Novel pyrrolo [1, 2-d] [1, 2, 4] triazinone derivatives as MGLU7 receptor negative allosteric modulators

Abstract

The present application relates to compounds of formula (I) wherein P, Q, A, B, m, n, R1, R2 and R3 are as defined in formula (I); the compounds are negative allosteric modulators of the metabotropic glutamate receptor subtype 7 (mGlu7) and are useful in the treatment or prevention of nervous, ear and psychiatric disorders associated with glutamate dysfunction and diseases in which mGlu7 metabotropic receptor subtype is involved. The present application also relates to pharmaceutical compositions comprising such compounds; methods of making such compounds and such compositions; and the use of such compounds for the prevention or treatment of neurological, ear and psychiatric disorders and diseases, in which mGlu7 is involved. # imgabs0 #

Description

Summary of the Invention

[0001]

[0002] The present invention relates to novel compounds of formula (I), wherein P, Q, A, B, m, n, R 1 , R 2 and R 3 are defined according to formula (I); said compounds are negative allosteric modulators of metabotropic glutamate receptor subtype 7 (mGlu7), and can be used for the treatment or prevention of nervous system, ear and mental disorders associated with glutamate dysfunction, and diseases involving metabotropic receptor subtype mGlu7. The present invention also relates to pharmaceutical compositions comprising such compounds; methods for preparing such compounds and such compositions; and the use of such compounds for the prevention or treatment of nervous system, ear and mental disorders and diseases (involving mGlu7). Background Art

[0003] Glutamate is the major amino acid transmitter in the mammalian central nervous system (CNS). Glutamate is associated with many physiological functions, such as learning and memory, sensory perception, development of synaptic plasticity, motor control, respiration, and regulation of cardiovascular function. In addition, glutamate is at the center of several different nervous system and mental diseases, in which there is an imbalance of glutamatergic neurotransmission.

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

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

[0006] Among the mGlu receptors, the mGlu7 subtype is the most widely distributed and is present presynaptically in a wide range of synapses, which is considered to be crucial for both normal CNS function and a range of mental and neurological disorders (Ohishi et al. (1995) J. Comp. Neurol. 360(4): 555-570; Kinzie et al. (1995) Neuroscience, 69(1): 167-176; Corti et al. (1998) Eur. J. Neurosci, 10(12): 3629-3641). mGlu7 is negatively coupled to adenylyl cyclase through the activation of Gαi-protein, and its activation as a presynaptic autoreceptor results in the inhibition of the release of glutamate and GABA at the synapse (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 forming a synaptic response at glutamatergic synapses and being a key regulator of inhibitory GABAergic transmission, where the ultimate goal is to fine-tune the overall excitability of the brain.

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

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

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

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

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

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

[0013] The recent discovery of several negative allosteric modulators has contributed to a better understanding of the functional role of mGlu7 in neural function. Administration in vivo of 6-(4-methoxyphenyl)-5-methyl-3-pyridin-4-yliso Zazolo[4,5-c]pyridin-4(5H)-one (MMPIP) has shown anxiolytic, antidepressant-like properties, as well as improved cognitive performance (in rodent models) (Palazzo et al. (2015) Pain, 156(6): 1060-1073). 7-Hydroxy-3-(4-iodophenoxy)-4H-chromen-4-one (XAP044) has shown anxiolytic, antidepressant and anti-stress-like effects, as well as reduced freezing in the fear-conditioning paradigm (Gee et al. (2014) J. Biol. Chem. 289(16): 10975-10987). In addition, (S)-6-(2,4-dimethylphenyl)-2-ethyl-6,7-dihydrobenzo[d] Zazol-4(5H)-one (ADX71743) has shown anxiolytic-like effects in the elevated plus maze and marble burying test, as well as reduced amphetamine-induced hyperactivity without altering baseline locomotor activity (Kalinichev etal. (2013) J. Pharmacol. Exp. Ther. 344(3): 624-636). Collectively, these data suggest that inhibition of mGlu7 with modulators could be used to treat mood disorders associated with anxiety, depression and PTSD.

[0014] In addition, the mGlu7 receptor is also involved in pathways affected during pain. Given its high and widespread expression in both the peripheral and central nervous systems, mGlu7 has been found to play a role in regulating pain behavior. The role of mGlu7 in pain has also recently been demonstrated by direct injection of AMN082 into the central nucleus of the amygdala (CeA) or the periaqueductal gray (PAG). Under normal conditions, activation of amygdala mGlu7 promotes pain responses, as shown by a decrease in the spinal withdrawal reflex threshold and an increase in auditory and ultrasonic vocalizations induced by brief knee compression (Palazzo et al. (2008) Neuropharmacol., 55(4): 537-545). In a similar manner, in rats, activation of PAG mGlu7 decreases the thermal nociceptive threshold measured using tail flick latency (Marabese et al. (2007) J. Neurophysiol., 98: 43-53). In a pain model in rodents, AMN082 inhibits hyperalgesia (Dolan et al. (2009) Behav. Pharmacol. 20(7): 596-604); Osikowicz et al. (2008) Pain 139(1): 117-126). In addition, the mGlu7 negative allosteric modulator ADX71743 has been shown to reduce visceral pain in a stress-sensitive model of visceral hypersensitivity (Moloney et al. (2015) Neurobiol. Stress 2: 28-33). Collectively, these data indicate that activation of the mGlu7 receptor exacerbates pain sensation, while mGlu7 inhibition alleviates it, thus suggesting that negative allosteric modulators of this receptor could be used to treat pain and pain-related disorders.

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

[0016] Finally, in addition to its widespread distribution throughout the CNS, mGlu7 also exhibits the highest degree of evolutionary conservation of all mGluRs (Flor et al. (1997) Neuropharmacol., 36: 153-159), indicating an important role of this receptor in CNS function. Moreover, it has a relatively low affinity for glutamate (Okamato et al. (1994) J. Biol. Chem., 269: 1231-1236), and thus it can remain inactive during normal transmission and become active only during periods of excessive glutamate release (Ferraguti F. and Shigemoto R. (2006) Cell Tissue Res., 326: 483-504). In summary, these data strongly emphasize the potential of mGlu7 modulators in clinical indications such as neuroprotection (treatment of stroke and head injury, ischemic injury and neurotoxicity).

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

[0018] In International Publications WO2017021178 and WO2017020944, Loge et al. have shown that pyrrolotriazinones can be used as antifungal agents and / or antiparasitic agents. However, none of the specifically disclosed compounds are structurally related to the compounds of the present invention. SUMMARY OF THE INVENTION

[0020] The present invention relates to compounds having activity as modulators of metabotropic glutamate receptor 7. The present invention provides compounds according to formula (I),

[0021]

[0022] their pharmaceutically acceptable acid addition salts or base addition salts, their stereochemical isomeric forms or their N-oxide forms, wherein:

[0023] R 1 is selected from the group consisting of (e.g., consisting of): hydrogen, -CH3 and -CF3;

[0024] R 2 and R 3 are each independently selected from the group consisting of (e.g., consisting of): hydrogen, halogen, -(C1-C6)alkyl, -(C1-C6)haloalkyl and -CF3;

[0025] P represents -(C1-C6)alkyl, or a cycloalkyl, aryl, heteroaryl, -(C1-C6)alkylene-heteroaryl or heterocycle of the following formula:

[0026]

[0027] wherein each cycloalkyl ring, aryl ring, heteroaryl ring, -(C1-C6)alkylene-heteroaryl ring or heterocycle is optionally substituted with m groups A, where m is an integer equal to 0, 1, 2, 3 or 4;

[0028] wherein 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; provided that at least one of Z 1 、Z 2 、Z 3 、Z 4 、Z 5 、Z 6 and Z 7 is N;

[0029] (A) m or (A) m each independently selected from the following groups (e.g., the group consisting of): hydrogen, halogen, -CN, -OH, -NO2, -CF3, -SH, -NH2 and optionally substituted groups selected from the following groups (e.g., the group consisting of): -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C2-C6)alkynyl, -(C2-C6)alkenyl, -(C3-C7)cycloalkyl, -(C1-C6)alkylene-(C3-C7)cycloalkyl, -(C3-C8)cycloalkenyl, -(C1-C6)cyanoalkyl, -(C1-C6)alkylene-heteroaryl, -(C1-C6)alkylene-aryl, aryl, heteroaryl, -(C1-C6)alkylene-heterocycle, heterocycle, -(C0-C6)alkylene-OR 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 - S - R 4 , -O-(C2-C6) alkylene - S - R 4 , -NR 4 -(C2-C6) alkylene - S - R 5 , -(C0-C6) alkylene - S(=O) - R 4 , -O-(C1-C6) alkylene - S(=O) - R 4 , -NR 4 -(C1-C6) alkylene - S(=O) - R 5 , -(C0-C6) alkylene - S(=O)2 - R 4 , -O-(C1-C6) alkylene - S(=O)2 - R 4 , -NR 4 -(C1-C6) alkylene - S(=O)2 - R 5 , -(C0-C6) alkylene - NR 4 R 5 , -O-(C2-C6) alkylene - NR 4 R 5 , -NR 4 -(C2-C6) alkylene - NR 5 R 6 , -(C0-C6) alkylene - S(=O)2NR 4 R 5 , -O-(C1-C6) alkylene - S(=O)2NR 4 R 5 , -NR 4 -(C1-C6) alkylene - S(=O)2NR 5 R 6 , -(C0-C6) alkylene - NR 4 -S(=O)2R 5 , -O-(C2-C6) alkylene - NR 4 -S(=O)2R 5 , -NR 4 -(C2-C6) alkylene - NR 5 -S(=O)2R 6 , -(C0-C6) alkylene - C(=O)-NR 4 R 5 , -O-(C1-C6) alkylene - C(=O)-NR 4 R 5 , -NR 4 -(C1-C6) alkylene - C(=O)-NR 5 R 6 , -(C0-C6) alkylene - NR 4C(=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 -(C0-C6) alkylene-C(=O)-OR 5 、-(C0-C6) alkylene-C(=O)-R 4 、-O-(C1-C6) alkylene-C(=O)-R 4 、-NR 4 -(C1-C6) alkylene-C(=O)-R 5 、-(C0-C6) alkylene-NR 4 -C(=O)-OR 5 、-C(=O)-(C1-C6) alkylene-NR 4 -C(=O)-OR 5 、-(C0-C6) alkylene-O-C(=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 ;

[0030] R 4 、R 5 、R 6 and R 7 each independently is hydrogen or an optionally substituted group selected from the following groups (e.g., a group consisting of): -(C1-C6) haloalkyl, -(C1-C6) alkyl, -(C1-C6) cyanoalkyl, -(C3-C7) cycloalkyl, -(C1-C6) alkylene-(C3-C7) cycloalkyl, heteroaryl, -(C1-C6) alkylene-heteroaryl, aryl, -(C1-C6) alkylene-heterocycle, heterocycle, -(C1-C6) alkylene-aryl, -(C0-C6) alkylene-O-(C0-C6) alkyl, -(C0-C6) alkylene-N-((C0-C6) alkyl)2, and -C(=O)-O-(C1-C6) alkyl;

[0031] Q represents an aryl, heteroaryl, or -(C5-C7) cycloalkenyl group of the following formula:

[0032]

[0033] wherein each aryl ring, heteroaryl ring, or -(C5-C7) cycloalkenyl ring is optionally substituted with n groups B, where n is an integer equal to 0, 1, 2, 3, 4, or 5; where B 1 is the group B;

[0034] (B) n or (B) n each independently selected from the following groups (e.g., a group consisting of): hydrogen, halogen, -CN, -OH, -NO2, -CF3, -SH, -NH2, and an optionally substituted group selected from the following groups (e.g., a group consisting of): -(C1-C6) alkyl, -(C1-C6) haloalkyl, -(C2-C6) alkynyl, -(C2-C6) alkenyl, -(C3-C7) cycloalkyl, -(C1-C6) alkylene-(C3-C7) cycloalkyl, -(C3-C8) cycloalkenyl, -(C1-C6) cyanoalkyl, -(C1-C6) alkylene-heteroaryl, -(C1-C6) alkylene-aryl, aryl, heteroaryl, -(C1-C6) alkylene-heterocycle, heterocycle, -(C0-C6) alkylene-OR 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-S-R 8 , -O-(C2-C6) alkylene-S-R 8 , -NR 8 -(C2-C6) alkylene-S-R 9 , -(C0-C6) alkylene-S(=O)-R 8 , -O-(C1-C6) alkylene-S(=O)-R 8 , -NR 8 -(C1-C6) alkylene-S(=O)-R 9 , -(C0-C6) alkylene-S(=O)2-R 8 , -O-(C1-C6) alkylene-S(=O)2-R 8 , -NR 8 -(C1-C6) alkylene-S(=O)2-R 9 , -(C0-C6) alkylene-NR 8 R 9 , -O-(C2-C6) alkylene-NR 8 R 9 , -NR 8 -(C2-C6) alkylene-NR 9 R 10 , -(C0-C6) alkylene-S(=O)2NR 8 R 9 , -O-(C1-C6) alkylene-S(=O)2NR 8 R 9 , -NR 8 -(C1-C6) alkylene-S(=O)2NR 9 R 10 , -(C0-C6) alkylene-NR 8 -S(=O)2R 9 , -O-(C2-C6) alkylene-NR 8 -S(=O)2R 9 , -NR 8 -(C2-C6) alkylene-NR 9 -S(=O)2R 10 , -(C0-C6) alkylene-C(=O)-NR 8 R 9 , -O-(C1-C6) alkylene-C(=O)-NR 8 R 9 , -NR 8-(C1-C6)alkylene-C(=O)-NR 9 R 10 、-(C0-C6)alkylene-NR 8 C(=O)-R 9 、-O-(C2-C6)alkylene-NR 8 C(=O)-R 9 、-NR 8 -(C2-C6)alkylene-NR 9 C(=O)-R 10 、-(C0-C6)alkylene-OC(=O)-R 8 、-O-(C2-C6)alkylene-OC(=O)-R 8 、-NR 8 -(C2-C6)alkylene-OC(=O)-R 9 、-(C0-C6)alkylene-C(=O)-OR 8 、-O-(C1-C6)alkylene-C(=O)-OR 8 、-NR 8 -(C1-C6)alkylene-C(=O)-OR 9 、-(C0-C6)alkylene-C(=O)-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-O-C(=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 )-NR10 R 11 ;

[0035] R 8 , R 9 , R 10 and R 11 each independently hydrogen or an optionally substituted group selected from the group consisting of -(C1-C6)haloalkyl, -(C1-C6)alkyl, -(C1-C6)cyanoalkyl, -(C3-C7)cycloalkyl, -(C1-C6)alkylene-(C3-C7)cycloalkyl, heteroaryl, -(C1-C6)alkylene-heteroaryl, aryl, -(C1-C6)alkylene-heterocycle, heterocycle, -(C1-C6)alkylene-aryl, -(C0-C6)alkylene-O-(0-C6)alkyl and -(C0-C6)alkylene-N-((C0-C6)alkyl)2;

[0036] wherein optionally, any two groups A are combined with intervening atoms to form a 3- to 10-membered bicyclic heterocyclic, aryl or heteroaryl ring, wherein each ring is optionally further substituted with 1 to 5 groups independently selected from (e.g., consisting of) the following groups: halogen, -CN, nitro, -(C1-C6)alkyl, -(C3-C7)alkyl, -(C0-C6)alkylene-O-(C0-C6)alkyl and -(C0-C6)alkylene-N-((C0-C6)alkyl)2;

[0037] Wherein optionally, the substituent R 4 , R 5 , R 6 or R 7 two of the 3- to 10-membered heterocyclic, aryl, or heteroaryl rings are combined with intervening atoms to form a 3- to 10-membered heterocyclic, aryl, or heteroaryl ring, wherein each ring is optionally further substituted with 1 to 5 groups independently selected from (e.g., consisting of) halogen, cyano, nitro, -(C1-C6)alkyl, -(C3-C7)alkyl, -(C0-C6)alkylene-O-(C0-C6)alkyl, and -(C0-C6)alkylene-N-((C0-C6)alkyl)2;

[0038] wherein optionally, from R 8 , R 9 , R 10 or R 11The two substituents combine with the intervening atom to form a 3- to 10-membered heterocyclic, aryl or heteroaryl ring, wherein each ring is optionally further substituted with 1 to 5 groups independently selected from the group (e.g., the group consisting of) consisting of: halogen, cyano, nitro, -(C1-C6)alkyl, -(C3-C7)alkyl, -(C0-C6)alkylene-O-(C0-C6)alkyl, and -(C0-C6)alkylene-N-((C0-C6)alkyl)2;

[0039] Optionally, any two groups B combine with the intervening atom to form a 3- to 10-membered bicyclic heterocyclic, aryl or heteroaryl ring, wherein each ring is optionally further substituted with 1 to 5 groups independently selected from the group (e.g., the group consisting of) consisting of: halogen, -CN, nitro, -(C1-C6)alkyl, -(C3-C7)alkyl, -(C0-C6)alkylene-O-(C0-C6)alkyl, and -(C0-C6)alkylene-N-((C0-C6)alkyl)2.

[0040] It has now unexpectedly been found that the compounds of general formula (I) exhibit potent activity and selectivity for the mGlu7 receptor. The compounds of the present invention exhibit advantageous properties relative to the compounds of the prior art. Improvements have been observed in one or more of the following characteristics of the compounds of the present invention: potency against the target, selectivity for the target, bioavailability, brain penetration, and pharmacodynamics.

[0041] P can be -(C1-C6)alkyl, or a cycloalkyl, heteroaryl, -(C1-C6)alkylene-heteroaryl or heterocycle of the following formula:

[0042]

[0043] Q can be an aryl, heteroaryl or -(C5-C7)cycloalkenyl of the following formula:

[0044]

[0045] Preferably, P represents a heteroaryl of the following formula:

[0046]

[0047] Wherein each group is optionally substituted with m groups A, where m is an integer equal to 0, 1, 2, 3 or 4.

[0048] Preferably, Q represents an aryl or heteroaryl of the following formula:

[0049]

[0050] Wherein each group is optionally substituted with n groups B, where n is an integer equal to 0, 1, 2, 3, 4 or 5.

[0051] Preferably, P represents a heteroaryl group of the following formula:

[0052]

[0053] wherein each group is optionally substituted by m groups A, where m is an integer equal to 0, 1, 2, 3 or 4; and Q represents an aryl or heteroaryl group of the following formula:

[0054]

[0055] wherein each group is optionally substituted by n groups B, where n is an integer equal to 0, 1, 2, 3, 4 or 5.

[0056] (A) m The cycloalkyl, heterocyclic, aryl and heteroaryl ring systems of may be selected from the following group (for example, the group consisting of): azetidinyl, 2-azabicyclo[2.2.1]heptan-2-yl, 7-azabicyclo[2.2.1]heptan-7-yl, benzimidazolyl, benzisothiazolyl, benzisoxazolyl, benzofuranyl, benzopyrazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, dihydrofuranyl, dihydrothienyl, dioxolanyl, 1,1-dioxo-thiomorpholinyl, furazanyl, furanyl, imidazolidinyl, imidazolinyl, imidazolinone, imidazolyl, imidazopyridazinyl, imidazopyridyl, indolyl, isoindolyl, isoquinolinyl, isothiazolinyl, isothiazolyl, isoxazolidinyl, isoxazolinyl, isoxazolyl, morpholinyl, naphthyl, naphthyridinyl, oxadiazolyl, oxazolidinyl, oxazolinyl, oxazolidinone, oxadiazolyl, oxazolidinyl, oxazolinyl, oxazolidinone, oxazopyridazinyl, oxazopyridyl, azolyl, oxetanyl, phenyl, piperazinone, piperazinyl, piperidinone, piperidinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolopyridyl, pyrazolyl, pyridazinyl, pyridone, pyridyl, pyrimidinyl, pyrrolidone, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrotriazolopyridyl, tetrahydrotriazolopyrimidinyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolinyl, thiazolone, thiazolopyridazinyl, thiazolopyridyl, thiazolyl, thiophenyl, thiomorpholinyl, thionaphthyl, thiopyranyl, triazolinyl, triazinyl, triazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl and cyclooctenyl, and each ring of the ring system is optionally independently substituted with 1 to 4 substituents R 4 , R 5 , R 6 or R 7 .

[0057] (B) n The cycloalkyl, heterocyclic, aryl and heteroaryl ring systems of may be selected from the following groups (e.g., the group consisting of): azetidinyl, 7-azabicyclo[2.2.1]heptan-7-yl, benzimidazolyl, benzisothiazolyl, benzisoxazolyl, benzofuranyl, benzopyrazolyl, benzothiazolyl, benzothiophenyl, benzotriazolyl, benzoxazolyl, dihydrofuranyl, dihydrothiophenyl, dioxolanyl, 1,1-dioxo-thiomorpholinyl, furazanyl, furanyl, imidazolidinyl, imidazolinyl, imidazolinone, imidazolyl, imidazolopyridazinyl, imidazolopyridyl, indolyl, isoindolyl, isoquinolinyl, isothiazolinyl, isothiazolyl, isoxazolidinyl, isoxazolinyl, isoxazolyl, morpholinyl, naphthyl, naphthyridinyl, isoxadiazolyl, isoxazolidinyl, isoxazolinyl, isoxazolone, isoxazolopyridazinyl, isoxazolopyridyl, oxazolyl, morpholinyl, naphthyl, naphthyridinyl, isoxadiazolyl, isoxazolidinyl, isoxazolyl, dioxazolyl, oxazolidinyl, oxazolinyl, oxazolone, oxazolopyridazinyl, oxazolopyridyl, Azolyl, oxetanyl, phenyl, piperazinonyl, piperazinyl, piperidinonyl, piperidinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridinonyl, pyridinyl, pyrimidinyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrotriazolopyridinyl, tetrahydrotriazolopyrimidinyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolinyl, thiazolinonyl, thiazolopyridazinyl, thiazolopyridinyl, thiazolyl, thienyl, thiomorpholinyl, thionaphthyl, thiopyranyl, triazolinyl, triazinyl, triazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl and cyclooctenyl, and each ring of the ring system is optionally independently substituted by 1 to 4 substituents R 8 , R 9 , R 10 or R 11 substitution.

[0058] B 1 may be the group B as described above. For example, B 1 may be hydrogen, -(C1-C6) alkyl or -(C3-C7) cycloalkyl.

[0059] R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 or R 11 The cycloalkyl, heterocyclic, aryl and heteroaryl ring systems of R may be selected from the following groups (for example, the group consisting of): azetidinyl, benzimidazolyl, benzisothiazolyl benzis azolyl, benzofuranyl, benzopyrazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benz azolyl, dihydrofuranyl, dihydrothienyl, dioxolanyl, 1,1-dioxo-thiomorpholinyl, furazanyl, furanyl, imidazolidinyl, imidazolinyl, imidazolinonyl, imidazolyl, imidazolopyridazinyl, imidazolopyridinyl, indolyl, isoindolyl, isoquinolinyl, isothiazolinyl, isothiazolyl, iso oxazolidinyl, iso oxazolinyl, iso oxazolyl, morpholinyl, naphthyl, naphthyridinyl, oxazolidinyl, oxazolinyl, oxazolinonyl, oxazolopyridazinyl, oxazolopyridinyl, azolyl, oxetanyl, phenyl, piperazinonyl, piperazinyl, piperidinonyl, piperidinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridinonyl, pyridinyl, pyrimidinyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrotriazolopyridinyl, tetrahydrotriazolopyrimidinyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolinyl, thiazolinonyl, thiazolopyridazinyl, thiazolopyridinyl, thiazolyl, thienyl, thiomorpholinyl, thionaphthyl, thiopyranyl, triazolinyl, triazinyl, triazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl and cyclooctenyl, and each ring of the ring system is optionally substituted with 1 to 5 groups independently selected from the following: hydrogen, halogen, -CN, nitro, -(C1-C6)alkyl, -(C0-C6)alkylene-O-(C0-C6)alkyl and -(C0-C6)alkylene-N-((C0-C6)alkyl)2.

[0060] For example, R 1 can be hydrogen; and R 2 and R 3 can each independently be selected from the following group (for example, the group consisting of): hydrogen and methyl.

[0061] (A) m or (A) m each can independently be selected from the following group (for example, the group consisting of): hydrogen, halogen, -CN, -OH, -CF3 and an optionally substituted group selected from the following group (for example, the group consisting of): -(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 , -NR 4 (C2-C6)alkylene-OR 5 , -(C0-C6)alkylene-S(=O)2-R 4 , -(C0-C6)alkylene-NR 4 R 5 , -O-(C2-C6)alkylene-NR 4 R 5 , -NR 4 -(C2-C6)alkylene-NR 5 R 6 , -(C0-C6)alkylene-S(=O)2NR 4 R5 、-(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 、-C(=O)-(C1-C6)alkylene-NR 4 -C(=O)-OR 5 and-NR 4 -(C0-C6)alkylene-C(=O)-OR 5 .

[0062] R 4 , R 5 and R 6 They may each independently be hydrogen, -(C1-C6)alkyl, -(C1-C6)haloalkyl or -C(=O)-O-(C1-C6)alkyl.

[0063] (B) n or (B) n Each of the above may be independently selected from the following group (e.g., a group consisting of): hydrogen, halogen, -CN, -CF3, and an optionally substituted group selected from the following group (e.g., a group consisting of): -(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 .

[0064] R 8 and R 9 Each may be independently selected from the group consisting of (eg, a group consisting of) hydrogen, -(C1-C6)haloalkyl, -(C1-C6)alkyl, -(C3-C7)cycloalkyl, and aryl.

[0065] Preferably, the compound of formula (I) is a compound according to formula (II):

[0066]

[0067] Its pharmaceutically acceptable acid addition salts or base addition salts, its stereochemical isomeric forms or its N-oxide forms, wherein Z 1 is selected from C or N, and (A) m 、Q、R 2 、R 3 and (B) n are as defined in any of the foregoing statements.

[0068] The compound of formula (I) can be a compound according to formula (III):

[0069]

[0070] Its pharmaceutically acceptable acid addition salts or base addition salts, its stereochemical isomeric forms or its N-oxide forms, wherein X is N or C, and P, (A) m 、R 2 、R 3 and (B) n are as defined in any of the foregoing statements.

[0071] The compound of formula (I) can be a compound according to formula (IV):

[0072]

[0073] Its pharmaceutically acceptable acid addition salts or base addition salts, its stereochemical isomeric forms or its N-oxide forms, wherein Z 1 is selected from C or N, X is selected from C or N, and (A) m 、R 2 、R 3 and (B) n are as defined in any of the foregoing statements.

[0074] The compound of formula (I) can be a compound according to formula (V):

[0075]

[0076] Its pharmaceutically acceptable acid addition salts or base addition salts, its stereochemical isomeric forms or its N-oxide forms, wherein:

[0077] Z 1 is selected from C or N, and (A) m 、R 2 、R 3 and (B) n are as defined in any of the foregoing statements.

[0078] For example, R 2 can be hydrogen or methyl, and R 3 can be methyl or hydrogen;

[0079] (A) m or (A) m each of which may independently be selected from the following groups (e.g., a group consisting of): hydrogen, halogen, -CF3, and optionally substituted groups selected from the following groups (e.g., a group consisting of): -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C3-C7)cycloalkyl, heterocycle, -(C0-C6)alkylene-OR 4 , -O-(C2-C6)alkylene-OR 4 , -NR 4 (C2-C6)alkylene-OR 5 , -(C0-C6)alkylene-NR 4 R 5 , -O-(C2-C6)alkylene-NR 4 R 5 , -NR 4 -(C2-C6)alkylene-NR 5 R 6 , -(C0-C6)alkylene-C(=O)-NR 4 R 5 , -(C0-C6)alkylene-NR 4 C(=O)-R 5 , -(C0-C6)alkylene-C(=O)-OR 4 , -(C0-C6)alkylene-C(=O)-R 4 , -C(=O)-(C1-C6)alkylene-NR 4 -C(=O)-OR 5 and -NR 4 -(C0-C6)alkylene-C(=O)-OR 5 , and R 4 , R 5 and R 6 may each independently be hydrogen, -(C1-C6)alkyl, -(C1-C6)haloalkyl or -C(=O)-O-(C1-C6)alkyl.

[0080] (B) n or (B) n each of which may independently be selected from the following groups (e.g., a group consisting of): hydrogen, halogen, and optionally substituted groups selected from the following groups (e.g., a group consisting of): -(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

[0081] R 8 and R 9 may each independently be hydrogen, -(C1-C6)alkyl, -(C3-C7)cycloalkyl or -(C1-C6)haloalkyl.

[0082] For example, each of (A) m or (A) m may independently be selected from the group consisting of (for example, the group consisting of): hydrogen, halogen, and optionally substituted groups selected from the group consisting of (for example, the group consisting of): -(C1-C6)alkyl, heterocycle, -(C0-C6)alkylene-OR 4 , -NR 4 (C2-C6)alkylene-OR 5 , -(C0-C6)alkylene-NR 4 R 5 , -O-(C2-C6)alkylene-NR 4 R 5 , -NR – -(C2-C6)alkylene-NR 5 R 6 , -(C0-C6)alkylene-C(=O)-OR 4 and -NR 4 -(C0-C6)alkylene-C(=O)-OR 5 .

[0083] R 4 , R 5 and R 6 may each independently be hydrogen, -(C1-C6)alkyl, -(C1-C6)haloalkyl or -C(=O)-O-(C1-C6)alkyl.

[0084] (B) n or (B) n may each independently be selected from the group consisting of (for example, the group consisting of): hydrogen, halogen, and optionally substituted groups selected from the group consisting of (for example, the group consisting of): -(C1-C6)alkyl, heterocycle and -(C0-C6)alkylene-OR 8 ; and

[0085] R 8 may be hydrogen, -(C1-C6)alkyl, -(C3-C7)cycloalkyl or -(C1-C6)haloalkyl.

[0086] Preferably, the compound of formula (II) is according to formula (VI):

[0087]

[0088] its pharmaceutically acceptable acid addition salts or base addition salts, its stereochemical isomeric forms or its N-oxide forms, wherein:

[0089] Z 1 is selected from C or N, and (A) m 、R 2 、R 3 and (B) n are as defined in any of the above statements.

[0090] For example, R 2 can be hydrogen or methyl, and R 3 can be methyl or hydrogen;

[0091] (A) m or (A) m each can independently be selected from the following groups (for example, the group consisting of): hydrogen, halogen, -CF3 and optionally substituted groups selected from the following groups (for example, the group consisting of): -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C3-C7)cycloalkyl, heterocycle, -(C0-C6)alkylene-OR 4 、-O-(C2-C6)alkylene-OR 4 、-NR 4 (C2-C6)alkylene-OR 5 、-(C0-C6)alkylene-NR 4 R 5 、-O-(C2-C6)alkylene-NR 4 R 5 、-NR 4 -(C2-C6)alkylene-NR 5 R 6 、-(C0-C6)alkylene-C(=O)-NR 4 R 5 、-(C0-C6)alkylene-NR 4 C(=O)-R 5 、-(C0-C6)alkylene-C(=O)-OR 4 、-(C0-C6)alkylene-C(=O)-R 4 、-C(=O)-(C1-C6)alkylene-NR 4 -C(=O)-OR 5 and -NR 4 -(C0-C6)alkylene-C(=O)-OR 5 ;

[0092] R 4 , R 5 and R 6 may each independently be hydrogen, -(C1-C6)alkyl, -C(=O)-O-(C1-C6)alkyl or -(C1-C6)haloalkyl;

[0093] (B) n or (B) n Each of the following may be independently selected from the following group (e.g., a group consisting of): hydrogen, halogen, and an optionally substituted group selected from the following group (e.g., a group consisting of): -(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

[0094] R 8 and R 9 They may each independently be hydrogen, -(C1-C6)alkyl, -(C3-C7)cycloalkyl or -(C1-C6)haloalkyl.

[0095] Preferably, the compound of formula (VI) is a compound according to formula (VII):

[0096]

[0097] A pharmaceutically acceptable acid addition salt or base addition salt thereof, a stereochemically isomeric form thereof or an N-oxide form thereof, wherein (A) m , Z 1 , R 2 , R 3 and (B) n As defined in any of the above statements.

[0098] Preferably, Z 1 Selected from C or N, R 2 is hydrogen or methyl, and R 3 is methyl or hydrogen;

[0099] (A) m or (A) mEach of the following may be independently selected from the following group (e.g., a group consisting of): hydrogen, halogen, and an optionally substituted group selected from the following group (e.g., a group consisting of): -(C1-C6)alkyl, heterocycle, -(C0-C6)alkylene-OR 4 、-NR 4 (C2-C6)alkylene-OR 5 、-(C0-C6)alkylene-NR 4 R 5 、-O-(C2-C6)alkylene-NR 4 R 5 、-NR 4 -(C2-C6)alkylene-NR 5 R 6 、-(C0-C6)alkylene-C(=O)-OR 4 and-NR 4 -(C0-C6)alkylene-C(=O)-OR 5 ;

[0100] R 4 , R 5 and R 6 may be independently hydrogen, -(C1-C6)alkyl, C1-C6)haloalkyl;

[0101] (B) n or (B) n Each of the following may be independently selected from the group consisting of hydrogen, halogen and an optionally substituted group selected from the group consisting of -(C1-C6)alkyl, heterocycle and -(C0-C6)alkylene-OR 8 ;and

[0102] R 8 It may be hydrogen, -(C1-C6)alkyl, -(C3-C7)cycloalkyl or -(C1-C6)haloalkyl.

[0103] For example, (A) m or (A) m Each of may be hydrogen.

[0104] Preferably, the compound of formula (VI) is a compound of formula (VIII):

[0105]

[0106] A pharmaceutically acceptable acid addition salt or base addition salt thereof, a stereochemically isomeric form thereof or an N-oxide form thereof, wherein (A) m , Z 1 , R 2 , R3 and (B) n as defined in any of the foregoing statements.

[0107] Preferably, Z 1 is selected from C or N, R 2 is hydrogen or methyl, R 3 is methyl or hydrogen;

[0108] (A) m or (A) m each independently may be selected from the following groups (e.g., the group consisting of): hydrogen, halogen, and optionally substituted groups selected from the following groups (e.g., the group consisting of): -(C1-C6)alkyl, heterocycle, -(C0-C6)alkylene-OR 4 , -NR 4 (C2-C6)alkylene-OR 5 , -(C0-C6)alkylene-NR 4 R 5 , -O-(C2-C6)alkylene-NR 4 R 5 , -NR 4 -(C2-C6)alkylene-NR 5 R 6 , -(C0-C6)alkylene-C(=O)-OR 4 and -NR 4 -(C0-C6)alkylene-C(=O)-OR 5 .

[0109] R 4 、R 5 and R 6 each independently may be hydrogen, -(C1-C6)alkyl, -(C1-C6)haloalkyl or -C(=O)-O-(C1-C6)alkyl.

[0110] (B) n or (B) n each independently may be selected from the following groups (e.g., the group consisting of): hydrogen, halogen, and optionally substituted groups selected from the following groups (e.g., the group consisting of): -(C1-C6)alkyl, heterocycle and -(C0-C6)alkylene-OR 8 ; and

[0111] R 8 may be hydrogen, -(C1-C6)alkyl, -(C3-C7)cycloalkyl or -(C1-C6)haloalkyl.

[0112] For example, (A) m or (A) m each may be hydrogen.

[0113] For example, each of (A) as described in any of the above statements m or (A) m may independently be selected from the following groups (for example, a group consisting of): hydrogen, halogen, and optionally substituted groups selected from the following groups (for example, a group consisting of): heterocycle, -(C0-C6)alkylene-OR 4 , -(C0-C6)alkylene-C(=O)-OR 4 , -NR 4 -(C0-C6)alkylene-C(=O)-OR 5 , -NR 4 (C2-C6)alkylene-OR 5 , -O-(C2-C6)alkylene-NR 4 R 5 , -NR 4 -(C2-C6)alkylene-NR 5 R 6 and -(C0-C6)alkylene-NR 4 R 5 ; and R 4 and R 5 may each independently be hydrogen, -(C1-C6)alkyl, -(C1-C6)haloalkyl, or -C(=O)-O-(C1-C6)alkyl.

[0114] For example, each of (B) as described in any of the above statements n or (B) n may independently be selected from the following groups (for example, a group consisting of): hydrogen, halogen, and optionally substituted groups selected from the following groups (for example, a group consisting of): -(C1-C6)alkyl, heterocycle, and -(C0-C6)alkylene-OR 8 ; and R 8 may be hydrogen, -(C1-C6)alkyl, -(C3-C7)cycloalkyl, or -(C1-C6)haloalkyl.

[0115] For example, each of (A) m or (A) m may independently be selected from the following groups (for example, a group consisting of): hydrogen, halogen, -CH2CH2OH, -COOCH2CH3, -COH(CH3)2, -O-methyl, -N(COOBu t )2, NHCOOBu t, morpholinyl, -NH2, -NHCH2CH2OCH3, -NHCH2CH2N(CH3)2, -OCHF2, -OCH2CH2N(CH3)2, CHOH(CH3)2, methyl and hydroxy-substituted pyrrolidinyl.

[0116] For example, (B) n or (B) n each of which may independently be selected from the following group (for example, the group consisting of): hydrogen, halogen, azetidinyl, -OCHF2, -OCF3, cyclopropyl, -O-cyclopropyl, -O-methyl, methyl, propyl, -O-cyclobutyl and azabicyclo[2.2.1]heptan-7-yl.

[0117] Some particularly preferred compounds of the present invention are the compounds mentioned in the following list, as well as their pharmaceutically acceptable acid addition salts or base addition salts, their stereochemical isomeric forms or their N-oxide forms:

[0118] 7-(2,4-dimethylphenyl)-6,8-dimethyl-3-(2-pyridyl)pyrrolo[1,2-d][1,2,4]triazin-4-one

[0119] 7-(3-methoxyphenyl)-6,8-dimethyl-3-(2-pyridyl)pyrrolo[1,2-d][1,2,4]triazin-4-one

[0120] 7-[3-(azetidin-1-yl)phenyl]-6,8-dimethyl-3-(2-pyridyl)pyrrolo[1,2-d][1,2,4]triazin-4-one

[0121] 7-(3-methoxy-2-methyl-phenyl)-6,8-dimethyl-3-(2-pyridyl)pyrrolo[1,2-d][1,2,4]triazin-4-one

[0122] 7-[3-(azetidin-1-yl)phenyl]-6,8-dimethyl-3-tetrahydropyran-4-yl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0123] 7-[3-(azetidin-1-yl)phenyl]-6,8-dimethyl-3-(4-pyridyl)pyrrolo[1,2-d][1,2,4]triazin-4-one

[0124] 7-[3-(azetidin-1-yl)phenyl]-3-(3-fluoro-2-pyridyl)-6,8-dimethyl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0125] 7-[3-(Cyclopropoxy)-2-methyl-phenyl]-6,8-dimethyl-3-(2-pyridyl)pyrrolo[1,2-d][1,2,4]triazin-4-one

[0126] 7-[3-(Azetidin-1-yl)phenyl]-6,8-dimethyl-3-(2-pyridylmethyl)pyrrolo[1,2-d][1,2,4]triazin-4-one

[0127] 7-[3-(Azetidin-1-yl)phenyl]-3-ethyl-6,8-dimethyl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0128] 7-[3-(Azetidin-1-yl)phenyl]-3-[5-(2-hydroxyethyl)-2-pyridyl]-6,8-dimethyl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0129] 7-[3-(Azetidin-1-yl)phenyl]-3,6,8-trimethyl-pyrrolo[1,2-d][1,2,4]triazin-4-one 7-[3-(Azetidin-1-yl)-2-methyl-phenyl]-6,8-dimethyl-3-(2-pyridyl)pyrrolo[1,2-d][1,2,4]triazin-4-one

[0130] 7-(Cyclohex-1-enyl)-6,8-dimethyl-3-(2-pyridyl)pyrrolo[1,2-d][1,2,4]triazin-4-one 7-[3-(Azetidin-1-yl)phenyl]-3-(5-fluoropyrimidin-2-yl)-6,8-dimethyl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0131] 7-[5-(Azetidin-1-yl)-2-methyl-phenyl]-6,8-dimethyl-3-(2-pyridyl)pyrrolo[1,2-d][1,2,4]triazin-4-one

[0132] 7-[3-(Difluoromethoxy)phenyl]-3-(5-fluoropyrimidin-2-yl)-6,8-dimethyl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0133] 7-[3-(Cyclopropoxy)-2-methyl-phenyl]-3-pyrimidin-2-yl-pyrrolo[1,2-d][1,2,4]triazin-4-one Ethyl 2-[7-[3-(cyclopropoxy)phenyl]-6,8-dimethyl-4-oxo-pyrrolo[1,2-d][1,2,4]triazin-3-yl]pyrimidine-5-carboxylate

[0134] 7-[3-(Cyclopropoxy)phenyl]-6,8-dimethyl-3-(2-pyridyl)pyrrolo[1,2-d][1,2,4]triazin-4-one

[0135] 7-[3-(Cyclopropoxy)phenyl]-3-(5-fluoropyrimidin-2-yl)-6,8-dimethyl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0136] 7-[3-(Azetidin-1-yl)phenyl]-3-(5-fluoro-2-pyridyl)-6,8-dimethyl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0137] 7-[3-(Azetidin-1-yl)phenyl]-6,8-dimethyl-3-pyrimidin-2-yl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0138] 7-[3-(Azetidin-1-yl)phenyl]-3-[5-(1-hydroxy-1-methylethyl)-2-pyridyl]-6,8-dimethyl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0139] 7-[3-(Azetidin-1-yl)phenyl]-3-(5-methoxypyrimidin-2-yl)-6,8-dimethyl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0140] 7-[3-(Azetidin-1-yl)phenyl]-3-(5-bromo-2-pyridyl)-6,8-dimethyl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0141] 7-[3-(Cyclopropoxy)-2-methyl-phenyl]-6,8-dimethyl-3-pyrimidin-2-yl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0142] N-[6-[7-[3-(Azetidin-1-yl)phenyl]-6,8-dimethyl-4-oxo-pyrrolo[1,2-d][1,2,4]triazin-3-yl]-3-pyridyl]-N-tert-butoxycarbonyl-carbamic acid tert-butyl ester 7-[3-(Cyclopropoxy)phenyl]-6,8-dimethyl-3-pyrimidin-2-yl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0143] 7-[3-(Azetidin-1-yl)-5-fluoro-phenyl]-6,8-dimethyl-3-(2-pyridyl)pyrrolo[1,2-d][1,2,4]triazin-4-one

[0144] tert-Butyl N-[6-[7-[3-(azetidin-1-yl)phenyl]-6,8-dimethyl-4-oxopyrrolo[1,2-d][1,2,4]triazin-3-yl]-3-pyridyl]carbamate

[0145] 7-[3-(azetidin-1-yl)phenyl]-6,8-dimethyl-3-(6-morpholin-3-ylpyridyl)pyrrolo[1,2-d][1,2,4]triazin-4-one

[0146] 7-[3-(azetidin-1-yl)phenyl]-3-cyclopropyl-6,8-dimethylpyrrolo[1,2-d][1,2,4]triazin-4-one

[0147] 3-(5-amino-2-pyridyl)-7-[3-(azetidin-1-yl)phenyl]-6,8-dimethylpyrrolo[1,2-d][1,2,4]triazin-4-one

[0148] 7-[3-(azetidin-1-yl)phenyl]-3-[5-(2-methoxyethylamino)-2-pyridyl]-6,8-dimethylpyrrolo[1,2-d][1,2,4]triazin-4-one

[0149] 7-[3-(azetidin-1-yl)phenyl]-3-[5-[2-(dimethylamino)ethylamino]-2-pyridyl]-6,8-dimethylpyrrolo[1,2-d][1,2,4]triazin-4-one

[0150] 7-[3-(difluoromethoxy)phenyl]-6,8-dimethyl-3-(2-pyridyl)pyrrolo[1,2-d][1,2,4]triazin-4-one

[0151] 6,8-dimethyl-3-(2-pyridyl)-7-[3-(trifluoromethoxy)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-one

[0152] 7-[3-(cyclopropoxy)phenyl]-3-(5-methoxypyrimidin-2-yl)-6,8-dimethylpyrrolo[1,2-d][1,2,4]triazin-4-one

[0153] 7-[3-(cyclopropoxy)phenyl]-3-[5-(difluoromethoxy)pyrimidin-2-yl]-6,8-dimethylpyrrolo[1,2-d][1,2,4]triazin-4-one

[0154] 7-[3-(cyclopropoxy)phenyl]-3-[5-[2-(dimethylamino)ethoxy]pyrimidin-2-yl]-6,8-dimethylpyrrolo[1,2-d][1,2,4]triazin-4-one

[0155] 7-[3-(azetidin-1-yl)phenyl]-3-[5-(difluoromethoxy)pyrimidin-2-yl]-6,8-dimethyl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0156] 7-[3-(azetidin-1-yl)phenyl]-3-[5-[2-(dimethylamino)ethoxy]pyrimidin-2-yl]-6,8-dimethyl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0157] 3-(5-aminopyrimidin-2-yl)-7-[3-(azetidin-1-yl)phenyl]-6,8-dimethyl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0158] 7-[3-(cyclopropoxy)phenyl]-3-[5-(1-hydroxy-1-methylethyl)-2-pyridyl]-6,8-dimethyl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0159] 7-(2,4-dimethylphenyl)-3-(5-methoxypyrimidin-2-yl)-6,8-dimethyl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0160] 7-[3-(cyclopropoxy)phenyl]-6,8-dimethyl-3-(5-morpholinopyrimidin-2-yl)pyrrolo[1,2-d][1,2,4]triazin-4-one

[0161] 3-(5-chloropyrimidin-2-yl)-7-[3-(cyclopropoxy)phenyl]-6,8-dimethyl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0162] 7-[3-(cyclopropoxy)-2-methylphenyl]-3-(5-fluoropyrimidin-2-yl)-6,8-dimethyl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0163] 7-[3-(cyclopropoxy)phenyl]-6,8-dimethyl-3-(5-methylpyrimidin-2-yl)pyrrolo[1,2-d][1,2,4]triazin-4-one

[0164] 7-[3-(cyclopropoxy)phenyl]-3-(3-fluoro-2-pyridyl)-6,8-dimethyl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0165] 7-[3-(Cyclopropoxy)-2-methyl-phenyl]-6,8-dimethyl-3-(5-methylpyrimidin-2-yl)pyrrolo[1,2-d][1,2,4]triazin-4-one

[0166] 6,8-Dimethyl-3-pyrimidin-2-yl-7-[3-(trifluoromethoxy)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-one

[0167] 7-[3-(Cyclopropoxy)-2-methyl-phenyl]-3-(5-fluoro-2-pyridyl)-6,8-dimethyl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0168] 7-[3-(Cyclopropoxy)phenyl]-3-(5-fluoro-2-pyridyl)-6,8-dimethyl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0169] 3-(5-Methoxypyrimidin-2-yl)-6,8-dimethyl-7-[3-(trifluoromethoxy)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-one

[0170] 7-[3-(Difluoromethoxy)phenyl]-3-(5-methoxypyrimidin-2-yl)-6,8-dimethyl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0171] 7-[3-(Difluoromethoxy)phenyl]-6,8-dimethyl-3-pyrimidin-2-yl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0172] 7-[3-(Cyclopropoxy)-2-methyl-phenyl]-3-[5-(1-hydroxy-1-methyl-ethyl)-2-pyridyl]-6,8-dimethyl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0173] 3-(5-Fluoropyrimidin-2-yl)-6,8-dimethyl-7-[3-(trifluoromethoxy)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-one

[0174] 7-(3-Methoxyphenyl)-6-methyl-3-pyrimidin-2-yl-pyrrolo[1,2-d][1,2,4]triazin-4-one 6-methyl-7-(4-methyl-2,3-dihydro-1,4-benz oxazin-8-yl)-3-(2-pyridyl)pyrrolo[1,2-d][1,2,4]triazin-4-one

[0175] 6-Methyl-7-(4-methyl-2,3-dihydro-1,4-benz -8-yl)-3-pyrimidin-2-yl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0176] 6-Methyl-7-(1-methylindolin-4-yl)-3-(2-pyridyl)pyrrolo[1,2-d][1,2,4]triazin-4-one 7-(1-cyclopropylindolin-4-yl)-6-methyl-3-(2-pyridyl)pyrrolo[1,2-d][1,2,4]triazin-4-one

[0177] 7-(1-Isopropylindolin-4-yl)-6-methyl-3-(2-pyridyl)pyrrolo[1,2-d][1,2,4]triazin-4-one

[0178] 7-(1-Cyclopropylindolin-4-yl)-6-methyl-3-pyrimidin-2-yl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0179] 7-(1-Isopropylindolin-4-yl)-6-methyl-3-pyrimidin-2-yl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0180] 7-(2,3-Dihydrobenzofuran-4-yl)-6-methyl-3-(2-pyridyl)pyrrolo[1,2-d][1,2,4]triazin-4-one

[0181] 7-[3-(Difluoromethoxy)phenyl]-6-methyl-3-(2-pyridyl)pyrrolo[1,2-d][1,2,4]triazin-4-one 7-[3-(Difluoromethoxy)-2-methyl-phenyl]-6-methyl-3-(2-pyridyl)pyrrolo[1,2-d][1,2,4]triazin-4-one

[0182] 7-(3-Methoxy-2-methyl-phenyl)-6-methyl-3-(2-pyridyl)pyrrolo[1,2-d][1,2,4]triazin-4-one

[0183] 7-(2-Chloro-3-methoxy-phenyl)-6-methyl-3-(2-pyridyl)pyrrolo[1,2-d][1,2,4]triazin-4-one 7-[3-(Difluoromethoxy)phenyl]-6-methyl-3-pyrimidin-2-yl-pyrrolo[1,2-d][1,2,4]triazin-4-one 7-[3-(Difluoromethoxy)-2-methyl-phenyl]-6-methyl-3-pyrimidin-2-yl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0184] 7-(3-Methoxy-2-methyl-phenyl)-6-methyl-3-pyrimidin-2-yl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0185] 7-(2-Chloro-3-methoxyphenyl)-6-methyl-3-pyrimidin-2-yl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0186] 6-Methyl-7-(1-methyl-2-oxo-indolin-4-yl)-3-(pyridin-2-yl)pyrrolo[1,2-d][1,2,4]triazin-4-one

[0187] 7-(2,4-Dimethylphenyl)-6,8-dimethyl-3-pyrimidin-2-yl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0188] 7-[3-(Cyclopropoxy)phenyl]-3-[5-(3-hydroxypyrrolidin-1-yl)pyrimidin-2-yl]-6,8-dimethyl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0189] 3-(5-Aminopyrimidin-2-yl)-7-[3-(cyclopropoxy)phenyl]-6,8-dimethyl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0190] 7-[3-(Cyclopropoxy)-2-methylphenyl]-3-(pyridin-2-yl)pyrrolo[1,2-d][1,2,4]triazin-4-one

[0191] 7-[3-(Cyclopropoxy)phenyl]-6-methyl-3-(pyridin-2-yl)pyrrolo[1,2-d][1,2,4]triazin-4-one

[0192] 7-[3-(Cyclopropoxy)-2-methylphenyl]-6-methyl-3-(pyridin-2-yl)pyrrolo[1,2-d][1,2,4]triazin-4-one

[0193] 7-[3-(Cyclopropoxy)-2-methylphenyl]-6-methyl-3-pyrimidin-2-yl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0194] 6,8-Dimethyl-7-(1-methyl-3,4-dihydro-2H-quinolin-5-yl)-3-pyrimidin-2-yl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0195] 6,8-Dimethyl-7-(1-methylindolin-4-yl)-3-pyrimidin-2-yl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0196] 7-[3-(Cyclopropoxy)phenyl]-6-methyl-3-pyrimidin-2-yl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0197] 6-Methyl-7-(1-methyl-3,4-dihydro-2H-quinolin-5-yl)-3-pyrimidin-2-yl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0198] 6-Methyl-7-(1-methylindolin-4-yl)-3-pyrimidin-2-yl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0199] 7-(3-Methoxyphenyl)-6,8-dimethyl-3-pyrimidin-2-yl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0200] 7-[5-(Cyclopropoxy)-2-methyl-phenyl]-6-methyl-3-pyrimidin-2-yl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0201] 7-[5-(Cyclopropoxy)-2-methyl-phenyl]-6,8-dimethyl-3-pyrimidin-2-yl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0202] 3-Ethyl-6,8-dimethyl-7-(1-methyl-3,4-dihydro-2H-quinolin-5-yl)pyrrolo[1,2-d][1,2,4]triazin-4-one

[0203] 7-(3-Methoxy-2-methyl-phenyl)-6,8-dimethyl-3-pyrimidin-2-yl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0204] 7-(1-Cyclopropylindol-4-yl)-6,8-dimethyl-3-pyrimidin-2-yl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0205] 6,8-Dimethyl-7-(1-methylindol-4-yl)-3-pyrimidin-2-yl-pyrrolo[1,2-d][1,2,4]triazin-4-one 7-(6-Methoxy-2-pyridyl)-6,8-dimethyl-3-pyrimidin-2-yl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0206] 7-(1-Cyclopropylindolin-4-yl)-6,8-dimethyl-3-pyrimidin-2-yl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0207] 3-Ethyl-6,8-dimethyl-7-(1-methylindolin-4-yl)pyrrolo[1,2-d][1,2,4]triazin-4-one

[0208] 7-(3-Fluoro-5-methoxyphenyl)-6-methyl-3-(2-pyridyl)pyrrolo[1,2-d][1,2,4]triazin-4-one

[0209] 7-(2-Fluoro-5-methoxyphenyl)-6-methyl-3-(2-pyridyl)pyrrolo[1,2-d][1,2,4]triazin-4-one

[0210] 7-(3-Fluoro-5-methoxyphenyl)-6-methyl-3-pyrimidin-2-yl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0211] 7-[2-Chloro-3-(cyclopropoxy)phenyl]-6-methyl-3-(2-pyridyl)pyrrolo[1,2-d][1,2,4]triazin-4-one

[0212] 7-(2-Fluoro-5-methoxyphenyl)-6-methyl-3-pyrimidin-2-yl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0213] 7-(2-Methoxy-4-pyridyl)-6-methyl-3-(2-pyridyl)pyrrolo[1,2-d][1,2,4]triazin-4-one

[0214] 7-(4-Fluoro-3-methoxyphenyl)-6-methyl-3-(2-pyridyl)pyrrolo[1,2-d][1,2,4]triazin-4-one

[0215] 7-(2-Fluoro-3-methoxyphenyl)-6-methyl-3-(2-pyridyl)pyrrolo[1,2-d][1,2,4]triazin-4-one

[0216] 7-[3-(Cyclopropoxy)-2-fluorophenyl]-6-methyl-3-(2-pyridyl)pyrrolo[1,2-d][1,2,4]triazin-4-one

[0217] 7-[2-Chloro-3-(cyclopropoxy)phenyl]-6-methyl-3-pyrimidin-2-yl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0218] 7-(4-Fluoro-3-methoxyphenyl)-6-methyl-3-pyrimidin-2-yl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0219] 7-(2-Fluoro-3-methoxyphenyl)-6-methyl-3-pyrimidin-2-yl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0220] 7-[3-(Cyclopropyloxy)-2-fluoro-phenyl]-6-methyl-3-pyrimidin-2-yl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0221] 7-(2-Methoxy-4-pyridinyl)-6-methyl-3-pyrimidin-2-yl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0222] 8-Bromo-7-(2-fluoro-3-methoxy-phenyl)-6-methyl-3-(2-pyridinyl)pyrrolo[1,2-d][1,2,4]triazin-4-one

[0223] 7-(3-Fluoro-2-methoxy-4-pyridinyl)-6-methyl-3-(2-pyridinyl)pyrrolo[1,2-d][1,2,4]triazin-4-one

[0224] 7-(3-Fluoro-2-methoxy-4-pyridinyl)-6-methyl-3-pyrimidin-2-yl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0225] 6-Methyl-7-(1-methyl-2,3-dihydropyrrolo[2,3-b]pyridin-4-yl)-3-(2-pyridinyl)pyrrolo[1,2-d][1,2,4]triazin-4-one

[0226] 6-Methyl-7-(1-methyl-2,3-dihydropyrrolo[2,3-b]pyridin-4-yl)-3-pyrimidin-2-yl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0227] 7-[3-(Difluoromethoxy)-2-methyl-phenyl]-6,8-dimethyl-3-pyrimidin-2-yl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0228] 7-(1-Cyclopropyl-3,4-dihydro-2H-quinolin-5-yl)-6,8-dimethyl-3-pyrimidin-2-yl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0229] 7-(4-Methoxyphenyl)-6,8-dimethyl-3-pyrimidin-2-yl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0230] 7-(2-Chloro-3-fluoro-phenyl)-6,8-dimethyl-3-pyrimidin-2-yl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0231] 7-[3-(Cyclobutyloxy)phenyl]-6,8-dimethyl-3-pyrimidin-2-yl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0232] 7-[3-(Cyclopropoxy)-2-fluoro-phenyl]-6,8-dimethyl-3-pyrimidin-2-yl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0233] 7-(2-Fluoro-5-methoxy-phenyl)-6,8-dimethyl-3-(pyridin-2-yl)pyrrolo[1,2-d][1,2,4]triazin-4-one

[0234] 7-(2-Fluoro-5-methoxy-phenyl)-6,8-dimethyl-3-pyrimidin-2-yl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0235] 7-(2-Fluoro-3-methoxy-phenyl)-6,8-dimethyl-3-(pyridin-2-yl)pyrrolo[1,2-d][1,2,4]triazin-4-one

[0236] 7-(6-Methoxypyridin-3-yl)-6,8-dimethyl-3-(pyridin-2-yl)pyrrolo[1,2-d][1,2,4]triazin-4-one

[0237] 7-(4-Methoxyphenyl)-6,8-dimethyl-3-(pyridin-2-yl)pyrrolo[1,2-d][1,2,4]triazin-4-one 7-[3-(7-azabicyclo[2.2.1]heptan-7-yl)phenyl]-6,8-dimethyl-3-pyrimidin-2-yl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0238] 7-(6-Methoxypyridin-3-yl)-6,8-dimethyl-3-(pyrimidin-2-yl)pyrrolo[1,2-d][1,2,4]triazin-4(3H)-one

[0239] 7-(2-Fluoro-3-methoxy-phenyl)-6,8-dimethyl-3-(pyrimidin-2-yl)pyrrolo[1,2-d][1,2,4]triazin-4(3H)-one

[0240] 7-(4-Methoxy-2-methyl-phenyl)-6,8-dimethyl-3-(pyrimidin-2-yl)pyrrolo[1,2-d][1,2,4]triazin-4(3H)-one

[0241] 7-(2-Fluoro-4-methoxy-phenyl)-6,8-dimethyl-3-(pyrimidin-2-yl)pyrrolo[1,2-d][1,2,4]triazin-4(3H)-one

[0242] 7-(2-Fluoro-4-methoxy-phenyl)-6,8-dimethyl-3-(pyridin-2-yl)pyrrolo[1,2-d][1,2,4]triazin-4(3H)-one

[0243] 7-(6-Methoxy-2-methylpyridin-3-yl)-6,8-dimethyl-3-(pyrimidin-2-yl)pyrrolo[1,2-d][1,2,4]triazin-4(3H)-one

[0244] 7-(3-Fluoro-2-methoxypyridin-4-yl)-6,8-dimethyl-3-(pyrimidin-2-yl)pyrrolo[1,2-d][1,2,4]triazin-4(3H)-one

[0245] 7-(2-Methoxypyridin-4-yl)-6,8-dimethyl-3-(pyrimidin-2-yl)pyrrolo[1,2-d][1,2,4]triazin-4(3H)-one

[0246] 7-(2-(Difluoromethoxy)pyridin-4-yl)-6,8-dimethyl-3-(pyridin-2-yl)pyrrolo[1,2-d][1,2,4]triazin-4(3H)-one

[0247] 7-(2-(Difluoromethoxy)pyridin-4-yl)-6,8-dimethyl-3-(pyrimidin-2-yl)pyrrolo[1,2-d][1,2,4]triazin-4(3H)-one

[0248] 7-(6-Methoxypyridin-3-yl)-6-methyl-3-(pyridin-2-yl)pyrrolo[1,2-d][1,2,4]triazin-4(3H)-one

[0249] 7-(2-Cyclopropoxy-3-methylpyridin-4-yl)-6-methyl-3-(pyridin-2-yl)pyrrolo[1,2-d][1,2,4]triazin-4(3H)-one

[0250] 7-(6-Methoxypyrimidin-3-yl)-6-methyl-3-(pyridin-2-yl)pyrrolo[1,2-d][1,2,4]triazin-4(3H)-one

[0251] 7-(2-Cyclopropoxy-3-methylpyrimidin-4-yl)-6-methyl-3-(pyridin-2-yl)pyrrolo[1,2-d][1,2,4]triazin-4(3H)-one

[0252] 7-(2-(Difluoromethoxy)pyridin-4-yl)-6-methyl-3-(pyridin-2-yl)pyrrolo[1,2-d][1,2,4]triazin-4(3H)-one, and

[0253] 7-(2-(Difluoromethoxy)pyrimidin-4-yl)-6-methyl-3-(pyridin-2-yl)pyrrolo[1,2-d][1,2,4]triazin-4(3H)-one.

[0254] The compounds of the above list can also be represented by the following skeletal formulas:

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263] The compounds according to any of the above statements may exhibit metabotropic glutamate receptor 7 modulator activity.

[0264] The disclosed compounds also include all pharmaceutically acceptable isotopic variations in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass commonly found in nature. Some examples of isotopes suitable for inclusion in the disclosed compounds include, but are not limited to, isotopes of hydrogen such as 2 H and 3 H; isotopes of carbon such as 11 C, 13 C and 14 C; isotopes of nitrogen such as 15 N; isotopes of oxygen such as 17 O and 18 O; isotopes of phosphorus such as 31 P, 32 P and 33 P; isotopes of sulfur such as 35 S; isotopes of fluorine such as 18 F; isotopes of chlorine such as 36 Cl; and isotopes of iodine such as 125 I. The present invention includes various isotopically labeled compounds as defined herein, for example those in which a radioactive isotope (e.g., 3 H and 14 C) is present, or those in which a non-radioactive isotope (e.g., 2 H and 13 C) is present.

[0265] Such isotopically labeled compounds can be used in metabolic studies (using 14C), reaction kinetics studies (e.g., using 2 H or 3 H), detection or imaging techniques (e.g., positron emission tomography (PET) or single - photon emission computed tomography (SPECT), including determination of drug or substrate tissue distribution), or radioactive treatment for patients. In particular, 11 C, 18 F, 15 O and 13 N or labeled compounds may be particularly suitable for PET studies to examine substrate receptor occupancy. In addition, substitution with heavier isotopes, especially deuterium (e.g., 2 H or D), may provide certain therapeutic advantages due to better metabolic stability (e.g., increased in - vivo half - life, or reduced dose requirements, or improvement of the therapeutic index). It should be understood that deuterium in this context is considered a substituent of the compounds of formula (I) to formula (VIII). Isotopically labeled compounds of formula (I) to formula (VIII) can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the appended examples using appropriate isotopically labeled reagents in place of the previously used unlabeled reagents.

[0266] In one aspect of the present invention, there is provided a pharmaceutical composition comprising a compound according to any of the above statements. The pharmaceutical composition may further comprise a pharmaceutically acceptable carrier and / or excipient. The pharmaceutical composition may comprise a therapeutically effective amount of a compound according to any of the above statements.

[0267] In one aspect of the present invention, there is provided a method for treating or preventing a disorder in a mammal, which comprises administering to a mammal in need of such treatment or prevention an effective amount of a compound / composition according to any of the above statements.

[0268] The treatment or prevention may be affected or facilitated by the modulating action of an allosteric mGlu7 modulator, such as a negative allosteric mGlu7 modulator.

[0269] The disorder may be one or more of a central nervous system disorder or an ear disease or disorder or a pain disorder.

[0270] Central nervous system disorders can be anxiety disorders, such as agoraphobia, generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), panic disorder, or post-traumatic stress disorder (PTSD).

[0271] Central nervous system disorders can be psychotic disorders, such as schizophrenia, delusional disorder, schizoaffective disorder, schizophreniform disorder, or substance-induced psychotic disorder.

[0272] Ear diseases and disorders can be one or more of the following: inner ear injury, age-related hearing impairment (presbycusis), Meniere's disease, sudden hearing loss, noise-induced hearing loss, otitis media, autoimmune inner ear disease, acute tinnitus, chronic tinnitus, drug-induced hearing loss, hidden hearing loss, cisplatin-induced hearing loss, aminoglycoside-induced hearing loss, ototoxicity, central auditory processing disorder, or vestibular disorder.

[0273] In another aspect of the present invention, there is provided a method for treating, preventing, ameliorating, controlling, or reducing the risk of a variety of nervous system and mental disorders associated with glutamate dysfunction in a mammal, the method comprising administering to a mammal in need of such treatment or prevention an effective amount of a compound / composition according to any of the foregoing statements. The treatment or prevention can be effected or facilitated by the modulatory action of an mGlu7 negative allosteric modulator.

[0274] Preferably, the method is for treating or preventing a disorder in a human.

[0275] In another aspect of the present invention, there is provided a compound or composition as set forth in any of the foregoing statements for use as a medicament.

[0276] In another aspect of the present invention, there is provided a compound or composition as set forth in any of the foregoing statements for use in a method of treatment or prevention as defined in any of the foregoing statements.

[0277] In another aspect of the present invention, there is provided the use of a compound according to any of the foregoing statements in the manufacture of a medicament for the treatment or prevention of a disorder as defined in any of the foregoing statements.

[0278] Definition of Terms

[0279] The following are definitions of various terms used in the specification and claims to describe the present invention.

[0280] For the avoidance of doubt, it should be understood that in this specification, "(C1-C6)" means a carbon group having 1, 2, 3, 4, 5 or 6 carbon atoms. "(C0-C6)" means a carbon group having 0, 1, 2, 3, 4, 5 or 6 carbon atoms. In this specification, "C" means a carbon atom, "N" means a nitrogen atom, "O" means an oxygen atom and "S" means a sulfur atom.

[0281] In the case where the subscript is the integer 0 (zero), the group indicated by the subscript means the absence of that group, i.e., there is a direct bond between the groups.

[0282] In the case where the subscript is the integer 0 (zero) and the group indicated by the subscript is an alkyl group, this means that the group is a hydrogen atom.

[0283] 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 equivalent to one bond. For example, the group -A-B-, where both A and B can be bonds, represents a single bond.

[0284] In this specification, unless otherwise specified, the term "alkyl" includes both straight-chain and branched-chain alkyl groups and can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, isohexyl or tert-hexyl. The term "(C0-C3)alkyl" refers to an alkyl group having 0, 1, 2 or 3 carbon atoms and can be methyl, ethyl, n-propyl or isopropyl.

[0285] In this specification, unless otherwise specified, the term "alkylene" includes both straight-chain and branched-chain difunctional saturated hydrocarbon groups and can be methylene (-CH2-), ethylene (-CH2-CH2-), n-propylene (-CH2-CH2-CH2-), isopropylene (-CH-(CH3)-CH2-), n-butylene (-CH2-CH2-CH2-CH2-), isobutylene (-CH2-CH-(CH3)-CH2-), tert-butylene (-CH2-C-(CH3)-CH2-), n-pentylene (-CH2-CH2-CH2-CH2-CH2-), isopentylene (-CH2-CH(CH3)-CH2-CH2-), neopentylene (-CH2-C(CH3)2-CH2-), n-hexylene (-CH2-CH2-CH2-CH2-CH2-CH2-), isohexylene (-CH2-CH-(CH3)-CH2-CH2-CH2-) or neohexylene (-CH2-C(CH3)2-CH2-CH2-). The term "O-(C1-C6)alkylene-aryl" means an alkyl chain having 0, 1, 2, 3, 4, 5 or 6 carbon atoms between the oxygen atom and the aryl group.

[0286] In this specification, unless otherwise specified, the term "cycloalkyl" refers to an optionally substituted non-heteroatom-containing carbocyclic ring, including monocyclic, bicyclic, and tricyclic saturated carbocyclic rings and fused ring systems. Such fused ring systems may include one ring that is partially or fully unsaturated (such as a benzene ring) to form a fused ring system such as a benzo-fused carbocyclic ring. Cycloalkyl includes fused ring systems, such as spiro-fused ring systems. Some examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, decalin, adamantane, indanyl, fluorenyl, and 1,2,3,4-tetrahydronaphthalene, etc. The term "(C3-C7)cycloalkyl" may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.

[0287] In this specification, unless otherwise specified, the term "alkenyl" includes both straight-chain and branched-chain alkenyl groups. The term "(C2-C6)alkenyl" refers to an alkenyl group having 2 to 6 carbon atoms and one or two double bonds, and may be, but is not limited to, vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, crotyl, pentenyl, isopentenyl, or hexenyl.

[0288] In this specification, unless otherwise specified, the term "alkenylene" includes both straight-chain and branched-chain disubstituted alkenyl groups. The term "(C2-C6)alkenylene" refers to an alkenylene group having 2 to 6 carbon atoms and one or two double bonds, and may be, but is not limited to, vinylene, allylene, propenylene, isopropenylene, butenylene, isobutenylene, crotylene, pentenylene, isopentenylene, or hexenylene.

[0289] In this specification, unless otherwise specified, the term "alkynyl" includes both straight-chain and branched-chain alkynyl groups. The term "(C2-C6)alkynyl", which has 2 to 6 carbon atoms and one or two triple bonds, and may be, but is not limited to, ethynyl, propargyl, butynyl, isobutynyl, pentynyl, isopentynyl, or hexynyl.

[0290] In this specification, unless otherwise specified, the term "alkynylene" includes both straight-chain and branched-chain disubstituted alkynylene groups. The term "(C2-C6)alkynylene", which has 2 to 6 carbon atoms and one or two triple bonds, and may be, but is not limited to, ethynylene, propargylene, butynylene, isobutynylene, pentynylene, isopentynylene, or hexynylene.

[0291] The term "aryl" refers to an optionally substituted monocyclic or bicyclic hydrocarbon ring system containing at least one unsaturated aromatic ring. Some examples and suitable values of the term "aryl" are phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indolyl, indenyl, etc.

[0292] In this specification, unless otherwise specified, the term "heteroaryl" refers to an optionally substituted monocyclic or bicyclic unsaturated aromatic ring system containing at least one heteroatom independently selected from N, O, or S. Some examples of "heteroaryl" can be, but are not limited to, benzimidazolyl, benzisothiazolyl, benzisoxazolyl, benzofuranyl, benzpyrazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furazanyl, furanyl, imidazolinone, imidazolyl, imidazopyridazinyl, imidazopyridyl, indolyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, isoxazolyl, furazanyl, furanyl, imidazolinone, imidazolyl, imidazopyridazinyl, imidazopyridyl, indolyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, isoxazolyl, diazolyl, oxazolinone, oxazopyridazinyl, oxazopyridyl, oxazolyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyrazolopyridyl, pyrazolyl, pyridazinyl, pyridinone, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrotriazolopyridyl, tetrahydrotriazolopyrimidinyl, tetrazolyl, thiadiazolyl, thiazolinone, thiazopyridazinyl, thiazopyridyl, thiazolyl, thienyl, thionaphthyl, triazinyl, and triazolyl.

[0293] In this specification, unless otherwise specified, the terms "alkylene-aryl", "alkylene-heteroaryl", and "alkylene-cycloalkyl" respectively refer to substituents that are connected to an aryl, heteroaryl, or cycloalkyl group through an alkyl group. The term "(C1-C6)alkylene-aryl" includes aryl-C1-C6-alkyl groups such as benzyl, 1-phenylethyl, 2-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 1-naphthylmethyl, and 2-naphthylmethyl. The term "(C1-C6)alkylene-heteroaryl" includes heteroaryl-C1-C6-alkyl groups, some examples of which are the same as those exemplified in the above definition, such as 2-furanylmethyl, 3-furanylmethyl, 2-thienylmethyl, 3-thienylmethyl, 1-imidazolylmethyl, 2-imidazolylmethyl, 3-imidazolylmethyl, 2- oxazolylmethyl, 3- oxazolylmethyl, 2-thiazolylmethyl, 3-thiazolylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 1-quinolylmethyl, etc.

[0294] In this specification, unless otherwise indicated, the term "heterocycle" refers to an optionally substituted monocyclic, bicyclic or tricyclic saturated, partially saturated or unsaturated ring system containing at least one heteroatom independently selected from N, O and S. The bicyclic or tricyclic ring system can be formed by the fusion of two or more rings, by bridging atoms (such as O, S, N) or by bridging groups (such as alkylene). Some examples of heterocyclic moieties include, but are not limited to: azetidinyl, dihydrofuranyl, dihydrothienyl, dioxolanyl, 1,1-dioxo-thiomorpholinyl, imidazolidinyl, imidazolinyl, isothiazolinyl, iso oxazolidinyl, iso oxazolinyl, morpholinyl, oxazolidinyl, oxazolinyl, oxetanyl, piperazinone, piperazinyl, piperidinone, piperidinyl, pyranyl, pyrrolidinone, pyrrolidinyl, pyrrolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, thiazolidinyl, thiazolinyl, thiomorpholinyl, thiopyranyl, triazolinyl, and the corresponding benzheterocycles (such as dihydrobenzofuranyl, dihydrobenzothienyl, dihydrobenz azinyl, dihydrofuropyridinyl, dihydroquinolinyl, dihydrothienopyridinyl, dihydroindolyl, pyrrolopyridinyl, tetrahydroquinolinyl, tetrahydroquinoxalinyl, etc.).

[0295] In this specification, unless otherwise indicated, 5-membered or 6-membered rings containing one or more atoms independently selected from C, N, O and S include aromatic rings, heteroaromatic rings, carbocyclic rings and heterocyclic rings, which may be saturated or unsaturated. Such rings include spiro and bridged bicyclic systems. Some examples of such rings can be, but are not limited to, dihydrofuranyl, dihydrothienyl, dioxolanyl, 1,1-dioxo-thiomorpholinyl, furazanyl, furanyl, imidazolidinyl, imidazolinyl, imidazolinone, imidazolyl, isothiazolinyl, isothiazolyl, iso oxazolidinyl, iso oxazolinyl, iso oxazolyl, morpholinyl, diazolyl, oxazolidinyl, oxazolinyl, oxazolonyl, oxazolyl, phenyl, piperazinone, piperazinyl, piperidinone, piperidinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinone, pyridinyl, pyrimidinyl, pyrrolidinone, pyrrolidinyl, pyrrolinyl, pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolinyl, thiazolonyl, thiazolyl, thienyl, thiomorpholinyl, thiopyranyl, triazolinyl, triazinyl, triazolyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl.

[0296] In this specification, unless otherwise specified, a 3- to 10-membered ring containing one or more atoms independently selected from C, N, O, and S includes aromatic rings, heteroaromatic rings, carbocyclic rings, and heterocyclic rings, which may be saturated or unsaturated. Some examples of such rings may be, but are not limited to, azetidinyl, benzimidazolyl, benzisothiazolyl, benzisoxazolyl, benzofuranyl, benzopyrazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, dihydrofuranyl, dihydrothienyl, dioxolanyl, 1,1-dioxo-thiomorpholinyl, furazanyl, furanyl, imidazolidinyl, imidazolinyl, imidazolinone, imidazolyl, imidazopyridazinyl, imidazopyridyl, indolyl, isoindolyl, isoquinolinyl, isothiazolinyl, isothiazolyl, isoxazolidinyl, isoxazolinyl, isoxazolyl, morpholinyl, naphthyl, naphthyridinyl, oxadiazolyl, oxazolidinyl, oxazolinyl, oxazolidinone, oxazopyridazinyl, oxazopyridyl, oxazolyl, oxetanyl, phenyl, piperazinone, piperazinyl, piperidinone, piperidinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolopyridyl, pyrazolyl, pyridazinyl, pyridone, pyridyl, pyrimidinyl, pyrrolidone, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrotriazolopyridinyl, tetrahydrotriazolopyrimidinyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolinyl, thiazolidinone, thiazopyridazinyl, thiazopyridyl, thiazolyl, thienyl, thiomorpholinyl, thionaphthyl, thiopyranyl, triazolinyl, triazinyl, triazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, and cyclooctenyl.

[0297] In this specification, unless otherwise specified, the term "halo" or "halogen" may be fluorine, chlorine, bromine, or iodine.

[0298] In this specification, unless otherwise specified, the term "haloalkyl" means an alkyl group as defined above substituted with one or more halo groups. The term "(C1-C6)haloalkyl" may include, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, and difluoroethyl. The term "O-C1-C6-haloalkyl" may include, but is not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, and fluoroethoxy.

[0299] ​​​​​​​​​​​​In the present specification, unless otherwise specified, the term "cyanoalkyl" means an alkyl group as defined above which is substituted by one or more cyano groups.

[0300] In the present specification, unless otherwise specified, the term "optionally substituted" means a group which further bears one or more substituents which may be acyl, (C1-C6)alkyl, -(C1-C6)haloalkyl, -(C3-C7)cycloalkyl, -(C1-C6)alkylene-(C3-C7)cycloalkyl, -(C3-C7)cycloalkyl-(C1-C6)alkylene, -(C0-C6)alkylene-(C3-C7)spiroalkyl-(C0-C6)alkylene, 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, formamide, (C1-C6)alkylene-oxycarbonyl, carbamate, sulfonamide, ester or sulfonyl.

[0301] In the present specification, unless otherwise specified, the term "independently" means that in the case of selecting more than one substituent from a plurality of possible substituents, these substituents may be the same or different.

[0302] In the present specification, unless otherwise specified, the term "solvate" means a variable stoichiometric complex composed of a solute (such as a compound of formula (I)) and a solvent. The solvent is a pharmaceutically acceptable solvent such as water; such a solvent does not interfere with the biological activity of the solute.

[0303] In the present specification, unless otherwise specified, the term "salt" means an acid addition salt or a base addition salt of a compound of the present invention. "Salt" particularly includes "pharmaceutically acceptable salt".

[0304] The pharmaceutically acceptable salts of the present invention can be synthesized from the basic or acidic moieties by conventional chemical methods. When both a basic group and an acidic group are present in the same molecule, the compounds of the present invention can also form internal salts, such as zwitterionic molecules.

[0305] In this specification, unless otherwise indicated, certain compounds can exist in one or more specific geometric, optical, enantiomeric, diastereomeric, epimeric, stereoisomeric, tautomeric, conformational, or anomeric forms, including but not limited to cis and trans forms; E- and Z-forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; d- and l-forms; (+) and (-) forms; keto-, enol-, and enolate-forms; α- and β-forms; axial and equatorial forms; and combinations thereof, collectively referred to as "isomers" or "isomeric forms".

[0306] For example, the group is a tautomer of

[0307] The term "isomers" includes compounds having one or more isotope substitutions. For example, H can be in any isotope form, including but not limited to 1 H, 2 H (D), and 3 H (T); C can be in any isotope form, including but not limited to 12 C, 13 C, 14 C; O can be in any isotope form, including but not limited to 16 O and 18 O, etc. F can be in any isotope form, including but not limited to 19 F and 18 F, etc.

[0308] In this specification, unless otherwise indicated, the term "negative allosteric modulator of mGlu7" or "allosteric modulator of mGlu7" also refers to its pharmaceutically acceptable acid addition salts or base addition salts, its stereochemical isomeric forms, or its N-oxide forms.

[0309] Drug Composition

[0310] The allosteric modulators of mGlu7 described herein, and their pharmaceutically acceptable salts, solvates and hydrates can be combined with a pharmaceutically acceptable carrier or diluent for use in pharmaceutical formulations. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solvents. The allosteric modulators of mGlu7 will be present in such pharmaceutical compositions in an amount sufficient to provide the desired dosage within the ranges described herein. Techniques for the formulation and administration of the compounds of the present invention are found in Remington: the Science and Practice of Pharmacy, 19th Edition, Mack Publishing Co., Easton, PA (1995).

[0311] The amount of the allosteric modulator of mGlu7 administered to a subject will depend on the type and severity of the disease or condition and the characteristics of the subject, such as general health, age, sex, weight and tolerance to the drug. Those skilled in the art will be able to determine the appropriate dosage based on these and other factors. The effective dosages of CNS drugs commonly used are well known to those skilled in the art. The total daily dosage generally ranges from about 0.05 to 2000 mg.

[0312] The present invention relates to pharmaceutical compositions providing from about 0.01 to 1000 mg of active ingredient per unit dosage. The composition can be administered by any suitable route. For example, oral administration in the form of capsules, etc., parenteral administration in the form of a solution for injection, topical administration in the form of an ointment or lotion, ophthalmic administration in the form of eye drops, rectal administration in the form of suppositories, intranasal or transdermal administration in the form of a delivery system such as a patch.

[0313] For oral administration, the allosteric modulator of mGlu7 can be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, pills, powders, syrups, solutions, suspensions, etc.

[0314] Tablets, pills, capsules, etc. contain from about 0.01 to about 99 weight percent of the active ingredient, and binders such as gum tragacanth, gum arabic, corn starch or gelatin; excipients such as dicalcium phosphate; disintegrants such as corn starch, potato starch, alginic acid; lubricants such as magnesium stearate; and sweeteners such as sucrose, lactose or saccharin. When the dosage unit form is a capsule, in addition to the above types of substances, it may also contain a liquid carrier such as a fatty oil.

[0315] A variety of other substances may be present as coatings or to modify the physical form of the dosage unit. For example, tablets may be coated with shellac, sugar, or both. In addition to the active ingredient, syrup or elixir may also contain sucrose as a sweetening agent, methylparaben and propylparaben as preservatives, dyes, and flavoring agents such as cherry or orange flavoring agents.

[0316] For parenteral administration, the disclosed allosteric modulators of mGlu7 or salts thereof may be combined with a sterile aqueous or organic medium to form an injectable solution or suspension. For example, solutions in sesame oil or peanut oil, aqueous propylene glycol, etc., as well as aqueous solutions of water-soluble pharmaceutically acceptable salts of the compounds may be used. Dispersions may also be prepared in glycerol, liquid polyethylene glycol, and mixtures thereof in oils. Under ordinary storage and use conditions, these preparations contain preservatives to prevent the growth of microorganisms.

[0317] In addition to the previously described formulations, the compounds may also be formulated as depot preparations. Such long-acting preparations may be administered, for example, by subcutaneous implantation or intramuscular injection. Thus, for example, the compounds may be formulated as an emulsion in an acceptable oil or ion exchange resin, or as a slightly soluble derivative, such as a slightly soluble salt.

[0318] Preferably, the disclosed allosteric modulators of mGlu7 or pharmaceutical preparations containing these compounds are administered to mammals in unit dosage forms. The unit dosage form may be any unit dosage form known in the art, including, for example, capsules, IV bags, tablets, or vials. The amount of the active ingredient in the unit dose composition is an effective amount and may vary depending on the particular treatment involved. It will be understood that it may be necessary to make routine variations in the dosage according to the age and condition of the patient. The dosage will also depend on the route of administration, which may be by a variety of routes, including oral, aerosol, rectal, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, and intranasal.

[0319] Synthesis Method

[0320] The compounds according to the invention, in particular the compounds according to formulae (I) to (VIII), can be prepared by methods known in the field of organic synthesis as described in the following synthetic schemes section. In all the schemes below, it is well understood that, in accordance with the general principles of chemistry, protecting groups for sensitive or reactive groups are used when necessary. The protecting groups are manipulated according to standard methods of organic synthesis (Green T.W. and Wuts P.G.M., (1991) Protecting Groups in Organic Synthesis, John Wiley & Sons). These groups are removed at a convenient stage of the compound synthesis using methods that are obvious to those skilled in the art. The choice of method, as well as the reaction conditions and the order of their execution, should be consistent with the preparation of the compounds of formulae (I) to (VIII).

[0321] 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 by derivation with a chiral auxiliary, where the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (e.g., an amino group) or an acidic functional group (e.g., a carboxyl group), the resolution can be conveniently carried out by fractional crystallization of the salt with an optically active acid from a variety of solvents or by other methods known in the literature (e.g., chiral column chromatography).

[0322] The resolution of the final product, intermediate, or starting material can be carried out by any suitable method known in the art (Eliel E.L., Wilen S.H. and Mander L.N. (1984) Stereochemistry of Organic Compounds, Wiley-Interscience).

[0323] Many of the heterocyclic compounds of the invention can be prepared using synthetic routes well known in the art (Katrizky A.R. and Rees C.W. (1984) Comprehensive Heterocyclic Chemistry, Pergamon Press).

[0324] The products from the reaction can be separated and purified by using standard techniques such as extraction, chromatography, recrystallization, and distillation.

[0325] The compounds of the invention can be prepared by general synthetic routes as disclosed in the following methods.

[0326] In one embodiment of the present invention, the compound of formula (I) can be prepared according to the synthetic sequence shown in Scheme 1. 1H-Pyrrole-2-carbaldehyde g1 can be oxidized in a suitable solvent such as carbon tetrachloride at a suitable temperature in the presence of N-bromosuccinimide to obtain the intermediate 4-bromo-1H-pyrrole-2-carbaldehyde g2. The intermediate g4 can be prepared by reacting the corresponding intermediate g2 with ethyl hydrazinecarboxylate g3 in a suitable solvent such as toluene at a suitable temperature. The intermediate g4 can be converted into a bromopyrrolo[1,2-d][1,2,4]triazinone derivative g5 by condensation in a suitable solvent such as DMF at a suitable temperature in the presence of a base such as sodium hydride. Then, the intermediate g5 can be converted into the intermediate g7 by suitable reactions known to those skilled in the art of organic synthesis, for example, by a Suzuki cross-coupling reaction mediated by a palladium complex catalyst such as PdCl2(dppf) in a suitable solvent such as a mixture of 1,4-dioxane / water in the presence of a base such as potassium carbonate. The final compound g9 can be obtained by an Ullmann coupling reaction with a suitable aryl halide or heteroaryl halide g8 mediated by a copper complex catalyst such as CuI in the presence of a base such as potassium phosphate at a suitable temperature, or by alkylation of g7 in a suitable solvent such as DMF in the presence of a base such as potassium carbonate or cesium carbonate.

[0327]

[0328] Scheme 1

[0329] Similarly, the final compound g9 can be prepared according to the synthetic sequence shown in Scheme 2. The bromopyrrolo[1,2-d][1,2,4]triazinone derivative g5 prepared according to step 3 of Scheme 1 can be converted into the intermediate g10 by an Ullmann coupling reaction mediated by a copper complex catalyst such as CuI in the presence of a base such as potassium phosphate, or by alkylation of g5 in the presence of a base such as potassium carbonate. The final compound g9 can be obtained by a Suzuki cross-coupling reaction mediated by a palladium complex catalyst such as PdCl2(dppf) in a suitable solvent such as a mixture of 1,4-dioxane / water in the presence of a base such as potassium carbonate.

[0330]

[0331] Scheme 2

[0332] In one embodiment of the present invention, the compound of formula (II) can be prepared according to the synthetic sequence shown in Scheme 3. The final compound g12 can be prepared according to the synthetic sequence shown in Scheme 3. The intermediate g7 prepared according to Step 4 of Scheme 1 can be converted into the intermediate g11 by an Ullmann coupling reaction with a heteroaryl halide mediated by a copper complex catalyst such as CuI in the presence of a base such as potassium phosphate in a suitable solvent such as 1,4-dioxane. The g11 is deprotected with a suitable acid such as TFA in a suitable solvent such as DCM to give the final compound g12.

[0333]

[0334] Scheme 3

[0335] In another specific aspect of formula (II), the final compound g14 can be prepared according to the synthetic sequence shown in Scheme 4. The intermediate g7 prepared according to Step 4 of Scheme 1 can be converted into the intermediate g13 by an Ullmann coupling reaction with a heteroaryl halide mediated by a copper complex catalyst such as CuI in the presence of a base such as N 1 ,N 2 -dimethylethane-1,2-diamine in a suitable solvent such as DMF. The final product g14 can be obtained by nucleophilic substitution of g13 using a suitable cyclic secondary amine in a suitable solvent such as butan-1-ol.

[0336]

[0337] Scheme 4

[0338] In another specific aspect of formula (I), the final compound g17 can be prepared according to the synthetic sequence shown in Scheme 5. The intermediate compound g15 (R 4 =H) prepared according to Step 1 of Scheme 2 can be converted into the compound g16 by a Suzuki cross-coupling reaction mediated by a palladium complex catalyst such as PdCl2(dppf) in the presence of a base such as potassium carbonate in a suitable solvent such as a mixture of 1,4-dioxane / water. The g16 is brominated with N-bromosuccinimide in a suitable solvent such as anhydrous THF at a suitable temperature to give the final compound g17.

[0339]

[0340] Scheme 5

[0341] In another specific aspect of formula (II), the final compound g20 can be prepared according to the synthetic sequence shown in Scheme 6. The intermediate compound g18 (R 4=H) can be converted to compound g19 by Miyaura boration mediated by a palladium complex catalyst such as PdCl2(dppf) in a suitable solvent such as anhydrous 1,4-dioxane in the presence of a base such as potassium acetate. The final compound g20 can be obtained by Suzuki cross-coupling reaction mediated by a palladium complex catalyst such as PdCl2(dppf) in a suitable solvent such as a mixture of 1,4-dioxane / water in the presence of a base such as potassium carbonate.

[0342]

[0343] Scheme 6

[0344] Experiment

[0345] Unless otherwise stated, all starting materials were obtained from commercial suppliers and used without further purification.

[0346] Specifically, the following abbreviations are used in the examples and throughout the specification.

[0347]

[0348]

[0349] All brine mentioned refers to a saturated aqueous solution of NaCl. Unless otherwise stated, all temperatures are in °C (degrees Celsius). Unless otherwise stated, all reactions are carried out at room temperature under an inert atmosphere.

[0350] Most reactions were monitored by thin layer chromatography (TLC silica gel 60F 254 , SigmaAldrich) on pre-coated silica gel plates and visualized with UV light. Flash column chromatography was carried out using a Biotage Isolera One 2.0.8 automated column on pre-packed columns of UltraPure Irregular Silica Gel (40 to 63 μm, 60 Å) with capacities of 4 g, 12 g, 25 g, 40 g, and 80 g obtained from Screening Devices BV. Examples

[0351] Example 1: 7-[3-(azetidin-1-yl)phenyl]-3-ethyl-6,8-dimethyl-pyrrolo[1,2-d][1,2,4]triazin-4-one (final compound 1-10)

[0352] 4-bromo-3,5-dimethyl-1H-pyrrole-2-carbaldehyde

[0353] According to Step 1 of Scheme 1: Under argon, NBS (3.0 g, 17 mmol) was added to a suspension of 3,5-dimethyl-1H-pyrrole-2-carbaldehyde (2.0 g, 16 mmol) in CCl4 (115 mL), followed by the addition of benzoyl peroxide (98 mg, 0.41 mmol). The mixture was heated under reflux overnight. The crude mixture was cooled, concentrated in vacuo, and purified by flash chromatography (Isolera, 80 g column, EtOAc:Hept, 50:50) to give the title compound as an olive green solid (2.55 g, 12.6 mmol, 78%).

[0354] 1 H-NMR (500 MHz, DMSO-d6) δ: 12.07 (s, 1H), 9.49 (s, 1H), 2.22 (s, 3H), 2.19 (s, 3H)

[0355] (E)-Ethyl 2-((4-bromo-3,5-dimethyl-1H-pyrrol-2-yl)methylene)hydrazine-1-carboxylate

[0356] According to Step 2 of Scheme 1: Ethyl hydrazinecarboxylate (1.97 g, 18.9 mmol) was added to a solution of 4-bromo-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (2.55 g, 12.6 mmol) in toluene (50 mL). The mixture was heated under reflux overnight. The crude mixture was cooled to room temperature. The solid product was filtered and purified by flash chromatography (Isolera, 80 g column, EtOAc:Hept, 50:50) to give the title compound as an olive green solid (3.0 g, 10 mmol, 82%).

[0357] 1 H-NMR (500 MHz, DMSO-d6) δ: 11.31 (s, 1H), 10.66 (s, 1H), 7.89 (s, 1H), 4.10 (t, J = 7.0 Hz, 2H), 2.14 (s, 3H), 1.99 (s, 3H), 1.22 (t, J = 7.1 Hz, 3H).

[0358] 7-Bromo-6,8-dimethylpyrrolo[1,2-d][1,2,4]triazin-4(3H)-one

[0359] According to Step 3 of Scheme I: At 0 °C, a solution of ethyl (E)-2-((4-bromo-3,5-dimethyl-1H-pyrrol-2-yl)methylene)hydrazine-1-carboxylate (2.5 g, 8.7 mmol) in DMF (10 mL) was added dropwise to a slurry of NaH (0.11 g, 95 wt%, 4.3 mmol) in DMF (2.8 mL), and then heated at 100 °C overnight. After cooling, the solvent was removed in vacuo and purified by flash column chromatography (Isolera, 80 g column, EtOAc:Hept, 50:50) to give the title compound as an orange solid (800 mg, 3.30 mmol, 38%).

[0360] 1 1H-NMR (500 MHz, CDCl3) δ: 8.84 (s, 1H), 7.81 (s, 1H), 2.79 (s, 3H), 2.24 (s, 3H).

[0361] 7-[3-(azetidin-1-yl)phenyl]-6,8-dimethylpyrrolo[1,2-d][1,2,4]triazin-4(3H)-one

[0362] According to Step 4 of Scheme 1: To a solution of 7-bromo-6,8-dimethylpyrrolo[1,2-d][1,2,4]triazin-4(3H)-one (47.1 mg, 0.195 mmol) in a mixture of 1,4-dioxane (0.6 mL) and water (70 μL) was added 1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)azetidine (51.7 mg, 0.295 mmol) and K2CO3 (51 mg, 0.37 mmol). The mixture was purged with argon, and then PdCl2(dppf) (10 mg, 14 μmol) was added. The microwave vial was capped, purged with argon again, and heated in the microwave at 110 °C for 1.5 h. Then TLC was performed, and TLC showed that the starting material was still present. Therefore, the reaction was heated in the microwave at 110 °C for an additional 1.5 h. The reaction was passed through filtration and rinsed with DCM (2 × 10 mL). The filtrate was concentrated in vacuo and purified by flash column chromatography (Isolera, 4 g column, EtOAc:Hept, 50:50). The product was washed with Et2O to give the title compound as a beige solid (4.0 mg, 13 μmol, 11%).

[0363] SFC-MS: RT = 2.96 min; MS m / z [M+H] + = 295.1.

[0364] 7-[3-(Azetidin-1-yl)phenyl]-3-ethyl-6,8-dimethyl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0365] According to Step 5 of Scheme 1: To a solution of 7-[3-(azetidin-1-yl)phenyl]-6,8-dimethylpyrrolo[1,2-d][1,2,4]triazin-4(3H)-one (50 mg, 0.17 mmol) in DMF (2 mL) was added bromoethane (0.19 g, 0.13 mL, 1.7 mmol) and K2CO3 (70 mg, 0.51 mmol). The vial was capped and stirred at 120 °C for 20 h. The mixture was extracted with Et2O (3 × 10 mL) and washed with brine (1 × 25 mL). The organic layer was separated, dried, filtered, concentrated in vacuo, and purified by flash column chromatography (Isolera, 12 g column, EtOAc:Hept, 50:50) to give the title compound (16 mg, 49 μmol, 29%).

[0366] LC-MS (ESI): RT = 13.33 min; MS m / z [M+H] + = 323.1; 1 1H-NMR (400 MHz, CDCl3) δ: 7.85 (s, 1H), 7.26 (t, J = 7.8 Hz, 1H), 6.60 (ddd, J = 7.5, 1.6, 1.0 Hz, 1H), 6.45 (ddd, J = 8.1, 2.4, 1.0 Hz, 1H), 6.32 - 6.26 (m, 1H), 4.10 (q, J = 7.2 Hz, 2H), 3.90 (t, J = 7.2 Hz, 4H), 2.74 (s, 3H), 2.44 - 2.33 (m, 2H), 2.18 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H).

[0367] Example 2: 7-[3-(Cyclopropoxy)-2-methyl-phenyl]-3-pyrimidin-2-yl-pyrrolo[1,2-d][1,2,4]triazin-4-one (Final Compound 1-18)

[0368] 4-Bromo-1H-pyrrole-2-carbaldehyde

[0369] According to Step 1 of Scheme 1: 1H-Pyrrole-2-carbaldehyde (5000 mg, 52.58 mmol) was added to ACN (100 mL) and cooled to 0 °C. NBS (9.358 g, 52.58 mmol) was dissolved in ACN (100 mL), and this solution was slowly added to the cooled mixture at 0 °C over a 30-minute period using a dropping funnel. The mixture was stirred for 30 minutes, then ice-cold water (100 mL) was added. The mixture was extracted with EtOAc (3 × 100 mL), and the combined organic layers were washed with brine (1 × 100 mL), dried over MgSO4, filtered, and the solvent was removed under reduced pressure. Purification by silica gel chromatography (n-hexane / EtOAc 100:0 → 90:10) gave the title compound as a white solid (5616.8 mg, 32.280 mmol, 61.40%).

[0370] 1 1H-NMR (400 MHz, CDCl3) δ: 9.80 (s, 1H), 9.33 (s, 1H), 7.11 (m, 1H), 6.98 (dd, 1H).

[0371] (E)-Ethyl 2-((4-bromo-1H-pyrrol-2-yl)methylene)hydrazine-1-carboxylate

[0372] According to Step 2 of Scheme 1: Ethyl hydrazinecarboxylate (4.844 g, 46.53 mmol) was added to 4-bromo-1H-pyrrole-2-carbaldehyde (5397 mg, 31.02 mmol) in toluene (60 mL). The mixture was then refluxed for 3 hours and subsequently allowed to cool to room temperature. The solvent was removed under reduced pressure, and the mixture was further purified by silica gel chromatography (n-hexane / EtOAc 100:0 → 50:50) to give the title compound as a clear white solid (5.911 g, 22.73 mmol, 73.27%).

[0373] 1 1H-NMR (400 MHz, DMSO-d6) δ: 11.66 (s, 1H), 10.88 (s, 1H), 7.82 (s, 1H), 6.93 (dd, J = 2.9, 1.6 Hz, 1H), 6.44 (dd, J = 2.6, 1.6 Hz, 1H), 4.13 (q, J = 7.1 Hz, 2H), 1.23 (t, J = 7.1 Hz, 3H).

[0374] 7-Bromopyrrolo[1,2-d][1,2,4]triazin-4(3H)-one

[0375] According to Step 3 of Scheme 1: At 0 °C, a solution of ethyl (E)-2-((4-bromo-1H-pyrrol-2-yl)methylene)hydrazine-1-carboxylate (5.80 g, 22.3 mmol) in DMF (80 mL) was added dropwise to a slurry of NaH (281.7 mg, 95 wt%, 11.15 mmol) in a mixture of DMF (10 mL) and water (2 mL). The reaction mixture was then stirred at 0 °C for about 30 minutes, and then the reaction mixture was heated to 100 °C for 20 hours. The reaction mixture was then concentrated under reduced pressure to give the title compound (4.0 g, 19 mmol, 84%).

[0376] 1 1H-NMR (400 MHz, CDCl3) δ: 9.36 (s, 1H), 7.99 - 7.94 (m, 1H), 7.79 (dd, J = 1.5, 0.7 Hz, 1H), 6.77 (d, J = 1.5 Hz, 1H).

[0377] 7-(3-Cyclopropoxy-2-methylphenyl)pyrrolo[1,2-d][1,2,4]triazin-4(3H)-one

[0378] According to Step 4 of Scheme 1: To a solution of 7-bromopyrrolo[1,2-d][1,2,4]triazin-4(3H)-one (100 mg, 467 μmol) in a mixture of 1,4-dioxane (1.5 mL) and water (0.17 mL) was added 2-(3-cyclopropoxy-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (128 mg, 467 μmol) and K2CO3 (187 mg, 1.36 mmol). The mixture was purged with argon, and then PdCl2(dppf) (37.6 mg, 51.4 μmol) was added. The reaction mixture was purged with argon again, and the vial was capped and heated at 110 °C for 20 hours. The reaction mixture was diluted with DCM, filtered, and concentrated under reduced pressure. Purification was carried out by silica gel chromatography (n-hexane / EtOAc 100:0 → 80:20) to give the title compound (68.2 mg, 242 μmol, 51.9%). filtered, and concentrated under reduced pressure. Purification was carried out by silica gel chromatography (n-hexane / EtOAc 100:0 → 80:20) to give the title compound (68.2 mg, 242 μmol, 51.9%).

[0379] 1H-NMR (400MHz, CDCl3) δ: 9.03 (s, 1H), 8.03 (d, J = 6.2Hz, 1H), 7.81 (dd, J = 1.5, 0.7Hz, 1H), 7.27 (dd, J = 2.1, 1.2Hz, 1 H),7.04-6.95(m,1H),6.84(d,J=1.5Hz,1H),6.81-6.75(m,0H),3.84-3.75(m,1H),2.24(s,3H),0.88-0.80(m,4H).

[0380] 7-[3-(Cyclopropyloxy)-2-methyl-phenyl]-3-pyrimidin-2-yl-pyrrolo[1,2-d][1,2,4]triazine-4-one

[0381] According to Scheme 1, step 5: To 7-(3-cyclopropyloxy-2-methylphenyl)pyrrolo[1,2-d][1,2,4]triazine-4(3H)-one (60.0 mg, 213 μmol) was added CuI (20.3 mg, 107 μmol), 2-bromopyrimidine (102 mg, 640 μmol), K3PO4 (113 mg, 533 μmol), 1,10-phenanthroline (23.1 mg, 128 μmol) and 1,4-dioxane (1.62 g, 1.57 mL, 18.3 mmol). The solution was purged with argon for 5 minutes, then the vial was capped and heated at 110 °C for 20 hours. The mixture was diluted with DCM and heated over 40 °C. Filter, concentrate in vacuo, and further purify using flash column chromatography. The resulting fractions were concentrated in vacuo, redissolved in MeOH, and further purified by preparative HPLC. The resulting fractions were concentrated in vacuo, redissolved in AcOH, and freeze-dried to give the title compound (12.7 mg, 35.3 μmol, 16.6%).

[0382] LC-MS: RT = 11.62 min; MS m / z [M+H] = 360.3; 1 H-NMR (400MHz, CDCl3) δ: 8.96 (d, J = 4.8Hz, 2H), 8.22 (d, J = 0.7Hz, 1H), 7.92 (dd, J = 1.5, 0.7Hz, 1H), 7.42 (t, J = 4.8Hz, 1H), 7.27 (d, J =2.1Hz,1H),7.24(t,J=7.9Hz,1H),7.03(dd,J=7.0,1.9Hz,1H),6.89(d,J=1.5Hz,1H),3.84-3.75(m,1H),2.25(s,3H),0.83(m,4H).

[0383] Example 3: 7-[3-(Azetidin-1-yl)phenyl]-3-[5-(1-hydroxy-1-methylethyl)-2-pyridyl]-6,8-dimethyl-pyrrolo[1,2-d][1,2,4]triazin-4-one (Final Compound 1-24)

[0384] 7-[3-(Azetidin-1-yl)phenyl]-3-[5-(1-hydroxy-1-methylethyl)-2-pyridyl]-6,8-dimethyl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0385] According to Step 5 of Scheme 1: To a solution of 7-[3-(azetidin-1-yl)phenyl]-6,8-dimethylpyrrolo[1,2-d][1,2,4]triazin-4(3H)-one (45 mg, 0.15 mmol, prepared according to Step 4 - Example 1 of Scheme 1) in 1,4-dioxane (1.2 mL) was added K3PO4 (81 mg, 0.38 mmol), CuI (15 mg, 0.076 mmol), 2-(6-bromopyridin-3-yl)propan-2-ol (99 mg, 0.46 mmol) and DMPA (8.1 mg, 9.9 μL, 0.092 mmol). The solution was purged with argon for 5 minutes, then the microwave vial was capped and heated overnight in a sand bath at 110 °C. Water (10 mL) was added and the mixture was extracted with EtOAc (3 × 50 mL) and washed with water (2 × 30 mL) and brine (50 mL). The combined organic layers were dried, filtered, concentrated in vacuo and purified by flash column chromatography (Isolera, 12 g column, EtOAc:Hept, 50:50) to give the title compound as a beige solid (15 mg, 33 μmol, 14%).

[0386] LC-MS (ESI): RT = 11.47 minutes; MS m / z [M+H] + = 430.4; 1 1H-NMR (400 MHz, CDCl3) δ: 8.73 (d, J = 2.5 Hz, 1H), 8.02 (s, 1H), 7.97 (dd, J = 8.4, 2.6 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.29 (d, J = 7.8 Hz, 2H), 6.62 (dt, J = 7.5, 1.3 Hz, 1H), 6.50 - 6.43 (m, 1H), 6.31 (t, J = 2.0 Hz, 1H), 3.91 (t, J = 7.2 Hz, 4H), 2.78 (s, 1H), 2.75 (s, 3H), 2.39 (p, J = 7.2 Hz, 2H), 2.23 (s, 3H), 1.64 (s, 6H).

[0387] Example 4: 6,8-Dimethyl-3-pyrimidin-2-yl-7-[3-(trifluoromethoxy)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-one (Final Compound 1-53)

[0388] 6,8-Dimethyl-7-(3-(trifluoromethoxy)phenyl)pyrrolo[1,2-d][1,2,4]triazin-4(3H)-one

[0389] According to Step 4 of Scheme 1: To a solution of 7-bromo-6,8-dimethylpyrrolo[1,2-d][1,2,4]triazin-4(3H)-one (100 mg, 413 μmol, prepared according to Step 3 - Example 1 of Scheme 1) in a mixture of 1,4-dioxane (2 mL) and water (0.2 mL) was added 4,4,5,5-tetramethyl-2-(3-(trifluoromethoxy)phenyl)-1,3,2-dioxaborolane (178 mg, 620 μmol) and K2CO3 (171 mg, 1.24 mmol). The mixture was purged with argon, and PdCl2(dppf) (75.6 mg, 103 μmol) was added. The reaction mixture was purged with argon again, the vial was capped, and heated in a microwave at 110 °C for 3 hours. Then the mixture was filtered, concentrated, and further purified by flash column chromatography to give the title compound (166 mg, 513 μmol, 124%). filtered, concentrated, and further purified by flash column chromatography to give the title compound (166 mg, 513 μmol, 124%).

[0390] 1 1H-NMR (400 MHz, CDCl3) δ: 9.43 (s, 1H), 7.96 (s, 2H), 7.56 - 7.47 (m, 1H), 7.30 - 7.24 (m, 1H), 7.22 (dt, J = 7.6, 1.3 Hz, 1H), 7.15 (dt, J = 2.5, 1.3 Hz, 1H), 2.77 (s, 3H), 2.23 (s, 3H).

[0391] 6,8-Dimethyl-3-pyrimidin-2-yl-7-[3-(trifluoromethoxy)phenyl]pyrrolo[1,2-d][1,2,4]triazin-4-one

[0392] According to Step 5 of Scheme 1: To a solution of 6,8-dimethyl-7-(3-(trifluoromethoxy)phenyl)pyrrolo[1,2-d][1,2,4]triazin-4(3H)-one (45 mg, 90 wt%, 0.13 mmol) in DMF (2.00 mL) was added 2-bromopyrimidine (60 mg, 0.38 mmol) and CuI (12 mg, 63 μmol), and purged with argon for 5 minutes. Then the reaction was stirred at 110 °C overnight. The mixture was diluted with DCM and filtered Filtered, concentrated in vacuo, and further purified using flash column chromatography. The resulting fractions were then concentrated in vacuo, redissolved in MeOH, and further purified by preparative HPLC. Finally, the resulting fractions were concentrated in vacuo, redissolved in AcOH and lyophilized to afford the title compound (6 mg, 0.01 mmol, 10%, 100% purity).

[0393] LC-MS (ESI): RT = 12.42 min; MS m / z [M+H] + = 402.2; 1 1H-NMR (400 MHz, CDCl3) δ: 8.96 (s, 2H), 8.10 (s, 1H), 7.52 (t, J = 8.0 Hz, 1H), 7.40 (t, J = 4.7 Hz, 1H), 7.33 - 7.19 (m, 2H), 7.17 (dt, J = 2.5, 1.2 Hz, 1H), 2.78 (s, 3H), 2.26 (s, 3H).

[0394] Example 5: 7-[3-(Azetidin-1-yl)phenyl]-6,8-dimethyl-3-(pyridin-2-yl)pyrrolo[1,2-d][1,2,4]triazin-4-one (Final Compound 1-3)

[0395] 7-Bromo-6,8-dimethyl-3-(pyridin-2-yl)pyrrolo[1,2-d][1,2,4]triazin-4(3H)-one

[0396] According to Scheme 2 Step 1: To a solution of 7-bromo-6,8-dimethylpyrrolo[1,2-d][1,2,4]triazin-4(3H)-one (538 mg, 2.22 mmol, prepared according to Scheme 1 Step 3 - Example 1) in DMF (15 mL) was added K3PO4 (1.18 g, 5.56 mmol), CuI (212 mg, 1.11 mmol), 2-bromopyridine (1.05 g, 638 μL, 6.67 mmol) and DMPA (136 mg, 16.0 μL, 1.33 mmol). The solution was purged with argon for 5 minutes, then the microwave vial was capped and heated in a microwave at 110 °C for 1.5 h. Water (10 mL) was added and the solution was acidified with 2N HCl until pH = 5. The mixture was extracted with EtOAc (3 × 50 mL) and washed with water (2 × 30 mL) and brine (50 mL). The combined organic layers were dried, filtered, concentrated in vacuo, and purified by flash column chromatography (Isolera, 25 g column, EtOAc:Hept, 50:50) to afford the title compound as a solid (365.7 mg, 1.146 mmol, 52%).

[0397] SFC-MS: RT = 3.06 min; MS m / z [M+H] + = 320.9.

[0398] 7-[3-(azetidin-1-yl)phenyl]-6,8-dimethyl-3-(pyridin-2-yl)pyrrolo[1,2-d][1,2,4]triazin-4-one

[0399] According to Step 2 of Protocol 2: To a solution of 7-bromo-6,8-dimethyl-3-(pyridin-2-yl)pyrrolo[1,2-d][1,2,4]triazin-4(3H)-one (40 mg, 0.13 mMol) in a mixture of 1,4-dioxane (0.6 mL) and water (70 μL) was added 1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)azetidine (49 mg, 0.19 mmol), K2CO3 (52 mg, 0.38 mmol). The mixture was purged with argon and then PdCl2(dppf) (10 mg, 14 μmol) was added. The microwave vial was then capped, purged again with argon, and heated in the microwave at 110 °C for 3 h. The reaction was quenched by filtration and rinsed with DCM (2 × 10 mL). The filtrate was concentrated in vacuo and purified by flash column chromatography (Isolera, 4 g column, EtOAc:Hept, 50:50). The product was crashed out using Et2O to afford the title compound (20 mg, 54 μmol, 43%) as a beige solid.

[0400] SFC-MS: RT = 3.94 min; MS m / z [M+H] + = 372.1; 1 1H-NMR (500 MHz, CDCl3) δ: 8.65 (ddd, J = 4.9, 2.0, 0.9 Hz, 1H), 8.04 (s, 1H), 7.87 - 7.81 (m, 1H), 7.66 (dt, J = 8.2, 1.0 Hz, 1H), 7.35 - 7.25 (m, 2H), 6.62 (dt, J = 7.5, 1.3 Hz, 1H), 6.46 (ddd, J = 8.1, 2.4, 1.0 Hz, 1H), 6.31 (t, J = 1.9 Hz, 1H), 3.91 (t, J = 7.2 Hz, 4H), 2.75 (s, 3H), 2.45 - 2.34 (m, 2H), 2.23 (s, 3H).

[0401] Example 6: 3-(5-Amino-2-pyridinyl)-7-[3-(azetidin-1-yl)phenyl]-6,8-dimethyl-pyrrolo[1,2-d][1,2,4]triazin-4-one (Final Compound 1-34)

[0402] tert-Butyl N-[6-[7-[3-(azetidin-1-yl)phenyl]-6,8-dimethyl-4-oxo-pyrrolo[1,2-d][1,2,4]triazin-3-yl]-3-pyridinyl]carbamate

[0403] According to Step 1 of Scheme 3: To a solution of 7-[3-(azetidin-1-yl)phenyl]-6,8-dimethylpyrrolo[1,2-d][1,2,4]triazin-4(3H)-one (40 mg, 0.14 mmol, prepared according to Step 4 of Scheme 1 - Example 1) in 1,4-dioxane (1.2 mL) was added K3PO4 (72 mg, 0.34 mmol), CuI (13 mg, 68 μmol), tert-butyl (6-bromopyridin-3-yl)carbamate (74 mg, 0.27 mmol) and 1,10-phenanthroline (15 mg, 82 μmol). The solution was purged with argon for 5 minutes, then the microwave vial was capped and heated overnight at 110 °C in a sand bath. The crude reaction mixture was filtered and washed with Et2O, concentrated in vacuo, and purified by flash column chromatography (Isolera, 12 g column, EtOAc:Hept, 50:50) to afford the title compound as a beige solid (40 mg, 75 μmol, 55%). LC-MS (ESI): RT = 13.54 min; MS m / z [M+H]

[0404] = 487.0. +

[0405] 3-(5-Amino-2-pyridinyl)-7-[3-(azetidin-1-yl)phenyl]-6,8-dimethyl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0406] ​According to Step 2 of Scheme 3: To a solution of tert-butyl N-[6-[7-[3-(azetidin-1-yl)phenyl]-6,8-dimethyl-4-oxopyrrolo[1,2-d][1,2,4]triazin-3-yl]-3-pyridyl]carbamate (8 mg, 0.02 mmol) in DCM (0.5 mL) was added TFA (74 mg, 50 μL, 0.65 mmol). The reaction was stirred overnight at room temperature. The crude mixture was extracted with 5% bicarbonate (20 mL) and DCM (10 mL), dried, concentrated in vacuo, and purified by flash column chromatography (Isolera, 12 g column, EtOAc:Hept, 50:50) to afford the title compound as a white solid (3.15 mg, 7.8 μmol, 50%).

[0407] LC-MS (ESI): RT = 12.59 min; MS m / z [M+H] + = 388.2; 1 1H-NMR (500 MHz, CDCl3) δ: 8.31 (s, 2H), 7.98 (s, 1H), 7.27 (s, 1H), 6.64 - 6.59 (m, 1H), 6.46 (ddd, J = 8.1, 2.4, 0.9 Hz, 1H), 6.31 (t, J = 2.0 Hz, 1H), 3.95 - 3.85 (m, 4H), 2.74 (s, 3H), 2.37 (dt, J = 15.3, 7.6 Hz, 2H), 2.22 (s, 3H).

[0408] Example 7: 7-[3-(Cyclopropoxy)phenyl]-6,8-dimethyl-3-(5-morpholinopyrimidin-2-yl)pyrrolo[1,2-d][1,2,4]triazin-4-one (Final Compound 1-47)

[0409] 7-[3-(Cyclopropoxy)phenyl]-3-(5-fluoropyrimidin-2-yl)-6,8-dimethyl-pyrrolo[1,2-d][1,2,4]triazin-4-one

[0410] According to Step 1 of Scheme 4: To a solution of 7-(3-cyclopropoxyphenyl)-6,8-dimethylpyrrolo[1,2-d][1,2,4]triazin-4(3H)-one (61 mg, 0.21 mmol, prepared according to Step 4 of Scheme 1) in DMF (2 mL) was added CuI (20 mg, 0.10 mmol), 2-bromo-5-fluoropyrimidine (37 mg, 0.21 mmol) and N 1 ,N 2-Dimethylethane-1,2-diamine (11 mg, 13 μL, 0.12 mmol). The solution was purged with argon for 5 minutes, then the microwave vial was capped, purged again with argon, and heated in the microwave at 110 °C for 3 hours. After complete conversion, water (10 mL) and saturated EDTA (2 mL) were added, and the mixture was extracted with Et2O (3 × 20 mL) and washed with saturated EDTA (10 mL), water (2 × 20 mL), and brine (20 mL). The combined organic layers were dried, filtered, concentrated in vacuo, and purified by flash column chromatography (Isolera, SILICYCLE 12 g column, EtOAc:Hept, 0% to 20%) to give the title compound (11 mg, 28 μmol, 14%).

[0411] LC-MS (ESI): RT = 12.84 min; MS m / z [M+H] + = 392.2; 1 1H-NMR (500 MHz, CDCl3) δ: 8.75 (s, 2H), 8.03 (s, 1H), 7.37 (dd, J = 8.3, 7.6 Hz, 1H), 7.08 (ddd, J = 8.2, 2.5, 1.0 Hz, 1H), 6.94 (dd, J = 2.6, 1.5 Hz, 1H), 6.87 (dt, J = 7.6, 1.3 Hz, 1H), 3.80 - 3.72 (m, 1H), 2.76 (s, 3H), 2.25 (s, 3H), 0.83 - 0.74 (m, 4H).

[0412] 7-[3-(Cyclopropoxy)phenyl]-6,8-dimethyl-3-(5-morpholinopyrimidin-2-yl)pyrrolo[1,2-d][1,2,4]triazin-4-one

[0413] According to Scheme 4 Step 2: To a stirred solution of 7-[3-(cyclopropoxy)phenyl]-3-(5-fluoropyrimidin-2-yl)-6,8-dimethyl-pyrrolo[1,2-d][1,2,4]triazin-4-one (15.8 mg, 40.6 μmol) in butan-1-ol (1 mL) was added morpholine (35.30 mg, 35.00 μL, 405.7 μmol). The microwave vial was capped and the solution was stirred at 160 °C overnight. The crude mixture was concentrated in vacuo and purified by flash chromatography to give the title compound (6.3 mg, 12 μmol, 30%).

[0414] LC-MS (ESI): RT = 12.21 min; MS m / z [M+H] = 459.4; 11H-NMR (500 MHz, CDCl3) δ: 8.46 (s, 2H), 8.00 (s, 1H), 7.36 (dd, J = 8.3, 7.5 Hz, 1H), 7.07 (ddd, J = 8.3, 2.6, 1.0 Hz, 1H), 6.95 (dd, J = 2.6, 1.5 Hz, 1H), 6.87 (ddd, J = 7.5, 1.6, 1.0 Hz, 1H), 3.92 - 3.89 (m, 4H), 3.48 (q, J = 7.0 Hz, 2H), 3.31 - 3.27 (m, 4H), 2.76 (s, 3H), 2.24 (s, 3H), 0.84 - 0.77 (m, 4H).

[0415] Example 8: 8 - Bromo - 7 - (2 - fluoro - 3 - methoxyphenyl) - 6 - methyl - 3 - (pyridin - 2 - yl)pyrrolo[1,2 - d][1,2,4]triazin - 4 - one (Final Compound 1 - 115)

[0416] 7 - (2 - Fluoro - 3 - methoxyphenyl) - 6 - methyl - 3 - (pyridin - 2 - yl)pyrrolo[1,2 - d][1,2,4]triazin - 4 - one

[0417] According to Step 1 of Scheme 5: To a stirred solution of 7 - bromo - 6 - methyl - 3 - (pyridin - 2 - yl)pyrrolo[1,2 - d][1,2,4]triazin - 4(3H) - one (100 mg, 0.329 mmol, prepared according to Step 1 of Scheme 2) in a mixture of 1,4 - dioxane (10 mL) and water (1 mL) was added 2 - (2 - fluoro - 3 - methoxyphenyl) - 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolane (91 mg, 0.36 mmol) and K2CO3 (132 mg, 0.954 mmol). Then, PdCl2(dppf) (29 mg, 0.040 mmol) was added in one portion, and the mixture was stirred overnight at 110 °C in a sealed pressure tube. The reaction mixture was diluted with DCM, filtered, and concentrated under reduced pressure. The first silica gel chromatography (n - hexane / EtOAc 100:0 → 1:1) gave the impure title compound. The second silica gel chromatography (DCM / EtOAc 100:0 → 95:5) gave the title compound as an off - white solid (93 mg, 0.266 mmol, 81%). Filtration and concentration under reduced pressure. The first silica gel chromatography (n - hexane / EtOAc 100:0 → 1:1) gave the impure title compound. The second silica gel chromatography (DCM / EtOAc 100:0 → 95:5) gave the title compound as an off - white solid (93 mg, 0.266 mmol, 81%).

[0418] TIC - MS: RT = 4.26 minutes; MS m / z [M + H] + = 351.3.

[0419] 8-Bromo-7-(2-fluoro-3-methoxyphenyl)-6-methyl-3-(pyridin-2-yl)pyrrolo[1,2-d][1,2,4]triazin-4(3H)-one

[0420] According to Step 2 of Scheme 5: NBS (136 mg, 0.765 mmol) was added to a stirred solution of 7-(2-fluoro-3-methoxyphenyl)-6-methyl-3-(pyridin-2-yl)pyrrolo[1,2-d][1,2,4]triazin-4(3H)-one (134 mg, 0.382 mmol) in anhydrous THF (10 mL). After 3 h, another portion of NBS (34 mg) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM (25 mL) and washed with saturated NaHCO3 (25 mL) and brine (10 mL). The organic phase was dried over MgSO4, filtered and the solvent was removed under reduced pressure. Silica gel chromatography (hexane / EtOAc 100:0 → 60:40) gave the title compound as a colorless solid (141 mg, 0.329 mmol, 86%).

[0421] TIC-MS: RT = 4.63 min; MS m / z [M+H] + = 429.2; 1 1H-NMR (500 MHz, CDCl3) δ: 8.71 (dd, J = 4.9, 1.9 Hz, 1H), 8.13 (s, 1H), 7.95 (td, J = 7.8, 1.9 Hz, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.41 (ddd, J = 7.4, 5.0, 1.1 Hz, 1H), 7.19 (td, J = 8.0, 1.4 Hz, 1H), 7.06 (td, J = 8.2, 1.6 Hz, 1H), 6.88 (ddd, J = 7.6, 6.0, 1.6 Hz, 1H), 3.95 (s, 3H), 2.73 (d, J = 1.2 Hz, 3H).

[0422] Example 9: 6-Methyl-7-(1-methyl-2,3-dihydropyrrolo[2,3-b]pyridin-4-yl)-3-(pyridin-2-yl)pyrrolo[1,2-d][1,2,4]triazin-4(3H)-one (Final Compound 1-118)

[0423] 6-Methyl-3-(pyridin-2-yl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-d][1,2,4]triazin-4(3H)-one

[0424] According to Scheme 6, Step 1: A stirred mixture of 7-bromo-6-methyl-3-(pyridin-2-yl)pyrrolo[1,2-d][1,2,4]triazin-4(3H)-one (200 mg, 0.655 mmol, prepared according to Step 1 of Scheme 2), bis(pinacolato)diboron (200 mg, 0.79 mmol), and KOAc (193 mg, 1.97 mmol) in anhydrous 1,4-dioxane (10 mL) was degassed with nitrogen for 10 minutes. PdCl2(dppf) (24 mg, 0.033 mmol) was added, and the resulting mixture was stirred in a sealed pressure tube at 100 °C. After 18 hours, an additional PdCl2(dppf) (24 mg, 0.033 mmol) was added, and the mixture was stirred at 100 °C for an additional 24 hours. After a total of 42 hours, the reaction mixture was diluted with DCM (30 mL) and filtered through a short plug. Water (10 mL) was added, and the layers were separated. The aqueous layer was extracted with DCM (2 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over MgSO4, filtered, and concentrated in vacuo. Silica gel chromatography (DCM / EtOAc 9:1) of the residue gave the impure title compound (105 mg) as a pale brown solid. A second silica gel chromatography (n-hexane / EtOAc 90:10 → 60:40) gave the title compound (64.2 g, 0.182 mmol, 28%) as an off-white solid.

[0425] 1 1H-NMR (500 MHz, CDCl3) δ: 8.67 (s, 1H), 8.02 (s, 1H), 7.89 (td, J = 7.8, 1.8 Hz, 1H), 7.72 (d, J = 8.2 Hz, 1H), 7.35 (dd, J = 7.3, 4.9 Hz, 1H), 6.90 (s, 1H), 3.00 (s, 3H), 1.34 (s, 12H).

[0426] 6-Methyl-7-(1-methyl-2,3-dihydropyrrolo[2,3-b]pyridin-4-yl)-3-(2-pyridinyl)pyrrolo[1,2-d][1,2,4]triazin-4-one

[0427] According to Step 2 of Scheme 6: To a stirred solution of 6-methyl-3-(pyridin-2-yl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-d][1,2,4]triazin-4(3H)-one (263 mg, 0.75 mmol) in a mixture of 1,4-dioxane (13 mL) and water (1.3 mL) was added 4-bromo-1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (155 mg, 0.82 mmol) and K2CO3 (300 mg, 2.17 mmol). Then PdCl2(dppf) (66 mg, 0.090 mmol) was added in one portion, and the mixture was stirred in a sealed pressure tube at 110 °C overnight. After 20 h, the reaction mixture was diluted with DCM (50 mL), filtered through a plug of MgSO4, and concentrated under reduced pressure. The first silica gel chromatography of the black residue (EtOAc / MeOH 100:0 → 99:1) gave the desired product contaminated with Pd catalyst residue as a brown solid (223 mg). The second silica gel chromatography (DCM / EtOAc 100:0 → 0:100) gave the title compound as an amber solid (211 mg). Finally, the third silica gel chromatography (DCM / MeOH 100:0 → 97:3) finally gave the desired product as a pale orange solid (193 mg). Precipitation from DCM / n-pentane (1:5) gave the title compound as a powdery beige solid (158 mg, 0.44 mmol, 59%).

[0428] TIC-MS: RT = minutes; MS m / z ES + =; 1 1H-NMR (500 MHz, CDCl3) δ: 8.65 (ddd, J = 4.9, 1.9, 0.8 Hz, 1H), 8.05 (s, 1H), 7.92 - 7.90 (m, 1H), 7.87 (td, J = 7.8, 1.9 Hz, 1H), 7.66 (dt, J = 8.0, 0.9 Hz, 1H), 7.35 (ddd, J = 7.5, 4.9, 1.0 Hz, 1H), 6.67 (s, 1H), 6.40 (d, J = 5.6 Hz, 1H), 3.51 (t, J = 8.2 Hz, 2H), 3.02 (s, 3H), 2.92 (t, J = 8.3 Hz, 2H), 2.78 (s, 3H).

[0429] The compounds in the following table have been synthesized according to the same method as in the previous Examples 1 to 9, as shown in the column denoted "Exp. nr". The compounds denoted with an asterisk have been exemplified in the Examples.

[0430] Table 1: Compounds prepared according to the examples.

[0431]

[0432]

[0433]

[0434]

[0435]

[0436]

[0437]

[0438]

[0439]

[0440]

[0441]

[0442]

[0443] Physicochemical Data

[0444] LC-MS Method:

[0445] Liquid chromatography - mass spectrometry (LC - MS) was performed on an LC - MS system consisting of a Dionex UltiMate 3000 pump, an autosampler, a column compartment, and a detector (Thermo Fisher Scientific, Dreieich, Germany) and an ESI quadrupole MS (MSQ Plus or ISQ EC, Thermo Fisher Scientific, Dreieich, Germany).

[0446] Method 1 :

[0447] Reverse phase (C 18), full scan (positive and negative) from 100 to 1000 m / z; eluents: H2O + 0.1% formic acid (A) and MeCN + 0.1% formic acid (B): 5% B at 0 min → 5% B at 1 min → 100% B at 6.8 min (linear gradient from 5% to 100% B within 5.8 min) → 100% B at 8 min (100% B for 1.2 min). The purity of the final compound was determined by the area percentage method using LS-MS for the UV trace recorded at 254 nm wavelength.

[0448] Method 2:

[0449] Reverse phase (C 18 ) was carried out on an Accucore TM C 18 column (100 × 3 mm); eluents: H2O + 0.1% formic acid (A) and MeCN + 0.1% formic acid (B). Gradient conditions used: linear gradient from 0% to 95% B within 10 min. Purity was determined by the area percentage method of the obtained PDA spectrum.

[0450] Liquid chromatography - mass spectrometry (LC - MS) was also carried out on an LC - MS system consisting of: Thermo Finnigan LCQ Fleet coupled with a Shimadzu preparative HPLC system (DGU - 20AR TM C 18 column (100 × 3 mm), two LC - 20AD pumps, an SPD - 20A PDA detector, and a CTO - 20A column oven). 3R

[0451] Method 3:

[0452] Reverse phase (C 18 ) eluents: H2O + 0.1% formic acid (A) and MeCN + 0.1% formic acid (B). Gradient conditions used: linear gradient from 5% to 100% B within 20 min. Purity was determined by the area percentage method of the obtained PDA spectrum.

[0453] SFC-MS Method:

[0454] Supercritical fluid chromatography - mass spectrometry (SFC - MS) was performed on an SFC - MS system consisting of a Waters Acquity UPC2 SFC system (convergence manager, sample manager, binary solvent manager, column manager, PDA detector, isocratic solvent manager, and QDa detector) and a Viridis HSS C 18 SB column or Viridis BEH column.

[0455] Method 4:

[0456] Reverse phase (SB - C 18 column); supercritical CO2; gradient conditions used: a linear gradient from 10% to 30% (90 / 9 / 1 MeOH / H2O / formic acid) in CO2 over 6 minutes. Purity was determined by the area percentage method of the obtained PDA spectra.

[0457] Method 5:

[0458] Reverse phase (SB - C 18 column); supercritical CO2; gradient conditions used: a linear gradient from 2% to 30% (90 / 9 / 1 MeOH / H2O / formic acid) in CO2 over 7 minutes. Purity was determined by the area percentage method of the obtained PDA spectra.

[0459] Method 6:

[0460] Reverse phase (BEH - C 18 column); supercritical CO2; gradient conditions used: a linear gradient from 2% to 30% (90 / 9 / 1 MeOH / H2O / formic acid) in CO2 over 12 minutes. Purity was determined by the area percentage method of the obtained PDA spectra.

[0461] Method 7:

[0462] Reverse phase (SB - C 18 column); supercritical CO2; gradient conditions used: a linear gradient from 2% to 30% (90 / 9 / 1 MeOH / H2O / formic acid) in CO2 over 12 minutes. Purity was determined by the area percentage method of the obtained PDA spectra.

[0463] NMR:

[0464] 11H-NMR spectra were recorded on a Bruker Avance III 400 MHz, Bruker Avance III 500 MHz or Bruker Avance I 500 (500 MHz) spectrometer. Chemical shifts are reported in parts per million (ppm, δ scale). The splitting pattern describes the apparent multiplicity and is designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad). Coupling constants (J) are given in Hertz (Hz).

[0465] Table 2 : Physicochemical data. (RT means retention time in minutes; [M+H] + means the protonated mass of the compound (free base); nd = not determined).

[0466]

[0467]

[0468]

[0469]

[0470]

[0471]

[0472]

[0473]

[0474]

[0475]

[0476]

[0477]

[0478]

[0479]

[0480]

[0481]

[0482]

[0483]

[0484] Pharmacology

[0485] The compounds provided in the present invention are negative allosteric modulators of mGlu7. Accordingly, these compounds are expected to act on mGlu7 due to their ability to block receptor function after binding to a site that is not the orthosteric glutamate recognition site.

[0486] Some compounds of formula (I) have been tested according to some of the following methods.

[0487] Example A

[0488] mGlu7 assay for HEK-expressed human mGLU7

[0489] Transfection and cell culture

[0490] The cDNA encoding the human metabotropic glutamate receptor 7 (hmGlu7) (Accession No. NM_181874.2, NCBI Nucleotide database browser) was subcloned into an expression vector that also contains a hygromycin resistance gene. At the same time, the cDNA encoding a G protein that redirects the activation signal to an intracellular calcium flux was subcloned into a different expression vector that also contains a puromycin resistance gene. Both vectors were transfected into HEK293 cells using PolyFect reagent (Qiagen) according to the supplier's protocol, and hygromycin and puromycin treatments allowed selection of antibiotic-resistant cells that had stably integrated one or more plasmid copies. Positive cell clones expressing hmGlu7 were identified in a functional assay measuring changes in calcium flux in response to glutamate and L-AP4 or a known mGlu7 orthosteric antagonist.

[0491] HEK-293 cells expressing hmGlu7 were maintained at 37 °C and 5% CO2 in a humidified atmosphere in a medium containing 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).

[0492] Fluorescence cell-based Ca 2+ mobilization assay

[0493] In using FLIPR 384Twenty-four hours prior to the fluorescence cell-based calcium mobilization assay performed by Molecular Devices (Sunnyvale, CA, USA), human mGlu7 HEK-293 cells were plated at a density of 25,000 cells / well in a black-wall, clear-bottom, poly-L-ornithine-coated 384-well plate in glutamate / glutamine-free DMEM medium containing fetal bovine serum (10%), penicillin (100 units / mL), streptomycin (100 μg / mL), and doxycycline (1 μg / mL) at 37 °C and 5% CO2 in a humidified atmosphere.

[0494] On the day of the assay, the medium was aspirated and the cells were loaded with a solution of 3 μM Fluo4-AM (LuBioScience, Lucerne, Switzerland) in 0.03% pluronic acid. After 1 hour at 37 °C / 5% CO2, the unincorporated dye was removed by washing the cell plate with assay buffer. All assays were performed in a buffer solution of pH 7.4 containing 20 mM HEPES, 143 mM NaCl, 6 mM KCl, 1 mM MgSO4, 1 mM CaCl2, 0.125 mM sulfinpyrazone, and 0.1% glucose.

[0495] After a 10-second baseline fluorescence recording, different concentrations of the compounds of the present invention were added to the cells. The change in fluorescence level was monitored for 180 seconds first to detect any agonist activity of the compounds. Then the cells were stimulated with the EC 80 L-AP4 concentration for an additional 110 seconds to measure the inhibitory activity of the compounds of the present invention. The EC 80 L-AP4 concentration is the concentration that produces 80% of the maximal glutamate response.

[0496] The concentration-response curves for L-AP4 or a representative compound of the present invention were generated using Prism GraphPad software (Graph Pad Inc, San Diego, USA). The curve was fitted to a four-parameter logistic equation:

[0497] (Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC 50 -X)*Hill slope)

[0498] which allowed determination of the IC 50 value.

[0499] The IC 50 value of the compounds of the present application is less than 10 μM.

[0500] Table 3 below shows the average IC obtained from at least three independent experiments on the selected molecules performed in duplicate 50 .

[0501] Table 3 : Activity data of the selected compounds

[0502]

[0503]

[0504]

[0505] * Table text description:

[0506] (+) : 1 μM < IC 50 < 10 μM

[0507] (++) : 100 nM < IC 50 < 1 μM

[0508] (+++) : IC 50 < 100 nM

[0509] The results shown in Table 3 indicate that the compounds described in the present invention are negative allosteric modulators of the human mGlu7 receptor.

[0510] Example B

[0511] Water associated zero maze:

[0512] This operation can be performed as previously described by Ritov and Richter-Levin (2014), with slight modifications. The apparatus consists of an annular platform with two opposing enclosed quadrants (wall height 35 cm) and two open quadrants (border height 5 mm). The plastic tank that holds the platform is filled with water (22 ± 2 °C, 50 cm deep), rising 10 cm below the platform level. Thus, the annular platform and the plastic tank constitute a unified arena. For this test, rats are first acclimated to the room for 4 minutes and then placed into one of the open quadrants, facing the enclosed part of the apparatus. The rats are allowed to explore the arena for a 5-minute period. During this time, rat behavior is tracked, recorded, and analyzed by the Etho-Vision system (Noldus Information Technology, Wageningen, Netherlands). The behavioral measurements analyzed include the time spent in the open quadrants, the distance traveled in the open quadrants, the distance traveled in the enclosed quadrants, and total freezing behavior. These parameters are used to evaluate the effects of exposure to various stressors and / or compounds. The pretreatment time and administration route of different test compounds are defined based on their pharmacokinetic properties.

[0513] Example C

[0514] Elevated plus maze:

[0515] The elevated plus-maze (EPM) test can be performed using Sprague-Dawley male rats. The EPM is made of plastic and consists of two open arms (50 cm × 10 cm) and two enclosed arms of the same dimensions (wall height 40 cm), elevated 86 cm above the floor. Both types of arms are made of black Plexiglas. The average illumination level on the open arms is 187 LUX and 100 LUX on the enclosed arms. At the start of the experiment, rats are brought into a holding room adjacent to the testing room and allowed to acclimatize to the environment for 30 minutes. At the start of the test, rats are placed in the center of the maze, facing an open arm and observed for 5 minutes. During this time, rat behavior is tracked, recorded, and analyzed by the Etho-Vision system (Noldus Information Technology, Wageningen, Netherlands). The behavioral measurements analyzed include the time spent in the open arms, the number of entries into the open arms, and the distance traveled. The pretreatment time and route of administration of different test compounds are defined based on their pharmacokinetic properties.

[0516] Example D

[0517] Fear conditioning model of post-traumatic stress disorder in rats:

[0518] The fear conditioning arena (30 cm × 20 cm × 25 cm, Med Associates) was made of Plexiglas in different environments. The system was placed in a soundproof and ventilated chamber. The arena floor consisted of a grid floor (19 parallel stainless steel rods with a diameter of 0.48 cm, spaced 1.6 cm apart) above a stainless steel waste pan. All the rods were connected to an electric shock generator and a scrambler. Speakers were mounted on the chamber walls to provide an auditory stimulus source. Fear conditioning was performed over two days. On the first day (training), the rats were placed in the training environment (environment A) and after a 120-second acclimation period, they were subjected to five pairings of CS and US. The CS tone (78 dB, 2 kHz, 5-ms rise / fall time) lasted for 30 seconds and co-terminated with a brief US foot shock (0.5 second, 0.66 mA). The inter-tone interval (start of tone to start of next tone) ranged from 60 seconds. The conditioning chamber was cleaned with 70% ethanol between subjects. The time elapsed during freezing during CS tone delivery was scored (CS freezing). On the second day (test day), the animals were placed in a new environment (environment B) and exposed to CS (120 seconds) after a 60-second acclimation to the environment. The time elapsed during freezing was measured during both the acclimation to the environment and during CS. The test compound was administered before and / or after the training period and the test period. The pretreatment time and route of administration of different test compounds were adjusted according to their pharmacokinetic properties.

[0519] Example E

[0520] Noise-induced hearing loss (NIHL) model in mice:

[0521] Young adult male CBA / CaJ mice can be used to evaluate the effect of the test compound on NIHL. The animals are exposed to octave band noise (8 to 16 Khz) at a sound pressure level of 110 dB for 2 hours. The test compound is administered before and / or after noise exposure. Hearing function is measured using distortion product of autoacoustic emission (DPOAE) or auditory brainstem response (ABR) audiograms at different time points 24 hours, 2, and 4 weeks after acoustic trauma. The pretreatment time and administration route of different test compounds are adjusted according to their pharmacokinetic properties. The experimental group is compared with the vehicle-treated group by measuring, for example, ABR threshold or ABR threshold shift.

[0522] Example F

[0523] Colorectal distension test for visceral pain in rats.

[0524] Male stress-sensitive Wistar Kyoto rats (250 to 300 g) were used in this study. The animals were fasted overnight (16 hours) and anesthetized with isoflurane on the day of the test. A 6-cm latex balloon was inserted into the colorectal lumen 1 cm from the anus. The animals were allowed to recover for 20 minutes and then colorectal distension was initiated. The paradigm used was ascending phasic distension from 0 mmHg to 80 mmHg over 8 minutes using a computer-driven electronic manostat. The parameters measured were the threshold pressure (mmHg) that elicited visually identifiable visceral pain behavior, and the total number of pain behaviors. The postures defined as visceral pain behaviors were abdominal contractions and / or abdominal withdrawal reflexes.

[0525] The test compound is administered before colorectal distension. The pretreatment time and administration route of different test compounds are adjusted according to their pharmacokinetic properties.

[0526] Formulation Examples

[0527] I. Typical examples of the formulation of the preparation of the present invention are as follows:

[0528] 1. Tablet

[0529]

[0530]

[0531] In this example, the active ingredient can be replaced by the same amount of any compound according to the invention, in particular by the same amount of any of the exemplified compounds.

[0532] 2. Suspension

[0533] Prepare an aqueous suspension for oral administration such that each 1 mL contains 1 to 5 mg of one of the active compounds, 50 mg of sodium carboxymethyl cellulose, 1 mg of sodium benzoate, 500 mg of sorbitol and water ad 1 mL.

[0534] 3. Injectable

[0535] Prepare a parenteral composition by stirring 1.5% by weight of the active ingredient of the invention in 10% by volume of propylene glycol and water.

[0536] 4. Ointment

[0537]

[0538] In this example, the active ingredient can be replaced by the same amount of any compound according to the invention, in particular by the same amount of any of the exemplified compounds.

[0539] Reasonable variations should not be regarded as a departure from the scope of the invention. Obviously, those skilled in the art can vary the described invention in many ways.

Claims

1. A compound of formula (I): Its pharmaceutically acceptable acid addition salts or base addition salts, its stereochemical isomeric forms, or its N-oxide forms, wherein: R 1 selected from the group consisting of hydrogen, -CH3 and -CF3; R 2 and R 3 each independently selected from the group consisting of hydrogen, halogen, -(C1-C6)alkyl, -(C1-C6)haloalkyl, and -CF3; P represents -(C1-C6)alkyl, or a cycloalkyl, aryl, heteroaryl, -(C1-C6)alkylene-heteroaryl or heterocycle of the following formula: Wherein each cycloalkyl, aryl, heteroaryl, -(C1-C6)alkylene-heteroaryl or heterocyclic ring is optionally substituted with m groups A, where m is an integer equal to 0, 1, 2, 3 or 4; Wherein 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; provided that at least one of Z 1 、Z 2 、Z 3 、Z 4 、Z 5 、Z 6 and Z 7 is N; (A) m or (A) m each independently selected from the following groups: hydrogen, halogen, -CN, -OH, -NO2, -CF3, -SH, -NH2 and optionally substituted groups selected from the following groups: -(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-S-R 4 , -O-(C2-C6)alkylene-S-R 4 , -NR 4 -(C2-C6)alkylene-S-R 5 , -(C0-C6)alkylene-S(=O)-R 4 , -O-(C1-C6)alkylene-S(=O)-R 4 , -NR 4 -(C1-C6)alkylene-S(=O)-R 5 , -(C0-C6)alkylene-S(=O)2-R 4 , -O-(C1-C6)alkylene-S(=O)2-R 4 , -NR 4 -(C1-C6)alkylene-S(=O)2-R 5 , -(C0-C6)alkylene-NR 4 R 5 , -O-(C2-C6)alkylene-NR 4 R 5 , -NR 4 -(C2-C6)alkylene-NR 5 R 6 , -(C0-C6) alkylene - S(=O)2NR 4 R 5 , -O-(C1-C6) alkylene - S(=O)2NR 4 R 5 , -NR 4 -(C1-C6) alkylene - S(=O)2NR 5 R 6 , -(C0-C6) alkylene - NR 4 -S(=O)2R 5 , -O-(C2-C6) alkylene - NR 4 -S(=O)2R 5 , -NR 4 -(C2-C6) alkylene - NR 5 -S(=O)2R 6 , -(C0-C6) alkylene - C(=O)-NR 4 R 5 , -O-(C1-C6) alkylene - C(=O)-NR 4 R 5 , -NR 4 -(C1-C6) alkylene - C(=O)-NR 5 R 6 , -(C0-C6) alkylene - NR 4 C(=O)-R 5 , -O-(C2-C6) alkylene - NR 4 C(=O)-R 5 , -NR 4 -(C2-C6) alkylene - NR 5 C(=O)-R 6 , -(C0-C6) alkylene - OC(=O)-R 4 , -O-(C2-C6) alkylene - OC(=O)-R 4 , -NR 4 -(C2-C6) alkylene - OC(=O)-R 5 , -(C0-C6) alkylene - C(=O)-OR 4 , -O-(C1-C6) alkylene - C(=O)-OR 4 , -NR 4 -(C0-C6) alkylene - C(=O)-OR 5 , -(C0-C6) alkylene - C(=O)-R 4 , -O-(C1-C6) alkylene - C(=O)-R 4 , -NR 4 -(C1-C6) alkylene - C(=O)-R 5 ,-(C0-C6)alkylene-NR 4 -C(=O)-OR 5 ,-C(=O)-(C1-C6)alkylene-NR 4 -C(=O)-OR 5 ,-(C0-C6)alkylene-O-C(=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 ; R 4 、R 5 、R 6 and R 7 each independently is hydrogen or an optionally substituted group selected from the group consisting of: -(C1-C6) haloalkyl, -(C1-C6) alkyl, -(C1-C6) cyanoalkyl, -(C3-C7) cycloalkyl, -(C1-C6) alkylene-(C3-C7) cycloalkyl, heteroaryl, -(C1-C6) alkylene-heteroaryl, aryl, -(C1-C6) alkylene-heterocycle, heterocycle, -(C1-C6) alkylene-aryl, -(C0-C6) alkylene-O-(C0-C6) alkyl, -(C0-C6) alkylene-N-((C0-C6) alkyl)2, and -C(=O)-O-(C1-C6) alkyl; Q represents an aryl, heteroaryl or -(C5-C7)cycloalkenyl of the following formula: each aryl, heteroaryl or -(C5-C7) cycloalkenyl ring is optionally substituted with n groups B, where n is an integer equal to 0, 1, 2, 3, 4 or 5; where B 1 is a group B (B) n or (B) n each independently selected from the following groups: hydrogen, halogen, -CN, -OH, -NO2, -CF3, -SH, -NH2 and optionally substituted groups selected from the following groups: -(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-S-R 8 , -O-(C2-C6)alkylene-S-R 8 , -NR 8 -(C2-C6)alkylene-S-R 9 , -(C0-C6)alkylene-S(=O)-R 8 , -O-(C1-C6)alkylene-S(=O)-R 8 , -NR 8 -(C1-C6)alkylene-S(=O)-R 9 , -(C0-C6)alkylene-S(=O)2-R 8 , -O-(C1-C6)alkylene-S(=O)2-R 8 , -NR 8 -(C1-C6)alkylene-S(=O)2-R 9 , -(C0-C6)alkylene-NR 8 R 9 , -O-(C2-C6)alkylene-NR 8 R 9 , -NR 8 -(C2-C6)alkylene-NR 9 R 10 , -(C0-C6) alkylene - S(=O)2NR 8 R 9 , -O-(C1-C6) alkylene - S(=O)2NR 8 R 9 , -NR 8 -(C1-C6) alkylene - S(=O)2NR 9 R 10 , -(C0-C6) alkylene - NR 8 -S(=O)2R 9 , -O-(C2-C6) alkylene - NR 8 -S(=O)2R 9 , -NR 8 -(C2-C6) alkylene - NR 9 -S(=O)2R 10 , -(C0-C6) alkylene - C(=O)-NR 8 R 9 , -O-(C1-C6) alkylene - C(=O)-NR 8 R 9 , -NR 8 -(C1-C6) alkylene - C(=O)-NR 9 R 10 , -(C0-C6) alkylene - NR 8 C(=O)-R 9 , -O-(C2-C6) alkylene - NR 8 C(=O)-R 9 , -NR 8 -(C2-C6) alkylene - NR 9 C(=O)-R 10 , -(C0-C6) alkylene - OC(=O)-R 8 , -O-(C2-C6) alkylene - OC(=O)-R 8 , -NR 8 -(C2-C6) alkylene - OC(=O)-R 9 , -(C0-C6) alkylene - C(=O)-OR 8 , -O-(C1-C6) alkylene - C(=O)-OR 8 , -NR 8 -(C1-C6) alkylene - C(=O)-OR 9 , -(C0-C6) alkylene - C(=O)-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-O-C(=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 ; R 8 、R 9 、R 10 and R 11 are each independently hydrogen or an optionally substituted group selected from the group consisting of: -(C1-C6) haloalkyl, -(C1-C6) alkyl, -(C1-C6) cyanoalkyl, -(C3-C7) cycloalkyl, -(C1-C6) alkylene-(C3-C7) cycloalkyl, heteroaryl, -(C1-C6) alkylene-heteroaryl, aryl, -(C1-C6) alkylene-heterocycle, heterocycle, -(C1-C6) alkylene-aryl--(C0-C6) alkylene-O-(C0-C6) alkyl and -(C0-C6) alkylene-N-((C0-C6) alkyl)2; Wherein optionally, any two groups A combine with an intervening atom to form a 3- to 10-membered bicyclic heterocyclic, aryl or heteroaryl ring, and each ring is optionally further substituted with 1 to 5 groups independently selected from the group consisting of: halogen, -CN, nitro, -(C1-C6)alkyl, -(C3-C7)alkyl, -(C0-C6)alkylene-O-(C0-C6)alkyl and -(C0-C6)alkylene-N-((C0-C6)alkyl)2; Optionally, two of the substituents R 4 , R 5 , R 6 or R 7 combine with an intervening atom to form a 3- to 10-membered heterocyclic, aryl or heteroaryl ring, where each ring is optionally further substituted with 1 to 5 groups independently selected from the group consisting of: halogen, cyano, nitro, -(C1-C6)alkyl, -(C3-C7)cycloalkyl, -(C0-C6)alkylene-O-(C0-C6)alkyl, and -(C0-C6)alkylene-N-((C0-C6)alkyl)2; Optionally, two substituents from R 8 , R 9 , R 10 or R 11 combine with an intervening atom to form a 3- to 10-membered heterocyclic, aryl or heteroaryl ring, where each ring is optionally further substituted with 1 to 5 groups independently selected from the group consisting of: halogen, cyano, nitro, -(C1-C6)alkyl, -(C3-C7)cycloalkyl, -(C0-C6)alkylene-O-(C0-C6)alkyl, and -(C0-C6)alkylene-N-((C0-C6)alkyl)2; and Wherein optionally, any two groups B combine with an intervening atom to form a 3- to 10-membered bicyclic heterocyclic, aryl or heteroaryl ring, and each ring is optionally further substituted with 1 to 5 groups independently selected from the group consisting of: halogen, -CN, nitro, -(C1-C6)alkyl, -(C3-C7)alkyl, -(C0-C6)alkylene-O-(C0-C6)alkyl and -(C0-C6)alkylene-N-((C0-C6)alkyl)2.

2. The compound according to claim 1 of formula (I), wherein P represents -(C1-C6)alkyl, or a cycloalkyl, heteroaryl, -(C1-C6)alkylene-heteroaryl or heterocycle of the following formula:

3. The compound according to claim 1 or 2 of formula (I), wherein Q represents an aryl, heteroaryl or -(C5-C7)cycloalkenyl of the following formula:

4. The compound according to any one of the preceding claims of formula (I), wherein P represents a heteroaryl of the following formula: Wherein each group is optionally substituted with m groups A, where m is an integer equal to 0, 1, 2, 3 or 4.

5. The compound according to any one of the preceding claims of formula (I), wherein Q represents an aryl or heteroaryl of the following formula: Wherein each group is optionally substituted with n groups B, where n is an integer equal to 0, 1, 2, 3, 4 or 5.

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

7. The compound according to any one of the preceding claims of formula (I), wherein: (B) n The cycloalkyl, heterocyclic, aryl, and heteroaryl ring systems of n are selected from the group consisting of: azetidinyl, benzimidazolyl, benzisothiazolyl, benzisoxazolyl, benzofuranyl, benzpyrazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, dihydrofuranyl, dihydrothienyl, dioxolanyl, 1,1-dioxo-thiomorpholinyl, furazanyl, furanyl, imidazolidinyl, imidazolinyl, imidazolinone, imidazolyl, imidazopyridazinyl, imidazopyridyl, indolyl, isoindolyl, isoquinolinyl, isothiazolinyl, isothiazolyl, isoxazolidinyl, isoxazolinyl, isoxazolyl, morpholinyl, naphthyl, naphthyridinyl, oxadiazolyl, oxazolidinyl, oxazolinyl, oxazolidinone, oxazolopyridazinyl, oxazolopyridyl, oxazolyl, oxetanyl, phenyl, piperazinone, piperazinyl, piperidinone, piperidinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolopyridyl, pyrazolyl, pyridazinyl, pyridone, pyridyl, pyrimidinyl, pyrrolidinone, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrotriazolopyridyl, tetrahydrotriazolopyrimidinyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolinyl, thiazolidinone, thiazolopyridazinyl, thiazolopyridyl, thiazolyl, thienyl, thiomorpholinyl, thionaphthyl, thiopyranyl, triazolinyl, triazinyl, triazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, and cyclooctenyl, and each ring of the ring system is optionally independently substituted with 1 to 4 substituents R isoxazolyl, benzofuranyl, benzpyrazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benz oxazolyl, dihydrofuranyl, dihydrothienyl, dioxolanyl, 1,1-dioxo-thiomorpholinyl, furazanyl, furanyl, imidazolidinyl, imidazolinyl, imidazolinone, imidazolyl, imidazopyridazinyl, imidazopyridyl, indolyl, isoindolyl, isoquinolinyl, isothiazolinyl, isothiazolyl, iso oxazolidinyl, iso oxazolinyl, iso oxazolyl, morpholinyl, naphthyl, naphthyridinyl, oxadiazolyl, oxazolidinyl, oxazolinyl, oxazolidinone, oxazolopyridazinyl, oxazolopyridyl, oxazolyl, oxetanyl, phenyl, piperazinone, piperazinyl, piperidinone, piperidinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolopyridyl, pyrazolyl, pyridazinyl, pyridone, pyridyl, pyrimidinyl, pyrrolidinone, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrotriazolopyridyl, tetrahydrotriazolopyrimidinyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolinyl, thiazolidinone, thiazolopyridazinyl, thiazolopyridyl, thiazolyl, thienyl, thiomorpholinyl, thionaphthyl, thiopyranyl, triazolinyl, triazinyl, triazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, and cyclooctenyl, and each ring of the ring system is optionally independently substituted with 1 to 4 substituents R 8 , R 9 , R 10 or R 11 .

8. The compound according to any one of the preceding claims of formula (I), wherein: R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 or R 11 The cycloalkyl, heterocyclic, aryl and heteroaryl ring systems of include those selected from the group consisting of azetidinyl, benzimidazolyl, benzisothiazolyl, benz oxazolyl, benzofuranyl, benzpyrazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benz oxazolidinyl, iso oxazolinyl, iso oxazolyl, morpholinyl, naphthyl, naphthyridinyl, diazolyl, oxazolidinyl, oxazolinyl, oxazolidinone, oxazopyridazinyl, oxazopyridyl, oxazolyl, oxetanyl, phenyl, piperazinone, piperazinyl, piperidinone, piperidinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolopyridyl, pyrazolyl, pyridazinyl, pyridone, pyridyl, pyrimidinyl, pyrrolidinone, pyrrolidinyl, pyrroline, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrotriazolopyridyl, tetrahydrotriazolopyrimidinyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolinyl, thiazolidinone, thiazopyridazinyl, thiazopyridyl, thiazolyl, thienyl, thiomorpholinyl, thionaphthyl, thiopyranyl, triazolinyl, triazinyl, triazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl and cyclooctenyl, and each ring of the ring system is optionally substituted with 1 to 5 groups independently selected from hydrogen, halogen, -CN, nitro, -(C1-C6)alkyl, -(C0-C6)alkylene-O-(C0-C6)alkyl and -(C0-C6)alkylene-N-((C0-C6)alkyl)2.

9. A compound according to any one of the preceding claims having the formula (I), wherein R 1 is hydrogen.

10. A compound according to any one of the preceding claims having the formula (I), wherein R 2 and R 3 are each independently selected from the group consisting of hydrogen and methyl.

11. A compound according to any one of the preceding claims having formula (I), wherein (A) m or (A) m each independently selected from the group consisting of: hydrogen, halogen, -CN, -OH, -CF3 and optionally substituted groups selected from the group consisting of: -(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 , -NR 4 (C2-C6)alkylene-OR 5 , -(C0-C6)alkylene-S(=O)2-R 4 , -(C0-C6)alkylene-NR 4 R 5 , -O-(C2-C6)alkylene-NR 4 R 5 , -NR 4 -(C2-C6)alkylene-NR 5 R 6 , -(C0-C6)alkylene-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 , -C(=O)-(C1-C6)alkylene-NR 4 -C(=O)-OR 5 and -NR 4 -(C0-C6)alkylene-C(=O)-OR 5 .

12. A compound according to any one of the preceding claims having the formula (I), wherein R 4 , R 5 and R 6 are each independently hydrogen, -(C1-C6)alkyl, -(C1-C6)haloalkyl or -C(=O)-O-(C1-C6)alkyl.

13. A compound according to any one of the preceding claims having formula (I), wherein (B) n or (B) n each independently selected from the group consisting of: hydrogen, halogen, -CN, -CF3 and optionally substituted groups selected from the group consisting of: -(C1-C6)alkyl, -(C3-C7)cycloalkyl, aryl, heteroaryl, heterocycle, -(C0-C6)alkylene-OR 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 .

14. A compound according to any one of the preceding claims having the formula (I), wherein R 8 and R 9 are each independently selected from the group consisting of: hydrogen, -(C1-C6) haloalkyl, -(C1-C6) alkyl, -(C3-C7) cycloalkyl, and aryl.

15. The compound according to any one of the preceding claims of formula (II): Its pharmaceutically acceptable acid addition salts or base addition salts, its stereochemical isomeric forms or its N-oxide forms, wherein Z 1 is selected from C or N.

16. The compound according to any one of claims 1 to 14 of formula (III): Its pharmaceutically acceptable acid addition salts or base addition salts, its stereochemical isomeric forms, or its N-oxide forms, wherein X is C or N.

17. The compound according to any one of the preceding claims of formula (IV): Its pharmaceutically acceptable acid addition salts or base addition salts, its stereochemical isomeric forms or its N-oxide forms, wherein Z 1 is selected from C or N, and X is selected from C or N.

18. A compound according to claim 17 having formula (V): Its pharmaceutically acceptable acid addition salts or base addition salts, its stereochemical isomeric forms or its N-oxide forms.

19. A compound according to claim 17 having formula (VI): Its pharmaceutically acceptable acid addition salts or base addition salts, its stereochemical isomeric forms or its N-oxide forms.

20. A compound according to any of the preceding claims, wherein: R 2 is hydrogen or methyl; R 3 is methyl or hydrogen; (A) m or (A) m each independently selected from the following groups: hydrogen, halogen, -CF3 and optionally substituted groups selected from the following groups: -(C1-C6)alkyl, -(C1-C6)haloalkyl, -(C3-C7)cycloalkyl, heterocycle, -(C0-C6)alkylene-OR 4 , -O-(C2-C6)alkylene-OR 4 , -NR 4 (C2-C6)alkylene-OR 5 , -(C0-C6)alkylene-NR 4 R 5 , -O-(C2-C6)alkylene-NR 4 R 5 , -NR 4 -(C2-C6)alkylene-NR 5 R 6 , -(C0-C6)alkylene-C(=O)-NR 4 R 5 , -(C0-C6)alkylene-NR 4 C(=O)-R 5 , -(C0-C6)alkylene-C(=O)-OR 4 , -(C0-C6)alkylene-C(=O)-R 4 , -C(=O)-(C1-C6)alkylene-NR 4 -C(=O)-OR 5 and -NR 4 -(C0-C6)alkylene-C(=O)-OR 5 ; R 4 , R 5 and R 6 are each independently hydrogen, -(C1-C6)alkyl, -(C1-C6)haloalkyl or -C(=O)-O-(C1-C6)alkyl; (B) n or (B) n each independently selected from the group consisting of: hydrogen, halogen, and optionally substituted groups selected from the group consisting of: -(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-(C1-C6)alkyl, -(C3-C7)cycloalkyl or -(C1-C6)haloalkyl.

21. A compound according to any of the preceding claims having formula (VII): Its pharmaceutically acceptable acid addition salts or base addition salts, its stereochemical isomeric forms or its N-oxide forms, wherein: Z 1 selected from C or N; R 2 is hydrogen or methyl; R 3 is methyl or hydrogen; (A) m or (A) m each independently selected from the group consisting of: hydrogen, halogen, and optionally substituted groups selected from the group consisting of: -(C1-C6)alkyl, heterocycle, -(C0-C6)alkylene-OR 4 , -NR 4 (C2-C6)alkylene-OR 5 , -(C0-C6)alkylene-NR 4 R 5 , -O-(C2-C6)alkylene-NR 4 R 5 , -NR 4 -(C2-C6)alkylene-NR 5 R 6 , -(C0-C6)alkylene-C(=O)-OR 4 and -NR 4 -(C0-C6)alkylene-C(=O)-OR 5 ; R 4 , R 5 and R 6 are each independently hydrogen, -(C1-C6)alkyl, -(C1-C6)haloalkyl or -C(=O)-O-(C1-C6)alkyl; (B) n or (B) n each independently selected from the group consisting of: hydrogen, halogen, and optionally substituted groups selected from the group consisting of: -(C1-C6)alkyl, heterocycle, and -(C0-C6)alkylene-OR 8 ; and R 8 is hydrogen-(C1-C6)alkyl, -(C3-C7)cycloalkyl or -(C1-C6)haloalkyl.

22. A compound according to any one of claims 1 to 20 having formula (VIII): Its pharmaceutically acceptable acid addition salts or base addition salts, its stereochemical isomeric forms or its N-oxide forms, wherein: Z 1 selected from C or N; R 2 is hydrogen or methyl; R 3 is methyl or hydrogen; (A) m or (A) m each independently selected from the following groups: hydrogen, halogen, and optionally substituted groups selected from the following groups: -(C1-C6)alkyl, heterocycle, -(C0-C6)alkylene-OR 4 , -NR 4 (C2-C6)alkylene-OR 5 , -(C0-C6)alkylene-NR 4 R 5 , -O-(C2-C6)alkylene-NR 4 R 5 , -NR 4 -(C2-C6)alkylene-NR 5 R 6 , -(C0-C6)alkylene-C(=O)-OR 4 and -NR 4 -(C0-C6)alkylene-C(=O)-OR 5 ; R 4 、R 5 and R 6 each independently is hydrogen, -(C1-C6)alkyl, -(C1-C6)haloalkyl or -C(=O)-O-(C1-C6)alkyl; (B) n or (B) n each independently selected from the group consisting of: hydrogen, halogen, and optionally substituted groups selected from the group consisting of: -(C1-C6)alkyl, heterocycle, and -(C0-C6)alkylene-OR 8 ; and R 8 is hydrogen, -(C1-C6)alkyl, -(C3-C7)cycloalkyl or -(C1-C6)haloalkyl.

23. The compound according to any one of the preceding claims, wherein (A) m or (A) m each independently is selected from the group consisting of: hydrogen, halogen, and an optionally substituted group selected from the group consisting of: heterocycle, -(C0-C6)alkylene-OR 4 , -(C0-C6)alkylene-C(=O)-OR 4 , -NR 4 -(C0-C6)alkylene-C(=O)-OR 5 , -NR 4 (C2-C6)alkylene-OR 5 , -O-(C2-C6)alkylene-NR 4 R 5 , -NR 4 -(C2-C6)alkylene-NR 5 R 6 and -(C0-C6)alkylene-NR 4 R 5 ; and R 4 , R 5 and R 6 are each independently hydrogen, -(C1-C6)alkyl, -(C1-C6)haloalkyl, or -C(=O)-O-(C1-C6)alkyl.

24. A compound according to any one of the preceding claims, wherein (B) n or (B) n each independently is selected from the group consisting of: hydrogen, halogen, and an optionally substituted group selected from the group consisting of: -(C1-C6)alkyl, heterocycle, and -(C0-C6)alkylene-OR 8 ; and R 8 is hydrogen, -(C1-C6)alkyl, -(C3-C7)cycloalkyl, or -(C1-C6)haloalkyl.

25. A compound according to any one of the preceding claims, wherein (A) m or (A) m each independently is selected from the group consisting of: hydrogen, halogen, -CH2CH2OH, -COOCH2CH3, -COH(CH3)2, -O-methyl, -N(COOBu t )2, NHCOOBu t , morpholinyl, -NH2, -NHCH2CH2OCH3, -NHCH2CH2N(CH3)2, -OCHF2, -OCH2CH2N(CH3)2, CHOH(CH3)2, methyl and hydroxy-substituted pyrrolidinyl; and / or (B) n or (B) n each independently is selected from the group consisting of: hydrogen, halogen, azetidinyl, -OCHF2, -OCF3, cyclopropyl, -O-cyclopropyl, -O-methyl, methyl, propyl, -O-cyclobutyl and azabicyclo[2.2.1]hept-7-yl.

26. A compound according to claims 1 to 25, wherein the compound can exist as optical isomers, and wherein the compound is a racemic mixture or one or both of the individual optical isomers.

27. A compound according to claims 1 to 26, wherein the compound is one or more selected from the following: And its pharmaceutically acceptable acid addition salts or base addition salts, its stereochemical isomeric forms or its N-oxide forms.

28. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any of claims 1 to 27 and a pharmaceutically acceptable carrier and / or excipient.

29. A method of treating or preventing a disorder in a mammal, the method comprising administering to a mammal in need of such treatment or prevention an effective amount of a compound / composition according to any of claims 1 to 28.

30. The method according to claim 29, wherein the treatment or prevention is affected or promoted by the modulating action of an allosteric modulator of mGlu7, such as a negative allosteric modulator of mGlu7.

31. A method of treating, preventing, ameliorating, controlling or reducing the risk of various neurological and psychiatric disorders associated with glutamate dysfunction in a mammal, the method comprising administering to a mammal in need of such treatment or prevention an effective amount of a compound / composition according to any of claims 1 to 28.

32. The method according to claim 31, wherein the treatment or prevention is affected or promoted by the modulating action of a negative allosteric modulator of mGlu7.

33. The method according to any one of claims 29 or 30, wherein the disorder is one or more of a central nervous system disorder, an ear disease or disorder or a pain disorder.

34. The method according to claim 33, wherein 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).

35. The method according to claim 33, wherein the central nervous system disorder is a psychotic disorder selected from the group consisting of schizophrenia, delusional disorder, schizoaffective disorder, schizophreniform disorder, and substance-induced psychotic disorder.

36. The method according to claim 33, wherein the ear disease and disorder is one or more of the following: inner ear injury, age-related hearing impairment (presbycusis), Meniere's disease, sudden sensorineural hearing loss, noise-induced hearing loss, otitis media, autoimmune inner ear disease, acute tinnitus, chronic tinnitus, drug-induced hearing loss, hidden hearing loss, cisplatin-induced hearing loss, aminoglycoside-induced hearing loss, ototoxicity, central auditory processing disorder, or vestibular disorder.

37. The method according to claim 33, wherein the pain disorder is one or more of the following: neuropathic pain, inflammatory pain, visceral pain, acute pain, chronic pain, severe pain, intractable pain, post-traumatic pain, postoperative pain, headache, or cancer pain.

38. The compound or composition according to any one of claims 1 to 28 for use as a medicament.

39. The compound or composition according to any one of claims 1 to 28 for use in a method of treatment or prophylaxis as defined in any one of claims 29, 30, 33, 34, 35, 36, or 37.

40. The compound or composition according to any one of claims 1 to 28 for use in a method as defined in claim 31 or 32.

41. Use of a compound according to any one of claims 1 to 28 in the manufacture of a medicament for treatment or prophylaxis as defined in any one of claims 29, 30, 33, 34, 35, 36, or 37.

42. Use of a compound according to any one of claims 1 to 28 in the manufacture of a medicament for treatment or prophylaxis as defined in claim 31 or 32.

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