JP2014166961A - Novel indazole derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a therapeutic agent for diseases related to cholinergic of central nervous system (CNS) and/or peripheral nervous system (PNS), diseases related to smooth muscular contraction, endocrine diseases, diseases related to neurodegeneration and the like, having a strong regulation action of an α7 nicotinic acetylcholine receptor (α7 nAChR).SOLUTION: There is provided a compound of the formula (I) and a salt thereof. (I), where A represents CRor a nitrogen atom, X-Y-Z represents N-CO-NRRand the like, R, R, Rand Rare same or different and represent a hydrogen atom and the like, W represents CH or a nitrogen atom, Rrepresents a hydrogen atom and the like, R, R, Rand Rare same or different and represent a hydrogen atom and the like, R, R, Rand Rare same or different and represent Ccycloalkyl which may be substituted and the like, Ris same or different and represents a hydrogen atom and the like and n represents 1 or 2.

Description

  The present invention relates to a novel indazole derivative which is a modulator of α7 nicotinic acetylcholine receptor (α7 nAChR). Due to their pharmacological properties, the compounds of the present invention can be used for diseases related to cholinergic activity of the central nervous system (CNS) and / or peripheral nervous system (PNS), diseases related to smooth muscle contraction, endocrine diseases, diseases related to neurodegeneration, It may be useful for the treatment of diseases such as inflammation or pain and diseases related to withdrawal symptoms caused by addictive drug abuse.

  In recent years, the potential neuroprotective effects of nicotine have been shown, in animals and cultured cells with excitotoxic injury, nutrient deficiency, ischemia, trauma, amyloid beta (Aβ) mediated neuronal cell death and protein aggregation mediated neurodegeneration. Various neurodegenerative models have been proposed. In many instances where nicotine exhibits a neuroprotective effect, it has been shown that the α7 subtype-containing nicotinic acetylcholine receptor is activated. These have been suggested that nicotine helps to mediate neuroprotective effects, and direct involvement of receptors including the α7 subtype has been recalled. These data suggest that the α7 nicotinic acetylcholine receptor represents a valid molecular target for neuroprotection. Thus, neuroprotection can be achieved by developing an active agonist / positive modulator of the receptor (positive allosteric modulator: PAM). In fact, α7 nicotinic receptor agonists have already been identified and evaluated as potential clues for the development of neuroprotective drugs. In recent years, the involvement of α7 nicotinic acetylcholine receptors in inflammation has also been reported. From the above, the development of a novel modulator of the receptor is expected to be a novel treatment for nervous system diseases, psychiatric diseases and inflammatory diseases.

  So far, there are disclosures concerning modulators of α7 nicotinic acetylcholine receptor (α7 nAChR), but the structure is different from the compounds of the present invention (Patent Document 1 and Patent Document 2).

International Publication No. 2003/093250 Pamphlet International Publication No. 2006/138510 Pamphlet

  An object of the present invention is to provide a novel compound having a potent α7 nicotinic acetylcholine receptor (α7 nAChR) regulating action and useful as a novel therapeutic agent and / or preventive agent for nervous system diseases, mental disorders and inflammatory diseases. Is to provide.

  As a result of intensive studies, the present inventors have found that a novel compound represented by the following formula (I) has a potent α7 nicotinic acetylcholine receptor (α7 nAChR) modulating action, and completed the present invention. I let you. According to the present invention, an indazole 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] Formula (I):

[Where:
A represents CR ^1D or a nitrogen atom,
X—Y—Z represents N—CO—NR ^4A R ^4B , CR ⁶ —CO—NR ^4A R ^4B , CR ⁶ —NR ⁷ —CO—NR ^4A R ^4B , CR ⁶ —NR ⁷ —COR ⁵ or CR ^6. -NR < ⁷ > -Ar,
R ^1A , R ^1B , R ^1C and R ^1D are the same or different and are halogen, hydroxyl group, C _1-6 alkoxy, —NR ⁸ R ⁹ , —COOR ⁸ , —CONR ⁸ R ⁹ , —NR ⁸ COR ⁹ , C _1-6 alkyl optionally substituted with 1 to 5 substituents selected from the group consisting of —SO ₂ NR ⁸ R ⁹ and —NR ⁸ SO ₂ R ⁹ ; halogen, hydroxyl group, C _1-6 Selected from the group consisting of alkyl, C _1-6 alkoxy, —NR ⁸ R ⁹ , —COOR ⁸ , —CONR ⁸ R ⁹ , —NR ⁸ COR ⁹ , —SO ₂ NR ⁸ R ⁹ and —NR ⁸ SO ₂ R ^9. C _3-10 cycloalkyl or 4-10 membered saturated heterocycle optionally substituted with 1 to 5 substituents as described above; halogen, hydroxyl, C _1-6 alkoxy, —NR ⁸ R ⁹ , —COOR ^8, - ^{ONR 8 R 9, -NR 8 COR} 9, which may be substituted with 1 to 5 substituents selected from the group consisting of -SO 2 ^NR 8 ^{R 9} and ^-NR 8 _SO 2 ^{R 9} _{C 1- 6} alkoxy; hydrogen atom; hydroxyl group; halogen; halogen, hydroxyl group, C _1-6 alkyl, C _1-6 alkoxy, —NR ⁸ R ⁹ , —COOR ⁸ , —CONR ⁸ R ⁹ and —NR ⁸ COR ⁹ 1-5 aryl which may be substituted with a substituent or heteroaryl selected from a nitro; ^-NR 8 ^{R 9; cyano; -COOR 8; -CONR 8 R 9} ; -NR 8 COR 9; - SO ₂ NR ⁸ R ^9; represents or ^-NR 8 _SO 2 ^{R 9,} wherein, X-Y-Z is, when it is ^{N-CO-NHEt, R 1B} is substituted with -CO-NHEt Instead of the aryl group,
W represents CH or a nitrogen atom,
R ² is halogen, hydroxyl group, C _1-6 alkoxy, —NR ¹⁰ R ¹¹ , —COOR ¹⁰ , —CONR ¹⁰ R ¹¹ , —NR ¹⁰ COR ¹¹ , —SO ₂ NR ¹⁰ R ¹¹ and —NR ¹⁰ SO ₂ R. C _1-6 alkyl which may be substituted with 1 to 5 substituents selected from the group consisting of ¹¹ ; halogen, hydroxyl group, C _1-6 alkoxy, —NR ¹⁰ R ¹¹ , —COOR ¹⁰ , —CONR C _3-10 which may be substituted with 1 to 5 substituents selected from the group consisting of ¹⁰ R ¹¹ , —NR ¹⁰ COR ¹¹ , —SO ₂ NR ¹⁰ R ¹¹ and —NR ¹⁰ SO ₂ R ^11. Cycloalkyl, 4-10 membered saturated heterocyclic ring or 4-10 membered saturated heterocyclic-carbonyl-; hydrogen atom; halogen, hydroxyl group, C _1-6 alkyl, C _1-6 al Aryl or heteroaryl optionally substituted with 1 to 5 substituents selected from the group consisting of alkoxy; C _1-6 alkylcarbonyl; —COOR ¹⁰ ; —CONR ¹⁰ R ¹¹ ; or SO ₂ NR ¹⁰ R ¹¹
R ^3A , R ^3B , R ^3C and R ^3D are the same or different and are substituted with 1 to 5 substituents selected from the group consisting of halogen, hydroxyl group, C _1-6 alkoxy and —NR ¹² R ^13. Optionally represents C _1-6 alkyl; hydrogen atom; halogen; hydroxyl group; or C _1-6 alkoxy,
R ^4A , R ^4B , R ⁵ and R ⁷ are the same or different and may be substituted C _1-10 alkyl; _optionally substituted C _3-10 cycloalkyl (the group may be aryl or hetero Optionally fused to aryl); optionally substituted 4-10 membered saturated heterocycle (the group optionally fused to aryl or heteroaryl); optionally substituted Aryl represents an optionally substituted heteroaryl; or represents a hydrogen atom, wherein (1) R ^4A and R ^4B are a 4- to 10-membered nitrogen-containing saturated heterocyclic ring that may be substituted together. (2) R ^4A and R ^4B are not both hydrogen atoms, and (3) R ⁵ is not a hydrogen atom,
R ⁶ may be the same or different, halogen, _{hydroxyl, C 1-6} alkoxy and ^-NR 14 may be substituted with 1 to 5 substituents selected from the group consisting of ^{R 15} _{C 1-6} alkyl C _3-10 cycloalkyl optionally substituted with 1 to 5 substituents selected from the group consisting of halogen, hydroxyl group, C _1-6 alkoxy and —NR ¹⁴ R ¹⁵ or 4 to 10 membered saturation Represents a heterocycle; a hydrogen atom; a halogen; a hydroxyl group; or C _1-6 alkoxy,
Ar is selected from the group consisting of halogen, hydroxyl group, C _1-6 alkyl, C _1-6 alkoxy, —NR ¹⁶ R ¹⁷ , —COOR ¹⁶ , —CONR ¹⁶ R ^17, and —NR ¹⁶ COR ^17. Represents aryl or heteroaryl optionally substituted by one substituent,
R ^{8 to} R ¹⁷ are the same or different, and when there are a plurality thereof, each independently represents a hydrogen atom or C _1-6 alkyl optionally substituted with 1 to 5 fluorines, , R ⁸ and R ⁹ , R ¹⁰ and R ¹¹ , R ¹² and R ¹³ , R ¹⁴ and R ¹⁵ , R ¹⁶ and R ¹⁷ together form a 4-10 membered nitrogen-containing saturated heterocyclic ring. Well,
n represents 1 or 2]
Or a pharmaceutically acceptable salt thereof.

[Item 2] <i> The optionally substituted alkyl, the optionally substituted cycloalkyl, and the optionally substituted 4 to 10-membered saturated heterocyclic ring in Item 1 are each independently
(1) optionally substituted aryl,
(2) optionally substituted heteroaryl,
(3) an optionally substituted 4- to 10-membered saturated heterocyclic ring,
(4) C _3-10 cycloalkyl which may be substituted,
(5) -CONR ¹⁸ R ¹⁹
(6) halogen,
(7) hydroxyl group,
(8) C _1-6 alkyl which may be substituted,
(9) C _1-6 alkoxy which may be substituted,
(10) C _1-6 alkylcarbonyl which may be substituted,
(11) -N (R ¹⁸ ) COR ¹⁹ , and (12) -NR ¹⁸ R ¹⁹ ,
Or a group that may be substituted with 1 to 5 substituents that are the same or different selected from the group consisting of:
<Ii> The optionally substituted aryl and the optionally substituted heteroaryl in Item 1 are each independently the same or different 1 to 5 selected from the group consisting of the following (a) to (i): A group which may be substituted with one substituent,
Here, the groups shown in the above (1) to (4) are:
(A) halogen,
(B) a hydroxyl group,
(C) optionally substituted C _1-6 alkyl,
(D) optionally substituted C _1-6 alkoxy,
^{(E) -NR} 18 ^{R 19,}
(F) -N (R ¹⁸ ) COR ¹⁹ ,
(G) cyano, and (h) -CONR ¹⁸ R ¹⁹ ,
(I) an optionally substituted C _1-6 alkylcarbonyl,
Means a group optionally substituted by 1 to 5 substituents which are the same or different selected from the group consisting of:
The groups shown in the above (8), (9) and (10) are substituted with the same or different 1 to 5 substituents selected from the group consisting of (b), (d), (e) and fluorine. (C), (d) and (i) are the same or different groups selected from the group consisting of —NR ¹⁸ R ¹⁹ , hydroxyl group, C _1-6 alkoxy and fluorine. Optionally substituted with 5 substituents),
R ¹⁸ and R ¹⁹ are each independently a hydrogen atom or C _1-10 alkyl _optionally substituted with 1 to 5 fluorines, or R ¹⁸ and R ^{19 taken} together 4 A 10-membered nitrogen-containing saturated heterocyclic ring may be formed,
Item 12. The compound according to Item 1 or a pharmaceutically acceptable salt thereof.

[Claim 3] R ^4A , R ^4B , R ⁵ and R ⁷ are the same or different and are aryl, heteroaryl, 4- to 10-membered saturated heterocyclic ring, C _3-10 cycloalkyl, fluorine, hydroxyl group, 1-5 C optionally substituted with 1 to 5 substituents selected from the group consisting of C _1-6 alkoxy optionally substituted with 1 fluorine, C _1-6 alkylcarbonyl and —NR ¹⁸ R ¹⁹ _1-10 alkyl; C _3-10 cycloalkyl; 4-10 membered saturated heterocyclic ring; or a hydrogen atom (the aryl, heteroaryl, saturated heterocyclic ring and cycloalkyl are fluorine, hydroxyl group, C _1-6 alkyl, (The group may be substituted with 1 to 5 substituents selected from the group consisting of fluorine, C _1-6 alkoxy and —NR ¹⁸ R ¹⁹ ). Even Substituted with 1 to 5 substituents selected from the group consisting of good C _1-6 alkoxy, C _1-6 alkylcarbonyl, aryl optionally substituted with 1-5 halogens, and —NR ¹⁸ R ¹⁹ Where, (1) R ^4A and R ^4B are taken together to form a 4- to 10-membered nitrogen-containing saturated heterocyclic ring (the ring is substituted with the same substituent as the above saturated heterocyclic ring). (2) R ^4A and R ^4B are not both hydrogen atoms, and (3) R ⁵ is not a hydrogen atom.
Item 3. The compound according to Item 1 or Item 2, or a pharmaceutically acceptable salt thereof.

[Claim 4] A is CR ^1D .
Item 4. The compound according to any one of Items 1 to 3, or a pharmaceutically acceptable salt thereof.

[Claim 5] ^{R 2} is fluorine, _{hydroxyl, C 1-6} alkoxy and ^-NR 10 may be substituted with 1 to 5 substituents selected from the group consisting of ^{R 11} _{C 1-6} alkyl; C _3-10 cycloalkyl optionally substituted with 1 to 5 substituents selected from the group consisting of fluorine, hydroxyl group, C _1-6 alkoxy and —NR ¹⁰ R ¹¹ , 4 to 10 membered saturated complex A ring or a 4- to 10-membered saturated heterocyclic-carbonyl-; a hydrogen atom; or a C _1-6 alkylcarbonyl.
Item 5. The compound according to any one of Items 1 to 4 or a pharmaceutically acceptable salt thereof.

[Claim 6] R ^1A , R ^1B , R ^1C and R ^1D are the same or different and are each selected from fluorine, hydroxyl group, C _1-6 alkoxy, —NR ⁸ R ⁹ , —CONR ⁸ R ⁹ and —NR ⁸ COR ^9. optionally substituted with 1 to 5 substituents selected from the group consisting of _{C 1-6} alkyl; fluorine, _{hydroxyl, C 1-6 alkyl, C 1-6} ^alkoxy, -NR ⁸ R 9, -CONR C _3-10 cycloalkyl or a 4-10 membered saturated heterocyclic ring optionally substituted with 1 to 5 substituents selected from the group consisting of ⁸ R ⁹ and —NR ⁸ COR ⁹ ; halogen, hydroxyl group, C _1-6 ^{alkoxy, -NR 8 R 9, -CONR 8} R 9 and ^-NR 8 1 to 5 amino substituted with a substituent which may be _{C 1-6} alkoxy selected from the group consisting of COR ^9; Hydrogen atom; hydroxyl group; Halogen; aryl, heteroaryl optionally substituted with 1 to 5 substituents selected from the group consisting of fluorine, C _1-6 alkyl, C _1-6 alkoxy and —NR ⁸ R ⁹ ; —NR ⁸ R ⁹ ; cyano; —CONR ⁸ R ⁹ ; or —NR ⁸ COR ⁹ .
Item 6. The compound according to any one of Items 1 to 5, or a pharmaceutically acceptable salt thereof.

[Claim 7] X-Y-Z ^{is, N-CO-NR 4A R} 4B, CR 6 -CO-NR 4A R 4B, CR 6 -NR 7 -CO-NR 4A R 4B or ^CR 6 ^-NR 7 -COR ⁵ ,
Item 7. The compound according to any one of Items 1 to 6, or a pharmaceutically acceptable salt thereof.

[Item 8] Either one of R ^{4A and} R ^4B is a hydrogen atom.
Item 8. The compound according to any one of Items 1 to 7, or a pharmaceutically acceptable salt thereof.

[Item 9] n is 1.
Item 9. The compound according to any one of Items 1 to 8, or a pharmaceutically acceptable salt thereof.

[Item 10] R ^1A , R ^1B , R ^1C and R ^1D are the same or different and are substituted with 1 to 5 substituents selected from the group consisting of fluorine, hydroxyl group and C _1-6 alkoxy. also _{C 1-6} alkyl; fluorine, hydroxyl and _{C 1-6} 1 to 5 amino optionally substituted with a substituent _{C 3-8} cycloalkyl selected from the group consisting of alkoxy; fluorine, hydroxyl and C _A C _1-6 alkoxy optionally substituted with 1 to 5 substituents selected from the group consisting of _1-6 alkoxy; a hydrogen atom; a hydroxyl group; a halogen; or a 4-10 membered saturated heterocyclic ring,
Item 10. The compound according to any one of Items 1 to 9, or a pharmaceutically acceptable salt thereof.

[Item 11] R ^4A , R ^4B , R ⁵ and R ⁷ are the same or different and are substituted with 4 to 10-membered saturated heterocyclic ring, C _3-10 cycloalkyl, fluorine, hydroxyl group, 1 to 5 fluorine atoms. is optionally _{C 1-6 alkoxy, C 1-6} alkylcarbonyl and ^-NR 18 1 to 5 amino optionally substituted with a substituent _{C 1-10} alkyl is selected from the group consisting of ^{R 19;} C _3-10 cycloalkyl; a 4-10 membered saturated heterocyclic ring; or a hydrogen atom (the saturated heterocyclic ring and cycloalkyl are fluorine, hydroxyl group, C _1-6 alkyl (the group is fluorine, C _1- C _1-6 alkoxy optionally substituted with 1 to 5 fluorines (optionally substituted with 1 to 5 substituents selected from the group consisting of ₆ alkoxy and —NR ¹⁸ R ¹⁹ ) _1-6 alkylcarbonyl two , Or it may be substituted with 1 to 5 substituents selected from the group consisting of ^-NR 16 ^{R 17),} wherein, ^{(1) R 4A} and ^{R 4B} are 4-10 membered together A nitrogen-containing saturated heterocyclic ring (which may be substituted with the same substituent as the saturated heterocyclic ring), and (2) R ^4A and R ^4B are both hydrogen atoms. (3) R ⁵ is not a hydrogen atom,
Item 11. The compound or a pharmaceutically acceptable salt thereof according to 1-10.

[Item 12] R ⁶ is C _1-6 alkyl, C _1-6 alkoxy, a hydroxyl group, fluorine, or a hydrogen atom.
Item 12. The compound according to any one of Items 1 to 11 or a pharmaceutically acceptable salt thereof.

[Item 13] W is CH.
Item 13. The compound according to any one of Items 1 to 12, or a pharmaceutically acceptable salt thereof.

[Claim 14] X-Y-Z is an ^N-CO-NR 4A ^{R 4B} or ^CR 6 ^-NR 7 -COR ^5,
Item 14. The compound according to any one of Items 1 to 13, or a pharmaceutically acceptable salt thereof.

[Item 15] C _1-6 alkyl in which R ^3A , R ^3B , R ^3C and R ^3D are the same or different and optionally substituted with 1 to 5 fluorines; C _1-6 alkoxy; a hydrogen atom; Or fluorine,
Item 15. The compound according to any one of Items 1 to 14 or a pharmaceutically acceptable salt thereof.
[Section 16] Ar is aryl optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, C _1-6 alkyl, C _1-6 alkoxy, and —NR ¹⁶ R ^17. ,
Item 16. The compound according to any one of Items 1 to 15 or a pharmaceutically acceptable salt thereof.
CLAIM | ITEM 17 XYZ is N-CO-NR < ^4A > R ^<4B >,
Item 17. The compound according to any one of Items 1 to 16 or a pharmaceutically acceptable salt thereof.

[Item 18] A pharmaceutical composition comprising the compound according to any one of items 1 to 17 or a pharmaceutically acceptable salt thereof.

[Item 19] A therapeutic agent for diseases caused by abnormalities in intracellular signal transduction involving acetylcholine, comprising the compound according to any one of items 1 to 17 or a pharmaceutically acceptable salt thereof as an active ingredient Or a preventive agent.

[Item 20] A disease caused by abnormal intracellular signaling involving acetylcholine is Alzheimer's disease, Down's syndrome, cognitive impairment, memory impairment / learning impairment, mild cognitive impairment, attention deficit / hyperactivity disorder, or cerebrovascular angiopathy is there,
Item 20. The therapeutic agent according to Item 19.

[Item 21] An acetylcholine characterized by administering a therapeutically effective amount of the compound according to any one of items 1 to 17 or a pharmaceutically acceptable salt thereof to a patient in need of treatment. A method for treating or preventing a disease caused by an abnormality in intracellular signaling involved.

[Item 22] The compound according to any one of Items 1 to 17 or a pharmaceutically acceptable salt thereof for the treatment or prevention of a disease caused by an abnormality in intracellular signal transduction involving acetylcholine.

CLAIM | ITEM 23 The compound or its pharmaceutically acceptable salt of any one of claim | item 1 -17 used for the treatment or prevention of the disease resulting from abnormality of the intracellular signal transduction which acetylcholine involves. A pharmaceutical composition comprising.

  The compound of the present invention is useful as a novel therapeutic agent and / or preventive agent for nervous system diseases, psychiatric diseases and inflammatory diseases (for example, senile dementia, attention deficit disorder, Alzheimer's disease and schizophrenia).

  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.
In addition, a deuterium converter obtained by converting any one or two or more ¹ H of the compound represented by the general formula (I) into ² H (D) is also included in the compound represented by the general formula (I). Is done.

Next, terms used in this specification will be described below.
“Alkyl” means a linear or branched saturated hydrocarbon group, for example, “C _1-4 alkyl”, “C _1-6 alkyl” or “C _1-10 alkyl” It means 1-4, 1-6 or 1-10 alkyl. Specific examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like in the case of “C _1-4 alkyl”. In the case of “C _1-6 alkyl”, in addition to the above, examples include pentyl, isopentyl, neopentyl, hexyl and the like, and in the case of “C _1-10 alkyl”, in addition to the above, heptyl, octyl and the like. Is mentioned.
“Cycloalkyl” means a monocyclic or polycyclic saturated hydrocarbon. For example, “C _3-10 cycloalkyl” means a cyclic alkyl having 3 to 10 carbon atoms and is partially bridged. Also included are those having a structure or those formed with an aryl or heteroaryl ring. Specific examples thereof include “C _3-10 cycloalkyl” such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl and the like.
“Alkoxy” means a group in which a linear or branched saturated hydrocarbon group is interposed through an oxygen atom. For example, “C _1-6 alkoxy” has 1 to 6 carbon atoms. Means alkoxy. Specific examples thereof include methoxy, ethoxy, propoxy, isopropoxy, butyloxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy and the like in the case of “C _1-6 alkoxy”.
Specific examples of “C _1-6 alkylcarbonyl” include acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, isobutylcarbonyl, t-butylcarbonyl and the like. Preferably, “C _1-3 alkylcarbonyl” is used, and more preferably, acetyl is used.

“Halogen” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Among them, preferred is a fluorine atom or a chlorine atom.
Specific examples of “aryl” include phenyl, 1-naphthyl, 2-naphthyl, anthracene and the like. Of these, phenyl is preferable.
“Heteroaryl” is 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, Examples thereof include an 11-membered aromatic heterocyclic group or a 3-ring 12-16 membered aromatic heterocyclic group. 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 Quinolyl, isoquinolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzotriazolyl, benzimidazolyl, thioxanthene, 6,11-dihydrodibenzo [B, E] thiepinyl Etc. Preferred heteroaryls include pyridyl, pyrimidinyl, quinolyl, and isoquinolyl.

  “4- to 10-membered saturated heterocycle” means a monocyclic or bicyclic saturated heterocycle composed of 4 to 10 atoms including 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms in addition to carbon atoms. It means a ring and includes a partially bridged structure, a partially spirolated structure, and a ring formed with an aryl or heteroaryl. For example, azetidine, pyrrolidine, piperidine, piperazine, morpholine, homopiperidine, tetrahydrofuran, tetrahydropyran and the like can be mentioned. In addition, “4 to 10-membered saturated heterocycle-carbonyl-” means a group in which carbonyl is bonded to the 4 to 10-membered saturated heterocycle.

Among the compounds of the present invention represented by the formula (I), A, XYZ, R ^{1A to} R ^1D , R ² , R ^{3A to} R ^3D , R ^4A , R ^4B , R ^{5 to} R ¹⁹ , Preferred examples of Ar and n are as follows, but the technical scope of the present invention is not limited to the scope of the compounds listed below.

A is preferably CR ^1D .
The preferred ^{X-Y-Z, X-} Y-Z ^{is, N-CO-NR 4A R} 4B, CR 6 -CO-NR 4A R 4B, CR 6 -NR 7 -CO-NR 4A R 4B or CR ⁶ -NR ⁷ -COR ^5, and more preferably include include ^N-CO-NR 4A ^{R 4B} or ^CR 6 ^-NR 7 -COR ^5, more preferably include ^{N-CO-NR 4A R 4B} .

R ^{1A to} R ^1D are preferably the same or different and selected from the group consisting of fluorine, hydroxyl group, C _1-6 alkoxy, —NR ⁸ R ⁹ , —CONR ⁸ R ⁹ and —NR ⁸ COR ⁹ . 5 substituents optionally substituted by _{C 1-6} alkyl; fluorine, _{hydroxyl, C 1-6 alkyl, C 1-6} ^{alkoxy, -NR 8 R 9, -CONR 8} R 9 and ^-NR 8 COR C _3-10 cycloalkyl or 4-10 membered saturated heterocyclic ring optionally substituted with 1 to 5 substituents selected from the group consisting of ⁹ ; halogen, hydroxyl, C _1-6 alkoxy, —NR C _1-6 alkoxy optionally substituted with 1 to 5 substituents selected from the group consisting of ⁸ R ⁹ , —CONR ⁸ R ⁹ and —NR ⁸ COR ⁹ ; hydrogen atom; hydroxyl group; halogen; Aryl, heteroaryl optionally substituted with 1 to 5 substituents selected from the group consisting of silicon, C _1-6 alkyl, C _1-6 alkoxy and —NR ⁸ R ⁹ ; —NR ⁸ R ⁹ cyano; -CONR ⁸ R ^9; or ^-NR 8 COR ^9, and the like. More preferably, identical or different, fluorine, hydroxyl and C _1-6 C _1-6 alkyl optionally substituted with 1 to 5 substituents selected from the group consisting of alkoxy; fluorine, hydroxyl and C C _3-8 cycloalkyl optionally substituted with 1 to 5 substituents selected from the group consisting of _1-6 alkoxy; 1 to 1 selected from the group consisting of fluorine, hydroxyl group and C _1-6 alkoxy Examples thereof include C _1-6 alkoxy optionally substituted with 5 substituents; a hydrogen atom; a hydroxyl group; a halogen; or a 4 to 10-membered saturated heterocyclic ring. More preferably, identical or different, fluorine and C _1-6 optionally substituted with 1-5 substituents selected from the group consisting of alkoxy C _1-6 alkyl; C _3-8 cycloalkyl; C _1-6 alkoxy; a hydrogen atom; or halogen. Most preferably, identical or different, one to five fluorine may be substituted with及C _1-6 alkyl; and the or halogen; hydrogen atom.

W is preferably CH.
Preferred as R ^2, fluorine, _{hydroxyl, C 1-6} alkoxy and ^-NR 10 may be substituted with 1 to 5 substituents selected from the group consisting of ^{R 11} _{C 1-6} alkyl; fluorine, C _3-10 cycloalkyl optionally substituted with 1 to 5 substituents selected from the group consisting of a hydroxyl group, C _1-6 alkoxy, and —NR ¹⁰ R ¹¹ , a 4- to 10-membered saturated heterocyclic ring, or 4- to 10-membered saturated heterocycle-carbonyl-; hydrogen atom; or C _1-6 alkylcarbonyl. More preferably, it includes fluorine and C _1-6 1 to 5 amino substituted with a substituent is C _1-6 optionally alkyl or hydrogen atoms selected from the group consisting of alkoxy, more preferably, C _{1 -6} alkyl or a hydrogen atom is mentioned, Most preferably, a hydrogen atom is mentioned.

R ^3A , R ^3B , R ^3C and R ^3D are preferably the same or different, and C _1-6 alkyl or C _1-6 alkoxy optionally substituted with 1 to 5 fluorines; hydrogen atom; or fluorine Is mentioned. More preferably, C _1-6 alkyl _optionally substituted with 1 to 5 fluorines; a hydrogen atom; or fluorine is included, and still more preferably, C _1-6 alkyl; a hydrogen atom; or fluorine is used. . When W is CH, the carbon atom of W may be substituted with the above R ^3A , R ^3B , R ^3C, or R ^3D substituent in the same manner as other carbon atoms of the ring to be formed.

R ^4A , R ^4B , R ⁵ and R ⁷ are preferably the same or different and are aryl, heteroaryl, 4- to 10-membered saturated heterocycle, C _3-10 cycloalkyl, fluorine, hydroxyl group, 1 to 5 optionally substituted by fluorine _{C 1-6 alkoxy, C 1-6} alkylcarbonyl and ^-NR 18 may be substituted with 1 to 5 substituents selected from the group consisting of ^{R 19} _{C 1 -10} alkyl; C _3-10 cycloalkyl; 4 to 10-membered saturated heterocyclic ring; or a hydrogen atom (the aryl, heteroaryl, saturated heterocyclic ring and cycloalkyl are fluorine, hydroxyl group, C _1-6 alkyl ( said group, fluorine _may be substituted with 1 to 5 substituents selected from the group consisting of _{C 1-6} alkoxy and ^-NR 18 ^{R 19)} is substituted with 1-5 fluorine Which may be _{C 1-6 alkoxy, C 1-6} alkylcarbonyl, 1-5 substituents selected from the group consisting of 1-5 ^-NR aryl and optionally substituted with halogen 18 ^{R 19} (1) R ^4A and R ^4B are taken together to form a 4- to 10-membered nitrogen-containing saturated heterocyclic ring (the ring is the same as the above saturated heterocyclic ring). (2) R ^4A and R ^4B are not both hydrogen atoms, and (3) R ⁵ is not a hydrogen atom. More preferably, it is the same or different and is a 4 to 10-membered saturated heterocyclic ring, C _3-10 cycloalkyl, fluorine, hydroxyl group, C _1-6 alkoxy optionally substituted with 1 to 5 fluorines, C ₁ C _1-10 alkyl optionally substituted with 1-5 substituents selected from the group consisting of _-6 alkylcarbonyl and -NR ¹⁸ R ¹⁹ ; C _3-10 cycloalkyl; 4-10 membered saturation Or a hydrogen atom (the saturated heterocyclic ring and cycloalkyl are selected from the group consisting of fluorine, hydroxyl group, C _1-6 alkyl (the group is fluorine, C _1-6 alkoxy and —NR ¹⁸ R ¹⁹⁾ ; 1-5 may be substituted with a substituent) 1-5 fluorines optionally substituted _{C 1-6} alkoxy _{being, C 1-6} alkylcarbonyl, or ^-NR 16 ^{R 17} That may be substituted with 1 to 5 substituents selected from the group) can be mentioned. More preferably, it is the same or different, and C _1-10 alkyl which may be substituted with 1 to 5 substituents selected from the group consisting of a 4 to 10-membered saturated heterocyclic ring and C _3-10 cycloalkyl. C _3-10 cycloalkyl; 4-10 membered saturated heterocyclic ring; or a hydrogen atom (the saturated heterocyclic ring and cycloalkyl are fluorine, hydroxyl group, C _1-6 alkyl (the group is fluorine, C ₁ C _1-6 alkoxy optionally substituted with 1 to 5 fluorines (optionally substituted with 1 to 5 substituents selected from the group consisting of _-6 alkoxy and —NR ¹⁸ R ¹⁹ ) C _1-6 alkylcarbonyl, or 1 to 5 substituents selected from the group consisting of —NR ¹⁶ R ¹⁷ ). Moreover, as another preferable aspect, it is mentioned that any one of R ^{< 4A>} or R ^<4B> is a hydrogen atom.

R ⁶ is preferably C _1-6 alkyl, C _1-6 alkoxy, hydroxyl group, fluorine or hydrogen atom. More preferably, a _C1-6 alkoxy, a hydroxyl group, a fluorine, or a hydrogen atom is mentioned, More preferably, a fluorine or a hydrogen atom is mentioned.
R ^{8 to} R ¹⁹ are the same or different and include a hydrogen atom or C _1-6 alkyl, preferably a hydrogen atom or C _1-4 alkyl.
Ar is preferably aryl optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, C _1-6 alkyl, C _1-6 alkoxy and —NR ¹⁶ R ¹⁷ . More preferably, aryl which may be substituted with 1 to 3 substituents selected from the group consisting of halogen and C _1-6 alkyl is exemplified.
As n, 1 or 2 is mentioned, Preferably 1 is mentioned.

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.
When this invention compound represented by a formula (I) has acidic functional groups, such as a carboxyl group, various bases and salts can be formed. Examples of the pharmaceutically acceptable salt in this case include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts, and ammonium salts. These salts can be obtained by a conventional method such as recrystallization after mixing the compound of the present invention represented by formula (I) with a base.

Note that the following abbreviations may be used to simplify the description in this specification. o-: ortho-, m-: meta-, p-: para-, t-: tert-, s-: sec-, CHCl 3: chloroform, _{CH 2} Cl 2: dichloromethane, THF: tetrahydrofuran, DMF: N, N-dimethylformamide, DMSO: dimethyl sulfoxide, PAM: positive allosteric modulator, HEPES: N-2-hydroquinethylpiperazine-N'-2-ethanesulfonic acid, BSA: bovine serum albumin, FDSS: Functional Drug Screening System, Boc : Tert-butoxycarbonyl, c-Hex: cyclohexyl, c-Pen: cyclopentyl, EDCI.HCl: N- (3-diethylaminopropyl) -N'-ethylcarbodiimide hydrochloride, HOBt: 1-hydroxybenzotriazo Le, DIEA: diisopropylethylamine, TEA: Triethylamine

The production method of the compound of the present invention is described below. The compound of the present invention represented by the formula (I) can be produced, for example, by the following production methods A ^{1 to} A ³ , B, C ¹ or C ² .

Production method A ¹
Of the compounds represented by formula (I), XYZ is N—CO—NR ^4A R ^4B and W is CH. Compounds A1 and A1 represented by formulas [A1] and [A2] Compound A2 can be produced, for example, by the following production method.

(In the formula, A, R ^{1A to} R ^1D , R ² , R ^{3A to} R ^3D , R ^4A , R ^4B and n are as defined in Item 1; P means an amino group protecting group)

2-methylaniline (compound a1) in which A is CR ^1D is, for example, Bioorganic & Medicinal Chemistry Letters 2002, 12 (20), 2925-2930, European Journal of Organic Chemistry 2010, 24, 4662-4670, International Publication No. 2009 / 001132 can be produced by the method described in the pamphlet or the like, or can be purchased as a commercial product.
Whether 2-methyl-3-aminopyridine in which A is a nitrogen atom compound a1 can be produced by, for example, the method described in International Publication No. 2008/157404, International Publication No. 2009/088103, or the like, Or it can be purchased as a commercial product.

[Step A-1]
This step is a step of obtaining compound a2 by reacting compound a1 with sodium nitrite and sodium tetrafluoroborane in an appropriate solvent in the presence of various acids. The acid used in this step is selected from mineral acids such as hydrochloric acid, nitric acid and sulfuric acid, and hydrochloric acid is preferable. Although the solvent used in this process is selected from the solvent etc. which are illustrated to the postscript, Preferably water is mentioned.

[Step A-2]
This step is a step in which compound a2 obtained in step A-1 is cyclized in the presence or absence of a salt and crown ether to obtain compound a3. The salt used in this step is selected from potassium acetate, sodium acetate, sodium bicarbonate, tert-butoxypotassium and the like, preferably potassium acetate. Although the solvent used in this process is selected from the solvent etc. which are illustrated to a postscript, Preferably chloroform or a dichloromethane is mentioned. As a similar reaction, for example, the method described in Tetrahedron Lett. 2002, 43, 2695-2697, Tetrahedron 2006, 62, 7772-7775, etc. can be used to produce the same reaction.

[Step A-3]
This step is a step of obtaining compound a4 by reacting compound a3 obtained in step A-2 with iodine in a suitable solvent in the presence of various bases. The base used in this step is selected from the bases exemplified below, and preferably sodium hydroxide or potassium hydroxide. The solvent used in this step is selected from the solvents exemplified below, and preferably dimethylformamide or chloroform.

[Step A-4]
In this step, compound a4 obtained in step A-3 is coupled with compound a8 in the presence of a catalyst and a base to obtain compound a5. Examples of the catalyst include those supported on a carrier such as a transition metal such as palladium, a salt thereof, a complex thereof, or a polymer. The base used in this step is selected from the bases exemplified below, and preferably sodium carbonate or potassium carbonate. Although the solvent used in this process is selected from the solvent etc. which are illustrated to a postscript, Preferably the mixed solvent of a dioxane-water is mentioned. Examples of the similar reaction include a method described in International Publication No. 2005/073219 pamphlet and the like, and the same method can be used to produce the same reaction.

[Step A-5]
This step is a step of obtaining compound a6 by reducing compound a5 obtained in step A-4 in the presence of a catalyst. As the reducing agent, hydrogen, formic acid salts such as ammonium formate, and hydrazine can be used. Examples of the catalyst include those supported on a carrier such as a transition metal such as palladium, nickel, rhodium, cobalt, or platinum, a salt thereof, a complex thereof, or a polymer. Although the solvent used in this process is selected from the solvent etc. which are illustrated to a postscript, Preferably ethanol or methanol is mentioned.

[Step A-6]
This step is a step of obtaining a compound a7 by deprotecting the protecting group P of the amino group of the compound a6 obtained in the above step A-5. This step can be carried out according to the method described in Protective Groups in Organic Synthesis (written by Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc., 1999).

[Step A-7]
This step is a step of obtaining compound A1 by reacting compound a7 obtained in step A-6 with compound a9 or a10 in a suitable solvent in the presence of various bases. The base used in this step is selected from the bases exemplified below, and preferably diisopropylethylamine or triethylamine. The solvent used in this step is selected from the solvents exemplified below, and preferably tetrahydrofuran or dimethylformamide is used.

[Step A-8]
In this step, compound A1 obtained in step A-7 is reacted with various alkyl halides, carboxylic acids, acid chlorides, isocyanates, etc. in the presence of various bases in the presence or absence of various bases. This is a step of obtaining A2. The base used in this step is selected from the bases exemplified below, and preferably diisopropylethylamine or triethylamine. The solvent used in this step is selected from the solvents exemplified below.

Production method A ²
Among the compounds represented by the formula (I), the compound A1 represented by the formula [A1] in which XYZ is N—CO—NR ^4A R ^4B and W is CH is, for example, It can also be manufactured by a manufacturing method.

(In the formula, A, R ^{1A to} R ^1D , R ^{3A to} R ^3D , R ^4A , R ^4B and n are as defined in Item 1, and Rx is a C _1-4 alkyl group or amino group protection. Group means P means amino protecting group)

  The 4-chloropiperidine derivative (compound a11) can be produced, for example, by the method described in Heterocycles 1990, 31 (7), 1201-1204, Journal of the Chemical Society, Perkin Transactions 2 1992, 6, 857-8, etc. Or can be purchased as a commercial product.

[Step A-9]
This step is a step of obtaining alkylmagnesium compound a12 by reacting compound a11 with magnesium metal, a Grignard reagent, or the like. The solvent used in this step is selected from the solvents exemplified below, and preferably tetrahydrofuran or diethyl ether.

[Step A-10]
This step is a step of obtaining compound a13 by reacting compound a12 obtained in step A-9 with a16 or a17 in a suitable solvent. The solvent used in this step is selected from the solvents exemplified below, and preferably tetrahydrofuran or diethyl ether.

[Step A-11]
This step is a step of obtaining compound a14 by reacting compound a13 obtained in step A-10 with various electrophiles in the presence of various bases in an appropriate solvent. As the electrophile, phenyl chlorocarbonate, benzyloxycarbonyl chloride, di-t-butyl dicarbonate and the like can be used. The base used in this step is selected from the bases exemplified below, and preferably sodium carbonate or potassium carbonate. The solvent used in this step is preferably toluene or tetrahydrofuran.

[Step A-12]
In this step, the compound a14 obtained in the above step A-11 is allowed to react with hydrazine in the presence of various bases in an appropriate solvent, or reacted with hydrazine following the addition of methylhydroxylamine. In this step, compound a15 is obtained. The base used in this step is selected from the bases exemplified below, and preferably pyridine or potassium carbonate. The solvent used in this step is selected from the solvents exemplified below, and preferably pyridine or dimethoxyethane. As a similar reaction, the method described in Journal of Organic Chemistry 2006, 71 (21), 8166-8172 can be mentioned, and it can be produced according to this method.

[Step A-13]
This step is a step of obtaining a compound a7 by deprotecting the amino-protecting group P of the compound a15 obtained in the step A-12. This step can be carried out according to the method described in Protective Groups in Organic Synthesis (written by Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc., 1999).

[Step A-14]
This step is a step of converting the compound a7 obtained in the step A-13 to the compound A4 under the conditions according to the step A-7.

Production method A ³
Of the compounds represented by the formula (I), the compound A3 represented by the formulas [A3] and [A4] in which XYZ is N—CO—NR ^4A R ^4B and W is N. Compound A4 can be produced, for example, by the following production method.

(In the formula, A, R ^{1A to} R ^1D , R ² , R ^{3A to} R ^3D , R ^4A , R ^4B and n are as defined in Item 1.)

  3- (1-Piperazinyl) -1H-indazole and the like (compound a18) are, for example, Organic Process Research & Development 2001, 5 (2), 179-183, International Publication No. 2010/054279 Pamphlet, Organic Process Research & Development 2003, 7 (4), 521-532, or can be purchased as a commercial product.

[Step A-15]
This step is a step of converting compound a18 into compound A3 under the conditions according to the above step A-7.

[Step A-16]
This step is a step of converting compound A3 obtained in step A-15 to compound A4 under the same conditions as in step A-8.

Manufacturing method B
Of the compounds represented by the formula (I), the compound B1 represented by the formulas [B1] and [B2] in which XYZ is CR ⁶ —CO—NR ^4A R ^4B and W is CH. And B2 can be produced, for example, by the following production method.

(In the formula, A, R ^{1A to} R ^1D , R ² , R ^{3A to} R ^3D , R ^4A , R ^4B , R ⁶ and n are as defined in Item 1 and Rx is C _1-4 alkyl. Meaning group)

  The 4-oxocyclohexanecarboxylate derivative (compound b1) can be obtained by a method described in, for example, Organic Syntheses 2007, 84, 233-241, Synlett 2000, 11, 1549-1552, International Publication No. 2010/141406, etc. It can be manufactured or purchased as a commercial product.

[Step B-1]
This step is a step of obtaining compound b2 by reacting compound b1 with compound b7 or b8 in an appropriate solvent in the presence of various bases. The base used in this step is selected from bases exemplified below, and preferably pyridine or potassium hexamethyldisilazide. Although the solvent used in this process is selected from the solvent etc. which are illustrated to a postscript, Preferably toluene or tetrahydrofuran is mentioned. As a similar reaction, the method described in Organic Process & Research & Development 2010, 14 (5), 1182-187 can be mentioned, and it can also be produced by this method.

[Step B-2]
In this step, compound b2 obtained in step B-1 is coupled with compound b9 in the presence of a catalyst and a salt to obtain compound b3. Examples of the catalyst include those supported on a carrier such as a transition metal such as palladium, a salt thereof, a complex thereof, or a polymer. The salt used in this step is selected from potassium acetate, sodium acetate, silver acetate and the like, preferably potassium acetate. The solvent used in this step is selected from the solvents exemplified below and preferably dimethyl sulfoxide and dimethoxyethane. Examples of the similar reaction include a method described in International Publication No. 2009/016462 pamphlet and the like, and it can be produced in the same manner using this method.

[Step B-3]
This step is a step of converting the compound b3 obtained in the step B-2 into the compound b4 under the conditions according to the step A-4.

[Step B-4]
This step is a step of converting the compound b4 obtained in the step B-3 into the compound b5 under the conditions according to the step A-5.

[Step B-5]
This step is a step of converting the ester compound b5 obtained in the step B-4 to the corresponding carboxylic acid compound b6. This step can be carried out according to the method described in Protective Groups in Organic Synthesis (written by Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc., 1999).

[Step B-6]
This step is a step of obtaining Compound B1 by reacting Compound b6 obtained in Step B-5 with Compound b10 in an appropriate solvent in the presence of various condensing agents. As the condensing agent used in this step, various condensing agents used in a conventional method can be used, but 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (including hydrochloride) is preferable. Is mentioned. The solvent used in this step is selected from the solvents exemplified below.

[Step B-7]
This step is a step of converting the compound B1 obtained in the step B-6 to the compound B2 under the conditions according to the step A-8.

Production method C ¹
Of the compounds represented by formula (I), XYZ is CR ⁶ —NR ⁷ —COR ⁵ , R ⁷ is a hydrogen atom, and W is CH. Compound C1 can be produced, for example, by the following production method.

(In the formula, A, R ^{1A to} R ^1D , R ² , R ^{3A to} R ^3D , R ⁵ , R ⁶ and n are as defined in Item 1.)

  The 4-aminocyclohexanecarboxylic acid derivative (compound c1) can be produced, for example, by the method described in Synthetic Communications 2002, 32 (13), 1985-1995, US Publication No. 2005/0020645, etc., or commercially available It can be purchased as a product.

[Step C-1]
This step is a step of converting compound c1 into the corresponding acid chloride compound c2 using a reagent such as oxalyl chloride, thionyl chloride and the like. The solvent used in this step is selected from the solvents exemplified below, and preferably dichloromethane or tetrahydrofuran is used.

[Step C-2]
This step is a step for producing the corresponding thioester c3 from compound c2 obtained in the above step C-1 using c8 in an appropriate solvent in the presence of various bases. The base used in this step is selected from the bases exemplified below, and preferred examples include triethylamine or diisopropylethylamine. The solvent used in this step is selected from the solvents exemplified below, and preferably tetrahydrofuran or dichloromethane.

[Step C-3]
In this step, compound c3 obtained in step C-2 is coupled with boronic acid compound c9 in the presence or absence of a catalyst and an organophosphorus compound to obtain compound c4. Examples of the catalyst include those supported on a carrier such as transition metals such as palladium and copper, salts thereof, complexes thereof, and polymers. The organic phosphorus compound used in this step is preferably triethyl phosphite. The solvent used in this step is selected from the solvents exemplified below, and preferably includes tetrahydrofuran. Examples of similar reactions include the methods described in Journal of American Chemical Society 2007, 129 (5), 1132-1140, Bioorganic Medicinal Chemistry Letters 2007, 17, 5647-5651.

[Step C-4]
This step is a step of converting the compound c4 obtained in the step C-3 into the compound c5 under the conditions according to the step A-12.

[Step C-5]
This step is a step of converting the compound c5 obtained in the step C-4 into the compound c6 under the conditions according to the step A-8. The compound represented by the formula (I) in which R ² is a hydrogen atom does not carry out this step.

[Step C-6]
This step is a step of converting the compound c6 obtained in the step C-5 to the corresponding amine compound c7. This step can be carried out according to the method described in Protective Groups in Organic Synthesis (written by Theodora W. Greene, Peter GM Wuts, published by John Wiley & Sons, Inc., 1999).

[Step C-7]
This step is a step of obtaining compound C1 by reacting compound c7 obtained in step C-6 with compound c10 or c11 in an appropriate solvent in the presence of various condensing agents or bases. As the condensing agent used in this step, various condensing agents used in a conventional method can be used, but 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (including hydrochloride) is preferable. Is mentioned. The base to be used is selected from the bases exemplified below, and preferably diisopropylethylamine or triethylamine is used. The solvent used in this step is selected from the solvents exemplified below and preferably dimethylformamide or tetrahydrofuran.
A compound represented by the formula (I) in which R ⁷ is not a hydrogen atom can also be produced by a method according to the above method.

Production method C ²
Of the compounds represented by the formula (I), the compound C2 represented by the formulas [C2] and [C3] in which XYZ is CR ⁶ -NR ⁷ -CONR ^4A R ^4B and W is CH. And C3 can be produced, for example, by the following production method.

(In the formula, A, R ^{1A to} R ^1D , R ² , R ^{3A to} R ^3D , R ^4A , R ^4B , R ⁶ , R ⁷ and n are as defined in item 1).

[Step C-8]
This step is a step of converting the compound c7 obtained in the step C-6 to the compound C2 under the conditions according to the step A-7.

[Step C-9]
In this step, compound C3 is obtained by reacting compound C2 obtained in step C-8 with compound c8 in the presence of various bases in an appropriate solvent. The base used in this step is selected from the bases exemplified below, and preferably diisopropylamine or triethylamine. The solvent used in this step is selected from the solvents exemplified below and preferably dimethylformamide or tetrahydrofuran.

  The base used in each step of each of the above production methods should be selected as appropriate depending on the reaction and the type of raw material compound. For example, alkali bicarbonates such as sodium bicarbonate and potassium bicarbonate, sodium carbonate , Alkali carbonates such as potassium carbonate, metal hydrides such as sodium hydride and potassium hydride, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, sodium methoxide, sodium t-butoxide Alkali metal alkoxides such as, organometallic bases such as butyllithium and lithium diisopropylamide, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine (DMAP), 1,8-diazabicyclo [5.4.0] -7- Organic bases such as undecene (DBU).

  The solvent used in each step of each of the above production methods should be selected as appropriate depending on the reaction and the type of raw material compound. For example, alcohols such as methanol, ethanol and isopropanol, acetone and methyl ketone, etc. Ketones, halogenated hydrocarbons such as methylene chloride and chloroform, ethers such as tetrahydrofuran (THF) and dioxane, aromatic hydrocarbons such as toluene and benzene, aliphatic hydrocarbons such as hexane and heptane , Esters such as ethyl acetate, propyl acetate, amides such as N, N-dimethylformamide (DMF), N-methyl-2-pyrrolidone, sulfoxides such as dimethyl sulfoxide (DMSO), and acetonitrile Nitriles, and these solvents are used alone or in combination of two or more. It is possible. Depending on the type of reaction, organic bases may be used as a solvent.

  The compound of the present invention represented by formula (I) or an intermediate thereof can be separated and purified by methods known to those skilled in the art. For example, extraction, distribution, reprecipitation, column chromatography (for example, silica gel column chromatography, ion exchange column chromatography or preparative liquid chromatography) or recrystallization may be mentioned. Examples of the recrystallization solvent include alcohol solvents such as methanol, ethanol and 2-propanol, ether solvents such as diethyl ether, ester solvents such as ethyl acetate, aromatic hydrocarbon solvents such as benzene and toluene, acetone and the like. Ketone solvents, halogen solvents such as dichloromethane and chloroform, hydrocarbon solvents such as hexane, aprotic solvents such as dimethylformamide and acetonitrile, water, or a mixed solvent of two or more selected from the above solvents Can be used. As other purification methods, the methods described in Experimental Chemistry Course (edited by the Chemical Society of Japan, Maruzen) Vol. 1 can be used.

  The compound of the present invention represented by the formula (I) or a pharmaceutically acceptable salt thereof may have an asymmetry or may have a substituent having an asymmetric carbon. Has optical isomers. The compounds of the present invention include mixtures of these isomers and isolated ones, which can be produced according to ordinary methods. Examples of the production method include a method using a raw material having an asymmetric point, or a method of introducing asymmetry at an intermediate stage. For example, in the case of optical isomers, optical isomers can be obtained by using optically active raw materials or by performing optical resolution at an appropriate stage of the production process. As the optical resolution method, for example, when the compound represented by the formula (I) or an intermediate thereof has a basic functional group, it is in an inert solvent (for example, alcohol solvents such as methanol, ethanol, 2-propanol) An ether solvent such as diethyl ether, an ester solvent such as ethyl acetate, a hydrocarbon solvent such as toluene, an aprotic solvent such as acetonitrile, or a mixed solvent of two or more selected from the above solvents), optical activity Acid (for example, monocarboxylic acid such as mandelic acid, N-benzyloxyalanine, lactic acid, tartaric acid, dicarboxylic acid such as o-diisopropylidene tartaric acid, malic acid, sulfonic acid such as camphorsulfonic acid, bromocamphorsulfonic acid) And a diastereomer method in which a salt is formed using. When the intermediate of the present compound represented by the formula (I) has an acidic functional group such as a carboxyl group, an optically active amine (for example, 1-phenylethylamine, quinine, quinidine, cinchonidine, cinchonine, strychnine, etc.) The optical resolution can also be carried out by forming a salt using an organic amine).

  The temperature at which the salt is formed is selected from the range from room temperature to the boiling point of the solvent. In order to improve the optical purity, it is desirable to raise the temperature once to near the boiling point of the solvent. When the precipitated salt is collected by filtration, it can be cooled as necessary to improve the yield. The amount of the optically active acid or amine used is in the range of about 0.5 to about 2.0 equivalents, preferably in the range of about 1 equivalent, relative to the substrate. Crystals in an inert solvent as necessary (for example, alcohol solvents such as methanol, ethanol, 2-propanol, ether solvents such as diethyl ether, ester solvents such as ethyl acetate, hydrocarbon solvents such as toluene, acetonitrile, etc. Or a mixed solvent of two or more selected from the above solvents) to obtain a highly pure optically active salt. Further, if necessary, an optically resolved salt can be treated with an acid or a base by a conventional method to obtain a free form.

  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 abbreviations used as substituents, Me means methyl and Ph means phenyl. TFA means trifluoroacetic acid. 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 line, br is broad, brs is wide single line, brs is wide multiple line, and J is coupling constant.

  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 (minutes). In addition, in each measured value, the measurement conditions used for the measurement are appended with A to C.

Measurement condition A
Detection equipment: Agilent 1100 series for API series (Applied Biosystems)
HPLC: API 150EX LC / MS system (Applied Biosystems)
Column: YMC CombiScreen Hydrosphere C18 (S-5μM, 12 nm, 4.6 × 50 mm)
Solvent: Solution A: 0.05% TFA / H ₂ O, Solution B: 0.05% TFA / MeOH
Gradient Condition:
0.0-6.0 min; A / B = 75: 25 to 1:99 (linear gradient)
Flow rate: 3.5 mL / min UV: 254 nm

Measurement condition B
Detection equipment: Agilent 1100 series for API series (Applied Biosystems)
HPLC: API 150EX LC / MS system (Applied Biosystems)
Column: YMC CombiScreen Hydrosphere C18 (S-5μM, 12 nm, 4.6 × 50 mm)
Solvent: Solution A: 0.05% TFA / H ₂ O, Solution B: 0.05% TFA / MeOH
Gradient Condition:
0.0-6.0 min; A / B = 90: 10-1: 99 (linear gradient)
Flow rate: 3.5 mL / min UV: 254, 220 nm

Measurement condition C
Detector, HPLC: LCMS-2010EV (Shimadzu)
Column: Xtimate (3μM, 2.1 × 30 mm) (Welch Materials)
Solvent: Liquid A: 0.019% TFA / H ₂ O, Liquid B: 0.038% TFA / MeOH
Gradient Condition:
0.0-1.35 minutes; A / B = 90: 10-20: 80 (linear gradient)
1.35-2.25 minutes; A / B = 20: 80
Flow rate: 0.8 mL / min UV: 220 nm
Column temperature: 50 ° C

Reference example 1
6-Fluoro-3- (4-piperidinyl) -1H-indazole

a) Preparation of phenyl-4- (2,4-difluorobenzoyl) piperidine-1-carboxylate (compound Q1)
To a toluene solution (25 ml) of (2,4-difluorophenyl) (1-methyl-4-piperidinyl) methanone (1.31 g) was added phenyl chlorocarbonate (0.861 g), and then potassium carbonate (0.829 g) was added. And stirred at 90 ° C. for 2 hours. After completion of the reaction, the mixture was subjected to liquid separation extraction with ethyl acetate-saturated aqueous sodium hydrogen carbonate solution. The obtained residue was purified by silica gel column chromatography (elution solvent; chloroform: methanol = 100: 3) to obtain Compound Q1 (0.722 g).
1H-NMR (400 MHz, CDCl ₃ ): 1.76 (2H, brs), 2.00 (2H, brm), 3.08-3.11 (1H, brm), 3.36-3.32 (1H, brm), 4.32 (2H, brs), 6.94-6.86 (1H, m), 7.03-6.97 (1H, m), 7.11 (2H, m), 7.20 (1H, m), 7.36 (2H, m), 7.89 (1H, m).

b) Preparation of phenyl-4- (6-fluoro-1H-indazol-3-yl) piperidine-1-carboxylate (Compound Q2) Hydrazine monohydrate in pyridine solution (8 ml) of Compound Q1 (810 mg) (234 mg) was added, and the mixture was heated and stirred at 150 ° C. for 1 hour under microwave irradiation. After completion of the reaction, the mixture was extracted with ethyl acetate-water, and the organic layer was dried over sodium sulfate and then distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate = 1: 1) to obtain Compound Q2 (390 mg).
¹ H-NMR (400 MHz, CDCl ₃ ): 2.10-2.07 (4H, brm), 3.28-3.22 (3H, brm), 4.43 (2H, brs), 6.93 (1H, m), 7.07 (3H, m) , 7.22-7.13 (1H, m), 7.37 (2H, m), 7.70 (1H, m).

c) Preparation of 6-fluoro-3- (4-piperidinyl) -1H-indazole (Reference Example 1) Compound Q2 (630 mg) in water / ethanol solution (19 mL / 19 mL) and potassium hydroxide (3.12 g) And heated and stirred at 90 ° C. for 15 hours. After completion of the reaction, the mixture was extracted with ethyl acetate-water, and the organic layer was dried over sodium sulfate and evaporated under reduced pressure to give Reference Example 1 (350 mg).
¹ H-NMR (400 MHz, CDCl ₃ ): 1.93 (2H, m), 2.02 (2H, brm), 2.83 (2H, m), 3.18 (1H, m), 3.24 (2H, m), 6.91 (1H , td, J = 9.0, 9.0, 7.9 Hz), 7.09 (1H, dd, J = 9.0, 2.2 Hz), 7.73 (1H, dd, J = 9.0, 5.1 Hz).

Reference example 2
4- (1H-Indazol-3-yl) cyclohexanecarboxylic acid

a) Preparation of ethyl 4- (trifluoromethylsulfonyloxy) -3-cyclohexenecarboxylate (compound Q3) Tf ₂ O (4.39 mL) was added to a toluene solution (70 ml) of pyridine (2.08 mL) under a nitrogen atmosphere. Added dropwise in minutes. To the reaction solution was added a toluene solution (3.0 mL) of ethyl-4-oxocyclohexanecarboxylate (4.00 g), and the mixture was heated and stirred at 40 ° C. for 1 day under a nitrogen atmosphere. After completion of the reaction, the mixture was extracted with toluene-water, and the organic layer was dried and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate = 4: 1) to obtain Compound Q3 (3.98 g).
¹ H-NMR (400 MHz, CDCl ₃ ): 1.24 (3H, t, J = 8.0 Hz), 1.89 (1H, m), 2.01 (1H, m), 2.38 (4H, brm), 2.56 (1H, m ), 3.68 (1H, brs), 4.13 (2H, q, J = 8.0 Hz), 5.74 (1H, s).

b) Preparation of ethyl 4- (4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl) -3-cyclohexenecarboxylate (compound Q4) DMSO solution of compound Q3 (3.15 g) (40 ml) was added with bis (pinacolato) diborane (2.51 g), potassium acetate (3.06 g) and 1,1'-bis (diphenylphosphino) ferrocenepalladium dichloride (458 mg), and then at 50 ° C under a nitrogen gas atmosphere. And stirred for 3 hours. After completion of the reaction, the mixture was extracted with ethyl acetate-water, and the organic layer was dried and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate = 5: 1) to obtain Compound Q4 (1.95 g).
¹ H-NMR (400 MHz, CDCl ₃ ): 1.22 (15H, m), 1.57 (1H, s), 1.97 (1H, s), 2.09 (1H, s), 2.22 (1H, s), 2.31 (2H , s), 2.46 (1H, s), 4.10 (2H, q, J = 7.1 Hz), 6.51 (1H, s).

c) Preparation of ethyl- (3-1H-indazoyl) cyclohexenecarboxylate (compound Q5) 3-iodoindazole (976 mg) and hydrogen carbonate in water / isopropanol solution (4 mL / 12 ml) of compound Q4 (1.57 g) Sodium (672 mg) and bis (triphenylphosphine) palladium (II) dichloride (232 mg) were added, and the mixture was heated and stirred at 140 ° C. for 1 hour under microwave irradiation in a nitrogen gas atmosphere. After completion of the reaction, Pd was removed by filtration, followed by liquid separation extraction with ethyl acetate-water, and the organic layer was dried and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 4: 3) to give Compound Q5 (769 mg).
¹ H-NMR (400 MHz, CDCl ₃ ): 1.27 (3H, t, J = 7.1 Hz), 1.83-1.93 (1H, brm), 2.23 (1H, m), 2.58 (2H, t, J = 9.5 Hz ), 2.69 (2H, m), 2.89 (1H, m), 4.17 (2H, q, J = 7.2 Hz), 6.57 (1H, s), 7.17 (1H, t, J = 8.0 Hz), 7.37 (1H , t, J = 8.0 Hz), 7.45 (1H, d, J = 8.0 Hz), 7.92 (1H, d, J = 8.0 Hz).

d) Preparation of ethyl-4- (3-1H-indazoyl) cyclohexanecarboxylate (Compound Q6) To an ethanol solution (40 ml) of Compound Q5 (1.48 g) obtained in the above experiment, platinum (IV) oxide ( 148 mg) was added, and catalytic reduction was performed for 3 days under a hydrogen gas atmosphere of 4.5 atm. After completion of the reaction, the mixture was filtered through Celite, and the filtrate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 3: 1) to give Compound Q6 (961 mg).
¹ H-NMR (400 MHz, CDCl ₃ ): 1.22 (3H, t, J = 7.2 Hz), 1.67-2.21 (8H, brm), 2.67 (1H, m), 3.19 (1H, m), 4.16 (2H , q, J = 7.2 Hz), 7.12 (1H, m), 7.35 (1H, m), 7.43 (1H, d, J = 8.0 Hz), 7.74 (1H, d, J = 8.0 Hz).

e) Preparation of ethyl-4- (3-1H-indazoyl) cyclohexanecarboxylic acid (Reference Example 2) 2 mol / L of Compound Q6 (757 mg) obtained in the above experiment was added to an ethanol solution (8.5 ml). Aqueous sodium hydroxide (4.17 mL) was added, and the mixture was stirred at room temperature for 1 day. After completion of the reaction, it was poured into water and washed with ethyl acetate. The aqueous layer was acidified with 10% aqueous citric acid solution and extracted with ethyl acetate. The organic layer was dried and evaporated under reduced pressure to give Reference Example 2 (676 mg).
¹ H-NMR (400 MHz, CD ₃ OD): 1.76-2.26 (8H, brm), 3.17 (1H, m), 3.72 (1H, m), 3.92-3.89 (1H, m), 5.46 (1H, m ), 7.07 (1H, m), 7.33 (1H, m), 7.44 (1H, d, J = 8.3 Hz), 7.75 (1H, d, J = 8.3 Hz).

Reference example 3
Cis-4- (3-indazoyl) cyclohexylamine (Reference Example 3)

a) Preparation of cis-S-phenyl 4- (benzyloxycarbonyl) cyclohexanethiolate (compound Q7)
Oxalyl chloride (399 μL) was added dropwise to a CH ₂ Cl ₂ solution (15.0 ml) of 4- (benzyloxycarbonyl) cyclohexanecarboxylic acid (832 mg) at 0 ° C. A small amount of DMF solution was added to the reaction solution at room temperature, and the mixture was stirred at room temperature for 1 hour. After evaporating the solvent under reduced pressure, THF (12.0 mL), thiophenol (314 μL) and triethylamine (1.35 mL) were added, and the mixture was stirred at room temperature for 1.5 hours. After completion of the reaction, the mixture was extracted with ethyl acetate-water, and the obtained organic layer was washed with saturated brine and dried over sodium sulfate. After the solvent was distilled off under reduced pressure, the obtained residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate = 3: 1) to obtain Compound Q7 (1.16 g).
¹ H-NMR (400 MHz, CDCl3): 1.75-1.84 (8H, brm), 2.74 (1H, s), 3.75 (1H, s), 4.81 (1H, s), 5.07 (2H, s), 7.31- 7.39 (10H, brm).

b) Preparation of benzyl-cis-4- (2-fluorobenzoyl) cyclohexylcarbamate (Compound Q8) To a THF solution (10 ml) of Compound Q7 (370 mg) obtained in the above experiment, 2-fluorophenylboronic acid was added. (168 mg), copper (I) thiophene-2-carboxylate (229 mg), tris (dibenzylideneacetone) bispalladium (92 mg) and triethyl phosphite (17 mg) were added, and 30 hours at 16 ° C. Stir. After completion of the reaction, the mixture was filtered, and the obtained filtrate was subjected to liquid separation extraction with ethyl acetate-water. The organic layer was washed with saturated brine and dried over sodium sulfate. After the solvent was distilled off under reduced pressure, the obtained residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate = 2: 1) to obtain Compound Q8 (297 mg).
¹ H-NMR (400 MHz, CDCl3): 7.70 (1H, m), 7.47 (1H, m), 7.31 (5H, m), 7.20 (1H, m), 7.09 (1H, m), 5.06 (2H, s), 4.88 (1H, br), 3.78 (1H, s), 3.22 (1H, m), 1.60-1.80 (8H, brm).

c) Preparation of benzyl-cis-4- (3-1H-indazoyl) cyclohexylcarbamate (Compound Q9) Hydrazine monohydrate was added to the pyridine solution (3 ml) of Compound Q8 (263 mg) obtained in the above experiment. (74 mg) was added, and the mixture was heated and stirred at 150 ° C. for 1 hour under microwave irradiation. After completion of the reaction, the mixture was extracted with ethyl acetate-water, and the organic layer was dried over sodium sulfate and then distilled off under reduced pressure. The obtained residue was purified by amino silica gel column chromatography (elution solvent; chloroform: ethyl acetate = 4: 1) to obtain Compound Q9 (109 mg).
¹ H-NMR (400 MHz, CDCl ₃ ): 1.75-2.00 (8H, brm), 3.19 (1H, m), 3.93 (1H, m), 5.09 (3H, m), 7.08 (1H, m), 7.28 -7.45 (7H, brm), 7.70 (1H, d, J = 8.3 Hz).

d) Production of cis-4- (3-1H-indazoyl) cyclohexylamine (Reference Example 3) To an ethanol solution (40 ml) of compound C3 (100 mg) obtained in the above experiment, Pd (OH) ₂ ( 10 mg) was added, and catalytic reduction was performed in a hydrogen gas atmosphere for 1 day. After completion of the reaction, the mixture was filtered through Celite, and the filtrate was evaporated under reduced pressure to obtain Reference Example 3 (62 mg). (E0485-190)
¹ H-NMR (400 MHz, CD ₃ OD): 1.86-2.02 (6H, m), 2.21 (2H, m), 3.38 (2H, m), 7.09 (1H, m), 7.33 (1H, m), 7.45 (1H, d, J = 8.3 Hz), 7.75 (1H, d, J = 8.3 Hz).

Example 1
N-cyclohexyl-4- (6-fluoro-1H-indazol-3-yl) piperidine-1-carboxamide

Cyclohexyl isocyanate (130 mg) was added to a tetrahydrofuran solution (30 ml) of Reference Example 1 (220 mg), and the mixture was stirred for 16 hours at room temperature. After completion of the reaction, the residue was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent; ethyl acetate) to give Example 1 (190 mg).
¹ H-NMR (400 MHz, CD ₃ OD): 1.15-1.36 (5H, m), 1.64 (1H, m), 1.76 (2H, m), 1.90-1.83 (4H, m), 1.99 (2H, m ), 2.96 (2H, m), 3.28 (1H, m), 3.54 (1H, m), 4.16 (2H, m), 6.15 (1H, m), 6.90 (1H, td, J = 9.0, 2.2 Hz) , 7.12 (1H, dd, J = 9.0, 2.2 Hz), 7.77 (1H, dd, J = 9.0, 5.1 Hz).

Example 2
N-cyclohexyl-4- (1-ethyl-6-fluoro-1H-indazol-3-yl) piperidine-1-carboxamide

Sodium hydride (9 mg) and bromoethane (25 mg) were added to a dimethylformamide solution (2 ml) of Example 1 (79 mg) at 0 ° C., and the mixture was stirred at 0 ° C. for 10 minutes. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate / hexane (3/2). The organic layer was dried over sodium sulfate and evaporated under reduced pressure. Example 2 (43 mg) was obtained by refine | purifying the obtained residue with silica gel column chromatography (elution solvent; ethyl acetate).
¹ H-NMR (400 MHz, CDCl ₃ ): 1.05-1.26 (3H, brm), 1.45 (1H, m), 1.45 (3H, t, J = 7.3 Hz), 1.60-1.74 (3H, m), 1.99 (6H, brm), 2.96 (2H, m), 3.18 (1H, m), 3.68 (1H, m), 4.07 (2H, m), 4.29 (2H, q, J = 7.3 Hz), 4.38 (1H, m), 6.86 (1H, td, J = 9.0, 2.1 Hz), 6.99 (1H, dd, J = 9.0, 2.1 Hz), 7.64 (1H, dd, J = 9.0, 5.1 Hz).

Example 3
N-cyclohexyl-4- (6-fluoro-1H-indazol-3-yl) piperazine-1-carboxamide

Cyclohexyl isocyanate (25 mg) was added to a tetrahydrofuran solution (2 ml) of 6-fluoro-3- (1-piperazinyl) -1H-indazole dihydrochloride (58 mg), and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction solution was poured into water, the resulting mixed solution was extracted with ethyl acetate, and the resulting organic layer was dried over sodium sulfate and evaporated under reduced pressure. Example 3 (41 mg) was obtained by refine | purifying the obtained residue with silica gel column chromatography (elution solvent; ethyl acetate).
¹ H-NMR (400 MHz, CD ₃ OD): 1.15-1.90 (11H, brm), 2.90-2.80 (4H, m), 3.54 (2H, m), 4.14 (2H, m), 6.14 (1H, m ), 6.44 (1H, m), 6.72 (1H, m), 6.80 (1H, m).

Example 4
N-Cyclohexyl-4- (3-1H-indazoyl) cyclohexanecarboxamide

Add DIEA (350 μL) and cyclohexylamine (68 μL) to a DMF suspension (2 ml) of Reference Example 2 (98 mg), EDCI · HCl (112 mg) and HOBt (125 mg), and mix at room temperature. Stir overnight. Liquid separation extraction was carried out with CHCl ₃ -water, and the obtained organic layer was washed with saturated brine and dried over sodium sulfate. After distilling off the solvent under reduced pressure, Example 2 (29 mg) was obtained by purification by silica gel column chromatography (elution solvent: hexane: ethyl acetate = 3: 1).
¹ H-NMR (400 MHz, CDCl ₃ ): 7.80 (1H, d, J = 8.3 Hz), 7.44 (1H, d, J = 8.3 Hz), 7.33 (1H, dd, J = 8.3, 7.2 Hz), 7.07 (1H, dd, J = 8.3, 7.2 Hz), 3.64 (1H, m), 2.46 (1H, m), 2.35 (2H, m), 2.03 (2H, m), 1.85 (4H, m), 1.67 -1.77 (6H, brm), 1.15-1.40 (4H, m).

Example 5
N- (cis-4- (3-1H-indazoyl) cyclohexyl) cyclohexanecarboxamide

Add DIEA (175 μL) and cyclohexanecarboxylic acid (24 mg) to a DMF suspension (1.5 ml) of Reference Example 3 (43 mg), EDCI · HCl (56 mg) and HOBt (62 mg) at room temperature. Stir for 5 hours. CH ₂ Cl ₂ - to separatory extraction with water, the resulting organic layer was dried over sodium sulfate. After evaporating the solvent under reduced pressure, Example 4 (18 mg) was obtained by purification by amino silica gel column chromatography (elution solvent; hexane: ethyl acetate = 1: 4).
¹ H-NMR (400 MHz, CDCl ₃ ): 1.22-1.26 (2H, m), 1.41 (2H, m), 1.65 (2H, s), 1.75-2.05 (12H, m), 3.21 (1H, m) , 4.15 (1H, m), 5.64 (1H, m), 7.13 (1H, m), 7.36 (1H, m), 7.44 (1H, d, J = 8.3 Hz), 7.71 (1H, d, J = 8.3 Hz), 9.85 (1H, s).

Example 6
1- (4- (3-1H-indazoyl) cyclohexyl) -3-cyclohexylurea

TEA (120 μL) and cyclohexyl isocyanate (24 μL) were added to a THF suspension (1.5 ml) of Reference Example 3 (58 mg), and the mixture was stirred at room temperature for 15 hours. CH ₂ Cl ₂ - to separatory extraction with water, the resulting organic layer was dried over sodium sulfate. After evaporating the solvent under reduced pressure, Example 5 (30 mg) was obtained by purification with amino silica gel column chromatography (elution solvent; ethyl acetate).
¹ H-NMR (400 MHz, CDCl ₃ ): 1.07 (2H, m), 1.25 (2H, m), 1.57-1.93 (12H, brm), 3.14 (1H, m), 3.46 (1H, m), 3.91 (1H, m), 4.12 (1H, m), 4.49 (1H, m), 7.08 (1H, m), 7.31 (1H, m), 7.38 (1H, m), 7.66 (1H, m).

Examples 7-51
The corresponding starting materials were used and reacted and treated in the same manner as in Examples 1 to 3 to obtain the compounds shown in Table 1.

Examples 52-60
Reaction and treatment were performed in the same manner as in Example 4 using the corresponding starting compounds, and the compounds shown in Table 2 were obtained.

Examples 61-66
Reaction and treatment were performed in the same manner as in Examples 5 and 6 using the corresponding starting compounds, and the compounds shown in Table 3 were obtained.

Test Examples Hereinafter, pharmacological test results of representative compounds of the present invention will be shown and the pharmacological action of the compounds will be described. However, the present invention is not limited to these test examples.

Test Example 1 PAM activity evaluation using human α7nACh receptor stably expressing cells (1) Human α7nAChR stable expressing cells Human α7nAChR stable expressing cells were prepared and subjected to culture. Specifically, the human α7nAChR gene was inserted into the pcDNA3.1 vector (cat # V790-20, invitrogen, Carlsbad, CA, USA), and the rat pituitary-derived GH4C1 cells (cat # CCL-82.2, ATCC, USA) Introduced. Thereafter, selection with Geneticin (cat # 10131-027, invitrogen, Carlsbad, CA, USA) was performed to obtain human α7nAChR stably expressing cells.
Medium includes 2.5% fetal bovine serum (cat # 2917354, ICN Biomedicals, Inc, USA), 15% inactivated horse serum (cat # 26050-088, invitrogen, Carlsbad, CA, USA), 1 μg / mL Geneticin, 5 μg / Collagen Type1 coated dish using F-10 Nutrient Mixture (Ham) medium (cat # 11550-043, invitrogen, Carlsbad, CA, USA) containing mL Puromycin (cat # 14861-84, invitrogen, Carlsbad, CA, USA) (cat # 4030-010, iwaki, Tokyo, Japan). During the culture, the medium was changed every 2-3 days, and the cells were collected by TrypLE Express (cat # 45604-021, invitrogen, Carlsbad, CA, USA) treatment every 7 days and subcultured.
Seven days after passage, cells were collected by TrypLE Express treatment in approximately 80% confluent state. Hanks (cat # 14065-056, invitrogen, Carlsbad, CA, USA) / 20mM Hepes (cat # 15630-080, invitrogen , Carlsbad, CA, USA) Buffer (pH 7.4), F-10 Nutrient Mixture (Ham), suspended in a reaction medium consisting of 0.1 mg / mL Geneticin to 20000 cells / 25 μL / well, and 384-well plate ( cat # 781090, Greiner, Germany).
On the day after seeding, Viviren (cat # E649X, Promega, Madison, WI, USA) was added to a final concentration of 4 μM (15 μL / well), and the mixture was allowed to stand for 4 hours at room temperature under light shielding after centrifugation.

(2) Preparation of test compound A DMSO solution with a concentration 1000 times the final concentration was prepared as a test compound, and this solution was added to Hanks / 20 mM HEPES / 0.2% BSA (cat # A3803, Sigma, St. Louis, MO, USA). To 6 times the final concentration.

(3) PAM activity evaluation FDSS7000 (Hamamatsu Photonics) was used for the detection of the luminescence signal by α7nAChR stimulation. Test compounds were added to the plates to which the cells and luminescent substrate had been added, and 150 seconds later, ACh at a concentration indicating EC ₂₀ was added alone. The luminescence signal (center wavelength: 465 nm) was measured for 138 seconds after the addition of ACh to calculate RLU (Max-Min), and the ratio of RLU (Max-Min) between the control well and the test compound added well was defined as PAM activity.
Table 4 shows data of α7PAM activity of representative compounds.

  As shown in Table 4, the compound of the present invention had α7 nAChR PAM activity in the PAM activity evaluation test. In particular, Examples 7, 9, 33, 47, 48, 51, 61 showed stronger PAM activity.

  As described above, the derivative represented by the formula (I), or a pharmaceutically acceptable salt thereof, has a strong α7 nicotinic acetylcholine receptor (α7 nAChR) modulating action, and the central nervous system ( CNS) and / or peripheral nervous system (PNS) cholinergic diseases, smooth muscle contraction diseases, endocrine diseases, neurodegenerative diseases, diseases such as inflammation or pain, and withdrawal symptoms caused by addictive drug abuse Useful for treatment of diseases and the like.

Claims (23)

Formula (I):
[Where:
A represents CR ^1D or a nitrogen atom,
X—Y—Z represents N—CO—NR ^4A R ^4B , CR ⁶ —CO—NR ^4A R ^4B , CR ⁶ —NR ⁷ —CO—NR ^4A R ^4B , CR ⁶ —NR ⁷ —COR ⁵ or CR ^6. -NR < ⁷ > -Ar,
R ^1A , R ^1B , R ^1C and R ^1D are the same or different and are halogen, hydroxyl group, C _1-6 alkoxy, —NR ⁸ R ⁹ , —COOR ⁸ , —CONR ⁸ R ⁹ , —NR ⁸ COR ⁹ , C _1-6 alkyl optionally substituted with 1 to 5 substituents selected from the group consisting of —SO ₂ NR ⁸ R ⁹ and —NR ⁸ SO ₂ R ⁹ ; halogen, hydroxyl group, C _1-6 Selected from the group consisting of alkyl, C _1-6 alkoxy, —NR ⁸ R ⁹ , —COOR ⁸ , —CONR ⁸ R ⁹ , —NR ⁸ COR ⁹ , —SO ₂ NR ⁸ R ⁹ and —NR ⁸ SO ₂ R ^9. C _3-10 cycloalkyl or 4-10 membered saturated heterocycle optionally substituted with 1 to 5 substituents as described above; halogen, hydroxyl, C _1-6 alkoxy, —NR ⁸ R ⁹ , —COOR ^8, - ^{ONR 8 R 9, -NR 8 COR} 9, which may be substituted with 1 to 5 substituents selected from the group consisting of -SO 2 ^NR 8 ^{R 9} and ^-NR 8 _SO 2 ^{R 9} _{C 1- 6} alkoxy; hydrogen atom; hydroxyl group; halogen; halogen, hydroxyl group, C _1-6 alkyl, C _1-6 alkoxy, —NR ⁸ R ⁹ , —COOR ⁸ , —CONR ⁸ R ⁹ and —NR ⁸ COR ⁹ 1-5 aryl which may be substituted with a substituent or heteroaryl selected from a nitro; ^-NR 8 ^{R 9; cyano; -COOR 8; -CONR 8 R 9} ; -NR 8 COR 9; - SO ₂ NR ⁸ R ^9; represents or ^-NR 8 _SO 2 ^{R 9,} wherein, X-Y-Z is, when it is ^{N-CO-NHEt, R 1B} is substituted with -CO-NHEt Instead of the aryl group,
W represents CH or a nitrogen atom,
R ² is halogen, hydroxyl group, C _1-6 alkoxy, —NR ¹⁰ R ¹¹ , —COOR ¹⁰ , —CONR ¹⁰ R ¹¹ , —NR ¹⁰ COR ¹¹ , —SO ₂ NR ¹⁰ R ¹¹ and —NR ¹⁰ SO ₂ R. C _1-6 alkyl which may be substituted with 1 to 5 substituents selected from the group consisting of ¹¹ ; halogen, hydroxyl group, C _1-6 alkoxy, —NR ¹⁰ R ¹¹ , —COOR ¹⁰ , —CONR C _3-10 which may be substituted with 1 to 5 substituents selected from the group consisting of ¹⁰ R ¹¹ , —NR ¹⁰ COR ¹¹ , —SO ₂ NR ¹⁰ R ¹¹ and —NR ¹⁰ SO ₂ R ^11. Cycloalkyl, 4-10 membered saturated heterocyclic ring or 4-10 membered saturated heterocyclic-carbonyl-; hydrogen atom; halogen, hydroxyl group, C _1-6 alkyl, C _1-6 al Aryl or heteroaryl optionally substituted with 1 to 5 substituents selected from the group consisting of alkoxy; C _1-6 alkylcarbonyl; —COOR ¹⁰ ; —CONR ¹⁰ R ¹¹ ; or SO ₂ NR ¹⁰ R ¹¹
R ^3A , R ^3B , R ^3C and R ^3D are the same or different and are substituted with 1 to 5 substituents selected from the group consisting of halogen, hydroxyl group, C _1-6 alkoxy and —NR ¹² R ^13. Optionally represents C _1-6 alkyl; hydrogen atom; halogen; hydroxyl group; or C _1-6 alkoxy,
R ^4A , R ^4B , R ⁵ and R ⁷ are the same or different and may be substituted C _1-10 alkyl; _optionally substituted C _3-10 cycloalkyl (the group may be aryl or hetero Optionally fused to aryl); optionally substituted 4-10 membered saturated heterocycle (the group optionally fused to aryl or heteroaryl); optionally substituted Aryl represents an optionally substituted heteroaryl; or represents a hydrogen atom, wherein (1) R ^4A and R ^4B are a 4- to 10-membered nitrogen-containing saturated heterocyclic ring that may be substituted together. (2) R ^4A and R ^4B are not both hydrogen atoms, and (3) R ⁵ is not a hydrogen atom,
R ⁶ may be the same or different, halogen, _{hydroxyl, C 1-6} alkoxy and ^-NR 14 may be substituted with 1 to 5 substituents selected from the group consisting of ^{R 15} _{C 1-6} alkyl C _3-10 cycloalkyl optionally substituted with 1 to 5 substituents selected from the group consisting of halogen, hydroxyl group, C _1-6 alkoxy and —NR ¹⁴ R ¹⁵ or 4 to 10 membered saturation Represents a heterocycle; a hydrogen atom; a halogen; a hydroxyl group; or C _1-6 alkoxy,
Ar is selected from the group consisting of halogen, hydroxyl group, C _1-6 alkyl, C _1-6 alkoxy, —NR ¹⁶ R ¹⁷ , —COOR ¹⁶ , —CONR ¹⁶ R ^17, and —NR ¹⁶ COR ^17. Represents aryl or heteroaryl optionally substituted by one substituent,
R ^{8 to} R ¹⁷ are the same or different, and when there are a plurality thereof, each independently represents a hydrogen atom or C _1-6 alkyl optionally substituted with 1 to 5 fluorines, , R ⁸ and R ⁹ , R ¹⁰ and R ¹¹ , R ¹² and R ¹³ , R ¹⁴ and R ¹⁵ , R ¹⁶ and R ¹⁷ together form a 4-10 membered nitrogen-containing saturated heterocyclic ring. Well,
n represents 1 or 2]
Or a pharmaceutically acceptable salt thereof. <I> The optionally substituted alkyl, the optionally substituted cycloalkyl and the optionally substituted 4 to 10 membered saturated heterocyclic ring in claim 1 are each independently
(1) optionally substituted aryl,
(2) optionally substituted heteroaryl,
(3) an optionally substituted 4- to 10-membered saturated heterocyclic ring,
(4) C _3-10 cycloalkyl which may be substituted,
(5) -CONR ¹⁸ R ¹⁹
(6) halogen,
(7) hydroxyl group,
(8) C _1-6 alkyl which may be substituted,
(9) C _1-6 alkoxy which may be substituted,
(10) C _1-6 alkylcarbonyl which may be substituted,
(11) -N (R ¹⁸ ) COR ¹⁹ , and (12) -NR ¹⁸ R ¹⁹ ,
Or a group that may be substituted with 1 to 5 substituents that are the same or different selected from the group consisting of:
<Ii> The optionally substituted aryl and the optionally substituted heteroaryl in Item 1 are each independently the same or different 1 to 5 selected from the group consisting of the following (a) to (i): A group which may be substituted with one substituent,
Here, the groups shown in the above (1) to (4) are:
(A) halogen,
(B) a hydroxyl group,
(C) optionally substituted C _1-6 alkyl,
(D) optionally substituted C _1-6 alkoxy,
^{(E) -NR} 18 ^{R 19,}
(F) -N (R ¹⁸ ) COR ¹⁹ ,
(G) cyano, and (h) -CONR ¹⁸ R ¹⁹ ,
(I) an optionally substituted C _1-6 alkylcarbonyl,
Means a group optionally substituted by 1 to 5 substituents which are the same or different selected from the group consisting of:
The groups shown in the above (8), (9) and (10) are substituted with the same or different 1 to 5 substituents selected from the group consisting of (b), (d), (e) and fluorine. (C), (d) and (i) are the same or different groups selected from the group consisting of —NR ¹⁸ R ¹⁹ , hydroxyl group, C _1-6 alkoxy and fluorine. Optionally substituted with 5 substituents),
R ¹⁸ and R ¹⁹ are each independently a hydrogen atom or C _1-10 alkyl _optionally substituted with 1 to 5 fluorines, or R ¹⁸ and R ^{19 taken} together 4 A 10-membered nitrogen-containing saturated heterocyclic ring may be formed,
The compound according to claim 1 or a pharmaceutically acceptable salt thereof. R ^4A , R ^4B , R ⁵ and R ⁷ are the same or different and are aryl, heteroaryl, 4- to 10-membered saturated heterocycle, C _3-10 cycloalkyl, fluorine, hydroxyl group, 1 to 5 fluorines. C _1-10 alkyl optionally substituted with 1 to 5 substituents selected from the group consisting of optionally substituted C _1-6 alkoxy, C _1-6 alkylcarbonyl and —NR ¹⁸ R ¹⁹ C _3-10 cycloalkyl; 4 to 10-membered saturated heterocyclic ring; or a hydrogen atom (the aryl, heteroaryl, saturated heterocyclic ring and cycloalkyl are fluorine, hydroxyl group, C _1-6 alkyl (the group is , _fluorine, optionally substituted by _{C 1-6} alkoxy and ^-NR 18 may be substituted with 1 to 5 substituents selected from the group consisting of ^{R 19)} 1-5 fluorine C _{-6 alkoxy, C 1-6} alkylcarbonyl, optionally substituted with 1-5 substituents selected from the group consisting of 1-5 ^-NR aryl and optionally substituted with halogen 18 ^{R 19} In this case, (1) R ^4A and R ^4B are combined together to form a 4- to 10-membered nitrogen-containing saturated heterocyclic ring (the ring may be substituted with the same substituent as the above saturated heterocyclic ring). (2) R ^4A and R ^4B are not both hydrogen atoms, and (3) R ⁵ is not a hydrogen atom.
The compound according to claim 1 or claim 2 or a pharmaceutically acceptable salt thereof. A is CR ^1D ,
The compound as described in any one of Claims 1-3, or its pharmaceutically acceptable salt. R ² is fluorine, _{hydroxyl, C 1-6} alkoxy and ^-NR 10 ^{R 11} 1 to 5 amino optionally substituted with a substituent _{C 1-6} alkyl selected from the group consisting of; fluorine, hydroxyl, C _3-10 cycloalkyl optionally substituted with 1 to 5 substituents selected from the group consisting of C _1-6 alkoxy and —NR ¹⁰ R ¹¹ , 4 to 10 membered saturated heterocycle or 4 to 10-membered saturated heterocycle-carbonyl-; hydrogen atom; or C _1-6 alkylcarbonyl.
The compound as described in any one of Claims 1-4, or its pharmaceutically acceptable salt. R ^1A , R ^1B , R ^1C and R ^1D are the same or different and are selected from the group consisting of fluorine, hydroxyl group, C _1-6 alkoxy, —NR ⁸ R ⁹ , —CONR ⁸ R ⁹ and —NR ⁸ COR ^9. 1-5 may be substituted with a substituent _{C 1-6} alkyl which is: fluorine, _{hydroxyl, C 1-6 alkyl, C 1-6} ^{alkoxy, -NR 8 R 9, -CONR 8} R 9 and C _3-10 cycloalkyl or 4-10 membered saturated heterocyclic ring optionally substituted with 1 to 5 substituents selected from the group consisting of —NR ⁸ COR ⁹ ; halogen, hydroxyl group, C _1-6 C _1-6 alkoxy optionally substituted with 1 to 5 substituents selected from the group consisting of alkoxy, —NR ⁸ R ⁹ , —CONR ⁸ R ⁹ and —NR ⁸ COR ⁹ ; hydrogen atom; hydroxyl group ;halogen Aryl or heteroaryl optionally substituted with 1 to 5 substituents selected from the group consisting of fluorine, C _1-6 alkyl, C _1-6 alkoxy and —NR ⁸ R ⁹ ; —NR ⁸ R ⁹ ; cyano; —CONR ⁸ R ⁹ ; or —NR ⁸ COR ⁹ .
The compound as described in any one of Claims 1-5, or its pharmaceutically acceptable salt. X—Y—Z is N—CO—NR ^4A R ^4B , CR ⁶ —CO—NR ^4A R ^4B , CR ⁶ —NR ⁷ —CO—NR ^4A R ^4B or CR ⁶ —NR ⁷ —COR ⁵ ;
The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof. Either one of R ^4A or R ^4B is a hydrogen atom,
The compound as described in any one of Claims 1-7, or its pharmaceutically acceptable salt. n is 1.
The compound as described in any one of Claims 1-8, or its pharmaceutically acceptable salt. ^{R 1A,} R 1B, R ^1C and ^{R 1D} are the same or different, fluorine, hydroxyl and _{C 1-6} optionally _{C 1} optionally substituted with 1 to 5 substituents selected from the group consisting of alkoxy _-6 alkyl; fluorine, hydroxyl and _{C 1-6} optionally _{C 3-8} cycloalkyl optionally substituted with 1 to 5 substituents selected from the group consisting of alkoxy; fluorine, hydroxyl and _{C 1-6} alkoxy A C _1-6 alkoxy optionally substituted with 1 to 5 substituents selected from the group consisting of: a hydrogen atom; a hydroxyl group; a halogen; or a 4-10 membered saturated heterocyclic ring,
The compound as described in any one of Claims 1-9, or its pharmaceutically acceptable salt. R ^4A , R ^4B , R ⁵ and R ⁷ are the same or different and may be substituted with a 4 to 10 membered saturated heterocyclic ring, C _3-10 cycloalkyl, fluorine, a hydroxyl group, or 1 to 5 fluorines. C _1-10 alkyl optionally substituted with 1 to 5 substituents selected from the group consisting of C _1-6 alkoxy, C _1-6 alkylcarbonyl and —NR ¹⁸ R ¹⁹ ; C _3-10 A cycloalkyl; a 4- to 10-membered saturated heterocycle; or a hydrogen atom (the saturated heterocycle and cycloalkyl are fluorine, hydroxyl, C _1-6 alkyl (the group is fluorine, C _1-6 alkoxy and — C _1-6 alkoxy optionally substituted with 1 to 5 fluorines, optionally substituted with 1 to 5 substituents selected from the group consisting of NR ¹⁸ R ¹⁹ , C _1-6 alkyl Carbonyl, or- May be substituted with 1 to 5 substituents selected from the group consisting of R ¹⁶ R ^17), wherein, ^{(1) R 4A} and ^{R 4B} are 4-10 membered nitrogen-containing together A saturated heterocyclic ring (which may be substituted with the same substituent as the saturated heterocyclic ring), and (2) R ^4A and R ^4B are not hydrogen atoms, 3) R ⁵ is not a hydrogen atom,
The compound according to claim 1 or a pharmaceutically acceptable salt thereof. R ⁶ is C _1-6 alkyl, C _1-6 alkoxy, hydroxyl group, fluorine or hydrogen atom,
The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof. W is CH,
The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof. X—Y—Z is N—CO—NR ^4A R ^4B or CR ⁶ —NR ⁷ —COR ⁵ ;
The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof. R ^3A , R ^3B , R ^3C and R ^3D are the same or different and are C _1-6 alkyl optionally substituted with 1 to 5 fluorines; C _1-6 alkoxy; hydrogen atom; or fluorine ,
The compound as described in any one of Claims 1-14, or its pharmaceutically acceptable salt. Ar is aryl optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, C _1-6 alkyl, C _1-6 alkoxy and —NR ¹⁶ R ¹⁷ .
The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof. X—Y—Z is N—CO—NR ^4A R ^4B ;
The compound as described in any one of Claims 1-16, or its pharmaceutically acceptable salt.   The pharmaceutical composition containing the compound as described in any one of Claims 1-17, or those pharmaceutically acceptable salts.   The therapeutic agent or preventive agent of the disease resulting from abnormality of the intracellular signal transduction which the acetylcholine in which the compound as described in any one of Claims 1-17 or those pharmacologically acceptable salts is an active ingredient is concerned. . The disease caused by abnormal intracellular signaling involving acetylcholine is Alzheimer's disease, Down's syndrome, cognitive impairment, memory impairment / learning impairment, mild cognitive impairment, attention deficit / hyperactivity disorder, or cerebrovascular angiopathy,
The therapeutic agent of Claim 19.   A cell in which acetylcholine is involved, which comprises administering a therapeutically effective amount of the compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof to a patient in need of treatment. A method for treating or preventing a disease caused by abnormal signal transduction.   The compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof for the treatment or prevention of a disease caused by an abnormality in intracellular signal transduction involving acetylcholine.   A pharmaceutical composition comprising the compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a disease caused by an abnormality in intracellular signal transduction involving acetylcholine. object.