HK1236925A1

HK1236925A1 - 6,7-dihydropyrazolo[1,5-a]pyrazin-4(5h)-one compounds and their use as negative allosteric modulators of mglur2 receptors

Info

Publication number: HK1236925A1
Application number: HK17110468.3A
Authority: HK
Inventors: Sergio-Alvar Alonso-De Diego; Michiel Luc Maria Van Gool; Óscar DELGADO-GONZÁLEZ; José Ignacio ANDRÉS-GIL; Andrés Avelino TRABANCO-SUÁREZ
Original assignee: Janssen Pharmaceutica Nv
Priority date: 2014-08-01
Filing date: 2015-07-30
Publication date: 2018-04-06

Description

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

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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_1-4Alkyl sulfideRadical and polyhalo-C_1-4An alkylthio group;

R²selected from the group consisting of: hydrogen; c_1-4An alkyl group; c_3-7A cycloalkyl group; het¹(ii) a An aryl group; -C (O) R⁵；-C(O)Het²；Het²(ii) a And C substituted with one or more substituents each independently selected from the group consisting of_1-4Alkyl, the group consisting of: halogen, C_3-7Cycloalkyl, aryl, Het¹And Het²(ii) a Wherein

R⁵Selected from the group consisting of: hydrogen, C_1-4Alkyl and C_3-7A cycloalkyl group;

aryl is phenyl optionally substituted with one or more substituents each independently selected from the group consisting of: halogen, C_1-4Alkyl, -C_1-4alkyl-OH, monohalo-C_1-4Alkyl, polyhalo-C_1-4Alkyl, -CN, -O-C_1-4Alkyl, -OH, -C_1-4alkyl-O-C_1-4Alkyl, -NR' R ", -NHC (O) C_1-4Alkyl, -C (O) NR' R ", -C (O) NH [ C (O) C_1-4Alkyl radical]、-S(O)₂NR'R"、-S(O)₂NH[C(O)C_1-4Alkyl radical]and-SO₂-C_1-4An alkyl group;

Het¹selected from the group consisting of: oxetanyl, tetrahydrofuranyl and tetrahydropyranyl;

Het²is (a) a 6-membered aromatic heterocyclyl substituent selected from the group consisting of: pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl, each of which may be optionally substituted with one or more substituents each independently selected from the group consisting of: halogen, C_1-4Alkyl, -C_1-4alkyl-OH, monohalo-C_1-4Alkyl, polyhalo-C_1-4Alkyl, -CN, -O-C_1-4Alkyl, -OH, -C_1-4alkyl-O-C_1-4Alkyl, -NR' R ", -NHC (O) C_1-4Alkyl, -C (O) NR' R ", -C (O) NH [ C (O) C_1-4Alkyl radical]、-S(O)₂NR'R"、-S(O)₂NH[C(O)C_1-4Alkyl radical]and-SO₂-C_1-4An alkyl group; or

(b) A 5-membered aromatic heterocyclic group selected from the group consisting of: thiazolyl, oxazolyl, 1H-pyrazolyl, and 1H-imidazolyl, each of which may be optionally substituted with one or more substituents each independently selected from the group consisting of: halogen, C_1-4Alkyl, -C_1-4alkyl-OH, monohalo-C_1-4Alkyl, polyhalo-C_1-4Alkyl, -CN, -O-C_1-4Alkyl, -OH, -C_1-4alkyl-O-C_1-4Alkyl, -NR' R ", -NHC (O) C_1-4Alkyl, -C (O) NR' R ", -C (O) NH [ C (O) C_1-4Alkyl radical]、-S(O)₂NR'R"、-S(O)₂NH[C(O)C_1-4Alkyl radical]and-SO₂-C_1-4An alkyl group;

r 'and R' are each independently selected from hydrogen and C_1-4An alkyl group; and is

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 invention also relates to 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 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: hydrogen; c_1-4An alkyl group; c_3-7A cycloalkyl group; het¹(ii) a An aryl group; -C (O) R⁵；-C(O)Het²；Het²(ii) a And C substituted with one or more substituents each independently selected from the group consisting of_1-4Alkyl, the group consisting of: c_3-7Cycloalkyl, aryl, Het¹And Het²(ii) a Wherein

aryl is phenyl which may be optionally substituted with one or more substituents each independently selected from the group consisting of: halogen, C_1-4Alkyl, -O-C_1-4Alkyl, -C_1-4alkyl-O-C_1-4Alkyl and-SO₂-C_1-4An alkyl group;

Het²is (a) a 6-membered aromatic heterocyclyl substituent selected from the group consisting of: pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl, each of which may be optionally substituted with one or more substituents each independently selected from the group consisting of: halogen, C_1-4Alkyl, -CN, -OH, -O-C_1-4Alkyl, -C (O) NR 'R' and-NR 'R'; or

(b) A 5-membered aromatic heterocyclic group selected from the group consisting of: thiazolyl, oxazolyl, 1H-pyrazolyl, and 1H-imidazolyl, each of which may be optionally substituted with one or more substituents each independently selected from the group consisting of: halogen, C_1-4Alkyl, -CN, -OH, -O-C_1-4Alkyl, -C (O) NR 'R' and-NR 'R';

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 compounds of formula (I) as defined above and stereoisomeric forms thereof, wherein

R¹Are each optionally substituted by oneOr two substituents each independently selected from the group consisting of phenyl or 2-pyridyl substituted by: halogen, C_1-4Alkyl, monohalo-C_1-4Alkyl, polyhalo-C_1-4Alkyl, -CN, -C_1-4alkyl-O-C_1-4Alkyl, -O-C_1-4Alkyl and monohalo-C_1-4Alkoxy and polyhalo-C_1-4An alkoxy group;

aryl is phenyl optionally substituted with one substituent selected from the group consisting of: halogen, C_1-4Alkyl, -O-C_1-4Alkyl and-SO 2-C_1-4An alkyl group;

Het²is (a) a 6-membered aromatic heterocyclyl substituent selected from the group consisting of: pyridinyl, pyrimidinyl, and pyrazinyl, 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' R "; or

(b) A 5-membered aromatic heterocyclic group selected from the group consisting of: thiazolyl, oxazolyl and 1H-imidazolyl, each of which may optionally be substituted by one C_1-4Alkyl substituents are takenGeneration;

R³Is hydrogen;

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

R²selected from the group consisting of: aryl, and Het²(ii) a Wherein

Aryl is phenyl optionally substituted with one halogen substituent;

(b) A 5-membered aromatic heterocyclic group selected from the group consisting ofThe group consisting of: thiazolyl, 1, 2-oxazolyl, 1, 3-oxazolyl and 1H-imidazolyl, each of which may optionally be substituted by one C_1-4Alkyl substituent group substitution;

r 'and R' are each hydrogen; and is

R³Is hydrogen;

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, C_1-4Alkyl, polyhalo-C_1-4Alkyl, -C_1-4alkyl-O-C1-4 alkyl, -O-C_1-4Alkyl and polyhalo-C_1-4An alkoxy group;

R²selected from the group consisting of: aryl, and Het²(ii) a Wherein

Aryl is phenyl optionally substituted with one halogen substituent;

Het²is (a) a pyridyl or pyrazinyl group, 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' R "; or (b) a thiazolyl group;

r 'and R' are each hydrogen; and is

>CR³R⁴Is selected from>CH(CH₃) And>CH(CH₂OCH₃)；

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

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

R²is Het²(ii) a Wherein

Het²Is pyridyl or pyrazinyl, 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' R ";

>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 having a configuration as depicted in the following formula (I'), wherein 6, 7-dihydropyrazolo [1,5-a]Pyrazin-4 (5H) -one core, R¹And R²In the plane of the figure and R⁴Projected 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, for example, a substituent other than hydrogen (e.g., a C1-4 alkyl substituent) having a configuration as depicted in the following formula (I'), wherein 6, 7-dihydropyrazolo [1,5-a ]]Pyrazin-4 (5H) -one core, R¹And R²In the plane of the figure and R³Projected 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) -7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -N- (6-fluoro-3-pyridyl) -7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -N- (6-amino-3-pyridyl) -7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -N-formyl-7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -7-methyl-N- (2-methyl-4-pyridyl) -4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -7-methyl-N- (2-methylpyridine-4-carbonyl) -4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -N, 7-dimethyl-4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -7-methyl-4-oxo-N-tetrahydropyran-4-yl-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -7-methyl-4-oxo-N-phenyl-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -N-tert-butyl-7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -N-cyclohexyl-7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -N-benzyl-7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -N- [ (6-amino-3-pyridinyl) methyl ] -7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -N- (4-fluorophenyl) -7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -N- (cyclopentylmethyl) -7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -7-methyl-4-oxo-N- (2-pyridyl) -5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -7-methyl-N- (2-methylpyrimidin-5-yl) -4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -7-methyl-N- [ (2-methyl-4-pyridinyl) methyl ] -4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -N- (cyclopropylmethyl) -7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- (3, 4-dichlorophenyl) -N- (6-fluoro-3-pyridyl) -7-methyl-4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -7-methyl-N- (3-methylsulfonylphenyl) -4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -7-methyl-N- (4-methylsulfonylphenyl) -4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -N- (1-cyclopropylethyl) -7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- (3, 4-dichlorophenyl) -7-methyl-N- (2-methyl-4-pyridinyl) -4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- (4-chlorophenyl) -7-methyl-N- (2-methyl-4-pyridyl) -4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -7-methyl-N- (2-methyl-4-pyridyl) -5- [ 3-methyl-4- (trifluoromethyl) phenyl ] -4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- [ 3-cyano-4- (trifluoromethyl) phenyl ] -7-methyl-N- (2-methyl-4-pyridyl) -4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- [ 3-methoxy-4- (trifluoromethyl) phenyl ] -7-methyl-N- (2-methyl-4-pyridyl) -4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -7-methyl-N- (2-methyl-4-pyridyl) -4-oxo-5- [5- (trifluoromethyl) -2-pyridyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- [ 3-fluoro-4- (trifluoromethyl) phenyl ] -7-methyl-N- (2-methyl-4-pyridyl) -4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -N- (cyclobutylmethyl) -7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -7-methyl-4-oxo-N- (tetrahydrofuran-2-ylmethyl) -5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -7-methyl-4-oxo-N- (tetrahydropyran-4-ylmethyl) -5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -N- (2-methoxyphenyl) -5- [ 6-methoxy-5- (trifluoromethyl) -2-pyridinyl ] -7-methyl-4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- (5-chloro-6-methoxy-2-pyridyl) -7-methyl-4-oxo-N-phenyl-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -N- (3-methoxyphenyl) -5- [ 6-methoxy-5- (trifluoromethyl) -2-pyridinyl ] -7-methyl-4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- [ 6-methoxy-5- (trifluoromethyl) -2-pyridinyl ] -7-methyl-4-oxo-N-phenyl-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -N- (4-methoxyphenyl) -5- [ 6-methoxy-5- (trifluoromethyl) -2-pyridinyl ] -7-methyl-4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -7-methyl-4-oxo-N- (tetrahydrofuran-3-ylmethyl) -5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -7-methyl-4-oxo-N- (4-pyridyl) -5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -N- (5-methoxy-3-pyridyl) -7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -7-methyl-4-oxo-N- (3-pyridyl) -5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -7-methyl-N- (2-methyl-3-pyridinyl) -4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -N- (3-fluoro-4-pyridyl) -7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -7-methyl-N- (5-methyl-3-pyridinyl) -4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -7-methyl-N- (4-methyl-3-pyridinyl) -4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- [3- (methoxymethyl) -4- (trifluoromethyl) phenyl ] -7-methyl-N- (2-methyl-4-pyridinyl) -4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -N- (5-fluoro-3-pyridyl) -7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- [ 3-chloro-4- (difluoromethyl) phenyl ] -7-methyl-N- (2-methyl-4-pyridyl) -4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -N- (6-methoxy-2-pyridyl) -7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -N- (cyclobutanecarbonyl) -7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -N- (5-fluoro-2-pyridyl) -7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -7-methyl-4-oxo-N-pyrimidin-2-yl-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -N- (5-methoxy-2-pyridyl) -7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- [3- (methoxymethyl) -4- (trifluoromethyl) phenyl ] -7-methyl-4-oxo-N- (2-pyridyl) -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

7- (methoxymethyl) -N- (2-methyl-4-pyridinyl) -4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -N- (3-fluoro-2-pyridyl) -7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -N- (3-methoxy-2-pyridyl) -7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- (3, 4-dichlorophenyl) -7-methyl-4-oxo-N- (2-pyridinyl) -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -7-methyl-5- [ 3-methyl-4- (trifluoromethyl) phenyl ] -4-oxo-N- (2-pyridyl) -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -7-methyl-N- (oxetan-3-yl) -4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -N-cyclobutyl-7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7R) -7- (methoxymethyl) -N- (2-methyl-4-pyridinyl) -4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -7- (methoxymethyl) -N- (2-methyl-4-pyridyl) -4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- [ 3-chloro-4- (trifluoromethyl) phenyl ] -7-methyl-4-oxo-N- (2-pyridyl) -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -N- (2, 6-dimethyl-4-pyridinyl) -7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -7-methyl-4-oxo-N-pyrazin-2-yl-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- [ 3-fluoro-4- (trifluoromethyl) phenyl ] -7-methyl-4-oxo-N- (2-pyridyl) -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -N-acetyl-7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- [ 4-chloro-3- (difluoromethoxy) phenyl ] -7-methyl-N- (2-methyl-4-pyridyl) -4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -7-methyl-N- (2-methyl-4-pyridyl) -4-oxo-5-phenyl-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -7-methyl-N-oxazol-2-yl-4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- [3- (fluoromethyl) -4- (trifluoromethyl) phenyl ] -7-methyl-4-oxo-N- (3-pyridyl) -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- [3- (fluoromethyl) -4- (trifluoromethyl) phenyl ] -7-methyl-N- (2-methyl-4-pyridyl) -4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -7-methyl-4-oxo-N-thiazol-2-yl-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -7-methyl-4-oxo-N-pyrimidin-4-yl-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -7-methyl-N- (6-methyl-2-pyridyl) -4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -N- (1H-imidazol-2-yl) -7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -N- (3-methoxy-4-pyridyl) -7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- [3- (fluoromethyl) -4- (trifluoromethyl) phenyl ] -7-methyl-4-oxo-N- (4-pyridyl) -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- [ 3-chloro-4- (trifluoromethyl) phenyl ] -7-methyl-4-oxo-N- (3-pyridyl) -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -7-methyl-N- (3-methyl-2-pyridyl) -4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- [ 3-chloro-4- (trifluoromethyl) phenyl ] -7-methyl-4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- (3, 4-dichlorophenyl) -N- (5-fluoro-2-pyridyl) -7-methyl-4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- (3, 4-dichlorophenyl) -7-methyl-4-oxo-N- (3-pyridinyl) -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -7-methyl-N- (4-methyl-2-pyridyl) -4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -7-methyl-N- (5-methyl-3-pyridyl) -5- [ 3-methyl-4- (trifluoromethyl) phenyl ] -4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -7-methyl-5- [ 3-methyl-4- (trifluoromethyl) phenyl ] -4-oxo-N- (3-pyridyl) -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- [ 3-chloro-4- (trifluoromethyl) phenyl ] -7-methyl-4-oxo-N-pyrazin-2-yl-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -7-methyl-5- [ 3-methyl-4- (trifluoromethyl) phenyl ] -4-oxo-N-pyrazin-2-yl-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- [ 3-chloro-4- (trifluoromethyl) phenyl ] -7-methyl-N- (2-methyl-4-pyridinyl) -4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -7-methyl-5- [ 3-methyl-4- (trifluoromethyl) phenyl ] -4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -N- (5-fluoro-4-methyl-3-pyridinyl) -7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- [ 3-chloro-4- (trifluoromethyl) phenyl ] -N- (5-fluoro-4-methyl-3-pyridinyl) -7-methyl-4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- (3, 4-dichlorophenyl) -7-methyl-4-oxo-N-pyrazin-2-yl-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- (3, 4-dichlorophenyl) -N- (2, 6-dimethyl-4-pyridinyl) -7-methyl-4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- [ 3-chloro-4- (trifluoromethyl) phenyl ] -N- (2, 6-dimethyl-4-pyridinyl) -7-methyl-4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- [ 3-chloro-4- (trifluoromethyl) phenyl ] -N- (5-fluoro-2-pyridyl) -7-methyl-4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- [ 3-chloro-4- (trifluoromethyl) phenyl ] -N- (4, 5-dimethyl-3-pyridinyl) -7-methyl-4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -N- (5-methoxy-4-methyl-3-pyridinyl) -7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- [ 3-chloro-4- (trifluoromethyl) phenyl ] -N- (5-methoxy-4-methyl-3-pyridyl) -7-methyl-4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -N- (2, 6-dimethyl-4-pyridinyl) -7-methyl-5- [ 3-methyl-4- (trifluoromethyl) phenyl ] -4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -N- (5-fluoro-2-pyridyl) -7-methyl-5- [ 3-methyl-4- (trifluoromethyl) phenyl ] -4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- (3, 4-dichlorophenyl) -7-methyl-4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- (3, 4-dichlorophenyl) -7-methyl-N- (5-methyl-3-pyridinyl) -4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -N- (5-fluoro-3-pyridyl) -7-methyl-5- [ 3-methyl-4- (trifluoromethyl) phenyl ] -4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -N- (5-methoxy-3-pyridyl) -7-methyl-5- [ 3-methyl-4- (trifluoromethyl) phenyl ] -4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- (4-chlorophenyl) -7-methyl-4-oxo-N- (3-pyridyl) -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- [ 3-fluoro-4- (trifluoromethyl) phenyl ] -7-methyl-4-oxo-N- (3-pyridyl) -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -N- (5-fluoro-2-pyridyl) -5- [ 3-methoxy-4- (trifluoromethyl) phenyl ] -7-methyl-4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- (3, 4-dichlorophenyl) -N- (5-methoxy-3-pyridinyl) -7-methyl-4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -7-methyl-N- (4-methyl-3-pyridyl) -5- [ 3-methyl-4- (trifluoromethyl) phenyl ] -4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- [ 3-methoxy-4- (trifluoromethyl) phenyl ] -7-methyl-N- (4-methyl-3-pyridyl) -4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -N- (5-fluoro-3-pyridyl) -5- [ 3-methoxy-4- (trifluoromethyl) phenyl ] -7-methyl-4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- (3, 4-dichlorophenyl) -N- (5-fluoro-3-pyridyl) -7-methyl-4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -N- (5-fluoro-2-pyridyl) -5- [ 3-fluoro-4- (trifluoromethyl) phenyl ] -7-methyl-4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- (3, 4-dichlorophenyl) -7-methyl-N- (4-methyl-3-pyridinyl) -4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- [ 3-methoxy-4- (trifluoromethyl) phenyl ] -7-methyl-N- (5-methyl-3-pyridyl) -4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- [ 3-chloro-4- (trifluoromethyl) phenyl ] -7-methyl-N- (3-methylisoxazol-5-yl) -4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -N- (5-methoxy-3-pyridyl) -5- [ 3-methoxy-4- (trifluoromethyl) phenyl ] -7-methyl-4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- [ 3-fluoro-4- (trifluoromethyl) phenyl ] -7-methyl-4-oxo-N-pyrazin-2-yl-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- [ 3-chloro-4- (trifluoromethyl) phenyl ] -N- (5-fluoro-3-pyridyl) -7-methyl-4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- [ 3-methoxy-4- (trifluoromethyl) phenyl ] -7-methyl-4-oxo-N-pyrazin-2-yl-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -N- (5-fluoro-3-pyridyl) -5- [ 3-fluoro-4- (trifluoromethyl) phenyl ] -7-methyl-4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- [ 3-methoxy-4- (trifluoromethyl) phenyl ] -7-methyl-4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -N- (5-fluoro-4-methyl-3-pyridinyl) -5- [ 3-fluoro-4- (trifluoromethyl) phenyl ] -7-methyl-4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -N- (5-fluoro-4-methyl-3-pyridinyl) -7-methyl-5- [ 3-methyl-4- (trifluoromethyl) phenyl ] -4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- (3, 4-dichlorophenyl) -N- (5-fluoro-4-methyl-3-pyridinyl) -7-methyl-4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- (4-chlorophenyl) -N- (5-fluoro-4-methyl-3-pyridyl) -7-methyl-4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- (4-chloro-3-methyl-phenyl) -N- (5-fluoro-4-methyl-3-pyridinyl) -7-methyl-4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -N- (2, 6-dimethyl-4-pyridinyl) -5- [ 3-methoxy-4- (trifluoromethyl) phenyl ] -7-methyl-4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- [ 3-fluoro-4- (trifluoromethyl) phenyl ] -7-methyl-N- (5-methyl-3-pyridyl) -4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- [ 3-chloro-4- (trifluoromethyl) phenyl ] -N- (5-methoxy-3-pyridyl) -7-methyl-4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -7-methyl-N- (6-methylpyrazin-2-yl) -4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- (4-chlorophenyl) -7-methyl-N- (4-methyl-3-pyridyl) -4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -N- (2, 6-dimethyl-4-pyridinyl) -5- [ 3-fluoro-4- (trifluoromethyl) phenyl ] -7-methyl-4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- [ 3-chloro-4- (trifluoromethyl) phenyl ] -7-methyl-N- (4-methyl-3-pyridinyl) -4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- (4-chloro-3-methyl-phenyl) -7-methyl-N- (4-methyl-3-pyridinyl) -4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- (4-chloro-3-methyl-phenyl) -N- (5-fluoro-3-pyridinyl) -7-methyl-4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- [ 3-chloro-4- (trifluoromethyl) phenyl ] -7-methyl-N- (5-methyl-3-pyridinyl) -4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- (4-chlorophenyl) -N- (5-fluoro-3-pyridyl) -7-methyl-4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- [ 3-fluoro-4- (trifluoromethyl) phenyl ] -7-methyl-4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- [ 3-fluoro-4- (trifluoromethyl) phenyl ] -7-methyl-N- (4-methyl-3-pyridyl) -4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- (4-chlorophenyl) -7-methyl-4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

7- (methoxymethyl) -4-oxo-N-pyrazin-2-yl-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- (4-chlorophenyl) -7-methyl-4-oxo-N-pyrazin-2-yl-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- (4-chloro-3-methyl-phenyl) -7-methyl-4-oxo-N-pyrazin-2-yl-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- (4-chloro-3-methyl-phenyl) -N- (2, 6-dimethyl-4-pyridinyl) -7-methyl-4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7R) -7- (methoxymethyl) -4-oxo-N- (3-pyridyl) -5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -7- (methoxymethyl) -4-oxo-N- (3-pyridyl) -5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7R) -5- [ 3-chloro-4- (trifluoromethyl) phenyl ] -7- (methoxymethyl) -4-oxo-N- (3-pyridyl) -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- [ 3-chloro-4- (trifluoromethyl) phenyl ] -7- (methoxymethyl) -4-oxo-N- (3-pyridyl) -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7R —) 7- (methoxymethyl) -4-oxo-N-pyrazin-2-yl-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -7- (methoxymethyl) -4-oxo-N-pyrazin-2-yl-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

4-oxo-N- (3-pyridyl) -5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide; (7S) -5- [ 3-chloro-4- (trifluoromethoxy) phenyl ] -7-methyl-4-oxo-N- (3-pyridyl) -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -N- [2- (fluoromethyl) -4-pyridinyl ] -7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -N- [2- (hydroxymethyl) -4-pyridinyl ] -7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -N- [2- (methoxymethyl) -4-pyridinyl ] -7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -N- [5- (hydroxymethyl) -3-pyridinyl ] -7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -N- [4- (hydroxymethyl) -3-pyridinyl ] -7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- (3, 4-dichlorophenyl) -N- (6-fluoropyrazin-2-yl) -7-methyl-4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -N- (6-fluoropyrazin-2-yl) -7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

5- [ 3-chloro-4- (trifluoromethyl) phenyl ] -7- (methoxymethyl) -4-oxo-N- (3-pyridinyl) -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

7- (methoxymethyl) -4-oxo-N- (3-pyridyl) -5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

(7S) -5- (4-chloro-3-methyl-phenyl) -7-methyl-4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide;

4- [ [ (7S) -7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carbonyl ] amino ] benzenesulfonyl fluoride;

and pharmaceutically acceptable salts and solvates of such compounds.

Specific compounds according to the invention include:

(7S) -N- (5-fluoro-3-pyridyl) -7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide hydrochloride;

(7S) -N- (3-fluoro-2-pyridyl) -7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide hydrochloride;

(7S) -5- [ 3-chloro-4- (trifluoromethyl) phenyl ] -7-methyl-N- (4-methyl-3-pyridinyl) -4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide hydrochloride.

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. A kind of concreteC of (A)_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 with 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-ethylamine,

di-N-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline, benzathine (benzathine), N-methyl-D-glucamine, hydrabamine salts, and salts with 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-a) may be prepared by coupling reaction of a compound of formula (II-a) with a compound of formula (III) according to conditions known to the skilled person. Such conditions include, for example, a suitable coupling agent, e.g., O- (benzotriazol-1-yl) -N, N, N ', N ' -tetramethyluronium Hexafluorophosphate (HBTU), N- (3-dimethylaminopropyl) -N ' -Ethylcarbodiimide (EDCI) or 2- (7-aza-1H-benzotriazol-1-yl) -1,1,3, 3-tetramethyluronium Hexafluorophosphate (HATU), in a suitable base, e.g., N, N-Diisopropylethylamine (DIPEA), triethylamine (Et)₃N) or 4- (dimethylamino) pyridine (DMAP)) in a suitable solvent (e.g., N, N-Dimethylformamide (DMF) or Dichloromethane (DCM)), in the presence of a suitable solventThe reaction conditions (e.g., at a convenient temperature, typically room temperature (rt)) are maintained for a period of time to ensure completion of the reaction. The compounds of formula (III) can be obtained commercially or prepared according to procedures known in the art. In reaction scheme 1, all variables are as defined in formula (I).

Reaction scheme 1

Experimental procedure 2

Alternatively, the final compound according to formula (I-a) can be prepared by Goldberg coupling reaction of a compound of formula (II-b) with an appropriate aryl/heteroaryl halide of formula (IV) wherein X is halogen, according to conditions known to the skilled person. Such conditions include, for example, the use of a suitable palladium catalyst system, e.g., tris (dibenzylideneacetone) dipalladium (0) (Pd)₂(dba)₃) In the presence of a ligand (e.g., 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (Xantphos)) in the presence of a suitable base (e.g., potassium phosphate (K)₃PO₄) In a suitable solvent, e.g. Tetrahydrofuran (THF), under suitable reaction conditions, e.g. at a convenient temperature, typically varying between 80 ℃ and 100 ℃, especially 90 ℃, for a period of time to ensure completion of the reaction. The compounds of formula (IV) may be obtained commercially or prepared according to procedures known in the art. In reaction scheme 2, all variables are as defined in formula (I).

Reaction scheme 2

Alternatively, it may be by one according to conditions known to the skilled personA Goldberg coupling reaction of a compound of formula (II-b) with an appropriate aryl/heteroaryl halide of formula (IV) wherein X is halogen, to prepare the final compound according to formula (I-a). Such conditions include, for example, the use of a suitable copper catalyst such as copper (I) iodide in the presence of a ligand (e.g., (+/-) -trans-1, 2-cyclohexanediamine) in the presence of a suitable base (e.g., potassium phosphate (K)₃PO₄) In the presence or absence of an organic base such as Triethylamine (TEA), in a suitable solvent such as 1, 4-dioxane, under suitable reaction conditions (e.g. at a convenient temperature, typically varying between 80 ℃ and 120 ℃, especially 100 ℃) for a period of time to ensure completion of the reaction. The compounds of formula (IV) may be obtained commercially or prepared according to procedures known in the art. In reaction scheme 2, all variables are as defined in formula (I).

Experimental procedure 3

Alternatively, the final compound according to formula (I-a) may be prepared by reaction between an activated ester of formula (II-c) and a compound of formula (III) according to conditions known to the skilled person. Such conditions include, for example, the use of a suitable base such as Et₃N and using a suitable activator such as DMAP in a suitable solvent (e.g. THF) under suitable reaction conditions (e.g. at a convenient temperature, typically varying between 60 ℃ and 80 ℃, especially 70 ℃) for a period of time to ensure completion of the reaction. The compounds of formula (III) can be obtained commercially or prepared according to procedures known in the art. In reaction scheme 3, all variables are as defined in formula (I).

Reaction scheme 3

Experimental procedure 4

Alternatively, the final compound according to formula (I-a) may be prepared by a one-pot carbonylation reaction of a compound of formula (V) together with a peptide-type coupling reaction with a suitable compound of formula (III) according to conditions known to the skilled person. Such conditions include, for example, the use of carbon monoxide and a suitable palladium catalyst system such as palladium (II) acetate in the presence of a ligand (e.g., 1, 1-bis (diphenylphosphino) ferrocene (dppf)) in the presence of a suitable base (e.g., Et₃N) in a suitable solvent (e.g. 1, 4-dioxane) for a period of time at suitable reaction conditions (e.g. at a convenient temperature, typically varying between 80 ℃ and 100 ℃, especially 90 ℃) to ensure completion of the reaction. The compounds of formula (III) can be obtained commercially or prepared according to procedures known in the art. In reaction scheme 4, all variables are as defined in formula (I).

Reaction scheme 4

Experimental procedure 5

Alternatively, it is possible to work according to conditions known to the skilled worker by means of an ester of the formula (II-d) (in which R is^yIs C_1-4Alkyl) with a compound of formula (III) to prepare the final compound according to formula (I-a). Such conditions include, for example, the use of suitable Lewis acids (Lewis acids) (e.g., trimethylaluminum (AlMe)₃) Or Grignard reagents (like for example isopropyl magnesium chloride lithium chloride complex solution or ethyl magnesium bromide) or a suitable base (e.g. lithium bis (trimethylsilyl) amide) in a suitable solvent (e.g. THF) under suitable reaction conditions (like for example at a convenient temperature, typically varying between 0 ℃ and 30 ℃) for a period of time to ensure completion of the reaction. Commercially available or according to procedures known in the artPreparing a compound of formula (III). In reaction scheme 5, all variables are as defined in formula (I).

Reaction scheme 5

Experimental procedure 6

Alternatively, the preparation of the final compound according to formula (I), herein referred to as compound of formula (I-b1), wherein R is R, may be carried out by a one-step oxidation of a compound of formula (II-e) according to conditions known to the skilled person²is-C (O) R⁵Or Het²And wherein R⁵Is as defined hereinbefore except that hydrogen (herein referred to as substituent R)^2a). Such conditions include, for example, the use of suitable oxidizing agents such as, for example, dess-martin periodinane(Dess-Martin) In a suitable solvent mixture (e.g. fluorobenzene and dimethyl sulphoxide (DMSO)) and under suitable reaction conditions (such as, for example, at a convenient temperature, typically varying between 80 ℃ and 100 ℃, especially 85 ℃) for a period of time to ensure completion of the reaction. In reaction scheme 6, all variables are as defined in formula (I).

Reaction scheme 6

Experimental procedure 7

Alternatively, the final compound according to formula (I-b1) may be prepared by acylation of a compound of formula (II-b) with a suitable acid chloride of formula (VI) according to conditions known to the skilled person (as defined in experimental procedure 6). Such conditions include, for example, the use of a suitable base such as, for example, pyridine, under suitable reaction conditions (e.g., at a convenient temperature, typically varying between 40 ℃ and 60 ℃, particularly 50 ℃) for a period of time to ensure completion of the reaction. The compounds of formula (VI) may be obtained commercially or prepared according to procedures known in the art. In reaction scheme 7, all variables are as defined in formula (I).

Reaction scheme 7

Experimental procedure 8

Alternatively, the final compound according to formula (I), herein referred to as compound of formula (I-b2), can be prepared by formylation of a compound of formula (II-b) with N, N-dimethylformamide dimethyl acetal (DMFDMA) according to conditions known to the skilled person, wherein R is²is-C (O) R⁵And wherein R⁵Is hydrogen. In reaction scheme 8, all variables are as defined in formula (I).

Reaction scheme 8

Experimental procedure 9

Alternatively, the final compound according to formula (I-a) may be prepared by a deprotection reaction of a compound of formula (I-a1) according to conditions known to the skilled person. The compound of formula (I-a1) can be obtained by: in alkaline medium (e.g. hydroxylamine hydrochloride and Et₃N) in an inert solvent (e.g. an ethanol/water mixture) under suitable reaction conditions (e.g. at a convenient temperature, typically varying between 80 ℃ and 120 ℃, especially 100 ℃) for a period of time to ensure completion of the reaction by removing the protecting group (like for example the dimethylpyrrole protecting group in the compound of formula (I-a 1). In reaction scheme 9, all variables are as defined in formula (I) and R^2bIs comprised as in R²And residues indicated within the scope of the protected forms thereof.

Reaction scheme 9

B. Preparation of intermediate compounds

Experimental procedure 10

The intermediate compound according to formula (II-a) may be prepared according to conditions known to the skilled person, following procedures known in the art, like for example a transition metal catalyzed insertion reaction of carbon monoxide with the intermediate compound of formula (V). Such conditions include, for example, the use of carbon monoxide and a suitable palladium catalyst system, e.g. palladium (II) acetate, in the presence of a ligand (e.g. dppf) in a suitable base (e.g. Et₃N) in a suitable solvent (e.g. 1, 4-dioxane and water) under suitable reaction conditions (e.g. at a convenient temperature, typically varying between 70 ℃ and 90 ℃, especially 80 ℃) for a period of time to ensure completion of the reaction. Alternatively, the ester of formula (II-d) may be saponified to give an intermediate compound of formula (II-a). The reaction can be carried out, for example, by: to the ester solution of formula (II-d) is added a hydroxide such as sodium hydroxide (NaOH) in a suitable polar solvent such as methanol (MeOH). Heating the reaction mixture may increase the reaction yield. Alternatively, the nitrile of formula (II-f) may be hydrolyzed to give a nitrile of formula (II-f)An intermediate compound of formula (II-a). The reaction can be carried out, for example, by: heating a nitrile solution of formula (II-f) in a suitable solvent, such as aqueous hydrochloric acid. Heating the reaction mixture may increase the reaction yield.

The intermediate compound according to formula (II-d) can be prepared according to conditions known to the skilled person, following procedures known in the art, like for example a transition metal catalyzed insertion reaction of carbon monoxide with the intermediate compound of formula (V), wherein R is^yIs C_1-4An alkyl group. Such conditions include, for example, the use of carbon monoxide and a suitable palladium catalyst system, e.g. palladium (II) acetate, in the presence of a ligand (e.g. dppf) in a suitable base (e.g. Et₃N) in a suitable solvent (e.g. 1, 4-dioxane and ethanol (EtOH)), under suitable reaction conditions (e.g. at a convenient temperature, typically varying between 80 ℃ and 100 ℃, especially 95 ℃) for a period of time to ensure completion of the reaction.

The intermediate compounds according to formula (II-f) may be prepared following procedures known in the art, like for example a palladium catalyzed reaction with zinc cyanide with an intermediate of formula (V). Such conditions include, for example, a Negishi type reaction of the intermediate compound of formula (V) with a suitable palladium catalyst system (e.g. 1,1' -bis (diphenylphosphino) ferrocene dichloropalladium (II)), in a suitable solvent (e.g. DMF), under suitable reaction conditions (e.g. at a convenient temperature, typically varying between 130 ℃ and 170 ℃, in particular 150 ℃) for a period of time to ensure completion of the reaction. Stirring and microwave radiation can increase the reaction rate.

In reaction scheme 10, halogen is defined as Cl, Br or I, R^yIs C_1-4Alkyl, and all other variables are as defined in formula (I).

Reaction scheme 10

Experimental procedure 11

The intermediate compound according to formula (II-b) may be prepared following procedures known in the art, like for example by acidic hydrolysis with an intermediate compound of formula (II-f). The reaction can be carried out, for example, by: the nitrile solution of formula (II-f) is heated in a suitable solvent, such as a concentrated sulfuric acid solution. Alternatively, the reaction can be carried out by reacting a compound of formula (II-a) with ammonium chloride (NH) according to conditions known to the skilled worker₄Cl) to prepare an intermediate of formula (II-b). Such conditions include, for example, a suitable coupling agent such as HBTU in the presence of a suitable base (e.g., DIPEA), in a suitable solvent (e.g., DMF), under suitable reaction conditions (e.g., at a convenient temperature, typically room temperature (rt)) for a period of time to ensure completion of the reaction. In reaction scheme 11, all variables are as defined in formula (I).

Reaction scheme 11

Experimental procedure 12

The intermediate compound according to formula (II-c) may be prepared by a palladium-catalyzed carbonylation reaction of an intermediate compound of formula (V) following procedures known in the art, such as, for example, using a carbon monoxide substitute, e.g., a benzoate-type derivative. Such conditions include, for example, the use of, for example, (2,4, 6-trichlorophenyl) formate and a suitable palladium catalytic system such as palladium (II) acetate in the presence of a ligand (e.g., 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (Xantphos)) in the presence of a suitable base (e.g., Et)₃N) in a suitable solvent (e.g., toluene), under suitable reaction conditions (e.g., at a convenient temperature, typicallyType I is carried out at a temperature varying between 60 ℃ and 80 ℃ and in particular at 70 ℃ for a time sufficient to ensure completion of the reaction. The phenyl formate type derivatives can be synthesized according to literature procedures. In reaction scheme 12, halogen is defined as Br or I and all other variables are as defined in formula (I).

Reaction scheme 12

Experimental procedure 13

The intermediate compound according to formula (V) can be prepared by Goldberg coupling reaction of a compound of formula (VII-a) with an appropriate aryl/heteroaryl halide of formula (VIII) 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 (I) catalyst (e.g., copper (I) iodide), in the presence of a ligand (e.g., N' -dimethylethylenediamine), in the presence of a base (e.g., an inorganic carbonate such as sodium carbonate (Na)₂CO₃) Or potassium carbonate (K)₂CO₃) In a suitable solvent (e.g. toluene or a mixture of toluene and DMF), under suitable reaction conditions, e.g. at a convenient temperature, typically varying between 100 ℃ and 140 ℃, in particular 110 ℃, for a period of time to ensure completion of the reaction. The compounds of formula (VIII) can be obtained commercially or prepared according to procedures known in the art.

Alternatively, intermediate compounds according to formula (V) may be prepared via: halogenation of the intermediate of formula (VII-b) with a halogenating agent (e.g. iodine) in the presence of cerium (IV) ammonium nitrate and in an inert solvent (e.g. acetonitrile) under suitable reaction conditions (e.g. at a convenient temperature, typically 70 ℃) for a period of time to ensure completion of the reaction.

In reaction scheme 13, halogen is defined as Br or I and all other variables are as defined in formula (I).

Reaction scheme 13

Experimental procedure 14

The intermediate compounds according to formula (VII-b) can be prepared by Goldberg coupling reaction of a compound of formula (IX-a) with an appropriate aryl/heteroaryl halide of formula (VIII) 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 (I) catalyst (e.g., copper (I) iodide), in the presence of a ligand (e.g., N' -dimethylethylenediamine), in the presence of a base (e.g., an inorganic carbonate such as Na₂CO₃Or K₂CO₃) In a suitable solvent (e.g. toluene or a mixture of toluene and DMF), under suitable reaction conditions, e.g. at a convenient temperature, typically varying between 100 ℃ and 140 ℃, especially 110 ℃, for a period of time to ensure completion of the reaction. The compounds of formula (VIII) can be obtained commercially or prepared according to procedures known in the art.

The intermediate compound according to formula (IX-a) may be prepared by: the protecting group (e.g. Boc group (t-butoxycarbonyl)) in the intermediate of formula (X-a) may be removed under suitable reaction conditions (e.g. at a convenient temperature, e.g. from 15 ℃ to 80 ℃, typically 80 ℃ or from 15 ℃ to 30 ℃, depending on the solvent system) 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 or acetonitrile or ethyl acetate (EtOAc)), followed by application of a protecting group (e.g. Boc group (t-butoxycarbonyl)) under suitable reaction conditions (e.g. at a convenient temperature, typically varying between 0 ℃ and 40 ℃, particularly from 15 ℃ to 30 ℃) to provide a reaction with a protecting group of formula (X-a) under suitable reaction conditions (e.g.Base (e.g. Na)₂CO₃、K₂CO₃Or NaHCO₃) Treatment is carried out for a period of time to ensure completion of the reaction.

An intermediate compound according to formula (X-a) (wherein R^xIs C_1-4Alkyl and PG is a protecting group such as Boc) can be prepared by: the phototransduction (Mitsunobu type reaction) of the intermediate compound of formula (XI-a) with a suitable alcohol of formula (XII) in the presence of a suitable triarylphosphine (e.g. triphenylphosphine) or a suitable trialkylphosphine and a suitable dialkylazodicarboxylate reagent (e.g. di-tert-butylazodicarboxylate or diethylazodicarboxylate) in a suitable inert solvent (e.g. THF) under suitable reaction conditions (e.g. at a convenient temperature, typically varying between 0 ℃ and room temperature, such as 20 ℃) for a period of time to ensure completion of the reaction. Intermediate compounds of formula (XII) and intermediate compounds of formula (IX-a) may be obtained commercially or synthesized according to literature procedures.

In reaction scheme 14, R^xIs C_1-4Alkyl, PG is a protecting group such as Boc and all other variables are as defined in formula (I).

Reaction scheme 14

Experimental procedure 15

The intermediate compound according to formula (VII-a), wherein halogen is bromine or iodine, may be prepared by: for example in the presence of an acidic medium (e.g. hydrochloric acid), in an inert solvent (e.g. 1, 4-dioxane or acetonitrile or ethyl acetate (EtOAc)), under suitable reaction conditions (e.g. at a convenient temperature, for example from 15 ℃ to 80 ℃, typically 80 ℃ or from 15 ℃ to 30 ℃, depending on the solvent system), to remove the compound of formula (X)The protecting group (e.g. Boc group) in the intermediate of-b) for a period of time to ensure completion of the reaction, followed by treatment with a base (e.g. Na) under suitable reaction conditions (e.g. at a convenient temperature, typically varying between 0 ℃ and 40 ℃, especially from 15 ℃ to 30 ℃)₂CO₃、K₂CO₃Or NaHCO₃) Treatment is carried out for a period of time to ensure completion of the reaction.

An intermediate compound of formula (X-b) (wherein halogen is defined as Br or I, R)^xIs C_1-4Alkyl and PG is a protecting group such as Boc) can be prepared by: the Mitsunobu type reaction (Mitsunobu type reaction) between the intermediate compound of formula (XI-b) and an appropriate alcohol of formula (XII) in the presence of a suitable triarylphosphine (e.g. triphenylphosphine) or a suitable trialkylphosphine and a suitable dialkyl azodicarboxylate reagent (e.g. di-tert-butyl azodicarboxylate or diethyl azodicarboxylate) in a suitable inert solvent (e.g. THF) under suitable reaction conditions (e.g. at a convenient temperature, typically varying between 0 ℃ and room temperature, such as 20 ℃) for a period of time to ensure completion of the reaction. Intermediate compounds of formula (XII) can be obtained commercially or synthesized according to literature procedures.

An intermediate compound of formula (IX-b) (wherein R^xIs C_1-4Alkyl) can be prepared via: halogenation of the intermediate of formula (XI-a) with a halogenating reagent (e.g. N-iodosuccinimide) in an inert solvent (e.g. DCM) under suitable reaction conditions (e.g. at a convenient temperature, typically room temperature) for a period of time to ensure completion of the reaction. Intermediate compounds of formula (IX-b) (wherein R is^xIs methyl and halogen is bromo) and the intermediate compound is a particularly preferred material for use in the synthesis (including large scale) of a variety of final compounds of formula (I) according to the general procedure described herein. Intermediate compounds of formula (XI-a) can be obtained commercially or synthesized according to literature procedures.

In reaction scheme 15, halogen is specifically bromine or iodine, R^xIs C_1-4Alkyl, PG is a protecting group (e.g. like Boc) and all other variables are as defined in formula (I).

Reaction scheme 15

Experimental procedure 16

The intermediate compounds according to formula (II-d) can be prepared by Goldberg coupling reaction of a compound of formula (XIII) with an appropriate aryl/heteroaryl halide of formula (VIII) 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 (I) catalyst (e.g., copper (I) iodide), in the presence of a ligand (e.g., N' -dimethylethylenediamine), in the presence of a base (e.g., an inorganic carbonate such as sodium carbonate (Na)₂CO₃) Or potassium carbonate (K)₂CO₃) In a suitable solvent (e.g. toluene or a mixture of toluene and DMF), under suitable reaction conditions, e.g. at a convenient temperature, typically varying between 100 ℃ and 140 ℃, in particular 110 ℃, for a period of time to ensure completion of the reaction. The compounds of formula (VIII) can be obtained commercially or prepared according to procedures known in the art.

The intermediate compound according to formula (XIII) can be prepared according to conditions known to the skilled person, following procedures known in the art, like for example a transition metal catalyzed insertion reaction of carbon monoxide with the intermediate compound of formula (VII-a). Such conditions include, for example, the use of carbon monoxide and a suitable palladium catalyst system, e.g., palladium (II) acetate, in the presence of a ligand (e.g., dppf) in a suitable base (e.g., Et)₃N), in a suitable solvent (e.g.,a mixture of 1, 4-dioxane and MeOH or EtOH) for a period of time at suitable reaction conditions (e.g. at a convenient temperature, typically varying between 70 ℃ and 90 ℃, especially 80 ℃) to ensure completion of the reaction.

In reaction scheme 16, R^yIs C_1-4Alkyl and all other variables are as defined in formula (I).

Reaction scheme 16

Experimental procedure 17

The intermediate compound according to formula (II-d) can be prepared by reaction of a compound of formula (II-b) with N, N-dimethylformamide dimethyl acetal (DMFDMA) according to conditions known to the skilled person, wherein R is^yIs C_1-4An alkyl group. In reaction scheme 17, all variables are as defined in formula (I).

Reaction scheme 17

Experimental procedure 18

The intermediate compounds according to formula (II-e) can be prepared by acylation of a compound of formula (XIV) with a suitable acid chloride of formula (VI) according to conditions known to the skilled person, wherein R is^2aSelected from the group consisting of: r⁵(other than hydrogen) and Het². Such conditions include, for example, the use of suitable bases like, for example, Et₃N, a suitable solvent like for example DCM. Cooling the reaction mixture may increase the reaction yield.

The intermediate compound according to formula (XIV) may be prepared following procedures known in the art, like for example the reduction of an intermediate of formula (II-f), e.g. by catalytic hydrogenation using a suitable metal like for example raney nickel and a suitable solvent, e.g. 7M ammonia solution in MeOH.

The compounds of formula (VI) may be obtained commercially or prepared according to procedures known in the art. In reaction scheme 18, R^2aSelected from the group consisting of: r⁵(other than hydrogen) and Het²And all other variables are as defined in formula (I).

Reaction scheme 18

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 disorders (NCDs) (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, due to prionsNCD of disease, and substance/drug induced NCD; 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, "BEH" means a bridged ethylsiloxane/silica hybrid; "Boc" or "BOC" means tert-butoxycarbonyl; "CI" means chemical ionization; "CSH" means a charged surface hybrid; "DAD" means a diode array detector; "THF" means tetrahydrofuran; "Et₃N "means triethylamine; "DIPE" means diisopropyl ether; "DMAP" means 4- (dimethylamino) pyridine, "DMF" means N, N-dimethylformamide; "dppf" means 1,1' -bis (diphenylphosphino) ferrocene; "Et₂O "meansDiethyl ether; "EtOAc" means ethyl acetate; "edci. hcl" means N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride; "DCM" means dichloromethane; "DMSO" means dimethyl sulfoxide; "DIPEA" means diisopropylethylamine; "L" means liter; "LRMS" means low resolution mass spectrometry/mass spectrometry; "HATU" means 2- (7-aza-1H-benzotriazol-1-yl) -1,1,3, 3-tetramethyluronium hexafluorophosphate; "HBTU" means O- (benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate; "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; "iPrOH" means isopropanol; "iPrNH₂"means isopropylamine; "MeOH" means methanol; "MSD" means a quality selection detector;means that (benzotriazol-1-yloxy) trispyrrolidinyl phosphonium hexafluorophosphate is a registered trademark of Merck KGaA; "Xantphos" means 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene; ' Pd₂(dba)₃"means tris (dibenzylideneacetone) dipalladium (0); "eq" means equivalent; "RP" means inverse; "RT" or "RT" means room temperature; "m.p." means melting point; "min" means minutes; "h" means hours; "s" means seconds; "TOF" means time of flight; "QTOF" means quadrupole-time of flight; "sat." means saturated; "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. Use markQuasi-technique, open column chromatography on silica gel, particle sizeMesh 230-. Automated flash column chromatography was performed on irregular gels (forward single-use flash columns) on different flash systems using easy-connect columns from different vendors.

Nuclear Magnetic Resonance (NMR): for many compounds, will¹H NMR spectra were recorded on a Bruker Avance III, Bruker DPX-400 or Bruker AV-500 spectrometer with standard pulse sequences operating 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.

The stereochemical configuration of a compound has been designated as "R" or "S", and for some compounds, although the compound itself has been isolated as a single stereoisomer and is enantiomerically pure, when absolute stereochemistry is not determined, the stereochemical configuration has been designated as "^*R 'or'^*S”。

Synthesis of intermediate Compounds

Intermediate 1(I-1)

1H-pyrazole-5-carboxylic acid ethyl ester (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 yieldIntermediate compound I-1(2.28g, 93% purity, 94%) as a white solid was used in the next step without further purification.

Intermediate 2(I-2)

4-iodo-1H-pyrazole-5-carboxylic acid ethyl ester (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)

N- [ (2R) -2-hydroxypropyl ] carbamic acid tert-butyl ester (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)

N- (2-hydroxy-3-methoxy-propyl) carbamic acid tert-butyl ester (I-4)

Intermediate I-4 was synthesized following a similar pathway as described for I-3. Starting from 1-amino-3-methoxy-2-propanol (2.3g, 21.9mmol) and introducing a purification step (flash column chromatography (silica; MeOH 0/100 to 5/95 in DCM)), I-4(3.1g, 69%) was obtained.

Intermediate 5(I-5)

2- [ (1S) -2- (tert-Butoxycarbonylamino) -1-methyl-ethyl ] -4-iodo-pyrazole-3-carboxylic acid ethyl ester (I-5)

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-5 as a colorless oil (4.9g, 91% purity, 93%).

Intermediate 6(I-6)

2- [ (1S) -2- (tert-Butoxycarbonylamino) -1-methyl-ethyl ] pyrazole-3-carboxylic acid ethyl ester (I-6)

Intermediate compound I-6 was synthesized following a similar pathway as described for intermediate I-5. Starting from intermediate I-1(25.82g, 184.25mmol) and intermediate I-3(47.16g, 239.5mmol), intermediate I-6(123g, quantitative) was obtained as a yellow oil, which was used without further purification in the next step.

Intermediate 7(I-7)

2- [ (1S) -2-amino-1-methyl-ethyl ] -4-iodo-pyrazole-3-carboxylic acid ethyl ester. Hydrochloride (I-7)

To a solution of intermediate I-5(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-7(3.5g, 97%).

Intermediate 8(I-8)

2- [ (1S) -2-amino-1-methyl-ethyl ] pyrazole-3-carboxylic acid ethyl ester. Hydrochloride (I-8)

Intermediate compound I-8 was synthesized following a similar pathway as described for intermediate I-7. Starting from intermediate I-6(54.79g, 184.25mmol) and 4M HCl solution in 1, 4-dioxane (415mL, 1.66mol), intermediate I-8(32.5g, 82% purity, 75%) was obtained as a white solid, which was used without further purification in the following step.

Intermediate 9(I-9)

(7S) -3-iodo-7-methyl-6, 7-dihydro-5H-pyrazolo [1,5-a ] pyrazin-4-one (I-9)

Intermediate I-7(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-9(92g, 90%).

Intermediate 10(I-10)

(7S) -7-methyl-6, 7-dihydro-5H-pyrazolo [1,5-a ] pyrazin-4-one (I-10)

Intermediate compound I-10 was synthesized following a similar pathway as described for intermediate I-9. Starting from intermediate I-8(32.5g, 139.1mmol), intermediate I-10(14.8g, 70%) was obtained as a solid.

Intermediate 11(I-11)

2- [1- [ (tert-Butoxycarbonylamino) methyl ] -2-methoxy-ethyl ] pyrazole-3-carboxylic acid ethyl ester (I-11)

To a stirred solution of I-1(1.78g, 12.671mmol), intermediate I-4(3.12g, 15.21mmol) and triphenylphosphine (8.31g, 31.68mmol) in THF (80mL) at 0 deg.C under nitrogen was added di-tert-butyl azodicarboxylate (7.30g, 31.68 mmol). The mixture was stirred at room temperature for 1 h. The solvent was evaporated and the residue was treated 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 50/50). The desired fractions were collected and the solvent was evaporated in vacuo to afford intermediate compound I-11(4g, 96%).

Intermediate 12(I-12)

2- [1- (aminomethyl) -2-methoxy-ethyl ] pyrazole-3-carboxylic acid ethyl ester (I-12)

To a solution of I-11(4g, 12.22mmol) in MeCN (55.3mL) was added HCl (4M in dioxane, 15.3mL, 61.1 mmol). The mixture was stirred at room temperature for 1 h. The mixture was evaporated in vacuo to afford intermediate compound I-12(2.77g), which was used as such without further purification.

Intermediate 13(I-13)

7- (methoxymethyl) -6, 7-dihydro-5H-pyrazolo [1,5-a ] pyrazin-4-one (I-13)

To a solution of intermediate I-12(2.77g, 12.189mmol) in MeOH (14.205mL) was added NaHCO₃(saturated aqueous solution, 40 mL). The mixture was stirred at room temperature for 16 h. The mixture was diluted with water and extracted with DCM, EtOAc and THF/EtOAc 1: 1. The organic layer was separated and dried (Na)₂SO₄) Filtered and the solvent evaporated in vacuo to afford intermediate compound I-13(1.92g), which was used as such without further purification.

Intermediate 14(I-14)

4-bromo-2- (methoxymethyl) -1- (trifluoromethyl) benzene (I-14)

To a solution of 5-bromo-2- (trifluoromethyl) -benzyl alcohol (1.96g, 7.666mmol) in THF (30.6mL) at 0 ℃ was added NaH (60% dispersion in mineral oil, 368mg, 9.20mmol) and the mixture was stirred at 0 ℃ for 10 min. Then, iodomethane (573 μ L, 9.22799 mmol) was added and the mixture was stirred at room temperature for 1 h. Then, additional methyl iodide (95 μ L, 1.5mmol) was added and the mixture was stirred for 2 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with saturated NaCl solution and dried (Na)₂SO₄) Filtered and concentrated in vacuo to yield intermediate compound I-14(2.06g), which was used as such without further purification.

Intermediate 15(I-15)

(7S) -7-methyl-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazin-4-one (I-15)

Intermediate I-14(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-15(9.6g, 98%) as a pale yellow oil.

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

intermediate I-20 was also prepared according to the procedure described below for I-34 using 2-chloro-5- (trifluoromethyl) pyridine as reagent.

Intermediate I-22 was also prepared according to the procedure described below for I-34.

Intermediate 33(I-33)

6-chloro-2-methoxy-pyridin-3-amine (I-33)

To a stirred solution of 3-amino-2, 6-dichloropyridine (3g, 18.4mmol) in 1, 4-dioxane (30mL) was added sodium methoxide (25 wt.% in MeOH, 3.7mL, 64.8 mmol). The mixture was stirred at 140 ℃ for 20min under microwave irradiation. The mixture is treated with NH₄The saturated solution of Cl and water was treated and stirred for 30 min. The mixture was then washed with Et₂O extraction, washing with brine and drying (Na)₂SO₄) Filtration and concentration of the solvent in vacuo gave intermediate compound I-33(3.09g, quantitative) as a brown solid, which was then purified by filtrationIt was used in the next step without further purification.

Intermediate 34(I-34)

6-chloro-3-iodo-2-methoxy-pyridine (I-34)

Copper (I) iodide (7.86) in MeCN (600mL) at 0 deg.C_g41.3mmol) and tert-butyl nitrite (48mL, 41.3mmol), intermediate I-33 in MeCN (600mL) was slowly added for 5 min. The mixture was stirred at 0 ℃ for 1 h. It was then stirred at 65 ℃ for 1 h. The crude product was filtered through celite. The mixture was diluted with water and Et₂And O is extracted. The organic phase was separated and dried (Na)₂SO₄) Filtered and the solvent was concentrated in vacuo to yield intermediate compound I-34(7.96g, 71%) as a brown oil, which was used in the next step without any further purification.

Intermediate 35(I-35)

6-chloro-2-methoxy-3- (trifluoromethyl) pyridine (I-35)

To a stirred suspension of intermediate I-34(7.96g, 29.53mmol) and methyl fluorosulfonyl difluoroacetate (8.6mL, 67.9mmol) in DMF (60mL) was added copper (I) iodide (8.44g, 44.3 mmol). The mixture was stirred at 100 ℃ for 16 h. The crude product was filtered through celite. The mixture was washed with Et₂O dilution and NH₄A saturated solution of Cl was washed. The organic layer was separated and dried (Na)₂SO₄) Filtered and the solvent carefully evaporated in vacuo (without heating) to yield intermediate compound I-35(8.92mg, 55% pure, 78%).

Intermediate 36(I-36)

(7S) -5- [ 6-methoxy-5- (trifluoromethyl) -2-pyridyl ] -7-methyl-6, 7-dihydropyrazolo [1,5-a ] pyrazin-4-one (I-36)

To intermediate I-10(5.74g, 37.98mmol), intermediate I-35(14.88g, 37.98mmol), bis Xantphos (4.40g, 7.60mmol), Cs in 1, 4-dioxane (140mL) in a sealed tube and under nitrogen₂CO₃(24.75g, 75.958mmol) to a stirred suspension was added Pd (PPh)₃)₄(4.39g, 3.798 mmol). The mixture was stirred at 100 ℃ for 16 h. The mixture was filtered through a pad of celite and washed with DCM. The organic layer was 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 concentrated in vacuo. The obtained product was purified by flash column chromatography (silica; EtOAc in DCM, 0/100 to 20/80). The desired fractions were collected and concentrated in vacuo to yield intermediate compound I-36(5.52g, 44%) as a brown oil, which solidified upon standing at room temperature.

Intermediate 37(I-37)

(7S) -5- [3- (fluoromethyl) -4- (trifluoromethyl) phenyl ] -7-methyl-6, 7-dihydropyrazolo [1,5-a ] pyrazin-4-one (I-37)

To a stirred solution of intermediate I-28(1.71g, 5.26mmol) in DCM (30mL) was added bis (2-methoxyethyl) amino-sulfur trifluoride (4.85mL, 26.33mmol) at 0 deg.C under nitrogen. The mixture was allowed to warm to room temperature and stirred at room temperature for 17 h. Then it is treated with NaHCO₃The saturated solution was treated at 0 ℃ and extracted with EtOAc. The organic layer was separated and dried (Na)₂SO₄) Filtered and concentrated 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 concentrated in vacuo to yield intermediate compound I-37(1.1mg, 64%) as a colorless oil, which solidified upon standing at room temperature.

Intermediate 38(I-38)

3-iodo-7S-methyl-5- (4-trifluoromethyl-phenyl) -6, 7-dihydro-5H-pyrazolo [1,5-a ] pyrazin-4-one (I-38)

To a solution of intermediate I-15(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. The organic layer was separated and 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-38(24.8g, 90%) as a solid.

In a procedure similar to that described for intermediate I-38, the following intermediates were synthesized:

intermediate 56(I-56)

(7S) -7-methyl-4-oxo-6, 7-dihydro-5H-pyrazolo [1,5-a ] pyrazine-3-carboxylic acid ethyl ester (I-56)

Intermediate I-9(8g, 28.87mmol), Pd (OAc) in EtOH (30mL) and 1, 4-dioxane (30mL) under a CO atmosphere (6atm) at 95 deg.C₂Et (129mg, 0.577mmol) and dppf (640mg, 1.155mmol) were added to a mixture₃N (12mL, 86.62mmol) was continued for 18 h. With saturated NaHCO₃The mixture was diluted and EtOAc was added. The aqueous phase was extracted with EtOAc and DCM/MeOH 9/1. The combined organics were dried (MgSO)₄) Filtered and evaporated. The crude product was purified by flash column chromatography (silica; EtOAc in DCM, 5/100 to 70/30). The desired fractions were collected and concentrated in vacuo to yield intermediate I-56(5g, 74%) as a beige solid.

Intermediate 56 '(I-56')

Starting from I-9 and using Pd (dppf) Cl₂Intermediate 56' was synthesized as a catalyst and DMF as a solvent following a procedure similar to that described for intermediate I-56. After the reaction had taken place, the reaction mixture was filtered through celite, the solvent was concentrated and the crude product was purified by flash column chromatography (silica; EtOAc in petroleum ether 1/10 to 1/0).

intermediate 65(I-65)

(7S) -7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carbonitrile (I-65)

Intermediate I-35(1.6g, 3.80mmol), zinc cyanide (579mg, 4.94mmol) and PdCl in DMF (14.7mL) at 150 deg.C₂(dppf) (139mg, 0.19mmol) was stirred for 16 h. The crude product was filtered through a pad of celite and the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica; DCM). The desired fractions were collected and evaporated in vacuo to afford intermediate compound I-65(1.21g, 99%).

The following intermediates can also be synthesized following a procedure similar to that described for intermediate I-65:

intermediate 69(I-69)

(7S) -7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide (I-69)

Procedure a): a mixture of intermediate I-65(468mg, 1.461mmol) in concentrated sulfuric acid (2.3mL) was stirred at room temperature for 18 h. The mixture was poured onto ice and then washed with NH₄The aqueous OH solution was carefully basified. The mixture was extracted with EtOAc. The organic layer was separated and dried (Na)₂SO₄) Filtration and concentration of the solvent in vacuo afforded intermediate compound I-69(488mg, 99%) as a white solid.

Procedure B): intermediate I-74(170mg, 0.501mmol), NH in DMF (5mL)₄HBTU (285mg, 0.752mmol) was added in portions to a stirred solution of Cl (53mg, 1.002mmol) and DIPEA (0.248mL, 1.503 mmol). The mixture was stirred at room temperature for 3 days. The mixture was poured into NaHCO₃Saturated solution and extracted with EtOAc. The organic layer was separated and dried (MgSO)₄) Filtered and evaporated in vacuo. From 75% H by inversion₂O(25mMNH₄HCO₃) 25% MeCN-MeOH to 0% H₂O(25mM NH₄HCO₃) -100% MeCN-MeOH to purify the crude product. The desired fractions were collected and the solvent was concentrated in vacuo. The crude product was triturated with DIPE to give intermediate compound I-69 as a white solid (145mg, 86%).

Intermediate 70(I-70)

(7S) -7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxylic acid methyl ester (I-70)

Procedure a): intermediate I-38(1.5g, 3.56mmol), Pd (OAc) in MeOH (15mL) and 1, 4-dioxane (15mL) under a CO atmosphere (6atm) at 95 ℃₂(16mg, 0.071mmol), dppf (78mg, 0.142mmol) and Et₃A mixture of N (1.48mL, 10.68mmol) was stirred for 18 h. With NaHCO₃The mixture was diluted with saturated solution and EtOAc was added. The aqueous phase was extracted again. The combined organic layers were washed with water (x2), brine (x2) and dried (MgSO 3)₄) Filtered and evaporated in vacuo. The crude product was purified by flash column chromatography (silica; EtOAc in heptane, 0/100 to 70/30). The desired fractions were collected and concentrated in vacuo to yield intermediate I-70(1.23g, 95%) as a beige solid.

Procedure B): to a solution of intermediate I-69(780mg, 2.31mmol) in MeOH (9.3mL) was added N, N-dimethylformamide dimethyl acetal (0.92mL, 6.92mmol) at room temperature. The mixture was stirred at 45 ℃ for 24 h. The mixture was washed with saturated aqueous NaHCO₄Diluted and extracted with DCM. The organic layer was dried (Na)₂SO₄) Filtered and concentrated in vacuo to yield intermediate I-70(795mg, 97%) as a white solid.

The following intermediates can also be synthesized following a procedure similar to procedure a) described for intermediate I-70:

intermediate 74(I-74)

(7S) -7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxylic acid (I-74)

Procedure a): to a mixture of intermediate I-70(500mg, 1.415mmol) in MeOH (5mL) was added NaOH (2M in water, 0.743mL, 1.486 mmol). The mixture was stirred at 50 ℃ for 4 h. HCl (1N) was then added at 0 ℃ to pH 4-5. The mixture was diluted with EtOAc and washed with water. The organic layer was then separated and dried (MgSO)₄) Filtered and the solvent evaporated in vacuo to yield intermediate compound I-74(500mg) as a beige solid, which was used in the next step without further purification.

The following intermediates can also be synthesized following a procedure similar to procedure a) described for intermediate I-74:

procedure B): to a stirred mixture of intermediate I-70(25mg, 0.071mmol) in 1, 4-dioxane (1mL) and water (0.1mL) was added LiOH (2mg, 0.078mmol) at room temperature. The mixture was stirred at room temperature for 24h and the solvent was concentrated in vacuo to give intermediate compound I-74(23mg, 74%), which was used as such without further purification.

Procedure C): a stirred solution of intermediate I-65(1.99g, 6.213mmol) in HCl (3.9mL, 37% in water) was stirred at 110 ℃ for 18 h. Then, HCl (3.9mL, 37% in water) was added and the mixture was stirred at 110 ℃ for 16 h. The mixture was then allowed to reach room temperature and the solvent was then evaporated in vacuo. Dissolving the residue in waterDissolved in water and extracted with DCM. The organic layer was separated and dried (Na)₂SO₄) Filtered and the solvent evaporated in vacuo to afford intermediate compound I-74(2g, 95%) as a cream solid.

Intermediate 75(I-75)

(7S) -5- [3- (fluoromethyl) -4- (trifluoromethyl) phenyl ] -7-methyl-4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxylic acid I-75

Procedure D): to intermediate I-52(170mg, 0.375mmol), Pd (OAc) in 1, 4-dioxane (30mL)₂Et (2mg, 0.008mmol), dppf (9mg, 0.016mmol) and 3-aminopyridine (35mg, 0.375mmol) were added to the mixture₃N (0.174mL, 1.257mmol), the mixture was stirred at 90 ℃ for 18h under a CO atmosphere (6 atm). The mixture was filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (silica; DCM/MeOH 9:1 in DCM 5/95 to 70/30). The desired fractions were collected and concentrated in vacuo to yield intermediate compound I-75(160mg, 85% pure, 98%).

The following compounds can also be synthesized following procedures a) -D) as indicated, analogous to the procedures for intermediates I-74 and I-75:

intermediate 86(I-86)

(7S) -3- (aminomethyl) -7-methyl-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazin-4-one (I-86)

In thatIn the reactor (Raney nickel short column, 1mL/min, 80 ℃, full of H₂2 cycles) hydrogenation of 7M NH in MeOH (26.4mL)₃Intermediate I-65(440mg, 1.374 mmol) in (1). The solvent was concentrated in vacuo to give intermediate compound I-86 as a colorless oil (460mg, 98%).

Intermediate 87(I-87)

(2,4, 6-Trichlorophenyl) (7S) -7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxylic acid ester (I-87)

Intermediate I-38(800mg, 1.90mmol) in 1, 4-dioxane (4.8mL), Pd (OAc)₂(13mg, 0.057mmol), Xantphos (66mg, 0.114mmol) and Et₃A mixture of N (0.528mL, 3.80mmol) was degassed for 5min and then stirred under nitrogen at 70 ℃ for 5 min. A solution of phenyl 2,4, 6-trichloroformate (prepared as described in organic chemistry communications (org. Lett.)2014, 5370-Astro 5373) (728mg, 3.230mmol) in degassed toluene (7.2mL) was then added over 4h using a syringe pump. The crude product was filtered through a filter and the solvent was concentrated in vacuo. The crude product was purified by flash column chromatography (silica; DCM). The desired fractions were collected and evaporated in vacuo to give a residue which was purified by RP HPLC (stationary phase: C)₁₈Xbridge 30x100mm 5 μm, flowMoving phase: gradient from 54% 0.1% NH in water₄CO₃H/NH₄OH pH9 solution, 46% MeCN to 64% 0.1% NH in Water₄CO₃H/NH₄OH pH9 solution, 36% MeCN) to yield intermediate compound I-87(390mg, 80% pure, 31%).

The following intermediates can also be synthesized following a procedure similar to that described for intermediate I-87:

intermediate 89(I-89)

(7S) -N- [ [6- (2, 5-dimethylpyrrol-1-yl) -3-pyridine ] methyl ] -7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide (I-89)

To a stirred solution of intermediate I-74(60mg, 0.177), 6- (2, 5-dimethyl-1H-pyrrol-1-yl) -3-pyridinemethanamine (CAS: 1531539-96-4, 43mg, 0.212mmol) and DIPEA (87.8. mu.L, 0.531mmol) in DMF (3mL) was added HBTU (0.101g, 0.266mmol) in portions. The mixture was stirred at room temperature for two days. With saturated NaHCO₃The mixture was diluted with aqueous solution and extracted with EtOAc. The organic layer was then separated and dried (MgSO)₄) Filtered and evaporated in vacuo. The crude product was purified by flash column chromatography (silica; EtOAc in DCM, 5/100 to 30/70). The desired fractions were collected and the solvent was concentrated in vacuo to yield intermediate compound I-89(75mg, 80%) as a colorless oil.

Intermediate 90(I-90)

N- [ [ (7S) -7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazin-3-yl ] methyl ] cyclobutanecarboxamide (I-90)

To intermediate I-86(240mg, 0.555mmol) in DCM (2.1mL),(289mg, 0.555mmol) and Et₃To a solution of N (116. mu.L, 0.832mmol) was added cyclobutanecarboxylic acid (56mg, 0.555 mmol). The mixture was stirred at room temperature for 1 h. The mixture was then diluted with water and extracted with DCM. The organic layer was dried (Na)₂SO₄) Filtered and concentrated in vacuo. By flash column chromatography (silica; 7N NH)₃0/100 to 3/97 in MeOH/DCM). The desired fractions were collected and the solvent was concentrated in vacuo. By RP HPLC (stationary phase: C18Xbridge 30X100mm 5 μm, mobile phase: gradient from 67% 0.1% NH in water₄CO₃H/NH₄OH pH9 solution, 33% MeCN to 50% 0.1% NH in Water₄CO₃H/NH₄OH pH9 solution, 50% MeCN) to yield intermediate compound I-90(145mg, 64%).

Intermediate 91(I-91)

N- [ [ (7S) -7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazin-3-yl ] methyl ] acetamide (I-91)

Intermediate I-86(0.24g, 0.74mmol) and Et in DCM (5mL) under nitrogen at-78 deg.C₃Acetyl chloride (52. mu.L, 0.74mmol) was added to a stirred solution of N (103. mu.L, 0.74 mmol). The mixture was stirred at-78 ℃ for 1h and then by addition of saturated aqueous Na₂CO₃Quenching is carried out. The mixture was allowed to reach room temperatureAnd the organic layer was separated and dried (Na)₂SO₄) Filtered and the solvent concentrated in vacuo. The crude product was purified by flash chromatography (silica; MeOH 0/100-8/92 in DCM) to give intermediate I-91(230mg, 76% pure, 64%).

The samples were purified by RP HPLC (stationary phase: C18Sunfire 19X 100mm 5 μm, mobile phase: gradient from 80% 0.1% HCOOH solution in water, 20% MeCN to 0% 0.1% HCOOH solution in water, 100% MeCN) and the residue was dissolved in DCM and washed with aqueous NaHCO₃Washing is carried out. The organic layer was dried (Na)₂SO₄) Filtration and concentration of the solvent in vacuo afforded intermediate compound I-91(20mg) as a colorless oil.

Intermediate 92(I-92)

At-78 deg.C (holding temperature)<To (5-fluoro-3-pyridyl) -carbamic acid 1, 1-dimethylethyl ester (CAS: 342603-20-7, 2.82g, 13.28mmol) was added dropwise butyl lithium (2.5M in hexane, 13.3mL, 33.21 mmol). The resulting mixture was warmed to-30 ℃ and stirred at this temperature for 2 h. The solution was cooled to-78 ℃ and methyl iodide (3.3mL, 53.15mmol) was added dropwise (maintaining temperature)<-70 ℃ C. The resulting solution was stirred at-78 ℃ for 1.5h and quenched by addition of water (5 mL). The mixture was diluted with EtOAc and water. The organic phase 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 30/70). The desired fractions were collected and concentrated in vacuo to yield intermediate I-92(2.67g, 89%) as a pale yellow oil.

Intermediate 93(I-93)

To a stirred solution of intermediate I-92(2.67g, 11.81mmol) in DCM (42mL) was added trifluoroacetic acid (4.54mL, 59.00 mmol). The mixture was stirred at room temperature for 1 h. The solvent was concentrated in vacuo. The residue was dissolved in DCM and taken up with Na₂CO₃The saturated solution is washed. The organic layer was separated and dried (Na)₂SO₄) Filtration and concentration of the solvent in vacuo afforded intermediate I-93(1.07g, 72%) as a light brown solid. The aqueous phase was further extracted with DCM/EtOH (9/1). The organic layer was separated and dried (Na)₂SO₄) Filtration and concentration of the solvent in vacuo afforded intermediate compound I-93(460mg, 83% pure, 25%) as a brown oil.

The following compounds can also be synthesized following a procedure similar to that described for compound I-93:

preparation of the Final Compounds

Example 1(E-1)

(7S) -7-methyl-4-oxo-N- (3-pyridyl) -5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide (Compound No. 1)

To intermediate I-74(130mg, 0.383mmol), 3-aminopyridine (36mg, 0.383mmol) in dry DCM (10mL) was added DMAP (70mg, 0.575 mmol). Molecular sieve powder (1g,activated) and the mixture was stirred at room temperature for 1 h. SubsectionEdci. hcl (110mg, 0.575mmol) was added in portions and the mixture was stirred at room temperature for 24 h. The mixture was filtered through a pad of celite and 10% aqueous NH₄The filtrate was washed twice with Cl solution. The organic layers were combined and dried (MgSO)₄) Filtered and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (silica; DCM/MeOH 20:1 in DCM 5/95 to 70/30). The desired fractions were collected and the solvent was concentrated in vacuo. The solid was triturated with DIPE to yield the final compound of compound No. 1 as a white solid (141mg, 87%).¹H NMR(300MHz,CDCl₃)ppm 1.79(d,J＝6.6Hz,3H)4.06(dd,J＝12.9,7.3Hz,1H)4.35(dd,J＝12.8,4.3Hz,1H)4.79-4.96(m,1H)7.27-7.35(m,1H)7.57(d,J＝8.4Hz,2H)7.82(d,J＝8.4Hz,2H)8.23-8.41(m,2H)8.37(s,1H)8.85(br.s.,1H)12.10(br.s.,1H)。

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

alternatively, compounds numbers 36, 41 and 47 were prepared according to a method analogous to that described in E-8, starting from I-59 ', I-64 ' and I-58 ', respectively; (. x) compounds No. 20, compound No. 21, compound No. 25, compound No. 26, compound No. 35, compound No. 36, compound No. 41, compound No. 46, compound No. 47, compound No. 52, compound No. 54 were alternatively prepared according to the methods described below (different purification reverse phase solvent systems) which gave the desired compounds and the corresponding carboxylic acid species:

example 1a (E-1a)

To intermediate I-40(237mg, 0.544mmol) in 1, 4-dioxane (30mL), Pd (OAc)₂Et (2mg, 0.011mmol), dppf (12mg, 0.022mmol) and 3-aminopyridine (77mg, 0.818mmol) were added to the mixture₃N (0.227mL, 1.635mmol) was stirred at 90 ℃ for 18h under a CO atmosphere (6 atm). The mixture was filtered and the solvent was concentrated in vacuo. From 75% H by inversion₂O (0.1% TFA) -25% MeCN 38% H2O (0.1% TFA) -62% MeCN to purify the crude product. The product was neutralized, concentrated and extracted with EtOAc to give the final compound of compound number 36 (25mg, 11%); intermediate compound I-77(149mg, 74%) was used in the subsequent steps without further purification.

The following compounds and intermediates can also be synthesized following a procedure similar to that described for compound number 36 and intermediate I-77(E-1 a):

example 2(E-2)

(7S) -N- (6-fluoro-3-pyridyl) -7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide (Compound No. 55)

Intermediate I-87(200mg, 0.385mmol), 5-amino-2-fluoropyridine (86mg, 0.771mmol) and Et in THF (6.7mL) under nitrogen at room temperature₃DMAP (2mg, 0.019mmol) was added to a stirred mixture of N (161. mu.L, 1.156 mmol). The mixture was stirred at 70 ℃ for 18 h. The solvent was concentrated in vacuo. By flash column chromatographySilicon oxide; 7N ammonia in MeOH in DCM, 0/100 to 3/97). The desired fractions were collected and the solvent was evaporated in vacuo. By RP HPLC (stationary phase: C18Xbridge 30X100mm 5 μm, mobile phase: gradient from 54% 0.1% NH in water₄CO₃H/NH₄OH pH9 solution, 46% MeCN to 64% 0.1% NH in Water₄CO₃H/NH₄OH pH9 solution, 36% MeCN) to yield compound number 55 final compound (75mg, 45%).¹H NMR(400MHz,CDCl₃)ppm 1.77(d,J＝6.7Hz,3H)4.05(dd,J＝12.9,7.4Hz,1H)4.33(dd,J＝12.8,4.3Hz,1H)4.85(quind,J＝6.7,4.5Hz,1H)6.89(dd,J＝8.8,3.2Hz,1H)7.55(d,J＝8.3Hz,2H)7.80(d,J＝8.6Hz,2H)8.28(ddd,J＝8.9,7.1,2.8Hz,1H)8.34(s,1H)8.45(dd,J＝2.3,1.2Hz,1H)12.08(br.s,1H)。

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

example 3(E-3)

(7S) -7-methyl-4-oxo-N-phenyl-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide (Compound No. 57)

To a stirred solution of intermediate I-74(150mg, 0.442mmol), aniline (48. mu.L, 0.53mmol) and DIPEA (219. mu.L, 1.326mmol) in DMF (3mL) was added HBTU (251mg, 0.663mmol) in portions. The mixture was stirred at room temperature for 16 h. With NaHCO₃Saturated solution of (2)The mixture was diluted and extracted with EtOAc. The organic layer was then separated and dried (MgSO)₄) Filtered and the solvent evaporated in vacuo. From 50% [25mM NH ] by reverse phase₄HCO₃pH＝8]-50％[MeCN:MeOH 1:1]To 0% [25mM NH ]₄HCO₃pH＝8]-100％[MeCN:MeOH 1:1]The crude product was purified. The desired fractions were collected and the solvent was concentrated in vacuo. This product was triturated with DIPE to give the final compound of compound No. 57 as a white solid (115mg, 62%).¹H NMR(300MHz,CDCl₃)ppm 1.77(d,J＝6.6Hz,3H)4.02(dd,J＝12.9,7.3Hz,1H)4.32(dd,J＝12.9,4.3Hz,1H)4.76-4.92(m,1H)7.03-7.13(m,1H)7.31(t,J＝7.9Hz,2H)7.55(d,J＝8.2Hz,2H)7.73(d,J＝7.6Hz,2H)7.79(d,J＝8.4Hz,2H)8.35(s,1H)11.86(br.s.,1H)。

The following compounds can also be synthesized following a procedure similar to that described for E-3:

example 4(E-4)

(7S) -5- (5-chloro-6-methoxy-2-pyridyl) -7-methyl-4-oxo-N-phenyl-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide (Compound No. 83)

A mixture of intermediate I-79(100mg, 0.297mmol), aniline (30. mu.L, 0.327mmol), HATU (147mg, 0.386mmol) and DIPEA (119. mu.L, 0.683mmol) in DMF (1.5mL) was stirred at 80 ℃ for 16 h. The mixture was diluted in DCM and with NaHCO₃Washing with saturated solution. The organic layer was separated and dried (Na)₂SO₄) Filtered and the solvent evaporated in vacuo. The crude product was triturated with MeOH to give compound No. 83 as a light yellow solid, final compound (75mg, 61%).¹H NMR(400MHz,CDCl₃)ppm 1.73(d,J＝6.7Hz,3H)4.03(s,3H)4.34(dd,J＝13.6,7.2Hz,1H)4.56(dd,J＝13.6,4.2Hz,1H)4.79(quind,J＝6.7,6.7,6.7,6.7,4.3Hz,1H)7.05-7.15(m,1H)7.29-7.40(m,2H)7.61(d,J＝8.1Hz,1H)7.74-7.77(m,2H)7.77(d,J＝8.3Hz,1H)8.34(s,1H)11.91(br.s,1H)。

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

example 5(E-5)

(7S) -5- [ 4-chloro-3- (difluoromethoxy) phenyl ] -7-methyl-N- (2-methyl-4-pyridyl) -4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide (Compound No. 84)

To intermediate I-49(290mg, 0.693mmol), Pd (OAc)₂Et (3mg, 0.013mmol) and dppf (14mg, 0.026mmol) were added to the mixture₃N (275. mu.L, 1.983 mmol); 4-amino-2-methylpyridine (71mg, 0.661mmol) in 1, 4-dioxane (30mL) was stirred at 90 ℃ for 18h under a CO atmosphere (6 atm). With NaHCO₃The mixture was diluted with EtOAc and extracted with EtOAc. 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 90/10). The desired fractions were collected and the solvent was concentrated in vacuo. The product was triturated with pentane to yield compound number 84 final compound (135mg, 45%).¹H NMR(300MHz,CDCl₃)ppm 1.76(d,J＝6.5Hz,3H)2.53(s,3H)3.99(dd,J＝12.9,7.6Hz,1H)4.26(dd,J＝12.9,4.3Hz,1H)4.75-4.90(m,1H)6.63(t,J＝72.7Hz,1H)7.22-7.29(m,1H)7.33(s,1H)7.47(d,J＝5.6Hz,1H)7.50(s,1H)7.61(d,J＝8.7Hz,1H)8.32(s,1H)8.36(d,J＝5.6Hz,1H)12.08(br.s.,1H)。

The following compounds can also be synthesized following a procedure similar to that described for E-5:

example 6(E-6)

(7S) -5- (3, 4-dichlorophenyl) -N- (5-fluoro-2-pyridyl) -7-methyl-4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide (Compound No. 98)

To compound number 76 (150mg, 0.442mmol), Xantphos (26mg, 0.044mmol), K in THF (6mL) in a sealed tube and under nitrogen₃PO₄(281mg, 1.326mmol) of the stirred mixture to which Pd was added₂(dba)₃(24mg, 0.026mmol) and 2-bromo-5-fluoropyridine (78mg, 0.442 mmol). The mixture was stirred at 90 ℃ for 4 h. With NaHCO₃The mixture was treated with EtOAc 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; EtOAc in heptane, 0/100 to 50/50). The desired fractions were collected and after trituration with DIPE, the solvent was concentrated in vacuo to yield the final compound of compound No. 98 as a cream solid (178mg, 93%).¹H NMR(400MHz,CDCl₃)ppm1.75(d,J＝6.7Hz,3H)3.97(dd,J＝12.9,7.4Hz,1H)4.26(dd,J＝12.8,4.3Hz,1H)4.82(quind,J＝6.7,4.4Hz,1H)7.26(dd,J＝8.6,2.5Hz,1H)7.43(ddd,J＝9.1,7.8,3.0Hz,1H)7.51(d,J＝2.5Hz,1H)7.55(d,J＝8.6Hz,1H)8.19(d,J＝3.0Hz,1H)8.34(s,1H)8.38(dd,J＝9.2,3.9Hz,1H)12.39(br.s,1H)。

The following compounds can also be synthesized following a procedure similar to that described for E-6:

EXAMPLE 7(E-7) (7S) -N- (3-methoxyphenyl) -5- [ 6-methoxy-5- (trifluoromethyl) -2-pyridyl ] -7-methyl-4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide (Compound No. 119)

Under the nitrogen atmosphere at the temperature of 0 ℃,to a stirred solution of M-anisidine (66 μ L, 0.585mmol) in THF (2.5mL) was added trimethylaluminum (2M in heptane, 293 μ L, 0.585 mmol). To this solution was added intermediate I-72(150mg, 0.390mmol) in THF (2mL) at 0 deg.C. The mixture was stirred at 150 ℃ for 5min under microwave irradiation. The excess trimethylaluminum was quenched with HCl 1N and diluted with DCM. 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 20/80). The desired fractions were collected and the solvent was evaporated in vacuo to yield the final compound of compound number 119 as a white solid (92mg, 49%).¹H NMR(400MHz,CDCl₃)ppm 1.74(d,J＝6.7Hz,3H)3.84(s,3H)4.06(s,3H)4.40(dd,J＝13.8,7.3Hz,1H)4.63(dd,J＝13.6,4.2Hz,1H)4.79(quind,J＝6.7,4.3Hz,1H)6.67(ddd,J＝7.6,2.5,1.6Hz,1H)7.14-7.26(m,2H)7.58(t,J＝2.1Hz,1H)7.78(d,J＝8.1Hz,1H)8.00(d,J＝8.6Hz,1H)8.34(s,1H)11.82(br.s,1H)。

The following compounds can also be synthesized following a procedure similar to that described for E-7:

example 8(E-8)

(7S) -7-methyl-5- [ 3-methyl-4- (trifluoromethyl) phenyl ] -4-oxo-N- (3-pyridyl) -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide (Compound No. 36)

To a stirred solution of 3-aminopyridine (1.15g, 12.25mmol) in THF (49.5mL) under nitrogen was added a complex solution of isopropyl magnesium chloride lithium chloride (1.3M in THF, 12.6mL, 16.33 mmol). The mixture was stirred at room temperature for 1 h. To intermediate in THF (49.5mL)I-59(3g, 8.16mmol) was added to the resulting solution and the mixture was stirred at 65 ℃ for 16 h. More solution of isopropylmagnesium chloride lithium chloride complex (1.3M in THF, 6.3mL, 8.16mmol) was added and the mixture was stirred at 70 ℃ for 1 h. Water was added and the mixture was extracted with EtOAc. The organic layer 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 100/0). The desired fractions were collected and the solvent was concentrated in vacuo. The crude product was purified by flash column chromatography (silica; MeOH in DCM, 0/100 to 10/90). The desired fractions were collected and the solvent was concentrated in vacuo. The residue was triturated with DIPE to give the final compound of compound No. 36 as a white solid (2g, 57%).¹H NMR(500MHz,CDCl₃)ppm 1.76(d,J＝6.4Hz,3H)2.58(s,3H)4.01(dd,J＝13.0,7.2Hz,1H)4.30(dd,J＝13.0,4.3Hz,1H)4.79-4.87(m,1H)7.25(dd,J＝8.1,4.6Hz,1H)7.32(d,J＝8.4Hz,1H)7.35(s,1H)7.77(d,J＝8.4Hz,1H)8.24(dt,J＝8.4,1.4Hz,1H)8.32(dd,J＝4.6,0.9Hz,1H)8.34(s,1H)8.81(d,J＝2.3Hz,1H)12.05(br.s.,1H)。

The following compounds can also be synthesized following a procedure similar to that described for E-8:

example 9(E-9)

(7S) -N- (5-fluoro-4-methyl-3-pyridine) -7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide (Compound No. 124)

To a stirred solution of intermediate I-93(75mg, 0.598mmol) in THF (5mL) was added lithium bis (trimethylsilyl) amide (1M in THF, 0.653mL, 0.653mmol) at 0 deg.C. The mixture was stirred at 0 ℃ for 30min, then cooled to-10 ℃ and intermediate I-61(200mg, 0.544mmol) in THF (3mL) was added. The mixture was stirred at-10 ℃ for 1 h. The mixture was diluted with water and extracted with EtOAc. The organic layer 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 20/80 and then 7N ammonia in MeOH in DCM 10/90). The desired fractions were collected and the solvent was concentrated in vacuo. The residue was triturated with DIPE to yield the final compound of compound No. 124 as a pale clear solid (76mg, 31%).¹H NMR(500MHz,CDCl₃)ppm 1.78(d,J＝6.4Hz,3H)2.25(d,J＝1.4Hz,3H)4.05(dd,J＝12.9,7.4Hz,1H)4.34(dd,J＝12.9,4.2Hz,1H)4.82-4.90(m,1H)7.53(d,J＝8.4Hz,2H)7.78(d,J＝8.4Hz,2H)8.22(s,1H)8.36(s,1H)8.94(s,1H)11.56(br.s,1H)。

The following compounds can also be synthesized following a procedure similar to that described for E-9:

example 10(E-10)

(7S) -5- [ 3-chloro-4- (trifluoromethyl) phenyl ] -N- (5-fluoro-4-methyl-3-pyridyl) -7-methyl-4-oxo-6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide (Compound No. 133)

To a stirred solution of ethylmagnesium bromide (1M in THF, 0.448mL, 0.448mmol) under nitrogen was added intermediate I-93(56mg, 0.448mmol) in THF (1 mL). The mixture was stirred at room temperature for 1 h. To a stirred solution of intermediate I-58(150mg, 0.373mmol) in THF (0.84mL) was added the resulting solution and the mixture was stirred at room temperature for 18 h. Water was added and the mixture was extracted with EtOAc. The organic layer 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 20/80 and then 7N ammonia in MeOH in DCM 10/90). The desired fractions were collected and the solvent was concentrated in vacuo. The residue was triturated with DIPE to yield compound number 133 final compound as an off-white solid (65mg, 36%).¹H NMR(500MHz,CDCl₃)ppm 1.78(d,J＝6.4Hz,3H)2.27(d,J＝1.4Hz,3H)4.05(dd,J＝12.7,7.5Hz,1H)4.32(dd,J＝12.9,4.2Hz,1H)4.86(quind,J＝6.9,4.3Hz,1H)7.43(dd,J＝8.4,1.4Hz,1H)7.59(d,J＝2.0Hz,1H)7.83(d,J＝8.4Hz,1H)8.23(br.s.,1H)8.37(s,1H)8.95(br.s.,1H)11.44(s,1H)。

Example 11(E-11)

To a solution of intermediate I-69 or Compound No. 73(30mg, 0.0887mmol) in DCM (0.568mL) was added N, N-dimethylformamide dimethyl acetal (15.315. mu.L, 0.115mmol) at room temperature. Then addingAnd the mixture was stirred at 70 ℃ for 40min under microwave irradiation. The mixture was filtered through a pad of celite and washed with DCM. The solvent was removed in vacuo and the residue was purified by flash column chromatography (EtOAc in DCM, gradient from 0:100 to 50: 50). The desired fractions were collected and concentrated in vacuo to yield the final compound of compound number 134 as a white solid (19g, 58.49%).¹H NMR(500MHz,CDCl₃)ppm 1.77(d,J＝6.6Hz,3H)4.04(dd,J＝13.0,7.5Hz,1H)4.32(dd,J＝13.0,4.3Hz,1H)4.85(quind,J＝6.8,4.3Hz,1H)7.52(d,J＝8.4Hz,2H)7.76(d,J＝8.4Hz,2H)8.34(s,1H)9.34(d,J＝9.2Hz,1H)12.35(br.d,J＝8.4Hz,1H)。

Example 12(E-12)

(7S) -7-methyl-N- (2-methylpyridine-4-carbonyl) -4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide (Compound No. 135)

To a stirred mixture of intermediate I-69(174mg, 0.514mmol) in pyridine (414. mu.L) was added 2-methyl-4-pyridinecarbonyl chloride (80mg,0.514mmol) under nitrogen. The mixture was stirred at 50 ℃ for 2 h. The solvent was concentrated in vacuo and the crude product was purified by flash column chromatography (silica, 7N ammonia in MeOH in DCM 0:100 to 4:96) to yield a colorless oil which was purified by RP HPLC (stationary phase: C18Xbridge 30X100mm 5 μm; mobile phase: gradient from 67% 0.1% NH in water₄CO₃H/NH₄OH pH9 solution, 33% MeCN to 50% 0.1% NH in Water₄CO₃H/NH₄OH pH9 solution, 50% MeCN) was further purified to yield the final compound of compound No. 135 (11mg, 5%).¹H NMR(500MHz,CDCl₃)ppm 1.77(d,J＝6.6Hz,3H)2.55(s,3H)4.09(dd,J＝13.0,7.5Hz,1H)4.36(dd,J＝13.0,4.3Hz,1H)4.86(quind,J＝6.9,4.2Hz,1H)7.56(br.d,J＝8.4Hz,2H)7.60(dd,J＝5.2,1.2Hz,1H)7.71(br.s,1H)7.79(br.d,J＝8.4Hz,2H)8.36(s,1H)8.60(d,J＝5.2Hz,1H)13.12(br.s,1H)。

Example 13(E-13)

(7S) -N- [ (6-amino-3-pyridyl) methyl ] -7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide (Compound No. 136)

Intermediate I-89(75mg, 0.144mmol), hydroxylamine hydrochloride (50mg, 0.72mmol) and Et in EtOH (2mL) and water (1mL)₃A mixture of N (20. mu.L, 0.144mmol) was stirred at reflux for 20 h. Hydroxylamine hydrochloride (50mg, 0.72mmol) and Et were added₃N (20. mu.L, 0.144 mmol). The mixture was refluxed for another 12h and then cooled. The cooled solution was quenched with HCl and Et₂O wash and adjust pH to 9-10 with 2M NaOH. The resulting mixture was extracted several times with DCM. The combined organic phases were dried (MgSO)₄) And the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica; DCM-MeOH9/1 in DCM 5/100 to 70/30). The desired fractions were collected and the solvent was evaporated in vacuo. The product was triturated with DIPE to yield the final compound of compound number 136 as a white solid (43mg, 66%).¹H NMR(300MHz,CDCl₃)ppm 1.65(d,J＝6.6Hz,3H)3.89(dd,J＝12.8,7.1Hz,1H)4.20(dd,J＝12.8,4.3Hz,1H)4.31(br.s.,2H)4.36(d,J＝5.8Hz,2H)4.65-4.78(m,1H)6.36(d,J＝8.4Hz,1H)7.37-7.45(m,3H)7.68(br.d,J＝8.4Hz,2H)7.94(d,J＝1.5Hz,1H)8.20(s,1H)9.99(br.t,J＝5.1,5.1Hz,1H)。

Example 14(E-14)

(7S) -N- (Cyclobutanecarbonyl) -7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl ] -6, 7-dihydropyrazolo [1,5-a ] pyrazine-3-carboxamide (Compound No. 137)

To a stirred solution of intermediate I-90(100mg, 0.246mmol) in fluorobenzene (2.5mL) and DMSO (100 μ L) was added dess-martin periodinane (167mg, 0.394mmol) at room temperature. The resulting mixture was stirred at 85 ℃ for 1h in a sealed tube. The compound was allowed to reach room temperature and then was washed with EtOAc and Na₂S₂O₃The aqueous solution was partitioned between. The organic layer was dried (MgSO₄) Filtered and the solvent concentrated in vacuo. The crude product was purified by flash column chromatography (silica; MeOH in DCM 10: 90). The desired fractions were collected and the solvent was concentrated in vacuo to give a residue which was purified by RPHPLC (stationary phase: C18Xbridge 30X100mm 5 μm, mobile phase: gradient from 54% 0.1% NH in water₄CO₃H/NH₄OH pH9 solution, 46% MeCN to 64% 0.1% NH in Water₄CO₃H/NH₄OH pH9, 36% MeCN) to yield compound number 137 final compound (45mg, 43%).¹H NMR(500MHz,CDCl₃)ppm 1.74(d,J＝6.4Hz,3H)1.81-1.90(m,1H)1.91-2.02(m,1H)2.18-2.28(m,2H)2.29-2.39(m,2H)3.66(quin,J＝8.5Hz,1H)4.02(dd,J＝13.0,7.2Hz,1H)4.31(dd,J＝13.0,4.3Hz,1H)4.78-4.86(m,1H)7.52(d,J＝8.1Hz,2H)7.76(d,J＝8.4Hz,2H)8.28(s,1H)12.18(br.s.,1H)。

The following compounds can also be synthesized following a procedure similar to that described for E-14:

example 15(E-15)

(7S) -N- [5- (hydroxymethyl) pyridin-3-yl ] -7-methyl-4-oxo-5- [4- (trifluoromethyl) phenyl ] -4,5,6, 7-tetrahydropyrazolo [1,5-a ] pyrazine-3-carboxamide (Compound No. 148)

To intermediate I-69(202.6mg, 0.599mmol), heteroaryl-halide [37669-64-0 ] in 1, 4-dioxane (8.1mL), was added](201.7mg, 0.898mmol) and K₃PO₄(381.4mg, 1.797mmol) to the stirred suspension was added copper (I) iodide (45.6mg, 0.240 mmol). The mixture was flushed with nitrogen for a few minutes and then (+/-) -trans-1, 2-cyclohexanediamine (28.8. mu.L, 0.240mmol) and TEA (0.250mL, 1.797mmol) were added. The compound was stirred at 100 ℃ for 18h under nitrogen in a sealed tube. More TEA (0.250mL, 1.797mmol) was then added and stirred at 100 ℃ for 4 h. The mixture was then diluted with NH4 OH/brine and extracted with EtOAc. The organic layer was separated and evaporated in vacuo. The crude product was purified by flash column chromatography (silica; EtOAc in DCM, 0/100 to 100/0). The desired fractions were collected and the solvent was concentrated in vacuo. The crude product was triturated with DIPE, filtered and dried to yield the final compound of compound number 148 as a white solid (122mg, 46%).

The following compounds can also be synthesized following a procedure similar to that described for E-15:

table 1 below lists additional compounds of formula (I).

TABLE 1The preparation of the following compounds followed the procedure exemplified in the experimental part (experimental number). Demonstration and description in the Experimental sectionCompounds are marked with an asterisk. For some compounds, the stereochemical configuration has been assigned when the absolute stereochemistry is not determined, although the compound itself has been isolated as a single stereoisomer and is enantiomerically pure^*R or^*S。

The values for salt stoichiometry or acid content in the compounds as provided herein are those obtained experimentally and may differ when using different analytical methods. By passing¹H NMR analysis and/or elemental analysis determines the hydrochloric acid content reported herein.

Analysis section

Melting Point

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

DSC823e(A)：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.

Mettler-toledo MP50(B): for a number of compounds, melting points were determined in open-tube capillaries on a mertler-toledo MP 50. Melting points were measured using a temperature gradient of 10 ℃/min. The maximum temperature was 300 ℃. Melting point data was read from a digital display and examined from a video recording system.

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). For molecules with multiple isotopic patterns (Br, Cl), the values recorded 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 in ℃ C.)(T); run time in minutes).

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. ═ undetermined

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

(. x) compounds are not directly ionizable. Specifying the type of adduct: [ M + CH ]₃COO]^-。

(x) the reported molecular ions correspond to [ M-H [ ]]^-(protonated molecules).

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 ^TWhere l is the path length in dm and c is the concentration in g/100ml for a sample at temperature T (c) and wavelength λ (in nm), if the wavelength of light used is 589nm (sodium D line), then the symbol D may be used instead, the sign of rotation (+ or-), always should be given.

Table 4.Optical rotation data.

SFC-MS

General procedure

SFC measurements were performed using an analytical system from Berger Instrument, Inc. (Berger Instrument), which includes a system for delivering carbon dioxide (CO)₂) FCM-1200 binary Pump fluid control Module with Modifiers, an automatic liquid sampler for CTC analysis, a device for heating the column from room temperature to 80 ℃And the TCM-20000 thermal control module. An agilent 1100UV photodiode array detector equipped with a high pressure flow cell withstanding 400 bar was used. The flow from the column was split to the MS spectrometer. The MS detector is configured with a barometric ionization source. The following ionization parameters for a waters ZQ mass spectrometer are: corona: 9 μ a, source temperature: 140 ℃, taper hole: 30V, the temperature of a probe is 450 ℃, the temperature of an extractor is 3V, the desolventizing gas is 400L/hr, and the cone hole gas is 70L/hr. Nitrogen was used as the atomizer gas. And (4) carrying out data acquisition by using a Watts-Micromass MassLynx-Openlynx data system.

Table 5.SFC-MS method of analysis (flow in mL/min; column temperature (T) in ℃ C.; pressure in MPa).

TABLE 6Analytical SFC data-R_tMeaning the retention time (in minutes), [ M + H]⁺Meaning the protonation mass of the compound, and the method is used for SFC/MS analysis of enantiomerically pure compounds. The measured values are compared to the mixture.

A denotes the first isomer eluted. B represents the second isomer eluted.

Examples of 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. In thatTable 7 shows the use of the compounds described below and suitable for identifying such compounds and more specifically the compounds according to formula (I)³⁵S]Negative allosteric modulators tested by GTP γ S binding assay method act on mGluR 2.

A) In vitro pharmacology

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), thereby measuring the non-hydrolyzable form of GTP, [2 ]³⁵S]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 2.6.110, John Wiley father (John Wiley)&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

The mGluR2 negative allosteric modulating activity of the test compounds was measured as follows. 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 research & development) to generate generations of the inventionConcentration-response curves for the table compounds. 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 it is going to M.E_{Maximum of}IC shown in₅₀pIC, when defined as the relative maximal effect (i.e. maximal% inhibition of glutamate response relative to control), will₅₀The value was calculated as-log IC₅₀。

Table 7.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 8 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 8.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

In a microprocessor-based sport activity area (arena) (height 39cm and diameter31cm closed grey PVC cylinder) were measured for locomotor activity. 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 9 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 9.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 10 provides the data obtained in the above tests 1) to 3).

Table 10.The data in tests 1) to 3) are summarized in the table: SCOP JNJ-42153605 means the reversal of the effect of JNJ42153605 on scopolamine-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.

Examples of compositions foreseen

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 skilled in the art.

Claims

1. A compound of formula (I)

Or a stereoisomeric form thereof, wherein

R²selected from the group consisting of: hydrogen; c_1-4An alkyl group; c_3-7A cycloalkyl group; het¹(ii) a An aryl group; -C (O) R⁵；-C(O)Het²；Het²(ii) a And C substituted with one or more substituents each independently selected from the group consisting of_1-4Alkyl, the group consisting of: halogen, C_3-7Cycloalkyl, aryl, Het¹And Het²；

Wherein

aryl is phenyl which may be optionally substituted with one or more substituents each independently selected from the group consisting of: halogen, C_1-4Alkyl, -C_1-4alkyl-OH, monohalo-C_1-4Alkyl, polyhalo-C_1-4Alkyl, -CN, -O-C_1-4Alkyl, -OH, -C_1-4alkyl-O-C_1-4Alkyl, -NR' R ", -NHC (O) C_1-4Alkyl, -C (O) NR' R ", -C (O) NH [ C (O) C_1-4Alkyl radical]、-S(O)₂NR'R"、-S(O)₂NH[C(O)C_1-4Alkyl radical]and-SO₂-C_1-4An alkyl group;

Het²is (a) a 6-membered aromatic heterocyclyl substituent selected from the group consisting of: pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl, each of which may be optionally substituted with one or more substituents each independently selected from the group consisting of: halogen, C_1-4Alkyl radical、-C_1-4alkyl-OH, monohalo-C_1-4Alkyl, polyhalo-C_1-4Alkyl, -CN, -O-C_1-4Alkyl, -OH, -C_1-4alkyl-O-C_1-4Alkyl, -NR' R ", -NHC (O) C_1-4Alkyl, -C (O) NR' R ", -C (O) NH [ C (O) C_1-4Alkyl radical]、-S(O)₂NR'R"、-S(O)₂NH[C(O)C_1-4Alkyl radical]and-SO₂-C_1-4An alkyl group; or (b) a 5-membered aromatic heterocyclic group selected from the group consisting of: thiazolyl, oxazolyl, 1H-pyrazolyl, and 1H-imidazolyl, each of which may be optionally substituted with one or more substituents each independently selected from the group consisting of: halogen, C_1-4Alkyl, -C_1-4alkyl-OH, monohalo-C_1-4Alkyl, polyhalo-C_1-4Alkyl, -CN, -O-C_1-4Alkyl, -OH, -C_1-4alkyl-O-C_1-4Alkyl, -NR' R ", -NHC (O) C_1-4Alkyl, -C (O) NR' R ", -C (O) NH [ C (O) C_1-4Alkyl radical]、-S(O)₂NR'R"、-S(O)₂NH[C(O)C_1-4Alkyl radical]and-SO₂-C_1-4An alkyl group;

R³Selected from hydrogen and 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 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, -CN, -C_1-4alkyl-O-C_1-4Alkyl, -O-C_1-4Alkyl, monohalo-C_1-4Alkoxy and polyhalo-C_1-4An alkoxy group;

aryl is phenyl optionally substituted with one substituent selected from the group consisting of: halogen, C_1-4Alkyl, -O-C_1-4Alkyl and-SO₂-C_1-4An alkyl group;

Het²is (a) a 6-membered aromatic heterocyclyl substituent selected from the group consisting of: pyridinyl, pyrimidinyl, and pyrazinyl, 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' R "; or (b) a 5-membered aromatic heterocyclic group selected from the group consisting of: thiazolyl, oxazolyl and 1H-imidazolyl, each of which may optionally be substituted by one C_1-4Alkyl substituent group substitution;

R³Is hydrogen;

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

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

R²selected from the group consisting of: aryl, and Het²(ii) a Wherein

Aryl is phenyl optionally substituted with one halogen substituent;

Het²is (a) a 6-membered aromatic heterocyclyl substituent selected from the group consisting of: pyridinyl, pyrimidinyl, and pyrazinyl, 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' R "; or (b) a 5-membered aromatic heterocyclic group selected from the group consisting of: thiazolyl, 1, 2-oxazolyl, 1, 3-oxazolyl and 1H-imidazolyl, each of which may optionally be substituted by one C_1-4Alkyl substituent group substitution;

r 'and R' are each hydrogen; and is

R³Is hydrogen;

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

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

R²selected from the group consisting of: aryl, and Het²(ii) a Wherein

Aryl is phenyl optionally substituted with one halogen substituent;

r 'and R' are each hydrogen; and is

>CR³R⁴Is selected from>CH(CH₃) And>CH(CH₂OCH₃)；

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

5. The compound of claim 1, or a stereoisomeric form thereof, wherein R³Is hydrogen and R⁴Is as defined in any one of claims 1 to 4, which compound, other than hydrogen, has the configuration as depicted in (I')

Wherein 6, 7-dihydropyrazolo [1, 5-a)]Pyrazin-4 (5H) -one core, R¹And R²At the position ofIn the plane of the figure and R⁴Projected above the graphics plane and the remaining variables are as defined in any one of claims 1 to 4,

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

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

7. A compound as defined in any one of claims 1 to 5 for use as a medicament.

8. A compound according to claim 7 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.

9. A compound according to claim 8 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.

10. The compound for use according to claim 8, wherein the central nervous system disorders or diseases are selected from the group consisting of: dementia or neurocognitive disorders, major depressive disorder, depression, treatment-refractory depression, attention deficit/hyperactivity disorder and schizophrenia.

11. A process for the preparation of a pharmaceutical composition according to claim 6, 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 5.

12. A method of treating or preventing a central nervous system disorder or condition 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 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 5.

13. A method of treating or preventing a central nervous system disorder or condition 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 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 5.

14. The method according to claim 12, wherein the central nervous system disorders or diseases are selected from the following: dementia or neurocognitive disorders, major depressive disorder, depression, treatment-refractory depression, attention deficit/hyperactivity disorder and schizophrenia.

15. A product comprising a compound as defined in any one of claims 1 to 5 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.