Novel pyrrolo[1,2-d][1,2,4]triazin-1-one derivatives as negative allosteric modulators of the MGLU7 receptor

Abstract

TIFF2025538049000047.tif38119 The present invention relates to novel compounds of formula (I), wherein P, Q, A, B, m, n, R 1 , R 2 and R 3 are defined as in Formula (I); which are negative allosteric modulators of metabotropic glutamate receptor subtype 7 (mGlu7) and are useful for treating or preventing neurological, otic, and psychiatric disorders associated with glutamate dysfunction, and disorders involving the mGlu7 subtype of metabotropic receptor. The present invention is also directed to pharmaceutical compositions comprising such compounds, processes for preparing such compounds and such compositions, and the use of such compounds for the prevention or treatment of neurological, otic, and psychiatric disorders involving mGlu7.

Description

[Technical Field]

[0001] TIFF2025538049000002.tif32111 The present invention relates to novel compounds of formula (I), wherein P, Q, A, B, m, n, R 1 , R 2 and R 3 are defined as in Formula (I); which are negative allosteric modulators of metabotropic glutamate receptor subtype 7 (mGlu7) and are useful for treating or preventing neurological, otic, and psychiatric disorders associated with glutamate dysfunction, and disorders involving the mGlu7 subtype of metabotropic receptor. The present invention is also directed to pharmaceutical compositions comprising such compounds, processes for preparing such compounds and such compositions, and the use of such compounds for the prevention or treatment of neurological, otic, and psychiatric disorders involving mGlu7. [Background technology]

[0002] Glutamate is the major amino acid transmitter in the mammalian central nervous system (CNS). Glutamate is associated with many physiological functions, including learning and memory, sensory perception, the development of synaptic plasticity, motor control, and the regulation of respiration and cardiovascular function. Furthermore, glutamate is central to several different neurological and psychiatric disorders in which an imbalance in glutamatergic neurotransmission is observed.

[0003] Glutamate mediates synaptic neurotransmission through activation of NMDA, AMPA, and kainate receptors, ionotropic glutamate receptor channels (iGluRs), which are responsible for fast excitatory transmission (Nakanishi et al. (1998) Rev., 26:230-235).

[0004] Furthermore, glutamate activates metabotropic glutamate receptors (mGluRs), which have a modulatory role contributing to the fine-tuning of synaptic efficacy (Niswender & Conn (2010) Ann. Rev. Pharmacol. Toxicol. 50:295-322). In contrast to iGluRs, mGluRs "modulate" rather than mediate synaptic transmission, acting at different levels: the tripartite synapse formed by the axon terminal, dendritic spine, and astrocyte junctions. mGluRs are seven-transmembrane domain-containing G protein-coupled receptors (GPCRs) and are involved in the regulation of calcium-sensitive receptors, GABA receptors, and ATP-dependent signaling pathways. B mGluRs belong to GPCR family 3, along with mGluRs and pheromone receptors. Glutamate activates mGluRs by binding to a site in the large extracellular amino-terminal domain of the receptor, termed the orthosteric binding site. This activation induces a conformational change in the remainder of the receptor, resulting in G protein activation and subsequent activation of a wide variety of intracellular signaling pathways. The mGluR family consists of eight members. These are classified into three groups (group I consisting of mGlu1 and mGlu5, group II consisting of mGlu2 and mGlu3, and group III consisting of mGlu4, mGlu6, mGlu7, and mGlu8) based on sequence homology, pharmacological profile, and the nature of the intracellular signaling pathways they activate (Schoepp et al. (1999) Neuropharmacology, 38:1431-1476).

[0005] Among mGlu receptors, the mGlu7 subtype is the most widely distributed and is present presynaptically at a wide range of synapses where it is suspected to be important for both normal central nervous system function and various neuropsychiatric disorders (Ohishi et al. 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 negatively couples to adenylate cyclase via activation of Gαi proteins, and its activation as a presynaptic autoreceptor leads to inhibition of synaptic glutamate and GABA release (Dalezios et al. (2002) Cereb. Cortex, 12(9):961-974; Cartmell and Schoepp (2000) J. Neurochem., 75:889-907; Somogyi et al. (2003) Eur. J. Neurosci. 17(12):2503-2520). Thus, it not only shapes synaptic responses at glutamatergic synapses but is also a key regulator of inhibitory GABAergic transmission, ultimately fine-tuning the overall excitability of the brain.

[0006] Previously, most available pharmacological tools targeting mGluRs were orthosteric ligands that are structural analogs of glutamate and therefore cross-react with multiple members of the family (Schoepp et al. (1999) Neuropharmacology, 38:1431-1476). However, new screening methods have made it possible to identify molecules selective for individual mGluRs that act via allosteric mechanisms, modulating the receptor by binding to sites distinct from the highly conserved orthosteric binding site. Molecules of this type have been discovered for several mGluRs (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 mGlu7 allosteric agonist (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, was recently reported to act through a binding pocket located in the extracellular Venus flytrap domain of the receptor (Gee et al. (2014) J. Biol. Chem. 18;289(16):10975-10987).Finally, several classes of compounds, including isoxazolopyridinone derivatives, phenylbenzamide derivatives, dihydrobenzoxazolone derivatives, and tetrahydrophthalazinone derivatives, have been described and 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).

[0007] Specifically, modulators of mGlu7, and preferably antagonists, inverse agonists, and negative allosteric modulators (NAMs), have been reported to have potential for the treatment of neurological, psychiatric, and mood disorders, as well as pain and otic diseases, based on experimental studies in laboratory animals that are believed to be relevant to clinical symptoms.

[0008] Combined expression of mGlu7 in brain regions and pharmacological manipulation of mGlu7 in genetically modified mice and wild-type animals have revealed a critical role for mGlu7 in many central nervous system disorders, including depression, schizophrenia, anxiety disorders, obsessive-compulsive disorder and related conditions, particularly acute and chronic stress-related disorders (reviewed by: Peterlik et al. (2016) Curr. Neuropharmacol. 14(5): 514-539) (reviewed by: Pallazo et al. (2016) Curr. Neuropharmacol. 14(5): 504-513).

[0009] mGlu7 has been shown to be localized in limbic nuclei, such as the amygdala, hippocampus, and locus coeruleus, which are known to be important for the expression of anxiolytic and antidepressant effects (Kinoshita et al. 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). Furthermore, studies using several behavioral models (light-dark box test, elevated plus maze test, staircase test, forced swim test, and tail suspension test) have shown that mGlu7 knockout animals not only exhibit anxiolytic and antidepressant phenotypes, but also show some impairments in amygdala-dependent behaviors, such as fear responses and conditioned taste aversion (Cryan et al. J. Neuroscience, 17:2409-2417). Therefore, pharmacological agents aimed at modulating mGlu7 activity may represent a novel therapeutic approach for the treatment of neurological and psychiatric disorders such as anxiety and depression.

[0010] Activation of mGlu7 with the allosteric agonist AMN082 increases plasma levels of the stress hormones corticosterone and ACTH (Mitsukawa et al. (2005) PNAS, 102(51):18712-18717). This effect is completely absent in mGlu7 knockout mice. These results are consistent with previous genetic studies demonstrating that mGlu7 is a critical regulator of stress responses in vivo (Mitsukawa et al. (2006) Neuropsychopharm., 31(6):1112-1122). In this paper, Mitsukawa et al. show that ablation of mGlu7 dysregulates the HPA axis and increases BDNF protein levels in the hippocampus, suggesting that this receptor may be involved in stress-related psychiatric disorders such as anxiety, depression, posttraumatic stress syndrome, and innate fear-induced behaviors such as conditioned fear acquisition / extinction and conditioned taste aversion. These data also support previous observations that mGlu7-deficient mice exhibited a markedly reduced fear-mediated freezing response to electric footshock and an impaired ability to associate a taste stimulus with a lassitude-inducing LiCl injection (conditioned taste aversion, CTA) (Masugi et al. (1999) J. Neurosc., 19(3):955-963). These mice also exhibited deficits in the acquisition and extinction learning of conditioned responses compared to wild-type animals (Goddyn et al. (2008) Neurobiol. Learn. Mem., 90(1):103-111).

[0011] The contradictory effects observed with the allosteric agonist AMN082 may be explained by rapid and prolonged mGlu7 receptor internalization consistent with functional antagonism, while its limited 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).

[0012] Recently, several negative allosteric modulators have been discovered, furthering our understanding of the functional role of mGlu7 in neuronal function. In vivo administration of 6-(4-methoxyphenyl)-5-methyl-3-pyridin-4-ylisoxazolo[4,5-c]pyridin-4(5H)-one (MMPIP) has demonstrated anxiolytic and antidepressant-like properties and 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 antistress, antidepressant, and anxiolytic-like effects and reduce freezing responses in a fear conditioning paradigm (Gee et al. (2014) J. Biol. Chem. 289(16):10975-10987). Furthermore, (S)-6-(2,4-dimethylphenyl)-2-ethyl-6,7-dihydrobenzo[d]oxazol-4(5H)-one (ADX71743) exhibited anxiolytic-like effects in the elevated plus maze and marble-burying tests and reduced amphetamine-induced hyperactivity without altering baseline locomotor activity (Kalinichev et al. (2013) J. Pharmacol. Exp. Ther. 344(3):624-636). Taken together, these data suggest that blocking mGlu7 with modulators may be useful for treating mood disorders related to anxiety, depression, and PTSD.

[0013] Additionally, mGlu7 receptors have also been implicated in pathways affected by pain. Widespread and highly expressed mGlu7 receptors in both the peripheral and central nervous systems have been implicated in regulating pain behavior. The role of mGlu7 in pain was recently demonstrated by direct injection of AMN082 into the central amygdala (CeA) or periaqueductal gray (PAG). Under normal conditions, activation of amygdala mGlu7 enhances pain responses, as demonstrated by a decrease in the spinal nociceptive threshold evoked by brief knee compression and an increase in audible and ultrasonic vocalizations (Palazzo et al. (2008) Neuropharmacol., 55(4):537-545). Similarly, activation of PAG mGlu7 reduced the thermoreceptor threshold measured using tail withdrawal latency in rats (Marabese et al. (2007) J. Neurophysiol.). In rodent pain models, AMN082 suppressed hyperalgesia (Dolan et al. (2009) Behav. Pharmacol. 20(7):596-604; Osikowicz et al. (2008) Pain 139(1):117-126). Furthermore, 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). Collectively, these data suggest that mGlu7 receptor activation exacerbates pain perception, whereas mGlu7 inhibition attenuates it. Therefore, negative allosteric modulators of this receptor may be useful for the treatment of pain and pain-related disorders.

[0014] Genome-wide studies have also shown an association between mGlu7 receptors and age-related hearing impairment (ARHI), also known as presbycusis. As a result, a highly significant and reproducible single nucleotide polymorphism (SNP) was identified 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. (2018) J. Int. Adv. Otol. 14(2):170-175). GRM7 variants have also been linked to noise-induced hearing loss (Lu et al., 2018) and tinnitus (Haider et al., 2017) (Front. Aging Neurosci., 2017), 9:346). Finally, immunohistochemistry has shown that mGlu7 expression is localized in neurons of the spiral ganglion, the inner and outer hair cells of the organ of Corti, and the hair cells of the vestibular apparatus formed by the saccule, utricle, and crista ampulla (Friedman et al., 2008) WO2008131439). These data suggest that mGlu7 receptor modulators may be useful in experimental treatments for hearing disorders related to the inner ear and auditory nervous system, including age-related hearing loss (presbycusis), noise-induced hearing loss, acute and chronic hearing loss, tinnitus, Meniere's disease, and vestibular disorders.

[0015] Finally, in addition to its widespread distribution throughout the CNS, mGlu7 exhibits the highest evolutionary conservation of all mGluRs (Flor et al. (1997) Neuropharmacol., 36:153-159), suggesting an important role for this receptor in CNS function. Furthermore, it has a relatively low affinity for glutamate (Okamato et al. Chem., 269:1231-1236), making it inactive during normal transmission and only activatable upon excessive glutamate release (Ferraguti F. and Shigemoto R. (2006) Cell Tissue Res., 326:483-504). Taken together, these data strongly highlight the potential of mGlu7 modulators for clinical applications such as neuroprotection (treatment of stroke, head trauma, ischemic injury, and neurotoxicity).

[0016] Taken together, these pharmacological and genetic data strongly support the potential of mGlu7 modulators for the treatment of a wide range of diseases and associated conditions across psychiatric, neurological, neurodevelopmental, otic, and pain disorders.

[0017] Pyrrolo[1,2-d][1,2,4]triazinones have been shown to be useful as allosteric EGFR inhibitors and NLRP3 inflammasome pathway inhibitors in WO 2021252661 to Scott et al. and WO 2021209539 to Ehrlich et al., respectively. However, none of the specifically disclosed compounds are structurally related to the compounds of the present invention. Summary of the Invention

[0018] The present invention relates to compounds having metabotropic glutamate receptor 7 modulator activity. The present invention provides compounds according to formula (I): TIFF2025538049000003.tif42123 A pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, or an N-oxide form thereof, wherein: R1 is selected, for example, from the group of hydrogen, —CH3 and —CF3; R 2 and R 3 are each independently selected from the group consisting of, for example, hydrogen, halogen, —(C1-C6)alkyl, —(C1-C6)haloalkyl, and —CF3; P represents a cycloalkyl, aryl, heteroaryl, or heterocycle of the formula: TIFF2025538049000004.tif69162 wherein each cycloalkyl ring, heteroaryl ring or heterocycle is optionally substituted with m radicals 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 each independently selected from C, N, O, or S; 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 and Z 7 at least one of is N; Each (A) m are independently selected from the group consisting of, for example, hydrogen, halogen, —CN, —OH, —NO2, —CF3, —SH, —NH2, and groups such as, for example, —(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 4 , -O-(C2-C6) alkylene-OR 4 , -NR 4 (C2-C6) alkylene-OR 5, -(C3-C6)alkynylene-OR 4 , -(C3-C6)alkynylene-NR 4 R 5 , -(C3-C6)alkenylene-OR 4 , -(C3-C6)alkenylene-NR 4 R 5 , -(C0-C6) alkylene-SR 4 , -O-(C2-C6) alkylene-SR 4 , -NR 4 -(C2-C6) alkylene-SR 5 , -(C0-C6) alkylene-S(=O)-R 4 , -O-(C1-C6) alkylene-S(=O)-R 4 , -NR 4 -(C1-C6)alkylene-S(=O)-R 5 , -(C0-C6) alkylene-S(=O)2-R 4 , -O-(C1-C6) alkylene-S(=O)2-R 4 , -NR 4 -(C1-C6)alkylene-S(=O)2-R 5 , -(C0-C6) alkylene-NR 4 R 5 , -O-(C2-C6) alkylene-NR 4 R 5 , -NR 4 -(C2-C6) alkylene-NR 5 R 6 , -(C0-C6) alkylene-S(=O)2NR 4 R 5 , -O-(C1-C6) alkylene-S(=O)2NR 4 R 5 , -NR 4 -(C1-C6)alkylene-S(=O)2NR 5 R 6 , -(C0-C6) alkylene-NR 4 -S(=O)2R 5 , -O-(C2-C6) alkylene-NR 4 -S(=O)2R 5 , -NR 4 -(C2-C6) alkylene-NR 5 -S(=O)2R 6, -(C0-C6) alkylene-C(=O)-NR 4 R 5 , -O-(C1-C6) alkylene-C(=O)-NR 4 R 5 , -NR 4 -(C1-C6)alkylene-C(=O)-NR 5 R 6 , -(C0-C6) alkylene-NR 4 C(=O)-R 5 , -O-(C2-C6) alkylene-NR 4 C(=O)-R 5 , -NR 4 -(C2-C6) alkylene-NR 5 C(=O)-R 6 , -(C0-C6) alkylene-OC(=O)-R 4 , -O-(C2-C6) alkylene-OC(=O)-R 4 , -NR 4 -(C2-C6) alkylene-OC(=O)-R 5 , -(C0-C6) alkylene-C(=O)-OR 4 , -O-(C1-C6) alkylene-C(=O)-OR 4 , -(C0-C6) alkylene-C(=O)-R 4 , -O-(C1-C6) alkylene-C(=O)-R 4 , -NR 4 -(C1-C6)alkylene-C(=O)-R 5 , -(C0-C6) alkylene-NR 4 -C(=O)-OR 5 , -C(=O)-(C1-C6)alkylene-NR 4 -C(=O)-OR 5 , -(C0-C6) alkylene-OC(=O)-NR 4 R 5 , -(C0-C6) alkylene-NR 4 -C(=O)-NR 5 R 6 , -O-(C2-C6) alkylene-NR 4 -C(=O)-NR 5 R 6 , -NR 4 -(C2-C6) alkylene-NR 5-C(=O)-NR 6 R 7 , -(C0-C6) alkylene-NR 4 -C(=S)-NR 5 R 6 , and -(C0-C6)alkylene-NR 4 -C(=NR 5 )-NR 6 R 7 an optionally substituted radical selected from the group consisting of: R 4 , R 5 , R 6 and R 7 are each independently, for example, hydrogen or an optionally substituted radical selected from the group consisting of -(C-C)haloalkyl, -C-C)alkyl, -(C-C)cyanoalkyl, -(C-C)cycloalkyl, -(C-C)alkylene-(C-C)cycloalkyl, heteroaryl, -(C-C)alkylene-heteroaryl, aryl, -(C-C)alkylene-heterocycle, heterocycle, -(C-C)alkylene-aryl, -(C-C)alkylene-O-(C-C)alkyl, -(C-C)alkylene-N-((C-C)alkyl)2, and -C(=O)-O-(C-C)alkyl; Q represents an aryl or heteroaryl of the formula: TIFF2025538049000005.tif50148 wherein each aryl or heteroaryl ring is optionally substituted with n radicals B, where n is an integer equal to 0, 1, 2, 3, 4, or 5; and B 1 is the radical B; Each (B) nis, for example, the group consisting of hydrogen, halogen, —CN, —OH, —NO2, —CF3, —SH, —NH2, and for example, —(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 8 , -O-(C2-C6) alkylene-OR 8 , -NR 8 (C2-C6) alkylene-OR 9 , -(C3-C6)alkynylene-OR 8 , -(C3-C6)alkynylene-NR 8 R 9 , -(C3-C6)alkenylene-OR 8 , -(C3-C6)alkenylene-NR 8 R 9 , -(C0-C6) alkylene-SR 8 , -O-(C2-C6) alkylene-SR 8 , -NR 8 -(C2-C6) alkylene-SR 9 , -(C0-C6) alkylene-S(=O)-R 8 , -O-(C1-C6) alkylene-S(=O)-R 8 , -NR 8 -(C1-C6)alkylene-S(=O)-R 9 , -(C0-C6) alkylene-S(=O)2-R 8 , -O-(C1-C6) alkylene-S(=O)2-R 8 , -NR 8 -(C1-C6)alkylene-S(=O)2-R 9 , -(C0-C6) alkylene-NR 8 R 9 , -O-(C2-C6) alkylene-NR 8 R 9 , -NR 8-(C2-C6) alkylene-NR 9 R 10 , -(C0-C6) alkylene-S(=O)2NR 8 R 9 , -O-(C1-C6) alkylene-S(=O)2NR 8 R 9 , -NR 8 -(C1-C6)alkylene-S(=O)2NR 9 R 10 , -(C0-C6) alkylene-NR 8 -S(=O)2R 9 , -O-(C2-C6) alkylene-NR 8 -S(=O)2R 9 , -NR 8 -(C2-C6) alkylene-NR 9 -S(=O)2R 10 , -(C0-C6) alkylene-C(=O)-NR 8 R 9 , -O-(C1-C6) alkylene-C(=O)-NR 8 R 9 , -NR 8 -(C1-C6)alkylene-C(=O)-NR 9 R 10 , -(C0-C6) alkylene-NR 8 C(=O)-R 9 , -O-(C2-C6) alkylene-NR 8 C(=O)-R 9 , -NR 8 -(C2-C6) alkylene-NR 9 C(=O)-R 10 , -(C0-C6) alkylene-OC(=O)-R 8 , -O-(C2-C6) alkylene-OC(=O)-R 8 , -NR 8 -(C2-C6) alkylene-OC(=O)-R 9 , -(C0-C6) alkylene-C(=O)-OR 8 , -O-(C1-C6) alkylene-C(=O)-OR 8 , -NR 8 -(C1-C6)alkylene-C(=O)-OR 9 , -(C0-C6) alkylene-C(=O)-R8 , -O-(C1-C6) alkylene-C(=O)-R 8 , -NR 8 -(C1-C6)alkylene-C(=O)-R 9 , -(C0-C6) alkylene-NR 8 -C(=O)-OR 9 , -(C0-C6) alkylene-OC(=O)-NR 8 R 9 , -(C0-C6) alkylene-NR 8 -C(=O)-NR 9 R 10 , -O-(C2-C6) alkylene-NR 8 -C(=O)-NR 9 R 10 , -NR 8 -(C2-C6) alkylene-NR 9 -C(=O)-NR 10 R 11 , -(C0-C6) alkylene-NR 8 -C(=S)-NR 9 R 10 , and -(C0-C6) alkylene-NR 8 -C(=NR 9 )-NR 10 R 11 independently selected from optionally substituted radicals selected from the group consisting of: R 8 , R 9 , R 10 and R 11 are each independently an optionally substituted radical selected from the group consisting of, for example, hydrogen or —(C-C)haloalkyl, —(C-C)alkyl, —(C-C)cyanoalkyl, —(C-C)cycloalkyl, —(C-C)alkylene-(C-C)cycloalkyl, heteroaryl, —(C-C)alkylene-heteroaryl, aryl, —(C-C)alkylene-heterocycle, heterocycle, —(C-C)alkylene-aryl, —(C-C)alkylene-O—(C-C)alkyl, and —(C-C)alkylene-N—((C-C)alkyl)2; wherein optionally, any two radicals A, combined with intervening atoms, form a 3-10 membered bicyclic heterocycle, aryl ring, or heteroaryl ring, wherein each ring is optionally further substituted with 1-5 radicals independently selected from the group consisting of, for example, halogen, —CN, nitro, —(C1-C6)alkyl, —(C3-C7)alkyl, —(C0-C6)alkylene-O—(C0-C6)alkyl, and —(C0-C6)alkylene-N—((C0-C6)alkyl); wherein optionally the substituent R 4 , R 5 , R 6 or R 7 two of which, combined with intervening atoms, form a 3-10 membered heterocyclic, aryl, or heteroaryl ring, wherein each ring is optionally further substituted with from 1 to 5 radicals independently selected from the group consisting of, e.g., halogen, cyano, nitro, —(C1-C6)alkyl, —(C3-C7)alkyl, —(C0-C6)alkylene-O—(C0-C6)alkyl, and —(C0-C6)alkylene-N—((C0-C6)alkyl); where R 8 , R 9 , R 10 or R 11 optionally two substituents from, combined with the intervening atoms, form a 3-10 membered heterocyclic, aryl, or heteroaryl ring, wherein each ring is optionally further substituted with one to five radicals independently selected from the group consisting of, for example, halogen, cyano, nitro, —(C1-C6)alkyl, —(C3-C7)alkyl, —(C0-C6)alkylene-O—(C0-C6)alkyl, and —(C0-C6)alkylene-N—((C0-C6)alkyl); wherein optionally, any two radicals B combine with intervening atoms to form a 3- to 10-membered bicyclic heterocycle, aryl ring, or heteroaryl ring, wherein each ring is optionally further substituted with 1 to 5 radicals independently selected from the group consisting of, for example, halogen, —CN, nitro, —(C-C)alkyl, —(C-C)alkyl, —(C-C)alkylene-O—(C-C)alkyl, and —(C-C)alkylene-N—((C-C)alkyl).

[0019] It has now been surprisingly found that compounds of general formula (I) exhibit potent activity and selectivity for mGlu7 receptors. The compounds of the present invention exhibit advantageous properties over prior art compounds. The compounds of the present invention have been observed to have improved target potency, target selectivity, bioavailability, brain penetration, and pharmacodynamic properties in one or more aspects.

[0020] Preferably, P represents a heteroaryl of the formula: TIFF2025538049000006.tif2384 where each radical is optionally substituted with m radicals A, and m is an integer equal to 0, 1, 2, 3, or 4.

[0021] Preferably, Q represents an aryl or heteroaryl of the formula: TIFF2025538049000007.tif22123 wherein each radical is optionally substituted with n radicals B, n being an integer equal to 0, 1, 2, 3, 4, or 5, where B 1 is the radical B.

[0022] Preferably, Q represents an aryl or heteroaryl of the formula: TIFF2025538049000008.tif2284 wherein each radical is optionally substituted with n radicals B, where n is an integer equal to 0, 1, 2, 3, 4 or 5.

[0023] Preferably, P represents a heteroaryl of the formula: TIFF2025538049000009.tif2283 wherein each radical is optionally substituted with m radicals A, m is an integer equal to 0, 1, 2, 3 or 4, and Q represents an aryl or heteroaryl of the formula: TIFF2025538049000010.tif2187 where each radical is optionally substituted with n radicals B, where n is an integer equal to 0, 1, 2, 3, 4, or 5

[0024] (A) mCycloalkyl, heterocyclic, aryl and heteroaryl ring systems are, for example, azetidinyl, 2-azabicyclo[2.2.1]heptan-2-yl, 7-azabicyclo[2.2.1]heptan-7-yl, benzimidazolyl, benzisothiazolyl, benzisoxazolyl, benzofuryl, benzopyrazolyl, benzothiazolyl, benzothiophenyl, benzotriazolyl, benzoxazolyl, dihydrofuranyl, dihydrothienyl, dioxolanyl, 1,1-dioxothiomorpholinyl, furazanyl, furyl, imidazolidinyl, imidazolinyl Imidazolonyl, imidazolyl, imidazopyridazinyl, imidazopyridyl, indolyl, isoindolyl, isoquinolinyl, isothiazolinyl, isothiazolyl, isoxazolidinyl, isoxazolinyl, isoxazolyl, morpholinyl, naphthyl, naphthyridinyl, oxadiazolyl, oxazolidinyl, oxazolinyl, oxazolonyl, oxazolopyridazinyl, oxazolopyridyl, oxazolyl, oxetanyl, phenyl, piperazinonyl, piperazinyl, piperidinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridonyl, pyridyl, pyrimidyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, quinazolyl, quinolyl, quinoxalinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl tetrahydrotriazolopyridyl, tetrahydrotriazolopyrimidinyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolinyl, thiazolonyl, thiazolopyridazinyl, thiazolopyridyl, thiazolyl, thienyl, thiomorpholinyl thionaphthyl, thiopyranyl, triazolinyl, triazinyl, triazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, and each ring of said ring system may be selected from the group consisting of 1 to 4 substituents R 4 , R 5 , R 6 or R 7 are independently and optionally substituted with

[0025] (B)n Cycloalkyl, heterocyclic, aryl and heteroaryl ring systems are, for example, azetidinyl, 2-azabicyclo[2.2.1]heptan-2-yl, 7-azabicyclo[2.2.1]heptan-7-yl, benzimidazolyl, benzisothiazolyl, benzisoxazolyl, benzofuryl, benzopyrazolyl, benzothiazolyl, benzothiophenyl, benzotriazolyl, benzoxazolyl, dihydrofuranyl, dihydrothienyl, dioxolanyl, 1,1-dioxothiomorpholinyl, furazanyl, furyl, imidazolidinyl, imidazolinyl Imidazolonyl, imidazolyl, imidazopyridazinyl, imidazopyridyl, indolyl, isoindolyl, isoquinolinyl, isothiazolinyl, isothiazolyl, isoxazolidinyl, isoxazolinyl, isoxazolyl, morpholinyl, naphthyl, naphthyridinyl, oxadiazolyl, oxazolidinyl, oxazolinyl, oxazolonyl, oxazolopyridazinyl, oxazolopyridyl, oxazolyl, oxetanyl, phenyl, piperazinonyl, piperazinyl, piperidinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridonyl, pyridyl, pyrimidyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, quinazolyl, quinolyl, quinoxalinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl tetrahydrotriazolopyridyl, tetrahydrotriazolopyrimidinyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolinyl, thiazolonyl, thiazolopyridazinyl, thiazolopyridyl, thiazolyl, thienyl, thiomorpholinyl thionaphthyl, thiopyranyl, triazolinyl, triazinyl, triazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, and each ring of said ring system may be selected from the group consisting of 1 to 4 substituents R 8 , R 9 , R 10 or R 11 are independently and optionally substituted with

[0026] B 1 may be the radical B as defined above. For example, B 1 may be hydrogen, —(C1-C6)alkyl, —(C3-C7)cycloalkyl, or —O—(C1-C6)haloalkyl.

[0027] R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 or R 11Cycloalkyl, heterocyclic, aryl and heteroaryl ring systems are, for example, azetidinyl, benzimidazolyl, benzisothiazolyl, benzisoxazolyl, benzofuryl, benzopyrazolyl, benzothiazolyl, benzothiophenyl, benzotriazolyl, benzoxazolyl, dihydrofuranyl, dihydrothienyl, dioxolanyl, 1,1-dioxothiomorpholinyl, furazanyl, furyl, imidazolidinyl, imidazolinyl Imidazolonyl, imidazolyl, imidazopyridazinyl, imidazopyridyl, indolyl, isoindolyl, isoquinolinyl, isothiazolinyl, isothiazolyl, isoxazolidinyl, isoxazolinyl, isoxazolyl, morpholinyl, naphthyl, naphthyridinyl, oxadiazolyl, oxazolidinyl, oxazolinyl, oxazolonyl, oxazolopyridazinyl, oxazolopyridyl, oxazolyl, oxetanyl, phenyl, piperazinonyl, piperazinyl, piperidinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridonyl, pyridyl, pyrimidyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, quinazolyl, quinolyl, quinoxalinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl and tetrahydrotriazolopyridyl, tetrahydrotriazolopyrimidinyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolinyl, thiazolonyl, thiazolopyridazinyl, thiazolopyridyl, thiazolyl, thienyl, thiomorpholinyl thionaphthyl, thiopyranyl, triazolinyl, triazinyl, triazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, wherein each ring in said ring system is optionally substituted with 1 to 5 radicals independently selected from hydrogen, halogen, —CN, nitro, —(C-C)alkyl, —(C-C)alkylene-O—(C-C)alkyl, and —(C-C)alkylene-N—((C-C)alkyl).

[0028] For example, R 1may be hydrogen, and R 2 and R 3 may each independently be selected from the group consisting of, for example, hydrogen, methyl, and halogen.

[0029] Each (A) m is, for example, hydrogen, halogen, —CN, —OH, —CF3, and for example, —(C1-C6)alkyl, —(C1-C6)haloalkyl, —(C3-C7)cycloalkyl, heterocycle, —(C0-C6)alkylene-OR 4 , -O-(C2-C6) alkylene-OR 4 , -NR 4 (C2-C6) alkylene-OR 5 , -(C0-C6) alkylene-NR 4 R 5 , -O-(C2-C6) alkylene-NR 4 R 5 , -NR 4 -(C2-C6) alkylene-NR 5 R 6 , -(C0-C6) alkylene-C(=O)-NR 4 R 5 , -(C0-C6) alkylene-NR 4 C(=O)-R 5 , -(C0-C6) alkylene-C(=O)-OR 4 and -(C0-C6) alkylene-C(=O)-R 4 and optionally substituted radicals selected from the group consisting of:

[0030] R 4 , R 5 and R 6 may each independently be hydrogen or -(C1-C6)alkyl.

[0031] For example, each (A) m Each of may be, for example, hydrogen, halogen, and (C0-C6) alkylene-OR 4 wherein R 4 can be -(C1-C6) alkyl.

[0032] Each (B) n is, for example, the group consisting of hydrogen, halogen, -CN, -CF3, and, for example, -(C1-C6)alkyl, -(C3-C7)cycloalkyl, aryl, heteroaryl, heterocycle, -(C0-C6)alkylene-OR 8 , -NR 8 (C2-C6) alkylene-OR 9 , -(C0-C6) alkylene-NR 8 R 9 , -(C0-C6) alkylene-C(=O)-OR 8 and -(C0-C6) alkylene-C(=O)-R 8 The groups may be independently selected from optionally substituted radicals selected from the group consisting of:

[0033] R 8 and R 9 may each independently be selected from the group consisting of, for example, hydrogen, —(C1-C6)haloalkyl, —(C1-C6)alkyl, and —(C3-C7)cycloalkyl.

[0034] For example, each (B) n is, for example, a heterocycle, -(C0-C6) alkylene-OR 8 and -(C1-C6)alkyl, wherein R 8 can be -(C1-C6) alkyl, -(C1-C6) haloalkyl, or -(C3-C7) cycloalkyl. For example, B 1 can be -(C1-C6) alkyl.

[0035] Preferably, the compound of formula (I) is a compound according to formula (II): TIFF2025538049000011.tif35119 A pharmaceutically acceptable acid 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 2 , R 3 and (B) nis as defined in any of the above statements.

[0036] Preferably, the compound of formula (I) is a compound according to formula (III): TIFF2025538049000012.tif35120 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, and P, (A) m , R 2 , R 3 and (B) n is as defined in any of the above statements.

[0037] Preferably, the compound of formula (I) is a compound according to formula (IV): TIFF2025538049000013.tif34114 Pharmaceutically acceptable acid or base addition salts thereof, stereochemically isomeric forms thereof or N-oxide forms thereof, wherein Z 1 is selected from C or N, X is selected from C or N, and (A) m , R 2 , R 3 and (B) n is as defined in any of the above statements.

[0038] Preferably, the compound of formula (I) is a compound according to formula (V): TIFF2025538049000014.tif34117 A pharmaceutically acceptable acid 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 , R 2 , R 3 and (B) n is as defined in any of the above statements.

[0039] Preferably, R 2 may be hydrogen, methyl or halogen, and R 3 may be methyl; Each (A) m is, for example, the group consisting of hydrogen, halogen, -CF3, and, for example, -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C3-C7)cycloalkyl, heterocycle, -(C0-C6)alkylene-OR 4 , -O-(C2-C6) alkylene-OR 4 , -(C0-C6) alkylene-NR 4 R 5 , -O-(C2-C6) alkylene-NR 4 R 5 , -NR 4 -(C2-C6) alkylene-NR 5 R 6 , -(C0-C6) alkylene-C(=O)-NR 4 R 5 , -(C0-C6) alkylene-NR 4 C(=O)-R 5 , -(C0-C6) alkylene-C(=O)-OR 4 and -(C0-C6) alkylene-C(=O)-R 4 may be independently selected from optionally substituted radicals selected from the group consisting of: R 4 , R 5 and R 6 may each independently be hydrogen, -(C1-C6)alkyl, or -(C1-C6)haloalkyl; Each (B) n is, for example, the group consisting of hydrogen, halogen, and, for example, -(C1-C6) alkyl, heterocycle, -(C0-C6) alkylene-OR 8 , -NR 8 (C2-C6) alkylene-OR 9 , -(C0-C6) alkylene-NR 8 R 9 , -(C0-C6) alkylene-C(=O)-OR 8 and -(C0-C6) alkylene-C(=O)-R 8 and R 8 and R 9may each independently be hydrogen, —(C1-C6)alkyl, —(C3-C7)cycloalkyl, or —(C1-C6)haloalkyl.

[0040] For example, each (A) m Each of may be, for example, hydrogen, halogen, and (C0-C6) alkylene-OR 4 wherein R 4 can be -(C1-C6) alkyl.

[0041] For example, each (B) n is, for example, hydrogen, halogen, a heterocycle, -(C0-C6) alkylene-OR 8 and -(C1-C6)alkyl, wherein R 8 may be -(C1-C6) alkyl, -(C1-C6) haloalkyl, or -(C3-C7) cycloalkyl. For example, B 1 can be -(C1-C6) alkyl.

[0042] Preferably, the compound of formula (II) is a compound of formula (VI): TIFF2025538049000015.tif38119 A pharmaceutically acceptable acid 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 , R 2 , R 3 and (B) n is as defined in any of the above statements.

[0043] For example, R 2 may be hydrogen, methyl or halogen, R 3 may be methyl; Each (A) mis, for example, the group consisting of hydrogen, halogen, -CF3, and, for example, -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C3-C7)cycloalkyl, heterocycle, -(C0-C6)alkylene-OR 4 , -O-(C2-C6) alkylene-OR 4 , -(C0-C6) alkylene-NR 4 R 5 , -O-(C2-C6) alkylene-NR 4 R 5 , -NR 4 -(C2-C6) alkylene-NR 5 R 6 , -(C0-C6) alkylene-C(=O)-NR 4 R 5 , -(C0-C6) alkylene-NR 4 C(=O)-R 5 , -(C0-C6) alkylene-C(=O)-OR 4 and -(C0-C6) alkylene-C(=O)-R 4 may be independently selected from optionally substituted radicals selected from the group consisting of: R 4 , R 5 and R 6 are each independently hydrogen, -(C1-C6)alkyl, or -(C1-C6)haloalkyl; Each (B) n is, for example, hydrogen, halogen, and, for example, -(C1-C6) alkyl, heterocycle, -(C0-C6) alkylene-OR 8 , -NR 8 (C2-C6) alkylene-OR 9 , -(C0-C6) alkylene-NR 8 R 9 , -(C0-C6) alkylene-C(=O)-OR 8 and -(C0-C6) alkylene-C(=O)-R 8 and R 8 and R 9may each independently be hydrogen, —(C1-C6)alkyl, —(C3-C7)cycloalkyl, or —(C1-C6)haloalkyl.

[0044] For example, or each (A)m can be, for example, H and -(C0-C6)alkylene-OR 4 wherein R 4 may be -(C1-C6) alkyl.

[0045] For example, each (B) n is, for example, hydrogen, halogen, a heterocycle, -(C0-C6) alkylene-OR 8 and -(C1-C6)alkyl, wherein R 8 may be -(C1-C6)alkyl, -(C1-C6)haloalkyl, or -(C3-C7)cycloalkyl.

[0046] Preferably, the compound of formula (VI) is a compound of formula (VII) or formula (VIII): TIFF2025538049000016.tif29147 A pharmaceutically acceptable acid or base addition salt thereof, its stereochemically isomeric form or its N-oxide form, wherein: (A) m , Z 1 , R 2 , R 3 and (B) n is as defined in any of the above statements.

[0047] Preferably, Z 1 is selected from C or N, and R 2 is hydrogen, methyl or halogen, and R 3 is methyl; Each (A) m is, for example, the group consisting of hydrogen, halogen, and, for example, -(C1-C6) alkyl, heterocycle, -(C0-C6) alkylene-OR 4 , -(C0-C6) alkylene-NR 4 R 5 , -O-(C2-C6) alkylene-NR4 R 5 , -NR 4 -(C2-C6)-Alkylene-NR 5 R 6 and -(C0-C6) alkylene-C(=O)-OR 4 may be independently selected from optionally substituted radicals selected from the group consisting of: R 4 , R 5 and R 6 each independently may be hydrogen, -(C1-C6)alkyl, or -(C1-C6)haloalkyl; Each (B) n is, for example, the group consisting of hydrogen, halogen, and, for example, -(C1-C6) alkyl, heterocycle, and -(C0-C6) alkylene-OR 8 and R 8 may be hydrogen, —(C1-C6)alkyl, —(C3-C7)cycloalkyl, or —(C1-C6)haloalkyl.

[0048] For example, each (A) m Each of may be, for example, hydrogen, halogen, and (C0-C6) alkylene-OR 4 wherein R 4 can be -(C1-C6) alkyl.

[0049] For example, each (B) n Each of these can be, for example, hydrogen, halogen, a heterocycle, -(C0-C6) alkylene-OR 8 and -(C1-C6)alkyl, wherein R 8 may be -(C1-C6) alkyl, -(C1-C6) haloalkyl, or -(C3-C7) cycloalkyl. For example, B 1 can be -(C1-C6) alkyl.

[0050] For example, Z 1 may be selected from C or N, R2 can be hydrogen, methyl or halogen, R 3 can be methyl, each (A)m can be, for example, independently selected from the group consisting of hydrogen, fluorine, and -O-methyl, and each (B)n can be, for example, independently selected from the group consisting of hydrogen, fluorine, methyl, heterocycle, -O-methyl, -O-(C3-C7)cycloalkyl, and O-CHF2. For example, each (B)n can be, for example, independently selected from the group consisting of hydrogen, fluorine, methyl, azetidinyl, -O-methyl, -O-cyclopropyl, and O-CHF2.

[0051] Particularly preferred compounds of the present invention are those listed below, as well as pharmaceutically acceptable acid or base addition salts thereof, stereochemically isomeric forms thereof or N-oxide forms thereof: 7-(2,4-dimethylphenyl)-6,8-dimethyl-2-(2-pyridyl)pyrrolo[1,2-d][1,2,4]triazin-1-one 7-[3-(azetidin-1-yl)phenyl]-6,8-dimethyl-2-(2-pyridyl)pyrrolo[1,2-d][1,2,4]triazin-1-one 7-(3-Methoxyphenyl)-6,8-dimethyl-2-(2-pyridyl)pyrrolo[1,2-d][1,2,4]triazin-1-one 7-[3-(azetidin-1-yl)phenyl]-6,8-dimethyl-2-pyrimidin-2-ylpyrrolo[1,2-d][1,2,4]triazin-1-one 7-[3-(Cyclopropoxy)phenyl]-6,8-dimethyl-2-pyrimidin-2-ylpyrrolo[1,2-d][1,2,4]triazin-1-one 7-[3-(cyclopropoxy)phenyl]-2-(5-fluoropyrimidin-2-yl)-6,8-dimethylpyrrolo[1,2-d][1,2,4]triazin-1-one 7-[3-(difluoromethoxy)phenyl]-2-(5-fluoropyrimidin-2-yl)-6,8-dimethylpyrrolo[1,2-d][1,2,4]triazin-1-one 7-[3-(Difluoromethoxy)phenyl]-6,8-dimethyl-2-pyrimidin-2-ylpyrrolo[1,2-d][1,2,4]triazin-1-one 7-[3-(Difluoromethoxy)phenyl]-2-(5-methoxypyrimidin-2-yl)-6,8-dimethylpyrrolo[1,2-d][1,2,4]triazin-1-one 6,8-Dimethyl-7-(1-methylindolin-4-yl)-2-pyrimidin-2-yl-pyrrolo[1,2-d][1,2,4]triazin-1-one 7-[3-(cyclopropoxy)phenyl]-2-(5-methoxypyrimidin-2-yl)-6,8-dimethylpyrrolo[1,2-d][1,2,4]triazin-1-one 7-[3-(cyclopropoxy)phenyl]-8-methyl-2-pyrimidin-2-yl-pyrrolo[1,2-d][1,2,4]triazin-1-one 8-Methyl-7-(1-methyl-3,4-dihydro-2H-quinolin-5-yl)-2-pyrimidin-2-yl-pyrrolo[1,2-d][1,2,4]triazin-1-one 7-(3-Methoxyphenyl)-8-methyl-2-pyrimidin-2-yl-pyrrolo[1,2-d][1,2,4]triazin-1-one 7-(3-Methoxy-2-methylphenyl)-8-methyl-2-pyrimidin-2-ylpyrrolo[1,2-d][1,2,4]triazin-1-one 8-Methyl-7-(1-methylindolin-4-yl)-2-pyrimidin-2-yl-pyrrolo[1,2-d][1,2,4]triazin-1-one 7-[3-(cyclopropoxy)-2-methylphenyl]-8-methyl-2-pyrimidin-2-ylpyrrolo[1,2-d][1,2,4]triazin-1-one 7-[3-(difluoromethoxy)-2-methylphenyl]-8-methyl-2-pyrimidin-2-ylpyrrolo[1,2-d][1,2,4]triazin-1-one 7-[3-(Difluoromethoxy)phenyl]-8-methyl-2-pyrimidin-2-ylpyrrolo[1,2-d][1,2,4]triazin-1-one 6-chloro-7-(3-methoxyphenyl)-8-methyl-2-pyrimidin-2-yl-pyrrolo[1,2-d][1,2,4]triazin-1-one 7-(2-Fluoro-3-methoxyphenyl)-8-methyl-2-pyrimidin-2-yl-pyrrolo[1,2-d][1,2,4]triazin-1-one 7-(3-Methoxyphenyl)-6,8-dimethyl-2-pyrimidin-2-yl-pyrrolo[1,2-d][1,2,4]triazin-1-one 6-Bromo-7-[3-(difluoromethoxy)phenyl]-8-methyl-2-pyrimidin-2-yl-pyrrolo[1,2-d][1,2,4]triazin-1-one 7-(2-Fluoro-5-methoxyphenyl)-8-methyl-2-pyrimidin-2-ylpyrrolo[1,2-d][1,2,4]triazin-1-one 7-(3-fluoro-5-methoxyphenyl)-8-methyl-2-pyrimidin-2-ylpyrrolo[1,2-d][1,2,4]triazin-1-one 6-Fluoro-7-(2-fluoro-3-methoxyphenyl)-8-methyl-2-(pyridin-2-yl)pyrrolo[1,2-d][1,2,4]triazin-1(2H)-one 7-(2-Cyclopropoxypyridin-4-yl)-8-methyl-2-(pyrimidin-2-yl)pyrrolo[1,2-d][1,2,4]triazin-1(2H)-one 7-(2-Methoxypyridin-4-yl)-8-methyl-2-(pyrimidin-2-yl)pyrrolo[1,2-d][1,2,4]triazin-1(2H)-one 7-(6-Methoxypyridin-3-yl)-8-methyl-2-(pyrimidin-2-yl)pyrrolo[1,2-d][1,2,4]triazin-1(2H)-one 7-(2-(difluoromethoxy)pyridin-4-yl)-8-methyl-2-(pyrimidin-2-yl)pyrrolo[1,2-d][1,2,4]triazin-1(2H)-one

[0052] The above list of compounds can also be represented by the following skeletal formula: TIFF2025538049000017.tif208151TIFF2025538049000018.tif86155

[0053] Compounds according to any of the above descriptions may exhibit metabotropic glutamate receptor 7 modulator activity.

[0054] The disclosed compounds also include all pharmaceutically acceptable isotopic variations in which at least one atom is replaced with an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Examples of isotopes suitable for inclusion in the disclosed compounds include: 2 H and 3 Isotopes of hydrogen such as H; 11 C. 13 C and 14 isotopes of carbon such as C; 15 isotopes of nitrogen such as N; 17 O and 18 isotopes of oxygen such as O; 31 P, 32 P and 33 isotopes of phosphorus such as P; 35 isotopes of sulfur such as S; 18 isotopes of fluorine such as F; 36 isotopes of chlorine such as Cl; 125 Isotopically labeled compounds include, but are not limited to, isotopes of iodine such as I. The present invention includes various isotopically labeled compounds as defined herein, e.g. 3 H and 14 In the presence of radioactive isotopes such as C, or 2 H and 13 This includes those in which non-radioactive isotopes such as C exist.

[0055] Such isotope-labeled compounds are useful in metabolic studies ( 14 C), reaction kinetic studies (e.g. 2 H or 3H), detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or radiotherapy of patients. 11 C. 18 F, 15 O and 13 N or N-labeled compounds may be particularly desirable for PET studies examining substrate receptor occupancy. Additionally, heavier isotopes, particularly deuterium (e.g., 2 Substitution with hydrogen (H or D) may confer therapeutic benefits resulting from improved metabolic stability, e.g., increased in vivo half-life, reduced dosage requirements, or improved therapeutic index. It is understood that deuterium in this context is considered a substituent of compounds of formulas (I)-(VIII). Isotopically labeled compounds of formulas (I)-(VIII) may generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples, using the appropriate isotopically labeled reagent in place of the previously employed non-labeled reagent.

[0056] In one aspect of the present invention, a pharmaceutical composition is provided comprising a compound according to any of the above descriptions. 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 descriptions.

[0057] In one aspect of the invention there is provided a method of treating or preventing a condition 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 above descriptions.

[0058] Treatment or prevention may be affected or facilitated by the modulatory effects of an mGlu7 allosteric modulator, such as an mGlu7 negative allosteric modulator.

[0059] The condition may be one or more of a central nervous system disorder, an ear disease or disorder, or a pain disorder.

[0060] Disorders of the central nervous system may include anxiety disorders such as agoraphobia, generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), panic disorder, and post-traumatic stress disorder (PTSD).

[0061] The central nervous system disorder is a psychotic disorder such as schizophrenia, delusional disorder, schizoaffective disorder, schizophreniform disorder, or substance-induced psychotic disorder.

[0062] The ear disease or disorder may be one or more of an inner ear disorder, 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, toxic hearing loss, central auditory processing disorder, or vestibular disorder.

[0063] In a further aspect of the present invention, there is provided a method for treating, preventing, ameliorating, controlling or reducing the risk of various neurological and psychiatric disorders associated with glutamate dysfunction 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 above descriptions, wherein the treatment or prevention can be influenced or facilitated by the modulatory effect of an mGlu7 negative allosteric modulator.

[0064] Preferably, the method is for the treatment or prevention of a condition in a human.

[0065] In a further aspect of the invention there is provided a compound or composition according to any of the above statements for use as a medicament.

[0066] In a further aspect of the invention there is provided a compound or composition as defined in any statement above for use in a method of treatment or prevention as defined in any statement above.

[0067] In a further aspect of the invention there is provided the use of a compound according to any of the above statements in the manufacture of a medicament for the treatment or prophylaxis of a condition as defined in any of the above statements.

[0068] [Term definition] Below are definitions of various terms used in the specification and claims to describe this invention.

[0069] As used herein, "(C1-C6)" refers to a carbon radical having 1, 2, 3, 4, 5, or 6 carbon atoms. "(C0-C6)" refers to a carbon radical having 0, 1, 2, 3, 4, 5, or 6 carbon atoms. As used herein, "C" refers to a carbon atom, "N" refers to a nitrogen atom, "O" refers to an oxygen atom, and "S" refers to a sulfur atom.

[0070] If the subscript is the integer 0 (zero), it indicates that the radical referred to by the subscript does not exist, i.e., there is a direct bond between the radicals.

[0071] If the subscript is the integer 0 (zero) and the radical it refers to is an alkyl, this indicates that the radical is a hydrogen atom.

[0072] As used herein, unless otherwise specified, the term "bond" refers to a saturated covalent bond. When two or more bonds are adjacent to each other, they are considered to be equivalent to one bond. For example, the radical -AB- represents a single bond, although both A and B may be bonds.

[0073] As used herein, unless otherwise specified, the term "alkyl" includes both straight-chain and branched-chain alkyl radicals, and may be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, neopentyl, n-hexyl, i-hexyl, or t-hexyl. The term "(C0-C3)alkyl" refers to an alkyl radical having 0, 1, 2, or 3 carbon atoms, and may be methyl, ethyl, n-propyl, or i-propyl.

[0074] As used herein, unless otherwise specified, the term "alkylene" includes both straight-chain and branched difunctional saturated hydrocarbon radicals, and includes methylene (-CH2-), ethylene (-CH2-CH2-), n-propylene (-CH2-CH2-CH2-), i-propylene (-CH-(CH3)-CH2-), n-butylene (-CH2-CH2-CH2-CH2-)), i-butylene (-CH2-CH-(CH3)-CH2-), t-butylene (-CH2-C-(CH3)-CH2-), n-pentylene (-CH2-CH2-CH2-CH2-CH2-), It may be i-pentylene (-CH-CH(CH)-CH-CH-), neopentylene (-CH-C(CH)-CH-), n-hexylene (-CH-CH-CH-CH-CH)-CH-CH-), i-hexylene (-CH-CH-(CH)-CH-CH-CH-), or neohexylene (-CH-C(CH)-CH-CH-). The term "O-(C-C)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.

[0075] As used herein, unless otherwise specified, the term "cycloalkyl" refers to an optionally substituted carbocycle containing no heteroatoms, including monocyclic, bicyclic, and tricyclic saturated carbocycles, and fused ring systems. Such fused ring systems can contain a partially or fully unsaturated ring, such as a benzene ring, to form fused ring systems such as benzofused carbocycles. Cycloalkyl includes fused ring systems such as spirofused ring systems. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentanyl, decahydronaphthalene, adamantane, indanyl, fluorenyl, 1,2,3,4-tetrahydronaphthalene, and the like. The term "(C3-C7)cycloalkyl" can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

[0076] As used herein, unless otherwise specified, the term "alkenyl" includes both straight-chain and branched-chain alkenyl radicals. The term "(C2-C6)alkenyl" refers to an alkenyl radical having 2 to 6 carbon atoms and 1 or 2 double bonds, which may be, but is not limited to, vinyl, aryl, propenyl, i-propenyl, butenyl, i-butenyl, crotyl, pentenyl, i-pentenyl, or hexenyl.

[0077] As used herein, unless otherwise specified, the term "alkenylene" includes both straight-chain and branched-chain disubstituted alkenyl radicals. The term "(C2-C6)alkenylene" refers to an alkenylene radical having 2 to 6 carbon atoms and 1 or 2 double bonds, which may be, but is not limited to, vinylene, arylene, propenylene, i-propenylene, butenylene, i-butenylene, crotenylene, pentenylene, i-pentenylene, or hexenylene.

[0078] As used herein, unless otherwise specified, the term "alkynyl" includes both straight-chain and branched-chain alkynyl radicals. The term (C2-C6)alkynyl has 2 to 6 carbon atoms and 1 or 2 triple bonds and may be, but is not limited to, ethynyl, propargyl, butynyl, i-butynyl, pentynyl, i-pentynyl, or hexynyl.

[0079] As used herein, unless otherwise specified, the term "alkynylene" includes both straight-chain and branched-chain disubstituted alkynylene radicals. The term (C2-C6)alkynylene has 2 to 6 carbon atoms and 1 or 2 triple bonds and may be, but is not limited to, ethynylene, propargylene, butynylene, i-butynylene, pentynylene, i-pentynylene, or hexynylene.

[0080] The term "aryl" refers to an optionally substituted monocyclic or bicyclic hydrocarbon ring system containing at least one unsaturated aromatic ring. Examples and suitable values ​​of the term "aryl" are phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indolyl, indenyl, and the like.

[0081] As used herein, unless otherwise indicated, 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. Examples of "heteroaryl" include benzimidazolyl, benzisothiazolyl, benzisoxazolyl, benzofuryl, benzopyrazolyl, benzothiazolyl, benzothiophenyl, benzotriazolyl, benzoxazolyl, furazanyl, furyl, imidazolonyl, imidazolyl, imidazopyridazinyl, imidazopyridyl, indolyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolonyl, oxazolopyridazinyl, oxazolopyridyl, oxazolyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyrazolopyridinyl, These include, but are not limited to, pyrazolyl, pyridazinyl, pyridonyl, pyridyl, pyrimidyl, pyrrolyl, quinazolyl, quinolyl, quinoxalinyl, tetrahydrotriazolopyridyl, tetrahydrotriazolopyrimidinyl, tetrazolyl, thiadiazolyl, thiazolonyl, thiazolopyridazinyl, thiazolopyridyl, thiazolyl, thienyl, thionaphthyl, triazinyl, and triazolyl.

[0082] As used herein, unless otherwise specified, the terms "alkylene-aryl," "alkylene-heteroaryl," and "alkylene-cycloalkyl" refer to substituents attached to an aryl, heteroaryl, or cycloalkyl radical via an alkyl radical, respectively. The term "(C-C)alkylene-aryl" includes aryl-C-C-alkyl radicals 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 radicals, where examples of heteroaryl 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-oxazolylmethyl, 3-oxazolylmethyl, 2-thiazolylmethyl, 3-thiazolylmethyl, 2-pyridinylmethyl, 3-pyridinylmethyl, 4-pyridinylmethyl, 1-quinolylmethyl, and the like.

[0083] As used herein, unless otherwise specified, 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 cyclization of two or more rings through a bridging atom (e.g., O, S, N) or a bridging group (e.g., alkylene). Examples of heterocyclic moieties include azetidinyl, dihydrofuranyl, dihydrothienyl, dioxolanyl, 1,1-dioxo-thiomorpholinyl, imidazolidinyl, imidazolinyl, isothiazolinyl, isoxazolidinyl, isoxazolinyl, morpholinyl, oxazolidinyl, oxazolinyl, oxetanyl, piperazinonyl, piperazinyl, piperidinonyl, piperidinyl, pyranyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, Examples include, but are not limited to, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, thiazolidinyl, thiazolinyl, thiomorpholinyl, thiopyranyl, triazolinyl, and the corresponding benz-annulated heterocycles (e.g., dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazinyl, dihydrofuropyridinyl, dihydroquinolinyl, dihydrothienopyridinyl, indolinyl, pyrrolopyridinyl, tetrahydroquinolinyl, tetrahydroquinoxalinyl, etc.).

[0084] In this specification, unless otherwise specified, five- or six-membered rings containing one or more atoms independently selected from C, N, O, and S include aromatic and heteroaromatic rings, as well as carbocyclic and heterocyclic rings which may be saturated or unsaturated. Such rings include spirocyclic and bridged bicyclic systems. Examples of such rings include dihydrofuranyl, dihydrothienyl, dioxolanyl, 1,1-dioxothiomorpholinyl, furazanyl, furyl, imidazolidinyl, imidazolinyl, imidazolonyl, imidazolyl, isothiazolinyl, isothiazolyl, isoxazolidinyl, isoxazolinyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolidinyl, oxazolinyl, oxazolonyl, oxazolyl, phenyl, piperazinonyl, piperazinyl, piperidinonyl, piperidinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridonyl, pyridyl, pyrimidyl, pyrrolidinonyl, pyrrolidinyl, These include, but are not limited to, pyrrolinyl, pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolinyl, thiazolonyl, thiazolyl, thienyl, thiomorpholinyl, thiopyranyl, triazolinyl, triazinyl, triazolyl, cyclopentyl, cyclopentenyl, cyclohexyl, and cyclohexenyl.

[0085] As used herein, 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, as well as carbocyclic and heterocyclic rings which may be saturated or unsaturated. Examples of such rings include azetidinyl, benzimidazolyl, benzisothiazolyl, benzisoxazolyl, benzofuryl, benzopyrazolyl, benzothiazolyl, benzothiophenyl, benzotriazolyl, benzoxazolyl, dihydrofuranyl, dihydrothienyl, dioxolanyl, 1,1-dioxothiomorpholinyl, furazanyl, furyl, imidazolidinyl, imidazolinyl, imidazolonyl, imidazolyl, imidazopyridyl, and the like. inyl, imidazopyridyl, indolyl, isoindolyl, isoquinolinyl, isothiazolinyl, isothiazolyl, isoxazolidinyl, isoxazolinyl, isoxazolyl, morpholinyl, naphthyl, naphthyridinyl, oxadiazolyl, oxazolidinyl, oxazolinyl, oxazolonyl, oxazolopyridazinyl, oxazolopyridyl, oxazolyl, oxetanyl, phenyl, piperazinonyl, piperazinyl, piperidinonyl, Piperidinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridonyl, pyridyl, pyrimidyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolyl, quinolyl, quinoxalinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrotriazolopyridyl, tetrahydrotriazolopyrimidinyl, tetrazolyl, These include, but are not limited to, thiadiazolyl, thiazolidinyl, thiazolinyl, thiazolonyl, thiazolopyridazinyl, thiazolopyridyl, thiazolyl, thienyl, thiomorpholinyl, thionaphthyl, thiopyranyl, triazolinyl, triazinyl, triazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, and cyclooctenyl.

[0086] As used herein, unless otherwise stated, the term "halo" or "halogen" may be fluoro, chloro, bromo or iodo.

[0087] As used herein, unless otherwise specified, the term "haloalkyl" refers to an alkyl radical as defined above substituted with one or more halo radicals. The term "(C-C)haloalkyl" may include, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, and difluoroethyl. The term "O-C-C-haloalkyl" may include, but is not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, and fluoroethoxy.

[0088] As used herein, unless otherwise stated, the term "cyanoalkyl" means an alkyl radical, as defined above, substituted with one or more cyano groups.

[0089] As used herein, unless otherwise indicated, the term "optionally substituted" includes acyl, (C-C) alkyl, -(C-C) haloalkyl, -(C-C) cycloalkyl, -(C-C) alkylene-(C-C) cycloalkyl, -(C-C) cycloalkyl-(C-C) alkylene, -(C-C) alkylene-(C-C) spiroalkyl-(C-C) refers to a radical further bearing one or more substituents which may be alkylene, hydroxy, (C-C)alkylene-oxy, dimethylamino(C-C)alkyl, mercapto, aryl, heterocycle, heteroaryl, (C-C)alkylene-aryl, (C-C)alkylene-heterocycle, (C-C)alkylene-heteroaryl, halogen, haloalkyl, trifluoromethyl, pentafluoroethyl, haloalkoxy, cyano, cyanomethyl, nitro, amino, amido, amidinyl, oxo, carboxyl, carboxamido, (C-C)alkylene-oxycarbonyl, carbamate, sulfonamido, ester, or sulfonyl.

[0090] As used herein, unless otherwise indicated, the term "independently" means that when multiple substituents are selected from multiple possible substituents, the substituents can be the same or different.

[0091] As used herein, unless otherwise specified, the term "solvate" refers to a complex of variable stoichiometry formed by a solute (e.g., a compound of Formula (I)) and a solvent, which is a pharmaceutically acceptable solvent, such as water, and which does not interfere with the biological activity of the solute.

[0092] As used herein, unless otherwise specified, the term "salt" refers to an acid addition salt or a base addition salt of a compound of the present invention. "Salt" specifically includes "pharmaceutically acceptable salts."

[0093] The pharmaceutically acceptable salts of the present invention can be synthesized from a basic or acidic moiety 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 can also form internal salts, e.g., zwitterionic molecules.

[0094] As used herein, unless otherwise specified, certain compounds may exist in one or more particular 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-, 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 "isomeric forms."

[0095] TIFF2025538049000019.tif21116

[0096] The term "isomer" includes compounds with one or more isotopic substitutions. For example, H is1 H, 2 H(D), and 3 H(T) may be in any isotopic form, including but not limited to; C may be 12 C. 13 C. 14 It may be in any isotopic form, including but not limited to C; O is 16 O and 18 F may be in any isotopic form, including but not limited to O. 19 F and 18 It may be in any isotopic form, including but not limited to F.

[0097] As used herein, unless otherwise specified, the term "negative allosteric modulator of mGlu7" or "allosteric modulator of mGlu7" also refers to a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, or an N-oxide form thereof.

[0098] [Pharmaceutical composition] The allosteric modulators of mGlu7 described herein, and their pharmaceutically acceptable salts, solvates, and hydrates, can be used in pharmaceutical formulations in combination with a pharmaceutically acceptable carrier or diluent. 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 in the range described herein. Techniques for the formulation and administration of the compounds of the present invention can be found in Remington: The Science and Practice of Pharmacy, 1999, Vol. th edition, Mack Publishing Co., Easton, PA (1995).

[0099] The amount of mGlu7 allosteric modulator administered to a subject will depend on the type and severity of the disease or condition, as well as the subject's characteristics, such as general health, age, sex, weight, and tolerance to drugs. Those skilled in the art will be able to determine the appropriate dosage based on these and other factors. Effective doses of commonly used central nervous system drugs are well known to those skilled in the art. Typically, the total daily dosage is approximately 0.05 to 2000 mg.

[0100] The present invention relates to pharmaceutical compositions that provide approximately 0.01 to 1000 mg of an active ingredient per unit dose. The compositions can be administered by any suitable route, for example, orally in capsules or other forms, parenterally in injectable solutions, topically in ointments or lotions, ophthalmically in eye drops, rectally in suppositories, or intranasally or transdermally in a delivery system such as a patch.

[0101] 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.

[0102] Tablets, pills, capsules, etc. contain about 0.01 to about 99% by weight of the active ingredient, and binders such as tragacanth gum, acacia, corn starch, gelatin, etc.; excipients such as dicalcium phosphate; disintegrating agents such as corn starch, potato starch, alginic acid, etc.; lubricants such as magnesium stearate; and sweeteners such as sucrose, lactose, saccharin, etc. When the dosage unit form is a capsule, it can contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.

[0103] Various other materials 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. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methylparaben and propylparaben as preservatives, a dye and flavoring such as cherry or orange flavor.

[0104] For parenteral administration, the disclosed allosteric modulators of mGlu7 or their salts can be combined with sterile aqueous or organic media to form injectable solutions or suspensions. For example, sesame oil, peanut oil, aqueous propylene glycol, etc. can be used, as can aqueous solutions of pharmaceutically acceptable water-soluble salts of the compounds. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain preservatives to prevent the growth of microorganisms.

[0105] In addition to the above-mentioned preparation, compound can also be formulated as depot preparation.This long-acting preparation can be administered by, for example, subcutaneous implantation or intramuscular injection.Therefore, for example, compound can be formulated as emulsion in acceptable oil, or ion exchange resin, or as poorly soluble derivative, such as poorly soluble salt.

[0106] Preferably, the disclosed allosteric modulators of mGlu7 or pharmaceutical preparations containing these compounds are in unit dosage form for administration to mammals. The unit dosage form can be any unit dosage form known in the art, including, for example, capsules, drip bags, tablets, or vials. The amount of active ingredient in a unit dosage composition is an effective amount and can vary according to the specific treatment involved. It is understood that it may be necessary to vary the dosage routinely depending on the age and condition of the patient. The dosage also varies depending on various administration routes, including oral, aerosol, rectal, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, and intranasal.

[0107] [Synthesis method] The compounds according to the present invention, particularly compounds according to Formulae (I)-(VIII), can be prepared by methods known in the art of organic synthesis, as defined in part by the following synthetic schemes. In all schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (Green TW and Wuts PGM, (1991) Protecting Groups in Organic Synthesis, John Wiley & Sons). These groups are removed at a convenient stage in the compound synthesis using methods readily apparent to those skilled in the art. The selection of processes and reaction conditions and the order of their execution will be consistent with the preparation of compounds of Formulae (I)-(VIII).

[0108] The compounds according to the present invention may be expressed as a mixture of enantiomers, which can be resolved into the individual pure R- or S-enantiomers. For example, if a specific enantiomer is required, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, and the resulting diastereomeric mixture is separated and the auxiliary is cleaved to provide the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group, such as an amino group, or an acidic functional group, such as a carboxyl group, this separation can be conveniently carried out by fractional crystallization from various solvents as an optically active acid salt, or by other methods known in the literature (e.g., chiral column chromatography).

[0109] Resolution of the final product, an intermediate, or a starting material can be effected by any suitable method known in the art (Eliel EL, Wilen SH and Mander L.N. (1984) Stereochemistry of Organic Compounds, Wiley-Interscience).

[0110] Many of the heterocyclic compounds of the present invention can be prepared using synthetic routes well known in the art (Katrizky AR and Rees CW (1984) Comprehensive Heterocyclic Chemistry, Pergamon Press).

[0111] The products from the reaction can be isolated and purified using standard techniques such as extraction, chromatography, recrystallization, and distillation.

[0112] The compounds of the present invention can be prepared by general synthetic routes as disclosed in the methods below.

[0113] In one embodiment of the present invention, the compound of formula (I) can be prepared according to the synthetic procedure shown in Scheme 1. Ethyl 1H-pyrrole-2-carboxylate g1 can be oxidized in the presence of N-bromosuccinimide in a suitable solvent, such as acetonitrile, at a suitable temperature to obtain intermediate ethyl 4-bromo-1H-pyrrole-2-carboxylate g2. Intermediate g4 can be prepared by reacting the corresponding intermediate g2 with hydrazine g3 in a suitable solvent, such as ethanol, at a suitable temperature. Intermediate g4 can be reacted with triethyl orthoformate g5 by condensation at a suitable temperature to obtain bromopyrrolo[1,2-d][1,2,4]triazinone derivative g6. Intermediate g6 can then be converted to intermediate g8 by a suitable reaction known to those skilled in the art of organic synthesis, for example, a Suzuki cross-coupling reaction mediated by a palladium complex, such as PdCl(dppf), in the presence of a base, such as potassium carbonate, in a suitable solvent, such as a 1,4-dioxane / water mixture. The final compound g10 can be obtained by Ullmann coupling reaction with an appropriate aryl or heteroaryl halide g9 via copper complex catalyst such as CuI in the presence of a base such as potassium phosphate at a suitable temperature, or by alkylation of g8 in the presence of a base such as potassium carbonate or cesium carbonate in a suitable solvent such as DMF.

[0114] TIFF2025538049000020.tif92159

[0115] Similarly, the final compound g10 can be prepared according to the synthetic procedure shown in Scheme 2. The bromopyrrolo[1,2-d][1,2,4]triazinone derivative g6, prepared according to Step 3 of Scheme 1, can be converted to intermediate g11 by an Ullmann coupling reaction catalyzed by a copper complex such as CuI in the presence of a base such as potassium phosphate, or by alkylation of g6 in the presence of a base such as potassium carbonate. The final compound g10 can be obtained by a Suzuki cross-coupling reaction catalyzed by a palladium complex such as PdCl(dppf) in the presence of a base such as potassium carbonate in a suitable solvent such as a 1,4-dioxane / water mixture.

[0116] TIFF2025538049000021.tif76159

[0117] In another particular embodiment of formula (I), the final compound g14 can be prepared according to the synthetic procedure shown in Scheme 3. Step 4 (R 4 Intermediate compound g12, prepared according to the procedure (III), can be converted to compound g13 by a copper complex catalyzed Ullmann coupling reaction in the presence of a base such as potassium phosphate in a suitable solvent such as 1,4-dioxane at a suitable temperature. Halogenation of g13 with N-bromosuccinimide or N-chlorosuccinimide in a suitable solvent such as THF at a suitable temperature gives final compound g14.

[0118] TIFF2025538049000022.tif31161

[0119] [experiment] Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification.

[0120] Specifically, the following abbreviations may be used in the examples and throughout the specification: g (grams), m (grams), g (grams);

[0121] TIFF2025538049000023.tif248164

[0122] Saline refers to a saturated aqueous solution of NaCl. All temperatures are in °C (degrees Celsius) unless otherwise noted. All reactions are conducted under an inert atmosphere at room temperature unless otherwise noted.

[0123] Most reactions were monitored by thin-layer chromatography using precoated silica gel plates (TLC Silica Gel 60 F254, Sigma-Aldrich) visualized with UV light. Flash column chromatography was performed using prepacked columns of UltraPure Irregular Silica Gel (40-63 μm, 60 A) with capacities of 4 g, 12 g, 25 g, 40 g, and 80 g (Screening Devices BV) and a Biotage Isolera One 2.0.8 autocolumn. [Example]

[0124] Example 7-[3-(Difluoromethoxy)phenyl]-2-(5-methoxypyrimidin-2-yl)-6,8-dimethylpyrrolo[1,2-d][1,2,4]triazin-1-one (Final Compound 1-9)

[0125] Ethyl 4-bromo-3,5-dimethyl-1H-pyrrole-2-carboxylate

[0126] According to Scheme 1, Step 1: To a mixture of ethyl 3,5-dimethyl-1H-pyrrole-2-carboxylate (350.0 mg, 2.093 mmol) and K2CO3 (307 mg, 2.22 mmol) in ACN (20 mL) was added NBS (384 mg, 2.16 mmol) in small portions at 0 °C. The reaction was allowed to warm to room temperature, and a white precipitate formed. The reaction was then stirred at room temperature for 40 h, diluted with water, and stirred for 30 min. The precipitate was collected by vacuum filtration, washed with EtOH:HO (1:2), and dried to afford the title compound (515 mg, 2.09 mmol, 99.9%) as a white solid.

[0127] 1 H-NMR (500 MHz, DMSO-d6) δ: 11.74 (s, 1H), 4.22 (q, J = 7.1 Hz, 2H), 2.18 (s, 3H), 2.16 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H).

[0128] 4-Bromo-3,5-dimethyl-1H-pyrrole-2-carbonylhydrazide

[0129] According to Scheme 1, Step 2: To a solution of ethyl 4-bromo-3,5-dimethyl-1H-pyrrole-2-carboxylate (3.34 g, 13.6 mmol) in EtOH (30 mL) was added hydrazine (62.1 g, 60.9 mL, 35 wt%, 679 mmol). The mixture was heated to 90 °C for 3 h while the reaction was monitored by TLC. White crystals formed. The mixture was concentrated and stirred for 30 min. The precipitate was then filtered and dried to give the title compound (3.90 g, 16.8 mmol, 124%).

[0130] 1 H-NMR (500 MHz, DMSO-d6) δ 11.29 (s, 1H), 8.59 (s, 1H), 4.31 (s, 2H), 2.14 (d, J = 8.7 Hz, 6H).

[0131] 7-Bromo-6,8-dimethylpyrrolo[1,2-d][1,2,4]triazin-1(2H)-one

[0132] According to Step 3 of Scheme I: 4-bromo-3,5-dimethyl-1H-pyrrole-2-carbonylhydrazide (2.0 g, 8.6 mmol) was dissolved in triethyl orthoformate (14 mL, 86 mmol) and the reaction was stirred at 150 °C overnight. The mixture was then concentrated, and the crude product was used in the next step without further purification. To the crude product (2.5 g, 8.7 mmol) in EtOH (70 mL) was added KOH (0.49 g, 8.7 mmol) and the reaction was stirred at 80 °C overnight. The mixture was concentrated and purified by flash column chromatography (Isolera, 80 g column, EtOAc:Hept, 50:50) to afford the title compound (1.3 g, 5.4 mmol, 62%) as a pale yellow solid.

[0133] 1 H-NMR (500 MHz, CDCl3) δ: 8.86 (s, 1H), 7.80 (s, 1H), 2.50 (s, 3H), 2.46 (s, 3H).

[0134] 7-(3-(difluoromethoxy)phenyl)-6,8-dimethylpyrrolo[1,2-d][1,2,4]triazin-1(2H)-one

[0135] According to Scheme 1, Step 4: To a solution of 7-bromo-6,8-dimethylpyrrolo[1,2-d][1,2,4]triazin-1(2H)-one (250 mg, 1.03 mmol) in 1,4-dioxane (3.0 mL) and water (0.33 mL) was added 2-(3-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (293 mg, 1.08 mmol), K2CO3 (428 mg, 3.10 mmol), and PdCl2(dppf) (83.1 mg, 114 μmol). The mixture was degassed under argon for 5 minutes. The reaction was stirred at 110 °C for 1 hour using a microwave oven. The mixture was diluted with DCM, filtered through Celite®, concentrated in vacuo, and further purified by flash column chromatography (0 to 50% ethyl acetate in heptane). The resulting fractions were concentrated in vacuo, redissolved in methanol, and then further purified by preparative HPLC. This final step was repeated twice. Finally, the resulting fractions were concentrated in vacuo, extracted with DCM / water, dried, and concentrated in vacuo to give the title compound (50 mg, 0.16 mmol, 15%, 97% purity).

[0136] LC-MS (ESI): RT = 10.66 min; MS m / z [M+H] + = 306.2.

[0137] 7-[3-(Difluoromethoxy)phenyl]-2-(5-methoxypyrimidin-2-yl)-6,8-dimethylpyrrolo[1,2-d][1,2,4]triazin-1-one

[0138] According to Step 5 of Scheme 1: To a solution of 7-(3-(difluoromethoxy)phenyl)-6,8-dimethylpyrrolo[1,2-d][1,2,4]triazin-1(2H)-one (25 mg, 82 μmol) in 1,4-dioxane (1.2 mL) was added CuI (7.8 mg, 41 μmol), 2-bromo-5-methoxypyrimidine (20 mg, 0.11 mmol), KPO (43 mg, 0.20 mmol), and 1,10-phenanthroline (8.9 mg, 49 μmol). The solution was purged with argon for 5 minutes, then the microwave vial was capped and heated at 110 °C overnight. The mixture was diluted with EtO, filtered through Celite®, concentrated in vacuo, and further purified by flash column chromatography (Isolera, 25 g column, 50:50 ethyl acetate:heptane). The resulting fraction was concentrated in vacuo, redissolved in methanol, and then further purified by preparative HPLC. The resulting fraction was concentrated in vacuo, extracted with DCM / water, dried, and concentrated in vacuo to give the title compound (2.7 mg, 6.4 μmol, 7.8%, purity 97.3%).

[0139] LC MS (ESI): RT = 7.52 min; MS m / z [M+H] + = 414.1; 1 H-NMR (500 MHz, CDCl3) δ: 8.55 (s, 2H), 8.02 (s, 1H), 7.49 (t, J = 7.9 Hz, 1H), 7.20 - 7.13 (m, 2H),7.09 (t, J = 2.0 Hz, 1H), 6.60 (t, J = 73.4 Hz, 1H), 4.01 (s, 3H), 2.53 (s, 3H), 2.48 (s, 3H).

[0140] Example 2: 7-[3-(azetidin-1-yl)phenyl]-6,8-dimethyl-2-(2-pyridyl)pyrrolo[1,2-d][1,2,4]triazin-1-one (final compound 1-2)

[0141] 7-(3-(azetidin-1-yl)phenyl)-6,8-dimethylpyrrolo[1,2-d][1,2,4]triazin-1(2H)-one

[0142] According to Scheme 1, Step 4: To a solution of 7-bromo-6,8-dimethylpyrrolo[1,2-d][1,2,4]triazin-1(2H)-one (50 mg, 0.21 mmol, prepared according to Example 1 of Scheme 1, Step 3) in a mixture of 1,4-dioxane (0.6 mL) and water (0.07 mL) was added 1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)azetidine (80 mg, 0.31 mmol) and K2CO3 (86 mg, 0.62 mmol). The solution was purged with argon for 5 minutes, then PdCl2(dppf) (17 mg, 23 μmol) was added and the mixture was stirred under argon for an additional 5 minutes. The reaction was heated in a microwave at 110 °C for 3 hours. Purification by flash chromatography (ethyl acetate / heptane, 1:1) gave a colorless oil (10 mg, 16% yield). Further purification (DCM / methanol (10%)) and precipitation of a beige solid with ethanol gave the title compound (1.73 mg, 5.1 μmol, 2.4% yield).

[0143] SFC-MS: RT = 4.26 min; MS m / z [M+H] + = 295.1.

[0144] 7-[3-(azetidin-1-yl)phenyl]-6,8-dimethyl-2-(2-pyridyl)pyrrolo[1,2-d][1,2,4]triazin-1-one

[0145] According to Scheme 1, Step 5: A solution of 7-(3-(azetidin-1-yl)phenyl)-6,8-dimethylpyrrolo[1,2-d][1,2,4]triazin-1(2H)-one (80 mg, 0.27 mmol) in DMF (1.9 mL) was treated with CuI (26 mg, 0.14 mmol), 2-bromopyridine (0.13 g, 78 μL, 0.82 mmol) and N 1 ,N 2-Dimethylethane-1,2-diamine (14 mg, 18 μL, 0.16 mmol) was added. The solution was purged with argon for 5 minutes, after which the microwave vial was capped and heated in a microwave at 110 °C for 1 hour and 30 minutes. Water (40 mL) was added, and the mixture was extracted with ethyl acetate (2 × 30 mL). The organic fraction was washed with water (2 × 30 mL) and saturated brine (30 mL). The combined organic layers were dried, filtered, concentrated under reduced pressure, and purified by flash column chromatography (Isolera, 4 g column, ethyl acetate:heptane, 50:50) to give the title compound (12 mg, 32 μmol, 12%).

[0146] SFC-MS: RT = 5.09 min; MS m / z [M+H] + = 372.3; 1 H-NMR (500 MHz, CDCl3) δ: 9.45 (s, 1H), 8.51 (ddd, J = 4.9, 1.9, 0.8 Hz, 1H), 8.03 (dt, J = 8.4, 1.0 Hz, 1H), 7.85 (ddd, J = 8.3, 7.4, 2.0 Hz, 1H), 7.28 (t, J = 7.8 Hz, 1H), 7.23 (ddd, J = 7.3, 4.9, 1.0 Hz, 1H), 6.63 (dt, J = 7.5, 1.3 Hz, 1H), 6.45 (ddd, J = 8.1, 2.4, 1.0 Hz, 1H), 6.33 (t, J = 2.0 Hz, 1H), 3.91 (t, J = 7.2 Hz, 4H), 2.60 (s, 3H), 2.45 - 2.35 (m, 2H), 2.32 (s, 3H).

[0147] Example 3: 6-Bromo-7-[3-(difluoromethoxy)phenyl]-8-methyl-2-pyrimidin-2-ylpyrrolo[1,2-d][1,2,4]triazin-1-one (Final Compound 1-23)

[0148] 7-[3-(Difluoromethoxy)phenyl]-8-methyl-2-pyrimidin-2-ylpyrrolo[1,2-d][1,2,4]triazin-1-one

[0149] According to Scheme 3, Step 1: To a solution of 7-(3-(difluoromethoxy)phenyl)-8-methylpyrrolo[1,2-d][1,2,4]triazin-1(2H)-one (59.07 mg, 182.5 μmol, prepared according to Scheme 1, Step 4) in 1,4-dioxane (1.3 mL) was added 2-bromopyrimidine (87.06 mg, 547.6 μmol), KPO (96.86 mg, 456.3 μmol), and 1,10-phenanthroline (19.74 mg, 109.5 μmol). The solution was purged with argon for 5 minutes, after which CuI (17.38 mg, 91.26 μmol) was added and the atmosphere was purged with argon for another 5 minutes. The microwave vial was capped and heated at 110 °C for 3 hours. The crude mixture was filtered through Celite®, washed with DCM, concentrated in vacuo, and purified by silica gel flash column chromatography (0% to 90% ethyl acetate in heptane solution). The product-containing fractions were concentrated in vacuo, and the resulting solid was recrystallized from methanol to give the title compound (18.95 mg, 51.31 μmol, 28.11%) as a white solid.

[0150] SFC-MS: RT = 3.08 min; MS m / z [M+H] + = 370.1.

[0151] 6-Bromo-7-[3-(difluoromethoxy)phenyl]-8-methyl-2-pyrimidin-2-ylpyrrolo[1,2-d][1,2,4]triazin-1-one

[0152] According to Scheme 3, Step 2: NBS (106 mg, 595 μmol) was added to a solution of 7-[3-(difluoromethoxy)phenyl]-8-methyl-2-pyrimidin-2-yl-pyrrolo[1,2-d][1,2,4]triazin-1-one (183 mg, 495 μmol) in THF (15 mL). The reaction was stirred at room temperature for 16 h, after which another portion of NBS (35 mg, 0.20 mmol) was added. The reaction was stirred for an additional 30 min, after which DCM (5 mL) was added. The mixture was then washed with 5% aqueous NaHCO3 solution (3 × 5 mL), and the combined organic phases were dried over Na2SO4 and filtered. The solvent was removed under reduced pressure to give the title compound (163 mg, 0.364 mmol, 73%, 75% purity) as a pale yellow solid. 30 mg of the resulting compound was purified by preparative HPLC, dissolved in chloroform, and washed once with saturated NaHCO3 solution. The solvent was evaporated under reduced pressure, and the residue was lyophilized in 1,4-dioxane to obtain the title compound.

[0153] SFC-MS: RT = 2.89min; MS m / z [M+H] + = 448.0; 1 H-(500 MHz, CDCl3) δ: 8.91 (d, J = 4.8 Hz, 2H), 8.20 (s, 1H), 7.49 (td, J = 7.8, 0.7 Hz, 1H), 7.36 (t, J = 4.8 Hz, 1H), 7.27 - 7.22 (m, 2H), 7.21 - 7.15 (m, 2H), 6.58 (t, J = 73.6 Hz, 1H), 2.56 (s, 3H).

[0154] The compounds in the following table were synthesized according to the same methods as in the previous Examples 1 to 3, as shown in the column labeled "Example Number." Compounds marked with an asterisk were exemplified in the Examples.

[0155] Table 1: Compounds prepared according to the examples. TIFF2025538049000024.tif3281 [Table 1] TIFF2025538049000026.tif244157TIFF2025538049000027.tif63154

[0156] Physicochemical Data LC-MS method: Liquid chromatography-mass spectrometry (LC-MS) was performed on an LC-MS system consisting of a Dionex UltiMate3000 pump, autosampler, column compartment, detector (Thermo Fisher Scientific, Dreieich, Germany) and ESI quadrupole MS (MSQ Plus or ISQ EC, Thermo Fisher Scientific, Dreieich, Germany).

[0157] Method 1: Reverse phase (C 18 ), full scan (positive and negative) 100-1000 m / z; eluent: HO + 0.1% formic acid (A) and MeCN + 0.1% formic acid (B): 0 min 5% B → 1 min 5% B → 6.8 min 100% B (linear gradient from 5% to 100% B within 5.8 min) → 8 min 100% B (1.2 min 100% B). The purity of the final compound was determined by LS-MS using the area percentage method of the UV trace recorded at a wavelength of 254 nm.

[0158] Method 2: Reverse phase (C 18 ) is Accucore TM C 18 The analysis was carried out using a cartridge (100 x 3 mm). Eluents were HO + 0.1% formic acid (A) and MeCN + 0.1% formic acid (B). Gradient conditions: B concentration was increased linearly from 0% to 95% within 10 min. Purity was determined by the area percentage method of the obtained PDA spectrum.

[0159] Liquid chromatography-mass spectrometry (LC-MS) was also performed using Thermo Finnigan LCQ Fleet and Accucore. TM C18 Shimadzu Preparative HPLC system (DGU-20AR) equipped with a cartridge (100x3mm) 3R The analysis was performed on an LC-MS system equipped with a degasser, two LC-20AD pumps, an SPD-20A PDA detector, and a CTO-20A column oven.

[0160] Method 3: Reverse phase (C 18 ); Eluent: HO + 0.1% formic acid (A) and MeCN + 0.1% formic acid (B). Gradient conditions used: linear gradient from 5% to 100% B concentration within 20 min. Purity was measured by the area percentage method of the obtained PDA spectrum.

[0161] SFC-MS method: Supercritical fluid chromatography-mass spectrometry (SFC-MS) was performed using a Waters Acquity UPC2 SFC system (convergence manager, sample manager, binary solvent manager, column manager, PDA detector, isocratic solvent manager, and QDa detector) and a Viridis HSS C column. 18 The analysis was performed on an SFC-MS system configured with an SB column or a Viridis BEH column.

[0162] Method 4: Reversed phase (SB-C 18 The gradient conditions used were: a linear gradient of 10–30% (90 / 9 / 1 MeOH / HO / formic acid) in CO (within 6 min). Purity was determined by the area percentage method of the PDA spectra obtained.

[0163] NMR 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 indicate apparent multiplicity and are designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), or br (broad). Coupling constants (J) are given in hertz (Hz).

[0164] Table 2: Physicochemical data. (RT is retention time (min); [MH] + is the protonated mass of the compound (free base); nd = undetermined). [Table 2] TIFF2025538049000029.tif219168TIFF2025538049000030.tif241169TIFF2025538049000031.tif172166

[0165] Pharmacology The compounds provided herein are negative allosteric modulators of mGlu7. As such, these compounds are expected to exert their effects at mGlu7 through their ability to block receptor function after binding to a site that is not the orthosteric glutamate recognition site.

[0166] Some of the compounds of formula (I) have been tested according to the following method.

[0167] Example A mGlu7 assay for HEK-expressed human mGlu7 Transfection and cell culture A cDNA encoding the human metabotropic glutamate receptor 7 (hmGlu7) (accession number NM_181874.2, NCBI Nucleotide Database Browser) was subcloned into an expression vector that also contained a hygromycin resistance gene. In parallel, a cDNA encoding a G protein that redirects activation signals into intracellular calcium flux was subcloned into another expression vector that also contained a puromycin resistance gene. HEK293 cells were transfected with both vectors using PolyFect reagent (Qiagen) according to the supplier's protocol, and antibiotic-resistant cells that stably integrated one or more copies of the plasmid were selected by hygromycin and puromycin treatment. Positive cell clones expressing hmGlu7 were identified in a functional assay measuring changes in calcium flux in response to glutamate and L-AP4 or known mGlu7 orthosteric antagonists.

[0168] HEK-293 cells expressing hmGlu7 were cultured in DMEM, fetal bovine serum (10%), Glutamax®, and 10% CO2. TM (2 mM), penicillin (100 units / mL), streptomycin (100 μg / mL), geneticin (100 μg / mL), hygromycin-B (40 μg / mL), and puromycin (1 μg / mL) in a medium containing 2 mM EDTA, at 37°C and 5% CO 2 , maintained in a humidified atmosphere.

[0169] Fluorescent cell-based Ca 2+ Recruitment assay

[0170] Human mGlu7 HEK-293 cells were analyzed by FLIPR 384Twenty-four hours before the fluorescent cell-based calcium mobilization assay using the Assay (Molecular Device, Sunnyvale, CA, USA), cells were plated in black-walled, clear-bottom, poly-L-ornithine-coated 384-well plates at a density of 25,000 cells / well in glutamine / glutamate-free DMEM medium containing fetal bovine serum (10%), penicillin (100 units / mL), streptomycin (100 μg / mL), and doxycyline (1 μg / mL) at 37°C and 5% CO . 2 , and plated in a humidified atmosphere.

[0171] On the day of the assay, the medium was aspirated, and cells were loaded with a 3 μM solution of Fluo4-AM (LuBioScience, Lucerne, Switzerland) in 0.03% pluronic acid. After 1 h at 37°C / 5% CO2, unincorporated dye was removed by washing the cell plates with assay buffer. All assays were performed in a pH 7.4 buffer containing 20 mM HEPES, 143 mM NaCl, 6 mM KCl, 1 mM MgSO4, 1 mM CaCl2, 0.125 mM sulfinpyrazone, and 0.1% glucose.

[0172] After 10 seconds of basal fluorescence recording, various concentrations of the compounds of the present invention were added to the cells. To detect the agonist activity of the compounds, the changes in the fluorescence level were first monitored for 180 seconds. Next, to measure the inhibitory activity of the compounds of the present invention, the cells were incubated at EC 80 The cells were stimulated with L-AP4 for an additional 110 seconds. 80 The L-AP4 concentration is that which gives 80% of the maximal glutamate response.

[0173] Concentration-response curves for L-AP4 or representative compounds of the present invention were generated using Prism GraphPad software (Graph Pad Inc, San Diego, USA). Curves were fitted to a four-parameter logistic equation to determine IC 50 Allows you to determine the value: (Y=Bottom+(Top-Bottom) / (1+10^((LogIC50 -X)*Hill Slope)) IC of the compounds of the present application 50 The value is less than 10 μM.

[0174] Table 3 below shows the average IC obtained from at least three independent experiments in which selected molecules were performed in duplicate. 50 represents.

[0175] Table 3: Activity data for selected compounds [Table 3]

[0176] The results shown in Table 3 demonstrate that the compounds described in this invention are negative allosteric modulators of the human mGlu7 receptor.

[0177] Example B Water-related zero maze: The procedure was performed as previously described (Ritov and Richter-Levin, 2014) with minor modifications. The apparatus consisted of a circular platform with two opposing enclosed quadrants (wall height: 35 cm) and two open quadrants (border height: 5 mm). The platform was held in a plastic tank filled with water up to 10 cm below the platform level (22 ± 2°C, 50 cm deep). The circular platform and the plastic tank thus constituted a unified arena. For testing, rats were first allowed to habituate to the room for 4 min and then placed in one of the open quadrants facing the enclosed part of the apparatus. The rats were allowed to explore the arena for 5 min. During this time, the rats' behavior was tracked, recorded, and analyzed using an EthoVision system (Noldus Information Technology, Wageningen, The Netherlands). Behavioral parameters analyzed included time spent in the open quadrants, distance traveled in the open quadrants, distance traveled in the enclosed quadrants, and freezing behavior. The effects of exposure to various stressors and compounds were assessed using these parameters. The pretreatment times and routes of administration of the various test compounds were defined based on their pharmacokinetic properties.

[0178] Example C Elevated plus maze: The elevated plus maze (EPM) test was performed using male Sprague-Dawley rats. The EPM was constructed of plastic and contained two open arms (50 cm x 10 cm) and two equally sized closed arms, with 40 cm-high walls and a height of 86 cm from the ground. Both arms were made of black Plexiglas. The average illuminance in the open arms was 187 lux, and the average illuminance in the closed arms was 100 lux. At the start of the experiment, rats were placed in a holding chamber directly adjacent to the experimental room and allowed to acclimate to the environment for 30 minutes. At the start of the test, rats were placed in the center of the maze, facing one of the open arms, and observed for 5 minutes. During this time, rat behavior was tracked, recorded, and analyzed using an EthoVision system (Noldus Information Technology, Wageningen, The Netherlands). Behavioral endpoints analyzed included time spent in the open arms, number of entries into the open arms, and distance traveled. The pretreatment time and administration route of the test compounds were defined based on their pharmacokinetic properties.

[0179] Example D Fear conditioning model of post-traumatic stress disorder in rats: The fear conditioning arena (30 cm x 20 cm x 25 cm, Med Associates) was made of Plexiglas and offered various contexts. The system was installed in a soundproof, ventilated box. The arena floor consisted of a grid floor (19 parallel 0.48 cm diameter stainless steel bars spaced 1.6 cm apart) on top of a stainless steel waste pan. All bars were wired to a shock generator and a scrambler. A speaker was attached to the wall of the chamber as a source of auditory stimuli. Fear conditioning was conducted over a 2-day period. On the first day (training), rats were placed in the training context (Context A). After a 120-second habituation period, they were subjected to five CS-US pairings. A CS tone (78 dB, 2 kHz, 5 ms rise / fall time) was presented for 30 seconds and terminated simultaneously with a brief US footshock (0.5 seconds, 0.66 mA). The interval between tones (from tone onset to the next tone onset) ranged from 60 seconds to 60 seconds. The conditioning chamber was cleaned with 70% ethanol between subjects. The time spent freezing during the presentation of the CS tone was scored (CS freezing). On the second day (test day), animals were placed in a new context (Context B) and, after a 60-second habituation period, were exposed to the CS (120 seconds). The time spent freezing was measured during both habituation and the CS. Test compounds were administered before or after the training and test phases. The pretreatment time and administration route of different test substances were adjusted based on their pharmacokinetic properties.

[0180] Example E Mouse model of noise-induced hearing loss (NIHL): The effects of test compounds on NIHL were evaluated in young adult male CBA / CaJ mice. Mice were exposed to octave-band noise (8-16 kHz) at a sound pressure level of 110 dB for 2 hours. Test compounds were administered before and / or after noise exposure. Hearing function was measured using auditory brain response (ABR) audiograms or distortion product of spontaneous acoustic emission (DPOAE) at 24 hours, 2 weeks, and 4 weeks after the acoustic trauma. The pretreatment time and administration route of the test compounds were adjusted based on their pharmacokinetic properties. Experimental groups were compared with the vehicle-treated group, e.g., through measurements of ABR thresholds and ABR threshold shifts.

[0181] Example F Colonic distension test for visceral pain in rats: This study used male Wistar Kyoto rats (250-300 g), which are stress-sensitive. Mice were fasted overnight (16 h) and anesthetized with isoflurane on the day of the study. A 6 cm latex balloon was inserted 1 cm from the anus into the colonic lumen. Mice were allowed to recover for 20 min before colonic distension began. The paradigm used was a stepwise distension procedure using a computer-driven electronic barostat, increasing from 0 mmHg to 80 mmHg over 8 min. The parameters measured were the threshold pressure (mmHg) that elicited visually identifiable visceral pain behavior and the total number of pain behaviors. Visceral pain behavior was defined as abdominal contraction and / or abdominal withdrawal reflex.

[0182] Test compounds were administered before colon distension. The pretreatment time and administration route of different test compounds were adjusted based on their pharmacokinetic properties.

[0183] Formulation example Representative formulations of the present invention are as follows: 1. Tablets Active ingredient 5-50mg Dicalcium phosphate 20mg Lactose 30mg Talcum 10mg Magnesium stearate 5mg Potato starch ad 200mg

[0184] In this embodiment, the active ingredient can be replaced with an equivalent amount of any of the compounds according to the invention, in particular with an equivalent amount of any of the exemplified compounds.

[0185] 2. Suspension An aqueous suspension is prepared for oral administration and contains 1 to 5 mg of active compound, 50 mg of sodium carboxymethylcellulose, 1 mg of sodium benzoate, 500 mg of sorbitol, and 1 mL of water per milliliter.

[0186] 3. Injections A parenteral composition is prepared by stirring 1.5% by weight of the active ingredient of the invention in 10% by volume of propylene glycol and water.

[0187] 4. Ointment Active ingredient: 5-1000mg Stearyl alcohol 3g 5g lanolin 15g white petroleum 100g water

[0188] In this embodiment, the active ingredient can be replaced in an equivalent amount with any of the compounds according to the invention, in particular with an equivalent amount with any of the exemplified compounds.

[0189] Reasonable variations are not to be considered as a departure from the scope of the invention.It will be obvious that the invention being described may be varied in many ways by those skilled in the art.

Claims

1. Formula (I): A compound of the formula: A pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, or an N-oxide form thereof, wherein: R 1 is hydrogen, -CH 3 and -CF 3 selected from the group R 2 and R 3 are each independently hydrogen, halogen, -(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) haloalkyl and -CF 3 selected from the group P represents a cycloalkyl, aryl, heteroaryl or heterocycle of the formula: wherein each cycloalkyl, heteroaryl or heterocycle is optionally substituted with m radicals 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 each independently selected from C, N, O, or S; 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 and Z 7 at least one of is N; Each (A) ｍ are independently hydrogen, halogen, -CN, -OH, -NO 2 , -CF 3 , -SH, -NH 2 The group consisting of -(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) haloalkyl, -(C 2 -C 6 ) alkynyl, -(C 2 -C 6 ) alkenyl, -(C 3 -C 7 ) cycloalkyl, -(C 1 -C 6 ) alkylene-(C 3 -C 7 ) cycloalkyl, -(C 3 -C 8 ) cycloalkenyl, -(C 1 -C 6 ) cyanoalkyl, -(C 1 -C 6 ) alkylene-heteroaryl, -(C 1 -C 6 ) alkylene-aryl, aryl, heteroaryl, -(C 1 -C 6 ) alkylene-heterocycle, heterocycle, -(C 0 -C 6 ) alkylene-OR 4 , -O-(C 2 -C 6 ) alkylene-OR 4 , -NR 4 (C 2 -C 6 ) alkylene-OR 5 , -(C 3 -C 6 ) alkynylene-OR 4 , -(C 3 -C 6 ) Alkynylene-NR 4 R 5 , -(C 3 -C 6 ) alkenylene-OR 4 , -(C 3 -C 6 ) Alkenylene-NR 4 R 5 , -(C 0 -C 6 ) Alkylene-SR 4 , -O-(C 2 -C 6 ) Alkylene-SR 4 , -NR 4 -(C 2 -C 6 ) Alkylene-SR 5 , -(C 0 -C 6 ) Alkylene-S(=O)-R 4 , -O-(C 1 -C 6 ) Alkylene-S(=O)-R 4 , -NR 4 -(C 1 -C 6 ) Alkylene-S(=O)-R 5 , -(C 0 -C 6 ) Alkylene-S(=O) 2 -R 4 , -O-(C 1 -C 6 ) Alkylene-S(=O) 2 -R 4 , -NR 4 -(C 1 -C 6 ) Alkylene-S(=O) 2 -R 5 , -(C 0 -C 6 ) Alkylene-NR 4 R 5 , -O-(C 2 -C 6 ) Alkylene-NR 4 R 5 , -NR 4 -(C 2 -C 6 ) Alkylene-NR 5 R 6 , -(C 0 -C 6 ) Alkylene-S(=O) 2 NR 4 R 5 , -O-(C 1 -C 6 ) Alkylene-S(=O) 2 NR 4 R 5 , -NR 4 -(C 1 -C 6 ) Alkylene-S(=O) 2 NR 5 R 6 , -(C 0 -C 6 ) Alkylene-NR 4 -S(=O) 2 R 5 , -O-(C 2 -C 6 ) Alkylene-NR 4 -S(=O) 2 R 5 , -NR 4 -(C 2 -C 6 ) Alkylene-NR 5 -S(=O) 2 R 6 , -(C 0 -C 6 )Alkylene-C(=O)-NR 4 R 5 , -O-(C 1 -C 6 )Alkylene-C(=O)-NR 4 R 5 , -NR 4 -(C 1 -C 6 )Alkylene-C(=O)-NR 5 R 6 , -(C 0 -C 6 ) Alkylene-NR 4 C(=O)-R 5 , -O-(C 2 -C 6 ) Alkylene-NR 4 C(=O)-R 5 , -NR 4 -(C 2 -C 6 ) Alkylene-NR 5 C(=O)-R 6 , -(C 0 -C 6 ) Alkylene-OC(=O)-R 4 , -O-(C 2 -C 6 ) Alkylene-OC(=O)-R 4 , -NR 4 -(C 2 -C 6 ) Alkylene-OC(=O)-R 5 , -(C 0 -C 6 ) Alkylene-C(=O)-OR 4 , -O-(C 1 -C 6 ) Alkylene-C(=O)-OR 4 , -(C 0 -C 6 ) alkylene-C(=O)-R 4 , -O-(C 1 -C 6 ) alkylene-C(=O)-R 4 , -NR 4 -(C 1 -C 6 ) alkylene-C(=O)-R 5 , -(C 0 -C 6 ) Alkylene-NR 4 -C(=O)-OR 5 , -C(=O)-(C 1 -C 6 ) Alkylene-NR 4 -C(=O)-OR 5 , -(C 0 -C 6 )Alkylene-OC(=O)-NR 4 R 5 , -(C 0 -C 6 ) Alkylene-NR 4 -C(=O)-NR 5 R 6 , -O-(C 2 -C 6 ) Alkylene-NR 4 -C(=O)-NR 5 R 6 , -NR 4 -(C 2 -C 6 ) Alkylene-NR 5 -C(=O)-NR 6 R 7 , -(C 0 -C 6 ) Alkylene-NR 4 -C(=S)-NR 5 R 6 , and -(C 0 -C 6 ) Alkylene-NR 4 -C(=NR 5 )-NR 6 R 7 an optionally substituted radical selected from the group consisting of: R 4 , R 5 , R 6 and R 7 are each independently hydrogen or -(C 1 -C 6 ) haloalkyl, -C 1 -C 6 ) alkyl, -(C 1 -C 6 ) cyanoalkyl, -(C 3 -C 7 ) cycloalkyl, -(C 1 -C 6 ) alkylene-(C 3 -C 7 ) cycloalkyl, heteroaryl, -(C 1 -C 6 ) alkylene-heteroaryl, aryl, -(C 1 -C 6 ) alkylene-heterocycle, heterocycle, -(C 1 -C 6 ) alkylene-aryl, -(C 0 -C 6 ) alkylene-O-(C 0 -C 6 ) alkyl, -(C 0 -C 6 ) alkylene-N-((C 0 -C 6 ) alkyl) 2 , and -C(=O)-O-(C 1 -C 6 ) alkyl, an optionally substituted radical selected from the group consisting of: Q represents an aryl or heteroaryl of the formula: wherein each aryl or heteroaryl ring is optionally substituted with n radicals B, where n is an integer equal to 0, 1, 2, 3, 4, or 5; and B 1 is radical B; Each (B) n is hydrogen, halogen, -CN, -OH, -NO 2 , -CF 3 , -SH, -NH 2 The group consisting of -(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) haloalkyl, -(C 2 -C 6 ) alkynyl, -(C 2 -C 6 ) alkenyl, -(C 3 -C 7 ) cycloalkyl, -(C 1 -C 6 ) alkylene-(C 3 -C 7 ) cycloalkyl, -(C 3 -C 8 ) cycloalkenyl, -(C 1 -C 6 ) cyanoalkyl, -(C 1 -C 6 ) alkylene-heteroaryl, -(C 1 -C 6 ) alkylene-aryl, aryl, heteroaryl, -(C 1 -C 6 ) alkylene-heterocycle, heterocycle, -(C 0 -C 6 ) alkylene-OR 8 , -O-(C 2 -C 6 ) alkylene-OR 8 , -NR 8 (C 2 -C 6 ) alkylene-OR 9 , -(C 3 -C 6 ) alkynylene-OR 8 , -(C 3 -C 6 ) Alkynylene-NR 8 R 9 , -(C 3 -C 6 ) alkenylene-OR 8 , -(C 3 -C 6 ) Alkenylene-NR 8 R 9 , -(C 0 -C 6 ) Alkylene-SR 8 , -O-(C 2 -C 6 ) Alkylene-SR 8 , -NR 8 -(C 2 -C 6 ) Alkylene-SR 9 , -(C 0 -C 6 ) Alkylene-S(=O)-R 8 , -O-(C 1 -C 6 ) Alkylene-S(=O)-R 8 , -NR 8 -(C 1 -C 6 ) Alkylene-S(=O)-R 9 , -(C 0 -C 6 ) Alkylene-S(=O) 2 -R 8 , -O-(C 1 -C 6 ) Alkylene-S(=O) 2 -R 8 , -NR 8 -(C 1 -C 6 ) Alkylene-S(=O) 2 -R 9 , -(C 0 -C 6 ) Alkylene-NR 8 R 9 , -O-(C 2 -C 6 ) Alkylene-NR 8 R 9 , -NR 8 -(C 2 -C 6 ) Alkylene-NR 9 R 10 , -(C 0 -C 6 ) Alkylene-S(=O) 2 NR 8 R 9 , -O-(C 1 -C 6 ) Alkylene-S(=O) 2 NR 8 R 9 , -NR 8 -(C 1 -C 6 ) Alkylene-S(=O) 2 NR 9 R 10 , -(C 0 -C 6 ) Alkylene-NR 8 -S(=O) 2 R 9 , -O-(C 2 -C 6 ) Alkylene-NR 8 -S(=O) 2 R 9 , -NR 8 -(C 2 -C 6 ) Alkylene-NR 9 -S(=O) 2 R 10 , -(C 0 -C 6 )Alkylene-C(=O)-NR 8 R 9 , -O-(C 1 -C 6 )Alkylene-C(=O)-NR 8 R 9 , -NR 8 -(C 1 -C 6 )Alkylene-C(=O)-NR 9 R 10 , -(C 0 -C 6 ) Alkylene-NR 8 C(=O)-R 9 , -O-(C 2 -C 6 ) Alkylene-NR 8 C(=O)-R 9 , -NR 8 -(C 2 -C 6 ) Alkylene-NR 9 C(=O)-R 10 , -(C 0 -C 6 ) Alkylene-OC(=O)-R 8 , -O-(C 2 -C 6 ) Alkylene-OC(=O)-R 8 , -NR 8 -(C 2 -C 6 ) Alkylene-OC(=O)-R 9 , -(C 0 -C 6 ) Alkylene-C(=O)-OR 8 , -O-(C 1 -C 6 ) Alkylene-C(=O)-OR 8 , -NR 8 -(C 1 -C 6 ) Alkylene-C(=O)-OR 9 , -(C 0 -C 6 ) alkylene-C(=O)-R 8 , -O-(C 1 -C 6 ) alkylene-C(=O)-R 8 , -NR 8 -(C 1 -C 6 ) alkylene-C(=O)-R 9 , -(C 0 -C 6 ) Alkylene-NR 8 -C(=O)-OR 9 , -(C 0 -C 6 )Alkylene-OC(=O)-NR 8 R 9 , -(C 0 -C 6 ) Alkylene-NR 8 -C(=O)-NR 9 R 10 , -O-(C 2 -C 6 ) Alkylene-NR 8 -C(=O)-NR 9 R 10 , -NR 8 -(C 2 -C 6 ) Alkylene-NR 9 -C(=O)-NR 10 R 11 , -(C 0 -C 6 ) Alkylene-NR 8 -C(=S)-NR 9 R 10 , and -(C 0 -C 6 ) Alkylene-NR 8 -C(=NR 9 )-NR 10 R 11 independently selected from optionally substituted radicals selected from the group consisting of: R 8 , R 9 , R 10 and R 11 are each independently hydrogen or -(C 1 -C 6 ) haloalkyl, -(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) cyanoalkyl, -(C 3 -C 7 ) cycloalkyl, -(C 1 -C 6 ) alkylene-(C 3 -C 7 ) cycloalkyl, heteroaryl, -(C 1 -C 6 ) alkylene-heteroaryl, aryl, -(C 1 -C 6 ) alkylene-heterocycle, heterocycle, -(C 1 -C 6 ) alkylene-aryl, -(C 0 -C 6 ) alkylene-O-(C 0 -C 6 ) alkyl, and -(C 0 -C 6 ) alkylene-N-((C 0 -C 6 ) alkyl) 2 is an optionally substituted radical selected from the group consisting of: wherein optionally, any two radicals A combine with intervening atoms to form a 3- to 10-membered bicyclic heterocycle, aryl ring, or heteroaryl ring, wherein each ring optionally contains halogen, —CN, nitro, —(C 1 -C 6 ) alkyl, -(C 3 -C 7 ) alkyl, -(C 0 -C 6 ) alkylene-O-(C 0 -C 6 ) alkyl and -(C 0 -C 6 ) alkylene-N-((C 0 -C 6 ) alkyl) 2 is further substituted with 1 to 5 radicals independently selected from the group consisting of: wherein optionally the substituent R 4 , R 5 , R 6 or R 7 two of which, combined with intervening atoms, form a 3- to 10-membered heterocyclic, aryl, or heteroaryl ring, wherein each ring optionally further comprises halogen, cyano, nitro, -(C 1 -C 6 ) alkyl, -(C 3 -C 7 ) alkyl, -(C 0 -C 6 ) alkylene-O-(C 0 -C 6 ) alkyl and -(C 0 -C 6 ) alkylene-N-((C 0 -C 6 ) alkyl) 2 substituted with 1 to 5 radicals independently selected from the group consisting of: where R 8 , R 9 , R 10 or R 11 optionally two substituents from, combined with said intervening atoms, form a 3- to 10-membered heterocyclic, aryl or heteroaryl ring, wherein each ring optionally contains one or more of halogen, cyano, nitro, -(C 1 -C 6 ) alkyl, -(C 3 -C 7 ) alkyl, -(C 0 -C 6 ) alkylene-O-(C 0 -C 6 ) alkyl and -(C 0 -C 6 ) alkylene-N-((C 0 -C 6 ) alkyl) 2 is further substituted with 1 to 5 radicals independently selected from the group consisting of: wherein optionally, any two radicals B combine with said intervening atoms to form a 3- to 10-membered bicyclic heterocycle, aryl ring, or heteroaryl ring, wherein each ring optionally contains ff halogen, —CN, nitro, —(C 1 -C 6 ) alkyl, -(C 3 -C 7 ) alkyl, -(C 0 -C 6 ) alkylene-O-(C 0 -C 6 ) alkyl and -(C 0 -C 6 ) alkylene-N-((C 0 -C 6 ) alkyl) 2 The compound is further substituted with 1 to 5 radicals independently selected from the group consisting of:

2. P represents a heteroaryl of the formula:

2. The compound of claim 1, having formula (I), wherein each radical is optionally substituted with m radicals A, and m is an integer equal to 0, 1, 2, 3, or 4.

3. Q: The compound of claim 1 having the formula (I).

4. Q represents an aryl or heteroaryl group of the formula:

2. The compound of claim 1 having formula (I), wherein each radical is optionally substituted with n radicals B, and n is an integer equal to 0, 1, 2, 3, 4, or 5.

5. (A) ｍ Cycloalkyl, heterocyclic, aryl and heteroaryl ring systems include azetidinyl, 2-azabicyclo[2.2.1]heptan-2-yl, 7-azabicyclo[2.2.1]heptan-7-yl, benzimidazolyl, benzisothiazolyl, benzisoxazolyl, benzofuryl, benzopyrazolyl, benzothiazolyl, benzothiophenyl, benzotriazolyl, benzoxazolyl, dihydrofuranyl, dihydrothienyl, dioxolanyl, 1,1-dioxothiomorpholinyl, furazanyl, furyl, imidazolidinyl, imidazolinyl Imidazolonyl, imidazolyl, imidazopyridazinyl, imidazopyridyl, indolyl, isoindolyl, isoquinolinyl, isothiazolinyl, isothiazolyl, isoxazolidinyl, isoxazolinyl, isoxazolyl, morpholinyl, naphthyl, naphthyridinyl, oxadiazolyl, oxazolidinyl, oxazolinyl, oxazolonyl, oxazolopyridazinyl, oxazolopyridyl, oxazolyl, oxetanyl, phenyl, piperazinonyl, piperazinyl, piperidinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridonyl, pyridyl, pyrimidyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, quinazolyl, quinolyl, quinoxalinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl tetrahydrotriazolopyridyl, tetrahydrotriazolopyrimidinyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolinyl, thiazolonyl, thiazolopyridazinyl, thiazolopyridyl, thiazolyl, thienyl, thiomorpholinyl thionaphthyl, thiopyranyl, triazolinyl, triazinyl, triazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, and each ring of said ring system is selected from the group consisting of 1 to 4 substituents R 4 , R 5 , R 6 or R 7 2. The compound of claim 1 having the formula (I), wherein:

6. (B) ｎ Cycloalkyl, heterocyclic, aryl and heteroaryl ring systems include azetidinyl, 2-azabicyclo[2.2.1]heptan-2-yl, 7-azabicyclo[2.2.1]heptan-7-yl, benzimidazolyl, benzisothiazolyl, benzisoxazolyl, benzofuryl, benzopyrazolyl, benzothiazolyl, benzothiophenyl, benzotriazolyl, benzoxazolyl, dihydrofuranyl, dihydrothienyl, dioxolanyl, 1,1-dioxothiomorpholinyl, furazanyl, furyl, imidazolidinyl, imidazolinyl Imidazolonyl, imidazolyl, imidazopyridazinyl, imidazopyridyl, indolyl, isoindolyl, isoquinolinyl, isothiazolinyl, isothiazolyl, isoxazolidinyl, isoxazolinyl, isoxazolyl, morpholinyl, naphthyl, naphthyridinyl, oxadiazolyl, oxazolidinyl, oxazolinyl, oxazolonyl, oxazolopyridazinyl, oxazolopyridyl, oxazolyl, oxetanyl, phenyl, piperazinonyl, piperazinyl, piperidinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridonyl, pyridyl, pyrimidyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, quinazolyl, quinolyl, quinoxalinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl tetrahydrotriazolopyridyl, tetrahydrotriazolopyrimidinyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolinyl, thiazolonyl, thiazolopyridazinyl, thiazolopyridyl, thiazolyl, thienyl, thiomorpholinyl thionaphthyl, thiopyranyl, triazolinyl, triazinyl, triazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, and each ring of said ring system is selected from the group consisting of 1 to 4 substituents R 8 , R 9 , R 10 or R 11 2. The compound of claim 1 having the formula (I), wherein:

7. R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 or R 11 Cycloalkyl, heterocyclic, aryl and heteroaryl ring systems include azetidinyl, benzimidazolyl, benzisothiazolyl, benzisoxazolyl, benzofuryl, benzopyrazolyl, benzothiazolyl, benzothiophenyl, benzotriazolyl, benzoxazolyl, dihydrofuranyl, dihydrothienyl, dioxolanyl, 1,1-dioxothiomorpholinyl, furazanyl, furyl, imidazolidinyl, imidazolinyl Imidazolonyl, imidazolyl, imidazopyridazinyl, imidazopyridyl, indolyl, isoindolyl, isoquinolinyl, isothiazolinyl, isothiazolyl, isoxazolidinyl, isoxazolinyl, isoxazolyl, morpholinyl, naphthyl, naphthyridinyl, oxadiazolyl, oxazolidinyl, oxazolinyl, oxazolonyl, oxazolopyridazinyl, oxazolopyridyl, oxazolyl, oxetanyl, phenyl, piperazinonyl, piperazinyl, piperidinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridonyl, pyridyl, pyrimidyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, quinazolyl, quinolyl, quinoxalinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl tetrahydrotriazolopyridyl, tetrahydrotriazolopyrimidinyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolinyl, thiazolonyl, thiazolopyridazinyl, thiazolopyridyl, thiazolyl, thienyl, thiomorpholinyl, thionaphthyl, thiopyranyl, triazolinyl, triazinyl, triazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, and each ring in said ring system is selected from the group consisting of hydrogen, halogen, —CN, nitro, —(C 1 -C 6 ) alkyl, -(C 0 -C 6 ) alkylene-O-(C 0 -C 6 ) alkyl and -(C 0 -C 6 ) alkylene-N-((C 0 -C 6 ) alkyl) 2 2. The compound of claim 1 having formula (I), optionally substituted with 1 to 5 radicals independently selected from:

8. R 1 The compound of claim 1 having the formula (I), wherein is hydrogen.

9. R 2 and R 3 9. The compound of claim 1, having formula (I), wherein:

10. Each of the above (A) ｍ represents hydrogen, halogen, -CN, -OH, -CF 3 and -(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) haloalkyl, -(C 3 -C 7 ) cycloalkyl, heterocycle, -(C 0 -C 6 ) Alkylene-OR 4 , -O-(C 2 -C 6 ) Alkylene-OR 4 , -NR 4 (C 2 -C 6 ) Alkylene-OR 5 , -(C 0 -C 6 ) Alkylene-NR 4 R 5 , -O-(C 2 -C 6 ) Alkylene-NR 4 R 5 , -NR 4 -(C 2 -C 6 ) Alkylene-NR 5 R 6 , -(C 0 -C 6 )Alkylene-C(=O)-NR 4 R 5 , -(C 0 -C 6 ) Alkylene-NR 4 C(=O)-R 5 , -(C 0 -C 6 ) Alkylene-C(=O)-OR 4 and -(C 0 -C 6 ) alkylene-C(=O)-R 4 2. The compound of claim 1 having formula (I), wherein:

11. R 4 , R 5 and R 6 are each independently hydrogen or -(C 1 -C 6 2. The compound of claim 1 having formula (I), wherein:

12. Each of the above (B) ｎ represents hydrogen, halogen, -CN, -CF 3 The group consisting of -(C 1 -C 6 ) alkyl, -(C 3 -C 7 ) cycloalkyl, aryl, heteroaryl, heterocycle, -(C 0 -C 6 ) Alkylene-OR 8 , -NR 8 (C 2 -C 6 ) Alkylene-OR 9 , -(C 0 -C 6 ) Alkylene-NR 8 R 9 , -(C 0 -C 6 ) Alkylene-C(=O)-OR 8 and -(C 0 -C 6 ) alkylene-C(=O)-R 8 2. The compound of claim 1 having formula (I), wherein:

13. R 8 and R 9 are each independently hydrogen, -(C 1 -C 6 ) haloalkyl, -(C 1 -C 6 ) alkyl, and -(C 3 -C 7 2. The compound of claim 1 having formula (I), wherein:

14. Formula (II): and a pharmaceutically acceptable acid 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.

15. Formula (III): and a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, or an N-oxide form thereof, wherein X is C or N.

16. Formula (IV): and 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 and Z 1 is C or N.

17. Formula (V): and a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof or an N-oxide form thereof.

18. Formula (VI): and a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof or an N-oxide form thereof.

19. R 2 is hydrogen, methyl or halogen; R 3 is methyl; Each of the above (A) m is hydrogen, halogen, -CF 3 and -(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) haloalkyl, -(C 3 -C 7 ) cycloalkyl, heterocycle, -(C 0 -C 6 ) Alkylene-OR 4 , -O-(C 2 -C 6 ) Alkylene-OR 4 , -(C 0 -C 6 ) Alkylene-NR 4 R 5 , -O-(C 2 -C 6 ) Alkylene-NR 4 R 5 , -NR 4 -(C 2 -C 6 ) Alkylene-NR 5 R 6 , -(C 0 -C 6 )Alkylene-C(=O)-NR 4 R 5 , -(C 0 -C 6 ) Alkylene-NR 4 C(=O)-R 5 , -(C 0 -C 6 ) Alkylene-C(=O)-OR 4 and -(C 0 -C 6 ) alkylene-C(=O)-R 4 independently selected from optionally substituted radicals selected from the group consisting of: R 4 , R 5 and R 6 are each independently hydrogen, -(C 1 -C 6 ) alkyl or -(C 1 -C 6 ) haloalkyl; Each of the above (B) n is the group consisting of hydrogen, halogens, and -(C 1 -C 6 ) alkyl, heterocycle, -(C 0 -C 6 ) alkylene-OR 8 , -NR 8 (C 2 -C 6 ) alkylene-OR 9 , -(C 0 -C 6 ) Alkylene-NR 8 R 9 , -(C 0 -C 6 ) alkylene-C(=O)-OR 8 and -(C 0 -C 6 ) alkylene-C(=O)-R 8 are independently selected from optionally substituted radicals selected from the group consisting of: R 8 and R 9 are each independently hydrogen, -(C 1 -C 6 ) alkyl, -(C 3 -C 7 ) cycloalkyl or -(C 1 -C 6 ) haloalkyl.

20. Formula (VII) or Formula (VIII): and 10. The compound of claim 1, in the form of a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof or an N-oxide form thereof.

21. Z 1 is selected from C or N; R 2 is hydrogen, methyl or halogen; R 3 is methyl; Each of the above (A) m is a group consisting of hydrogen, halogens, and -(C 1 -C 6 ) alkyl, heterocycle, -(C 0 -C 6 ) Alkylene-OR 4 , -(C 0 -C 6 ) Alkylene-NR 4 R 5 , -O-(C 2 -C 6 ) Alkylene-NR 4 R 5 , -NR 4 -(C 2 -C 6 )-Alkylene-NR 5 R 6 and -(C 0 -C 6 ) Alkylene-C(=O)-OR 4 independently selected from optionally substituted radicals selected from the group consisting of: R 4 , R 5 and R 6 are each independently hydrogen, -(C 1 -C 6 ) alkyl or -(C 1 -C 6 ) haloalkyl; Each of the above (B) n is the group consisting of hydrogen, halogen, and -(C 1 -C 6 ) alkyl, heterocycle and -(C 0 -C 6 ) Alkylene-OR 8 are independently selected from optionally substituted radicals selected from the group consisting of: R 8 is hydrogen, -(C 1 -C 6 ) alkyl, -(C 3 -C 7 ) cycloalkyl or -(C 1 -C 6 21. The compound of claim 20, wherein:

22. Each of the above (A) ｍ is hydrogen, halogen, and (C 0 -C 6 ) alkylene-OR 4 2. The compound of claim 1, independently selected from the group consisting of:

23. R 4 Ha-(C 1 -C 6 23. The compound of claim 22, wherein:

24. Each of the above (B) ｎ is hydrogen, halogen, heterocycle, -(C 0 -C 6 ) Alkylene-OR 8 , and -(C 1 -C 6 2. The compound of claim 1, wherein each of the aryl groups is independently selected from the group consisting of: aryl, aryl, aryl; ...

25. R 8 is -(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) haloalkyl, or -(C 3 -C 7 ) cycloalkyl.

26. Z 1 is selected from C or N, and R 2 is hydrogen, methyl or halogen, and R 3 is methyl, each (A)m is independently selected from the group consisting of hydrogen, fluorine, and —O-methyl, and / or each (B)n is hydrogen, fluorine, methyl, a heterocycle, —O-methyl, —O—(C 3 -C 7 ) cycloalkyl, and O-CHF 2 26. The compound of any one of claims 14, or 16-25, independently selected from the group consisting of:

27. 10. The compound of claim 1, wherein the compound can exist as optical isomers, and the compound is a racemic mixture or one or both of the individual optical isomers.

28. The compound is one or more selected from the following:

10. The compound of claim 1, in the form of a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof or an N-oxide form thereof.

29. 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 for treating or preventing a condition in a mammal, comprising administering to the mammal in need of such treatment or prevention an effective amount of a compound / composition described in any one of claims 1 to 29.

31. 31. The method of claim 30, wherein the treatment or prevention is affected or facilitated by the modulatory effect of 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, comprising administering to the mammal in need of such treatment or prevention an effective amount of a compound / composition described in any one of claims 1 to 29.

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

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

35. 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. 35. 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. 35. The method of claim 34, wherein the ear disease or disorder is one or more of an inner ear disorder, age-related hearing impairment (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, toxic hearing loss, central auditory processing disorder, or vestibular disorder.

38. 35. 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 pain, or cancer pain.

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

40. 39. 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. 34. A compound or composition according to any one of claims 1 to 29 for use in a method according to claim 32 or 33.

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

43. 34. Use of a compound according to any one of claims 1 to 29 in the manufacture of a medicament for the treatment or prevention of a disease according to claim 32 or 33.

Images