WO2010053127A1 - MODULATOR OF α1GABAA RECEPTOR OR α5GABAA RECEPTOR - Google Patents

Abstract

Disclosed are: an a1GABAA receptor modulator or an a5GABAA receptor modulator comprising, as an active ingredient, a pyridopyrimidone derivative represented by general formula (I) [wherein R1 represents a hydrogen atom, a lower alkyl which may have a substituent, or the like; R2 represents a lower alkyl which may have a substituent, or the like; R3 represents -NR6R7 (wherein R6 represents a hydrogen atom, or the like; and R7 represents a hydrogen atom, a lower alkyl which may have a substituent, or the like), or the like; and R4 and R5 independently represent a halogen, a lower alkyl which may have a substituent, or the like] or a pharmaceutically acceptable salt thereof; and others.

Description

α1GABAA receptor or α5GABAA receptor modulator

The present invention relates to an α1GABA _A receptor modulator or α5GABA _A receptor modulator having a pyridopyrimidone derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

GABA (γ-aminobutyric acid) is synthesized from glutamate by glutamate decarboxylase and acts as an inhibitory neurotransmitter in a wide range of brain regions. There are three types of receptors for GABA: GABA _A and GABA _C receptors with built-in ion channels and GA protein _B- coupled GABA _B receptors, of which GABA _A receptors are four-transmembrane subunits. A heteropentameric structure consisting of The subunit types are: α: 6 species (α1-6), β: 3 species (β1-3), γ: 3 species (γ1-3), ρ: 3 species (ρ1-3) and δ, ε , Θ is one each, but most receptors are composed of three types, α, β, and γ. GABA _A receptors, Cl contained in the receptor by binding of GABA ^- increasing the permeability of the ion channel, Cl ^- is possible to suppress the excitation of nerve cells are known by influx of ions. Further, when an agonist binds to the benzodiazepine binding site contained in the GABA _A receptor, and acts to enhance the action of GABA for GABA _A receptor, Cl ^- increase the flux of ions. As a result, benzodiazepine derivatives such as diazepam have anticonvulsant, anti-anxiety, muscle relaxation, hypnosis, and amnesia effects, so GABA _A receptors are epilepsy, anxiety, muscle contraction, arousal, learning / memory, etc. [Journal of Pharmacology and Experimental Therapeutics, Vol. 300, p. 2 (2002)]. The pharmacological actions of these GABA and benzodiazepine derivatives are considered to be based on the diversity of α subunits constituting the GABA _A receptor and the distribution of in vivo expression of each subtype. Among these, GABA _A receptors containing α1 subunits (α1GABA _A receptors) are known to be widely distributed in the brain. Studies using point mutant mice have reported that α1GABA _A receptor agonist activity is important for sedation, amnesia, and anticonvulsant effects of benzodiazepines [Nature, vol. 401, p. .796 (1999), Nature Neuroscience, Volume 3, p. 587 (2000)]. Zolpidem, a sleep-inducing agent, has also been reported to act by α1GABA _A receptor agonist activity, and α1GABA _A receptor is thought to be involved in sedation, muscle contraction, sleep, learning / memory, epilepsy, etc. [Neuroreport, Volume 15, p.2299 (2004)]. Inversely, benzodiazepine receptor inverse agonists have been reported to improve cognitive function and promote arousal [Nature (321), p.864 (1986), pharmacology, biochemistry, And Behavior (Pharmacology Biochemistry and Behavior), Volume 35, p. 889 (1990)]. Benzodiazepine receptor antagonists have been reported for use in overdose benzodiazepines to release sedation and improve respiratory depression [Emergency Medicine Journal, Vol. 23, p. 162. (2006)]. Thus, ligands for the α1GABA _A receptor include, for example, sleep disorders, depression, epilepsy, Alzheimer's disease, Down syndrome, cerebrovascular dementia, and cognitive impairment associated with psychiatric / neurological diseases ( Treatment and / or prevention of central nervous system diseases such as ataxia, bipolar disorder, depression, chronic fatigue syndrome, etc., or release of sedation with sedative hypnotics, anesthetics, muscle relaxants, benzodiazepines and Expected to improve respiratory depression. GABA _A receptor containing α2 subunit (α2GABA _A receptor) exists mainly in the limbic system, and GABA _A receptor containing α3 subunit (α3GABA _A receptor) exists in monoaminergic neurons. It is believed to be involved [Current Opinion in Pharmacology, Vol. 6, p. 18 (2006)]. GABA _A receptor containing α5 subunit (α5GABA _A receptor) is localized particularly in the hippocampus, and mice lacking this receptor reported higher spatial learning / memory ability than wild type. [The Journal of Neuroscience, Vol. 22, p. 5572 (2002)]. In addition, it has been reported that inverse agonists to α5GABA _A receptor show an effect of improving cognitive function, and α5GABA _A receptor is considered to be involved in learning and memory [Journal of Medicinal Chemistry (Journal of Medicinal Chemistry), 47, p. 5829 (2004)]. Therefore, ligands for α5GABA _A receptor, especially inverse agonists, are cognitive dysfunctions associated with Alzheimer's disease, Down's syndrome, cerebrovascular dementia, neuropsychiatric disorders (e.g. attention deficit hyperactivity disorder, schizophrenia, Bipolar disorder, depression, chronic fatigue syndrome, etc.), and are expected as therapeutic and / or preventive drugs for central nervous system diseases such as drug dependence (such as alcoholism).

Examples of α1GABA _A receptor modulators include imidazopyridine derivatives (Patent Document 1), imidazopyrazine derivatives (Patent Document 2), pyrazolopyrimidine derivatives (Patent Document 3), quinolone derivatives (Patent Document 4), cinnoline derivatives ( A large number of compounds such as Patent Document 5) are known.
Examples of α5GABA _A receptor modulators include imidazotriazolobenzodiazepine derivatives (Patent Document 6), imidazopyridine derivatives (Patent Document 7), triazoloindane derivatives (Patent Document 8), and triazolopyridazine derivatives (Patent Document 9). Many compounds such as phenylpyridazine derivatives (Patent Document 10) are known.

On the other hand, as a pyridopyrimidone derivative, for example, a compound represented by the following formula (A) (Patent Document 11) is known as a compound having a lower alkyl substituted with an aryl group at the 2-position. Further, compounds represented by the following formulas (B) and (C) (Patent Document 12, Non-Patent Document 1) and the like are also known as compounds having an amino group substituted with a lower alkyl group at the 2-position. Further, as a compound having a lower alkyl substituted with an aryl group at the 1-position and a lower alkyl group substituted at the 2-position, a compound represented by the following (D) (Patent Document 13) is also known. As compounds having a lower alkyl group at the 1-position and a hydrogen atom at the 2-position, compounds represented by the following formulas (E) and (F) (Non-patent Document 2) are also known.

European Patent Application No. 1803722 International Publication No. 2007/110438 Pamphlet International Publication No. 2008/015253 Pamphlet International Publication No. 2008/017710 Pamphlet International Publication No. 2007/073283 Pamphlet US Patent Application Publication No. 2007/0082890 International Publication No. 2007/082806 Pamphlet US Pat. No. 7,022,724 International Publication No. 1998/004560 Pamphlet International Publication No. 2004/014865 Pamphlet International Publication No. 2002/030911 Pamphlet US Pat. No. 3,931,183 European Patent Application No. 481614

“Journal of Combinatorial Chemistry”, 2005, Volume 7, p.96 CAS Registry Database (CAS REGISTRY Database), Registry Number: 1001050-71-0, 1001050-70-9

An object of the present invention is to provide an α1GABA _A receptor modulator, an α5GABA _A receptor modulator or the like containing a pyridopyrimidone derivative as an active ingredient.
Another object is to provide an α1GABA _A receptor modulator, a novel pyridopyrimidone derivative having an α5GABA _A receptor modulatory activity, or a pharmaceutically acceptable salt thereof.

The present invention relates to the following (1) to (30).
(1) General formula (I)

[Wherein, R ¹ represents a hydrogen atom, optionally substituted lower alkyl or optionally substituted cycloalkyl, and R ² represents optionally substituted lower alkyl. , An optionally substituted cycloalkyl, an optionally substituted aralkyl or an optionally substituted aromatic heterocyclic alkyl, R ³ represents —NR ⁶ R ⁷ ( In the formula, R ⁶ and R ⁷ are the same or different, and may be a hydrogen atom, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted. Lower alkynyl, optionally substituted lower alkanoyl, optionally substituted lower alkoxy, optionally substituted cycloalkyl, optionally substituted aryl, Aralkyl optionally having a substituent, having a substituent Aroyl which may have, aliphatic heterocyclic group which may have a substituent, aromatic heterocyclic group which may have a substituent, aliphatic heterocyclic alkyl which may have a substituent Or an aromatic heterocyclic alkyl which may have a substituent, or a nitrogen-containing heterocyclic group in which R ⁶ and R ⁷ may have a substituent together with an adjacent nitrogen atom. Represents an optionally substituted aryl or an optionally substituted aromatic heterocyclic group, and R ⁴ and R ⁵ are the same or different and represent a hydrogen atom, halogen, hydroxy, Nitro, azide, amino, cyano, carboxy, formyl, lower alkyl optionally having substituent, lower alkenyl optionally having substituent, lower alkynyl optionally having substituent, substituent Lower alkanoyl optionally substituted Lower alkoxy which may have a group, cycloalkyl which may have a substituent, lower alkylamino which may have a substituent, di-lower alkylamino which may have a substituent, Aryl which may have a substituent, aralkyl which may have a substituent, aroyl which may have a substituent, aliphatic heterocyclic group which may have a substituent, substituent Represents an aromatic heterocyclic group which may have a substituent, an aliphatic heterocyclic alkyl which may have a substituent or an aromatic heterocyclic alkyl which may have a substituent.] An α1GABA _A receptor modulator comprising a derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
(2) General formula (I)

[Wherein, R ¹ represents a hydrogen atom, optionally substituted lower alkyl or optionally substituted cycloalkyl, and R ² represents optionally substituted lower alkyl. , An optionally substituted cycloalkyl, an optionally substituted aralkyl or an optionally substituted aromatic heterocyclic alkyl, R ³ represents —NR ⁶ R ⁷ ( In the formula, R ⁶ and R ⁷ are the same or different, and may be a hydrogen atom, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted. Lower alkynyl, optionally substituted lower alkanoyl, optionally substituted lower alkoxy, optionally substituted cycloalkyl, optionally substituted aryl, Aralkyl optionally having a substituent, having a substituent Aroyl which may have, aliphatic heterocyclic group which may have a substituent, aromatic heterocyclic group which may have a substituent, aliphatic heterocyclic alkyl which may have a substituent Or an aromatic heterocyclic alkyl which may have a substituent, or a nitrogen-containing heterocyclic group in which R ⁶ and R ⁷ may have a substituent together with an adjacent nitrogen atom. Represents an optionally substituted aryl or an optionally substituted aromatic heterocyclic group, and R ⁴ and R ⁵ are the same or different and represent a hydrogen atom, halogen, hydroxy, Nitro, azide, amino, cyano, carboxy, formyl, lower alkyl optionally having substituent, lower alkenyl optionally having substituent, lower alkynyl optionally having substituent, substituent Lower alkanoyl optionally substituted Lower alkoxy which may have a group, cycloalkyl which may have a substituent, lower alkylamino which may have a substituent, di-lower alkylamino which may have a substituent, Aryl which may have a substituent, aralkyl which may have a substituent, aroyl which may have a substituent, aliphatic heterocyclic group which may have a substituent, substituent An aromatic heterocyclic group which may have a substituent, an aliphatic heterocyclic alkyl which may have a substituent or an aromatic heterocyclic alkyl which may have a substituent] An α5GABA _A receptor modulator comprising a derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
(3) General formula (IA)

[Wherein, R ^1A represents a hydrogen atom, optionally substituted lower alkyl, or optionally substituted cycloalkyl, and R ^2A represents optionally substituted lower alkyl. , An optionally substituted cycloalkyl, an optionally substituted aralkyl or an optionally substituted aromatic heterocyclic alkyl, R ^3A represents —NR ^6A R ^7A ( In the formula, R ^6A and R ^7A are the same or different and each may have a hydrogen atom, a lower alkyl optionally having substituent (s), a lower alkenyl optionally having substituent (s), or a substituent (s). Lower alkynyl, optionally substituted lower alkanoyl, optionally substituted lower alkoxy, optionally substituted cycloalkyl, optionally substituted aryl, Aralkyl which may have a substituent, Substituent Aroyl which may have, aliphatic heterocyclic group which may have a substituent, aromatic heterocyclic group which may have a substituent, aliphatic heterocyclic group which may have a substituent Represents a ring alkyl or an optionally substituted aromatic heterocyclic alkyl, or a nitrogen-containing heterocyclic ring in which R ^6A and R ^7A may have a substituent together with the adjacent nitrogen atom Represents an optionally substituted aryl or an optionally substituted aromatic heterocyclic group, and R ^4A and R ^5A are the same or different and each represents a hydrogen atom, a halogen, Hydroxy, nitro, azide, amino, cyano, carboxy, formyl, lower alkyl optionally having substituent, lower alkenyl optionally having substituent, lower alkynyl optionally having substituent, Lower alkanoyl optionally having a substituent A lower alkoxy optionally having a substituent, a cycloalkyl optionally having a substituent, a lower alkylamino optionally having a substituent, a di-lower alkyl optionally having a substituent Amino, aryl optionally having substituent (s), aralkyl optionally having substituent (s), aroyl optionally having substituent (s), aliphatic heterocyclic group optionally having substituent (s), The aromatic heterocyclic group which may have a substituent, the aliphatic heterocyclic alkyl which may have a substituent, or the aromatic heterocyclic alkyl which may have a substituent is represented. However, when R ^2A is butyl or isobutyl and R ^5A is trifluoromethyl, R ^3A is not unsubstituted aryl] or a pharmaceutically acceptable salt thereof (however, 2-butyl Except -5-methyl-7-methylamino-1-[(2 '-(tetrazol-5-yl) biphen-4-yl) methyl] pyrido [2,3-d] pyrimidin-4 (1H) -one ).
(4) The pyridopyrimidone derivative or the pharmaceutically acceptable salt thereof according to (3), wherein R ^1A is a hydrogen atom.
(5) The pyridopyrimidone derivative or the pharmaceutically acceptable salt thereof according to (3) or (4), wherein R ^3A is —NR ^6A R ^7A (wherein R ^6A and R ^7A are as defined above). .
(6) R ^3A is —NR ^6AA R ^7AA (wherein R ^6AA and R ^7AA together with the adjacent nitrogen atom form an ^optionally substituted nitrogen-containing heterocyclic group) The pyridopyrimidone derivative according to (3) or (4) or a pharmaceutically acceptable salt thereof.
(7) R ^3A is tetrahydroisoquinolin-2-yl or tetrahydroisoquinolin-2-yl having 1 or 2 substituents, or a pyridopyrimidone derivative according to (3) or (4) or a pharmaceutically acceptable salt thereof salt.
(8) The pyridopyrimidone derivative or the pharmaceutically acceptable derivative thereof according to (3) or (4), wherein R ^3A is isoindoline-2-yl or isoindoline-2-yl having 1 or 2 substituents salt.
(9) R ^3A is piperazin-1-yl substituted with an aromatic heterocyclic group at the 4-position or tetrahydropyridin-1-yl substituted with an aromatic heterocyclic group at the 4-position (3) or (4) The described pyridopyrimidone derivative or a pharmaceutically acceptable salt thereof.
(10) The pyridopyrimidone derivative or a pharmaceutically acceptable salt thereof according to any one of (3) to (9), wherein R ^2A is lower alkyl optionally having substituent (s).
(11) The pyridopyrimidone derivative or a pharmaceutically acceptable salt thereof according to any one of (3) to (9), wherein R ^2A is cycloalkyl which may have a substituent.
(12) The pyridopyrimidone derivative or a pharmaceutically acceptable salt thereof according to any one of (3) to (11), wherein R ^4A is a hydrogen atom.
(13) The pyridopyrimidone derivative or a pharmaceutically acceptable salt thereof according to any one of (3) to (12), wherein R ^5A is a hydrogen atom or lower alkyl optionally having substituent (s).
(14) Any of the following pyridopyrimidone derivatives or a pharmacologically acceptable salt thereof.
1) 1-propyl-7- [4- (pyridin-2-yl) piperazin-1-yl] pyrido [2,3-d] pyrimidin-4 (1H) -one 2) 1-propyl-7- [4 -(Pyrazin-2-yl) piperazin-1-yl] pyrido [2,3-d] pyrimidin-4 (1H) -one 3) 7- (isoindoline-2-yl) -1-propylpyrido [2,3 -D] pyrimidin-4 (1H) -one 4) 1-propyl-7- [4- (pyridin-3-yl) -1,2,3,6-tetrahydropyridin-1-yl] pyrido [2,3 -D] pyrimidin-4 (1H) -one 5) 1-tert-butyl-7- (6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl) pyrido [2,3-d Pyrimidine-4 (1H) -one 6) 7- (6,7-dimethoxy 1,2,3,4-tetrahydroisoquinolin-2-yl) -2-methyl-1-propylpyrido [2,3-d] pyrimidin-4 (1H) -one 7) 7- (6,7-dimethoxy-1 , 2,3,4-Tetrahydroisoquinolin-2-yl) -5-methyl-1-propylpyrido [2,3-d] pyrimidin-4 (1H) -one 8) 5-methyl-1-propyl-7- [ 4- (pyrazin-2-yl) piperazin-1-yl] pyrido [2,3-d] pyrimidin-4 (1H) -one (15) The pyridopyrimidone derivative according to any one of (3) to (14) or An α1GABA _A receptor modulator comprising a pharmaceutically acceptable salt as an active ingredient.
(16) Treatment of a disease involving an α1GABA _A receptor comprising the pyridopyrimidone derivative according to any one of (1) or (3) to (14) or a pharmaceutically acceptable salt thereof as an active ingredient and / or Preventive agent.
(17) An α5GABA _A receptor modulator comprising the pyridopyrimidone derivative or the pharmaceutically acceptable salt thereof according to any one of (3) to (14) as an active ingredient.
(18) Treatment of a disease involving an α5GABA _A receptor comprising the pyridopyrimidone derivative according to any one of (2) or (3) to (14) or a pharmaceutically acceptable salt thereof as an active ingredient and / or Preventive agent.
(19) _A method for modulating an α1GABA _A receptor, comprising administering an effective amount of the compound according to any one of (1) or (3) to (14) or a pharmaceutically acceptable salt thereof.
(20) Treatment of a disease associated with α1GABA _A receptor, comprising administering an effective amount of the compound according to any one of (1) or (3) to (14) or a pharmaceutically acceptable salt thereof. And / or preventive methods.
(21) _A method for modulating an α5GABA _A receptor, comprising administering an effective amount of the compound according to any one of (2) or (3) to (14) or a pharmaceutically acceptable salt thereof.
(22) Treatment of a disease associated with α5GABA _A receptor, comprising administering an effective amount of the compound according to any one of (2) or (3) to (14) or a pharmaceutically acceptable salt thereof. And / or preventive methods.
(23) Use of the compound according to any one of (1) or (3) to (14) or a pharmaceutically acceptable salt thereof for the production of an α1GABA _A receptor modulator.
(24) The compound according to any one of (1) or (3) to (14) or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic and / or prophylactic agent for a disease involving an α1GABA _A receptor Use of.
(25) Use of the compound according to any of (2) or (3) to (14) or a pharmaceutically acceptable salt thereof for the production of an α5GABA _A receptor modulator.
(26) The compound or a pharmaceutically acceptable salt thereof according to any one of (2) or (3) to (14) for the manufacture of a therapeutic and / or prophylactic agent for a disease involving an α5GABA _A receptor Use of.
(27) An agent comprising the compound according to any one of (1) or (3) to (14) or a pharmaceutically acceptable salt thereof for use in regulating an α1GABA _A receptor.
(28) The compound according to any one of (1) or (3) to (14) or a pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of a disease involving an α1GABA _A receptor. Containing agent.
(29) An agent comprising the compound according to any one of (2) or (3) to (14) or a pharmaceutically acceptable salt thereof for use in modulating an α5GABA _A receptor.
(30) The compound according to any one of (2) or (3) to (14) or a pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of a disease involving an α5GABA _A receptor. Containing agent.

The present invention provides an α1GABA _A receptor modulator or α5GABA _A receptor modulator containing a pyridopyrimidone derivative as an active ingredient.
In addition, various diseases involving α1GABA _A receptor that regulate α1GABA _A receptor (eg sleep disorders, depression, epilepsy, Alzheimer's disease, Down's syndrome, cerebrovascular dementia, cognitive impairment associated with psychiatric / neurological disorders) (E.g., central nervous disease such as attention deficit hyperactivity disorder, schizophrenia, bipolar disorder, depression, chronic fatigue syndrome)) treatment and / or prevention drugs, or sedative hypnotics, anesthetics, Useful as a muscle relaxant, benzodiazepine release sedation and respiratory suppression, or has α5GABA _A receptor modulation, such as Alzheimer's disease, schizophrenia, cerebrovascular dementia, drug dependence ( A novel pyridopyrimidone derivative or a pharmaceutically acceptable salt thereof, which is useful for the treatment and / or prevention of alcohol dependence, etc. .

Hereinafter, the compound represented by formula (I) is referred to as compound (I). The same applies to the compounds of other formula numbers.
In the definition of each group of general formulas (I) and (IA)
Examples of the lower alkyl portion of lower alkyl, lower alkanoyl, lower alkoxy, lower alkylamino and di-lower alkylamino include linear or branched alkyl having 1 to 10 carbon atoms, and more specifically methyl, ethyl Propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl and the like. The two lower alkyl moieties of the di-lower alkylamino may be the same or different.

Examples of lower alkenyl include linear or branched alkenyl having 2 to 10 carbon atoms, and more specifically, vinyl, allyl, 1-propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, etc. Can be given.
Examples of lower alkynyl include linear or branched alkynyl having 2 to 10 carbon atoms, and more specifically, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like.

Examples of cycloalkyl include cycloalkyl having 3 to 8 carbon atoms, and more specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
Examples of aryl and the aryl moiety of aralkyl and aroyl include aryl having 6 to 14 carbon atoms, and more specifically, phenyl, naphthyl, azulenyl, anthryl and the like.

Examples of the aromatic heterocyclic group part of the aromatic heterocyclic group and the aromatic heterocyclic alkyl include, for example, a 5-membered or 6-membered monocyclic fragrance containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom. A heterocyclic heterocyclic group, a bicyclic or tricyclic condensed 3- to 8-membered ring, and a condensed aromatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom More specifically, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, benzothiophenyl, benzo Oxazolyl, benzothiazolyl, isoi Drill, indolyl, indazolyl, benzimidazolyl, benzotriazolyl, oxazolopyrimidinyl, thiazolopyrimidinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, imidazopyridinyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxadinyl .

Examples of the aliphatic heterocyclic group and the aliphatic heterocyclic group part of the aliphatic heterocyclic alkyl include, for example, a 5-membered or 6-membered monocyclic fat containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom. A heterocyclic heterocyclic group, a bicyclic or tricyclic condensed 3- to 8-membered ring, and a condensed aliphatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom More specifically, aziridinyl, azetidinyl, pyrrolidinyl, piperidino, piperidinyl, azepanyl, 1,2,5,6-tetrahydropyridyl, imidazolidinyl, pyrazolidinyl, piperazinyl, homopiperazinyl, pyrazolinyl, oxiranyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl 5,6-dihydro-2H-pyranyl, oxazolidinyl, mole Lino, morpholinyl, thioxazolidinyl, thiomorpholinyl, 2H-oxazolyl, 2H-thioxazolyl, dihydroindolyl, dihydroisoindolyl, dihydrobenzofuranyl, benzimidazolidinyl, dihydrobenzoxazolyl, dihydrobenzothioxazolyl Benzodioxolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, dihydro-2H-chromanyl, dihydro-1H-chromanyl, dihydro-2H-thiochromanyl, dihydro-1H-thiochromanyl, tetrahydroquinoxalinyl, tetrahydroquinazolinyl And dihydrobenzodioxanyl.

Examples of the aralkyl and the alkylene moiety of the aromatic heterocyclic alkyl and the aliphatic heterocyclic alkyl include linear or branched alkylene having 1 to 10 carbon atoms, and more specifically methylene, ethylene, propylene, tetra Examples include methylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene, decamethylene and the like.

Halogen means each atom of fluorine, chlorine, bromine and iodine.
Examples of the nitrogen-containing heterocyclic group formed together with the adjacent nitrogen atom include a 5-membered or 6-membered monocyclic heterocyclic group containing at least one nitrogen atom (the monocyclic heterocyclic group is , Which may contain other nitrogen atoms, oxygen atoms or sulfur atoms), condensed bicyclic or tricyclic condensed 3- to 8-membered rings and containing at least one nitrogen atom ( The condensed ring heterocyclic group may contain other nitrogen atom, oxygen atom or sulfur atom), and more specifically, aziridinyl, azetidinyl, pyrrolidinyl, piperidino, azepanyl, pyrrolyl, imidazolidinyl, Imidazolyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, piperazinyl, homopiperazinyl, oxazolidinyl, 2H-oxazolyl, thioxazolidinyl, 2H-thioxazolyl, Horino, thiomorpholinyl, dihydroindolyl, tetrahydropyridinyl, dihydroisoindolyl, indolyl, isoindolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, tetrahydrobenzoxepinyl, tetrahydropyridindolyl, dihydropyridoindolyl, tetrahydronaphthylidini , Tetrahydrotriazolopyrazinyl, dihydrobenzoxazolyl, dihydrobenzothioxazolyl, benzoimidazolidinyl, benzimidazolyl, dihydroindazolyl, indazolyl, benzotriazolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, imidazolpyridinyl , Purinyl, tetrahydrobenzoazepinyl and the like.

Lower alkyl optionally having substituent, lower alkenyl optionally having substituent, lower alkynyl optionally having substituent, lower alkanoyl optionally having substituent, substituent The lower alkoxy which may have a substituent, the lower alkylamino which may have a substituent, and the di-lower alkylamino which may have a substituent may be the same or different. 1-3, halogen, hydroxy, sulfanyl, nitro, cyano, carboxy, carbamoyl, C _3-8 cycloalkyl, C _1-10 alkoxy, C _3-8 cycloalkoxy, C _6-14 aryloxy, C _{7-16 aralkyloxy, C 2-11 alkanoyloxy, C 7-15 aroyloxy, C 1-10} alkylsulfanyl, ^-NR X ^{R Y} Wherein, ^{R X} and ^{R Y} are the same or different, a hydrogen _{atom, C 1-10 alkyl, C 3-8 cycloalkyl, C 6-14} aryl, an aromatic heterocyclic _{group, C 7-16} aralkyl, _{C 2 -11} alkanoyl, C _7-15 aroyl, C _1-10 alkoxycarbonyl or C _7-16 aralkyloxycarbonyl), C _2-11 alkanoyl, C _7-15 aroyl, C _1-10 alkoxycarbonyl, C _{6- And} a substituent selected from the group consisting of ₁₄ aryloxycarbonyl, C _1-10 alkylcarbamoyl, and diC _1-10 alkylcarbamoyl.

Aryl optionally having substituent (s), Aralkyl optionally having substituent (s), Aroyl optionally having substituent (s), Aromatic heterocyclic group or substituent optionally having substituent (s) Examples of the substituent in the aromatic heterocyclic alkyl optionally having the same or different, for example, halogen, hydroxy, sulfanyl, nitro, cyano, carboxy, carbamoyl, C _1-10 alkyl, having 1 to 3 substituents, Trifluoromethyl, C _3-8 cycloalkyl, C _6-14 aryl, aliphatic heterocyclic group, aromatic heterocyclic group, C _1-10 alkoxy, C _3-8 cycloalkoxy, C _6-14 aryloxy, C _{7-16 aralkyloxy, C 2-11 alkanoyloxy, C 7-15 aroyloxy, C 1-10} alkylsulfanyl, ^-NR X ^{R Y} (wherein , ^{R X} and ^{R Y} are the same meanings as defined above, _{respectively), C 2-11 alkanoyl, C 7-15 aroyl, C 1-10 alkoxycarbonyl, C 6-14 aryloxycarbonyl, C 1-10} alkylcarbamoyl, and And a substituent selected from the group consisting of di-C _1-10 alkylcarbamoyl.

Combined with an optionally substituted cycloalkyl, an optionally substituted aliphatic heterocyclic group, an optionally substituted aliphatic heterocyclic alkyl or an adjacent nitrogen atom The substituents in the nitrogen-containing heterocyclic group which may have a substituent may be the same or different, for example, oxo, halogen, hydroxy, hydroxyethyl, sulfanyl, nitro, cyano having 1 to 3 substituents. Carboxy, carbamoyl, C _1-10 alkyl, trifluoromethyl, C _3-8 cycloalkyl, C _6-14 aryl, aliphatic heterocyclic group, aromatic heterocyclic group, C _1-10 alkoxy, C _3-8 Cycloalkoxy, C _6-14 aryloxy, C _7-16 aralkyloxy, C _2-11 alkanoyloxy, C _7-15 aroyloxy, C _1-10 Alkylsulfanyl, —NR ^XA R ^YA (wherein R ^XA and R ^YA are the same or different and represent a hydrogen atom, C _1-10 alkyl, C _3-8 cycloalkyl, C _6-14 aryl, aromatic heterocyclic group) , C _7-16 aralkyl, C _2-11 alkanoyl, C _7-15 aroyl, aromatic heterocyclic carbonyl, C _1-10 alkoxycarbonyl or C _7-16 aralkyloxycarbonyl), aromatic heterocyclic carbonyl, fatty _{Consisting of a} group heterocyclic alkyl, C _2-11 alkanoyl, C _7-15 aroyl, C _1-10 alkoxycarbonyl, C _6-14 aryloxycarbonyl, C _1-10 alkylcarbamoyl, and di-C _1-10 alkylcarbamoyl And substituents selected from the group.

C _1-10 alkyl and C _1-10 alkoxy, C _2-11 alkanoyloxy, C _1-10 alkylsulfanyl, C _2-11 alkanoyl, C _1-10 alkoxycarbonyl, C _1-10 alkylcarbamoyl and Examples of the C _1-10 alkyl moiety of diC _1-10 alkylcarbamoyl include the groups exemplified above for the lower alkyl. The two C _1-10 alkyls in the diC _1-10 alkylcarbamoyl may be the same or different.

The C _3-8 cycloalkyl and C _3-8 cycloalkyl moiety cycloalkoxy, e.g. groups mentioned for illustrative said cycloalkyl is exemplified.
Examples of the aryl moiety of C _6-14 aryl and C _6-14 aryloxy, C _7-15 aroyl, C _7-15 aroyloxy and C _6-14 aryloxycarbonyl include the groups exemplified in the above aryl examples. The

Examples of the aromatic heterocyclic moiety of the aromatic heterocyclic carbonyl include the groups exemplified above for the aromatic heterocyclic group.
Examples of the aryl moiety of C _7-16 aralkyloxy, C _7-16 aralkyl, and C _7-16 aralkyloxycarbonyl include the groups exemplified in the above aryl, and examples of the alkyl moiety include, for example, the alkylene part of the aralkyl. The groups mentioned in the above examples are exemplified.

Examples of the aliphatic heterocyclic group, the aromatic heterocyclic group, and the halogen include the groups exemplified in the aliphatic heterocyclic group, the aromatic heterocyclic group, and the halogen. The aliphatic heterocyclic alkyl has the same meaning as described above.
As the compound (IA), R ^1A is a hydrogen atom, R ^2A is ^optionally substituted lower alkyl, R ^3A is —NR ^6A R ^7A (wherein R ^6A and R ^7A are each As defined above, a compound in which R ^4A is a hydrogen atom or R ^5A is a hydrogen atom or an optionally substituted lower alkyl is preferable. Further, as the compound (IA), in the formula, R ^1A is a hydrogen atom, R ^2A is an ^optionally substituted lower alkyl, R ^3A is —NR ^6AA R ^7AA (wherein R ^6AA and R ^7AA Are as defined above), and compounds in which R ^4A is a hydrogen atom or R ^5A is a hydrogen atom or a lower alkyl optionally having substituent (s) are preferred. Further, as compound (IA), R ^1A is a hydrogen atom, R ^2A is a lower alkyl optionally having substituent (s), R ^3A is tetrahydroisoquinolin-2-yl or a tetrahydro having 1 or 2 substituents Isoquinolin-2-yl, isoindoline-2-yl or isoindoline-2-yl having 1 or 2 substituents, or piperazin-1-yl or 4-position substituted with an aromatic heterocyclic group at the 4-position More preferably, the compound is tetrahydropyridin-1-yl substituted with an aromatic heterocyclic group, and R ^4A is a hydrogen atom or R ^5A is a hydrogen atom or a lower alkyl which may have a substituent.

The α1GABA _A receptor modulator means an α1GABA _A receptor agonist, an α1GABA _A receptor antagonist, or an α1GABA _A receptor inverse agonist.
The α5GABA _A receptor modulator means an α5GABA _A receptor agonist, an α5GABA _A receptor antagonist or an α5GABA _A receptor inverse agonist, and an α5GABA _A receptor inverse agonist is preferred.
Pharmaceutically acceptable salts of compounds (I) and (IA) include, for example, pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts, and the like. Examples of pharmaceutically acceptable acid addition salts of compounds (I) and (IA) include inorganic acid salts such as hydrochloride, sulfate, and phosphate, acetate, maleate, fumarate, and citric acid. Examples of the pharmaceutically acceptable metal salt include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminum salt, and the like. Examples of the pharmaceutically acceptable ammonium salt include salts such as ammonium and tetramethylammonium. Examples of the pharmaceutically acceptable organic amine addition salt include morpholine and piperidine. Examples of pharmaceutically acceptable amino acid addition salts include lysine, glycine, phenylalanine, aspartic acid, glutamine. Addition salts and the like.

The α1GABA _A receptor modulator of the present invention can be used for various diseases involving the α1GABA _A receptor (for example, sleep disorders, depression, epilepsy, Alzheimer's disease, Down's syndrome, cerebrovascular dementia, and cognitive impairment associated with psychiatric / neurological disorders. (E.g., central nervous disease such as attention deficit / hyperactivity disorder, schizophrenia, bipolar disorder, depression, chronic fatigue syndrome)) treatment and / or prevention drugs, or sedative hypnotics, anesthetics, It is used as a muscle relaxant, a benzodiazepine-based sedation release agent, and an agent for improving respiratory depression.

Examples of the disease involving the α5GABA _A receptor to be treated and / or prevented by the α5GABA _A receptor modulator of the present invention include Alzheimer's disease, Down's syndrome, cerebrovascular dementia, and cognitive dysfunction associated with a psychiatric / neurological disorder ( For example, attention-deficit / hyperactivity disorder, schizophrenia, bipolar disorder, depression, chronic fatigue syndrome, etc.), central nervous system diseases such as drug dependence (such as alcoholism), and the like.

Next, a method for producing compound (I) is described.
In the production method shown below, when the defined group changes under the conditions of the production method or is inappropriate for carrying out the method, a method for introducing and removing a protective group commonly used in organic synthetic chemistry [for example, Protective Groups in Organic Synthesis, TW Greene, John Wiley & Sons Inc. (1999)] Thus, the target compound can be produced. Further, the order of reaction steps such as introduction of substituents can be changed as necessary.

Compound (I) can be produced according to the following steps.
Manufacturing method 1
Among compounds (I), compound (IA) in which R ³ is —NR ⁶ R ⁷ (wherein R ⁶ and R ⁷ are as defined above) can be produced by the following steps. .

[Wherein R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined above, and Y ¹ , Y ² and Y ³ are the same or different and represent a chlorine atom, a bromine atom or an iodine atom. R ^a represents lower alkyl. ]
Process 1
Compound (a-3) is preferably compound (a-1), preferably 1 to 20 equivalents of compound (a-2), in the absence of solvent or in a solvent, preferably 1 to 20 equivalents of a base. The reaction can be carried out at a temperature between −10 ° C. and the boiling point of the solvent used or, if necessary, at a temperature higher than the boiling point using a microwave reactor for 5 minutes to 72 hours.

Compound (a-1) is obtained as a commercially available product, or by the method described in US5200522 or a method analogous thereto. Alternatively, a known method from the corresponding carboxylic acid compound [for example, Experimental Chemistry Course 5th edition, Volume 16, p.119, edited by The Chemical Society of Japan, Maruzen (2005)] or a method according to them, or the corresponding nitrile It can also be obtained by subjecting the compound to hydrolysis [for example, Experimental Chemistry Course, 5th Edition, Volume 16, p.135, edited by The Chemical Society of Japan, Maruzen (2005)]. Compound (a-2) is obtained as a commercially available product or obtained by a known method [for example, Experimental Chemistry Course 5th edition, Volume 14, p.351, edited by The Chemical Society of Japan, Maruzen (2005)] or a method analogous thereto. It is done. Examples of the base include pyridine, triethylamine, diisopropylethylamine, N-methylmorpholine, N-methylpiperidine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), N, N-dimethylaminopyridine. (DMAP), potassium acetate, potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, potassium phosphate and the like. Examples of the solvent include methanol, ethanol, dichloromethane, chloroform, 1,2-dichloroethane, toluene, xylene, acetonitrile, tetrahydrofuran (THF), ethyl acetate, diethyl ether, 1,2-dimethoxyethane (DME), 1,4- Examples include dioxane, N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), pyridine, water, etc., either alone or in combination. Can be used.
Process 2
Compound (a-5) is preferably compound (a-3) with 1 to 200 equivalents of compound (a-4a) in the absence of a solvent or in a solvent, preferably in the presence of 1 to 20 equivalents of an acid. The reaction can be carried out at a temperature between −10 ° C. and the boiling point of the solvent used for 5 minutes to 72 hours.

Compound (a-4a) is obtained as a commercially available product or obtained by a known method [for example, Experimental Chemistry Course 5th edition, Volume 16, p.95, edited by The Chemical Society of Japan, Maruzen (2005)] or a method analogous thereto. It is done. Examples of the acid include hydrochloric acid, sulfuric acid, trifluoroacetic acid, methanesulfonic acid, paratoluenesulfonic acid, and the like. Examples of the solvent include methanol, ethanol, dichloromethane, chloroform, 1,2-dichloroethane, toluene, xylene, acetonitrile, THF, ethyl acetate, diethyl ether, DME, 1,4-dioxane, DMF, DMA, NMP, DMSO, pyridine. , Acetic acid, acetic anhydride, water and the like, and these can be used alone or in combination.

In addition, compound (a-5) is preferably compound (a-3), preferably 1 to 20 equivalents of compound (a-4b), without solvent or in a solvent, preferably 1 to 20 equivalents of a base. It can also be obtained by reacting in the presence at a temperature between −10 ° C. and the boiling point of the solvent used for 5 minutes to 72 hours.
Compound (a-4b) can be obtained as a commercially available product or by a known method [for example, Experimental Chemistry Course 5th edition, Volume 16, p.99, edited by The Chemical Society of Japan, Maruzen (2005)] or a method analogous thereto. It is done. Examples of the base include pyridine, triethylamine, diisopropylethylamine, N-methylmorpholine, N-methylpiperidine, DBU, DMAP, potassium acetate, potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, lithium hydroxide, Examples thereof include potassium hydroxide and potassium phosphate. Examples of the solvent include methanol, ethanol, dichloromethane, chloroform, 1,2-dichloroethane, toluene, xylene, acetonitrile, THF, ethyl acetate, diethyl ether, DME, 1,4-dioxane, DMF, DMA, NMP, DMSO, pyridine. , Acetic acid, acetic anhydride, water and the like, and these can be used alone or in combination.
Process 3
Compound (IA) is preferably compound (a-5) with 1 to 20 equivalents of compound (a-6) in the absence of a solvent or in a solvent, preferably in the presence of 1 to 20 equivalents of a base. The reaction can be carried out at a temperature between −10 ° C. and the boiling point of the solvent used or, if necessary, at a temperature higher than the boiling point using a microwave reactor for 5 minutes to 72 hours.

Compound (a-6) is obtained as a commercially available product or obtained by a known method [for example, Experimental Chemistry Course 5th edition, Volume 14, p.351, edited by The Chemical Society of Japan, Maruzen (2005)] or a method analogous thereto. It is done. Examples of the base include pyridine, triethylamine, diisopropylethylamine, N-methylmorpholine, N-methylpiperidine, DBU, DMAP, potassium acetate, potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, lithium hydroxide, Examples thereof include potassium hydroxide and potassium phosphate. Examples of the solvent include methanol, ethanol, dichloromethane, chloroform, 1,2-dichloroethane, toluene, xylene, acetonitrile, THF, ethyl acetate, diethyl ether, DME, 1,4-dioxane, DMF, DMA, NMP, DMSO, pyridine. , Acetic acid, acetic anhydride, water and the like, and these can be used alone or in combination.
Manufacturing method 2
Among the compounds (I), the compound (IB) in which R ³ is an optionally substituted aryl or an optionally substituted aromatic heterocyclic group is produced by the following steps. be able to.

[Wherein, R ¹ , R ² , R ⁴ , R ⁵ and Y ² are the same as defined above, and A is an aryl which may have a substituent or an aromatic which may have a substituent. Represents a heterocyclic group, M is B (OR ^ma ) (OR ^mb ) (wherein R ^ma and R ^mb are the same or different and represent a hydrogen atom, C _1-6 alkyl, or R ^ma and R ^mb are Together with C _1-6 alkylene which may be substituted by methyl) or SnR ^mc R ^md R ^me (wherein R ^mc , R ^md and R ^me are the same or different and are C _1-6 alkyl or phenyl Represents). ]
Process 1
Compound (IB) is preferably compound (a-5), preferably 1 to 10 equivalents of compound (a-7), and preferably in the presence of 0.001 to 1 equivalents of a palladium catalyst, preferably 0.1 to 1 equivalents of palladium catalyst. The reaction can be carried out in the presence of ˜10 equivalents of base at a temperature between −10 ° C. and the boiling point of the solvent used for 5 minutes to 72 hours.

Compound (a-7) can be obtained as a commercial product, or can be obtained by a known method [for example, Experimental Chemistry Course 5th edition, Volume 18, p.95, 183, edited by The Chemical Society of Japan, Maruzen (2004)] or It can be obtained by a method according to them.
Examples of the palladium catalyst include compounds in which a phosphine ligand is coordinated to a palladium atom, and examples of the palladium source include palladium acetate, palladium trifluoroacetate, tris (dibenzylideneacetone) dipalladium, and chloroform adducts thereof. can give. Examples of the phosphine ligand include triphenylphosphine, 1,1, -bis (diphenylphosphino) ferrocene, o-tolylphosphine, etc., and these are preferably used in an amount of 1 to 10 equivalents relative to the palladium source. . A commercially available reagent such as tetrakis (triphenylphosphine) palladium can also be used. Examples of the base include pyridine, triethylamine, diisopropylethylamine, N-methylmorpholine, N-methylpiperidine, DBU, DMAP, potassium acetate, potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, lithium hydroxide, Examples thereof include potassium hydroxide and potassium phosphate. Examples of the solvent include methanol, ethanol, dichloromethane, chloroform, 1,2-dichloroethane, toluene, xylene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, DMSO, pyridine. , Water and the like, and these may be used alone or in combination.

The intermediates and target compounds in each of the above production methods are isolated and purified by separation and purification methods commonly used in synthetic organic chemistry, such as filtration, extraction, washing, drying, concentration, recrystallization, and various chromatography. be able to. The intermediate can be subjected to the next reaction without any particular purification.
Some compounds (I) and (IA) may have stereoisomers such as positional isomers, geometric isomers, optical isomers, tautomers, etc., but all possible Isomers and mixtures thereof are used or included in the present invention.

When it is desired to obtain a salt of compound (I) or (IA), it can be purified as it is when compound (I) or (IA) is obtained in the form of a salt. Isolation and purification may be performed by dissolving or suspending (I) or (IA) in a suitable solvent and adding an acid or base to form a salt.
In addition, compounds (I) and (IA) and pharmaceutically acceptable salts thereof may exist in the form of adducts with water or various solvents, and these adducts are also used in the present invention. Or included.

Specific examples of compounds (I) and (IA) obtained by the present invention are shown in Table 1. However, the compounds used in the present invention or the compounds of the present invention are not limited thereto.

Next, the pharmacological activity of a typical compound (I) will be described with reference to test examples.
Test Example 1 GABA _A receptor (α1β3γ2s) binding action [ ³ H] Ro15-1788 binding inhibition test was performed by the method of Strakhova et al. [Molecular Pharmacology, Vol. 58, p.1434-1440 (2000) )].
In the membrane preparation, α1 subunit (Accession No. NM_183326), β3 subunit (Accession No. NM_017065), and γ2s subunit (Accession No. NM_183327) of rat GABA receptor were expressed simultaneously and transiently. A membrane fraction prepared from CHO-K1 cells was used. Membrane specimens (final protein concentration 800 μg / mL) were combined with test compound and [ ³ H] Ro15-1788 (PerkinElmer, final concentration 1 nmol / L) with assay buffer [10 mmol / L Tris-HCl (pH 7 .4), 1 mmol / L EDTA] at 4 ° C. for 1 hour, and then filtered through a 0.3% polyethyleneimine-treated filter (UniFilter GF / B, Packard BioScience). After washing with assay buffer, the radioactivity on the filter was determined with a micro scintillation counter (TopCount NXT, Packard Instruments).

The inhibitory activity of the test compound on [ ³ H] Ro15-1788 binding to the rat GABA _A receptor was calculated by the following formula. The test compound concentration is 10 μmol / L. The total binding amount in the formula is the radioactivity in the absence of the test compound, and the non-specific binding amount is the radiation in the presence of 10 μmol / L flunitrazepam (Sigma-Aldrich). Active.

Compounds 1, 2, 5, 10, 14, 16, 17, 20, 22, 23, 24, 25, 29, 30, 31, 32, 33, 34 inhibit binding by 50% or more at a concentration of 10 μmol / L Showed activity.
From the above, it was confirmed that the compound (I) has a strong affinity for the α1GABA _A receptor.
Test Example 2 GABA _A receptor (α5β3γ2s) binding action [ ³ H] Ro15-1788 binding inhibition test was performed by the method of Strakhova et al. [Molecular Pharmacology, Vol. 58, p.1434-1440 (2000) )].

In the membrane preparation, α5 subunit (Accession No. NM_017295), β3 subunit (Accession No. NM_017065), and γ2s subunit (Accession No. NM_183327) of rat GABA receptor were expressed simultaneously and transiently. A membrane fraction prepared from CHO-K1 cells was used. Membrane specimens (final protein concentration 150 μg / mL) were combined with test compound and [ ³ H] Ro15-1788 (PerkinElmer, final concentration 1 nmol / L) with assay buffer [10 mmol / L Tris-HCl (pH 7 .4), 1 mmol / L EDTA] at 4 ° C. for 1 hour, and then filtered through a 0.3% polyethyleneimine-treated filter (UniFilter GF / B, Packard BioScience). After washing with assay buffer, the radioactivity on the filter was determined with a micro scintillation counter (TopCount NXT, Packard Instruments).

The inhibitory activity of the test compound on [ ³ H] Ro15-1788 binding to the rat GABA _A receptor was calculated by the following formula. The test compound concentration is 1 μmol / L, and the total binding amount in the formula is the radioactivity in the absence of the test compound, and the nonspecific binding amount is the radiation in the presence of 10 μmol / L flunitrazepam (Sigma-Aldrich). Active.

Compounds 1, 2, 4, 5, 10, 11, 14, 15, 16, 17, 19, 20, 22, 23, 24, 25, 26, 29, 30, 31, 32 are at a concentration of 1 μmol / L. The binding inhibitory activity was 50% or more.
From the above, it was confirmed that Compound (I) has a strong affinity for the α5GABA _A receptor.
Test Example 3 α5GABA _A receptor reverse agonist activity test was performed according to the method of Adkins et al. [The Journal of Biological Chemistry, 276, p.38934-38939 (2001)]. It was.

In cells co-expressing the α5, β3, and γ2s subunits of the rat GABA _A receptor, several test compounds of the present invention inhibit changes in membrane potential when stimulated with 100 nM GABA. did. From these results, it was confirmed that these compounds have reverse agonist activity against rat α5GABA _A receptor. In other words, these compounds are associated with α5GABA _A receptor-related diseases (Alzheimer's disease, Down syndrome, cerebrovascular dementia, cognitive dysfunction associated with psychiatric / neurological disorders (eg attention deficit hyperactivity disorder, schizophrenia, bipolar) Sexual disorders, depression, chronic fatigue syndrome, etc.), central nervous diseases such as drug dependence (such as alcoholism), etc.) and / or prevention.
Test Example 4 The action test on scopolamine-induced spatial memory impairment was performed according to the method of Itoh et al. [European Journal of Pharmacology, Vol. 236, page 341 (1993)].

Saline solution or scopolamine ((-)-scopolamine hydrobromide trihydrate, Sigma-Aldrich) was intraperitoneally administered (0.75 mg / kg) to ddY mice (male, SLC). 30 minutes after scopolamine treatment, the mouse was connected to a Y-maze experiment device [three arms (length 25 cm, width 5 cm, height 20 cm) made of black acrylic wall, each connected at an angle of 120 degrees. The three devices were distinguished from A, B, and C respectively with the device, and allowed to explore the maze freely for 7 minutes. At this time, the state where all the limbs of the animal were in one arm was defined as entry into the arm, and the order in which the animal entered the arm was recorded. We defined the behavior of entering three different arms in succession as spontaneous alternation behavior, and obtained the number of alternation behaviors. The ratio of the number of replacement actions to the number of entries obtained by subtracting 2 from the number of entries of all arms was calculated as the spontaneous replacement action rate (%).
(Equation 3)
Spontaneous alternation rate (%) = {number of alternations / (number of ingresses of all arms -2)} x 100
In the scopolamine treatment group, a significant decrease in the spontaneous alternation behavior rate was observed compared with the physiological saline administration group, and spatial memory impairment was confirmed. The test compound or solvent was orally administered 30 minutes before scopolamine treatment, and the effect on scopolamine-induced spatial memory impairment was compared between the test compound administration group and the solvent group.

Compounds 1, 4, 11, 15, 19, 30, 31, and 32 improved the decrease in spontaneous alternation behavior rate (scopolamine-induced memory impairment) caused by scopolamine.
From the results of the above test, these compounds were considered to be useful for the treatment and / or prevention of diseases involving the α5GABA _A receptor (such as Alzheimer's disease).
Test Example 5 Effects on AF64A-induced spatial memory impairment using the mouse radial water maze test The treatment of the choline neurotoxin AF64A was performed by the method of Fisher et al. [Journal of Pharmacology and Experimental Therapeutics), 222, 140 (1982)], and the radial water maze test was performed according to the method of Alamed et al. [Nature Protocol, 1, 1671 (2006)]. .

AF64A was prepared from Acetyl AF64A (Acetylethylcholine mustard hydrochloride, Sigma-Aldrich) and administered into the left ventricle of ddY mice (male, SLC Japan) (10 nmol / 5 μL / mouse). Mice were used for the study with a recovery period of one week or longer. Any of the radial water maze experimental device [6 arms made of black acrylic wall (33cm long, 20cm wide, 25cm deep) connected at an angle of 60 degrees each] A platform was placed at one end of the arm. The mouse was placed in one end of the arm other than the one with the platform and allowed to swim freely for 1 minute in the maze. At this time, the state where all the limbs of the mouse were in one arm was defined as entry into the arm, and the number of times the mouse entered the arm without the platform before reaching the platform was recorded as the number of errors. The above 1 minute work was set as 1 trial, and 15 trials were carried out by changing the starting point for each trial. After 15 trials, mice were grouped so that the average number of errors in the last 3 trials was equal. The next day, the test compound or solvent was orally administered to the mice, and 15 trials were performed again 30 minutes after the treatment. Using the number of errors as an index, the effect on AF64A-induced spatial memory impairment was compared between the test compound administration group and the solvent group.

It was shown that AF64A-induced spatial memory impairment was improved in the group administered with the compound of the present invention as a test compound.
From the results of the above test, it was considered that Compound (I) or a pharmaceutically acceptable salt thereof is useful for the treatment and / or prevention of diseases involving Al5GABA _A receptor (such as Alzheimer's disease).
Test Example 6 The effect test on ethanol-induced fear-conditioned memory impairment was performed according to the method of Melia et al. [Neuroscience, 74, 313 (1996)].

Ethanol was administered intraperitoneally (0.75 g / kg) to SD rats (male, Charles). Thirty minutes after the ethanol treatment, the rat was placed in the experimental box of the contextual learning experimental device (Ohara Seisakusho) and presented with foot shock (0.5 mA, 1 second) three times as an unconditional stimulus. The next day, rats were placed in the same experimental box for 4 minutes to measure the onset time of freezing, an indicator of conditioned fear memory. The behavior of animals in the test cage was recorded by a CCD camera installed on the ceiling of the experiment box and analyzed with a PC system. An immobile state that continued for 2 seconds or more was defined as freezing, and the freezing rate was calculated by the following formula.
(Equation 4)
Freezing rate (%) = (Freezing time / measurement time) x 100
Test compounds or solvents were administered orally 30 minutes before ethanol treatment. Using freezing as an index, the effect on ethanol-induced fear-conditioned memory impairment was compared between the test compound-administered group and the solvent group.

As a test compound, it was shown that ethanol-induced fear-conditioned memory impairment was improved in the group administered the compound of the present invention.
From the results of the above test, compound (I) or a pharmaceutically acceptable salt thereof was found to be associated with a disease involving α5GABA _A receptor (eg, Alzheimer's disease, cognitive dysfunction associated with psychiatric / neurological disorder (eg, attention deficit hyperactivity) Disability, Schizophrenia, Bipolar Disorder, Depression, Chronic Fatigue Syndrome, etc.), Drug Addiction (such as Alcoholism), etc.).
Test Example 7 The action test on the delayed non-sample matching task was performed according to the method of Roux et al. [Pharmacology Biochemistry and Behavior, 49, 683 (1994)].

Using a 2-lever operant device (Muromachi Kikai Kogyo Co., Ltd.), you can learn that you can get food pellets (Dustless Precision Pellets 45 mg, BIO-SERV) as a reward by pushing the lever on F344 rats (male, Japan SLC). I let you. Rats who acquired at least 10 lever presses within 15 minutes were trained on delayed alternation tasks. The delayed alternation task initially presented a left or right lever and rewarded after a lever press response. Two levers were presented in the test cage after 5 seconds, and a positive selection was given when a lever different from the lever presented 5 seconds ago was pressed. If it responded to the same lever, it was misselected and not rewarded. If there was no lever press within 20 seconds, the lever was retracted without reward. The session ended with 35 trials of 2 lever presses or 30 minutes after the start. After 4 weeks of training, rats with a positive selection rate of less than 60% in the last 2 sessions were excluded from the experimental group. Next, delay times of 5, 10 and 20 seconds were provided between the 1 lever and the 2 lever presentation. The three types of delay time were randomly generated and set to be uniform throughout the session. The session ended after 36 complete trials or 30 minutes after the start. This training was conducted for 4 days.

The test compound or solvent was orally administered to the rats subjected to the above training, and the test was performed 30 minutes after the treatment. The effect on the positive selection rate of rats and the time until selection (selection reaction time) after 2 levers were presented was compared between the test compound administration group and the solvent group.
In the group administered with the compound of the present invention as the test compound, the selection reaction time was shortened without affecting the positive selectivity. As a result, it was suggested that the test compound has an attention function and an information processing ability improvement effect.

From the results of the above test, compound (I) or a pharmaceutically acceptable salt thereof is a cognitive dysfunction associated with α5GABA _A receptor-related diseases (Alzheimer's disease, Down's syndrome, cerebrovascular dementia, psychiatric / neurological disorder) (Eg, attention deficit / hyperactivity disorder, schizophrenia, bipolar disorder, depression, chronic fatigue syndrome, etc.)) were considered useful for the treatment and / or prevention.
Test Example 8 Effects on pentylenetetrazole-induced convulsions Non-selective benzodiazepine receptor inverse agonists are known to enhance pentylenetetrazole-induced convulsions [Progress in Neuropsychopharmacology and Biological Psychiatry (Progress in Neuro-Psychopharmacology and Biological Psychiatry), 12, 951 (1988)]. Then, the effect | action with respect to a pentylenetetrazole induced convulsions was examined using the compound of this invention. The test was conducted according to the method of Kawasaki et al. [Progress in Neuro-Psychopharmacology and Biological Psychiatry, Volume 20, page 1413 (1996)].

Pentylenetetrazole (40 or 60 mg / kg, Tokyo Chemical Industry) was intraperitoneally administered to ddY mice (male, Japan SLC), and the presence or absence of convulsions was recorded for 1 hour immediately after that. Test compounds or solvents were administered orally 60 minutes prior to pentylenetetrazole treatment. The effect on pentylenetetrazole-induced convulsions was compared between the test compound administration group and the solvent group.
As a test compound, it was shown that pentylenetetrazole-induced convulsions were not enhanced in the group administered with the compound of the present invention.
Test Example 9 Examination of anxiety-inducing action Non-selective benzodiazepine receptor inverse agonists are known to induce anxiety [Pharmacology Biochemistry and Behavior, Volume 32] 777 pages (1988)]. Then, the effect | action with respect to anxiety induction was examined using the compound of this invention. The test was performed according to the method of Tordera et al. [European Journal of Neuroscience, 25, 281 (2007)].

Test compounds or solvents were orally administered to ddY mice (male, Japan SLC). After 60 minutes of treatment, the mouse was placed in the light room of a light / dark box device (Unicom) and allowed to freely explore the device for 5 minutes. At this time, the state where all the limbs of the animal were in the bright room was defined as entry into the bright room, and the staying time and the number of times of entry of the animal were measured. The presence or absence of anxiety-inducing action was compared between the test compound administration group and the solvent group using the staying time in the light room and the number of times of entry as indices.

It was shown that anxiety was not induced in the group administered with the compound of the present invention as the test compound.
Compound (I) or (IA) or a pharmaceutically acceptable salt thereof can be administered alone as it is, but it is usually desirable to provide them as various pharmaceutical preparations. These pharmaceutical preparations are used for animals or humans.

The pharmaceutical preparation according to the present invention contains the compound (I) or (IA) or a pharmaceutically acceptable salt thereof as an active ingredient alone or as a mixture with any other active ingredient for treatment. Can do. In addition, these pharmaceutical preparations are produced by any method well known in the technical field of pharmaceutics by mixing the active ingredient with one or more pharmaceutically acceptable carriers.

As the administration route, it is desirable to use one that is most effective in the treatment, and examples thereof include oral administration and parenteral administration such as intravenous administration.
Examples of the dosage form include tablets and injections.
Suitable for oral administration, such as tablets, excipients such as lactose and mannitol, disintegrants such as starch, lubricants such as magnesium stearate, binders such as hydroxypropylcellulose, and surface activity such as fatty acid esters And a plasticizer such as glycerin.

Formulations suitable for parenteral administration preferably comprise a sterile aqueous solution containing the active compound that is isotonic with the blood of the recipient. For example, in the case of an injection, a solution for injection is prepared using a carrier comprising a salt solution, a glucose solution, or a mixture of salt water and a glucose solution.
Also in these parenteral agents, one kind selected from excipients, disintegrating agents, lubricants, binders, surfactants, plasticizers and diluents, preservatives, flavors and the like exemplified for oral agents. Or more auxiliary components may be added.

Compound (I) or (IA) or a pharmaceutically acceptable salt thereof is usually administered systemically or locally in an oral or parenteral form when used for the above purpose. The dose and frequency of administration vary depending on the administration form, patient age, body weight, nature or severity of symptoms to be treated, etc., but usually oral, 0.01 to 1000 mg per adult, preferably Administer once or several times daily in the range of 0.05 to 500 mg. In the case of parenteral administration such as intravenous administration, usually 0.001 to 1000 mg, preferably 0.01 to 300 mg per adult is administered once to several times a day, or intravenously in the range of 1 to 24 hours per day. Administer continuously. However, the dose and the number of doses vary depending on the various conditions described above.

EXAMPLES Hereinafter, although an Example and a reference example demonstrate this invention further more concretely, the scope of the present invention is not limited to these Examples.
The proton nuclear magnetic resonance spectrum ( ¹ H NMR) used in Examples is measured at 270 MHz or 300 MHz, and exchangeable protons may not be clearly observed depending on the compound and measurement conditions. In addition, although what is used normally is used as description of the multiplicity of a signal, br represents that it is an apparent wide signal.

1-propyl-7- [4- (pyridin-2-yl) piperazin-1-yl] pyrido [2,3-d] pyrimidin-4 (1H) -one (Compound 1)
Compound b (100 mg, 0.447 mmol) obtained in Reference Example 2 is dissolved in THF (2 mL), 1- (2-pyridyl) piperazine (0.341 mL, 2.24 mmol) is added, and a microwave synthesizer is used. The mixture was stirred at 90 ° C for 30 minutes. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform / methanol = 10/1 (volume ratio)) to give the title compound (127 mg, 81%).
¹ H-NMR (CDCl ₃ , δ ppm): 1.00 (t, J = 7.4 Hz, 3H), 1.90 (tq, J = 7.1, 7.4 Hz, 2H), 3.71-3.75 (m, 4H), 3.88-3.92 (m, 4H), 4.14 (t, J = 7.1 Hz, 2H), 6.67-6.71 (m, 2H), 6.78 (d, J = 9.1 Hz, 1H), 7.51-7.57 (m, 1H), 8.20- 8.24 (m, 2H), 8.33 (d, J = 9.1 Hz, 1H).
ESIMS m / z: [M + H] ⁺ 351.

7- [4- (Piperidin-1-yl) piperidin-1-yl] -1-propylpyrido [2,3-d] pyrimidin-4 (1H) -one (Compound 2)
In the same manner as in Example 1, the title compound (31.0 mg, 65%) was obtained using 4- (piperidin-1-yl) piperidine.
¹ H NMR (CDCl ₃ , δ ppm): 0.99 (t, J = 7.2 Hz, 3H), 1.51-1.94 (m, 10H), 1.99-2.17 (m, 2H), 2.56-2.80 (m, 5H), 3.00 (t, J = 11.9 Hz, 2H), 4.10 (t, J = 7.2 Hz, 2H), 4.56 (d, J = 13.2 Hz, 2H), 6.75 (d, J = 8.9 Hz, 1H), 8.18 ( s, 1H), 8.27 (d, J = 8.9 Hz, 1H).
ESIMS m / z: [M + H] ⁺ 356.

7- (N-methylbutylamino) -1-propylpyrido [2,3-d] pyrimidin-4 (1H) -one (compound 3)
In the same manner as in Example 1, the title compound (9.6 mg, 27%) was obtained using N-methylbutylamine.
¹ H NMR (CDCl ₃ , δ ppm): 0.94-1.05 (m, 6H), 1.38 (td, J = 14.8, 7.4 Hz, 2H), 1.63 (dt, J = 14.8, 7.4 Hz, 2H), 1.88 ( td, J = 14.8, 7.4 Hz, 2H), 3.16 (s, 3H), 3.60 (t, J = 7.4 Hz, 2H), 4.12 (t, J = 7.4 Hz, 2H), 6.62 (d, J = 9.2 Hz, 1H), 8.20-8.34 (m, 2H).
ESIMS m / z: [M + H] ⁺ 275.

1-propyl-7- [4- (pyrazin-2-yl) piperazin-1-yl] pyrido [2,3-d] pyrimidin-4 (1H) -one (compound 4)
In the same manner as in Example 1, the title compound (337 mg, 96%) was obtained using 2- (piperazin-1-yl) pyrazine.
¹ H NMR (CDCl ₃ , δ ppm): 1.01 (t, J = 7.2 Hz, 3H), 1.90 (tq, J = 7.2, 7.2 Hz, 2H), 3.77-3.86 (m, 4H), 3.87-3.98 ( m, 4H), 4.14 (t, J = 7.2 Hz, 2H), 6.78 (d, J = 9.0 Hz, 1H), 7.91-7.98 (m, 1H), 8.09-8.16 (m, 1H), 8.16-8.25 (m, 2H), 8.34 (d, J = 9.0 Hz, 1H).
ESIMS m / z: [M + H] ⁺ 352.

7- [4- (2-Hydroxyethyl) piperazin-1-yl] -1-propylpyrido [2,3-d] pyrimidin-4 (1H) -one (Compound 5)
In the same manner as in Example 1, the title compound (16.0 mg, 100%) was obtained using 2- (piperazin-1-yl) ethanol.
ESIMS m / z: [M + H] ⁺ 318.

7- [4- (Benzo [d] [1,3] dioxol-5-ylmethyl) piperazin-1-yl] -1-propylpyrido [2,3-d] pyrimidin-4 (1H) -one (Compound 6)
In the same manner as in Example 1, the title compound (13.0 mg, 65%) was obtained using 1- (benzo [d] [1,3] dioxol-5-ylmethyl) piperazine.
ESIMS m / z: [M + H] ⁺ 408.

7- (6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl) -1-propylpyrido [2,3-d] pyrimidin-4 (1H) -one (Compound 7)
In the same manner as in Example 1, the title compound (9.00 mg, 46%) was obtained using 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline.
ESIMS m / z: [M + H] ⁺ 381.

7- [2- (3,4-Dimethoxyphenyl) -N-methylethylamino] -1-propylpyrido [2,3-d] pyrimidin-4 (1H) -one (Compound 8)
In the same manner as in Example 1, the title compound (28.0 mg, 54%) was obtained using 2- (3,4-dimethoxyphenyl) -N-methylethylamine.
¹ H NMR (CDCl ₃ , δ ppm): 0.99 (t, J = 7.4 Hz, 3H), 1.89 (tq, J = 7.4, 7.4 Hz, 2H), 2.90 (t, J = 7.4 Hz, 2H), 3.06 (s, 3H), 3.85-3.87 (m, 8H), 4.15 (t, J = 7.4 Hz, 2H), 6.59-6.86 (m, 4H), 8.23-8.32 (m, 2H).
ESIMS m / z: [M + H] ⁺ 383

7- [N-Methyl-N- (2-naphthylmethyl) amino] -1-propylpyrido [2,3-d] pyrimidin-4 (1H) -one (Compound 9)
In the same manner as in Example 1, the title compound (29.0 mg, 60%) was obtained using N-methyl-N- (2-naphthylmethyl) amine.
¹ H NMR (CDCl ₃ , δ ppm): 0.70 (br s, 3H), 1.59-1.70 (m, 2H), 3.25 (s, 3H), 3.96 (br s, 2H), 5.34 (s, 2H), 6.71 (d, J = 9.1 Hz, 1H), 7.18 (d, J = 7.5 Hz, 1H), 7.41 (t, J = 7.5 Hz, 1H), 7.51-7.58 (m, 2H), 7.81 (d, J = 7.5 Hz, 1H), 7.88-8.01 (m, 2H), 8.15 (s, 1H), 8.32 (d, J = 9.1 Hz, 1H).
ESIMS m / z: [M + H] ⁺ 359.

7- (3,4-Dihydro-1H-pyrido [3,4-b] indol-2 (9H) -yl) -1-propylpyrido [2,3-d] pyrimidin-4 (1H) -one (compound 10 )
In the same manner as in Example 1, the title compound (42.0 mg, 87%) was obtained using 1,2,3,4-tetrahydro-9H-pyrido [3,4-b] indole.
¹ H NMR (CDCl ₃ , δ ppm): 1.02 (t, J = 7.0 Hz, 3H), 1.92 (tq, J = 7.0, 7.0 Hz, 2H), 2.96 (m, 2H), 4.10-4.20 (m, 4H), 4.94 (s, 2H), 6.86 (d, J = 9.3 Hz, 1H), 7.10-7.21 (m, 2H), 7.37 (d, J = 7.6 Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H), 8.19 (s, 1H), 8.27-8.37 (m, 2H).
ESIMS m / z: [M + H] ⁺ 360.

7- (Isoindoline-2-yl) -1-propylpyrido [2,3-d] pyrimidin-4 (1H) -one (Compound 11)
In the same manner as in Example 1, the title compound (306 mg, 100%) was obtained using isoindoline.
¹ H NMR (CDCl ₃ , δ ppm): 1.03 (t, J = 7.3 Hz, 3H), 1.95 (tq, J = 7.3, 7.3 Hz, 2H), 4.21 (t, J = 7.3 Hz, 2H), 4.85 (br s, 2H), 4.97 (br s, 2H), 6.63 (d, J = 8.6 Hz, 1H), 7.33-7.42 (m, 4H), 8.22 (s, 1H), 8.36 (d, J = 8.6 Hz, 1H).
ESIMS m / z: [M + H] ⁺ 307.

7- (3,5-Dimethoxyphenylamino) -1-propylpyrido [2,3-d] pyrimidin-4 (1H) -one (Compound 12)
3,5-Dimethoxyaniline (0.2 mL) was added to compound b (30.0 mg, 0.130 mmol) obtained in Reference Example 2, and the mixture was stirred at 110 ° C. for 70 minutes using a microwave reactor. The reaction solution was purified by silica gel column chromatography (chloroform / methanol = 19/1 (volume ratio)) to obtain the title compound (7.50 mg, 18%).
¹ H NMR (CDCl ₃ , δ ppm): 1.03 (t, J = 7.5 Hz, 3H), 1.91 (tq, J = 7.5, 7.5 Hz, 2H), 3.81 (s, 6H), 4.17 (t, J = 7.5 Hz, 2H), 6.29 (t, J = 2.2 Hz, 1H), 6.73 (d, J = 2.2 Hz, 2H), 6.83 (d, J = 8.8 Hz, 1H), 7.03 (s, 1H), 8.23 (s, 1H), 8.34 (d, J = 8.8 Hz, 1H).
ESIMS m / z: [M + H] ⁺ 341.

7- (5,6,7,8-tetrahydro- [1,2,4] triazolo [1,5-a] pyrazin-7-yl) -1-propylpyrido [2,3-d] pyrimidine-4 (1H ) -One (compound 13)
In the same manner as in Example 1, the title compound (21.0 mg, 50%) was obtained using 5,6,7,8-tetrahydro- [1,2,4] triazolo [1,5-a] pyrazine.
¹ H NMR (CDCl ₃ , δ ppm): 1.02 (t, J = 7.2 Hz, 3H), 1.91 (tq, J = 7.2, 7.2 Hz, 2H), 4.18 (t, J = 7.2 Hz, 2H), 4.29 (t, J = 5.3 Hz, 2H), 4.40 (t, J = 5.3 Hz, 2H), 5.05 (s, 2H), 6.89 (d, J = 8.9 Hz, 1H), 7.96 (s, 1H), 8.24 (s, 1H), 8.44 (d, J = 8.9 Hz, 1H).
ESIMS m / z: [M + H] ⁺ 312.

7- (7,8-Dimethoxy-2,3,4,5-tetrahydro-1H-benzo [c] azepin-2-yl) -1-propylpyrido [2,3-d] pyrimidin-4 (1H) -one (Compound 14)
In the same manner as in Example 1, the title compound (37.0 mg, 71%) was obtained using 7,8-dimethoxy-2,3,4,5-tetrahydro-1H-benzo [c] azepine.
¹ H NMR (CDCl ₃ , δ ppm): 1.01 (t, J = 7.4 Hz, 3H), 1.83-2.00 (m, 4H), 2.90-3.00 (m, 2H), 3.83 (s, 3H), 3.89 ( s, 3H), 3.96-4.18 (m, 4H), 4.72 (br s, 2H), 6.69 (s, 1H), 6.74 (d, J = 8.8 Hz, 1H), 6.85 (s, 1H), 8.15 ( s, 1H), 8.23 (d, J = 8.8 Hz, 1H).
ESIMS m / z: [M + H] ⁺ 395.

1-propyl-7- [4- (pyridin-3-yl) -1,2,3,6-tetrahydropyridin-1-yl] pyrido [2,3-d] pyrimidin-4 (1H) -one (compound 15)
In the same manner as in Example 1, using the compound r obtained in Reference Example 18, the title compound (44.0 mg, 95%) was obtained.
¹ H NMR (CDCl ₃ , δ ppm): 1.02 (t, J = 7.3 Hz, 3H), 1.92 (tq, J = 7.3, 7.3 Hz, 2H), 2.72 (s, 2H), 4.04 (t, J = 5.5 Hz, 2H), 4.16 (t, J = 7.3 Hz, 2H), 4.35 (br s, 2H), 6.25 (t, J = 3.5 Hz, 1H), 6.78 (d, J = 9.0 Hz, 1H), 7.27-7.33 (m, 1H), 7.67-7.72 (m, 1H), 8.20 (s, 1H), 8.34 (d, J = 9.0 Hz, 1H), 8.54 (d, J = 4.0 Hz, 1H), 8.70 (s, 1H).
ESIMS m / z: [M + H] ⁺ 348.

7- [4- (2-Furoyl) piperazin-1-yl] -1-propylpyrido [2,3-d] pyrimidin-4 (1H) -one (Compound 16)
In the same manner as in Example 1, the title compound (130 mg, 79%) was obtained using 1- (2-furoyl) piperazine.
¹ H-NMR (CDCl ₃ , δ ppm): 1.00 (t, J = 7.4 Hz, 3H), 1.82-1.95 (m, 2H), 3.83-3.87 (m, 4H), 3.95-4.04 (m, 4H) , 4.13 (t, J = 7.4 Hz, 2H), 6.54 (dd, J = 1.8, 3.5 Hz, 1H), 6.76 (d, J = 9.1 Hz, 1H), 7.12 (d, J = 3.5 Hz, 1H) , 7.53-7.45 (m, 1H), 8.21 (s, 1H), 8.35 (d, J = 9.1 Hz, 1H).
ESIMS m / z: [M + H] ⁺ 368.

1-cyclobutyl-7- (cyclobutylamino) pyrido [2,3-d] pyrimidin-4 (1H) -one (compound 17)
In the same manner as in Example 1, the title compound (95.0 mg, 83%) was obtained using Compound c and cyclobutylamine obtained in Reference Example 3.
¹ H-NMR (CDCl ₃ , δ ppm): 1.67-2.05 (m, 6H), 2.34-2.63 (m, 6H), 5.05-5.36 (m, 2H), 6.42 (d, J = 8.9 Hz, 1H) , 8.21 (d, J = 8.9 Hz, 1H), 8.32 (s, 1H).
ESIMS m / z: [M + H] ⁺ 271.

1-cyclobutyl-7- [4- (pyridin-4-yl) piperazin-1-yl] pyrido [2,3-d] pyrimidin-4 (1H) -one (compound 18)
In the same manner as in Example 1, the title compound (1.40 mg, 8%) was obtained using Compound c, 1- (pyridin-4-yl) piperazine, obtained in Reference Example 3.
ESIMS m / z: [M + H] ⁺ 363.

1-tert-Butyl-7- (6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl) pyrido [2,3-d] pyrimidin-4 (1H) -one (Compound 19)
In the same manner as in Example 1, the title compound (37.4 mg, 75%) was obtained using the compound d obtained in Reference Example 4 and 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline.
¹ H-NMR (CDCl ₃ , δ ppm): 1.91 (s, 9H), 2.94 (t, J = 5.9 Hz, 2H), 3.88 (s, 6H), 3.97 (t, J = 5.9 Hz, 2H), 4.76 (s, 2H), 6.68 (s, 1H), 6.69 (s, 1H), 6.80 (d, J = 8.9 Hz, 1H), 8.37 (d, J = 8.9 Hz, 1H), 8.50 (s, 1H ).
ESIMS m / z: [M + H] ⁺ 395.

7- (6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl) -1-methylpyrido [2,3-d] pyrimidin-4 (1H) -one (Compound 20)
In the same manner as in Example 1, the title compound (15.3 mg, 57%) was obtained using the compound e obtained in Reference Example 5 and 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline.
¹ H-NMR (CDCl ₃ , δ ppm): 2.88-2.97 (m, 2H), 3.77-3.97 (m, 11H), 4.77 (s, 2H), 6.58 (d, J = 16.5 Hz, 1H), 6.76 (s, 1H), 6.80 (d, J = 8.9 Hz, 1H), 8.26-8.32 (m, 2H).
ESIMS m / z: [M + H] ⁺ 353.

1- (2-Hydroxyethyl) -7- [4- (pyridin-2-yl) piperazin-1-yl] pyrido [2,3-d] pyrimidin-4 (1H) -one (Compound 21)
In the same manner as in Example 1, the compound (f) obtained in Reference Example 6 was used to obtain the title compound (16.0 mg, 33%).
¹ H NMR (DMSO-d ₆ , δ ppm): 3.61-3.38 (m, 4H), 3.73 (dt, J = 5.3 Hz, 2H), 3.81-3.88 (m, 4H), 4.24 (t, J = 5.3 Hz, 2H), 4.96 (t, J = 5.3 Hz, 1H), 6.67 (dd, J = 7.0, 4.8 Hz, 1H), 6.88 (d, J = 8.8 Hz, 1H), 7.05 (d, J = 8.8 Hz, 1H), 7.54-7.60 (m, 1H), 8.07 (d, J = 8.8 Hz, 1H), 8.12-8.17 (m, 1H), 8.32 (s, 1H).
ESIMS m / z: [M + H] ⁺ 353.

1-ethyl-7- (4-phenylpiperidin-1-yl) pyrido [2,3-d] pyrimidin-4 (1H) -one (compound 22)
In the same manner as in Example 1, the title compound (10.0 mg, 57%) was obtained using Compound g obtained in Reference Example 7 and 4-phenylpiperidine.
ESIMS m / z: [M + H] ⁺ 335.

1-ethyl-7- [4- (pyrazin-2-yl) piperazin-1-yl] pyrido [2,3-d] pyrimidin-4 (1H) -one (Compound 23)
In the same manner as in Example 1, the title compound (8.4 mg, 50%) was obtained using the compound g obtained in Reference Example 7 and 2- (piperazin-1-yl) pyrazine.
ESIMS m / z: [M + H] ⁺ 338.

7- (6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl) -1-ethylpyrido [2,3-d] pyrimidin-4 (1H) -one (Compound 24)
In the same manner as in Example 1, the title compound (8.80 mg, 48%) was obtained using Compound g obtained in Reference Example 7 and 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline.
ESIMS m / z: [M + H] ⁺ 367.

1-cyclopropyl-7- (6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl) pyrido [2,3-d] pyrimidin-4 (1H) -one (compound 25)
In the same manner as in Example 1, the title compound (6.80 mg, 36%) was obtained using compound h obtained in Reference Example 8 and 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline.
ESIMS m / z: [M + H] ⁺ 379.

7- (6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl) -1-isopropylpyrido [2,3-d] pyrimidin-4 (1H) -one (Compound 26)
In the same manner as in Example 1, the title compound (11.0 mg, 60%) was obtained using Compound i obtained in Reference Example 9 and 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline.
ESIMS m / z: [M + H] ⁺ 381.

1-isobutyl-7- [4- (pyrazin-2-yl) piperazin-1-yl] pyrido [2,3-d] pyrimidin-4 (1H) -one (Compound 27)
In the same manner as in Example 1, the title compound (12.0 mg, 67%) was obtained using the compound j obtained in Reference Example 10 and 2- (piperazin-1-yl) pyrazine.
ESIMS m / z: [M + H] ⁺ 366.

1- (2,2-Difluoroethyl) -7- [4- (pyridin-2-yl) piperazin-1-yl] pyrido [2,3-d] pyrimidin-4 (1H) -one (Compound 28)
In the same manner as in Example 1, the compound (k) obtained in Reference Example 11 was used to obtain the title compound (9.00 mg, 20%).
¹ H NMR (CDCl ₃ , δ ppm): 3.72-3.79 (m, 4H), 3.85-3.92 (m, 4H), 4.49 (td, J = 13.2, 4.1 Hz, 2H), 6.18 (tt, J = 56.1 , 4.1 Hz, 1H), 6.66-6.74 (m, 2H), 6.81 (d, J = 9.0 Hz, 1H), 7.51-7.58 (m, 1H), 8.19 (s, 1H), 8.21-8.26 (m, 1H), 8.32 (d, J = 9.0 Hz, 1H).
ESIMS m / z: [M + H] ⁺ 373.

7- (6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl) -1- (2-methoxyethyl) pyrido [2,3-d] pyrimidin-4 (1H) -one ( Compound 29)
In the same manner as in Example 1, the title compound (8.60 mg, 43%) was obtained using Compound 1 obtained in Reference Example 12 and 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline.
ESIMS m / z: [M + H] ⁺ 397.

7- (6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl) -2-methyl-1-propylpyrido [2,3-d] pyrimidin-4 (1H) -one (compound 30 )
In the same manner as in Example 1, the title compound (22.0 mg, 45%) was obtained using compound m obtained in Reference Example 13 and 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline.
¹ H NMR (CDCl ₃ , δ ppm): 1.08 (t, J = 7.5 Hz, 3H), 1.85 (tq, J = 7.6, 7.6 Hz, 2H), 2.63 (s, 3H), 2.92 (t, J = 5.9 Hz, 2H), 3.88 (s, 3H), 3.89 (s, 3H), 3.95 (t, J = 5.9 Hz, 2H), 4.29 (t, J = 7.6 Hz, 2H), 4.75 (s, 2H) , 6.68 (s, 1H), 6.69 (s, 1H), 6.76 (d, J = 8.8 Hz, 1H), 8.32 (d, J = 8.8 Hz, 1H).
ESIMS m / z: [M + H] ⁺ 395.

7- (6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl) -5-methyl-1-propylpyrido [2,3-d] pyrimidin-4 (1H) -one (compound 31 )
In the same manner as in Example 1, the title compound (41.0 mg, 82%) was obtained using Compound o obtained in Reference Example 15 and 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline.
¹ H NMR (CDCl ₃ , δ ppm): 1.01 (t, J = 7.3 Hz, 3H), 1.90 (tq, J = 7.3, 7.3 Hz, 2H), 2.82 (s, 3H), 2.91 (t, J = 5.9 Hz, 2H), 3.88-3.95 (m, 8H), 4.14 (t, J = 7.3 Hz, 2H), 4.72 (s, 2H), 6.52 (s, 1H), 6.69 (s, 2H), 8.12 ( s, 1H).
ESIMS m / z: [M + H] ⁺ 395.

5-Methyl-1-propyl-7- [4- (pyrazin-2-yl) piperazin-1-yl] pyrido [2,3-d] pyrimidin-4 (1H) -one (Compound 32)
In the same manner as in Example 1, the title compound (42.0 mg, 91%) was obtained using the compound o obtained in Reference Example 15 and 2- (piperazin-1-yl) pyrazine.
¹ H NMR (CDCl ₃ , δ ppm): 1.00 (t, J = 7.3 Hz, 3H), 1.88 (tq, J = 7.3, 7.3 Hz, 2H), 2.83 (s, 3H), 3.74-3.82 (m, 4H), 3.85-3.92 (m, 4H), 4.11 (t, J = 7.3 Hz, 2H), 6.52 (s, 1H), 7.93 (d, J = 2.6 Hz, 1H), 8.09-8.15 (m, 2H ), 8.17-8.21 (m, 1H).
ESIMS m / z: [M + H] ⁺ 366.

7- (6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl) -1-propyl-5- (trifluoromethyl) pyrido [2,3-d] pyrimidine-4 (1H) -On (compound 33)
In the same manner as in Example 1, the title compound (18.0 mg, 58%) was obtained using the compound q obtained in Reference Example 17 and 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline.
¹ H NMR (CDCl ₃ , δ ppm): 1.02 (t, J = 7.2 Hz, 3H), 1.90 (tq, J = 7.2, 7.2 Hz, 2H), 2.95 (t, J = 5.9 Hz, 2H), 3.89 (s, 3H), 3.90 (s, 3H), 3.97 (br s, 2H), 4.17 (t, J = 7.2 Hz, 2H), 4.77 (s, 2H), 6.70 (s, 2H), 7.10 (s , 1H), 8.17 (s, 1H).
ESIMS m / z: [M + H] ⁺ 449.

7-Phenyl-1-propylpyrido [2,3-d] pyrimidin-4 (1H) -one (Compound 34)
To a mixture of Compound b (11 mg, 0.050 mmol), phenylboronic acid (9.1 mg, 0.075 mmol) and tetrakistriphenylphosphine (5.8 mg, 0.005 mmol) obtained in Reference Example 2, 1,4-dioxane (0.2 mL) And 2 mol / L sodium carbonate aqueous solution (0.015 mmol) was added, and it stirred at 90 degreeC for 1 hour. The reaction solution was filtered, the filtrate was extracted with ethyl acetate, and the residue obtained by concentration was purified by silica gel column chromatography (chloroform: methanol = 20/1 (volume ratio)) to give the title compound (7.0 mg , 53%).
¹ H NMR (DMSO-d ₆ , δ ppm): 0.95 (t, J = 8.1 Hz, 3H), 1.86-1.94 (m, 2H), 4.09 (t, J = 8.1 Hz, 2H), 7.56-7.63 ( m, 3H), 8.19 (d, J = 8.1 Hz, 1H), 8.20-8.26 (m, 2H), 8.50 (d, J = 8.1 Hz, 1H), 8.73 (s, 1H).
ESIMS m / z: [M + H] ⁺ 266.
Reference example 1
2,6-dichloronicotinamide (compound a)
2,6-dichloronicotinic acid (5.00 g, 26.0 mmol) was dissolved in chloroform (12.5 mL), thionyl chloride (5.69 mL, 78.0 mmol) was added, and the mixture was stirred for 1.5 hours under heating to reflux. After evaporating the solvent under reduced pressure, toluene was added to the residue, and thionyl chloride was azeotroped under reduced pressure. The residue was added dropwise to ice-cooled 28% aqueous ammonia (10 mL), and the resulting crystals were collected by filtration and washed with water to give the title compound (4.67 g, 94%).
¹ H NMR (CDCl ₃ , δ ppm): 6.10 (br s, 1H), 6.69 (br s, 1H), 7.41 (d, J = 8.1 Hz, 1H), 8.24 (d, J = 8.1 Hz, 1H) .
Reference example 2
7-chloro-1-propylpyrido [2,3-d] pyrimidin-4 (1H) -one (compound b)
Process 1
Compound a (382 mg, 2.00 mmol) obtained in Reference Example 1 is dissolved in 1,4-dioxane (2.5 mL), propylamine (0.820 mL, 10.0 mmol) is added, and 110 ° using a microwave reactor. Stir at C for 30 min. Saturated aqueous sodium hydrogen carbonate solution (1 mL) was added to the reaction mixture, the mixture was filtered through diatomaceous earth, extracted with ethyl acetate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1 to 1/3 (volume ratio)) to give 6-chloro-2- (propylamino) nicotinamide (388 mg, 91%). Obtained.
¹ H NMR (CDCl ₃ , δ ppm): 0.99 (t, J = 7.2 Hz, 3H), 1.65 (tq, J = 7.2, 7.2 Hz, 2H), 3.44 (td, J = 7.2, 5.4 Hz, 2H) , 5.75 (br s, 2H), 6.45 (d, J = 8.1 Hz, 1H), 7.51 (d, J = 8.1 Hz, 1H), 8.48 (br s, 1H).
Process 2
6-Chloro-2- (propylamino) nicotinamide obtained in Step 1 (1.07 g, 5.00 mmol) is dissolved in trimethyl orthoformate (10 mL), methanesulfonic acid (0.330 mL, 5.00 mmol) is added, and 50 The mixture was stirred at ° C for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 19/1 (volume ratio)) to obtain the title compound (0.930 g, 83%).
¹ H NMR (CDCl ₃ , δ ppm): 1.02 (t, J = 7.3 Hz, 3H), 1.92 (tq, J = 7.3, 7.3 Hz, 2H), 4.24 (t, J = 7.3 Hz, 2H), 7.44 (d, J = 8.3 Hz, 1H), 8.34 (s, 1H), 8.54 (d, J = 8.3 Hz, 1H).
Reference example 3
7-chloro-1-cyclobutylpyrido [2,3-d] pyrimidin-4 (1H) -one (compound c)
In the same manner as in Reference Example 2, the title compound (1.71 g, 55%) was obtained using cyclobutylamine instead of propylamine.
¹ H NMR (CDCl ₃ , δ ppm): 1.78-1.96 (m, 2H), 2.40-2.64 (m, 4H), 5.02-5.19 (m, 1H), 7.65 (d, J = 8.1 Hz, 1H), 8.44 (d, J = 8.1 Hz, 1H), 8.74 (s, 1H).
Reference example 4
1-tert-Butyl-7-chloropyrido [2,3-d] pyrimidin-4 (1H) -one (compound d)
In the same manner as in Reference Example 2, the title compound (500 mg, 48%) was obtained using tert-butylamine instead of propylamine.
¹ H-NMR (CDCl ₃ , δ ppm): 1.89 (s, 9H), 7.44 (d, J = 8.2 Hz, 1H), 8.57 (d, J = 8.2 Hz, 1H), 8.63 (s, 1H).
Reference Example 5
7-chloro-1-methylpyrido [2,3-d] pyrimidin-4 (1H) -one (compound e)
In the same manner as in Reference Example 2, the title compound (76.8 mg, 27%) was obtained using methylamine hydrochloride instead of propylamine.
¹ H-NMR (DMSO-d _6, δ ppm): 3.72 (d, J = 0.7 Hz, 3H), 7.66 (dd, J = 0.9, 8.2 Hz, 1H), 8.44 (d, J = 0.9, 8.2 Hz , 1H), 8.67 (s, 1H).
Reference Example 6
7-Chloro-1- (2-hydroxyethyl) pyrido [2,3-d] pyrimidin-4 (1H) -one (compound f)
In the same manner as in Reference Example 2, the title compound (96.0 mg, 21%) was obtained using 2-aminoethanol instead of propylamine.
¹ H NMR (CDCl ₃ , δ ppm): 3.39 (t, J = 5.4 Hz, 1H), 4.07 (dt, J = 5.4, 4.8 Hz, 2H), 4.43 (t, J = 4.8 Hz, 2H), 7.41 (d, J = 8.3 Hz, 1H), 8.33 (s, 1H), 8.40 (d, J = 8.3 Hz, 1H).
Reference Example 7
7-Chloro-1-ethylpyrido [2,3-d] pyrimidin-4 (1H) -one (compound g)
In the same manner as in Reference Example 2, the title compound (193 mg, 61%) was obtained using 70% aqueous solution of ethylamine instead of propylamine.
¹ H NMR (CDCl ₃ , δ ppm): 1.51 (t, J = 7.3 Hz, 3H), 4.35 (q, J = 7.3 Hz, 2H), 7.44 (d, J = 8.3 Hz, 1H), 8.37 (s , 1H), 8.55 (d, J = 8.3 Hz, 1H).
Reference Example 8
7-Chloro-1-cyclopropylpyrido [2,3-d] pyrimidin-4 (1H) -one (Compound h)
In the same manner as in Reference Example 2, the title compound (193 mg, 61%) was obtained using cyclopropylamine instead of propylamine.
¹ H NMR (CDCl ₃ , δ ppm): 0.97-1.09 (m, 2H), 1.23-1.37 (m, 2H), 3.40-3.52 (m, 1H), 7.46 (d, J = 8.3 Hz, 1H), 8.46 (s, 1H), 8.52 (d, J = 8.3 Hz, 1H).
Reference Example 9
7-Chloro-1-isopropylpyrido [2,3-d] pyrimidin-4 (1H) -one (compound i)
In the same manner as in Reference Example 2, the title compound (372 mg, 83%) was obtained using isopropylamine instead of propylamine.
¹ H NMR (CDCl ₃ , δ ppm): 1.59 (d, J = 7.0 Hz, 6H), 5.43-5.57 (m, 1H), 7.44 (d, J = 8.1 Hz, 1H), 8.47 (s, 1H) , 8.57 (d, J = 8.1 Hz, 1H).
Reference Example 10
7-chloro-1-isobutylpyrido [2,3-d] pyrimidin-4 (1H) -one (compound j)
In the same manner as in Reference Example 2, the title compound (220 mg, 46%) was obtained using isobutylamine instead of propylamine.
¹ H NMR (CDCl ₃ , δ ppm): 1.00 (d, J = 7.0 Hz, 6H), 2.21-2.35 (m, 1H), 4.06, (d, J = 7.3 Hz, 2H), 7.44 (d, J = 8.3 Hz, 1H), 8.30 (s, 1H), 8.55 (d, J = 8.3 Hz, 1H).
Reference Example 11
7-Chloro-1- (2,2-difluoroethyl) pyrido [2,3-d] pyrimidin-4 (1H) -one (compound k)
In the same manner as in Reference Example 2, the title compound (103 mg, 42%) was obtained using 2,2-difluoroethylamine instead of propylamine.
¹ H NMR (CDCl ₃ , δ ppm): 4.60 (td, J = 13.3, 4.1 Hz, 2H), 6.22 (tt, J = 55.5, 4.1 Hz, 1H), 7.50 (d, J = 8.2 Hz, 1H) , 8.34 (s, 1H), 8.56 (d, J = 8.2 Hz, 1H).
Reference Example 12
7-Chloro-1- (2-methoxyethyl) pyrido [2,3-d] pyrimidin-4 (1H) -one (compound l)
In the same manner as in Reference Example 2, the title compound (193 mg, 54%) was obtained using 2-methoxyethylamine instead of propylamine.
¹ H NMR (CDCl ₃ , δ ppm): 3.34 (s, 3H), 3.70 (t, J = 4.9 Hz, 2H), 4.45 (t, J = 4.9 Hz, 2H), 7.44 (d, J = 8.1 Hz , 1H), 8.38 (s, 1H), 8.55 (d, J = 8.1 Hz, 1H).
Reference Example 13
7-Chloro-2-methyl-1-propylpyrido [2,3-d] pyrimidin-4 (1H) -one (compound m)
6-Chloro-2- (propylamino) nicotinamide (107 mg, 0.5 mmol) obtained in Step 1 of Reference Example 2 was dissolved in chloroform (5.0 mL), and acetyl chloride (0.23 mL, 3.0 mmol) was cooled with ice. And stirred for 7 hours under reflux. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 49/1 (volume ratio)) to obtain the title compound (83 mg, 70%).
¹ H NMR (CDCl ₃ , δ ppm): 1.07 (t, J = 7.5 Hz, 3H), 1.83 (tq, J = 7.5, 7.5 Hz, 2H), 2.69 (s, 3H), 4.30-4.35 (m, 2H), 7.39 (d, J = 8.2 Hz, 1H), 8.52 (d, J = 8.2 Hz, 1H).
Reference Example 14
2,6-dichloro-4-methylnicotinamide (compound n)
2,6-Dichloro-3-cyano-4-methylpyridine (560 mg, 3.00 mmol) was dissolved in 80% aqueous sulfuric acid solution (5.0 mL) and stirred at 100 ° C. for 3 hours. The reaction mixture was poured onto ice, neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (605 mg, 98%).
¹ H NMR (CDCl ₃ , δ ppm): 2.42 (s, 3H), 5.88 (br s, 1H), 6.11 (br s, 1H), 7.18 (s, 1H).
Reference Example 15
7-chloro-5-methyl-1-propylpyrido [2,3-d] pyrimidin-4 (1H) -one (compound o)
In the same manner as in Reference Example 2, the title compound (154 mg, 65%) was obtained using Compound n (205 mg, 1.0 mmol) obtained in Reference Example 14 instead of 2,6-dichloronicotinamide.
¹ H NMR (CDCl ₃ , δ ppm): 1.00 (t, J = 7.4 Hz, 3H), 1.88 (tq, J = 7.4, 7.4 Hz, 2H), 2.88 (s, 3H), 4.19 (t, J = 7.4 Hz, 2H), 7.21 (s, 1H), 8.24 (s, 1H).
Reference Example 16
2,6-dichloro-4- (trifluoromethyl) nicotinamide (compound p)
In the same manner as in Reference Example 14, the title compound (226 mg, 58%) was obtained using 2,6-dichloro-3-cyano-4- (trifluoromethyl) pyridine.
¹ H NMR (CDCl ₃ , δ ppm): 5.84 (br s, 1H), 6.14 (br s, 1H), 7.58 (s, 1H).
Reference Example 17
7-Chloro-1-propyl-5- (trifluoromethyl) pyrido [2,3-d] pyrimidin-4 (1H) -one (compound q)
In the same manner as in Reference Example 2, the title compound (22.0 mg, 21%) was obtained using the compound p (93 mg, 0.36 mmol) obtained in Reference Example 16 instead of 2,6-dichloronicotinamide.
¹ H NMR (CDCl ₃ , δ ppm): 1.03 (t, J = 7.4 Hz, 3H), 1.90 (tq, J = 7.4, 7.4 Hz, 2H), 4.24 (t, J = 7.4 Hz, 2H), 7.73 (s, 1H), 8.31 (s, 1H).
Reference Example 18
3- [1,2,3,6-Tetrahydropyridin-4-yl] pyridine (compound r)
Process 1
4- (trifluoromethylsulfonyloxy) -1,2,3,6-tetrahydropyridine-1-carboxylic acid tert-butyl ester (497 mg, obtained according to the method described in Synthesis, p993 (1991). 1.50 mmol), lithium chloride (191 mg, 4.5 mmol), pyridin-3-ylboronic acid (283 mg, 2.30 mmol), and tetrakistriphenylphosphine palladium (87.0 mg, 0.0750 mmol) in 1,2-dimethoxyethane (5.0 2 mol / L aqueous sodium carbonate solution (2.3 mL) was added, and the mixture was stirred for 1 hour under heating and refluxing in an argon atmosphere. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 19/1 to 17/3 (volume ratio)) to give 4- (pyridin-3-yl) -1,2,3,6-tetrahydropyridine. -1-carboxylic acid tert-butyl ester (390 mg, quantitative) was obtained.
¹ H NMR (CDCl ₃ , δ ppm): 1.50 (s, 9H), 2.53 (br s, 2H), 3.66 (t, J = 5.7 Hz, 2H), 4.08-4.12 (m, 2H), 6.10 (s , 1H), 7.43-7.73 (m, 2H), 8.50 (dd, J = 4.8, 1.7 Hz, 1H), 8.65 (d, J = 1.7 Hz, 1H).
Process 2
4- (Pyridin-3-yl) -1,2,3,6-tetrahydropyridine-1-carboxylic acid tert-butyl ester (423 mg, 1.62 mmol) obtained in Step 1 was added to a 1% hydrogen chloride methanol solution (5.0 The reaction mixture was dissolved in mL) and stirred for 3 days under reflux. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to obtain the title compound (200 mg, 77%).
¹ H NMR (CDCl ₃ , δ ppm): 2.42-2.52 (m, 2H), 3.13 (t, J = 5.8 Hz, 2H), 3.53-3.61 (m, 2H), 6.16-6.25 (m, 1H), 7.21-7.32 (m, 1H), 7.61-7.73 (m, 1H), 8.48 (dd, J = 4.6, 2.0 Hz, 1H), 8.65 (d, J = 2.0 Hz, 1H).

According to the present invention, it is possible to provide an α1GABA _A receptor modulator or an α5GABA _A receptor modulator containing a pyridopyrimidone derivative as an active ingredient.
In addition, various diseases involving α1GABA _A receptor that regulate α1GABA _A receptor (eg sleep disorders, depression, epilepsy, Alzheimer's disease, Down's syndrome, cerebrovascular dementia, cognitive impairment associated with psychiatric / neurological disorders) Treatment and / or prevention of central nervous disease (eg attention deficit hyperactivity disorder, schizophrenia, bipolar disorder, depression, chronic fatigue syndrome, etc.), or sedative hypnotics, anesthetics, muscles relaxants useful as such improve drug release and respiratory depression sedation by benzodiazepines, or having Arufa5GABA _a receptor modulating effects, such as Alzheimer's disease, schizophrenia, vascular dementia, drug addiction (alcohol A novel pyridopyrimidone derivative or a pharmaceutically acceptable salt thereof, which is useful for the treatment and / or prevention of such as addiction) Can.

Claims (30)

Formula (I)

[Wherein, R ¹ represents a hydrogen atom, optionally substituted lower alkyl or optionally substituted cycloalkyl, and R ² represents optionally substituted lower alkyl. , An optionally substituted cycloalkyl, an optionally substituted aralkyl or an optionally substituted aromatic heterocyclic alkyl, R ³ represents —NR ⁶ R ⁷ ( In the formula, R ⁶ and R ⁷ are the same or different, and may be a hydrogen atom, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted. Lower alkynyl, optionally substituted lower alkanoyl, optionally substituted lower alkoxy, optionally substituted cycloalkyl, optionally substituted aryl, Aralkyl optionally having a substituent, having a substituent Aroyl which may have, aliphatic heterocyclic group which may have a substituent, aromatic heterocyclic group which may have a substituent, aliphatic heterocyclic alkyl which may have a substituent Or an aromatic heterocyclic alkyl which may have a substituent, or a nitrogen-containing heterocyclic group in which R ⁶ and R ⁷ may have a substituent together with an adjacent nitrogen atom. Represents an optionally substituted aryl or an optionally substituted aromatic heterocyclic group, and R ⁴ and R ⁵ are the same or different and represent a hydrogen atom, halogen, hydroxy, Nitro, azide, amino, cyano, carboxy, formyl, lower alkyl optionally having substituent, lower alkenyl optionally having substituent, lower alkynyl optionally having substituent, substituent Lower alkanoyl optionally substituted Lower alkoxy which may have a group, cycloalkyl which may have a substituent, lower alkylamino which may have a substituent, di-lower alkylamino which may have a substituent, Aryl which may have a substituent, aralkyl which may have a substituent, aroyl which may have a substituent, aliphatic heterocyclic group which may have a substituent, substituent Represents an aromatic heterocyclic group which may have a substituent, an aliphatic heterocyclic alkyl which may have a substituent or an aromatic heterocyclic alkyl which may have a substituent.] An α1GABA _A receptor modulator comprising a derivative or a pharmaceutically acceptable salt thereof as an active ingredient. Formula (I)

[Wherein, R ¹ represents a hydrogen atom, optionally substituted lower alkyl or optionally substituted cycloalkyl, and R ² represents optionally substituted lower alkyl. , An optionally substituted cycloalkyl, an optionally substituted aralkyl or an optionally substituted aromatic heterocyclic alkyl, R ³ represents —NR ⁶ R ⁷ ( In the formula, R ⁶ and R ⁷ are the same or different, and may be a hydrogen atom, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted. Lower alkynyl, optionally substituted lower alkanoyl, optionally substituted lower alkoxy, optionally substituted cycloalkyl, optionally substituted aryl, Aralkyl optionally having a substituent, having a substituent Aroyl which may have, aliphatic heterocyclic group which may have a substituent, aromatic heterocyclic group which may have a substituent, aliphatic heterocyclic alkyl which may have a substituent Or an aromatic heterocyclic alkyl which may have a substituent, or a nitrogen-containing heterocyclic group in which R ⁶ and R ⁷ may have a substituent together with an adjacent nitrogen atom. Represents an optionally substituted aryl or an optionally substituted aromatic heterocyclic group, and R ⁴ and R ⁵ are the same or different and represent a hydrogen atom, halogen, hydroxy, Nitro, azide, amino, cyano, carboxy, formyl, lower alkyl optionally having substituent, lower alkenyl optionally having substituent, lower alkynyl optionally having substituent, substituent Lower alkanoyl optionally substituted Lower alkoxy which may have a group, cycloalkyl which may have a substituent, lower alkylamino which may have a substituent, di-lower alkylamino which may have a substituent, Aryl which may have a substituent, aralkyl which may have a substituent, aroyl which may have a substituent, aliphatic heterocyclic group which may have a substituent, substituent An aromatic heterocyclic group which may have a substituent, an aliphatic heterocyclic alkyl which may have a substituent or an aromatic heterocyclic alkyl which may have a substituent] An α5GABA _A receptor modulator comprising a derivative or a pharmaceutically acceptable salt thereof as an active ingredient. General formula (IA)

[Wherein, R ^1A represents a hydrogen atom, optionally substituted lower alkyl, or optionally substituted cycloalkyl, and R ^2A represents optionally substituted lower alkyl. , An optionally substituted cycloalkyl, an optionally substituted aralkyl or an optionally substituted aromatic heterocyclic alkyl, R ^3A represents —NR ^6A R ^7A ( In the formula, R ^6A and R ^7A are the same or different and each may have a hydrogen atom, a lower alkyl optionally having substituent (s), a lower alkenyl optionally having substituent (s), or a substituent (s). Lower alkynyl, optionally substituted lower alkanoyl, optionally substituted lower alkoxy, optionally substituted cycloalkyl, optionally substituted aryl, Aralkyl which may have a substituent, Substituent Aroyl which may have, aliphatic heterocyclic group which may have a substituent, aromatic heterocyclic group which may have a substituent, aliphatic heterocyclic group which may have a substituent Represents a ring alkyl or an optionally substituted aromatic heterocyclic alkyl, or a nitrogen-containing heterocyclic ring in which R ^6A and R ^7A may have a substituent together with the adjacent nitrogen atom Represents an optionally substituted aryl or an optionally substituted aromatic heterocyclic group, and R ^4A and R ^5A are the same or different and each represents a hydrogen atom, a halogen, Hydroxy, nitro, azide, amino, cyano, carboxy, formyl, lower alkyl optionally having substituent, lower alkenyl optionally having substituent, lower alkynyl optionally having substituent, Lower alkanoyl optionally having a substituent A lower alkoxy optionally having a substituent, a cycloalkyl optionally having a substituent, a lower alkylamino optionally having a substituent, a di-lower alkyl optionally having a substituent Amino, aryl optionally having substituent (s), aralkyl optionally having substituent (s), aroyl optionally having substituent (s), aliphatic heterocyclic group optionally having substituent (s), The aromatic heterocyclic group which may have a substituent, the aliphatic heterocyclic alkyl which may have a substituent, or the aromatic heterocyclic alkyl which may have a substituent is represented. However, when R ^2A is butyl or isobutyl and R ^5A is trifluoromethyl, R ^3A is not unsubstituted aryl] or a pharmaceutically acceptable salt thereof (however, 2-butyl Except -5-methyl-7-methylamino-1-[(2 '-(tetrazol-5-yl) biphen-4-yl) methyl] pyrido [2,3-d] pyrimidin-4 (1H) -one ). The pyridopyrimidone derivative or a pharmaceutically acceptable salt thereof according to claim 3, wherein R ^1A is a hydrogen atom. The pyridopyrimidone derivative or a pharmaceutically acceptable salt thereof according to claim 3 or 4, wherein R ^3A is -NR ^6A R ^7A (wherein R ^6A and R ^7A are as defined above). R ^3A is -NR ^6AA R ^7AA (wherein R ^6AA and R ^7AA together with an adjacent nitrogen atom form an ^optionally substituted nitrogen-containing heterocyclic group). Or the pyridopyrimidone derivative according to 4, or a pharmaceutically acceptable salt thereof. The pyridopyrimidone derivative or a pharmaceutically acceptable salt thereof according to claim 3 or 4, wherein R ^3A is tetrahydroisoquinolin-2-yl or tetrahydroisoquinolin-2-yl having 1 or 2 substituents. The pyridopyrimidone derivative or a pharmaceutically acceptable salt thereof according to claim 3 or 4, wherein R ^3A is isoindoline-2-yl or isoindoline-2-yl having 1 or 2 substituents. The pyridopyrimidone derivative according to claim 3 or 4, wherein R ^3A is piperazin-1-yl substituted with an aromatic heterocyclic group at the 4-position or tetrahydropyridin-1-yl substituted with an aromatic heterocyclic group at the 4-position; Its pharmaceutically acceptable salt. The pyridopyrimidone derivative or a pharmaceutically acceptable salt thereof according to any one of claims 3 to 9, wherein R ^2A is lower alkyl optionally having substituent (s). The pyridopyrimidone derivative or a pharmaceutically acceptable salt thereof according to any one of claims 3 to 9, wherein R ^2A is cycloalkyl which may have a substituent. The pyridopyrimidone derivative or a pharmaceutically acceptable salt thereof according to any one of claims 3 to 11, wherein R ^4A is a hydrogen atom. The pyridopyrimidone derivative or a pharmaceutically acceptable salt thereof according to any one of claims 3 to 12, wherein R ^5A is a hydrogen atom or optionally substituted lower alkyl. Any of the following pyridopyrimidone derivatives or a pharmacologically acceptable salt thereof.
1) 1-propyl-7- [4- (pyridin-2-yl) piperazin-1-yl] pyrido [2,3-d] pyrimidin-4 (1H) -one 2) 1-propyl-7- [4 -(Pyrazin-2-yl) piperazin-1-yl] pyrido [2,3-d] pyrimidin-4 (1H) -one 3) 7- (isoindoline-2-yl) -1-propylpyrido [2,3 -D] pyrimidin-4 (1H) -one 4) 1-propyl-7- [4- (pyridin-3-yl) -1,2,3,6-tetrahydropyridin-1-yl] pyrido [2,3 -D] pyrimidin-4 (1H) -one 5) 1-tert-butyl-7- (6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl) pyrido [2,3-d Pyrimidine-4 (1H) -one 6) 7- (6,7-dimethoxy 1,2,3,4-tetrahydroisoquinolin-2-yl) -2-methyl-1-propylpyrido [2,3-d] pyrimidin-4 (1H) -one 7) 7- (6,7-dimethoxy-1 , 2,3,4-Tetrahydroisoquinolin-2-yl) -5-methyl-1-propylpyrido [2,3-d] pyrimidin-4 (1H) -one 8) 5-methyl-1-propyl-7- [ 4- (pyrazin-2-yl) piperazin-1-yl] pyrido [2,3-d] pyrimidin-4 (1H) -one An α1GABA _A receptor modulator comprising the pyridopyrimidone derivative or a pharmaceutically acceptable salt thereof according to any one of claims 3 to 14 as an active ingredient. _A therapeutic and / or prophylactic agent for a disease involving an α1GABA _A receptor comprising the pyridopyrimidone derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 or 3 to 14 as an active ingredient. An α5GABA _A receptor modulator comprising as an active ingredient the pyridopyrimidone derivative according to any one of claims 3 to 14 or a pharmaceutically acceptable salt thereof. _A therapeutic and / or prophylactic agent for a disease involving an α5GABA _A receptor, comprising the pyridopyrimidone derivative or the pharmaceutically acceptable salt thereof according to any one of claims 2 and 3 to 14 as an active ingredient. _A method for modulating an α1GABA _A receptor comprising administering an effective amount of a compound according to any one of claims 1 or 3 to 14 or a pharmaceutically acceptable salt thereof. _A method for treating and / or preventing a disease involving α1GABA _A receptor, comprising administering an effective amount of the compound according to any one of claims 1 or 3 to 14 or a pharmaceutically acceptable salt thereof. _A method for modulating an α5GABA _A receptor comprising administering an effective amount of a compound according to any one of claims 2 or 3 to 14 or a pharmaceutically acceptable salt thereof. _A method for treating and / or preventing a disease involving an α5GABA _A receptor, comprising administering an effective amount of the compound according to any one of claims 2 and 3 to 14 or a pharmaceutically acceptable salt thereof. Use of the compound according to any one of claims 1 to 3 to 14 or a pharmaceutically acceptable salt thereof for the production of an α1GABA _A receptor modulator. Use of the compound according to any one of claims 1 to 3 to 14 or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic and / or prophylactic agent for a disease involving an α1GABA _A receptor. Use of the compound according to any one of claims 2 to 3 to 14 or a pharmaceutically acceptable salt thereof for the manufacture of an α5GABA _A receptor modulator. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 2 to 3-14 for the manufacture of a therapeutic and / or prophylactic agent for a disease involving an α5GABA _A receptor. An agent comprising the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 to 14 for use in modulating α1GABA _A receptor. An agent comprising the compound according to any one of claims 1 to 3 to 14 or a pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of a disease involving an α1GABA _A receptor. An agent comprising the compound or a pharmaceutically acceptable salt thereof according to any one of claims 2 to 3 to 14 for use in modulating an α5GABA _A receptor. An agent comprising the compound or a pharmaceutically acceptable salt thereof according to any one of claims 2 to 3-14 for use in the treatment and / or prevention of a disease involving an α5GABA _A receptor.