JP2013028538A - Novel amide derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a novel compound which has strong beta amyloid 40 and beta amyloid 42 production inhibitory activity and is useful as a therapeutic agent and/or a prophylactic agent for psychoneurotic diseases that are caused by beta amyloid and typified by Alzheimer's disease.SOLUTION: This invention relates to a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. [In the formula, Xrepresents CQor the like, Xrepresents CQor the like, Xrepresents CQor the like, Q, Qand Qeach independently represent a hydrogen atom or the like, Y represents Calkylene which may be substituted, Z represents a single bond or -(a 4-9-membered nitrogen-containing saturated heterocyclic divalent group which may be substituted)-W-, W represents -(CH)- or the like, A represents aryl or the like, Rrepresents Calkyl or the like, Rrepresents Calkoxy or the like, Rrepresents a hydrogen atom or the like, and n represents an integer of 0-4].

Description

  The present invention relates to a novel amide derivative useful as a medicament having a beta amyloid (Aβ) production inhibitory action. More specifically, the present invention relates to a novel amide derivative useful as a therapeutic and / or prophylactic agent for neurodegenerative diseases involving Aβ such as Alzheimer's disease and Down's syndrome.

  Alzheimer's disease is a neurodegenerative disease characterized by senile plaque formation and neurofibrillary tangles as well as neuronal degeneration and loss, and is a type of dementia that causes cognitive decline and personality changes. Currently, treatment of Alzheimer's disease is limited to symptomatic treatment with drugs aimed at symptom improvement using acetylcholinesterase inhibitors and the like, and there is no effective method for treatment and / or prevention of the cause of Alzheimer's disease .

  Aβ aggregates to form senile plaques and causes neuronal degeneration / dropout. Aβ can be divided into several types depending on the number of amino acids. Among them, Aβ40 with 40 amino acids and Aβ42 with 42 amino acids are highly aggregated, and are easily deposited in the brain earlier than other species. Is known to be strong. In familial Alzheimer's disease, it is known that production of Aβ42 with higher aggregation is enhanced. For these reasons, the expression of Alzheimer's disease is thought to be closely related to the production of Aβ. Therefore, it is considered that a drug that suppresses the production of Aβ40 and Aβ42 can be a therapeutic and / or prophylactic agent for Alzheimer's disease. Aβ is considered as one of the causes of Down's syndrome or other diseases caused by Aβ (eg, cognitive impairment, memory impairment, learning impairment, mild cognitive impairment, cerebrovascular angiopathy, etc.).

  Amyloid precursor protein (APP) is first cleaved by beta secretase, and then cleaved by gamma secretase having presenilin as a constituent factor to produce Aβ. Therefore, a drug targeting beta and gamma secretase suppresses Aβ production and is expected to be a therapeutic and / or prophylactic agent for Alzheimer's disease. Various compounds that suppress Aβ production have been known so far, but the chemical structure is different from the compound of the present invention having an amide as the main structure (for example, Patent Document 1). On the other hand, SST receptor subtype 5 antagonists whose main structure is an amide shown below are known.

  However, the use is completely different from the compound of the present invention, which is an Aβ production inhibitor, and the structure is also different (for example, Patent Document 2).

International Publication No. 05/115990 International Publication No. 06/128803

  An object of the present invention is to provide a novel compound having a strong Aβ40 and Aβ42 production inhibitory effect and useful as a therapeutic and / or prophylactic agent for a neuropsychiatric disorder caused by Aβ represented by Alzheimer's disease.

  As a result of intensive studies, the present inventors have found that a novel compound represented by the following formula (I) has a strong Aβ production inhibitory action and completed the present invention. According to the present invention, an amide derivative represented by the following formula (I) or a pharmaceutically acceptable salt thereof (hereinafter also referred to as “the compound of the present invention”) is provided.

  [Item 1] The following formula (I):

[Where:
X ¹ represents CQ ¹ or a nitrogen atom, X ² represents CQ ² or a nitrogen atom, X ³ represents CQ ³ or a nitrogen atom,
Q ¹ , Q ² and Q ³ are the same or different and each represents a hydrogen atom, halogen, C _1-6 alkyl or C _1-6 alkoxy,
Y represents C _0-6 alkylene which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of halogen, hydroxyl group, C _1-3 alkoxy and aryl;
Z represents a single bond or — (a divalent group of a 4- to 9-membered nitrogen-containing saturated heterocyclic ring) —W—, wherein Z is — (a divalent group of a 4- to 9-membered nitrogen-containing saturated heterocyclic ring). ) -W-, the nitrogen-containing saturated heterocyclic ring is C _1-6 alkyl, CF ₃ , hydroxy-C _0-6 alkyl, C _1-6 alkoxy-C _0-6 alkyl, aryl at the substitutable position. And may be substituted with 1 to 3 identical or different substituents selected from the group consisting of fluorine atoms,
W _{is, - (CH 2) n -} , - CO (CH 2) n -, - COO (CH 2) n - or -CONR ⁴ _{(CH 2) n} - represents, wherein each said - (CH ₂ )-Is the same or different and is substituted with 1-2 C _1-6 alkyl, CF ₃ , hydroxy-C _0-6 alkyl, C _1-6 alkoxy-C _0-6 alkyl, aryl or fluorine atoms. Or two hydrogen atoms may be substituted with C _2-6 alkylene to form one saturated carbocycle,
A represents aryl, saturated carbocycle or heteroaryl, wherein the aryl, saturated carbocycle or heteroaryl is halogen, CF ₃ , CF ₃ O, hydroxyl, cyano, nitro, aryl-C _{0- 4} alkyl, heteroaryl-C _0-4 alkyl, C _1-6 alkyl, C _3-8 cycloalkyl-C _0-4 alkyl, 4-8 membered saturated heterocycle-C _0-4 alkyl, C _1-6 Substituted with 1 to 5 identical or different substituents selected from the group consisting of alkoxycarbonyl, C _0-4 alkyl-aminocarbonyl, C _1-4 alkylenedioxy, aryloxy and C _1-6 alkoxy Where Y is C _1-6 alkylene when A is aryl or heteroaryl and Z is a single bond;
R ¹ represents halogen, C _1-6 alkyl or C _1-6 alkoxy,
R ² represents halogen, C _1-6 alkyl, C _1-6 alkoxy or C _1-6 alkoxy-C _1-6 alkoxy,
R ³ and R ⁴ are the same or different and each represents a hydrogen atom or C _1-6 alkyl;
n represents an integer of 0 to 4. ]
Or a pharmaceutically acceptable salt thereof.

[Claim 2] W _{is, - (CH 2) n -} , - CO (CH 2) n - or -CONR ⁴ _{(CH 2) n} - is,
Item 12. The compound according to Item 1 or a pharmaceutically acceptable salt thereof.
[Item 3] Z is-(a divalent group of a 4- to 9-membered nitrogen-containing saturated heterocyclic ring) -W-, and W and a nitrogen atom of the nitrogen-containing saturated heterocyclic ring are bonded.
Item 3. The compound according to Item 1 or Item 2, or a pharmaceutically acceptable salt thereof.
[Item 4] A divalent group of a 4- to 9-membered nitrogen-containing saturated heterocyclic ring of Z is an azetidine divalent group, a morpholine divalent group, a pyrrolidine divalent group which may be crosslinked with C _1-4 alkylene, C _A piperidine divalent group optionally cross-linked with _0-4 alkylene or a homopiperidine divalent group optionally cross-linked with C _2-4 alkylene,
Item 4. The compound according to any one of Items 1 to 3, or a pharmaceutically acceptable salt thereof.
[Item 5] R ² is a fluorine atom, a chlorine atom, C _1-3 alkyl, C _1-3 alkoxy, or C _1-3 alkoxy-C _1-3 alkoxy.
Item 5. The compound according to any one of Items 1 to 4 or a pharmaceutically acceptable salt thereof.
[Item 6] R ¹ is C _1-3 alkyl.
Item 6. The compound according to any one of Items 1 to 5, or a pharmaceutically acceptable salt thereof.
[Item 7] R ¹ is methyl positioned at the 4-position of the imidazole ring.
Item 7. The compound according to any one of Items 1 to 6, or a pharmaceutically acceptable salt thereof.
[Item 8] W is a single bond, -CO- or CONH-.
Item 8. The compound according to any one of Items 1 to 7, or a pharmaceutically acceptable salt thereof.
[Item 9] X ¹ is CQ ¹ or a nitrogen atom, X ² is CQ ² , and X ³ is CQ ³ .
Item 9. The compound according to any one of Items 1 to 8, or a pharmaceutically acceptable salt thereof.
[Item 10] X ¹ , X ² and X ³ are each CH.
Item 10. The compound according to any one of Items 1 to 9, or a pharmaceutically acceptable salt thereof.
[Item 11] A group wherein A is halogen, CF ₃ , CF ₃ O, nitro, aryl, heteroaryl, C _1-4 alkyl, C _3-8 cycloalkyl, 4- to 8-membered saturated heterocycle and aryloxy An aryl or saturated carbocycle optionally substituted with 1 to 3 identical or different substituents selected from
Item 11. The compound according to any one of Items 1 to 10, or a pharmaceutically acceptable salt thereof.
[Item 12] Y is C _0-4 alkylene optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of a fluorine atom and C _1-3 alkoxy.
Item 12. The compound according to any one of Items 1 to 11 or a pharmaceutically acceptable salt thereof.
[Item 13] Z is a single bond.
Item 13. The compound according to any one of Items 1, 2, 5 to 7, and 9 to 12, or a pharmaceutically acceptable salt thereof.

CLAIM | ITEM 14 The compound of claim | item 1 selected from the following compounds:
N- (4-tert-butylbenzyl) -3-methoxy-4- (4-methyl-1H-imidazol-1-yl) benzamide (Example 23),
3-methoxy-4- (4-methyl-1H-imidazol-1-yl) -N- [2- (3-phenoxyphenyl) ethyl] benzamide (Example 29),
3-methoxy-4- (4-methyl-1H-imidazol-1-yl) -N- {2- [2- (trifluoromethyl) phenyl] ethyl} benzamide (Example 30),
N- (3,5-dichlorobenzyl) -3-methoxy-4- (4-methyl-1H-imidazol-1-yl) benzamide (Example 39),
3-methoxy-4- (4-methyl-1H-imidazol-1-yl) -N- (naphthalen-1-ylmethyl) benzamide (Example 49),
3-methoxy-4- (4-methyl-1H-imidazol-1-yl) -N- [1- (naphthalen-1-yl) ethyl] benzamide (Example 50),
3-methoxy-4- (4-methyl-1H-imidazol-1-yl) -N- [2- (naphthalen-2-yl) ethyl] benzamide (Example 52),
6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -N- (naphthalen-1-ylmethyl) pyridine-2-carboxamide (Example 56),
N- [1- (3-Chlorobenzyl) piperidin-4-yl] -3-methoxy-4- (4-methyl-1H-imidazol-1-yl) benzamide (Example 62),
3-methoxy-4- (4-methyl-1H-imidazol-1-yl) -N- [1- (phenylcarbonyl) piperidin-3-yl} benzamide (Example 64),
3-methoxy-4- (4-methyl-1H-imidazol-1-yl) -N- {1- [3- (3-methylphenyl) propanoyl] piperidin-3-yl} benzamide (Example 67),
N- {1-[(2-chlorophenyl) acetyl] piperidin-3-yl} -3-methoxy-4- (4-methyl-1H-imidazol-1-yl) benzamide (Example 71),
3-methoxy-4- (4-methyl-1H-imidazol-1-yl) -N- (1- {3- [4- (trifluoromethyl) phenyl] propanoyl} piperidin-3-yl) benzamide (Examples) 79),
N-({1-[(3-fluorophenyl) acetyl] piperidin-4-yl} methyl) -3-methoxy-4- (4-methyl-1Himidazol-1-yl) benzamide (Example 81),
N- (2-chlorobenzyl) -3-({[3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl] carbonyl} amino) piperidine-1-carboxamide (Example 87) ,
N- [2- (3-chlorophenyl) ethyl] -3-({[3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl] carbonyl} amino) piperidine-1-carboxamide ( Example 98),
3-methoxy-4- (4-methyl-1H-imidazol-1-yl) -N- {1- [3- (trifluoromethyl) benzyl] piperidin-3-yl} benzamide (Example 112),
3-Methoxy-4- (4-methyl-1H-imidazol-1-yl) -N {(3R) -1- [3- (trifluoromethyl) benzyl] piperidin-3-yl} benzamide (Example 113) ,
6-methoxy-5- (4-methyl-1H-imidazol-1-yl) -N-{(3S) -1- [3- (trifluoromethyl) benzyl] piperidin-3-yl} pyridine-2-carboxy An amide (Example 117),
3-methoxy-N- [1- (2-methoxybenzyl) piperidin-3-yl] -4- (4-methyl-1H-imidazol-1-yl) benzamide (Example 118),
N- [1- (3-fluorobenzyl) piperidin-3-yl] -3-methoxy-4- (4-methyl-1H-imidazol-1-yl) benzamide (Example 119), and N- (biphenyl- 3-ylmethyl) -3- (2-methoxyethoxy) -4- (4-methyl-1H-imidazol-1-yl) benzamide (Example 136).

[Item 15] The compound according to item 1, selected from the following compounds:
N- (biphenyl-3-ylmethyl) -3-methoxy-4- (4-methyl-1H-imidazol-1-yl) benzamide (Example 1),
N- (biphenyl-3-ylmethyl) -6-methoxy-5- (4-methyl-1H-imidazol-1-yl) pyridine-2-carboxamide (Example 6),
N- [2- (biphenyl-4-yl) ethyl] -3-methoxy-4- (4-methyl-1H-imidazol-1-yl) benzamide (Example 53),
N- {1-[(4-chlorophenyl) carbonyl] piperidin-3-yl} -3-methoxy-4- (4-methyl-1H-imidazol-1-yl) benzamide (Example 70),
3-Methoxy-4- (4-methyl-1H-imidazol-1-yl) -N {(3S) -1- [3- (trifluoromethyl) benzyl] piperidin-3-yl} benzamide (Example 114) ,
3-methoxy-4- (4-methyl-1H-imidazol-1-yl) -N- {1- [4- (trifluoromethyl) benzyl] piperidin-3-yl} benzamide (Example 121),
3-methoxy-N- [1- (4-methylbenzyl) piperidin-3-yl] -4- (4-methyl-1H-imidazol-1-yl) benzamide (Example 122),
N- [1- (3-Chlorobenzyl) piperidin-3-yl] -3-methoxy-4- (4-methyl-1H-imidazol-1-yl) benzamide (Example 123),
N- [1- (4-Bromobenzyl) piperidin-3-yl] -3-methoxy-4- (4-methyl-1H-imidazol-1-yl) benzamide (Example 125),
3-methoxy-4- (4-methyl-1H-imidazol-1-yl) -N- {1- [3- (trifluoromethyl) phenyl] piperidin-3-yl} benzamide (Example 132),
N- [1- (4-Chlorobenzyl) piperidin-3-yl] -3-methoxy-4- (4-methyl-1H-imidazol-1-yl) benzamide (Example 133),
3-methoxy-4- (4-methyl-1H-imidazol-1-yl) -N-({1- [3- (trifluoromethyl) phenyl] piperidin-4-yl} methyl) benzamide (Example 134) as well as,
3-Methoxy-4- (4-methyl-1H-imidazol-1-yl) -N-({1- [3- (trifluoromethyl) phenyl] piperidin-3-yl} methyl) benzamide (Example 135) .

[Item 16] A pharmaceutical composition comprising the compound according to any one of items 1 to 15 or a pharmaceutically acceptable salt thereof.
[Item 17] A therapeutic or prophylactic agent for a disease caused by beta amyloid, comprising the compound according to any one of items 1 to 15 or a pharmaceutically acceptable salt thereof as an active ingredient.
[Item 18] The therapeutic or preventive agent according to item 17, wherein the disease caused by beta amyloid is Alzheimer's disease, Down's syndrome, cognitive impairment, memory impairment / learning impairment, mild cognitive impairment, or cerebrovascular angiopathy.

  The compound of the present invention is a therapeutic agent and / or prophylaxis for Alzheimer's disease, Down's syndrome or other diseases caused by Aβ (for example, cognitive impairment, memory impairment / learning impairment, mild cognitive impairment, senile dementia, amyloidosis, cerebrovascular angiopathy, etc.) Useful as an agent.

  Since the compounds of the present invention may exist in the form of hydrates and / or solvates, these hydrates and / or solvates are also encompassed by the compounds of the present invention.

  The compound of formula (I) may have one or more asymmetric carbon atoms and may cause geometric isomerism and axial chirality, and therefore exist as several stereoisomers. There is. In the present invention, these stereoisomers, mixtures thereof and racemates are included in the compound represented by the formula (I) of the present invention.

  Next, terms used in this specification will be described below.

“Alkyl” means a linear or branched saturated hydrocarbon group, for example, “C _0-4 alkyl” or “C _1-6 alkyl” means 0 carbon atoms, A bond or 1 to 3 or a substituent of 1 to 6 is meant. Specific examples thereof include “C _0-4 alkyl” such as a single bond, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc., and “C _1-6 alkyl”. In the case of "", methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl or hexyl.
“Alkoxy” means a group in which a linear or branched saturated hydrocarbon group is bonded via an oxygen atom. For example, “C _1-3 alkoxy” or “C _1-6 alkoxy” "Means alkoxy having 1 to 3 or 1 to 6 carbon atoms, respectively. Specific examples thereof include methoxy, ethoxy, propoxy, isopropoxy and the like in the case of “C _1-3 alkoxy”, and in the case of “C _1-6 alkoxy”, in addition to the above, butyloxy, pentyloxy And hexyloxy.

“Halogen” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
Specific examples of “aryl” include phenyl, 1-naphthyl, 2-naphthyl and the like. Of these, phenyl is preferable.
Examples of the “saturated carbocycle” include a 3- to 11-membered monocyclic or bicyclic saturated carbocyclic group, and a group that partially forms an aromatic ring is also included. Specifically, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, bornyl, pinanyl, noradamantyl, adamantyl, 2-indanyl, 2-indenyl, 5,6,7,8-tetrahydro-2-naphthyl, etc. Is mentioned. Among them, preferred is cyclopentyl, cyclohexyl, bornyl or adamantyl.
As the “heteroaryl”, a monocyclic 5- to 7-membered aromatic heterocyclic group containing 1 to 4 atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, or bicyclic 8- An 11-membered aromatic heterocyclic group is mentioned. Specifically, pyridyl, pyridazinyl, isothiazolyl, pyrrolyl, furyl, thienyl, thiazolyl, imidazolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrazinyl, triazinyl, triazolyl, imidazolidinyl, oxadiazolyl, triazolyl, tetrazolyl, indolyl, indolyl, indolyl, indryl Examples include quinolyl, isoquinolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzotriazolyl, benzimidazolyl and the like. Preferred heteroaryls include pyridyl, pyrimidinyl, quinolyl, and isoquinolyl.

“Alkylene” means a straight chain, cyclic, or straight chain divalent saturated hydrocarbon group including a ring and a branch. For example, “C _1-4 alkylene” means alkylene having 1 to 4 carbon atoms, methylene, ethylene, propylene, butylene, 2-methylethylene, cyclopropylmethylene, 1,1-cyclopropylene, 1,3-cyclobutylene and the like can be mentioned. “C _0-6 alkylene” means an alkylene having 0 to 6 carbon atoms. Specific examples thereof include, in addition to the above, a single bond, pentylene, hexylene, 2-methylbutylene, 1,3- And cyclopentylene. In addition, methylene (— (CH ₂ ) —) may be substituted with one C _2-6 alkylene to form a saturated carbocycle, which means that one C _3-7 saturated carbocycle is 1 It means a divalent group bonded by one carbon atom.

The “4- to 8-membered saturated heterocyclic ring” means a heterocyclic ring composed of 4 to 8 atoms including 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms in addition to carbon atoms. For example, azetidine, pyrrolidine, piperidine, piperazine, morpholine, homopiperidine, tetrahydrofuran, tetrahydropyran and the like can be mentioned.
The “4- to 9-membered nitrogen-containing saturated heterocyclic divalent group” is a monocyclic or bicyclic group composed of 4 to 9 atoms including at least 1 to 2 nitrogen atoms in addition to carbon atoms. It means a divalent group of a saturated ring (wherein the saturated ring may further be substituted with one carbon atom by an oxygen atom or a sulfur atom). Specific examples of the monocyclic saturated heterocyclic ring include azetidine, pyrrolidine, piperidine, piperazine, morpholine, homopiperidine (for example, a-12 or a-13) and the like.

  Specific examples of the divalent group of the bicyclic nitrogen-containing saturated heterocyclic ring include the following groups in addition to the divalent group of the specific examples of the monocyclic saturated heterocyclic ring.

_{"C 3-8} cycloalkyl _{-C 0-4} alkyl" _{refers, C 1-4} 1 of the hydrogen atoms are _{C 3-8} group substituted with a cycloalkyl or _{C 3-8} cycloalkyl alkyl _{(C 0- 4} alkyl means C ₀ alkyl, ie in the case of a single bond. The position to be replaced is not limited to the end but is an arbitrary position. Similar to “C _3-8 cycloalkyl-C _0-4 alkyl”, “4-8 membered saturated heterocyclic-C _0-4 alkyl”, “C _1-6 alkoxy-C _1-6 alkoxy”, “ "Aryl-C _0-4 alkyl", "heteroaryl-C _0-4 alkyl" and "-(4-8 membered nitrogen-containing saturated heterocycle) -W-" are one hydrogen of each latter substituent. It means a group in which an atom is replaced with each former group.

Among the compounds of the present invention represented by the formula (I), X ^{1 to} X ³ , Y, Z, W, A, R ^{1 to} R ⁴ and n are preferable as follows. The technical scope is not limited to the scope of the compounds listed below.

The preferred combinations of X ^{1, X 2} and ^{X 3,} X 1, ^{X 2} and ^{X 3} is a benzene ring or ^{X 1} is ^CQ 1, CQ ² and CQ ³ is a nitrogen atom, is ^{X 2} and ^{X 3} Examples include pyridine rings which are CQ ² and CQ ³ respectively.
Q ¹ , Q ² and Q ³ are preferably the same or different and include a hydrogen atom, halogen or C _1-6 alkyl. More preferred is a hydrogen atom or halogen, and most preferred is a hydrogen atom.
Y is preferably unsubstituted or C _0-6 alkylene substituted with 1 to 3 identical or different substituents selected from the group consisting of halogen and C _1-3 alkoxy. More preferably, unsubstituted _C0-4 alkylene is mentioned. Most preferably, unsubstituted _C0-2 alkylene is mentioned.
Z is preferably a single bond or-(a divalent group of a 4- to 9-membered nitrogen-containing saturated heterocyclic ring) -W-. More preferably, a single bond or-(bivalent group of a 4-7 membered nitrogen-containing saturated heterocyclic ring) -W- is mentioned. Preferable bonding positions of W and Y include any carbon atom on the nitrogen-containing saturated heterocyclic ring, and more preferably include a carbon atom that is not bonded to a nitrogen atom. A preferable bonding position with W includes a bonding position with a nitrogen atom of a nitrogen-containing saturated heterocyclic ring. The divalent group of the 4- to 9-membered nitrogen-containing saturated heterocyclic group of Z is preferably an azetidine divalent group, a morpholine divalent group, a pyrrolidine divalent group optionally cross-linked with C _1-4 alkylene, C _{0- 4} be crosslinked by alkylene include divalent good homopiperidine be crosslinked with even better piperidine divalent or C _2-4 alkylene. More preferably, it is a pyrrolidine divalent group which may be crosslinked with C _1-4 alkylene or a piperidine divalent which may be crosslinked with C _0-4 alkylene.
W is preferably — (CH ₂ ) _n — or —CO (CH ₂ ) _n —. More preferably, - _{(CH 2) n} - and the like. Most preferably, a single bond, a methylene, or ethylene is mentioned.

A is preferably phenyl, naphthyl or a saturated carbocycle. More preferred are phenyl, 1-naphthyl, 2-naphthyl, 5,6,7,8-tetrahydro-2-naphthyl, bornyl, adamantyl or cyclohexyl, more preferred is phenyl or cyclohexyl, most preferred. Includes phenyl. When a substituent is substituted on A, the substituent is preferably halogen, CF ₃ , cyano, nitro, aryl-C _0-4 alkyl, C _1-6 alkyl, C _3-8 saturated heterocycle-C _0-4. Examples include alkyl, C _1-6 alkoxycarbonyl, C _1-4 alkylenedioxy, aryloxy or C _1-6 alkoxy. More preferably, halogen, CF _3, cyano, _{aryl, C 1-6} alkyl, aryloxy or _{C 1-6} alkoxy. Most preferably, halogen, CF ₃ , aryl or aryloxy is used.
R ¹ is preferably halogen or C _1-6 alkyl. More _{preferably, C 1-6} alkyl and the like, more _{preferably, C 1-3} alkyl and the like, most preferably, methyl.
R ² is preferably halogen, C _1-6 alkyl or C _1-6 alkoxy. More preferably _{include C 1-6} alkyl or _{C 1-6} alkoxy. More preferably, _C1-3 alkoxy is mentioned, Most preferably, methoxy is mentioned.
R ³ is preferably a hydrogen atom or C _1-3 alkyl. More preferably, a hydrogen atom or methyl is mentioned, Most preferably, a hydrogen atom is mentioned.
R ⁴ is preferably a hydrogen atom or C _1-3 alkyl. More preferably, a hydrogen atom or methyl is mentioned, Most preferably, a hydrogen atom is mentioned.
n is preferably 0, 1 or 2, more preferably 0 or 1, and most preferably 1.

  The pharmaceutically acceptable salt of the compound represented by the formula (I) is a pharmaceutically acceptable acid addition of the compound of the formula (I) having a group capable of forming an acid addition salt in the structure. Means salt. Specific examples of acid addition salts include hydrochloride, hydrobromide, hydroiodide, sulfate, perchlorate, phosphate and other inorganic acid salts, oxalate, malonate, maleate Acid salt, fumarate, lactate, malate, citrate, tartrate, benzoate, trifluoroacetate, acetate, methanesulfonate, p-toluenesulfonate, trifluoromethanesulfonate And organic acid salts such as glutamic acid salts and aspartic acid salts.

Note that the following abbreviations may be used to simplify the description in this specification. p-: para-, t-: tert-, s-: sec-, THF: tetrahydrofuran, DMF: N, N-dimethylformamide, DMA: N, N-dimethylacetamide, DME: ethylene glycol dimethyl ether, NMP: N- Methyl-2-pyrrolidone, DMSO: dimethyl sulfoxide, d ₆ -DMSO: deuterated dimethyl sulfoxide.

Production method of the compound of the present invention The compound of the present invention represented by the formula (I) can be produced by the production method A, B, C, D or E shown below. The compound represented by the formula (I) or a pharmaceutically acceptable salt thereof is a novel compound and can be produced, for example, by the method described below, the examples described later and a method analogous thereto. The compound used in the following production method may form a salt as long as the reaction is not hindered.

[Production method A]
The compound of the formula (I) can be produced by the following production method.

(Wherein X ¹ , X ² , X ³ , Y, Z, A, R ¹ , R ² and R ³ are the same as defined in item 1).

  Compound (I) is obtained by performing a condensation reaction between compound (II) and compound (III). This reaction can be performed according to a conventional method. For example, this reaction is achieved by converting compound (II) into a reactive derivative (eg, lower alkyl ester, active ester, acid anhydride, acid halide, etc.) and reacting with compound (III). The starting compound (III) is commercially available or synthesized by a method according to a known method. Specific examples of the active ester include p-nitrophenyl ester, N-hydroxysuccinimide ester, pentafluorophenyl ester and the like. Specific examples of the acid anhydride include mixed acid anhydrides with ethyl chlorocarbonate, isobutyl chlorocarbonate, isovaleric acid, pivalic acid and the like.

  Compound (I) can also be produced by reacting compound (II) with compound (III) in the presence of a condensing agent. Specific examples of the condensing agent include N, N′-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide monohydrochloride, N, N′-carbonyldiimidazole, benzotriazol-1-yl -Oxytris (pyrrolidino) phosphonium-hexafluorophosphate, hexafluorophosphate 2- (7-aza-1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium (HATU), etc. Can be mentioned. Use these condensing agents alone or in combination with these condensing agents and peptide synthesis reagents such as N-hydroxysuccinimide, N-hydroxybenzotriazole, 1-hydroxy-7-azabenzo-1-triazole. Can do.

  The reaction between compound (II) and compound (III) is carried out in a solvent or without a solvent. Specific examples of the solvent should be selected according to the type of raw material compound, etc., for example, toluene, THF, 1,4-dioxane, DME, dichloromethane, chloroform, ethyl acetate, acetone, acetonitrile, DMF, DMSO and the like. Can be used alone or as a mixed solvent. Compound (III) may be used in the form of an acid addition salt such as an aqueous solution or hydrochloride, and a free base may be generated in the reaction system. This reaction is usually carried out in the presence of a base. Specific examples of the base used include inorganic bases such as potassium carbonate and sodium hydrogen carbonate, triethylamine, ethyldiisopropylamine, N-methylmorpholine, pyridine. And organic bases such as 4-dimethylaminopyridine. While the reaction temperature varies depending on the kind of raw material compound used, it is generally about −30 ° C. to about 150 ° C., preferably about −10 ° C. to about 70 ° C.

[Production method B]
In formula (I), Z is — (a divalent group of a 4- to 9-membered nitrogen-containing saturated heterocyclic ring) —W—, and W is —CO (CH ₂ ) _n — or —COO (CH ₂ ) _n —. , —CONR ⁴ (CH ₂ ) _n — [compound of the following formula (Ia)] can also be produced by the following production method.

(In the formula, X ¹ , X ² , X ³ , Y, A, R ¹ , R ² , R ³ , R ⁴ and n are the same as defined in item 1, and Z ¹ is 4 to 9 membered. A divalent group of a nitrogen-containing saturated heterocyclic ring, and W ¹ is — (CH ₂ ) _n —, —O (CH ₂ ) _n —, —, or —NR ⁴ (CH ₂ ) _n —.

  Compound (Ia) is obtained by performing a condensation reaction of compound (IV) with various carboxylic acids and the like. This reaction can be performed according to a conventional method. For example, this reaction can be achieved by reacting compound (IV) in the presence of various carboxylic acids or the like and a condensing agent in a suitable solvent or without a solvent. Specific examples of the condensing agent include N, N′-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide monohydrochloride, N, N′-carbonyldiimidazole, dimethylaminosulfonic acid chloride. 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, benzotriazol-1-yl-oxytris (pyrrolidino) phosphonium-hexafluorophosphate, hexafluorophosphate 2- (7-aza-1H-benzotriazole -1-yl) -1,1,3,3-tetramethyluronium (HATU) and the like. These condensing agents can be used alone or in combination with peptide condensing reagents such as N-hydroxysuccinimide, N-hydroxybenzotriazole, 1-hydroxy-7-azabenzo-1-triazole. .

  Specific examples of the solvent should be selected according to the type of the raw material compound, and include, for example, dichloromethane, chloroform, dichloroethane, THF, 1,4-dioxane, DME, acetonitrile, DMF, DMA, NMP, DMSO and the like. Can be used alone or as a mixed solvent. Compound (IV) may be used in the form of an acid addition salt such as hydrochloride, and a free base may be generated in the reaction system. This reaction is usually carried out in the presence of a base. Specific examples of the base used include inorganic bases such as potassium carbonate and sodium hydrogen carbonate, triethylamine, ethyldiisopropylamine, N-methylmorpholine, pyridine. And organic bases such as 4-dimethylaminopyridine. While the reaction temperature varies depending on the raw material compound and the type of reagent used, it is generally −20 to 200 ° C., preferably 0 to 100 ° C.

  Compound (Ia) can also be obtained by reacting compound (IV) with various acid chlorides, acid anhydrides, chloroformates, carbamoyl chlorides, isocyanates and the like in an appropriate solvent or without solvent. Specific examples of the solvent should be selected according to the type of the raw material compound, and include, for example, dichloromethane, chloroform, dichloroethane, THF, 1,4-dioxane, DME, acetonitrile, DMF, DMA, NMP, DMSO and the like. Can be used alone or as a mixed solvent. Compound (IV) may be used in the form of an acid addition salt such as hydrochloride, and a free base may be generated in the reaction system. This reaction is usually carried out in the presence of a base. Specific examples of the base used include inorganic bases such as potassium carbonate and sodium hydrogen carbonate, triethylamine, ethyldiisopropylamine, N-methylmorpholine, pyridine. And organic bases such as 4-dimethylaminopyridine. While the reaction temperature varies depending on the raw material compound and the type of reagent used, it is generally −20 to 200 ° C., preferably 0 to 100 ° C.

[Production Method C]
In formula (I), Z is — (a divalent group of a 4 to 9-membered nitrogen-containing saturated heterocyclic ring) —W—, W is — (CH ₂ ) _n —, and n is an integer of 1 to 4. The compound [compound of the following formula (Ib)] can be produced by the following production method.

(In the formula, X ¹ , X ² , X ³ , Y, A, R ¹ , R ² and R ³ are the same as defined in item 1, and Z ¹ is a 4- to 9-membered nitrogen-containing saturated heterocyclic ring. And n is an integer of 1 to 4.)

  Compound (Ib) is obtained by performing reductive amination reaction from compound (IV). This reaction can be performed according to a conventional method. For example, this reaction can be achieved by reacting compound (IV) in the presence of various ketones or aldehydes and a reducing agent in the presence or absence of a suitable solvent. Specific examples of the reducing agent include sodium borohydride, lithium aluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride and the like. Specific examples of the solvent should be selected according to the type of the raw material compound, etc., for example, dichloromethane, chloroform, dichloroethane, THF, 1,4-dioxane, DME, acetonitrile, DMF, DMA, NMP, DMSO, acetic acid, Water or alcohols such as methanol, ethanol, isopropanol and the like can be mentioned, and these can be used alone or as a mixed solvent. While the reaction temperature varies depending on the raw material compound and the type of reagent used, it is generally −20 to 200 ° C., preferably 0 to 100 ° C.

  Compound (Ib) can also be obtained by reacting compound (IV) with various benzyl halides, phenethyl halides and the like in a suitable solvent or without solvent. Specific examples of the solvent should be selected according to the type of the raw material compound, and include, for example, dichloromethane, chloroform, dichloroethane, THF, 1,4-dioxane, DME, acetonitrile, DMF, DMA, NMP, DMSO and the like. Can be used alone or as a mixed solvent. Compound (IV) may be used in the form of an acid addition salt such as hydrochloride, and a free base may be generated in the reaction system. This reaction is usually carried out in the presence of a base. Specific examples of the base used include inorganic bases such as potassium carbonate and sodium hydrogen carbonate, triethylamine, ethyldiisopropylamine, N-methylmorpholine, pyridine. And organic bases such as 4-dimethylaminopyridine. While the reaction temperature varies depending on the raw material compound and the type of reagent used, it is generally −20 to 200 ° C., preferably 0 to 100 ° C.

[Production Method D]
In the formula (I), a compound in which Z is — (a divalent group of a 4- to 9-membered nitrogen-containing saturated heterocyclic ring) —W—, W is — (CH ₂ ) _n —, and n is 0 [below The compound of the formula (Ic)] can be produced by the following production method.

(In the formula, X ¹ , X ² , X ³ , Y, A, R ¹ , R ² and R ³ are the same as defined in item 1, and Z ¹ is a 4- to 9-membered nitrogen-containing saturated heterocyclic ring. The divalent group of

When compound (IV) is coupled with various substituted phenyl halides, compound (Ic) is obtained. This reaction can be performed according to a conventional method. For example, the compound (Ic) is prepared by mixing the compound (IV) and various substituted phenyl halides with a transition metal catalyst such as a palladium catalyst typified by tetrakistriphenylphosphine palladium and trisdibenzylideneacetone dipalladium and 2 It can be obtained by conducting a coupling reaction in the presence of a ligand typified by-(di-t-butylphosphino) biphenyl. In these coupling reactions, in addition to the above reagents, inorganic bases such as alkali metal carbonates (for example, sodium carbonate, potassium carbonate, cesium carbonate) and potassium phosphate, or alkali metal alkoxides (for example, sodium-t-butoxide) Alternatively, the reaction can be carried out in the presence of an organic base such as triethylamine or diisopropylethylamine, or an inorganic salt such as lithium chloride or cesium fluoride. Specific examples of the solvent should be selected according to the type of raw material compound and the type of reagent used. For example, toluene, THF, 1,4-dioxane, DME, ethyl acetate, acetone, acetonitrile, DMF or methanol, ethanol And alcohols such as isopropanol and t-butanol, water, and the like can be used, and these can be used alone or as a mixed solvent. While the reaction temperature varies depending on the raw material compound and the type of reagent used, it is generally 0 to 200 ° C, preferably 60 to 150 ° C.
[Production Method E]
The compound of the formula (I) can also be produced by the following production method.

(In the formula, X ¹ , X ² , X ³ , Y, Z, A, R ¹ , R ² and R ³ are the same as defined in Item 1. Hal is halogen.)

  When compound (V) is reacted with substituted or unsubstituted imidazole, compound (I) is obtained. This reaction can be performed according to a conventional method. For example, compound (I) is compound (V) and a substituted or unsubstituted imidazole without catalyst in a suitable solvent, and a copper catalyst typified by cuprous halide, cuprous oxide or cupric oxide. Β-ketoesters typified by 2-oxocyclohexanecarboxylate, diamines typified by trans-1,2-cyclohexanediamine, or ligands such as 8-hydroxyquinoline and 4,7-dimethoxy-1,8-phenanthracene It can be obtained by conducting a coupling reaction in the presence. In these coupling reactions, in addition to the above reagents, inorganic metals such as alkali metal carbonates (for example, sodium carbonate, potassium carbonate, cesium carbonate, etc.), sodium alkoxides (for example, sodium methoxide, sodium ethoxide, etc.), potassium phosphate, etc. It can also be carried out in the presence of a base or an organic base such as triethylamine or diisopropylethylamine, or an inorganic salt such as lithium chloride or cesium fluoride. Specific examples of the solvent should be selected according to the type of raw material compound and the type of reagent used, and examples thereof include DMF, DMSO, NMP, acetonitrile, 1,4-dioxane, xylene, ionic liquid, and the like. It can be used alone or as a mixed solvent. While the reaction temperature varies depending on the raw material compound and the type of reagent used, it is generally 0 to 200 ° C, preferably 60 to 150 ° C.

  Compounds of formula (I), (Ia), (Ib), and (Ic) produced by the above production method A, B, C, D, or E are isolated by usual methods such as chromatography and recrystallization. -It can be purified.

  Next, the raw material compound used in the above production method A, B, C, D, or E can be produced by the following method.

  Compound (IV) used in the above production methods B, C and D is produced according to the method represented by the following reaction formula.

(In the formula, X ¹ , X ² , X ³ , Y, Z ¹ , R ¹ , R ² and R ³ are the same as defined in item 1, and Z ¹ is a 4- to 9-membered nitrogen-containing saturated complex. Ring is a divalent group, and P is an amino protecting group such as t-butoxycarbonyl, benzyloxycarbonyl, etc.)

  Compound (IV) is obtained by carrying out deprotection reaction of compound (VI). This reaction can be performed according to a conventional method. For example, this reaction can be achieved by carrying out the reaction in the presence of compound (VI) and an acid or a base in an appropriate solvent or without a solvent. Raw material compound (VI) can be produced by a method according to production method A using the corresponding raw material compound. Specific examples of the acid include hydrochloric acid, sulfuric acid, trifluoroacetic acid, p-toluenesulfonic acid, boron trichloride and the like. Specific examples of the base include sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, barium carbonate, sodium t-butoxide, potassium t-butoxide and the like. Specific examples of the solvent should be selected according to the type of raw material compound, etc., for example, dichloromethane, chloroform, dichloroethane, THF, 1,4-dioxane, DME, acetonitrile, DMF, DMA, NMP, DMSO, water or Alcohols such as methanol, ethanol and isopropanol can be mentioned, and these can be used alone or as a mixed solvent. While the reaction temperature varies depending on the raw material compound and the type of reagent used, it is generally −20 to 200 ° C., preferably 0 to 120 ° C. This deprotection reaction can also be achieved by catalytic reduction using a palladium catalyst or the like under a hydrogen stream depending on the protecting group.

  The compound (V) used in the production method E is produced according to the method represented by the following reaction formula.

(In the formula, X ¹ , X ² , X ³ , Y, Z, A, R ² and R ³ are the same as defined in Item 1. Hal is halogen.)

  Compound (V) is obtained by performing a condensation reaction between compound (VII) and compound (VIII). This reaction can be performed according to a conventional method. For example, this reaction can be achieved by reacting compound (VII) and compound (VIII) in the presence of a condensing agent or the like in a suitable solvent or without solvent. The starting compound (VII) is commercially available or synthesized by a method according to a known method. For example, this reaction is achieved by converting compound (VII) into a reactive derivative (eg, lower alkyl ester, active ester, acid anhydride, acid halide, etc.) and reacting with compound (VIII). Specific examples of the active ester include p-nitrophenyl ester, N-hydroxysuccinimide ester, pentafluorophenyl ester and the like. Specific examples of the acid anhydride include mixed acid anhydrides with ethyl chlorocarbonate, isobutyl chlorocarbonate, isovaleric acid, pivalic acid and the like.

  Compound (V) can also be produced by reacting compound (VII) with compound (VIII) in the presence of a condensing agent. Specific examples of the condensing agent include N, N′-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide monohydrochloride, N, N′-carbonyldiimidazole, benzotriazol-1-yl -Oxytris (pyrrolidino) phosphonium-hexafluorophosphate, hexafluorophosphate 2- (7-aza-1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium (HATU), etc. Can be mentioned. Use these condensing agents alone or in combination with these condensing agents and peptide synthesis reagents such as N-hydroxysuccinimide, N-hydroxybenzotriazole, 1-hydroxy-7-azabenzo-1-triazole. Can do.

  The reaction between compound (VII) and compound (VIII) is performed in a solvent or without a solvent. Specific examples of the solvent should be selected according to the type of raw material compound, etc., for example, toluene, THF, 1,4-dioxane, DME, dichloromethane, chloroform, ethyl acetate, acetone, acetonitrile, DMF, DMSO and the like. Can be used alone or as a mixed solvent. Compound (VIII) may be used in the form of an acid addition salt such as an aqueous solution or hydrochloride, and a free base may be generated in the reaction system. This reaction is usually carried out in the presence of a base. Specific examples of the base used include inorganic bases such as potassium carbonate and sodium hydrogen carbonate, triethylamine, ethyldiisopropylamine, N-methylmorpholine, pyridine. And organic bases such as 4-dimethylaminopyridine. While the reaction temperature varies depending on the kind of raw material compound used, it is generally about −30 ° C. to about 150 ° C., preferably about −10 ° C. to about 70 ° C.

  Optical isomers can be separated by performing a known separation step such as a method using an optically active column or a fractional crystallization method in an appropriate step of the production method. An optically active substance can also be used as a starting material.

  The pharmaceutically acceptable salt of compound (I) may be purified as it is when the salt of compound (I) is obtained by the above production method. When the free base of compound (I) is obtained, compound (I) may be dissolved or suspended in a suitable solvent, and an acid may be added to form a salt.

  As described later, the compounds of the present invention can be useful therapeutic agents for various neuropsychiatric diseases including Alzheimer's therapeutic agents. The administration route of the compound of the present invention may be any of oral administration, parenteral administration and rectal administration, and the daily dose varies depending on the type of compound, administration method, patient symptom / age and the like. For example, in the case of oral administration, usually about 0.01 to 1000 mg, more preferably about 0.1 to 500 mg per kg body weight of a human or mammal can be administered in 1 to several divided doses. In the case of parenteral administration such as intravenous injection, usually, for example, about 0.01 mg to 300 mg, more preferably about 1 mg to 100 mg per kg body weight of a human or mammal can be administered.

  The compound of the present invention is usually administered in the form of a preparation prepared by mixing with a pharmaceutical carrier when used for the above-mentioned pharmaceutical use. As the pharmaceutical carrier, a non-toxic substance that is commonly used in the pharmaceutical field and does not react with the compound of the present invention is used. Specifically, for example, citric acid, glutamic acid, glycine, lactose, inositol, glucose, mannitol, dextran, sorbitol, cyclodextrin, starch, partially pregelatinized starch, sucrose, methyl paraoxybenzoate, propyl paraoxybenzoate, and metasilicate aluminum Magnesium sulfate, synthetic aluminum silicate, crystalline cellulose, sodium carboxymethylcellulose, hydroxypropyl starch, carboxymethylcellulose calcium, ion exchange resin, methylcellulose, gelatin, gum arabic, pullulan, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose , Polyvinylpyrrolidone, polyvinyl alcohol, alginic acid, sodium alginate Light anhydrous silicic acid, magnesium stearate, talc, tragacanth, bentonite, bee gum, carboxyvinyl polymer, titanium oxide, sorbitan fatty acid ester, sodium lauryl sulfate, glycerin, fatty acid glycerin ester, purified lanolin, glycerogelatin, polysorbate, macrogol, vegetable oil Wax, propylene glycol, ethanol, benzyl alcohol, sodium chloride, sodium hydroxide, hydrochloric acid, water and the like.

  Examples of the dosage form include tablets, capsules, granules, powders, syrups, suspensions, injections, suppositories, eye drops, ointments, coatings, patches, inhalants and the like. These preparations can be prepared according to a conventional method. In the case of a liquid preparation, it may be dissolved or suspended in water or other appropriate medium at the time of use. Tablets and granules may be coated by a known method. In addition, these formulations may contain other therapeutically valuable ingredients.

  Hereinafter, the present invention will be described in more detail with reference to Reference Examples, Examples and Test Examples, but these do not limit the present invention. The compound was identified by elemental analysis, mass spectrum, high performance liquid chromatography / mass spectrometer; LCMS, IR spectrum, NMR spectrum, high performance liquid chromatography (HPLC) and the like.

  In order to simplify the description of the specification, the following abbreviations may be used in the reference examples, examples, and tables in the examples. As an abbreviation used as a substituent, Me means a methyl group and Ph means a phenyl group. The symbols used in NMR are as follows: s is a single line, d is a double line, dd is a double double line, t is a triple line, td is a triple double line, q is a quadruple line, m is Multiple lines, br means broad, brs means wide single line, brd means wide double line, and brt means wide triple line.

High-performance liquid chromatograph / mass spectrometer; LCMS measurement conditions are as follows, and the observed mass spectrometry value [MS (m / z)] is represented by MH +, and the retention time is represented by Rt (min).
Detection equipment:
Perkin-Elmer Sciex API 150EX Mass Spectrometer (40 eV)
HPLC:
Shimadzu LC 10ATVP
Column:
Shiseido CAPCELL PAK C18 ACR (S-5um, 4.6mm x 50mm)
Solvent:
Liquid A: 0.035% TFA / MeOH, Liquid B: 0.05% TFA / H ₂ O
Gradient Condition:
0.0-0.5 min; A / B = 10: 90
0.5-5.9 min; A / B = 10: 90 to 99: 1 (linear gradient)
5.9-6.4 min; A / B = 99: 1
Flow rate:
2.8 mL / min
UV:
220nm
Column temperature:
40 ° C

Reference example 1 :
3-Methoxy-4- (4-methyl-1H-imidazol-1-yl) -N- (piperidin-3-yl) benzamide hydrochloride

[Step 1]: 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) benzoic acid (500 mg), 1-Boc-3-aminopiperidine (440 mg), 1-ethyl-3- (3 -A solution of dimethylaminopropylcarbodiimide) hydrochloride (422 mg), 1-hydroxybenzotriazole monohydrate (297 mg) and triethylamine (596 μl) in DMF (5 ml) was stirred at room temperature overnight. A 10% aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate, and washed successively with a saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, the reaction mixture was concentrated under reduced pressure, purified by silica gel chromatography (0% to 10% methanol / chloroform), and tert-butyl 3-({[3-methoxy-4- (4 -Methyl-1H-imidazol-1-yl) phenyl] carbonyl} amino) piperidine-1-carboxylate (703 mg) was obtained as a colorless amorphous.

[Step 2]: The compound (703 mg) obtained in Reference Example 1 [Step 1] was dissolved in dioxane (5 ml), and a 4M HCl / dioxane solution (5 ml) was added dropwise. After stirring at room temperature for 5 hours, the reaction mixture was concentrated under reduced pressure to give 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) -N- (piperidin-3-yl) benzamide hydrochloride (878 mg). Obtained as a light brown solid.

¹ H-NMR (CD ₃ OD) δ: 9.20 (1H, s), 7.80 (1H, s), 7.67 (1H, d), 7.66 (1H, d) 7.62 (1H, s), 4.31 (1H, m ), 4.01 (3H, s), 3.53 (1H, m), 3.34 (2H, m), 3.03 (2H, m), 2.43 (3H, s), 2.11 (2H, m), 1.83 (2H, m) .
LC-MS: [M + H] ⁺ / Rt = 315 / 2.42 min.

Reference Example 2-6 :
The corresponding starting materials were used and reacted and treated in the same manner as in Reference Example 1 to obtain the compounds shown in Table 1.

Reference Example 7 :
N- (biphenyl-3-ylmethyl) -4-bromo-3- (2-methoxyethoxy) benzamide

  4-Bromo-3- (2-methoxyethoxy) benzoic acid (700 mg), m-phenylbenzylamine (559 mg), 1-ethyl-3- (3-dimethylaminopropylcarbodiimide) hydrochloride (728 mg), 1-hydroxy A solution of benzotriazole monohydrate (515 mg) and triethylamine (531 μl) in DMF (10 ml) was stirred at room temperature overnight. A 10% aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate, and washed successively with a saturated aqueous sodium hydrogen carbonate solution and saturated brine. After drying the organic layer over anhydrous magnesium sulfate, the reaction mixture was concentrated under reduced pressure, purified by silica gel chromatography (hexane / ethyl acetate = 0% to 100%), and N- (biphenyl-3-ylmethyl) -4-bromo- 3- (2-methoxyethoxy) benzamide (979 mg) was obtained as a colorless amorphous.

Example 1 :
N- (biphenyl-3-ylmethyl) -3-methoxy-4- (4-methyl-1H-imidazol-1-yl) benzamide

  3-methoxy-4- (4-methyl-1H-imidazol-1-yl) benzoic acid (100 mg), m-phenyl-benzylamine (95 mg), 1-ethyl-3- (3-dimethylaminopropylcarbodiimide) hydrochloric acid A solution of salt (100 mg), 1-hydroxybenzotriazole monohydrate (70 mg), N, N-diisopropylethylamine (120 ml) in DMF (4 ml) was stirred at room temperature overnight. A 10% aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate, and washed successively with a saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, the reaction mixture was concentrated under reduced pressure, and the residue was purified with a silica gel column (chloroform: methanol = 99: 1 to 85:15), and N- (biphenyl-3-ylmethyl) -3- Methoxy-4- (4-methyl-1H-imidazol-1-yl) benzamide (170 mg) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 2.24 (s, 3H), 3.85 (s, 3H), 4.69 (d, J = 5.6 Hz, 2H), 6.90 (s, 1H), 7.04-7.66 (m, 14H ).
LC-MS: [M + H] ⁺ / Rt = 398 / 5.18min

Example 2-63 :
Reaction and treatment were performed in the same manner as in Example 1 using the corresponding starting compounds, and the compounds shown in Table 2 were obtained.

Example 64
3-Methoxy-4- (4-methyl-1H-imidazol-1-yl) -N- [1- (phenylcarbonyl) piperidin-3-yl} benzamide

After desalting 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) -N- (piperidin-3-yl) benzamide hydrochloride (24 mg) obtained in Reference Example 1 [Step 2] , Dissolved in DMF (1 ml), benzoic acid (13 mg), 1-ethyl-3- (3-dimethylaminopropylcarbodiimide (36 μl), 1-hydroxy-7-azabenzotriazole (28 mg) and triethylamine (29 μl). The reaction mixture was added with saturated aqueous sodium hydrogen carbonate solution, extracted with chloroform and washed with water, the reaction mixture was concentrated under reduced pressure, and reverse-phase HPLC (water / methanol = 10% -90%) was added. 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) -N- [1- (phenylcarbonyl) piperidin-3-yl} benz The amide (3.3 mg) was obtained as a colorless amorphous.
LC-MS: [M + H] ⁺ / Rt: 419 / 4.11 min

Examples 65-80 :
Reaction and treatment were performed in the same manner as in Example 64 using the corresponding starting compounds, and the compounds shown in Table 3 were obtained.

Example 81 :
N-({1-[(3-Fluorophenyl) acetyl] piperidin-4-yl} methyl) -3-methoxy-4- (4-methyl-1H-imidazol-1-yl) benzamide

  3-methoxy-4- (4-methyl-1H-imidazol-1-yl) -N- (piperidin-4-ylmethyl) benzamide (33 mg), 3-fluorophenylacetic acid (15 mg) obtained in Reference Example 15 Hexafluorophosphate 2- (7-aza-1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium (HATU) (46 mg), triethylamine (20 mg) in DMF (1 ml) The solution was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate, the reaction mixture was concentrated under reduced pressure, and the residue was purified by medium pressure column chromatography (chloroform / methanol = 100/0 → 90/10), and N-({1- [2- (3-Fluorophenyl) acetyl] piperidin-4-yl} methyl) -3-methoxy-4- (4-methyl-1H-imidazol-1-yl) benzamide (40 mg) was obtained as amorphous.

¹ H-NMR (CDCl ₃ ) δ: 7.71 (1H, d), 7.60 (1H, d), 7.35 (1H, dd), 7.29-7.22 (2H, m), 7.07-6.90 (5H, m), 4.64 (1H, d), 3.89-3.85 (4H, m), 3.71 (2H, s), 3.45-3.36 (1H, m), 3.27-3.18 (1H, m), 3.03-2.96 (1H, m), 2.62 -2.55 (1H, m), 2.28 (3H, d), 1.90-1.72 (3H, m), 1.21-0.95 (2H, m).
LC-MS: [M + H] ⁺ / Rt: 465 / 4.47 min

Examples 82-86 :
Reaction and treatment were carried out in the same manner as in Example 81 using the corresponding starting compounds, and the compounds shown in Table 4 were obtained.

Example 87 :
N- (2-chlorobenzyl) -3-{[3-methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl] carbonylamino} piperidine-1-carboxamide

After desalting 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) -N- (piperidin-3-yl) benzamide hydrochloride (24 mg) obtained in Reference Example 1 [Step 2] , THF (1 ml) was added, 2-chlorobenzyl isocyanate (14 mg) was added, and the mixture was stirred at room temperature for 3 hours. Methanol (1 ml) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, purified by reverse phase HPLC (water / methanol = 10% -90%), and N- (2-chlorobenzyl). ) -3-({[3-Methoxy-4- (4-methyl-1H-imidazol-1-yl) phenyl] carbonyl} amino) piperidine-1-carboxamide (27.9 mg) was obtained as a colorless amorphous.
LC-MS: [M + H] ⁺ / Rt: 482 / 4.55 min

Examples 88-111 :
The corresponding starting materials were used and reacted in the same manner as in Example 87 to obtain the compounds shown in Table 5.

Example 112
3-methoxy-4- (4-methyl-1H-imidazol-1-yl) -N- {1- [3- (trifluoromethyl) benzyl] piperidin-3-yl} benzamide

  3-methoxy-4- (4-methyl-1H-imidazol-1-yl) -N- (piperidin-3-yl) benzamide hydrochloride (65 mg) obtained in Reference Example 1 [Step 2], 3-tri A solution of fluoromethylbenzyl bromide (31 μl) and potassium carbonate (111 mg) in DMF (2 ml) was stirred at room temperature overnight. A 10% aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate, and washed successively with a saturated aqueous sodium hydrogen carbonate solution and saturated brine. After drying the organic layer over anhydrous magnesium sulfate, the reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography (chloroform / methanol = 0% -10%) to give 3-methoxy-4- (4-methyl-1H-imidazole- 1-yl) -N- (1- (3- (trifluoromethyl) benzyl) piperidin-3-yl) benzamide (31 mg) was obtained as a colorless amorphous.

¹ H-NMR (CDCl ₃ ) δ: 7.77 (1H, s), 7.63 (2H, d), 7.46 (3H, m), 7.31 (1H, d) 7.24 (1H, d), 6.97 (1H, s) , 6.86 (1H, s), 4.29 (1H, m), 3.94 (3H, s), 3.65 (1H, d), 3.49 (1H, d), 2.74 (1H, m), 2.61 (1H, m), 2.48 (1H, m), 2.31 (2H, s), 2.27 (1H, m), 1.86 (1H, m), 1.77 (1H, m), 1.61 (2H, m), 1.13 (1H, s).
LC-MS: [M + H] ⁺ / Rt: 473 / 3.99 min

Examples 113-128 :
Reaction and treatment were carried out in the same manner as in Example 112 using the corresponding starting compounds, and the compounds shown in Table 6 were obtained.

Example 129 :
N-{[1- (4-Fluorophenyl) piperidin-4-yl] methyl} -3-methoxy-4- (4-methyl-1H-imidazol-1-yl) benzamide

  3-methoxy-4- (4-methyl-1H-imidazol-1-yl) -N- (piperidin-4-ylmethyl) benzamide (33 mg), 4-fluorobenzaldehyde (12 mg), sodium obtained in Reference Example 4 A solution of triacetoxyborohydride (32 mg) and acetic acid (9 mg) in THF (1 ml) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate, the reaction mixture was concentrated under reduced pressure, the residue was purified by column chromatography (chloroform / methanol = 100/0 → 90/10), and N-{[1- (4-fluorophenyl). ) Piperidin-4-yl] methyl} -3-methoxy-4- (4-methyl-1H-imidazol-1-yl) benzamide (7 mg) was obtained as amorphous.

¹ H-NMR (CDCl ₃ ) δ: 7.74 (1H, d), 7.59 (1H, s), 7.30-7.26 (4H, m), 7.02-6.94 (3H, m), 6.34 (1H, t), 3.92 (3H, s), 3.49 (2H, s), 3.38 (2H, t), 2.91 (2H, d), 2.30 (3H, d), 2.06-1.96 (2H, m), 1.72-1.68 (3H, m ), 1.47-1.30 (2H, m).
LC-MS: [M + H] ⁺ / Rt: 437 / 3.56 min.

Examples 130-131 :
Reaction and treatment were carried out in the same manner as in Example 129 using the corresponding starting compounds, and the compounds shown in Table 7 were obtained.

Example 132 :
3-methoxy-4- (4-methyl-1H-imidazol-1-yl) -N- {1- [3- (trifluoromethyl) phenyl] piperidin-3-yl} benzamide

  3-methoxy-4- (4-methyl-1H-imidazol-1-yl) -N- (piperidin-3-yl) benzamide (92 mg), 1-bromo-3 obtained in Reference Example 1 [Step 1] -(Trifluoromethyl) benzene (65 mg), tris (dibenzylideneacetone) dipalladium (27 mg), 2- (di-t-butylphosphino) biphenyl (17 mg), sodium-t-butoxide (42 mg) in toluene (42 mg) 1 ml) The solution was stirred at 40 ° C. overnight under a nitrogen atmosphere. The reaction solution was diluted with chloroform and filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (chloroform / methanol = 100/0 → 90/10) to give 3-methoxy-4- (4-methyl-1H-imidazol-1-yl) -N -{1- [3- (Trifluoromethyl) phenyl] piperidin-3-yl} benzamide (67 mg) was obtained as amorphous.

¹ H-NMR (CDCl ₃ ) δ: 7.72 (1H, d), 7.61 (1H, d), 7.38-7.23 (4H, m), 7.15-7.08 (3H, m), 6.94-6.93 (1H, m) , 6.83 (1H, d), 4.46-4.32 (1H, m), 3.89 (3H, s), 3.57-3.52 (1H, m), 3.25-3.15 (3H, m), 2.28 (3H, d), 1.95 -1.78 (4H, m).
LC-MS: [M + H] ⁺ / Rt = 459 / 5.34 min.

Examples 133-135 :
Reaction and treatment were performed in the same manner as in Example 132 using the corresponding starting compounds, and the compounds shown in Table 8 were obtained.

Example 136 :
N- (biphenyl-3-yl-methyl) -3- (2-methoxyethoxy) -4- (4-methyl-1H-imidazol-1-yl) benzamide

N- (biphenyl-3-yl-methyl) -4-bromo-3- (2-methoxyethoxy) benzamide (0.43 g), 4-methylimidazole (0.14 g), bromide obtained in Reference Example 7 Cuprous (0.03 g), cesium carbonate (0.39 g) and ethyl 2-cyclohexanone carboxylate (0.08 g) were suspended in DMSO (1 ml) and stirred at 100 ° C. overnight under a nitrogen stream. After cooling to room temperature, water and ethyl acetate were added, and insoluble materials were removed by Celite filtration. The filtrate was separated, and the organic layer was washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the crude product obtained by concentrating the reaction mixture under reduced pressure was purified by silica gel chromatography to obtain N- (biphenyl-3-ylmethyl) -3- (2-methoxyethoxy)- 4- (4-Methyl-1H-imidazol-1-yl) benzamide (0.02 g) was obtained.
LC-MS: [M + H] ⁺ / Rt = 442 / 5.25 min
Test example

  The pharmacological test results of the representative compounds of the present invention are shown below, but the present invention is not limited to these test examples.

Evaluation of Aβ production inhibitory action using rat embryo-derived neurons (1) Rat embryo-derived primary cultured neurons Cells were removed from cerebral cortex from Wistar rats (Charles River Japan, Yokohama, Japan), 16-17 days old. Isolated and subjected to culture. Specifically, fetuses were removed from pregnant rats euthanized by CO ₂ inhalation, and fetal brains were removed in ice-cold Hepes buffer. Next, the cerebral cortex is collected under a stereomicroscope, and the tissue is shaken in a 0.3 mg / ml pain (Sigma-aldrich, cat # P4762, St. Louis, MO, USA) solution at 37 ° C. for 5 minutes. Distributed. The dispersion reaction was stopped by exchanging it with a culture solution containing 10% fetal calf serum, and the tissue was physically dispersed by pipetting after washing with Hepes buffer solution. Nylon mesh (cell strainer, cat # 352350, Becton Dickinson) Labware, Franklin Lakes, NJ, USA) was used to remove the cell mass, and a nerve cell suspension was obtained. The suspension was centrifuged at 1000 rpm for 4 minutes, and the supernatant was removed. Next, after resuspending the cells with a small amount of Hepes buffer, the number of cells was counted, and the neurons were diluted with a medium so as to be 1 × 10 ⁵ cells per well, and coated with poly-D-lysine 96 It was seed | inoculated to the well plate (cat # 356461, Becton Dickinson Labware, Franklin Lakes, NJ, USA). The medium includes 0.5 mM L-glutamine (cat # 25030-081, Invitrogen, Carlsbad, CA, USA), penicillin streptomycin (cat # 15140-122, Invitrogen, Carlsbad, CA, USA) and 2% B27 Supplement (cat # cat #). Neurobasal medium (cat # 21103-049, Invitrogen, Carlsbad, CA, USA) including 17504-044, Invitrogen, Carlsbad, CA, USA) was used. The seeded cells were cultured for 3 days in a 37 ° C. incubator under 5% CO ₂ .

(2) Compound addition, sampling, and evaluation of cell survival On the third day of culture, test compounds were added as follows. A DMSO solution of the test compound was prepared at a concentration 100 times the final concentration. This solution was diluted 100 times with the medium. The whole amount of the cell culture medium was removed, and 100 or 200 μl / well of a medium containing the test compound was added. A medium containing DMSO containing no test compound was added to the control group. After culturing for 1 to 3 days after compound addition, the medium was collected and used as a sample for Aβ measurement by ELISA. Moreover, the cell after collect | recovering culture media evaluated cell survival using Cell Counting Kit-8 (cat # 347-07621, Dojindo, Kumamoto, Japan). Specifically, 100 μl / well of a medium warmed to 37 ° C. containing 10% Cell Counting Kit-8 reagent was added to the cells from which the medium was removed, and the cells were cultured in a 37 ° C. incubator under 5% CO _{2 for} 1 to 3 hours. Thereafter, the absorbance at 450 nm of each well was measured. At the time of measurement, a background (bkg) obtained by adding a medium containing Cell Counting Kit-8 reagent to a well in which cells were not seeded was set. The value of each well was calculated according to the following formula and evaluated as a ratio (% control) to the control group (ctrl) treated with DMSO.
% Control = (A450_sample-A450_bkg) / (A450_ctrl-A450_bkg) x 100
A450_sample: 450 nm absorbance of the test compound-treated well A450_bkg: 450 nm absorbance of the background well A450_ctrl: 450 nm absorbance of the DMSO-treated well

(3) Aβ ELISA
Quantification of Aβ by ELISA was carried out using Wako Pure Chemical Industries, Ltd. Human / Ratβamyloid (42) ELISA kit, High-Sensitive (cat # 292-64501) and Human / Ratβamyloid (40) ELISA kit (cat # 294-62501). Using the protocol recommended by the manufacturer (the method described in the package insert). The measurement results were expressed as a percentage of the inhibitory activity of each test compound, with the Aβ concentration in the medium of the control group being 100%.
(4) Table 9 shows data on the Aβ production inhibitory action of typical compounds.

  When the representative compound of the present invention was evaluated by the above-described biological test, a compound showing an Aβ production inhibitory action at a concentration of 2.5 μM was found. In particular, Examples 6, 121, 122, 125, 132, 133, 134 and 135 showed strong Aβ production inhibitory action at a concentration of 2.5 μM.

  As explained above, the compound of the present invention exhibits a strong beta amyloid production inhibitory effect. Therefore, the compound of the present invention is a therapeutic agent for Alzheimer's disease, Down's syndrome or other diseases caused by beta amyloid (for example, cognitive impairment, memory impairment / learning impairment, mild cognitive impairment, senile dementia, amyloidosis, cerebrovascular angiopathy, etc.) And / or useful as a preventive agent.

Claims (16)

The following formula (I):

[Wherein, X ¹ represents CQ ¹ or a nitrogen atom, X ² represents CQ ² or a nitrogen atom, X ³ represents CQ ³ or a nitrogen atom,
Q ¹ , Q ² and Q ³ are the same or different and each represents a hydrogen atom, halogen, C _1-6 alkyl or C _1-6 alkoxy,
Y represents C _0-6 alkylene which may be substituted with the same or different 1 to 3 substituents selected from the group consisting of halogen, hydroxyl group, C _1-3 alkoxy and aryl;
Z represents a single bond or — (a divalent group of a 4- to 9-membered nitrogen-containing saturated heterocyclic ring) —W—, wherein Z is — (a divalent group of a 4- to 9-membered nitrogen-containing saturated heterocyclic ring). ) -W-, the nitrogen-containing saturated heterocyclic ring is C _1-6 alkyl, CF ₃ , hydroxy-C _0-6 alkyl, C _1-6 alkoxy-C _0-6 alkyl, aryl at the substitutable position. And may be substituted with 1 to 3 identical or different substituents selected from the group consisting of fluorine atoms,
W _{is, - (CH 2) n -} , - CO (CH 2) n -, - COO (CH 2) n - or -CONR ⁴ _{(CH 2) n} - represents, wherein each said - (CH ₂ )-Is the same or different and is substituted with 1-2 C _1-6 alkyl, CF ₃ , hydroxy-C _0-6 alkyl, C _1-6 alkoxy-C _0-6 alkyl, aryl or fluorine atoms. Or two hydrogen atoms may be substituted with C _2-6 alkylene to form one saturated carbocycle,
A represents aryl, saturated carbocycle or heteroaryl, wherein the aryl, saturated carbocycle or heteroaryl is halogen, CF ₃ , CF ₃ O, hydroxyl, cyano, nitro, aryl-C _{0- 4} alkyl, heteroaryl-C _0-4 alkyl, C _1-6 alkyl, C _3-8 cycloalkyl-C _0-4 alkyl, 4-8 membered saturated heterocycle-C _0-4 alkyl, C _1-6 Substituted with 1 to 5 identical or different substituents selected from the group consisting of alkoxycarbonyl, C _0-4 alkyl-aminocarbonyl, C _1-4 alkylenedioxy, aryloxy and C _1-6 alkoxy Where Y is C _1-6 alkylene when A is aryl or heteroaryl and Z is a single bond;
R ¹ represents halogen, C _1-6 alkyl or C _1-6 alkoxy,
R ² represents halogen, C _1-6 alkyl, C _1-6 alkoxy or C _1-6 alkoxy-C _1-6 alkoxy,
R ³ and R ⁴ are the same or different and each represents a hydrogen atom or C _1-6 alkyl;
n represents an integer of 0 to 4. ]
Or a pharmaceutically acceptable salt thereof. W _{is, - (CH 2) n -} , - CO (CH 2) n - or -CONR ⁴ _{(CH 2) n} - is,
The compound according to claim 1 or a pharmaceutically acceptable salt thereof. Z is-(a divalent group of a 4- to 9-membered nitrogen-containing saturated heterocyclic ring) -W-, and W and a nitrogen atom of the nitrogen-containing saturated heterocyclic ring are bonded;
The compound according to claim 1 or claim 2 or a pharmaceutically acceptable salt thereof. A divalent group of a 4- to 9-membered nitrogen-containing saturated heterocyclic group of Z is an azetidine divalent group, a morpholine divalent group, a pyrrolidine divalent group optionally cross-linked with C _1-4 alkylene, or a C _0-4 alkylene. A piperidine divalent group which may be cross-linked with or a homopiperidine divalent group which may be cross-linked with C _2-4 alkylene,
The compound as described in any one of Claims 1-3, or its pharmaceutically acceptable salt. R ² is a fluorine atom, a chlorine atom, C _1-3 alkyl, C _1-3 alkoxy or C _1-3 alkoxy-C _1-3 alkoxy,
The compound as described in any one of Claims 1-4, or its pharmaceutically acceptable salt. R ¹ is C _1-3 alkyl,
The compound as described in any one of Claims 1-5, or its pharmaceutically acceptable salt. R ¹ is methyl located at the 4-position of the imidazole ring,
The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof. W is a single bond, —CO— or CONH—.
The compound as described in any one of Claims 1-7, or its pharmaceutically acceptable salt. X ¹ is CQ ¹ or a nitrogen atom, X ² is CQ ² and X ³ is CQ ³ .
The compound as described in any one of Claims 1-8, or its pharmaceutically acceptable salt. X ¹ , X ² and X ³ are each CH.
The compound as described in any one of Claims 1-9, or its pharmaceutically acceptable salt. A is selected from the group consisting of halogen, CF ₃ , CF ₃ O, nitro, aryl, heteroaryl, C _1-4 alkyl, C _3-8 cycloalkyl, 4-8 membered saturated heterocycle and aryloxy An aryl or saturated carbocycle optionally substituted with 1 to 3 identical or different substituents,
The compound as described in any one of Claims 1-10, or its pharmaceutically acceptable salt. Y is C _0-4 alkylene which may be substituted with 1 to 3 identical or different substituents selected from the group consisting of a fluorine atom and C _1-3 alkoxy;
The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof. Z is a single bond,
The compound according to any one of claims 1, 2, 5 to 7, and 9 to 12, or a pharmaceutically acceptable salt thereof.   A pharmaceutical composition comprising the compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof.   The therapeutic agent or preventive agent of the disease resulting from the beta amyloid which uses the compound as described in any one of Claims 1-13, or those pharmacologically acceptable salts as an active ingredient.   The therapeutic or prophylactic agent according to claim 15, wherein the disease caused by beta amyloid is Alzheimer's disease, Down's syndrome, cognitive impairment, memory impairment / learning impairment, mild cognitive impairment, or cerebrovascular angiopathy.