JP2015214492A - 3-(4-piperidyl)-imidazole derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a therapeutic agent which has strong action of adjusting α7 nicotinic acetylcholine receptor(α7 nAChR) and is used in treatment of diseases related to the cholinergic activity of the central nervous system(CNS) and/or the peripheral nervous system(PNS), diseases related to smooth muscle contraction, endocrine diseases and diseases related to neurodegeneration, etc.SOLUTION: Compounds of formula (I) and their pharmaceutically acceptable salts are provided. In formula (I), Rto Rmay be identical or different and are an optionally substituted 1-6C alkyl group, a hydrogen atom, etc.; Ris a hydrogen atom, etc.; Rto Rmay be identical or different and are a hydrogen atom, etc.; Ris a four- to 10-membered saturated heterocyclic group, etc.; Rto Rmay be identical or different and are a 1-6C alkyl group, etc.; and n is 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, diseases related to withdrawal symptoms caused by addictive drug abuse, and the like.

  In recent years, the potential neuroprotective effect of nicotine has been shown, in animals and cultured cells with excitotoxic injury, nutritional deficiency, ischemia, trauma, amyloid beta (Aβ) mediated neuronal cell death or 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. That is, 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:
R ^{1A to} R ^1D are the same or different and are selected from the group consisting of fluorine, hydroxyl group, C _1-6 alkoxy, C _3-6 cycloalkyl, —NR ⁵ R ⁶ , —CONR ⁵ R ⁶ and —NR ⁵ COR ^6. C _1-6 alkyl optionally substituted with 1 to 5 independently selected substituents; C _3-10 cycloalkyl, C _3-10 cycloalkoxy, 4-10 membered saturated heterocyclic group or 4- to 10-membered saturated heterocyclic-O- (the cycloalkyl, the cycloalkoxy, the saturated heterocyclic group, and the saturated heterocyclic-O- are, respectively, fluorine, a hydroxyl group, C _1-6 alkyl, and C _1-6. ^May be substituted with 1 to 5 substituents independently selected from the group consisting of alkoxy, —NR ⁵ R ⁶ , —CONR ⁵ R ⁶ and —NR ⁵ COR ⁶ ); fluorine, hydroxyl group, C _1-6 Alkyki C _1-6 alkoxy optionally substituted with 1 to 5 substituents independently selected from the group consisting of —NR ⁵ R ⁶ , —CONR ⁵ R ⁶ and —NR ⁵ COR ⁶ ; aryl Or heteroaryl (the aryl and the heteroaryl are each a halogen, a hydroxyl group, C _1-6 alkyl optionally substituted with 1 to 5 fluorines, C _1-6 alkoxy, —NR ⁵ R ⁶ , —CONR; Optionally substituted with 1 to 5 substituents independently selected from the group consisting of ⁵ R ⁶ and —NR ⁵ COR ⁶ ); hydrogen atom; hydroxyl group; halogen; —NR ⁵ R ⁶ ; cyano; ^{-CONR 5 R 6; -NR 5 COR} 6; or represents _-SO 2 ^{R 5,}
R ² is fluorine and _{C 1-6 C 1-6} alkyl which may be independently from the group consisting of alkoxy substituted with 1 to 5 substituents selected; consisting of fluorine and _{C 1-6} alkoxy C _3-10 cycloalkyl optionally substituted with 1 to 5 substituents independently selected from the group; hydrogen atom; C _1-6 alkylcarbonyl; C _3-10 cycloalkylcarbonyl; or —CONR ⁷ represents R ⁸ and
R ^{3A to} R ^3E may be the same or different and may be substituted with 1 to 5 substituents independently selected from the group consisting of fluorine, hydroxyl group, C _1-6 alkoxy and —NR ⁹ R ^10. Good C _1-6 alkyl; C _1-6 alkoxy optionally substituted with 1 to 5 fluorines; hydrogen atom; or fluorine, wherein two or more of R ^{3A to} R ^3E are When it is C _1-6 alkyl, they may be bridged together (the alkyl is independent of the group consisting of fluorine, hydroxyl, C _1-6 alkyl, C _1-6 alkoxy and —NR ⁹ R ^10. Optionally substituted with 1 to 5 substituents selected from
R ⁴ is phenyl, phenoxy, monocyclic heteroaryl, 4- to 10-membered saturated heterocyclic group, C _3-10 cycloalkyl, fluorine, hydroxyl group, or C ₁ -optionally substituted with 1 to 5 fluorines. C _1-10 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of ₆ alkoxy and —NR ¹¹ R ¹² (excluding unsubstituted methyl); C _{3 -10} cycloalkyl; 4-10 membered saturated heterocyclic group; phenyl; or monocyclic heteroaryl [wherein cycloalkyl, saturated heterocyclic group, said phenyl and said heteroaryl, halogen, respectively, hydroxyl, C _1-6 Alkyl (the group may be substituted with 1 to 5 substituents independently selected from the group consisting of fluorine, hydroxyl, C _1-6 alkoxy and —NR ¹¹ R ¹² ), C _{3− 6} Black _{alkyl, C 3-6} cycloalkoxy, are independently selected from one to five fluorine optionally substituted _{C 1-6 alkoxy,} the group consisting of _{C 1-6} alkylcarbonyl and ^-NR 11 ^{R 12} Which may be substituted with 1 to 5 substituents]
R ^{5 to} R ¹² are the same or different, and when there are a plurality of R ^{5 to} R ¹² , each independently represents a hydrogen atom or C _1-6 alkyl optionally substituted with 1 to 5 fluorines, Each pair of ⁵ and R ⁶ , R ⁷ and R ⁸ , R ⁹ and R ¹⁰ , and R ¹¹ and R ¹² is (1) when one is a hydrogen atom, the other is not a hydrogen atom, and ( 2) When both are C _1-6 alkyl, they may be combined together to form a 4-10 membered saturated heterocyclic ring which may be substituted with 1-5 fluorines,
n represents 1 or 2]
Or a pharmaceutically acceptable salt thereof.

[Item 2] n is 1.
Item 12. The compound according to Item 1 or a pharmaceutically acceptable salt thereof.

[Section 3] R ^{3A to} R ^3E are the same or different and each is optionally substituted with 1 to 5 fluorine atoms, C _1-6 alkyl; C _1-6 alkoxy; a hydrogen atom; or fluorine.
Item 3. The compound according to Item 1 or 2, or a pharmaceutically acceptable salt thereof.

[Claim 4] R ^{1A to} R ^1D are the same or different and are 1 to 5 substituents independently selected from the group consisting of fluorine, C _3-6 cycloalkyl, hydroxyl group and C _1-6 alkoxy. C _1-6 alkyl which may be substituted; C _3-8 cycloalkyl or C _3-8 cycloalkoxy (the cycloalkyl and the cycloalkoxy are fluorine, hydroxyl group, C _1-6 alkyl and C _1-6 , respectively) Optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkoxy); 4-10 membered saturated heterocycle optionally substituted with C _1-6 alkyl; fluorine, hydroxyl and C _1-6 1 to 5 amino optionally substituted with a substituent C _1-6 alkoxy independently selected from the group consisting of alkoxy; or halogen; hydrogen atom
Item 4. The compound according to any one of Items 1 to 3, or a pharmaceutically acceptable salt thereof.

[Item 5] R ⁴ is a 4 to 10-membered saturated heterocyclic ring, C _3-10 cycloalkyl, fluorine, a hydroxyl group, C _1-6 alkoxy optionally substituted with 1 to 5 fluorines, and —NR ^11. C _1-10 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of R ¹² (excluding unsubstituted methyl); C _3-10 cycloalkyl; 4 A 10-membered saturated heterocyclic group; or a nitrogen-containing monocyclic heteroaryl [the cycloalkyl, the saturated heterocyclic group, and the heteroaryl are each a fluorine, a hydroxyl group, or a C _1-6 alkyl (the group is fluorine, C Optionally substituted with 1 to 5 substituents independently selected from the group consisting of _1-6 alkoxy and —NR ¹¹ R ¹² ), C _3-6 cycloalkyl, C _3-6 cycloalkoxy, Place with 1-5 fluorines Also it is' substituted with 1 to 5 substituents are also independently selected from the group consisting of a C _1-6 alkoxy and -NR ¹¹ R ¹² have been,
Item 5. The compound according to any one of Items 1 to 4 or a pharmaceutically acceptable salt thereof.

[Item 6] R ² is C _1-6 alkyl _optionally substituted with 1 to 5 fluorines; C _3-10 cycloalkyl; or a hydrogen atom.
Item 6. The compound according to any one of Items 1 to 5, or a pharmaceutically acceptable salt thereof.

[Claim 7] R ^{3A to} R ^3E are all hydrogen atoms.
Item 7. The compound according to any one of Items 1 to 6, or a pharmaceutically acceptable salt thereof.

[Claim ^{8] R} 1A ^{~R 1D} are the same or different, optionally substituted with 1 to 5 substituents selected independently from the group consisting of fluorine and _{C 1-6} alkoxy _{C 1- 6} alkyl; C _3-8 cycloalkyl or C _3-8 cycloalkoxy, wherein the cycloalkyl and the cycloalkoxy are each independently selected from the group consisting of fluorine, C _1-6 alkyl, and C _1-6 alkoxy may be substituted with 1 to 5 substituents); fluorine and C _1-6 optionally substituted with 1-5 substituents independently selected from the group consisting of alkoxy C _{1- 6} alkoxy; a hydrogen atom; or halogen,
Item 8. The compound according to any one of Items 1 to 7, or a pharmaceutically acceptable salt thereof.

[Item 9] R ⁴ is substituted with 1 to 5 substituents independently selected from the group consisting of C _1-6 alkoxy optionally substituted with 1 to 5 fluorines and fluorine. C _1-10 alkyl (excluding unsubstituted methyl); C _3-10 cycloalkyl; or 4-10 membered saturated heterocyclic group [the cycloalkyl and the saturated heterocyclic group are each fluorine, C _1-6 alkyl (which group may be substituted with 1 to 5 substituents independently selected from the group consisting of fluorine and C _1-6 alkoxy) and 1 to 5 fluorines Which may be substituted with 1 to 5 substituents independently selected from the group consisting of optionally substituted C _1-6 alkoxy].
Item 9. The compound according to any one of Items 1 to 8, or a pharmaceutically acceptable salt thereof.

[Claim ^{10] R} 1A ^{~R 1D} are the same or different, optionally substituted with 1 to 5 substituents selected independently from the group consisting of fluorine and _{C 1-6} alkoxy _{C 1- 6} alkyl; C _3-8 cycloalkyl; C _3-8 cycloalkoxy; C _1-6 alkoxy optionally substituted with 1 to 5 fluorines; hydrogen atom; or halogen,
Item 10. The compound according to any one of Items 1 to 9, or a pharmaceutically acceptable salt thereof.

[Item 11] R ⁴ represents C _3-10 cycloalkyl or a 4- to 10-membered saturated heterocyclic group [the cycloalkyl and the saturated heterocyclic group are each fluorine and C _1-6 alkyl (the group is fluorine and C _1-6 1-5 may be substituted with a substituent) and one to five fluorine optionally substituted C _1-6 alkoxy are independently selected from the group consisting of alkoxy May be substituted with 1 to 5 substituents independently selected from the group consisting of:
Item 11. The compound according to any one of Items 1 to 10, or a pharmaceutically acceptable salt thereof.

[Item 12] The compound according to Item 1 or a pharmaceutically acceptable salt thereof selected from the following compounds:
Tetrahydro-2H-pyran-4-yl {4- [7- (trifluoromethoxy) -1H-indazol-3-yl] piperidin-1-yl} methanone (Example 1),
[4- (7-ethyl-1H-indazol-3-yl) piperidin-1-yl] (5-fluoropyridin-2-yl) methanone (Example 2),
Cyclohexyl [4- (6-fluoro-1H-indazol-3-yl) piperidin-1-yl] methanone (Example 3),
[4- (6-Ethyl-1H-indazol-3-yl) piperidin-1-yl] (tetrahydro-2H-pyran-4-yl) methanone (Example 6),
[4- (6-Ethyl-1H-indazol-3-yl) piperidin-1-yl] (5-fluoropyridin-2-yl) methanone (Example 24),
[4- (7-ethyl-1H-indazol-3-yl) piperidin-1-yl] (tetrahydro-2H-pyran-4-yl) methanone (Example 25),
[4- (7-ethyl-1H-indazol-3-yl) piperidin-1-yl] (4-fluorophenyl) methanone (Example 27),
(4,4-difluorocyclohexyl) [4- (6-ethyl-1H-indazol-3-yl) piperidin-1-yl] methanone (Example 28),
(4,4-difluorocyclohexyl) [4- (7-ethyl-1H-indazol-3-yl) piperidin-1-yl] methanone (Example 29),
(5-chloropyridin-2-yl) [4- (7-ethyl-1H-indazol-3-yl) piperidin-1-yl] methanone (Example 32),
[4- (7-ethyl-1H-indazol-3-yl) piperidin-1-yl] [5- (trifluoroethyl) pyridin-2-yl] methanone (Example 33),
(4,4-difluorocyclohexyl) [4- (7-methoxy-1H-indazol-3-yl) piperidin-1-yl] methanone (Example 36),
[4- (7-methoxy-1H-indazol-3-yl) piperidin-1-yl] [5- (trifluoromethyl) pyridin-2-yl] methanone (Example 40),
[4- (7-cyclopropyl-1H-indazol-3-yl) piperidin-1-yl] (tetrahydro-2H-pyran-4-yl) methanone (Example 46),
[4- (7-ethyl-1H-indazol-3-yl) piperidin-1-yl] (trans-4-methoxycyclohexyl) methanone (Example 49),
(Trans-4-methoxycyclohexyl) {4- [7- (trifluoromethoxy) -1H-indazol-3-yl] piperidin-1-yl} methanone (Example 52), and
[4- (6-Ethyl-1H-indazol-3-yl) piperidin-1-yl] (trans-4-methoxycyclohexyl) methanone (Example 53).

CLAIM | ITEM 13 The compound of claim | item 1 selected from the following compounds, or its pharmaceutically acceptable salt:
Tetrahydro-2H-pyran-4-yl {4- [7- (trifluoromethoxy) -1H-indazol-3-yl] piperidin-1-yl} methanone (Example 1),
[4- (7-ethyl-1H-indazol-3-yl) piperidin-1-yl] (5-fluoropyridin-2-yl) methanone (Example 2),
[4- (6-Ethyl-1H-indazol-3-yl) piperidin-1-yl] (5-fluoropyridin-2-yl) methanone (Example 24),
[4- (7-ethyl-1H-indazol-3-yl) piperidin-1-yl] (tetrahydro-2H-pyran-4-yl) methanone (Example 25),
[4- (7-cyclopropyl-1H-indazol-3-yl) piperidin-1-yl] (tetrahydro-2H-pyran-4-yl) methanone (Example 46),
[4- (7-ethyl-1H-indazol-3-yl) piperidin-1-yl] (trans-4-methoxycyclohexyl) methanone (Example 49), and
(Trans-4-methoxycyclohexyl) {4- [7- (trifluoromethoxy) -1H-indazol-3-yl] piperidin-1-yl} methanone (Example 52).

[Item 14] A pharmaceutical composition comprising the compound according to any one of items 1 to 13 or a pharmaceutically acceptable salt thereof.

[Item 15] A therapeutic agent for a disease involving acetylcholine, comprising the compound according to any one of Items 1 to 13 or a pharmaceutically acceptable salt thereof as an active ingredient.

[Item 16] The disease involving acetylcholine is a nervous system disease, mental disease or inflammatory disease.
Item 16. The therapeutic agent according to Item 15.

[Claim 17] The nervous system disease, psychiatric disorder or inflammatory disease is dementia, schizophrenia, CIAS (cognitive impairment associated with schizophrenia), Alzheimer's disease, Down's syndrome, attention deficit disorder or cerebrovascular angiopathy.
Item 17. The therapeutic agent according to Item 16.

[Item 18] A pharmaceutical comprising a combination of the compound according to any one of Items 1 to 13 or a pharmaceutically acceptable salt thereof and at least one drug selected from atypical antipsychotics. .

[Item 19] Acetylcholine characterized by administering a therapeutically effective amount of the compound according to any one of Items 1 to 13 or a pharmaceutically acceptable salt thereof to a patient in need of treatment. For the treatment of diseases caused by abnormal intracellular signaling involving

[Item 20] The compound according to any one of items 1 to 13 or a pharmaceutically acceptable salt thereof for the treatment of a disease caused by an abnormality in intracellular signal transduction involving acetylcholine.

[Item 21] A pharmaceutical comprising the compound according to any one of items 1 to 13 or a pharmaceutically acceptable salt thereof for use in the treatment of a disease caused by an abnormality in intracellular signal transduction involving acetylcholine Composition.

  The compound of the present invention can be used for nervous system diseases, psychiatric diseases and inflammatory diseases (for example, dementia, schizophrenia, CIAS (cognitive impairment associated with schizophrenia), Alzheimer's disease, Down's syndrome, attention deficit disorder, cerebrovascular angiopathy, etc. ) As a novel therapeutic agent and / or preventive agent. In addition, the compound of the present invention is useful for the treatment and / or prevention of neurological diseases such as schizophrenia, mental disorders and the like as a concomitant drug with an atypical antipsychotic drug.

  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. Examples of solvates include ethanol solvates.

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” Means alkyl having 1 to 4, 1 to 6 or 1 to 10 carbon atoms. 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, pentyl, isopentyl, neopentyl, hexyl and the like can be mentioned. In the case of “C _1-10 alkyl”, heptyl, octyl and the like are further added to the above. Is mentioned.
“Cycloalkyl” means a monocyclic or polycyclic saturated hydrocarbon group such as “C _3-6 cycloalkyl”, “C _3-8 cycloalkyl” or “C _3-10 cycloalkyl”. Means a cyclic alkyl having 3 to 6, 3 to 8 or 3 to 10 carbon atoms, having a partially bridged structure, a partially constructed spiro ring, or a condensed ring with aryl or heteroaryl. The formed one is also included. Specific examples thereof include “C _3-6 cycloalkyl” such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. In the case of “C _3-8 cycloalkyl”, in addition to the above, cycloheptyl, cyclooctyl and the like can be mentioned. In the case of “C _3-10 cycloalkyl”, in addition to the above, adamantyl, spiro [2,5] octane and the like can be mentioned. “Cycloalkoxy” means a group in which a monocyclic or polycyclic saturated hydrocarbon group similar to the above is bonded to one of oxygen atoms. “Cycloalkylcarbonyl” means a group in which a monocyclic or polycyclic saturated hydrocarbon group similar to the above is bonded to one of carbonyls.
“Alkoxy” means a group in which a linear or branched saturated hydrocarbon group is bonded to one of oxygen atoms. For example, “C _1-6 alkoxy” means the number of carbon atoms. Means 1-6 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”.
“Alkylcarbonyl” means a group in which a linear or branched saturated hydrocarbon group is bonded to one of the carbonyls. For example, “C _1-6 alkylcarbonyl” means the number of carbon atoms. Means a group in which a carbonyl is interposed in an alkyl group of 1-6. Specific examples thereof include acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, isobutylcarbonyl, t-butylcarbonyl and the like. Preferably, " _C1-3 alkylcarbonyl" is mentioned, More preferably, acetyl is mentioned.

“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 or bicyclic ring containing 1 to 4 atoms independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. Or an 8- to 11-membered aromatic heterocyclic group or a 3- to 12- to 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, pyrazinyl and pyrazolyl. More preferred is pyridyl or pyrimidinyl, and most preferred is pyridyl.
Examples of the “monocyclic heteroaryl” include monocyclic 5- to 7-membered aromatic heterocyclic groups containing 1 to 4 atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. Specific examples include pyridyl, pyridazinyl, isothiazolyl, pyrrolyl, furyl, thienyl, thiazolyl, imidazolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrazinyl, triazinyl, triazolyl, imidazolidinyl, oxadiazolyl, triazolyl, tetrazolyl and the like. Preferable monocyclic heteroaryl includes pyridyl and pyrimidinyl, and most preferably includes pyridyl.
The “nitrogen-containing monocyclic heteroaryl” means a 5- to 7-membered monocyclic heteroaryl containing 1 to 4 nitrogen atoms among the above monocyclic heteroaryl. Preferred examples include monocyclic heteroaryl containing 1 or 2 nitrogen atoms, such as pyridyl, pyridazinyl, pyrrolyl, imidazolyl, pyrimidinyl, pyrazolyl, pyrazinyl, imidazolidinyl and the like. More preferred are pyridyl and pyrimidinyl.

  The “4- to 10-membered saturated heterocyclic ring” is 4 to 10 atoms including 1 to 2 atoms independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom. It means a monocyclic or bicyclic saturated heterocyclic ring, and includes a partially bridged structure, a partially spirolated ring, or a ring condensed with aryl or heteroaryl. For example, azetidine, pyrrolidine, piperidine, piperazine, morpholine, homopiperidine, tetrahydrofuran, tetrahydropyran and the like can be mentioned. More preferred are tetrahydropyran and tetrahydrofuran. The “4 to 10-membered saturated heterocyclic group” means a monovalent group of the above 4 to 10-membered saturated heterocyclic ring. “4- to 10-membered saturated heterocyclic-O—” means a group in which a monocyclic or bicyclic saturated heterocyclic group similar to the above is bonded to one of oxygen atoms.

Among the compounds of the present invention represented by the formula (I), R ^{1A to} R ^1D , R ² , R ^{3A to} R ^3E , R ⁴ , R ^{5 to} R ¹² and n are preferable as follows. However, the technical scope of the present invention is not limited to the scope of the compounds listed below.

R ^{1A to} R ^1D are preferably the same or different and substituted with 1 to 5 substituents independently selected from the group consisting of fluorine, C _3-6 cycloalkyl, hydroxyl group and C _1-6 alkoxy. An optionally _substituted C _1-6 alkyl; a C _3-8 cycloalkyl or a C _3-8 cycloalkoxy, wherein the cycloalkyl and the cycloalkoxy are each from fluorine, hydroxyl, C _1-6 alkyl and C _1-6 alkoxy; Optionally substituted with 1 to 5 substituents independently selected from the group consisting of: a 4- to 10-membered saturated heterocyclic group optionally substituted with C _1-6 alkyl; fluorine, hydroxyl group include or halogen; hydrogen atom; a C _1-6 alkoxy optionally substituted with 1 to 5 substituents selected independently from the group consisting of C _1-6 alkoxy
More preferably, identical or different, fluorine and C _1-6 optionally substituted with 1-5 substituents independently selected from the group consisting of alkoxy C _1-6 alkyl; C _3-8 Cycloalkyl or C _3-8 cycloalkoxy (wherein the cycloalkyl and the cycloalkoxy are independently selected from the group consisting of fluorine, C _1-6 alkyl and C _1-6 alkoxy, respectively) C _1-6 alkoxy optionally substituted with 1 to 5 substituents independently selected from the group consisting of fluorine and C _1-6 alkoxy; a hydrogen atom; or Halogen is mentioned.
More preferably, identical or different, fluorine and C _1-6 optionally substituted with 1-5 substituents independently selected from the group consisting of alkoxy C _1-6 alkyl; C _3-8 Cycloalkyl; C _3-8 cycloalkoxy; C _1-6 alkoxy optionally substituted with 1 to 5 fluorines; hydrogen atom; fluorine; or chlorine.
More preferably, the same or different, C _1-6 alkyl; C _3-8 cycloalkyl; C _3-8 cycloalkoxy; C _1-6 alkoxy optionally substituted with 1 to 5 fluorines; hydrogen atom Fluorine, or chlorine.
Most preferably, they are the same or different and include C _1-6 alkyl or C _3-8 cycloalkyl.

R ² is preferably C _1-6 alkyl _optionally substituted with 1 to 5 fluorines; C _3-10 cycloalkyl; or a hydrogen atom. More preferably, include C _1-6 alkyl or hydrogen atom, more preferably include a hydrogen atom.

R ^{3A to} R ^3E are preferably C _1-6 alkyl optionally substituted with 1 to 5 substituents; C _1-6 alkoxy; a hydrogen atom; or fluorine. More preferably,
C _1-6 alkyl or hydrogen atom. More preferably, a hydrogen atom is mentioned.

R ⁴ is preferably a 4- to 10-membered saturated heterocyclic group, C _3-10 cycloalkyl, fluorine, a hydroxyl group, C _1-6 alkoxy optionally substituted with 1 to 5 fluorines, and —NR ¹¹ R. C _1-10 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of ¹² (excluding unsubstituted methyl); C _3-10 cycloalkyl; A 10-membered saturated heterocyclic group; or a nitrogen-containing monocyclic heteroaryl [the cycloalkyl, the saturated heterocyclic group, and the heteroaryl are each a fluorine, a hydroxyl group, or a C _1-6 alkyl (the group is fluorine, C ₁ Optionally substituted with 1 to 5 substituents independently selected from the group consisting of _-6 alkoxy and -NR ¹¹ R ¹² ), C _3-6 cycloalkyl, C _3-6 cycloalkoxy, 1 ~ 5 pieces Substituted with hydrogen include also may] be substituted with 1 to 5 substituents are also independently selected from the group consisting of a C _1-6 alkoxy and -NR ¹¹ R ^12.
More preferably, one to five fluorine may be substituted with 1 to 5 substituents selected independently from the group consisting of a C _1-6 alkoxy and fluoro substituted with C _{1 -10} alkyl (excluding unsubstituted methyl); C _3-10 cycloalkyl; or 4 to 10-membered saturated heterocyclic group [the cycloalkyl and saturated heterocyclic group are each fluorine, C _1-6 Alkyl (which group may be substituted with 1 to 5 substituents independently selected from the group consisting of fluorine and C _1-6 alkoxy) and 1 to 5 fluorines. _Or may be substituted with 1 to 5 substituents independently selected from the group consisting of C _1-6 alkoxy.
More preferably, C _3-10 cycloalkyl or a 4- to 10-membered saturated heterocyclic group [the cycloalkyl and the saturated heterocyclic group are each fluorine, C _1-6 alkyl (the group is fluorine and C _{1- From} 1 to 5 substituents independently selected from the group consisting of ₆ alkoxy) and from the group consisting of C _1-6 alkoxy optionally substituted by 1 to 5 fluorines May be substituted with 1 to 5 substituents independently selected].
Most preferably, C _3-10 cycloalkyl and a 4- to 10-membered saturated heterocyclic group (the cycloalkyl and the saturated heterocyclic group may each be substituted with C _1-6 alkoxy) are exemplified.
Examples of preferred substituents when R ⁴ is C _3-10 cycloalkyl, a 4- to 10-membered saturated heterocyclic group or a nitrogen-containing monocyclic heteroaryl are the same or different, and fluorine and C ₁ C _1-6 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of _-6 alkoxy; C _3-8 cycloalkyl; C _3-8 cycloalkoxy; 1-5 C _1-6 alkoxy optionally substituted with 1 fluorine; or halogen.

R ^{5 to} R ¹² may be the same or different and include a hydrogen atom or C _1-6 alkyl _optionally substituted with 1 to 5 fluorines, preferably a hydrogen atom or C _1-4 alkyl. More preferably, _C1-4 alkyl is mentioned. Each pair of R ⁵ and R ⁶ , R ⁷ and R ⁸ R ⁹ and R ¹⁰ and R ¹¹ and R ¹² is (1) when one is a hydrogen atom, the other is not a hydrogen atom, and (2) When both are C _1-6 alkyl, they may be combined to form a 4 to 10 membered saturated heterocyclic ring which may be substituted with 1 to 5 fluorines.
As n, 1 or 2 is mentioned, Preferably 1 is mentioned.

The pharmaceutically acceptable salt of the compound represented by formula (I) means forming a salt with the pharmaceutically acceptable acid or base of the compound of formula (I). When the compound of the present invention represented by the formula (I) has a basic functional group such as an amino group, it can form salts with various acids. 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. Specific examples of the base addition salt 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 the formula (I) with an acid or 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, 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-hydroxybenzotriazole, diEA: diisopropyl Ethylamine, 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 ⁴ .

Production method A ¹
Among the compounds represented by the formula (I), the compounds A1 and A2 represented by the formulas [A1] and [A2] in which R ^3A is a hydrogen atom can be produced by, for example, the following production method.

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

  As the protecting group for the amino group represented by P, the protecting group described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, John Wiley & Sons, Inc., 1999) can be used. The 2-methylanilines a1 are described in, 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 manufactured by the method currently used, or can be purchased as a commercial item.

[Step A-1]
In this step, compound a1 is reacted with a nitrite compound in an appropriate solvent in the presence of various acids or inorganic salts to obtain an azide compound, and then cyclized in the presence or absence of crown ether to give compound a2. It is a process to obtain. Of the acids or inorganic salts used in the azidation step, acids are preferred, and among them, mineral acids such as hydrochloric acid, nitric acid, sulfuric acid are preferred, and hydrochloric acid is more preferred. The nitrite compound used in the azidation step is preferably amyl nitrite or sodium nitrite. In this case, the reaction temperature is preferably −78 ° C. to 100 ° C., and the reaction time is preferably several minutes to several hours. Examples of the salt used in the cyclization step include sodium tetrafluoroborane, potassium acetate, sodium acetate, sodium hydrogen carbonate, and potassium tert-butoxy, and preferably sodium tetrafluoroborane and potassium acetate. In this case, the reaction temperature is preferably 0 ° C. to 100 ° C., and the reaction time is preferably several hours to several days. The solvent used in the azidation step is selected from the solvents exemplified below, preferably water and acetic acid. Although the solvent used in a cyclization process is selected from the solvent etc. which are illustrated by the postscript, Preferably chloroform or a dichloromethane is mentioned. This reaction can be similarly produced using the method described in Tetrahedron Lett. 2002, 43, 2695-2697, Tetrahedron 2006, 62, 7772-7775, and the like.

[Step A-2]
This step is a step of iodination of the compound a2 obtained in the above step A-1, and various iodination reagents can be used. For example, compound a3 can be obtained by reacting iodine in an appropriate solvent in the presence of various bases. In this case, the reaction temperature is preferably -78 ° C to 100 ° C, and the reaction time is preferably several minutes to several days. 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-3]
In this step, compound a3 obtained in step A-2 is coupled with compound a7 in the presence of a catalyst and a base to give compound a4. 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. In this case, the reaction temperature is preferably from room temperature to 150 ° C., the reaction time is preferably from several minutes to several days, and the reaction can be carried out under microwave irradiation. The base used in this step is selected from the bases exemplified below, and preferably sodium carbonate, potassium carbonate and the like. Although the solvent used in this process is selected from the solvent etc. which are illustrated by the postscript, Preferably the mixed solvent of dioxane-water is mentioned. This reaction includes the method described in International Publication No. 2005/073219 pamphlet, and can be similarly produced using this method. In this reaction, various boranoic acid reagents that proceed in the same manner as compound a7 can also be used.

[Step A-4]
This step is a step of obtaining compound a5 by reducing compound a4 obtained in step A-3 above in the presence of a catalyst. As the reducing agent, for example, hydrogen, formic acid salts such as ammonium formate, and hydrazine can be used. In this case, the reaction temperature is preferably 0 ° C. to 100 ° C., and the reaction time is preferably several minutes to several days. Examples of the catalyst include those supported on a carrier such as a transition metal such as palladium, nickel, rhodium, cobalt, 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 by the postscript, Preferably ethanol or methanol is mentioned.

[Step A-5]
This step is a step of obtaining a compound a6 by deprotecting the protecting group P of the amino group of the compound a5 obtained in the step A-4. This step can be carried out according to the method described in Protective Groups in Organic Synthesis (Theodora W. Greene, Peter GM Wuts, John Wiley & Sons, Inc., 1999).

[Step A-6]
In this step, compound a6 obtained in the above step A-5 is reacted with compound a8 or a9 in a suitable solvent in the presence or absence of various condensing agents and / or bases to give compound A1. It is a process to obtain. As the condensing agent used in this step, various condensing agents used in a conventional method can be used, but preferably 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (including hydrochloride). Is mentioned. In this case, the reaction temperature is preferably 0 ° C. to 100 ° C., and the reaction time is preferably several minutes to several days. The base to be used 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, preferably tetrahydrofuran, dimethylformamide or chloroform.

[Step A-7]
In this step, compound A1 obtained in step A-6 is mixed with various alkyl halides, carboxylic acids, boranoic acids, acid chlorides, isocyanates in the presence or absence of various condensing agents and / or bases in an appropriate solvent. In this step, compound A2 is obtained by reacting with the above. In this case, the reaction temperature is preferably -78 ° C to 150 ° C, and the reaction time is preferably several minutes to several days. The base used in this step is selected from the bases exemplified below, and preferably sodium hydride, diisopropylethylamine, or sodium carbonate. The condensing agent used in this step is preferably 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, 1-hydroxybenzotriazole or the like. The solvent used in this step is selected from the solvents exemplified below.

Production method A ²
Of the compound represented by formula (I) and the compound represented by formula (I), compound A1 ′ represented by formula [A1 ′] in which R ² is a hydrogen atom is produced by, for example, the following production method. be able to.

(In the formula, R ^{1A to} R ^1D , R ^{3A to} R ^3E , R ⁴ and n are as defined in Item 1, and Rx means a C _1-6 alkyl group or an amino group protecting group. , Ry means chlorine, bromine or iodine atom)

  Can the 4-halogenated piperidines a10 be produced by a method described in, for example, Heterocycles 1990, 31 (7), 1201-1204, Journal of the Chemical Society, Perkin Transactions 2 1992, 6, 857-8. Or can be purchased as a commercial product.

[Step A-8]
This step is a step of obtaining Grignard reagent a11 by reacting compound magnesium with metal magnesium. In this case, the reaction temperature is preferably -78 ° C to 100 ° C, and the reaction time is preferably several minutes to several days. The solvent used in this step is selected from the solvents exemplified below, preferably tetrahydrofuran or diethyl ether.

[Step A-9]
This step is a step of obtaining compound a12 by reacting compound a11 obtained in the above step A-8 with a15 or a16 in a suitable solvent. In this case, the reaction temperature is preferably -78 ° C to 100 ° C, and the reaction time is preferably several minutes to several days. The solvent used in this step is selected from the solvents exemplified below, preferably tetrahydrofuran or diethyl ether.

[Step A-10]
In this step, the compound a12 obtained in the above step A-9 is reacted in the presence of various bases in the presence of only hydrazine in a suitable solvent, or by adding methylhydroxylamine followed by reaction with hydrazine, In this step, compound a13 is obtained. In this case, the reaction temperature is preferably −78 ° C. to 150 ° C., the reaction time is preferably several minutes to several days, and the reaction can be carried out under microwave irradiation. 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. This reaction includes the method described in Journal of Organic Chemistry 2006, 71 (21), 8166-8172, and can be produced according to this method.

[Step A-11]
This step is a step of converting the compound a13 obtained in the step A-10 to the compound a14 under the conditions according to the step A-5.

[Step A-12]
This step is a step of converting the compound a14 obtained in the step A-11 to the compound A1 ′ under the conditions according to the step A-6.

[Step A-13]
This step is a step of converting the compound A1 ′ obtained in the step A-12 to a compound of the formula (I) under the conditions according to the step A-7.

Production method A ³
Among the compounds represented by the formula (I), the compound A1 ′ represented by the formula [A1 ′] in which R ² is a hydrogen atom can also be produced, for example, by the following production method.

(In the formula, R ^{1A to} R ^1D , R ^{3A to} R ^3E , R ⁴ and n are as defined in Item 1, Ry represents a chlorine, bromine or iodine atom, and P represents an amino group protecting group. Means)

  The 2-fluoro-halogenated benzenes a15 are described in, for example, Bioorganic & Medicinal Chemistry letters, 2011, 21 (24), 7344-7350, International Publication No. 2010/026124, International Publication No. 2007/082098. Or can be purchased as a commercial product.

[Step A-14]
This step is a step of obtaining aryllithium compound a16 by performing halogen metal exchange reaction by reacting compound a15 with alkyllithium or the like. In this case, the reaction temperature is preferably −78 ° C. to room temperature, and the reaction time is preferably several minutes to several hours. The alkyl lithium used in this step is preferably n-butyl lithium. The solvent used in this step is selected from the solvents exemplified below, preferably tetrahydrofuran or diethyl ether.

[Step A-15]
This step is a step of obtaining wine levamide a18 by reacting compound a17 with methoxymethylamine 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 preferably 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (including hydrochloride). Is mentioned. In this case, the reaction temperature is preferably -78 ° C to 100 ° C, and the reaction time is preferably several minutes to several days. The solvent used in this step is selected from the solvents exemplified below.

[Step A-16]
This step is a step of obtaining compound a19 by reacting compound a18 with compound a16 in a suitable solvent. In this case, the reaction temperature is preferably -78 ° C to 100 ° C, and the reaction time is preferably several minutes to several days. The solvent used in this step is selected from the solvents exemplified below, preferably tetrahydrofuran or diethyl ether.

[Step A-17]
This step is a step of converting the compound a19 obtained in the step A-16 to the compound a20 under the conditions according to the step A-10.

[Step A-18]
This step is a step of converting the compound a20 obtained in the step A-17 to the compound a21 under the conditions according to the step A-5.

[Step A-19]
This step is a step of converting compound a21 obtained in step A-18 to compound A1 ′ under the same conditions as in step A-6.

Production method A ⁴
Among the compounds represented by the formula (I), the compound A1 ′ represented by the formula [A1 ′] in which R ² is a hydrogen atom can also be produced, for example, by the following production method.

(Wherein R ^{1A to} R ^1D , R ^{3A to} R ^3E , R ⁴ and n are as defined in item 1; Ar is C _1-6 alkyl, C _1-6 alkoxy, halogen, nitro, etc. (It means phenyl which may be substituted, and P means an amino-protecting group)

  The 4-piperidylcarboxylic acids a23 can be produced, for example, by the method described in International Publication No. 2010/117323 pamphlet or the like, or can be purchased as a commercial product.

[Step A-20]
This step is a step of obtaining thioester a24 by activating compound a23 with various activating reagents or condensing agents and reacting compound a28. In this case, the reaction temperature is preferably -78 ° C to 100 ° C, and the reaction time is preferably several minutes to several days. The activating reagent used in this step is preferably oxalyl chloride. Various condensing agents can be used as the condensing agent used in this step, and preferably N, N′-dicyclohexylcarbodiimide is used. The base used in this step is preferably diisopropylethylamine, and the solvent used in this step is selected from the solvents exemplified below.

[Step A-21]
This step is a step of obtaining compound a25 by reacting compound a24 with boranoic acid a29 in the presence of a palladium catalyst, a copper complex and a phosphorus ligand in an appropriate solvent. In this case, the reaction temperature is preferably from room temperature to 150 ° C., the reaction time is preferably from several minutes to several days, and the reaction can be carried out under microwave irradiation. The palladium catalyst used in this step is preferably trisdibenzylideneacetone bis-palladium, and the copper complex is preferably copper thiophenecarboxylate. As a phosphorus ligand, Preferably triethyl phosphite is mentioned, A solvent is selected from the solvent etc. which are illustrated by the postscript, Preferably tetrahydrofuran is mentioned. Examples of the similar reaction include the methods described in Journal of the American Chemical Society 2007, 129 (5), 1132-1140, Journal of the American Chemical Society 2007, 129 (51), 15734-15735, etc. It can be similarly manufactured using this method.

[Step A-22]
This step is a step of converting compound a25 into compound a26 under the conditions according to the above step A-10.

[Step A-23]
This step is a step of converting the compound a26 obtained in the step A-22 to the compound a27 under the conditions according to the step A-5.

[Step A-24]
This step is a step of converting compound a27 into compound A1 ′ under the conditions according to the above step A-6.

  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 butyl lithium and lithium diisopropylamide, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine (DMAP), 1,8-diazabicyclo [5.4.0]- Organic bases such as 7-undecene (DBU) Can be mentioned.

  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 It may be used by mixing 2 or more kinds. 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 (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 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, an alcohol solvent 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 compound of the present invention represented by formula (I) or an intermediate thereof has an acidic functional group such as a carboxyl group, an optically active amine (for example, 1-phenylethylamine, quinine, quinidine, cinchonidine, cinchonine, strychnine) 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 −50 ° C. to the boiling point of the solvent, preferably from 0 ° C. to the boiling point, more preferably 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.

  The compounds of the present invention can be used for nervous system diseases, mental disorders and inflammatory diseases (eg, dementia, schizophrenia, CIAS (cognitive impairment associated with schizophrenia), Alzheimer's disease, Down's syndrome, attention deficit disorder, cerebrovascular angiopathy. Etc.) and can be used as novel therapeutic agents and / or preventive agents. The administration route of the compound of the present invention may be any of oral administration, parenteral administration and rectal administration, and the daily dose varies depending on the type of compound, administration method, patient symptom / age and the like. For example, in the case of oral administration, usually about 0.01 to 1000 mg, more preferably about 0.1 to 500 mg per kg body weight of a human or mammal can be administered in 1 to several divided doses. In the case of parenteral administration such as intravenous injection, usually, for example, about 0.01 mg to 300 mg, more preferably about 1 mg to 100 mg per kg body weight of a human or mammal can be administered.

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

  The compounds of the present invention can be used in combination with atypical antipsychotics. Examples of atypical antipsychotics include olanzapine, risperidone, paliperidone, quetiapine, ziprasidone, aripiprazole, asenapine, iloperidone, clozapine, sertindole, blonanserin and lurasidone.

  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 D.

Measurement condition A
Detector: 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: Liquid A: 0.05% TFA / H ₂ O, Liquid B: 0.05% TFA / MeOH
Gradient Condition:
0.0-6.0 min; A / B = 75: 25 to 1:99 (linear graent)
Flow rate: 3.5 mL / min UV: 254 nm

Measurement condition B
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 min; A / B = 90: 10-20: 80 (linear graent)
1.35-2.25 minutes; A / B = 20: 80
Flow rate: 0.8 mL / min UV: 220 nm
Column temperature: 50 ° C

Measurement condition C
Detection equipment: Perkin-Elmer Sciex API 150EX Massspectrometer (40eV)
HPLC: Shimadzu LC 10ATVP
Column: Shiseido CAPCELL PAK C18 ACR (S-5μm, 4.6 mm x 50 mm)
Solvent: Liquid A: 0.035% TFA / CH ₃ CN, Liquid B: 0.05% TFA / H ₂ O
Gradient Condition:
0.0-0.5 min; A / B = 1: 99
0.5-4.8 min; A / B = 99: 1
4.8-5.0 min; A / B = 99: 1
Flow rate: 3.5 mL / min UV: 220 nm
Column temperature: 40 ° C

Measurement condition D
Detector: Shimadzu LCMS-2020
Column: Phenomenex Kinetex (1.7μm C18, 50 mm x 2.10 mm)
Solvent: A solution: MeOH, B solution: 0.05% TFA / H ₂ O
Gradient Condition:
0.0 min; A / B = 30: 70
0.0-1.9 min; A / B = 99: 1
1.9-3.0 minutes; A / B = 30: 70
Flow rate: 0.5 mL / min UV: 220 nm
Column temperature: 40 ° C

Reference example 1
3- (Piperidin-4-yl) -7- (trifluoromethoxy) -1H-indazole

a) Preparation of benzyl 4-[(phenylsulfanyl) carbonyl] piperidine-1-carboxylate (Compound Q1) 1- (benzyloxycarbonyl) piperidine-4-carboxylic acid (2.63 g) in dichloromethane (30 mL) Oxalyl chloride (1.33 mL) was added dropwise at ° 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 3 hours. After evaporating the solvent under reduced pressure, THF (30 mL), thiophenol (1.02 mL) and triethylamine (4.50 mL) were added, and the mixture was stirred at room temperature for 16 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 = 4: 1) to obtain Compound Q1 (3.15 g).
¹ H-NMR (400 MHz, CDCl ₃ ): 7.24–7.48 (10H, brm), 5.11 (2H, s), 4.18 (2H, br), 2.92 (2H, m), 2.73 (1H, m), 1.95 (2H, m), 1.73 (2H, m).

b) Preparation of benzyl 4-{[2-fluoro-3- (trifluoromethoxy) phenyl] carbonyl} piperidine-1-carboxylate (Compound Q2) A solution of Compound Q1 (1.32 g) obtained in the above experiment in tetrahydrofuran (28 mL), [2-fluoro-3- (trifluoromethoxy) phenyl] boranoic acid (1.00 g), copper (I) thiophene-2-carboxylate (0.85 g), tris (dibenzylideneacetone) bispalladium (0.339 g) and triethyl phosphite (61 mg) were added, and the mixture was stirred at 30 ° C. under a nitrogen atmosphere for 1 day. After completion of the reaction, the mixture was filtered through Celite, 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 = 3: 1) to obtain Compound Q2 (897 mg).
¹ H-NMR (400 MHz, CDCl ₃ ): 7.69 (1H, m), 7.48 (1H, m), 7.36-7.19 (6H, m), 5.12 (2H, m), 4.19 (2H, s), 3.25 (1H, s), 2.97 (2H, s), 1.91 (2H, s), 1.65 (2H, s).

c) Preparation of benzyl 4- (7-trifluoromethoxy-1H-indazol-3-yl) piperidine-1-carboxylate (Compound Q3) Hydrazine monohydrate in a pyridine solution (4 mL) of Compound Q2 (885 mg) The product (400 mg) was added, and the mixture was heated and stirred at 150 ° C. for 4 hours 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 = 3: 1) to obtain Compound Q3 (765 mg).
¹ H-NMR (400 MHz, CDCl ₃ ): 7.64 (1H, d, J = 8.0 Hz), 7.33-7.29 (6H, m), 7.11 (1H, t, J = 8.0 Hz), 5.15 (2H, s ), 4.32 (2H, brs), 3.26 (1H, m), 3.02 (2H, brs), 2.01-1.96 (4H, m).

d) Production of 3- (piperidin-4-yl) -7- (trifluoromethoxy) -1H-indazole (Reference Example 1) Compound Q3 (760 mg) in ethanol (10 mL) solution in palladium hydroxide / carbon ( 100 mg) was added, and the mixture was stirred at room temperature for 18 hours under a hydrogen atmosphere. After filtration through celite, the solvent was distilled off to obtain Reference Example 1 (526 mg).
¹ H-NMR (400 MHz, CDCl ₃ ): 7.72 (1H, d, J = 8.0 Hz), 7.25 (1H, m), 7.12 (1H, t, J = 8.0 Hz), 3.23-3.31 (3H, m ), 2.87 (2H, m), 1.95-2.12 (4H, m).

Reference example 2
7-Ethyl-3- (piperidin-4-yl) -1H-indazole dihydrochloride

a) Production of 2-bromo-6-methylbenzenediazonium tetrafluoroborate (compound Q4)
Concentrated hydrochloric acid (11.3 mol / L, 5.95 mL) was added to a suspension of 2-bromo-6-methylaniline (4.17 g) in water (41 ml). A sodium nitrite aqueous solution (3.09 g, water 18 mL) was added dropwise to the reaction suspension at −3 ° C., followed by stirring at −3 ° C. for 30 minutes. Under ice cooling, an aqueous sodium tetrafluoroborate solution (7.38 g, water 18 mL) was added, and the mixture was stirred at room temperature for 3 hours. The precipitated solid was collected by filtration and dried to obtain Compound Q4 (4.55 g).

b) Preparation of 7-bromo-1H-indazole (Compound Q5) Potassium acetate (3.91 g) and 18-crown-6 (0.42 g) were added to a chloroform suspension (45 mL) of Compound Q4 (4.55 g), Stir at room temperature for 1 day. 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 = 3: 1) to obtain Compound Q5 (2.61 g).
¹ H-NMR (400 MHz, CDCl ₃ ): 8.19 (1H, s), 7.71 (1H, d, J = 8.0 Hz), 7.56 (1H, d, J = 7.3 Hz), 7.07 (1H, t, J = 7.8 Hz).

c) Preparation of 7-vinyl-1H-indazole (Compound Q6) Compound Q5 (2.61 g), 2,4,6-trivinylcyclotriboroxan (3.49 g) obtained in the above experiment, cesium carbonate (12.89) g) 1,1′-bis (diphenylphosphino) ferrocene palladium dichloride (1.93 g) in dioxane (80 mL) -water (20 mL) was stirred at 90 ° C. for 15 hours under a nitrogen atmosphere. After completion of the reaction, the solvent was distilled off, followed by liquid separation extraction with ethyl acetate-water, and the resulting organic layer was washed with saturated brine and then dried over sodium sulfate. The obtained residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate = 3: 1) to obtain Compound Q6 (1.44 g).
¹ H-NMR (400 MHz, CDCl ₃ ): 8.13 (1H, s), 7.68 (1H, d, J = 7.6 Hz), 7.39 (1H, d, J = 7.6 Hz), 7.16 (1H, t, J = 7.6 Hz), 7.01 (1H, dd, J = 17.8 Hz, 11.5 Hz), 5.86 (1H, d, J = 17.8 Hz), 5.53 (1H, d, J = 11.5 Hz).

d) Preparation of 7-ethyl-1H-indazole (Compound Q7) To a solution of Compound Q6 (1.57 g) in ethanol (50 mL) was added palladium hydroxide / carbon (160 mg), and at room temperature in a hydrogen atmosphere for 18 hours. Stir. After filtration through celite, the solvent was distilled off to obtain compound Q7 (1.50 g).
¹ H-NMR (400 MHz, CDCl ₃ ): 8.11 (1H, s), 7.60 (1H, d, J = 8.0 Hz), 7.21 (1H, d, J = 6.8 Hz), 7.13 (1H, t, J = 7.4 Hz), 2.96 (2H, q, J = 7.6 Hz), 1.39 (3H, t, J = 7.6 Hz).

e) Preparation of 7-ethyl-3-iodo-1H-indazole (Compound Q8) To a solution of Compound Q7 (1.49 g) in N, N-dimethylformamide (20 mL) under ice-cooling, potassium hydroxide (1.14 g) And iodine (3.10 g) were added, and the mixture was stirred at room temperature for 15 hours. After completion of the reaction, an aqueous sodium thiosulfate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a 10% aqueous citric acid solution and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate = 3: 1) to obtain Compound Q8 (2.27 g).
¹ H-NMR (400 MHz, CDCl ₃ ): 7.35 (1H, d, J = 7.6 Hz), 7.26 (1H, d, J = 7.6 Hz), 7.19 (1H, t, J = 7.6 Hz), 2.93 ( 2H, q, J = 7.6 Hz), 1.37 (3H, t, J = 7.6 Hz).

f) Preparation of tert-butyl 4- (7-ethyl-1H-indazol-3-yl) -3,6-dihydropyridine-1 (2H) -carboxylate (compound Q9) Compound Q8 (1.13 g), tert-butyl 4- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) piperidine-1-carboxylate (1.80 g), sodium bicarbonate (697 mg), dichloro (bistriphenylphosphine ) A mixture of palladium (291 mg), isopropanol (12 mL) and water (4 mL) was stirred at 140 ° C. for 1 hour under microwave irradiation. The reaction solution was returned to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate = 1: 1) to obtain Compound Q9 (2.16 g).
¹ H-NMR (400 MHz, CDCl ₃ ): 7.75 (1H, d, J = 8.0 Hz), 7.22 (1.0H, m), 7.16 (1H, t, J = 8.0 Hz), 6.52 (1H, brs) , 4.18 (2H, brs), 3.68 (2H, m), 2.94 (2H, q, J = 7.6 Hz), 2.80 (2H, brs), 1.49 (9H, s), 1.37 (4H, t, J = 7.6 Hz).

g) Preparation of tert-butyl 4- (7-ethyl-1H-indazol-3-yl) piperidine-1-carboxylate (Compound Q10) Compound Q9 (1.23 g) in ethanol (45 mL) was added platinum oxide ( 215 mg) was added, and the mixture was stirred under a hydrogen atmosphere for 2 days. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain Compound Q10 (1.82 g).
¹ H-NMR (400 MHz, CDCl ₃ ): 7.58 (1H, d, J = 7.6 Hz), 7.19 (1H, d, J = 7.6 Hz), 7.09 (1H, t, J = 7.6 Hz), 4.24 ( 2H, brs), 3.24 (1H, s), 2.92-2.82 (4H, m), 2.06-1.90 (4H, m), 1.53-1.41 (11H, m), 1.36 (3H, t, J = 7.6 Hz) .

h) Preparation of 7-ethyl-3- (piperidin-4-yl) -1H-indazole dihydrochloride (Reference Example 2) Compound Q10 (1.82 g) in chloroform (28 mL) in 4 mol / L hydrogen chloride / Dioxane solution (6.90 mL) was added, and the mixture was stirred at room temperature for 20 hours. The solvent was distilled off, the residue was washed with ethyl acetate, and the precipitated crystals were collected by filtration to obtain Reference Example 2 (1.66 g).

Example 1
(Tetrahydro-2H-pyran-4-yl) {4- [7- (trifluoromethoxy) -1H-indazol-3-yl] piperidin-1-yl} methanone

Reference Example 1 (285 mg), EDCI · HCl (280 mg) and HOBt (196 mg) in N, N-dimethylformamide suspension (5.0 mL) in diisopropylethylamine (700 μL) and tetrahydro-2H-pyran-4 -Carboxylic acid (130 mg) was added and stirred at room temperature for 10 hours. After completion of the reaction, liquid separation extraction was performed with dichloromethane-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 (eluent: hexane: ethyl acetate = 1: 9) to give Example 1 (186 mg).
¹ H-NMR (400 MHz, CDCl ₃ ): 10.11 (1H, s), 7.65 (1H, d, J = 8.0 Hz), 7.27 (1H, d, J = 8.0 Hz), 7.14 (1H, t, J = 8.0 Hz), 4.72 (1H, m), 4.07 (3H, m), 3.48 (2H, m), 3.33 (2H, m), 2.82 (2H, m), 2.14 (2H, brs), 1.97 (4H , brs), 1.63 (4H, m).

Example 2
[4- (7-Ethyl-1H-indazol-3-yl) piperidin-1-yl] (5-fluoropyridin-2-yl) methanone

Reference Example 2 (45 mg), EDCI · HCl (43 mg) and HOBt (30 mg) in N, N-dimethylformamide suspension (1.5 mL) were mixed with diisopropylethylamine (105 μL) and 5-fluoropicolinic acid (20 mg) was added and stirred at room temperature for 1 day. After completion of the reaction, liquid separation extraction was performed with dichloromethane-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 (eluent: hexane: ethyl acetate = 1: 4) to give Example 2 (32 mg).
¹ H-NMR (400 MHz, CDCl ₃ ): 8.37 (1H, d, J = 2.8 Hz), 7.67 (1H, dd, J = 8.4, 4.5 Hz), 7.53 (1H, d, J = 7.6 Hz), 7.43 (1H, td, J = 8.4, 2.8 Hz), 7.12 (1H, d, J = 7.6 Hz), 7.03 (1H, t, J = 7.6 Hz), 4.75 (1H, d, J = 13.2 Hz), 4.06 (1H, t, J = 7.2 Hz), 3.37-3.22 (2H, m), 3.08-3.01 (1H, m), 2.83 (2H, q, J = 7.6 Hz), 2.06 (4H, m), 1.29 (3H, t, J = 7.6 Hz).

Examples 3-75
Reaction and treatment were performed in the same manner as in Example 1 or 2 using the corresponding raw material compounds, and the compounds shown in Table 1 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 α7 nACh receptor stable expression cells (1) Human α7 nAChR stable expression cells Human α7 nAChR stable expression cells were prepared and subjected to culture. Specifically, rat pituitary-derived GH4C1 cells (cat # CCL-82.2, ATCC, USA) were used as host cells. Aequorin by introducing pcDNA3.1Zeo vector into which the base sequence encoding the protein of GenBank BAC81731 was inserted and pcDNA3.1 vector (cat # V790-20, invitrogen, Carlsbad, CA, USA) into which the human α7 nAChR gene was inserted Then, human α7 nAChR stably expressing cells were obtained. For selection, Zeocin (cat # R25001, invitrogen, Carlsbad, CA, USA) and Geneticin (cat # 10131-027, invitrogen, Carlsbad, CA, USA) were used.
The medium includes 2.5% fetal bovine serum (cat # 2917354, ICN Biome di cals, Inc, USA), 15% inactivated horse serum (cat # 26050-088, invitrogen, Carlsbad, CA, USA), 1 μg / mL Using F-10 Nutrient Mixture (Ham) medium (cat # 11550-043, invitrogen, Carlsbad, CA, USA) containing Geneticin, 5 μg / mL Puromycin (cat # 14861-84, invitrogen, Carlsbad, CA, USA) Cultivation was performed in a collagen Type 1 coat dish (cat # 4030-010, iwaki, Tokyo, Japan). During the culture, the medium was changed every 2-3 days, and 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 a state of about 80% confluence, Hanks (cat # 14065-056, invitrogen, Carlsbad, CA, USA) / 20 mMol / L Hepes (cat # 15630-080) Invitrogen, Carlsbad, CA, USA) Suspended to 20,000 cells / 25 μL / well in a reaction medium consisting of Buffer (pH 7.4), F-10 Nutrient Mixture (Ham), 0.1 mg / mL Geneticin, and 384 wells Plates (cat # 781090, Greiner, Germany) were seeded.
The day after sowing, Viviren (cat # E649X, Promega, Majison, WI, USA) was added to a final concentration of 4 μmol / L (15 μL / well), and the mixture was allowed to stand at room temperature for 4 hours after centrifugation.

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

(3) PAM activity evaluation FDSS7000 (Hamamatsu Photonics) was used for the detection of the luminescent signal by α7 nAChR stimulation. Test compounds were added to the plates to which cells and luminescent substrate had been added, and ACh at a concentration indicating EC ₂₀ was added alone after 150 seconds. Rlu (Max-Min) was calculated by measuring the emission signal (center wavelength: 465 nm) for 138 seconds after the addition of ACh, and the ratio of Rlu (Max-Min) between the control well and the test compound added well was defined as PAM activity. . Table 2 shows the α7 PAM activity data of representative compounds.

  As shown in Table 2, the compounds of the present invention had α7 nAChR PAM activity in the PAM activity evaluation test. In particular, Examples 24, 28, 29 and 36 showed stronger PAM activity.

Test Example 2 Solubility The solubility of the test compound in a buffer solution at pH = 7.4 and pH = 1.2 was measured. Each isotonic buffer at pH = 7.4 was prepared by mixing 1.75% Na ₂ HPO ₄ and 5.53% citric acid aqueous solution while monitoring with a pH meter. A buffer solution (pH 1 solution) having a pH of 1.2 was prepared according to the pharmacopoeia. Quantification was performed using Waters HPLC. The results of the solubility test conducted according to Test Example 2 using the Example compounds are shown below.

  The compounds of the present invention showed relatively good solubility.

  As described above, the compound 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 diseases related to cholinergic activity of the peripheral nervous system (PNS), diseases related to smooth muscle contraction, endocrine diseases, diseases related to neurodegeneration, diseases such as inflammation or pain, diseases related to withdrawal symptoms caused by addictive drug abuse It is useful for the treatment of

Claims (21)

Formula (I):
[Where:
R ^{1A to} R ^1D are the same or different and are selected from the group consisting of fluorine, hydroxyl group, C _1-6 alkoxy, C _3-6 cycloalkyl, —NR ⁵ R ⁶ , —CONR ⁵ R ⁶ and —NR ⁵ COR ^6. C _1-6 alkyl optionally substituted with 1 to 5 independently selected substituents; C _3-10 cycloalkyl, C _3-10 cycloalkoxy, 4-10 membered saturated heterocyclic group or 4- to 10-membered saturated heterocyclic-O- (the cycloalkyl, the cycloalkoxy, the saturated heterocyclic group, and the saturated heterocyclic-O- are, respectively, fluorine, a hydroxyl group, C _1-6 alkyl, and C _1-6. ^May be substituted with 1 to 5 substituents independently selected from the group consisting of alkoxy, —NR ⁵ R ⁶ , —CONR ⁵ R ⁶ and —NR ⁵ COR ⁶ ); fluorine, hydroxyl group, C _1-6 Alkyki C _1-6 alkoxy optionally substituted with 1 to 5 substituents independently selected from the group consisting of —NR ⁵ R ⁶ , —CONR ⁵ R ⁶ and —NR ⁵ COR ⁶ ; aryl Or heteroaryl (the aryl and the heteroaryl are each a C _1-6 alkyl, C _1-6 alkoxy, —NR ⁵ R ⁶ , —CONR, each of which may be substituted with halogen, hydroxyl group, 1 to 5 fluorine atoms; Optionally substituted with 1 to 5 substituents independently selected from the group consisting of ⁵ R ⁶ and —NR ⁵ COR ⁶ ); hydrogen atom; hydroxyl group; halogen; —NR ⁵ R ⁶ ; cyano; ^{-CONR 5 R 6; -NR 5 COR} 6; or represents _-SO 2 ^{R 5,}
R ² is fluorine and _{C 1-6 C 1-6} alkyl which may be independently from the group consisting of alkoxy substituted with 1 to 5 substituents selected; consisting of fluorine and _{C 1-6} alkoxy C _3-10 cycloalkyl optionally substituted with 1 to 5 substituents independently selected from the group; hydrogen atom; C _1-6 alkylcarbonyl; C _3-10 cycloalkylcarbonyl; or —CONR ⁷ represents R ⁸ and
R ^{3A to} R ^3E may be the same or different and may be substituted with 1 to 5 substituents independently selected from the group consisting of fluorine, hydroxyl group, C _1-6 alkoxy and —NR ⁹ R ^10. Good C _1-6 alkyl; C _1-6 alkoxy optionally substituted with 1 to 5 fluorines; hydrogen atom; or fluorine, wherein two or more of R ^{3A to} R ^3E are When it is C _1-6 alkyl, they may be bridged together (the alkyl is independent of the group consisting of fluorine, hydroxyl, C _1-6 alkyl, C _1-6 alkoxy and —NR ⁹ R ^10. Optionally substituted with 1 to 5 substituents selected from
R ⁴ is phenyl, phenoxy, monocyclic heteroaryl, 4- to 10-membered saturated heterocyclic group, C _3-10 cycloalkyl, fluorine, hydroxyl group, or C ₁ -optionally substituted with 1 to 5 fluorines. C _1-10 alkyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of ₆ alkoxy and —NR ¹¹ R ¹² (excluding unsubstituted methyl); C _{3 -10} cycloalkyl; 4- to 10-membered saturated heterocyclic group; phenyl; or monocyclic heteroaryl [the cycloalkyl, the saturated heterocyclic group, the phenyl and the heteroaryl are each a halogen, a hydroxyl group, or a C _1-6 Alkyl (the group may be substituted with 1 to 5 substituents independently selected from the group consisting of fluorine, hydroxyl, C _1-6 alkoxy and —NR ¹¹ R ¹² ), C _{3− 6} Black _{alkyl, C 3-6} cycloalkoxy, are independently selected from one to five fluorine optionally substituted _{C 1-6 alkoxy,} the group consisting of _{C 1-6} alkylcarbonyl and ^-NR 11 ^{R 12} Which may be substituted with 1 to 5 substituents]
R ^{5 to} R ¹² are the same or different, and when there are a plurality of R ^{5 to} R ¹² , each independently represents a hydrogen atom or C _1-6 alkyl optionally substituted with 1 to 5 fluorines, Each pair of ⁵ and R ⁶ , R ⁷ and R ⁸ , R ⁹ and R ¹⁰ , and R ¹¹ and R ¹² is (1) when one is a hydrogen atom, the other is not a hydrogen atom, and ( 2) When both are C _1-6 alkyl, they may be combined together to form a 4-10 membered saturated heterocyclic ring which may be substituted with 1-5 fluorines,
n represents 1 or 2]
Or a pharmaceutically acceptable salt thereof. n is 1.
The compound according to claim 1 or a pharmaceutically acceptable salt thereof. R ^{3A to} R ^3E are the same or different and each is a C _1-6 alkyl optionally substituted with 1 to 5 fluorines; C _1-6 alkoxy; a hydrogen atom; or fluorine.
The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof. R ^{1A to} R ^1D are the same or different and are substituted with 1 to 5 substituents independently selected from the group consisting of fluorine, C _3-6 cycloalkyl, hydroxyl group and C _1-6 alkoxy. C _1-6 alkyl; C _3-8 cycloalkyl or C _3-8 cycloalkoxy (the cycloalkyl and cycloalkoxy are each a group consisting of fluorine, hydroxyl group, C _1-6 alkyl and C _1-6 alkoxy) Optionally substituted with 1 to 5 substituents independently selected from: 4 to 10-membered saturated heterocycle optionally substituted with C _1-6 alkyl; fluorine, hydroxyl group and C ₁ C- ₆ alkoxy optionally substituted with 1 to 5 substituents independently selected from the group consisting of _-6 alkoxy; a hydrogen atom; or halogen,
The compound as described in any one of Claims 1-3, or its pharmaceutically acceptable salt. R ⁴ consists of a ⁴ to 10-membered saturated heterocyclic ring, C _3-10 cycloalkyl, fluorine, a hydroxyl group, C _1-6 alkoxy optionally substituted with 1 to 5 fluorines, and —NR ¹¹ R ^12. C _1-10 alkyl optionally substituted with 1 to 5 substituents independently selected from the group (excluding unsubstituted methyl); C _3-10 cycloalkyl; 4-10 membered A saturated heterocyclic group; or a nitrogen-containing monocyclic heteroaryl [the cycloalkyl, the saturated heterocyclic group, and the heteroaryl are, respectively, fluorine, a hydroxyl group, and a C _1-6 alkyl (the group is fluorine, C _1-6 alkoxy And optionally substituted with 1 to 5 substituents independently selected from the group consisting of —NR ¹¹ R ¹² ), C _3-6 cycloalkyl, C _3-6 cycloalkoxy, 1 to 5 Substituted with fluorine Also be 'substituted with 1 to 5 substituents are also independently selected from the group consisting of a _{C 1-6} alkoxy and ^-NR 11 ^{R 12} and,
The compound as described in any one of Claims 1-4, or its pharmaceutically acceptable salt. R ² is C _1-6 alkyl _optionally substituted with 1 to 5 fluorines; C _3-10 cycloalkyl; or a hydrogen atom,
The compound as described in any one of Claims 1-5, or its pharmaceutically acceptable salt. R ^{3A to} R ^3E are all hydrogen atoms.
The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof. R ^{1A to} R ^1D are the same or different and are optionally substituted with 1 to 5 substituents independently selected from the group consisting of fluorine and C _1-6 alkoxy; C _1-6 alkyl; C _3-8 cycloalkyl or C _3-8 cycloalkoxy (wherein the cycloalkyl and the cycloalkoxy are each independently selected from the group consisting of fluorine, C _1-6 alkyl and C _1-6 alkoxy) C _1-6 alkoxy optionally substituted with 1 to 5 substituents independently selected from the group consisting of fluorine and C _1-6 alkoxy; hydrogen An atom; or halogen,
The compound as described in any one of Claims 1-7, or its pharmaceutically acceptable salt. R ⁴ is optionally substituted with 1 to 5 substituents selected independently from the group consisting of one to five fluorine may be substituted with C _1-6 alkoxy and fluorinated C _{1 -10} alkyl (excluding unsubstituted methyl); C _3-10 cycloalkyl; or 4 to 10-membered saturated heterocyclic group [the cycloalkyl and saturated heterocyclic group are each fluorine, C _1-6 Alkyl (which group may be substituted with 1 to 5 substituents independently selected from the group consisting of fluorine and C _1-6 alkoxy) and 1 to 5 fluorines. _Or may be substituted with 1 to 5 substituents independently selected from the group consisting of C _1-6 alkoxy].
The compound as described in any one of Claims 1-8, or its pharmaceutically acceptable salt. R ^{1A to} R ^1D are the same or different and are optionally substituted with 1 to 5 substituents independently selected from the group consisting of fluorine and C _1-6 alkoxy; C _1-6 alkyl; C _3-8 cycloalkyl; C _3-8 cycloalkoxy; C _1-6 alkoxy optionally substituted with 1 to 5 fluorines; hydrogen atom; or halogen,
The compound as described in any one of Claims 1-9, or its pharmaceutically acceptable salt. R ⁴ represents C _3-10 cycloalkyl or a 4- to 10-membered saturated heterocyclic group [the cycloalkyl and the saturated heterocyclic group are each fluorine, C _1-6 alkyl (the group is fluorine and C _{1- From} 1 to 5 substituents independently selected from the group consisting of ₆ alkoxy) and from the group consisting of C _1-6 alkoxy optionally substituted by 1 to 5 fluorines May be substituted with 1 to 5 substituents independently selected].
The compound as described in any one of Claims 1-10, or its pharmaceutically acceptable salt. The compound according to claim 1 or a pharmaceutically acceptable salt thereof selected from the following compounds:
Tetrahydro-2H-pyran-4-yl {4- [7- (trifluoromethoxy) -1H-indazol-3-yl] piperidin-1-yl} methanone,
[4- (7-ethyl-1H-indazol-3-yl) piperidin-1-yl] (5-fluoropyridin-2-yl) methanone,
Cyclohexyl [4- (6-fluoro-1H-indazol-3-yl) piperidin-1-yl] methanone,
[4- (6-ethyl-1H-indazol-3-yl) piperidin-1-yl] (tetrahydro-2H-pyran-4-yl) methanone,
[4- (6-Ethyl-1H-indazol-3-yl) piperidin-1-yl] (5-fluoropyridin-2-yl) methanone,
[4- (7-ethyl-1H-indazol-3-yl) piperidin-1-yl] (tetrahydro-2H-pyran-4-yl) methanone,
[4- (7-ethyl-1H-indazol-3-yl) piperidin-1-yl] (4-fluorophenyl) methanone,
(4,4-difluorocyclohexyl) [4- (6-ethyl-1H-indazol-3-yl) piperidin-1-yl] methanone,
(4,4-difluorocyclohexyl) [4- (7-ethyl-1H-indazol-3-yl) piperidin-1-yl] methanone,
(5-chloropyridin-2-yl) [4- (7-ethyl-1H-indazol-3-yl) piperidin-1-yl] methanone,
[4- (7-ethyl-1H-indazol-3-yl) piperidin-1-yl] [5- (trifluoroethyl) pyridin-2-yl] methanone,
(4,4-difluorocyclohexyl) [4- (7-methoxy-1H-indazol-3-yl) piperidin-1-yl] methanone,
[4- (7-methoxy-1H-indazol-3-yl) piperidin-1-yl] [5- (trifluoromethyl) pyridin-2-yl] methanone,
[4- (7-cyclopropyl-1H-indazol-3-yl) piperidin-1-yl] (tetrahydro-2H-pyran-4-yl) methanone,
[4- (7-ethyl-1H-indazol-3-yl) piperidin-1-yl] (trans-4-methoxycyclohexyl) methanone,
(Trans-4-methoxycyclohexyl) {4- [7- (trifluoromethoxy) -1H-indazol-3-yl] piperidin-1-yl} methanone, and
[4- (6-Ethyl-1H-indazol-3-yl) piperidin-1-yl] (trans-4-methoxycyclohexyl) methanone. The compound according to claim 1 or a pharmaceutically acceptable salt thereof selected from the following compounds:
Tetrahydro-2H-pyran-4-yl {4- [7- (trifluoromethoxy) -1H-indazol-3-yl] piperidin-1-yl} methanone,
[4- (7-ethyl-1H-indazol-3-yl) piperidin-1-yl] (5-fluoropyridin-2-yl) methanone,
[4- (6-Ethyl-1H-indazol-3-yl) piperidin-1-yl] (5-fluoropyridin-2-yl) methanone,
[4- (7-ethyl-1H-indazol-3-yl) piperidin-1-yl] (tetrahydro-2H-pyran-4-yl) methanone,
[4- (7-cyclopropyl-1H-indazol-3-yl) piperidin-1-yl] (tetrahydro-2H-pyran-4-yl) methanone,
[4- (7-ethyl-1H-indazol-3-yl) piperidin-1-yl] (trans-4-methoxycyclohexyl) methanone, and
(Trans-4-methoxycyclohexyl) {4- [7- (trifluoromethoxy) -1H-indazol-3-yl] piperidin-1-yl} methanone.   A pharmaceutical composition comprising the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof.   The therapeutic agent of the disease in which the acetylcholine in which the compound as described in any one of Claims 1-13 or its pharmacologically acceptable salt is involved as an active ingredient is involved. The disease involving acetylcholine is a nervous system disease, mental disease or inflammatory disease,
The therapeutic agent according to claim 15. The nervous system disease, psychiatric disease or inflammatory disease is dementia, schizophrenia, CIAS (cognitive impairment associated with schizophrenia), Alzheimer's disease, Down's syndrome, attention deficit disorder or cerebrovascular angiopathy,
The therapeutic agent of Claim 16.   A medicament comprising a combination of the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof and at least one drug selected from atypical antipsychotic drugs.   Involves acetylcholine, characterized in that a patient in need of treatment is administered a therapeutically effective amount of a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof. A method for treating a disease caused by abnormal intracellular signaling.   The compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof for the treatment 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 13, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease caused by an abnormality in intracellular signal transduction involving acetylcholine.