-t-butyl-4-methylphenol (CAS # 2409- 55-4). The properties of the compounds are as follows. ESI-MS; m/z 433 [M++H]. 'H-NMRCCDCla) δ (ppm): 1.36 (s, 9H), 2.31 (s, 3H), 3.82 (s, 3H), 4.11 (s, 3H), 4.14 (s, 2H), 6.84 (d, J = 8.4 Hz, 1H), 7.01 (brs, 1H), 7.17 (dd, J = 8.4, 2.4 Hz, 1H), 7.25-7.30 (m, 1H), 115 201035076 7.66 (d, J = BO Hz, 1H) , 7.84 (brs, lH), 7.85 (d, J = 8.0 Hz, 1H), 11.10 (brs, 1H). Example 27 2-Methoxy-3-(4-methyl-1H_.m.sup.+.sup..sup..sup..sup..sup..sup.. Synthesis of base]-'1

1,3-indole (diphenylphosphino)propane (5.9 mg), copper oxide (1) (1 〇 2 mg) and acetic acid (ΙΙ) (1.6 mg) were added to the preparation example 8 in a pure gas atmosphere. 2-oxo-3-(4-methyl-1-oxime-imidapyridinyl)tributyltindanyl d to pyridine i mg) and Preparation Example 15 obtained 3,+methyl as trifluoromethylbenzene=)-111- 12,4] San Na L5 mg) in the &quot; Quiche each bite off $ ml) Receiver in the boots to mix two hours deduction points. After allowing it to cool, the insoluble matter in the reaction's liquid is concentrated by sputum. The addition of acetic acid B is intended to remove water i, and the organic layer remaining in the reduced room is separated by salt water washing and iron = residue and organic layer. The mash is removed, and then the organic layer is dehydrated with anhydrous sodium. The desiccant borrows fossils, and the glands are known as s; The residue was read by NH-phosphorus ruthenium chromatography. The properties of the foot-ruthenium were as follows. Compound (9.2 mg). Compound 'H-NMRCCDCMa^^ 3H), 4.16 (s,3H), 7.00 (t T (CU — U Hz, 3H), 3.92 (s, , 7.66 (t, J = 8 〇Hz, 1H), 7.70 116 201035076 (d, J 7.6 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.82 (d, J = 1.2

Hz, 1H), 7_86 (d, J = 8.0 Hz, 1H). Test Example 1 Quantification of Αβ-peptide in neuronal culture from rat embryonic brain The inventors conducted the following tests to show the use of the compound of the formula (I) according to the present invention. (1) Rat primary nerve A neuronal culture was prepared from the cerebral cortex of an embryonic 18-day-old Wistar rat (ChaHes River Japan, Yokohama, Japan). Specifically, the 'embryonic line' was removed from the pregnant rat in a sterile manner under ether anesthesia. The brain was isolated from the embryo and immersed in ice-cold L_15 medium (Invitrogen c〇rp. catalogue number U415-064, Casper, California, or SIGMA L1518, for example). The cerebral cortex is collected from the isolated brain under a stereoscopic microscope. The collected cortical fragments were contained in 0.25% trypsin (Invitrogen, catalog number 15〇5〇〇65, Casper, California, USA) and 0.01% DNase (Sigma 〇5〇25, USA) The enzyme solution of St. Louis, Missouri is within 37. The cells were dispersed by enzyme-catalyzed treatment for 3 minutes. Here, the enzyme-catalyzed reaction is terminated by adding deactivated horse serum to the solution. The enzyme-treated solution was centrifuged at 5% rpm for 5 minutes to remove the supernatant. 5 ml to 1 ml of medium was added to the resulting cytoplasmic mass. Supplemented with 2% B27 supplement (Invitrogen, Inc., catalog number 175〇4_〇44, Casper, California, USA) ' 25 μΜ 2-巯 ethanol (2-ME, and light type number 139-06861 , Osaka, Japan) '〇.5 mM L-glutamine (Invitrogen, catalog number 25030-081, Casper, California, USA), and antibiotics _ anti-mold 117 201035076 Antibiotics-Antimycotics ( Invitrogen, the neurobasal medium of the catalog number 15240-062 'Casper, California, USA' was used as the medium (neural basic/B27/2-ME). However, a neuronal minimal medium (neural basis/B27) not supplemented with 2-ME was used for assay analysis. The cells were again dispersed by a gentle drop tube drop in which the cell mass of the medium had been added. The cell dispersion was removed through a 40 micron nylon mesh (Cell Strainer' catalog number 35-2340, Becton Dickinson Labware, Franklin Lake, New Jersey, USA) The remaining cytoplasmic mass, thus obtaining a neuronal cell suspension. The neuronal cell suspension was diluted with a medium and then seeded at a primary cell density of 5 x 10 5 cells/cm 2 in a volume of 100 μl/well in 96-well polystyrene pre-coated with poly-L or D-lysine. Orifice (Falcon, catalog number 35-3075, Baker East Dickinson Laboratoryware Company, Franklin Lake, New Jersey, USA, coated with poly-L-lysine using the method described later; or 100 Euro BIOCOAT Cellular Environment Poly-D-Amino Acid Cell Vessel 96-well plate, catalog number 35-6461, Baker East Dickinson Laboratoryware Company, Franklin Lake, New Jersey, USA). The poly-L-lysine coating was carried out as follows. 100 μg/ml poly-L-lysine (Sigma Sigma P2636, St. Louis, MO, USA) was prepared aseptically in 0.15 Torr borate buffer (pH 8.5). A 100 μg/well solution was added to a 96-well polystyrene culture plate and incubated at room temperature for 1 hour or several hours or at 4 ° C overnight or longer. Subsequently, the coated 96-well polystyrene culture plate was washed four times or more with sterile water, and then dried or washed in sterile PBS or medium, and used for cell seeding. The cells that have been inoculated are cultured in a culture plate at 5% CO 2-95% air at 37 ° C. Then, the entire amount of the medium was replaced with fresh nerve basic/B27/2-ME medium, and then the cells were cultured for three times. Addition of compound The drug was added to the culture well plate on the fourth day of culture as follows. The total amount of the medium was removed from the well, and a neuronal minimal medium (neural basic/B27) containing 2% B-27 without 2-ME was added thereto. The solution of the sample compound in dimethyl lime (hereinafter abbreviated as DMSO) was diluted with nerve basic / B27 to a concentration 10 times higher than the final concentration. 20 μl/well of the dilution was added thereto and thoroughly mixed with the medium. The final concentration of DMSO is 1% or less. Only DMSO was added to the control group. After the sample was added, the cells were cultured for three days, and the entire amount of the medium was collected. The resulting medium was used as an ELISA sample. Evaluation of cell survival Cell viability was assessed by MTT assay according to the procedure described below. After collecting the medium, 100 μl/well was added to each well via a pre-warmed medium. Further '8 μl/well of 8 mg/ml MTT (Sigma Sigma M2128, St. Louis, Suri, USA) in D-PBS(-) (Dulbecco, s) A solution of saline, Sigma D8537, St. Louis, Missouri, USA was added to each well. A 96-well polystyrene culture well plate was placed at 37 in the incubator.培养 Incubate in 5% carbon monoxide - 95% air for 2 minutes. 1 〇〇 microliter/well MTT dissolution buffer was added to it and 37 in the incubator. 〇 5% carbon dioxide -95 / 〇 air ' MTT form azo (formazan) crystals are fully dissolved in the buffer. The absorbance of each well at 550 nm was then measured. MTT Lysis Buffer 119 201035076 Prepared as follows. 100 g of SDS (sodium lauryl sulfate (sodium lauryl sulfate), and 191-07145, Osaka, Japan) dissolved in 250 ml of yttrium, yttrium-dimethyl decylamine (and 045-02916 'Osaka, Japan) with 250 A mixture of milliliters of distilled water. Each of 350 liters of concentrated hydrochloric acid and acetic acid was additionally added to the solution to allow the solution to have a final pH of about 4.7. At the time of measurement, each well which was not seeded and contained only the medium and the MTT solution was set as the background (bkg). Substituting the measured values into the following equations includes subtracting the bkg value therefrom. Thus, the ratio of the control group (not treated with the drug, CTRL) (% of CTRL) was calculated to compare and evaluate the cell survival activity.

% of CTRL = ((A550—sample - A550_bkg)/(A550—CTRL -bkg)) x 100 (A550—sample: absorbance ratio of sample hole at 550 nm, A550_bkg: absorbance ratio of background hole at 550 nm, A550_CTRL: absorbance ratio of the control well at 550 nm)

Αβ ELISA for Αβ ELISA 'Used from Heguang Purification Industry Co., Ltd. / Rat β-class powder (42) ELISA kit group and light (#290-62601) or human starch β from IBL (1-42) ) Verification Analysis Suite Group (#27711). Αβ ELISΑ is carried out according to the manufacturer's recommended protocol (the method is described in the attached document). However, the Αβ calibration curve was formed using β-class phenopeptide 1-42, rat (Calbiochem #171596 [Ap42]). (2) From the Αβ concentration result, the concentration (IC50) of each compound which lowered the Αβ concentration to 50% of the control group was calculated. These data are shown in Table 5. 120 201035076 Table 5 Test compound Αβ yield reduction effect IC5〇(nM) Example 7 31 Example 8 8 'Example 13 11 Example 14 18 ~~ Example 15 —- _ 20 Example 26 —--- 18 〇The results from Table 5 are obviously easy It was confirmed that the compound of the present invention has an AM2 yield-reducing effect. Thus, the compound of the formula tI] according to the present invention or a pharmacologically acceptable salt thereof has an Αβ42 yield-reducing effect. Thus, the present invention particularly provides a therapeutic agent for a neurodegenerative disease such as Alzheimer's disease or Down's syndrome caused by di-inhibition. Industrial Applicability _ This (4) butterfly compound has a Αρ yield reduction effect, such as 〇 This is particularly useful as a therapeutic agent for neurodegenerative diseases caused by sputum such as Alzheimer's disease or Down's syndrome. [Simple diagram 3 (none) [Explanation of main component symbols] (none) 121

Claims (1)

[1] 201035076 VII. Patent application scope: 1. A compound represented by formula [I]: (Ri)m 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; η represents 0 to 2 An integer; W represents a nitrogen atom or a carbon atom; and ring Α represents one selected from the group consisting of formulas [2] to [8] 2 6 Each of them may have one to three substituents selected from the group of substituents bl, wherein · represents a bond to the position of the formula [9]: 122 201035076 Ο 9 and Α· indicate the position of the bond to the XI X! represents i) a single bond, ii) a C1-6 alkylene group, iii) a vinyl group which may have 1 to 2 C2-6 alkyl groups or iv) -X2- (wherein X2 represents -NR3-, -ο-, -c(o)-, -nr3c(o)-, -c(o)nr3-, -s-, -S(O)- or -S(0)2- and R3 represent a hydrogen atom, a Cl-6 alkyl group, a C3-6 cycloalkyl group, a C2-6 alkanoyl group or a C1-6 alkylsulfonyl group; and a ring B represents a group selected from the group consisting of the formulas [10] to [27] Monocyclic or fused ring aromatic ring groups in the group: 10 , 11 , 12 , 13 , 14 ’ 15 Each of them may have 1 to 3 substituents selected from the following substituent group cl [Substituent group a1: C1-6 alkyl 'C3-8 cycloalkyl, C2-6 alkenyl, C1- 6 alkoxy, C 2-6 alkenyloxy, C 3-8 cycloalkyloxy, amine (wherein the amine group may have a C 2-6 alkyl fluorenyl * C 1-6 alkyl sulfonyl group or 1 to 2 a C1-6 alkyl group or a C3-8 cycloalkyl group), a cyano group, a decyl group, a halogen atom, a hydroxyl group and a nitro group; 123 201035076 a substituent group bl: a C1-6 alkyl group (wherein the alkyl group can be Substituted with 1 to 3 halogen atoms), C2-6 alkenyl, C3-8 cycloalkyl, C6-14 aryl, C6-14 aryl-C1-6 alkyl, C1-6 alkoxy, C2- 6-alkenyloxy, C3_8 cycloalkyloxy, C2-6 alkanoyl, C4-9 cycloalkylcarbonyl, C7-15 aromatic, C1-6 alkyl, C2-6 fluorenyl a C3-8 ring is a sulfonyl group, a C6-14 arylsulfonyl group, a C1-6 alkylthio group, a C2-6 alkenylthio group, a C3-8 cycloalkylthio group, an amine sulfonyl group (wherein The amine sulfonyl group may have 1 to 2 C 1-6 alkyl groups, C 2-6 alkenyl groups or C 3-8 cycloalkyl groups, and an amine group (wherein the amine group may have a C 2-6 alkyl fluorenyl group, C 1 - 6 alkylsulfonyl or C3-8 cycloalkylsulfonyl or 1 2 C1-6 alkyl or C3-8 cycloalkyl), cyano, formyl, halogen, hydroxy, nitro, oxy, 1-pyrrolidyl ' 1-piperidinyl, 1-highper Pyridyl, porphyrin-1-yl, 1,2,3,4-tetrahydroquinolin-1-yl and 4-carbolinyl; substituent group cl): i) amine group (wherein the amine group) It may have a C2-6 alkano group, a C1-6 alkylsulfonyl group or a C3-8 cycloalkylsulfonyl group or a 1 to 2 C1-6 alkyl group or a C3-8 cycloalkyl group), ii) a cyanogen a group, iii) a halogen atom, iv) a hydroxyl group, and v) vi) a C1-6 alkyl group, v-ii) a C2-6 alkenyl group, a v-iii) C2-6 alkynyl group, a v-iv) C1-6 alkane Oxy, vv) C1-6 alkylthio, v-vi) C1-alkylaminecarbonyl, v-vii) C1-6 alkylsulfonyl, v-viii) C1-6 alkylamine V-ix) C2-6 sulphur-based, vx) phenyl, v-xi)e ratio α-based, v-xii) tower π well group, v_xiii) mouth bite group, v_xiv) ΐ-α 洛洛基基, Ν-χν) 1-η bottom bite, v-xvi) 1-high base and v-xvii) 4-indolyl, each of which may be selected from C1-6 alkyl and _ atoms 1 to 3 substituents in the group]. 124 201035076 2·If you apply for a compound or a pharmacologically acceptable salt thereof, the ring is selected from the group consisting of formulas [3] to _: 3. The compound of claim 2 or a pharmacologically acceptable salt or ester thereof, wherein ring A is represented by formula [3]: 4. A compound according to claim 1 or a pharmacologically acceptable salt thereof or vinegar' wherein ring B is phenyl, pyridyl, oxazolyl or oxazolyl. Sodium, dihydrobenzofuranyl or thienyl. 5. A compound of claim 1 or a pharmaceutically acceptable salt thereof or vinegar 'where X is i) a single bond, Π) C1_6 is extended or m) K wherein x2 represents -NR3- or _C (0) jR3 represents a hydrogen atom, a Cl-6 alkyl group, a C3_6 cycloalkyl group, a C2-6 alkano group or a Ci-6 alkylsulfonyl group). 6. A compound according to claim 1 or a pharmacologically acceptable salt or ester thereof, wherein 1 is (: 1-6 alkyl or a tooth atom and a paw is from 〖 to 2. a 7. The compound of Item 1, or a pharmaceutically acceptable salt or ester thereof, wherein &amp; is a C1-6 alkoxy group. 125 201035076 8. A compound according to claim 1 or a pharmacologically acceptable salt thereof or An ester wherein the substituent of the ring A is selected from the group consisting of C1-6 alkyl (wherein the alkyl group may be substituted with 1 to 3 halogen atoms), C3-8 cycloalkyl, C6-14 aryl, C6-14 aryl-C1-6 alkyl, C1-6 alkoxy, C3-8 cycloalkyloxy, C2-6 alkyl fluorenyl, C7-15 aryl fluorenyl, C1- 6 alkylsulfonyl, C3-8 cycloalkylsulfonyl, C6-14 arylsulfonyl, cyano, decyl, halogen, hydroxy and oxy. 9. 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: ϋ i) an amine group (wherein the amine The group may have a C2-6 alkyl fluorenyl 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 alkoxy group, v)-iii) a C1-6 alkylthio group, And v)-iv) a phenyl group each of which may have 1 to 3 substituents selected from the group consisting of a C1-6 alkyl group and a halogen atom. 10. A compound selected from the group consisting of the following formulas [A-1] to [A-6]: 126 201035076 Or a pharmaceutically acceptable salt or ester thereof. A pharmaceutically acceptable salt, or a pharmacologically acceptable salt thereof, or as an active ingredient, as claimed in any of the above-mentioned items. 12. The drug of claim 11 is for the treatment of Alzheimer's disease, dementia, Down's syndrome, or powdery mildew. 127 201035076 IV. Designated representative map: (1) The representative representative of the case is: ( ). (None) (2) A brief description of the symbol of the representative figure: 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: