JP2012051807A - Arylimidazole compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a novel low molecular weight compound that inhibits the production of amyloid beta (Aβ).SOLUTION: A compound represented by formula (I) [in the formula, the ring A represents a triazolyl group that may be substituted, or the like; the ring B represents a phenyl group or the like that may be substituted, or the like; Xrepresents a single bond or the like; Rand Reach represent a 1-6C alkyl group or the like; m represents an integer of 0 to 3; and n represents an integer of 0 to 2], a pharmacologically acceptable salt thereof, and a pharmacologically acceptable ester thereof are effective as a therapeutic agent for a disease caused by Aβ.

Description

  The present invention relates to a pharmaceutical, particularly a polycyclic arylimidazole derivative effective for the treatment of a neurodegenerative disease caused by amyloid beta (hereinafter referred to as Aβ) such as Alzheimer's disease and Down's syndrome, and a pharmaceutical comprising the same, particularly Aβ The present invention relates to a medicament for the treatment of diseases caused by the disease.

Alzheimer's disease is a disease characterized by the formation of senile plaques and neurofibrillary tangles as well as neuronal degeneration and loss. Currently, treatment of Alzheimer's disease is limited to symptomatic treatment with symptom ameliorating agents represented by acetylcholinesterase inhibitors, and no fundamental therapeutic agent that suppresses the progression of the disease has been developed. Development of a method for controlling the cause of the pathological condition is necessary for the creation of a fundamental therapeutic agent for Alzheimer's disease.
Aβ protein, which is a metabolite of amyloid precursor protein (hereinafter referred to as APP), is considered to be greatly involved in the degeneration / dropout of nerve cells and the development of dementia symptoms (for example, Non-Patent Documents 1 and 2). reference). The main molecular species of Aβ protein are Aβ40 consisting of 40 amino acids and Aβ42 with 2 amino acids added at the C-terminus. These Aβ40 and 42 are highly aggregating (see, for example, Non-Patent Document 3), are the main constituents of senile plaques (see, for example, Non-Patent Documents 3, 4, and 5), and are further affected by familial Alzheimer's disease The APP and presenilin gene mutations seen are known to increase these Aβ40 and 42 (see, for example, Non-Patent Documents 6, 7, and 8). Therefore, a compound that decreases the production of Aβ is expected as a progression inhibitor or preventive agent for Alzheimer's disease.
Aβ is produced by cleaving APP with beta-secretase followed by cleaving with gamma-secretase. Accordingly, attempts have been made to create inhibitors of gamma secretase and beta secretase for the purpose of reducing Aβ production. Many of these secretase inhibitors already known include, for example, L-685,458 (see, for example, Non-Patent Document 9), LY-411,575 (see, for example, Non-Patent Documents 10, 11, and 12), LY. -450, 139 (see Non-Patent Documents 13, 14, 15) and the like, which are peptides or peptide mimetics. As non-peptidic compounds, for example, MRK-560 (see Non-Patent Documents 16 and 17) and Patent Document 1 disclose a group of compounds having a plurality of aromatic rings. The compound represented by the formula (VI) is different from the present invention in that it is limited to a compound group having a 2-aminothiazolyl group as a main structure.

WO 2004/110350

Klein WL, 7 others, Alzheimer's disease-affected brain: Presence of oligomeric Aβ lig ed s e s e s e s e s e s e s e s e s e s e s e m e s e n e s e n e s e s e s e s e s e s e m e n e s e n e s e n e s e n e s e s e s ), P. 10417-10422. Nitsch RM, 16 others, Antibodies against β-amyloid slow cognitive deline in Alzheimer's disease, Neuron, 2003, May 22; 38, p. 547-554. Jarret JT, two others, The carboterminous of the β amyloid protein, the clinical for the seeding of the bioformation: Implications for the pathology. 4693-4697. Glenner GG, 1 other person, Alzheimer's disease: initial report of the purification and charactarization of a novel cerebral vascular bioprotein, Biochemal chemistry, Biochemal 885-890. Masters CL, 5 others, Amyloid plaque core protein in Alzheimer disease and Down syndrome, Processed of the National Academy of Science, USA, 1985, Jun. 82, Jun. 4245-4249. Gouras GK, 11 others, Intraneuronal Aβ42 accumulation in human brain, American Journal of Pathology, 2000, Jan, 156 (1), p. 15-20. Scheuner D, outside 20 people, Secreted amyloid β-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease, Nature Medicine, 1996, Aug, 2 (8), p. 864-870. Former MS, 4 others, Differential effects of the swedish mutant amyloid prescription for 19 and 19, and the like. 32247-32253. Shearman MS, Nine others, L-685,458, an Aspartyl Protease Transition State Mimic, Is a Potent Inhibitor of Amyloid β-Protein Precursor γ-Secrecise 30. 8698-8704. Shearman MS, 6 others, Catalytic Site-Directed γ-Secretase Complex Inhibitors Do Not Discriminate Pharmacologically Between Notch S3 and β-PP. 7580-7586. Lanz TA, three others, Studios of Aβ pharmacodynamics in the brain, cerebrospinal fluid, and plasma in young (plue-free-2, 3-in-the-tissue). ) -2-hydroxyethylanoyl] -N1-[(7S) -5-methyl-6-oxo-6,7-dihydro-5H-dibenzo [b, d] azepin-7-yl] -L-alaninamide (LY-4111575) ), The Journal of Pharmacology and Experimental Ther. peutics, 2004, Apr, 309 (1), p. 49-55. Wong GT, outside 12 people, Chronic treatment with the γ-secretase inhibitor LY-411,575 inhibits β-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation, The Journal of Biological Chemistry, 2004, Mar, 26,279 (13) , P. 12876-12882. Gitter BD, 10 others, Stereoselective inhibition of amyloid beta peptide segmentation by LY450139, a novel functional gamma secretinhibitor, Nig. 571. Lanz TA, 18 others, Concentration-dependent modulation of amyloid-β in vivo and in vitro using the γ-secretate inhibitor, LY-450139, The Journal of the Pharm. 924-933. Siemers ER, 13 others, Effects of a γ-secretase inhibitor in a randomized study of patents with Alzheimer disease, Neurology, 2006, 66, p. 602-604. Best JD, Nine others, In vivo characterisation of Aβ (40) changes in brain and cerebrospinous fluiding the novel γ-secretase inhibitor N- [4-l-ul-cyl-4- [y] -ro] -Difluorophenyl) cyclohexyl] -1,1,1-trifluorethanesulfamide (MK-560) in the rat, The Journal of Pharmaceutical and Experimental3, M2 (MK-560). 786-790. Best JD, 13 others The novel γ-secretase inhibitor N- [cis-4-[(4-chlorophenyl) sulfonyl] -4- (2,5-difluorophenyl) cyclohexyl] -1,1,1-trifluorfluor (K) 560) reduced amyloid plaque deposition without evidence notch-related pathology in the Tg2576 mouse, The Journal of Pharmorology. 552-558.

  As described above, a compound that suppresses the production of Aβ from APP is expected as a therapeutic or preventive agent for diseases caused by Aβ represented by Alzheimer's disease, but has an excellent medicinal effect and suppresses the production of Aβ. The non-peptidic compounds that do are not yet known. Accordingly, there is a need for novel low molecular weight compounds that suppress Aβ production.

  The present inventors have conducted intensive studies, found a non-peptide polycyclic compound that suppresses the production of Aβ from APP, and found a therapeutic agent for a disease caused by Aβ represented by Alzheimer's disease. Completed the invention.

That is, the present invention relates to the following 1) to 12):
1) Formula [I]

[Wherein, R ₁ and R ₂ are the same or different and each represents a substituent selected from the following substituent group a1;
m represents an integer of 0-3,
n represents an integer of 0-2,
W represents a nitrogen atom or a carbon atom,
Ring A may have 1 to 3 substituents selected from the following substituent group b1 and are represented by formula [2] to formula [8].

[In the formula, ● represents the formula [9]

The binding site to A, A ● represents the binding site to X ₁ ] represents a ring selected from the group consisting of: i) a single bond, ii) a C 1-6 alkylene group, and iii) 1-2. pieces or may vinylene group which may have a C2-6 alkyl group iv) -X ₂ - (wherein, _{X 2 is, -NR 3 -, - O -} , - C (O) -, - NR 3 C (O) —, —C (O) NR ₃ —, —S—, —S (O) — or —S (O) ₂ —, wherein R ₃ represents a hydrogen atom, a C 1-6 alkyl group, C _3- 6 cycloalkyl group, C2-6 alkanoyl group or C1-6 alkylsulfonyl group)
Ring B may have 1 to 3 substituents selected from the following substituent group c1 and are represented by formulas [10] to [27].

A monocyclic or condensed aromatic ring group selected from the group consisting of

Substituent group a1: C1-6 alkyl group, C3-8 cycloalkyl group, C2-6 alkenyl group, C1-6 alkoxy group, C2-6 alkenyloxy group, C3-8 cycloalkyloxy group, amino group (the amino group) Group may have one, C2-6 alkanoyl group or C1-6 alkylsulfonyl group or 1-2, C1-6 alkyl group or C3-8 cycloalkyl group), cyano group, formyl Group, halogen atom, hydroxyl group and nitro group

Substituent group b1: C1-6 alkyl group (the alkyl group may be substituted with 1-3 halogen atoms), C2-6 alkenyl group, C3-8 cycloalkyl group, C6-14 aryl group, C6 -14 aryl C1-6 alkyl group, C1-6 alkoxy group, C2-6 alkenyloxy group, C3-8 cycloalkyloxy group, C2-6 alkanoyl group, C4-9 cycloalkylcarbonyl group, C7-15 aroyl group, C1-6 alkylsulfonyl group, C2-6 alkenylsulfonyl group, C3-8 cycloalkylsulfonyl group, C6-14 arylsulfonyl group, C1-6 alkylthio group, C2-6 alkenylthio group, C3-8 cycloalkylthio group, amino A sulfonyl group (the aminosulfonyl group is 1-2, C1-6 alkyl group, C2-6 alkyl An aryl group (which may have a C3-8 cycloalkyl group), an amino group (the amino group is one C2-6 alkanoyl group, a C1-6 alkylsulfonyl group or a C3-8 cycloalkylsulfonyl group, Or 1-2, which may have a C1-6 alkyl group or a C3-8 cycloalkyl group), a cyano group, a formyl group, a halogen atom, a hydroxyl group, a nitro group, an oxo group, a 1-pyrrolidinyl group, 1 -Piperidinyl group, 1-homopiperidinyl group, indolin-1-yl group, 1,2,3,4-tetrahydroquinolin-1-yl group and 4-morpholinyl group

Substituent group c1: i) amino group (the amino group is one C2-6 alkanoyl group, C1-6 alkylsulfonyl group, C3-8 cycloalkylsulfonyl group, or 1-2 C1-6 1) selected from the group consisting of an alkyl group or a C3-8 cycloalkyl group), ii) a cyano group, iii) a halogen atom, iv) a hydroxyl group, and v) a C1-6 alkyl group and a halogen atom. -3) V-1) C1-6 alkyl group, v-ii) C2-6 alkenyl group, v-iii) C2-6 alkynyl group, v-iv) C1-6 alkoxy Group, vv) C1-6 alkylthio group, v-vi) C1-6 alkylaminocarbonyl group, v-vii) C1-6 alkylsulfonyl group, v-viii) C1-6 alkylaminosulfonate. Group, v-ix) C2-6 alkanoyl group, vx) phenyl group, v-xi) pyridyl group, v-xii) pyridazinyl group, v-xiii) pyrimidinyl group, v-xiv) 1-pyrrolidinyl group, v -Xv) 1-piperidinyl group, v-xvi) 1-homopiperidinyl group and v-xvii) 4-morpholinyl group]
Or a pharmacologically acceptable salt or ester thereof;
2) Ring A is represented by formula [3] to formula [8].

A compound selected from the group consisting of 1) or a pharmacologically acceptable salt or ester thereof;
3) Ring A is represented by the formula [3]

Or a pharmacologically acceptable salt or ester thereof according to 2) above;
4) The compound according to 1) or a pharmacologically acceptable salt or ester thereof, wherein ring B is a phenyl group, a pyridyl group, an oxazolyl group, an imidazolyl group, a thiazolyl group, a dihydrobenzofuranyl group or a thienyl group. ;
5) X ₁ is i) a single bond, ii) a C 1-6 alkylene group or iii) —X ₂ — (where X ₂ represents —NR ₃ — or —C (O) —, and R ₃ represents Or a hydrogen atom, a C1-6 alkyl group, a C3-6 cycloalkyl group, a C2-6 alkanoyl group or a C1-6 alkylsulfonyl group), or a pharmacologically acceptable compound thereof. Salt or ester;
6) The compound according to 1) or a pharmacologically acceptable salt or ester thereof, wherein R ₁ is a C 1-6 alkyl group or a halogen atom, and m is 1-2;
7) The compound according to 1) above, wherein R ₂ is a C 1-6 alkoxy group, and n is 1, or a pharmaceutically acceptable salt or ester thereof;
8) The substituent of ring A is a C1-6 alkyl group (the alkyl group may be substituted with 1-3 halogen atoms), a C3-8 cycloalkyl group, a C6-14 aryl group, a C6- 14 aryl C1-6 alkyl group, C1-6 alkoxy group, C3-8 cycloalkyloxy group, C2-6 alkanoyl group, C7-15 aroyl group, C1-6 alkylsulfonyl group, C3-8 cycloalkylsulfonyl group, C6 -14 The compound or pharmacologically acceptable salt or ester thereof described in 1) above, selected from the group consisting of arylsulfonyl group, cyano group, formyl group, halogen atom, hydroxyl group and oxo group;
9) The substituent of ring B is i) an amino group (the amino group is one C2-6 alkanoyl group, C1-6 alkylsulfonyl group or C3-8 cycloalkylsulfonyl group, or 1-2) A group having a C1-6 alkyl group or a C3-8 cycloalkyl group), ii) a cyano group, iii) a halogen atom, iv) a hydroxyl group, and v) a C1-6 alkyl group and a halogen atom. V) -i) C1-6 alkyl group, v) -ii) C1-6 alkoxy group, v) -iii) C1-6 alkylthio group, which may have 1 to 3 substituents selected from And v) -iv) the compound according to 1) or a pharmacologically acceptable salt or ester thereof selected from the group consisting of phenyl groups;
10) The following formulas [A-1] to [A-6]

One compound selected from the group consisting of, or a pharmacologically acceptable salt or ester thereof;
11) A pharmaceutical comprising as an active ingredient the compound according to any one of 1) to 10) above or a pharmacologically acceptable salt or ester thereof;
12) The medicament according to 11) above for the treatment of Alzheimer's disease, dementia, Down syndrome or amyloidosis.

  The compound of the general formula [I] of the present invention or a pharmacologically acceptable salt or ester thereof and a therapeutic agent for a disease caused by Aβ thereof is a novel invention not described in any literature.

  Hereinafter, the meanings of symbols, terms, and the like described in the present specification will be described, and the present invention will be described in detail.

  In the present specification, the structural formula of a compound may represent a certain isomer for convenience, but the present invention is not limited to all geometrical isomers, optical isomers based on asymmetric carbon, and stereoisomerism that occur in the structure of the compound. Isomers such as isomers and tautomers, and mixtures of isomers, and are not limited to the description of the formula for convenience, and may be either isomer or a mixture. Therefore, there may be an optically active substance and a racemate having an asymmetric carbon atom in the molecule, but there is no limitation in the present invention, and both are included. Further, although there may be a crystalline polymorph, it is not limited in the same manner, and any single crystalline form or a mixture thereof may be used, and a hydrate may be used in addition to the anhydride.

“Disease caused by Aβ”
Alzheimer's disease (e.g., Klein WL, 7 others, Alzheimer's disease-affected brain: Presence of oligomeric Aβ ligation, ADDLs sig- nal sig- nal sig- nal sig- nal sig- nal sig- nal sig- nal sig- nal sig- nal. (18), p. 10417-10422; Nitsch RM, 16 others, Antibodies against β-amyloid cognitive deline in Alzheimer's disease, Neuron, 2003, May 22, 38 (4), 5 (5), p. Jarrett JT, outside two people, The carboxy terminus of the β amyloid protein is critical for the seeding of amyloid formation: Implications for the pathogenesis of Alzheimers' disease, Biochemistry, 1993, May 11,32 (18), p.4693-4697 Glenner GG, 1 other, Alzheimer's disease; initial report of the purification and novelty of novel cerebral amyloidoid protein, Biochemical biophysical research communications, 1984, May 16, 120 (3), p. 885-890; Masters CL, 6 others, Amyloid plaque core protein in N edi ce ce n ed and Proce ed in Proceeds in Ace. (12), p. 4245-4249; Gouras GK, 11 others, International Aβ42 accumulation in human brain, American journal of pathology, 2000, Jan, 156 (1), p. 15-20; Scheuner D, outside 20 people, Secreted amyloid β-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease, Nature Medicine, 1996, Aug, 2 (8), p. 864-870; Forman MS, and four others, Differential effects of the swedish mutant amyloid precursor protein on β-amyloid accumulation and secretion in neurons and nonneuronal cells, The journal of biological chemistry, 1997, Dec 19,272 (51), p . 32247-32253),
Senile dementia (see, for example, Brass JP, Brain metabolism and brain disease: Is metabolite defensiveness the proximity cause of Alzheimer dementia?
Frontotemporal dementia (see, for example, Evin G, et al., 11 alternative transcripts of presenilin-1 associated with frontotemporal dementia, Neuroport, 2002, Apr 16, 7 (19), 7 (19)).
Pick disease (see, for example, Yasuhara O, 3 others, Accumulation of amyloid preparations in brain conditions of patents with Pick disease, Neuroscience Letters, 1994, 17, Apr. 1, 63, Apr.).
Down syndrome (e.g., Teller JK, 10 others, Presence of soluble amyloid β-peptide precedes amyloid plaque formation in Down's syndrome, Nature et al., 1996, Tl. 6 people, Plasma levels of amyloid β proteins Aβ1-40 and Aβ1-42 (43) are elevated in Down's syndrome, Annals of Neurology, 1997, Feb. 27, 27 (1), 27 (1), 27 (1), 27 (1), 27 (1).
Cerebrovascular angiopathy (e.g. Hayashi Y, 9 others, Evidence for presenilin-1 evolution in amyloid angiopathy in the Alzheimer's disease, p. 9 ; Barelli H, 15 others, Characterization of new polyantibodies specific for 40 and 42 amino acid-and-the-factory-e-beta-peptides: histochemistry of sporadic Alzheimer's disease and cerebral amyloid angiopathy cases, Molecular Medicine, 1997, Oct, 3 (10), p.695-707; Calhoun ME, outside 10 people, Neuronal overexpression of mutant amyloid precursor protein results in prominent deposition of cerebroscular amyloid, Proceeding National Academy of Science USA, 1999, Nov 23, 96 (24), p.14088-14093; Cerebral amyloid angiopathy is a pathogenic lesion in Alzheimer's Disease due to a novel presenilin-1 mutation, Brain, 2001, Dec, 124 (12), see p.2383-2392),
Hereditary cerebral hemorrhage with amyloidosis (Dutch type) (for example, Cras P, and nine other people, Presenile Alzheimer dementia characterized by amyloid angiopathy and large amyloid core type senile plaques in the APP 692Ala -> Gly mutation, Acta Neuropathologica (Berl), 1998 , Sep, 96 (3), pp. 253-260; Herzig MC, 14 others, Aβ is targeted to the vasculature in heraldary cerebral heterothermal energy cience, 2004, Sep, 7 (9), p. 954-960; Aug, 84 (16), p. 5991-5994; Levy E, 8 others, Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Jut type, 1, 48 type. 4959), p. 1122-1126),
Cognitive impairment (see, for example, Laws SM, 7 others, Association bethethe the presenilin-1 mutation Glu318Gly and compliments of memory immediate, Neurobiology of Ann, 58, J., 58).
Memory failure / learning failure (for example, Vaucher E, 5 others, Object recognition memory and cholinergic parameters, in-pressing human presenilin 1 transgene, 1998, 2). 14 people, Aβ peptide vaccine presents memory loss in an animal model of Alzheimer's disease, Nature, 2000 Dec 21-28, 408 (6815), p. 982-985, ren A. ficits in transgenic mice expressing the 751-amino acid isoform of human β-amyloid precursor protein, Proceeding National Academy of Science USA, 1995, June 6,92 (12), see p.5341-5345),
Amyloidosis, amyloidosis,
Cerebral ischemia (e.g. Laws SM, 7 others, Association bet the the presenilin-1 mutation Glu318Gly and compliments of memory immediate, Neurobiology, J. 58, J. 58, J. , And other 10 people, β-amyloid precursor protein transigenic mie tat harbor diffuse Academy of Science USA, 2002, Feb 5,99 (3), p.1610-1615; Zhang F, and four others, Increased susceptibility to ischemic brain damage in transgenic mice overexpressing the amyloid precursor protein, The journal of neuroscience, 1997, Oct 15, 17 (20), p. 7655-7661),
Cerebrovascular dementia (see, for example, Sadowski M, et al., 6 Links betheween the pathology of Alzheimer's disease and vascular dementia, Neurochemical Research, 2004, Jun, 29, 66, 12).
Ocular palsy (eg, O'Riorandan S, et al., 7 Presenilin-1 mutation (E280G), spasmic paraparesis, and cranial MRI white matter, neurology, Neurology, 2002, Oct. 8 (October 8). 1110),
Multiple sclerosis (eg, Gehrmann J, 4 others, Amyloid precursor protein (APP) expression in multiple sclerosis regions, Glia, 1995, Oct, 15 (2), p. 141-51; Reynolds W, F. See Myeloperoxidase polymorphism is associated with gender specific risk for Alzheimer's disease, Experiential Neurology, 1999, Jan, 155, (41).
Head injury, skull injury (see, for example, Smith DH, 4 others, Protein accumulation in traumatic brain injury, NeuroMolecular Medicine, 2003, 4 (1-2), p. 59-72),
Apraxia (see, for example, Matsubara-Tsutsui M, 7 others, Molecular evidence of presenilin 1 mutation in domestic onset dementia, American journal of America. ,
Prion disease,
Familial amyloid neuropathy,
Triplet repeat diseases (for example, Kirkitadze MD, and two others, Paradigm shifts in Alzheimer's disease and other neurodegenerative disorders: the emerging role of oligomeric assemblies, Journal of Neuroscience Research, 2002, Sep 1,69 (5), p.567 -577; Ever BO, 8 others, Inflammability genes are upregulated in expanded ataxin-3-expressing cell lines and spinocerebellata type 3 strains, Brains, Japan l of Neuroscience, 2001, Aug 1, 21 (15), p. 5389-5396; Mann DM, et al., Deposition of amy sid ens ed s ed ens ed ens ens ed s ed ens ens ens ed ens ens ens ded ens 's syndrome, Neuroscience Letters, 1990, Feb 5, 109 (1-2), p. 68-75),
Parkinson's disease (see, for example, Primeavera J, 4 others, Brain accumulation of amyloid-β in Non-Alzheimer Neurodegeneration, Journal of Alzheimer's Disease, 1999, 3 (October 3).
Review body type dementia (for example, Giasson BI, 2 others, Interactions of amyloidogenic proteins. NeuroMolecular Medicine, 2003, 4 (1-2), p. 49-58; Masliah E, 6 others, β-amyloid -Synchronic accumulation and neurodefects in atracgenic mouse model linking Alzheimer's disease and Parkinson's disease, Proceeding National Aid. arrachina M, outside six, Amyloid-β deposition in the cerebral cortex in Dementia with Lewy bodies is accompanied by a relative increase in AβPP mRNA isoforms containing the Kunitz protease inhibitor, Neurochemistry International, 2005, Feb, 46 (3), p. 253-260; Primavera J, 4 others, Brain accumulation of amyloid-β in Non-Alzheimer Neurodegeneration, Journal of Alzheimer's Disease, 19 99, Oct, 1 (3), p.183-193),
Parkinsonism-dementia complex (for example, Schmidt ML, outside six, Amyloid plaques in Guam amyotrophic lateral sclerosis / parkinsonism-dementia complex contain species of Aβ similar to those found in the amyloid plaques of Alzheimer's disease and pathological aging, Acta Neuropathologica (Berr), 1998, Feb, 95 (2), p. 117-122; Ito H, 3 others, Demonstration of β amyloid protein-containing neurofibrile. ary tangles in parkinsonism-dementia complex on Guam, Neuropathology and applied neurobiology, 1991, Oct, 17 (5), see p.365-373),
Frontotemporal dementia and parkinsonism linked to the 17th chromosome (eg, Rosso SM, 3 others, Coexistent au and amiloid pathology in hereditary ensemble and temperamental ensembles, Nand 115-119),
Argyrophilic grain type dementia (for example, Tolnay M, and four others, Low amyloid (Aβ) plaque load and relative predominance of diffuse plaques distinguish argyrophilic grain disease from Alzheimer's disease, Neuropathology and applied neurobiology, 1999, Aug, 25 ( 4), p.295-305),
Niemann-Pick disease (for example, Jin LW, and three others, Intracellular accumulation of amyloidogenic fragments of amyloid-β precursor protein in neurons with Niemann-Pick type C defects is associated with endosomal abnormalities, American Journal of Pathology, 2004, Mar, 164 (3), p. 975-985),
Amyotrophic lateral sclerosis (e.g., Sasaki S, et al., Immunoreactivity of β-amyloid pretreatment protein in amyotrophic lateral sclerosis, Acta Neuropathology, 1997, 4). Tamoka A, 4 others, Increased amyloid β protein in the skin of patents with amyotropic lateral sclerosis, Journal 3 neuro, 2000, Aug. 247, Aug. 247. n amyotrophic lateral sclerosis, Acta Neuropathology, 2004, Jun, 107 (6), p. 515-522, Turn B e, et al. 29 (12), p.2281-2286),
Hydrocephalus (for example, Weller RO, Pathology of cerebrospinal fluid and interstitial fluid of the CNS: Significance for Alzheimer disease, prion disorders and multiple sclerosis, Journal of Neuropathology and Experimental Neurology, 1998, Oct, 57 (10), p.885- 894; Silverberg GD, 4 others, Alzheimer's disease, normal-pressure hydrocephalus, and sensitive changes in CSF circulation physicyl gy: a hyperthesis, Lancet neurology, 2003, Aug, 2 (8), p. 506-511; the New York academy of sciences, 2000, Apr, 903, p.110-117; Yow HY, et al. isease, Neurology and applied neurobiology, 2002,28, p.149; Weller RO, and four others, Cerebrovasculardisease is a major factor in the failure of elimination of Aβ from the aging human brain, Annals of the New York academy of sciences, 2002 , Nov, 977, p. 162-168),
Paraparesis (eg, O'Riordan S, 7 others, Presenilin-1 mutation (E280G), spasmic paraparesis, and cranial MRI white matter, neurology, Neurology, 2002, Oct. 8, p. 1110; Matsubara-Tsutsui M, 7 others, Molecular evidence of presenilin 1 mutation in domestic early on dementia, American Journal of Medicine 3 et al. Name, Variable pheno yp of Alzheimer's disease with parasitic paralogy, Anals of Neurology, 2001, 49 (1), p.125-129; Crook R, 17 others, Avariant of Alzheimer's wise of exon 9 of presenilin 1, Nature Medicine, 1998, Apr; 4 (4), p. 452-455),
Progressive supranuclear palsy (for example, Barrachina M, outside six, Amyloid-β deposition in the cerebral cortex in Dementia with Lewy bodies is accompanied by a relative increase in AβPP mRNA isoforms containing the Kunitz protease inhibitor, Neurochemistry International, 2005, Feb. 46 (3), p.253-260; Primavera J, 4 others, Brain accumulation of amyloid-β in Non-Alzheimer Neurodegeneration, Journal of Alzheim. r's Disease, 1999, Oct, 1 (3), see p.183-193),
Cerebral hemorrhage (for example, Atwood CS, and three others, Cerebrovascular requirement for sealant, anti-coagulant and remodeling molecules that allow for the maintenance of vascular integrity and blood supply, Brain Research Reviews, 2003, Sep, 43 (1), p.164 -78; Lowenson JD, two others, Protein aging: Extracellular amyloid formation and intracellular repair, Trends in cardiovascular medicine, 1994, 4 (1), p.3. 8 reference),
Convulsions (see, for example, Singleton AB, et al., 13 of Pathology of early-onset Alzheimer's disease cases the ther 113-114 ins presenilin-1 mutation, Brain, 2000, Dec, 24, p. 123, p. 123, p. 123).
Mild cognitive impairment (eg, Gattaz WF, 4 others, Platelet phospholipase A2 activity in Alzheimer's dissemination and mild cognitive impulse, Journal A1. 14 people, Plasma levels of amyloid β-protein 42 are increased in women with mild cognitive impulse, Neurology, 2004, Sep 14, 63 (5), p. 828-8.
Atherosclerosis (eg, De Meyer GR, 8 others, Platelet phagocytosis and processing of β-amyloid pretreatment protein as a mechanism of macro14, 204 reference)
And so on.

  The “substituent group a1”, “substituent group b1” and “substituent group c1” in the compound represented by the above formula (I) effective for the treatment of diseases caused by Aβ according to the present invention are the following: Indicates a group.

  Substituent group a1 includes a C1-6 alkyl group, a C3-8 cycloalkyl group, a C2-6 alkenyl group, a C1-6 alkoxy group, a C2-6 alkenyloxy group, a C3-8 cycloalkyloxy group, an amino group The amino group may have one C2-6 alkanoyl group or C1-6 alkylsulfonyl group or 1-2 C1-6 alkyl group or C3-8 cycloalkyl group), a cyano group, A formyl group, a halogen atom, a hydroxyl group and a nitro group are shown.

  Substituent group b1 includes a C1-6 alkyl group (the alkyl group may be substituted with 1-3 halogen atoms), a C2-6 alkenyl group, a C3-8 cycloalkyl group, a C6-14 aryl group. C6-14 aryl C1-6 alkyl group, C1-6 alkoxy group, C2-6 alkenyloxy group, C3-8 cycloalkyloxy group, C2-6 alkanoyl group, C4-9 cycloalkylcarbonyl group, C7-15 aroyl Group, C1-6 alkylsulfonyl group, C2-6 alkenylsulfonyl group, C3-8 cycloalkylsulfonyl group, C6-14 arylsulfonyl group, C1-6 alkylthio group, C2-6 alkenylthio group, C3-8 cycloalkylthio group , Aminosulfonyl group (the aminosulfonyl group is 1-2 C1-6 alkyl group, C2- An alkenyl group or a C3-8 cycloalkyl group), an amino group (the amino group is one C2-6 alkanoyl group, a C1-6 alkylsulfonyl group or a C3-8 cycloalkylsulfonyl group, Or 1-2, which may have a C1-6 alkyl group or a C3-8 cycloalkyl group), a cyano group, a formyl group, a halogen atom, a hydroxyl group, a nitro group, an oxo group, a 1-pyrrolidinyl group, 1-piperidinyl group, 1-homopiperidinyl group, indolin-1-yl group, 1,2,3,4-tetrahydroquinolin-1-yl group and 4-morpholinyl group are shown.

  Substituent group c1 is an amino group (the amino group is one C2-6 alkanoyl group, C1-6 alkylsulfonyl group, C3-8 cycloalkylsulfonyl group, or 1-2 C1-6 alkyl group). 1) selected from the group consisting of a group or a C3-8 cycloalkyl group), ii) a cyano group, iii) a halogen atom, iv) a hydroxyl group, and v) a C1-6 alkyl group and a halogen atom. Which may have three substituents, vi) C1-6 alkyl group, v-ii) C2-6 alkenyl group, v-iii) C2-6 alkynyl group, v-iv) C1-6 alkoxy group , Vv) C1-6 alkylthio group, v-vi) C1-6 alkylaminocarbonyl group, v-vii) C1-6 alkylsulfonyl group, v-viii) C1-6 alkylaminosulfonyl , V-ix) C2-6 alkanoyl group, vx) phenyl group, v-xi) pyridyl group, v-xii) pyridazinyl group, v-xiii) pyrimidinyl group, v-xiv) 1-pyrrolidinyl group, v- xv) 1-piperidinyl group, v-xvi) 1-homopiperidinyl group and v-xvii) 4-morpholinyl group.

  The “halogen atom” refers to a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc., preferably a fluorine atom, a chlorine atom, or a bromine atom.

  “C 1-6 alkyl group” means an alkyl group having 1 to 6 carbon atoms. Preferred groups include, for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, and an isobutyl group. Tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, n-hexyl group, 1-methylpropyl group, 1,2-dimethylpropyl group, 1-ethylpropyl group, 1-methyl-2-ethylpropyl Group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1-methylbutyl group, 2-methylbutyl group, 1,1-dimethylbutyl group, 2,2-dimethylbutyl group, 2- Examples thereof include straight chain or branched alkyl groups such as ethylbutyl group, 1,3-dimethylbutyl group, 2-methylpentyl group, and 3-methylpentyl group.

  “C 1-6 alkylene group” means an alkylene group having 1 to 6 carbon atoms, and preferred groups include, for example, a methylene group, an ethylene group, a methylmethylene group, a propylene group, a methylethylene group, an ethylmethylene group, Examples include linear or branched alkyl groups such as dimethylmethylene group, butylene group, methylpropylene group, ethylethylene group, dimethylethylene group, propylmethylene group, pentylene group, and hexylene group. Among them, for example, methylene group, ethylene group, A methylmethylene group, a propylene group, a methylethylene group, an ethylmethylene group and a dimethylmethylene group are preferred.

  The “C 3-8 cycloalkyl group” refers to a cyclic alkyl group having 3 to 8 carbon atoms. Preferred groups in the group include, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and the like. Can be mentioned.

  The “C2-6 alkenyl group” refers to an alkenyl group having 2 to 6 carbon atoms, and preferred groups include, for example, vinyl group, allyl group, 1-propenyl group, isopropenyl group, 1-butene-1- Linear or branched alkenyl such as yl, 1-buten-2-yl, 1-buten-3-yl, 2-buten-1-yl, 2-buten-2-yl Groups.

  "C2-6 alkynyl group" refers to an alkynyl group having 2 to 6 carbon atoms, and preferred groups include, for example, ethynyl group, 1-propynyl group, 2-propynyl group, butynyl group, pentynyl group, hexynyl group And a linear or molecular chain alkynyl group.

  The “C 3-8 cycloalkyloxy group” refers to a group in which one hydrogen atom is substituted with an oxygen atom in a cyclic alkyl group having 3 to 8 carbon atoms. Preferred examples of the group include a cyclopropoxy group , Cyclobutoxy group, cyclopentoxy group, cyclohexoxy group, cycloheptyloxy group, cyclooctyloxy group and the like.

  The “C 3-8 cycloalkylthio group” refers to a group in which one hydrogen atom is substituted with a sulfur atom in a cyclic alkyl group having 3 to 8 carbon atoms. Preferred examples of the group include a cyclopropylthio group. , Cyclobutylthio group, cyclopentylthio group, cyclohexylthio group, cycloheptylthio group, cyclooctylthio group, and the like.

  The “C 1-6 alkoxy group” refers to a group having 1 to 6 carbon atoms in which a hydrogen atom is substituted with an oxygen atom. Preferred groups include, for example, a methoxy group, an ethoxy group, and an n-propoxy group. , Isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, n-pentoxy group, i-pentoxy group, sec-pentoxy group, tert-pentoxy group, n-hexoxy group, i- Hexoxy group, 1,2-dimethylpropoxy group, 2-ethylpropoxy group, 1-methyl-2-ethylpropoxy group, 1-ethyl-2-methylpropoxy group, 1,1,2-trimethylpropoxy group, 1,1 , 2-trimethylpropoxy group, 1,1-dimethylbutoxy group, 2,2-dimethylbutoxy group, 2-ethylbutoxy group, 1,3 Dimethylbutoxy group, 2-methyl pentoxy group, 3-methyl pentoxy group, and the like.

  The “C 1-6 alkylthio group” refers to a group in which one hydrogen atom is substituted with a sulfur atom in an alkyl group having 1 to 6 carbon atoms. Preferred groups include, for example, a methylthio group, an ethylthio group, and an n-propylthio group. Group, isopropylthio group, n-butylthio group, isobutylthio group, tert-butylthio group, n-pentylthio group, isopentylthio group, neopentylthio group, n-hexylthio group, 1-methylpropylthio group and the like. .

  The “C2-6 alkanoyl group” refers to a group in which one hydrogen atom is substituted with a carbonyl group in an alkyl group having 1 to 6 carbon atoms. Preferred groups include, for example, an acetyl group, a propionyl group, a butyryl group, and the like. Is mentioned.

  The “C 1-6 alkylsulfonyl group” means a group in which one hydrogen atom is substituted with a sulfonyl group in an alkyl group having 1 to 6 carbon atoms. Preferred groups include, for example, a methanesulfonyl group, an ethanesulfonyl group and the like. Is mentioned.

  The “C2-6 alkenyloxy group” refers to a group in which one hydrogen atom is substituted with an oxygen atom in an alkenyl group having 2 to 6 carbon atoms. Preferred groups include, for example, a vinyloxy group, an allyloxy group, 1-propenyloxy group, isopropenyloxy group, 1-buten-1-yloxy group, 1-buten-2-yloxy group, 1-buten-3-yloxy group, 2-buten-1-yloxy group, 2-butene Examples thereof include a linear or branched alkenyloxy group such as a 2-yloxy group.

  The “C2-6 alkenylthio group” refers to a group in which one hydrogen atom is substituted with a sulfur atom in an alkenyl group having 2 to 6 carbon atoms. Preferred groups include, for example, a vinylthio group, an allylthio group, 2-propenylthio group, 1-buten-1-ylthio group, 1-buten-2-ylthio group, 1-buten-3-ylthio group, 2-buten-1-ylthio group, 2-buten-2-ylthio group Straight chain or branched chain alkenylsulfonyl groups and the like.

  The “C2-6 alkenylsulfonyl group” refers to a group in which one hydrogen atom is substituted with a sulfonyl group in an alkenyl group having 2 to 6 carbon atoms. Preferred examples include a vinylsulfonyl group and an allylsulfonyl group. , 2-propenylsulfonyl group, 1-buten-1-ylsulfonyl group, 1-buten-2-ylsulfonyl group, 1-buten-3-ylsulfonyl group and the like.

  The “C 3-8 cycloalkylsulfonyl group” refers to a group in which one hydrogen atom is substituted with a sulfonyl group in a cyclic alkyl group having 3 to 8 carbon atoms. Preferred examples of the group include cyclopropylsulfonyl Group, cyclobutylsulfonyl group, cyclopentylsulfonyl group, cyclohexylsulfonyl group, cycloheptylsulfonyl group and the like.

  The “C6-14 aryl group” means a monocyclic, bicyclic or tricyclic aromatic hydrocarbon ring group having 6 to 14 carbon atoms. Preferred groups in the group include, for example, a phenyl group and an indenyl group. Monocyclic, bicyclic or tricyclic 6 to 14-membered aromatic hydrocarbon ring groups such as naphthyl group, azulenyl group, heptalenyl group, biphenyl group, fluorenyl group, phenalenyl group, anthryl group and phenanthryl group Be

  The “C7-15 aroyl group” means a group in which one hydrogen atom is substituted with a carbonyl group in the C6-14 aryl group, and preferred groups include, for example, benzoyl group, indenecarbonyl group, naphthoyl group, biphenyl. Examples include carbonyl group, fluorenylcarbonyl group, phenanthrylcarbonyl group, anthrylcarbonyl group, etc.

  The “C6-14 aryl C1-6 alkyl group” refers to a group in which one hydrogen atom is substituted with the C6-14 aryl group in the C1-6 alkyl group. Preferred groups include, for example, a benzyl group, Examples include phenethyl group, phenylpropyl group, naphthylmethyl group, biphenylmethyl group, etc.

  The “C6-14 arylsulfonyl group” refers to a group in which one hydrogen atom is substituted with a sulfonyl group in the C6-14 aryl group. Preferred groups include, for example, a benzenesulfonyl group, a naphthalenesulfonyl group, a biphenylsulfonyl group. Group etc.

  The “C4-9 cycloalkylcarbonyl group” refers to a group in which a cyclic alkyl group having 3 to 8 carbon atoms is substituted with a carbonyl group. Preferred groups in the group include, for example, a cyclopropylcarbonyl group, a cyclobutylcarbonyl group, A cyclopentylcarbonyl group, a cyclohexylcarbonyl group, a cycloheptylcarbonyl group, etc. are mentioned.

  The “C 1-6 alkylaminocarbonyl group” is a group in which one hydrogen atom is substituted with an aminocarbonyl group in an alkyl group having 1 to 6 carbon atoms. Preferred groups include, for example, a methylaminocarbonyl group, ethyl Examples include aminocarbonyl group, propylaminocarbonyl group, butylaminocarbonyl group, hexylaminocarbonyl and the like.

  The “C 1-6 alkylaminosulfonyl group” refers to a group in which one hydrogen atom is substituted with an aminocarbonyl group in an alkyl group having 1 to 6 carbon atoms. Preferred groups include, for example, a methylaminosulfonyl group, ethyl Examples include aminosulfonyl group, propylaminosulfonyl group, butylaminosulfonyl group, hexylaminosulfonyl and the like.

When W is a nitrogen atom and R ² is a hydroxyl group, for example, the formula

It is intended to include tautomers represented by

“In the definition of ring B, 1 to 3 substituents selected from the substituent group c1 may be present at any substitutable position on the ring, and ring B may be any substituent on the ring. It may be connected to X ₁ at a possible position, for example ring B is of formula 19

In the following formulas 19-1 to 19-7

X ₁ may be connected at a substitutable position represented by

  In the present invention, the “pharmacologically acceptable salt” is any compound that forms a pharmacologically acceptable salt with the compound of the general formula [I] that serves as a therapeutic agent for diseases caused by Aβ. There is no particular limitation. Specifically, for example, preferably a hydrohalide (eg, hydrofluoride, hydrochloride, hydrobromide, hydroiodide, etc.), an inorganic acid salt (eg, sulfate, nitrate, perchlorate) Acid salt, phosphate, carbonate, bicarbonate, etc.), organic carboxylate (eg acetate, oxalate, maleate, tartrate, fumarate, citrate, etc.), organic sulfonate (Eg methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, camphorsulfonate, etc.), amino acid salts (eg aspartate, glutamate, etc.), quaternary Examples thereof include amine salts, alkali metal salts (for example, sodium salts and potassium salts), and alkaline earth metal salts (for example, magnesium salts and calcium salts).

Next, the compound of the formula [I] of the present invention will be described.
In the compounds of formula [I], R ₁ is a C1-6 alkyl group or a halogen atom, n is the compound or preferably a pharmacologically acceptable salt thereof is an integer of 1-2, R ₁ Is a C1-6 alkyl group, n is an integer of 1-2, or a pharmacologically acceptable salt thereof, R ₁ is a methyl group, and n is 1. Most preferred are compounds or pharmacologically acceptable salts thereof.

In the compound of the formula [I], a compound or a pharmacologically acceptable salt thereof, in which R ₂ is a halogen atom, a hydroxyl group or a C 1-6 alkoxy group and n is an integer of 1-2, A compound in which R ₂ is a C 1-6 alkoxy group and n is an integer of 1-2 or a pharmacologically acceptable salt thereof is more preferable, R ₂ is a methoxy group, and n is 1 Or a pharmacologically acceptable salt thereof is particularly preferred.

In the compound of the formula [I], X ₁ is i) a single bond, ii) a C 1-6 alkylene group which may have 1-2 C 1-6 alkyl groups, or iii) —X ₂ — (here In the formula, X ₂ represents —NR ₃ — or —CO—, and R ₃ represents a hydrogen atom, a C 1-6 alkyl group, a C 3-6 cycloalkyl group, a C 2-6 alkanoyl group or a C 1-6 alkylsulfonyl group. Or a pharmacologically acceptable salt thereof.

  In the compound of the formula [I], the ring A is represented by the following formula 3-8:

Or a pharmacologically acceptable salt thereof, wherein

Is particularly preferred.

  In the compound of formula [I], ring B may be substituted with 1-3 substituents selected from substituent group c1.

Or a pharmacologically acceptable salt thereof is preferred.

  Substituent group b1 includes (1) C1-6 alkyl group (the alkyl group may be substituted with 1-3 halogen atoms), (2) C3-8 cycloalkyl group, (3) C6- 14 aryl group, (4) C6-14 aryl C1-6 alkyl group, (5) C1-6 alkoxy group, (6) C3-8 cycloalkyloxy group, (7) C2-6 alkanoyl group, (8) C7 -15 aroyl group, (9) C1-6 alkylsulfonyl group, (10) C3-8 cycloalkylsulfonyl group, (11) C6-14 arylsulfonyl group, (12) cyano group, (13) formyl group, (14 ) A substituent group consisting of a halogen atom, (15) hydroxyl group and (16) oxo group is preferred.

  Substituent group c1 is (1) an amino group (the amino group is one C2-6 alkanoyl group, C1-6 alkylsulfonyl group or C3-8 cycloalkylsulfonyl group, or 1-2, A C1-6 alkyl group or a C3-8 cycloalkyl group), (2) a cyano group, (3) a halogen atom, (4) a hydroxyl group, and (5) a C1-6 alkyl group and a halogen atom. (5) -1) a C1-6 alkyl group, (5) -2) a C1-6 alkoxy group, which may have 1 to 3 substituents selected from the group consisting of (5) -3) A substituent group consisting of a C1-6 alkylthio group and (5) -4) a phenyl group is preferred.

  Particularly, for example, the following formulas [A-1] to [A-6]

At least one compound or pharmacologically acceptable salt selected from the group consisting of these is preferable, and is used as a therapeutic agent for diseases caused by amyloid beta, such as diseases such as Alzheimer's disease, senile dementia, Down's syndrome or amyloidosis. Useful.

The method for producing the compound of the general formula [I] of the present invention will be described below.
Formula [I]

[Wherein R ₁ , R ₂ , m, n, W, ring A, X ₁ and ring B have the same meaning as described above. The compound represented by this is synthesized, for example, according to the following general production method-1 to general production method-7. In order to conveniently produce the compounds of the present invention, suitable protecting groups known to those skilled in the art in each step (for example, T. Greene et al., “Protective Groups in Organic Synthesis” (John Wiley & Sons. Inc., New York). (See 1981) and appropriately including a protection reaction step and a deprotection reaction step.Conveniently, in preparing the compounds of the present invention, suitable substituent conversions known to those skilled in the art are suitable for each step. Needless to say, it includes introduction of a substituent, etc. In addition, when the compound of the present invention is conveniently produced, it is generated in the structure of the compound by a technique known to those skilled in the art such as fractional recrystallization and column chromatography suitable for each step. All geometric isomers, optical isomers based on asymmetric carbon, stereoisomers, tautomerism Needless to say, isomers and isomer mixtures can be produced as a single compound.

[General production method-1]
A typical [General production method-1] of the compound of the general formula [I] according to the present invention will be described below.

[Wherein R ₁ , R ₂ , m, n, W, ring A, X ₁ and ring B have the same meaning as described above, and X _A represents a halogen atom such as a chlorine atom, a bromine atom or an iodine atom, methanesulfonate group, p-toluenesulfonic acid ester group, a sulfonic acid ester group such as a trifluoromethanesulfonate group, X _B is trialkylstannyl group, boronic acid, boronic acid ester such as boronic acid pinacol ester Indicates a group. ]

In the above [General production method-1], the compound of the general formula (a-1) and the compound of the general formula (b-2) are subjected to a coupling reaction in [Step 1-1], and the general formula [I] or preparing a compound or compound [step 1-1] in the coupling reaction of a compound of the general formula the substituents X _a and X _B are interchanged (a-2) (b- 1) And a process for producing a compound of the general formula [I].

The coupling reaction in [Step 1-1] varies depending on the starting materials, but is not particularly limited as long as it is like this reaction, and a method known to those skilled in the art can be used. Suzuki-Miyaura reaction ( See, for example, A. Suzuki, “Chem. Rev.”, 1995, 95, p. 2457), or Stille coupling reactions (eg, JK Stille, “Angew. Chem. Int. Ed. Engl.”). 1986, 25, p.508).

The Suzuki-Miyaura reaction is preferably, for example, 1.0- to the compound of general formula (a-1) which is a halogen compound or a trifluoromethanesulfonic acid ester compound and the compound of general formula (a-1). 5.0 equivalents of the compound of the general formula (b-2) (wherein X _B is preferably a boronic acid ester group such as a boronic acid group or a boronic acid pinacol ester) is represented by the general formula (a-1). It is preferable to perform a coupling reaction in the presence of 0.01 to 0.5 equivalent of a transition metal catalyst. This reaction is preferably carried out in the presence of a solvent from the viewpoints of operability and agitation. The solvent used varies depending on the starting material and the transition metal catalyst used, and dissolves the starting material to some extent without inhibiting the reaction. Although it will not specifically limit if it is a thing, Preferably, for example, acetonitrile, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, xylene, 1-methyl-2-pyrrolidone, N, N-dimethylformamide Etc., water, or a mixed solvent thereof. The reaction temperature should be a temperature sufficient to complete the coupling reaction, and is preferably room temperature to 200 ° C. This reaction is preferably performed in an inert gas atmosphere, more preferably in a nitrogen or argon atmosphere. Under preferred reaction conditions, the reaction is complete in 1-24 hours and the progress of the reaction can be monitored by known chromatographic techniques. The transition metal catalyst is preferably a known palladium complex, more preferably, for example, palladium (II) acetate, dichlorobis (triphenylphosphine) palladium (II), tetrakis (triphenylphosphine) palladium (0), or tris (dibenzylideneacetone). ) Known palladium complexes such as dipalladium (0). In addition, a phosphorus ligand (preferably, for example, triphenylphosphine, tri-o-tolylphosphine, tricyclohexylphosphine, or tri-tert-butylphosphine) or the like may be appropriately added to allow the reaction to proceed efficiently. Good. In order for the reaction to proceed efficiently, a quaternary ammonium salt, preferably, for example, tetrabutylammonium chloride or tetrabutylammonium bromide may be appropriately added. In this reaction, a preferable result can be obtained in the presence of a base. In this case, the base to be used varies depending on the starting material, the solvent to be used and the like and is not particularly limited. However, for example, sodium hydroxide is preferable. , Barium hydroxide, potassium fluoride, cesium fluoride, sodium carbonate, potassium carbonate, cesium carbonate, or potassium phosphate. Under preferred reaction conditions, the reaction is complete in 1-24 hours and the progress of the reaction can be monitored by known chromatographic techniques.

The Stille coupling reaction is preferably carried out, for example, with respect to a compound of the general formula (a-1) which is a halogen compound or a trifluoromethanesulfonic acid ester compound and a compound of the general formula (a-1) 1.0- 5.0 equivalent of the compound of the general formula (b-2) (in this case, X _B is preferably a trialkylstannyl group) is 0.01-- with respect to the compound of the general formula (a-1). The coupling reaction is preferably performed in the presence of 0.2 equivalent of a transition metal catalyst. In order to make the reaction proceed efficiently, 0.1-5.0 equivalents of copper (I) halide and / or lithium chloride are also preferably used as appropriate. Preferable solvents used in this reaction include, for example, toluene, xylene, N, N-dimethylformamide, N, N-dimethylacetamide, 1-methyl-2-pyrrolidone, dimethyl sulfoxide and the like. The reaction temperature should be a temperature sufficient to complete the coupling reaction, and is preferably room temperature to 150 ° C. Preferred transition metal catalysts are palladium complexes, preferably for example palladium (II) acetate, dichlorobis (triphenylphosphine) palladium (II), tetrakis (triphenylphosphine) palladium (0) or tris (dibenzylideneacetone) dipalladium. Known palladium complexes such as (0) are mentioned, more preferably, for example, palladium (II) acetate, tetrakis (triphenylphosphine) palladium (0), tris (dibenzylideneacetone) dipalladium (0) and the like. . In order for the reaction to proceed efficiently, for example, a phosphorus ligand (preferably, for example, triphenylphosphine, tri-o-tolylphosphine, 1,3-bis (diphenylphosphino) propane, tri-tert-butylphosphine, etc.) Etc. may be added as appropriate. This reaction is preferably performed in an inert gas atmosphere, more preferably in a nitrogen or argon atmosphere. Under preferred reaction conditions, the reaction is complete in 1-24 hours and the progress of the reaction can be monitored by known chromatographic techniques.

[Step 1-2] is an example of preparation of compounds of the compounds of the general formula (a-2) the substituent X _A and X _B are interchanged (b-2). Although this process changes with starting materials, if it is the conditions of this reaction, it will not be specifically limited, It is a method well-known to those skilled in the art. Preferably, for example, the Suzuki-Miyaura reaction (see, for example, A. Suzuki, “Chem. Rev.”, 1995, 95, p. 2457) or Stille coupling reaction (see, for example, JK Stille, “Angew”). Chem. Int. Ed. Engl. ”(See 1986, 25, p. 508) and the like.

[Preparation of compound of general formula (a-1)]
The following formula shows an example of the preparation of the compound of the general formula (a-1).

[Wherein, R ₁ , R ₂ , m, n, W, and X _A represent the same meaning as described above, R _A and R _B represent the same meaning as R ₁ , L ₁ represents a chlorine atom, a bromine atom, a halogen atom such as iodine atom, methanesulfonate group, p-toluenesulfonic acid ester group, a sulfonic acid ester group such as a trifluoromethanesulfonate group, L ₂ is fluorine atom, a chlorine atom, a bromine atom, A halogen atom such as an iodine atom, a sulfonic acid ester group such as a methanesulfonic acid ester group, a paratoluenesulfonic acid ester group, or a trifluoromethanesulfonic acid ester group, or a boronic acid group. ]

  The compound of the general formula (a-1) is prepared by using the amine compound (a-3) as a starting material, formylation of [Step 2-1], alkylation reaction of [Step 2-2], [Step 2-3]. The imidazole ring can be prepared or the compound of the general formula (a-4) can be used as a starting material and prepared by the coupling reaction of [Step 2-4].

  [Step 2-1] varies depending on the starting material, but is not particularly limited as long as it is a condition like this reaction, and a method known to those skilled in the art can be used and has been reported in many literatures ( For example, the method of T. Greene et al., “Protective Groups in Organic Synthesis” (John Wiley & Sons. Inc., New York, 1981) can be used.

  [Step 2-2] varies depending on the starting material, but is not particularly limited as long as it is a condition like this reaction, and methods known to those skilled in the art can be used. Preferably, for example, with respect to the compound of the general formula (a-5) and the compound of the general formula (a-5), in the presence of 1.0 to 10.0 equivalents of a base, the compound of the general formula (a-5) The method of stirring the compound of general formula (c-1) of 1.0-10.0 equivalent with respect to a compound in a solvent is mentioned. The base used varies depending on the starting material and is not particularly limited. Preferably, for example, an alkali metal hydride (for example, sodium hydride or lithium hydride), an alkali metal salt (for example, potassium carbonate, Sodium carbonate or cesium carbonate) or metal alkoxide (for example, sodium methoxide or potassium tert-butoxide). The solvent to be used varies depending on the starting material and is not particularly limited, but is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. Preferably, for example, tetrahydrofuran, 1,4-dioxane is used. Or an ether solvent such as diethyl ether, a halogen solvent such as methylene chloride, 1,2-dichloroethane or chloroform, a polar solvent such as N, N-dimethylformamide or N-methylpyrrolidone, a nonpolar solvent such as toluene or benzene, Or a mixture thereof. The reaction temperature should be a temperature sufficient to complete the reaction without promoting formation of undesirable by-products, and is preferably 0 ° C. to 200 ° C., for example. Under preferred reaction conditions, the reaction is complete in 1 to 24 hours 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, extraction operations or / and crystallization.

  [Step 2-3] varies depending on the starting material, but is not particularly limited as long as it is a condition like this reaction, and a method known to those skilled in the art can be used and has been reported in many literatures ( For example, a method described in The Chemistry of Heterocyclic Compounds. Imidazole and Derivatives, Part I, p33, Inters. Publish. 1953) can be used. Preferably, for example, a method of preparing a compound of the general formula (a-1) by constructing an imidazole ring using a compound of the general formula (a-6) and ammonia, ammonium salt, formamide or the like as a nitrogen source. The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Preferably, for example, a nonpolar solvent such as toluene or benzene, an alcohol solvent such as methanol or ethanol, acetic acid, etc. Alternatively, an organic acid such as trifluoroacetic acid, a sulfonic acid such as paratoluenesulfonic acid or trifluoromethanesulfonic acid, water, or a mixture thereof. In some cases, formamide can be used as a nitrogen atom source and a solvent. The reaction temperature should be a temperature that can complete the reaction without promoting formation of undesirable by-products, and is preferably room temperature to 250 ° C., for example. In addition, when the reaction is carried out using an airtight container, the yield may be improved. Under preferred reaction conditions, the reaction is complete in 1 to 24 hours 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, extraction operations or / and crystallization.

The coupling reaction of [Step 2-4] varies depending on the starting material, but is not particularly limited as long as it is the same as in this reaction, and methods known to those skilled in the art can be used and reported in many literatures. (For example, as described in DD Davey et al., “J. Med. Chem.”, 1991, Vol. 34, p. 2671-2677). For example, 1.0 to 5.0 equivalents of an imidazole compound with respect to the compound of the general formula (a-4) (in this case, L ₂ is preferably a halogen atom) and the compound of the general formula (a-4) In this method, the compound (c-2) is stirred in a solvent in the presence or absence of 1.0-5.0 equivalents of a base relative to the compound of the general formula (a-4). Preferable examples of the base to be used include sodium hydride, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, barium carbonate, pyridine, lutidine, triethylamine and the like. The solvent to be used is not particularly limited as long as it varies depending on the starting material and dissolves the starting material to some extent without inhibiting the reaction. Preferably, for example, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, N, N-dimethylformamide is used. Or N-methylpyrrolidone or the like. Optionally, a base may be used as a solvent. The reaction temperature should be a temperature that is sufficient to complete the reaction without promoting formation of undesirable by-products, and is preferably room temperature to 150 ° C., for example. Under preferred reaction conditions, the reaction is complete in 1-24 hours 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.

The coupling reaction in [Step 2-4] includes, for example, a method of stirring in a solvent under a copper catalyst with a compound of general formula (a-4) (in this case, L ₂ is preferably a boronic acid group or the like). (See, for example, JP Collman et al., “Org. Letters.”, 2000, Vol. 2, p. 1233-1236). Preferably, for example, 0.01-1.0 equivalent of copper such as copper, copper bromide or copper iodide with respect to the compound of general formula (a-4) and the compound of general formula (a-4) The method of stirring 0.1-10.0 equivalent imidazole compound (c-2) in a solvent with respect to the compound of general formula (a-4) in presence of a reagent is mentioned. The copper reagent to be used varies depending on the starting material and is not particularly limited, but preferably, for example, copper (I) halide, copper (II) acetate, copper (II) nitrate or di-mu-hydroxo- Bis [(N, N, N ′, N′-tetramethylethylenediamine) copper (II)] chloride and the like. The solvent to be used is not particularly limited as long as it varies depending on starting materials, reagents and the like, and does not inhibit the reaction and dissolves the starting material to some extent, but preferably, for example, tetrahydrofuran, 1,4-dioxane or diethyl ether Ether solvents such as methylene chloride, halogen solvents such as 1,2-dichloroethane or chloroform, polar solvents such as ethyl acetate, N, N-dimethylformamide or N-methylpyrrolidone, toluene, benzene or dichlorobenzene, etc. A nonpolar solvent, or a mixture thereof. Bases may be used depending on the starting materials, reagents, etc., preferably, for example, organic bases such as triethylamine, pyridine or tetramethylethylenediamine, alkali metal salts such as potassium carbonate, sodium carbonate, potassium acetate, sodium acetate or cesium carbonate Or metal alkoxides such as sodium methoxide or potassium tert-butoxide. The reaction temperature should be a temperature sufficient to complete the reaction without promoting formation of undesirable by-products, and is preferably room temperature to 200 ° C., for example. Further, when this reaction is carried out in an oxygen atmosphere or in an air stream, good results such as shortening of the reaction time and improvement of the yield can be obtained. Under preferred reaction conditions, the reaction is complete in 1 to 24 hours 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, extraction operations or / and crystallization.
In addition, the compound of formula (a-3), the compound of formula (a-4), the compound of formula (c-1), the compound of formula (c-2) is a known compound or a commercially available compound, These compounds can be produced from these compounds by conventional methods.

[Preparation of compound of general formula (b-1)]
The following formula shows an example described for the preparation of the compound of the general formula (b-1).

[Wherein, X ₁ , X _A , ring A and ring B represent the same meaning as described above, and L ₃ represents a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, a methanesulfonate group, paratoluene. A sulfonic acid ester group such as a sulfonic acid ester group or a trifluoromethanesulfonic acid ester group, a boronic acid group, a nitro group or an azide group; X ₁ represents an oxygen atom or a nitrogen atom (the nitrogen atom is a C 1-6 alkyl group, Which may have a substituent such as a group). ]

  The compound of the general formula (b-1) is obtained by using the compound of the general formula (d-1) as a starting material, the condensation reaction of [Step 3-1], the reduction reaction of [Step 3-2], and [Step 3-3]. It can be prepared through the Sandmeyer reaction.

  The coupling reaction in [Step 3-1] varies depending on the starting material, but is not particularly limited as long as it is the same as the reaction, and a method known to those skilled in the art can be used. For example, the general formula (d- 1.0-5.0 equivalents of the compound of general formula (d-2) to the compound of general formula (d-1) and the compound of general formula (d-1) This is a method of stirring in a solvent in the presence or absence of 1.0 to 5.0 equivalents of a base. Preferable examples of the base to be used include sodium hydride, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, barium carbonate, pyridine, lutidine, triethylamine and the like. The solvent to be used is not particularly limited as long as it varies depending on the starting material and dissolves the starting material to some extent without inhibiting the reaction. Preferably, for example, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, N, N-dimethylformamide is used. Or N-methylpyrrolidone or the like. Optionally, a base may be used as a solvent. The reaction temperature should be a temperature that is sufficient to complete the reaction without promoting formation of undesirable by-products, and is preferably room temperature to 150 ° C., for example. Under preferred reaction conditions, the reaction is complete in 1-24 hours 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.

  The reduction reaction of the nitro group in [Step 3-2] varies depending on the starting material, but is not particularly limited as long as it is the same as this reaction, and a reduction reaction known to those skilled in the art can be used. (For example, described in the Chemical Society of Japan, 4th edition, Experimental Chemistry Course (Volume 20) Organic Synthesis [IV], Maruzen Co., Ltd., November 1992, p. 279-280). be able to.

The Sandmeyer reaction in [Step 3-3] varies depending on the starting materials, but is not particularly limited as long as it is like this reaction, and techniques known to those skilled in the art can be used and reported in many literatures. (For example, described in Japanese Chemical Society, 4th edition, Experimental Chemistry Course (Volume 19) Organic Synthesis [I], Maruzen Co., Ltd., November 1992, p. 450-453).
In addition, the compound of a formula (d-1) and the compound of a formula (d-2) are a well-known compound or a commercially available compound, or a compound which can be manufactured from these compounds by a conventional method.

[General production method-2]
A typical [General production method-2] of the compound of the general formula [I] according to the present invention will be described below.

[Wherein R ₁ , R ₂ , X ₁ , m, n, W, ring A and ring B have the same meaning as described above, and P ₁ represents a methyl group, an ethyl group, a benzyl group, an allyl group, etc. Indicates a protecting group for an imidate group. ]

  In the above [General production method-2], the compound of the general formula (a-7) and the compound of the general formula (e-1) are subjected to a cyclization reaction in [Step 4-1], and the general formula [I] An example of a method for producing the compound is shown.

  The construction reaction of the A ring in [Step 4-1] varies depending on the starting materials, but is not particularly limited as long as it is a condition like this reaction, and a method known to those skilled in the art can be used. Preferably, for example, 1.0 to 5.0 equivalents of the compound of the general formula (a-1) and the compound of the general formula (e-1) with respect to the compound of the general formula (a-7) A method of stirring in a solvent in the presence of 1.0 to 10.0 equivalents of a base with respect to the compound (a-7) can be mentioned. This reaction is preferably carried out in the presence of a solvent from the viewpoint of operability and stirring efficiency. The solvent to be used varies depending on the starting material, and is particularly limited as long as it dissolves the starting material to some extent without inhibiting the reaction. Preferably, for example, alcohol solvents such as methanol, ethanol or tert-butanol, ether solvents such as tetrahydrofuran, 1,4-dioxane or diethyl ether, halogens such as methylene chloride, 1,2-dichloroethane or chloroform System solvents, acetonitrile, propionitrile, polar solvents such as N, N-dimethylformamide or N-methylpyrrolidone, nonpolar solvents such as toluene or benzene, or mixtures thereof. The base to be used varies depending on the starting material and is not particularly limited. Preferably, for example, an alkali metal hydride (for example, sodium hydride or lithium hydride), an alkali metal salt (for example, potassium carbonate, Sodium carbonate or cesium carbonate), metal alkoxide (for example, sodium methoxide or potassium tert-butoxide), or organic base (for example, triethylamine, N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0]) Undec-7-ene or imidazole). The reaction temperature should be a temperature sufficient to complete the reaction without promoting formation of undesirable by-products, and is preferably room temperature to 200 ° C., for example. Under preferred reaction conditions, the reaction is completed in 1 to 7 days 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, extraction operations or / and crystallization.

[Preparation of compound of general formula (a-7)]
The following formula shows an example of the preparation of the compound of the general formula (a-7).

[Wherein R ₁ , R ₂ , m, n, X _A and W represent the same meaning as described above, and P ₂ represents a protecting group for a nitrogen atom such as a tert-butoxycarbonyl group or a benzyloxycarbonyl group. , _{M a} represents zinc, a metal such as copper. ]

  The compound of general formula (a-7) is obtained by using the compound of general formula (a-1) as a starting material, the coupling reaction of [Step 5-1], the hydrolysis reaction of [Step 5-2], and [Step 5]. -3] hydrazide and [Step 5-4] deprotection reaction.

  The coupling reaction in [Step 5-1] varies depending on the starting material, but is not particularly limited as long as it is the same as the reaction, and a method known to those skilled in the art can be used. Compound, a compound of general formula (a-1) which is a trifluoromethanesulfonic acid ester compound, and 1.0-5.0 equivalents of compound of general formula (h-1) to the compound of general formula (a-1) A metal cyanide such as zinc (II) cyanide represented by the compound is subjected to a coupling reaction in the presence of 0.01 to 0.2 equivalent of a transition metal catalyst with respect to the compound of the general formula (a-1). Is preferred. This reaction is preferably carried out in the presence of a solvent from the viewpoint of operability and stirring efficiency. The solvent used varies depending on the starting material and the transition metal catalyst used, and dissolves the starting material to some extent without inhibiting the reaction. Although it will not specifically limit if it is a thing, Preferably, for example, acetonitrile, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, xylene, 1-methyl-2-pyrrolidone, or N, N-dimethyl And formamide. The reaction temperature should be a temperature sufficient to complete the coupling reaction, and is preferably room temperature to 150 ° C. This reaction is preferably performed in an inert gas atmosphere, more preferably in a nitrogen or argon atmosphere. The transition metal catalyst is preferably, for example, a palladium complex, and more preferably, for example, palladium (II) acetate, dichlorobis (triphenylphosphine) palladium (II), tetrakis (triphenylphosphine) palladium (0), or tris ( Known palladium complexes such as dibenzylideneacetone) dipalladium (0) can be mentioned. In order for the reaction to proceed efficiently, a phosphorus ligand (preferably, for example, triphenylphosphine, tri-o-tolylphosphine, tri-tert-butylphosphine, or 2- (di-tert-butylphosphino) It is also preferable to appropriately add biphenyl and the like. In addition, a preferable result may be obtained in the presence of a base, and the base to be used is not particularly limited as long as it is used in this reaction-like coupling reaction, but preferably, for example, triethylamine, N, N -Diisopropylethylamine, N, N-dicyclohexylmethylamine, tetrabutylammonium chloride, etc. are mentioned. Under preferred reaction conditions, the reaction is complete in 1-24 hours and the progress of the reaction can be monitored by known chromatographic techniques.

  The hydrolysis reaction of the nitrile in [Step 5-2] varies depending on the starting material, but is not particularly limited as long as it is a condition like this reaction, and methods known to those skilled in the art can be used. The method described (for example, described in the Chemical Society of Japan, 4th edition, Experimental Chemistry Course (Vol. 22) Organic Synthesis [IV], Maruzen Co., Ltd., November 1992, p. 12-13) is used. it can.

  The hydrazide reaction in [Step 5-3] varies depending on the starting material, but is not particularly limited as long as it is the same as this reaction, and amidation reactions known to those skilled in the art can be used. (For example, described in the Chemical Society of Japan, 4th edition, Experimental Chemistry Course (Vol. 22) Organic Synthesis [IV], Maruzen Co., Ltd., November 1992, p.137-144). Can do.

The deprotection reaction in [Step 5-4] varies depending on the starting material, but is not particularly limited as long as it is the same as in this reaction, and a deprotection reaction known to those skilled in the art can be used. (See, for example, T. Greene et al., “Protective Groups in Organic Synthesis” (see John Wiley & Sons. Inc., New York, 1981)).
In addition, the compound of a formula (f-1) and the compound of a formula (h-1) are a well-known compound or a commercially available compound, or are compounds which can be manufactured from these compounds by a conventional method.

[Preparation of compound of general formula (e-1)]
The following formula shows an example described for the preparation of the compound of general formula (e-1).

[Wherein, X ₁ , ring B and P ₁ have the same meaning as described above. ]

  The compound of general formula (e-1) can be prepared by the imidateization of [Step 6-1] using the compound of general formula (e-2) as a starting material.

[Step 6-1] varies depending on the starting material, but is not particularly limited as long as it is a condition like this reaction, and methods known to those skilled in the art can be used. Preferably, for example, a method in which the compound of the general formula (e-2) is stirred with an alcohol solvent in the presence of 5.0 to 100.0 equivalents of acid with respect to the compound of the general formula (e-2). It is done. The acid used varies depending on the starting material and is not particularly limited. However, for example, hydrogen chloride gas and acetyl chloride are preferable. The solvent to be used varies depending on the starting material and is not particularly limited, but is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. For example, methanol, ethanol, tert-butanol, etc. Alcohol solvents are preferred. For example, a mixed solvent of a halogen solvent such as methylene chloride, 1,2-dichloroethane, or chloroform, a polar solvent such as N, N-dimethylformamide, or N-methylpyrrolidone, or a nonpolar solvent such as toluene or benzene preferable. The reaction temperature should be a temperature sufficient to complete the reaction without promoting formation of undesirable by-products, and is preferably 0 ° C. to 100 ° C., for example. Under preferred reaction conditions, the reaction is completed in 1 to 7 days 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, extraction operations or / and crystallization.
In addition, the compound of a formula (e-2) is a well-known compound or a commercially available compound, or a compound which can be manufactured from these compounds by a conventional method.

[General production method-3]
A typical [General production method-3] of the compound of the general formula (Ia) and the compound of the general formula (Ib) according to the present invention will be described below.

[Wherein, R ₁ , R ₂ , m, n, W, X ₁ and ring B have the same meaning as described above. ]

  In the above [General production method-3], the carboxylic acid compound (a-9) is used as a starting material, [Step 7-1] is amidated, and [Step 7-2] is dehydrated. , 3,4] An example of a method for producing the compound of the general formula (Ia) having oxadiazole is shown, and further, by rewinding the ring in [Step 7-3], [1,2,4] An example of the method for producing the compound of the general formula (Ib) having triazole is shown.

  The amidation in [Step 7-1] is the same method as in [Step 5-3], and the compound of general formula (a-11) can be prepared from the compound of general formula (a-9).

  The dehydration reaction in [Step 7-2] varies depending on the starting material, but is not particularly limited as long as it is a condition like this reaction, and is a known method described in many literatures (for example, Eur. J. Med. Chem., 42, 934, 2007). For example, the compound of the general formula (a-11) and the compound of the general formula (a-11) are stirred in a solvent in the presence of 1.0 to 100.0 equivalents of a dehydrating reagent. The dehydrating reagent to be used varies depending on the starting material and is not particularly limited. However, for example, phosphorus oxychloride, diphosphorus pentoxide, phosphorus pentachloride, thionyl chloride, polyphosphoric acid, triphenylphosphine-tetrachloride. Carbon, triphenylphosphine-carbon tetrabromide and the like. The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Preferably, for example, an ether solvent such as tetrahydrofuran, 1,4-dioxane or diethyl ether, or chloride Halogen solvents such as methylene, 1,2-dichloroethane or chloroform; polar solvents such as N, N-dimethylformamide or N-methylpyrrolidone and acetonitrile; nonpolar solvents such as toluene, benzene and dichlorobenzene; and A mixture thereof. Moreover, a dehydrating reagent may be used as a solvent. The reaction temperature should be a temperature sufficient to complete the reaction without promoting formation of undesirable by-products, and is preferably 0 to 200 ° C., for example. Under preferred reaction conditions, the reaction is complete in 1 to 24 hours 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, extraction operations or / and crystallization.

  The conversion from the oxazole ring to the triazole ring in [Step 7-3] varies depending on the starting material, but is not particularly limited as long as it is a condition like this reaction, and methods known to those skilled in the art can be used. Preferably, for example, 5-50 equivalents of ammonia, ammonium salt, formamide or the like is used as a nitrogen source with respect to the compound of the general formula (Ia) and the compound of the general formula (Ia), and the mixture is stirred in a solvent. The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Preferably, for example, an organic acid such as acetic acid or trifluoroacetic acid, a nonpolar solvent such as toluene or benzene, An alcohol solvent such as methanol or ethanol, a sulfonic acid such as p-toluenesulfonic acid or trifluoromethanesulfonic acid, water, or a mixture thereof. In some cases, formamide can be used as a nitrogen atom source and a solvent. The reaction temperature should be a temperature that can complete the reaction without promoting formation of undesirable by-products, and is preferably room temperature to 250 ° C., for example. In addition, when the reaction is carried out using an airtight container, the yield may be improved. Under preferred reaction conditions, the reaction is complete in 1 to 24 hours 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, extraction operations or / and crystallization.

  In addition, when a primary amine is used as a nitrogen source in [Step 7-3], a substituent can be regioselectively introduced into the 4-position of [1,2,4] triazole.

[Preparation of compound of general formula (f-2)]
The following formula shows an example described for the preparation of the compound of general formula (f-2).

[Wherein, X ₁ , P ₂ and ring B have the same meaning as described above. ]

The compound of the general formula (f-2) can be prepared from the carboxylic acid compound (f-3) as a starting material, through hydrazide formation in [Step 8-1] and deprotection reaction in [Step 8-2].
Further, as shown in [Step 8-3], the ester compound (f-5) can be directly led to the compound (f-2).

  The amidation in [Step 8-1] is the same method as in [Step 5-3], and the compound of general formula (f-4) can be prepared from the compound of general formula (f-3).

  Deprotection in [Step 8-2] is the same method as in [Step 5-4], and the compound of general formula (f-2) can be prepared from the compound of general formula (f-4).

  The hydrazide reaction in [Step 8-3] varies depending on the starting materials, but is not particularly limited as long as it is like this reaction, and amidation reactions known to those skilled in the art can be used. (For example, described in Japanese Chemical Society, 4th edition, Experimental Chemistry Course (Vol.22) Organic Synthesis [IV], Maruzen Co., Ltd., November 1992, p.265-267). Can do.

  When a substituted carbazate (for example, N′-methylhydrazinecarboxylic acid benzyl ester hydrochloride, CAS No. 880-21-7 or the like) is used instead of the compound of the general formula (f-1), the nitrogen is substituted on the nitrogen. A derivative of the general formula (f-2) having a group is obtained. By using this in [Step 7], a substituent can be regioselectively introduced into the [1,2,4] triazole ring of compound (Ib).

Among the compounds of the general formula [I] according to the present invention, when X ₁ is —NH—, in addition to the methods shown in the above general production method-1 to general production method-3, general production It can also be produced according to a method such as Method-4 to General Production Method-7.

[General production method-4]
A typical [General production method-4] of the compound of the general formula (Ic) according to the present invention will be described below.

[Wherein, R ₁ , R ₂ , m, n, W and ring B have the same meaning as described above. ]

  In the above [General production method-4], carboxylic acid compound (a-9) is used as a starting material, and [1,2,4] oxadiazole is added to ring A in the cyclization reaction of [Step 9-1]. 1 shows an example of a method for producing a compound of the general formula (Ic).

  The cyclization reaction in [Step 9-1] varies depending on the starting material, but is not particularly limited as long as it is the same as in this reaction, and is a known method described in many literatures (for example, Patent Publication DE-102004061750). Reference) can be used.

  The hydroxyguanidine compound (g-1) can be easily obtained by reacting a cyanamide compound with hydroxylamine by a method known to those skilled in the art (for example, described in J. Chem. Soc., Chem. Commun., Page 806, 1970). Can be prepared.

[General production method-5]
A typical [General production method-5] of the compound of the general formula (Id), the compound of the general formula (Ie) and the compound of the general formula (If) according to the present invention will be described below.

[Wherein, R ₁ , R ₂ , m, n, W, and ring B have the same meaning as described above. ]

In the above [General production method-5], the hydrazide compound (a-7) is used as a starting material, and [1, 10] is subjected to thioamidation in [Step 10-1] and cyclization reaction in [Step 10-2]. [3,4] An example of a method for producing a compound of the general formula (Id) having oxadiazole, and [1, 10] from [1] in the cyclization reaction of [Step 10-3] from the thioamide compound (a-12). 3,4] shows an example of a method for producing a compound of general formula (Ie) having thiadiazole.
Further, a method for producing a compound of general formula (If) having [1,2,4] triazole in ring A by the cyclization reaction of [Step 10-4] using hydrazide compound (a-7) as a starting material. An example is shown.

  The thioamidation in [Step 10-1] and the cyclization reaction in [Step 10-2] are different depending on the starting materials, but are not particularly limited as long as they are the same conditions as in this reaction, and are known in many documents. (For example, J. Org. Chem., 71, 9548, described in 2006) can be used.

  The isothiocyanate compound (g-2) is commercially available, or can be easily prepared by a reaction known to those skilled in the art, for example, by reacting a commercially available aniline compound with thiocarbonyldiimidazole or thiophosgene.

  The cyclization reaction in [Step 10-3] varies depending on the starting materials, but is not particularly limited as long as it is the same as the reaction-like conditions, and is a known method (for example, Rev. Room. Chim) described in many literatures. , 50, 19 pages, 2005) can be used.

  The cyclization reaction in [Step 10-4] varies depending on the starting material, but is not particularly limited as long as it is a condition like this reaction, and is a known method described in many literatures (for example, Eur. J. Med). Chem., 42, 152, 2007).

  The 2-methylisothiourea compound (g-3) is commercially available or can be easily prepared by a reaction known to those skilled in the art, for example, by reacting methyl iodide with a commercially available thiourea compound.

[General production method-6]
A typical [General production method-6] of the compound of the general formula (Ig) according to the present invention will be described below.

[Wherein, R ₁ , R ₂ , m, n, W 1 _, X _A and ring B have the same meaning as described above. ]

  [General production method-6] uses compound (a-1) as a starting material, and has imidazole in ring A in the bromoacetylation of [Step 11-1] and the cyclization reaction of [Step 11-2]. 1 shows an example of a method for producing a compound of the general formula [Ig].

  The bromoacetylation in [Step 11-1] varies depending on the starting material, but is not particularly limited as long as it is a condition like this reaction, and is a known method described in many literatures (for example, Bioorg. Med. Chem). Lett., 13, 2059, described in 2003).

The cyclization reaction in [Step 11-2] varies depending on the starting material, but is not particularly limited as long as it is a condition like this reaction. Chem., 41, 155, 2006).
In addition, the compound of a formula (g-4) is a well-known compound or a commercially available compound, or a compound which can be manufactured from these compounds by a conventional method.

[General production method-7]
A typical [General production method-7] of the compound of the general formula (Ih) and the compound of the general formula (Ii) according to the present invention will be described below.

[Wherein, R ₁ , R ₂ , m, n, W and ring B have the same meaning as described above. ]

  In the above [General production method-7], compound (a-8) is used as a starting material, and [Step 12-1] is subjected to hydroxyamidation and [Step 12-2] is subjected to cyclization reaction to [ 2,4] A method for producing the general formula (Ih) having oxadiazole, and further starting from the hydroxyamidine compound (a-14) as a starting material, the cyclization reaction of [Step 12-3] with [1 , 2, 4] shows an example of a method for producing a compound of general formula (Ii) having thiadiazole.

  The hydroxyamidination reaction in [Step 12-1] varies depending on the starting material, but is not particularly limited as long as it is a condition like this reaction, and is a known method described in many literatures (for example, Synth. Commun. 26, 4351, described in 1996).

  The cyclization reaction of [Step 12-2] is achieved by heating the hydroxyamidine compound (a-14) and the 2-methylisothiourea compound (g-3) in a solvent in the presence of a base. .

  The cyclization reaction of [Step 12-3] is achieved by heating the hydroxyamidine compound (a-14) and the isothiocyanate compound (g-2) in a solvent.

  As explained in detail above, the compounds of general formula [I] can be prepared according to general methods 1 to 7 for the compounds of the present invention, and also by other methods known per se to those skilled in the art. Can be manufactured. With respect to these production methods, examples described later can be referred to, and based on these examples, the compound of the general formula [I] can be easily produced by a method known per se to those skilled in the art.

The compound of the formula [I] of the present invention or a pharmacologically acceptable salt or ester thereof is effective for the treatment of diseases caused by Aβ, and also in pharmacokinetics, toxicity, stability, absorbability, etc. It is excellent.
The therapeutic agent for diseases caused by Aβ, which comprises the compound of formula [I] of the present invention or a pharmacologically acceptable salt or ester thereof as an active ingredient, can be formulated by a conventional method, Preferred dosage forms include, for example, tablets, powders, fine granules, granules, coated tablets, capsules, syrups, troches, inhalants, suppositories, injections, ointments, eye drops, eye ointments, dots Examples include nasal drops, ear drops, poultices, lotions and the like. For formulation, for example, excipients, binders, lubricants, coloring agents, flavoring agents, and stabilizers, emulsifiers, absorption promoters, surfactants, pH adjusters, preservatives as necessary. Antioxidants and the like can be used, and it can be formulated by a conventional method by blending components generally used as raw materials for pharmaceutical preparations. Examples of these components include animal and vegetable oils such as soybean oil, beef tallow and synthetic glycerides; hydrocarbons such as liquid paraffin, squalane and solid paraffin; ester oils such as octyldodecyl myristate and isopropyl myristate; Higher alcohols such as behenyl alcohol; silicone resin; for example, silicone oil; polyoxyethylene fatty acid ester, sorbitan fatty acid ester, glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene block copolymer, etc. Surfactants; for example, hydroxyethyl cellulose, polyacrylic acid, carboxyvinyl polymer, polyethylene glycol, polyvinyl pyrrolidone, Water-soluble polymers such as chilled cellulose; lower alcohols such as ethanol and isopropanol; polyhydric alcohols such as glycerin, propylene glycol, dipropylene glycol, and sorbitol; sugars such as glucose and sucrose; Examples thereof include inorganic powders such as aluminum magnesium and aluminum silicate, and purified water. Examples of the excipient include lactose, corn starch, sucrose, glucose, mannitol, sorbitol, crystalline cellulose, silicon dioxide, and the like, and examples of the binder include polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, gum arabic, tragacanth, gelatin, Shellac, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polypropylene glycol polyoxyethylene block polymer, meglumine, etc., as disintegrants, for example, starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, Calcium citrate, dextrin, pectin, carboxymethylcellulose / calcium and the like are lubricants such as magnesium stearate , Talc, polyethylene glycol, silica, hydrogenated vegetable oil, etc., which are allowed to be added to pharmaceuticals as colorants, flavourants include cocoa powder, mint brain, aroma powder, mint oil, dragonfly, For example, cinnamon powder is used.

  For example, oral preparations include compounds that are active ingredients, or salts or esters thereof, or hydrates and excipients thereof, and further, for example, binders, disintegrants, lubricants, coloring agents, flavoring agents, and the like. After the addition, for example, powders, fine granules, granules, tablets, coated tablets, capsules and the like are prepared by conventional methods. In the case of tablets / granules, for example, sugar coating or other appropriate coating may be used if necessary. In the case of syrups, injectable preparations, etc., for example, a pH adjusting agent, a solubilizer, an isotonic agent and the like, and if necessary, a solubilizing agent, a stabilizer and the like are added to prepare a preparation by a conventional method. Moreover, in the case of an external preparation, a manufacturing method in particular is not limited, It can manufacture by a conventional method. As a base material to be used, various raw materials usually used for pharmaceuticals, quasi drugs, cosmetics and the like can be used. For example, animal and vegetable oils, mineral oils, ester oils, waxes, higher alcohols, fatty acids , Silicon oil, surfactants, phospholipids, alcohols, polyhydric alcohols, water-soluble polymers, clay minerals, purified water, etc., and pH adjusters, antioxidants as necessary Chelating agents, antiseptic / antifungal agents, coloring agents, fragrances and the like can be added. Furthermore, components having a differentiation-inducing action, such as blood flow promoters, bactericides, anti-inflammatory agents, cell activators, vitamins, amino acids, humectants, keratolytic agents, and the like can be blended as necessary.

  The dosage of the therapeutic agent according to the present invention varies depending on, for example, the degree of symptoms, age, sex, body weight, dosage form / salt type, specific type of disease, etc. Per oral administration, about 30 μg to 10 g, preferably 100 μg to 5 g, more preferably 100 μg to 100 mg, and about 30 μg to 1 g, preferably about 30 μg to 1 g, of a compound of formula [I] or a pharmacologically acceptable salt thereof. Is administered in a dose of 100 μg to 500 mg, more preferably 100 μg to 30 mg, once or several times.

The compound of formula [I] or a pharmacologically acceptable salt or ester of the present invention is used for the treatment of diseases caused by amyloid beta, such as Alzheimer's disease, senile dementia, Down's syndrome or amyloidosis. You may use together with the compound which has a mechanism.
Specifically, for example, cholinesterase inhibitors (eg, donepezil, superzine A, tacrine, rivastigmine, galantamine); AMPA receptor antagonists (eg, 3- (2-cyanophenyl) -5- (2-pyridyl) -1-phenyl-1 1,2-dihydropyridine compounds such as 2-dihydropyridin-2-one); NMDA receptor antagonists (eg, memantine); acetylcholine-releasing stubrants (eg, priracetam; aniracetam); calcium channel agonists (eg, nefiracetam); Wenger (eg EGb 761); platelet activating factor antagonist (eg E Gb 761); platelet aggregation antagonists (eg EGb 761, triflusal); insulin sensitizers (eg rosiglitazone); peroxisome proliferator-activated receptor agonists (eg rosiglitazole); peroxisome proliferator-activated receptors Gamma agonists (eg, rosiglitazole); monoamine oxidase B inhibitors (eg, rasagiline, selegine, procaine); carnitine acetyl transferase stemrants (eg, levacecarine); NSAIDs (eg, triflusal, celecoxib-2; Growth factor agonists (eg, xaliproden, FPF 1070); beta-amyloid inhibitors (eg, tarenflurbil, tramiprosate, leuplorelin-D); immunomoderators (eg, tarenflurbil, immune globulin, icosapenteper) thruropine releasing hormone (eg, tartirelin); dopamine D2 receptor antagonist (eg, risperidone); serotonin 2 receptor antagonist (eg, risperidone); muscarinic M1 receptor agonist (eg, cevimeline); 1 adrenoceptor agonist (eg, modafinil); serotonin 3 receptor antagonist (eg, arosetron); dopamine D2 receptor agonist (eg, aripiprazole); dopamine D2 receptor antagonist (eg, aripiprazole); serotonin 1A receptor agonist (eg, aripiprazole) A serotonin 2A receptor antagonist (eg, aripiprazole); a glucoluticoid antagonist (eg, mipripristone); a progesterone antagonist (eg, mifepristone); an HMG-CoA reductase inhibitor (eg, atorvastatin, simvastatin); Phosphodiesterase inhibitors (for example, propofylline); acetylcholine receptor agonists (for example, choline alcoholate); transmembrane enhancers (for example, choline alfoscaterate); (Eg, dronabinol); angiogenesis inhibitors (eg, paclitaxel); immunosuppressive agents (eg, paclitaxel); tubulin antagonists (eg, paclitaxel); thromboxane A synthase inhibitors (eg, triflusal); Oxidants (eg, idebenone); alpha adrenergic receptor antagonists (eg, nicgoline); estrogen antagonists (eg, conjugated estrogens, trilostane); 3-beta hydroxysteroid dehydrogenase inhibitors (eg, trilostane); signal transduction pathway inhibitors (eg, trilostane) A melatonin receptor agonist (eg, ramelteon); an immunostimulant (eg, immunoglobulin, icosapentyl ester, procaine); an HIV entry inhibitor (eg, procaine); a sodium channel antagonist (eg, pro) microtubule inhibitors (eg, CPH 82); glycine NMDA agonists (eg, cycloserine); adenosine A1 receptor antagonists (eg, KW 3902); ATPase sturmurants (eg, triacetyluridine); mitochordrial function enhancers (eg, growth hormone releasing factor agonist (eg tesamoreline); butylcholine esterase inhibitor (eg bisnorcymserline); alpha adrenergic receptor antagonist (eg nicergoline); NO synthase type II inhibitor (eg arundic acid); Agent (eg PBT 2) An amyloid fibril formation inhibitor (eg TTP488, PF 4494700); a serotonin 4 receptor agonist (eg PRX 03140); a serotonin 6 receptor antagonist (eg SB 742457); a benzodiazepine receptor inverse agonist (eg radequinil); a Ca channel antagonist ( For example, a compound having a mechanism such as safinamide); a nicotine receptor agonist (eg, isproline); or a BACE inhibitor (eg, CTS 21166).

More specific compounds include, for example, donepezil, huperzine A, tacrine, rivastigmine, galantamine, paramracetam, aniracetam, nefiracetam, EGb761, rosiglecinece, rastiginece, ) -1-phenyl-1,2-dihydropyridin-2-one, tamampane, becampane, memantine, xaliproden, tarenflurbil, tramiprosate, leuplorelin-D, tartilelin, risperidone, cevimeline, mod afinil, alosetron, aripiprazole, mifepristone, atorvastatin, propentofylline, choline alfoscerate, FPF 1070 (CAS Number 143637-01-8), rimonabant, dronabinol, docosahexaenoic acid, paclitaxel, triflusal, idebenone, nicergoline, conjugated estrogens, trilostane, simvastatin, selegiline , Ramelteon, immunoglobulin, icosapentyl ester, procaine, CPH 82, cycloserin , KW 3902 (CAS Number 136199-02-5), triacetyluridine, estrogen dementia therapeutics (eg, MIGENIX, Vancouver, Canada, TP), Tesmorelin, Biznorms, 44. , SB 742457, radiquinil, safinamide, ispronicline, CTS 21166, Bapinezumab, NP 031112, (2S, 3aS, 7aS) -1 {[(R, R) -2-phenylcyclopropyl] carbonyl} -2-[(thiazolidine- 3-yl) Carboni ] Octahydro-1H-indole, citalopram, venlafaxine, levprorelin, pasterone, peptide T (CAS Number 53-43-0), besipidine, lexipaphant, Nr. 142935-03-3), nerispiridine, dexanabinol, sabcomline, GTS 21 (CAS Number 156223-05-1), CX 516 (CAS Number 154235-83-3), ABT 089 (CAS Number 161417a-03, PS17417-03-4) , Tesofenseine, S IB 1553A (i. e. , 4-[[2- (1-Methyl-yl-2-pyrrolidinyl) ethyl] thia] phenol), ladostigil, radiquinil, GPI 1485, ispronicline, arundic acid, MEM 1003 (ie, 3-isopropyl 5- (2-Methoxyl) 4- (2-chloro-3-cyanophenyl) -2,6-dimethylpyridine-3,5-dicarboxylase), V 3381 (ie, 2- (2,3-dihydro-) 1H-inden-3-ylamino) acetamide hydrochloride), farampator, paliloden, pasterone-paladin, urocortin, DP b99 (ie, 2,2 '-(ethylenedioxy) bis (2,1-phenylene) bis [N- [2- [2- (octylo Xyl) ethoxy] -2-oxoethyl] imino] bis (acetic acid)), capserod, DU 125530, bapenezumab, AL 108 (ie, L-Asparaginyl-L-alanyl-L-polyryl-L-valyl-L- seryl-L-isourecyl-L-propyl-L-glutamine), DAS 431, DEBIO 9902, DAR 100, mitoquinone, IPL 455903 (ie, 5 (S)-[3- (cyclopentyloxy) -4-methoxy) Phenyl] -3 (S)-(3-methylbenzyl) piperidin-2-one), E2CDS, PYM 50028, PBT 2, lecozotan, SB 742457, CX 717, AVE 1625 (ie, 1- (bis 4-chlorophenyl) methyl) -3-((3,5-difluorophenyl) (methylsulfonyl) methylene) azetidine), LY 450139 (ie, N2- [2 (s) -hydroxy-3-methylbutyryl]- N1- [3-methyl-2-oxo-2,3,4,5-tetrahydro-1H-3-benzazepin-1 (S) -yl] -L-alaninamide), EM 1421 (ie, 4). , 4 '-[(2R, 3S) -2,3-dimethylbutane-1,4-diyl] bis (1,2-dimethoxybenzene), SRN 001, TTP 488, PRX 03140, dimebolin, glycine-proline-glutamate , C105, AL 208, MEM 3454, AC 1202, L 830982, LY 451395 (i. e. , (R) -N- [2- [4 ′-(methylsulfonamidomethyl) biphenyl-4-yl] propyl] propane-2-sulfonamide), MK 0249, LY 2062430, diethylnorspermine, neboglamine, S 18986, SA 4503 (CAS Number 165377-44-6), GRI 1, S 17092 (ie, (2S, 3aS, 7aS) -1 {[(R, R) -2-phenylcyclopropyl] carbonyl} -2- [(Thiazolidin-3-yl) carbonyl] octahydro-1H-indole), SL 251188, EUK 189, R 1450, 6,6-dimethyl-3- (2-hydroxyethyl) thio-1- (thiazol-2-yl) ) -6,7-dihydro-2-benzothiophene-4 ( H) -ON, CERE 110, dexfaroxan, CAD 106, HF 0220, HF 0420, EHT 0202, VP 025, MEM 1414, BGC 2012259 (ie, N, N-Dimethylcarbamic acid, 4- [1 (S) -(Methylamino) -3- (4-nitrophenoxy) propyl] phenyl ester), EN 100, ABT 834, ABT 239 (ie, 4- [2- [2-[(2R) -2-methyl) Pyrrolidinyl] ethyl] -benzofuran-5-yl] benzonitrile), SGS 518, R 1500, C 9138, SSR 180711, alfatradiol, R 1577, T 817MA (ie, 1- [3- [2- (1-Benzothien-5-yl) ethoxy] propyl] aze Din-3-ol maleate), CNP 1061 (ie, 4-methyl-5- (2-nitrooxyethyl) thiazole), KTX 0101 (ie, sodium betahydroxybutyrate), GSK 189254 (Ie, 6- [3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo [d] azepin-7-yloxy] -N-methylnicotinamide), AZD 1080, ACC 001, PRX 07034, midazolam, R-phenserine, AZD 103 (CAS Number 488-59-5), SN 522, NGX 267 (CAS Number 503431-81-0), N-PEP-12, RN 1219, FGLL, AVE 8112, EV 101, NP 031112, MK 0752, M K 0952, LX 6171, PAZ 417, AV 965, PF 3084014, SYN 114, GSI 953, SAM 315, SAM 531, D-line, leptrinim potassium, BR 16A (CAS Number 149175-77-9), RPR 3 Number 190841-57-7), NXD 2858, REN 1654, CDD 0102, NC 1900 (CAS Number 132925-74-7), ciclosporin, NCX 2216 (i. e. , (E) -4- (nitrooxy) butyl 3- [4- [2- (2-fluorobiphenyl-4-yl) propanoyloxy] -3-methoxyphenyl] acrylate), NXD 3109, NXD 1191, ZSET 845 (Ie, 3,3-diphenylimidazo [1,2-a] pyridin-2- (3H) -one), ET 002, NT 13, RO 638695 (ie, [1,6- ( 1,6-dioxohexyl)] dipyrrolidine- (2R) -carboxylic acid), bisnorcymserine, BA 1016, XD 4241, EUK 207 (ie, (SP-5-13)-(acetato-κO) [13 , 16,19,22-tetraoxa-3,6-diazatricyclo [21.3.18,12] octacosa-1 (27), 2,6,8,1 , 12 (28), 23,25-octaene-27, 28-diolato (2-)-κN3, κN6, κO27, κO28] magnesium salt), LG 617 inhibitors, ZSET 1446, PAN 811, F 14413 (i.e. , 2- [5-Fluoro-2 (S) -methoxy-2,3-dihydro-1,4-benzodioxin-2-yl] -4,5-dihydro-1H-imidazole), FP 7832 (i. e., N- [2- (5-Methoxy-1-nitroso-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-amino-5- (4-chlorophenylethini) ) -4- (4-trans-hydroxycyclohexylamino) pyrimidine), DP 155,5-chloro-N- [3- [2- (dimethylamino) ethyl] -1H-indol-5-yl] naphthalene-2 -Sulfonamide, TAK 070, superzine, N- [2- (3,5-dimethyladamanto-1-yl) ethyl] acetamide hydrochloride, 6- [4-[(dimethylamino) methyl] -5-ethyl-2 -Methoxyphenyl] pyridin-2-amine, 4,6-diphenyl-3- (4- (pyrimidin-2-yl) piperazin-1-yl) pyridazine, N-[(1S, 2R) -3- (3 5-Difluorophenyl) -1-hydroxy-1-[(5S, 6R) -5-methyl-6- (neopentyloxy) morpholin-3-yl] propane- -Yl] acetamide hydrochloride, N-[(1R, 2S) -3- (3,5-difluorophenyl) -1-hydroxy-1-[(2R, 4R) -4-phenoxypyrrolidin-2-yl] propane -2-yl] -3-[(R) -2- (methoxymethyl) pyrrolidine-1-carbonyl] -5-methylbenzamide, R 1589, midafotel, phenserine, coloracetam, physostigmine, ciprialisant, nitroflurbiprofen, PPI 1019 (i . e. , (3α, 5β, 7α, 12α) -trihydroxycholan-24-oyl-L-leucyl-L-valyl-L-phenylalanyl-L-phenylalanyl-L-alanine), daspone, MDL 100453 (CAS12383er 7 ), NS 377, midifylline, propofol phosphate, metrifonate, c
eronapril, tenilsetam, sufoxazine, seglitide, ebirate, nebracetam, milacemide, iododorubicin, SM 10888 (CAS-1 129 297-21-8), U 80816 (CAS 13 129 ber 21-8) ), SUT 8701 (CAS Number 12353577-73-1), apovincamine, FR 121196 (CAS Number 133920-65-7), LY 274614 (CAS Number 136109-04-1), CL 27538 (CAS 115 1655-2) ), Igmesine, K 725 9 (CAS Number 133367-88-6), vinconate, itasetron, CL 287663 (CAS Number 125109-98-0), WAY 100299 (CAS Number 136013-69-9), SR 46559A (CAS Number 1333733-3733) , 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) benzoyl) amino] Oxahyrodazepin-2-one), RU 33965 (CAS Number 122321-05-5), SDZ 210086 (ie, (−)-1 ′, 2 (S) -dimethylspiro [1,3-dioxane -4,4'-piperidine]), L 688660 (CAS Number 144860-79-7), L 689560 (CAS Number 139051-78-8), ST 618 (ie, 1- (6,7-dimethoxy) -1,2,3,4-tetetrahydro-2-naphthyl) -4-hydroxypyrrolidin-2-one), U 74500A (CAS Number 110101-65-0), GEA 857 (CAS Number 120493-42-7) , BIBN 99 (CAS Number 145301-48-0), DX 9366 , ONO 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), azeet , MR 16728 (CAS Number 147614-21-9), dabelotine, MDL 102503 (i. e. , 8- [1 (R) -methyl-2-phenylethyl] -1,3-dipropyl-7H-xanthine), PD 141606 (ie, (±)-(Z) -3- (3-phenyl) 2-propynyloxyimino) -1-azabicyclo [2.2.1] heptane), SNK 882 (CAS Number 152221-12-0), L 696986 (CAS Number 141553-5-5-9), tazomelline, LY 235959 ( CAS Number 137433-06-8), 2- (2-Thioxopyrrolidin-1-yl) acetamide, AK 30 NGF, ABT 418 (CAS Number 147402-53-7), itameline, HUP 13, sipopirdine, KST 5452 ( CAS Number 15799 -88-4), TJ 54, U 92798 (ie, 7- [4- [Bis (4-fluorophenyl) methyl] perhydro-1,4-diazepin-1-ylmethyl] -4-isopropyl-2 -Methoxy-2,4,6-cycloheptatrien-1-one), U 92032 (CAS Number 142223-92-5), 3- (sulfamoyloxy) estradia-1,3,5 (10) -triene -17-on, P 11012 (CAS Number 164723-36-8), A 82695 (CAS Number 147388-86-1), FR 76659 (CAS Number 116904-25-7), axifylline, CX 417, 7 MEOTA (CAS Number 5778-80-3), BU 4514N (CA Number 151013-39-7), pregnenolone, mexidol, ST 857 (CAS Number 154755-62-2), RU 49041 (CAS Number 123828-80-8), RU 35929 (CAS Number 111711-87-8), P , P 128 (CAS Number 157716-52-4), eurystatin A, eurystatin B, LK 12, NBI 108, NBI 107, NBI 117, L 705106, bacoside A + B, crusenamide, SM 21-2 (CAS 15-2 N56 51 2), adaptide, RS 17017 (i. e. , 1- (4-amino-5-chloro-2-methoxyphenyl) -5- (1-piperidinyl) -1-pentanone hydrochloride), AF 150 (S) (ie, (S)-[1 -Methyl-piperidine-4-spiro- (2'-methylthiazoline)]), RO 153505 (CAS Number 7877-13-13), PV 113 (ie, 1,2,3,4-tetrahydropyrrole) [1,2-a] -pyrazine), arisugacin, A 98284 (ie, 2 (R)-(3-methylxazol-5-yl) quinuclidine), AP 5 (CAS Number 136694-85-0) ), BD 1054, SDZ NDD 094 (ie, bis- (2- (2-methylimidazol-1-yl] methyl) -pyridine-tris (hydrogen-fumaray) G), AZ 36041 (CAS Number 173324-76-0), quilostigmine, A 84543 (ie, 3- [1-methylpyrrolidin-2- (S) -ylmethoxy] pyridine fumarate), BTG 4247 (i E., (2- [2-Chloroethoxy [4- (dimethylamino) phenyl] phosphoryl] -acetohydrazine), CGP 50068 (CAS Number 158647-49-5), cerebraclast, desferri-nordoxaneamine, isolichenan, MHP 133 (Ie, 3- (N, N-dimethoxycarbamoyloxy) -1-methyl-2- (4-phenyl-semicarbazomethyl) pyridium chloride), FR 152558 (CAS Number 1 1098-08-7), 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 1233829-33-4), PD 151832 (CAS Number 149929-39-5), UCL 1199 (ie, 4- [2-[(5-nitro Pyridin-2-ylsulfanyl) ethyl] -1H-imidazole), isovanihuperzine A, SIB 1765F (CAS Number 179120-52-6), JWS USC 751X (i. e. , 3-[[[2-[[(5-Dimethylaminoethyl) -2-furanyl] methyl] thio] ethyl] amino] -4-nitropyridazine), GR 175737 (ie, 3- (4- Chlorobenzyl) -5- [2- (1H-imidazol-4-yl) ethyl] -1,2,4-oxadiazole), KS 505A (CAS Number 131774-53-3), ZTTA 1 (i.e. , N-benzyloxycarbonyl-thiopropyl-thiopropynal-dimethylacetal), AGN 190837 (CAS Number 136527-40-7), P 10358 (188240-59-7), WAY 131256 (CAS Number 174001-71-9). ), DBO 83 (ie, 3- (6-chloropyrazin-3-yl) -diaza Bicyclo [3.2.1] octane dihydrochloride monohydrate), FUB 181 (CAS Number 152029-80-6), RJR 2557, WSU 2088, LVV-haemorphin-7, M 40 (ie, galanin [1-12] -Pro3- (Ala-Leu) ₂ -Ala-NH ₂ ), SIB 1757, SKF 74652 (ie, [5-chloro-2- (4-methoxyphenyl) -3-benzofuranyl ] [4- [3- (Dimethylamino) -propoxy] phenyl] methanone), CGP 71982, SCH 57790 (ie, 4-cyclohexyl-alpha- [4-[[4-methoxyphenyl] sulfinyl] phenyl] -1-piperazine acetonitrile), Putrescine-D-YiAbeta11 DU 14 (ie, p-O- (sulfamoyl) -N-tetradecanoyltyramine), CLZ 4, SL 340026, PPRT 424, ciproxifan, UR 1827 (ie, 2- (1-benzylpiperidine) -4-yl) -1- [4- (5-methylpyrimidin-4-ylamino) phenyl] -1-ethanone), caproctinamine, TGS 20 (ie, L-pyroglutamyl-D-alanine amide), PG 9 (ie, alpha-tropanyl 2-[(4-bromo) phenyl] propionate), TEI 3356 (ie, (16S) -15-deoxy-16-hydroxy-16-methyl-9- ( O) -methano-DELTA6 (9alpha) -prostaglandin I1), LY 3920 98 (i. e. , Thiophene, 3-[(2-Methylethyl-2) sulfonylaminopropyl-2] phenyl-4-yl-), PG 1000, DM 232, NEPP 11 (ie, 12-iso-15-deoxy- 18- (4-methyl) phenyl-13,14-dihydro-delta7-prostaglandin A1 methyl ester), VA 100 (ie, (2,3-dihydro-2-[[(4-fluorobenzoyl ) Amino] ethyl] -1-methyl-5-phenyl-1H-1,4-benzodiazepine), VA 101 (ie, (2,3-dihydro-2-[[(2-thienylcarbonyl) amino]) Ethyl] -1-methyl-5-phenyl-1H-1,4-benzodiazepine), NC 111585 (ie, (3S) -1,3-Bis- [3-[(3- Zabicyclo [2.2.2] octanyl) -1,2,5-thiadiazol-4-yloxy] -1-propyn-1-yl] benzene, 2L-(+)-tartate), IN 201, imoproxifan, kanokodiol, picoside I, picoside II, DM 235 (ie, 1- (4-benzoylpiperazin-1-yl) propan-1-one), monoclonal antibody 10D5, JLK2, JLK 6, JLK 7, DAPT (ie , N- [N- (3,5-difluorophenacetyl) -L-alanyl] -S-phenylglycine t-butyl ester), huperine X, SGS 111 (ie, (S) -ethyl 2- [1- (2-Phenylacetyl) pyrrolidine-2-carboxamide] acetate ), NP 7557, C 9136, C 7617, R 1485, rofecoxib, velincrine, montilelin, lazabemide, ORG 2766 (CAS Number 50913-82-1).
), Sabeluzole, adafenoxate, CAS Number 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 76820-40-1), BMS 181168 (CAS Number 123259-91-6), BY 1949 (CAS) number 90158-59-1), AWD 5239 (CAS Number 109002-93-9), YM 796 (171252-79-2), aloracetam, CI 933 (CAS Number 91829-95-7), ST 793 (CAS Number 99306) -37-3), cebaracetam, zifrosilone, talsaclidene, albumine, JTP 2942 (148152-77-6), OPC 14117 (CAS Number 103233-65-4), elziverine, AP 521 (ie, N. (1. , 3-Benzodioxol-5-ylmethyl) -1,2,3,4-tetrahydro [1] benzothieno [2,3-c] pyridine-3 (R) -carboxamide salt Salt), S 8510 (CAS Number 151466-23-8), JTP 4819 (CAS Number 1622203-65-8), icopezil, SC 110, FK 960 (CAS Number 133920-70-4), DMP 543 (CAS Number 16058) -45-4), ganstigmine, CI 1017 (ie, (R)-(-)-(Z) -1-azabicyclo [2.2.1] heptan-3-one, O- (3- ( 3'-methoxyphenyl) -2-propionyl) -oxime maleic acid), T 82 (ie, 2- [2- (1-benzylpiperidin-4-yl) ethyl] -2,3-dihydro-9 -Methoxy-1H-pyrrolo [3,4-b] quinolin-1-one 1/2 fumarate), NGD 971, va ccine of Aspartyl-alanyl-glutamyl-phenylalanyl-arginyl-histidyl-aspartyl-seryl-glycyl-tyrosyl-glutamyl-valyl-histidyl-histidyl-glutaminyl-lysyl-leucyl-valyl-phenylalanyl-phenylalanyl-alanyl-glutamyl-aspartyl-valyl- glycyl-seryl-asparaginyl-lysyl-glycyl-alanyl-isoleucyl-isolycyl-lycyl-leucyl-methyl-valyl-glycyl-valyl-valyl isoleucyl-alanine, PBT 1 (CAS Number 130-26-7), TCH 346, FK 962 (i. e. , N- (1-acetylpiperidin-4-yl) -4-fluorobenzamide), voxergolide, KW 6055 (CAS Number 63233-46-5), thiopicarpine, ZK 93426 (CAS Number 89592-45-0), SDZ NVI 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-oxazino [6,5-b] indol-6-yl ester-L-tartrate), gedocarni 1, terbequinil, HOE 065 (CAS Number 123060-44-6), SL 650102, GR 2503035, ALE 26015, SB 271046 (ie, 5-chloro-N- (4-methoxy-3-piperazine-1- Yl-phenyl) -3-methyl-2-benzothiophenesulfonamide), iAbeta5, SCH 211803 (ie, Piperidine, 1- [1- (3-methyl-2-aminophenyl) carbonylpiperidin-4-yl ] -4-[(3-chlorophenyl) sulfonylphenyl-4] methyl-), EVT 301, alpha-Linolenic acid / linoleic acid, Kamikihi-To, siagoside, FG 7142 (CAS Number 7) 538-74-6), RU 47067 (CAS Number 11711-92-3), RU 35963 (CAS Number 139886-03-6), FG 7080 (CAS Number 10032-18-1), E 2030 (CAS Number 142007-). 70-3), transforming growth factor beta-1, A 72055 (ie, 2 ′, 1-dimethylspiro [piperidine-4,5′-oxazolidine] -3′-carboxaldehyde), NS 626 dimiracetam, GT 3001, GT 2501, GT 2342, GT 2016 (CAS Number 152241-24-2), ORG 20091 (CAS Number 141545-50-8), BCE 001 (CAS Number 9567) -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 (i. e. , 2- [4,8-Dimethyl-3 (E), 7 (E) -monoadienyl] -3,5-dihydroxy-2-methyl-3,4,7,9-tetrahydro-2H-fluoro [3,4 -H] -1-benzopyran-7-one), MF 247 (ie, N- [10- (dimethylmino) decyl] carbamic acid (3aS, 8aR) -1,3a, 8-trimethyl-1,2 , 3,3a, 8,8a-hexahydropyrrolo [2,3-b] indol-5-yl ester), JTP 3399 (ie, N-benzyl-2 (S)-[2 (S)- (Phenoxyacetyl) pyrrolidin-1-ylcarbonyl] pyrrolidine-1-carboxamide), KF 17329, thioperamide, F 3796 (ie, 1- [2- (1-benzylpiperidin-4-yl) ethyl -3- [3,4- (methylene-dioxy) benzoyl] thiourea), GT 4001, GT 4002, FPL 14995 (CAS Number 123319-03-9), RU 34332 (CAS Number 136157-58-5), SR 96777A (CAS Number 115767-94-7), SIB T1980, NS 649 (CAS Number 146828-02-6), PD 142505 (CAS Number 149929-08-8), GYKI 52466 (CAS Number 102771-26-6) 246173 (CAS Number 159723-57-6), SCH 50911 (CAS Number 160415-07-6), Z 4105 (CAS Number 119737-5) 2-9), RS 67333 (CAS Number 168986-60-5), NS 1546, ZM 241385 (CAS Number 139180-30-6), RO 249975 (ie, [1S, 3S (2'S), 5R] -3- (1-benzyl-5-oxopyrrolidin-2-ylmethyl) -5- (1H-imidazol-5-ylmethyl) cyclohexane-1-acetamide), AF 185 (ie, 8-methyl- 3- (2-propynyl) -1,3,8-triazaspiro [4,5] decane-2,4-dione), CEP 427, CX 423, CX 438, CX 480, CDP-ethanolamine, GT 4003, GT 4011 , GT 5011, MS 430 (CAS Number 122113-44-4), MBF 37 (I. e. , [3,3-Bis (hydroxymethyl) -8-hydroxy-3,4-dihydro-2H-1,4-benzoxazin-5-yl] [3 ′, 5′-dihydroxy-4 ′-(2-oxo -2-phenylethoxy) phenyl] methanone), NGD 187 (CAS Number 163565-48-8), DUP 856, MR 3066, MF 8615 (ie, 5-amino-6-chloro-4-hydroxy-3) , 4-dihydro-1H-thiopyrano- [3,4-b] quinolinone), himbacine, ABS 300, RJR 2403 (CAS Number 538-79-4), MF 268 (CAS Number 174721-00-7), RO 465934 (Ie, N, N-dimethylcarbamic acid 3- (2-cyclohexyl) -2,3,3a, , 5,9b-Hexahydro-1H-benzo [e] indol-6-yl ester), NS 393, RGH 2716 (CAS Number 136406-68-4), WIN 678702 (12,12-bis (3-furyl)- 6,11-dihydro-6,11-ethanobenzo [b] quinolizinium chloride), RS 66252 (ie, 1-butyl-2-[(2 ′-(2H-tetrazol-5-yl) -biphenyl) -4-yl) methyl] -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, P 26 ( AS Number 152191-74-7), RGH 5279 (ie, (-)-(13aR, 13bS) -13a-ethyl-2,3,5,6,13a, 13b-hexahydro-1H-indolo [3 , 2,1-de] pyrido [3,2,1-ij] [1,5] naphthyridine-12-carboxylic acid 2-acetoxyethyl ester), AIT 083, CeNeS, estradiol (ie, 1, 3) , 5 (10) -estraditriene-3,17beta-diol), WAY 132983 ((3R, 4R) -3- (3-hexasulfanylpyrazin-2-yloxy) -1-azabicyclo [2.2.1] Heptane hydrochloride), ABS 205, ABS 401, SX 3507 (i. e. , 3- (3-propyl-1,2,4-oxadiazol-5-yl) quinoxalin-2 (1H) -one), ARR 17779 (ie, (−)-spiro [1-azabicyclo [ 2.2.2] octaene-3,5-oxazolidine] -2-one), XE 991 (ie, 10,10-bis (4-pyridylmethyl) anthracen-10 (9H) -one), phenethylnorcymerineline. , RO 657199, RJR 1781 (ie, R (+)-2- (3-pyridyl) -1-azabicyclo [2.2.2.] Octane), RJR 1782 (ie, S (- ) -2- (3-pyridyl) -1-azabicyclo [2.2.2.] Octane), gilatide, tolserine, TC 2559 (ie, (E) -N-methyl). 4- [3- (5-ethoxypyridin) yl] -3-buten-1-amine), ER 127528 (ie, 1- (3-fluorobenzyl) -4-[(2-fluoro-5, 6-dimethoxy-1-indanon-2-yl) methyl] piperidine hydrochloride), thiatoserine, targacept, axonyx, cymserine, thiacymaserine, monoclonal antibody 266, Apan-CH, DP 103, SPI 339 (i.e. [3- (4-oxo-4,5,6,7-tetrahydroindol-1-yl) propionylamino] benzoic acid ethyl ester), S 37245 (ie, 4- (1,4-benzodioxane- 5-yl) -1- [3 (S) -hydroxy-5-nitro-in N-2-yl] -piperazine), LLG 88, AZD 2858, trometamol, AN 240, NG 002 (ie, 5-hydroxy-5- (2-hydroxy-1-methylethyl) -4-methoxyfuran. -2 (5H) -one), UCB 29427 (ie, 2-cyclopropyl-4- (cyclopropylamino) -6- (morpholino) -1,3,5-triazine), TRH-SR, RO 401641 (CAS Number 122199-02-4), MPV 1743AIII (CAS Number 150586-64-4), IDRA 21 (CAS Number 225033-72-6), CEP 431, ACPD (CAS Number 67684-64-4), CT 3577 (i. e. , 3,7-dimethyl-1- [11- (3,4,5-trimethoxybenzylamino) -11-oxoundecyl] xanthine), CT 2583, NXD 9062, Desferri-nordanamine, DP b99, PBT 1, T 817MA , Alfradidiol (CAS No. 57-91-0), AL 108, SL 650102, RS 67333 (CAS No. 168986-60-5), RS 17017, SGS 518, SYN 114, SB 271046, RO 657199, PRX 07034, Suritozole (CAS No. 110623-33-19), Terbequinil (CAS No. 1113079-82-6), FG 7142 (CAS No. 78538-74-6). RU 34332 (CAS No. 136157-58-5), SX 3507, RO 153505 (CAS No. 78771-1-13-8), RU 33965 (CAS No. 122321-05-5), S 8510 (CAS No. 151466-) 23-8), Sabeluzole (CAS No. 104383-17-7), Cerebroblast (CAS No. 118790-71-9), NS 626, NS 649 (CAS No. 146828-02-6), U 92032 (CAS No. .142223-92-5), MEM 1003, U 92798, RGH 2716 (CAS No. 133406-68-4), Safinamide (CAS No. 133865-89-1), AZD 0328, MEM 63908, ABT 4 8 (CAS No. 147402-53-7), ARR 17779, RJR 2403 (CAS No. 538-79-4), TC 2559, A 82695 (CAS No. 147388-86-1), A 84543, A 98284 DBO 83, RJR 2557, SIB 1765F (CAS No. 179120-52-6), GTS 21 (CAS No. 156223-05-1), MEM 3454, SIB 1553A, EVP 6124, SSR 180711, ABT 089 (CAS No. 161417-03-4), ABT 107, ABT 560, TC 5619, TAK 070, N-[(1S, 2R) -3- (3,5-difluorophenyl) -1-hydroxy-1-[(5S, 6R ) -5-Methyl-6- (neopentyloxy) Ruphorin-3-yl] propan-2-yl] acetamide hydrochloride, 6-fluoro-5- (2-fluoro-5-methylphenyl) -3,4-dihydropyridine, 2-amino-6- [2- (3 '-Methoxybiphenyl-3-yl) ethyl] -3,6-dimethyl-5,6-hydroxypyrimidin-4 (3H) -one, AZD 1080, ARA 014418, XD 4241, Z 321 (CAS No. 130849-58) -0), ONO 1603 (CAS No. 114668-76-7), JTP 3399, Eurystatin A (CAS No. 137563-63-4), Eurystatin B (CAS No. 137563-64-5), P 128 (CAS) No. 157716-52-4), Y 29794 (CAS No. 129184-48-1), ZTTA 1, JTP 4819 (CAS No. 162203-65-8), Monoclonal antigen 266, duloxetine, escitaloplexate, fluoxetine, fluoxetine paroxetine, sertraline, dapoxetine, desvenlafaxine, sibutramine, nefazodone, milnaciplan, desipramine, duloxetine, or bifaffinine.

Hereinafter, the present invention will be described in more detail with reference to examples. However, these are illustrative, and the therapeutic agents for diseases caused by Aβ according to the present invention are not limited to the following specific examples. It is not limited. Those skilled in the art can make various modifications to the scope of the claims of the present specification as well as the following reference examples and examples, and the present invention can be implemented to the maximum extent. It is included in the scope of claims.
When an example compound has a stereoisomer and the absolute configuration is not determined, the compound name and the structural formula to which optical rotation is given in the following examples may not necessarily correspond in order.

The following abbreviations are used in the following examples.
DMF: N, N-dimethylformamide THF: Tetrahydrofuran EDC: 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride HOBT: 1-hydroxybenzotriazole IPEA: diisopropylethylamine TEA: with particular reference to triethylamine chromatography If not, BW-300 manufactured by Fuji Silysia was used as the carrier.

Production Example 1
Synthesis of 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) pyridine-2-carbonitrile

Synthesis of N- (6-bromo-2-methoxypyridin-3-yl) formamide

Acetic anhydride (203 mL) was added dropwise to formic acid (204 mL) under water cooling, and the mixture was stirred at the same temperature for 25 minutes. To this reaction mixture, 6-bromo-2-methoxypyridin-3-amine powder (CAS # 89466-18-2, 146 g) was added over 10 minutes, and then the reaction solution was stirred at the same temperature for 30 minutes. The water bath was removed, and tert-butyl methyl ether (300 mL) and n-heptane (500 mL) were successively added dropwise to the reaction solution, and then the reaction solution was stirred for 30 minutes. The precipitated powder was collected by filtration. The obtained powder was pulverized in a mortar, washed with tert-butyl methyl ether, and dried under reduced pressure to obtain 137.4 g of the title compound.
The combined filtrate and washings were then concentrated under reduced pressure. The residue was triturated with tert-butyl methyl ether and dried under reduced pressure to give 21.9 g of the title compound. The physical properties of this product are as follows.
¹ H-NMR (CDCl ₃ ) δ (ppm): 4.03 (s, 3H), 7.08 (d, J = 8.0 Hz, 1H), 7.61 (brs, 1H), 8.47- 8.51 (m, 2H).

Synthesis of N- (6-bromo-2-methoxypyridin-3-yl) -N- (2-oxopropyl) formamide

To a suspension of N- (6-bromo-2-methoxypyridin-3-yl) formamide (159.3 g), cesium carbonate (359 g) and potassium iodide (11.4 g) in DMF (800 mL) over 7 minutes After dropwise addition of chloroacetone (82 mL), the reaction solution was stirred at room temperature for 1 hour and 20 minutes. The reaction solution was concentrated under reduced pressure. Ethyl acetate and water were added to the resulting residue, and the organic layer was partitioned. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 215.2 g of the title compound. The physical properties of this product are as follows.
¹ H-NMR (CDCl ₃ ) 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 6-bromo-2-methoxy-3- (4-methyl-1H-imidazol-1-yl) pyridine

A suspension of ammonium acetate (267 g) and N- (6-bromo-2-methoxypyridin-3-yl) -N- (2-oxopropyl) formamide (199 g) in glacial acetic acid (400 mL) Stir for 10 minutes. The reaction solution was returned to room temperature, and ethyl acetate and ice water were added to the reaction solution, followed by ice cooling. Subsequently, concentrated aqueous ammonia (500 mL) was added dropwise, and then the organic layer was partitioned. The obtained organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and then the organic layer was subjected to short silica gel column chromatography (carrier: Wakogel ^™ Wako Pure Chemical Industries, Ltd. C-200; elution solvent) Ethyl acetate). The elution fraction was concentrated. The obtained residue was triturated with ethyl acetate-tert-butyl methyl ether and dried under reduced pressure to give 107.7 g of the title compound.
The trituration mother liquor was then concentrated. The obtained residue was purified by silica gel column chromatography (carrier: Wakogel ^™ C-200; elution solvent: toluene-ethyl acetate system). The target fraction was concentrated. The resulting residue was triturated with tert-butyl methyl ether and dried under reduced pressure to give 12.9 g of the title compound.
The physical properties of this product are as follows.
¹ H-NMR (CDCl ₃ ) 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-methyl-1H-imidazol-1-yl) pyridine-2-carbonitrile

To a suspension of 6-bromo-2-methoxy-3- (4-methyl-1H-imidazol-1-yl) pyridine (50 g) and zinc (II) cyanide (35 g) in N-methylpyrrolidone (400 mL), Tetrakis (triphenylphosphine) palladium (0) (8.5 g) was added, and the mixture was stirred at 100 ° C. for 1 hour and 10 minutes. The reaction solution was added dropwise to a stirred mixed solution of ice water (1.5 L) and concentrated aqueous ammonia solution (150 mL). The precipitated powder was filtered. The obtained powder was washed with water and then air-dried overnight to obtain 56.5 g of the title compound. The physical properties of this product are as follows.
¹ H-NMR (CDCl ₃ ) 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).

Production Example 2
Synthesis of 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) pyridine-2-carboxylic acid

Lithium hydroxide was added to a suspension of 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) pyridine-2-carbonitrile (52.4 g) obtained in Production Example 1 in water (464 mL). Powder (13 g) was added and heated to 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 (100 mL × 4). Concentrated hydrochloric acid was added to the filtrate under ice cooling to adjust the pH to 4-5. The precipitated powder was collected by filtration. The obtained powder was washed with water and air-dried for 3 days to obtain 51.9 g of the title compound. The physical properties of this product are as follows.
¹ H-NMR (DMSO-D ₆ ) 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).

Production Example 3
Synthesis of N ′-[6-methoxy-5- (4-methyl-1H-imidazol-1-yl) pyridine-2-carbonyl] hydrazinecarboxylic acid tert-butyl ester

6-methoxy-5- (4-methyl-1H-imidazol-1-yl) pyridine-2-carboxylic acid (546 mg) and tert-butylcarbazate (371 mg) DMF (10 mL) obtained in Production Example 2 To the solution was added IPEA (2 mL), HOBT (632 mg), and EDC (896 mg) and the reaction was stirred at room temperature for 20 hours. Brine was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH ^TM manufactured by Fuji Silysia Chemical Ltd .; elution solvent: ethyl acetate-heptane) to obtain 740.7 mg of the title compound. The physical properties of the title compound are as follows.
ESI-MS; m / z 348 [M ⁺ + H].

Production Example 4
6-methoxy-5- (4-methyl-1H-imidazol-1-yl) pyridine-2-carboxylic acid hydrazide and 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) pyridine-2- Synthesis of carboxylic acid hydrazide hydrochloride

Synthesis of N '-[6-methoxy-5- (4-methyl-1H-imidazol-1-yl) pyridine-2-carbonyl] hydrazinecarboxylic acid benzyl ester

To a DMF (184 mL) solution of 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) pyridine-2-carboxylic acid (51.9 g) and IPEA (44 mL) obtained in Production Example 2, Benzyl carbazate (27.8 g), HOBT (24.8 g) and EDC (35.4 g) were sequentially added, and the mixture was stirred at room temperature for 6 hours and 30 minutes. Ethyl acetate, ice water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction solution, and the organic layer was partitioned. The obtained organic layer was dried over anhydrous magnesium sulfate and filtered through a pad of NH-silica gel. The resulting filtrate was concentrated under reduced pressure. Ethyl acetate was added to the resulting residue, and the powder was collected by filtration. The obtained powder was air-dried to obtain 28.4 g of the title compound.
Furthermore, the extracted aqueous layer was re-extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered through a pad of NH-silica gel. The resulting filtrate was concentrated under reduced pressure. Ethyl acetate was added to the resulting residue, and the powder was collected by filtration. The obtained powder was air-dried to obtain 9.15 g of the title compound. The physical properties of this product are as follows.
¹ H-NMR (CDCl ₃ ) 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-imidazol-1-yl) pyridine-2-carboxylic acid hydrazide and 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) pyridine-2- Synthesis of carboxylic acid hydrazide hydrochloride

To a solution of N ′-[6-methoxy-5- (4-methyl-1H-imidazol-1-yl) pyridine-2-carbonyl] hydrazinecarboxylic acid benzyl ester (28.4 g) in methanol (300 mL), 10% palladium Carbon (50% wet, 2.84 g) was added and hydrogenated at medium pressure (2-3 atm) for 5 hours. After adding chloroform (600 mL) to the reaction solution, palladium carbon was removed by Celite filtration. The filtrate was concentrated under reduced pressure to obtain 19.5 g of a free form of the title compound. The physical properties of this product are as follows.
¹ H-NMR (CDCl ₃ ) δ (ppm): 2.30 (d, J = 1.2 Hz, 3H), 4.06 (s, 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 hydrogenation reaction was performed in a chloroform-methanol mixed solvent and the same operation was performed to obtain the hydrochloride of the title compound. The physical properties of this product are as follows.
¹ H-NMR (CDCl ₃ ) 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 (d, J = 7.6 Hz, 1H), 8.69. (Brs, 1H).

Production Example 5
Synthesis of 2-bromo-1- [6-methoxy-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

6-Bromo-2-methoxy-3- (4-methyl-1H-imidazol-1-yl) pyridine (2.66 g) obtained in Production Example 1 and bis (triphenylphosphine) palladium (II) chloride (350 mg) ) Was added to a suspension of dioxane (25 mL), and 1-ethoxyvinyltri-n-butyltin (3.7 mL) was added, followed by stirring at 100 ° C. for 5 hours and 45 minutes. After allowing the reaction solution to cool to room temperature, the reaction solution was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (carrier: Wakogel ^™ C-200, heptane: ethyl acetate 1: 0 → 9: 1 → 3: 1 → 1: 1). The powder obtained by concentrating the objective fraction was triturated with diethyl ether-n-hexane and dried under reduced pressure to obtain 1.57 g of the title compound. The mother liquor was then concentrated to give 858 mg of the title compound. The physical properties of this product are as follows.
¹ H-NMR (CDCl ₃ ) 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-1- [6-methoxy-5- (4-methyl-1H-imidazol-1-yl) pyridin-2-yl] ethanone dihydrochloride

To a solution of 6- (1-ethoxyvinyl) -2-methoxy-3- (4-methyl-1H-imidazol-1-yl) pyridine (791 mg) in THF (15 mL) -water (2 mL) at room temperature, N- Bromosuccinimide (543 mg) was added and stirred at the same temperature for 15 minutes. A saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. The obtained organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Anhydrous magnesium sulfate was filtered off from the organic layer, and 4N hydrogen chloride-ethyl acetate solution was added to the obtained filtrate, and then the filtrate was concentrated under reduced pressure to obtain 1.06 g of the title compound. The physical properties of this product are as follows.
^{ESI-MS; m / z 310} [M + + H-2HCl].

Production Example 6
Synthesis of N- (2,5-dimethylphenyl) -N′-hydroxyguanidine

A solution of N-cyano-2,5-dimethylaniline (CAS # 10533-09-2,468 mg), hydroxylamine monohydrochloride (334 mg) and potassium carbonate (885 mg) in ethanol was refluxed for 30 minutes. After returning to room temperature, water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane → ethyl acetate → ethyl acetate: methanol 85:15) to obtain 56.0 mg of the title compound. The physical properties of this product are as follows.
ESI-MS; m / z 180 [M ⁺ + H].

Production Example 7
Synthesis of N-hydroxy-6-methoxy-5- (4-methyl-1H-imidazol-1-yl) pyridine-2-carboxamidine

According to the synthesis method of Production Example 6, from the 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) pyridine-2-carbonitrile (50.0 mg) obtained in Production Example 1, the title 46 mg of compound was obtained. The physical properties of this product are as follows.
¹ H-NMR (CDCl ₃ ) 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 = 7.6 Hz, 1H), 7.82 (S, 1H).

Production Example 8
Synthesis of 2-methoxy-3- (4-methyl-1H-imidazol-1-yl) -6-tributylstannylpyridine

6-Bromo-2-methoxy-3- (4-methyl-1H-imidazol-1-yl) pyridine (10 g) and hexa-n-butylditine (31.8 mL) obtained in Production Example 1 were dissolved in toluene (300 mL). ), Tetrakis (triphenylphosphine) palladium (2.2 g) was added, and the mixture was heated to reflux for 4 hours under a nitrogen atmosphere. After allowing to cool, the reaction solution was filtered through Celite to remove insoluble matters, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography and then by silica gel column chromatography to obtain the title compound (5.4 g). The physical properties of this product are as follows.
¹ H-NMR (CDCl ₃ ) 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), 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).

Production Example 9
Synthesis of N- (2,5-dimethylphenyl) -2-{[6-methoxy-5- (4-methyl-1H-imidazol-1-yl) pyridin-2-yl] carbonyl} hydrazinecarbothioamide

  6-methoxy-5- (4-methyl-1H-imidazol-1-yl) pyridine-2-carboxylic acid hydrazide (119 mg), TEA (100 μL), 2,5-dimethylphenylisothiocyanate obtained in Production Example 4 A mixed solution of natto (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 obtain 100 mg of the title compound.

Production Example 10
Synthesis of 1- (5-diethylamino-2-methylphenyl) -2-methylisothiourea hydroiodide

To a solution of (5-diethylamino-2-methylphenyl) thiourea (CAS # 81062-71-6, 0.5 g) in methanol (7 mL) was added iodomethane (0.197 mL), and the reaction mixture was heated under reflux for 22 hours. Stir. Then, it concentrated under pressure reduction and 0.7773g of title compounds were obtained. The physical properties of this product are as follows.
ESI-MS; m / z 252 [M ⁺ + H-HI].

Production Example 11
Synthesis of 1- (5-isopropyl-4-methoxy-2-methylphenyl) -2-methylisothiourea hydroiodide

According to the method of Preparation Example 10, 0.222 g of the title compound was obtained from (5-isopropyl-4-methoxy-2-methylphenyl) thiourea (CAS # 1056049-53-6, 0.139 g). The physical properties of this product are as follows.
ESI-MS; m / z 253 [M ^< + ^> + H-HI].

Production Example 12
Synthesis of 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) pyridine-2-carboxylic acid N ′-[2- (5-isopropyl-4-methoxy-2-methylphenyl) acetyl] hydrazide

Synthesis of (5-isopropyl-4-methoxy-2-methylphenyl) acetic acid methyl ester

Under ice-cooling, thionyl chloride (3.5 mL) was added dropwise to a solution of (5-isopropyl-4-methoxy-2-methylphenyl) acetic acid (CAS # 81354-65-6, 5.5 g) in methanol (50 mL). Thereafter, the reaction solution was returned to room temperature and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution and tert-butyl methyl ether were added, and the organic layer was separated. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The desiccant was filtered off, the organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (5.0 g). The physical properties of this product are as follows.
¹ H-NMR (CDCl ₃ ) δ (ppm): 1.19 (d, J = 7.2 Hz, 3H), 1.19 (d, J = 7.2 Hz, 3H), 2.28 (s, 3H) ), 3.25 (qq, J = 7.2, 7.2 Hz, 1H), 3.58 (s, 2H), 3.68 (s, 3H), 3.80 (s, 3H), 6. 66 (s, 1H), 7.00 (s, 1H).

Synthesis of (5-isopropyl-4-methoxy-2-methylphenyl) acetic acid hydrazide

Hydrazine monohydrate (0.8 mL) was added to a solution of (5-isopropyl-4-methoxy-2-methylphenyl) acetic acid methyl ester (780 mg) in ethanol (10 mL), and the mixture was heated to reflux at 80 ° C. for 10 hours. Thereafter, hydrazine monohydrate (0.8 mL) was added, and the mixture was further heated to reflux at 80 ° C. for 3.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (374 mg). The physical properties of this product are as follows.
ESI-MS; m / z 237 [M ⁺ + H].
¹ H-NMR (CDCl ₃ ) 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).

Synthesis of 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) pyridine-2-carboxylic acid N '-[2- (5-isopropyl-4-methoxy-2-methylphenyl) acetyl] hydrazide

(5-Isopropyl-4-methoxy-2-methylphenyl) acetic acid hydrazide (338 mg), 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) pyridin-2- obtained in Preparation Example 2 To a solution of carboxylic acid (476 mg) and HOBT (290 mg) in DMF (10 mL), IPEA (996 μL) was added under ice cooling. Subsequently, EDC (411 mg) was added at the same temperature, and then the reaction solution was returned to room temperature and stirred overnight. Ethyl acetate and aqueous sodium hydrogen carbonate solution were added to the reaction solution, and the organic layer was separated. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The desiccant was filtered off, the organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (515 mg). The physical properties of this product are as follows.
ESI-MS; m / z 452 [M ⁺ + H].
¹ H-NMR (CDCl ₃ ) 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).

Production Example 13
6-methoxy-5- (4-methyl-1H-imidazol-1-yl) pyridine-2-carboxylic acid N ′-[2- (5-isopropyl-4-methoxy-2-methylphenyl) acetyl] -N ′ -Synthesis of methyl hydrazide

Synthesis of N '-[2- (5-isopropyl-4-methoxy-2-methylphenyl) acetyl] -N'-methylhydrazinecarboxylic acid benzyl ester

(5-Isopropyl-4-methoxy-2-methylphenyl) acetic acid (CAS # 81354-65-6, 1 g), N′-methylhydrazinecarboxylic acid benzyl ester hydrochloride (CAS # 880-21-7, 1.2 g) ), IPEA (3.1 mL) was added to a DMF (20 mL) solution of HOBT (909 mg) under ice cooling. Then, EDC (1.3 g) was added at the same temperature, and the reaction solution was returned to room temperature and stirred overnight. Ethyl acetate and aqueous sodium hydrogen carbonate solution were added to the reaction solution, and the organic layer was separated. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The desiccant was filtered off, the organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (1 g). The physical properties of this product are as follows.
ESI-MS; m / z 385 [M ⁺ + H].

Synthesis of (5-isopropyl-4-methoxy-2-methylphenyl) acetic acid N-methylhydrazide

N ′-[2- (5-Isopropyl-4-methoxy-2-methylphenyl) acetyl] -N′-methylhydrazinecarboxylic acid benzyl ester (1 g) was dissolved in ethanol (30 mL), and H-Cube ^™ (THALES Nanotechnology Inc .: continuous hydrogenation equipment))) using a 10% palladium on carbon cartridge in the system and catalytic hydrogenation for 5 hours. The organic layer was concentrated under reduced pressure to obtain the title compound (678 mg). The physical properties of this product are as follows.
ESI-MS; m / z 251 [M ⁺ + H].

6-methoxy-5- (4-methyl-1H-imidazol-1-yl) pyridine-2-carboxylic acid N ′-[2- (5-isopropyl-4-methoxy-2-methylphenyl) acetyl] -N ′ -Synthesis of methyl hydrazide

(5-Isopropyl-4-methoxy-2-methylphenyl) acetic acid N-methylhydrazide (160 mg), 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) pyridine obtained in Preparation Example 2 IPEA (444 μL) and EDC (183 mg) were sequentially added to a DMF (4 mL) solution of 2-carboxylic acid (890 mg) and HOBT (129 mg), and the reaction solution was stirred at room temperature for 5 hours. Ethyl acetate and aqueous sodium hydrogen carbonate solution were added to the reaction solution, and the organic layer was separated. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The desiccant was filtered off, the organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (246 mg). The physical properties of this product are as follows.
¹ H-NMR (CDCl ₃ ) 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).

Production Example 14
Synthesis of 2- (5-tert-butyl-2-methoxyphenyl) -5-chloropentaneimidic acid ethyl ester hydrochloride and 2- (5-tert-butyl-2-methoxyphenyl) acetimidic acid ethyl ester hydrochloride

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

To a DMF (25 mL) solution of 4-tert-butyl-2-methylphenol (CAS # 98-27-1, 5.0 g), potassium carbonate (8.4 g) and methyl iodide (2.9 mL) were added. Stir at room temperature for 3 days. Ice water and hexane were added to the reaction solution, and the organic layer was partitioned. The obtained organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 5.16 g of the title compound. The physical properties of this product are as follows.
¹ H-NMR (CDCl ₃ ) 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-bromomethyl-4-tert-butyl-1-methoxybenzene

To a solution of 4-tert-butyl-1-methoxy-2-methylbenzene (5.16 g) in carbon tetrachloride (25 mL), N-bromosuccinimide (5.66 g) and 2,2′-azobis (isobutyro) (Nitrile) (71 mg) was added, and the mixture was heated to reflux for 1.5 hours. The reaction solution was cooled with water, and insoluble matters were removed by filtration. The filtrate was concentrated under reduced pressure to give 7.78 g of the title compound. The physical properties of this product are as follows.
¹ H-NMR (CDCl ₃ ) δ (ppm): 1.30 (s, 9H), 3.88 (s, 3H), 4.58 (s, 2H), 6.81 (d, J = 8. 4Hz, 1H), 7.31 (dd, J = 8.4, 2.4Hz, 1H), 7.34 (d, J = 2.4Hz, 1H).

Synthesis of (5-tert-butyl-2-methoxyphenyl) acetonitrile

To a solution of 2-bromomethyl-4-tert-butyl-1-methoxybenzene (7.78 g) in dimethyl sulfoxide (50 mL) was added potassium cyanide (2.96 g), and the mixture was stirred at room temperature for 16 hours. Ice and tert-butyl methyl ether were added to the reaction solution, and the organic layer was partitioned. The aqueous layer was re-extracted with tert-butyl methyl ether. The combined organic layers were washed successively with water (twice) and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (carrier: Chromatorex ^™ NH; elution solvent heptane → ethyl acetate: heptane 1:49). The residue obtained by concentrating the target fraction was triturated with hexane to obtain 1.90 g of the title compound. After concentrating the trituration mother liquor, the resulting residue was triturated with hexane to give 0.47 g of the title compound. The physical properties of this product are as follows.
¹ H-NMR (CDCl ₃ ) δ (ppm): 1.31 (s, 9H), 3.68 (s, 2H), 3.85 (s, 3H), 6.82 (d, J = 8. 4Hz, 1H), 7.32 (dd, J = 8.4, 2.4Hz, 1H), 7.36 (d, J = 2.4Hz, 1H).

Synthesis of 2- (5-tert-butyl-2-methoxyphenyl) -5-chloropentanenitrile

Under ice cooling, a hexane solution (2.69 M, 3.0 mL) of n-butyllithium was added to a THF (15 mL) solution of N, N-diisopropylamine (1.2 mL), and the mixture was stirred at the same temperature for 10 minutes. The solution was cooled to −78 ° C., and a solution of (5-tert-butyl-2-methoxyphenyl) acetonitrile (1.5 g) in THF (6.5 mL) was added dropwise. The solution was stirred at −30 ° C. for 25 minutes and then cooled again to −78 ° C. 1-Chloro-3-iodopropane (1.2 mL) was added dropwise to this solution, and then the reaction solution was gradually warmed to room temperature. The reaction solution was ice-cooled, and a solution of lithium hexamethyldisilazide in tetrahydrofuran (1.0 M, 4.4 mL) was added to the reaction solution. Then, a lithium diisopropylamide solution prepared from a hexane solution (2.69 M, 1.5 mL) of N, N-diisopropylamine (0.6 mL) and n-butyllithium was added to the reaction solution. A saturated aqueous ammonium chloride solution was added to the reaction solution, ethyl acetate and water were added, and the organic layer was partitioned. The obtained organic layer was washed successively with 1N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (carrier: Merck silica gel 60 (230-400 mesh); elution solvent heptane → ethyl acetate: heptane 1:49) to obtain (5-tert-butyl-2-methoxyphenyl). ) 864 mg of a 1: 7 mixture of acetonitrile and the title compound was obtained. The physical properties of the title compound are as follows.
¹ H-NMR (CDCl ₃ ) 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 Hz, 1H).

Synthesis of 2- (5-tert-butyl-2-methoxyphenyl) -5-chloropentaneimidic acid ethyl ester hydrochloride and 2- (5-tert-butyl-2-methoxyphenyl) acetimidic acid ethyl ester hydrochloride

1: 7 mixture (864 mg) of ethanol with (5-tert-butyl-2-methoxyphenyl) acetonitrile and 2- (5-tert-butyl-2-methoxyphenyl) -5-chloropentanenitrile under ice cooling Hydrogen chloride gas was bubbled into the (8 mL) solution for 15 minutes. The reaction solution was stirred at room temperature for 1 day. The reaction was concentrated under reduced pressure to give a mixture of title compounds.
2- (5-tert-Butyl-2-methoxyphenyl) -5-chloropentaneimidic acid ethyl ester The physical properties of hydrochloride are as follows.
ESI-MS; m / z 326 [M ^< + ^> + H-HCl].
Properties of 2- (5-tert-butyl-2-methoxyphenyl) acetimidic acid ethyl ester hydrochloride are as follows.
ESI-MS; m / z 250 [M ^< + ^> + H-HCl].

Production Example 15
Synthesis of 3-bromo-1-methyl-5- (2-trifluoromethylphenoxy) -1H- [1,2,4] triazole

1-methyl-3-nitro-5- (2-trifluoromethylphenoxy) -1H- [1,2,4] triazole

To a solution of 1-methyl-3-nitro-5-bromo-1H- [1,2,4] triazole (CAS # 31123-19-0, 100 mg) in DMF (3 mL), 2-hydroxybenzotrifluoride (157 mg) , Potassium carbonate (134 mg) was added, and the mixture was stirred at 95 ° C. for 6 hours 30 minutes. After allowing to cool, diethyl ether and water were added to the reaction solution, and the organic layer was separated. The obtained organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the organic layer was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography to obtain the title compound (118 mg). The physical properties of this product are as follows.
¹ H-NMR (CDCl ₃ ) 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) -1H- [1,2,4] triazol-3-ylamine

To a solution of 1-methyl-3-nitro-5- (2-trifluoromethylphenoxy) -1H- [1,2,4] triazole (35 mg) in methanol (5 mL) was added 10% palladium on carbon (20 mg), The mixture was stirred at room temperature for 13 hours and 30 minutes in a 1 atmosphere hydrogen atmosphere. The palladium carbon was removed by filtration through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography to obtain the title compound (45.8 mg). The physical properties of this product are as follows.
¹ H-NMR (CDCl ₃ ) 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-trifluoromethylphenoxy) -1H- [1,2,4] triazole

1-methyl-5- (2-trifluoromethylphenoxy) -1H- [1,2,4] triazol-3-ylamine (45 mg) was dissolved in acetonitrile (2 mL) and copper (II) bromide (194 mg) was dissolved. , Isoamyl nitrite (61.2 mg) was added, and the mixture was stirred at 70 ° C. for 1 hour and 30 minutes. After allowing to cool, the reaction mixture was concentrated under reduced pressure. Ethyl acetate and saturated aqueous ammonium chloride solution were added to the residue, and the organic layer was separated. The obtained organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the organic layer was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography to obtain the title compound (11.5 mg). The physical properties of this product are as follows.
¹ H-NMR (CDCl ₃ ) δ (ppm): 3.80 (s, 3H), 7.37 (t, J = 7.6 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H) ), 7.70 (d, J = 7.6 Hz, 2H).

Example 1
(2,5-Dimethylphenyl)-{5- [6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -pyridin-2-yl]-[1,2,4] oxadiazole Synthesis of -3-yl} -amine

N- (2,5-dimethylphenyl) -N′-hydroxyguanidine (56.0 mg) obtained in Production Example 6 and 6-methoxy-5- (4-methyl-1H-imidazole) obtained in Production Example 2 -1-yl) -pyridine-2-carboxylic acid (72.8 mg), EDC (89.7 mg), TEA (87 μL) in DMF solution (3 mL) was added HOBT (63.2 mg), and the reaction solution was allowed to react at room temperature. After stirring overnight, the mixture was stirred at 80 ° C. for 8 hours. Water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane → ethyl acetate: methanol 90:10), and the concentrated residue was washed with diethyl ether to give 16 mg of the title compound. The physical properties of this product are as follows.
¹ H-NMR (CDCl ₃ ) 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), 7.06-7.10 (m, 2H), 7.72 (d, J = 7.6 Hz, 1H), 7.82 (s, 1H) , 7.89 (d, J = 7.6 Hz, 1H), 7.93 (s, 1H).

Example 2
(2,5-Dimethylphenyl)-{3- [6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -pyridin-2-yl]-[1,2,4] thiadiazole-5 Synthesis of -yl} -amine

2,5-dimethylphenyl isothiocyanate (CAS # 19241-15-729.7 mg) and N-hydroxy-6-methoxy-5- (4-methyl-1H-imidazole-1-) obtained in Preparation Example 7 Yl) A solution of pyridine-2-carboxamidine (30.0 mg) in DMF (2 mL) was stirred at 80 ° C. for 3 hours and then at room temperature overnight. Water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane → ethyl acetate → ethyl acetate: methanol 80:20), and then the concentrated residue was washed with diethyl ether to obtain 10 mg of the title compound. The physical properties of this product are as follows.
¹ H-NMR (CD ₃ OD) δ (ppm): 2.25 (d, J = 0.8 Hz, 3H), 2.31 (s, 3H), 2.36 (s, 3H), 4.15 (S, 3H), 7.01 (d, J = 7.6 Hz, 1H), 7.19 (d, J = 7.6 Hz, 1H), 7.22-7.25 (m, 2H), 7 .56 (s, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 8.00 (d, J = 0.8 Hz, 1H).

  In the same manner as in Example 2, the compound of Example 3 was obtained (Table 1).

Example 4
(2,5-Dimethylphenyl)-{3- [6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -pyridin-2-yl]-[1,2,4] oxadiazole Synthesis of -5-yl} -amine

1- (2,5-Dimethylphenyl) -2-methyl-isothiourea monoiodide (CAS # 911147-36-3, 65.1 mg), N-hydroxy-6- 6 obtained in Preparation Example 7 A solution of methoxy-5- (4-methyl-1H-imidazolyl-1-yl) pyridine-2-carboxamidine (50.0 mg) and TEA (56.3 μL) in ethanol (2 mL) was refluxed for 10 hours, and then 75 ° C. Stir overnight. Water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (elution solvent: heptane → ethyl acetate → ethyl acetate: methanol 80:20) and then by preparative thin layer silica gel chromatography (developing solvent: heptane: ethyl acetate = 1: 10). 2.0 mg of the title compound was obtained. The physical properties of this product are as follows.
ESI-MS; m / z 377 [M ⁺ + H]. ¹ H-NMR (CDCl ₃ ) 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-methoxy-5- (4-methyl-1H-imidazol-1-yl) -pyridin-2-yl]-[1,3,4] oxadiazole Of 2-yl} -amine

N- (2,5-dimethylphenyl) -2-{[6-methoxy-5- (4-methyl-1H-imidazol-1-yl) pyridin-2-yl] carbonyl} hydrazine obtained in Production Example 9 A solution of carbothioamide (30 mg), paratoluenesulfonyl chloride (41.8 mg), pyridine (35.4 μL) in THF (2 mL) was stirred at 65 ° C. for 4 hours. Water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane → ethyl acetate → ethyl acetate: methanol 80:20) to give 5.0 mg of the title compound. The physical properties of this product are as follows.
ESI-MS; m / z 377 [M ⁺ + H].
¹ H-NMR (CDCl ₃ ) 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, J = 7.6 Hz, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.89 (brs, 2H).

Example 6
(2,5-Dimethylphenyl)-{5- [6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -pyridin-2-yl]-[1,3,4] thiadiazole-2 Synthesis of -yl} -amine

N- (2,5-dimethylphenyl) -2-{[6-methoxy-5- (4-methyl-1H-imidazol-1-yl) pyridin-2-yl] carbonyl} obtained in Production Example 9 A solution of hydrazine carbothioamide (10.0 mg) in phosphoric acid (300 μL) was stirred at 90 ° C. for 1 hour. Under ice-cooling, ethyl acetate and 2N aqueous sodium hydroxide solution were added to the reaction solution to neutralize the reaction solution, and then the organic layer was partitioned. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane → ethyl acetate → ethyl acetate: methanol 80:20) to obtain 3.0 mg of the title compound. The physical properties of this product are as follows.
ESI-MS; m / z 393 [M ⁺ + H].
¹ H-NMR (CDCl ₃ ) δ (ppm): 2.30 (s, 3H), 2.32 (s, 3H), 2.38 (s, 3H), 4.03 (s, 3H), 6 .98-7.00 (m, 2H), 7.17 (d, J = 7.6 Hz, 1H), 7.35-7.37 (m, 1H), 7.65 (d, J = 7. 6 Hz, 1H), 7.83 (d, J = 1.2 Hz, 1H), 7.92 (d, J = 7.6 Hz, 1H).

Example 7
N * 1 *, N * 1 * -diethyl-N * 3 *-{5- [6-methoxy-5- (4-methyl-1H-imidazol-1-yl) pyridin-2-yl] -2H- [ Synthesis of 1,2,4] triazol-3-yl} -4-methylbenzene-1,3-diamine

4N hydrochloric acid to N ′-[6-methoxy-5- (4-methyl-1H-imidazol-1-yl) pyridine-2-carbonyl] hydrazinecarboxylic acid tert-butyl ester (30 mg) obtained in Production Example 3 Of ethyl acetate (2 mL) was added and the reaction was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure. To the resulting crude 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) pyridine-2-carboxylic acid hydrazide hydrochloride, pyridine (3 mL), TEA (0.12 mL), in Production Example 10 The obtained 1- (5-diethylamino-2-methylphenyl) -2-methylisothiourea hydroiodide (39.4 mg) was added, and the mixture was stirred with heating under reflux for 18 hours. The reaction solution was cooled to room temperature, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted 3 times with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: ethyl acetate → ethyl acetate-methanol), and further purified by silica gel column chromatography (elution solvent: ethyl acetate-methanol) to give the title compound 3 Obtained .01 mg.
The physical properties of the title compound are as follows.
ESI-MS; m / z 433 [M ⁺ + H].
¹ H-NMR (CDCl ₃ ) 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-imidazol-1-yl) pyridin-2-yl] -2H- [1, Synthesis of 2,4,] triazol-3-yl} amine

In accordance with the method of Example 7, N ′-[6-methoxy-5- (4-methyl-1H-imidazol-1-yl) pyridine-2-carbonyl] hydrazinecarboxylic acid tert- obtained in Production Example 3 From the butyl ester (406 mg) and 1- (5-isopropyl-4-methoxy-2-methylphenyl) -2-methylisothiourea hydroiodide obtained in Preparation Example 11 (669 mg), the title compound was converted to 47 .9 mg was obtained. The physical properties of the title compound are as follows.
ESI-MS; m / z 434 [M ⁺ + H].
¹ H-NMR (CDCl ₃ ) 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), 4.10 (s, 3H), 6.26 (bs, 1H), 6.72 (s, 1H), 6.96-7.06 (m, 1H), 7.60-7.90 (m, 4H).

The compound of Example 9-11 was obtained in the same manner as in Example 7 (Table 2).

Example 12
6- [5- (5-Isopropyl-4-methoxy-2-methylbenzyl)-[1,3,4] oxadiazol-2-yl] -2-methoxy-3- (4-methyl-1H-imidazole Synthesis of -1-yl) pyridine

6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -pyridine-2-carboxylic acid N ′-[2- (5-isopropyl-4-methoxy-2-) obtained in Production Example 12 A solution of (methylphenyl) acetyl] hydrazide (515 mg) in phosphorus oxychloride (8 mL) was stirred with heating at 120 ° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure, tert-butyl methyl ether and saturated aqueous sodium hydrogen carbonate solution were added, and the organic layer was separated. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The desiccant was filtered off, the organic layer was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (187 mg). The physical properties of this product are as follows.
ESI-MS; m / z 434 [M ⁺ + H].
¹ H-NMR (CDCl ₃ ) 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-methoxy-2-methylbenzyl) -1H- [1,2,4] triazol-3-yl] -2-methoxy-3- (4-methyl-1H-imidazole Synthesis of -1-yl) pyridine

6- [5- (5-Isopropyl-4-methoxy-2-methylbenzyl)-[1,3,4] oxadiazol-2-yl] -2-methoxy-3- () obtained in Example 12 Sodium acetate (961 mg) heated and dried under reduced pressure was added to a solution of 4-methyl-1H-imidazol-1-yl) pyridine (180 mg) in acetic acid (10 mL), and the mixture was stirred with heating at 150 ° C. for 3 days. After allowing to cool, the reaction mixture was concentrated under reduced pressure, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added, and the organic layer was separated. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The desiccant was filtered off, the organic layer was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (144 mg). The physical properties of this product are as follows.
ESI-MS; m / z 433 [M ⁺ + H].
¹ H-NMR (CDCl ₃ ) 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-methylbenzyl) -2-methyl-2H- [1,2,4] triazol-3-yl] -2-methoxy-3- (4-methyl Of 1H-imidazol-1-yl) pyridine

6- [5- (5-Isopropyl-4-methoxy-2-methylbenzyl) -1H- [1,2,4] triazol-3-yl] -2-methoxy-3- (obtained in Example 13 To a solution of 4-methyl-1H-imidazol-1-yl) pyridine (100 mg) and methyl iodide (29 μL) in DMF (3 mL) was added 60% sodium hydride (19 mg) under ice cooling. The reaction solution was returned to room temperature and stirred for 1 hour under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The desiccant was filtered off, the organic layer was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (74 mg). The physical properties of this product are as follows.
ESI-MS; m / z 447 [M ⁺ + H].
¹ H-NMR (CDCl ₃ ) 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-methylbenzyl) -1-methyl-1H- [1,2,4] triazol-3-yl] -2-methoxy-3- (4-methyl Of 1H-imidazol-1-yl) pyridine

6-methoxy-5- (4-methyl-1H-imidazol-1-yl) pyridine-2-carboxylic acid N ′-[2- (5-isopropyl-4-methoxy-2-methyl) obtained in Production Example 13 Phenyl) acetyl] -N′-methylhydrazide (150 mg) in phosphorus oxychloride (4 mL) was stirred with heating at 120 ° C. for 1.5 hours. The reaction solution was concentrated under reduced pressure. To the obtained residue, acetic acid (5 mL) and ammonium acetate (249 mg) heated and dried under reduced pressure were added, and the reaction mixture was heated and stirred at 150 ° C. for 2.5 hours. After allowing to cool, the reaction mixture was concentrated under reduced pressure. To the obtained residue, ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added, and the organic layer was separated. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The desiccant was filtered off, the organic layer was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (38 mg). The physical properties of this product are as follows.
ESI-MS; m / z 447 [M ⁺ + H].
¹ H-NMR (CDCl ₃ ) δ (ppm): 1.13 (d, J = 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), 4.172 (s, 3H), 6.68 (s, 1H), 6.84 (s, 1H), 7.01 (s, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.81-7.85 (m, 2H).

  In the same manner as in Example 12 and Example 13, the compounds of Examples 16-20 were obtained (Table 3).

Example 21 and Example 22
2-Methoxy-3- (4-methyl-1H-imidazol-1-yl) -6- [1-methyl-5- (2-trifluoromethylbenzyl) -1H- [1,2,4] triazole-3 -Yl] -pyridine and 2-methoxy-3- (4-methyl-1H-imidazol-1-yl) -6- {1-methyl-5- [1- (2-trifluoromethylphenyl) ethyl] -1H -Synthesis of [1,2,4] triazol-3-yl} pyridine

2-Methoxy-3- (4-methyl-1H-imidazol-1-yl) -6- [5- (2-trifluoromethylbenzyl) -1H- [1,2,4] obtained in Example 18 Methyl iodide (144 μL) was added to a mixed solution (6 mL) of triazol-3-yl] -pyridine (400 mg) and sodium hydride (101 mg), and the mixture was stirred for 2 hours. Water was added to the reaction mixture, ethyl acetate was added, and the organic layer was partitioned. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by thin layer silica gel chromatography to give 2-methoxy-3- (4-methyl-1H-imidazol-1-yl) -6- [1-methyl-5- (2-trifluoromethyl). Benzyl) -1H- [1,2,4] triazol-3-yl] -pyridine 127.7 mg and 2-methoxy-3- (4-methyl-1H-imidazol-1-yl) -6- {1-methyl 35.7 mg of -5- [1- (2-trifluoromethylphenyl) ethyl] -1H- [1,2,4] triazol-3-yl} pyridine was obtained.
2-Methoxy-3- (4-methyl-1H-imidazol-1-yl) -6- [1-methyl-5- (2-trifluoromethylbenzyl) -1H- [1,2,4] triazole-3 The physical properties of -yl] -pyridine are as follows.
ESI-MS; m / z 429 [M ⁺ + H].
¹ H-NMR (CDCl ₃ ) 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- {1-methyl-5- [1- (2-trifluoromethylphenyl) ethyl] -1H- [1,2, 4] Properties of triazol-3-yl} pyridine are as follows.
ESI-MS; m / z 444 [M ⁺ + H].
¹ H-NMR (CDCl ₃ ) 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 (brs, 1H), 7.96 (d, J = 8.0 Hz, 1H).

Example 23
Synthesis of (2,5-dimethylphenyl)-{4- [6-methoxy-5- (4-methyl-1H-imidazol-1-yl) pyridin-2-yl] -1H-imidazol-2-yl} amine

2-Bromo-1- [6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -pyridin-2-yl] -ethanone dihydrochloride (17.3 mg) obtained in Preparation Example 5. And IPEA (0.0394 mL) were added to a DMF (1 mL) solution of N- (2,5-dimethylphenyl) -guanidine (CAS # 46049-94-9, 7.38 mg) at 4O 0 C. Stir for 5 hours. The reaction solution was cooled to room temperature, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted 3 times with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: ethyl acetate → ethyl acetate-methanol) to obtain 1.05 mg of the title compound. The physical properties of the title compound are as follows.
ESI-MS; m / z 375 [M ⁺ + H].
¹ H-NMR (CD ₃ OD) 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).

  In the same manner as in Example 23, the compound of Example 24 was obtained (Table 4).

Example 25
6- [5- (5-tert-Butyl-2-methoxybenzyl) -1H- [1,2,4] -triazol-3-yl] -2-methoxy-3- (4-methyl-1H-imidazole- Synthesis of 1-yl) pyridine

A suspension of 6-methoxy-5- (4-methyl-1H-imidazol-1-yl) pyridine-2-carboxylic acid hydrazide hydrochloride (135 mg) and imidazole (194 mg) obtained in Production Example 4 in DMF (2 mL) To the liquid, 2- (5-tert-butyl-2-methoxyphenyl) -5-chloropentaneimidic acid ethyl ester hydrochloride obtained in Preparation Example 14 and 2- (5-tert-butyl-2-methoxyphenyl) ) Acetimidic acid ethyl ester A mixture with a hydrochloride salt (192 mg) in ethanol (2 mL) was added and stirred at room temperature overnight. Subsequently, the reaction solution was stirred at 100 ° C. for 3 hours and 40 minutes. After allowing the reaction solution to cool, ethyl acetate and water, 1N hydrochloric acid (1 mL) were added to the reaction solution, and the organic layer was partitioned. The obtained organic layer was washed successively with half-saturated brine and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (carrier: Chromatorex ^™ NH; elution solvent ethyl acetate: heptane 1: 2 → 2: 1 → 0: 1), then CHIRALCEL ^™ IA (2 cm × 25 cm: manufactured by Daicel Chemical Industries, Ltd.) Purification by mobile phase: 15% ethanol-hexane) gave 7.2 mg of the title compound. The physical properties of this product are as follows.
ESI-MS; m / z 433 [M ⁺ + H].
¹ H-NMR (CDCl ₃ ) 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-tert-Butyl-4-methoxybenzyl) -1H- [1,2,4] -triazol-3-yl] -2-methoxy-3- (4-methyl-1H-imidazole- Synthesis of 1-yl) pyridine

In the same manner as in Example 25, 25.7 mg of the title compound was obtained using 2-tert-butyl-4-methylphenol (CAS # 2409-55-4) as a starting material. The physical properties of this product are as follows.
ESI-MS; m / z 433 [M ⁺ + H].
¹ H-NMR (CDCl ₃ ) 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), 7.66 (d, J = 8.0 Hz, 1H), 7.84 (brs, s), 7.85 (d, J = 8.0 Hz, 1H), 11.10 (brs, 1H).

Example 27
2-Methoxy-3- (4-methyl-1H-imidazol-1-yl) -6- [1-methyl-5- (2-trifluoromethylphenoxy) -1H- [1,2,4] triazole-3 -Yl] -pyridine synthesis

2-methoxy-3- (4-methyl-1H-imidazol-1-yl) -6-tributylstannylpyridine (34.1 mg) obtained in Production Example 8 and 3-bromo obtained in Production Example 15 To a solution of -1-methyl-5- (2-trifluoromethylphenoxy) -1H- [1,2,4] triazole (11.5 mg) in 1-methyl-2-pyrrolidinone (0.5 mL) under a nitrogen atmosphere 1,3 bis (diphenylphosphino) propane (5.9 mg), copper (I) oxide (10.2 mg) and palladium (II) acetate (1.6 mg) were sequentially added, and the mixture was stirred at 120 ° C. for 2 hours 30 minutes. did. After standing to cool, the insoluble material in the reaction solution was filtered off through Celite, and the filtrate 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 saturated brine and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the organic layer was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography to obtain the title compound (9.2 mg). The physical properties of this product are as follows.
¹ H-NMR (CDCl ₃ ) δ (ppm): 2.30 (d, J = 1.2 Hz, 3H), 3.92 (s, 3H), 4.16 (s, 3H), 7.00 ( t, J = 1.2 Hz, 1H), 7.37 (t, J = 8.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.66 (t, J = 8 0.0 Hz, 1H), 7.70 (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 Aβ Peptide in Rat Embryonic Brain-Derived Neuronal Culture In order to show the usefulness of the compound of the general formula (I) of the present invention, the present inventors conducted the following tests.

(1) Rat primary neuronal cell culture Embryonic 18-day-old Wistar rats (Charles River Japan, Yokohama, Japan) were isolated and subjected to culture. Specifically, fetuses were aseptically removed from pregnant rats under ether anesthesia. The brain was removed from the fetus and immersed in ice-cold L-15 medium (Invitrogen Corp. Cat # 11415-064, Carlsbad, CA USA, SIGMA L1518, etc.). Cerebral cortex was collected from the isolated brain under a stereomicroscope. The collected cerebral cortical fragment was converted into an enzyme solution containing 0.25% trypsin (Invitrogen Corp. Cat # 15050-065, Carlsbad, CA USA) and 0.01% DNase (Sigma D5025, St. Louis, MO, USA). The cells were dispersed by treating with an enzyme at 37 ° C. for 30 minutes. At this time, the enzyme reaction was stopped by adding inactivated horse serum. This enzyme-treated solution was centrifuged at 1500 rpm for 5 minutes, and the supernatant was removed. 5 to 10 mL of a medium was added to the obtained cell mass. The medium includes Neurobasal medium (Invitrogen Corp. Cat # 21103-049, Carlsbad, CA USA), 2% B27 supplement (Invitrogen Corp. Cat # 17504-044, Carlsbad, CA USA) and 25 μMol2- (2) MaMol 2- (2) , WAKO Cat # 139-06861, Osaka, Japan) and 0.5 mM L-glutamine (Invitrogen Corp. Cat # 25030-081, Carlsbad, CA USA) and Antibiotics-Antiticotics0C CA USA) added ( eurobasal / B27 / 2-ME) was used. However, in the assay, a medium (Neurobasal / B27) to which 2-ME alone was not added was used. The cells were redispersed in the cell mass to which the medium was added by a gentle pipetting operation. This cell dispersion was filtered through a 40 μm nylon mesh (cell strainer, Cat # .35-2340, Becton Dickinson Labware, Franklin Lakes, NJ, USA) to obtain a neuronal cell suspension. . This neuronal cell suspension was diluted with a medium, and a 96-well polystyrene incubator previously coated with poly-L or D-lysine (Falcon Cat # .35-3075, Becton Dickinson Labware, Franklin Lakes, NJ, USA) Or poly-L-lysine coat by the following method, or BIOCOAT ^™ cell environments Poly-D-lysine cell wall 96-well plate, Cat # .35-6461, Becton Dickinson Labra, USA, ) Was seeded at 100 μl / well so that the initial cell density was 5 × 10 ⁵ cells / cm ² . Poly-L-lysine coating was performed as follows. A 100 μg / mL poly-L-lysine (SIGMA P2636, St. Louis, MO, USA) solution was aseptically prepared using 0.15 MBorate buffer (pH 8.5). The solution was added to a 96-well polystyrene incubator at 100 μg / well and incubated at room temperature for 1 hour or longer, or at 4 ° C. overnight or longer. Thereafter, the coated 96-well polystyrene incubator was washed four times or more with sterilized water, dried, or rinsed with sterile PBS or a medium, and used for cell seeding. The seeded cells were cultured for one day in a 37 ° C. incubator under 5% CO ₂ -95% air, and the whole medium was replaced with a fresh Neurobasal / B27 / 2-ME medium, followed by culturing for 3 days.

On the fourth day of compound addition culture, drug addition was performed as follows. The whole medium was extracted and Neurobasal medium (Neurobasal / B27) containing 2% B-27 without 2-ME was added at 180 μl / well. A dimethyl sulfoxide (hereinafter abbreviated as DMSO) solution of the test compound was diluted with Neurobasal / B27 so that the final concentration was 10 times. This diluted solution was added at 20 μl / well and mixed well. The final DMSO concentration was 1% or less. Only DMSO was added to the control group.

After adding the sampling compound, the cells were cultured for 3 days, and the whole medium was collected. The obtained culture medium was an ELISA sample.

Evaluation of cell survival Cell survival was evaluated by MTT assay by the following method. 100 μl / well of the warmed medium was added to the well after recovery of the medium, and further 8 mg / mL of MTT dissolved in D-PBS (−) (DULBECCO'S PHOSPHATE BUFFERED SALINE, SIGMA D8537, St. Louis, MO, USA) SIGMA M2128, St. Louis, MO, USA) solution was added at 8 μl / well. This 96-well polystyrene incubator was incubated for 20 minutes in a 37 ° C. incubator under 5% CO ₂ -95% air. MTT dissolution buffer was added thereto at 100 μl / well, and MTT formazan crystals were well dissolved in a 37 ° C. incubator under 5% CO ₂ -95% air, and then the absorbance at 550 nm of each well was measured. MTT lysis buffer was prepared as follows. 100 g SDS (sodium dodecyl sulfate (sodium lauryl sulfate), WAKO191-07145, Osaka, Japan) was dissolved in a solution obtained by mixing 250 mL each of N, N-dimethylformamide (WAKO 045-02916, Osaka, Japan) and distilled water. . Further, 350 μl of concentrated hydrochloric acid and acetic acid were added to this solution to bring the final pH of the solution to about 4.7.
At the time of measurement, a background (bkg) obtained by adding only a medium and an MTT solution to a well not seeded with cells was set. For each measured value, bkg was subtracted according to the following formula, a ratio (% of CTRL) to the control group (group not treated with drug, CTRL) was calculated, and cell survival activity was compared and evaluated.
% Of CTRL = ((A550_sample-A550_bkg) /
(A550_CTRL-bkg)) x100
(A550_sample: 550 nm absorbance of sample well, A550_bkg: 550 nm absorbance of background well, A550_CTRL: 550 nm absorbance of control well)

Aβ ELISA
Aβ ELISA can be obtained from Wako Pure Chemical Industries, Ltd., human / rat β amyloid (42) ELISA kit Wako (# 290-62601) or Immune Biology Institute (IBL Co., Ltd.). Human Amyloid beta (1-42) Assay Kit (# 27711) was used. The method was performed according to the manufacturer's recommended protocol (the method described in the package insert). However, the Aβ calibration curve was prepared using beta-amyloid peptide 1-42, rat (Calbiochem. # 171596 [Aβ ₄₂ ]).

(2) The measurement results are shown in Table 5 as a percentage (% of CTRL) to the Aβ concentration in the medium of the control group.

  As is apparent from the results in Table 5, it was confirmed that the compound of the present invention has an Aβ42 production lowering effect.

  Therefore, since the compound of the general formula [I] of the present invention or a pharmacologically acceptable salt thereof has an Aβ42 production reducing action, according to the present invention, Aβ such as Alzheimer's disease and Down's syndrome is caused. A therapeutic agent for a neurodegenerative disease can be provided.

  Since the compound of the general formula [I] of the present invention has an Aβ production reducing action, it is particularly useful as a therapeutic agent for neurodegenerative diseases caused by Aβ such as Alzheimer's disease and Down's syndrome.

Claims (12)

Formula [I]

[Wherein, R ₁ and R ₂ are the same or different and each represents a substituent selected from the following substituent group a1;
m represents an integer of 0-3,
n represents an integer of 0-2,
W represents a nitrogen atom or a carbon atom,
Ring A may have 1 to 3 substituents selected from the following substituent group b1 and are represented by formula [2] to formula [8].

[In the formula, ● represents the formula [9]

A binding site to A, A ● represents a binding site to X1, and represents a ring selected from the group consisting of:
X ₁ is i) a single bond, ii) a C 1-6 alkylene group, iii) a vinylene group optionally having 1-2 C 2-6 alkyl groups, or iv) —X ₂ — (where X ₂ Is —NR ₃ —, —O—, —C (O) —, —NR ₃ C (O) —, —C (O) NR ₃ —, —S—, —S (O) — or —S ( O) ₂ — and R ₃ represents a hydrogen atom, a C 1-6 alkyl group, a C 3-6 cycloalkyl group, a C 2-6 alkanoyl group or a C 1-6 alkylsulfonyl group),
Ring B may have 1 to 3 substituents selected from the following substituent group c1 and are represented by formulas [10] to [27].

A monocyclic or condensed aromatic ring group selected from the group consisting of

Substituent group a1: C1-6 alkyl group, C3-8 cycloalkyl group, C2-6 alkenyl group, C1-6 alkoxy group, C2-6 alkenyloxy group, C3-8 cycloalkyloxy group, amino group (the amino group) Group may have one, C2-6 alkanoyl group or C1-6 alkylsulfonyl group or 1-2, C1-6 alkyl group or C3-8 cycloalkyl group), cyano group, formyl Group, halogen atom, hydroxyl group and nitro group

Substituent group b1: C1-6 alkyl group (the alkyl group may be substituted with 1-3 halogen atoms), C2-6 alkenyl group, C3-8 cycloalkyl group, C6-14 aryl group, C6 -14 aryl C1-6 alkyl group, C1-6 alkoxy group, C2-6 alkenyloxy group, C3-8 cycloalkyloxy group, C2-6 alkanoyl group, C4-9 cycloalkylcarbonyl group, C7-15 aroyl group, C1-6 alkylsulfonyl group, C2-6 alkenylsulfonyl group, C3-8 cycloalkylsulfonyl group, C6-14 arylsulfonyl group, C1-6 alkylthio group, C2-6 alkenylthio group, C3-8 cycloalkylthio group, amino A sulfonyl group (the aminosulfonyl group is 1-2, C1-6 alkyl group, C2-6 alkyl An aryl group (which may have a C3-8 cycloalkyl group), an amino group (the amino group is one C2-6 alkanoyl group, a C1-6 alkylsulfonyl group or a C3-8 cycloalkylsulfonyl group, Or 1-2, which may have a C1-6 alkyl group or a C3-8 cycloalkyl group), a cyano group, a formyl group, a halogen atom, a hydroxyl group, a nitro group, an oxo group, a 1-pyrrolidinyl group, 1 -Piperidinyl group, 1-homopiperidinyl group, indolin-1-yl group, 1,2,3,4-tetrahydroquinolin-1-yl group and 4-morpholinyl group

Substituent group c1: i) amino group (the amino group is one C2-6 alkanoyl group, C1-6 alkylsulfonyl group, C3-8 cycloalkylsulfonyl group, or 1-2 C1-6 1) selected from the group consisting of an alkyl group or a C3-8 cycloalkyl group), ii) a cyano group, iii) a halogen atom, iv) a hydroxyl group, and v) a C1-6 alkyl group and a halogen atom. -3) V-1) C1-6 alkyl group, v-ii) C2-6 alkenyl group, v-iii) C2-6 alkynyl group, v-iv) C1-6 alkoxy Group, vv) C1-6 alkylthio group, v-vi) C1-6 alkylaminocarbonyl group, v-vii) C1-6 alkylsulfonyl group, v-viii) C1-6 alkylaminosulfonate. Group, v-ix) C2-6 alkanoyl group, vx) phenyl group, v-xi) pyridyl group, v-xii) pyridazinyl group, v-xiii) pyrimidinyl group, v-xiv) 1-pyrrolidinyl group, v -Xv) 1-piperidinyl group, v-xvi) 1-homopiperidinyl group and v-xvii) 4-morpholinyl group]
Or a pharmacologically acceptable salt or ester thereof. Ring A is represented by formula [3] to formula [8].

The compound according to claim 1, or a pharmacologically acceptable salt or ester thereof, which is a ring selected from the group consisting of: Ring A is represented by the formula [3]

The compound according to claim 2, or a pharmacologically acceptable salt or ester thereof.   The compound according to claim 1, wherein Ring B is a phenyl group, a pyridyl group, an oxazolyl group, an imidazolyl group, a thiazolyl group, a dihydrobenzofuranyl group or a thienyl group, or a pharmaceutically acceptable salt or ester thereof. X ₁ represents i) a single bond, ii) a C 1-6 alkylene group or iii) —X ₂ — (wherein X ₂ represents —NR ₃ — or —C (O) —, and R ₃ represents hydrogen. Or a pharmacologically acceptable salt thereof, or a pharmacologically acceptable salt thereof, which is an atom, a C1-6 alkyl group, a C3-6 cycloalkyl group, a C2-6 alkanoyl group or a C1-6 alkylsulfonyl group). ester. The compound according to claim ₁ , wherein R ₁ is a C1-6 alkyl group or a halogen atom, and m is 1-2, or a pharmaceutically acceptable salt or ester thereof. The compound according to claim 1, wherein R ₂ is a C 1-6 alkoxy group, and n is 1, or a pharmaceutically acceptable salt or ester thereof. The substituent of ring A is a C1-6 alkyl group (the alkyl group may be substituted with 1-3 halogen atoms), a C3-8 cycloalkyl group, a C6-14 aryl group, a C6-14 aryl. C1-6 alkyl group, C1-6 alkoxy group, C3-8 cycloalkyloxy group, C2-6 alkanoyl group, C7-15 aroyl group, C1-6 alkylsulfonyl group, C3-8 cycloalkylsulfonyl group, C6-14 The compound according to claim 1, or a pharmacologically acceptable salt or ester thereof, selected from the group consisting of an arylsulfonyl group, a cyano group, a formyl group, a halogen atom, a hydroxyl group and an oxo group. The substituent of ring B is i) an amino group (the amino group is one, a C2-6 alkanoyl group, a C1-6 alkylsulfonyl group or a C3-8 cycloalkylsulfonyl group, or 1-2, Selected from the group consisting of a C1-6 alkyl group or a C3-8 cycloalkyl group), ii) cyano group, iii) halogen atom, iv) hydroxyl group, and v) C1-6 alkyl group and halogen atom. V) -i) C1-6 alkyl group, v) -ii) C1-6 alkoxy group, v) -iii) C1-6 alkylthio group and v ) -Iv) The compound according to claim 1 or a pharmacologically acceptable salt or ester thereof selected from the group consisting of phenyl groups. The following formula [A-1] to formula [A-6]

One compound selected from the group consisting of, or a pharmaceutically acceptable salt or ester thereof.   A pharmaceutical comprising the compound according to any one of claims 1 to 10, or a pharmacologically acceptable salt or ester thereof as an active ingredient.   The medicament according to claim 11, for the treatment of Alzheimer's disease, dementia, Down's syndrome or amyloidosis.