Novel 6-membered ring heterocyclic compounds as gabab positive allosteric modulators

Abstract

The present invention relates to novel compounds of Formula (I), wherein P, Q, A, B, m, n, R1, Z, J and L are defined as in Formula (I); which are gamma-(y)-aminobutyric acid type B receptor ("GABAB-R") positive allosteric modulators which are useful for the treatment or prevention of neurological and psychiatric disorders associated with GABA dysfunction and diseases in which the GABAB receptor is involved. The invention is also directed to pharmaceutical compositions comprising such compounds, to processes of preparing such compounds and such compositions, and to the use of such compounds for the prevention or treatment of neurological and psychiatric disorders and diseases in which GABAB-R is involved.

Description

[0001] NOVEL 6-MEMBERED RING HETEROCYCLIC COMPOUNDS AS GABAB POSITIVE ALLOSTERIC MODULATORS

[0002] SUMMARY OF THE INVENTION

[0003] The present invention relates to novel compounds of Formula (I), wherein P, Q, A, B, m, n, R1, Z, J and L are defined as in Formula (I); which are gamma-(y)-aminobutyric acid type B receptor (“GABAB-R”) positive allosteric modulators which are useful for the treatment or prevention of neurological and psychiatric disorders associated with GABA dysfunction and diseases in which the GABAB receptor is involved. The invention is also directed to pharmaceutical compositions comprising such compounds, to processes of preparing such compounds and such compositions, and to the use of such compounds for the prevention or treatment of neurological and psychiatric disorders and diseases in which GABAB-R is involved.

[0004] BACKGROUND OF THE INVENTION

[0005] The amino acid GABA (y-aminobutyric acid) is the main inhibitory neurotransmitter in the adult mammalian brain and regulates many physiological and psychological processes. GABA acts through two major classes of receptors: ionotropic GABAA (including GABAc) receptors and metabotropic GABAB receptors (Hill and Bowery, Nature 1981, 290:149-152; Bormann, Trends Pharmacol. Set. 2000, 21 : 16-19). GABAB receptors are present in most regions of the mammalian brain on presynaptic terminals and postsynaptic neurons and are involved in the fine-tuning of inhibitory synaptic transmission. Due to their strategic position in neuronal networks to modulate the activity of the various neurotransmitter systems, GABAB receptors are a target of choice for pharmacological agents intended to treat central and peripheral nervous system disorders (Bettier et al., Physiol Rev. 2004, 84:835-867; Cryan and Kaupmann, Trends Pharmacol. Sci. 2005, 26:36-43).

[0006] The GABAB receptor belongs to the Class-Ill family of G protein-coupled receptors (GPCRs), which are the receptors for glutamate, Ca2+, pheromones and putative taste compounds (Pin et al., Pharmaco. Ther. 2003, 98:325-354). All members of this family share the characteristic of a large extracellular amino-terminal domain that contains a so-called “Venus Flytrap” orthosteric ligand binding site and seven transmembrane (7TM) helical segments plus an intracellular carboxyl-terminal domain that are involved in receptor activation and G-protein coupling (Bockaert and Pin, EMBO J. 1999, 18: 1723; Galvez et al., J. Biol. Chem. 1999, 274: 13362-13369). A distinct feature, however, of the GABAB receptor is that it operates as a heterodimer of at least two homologous subunits termed GABABI and GABAB2 (Kaupman et al, Nature 1997, 386:239-246; Gordon et al., J. Biol. Chem. 1999, 12:7607-7610; Margeta-Mitrovic et al., PNAS 2001, 98:14649-14654; Bettier et al., Physiol. Rev. 2004, 84:835-867). Orthosteric GABAB receptor ligands bind only at the TV-terminal Venus flytrap region of the GABABI subunit, which in turn activates the associated GABAB2 subunit of the heterodimer. It is this later subunit that is responsible for coupling and activation of G- protein (Galvez et al., EMBO J. 2001, 20:2152-2159; Duthey et al., J. Biol. Chem. 2002, 277:3236-3241; Pin et al., Biochem. Pharmacol. 2004, 68: 1565-1572). The resulting effect is an inhibition of the adenylyl cyclase activity and subsequent cyclic AMP formation and the modulation of activity of inwardly rectifying potassium channels and voltage- sensitive calcium channels.

[0007] Several studies using knock-out (KO) mice have demonstrated the role of the heterodimeric GABABIB2 receptor in several central nervous system disorders. Mice lacking the GABABI subunit exhibit spontaneous seizures and hyperalgesia (Schuler et al., Neuron 2001, 31, 47-58). These behavioral characteristics are paralleled by a loss of all biochemical and electrophysiological GABAB responses in these KO mice. In these studies, a clear impairment of passive avoidance performance was also observed indicating impaired memory processes. GABABI deficient mice were also found to be more anxious than their wild-type counterparts (Mombereau et al., Neuropsychopharmacology 2004, 29: 1050-1062). Analogous results were obtained with GABAB2 KO mice, which presented all the same behavioural characteristics than the one observed for the GABABI KO mice (Gassman et al., J. Neurosci. 2004, 24:6086-6097). Moreover, it has also been shown that a hypoactivity of the GABA system was linked to spasticity, epilepsy, anxiety, stress, sleep disorders, depression, addiction, and pain (Dalvi and Rodgers, Psychopharmacology 1996, 128:380-397; for a review Ong and Kerr, CNS Drug Dev. 2005, 11 :317-334); while on the contrary, a hyperactivity of the GABAergic system was associated with schizophrenia (Blum and Mann, Ini. J. Neuropsychopharmacol. 2002, 5: 159-179).

[0008] Baclofen is a potent and selective agonist at the GABAB receptor and is presently a frequently and widely used clinical drug in the treatment of spasticity and rigidity (Romito et al., SAGE Open Medicine 2021, 9: 1-13). Moreover, all effective pharmacological agents used to treat panic disorder increase GABA synaptic transmission and anxiolytics and antidepressants that lack GABA activity are not effective in panic disorders. Baclofen was shown to be significantly effective in reducing the number of panic attacks and symptoms of anxiety as assessed with the Hamilton anxiety scale, Zung Scale, and Katz-R nervousness subscale (Breslow et al., Am. J. Psychiatry 1989, 146:353-356). Drake and co-workers hypothesized that baclofen would be an effective treatment in the symptomatic management of veterans with chronic posttraumatic stress disorder (PTSD). Their results demonstrated that the therapy, well tolerated, resulted in significant improvements of the overall symptoms of PTSD and co-morbide depression and anxiety in patients with chronic PTSD due to combat (Drake et al., Ann. Pharmacother. 2003, 37: 1177-1181). Additionally, a study looking at the effect of baclofen on the prepulse inhibition (PPI) of the acoustic startle response (ASR) proposed GABAB receptors as putative new targets in the pharmacological therapy of psychotic disorders (Bortalo et al., Psychopharmacology 2004, 171, 322-330). Notably, baclofen has shown potential for efficacy in substance use disorders. For example, it attenuated the reinforcing properties of cocaine and motivation to self-administer cocaine in rats (Roberts et al., Neuropschopharmacology 1996, 15:417-423; Roberts and Andrews, Psychopharmacology 1997, 131 :271-277) and dose-dependently decreased morphine-, cocaine- and nicotine-induced dopamine release in the nucleus accumbens shell (Fadda et al., Synapse 2003, 50: 1-6). Baclofen also reduced operant alcohol self-admini strati on and motivation for alcohol in nondependent rats (Anstrom et al., Alcohol Clinical and Experimental Research 2003, 27:900-908; Janak and Michael Gill, Alcohol 2003, 30: 1-7), dependent rats (Walker and Koob, Alcohol Clinical and Experimental Research 2007, 31 : 11-18), as well as selectively bred strains of alcohol preferring rats (Liang et al., Neuropharmacology 2006, 50:632-639; Maccioni et al., Alcohol 2005, 36: 161-168). Additionally, baclofen prevented the acquisition of alcohol drinking (Colombo et al., Alcohol and Alcoholism 2002, 37:499-503) and suppressed extinction responding for alcohol in Sardinian alcohol-preferring rats (Colombo et al., Psychopharmacology 2003, 167:221-224). Baclofen was approved for the treatment of alcohol dependence in France in 2018 despite mixed evidence on clinical efficacy (Beaurepaire and Jaury, Alcohol and Alcoholism 2024, 59:1-10; Romito et al., SAGE Open Medicine 2021, 9: 1-13). Baclofen suffers from several limitations that may impact its performance in the clinic, including a poor blood-brain-barrier penetration, very short duration of action, muscle relaxing property, hypothermic and sedative side effects, as well as patients' increasing tolerance (Hefferan et al., Neuroscience Letters 2006, 403, 195-200; Romito et al., SAGE Open Medicine 2021, 9: 1-13).

[0009] An avenue for developing selective compounds acting at GPCRs is to identify molecules that act through allosteric mechanisms, modulating the receptor by binding to a site different from the highly conserved orthosteric binding site. This concept has assumed a greater importance in the pharmacology of family III receptors in general. For example, allosteric modulators have been described for Ca2+'sensing receptors (Nemeth et al., U.S. Pat. No. 6,031,003), for metabotropic glutamate receptors (reviewed in Mutel, Expert Opin. Ther. Patents 2002, 12: 1-8; Ritzen, Mathiesen and Thomsen, Basic Clin. Pharmacol. Toxicol. 2005, 97:202-13), and more precisely for GABAB receptors (Urwyler et al., Mol. Pharmacol. 2001, 60:963-971; W02005 / 094828; W02006 / 001750; W02006 / 063732; W02006 / 048146;

[0010] W02006 / 07486; WO2006 / 136442; W02007 / 014843; W02007 / 073297;

[0011] W02007 / 073298; W02007 / 073299; W02007 / 073300). These ligands do not activate the receptor by themselves, but, for example in the case of the GABAB receptor, increase the potency of GABA in the presence of this endogenous agonist (Pin et al., Mol. Pharmacol. 2001, 60, 881-884; Urwyler et al., Neuropharmacol. 2005, 48:343- 353). Mutational analyses have demonstrated unequivocally that the binding of known GABAB receptor positive allosteric modulators does not occur at the orthosteric site, but instead at an allosteric site within the seven-transmembrane region of the GABAB2 subunit at least for CGP7930 (Binet et al., J. Biol. Chem. 2004, 279:29085-29901).

[0012] As a therapeutic principle, positive allosteric modulators are expected to have several advantages over compounds acting as orthosteric agonists, because they are only effective in the presence of the endogenous ligand and therefore act in line with physiological neurotransmission in its temporal and spatial organization. Orthosteric agonists, on the other hand, activate receptors independently of synaptic activity, possibly leading to unwanted side effects.

[0013] Cryan and co-workers suggested in a study using GS39783 (A,7V'-Dicyclopentyl-2- methylsulfanyl-5-nitro-pyrimidine-4,6-diamine) that a positive modulation of GABAB receptors may serve as a novel therapeutic strategy for the development of anxiolytics with a better side effect profile as compared to baclofen (Cryan et al., J. Pharm. Exp. Therap. 2004, 310:952-963). They showed that GS39783 is active in models of anxiety such as elevated plus maze (rat), elevated zero maze (mice and rats), and the stress- induced hyperthermia (mice) tests. Moreover, as expected for a positive allosteric modulator that does not have any effect on receptor activity in absence of GABA, but does enhance allosterically the affinity of the GABAB receptor for the endogenous GABA, no side effect on locomotor activity, rotarod, body temperature and traction test was observed for doses ranging from 0.1 to 200 mg / kg, p.o. In comparison, baclofen presented those side effects even at efficacious doses in anxiety models. Similarly, acute or repeated dosing with GABAB PAMS such as BHF177, rac-BHFF, ADX71441, CMPPE, COR659, ASP8062, KK-92A, and ORM-27669 reduced excessive alcohol drinking, relapse- and binge-like drinking, operant alcohol self-administration, reinstatement of alcohol seeking, and alcohol-induced conditioned place preference in rodents (Colombo G., Alcohol and Alcoholism 2024, 59: 1-9). In conclusion, these data suggest that the positive allosteric modulators of GABAB receptors could be useful medications for the treatment of anxiety and substance use disorders without the sideeffects associated with baclofen.

[0014] 3,3'-Diarylpropyl-l-arylethylamines and 3-aryl propyl- 1 -arylethylamine have been reported as a class of GABAB receptor modulators as they potentiate baclofen-induced responses in the brain (Kerr et al., Aust. J. Chem. 2006, 59, 445-456) and they modulate both pre- and postsynaptic GABAB receptors in rat brain slices (Ong et al., Eur. J. Pharm. 2005, 507, 35-42). Chemical classes of GABAB positive allosteric modulators have been reviewed (Nieto et al., Curr. Topics Behav. Neurosci. 2022, 52, 81-118) and include 5-membered heterocycles (eg COR659), triazinediones (ADX71141), bicyclic heterocycles such as quinolines, xanthines, pteridine-2, 4(1 / 7, 3J7)-diones, thieno[2,3]pyrimidines, pyrazolo[l,5a]pyri mi dines, and tricyclic structures such as [l,2,4]triazolo[4,3a]pyrimidin-7(8 / 7)-one (eg ORM-27669).

[0015] The present invention relates to uracil derivatives which have been described previously in several publications. For example, pyrimidine nucleosides were obtained by late-stage base heterocyclization reactions in Cavalli, E. S. et al. Organic Leters 2022, 24(49), 8931-8935. Additionally, Giovannoni M. P. et al. in Drug Development Research 2011, 72(3), 274-288, synthetized pyrimidine-2, 4-dione derivatives and evaluated their activity as PDE4 inhibitors.

[0016] Patent publication W02008 / 056257 and U.S. Pat. Nos. 8,344,138 and 8, 779,129 describe triazadione derivatives having GABAB receptor modulatory activity.

[0017] It has now surprisingly been found that the compounds of general Formula (I) show potent activity and selectivity on GABAB receptor.

[0018] The present invention relates to a method of treating or preventing a condition in a mammal, including a human, the treatment or prevention of which is affected or facilitated by the neuromodulatory effect of GABAB modulators. SUMMARY OF THE INVENTION

[0019] The invention relates to compounds having GABAB modulator activity. In its most general compound aspect, the present invention provides a compound according to Formula (I), a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof or an A-oxide form thereof, wherein:

[0020] R1is selected from the group of (for example the group consisting of) -O-(Ci- Ce)alkyl, -O-(Ci-C6)deuterioalkyl, -O-(C3-C7)cycloalkyl, -(Ci-Ce)alkyl and -(C3- C7)cycloalkyl;

[0021] Z is selected from CH or N;

[0022] J is selected from the group of (for example the group consisting of) -CH2-, - CHR2- and -CR2R3-;

[0023] R2and R3are each independently a radical selected from the group of (for example the group consisting of) -(Ci-Ce)alkyl, -(Ci-Ce)haloalkyl, -(C3-C7)cycloalkyl and R2and R3together with the atom to which they are attached form a -(C3-C7)cycloalkyl;

[0024] P represents an aryl or heteroaryl of formula: wherein each aryl or heteroaryl ring is optionally substituted with m radicals A, wherein m is an integer equal to zero, 1, 2, 3, 4 or 5; the or each (A)mis independently selected from the group of (for example the group consisting of) hydrogen, halogen, -CN, -CF3 and an optionally substituted radical selected from the group of (for example the group consisting of) -(Ci-Ce)alkyl, -(Ci- Ce)haloalkyl, -(C3-C7)cycloalkyl, -(Ci-C6)alkylene-(C3-C7)cycloalkyl, aryl, -(Ci- Ce)alkylene-aryl, heteroaryl, -(Ci-C6)alkylene-heteroaryl, heterocycle, -(Ci- C6)alkylene-heterocycle, -(Co-Ce)alkylene-OR4, -O-(C2-Ce)alkylene-OR4-NR4(C2- C6)alkylene-OR5, -(Co-C6)alkylene-S-R4, -O-(C2-C6)alkylene-S-R4, -NR4-(C2- C6)alkylene-S-R5, -(C0-C6)alkylene-S(=O)-R4, -O-(Ci-C6)alkylene-S(=O)-R4, -NR4- (Ci-C6)alkylene-S(=O)-R5, -(C0-C6)alkylene-S(=O)2-R4, -O-(Ci-C6)alkylene-S(=O)2- R4, -NR4-(Ci-C6)alkylene-S(=O)2-R5, -(Co-C6)alkylene-NR4R5, -O-(C2-C6)alkylene- NR4R5, -NR4-(C2-C6)alkylene-NR5R6, -(C0-C6)alkylene-C(=O)-NR4R5, -O-(Ci- C6)alkylene-C(=O)-NR4R5, -NR4-(Ci-C6)alkylene-C(=O)-NR5R6, -(Co-C6)alkylene- NR4C(=O)-R5, -O-(C2-C6)alkylene-NR4C(=O)-R5, -NR4-(C2-C6)alkylene-NR5C(=O)- R6, -(C0-C6)alkylene-OC(=O)-R4, -O-(C2-C6)alkylene-OC(=O)-R4, -NR4-(C2- C6)alkylene-OC(=O)-R5, -(C0-C6)alkylene-C(=O)-OR4, -O-(Ci-C6)alkylene-C(=O)- OR4, -NR4-(Ci-C6)alkylene-C(=O)-OR5, -(C0-C6)alkylene-C(=O)-R4, -O-(Ci- C6)alkylene-C(=O)-R4and -NR4-(Ci-C6)alkylene-C(=O)-R5;

[0025] R4, R5and R6are each independently hydrogen or an optionally substituted radical selected from the group of (for example the group consisting of) -(Ci-Ce)alkyl, -(Ci- Ce)haloalkyl, -(Ci-Ce)cyanoalkyl, -(C3-C7)cycloalkyl, -(Ci-Ce)alkylene-(C3- C7)cycloalkyl, aryl, -(Ci-Ce)alkylene-aryl, heteroaryl, -(Ci-C6)alkylene-heteroaryl, heterocycle, -(Ci-C6)alkylene-heterocycle, -(Co-C6)alkylene-0-(Co-Ce)alkyl and -(Co- Ce)alkylene-N-((Co-C6)alkyl)2 and R4and R5or R5and R6together with the atom to which they are attached form a -(C3-C7)cycloalkyl;

[0026] L is selected from the group of (for example the group consisting of) a bond, or an optionally substituted radical -(Ci-Ce)alkyl;

[0027] Q represents a -(C3-C7)cycloalkyl, aryl, heteroaryl or heterocycle of formula:

[0028] wherein each -(C3-C7)cycloalkyl, aryl, heteroaryl or heterocycle ring is optionally substituted with n radicals B, wherein n is an integer equal to zero, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 and 13; wherein Z1, Z2, Z3, Z4, Z5and Z6are each independently selected from C or N; x is an integer equal to 1, 2, 3 and 4; the or each (B)nis independently selected from the group of (for example the group consisting of) hydrogen, halogen, -CN, -CF3, -OH, -SH, -NH2 and an optionally substituted radical selected from the group of (for example the group consisting of) - (Ci-Ce)alkyl, -(Ci-Ce)haloalkyl, -(C3-C7)cycloalkyl, -(Ci-Ce)alkylene-(C3- C7)cycloalkyl, heterocycle, -(Co-Ce)alkylene-OR7, -O-(C2-Ce)alkylene-OR7-NR7(C2- C6)alkylene-OR8, -(Co-C6)alkylene-S-R7, -O-(C2-C6)alkylene-S-R7, -NR7-(C2- C6)alkylene-S-R8, -(Co-C6)alkylene-NR7R8, -O-(C2-C6)alkylene-NR7R8, -NR7-(C2- C6)alkylene-NR8R9and -(Co-C6)alkylene-C(=0)-NR7R8; R7, R8and R9are each independently hydrogen or an optionally substituted radical selected from the group of (for example the group consisting of) - (Ci-Ce)alkyl, -(Ci-Ce)haloalkyl, -(Ci-Ce)cyanoalkyl, -(C3-C7)cycloalkyl, -(Ci- C6)alkylene-(C3-C7)cycloalkyl, -(Co-C6)alkylene-0-(Co-Ce)alkyl and -(Co-Ce)alkylene- N-((Co-Ce)alkyl)2 and R7and R8or R8and R9together with the atom to which they are attached form a -(C3-C7)cycloalkyl; wherein when Q is an aryl or heteroaryl; L is an optionally substituted radical -(Ci- Ce)alkyl.

[0029] Surprisingly, it has been found that the compounds of general Formula (I) show potent activity and selectivity on the GABAB receptor. The compounds of the invention demonstrate advantageous properties over compounds of the prior art. Improvements have been observed in one or more of the following characteristics of the compounds of the invention: the potency on the target, the selectivity for the target, the bioavailability, the brain penetration, and the pharmacodynamics.

[0030] Preferably, R1is selected from the group of (for example the group consisting of) -O- (Ci-Ce)alkyl, -O-(Ci-C6)deuterioalkyl, -O-(C3-C7)cycloalkyl, -(C2)alkyl and - (C3)cycloalkyl.

[0031] Preferably, R1is -O-(Ci-Ce)alkyl.

[0032] The cycloalkyl, heterocycle, aryl and heteroaryl ring systems of (A)mmay be selected from the group of (for example the group consisting of) azetidinyl, 5- azaspiro[2.3]hexanyl, dihydrofuranyl, furyl, imidazolidinyl, imidazolinyl, imidazolonyl, imidazolyl, isothiazolinyl, isothiazolyl, isoxazolidinyl, isoxazolinyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolidinyl, oxazolinyl, oxazolonyl, oxazolyl, oxetanyl, phenyl, piperazinonyl, piperazinyl, piperidinonyl, piperidinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridonyl, pyridyl, pyrimidyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolinyl, thiazolonyl, thiazolyl, thienyl, thiomorpholinyl, triazolinyl, triazinyl, triazolyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, and each ring of said ring system is optionally substituted independently with 1 to 3 substituents R4, R5or R6.

[0033] The cycloalkyl and heterocycle ring systems of (B)nmay be selected from the group of (for example the group consisting of) azetidinyl, isoxazolidinyl, isoxazolinyl, morpholinyl, piperazinonyl, piperazinyl, piperidinonyl, piperidinyl, pyrrolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, thiomorpholinyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, and each ring of said ring system is optionally substituted independently with 1 to 3 substituents R7, R8or R9.

[0034] The or each (A)mmay be independently selected from the group of (for example the group consisting of) hydrogen, halogen, -CF3 and an optionally substituted radical selected from the group of (for example the group consisting of) -(Ci-Ce)alkyl, -(Ci- Ce)haloalkyl, -(C3-C7)cycloalkyl, heteroaryl, heterocycle and -(Co-Ce)alkylene-OR4;

[0035] R4may be hydrogen or an optionally substituted radical selected from the group of (for example the group consisting of) -(Ci-Ce)alkyl and -(Ci-C6)haloalkyl.

[0036] The or each (B)nmay be independently selected from the group of (for example the group consisting of) hydrogen, halogen, -CN, -CF3, -OH and an optionally substituted radical selected from the group of (for example the group consisting of) - (Ci-Ce)alkyl, -(Ci-Ce)haloalkyl, -(C3-C7)cycloalkyl, -(Co-Ce)alkylene-OR7and -(Co- Ce)alkylene-NR7R8;

[0037] R7and R8each may be independently hydrogen or an optionally substituted radical - (Ci-C6)alkyl. The or each (A)mmay be independently selected from the group of (for example the group consisting of) hydrogen, halogen, and a radical -(Co-Ce)alkylene-OR4.

[0038] R4may be -(Ci-Ce)alkyl.

[0039] The or each (B)nmay be independently selected from the group of (for example the group consisting of) hydrogen, halogen, -OH and an optionally substituted radical selected from the group of (for example the group consisting of) -(Ci-Ce)alkyl, -(Ci- Ce)haloalkyl, -(C3-C7)cycloalkyl and -(Co-Ce)alkylene-OR7;

[0040] R7may be hydrogen or an optionally substituted radical -(Ci-Ce)alkyl.

[0041] For example, A may be hydrogen, halogen or -O-(Ci-Ce)alkyl and m may be 1, 2, 3, 4 or 5. For example, B may be hydrogen, halogen, -OH and a radical selected from the group of (for example the group consisting of) -(Ci-Ce)alkyl, -(Ci-Ce)haloalkyl, -(Co- C6)alkylene-O-(Ci-Ce)alkyl and-(Co-C6)alkylene-0-(Ci-Ce)haloalkyl and n may be 1, 2, 3, 4 or 5.

[0042] Preferably, the compounds of Formula (I) are the compounds according to Formula (II): a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof or an A-oxide form thereof, wherein:

[0043] R1is -O-(Ci-C6)alkyl; J is selected from the group of (for example the group consisting of) -CH2- and - CHR2;

[0044] R2is selected from the group of (for example the group consisting of) -(Ci- Ce)alkyl and -(C3-C7)cycloalkyl; optionally substituted radical -(Ci-Ce)alkyl; represents a heteroaryl of formula:

[0045] Z, A, B, m and n, are as defined in any statement set out above.

[0046] Preferably, the compounds of Formula (I) or Formula (II) are the compounds according to Formula (III): a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof or an A-oxide form thereof wherein:

[0047] L is an optionally substituted radical -(Ci-Ce)alkyl; the or each (A)mis independently selected from the group of (for example the group consisting of) hydrogen, halogen, -CF3 and an optionally substituted radical selected from the group of (for example the group consisting of) -(Ci-Ce)alkyl, -(Ci- Ce)haloalkyl, -(C3-C7)cycloalkyl and -(Co-Ce)alkylene-OR4; R4is an optionally substituted radical selected from the group of (for example the group consisting of) -(Ci-Ce)alkyl and -(Ci-Ce)haloalkyl; the or each (B)nis independently selected from the group of (for example the group consisting of) hydrogen, halogen, -CF3 and an optionally substituted radical selected from the group of (for example the group consisting of) -(Ci-Ce)alkyl, -(Ci- Ce)haloalkyl, -(Co-Ce)alkylene-OR7and -(Co-Ce)alkylene-NR7R8;

[0048] R7and R8are each independently hydrogen or an optionally substituted radical - (Ci-C6)alkyl; and R1, J, R2, Z1, Z2, Z3, Z4, Z5, m and n are as defined in any statement set out above.

[0049] Preferably, the compounds of Formula (I) or Formula (II) are the compounds according to Formula (IV): a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof or an V-oxide form thereof wherein:

[0050] L is an optionally substituted radical -(Ci-Ce)alkyl; the or each (A)mis independently selected from the group of (for example the group consisting of) hydrogen, halogen, -CF3 and an optionally substituted radical selected from the group of (for example the group consisting of) -(Ci-Ce)alkyl, -(Ci- Ce)haloalkyl and -(Co-Ce)alkylene-OR4;

[0051] R4is an optionally substituted radical -(Ci-Ce)alkyl; the or each (B)nis independently selected from the group of (for example the group consisting of) hydrogen, halogen, -CF3 and an optionally substituted radical selected from the group of (for example the group consisting of) -(Ci-Ce)alkyl, -(Ci- Ce)haloalkyl, -(Co-Ce)alkylene-OR7and -(Co-Ce)alkylene-NR7R8;

[0052] R7and R8are each independently hydrogen or an optionally substituted radical - (Ci-C6)alkyl; and R1, J, R2, Z1, Z2, Z3, Z4, Z5, m and n are as defined in any statement set out above.

[0053] Preferably, the compounds of Formula (I) are the compounds according to Formula (V): a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof or an 7V-oxide form thereof wherein:

[0054] R1is -O-(Ci-C6)alkyl;

[0055] Z is selected from CH or N;

[0056] J is selected from the group of (for example the group consisting of) -CH2-, - CHR2- and -CR2R3-;

[0057] R2and R3are each independently a radical selected from the group of (for example the group consisting of) -(Ci-Ce)alkyl and R2and R3together with the atom to which they are attached form a -(C3-C7)cycloalkyl; x is an integer equal to 1, 2, 3 and 4; the or each (A)mis independently selected from the group of (for example the group consisting of) hydrogen, halogen and an optionally substituted radical pyridinyl and m is defined in any statement set out above. Particular preferred compounds of the invention are compounds as mentioned in the following list, as well as a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof or an A -oxi de form thereof:

[0058] 4-(l-(4-chloro-3-methoxyphenyl)ethyl)-6-methoxy-2-(l-(4-methylpyridin-3-yl)ethyl)-

[0059] 1,2, 4-tri azine-3, 5(277, 477)-di one

[0060] 2-((3-fluoropyridin-4-yl)methyl)-6-methoxy-4-(l-(3-methoxy-4- (trifluoromethyl)phenyl)ethyl)- 1,2, 4-tri azine-3, 5(277, 477)-di one 2-((3 -isopropyloxetan-3 -yl)methyl)-6-methoxy-4-( 1 -(3 -methoxy-4- (trifluoromethyl)phenyl)ethyl)- 1,2, 4-tri azine-3, 5(277, 477)-di one

[0061] 4-(l-(4-chl oro-3 -methoxyphenyl)ethyl)-6-m ethoxy -2-((3-methylpyrazin-2-yl)methyl)-

[0062] 1,2, 4-tri azine-3, 5(277, 477)-di one

[0063] 4-( 1 -(4-chl oro-3 -methoxyphenyl)ethyl)-2-(5 , 5 -dimethyltetrahy drofuran-3 -y 1 )- 6 - methoxy- 1,2, 4-tri azine-3, 5(277, 477)-di one

[0064] 4-(l-(4-chloro-3-methoxyphenyl)ethyl)-2-(imidazo[l,2-a]pyridin-5-ylmethyl)-6- methoxy- 1 ,2,4-triazine-3 , 5(277, 477)-di one

[0065] 4-(l -(4-chl oro-3 -methoxyphenyl)ethyl)-2-((3 -chi oropyri din-2 -yl)methyl)-6-m ethoxy-

[0066] 1,2, 4-tri azine-3, 5(277, 477)-di one

[0067] 4-(l -(4-chloro-3-methoxyphenyl)ethyl)-6-m ethoxy -2-(pyrazolo[l,5-a]pyri din-3- ylmethyl)-l, 2, 4-tri azine-3, 5(277, 477)-di one

[0068] 4-(4-chl oro-3 -methoxybenzyl)-2-((2,6-dimethylpyri din-3 -yl)methyl)-6-methoxy- 1,2, 4- tri azine-3 , 5(2H, 477)-di one

[0069] 4-(l -(4-chloro-3-methoxyphenyl)ethyl)-6-m ethoxy -2-((2-methylbenzo[ ]oxazol-7- yl)methyl)- 1,2, 4-tri azine-3, 5(277, 477)-di one

[0070] 4-(l -(4-chl oro-3 -methoxyphenyl)ethyl)-6-m ethoxy -2-((l -methyl- 177-indazol -4- yl)methyl)-l, 2, 4-tri azine-3, 5(277, 477)-di one

[0071] 4-(l-(4-chloro-3-methoxyphenyl)ethyl)-6-methoxy-2-((l-methyl-2- oxabicyclo[3.1.1]heptan-5-yl)methyl)- 1,2, 4-tri azine-3, 5(277, 477)-di one

[0072] 4-(l -(4-chloro-3-methoxyphenyl)ethyl)-2-((3,5-difluoropyri din-2 -yl)methyl)-6- methoxy- 1,2, 4-tri azine-3, 5(277, 477)-di one

[0073] 4-(l -(4-chl oro-3 -methoxyphenyl )ethyl)-6-m ethoxy -2-((6-methyli mi dazofl ,2-a]pyri din-

[0074] 5-yl)methyl)-l, 2, 4-tri azine-3, 5(277, 477)-di one

[0075] 4-(l-(4-chloro-3-methoxyphenyl)ethyl)-2-(imidazo[l,5-a]pyridin-8-ylmethyl)-6- methoxy- 1,2, 4-tri azine-3, 5(277, 477)-di one

[0076] 4-(l-(4-chloro-3-methoxyphenyl)ethyl)-2-((5-fluoropyridin-3-yl)methyl)-6-methoxy-

[0077] 1,2, 4-tri azine-3, 5(277, 477)-di one

[0078] 4-(l-(4-chloro-3-methoxyphenyl)ethyl)-6-methoxy-2-((5-(trifluoromethyl)pyri din-3- yl)methyl)- 1,2, 4-tri azine-3, 5(277, 477)-di one

[0079] 4-(l-(4-chloro-3-methoxyphenyl)ethyl)-2-((2,4-dimethyloxazol-5-yl)methyl)-6- methoxy- 1,2, 4-tri azine-3, 5(277, 477)-di one

[0080] 4-( l -(4-chl oro-3 -methoxyphenyl (ethyl )-2-(i mi dazo[ l ,2-a]pyri di n-8-yl methyl )-6- methoxy- 1,2, 4-tri azine-3, 5(277, 477)-di one

[0081] 4-( 1 -(4-chloro-3 -methoxyphenyl)ethyl)-6-m ethoxy -2-((3 -(tri fluoromethyl)pyrazin-2- yl)methyl)- 1,2, 4-tri azine-3, 5(277, 477)-di one 4-( l -(4-chloro-3-methoxyphenyl)ethyl)-6-methoxy-2-((5-(trifluoromethyl (thiazoleyl (methyl )- l, 2, 4-tri azine-3, 5(277, 477)-di one

[0082] 4-(l-(4-chloro-3-methoxyphenyl)ethyl)-6-methoxy-2-(l-(6-methylpyridin-3-yl)ethyl)-

[0083] 1,2, 4-tri azine-3, 5(2 7, 4Z7)-di one

[0084] 3 -( 1 -(4-chl oro-3 -methoxyphenyl)ethyl)-5 -methoxy- 1 -((4-methoxypyri din-3 - yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0085] 3 -( 1 -(4-chl oro-3 -methoxyphenyl)ethyl)-5 -methoxy- 1 -((4-(trifluoromethyl)pyri din-3 - yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one l-((2-oxabicyclo[2.1.1 ]hexan-4-yl)methyl)-3-(l -(4-chl oro-3-m ethoxyphenyl)ethyl)-5- methoxypyrimidine-2, 4(1 / , 3 / )-di one

[0086] 4-(l -(4-chl oro-3 -methoxyphenyl)ethyl)-6-m ethoxy -2-((l-(pyridin-4- yl)cyclopropyl)methyl)-l,2,4-triazine-3,5(2 / / ,4 / 7)-dione

[0087] 3-(4-chloro-3-methoxybenzyl)-5-methoxy-l-(l-(5-methylpyridin-3- yl)ethyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0088] 5 -m ethoxy-3 -(3 -methoxy -4-(trifluoromethyl)b enzyl)- 1 -((4-methylpyri din-3 - yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0089] 3-((3-(l -(4-chloro-3-methoxyphenyl)ethyl)-5-m ethoxy -2, 4-di oxo-3, 4- dihydropyrimidin- 1 (2 / 7)-yl)methyl)benzonitrile

[0090] 5-methoxy-3-(3-methoxy-4-(trifluoromethyl)benzyl)-l-(l-(5-methylpyri din-3- yl)ethyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0091] 3-(4-fluoro-3-(trifluoromethyl)benzyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0092] 3-(4-chl oro-3 -(trifluoromethoxy )benzyl)-5-methoxy-l -((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0093] 3-(4-chloro-3-(trifluoromethyl)benzyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0094] 3-(4-chloro-3-fluorobenzyl)-5-methoxy-l-((5-methylpyridazin-4-yl)methyl)pyrimidine-

[0095] 2,4(l / 7,3 / 7)-dione

[0096] 3-(3-chloro-4-(trifluoromethyl)benzyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0097] 3-(4-chloro-3-isopropoxybenzyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0098] 5-methoxy-3-(3-methoxy-4-(trifluoromethyl)benzyl)-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0099] 4-(l-(4-chloro-3-methoxyphenyl)ethyl)-6-methoxy-2-(l-(pyridin-3-yl)ethyl)-l,2,4- tri azine-3 , 5(2 / 7, 4 / 7)-di one

[0100] 3 -((4-( 1 -(4-chl oro-3 -methoxyphenyl)ethyl)-6-m ethoxy-3 , 5 -di oxo-4, 5 -dihydro- 1,2,4- triazin-2(3 / 7)-yl)methyl)-4-methylbenzonitrile

[0101] 4-(l-(4-chloro-3-methoxyphenyl)ethyl)-2-((3,5-dimethylisothiazol-4-yl)methyl)-6- methoxy- 1 ,2, 4-tri azine-3 , 5(2 / 7, 4 / 7)-di one

[0102] 4-(l-(4-chloro-3-methoxyphenyl)ethyl)-6-methoxy-2-((3-methylisoxazol-4-yl)methyl)-

[0103] 1,2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one

[0104] 4-(l-(4-chloro-3-methoxyphenyl)ethyl)-6-methoxy-2-(l-(3-methylisoxazol-4-yl)ethyl)-

[0105] 1,2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one

[0106] 4-(l -(4-chl oro-3 -methoxyphenyl)ethyl)-2-((2, 4-dimethylpyri din-3 -yl)methyl)-6- methoxy- 1,2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one 4-(l -(4-chl oro-3 -methoxyphenyl)ethyl)-2-((3-cy cl opropyl-6-methylpyridazin-4- yl)methyl)-6-methoxy-l,2,4-triazine-3,5(2 / 7,4 / 7)-dione 4-(4-chloro-3-methoxybenzyl)-2-(l-(5-fluoropyridin-3-yl)ethyl)-6-methoxy-l,2,4- triazine-3 , 5(2H, 4 / 7)-di one

[0107] 4-(l -(4-chloro-3-methoxyphenyl)ethyl)-6-m ethoxy -2-((5-methyloxazol-4-yl)methyl)- l,2,4-triazine-3,5(2 / 7,4 / 7)-dione

[0108] 3-(l-(4-chloro-3-methoxyphenyl)ethyl)-5-methoxy-l-((l-methyl-l / 7-pyrrolo[2,3- Z>]pyri din-4-yl)methyl)pyrimidine-2, 4(1 7, 3Z7)-di one

[0109] 4-(l-(4-chloro-3-methoxyphenyl)ethyl)-2-((3-isopropoxypyridazin-4-yl)methyl)-6- methoxy- 1, 2, 4-triazine-3, 5(2 / 7, 4 / 7)-di one

[0110] 3 -( 1 -(4-chl oro-3 -methoxyphenyl)ethyl)- 1 -((2-(dimethylamino)pyri din-3 -y l)methyl)-5 - methoxypyrimidine-2, 4(1 / , 3 / )-di one l-((2-(dimethylamino)pyridin-3-yl)methyl)-5-methoxy-3-(3-methoxy-4-

[0111] (trifluoromethyl)benzyl)pyrimidine-2,4(lH,3H)-dione

[0112] 3-(4-chl oro-3-cyclopropylbenzyl)-5-methoxy-l -((4-methylpyri din-3- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0113] 4-(l-(4-chloro-3-methoxyphenyl)ethyl)-6-methoxy-2-((3-methoxy-5-methylpyridazin-

[0114] 4-yl)methyl)-l,2,4-triazine-3,5(2 / 7,4 / 7)-dione l-((2-oxabicyclo[2.1.1]hexan-4-yl)methyl)-3-(4-chloro-3-(5-azaspiro[2.3]hexan-5- yl)benzyl)-5-methoxypyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0115] 3-(4-chloro-3-cyclopropylbenzyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0116] 3-((4-(l -(4-chlorophenyl)ethyl)-6-methoxy-3,5-di oxo-4, 5-dihydro- 1,2, 4-triazin-2(3 / 7)- yl)methyl)benzonitrile

[0117] 3-((3-(4-chloro-3-(pyridin-3-yl)benzyl)-5-methoxy-2,4-dioxo-3,4-dihydropyrimidin-

[0118] 1 (2 / 7)-yl)methyl)benzonitrile

[0119] 3 -(3 -chi oro-4-(trifluoromethyl)benzyl)-5-m ethoxy- l-((2-methylpyri din-3- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0120] 3-((3-(4-chloro-3-(pyridin-3-yl)benzyl)-5-methoxy-2,4-dioxo-3,4-dihydropyrimidin- l(2 / 7)-yl)methyl)-2-methylbenzonitrile

[0121] 4-(3-chloro-4-(trifluoromethyl)benzyl)-2-((2,4-dimethylpyridin-3-yl)methyl)-6- methoxy- 1 ,2, 4-triazine-3 , 5(2 / 7, 4 / 7)-di one

[0122] 4-(3-chloro-4-(trifluoromethyl)benzyl)-2-((3-isopropyloxetan-3-yl)methyl)-6-methoxy- l,2,4-triazine-3,5(2 / 7,4 / 7)-dione

[0123] 4-(3-chloro-4-(trifluoromethyl)benzyl)-6-methoxy-2-(l -(4-methylpyri din-3 -yl)ethyl)- l,2,4-triazine-3,5(2 / 7,4 / 7)-dione

[0124] 4-(3 -chi oro-4-(trifluoromethyl)benzyl)-6-m ethoxy -2-((6-methylimidazo[l,2-a]pyri din-

[0125] 5-yl)methyl)-l,2,4-triazine-3,5(2 / 7,4 / 7)-dione

[0126] 3-((3-(4-chloro-3-(pyridin-3-yl)benzyl)-5-methoxy-2,4-dioxo-3,4-dihydropyrimidin- l(2 / 7)-yl)methyl)-5-fluorobenzonitrile

[0127] 3-(l-(4-chloro-3-methoxyphenyl)-2-methylpropyl)-5-methoxy-l -((4-methylpyri din-3- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0128] 4-(l -(4-chl orophenyl)propyl)-6-methoxy-2-((4-methylpyri din-3 -yl)m ethyl)- 1,2, 4- tri azine-3 , 5(2 / 7, 4 / 7)-di one

[0129] 3 -( 1 -(4-chl oro-3 -methoxyphenyl)-2-methylpropyl)- 1 -((2,4-dimethylpyridin-3 - yl)methyl)-5-methoxypyrimidine-2, 4(1 / 7, 3 / 7)-di one 4-(4-chloro-3-(5-azaspiro[2.3]hexan-5-yl)benzyl)-6-methoxy-2-((4-methylpyridin-3- yl)methyl)- 1,2, 4-tri azine-3, 5(2 7, 4Z7)-di one

[0130] 3-((4-(4-chloro-3-(5-azaspiro[2.3]hexan-5-yl)benzyl)-6-methoxy-3,5-dioxo-4,5- dihydro- 1,2, 4-tri azin-2(3 / 7)-yl)methyl)benzonitrile

[0131] 4-(4-chl oro-3 -(pyri din-3 -yl (benzyl )-6-methoxy-2-(tetrahydro-27 / -pyran-4-yl )- l, 2, 4- tri azine-3 , 5(2H, 4 / 7)-di one

[0132] 3-((4-(4-chl oro-3 -(pyri din-3-yl)benzyl)-6-methoxy-3,5-di oxo-4, 5-dihydro- 1,2, 4-tri azin-

[0133] 2(3 / 7)-yl)methyl)-2-methylbenzonitrile

[0134] 4-(3-fluoro-4-isopropylbenzyl)-6-methoxy-2-((4-methylpyridin-3-yl)methyl)-l,2,4- tri azine-3 , 5(2H, 4 / 7)-di one

[0135] 4-(3 -chi oro-4-(trifluoromethyl)benzyl)-2-((5-fluoro-2-methylpyri din-3 -yl)methyl)-6- methoxy- 1,2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one

[0136] 3-((4-(4-chloro-3-(5-fluoropyridin-3-yl)benzyl)-6-methoxy-3,5-di oxo-4, 5-dihydro-

[0137] 1,2, 4-tri azin-2(3 / 7)-yl)methyl)-2-methylbenzonitrile

[0138] 4-(4-chloro-3-isopropylbenzyl)-6-methoxy-2-((4-methylpyridin-3-yl)methyl)-l,2,4- tri azine-3, 5(2 / 7, 4 / 7)-di one l-((2-oxabicyclo[2.1. l]hexan-4-yl)methyl)-3-(4-chloro-3-(pyridin-3-yl)benzyl)-5- methoxypyrimidine-2, 4(1 / , 3 / )-di one

[0139] 3-(4-chl oro-3 -(pyri din-3-yl)benzyl)-5-methoxy-l -((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0140] 4-(4-chloro-3-(5-azaspiro[2.3]hexan-5-yl)benzyl)-6-methoxy-2-((5-methylpyridazin-4- yl)methyl)-l, 2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one

[0141] 4-(4-chloro-3-(5-fluoropyridin-3-yl)benzyl)-2-((3-isopropyloxetan-3-yl)methyl)-6- methoxy- 1 ,2, 4-tri azine-3 , 5(2 / 7, 4 / 7)-di one

[0142] 4-(4-chloro-3-(5-fluoropyridin-3-yl)benzyl)-6-methoxy-2-((6-methylimidazo[l,2- a]pyridin-5-yl)methyl)- 1,2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one

[0143] 4-(l-(4-chlorophenyl)propyl)-6-methoxy-2-(tetrahydro-2 / 7-pyran-4-yl)- 1,2, 4-tri azine-

[0144] 3 , 5 (2 / 7,4 / 7)-dione l-((2-oxabicyclo[2.1. l]hexan-4-yl)methyl)-3-(4-chloro-3-(pyrimidin-5-yl)benzyl)-5- methoxypyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0145] 4-(4-chloro-3-(5-fluoropyridin-3-yl)benzyl)-6-methoxy-2-(l-(5-methylpyri din-3- yl)ethyl)- 1,2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one

[0146] 3-((3-(4-chloro-3-(5-fluoropyridin-3-yl)benzyl)-5-methoxy-2,4-dioxo-3,4- dihydropyrimidin- 1 (2 / 7)-yl)methyl)-2-methylbenzonitrile

[0147] 4-(4-chloro-3-(5-fluoropyridin-3-yl)benzyl)-6-methoxy-2-(l-(4-methylpyri din-3- yl)ethyl)- 1,2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one

[0148] 4-(l-(4-chlorophenyl)-2-methylpropyl)-2-((2,4-dimethylpyri din-3 -yl)methyl)-6- methoxy- 1 ,2, 4-tri azine-3 , 5(2 / 7, 4 / 7)-di one

[0149] 4-(l-(4-chlorophenyl)-2-methylpropyl)-2-((3,5-dimethylisoxazol-4-yl)methyl)-6- methoxy- 1 ,2, 4-tri azine-3 , 5(2 / 7, 4 / 7)-di one

[0150] 4-(l-(4-chlorophenyl)-2-methylpropyl)-6-methoxy-2-((4-methylpyri din-3 -yl)methyl)-

[0151] 1,2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one

[0152] 4-(l-(4-chlorophenyl)-2-methylpropyl)-2-((2-(dimethylamino)pyri din-3 -yl)methyl)-6- methoxy- 1 ,2, 4-tri azine-3 , 5(2 / 7, 4 / 7)-di one

[0153] 4-(l-(4-chlorophenyl)-2-methylpropyl)-6-methoxy-2-((6-methylimidazo[l,2-a]pyridin-

[0154] 5-yl)methyl)-l, 2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one 4-(l-(4-chlorophenyl)propyl)-6-methoxy-2-(pyrazolo[l,5-a]pyridin-3-ylmethyl)-l,2,4- triazine-3 , 5(2H, 4 / 7)-di one 4-(4-chloro-3-(5-fluoropyridin-3-yl)benzyl)-6-methoxy-2-((4-methylpyri din-3- yl)methyl)- 1,2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one

[0155] 3-(4-chloro-3-(5-fluoropyridin-3-yl)benzyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0156] 3 -( 1 -(4-chlorophenyl)-2-methylpropyl)-5 -methoxy- 1 -((5 -methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0157] 3-(4-chloro-3-(pyridin-3-yl)benzyl)-5-methoxy-l-(tetrahydro-2 / / -pyran-4- yl)pyrimidine-2,4(l / / ,3 / / )-dione

[0158] 4-(4-chloro-3-(5-fluoropyridin-3-yl)benzyl)-2-((2-(dimethylamino)pyri din-3- yl)methyl)-6-methoxy-l,2,4-triazine-3,5(2 / / ,4 / / )-dione

[0159] 4-(3 -chi oro-4-(trifluoromethyl)benzyl)-2-((5-fluoro-4-methylpyri din-3 -yl)methyl)-6- methoxy- 1 ,2, 4-triazine-3 , 5(2 / 7, 4 / Z)-di one

[0160] 3-(4-chloro-3-(pyridin-3-yl)benzyl)-5-methoxy-l-((3-methylpyrazin-2- yl)methyl)pyrimidine-2, 4(1 7, 3 / )-di one

[0161] 3-(4-chloro-3-(pyridin-3-yl)benzyl)-5-methoxy-l-((2-methylpyridin-3- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0162] 3 -(4-chl oro-3 -(pyri din-3 -yl)benzyl)- 1 -((3 -fluoropyri din-2 -yl)methyl)-5- methoxypyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0163] 4-(l-(4-chlorophenyl)propyl)-6-methoxy-2-((l-methyl-l / / -indazol-4-yl)methyl)-l,2,4- tri azine-3, 5(2 / 7, 4 / 7)-di one

[0164] 4-(l-(4-chlorophenyl)propyl)-2-(imidazo[l,5-a]pyridin-l-ylmethyl)-6-methoxy-l,2,4- tri azine-3, 5(2 / 7, 4 / 7)-di one

[0165] 4-(l-(4-chlorophenyl)-2-methylpropyl)-6-methoxy-2-(tetrahydro-2 / / -pyran-4-yl)-l,2,4- tri azine-3, 5(2 / 7, 4 / 7)-di one

[0166] 3-(4-chloro-3-(4-methylpyridin-3-yl)benzyl)-5-methoxy-l-(tetrahydro-2 / / -pyran-4- yl)pyrimidine-2,4(l / / ,3 / 7)-dione

[0167] 3-(4-chloro-3-isopropylbenzyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0168] 4-(l-(4-chlorophenyl)propyl)-6-methoxy-2-((2-methyl-2 / / -indazol-4-yl)methyl)-l,2,4- tri azine-3, 5(2 / 7, 4 / 7)-di one

[0169] 4-(l -(4-chl orophenyl)-2-methylpropyl)-6-methoxy-2-((2-(trifluoromethyl)pyri din-3- yl)methyl)-l,2,4-triazine-3,5(2 / / ,4 / 7)-dione

[0170] 4-(4-chloro-3-isopropylbenzyl)-6-m ethoxy -2-((5-methylpyridazin-4-yl)methyl)- 1,2, 4- tri azine-3, 5(2 / 7, 4 / 7)-di one

[0171] 4-(l-(4-chlorophenyl)-2-methylpropyl)-6-methoxy-2-((4-methyltetrahydro-2 / / -pyran-4- yl)methyl)-l, 2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one

[0172] 3 -( 1 -(4-chl orophenyl)propyl)-5 -methoxy- 1 -((3 -(trifluoromethyl)pyridin-2- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0173] 2-((2-oxabicyclo[2.1.1]hexan-4-yl)methyl)-4-(l -(4-chl orophenyl)-2-methylpropyl)-6- methoxy- 1 ,2, 4-tri azine-3 , 5(2 / 7, 4 / 7)-di one

[0174] 3-(l-(4-chlorophenyl)propyl)-5-methoxy-l-(tetrahydro-2 / / -pyran-4-yl)pyrimidine-

[0175] 2,4(l / / ,3 / 7)-dione

[0176] 4-(l-(4-chlorophenyl)propyl)-6-methoxy-2-((2-methylpyrazolo[l,5-a]pyri din-3- yl)methyl)- 1,2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one 3 -( 1 -(4-chlorophenyl)-2-methylpropyl)-5 -methoxy- 1 -(tetrahydro-27 / -pyran-4- yl)pyrimidine-2,4(l / 7,3 / 7)-dione

[0177] 3-(l-(4-chlorophenyl)propyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0178] 3 -( 1 -(4-chlorophenyl)propyl)-5 -methoxy- 1 -((2-(trifluoromethyl)pyri din-3 - yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0179] 4-(l-(4-chlorophenyl)propyl)-6-methoxy-2-((5,6,7,8-tetrahydroimidazo[l,2-a]pyridin-

[0180] 5-yl)methyl)-l,2,4-triazine-3,5(2 / / ,4 / / )-dione

[0181] 3 -( 1 -(4-chlorophenyl)propyl)-5 -methoxy- 1 -((4-(trifluoromethyl)pyri din-3 - yl)methyl)pyrimidine-2, 4(1 / , 3 / )-di one l-((2-oxabicyclo[2.1. l]hexan-4-yl)methyl)-3-(4-chloro-3-(5-fluoropyridin-3- yl)benzyl)-5-methoxypyrimidine-2, 4(1 / 7, 3 / 7)-di one 4-(l-(4-chlorophenyl)ethyl)-6-cyclopropoxy-2-((4-methylpyridin-3-yl)methyl)-l,2,4- tri azine-3 , 5(2 / 7, 4 / 7)-di one

[0182] 4-(l-(4-chlorophenyl)propyl)-2-cyclohexyl-6-methoxy-l,2,4-triazine-3,5(2 / 7,4 / 7)-dione

[0183] 4-(l-(4-chlorophenyl)propyl)-6-methoxy-2-((3-(trifluoromethyl)pyrazin-2-yl)methyl)- 1, 2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one 4-(l-(4-chlorophenyl)cyclopropyl)-6-methoxy-2-(tetrahydro-2 / 7-pyran-4-yl)-l,2,4- tri azine-3 , 5(2 / 7, 4 / 7)-di one

[0184] 4-( 1 -(4-chlorophenyl)propyl)-6-methoxy-2-(oxepan-4-yl)- 1 ,2, 4-tri azine-3 , 5 (2 / 7, 4 / 7)- dione 3-(l-(4-chlorophenyl)propyl)-5-methoxy-l-((2-methylpyridin-3-yl)methyl)pyrimidine-

[0185] 2,4(l / 7,3 / 7)-dione

[0186] 3-(l-(4-chlorophenyl)propyl)-l-((3-chloropyridin-4-yl)methyl)-5-methoxypyrimidine-

[0187] 2,4(l / 7,3 / 7)-dione

[0188] 4-(l-(4-chlorophenyl)propyl)-2-((3 -chi oropyridin-2-yl)methyl)-6-m ethoxy- 1,2, 4- tri azine-3 , 5(2 / 7, 4 / 7)-di one

[0189] 3-(l-(4-chlorophenyl)propyl)-5-methoxy-l-((4-methylpyridin-3-yl)methyl)pyrimidine-

[0190] 2,4(l / 7,3 / 7)-dione

[0191] 4-( 1 -(4-chlorophenyl)propyl)-6-methoxy-2-((l -methoxy cy cl obutyl)methyl)- 1 ,2,4- tri azine-3 , 5(2 / 7, 4 / 7)-di one

[0192] 4-(4-chloro-3-fluorobenzyl)-2-cy cl ohexyl-6-meth oxy-1, 2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one

[0193] 4-(l-(4-chlorophenyl)propyl)-6-methoxy-2-(spiro[3.3]heptan-2-yl)-l, 2, 4-tri azine-

[0194] 3 , 5 (2 / 7,4 / 7)-dione

[0195] 3-((4-chlorophenyl)(cyclopropyl)methyl)-l-((3-chloropyridin-2-yl)methyl)-5- methoxypyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0196] 4-((4-chlorophenyl)(cyclopropyl)methyl)-6-methoxy-2-((l-methyl-2- oxabicyclo[3.1.1]heptan-5-yl)methyl)- 1,2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one 4-((4-chlorophenyl)(cy cl opropyl)methyl)-2-cy cl opentyl-6-methoxy- 1,2, 4-tri azine-

[0197] 3 , 5 (2 / 7,4 / 7)-dione

[0198] 3-((4-chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-((2-(trifluoromethyl)pyri din-3- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0199] 4-((4-chlorophenyl)(cyclopropyl)methyl)-6-methoxy-2-((l- methoxycy cl obutyl)methyl)- 1,2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one 4-((4-chlorophenyl)(cyclopropyl)methyl)-6-methoxy-2-(spiro[2.5]octan-6-yl)-l,2,4- triazine-3 , 5(2H, 4 / 7)-di one 4-((4-chlorophenyl)(cyclopropyl)methyl)-6-methoxy-2-(tetrahydro-2 / / -pyran-4-yl)-

[0200] 1.2.4-tri azine-3, 5(2 / 7, 4 / 7)-di one

[0201] 4-(l-(4-chlorophenyl)-2-methylpropyl)-6-methoxy-2-((l-methyl-2- oxabicyclo[3.1.1]heptan-5-yl)methyl)- 1,2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one

[0202] 2-((2-oxabicyclo[2.1. l]hexan-4-yl)methyl)-4-((4-chlorophenyl)(cyclopropyl)methyl)-6- methoxy- 1 ,2,4-triazine-3 , 5(2 / 7, 4 / 7)-di one

[0203] 1-((2-oxabicyclo[2.1. l]hexan-4-yl)methyl)-3-((4-chlorophenyl)(cyclopropyl)methyl)-5- methoxypyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0204] 4-((4-chl orophenyl)(cy cl opropyl)methyl)-2-((3-chloropyri din-2 -yl)methyl)-6-methoxy-

[0205] 1.2.4-triazine-3,5(2 / / ,4 / / )-dione

[0206] 4-((4-chlorophenyl)(cyclopropyl)methyl)-6-methoxy-2-((3-(trifluoromethyl)pyrazin-2- yl)methyl)-l,2,4-triazine-3,5(2 / / ,4 / / )-dione

[0207] 4-((4-chlorophenyl)(cyclopropyl)methyl)-2-((3-fluoropyridin-2-yl)methyl)-6-methoxy-

[0208] 1.2.4-triazine-3,5(2 / / ,4 / / )-dione

[0209] 4-(l-(4-chlorophenyl)butyl)-6-methoxy-2-((3-methylpyrazin-2-yl)methyl)-l,2,4- tri azine-3, 5(2 7, 4 / 7)-di one

[0210] 3-(l-(4-chlorophenyl)butyl)-5-methoxy-l-((2-methylpyridin-3-yl)methyl)pyrimidine-

[0211] 2,4(l / / ,3 / 7)-dione

[0212] 4-(l-(4-chlorophenyl)butyl)-2-((3 -chi oropyri din-2 -yl)methyl)-6-m ethoxy- 1,2, 4- tri azine-3 , 5(2 / 7, 4 / 7)-di one

[0213] 3-((4-chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-((2-methylpyri din-3- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0214] 2-((2-oxabicyclo[2.1. l]hexan-l-yl)methyl)-4-((4-chlorophenyl)(cyclopropyl)methyl)-6- methoxy- 1 ,2, 4-tri azine-3 , 5(2 / 7, 4 / 7)-di one

[0215] 3 -( 1 -(4-chlorophenyl)butyl)-5 -methoxy- 1 -((2-(trifluoromethyl)pyri din-3 - yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0216] 4-((4-chlorophenyl)(cyclopropyl)methyl)-6-methoxy-2-((3-methylisoxazol-4- yl)methyl)- 1,2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one

[0217] 2-((2-oxabicyclo[2.1.1]hexan-4-yl)methyl)-4-(l-(4-chlorophenyl)butyl)-6-methoxy-

[0218] 1.2.4-tri azine-3, 5(2 / 7, 4 / 7)-di one

[0219] 4-((4-chlorophenyl)(cyclopropyl)methyl)-2-((3-isopropyloxetan-3-yl)methyl)-6- methoxy- 1 ,2, 4-tri azine-3 , 5(2 / 7, 4 / 7)-di one

[0220] 4-(l-(4-chlorophenyl)propyl)-2-(4,4-difluorocy cl ohexyl)-6-methoxy- 1,2, 4-tri azine-

[0221] 3 , 5 (2 / 7,4 / 7)-dione

[0222] 3-((4-chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-(tetrahydro-2 / 7-pyran-4- yl)pyrimidine-2,4(l / 7,3 / 7)-dione

[0223] 3-(cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l-(tetrahydro-2 / 7-pyran-4- yl)pyrimidine-2,4(l / 7,3 / 7)-dione

[0224] (5)-4-((4-chlorophenyl)(cyclopropyl)methyl)-6-methoxy-2-(tetrahydro-2 / 7-pyran-4-yl)-

[0225] 1,2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one

[0226] (7?)-4-((4-chlorophenyl)(cyclopropyl)methyl)-6-methoxy-2-(tetrahydro-2 / 7-pyran-4-yl)-

[0227] 1,2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one

[0228] 4-( 1 -(4-chlorophenyl)propyl)-6-methoxy-2-((l -methoxy cy cl opentyl)methyl)- 1 ,2,4- tri azine-3 , 5(2 / 7, 4 / 7)-di one 2-((2-oxabicyclo[3.1.1 ]heptan- 1 -yl)methyl)-4-((4-chlorophenyl)(cyclopropyl)methyl)-

[0229] 6-methoxy-l, 2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one

[0230] 4-((4-chlorophenyl)(cyclopropyl)methyl)-6-methoxy-2-((tetrahydro-2 / 7-pyran-4- yl)methyl)- 1,2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one

[0231] 4-((4-chlorophenyl)(cyclopropyl)methyl)-6-methoxy-2-((3-methylpyrazin-2- yl)methyl)- 1,2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one

[0232] 4-(l-(4-chlorophenyl)propyl)-2-(4,4-dimethylcy cl ohexyl)-6-m ethoxy- 1, 2, 4-tri azine-

[0233] 3,5(2 / 7,4 / 7)-dione

[0234] 3-(l-(4-chlorophenyl)butyl)-5-methoxy-l-(tetrahydro-2 / 7-pyran-4-yl)pyrimidine-

[0235] 2,4(l / 7,3 / 7)-dione

[0236] 3-((4-chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-(pyridazin-4- ylmethyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0237] 4-((4-chlorophenyl)(cyclopropyl)methyl)-2-((2-hydroxypyridin-4-yl)methyl)-6- methoxy- 1,2, 4-tri azine-3, 5(2 7, 4Z7)-di one

[0238] 3-((4-chlorophenyl)(cyclopropyl)methyl)-l-((2-(dimethylamino)pyridin-3-yl)methyl)-

[0239] 5-methoxypyrimidine-2, 4(1 / , 3 / )-di one

[0240] 3-((4-chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-((4-methoxypyri din-3- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0241] 3-(l-(4-chlorophenyl)butyl)-5-methoxy-l-((5-methylpyridazin-4-yl)methyl)pyrimidine-

[0242] 2,4(l / 7,3 / 7)-dione

[0243] 4-(l-(4-chlorophenyl)butyl)-6-methoxy-2-((3-(trifluoromethyl)pyrazin-2-yl)methyl)- 1,2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one

[0244] 4-((4-chlorophenyl)(cyclopropyl)methyl)-2-((3,5-difluoropyridin-2-yl)methyl)-6- methoxy- 1 ,2, 4-tri azine-3 , 5(2 / 7, 4 / 7)-di one

[0245] 3-((4-chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-((4-methyltetrahydro-2 / 7-pyran-

[0246] 4-yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0247] 4-(l-(4-chlorophenyl)propyl)-6-methoxy-2-((2-methyltetrahydrofuran-2-yl)methyl)- 1,2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one

[0248] 4-(l-(4-chlorophenyl)butyl)-6-methoxy-2-((l-methyl-2-oxabicyclo[3.1.1]heptan-5- yl)methyl)- 1,2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one

[0249] 3-((4-chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0250] 3-((4-chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-(2-oxaspiro[3.3]heptan-6- yl)pyrimidine-2,4(l / 7,3 / 7)-dione

[0251] 4-((4-chlorophenyl)(cyclopropyl)methyl)-6-methoxy-2-((4-methyltetrahydro-2 / 7-pyran-

[0252] 4-yl)methyl)-l, 2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one

[0253] 4-((5-chloropyridin-2-yl)(cyclopropyl)methyl)-6-methoxy-2-(tetrahydro-2 / 7-pyran-4- yl)-l, 2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one

[0254] 4-((5-chloropyridin-3-yl)(cyclopropyl)methyl)-6-methoxy-2-(tetrahydro-2 / 7-pyran-4- yl)-l, 2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one

[0255] 3-((4-chlorophenyl)(cyclopropyl)methyl)-l-((5-fluoropyridin-3-yl)methyl)-5- methoxypyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0256] 3-((4-chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-(pyrimidin-5- ylmethyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0257] 4-((4-chlorophenyl)(cyclopropyl)methyl)-2-((2-(dimethylamino)pyridin-4-yl)methyl)-

[0258] 6-methoxy-l, 2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one 3-((4-chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-((3-methylpyrazin-2- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0259] 4-((4-chlorophenyl)(cyclopropyl)methyl)-6-methoxy-2-(2-oxaspiro[3.3]heptan-6-yl)-

[0260] 1.2.4-triazine-3,5(2 / 7,4 / 7)-dione

[0261] 4-( l-(4-chlorophenyl (butyl )-6-methoxy-2-(tetrahydro-27 / -pyran-4-yl)- l, 2, 4-tri azine-

[0262] 3,5(2 / 7,4 / 7)-dione

[0263] 4-(cyclopropyl(4-fluorophenyl)methyl)-2-((3-fluoropyridin-2-yl)methyl)-6-methoxy-

[0264] 1.2.4-tri azine-3, 5(2 / 7, 4 / 7)-di one

[0265] (5)-3-((4-chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-(tetrahydro-2 / / -pyran-4- yl)pyrimidine-2,4(l / 7,3 / 7)-dione

[0266] (7?)-3 -((4-chl orophenyl)(cy cl opropyl)methyl)-5 -methoxy- l-(tetrahydro-2 / 7-pyran-4- yl)pyrimidine-2,4(l / 7,3 / 7)-dione

[0267] 3-(cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0268] 3-(cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l-(pyrimidin-5- ylmethyl)pyrimidine-2, 4(1 / , 3 / )-di one

[0269] 4-((4-chlorophenyl)(cyclobutyl)methyl)-6-methoxy-2-(tetrahydro-2 / 7-pyran-4-yl)-

[0270] 1.2.4-triazine-3,5(2 / / ,4 / 7)-dione

[0271] 3-(cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l-((3-methylpyrazin-2- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0272] (7?)-4-((4-chlorophenyl)(cyclopropyl)methyl)-2-((3-fluoropyridin-2-yl)methyl)-6- methoxy- 1 ,2,4-triazine-3 , 5(2 / 7, 4 / 7)-di one

[0273] (5)-4-((4-chlorophenyl)(cyclopropyl)methyl)-2-((3-fluoropyridin-2-yl)methyl)-6- methoxy- 1 ,2,4-triazine-3 , 5(2 / 7, 4 / 7)-di one

[0274] 3-((5-chloropyridin-2-yl)(cyclopropyl)methyl)-5-methoxy-l-(tetrahydro-2 / 7-pyran-4- yl)pyrimidine-2,4(l / 7,3 / 7)-dione

[0275] 3-((5-chloropyridin-2-yl)(cyclopropyl)methyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0276] 3-(cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l-((4-methylpyrimidin-5- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0277] 3-(cyclopropyl(3,4-difluorophenyl)methyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0278] (7?)-3-(cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l-(tetrahydro-2 / 7-pyran-4- yl)pyrimidine-2,4(l / 7,3 / 7)-dione

[0279] (5)-3-(cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l-(tetrahydro-2 / 7-pyran-4- yl)pyrimidine-2,4(l / 7,3 / 7)-dione

[0280] 4-(cyclopropyl(3,4-difluorophenyl)methyl)-6-methoxy-2-(tetrahydro-2 / 7-pyran-4-yl)-

[0281] 1.2.4-triazine-3,5(2 / 7,4 / 7)-dione

[0282] (7?)-3-((4-chlorophenyl)(cy cl opropyl)methyl)-5 -methoxy- 1 -((5 -m ethylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0283] (5)-3-((4-chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0284] 3-((4-chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-((4-methylpyrimidin-5- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0285] 3-(cyclopropyl(3,4-difluorophenyl)methyl)-5-methoxy-l-((3-methylpyrazin-2- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one 3-(cyclopropyl(3,4-difluorophenyl)methyl)-5-methoxy-l-(tetrahydro-2 / 7-pyran-4- yl)pyrimidine-2,4( l7 / ,3 / )-dione

[0286] (5)-3-(cyclopropyl(3,4-difluorophenyl)methyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0287] (7?)-3-(cyclopropyl(3,4-difluorophenyl)methyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0288] ( / ?)-3-(cyclopropyl(3,4-difluorophenyl)methyl)-5-methoxy-l-(tetrahydro-2 / / -pyran-4- yl)pyrimidine-2,4(l / / ,3 / / )-dione

[0289] (5)-3-(cyclopropyl(3,4-difluorophenyl)methyl)-5-methoxy-l-(tetrahydro-2 / / -pyran-4- yl)pyrimidine-2,4(l / / ,3 / / )-dione

[0290] (5)-3-(cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / , 3 / )-di one

[0291] ( / ?)-3-(cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0292] 3-(cyclopropyl(6-methoxypyridin-3-yl)methyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0293] 4-((4-chlorophenyl)(cyclopropyl)methyl)-6-methoxy-2-((5-methylpyridazin-4- yl)methyl)-l,2,4-triazine-3,5(2 / 7,4 / 7)-dione

[0294] 3-(cyclopropyl(2,4-difluoro-3-methoxyphenyl)methyl)-5-methoxy-l-((5- methylpyridazin-4-yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0295] (7?)-4-((4-chlorophenyl)(cyclopropyl)methyl)-6-methoxy-2-((5-methylpyridazin-4- yl)methyl)-l,2,4-triazine-3,5(2 / 7,4 / 7)-dione

[0296] (5)-4-((4-chlorophenyl)(cyclopropyl)methyl)-6-methoxy-2-((5-methylpyridazin-4- yl)methyl)-l,2,4-triazine-3,5(2 / 7,4 / 7)-dione

[0297] 4-(cyclopropyl(2,4-difluoro-3-methoxyphenyl)methyl)-6-methoxy-2-((5- methylpyridazin-4-yl)methyl)-l,2,4-triazine-3,5(2 / 7,4 / 7)-dione

[0298] 4-(cyclopropyl(4-fluorophenyl)methyl)-6-methoxy-2-((5-methylpyridazin-4- yl)methyl)-l,2,4-triazine-3,5(2 / 7,4 / 7)-dione

[0299] 4-(cyclopropyl(3,4-difluorophenyl)methyl)-6-methoxy-2-((5-methylpyridazin-4- yl)methyl)-l,2,4-triazine-3,5(2 / 7,4 / 7)-dione

[0300] 3-((4-chloro-3-fluorophenyl)(cyclopropyl)methyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0301] (7?)-3-((4-chloro-3-fluorophenyl)(cyclopropyl)methyl)-5-methoxy-l-((5- methylpyridazin-4-yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0302] (5)-3-((4-chloro-3-fluorophenyl)(cyclopropyl)methyl)-5-methoxy-l-((5- methylpyridazin-4-yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0303] (7?)-3-(l-(4-chlorophenyl)propyl)-5-methoxy-l-(tetrahydro-2 / 7-pyran-4-yl)pyrimidine-

[0304] 2,4(l / 7,3 / 7)-dione

[0305] (5)-3-(l-(4-chlorophenyl)propyl)-5-methoxy-l-(tetrahydro-2 / 7-pyran-4-yl)pyrimidine-

[0306] 2,4(l / 7,3 / 7)-dione

[0307] 3-((4-chlorophenyl)(cyclopropyl)methyl)-l-(2,2-dimethyl-l,3-dioxan-5-yl)-5- methoxypyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0308] (5)-4-((4-chlorophenyl)(cyclobutyl)methyl)-6-methoxy-2-(tetrahydro-2 / 7-pyran-4-yl)-

[0309] 1.2.4-triazine-3,5(2Z7,4 / 7)-dione

[0310] (7?)-4-((4-chlorophenyl)(cyclobutyl)methyl)-6-methoxy-2-(tetrahydro-2 / 7-pyran-4-yl)-

[0311] 1.2.4-triazine-3,5(2 / 7,4 / 7)-dione 3-((4-chlorophenyl)(cyclobutyl)methyl)-5-methoxy-l-(pyrimidin-5- ylmethyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0312] (5)-3-((4-chlorophenyl)(cyclobutyl)methyl)-5-methoxy-l-(pyrimidin-5- ylmethyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0313] ( / ?)-3-((4-chlorophenyl)(cyclobutyl)methyl)-5-methoxy-l-(pyrimidin-5- ylmethyl)pyrimidine-2, 4(1 / , 3 / )-di one

[0314] (5)-3-(cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l-((3-methylpyrazin-2- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0315] (7?)-3-(cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l-((3-methylpyrazin-2- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0316] 4-(cyclobutyl(4-fluorophenyl)methyl)-6-methoxy-2-(tetrahydro-2 / 7-pyran-4-yl)-l,2,4- triazine-3 , 5(2 / 7, 4 / 7)-di one

[0317] (5)-4-(cyclobutyl(4-fluorophenyl)methyl)-6-methoxy-2-(tetrahydro-2 / 7-pyran-4-yl)- l,2,4-triazine-3,5(2 / 7,4 / 7)-dione

[0318] (7?)-4-(cyclobutyl(4-fluorophenyl)methyl)-6-methoxy-2-(tetrahydro-2 / 7-pyran-4-yl)-

[0319] 1.2.4-triazine-3,5(2 / 7,4 / 7)-dione and

[0320] 4-(cyclobutyl(3,4-difluorophenyl)methyl)-6-methoxy-2-(tetrahydro-2 / 7-pyran-4-yl)-

[0321] 1.2.4-triazine-3,5(2 / 7,4 / 7)-dione.

[0322] The above list of compounds can also be represented by the following skeletal formulae:

[0323]

[0324] Preferably, the compound is one or more selected from the following list, as well as a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof or an 7V-oxide form thereof: 4-(l-(4-chloro-3-methoxyphenyl)ethyl)-6-methoxy-2-(l-(4-methylpyridin-3-yl)ethyl)-

[0325] 1.2.4-triazine-3,5(2Z7,4Z7)-dione

[0326] 2-((3-fluoropyridin-4-yl)methyl)-6-methoxy-4-(l-(3-methoxy-4-

[0327] (trifluoromethyl)phenyl)ethyl)- l,2,4-triazine-3,5(27 / ,47 / )-dione

[0328] 4-(l-(4-chl oro-3 -methoxyphenyl)ethyl)-6-m ethoxy -2-((3-methylpyrazin-2-yl)methyl)-

[0329] 1.2.4-triazine-3,5(2 / 7,4 / 7)-dione

[0330] 4-(l-(4-chl oro-3 -methoxyphenyl)ethyl)-2-((3 -chi oropyri din-2 -yl)methyl)-6-m ethoxy-

[0331] 1.2.4-triazine-3,5(2 / 7,4 / 7)-dione

[0332] 4-(4-chl oro-3 -methoxybenzyl)-2-((2,6-dimethylpyri din-3 -yl)methyl)-6-methoxy- 1,2, 4- tri azine-3, 5(2 / 7, 4 / 7)-di one

[0333] 4-(l -(4-chloro-3-methoxyphenyl)ethyl)-2-((3,5-difluoropyri din-2 -yl)methyl)-6- methoxy- 1, 2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one

[0334] 4-(l-(4-chloro-3-methoxyphenyl)ethyl)-2-((5-fluoropyridin-3-yl)methyl)-6-methoxy-

[0335] 1.2.4-triazine-3,5(2 / / ,4 / / )-dione

[0336] 4-(l-(4-chloro-3-methoxyphenyl)ethyl)-6-methoxy-2-((5-(trifluoromethyl)pyri din-3- yl)methyl)-l,2,4-triazine-3,5(2 / / ,4 / / )-dione

[0337] 4-( 1 -(4-chloro-3 -methoxyphenyl)ethyl)-6-m ethoxy -2-((3-(trifluoromethyl)pyrazin-2- yl)methyl)-l,2,4-triazine-3,5(2 / / ,4 / / )-dione

[0338] 4-(l-(4-chloro-3-methoxyphenyl)ethyl)-6-methoxy-2-(l-(6-methylpyridin-3-yl)ethyl)- l,2,4-triazine-3,5(2 / / ,4 / / )-dione

[0339] 3 -( 1 -(4-chl oro-3 -methoxyphenyl)ethyl)-5 -methoxy- 1 -((4-methoxypyri din-3 - yl)methyl)pyrimidine-2, 4(1 / , 3 / )-di one

[0340] 3 -( 1 -(4-chl oro-3 -methoxyphenyl)ethyl)-5 -methoxy- 1 -((4-(trifluoromethyl)pyri din-3 - yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0341] 3-(4-chloro-3-methoxybenzyl)-5-methoxy-l-(l-(5-methylpyridin-3- yl)ethyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0342] 5 -m ethoxy-3 -(3 -methoxy -4-(trifluoromethyl)b enzyl)- 1 -((4-methylpyri din-3 - yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0343] 5-methoxy-3-(3-methoxy-4-(trifluoromethyl)benzyl)-l-(l-(5-methylpyri din-3- yl)ethyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0344] 3-(4-fluoro-3-(trifluoromethyl)benzyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0345] 3-(4-chl oro-3 -(trifluoromethoxy )benzyl)-5-methoxy-l -((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0346] 3-(4-chloro-3-(trifluoromethyl)benzyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0347] 3-(4-chloro-3-fluorobenzyl)-5-methoxy-l-((5-methylpyridazin-4-yl)methyl)pyrimidine-

[0348] 2,4(l / 7,3 / 7)-dione

[0349] 3-(3-chloro-4-(trifluoromethyl)benzyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0350] 3-(4-chloro-3-isopropoxybenzyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0351] 5-methoxy-3-(3-methoxy-4-(trifluoromethyl)benzyl)-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0352] 4-(l-(4-chloro-3-methoxyphenyl)ethyl)-6-methoxy-2-(l-(pyridin-3-yl)ethyl)-l,2,4- tri azine-3 , 5(2 / 7, 4 / 7)-di one 4-( l -(4-chl oro-3 -methoxyphenyl )ethyl)-2-((2,4-di methyl pyri di n-3-yl (methyl )-6- methoxy- 1 ,2,4-triazine-3 , 5(2 7, 4 / 7)-di one

[0353] 4-(l-(4-chl oro-3 -methoxyphenyl)ethyl)-2-((3-cy cl opropyl-6-methylpyridazin-4- yl)methyl)-6-methoxy- 1,2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one

[0354] 4-(4-chloro-3-methoxybenzyl)-2-(l-(5-fluoropyridin-3-yl)ethyl)-6-methoxy-l,2,4- tri azine-3, 5(2 / 7, 4 / 7)-di one

[0355] 4-(l-(4-chloro-3-methoxyphenyl)ethyl)-2-((3-isopropoxypyridazin-4-yl)methyl)-6- methoxy- 1 ,2,4-triazine-3 , 5(2 / 7, 4 / 7)-di one

[0356] 3 -( 1 -(4-chl oro-3 -methoxyphenyl)ethyl)- 1 -((2-(dimethylamino)pyri din-3 -y l)methyl)-5 - methoxypyrimidine-2, 4(1 / 7, 3 / 7)-di one l-((2-(dimethylamino)pyridin-3-yl)methyl)-5-methoxy-3-(3-methoxy-4-

[0357] (trifluoromethyl)benzyl)pyrimidine-2,4(lH,3H)-dione

[0358] 3-(4-chloro-3-cyclopropylbenzyl)-5-methoxy-l -((4-methylpyri din-3- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0359] 4-(l-(4-chloro-3-methoxyphenyl)ethyl)-6-methoxy-2-((3-methoxy-5-methylpyridazin-

[0360] 4-yl)methyl)-l,2,4-triazine-3,5(2 / 7,4 / 7)-dione

[0361] 3-(4-chloro-3-cyclopropylbenzyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0362] 3 -(3 -chi oro-4-(trifluoromethyl)benzyl)-5 -methoxy- l-((2-methylpyri din-3 - yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0363] 4-(3-chloro-4-(trifluoromethyl)benzyl)-2-((2,4-dimethylpyridin-3-yl)methyl)-6- methoxy- 1 ,2,4-triazine-3 , 5(2 / 7, 4 / 7)-di one

[0364] 4-(3-chloro-4-(trifluoromethyl)benzyl)-6-methoxy-2-(l -(4-methylpyri din-3 -yl)ethyl)- l,2,4-triazine-3,5(2 / 7,4 / 7)-dione

[0365] 3-(l -(4-chloro-3-methoxyphenyl)-2-methylpropyl)-5-methoxy-l -((4-methylpyri din-3- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0366] 4-(l -(4-chl orophenyl)propyl)-6-methoxy-2-((4-methylpyri din-3 -yl)m ethyl)- 1,2, 4- tri azine-3 , 5(2 / 7, 4 / 7)-di one

[0367] 3 -( 1 -(4-chl oro-3 -methoxyphenyl)-2-methylpropyl)- 1 -((2,4-dimethylpyridin-3 - yl)methyl)-5-methoxypyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0368] 4-(4-chloro-3-(5-azaspiro[2.3]hexan-5-yl)benzyl)-6-methoxy-2-((4-methylpyri din-3- yl)methyl)-l, 2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one

[0369] 4-(3-fluoro-4-isopropylbenzyl)-6-methoxy-2-((4-methylpyridin-3-yl)methyl)-l,2,4- tri azine-3 , 5(2 / 7, 4 / 7)-di one

[0370] 4-(3 -chi oro-4-(trifluoromethyl)benzyl)-2-((5-fluoro-2-methylpyri din-3 -yl)methyl)-6- methoxy- 1 ,2, 4-tri azine-3 , 5(2 / 7, 4 / 7)-di one

[0371] 4-(4-chloro-3-isopropylbenzyl)-6-methoxy-2-((4-methylpyridin-3-yl)methyl)-l,2,4- tri azine-3 , 5(2 / 7, 4 / 7)-di one

[0372] 3-(4-chloro-3-(pyridin-3-yl)benzyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0373] 4-(4-chloro-3-(5-azaspiro[2.3]hexan-5-yl)benzyl)-6-methoxy-2-((5-methylpyridazin-4- yl)methyl)- 1,2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one

[0374] 4-(4-chloro-3-(5-fluoropyridin-3-yl)benzyl)-6-methoxy-2-(l-(5-methylpyri din-3- yl)ethyl)- 1,2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one

[0375] 4-(4-chloro-3-(5-fluoropyridin-3-yl)benzyl)-6-methoxy-2-(l -(4-methylpyri din-3- yl)ethyl)- 1,2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one 4-( l -(4-chlorophenyl )-2-methyl propyl )-2-((2,4-di methyl pyri di n-3-yl (methyl )-6- methoxy- 1 ,2,4-triazine-3 , 5(2 7, 4 / 7)-di one

[0376] 4-(l-(4-chlorophenyl)-2-methylpropyl)-6-methoxy-2-((4-methylpyri din-3 -yl)methyl)- 1, 2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one

[0377] 4-(l-(4-chlorophenyl)-2-methylpropyl)-2-((2-(dimethylamino)pyri din-3 -yl)methyl)-6- methoxy- 1,2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one

[0378] 4-(4-chloro-3-(5-fluoropyridin-3-yl)benzyl)-6-methoxy-2-((4-methylpyri din-3- yl)methyl)-l,2,4-triazine-3,5(2 / / ,4 / / )-dione

[0379] 3-(4-chloro-3-(5-fluoropyridin-3-yl)benzyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / , 3 / )-di one

[0380] 3 -( 1 -(4-chlorophenyl)-2-methylpropyl)-5 -methoxy- 1 -((5 -methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0381] 4-(4-chloro-3-(5-fluoropyridin-3-yl)benzyl)-2-((2-(dimethylamino)pyri din-3- yl)methyl)-6-methoxy-l,2,4-triazine-3,5(2 / 7,4 / 7)-dione

[0382] 4-(3 -chi oro-4-(trifluoromethyl)benzyl)-2-((5-fluoro-4-methylpyri din-3 -yl)methyl)-6- methoxy- 1 ,2, 4-triazine-3 , 5(2 / 7, 4 / 7)-di one

[0383] 3-(4-chloro-3-(pyridin-3-yl)benzyl)-5-methoxy-l-((3-methylpyrazin-2- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0384] 3-(4-chloro-3-(pyridin-3-yl)benzyl)-5-methoxy-l-((2-methylpyridin-3- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0385] 3 -(4-chl oro-3 -(pyri din-3 -yl)benzyl)- 1 -((3 -fluoropyri din-2 -yl)methyl)-5- methoxypyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0386] 3-(4-chloro-3-isopropylbenzyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0387] 4-(l -(4-chl orophenyl)-2-methylpropyl)-6-methoxy-2-((2-(trifluoromethyl)pyri din-3- yl)methyl)-l,2,4-triazine-3,5(2 / 7,4 / 7)-dione

[0388] 4-(4-chloro-3-isopropylbenzyl)-6-m ethoxy -2-((5-methylpyridazin-4-yl)methyl)- 1,2, 4- tri azine-3 , 5(2 / 7, 4 / 7)-di one

[0389] 3 -( 1 -(4-chl orophenyl)propyl)-5 -methoxy- 1 -((3 -(trifluoromethyl)pyridin-2- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0390] 3-(l-(4-chlorophenyl)propyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0391] 3 -( 1 -(4-chl orophenyl)propyl)-5 -methoxy- 1 -((2-(trifluoromethyl)pyri din-3 - yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0392] 3 -( 1 -(4-chl orophenyl)propyl)-5 -methoxy- 1 -((4-(trifluoromethyl)pyri din-3 - yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0393] 4-(l -(4-chl orophenyl)propyl)-6-methoxy-2-((3 -(tri fluoromethyl)pyrazin-2-yl)methyl)-

[0394] 1, 2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one

[0395] 3-(l-(4-chlorophenyl)propyl)-5-methoxy-l-((2-methylpyridin-3-yl)methyl)pyrimidine-

[0396] 2,4(l / 7,3 / 7)-dione

[0397] 3-(l-(4-chlorophenyl)propyl)-l-((3-chloropyridin-4-yl)methyl)-5-methoxypyrimidine-

[0398] 2,4(l / 7,3 / 7)-dione

[0399] 4-(l -(4-chl orophenyl)propyl)-2-((3 -chi oropyridin-2-yl)methyl)-6-m ethoxy- 1,2, 4- tri azine-3 , 5(2 / 7, 4 / 7)-di one

[0400] 3-(l-(4-chlorophenyl)propyl)-5-methoxy-l-((4-methylpyridin-3-yl)methyl)pyrimidine-

[0401] 2,4(l / 7,3 / 7)-dione 3-((4-chlorophenyl)(cyclopropyl)methyl)-l-((3-chloropyridin-2-yl)methyl)-5- methoxypyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0402] 3-((4-chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-((2-(trifluoromethyl)pyri din-3- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0403] 4-((4-chl orophenyl)(cy cl opropyl)methyl)-2-((3-chloropyri din-2 -yl)methyl)-6-methoxy- l,2,4-triazine-3,5(2 / / ,4 / / )-dione

[0404] 4-((4-chlorophenyl)(cyclopropyl)methyl)-6-methoxy-2-((3-(trifluoromethyl)pyrazin-2- yl)methyl)-l,2,4-triazine-3,5(2 / / ,4 / / )-dione

[0405] 4-((4-chlorophenyl)(cyclopropyl)methyl)-2-((3-fluoropyridin-2-yl)methyl)-6-methoxy-

[0406] 1.2.4-triazine-3,5(2 / / ,4 / / )-dione

[0407] 4-(l-(4-chlorophenyl)butyl)-6-methoxy-2-((3-methylpyrazin-2-yl)methyl)-l,2,4- triazine-3 , 5(2 / , 4 / )-di one

[0408] 3-(l-(4-chlorophenyl)butyl)-5-methoxy-l-((2-methylpyridin-3-yl)methyl)pyrimidine-

[0409] 2,4(l / / ,3 / 7)-dione

[0410] 4-(l-(4-chlorophenyl)butyl)-2-((3 -chi oropyri din-2 -yl)methyl)-6-m ethoxy- 1,2, 4- tri azine-3, 5(2 / 7, 4 / 7)-di one

[0411] 3-((4-chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-((2-methylpyri din-3- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0412] 3 -( 1 -(4-chlorophenyl)butyl)-5 -methoxy- 1 -((2-(trifluoromethyl)pyri din-3 - yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0413] 4-((4-chlorophenyl)(cyclopropyl)methyl)-6-methoxy-2-((3-methylpyrazin-2- yl)methyl)-l, 2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one

[0414] 3-((4-chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-(pyridazin-4- ylmethyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0415] 4-((4-chlorophenyl)(cyclopropyl)methyl)-2-((2-hydroxypyridin-4-yl)methyl)-6- methoxy- 1 ,2, 4-tri azine-3 , 5(2 / 7, 4 / 7)-di one

[0416] 3-((4-chlorophenyl)(cyclopropyl)methyl)-l-((2-(dimethylamino)pyridin-3-yl)methyl)-

[0417] 5-methoxypyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0418] 3-((4-chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-((4-methoxypyri din-3- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0419] 3-(l-(4-chlorophenyl)butyl)-5-methoxy-l-((5-methylpyridazin-4-yl)methyl)pyrimidine-

[0420] 2,4(l / 7,3 / 7)-dione

[0421] 4-(l-(4-chlorophenyl)butyl)-6-methoxy-2-((3-(trifluoromethyl)pyrazin-2-yl)methyl)-

[0422] 1.2.4-tri azine-3, 5(2 / 7, 4 / 7)-di one

[0423] 4-((4-chlorophenyl)(cyclopropyl)methyl)-2-((3,5-difluoropyridin-2-yl)methyl)-6- methoxy- 1 ,2, 4-tri azine-3 , 5(2 / 7, 4 / 7)-di one

[0424] 3-((4-chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0425] 3-((4-chlorophenyl)(cyclopropyl)methyl)-l-((5-fluoropyridin-3-yl)methyl)-5- methoxypyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0426] 3-((4-chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-(pyrimidin-5- ylmethyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0427] 4-((4-chlorophenyl)(cyclopropyl)methyl)-2-((2-(dimethylamino)pyridin-4-yl)methyl)-

[0428] 6-methoxy-l, 2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one

[0429] 3-((4-chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-((3-methylpyrazin-2- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one 4-(cyclopropyl(4-fluorophenyl)methyl)-2-((3-fluoropyridin-2-yl)methyl)-6-methoxy- l,2,4-triazine-3,5(2Z7,4Z7)-dione

[0430] 3-(cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0431] 3-(cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l-(pyrimidin-5- ylmethyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0432] 3-(cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l-((3-methylpyrazin-2- yl)methyl)pyrimidine-2, 4(1 / , 3 / )-di one

[0433] ( / ?)-4-((4-chlorophenyl)(cyclopropyl)methyl)-2-((3-fluoropyridin-2-yl)methyl)-6- methoxy- 1 ,2,4-triazine-3 , 5(2 / 7, 4 / 7)-di one

[0434] (5)-4-((4-chlorophenyl)(cyclopropyl)methyl)-2-((3-fluoropyridin-2-yl)methyl)-6- methoxy- 1 ,2,4-triazine-3 , 5(2 / 7, 4 / 7)-di one

[0435] 3-(cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l-((4-methylpyrimidin-5- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0436] 3-(cyclopropyl(3,4-difluorophenyl)methyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0437] (7?)-3-((4-chlorophenyl)(cy cl opropyl)methyl)-5 -methoxy- 1 -((5 -m ethylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0438] (5)-3-((4-chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0439] 3-((4-chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-((4-methylpyrimidin-5- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0440] 3-(cyclopropyl(3,4-difluorophenyl)methyl)-5-methoxy-l-((3-methylpyrazin-2- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0441] (5)-3-(cyclopropyl(3,4-difluorophenyl)methyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0442] (7?)-3-(cyclopropyl(3,4-difluorophenyl)methyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0443] (5)-3-(cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0444] (7?)-3-(cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0445] 4-((4-chlorophenyl)(cyclopropyl)methyl)-6-methoxy-2-((5-methylpyridazin-4- yl)methyl)-l,2,4-triazine-3,5(2 / 7,4 / 7)-dione

[0446] 3-(cyclopropyl(2,4-difluoro-3-methoxyphenyl)methyl)-5-methoxy-l-((5- methylpyridazin-4-yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0447] (7?)-4-((4-chlorophenyl)(cyclopropyl)methyl)-6-methoxy-2-((5-methylpyridazin-4- yl)methyl)-l,2,4-triazine-3,5(2 / 7,4 / 7)-dione

[0448] (5)-4-((4-chlorophenyl)(cyclopropyl)methyl)-6-methoxy-2-((5-methylpyridazin-4- yl)methyl)-l,2,4-triazine-3,5(2 / 7,4 / 7)-dione

[0449] 4-(cyclopropyl(2,4-difluoro-3-methoxyphenyl)methyl)-6-methoxy-2-((5- methylpyridazin-4-yl)methyl)-l,2,4-triazine-3,5(2 / 7,4 / 7)-dione

[0450] 4-(cyclopropyl(4-fluorophenyl)methyl)-6-methoxy-2-((5-methylpyridazin-4- yl)methyl)-l,2,4-triazine-3,5(2 / 7,4 / 7)-dione

[0451] 4-(cyclopropyl(3,4-difluorophenyl)methyl)-6-methoxy-2-((5-methylpyridazin-4- yl)methyl)-l,2,4-triazine-3,5(2 / 7,4 / 7)-dione 3-((4-chloro-3-fluorophenyl)(cyclopropyl)methyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0452] (7?)-3-((4-chloro-3-fluorophenyl)(cyclopropyl)methyl)-5-methoxy-l-((5- methylpyridazin-4-yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0453] (5)-3-((4-chloro-3-fluorophenyl)(cyclopropyl)methyl)-5-methoxy-l-((5- methylpyridazin-4-yl)methyl)pyrimidine-2, 4(1 / , 3 / )-di one

[0454] 3-((4-chlorophenyl)(cyclobutyl)methyl)-5-methoxy-l-(pyrimidin-5- ylmethyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0455] (5)-3-((4-chlorophenyl)(cyclobutyl)methyl)-5-methoxy-l-(pyrimidin-5- ylmethyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0456] (7?)-3-((4-chlorophenyl)(cyclobutyl)methyl)-5-methoxy-l-(pyrimidin-5- ylmethyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0457] (5)-3-(cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l-((3-methylpyrazin-2- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one and

[0458] (7?)-3-(cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l-((3-methylpyrazin-2- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one.

[0459] The above list of compounds can also be represented by the following skeletal formulae:

[0460]

[0461] Preferably, the compound is one or more selected from the following list, as well as a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof or an / / -oxide form thereof:

[0462] 3 -( 1 -(4-chl oro-3 -methoxyphenyl)ethyl)-5 -methoxy- 1 -((4-methoxypyri din-3 - yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0463] 3 -( 1 -(4-chl oro-3 -methoxyphenyl)ethyl)-5 -methoxy- 1 -((4-(trifluoromethyl)pyri din-3 - yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0464] 3-(4-chloro-3-methoxybenzyl)-5-methoxy-l-(l-(5-methylpyridin-3- yl)ethyl)pyrimidine-2, 4(17 / , 3 / / )-di one 5 -m ethoxy-3 -(3 -methoxy -4-(trifluoromethyl)b enzyl)- 1 -((4-methylpyri din-3 - yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0465] 5-methoxy-3-(3-methoxy-4-(trifluoromethyl)benzyl)-l-(l-(5-methylpyri din-3- yl)ethyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0466] 3-(4-fluoro-3-(trifluoromethyl)benzyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / , 3 / )-di one

[0467] 3-(4-chloro-3-(trifluoromethoxy)benzyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0468] 3-(4-chloro-3-(trifluoromethyl)benzyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0469] 3-(4-chloro-3-fluorobenzyl)-5-methoxy-l-((5-methylpyridazin-4-yl)methyl)pyrimidine-

[0470] 2,4(l / 7,3 / 7)-dione

[0471] 3-(3-chloro-4-(trifluoromethyl)benzyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0472] 3-(4-chloro-3-isopropoxybenzyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0473] 5-methoxy-3-(3-methoxy-4-(trifluoromethyl)benzyl)-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0474] 3 -( 1 -(4-chl oro-3 -methoxyphenyl)ethyl)- 1 -((2-(dimethylamino)pyri din-3 -y l)methyl)-5 - methoxypyrimidine-2, 4(1 / 7, 3 / 7)-di one l-((2-(dimethylamino)pyridin-3-yl)methyl)-5-methoxy-3-(3-methoxy-4-

[0475] (trifluoromethyl)benzyl)pyrimidine-2,4(lH,3H)-dione

[0476] 3-(4-chloro-3-cyclopropylbenzyl)-5-methoxy-l -((4-methylpyri din-3- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0477] 3-(4-chloro-3-cyclopropylbenzyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0478] 3 -(3 -chi oro-4-(trifluoromethyl)benzyl)-5 -methoxy- l-((2-methylpyri din-3 - yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0479] 3-(l -(4-chloro-3-methoxyphenyl)-2-methylpropyl)-5-methoxy-l -((4-methylpyri din-3- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0480] 3 -( 1 -(4-chl oro-3 -methoxyphenyl)-2-methylpropyl)- 1 -((2,4-dimethylpyridin-3 - yl)methyl)-5-methoxypyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0481] 3-(4-chloro-3-(pyridin-3-yl)benzyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0482] 3-(4-chloro-3-(5-fluoropyridin-3-yl)benzyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0483] 3 -( 1 -(4-chl orophenyl)-2-methylpropyl)-5 -methoxy- 1 -((5 -methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0484] 3-(4-chloro-3-(pyridin-3-yl)benzyl)-5-methoxy-l-((3-methylpyrazin-2- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0485] 3-(4-chloro-3-(pyridin-3-yl)benzyl)-5-methoxy-l-((2-methylpyridin-3- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0486] 3 -(4-chl oro-3 -(pyri din-3 -yl)benzyl)- 1 -((3 -fluoropyri din-2 -yl)methyl)-5- methoxypyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0487] 3-(4-chloro-3-isopropylbenzyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one 3 -( 1 -(4-chlorophenyl)propyl)-5 -methoxy- 1 -((3 -(trifluoromethyl)pyridin-2- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0488] 3-(l-(4-chlorophenyl)propyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0489] 3 -( 1 -(4-chlorophenyl)propyl)-5 -methoxy- 1 -((2-(trifluoromethyl)pyri din-3 - yl)methyl)pyrimidine-2, 4(1 / , 3 / )-di one

[0490] 3 -( 1 -(4-chlorophenyl)propyl)-5 -methoxy- 1 -((4-(trifluoromethyl)pyri din-3 - yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0491] 3-(l-(4-chlorophenyl)propyl)-5-methoxy-l-((2-methylpyridin-3-yl)methyl)pyrimidine-

[0492] 2,4(l / 7,3 / 7)-dione

[0493] 3-(l-(4-chlorophenyl)propyl)-l-((3-chloropyridin-4-yl)methyl)-5-methoxypyrimidine-

[0494] 2,4(l / 7,3 / 7)-dione

[0495] 3-(l-(4-chlorophenyl)propyl)-5-methoxy-l-((4-methylpyridin-3-yl)methyl)pyrimidine-

[0496] 2,4(l / 7,3 / 7)-dione

[0497] 3-((4-chlorophenyl)(cyclopropyl)methyl)-l-((3-chloropyridin-2-yl)methyl)-5- methoxypyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0498] 3-((4-chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-((2-(trifluoromethyl)pyri din-3- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0499] 3-(l-(4-chlorophenyl)butyl)-5-methoxy-l-((2-methylpyridin-3-yl)methyl)pyrimidine-

[0500] 2,4(l / 7,3 / 7)-dione

[0501] 3-((4-chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-((2-methylpyri din-3- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0502] 3 -( 1 -(4-chlorophenyl)butyl)-5 -methoxy- 1 -((2-(trifluoromethyl)pyri din-3 - yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0503] 3-((4-chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-(pyridazin-4- ylmethyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0504] 3-((4-chlorophenyl)(cyclopropyl)methyl)-l-((2-(dimethylamino)pyridin-3-yl)methyl)-

[0505] 5-methoxypyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0506] 3-((4-chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-((4-methoxypyri din-3- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0507] 3-(l-(4-chlorophenyl)butyl)-5-methoxy-l-((5-methylpyridazin-4-yl)methyl)pyrimidine-

[0508] 2,4(l / 7,3 / 7)-dione

[0509] 3-((4-chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0510] 3-((4-chlorophenyl)(cyclopropyl)methyl)-l-((5-fluoropyridin-3-yl)methyl)-5- methoxypyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0511] 3-((4-chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-(pyrimidin-5- ylmethyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0512] 3-((4-chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-((3-methylpyrazin-2- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0513] 3-(cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0514] 3-(cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l-(pyrimidin-5- ylmethyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0515] 3-(cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l-((3-methylpyrazin-2- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one 3-(cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l-((4-methylpyrimidin-5- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0516] 3-(cyclopropyl(3,4-difluorophenyl)methyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0517] ( / ?)-3-((4-chlorophenyl)(cy cl opropyl)methyl)-5 -methoxy- 1 -((5 -m ethylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / , 3 / )-di one

[0518] (5)-3-((4-chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0519] 3-((4-chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-((4-methylpyrimidin-5- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0520] 3-(cyclopropyl(3,4-difluorophenyl)methyl)-5-methoxy-l-((3-methylpyrazin-2- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0521] (5)-3-(cyclopropyl(3,4-difluorophenyl)methyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0522] (7?)-3-(cyclopropyl(3,4-difluorophenyl)methyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0523] (5)-3-(cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0524] (7?)-3-(cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0525] 3-(cyclopropyl(2,4-difluoro-3-methoxyphenyl)methyl)-5-methoxy-l-((5- methylpyridazin-4-yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0526] 3-((4-chloro-3-fluorophenyl)(cyclopropyl)methyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0527] (7?)-3-((4-chloro-3-fluorophenyl)(cyclopropyl)methyl)-5-methoxy-l-((5- methylpyridazin-4-yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0528] (5)-3-((4-chloro-3-fluorophenyl)(cyclopropyl)methyl)-5-methoxy-l-((5- methylpyridazin-4-yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0529] 3-((4-chlorophenyl)(cyclobutyl)methyl)-5-methoxy-l-(pyrimidin-5- ylmethyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0530] (5)-3-((4-chlorophenyl)(cyclobutyl)methyl)-5-methoxy-l-(pyrimidin-5- ylmethyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0531] (7?)-3-((4-chlorophenyl)(cyclobutyl)methyl)-5-methoxy-l-(pyrimidin-5- ylmethyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0532] (5)-3-(cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l-((3-methylpyrazin-2- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one and

[0533] (A’)-3-(cycl opropyl(4-fluorophenyl (methyl )-5-methoxy- l -((3 -methylpyrazin-2- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one.

[0534] The above list of compounds can also be represented by the following skeletal formulae:

[0535]

[0536] Preferably, the compound is one or more selected from the following list, as well as a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof or an 7V-oxide form thereof:

[0537] 4-(l-(4-chloro-3-methoxyphenyl)ethyl)-6-methoxy-2-(l-(4-methylpyridin-3-yl)ethyl)- l,2,4-triazine-3,5(2Z7,4J7)-dione

[0538] 2-((3-fluoropyridin-4-yl)methyl)-6-methoxy-4-(l-(3-methoxy-4-

[0539] (trifluoromethyl)phenyl)ethyl)-l,2,4-triazine-3,5(2JH,4J7)-dione

[0540] 4-(l-(4-chl oro-3 -methoxyphenyl)ethyl)-6-m ethoxy -2-((3-methylpyrazin-2-yl)methyl)- l,2,4-triazine-3,5(2Z7,4J7)-dione

[0541] 4-(l-(4-chl oro-3 -methoxyphenyl)ethyl)-2-((3 -chi oropyri din-2 -yl)methyl)-6-m ethoxy-

[0542] 1.2.4-triazine-3,5(2Z7,4J7)-dione

[0543] 4-(4-chl oro-3 -methoxybenzyl)-2-((2,6-dimethylpyri din-3 -yl)methyl)-6-methoxy- 1,2, 4- tri azine-3, 5(277, 4J7)-di one

[0544] 4-(l -(4-chloro-3-methoxyphenyl)ethyl)-2-((3,5-difluoropyri din-2 -yl)methyl)-6- methoxy- 1, 2, 4-triazine-3, 5(277, 477)-di one 4-(l-(4-chloro-3-methoxyphenyl)ethyl)-2-((5-fluoropyridin-3-yl)methyl)-6-methoxy-

[0545] 1.2.4-triazine-3,5(277,477)-dione

[0546] 4-(l-(4-chloro-3-methoxyphenyl)ethyl)-6-methoxy-2-((5-(trifluoromethyl)pyri din-3- yl)methyl)-l,2,4-triazine-3,5(277,477)-dione

[0547] 4-( 1 -(4-chloro-3 -methoxyphenyl)ethyl)-6-m ethoxy -2-((3 -(tri fluoromethyl)pyrazin-2- yl)methyl)-l,2,4-triazine-3,5(277,477)-dione

[0548] 4-(l-(4-chloro-3-methoxyphenyl)ethyl)-6-methoxy-2-(l-(6-methylpyridin-3-yl)ethyl)- l,2,4-triazine-3,5(277,477)-dione 4-(l-(4-chloro-3-methoxyphenyl)ethyl)-6-methoxy-2-(l-(pyridin-3-yl)ethyl)-l,2,4- triazine-3 , 5(2H, 4 / 7)-di one

[0549] 4-(l-(4-chl oro-3 -methoxyphenyl)ethyl)-2-((2, 4-dimethylpyri din-3 -yl)methyl)-6- methoxy- 1,2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one

[0550] 4-(l-(4-chl oro-3 -methoxyphenyl)ethyl)-2-((3-cy cl opropyl-6-methylpyridazin-4- yl)methyl)-6-methoxy- 1,2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one

[0551] 4-(4-chloro-3-methoxybenzyl)-2-(l-(5-fluoropyridin-3-yl)ethyl)-6-methoxy-l,2,4- tri azine-3, 5(2 / 7, 4 / 7)-di one

[0552] 4-(l-(4-chloro-3-methoxyphenyl)ethyl)-2-((3-isopropoxypyridazin-4-yl)methyl)-6- methoxy- 1 ,2, 4-triazine-3 , 5(2 / 7, 4 / Z)-di one

[0553] 4-(l-(4-chloro-3-methoxyphenyl)ethyl)-6-methoxy-2-((3-methoxy-5-methylpyridazin-

[0554] 4-yl)methyl)-l,2,4-triazine-3,5(2 / / ,4 / / )-dione

[0555] 4-(3-chloro-4-(trifluoromethyl)benzyl)-2-((2,4-dimethylpyridin-3-yl)methyl)-6- methoxy- 1,2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one

[0556] 4-(3-chloro-4-(trifluoromethyl)benzyl)-6-methoxy-2-(l -(4-methylpyri din-3 -yl)ethyl)-

[0557] 1.2.4-triazine-3,5(2 / / ,4 / / )-dione

[0558] 4-(l-(4-chlorophenyl)propyl)-6-methoxy-2-((4-methylpyri din-3 -yl)m ethyl)- 1,2, 4- tri azine-3, 5(2 7, 4 7)-di one

[0559] 4-(4-chloro-3-(5-azaspiro[2.3]hexan-5-yl)benzyl)-6-methoxy-2-((4-methylpyri din-3- yl)methyl)-l, 2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one

[0560] 4-(3-fluoro-4-isopropylbenzyl)-6-methoxy-2-((4-methylpyridin-3-yl)methyl)-l,2,4- tri azine-3 , 5(2 / 7, 4 / 7)-di one

[0561] 4-(3 -chi oro-4-(trifluoromethyl)benzyl)-2-((5-fluoro-2-methylpyri din-3 -yl)methyl)-6- methoxy- 1,2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one

[0562] 4-(4-chloro-3-isopropylbenzyl)-6-methoxy-2-((4-methylpyridin-3-yl)methyl)-l,2,4- tri azine-3 , 5(2 / 7, 4 / 7)-di one

[0563] 4-(4-chloro-3-(5-azaspiro[2.3]hexan-5-yl)benzyl)-6-methoxy-2-((5-methylpyridazin-4- yl)methyl)- 1,2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one

[0564] 4-(4-chloro-3-(5-fluoropyridin-3-yl)benzyl)-6-methoxy-2-(l-(5-methylpyri din-3- yl)ethyl)- 1,2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one

[0565] 4-(4-chloro-3-(5-fluoropyridin-3-yl)benzyl)-6-methoxy-2-(l -(4-methylpyri din-3- yl)ethyl)- 1,2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one

[0566] 4-(l-(4-chlorophenyl)-2-methylpropyl)-2-((2, 4-dimethylpyri din-3 -yl)methyl)-6- methoxy- 1,2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one

[0567] 4-(l-(4-chlorophenyl)-2-methylpropyl)-6-methoxy-2-((4-methylpyri din-3 -yl)methyl)-

[0568] 1.2.4-tri azine-3, 5(2 / 7, 4 / 7)-di one

[0569] 4-(l-(4-chlorophenyl)-2-methylpropyl)-2-((2-(dimethylamino)pyri din-3 -yl)methyl)-6- methoxy- 1,2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one 4-(4-chloro-3-(5-fluoropyridin-3-yl)benzyl)-6-methoxy-2-((4-methylpyri din-3- yl)methyl)- 1,2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one

[0570] 4-(4-chloro-3-(5-fluoropyridin-3-yl)benzyl)-2-((2-(dimethylamino)pyri din-3- yl)methyl)-6-methoxy- 1,2, 4-tri azine-3, 5(2 / 7, 477)-di one

[0571] 4-(3 -chi oro-4-(trifluoromethyl)benzyl)-2-((5-fluoro-4-methylpyri din-3 -yl)methyl)-6- methoxy- 1,2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one

[0572] 4-(l-(4-chlorophenyl)-2-methylpropyl)-6-methoxy-2-((2-(trifluoromethyl)pyri din-3- yl)methyl)- 1,2, 4-tri azine-3, 5(2 / 7, 4 7)-di one 4-(4-chloro-3-isopropylbenzyl)-6-m ethoxy -2-((5-methylpyridazin-4-yl)methyl)- 1,2, 4- triazine-3 , 5(2H, 4 / / )-di one

[0573] 4-(l-(4-chlorophenyl)propyl)-6-methoxy-2-((3-(trifluoromethyl)pyrazin-2-yl)methyl)-

[0574] 1,2, 4-tri azine-3, 5(2 / / , 4 / / )-di one

[0575] 4-(l-(4-chlorophenyl)propyl)-2-((3 -chi oropyridin-2-yl)methyl)-6-m ethoxy- 1,2, 4- tri azine-3 , 5(2H, 4 / / )-di one

[0576] 4-((4-chl orophenyl)(cy cl opropyl)methyl)-2-((3-chloropyri din-2 -yl)methyl)-6-methoxy-

[0577] 1,2, 4-tri azine-3, 5(2 / / , 4 / / )-di one

[0578] 4-((4-chlorophenyl)(cyclopropyl)methyl)-6-methoxy-2-((3-(trifluoromethyl)pyrazin-2- yl)methyl)- 1,2, 4-tri azine-3, 5(2 / / , 4 / / )-di one

[0579] 4-((4-chlorophenyl)(cyclopropyl)methyl)-2-((3-fluoropyridin-2-yl)methyl)-6-methoxy-

[0580] 1, 2, 4-tri azine-3, 5(2 / / , 4 / Z)-di one

[0581] 4-(l-(4-chlorophenyl)butyl)-6-methoxy-2-((3-methylpyrazin-2-yl)methyl)-l,2,4- tri azine-3 , 5(2 / / , 4 / Z)-di one

[0582] 4-(l-(4-chlorophenyl)butyl)-2-((3 -chi oropyri din-2 -yl)methyl)-6-m ethoxy- 1,2, 4- tri azine-3 , 5(2 / / , 4 / / )-di one

[0583] 4-((4-chlorophenyl)(cyclopropyl)methyl)-6-methoxy-2-((3-methylpyrazin-2- yl)methyl)- 1,2, 4-tri azine-3, 5(2 / / , 4 / / )-di one

[0584] 4-((4-chlorophenyl)(cyclopropyl)methyl)-2-((2-hydroxypyridin-4-yl)methyl)-6- methoxy- 1 ,2, 4-tri azine-3 , 5(2 / / , 4 / / )-di one

[0585] 4-(l-(4-chlorophenyl)butyl)-6-methoxy-2-((3-(trifluoromethyl)pyrazin-2-yl)methyl)-

[0586] 1,2, 4-tri azine-3, 5(2 / / , 4 / / )-di one

[0587] 4-((4-chlorophenyl)(cyclopropyl)methyl)-2-((3,5-difluoropyridin-2-yl)methyl)-6- methoxy- 1 ,2, 4-tri azine-3 , 5(2 / / , 4 / / )-di one

[0588] 4-((4-chlorophenyl)(cyclopropyl)methyl)-2-((2-(dimethylamino)pyridin-4-yl)methyl)-

[0589] 6-methoxy-l, 2, 4-tri azine-3, 5(2 / / , 4 / / )-di one

[0590] 4-(cyclopropyl(4-fluorophenyl)methyl)-2-((3-fluoropyridin-2-yl)methyl)-6-methoxy-

[0591] 1,2, 4-tri azine-3, 5(2 / / , 4 / / )-di one

[0592] ( / ?)-4-((4-chlorophenyl)(cyclopropyl)methyl)-2-((3-fluoropyridin-2-yl)methyl)-6- methoxy- 1 ,2, 4-tri azine-3 , 5(2 / / , 4 / / )-di one

[0593] (5)-4-((4-chlorophenyl)(cyclopropyl)methyl)-2-((3-fluoropyridin-2-yl)methyl)-6- methoxy- 1 ,2, 4-tri azine-3 , 5(2 / / , 4 / / )-di one

[0594] 4-((4-chlorophenyl)(cyclopropyl)methyl)-6-methoxy-2-((5-methylpyridazin-4- yl)methyl)- 1,2, 4-tri azine-3, 5(2 / / , 4 / / )-di one

[0595] ( ?)-4-((4-chlorophenyl)(cyclopropyl)methyl)-6-methoxy-2-((5-methylpyridazin-4- yl)methyl)- 1,2, 4-tri azine-3, 5(2 / / , 4 / / )-di one

[0596] (5)-4-((4-chlorophenyl)(cyclopropyl)methyl)-6-methoxy-2-((5-methylpyridazin-4- yl)methyl)- 1,2, 4-tri azine-3, 5(2 / / , 4 / / )-di one

[0597] 4-(cyclopropyl(2,4-difluoro-3-methoxyphenyl)methyl)-6-methoxy-2-((5- methylpyridazin-4-yl)methyl)- 1,2, 4-tri azine-3, 5(2 / / , 4 / / )-di one

[0598] 4-(cyclopropyl(4-fluorophenyl)methyl)-6-methoxy-2-((5-methylpyridazin-4- yl)methyl)-l,2,4-triazine-3,5(2 / / ,4 / / )-dione and

[0599] 4-(cyclopropyl(3,4-difluorophenyl)methyl)-6-methoxy-2-((5-methylpyridazin-4- yl)methyl)- 1,2, 4-tri azine-3, 5(2 / / , 4 / / )-di one. The above list of compounds can also be represented by the following skeletal formulae:

[0600]

[0601] Preferably, the compound is one or more selected from the following list, as well as a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof or an 7V-oxide form thereof: 4-( 1 -(4-chl oro-3 -methoxyphenyl)ethyl)-2-(5 , 5 -dimethyltetrahy drofuran-3 -y 1 )- 6 - methoxy- 1 ,2, 4-triazine-3 , 5(2 / 7, 4 / 7)-di one

[0602] 4-(4-chl oro-3 -(pyri din-3 -yl)benzyl)-6-methoxy-2-(tetrahydro-2 / 7-pyran-4-yl)- 1,2, 4- tri azine-3, 5(2 / 7, 4 / 7)-di one

[0603] 4-(l -(4-chl orophenyl)propyl)-6-methoxy-2-(tetrahydro-2 / 7-pyran-4-yl)- 1,2, 4-tri azine-

[0604] 3,5(2 / 7,4 / 7)-dione

[0605] 3-(4-chloro-3-(pyridin-3-yl)benzyl)-5-methoxy-l-(tetrahydro-2 / / -pyran-4- yl)pyrimidine-2,4(l / / ,3 / / )-dione

[0606] 4-(l-(4-chlorophenyl)-2-methylpropyl)-6-methoxy-2-(tetrahydro-2 / / -pyran-4-yl)-l,2,4- triazine-3 , 5(2 / , 4 / )-di one

[0607] 3-(4-chloro-3-(4-methylpyridin-3-yl)benzyl)-5-methoxy-l-(tetrahydro-2 / 7-pyran-4- yl)pyrimidine-2,4(l / / ,3 / 7)-dione

[0608] 3-(l-(4-chlorophenyl)propyl)-5-methoxy-l-(tetrahydro-2 / 7-pyran-4-yl)pyrimidine-

[0609] 2,4(l / / ,3 / 7)-dione

[0610] 3 -( 1 -(4-chl orophenyl)-2-methylpropyl)-5 -methoxy- 1 -(tetrahy dro-2 / 7-pyran-4- yl)pyrimidine-2,4(l / / ,3 / 7)-dione

[0611] 4-(l-(4-chlorophenyl)cyclopropyl)-6-methoxy-2-(tetrahydro-2 / 7-pyran-4-yl)-l,2,4- tri azine-3, 5(2 / 7, 4 / 7)-di one

[0612] 4-( 1 -(4-chl orophenyl)propyl)-6-methoxy-2-(oxepan-4-yl)- 1 ,2, 4-tri azine-3 , 5 (2 / 7, 4 / 7)- dione

[0613] 4-((4-chlorophenyl)(cyclopropyl)methyl)-6-methoxy-2-(tetrahydro-2 / 7-pyran-4-yl)-

[0614] 1,2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one

[0615] 3-((4-chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-(tetrahydro-2 / 7-pyran-4- yl)pyrimidine-2,4(l / 7,3 / 7)-dione

[0616] 3-(cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l-(tetrahydro-2 / 7-pyran-4- yl)pyrimidine-2,4(l / 7,3 / 7)-dione

[0617] (5)-4-((4-chlorophenyl)(cyclopropyl)methyl)-6-methoxy-2-(tetrahydro-2 / 7-pyran-4-yl)-

[0618] 1,2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one

[0619] (7?)-4-((4-chlorophenyl)(cyclopropyl)methyl)-6-methoxy-2-(tetrahydro-2 / 7-pyran-4-yl)-

[0620] 1,2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one

[0621] 3-(l-(4-chlorophenyl)butyl)-5-methoxy-l -(tetrahy dro-2 / 7-pyran-4-yl)pyrimidine-

[0622] 2,4(l / 7,3 / 7)-dione

[0623] 4-(l -(4-chl orophenyl)butyl)-6-methoxy-2-(tetrahydro-2Z7-pyran-4-yl)- 1,2, 4-tri azine-

[0624] 3 , 5 (2 / 7,4 / 7)-dione

[0625] (5)-3-((4-chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-(tetrahydro-2 / 7-pyran-4- yl)pyrimidine-2,4(l / 7,3 / 7)-dione

[0626] (7?)-3-((4-chlorophenyl)(cyclopropyl)methyl)-5 -methoxy- 1 -(tetrahy dro-2 / 7-pyran-4- yl)pyrimidine-2,4(l / 7,3 / 7)-dione

[0627] 4-((4-chlorophenyl)(cyclobutyl)methyl)-6-methoxy-2-(tetrahydro-2 / 7-pyran-4-yl)-

[0628] 1,2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one

[0629] (7?)-3-(cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l-(tetrahydro-2 / 7-pyran-4- yl)pyrimidine-2,4(l / 7,3 / 7)-dione

[0630] (5)-3-(cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l-(tetrahydro-2 / 7-pyran-4- yl)pyrimidine-2,4(l / 7,3 / 7)-dione

[0631] 4-(cyclopropyl(3,4-difluorophenyl)methyl)-6-methoxy-2-(tetrahydro-2 / 7-pyran-4-yl)-

[0632] 1,2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one 3-(cyclopropyl(3,4-difluorophenyl)methyl)-5-methoxy-l-(tetrahydro-2J / -pyran-4- yl)pyrimidine-2,4( l / / ,3 / / )-dione

[0633] (A>)-3-(cyclopropyl(3,4-difluorophenyl)methyl)-5-methoxy-l-(tetrahydro-2 / / -pyran-4- yl)pyrimidine-2,4( l / / ,3 / / )-dione

[0634] (5)-3-(cyclopropyl(3,4-difluorophenyl)methyl)-5-methoxy-l-(tetrahydro-2J / -pyran-4- yl)pyrimidine-2,4( l / / ,3 / / )-dione

[0635] (7?)-3-(l-(4-chlorophenyl)propyl)-5-methoxy-l-(tetrahydro-2J / -pyran-4-yl)pyrimidine-

[0636] 2,4(U / ,3J7)-dione

[0637] (5)-3-(l-(4-chlorophenyl)propyl)-5-methoxy-l-(tetrahydro-2J7-pyran-4-yl)pyrimidine-

[0638] 2,4(U / ,3J7)-dione

[0639] (5)-4-((4-chlorophenyl)(cyclobutyl)methyl)-6-methoxy-2-(tetrahydro-2J / -pyran-4-yl)- l,2,4-triazine-3,5(2J / ,4J7)-dione

[0640] (A>)-4-((4-chlorophenyl)(cyclobutyl)methyl)-6-methoxy-2-(tetrahydro-2 / / -pyran-4-yl)-

[0641] 1.2.4-triazine-3,5(2J / ,4J7)-dione

[0642] 4-(cyclobutyl(4-fluorophenyl)methyl)-6-methoxy-2-(tetrahydro-2J / -pyran-4-yl)-l,2,4- triazine-3 , 5(2H, 4J7)-di one

[0643] CS')-4-(cyclobiityl(4-fliiorophenyl)methyl)-6-methoxy-2-(tetrahydro-2 / / -pyran-4-yl)-

[0644] 1.2.4-triazine-3,5(2Z / ,4J7)-dione

[0645] (A>)-4-(cyclobiityl(4-fliiorophenyl)methyl)-6-methoxy-2-(tetrahydro-2 / / -pyran-4-yl)-

[0646] 1.2.4-triazine-3,5(2Z / ,4J7)-dione and

[0647] 4-(cyclobutyl(3,4-difluorophenyl)methyl)-6-methoxy-2-(tetrahydro-2J7-pyran-4-yl)-

[0648] 1.2.4-triazine-3,5(2Z / ,4J7)-dione.

[0649] The above list of compounds can also be represented by the following skeletal formulae:

[0650]

[0651] The compounds according to any statement above may exhibit GABAB modulator activity. The disclosed compounds also include all pharmaceutically acceptable isotopic variations, in which at least one atom is replaced by an atom having the same atomic number, but an atomic mass different from the atomic mass usually found in nature. Examples of isotopes suitable for inclusion in the disclosed compounds include, without limitation, isotopes of hydrogen, such as2H and3H; isotopes of carbon, such asnC,13C and14C; isotopes of nitrogen, such as15N; isotopes of oxygen, such as17O and18O; isotopes of phosphorus, such as31P,32P and33P; isotopes of sulfur, such as35S; isotopes of fluorine, such as18F; isotopes of chlorine, such as36C1; and isotopes of iodine, such as125I. The invention includes various isotopically labelled compounds as defined herein, for example those into which radioactive isotopes, such as3H and14C, or those into which non-radioactive isotopes, such as2H and13C are present.

[0652] Such isotopically labelled compounds are useful in metabolic studies (with14C), reaction kinetic studies (with for example2H or3H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular,nC,18F,15O and13N or labelled compounds may be particularly desirable for PET studies for examining substrate receptor occupancy. Further, substitution with heavier isotopes, particularly deuterium (e.g.,2H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements or an improvement in therapeutic index. It is understood that deuterium in this context is regarded as a substituent of a compound of Formula (I) to (V). Isotopically-labelled compounds of Formula (I) to (V) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using appropriate isotopically-labelled reagents in place of the non-labelled reagent previously employed.

[0653] This present invention provides novel compounds of Formula (I) as defined herein; invention compounds are gamma-aminobutyric acid type B receptor (“GABAB”) modulators (enhancers); in particular, they are positive allosteric modulators of GABAB receptors, which are useful for treating or preventing diseases or disorders of the central nervous system. The compounds of the present invention do not appear to bind to the GABA recognition site, the orthosteric ligand site, but instead to an allosteric site within the seven-transmembrane region of the receptor. In the presence of GABA or an agonist of GABAB receptor, the compounds of this invention potentiate the GABAB receptor response.

[0654] In an aspect of the present invention there is provided a pharmaceutical composition comprising a compound according to any statement set out above. The pharmaceutical composition may further comprise a pharmaceutically acceptable carrier and / or excipient. The pharmaceutical composition may comprise a therapeutically effective amount of the compound according to any statement set out above.

[0655] The pharmaceutical composition may be for use in therapy.

[0656] In an aspect of the present invention there is provided a method of treating or preventing a condition in a mammal, comprising administering to a mammal in need of such treatment or prevention, an effective amount of a compound / composition according to any statement set out above.

[0657] The treatment or prevention may be affected or facilitated by the modulatory effect of a GABAB modulator such as a GABAB positive allosteric modulator.

[0658] The condition may be one or more of a central nervous system disorder.

[0659] The condition may be a substance use disorder (SUD). The substance use disorder may be alcohol use disorder (AUD), which can include alcohol craving, alcohol abuse, alcohol dependence, alcohol withdrawal, alcohol withdrawal symptoms (alcohol withdrawal delirium), and alcohol-induced psychotic disorder; opioid use disorder (OUD), which can include opioid craving, opioid abuse, opioid dependence, and opioid withdrawal; cannabis use disorder (CUD), which can include cannabis craving, cannabis abuse, cannabis dependence, and cannabis withdrawal; and stimulant use disorder, which can include stimulant craving, stimulant abuse, stimulant dependence, stimulant addiction, and stimulant withdrawal. The opioid can be a street drug (e.g., heroin) or a prescription drug (e.g., fentanyl, oxycodone, hydrocodone, hydromorphone, oxymorphone, meperidine, morphine, codeine, and methadone), or derivatives of the same. The stimulant can be cocaine, nicotine, amphetamine, methamphetamine, cathinone, or derivatives of the same.

[0660] The condition may be an addiction disorder. The addiction disorder may be gambling addiction, gaming addiction, sex addiction, screen addiction, and social media addiction.

[0661] The addiction disorder may also be food addiction, and binge-eating disorder.

[0662] The treatment may comprise any one or more of suppressing withdrawal symptoms, eliminating withdrawal symptoms, reducing craving, eliminating craving, reducing use, preventing use, and mitigating relapse.

[0663] The condition may be an anxiety disorder. The anxiety disorder may be one or more of agoraphobia, generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), panic disorder, posttraumatic stress disorder (PTSD), social phobia, other phobias, and substance-induced anxiety disorder.

[0664] The condition may be a psychotic disorder. The psychotic disorder may be schizophrenia, delusional disorder, schizoaffective disorder, schizophreniform disorder, and substance-induced psychotic disorder. The condition may be a personality disorders. The personality disorder may be obsessive-compulsive personality disorder, schizoid disorder, schizotypal disorder and attention-deficit / hyperactivity disorder.

[0665] The condition may be a neurodevelopmental disorders (such as autism spectrum disorder, Fragile X syndrome). The condition may be narcolepsy.

[0666] The condition may be neuropathic pain associated with SUD; and polysubstance use disorders or multiple drug use disorders.

[0667] In a further aspect of the present invention, there is provided a method of treating, preventing, ameliorating, controlling or reducing the risk of various neurological and psychiatric disorders associated with GABA dysfunction in a mammal, comprising administering to a mammal in need of such treatment or prevention, an effective amount of a compound / composition according to any statement set out above.

[0668] The treatment or prevention may be affected or facilitated by the modulatory effect of GAB AB positive allosteric modulators.

[0669] The condition may be one or more of a central nervous system disorder. The condition may be any of the conditions according to any statement set out above.

[0670] The present invention relates to the use of a compound or a pharmaceutical composition for the manufacture of a medicament. The present invention relates to the use of a compound or a pharmaceutical composition in the manufacture of a medicament for a method of treatment or prevention as defined in any statement set out above.

[0671] In a further aspect of the present invention, there is provided the compounds or compositions as set out in any statement above for use as a medicament.

[0672] In a further aspect of the present invention, there is provided the compounds or compositions as set out in any statement above for use in a method of treatment or prevention as defined in any statement set out above.

[0673] The terms “treating,” “treatment,” and the like are used herein to generally mean obtaining a desired pharmacological and physiological effect and refer to complete elimination as well as to any clinically or quantitatively measurable reduction in the condition for which the subject is being treated. “Treatment” is an intervention performed with the intention of slowing or preventing the development or altering the pathology or symptoms of a condition. More specifically, the compounds described herein can be provided in a therapeutically effective amount to inhibit the disorder (i.e., arrest or reduce the development of the disorder or its clinical symptoms) or relieve the disorder (i.e., cause regression of the disorder or its clinical symptoms).

[0674] In the context of substance use disorders, “therapeutically effective” amounts of the compound or composition can refer to amounts that are effective in: (a) treating the substance use disorder; (b) suppressing withdrawal symptoms; (c) eliminating withdrawal symptoms; (d) reducing craving; (e) eliminating craving; (f) reducing use; (g) preventing use (i.e. inducing abstinence); (h) mitigating relapse; or (i) a combination of two or more of the foregoing. DEFINITION OF TERMS

[0675] Listed below are definitions of various terms used in the specification and claims to describe the present invention.

[0676] For the avoidance of doubt it is to be understood that in this specification “(Ci-Ce)” means a carbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms. “(Co-Ce)” means a carbon radical 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 sulphur atom.

[0677] In the case where a subscript is the integer 0 (zero) the radical to which the subscript refers, indicates that the radical is absent, i.e. there is a direct bond between the radicals.

[0678] In the case where a subscript is the integer 0 (zero) and the radical to which the subscript refers is alkyl, this indicates the radical is a hydrogen atom.

[0679] In this specification, unless stated otherwise, the term “bond” refers to a saturated covalent bond. When two or more bonds are adjacent to one another, they are assumed to be equal to one bond. For example, a radical -A-B-, wherein both A and B may be a bond, the radical is depicting a single bond.

[0680] In this specification, unless stated otherwise, the term “alkyl” includes both straight and branched chain alkyl radicals and may be methyl, ethyl, / / -propyl, z-propyl, / / -butyl, i- butyl, 5-butyl, / -butyl, / / -pentyl, / -pentyl, / -pentyl, / / eo-pentyl, / / -hexyl, / -hexyl or t- hexyl. In this specification, unless stated otherwise, the term “deuterioalkyl,” as used herein, means an alkyl group, as defined herein, in which one or more hydrogen atoms in the alkyl are the isotope deuterium, i.e.,2H. Representative examples of deuterioalkyl include -CD3, -CH2D, -CHD2, -CH2CD3, and -CD2CD3.

[0681] In this specification, unless stated otherwise, the term “alkylene” includes both straight and branched difunctional saturated hydrocarbon radicals and may be methylene (-CH2- ), ethylene (-CH2-CH2-), / / -propylene (-CH2-CH2-CH2-), z-propylene (-CH-(CH3)-CH2- ), / / -butylene (-CH2-CH2-CH2-CH2-), z-butylene (-CH2-CH-(CH3)-CH2-), Z-butylene (- CH2-C-(CH3)-CH2-), / / -pentylene (-CH2-CH2-CH2-CH2-CH2-), z-pentylene (-CH2- CH(CH3)-CH2-CH2-), z / eo-pentylene (-CH2-C(CH3)2-CH2-), z / -hexylene (-CH2-CH2- CH2-CH2-CH2-CH2-), z-hexylene (-CH2-CH-(CH3)-CH2-CH2-CH2-) or z / eo-hexylene (- CH2-C(CH3)2-CH2-CH2-).

[0682] In this specification, unless stated otherwise, the term “cycloalkyl” refers to an optionally substituted carbocycle containing no heteroatoms, including mono-, bi-, and tricyclic saturated carbocycles, as well as fused ring systems. Such fused ring systems can include one ring that is partially or fully unsaturated such as a benzene ring to form fused ring systems such as benzo- fused carbocycles. Cycloalkyl includes such fused ring systems as spirofused ring systems. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclofl.1.1 ]pentanyl, decahydronaphthalene, adamantane, indanyl, fluorenyl and 1,2,3,4-tetrahydronaphthalene and the like. The term “(C3-C7)cycloalkyl” may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.

[0683] The term “aryl” refers to an optionally substituted monocyclic or bicyclic hydrocarbon ring system containing at least one unsaturated aromatic ring. Examples and suitable values of the term “aryl” are phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indyl, indenyl and the like. In this specification, unless stated otherwise, the term “heteroaryl” refers to an optionally substituted monocyclic or bicyclic unsaturated, aromatic ring system containing at least one heteroatom selected independently from N, O or S. Examples of “heteroaryl” may be, but are not limited to benzimidazolyl, benzisothiazolyl benzisoxazolyl, benzofuryl, benzopyrazolyl, benzothiazolyl, benzothiophenyl, benzotri azolyl, benzoxazolyl, furazanyl, furyl, imidazolonyl, imidazolyl, imidazopyridazinyl, imidazopyridyl, indolyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolonyl, oxazolopyridazinyl, oxazolopyridyl, oxazolyl, phtalazinyl, pteridinyl, purinyl, pyrazinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridonyl, pyridyl, pyrimidyl, pyrrolyl, quinazolyl, quinolyl, quinoxalinyl, tetrahydrotriazolopyridyl, tetrahydrotriazolopyrimidinyl, tetrazolyl, thiadiazolyl, thiazolonyl, thiazolopyridazinyl, thiazolopyridyl, thiazolyl, thienyl, thionaphthyl, triazinyl and triazolyl.

[0684] In this specification, unless stated otherwise, the term “alkylene-aryl”, “alkyleneheteroaryl” and “alkylene-cycloalkyl” refers respectively to a substituent that is attached via the alkyl radical to an aryl, heteroaryl or cycloalkyl radical, respectively. The term “(Ci-C6)alkylene-aryl” includes aryl-Ci-Ce-alkyl radicals such as benzyl, 1- phenylethyl, 2-phenylethyl, 1 -phenylpropyl, 2-phenylpropyl, 3 -phenylpropyl, 1- naphthylmethyl and 2-naphthylmethyl. The term “(Ci-C6)alkylene-heteroaryl” includes heteroaryl-Ci-Ce-alkyl radicals, wherein examples of heteroaryl are the same as those illustrated in the above definition, such as 2-furylmethyl, 3 -furylmethyl, 2- thienylmethyl, 3 -thienylmethyl, 1 -imidazolylmethyl, 2-imidazolylmethyl, 3- imidazolylmethyl, 2-oxazolylmethyl, 3-oxazolylmethyl, 2-thiazolylmethyl, 3- thiazolylmethyl, 2-pyridinylmethyl, 3-pyridinylmethyl, 4-pyridinylmethyl, 1- quinolylmethyl and the like.

[0685] In this specification, unless stated otherwise, the term “heterocycle” refers to an optionally substituted, monocyclic, bicyclic or tricyclic saturated, partially saturated or unsaturated ring system containing at least one heteroatom selected independently from N, O and S. Bicyclic or tricyclic ring systems may be formed by annelation of two or more rings, by a bridging atom (e.g. O, S, N) or by a bridging group (e.g. alkylene). Examples of heterocyclic moieties include, but are not limited to: azetidinyl, dihydrofuranyl, dihydrothienyl, dioxolanyl, 1,1-dioxo-thiomorpholinyl, imidazolidinyl, imidazolinyl, isothiazolinyl, isoxazolidinyl, isoxazolinyl, morpholinyl, oxazolidinyl, oxazolinyl, oxetanyl, piperazinonyl, piperazinyl, piperidinonyl, piperidinyl, pyranyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, thiazolidinyl, thiazolinyl, thiomorpholinyl, thiopyranyl, triazolinyl, and the corresponding benzannulated heterocycles (e.g. dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazinyl, dihydrofuropyridinyl, dihydroquinolinyl, dihydrothienopyridinyl, indolinyl, pyrrolopyridinyl, tetrahydroquinolinyl, tetrahydroquinoxalinyl, and the like).

[0686] In this specification, unless stated otherwise, the term “halo” or “halogen” may be fluoro, chloro, bromo or iodo.

[0687] In this specification, unless stated otherwise, the term “haloalkyl” means an alkyl radical as defined above, substituted with one or more halo radicals. The term “(Ci- C6)haloalkyl” may include, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl and difluoroethyl.

[0688] In this specification, unless stated otherwise, the term “cyanoalkyl” means an alkyl radical as defined above, substituted with one or more cyano.

[0689] In this specification, unless stated otherwise, the term “optionally substituted” refers to radicals further bearing one or more substituents which may be, acyl, (Ci-Ce)alkyl, - (Ci-Ce)haloalkyl, -(C3-C7)cycloalkyl, -(Ci-C6)alkylene-(C3-C7)cycloalkyl, -(C3- C7)cycloalkyl-(Ci-C6)alkylene, -(Co-C6)alkylene-(C3-C7)spiroalkyl-(Co-C6)alkylene, hydroxy, (Ci-C6)alkylene-oxy, dimethylamino(Ci-C3)alkyl, mercapto, aryl, heterocycle, heteroaryl, (Ci-C6)alkylene-aryl, (Ci-C6)alkylene-heterocycle, (Ci- C6)alkylene-heteroaryl, halogen, haloalkyl, trifluoromethyl, pentafluoroethyl, haloalkoxy, cyano, cyanomethyl, nitro, amino, amido, amidinyl, oxo, carboxyl, carboxamide, (Ci-C6)alkylene-oxycarbonyl, carbamate, ester or sulfonyl.

[0690] In this specification, unless stated otherwise, the term “independently” means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different.

[0691] In this specification, unless stated otherwise, the term “solvate” refers to a complex of variable stoichiometry formed by a solute (e.g. a compound of Formula (I)) and a solvent. The solvent is a pharmaceutically acceptable solvent such as water; such solvent may not interfere with the biological activity of the solute.

[0692] In this specification, unless stated otherwise, the term “salt” refers to an acid addition or base addition salt of a compound of the invention. “Salts” include in particular “pharmaceutically acceptable salts”.

[0693] The pharmaceutically acceptable salts of the invention can be synthesized from a basic or acidic moiety, by conventional chemical methods. Such methods can be found e.g. in P. H. Stahl and C. G. Wermuth “Handbook of Pharmaceutical Salts: Properties, Selection, and Use”, Wiley-VCH, 2002. When both a basic and an acid group are present in the same molecule, the compounds of the invention may also form internal salts, e.g., zwitterionic molecules.

[0694] In this specification, unless stated otherwise, certain compounds may exist in one or more particular geometric, optical, enantiomeric, diastereoisomeric, epimeric, stereoisomeric, tautomeric, conformational, or anomeric forms, including, but not limited to, R-, S-; D- and / .-forms; d- and / -forms; (+) and (-) forms; a- and P-forms; axial and equatorial forms; and combinations thereof, collectively referred to as “isomers” or “isomeric forms”. 1H

[0695] For example, the radical is a tautomer of

[0696] The term “isomer” includes compounds with one or more isotopic substitutions. For example, H may be in any isotopic form, including, but not limited to, 'H,2H (D), and3H (T); C may be in any isotopic form, including, but not limited to,12C,13C,14C; O may be in any isotopic form, including, but not limited to,16O and18O; and the like. F may be in any isotopic form, including, but not limited to,19F and18F; and the like.

[0697] In this specification, unless stated otherwise, the term "positive allosteric modulator of GABAB" or "allosteric modulator of GABAB" refers also to a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof or an A-oxide form thereof.

[0698] PHARMACEUTICAL COMPOSITIONS

[0699] Allosteric modulators of GAB AB described herein, and the pharmaceutically acceptable salts, solvates, and hydrates thereof can be used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The allosteric modulators of GABAB will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described herein. Techniques for formulation and administration of the compounds of the instant invention can be found in “Remington: The Science and Practice of Pharmacy”, 23rdedition, (2021) Academic Press.

[0700] The amount of allosteric modulators of GAB AB administered to the subject will depend on the type and severity of the disease or condition and on the characteristics of the subject, such as general health, age, sex, body weight and tolerance to drugs. The skilled artisan will be able to determine appropriate dosages depending on these and other factors. Effective dosages for commonly used CNS drugs are well known to the skilled person. The total daily dose usually ranges from about 0.05 - 2000 mg.

[0701] The present invention relates to pharmaceutical compositions which provide from about 0.01 to 1000 mg of the active ingredient per unit dose. Examples include from about 0.02 to 500 mg; 0.05 to 500 mg; 0.1 to 500 mg; 0.5 to 250 mg; 1 to 250 mg; 5 to 500 mg; 1 to 100 mg; and 50 to 200 mg, such as 25 mg; 50 mg; 100 mg; 150 mg; 200 mg; or 300 mg of the active ingredient per unit dose. The compositions may be administered by any suitable route. For example, orally in the form of capsules and the like, sublingually, intranasally, parenterally in the form of solutions for injection, topically in the form of onguents or lotions, ocularly in the form of eye-drops, rectally in the form of suppositories, or transcutaneously in the form of a delivery system like patches.

[0702] For oral administration, the allosteric modulators of GABAB thereof can be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, pills, powders, syrups, solutions, suspensions and the like.

[0703] The tablets, pills, capsules, and the like contain from about 0.01 to about 99 weight percent of the active ingredient and a binder such as gum tragacanth, acacias, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid, a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose, or saccharin. When a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.

[0704] Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar, or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry, or orange flavor.

[0705] For parenteral administration the disclosed allosteric modulators of GABAB, or salts thereof, can be combined with sterile aqueous or organic media to form injectable solutions or suspensions. For example, solutions in sesame or peanut oil, aqueous propylene glycol and the like can be used, as well as aqueous solutions of water-soluble pharmaceutically acceptable salts of the compounds. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

[0706] In addition to the formulations described previously, the compounds may also be formulated as a modified-release or depot preparation. Such long-acting formulations may be administered for example, orally, or by subcutaneous administration, or by intramuscular administration. Thus, for example, the compounds may be formulated as an emulsion in an acceptable oil, or ion exchange resins, or as sparingly soluble derivatives, for example, as sparingly soluble salts.

[0707] Preferably disclosed allosteric modulators of GABAB or pharmaceutical formulations containing these compounds are in unit dosage form for administration to a mammal. The unit dosage form can be any unit dosage form known in the art including, for example, a capsule, an IV bag, a tablet, or a vial. The quantity of active ingredient in a unit dose of composition is an effective amount and may be varied according to the particular treatment involved. It may be appreciated that it may be necessary to make routine variations to the dosage depending on 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, sublingual, aerosol, rectal, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, and intranasal.

[0708] METHODS OF SYNTHESIS

[0709] The compounds according to the invention, in particular the compounds according to the Formula (I) to (V), may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthesis schemes. In all the schemes described below it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (Wuts P.G.M., (2014) Greene ’s Protective Groups in Organic Synthesis, John Wiley & Sons). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection of process as well as the reaction conditions and order of their execution shall be consistent with the preparation of compounds of Formula (I) to (V).

[0710] The compounds according to the invention may be represented as a mixture of enantiomers, which may be resolved into the individual pure (R)- or S)-enantiomers. If for instance, a particular enantiomer is required, it may be prepared by asymmetric synthesis or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group such as an amino or an acidic functional group such as carboxyl, this resolution may be conveniently performed by fractional crystallization from various solvents as the salts of an optical active acid or by other methods known in the literature (e.g. chiral column chromatography).

[0711] Resolution of the final product, an intermediate or a starting material may be performed by any suitable method known in the art (Eliel E. L. and Wilen S. H. (1994) Stereochemistry of Organic Compounds, Wiley-Interscience).

[0712] Many of the heterocyclic compounds of the invention can be prepared using synthetic routes well known in the art (Katrizky A. R. et al. (2008) Comprehensive Heterocyclic Chemistry, Elsevier Science).

[0713] The product from the reaction can be isolated and purified by employing standard techniques, such as extraction, chromatography, recrystallization, and distillation.

[0714] The compounds of the invention may be prepared by general route of synthesis as disclosed in the following methods. The schemes in this section are not intended to constrain the scope of the invention in any way.

[0715] In one embodiment of the present invention, compounds of Formula (I) may be prepared according to the synthetic sequence illustrated in Scheme 1. Uracil compound gl may be protected by several groups such as: TSE, Boc using standard conditions. Alcohol g4 can be prepared from the corresponding compound g3 by reduction with for example, NaBEk Then protected uracil g2 may be alkylated by alcohol derivative g4 via Mitsunobu reaction in the presence of triphenyl phosphine and DIAD, for example. Subsequently, g5 is deprotected in the presence of TBAF. In parallel, compound glO may be prepared from the corresponding carboxylic acid submitted to the following reactions consecutively: esterification, reduction, and halogenation, gll can be obtained from the alkylation of g6 by glO, in the presence of a base such as potassium carbonate and the like, in a solvent such as DMF. Finally, if R2is not a hydrogen, the racemate gll can be separated by chiral resolution to lead to the corresponding (R) and

[0716] (5) enantiomers. Scheme 1

[0717] In one embodiment of the present invention, compounds g!9 may be prepared according to the synthetic sequence illustrated in Scheme 2. Triazinedione g!4 may be protected by acetyl using standard conditions. The resulting protected compound g!4 may be alkylated by alcohol derivative g!6 via Mitsunobu reaction in the presence of triphenyl phosphine and DEAD, for example. Subsequently, g!7 may be deprotected smoothly in the presence of MeOH. g!9 can be obtained via either alkylation in the presence of a base such as potassium carbonate and the like, in a solvent such as DMF or via Mitsunobu reaction, using conditions known from a person skilled in the art. Finally, if R2is not a hydrogen, the racemate g!9 can be submitted to chiral separation via HPLC conditions with chiral columns to lead to the corresponding (R) and (5) enantiomers.

[0718]

[0719] Scheme 2

[0720] In one embodiment of the present invention, compounds g23 may be prepared according to the synthetic sequence illustrated in Scheme 3. Compound g!4 may be alkylated by halogen derivatives such as g22 in the presence of a base such as CS2CO3 and the like, in a solvent such as DMF. Finally, if R2is not a hydrogen, the racemate g23 can be submitted to chiral separation via HPLC conditions with chiral columns to lead to the corresponding (R) and CS') enantiomers.

[0721] Scheme 3

[0722] In one embodiment of the present invention, compounds g30 may be prepared according to the synthetic sequence illustrated in Scheme 4. Triazinedione g26 may be protected by acetyl using standard conditions. The resulting protected compound g27 may be alkylated by alcohol derivative g!6 via Mitsunobu reaction in the presence of triphenyl phosphine and DEAD, for example. By stirring the reaction mixture overnight, the acetyl group can be cleaved and deprotected compound g28 is obtained. Subsequently, g28 may be alkylated by halogeno derivatives g22 in the presence of a base such as DBU and the like, in a solvent such as DMF. Alkoxylation of the triazinedione g29, can be done in the presence of a solvent such as MeOH, EtOH and the like and a weak base such as DMF. Finally, if R2is not a hydrogen, the racemate g30 can be submitted to chiral separation via HPLC conditions with chiral columns to lead to the corresponding (R) and (5) enantiomers.

[0723] Scheme 4

[0724] In one embodiment of the present invention, compounds g!9 may be prepared according to the synthetic sequence illustrated in Scheme 5. Triazinedione g28 can be alkylated by compounds such as glO, in the presence of a base, such as DBU and the like. The resulting bromo-triazinedione g33, can lead to compounds g!9, after substitution by alkoxide derivatives, in the presence of the corresponding alcohol used as the solvent and a base such as DBU.

[0725] Scheme 5

[0726] In one embodiment of the present invention, compound g44 may be prepared according to the synthetic sequence illustrated in Scheme 6. Hydrazine g36 can be prepared from ketone g34 and B0CNH-NH2, followed by reduction of the resulting hydrazone, in the presence of NaBHjCN. In parallel, isocyanate g38 can be synthesized from the corresponding primary amine g37 and triphosgene. Nucleophilic addition of the protected hydrazine g36 with isocyanate g38 can lead to compound g39. After deprotection of compound g39, in acidic conditions, such as for example an aqueous solution of HC1 and acylation, with ethyl 2-chloro-2-oxoacetate, compound g42 is obtained. Subsequently, cyclization of g42 in the presence of a base, such as KO / Bu and the like, can lead to substituted 1, 2, 4-triazine-3, 5, 6-trione g43. Finally, after methylation, in the presence of alkylating agent such as MesOBF^ the corresponding triazinedione g44 can be prepared.

[0727] Scheme 6

[0728] EXPERIMENTAL

[0729] Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification.

[0730] Specifically, the following abbreviations may be used in the examples and throughout the specification.

[0731] All references to brine refer to a saturated aqueous solution of NaCl. Unless otherwise indicated, all temperatures are expressed in °C (degrees Centigrade). All reactions are conducted under an inert atmosphere at rt unless otherwise noted. Most of the reactions were monitored by thin-layer chromatography on 0.25mm Merck silica gel plates (60F-254), visualized with UV light.

[0732] EXAMPLES EXAMPLE 1: 3-((4-Chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-((5- niethylpyrid:izin-4-yl)methyl)pyrimidine-2.4( 1 / / .3 / / )-dione (Final Compound 1- 174), (7?)-3-((4-chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-((5- nietliylpyrid:izin-4-yl)niethyl)pyriniidine-2.4( 1 / / .3 / / )-dione (Final Compound 1- 201) and (5)-3-((4-chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-((5- niethylpyrid:izin-4-yl)niethyl)pyriinidine-2.4( 1 / / .3 / / )-dione (Final Compound 1- 202)

[0733] 5-Methoxy-l-( (2-(trimethylsilyl)ethoxy)methyl)pyrimidine-2, 4( 1H, 3H)-dione

[0734] According to Scheme 1 Step 1 : A suspension of 5-methoxypyrimidine-2, 4(1 / 7, 377)- dione (10.0 g, 70.4 mmol) and diammonium sulfate (279 mg, 2.11 mmol) in Z>A(trimethylsilyl)amine (26.1 g, 162 mmol, 33.7 mL, 2.3 equiv) was stirred under reflux overnight. The reaction mixture was cooled (0 - 5 °C) and [2- (chloromethoxy)ethyl]trimethylsilane (12.3 g, 73.9 mmol, 13.1 mL, 1.05 equiv) was added. The resulting mixture was warmed to rt and was stirred for 1 h. MeOH (30 mL) was added dropwise and stirring was continued for 30 min. After addition of water (50 mL), the reaction mixture was filtered and was extracted with DCM (3 x 50 mL). The organic layers were combined, washed with brine (50 mL), dried over Na2SO4 and evaporated in vacuo to give 5 -methoxy- 1 -((2-

[0735] (trimethylsilyl)ethoxy)methyl)pyrimidine-2, 4(177, 377)-dione (19.0 g, 97.5% purity, 68.0 mmol, 96.7% yield).

[0736] LC-MS (ESI): m / z = 273.2 [M+H]+, RT = 1.19 min.

[0737] ( 4-Chlorophenyl)(cyclopropyl)methanol

[0738] According to Scheme 1 Step 2: To the solution of (4- chlorophenyl)(cyclopropyl)methanone (10.0 g, 55.4 mmol) in MeOH (100 mL) was added NaBH4 (4.19 g, 111 mmol) portionwise, at 0 °C. The resulting mixture was stirred for 3 h at rt. An aqueous solution of NH4CI (20 mL) was added and the product was extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4, and concentrated under reduced pressure to afford (4- chlorophenyl)(cyclopropyl)methanol as a yellow oil (10.9 g, 53.7 mmol, 97% yield). 'H-NMR (CDCI3, 500 MHz): 5 0.43 (m, 2H), 0.65 (m, 2H), 1.20 (m, 1H), 2.15 (m, 1H), 3.96 (d, 1H), 7.33 (m, 4H).

[0739] 3-(( 4-Chlorophenyl)(cyclopropyl)methyl) -5-methoxy-l-( 2- ( trimethylsilyl)ethoxy)methyl)pyrimidine-2, 4(1H, 3H)-dione According to Scheme 1 Step 3: To a solution of 5-methoxy-l-((2- (trimethylsilyl)ethoxy)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-dione (10.0 g, 36.7 mmol) in THF (100 mL), were added triphenylphosphine (15.4 g, 58.8 mmol), (4- chlorophenyl)(cyclopropyl)methanol (7.38 g, 40.4 mmol) and DIAD (9.65 g, 47.7 mmol, 9.4 mL, 1.3 equiv). The reaction mixture was stirred overnight at rt. The reaction mixture was evaporated and was purified by FCC (SiCh, Hexane / EtOAc) to give 3-((4-chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-((2-

[0740] (trimethylsilyl)ethoxy)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-dione (5.0 g, 88% purity, 10.1 mmol, 27% yield).

[0741] LC-MS (ESI): m / z = 437.2 [M+H]+, RT = 1.336 min.

[0742] 3-( 4-Chlorophenyl)(cyclopropyl)methyl)-5-methoxypyrimidine-2, 4(1H, 3H)-dione According to Scheme 1 Step 4: To a suspension of compound 3-((4- chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-((2- (trimethylsilyl)ethoxy)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-dione (5.0 g, 11.5 mmol) in dry THF (20 mL), were added ethane- 1,2-diamine (1.38 g, 22.9 mmol, 1.53 mL, 2.0 equiv) and TBAF (4.49 g, 17.2 mmol, 17.2 mL, 1.5 equiv) at rt and the resulting mixture was heated to 60 °C and stirred overnight. The reaction mixture was quenched with water (20 mL) and was extracted with EtOAc (3 x 15 mL). The organic layers were combined, washed with brine (2 x 20 mL), dried over Na2SO4, and evaporated in vacuo to give crude material. The resulting compound was used in the next step without further purification.

[0743] LC-MS (ESI): m / z = 307.0 [M+H]+, RT = 1.177 min.

[0744] Methyl 5-methylpyridazine-4-carboxylate

[0745] According to Scheme 1 Step 5: To a solution of 5-methylpyridazine-4-carboxylic acid hydrochloride (3.30 g, 18.9 mmol) in MeOH (20 mL), was added H2SO4 (1.85 g, 18.9 mmol, 1.01 mL), and the resulting mixture heated to 60 °C and stirred overnight. The reaction mixture was cooled to rt, evaporated, basified to pH=8-9, and extracted with EtOAc. The reaction mixture was dried over Na2SO4, filtered, and evaporated to give methyl 5-methylpyridazine-4-carboxylate (2.05 g, 95% purity, 12.8 mmol, 67.7% yield).

[0746] (5-Methylpyridazin-4-yl)methanol

[0747] According to Scheme 1 Step 6: To a solution of methyl 5-methylpyridazine-4- carboxylate (1.08 g, 7.1 mmol) in water (10 mL) was added NaHCCh (1.79 g, 21.3 mmol) and the resulting mixture cooled to 0 °C. NaBEL (537 mg, 14.2 mmol) was added portionwise and the reaction stirred for 2 h at 0 - 10 °C. Water was removed under reduced pressure and the residue diluted with MeOH. The reaction mixture was filtered and the filtrate evaporated in vacuo to give (5-methylpyridazin-4-yl)methanol (2.0 g, 44% purity). The crude residue was used in the next step without further purification.

[0748] 4-(Chloromethyl)-5-methylpyridazine hydrochloride

[0749] According to Scheme 1 Step 7: A solution of (5-methylpyridazin-4-yl)methanol (2.5 g, 20.1 mmol) in SOCh (197 g, 1.65 mol, 120 mL) was stirred overnight at rt and was evaporated to give 4-(chloromethyl)-5-methylpyridazine hydrochloride (2.90 g, 88% purity, 14.3 mmol) as a crude residue.

[0750] LC-MS (ESI): m / z = 143.0 [M+H]+, RT = 0.679 min.

[0751] 3-(( 4-Chlorophenyl)(cyclopropyl)methyl) -5-methoxy-l-( <3-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1H, 3H)-dione

[0752] According to Scheme 1 Step 8: To a solution of 3-((4- chl orophenyl)(cy cl opropyl)methyl)-5-methoxypyrimidine-2, 4(1 / 7, 3J7)-di one (2.0 g, 6.52 mmol) in DMF (50 mL), were added 4-(chloromethyl)-5-methylpyridazine hydrochloride (2.33 g, 13.0 mmol) and K2CO3 (3.6 g, 26.1 mmol). The reaction mixture was stirred at rt overnight. The reaction mixture was then diluted with water and the product extracted with EtOAc, washed with brine, dried over Na2SO4, and evaporated to give 3-((4-chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one as a beige solid (1.4 g, 95% purity, 3.22 mmol, 49.4% yield).

[0753] 'H-NMR (DMSO-tL, 400 MHz): 5 0.23 (m, 1H), 0.47 (m, 2H), 0.83 (m, 1H), 1.96 (m, 1H), 2.31 (s, 3H), 3.66 (s, 3H), 4.98 (m, 3H), 7.35 (d, 2H), 7.40 (d, 2H), 7.56 (s, 1H), 8.74 (m, 1H), 9.05 (s, 1H);

[0754] LC-MS (ESI): m / z = 413.2 [M+H]+, RT = 1.30 min.

[0755] (R)-3-((4-Chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2,4(lH,3H)-dione and (S)-3-((4- chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1H, 3H)-dione

[0756] According to Scheme 1 Step 9: 1.0 g of 3-((4-chlorophenyl)(cyclopropyl)methyl)-5- m ethoxy- 1 -((5 -methylpyridazin-4-yl)methyl)pyrimidine-2,4( 1 / 7, 3 / 7)-di one was purified by chiral HPLC (CHIRALPAK IA (250x20 mm, 5 pm) column; mobile phase: Hexane / IPA / MeOH, 70: 15: 15; Flow rate: 13 mL / min) to afford:

[0757] (7?)-3-((4-Chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-dione as a beige solid (428.5 mg, RT = 12.03 min). RT was determined by analytical HPLC (CHIRALPAK IA (250x4.6 mm, 5 pm) column; Hexane / IPA / MeOH, 50:25:25 mobile phase; flow rate : 0.6 mL / min);

[0758] ‘H-NMR (DMSO-tL, 600 MHz): 5 0.12 - 0.27 (m, 1H), 0.34 - 0.53 (m, 2H), 0.76 - 0.85 (m, 1H), 1.87 - 2.08 (m, 1H), 2.35 (s, 3H), 3.63 (s, 3H), 4.81 - 5.19 (m, 3H), 7.34 (d, 2H), 7.37 (d, 2H), 7.55 (s, 1H), 8.54 - 8.86 (m, 1H), 9.03 (s, 1H);

[0759] LC-MS (ESI): m / z = 413.2 [M+H]+, RT = 3.35 min;

[0760] And (5)-3-((4-chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one (423.6 mg, RT = 17.74 min) as a beige solid. RT was determined by analytical HPLC using the same conditions as above;

[0761] ‘H-NMR (DMSO-tL, 600 MHz): 5 0.12 - 0.27 (m, 1H), 0.34 - 0.53 (m, 2H), 0.76 - 0.85 (m, 1H), 1.87 - 2.08 (m, 1H), 2.35 (m, 3H), 3.63 (s, 3H), 4.81 - 5.19 (m, 3H), 7.34 (d, 2H), 7.37 (d, 2H), 7.55 (s, 1H), 8.54 - 8.86 (m, 1H), 9.03 (s, 1H); LC-MS (ESI): m / z = 413.2 [M+H]+, RT = 3.34 min.

[0762] EXAMPLE 2: 4-(Cyclopropyl(4-fluorophenyl)methyl)-2-((3-fluoropyridin-2- yl)methyl)-6-methoxy-l,2,4-triazine-3,5(2H,4ET)-dione (Final Compound 1-185) 2-Acetyl-6-methoxy-l, 2, 4-triazine-3, 5(2H, 4H)-dione

[0763] According to Scheme 1 Step 1 : 6-Methoxy-l,2,4-triazine-3,5(2J / ,4J7)-dione (10.0 g, 69.9 mmol) and AcOEt (42.8 g, 419 mmol, 39.6 mL, 6.0 equiv) were mixed and refluxed for 4.5 h. After evaporation of the solvent, the crude product was recrystallized from Et2O to give 2-acetyl-6-methoxy-l,2,4-triazine-3,5(2J / ,4J7)-dione (9.20 g, 49.4 mmol, 70.7% yield).

[0764] LC-MS (ESI): m / z = 144.0 [M+H]+, RT = 0.530 min.

[0765] Cyclopropyl(4-fluorophenyl)methanol

[0766] According to Scheme 1 Step 2: To a stirred solution of cyclopropyl(4- fluorophenyl)methanone (5.00 g, 30.5 mmol) in MeOH (40 mL) at 0 °C was added NaBEL (1.50 g, 39.6 mmol) portionwise. The reaction mixture was allowed to reach rt and stirred for a further 4 h. To the reaction mixture was added saturated aqueous NH4CI solution and EtOAc. The phases were separated. The aqueous phase was extracted twice with EtOAc, and the combined organic phases were dried (Na2SO4), filtered, and concentrated in vacuo to afford 5.01 g of a yellow oil (99%, cyclopropyl(4-fluorophenyl)methanol).

[0767] 'H-NMR (CDCI3, 400 MHz): 5 0.43 (m, 2H), 0.61 (m, 2H), 1.19 (m, 1H), 1.98 (m, 1H), 3.99 (d, 1H), 7.04 (m, 2H), 7.39 (m, 2H).

[0768] 2-Acetyl-4-(cyclopropyl(4-fluorophenyl)methyl)-6-methoxy-l, 2, 4-triazine-3, 5(2H, 4H)~ dione

[0769] According to Scheme 2 Step 2: To a solution of 2-acetyl-6-m ethoxy- 1,2, 4-triazine- 3,5(2J / ,4J7)-dione (557 mg, 3.01 mmol) and triphenylphosphine (1.03 g, 3.91 mmol) in DCM, was added DEAD (681 mg, 3.91 mmol) dropwise followed after complete dissolution by the addition of cyclopropyl(4-fluorophenyl)methanol) (444 mg, 3.01 mmol). The reaction mixture was stirred overnight at rt. The reaction mixture was then evaporated and the resultant residue used in the next step without further purification. LC-MS (ESI): m / z = 279.0 [M+H]+, RT = 1.119 min.

[0770] 4-(Cyclopropyl(4-fluorophenyl)methyl)-6-methoxy-l,2,4-triazine-3,5(2H,4H)-dione According to Scheme 2 Step 3: 2-Acetyl-4-(cyclopropyl(4-fluorophenyl)methyl)-6- methoxy-l,2,4-triazine-3,5(2J / ,4J7)-dione (444 mg, 3.01 mmol) was dissolved in water- MeOH solution (1:2) and was stirred overnight at rt. The solution was evaporated under vacuum, and the residue dissolved in DCM, dried over Na2SO4, and evaporated under vacuum to give 4-(cy cl opropyl(4-fluorophenyl)methyl)-6-m ethoxy- 1,2, 4-triazine- 3,5(2J / ,4J7)-dione (70 mg, 85% purity, 204 pmol, 6.8% yield).

[0771] 'H-NMR (CDC13, 500 MHz): 5 0.47 (m, 2H), 0.64 (m, 1H), 0.84 (m, 1H), 2.27 (m, 1H), 3.80 (s, 3H), 5.12 (d, 1H), 7.01 (m, 2H), 7.33 (m, 2H), 10.28 (br. s, 1 H);

[0772] LC-MS (ESI): m / z = 292.0 [M+H]+, RT = 1.217 min.

[0773] 4-(Cyclopropyl(4-fluorophenyl)methyl)-2-((3-fluoropyridin-2-yl)methyl)-6-methoxy-

[0774] 1.2.4-triazine-3, 5(2H, 4H)-dione

[0775] According to Scheme 2 Step 4: 4-(Cyclopropyl(4-fluorophenyl)methyl)-6-methoxy-

[0776] 1.2.4-triazine-3,5(2J / ,4J7)-dione (70 mg, 204 pmol), 2-(chloromethyl)-3-fluoropyridine (42 mg, 288 pmol), and DBU (73 mg, 481 pmol) were mixed in DMF and the reaction mixture was stirred overnight at rt. The reaction mixture was then concentrated under vacuum, dissolved in EtOAc, and washed with brine twice. The organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by HPLC (Chromatorex Cis SMB 100-5 T 100x19 mm 5 pm column; 0 - 5 min; 40 - 90% H20 / Me0H; flow rate: 30 mL / min (loading pump 4 mL / min MeOH)) to give 4- (cyclopropyl(4-fluorophenyl)methyl)-2-((3-fluoropyridin-2-yl)methyl)-6-methoxy- l,2,4-triazine-3,5(2J / ,4J7)-dione (39 mg, 95% purity, 92 pmol, 45% yield) as a beige solid. 'H-NMR (CDC13, 400 MHz): 5 0.47 (m, 2H), 0.64 (m, 1H), 0.84 (m, 1H), 2.27 (m, 1H), 3.80 (s, 3H), 5.12 (d, 1H), 5.25 (m, 2H), 7.01 (m, 2H), 7.25 (m, 1H), 7.40 (m, 1H), 7.53 (dd, 2H), 8.33 (d, 1H);

[0777] LC-MS (ESI): m / z = 401.2 [M+H]+, RT = 3.594 min.

[0778] EXAMPLE 3 : 4-((4-Chlorophenyl)(cyclopropyl)methyl)-2-((2-hydroxypyridin-4- yl)methyl)-6-methoxy-l ,2,4-t ri:izine-3.5(2 / / .4 / / )-dione (Final Compound 1-165)

[0779] According to Scheme 2 Step 4’ : DEAD (317 mg, 1.82 mmol, 290 pL, 1.4 equiv) was added to a solution of 4-(hydroxymethyl)pyridin-2(U7)-one (163 mg, 1.3 mmol) and triphenylphosphine (409 mg, 1.56 mmol) in DCM and the reaction mixture was stirred for 30 min. After dissolution of the reagents, 4-((4-chlorophenyl)(cyclopropyl)methyl)- 6-methoxy-l,2,4-triazine-3,5(2Z7,4J7)-dione (400 mg, 1.3 mmol) was added dropwise and the reaction mixture was stirred overnight at rt. After completion of the reaction, the solution was evaporated under vacuum and the crude residue purified by HPLC (Chromatorex Cis SMB100-5T 100x19 mm 5 pm column; 0 - 1 - 6 min; 20 - 20 - 60% H2O / MeCN / 0.1%FA; flow rate: 30 mL / min (loading pump 4 mL / min MeCN)) affording 30.8 mg (6% yield) as a white solid.

[0780] 'H-NMR (DMSO-tC, 600 MHz): 5 0.27 (m, 1H), 0.50 (m, 2H), 0.82 (m, 1H), 1.98 (m, 1H), 3.75 (s, 3H), 4.76 (m, 2H), 4.96 (d, 1H), 6.05 (d, 1H), 6.16 (s, 1H), 7.31 (d, 1H), 7.35 (d, 2H), 7.48 (d, 2H), 11.48 (s, 1H);

[0781] LC-MS (ESI): m / z = 415.0 [M+H]+, RT = 3.272 min.

[0782] EXAMPLE 4: 3-(Cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l-(tetrahydro- 2 / / -pyran-4-yl)pyrimidine-2.4( l / / .3 / / )-dione (Final Compound 1-155), (l?)-3- (cydopropyl(4-fluorophenyl)methyl)-5-methoxy-l-(tetrahydro-2Z / -pyran-4- yl)pyrimidine-2,4( l / / .3 / / )-dione (Final Compound 1-198) and (5)-3- (cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l-(tetrahydro-2Z / -pyran-4- yl)pyrimidine-2.4( 1 / / .3 / / )-dione (Final Compound 1-199) 3-(Cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l-((2- ( trimethylsilyl)ethoxy)methyl)pyrimidine-2, 4(1H, 3H)-dione According to Scheme 1 Step 3: To a solution of 5-methoxy-l-((2- (trimethylsilyl)ethoxy)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-dione (10.7 g, 39.3 mmol) in THF (200 mL), were added triphenylphosphine (15.5 g, 58.9 mmol) and cyclopropyl(4- fluorophenyl)methanol (7.18 g, 43.2 mmol). The resulting mixture was stirred for 10 min followed by the dropwise addition of DIAD (10.3 g, 51.1 mmol, 10.1 mL, 1.3 equiv). The reaction mixture was stirred overnight at rt. The solvent was then removed in vacuo and the crude material purified by FCC (SiCL, Hexane / EtOAc) to give 3- (cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l-((2- (trimethylsilyl)ethoxy)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-dione (10.0 g, 23.8 mmol, 60.6% yield).

[0783] 'H-NMR (DMSO-t / e, 400 MHz): 5 0.06 (s, 9H), 0.30 (m, 1H), 0.45 (m, 2H), 0.92 (m, 1H), 1.34 (m, 2H), 2.07 (m, 1H), 3.43 (m, 2H), 3.63 (s, 3H), 4.85 (m, 2H), 5,24 (m, 1H), 7.23 (m, 2H), 7.48 (m, 2H), 7.58 (m, 1H);

[0784] LC-MS (ESI): m / z = 421.2 [M+H]+, RT = 1.684 min.

[0785] 3-(Cyclopropyl(4-fluorophenyl)methyl)-5-methoxypyrimidine-2, 4(lH,3H)-dione:

[0786] According to Scheme 1 Step 4: To a suspension of 3-(cyclopropyl(4- fluorophenyl)methyl)-5-methoxy-l-((2-(trimethylsilyl)ethoxy)methyl)pyrimidine- 2,4(l / 7,3 / 7)-dione (10.0 g, 23.8 mmol) in dry THF (50 mL), were added at rt TBAF (9.33 g, 35.7 mmol, 35.7 mL, 1.5 equiv) and ethane-l,2-diamine (2.86 g, 47.6 mmol, 3.18 mL, 2.0 equiv). The resulting mixture was refluxed for 2 days. After cooling the reaction mixture to rt, the reaction mixture was quenched with water (50 mL) and extracted with EtOAc (3 x 50 mL). The organic layers were combined, washed with brine (2 x 50 mL), dried over Na2SO4, filtered, and evaporated in vacuo to give 3- (cy clopropyl(4-fluorophenyl)methyl)-5-methoxypyrimidine-2, 4(1 / 7, 3 / 7)-di one (8.4 g, 50.0% purity, 14.5 mmol, 60.8% yield). The obtained product was used in the next step without further purification.

[0787] LC-MS (ESI): m / z = 289.0 [M-H]+, RT = 1.059 min.

[0788] 3-(Cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l-(tetrahydro-2H-pyran-4- yl)pyrimidine-2, 4(1H, 3H)-dione According to Scheme 3 Step 1 : To a solution of 3-(cyclopropyl(4- fluorophenyl)methyl)-5-methoxypyrimidine-2, 4(1 / 7, 3 / 7)-dione (3.00 g, 10.3 mmol) and CS2CO3 (16.9 g, 51.8 mmol) in DMF (50 mL) was added 4-bromotetrahydro-2 / 7-pyran (7.62 g, 46.2 mmol, 4.89 mL, 4.5 equiv). The reaction mixture was stirred overnight at 65 °C. After cooling to rt, the reaction mixture was diluted with water and the product extracted with EtOAc. The organic phase was concentrated under reduced pressure. The residue was purified by FCC (SiCL; Hexane / THF 1 : 1) to afford 3-(cyclopropyl(4- fluorophenyl)methyl)-5-methoxy-l-(tetrahydro-2 / 7-pyran-4-yl)pyrimidine-2, 4(1 / 7, 3 / 7)- dione (1.01 g, 95% purity, 2.56 mmol, 25% yield) as a yellow oil.

[0789] 'H-NMR (DMSO-tL, 400 MHz): 5 0.12 (m, 1H), 0.40 (m, 1H), 0.51 (m, 1H), 0.80 (m, 1H), 1.60 (m, 2H), 2.01 (m, 3H), 3.38 (m, 2H), 3.65 (m, 3H), 3.92 (m, 2H), 4.52 (m, 1H), 5.03 (m, 1H), 7.11 (m, 2H), 7.37 (m, 3H);

[0790] LC-MS (ESI): m / z = 375.0 [M+H]+, RT = 3.195 min.

[0791] (R)-3-(Cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l-(tetrahydro-2H-pyran-4- yl)pyrimidine-2, 4(1H, 3H)-dione and (S)-3-(cyclopropyl(4-fluorophenyl)methyl)-5- methoxy-l-(tetrahydro-2H-pyran-4-yl)pyrimidine-2, 4(lH,3H)-dione

[0792] According to Scheme 3 Step 2: 1.01 g of 3-(cyclopropyl(4-fluorophenyl)methyl)-5- methoxy-l-(tetrahydro-2 / 7-pyran-4-yl)pyrimidine-2,4(l / 7,3 / 7)-dione was resolved by chiral preparative SFC (CHIRALPAK AD-H (250x20 mm, 5 pm) column; mobile phase: CCL / MeOH, 90: 10; Flow rate: 50 mL / min) to afford: (5)-3-(cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l-(tetrahydro-2 / 7-pyran-4- yl)pyrimidine-2, 4(1 / 7, 3 / 7)-dione (370 mg, RT = 5.785 min) as a white solid. RT was determined by analytical SFC (CHIRALPAK AD-H (250x4.6 mm, 5 pm) column; CCL / MeOH, 90: 10, mobile phase; flow rate: 2.0 mL / min);

[0793] ‘H-NMR (DMSO-tL, 500 MHz): 5 0.19 (m, 1H), 0.40 (m, 1H), 0.51 (m, 1H), 0.78 (m, 1H), 1.60 (m, 2H), 2.01 (m, 3H), 3.38 (m, 2H), 3.65 (m, 3H), 3.92 (m, 2H), 4.52 (m, 1H), 5.03 (m, 1H), 7.11 (m, 2H), 7.37 (m, 3H);

[0794] LC-MS (ESI): m / z = 375.2 [M+H]+, RT = 1.204 min; And (A)-3-(cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l-(tetrahydro-2J / -pyran-4- yl)pyrimidine-2,4(U / ,3J7)-dione (390 mg, RT = 7.454 min) as a white solid. RT was determined by analytical SFC using the same conditions as above;

[0795] 'H-NMR (DMSO-t / e, 500 MHz): 5 0.19 (m, 1H), 0.40 (m, 1H), 0.50 (m, 1H), 0.76 (m, 1H), 1.57 (m, 2H), 2.02 (m, 3H), 3.39 (m, 2H), 3.65 (m, 3H), 3.94 (m, 2H), 4.53 (m, 1H), 5.04 (m, 1H), 7.11 (m, 2H), 7.37 (m, 3H);

[0796] LC-MS (ESI): m / z = 375.2 [M+H]+, RT = 1.204 min.

[0797] EXAMPLE 5: 4-((4-Chlorophenyl)(cyclopropyl)methyl)-6-methoxy-2-(tetrahydro- 2 / / -pyran-4-yl)-l .2.4-1 riazine-3.5(2 / / .4 / / )-dione (Final Compound 1-137), (.S’)-4- ((4-chlorophenyl)(cyclopropyl)niethyl)-6-methoxy-2-(tetr:ihydro-2 / / -pyr:in-4-yl)- 1.2.4-triazine-3.5(2 / / .4 / / )-dione (Final Compound 1-156) and (l?)-4-((4- chlorophenyl)(cyclopropyl)methyl)-6-methoxy-2-(tetr:ihydro-2 / / -pyran-4-yl)- 1.2.4-triazine-3.5(2 / / .4 / / )-dione (Final Compound 1-157)

[0798] 2-Acetyl-6-bromo-l, 2, 4-triazine-3, 5(2H, 4H)-dione

[0799] According to Scheme 4 Step 1 : Anhydride acetic (65 mmol, 2.5 eq.) followed by DMAP (19.1 mg, 156 pmol, 0.006 eq.) were added to a solution of 6-bromo- 1,2,4- triazine-3, 5(2 / 7, 4 / / )-dione (5.00 g, 26.0 mmol) in THF (25 mL). The reaction mixture was stirred at 50 °C and left overnight. Upon completion, the THF was removed by concentration and the oil was azeotroped with heptane (10 volumes) to give a solid. The crude solid was further slurried in Et2O (25 mL), filtered, washed with Et2O (10 mL) and dried under vacuum to give 2-acetyl-6-bromo-l,2,4-triazine-3,5(2Z7,4J7)-dione (4.74 g, 20.3 mmol, 78% yield) as a white solid.

[0800] 6-Bromo-4-((4-chlorophenyl)(cyclopropyl)methyl)-l, 2, 4-triazine-3, 5(2H, 4H)-dione According to Scheme 4 Step 2: DEAD (5.98 g, 34.4 mmol) was added dropwise to a solution of 2-acetyl-6-bromo-l,2,4-triazine-3,5(2Z7,4J7)-dione (6.70 g, 28.6 mmol), (4- chlorophenyl)(cyclopropyl)methanol (7.84 g, 42.9 mmol) and triphenylphosphine (11.3 g, 43.0 mmol) in THF (70 mL) at 5 °C, under an argon atmosphere. The resulting solution was stirred for 8 h at 25 °C. The reaction mixture was evaporated under reduced pressure and the crude material purified by FCC (SiCE) to give 6-bromo-4-((4- chlorophenyl)(cyclopropyl)methyl)- l ,2,4-triazine-3,5(27 / ,47 / )-dione (4.0 g, 11.2 mmol, 39% yield).

[0801] 'H-NMR (CDC13, 400 MHz): 5 0.44 (m, 2H), 0.67 (m, 1H), 0.86 (m, 1H), 1.64 (m, 1H), 5.04 (d, 1H), 7.33 (m, 2H), 7.46 (m, 2H), 9.85 (br. s, 1H);

[0802] LC-MS (ESI): m / z = 354.9 [M-2H]+, RT = 1.377 min.

[0803] 6-Bromo-4-( ( 4-chlorophenyl) ( cyclopropyl )methyl)-2-(tetrahydro-2H-pyran-4-yl)-l, 2,4- triazine-3, 5(2H, 4H) -dione

[0804] According to Scheme 4 Step 3: To a solution of 6-bromo-4-((4- chlorophenyl)(cyclopropyl)methyl)-l,2,4-triazine-3,5(2J / ,4J7)-dione (500 mg, 1.40 mmol) in DMF (5.0 mL), were added DBU (213 mg, 1.40 mmol) and 4- bromotetrahydro-27 / -pyran (231 mg, 1.40 mmol). The reaction mixture was heated at 100 °C overnight. After cooling to rt, the reaction mixture was diluted in EtOAc (5 mL), washed with brine (3x 10 mL), dried over Na2SO4, and concentrated under reduced pressure to give 6-bromo-4-((4-chlorophenyl)(cyclopropyl)methyl)-2- (tetrahydro-2J / -pyran-4-yl)-l,2,4-triazine-3,5(2J / ,4J7)-dione (600 mg, 62% purity, 843 pmol, 60% yield).

[0805] LC-MS (ESI): m / z = 442.0 [M-2H]’, RT = 1.471 min.

[0806] 4-(( 4-Chlorophenyl)(cyclopropyl)methyl) -6-methoxy-2-(tetrahydro-2H-pyran-4-yl)-

[0807] 1.2.4-triazine-3, 5(2H, 4H)-dione

[0808] According to Scheme 4 Step 4: DBU (207 mg, 1.36 mmol) was added to a suspension of 6-bromo-4-((4-chlorophenyl)(cyclopropyl)methyl)-2-(tetrahydro-2J / -pyran-4-yl)-

[0809] 1.2.4-triazine-3,5(2J / ,4J7)-dione (600 mg, 62% purity, 843 pmol) in MeOH (10 mL). The reaction mixture was stirred overnight at rt and then evaporated under reduced pressure. The crude material was purified by HPLC (SunFire 19x100 mm 5 pm column; 2 - 8 min; 50 - 75%; water / MeCN; flow rate: 30 mL / min (loading pump 4 mL / min MeCN)) to give 4-((4-chlorophenyl)(cyclopropyl)methyl)-6-methoxy-2- (tetrahydro-2J / -pyran-4-yl)-l,2,4-triazine-3,5(2J / ,4J7)-dione (283 mg, 722 pmol, 86% yield) as a white solid. 'H-NMR (DMSO-tL, 600 MHz): 5 (m, 1H), 0.47 (m, 1H), 0.51 (m, 1H), 0.81 (m, 1H), 1.52 - 1.74 (m, 2H), 1.86 - 1.97 (m, 2H), 2.01 (m, 1H), 3.39 (t, 2H), 3.81 (s, 3H), 3.88

[0810] - 3.96 (m, 2H), 4.48 - 4.66 (m, 1H), 4.96 (d, 1H), 7.35 (d, 2H), 7.44 (d, 2H);

[0811] LC-MS (ESI): m / z = 392.0 [M+H]+, RT = 2.790 min.

[0812] (S)-4-((4-Chlorophenyl)(cyclopropyl)methyl)-6-methoxy-2-(tetrahydro-2H-pyran-4-yl)~

[0813] 1.2.4-triazine-3, 5(2H, 4H)-dione and (R)-4-((4-chlorophenyl)(cyclopropyl)methyl)-6- methoxy-2-(tetrahydro-2H-pyran-4-yl)-l, 2, 4-triazine-3,5(2H, 4H)-dione

[0814] According to Scheme 4 Step 5: 75 mg of 4-((4-chlorophenyl)(cyclopropyl)methyl)-6- methoxy-2-(tetrahydro-2J / -pyran-4-yl)-l,2,4-triazine-3,5(2J / ,4J7)-dione was separated by chiral HPLC (CHIRALPAK AD-H (250x20 mm, 5 pm) column; mobile phase: Hexane / IPA / MeOH, 90:5:5; Flow rate: 10 mL / min) to afford:

[0815] (5)-4-((4-chlorophenyl)(cyclopropyl)methyl)-6-methoxy-2-(tetrahydro-2J / -pyran-4-yl)-

[0816] 1.2.4-triazine-3,5(2J / ,4J7)-dione (37.6 mg, RT = 10.881 min) as a white solid. RT was determined by analytical HPLC (CHIRALPAK AD-H (250x4.6 mm, 5 pm) column; Hexane / IPA / MeOH, 90:5:5, mobile phase; flow rate: 1.0 mL / min);

[0817] ‘H-NMR (DMSO-tL, 600 MHz): 5 0.22 - 0.31 (m, 1H), 0.41 - 0.54 (m, 2H), 0.77 - 0.86 (m, 1H), 1.54 - 1.74 (m, 2H), 1.84 - 1.95 (m, 2H), 1.98 - 2.05 (m, 1H), 3.35 - 3.43 (m, 2H), 3.81 (s, 3H), 3.88 - 3.95 (m, 2H), 4.46 - 4.63 (m, 1H), 4.96 (d, 1H), 7.35 (d, 2H), 7.44 (d, 2H);

[0818] LC-MS (ESI): m / z = 392.0 [M+H]+, RT = 1.576 min;

[0819] And (A’)-4-((4-chlorophenyl)(cyclopropyl)methyl)-6-methoxy-2-(tetrahydro-27 / -pyran- 4-yl)-l,2,4-triazine-3,5(2J / ,4J7)-dione (34.7 mg, RT = 13.056 min) as a white solid. RT was determined by analytical HPLC using the same conditions as above;

[0820] ‘H-NMR (DMSO-tL, 600 MHz): 5 0.23 - 0.30 (m, 1H), 0.43 - 0.54 (m, 2H), 0.76 - 0.86 (m, 1H), 1.54 - 1.74 (m, 2H), 1.84 - 1.96 (m, 2H), 1.96 - 2.04 (m, 1H), 3.35 - 3.43 (m, 2H), 3.81 (s, 3H), 3.86 - 3.95 (m, 2H), 4.49 - 4.65 (m, 1H), 4.96 (d, 1H), 7.35 (d, 2H), 7.44 (d, 2H);

[0821] LC-MS (ESI): m / z = 392.0 [M+H]+, RT = 1.576 min. EXAMPLE 6: 4-(l-(4-Chlorophenyl)ethyl)-6-cyclopropoxy-2-((4-methylpyridin-3- yl)methyl)-l,2,4-triazine-3,5(2H,4ET)-dione (Final Compound 1-119)

[0822] 6-Bromo-4-( 1 -( 4-chlorophenyl)ethyl)-2-((4-methylpyridin-3-yl)methyl)-l, 2, 4-triazine- 3, 5(2H, 4H)-dione

[0823] According to Scheme 5 Step 1 : A solution of 6-bromo-4-(l-(4-chlorophenyl)ethyl)- l,2,4-triazine-3,5(2J / ,4J7)-dione (300 mg, 908 pmol), 3-(chloromethyl)-4- methylpyridine hydrochloride (194 mg, 1.09 mmol) and DBU (276 mg, 1.81 mmol) was stirred overnight at rt. The reaction mixture was concentrated under vacuum, diluted in EtOAc, and washed with brine twice. The organic layer was dried over Na2SO4 and concentrated under vacuum to give crude 6-bromo-4-(l-(4- chlorophenyl)ethyl)-2-((4-methylpyridin-3-yl)methyl)-l,2,4-triazine-3,5(2J / ,4J7)-dione (13.3 mg, 30.5 pmol, 3.4% yield).

[0824] LC-MS (ESI): m / z = 437.0 [M+H]+, RT = 1.068 min;

[0825] 4-( 1 -(4-Chlorophenyl)ethyl)-6-cyclopropoxy-2-( 4-methylpyridin-3-yl)methyl)-l, 2, 4- triazine-3, 5(2H, 4H) -dione

[0826] According to Scheme 5 Step 1 : A solution of 6-bromo-4-(l-(4-chlorophenyl)ethyl)-2- ((4-methylpyridin-3-yl)methyl)-l,2,4-triazine-3,5(2J / ,4J7)-dione (100 mg, 230 pmol) and DBU (52.4 mg, 344 pmol) in cyclopropanol (30 mL) was stirred overnight at rt. The solution was concentrated under reduced pressure, dissolved in DCM, washed with water twice, dried over Na2SC>4, and concentrated under vacuum to give 4-(l-(4- chlorophenyl)ethyl)-6-cy cl opropoxy-2-((4-methylpyri din-3 -yl)methyl)-l, 2, 4-tri azine- 3,5(2J / ,4J7)-dione (13 mg, 95% purity, 31 pmol, 13% yield) as a beige solid.

[0827] 'H-NMR (CDC13, 400 MHz): 5 0.72 (m, 2H), 0.78 (m, 2H), 1.87 (d, 3H), 2.44 (s, 3H), 3.93 (m, 1H), 5.04 (d, 1H), 5.11 (d, 1H), 6.16 (m, 1H), 7.16 (d, 1H), 7.30 (m, 2H), 7.41 (d, 2H), 8.44 (d, 1H), 8.57 (s, 1H);

[0828] LC-MS (ESI): m / z = 413.2 [M+H]+, RT = 3.208 min.

[0829] EXAMPLE 7 : 4-(l-(4-Chlorophenyl)cyclopropyl)-6-methoxy-2-(tetrahydro-2 / / - pyran-4-yl)-l .2.4-triazine-3.5(2 / / .4 / / )-dione (Final Compound 1-122) tert-Butyl 2-(tetrahydro-4H-pyran-4-ylidene)hydrazine-l -carboxylate

[0830] According to Scheme 6 Step 1 : A mixture of tert-butyl hydrazinecarboxylate (3.60 g, 27.2 mmol) and tetrahydro-47 / -pyran-4-one (3.00 g, 30.0 mmol) in MeOH was stirred at rt overnight. The reaction mixture was evaporated in vacuum to give tert-butyl 2- (tetrahydro-47 / -pyran-4-ylidene)hydrazine- l -carboxylate (5.80 g, 27.1 mmol, 99.4% yield), which was used in the next step without further purification.

[0831] LC-MS (ESI): m / z = 157.0 [M+H]+, RT = 0.835 min. tert-Butyl 2-(tetrahydro-2H-pyran-4-yl)hydrazine-l-carboxylate

[0832] According to Scheme 6 Step 2: NaBEECN (1.70 g, 27.1 mmol) was added slowly to a solution of tert-butyl 2-(tetrahydro-47 / -pyran-4-ylidene)hydrazine- l -carboxylate (5.80 g, 27.1 mmol) in AcOH (50%). The reaction mixture was stirred for 1.5 h at rt, neutralized with NaOH (1 N), and extracted with DCM. The organic phase was washed with sat. NaHCCE, dried over Na2SO4, and evaporated to give tert-butyl 2-(tetrahydro- 27 / -pyran-4-yl)hydrazine- l -carboxylate (5.0 g, 85.5% yield) as a white solid.

[0833] LC-MS (ESI): m / z = 161.0 [M+H]+, RT = 0.969 min.

[0834] 1 -Chlor o-4-( I -isocyanatocyclopropyl) benzene

[0835] According to Scheme 6 Step 3: A solution of l-(4-chlorophenyl)cyclopropan-l -amine hydrochloride (2.00 g, 9.80 mmol) and triethylamine (3.47 g, 34.3 mmol) in DCM was added to a solution of triphosgene (1.02 g, 3.43 mmol) in DCM over a period of 1 h at 0 - 5 °C, under argon. After stirring for 1 h at 0 °C, the reaction mixture was washed with cold NaHCCE solution, dried over MgSCh, and evaporated to afford l-chloro-4-(l- isocyanatocyclopropyl)benzene (1.89 g, 9.76 mmol, 99.6% yield). tert-Butyl 2-((l-(4-chlorophenyl)cyclopropyl)carbamoyl)-2-(tetrahydro-2H-pyran-4- yl)hydrazine-l -carboxylate

[0836] According to Scheme 6 Step 4: l-Chloro-4-(l-isocyanatocyclopropyl)benzene (1.89 g, 9.76 mmol) and tert-butyl 2-(tetrahy dro-27 / -pyran-4-y I )hydrazine- l -carboxy late (2.11 g, 9.76 mmol) were mixed in THF and stirred at 50 °C overnight. The reaction mixture was evaporated under vacuum to give tert-butyl 2-((l-(4- chlorophenyl)cyclopropyl)carbamoyl)-2-(tetrahydro-2H-pyran-4-yl)hydrazine-l- carboxylate (2.80 g, 6.83 mmol, 70% yield) as a yellow solid.

[0837] LC-MS (ESI): m / z = 354.1 [M+H]+, RT = 1.365 min.

[0838] N-(l-(4-chlorophenyl)cyclopropyl)-l-(tetrahydro-2H-pyran-4-yl)hydrazine-l- carboxamide hydrochloride

[0839] According to Scheme 6 Step 5: Zc / V-Butyl 2-((l-(4- chlorophenyl)cyclopropyl)carbamoyl)-2-(tetrahydro-2J / -pyran-4-yl)hydrazine-l- carboxylate (2.80 g, 6.83 mmol) and HClaq(17.1 mmol, 5.29 mL, 2.5 equiv) were mixed in MeOH and stirred at rt overnight. The solution was evaporated under vacuum to give 7V-( 1 -(4-chlorophenyl)cy clopropyl)- 1 -(tetrahy dro-27 / -py ran -4-yl )hy drazine- 1 - carboxamide hydrochloride (2.1 g, 6.06 mmol, 88.6% yield) as a yellow solid.

[0840] LC-MS (ESI): m / z = 310.2 [M+H]+, RT = 1.034 min.

[0841] Ethyl 2-(2-((l-(4-chlorophenyl)cyclopropyl)carbamoyl)-2-(tetrahydro-2H-pyran-4- yl)hydrazineyl) -2 -oxoacetate

[0842] According to Scheme 6 Step 6: A solution of ethyl 2-chloro-2-oxoacetate (305 mg, 2.24 mmol, 250 pL, 1.2 equiv) in DCM was added dropwise at 0 °C to a solution of A-(l-(4- chlorophenyl)cy clopropyl )-l -(tetrahydro-27 / -pyran-4-yl)hydrazine- l -carboxamide hydrochloride (645 mg, 1.86 mmol) and the reaction mixture stirred overnight at rt. The reaction mixture was washed with brine, dried over Na2SO4, and evaporated under vacuum to give ethyl 2-(2-((l-(4-chlorophenyl)cyclopropyl)carbamoyl)-2-(tetrahydro- 2J / -pyran-4-yl)hydrazineyl)-2-oxoacetate (400 mg, 87% yield).

[0843] LC-MS (ESI): m / z = 410.2 [M+H]+, RT = 1.068 min.

[0844] 4-(l-(4-Chlorophenyl)cyclopropyl)-2-(tetrahydro-2H-pyran-4-yl)-l,2,4-triazinane- 3, 5, 6-trione

[0845] According to Scheme 6 Step 7: Ethyl 2-(2-((l-(4- chlorophenyl)cyclopropyl)carbamoyl)-2-(tetrahydro-27 / -pyran-4-yl)hydrazineyl)-2- oxoacetate (160 mg, 390 pmol) was added to solution of KO / Bu (43.8 mg, 390 pmol) in MeOH and the reaction mixture was stirred at rt overnight. The reaction mixture was evaporated under vacuum, dissolved in EtOAc, and washed with a solution of NaHCCh twice. The organic layer was dried over Na2SO4 and evaporated under vacuum to give 4-(l -(4-chlorophenyl)cyclopropyl)-2-(tetrahydro-27 / -pyran-4-yl)- 1 ,2,4-triazinane- 3, 5, 6-trione (100 mg, 70.5% yield).

[0846] 4-( 1 -(4-Chlorophenyl)cyclopropyl)-6-methoxy-2-( tetrahydro-2H-pyran-4-yl)-l , 2, 4- triazine-3, 5(2H, 4H) -dione

[0847] According to Scheme 6 Step 8: MesOBF4 (204 mg, 1.38 mmol) was added to a solution of 4-( l -(4-chlorophenyl)cyclopropyl)-2-(tetrahydro-27 / -pyran-4-yl)- l ,2,4-triazinane- 3, 5, 6-trione (100 mg, 275 pmol) in DCM at 0 °C and the reaction mixture was stirred overnight. When the reaction was completed, the reaction mixture was washed twice with a saturated solution of NaHCCE, dried over Na2SO4, and evaporated under vacuum. The crude residue was purified by HPLC (Chromatorex Cis SMB100-5T 100x19 mm 5 pm column; 0 - 5 min; 30 - 80% H2O / MeCN; flow rate: 30 mL / min (loading pump 4 mL / min MeCN)) to give 4-(l-(4-chlorophenyl)cyclopropyl)-6- methoxy-2-(tetrahydro-2J / -pyran-4-yl)-l,2,4-triazine-3,5(2J / ,4J7)-dione (50 mg, 48% yield) as a white solid.

[0848] 'H-NMR (CDC13, 400 MHz): 5 1.37 (m, 2H), 1.51 (m, 2H), 1.69 (m, 2H), 2.02 (m, 2H), 3.47 (t, 2H), 3.84 (s, 3H), 4.04 (m, 2H), 4.70 (m, 1H), 7.23 (m, 2H), 7.58 (d, 2H); LC-MS (ESI): m / z = 378.2 [M+H]+, RT = 3.748 min.

[0849] The compounds in the following table have been synthezised according to the same methods as previous Examples 1 to 7, as denoted in the column denoted as "Exp. nr". The compounds denoted with the asterisk (“*”) have been exemplified in the Examples.

[0850] Table 1: Compounds prepared according to the Examples.

[0851]

[0852]

[0853]

[0854]

[0855]

[0856]

[0857]

[0858]

[0859]

[0860] Physico-Chemical Data

[0861] Melting points: a) Melting point determination was performed on a Buchi B-540 apparatus. b) DSC analysis

[0862] DSC data were collected on Mettler Toledo DSC 822e calorimeter equipped with a refrigerated cooling system. The sample was placed into aluminium DSC pans covered with a pinhole punched lid. The sample cell was heated at a rate 10 °C / min. over the temperature range 25 to 350 °C. A nitrogen purge of 50 mL / min. was maintained over the sample. Melting points are expressed as integers at onset temperature of melting.

[0863] UPLC-MS method: - I l l -

[0864] UPLC-MS was carried out on an Zorbax SB-Cis cartridge (1.8 m, 4.6 x 50 mm) from Agilent, with a flow rate of 3 mL / min, at a temperature of 50 °C.

[0865] Mobile phases are Solvent A: MeCN / H2O / formic acid 0.1% (900: 100:2) and Solvent B: H2O / formic acid 0.1% (1000:2).

[0866] The gradient conditions used are: 3% Solvent A and 97% Solvent B to 100% A at 4.0 min, kept till 4.6 min and equilibrated to initial conditions at 4.61 min until 4.7 min.

[0867] Injection volume 5-20 pL. ES MS detector was used, acquiring both in positive and negative ionization modes. MS Ionization mode: Electrospray ionization (ESI); MS Scan range: 83 - 1000 m / z; UV detection: 215 nm, 254nm, 280 nm.

[0868] LC-MS methods:

[0869] Method 1 :

[0870] LC-MS were recorded on a Waters Micromass ZQ 2996 system by the following conditions:

[0871] Reverse phase HPLC was carried out on a Poroshell 120 SB-Cis column (4.6x30mm 2.7 pm) from Agilent, with a flow rate of 3 mL / min, at a temperature of 60 °C.

[0872] Mobile phases are Solvent A: water (0.1% formic acid) and Solvent B: MeCN (0.1% formic acid).

[0873] The gradient conditions used are: 0.01 min - 1% Solvent B, 1.5 min - 100% Solvent B, 1.73 min - 100% Solvent B. Injection volume 5-20 pL. MS Ionization mode: Electrospray ionization (ESI), ES MS detector was used, acquiring both in positive and negative ionization modes, MS Scan range: 83 - 600 m / z.

[0874] Method 2:

[0875] Reverse phase HPLC was carried out on a Poroshell 120 SB-Cis column (4.6x30mm 2.7 pm) from Agilent, with a flow rate of 1.5 mL / min, at a temperature of 60 °C. Mobile phases are Solvent A: water (0.1% formic acid) and Solvent B: MeCN (0.1% formic acid).

[0876] The gradient conditions used are: 0.01 min - 1% Solvent B, 5.00 min - 100% Solvent B, 5.99 min - 100% Solvent B. Injection volume 5-20 pL. MS Ionization mode: Electrospray ionization (ESI), ES MS detector was used, acquiring both in positive and negative ionization modes, MS Scan range: 83 - 1000 m / z.

[0877] Method 3 :

[0878] Reverse phase HPLC was carried out on a Poroshell 120 SB-Cis column (4.6x30mm 2.7 pm) from Agilent, with a flow rate of 3 mL / min, at a temperature of 60 °C.

[0879] Mobile phases: Solvent A: water (0.1% formic acid); Solvent B: MeCN (0.1% formic acid).

[0880] The gradient conditions used: 0.01 min - 1% Solvent B, 1.5 min - 100% Solvent B, 1.73 min - 100% Solvent B. Injection volume 5-20 pL. MS Ionization mode: Electrospray ionization (ESI), ES MS detector was used, acquiring both in positive and negative ionization modes, MS Scan range: 83 - 600 m / z.

[0881] NMR:

[0882] 1H-NMR spectra were recorded on a Bruker NMR-spectrometer Avance (600 MHz or 500 MHz) or Varian UNITY-Plus 400 (400 MHz) spectrometer. Chemical shifts are expressed in parts per million (ppm, 6 units). Splitting patterns describe apparent multiplicities and are designated as s (singlet), d (doublet), t (triplet), q (quadruplet), m (multiplet), br (broad).

[0883] Table 2: Physico-chemical data. (RT means retention time in minutes; [MH]+means the protonated mass of the compound (free base); nd = not determined).

[0884]

[0885] PHARMACOLOGY

[0886] The compounds provided in this invention are positive allosteric modulators of metabotropic GABA receptors; in particular they are positive allosteric modulators of GAB AB receptors. The compounds of the present invention do not appear to bind to the GABA recognition site, the orthosteric ligand site, but instead to an allosteric site within the seven transmembrane regions of the receptor. In the presence of GABA or an agonist of GABAB receptor, the compounds of this invention increase the GAB AB response. The compounds provided in this invention are expected to have their effect at GABAB receptors by virtue of their ability to increase the response of such receptors to GABA or GABAB agonists, enhancing the response of the receptor. Hence, the present invention relates to a compound for use as a medicine, as well as to the use of a compound according to the invention or a pharmaceutical composition according to the invention for the manufacture of a medicament for treating or preventing a condition in a mammal, including a human, the treatment or prevention of which is affected or facilitated by the neuromodulatory effect of GABAB allosteric modulators, in particular positive GABAB allosteric modulators. Some of the compounds of Formula (I) have been tested according to the following methods.

[0887] Because such positive allosteric modulators of GABAB receptors, including compounds of Formula (I), enhance the response of GABAB receptors to GABA, it is an advantage that the present methods utilize endogenous GABA.

[0888] Because positive allosteric modulators of GABAB receptors, including compounds of Formula (I), enhance the response of GABAB receptors to agonists, it is understood that the present invention extends to the treatment of neurological and psychiatric disorders associated with GABA dysfunction by administering an effective amount of a positive allosteric modulator of GABAB receptors, including compounds of Formula (I), in combination with a GABAB receptor agonist.

[0889] The compounds of the invention may be administered alone as a monotherapy or may administered in combination with one or more additional therapeutic agents. The selection of the one or more additional therapeutic agents will of course vary depending on the disease or condition to be treated and its severity. Such combination treatment may be achieved by way of simultaneous, sequential or separate dosing of the individual components of the treatment.

[0890] According to an aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the invention, or a pharmaceutically acceptable or a pharmaceutically acceptable acid or base additions salt thereof, a stereochemically isomeric form thereof or an A -oxi de form thereof, in combination with one or more additional therapeutic agents in association with a pharmaceutically acceptable carrier and / or excipient.

[0891] Examples of other therapeutic agents that may be used as part of a combination therapy with a compound of the present invention (e.g., as one of two or more active agents as part of double or more combinations) include, but are not limited to, the following:

[0892] (i) other agents useful in the treatment of substance use and addictive disorders such as buprenorphine, nalmefene, naloxone, metyrapone, naltrexone, ketoconazole, mirtazapine, atomoxetine, gabapentin, muscimol, baclofen, progabide, pregabalin, riluzole, vigabatrin, valproic acid, tiagabine, lamotrigine, phenytoin, carbamazepine, topiramate, a barbiturate, carisoprodol, chloral hydrate, glutethimide, L-theanine, kava, methaqualone, neuroactive steroids, z-drugs, propofol, scullcap, valerian, gammabutyrolactone, gamma-hydroxybutyric acid, phenibut, deramciclane, hyperforin, gabaculine, phenelzine, valproate, vigabatrin, lemon balm (Melissa officinalis), GABA, L-glutamine, picamilon, and tetanospasmin; (ii) alpha 7 nicotinic agonists such as, for example, compounds disclosed in W096 / 006098, WO97 / 030998, WO99 / 003859, WO00 / 042044, W001 / 029034, W001 / 60821, WOOl / 36417, W002 / 096912, W003 / 087102, W003 / 087103, W003 / 087104, W02004 / 016617, W02004 / 016616, and W02004 / 019947;

[0893] (iii) delta opioid agonists such as, for example, compounds disclosed in WO97 / 23466 and WO02 / 094794;

[0894] (iv) antidepressants such as, for example, amitriptyline, amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin duloxetine, elzasonan, escitaiopram, fluvoxamine, fluoxetine, gepirone, imipramine, ipsapirone, maprotiline, nortriptyline, nefazodone, paroxetine, phenelzine, protriptyline, reboxetine, robaizotan, sertraline, sibutramine, tianeptine, thionisoxetine, tranylcypromaine, trazodone, trimipramine, venlafaxine, vortioxetine and equivalents and pharmaceutically active isomer(s) and / or metaboiite(s) thereof;

[0895] (v) antipsychotics including, for example, amisulpride, aripiprazole, asenapine, benzisoxidil, bifeprunox, brexpiprazole, carbamazepine, cariprazine, clozapine, chlorpromazine, debenzapine, divalproex, duloxetine, eszopiclone, haloperidol, iloperidone, lamotrigine, loxapine, iurasidone, mesoridazine, olanzapine, paliperidone, perlapine, perphenazine, phenothiazine, phenyibutlypiperidine, pimozide, prochlorperazine, quetiapine, risperidone, sertindole, sulpiride, suproclone, suri clone, thioridazine, trifluoperazine, trimetozine, valproate, valproic acid, zopiclone, zotepine, zicronapine, ziprasidone, and equivalents and pharmaceutically active isomer(s) and / or metabolite(s) thereof;

[0896] (vi) anxiolytics including, for example, alnespirone, azapirones, benzodiazepines, barbiturates, and equivalents and pharmaceutically active isomer(s) and / or metabolite(s) thereof. Example anxiolytics include adinazolam, alprazolam, balezepam, bentazepam, bromazepam, brotizolam, buspirone, clonazepam, clorazepate, chlordiazepoxide, cyprazeparn, diazepam, diphenhydramine, estazolam, fenobam, flunitrazepam, flurazepam, fosazepam, lorazepam, lormetazepam, meprobamate, midazolam, nitrazepam, oxazepam, prazepam, quazepam, reclazepam, tracazolate, trepipam, temazepam, triazolam, uidazepam, and zolazepam; and equivalents and pharmaceutically active isomer(s) and / or metabolite(s) thereof;

[0897] (vii) neuropathic pain therapies including, for example, capsaicin, gabapentin, iidoderm, and pregabalin, and equivalents and pharmaceutically active isomer(s) and / or metabolite(s) thereof;

[0898] (viii) nociceptive pain therapies such as, for example, celecoxib, etoricoxib, lumiracoxib, rofecoxib, valdecoxib, diclofenac, loxoprofen, naproxen, and paracetamol, and equivalents and pharmaceutically active isomer(s) and / or metaboiite(s) thereof;

[0899] (ix) insomnia therapies including, for example, allobarbital, aionimid, amobarbital, benzoctamine, butabarbital, capuride, chloral, cloperidone, clorethate, dexclamol, ethchlorvynol, eszopiclone, etomidate, glutethimide, halazepam, hydroxyzine, iorediplon, mecloqualone, melatonin, mephobarbital, methaqualone, midaflur, nisobamate, pentobarbital, phenobarbital, propofol, ralmeteon, roletamide, suvorexant, triclofos, secobarbital, zaleplon, and Zolpidem, zopiclone and equivalents and pharmaceutically active isomer(s) and / or metabolite(s) thereof; and

[0900] (x) mood stabilizers including, for example, carbamazepine, divalproex, gabapentin, lamotrigine, lithium, olanzapine, quetiapine, valproate, valproic acid, and verapamil, and equivalents and pharmaceutically active isomer(s) and / or metabolite(s) thereof.

[0901] Example A

[0902] [35S] GTPyS binding assay

[0903] The [35S]GTPyS binding is a functional membrane-based assay used to study G-protein coupled receptor (GPCR) function, based on assessment of the initial step in receptor- mediated G protein activation in membranes prepared from cells expressing recombinant GPCR, here the GABAB receptor. The GTPyS binding assay is designed to evaluate the efficacy and potency of ligands by measuring the incorporation of radiolabeled GTPyS into G-proteins, providing quantitative data on receptor activation (Harper, Curr. Protoc. Pharmacol. 1998, 2.6,1-10, John Wiley & Sons, Inc.). This method is used commonly to study human GABAB receptor activation, and to characterize pharmacologically compounds (such as agonists, antagonists, allosteric modulators) binding to it (Urwyler et al., The Journal of Pharmacology and Experimental Therapeutics 2003, 307,322-330; De Lapp et al., GTPyS Binding Assays in: Markossian S, Grossman A, Brimacombe K, et al., editors. Assay Guidance Manual 2012).

[0904] Briefly, HEK293 cells were transfected with plasmids expressing GABAnia and GABAB2 receptor subunits and cell membranes prepared according to Urwyler et al., Molecular Pharmacology 2001, 60:963-971. Positive allosteric modulator compounds were incubated with cell membrane preparations at increasing concentrations (from 0.1 pM to 30 pM), in the presence of a pre-determined EC20 of GABA to evaluate their potency (EC50) and efficacy (% enhancement compared to 100% elicited by maximal concentration of GABA). Following 60 minutes incubation, the levels of radioactivity from bound [35S]-GTPyS was detected using a scintillation counter (Top-Count, Perkin- Elmer, Downers Grove, USA). The data generated was analysed using Prism (Graph Pad Software Inc, San Diego, USA) or Bioassay Enterprise (CambridgeSoft). The concentration-response curves were fitted to a four-parameter logistic equation (Y=Bottom + (Top-Bottom) / (l+10A((LogEC5o-X)*Hill Slope) allowing determination of EC50 values for each compound. Final EC50 mean values were calculated based on duplicates of minimum of 2 experiments.

[0905] The Table 3 below represents the mean EC50 obtained from at least three independent experiments of selected molecules performed in duplicate.

[0906] Table 3: Activity data for selected compounds

[0907] *Table legend:

[0908] NA: EC5O >1O pM

[0909] (+): 500 nM < EC50 <10 pM (++): 50 nM < EC50 < 500 nM

[0910] (+++): EC50 < 50 nM

[0911] The results shown in Table 3 demonstrate that the compounds described in the present invention are positive allosteric modulators of human GAB AB receptors.

[0912] Example B

[0913] Alcohol self-administration test in rats The 20 % alcohol self-administration model is considered a gold standard and is a routinely used method in the field to assess the reinforcing value of a substance (Augier et al., Neuropharmacology 2017, 42: 1789-1799).

[0914] Animals: Male Wistart rats (6-7 weeks old at arrival to facility) were housed in a temperature (23.0 ± 1.5 °C) and humidity (50 ± 10%) controlled facility on a reversed 12h / 12h cycle (lights off 07:00-19:00 / on: 19:00-07:00). Testing started at 8 weeks old and during dark phase. Animals had access to food and tap water ad libitum. The animals had not been subjected to other experiments before the study. Manipulations of animals were conducted carefully to reduce stress at the minimum. All experiments were performed in compliance with government regulations. Experimental protocols were approved by Animal Ethics Committees.

[0915] Assessment of alcohol operant self-administration: Experiments were conducted in a blinded design at room temperature (22.0 ± 1.5°C), and under red light in quiet conditions (no noise except those generated by ventilation and by the apparatus used for experiments). The experiments were conducted in identical operant boxes (Med Associates, Fairfax, VT, USA) (29.53 x 23.5 x 27.31 cm), placed in a sound attenuated cubicle with a ventilated fan. The boxes contained two levers and a cue light above each lever. A syringe filled with ethanol 20% was placed on a pump and attached to one cup through a polyethylene tubing. During the task, animals were operant conditioned to perform one action, typically a lever press, to receive a drug. As described by Augier et al. (Neuropharmacology 2017, 42: 1789-1799), rats were trained to self-administer a 20% alcohol solution 5 days a week during 30 minutes. During each 30-minute session, both levers were available with only one resulting in 0.1 mL ethanol delivery in the cup. Each reward was followed by a 5-second time-out during which lever presses did not lead to drug delivery but were still recorded. Once a stable self-administration was reached, rats were tested at the peak exposure, under a randomized counterbalanced order in a within-subject design across the test compound doses. Between each dosing cycle, rats were allowed to washout the drug with at least three consecutive self-administration sessions. Thus, at the end of the test, all rats were injected with each of the doses and served as their own control. Compound administration: Test compounds were dissolved in a solution of 10% 0 cyclodextrin in purified water. Test compounds were administered 30 minutes before testing by oral gavage (p.o.) in a volume of 1 mL / kg.

[0916] Statistical analyses'. Data were first examined for significant violations to the assumption of homogeneity of variances using Levene’s test. The qualified data were analyzed using analysis of variance (ANOVA), with factors for the respective analysis indicated in conjunction with its results. All post-hoc analyses were conducted when appropriate using a Tukey-HSD test. A difference was considered statistically significant at p < 0.05.

[0917] Effect of compounds on alcohol self-administration'. At doses of about 0.1 to 0.3 mg / kg, selected compounds of the invention reduced alcohol self-administration, as measured by the the total number of active presses and number of alcohol reinforcers, in a-dose dependent manner. There was no meaningful significant change in the number of presses on the inactive lever compared to baseline,

[0918] Example C

[0919] Marble Burying test

[0920] Anxiety models in rodents are used as standard tests to demonstrate anxiolytic-like properties of novel compounds. Mice exhibit a tendency to bury harmless novel objects when encountered in a test cage. Marble burying behavior in mice is reduced by compounds which are efficacious anxiolytics in humans. Thus, marble burying in mice has been used as a model for the prediction of anxiolytic-like effects of compounds (Millan, M.J. et al., Neuropharmacology 2002, 42, 677-684).

[0921] Subjects: The present studies were performed in accordance with the animal care and use policies. Male C57BL6 / j mice (20-30 g), were group housed in a temperature and humidity controlled facility on a 12 hour light / dark cycle for at least 5 days before use. Mice had access to food and water ad libitum except during marble burying experiments. Assessment of marble burying: The effect of compounds on marble burying behaviour in mice was tested. On the day of the test, animals were marked on their tails and weighed in a separate preparation room, 1 hour before drug administration. Test compound or vehicle was administered p.o. 60 minutes prior to the test session. Marble burying behaviour was tested in a separate experimental room. For the test, mice were placed individually into Plexiglas transparent open-boxes (42 x 22 x 40 cm) with 5 cm of sawdust and 25 marbles evenly spaced against the walls of the cage. The mice were left undisturbed in the cages for 30 minutes. After removal of the mice from the test cages, the number of marbles buried was counted. A marble was considered buried if it was 2 / 3 or more covered.

[0922] Compound administration: Test compounds were dissolved in a solution of 1% CMC / 0.25% Tween 80 in distilled water. Test compounds were administered 60 minutes before testing by oral gavage (p.o.) in a volume of 10 mL / kg. In each assay, a vehicle and reference positive control groups were tested.

[0923] Statistical analyses: Statistical analyses were performed using GraphPad PRISM version 4.01 statistical software (GraphPad, San Diego, CA, USA). Data were analyzed using ANOVA folloed by Bonferroni's test. The significance level was set at p < 0.05 when compared to the vehicle group.

[0924] Effect of compounds in the marble burying test in mice: At doses ranging from about 0.2 to 30 mg / kg, selected compounds of the invention significantly attenuated the marble burying behavior in mice.

[0925] FORMULATION EXAMPLES

[0926] Typical examples of recipes for the formulation of the invention are as follows:

[0927] 1. Tablets

[0928] Active ingredient 5 to 50 mg

[0929] Di-calcium phosphate 20 mg

[0930] Lactose 30 mg Talcum 10 mg

[0931] Magnesium stearate 5 mg

[0932] Potato starch ad 200 mg

[0933] In this Example, active ingredient can be replaced by the same amount of any of the compounds according to the present invention, in particular by the same amount of any of the exemplified compounds.

[0934] 2. Suspension

[0935] An aqueous suspension is prepared for oral administration so that each 1 milliliter 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.

[0936] 3. Injectable

[0937] A parenteral composition is prepared by stirring 1.5% by weight of active ingredient of the invention in 10% by volume propylene glycol and water.

[0938] 4. Ointment

[0939] Active ingredient 5 to 1000 mg

[0940] Stearyl alcohol 3 g

[0941] Lanoline 5 g

[0942] White petroleum 15 g

[0943] Water ad 100 g

[0944] In this Example, active ingredient can be replaced with the same amount of any of the compounds according to the present invention, in particular by the same amount of any of the exemplified compounds. Reasonable variations are not to be regarded as a departure from the scope of the invention. It will be obvious that the described invention may be varied in many ways by those skilled in the art.

Claims

CLAIMS1. A compound having the Formula (I):a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof or an A-oxide form thereof, wherein:R1is selected from the group of -O-(Ci-Ce)alkyl, -O-(Ci-C6)deuterioalkyl, - O-(C3-C7)cycloalkyl, -(C2)alkyl and -(C3)cycloalkyl;Z is selected from CH or N;J is selected from the group of -CH2-, -CHR2- and -CR2R3-;R2and R3are each independently a radical selected from the group of -(Ci- Ce)alkyl, -(Ci-Ce)haloalkyl, -(C3-C7)cycloalkyl and R2and R3together with the atom to which they are attached form a -(C3-C7)cycloalkyl;P represents an aryl or heteroaryl of formula:wherein each aryl or heteroaryl ring is optionally substituted with m radicals A, wherein m is an integer equal to zero, 1, 2, 3, 4 or 5; the or each (A)mis independently selected from the group of hydrogen, halogen, -CN, -CF3 and an optionally substituted radical selected from the group of -(Ci-Ce)alkyl, -(Ci-Ce)haloalkyl, -(C3-C7)cycloalkyl, -(Ci-Ce)alkylene-(C3- C7)cycloalkyl, aryl, -(Ci-Ce)alkylene-aryl, heteroaryl, -(Ci-Ce)alkylene- heteroaryl, heterocycle, -(Ci-C6)alkylene-heterocycle, -(Co-Ce)alkylene-OR4, -O- (C2-C6)alkylene-OR4-NR4(C2-C6)alkylene-OR5, -(Co-C6)alkylene-S-R4, -O-(C2-C6)alkylene-S-R4, -NR4-(C2-C6)alkylene-S-R5, -(Co-C6)alkylene-S(=0)-R4, -O- (Ci-C6)alkylene-S(=O)-R4, -NR4-(Ci-C6)alkylene-S(=O)-R5, -(Co-C6)alkylene- S(=O)2-R4, -O-(Ci-C6)alkylene-S(=O)2-R4, -NR4-(Ci-C6)alkylene-S(=O)2-R5, - (Co-C6)alkylene-NR4R5, -O-(C2-C6)alkylene-NR4R5, -NR4-(C2-C6)alkylene- NR5R6, -(C0-C6)alkylene-C(=O)-NR4R5, -O-(Ci-C6)alkylene-C(=O)-NR4R5, - NR4-(Ci-C6)alkylene-C(=O)-NR5R6, -(Co-C6)alkylene-NR4C(=0)-R5, -O-(C2- C6)alkylene-NR4C(=O)-R5, -NR4-(C2-C6)alkylene-NR5C(=O)-R6, -(Co- C6)alkylene-OC(=O)-R4, -O-(C2-C6)alkylene-OC(=O)-R4, -NR4-(C2-C6)alkylene- OC(=O)-R5, -(C0-C6)alkylene-C(=O)-OR4, -O-(Ci-C6)alkylene-C(=O)-OR4, - NR4-(Ci-C6)alkylene-C(=O)-OR5, -(Co-C6)alkylene-C(=0)-R4, -O-(Ci- C6)alkylene-C(=O)-R4and -NR4-(Ci-C6)alkylene-C(=O)-R5;R4, R5and R6are each independently hydrogen or an optionally substituted radical selected from the group of -(Ci-Ce)alkyl, -(Ci-Ce)haloalkyl, -(Ci- Ce)cyanoalkyl, -(C3-C7)cycloalkyl, -(Ci-C6)alkylene-(C3-C7)cycloalkyl, aryl, - (Ci-Ce)alkylene-aryl, heteroaryl, -(Ci-C6)alkylene-heteroaryl, heterocycle, -(Ci- C6)alkylene-heterocycle, -(Co-C6)alkylene-0-(Co-Ce)alkyl and -(Co-Ce)alkylene- N-((Co-Ce)alkyl)2, and R4and R5or R5and R6together with the atom to which they are attached form a -(C3-C7)cycloalkyl;L is selected from the group of a bond, or an optionally substituted radical -(Ci-C6)alkyl;Q represents a -(C3-C7)cycloalkyl, aryl, heteroaryl or heterocycle of formula:wherein each -(C3-C7)cycloalkyl, aryl, heteroaryl or heterocycle ring is optionally substituted with n radicals B, wherein n is an integer equal to zero, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 and 13; wherein Z1, Z2, Z3, Z4, Z5and Z6are each independently selected from C or N; x is an integer equal to 1, 2, 3 and 4; the or each (B)nis independently selected from the group of hydrogen, halogen, - CN, -CF3, -OH, -SH, -NH2 and an optionally substituted radical selected from the group of -(Ci-Ce)alkyl, -(Ci-Ce)haloalkyl, -(C3-C7)cycloalkyl, -(Ci-Ce)alkylene- (C3-C7)cycloalkyl, heterocycle, -(Co-Ce)alkylene-OR7, -O-(C2-Ce)alkylene-OR7- NR7(C2-C6)alkylene-OR8, -(Co-C6)alkylene-S-R7, -O-(C2-C6)alkylene-S-R7, - NR7-(C2-C6)alkylene-S-R8, -(Co-C6)alkylene-NR7R8, -O-(C2-C6)alkylene-NR7R8, -NR7-(C2-C6)alkylene-NR8R9and -(Co-C6)alkylene-C(=0)-NR7R8; R7, R8and R9are each independently hydrogen or an optionally substituted radical selected from the group of -(Ci-Ce)alkyl, -(Ci-Ce)haloalkyl, -(Ci-Ce)cyanoalkyl, -(C3-C7)cycloalkyl, -(Ci-C6)alkylene-(C3-C7)cycloalkyl, -(Co- Ce)alkylene-0-(Co-C6)alkyl and -(Co-C6)alkylene-N-((Co-Ce)alkyl)2 and R7and R8or R8and R9together with the atom to which they are attached form a -(C3- C7)cycloalkyl; wherein when Q is a aryl or heteroaryl; L is an optionally substituted radical -(Ci- Ce)alkyl.

2. The compound according to claim 1 having the Formula (I) wherein:R1is -O-(Ci-C6)alkyl.

3. The compound according to any preceding claim having the Formula (I) wherein: the cycloalkyl, heterocycle, aryl and heteroaryl ring systems of (A)mis selected from the group of azetidinyl, 5-azaspiro[2.3]hexanyl, dihydrofuranyl, furyl, imidazolidinyl, imidazolinyl, imidazolonyl, imidazolyl, isothiazolinyl, isothiazolyl, isoxazolidinyl, isoxazolinyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolidinyl, oxazolinyl, oxazolonyl, oxazolyl, oxetanyl, phenyl, piperazinonyl, piperazinyl, piperidinonyl, piperidinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridonyl, pyridyl, pyrimidyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolinyl, thiazolonyl, thiazolyl, thienyl, thiomorpholinyl, triazolinyl, triazinyl, triazolyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, and each ring of said ring system is optionally substituted independently with 1 to 3 substituents R4, R5or R6.

4. The compound according to any preceding claim having the Formula (I) wherein: the cycloalkyl and heterocycle ring systems of (B)nis selected from the group of azetidinyl, isoxazolidinyl, isoxazolinyl, morpholinyl, piperazinonyl, piperazinyl, piperidinonyl, piperidinyl, pyrrolidinonyl, pyrrolidinyl, tetrahydrofuranyl,tetrahydropyranyl, thiomorpholinyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, and each ring of said ring system is optionally substituted independently with 1 to 3 substituents R7, R8or R9.

5. The compound according to any preceding claim having the Formula (I), wherein: the or each (A)mis independently selected from the group of hydrogen, halogen, -CF3 and an optionally substituted radical selected from the group of - (Ci-Ce)alkyl, -(Ci-Ce)haloalkyl, -(C3-C7)cycloalkyl, heteroaryl, heterocycle and - (Co-Ce)alkylene-OR4; andR4is hydrogen or an optionally substituted radical selected from the group of - (Ci-Ce)alkyl and -(Ci-C6)haloalkyl.

6. The compound according to any preceding claim having the Formula (I), wherein: the or each (B)nis independently selected from the group of hydrogen, halogen, - CN, -CF3, -OH and an optionally substituted radical selected from the group of - (Ci-Ce)alkyl, -(Ci-Ce)haloalkyl, -(C3-C7)cycloalkyl, -(Co-Ce)alkylene-OR7and - (Co-Ce)alkylene-NR7R8; andR7and R8are each independently hydrogen or an optionally substituted radical - (Ci-C6)alkyl.

7. The compound according to any preceding claim having the Formula (II):a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof or an 7V-oxide form thereof, wherein:R1is -O-(Ci-C6)alkyl;J is selected from the group of -CH2- and -CHR2; R2is selected from the group of -(Ci-Ce)alkyl and -(C3-C7)cycloalkyl;L is an optionally substituted radical -(Ci-Ce)alkyl;8. The compound according to any preceeding claim having the Formula (III):a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof or an 7V-oxide form thereof wherein:L is an optionally substituted radical -(Ci-Ce)alkyl; the or each (A)mis independently selected from the group of hydrogen, halogen, -CF3 and an optionally substituted radical selected from the group of - (Ci-Ce)alkyl, -(Ci-Ce)haloalkyl, -(C3-C7)cycloalkyl and -(Co-Ce)alkylene-OR4;R4is an optionally substituted radical selected from the group of -(Ci-Ce)alkyl and -(Ci-Ce)haloalkyl;the or each (B)nis independently selected from the group of hydrogen, halogen, - CF3 and an optionally substituted radical selected from the group of -(Ci-Ce)alkyl, -(Ci-Ce)haloalkyl, -(Co-Ce)alkylene-OR7and -(Co-Ce)alkylene-NR7R8; andR7and R8are each independently hydrogen or an optionally substituted radical - (Ci-C6)alkyl.

9. The compound according to any one of claims 1 to 7 having the Formula (IV):a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof or an V-oxide form thereof wherein:L is an optionally substituted radical -(Ci-Ce)alkyl; the or each (A)mis independently selected from the group of hydrogen, halogen, - CF3 and an optionally substituted radical selected from the group of -(Ci-Ce)alkyl, -(Ci-Ce)haloalkyl and -(Co-Ce)alkylene-OR4;R4is an optionally substituted radical -(Ci-Ce)alkyl; the or each (B)nis independently selected from the group of hydrogen, halogen, - CF3 and an optionally substituted radical selected from the group of -(Ci-Ce)alkyl, -(Ci-Ce)haloalkyl, -(Co-Ce)alkylene-OR7and -(Co-Ce)alkylene-NR7R8; andR7and R8are each independently hydrogen or an optionally substituted radical - (Ci-C6)alkyl.

10. The compound according to any one of claims 1 to 5 having the Formula (V):a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof or an A-oxide form thereof wherein:R1is -O-(Ci-C6)alkyl;Z is selected from CH or N;J is selected from the group of -CH2-, -CHR2- and -CR2R3-;R2and R3are each independently a radical selected from the group of -(Ci- Ce)alkyl and R2and R3together with the atom to which they are attached form a - (C3-C7)cycloalkyl; x is an integer equal to 1, 2, 3 and 4; and the or each (A)mis independently selected from the group of hydrogen, halogen and an optionally substituted radical pyridinyl.

11. The compound according to any one of claims 1 to 9, wherein: the or each (A)mis independently selected from the group of hydrogen, halogen, and a radical -(Co-Ce)alkylene-OR4; andR4is -(Ci-C6)alkyl.

12. The compound according to any one of claims 1 to 9, wherein: the or each (B)nis independently selected from the group of hydrogen, halogen, - OH and an optionally substituted radical selected from the group of -(Ci-Ce)alkyl, -(Ci-Ce)haloalkyl, -(C3-C7)cycloalkyl and -(Co-Ce)alkylene-OR7; andR7is hydrogen or an optionally substituted radical -(Ci-Ce)alkyl.

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

14. The compound according to claim 1, wherein said compound is one or more selected from:and a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof or an A -oxi de form thereof.

15. The compound according to claim 14, wherein said compound is one or more selected from:and a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof or an A -oxi de form thereof.

16. The compound according to claims 15, wherein said compound is one or more selected from:and a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof or an A -oxi de form thereof.

17. The compound according to claims 15, wherein said compound is one or more selected from:and a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof or an A -oxi de form thereof.

18. The compound according to claims 14, wherein said compound is one or more selected from:and a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof or an A -oxi de form thereof.

19. The compound according to claim 1, wherein said compound is one or more selected from:4-(l-(4-chl oro-3 -methoxyphenyl)ethyl)-6-methoxy-2-(l-(4-methylpyridin-3-yl)ethyl)-1 ,2,4-triazine-3 , 5(2 / 7, 4 / 7)-di one2-((3 -fluoropyridin-4-yl)methyl)-6-methoxy-4-( 1 -(3 -methoxy -4- (trifluoromethyl)phenyl)ethyl)- 1 ,2,4-triazine-3 , 5(2 / 7, 4 / 7)-di one 2-((3-isopropyloxetan-3-yl)methyl)-6-methoxy-4-(l-(3-methoxy-4- (trifluoromethyl)phenyl)ethyl)- 1 ,2,4-triazine-3 , 5(2 / 7, 4 / 7)-di one4-(l -(4-chl oro-3 -methoxyphenyl)ethyl)-6-methoxy-2-((3 -methylpyrazin-2-yl)methyl)-1 ,2,4-triazine-3 , 5(2 / 7, 4 / 7)-di one4-(l -(4-chl oro-3 -methoxyphenyl)ethyl)-2-(5,5-dimethyltetrahydrofuran-3-yl)-6- methoxy-l,2,4-triazine-3,5(2 / 7,4 / 7)-dione4-(l -(4-chl oro-3 -methoxyphenyl)ethyl)-2-(imidazo[l,2-a]pyridin-5-ylmethyl)-6- methoxy-l,2,4-triazine-3,5(2 / 7,4 / 7)-dione4-(l-(4-chloro-3-methoxyphenyl)ethyl)-2-((3-chloropyridin-2-yl)methyl)-6-methoxy-1 ,2,4-triazine-3 , 5(2 / 7, 4 / 7)-di one4-(l -(4-chl oro-3 -methoxyphenyl)ethyl)-6-methoxy-2-(pyrazolo[l,5-a]pyri din-3- ylmethyl)-l,2,4-triazine-3,5(2 / 7,4 / 7)-dione4-(4-chloro-3-methoxybenzyl)-2-((2,6-dimethylpyridin-3-yl)methyl)-6-methoxy-l,2,4- tri azine-3, 5(2 / 7, 4 / 7)-di one4-(l -(4-chl oro-3 -methoxyphenyl)ethyl)-6-methoxy-2-((2-methylbenzo| 7]oxazol-7- yl)methyl)-l, 2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one4-(l-(4-chloro-3-methoxyphenyl)ethyl)-6-methoxy-2-((l -methyl- 1 / -indazol-4- yl)methyl)-l, 2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one4-(l-(4-chloro-3-methoxyphenyl)ethyl)-6-methoxy-2-((l-methyl-2- oxabicy clo[3.1.1]heptan-5-yl)methyl)-l, 2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one4-(l -(4-chl oro-3 -methoxyphenyl)ethyl)-2-((3,5-difluoropyridin-2-yl)methyl)-6- methoxy-1 ,2,4-triazine-3 , 5(277, 4 / 7)-di one4-(l -(4-chl oro-3 -methoxyphenyl)ethyl)-6-methoxy-2-((6-methylimidazo[ 1 ,2-a]pyridin-5-yl)methyl)-l,2,4-triazine-3,5(2 / 7,4 / 7)-dione4-(l -(4-chl oro-3 -methoxyphenyl)ethyl)-2-(imidazo[l,5-a]pyridin-8-ylmethyl)-6- methoxy-l,2,4-triazine-3,5(2 / 7,4 / 7)-dione4-(l -(4-chl oro-3 -methoxyphenyl)ethyl)-2-((5-fluoropyridin-3-yl)methyl)-6-methoxy-1 ,2,4-triazine-3 , 5(2 / 7, 4 / 7)-di one4-(l-(4-chloro-3-methoxyphenyl)ethyl)-6-methoxy-2-((5-(trifluoromethyl)pyri din-3- yl)methyl)-l,2,4-triazine-3,5(2 / / ,4 / / )-dione4-(l -(4-chl oro-3 -methoxyphenyl)ethyl)-2-((2,4-dimethyloxazol-5-yl)methyl)-6- methoxy-l,2,4-triazine-3,5(2 / / ,4 / / )-dione4-(l -(4-chl oro-3 -methoxyphenyl)ethyl)-2-(imidazo[ 1 ,2-a]pyridin-8-ylmethyl)-6- methoxy-l,2,4-triazine-3,5(2 / / ,4 / / )-dione4-(l -(4-chl oro-3 -methoxyphenyl)ethyl)-6-methoxy-2-((3 -(trifluoromethyl)pyrazin-2- yl)methyl)-l,2,4-triazine-3,5(2 / / ,4 / / )-dione4-(l -(4-chl oro-3 -methoxyphenyl)ethyl)-6-methoxy-2-((5-(trifluoromethyl)thiazol-4- yl)methyl)-l,2,4-triazine-3,5(2 / / ,4 / / )-dione4-(l -(4-chl oro-3 -methoxyphenyl)ethyl)-6-methoxy-2-(l-(6-methylpyridin-3-yl)ethyl)-1 ,2,4-triazine-3 , 5(2 / 7, 4 / 7)-di one3 -(1 -(4-chl oro-3 -methoxyphenyl)ethyl)-5-methoxy- 1 -((4-methoxypyri din-3 - yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one3-(l -(4-chl oro-3 -methoxyphenyl)ethyl)-5-methoxy-l-((4-(trifluoromethyl)pyri din-3- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one l-((2-oxabicyclo[2.

1. l]hexan-4-yl)methyl)-3-(l-(4-chloro-3-methoxyphenyl)ethyl)-5- methoxypyrimidine-2, 4(1 / 7, 3 / 7)-di one4-(l -(4-chl oro-3 -methoxyphenyl)ethyl)-6-methoxy-2-((l-(pyridin-4- yl)cyclopropyl)methyl)-l,2,4-triazine-3,5(2 / 7,4 / 7)-dione3 -(4-chl oro-3 -methoxybenzyl)-5 -methoxy- 1 -( 1 -(5 -methylpyri din-3 - yl)ethyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one5-methoxy-3-(3-methoxy-4-(trifluorornethyl)benzyl)-l-((4-rnethylpyri din-3- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one3-((3-(l-(4-chloro-3-methoxyphenyl)ethyl)-5-methoxy-2,4-dioxo-3,4- dihydropyrimidin-l(2 / 7)-yl)methyl)benzonitrile5-methoxy-3-(3-methoxy-4-(trifluorornethyl)benzyl)-l-(l-(5-rnethylpyri din-3- yl)ethyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one3-(4-fluoro-3-(trifluoromethyl)benzyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one3-(4-chloro-3-(trifluoromethoxy)benzyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one3-(4-chloro-3-(trifluoromethyl)benzyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one3-(4-chloro-3-fluorobenzyl)-5-methoxy-l-((5-methylpyridazin-4-yl)methyl)pyrimidine-2,4(l / 7,3 / 7)-dione3-(3-chloro-4-(trifluoromethyl)benzyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one3-(4-chloro-3-isopropoxybenzyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one5-methoxy-3-(3-methoxy-4-(trifluoromethyl)benzyl)-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one4-(l -(4-chl oro-3 -methoxyphenyl)ethyl)-6-methoxy-2-( 1 -(pyri din-3 -yl)ethyl)- 1 ,2,4- triazine-3, 5(2 / / , 4 / / )-di one3-((4-(l -(4-chl oro-3 -methoxyphenyl)ethyl)-6-methoxy-3,5-di oxo-4, 5-dihydro- 1,2, 4- triazin-2(3 / 7)-yl)methyl)-4-methylbenzonitrile4-(l -(4-chl oro-3 -methoxyphenyl)ethyl)-2-((3,5-dimethylisothiazol-4-yl)methyl)-6- methoxy-l,2,4-triazine-3,5(2 / / ,4 / 7)-dione4-(l -(4-chl oro-3 -methoxyphenyl)ethyl)-6-methoxy-2-((3-methylisoxazol-4-yl)methyl)-1 ,2,4-triazine-3 , 5(2 / 7, 4 / 7)-di one4-(l -(4-chl oro-3 -methoxyphenyl)ethyl)-6-methoxy-2-(l-(3-methylisoxazol-4-yl)ethyl)-1 ,2,4-triazine-3 , 5(2 / 7, 4 / 7)-di one4-(l -(4-chl oro-3 -methoxyphenyl)ethyl)-2-((2,4-dimethylpyridin-3-yl)methyl)-6- methoxy-l,2,4-triazine-3,5(2 / 7,4 / 7)-dione4-(l -(4-chl oro-3 -methoxyphenyl)ethyl)-2-((3-cy cl opropyl-6-methylpyridazin-4- yl)methyl)-6-methoxy-l,2,4-triazine-3,5(2 / 7,4 / 7)-dione4-(4-chloro-3-methoxybenzyl)-2-(l-(5-fluoropyridin-3-yl)ethyl)-6-methoxy-l,2,4- triazine-3, 5(2 / 7, 4 / 7)-di one4-(l -(4-chl oro-3 -methoxyphenyl)ethyl)-6-methoxy-2-((5-methyloxazol-4-yl)methyl)-1 ,2,4-triazine-3 , 5(2 / 7, 4 / 7)-di one3 -(1 -(4-chl oro-3 -methoxyphenyl)ethyl)-5-methoxy- 1 -((1 -methyl- l / 7-pyrrolo[2,3 -Z>]pyridin-4-yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one4-(l -(4-chl oro-3 -methoxyphenyl)ethyl)-2-((3-isopropoxypyridazin-4-yl)methyl)-6- methoxy-l,2,4-triazine-3,5(2 / 7,4 / 7)-dione3-(l -(4-chl oro-3 -rnethoxyphenyl)ethyl)-l-((2-(dimethylamino)pyridin-3-yl)methyl)-5- methoxypyrimidine-2, 4(1 / 7, 3 / 7)-di one l-((2-(dimethylamino)pyridin-3-yl)methyl)-5-methoxy-3-(3-methoxy-4-(trifluoromethyl)benzyl)pyrimidine-2,4(lH,3H)-dione3-(4-chloro-3-cyclopropylbenzyl)-5-methoxy-l-((4-methylpyridin-3- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one4-(l -(4-chl oro-3 -rnethoxyphenyl)ethyl)-6-methoxy-2-((3-methoxy-5-methylpyridazin-4-yl)methyl)-l,2,4-triazine-3,5(2 / 7,4 / 7)-dione l-((2-oxabicyclo[2.1.1]hexan-4-yl)methyl)-3-(4-chloro-3-(5-azaspiro[2.3]hexan-5- yl)benzyl)-5-methoxypyrimidine-2,4(l / 7,3 / 7)-dione3-(4-chloro-3-cyclopropylbenzyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one3-((4-(l -(4-chl orophenyl)ethyl)-6-m ethoxy-3, 5 -di oxo-4, 5-dihy dro-1, 2, 4-triazin-2(3 / 7)- yl)methyl)benzonitrile3 -((3 -(4-chl oro-3 -(pyri din-3-yl)benzyl)-5-methoxy-2,4-di oxo-3, 4-dihydropyrimidin-1 (2 / 7)-yl)methyl)benzonitrile3-(3-chloro-4-(trifluoromethyl)benzyl)-5-methoxy-l-((2-methylpyri din-3- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one3 -((3 -(4-chl oro-3 -(pyri din-3-yl)benzyl)-5-methoxy-2,4-di oxo-3, 4-dihy dropyrimidin- l(2 / 7)-yl)methyl)-2-methylbenzonitrile4-(3-chloro-4-(trifluoromethyl)benzyl)-2-((2,4-dimethylpyridin-3-yl)methyl)-6- methoxy-1 ,2,4-triazine-3 , 5(2 7, 4 / 7)-di one4-(3-chloro-4-(trifluoromethyl)benzyl)-2-((3-isopropyloxetan-3-yl)methyl)-6-methoxy-1 ,2,4-triazine-3 , 5(2 / 7, 4 / 7)-di one4-(3 -chi oro-4-(trifluoromethyl)benzyl)-6-methoxy-2-(l-(4-methylpyri din-3 -yl)ethyl)-1.2.4-triazine-3 , 5(2 / 7, 4 / 7)-di one4-(3-chloro-4-(trifluoromethyl)benzyl)-6-methoxy-2-((6-methylimidazo[l,2-a]pyridin-5-yl)methyl)-l,2,4-triazine-3,5(2 / / ,4 / 7)-dione3-((3-(4-chloro-3-(pyridin-3-yl)benzyl)-5-methoxy-2,4-dioxo-3,4-dihydropyrimidin- l(2 / 7)-yl)methyl)-5-fluorobenzonitrile3-(l-(4-chl oro-3 -methoxyphenyl)-2-methylpropyl)-5-methoxy-l-((4-methylpyri din-3- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one4-(l-(4-chlorophenyl)propyl)-6-methoxy-2-((4-methylpyridin-3-yl)methyl)-l,2,4- tri azine-3, 5(2 / 7, 4 / 7)-di one3-(l-(4-chloro-3-methoxyphenyl)-2-methylpropyl)-l-((2,4-dimethylpyridin-3- yl)methyl)-5-methoxypyrimidine-2, 4(1 / 7, 3 / 7)-di one4-(4-chloro-3-(5-azaspiro[2.3]hexan-5-yl)benzyl)-6-methoxy-2-((4-methylpyri din-3- yl)methyl)-l, 2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one3-((4-(4-chloro-3-(5-azaspiro[2.3]hexan-5-yl)benzyl)-6-methoxy-3,5-dioxo-4,5- dihydro- 1 ,2,4-triazin-2(3 / 7)-yl)methyl)benzonitrile4-(4-chl oro-3 -(pyri din-3 -yl)benzyl)-6-methoxy-2-(tetrahydro-2Z7-pyran-4-yl)- 1,2, 4- tri azine-3, 5(2 / 7, 4 / 7)-di one3 -((4-(4-chl oro-3 -(pyri din-3-yl)benzyl)-6-methoxy-3,5-di oxo-4, 5-dihydro- 1,2, 4-tri azin-2(3 / 7)-yl)methyl)-2-methylbenzonitrile4-(3-fluoro-4-isopropylbenzyl)-6-methoxy-2-((4-methylpyridin-3-yl)methyl)-l,2,4- tri azine-3, 5(2 / 7, 4 / 7)-di one4-(3-chloro-4-(trifluoromethyl)benzyl)-2-((5-fluoro-2-methylpyridin-3-yl)methyl)-6- methoxy-1, 2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one3 -((4-(4-chl oro-3 -(5 -fluoropyri din-3 -yl)benzyl)-6-methoxy-3 , 5 -di oxo-4, 5 -dihy dro-1.2.4-tri azin-2(3 / 7)-yl)methyl)-2-methylbenzonitrile4-(4-chloro-3-isopropylbenzyl)-6-methoxy-2-((4-methylpyridin-3-yl)methyl)-l,2,4- tri azine-3, 5(2 / 7, 4 / 7)-di one l-((2-oxabicyclo[2.

1. l]hexan-4-yl)methyl)-3-(4-chloro-3-(pyridin-3-yl)benzyl)-5- methoxypyrimidine-2, 4(1 / 7, 3 / 7)-di one3-(4-chloro-3-(pyridin-3-yl)benzyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one4-(4-chloro-3-(5-azaspiro[2.3]hexan-5-yl)benzyl)-6-methoxy-2-((5-methylpyridazin-4- yl)methyl)-l, 2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one4-(4-chloro-3-(5-fluoropyridin-3-yl)benzyl)-2-((3-isopropyloxetan-3-yl)methyl)-6- methoxy-l,2,4-triazine-3,5(2 / 7,4 / 7)-dione4-(4-chl oro-3 -(5 -fluoropyri din-3 -yl)benzyl)-6-methoxy-2-((6-methylimidazo[ 1,2- a]pyridin-5-yl)methyl)-l, 2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one4-(l-(4-chlorophenyl)propyl)-6-methoxy-2-(tetrahydro-2 / 7-pyran-4-yl)-l,2,4-triazine-3 , 5 (2 / 7,4 / 7)-dione l-((2-oxabicyclo[2.

1. l]hexan-4-yl)methyl)-3-(4-chloro-3-(pyrimidin-5-yl)benzyl)-5- methoxypyrimidine-2, 4(1 / 7, 3 / 7)-di one4-(4-chl oro-3 -(5 -fluoropyri din-3 -yl)benzyl)-6-methoxy-2-( 1 -(5 -methylpyri din-3 - yl)ethyl)-l, 2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one3 -((3 -(4-chl oro-3 -(5 -fluoropyri din-3 -yl)benzyl)-5-methoxy-2,4-dioxo-3,4- dihydropyrimidin-l(2 / 7)-yl)methyl)-2-m ethylbenzonitrile4-(4-chl oro-3 -(5 -fluoropyri din-3 -yl)benzyl)-6-methoxy-2-( 1 -(4-methylpyri din-3 - yl)ethyl)-l, 2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one4-(l -(4-chl orophenyl)-2-methylpropyl)-2-((2,4-dimethylpyridin-3-yl)methyl)-6- methoxy-l,2,4-triazine-3,5(2 / 7,4 / 7)-dione4-(l -(4-chl orophenyl)-2-methylpropyl)-2-((3,5-dimethylisoxazol-4-yl)methyl)-6- methoxy-l,2,4-triazine-3,5(2 / 7,4 / 7)-dione4-(l -(4-chl orophenyl)-2-methylpropyl)-6-methoxy-2-((4-methylpyridin-3-yl)methyl)-1 ,2,4-triazine-3 , 5(2 / 7, 4 / 7)-di one4-(l -(4-chl orophenyl)-2-methylpropyl)-2-((2-(dimethylamino)pyridin-3-yl)methyl)-6- methoxy-l,2,4-triazine-3,5(2 / 7,4 / 7)-dione4-(l -(4-chl orophenyl)-2-methylpropyl)-6-methoxy-2-((6-methylimidazo[l,2-a]pyri din-5-yl)methyl)- 1,2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one4-(l-(4-chlorophenyl)propyl)-6-methoxy-2-(pyrazolo[l,5-a]pyridin-3-ylmethyl)-l,2,4- tri azine-3, 5(2 / 7, 4 / 7)-di one4-(4-chloro-3 -(5 -fluoropyri din-3 -yl)benzyl)-6-methoxy-2-((4-methylpyri din-3- yl)methyl)-l,2,4-triazine-3,5(2 / / ,4 / / )-dione3-(4-chloro-3-(5-fluoropyridin-3-yl)benzyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / , 3 / )-di one3-(l-(4-chlorophenyl)-2-methylpropyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one3 -(4-chl oro-3 -(pyri din-3 -yl)benzyl)-5 -methoxy- 1 -(tetrahy dro-2 / 7-pyran-4- yl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one4-(4-chloro-3 -(5 -fluoropyri din-3 -yl)benzyl)-2-((2-(dimethylamino)pyri din-3- yl)methyl)-6-methoxy-l,2,4-triazine-3,5(2 / 7,4 / 7)-dione4-(3-chloro-4-(trifluoromethyl)benzyl)-2-((5-fluoro-4-methylpyridin-3-yl)methyl)-6- methoxy-l,2,4-triazine-3,5(2 / 7,4 / 7)-dione3 -(4-chl oro-3 -(pyri din-3 -yl)benzyl)-5 -methoxy- 1 -((3 -methylpyrazin-2- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one3 -(4-chl oro-3 -(pyri din-3 -yl)benzyl)-5 -methoxy- 1 -((2 -methylpyri din-3 - yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one3-(4-chloro-3-(pyridin-3-yl)benzyl)-l-((3-fluoropyridin-2-yl)methyl)-5- methoxypyrimidine-2, 4(1 / 7, 3 / 7)-di one4-(l -(4-chl orophenyl)propyl)-6-methoxy-2-((l-methyl-lZ / -indazol-4-yl)m ethyl)- 1,2, 4- tri azine-3, 5(2 / 7, 4 / 7)-di one4-(l -(4-chl orophenyl)propyl)-2-(imidazo[ 1 , 5-a]pyridin- 1 -ylmethyl)-6-methoxy- 1 ,2,4- tri azine-3, 5(2 / 7, 4 / 7)-di one4-(l-(4-chlorophenyl)-2-methylpropyl)-6-methoxy-2-(tetrahydro-2 / 7-pyran-4-yl)-l,2,4- tri azine-3, 5(2 / 7, 4 / 7)-di one3 -(4-chl oro-3 -(4-methylpyri din-3-yl)benzyl)-5-methoxy-l -(tetrahy dro-2 / 7-pyran-4- yl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one3-(4-chloro-3-isopropylbenzyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one4-(l-(4-chlorophenyl)propyl)-6-methoxy-2-((2-methyl-2 / / -indazol-4-yl)methyl)-l,2,4- triazine-3, 5(2H, 4 / 7)-di one 4-(l-(4-chlorophenyl)-2-methylpropyl)-6-methoxy-2-((2-(trifluoromethyl)pyri din-3- yl)methyl)-l, 2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one4-(4-chloro-3-isopropylbenzyl)-6-methoxy-2-((5-methylpyridazin-4-yl)methyl)-l,2,4- tri azine-3, 5(2H, 4 / 7)-di one4-(l-(4-chlorophenyl)-2-methylpropyl)-6-methoxy-2-((4-methyltetrahydro-2 / / -pyran-4- yl)methyl)-l, 2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one3-(l-(4-chlorophenyl)propyl)-5-methoxy-l-((3-(trifluoromethyl)pyri din-2- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one2-((2-oxabicyclo[2.

1. l]hexan-4-yl)methyl)-4-(l-(4-chlorophenyl)-2-methylpropyl)-6- methoxy-1, 2, 4-tri azine-3, 5(2 / 7, 4 / Z)-di one3-(l-(4-chlorophenyl)propyl)-5-methoxy-l-(tetrahydro-2 / / -pyran-4-yl)pyrimidine-2,4(l / / ,3 / / )-dione4-(l-(4-chlorophenyl)propyl)-6-methoxy-2-((2-methylpyrazolo[l,5-a]pyri din-3- yl)methyl)-l, 2, 4-tri azine-3, 5(2 / 7, 4 / Z)-di one3-(l-(4-chlorophenyl)-2-methylpropyl)-5-methoxy-l-(tetrahydro-2 / / -pyran-4- yl)pyrimidine-2, 4(1 7, 3 7)-di one3-(l-(4-chlorophenyl)propyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one3-(l-(4-chlorophenyl)propyl)-5-methoxy-l-((2-(trifluoromethyl)pyri din-3- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one4-(l-(4-chlorophenyl)propyl)-6-methoxy-2-((5,6,7,8-tetrahydroimidazo[l,2-a]pyridin-5-yl)methyl)- 1,2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one3-(l-(4-chlorophenyl)propyl)-5-methoxy-l-((4-(trifluoromethyl)pyri din-3- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one l-((2-oxabicyclo[2.

1. l]hexan-4-yl)methyl)-3-(4-chloro-3-(5-fluoropyridin-3- yl)benzyl)-5-methoxypyrimidine-2,4(l / / ,3 / 7)-dione4-(l-(4-chlorophenyl)ethyl)-6-cyclopropoxy-2-((4-methylpyridin-3-yl)methyl)-l,2,4- tri azine-3, 5(2 / 7, 4 / 7)-di one4-(l-(4-chlorophenyl)propyl)-2-cy cl ohexyl-6-methoxy- 1,2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one4-(l-(4-chlorophenyl)propyl)-6-methoxy-2-((3-(trifluoromethyl)pyrazin-2-yl)methyl)-1 ,2, 4-tri azine-3 , 5(2 / 7, 4 / 7)-di one4-(l-(4-chlorophenyl)cyclopropyl)-6-methoxy-2-(tetrahydro-2 / / -pyran-4-yl)-l,2,4- tri azine-3, 5(2 / 7, 4 / 7)-di one4-(l-(4-chlorophenyl)propyl)-6-methoxy-2-(oxepan-4-yl)- 1,2, 4-tri azine-3, 5(2 / 7, 4 / 7)- dione3-(l-(4-chlorophenyl)propyl)-5-methoxy-l-((2-methylpyridin-3-yl)methyl)pyrimidine-2,4(l / / ,3 / 7)-dione3-(l-(4-chlorophenyl)propyl)-l-((3-chloropyridin-4-yl)methyl)-5-methoxypyrimidine-2,4(l / / ,3 / 7)-dione4-(l -(4-chlorophenyl)propyl)-2-((3 -chloropyridin-2-yl)methyl)-6-methoxy- 1 ,2,4- tri azine-3, 5(2 / 7, 4 / 7)-di one3-(l-(4-chlorophenyl)propyl)-5-methoxy-l-((4-methylpyridin-3-yl)methyl)pyrimidine-2,4(l / / ,3 / 7)-dione4-(l-(4-chlorophenyl)propyl)-6-methoxy-2-((l-methoxycyclobutyl)methyl)-l,2,4- triazine-3, 5(2H, 4 / 7)-di one4-(4-chloro-3-fluorobenzyl)-2-cy cl ohexyl-6-methoxy- 1,2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one4-(l-(4-chlorophenyl)propyl)-6-methoxy-2-(spiro[3.3]heptan-2-yl)- 1,2, 4-tri azine- 3,5(2 / 7,4 / 7)-dione3-((4-chlorophenyl)(cyclopropyl)methyl)-l-((3-chloropyridin-2-yl)methyl)-5- methoxypyrimidine-2, 4(1 / 7, 3 / 7)-di one4-((4-chlorophenyl)(cyclopropyl)methyl)-6-methoxy-2-((l-methyl-2- oxabicy clo[3.1.1]heptan-5-yl)methyl)-l, 2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one4-((4-chlorophenyl)(cyclopropyl)methyl)-2-cyclopentyl-6-methoxy-l,2,4-triazine- 3,5(2 / 7,4 / 7)-dione3-((4-chlorophenyl)(cy cl opropyl)methyl)-5-methoxy-l-((2-(trifluoromethyl)pyri din-3- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one4-((4-chlorophenyl)(cyclopropyl)methyl)-6-methoxy-2-((l- methoxycyclobutyl)methyl)-l,2,4-triazine-3,5(2 / / ,4 / / )-dione4-((4-chlorophenyl)(cyclopropyl)methyl)-6-methoxy-2-(spiro[2.5]octan-6-yl)-l,2,4- triazine-3, 5(2 / , 4 / )-di one 4-((4-chlorophenyl)(cyclopropyl)methyl)-6-methoxy-2-(tetrahydro-2 / 7-pyran-4-yl)-1 ,2,4-triazine-3 , 5(2 / 7, 4 / 7)-di one4-(l-(4-chlorophenyl)-2-methylpropyl)-6-methoxy-2-((l-methyl-2- oxabicyclo[3.1.1]heptan-5-yl)methyl)-l,2,4-triazine-3,5(2 / 7,4 / 7)-dione2-((2-oxabicyclo[2.

1. l]hexan-4-yl)methyl)-4-((4-chlorophenyl)(cyclopropyl)methyl)-6- methoxy-1 ,2,4-triazine-3 , 5(2 / 7, 4 / 7)-di one1-((2-oxabicyclo[2.

1. l]hexan-4-yl)methyl)-3-((4-chlorophenyl)(cyclopropyl)methyl)-5- methoxypyrimidine-2, 4(1 / 7, 3 / 7)-di one 4-((4-chlorophenyl)(cyclopropyl)methyl)-2-((3-chloropyridin-2-yl)methyl)-6-methoxy-1 ,2,4-triazine-3 , 5(2 / 7, 4 / 7)-di one4-((4-chlorophenyl)(cyclopropyl)methyl)-6-methoxy-2-((3-(trifluoromethyl)pyrazin-2- yl)methyl)-l,2,4-triazine-3,5(2 / 7,4 / 7)-dione4-((4-chlorophenyl)(cy cl opropyl)methyl)-2-((3-fluoropyri din-2 -yl)methyl)-6-methoxy-1 ,2,4-triazine-3 , 5(2 / 7, 4 / 7)-di one 4-(l-(4-chlorophenyl)butyl)-6-methoxy-2-((3-methylpyrazin-2-yl)methyl)-l,2,4- triazine-3, 5(2 / 7, 4 / 7)-di one3-(l-(4-chlorophenyl)butyl)-5-methoxy-l-((2-methylpyridin-3-yl)methyl)pyrimidine-2,4(l / 7,3 / 7)-dione4-(l-(4-chlorophenyl)butyl)-2-((3-chloropyridin-2-yl)methyl)-6-methoxy-l,2,4- tri azine-3, 5(2 / 7, 4 / 7)-di one3-((4-chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-((2-methylpyridin-3- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one2-((2-oxabicyclo[2.

1. l]hexan-l-yl)methyl)-4-((4-chlorophenyl)(cyclopropyl)methyl)-6- methoxy-1, 2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one3-(l-(4-chlorophenyl)butyl)-5-methoxy-l-((2-(trifluoromethyl)pyri din-3- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one4-((4-chlorophenyl)(cyclopropyl)methyl)-6-methoxy-2-((3-methylisoxazol-4- yl)methyl)-l, 2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one2-((2-oxabicyclo[2.

1. l]hexan-4-yl)methyl)-4-(l -(4-chl orophenyl)butyl)-6-methoxy-1.2.4-triazine-3 , 5(2 7, 4 / 7)-di one4-((4-chlorophenyl)(cyclopropyl)methyl)-2-((3-isopropyloxetan-3-yl)methyl)-6- methoxy-1 ,2,4-triazine-3 , 5(2 / 7, 4 / 7)-di one4-(l -(4-chl orophenyl)propyl)-2-(4,4-difluorocyclohexyl)-6-methoxy- 1,2, 4-tri azine-3,5(2 / 7,4 / 7)-dione3-((4-chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-(tetrahydro-2 / 7-pyran-4- yl)pyrimidine-2, 4(1 / , 3 / )-di one3-(cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l-(tetrahydro-2 / 7-pyran-4- yl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one(5)-4-((4-chlorophenyl)(cyclopropyl)methyl)-6-methoxy-2-(tetrahydro-2 / 7-pyran-4-yl)-1.2.4-triazine-3 , 5(2 / 7, 4 / 7)-di one(7?)-4-((4-chlorophenyl)(cyclopropyl)methyl)-6-methoxy-2-(tetrahydro-2 / 7-pyran-4-yl)-1.2.4-triazine-3 , 5(2 / 7, 4 / 7)-di one4-(l-(4-chlorophenyl)propyl)-6-methoxy-2-((l-methoxycyclopentyl)methyl)-l,2,4- tri azine-3, 5(2 / 7, 4 / 7)-di one2-((2-oxabicyclo[3.1.1]heptan-l-yl)methyl)-4-((4-chlorophenyl)(cy cl opropyl)m ethyl)-6-methoxy-l, 2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one4-((4-chlorophenyl)(cyclopropyl)methyl)-6-methoxy-2-((tetrahydro-2 / 7-pyran-4- yl)methyl)-l, 2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one4-((4-chlorophenyl)(cyclopropyl)methyl)-6-methoxy-2-((3-methylpyrazin-2- yl)methyl)-l, 2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one4-(l-(4-chlorophenyl)propyl)-2-(4,4-dimethylcy cl ohexyl)-6-methoxy-l, 2, 4-tri azine-3 , 5 (2 / 7,4 / 7)-dione3-(l -(4-chl orophenyl)butyl)-5-methoxy-l-(tetrahydro-2 / 7-pyran-4-yl)pyrimidine-2,4(l / 7,3 / 7)-dione3-((4-chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-(pyridazin-4- ylmethyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one4-((4-chlorophenyl)(cyclopropyl)methyl)-2-((2-hydroxypyridin-4-yl)methyl)-6- methoxy-1, 2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one3 -((4-chl orophenyl)(cy cl opropyl)methyl)-l-((2-(dimethylamino)pyri din-3 -yl)m ethyl)-5-methoxypyrimidine-2, 4(1 / 7, 3 / 7)-di one3-((4-chlorophenyl)(cy cl opropyl)methyl)-5-methoxy-l-((4-methoxypyri din-3- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one3-(l -(4-chl orophenyl)butyl)-5-methoxy-l-((5-methylpyridazin-4-yl)methyl)pyrimidine-2,4(l / 7,3 / 7)-dione4-(l -(4-chl orophenyl)butyl)-6-methoxy-2-((3-(trifluoromethyl)pyrazin-2-yl)methyl)-1.2.4-tri azine-3 , 5(2 / 7, 4 / 7)-di one4-((4-chlorophenyl)(cyclopropyl)methyl)-2-((3,5-difluoropyridin-2-yl)methyl)-6- methoxy-1, 2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one3-((4-chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-((4-methyltetrahydro-2 / 7-pyran-4-yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one4-(l -(4-chl orophenyl)propyl)-6-methoxy-2-((2-methyltetrahydrofuran-2-yl)methyl)-1 ,2, 4-tri azine-3 , 5(2 / 7, 4 / 7)-di one4-(l -(4-chl orophenyl)butyl)-6-methoxy-2-((l-methyl-2-oxabicyclo[3.1.1]heptan-5- yl)methyl)-l, 2, 4-tri azine-3, 5(2 / 7, 4 / 7)-di one3-((4-chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one3-((4-chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-(2-oxaspiro[3.3]heptan-6- yl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one4-((4-chlorophenyl)(cyclopropyl)methyl)-6-methoxy-2-((4-methyltetrahydro-2 / / -pyran-4-yl)methyl)-l,2,4-triazine-3,5(2 / / ,4 / / )-dione4-((5-chloropyridin-2-yl)(cyclopropyl)methyl)-6-methoxy-2-(tetrahydro-2 / 7-pyran-4- yl)-l,2,4-triazine-3,5(2 / 7,4 / 7)-dione4-((5-chloropyridin-3-yl)(cyclopropyl)methyl)-6-methoxy-2-(tetrahydro-2 / 7-pyran-4- yl)-l,2,4-triazine-3,5(2 / 7,4 / 7)-dione3-((4-chlorophenyl)(cyclopropyl)methyl)-l-((5-fluoropyridin-3-yl)methyl)-5- methoxypyrimidine-2, 4(1 / , 3 / )-di one3-((4-chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-(pyrimidin-5- ylmethyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one4-((4-chlorophenyl)(cyclopropyl)methyl)-2-((2-(dimethylamino)pyridin-4-yl)methyl)-6-methoxy-l,2,4-triazine-3,5(2 / 7,4 / 7)-dione3-((4-chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-((3-methylpyrazin-2- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one4-((4-chlorophenyl)(cyclopropyl)methyl)-6-methoxy-2-(2-oxaspiro[3.3]heptan-6-yl)-1 ,2,4-triazine-3 , 5(2 / 7, 4 / 7)-di one4-(l-(4-chlorophenyl)butyl)-6-methoxy-2-(tetrahydro-2 / 7-pyran-4-yl)-l,2,4-triazine-3 , 5 (2 / 7,4 / 7)-dione4-(cy cl opropyl(4-fluorophenyl)methyl)-2-((3-fluoropyri din-2 -yl)methyl)-6-methoxy-1 ,2,4-triazine-3 , 5(2 / 7, 4 / 7)-di one(5)-3-((4-chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-(tetrahydro-2 / 7-pyran-4- yl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one(7?)-3-((4-chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-(tetrahydro-2 / 7-pyran-4- yl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one3-(cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one3-(cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l-(pyrimidin-5- ylmethyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one4-((4-chlorophenyl)(cyclobutyl)methyl)-6-methoxy-2-(tetrahydro-2 / 7-pyran-4-yl)-1 ,2,4-triazine-3 , 5(2 / 7, 4 / 7)-di one3 -(cyclopropyl(4-fluorophenyl)methyl)-5-methoxy- 1 -((3 -methylpyrazin-2- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one(7?)-4-((4-chlorophenyl)(cyclopropyl)methyl)-2-((3-fluoropyridin-2-yl)methyl)-6- methoxy-1 ,2,4-triazine-3 , 5(2 / 7, 4 / 7)-di oneCS')-4-((4-chlorophenyl)(cyclopropyl)methyl)-2-((3-fliioropyridin-2-yl)methyl)-6- methoxy-1 ,2,4-triazine-3 , 5(2 / 7, 4 / 7)-di one3-((5-chloropyridin-2-yl)(cyclopropyl)methyl)-5-methoxy-l-(tetrahydro-2 / 7-pyran-4- yl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one3-((5-chloropyridin-2-yl)(cyclopropyl)methyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one3-(cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l-((4-methylpyrimidin-5- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one3-(cyclopropyl(3,4-difluorophenyl)methyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one(7?)-3-(cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l-(tetrahydro-2 / 7-pyran-4- yl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one(5)-3-(cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l-(tetrahydro-2 / / -pyran-4- yl)pyrimidine-2, 4(1 / , 3 / )-di one4-(cyclopropyl(3,4-difluorophenyl)methyl)-6-methoxy-2-(tetrahydro-2 / 7-pyran-4-yl)-1 ,2,4-triazine-3 , 5(2 / 7, 4 / 7)-di one(7?)-3-((4-chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one(5)-3-((4-chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one3-((4-chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-((4-methylpyrimidin-5- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one3-(cyclopropyl(3,4-difluorophenyl)methyl)-5-methoxy-l-((3-methylpyrazin-2- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one3-(cyclopropyl(3,4-difluorophenyl)methyl)-5-methoxy-l-(tetrahydro-2 / 7-pyran-4- yl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one(5)-3-(cyclopropyl(3,4-difluorophenyl)methyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one(7?)-3-(cyclopropyl(3,4-difluorophenyl)methyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one(7?)-3-(cyclopropyl(3,4-difluorophenyl)methyl)-5-methoxy-l-(tetrahydro-2 / 7-pyran-4- yl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one(5)-3-(cyclopropyl(3,4-difluorophenyl)methyl)-5-methoxy-l-(tetrahydro-2 / 7-pyran-4- yl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one(5)-3-(cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one(7?)-3-(cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one3-(cyclopropyl(6-methoxypyridin-3-yl)methyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one4-((4-chlorophenyl)(cyclopropyl)methyl)-6-methoxy-2-((5-methylpyridazin-4- yl)methyl)-l,2,4-triazine-3,5(2 / 7,4 / 7)-dione3-(cyclopropyl(2,4-difluoro-3-methoxyphenyl)methyl)-5-methoxy-l-((5- methylpyridazin-4-yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one(A>)-4-((4-chlorophenyl)(cyclopropyl)methyl)-6-methoxy-2-((5-methylpyridazin-4- yl)methyl)-l,2,4-triazine-3,5(2 / 7,4 / 7)-dione(5)-4-((4-chlorophenyl)(cyclopropyl)methyl)-6-methoxy-2-((5-methylpyridazin-4- yl)methyl)-l,2,4-triazine-3,5(2 / 7,4 / 7)-dione4-(cyclopropyl(2,4-difluoro-3-methoxyphenyl)methyl)-6-methoxy-2-((5- methylpyridazin-4-yl)methyl)-l,2,4-triazine-3,5(2 / 7,4 / 7)-dione4-(cyclopropyl(4-fluorophenyl)methyl)-6-methoxy-2-((5-methylpyridazin-4- yl)methyl)-l,2,4-triazine-3,5(2 / 7,4 / 7)-dione4-(cy cl opropyl(3,4-difluorophenyl)methyl)-6-m ethoxy -2-((5-methylpyridazin-4- yl)methyl)-l,2,4-triazine-3,5(2 / 7,4 / 7)-dione3-((4-chloro-3-fluorophenyl)(cyclopropyl)methyl)-5-methoxy-l-((5-methylpyridazin-4- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one(7?)-3-((4-chloro-3-fluorophenyl)(cyclopropyl)methyl)-5-methoxy-l-((5- methylpyridazin-4-yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one(5)-3-((4-chloro-3-fluorophenyl)(cyclopropyl)methyl)-5-methoxy-l-((5- methylpyridazin-4-yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one(A>)-3-( l-(4-chlorophenyl)propyl)-5-methoxy-l-(tetrahydro-27 / -pyran-4-yl)pyrimidine-2,4(l / 7,3 / 7)-dione(5)-3-(l-(4-chlorophenyl)propyl)-5-methoxy-l-(tetrahydro-2 / 7-pyran-4-yl)pyrimidine-2,4(l / 7,3 / 7)-dione3-((4-chlorophenyl)(cyclopropyl)methyl)-l-(2,2-dimethyl-l,3-dioxan-5-yl)-5- methoxypyrimidine-2, 4(1 / 7, 3 / 7)-di one(5)-4-((4-chlorophenyl)(cyclobutyl)methyl)-6-methoxy-2-(tetrahydro-2 / / -pyran-4-yl)-1.2.4-triazine-3 , 5(2 7, 4 / 7)-di one(A>)-4-((4-chlorophenyl)(cyclobutyl)methyl)-6-methoxy-2-(tetrahydro-2 / / -pyran-4-yl)-1.2.4-triazine-3 , 5(2 / 7, 4 / 7)-di one3-((4-chlorophenyl)(cyclobutyl)methyl)-5-methoxy-l-(pyrimidin-5- ylmethyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one(5)-3-((4-chlorophenyl)(cyclobutyl)methyl)-5-methoxy-l-(pyrimidin-5- ylmethyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one(7?)-3-((4-chlorophenyl)(cyclobutyl)methyl)-5-methoxy-l-(pyrimidin-5- ylmethyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di oneCS')-3-(cyclopropyl(4-fluorophenyl)methyl)-5-methoxy- l-((3-methylpyrazin-2- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one(7?)-3-(cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l-((3-methylpyrazin-2- yl)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one4-(cyclobutyl(4-fluorophenyl)methyl)-6-methoxy-2-(tetrahydro-2 / 7-pyran-4-yl)-l,2,4- triazine-3, 5(2 / 7, 4 / 7)-di one(5)-4-(cyclobutyl(4-fluorophenyl)methyl)-6-methoxy-2-(tetrahydro-2 / 7-pyran-4-yl)-1 ,2,4-triazine-3 , 5(2 / 7, 4 / 7)-di one(7?)-4-(cyclobutyl(4-fluorophenyl)methyl)-6-methoxy-2-(tetrahydro-2 / 7-pyran-4-yl)-1 ,2,4-triazine-3 , 5(2 / 7, 4 / 7)-di one4-(cyclobutyl(3,4-difluorophenyl)methyl)-6-methoxy-2-(tetrahydro-2 / 7-pyran-4-yl)-1 ,2,4-triazine-3 , 5(2 / 7, 4 / 7)-di one and a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof or an A-oxide form thereof.

20. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 19 and a pharmaceutically acceptable carrier and / or excipient.

21. The pharmaceutical composition of claim 20, for use in therapy.

22. A method of treating or preventing a condition in a mammal, comprising administering to a mammal in need of such treatment or prevention, an effective amount of a compound according to any one of claims 1 to 19 or a composition according to claim 20.

23. The method according to claim 22, wherein the treatment or prevention is affected or facilitated by the modulatory effect of a GABAB allosteric modulator, such as a GABAB positive allosteric modulator.

24. A method of treating, preventing, ameliorating, controlling or reducing the risk of various neurological and psychiatric disorders associated with GABA dysfunction in a mammal, comprising administering to a mammal in need of such treatment or prevention, an effective amount of a compound according to any one of claims 1 to 19 or a composition according to claim 20.

25. The method according to claim 24, wherein the treatment or prevention is affected or facilitated by the modulatory effect of a GABAB positive allosteric modulator.

26. The method according to any one of claims 22 to 25, wherein the condition is one or more of a central nervous system disorder.

27. The method according to any one of claims 22 to 25, wherein the condition is a substance use disorder (SUD).

28. The method of claim 27, wherein the SUD is selected from any one or more of alcohol use disorder (AUD), opioid use disorder (OUD), cannabis use disorder (CUD), and stimulant use disorder.

29. The method of claim 28, wherein the AUD comprises one of more of alcohol craving, alcohol abuse, alcohol dependence, alcohol withdrawal, alcohol withdrawal delirium, and alcohol-induced psychotic disorder.

30. The method of claim 28, wherein the OUD comprises any one or more of opioid craving, opioid abuse, opioid dependence, and opioid withdrawal.

31. The method of claim 28, wherein the CUD comprises any one or more of cannabis craving, cannabis abuse, cannabis dependance, and cannabis withdrawal.

32. The method of claim 28, wherein the stimulant use disorder comprises any one or more of stimulant craving, stimulant abuse, stimulant dependance, stimulant addiction, and stimulant withdrawal.

33. The method of claim 28, wherein the opioid comprises any one or more of heroin, fentanyl, oxycodone, hydrocodone, hydromorphone, oxymorphone, meperidine, morphine, codeine, methadone, and derivatives of the same.

34. The method of claim 28, wherein the stimulant comprises any one or more of cocaine, nicotine, amphetamine, methamphetamine, cathinone, and derivatives of the same.

35. The method according to any one of claims 22 to 25, wherein the condition is an addiction disorder.

36. The method according to claim 35, wherein the addiction disorder is selected from any one or more of gambling addiction, gaming addiction, sex addiction, screen addiction, and social media addiction.

37. The method according to claim 35, wherein the addiction disorder is selected from food addiction, and binge-eating disorder.

38. The method of the any one of claims 22 to 37, wherein the treatment comprises any one or more of suppressing withdrawal symptoms, eliminating withdrawal symptoms, reducing craving, eliminating craving, reducing use, preventing use, and mitigating relapse.

39. The method according to any one of claims 22 to 25, wherein the condition is an anxiety disorder.

40. The method according to claim 39, wherein the anxiety disorder comprises any one or more of agoraphobia, generalized anxiety disorder (GAD), obsessive- compulsive disorder (OCD), panic disorder, posttraumatic stress disorder (PTSD), social phobia, other phobias, and substance-induced anxiety disorder.

41. The method according to any one of claims 22 to 25, wherein the condition is a psychotic disorder.

42. The method according to claim 41, wherein the psychotic disorder is selected from any one or more of schizophrenia, delusional disorder, schizoaffective disorder, schizophreniform disorder, and substance-induced psychotic disorder.

43. The method according to any one of claims 22 to 25, wherein the condition is a personality disorder.

44. The method of claim 43, wherein the personality disorder is selected from any one or more of obsessive-compulsive personality disorder, schizoid disorder, schizotypal disorder, and attention-deficit / hyperactivity disorder.

45. The method according to any one of claims 22 to 25, wherein the condition is any one or more of neuropathic pain associated with SUD, and polysubstance use disorders or multiple drug use disorders.

46. Use of a compound according to any one of claims 1 to 19 in the manufacture of a medicament.

47. Use of a compound according to any one of claims 1 to 19 in the manufacture of a medicament for a treatment or prevention as defined in any one of claims 22 to 45.

48. A compound according to any one of claims 1 to 19 for use as a medicament.

49. A compound according to any one of claims 1 to 19 for use in a method according to any one of claims 22 to 44.

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