Novel bicyclic [1, 2, 4] triazolone derivatives as negative allosteric modulators of MGLU7 receptor

Abstract

The present application relates to compounds of formula (I) wherein P, Q, A, B, m, n and R1 are as defined in formula (I); the compounds are negative allosteric modulators of the metabotropic glutamate receptor subtype 7 (mGlu7) and are useful in the treatment or prevention of nervous, ear and psychiatric disorders associated with glutamate dysfunction and diseases in which mGlu7 metabotropic receptor subtype is involved. The present application also relates to pharmaceutical compositions comprising such compounds, to methods of preparing such compounds and such compositions, and to the use of such compounds for the prevention or treatment of neurological, ear and psychiatric disorders and diseases in which mGlu7 is involved. # imgabs0 #

Description

Summary of the Invention

[0001]

[0002] The present invention relates to novel compounds of formula (I), wherein P, Q, A, B, m, n and R 1 According to the definition in formula (I), the compound is a negative allosteric modulator of metabotropic glutamate receptor subtype 7 (mGlu7) and can be used to treat or prevent nervous system, ear and psychiatric disorders associated with glutamate dysfunction and diseases in which the metabotropic receptor subtype mGlu7 is involved. The present invention also relates to pharmaceutical compositions comprising such compounds, methods for preparing such compounds and such compositions, and the use of such compounds for preventing or treating nervous system, ear and psychiatric disorders and diseases (in which mGlu7 is involved). Background Art

[0003] Glutamate is the primary amino acid transmitter in the mammalian central nervous system (CNS). Glutamate is involved in numerous physiological functions, including learning and memory, sensory perception, the development of synaptic plasticity, motor control, respiration, and the regulation of cardiovascular function. Furthermore, glutamate is central to several different neurological and psychiatric disorders in which imbalances in glutamatergic neurotransmission are present.

[0004] Glutamate mediates synaptic neurotransmission by activating ionotropic glutamate receptors (iGluRs), NMDA, AMPA, and kainate receptors, which are responsible for fast excitatory conduction (Nakanishi et al. (1998) Brain Res. Rev., 26:230-235).

[0005] In addition, glutamate activates metabotropic glutamate receptors (mGluRs) with regulatory effects, which contribute to the fine-tuning of synaptic efficacy (Niswender & Conn (2010) Ann. Rev. Pharmacol. Toxicol. 50: 295-322). In contrast to iGluRs, mGluRs do not mediate but rather "regulate" synaptic transmission at different levels of the tripartite synapse formed by the junction of axon terminals, dendritic spines, and astrocytes. mGluRs are G protein-coupled receptors (GPCRs) containing seven transmembrane domains, which interact with calcium-sensing receptors, GABA B The receptors, along with the pheromone receptors, belong to family 3 GPCRs. Glutamate activates mGluRs by binding to a site on the large extracellular amino-terminal domain of the receptor (referred to herein as the orthosteric binding site). This activation induces conformational changes in the rest of the receptor, which leads to activation of G proteins and subsequent activation of a large number of intracellular signaling pathways. The mGluR family consists of eight members. Based on sequence homology, pharmacological characteristics, and the properties of the activated intracellular signaling cascades, they are classified into three groups (Group I comprising mGlu1 and mGlu5; Group II comprising mGlu2 and mGlu3; Group III comprising mGlu4, mGlu6, mGlu7, and mGlu8) (Schoepp et al. (1999) Neuropharmacology, 38: 1431-1476).

[0006] Among mGlu receptors, the mGlu7 subtype is the most widely distributed and is present presynaptically in a wide range of synapses and is thought to be crucial for both normal CNS function and a range of psychiatric and neurological disorders (Ohish et al. (1995) J. Comp. Neurol. 360(4):555-570; Kinzie et al. (1995) Neuroscience, 69(1):167-176; Corti et al. (1998) Eur. J. Neurosci, 10(12):3629-3641). mGlu7 is negatively coupled to adenylate cyclase by activating Gαi-protein, and its activation as a presynaptic autoreceptor leads to inhibition of glutamate and GABA release at the synapse (Dalezios et al. (2002) Cereb. Cortex, 12(9):961-974; Cartmell and Schoepp (2000) J. Neurochem., 75:889-907; Somogy et al. (2003) Eur. J. Neurosci. 17(12):2503-2520), thus shaping synaptic responses at glutamatergic synapses and being a key regulator of inhibitory GABAergic transmission, with the ultimate goal of fine-tuning the overall excitability of the brain.

[0007] Previously, most of the available pharmacological tools for targeting mGluRs were orthosteric ligands, which cross-react with several members of the family because they are structural analogs of glutamate (Schoepp et al. (1999) Neuropharmacology, 38: 1431-1476). However, using new screening methods, it has been possible to identify molecules that are selective for individual mGluRs, which act through an allosteric mechanism, modulating the receptor by binding to a site different from the highly conserved orthosteric binding site. These types of molecules have been found for several mGluRs (reviewed in Hellyer et al. (2017) Curr. Opin. Pharmacol. 32: 49-55; Stansley & Conn (2019) Trends Pharmacol. Sci. 40 (4): 240-52; Dogra & Conn, (2022) Mol. 101 (5): 275-285). In recent years, several small molecules targeting the mGlu7 receptor have been identified (reviewed in Vasquez-Villa & Trabanco (2019) Med. Chem. Comm. 10: 193-9). AMN082 has been described as a potent, selective, and systemically active allosteric agonist of mGlu7 (Mitsukawa et al. (2005) Proc. Natl. Acad. Sci. USA, 102: 18712-18717). 7-Hydroxy-3-(4-iodophenoxy)-4H-chromen-4-one (XAP044), an allosteric antagonist of mGlu7 (Gee et al. (2014) J. Biol. Chem. 18; 289(16): 10975-10987), has also been recently described. It acts by targeting the binding pocket of the extracellular Venus flytrap domain of the receptor. Finally, several classes of compounds are described, such as Azopyridone derivatives, phenylbenzamide derivatives, dihydrobenzo Azoles are oxazolone derivatives, tetrahydrophthalazinone derivatives, and are pharmacologically characterized as selective mGlu7 negative allosteric modulators (Suzuki et al. (2007) J. Pharmacol. Exp. Ther., 323: 147-156; Kalinichev et al. (2013) J. Pharmacol. Exp. Ther. 344(3): 624-636; Reed et al. (2017) ACS Med. Chem. Lett. (12): 1326-1330 and Duvey et al (2019) WO2019063569).

[0008] In particular, based on experimental studies in laboratory animals (thought to be relevant to clinical syndromes), modulators of mGlu7, and preferably antagonists, inverse agonists and negative allosteric modulators (NAMs), are reported to have the potential to treat neurological, psychiatric, mood disorders, as well as pain and otic disorders.

[0009] Pharmacological manipulation of mGlu7 in genetically modified mice and wild-type animals, as well as combinatorial expression of mGlu7 in brain regions, revealed an important role for mGlu7 in many CNS disorders, including depression, schizophrenia, anxiety, obsessive-compulsive disorder and related symptoms (reviewed by Pallazo et al. (2016) Curr. Neuropharmacol. 14(5): 504-513), and in particular in acute and chronic stress-related conditions (reviewed by Peterlik et al. (2016) Curr Neuropharmacol. 14(5): 514-539).

[0010] It has been shown that mGlu7 is located in the core of the limbic system, such as the amygdala, hippocampus and locus coerulus, which is known to be crucial for the manifestation of antidepressant effects and anxiety relief (Kinoshita et al. (1998) J. Comp. Neurol., 393(3):332-352; Makoff et al. (1996) Brain Res. Mol. Brain Res., 40(1):165-170; Kinzie et al. (1995) Neuroscience, 69(1):167-176). In addition, the study of several behavioral models (light-dark box test, elevated plusmaze, staircase test, forced swim test and tail suspension test) has shown that animals with mGlu7 knockout exhibit anxiolytic and antidepressant phenotypes, but also have some defects (fear response and conditioned taste aversion) in amygdala-dependent behaviors (Cryan et al. (2003) Eur. J. Neuroscience, 17: 2409-2417). Therefore, the pharmacological agent (pharmacologicalagent) intended to regulate mGlu7 activity may represent a new therapeutic approach for the treatment of nervous system and psychiatric disorders (e.g., anxiety and depression).

[0011] Activation of mGlu7 using the allosteric agonist AMN082 increased the plasma levels of stress hormones corticosterone and ACTH (Mitsukawa et al. (2005) PNAS, 102 (51): 18712-18717). This effect is completely absent in mGlu7 knockout mice. Those results are consistent with previous genetic studies, indicating that mGlu7 is an important regulator of stress response in vivo (Mitsukawa et al. (2006) Neuropsychopharm., 31 (6): 1112-1122). In this article, Mitsukawa et al. show that ablation of mGlu7 leads to dysregulation of the HPA axis and increases hippocampal BDNF protein levels, indicating that this receptor may be related to stress-related mental disorders, such as anxiety, depression, post-traumatic stress syndrome, and behaviors induced by innate fear (such as the acquisition and extinction of conditioned fear or conditioned taste aversion). These data also confirm previous observations, in which mGlu7-deficient mice showed a significant decrease in fear-mediated freezing responses during foot shock and a weakened ability to associate taste stimuli with the disturbing LiCl injection (conditioned taste aversion, CTA) (Masugi et al. (1999) J. Neurosc., 19(3):955-963). Compared to wild-type animals, these mice also showed defects in the acquisition and extinction learning of conditioned responses (Goddyn et al. (2008) Neurobiol. Learn. Mem., 90(1):103-111).

[0012] The paradoxical effects observed with the allosteric agonist AMN082 can be explained by rapid and sustained mGlu7 receptor internalization, consistent with functional antagonism, and its lack of selectivity in vivo suggests potential off-target involvement (Sukoff Rizzo et al. (2011) J. Pharmacol. Exp. Ther., 338(1):345-352; Pelkey ​​et al. (2007) Neuropharmacology 52(1):108-117).

[0013] The recent discovery of several negative allosteric modulators has helped to better understand the functional role of mGlu7 in neuronal function. MMPIP has been shown to have anxiolytic and antidepressant properties, as well as improved cognitive performance in rodent models (Palazzo et al. (2015) Pain, 156(6):1060-1073). 7-Hydroxy-3-(4-iodophenoxy)-4H-chromen-4-one (XAP044) has been shown to produce anti-stress, antidepressant, and anxiolytic-like effects, as well as reduce freezing in a fear-conditioning paradigm (Gee et al. (2014) J. Biol. Chem. 289(16):10975-10987). In addition, (S)-6-(2,4-dimethylphenyl)-2-ethyl-6,7-dihydrobenzo[d] Azoles-4 (5H) -one (ADX71743) showed anxiolytic effects in elevated plus maze and marble burying test (marble burying test), and reduced the hyperactivity (Kalinichev et al. (2013) J.Pharmacol.Exp.Ther.344 (3): 624-636) of amphetamine induction without changing baseline locomotor activity. In a word, these data show that suppressing mGlu7 with modulators can be used to treat the mood disorders relevant to anxiety, depression and PTSD.

[0014] In addition, mGlu7 receptors are also related to pathways affected during pain. Considering that it has high and wide expression in both the peripheral nervous system and the central nervous system, it is found that mGlu7 plays a role in regulating pain behavior. Recently, AMN082 has also been directly injected into the central nucleus of the amygdala (centralnucleus of the amygdala, CeA) or periaqueductal gray (periaqueductal gray, PAG) to show the effect of mGlu7 in pain. Under normal circumstances, the activation of amygdala mGlu7 promotes pain response, as shown by the reduction of spinal withdrawal reflex threshold (spinal withdrawal reflexthreshold) and the improvement of hearing and ultrasonic vocalization induced by transient knee compression (Palazzo et al. (2008) Neuropharmacol., 55 (4): 537-545). In a similar manner, in rats, activation of PAG mGlu7 reduces the thermal perception threshold measured using tail flick latency (Marabese et al. (2007) J. Neurophysiol., 98: 43-53). In a rodent pain model, AMN082 inhibits hyperalgesia (Dolan et al. (2009) Behav. Pharmacol. 20 (7): 596-604); Osikowicz et al. (2008) Pain 139 (1): 117-126). In addition, the mGlu7 negative allosteric modulator ADX71743 was shown to reduce visceral pain in a stress-sensitive model of visceral hypersensitivity (Moloney et al. (2015) Neurobiol. Stress 2: 28-33). Together, these data indicate that activation of the mGlu7 receptor exacerbates pain perception, whereas mGlu7 inhibition attenuates it, thus suggesting that negative allosteric modulators of this receptor may be useful in treating pain and pain-related disorders.

[0015] Genome-wide studies have also implicated the mGlu7 receptor in age-related hearing impairment (ARHI), also known as presbycusis. This led to the identification of highly significant and recurrent single nucleotide polymorphisms (SNPs) located in GRM7, the gene encoding the mGlu7 receptor (Van Laer et al. (2010) Eur. J. Hum. Genet., 18(6):685-693; Friedman et al. (2009) Hum. Mol. Genet., 18(4):785-796; Newman et al. (2012) Hear Res. 294:125-132; Luo et al. (2013) PLoS One, 8(10):e77153; Haider et al. (2017) Front. Aging Neurosci. 9:346; Matyas et al. (2019) Pathol. Oncol. Res. 25(4):1645-52; Chang et al. (2013) PLoS One, 8(10):e77153). al. (2018) J. Int. Adv. Otol. 14(2): 170-175). GRM7 variants have also been identified as being associated with noise-induced hearing loss, as reported by Lu et al. (BMC Med. Genet. (2018), 19(1): 4), and with tinnitus, as reported by Haider et al. (Front. Aging Neurosci. (2017), 9: 346). Finally, mGlu7 expression studied by immunohistochemistry is localized in neurons of the spiral ganglion, inner and outer hair cells of the organ of Corti, and hair cells of the vestibular organ formed by the sacculus, utriculus, and crista ampullaris (Friedman et al. (2008) WO2008131439). These data suggest that mGlu7 receptor modulators have potential use in experimental treatment of ear disorders related to the inner ear and auditory nervous system, such as age-related hearing impairment (presbycusis), noise-induced hearing loss, acute and chronic hearing loss, tinnitus, Meniere's disease, and vestibular disorders.

[0016] Finally, except that mGlu7 is widely distributed in the whole CNS, mGlu7 also shows the highest evolutionary conservation (Flor et al. (1997) Neuropharmacol., 36:153-159) of all mGluRs, shows the important role of this receptor in CNS function.In addition, it has relatively low affinity (Okamato et al. (1994) J.Biol.Chem., 269:1231-1236) to glutamate, therefore it can keep inactive during normal transmission, only during the period of excessive glutamate release, just become active (Ferraguti F.and Shigemoto R. (2006) Cell Tissue Res., 326:483-504).In a word, these data strongly emphasize the potential of mGlu7 modulators in clinical indications such as neuroprotection (treating stroke and head injury, ischemic injury and neurotoxicity).

[0017] Together, these pharmacological and genetic data strongly support the potential of mGlu7 modulators for the treatment of diseases and associated symptoms in a wide range of psychiatric, neurological, neurodevelopmental, otic, and pain disorders.

[0018] Buschmann et al. have shown in International Publication No. WO2017046318 that [1,2,4]triazolo[4,3-a]pyridin-3(2H)-one can be used as an antiviral agent. However, none of the specifically disclosed compounds are structurally related to the compounds of the present invention.

[0019] Andree et al. describe 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one as a herbicide in German patent application DE 3917469. However, none of the specifically disclosed compounds are structurally related to the compounds of the present invention. Summary of the Invention

[0021] The present invention relates to compounds having activity as modulators of metabotropic glutamate receptor 7. The present invention provides compounds according to formula (I),

[0022]

[0023] A pharmaceutically acceptable acid addition salt or base addition salt thereof, a stereochemically isomeric form thereof or an N-oxide form thereof, wherein:

[0024] for

[0025] R 1selected from the group consisting of (e.g., a group consisting of) hydrogen, deuterium, halogen, -(C1-C6)alkyl, -(C1-C6)haloalkyl, and -CF3;

[0026] P represents a cycloalkyl group, an aryl group, a heteroaryl group or a heterocycle of the following formula:

[0027]

[0028] wherein each cycloalkyl, aryl, heteroaryl or heterocyclic ring is optionally substituted with m groups A, where m is an integer equal to 0, 1, 2, 3 or 4;

[0029] where Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 and Z 7 are independently selected from C, N, O or S; provided that Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 and Z 7 At least one of is N;

[0030] (A) m or (A) m each of which is independently selected from the group consisting of hydrogen, halogen, -CN, -OH, -NO2, -CF3, -SH, -NH2, and optionally substituted groups selected from the group consisting of -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C2-C6)alkynyl, -(C2-C6)alkenyl, -(C3-C7)cycloalkyl, -(C1-C6)alkylene-(C3-C7)cycloalkyl, -(C3-C8)cycloalkenyl, -(C1-C6)cyanoalkyl, -(C1-C6)alkylene-heteroaryl, -(C1-C6)alkylene-aryl, aryl, heteroaryl, -(C1-C6)alkylene-heterocycle, heterocycle, -(C0-C6)alkylene-OR 2 、-O-(C2-C6)alkylene-OR 2 、-NR 2 (C2-C6)alkylene-OR 3 、-(C3-C6)alkynylene-OR 2 、-(C3-C6)alkynylene-NR 2 R 3 、-(C3-C6)alkenylene-OR 2 、-(C3-C6)alkenylene-NR2 R 3 、-(C0-C6)alkylene-SR 2 、-O-(C2-C6)alkylene-SR 2 、-NR 2 -(C2-C6)alkylene-SR 3 、-(C0-C6)alkylene-S(=O)-R 2 、-O-(C1-C6)alkylene-S(=O)-R 2 、-NR 2 -(C1-C6)alkylene-S(=O)-R 3 、-(C0-C6)alkylene-S(=O)2-R 2 、-O-(C1-C6)alkylene-S(=O)2-R 2 、-NR 2 -(C1-C6)alkylene-S(=O)2-R 3 、-(C0-C6)alkylene-NR 2 R 3 、-O-(C2-C6)alkylene-NR 2 R 3 、-NR 2 -(C2-C6)alkylene-NR 3 R 4 、-(C0-C6)alkylene-S(=O)2NR 2 R 3 、-O-(C1-C6)alkylene-S(=O)2NR 2 R 3 、-NR 2 -(C1-C6)alkylene-S(=O)2NR 3 R 4 、-(C0-C6)alkylene-NR 2 -S(=O)2R 3 、-O-(C2-C6)alkylene-NR 2 -S(=O)2R 3 、-NR 2 -(C2-C6)alkylene-NR 3 -S(=O)2R 4 、-(C0-C6)alkylene-C(=O)-NR 2 R 3 、-O-(C1-C6)alkylene-C(=O)-NR 2 R 3 、-NR 2 -(C1-C6)alkylene-C(=O)-NR 3 R 4、-(C0-C6)alkylene-NR 2 C(=O)-R 3 、-O-(C2-C6)alkylene-NR 2 C(=O)-R 3 、-NR 2 -(C2-C6)alkylene-NR 3 C(=O)-R 4 、-(C0-C6)alkylene-OC(=O)-R 2 、-O-(C2-C6)alkylene-OC(=O)-R 2 、-NR 2 -(C2-C6)alkylene-OC(=O)-R 3 、-(C0-C6)alkylene-C(=O)-OR 2 、-O-(C1-C6)alkylene-C(=O)-OR 2 、-NR 2 -(C0-C6)alkylene-C(=O)-OR 3 、-(C0-C6)alkylene-C(=O)-R 2 、-O-(C1-C6)alkylene-C(=O)-R 2 、-NR 2 -(C1-C6)alkylene-C(=O)-R 3 、-(C0-C6)alkylene-NR 2 -C(=O)-OR 3 、-C(=O)-(C1-C6)alkylene-NR 2 -C(=O)-OR 3 、-(C0-C6)alkylene-OC(=O)-NR 2 R 3 、-(C0-C6)alkylene-NR 2 -C(=O)-NR 3 R 4 、-O-(C2-C6)alkylene-NR 2 -C(=O)-NR 3 R 4 、-NR 2 -(C2-C6)alkylene-NR 3 -C(=O)-NR 4 R 5 、-(C0-C6)alkylene-NR 2 -C(=S)-NR 3 R 4 and -(C0-C6)alkylene-NR 2 -C(=NR 3 )-NR4 R 5 ;

[0031] R 2 、R 3 、R 4 and R 5 each independently hydrogen or an optionally substituted group selected from (e.g., consisting of) -(C1-C6)haloalkyl, -(C1-C6)alkyl, -(C1-C6)cyanoalkyl, -(C3-C7)cycloalkyl, -(C1-C6)alkylene-(C3-C7)cycloalkyl, heteroaryl, -(C1-C6)alkylene-heteroaryl, aryl, -(C1-C6)alkylene-heterocycle, heterocycle, -(C1-C6)alkylene-aryl, -(C0-C6)alkylene-O-(C0-C6)alkyl, -(C0-C6)alkylene-N-((C0-C6)alkyl)2, and -C(═O)—O-(C1-C6)alkyl;

[0032] Q represents an aryl or heteroaryl group of the formula:

[0033]

[0034] wherein each aryl ring or heteroaryl ring is optionally substituted by n groups B, wherein n is an integer equal to 0, 1, 2, 3, 4 or 5; wherein B 1 is group B;

[0035] (B) n or (B) n each of which is independently selected from the group consisting of hydrogen, halogen, -CN, -OH, -NO2, -CF3, -SH, -NH2, and optionally substituted groups selected from the group consisting of -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C2-C6)alkynyl, -(C2-C6)alkenyl, -(C3-C7)cycloalkyl, -(C1-C6)alkylene-(C3-C7)cycloalkyl, -(C3-C8)cycloalkenyl, -(C1-C6)cyanoalkyl, -(C1-C6)alkylene-heteroaryl, -(C1-C6)alkylene-aryl, aryl, heteroaryl, -(C1-C6)alkylene-heterocycle, heterocycle, -(C0-C6)alkylene-OR 6 、-O-(C2-C6)alkylene-OR 6 、-NR 6 (C2-C6)alkylene-OR 7 、-(C3-C6)alkynylene-OR 6 、-(C3-C6)alkynylene-NR 6 R 7、-(C3-C6)alkenylene-OR 6 、-(C3-C6)alkenylene-NR 6 R 7 、-(C0-C6)alkylene-SR 6 、-O-(C2-C6)alkylene-SR 6 、-NR 6 -(C2-C6)alkylene-SR 7 、-(C0-C6)alkylene-S(=O)-R 6 、-O-(C1-C6)alkylene-S(=O)-R 6 、-NR 6 -(C1-C6)alkylene-S(=O)-R 7 、-(C0-C6)alkylene-S(=O)2-R 6 、-O-(C1-C6)alkylene-S(=O)2-R 6 、-NR 6 -(C1-C6)alkylene-S(=O)2-R 7 、-(C0-C6)alkylene-NR 6 R 7 、-O-(C2-C6)alkylene-NR 6 R 7 、-NR 6 -(C2-C6)alkylene-NR 7 R 8 、-(C0-C6)alkylene-S(=O)2NR 6 R 7 、-O-(C1-C6)alkylene-S(=O)2NR 6 R 7 、-NR 6 -(C1-C6)alkylene-S(=O)2NR 7 R 8 、-(C0-C6)alkylene-NR 6 -S(=O)2R 7 、-O-(C2-C6)alkylene-NR 6 -S(=O)2R 7 、-NR 6 -(C2-C6)alkylene-NR 7 -S(=O)2R 8 、-(C0-C6)alkylene-C(=O)-NR 6 R 7 、-O-(C1-C6)alkylene-C(=O)-NR 6 R 7 、-NR 6-(C1-C6)alkylene-C(=O)-NR 7 R 8 、-(C0-C6)alkylene-NR 6 C(=O)-R 7 、-O-(C2-C6)alkylene-NR 6 C(=O)-R 7 、-NR 6 -(C2-C6)alkylene-NR 7 C(=O)-R 8 、-(C0-C6)alkylene-OC(=O)-R 6 、-O-(C2-C6)alkylene-OC(=O)-R 6 、-NR 6 -(C2-C6)alkylene-OC(=O)-R 7 、-(C0-C6)alkylene-C(=O)-OR 6 、-O-(C1-C6)alkylene-C(=O)-OR 6 、-NR 6 -(C1-C6)alkylene-C(=O)-OR 7 、-(C0-C6)alkylene-C(=O)-R 6 、-O-(C1-C6)alkylene-C(=O)-R 6 、-NR 6 -(C1-C6)alkylene-C(=O)-R 7 、-(C0-C6)alkylene-NR 6 -C(=O)-OR 7 、-(C0-C6)alkylene-OC(=O)-NR 6 R 7 、-(C0-C6)alkylene-NR 6 -C(=O)-NR 7 R 8 、-O-(C2-C6)alkylene-NR 6 -C(=O)-NR 7 R 8 、-NR 6 -(C2-C6)alkylene-NR 7 -C(=O)-NR 8 R 9 、-(C0-C6)alkylene-NR 6 -C(=S)-NR 7 R 8 and -(C0-C6)alkylene-NR 6 -C(=NR 7 )-NR8 R 9 ;

[0036] R 6 、R 7 、R 8 and R 9 each independently hydrogen or an optionally substituted group selected from (e.g., consisting of) -(C1-C6)haloalkyl, -(C1-C6)alkyl, -(C1-C6)cyanoalkyl, -(C3-C7)cycloalkyl, -(C1-C6)alkylene-(C3-C7)cycloalkyl, heteroaryl, -(C1-C6)alkylene-heteroaryl, aryl, -(C1-C6)alkylene-heterocycle, heterocycle, -(C1-C6)alkylene-aryl, -(C0-C6)alkylene-O-(C0-C6)alkyl and -(C0-C6)alkylene-N-((C0-C6)alkyl)2;

[0037] wherein optionally, any two groups A are combined with intervening atoms to form a 3- to 10-membered bicyclic heterocyclic, aryl, or heteroaryl ring, wherein each ring is optionally further substituted with 1 to 5 groups independently selected from (e.g., consisting of) halogen, -CN, nitro, -(C1-C6)alkyl, -(C3-C7)alkyl, -(C0-C6)alkylene-O-(C0-C6)alkyl, and -(C0-C6)alkylene-N-((C0-C6)alkyl);

[0038] wherein optionally, the substituent R 2 、R 3 、R 4 or R 5 wherein two of the alkylene groups are combined with intervening atoms to form a 3- to 10-membered heterocyclic, aryl, or heteroaryl ring, wherein each ring is optionally further substituted with 1 to 5 groups independently selected from (e.g., consisting of) halogen, cyano, nitro, -(C1-C6)alkyl, -(C3-C7)alkyl, -(C0-C6)alkylene-O-(C0-C6)alkyl, and -(C0-C6)alkylene-N-((C0-C6)alkyl);

[0039] wherein optionally, from R 6 、R 7 、R 8 or R 9wherein two substituents of are combined with intervening atoms to form a 3- to 10-membered heterocyclic, aryl, or heteroaryl ring, wherein each ring is optionally further substituted with 1 to 5 groups independently selected from (e.g., consisting of) halogen, cyano, nitro, -(C1-C6)alkyl, -(C3-C7)alkyl, -(C0-C6)alkylene-O-(C0-C6)alkyl, and -(C0-C6)alkylene-N-((C0-C6)alkyl);

[0040] wherein optionally, any two groups B are combined with intervening atoms to form a 3- to 10-membered bicyclic heterocyclic, aryl, or heteroaryl ring, wherein each ring is optionally further substituted with 1 to 5 groups independently selected from (e.g., consisting of) halogen, -CN, nitro, -(C1-C6)alkyl, -(C3-C7)alkyl, -(C0-C6)alkylene-O-(C0-C6)alkyl, and -(C0-C6)alkylene-N-((C0-C6)alkyl)2.

[0041] B 1 It can be a group B as described above. For example, B 1 It may be hydrogen, -(C1-C6)alkyl or -(C3-C7)cycloalkyl.

[0042] Now surprisingly found that the compound of general formula (I) demonstrates activity and selectivity to the mGlu7 receptor potent effect.Compound of the present invention shows favorable characteristics relative to the compound of prior art.In one or more of the following characteristics of the compounds of this invention, observed improvement: to the effectiveness of target, to the selectivity of target, bioavailability, brain penetration and pharmacodynamics.

[0043] Preferably, P represents a heteroaryl group of the formula:

[0044]

[0045] wherein each group is optionally substituted by m groups A, wherein m is an integer equal to 0, 1, 2, 3 or 4.

[0046] Preferably, Q represents an aryl or heteroaryl group of the formula:

[0047]

[0048] wherein each group is optionally substituted by n groups B, wherein n is an integer equal to 0, 1, 2, 3, 4 or 5.

[0049] For example, Q can be

[0050] Preferably, P represents a heteroaryl group of the formula:

[0051]

[0052] wherein each group is optionally substituted by m groups A, wherein m is an integer equal to 0, 1, 2, 3 or 4; and Q represents an aryl or heteroaryl group of the formula:

[0053]

[0054] wherein each group is optionally substituted by n groups B, wherein n is an integer equal to 0, 1, 2, 3, 4 or 5.

[0055] (A) m The cycloalkyl, heterocyclic, aryl and heteroaryl ring systems of the present invention may be selected from the group consisting of (e.g., the group consisting of): azetidinyl, 2-azabicyclo[2.2.1]heptan-2-yl, 7-azabicyclo[2.2.1]heptan-7-yl, benzimidazolyl, benzisothiazolyl, benzisothiazolyl, oxazolyl, benzofuranyl, benzopyrazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzo oxazolyl, dihydrofuranyl, dihydrothiophenyl, dioxolanyl, 1,1-dioxo-thiomorpholinyl, furazanyl, furanyl, imidazolidinyl, imidazolinyl, imidazolinonyl, imidazolyl, imidazopyridazinyl, imidazopyridinyl, indolyl, isoindolyl, isoquinolyl, isothiazolinyl, isothiazolyl, isothiazolyl, isothiazolyl, Oxazolidinyl, isocyanate Oxazoline, iso Azolyl, morpholinyl, naphthyl, naphthyridinyl, Oxazolyl, Oxazolidinyl, Oxazoline, Oxazolone, Oxalopyridazinyl, Azolopyridinyl, oxetanyl, phenyl, piperazinyl, piperazinyl, piperidinyl, piperidinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrotriazolopyrid ... cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl and cyclooctenyl, and each ring of the ring system is optionally substituted independently with 1 to 4 substituents R 2 、R 3 、R 4 or R 5 replace.

[0056] (B) n The cycloalkyl, heterocyclic, aryl and heteroaryl ring systems may be selected from the group consisting of (e.g., consisting of) azetidinyl, 2-azabicyclo[2.2.1]heptan-2-yl, 7-azabicyclo[2.2.1]heptan-7-yl, benzimidazolyl, benzisothiazolyl, benzisothiazolyl, oxazolyl, benzofuranyl, benzopyrazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzo oxazolyl, dihydrofuranyl, dihydrothiophenyl, dioxolanyl, 1,1-dioxo-thiomorpholinyl, furazanyl, furanyl, imidazolidinyl, imidazolinyl, imidazolinonyl, imidazolyl, imidazopyridazinyl, imidazopyridinyl, indolyl, isoindolyl, isoquinolyl, isothiazolinyl, isothiazolyl, isothiazolyl, isothiazolyl, Oxazolidinyl, isocyanate Oxazoline, iso Azolyl, morpholinyl, naphthyl, naphthyridinyl, Oxazolyl, Oxazolidinyl, Oxazoline, Oxazolone, Oxalopyridazinyl, Azolopyridinyl, oxetane, phenyl, piperazinyl, piperazinyl, piperidinyl, piperidinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridinonyl, pyridinyl, pyrimidinyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrotriazolopyridinyl, tetrahydrotriazolopyrimidinyl 1 to 4 substituents R, wherein each ring of the ring system is optionally substituted independently with 1 to 4 substituents R 6 、R 7 、R 8 or R 9 replace.

[0057] R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 or R 9 The cycloalkyl, heterocyclic, aryl and heteroaryl ring systems of the present invention may be selected from the group consisting of (e.g., the group consisting of): azetidinyl, benzimidazolyl, benzisothiazolyl, benzisothiazolyl, oxazolyl, benzofuranyl, benzopyrazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzo oxazolyl, dihydrofuranyl, dihydrothiophenyl, dioxolanyl, 1,1-dioxo-thiomorpholinyl, furazanyl, furanyl, imidazolidinyl, imidazolinyl, imidazolinonyl, imidazolyl, imidazopyridazinyl, imidazopyridinyl, indolyl, isoindolyl, isoquinolyl, isothiazolinyl, isothiazolyl, isothiazolyl, isothiazolyl, Oxazolidinyl, isocyanate Oxazoline, iso Azolyl, morpholinyl, naphthyl, naphthyridinyl, Oxazolyl, Oxazolidinyl, Oxazoline, Oxazolone, Oxalopyridazinyl, Azolopyridinyl, oxetane, phenyl, piperazinyl, piperazinyl, piperidinyl, piperidinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridinonyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrotriazolopyridinyl, tetrahydrotriazolopyrimidinyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolinyl, thiazolonyl, thiazolopyridazinyl, thiazolopyridinyl , thiazolyl, thienyl, thiomorpholinyl, thionaphthyl, thiopyranyl, triazolinyl, triazinyl, triazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl and cyclooctenyl, and each ring of the ring system is optionally substituted with 1 to 5 groups independently selected from the group consisting of hydrogen, halogen, -CN, nitro, -(C1-C6)alkyl, -(C0-C6)alkylene-O-(C0-C6)alkyl and -(C0-C6)alkylene-N-((C0-C6)alkyl)2.

[0058] For example, R 1 It may be hydrogen.

[0059] (A) m or (A) m Each of the following may be independently selected from the following group (e.g., a group consisting of): hydrogen, halogen, -CN, -OH, -CF3, and an optionally substituted group selected from the following group (e.g., a group consisting of): -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C3-C7)cycloalkyl, -(C1-C6)cyanoalkyl, aryl, heterocycle, -(C0-C6)alkylene-OR 2 、-O-(C2-C6)alkylene-OR 2 、-O-(C2-C6)alkylene-NR 2 R 3 、-NR 2 -(C2-C6)alkylene-NR 3 R 4 、-(C0-C6)alkylene-S(=O)2-R 2 、-(C0-C6)alkylene-NR 2 R 3 、-(C0-C6)alkylene-S(=O)2NR 2 R 3 、-(C0-C6)alkylene-C(=O)-NR 2 R 3 、-(C0-C6)alkylene-NR 2 C(=O)-R 3、-(C0-C6)alkylene-C(=O)-OR 2 、-(C0-C6)alkylene-C(=O)-R 2 and -C(=O)-(C1-C6)alkylene-NR 2 -C(=O)-OR 3 .

[0060] R 2 、R 3 and R 4 They may each independently be hydrogen, -(C1-C6)haloalkyl or -(C1-C6)alkyl.

[0061] (B) n or (B) n Each of the following may be independently selected from the group consisting of hydrogen, halogen, -CN, -CF3 and optionally substituted groups selected from the group consisting of -(C1-C6)alkyl, -(C3-C7)cycloalkyl, aryl, heteroaryl, heterocycle, -(C0-C6)alkylene-OR 6 、-NR 6 (C2-C6)alkylene-OR 7 、-(C0-C6)alkylene-NR 6 R 7 、-(C0-C6)alkylene-C(=O)-OR 6 and -(C0-C6)alkylene-C(=O)-R 6 .

[0062] n can be an integer equal to 0, 1 or 2.

[0063] R 6 and R 7 Each may be independently selected from the group consisting of (eg, a group consisting of) hydrogen, -(C1-C6)haloalkyl, -(C1-C6)alkyl, -(C3-C7)cycloalkyl, and aryl.

[0064] R 6 and R 7 Each may be independently selected from the group consisting of (eg, a group consisting of) hydrogen, -(C1-C6)alkyl, -(C3-C7)cycloalkyl, and aryl.

[0065] R 6 and R 7 Each may be independently selected from the group consisting of (eg, a group consisting of): -(C1-C6)alkyl and -(C3-C7)cycloalkyl.

[0066] Preferably, the compound of formula (I) is a compound according to formula (II):

[0067]

[0068] a pharmaceutically acceptable acid addition salt or base addition salt thereof, a stereochemically isomeric form thereof or an N-oxide form thereof, wherein Z 1 is selected from C or N, and (A) m ,Q,R 1 and (B) n As defined in any of the above statements.

[0069] The compound of formula (I) may be a compound according to formula (III):

[0070]

[0071] A pharmaceutically acceptable acid addition salt or base addition salt thereof, a stereochemically isomeric form thereof or an N-oxide form thereof, wherein X is N or C, and P, (A) m 、R 1 and (B) n As defined in any of the above statements.

[0072] With respect to compounds of formula (I), (II) or (III), Can be

[0073] The compound of formula (I) may be a compound according to formula (IV):

[0074]

[0075] A pharmaceutically acceptable acid addition salt or base addition salt thereof, a stereochemically isomeric form thereof or an N-oxide form thereof, wherein X is N or C, and P, (A) m and (B) n As defined in any of the above statements.

[0076] The compound of formula (I) may be a compound according to formula (V):

[0077]

[0078] A pharmaceutically acceptable acid addition salt or base addition salt thereof, a stereochemically isomeric form thereof or an N-oxide form thereof, wherein X is N or C, and P, (A) m and (B) n As defined in any of the above statements.

[0079] The compound of formula (I) may be a compound according to formula (VI):

[0080]

[0081] Its pharmaceutically acceptable acid addition salt or base addition salt, its stereochemical isomeric form or its N-oxide form, wherein X is N or C, Z 1 is N or C, and (A) m and (B) n As defined in any of the above statements.

[0082] The compound of formula (I) may be a compound according to formula (VII):

[0083]

[0084] Its pharmaceutically acceptable acid addition salt or base addition salt, its stereochemical isomeric form or its N-oxide form, wherein X is N or C, Z 1 is N or C, and (A) m and (B) n As defined in any of the above statements.

[0085] The compound of formula (I) may be a compound according to formula (VIII):

[0086]

[0087] A pharmaceutically acceptable acid addition salt or base addition salt thereof, a stereochemically isomeric form thereof or an N-oxide form thereof, wherein:

[0088] Z 1 Selected from C or N;

[0089] (A) m or (A) m Each of the following may be independently selected from the following group (e.g., a group consisting of): hydrogen, halogen, -CF3, and an optionally substituted group selected from the following group (e.g., a group consisting of): -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C3-C7)cycloalkyl, heterocycle, -(C0-C6)alkylene-OR 2 、-O-(C2-C6)alkylene-OR 2 、-(C0-C6)alkylene-NR 2 R 3 、-O-(C2-C6)alkylene-NR 2 R 3 、-NR 2 -(C2-C6)alkylene-NR 3 R 4 、-(C0-C6)alkylene-C(=O)-NR 2 R 3 、-(C0-C6)alkylene-NR 2 C(=O)-R 3、-(C0-C6)alkylene-C(=O)-OR 2 、-(C0-C6)alkylene-C(=O)-R 2 and -C(=O)-(C1-C6)alkylene-NR 2 -C(=O)-OR 3 ;

[0090] R 2 、R 3 and R 4 may each independently be hydrogen, -(C1-C6)alkyl or -(C1-C6)haloalkyl;

[0091] (B) n or (B) n Each of the following may be independently selected from the group (e.g., consisting of) hydrogen, halogen, and an optionally substituted group selected from the group (e.g., consisting of) -(C1-C6)alkyl, heterocycle, -(C0-C6)alkylene-OR 6 、-NR 6 (C2-C6)alkylene-OR 7 、-(C0-C6)alkylene-NR 6 R 7 、-(C0-C6)alkylene-C(=O)-OR 6 and -(C0-C6)alkylene-C(=O)-R 6 ;and

[0092] R 6 and R 7 can each independently be hydrogen, -(C1-C6)alkyl, -(C3-C7)cycloalkyl or -(C1-C6)haloalkyl. 6 and R 7 Each of n and n is independently hydrogen, -(C1-C6)alkyl or -(C3-C7)cycloalkyl. For example, n can be an integer equal to 0, 1 or 2.

[0093] For example, (A) m or (A) m Each of can be hydrogen. For example, (B) n or (B) n Each of the following may be independently selected from the group (eg, the group consisting of): -(C1-C6)alkyl, heterocycle, and -(C0-C6)alkylene-OR 6 , where R 6 It may independently be -(C1-C6)alkyl or -(C3-C7)cycloalkyl.

[0094] For example, (A) m or (A)m Each of can be hydrogen. For example, (B) n or (B) n Each of may be independently selected from the group consisting of (eg, a group consisting of) methyl, -O-methyl, -O-cyclopropanyl, and azetidinyl.

[0095] The compound of formula (I) may be a compound according to formula (IX):

[0096]

[0097] A pharmaceutically acceptable acid addition salt or base addition salt thereof, a stereochemically isomeric form thereof or an N-oxide form thereof, wherein:

[0098] Z 1 Selected from C or N;

[0099] (A) m or (A) m Each of the following may be independently selected from the following group (e.g., a group consisting of): hydrogen, halogen, -CF3, and an optionally substituted group selected from the following group (e.g., a group consisting of): -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C3-C7)cycloalkyl, heterocycle, -(C0-C6)alkylene-OR 2 、-O-(C2-C6)alkylene-OR 2 、-(C0-C6)alkylene-NR 2 R 3 、-O-(C2-C6)alkylene-NR 2 R 3 、-NR 2 -(C2-C6)alkylene-NR 3 R 4 、-(C0-C6)alkylene-C(=O)-NR 2 R 3 、-(C0-C6)alkylene-NR 2 C(=O)-R 3 、-(C0-C6)alkylene-C(=O)-OR 2 、-(C0-C6)alkylene-C(=O)-R 2 and -C(=O)-(C1-C6)alkylene-NR 2 -C(=O)-OR 3 ;

[0100] R 2 、R 3 and R 4may each independently be hydrogen, -(C1-C6)alkyl or -(C1-C6)haloalkyl;

[0101] (B) n or (B) n Each of the following may be independently selected from the group (e.g., consisting of) hydrogen, halogen, and an optionally substituted group selected from the group (e.g., consisting of) -(C1-C6)alkyl, heterocycle, -(C0-C6)alkylene-OR 6 、-NR 6 (C2-C6)alkylene-OR 7 、-(C0-C6)alkylene-NR 6 R 7 、-(C0-C6)alkylene-C(=O)-OR 6 and -(C0-C6)alkylene-C(=O)-R 6 ;and

[0102] R 6 and R 7 Each may independently be hydrogen, -(C1-C6)alkyl, -(C3-C7)cycloalkyl or -(C1-C6)haloalkyl.

[0103] For example, (A) m or (A) m Each of can be hydrogen. For example, (B) n or (B) n Each of the following may be independently selected from the group (e.g., the group consisting of): -(C1-C6)alkyl and -(C0-C6)alkylene-OR 6 , where R 6 It may independently be -(C1-C6)alkyl or -(C3-C7)cycloalkyl.

[0104] For example, (A) m or (A) m Each of can be hydrogen. For example, (B) n or (B) n Each of may be independently selected from the group consisting of (eg, a group consisting of) methyl, -O-methyl, and -O-cyclopropane.

[0105] Particularly preferred compounds of the present invention are the compounds mentioned in the following list, as well as their pharmaceutically acceptable acid addition salts or base addition salts, their stereochemically isomeric forms or their N-oxide forms:

[0106] 6-(2,4-Dimethylphenyl)-2-(pyridin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one

[0107] 6-(2,4-Dimethylphenyl)-2-(pyrimidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one

[0108] 6-(2,4-Dimethylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one

[0109] 6-(3-(azetidin-1-yl)phenyl)-2-(pyridin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one

[0110] 6-(3-methoxyphenyl)-2-(pyridin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one

[0111] 6-(3-(azetidin-1-yl)phenyl)-2-(pyrimidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one

[0112] 6-(3-methoxyphenyl)-2-(pyrimidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one

[0113] 6-(3-methoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one

[0114] 6-(3-methoxy-2-methylphenyl)-2-(pyridin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one

[0115] 6-(3-methoxy-2-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one

[0116] 6-(3-methoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one

[0117] 6-(3-cyclopropyloxyphenyl)-2-(pyrimidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one

[0118] 6-(3-cyclopropyloxyphenyl)-2-(pyridin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one

[0119] 6-(3-cyclopropyloxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one

[0120] 6-(4-Methoxyphenyl)-2-(pyridin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one

[0121] 6-(4-Methoxyphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one

[0122] (-)6-(2,4-Dimethylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one

[0123] (+)6-(2,4-Dimethylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one

[0124] 6-(2-methoxyphenyl)-2-(pyridin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one

[0125] 6-(4-methoxy-2-methylphenyl)-2-(pyridin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one

[0126] 6-(4-methoxy-2-methylphenyl)-2-(pyrimidin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one and

[0127] 6-(4-methoxy-2-methylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one.

[0128] The compounds listed above can also be represented by the following skeletal formula:

[0129]

[0130]

[0131] Compounds according to any of the statements above may exhibit metabotropic glutamate receptor 7 modulator activity.

[0132] The disclosed compounds also include all pharmaceutically acceptable isotopic variations in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Some examples of suitable isotopes for inclusion in the disclosed compounds include, but are not limited to, isotopes of hydrogen, such as 2 H and 3 H; isotopes of carbon, e.g. 11 C. 13 C and 14 C; isotopes of nitrogen, e.g. 15 N; isotopes of oxygen, e.g. 17 O and 18 O; isotopes of phosphorus, e.g. 31 P. 32 P and 33 P; isotopes of sulfur, e.g. 35 S; isotopes of fluorine, e.g. 18 F; isotopes of chlorine, e.g. 36 Cl; and isotopes of iodine, e.g. 125 I. The present invention includes various isotopically labeled compounds as defined herein, for example, wherein a radioactive isotope (e.g. 3 H and 14 C), or those compounds in which non-radioactive isotopes (e.g. 2 H and 13 C) those compounds.

[0133] Such isotope-labeled compounds can be used for metabolic studies (using 14 C), reaction kinetics studies (e.g. 2 H or 3 H), detection or imaging techniques (such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including drug or substrate tissue distribution determinations), or radiotherapy for patients. In particular, 11 C. 18 F. 15 O and 13 Compounds labeled with N or deuterium may be particularly suitable for PET studies examining substrate receptor occupancy. 2The substitution of deuterium with H or D) may provide certain therapeutic advantages due to better metabolic stability (e.g., increased in vivo half-life, or reduced dosage requirements, or improvement in therapeutic index). It should be understood that deuterium in this context is considered to be a substituent of compounds of formula (I) to (IX). Isotopically labeled compounds of formula (I) to (IX) can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the accompanying examples using suitable isotopically labeled reagents instead of previously used non-labeled reagents.

[0134] In one aspect of the present invention, a pharmaceutical composition comprising a compound according to any of the above statements is provided. The pharmaceutical composition may further comprise a pharmaceutically acceptable carrier and / or excipient. The pharmaceutical composition may comprise a therapeutically effective amount of a compound according to any of the above statements.

[0135] In one aspect of the invention, there is provided a method of treating or preventing a disorder in a mammal, comprising administering to a mammal in need of such treatment or prevention an effective amount of a compound / composition according to any of the statements above.

[0136] Such treatment or prevention may be affected or facilitated by modulation by an mGlu7 allosteric modulator, such as an mGlu7 negative allosteric modulator.

[0137] The condition may be one or more of a central nervous system disorder or an otic disease or disorder or a pain disorder.

[0138] The central nervous system disorder may be an anxiety disorder, such as agoraphobia, generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), panic disorder, or post-traumatic stress disorder (PTSD).

[0139] The central nervous system disorder may be a psychotic disorder, such as schizophrenia, delusional disorder, schizoaffective disorder, schizophreniform disorder, or substance-induced psychotic disorder.

[0140] The ear diseases and disorders may be one or more of the following: inner ear damage, age-related hearing loss (presbycusis), Meniere's disease, sudden hearing loss, noise-induced hearing loss, otitis media, autoimmune inner ear disease, acute tinnitus, chronic tinnitus, drug-induced hearing loss, hidden hearing loss, cisplatin-induced hearing loss, aminoglycoside-induced hearing loss, ototoxicity, central auditory processing disorder, or vestibular disorder.

[0141] In another aspect of the present invention, there is provided a method for treating, preventing, improving, controlling or reducing the risk of various nervous system and mental disorders associated with glutamate dysfunction in a mammal, the method comprising administering an effective amount of a compound / composition according to any of the above statements to a mammal in need of such treatment or prevention. The treatment or prevention can be influenced or promoted by the modulatory action of an mGlu7 negative allosteric modulator.

[0142] Preferably, the method is for treating or preventing a disorder in a human.

[0143] In another aspect of the invention there is provided a compound or composition as set forth in any of the statements above for use as a medicament.

[0144] In another aspect of the invention there is provided a compound or composition as set out in any of the statements above for use in a method of treatment or prevention as defined in any of the statements above.

[0145] In another aspect of the invention there is provided the use of a compound according to any of the statements above in the preparation of a medicament for the treatment or prevention of a condition as defined in any of the statements above.

[0146] Definition of terms

[0147] Listed below are definitions of various terms used in the specification and claims to describe the present invention.

[0148] For the avoidance of doubt, it should be understood that in this specification, "(C1-C6)" means a carbon group having 1, 2, 3, 4, 5, or 6 carbon atoms. "(C0-C6)" means a carbon group having 0, 1, 2, 3, 4, 5, or 6 carbon atoms. In this specification, "C" means a carbon atom, "N" means a nitrogen atom, "O" means an oxygen atom, and "S" means a sulfur atom.

[0149] When the subscript is the integer 0 (zero), the group referred to by the subscript indicates that the group does not exist, that is, there is a direct bond between the groups.

[0150] Where a subscript is the integer 0 (zero) and the group to which the subscript refers is an alkyl group, this means that the group is a hydrogen atom.

[0151] In this specification, unless otherwise indicated, the term "bond" refers to a saturated covalent bond. When two or more bonds are adjacent to each other, they are assumed to be equal to one bond. For example, the group -AB-, where both A and B can be a bond, represents a single bond.

[0152] In this specification, unless otherwise indicated, the term "alkyl" includes both straight and branched chain alkyl groups and can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, isohexyl or tert-hexyl. The term "(C0-C3)alkyl" refers to an alkyl group having 0, 1, 2 or 3 carbon atoms and can be methyl, ethyl, n-propyl or isopropyl.

[0153] In this specification, unless otherwise specified, the term "alkylene" includes both straight-chain and branched difunctional saturated hydrocarbon groups, and may be methylene (-CH2-), ethylene (-CH2-CH2-), n-propylene (-CH2-CH2-CH2-), isopropylene (-CH-(CH3)-CH2-), n-butylene (-CH2-CH2-CH2-CH2-), isobutylene (-CH2-CH-(CH3)-CH2-), tert-butylene (-CH2-C-(CH3)-CH2-), -CH2-), n-pentylene (-CH2-CH2-CH2-CH2-CH2-), isopentylene (-CH2-CH(CH3)-CH2-CH2-), neopentylene (-CH2-C(CH3)2-CH2-), n-hexylene (-CH2-CH2-CH2-CH2-CH2-CH2-), isohexylene (-CH2-CH-(CH3)-CH2-CH2-CH2-), or neohexylene (-CH2-C(CH3)2-CH2-CH2-). The term "O-(C1-C6)alkylene-aryl" refers to an alkyl chain having 0, 1, 2, 3, 4, 5, or 6 carbon atoms between the oxygen atom and the aryl group.

[0154] In this specification, unless otherwise indicated, the term "cycloalkyl" refers to an optionally substituted carbocyclic ring containing no heteroatoms, including monocyclic, bicyclic, and tricyclic saturated carbocyclic rings and fused ring systems. Such fused ring systems may include a partially or completely unsaturated ring (e.g., a benzene ring) to form a fused ring system such as a benzo-fused carbocyclic ring. Cycloalkyl includes fused ring systems, such as spirofused ring systems. Some examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentane, decahydronaphthalene, adamantane, indanyl, fluorenyl, and 1,2,3,4-tetrahydronaphthalene. The term "(C3-C7)cycloalkyl" may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.

[0155] In this specification, unless otherwise indicated, the term "alkenyl" includes both straight-chain and branched alkenyl groups. The term "(C2-C6)alkenyl" refers to an alkenyl group having 2 to 6 carbon atoms and one or two double bonds, and may be, but is not limited to, vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, crotyl, pentenyl, isopentenyl or hexenyl.

[0156] In this specification, unless otherwise indicated, the term "alkenylene" includes both straight-chain and branched disubstituted alkenyl groups. The term "(C2-C6)alkenylene" refers to an alkenylene group having 2 to 6 carbon atoms and one or two double bonds, and may be, but is not limited to, vinylene, allylene, propenylene, isopropenylene, butenylene, isobutenylene, crotylene, pentenylene, isopentenylene or hexenylene.

[0157] In this specification, unless otherwise stated, the term "alkynyl" includes both straight and branched chain alkynyl groups. The term (C2-C6)alkynyl, which has 2 to 6 carbon atoms and one or two triple bonds, can be, but is not limited to, ethynyl, propargyl, butynyl, isobutynyl, pentynyl, isopentenyl or hexynyl.

[0158] In this specification, unless otherwise stated, the term "alkynylene" includes both straight-chain and branched disubstituted alkynylene groups. The term (C2-C6)alkynylene has 2 to 6 carbon atoms and one or two triple bonds and can be, but is not limited to, ethynylene, propargylene, butynylene, isobutynylene, pentynylene, isopentenylene or hexynylene.

[0159] The term "aryl" refers to an optionally substituted monocyclic or bicyclic hydrocarbon ring system comprising at least one unsaturated aromatic ring. Some examples and suitable values ​​of the term "aryl" are phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indolyl, indenyl, and the like.

[0160] In this specification, unless otherwise stated, the term "heteroaryl" refers to an optionally substituted monocyclic or bicyclic unsaturated aromatic ring system containing at least one heteroatom independently selected from N, O or S. Some examples of "heteroaryl" can be, but are not limited to, benzimidazolyl, benzisothiazolyl, benzisothiazolyl, benzo ... oxazolyl, benzofuranyl, benzopyrazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzo oxazolyl, furazanyl, furanyl, imidazolinone, imidazolyl, imidazopyridazinyl, imidazopyridinyl, indolyl, isoindolyl, isoquinolyl, isothiazolyl, isothiazolyl, Azolyl, naphthyridinyl, Oxazolyl, Oxazolone, Oxalopyridazinyl, Azolopyridinyl, oxazolyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridonyl, pyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrotriazolopyridinyl, tetrahydrotriazolopyrimidinyl, tetrazolyl, thiadiazolyl, thiazolonyl, thiazolopyridazinyl, thiazolopyridinyl, thiazolyl, thienyl, thionaphthyl, triazinyl and triazolyl.

[0161] In this specification, unless otherwise stated, the terms "alkylene-aryl", "alkylene-heteroaryl" and "alkylene-cycloalkyl" refer to substituents attached to an aryl, heteroaryl or cycloalkyl group, respectively, through an alkyl group. The term "(C1-C6)alkylene-aryl" includes aryl-C1-C6-alkyl groups such as benzyl, 1-phenylethyl, 2-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 1-naphthylmethyl and 2-naphthylmethyl. The term "(C1-C6)alkylene-heteroaryl" includes heteroaryl-C1-C6-alkyl groups, some examples of which are the same as those exemplified in the above definition, such as 2-furylmethyl, 3-furylmethyl, 2-thienylmethyl, 3-thienylmethyl, 1-imidazolylmethyl, 2-imidazolylmethyl, 3-imidazolylmethyl, 2- Azolylmethyl, 3- azolylmethyl, 2-thiazolylmethyl, 3-thiazolylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 1-quinolylmethyl and the like.

[0162] In this specification, unless otherwise indicated, the term "heterocycle" refers to an optionally substituted monocyclic, bicyclic or tricyclic saturated, partially saturated or unsaturated ring system containing at least one heteroatom independently selected from N, O and S. Bicyclic or tricyclic ring systems can be formed by annulation of two or more rings, through bridging atoms (such as O, S, N) or through bridging groups (such as alkylene). Some examples of heterocyclic moieties include, but are not limited to, azetidinyl, dihydrofuranyl, dihydrothiophenyl, dioxolanyl, 1,1-dioxo-thiomorpholinyl, imidazolidinyl, imidazolinyl, isothiazolin ... Oxazolidinyl, isocyanate Oxazolinyl, morpholinyl, Oxazolidinyl, oxazolinyl, oxetanyl, piperazinyl, piperazinyl, piperidinyl, piperidinyl, pyranyl, pyrrolidinyl, pyrrolidinyl, pyrrolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, thiazolidinyl, thiazolinyl, thiomorpholinyl, thiopyranyl, triazolinyl, and the corresponding benzoheterocycles (e.g., dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzo oxazinyl, dihydrofuropyridinyl, dihydroquinolinyl, dihydrothienopyridinyl, indolinyl, pyrrolopyridinyl, tetrahydroquinolinyl, tetrahydroquinoxalinyl, etc.).

[0163] In this specification, unless otherwise indicated, 5- or 6-membered rings containing one or more atoms independently selected from C, N, O, and S include aromatic and heteroaromatic rings and carbocyclic and heterocyclic rings, which may be saturated or unsaturated. Such rings include spirocyclic and bridged bicyclic ring systems. Some examples of such rings may be, but are not limited to, dihydrofuranyl, dihydrothiophenyl, dioxolanyl, 1,1-dioxo-thiomorpholinyl, furazanyl, furanyl, imidazolidinyl, imidazolinyl, imidazolinonyl, imidazolyl, isothiazolinyl, isothiazol ... Oxazolidinyl, isocyanate Oxazoline, iso Azolyl, morpholinyl, Oxazolyl, Oxazolidinyl, Oxazoline, Oxazolone, oxazolyl, phenyl, piperazinyl, piperazinyl, piperidinyl, piperidinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinonyl, pyridinyl, pyrimidinyl, pyrrolidonyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolinyl, thiazolonyl, thiazolyl, thienyl, thiomorpholinyl, thiopyranyl, triazolinyl, triazinyl, triazolyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl.

[0164] In this specification, unless otherwise specified, 3 to 10 membered rings containing one or more atoms independently selected from C, N, O and S include aromatic and heteroaromatic rings and carbocyclic and heterocyclic rings, which may be saturated or unsaturated. Some examples of such rings may be, but are not limited to, azetidinyl, benzimidazolyl, benzisothiazolyl, benzisothiazolyl, benzothiazolyl, benzoiso ... oxazolyl, benzofuranyl, benzopyrazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzo oxazolyl, dihydrofuranyl, dihydrothiophenyl, dioxolanyl, 1,1-dioxo-thiomorpholinyl, furazanyl, furanyl, imidazolidinyl, imidazolinyl, imidazolinonyl, imidazolyl, imidazopyridazinyl, imidazopyridinyl, indolyl, isoindolyl, isoquinolyl, isothiazolinyl, isothiazolyl, isothiazolyl, isothiazolyl, Oxazolidinyl, isocyanate Oxazoline, iso Azolyl, morpholinyl, naphthyl, naphthyridinyl, Oxazolyl, Oxazolidinyl, Oxazoline, Oxazolone, Oxalopyridazinyl, Azolopyridinyl, oxetane, phenyl, piperazinyl, piperazinyl, piperidinyl, piperidinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydro triazolopyridinyl, tetrahydrotriazolopyrimidinyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolinyl, thiazolonyl, thiazolone, thiazolopyridazinyl, thiazolopyridinyl, thiazolyl, thienyl, thiomorpholinyl, thionaphthyl, thiopyranyl, triazolinyl, triazinyl, triazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl and cyclooctenyl.

[0165] In this specification, unless stated otherwise, the term "halo" or "halogen" may be fluoro, chloro, bromo or iodo.

[0166] In this specification, unless otherwise indicated, the term "haloalkyl" means an alkyl group as defined above that is substituted with one or more halo groups. The term "(C1-C6)haloalkyl" may include, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, and difluoroethyl. The term "O-C1-C6-haloalkyl" may include, but is not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, and fluoroethoxy.

[0167] In this specification, unless stated otherwise, the term "cyanoalkyl" means an alkyl group as defined above substituted with one or more cyano groups.

[0168] In the present specification, unless otherwise stated, the term "optionally substituted" refers to a group further carrying one or more substituents, which may be acyl, (C1-C6) alkyl, -(C1-C6) haloalkyl, -(C3-C7) cycloalkyl, -(C1-C6) alkylene-(C3-C7) cycloalkyl, -(C3-C7) cycloalkyl-(C1-C6) alkylene, -(C0-C6) alkylene-(C3-C7) spiroalkyl-(C0-C6) alkylene, hydroxyl, (C1-C6) alkylene, -(C1-C6) alkylene-(C3-C7) spiroalkyl-(C0-C6) alkylene, )alkylene-oxy, dimethylamino(C1-C3)alkyl, mercapto, aryl, heterocycle, heteroaryl, (C1-C6)alkylene-aryl, (C1-C6)alkylene-heterocycle, (C1-C6)alkylene-heteroaryl, halogen, haloalkyl, trifluoromethyl, pentafluoroethyl, haloalkoxy, cyano, cyanomethyl, nitro, amino, amido, amidinyl, oxo, carboxyl, carboxamide, (C1-C6)alkylene-oxycarbonyl, carbamate, sulfonamide, ester or sulfonyl.

[0169] In this specification, unless stated otherwise, the term "independently" means that where more than one substituent is selected from a plurality of possible substituents, these substituents may be the same or different.

[0170] In this specification, unless otherwise indicated, the term "solvate" refers to a complex of variable stoichiometry consisting of a solute (e.g., a compound of formula (I)) and a solvent. The solvent is a pharmaceutically acceptable solvent such as water; such a solvent may not interfere with the biological activity of the solute.

[0171] In the present specification, unless otherwise specified, the term "salt" refers to an acid addition salt or a base addition salt of the compound of the present invention. "Salt" particularly includes "pharmaceutically acceptable salts".

[0172] The pharmaceutically acceptable salts of the present invention can be synthesized from basic or acidic moieties by conventional chemical methods. When both a basic group and an acidic group are present in the same molecule, the compounds of the present invention may also form internal salts, such as zwitterionic molecules.

[0173] In this specification, unless otherwise indicated, certain compounds may exist in one or more specific geometric, optical, enantiomeric, diastereomeric, epimeric, stereoisomeric, tautomeric, conformational or anomeric forms, including but not limited to cis and trans forms; E- and Z- forms; endo- and exo- forms; R-, S-, and meso- forms; D- and L- forms; d- and l- forms; (+) and (-) forms; keto-, enol-, and enolate- forms; α- and β- forms; axial and equatorial forms; and combinations thereof, collectively referred to as "isomers" or "isomer forms."

[0174] For example, the group yes tautomers.

[0175] The term "isomer" includes compounds having one or more isotopic substitutions. For example, H can be in any isotopic form, including but not limited to 1 H. 2 H(D) and 3 H(T); C can be in any isotopic form, including but not limited to 12 C. 13 C. 14 C; O can be in any isotopic form, including but not limited to 16 O and 18 O, etc. F may be in any isotopic form, including but not limited to 19 F and 18 F, etc.

[0176] In the present specification, unless otherwise indicated, the term "negative allosteric modulator of mGlu7" or "allosteric modulator of mGlu7" also refers to a pharmaceutically acceptable acid addition salt or base addition salt thereof, a stereochemically isomeric form thereof or an N-oxide form thereof.

[0177] Pharmaceutical composition

[0178] The allosteric modulators of mGlu7 described herein, and pharmaceutically acceptable salts, solvates and hydrates thereof can be used in pharmaceutical preparations in combination with pharmaceutically acceptable carriers or diluents. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The allosteric modulators of mGlu7 will be present in such pharmaceutical compositions in an amount sufficient to provide the desired dosage within the scope described herein. The preparation of the compound of the present invention and the technology used can be found in Remington:the Science and Practice of Pharmacy, 19th edition, Mack Publishing Co., Easton, PA (1995).

[0179] The amount of the allosteric modulator of mGlu7 that is applied to object will depend on the type and severity of disease or illness and the characteristic of object, for example general health, age, sex, body weight and to the tolerance of medicine.Technician will be able to determine suitable dosage according to these and other factors.The effective dose of commonly used CNS medicine is well known to technician.The scope of daily total dose is generally about 0.05 to 2000mg.

[0180] The present invention relates to pharmaceutical compositions providing about 0.01 to 1000 mg of active ingredient per unit dose. The compositions can be administered by any suitable route. For example, oral administration in the form of capsules, parenteral administration in the form of solutions for injection, topical administration in the form of ointments or lotions, ocular administration in the form of eye drops, rectal administration in the form of suppositories, intranasal administration in the form of patch-like delivery systems, or transdermal administration.

[0181] For oral administration, the allosteric modulators of mGlu7 can be combined with suitable solid or liquid carriers or diluents to form capsules, tablets, pills, powders, syrups, solutions, suspensions and the like.

[0182] Tablets, pills, capsules, and the like contain from about 0.01 to about 99 weight percent of the active ingredient, along with a binder such as gum tragacanth, gum arabic, corn starch, or gelatin; an excipient such as dicalcium phosphate; a disintegrant such as corn starch, potato starch, or alginic acid; a lubricant such as magnesium stearate; and a sweetener such as sucrose, lactose, or saccharin. When the dosage unit form is a capsule, in addition to the above-mentioned substances, it may also contain a liquid carrier such as a fatty oil.

[0183] Various other substances may be present as coatings or to modify the physical form of the dosage unit. For example, tablets may be coated with shellac, sugar, or both. In addition to the active ingredient, a syrup or elixir may contain sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye, and flavorings such as cherry or orange flavor.

[0184] For parenteral administration, the allosteric modulator of disclosed mGlu7 or its salt can be combined with aseptic aqueous or organic medium to form injectable solution or suspension.For example, the solution in sesame oil or peanut oil, aqueous propylene glycol etc., and the aqueous solution of the water-soluble pharmaceutically acceptable salt of compound can be used.Dispersion can also be prepared in glycerol, liquid polyethylene glycol and its mixture in oil.Under common storage and use conditions, these preparations comprise preservative to prevent the growth of microorganisms.

[0185] In addition to the preparations described previously, the compound can also be formulated as a storage formulation. Such a long-acting formulation can be administered, for example, by subcutaneous implantation or intramuscular injection. Thus, for example, the compound can be formulated as an emulsion in an acceptable oil or ion exchange resin, or as a slightly soluble derivative, such as a slightly soluble salt.

[0186] The allosteric modulator of preferred disclosed mGlu7 or the pharmaceutical preparation that comprises these compounds are applied to mammal with unit dosage form.Unit dosage form can be any unit dosage form known in the art, comprises for example capsule, IV bag, tablet or medicine bottle (vial).The amount of active ingredient is effective amount and can change according to involved specific treatment in the unit dose composition.It is understandable that it is necessary to carry out conventional change to dosage according to patient's age and situation.Dosage will also depend on route of administration, and it can, by various approaches, comprise oral, aerosol, through rectum, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal and intranasal carrying out.

[0187] Synthesis method

[0188] Compound according to the present invention, particularly according to compound of formula (I) to (IX), can be prepared as described in the following synthesis scheme part by method known in the field of organic synthesis.In following all schemes, it is well understood that, according to the general principles of chemistry, the protecting group of sensitive or reactive group is used when necessary.Protecting group is operated (Green TWand Wuts PGM, (1991) Protecting Groups in Organic Synthesis, John Wiley & Sons) according to the standard method of organic synthesis.Use the method obvious to those skilled in the art to remove these groups at the convenient stage of compound synthesis.The selection of method and reaction conditions and its execution order should be consistent with the preparation of compound of formula (I) to (IX).

[0189] The compounds according to the present invention can be expressed as mixtures of enantiomers, which can be resolved into individual pure R- or S-enantiomers. For example, if a specific enantiomer is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), the resolution can be conveniently performed by fractional crystallization of an optically active acid salt from a variety of solvents or by other methods known in the literature (e.g., chiral column chromatography).

[0190] Resolution of final products, intermediates or starting materials can be carried out by any suitable method known in the art (Eliel E. L., Wilen SH and Mander LN (1984) Stereochemistry of Organic Compounds, Wiley-Interscience).

[0191] Many of the heterocyclic compounds of the present invention can be prepared using synthetic routes well known in the art (Katrizky A.R. and. Rees CW (1984) Comprehensive Heterocyclic Chemistry, Pergamon Press).

[0192] The product from this reaction can be isolated and purified using standard techniques such as extraction, chromatography, recrystallization, and distillation.

[0193] The compounds of the present invention can be prepared by general synthetic routes as disclosed in the following methods.

[0194] In one embodiment of the present invention, the compound of formula (I) can be prepared according to the synthetic sequence shown in Scheme 1. Intermediate g3 can be prepared by reacting the corresponding 5-bromo-2-fluoropyridine g1 with hydrazine g2 in a suitable solvent such as ethanol at a suitable temperature. Intermediate g3 can be reacted with 1,1'-carbonyldiimidazole (CAS No. 530-62-1) to obtain 6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one derivative g4 by condensation at a suitable temperature. Intermediate g4 can then be converted into intermediate g6 by a suitable reaction known to those skilled in the art of organic synthesis, for example, by a Suzuki cross-coupling reaction mediated by a palladium complex catalyst such as PdCl2(dppf) in a suitable solvent such as a mixture of 1,4-dioxane / water in the presence of a base such as potassium carbonate. The final compound g8 can be obtained by Ullmann coupling reaction with a suitable aryl halide or heteroaryl halide g7 mediated by a copper complex catalyst such as CuI in the presence of a base such as potassium phosphate at a suitable temperature. The final compound g9 can then be obtained by reduction using a nickel-aluminum alloy in an autoclave under hydrogen pressure.

[0195]

[0196] Solution 1

[0197] experiment

[0198] Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification.

[0199] Specifically, the following abbreviations may be used in the Examples and throughout the specification.

[0200]

[0201]

[0202] All references to brine refer to saturated aqueous solutions of NaCl. Unless otherwise stated, all temperatures are expressed in ° C. (Celsius). Unless otherwise stated, all reactions were carried out at room temperature under an inert atmosphere.

[0203] Most reactions were performed by thin layer chromatography on pre-coated silica gel plates (TLC silica gel 60F 254, SigmaAldrich) monitoring, with UV light visualization.Use Biotage Isolera One 2.0.8 automatic column, the capacity that obtains from Screening Devices BV is 4g, 12g, 25g, 40g and 80g ultrapure irregular silica gel (UltraPure IrregularSilicaGel) (40 to 63 μ m, 60A) pre-packed column, carry out flash column chromatography. Example

[0204] Example 1: 6-(2,4-dimethylphenyl)-2-(pyridin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (final compound 1-1) and

[0205] 6-(2,4-dimethylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (final compounds 1-3, 1-17 and 1-18)

[0206] 5-Bromo-2-hydrazinopyridine

[0207] According to Scheme 1 Step 1: Hydrazine monohydrate (42.67 g, 41.79 mL, 15 eq., 852.3 mmol) was added to a solution of 5-bromo-2-fluoropyridine (10.0 g, 5.85 mL, 1 eq., 56.8 mmol) in EtOH (125 mL) and stirred at room temperature overnight. The remaining mixture was concentrated under reduced pressure. The residue was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated to dryness to yield 5-bromo-2-hydrazinylpyridine (9.47 g, 50.4 mmol, 88.6%). MF: C5H6BrN3 (188.03 g / mol), 1 H-NMR (500MHz, DMSO-d6) δ8.03(dd,J=2.5,0.7Hz,1H),7.65(s,1H),7.59(dd,J=8.9,2.5Hz,1H),6.69(dd,J=8.9,0.7Hz,1H),4.17(s,2H). 13 C-NMR (126 MHz, DMSO-d6) δ 161.20, 147.93, 139.53, 108.58, 105.93. TLC (chloroform / MeOH 5:1) Rf = 0.7 (SM at 0.9).

[0208] 6-Bromo-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one

[0209] According to Scheme 1, Step 2: 5-Bromo-2-hydrazinylpyridine (9.47 g, 1 eq., 50.36 mmol) was added dropwise to a solution of CDI (16.33 g, 2 eq., 100.7 mmol) in THF (600 mL) at 0°C over 60 minutes. The mixture was stirred at room temperature overnight. The reaction mixture was diluted with saturated NaHCO3 solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was dissolved in EtOAc and washed with aqueous HCl (pH = 4), washed with brine, dried over MgSO4, and concentrated in vacuo to produce 6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (4.55 g, 21.3 mmol, 42.2%) as a bright orange solid. MF: C6H4BrN3O (214.02 g / mol), 1 H-NMR (500MHz, DMSO-d6) δ12.60 (s, 1H), 8.07 (dd, J = 1.7, 1.1 Hz, 1H), 7.25 (dd, J = 9.9, 1.7 Hz, 1H), 7.22 (dd, J = 9.9, 1.1 Hz, 1H). 13 C-NMR (126 MHz, DMSO-d6) δ 149.58, 141.28, 133.64, 124.33, 117.68, 104.91. TLC (chloroform / MeOH 5:1) RT = 0.5 (SM at 0.7), SFC-MS; > 95%, PDA (190.0-800.0 nm); m / z = 214.0; 216.0 [M+H], RT = 2.10 min,

[0210] Method: 2-30 MeOH HSS 6 min

[0211] 6-(2,4-Dimethylphenyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one

[0212] According to Scheme 1, Step 3: A microwave vial was charged with 6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (500 mg, 1 eq, 2.34 mmol), (2,4-dimethylphenyl)boronic acid (701 mg, 2 eq, 4.67 mmol), K2CO3 (969 mg, 3 eq, 7.01 mmol), 1,4-dioxane (13 mL) and water (1.4 mL). The reaction was degassed with argon in a sonicator for 5 minutes. PdCl2(dppf) (188 mg, 0.11 eq, 257 μmol) was then added and the reaction mixture was degassed again with argon in a sonicator for 5 minutes. The vial was capped and the reaction was heated to 110°C overnight. The reaction mixture was filtered through celite. The filter was washed with dioxane, MeOH, and DCM, and the mixture was concentrated in vacuo and purified using flash column chromatography. The resulting fractions were concentrated in vacuo to yield 6-(2,4-dimethylphenyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (271 mg, 1.13 mmol, 48.5%) as a bright yellow solid.

[0213] MF:C 14 H 13 N3O (239.28 g / mol) 1 H-NMR (500MHz, DMSO-d6) δ12.53(s,1H),7.61(s,1H),7.27(d,J=9.6Hz,1H),7.21(dd,J=9.6,1 .6Hz,1H),7.17(d,J=7.7Hz,1H),7.14(s,1H),7.08(d,J=7.7Hz,1H),2.32(s,3H),2.24(s,3H). 13 C-NMR (126 MHz, DMSO-d6) δ 150.36, 142.13, 137.90, 135.79, 133.85, 133.52, 131.66, 129.87, 127.25, 124.51, 121.78, 115.47, 21.11, 20.35. TLC (CHCl3 / MeOH 5:1) RT = 0.5 (SM at 0.5), SFC-MS; > 95%; PDA (190.0-800.0 nm); m / z = 240.2 [M+H], RT = 2.48 min, method: 2-30 MeOH HSS 6 min

[0214] 6-(2,4-dimethylphenyl)-2-(pyridin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (final compound 1-1)

[0215] According to Scheme 1, Step 4: A microwave vial was charged with 6-(2,4-dimethylphenyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (120 mg, 1 eq, 502 μmol), 2-bromopyridine (238 mg, 143 μL, 3 eq, 1.50 mmol), 1,10-phenanthroline (90.4 mg, 1 eq, 502 μmol), tripotassium phosphate (213 mg, 83.0 μL, 2 eq, 1.00 mmol) and 1,4-dioxane (3.5 mL). The reaction mixture was degassed with argon for 5 minutes. Then, CuI (47.8 mg, 0.5 eq, 251 μmol) was added and the reaction mixture was degassed with argon again for 5 minutes. The microwave vial was capped and the mixture was heated to 110°C overnight. The reaction mixture was filtered through celite and the filter was washed with DCM. The filtrate was concentrated in vacuo and purified using column chromatography (silica gel, 40 g, EtOAc / Hept 0% to 100%) to yield 6-(2,4-dimethylphenyl)-2-(pyridin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (69.64 mg, 220.1 μmol, 43.9%) as white crystals. MF: C 19 H 16 N4O (316.36 g / mol), TLC (CHCl3 / MeOH) RT = 0.9 (SM at 0.6), 1 H-NMR (500MHz, CDCl3) δ8.66(ddd,J=4.8,1.9,0.8Hz,1H),8.39(dt,J=8.5,1.0Hz,1H),7.89(ddd,J=8.4,7.4,2.0HZ,1H),7.77(t,J=1.4Hz ,1H),7.33-7.24(m,2H),7.20(dd,J=9.6,1.6Hz,1H),7.16(d,J=7.7Hz,1H),7.15(s,1H),7.11(d,J=7.7Hz,1H),2.40(s,3H),2.31(s,3H). 13C-NMR (126 MHz, CDCl3) δ 149.67, 149.09, 147.79, 142.07, 138.54, 138.46, 135.64, 134.96, 133.06, 131.57, 129.49, 127.04, 125.67, 121.72, 121.66, 114.97, 114.49, 21.11, 20.23. TLC (CHCl3 / MeOH) RT = 0.9 (SM at 0.6), SFC-MS; > 95%; PDA (190.0-800.0 nm); m / z = 317.1 [M+H], RT = 2.93 min, method: 2-30 MeOH HSS 6 min LC-MS (ESI): >95% PDA (254 nm); m / z = 317.13 [M+H], RT = 7.82 min, method: instrument method 10 min run + MS (0-95 MilliQ-MeCN) Accucore TM C 18 10 minutes.

[0216] 6-(2,4-Dimethylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one

[0217] According to Scheme 1, Step 5: Charge a glass vial with 6-(2,4-dimethylphenyl)-2-(pyridin-2-yl)-[1,2,4]triazolo[4,3- a ]pyridine-3(2 H )-one (20 mg, 1 eq, 63 μmol), EtOH (1.5 mL), NaOH (5.1 mg, 0.13 mL, 1 M, 2 eq, 0.13 mmol), and a spatula tip of nickel-aluminum alloy were added under water. The vial was placed in an autoclave, which was evacuated and backfilled 3× with argon. The autoclave was then placed under H2 pressure (60 bar) and heated to 40°C over the weekend. The reaction mixture was filtered through celite, and the filter was washed with MeOH. The filtrate was concentrated under reduced pressure to yield the crude product 6-(2,4-dimethylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (17 mg, 53 μmol, 84%) as an off-white solid. The crude product was dissolved in MeOH and purified using preparative HPLC (water / ACN 0% to 100% with 0.1% formic acid). The product containing fractions were concentrated in vacuo. The remaining solid was redissolved in AcOH and freeze-dried overnight to yield 13 mg of the final purified compound as a white solid.

[0218] MF:C 19 H 20 N4O (320.16 g / mol), TLC (CHCl3 / MeOH) RT = 0.8 (purple) (SM = 0.9 (blue)), 1 H-NMR (500MHz, CDCl3) δ8.56 (ddd, J=4.9, 2.0, 0.9Hz, 1H), 8.24 (dt, J=8.3, 1.0Hz, 1H), 7.82 (ddd, J=8.3, 7.3, 1.9Hz, 1 H),7.18(ddd,J=7.4,4.9,1.0Hz,1H),7.14-7.09(m,1H),7.06-7.02(m,2H),4.06(ddd,J=12.6,5.3,1.4Hz,1H),3.50(d d, J=12.6, 11.0Hz, 1H), 3.34 (tdd, J=11.2, 5.3, 2.7Hz, 1H), 3.13 (ddd, J=17.4, 5.1, 2.9Hz, 1H), 2.90 (ddd, J=17.7, 12. 0,6.0Hz,1H),2.39(s,3H),2.34(s,3H),2.19(dddd,J=11.6,7.1,3.5,2.1Hz,1H),2.09(dtd,J=13.5,11.8,5.0Hz,1H). 13 C-NMR (126 MHz, CDCl3) δ 152.05, 149.59, 148.73, 144.98, 138.31, 136.98, 135.69, 135.48, 131.75, 127.37, 125.37, 120.82, 113.38, 45.69, 35.00, 26.29, 22.84, 20.91, 19.33. LC-MS (ESI): >95% PDA (254 nm); m / z = 321.14 [M+H], RT = 7.26 min, method: instrumental method 10 min run + MS (0-95 MilliQ-MeCN) Accucore TM C 18 10 minutes.

[0219] The product was dissolved in MeOH and purified using chiral preparative HPLC (AD-H column 20% EtOH in heptane) to produce two fractions. The fractions were concentrated separately in vacuo. The remaining solid was redissolved in glacial acetic acid and freeze-dried overnight to produce

[0220] (-)6-(2,4-Dimethylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one

[0221] 1 H-NMR (500MHz, CDCl3) δ8.57-8.51 (m, 1H), 8.21 (dt, J=8.4, 1.0Hz, 1H), 7.79 (ddd, J=8.4, 7.3, 1.9Hz ,1H),7.16(ddd,J=7.4,4.9,1.0Hz,1H),7.12-7.07(m,1H),7.04(m,2H),4.04(ddd,J=12.7,5.4,1.5 Hz,1H),3.52-3.43(m,1H),3.32(tdd,J=11.2,5.3,2.7Hz,1H),3.11(ddd,J=17.4,5.0,2.9Hz,1H),2 .88(ddd,J=17.6,12.0,5.9Hz,1H),2.37(s,3H),2.32(s,3H),2.20-2.13(m,1H),2.12-1.99(m,1H).

[0222] LC-MS (ESI): >95% PDA (254 nm); m / z = 321.12 [M+H], RT = 7.30 min, method: instrument method 10 min run + MS (0-95 MilliQ-MeCN) Accucore TM C 18 10 minutes.

[0223] Analytical chiral HPLC >95%; >99% ee (215 nm; 254 nm) RT = 50.26 min, Method: Instrumental method 90 min run (15% EtOH in heptane, 900 μL / min) AD-H column.

[0224] Polarimeter [α] 589.28 = -44.118 in EtOAc at 20°C.

[0225] (+)6-(2,4-Dimethylphenyl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one

[0226] 1H-NMR (500MHz, CDCl3) δ8.54 (ddd, J=4.9, 2.0, 0.9Hz, 1H), 8.21 (dt, J=8.4, 1.0Hz, 1H), 7.79 (ddd, J=8.4, 7.3, 1. 9Hz,1H),7.16(ddd,J=7.3,4.9,1.0Hz,1H),7.11-7.08(m,1H),7.04(m,2H),4.04(ddd,J=12.55.31.4Hz,1H),,3 .48(dd,J=12.6,11.0Hz,1H),3.32(tdd,J=11.2,5.3,2.7Hz,1H),3.11(ddd,J=17.4,5.0,2.9Hz,1H),2.88(ddd, J=17.7,12.0,6.0Hz,1H),2.37(s,3H),2.32(s,3H),2.16(ddtd,J=13.3,5.8,2.8,1.3Hz,1H),2.11-1.99(m,1H).

[0227] LC-MS (ESI): >95% PDA (254 nm); m / z = 321.13 [M + H], RT = 7.26 min, method: instrument method 10 min run + MS (0-95 MilliQ-MeCN) Accucore TM C 18 10 minutes.

[0228] Analytical chiral HPLC>95%;>99% ee (215nm; 254nm) RT=29.769 minutes, Method: Instrumental method 90 minute run (15% EtOH in heptane, 900 μL / min) AD-H column polarimeter [α] 589.28 = +50.000 in EtOAc at 20 °C.

[0229] The compounds in the table below have been synthesized according to the same method as in the previous Example 1, as indicated in the column denoted "Exp. nr." The compounds indicated with an asterisk have been exemplified in the examples.

[0230] Table 1 : Compounds prepared according to Examples.

[0231]

[0232]

[0233]

[0234]

[0235] Physical and chemical data

[0236] LC-MS method:

[0237] Liquid chromatography-mass spectrometry (LC-MS) was performed on a LC-MS system consisting of a Dionex UltiMate 3000 pump, autosampler, column compartment, and detector (Thermo Fisher Scientific, Dreieich, Germany) and an ESI quadrupole MS (MSQ Plus or ISQ EC, Thermo Fisher Scientific, Dreieich, Germany).

[0238] Method 1:

[0239] Reverse (C 18 ) in Accucore TM C 18 Column (100×3 mm); eluent: H2O+0.1% formic acid (A) and MeCN+0.1% formic acid (B). Gradient conditions used: linear gradient from 0% to 95% B in 10 minutes. Purity was determined by the area percentage method of the obtained PDA spectra.

[0240] Liquid chromatography-mass spectrometry (LC-MS) was also performed on an LC-MS system consisting of: TM C 18 Shimadzu preparative HPLC system (DGU-20AR 3R Thermo Finnigan LCQ Fleet was coupled with a degasser, two LC-20AD pumps, an SPD-20APDA detector and a CTO-20A column oven.

[0241] NMR:

[0242] 1H-NMR spectra were recorded on a Bruker Avance III 400 MHz, Bruker Avance III 500 MHz or Bruker Avance I 500 (500 MHz) spectrometer. Chemical shifts are expressed in parts per million (ppm, δ units). Splitting patterns describe apparent multiplicities and are designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad peak). Coupling constants (J) are given in Hertz (Hz).

[0243] Table 2: Physicochemical data. (RT means retention time in minutes; [MH] + refers to the protonated mass of the compound (free base); nd = not determined).

[0244] Protonated mass of compound (free base); nd = not determined).

[0245]

[0246]

[0247]

[0248]

[0249]

[0250] Pharmacology

[0251] The compounds provided in the present invention are negative allosteric modulators of mGlu7. Therefore, these compounds are expected to have an effect on mGlu7 due to their ability to block receptor function after binding to a site other than the orthosteric glutamate recognition site.

[0252] Some compounds of formula (I) have been tested according to some of the following methods.

[0253] Example A

[0254] mGlu7 assay for HEK expressing human mGlu7

[0255] Transfection and cell culture

[0256] The cDNA (accession number NM_181874.2, NCBI Nucleotide database browser) of coding human metabotropic glutamate 7 receptors (hmGlu7) is subcloned into the expression vector that also comprises hygromycin resistance gene.Meanwhile, the cDNA that makes coding activation signal turn to the G protein of intracellular calcium flux is subcloned into the different expression vectors that also comprise puromycin resistance gene.With PolyFect reagent (Qiagen) according to the scheme of supplier, these two kinds of vectors are all transfected into HEK293 cell, and hygromycin and puromycin process allow to select the antibiotic resistant cell that has stably integrated one or more plasmid copies.Identify the positive cell clone of expression hmGlu7 in the functional assay of measuring the change of calcium flux in response to glutamate and L-AP4 or known mGlu7 positive antagonist.

[0257] HEK-293 cells expressing hmGlu7 were maintained at 37°C and 5% CO2 in a humidified atmosphere containing DMEM, fetal bovine serum (10%), Glutamax TM The cells were cultured in a medium containing 2 mM penicillin (100 units / mL), streptomycin (100 μg / mL), geneticin (100 μg / mL), hygromycin-B (40 μg / mL), and puromycin (1 μg / mL).

[0258] Fluorescent cell-based Ca 2+ Mobilization assay

[0259] Using FLIPR 384 Human mGlu7 HEK-293 cells were plated at a density of 25,000 cells / well in black-walled, clear-bottom, poly-L-ornithine-coated 384-well plates in glutamate / glutamine-free DMEM medium containing fetal bovine serum (10%), penicillin (100 units / mL), streptomycin (100 μg / mL), and doxycycline (1 μg / mL) at 37°C and 5% CO2 in a humidified atmosphere 24 hours prior to the fluorescence cell-based calcium mobilization assay performed by the ELISA kit (Molecular Device, Sunnyvale, CA, USA).

[0260] On the day of measurement, aspirate culture medium and load cells with the solution of 3 μM Fluo4-AM (LuBioScience, Lucerne, Switzerland) in 0.03% pluronic acid (pluronic acid).At 37 ℃ / 5% CO2, after 1 hour, the dye that is not incorporated into is removed by washing the cell plate with assay buffer.All assays are carried out in the buffer solution of pH 7.4 containing 20mM HEPES, 143mM NaCl, 6mM KCl, 1mM MgSO4, 1mM CaCl2, 0.125mM sulfinpyrazone and 0.1% glucose.

[0261] After 10 seconds of basal fluorescence recording, different concentrations of the compounds of the invention were added to the cells. Changes in fluorescence levels were first monitored for 180 seconds to detect any agonist activity of the compounds. 80 The cells were stimulated for an additional 110 seconds at a concentration of L-AP4 in order to measure the inhibitory activity of the compounds of the invention. 80 The L-AP4 concentration was that which produced 80% of the maximal glutamate response.

[0262] Concentration response curves of L-AP4 or representative compounds of the invention were generated using Prism GraphPad software (Graph Pad Inc, San Diego, USA). The curves were fitted to a four-parameter logistic equation:

[0263] (Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*Hill Slope)

[0264] Allows determination of IC 50 value.

[0265] IC of the compounds of the present application 50 The value was less than 10 μM.

[0266] Table 3 below shows the average IC values ​​obtained from at least three independent experiments performed in duplicate for selected molecules. 50 .

[0267] Table 3 : Activity data of selected compounds

[0268] Co.Nr. <![CDATA[Ca 2+ Flux*]]> Co.nr. <![CDATA[Ca 2+ Flux*]]> Co.nr. <![CDATA[Ca 2+ Flux*]]> 1-1 +++ 1-9 +++ 1-17 + 1-2 ++ 1-10 ++ 1-18 +++ 1-3 +++ 1-11 ++ 1-19 + 1-4 ++ 1-12 ++ 1-20 ++ 1-5 ++ 1-13 ++ 1-21 + 1-6 ++ 1-14 ++ 1-22 ++ 1-7 + 1-15 + 1-8 + 1-16 +

[0269] *Table description:

[0270] (+): 1μM <IC 50 <10μM

[0271] (++): 100nM <IC 50 <1μM

[0272] (+++):IC 50 <100nM

[0273] The results shown in Table 3 indicate that the compounds described in the present invention are negative allosteric modulators of the human mGlu7 receptor.

[0274] Example B

[0275] Water associated zero maze:

[0276] The procedure can be performed as previously described by Ritov and Richter-Levin (2014), but with slight modifications. The apparatus consists of an annular platform with two opposing closed quadrants (wall height 35 cm) and two open quadrants (border height 5 mm). The plastic tank that holds the platform is filled with water (22±2°C, 50 cm deep) and raised to 10 cm below the platform level. Thus, the annular platform and the plastic tank constitute a unified arena. For this test, the rats are first acclimated to the room for 4 minutes and then placed in one of the open quadrants, facing the closed part of the apparatus. The rats are allowed to explore the arena for a period of 5 minutes. During this time, the rats' behavior is tracked, recorded, and analyzed using the Etho-Vision system (Noldus Information Technology, Wageningen, Netherlands). The behavioral measures analyzed include the time spent in the open quadrants, the distance traveled in the open quadrants, the distance traveled in the closed quadrants, and total freezing behavior. These parameters are used to evaluate the effects of exposure to various stressors and / or compounds. Pretreatment times and administration routes for different test compounds are defined based on their pharmacokinetic properties.

[0277] Example C

[0278] Elevated plus maze:

[0279] Elevated plus maze (EPM) test can be carried out using Sprague-Dawley male rats.EPM is made of such plastics, and it has two open arms (arm) (50cm × 10cm) and two closed arms with the same size (wall height is 40cm), which is 86cm higher than the ground.Both arms are made of black Plexiglas.The average lighting level on the open arms is 187LUX, and on the closed arms, it is 100LUX.When the experiment begins, rats are brought into the waiting room (holding room) directly adjacent to the testing room, and are allowed to adapt to 30 minutes in this environment.When the test begins, rats are placed in the center of the maze, facing an open arm and observing for 5 minutes.During this time, the behavior of rats is tracked, recorded and analyzed by Etho-Vision system (NoldusInformation Technology, Wageningen, Netherlands).The behavioral measurement analyzed includes the time spent in the open arms, the number of times of entering the open arms and the distance traveled. The pretreatment time and administration route of different test compounds were defined based on their pharmacokinetic properties.

[0280] Example D

[0281] Fear conditioning model of post-traumatic stress disorder in rats:

[0282] The fear conditioning arena (30 cm × 20 cm × 25 cm, Med Associates) is made of Plexiglas in different environments. The system is placed in a soundproof ventilated box. The bottom of the arena is composed of a grid floor (19 parallel stainless steel rods with a diameter of 0.48 cm, spaced 1.6 cm apart) above a stainless steel waste pan. All rods are connected to the shock generator and scrambler. Speakers are mounted on the wall of the chamber to provide auditory stimulation. Fear conditioning operations are performed over two days. On the first day (training), rats are placed in the training environment (environment A) and after a 120-second adaptation period, they receive five pairs of CS and US. The CS tone (78 dB, 2 kHz, 5 milliseconds rise / fall time) lasts for 30 seconds and ends with a brief US foot shock (0.5 seconds, 0.66 mA). The inter-tone interval (from the onset of a tone to the onset of the next tone) ranged from 60 seconds. The conditioning chamber was cleaned with 70% ethanol between subjects. The time spent freezing during the CS tone delivery was scored (CS freezing). On the second day (test day), the animals were placed in a new environment (environment B) and exposed to the CS (120 seconds) after 60 seconds of acclimatization. The time spent freezing was measured during both acclimatization and CS. The test compound was administered before and / or after the training period and the test period. The pretreatment time and administration route of the different test compounds were adjusted according to their pharmacokinetic properties.

[0283] Example E

[0284] Noise-induced hearing loss (NIHL) model in mice:

[0285] Young adult male CBA / CaJ mice were used to evaluate the effects of the test compounds on NIHL. Within 2 hours, the animals were exposed to octave band noise (8 to 16 kHz) at a sound pressure level of 110 dB. The test compounds were administered before and / or after noise exposure. Hearing function was measured using distortion products of autoacoustic emission (DPOAE) or auditory brainstem response (ABR) audiograms at different time points 24 hours, 2 and 4 weeks after the acoustic trauma. The pretreatment time and route of administration of different test compounds were adjusted according to their pharmacokinetic properties. The experimental group was compared with the vehicle-treated group by measuring, for example, ABR threshold or ABR threshold shift.

[0286] Example F

[0287] Colorectal distension test for visceral pain in rats.

[0288] Male stress-sensitive Wistar Kyoto rats (250 to 300 g) were used in this study. Animals were fasted overnight (16 hours) and anesthetized with isoflurane on the day of testing. A 6 cm latex balloon was inserted into the colorectal cavity, 1 cm from the anus. The animals were allowed to recover for 20 minutes and then colorectal dilation was started. The paradigm used was an ascending phasic distension from 0 mmHg to 80 mmHg in 8 minutes using a computer-driven electronic regulator. The parameters measured were the threshold pressure (mmHg) that caused visually recognizable visceral pain behavior, and the total number of pain behaviors. The posture defined as visceral pain behavior was abdominal contraction and / or abdominal withdrawal reflex.

[0289] The test compounds were administered before colorectal distension. The pretreatment time and administration route of different test compounds were adjusted according to their pharmacokinetic properties.

[0290] Preparation Examples

[0291] Typical examples of the formulations of the present invention are as follows:

[0292] 1. tablet

[0293]

[0294]

[0295] In this instance, the active ingredient can be replaced by the same amount of any compound according to the invention, in particular by the same amount of any of the exemplified compounds.

[0296] 2. suspension

[0297] An aqueous suspension for oral administration is prepared so that each 1 ml contains 1 to 5 mg of one of the active compounds, 50 mg of sodium carboxymethylcellulose, 1 mg of sodium benzoate, 500 mg of sorbitol and water ad 1 mL.

[0298] 3. Injectable

[0299] A parenteral composition is prepared by stirring 1.5% by weight of the active ingredient of the invention in 10% by volume propylene glycol and water.

[0300] 4. ointment

[0301]

[0302] In this example, the active ingredient can be replaced by the same amount of any compound according to the invention, in particular by the same amount of any of the exemplified compounds.

[0303] Reasonable variations are not to be regarded as departure from the scope of the invention.It will be obvious that the invention described may be modified in many ways by a person skilled in the art.

Claims

1. A compound of formula (I): A pharmaceutically acceptable acid addition salt or base addition salt thereof, a stereochemically isomeric form thereof or an N-oxide form thereof, wherein: for R 1 Selected from the group consisting of hydrogen, deuterium, halogen, -(C1-C6)alkyl, -(C1-C6)haloalkyl, and -CF3; P represents a cycloalkyl group, an aryl group, a heteroaryl group or a heterocycle of the following formula: wherein each cycloalkyl, aryl or heteroaryl ring is optionally substituted with m groups A, where m is an integer equal to 0, 1, 2, 3 or 4; where Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 and Z 7 are independently selected from C, N, O or S; provided that Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 and Z 7 At least one of is N; (A) m or (A) m Each of which is independently selected from the group consisting of hydrogen, halogen, -CN, -OH, -NO2, -CF3, -SH, -NH2, and an optionally substituted group selected from the group consisting of -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C2-C6)alkynyl, -(C2-C6)alkenyl, -(C3-C7)cycloalkyl, -(C1-C6)alkylene-(C3-C7)cycloalkyl, -(C3-C8)cycloalkenyl, -(C1-C6)cyanoalkyl, -(C1-C6)alkylene-heteroaryl, -(C1-C6)alkylene-aryl, aryl, heteroaryl, -(C1-C6)alkylene-heterocycle, heterocycle, -(C0-C6)alkylene-OR 2 、-O-(C2-C6)alkylene-OR 2 、-NR 2 (C2-C6)alkylene-OR 3 、-(C3-C6)alkynylene-OR 2 、-(C3-C6)alkynylene-NR 2 R 3 、-(C3-C6)alkenylene-OR 2 、-(C3-C6)alkenylene-NR 2 R 3 、-(C0-C6)alkylene-SR 2 、-O-(C2-C6)alkylene-SR 2 、-NR 2 -(C2-C6)alkylene-SR 3 、-(C0-C6)alkylene-S(=O)-R 2 、-O-(C1-C6)alkylene-S(=O)-R 2 、-NR 2 -(C1-C6)alkylene-S(=O)-R 3 、-(C0-C6)alkylene-S(=O)2-R 2 、-O-(C1-C6)alkylene-S(=O)2-R 2 、-NR 2 -(C1-C6)alkylene-S(=O)2-R 3 、-(C0-C6)alkylene-NR 2 R 3 、-O-(C2-C6)alkylene-NR 2 R 3 、-NR 2 -(C2-C6)alkylene-NR 3 R 4 、-(C0-C6)alkylene-S(=O)2NR 2 R 3 、-O-(C1-C6)alkylene-S(=O)2NR 2 R 3 、-NR 2 -(C1-C6)alkylene-S(=O)2NR 3 R 4 、-(C0-C6)alkylene-NR 2 -S(=O)2R 3 、-O-(C2-C6)alkylene-NR 2 -S(=O)2R 3 、-NR 2 -(C2-C6)alkylene-NR 3 -S(=O)2R 4 、-(C0-C6)alkylene-C(=O)-NR 2 R 3 、-O-(C1-C6)alkylene-C(=O)-NR 2 R 3 、-NR 2 -(C1-C6)alkylene-C(=O)-NR 3 R 4 、-(C0-C6)alkylene-NR 2 C(=O)-R 3 、-O-(C2-C6)alkylene-NR 2 C(=O)-R 3 、-NR 2 -(C2-C6)alkylene-NR 3 C(=O)-R 4 、-(C0-C6)alkylene-OC(=O)-R 2 、-O-(C2-C6)alkylene-OC(=O)-R 2 、-NR 2 -(C2-C6)alkylene-OC(=O)-R 3 、-(C0-C6)alkylene-C(=O)-OR 2 、-O-(C1-C6)alkylene-C(=O)-OR 2 、-NR 2 -(C0-C6)alkylene-C(=O)-OR 3 、-(C0-C6)alkylene-C(=O)-R 2 、-O-(C1-C6)alkylene-C(=O)-R 2 、-NR 2 -(C1-C6)alkylene-C(=O)-R 3 、-(C0-C6)alkylene-NR 2 -C(=O)-OR 3 、-C(=O)-(C1-C6)alkylene-NR 2 -C(=O)-OR 3 、-(C0-C6)alkylene-OC(=O)-NR 2 R 3 、-(C0-C6)alkylene-NR 2 -C(=O)-NR 3 R 4 、-O-(C2-C6)alkylene-NR 2 -C(=O)-NR 3 R 4 、-NR 2 -(C2-C6)alkylene-NR 3 -C(=O)-NR 4 R 5 、-(C0-C6)alkylene-NR 2 -C(=S)-NR 3 R 4 and -(C0-C6)alkylene-NR 2 -C(=NR 3 )-NR 4 R 5 ; R 2 、R 3 、R 4 and R 5 each independently hydrogen or an optionally substituted group selected from the group consisting of -(C1-C6)haloalkyl, -(C1-C6)alkyl, -(C1-C6)cyanoalkyl, -(C3-C7)cycloalkyl, -(C1-C6)alkylene-(C3-C7)cycloalkyl, heteroaryl, -(C1-C6)alkylene-heteroaryl, aryl, -(C1-C6)alkylene-heterocycle, heterocycle, -(C1-C6)alkylene-aryl, -(C0-C6)alkylene-O-(C0-C6)alkyl, -(C0-C6)alkylene-N-((C0-C6)alkyl)2, and -C(═O)—O-(C1-C6)alkyl; Q represents an aryl or heteroaryl group of the formula: wherein each aryl or heteroaryl ring is optionally substituted by n groups B, wherein n is an integer equal to 0, 1, 2, 3, 4 or 5; wherein B 1 is group B; (B) n or (B) n Each of which is independently selected from the group consisting of hydrogen, halogen, -CN, -OH, -NO2, -CF3, -SH, -NH2, and an optionally substituted group selected from the group consisting of -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C2-C6)alkynyl, -(C2-C6)alkenyl, -(C3-C7)cycloalkyl, -(C1-C6)alkylene-(C3-C7)cycloalkyl, -(C3-C8)cycloalkenyl, -(C1-C6)cyanoalkyl, -(C1-C6)alkylene-heteroaryl, -(C1-C6)alkylene-aryl, aryl, heteroaryl, -(C1-C6)alkylene-heterocycle, heterocycle, -(C0-C6)alkylene-OR 6 、-O-(C2-C6)alkylene-OR 6 、-NR 6 (C2-C6)alkylene-OR 7 、-(C3-C6)alkynylene-OR 6 、-(C3-C6)alkynylene-NR 6 R 7 、-(C3-C6)alkenylene-OR 6 、-(C3-C6)alkenylene-NR 6 R 7 、-(C0-C6)alkylene-SR 6 、-O-(C2-C6)alkylene-SR 6 、-NR 6 -(C2-C6)alkylene-SR 7 、-(C0-C6)alkylene-S(=O)-R 6 、-O-(C1-C6)alkylene-S(=O)-R 6 、-NR 6 -(C1-C6)alkylene-S(=O)-R 7 、-(C0-C6)alkylene-S(=O)2-R 6 、-O-(C1-C6)alkylene-S(=O)2-R 6 、-NR 6 -(C1-C6)alkylene-S(=O)2-R 7 、-(C0-C6)alkylene-NR 6 R 7 、-O-(C2-C6)alkylene-NR 6 R 7 、-NR 6 -(C2-C6)alkylene-NR 7 R 8 、-(C0-C6)alkylene-S(=O)2NR 6 R 7 、-O-(C1-C6)alkylene-S(=O)2NR 6 R 7 、-NR 6 -(C1-C6)alkylene-S(=O)2NR 7 R 8 、-(C0-C6)alkylene-NR 6 -S(=O)2R 7 、-O-(C2-C6)alkylene-NR 6 -S(=O)2R 7 、-NR 6 -(C2-C6)alkylene-NR 7 -S(=O)2R 8 、-(C0-C6)alkylene-C(=O)-NR 6 R 7 、-O-(C1-C6)alkylene-C(=O)-NR 6 R 7 、-NR 6 -(C1-C6)alkylene-C(=O)-NR 7 R 8 、-(C0-C6)alkylene-NR 6 C(=O)-R 7 、-O-(C2-C6)alkylene-NR 6 C(=O)-R 7 、-NR 6 -(C2-C6)alkylene-NR 7 C(=O)-R 8 、-(C0-C6)alkylene-OC(=O)-R 6 、-O-(C2-C6)alkylene-OC(=O)-R 6 、-NR 6 -(C2-C6)alkylene-OC(=O)-R 7 、-(C0-C6)alkylene-C(=O)-OR 6 、-O-(C1-C6)alkylene-C(=O)-OR 6 、-NR 6 -(C1-C6)alkylene-C(=O)-OR 7 、-(C0-C6)alkylene-C(=O)-R 6 、-O-(C1-C6)alkylene-C(=O)-R 6 、-NR 6 -(C1-C6)alkylene-C(=O)-R 7 、-(C0-C6)alkylene-NR 6 -C(=O)-OR 7 、-(C0-C6)alkylene-OC(=O)-NR 6 R 7 、-(C0-C6)alkylene-NR 6 -C(=O)-NR 7 R 8 、-O-(C2-C6)alkylene-NR 6 -C(=O)-NR 7 R 8 、-NR 6 -(C2-C6)alkylene-NR 7 -C(=O)-NR 8 R 9 、-(C0-C6)alkylene-NR 6 -C(=S)-NR 7 R 8 and -(C0-C6)alkylene-NR 6 -C(=NR 7 )-NR 8 R 9 ; R 6 、R 7 、R 8 and R 9 each independently hydrogen or an optionally substituted group selected from the group consisting of -(C1-C6)haloalkyl, -(C1-C6)alkyl, -(C1-C6)cyanoalkyl, -(C3-C7)cycloalkyl, -(C1-C6)alkylene-(C3-C7)cycloalkyl, heteroaryl, -(C1-C6)alkylene-heteroaryl, aryl, -(C1-C6)alkylene-heterocycle, heterocycle, -(C1-C6)alkylene-aryl, -(C0-C6)alkylene-O-(C0-C6)alkyl and -(C0-C6)alkylene-N-((C0-C6)alkyl)2; wherein optionally, any two groups A are combined with intervening atoms to form a 3- to 10-membered bicyclic heterocyclic, aryl, or heteroaryl ring, wherein each ring is optionally further substituted with 1 to 5 groups independently selected from the group consisting of halogen, -CN, nitro, -(C1-C6)alkyl, -(C3-C7)alkyl, -(C0-C6)alkylene-O-(C0-C6)alkyl, and -(C0-C6)alkylene-N-((C0-C6)alkyl)2; wherein optionally, the substituent R 2 、R 3 、R 4 or R 5 in which two are combined with intervening atoms to form a 3- to 10-membered heterocyclic, aryl, or heteroaryl ring, wherein each ring is optionally further substituted with 1 to 5 groups independently selected from the group consisting of halogen, cyano, nitro, -(C1-C6)alkyl, -(C3-C7)alkyl, -(C0-C6)alkylene-O-(C0-C6)alkyl, and -(C0-C6)alkylene-N-((C0-C6)alkyl)2; wherein optionally, from R 6 、R 7 、R 8 or R 9 The two substituents of are combined with the intervening atoms to form a 3- to 10-membered heterocyclic, aryl, or heteroaryl ring, wherein each ring is optionally further substituted with 1 to 5 groups independently selected from the group consisting of halogen, cyano, nitro, -(C1-C6)alkyl, -(C3-C7)alkyl, -(C0-C6)alkylene-O-(C0-C6)alkyl, and -(C0-C6)alkylene-N-((C0-C6)alkyl)2; wherein optionally, any two groups B are combined with intervening atoms to form a 3- to 10-membered bicyclic heterocyclic, aryl, or heteroaryl ring, wherein each ring is optionally further substituted with 1 to 5 groups independently selected from the group consisting of halogen, -CN, nitro, -(C1-C6)alkyl, -(C3-C7)alkyl, -(C0-C6)alkylene-O-(C0-C6)alkyl, and -(C0-C6)alkylene-N-((C0-C6)alkyl)2.

2. A compound according to claim 1 having formula (I), wherein P represents a heteroaryl group of the formula: wherein each group is optionally substituted by m groups A, wherein m is an integer equal to 0, 1, 2, 3 or 4.

3. A compound according to claim 1 or 2 having formula (I), wherein: Q represents an aryl or heteroaryl group of the formula: wherein each group is optionally substituted by n groups B, wherein n is an integer equal to 0, 1, 2, 3, 4 or 5.

4. A compound according to any preceding claim, having formula (I), wherein: (A) m The cycloalkyl, heterocyclic, aryl and heteroaryl ring systems are selected from the group consisting of azetidinyl, 2-azabicyclo[2.2.1]heptan-2-yl, 7-azabicyclo[2.2.1]heptan-7-yl, benzimidazolyl, benzisothiazolyl, benzisothiazolyl, oxazolyl, benzofuranyl, benzopyrazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzo oxazolyl, dihydrofuranyl, dihydrothiophenyl, dioxolanyl, 1,1-dioxo-thiomorpholinyl, furazanyl, furanyl, imidazolidinyl, imidazolinyl, imidazolinonyl, imidazolyl, imidazopyridazinyl, imidazopyridinyl, indolyl, isoindolyl, isoquinolyl, isothiazolinyl, isothiazolyl, isothiazolyl, isothiazolyl, Oxazolidinyl, isocyanate Oxazoline, iso Azolyl, morpholinyl, naphthyl, naphthyridinyl, Oxazolyl, Oxazolidinyl, Oxazoline, Oxazolone, Oxalopyridazinyl, Azolopyridinyl, oxetane, phenyl, piperazinyl, piperazinyl, piperidinyl, piperidinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridinonyl, pyridinyl, pyrimidinyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrotriazolopyridinyl, tetrahydrotriazolopyrimidinyl 1 to 4 substituents R, wherein each ring of the ring system is optionally substituted independently with 1 to 4 substituents R 2 、R 3 、R 4 or R 5 replace.

5. A compound according to any preceding claim, having formula (I), wherein: (B) n The cycloalkyl, heterocyclic, aryl and heteroaryl ring systems are selected from the group consisting of azetidinyl, 2-azabicyclo[2.2.1]heptan-2-yl, 7-azabicyclo[2.2.1]heptan-7-yl, benzimidazolyl, benzisothiazolyl, benzisothiazolyl, oxazolyl, benzofuranyl, benzopyrazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzo oxazolyl, dihydrofuranyl, dihydrothiophenyl, dioxolanyl, 1,1-dioxo-thiomorpholinyl, furazanyl, furanyl, imidazolidinyl, imidazolinyl, imidazolinonyl, imidazolyl, imidazopyridazinyl, imidazopyridinyl, indolyl, isoindolyl, isoquinolyl, isothiazolinyl, isothiazolyl, isothiazolyl, isothiazolyl, Oxazolidinyl, isocyanate Oxazoline, iso Azolyl, morpholinyl, naphthyl, naphthyridinyl, Oxazolyl, Oxazolidinyl, Oxazoline, Oxazolone, Oxalopyridazinyl, Azolopyridinyl, oxetane, phenyl, piperazinyl, piperazinyl, piperidinyl, piperidinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridinonyl, pyridinyl, pyrimidinyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrotriazolopyridinyl, tetrahydrotriazolopyrimidinyl 1 to 4 substituents R, wherein each ring of the ring system is optionally substituted independently with 1 to 4 substituents R 6 、R 7 、R 8 or R 9 replace.

6. A compound according to any preceding claim, having formula (I), wherein: R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 or R 9 The cycloalkyl, heterocyclic, aryl and heteroaryl ring systems are selected from the group consisting of azetidinyl, benzimidazolyl, benzisothiazolyl, benzisothiazolyl, oxazolyl, benzofuranyl, benzopyrazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzo oxazolyl, dihydrofuranyl, dihydrothiophenyl, dioxolanyl, 1,1-dioxo-thiomorpholinyl, furazanyl, furanyl, imidazolidinyl, imidazolinyl, imidazolinonyl, imidazolyl, imidazopyridazinyl, imidazopyridinyl, indolyl, isoindolyl, isoquinolyl, isothiazolinyl, isothiazolyl, isothiazolyl, isothiazolyl, Oxazolidinyl, isocyanate Oxazoline, iso Azolyl, morpholinyl, naphthyl, naphthyridinyl, Oxazolyl, Oxazolidinyl, Oxazoline, Oxazolone, Oxalopyridazinyl, Azolopyridinyl, oxetane, phenyl, piperazinyl, piperazinyl, piperidinyl, piperidinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridinonyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrotriazolopyridinyl, tetrahydrotriazolopyrimidinyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolinyl, thiazolonyl, thiazolopyridazinyl, thiazolopyridinyl , thiazolyl, thienyl, thiomorpholinyl, thionaphthyl, thiopyranyl, triazolinyl, triazinyl, triazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl and cyclooctenyl, and each ring of the ring system is optionally substituted with 1 to 5 groups independently selected from the group consisting of hydrogen, halogen, -CN, nitro, -(C1-C6)alkyl, -(C0-C6)alkylene-O-(C0-C6)alkyl and -(C0-C6)alkylene-N-((C0-C6)alkyl)2.

7. A compound according to any preceding claim, having formula (I), wherein R 1 It's hydrogen.

8. A compound according to any preceding claim, having formula (I), wherein (A) m or (A) m Each of them is independently selected from the following group: hydrogen, halogen, -CN, -OH, -CF3 and an optionally substituted group selected from the following group: -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C3-C7)cycloalkyl, -(C1-C6)cyanoalkyl, aryl, heterocycle, -(C0-C6)alkylene-OR 2 、-O-(C2-C6)alkylene-OR 2 、-O-(C2-C6)alkylene-NR 2 R 3 、-NR 2 -(C2-C6)alkylene-NR 3 R 4 、-(C0-C6)alkylene-S(=O)2-R 2 、-(C0-C6)alkylene-NR 2 R 3 、-(C0-C6)alkylene-S(=O)2NR 2 R 3 、-(C0-C6)alkylene-C(=O)-NR 2 R 3 、-(C0-C6)alkylene-NR 2 C(=O)-R 3 、-(C0-C6)alkylene-C(=O)-OR 2 、-(C0-C6)alkylene-C(=O)-R 2 and -C(=O)-(C1-C6)alkylene-NR 2 -C(=O)-OR 3 .

9. A compound according to any preceding claim, having formula (I), wherein R 2 、R 3 and R 4 Each is independently hydrogen, -(C1-C6)haloalkyl or -(C1-C6)alkyl.

10. A compound according to any preceding claim, having formula (I), wherein (B) n or (B) n Each of the following is independently selected from the group consisting of hydrogen, halogen, -CN, -CF3, and optionally substituted groups selected from the group consisting of -(C1-C6)alkyl, -(C3-C7)cycloalkyl, aryl, heteroaryl, heterocycle, -(C0-C6)alkylene-OR 6 、-NR 6 (C2-C6)alkylene-OR 7 、-(C0-C6)alkylene-NR 6 R 7 、-(C0-C6)alkylene-C(=O)-OR 6 and -(C0-C6)alkylene-C(=O)-R 6 .

11. A compound according to any preceding claim, having formula (I), wherein R 6 、R 7 Each is independently selected from the group consisting of hydrogen, -(C1-C6)haloalkyl, -(C1-C6)alkyl, -(C3-C7)cycloalkyl and aryl.

12. A compound according to any preceding claim, having formula (I), wherein R 6 and R 7 Each is independently selected from the group consisting of hydrogen, -(C1-C6)alkyl, -(C3-C7)cycloalkyl and aryl.

13. A compound according to any preceding claim, having formula (I), wherein n is an integer equal to 0, 1 or 2.

14. A compound according to any preceding claim having formula (II): a pharmaceutically acceptable acid addition salt or base addition salt thereof, a stereochemically isomeric form thereof or an N-oxide form thereof, wherein Z 1 Selected from C or N.

15. A compound according to any one of claims 1 to 13 having the formula (III): or a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, or an N-oxide form thereof, wherein X is N or C.

16. A compound according to any preceding claim, wherein yes 17. A compound according to any one of claims 1 to 13 and 15 having formula (IV): or a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, or an N-oxide form thereof, wherein X is N or C.

18. A compound according to one of claims 1 to 13 and 15 having the formula (V): or a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, or an N-oxide form thereof, wherein X is N or C.

19. A compound according to any one of claims 1 to 15 and 17 having the formula (VI): or a pharmaceutically acceptable acid addition salt or base addition salt thereof, a stereochemically isomeric form thereof, or an N-oxide form thereof, wherein X is N or C and Z 1 It is N or C.

20. A compound according to any one of claims 1 to 15 and 18 having formula (VII): or a pharmaceutically acceptable acid addition salt or base addition salt thereof, a stereochemically isomeric form thereof, or an N-oxide form thereof, wherein X is N or C, and Z 1 It is N or C.

21. A compound according to any preceding claim, wherein: (A) m or (A) m Each of the following is independently selected from the group consisting of hydrogen, halogen, -CF3, and an optionally substituted group selected from the group consisting of -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C3-C7)cycloalkyl, heterocycle, -(C0-C6)alkylene-OR 2 、-O-(C2-C6)alkylene-OR 2 、-(C0-C6)alkylene-NR 2 R 3 、-O-(C2-C6)alkylene-NR 2 R 3 、-NR 2 -(C2-C6)alkylene-NR 3 R 4 、-(C0-C6)alkylene-C(=O)-NR 2 R 3 、-(C0-C6)alkylene-NR 2 C(=O)-R 3 、-(C0-C6)alkylene-C(=O)-OR 2 、-(C0-C6)alkylene-C(=O)-R 2 and -C(=O)-(C1-C6)alkylene-NR 2 -C(=O)-OR 3 ; R 2 、R 3 and R 4 are each independently hydrogen, -(C1-C6)alkyl or -(C1-C6)haloalkyl; (B) n or (B) n Each of the following is independently selected from the group consisting of hydrogen, halogen, and an optionally substituted group selected from the group consisting of: -(C1-C6)alkyl, heterocycle, -(C0-C6)alkylene-OR 6 、-NR 6 (C2-C6)alkylene-OR 7 、-(C0-C6)alkylene-NR 6 R 7 、-(C0-C6)alkylene-C(=O)-OR 6 and -(C0-C6)alkylene-C(=O)-R 6 ;and R 6 and R 7 Each is independently hydrogen, -(C1-C6)alkyl, -(C3-C7)cycloalkyl or -(C1-C6)haloalkyl.

22. A compound according to any one of claims 1 to 15, 17 and 19 having formula (VIII): A pharmaceutically acceptable acid addition salt or base addition salt thereof, a stereochemically isomeric form thereof or an N-oxide form thereof, wherein: Z 1 Selected from C or N; (A) m or (A) m Each of the following is independently selected from the group consisting of hydrogen, halogen, -CF3, and an optionally substituted group selected from the group consisting of -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C3-C7)cycloalkyl, heterocycle, -(C0-C6)alkylene-OR 2 、-O-(C2-C6)alkylene-OR 2 、-(C0-C6)alkylene-NR 2 R 3 、-O-(C2-C6)alkylene-NR 2 R 3 、-NR 2 -(C2-C6)alkylene-NR 3 R 4 、-(C0-C6)alkylene-C(=O)-NR 2 R 3 、-(C0-C6)alkylene-NR 2 C(=O)-R 3 、-(C0-C6)alkylene-C(=O)-OR 2 、-(C0-C6)alkylene-C(=O)-R 2 and -C(=O)-(C1-C6)alkylene-NR 2 -C(=O)-OR 3 ; R 2 、R 3 and R 4 are each independently hydrogen, -(C1-C6)alkyl or -(C1-C6)haloalkyl; (B) n or (B) n Each of the following is independently selected from the group consisting of hydrogen, halogen, and an optionally substituted group selected from the group consisting of: -(C1-C6)alkyl, heterocycle, -(C0-C6)alkylene-OR 6 、-NR 6 (C2-C6)alkylene-OR 7 、-(C0-C6)alkylene-NR 6 R 7 、-(C0-C6)alkylene-C(=O)-OR 6 and -(C0-C6)alkylene-C(=O)-R 6 ;and R 6 and R 7 Each is independently hydrogen, -(C1-C6)alkyl, -(C3-C7)cycloalkyl or -(C1-C6)haloalkyl.

23. A compound according to any one of claims 1 to 15, 18 and 20 having the formula (IX): A pharmaceutically acceptable acid addition salt or base addition salt thereof, a stereochemically isomeric form thereof or an N-oxide form thereof, wherein: Z 1 Selected from C or N; (A) m or (A) m Each of the following is independently selected from the group consisting of hydrogen, halogen, -CF3, and an optionally substituted group selected from the group consisting of -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C3-C7)cycloalkyl, heterocycle, -(C0-C6)alkylene-OR 2 、-O-(C2-C6)alkylene-OR 2 、-(C0-C6)alkylene-NR 2 R 3 、-O-(C2-C6)alkylene-NR 2 R 3 、-NR 2 -(C2-C6)alkylene-NR 3 R 4 、-(C0-C6)alkylene-C(=O)-NR 2 R 3 、-(C0-C6)alkylene-NR 2 C(=O)-R 3 、-(C0-C6)alkylene-C(=O)-OR 2 、-(C0-C6)alkylene-C(=O)-R 2 and -C(=O)-(C1-C6)alkylene-NR 2 -C(=O)-OR 3 ; R 2 、R 3 and R 4 are each independently hydrogen, -(C1-C6)alkyl or -(C1-C6)haloalkyl; (B) n or (B) n Each of the following is independently selected from the group consisting of hydrogen, halogen, and an optionally substituted group selected from the group consisting of: -(C1-C6)alkyl, heterocycle, -(C0-C6)alkylene-OR 6 、-NR 6 (C2-C6)alkylene-OR 7 、-(C0-C6)alkylene-NR 6 R 7 、-(C0-C6)alkylene-C(=O)-OR 6 and -(C0-C6)alkylene-C(=O)-R 6 ;and R 6 and R 7 Each is independently hydrogen, -(C1-C6)alkyl, -(C3-C7)cycloalkyl or -(C1-C6)haloalkyl.

24. A compound according to any preceding claim, wherein: (A) m or (A) m Each of is hydrogen; (B) n or (B) n Each of which is independently selected from the group consisting of -(C1-C6)alkyl, heterocycle, and -(C0-C6)alkylene-OR 6 , where R 6 It is -(C1-C6)alkyl or -(C3-C7)cycloalkyl.

25. The compound of claim 22, wherein (A) m or (A) m each of which is hydrogen; and (B) n or (B) n Each of the groups is independently selected from the group consisting of methyl, -O-methyl, -O-cyclopropane and azetidinyl.

26. The compound of claim 23, wherein (A) m is hydrogen; and / or (B) n or (B) n Each of is independently selected from the group consisting of methyl, -O-methyl, and -O-cyclopropane.

27. The compound of any preceding claim, wherein the compound may exist as optical isomers, and wherein the compound is a racemic mixture or one or both of the individual optical isomers.

28. The compound according to any preceding claim, wherein the compound is selected from one or more of the following: and pharmaceutically acceptable acid addition salts or base addition salts thereof, their stereochemically isomeric forms or their N-oxide forms.

29. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 28 and a pharmaceutically acceptable carrier and / or excipient.

30. A method of treating or preventing a disorder in a mammal, said method comprising administering to a mammal in need of such treatment or prevention an effective amount of a compound / composition according to claims 1 to 29.

31. The method of claim 30, wherein the treatment or prevention is affected or promoted by modulation by an mGlu7 allosteric modulator, such as an mGlu7 negative allosteric modulator.

32. A method for treating, preventing, ameliorating, controlling or reducing the risk of various neurological and psychiatric disorders associated with glutamate dysfunction in a mammal, said method comprising administering to a mammal in need of such treatment or prevention an effective amount of a compound / composition according to any one of claims 1 to 29.

33. The method of claim 32, wherein the treatment or prevention is affected or promoted by modulation by an mGlu7 negative allosteric modulator.

34. The method of any one of claims 30 or 31, wherein the condition is one or more of a central nervous system disorder, an otic disease or disorder, or a pain disorder.

35. The method of claim 34, wherein the central nervous system disorder is an anxiety disorder, such as agoraphobia, generalized anxiety disorder (GAD), obsessive compulsive disorder (OCD), panic disorder, or post-traumatic stress disorder (PTSD).

36. The method of claim 34, wherein the central nervous system disorder is a psychotic disorder selected from the group consisting of schizophrenia, delusional disorder, schizoaffective disorder, schizophreniform disorder, and substance-induced psychotic disorder.

37. The method of claim 34, wherein the ear diseases and disorders are one or more of: inner ear damage, age-related hearing loss (presbycusis), Meniere's disease, sudden hearing loss, noise-induced hearing loss, otitis media, autoimmune inner ear disease, acute tinnitus, chronic tinnitus, drug-induced hearing loss, hidden hearing loss, cisplatin-induced hearing loss, aminoglycoside-induced hearing loss, ototoxicity, central auditory processing disorder, or vestibular disorder.

38. The method of claim 34, wherein the pain disorder is one or more of: neuropathic pain, inflammatory pain, visceral pain, acute pain, chronic pain, severe pain, intractable pain, post-traumatic pain, post-operative pain, headache, or cancer pain.

39. A compound or composition according to any one of claims 1 to 29 for use as a medicament.

40. A compound or composition according to any one of claims 1 to 29 for use in a method of treatment or prevention as defined in any one of claims 30, 31 , 34, 35, 36, 37 or 38.

41. A compound or composition according to any one of claims 1 to 29 for use in a method as defined in claim 32 or 33.

42. Use of a compound according to any one of claims 1 to 29 in the preparation of a medicament for use in the treatment or prevention as defined in any one of claims 30, 31 , 34, 35, 36, 37 or 38.

43. Use of a compound according to any one of claims 1 to 29 in the preparation of a medicament for treatment or prevention as defined in claim 32 or 33.

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