Fused heterocyclic derivatives as negative allosteric modulators of the MGLU7 receptor

Abstract

JPEG2024517500000289.jpg1435(I) The present invention relates to novel compounds of formula (I) in which 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 receptors. 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] JPEG2024517500000002.jpg1435 formula (I) The present invention relates to novel compounds of formula (I) in which 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 receptors. 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, perception, development of synaptic plasticity, motor control, respiration, and regulation of cardiovascular function. Moreover, glutamate is central to several different neurological and psychiatric disorders, in which an imbalance in glutamatergic neurotransmission is found.

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

[0004] In addition, glutamate activates metabotropic glutamate receptors (mGluRs), which have a regulatory 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 of the tripartite synapse formed by the junction of the axon terminal, dendritic spine, and astrocyte. mGluRs are seven-transmembrane domain-containing G protein-coupled receptors (GPCRs) and are involved in the regulation of calcium-sensing receptors, GABA receptors, and GABA receptor-binding proteins. B mGluRs belong to GPCR family 3 along with the 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, which results in activation of the G protein and subsequently of a wide variety of intracellular signaling pathways. The mGluR family is made up of eight members. They 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 their 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 both in normal CNS function and in a variety of psychiatric and neurological 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 G-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 not only shaping synaptic responses at glutamatergic synapses but also being a key regulator of inhibitory GABAergic transmission, with the ultimate goal of fine-tuning the overall excitability of the brain.

[0006] Previously, most of the available pharmacological tools targeting mGluRs were orthosteric ligands that are structural analogues 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 kind 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) has recently been reported as an allosteric antagonist of mGlu7, acting through a binding pocket localized 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 ear 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 CNS disorders (reviewed in: Pallazo et al. (2016) Curr. Neuropharmacol. 14(5): 504-513), including depression, schizophrenia, anxiety disorders, obsessive-compulsive disorder and related conditions, especially acute and chronic stress-related disorders (reviewed in: Peterlik et al. (2016) Curr. Neuropharmacol. 14(5): 514-539).

[0009] mGlu7 has been shown to be present 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;Kinzieet al.(1995)Neuroscience,69(1):167-176). Furthermore, studies using several behavioral models (light-dark box test, elevated plus maze, staircase test, forced swimming test, tail suspension test) have shown that mGlu7 knockout animals show anxiolytic and antidepressant phenotypes, but also show some impairment in amygdala-dependent behaviors (fear response and conditioned taste aversion) (Cryan et al. J. Neuroscience,17:2409-2417). Pharmacological agents aimed at modulating mGlu7 activity may therefore 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 showing that mGlu7 is a key 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 causes dysregulation of the HPA axis and increases BDNF protein levels in the hippocampus, implicating this receptor in stress-related psychiatric disorders such as anxiety, depression, post-traumatic 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 showed a marked reduction in fear-mediated freezing responses to electric footshock and a deficit in the ability to associate taste stimuli with a lassitude-inducing LiCl injection (conditioned taste aversion, CTA) (Masugi et al. (1999) J. Neurosc., 19(3):955-963). These mice also showed deficits in acquisition of conditioned responses and extinction learning 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 its rapid and prolonged mGlu7 receptor internalization consistent with functional antagonism, while its rare 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, improving our understanding of the functional role of mGlu7 in neuronal function. 6-(4-Methoxyphenyl)-5-methyl-3-pyridin-4-ylisoxazolo[4,5-c]pyridin-4(5H)-one (MMPIP) has been shown to exert anxiolytic and antidepressant-like properties and improve cognitive performance in rodent models when administered in vivo (Palazzo et al. (2015) Pain, 156(6):1060-1073). 7-Hydroxy-3-(4-iodophenoxy)-4H-chromen-4-one (XAP044) has been shown to exert antistress, antidepressant, and anxiolytic-like effects and to 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 in treating mood disorders related to anxiety, depression, and PTSD.

[0013] In addition, mGlu7 receptors have also been implicated in pathways affected during pain. mGlu7 is widely and highly expressed in both the peripheral and central nervous systems, suggesting its role in controlling pain behavior. The role of mGlu7 in pain was also recently demonstrated by direct injection of AMN082 into the central amygdala (CeA) or periaqueductal gray (PAG). Under normal conditions, activation of amygdala mGlu7 promoted pain responses, as shown by a decrease in the spinal nociceptive threshold and an increase in audible and ultrasonic vocalizations induced by brief compression of the knee (Palazzo et al. (2008) Neuropharmacol., 55(4):537-545). In a similar manner, activation of PAG mGlu7 decreased thermoreceptive thresholds 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). Taken together, these data suggest that activation of mGlu7 receptors exacerbates pain perception and mGlu7 inhibition attenuates it. Thus, it is suggested that 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 the mGlu7 receptor and age-related hearing impairment (ARHI), also known as presbycusis. They identified a highly significant and reproducible single nucleotide polymorphism (SNP) located in GRM7, the gene encoding the mGlu7 receptor (Van Laer et al. (2010) Eur. J. Hum. Genet., 18(6):685-693; Friedman et al. (2009) Hum. Mol. Genet., 18(4):785-796; Newman et al. (2012) Hear Res. 294:125-132; Luo et al. (2013) PLoS One, 8(10):e77153; Haider et al.(2017) Front. Aging Neurosci. 9:346; Matyas et al. (2019) Pathol. Oncol. Res. 25(4):1645-52; Chang et al. (2018) J. Int. Adv. Otol. 14(2):170-175). GRM7 variants have also been linked to noise-induced hearing loss reported by Lu et al. (BMC Med. Genet. (2018), 19(1):4) and tinnitus reported by Haider et al. (Front. Aging Neurosci. (2017), 9:346). Finally, mGlu7 expression, examined by immunohistochemistry, is located in neurons of the spiral ganglion, the inner and outer hair cells of the organ of Corti, and in hair cells of the vestibular apparatus formed by the saccule, utricle, and crista ampullaris (Friedman et al.(2008)WO2008131439). These data suggest that mGlu7 receptor modulators may be useful for experimental treatment of 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 being widely distributed throughout the CNS, mGlu7 shows 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), and is therefore inactive during normal transmission and can only be activated when glutamate is released in excess (Ferraguti F. and Shigemoto R. (2006) Cell Tissue Res., 326:483-504). Taken together, these data strongly highlight the potential of mGlu7 modulators in 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] Pyrrolopyridazinones have been shown to be useful as immunosuppressants by Bantick et al. in International Publication WO9929695. BA Stearns et al. in Bioorg. & Med. Chem. Let ((2004), 14, 1295-1298) describe 6-aryl-6H-pyrrolo[3,4-d]pyridazine derivatives that exhibit high affinity for the α2δ subunit of voltage-dependent calcium channels. 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. In the most general compound embodiment, the present invention provides compounds according to formula (I): JPEG2024517500000003.jpg1435 formula (I) A pharma- ceutically acceptable acid or base addition salt thereof, its stereochemically isomeric forms, or its N-oxide forms, wherein: R 1 is selected from the group (for example) hydrogen, -CH3 and -CF3; R 2 and R 3 are each independently selected from the group (for example) hydrogen, -(C1-C6)alkyl, -(C1-C6)haloalkyl, and -CF3; P represents a cycloalkyl, aryl or heteroaryl of the formula: JPEG2024517500000004.jpg3783 wherein each cycloalkyl, aryl or heteroaryl ring is optionally substituted with m radicals A, where m is an integer equal to 0, 1, 2, 3 or 4; Here, 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) mare independently selected from the group consisting of (e.g.) hydrogen, halogen, -CN, -OH, -NO2, -CF3, -SH, -NH2, and (e.g.) -(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)NR 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 , -NR 4 -(C1-C6)alkylene-C(=O)-OR 5 , -(C0-C6)alkylene-C(=O)-R4 , -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 7are 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; Q is aryl or heteroaryl optionally substituted with n radicals B, where n is an integer equal to 0, 1, 2, 3, 4 or 5; Each (B) n is selected from the group consisting of (for example) 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)NR 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)-R 8 , -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 the group consisting of optionally substituted radicals selected from the group consisting of: R 8 , R 9 , R 10 and R 11 are each independently (for example) hydrogen or -(C1-C6)haloalkyl, -C1-C6)alkyl, -(C1-C6)cyanoalkyl, -(C3-C7)cycloalkyl, -(C1-C6)alkylene-(C3-C7)cycloalkyl, heteroaryl, -(C1-C6)alkylene-heteroaryl, aryl, -(C1-C6)alkylene-heterocycle, heterocycle, -(C1-C6)alkylene-aryl, -(C0-C6)alkylene-O-(C0-C6)alkyl, -(C0-C6)alkylene-N-((C0-C6)aryl), where optionally any two radicals A, combined with the intervening atoms, form a 3-10 membered bicyclic heterocycle, aryl or heteroaryl ring, where each ring is optionally further substituted with 1-5 radicals independently selected from the group consisting of (e.g.) halogen, -CN, nitro, -(C1-C6)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 the intervening atoms, form a 3-10 membered heterocyclic, aryl or heteroaryl ring, wherein each ring is optionally further substituted with 1-5 radicals independently selected from the group consisting of (e.g.) halogen, cyano, nitro, -(C1-C6)alkyl, -(C0-C6)alkylene-O-(C0-C6)alkyl and -(C0-C6)alkylene-N-((C0-C6)alkyl); Here, R 8 , R 9 , R 10 or R 11optionally two substituents from, combined with the intervening atoms, form a 3-10 membered heterocyclic, aryl or heteroaryl ring, where each ring is optionally further substituted with 1-5 radicals independently selected from the group consisting of (e.g.) halogen, cyano, nitro, -(C1-C6)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 3-10 membered bicyclic heterocycle, aryl or heteroaryl ring, where each ring is optionally further substituted with 1-5 radicals independently selected from the group consisting of (e.g.) halogen, -CN, nitro, -(C1-C6)alkyl, -(C0-C6)alkylene-O-(C0-C6)alkyl and -(C0-C6)alkylene-N-((C0-C6)alkyl).

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

[0020] Preferably, Q represents an aryl or heteroaryl group of the formula: JPEG2024517500000005.jpg23107 wherein each radical is optionally substituted with n radicals B, n being an integer equal to 0, 1, 2, 3, 4 or 5. 1 may be a radical B as described above. For example, B 1 may be hydrogen, -(C1-C6)alkyl or -(C3-C7)cycloalkyl.

[0021] For example, Q may represent an aryl or heteroaryl group of the formula: JPEG2024517500000006.jpg1392 wherein each radical is optionally substituted with n radicals B, n being an integer equal to 0, 1, 2, 3, 4 or 5. 1 may be a radical B as described above. For example, B 1 may be hydrogen, -(C1-C6)alkyl or -(C3-C7)cycloalkyl.

[0022] For example, P may represent a cycloalkyl, aryl, or heteroaryl of the formula: JPEG2024517500000007.jpg2388 wherein each radical is optionally substituted with m radicals A, where m is an integer equal to 0, 1, 2, 3 or 4.

[0023] For example, P is optionally substituted with m radicals A. JPEG2024517500000008.jpg1321, where m is an integer equal to zero, 1, 2, 3, 4, or 5; and Q can be phenyl optionally substituted with n radicals B, where n is an integer equal to zero, 1, 2, 3, 4, or 5.

[0024] (A) mCycloalkyl, heterocyclic, aryl and heteroaryl ring systems include (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, piperazinyl, piperazinyl, piperidinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridonyl, pyridyl, pyrimidyl, pyrrolidinonyl, pyrrolidinyl, 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, each ring of said ring system being selected from the group consisting of: 4 , R 5 , R 6 or R 7 are independently and optionally substituted with

[0025] (B) nCycloalkyl, heterocyclic, aryl and heteroaryl ring systems include (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, piperazinyl, piperazinyl, piperidinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridonyl, pyridyl, pyrimidyl, pyrrolidinonyl, pyrrolidinyl, 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, each ring of said ring system being selected from the group consisting of: 8 , R 9 , R 10 or R 11 are independently and optionally substituted with

[0026] R 4 , R 5 , R 6 , R 7, R 8 , R 9 , R 10 or R 11Cycloalkyl, heterocyclic, aryl and heteroaryl ring systems include (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, piperazinyl, piperazinyl, piperidinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolopyridinyl pyrazolyl, pyridazinyl, pyridonyl, pyridyl, pyrimidyl, pyrrolidinonyl, pyrrolidinyl, pyrrolidinyl, pyrrolinyl, quinazolyl, quinolyl, quinoxalinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl and each ring in said ring system may be selected from the group consisting of 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, -(C1-C6)alkyl, -(C0-C6)alkylene-O-(C0-C6)alkyl, and -(C0-C6)alkylene-N-((C0-C6)alkyl).

[0027] For example, R 2 and R3 may each independently be selected from the group of (for example) hydrogen, methyl and ethyl, and may be, for example, methyl. For example, R 2 and R 3 may both be methyl.

[0028] Each (A) m is (for example) hydrogen, halogen, -CN, -OH, -CF3, and (for example) -(C1-C6) alkyl, -(C1-C6) haloalkyl, -(C3-C7) cycloalkyl, -(C1-C6) cyanoalkyl, aryl, heterocycle, -(C0-C6) alkylene-OR 4 , -O-(C2-C6)alkylene-OR 4 , -(C0-C6)alkylene-S(=O)2-R 4 , -(C0-C6)alkylene-NR 4 R 5 , -(C0-C6)alkylene-S(=O)2NR 4 R 5 , -(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 , -(C0-C6)alkylene-C(=O)-R 4 and -C(=O)-(C1-C6)alkylene-NR 4 -C(=O)-OR 5 The optionally substituted radicals may be optionally substituted with halogen, -(C1-C6)alkyl, OH, or CN.

[0029] R 4 and R 5 may each independently be hydrogen or -(C1-C6)alkyl.

[0030] Each (B) nis selected from the group consisting of (for example) 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 optionally substituted radicals may be optionally substituted with halogen or -(C1-C6)alkyl. Optionally, two -(C0-C6)alkylene-OR 8 The radicals may combine with intervening atoms to form a 9-membered bicyclic heterocycle, for example, cyclic diethyl.

[0031] R 8 and R 9 may each independently be selected from the group consisting of (for example) hydrogen, -(C1-C6)haloalkyl, -(C1-C6)alkyl, -(C3-C7)cycloalkyl, and aryl.

[0032] For example, R 2 and R 3 may each independently be selected from the group consisting of (for example) methyl and ethyl. For example, R 2 and R 3 may both be methyl.

[0033] Each (A) m is selected from the group consisting of (for example) hydrogen, halogen, -CN, -OH, -CF3, and (for example) -(C1-C6) alkyl, -(C1-C6) haloalkyl, -(C3-C7) cycloalkyl, -(C1-C6) cyanoalkyl, aryl, heterocycle, -(C0-C6) alkylene-OR 4 , -O-(C2-C6)alkylene-OR 4, -(C0-C6)alkylene-S(=O)2-R 4 , -(C0-C6)alkylene-NR 4 R 5 , -(C0-C6)alkylene-S(=O)2NR 4 R 5 , -(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 , -(C0-C6)alkylene-C(=O)-R 4 and -C(=O)-(C1-C6)alkylene-NR 4 -C(=O)-OR 5 Each of the radicals may be independently selected from an optionally substituted radical selected from the group consisting of:

[0034] R 4 and R 5 may each independently be hydrogen or -(C1-C6)alkyl.

[0035] Each (B) n may be independently selected from the group consisting of optionally substituted radicals selected from the group consisting of (e.g.) hydrogen, halogen, and (e.g.) -(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 is an optionally substituted radical selected from the group consisting of:

[0036] R 8 and R 9 may each independently be hydrogen or -(C1-C6)alkyl.

[0037] For example, R 2 and R 3 may each independently be selected from the group consisting of (for example) hydrogen, methyl and ethyl. For example, R 2 and R 3 may both be methyl.

[0038] Each (A) m is selected from the group consisting of (for example) hydrogen, halogen, -CN, -OH, -CF3, and (for example) -(C1-C6) alkyl, -(C3-C7) cycloalkyl, heterocycle, and -(C0-C6) alkylene-OR 4 and optionally substituted radicals selected from the group consisting of:

[0039] R 4 may be selected from hydrogen or -(C1-C6)alkyl.

[0040] Each (B) n is selected from the group consisting of (for example) hydrogen, halogen, -CN, -CF3, and (for example) -(C1-C6) alkyl, -(C3-C7) cycloalkyl, aryl, heteroaryl, heterocycle, -(C0-C6) alkylene-OR 8 , -(C0-C6)alkylene-NR 8 R 9 , -(C0-C6)alkylene-C(=O)-OR 8 and -(C0-C6)alkylene-C(=O)-R 8 and optionally substituted radicals selected from the group consisting of:

[0041] R 8 and R 9 may each be independently selected from the group consisting of (for example) hydrogen, -(C1-C6)haloalkyl, -(C1-C6)alkyl, -(C3-C7)cycloalkyl and aryl, e.g., -(C1-C6)haloalkyl may be -CF3. For example, (C3-C7)cycloalkyl may be -(C3)cycloalkyl.

[0042] For example, A can be hydrogen, halogen, or -(C1-C6)alkyl-OH, and m can be 1. For example, B can be -(C1-C6)alkyl, -(C3-C7)cycloalkyl, a heterocycle, -O-(C3-C7)cycloalkyl, or -O-(C1-C6)alkyl, and n can be 1 or 2. For example, a heterocycle is It could also be JPEG2024517500000009.jpg68.

[0043] Preferably, the compound of formula (I) is a compound of formula (II): JPEG2024517500000010.jpg1335 formula (II) a pharma- ceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof or an N-oxide form thereof, wherein: (A) m , P, R 2 , R 3 and (B) n is as defined in any of the above descriptions.

[0044] The compound of formula (I) may be a compound according to formula (IIa). JPEG2024517500000011.jpg1636 formula (IIa) A pharma- ceutically acceptable acid or base addition salt thereof, its stereochemically isomeric forms or its N-oxide forms, wherein: Z 1 , Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C or N, and (A) m , R 1 , R 2 , R 3 , Q and (B) n is as defined in any of the above descriptions.

[0045] Preferably, the compound of formula (II) is according to formula (III): JPEG2024517500000012.jpg1536 formula (III) A pharma- ceutically acceptable acid or base addition salt thereof, its stereochemically isomeric forms or its N-oxide forms, wherein: Z 1 , Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C or N, and (A) m , R 2 , R 3 and (B) n is as defined in any of the above descriptions.

[0046] Preferably, the compound of formula (III) is a compound according to formula (IV): JPEG2024517500000013.jpg1436 formula (IV) A pharma- ceutically acceptable acid or base addition salt thereof, its stereochemically isomeric forms or its N-oxide forms, comprising: (A) m , R 2 , R 3 and (B) n is as defined in any of the above descriptions.

[0047] Preferably, R 2 and R 3 is independently selected from the group consisting of (for example) methyl and ethyl; Each (A) m is selected from the group consisting of (for example) hydrogen, halogen, -CN, -OH, -CF3, and (for example) -(C1-C6) alkyl, -(C1-C6) haloalkyl, -(C3-C7) cycloalkyl, -(C1-C6) cyanoalkyl, aryl, heterocycle, -(C0-C6) alkylene-OR 4 , -O-(C2-C6)alkylene-OR 4 , -(C0-C6)alkylene-S(=O)2-R 4 , -(C0-C6)alkylene-NR 4 R 5 , -(C0-C6)alkylene-S(=O)2NR4 R 5 , -(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 , -(C0-C6)alkylene-C(=O)-R 4 and -C(=O)-(C1-C6)alkylene-NR 4 -C(=O)-OR 5 independently selected from the group consisting of optionally substituted radicals selected from the group consisting of: R 4 and R 5 are each independently hydrogen or -(C1-C6)alkyl; Each (B) n is selected from the group consisting of (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 9 are each independently hydrogen or -(C1-C6)alkyl. Preferably, R 2 and R 3 One or both may be methyl.

[0048] Preferably, the compound of formula (III) is a compound of formula (V): JPEG2024517500000014.jpg1436 formula (V) A pharma- ceutically acceptable acid or base addition salt thereof, its stereochemically isomeric forms or its N-oxide forms, wherein: Z 1 is selected from C or N; R 2 and R 3 is independently selected from the group consisting of (for example) hydrogen, methyl and ethyl; Each (A) m is selected from the group consisting of (for example) hydrogen, halogen, -CN, -OH, -CF3, and (for example) -(C1-C6) alkyl, -(C3-C7) cycloalkyl, heterocycle, and -(C0-C6) alkylene-OR 4 independently selected from optionally substituted radicals selected from the group consisting of: R 4 is selected from hydrogen or -(C1-C6)alkyl; Each (B) n is selected from the group consisting of (for example) hydrogen, halogen, -CN, -CF3, and (for example) -(C1-C6) alkyl, -(C3-C7) cycloalkyl, aryl, heteroaryl, heterocycle, -(C0-C6) alkylene-OR 8 , -(C0-C6)alkylene-NR 8 R 9 , -(C0-C6)alkylene-C(=O)-OR 8 and -(C0-C6)alkylene-C(=O)-R 8 an optionally substituted radical selected from the group consisting of: R 8 and R 9 are each independently selected from the group consisting of (for example) hydrogen, -(C1-C6)haloalkyl, -(C1-C6)alkyl, -(C3-C7)cycloalkyl, and aryl.

[0049] Preferably, in the compound defined by formula (V), R 2 and R 3 One or both can be methyl.

[0050] For example, A can be hydrogen, halogen, or -(C1-C6)alkyl-OH, and m can be 1. For example, B can be -(C1-C6)alkyl, -(C3-C7)cycloalkyl, a heterocycle, -O-(C3-C7)cycloalkyl, or -O-(C1-C6)alkyl, and n can be 1 or 2. For example, a heterocycle is It could also be JPEG2024517500000015.jpg68.

[0051] Particularly preferred compounds of the present invention are those listed below, as well as their pharma- ceutically acceptable acid or base addition salts, their stereochemically isomeric forms or their N-oxide forms: 5,7-Dimethyl-2-phenyl-6-(p-tolyl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 2-(2-Methoxyphenyl)-5,7-dimethyl-6-(p-tolyl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(4-chlorophenyl)-5,7-dimethyl-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 5,7-Dimethyl-2,6-diphenyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 2-(2-Methoxyphenyl)-5,7-dimethyl-6-phenyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 5,7-Dimethyl-2-phenyl-6-(m-tolyl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 5,7-Dimethyl-2-phenyl-6-(o-tolyl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(4-chlorophenyl)-5,7-dimethyl-2-phenyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 5,7-Dimethyl-6-phenyl-2-(pyridin-3-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 2-(3-Fluorophenyl)-5,7-dimethyl-6-phenyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 2-(4-Fluorophenyl)-5,7-dimethyl-6-phenyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 2-(3-Methoxyphenyl)-5,7-dimethyl-6-phenyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 2-(4-Methoxyphenyl)-5,7-dimethyl-6-phenyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 5,7-Dimethyl-6-phenyl-2-(m-tolyl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 5,7-Dimethyl-6-phenyl-2-(p-tolyl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 3-(5,7-Dimethyl-1-oxo-6-phenyl-1H-pyrrolo[3,4-d]pyridazin-2(6H)-yl)benzonitrile 4-(5,7-Dimethyl-1-oxo-6-phenyl-1H-pyrrolo[3,4-d]pyridazin-2(6H)-yl)benzonitrile 6-(2-Methoxyphenyl)-5,7-dimethyl-2-phenyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(2-chlorophenyl)-5,7-dimethyl-2-phenyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 2-(2-chlorophenyl)-5,7-dimethyl-6-phenyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 2-(2-Fluorophenyl)-5,7-dimethyl-6-phenyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 5,7-Dimethyl-6-phenyl-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(4-(dimethylamino)phenyl)-5,7-dimethyl-2-phenyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(4-Methoxyphenyl)-5,7-dimethyl-2-phenyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 5,7-Dimethyl-2-phenyl-6-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-Methoxyphenyl)-5,7-dimethyl-2-phenyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 2-(4-Acetylphenyl)-5,7-dimethyl-6-phenyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 4-(5,7-Dimethyl-1-oxo-6-phenyl-1H-pyrrolo[3,4-d]pyridazin-2(6H)-yl)benzenesulfonamide 6-(2-Fluorophenyl)-5,7-dimethyl-2-phenyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 5,7-Dimethyl-2-(4-(methylsulfonyl)phenyl)-6-phenyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(4-Acetylphenyl)-5,7-dimethyl-2-phenyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(2,4-dimethylphenyl)-5,7-dimethyl-2-phenyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 5,7-Dimethyl-6-(3-morpholinophenyl)-2-phenyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-Bromophenyl)-5,7-dimethyl-2-phenyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-(dimethylamino)phenyl)-5,7-dimethyl-2-phenyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-Acetylphenyl)-5,7-dimethyl-2-phenyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 5,7-Dimethyl-6-phenyl-2-(pyridin-4-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 2-(4-(methoxymethyl)phenyl)-5,7-dimethyl-6-phenyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 5,7-Dimethyl-2-(pyridin-3-yl)-6-(p-tolyl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 5,7-Dimethyl-2-(pyridin-3-yl)-6-(m-tolyl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-Methoxyphenyl)-5,7-dimethyl-2-(pyridin-3-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(4-((2-methoxyethyl)amino)phenyl)-5,7-dimethyl-2-phenyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-((2-methoxyethyl)amino)phenyl)-5,7-dimethyl-2-phenyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-Methoxyphenyl)-5,7-dimethyl-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 5,7-Dimethyl-2-(pyridin-2-yl)-6-(m-tolyl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(4-Methoxyphenyl)-5,7-dimethyl-2-(pyridin-3-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(4-Methoxyphenyl)-5,7-dimethyl-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 5,7-Dimethyl-2-(pyridin-2-yl)-6-(p-tolyl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 5,7-Dimethyl-6-(3-(2-oxopyrrolidin-1-yl)phenyl)-2-phenyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 5,7-Dimethyl-2-(6-methylpyridin-3-yl)-6-phenyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-hydroxyphenyl)-5,7-dimethyl-2-phenyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 2-(6-Methoxypyridin-3-yl)-5,7-dimethyl-6-phenyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 5,7-Dimethyl-2-(pyridin-2-yl)-6-(3-(trifluoromethyl)phenyl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 3-(5,7-Dimethyl-1-oxo-2-(pyridin-2-yl)-1H-pyrrolo[3,4-d]pyridazin-6(2H)-yl)benzonitrile 6-(benzo[d][1,3]dioxol-5-yl)-5,7-dimethyl-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 5,7-Dimethyl-6-(5-methylpyridin-2-yl)-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 4-(5,7-Dimethyl-1-oxo-6-phenyl-1H-pyrrolo[3,4-d]pyridazin-2(6H)-yl)benzamide 5,7-Dimethyl-6-phenyl-2-(pyrimidin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 5,7-Dimethyl-2-(pyridin-2-yl)-6-(3-(pyrrolidin-1-yl)phenyl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 2-(4-ethoxyphenyl)-5,7-dimethyl-6-phenyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-Methoxyphenyl)-5,7-dimethyl-2-(quinolin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(2-Methoxypyridin-4-yl)-5,7-dimethyl-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-Methoxyphenyl)-4,5,7-trimethyl-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 5,7-Dimethyl-6-(3-morpholinophenyl)-2-(pyridin-3-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one N-(4-(6-(3-methoxyphenyl)-5,7-dimethyl-1-oxo-1H-pyrrolo[3,4-d]pyridazin-2(6H)-yl)benzyl)acetamide 2-(4-(hydroxymethyl)phenyl)-6-(3-methoxyphenyl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 2-(4-Methoxyphenyl)-5,7-dimethyl-6-(3-morpholinophenyl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 4-(5,7-Dimethyl-6-(3-morpholinophenyl)-1-oxo-1H-pyrrolo[3,4-d]pyridazin-2(6H)-yl)benzenesulfonamide 2-(4-(methoxymethyl)phenyl)-5,7-dimethyl-6-(3-morpholinophenyl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-Methoxyphenyl)-5,7-dimethyl-2-(4-morpholinophenyl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 2-([1,1'-biphenyl]-4-yl)-6-(3-methoxyphenyl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(4-chloro-3-methoxyphenyl)-5,7-dimethyl-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 3-(6-(3-methoxyphenyl)-5,7-dimethyl-1-oxo-1H-pyrrolo[3,4-d]pyridazin-2(6H)-yl)benzamide 6-(3-Methoxyphenyl)-2-(6-methoxypyridin-2-yl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 4-(6-(3-Methoxyphenyl)-5,7-dimethyl-1-oxo-1H-pyrrolo[3,4-d]pyridazin-2(6H)-yl)-N,N-dimethylbenzamide 6-([1,1'-biphenyl]-3-yl)-5,7-dimethyl-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazine-1-1 6-(3-ethoxyphenyl)-5,7-dimethyl-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 7-Ethyl-6-(3-methoxyphenyl)-5-methyl-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-Methoxy-4-methylphenyl)-5,7-dimethyl-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(1H-indol-6-yl)-5,7-dimethyl-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 2-(4-Methoxyphenyl)-5,7-dimethyl-6-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 5,7-Dimethyl-6-(pyridin-2-yl)-2-m-tolyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-Methoxyphenyl)-2-(5-methoxypyridin-2-yl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 5,7-Dimethyl-6-(3-morpholinophenyl)-2-(m-tolyl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-ethylphenyl)-5,7-dimethyl-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(4-ethylphenyl)-5,7-dimethyl-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 4-(5,7-Dimethyl-1-oxo-6-phenyl-1H-pyrrolo[3,4-d]pyridazin-2(6H)-yl)-N,N-dimethyl benzenesulfonamide 2-(4-(aminomethyl)phenyl)-6-(3-methoxyphenyl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 7-Ethyl-6-(3-methoxyphenyl)-5-methyl-2-phenyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 5,7-Dimethyl-6-(3-morpholinophenyl)-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-Methoxyphenyl)-5,7-dimethyl-2-(6-morpholinopyridin-3-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 2-(4-(hydroxymethyl)phenyl)-5,7-dimethyl-6-phenyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 5,7-Dimethyl-2-(4-morpholinophenyl)-6-phenyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-Methoxyphenyl)-2-(5-methoxypyridin-3-yl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-Methoxyphenyl)-5,7-dimethyl-2-(pyrimidin-5-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 5,7-Dimethyl-6-(1-methyl-1H-indol-6-yl)-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-Methoxyphenyl)-2-(4-methoxyphenyl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 2-(4-(hydroxymethyl)phenyl)-6-(4-methoxyphenyl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 5,7-Dimethyl-2-(m-tolyl)-6-(p-tolyl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-(diethylamino)phenyl)-5,7-dimethyl-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 5,7-Dimethyl-2-phenyl-6-(3-(pyrrolidin-1-yl)phenyl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-(azetidin-1-yl)phenyl)-5,7-dimethyl-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 2,6-Bis(4-methoxyphenyl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one N-(4-(5,7-dimethyl-1-oxo-6-phenyl-1H-pyrrolo[3,4-d]pyridazin-2(6H)-yl)benzyl)acetamide 2-Methoxy-4-(6-(3-methoxyphenyl)-5,7-dimethyl-1-oxo-1H-pyrrolo[3,4-d]pyridazin-2(6H)-yl)benzoic acid methyl ester N-(4-(6-(4-methoxyphenyl)-5,7-dimethyl-1-oxo-1H-pyrrolo[3,4-d]pyridazin-2(6H)-yl)benzyl)acetamide 6-(3-(methoxymethyl)phenyl)-5,7-dimethyl-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-(methoxymethyl)phenyl)-5,7-dimethyl-2-phenyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-Methoxyphenyl)-5,7-dimethyl-2-(4-((methylamino)methyl)phenyl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-(dimethylamino)phenyl)-5,7-dimethyl-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 5,7-Dimethyl-6-(3-(2-oxopyrrolidin-1-yl)phenyl)-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 3-(6-(3-methoxyphenyl)-5,7-dimethyl-1-oxo-1H-pyrrolo[3,4-d]pyridazin-2(6H)-yl)-N,N-dimethylbenzamide 4-(6-(3-Methoxyphenyl)-5,7-dimethyl-1-oxo-1H-pyrrolo[3,4-d]pyridazin-2(6H)-yl)-N-methylbenzamide 2-(3-(hydroxymethyl)phenyl)-6-(3-methoxyphenyl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one N-(3-(6-(3-methoxyphenyl)-5,7-dimethyl-1-oxo-1H-pyrrolo[3,4-d]pyridazin-2(6H)-yl)benzyl)acetamide 2-(3-(methoxymethyl)phenyl)-6-(3-methoxyphenyl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 2-(3,4-dimethoxyphenyl)-6-(3-methoxyphenyl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 2-(4-(3-hydroxypropyl)phenyl)-6-(3-methoxyphenyl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-Methoxyphenyl)-5,7-dimethyl-2-(4-(methylsulfonyl)phenyl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 4-(6-(3-Methoxyphenyl)-5,7-dimethyl-1-oxo-1H-pyrrolo[3,4-d]pyridazin-2(6H)-yl)benzenesulfonamide 6-(3-Methoxyphenyl)-2-(2-methoxypyridin-4-yl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-Methoxyphenyl)-5,7-dimethyl-2-(5-(trifluoromethyl)pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-Methoxyphenyl)-2-(4-methoxypyridin-2-yl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 3-(6-(3-methoxyphenyl)-5,7-dimethyl-1-oxo-1H-pyrrolo[3,4-d]pyridazin-2(6H)-yl)benzonitrile 3-(6-(4-Methoxyphenyl)-5,7-dimethyl-1-oxo-1H-pyrrolo[3,4-d]pyridazin-2(6H)-yl)benzonitrile 4-(6-(3-Methoxyphenyl)-5,7-dimethyl-1-oxo-1H-pyrrolo[3,4-d]pyridazin-2(6H)-yl)benzonitrile 6-(3-Methoxyphenyl)-2-(6-methoxypyridin-3-yl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 2-(4-(methoxymethyl)phenyl)-6-(3-methoxyphenyl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 2-(2-Hydroxypyridin-4-yl)-6-(3-methoxyphenyl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 2,6-Bis(3-methoxyphenyl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 2-(6-hydroxypyridin-3-yl)-6-(3-methoxyphenyl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(4-Acetylphenyl)-5,7-dimethyl-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one Ethyl 3-(5,7-dimethyl-1-oxo-2-(pyridin-2-yl)-1H-pyrrolo[3,4-d]pyridazin-6(2H)-yl)benzoate Ethyl 3-(5,7-dimethyl-1-oxo-2-phenyl-1H-pyrrolo[3,4-d]pyridazin-6(2H)-yl)benzoate 2-(4-(2-hydroxypropan-2-yl)phenyl)-6-(3-methoxyphenyl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazine-1 -1 6-(3-(furan-2-yl)phenyl)-5,7-dimethyl-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-cyclopropylphenyl)-5,7-dimethyl-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 2-(4-(1-hydroxyethyl)phenyl)-6-(3-methoxyphenyl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-isopropoxyphenyl)-5,7-dimethyl-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 5-Ethyl-6-(3-methoxyphenyl)-7-methyl-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-(azetidin-1-yl)phenyl)-5,7-dimethyl-2-phenyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-(1H-pyrrol-1-yl)phenyl)-5,7-dimethyl-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 5,7-Dimethyl-6-(3-(piperidin-1-yl)phenyl)-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 2-(3-ethoxyphenyl)-6-(3-methoxyphenyl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 2-(4-hydroxyphenyl)-6-(3-methoxyphenyl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 2-(3-(6-(3-methoxyphenyl)-5,7-dimethyl-1-oxo-1H-pyrrolo[3,4-d]pyridazin-2(6H)-yl)phenyl)acetonitrile 2-(3-Acetylphenyl)-6-(3-methoxyphenyl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 2-(2-Methoxyphenyl)-6-(3-methoxyphenyl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 2-(2-fluorophenyl)-6-(3-methoxyphenyl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 2-(2-chlorophenyl)-6-(3-methoxyphenyl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-(azetidin-1-yl)phenyl)-5,7-dimethyl-2-(3-(methylsulfonyl)phenyl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 3-(6-(3-(azetidin-1-yl)phenyl)-5,7-dimethyl-1-oxo-1H-pyrrolo[3,4-d]pyridazin-2(6H)-yl)benzamide 6-(3-(3,3-difluoroazetidin-1-yl)phenyl)-5,7-dimethyl-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-(azetidin-1-yl)phenyl)-5,7-dimethyl-2-(6-methylpyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-(azetidin-1-yl)phenyl)-5,7-dimethyl-2-(5-methylpyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-(azetidin-1-yl)phenyl)-5,7-dimethyl-2-(pyridin-4-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-(azetidin-1-yl)phenyl)-5,7-dimethyl-2-(6-methylpyridin-3-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-(azetidin-1-yl)phenyl)-5,7-dimethyl-2-(5-methylpyridin-3-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-(azetidin-1-yl)phenyl)-5,7-dimethyl-2-(3-methylpyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(6-(3-(azetidin-1-yl)phenyl)-5,7-dimethyl-1-oxo-1H-pyrrolo[3,4-d]pyridazin-2(6H)-yl)nicotinonitrile 6-(3-(azetidin-1-yl)phenyl)-5,7-dimethyl-2-(4-methylpyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-(azetidin-1-yl)phenyl)-2-(4-(2-methoxyethoxy)phenyl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-(azetidin-1-yl)phenyl)-2-(3-(hydroxymethyl)-4-methoxyphenyl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-(azetidin-1-yl)phenyl)-5,7-dimethyl-2-(pyridin-3-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-(azetidin-1-yl)phenyl)-2-(2,6-dimethylpyridin-4-yl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-(azetidin-1-yl)phenyl)-2-(4-(hydroxymethyl)-3-methoxyphenyl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-(azetidin-1-yl)phenyl)-5,7-dimethyl-2-(3-morpholinophenyl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-(azetidin-1-yl)phenyl)-5,7-dimethyl-2-(4-(pyrrolidin-1-yl)phenyl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-(azetidin-1-yl)phenyl)-2-(4-(2-hydroxyethyl)phenyl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-(azetidin-1-yl)phenyl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 2-(4-Acetylphenyl)-6-(3-(azetidin-1-yl)phenyl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-Methoxyphenyl)-5,7-dimethyl-2-(5-methylpyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-(azetidin-1-yl)phenyl)-2-(5-fluoropyridin-2-yl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-(azetidin-1-yl)phenyl)-5,7-dimethyl-2-(4-(piperazin-1-yl)phenyl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3,5-dimethoxyphenyl)-5,7-dimethyl-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-(azetidin-1-yl)phenyl)-2-(2-methoxyphenyl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-(azetidin-1-yl)phenyl)-2-(2-fluorophenyl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-(azetidin-1-yl)phenyl)-5,7-dimethyl-2-(4-(3-oxopiperazin-1-yl)phenyl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-(3,3-dimethylpyrrolidin-1-yl)phenyl)-5,7-dimethyl-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 2-(4-(6-(3-(azetidin-1-yl)phenyl)-5,7-dimethyl-1-oxo-1H-pyrrolo[3,4-d]pyridazin-2(6H)-yl)phenyl)-N-methylacetamide 6-(3-(azetidin-1-yl)phenyl)-2-(4-iodophenyl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-(azetidin-1-yl)phenyl)-5,7-dimethyl-2-(2-methylpyridin-4-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-(azetidin-1-yl)phenyl)-2-(5-chloropyridin-2-yl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one tert-Butyl 2-(4-(6-(3-(azetidin-1-yl)phenyl)-5,7-dimethyl-1-oxo-1H-pyrrolo[3,4-d]pyridazin-2(6H)-yl)phenyl)-2-oxoethylcarbamate 2-(4-(6-(3-(azetidin-1-yl)phenyl)-5,7-dimethyl-1-oxo-1H-pyrrolo[3,4-d]pyridazin-2(6H)-yl)phenyl)acetamide 6-(4-Cyclopropylphenyl)-5,7-dimethyl-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 5,7-Dimethyl-6-(3-phenoxyphenyl)-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-(azetidin-1-yl)phenyl)-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-(azetidin-1-yl)phenyl)-2-(4-(2-fluoroethyl)phenyl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-(azetidin-1-yl)phenyl)-2-cyclopentyl-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(4-Fluoro-2-methoxyphenyl)-5,7-dimethyl-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-(azetidin-1-yl)-4-fluorophenyl)-5,7-dimethyl-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(2-Methoxyphenyl)-5,7-dimethyl-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(2-Fluoro-5-methoxyphenyl)-5,7-dimethyl-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-(azetidin-1-yl)-5-fluorophenyl)-5,7-dimethyl-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(5-(azetidin-1-yl)-2-fluorophenyl)-5,7-dimethyl-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(2-chloro-3-methoxyphenyl)-5,7-dimethyl-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(1-cyclopropyl-1H-indol-4-yl)-5,7-dimethyl-2-(pyrimidin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-(2H-1,2,3-triazol-2-yl)phenyl)-5,7-dimethyl-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-Cyclopropoxy-2-methylphenyl)-5,7-dimethyl-2-(pyrimidin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(2,4-Dimethylphenyl)-5,7-dimethyl-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-(difluoromethoxy)phenyl)-5,7-dimethyl-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(2-chloro-3-methoxyphenyl)-5,7-dimethyl-2-(pyrimidin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(2-chloro-3-methoxyphenyl)-5,7-dimethyl-2-(5-methylpyrimidin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazine-1- 1 6-(3-cyclopropoxy-2-methylphenyl)-5,7-dimethyl-2-(5-methylpyrimidin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 2-(5-tert-butylpyridin-2-yl)-6-(3-methoxyphenyl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 2-(5-Cyclopropylpyrimidin-2-yl)-6-(3-methoxy-2-methylphenyl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-(azetidin-1-yl)-5-fluorophenyl)-2-(5-fluoropyrimidin-2-yl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-(azetidin-1-yl)-5-fluorophenyl)-2-(3-fluoropyridin-2-yl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 5,7-Dimethyl-6-(1-methylindolin-4-yl)-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-cyclopropoxy-2-methylphenyl)-2-(3-fluoropyridin-2-yl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-cyclopropoxy-2-methylphenyl)-2-(5-fluoropyrimidin-2-yl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(1-cyclopropyl-1H-indol-4-yl)-2-(3-fluoropyridin-2-yl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(1-cyclopropyl-1H-indol-4-yl)-2-(5-fluoropyrimidin-2-yl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(2-chloro-3-cyclopropoxyphenyl)-5,7-dimethyl-2-(pyrimidin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 2-(5-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(3-methoxyphenyl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(5-(azetidin-1-yl)-2-fluorophenyl)-2-(3-fluoropyridin-2-yl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(5-(azetidin-1-yl)-2-fluorophenyl)-2-(5-fluoropyrimidin-2-yl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-(azetidin-1-yl)phenyl)-5,7-dimethyl-2-(4-morpholinophenyl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-hydroxy-2-methylphenyl)-5,7-dimethyl-2-(4-morpholinophenyl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-cyclopropoxy-2-methylphenyl)-5,7-dimethyl-2-(4-morpholinophenyl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-(azetidin-1-yl)phenyl)-2-(bicyclo[1.1.1]pentan-1-yl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-(azetidin-1-yl)phenyl)-5,7-dimethyl-2-(pyrimidin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-(azetidin-1-yl)phenyl)-2-(5-methoxypyrimidin-2-yl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-(azetidin-1-yl)phenyl)-2-(3-fluoropyridin-2-yl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-(azetidin-1-yl)phenyl)-2-(5-fluoropyrimidin-2-yl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-(azetidin-1-yl)phenyl)-5,7-dimethyl-2-(thiazol-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-(azetidin-1-yl)phenyl)-5,7-dimethyl-2-(5-methylpyrimidin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-(azetidin-1-yl)phenyl)-2-(4-methoxypyridin-2-yl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-Methoxy-2-methylphenyl)-5,7-dimethyl-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-Methoxy-2-methylphenyl)-5,7-dimethyl-2-(pyrimidin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-(difluoromethoxy)-2-methylphenyl)-5,7-dimethyl-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(2-fluoro-3-methoxy-phenyl)-5,7-dimethyl-3-(2-pyridyl)pyrrolo[3,4-d]pyridazin-4-one 6-(2-Fluoro-3-methoxy-phenyl)-5,7-dimethyl-3-pyrimidin-2-yl-pyrrolo[3,4-d]pyridazin-4-one 6-[3-(cyclopropoxy)-2-fluoro-phenyl]-5,7-dimethyl-3-(2-pyridyl)pyrrolo[3,4-d]pyridazin-4-one 6-[3-(cyclopropoxy)-2-fluoro-phenyl]-5,7-dimethyl-3-pyrimidin-2-yl-pyrrolo[3,4-d]pyridazin-4-one 6-(2-Cyclopropoxy-3-fluoropyridin-4-yl)-5-methyl-2-(pyrimidin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(6-Methoxypyridin-3-yl)-5,7-dimethyl-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(2-fluoro-6-methoxypyridin-3-yl)-5,7-dimethyl-2-(pyrimidin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazine- 1-1 6-(2-Cyclopropoxy-3-methylpyridin-4-yl)-5-methyl-2-(pyrimidin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(6-Methoxypyridin-3-yl)-5,7-dimethyl-2-(pyrimidin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(6-Methoxy-2-methylpyridin-3-yl)-5,7-dimethyl-2-(pyrimidin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-cyclopropoxy-2-fluorophenyl)-5-methyl-2-(pyrimidin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one

[0052] The above list of compounds can also be represented by the following skeletal formula: JPEG2024517500000016.jpg14108 JPEG2024517500000017.jpg15108 JPEG2024517500000018.jpg15108 JPEG2024517500000019.jpg19108 JPEG2024517500000020.jpg19108 JPEG2024517500000021.jpg22108 JPEG2024517500000022.jpg16108 JPEG2024517500000023.jpg14108 JPEG2024517500000024.jpg17108 JPEG2024517500000025.jpg15108 JPEG2024517500000026.jpg19108 JPEG2024517500000027.jpg16108 JPEG2024517500000028.jpg15108 JPEG2024517500000029.jpg16108 JPEG2024517500000030.jpg18108 JPEG2024517500000031.jpg14108 JPEG2024517500000032.jpg18108 JPEG2024517500000033.jpg17108 JPEG2024517500000034.jpg15108 JPEG2024517500000035.jpg18108 JPEG2024517500000036.jpg15108 JPEG2024517500000037.jpg21108 JPEG2024517500000038.jpg16108 JPEG2024517500000039.jpg17108 JPEG2024517500000040.jpg17108 JPEG2024517500000041.jpg18108 JPEG2024517500000042.jpg17108 JPEG2024517500000043.jpg18108 JPEG2024517500000044.jpg15108 JPEG2024517500000045.jpg17108 JPEG2024517500000046.jpg17108 JPEG2024517500000047.jpg19108 JPEG2024517500000048.jpg17108 JPEG2024517500000049.jpg18108 JPEG2024517500000050.jpg16108 JPEG2024517500000051.jpg15108 JPEG2024517500000052.jpg17108 JPEG2024517500000053.jpg22108 JPEG2024517500000054.jpg22108 JPEG2024517500000055.jpg16108 JPEG2024517500000056.jpg19108 JPEG2024517500000057.jpg22108 JPEG2024517500000058.jpg17108 JPEG2024517500000059.jpg19108 JPEG2024517500000060.jpg22108 JPEG2024517500000061.jpg17108 JPEG2024517500000062.jpg21108 JPEG2024517500000063.jpg18108 JPEG2024517500000064.jpg20108 JPEG2024517500000065.jpg18108 JPEG2024517500000066.jpg20107 JPEG2024517500000067.jpg15108 JPEG2024517500000068.jpg16107 JPEG2024517500000069.jpg18108 JPEG2024517500000070.jpg18108 JPEG2024517500000071.jpg21108 JPEG2024517500000072.jpg16107 JPEG2024517500000073.jpg14108 JPEG2024517500000074.jpg15108 JPEG2024517500000075.jpg18108 JPEG2024517500000076.jpg16108 JPEG2024517500000077.jpg14108 JPEG2024517500000078.jpg13108 JPEG2024517500000079.jpg15108 JPEG2024517500000080.jpg16108 JPEG2024517500000081.jpg17108 JPEG2024517500000082.jpg18108 JPEG2024517500000083.jpg13108 JPEG2024517500000084.jpg17108 JPEG2024517500000085.jpg16108 JPEG2024517500000086.jpg14108 JPEG2024517500000087.jpg14108 JPEG2024517500000088.jpg17108 JPEG2024517500000089.jpg16108 JPEG2024517500000090.jpg15108 JPEG2024517500000091.jpg15108 JPEG2024517500000092.jpg18108 JPEG2024517500000093.jpg14108 JPEG2024517500000094.jpg12107 JPEG2024517500000095.jpg13108 JPEG2024517500000096.jpg12107.

[0053] Preferably, the compound is one or more selected from the following list, as well as a pharma- ceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, or an N-oxide form thereof: 6-(3-(azetidin-1-yl)phenyl)-5,7-dimethyl-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-(azetidin-1-yl)-5-fluorophenyl)-5,7-dimethyl-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(5-(azetidin-1-yl)-2-fluorophenyl)-5,7-dimethyl-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(1-cyclopropyl-1H-indol-4-yl)-5,7-dimethyl-2-(pyrimidin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-Cyclopropoxy-2-methylphenyl)-5,7-dimethyl-2-(pyrimidin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-(azetidin-1-yl)-5-fluorophenyl)-2-(5-fluoropyrimidin-2-yl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-(azetidin-1-yl)-5-fluorophenyl)-2-(3-fluoropyridin-2-yl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-cyclopropoxy-2-methylphenyl)-2-(5-fluoropyrimidin-2-yl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(1-cyclopropyl-1H-indol-4-yl)-2-(5-fluoropyrimidin-2-yl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 2-(5-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-(3-methoxyphenyl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-(azetidin-1-yl)phenyl)-2-(3-fluoropyridin-2-yl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-(azetidin-1-yl)phenyl)-2-(5-fluoropyrimidin-2-yl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-[3-(cyclopropoxy)-2-fluoro-phenyl]-5,7-dimethyl-3-pyrimidin-2-yl-pyrrolo[3,4-d]pyridazin-4-one

[0054] The above list of compounds can also be represented by the following skeletal formula: JPEG2024517500000097.jpg1429 JPEG2024517500000098.jpg1529 JPEG2024517500000099.jpg1529 JPEG2024517500000100.jpg1432JPEG2024517500000101.jpg1332 JPEG2024517500000102.jpg1531 JPEG2024517500000103.jpg1530 JPEG2024517500000104.jpg1435 JPEG2024517500000105.jpg1433 JPEG2024517500000106.jpg1634 JPEG2024517500000107.jpg1429 JPEG2024517500000108.jpg1431 JPEG2024517500000109.jpg1332

[0055] Preferably, the compound is one or more selected from the following list, as well as a pharma- ceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof, or an N-oxide form thereof: 6-(3-(azetidin-1-yl)phenyl)-5,7-dimethyl-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-Cyclopropoxy-2-methylphenyl)-5,7-dimethyl-2-(pyrimidin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-(3-cyclopropoxy-2-methylphenyl)-2-(5-fluoropyrimidin-2-yl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one 6-[3-(cyclopropoxy)-2-fluoro-phenyl]-5,7-dimethyl-3-pyrimidin-2-yl-pyrrolo[3,4-d]pyridazin-4-one

[0056] The above list of compounds can also be represented by the following skeletal formula: JPEG2024517500000110.jpg1428 JPEG2024517500000111.jpg1230 JPEG2024517500000112.jpg1332JPEG2024517500000113.jpg1332

[0057] Compounds according to any of the above descriptions may exhibit metabotropic glutamate receptor 7 modulator activity.

[0058] The disclosed compounds also include all pharma- ceutically 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 normally 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 and14 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 These include those in which non-radioactive isotopes such as C exist.

[0059] Such isotope-labeled compounds are useful in metabolic studies ( 14 C), reaction kinetic studies (e.g. 2 H or 3 H), detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution 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 deuterium (H or D) may confer therapeutic benefits resulting from improved metabolic stability, e.g., increased half-life in vivo, reduced dosage requirements, or improved therapeutic index. It is understood that deuterium in this context is considered a substituent of compounds of formulae (I)-(V). Isotopically labeled compounds of formulae (I)-(V) may generally be prepared by conventional techniques known to those skilled in the art, or by processes similar to those described in the accompanying Examples, using the appropriate isotopically labeled reagent in place of the previously employed non-labeled reagent.

[0060] In one aspect of the present invention, a pharmaceutical composition is provided that comprises a compound according to any of the above statements.The pharmaceutical composition may further comprise a pharma- ceutically acceptable carrier and / or excipient.The pharmaceutical composition may comprise a therapeutically effective amount of a compound according to any of the above statements.

[0061] 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.

[0062] Treatment or prevention may be affected or facilitated by the modulatory effects of an mGlu7 allosteric modulator, such as an mGlu7 negative allosteric modulator. The condition may be one or more of a central nervous system disorder, an ear disease or disorder, or a pain disorder.

[0063] The central nervous system disorder may be post-traumatic stress disorder (PTSD).

[0064] The ear disease or disorder may be one or more of an inner ear disorder, age-related hearing loss (presbycusis), Meniere's disease, sudden deafness, noise-induced deafness, otitis media, autoimmune inner ear disease, acute tinnitus, chronic tinnitus, drug-induced deafness, hidden deafness, cisplatin-induced deafness, aminoglycoside-induced deafness, toxic deafness, central auditory processing disorder or vestibular disorder.

[0065] In a further aspect of the invention, there is provided a method for the treatment, prevention, amelioration, control or reduction of 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, which treatment or prevention may be influenced or facilitated by the modulatory effect of an mGlu7 negative allosteric modulator.

[0066] Preferably, the method is for the treatment or prevention of a condition in a human.

[0067] In a further aspect of the invention there is provided a compound or composition as defined in any of the above statements for use as a medicament.

[0068] 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 prophylaxis as defined in any statement above.

[0069] 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.

[0070] Below are definitions of various terms used in the specification and claims to describe this invention.

[0071] 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.

[0072] If the subscript is the integer 0 (zero), it indicates that the radical to which the subscript refers does not exist; that is, there is a direct bond between the radicals.

[0073] When the subscript is the integer 0 (zero) and the radical to which it refers is an alkyl, this indicates that the radical is a hydrogen atom.

[0074] In this specification, unless otherwise specified, the term "bond" refers to a saturated covalent bond. When two or more bonds are adjacent to each other, they are assumed to be equal to one bond. For example, the radical -AB- represents a single bond, although both A and B may be bonds.

[0075] As used herein, unless otherwise stated, the term "alkyl" includes both straight 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.

[0076] As used herein, unless otherwise indicated, 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 (-CH2-CH(CH3)-CH2-CH2-), neopentylene (-CH2-C(CH3)2-CH2-), n-hexylene (-CH2-CH2-CH2-CH2)-CH2-CH2-), i-hexylene (-CH2-CH-(CH3)-CH2-CH2-CH2-CH2-), or neohexylene (-CH2-C(CH3)2-CH2-CH2-). The term "O-(C1-C6)alkylene-aryl" refers to an alkyl chain having 0, 1, 2, 3, 4, 5 or 6 carbon atoms between the oxygen atom and the aryl group.

[0077] As used herein, unless otherwise noted, 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 include one 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.

[0078] As used herein, unless otherwise specified, the term "alkenyl" includes both straight 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.

[0079] As used herein, unless otherwise indicated, 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.

[0080] As used herein, unless otherwise noted, the term "alkynyl" includes both straight 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.

[0081] As used herein, unless otherwise indicated, the term "alkynylene" includes both straight 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.

[0082] 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.

[0083] 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.

[0084] As used herein, unless otherwise noted, 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 "(C1-C6)alkylene-aryl" includes aryl-C1-C6-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 the 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.

[0085] As used herein, unless otherwise indicated, the term "heterocycle" refers to an optionally substituted, monocyclic, bicyclic, or tricyclic, saturated, partially saturated, or unsaturated ring system containing at least one heteroatom independently selected from N, O, and S. Bicyclic or tricyclic ring systems may 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.).

[0086] In this specification, unless otherwise stated, 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.

[0087] 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.

[0088] As used herein, unless otherwise stated, the term "halo" or "halogen" may be fluoro, chloro, bromo or iodo.

[0089] As used herein, unless otherwise stated, the term "haloalkyl" refers to an alkyl radical as defined above, substituted with one or more halo radicals. The term "(C1-C6)haloalkyl" can include, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl and difluoroethyl. The term "O-C1-C6-haloalkyl" can include, but is not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy and fluoroethoxy.

[0090] As used herein, unless otherwise stated, the term "cyanoalkyl" means an alkyl radical, as defined above, substituted with one or more cyano.

[0091] As used herein, unless otherwise indicated, the term "optionally substituted" includes any of the following: acyl, (C1-C6) alkyl, -(C1-C6) haloalkyl, -(C3-C7) cycloalkyl, -(C1-C6) alkylene-(C3-C7) cycloalkyl, -(C3-C7) cycloalkyl-(C1-C6) alkylene, -(C0-C6) alkylene-(C3-C7) spiroalkyl-(C0-C6) refers to a radical further bearing one or more substituents which may be alkylene, hydroxy, (C1-C6)alkylene-oxy, dimethylamino(C1-C3)alkyl, mercapto, aryl, heterocycle, heteroaryl, (C1-C6)alkylene-aryl, (C1-C6)alkylene-heterocycle, (C1-C6)alkylene-heteroaryl, halogen, haloalkyl, trifluoromethyl, pentafluoroethyl, haloalkoxy, cyano, cyanomethyl, nitro, amino, amido, amidinyl, oxo, carboxyl, carboxamido, (C1-C6)alkylene-oxycarbonyl, carbamate, sulfonamide, ester, or sulfonyl.

[0092] 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.

[0093] As used herein, unless otherwise indicated, the term "solvate" refers to a complex of variable stoichiometry formed by a solute (e.g., a compound of formula (I)) and a solvent, the solvent being a pharma- ceutically acceptable solvent, such as water, that does not inhibit the biological activity of the solute.

[0094] 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."

[0095] The pharma- ceutically 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.

[0096] As used herein, unless otherwise specified, a particular compound 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." For example, the radical JPEG2024517500000114.jpg1313 is It is a tautomer of JPEG2024517500000115.jpg1311.

[0097] The term "isomer" includes compounds with one or more isotopic substitutions. For example, H is 1 H, 2 H(D), and 3 H(T) may be in any isotopic form, including but not limited to H(T); 12 C. 13 C. 14 C may be in any isotopic form, including but not limited to C; 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 the form of any isotopic form, including but not limited to F.

[0098] As used herein, unless otherwise specified, the term "negative allosteric modulator of mGlu7" or "allosteric modulator of mGlu7" also refers to a pharma- ceutically acceptable acid or base addition salt thereof, its stereochemically isomeric forms, or its N-oxide forms.

[0099] Pharmaceutical Compositions The allosteric modulators of mGlu7 described herein, and their pharma- ceutically acceptable salts, solvates and hydrates, can be used in pharmaceutical preparations in combination with a pharma- ceutically acceptable carrier or diluent. Suitable pharma- ceutical 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 instant compounds of the invention can be found in Remington: the Science and Practice of Pharmacy, 1999, 10:131-135, 19 ... th edition, Mack Publishing Co., Easton, PA (1995).

[0100] The amount of allosteric modulator of mGlu7 administered to a subject will depend on the type and severity of the disease or condition, as well as the characteristics of the subject, such as general health, age, sex, weight, and tolerance to drugs. Those skilled in the art will be able to determine appropriate dosages depending on these and other factors. Effective amounts of commonly used central nervous system drugs are well known to those skilled in the art. Typically, the total daily dosage is about 0.05-2000 mg.

[0101] The present invention relates to a pharmaceutical composition that provides about 0.01-1000 mg of active ingredient per unit dose. The composition can be administered by any suitable route. For example, it can be administered orally in the form of a capsule, parenterally in the form of an injectable solution, topically in the form of an ointment or lotion, ophthalmically in the form of eye drops, rectally in the form of a suppository, intranasally or transdermally in the form of a delivery system such as a patch.

[0102] For oral administration, the allosteric modulators of mGlu7 can be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, pills, powders, syrups, solutions, suspensions, and the like.

[0103] Tablets, pills, capsules, etc. contain about 0.01 to about 99% by weight of the active ingredient, and binders such as tragacanth, 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, etc., 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.

[0104] 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, methyl and propylparabens as preservatives, a dye and flavoring, such as cherry or orange flavor.

[0105] 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 or peanut oil, aqueous propylene glycol, etc. can be used, as can aqueous solutions of pharma- ceutically acceptable water-soluble salts of the compounds. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Under normal conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

[0106] In addition to the above-mentioned preparation, compound can also be formulated as depot preparation.Such 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, for example, poorly soluble salt.

[0107] 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 the unit dosage composition is an effective amount and can be varied 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 according to various routes of administration, including oral, aerosol, rectal, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, and intranasal.

[0108] Synthesis method Compounds according to the invention, particularly compounds according to formulae (I)-(V), 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 of the compound synthesis using methods readily apparent to one skilled in the art. The selection of processes as well as reaction conditions and the order of their execution are consistent with the preparation of compounds of formulae (I)-(V).

[0109] The compounds according to the invention can be represented 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 the salt of an optically active acid or by other methods known in the literature (such as chiral column chromatography).

[0110] Resolution of the final product, intermediate, or 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).

[0111] Many of the heterocyclic compounds of the invention can be prepared using synthetic routes well known in the art (Katrizky AR and Rees CW (1984) Comprehensive Heterocyclic Chemistry, Pergamon Press).

[0112] The products from the reaction can be isolated and purified using standard techniques such as extraction, chromatography, recrystallization, and distillation.

[0113] The compounds of the invention can be prepared by general synthetic routes as disclosed in the methods below.

[0114] In one embodiment of the present invention, compounds of formula (I) can be prepared according to the synthetic sequence shown in Scheme 1. The α,γ-diketo derivatives g2 can be prepared by reacting the corresponding β-ketoester derivatives g1 with haloacetyl derivatives in the presence of a base, such as sodium hydride, in a suitable solvent, such as THF, at a suitable temperature. The intermediates g2 can then be converted to N-arylpyrrole derivatives g4 by reacting with a suitable aniline derivative g3 in a suitable solvent, such as toluene, acetonitrile, etc., in the presence of a catalyst, such as an acid, such as acetic acid, p-toluenesulfonic acid, etc., at a suitable temperature (e.g. Bioorg.Med. Chem. Lett. 2010, 20(1), 189; Bioorg. Med. Chem. Lett. 2008, 16(23), 10001).

[0115] Pyrrole derivatives g5 can be prepared from derivatives g4 by a carbonylation reaction known in the art of organic synthesis, such as, but not limited to, the Vilsmeier reaction, in a suitable solvent at a suitable temperature (see, for example, Tetrahedron 2006, 62, 6018).

[0116] Intermediate g5 can finally be condensed with a suitable phenylhydrazine derivative g6 in the presence of a catalyst, e.g., an acid, e.g., acetic acid, p-toluenesulfonic acid, etc., in a polar solvent, e.g., EtOH, dioxane, etc., at a suitable temperature to give the final compound g7 (see, e.g., Bioorg. Med. Chem. 2010, 18(1), 202).

[0117] JPEG2024517500000116.jpg28105 Scheme 1

[0118] Similarly, the final compound g7 can be prepared according to the synthetic sequence shown in Scheme 2. Intermediate g5 can be first converted to intermediate g8 by reaction with hydrazine in the presence of a catalyst such as an acid such as acetic acid, paratoluenesulfonic acid, etc., in a polar solvent such as EtOH, dioxane, etc., at a suitable temperature (see, for example, Bioorg. Med. Chem. Lett. 2004, 14, 1295). The final compound g7 can then be obtained by methods known in the art of organic synthesis such as the Chan-Lam coupling reaction mediated by a copper complex catalyst such as Cu(OAc)2 in the presence of a base such as triethylamine, pyridine, etc., in a reaction inert solvent such as DMF, dioxane, etc., at a suitable temperature.

[0119] JPEG2024517500000117.jpg13105 Scheme 2

[0120] In another particular embodiment of formula (I), intermediate derivative g5 used for the preparation of final compound g7 can be prepared according to Scheme 3. Intermediate derivative g10 prepared according to Scheme 1, where X represents any kind of functional group, such as but not limited to halogen, cyano, ester, ether, carboxylic acid, carbonyl, etc., can be converted to intermediate g5 by suitable reactions known to those skilled in the art of organic synthesis, such as but not limited to cross-coupling reactions, such as Buchwald, Heck, Suzuki, Ullmann, Stille coupling reactions, mediated by palladium complex catalysts such as Pd(PPh3)4, PdCl2(dppf), or copper complex catalysts such as CuI, Cu(OAc)2, in a reaction inert solvent such as DMF, dioxane, etc., at a suitable temperature.

[0121] JPEG2024517500000118.jpg1459 Scheme 3

[0122] Similarly, the final compound g7 can be prepared according to the synthetic sequence shown in Scheme 4. Intermediate g11 prepared according to Scheme 1 or 2, where X is a functional group such as halogen, cyano, ester, ether, carboxylic acid, carbonyl, etc., can be converted to the final compound g7 by appropriate reactions such as those described for Scheme 3.

[0123] JPEG2024517500000119.jpg1375 Scheme 4

[0124] In another particular embodiment of formula (I), the final compound g7 can be prepared according to Scheme 5. Intermediate g12 prepared according to Scheme 1 or 2, where X is a functional group such as halogen, cyano, ester, ether, carboxylic acid, carbonyl, etc., can be converted to the final compound g7 by a suitable cross-coupling reaction, as described for Scheme 3.

[0125] JPEG2024517500000120.jpg1372 Scheme 5

[0126] In another particular embodiment of formula (I), the final compound g14 can be prepared according to Scheme 6. Intermediate g13 prepared according to Scheme 1 or 2 can be demethylated under acidic conditions, such as in the presence of HCl, leading to the final compound g14.

[0127] JPEG2024517500000121.jpg1385 Scheme 6

[0128] In another embodiment of formula (I), the final compound g20 can be prepared according to Scheme 7. Intermediate g17 can be prepared by the reaction of N 1 , N 2 The intermediate g17 can be converted to the 2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one derivative g19 by reaction with 1-(isocyanomethylsulfonyl)-4-methylbenzene g18 in the presence of a base such as NaH in a suitable solvent such as THF at a suitable temperature. The final compound g20 can then be obtained by a method such as the Ullmann coupling reaction between the intermediate g19 and a bromoaryl such as g20 as described in step 1.

[0129] JPEG2024517500000122.jpg28105 Scheme 7

[0130] The pyrrole derivative g5 can be condensed with a suitable heteroaryl hydrazine derivative g6 under acidic conditions, e.g., acetic acid, in a polar solvent, e.g., EtOH, dioxane, etc., followed by cyclization in neat form at a suitable temperature to give the final compound g7.

[0131] JPEG2024517500000123.jpg13107 Scheme 8

[0132] The methyl ether aryl g23 can be cleaved in the presence of a Lewis acid such as BBr3 to give the corresponding hydroxyaryl g24, which can be alkylated to give the ether compound g25, which can then be cyclized with the appropriate heteroaryl hydrazine derivative g6 under acidic conditions to give the final compound g26.

[0133] JPEG2024517500000124.jpg2676 Scheme 9

[0134] experiment Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification.

[0135] Specifically, the following abbreviations may be used in the examples and throughout the specification:

[0136] TIFF2024517500000125.tif99158TIFF2024517500000126.tif102156

[0137] 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.

[0138] Most reactions were monitored by thin-layer chromatography using 0.25 mm Merck silica gel plates (60F-254) and visualized under UV light. Flash column chromatography was performed on prepacked silica gel cartridges (15-40 μM, Merck). EXAMPLES

[0139] Example 1: 6-(3-Methoxyphenyl)-5,7-dimethyl-2-phenyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one (final compound 1-26)

[0140] Ethyl 2-acetyl-4-oxopentanoate

[0141] According to Scheme 1, Step 1: To a stirred solution of ethyl-3-oxobutanoate (200 g, 1.54 mol) in THF (1 L) at 0° C., NaH (60% w / w, 67.6 g, 1.70 mol) was added in portions over 2 h. After 30 min, 1-chloropropan-2-one (156 g, 1.70 mol) was added over 1 h and the reaction mixture was allowed to warm to rt overnight. Et2O (250 mL) was added, followed by brine (500 mL) and the organic layer was separated. The aqueous layer was extracted twice with Et2O (2× 250 mL). The organic layers were combined, dried over Na2SO4, filtered and evaporated under reduced pressure. The crude oil was distilled (126° C. / 14 mmHg) to give the title compound as a pale yellow oil (140 g, 49%).

[0142] 1-(3-Methoxyphenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate ethyl

[0143] According to Scheme 1, Step 2: To a solution of ethyl 2-acetyl-4-oxopentanoate (8.00 g, 43.0 mmol) in toluene (140 mL) was added 3-methoxyaniline (6.35 g, 51.6 mmol) and AcOH (0.09 g, 1.5 mmol). The reaction mixture was heated under reflux in a Dean-Stark apparatus overnight, then cooled to rt and concentrated under reduced pressure to give the title compound as a brown oil (11.7 g, 100%).

[0144] Ethyl 4-formyl-1-(3-methoxyphenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate

[0145] According to Scheme 1, step 3: To a stirred solution of POCl3 (1.76 g, 11.5 mmol) in DCM (13 mL) at 0 °C, a solution of DMF (0.84 g, 11.5 mmol) in DCM (10 mL) was added dropwise while maintaining the temperature at 0 °C. Once the addition was complete, the reaction mixture was stirred at 0 °C for 20 min and warmed to rt. Then, a solution of 1-(3-methoxyphenyl)-2,5-dimethyl-1H-pyrrole-3-ethyl carboxylate (2.85 g, 10.4 mmol) in DCM (13 mL) was added dropwise to the reaction mixture at 0 °C and stirred at this temperature for 1 h, then stirred at rt overnight. Cold water was added and the pH was adjusted to 10-11 with 6 M aqueous NaOH. The resulting solution was extracted with DCM. The organic layer was washed with brine, dried over MgSO4 and concentrated under reduced pressure to give the title compound as a brown solid (3.62 g, 92%), which was used in the next step without further purification.

[0146] 6-(3-Methoxyphenyl)-5,7-dimethyl-2-phenyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one

[0147] According to Scheme 1, Step 4: To a stirred solution of ethyl 4-formyl-1-(3-methoxyphenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (279 mg, 0.93 mmol) in dioxane (3 mL) was added phenylhydrazine (103 mg, 0.93 mmol) and AcOH (278 mg, 4.63 mmol). The reaction mixture was heated to 160° C. under microwave irradiation for 20 min, cooled to rt, washed with Et2O, filtered and dried to give the title compound as a white solid (146 mg, 46%).

[0148] Mp:213-215°C;UPLC-MS:RT=1.09min;MS m / z ES + =346;1 H-NMR(300MHz, DMSO-d6)δ:8.34(1H, s), 7.56-7. 42(5H, m), 7.35-7.29(1H, m), 7.18-7.15(1H, dd), 7.05-6.98(2H, m), 3.82(3H, s), 2.40(3H, s), 2.27(3H, s).

[0149] Example 2: 2-(2-Methoxyphenyl)-5,7-dimethyl-6-p-tolyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one (Final Compound 1-2)

[0150] 5,7-Dimethyl-6-p-tolyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one

[0151] According to Scheme 2, Step 1: To a stirred solution of ethyl 4-formyl-2,5-dimethyl-1-p-tolyl-1H-pyrrole-3-carboxylate (1.66 g, 5.82 mmol) in EtOH (50 mL) was added hydrazine monohydrate (2.91 g, 58.2 mmol). The mixture was stirred at reflux overnight, cooled to rt, concentrated, filtered and dried to give the title compound as a white solid (1.31 g, 89%).

[0152] 2-(2-Methoxyphenyl)-5,7-dimethyl-6-p-tolyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one

[0153] According to Scheme 2, Step 2: To a stirred solution of 5,7-dimethyl-6-p-tolyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one (0.20 g, 0.79 mmol) in dioxane (3 mL) was added 1-iodo-2-methoxybenzene (185 mg, 0.79 mmol), CuI, trans-cyclohexane-1,2-diamine (18 mg, 158 μmol), and K3PO4 (503 mg, 2.37 mmol). The reaction mixture was heated at 110 °C overnight, cooled to rt, and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel eluting with DCM / MeOH (99:1) to give the title compound as a beige solid (97 mg, 34%).

[0154] Mp:202°C;LC-MS:RT=2.83min;MSm / z ES + =360; 1 H-NMR(300MHz, CDCl3)δ:8.05(1H, s), 7.51(2H, d), 7.35(2H, d), 7.15 (2H, d), 7.00(2H, d), 3.85(3H, s), 2.55(6H, s), 2.30(3H, s).

[0155] Example 3: 2-(2-fluorophenyl)-5,7-dimethyl-6-phenyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one (final compound 1-21)

[0156] According to Scheme 2, Step 2: To a stirred solution of 5,7-dimethyl-6-phenyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one (100 mg, 0.42 mmol) in DMF (2 mL) was added 1-fluoro-2-iodobenzene (111 mg, 0.50 mmol), CuI (40.0 mg, 0.21 mmol) and K2CO3 (116 mg, 0.84 mmol). The reaction mixture was heated at 140° C. under microwave irradiation for 30 min, cooled to rt, poured into water and extracted with DCM. The organic layers were combined, washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel eluting with DCM / EtOAc (95:5) to give the title compound as a beige solid (57 mg, 41%).

[0157] Mp:226°C;UPLC-MS:RT=1.05min;MS m / z ES + =334; 1 H-NMR(300MHz, DMSO-d6)δ:8.34(1H, s), 7.69-7.55(3H, m), 7.50-7.42(4H, m), 7.39-7.29(2H, m), 2.38(3H, s), 2.36(3H, s), 2.25(3H, s).

[0158] Example 4: 2-(4-Methoxyphenyl)-5,7-dimethyl-6-phenyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one (final compound 1-13)

[0159] According to Scheme 2, Step 2: To a stirred solution of 5,7-dimethyl-6-phenyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one (150 mg, 0.63 mmol) in DMF (6 mL) was added 4-methoxyphenylboronic acid (114 mg, 0.75 mmol), Cu(OAc)2 (228 mg, 1.25 mmol) and Et3N (127 mg, 1.25 mmol). The mixture was stirred at 80° C. for 6 h, cooled to rt, poured into NH4OH and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by preparative HPLC to give the title compound as a white solid (29 mg, 13%).

[0160] UPLC-MS: RT = 1.05 min; MS m / z ES + =346; 1 H-NMR (300MHz, DMSO-d6)δ:8.32(1H, s), 7.68-7.58(3H, m), 7.46-7.37(4H, m), 7.01(2H, d), 3.80(3H, s), 2.40(3H, s), 2.21(3H, s).

[0161] Example 5: 5,7-Dimethyl-2-phenyl-6-(3-(pyrrolidin-1-yl)phenyl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one (Final Compound 1-101)

[0162] 4-Formyl-2,5-dimethyl-1-(3-(pyrrolidin-1-yl)phenyl)-1H-pyrrole-3-carboxylate ethyl

[0163] According to Scheme 3: To a stirred solution of ethyl 1-(3-bromophenyl)-4-formyl-2,5-dimethyl-1H-pyrrole-3-carboxylate (1.00 g, 2.86 mmol) in DMF (14 mL) was added pyrrolidine (406 mg, 5.71 mmol), Xantphos (248 mg, 0.43 mmol), PdCl2(dppf) (233 mg, 0.29 mmol) and Cs2CO3 (1.40 g, 4.28 mmol). The reaction mixture was stirred in a sealed tube at 130° C. for 3 h, cooled to rt, diluted with DCM, filtered over celite and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel eluting with DCM / MeOH (99:1) to give the title compound as a yellow solid (513 mg, 53%).

[0164] 5,7-Dimethyl-2-phenyl-6-(3-(pyrrolidin-1-yl)phenyl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one

[0165] According to Scheme 1, step 4: Prepared according to final compound 1-26 from ethyl 4-formyl-2,5-dimethyl-1-(3-(pyrrolidin-1-yl)phenyl)-1H-pyrrole-3-carboxylate (120 mg, 0.35 mmol) and purified by preparative HPLC to give the title compound as a brown solid (513 mg, 53%).

[0166] Mp:228-229°C;UPLC-MS:RT=1.29min;MS m / z ES + =385; 1 H-NMR(300MHz, DMSO-d6)δ:8.32(1H, s), 7.52-7.29(6H, m), 6.70(1H, dd), 6.55(1H, dd), 6.45-6.44(1H, m), 4.45-4.44(1H, m), 3.27-3.25(4H, m), 2.41(3H, s), 2.28(3H, s), 1.97-1.95(4H, m).

[0167] Example 6: 6-(3-acetylphenyl)-5,7-dimethyl-2-phenyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one (final compound 1-36)

[0168] According to Scheme 4: To a stirred solution of 6-(3-bromophenyl)-5,7-dimethyl-2-phenyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one (final compound 1-34, 120 mg, 0.30 mmol) in DMF (1.5 mL), 1-(vinyloxy)butane (152 mg, 1.52 mmol), Et3N (92 mg, 0.91 mmol) and PdCl2(dppf) (25 mg, 30 μmol) were added. The reaction mixture was stirred at 130 °C for 25 min under nitrogen atmosphere and microwave irradiation. 1M HCL (1.5 mL) was added and the reaction mixture was stirred at rt for 10 min and diluted with DCM. The organic layers were combined, washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by preparative HPLC to give the title compound as a white solid (15 mg, 14%).

[0169] Mp:202-204°C;UPLC-MS:RT=0.97min;MS m / z ES + =358; 1 H-NMR(300MHz, DMSO-d6)δ:8.36 (1H, s), 8.17-8.14(1H, m), 8.00(1H, s), 7.83-7.73(2H, m), 7.53-7.43(4H, m), 7.35-7.31(1H, m), 2.65(3H, s), 2.40(3H, s), 2.27(3H, s).

[0170] Example 7: 6-(3-(2-methoxyethylamino)phenyl)-5,7-dimethyl-2-phenyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one (final compound 1-43)

[0171] According to scheme 4: To a stirred solution of 6-(3-bromophenyl)-5,7-dimethyl-2-phenyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one (final compound 1-34, 120 mg, 0.30 mmol) in DMF (1 mL) was added 2-methoxyethanolamine (34 mg, 0.46 mmol), Xantphos (26 mg, 46 μmol), PdCl2(dppf) (25 mg, 30 μmol) and Cs2CO3 (149 mg, 0.46 mmol). The mixture was stirred in a sealed tube at 130° C. for 4 h, cooled to rt, diluted with DCM, filtered over celite and concentrated under reduced pressure. The crude material was purified by preparative HPLC to give the title compound as a brown solid (15 mg, 13%).

[0172] Mp:116-119°C;UPLC-MS:RT=1.04min;MS m / z ES + =389; 1 H-NMR(300MHz, DMSO-d6)δ:8.31 (1H, s), 7.52-7.44(4H, m), 7.34-7.25(2H, m), 6.80(1H, d), 6.53-6.49(2H, m), 6.07 (1H, t), 3.50(2H, t), 3.33-3.22(5H, m), 2.41(3H, s), 2.27(3H, s).

[0173] Example 8: 6-(3-hydroxyphenyl)-5,7-dimethyl-2-phenyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one (final compound 1-51)

[0174] According to scheme 4: To a stirred solution of 6-(3-methoxyphenyl)-5,7-dimethyl-2-phenyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one (final compound 1-26, example 1, 30 mg, 87 μmol) in DCM (1 mL) at 0° C., dropwise BBr3 (0.17 mL, 0.17 mmol) was added. The mixture was stirred at rt for 1 h, diluted with DCM and slowly hydrolyzed with water. The organic layer was washed with water and NH4Cl, dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was washed with Et2O, filtered and dried under reduced pressure to give the title compound as a beige solid (12 mg, 42%).

[0175] Mp:252-254°C;UPLC-MS:RT=0.91min;MS m / z ES + =332; 1 H-NMR(300MHz, DMSO-d6)δ:10.05(1H, s), 8.32(1H, s), 7.52-7.39(5H, m), 7.34-7.29(1H, m), 6.98(1H, dd), 6.81(1H, d), 6.75(1H, s), 2.39(3H, s), 2.25(3H, s).

[0176] Example 9: 2-(4-(aminomethyl)phenyl)-6-(3-methoxyphenyl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one (final compound 1-88)

[0177] tert-Butyl 4-(6-(3-methoxyphenyl)-5,7-dimethyl-1-oxo-1H-pyrrolo[3,4-d]pyridazin-2(6H)-yl)benzylcarbamate

[0178] According to Scheme 2, step 2: Prepared according to final compound 1-13 from 6-(3-methoxyphenyl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one (140 mg, 0.52 mmol), 4-((tert-butoxycarbonylamino)methyl)phenylboronic acid (157 mg, 0.62 mmol), Cu(OAc)2 (103 mg, 0.52 mmol) and K2CO3 (86 mg, 0.62 mmol) and purified by flash chromatography on silica gel eluting with DCM / MeOH (99:1) to give the title compound as a brown solid (400 mg, 89%).

[0179] 2-(4-(aminomethyl)phenyl)-6-(3-methoxyphenyl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one

[0180] According to Scheme 5: To a stirred solution of tert-butyl 4-(6-(3-methoxyphenyl)-5,7-dimethyl-1-oxo-1H-pyrrolo[3,4-d]pyridazin-2(6H)-yl)benzylcarbamate (100 mg, 0.21 mmol) in DCM (2 mL) was added dropwise trifluoroacetic acid (288 mg, 2.53 mmol). The reaction mixture was stirred at rt for 4 h and diluted with DCM and water. The organic layer was washed with water and NaHCO3, dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using DCM / MeOH (95:5) as eluent and recrystallized from Et2O to give the title compound as a brown solid (7 mg, 9%).

[0181] Mp:145-155°C;UPLC-MS:RT=0.72min;MS m / z ES + =375; 1H-NMR(300MHz, DMSO-d6)δ:8.33 (1H, s), 7.57-7.41(5H, m), 7.16(1H, dd), 7.03-6.98(2H, m), 3.87(2H, s), 3.82(3H, s), 2.40(3H, s), 2.27(3H, s).

[0182] Example 10: 6-(3-Methoxyphenyl)-5,7-dimethyl-2-(4-((methylamino)methyl)phenyl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one (final compound 1-109)

[0183] tert-Butyl 4-(6-(3-methoxyphenyl)-5,7-dimethyl-1-oxo-1H-pyrrolo[3,4-d]pyridazin-2(6H)-yl)benzyl(methyl)carbamate

[0184] According to Scheme 5: To a stirred solution of tert-butyl 4-(6-(3-methoxyphenyl)-5,7-dimethyl-1-oxo-1H-pyrrolo[3,4-d]pyridazin-2(6H)-yl)benzylcarbamate (235 mg, 0.49 mmol) in DMF (2 mL) was added iodomethane (211 mg, 1.49 mmol) and NaH (60% w / w, 59 mg, 1.49 mmol) in portions. The reaction mixture was stirred at rt for 3 h and water was carefully added. The reaction mixture was extracted with DCM and the combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound as a brown solid (300 mg, 99%), which was used in the next step without further purification.

[0185] 6-(3-Methoxyphenyl)-5,7-dimethyl-2-(4-((methylamino)methyl)phenyl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one

[0186] According to Scheme 5: Prepared according to final compound 1-88 from tert-butyl 4-(6-(3-methoxyphenyl)-5,7-dimethyl-1-oxo-1H-pyrrolo[3,4-d]pyridazin-2(6H)-yl)benzyl(methyl)carbamate (300 mg, 0.61 mmol), purified by flash chromatography on silica gel using DCM / MeOH / NH4OH (95:5:0.1) as eluent and recrystallized in Et2O to give the title compound as a pale pink solid (34 mg, 14%).

[0187] Mp:150-154°C;UPLC-MS:RT =0.73min;MS m / z ES + =389; 1 H-NMR(300MHz, DMSO-d6)δ:8.33(1H, s), 7.56-7.39(5H, m), 7.16(1H, dd), 7.03-6.98(2H, m), 3.82(3H, s), 3.79(2H, s), 2.40(3H, s), 2.36(3H, s), 2.27(3H, s).

[0188] Example 11: 6-([1,1'-biphenyl]-3-yl)-5,7-dimethyl-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one (final compound 1-76)

[0189] 6-(3-Bromophenyl)-5,7-dimethyl-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one

[0190] According to Scheme 1, step 4: Prepared according to final compound 1-26 from ethyl 1-(3-bromophenyl)-4-formyl-2,5-dimethyl-1H-pyrrole-3-carboxylate (2.00 g, 5.71 mmol), 2-hydrazinylpyridine (1.25 g, 11.4 mmol) and AcOH (1.72 g, 28.6 mmol) and purified by flash chromatography eluting with DCM / MeOH / NH4OH (94:6:1) to give the title compound as a beige solid (1.45 g, 64%).

[0191] 6-([1,1'-biphenyl]-3-yl)-5,7-dimethyl-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazine-1-1

[0192] According to Scheme 4: To a stirred solution of 6-(3-bromophenyl)-5,7-dimethyl-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one (80 mg, 0.20 mmol) in DME / water (8:2, 1.6 mL) was added phenylboronic acid (62 mg, 0.51 mmol), K3PO4 (107 mg, 0.51 mmol) and PdCl2(dppf) (15 mg, 20 μmol). The mixture was stirred in a sealed tube under nitrogen atmosphere at 130° C. for 45 min, cooled to rt, diluted with DCM, filtered through Celite and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel eluting with DCM / MeOH (98:2) to give the title compound as a grey solid (21 mg, 26%).

[0193] Mp:106-109°C;UPLC-MS:RT=1.06min;MS m / z ES + =393; 1 H-NMR(300MHz, DMSO-d6)δ:8.58 (1H, dd), 8.33(1H, s), 7.97-7.89(2H, m), 7.82-7.69(4H, m), 7.55-7.39(6H, m), 2.43(3H, s), 2.32(3H, s).

[0194] Example 12: 6-(3-(diethylamino)phenyl)-5,7-dimethyl-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one (final compound 1-100)

[0195] 6-(3-aminophenyl)-5,7-dimethyl-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one

[0196] According to Scheme 4: To a stirred solution of 5,7-dimethyl-6-(3-nitrophenyl)-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one (1.10 g, 3.04 mmol) in DCM (12 mL) was added zinc powder (2.00 g, 30.4 mmol) and AcOH (1.83 g, 30.4 mmol) dropwise. The reaction mixture was stirred at rt for 6 h, filtered through Celite, and concentrated under reduced pressure. The crude residue was washed with Et2O and dried to give the title compound as a brown solid (810 mg, 80%), which was used in the next step without further purification.

[0197] 6-(3-(diethylamino)phenyl)-5,7-dimethyl-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one

[0198] According to Scheme 4: To a stirred solution of 6-(3-aminophenyl)-5,7-dimethyl-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one (100 mg, 0.30 mmol) in ACN (4 mL) at 0° C., acetaldehyde (133 mg, 3.02 mmol) and AcOH (181 mg, 3.02 mmol) were added. The reaction mixture was stirred at 0° C. for 20 min, and then NaBH(OAc)3 (192 mg, 0.91 mmol) was added. The mixture was stirred at rt for 1 h, poured into water and extracted with DCM. The organic layer was washed with NaHCO3 and NH4Cl, dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using DCM / MeOH (98:2) as eluent. The resulting solid was washed with Et2O to give the title compound as an orange solid (26 mg, 22%).

[0199] Mp<85°C;UPLC-MS:RT=0.98min;MS m / z ES + =388; 1 H-NMR(300MHz, DMSO-d6)δ:8.59-8.54(1H, m), 8.29(1H, s), 7.98-7.90(1H, m), 7.51-7.46(1H, m), 7.45-7.39(1H, m), 7.39-7.31(1H, m), 6.82(1H, dd), 6.60-6.55(1H, m), 6.52(1H, dd), 3.37(4H, q), 2.40(3H, s), 2.28(3H, s), 1.10(6H, t).

[0200] Example 13: 2-(6-hydroxypyridin-3-yl)-6-(3-methoxyphenyl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one (final compound 1-131)

[0201] According to Scheme 6: To a solution of 6-(3-methoxyphenyl)-2-(6-methoxypyridin-3-yl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one (60 mg, 159 μmol) in THF (0.5 mL) was added dropwise 6M HCl (775 μL) and NaI (23.9 mg, 159 μmol). The mixture was stirred at 60° C. for 5 h. The solvent was evaporated under reduced pressure. The residue was basified with 1M aqueous NaHCO3 and extracted with DCM. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to give a red liquid. The crude was purified by preparative HPLC to give the title compound as an orange oil (19.4 mg, 34%).

[0202] Mp:207-209°C;UPLC-MS:RT=0.79min;MS m / z ES + =363; 1 H-NMR(300MHz, CDCl3)δ:8.05(1H, s), 7.95-7.88(2H, m), 7.51-7.43(1H, m), 7.07(1H, dd), 6.80(1H, dd), 6.75-6.66(2H, m), 3.88(3H, s), 2.51(3H, s), 2.28(3H, s).

[0203] Example 14: 2-(4-(2-hydroxypropan-2-yl)phenyl)-6-(3-methoxyphenyl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one (final compound 1-135)

[0204] According to Scheme 5: To a stirred solution of 2-(4-acetylphenyl)-6-(3-methoxyphenyl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one (75 mg, 0.19 mmol) in THF (1.5 mL) at 0° C., methylmagnesium bromide (0.19 mL, 0.58 mmol) was added. The mixture was stirred at 0° C. for 30 min. The mixture was diluted with DCM and quenched with an aqueous solution of NH4Cl. The mixture was washed with NaHCO3 and then NH4Cl. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to give a yellow solid. The crude solid was purified by flash chromatography on silica gel eluting with DCM / MeOH (98 / 2), triturated with DCM / MeOH (1 / 9), and concentrated under reduced pressure to give the title compound as a beige solid (16 mg, 20%).

[0205] Mp:103-108°C;UPLC-MS:RT=1.01 min;MS m / z ES + =404; 1 H-NMR(300MHz, DMSO-d6)δ:8.32(1H, s), 7.59-7.49(3H, m), 7.42-7.39(2H, m), 7.18-7.15(2H, m), 7.04-6.98(2H, m), 5.08(1H, s), 3.82(3H, s), 2.40(1H, s), 2.26(1H, s), 1.46(6H, s).

[0206] Example 15: 2-(4-(1-hydroxyethyl)phenyl)-6-(3-methoxyphenyl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one (final compound 1-138)

[0207] According to Scheme 5: To a stirred solution of 2-(4-acetylphenyl)-6-(3-methoxyphenyl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one (75 mg, 0.19 mmol) in THF (2 mL) at 0° C., NaBH4 (7 mg, 0.19 mmol) was added. The mixture was stirred at rt for 45 min. The mixture was diluted with DCM, quenched with NH4Cl, and washed with NaHCO3. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to give a beige solid. The crude solid was purified by flash chromatography on silica gel using DCM / MeOH (98 / 2) as eluent to give a solid. The resulting solid was washed with Et2O to give the title compound as a beige solid (40 mg, 53%).

[0208] Mp:192-195°C;UPLC-MS:RT=0.97min;MS m / z ES + =390; 1 H-NMR(300MHz, DMSO-d6)δ:8.32(1H, d), 7.58-7.50(1H, m), 7.45-7.37(4H, m), 7.16(1H, dd), 7.04-6.97(2H, m), 5.22(1H, d), 4.81-4.73(1H, m), 3.82(3H, s), 2.40(3H, s), 2.26(3H, s), 1.35(3H, d).

[0209] Example 16: 6-(3-(azetidin-1-yl)phenyl)-5,7-dimethyl-2-(4-(pyrrolidin-1-yl)phenyl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one (final compound 1-168)

[0210] According to Scheme 5: To a solution of 6-(3-(azetidin-1-yl)phenyl)-2-(4-bromophenyl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one (120 mg, 0.27 mmol) in DMF (5 mL) under argon atmosphere in a sealed tube, pyrrolidine (56 mg, 0.80 mmol), Xantphos (15 mg, 27 μmol) and Cs2CO3 (0.13 g, 0.40 mmol) were added. The mixture was degassed under argon for 10 min and PdCl2(dppf) (10 mg, 13 μmol) was added. The mixture was degassed again for 5 min and stirred at 130 °C for 16 h. After adding water (15 mL), the reaction mixture was extracted with EtOAc (4x25 mL). The organic layers were combined, washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude material was purified by chromatography on silica eluting with hexane / EtOAc (70 / 30) to give the title compound as a yellow solid (22 mg, 19%).

[0211] UPLC-MS: RT = 3.61 min; MS m / z ES + =440; 1 H-NMR(300MHz, CDCl3)δ:8.10(1H, s), 7.40-7.30(3H, m), 6.60(2H, d), 6.55-6.45(2H, m), 6.20-6.19(1H, m), 3.90(4H, t), 3.30(4H, t), 2.50(3H, s), 2.45-2.35(2H, m), 2.30(3H, s), 2.10-1.90(4H, m).

[0212] Example 17: 6-(3-(azetidin-1-yl)phenyl)-2-(4-(2-hydroxyethyl)phenyl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one (final compound 1-169)

[0213] According to Scheme 5: Ethyl 2-(4-(6-(3-(azetidin-1-yl)phenyl)-5,7-dimethyl-1-oxo-1H-pyrrolo[3,4-d]pyridazin-2(6H)-yl)phenyl)acetate (100 mg, 0.22 mmol) was dissolved in Et2O (4 mL). To the solution was added LiBH4 under argon atmosphere followed by dropwise addition of MeOH (0.1 mL). After complete addition, the mixture was stirred at rt for 1 h and the reaction mixture was evaporated under reduced pressure. To the residue was added a saturated solution of NH4Cl and the reaction mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give an oil. The crude oil was purified by chromatography on silica eluting with DCM / MeOH to give the title compound (20 mg, 22%).

[0214] UPLC-MS: RT = 2.96 min; MS m / z ES + =415; 1 H-NMR(400MHz, CDCl3)δ:8.10(1H, s), 7.50(2H, d), 7.40-7.30(3H, m), 6.60-6.50(2H, m), 6.20-6.19(1H, m), 4.00-3.80(6H, m), 3.00-2.80(2H, t), 2.50(3H, s), 2.45-2.35(2H, m), 2.30(3H, s).

[0215] Example 18: 6-(3-(azetidin-1-yl)phenyl)-2-(4-(2-hydroxypropan-2-yl)phenyl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one (final compound 1-170)

[0216] According to Scheme 5: 2-(4-acetylphenyl)-6-(3-(azetidin-1-yl)phenyl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one (200 mg, 0.48 mmol) was dissolved in dry THF (5 mL). After the solution was cooled to -30 °C, methylmagnesium iodide 3M in Et2O (0.242 mL, 0.727 mmol) was added dropwise to the solution and the reaction mixture was stirred at -30 °C for 15 min. Then the mixture was warmed to rt and stirred for 30 min. The reaction mixture was quenched with aqueous NH4Cl and the aqueous phase was extracted with EtOAc (3 x 25 mL). The organic layers were combined, washed with water (2 x 10 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel with hexane / EtOAc (75 / 25) to give the title compound as a yellow solid (40 mg, 19%).

[0217] UPLC-MS: RT=1.27min; MS m / z ES + =422; 1 H-NMR(400MHz, CDCl3)δ:8.07(1H, s), 7.60(4H, s), 7.37-7.33(1H, m), 6.57-6.52(2H, m), 6.20-6.19(1H, m), 3.90(4H, t), 2.50(3H, s), 2.45-2.42(2H, m), 2.30(3H, s), 1.60(6H, s).

[0218] Example 19: 6-(3-(azetidin-1-yl)phenyl)-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one (final compound 1-188)

[0219] 2-(Pyridin-2-yl)pyridazin-3(2H)-one

[0220] According to Scheme 7, Step 1: Pyridazin-3(2H)-one (250 mg, 2.60 mmol), 2-bromopyridine (0.25 mL, 2.60 mmol), KPO (1.10 g, 5.20 mmol), N 1 ,N 2 Final compound 1-2, prepared according to Scheme 2, step 2, from -dimethylcyclohexane-1,2-diamine (111 mg, 0.78 mmol) and CuI (99 mg, 0.52 mmol) to afford the title compound as an orange oil (300 mg, 67%).

[0221] 2-(Pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one

[0222] According to Scheme 7, step 2: To a solution of NaH (520 mg, 13.0 mmol) in THF (15 mL) at 0° C. was added 2-(pyridin-2-yl)pyridazin-3(2H)-one (750 mg, 4.33 mmol) and a solution of 1-(isocyanomethylsulfonyl)-4-methylbenzene (930 mg, 4.76 mmol) in THF. After stirring the reaction mixture at rt for 12 h, the solution was carefully quenched with water. After evaporation of the solvent, the resulting black solid was treated with DCM and MeOH and the mixture was filtered. The solvent was removed under reduced pressure to give a black solid, which was purified by flash chromatography on silica gel eluting with DCM / MeOH (95:5) to give the title compound as an off-white solid (340 mg, 37%).

[0223] 6-(3-(azetidin-1-yl)phenyl)-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one

[0224] According to Scheme 7, Step 3: 2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one (100 mg, 0.47 mmol), 1-(3-bromophenyl)azetidine (100 mg, 0.47 mmol), KPO (200 mg, 0.94 mmol), N 1 ,N 2 Final compound 1-2, prepared according to Scheme 2, step 2, from -dimethylcyclohexane-1,2-diamine (20.1 mg, 141 μmol) and CuI (17.9 mg, 94 μmol) to afford the title compound as an off-white solid (18 mg, 11%).

[0225] Mp:190-192°C;UPLC-MS:RT=0.84min;MS m / z ES + =345; 1 H-NMR(300MHz, CDCl3)δ:8.60(1H, s), 8.21(1H, s), 7.91-7.62(3H, m), 7.38(1H, d), 7.28-7.18(2H, m), 6.78-6.71(1H, m), 6.43-6.37(2H, m), 3.88(4H, t), 2.35(2H, q).

[0226] Example 20: 6-(3-(azetidin-1-yl)phenyl)-2-(4-(2-fluoroethyl)phenyl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one (final compound 1-189)

[0227] According to Scheme 5: A solution of 6-(3-(azetidin-1-yl)phenyl)-2-(4-(2-hydroxyethyl)phenyl)-5,7-dimethyl-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one (200 mg, 0.48 mmol) in DCM (33 mL) was added dropwise to a solution of DAST reagent (128 μL, 0.96 mmol) in DCM (5 mL) at −78° C. under nitrogen. The reaction mixture was stirred at −78° C. for 1 h and at rt for 30 min. The mixture was poured into ice water and the aqueous layer was extracted three times with DCM / MeOH. The organic layers were combined, dried over MgSO4 and concentrated under reduced pressure. The crude residue was purified by preparative HPLC to give the title compound as a white solid (10 mg, 5%).

[0228] UPLC-MS: RT = 0.84 min; MS m / z ES + =345; 1 H-NMR(300MHz, CDCl3)δ:8.06(1H, s), 7.54(2H, d), 7.37-7.26(3H, m), 6.56(2H, t), 6.20(1H, s), 4.41(1H, t), 4.55(1H, t), 3.93(4H, t), 3.09(1H, t), 3.02(1H, t), 2.51(3H, s), 2.41(1H, t), 2.28(3H, s).

[0229] Example 21: 5,7-Dimethyl-6-(1-methyl-1H-indol-6-yl)-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one (final compound 1-96)

[0230] According to Scheme 4: A mixture of 6-(1H-indol-6-yl)-5,7-dimethyl-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one (44 mg, 0.124 mmol) and NaH (4.46 mg, 186 μmol) in chloroform (0.5 mL) was stirred at rt for 30 min. Then, iodomethane (9.25 μl, 149 μmol) was added dropwise and the solution was stirred at rt overnight. The reaction mixture was quenched with water, diluted with DCM and NaHCO3 was added to the mixture. The organic layer was separated, dried over MgSO4, filtered and evaporated under reduced pressure to give a brown solid. The crude solid was purified by LC prep to give the title compound as a black oil (4.2 mg, 9%).

[0231] UPLC-MS: RT = 0.94 min; MS m / z ES + =370; 1 H-NMR(300MHz, CDCl3)δ:8.69-8.63 1H, m), 8.16(1H, s), 7.85-7.70(3H, m), 7.29-7.18(3H, m), 6.93(1H, dd), 6.61(1H, dd), 3.84(3H, s), 2.50(3H, s), 2.27(3H, s).

[0232] Example 22: 6-(3-(azetidin-1-yl)phenyl)-5,7-dimethyl-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one (final compound 1-102)

[0233] (E)-1-(3-bromophenyl)-2,5-dimethyl-4-((2-(pyridin-2-yl)hydrazono)methyl)-1H-pyrrole-3-carboxylate ethyl

[0234] According to Scheme 8, step 1: To a solution of ethyl 1-(3-bromophenyl)-4-formyl-2,5-dimethyl-1H-pyrrole-3-carboxylate (12.0 g, 34.3 mmol) in dioxane (150 mL) was added 2-hydrazinylpyridine (4.11 g, 37.7 mmol) and acetic acid (14.4 g, 240 mmol, 13.8 mL). After refluxing the resulting mixture for 2 h, the solvent was evaporated under reduced pressure and EtOAc (200 mL) was added. The organic layer was washed with NaHCO3 (aq 15%) (75 mL), dried over Na2SO4 and concentrated under reduced pressure. The resulting solid was treated with hexane to give (E)-ethyl 1-(3-bromophenyl)-2,5-dimethyl-4-((2-(pyridin-2-yl)hydrazono)methyl)-1H-pyrrole-3-carboxylate (14 g, 88%).

[0235] LC-MS:RT=1.29min; [M+3H] + m / z: 443; 1 H NMR(500 MHz, DMSO-d6)δ:8.59(1H, s), 8.09(1H, d), 7.78(1H, d), 7.70(1H, s), 7.52(2H, m), 7.39(1H, d), 7.00(1H, d), 6.65(1H, t), 4.23(2H, q), 2.22(3H, s), 2.20(3H, s), 1.19(3H, t).

[0236] 6-(3-Bromophenyl)-5,7-dimethyl-2-(pyridin-2-yl)-1H,2H,6H-pyrrolo[3,4-d]pyridazin-1-one

[0237] According to Scheme 8, Step 2: (E)-ethyl 1-(3-bromophenyl)-2,5-dimethyl-4-((2-(pyridin-2-yl)hydrazono)methyl)-1H-pyrrole-3-carboxylate (12.0 g, 27.2 mmol) was heated in an oil bath at 165-170 °C for 2 hours to give 6-(3-bromophenyl)-5,7-dimethyl-2-(pyridin-2-yl)-1H,2H,6H-pyrrolo[3,4-d]pyridazin-1-one (10.0 g, 88.4%). The raw material was used without further purification.

[0238] LC-MS:RT=1.38min, [M+3H] + m / z: 397; 1 H NMR(400 MHz, DMSO-d6)δ:8.57(1H, d), 8.31(1H, s), 7.94(1H, t), 7.81(2H, m), 7.59(1H, t), 7.51(2H, m), 7.42(1H, t), 2.39(3H, s), 2.26(3H, s).

[0239] 6-(3-(azetidin-1-yl)phenyl)-5,7-dimethyl-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one

[0240] According to Scheme 4: 6-(3-bromophenyl)-5,7-dimethyl-2-(pyridin-2-yl)-1H,2H,6H-pyrrolo[3,4-d]pyridazin-1-one (11.0 g, 27.8 mmol), azetidine hydrochloride (5.21 g, 55.7 mmol), Xantphos (1.61 g, 2.78 mmol), Pd(dppf)Cl2*DCM (2.27 g, 2.78 mmol) and cesium carbonate (31.7 g, 97.4 mmol) in DMF (200 mL) were stirred for 5 h at 130° C. The mixture was then diluted with DCM (100 mL) and filtered through a silica pad. The filtrate was concentrated under reduced pressure to give 6-(3-(azetidin-1-yl)phenyl)-5,7-dimethyl-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one (11.0 g, 60% purity LC / MS, 17.8 mmol, 64% yield) as a black solid. The crude solid was dissolved in EtOAc (200 mL), washed with water (50 mL) and Si-Thiol (1 g) was added. The resulting suspension was stirred at room temperature for 8 h, the scavenger was filtered off and the mother liquor was concentrated under reduced pressure. The resulting residue was purified by flash chromatography (normal phase, CHCl3 / MTBE as eluent) to give 4.4 g of product with 95% purity. Crystallization from acetonitrile, then from toluene and finally from acetonitrile gave 1.7 g of product.

[0241] LC-MS:RT=1.37min, [M+H] + m / z: 372; 1 H NMR(500 MHz, DMSO-d6)δ:8.56(1H, d), 8.28(1H, s), 7.93(1H, t), 7.48(1H, d), 7.41(1H, m), 7.37(1H, t), 6.63(1H, d), 6.57(1H, d), 6.37(1H, s), 3.85(4H, t), 2.39(3H, s), 2.32(2H, t), 2.26(3H, s).

[0242] Example 23: 6-(2-chloro-3-cyclopropoxyphenyl)-5,7-dimethyl-2-(pyrimidin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one (final compound 1-215)

[0243] 1-(2-chloro-3-hydroxy-phenyl)-4-formyl-2,5-dimethyl-pyrrole-3-carboxylate ethyl

[0244] According to Scheme 9, step 1: To a cold solution of ethyl 1-(2-chloro-3-methoxy-phenyl)-4-formyl-2,5-dimethyl-pyrrole-3-carboxylate (77.0 mg, 0.23 mmol) in DCM (1 mL) was added BBr3 (1 M solution in DCM, 8 mL). The reaction mixture was stirred on an ice bath for 3 h and poured into a saturated solution of NaHCO3. The product was extracted with DCM (3 x 30 mL). The combined organic extracts were washed with brine (45 mL), dried over Na2SO4, filtered and evaporated to give the title compound (60 mg) as a light brown solid. The crude product was used in the next step without further purification.

[0245] UPLC-MS / UV (2min, low pH): RT=1.04min, m / z=322[M+H] + .

[0246] 1-[2-chloro-3-(cyclopropoxy)phenyl]-4-formyl-2,5-dimethyl-pyrrole-3-carboxylate ethyl

[0247] According to Scheme 9, step 2: Ethyl 1-(2-chloro-3-hydroxy-phenyl)-4-formyl-2,5-dimethyl-pyrrole-3-carboxylate (60.0 mg, 185 μmol), bromocyclopropane (67.0 mg, 554 μmol) and cesium carbonate (120 mg, 369 μmol) were suspended in DMF (0.6 mL). The reaction mixture was irradiated in a microwave at 170 °C for 6 h. Water (15 mL) was added and extracted with EtOAc (3x15 mL). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered and evaporated. The crude was purified by FCC (Interchym system, 4 g 15 μm SiO2 column, weak eluent: cyclohexane, strong eluent: cyclohexane / EtOAc = 1 / 1, 0-60% of strong eluent) to give the title compound (26 mg, purity ~80 %) as a yellow oil.

[0248] UPLC-MS / UV (2 min, low pH): RT = 1.32 min, m / z = 362 / 364 [M+H]+.

[0249] 6-[2-chloro-3-(cyclopropoxy)phenyl]-5,7-dimethyl-3-pyrimidin-2-yl-pyrrolo[3,4-d]pyridazin-4-one

[0250] According to Scheme 9, step 3: Ethyl 1-[2-chloro-3-(cyclopropoxy)phenyl]-4-formyl-2,5-dimethyl-pyrrole-3-carboxylate (26.0 mg, 71.9 μmol) and pyrimidin-2-yl-hydrazine (8.70 mg, 79.0 μmol) were dissolved in dioxane (300 μL) and acetic acid (41 μL, 719 μmol) was added. The reaction mixture was MW irradiated (Biotage) at 160° C. for 6 h. The reaction mixture was basified with saturated NaHCO3 (15 mL) and extracted with EtOAc (3×15 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4, filtered and evaporated to dryness. The crude was purified by preparative HPLC to give the title compound (14 mg) as a white solid.

[0251] Mp:228°C;UPLC-MS / UV(8 min, high pH):RT=4.16min, m / z=408 / 410 [M + H] + ; 1 H NMR(300 MHz, DMSO-d6)δ:8.96(2H, d), 8.31(1H, s), 7.72-7.66(1H, m), 7.65-7.57(2H, m), 7.27-7.20(1H, m), 4.12-4.03(1H, m), 2.28(3H, m), 2.18(3H, s), 0.93-0.84(2H, m), 0.83-0.74(2H, m).

[0252] Example 24: 6-(3-(2H-1,2,3-triazol-2-yl)phenyl)-5,7-dimethyl-2-(pyridin-2-yl)-2,6-dihydro-1H-pyrrolo[3,4-d]pyridazin-1-one (final compound 1-199)

[0253] Ethyl 4-formyl-2,5-dimethyl-1-[3-(triazol-2-yl)phenyl]pyrrole-3-carboxylate

[0254] According to Scheme 3: 1-(3-bromophenyl)-4-formyl-2,5-dimethyl-pyrrole-3-ethyl carboxylate (440 mg, 1.26 mmol), 2H-triazole (130 mg, 1.88 mol), K3PO4 (800 mg, 3.77 mmol) and 2-(di-tert-butylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl (60.9 mg, 0.13 mmol) were suspended in toluene (7 mL) under argon atmosphere. The suspension was bubbled with argon for 10 min and tBuBrettPhos Pd G3 (53.7 g, 0.06 mmol) was added. The vial was sealed and the reaction mixture was stirred at 130 °C. After 4 h, the reaction mixture was cooled to room temperature and EtOAc (20 mL) and water (50 mL) were added. The layers were separated and the product was extracted with EtOAc (2x30mL). The organic layers were combined, washed with brine (40mL), dried over Na2SO4, filtered and evaporated. The crude was purified using FCC (Interchym system, 12g 15μm SiO2 column, weak eluent: cyclohexane, strong eluent: cyclohexane / EtOAc=1 / 1, 0-50% strong eluent) to give the title compound (276mg) as a yellow oil.

[0255] UPLC-MS / UV(2min, high pH):RT=1.20min, m / z=339.0 [M+H] + .

[0256] 5,7-Dimethyl-3-(2-pyridyl)-6-[3-(triazol-2-yl)phenyl]pyrrolo[3,4-d]pyridazin-4-one

[0257] According to Scheme 1, step 4: Prepared from ethyl 4-formyl-2,5-dimethyl-1-[3-(triazol-2-yl)phenyl]pyrrole-3-carboxylate according to final compound 1-26 and purified by preparative HPLC to give the title compound as a white solid.

[0258] Mp:173°C;UPLC-MS / UV(8min, high pH):RT=3.97min;MS m / z ES+ =384; 1 H NMR(500 MHz, DMSO-d6)δ:8.59-8.55(1H, m), 8.33(1H, s), 8.28-8.24(1H, m), 8.21(2H, s), 8.06(1H, s), 7.95(1H, dt), 7.85(1H, t), 7.56-7.53(1H, m), 7.51(1H, d), 7.46-7.41(1H, m), 2.43(3H, s), 2.32(3H, s).

[0259] The compounds in the following table were synthesized according to the same methods as in the previous Examples 1 to 24, as shown in the column labeled "Example No." Compounds marked with an asterisk were exemplified in the Examples.

[0260] TIFF2024517500000127.tif95155TIFF2024517500000128.tif198119TIFF20245175000 00129.tif201120TIFF2024517500000130.tif199121TIFF2024517500000131.tif255159 TIFF2024517500000132.tif197118TIFF2024517500000133.tif196118TIFF20245175000 00134.tif197117TIFF2024517500000135.tif193118TIFF2024517500000136.tif192119 TIFF2024517500000137.tif196119TIFF2024517500000138.tif199117TIFF20245175000 00139.tif249160TIFF2024517500000140.tif250158TIFF2024517500000141.tif253157 TIFF2024517500000142.tif248156TIFF2024517500000143.tif252158TIFF20245175000 00144.tif199120TIFF2024517500000145.tif198120TIFF2024517500000146.tif230161

[0261] Physicochemical data Melting point: a) Melting point determinations were performed on a Buchi B-540 apparatus. b) DSC analysis DSC data taken from a Mettler Toledo DSC 822 equipped with a refrigerated cooling system e The data were collected in a calorimeter. Samples were placed in aluminum DSC pans with pinhole punched lids. The sample cells were heated at a rate of 10 °C / min over the temperature range of 25-350 °C. Nitrogen purging was performed at 50 mL / min. Melting points were expressed as integer values ​​of the onset of melting temperature.

[0262] UPLC-MS Method: Method 1: UPLC-MS was recorded on a Waters ACQUITY UPLC under the following conditions: Reverse phase HPLC was performed using Waters BEH-C 18 A cartridge (1.7 μm, 2.1x50 mm) was used with a flow rate of 0.8 mL / min. The gradient conditions used were: 90% A (water + 0.1% formic acid), 10% B (ACN + 0.1% formic acid) to 100% B in 1.3 min, held until 1.7 min, equilibrated to initial conditions from 1.8 min to 2.0 min. The injection volume was 5 μL. An ES MS detector was used, acquiring both positive and negative ionization modes. Method 2: UPLC-MS was recorded on a Waters ACQUITY UPLC under the following conditions: Reverse phase HPLC was performed using Waters HSS T3 cartridges (1.8 μm, 2.1x50 mm) at a flow rate of 0.8 mL / min. The gradient conditions used were: 98% A (water + 0.1% formic acid), 2% B (ACN + 0.1% formic acid) to 70% B at 1.3 min, 90% B at 1.35 min, hold until 1.75 min, equilibrated to initial conditions from 1.8 min to 2.0 min. Injection volume was 5 μL. ES MS detector was used, acquisition in both positive and negative ionization modes. Method 5: Waters Acquity UPLC coupled with SQD Mass Spectrometry System; High pH Methods (2 min) Reverse phase HPLC was performed using Acquity's BEH-C 18 A cartridge (1.7 μm, 2.1x50 mm) was used with a flow rate of 0.9 mL / min. Gradient conditions were as follows: 97% A (water + 0.05% ammonia), 3% B (ACN + 0.03% ammonia) to 97% B at 1.50 min, hold to 1.90 min, equilibrated to initial conditions from 1.91 min to 2.0 min. Injection volume was 2 μL. ES MS detector was used for acquisition in both positive and negative ionization modes. Method 6: Waters Acquity UPLC coupled with SQD Mass Spectrometry; Low pH Methods (2 min) Reverse phase HPLC was performed using Acquity's BEH-C 18 A cartridge (1.7 μm, 2.1x50 mm) was used with a flow rate of 0.9 mL / min. Gradient conditions were as follows: 97% A (water + 0.1% formic acid), 3% B (ACN + 0.1% formic acid) to 97% B at 1.50 min, held to 1.90 min, equilibrated to initial conditions from 1.91 min to 2.0 min. Injection volume was 2 μL. ESMS detector was used, acquisition in both positive and negative ionization modes. Method 7: Waters Acquity UPLC coupled with SQD Mass Spectrometry System; High pH Method (8 min) Reverse phase HPLC was performed using Acquity's BEH-C 18 A cartridge (1.7 μm, 2.1x100 mm) was used with a flow rate of 0.6 mL / min. Gradient conditions were as follows: 97% A (water + 0.05% ammonia), 3% B (ACN + 0.05% ammonia) to 97% B at 7.0 min, hold to 7.50 min, equilibration to initial conditions from 7.6 min to 8.0 min. Injection volume was 2 μL. ES MS detector was used and acquisition was performed in both positive and negative ionization modes. Method 8: Waters Acquity UPLC coupled with SQD Mass Spectrometry; Low pH Method (8 min) Reverse phase HPLC was performed using Acquity's BEH-C 18 A cartridge (1.7 μm, 2.1x100 mm) was used with a flow rate of 0.6 mL / min. Gradient conditions were as follows: 97% A (water + 0.1% formic acid), 3% B (ACN + 0.1% formic acid) at 7.0 min, maintained at 97% B until 7.50 min, and equilibrated to the initial condition from 7.6 min to 8.0 min. Injection volume was 2 μL. ESMS detector was used and acquisition was performed in both positive and negative ionization modes.

[0263] LC-MS method: Method 3: LC-MS was recorded on a Waters Micromass ZQ 2996 system under the following conditions: Reverse phase HPLC was performed using Agilent Zorbax SB-C 18 A cartridge (1.8 μm, 4.6x30 mm) was used, with a flow rate of 1.5 mL / min. Gradient conditions were as follows: 90% A (water + 0.05% formic acid), 10% B (ACN + 0.05% formic acid) to 100% B in 3.5 min, held until 3.7 min, and equilibrated to the initial condition from 3.8 min to 4.5 min. Injection volumes were 5-20 μL. An ES MS detector was used for acquisition in both positive and negative ionization modes. Cone voltage was 30 V for both positive and negative ionization modes. Method 4: LC-MS was recorded using an Agilent Model 120 series system under the following conditions: Reverse phase HPLC was performed using an Agilent Atlantis d C 18 A cartridge (3 μm, 50x3 mm) was used, with a flow rate of 1.2 mL / min. Gradient conditions were as follows: 95% A (water + 0.1% formic acid), 5% B (ACN + 0.1% formic acid) to 100% B in 3.5 min, held until 3.8 min, and equilibrated to the initial state from 3.9 min to 4.5 min. Injection volume was 5 μL. An ES MS detector was used for acquisition in both positive and negative ionization modes. Cone voltage was 30 V for both positive and negative ionization modes. Method 9: LC-MS was recorded on an Agilent Technologies 1260 Infinity LC / MSD system equipped with a DADELSD Alltech 3300 and an Agilent LCMSD G6120B mass spectrometer under the following conditions: Reversed-phase UHPLC was performed using Agilent's UHPLC Guard Infinity Lab Poroshell 120 SB-C 18 The cartridge (2.7 μm, 4.6x30 mm) was used, with a flow rate of 3 mL / min and a temperature of 60°C. The gradient conditions were as follows: 1% A (ACN:water (99:1%) + 0.1% formic acid), 99 % B (water + 0.1% formic acid) to 100% A in 1.5 min, held to 2.2 min, and equilibrated to initial conditions at 2.21 min. The injection volume was 0.5 μL. An ES MS detector was used, acquiring in both positive and negative ionization modes.

[0264] Preparative HPLC purification: Purification was performed using an Agilent 1290 Infinity II series preparative HPLC system (1290 Infinity II binary pump, 1260 Infinity II diode array detector, LC / MSD mass detector) and a Waters SunFire (C 18 , 19x100mm, 5μm) or Waters XBridge (C 18 A 19x100mm, 5μm) column was used with HO+0,1% formic acid or HO+0,1% ammonia (25% ammonia in water) and ACN as eluents. The eluents used ranged from 10% ACN to 100% ACN.

[0265] NMR 1 H NMR spectra were recorded on a Bruker Avance (400 MHz, 300 MHz) or Varian 400 MHz spectrometer. Chemical shifts are expressed in parts per million (ppm, δ units). Splitting patterns indicate apparent multiplicity and are denoted as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and br (broad line).

[0266] NMR spectra were recorded on a Bruker DPX 300 MHz equipped with a RT 5 mm BBI probe, a Bruker AV400 MHz equipped with a RT 5 mm BBO probe, a Bruker DRX 500 MHz equipped with RT 5 mm SEI and TXI probes, a Bruker Avance III 600 spectrometer equipped with a 5 mm RT BBI probe, and a Varian Unity Plus 400 MHz spectrometer. Samples were recorded at 25 °C using DMSO-d6, CDCl3, pyridine-d5 or toluene-d8 as solvents and TMS as internal standard.

[0267] TIFF2024517500000147.tif217170TIFF2024517500000148.tif186129TIFF2024517500000149.tif197127TIFF2024517500000150.tif18 7129TIFF2024517500000151.tif189131TIFF2024517500000152.tif193129TIFF2024517500000153.tif182131TIFF2024517500000154.t if188131TIFF2024517500000155.tif198129TIFF2024517500000156.tif202127TIFF2024517500000157.tif200129TIFF20245175000001 58.tif247168TIFF2024517500000159.tif196128TIFF2024517500000160.tif188131TIFF2024517500000161.tif249169TIFF20245175000 00162.tif187130TIFF2024517500000163.tif193130TIFF2024517500000164.tif189130TIFF2024517500000165.tif250170TIFF2024517 500000166.tif184128TIFF2024517500000167.tif186129TIFF2024517500000168.tif193130TIFF2024517500000169.tif187131TIFF202 4517500000170.tif199126TIFF2024517500000171.tif188128TIFF2024517500000172.tif187129TIFF2024517500000173.tif191129TIF F2024517500000174.tif193128TIFF2024517500000175.tif185130TIFF2024517500000176.tif193128TIFF2024517500000177.tif124130

[0268] 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.

[0269] Some of the compounds of formula (I) have been tested according to the following methods.

[0270] Example A mGlu7 assay for HEK-expressed human mGlu7 Transfection and cell culture A cDNA encoding the human metabotropic glutamate 7 receptor (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 to intracellular calcium flux was subcloned into another expression vector that also contained a puromycin resistance gene. Transfection of both these vectors into HEK293 cells was performed using PolyFect reagent (Qiagen) according to the supplier's protocol, and hygromycin and puromycin treatment allowed the selection of antibiotic-resistant cells that had stably integrated one or more copies of the plasmid. 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.

[0271] HEK-293 cells expressing hmGlu7 were cultured in DMEM, fetal bovine serum (10%), Glutamax 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) were incubated at 37°C and 5% CO 2 , and maintained in a humidified atmosphere.

[0272] Fluorescent cell-based Ca 2+ Recruitment assay Human mGlu7 HEK-293 cells were analyzed by FLIPR 384 24 h prior to the fluorescent cell-based calcium mobilization assay using the Assay (Molecular Device, Sunnyvale, CA, USA), cells were cultured 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.

[0273] On the day of the assay, the medium was aspirated and the 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 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.

[0274] 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. Then, to measure the inhibitory activity of the compounds of the present invention, the cells were incubated with 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.

[0275] 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 obtain IC 50 Allows you to determine the value: (Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*Hill Slope)) IC of the compounds of the present application 50 The value is less than 10 μM.

[0276] Table 3 below shows the average IC obtained from at least three independent experiments performed in duplicate for selected molecules. 50 It represents.

[0277] TIFF2024517500000178.tif39156TIFF2024517500000179.tif198121TIFF2024517500000180.tif203118TIFF2024517500000181.tif57154

[0278] The results shown in Table 3 indicate that the compounds described in this invention are negative allosteric modulators of the human mGlu7 receptor.

[0279] Example B Water-related zero maze: The procedure was performed as previously described by 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 plastic tank holding the platform was filled with water up to 10 cm below the platform level (22 ± 2 °C, depth 50 cm). Thus, the circular platform and the plastic tank constituted one unified arena. For testing, rats were first habituated to the room for 4 min and then placed in one of the open quadrants facing the closed 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 with an EthoVision system (Noldus Information Technology, Wageningen, The Netherlands). Behavioral indices analyzed included time spent in the open quadrants, distance traveled in the open quadrants, distance traveled in the closed quadrants, and total freezing behavior. The effects of exposure to various stressors and compounds were evaluated using these parameters. The pretreatment times and administration routes of the various test compounds were defined based on their pharmacokinetic properties.

[0280] Example C Elevated plus maze: The elevated plus maze (EPM) test was performed with male Sprague-Dawley rats. The EPM was made of plastic and had two open arms (50 cm x 10 cm) and two equally sized closed arms with 40 cm high walls at a height of 86 cm from the ground. Both arms were made of black plexiglass. The mean illuminance in the open arms was 187 lux, and the mean illuminance in the closed arms was 100 lux. At the start of the experiment, the rats were placed in a holding room directly next to the experimental room and allowed to acclimate to the environment for 30 min. At the start of the test, the rats were placed in the center of the maze, facing one of the open arms, and observed for 5 min. During this time, the rats' behavior was tracked, recorded, and analyzed by an EthoVision system (Noldus Information Technology, Wageningen, The Netherlands). The behavioral indices analyzed included the time spent in the open arms, the number of entries into the open arms, and the distance traveled. The pretreatment time and the route of administration of the test compounds were defined based on their pharmacokinetic properties.

[0281] Example D Fear conditioning model of post-traumatic stress disorder in rats: The fear conditioning arena (30 cm × 20 cm × 25 cm, Med Associates) was made of Plexiglas and contained a variety of contexts. The system was installed in a soundproof ventilated box. The floor of the arena consisted of a grid floor (19 parallel rows of 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 took place over 2 days. On the first day (training), rats were placed in the training context (context A) and, after a 120 s habituation period, were subjected to five CS-US pairings. The CS tone (78 dB, 2 kHz, rise / fall time 5 ms) was presented for 30 s and terminated simultaneously with a brief US footshock (O.5 s, 0.66 mA). The interval between tones (from tone onset to the next tone onset) ranged from 60 s to 60 s. The conditioning chambers were 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 60 s of habituation, exposed to the CS (120 s). The time spent freezing was measured during both habituation and the CS. Test compounds were administered before or after the training and testing phases. Pretreatment times and routes of administration of the different test substances were adjusted based on their pharmacokinetic properties.

[0282] Example E Mouse model of noise-induced hearing loss (NIHL): The effect of test compounds on NIHL was 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. Pretreatment times and administration routes of test compounds were adjusted based on pharmacokinetic properties. Experimental groups were compared to vehicle-treated groups, e.g., through measurements of ABR thresholds and ABR threshold shifts.

[0283] Example F Colonic distension test for visceral pain in rats: In this study, we used male Wistar Kyoto rats (250–300 g), which are sensitive to stress. 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 was initiated. The paradigm used was stepwise distension, increasing from 0 mmHg to 80 mmHg over 8 min, using a computer-driven electronic barostat. The parameters measured were the threshold pressure (mmHg) that elicited visually identifiable visceral pain behaviors and the total number of pain behaviors. Postures defined as visceral pain behaviors were abdominal contraction and / or abdominal withdrawal reflex. Test compounds were administered prior to colon distension. Pretreatment times and administration routes of different test compounds were adjusted based on their pharmacokinetic properties.

[0284] Formulation example Representative examples of 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

[0285] In this embodiment, the active ingredient can be replaced by an equivalent amount of any of the compounds according to the invention, in particular by an equivalent amount of any of the exemplified compounds.

[0286] 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.

[0287] 3. Injections A parenteral composition is prepared by stirring 1.5% by weight of the active ingredient of the invention in 10% by volume propylene glycol and water.

[0288] 4. Ointment Active ingredient: 5-1000mg Stearyl alcohol 3g Lanolin 5g 15g white petroleum 100g water

[0289] 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.

[0290] Reasonable variations are not to be considered as departing from the scope of the invention.It will be apparent that the invention described can be varied in many ways by those skilled in the art.

Claims

1. Formula (I): A compound of the formula: A pharma- ceutically acceptable acid or base addition salt thereof, its stereochemically isomeric forms, or its N-oxide forms, wherein: R 1 is hydrogen, -CH 3 and -CF 3 is selected from the group R 2 and R 3 are each independently hydrogen, -(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) haloalkyl and -CF 3 is selected from the group P represents a cycloalkyl, aryl or heteroaryl of the formula: wherein each cycloalkyl, aryl or heteroaryl ring is optionally substituted with m radicals A, where m is an integer equal to 0, 1, 2, 3 or 4; Here, 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 , -NR 4 -(C 1 -C 6 )Alkylene-C(=O)-OR 5 , -(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 is an optionally substituted radical selected from the group consisting of: Q is aryl or heteroaryl optionally substituted with n radicals B, where n is an integer equal to 0, 1, 2, 3, 4 or 5; Each (B) n are hydrogen, halogens, -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 the group consisting of 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, -(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 or heteroaryl ring, each ring optionally containing 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 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 these, in combination with said intervening atoms, form a 3- to 10-membered heterocycle, aryl ring, or heteroaryl ring, each of which may optionally further comprise halogen, cyano, 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 substituted with 1 to 5 radicals independently selected from the group consisting of: Here, R 8 , R 9 , R 10 or R 11 and optionally two substituents from are combined with said intervening atoms to form a 3- to 10-membered heterocyclic, aryl or heteroaryl ring, wherein each ring is optionally selected from halogen, cyano, 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 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 or heteroaryl ring, each ring optionally containing 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 is further substituted with 1 to 5 radicals independently selected from the group consisting of: compound.

2. Q represents an aryl or heteroaryl group of the formula: wherein each radical is optionally substituted with n radicals B, n being an integer equal to 0, 1, 2, 3, 4 or 5; 1 is a radical B.

3. Q represents an aryl or heteroaryl of the formula: wherein each radical is optionally substituted with n radicals B, n being an integer equal to 0, 1, 2, 3, 4 or 5; 1 is the radical B, Here, B 1 is hydrogen, -(C 1 -C 6 ) alkyl or -(C 3 -C 7 3. The compound of claim 2 having formula (I), wherein:

4. P represents a cycloalkyl, aryl or heteroaryl of the formula:

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

5. (A) ｍ 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, piperazinyl, piperazinyl, piperidinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolopyridinyl pyrazolyl, pyridazinyl, pyridonyl, pyridyl, pyrimidyl, pyrrolidinonyl, pyrrolidinyl, 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, each ring of said ring system being selected from the group consisting of: 4 , R 5 , R 6 or R 7 5. The compound of claim 1 having formula (I), wherein:

6. (B) ｎ 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, piperazinyl, piperazinyl, piperidinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolopyridinyl pyrazolyl, pyridazinyl, pyridonyl, pyridyl, pyrimidyl, pyrrolidinonyl, pyrrolidinyl, 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, each ring of said ring system being selected from the group consisting of: 8 , R 9 , R 10 or R 11 6. The compound of claim 1 having 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, piperazinyl, piperazinyl, piperidinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolopyridinyl pyrazolyl, pyridazinyl, pyridonyl, pyridyl, pyrimidyl, pyrrolidinonyl, pyrrolidinyl, 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 7. The compound according to any one of claims 1 to 6, having formula (I), optionally substituted with 1 to 5 radicals independently selected from:

8. R 2 and R 3 are each independently selected from the group consisting of hydrogen, methyl and ethyl, where R 4 and R 5 Each independently represents hydrogen or -(C 1 -C 6 8. The compound according to any one of claims 1 to 7, having formula (I), wherein:

9. Each of the above (A) ｍ are hydrogen, halogens, -CN, -OH, -CF 3 , and -(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) haloalkyl, -(C 3 -C 7 )cycloalkyl, -(C 1 -C 6 ) cyanoalkyl, aryl, heterocycle, -(C 0 -C 6 ) Alkylene-OR 4 , -O-(C 2 -C 6 ) Alkylene-OR 4 , -(C 0 -C 6 ) Alkylene-S(=O) 2 -R 4 , -(C 0 -C 6 ) Alkylene-NR 4 R 5 , -(C 0 -C 6 ) Alkylene-S(=O) 2 NR 4 R 5 , -(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 , -(C 0 -C 6 )Alkylene-C(=O)-R 4 and -C(=O)-(C 1 -C 6 ) Alkylene-NR 4 -C(=O)-OR 5 and optionally substituted radicals selected from the group consisting of: Here, each of the (B) ｎ is 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 and optionally substituted radicals selected from the group consisting of: Here, R 8 and R 9 are each independently hydrogen, -(C 1 -C 6 ) haloalkyl, -(C 1 -C 6 ) alkyl, -(C 3 -C 7 9. The compound according to any one of claims 1 to 8, having formula (I), wherein: R is selected from the group consisting of cycloalkyl and aryl.

10. A compound of formula (II): which is a pharma- ceutically acceptable acid or base addition salt thereof, its stereochemically isomeric form or its N-oxide form. or A pharma- ceutically acceptable acid or base addition salt thereof, its stereochemically isomeric forms or its N-oxide forms, wherein: Z 1 , Z 2 , Z 3 , Z 4 and Z 5 are each independently selected from C or N, Formula (III): or A compound represented by formula (IV): which is a pharma- ceutically acceptable acid or base addition salt thereof, its stereochemically isomeric form or its N-oxide form.

10. The compound of any one of claims 1 to 9, having the formula:

11. R 2 and R 3 is independently selected from the group consisting of methyl and ethyl; Each (A) m are hydrogen, halogens, -CN, -OH, -CF 3 The group consisting of -(C 1 -C 6 ) alkyl, -(C 1 -C 6 ) haloalkyl, -(C 3 -C 7 )cycloalkyl, -(C 1 -C 6 ) cyanoalkyl, aryl, heterocycle, -(C 0 -C 6 ) Alkylene-OR 4 , -O-(C 2 -C 6 ) Alkylene-OR 4 , -(C 0 -C 6 ) Alkylene-S(=O) 2 -R 4 , -(C 0 -C 6 ) Alkylene-NR 4 R 5 , -(C 0 -C 6 ) Alkylene-S(=O) 2 NR 4 R 5 , -(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 , -(C 0 -C 6 )Alkylene-C(=O)-R 4 and -C(=O)-(C 1 -C 6 ) Alkylene-NR 4 -C(=O)-OR 5 independently selected from the group consisting of optionally substituted radicals selected from the group consisting of: R 4 and R 5 Each independently represents hydrogen or -(C 1 -C 6 ) alkyl; Each (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 and R 8 and R 9 Each independently represents hydrogen or -(C 1 -C 6 ) alkyl; Here, R 2 and R 3 The compound of claim 10 having the formula (IV), wherein one or both of are methyl.

12. Formula (V): having A pharma- ceutically acceptable acid or base addition salt thereof, its stereochemically isomeric forms or its N-oxide forms, wherein: Z 1 is selected from C or N; R 2 and R 3 is independently selected from the group consisting of hydrogen, methyl and ethyl; Each (A) m are hydrogen, halogens, -CN, -OH, -CF 3 and -(C 1 -C 6 ) alkyl, -(C 3 -C 7 ) cycloalkyl, heterocycle, and -(C 0 -C 6 ) Alkylene-OR 4 independently selected from the group consisting of optionally substituted radicals selected from the group consisting of: R 4 is hydrogen or -(C 1 -C 6 ) alkyl; Each (B) n is hydrogen, halogen, -CN, -CF 3 and -(C 1 -C 6 ) alkyl, -(C 3 -C 7 ) cycloalkyl, aryl, heteroaryl, heterocycle, -(C 0 -C 6 ) Alkylene-OR 8 , -(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 and R 8 and R 9 are each independently hydrogen, -(C 1 -C 6 ) haloalkyl, -(C 1 -C 6 ) alkyl, -(C 3 -C 7 ) selected from the group consisting of cycloalkyl and aryl; For example, here, R 2 and R 3 11. The compound of claim 10, wherein one or both of is methyl.

13. 13. The compound according to any one of claims 1 to 12, wherein the compound can exist as optical isomers, and the compound is a racemic mixture or one or both of the individual optical isomers.

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

14. A compound according to any one of claims 1 to 13, in the form of a pharma- ceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof or an N-oxide form thereof.

15. 15. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 14 and a pharma- ceutically acceptable carrier and / or excipient.

16. A compound or composition according to any one of claims 1 to 15 for use in the treatment or prevention of a condition in a mammal that is affected or promoted by the modulatory effect of an mGlu7 allosteric modulator, such as an mGlu7 negative allosteric modulator.

17. 1. A compound or composition for use in treating, preventing, ameliorating, controlling or reducing the risk of various neurological and psychiatric disorders associated with glutamate dysfunction in a mammal, comprising: For example, wherein the treatment or prevention is affected or facilitated by the modulatory effect of an mGlu7 negative allosteric modulator.

18. the condition is one or more of a central nervous system disorder, an ear disease or disorder, or a pain disorder; For example, the central nervous disorder is an anxiety disorder such as agoraphobia, generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), panic disorder, or post-traumatic stress disorder (PTSD); For example, the ear disease or disorder is one or more of an inner ear disorder, age-related hearing loss (senile hearing loss), Meniere's disease, sudden hearing loss, noise-induced hearing loss, otitis media, autoimmune inner ear disease, acute tinnitus, chronic tinnitus, drug-induced hearing loss, latent hearing loss, cisplatin-induced hearing loss, aminoglycoside-induced hearing loss, toxic hearing loss, central auditory processing disorder, or vestibular disorder; For example, 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.

19. 16. A compound or composition according to any one of claims 1 to 15 for use as a medicament.

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