HK1236530A1

HK1236530A1 - 6,7-dihydropyrazolo[1,5-a]pyrazin-4(5h)-one compounds and their use as negative allosteric modulators of mglur2 receptors

Info

Publication number: HK1236530A1
Application number: HK17110411.1A
Authority: HK
Inventors: José Ignacio ANDRÉS-GIL; Michiel Luc Maria Van Gool; Andrés Avelino TRABANCO-SUÁREZ; Ana Isabel De Lucas Olivares; Sergio-Alvar Alonso-De Diego; Óscar DELGADO-GONZÁLEZ
Original assignee: Janssen Pharmaceutica Nv
Priority date: 2014-08-01
Filing date: 2015-07-30
Publication date: 2018-03-29

Description

6, 7-dihydropyrazolo [1,5-a ] pyrazin-4 (5H) -one compounds and their use as negative allosteric modulators of MGLUR2 receptors

__________________________________________________________________

Technical Field

The present invention relates to novel 6, 7-dihydropyrazolo [1,5-a ] pyrazin-4 (5H) -one derivatives as Negative Allosteric Modulators (NAMs) of the metabotropic glutamate receptor subtype 2 ("mGluR 2"). The invention is also directed to pharmaceutical compositions comprising such compounds, to processes for preparing such compounds and compositions, and to the use of such compounds and compositions for the prevention or treatment of disorders in which the mGluR2 subtype of metabotropic receptors is involved.

Background

The glutamatergic system in the CNS is one of the neurotransmitter systems that play a key role in several brain functions. Metabotropic glutamate receptors (mGluRs) belong to the G-protein coupled family, and eight distinct subtypes distributed in different brain regions have been identified to date (Ferraguti & Shigemoto, Cell & Tissue Research, 326:483-504, 2006). mglurs are involved in the regulation of synaptic transmission and neuronal excitability in the CNS by binding to glutamate. This activates the receptor to attract intracellular signaling partners, leading to cellular events (nisswender) & Conn (kann), Annual Review of Pharmacology & toxicy (Annual Review of Pharmacology and Toxicology) 50: 295-.

Mglurs are further divided into three subgroups based on their pharmacological and structural properties: group I (mGluR1 and mGluR5), group II (mGluR2 and mGluR3), and group III (mGluR4, mGluR6, mGluR7 and mGluR 8). Orthosteric (orthosteric) and allosteric-regulated group II ligands are believed to be potentially useful in the treatment of different neurological disorders, including psychosis, mood disorders, alzheimer's disease, and cognitive or memory deficits. This is consistent with their original localization in brain regions such as cortex, hippocampus, and striatum (Philadelphia & locoren, cell & tissue research, 326:483-504, 2006). In particular, antagonists and negative allosteric modulators are reported to have potential for the treatment of mood disorders and cognitive or memory dysfunction. This is based on the discovery of group II receptor antagonists and negative allosteric modulators in experimental animals subjected to a series of experimental conditions thought to be associated with these clinical syndromes (Goeldner et al, Neuropharmacology 64: 337-S346, 2013). For example, clinical trials (clinical trial government Identifier (NCT 01457677) retrieved on 2/19/2014) were conducted with the mGluR2/3 antagonist decoglurantRO4995819(f. hoffmann-La Roche Ltd.)) in adjuvant therapy of patients with major depressive disorder with inadequate response to ongoing antidepressant therapy. WO 2013066736 (Merck Sharp & Dohme Corp.) describes quinoline carboxamide and quinoline nitrile compounds as mGluR2 NAM. WO 2013174822 (Domain therapy) describes 4H-pyrazolo [1,5-a ] quinazolin-5-one and 4H-pyrrolo [1,2-a ] quinazolin-5-one and their mGluR2 NAM activity in vitro. WO2014064028(f. hoffman-La Roche AG) discloses one option for mGlu2/3 negative allosteric modulators and their potential use in the treatment of Autism Spectrum Disorders (ASD).

Group II receptors are located primarily at presynaptic nerve terminals, where they exert an influence on a negative feedback loop to release glutamate into the synapse (Kelmenti et al, Primary psychiatric 13:80-86,2006). Therefore, inhibition of the function of these receptors by antagonists or negative allosteric modulators removes the barrier to glutamate release, resulting in enhanced glutamatergic signaling. This effect is believed to underlie the antidepressant-like and cognitive (cognitive) effects observed in preclinical species with inhibitors of group II receptors. In addition, treatment of mice with group II orthosteric antagonists has been shown to enhance signaling by growth factors, such as Brain Derived Neurotrophic Factor (BDNF) (Koike et al, Behavioural Brain Research 238:48-52,2013). Since BDNF and other growth factors have been shown to be critically involved in mediating synaptic plasticity, this mechanism appears to contribute to the antidepressant and pro-cognitive properties of these compounds. Inhibition of mglurs of the group II receptor family is therefore considered to represent a potential therapeutic mechanism for neurological disorders including depression and cognitive or memory dysfunction.

Description of the invention

The present invention is directed to 6, 7-dihydropyrazolo [1,5-a ] pyrazin-4 (5H) -one derivatives of formula (I)

And stereoisomeric forms thereof, wherein

R¹Is phenyl or 2-pyridyl, each of which may be optionally substituted with one or more substituents each independently selected from the group consisting of: halogen, C_1-4Alkyl, monohalo-C_1-4Alkyl, polyhalo-C_1-4Alkyl, -C_1-4alkyl-OH, -CN, -C_1-4alkyl-O-C_1-4Alkyl radical, C_3-7Cycloalkyl, -O-C_1-4Alkyl, monohalo-C_1-4Alkoxy, polyhalo-C_1-4Alkoxy radical, SF₅、C_1-4Alkylthio, monohalo-C_1-4Alkylthio and polyhalo-C_1-4An alkylthio group;

R²selected from the group consisting of: phenyl and pyridyl, each of which may be optionally substituted with one or more substituents each independently selected from the group consisting of: halogen, C_1-4Alkyl, monohalo-C_1-4Alkyl, polyhalo-C_1-4Alkyl, -OH, -O-C_1-4Alkyl, -C_1-4alkyl-O-C_1-4Alkyl, monohalo-C_1-4Alkoxy, polyhalo-C_1-4Alkoxy, -C_1-4alkyl-OH, and NR^5aR^5b；

Wherein R is^5aAnd R^5bEach independently selected from hydrogen and C_1-4An alkyl group;

R³selected from hydrogen and C_1-4An alkyl group;

R⁴selected from the group consisting of: hydrogen, C_1-4Alkyl, monohalo-C_1-4Alkyl, polyhalo-C_1-4Alkyl, -C_1-4alkyl-O-C_1-4Alkyl, and-C_1-4alkyl-OH;

and N-oxides, and pharmaceutically acceptable salts and solvates thereof.

The invention also relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier or excipient.

Additionally, the present invention relates to a compound of formula (I) for use as a medicament, and to a compound of formula (I) for use in the treatment or prevention of a central nervous system disorder or disease selected from: mood disorders; delirium, dementia, amnesia and other cognitive disorders; disorders usually first diagnosed in infancy, childhood or adolescence; a substance-related disorder; schizophrenia and other psychotic disorders; a somatoform disorder; and hypersomnic sleep disorder (hypersomnic sleep disorder).

The present invention also relates to the use of a compound of formula (I) in combination with a further pharmaceutical agent for use in the treatment or prevention of a central nervous system disorder or disease selected from: mood disorders; delirium, dementia, amnesia and other cognitive disorders; disorders usually first diagnosed in infancy, childhood or adolescence; a substance-related disorder; schizophrenia and other psychotic disorders; a somatoform disorder; and hypersomnia sleep disorder.

Furthermore, the present invention relates to a process for the preparation of a pharmaceutical composition according to the invention, characterized in that a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of a compound of formula (I).

The present invention also relates to a method of treating or preventing a central nervous system disorder selected from: mood disorders; delirium, dementia, amnesia and other cognitive disorders; disorders usually first diagnosed in infancy, childhood or adolescence; a substance-related disorder; schizophrenia and other psychotic disorders; a somatoform disorder; and hypersomnic sleep disorders, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a therapeutically effective amount of a pharmaceutical composition according to the invention.

The invention also relates to a product as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of a central nervous system disorder or disease selected from: mood disorders; delirium, dementia, amnesia and other cognitive disorders; disorders usually first diagnosed in infancy, childhood or adolescence; a substance-related disorder; schizophrenia and other psychotic disorders; a somatoform disorder; and hypersomnic sleep disorder, which product comprises a compound of formula (I) and an additional pharmaceutical agent.

The present invention relates to novel 6, 7-dihydropyrazolo [1,5-a ] pyrazin-4 (5H) -one derivatives which are designed to bind irreversibly to mGluR2 receptors.

Detailed description of the invention

The invention relates in particular to compounds of formula (I) as defined above and stereoisomeric forms thereof, wherein

R¹Is phenyl or 2-pyridyl, each of which may be optionally substituted with one or two substituents each independently selected from the group consisting of: halogen, C_1-4Alkyl, monohalo-C_1-4Alkyl, polyhalo-C_1-4Alkyl, -C_1-4alkyl-O-C_1-4Alkyl, monohalo-C_1-4Alkoxy, polyhalo-C_1-4Alkoxy, -C_1-4alkyl-OH, -CN, C_3-7Cycloalkyl group, and SF₅；

R²Selected from the group consisting of: phenyl and pyridyl, each of which may be optionally substituted with one or two substituents each independently selected from the group consisting of: halogen, C_1-4Alkyl, monohalo-C_1-4Alkyl, polyhalo-C_1-4Alkyl, -OH, -O-C_1-4Alkyl, -C_1-4alkyl-O-C_1-4Alkyl, monohalo-C_1-4Alkoxy, polyhalo-C_1-4Alkoxy, -C_1-4alkyl-OH, and NR^5aR^5b；

R³selected from hydrogen and C_1-4An alkyl group;

and N-oxides, and pharmaceutically acceptable salts and solvates thereof.

In a further embodiment, the present invention relates to a compound of formula (I) as defined herein and stereoisomeric forms thereof, wherein

R¹Is phenyl or 2-pyridyl, each of which may be optionally substituted with one or two substituents each independently selected from the group consisting of: halogen, C_1-4Alkyl, monohalo-C_1-4Alkyl, polyhalo-C_1-4Alkyl, -O-C_1-4Alkyl, -C_1-4alkyl-O-C_1-4Alkyl, monohalo-C_1-4Alkoxy, and polyhalo-C_1-4An alkoxy group;

R²selected from the group consisting of: phenyl and pyridyl, each of which may be optionally substituted with one or two substituents each independently selected from the group consisting of: halogen, C_1-4Alkyl, monohalo-C_1-4Alkyl, polyhalo-C_1-4Alkyl, -O-C_1-4Alkyl, -C_1-4alkyl-O-C_1-4Alkyl, monohalo-C_1-4Alkoxy, polyhalo-C_1-4Alkoxy, and NR^5aR^5b；

R³is hydrogen;

R⁴selected from the group consisting of: c_1-4Alkyl, and-C_1-4alkyl-O-C_1-4An alkyl group;

and N-oxides, and pharmaceutically acceptable salts and solvates thereof.

R¹Is phenyl or 2-pyridyl, each of which may be optionally substituted with one or two substituents each independently selected from the group consisting of: halogen, polyhalo-C_1-4Alkyl, and-O-C_1-4An alkyl group;

R²is selected from the group consisting of: phenyl and pyridyl, each of which may be optionally substituted with one or two substituents each independently selected from the group consisting of: halogen, C_1-4Alkyl, -O-C_1-4Alkyl, and NR^5aR^5b；

R³is hydrogen;

R⁴is C_1-4An alkyl group;

and N-oxides, and pharmaceutically acceptable salts and solvates thereof.

R¹Is phenyl optionally substituted with one or two substituents each independently selected from the group consisting of: halogen, polyhalo-C_1-4Alkyl, and-O-C_1-4An alkyl group;

or R¹Is optionally polyhalo-C_1-4Alkyl-substituted 2-pyridyl;

R²selected from the group consisting of: phenyl and pyridyl, wherein the pyridyl is optionally substituted with one substituent selected from the group consisting of: halogen, C_1-4Alkyl, -O-C_1-4Alkyl, and NR^5aR^5b；

R³is hydrogen;

R⁴is C_1-4An alkyl group;

and N-oxides, and pharmaceutically acceptable salts and solvates thereof.

In a further embodiment, the invention relates to compounds of formula (I) as defined herein and stereoisomeric forms thereof, wherein R²Is substituted by an NH₂Substituted pyridyl, and R¹、R³And R⁴As defined herein.

R¹Is 4- (trifluoromethyl) phenyl or 3-chloro-4- (trifluoromethyl) phenyl;

R²is substituted by an NH₂A substituted pyridyl group;

>CR³R⁴is that>CH(CH₃)；

And N-oxides, and pharmaceutically acceptable salts and solvates thereof.

In a further embodiment, the invention relates to a compound of formula (I) as defined herein, wherein R is³Is hydrogen and R⁴Is a substituent other than hydrogen, which compound has the configuration as depicted in the following formula (I'), wherein 6, 7-dihydropyrazolo [1,5-a ] is]Pyrazin-4 (5H) -one core, R¹And R²In the plane of the figure and R⁴Protruding above the graphics plane (bonds shown in bold wedges) and the remaining variables are as defined in formula (I) herein

In a still further embodiment, the invention relates to a compound of formula (I) as defined herein, wherein R is⁴Is hydrogen and R³Is a substituent other than hydrogen (e.g., C1-4 alkyl substituent), having the configuration as depicted in formula (I ") below, wherein 6, 7-dihydropyrazolo [1,5-a ]]Pyrazin-4 (5H) -one core, R¹And R²In the plane of the figure and R³Protruding above the graphics plane (bonds shown in bold wedges) and the remaining variables are as defined in formula (I) herein

Specific compounds according to the invention include:

(7S) -3- [2- (6-amino-3-pyridinyl) ethynyl ] -7-methyl-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazin-4-one;

(7S) -3- [2- (6-amino-3-pyridinyl) ethynyl ] -5- (3-chloro-4-methoxy-phenyl) -7-methyl-6, 7-dihydropyrazolo [1,5-a ] pyrazin-4-one;

(7S) -3- [2- (6-amino-3-pyridinyl) ethynyl ] -5- (3, 4-dichlorophenyl) -7-methyl-6, 7-dihydropyrazolo [1,5-a ] pyrazin-4-one;

(7S) -3- [2- (6-amino-3-pyridinyl) ethynyl ] -7-methyl-5- [5- (trifluoromethyl) -2-pyridinyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazin-4-one;

(7S) -7-methyl-3- (2-phenylethynyl) -5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazin-4-one;

(7S) -7-methyl-3- [2- (2-methyl-4-pyridinyl) ethynyl ] -5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazin-4-one;

(7S) -7-methyl-3- [2- (6-methyl-3-pyridinyl) ethynyl ] -5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazin-4-one;

(7S) -3- [2- (2-amino-4-pyridinyl) ethynyl ] -7-methyl-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazin-4-one;

(7S) -5- (3, 4-dichlorophenyl) -3- [2- (6-methoxy-3-pyridinyl) ethynyl ] -7-methyl-6, 7-dihydropyrazolo [1,5-a ] pyrazin-4-one;

(7S) -5- (3, 4-dichlorophenyl) -7-methyl-3- [2- [6- (methylamino) -3-pyridinyl ] ethynyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazin-4-one;

(7S) -5- (3, 4-dichlorophenyl) -3- [2- (6-fluoro-3-pyridinyl) ethynyl ] -7-methyl-6, 7-dihydropyrazolo [1,5-a ] pyrazin-4-one;

(7S) -5- (3, 4-dichlorophenyl) -3- [2- [6- (dimethylamino) -3-pyridinyl ] ethynyl ] -7-methyl-6, 7-dihydropyrazolo [1,5-a ] pyrazin-4-one;

(7S) -3- [2- (6-amino-3-pyridinyl) ethynyl ] -5- [ 3-chloro-4- (trifluoromethyl) phenyl ] -7-methyl-6, 7-dihydropyrazolo [1,5-a ] pyrazin-4-one;

(7S) -3- [2- (6-amino-3-pyridinyl) ethynyl ] -5- [3- (hydroxymethyl) -4- (trifluoromethyl) phenyl ] -7-methyl-6, 7-dihydropyrazolo [1,5-a ] pyrazin-4-one;

(7S) -3- [2- (6-amino-3-pyridinyl) ethynyl ] -5- [3- (fluoromethyl) -4- (trifluoromethyl) phenyl ] -7-methyl-6, 7-dihydropyrazolo [1,5-a ] pyrazin-4-one;

(7S) -3- [2- (6-amino-3-pyridinyl) ethynyl ] -5- [ 6-methoxy-5- (trifluoromethyl) -2-pyridinyl ] -7-methyl-6, 7-dihydropyrazolo [1,5-a ] pyrazin-4-one

(7S) -5- [ 6-methoxy-5- (trifluoromethyl) -2-pyridinyl ] -7-methyl-3- [2- [6- (methylamino) -3-pyridinyl ] ethynyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazin-4-one

(7S) -5- [ 6-chloro-5- (trifluoromethyl) -2-pyridinyl ] -7-methyl-3- [2- [6- (methylamino) -3-pyridinyl ] ethynyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazin-4-one

(7S) -3- [2- [ 6-amino-5- (hydroxymethyl) -3-pyridinyl ] ethynyl ] -7-methyl-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazin-4-one

(7S) -3- [2- [ 6-amino-4- (hydroxymethyl) -3-pyridinyl ] ethynyl ] -7-methyl-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazin-4-one

(7S) -3- [2- [5- (hydroxymethyl) -3-pyridinyl ] ethynyl ] -7-methyl-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazin-4-one

(7S) -3- [2- [5- (methoxymethyl) -3-pyridinyl ] ethynyl ] -7-methyl-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazin-4-one

(7S) -3- [2- [5- (fluoromethyl) -3-pyridinyl ] ethynyl ] -7-methyl-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazin-4-one

(7S) -3- [2- [ 6-amino-5- (fluoromethyl) -3-pyridinyl ] ethynyl ] -7-methyl-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazin-4-one

(7S) -3- [2- [ 6-amino-5- (methoxymethyl) -3-pyridinyl ] ethynyl ] -7-methyl-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazin-4-one

(7S) -3- [2- (6-amino-3-pyridinyl) ethynyl ] -5- [6- (fluoromethyl) -5- (trifluoromethyl) -2-pyridinyl ] -7-methyl-6, 7-dihydropyrazolo [1,5-a ] pyrazin-4-one

(7S) -3- [2- (6-amino-3-pyridinyl) ethynyl ] -5- [ 3-fluoro-4- (trifluoromethyl) phenyl ] -7-methyl-6, 7-dihydropyrazolo [1,5-a ] pyrazin-4-one

(7S) -3- [2- (2-amino-3-pyridinyl) ethynyl ] -7-methyl-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazin-4-one

(7S) -3- [2- (6-amino-3-pyridinyl) ethynyl ] -7-methyl-5- [4- (1,2,2, 2-tetrafluoroethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazin-4-one

(7S) -3- [2- [ 6-amino-4- (methoxymethyl) -3-pyridinyl ] ethynyl ] -7-methyl-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazin-4-one

(7S) -7-methyl-3- [2- [2- (methylamino) -3-pyridinyl ] ethynyl ] -5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazin-4-one

(7S) -3- [2- [ 6-amino-4- (fluoromethyl) -3-pyridinyl ] ethynyl ] -7-methyl-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazin-4-one

(7S) -3- [2- [ 6-amino-4- (hydroxymethyl) -3-pyridinyl ] ethynyl ] -5- [ 3-chloro-4- (trifluoromethyl) phenyl ] -7-methyl-6, 7-dihydropyrazolo [1,5-a ] pyrazin-4-one

And pharmaceutically acceptable salts and solvates of such compounds.

The invention further relates to derivatives designed to bind irreversibly to the mGluR2 receptor, in particular to the allosteric pocket thereof.

In one embodiment, these compounds are of formula (I-a)

And stereoisomeric forms thereof, wherein

R²is a quilt-S (O)₂Phenyl substituted with F;

R³selected from hydrogen and C_1-4An alkyl group;

and N-oxides, and pharmaceutically acceptable salts and solvates thereof.

The title of the compounds of the present invention was generated according to the nomenclature agreed upon by the International Union of Pure and Applied Chemistry (IUPAC) and produced by AccelrysDirect, revision 8.0SP1 (Microsoft Windows 64-bit Oracle11) (8.0.100.4), OpenEye: 1.2.0. In the case of tautomeric forms, the name of the depicted tautomeric form of the structure results. However, it should be understood that other non-depicted tautomeric forms are also included within the scope of the invention.

Definition of

The symbol "C" as used herein alone or as part of another group unless otherwise specified_1-4Alkyl "defines a saturated straight or branched chain hydrocarbon group having from 1 to 4 carbon atoms, such as methyl, ethyl, 1-propyl, 1-methylethyl, butyl, 1-methyl-propyl, 2-methyl-1-propyl, 1-dimethylethyl and the like. The symbol "-C" as used herein alone or as part of another group_1-4alkyl-OH "means C as defined previously substituted at any available carbon atom with an OH group_1-4An alkyl group.

The symbol "halogen (halo or halo)" as used herein alone or as part of another group refers to fluorine, chlorine, bromine or iodine, with fluorine or chlorine being preferred.

The symbol "monohalo-C" as used herein alone or as part of another group_1-4Alkyl, polyhalo-C_1-4Alkyl "means C as defined before substituted by 1,2, 3 or, where possible, by more halogen atoms as defined before_1-4An alkyl group.

The symbol "C" as used herein_3-7Cycloalkyl "refers to saturated cyclic hydrocarbon groups having from 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Specific C_3-7The cycloalkyl group is cyclopropyl.

N-oxide forms of the compounds according to formula (I) are meant to include those compounds of formula (I) in which one or several nitrogen atoms are oxidized to the so-called N-oxide, in particular those N-oxides in which the nitrogen atom in the pyridyl group is oxidized. The N-oxide may be formed following procedures known to the skilled artisan. The N-oxidation reaction can generally be carried out by reacting the starting material of formula (I) with a suitable organic peroxide or inorganic peroxide. Suitable inorganic peroxides include, for example, hydrogen peroxide, alkali metal (alkali metal) or basic metal (alkaline metal) peroxides, such as sodium peroxide, potassium peroxide/suitable organic peroxides may include peroxy acids, such as, for example, perbenzoic acid or halogen-substituted perbenzoic acids, such as 3-chloroperoxybenzoic acid (3-chloroperbenzoic acid or 3-chloroperbenzoic acid), peroxy alkanoic acids, such as peroxyacetic acid, alkyl hydroperoxides, such as tert-butyl hydroperoxide. Suitable solvents are, for example, water, lower alkanols, such as ethanol and the like, hydrocarbons, such as toluene, ketones, such as 2-butanone, halogenated hydrocarbons, such as dichloromethane, and mixtures of such solvents.

Whenever the term "substituted" is used in the present invention, unless otherwise specified or clear from context, it is meant to indicate that one or more hydrogens (preferably from 1 to 3 hydrogens, more preferably from 1 to 2 hydrogens, more preferably 1 hydrogen) on the atom or group indicated in the expression using "substituted" is replaced by a selection from the indicated group, provided that the normal valency is not exceeded, and that the substitution results in a chemically stable compound (i.e., a compound that is sufficiently robust to withstand separation from the reaction mixture to a useful degree of purity, and sufficiently robust to withstand being formulated into a therapeutic agent).

The term "subject" as used herein refers to an animal, preferably a mammal, most preferably a human, who is or has been the subject of treatment, observation or experiment.

The term "therapeutically effective amount" as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.

As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

It will be appreciated that some compounds of formula (I) and pharmaceutically acceptable addition salts and solvates thereof may contain one or more chiral centers and exist as stereoisomeric forms.

As used herein, the term "compounds of the present invention" is meant to include compounds of formula (I) and salts and solvates thereof.

As used herein, any formula having bonds that are shown only as solid lines and not as solid or dashed wedge bonds, or otherwise represented as having a particular configuration (e.g., R, S) around one or more atoms, contemplates each possible stereoisomer, or a mixture of two or more stereoisomers.

In this context, the term "compound of formula (I)" is meant to include its stereoisomers and its tautomeric forms.

The terms "stereoisomer", "stereoisomeric form" or "stereochemically isomeric form" are used interchangeably hereinabove or hereinbelow.

The present invention includes all stereoisomers of the compounds of the invention, either in pure stereoisomeric form or in a mixture of two or more stereoisomers.

Enantiomers are stereoisomers that are non-superimposable mirror images of each other. The 1:1 mixture of enantiomeric pairs is a racemate or a racemic mixture.

Diastereomers (diastereomers) (or diastereomers) are stereoisomers of diastereomers, i.e., they are not related in mirror image form. If the compound contains a double bond, these substituents may be in the E or Z configuration.

The substituents on the divalent cyclic (partially) saturated groups may have either the cis- (cis-) or trans- (trans-) configuration, for example, if the compound comprises a disubstituted cycloalkyl group, the substituents may be in either the cis or trans configuration.

Therefore, the present invention includes enantiomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof, whenever chemically possible.

The meaning of all those terms (i.e. enantiomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof) are known to the skilled person.

The absolute configuration is specified according to the Kam-Yin Gao-prilor (Cahn-Ingold-Prelog) system. The configuration at the asymmetric atom is specified by R or S. Resolved stereoisomers whose absolute configuration is unknown can be designated (+) or (-) depending on the direction in which they rotate plane polarized light. For example, resolved enantiomers of unknown absolute configuration may be designated (+) or (-), depending on the direction in which they rotate plane polarized light.

When a particular stereoisomer is identified, this means that the stereoisomer is substantially free of, i.e., associated with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, specifically less than 2% and most preferably less than 1% of the other isomers. Thus, for example, when a compound of formula (I) is designated, for example, as (R), this means that the compound is substantially free of the (S) isomer; when a compound of formula (I) is designated e.g. as E, this means that the compound is substantially free of the Z isomer; when a compound of formula (I) is designated, for example, as cis, this means that the compound is substantially free of trans isomer.

Some compounds according to formula (I) can also exist in their tautomeric form. Such forms are intended to be included within the scope of the present invention to the extent that they may exist, although not explicitly indicated in the above formulas.

It follows that a single compound can exist in stereoisomeric and tautomeric forms.

For therapeutic use, salts of compounds of formula (I) are those in which the counterion is pharmaceutically acceptable. However, salts of pharmaceutically unacceptable acids and bases may also find use, for example, in the preparation or purification of pharmaceutically acceptable compounds. All salts, whether pharmaceutically acceptable or not, are included within the scope of the invention.

Pharmaceutically acceptable acid addition salts and base addition salts as mentioned hereinbefore and hereinafter are meant to include therapeutically active non-toxic acid addition salt and base addition salt forms which the compounds of formula (I) are capable of forming. Pharmaceutically acceptable acid addition salts may be conveniently obtained by treating the base form with such an appropriate acid. Suitable acids include, for example, inorganic acids such as hydrohalic acids (e.g., hydrochloric or hydrobromic acid), sulfuric acid, nitric acid, phosphoric acid, and the like; or organic acids such as, for example, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid (i.e., oxalic acid), malonic acid, succinic acid (i.e., succinic acid), maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclamic acid, salicylic acid, p-aminosalicylic acid, pamoic acid, and the like. Conversely, the salt form may be converted to the free base form by treatment with a suitable base.

The compounds of formula (I) containing an acidic proton may also be converted into their non-toxic metal or amine addition salt forms by treatment with suitable organic and inorganic bases. Suitable base salt forms include, for example, ammonium salts, alkali metal and alkaline earth metal salts, such as lithium, sodium, potassium, magnesium, calcium salts and the like, salts of the following organic bases: such as primary, secondary and tertiary aliphatic and aromatic amines such as methylamine, ethylamine, propylamine, isopropylamine, the four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline; benzathine (benzathine), N-methyl-D-glucamine, hydrabamine salt (hydrabamine), and salts of the following amino acids: such as for example arginine, lysine and the like. Conversely, the salt form may be converted to the free acid form by treatment with an acid.

The term solvate includes solvent addition forms as well as salts thereof which the compounds of formula (I) are capable of forming. Examples of such solvent addition forms are, for example, hydrates, alcoholates and the like.

Within the framework of the present application, an element (especially when mentioned in relation to a compound according to formula (I)) includes all isotopes and isotopic mixtures of such elements, naturally occurring or synthetically produced, in natural abundance or in an isotopically enriched form, for example²H. The radiolabeled compound of formula (I) may include a radioisotope selected from the group consisting of:³H、¹¹C、¹⁴C、¹⁸F、¹²²I、¹²³I、¹²⁵I、¹³¹I、⁷⁵Br、⁷⁶Br、⁷⁷br and⁸²br is added. Preferably, the radioisotope is selected from the group consisting of:³H、¹¹c and¹⁸F。

preparation of

The compounds according to the invention can generally be prepared by a series of steps, each of which is known to the skilled worker. In particular, these compounds can be prepared according to the following synthetic methods.

The compounds of formula (I) may be synthesized as racemic mixtures of enantiomers which can be separated from one another according to art-known resolution procedures. The compounds of formula (I) can be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. The diastereomeric salt forms are then separated, for example, by selective or fractional crystallization, and the enantiomers are liberated therefrom by base. An alternative way of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography using a chiral stationary phase or chiral Supercritical Fluid Chromatography (SFC). The pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction proceeds stereospecifically.

The absolute configuration of the compounds of the invention reported herein was determined by analysis of the racemic mixture by Supercritical Fluid Chromatography (SFC), followed by SFC comparison of one or more isolated enantiomers obtained by asymmetric synthesis, followed by Vibrational Circular Dichroism (VCD) analysis of one or more specific enantiomers.

A. Preparation of the Final Compounds

Experimental procedure 1

The final compound according to formula (I) can be prepared by Sonogashira type coupling reaction of a compound of formula (II) with an appropriate acetylene of formula (V) according to reaction conditions known to the skilled person. Such reaction conditions include the use of a palladium catalyst (e.g. bis (triphenylphosphine) palladium (II) chloride) and a copper (I) catalyst (e.g. copper (I) iodide) in the presence of a base (e.g. triethylamine) in a suitable solvent (e.g. N, N-dimethylformamide) under suitable reaction conditions (e.g. degassing the reaction mixture with an inert gas (e.g. nitrogen) for a period of time to ensure completion of the reaction, e.g. at a convenient temperature, particularly 55 ℃). The compounds of formula (V) may be obtained commercially or prepared according to procedures known in the art. In reaction scheme 1, halogen is defined as bromine or iodine and all other variables are as defined in formula (I).

Reaction scheme 1

Experimental procedure 2

Alternatively, the final compound according to formula (I) can be prepared by a Sonogashira-type coupling reaction of a compound of formula (III) with an appropriate aryl/heteroaryl halide of formula (VI) wherein X is halogen, in particular bromine or iodine, according to conditions known to the skilled person. Such reaction conditions include the use of a palladium catalyst (e.g. bis (triphenylphosphine) palladium (II) chloride) and a copper (I) catalyst (e.g. copper (I) iodide) in the presence of a base (e.g. triethylamine) in a suitable solvent (e.g. N, N-dimethylformamide) under suitable reaction conditions (e.g. degassing the reaction mixture with an inert gas (e.g. nitrogen) for a period of time to ensure completion of the reaction, e.g. at a convenient temperature, particularly 55 ℃). The compounds of formula (VI) may be obtained commercially or prepared according to procedures known in the art. In reaction scheme 2, all other variables are as defined in formula (I).

Reaction scheme 2

Experimental procedure 3

Alternatively, the final compound according to formula (I) may be prepared by Goldberg coupling reaction of a compound of formula (IV) with an appropriate aryl/heteroaryl halide of formula (VII) wherein X is halogen, in particular bromine or iodine, according to conditions known to the skilled person. Such conditions include, for example, the use of a suitable copper catalyst (e.g., copper (I) iodide), in the presence of a ligand (e.g., (+/-) -trans-1, 2-cyclohexanediamine), in the presence of a suitable base (e.g., K)₃PO₄) In a suitable solvent (e.g. 1, 4-dioxane) for a period of time and under suitable reaction conditions (e.g. at a convenient temperature, typically varying between 80 ℃ and 120 ℃, particularly 100 ℃) to ensure completion of the reaction. Can be obtained commercially or prepared according to procedures known in the art having formula (VII)) The compound of (1). In reaction scheme 3, all other variables are as defined in formula (I).

Reaction scheme 3

Experimental procedure 4

Alternatively, by a compound of formula (I-a) (wherein R is^1’Is a quilt C_1-4alkyl-OH substituted phenyl or 2-pyridyl) to prepare the final compound according to formula (I). The compound of formula (Ia) may be treated in a suitable solvent, such as for example DCM, in the presence of a fluorinating agent, such as for example (diethylamino) sulphur trifluoride, and the reaction mixture stirred at 0 ℃ for a period of time to ensure completion of the reaction. In reaction scheme 4, all variables are as defined in formula (I).

Reaction scheme 4

Experimental procedure 5

Alternatively, by a compound of formula (I-b) (wherein R is^2’Is a substituent selected from 2-halo-pyridyl group) to prepare the final compound according to formula (I). The compound of formula (I-b) is treated with an amine or alcohol in a suitable solvent, like for example ethanol (EtOH) or Tetrahydrofuran (THF), under suitable reaction conditions (e.g. heating under microwave irradiation, at convenient temperatures, in particular 130 ℃) for a period of time to ensure completion of the reaction. In reaction scheme 5, all variables are as defined in formula (I).

Reaction scheme 5

B. Preparation of intermediate compounds

Experimental procedure 6

The intermediate compound according to formula (II) may be prepared by halogenation of an intermediate of formula (VIII) with a halogenating agent, such as iodine, under suitable reaction conditions (e.g. at a convenient temperature, typically 70 ℃) in the presence of ammonium cerium (IV) nitrate and in an inert solvent, such as acetonitrile, for a period of time to ensure completion of the reaction.

The intermediate compound according to formula (VIII) may be prepared by reacting an intermediate compound of formula (IX) with a suitable aryl/heteroaryl halide of formula (VII) (when X is a halogen) with a suitable copper (I) catalyst (e.g. copper (I) iodide) (Goldberg) in the presence of a ligand (e.g. N, N' -dimethyl-ethylenediamine) in the presence of a base (e.g. sodium carbonate) in a suitable solvent (e.g. toluene or a mixture of toluene and N, N-dimethylformamide) under suitable reaction conditions (e.g. conveniently at a temperature, typically varying between 100 ℃ and 140 ℃), for a period of time to ensure completion of the reaction. The intermediate compounds of formula (VII) can be obtained commercially or prepared according to procedures known in the art.

In reaction scheme 6, halogen is defined as iodine or bromine and all other variables are as defined in formula (I).

Reaction scheme 6

Experimental procedure 7

The intermediate compound according to formula (III) may be prepared by deprotection reaction of a compound of formula (X) according to conditions known to the skilled person. The compound of formula (III) may be prepared by removing the protecting group (like for example a trimethylsilane protecting group) in (X) in the presence of a base medium (for example potassium carbonate) in an inert solvent (for example methanol or a mixture of methanol and ethyl acetate) under suitable reaction conditions (for example at a convenient temperature, typically room temperature) for a period of time to ensure completion of the reaction.

The intermediate compound according to formula (X) can be prepared by coupling reaction of a compound of formula (II) with Sonogashira type of trimethylsilylacetylene according to reaction conditions known to the skilled person. Such reaction conditions include the use of a palladium catalyst (e.g. bis (triphenylphosphine) palladium (II) chloride) and a copper (I) catalyst (e.g. copper (I) iodide), in the presence of a base (e.g. triethylamine), in a suitable solvent (e.g. N, N-dimethylformamide), under suitable reaction conditions (e.g. degassing the reaction mixture with an inert gas (e.g. nitrogen) and under suitable reaction conditions (e.g. at a convenient temperature, particularly 55 ℃) for a period of time to ensure completion of the reaction.

In reaction scheme 7, halogen is defined as iodine or bromine and all other variables are as defined in formula (I).

Reaction scheme 7

Experimental procedure 8

The intermediate compound according to formula (IV) can be prepared by Sonogashira type coupling reaction of a compound of formula (XI) with an appropriate acetylene of formula (V) according to reaction conditions known to the skilled person. Such reaction conditions include the use of a palladium catalyst (e.g. bis (triphenylphosphine) palladium (II) chloride) and a copper (I) catalyst (e.g. copper (I) iodide), in the presence of a base (e.g. triethylamine), in a suitable solvent (e.g. N, N-dimethylformamide), under suitable reaction conditions (e.g. degassing the reaction mixture with an inert gas (e.g. nitrogen) and under suitable reaction conditions (e.g. at a convenient temperature, particularly 55 ℃) for a period of time to ensure completion of the reaction.

The intermediate compound according to formula (XI) may be prepared by halogenation of an intermediate of formula (IX) with a halogenating agent (e.g. iodine) under suitable reaction conditions (e.g. at a convenient temperature, typically 70 ℃) in the presence of cerium (IV) ammonium nitrate and in an inert solvent (e.g. acetonitrile) for a period of time to ensure completion of the reaction.

In reaction scheme 8, halogen is defined as iodine or bromine and all other variables are as defined in formula (I).

Reaction scheme 8

Experimental procedure 9

The intermediate compound of formula (IX) may be prepared by removing the protecting group (e.g. the tert-butoxycarbonyl group) in the intermediate of formula (XII) for a period of time to ensure completion of the reaction, for example in the presence of an acidic medium (e.g. hydrochloric acid) in an inert solvent (e.g. 1, 4-dioxane) under suitable reaction conditions (e.g. at a convenient temperature, typically 80 ℃), followed by treatment with a base (e.g. sodium carbonate or sodium bicarbonate) under suitable reaction conditions (e.g. at a convenient temperature, typically varying between 0 ℃ and 40 ℃) for a period of time to ensure completion of the reaction.

An intermediate compound of formula (XII) (wherein R⁶Is C_1-4Alkyl and PG is oneProtecting groups such as t-butoxycarbonyl groups) may be prepared by: the Mitsunobu reaction between a compound of formula (XIII) and a suitable alcohol of formula (XIV) in the presence of a suitable triarylphosphine, for example triphenylphosphine, or a suitable trialkylphosphine, and a suitable dialkylazodicarboxylate reagent, for example di-tert-butylazodicarboxylate, in a suitable inert solvent, for example tetrahydrofuran, under suitable reaction conditions, for example at a convenient temperature, typically room temperature, for a period of time to ensure completion of the reaction.

Intermediate compounds of formula (XIII) or (XIV) can be obtained commercially or synthesized according to literature procedures. In reaction scheme 9, R⁶Is C_1-4Alkyl, PG is a protecting group and all other variables are as defined in formula (I).

Reaction scheme 9

To obtain the HCl salt forms of these compounds, several procedures known to those of ordinary skill in the art can be used. In a typical procedure, for example, the free base can be dissolved in DIPE or Et₂O and subsequently, dropwise addition of a 6N HCl solution in 2-propanol, or in Et₂1N HCl solution in O. The mixture is typically stirred for 10 minutes, and then the product can be filtered off. The HCl salt is typically dried in vacuo.

It will be appreciated by those of ordinary skill in the art that in the processes described above, it may be desirable to block the functional groups of the intermediate compound by protecting groups. In case the functional group of the intermediate compound is blocked by a protecting group, it may be deprotected after one reaction step.

Pharmacology of

The compounds provided in the present invention are Negative Allosteric Modulators (NAMs) of metabotropic glutamate receptors, in particular they are negative allosteric modulators of mGluR 2. The compounds of the invention do not appear to bind to the glutamate recognition site, orthosteric ligand site, within the seven transmembrane regions of the receptor, but instead bind to allosteric sites. In the presence of glutamate, these compounds of the invention reduce mGluR2 responses. The compounds provided in the present invention are expected to act at mGluR2 by virtue of their ability to reduce the response of such receptors to glutamate, thereby attenuating the response of the receptor.

As used herein, the term "treatment" is intended to refer to all processes in which there may be a slowing, interrupting, arresting or stopping of the progression of a disease or the relief of symptoms, but does not necessarily indicate the total elimination of all symptoms.

The present invention therefore relates to a compound according to general formula (I), or a stereoisomeric form thereof, or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, in particular a compound of formula (I), or a stereoisomeric form thereof, or a pharmaceutically acceptable salt or solvate thereof, for use as a medicament.

The invention also relates to the use of a compound according to general formula (I), or a stereoisomeric form thereof, or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, in particular a compound of formula (I), or a stereoisomeric form thereof, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to the invention for the manufacture of a medicament.

The present invention also relates to a compound according to general formula (I), or a stereoisomeric form thereof, or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, in particular a compound of formula (I), or a stereoisomeric form thereof, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to the present invention, for use in the treatment or prevention, in particular treatment, of a disorder in a mammal, including a human, which is affected by or facilitates the neuromodulatory effect of an allosteric modulator, in particular a negative allosteric modulator thereof, of mGluR 2.

The invention also relates to the use of a compound according to general formula (I), or a stereoisomeric form thereof, or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, in particular a compound of formula (I), or a stereoisomeric form thereof, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to the invention for the manufacture of a medicament for the treatment or prevention, in particular treatment, of a disorder (influenced by or assisting in the neuromodulation of allosteric modulators of mGluR2, in particular negative allosteric modulators thereof), in a mammal, including a human.

The present invention also relates to a compound according to general formula (I), or a stereoisomeric form thereof, or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, in particular a compound of formula (I) or a stereoisomeric form thereof, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to the invention for use in the treatment, prevention, amelioration, control of or reducing the risk of various neurological and psychiatric disorders which are affected or assisted by the neuromodulatory effect of negative allosteric modulators of mGluR2 in mammals, including humans.

Furthermore, the present invention relates to the use of a compound according to general formula (I), or a stereoisomeric form thereof, or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, in particular a compound of formula (I), or a stereoisomeric form thereof, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to the present invention for the manufacture of a medicament for the treatment, prevention, amelioration, control of a variety of neurological and psychiatric disorders, or reduction of risk thereof, affected or assisted by the neuromodulatory effect of negative allosteric modulators of mGluR2, in mammals, including humans, in relation to glutamate dysfunction.

In particular, neurological and psychiatric disorders associated with glutamate dysfunction include one or more of the following central nervous system disorders or diseases: mood disorders; delirium, dementia, amnesia and other cognitive disorders; disorders usually first diagnosed in infancy, childhood or adolescence; a substance-related disorder; schizophrenia and other psychotic disorders; a somatoform disorder; and hypersomnia sleep disorder.

In particular, the central nervous system disorder is a psychiatric disorder selected from the group of: schizophrenia (particularly in antipsychotic-stabilized patients), schizophreniform disorders, schizoaffective disorders, delusional disorders, brief psychotic disorders, and substance-induced psychotic disorders.

In particular, the central nervous system disorder is a substance-related disorder selected from the group of: alcohol dependence, alcohol abuse, amphetamine dependence, amphetamine abuse, caffeine dependence, caffeine abuse, cannabis dependence, cannabis abuse, cocaine dependence, cocaine abuse, hallucinogen dependence, hallucinogen abuse, nicotine dependence, nicotine abuse, opioid dependence, opioid abuse, phencyclidine dependence, and phencyclidine abuse.

In particular, the central nervous system disorder is a mood disorder selected from the group of: major depressive disorder, depression, treatment-refractory depression, dysthymic disorder, circulatory mood disorder, and substance-induced mood disorder.

In particular, the central nervous system disorder is a disorder usually first diagnosed in infancy, childhood or adolescence selected from: mental retardation, learning disorders, motor skill disorders, communication disorders, attention deficit, and disruptive behavior disorders (e.g., attention deficit/hyperactivity disorder (ADHD)). An additional disorder that is often first diagnosed in infancy, childhood, or adolescence is autistic disorder.

Specifically, the central nervous system disorder is a cognitive disorder selected from the group of dementia, particularly dementia of the alzheimer's type, vascular dementia, dementia due to HIV disease, dementia due to head trauma, dementia due to parkinson's disease, dementia due to huntington's disease, dementia due to pick's disease, dementia due to creutzfeldt-jakob disease, and substance-induced persisting dementia.

In particular, the central nervous system disorder is a amnestic disorder, such as substance-induced persisting amnestic disorder.

As already mentioned above, the term "treatment" does not necessarily indicate a total elimination of all symptoms, but may also refer to symptomatic treatment in any of the disorders mentioned above. In particular, symptoms that may be treated include, but are not limited to, memory impairment (particularly in dementia or in major depressive disorder), age-related cognitive decline, mild cognitive impairment, and depressive symptoms.

Of the disorders mentioned above, the treatment of dementia, major depressive disorder, depression, treatment-resistant depression, attention deficit/hyperactivity disorder and schizophrenia (especially in antipsychotic-stable patients) is of particular importance.

The fourth edition of the American psychiatric Manual of mental disorders (DSM-IV) provides a Diagnostic tool for the identification of the disorders described herein. One of ordinary skill in the art will recognize that alternative glosses, taxonomies of diseases, and classification systems exist for the neurological and psychiatric disorders described herein, and these are developed as medicine and science advances.

The skilled artisan will be familiar with alternative glossaries, disease taxonomies, and classification systems for diseases or conditions referred to herein. For example, "american psychiatric association: diagnostic and statistical handbook of psychiatric disorders, fifth edition, Arlington, Va, American psychiatric Association, 2013 "(DSM-5)^TM) Use is made of terms such as depressive disorder, in particular major depressive disorder, persistent depressive disorder (dysthymia), substance-drug-induced depressive disorder; neurocognitive disorder (NCD) (both severe and moderate)) In particular neurocognitive disorders due to alzheimer's disease, vascular NCDs (e.g. vascular NCDs manifested as multiple infarctions), NCDs due to HIV infection, NCDs due to Traumatic Brain Injury (TBI), NCDs due to parkinson's disease, NCDs due to huntington's disease, frontotemporal NCDs, NCDs due to prion disease, and substance/drug induced NCDs; neurodevelopmental disorders, in particular intellectual disabilities, specific learning disorders, neurodevelopmental dyskinesia, communication disorders, and attention deficit/hyperactivity disorder (ADHD); substance-related and addictive disorders, particularly alcohol use disorders, amphetamine use disorders, cannabis use disorders, cocaine use disorders, other hallucinogen use disorders, tobacco use disorders, opioid use disorders, and phencyclidine use disorders; schizophrenia spectrum and other psychotic disorders, in particular schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, substance/drug induced psychotic disorder; somatic disorder; disorders of lethargy; and circulatory mood disorder (the disorder is in DSM-5)^TMFalls under bipolar and associated obstacle classification). The skilled person may use such terms as alternative nomenclature for some of the diseases or conditions mentioned herein. Additional neurodevelopmental disorders include Autism Spectrum Disorder (ASD), according to DSM-5^TMSuch disorders encompass disorders previously known by the terms early childhood autism, canary's autism, high functional autism, atypical autism, pervasive developmental disorders not otherwise specified, childhood disintegrative disorders (childhood disintegrative), and Asperger's disorder. In particular, the disorder is autism. Indicators associated with ASD include those in which the individual has a genetic disorder, such as Rett syndrome or fragile X syndrome.

The present invention therefore also relates to a compound according to general formula (I), or a stereoisomeric form thereof, or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, in particular a compound of formula (I), or a stereoisomeric form thereof, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of any one of the diseases mentioned hereinbefore.

The present invention also relates to a compound according to general formula (I), or a stereoisomeric form thereof, or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, in particular a compound of formula (I), or a stereoisomeric form thereof, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of any one of the diseases mentioned above.

The present invention also relates to a compound according to general formula (I), or a stereoisomeric form thereof, or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, in particular a compound of formula (I), or a stereoisomeric form thereof, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment or prevention, in particular treatment, of any one of the diseases mentioned hereinbefore.

The invention also relates to the use of a compound according to general formula (I), or a stereoisomeric form thereof, or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, in particular a compound of formula (I), or a stereoisomeric form thereof, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment or prevention of any one of the disease conditions mentioned hereinbefore.

The compounds of the present invention may be administered to a mammal, preferably a human, in order to treat or prevent any of the diseases mentioned hereinbefore.

In view of the utility of the compounds of formula (I), there is provided a method of treating warm-blooded animals, including humans, suffering from any one of the diseases mentioned hereinbefore, and a method of preventing warm-blooded animals, including humans, from any one of the diseases mentioned hereinbefore.

The method comprises administering (i.e. systemically or topically, preferably orally) a therapeutically effective amount of a compound of formula (I), a stereoisomeric form thereof, or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, in particular a compound of formula (I) or a stereoisomeric form thereof, or a pharmaceutically acceptable salt or solvate thereof, to warm-blooded animals, including humans.

The present invention therefore also relates to a method for the prophylaxis and/or treatment of any of the diseases mentioned hereinbefore, which method comprises administering to a subject in need thereof a therapeutically effective amount of a compound according to the invention.

One of ordinary skill in the art will recognize that a therapeutically effective amount of a NAM of the invention is an amount sufficient to modulate the activity of mGluR2, and that this amount will vary depending on, among other factors, the type of disorder, the concentration of the compound in the therapeutic formulation, and the condition of the patient. Generally, the amount of NAM to be administered as a therapeutic for the treatment of diseases in which modulation of mGluR2 is beneficial (e.g. the disorders described herein) will be at the discretion of the attending physician.

Generally, a suitable dose is a dose that results in a concentration of NAM at the treatment site in the range of 0.5nM to 200 μ Μ and more commonly 5nM to 50 μ Μ. To achieve these therapeutic concentrations, patients in need of treatment appear to be administered daily the following therapeutically effective amounts: from about 0.01mg/kg to about 50mg/kg body weight, preferably from about 0.01mg/kg to about 25mg/kg body weight, more preferably from about 0.01mg/kg to about 10mg/kg body weight, more preferably from about 0.01mg/kg to about 2.5mg/kg body weight, even more preferably from about 0.05mg/kg to about 1mg/kg body weight, more preferably from about 0.1 to about 0.5mg/kg body weight. The amount of a compound according to the invention (also referred to herein as an active ingredient) required to achieve a therapeutic effect will vary (of course-on an as-matter basis) with the particular compound, the route of administration, the age and condition of the recipient, and the particular disorder or disease being treated. The method of treatment may also include administering the active ingredient on a regimen of between once and four intakes per day. In these methods of treatment, it is preferred to formulate the compounds according to the invention prior to entry. Suitable pharmaceutical formulations are prepared by known procedures using well known and readily available ingredients, as described below.

The compounds of the invention may be used in combination with one or more other drugs in the treatment, prevention, control, amelioration, or reduction of risk of diseases or conditions for which compounds of formula (I) or other drugs may have utility, where the drugs in combination are safer or more effective than either drug used alone. Examples of such combinations include such combinations of a compound of the invention with one or more antipsychotic agents, NMDA receptor antagonists (e.g., memantine), NR2B antagonists, acetylcholinesterase inhibitors (e.g., donepezil, galantamine, physostigmine, and rivastigmine), and/or antidepressant neurotransmitter reuptake inhibitors. Specific combinations include a compound of the invention in combination with an antipsychotic agent, or a compound of the invention in combination with memantine and/or an NR2B antagonist.

Pharmaceutical composition

The invention also provides compositions for use in the prevention or treatment of diseases in which modulation of mGluR2 receptors is beneficial, such as the disorders described herein. While it is possible for the active ingredient to be administered alone, it is preferred that it be presented in the form of a pharmaceutical composition. Accordingly, the present invention also relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and, as active ingredient, a therapeutically effective amount of a compound according to the invention, in particular a compound according to formula (I), an N-oxide, a pharmaceutically acceptable salt, a solvate thereof or a stereochemically isomeric form thereof, more in particular a compound according to formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof or a stereochemically isomeric form thereof. The carrier or diluent must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.

The compounds according to the present invention may be formulated into a variety of pharmaceutical forms for administration purposes, in particular compounds according to formula (I), the N-oxides, the pharmaceutically acceptable salts, the solvates and the stereochemically isomeric forms thereof, more in particular compounds according to formula (I), the pharmaceutically acceptable salts, the solvates and the stereochemically isomeric forms thereof, or any subgroup or combination thereof. As suitable compositions, all compositions usually used for systemic administration of drugs can be mentioned.

The pharmaceutical compositions of the present invention may be prepared by any method well known in the art of pharmacy, for example using methods such as those described in narro (Gennaro) et al. Remington's Pharmaceutical sciences (18 th edition, Mack Publishing Company, 1990, see especially section 8: Pharmaceutical formulations and their Manufacture (Part 8: Pharmaceutical preparations and the manufacturing of the same)). To prepare the pharmaceutical compositions of this invention, a therapeutically effective amount of the particular compound, optionally in salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier or diluent which may take a wide variety of forms depending on the form of preparation desired for administration. It is desirable that these pharmaceutical compositions are in a single dosage form particularly suitable for oral, topical, rectal, or transdermal administration, by parenteral injection, or by inhalation. For example, in preparing such compositions in oral dosage form, any of the usual pharmaceutical media may be employed, in the case of oral liquid preparations (such as, for example, suspensions, syrups, elixirs, emulsions and solutions), such as, for example, water, glycols, oils, alcohols and the like; or solid carriers such as, for example, starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Oral administration is preferred because of the ease of administration, and tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will typically comprise sterile water, at least in large part, but may also comprise other ingredients, such as surfactants to aid solubility. Injectable solutions, for example, may be prepared in which the carrier comprises a physiological saline solution, a glucose solution, or a mixture of physiological saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations. In compositions suitable for transdermal administration, the carrier may optionally include a penetration enhancer and/or suitable wetting agent, optionally in combination with small proportions of suitable additives of any nature which do not introduce significant deleterious effects on the skin. The additives may facilitate administration to the skin and/or may aid in the preparation of the desired composition. These compositions can be administered in different ways, e.g. as a transdermal patch, as drops (spot-on), as an ointment.

It is particularly advantageous to formulate the above pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form, as used herein, refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets (powderpackets), wafers, suppositories, injectable solutions or suspensions and the like, teaspoonful, tablespoonful and segregated multiples thereof.

Since the compounds according to the invention are orally administrable compounds, pharmaceutical compositions comprising auxiliary compounds for oral administration are particularly advantageous.

In order to enhance the solubility and/or stability of the compounds of formula (I) in pharmaceutical compositions, it is advantageous to employ alpha-, beta-or gamma-cyclodextrins or derivatives thereof, in particular hydroxyalkyl-substituted cyclodextrins, such as 2-hydroxypropyl-beta-cyclodextrin or sulfobutyl-beta-cyclodextrin. Auxiliary solvents, such as alcohols, may also improve the solubility and/or stability of the compounds according to the invention in pharmaceutical compositions.

As is well known to those of ordinary skill in the art, the precise dose and frequency of administration will depend on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight, sex, extent of disease and general physical condition of the particular patient, as well as other drugs that the individual may take. Furthermore, it is apparent that the effective daily amount may be reduced or increased depending on the response of the subject being treated and/or depending on the evaluation of the physician prescribing the compounds of the instant invention.

Depending on the mode of administration, the pharmaceutical composition will comprise from 0.05 to 99% by weight, preferably from 0.1 to 70% by weight, more preferably from 0.1 to 50% by weight of the active ingredient, and from 1 to 99.95% by weight, preferably from 30 to 99.9% by weight, more preferably from 50 to 99.9% by weight of a pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition.

The amount of compound of formula (I) that can be combined with a carrier material to produce a single dosage form will vary depending upon the disease being treated, the type of mammal, and the particular mode of administration. However, as a general guide, unit doses of these compounds suitable for the invention may, for example, preferably contain between 0.1mg and about 1000mg of the active compound. Preferred unit doses are between 1mg and about 500 mg. More preferred unit doses are between 1mg and about 300 mg. Even more preferred unit doses are between 1mg to about 100 mg. Such unit doses may be administered more than once a day, for example 2, 3,4, 5 or 6 times a day, but preferably 1 or 2 times a day, such that for a 70kg adult the total dose per administration ranges from 0.001 to about 15mg per kg subject body weight. The preferred dose is 0.01 to about 1.5mg per kg body weight of the subject per administration, and such therapy may last for many weeks or months, and in some cases, for many years. However, as is well understood by those skilled in the art, it will be understood that the specific dose level for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed; the age, weight, general health, sex, and diet of the individual being treated; time and route of administration; the rate of excretion; other drugs that have been previously administered; and the severity of the particular disease undergoing treatment.

Typical doses may be in the form of a tablet of 1mg to about 100mg or 1mg to about 300mg taken once or more a day, or a time-release capsule or tablet taken once a day and containing a proportionally higher amount of the active ingredient. The time-release effect can be obtained by capsule materials that dissolve at different pH values, by slow-release capsules caused by osmotic pressure, or by any other known means of controlled release.

As will be understood by those skilled in the art, it may be necessary in some instances to use dosages outside of these ranges. Further, it should be noted that the clinician or treating physician will know how and when to initiate, interrupt, adjust, or terminate therapy in conjunction with individual patient responses.

As already mentioned, the present invention also relates to a pharmaceutical composition comprising a compound according to the invention and one or more other drugs for use as a medicament or for use in the treatment, prevention, control, amelioration or reduction of risk of a disease or condition for which a compound of formula (I) or other drug may have utility. Also contemplated is the use of such a composition for the manufacture of a medicament and the use of such a composition for the manufacture of a medicament for the treatment, prevention, control, amelioration or reduction of risk of a disease or condition for which a compound of formula (I) or other medicament may have utility. The invention also relates to a combination of a compound according to the invention and an additional drug selected from the group of: antipsychotics; NMDA receptor antagonists (e.g., memantine); NR2B antagonists; acetylcholinesterase inhibitors (e.g., donepezil, galantamine, physostigmine, and rivastigmine) and/or antidepressant neurotransmitter reuptake inhibitors. In particular, the invention also relates to a combination of a compound according to the invention and one or more antipsychotics, or to a combination of a compound according to the invention and memantine and/or an NR2B antagonist. The invention also relates to such a combination for use as a medicament. The invention also relates to a product comprising (a) a compound according to the invention, an N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof, in particular a pharmaceutically acceptable salt thereof or a solvate thereof, and (b) an additional component selected from: an antipsychotic, an NMDA receptor antagonist (e.g. memantine), an NR2B antagonist, an acetylcholinesterase inhibitor and/or one or more antidepressant neurotransmitter re-uptake inhibitor, as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of a disorder in a mammal, including a human, whose treatment or prevention is affected or facilitated by the neuromodulatory effect of an mGluR2 allosteric modulator, in particular a negative mGluR2 allosteric modulator. More specifically, the additional component (b) is selected from one or more antipsychotics or memantine and/or an NR2B antagonist. The different drugs of such a combination or product may be combined in a single formulation together with a pharmaceutically acceptable carrier or diluent, or they may each be present in separate formulations together with a pharmaceutically acceptable carrier or diluent.

The following examples are intended to illustrate but not limit the scope of the invention.

Chemistry

Some methods for preparing compounds of the invention are shown in the examples below. Unless otherwise indicated, all starting materials were obtained from commercial suppliers and used without further purification.

Hereinafter, "CI" means chemical ionization; "CSH" means a charged surface hybrid; "DAD" means a diode array detector; "THF" means tetrahydrofuran; "Et₃N "means triethylamine; "DIPE" means diisopropylAn ether; "DMF" means N, N-dimethylformamide; "Et₂O "means diethyl ether; "EtOAc" means ethyl acetate; "DCM" means dichloromethane; "DMSO" means dimethylsulfoxide; "L" means liter; "LRMS" means low resolution mass spectrometry/mass spectrometry; "HPLC" means high performance liquid chromatography; "HRMS" means high resolution mass spectrometry/mass spectrometry; "mL" or "mL" means milliliters; "NH₄Ac "means ammonium acetate; "EtOH" means ethanol; "ES" means electrospray; "Xantphos" means 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene; "MeOH" means methanol; "eq" means equivalent; "RP" means inverse; "RT" or "RT" means room temperature; "m.p." means melting point; "min" means minutes; "h" means hours; "RRHD" means fast resolution high definition; "s" means seconds; "TOF" means time of flight; "sat." means saturated; "QTOF" means quadrupole-time of flight; "SFC" means supercritical fluid chromatography; "sol." means a solution; "SQD" means a single quadrupole detector; by "UPLC" is meant ultra performance liquid chromatography.

The microwave-assisted reaction is carried out in a single-mode reactor Initiator^TMSixty EXP microwave reactor (Biotage AB) or in a multimode reactor MicroSYNTH Labstation (Milestone)).

Thin Layer Chromatography (TLC) was performed on silica gel 60F254 plates (Merck) using reagent grade solvents. Open column chromatography on silica gel, particle size, using standard techniquesMesh 230-. Automated flash column chromatography was performed on different flash systems on irregular gels (forward single use flash columns) from different vendors using easy connect columns.

Nuclear Magnetic Resonance (NMR): for many compounds, will¹H NMR spectroscopy was performed on a Bruker Avance III, Bruker DPX-400 or Bruker AV-500 spectrometer with standard pulse sequencesRecord, operate at 400MHz and 500MHz, respectively. Chemical shifts () are reported in parts per million (ppm) from the low field of Tetramethylsilane (TMS) used as an internal standard.

Synthesis of intermediate Compounds

Intermediate 1(I-1)

To a solution of 1-H-pyrazole-3-carboxylic acid (1.93g, 17.22mmol) in EtOH (20mL) was added sulfuric acid (10mL, 187.6 mmol). The mixture was stirred at 90 ℃ for 15h, then allowed to cool to room temperature and the solvent was evaporated in vacuo. The residue is poured into water and washed with K₂CO₃The solution was basified and extracted with EtOAc. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated in vacuo to yield intermediate compound I-1(2.28g, 93% purity, 94%) as a white solid, which was used in the next step without further purification.

Intermediate 2(I-2)

Intermediate I-1(100g, 0.68mol), N-iodosuccinimide (213.5g, 0.95mol) were dissolved in DCM (2L). The mixture was stirred at room temperature for 24 h. With Na₂S₂O₃And Na₂CO₃The mixture was treated with a saturated solution of DCM and extracted with DCM. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated in vacuo to yield intermediate compound I-2(160g, 85%) as a white solid.

Intermediate 3(I-3)

To a stirred solution of (R) - (-) -1-amino-2-propanol in DCM (50mL) was added di-tert-butyl dicarbonate (58.1g, 266.3mmol) in DCM (50mL) at 0 deg.C under nitrogen. The mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with cold water and extracted with DCM. The organic layer was separated and dried (Na)₂SO₄) Filtered and the solvent evaporated in vacuo to yield intermediate I-3(47g, quantitative) as a colorless oil. The product was used in the next step without further purification.

Intermediate 4(I-4)

To a stirred solution of intermediate I-2(3g, 11.28mmol), intermediate I-3(4.44g, 22.55mmol) and triphenylphosphine (5.32g, 20.3mmol) in THF (56mL) under nitrogen was added di-tert-butyl azodicarboxylate (4.67g, 20.3 mmol). The mixture was stirred at room temperature for 5 h. The solvent was evaporated in vacuo and the crude product was triturated with DIPE. The solid was filtered and the filtrate was evaporated in vacuo. The crude product was purified by flash column chromatography (silica; EtOAc in heptane, 0/100 to 30/70). The desired fractions were collected and the solvent was evaporated in vacuo to afford intermediate I-4(4.9g, 91% purity, 93%) as a colorless oil.

Intermediate 5(I-5)

Intermediate compound I-5 was synthesized following a similar pathway as described for intermediate I-4. Starting from intermediate I-1(25.82g, 184.25mmol) and intermediate I-3(47.16g, 239.5mmol), intermediate I-5(123g, quantitative) was obtained as a yellow oil, which was used in the next step without further purification.

Intermediate 6(I-6)

To a solution of intermediate I-4(4.2g, 9.63mmol) in acetonitrile (20mL) was added a 4M HCl solution in 1, 4-dioxane (10mL, 40 mmol). The mixture was stirred at 80 ℃ for 2 h. The solvent was evaporated in vacuo to give intermediate compound I-6(3.5g, 97%).

Intermediate 7(I-7)

Intermediate compound I-7 was synthesized following a similar pathway as described for intermediate I-6. Starting from intermediate I-5(54.79g, 184.25mmol) and 4M HCl solution in 1, 4-dioxane (415mL, 1.66mol), intermediate I-7 was obtained as a white solid (32.5g, 82% purity, 75%) which was used without further purification in the following step.

Intermediate 8(I-8)

Intermediate I-6(180g, 350.4mmol) as the HCl salt was dissolved in NaHCO₃In a saturated solution of (2L). The mixture was stirred at room temperature for 12 h. The mixture was diluted with water and extracted with DCM. The organic layer was separated and dried (Na)₂SO₄) Filtered and the solvent evaporated in vacuo. The residue was then washed with tert-butyl methyl ether to give intermediate compound I-8(92g, 90%).

Intermediate 9(I-9)

Intermediate compound I-9 was synthesized following a similar pathway as described for intermediate I-8. Starting from intermediate I-7(32.5g, 139.1mmol), intermediate I-9(14.8g, 70%) was obtained as a solid.

Intermediate 10(I-10)

Intermediate I-9(5g, 33.01mmol), copper (I) iodide (3.78g, 19.85mmol) and K in toluene (150mL)₂CO₃(9.14g, 66.15mmol) of the mixture was flushed with nitrogen for a few minutes. Then 4-bromobenzotrifluoride (9.3mL, 66.1mmol) and N, N' -dimethylethylenediamine (2.1mL, 19.8mmol) were added. The mixture was stirred at room temperature for 10min and then at 100 ℃ for 16h under nitrogen. Then, DMF (20mL) was added and the mixture was stirred at 100 ℃ for 8 h. Then, water, a concentrated solution of ammonia, and DCM were added. The organic layer was separated and dried (Na)₂SO₄) Filtered and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (silica; EtOAc in DCM, 0/100 to 50/50). The desired fractions were collected and the solvent was evaporated in vacuo to yield intermediate compound I-14 as a pale yellow oil (9.6g, 98%).

In a procedure similar to that described for intermediate I-10, the following intermediates were synthesized:

intermediate I-12 can also be prepared according to the following procedure:

to intermediate I-9(1g, 6.615mmol), 2-chloro-5- (trifluoromethyl) pyridine (1.801g, 9.923mmol), XantPhos (765mg, 1.323mmol), Cs in 1, 4-dioxane (30mL), in a sealed tube and under nitrogen₂CO₃(4.311g, 13.23mmol) to a stirred suspension was added Pd (PPh)₃)₄(764mg, 0.662 mmol). The mixture was stirred at 90 ℃ for 40 h. The mixture was then diluted with water and extracted with DCM. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (silica; EtOAc in heptane, 0/100 to 75/25). The desired fractions were collected and the solvent was concentrated in vacuo to yield intermediate compound I-12(2.15g, quantitative) as a solid.

In a procedure similar to that described for intermediate I-12, the following intermediates were synthesized:

intermediate 15(I-15)

To a solution of intermediate I-10(19.2g, 65.0mmol) and ammonium cerium (IV) nitrate (24.95g, 45.5mmol) in MeCN (350mL) was added iodine (11.55g, 45.5 mmol). The mixture was stirred at 70 ℃ for 1 h. The mixture was then diluted with EtOAc and Na₂S₂O₃Washed with brine. Separating the organic layerAnd dried (Na)₂SO₄) Filtered and the solvent evaporated in vacuo. The residue was precipitated with DIPE and then purified by short column chromatography (silica, DCM) and then by flash column chromatography (silica; DCM in heptane, 50/50 to 100/0). The desired fractions were collected and the solvent was evaporated in vacuo to yield intermediate compound I-15(24.8g, 90%) as a solid.

In a procedure similar to that described for intermediate I-15, the following intermediates were synthesized:

intermediate 20(I-20)

To intermediate I-15(1g, 2.37mmol), trimethylsilylacetylene (0.68mL, 4.75mmol), copper (I) iodide (5mg, 0.02mmol) and Et in degassed DMF (10mL) was added₃PdCl was added to a stirred solution of N (0.99mL, 7.12mmol)₂(PPh₃)₂(50mg, 0.071 mmol). The mixture was stirred at 55 ℃ for 1.5h and at room temperature for 1 h. Water, concentrated solution of ammonia and EtOAc were then added. The organic layer was separated and dried (Na)₂SO₄) Filtered and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (silica; EtOAc in heptane, 0/100 to 50/50). The desired fractions were collected and the solvent was evaporated in vacuo to yieldIntermediate I-20(0.97g, quantitative) was obtained as a brown solid.

In a similar procedure to that described for intermediate I-20, the following intermediates were synthesized:

intermediate 22(I-22)

To a stirred solution of intermediate I-15(0.97g, 2.48mmol) in MeOH (10mL) under nitrogen at room temperature was added K₂CO₃(171mg, 1.24 mmol). The mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo and the residue was diluted with water and extracted with EtOAc. The organic layer was separated and dried (Na)₂SO₄) Filtered and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (silica; EtOAc in DCM, 0/100 to 30/70). The desired fractions were collected and the solvent was evaporated in vacuo to yield intermediate compound I-22(549mg, 69%) as a beige solid.

In a similar procedure to that described for intermediate I-22, the following intermediates were synthesized:

intermediate 24(I-24)

To intermediate I-8(913mg, 3.297mmol), 5-ethynyl-2-aminopyridine (779mg, 6.594mmol), Et in DMF (7.659mL)₃N(1.4mL，9.891mmol)、PdCl₂(PPh₃)₂(46mg, 0.0659mmol) and PPh₃(17.295mg, 0.0659mmol) to the stirred mixture was added copper (I) iodide (6.279mg, 0.033 mmol). The mixture was purged with nitrogen for 5 minutes, and then stirred at 90 ℃ for 16 h. The mixture was diluted with water and extracted with EtOAc. The organic phase was separated and dried (Na)₂SO₄) Filtered and the solvent concentrated in vacuo. The crude product was purified by flash column chromatography (silica; MeOH in DCM, 0/100 to 6/94). The desired fractions were collected and the solvent was concentrated in vacuo. The residue was precipitated with DIPE and filtered to give intermediate compound I-24 as a yellow solid (581mg, 66%).

Intermediate 27(I-27)

At 0 ℃ and in N₂Next, to 6-chloro-3- (trifluoromethyl) -pyridinemethanol [1564493-51-1 ] in DCM (17.3mL)](0.307g, 1.45mmol) to the stirred solution was added dropwise diethylaminosulfur trifluoride (0.533mL, 4.35 mmol). The mixture was warmed to room temperature and stirred for 2 hours. With saturated NaHCO at 0 deg.C₃The mixture was carefully treated with aqueous solution and extracted with diethyl ether. The organic layer was separated and dried (Na)₂SO₄) Filtered and evaporated in vacuo (at 25 ℃ C. and 300 mbar) to yield intermediate I-27(0.392g, 72%) as a brown oil, which was used without further purification.

Intermediate 30(I-30)

To a stirred solution of 2-amino-5-bromo-3-pyridinemethanol (200mg, 0.985mmol) in THF (14mL) at 0 deg.C was added sodium hydride (75.486mg, 1.97 mmol). The mixture was stirred at room temperature for 15min and CH3I (122.645. mu.l, 1.97mmol) was added. The mixture was stirred at room temperature for 1.5 hours. The mixture was treated with water and extracted with ethyl acetate. The organic layer was separated and dried (Na)₂SO₄) Filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (silica; ethyl acetate in DCM, 0/100 to 30/70). The desired fractions were collected and evaporated in vacuo to yield intermediate compound I-30(74.1mg, 35%).

In a similar procedure to that described for intermediate I-30, the following intermediates were synthesized:

intermediate 31(I-31)

To a stirred mixture of 2-amino-5-bromo-4-pyridinemethanol (0.2 g; 0.985mmol) in DCM (14mL) were added CXtalfluor-E (0.338 g; 1.478mmol) and trimethylamine trihydrofluoride (0.241 mL; 1.478mmol) in a sealed tube at 0 deg.C and under nitrogen. The mixture was allowed to warm and stir for 18 hours. With saturated NaHCO at 0 deg.C₃The mixture was carefully treated with brine and extracted with DCM. The organic layer was separated and dried (Na)₂SO₄) Filtered and evaporated in vacuo. The residue was purified by flash column chromatography (silica; ethyl acetate in DCM, 0/100 to 30/70). The desired fractions were collected and concentrated in vacuo to yield intermediate compound I-31(94.4 m) as a beige solidg，47％)。

Preparation of the Final Compounds

Example 1(E-1)

(7S) -3- [2- (6-amino-3-pyridyl) ethynyl ] -7-methyl-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazin-4-one (Compound No. 1)

To intermediate I-15(250mg, 0.594mmol), 5-ethynyl-2-aminopyridine (140mg, 1.187mmol), Et in DMF (1.4mL)₃N(248μL，1.781mmol)、PdCl₂(PPh₃)₂(8mg, 0.012mmol) and PPh₃To a stirred mixture (3mg, 0.0119mmol) was added copper (I) iodide (1.131mg, 5. mu. mol). The mixture was purged with nitrogen for 5 minutes, and then stirred at 90 ℃ for 5 h. The mixture was diluted with water and extracted with EtOAc. The organic phase was separated and dried (Na)₂SO₄) Filtered and the solvent concentrated in vacuo. The crude product was purified by flash column chromatography (silica; MeOH in DCM, 0/100 to 6/94). The desired fractions were collected and the solvent was concentrated in vacuo. The solid was precipitated with DIPE/heptane then DIPE and filtered to yield compound number 1 final compound as a light yellow solid (190mg, 78%).¹HNMR(400MHz,CDCl₃)ppm 1.70(d,J＝6.5Hz,3H)3.97(dd,J＝12.6,7.3Hz,1H)4.24(dd,J＝12.7,4.2Hz,1H)4.58(br.s,2H)4.73(quind,J＝6.7,4.3Hz,1H)6.43(dd,J＝8.6,0.7Hz,1H)7.52(d,J＝8.3Hz,2H)7.57(dd,J＝8.6,2.1Hz,1H)7.70(d,J＝8.6Hz,2H)7.74(s,1H)8.27(d,J＝1.6Hz,1H)。

The following compounds can also be synthesized following a procedure similar to that described for E-1:

compound No. 2 can also be synthesized according to the following procedure analogous to the procedure for the synthesis of compound No. 8:

example 2(E-2)

(7S) -3- [2- (6-amino-3-pyridinyl) ethynyl ] -5- (3-chloro-4-methoxy-phenyl) -7-methyl-6, 7-dihydropyrazolo [1,5-a ] pyrazin-4-one (Compound No. 8)

Intermediate I-24(150mg, 0.561mmol), 4-bromo-2-chloro-1-methoxy-benzene (199mg, 0.898mmol), K in toluene (3.6mL), in a sealed tube and under nitrogen₂CO₃To a stirred suspension of (155mg, 1.122mmol) and N, N' -dimethylethylenediamine (36. mu.L, 0.337mmol) was added copper (I) iodide (64mg, 0.337 mmol). The mixture was stirred at 100 ℃ for 20 h. Then, additional copper (I) iodide (43mg, 0.224mmol) was added and the resulting mixture was stirred at 100 ℃ for 16 h. Then, additional N, N' -dimethylethylenediamine (24 μ L, 0.224mmol) and DMF (0.5mL) was added and the mixture was stirred at 100 ℃ for 6 h. The mixture was filtered through a pad of celite and washed with DCM. The filtrate was evaporated in vacuo. The crude product was purified by flash column chromatography (silica; 7N ammonia in MeOH, in DCM, 0/100 to 3/97). The desired fractions were collected and the solvent was concentrated in vacuo to yield compound number 8 final compound as a yellow solid (60mg, 26%).¹H NMR(500MHz,CDCl₃)ppm 1.68(d,J＝6.6Hz,3H)3.86(dd,J＝12.9,7.1Hz,1H)3.92(s,3H)4.16(dd,J＝12.9,4.2Hz,1H)4.57(br.s.,2H)4.65-4.73(m,1H)6.42(d,J＝8.4Hz,1H)6.97(d,J＝9.0Hz,1H)7.20-7.30(m,1H)7.39(d,J＝2.6Hz,1H)7.56(dd,J＝8.5,2.2Hz,1H)7.73(s,1H)8.27(d,J＝1.7Hz,1H)。

The following compounds can also be synthesized following a procedure similar to that described for compound E-2:

example 3(E-3)

(7S) -5- (3, 4-dichlorophenyl) -3- [2- [6- (dimethylamino) -3-pyridinyl ] ethynyl ] -7-methyl-6, 7-dihydropyrazolo [1,5-a ] pyrazin-4-one (Compound No. 12)

A mixture of compound No. 7 (50mg, 0.12mmol) and diethylamine (0.903mL, 1.806mmol) in EtOH (1mL) in a sealed tube was stirred at 130 deg.C for 15min under microwave irradiation. The mixture was diluted with EtOAc and NaHCO₃And washed with water. The organic layer was dried (MgSO₄) Filtered and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (silica; EtOAc in DCM, 0/100 to 50/50). The desired fractions were collected and the solvent was concentrated in vacuo to yield the final compound of compound No. 12 as a yellow solid (43mg, 81%).¹H NMR(400MHz,CDCl₃)ppm 1.68(d,J＝6.7Hz,3H)3.10(s,6H)3.89(dd,J＝12.6,7.3Hz,1H)4.18(dd,J＝12.5,4.2Hz,1H)4.70(quind,J＝6.7,4.3Hz,1H)6.43(dd,J＝8.8,0.7Hz,1H)7.23-7.27(m,1H)7.50(d,J＝8.6Hz,1H)7.52(d,J＝2.5Hz,1H)7.57(dd,J＝8.8,2.3Hz,1H)7.73(s,1H)8.34(dd,J＝2.3,0.7Hz,1H)。

Example 4(E-4) (Compound No. 15)

To a stirred solution of compound No. 14 (438mg, 0.992mmol) in DCM (6.2mL) was added bis (2-methoxyethyl) amino-sulfur trifluoride (0.915mL, 4.961mmol) under nitrogen at 0 ℃. The mixture was stirred at 0 ℃ for 45 min. The mixture was then washed with NaHCO₃The saturated solution was treated at 0 ℃ and extracted with DCM and EtOAc. The organic phase was separated and dried (Na)₂SO₄) Filtered and the solvent concentrated in vacuo. The crude product was purified by flash column chromatography (silica; EtOAc in DCM, 0/100 to 50/50). The desired fractions were collected and the solvent was concentrated in vacuo. With Et₂O grinding the residue toThe impurity-containing fractions were produced as yellow solids and purified by RP HPLC (stationary phase: C18 Xbridge 50X 1005 μm, mobile phase: gradient from 80% 10mM NH in water₄CO₃H pH 9 solution, 20% MeCN to 0% 10mM NH in Water₄CO₃H pH 9 solution, 100% MeCN) to yield the final compound of compound No. 15 as a pale yellow solid (55mg, 12%).¹H NMR(400MHz,CDCl₃)ppm 1.71(d,J＝6.5Hz,3H)3.99(dd,J＝12.7,7.4Hz,1H)4.26(dd,J＝12.5,4.2Hz,1H)4.59(br.s,2H)4.74(quind,J＝6.7,4.4Hz,1H)5.63(d,J＝46.7Hz,2H)6.43(dd,J＝8.6,0.7Hz,1H)7.52(dd,J＝8.4,0.8Hz,1H)7.57(dd,J＝8.6,2.3Hz,1H)7.67(s,1H)7.72-7.76(m,2H)8.27(dd,J＝2.2,0.6Hz,1H)。

The following compounds can also be synthesized following a procedure similar to that described for compound E-4:

the mixture was stirred from-78 ℃ to 0 ℃ over 4h instead of stirring at 0 ℃ for 45 min.

Example 5(E-5) (Compound No. 27)

To a stirred solution of compound No. 28 (prepared according to E-1) (68.8mg, 0.161mmol) in THF (4.07mL) at 0 ℃ was added sodium hydride (12.365mg, 0.323 mmol). The mixture was stirred at room temperature for 15min and iodomethane (20.09 μ l, 0.323mmol) was added. The mixture was stirred at room temperature for 2 hours. More sodium hydride (5.56 mg; 0.145mmol) and methyl iodide were added at 0 deg.C(5.02. mu.L; 0.0807mmol) and the mixture is stirred at room temperature for a further 18 hours. With saturated NH₄The mixture was treated with Cl/brine and extracted with ethyl acetate. The organic layer was separated and dried (Na)₂SO₄) Filtered and concentrated in vacuo. By flash column chromatography (silica; ethyl acetate in CH)₂Cl₂0/100 to 100/0) purifying the residue. The desired fractions were collected and concentrated in vacuo. This product was then triturated with diethyl ether to give compound No. 27 as a beige solid (15.9 mg; 22%).

TABLE 1The preparation of the following compounds followed the procedure exemplified in the experimental part (experimental number). The compounds exemplified and described in the experimental section are marked with an asterisk.

Analysis section

Melting Point

The values are peaks and the values obtained have experimental uncertainties typically associated with this analytical method.

Mettler (Mettler) FP 81HT/FP90 instrument (A):for the various compounds, melting points were determined in open-tube capillaries on a Mettler FP 81HT/FP90 apparatus. Melting points were measured with a temperature gradient of 1 deg.C/min, 3 deg.C/min, 5 deg.C/min, or 10 deg.C/min. The maximum temperature was 300 ℃. The melting point was read from a digital display.

Mettler FP62 device(B) The method comprises the following steps For the various compounds, melting points were determined in open-tube capillaries on a mettler FP62 device. Melting points were measured with a temperature gradient of 1 deg.C/min, 3 deg.C/min, 5 deg.C/min, or 10 deg.C/min. The maximum temperature was 300 ℃. The melting point was read from a digital display.

DSC823e(C)：For various compounds, the melting point (m.p.) was determined using a DSC823e (mettler-toledo) apparatus. Melting points were measured using a temperature gradient of 10 ℃/min. The maximum temperature was 300 ℃. The peak was recorded.

LCMS

General procedure

High Performance Liquid Chromatography (HPLC) measurements were performed using LC pumps, Diode Arrays (DADs) or UV detectors and columns as specified in the corresponding methods. Additional detectors were included if necessary (see method table below).

The flow from the column is brought to a Mass Spectrometer (MS) equipped with an atmospheric pressure ion source. It is within the knowledge of the skilled person to set tuning parameters (e.g. scan range, residence time, etc.) in order to obtain ions of nominal monoisotopic Molecular Weight (MW) and/or ions of precise mass mono-isotopic molecular weight that allow identification of compounds. Data acquisition is performed using appropriate software.

Retention time (R) by experiment_t) And an ion describing compound. If not specified differently in the data sheet, the reported molecular ion corresponds to [ M + H [ ]]⁺(protonated molecules) and/or [ M-H]^-(deprotonated molecules). For molecules with multiple isotopic patterns (Br, Cl, etc.)The reported values are the values obtained for the lowest isotopic mass. All results obtained have experimental uncertainties typically associated with the methods used.

Table 2.LC-MS method (flow in mL/min; column temperature (T) in deg.C; run time in minutes).

(x) different MS coordination parameters

Table 3.Analytical data-melting point (M.p.) and LCMS: [ M + H ]]⁺Means the protonation mass of the free base of the compound, R_tMeaning retention time (in min) and method means method for LCMS. For some compounds, the exact mass was determined.

n.d. indicates no determination

(x) detecting a plurality of crystal forms. Main/peak correlated MP

Optical rotation

Optical rotation was measured on a Perkin-Elmer341 polarimeter with sodium lamp and recorded as follows: [ alpha ] ° (lambda, c g/100ml, solvent, T ℃).

[α]_λ ^T(100 α)/(l x c) where l is the path length in dm andc is the concentration in g/100ml for the sample at temperature T (. degree. C.) and wavelength λ in nm. If the light wavelength used is 589nm (sodium D line), the symbol D may be used instead. The rotation sign (+ or-) should always be given. When using this equation, the concentration and solvent are often provided in parentheses after the rotation.

The rotation is reported using degrees and the concentration is given without units (it is assumed to be g/100 mL).

Table 4.Optical rotation data.

Examples of pharmacology

A) In vitro pharmacology

These compounds provided in the present invention are negative allosteric modulators of mGluR 2. These compounds appear to inhibit glutamate responses by binding to allosteric sites rather than glutamate binding sites. mGluR2 responds less to certain concentrations of glutamate when a compound of formula (I) is present. By virtue of their ability to reduce receptor function, compounds of formula (I) are expected to have a substantial effect at mGluR 2. The use of the compounds described below and suitable for identifying such compounds and more specifically the compounds according to formula (I) is shown in Table 5³⁵S]Negative allosteric modulators tested by GTP γ S binding assay method act on mGluR 2.

1)[³⁵S]GTP γ S binding assay

[³⁵S]The GTP γ S binding assay is a functional membrane-based assay for studying the function of a G-protein coupled receptor (GPCR), whereby the non-hydrolyzable form of GTP is measured³⁵S]GTP γ S (with γ -emission)³⁵S-labeled guanosine 5 '-triphosphate) the subunit of G-protein α catalyzes the exchange of guanosine 5' -diphosphate (GDP) by Guanosine Triphosphate (GTP) and when the GPCR is activated by an agonist³⁵S]GTP γ S is incorporated and cannot be cleaved to continue the exchange cycle (Huper (Harper) (1998) Pharmacology guide for Current Protocols in Pharmacology 2.6.1-10, John Wiley father, John&Sons, Inc.)). Radioactivity [ alpha ]³⁵S]The amount of GTP γ S incorporation is a direct measure of the G-protein activity and thus the activity of the antagonist can be determined the mGlu2 receptor shows preferential coupling to the G α i-protein (preferential coupling for this method) and is therefore widely used to study receptor activation of the mGlu2 receptor in recombinant cell lines and in tissues, herein we describe³⁵S]Use of a GTP γ S binding assay using membranes from cells transfected with the human mGlu2 receptor and adapted from schafhauser et al (Molecular Pharmacology), 2003, 4: 798-.

Membrane preparation

CHO-cells were cultured to pre-fusion and stimulated with 5mM butyrate for 24 h. Cells were then collected by scraping in PBS and the cell suspension was centrifuged (10 min at 4000RPM in a bench top centrifuge). The supernatant was discarded and the pellet was gently resuspended in 50mM Tris-HCl (pH7.4) by mixing with an Ultra Turrax homogenizer. The suspension was centrifuged at 12,400RPM (Sorvall F14S-6X250Y) for 10 minutes and the supernatant discarded. The pellet was homogenized in 5mM Tris-HCl (pH7.4) using an UltraTurrax homogenizer and centrifuged again (13,000RPM, 20min, 4 ℃). The final pellet was resuspended in 50mM Tris-HCl (pH7.4) and stored in appropriate aliquots at-80 ℃ prior to use. Protein concentration was determined by the Bradford method (Bio-Rad, USA), and bovine serum albumin was used as a standard.

[ ³⁵ S]GTP γ S binding assay

Measured as followsmGluR2 negative allosteric modulating activity of the test compounds. Test compounds and glutamic acid were diluted in a solution containing 10mM HEPES acid, 10mM HEPES salt (pH7.4), 100mM NaCl, 3mM MgCl₂And 10 μ M GDP in assay buffer. Membranes containing the human mGlu2 receptor were thawed on ice and diluted in assay buffer supplemented with 18 μ g/ml saponin. The film is determined with the compound (. about.EC)₈₀) Glutamic acid (60. mu.M) was preincubated at 30 ℃ for 30 min. When adding³⁵S]After GTP γ S (final concentration 0.1nM), the assay mixture is briefly shaken and further incubated to allow incorporation upon activation³⁵S]GTP γ S (30 min, 30 ℃). In 10mM HEPES acid, 10mM HEPES salt (pH7.4), 100mM NaCl, 3mM MgCl₂The final assay mixture of 10 μ M GDP and 10 μ g/ml saponin contained 7 μ g of membrane protein. The total reaction volume was 200. mu.l. The reaction was terminated by rapid filtration using a 96-well filtermate universal collector via a Unifilter-96GF/B plate (Perkin Elmer, ma, usa). With ice-cold 10mM NaH₂PO₄/10mM Na₂HPO₄(pH7.4) the filter was washed 6 times. The filters were then air-dried and 30 μ Ι of liquid scintillation cocktail (microscent-O) was added to each well. The membrane and radioactivity were counted in a Topcount.

Data analysis

Using Lexis software interface (at J)&J development) generated concentration-response curves for representative compounds of the invention. Data was calculated as% of control glutamate response, defined as response at addition of EC₈₀-response at equivalent concentrations of glutamate. Sigmoidal concentration-response curves plotting these percentages against the log concentration of the test compound were analyzed using nonlinear regression analysis. The concentration giving half-maximal inhibition was calculated as IC₅₀。

When M denotes IC₅₀According to-log IC₅₀Calculating pIC₅₀The value is obtained. Will E_maxDefined as the relative maximal effect (i.e. maximal% inhibition of glutamate response relative to control).

Table 5.Pharmacological data of the Compounds according to the invention

B) In vivo pharmacology

1) Reversal of LY-404039-induced reduction of eyelid opening in apomorphine-challenged rats.

Male Wiggangwistatar (Wiga Wistar) rats (Crl: WI; Charles river Germany; 220 + -40 g) were raised under standard laboratory conditions (21 deg.C + -2 deg.C; 50% -65% relative humidity; set for a 12h light-dark cycle; light exposure at 6.00 h) and fasted overnight (tap water was kept freely available) before starting the experiment. During the test period, they were housed in individual cages. Eyelid opening scores were given every 5min in animals pretreated with LY-404039(2.5mg/kg, given subcutaneously) or not pretreated 1h prior to apomorphine injection, within the first hour after apomorphine injection (1.0mg/kg, i.v.). Animals were also pretreated with test compounds or solvents at pre-determined intervals prior to apomorphine challenge. The scoring system is as follows: (5) eyeball protrusion, (4) wide-open, (3) three-quarters open, (2) half-open, (1) one-quarter open, and (0) closed. Scores for eyelid opening were accumulated over a 60-min observation period. Cumulative eyelid opening scores >26 were selected as drug-induced reversal of the reduction of the eyelid opening induced by LY-404039 (appearing in 3.2% of control animals pretreated with LY-404039 (n-154) versus 99.5% of control rats not pretreated with LY-404039 (n-6335)).

Table 6 shows the eyelid opening scores in control animals receiving apomorphine alone and in animals receiving apomorphine and LY-404039. The median eyelid opening was 43 in animals receiving apomorphine alone, and 17 in animals receiving apomorphine and LY-404039. In animals treated with apomorphine alone, the eyelid opening score was almost always (in 95.5% of rats) greater than 34, whereas in animals treated with the combination (apomorphine + LY-404039), only 3.2% of the animals showed an eyelid opening greater than 26.

Table 6.Eyelid opening scores in control animals.

2) Reversal of mGluR2PAM JNJ-42153605-induced inhibition of hyoscyamine-induced excitatory locomotion

Device for measuring the position of a moving object

The locomotor activity was measured in a microprocessor-based locomotor activity filter paper (arena) (closed grey PVC cylinder with a height of 39cm and a diameter of 31 cm). Place each place in an infrared LED (8x 8LED) light box (white PVC square box; 40x 40 cm)²(ii) a Height 12.5 cm). An infrared light-sensitive tube camera and a white light source are mounted on the ceiling above the observation room to track the animal. The total distance traveled (cm) was recorded and analyzed using a Noldus Ethovision XT Video Tracking System (version 7.0.418; Noldus, Vangen, Netherlands). The intensity of the light inside the activity cage (measured in the center of the floor level) varies between 4LUX and 8 LUX.

General procedure

Rats were pretreated with test compound or vehicle 60min before starting recording activity and placed in individual cages. Rats were challenged 30min before the start of recording activity with JNJ-42153605(3- (cyclopropylmethyl) -7- (4-phenylpiperidin-1-yl) -8- (trifluoromethyl) [1,2,4] umizolo [4,3-a ] pyridine; WO 2010/130424; Cid (odd) et al J.Med.chem. (J.Pharmacol.) 2012,55, 8770-. Immediately after injecting the hyoscyamine, the rats were placed in an activity monitor and the total distance walked within the first 30min was measured.

Solvent pretreated control rats.

The frequency distribution obtained in time series of solvent-pretreated control rats is given in table 7 below. Animals receiving the combination of JNJ-42153605 and hyoscyamine (n ═ 433) almost always walked over distances of less than 1500cm (<1500cm) (only 2.5% of the control rats walked over distances of more than 1500cm (>1500 cm)). In another aspect, animals challenged with hyoscyamine alone (n ═ 215) always walked over a total distance of more than 1500cm (>1500cm) and almost always (in 95.8% of rats) over a distance of 4400cm (>4400 cm). Rats that did not receive any challenge almost always walked over distances of more than 1500cm (>1500cm) (in 93.3% of rats) and less than 4400cm (<4400cm) (in 98.9% of rats). For reversal of inhibitory effect of JNJ-42153605 on hyoscyamine-induced excitatory locomotion, the following criteria were used, all or nothing: (1) reversing: the total distance is >1500 cm.

Table 7.Frequency distribution obtained in time series of solvent pretreated control rats. N is a radical of_{To be tested}Meaning the number of animals tested.

3) Induced mydriasis

The pupil diameter of the vego (Wiga) rats was measured with a microscope micrometer (1 unit: 1/24 mm). Criteria for drug induction: mydriasis (in control: 1.9%) 1h after administration of test compound, pupil diameter >25 units (test 1), or 1,2 or 3h after administration of test compound (test 2, where the pupil diameter over 3h is recorded).

The following table 8 provides the data obtained in the above tests 1) to 3).

Table 8.The data in tests 1) to 3) are summarized in the table: SCOP JNJ-42153605 means the reversal of the effect of JNJ 42153605 on hyoscyamine-induced excitatory locomotion; APO LY-404039 means the reversal of LY-404039-induced reduction of eyelid opening in apomorphine-challenged rats; MYD means induced mydriasis; ED (electronic device)₅₀Meaning half the effective dose; PO means oral route; SC means subcutaneous route.

Prophetic composition examples

As used throughout these examples, "active ingredient" relates to the final compound of formula (I), pharmaceutically acceptable salts thereof, solvates thereof and stereochemically isomeric forms and tautomers thereof.

Typical examples of formulations for the formulations of the present invention are as follows:

1. tablet formulation

In this example, the active ingredient may be replaced by the same amount of any of the compounds according to the invention, in particular by the same amount of any of the exemplified compounds.

2. Suspension liquid

Aqueous suspensions were prepared for oral administration so as to contain 1 to 5mg of one of these active compounds, 50mg of sodium carboxymethylcellulose, 1mg of sodium benzoate, 500mg of sorbitol and water (make up to 1ml) per 1 ml.

3. Injectable preparation

The parenteral composition is prepared by stirring 1.5% by weight of the active ingredient of the invention in 10% by volume of propylene glycol in water.

4. Ointment

Reasonable variations are not to be regarded as a departure from the scope of the invention. It will be obvious that the invention described herein may be varied in many ways by one of ordinary skill in the art.

Claims

1. A compound of formula (I)

Or a stereoisomeric form thereof, wherein

R²is phenyl or pyridyl, each of which may be optionally substituted with one or more substituents each independently selected from the group consisting of: halogen, C_1-4Alkyl, monohalo-C_1-4Alkyl, polyhalo-C_1-4Alkyl, -OH, -O-C_1-4Alkyl, -C_1-4alkyl-O-C_1-4Alkyl, monohalo-C_1-4Alkoxy, polyhalo-C_1-4Alkoxy, -C_1-4alkyl-OH, and NR^5aR^5b；

Wherein R is^5aAnd R^5bEach independently is hydrogen or C_1-4An alkyl group;

R³is hydrogen or C_1-4An alkyl group;

or an N-oxide, or a pharmaceutically acceptable salt or solvate thereof.

2. A compound according to claim 1, or one of its stereoisomeric forms, wherein

R¹Is phenyl each of which may be optionally substituted with one or two substituents each independently selected from the group consisting of

2-pyridyl, the group consisting of: halogen, C_1-4Alkyl, monohalo-C_1-4Alkyl, polyhalo-C_1-4Alkyl, -C_1-4alkyl-O-C_1-4Alkyl, and monohalo-C_1-4Alkoxy, polyhalo-C_1-4An alkoxy group;

R²is phenyl or pyridyl, each of which may be optionally substituted with one or two substituents each independently selected from the group consisting of: halogen, C_1-4Alkyl, monohalo-C_1-4Alkyl, polyhalo-C_1-4Alkyl, -O-C_1-4Alkyl, -C_1-4alkyl-O-C_1-4Alkyl, monohalo-C_1-4Alkoxy, polyhalo-C_1-4Alkoxy, and NR^5aR^5b；

Wherein R is^5aAnd R^5bEach independently is hydrogen or C_1-4An alkyl group;

R³is hydrogen;

R⁴is selected from C_1-4Alkyl, or-C_1-4alkyl-O-C_1-4An alkyl group;

or an N-oxide, or a pharmaceutically acceptable salt or solvate thereof.

3. A compound according to claim 1 or 2, or one of its stereoisomeric forms, wherein

2-pyridyl, the group consisting of: halogen, polyhalo-C_1-4Alkyl, and-O-C_1-4An alkyl group;

R²is phenyl or pyridyl, each of which may be optionally substituted with one or two substituents each independently selected from the group consisting of: halogen, C_1-4Alkyl, -O-C_1-4Alkyl, and NR^5aR^5b；

Wherein R is^5aAnd R^5bEach independently is hydrogen or C_1-4An alkyl group;

R³is hydrogen;

R⁴is C_1-4An alkyl group;

or an N-oxide, or a pharmaceutically acceptable salt or solvate thereof.

4. The compound of claim 1, wherein R³Is hydrogen and R⁴Is a substituent other than hydrogen, which compound has the configuration as depicted in formula (I

Wherein 6, 7-dihydropyrazolo [1, 5-a)]Pyrazin-4 (5H) -one core, R¹And R²In the plane of the figure and R⁴Protruding above the graphics plane; and the remaining variables are as defined in claim 1.

5. A pharmaceutical composition comprising a therapeutically effective amount of a compound as defined in any one of claims 1 to 4 and a pharmaceutically acceptable carrier or excipient.

6. A compound as defined in any one of claims 1 to 4 for use as a medicament.

7. The compound according to claim 6, for use in the treatment or prevention of a central nervous system disorder or disease selected from the group consisting of: mood disorders; delirium, dementia, amnesia and other cognitive disorders; disorders usually first diagnosed in infancy, childhood or adolescence; a substance-related disorder; schizophrenia and other psychotic disorders; a somatoform disorder; and hypersomnia sleep disorder.

8. The compound according to claim 6, for use in the treatment or prevention of a central nervous system disorder or disease selected from the group consisting of: depressive disorder; a neurocognitive disorder; neurodevelopmental disorders; substance-related disorders and addictive disorders; schizophrenia spectrum and other psychiatric disorders; somatic disorder and related disorders; and somnolence disorder.

9. The compound for use according to claim 7, wherein the central nervous system disorders or diseases are selected from: dementia, neurocognitive disorders, major depressive disorder, depression, treatment-refractory depression, attention deficit/hyperactivity disorder, and schizophrenia.

10. A process for the preparation of a pharmaceutical composition according to claim 5, characterized in that a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of a compound as defined in any one of claims 1 to 4.

11. A method of treating or preventing a central nervous system disorder or condition selected from: mood disorders; delirium, dementia, amnesia and other cognitive disorders; disorders usually first diagnosed in infancy, childhood or adolescence; a substance-related disorder; schizophrenia and other psychotic disorders; a somatoform disorder; and hypersomnic sleep disorders, which method comprises administering to a subject in need thereof a therapeutically effective amount of a compound as defined in any one of claims 1 to 4.

12. A method of treating or preventing a central nervous system disorder or condition selected from: depressive disorder; a neurocognitive disorder; neurodevelopmental disorders; substance-related disorders and addictive disorders; schizophrenia spectrum and other psychiatric disorders; somatic disorder and related disorders; and disorders of lethargy; the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound as defined in any one of claims 1 to 4.

13. The method according to claim 11, wherein the central nervous system disorders or diseases are selected from the following: dementia, neurocognitive disorders, major depressive disorder, depression, treatment-refractory depression, attention deficit/hyperactivity disorder, and schizophrenia.

14. A product comprising a compound as defined in any one of claims 1 to 4 and an additional pharmaceutical agent as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of a central nervous system disorder or disease selected from: mood disorders; delirium, dementia, amnesia and other cognitive disorders; disorders usually first diagnosed in infancy, childhood or adolescence; a substance-related disorder; schizophrenia and other psychotic disorders; a somatoform disorder; and hypersomnia sleep disorder.

15. A product comprising a compound as defined in any one of claims 1 to 4 and an additional pharmaceutical agent as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of a central nervous system disorder or disease selected from: depressive disorder; a neurocognitive disorder; neurodevelopmental disorders; substance-related disorders and addictive disorders; schizophrenia spectrum and other psychiatric disorders; somatic disorder and related disorders; and somnolence disorder.