Novel pyrimidinedione derivatives as GABA b positive allosteric modulators

Abstract

(I) The present invention relates to novel compounds of Formula (I), wherein Z1, Z2, Z3, Z4, A, B, m, n, R1 and R2 are defined as in Formula (I); which are gamma-()- aminobutyric acid type B receptor ("GABAB-R") positive allosteric modulators which are useful for the treatment or prevention of central and peripheral nervous system 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 disorders and diseases in which GABAB-R is involved.

Description

[0001] NOVEL PYRIMIDINEDIONE DERIVATIVES AS GABAB POSITIVE ALLOSTERIC MODULATORS

[0002] SUMMARY OF THE INVENTION

[0003] The present invention relates to novel compounds of Formula (I), wherein Zi, Z2, Z3, Z4, A, B, m, n, R1and R2are 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 central and peripheral nervous system 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 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 non- dependent 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] Baclofen has also shown clinical efficacy in patients with chronic cough. For example, in an observational / real world retrospective cohort study in refractory cough patients, baclofen was as efficatious as gabapentin (Zhang et al., Ther Advances in Resp. Dis. 2023, 17: 1-12). Also, in open label clinical trials, baclofen reduced chronic cough induced by treatment with ACE inhibitors (Dicpinigaitis, Ann. Pharmacotherapy. 1996, 30: 1242-1245) or associated with GERD (Xu et al., World J. Gastroentherol 2013, 19:4386-4392; Dong et al., Aliment. Pharmacol. Ther. 2019, 49:714-722). The antitussive efficacy of baclofen in GERD patients was rapid, as across 8 week treatment, cough symptom score began to decrease at week 2, with further decreases on weeks 6 and 8 and was observed in patients with both acid and non-acid reflux (Xu et al., World J. Gastroentherol. 2013, 19:4386-4392). In doule-blind, placebo-controlled clinical trials evaluating capsaicin inhalation-induced cough in healthy volunteers, baclofen showed antitussive efficacy at low active doses (20 mg QD), rapid onset (14- day treatment; Dispinigaitis et al., World J. Clin Pharmacol. 1998, 38:364-367) and more than 4-fold increases in cough threshold in 10 out of 12 subjects. Baclofen also showed antitussive efficacy in animal models of cough (Bolser et al., Br. J. Pharmacol. 1993, 110:491-495; Castello & Pitts, Laryngoscope 2013, 123:3088-3092; Olsen et al., Front. Physiol. 2021, 12: Article 640682)

[0010] 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;

[0011] W02006 / 07486; WO2006 / 136442; W02007 / 014843; W02007 / 073297;

[0012] 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).

[0013] 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.

[0014] Cryan and co-workers suggested in a study using GS39783 ( -Di cyclopentyl -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 PA S 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.

[0015] 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).

[0016] 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. It has now surprisingly been found that the compounds of general Formula (I) show potent activity and selectivity on GABAB receptor.

[0017] 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.

[0018] 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 / f-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] R2is selected from the group of (for example the group consisting of) hydrogen, - (Ci-Ce)alkyl, -(C3-C7)cycloalkyl and -(Ci-Ce)haloalkyl;

[0022] Zi and Z2 are each independently selected from C or N;

[0023] Z3 and Z4 are each independently selected from C or N; wherein when Z3 is C, Z4 is N; and wherein when Z4 is C, Z3 is N; m is an integer equal to zero, 1, 2, 3 or 4; 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, -(Ci-C6)alkylene-(C3-C7)cycloalkyl, aryl, heteroaryl, heterocycle, -(Co-Ce)alkylene-OR3, -O-(C2-Ce)alkylene-OR3, -O-(C2-Ce)alkylene- NR3R4, -(Co-C6)alkylene-NR3R4, -NR3(C2-C6)alkylene-OR4, -NR3-(C2-C6)alkylene- NR4R5, -(C0-C6)alkylene-OC(=O)-R3, -O-(C2-C6)alkylene-OC(=O)-R3, -NR3-(C2- C6)alkylene-OC(=O)-R4, -(C0-C6)alkylene-C(=O)-OR3, -O-(Ci-C6)alkylene-C(=O)- OR3and -NR3-(Ci-C6)alkylene-C(=O)-OR4;

[0024] R3, R4and R5are 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, -(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; n is an integer equal to 1, 2, 3, 4, 5 or 6; 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, -(C3-C7)cycloalkyl, -(Ci-C6)alkylene-(C3-C7)cycloalkyl, -(Co- Ce)alkylene-OR6, -O-(C2-C6)alkylene-OR6-O-(C2-Ce)alkylene-NR6R7, -(Co- C6)alkylene-NR6R7, -NR6(C2-C6)alkylene-OR7, -NR6-(C2-C6)alkylene-NR7R8, -(Co- C6)alkylene-OC(=O)-R6, -O-(C2-C6)alkylene-OC(=O)-R6, -NR6-(C2-C6)alkylene- OC(=O)-R7, -(C0-C6)alkylene-C(=O)-OR6, -O-(Ci-C6)alkylene-C(=O)-OR6and -NR6- (Ci-C6)alkylene-C(=O)-OR7;

[0025] R6, R7and R8are 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, -(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. 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.

[0026] Preferably,

[0027] R1is -O-(Ci-C6)alkyl.

[0028] The cycloalkyl, heterocycle, aryl and heteroaryl ring systems of (A)mmay be selected from the group of (for example the group consisting of) azetidinyl, 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 R3, R4or R5.

[0029] The cycloalkyl ring system of (B)nmay be selected from the group of (for example the group consisting of) cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, and each ring of said ring system is optionally substituted independently with 1 to 3 substituents R6, R7or R8.

[0030] The or each (A)mmay be independently selected from the group of (for example the group consisting of) hydrogen, halogen, and an optionally substituted radical selected from the group of (for example the group consisting of) -(Ci-Ce)alkyl, -(Ci- Ce)haloalkyl and -(Co-C6)alkylene-OR3. The optionally substituted radical may be optionally substituted with halogen or-(Ci-Ce)alkyl.

[0031] R3may 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.

[0032] The or each (B)nmay be independently selected from the group of (for example the group consisting of) hydrogen, halogen, and an optionally substituted radical selected from the group of (for example the group consisting of) -(Ci-Ce)alkyl, -(Ci- Ce)haloalkyl and -(C3-C7)cycloalkyl;

[0033] The or each (A)mmay be independently selected from the group of (for example the group consisting of) hydrogen, halogen, and -(Co-C6)alkylene-OR3.

[0034] R3may be -(Ci-Ce)alkyl.

[0035] The or each (B)nmay be independently selected from the group of (for example the group consisting of) hydrogen and -(Ci-Ce)alkyl.

[0036] For example, A may be hydrogen, halogen or -O-(Ci-Ce)alkyl and m may be 1, 2 or 3. For example, B may be hydrogen or -(Ci-Ce)alkyl and n may be 1.

[0037] 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 Zi, Z2, A, B, m, n, R1and R2are as defined in any statement set out above. The compounds of Formula (I) or Formula (II) may be the compounds according to

[0038] Formula (III): a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof or an V-oxide form thereof wherein: R2is selected from the group of (for example the group consisting of) -(Ci- Ce)alkyl and -(C3-C7)cycloalkyl and Zi, Z2, A, B, m and n are as defined in any statement set out above.

[0039] Preferably, the compounds of Formula (I), Formula (II) or Formula (III) are 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: A, m and R2are as defined in any statement set out above.

[0040] Preferably, R2is selected from the group of (for example the group consisting of) ethyl, propyl and cyclopropyl;

[0041] The or each (A)mmay be independently selected from the group of (for example the group consisting of) hydrogen and halogen.

[0042] 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

[0043] 3-(l-(4-chloro-3-methoxyphenyl)ethyl)-l-(l / 7-indazol-4-yl)-5-methoxypyrimidine- 2,4(l / 7,3 / 7)-dione

[0044] 3 -( 1 -(4-chl oro-3 -methoxyphenyl)ethyl)- 1 -(7 -fluoro- l / 7-indazol-4-yl)-5- methoxypyrimidine-2, 4(1 / 7, 3 / 7)-di one 3-(l-(4-chlorophenyl)propyl)-l-(l / 7-indazol-4-yl)-5-methoxypyrimidine-2, 4(1 / 7, 3 / 7)- dione

[0045] 3-(l-(4-chlorophenyl)-2-methylpropyl)-l-(l / 7-indazol-4-yl)-5-methoxypyrimidine-

[0046] 2,4(l / 7,3 / 7)-dione

[0047] 3-(l-(4-chlorophenyl)propyl)-5-methoxy-l-(l / 7-pyrazolo[4,3-c]pyridin-4- yl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0048] 3 -( 1 -(4-chl orophenyl)propyl)- 1 -(7-fluoro- l / 7-indazol-4-yl)-5-methoxypyrimidine-

[0049] 2,4(l / 7,3 / 7)-dione

[0050] 3-(l-(4-chlorophenyl)propyl)-5-methoxy-l-(l / 7-pyrazolo[3,4-Z>]pyridin-4- yl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one 3-(l-(4-chlorophenyl)propyl)-5-methoxy-l-(l-methyl-l / 7-pyrrolo[3,2-c]pyridin-4- yl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0051] 3-((4-chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-(l / 7-pyrazolo[3,4-Z>]pyridin-4- yl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0052] 3-((4-chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-(l / 7-pyrazolo[4,3-c]pyridin-4- yl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one 3-(l-(4-chlorophenyl)butyl)-5-methoxy-l-(l / 7-pyrazolo[3,4-Z>]pyridin-4- yl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0053] 3-(cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l-(l / 7-pyrazolo[3,4-Z>]pyridin-4- yl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0054] 3-(l-(4-chlorophenyl)butyl)-l -(7-fluoro- l / 7-indazol-4-yl)-5-methoxypyrimidine-

[0055] 2,4(l / 7,3 / 7)-dione

[0056] (7?)-3 -((4-chl orophenyl)(cy cl opropyl)methyl)-5 -methoxy- l-(l / 7-pyrazolo[3 ,4-

[0057] Z>]pyridin-4-yl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one (5)-3-((4-chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-(l / 7-pyrazolo[3,4-

[0058] Z>]pyridin-4-yl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0059] 3-((4-chlorophenyl)(cyclopropyl)methyl)-l-(7-fluoro-l / 7-indazol-4-yl)-5- methoxypyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0060] 3-((4-chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-(17 / -pyrrolo[2,3-Z>]pyri din-4- yl)pyrimidine-2, 4(177, 3 / 7)-di one

[0061] ( / ?)-3-(cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l-(17 / -pyrazolo[3,4-Z>]pyridin-

[0062] 4-yl)pyrimidine-2,4(l / 7,3 / 7)-dione

[0063] (5)-3-(cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l-(17 / -pyrazolo[3,4-Z>]pyridin-

[0064] 4-yl)pyrimidine-2,4(l / 7,3 / 7)-dione

[0065] 3-(cyclopropyl(3,4-difluorophenyl)methyl)-5-methoxy-l-(17 / -pyrazolo[3,4-Z>]pyridin-

[0066] 4-yl)pyrimidine-2,4(l / 7,3 / 7)-dione

[0067] (5)-3-(cyclopropyl(3,4-difluorophenyl)methyl)-5-methoxy-l-(l / / -pyrazolo[3,4-

[0068] Z>]pyridin-4-yl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0069] (7?)-3-(cyclopropyl(3,4-difluorophenyl)methyl)-5-methoxy-l-(l / 7-pyrazolo[3,4-

[0070] Z>]pyridin-4-yl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0071] 3-(cyclopropyl(2,4-difluoro-3-methoxyphenyl)methyl)-5-methoxy-l-(l / 7- pyrazolo[3,4-Z>]pyridin-4-yl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0072] (5)-3-(cyclopropyl(2,4-difluoro-3-methoxyphenyl)methyl)-5-methoxy-l-(l / 7- pyrazolo[3,4-Z>]pyridin-4-yl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0073] (7?)-3-(cyclopropyl(2,4-difluoro-3-methoxyphenyl)methyl)-5-methoxy-l-(l / 7- pyrazolo[3,4-Z>]pyridin-4-yl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0074] (5)-3-(l-(4-chlorophenyl)propyl)-5-methoxy-l-(l / 7-pyrazolo[4,3-c]pyridin-4- yl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0075] (7?)-3-(l-(4-chlorophenyl)propyl)-5-methoxy-l-(l / 7-pyrazolo[4,3-c]pyridin-4- yl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0076] (5)-3-(l-(4-chlorophenyl)propyl)-5-methoxy-l-(l / 7-pyrazolo[3,4-Z>]pyridin-4- yl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0077] (7?)-3-(l-(4-chlorophenyl)propyl)-5-methoxy-l-(l / 7-pyrazolo[3,4-Z>]pyridin-4- yl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0078] (5)-3-(l-(3,4-difluorophenyl)propyl)-5-methoxy-l-(l / 7-pyrazolo[3,4-Z>]pyridin-4- yl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0079] (7?)-3-(l-(3,4-difluorophenyl)propyl)-5-methoxy-l-(l / 7-pyrazolo[3,4-Z>]pyridin-4- yl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0080] (5)-3-(l-(4-chloro-3-fluorophenyl)propyl)-5-methoxy-l-(l / 7-pyrazolo[3,4-Z>]pyridin-

[0081] 4-yl)pyrimidine-2,4(l / 7,3 / 7)-dione and

[0082] (7?)-3-(l -(4-chl oro-3 -fluorophenyl)propyl)-5-methoxy-l-(l / / -pyrazolo[3,4-Z>]pyri din- 4-yl)pyrimidine-2,4(l / 7,3 / 7)-dione.

[0083] The above list of compounds can also be represented by the following skeletal formulae :

[0084]

[0085] 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 V-oxide form thereof:

[0086] 3-(l-(4-chlorophenyl)propyl)-5-methoxy-l-(177-pyrazolo[4,3-c]pyridin-4- yl)pyrimidine-2, 4(177, 377)-di one

[0087] 3-(l-(4-chlorophenyl)propyl)-5-methoxy-l-(177-pyrazolo[3,4-Z>]pyridin-4- yl)pyrimidine-2, 4(177, 377)-di one

[0088] 3-((4-chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-(177-pyrazolo[3,4-Z>]pyridin-

[0089] 4-yl)pyrimidine-2,4(lJ7,3J7)-dione

[0090] 3-((4-chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-(177-pyrazolo[4,3-c]pyridin-4- yl)pyrimidine-2, 4(177, 377)-di one

[0091] 3-(l-(4-chlorophenyl)butyl)-5-methoxy-l-(177-pyrazolo[3,4-Z>]pyridin-4- yl)pyrimidine-2, 4(177, 377)-di one

[0092] 3-(cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l-(177-pyrazolo[3,4-Z>]pyridin-4- yl)pyrimidine-2, 4(177, 377)-di one

[0093] (7?)-3-((4-chlorophenyl)(cy cl opropyl)methyl)-5 -methoxy- l-(177-pyrazolo[3 ,4-

[0094] Z>]pyridin-4-yl)pyrimidine-2, 4(177, 377)-di one

[0095] (5)-3-((4-chlorophenyl)(cyclopropyl)methyl)-5-methoxy-l-(177-pyrazolo[3,4-

[0096] Z>]pyridin-4-yl)pyrimidine-2, 4(177, 377)-di one

[0097] (7?)-3-(cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l-(17 / -pyrazolo[3,4-

[0098] Z>]pyridin-4-yl)pyrimidine-2, 4(177, 377)-di one

[0099] (5)-3-(cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l-(17 / -pyrazolo[3,4-Z>]pyridin-

[0100] 4-yl)pyrimidine-2,4(177,377)-dione

[0101] 3-(cyclopropyl(3,4-difluorophenyl)methyl)-5-methoxy-l-(177-pyrazolo[3,4-Z>]pyridin-

[0102] 4-yl)pyrimidine-2,4(177,377)-dione (5)-3-(cyclopropyl(3,4-difluorophenyl)methyl)-5-methoxy-l-(l / 7-pyrazolo[3,4-

[0103] Z>]pyridin-4-yl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0104] (7?)-3-(cyclopropyl(3,4-difluorophenyl)methyl)-5-methoxy-l-(l / 7-pyrazolo[3,4-

[0105] Z>]pyridin-4-yl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0106] 3-(cyclopropyl(2,4-difluoro-3-methoxyphenyl)methyl)-5-methoxy-l-(l / / - pyrazolo[3,4-Z>]pyridin-4-yl)pyrimidine-2, 4(1 7, 3Z7)-di one

[0107] (5)-3-(cyclopropyl(2,4-difluoro-3-methoxyphenyl)methyl)-5-methoxy-l-(l / 7- pyrazolo[3,4-Z>]pyridin-4-yl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0108] (7?)-3-(cyclopropyl(2,4-difluoro-3-methoxyphenyl)methyl)-5-methoxy-l-(l / 7- pyrazolo[3,4-Z>]pyridin-4-yl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0109] (5)-3-(l-(4-chlorophenyl)propyl)-5-methoxy-l-(l / 7-pyrazolo[4,3-c]pyridin-4- yl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0110] (7?)-3-(l-(4-chlorophenyl)propyl)-5-methoxy-l-(l / 7-pyrazolo[4,3-c]pyridin-4- yl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0111] (5)-3-(l-(4-chlorophenyl)propyl)-5-methoxy-l-(l / 7-pyrazolo[3,4-Z>]pyridin-4- yl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0112] (7?)-3-(l-(4-chlorophenyl)propyl)-5-methoxy-l-(l / 7-pyrazolo[3,4-Z>]pyridin-4- yl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0113] (5)-3-(l-(3,4-difluorophenyl)propyl)-5-methoxy-l-(l / 7-pyrazolo[3,4-Z>]pyridin-4- yl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0114] (7?)-3-(l-(3,4-difluorophenyl)propyl)-5-methoxy-l-(l / 7-pyrazolo[3,4-Z>]pyridin-4- yl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0115] (5)-3-(l-(4-chloro-3-fluorophenyl)propyl)-5-methoxy-l-(l / 7-pyrazolo[3,4-Z>]pyridin-

[0116] 4-yl)pyriniidine-2,4(l / 7,3 / 7)-dione and

[0117] (7?)-3-(l -(4-chl oro-3 -fluorophenyl)propyl)-5-methoxy-l-(l / / -pyrazolo[3,4-Z>]pyri din- 4-yl)pyriniidine-2,4(l / 7,3 / 7)-dione.

[0118] The above list of compounds can also be represented by the following skeletal formulae :

[0119]

[0120] 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:

[0121] 3-(l-(4-chlorophenyl)propyl)-5-methoxy-l-(177-pyrazolo[3,4-Z>]pyridin-4- yl)pyrimidine-2, 4(177, 3J7)-di one

[0122] (5)-3-(l-(4-chlorophenyl)propyl)-5-methoxy-l-(177-pyrazolo[3,4-Z>]pyridin-4- yl)pyrimidine-2, 4(177, 377)-di one ( / ?)-3-( l -(4-chlorophenyl (propyl )-5-methoxy- l -( I / / -pyrazolo[3,4-7]pyridin-4- yl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0123] (5)-3-(l-(3,4-difluorophenyl)propyl)-5-methoxy-l-(l / / -pyrazolo[3,4-Z>]pyridin-4- yl)pyrimidine-2, 4(1 / 7, 3 / 7)-di one

[0124] ( / ?)-3-(l-(3,4-difluorophenyl)propyl)-5-methoxy-l-(l / / -pyrazolo[3,4-Z>]pyridin-4- yl)pyrimidine-2, 4(177, 3Z7)-di one

[0125] (5)-3-(l-(4-chloro-3-fluorophenyl)propyl)-5-methoxy-l-(17 / -pyrazolo[3,4-Z>]pyridin-

[0126] 4-yl)pyrimidine-2,4(l / 7,3 / 7)-dione and

[0127] (7?)-3-(l -(4-chl oro-3 -fluorophenyl)propyl)-5-methoxy-l-(17 / -pyrazolo[3,4-Z>]pyri din- 4-yl)pyrimidine-2,4(l / 7,3 / 7)-dione.

[0128] The above list of compounds can also be represented by the following skeletal formulae: The compounds according to any statement above may exhibit GABAB modulator activity.

[0129] 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.

[0130] Examples of isotopes suitable for inclusion in the disclosed compounds include, without limitation, isotopes of hydrogen, such as2H and3H; isotopes of carbon, such as nC,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.

[0131] 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 deuterieum (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 (IV). Isotopically-labelled compounds of Formula (I) to (IV) 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.

[0132] 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. Compounds of the present invention are useful for the treatment of central nervous system disorders as well as peripheral conditions where stimulation of the GABAB receptor may offer therapeutic benefit.

[0133] 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.

[0134] 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.

[0135] The treatment or prevention may be affected or facilitated by the modulatory effect of a GABAB modulator such as a GABAB positive allosteric modulator.

[0136] 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.

[0137] The treatment or prevention may be affected or facilitated by the modulatory effect of a GABAB modulator such as a GABAB positive allosteric modulator. The present invention relates to a method of treating or preventing chronic cough, refractory chronic cough, cough associated with asthma, chronic hiccups, allergic rhinitis, gastro-oesophageal reflux, chronic bronchitis or chronic obstructive pulmonary disease and cough associated with a cardiovascular disease such as left ventricular failure.

[0138] In an aspect of the present invention there is provided a method of treating or preventing chronic cough and refractory chronic cough comprising administering to a mammalian patient in need of such treatment or prevention, an effective amount of a compound / composition according to any statement set out above.

[0139] In some embodiments, described herein the chronic cough can be associated with pulmonary infections such as tuberculosis or COVID, lung cancer, COPD and pulmonary fibrosis.

[0140] The present invention relates to a method of treating or preventing inflammatory pain, post-operative pain, neuropathic pain (including polyneuropathic pain such as chemotherapy-induced or diabetic pain), visceral pain (including pain related to fibromyalgia), trigeminal neuralgia and other orofacial pain conditions as well as bone pain and osteoarthritic pain.

[0141] In an aspect of the present invention there is provided a method of treating or preventing inflammatory or neuropathic pain, post-operative pain comprising administering to a mammalian patient in need of such treatment or prevention, an effective amount of a compound / composition according to any statement set out above.

[0142] The present invention relates to a method of treating or preventing muscle spasticity for example in Charcot Marie Tooth disease (CMT), dystonia, skeletal muscle rigidity, spinal cord injury, multiple sclerosis, amyotrophic lateral sclerosis, essential tremor, Stiff Person Syndrome, cerebral palsy, urge urinary incontinence, gastroesophageal reflux disease, transient lower oesophageal sphincter relaxations, functional gastrointestinal disorders and irritable bowel syndrome.

[0143] In an aspect of the present invention there is provided a method of treating or preventing urge urinary incontinence 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.

[0144] Compounds and pharmaceutical compositions of the present invention may be used for treating substance use disorders (SUD), for example 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.

[0145] Compounds and pharmaceutical compositions of the present invention may also be used in treating other addiction disorders (such as gambling addiction, gaming addiction, sex addiction, screen addiction, and social media addiction); anxiety disorders (such as agoraphobia, generalized anxiety disorder (GAD), obsessive- compulsive disorder (OCD), panic disorder, posttraumatic stress disorder (PTSD), social phobia, other phobias, and substance-induced anxiety disorder); psychotic disorders (such as schizophrenia, delusional disorder, schizoaffective disorder, schizophreniform disorder, and substance-induced psychotic disorder); personality disorders (such as obsessive-compulsive personality disorder, schizoid, and schizotypal disorder); narcolepsy and attention-deficit / hyperactivity disorder.

[0146] Compounds and pharmaceutical compositions of the present invention may also be used in treating other addiction disorders such as food addiction and binge-eating disorder.

[0147] The compounds and compositions can be used to treat neurodevelopmental disorders such as autism spectrum disorder, obsessive-compulsive disorder, Fragile X syndrome.

[0148] The present invention relates to the use of a compound or a pharmaceutical composition for the manufacture of a medicament.

[0149] 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.

[0150] 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.

[0151] 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.

[0152] 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).

[0153] 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;

[0154] (g) preventing use (i.e. inducing abstinence); (h) mitigating relapse; or (i) a combination of two or more of the foregoing.

[0155] DEFINITION OF TERMS

[0156] Listed below are definitions of various terms used in the specification and claims to describe the present invention.

[0157] 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.

[0158] 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.

[0159] 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.

[0160] 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.

[0161] 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.

[0162] 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.

[0163] 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-), / -propylene (-CH-(CH3)-CH2- ), / / -butylene (-CH2-CH2-CH2-CH2-), / -butylene (-CH2-CH-(CH3)-CH2-), / -butylene (- CH2-C-(CH3)-CH2-), / / -pentylene (-CH2-CH2-CH2-CH2-CH2-), / -pentylene (-CH2- CH(CH3)-CH2-CH2-), / / eo-pentylene (-CH2-C(CH3)2-CH2-), / / -hexylene (-CH2-CH2- CH2-CH2-CH2-CH2-), / -hexylene (-CH2-CH-(CH3)-CH2-CH2-CH2-) or / / eo-hexylene (- CH2-C(CH3)2-CH2-CH2-).

[0164] 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.

[0165] 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.

[0166] 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.

[0167] In this specification, unless stated otherwise, the term “alkylene-cycloalkyl” refers to a substituent that is attached via the alkyl radical to a cycloalkyl radical. The term “(Ci- C6)alkylene-cycloalkyl” includes -(Ci-C6)alkylene-(C3-C7)cycloalkyl radicals such as cyclopropylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclobutylmethyl, cyclobutylethyl, cyclobutylpropyl, cyclopentylmethyl, cyclopentylethyl, cyclopentyl propyl, cyclohexylmethyl, cyclohexylethyl and cyclohexylpropyl, and the like.

[0168] 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).

[0169] In this specification, unless stated otherwise, the term “halo” or “halogen” may be fluoro, chloro, bromo or iodo.

[0170] 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.

[0171] In this specification, unless stated otherwise, the term “cyanoalkyl” means an alkyl radical as defined above, substituted with one or more cyano. 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-Ce)alkylene-oxy, dimethylamino(Ci-C3)alkyl, mercapto, aryl, heterocycle, heteroaryl, (Ci-Ce)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, sulfonamide, ester or sulfonyl.

[0172] 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.

[0173] 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.

[0174] 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”.

[0175] The pharmaceutically acceptable salts of the invention can be synthesized from a basic or acidic moiety, by conventional chemical methods. 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.

[0176] 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”. o

[0177] HA

[0178] For example, the radical AA'. isa tautomer of

[0179] 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.

[0180] 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.

[0181] PHARMACEUTICAL COMPOSITIONS

[0182] 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. 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.

[0183] 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.

[0184] 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.

[0185] 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. 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.

[0186] 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.

[0187] 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.

[0188] 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.

[0189] METHODS OF SYNTHESIS

[0190] The compounds according to the invention, particularly the compounds according to the Formula (I) to (IV), 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 (IV).

[0191] The compounds according to the invention may be represented as a mixture of enantiomers, which may be resolved into the individual pure R- or 5-enanti omers. 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). 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).

[0192] 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).

[0193] The product from the reaction can be isolated and purified by employing standard techniques, such as extraction, chromatography, recrystallization and distillation.

[0194] 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.

[0195] In one embodiment of the present invention, compounds of Formula (I) may be prepared according to the synthetic sequence illustrated in Scheme 1.

[0196] Uracil compound gl may be protected by Boc group or SEM group using standard conditions. Aldehyde g3 undergoes addition of Grignard reagent to yield alcohol g4. Subsequently, alcohol g4 can be transformed into bromobenzyl g5 in presence of sulfuryl dibromide. Protected uracil g2 may be alkylated by the bromo derivative g5 in the presence of a base, such as, for example, K2CO3 and the like, in an appropriate solvent, such as, for example, DMF and the like, at an appropriate temperature. Intermediate g6 can be deprotected under acidic conditions to yield g7. In parallel, bicycle g8 can be protected by methylenoxy-Boc or by THP under standard conditions. The compound glO can be obtained by methods such as Ullmann coupling reactions, known in the art of organic synthesis, mediated by copper complex catalysts such as Cui, in the presence of a ligand such as DMEDA, in the presence of a base such as K3PO4, in a solvent such as dioxane, at an appropriate temperature. Finally, glO can be deprotected under classical conditions and chiral separation can lead to the corresponding enantiomers, g!2 and g!3.

[0197]

[0198] Scheme 1

[0199] In one embodiment of the present invention, compounds of intermediate g6 may be prepared according to the synthetic sequences illustrated in Scheme 2. The intermediate g6 can be obtained after Mitsunobu reaction between protected uracil g2 and secondary alcohol g4 using standard methods well known from persons skilled in the art. Subsequently, the expected compounds g!2 and g!3 can be obtained using methods described above.

[0200] Scheme 2

[0201] In one embodiment of the present invention, compounds of intermediate g!5 may be prepared according to the synthetic sequences illustrated in Scheme 3. g!5 can be obtained after Ullmann coupling, mediated by copper complex catalysts such as Cui, in the presence of a ligand such as DMEDA, in the presence of a base such as K2CO3, in a solvent such as dioxane, at an appropriate temperature. Finally, g!5 can lead after chiral separation to the corresponding enantiomers.

[0202] Scheme 3

[0203] EXPERIMENTAL

[0204] Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification.

[0205] Specifically, the following abbreviations may be used in the examples and throughout the specification.

[0206] 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 room temperature unless otherwise noted.

[0207] Most of the reactions were monitored by thin-layer chromatography on 0.25mm Merck silica gel plates (60F-254), visualized with UV light. Flash column chromatography was performed on prepacked silica gel cartridges (15-40 pM, Merck).

[0208] EXAMPLES

[0209] EXAMPLE 1: 3-( l-(4-Chlorophenyl)propyl)-5-methoxy-l-( l / / -pyrazolo|3.4- / ?|pyridin-4-yl)pyrimidine-2.4( l / / .3 / / )-dione (Final Compound 1-7), (l?)-3-(l-(4- chlorophenyl)propyl)-5-methoxy-l-( lH-pyrazolo[3,4- / >]pyridin-4-yl)pyrimidine- 2,4( l / / .3 / / )-dione (Final compounds 1-29) and (5)-3-(l-(4-chlorophenyl)propyl)-5- methoxy-l-(lH-pyrazolo[3,4- / >]pyridin-4-yl)pyrimidine-2,4( l / / .3 / / )-dione (Final compounds 1-28) tert-Butyl 5-methoxy-2, 4-dioxo-3, 4-dihydropyrimidine-l(2H) -carboxylate

[0210] According to Scheme 1 Step 1 : DMAP (215 mg, 1.76 mmol) was added to solution of 5-methoxypyrimidine-2, 4(1 / 7, 3J7)-dione (25.0 g, 176 mmol) in MeCN. BOC2O (46.1 g, 211 mmol, 48.6 mL) was added and the reaction mixture was stirred overnight at rt. The solution was evaporated under vacuum and washed with MTBE to give crude tertbutyl 5 -m ethoxy-2, 4-di oxo-3, 4-dihydropyrimidine-l(2J7)-carboxylate (25.9 g, 107 mol, 60.9% yield).

[0211] LC-MS (ESI): m / z = 243.0 [M+H]+, RT = 0.755 min. l-(4-Chlorophenyl)propan-l-ol According to Scheme 1 Step 2: To a solution of 4-chlorobenzaldehyde (20.0 g, 143 mmol) in THF was added ethylmagnesium chloride (25.28 g, 287.3 mmol, 143.6 mL) at -15 °C under an argon atmosphere. The mixture was stirred overnight at rt and was then quenched with cold saturated NH4CI solution. The organic layer was separated and concentrated under reduced pressure. The residue was diluted and extracted with EtOAc. The aqueous layer was diluted with water and was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give l-(4-chlorophenyl)propan-l-ol as a yellow oil (24.0 g, 141.1 mol, 98% yield) which was directly used in next step without further purification.

[0212] GC-MS: m / z = 170.0 [M+H]+, RT = 6.47 min.

[0213] 1-(1 -Bromopropyl)-4-chlorobenzene

[0214] According to Scheme 1 Step 3: Thionyl bromide (58.5 g, 284 mmol, 21.7 mL) was added to a solution of l-(4-chlorophenyl)propan-l-ol (24.0 g, 141 mmol) in DCM and the reaction mixture stirred overnight at rt. The solution was evaporated under vacuum to give crude l-(l-bromopropyl)-4-chlorobenzene as a yellow oil (30.0 g, 91.3% yield) which was used in the next step without further purification.

[0215] GC-MS: m / z = 233.8 [M+H]+, RT = 7.08 min. tert-Butyl 3-( 1 -(4-chlorophenyl)propyl)-5-methoxy-2, 4-dioxo-3, 4-dihydropyrimidine-

[0216] 1 ( 2H)-carboxylate

[0217] According to Scheme 1 Step 4: tert-Butyl 5-methoxy-2,4-dioxo-3,4-dihydropyrimidine- l(2rt)-carboxylate (25.9 g, 107 mmol), l-(l-bromopropyl)-4-chlorobenzene (30.0 g, 129 mmol) and K2CO3 (44.4 g, 322 mmol) were suspended in DMF and the reaction mixture stirred for 2 days at rt. The reaction mixture was concentrated under vacuum and diluted in EtOAc. The organic phase was washed twice with brine, dried over Na2SO4, and concentrated under vacuum to give tert-butyl 3-(l-(4- chlorophenyl)propyl)-5-methoxy-2,4-di oxo-3, 4-dihydropyrimidine-l(2rt)-carboxylate (37.5 g, 95.1 mol, 88.8% yield) which was used in the next step without further purification. 3-( 1 -(4-Chlorophenyl)propyl)-5-methoxypyrimidine-2, 4(1H, 3H)-dione

[0218] According to Scheme 1 Step 5: Trifluoroacetic acid (54.2 g, 475 mmol, 36.7 mL) was added to a solution of tert-butyl 3-(l-(4-chlorophenyl)propyl)-5-methoxy-2,4-dioxo- 3,4-dihydropyrimidine-l(2 / 7)-carboxylate (37.5 g, 95.1 mmol) in DCM and the reaction mixture stirred overnight at 40 °C. The solution was evaporated under vacuum and the resulting crude purified by silica gel flash-chromatography to give 3-(l-(4- chlorophenyl)propyl)-5-methoxypyrimidine-2, 4(1 / 7, 3Z7)-di one (3.2 g, 25% yield).

[0219] 'H-NMR (CDC13, 500 MHz): 5 0.94 (t, 3H), 2.42 (m, 2H), 3.89 (s, 3H), 5.97 (m, 1H), 6.68 (m, 1H), 7.25 (m, 2H), 7.39 (m, 2H), 11.8 (s, 1H);

[0220] LC-MS (ESI): m / z = 295.0 [M+H]+, RT = 1.084 min. tert-Butyl( ( 4-( 3-( 1 -( 4-chlorophenyl)propyl)-5-methoxy-2, 4-dioxo-3, 4- dihydropyrimidin-l(2H)-yl)-lH-pyrazolo[3,4-b]pyridin-l-yl)methyl) carbonate According to Scheme 1 Step 7: To a solution of 3-(l-(4-chlorophenyl)propyl)-5- methoxypyrimidine-2, 4(1 / 7, 3 / 7)-di one (3.20 g, 10.9 mmol) in 1,4-di oxane under an argon atmosphere were added (4-bromo-l / 7-pyrazolo[3,4-Z>]pyridin-l-yl)methyl tert- butyl carbonate (4.27 g, 13.1 mmol), copper(I) iodide (2.27 g, 12.0 mmol), tripotassium phosphate (6.92 g, 32.6 mmol) and DMEDA (1.05 g, 12.0 mmol, 1.29 mL). The resulting mixture was heated to 110° C and stirred for 2 days. After two days, the reaction mixture was cooled to rt, the solvent was removed by evaporation and the residue was suspended into equal amounts of water and EtOAc. The organic layer was separated from the aqueous layer and washed with brine. After drying over Na2SO4, and removal of the solvent, tert-butyl((4-(3-(l-(4-chlorophenyl)propyl)-5-methoxy-2,4- di oxo-3 ,4-dihydropyrimidin- 1 (2 / 7)-yl)- l / 7-pyrazolo[3 ,4-Z>]pyridin- 1 - yl)methyl)carbonate (5.23 g, 87.27% yield) was afforded.

[0221] LC-MS (ESI): m / z = 541.2 [M+H]+, RT = 1.443 min.

[0222] 3-( 1 -(4-Chlorophenyl)propyl)-5-methoxy-l-( lH-pyrazolo[ 3, 4-b ]pyridin-4- yl)pyrimidine-2, 4(1H, 3H)-dione

[0223] According to Scheme 1 Step 8: An aqueous solution of hydrogen chloride (696 mg, 19.3 mmol, 580 pL) was added to a solution of tert-butyl((4-(3-(l-(4- chi orophenyl)propyl)-5-methoxy-2,4-di oxo-3, 4-dihydropyrimidin- l (2 / / )-yl)- l / / - pyrazolo[3,4-Z>]pyridin-l-yl)methyl)carbonate (5.24 g, 9.67 mmol) in MeOH (150 mL). The reaction mixture was stirred overnight at 50 °C. Then, an additional portion of hydrogen chloride (696 mg, 19.3 mmol, 580.0 pL) was added and the reaction mixture was stirred for 16 h. The reaction mixture was cooled to rt and evaporated under vacuum to give crude product. Ammonia (solution in MeOH, 100 mL) was added to the crude product and the reaction mixture was stirred overnight at 50 °C then evaporated under reduced pressure. The residue was purified by silica gel flashchromatography to give 3-(l-(4-chlorophenyl)propyl)-5-methoxy-l-(U / -pyrazolo[3,4- Z>]pyridin-4-yl)pyrimidine-2, 4(1 / 7, 3J7)-dione (3.0 g, 75.3% yield) as a white solid.

[0224] 'H-NMR (400 MHz, CDC13): 8 (ppm) 0.97 (t, 3H), 1.22 (m, 1H), 2.42 (m, 2H), 3.73 (s, 3H), 6.09 (m, 1H), 6.91 (d, 1H), 7.20 (m, 3H), 7.48 (m, 2H), 7.91 (s, 1H), 8.69 (m, 1H).

[0225] LC-MS (ESI): m / z = 411.0 [M+H]+, RT = 1.105 min.

[0226] (R)-3-( 1 -( 4-chlorophenyl)propyl)-5-methoxy-l-( lH-pyrazolo[ 3, 4-b ]pyridin-4- yl)pyrimidine-2, 4(1H, 3H)-dione and (S)-3-( 1 -( 4-chlorophenyl)propyl)-5-methoxy-l- ( lH-pyrazolo[ 3, 4-b ]pyridin-4-yl)pyrimidine-2,4(lH, 3H) -dione

[0227] According to Scheme 1 Step 9: 1 g of 3-(l-(4-chlorophenyl)propyl)-5-methoxy-l-(U7- pyrazolo[3,4-Z>]pyridin-4-yl)pyrimidine-2,4(U / ,3J7)-dione was purified by chiral HPLC (CHIRALCEL OD-H (250x20 mm, 5 mkm) column, mobile phase: Hexane / IPA / MeOH, 50:25:25, Flow Rate: 12 mL / min) to afford : (5)-3-(l-(4-chlorophenyl)propyl)-5-methoxy-l-(lH-pyrazolo[3,4-b]pyridin-4- yl)pyrimidine-2,4(lH,3H)-dione (458.3 mg, RT = 15.266 min) as a beige solid.

[0228] RT was determined by analytical HPLC (Chiralcel OD-H (250x4.6 mm, 5 mkm); Hexane / IPA / MeOH, 50:25:25 as a mobile phase; flow rate: 0.6 mL / min);

[0229] ‘H-NMR (500 MHz, CDCI3): 6 1.01 (t, 3H), 1.18 (q, 2H), 2.39 (t, 1H), 3.78 (s, 3H), 6.11 (m, 1H), 6.95 (s, 1H), 7.17 (m, 1H), 7.30 (m, 2H), 7.49 (m, 2H), 7.91 (d, 1H), 8.68 (s, 1H);

[0230] LC-MS (ESI): m / z = 411.2 [M+H]+, RT = 3.412 min; And (7?)-3-(l-(4-chlorophenyl)propyl)-5-methoxy-l-(l / 7-pyrazolo[3,4-Z>]pyridin-4- yl)pyrimidine-2, 4(177, 3J7)-dione (459.0 mg, RT = 28.821min) as a beige solid.

[0231] RT was determined by analytical HPLC using the same conditions as above;

[0232] 'H-NMR (500 MHz, CDC13): 8 1.01 (t, 3H), 1.18 (q, 2H), 2.39 (t, 1H), 3.78 (s, 3H), 6.11 (m, 1H), 6.95 (s, 1H), 7.17 (m, 1H), 7.30 (m, 2H), 7.49 (m, 2H), 7.91 (d, 1H), 8.68 (s, 1H);

[0233] LC-MS (ESI): m / z = 411.2 [M+H]+, RT = 3.412 min;

[0234] EXAMPLE 2: 3-(Cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l-(lH- pyr:izolo|3.4- / >|pyridin-4-yl)pyrimidine-2.4( l / / .3 / / )-dione (Final Compound 1-12), (7?)-3-(cydopropyl(4-fluorophenyl)methyl)-5-methoxy-l-( lZ / -pyrazolo[3,4- / >]pyridin-4-yl)pyrimidine-2,4( l / / .3 / / )-dione (Final Compound 1-18) and (5)-3- (cyclopropyl(4-fluorophenyl)methyl)-5-methoxy- 1 -( 1 J / -pyrazolo[3,4- / >]pyridin-4- yl)pyrimidine-2,4( l / / .3 / / )-dione (Final Compound 1-19) Cyclopropyl(4-fluorophenyl)methanol

[0235] 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 NaBH4 (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 cyclopropyl(4-fluorophenyl)methanol) as a yellow oil (5.01 g, 99%).

[0236] '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).

[0237] 5-Methoxy-l-( (2-(trimethylsilyl)ethoxy)methyl)pyrimidine-2, 4( 1H, 3H)-dione

[0238] 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 bis(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 allowed to reach 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). Organic layers were combined, washed with brine (50 mL), dried over Na2SO4, and evaporated in vacuo to give 5 -methoxy- 1 -((2-

[0239] (trimethylsilyl)ethoxy)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-dione (19.0 g, 97.5% purity, 68.0 mmol, 96.7% yield).

[0240] LC-MS (ESI): m / z = 273.2 [M+H]+, RT = 1.19 min.

[0241] 3-(Cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l-((2-

[0242] ( trimethylsilyl)ethoxy)methyl)pyrimidine-2, 4(1H, 3H)-dione

[0243] According to Scheme 2: To the solution of 5 -methoxy- 1 -((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. Then, the solvent was removed in vacuo and the crude material was purified by FCC (SiCh, Hexane / EtOAc) to give 3- (cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l-((2-

[0244] (trimethylsilyl)ethoxy)methyl)pyrimidine-2, 4(1 / 7, 3 / 7)-dione (10.0 g, 23.8 mmol, 60.6% yield).

[0245] 'H-NMR (DMSO-tL, 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);

[0246] LC-MS (ESI): m / z = 421.2 [M+H]+, RT = 1.684 min.

[0247] 3-(Cyclopropyl(4-fluorophenyl)methyl)-5-methoxypyrimidine-2,4(lH, 3H)-dione:

[0248] According to Scheme 1 Step 5: 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), TBAF (9.33 g, 35.7 mmol, 35.7 ml, 1.5 equiv) and ethane- 1,2-diamine (2.86 g, 47.6 mmol, 3.18 mL, 2.0 equiv) were added at rt. The resulting mixture was refluxed for 2 days. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (3 x 50 mL). Organic layers were combined, washed with brine (2 x 50 mL), dried over Na2SO4, filtered and evaporated in vacuo to give 3-(cyclopropyl(4-fluorophenyl)methyl)-5- methoxypyrimidine-2, 4(1 / 7, 3 / 7)-dione (8.4 g, 50.0% purity, 14.5 mmol, 60.8% yield). The obtained product was used in the next step without further purification.

[0249] LC-MS (ESI): m / z = 289.0 [M-H]+, RT = 1.059 min.

[0250] 4-Bromo-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazolo[ 3, 4-b ]pyridine

[0251] According to Scheme 1 Step 6: 4-B romo-l / 7-pyrazolo[3,4-Z>]pyri dine (253 mg, 1.28 mmol), 3,4-dihydro-2 / 7-pyran (323 mg, 3.84 mmol, 350 pL, 3.0 equiv), and 4- m ethylbenzene- 1 -sulfonic acid (11.0 mg, 64.0 pmol) were mixed in DCM (5.0 mL) and stirred overnight at rt. After stirring for 16 h, the solvent was removed in vacuo and 4- bromo-l-(tetrahydro-2 / 7-pyran-2-yl)-l / 7-pyrazolo[3,4-Z>]pyridine (361 mg, 1.28 mmol, 100% yield) was obtained and used in the next step without further purification.

[0252] 3-(Cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l-(l-(tetrahydro-2H-pyran-2-yl)- lH-pyrazolo[ 3, 4-b ]pyridin-4-yl)pyrimidine-2, 4(1H, 3H)-dione

[0253] According to Scheme 1 Step 7: 4-Bromo- l -(tetrahydro-27 / -pyran-2-yl)- l / 7- pyrazolo[3,4-Z>]pyridine (199 mg, 706 pmol), 3-(cyclopropyl(4-fluorophenyl)methyl)-

[0254] 5-methoxypyrimidine-2, 4(1 / 7, 3 / 7)-dione (205 mg, 706 pmol), DMEDA (62.2 mg, 705 pmol), copper(I) iodide (134 mg, 706 pmol), and potassium carbonate (293 mg, 2.12 mmol) were mixed in 1,4-di oxane and stirred at 100 °C under an argon atmosphere for 1 day. After cooling the reaction mixture to rt, EtOAc was added. The organic phase was extracted, washed twice with brine, dried over Na2SO4 and concentrated under vacuum to give 3-(cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l-(l-(tetrahydro- 2 / 7-pyran-2-yl)-l / 7-pyrazolo[3,4-Z>]pyridin-4-yl)pyrimidine-2,4(l / 7,3 / 7)-dione (340 mg, 692 pmol, 98% yield).

[0255] 3-(Cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l-( lH-pyrazolo[ 3, 4-b ]pyridin-4- yl)pyrimidine-2, 4(1H, 3H)-dione According to Scheme 1 Step 8: 3-(Cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l- (1 -(tetrahydro-2 / / -pyran-2-yl)- l / / -pyrazolo[3,4- / ]pyridin-4-yl)pyrimidine-2, 4(1 / 7, 3H)- dione (340 mg, 692 pmol) was dissolved in MeOH (20 mL) with a few drops of aqueous HC1. The reaction mixture was stirred overnight at rt. After complete conversion, the reaction mixture was evaporated under reduced pressure. The resulting crude residue was dissolved in EtOAc and the organic phase was washed with an aqueous solution of Na2COs. The organic phase was dried over Na2SO4 and evaporated in vacuo. The residue was purified by preparative HPLC (Chromatorex Cis SMB 100- 5T 100x19 mm 5 pm column; 0 - 5 min; 50 - 100% EEO / MeOH; flow rate 30 mL / min (loading pump 4 mL / min MeOH)) to give 3-(cyclopropyl(4-fluorophenyl)methyl)-5- m ethoxy- l-(l / 7-pyrazolo[3,4-Z>]pyridin-4-yl)pyrimidine-2,4( 1 / 7, 3 / 7)-di one (161 mg, 395 pmol, 57.1% yield).

[0256] 'H-NMR (DMSO-tL, 500 MHz): 5 0.55 (m, 2H), 0.89 (m, 1H), 2.11 (m, 1H), 3.13 (m, 1H), 3.63 (s, 3H), 5.12 (m, 1H), 7.10 (m, 2H), 7.48 (m, 4H), 8.01 (m, 1H), 8.61 (s, 1H), 13.82 (s, 1H);

[0257] LC-MS (ESI): m / z = 408.2 [M-H]+, RT = 3.463 min.

[0258] (R)-3-( Cyclopropyl( 4-fluorophenyl)methyl)-5-methoxy-l-(lH-pyrazolo[ 3, 4-b ]pyridin- 4-yl)pyrimidine-2, 4(1H, 3H)-dione and (S)-3-(cyclopropyl(4-fluorophenyl)methyl)-5- methoxy-l-(lH-pyrazolo[ 3, 4-b ]pyridin-4-yl)pyrimidine-2, 4(1H, 3H)-dione

[0259] According to Scheme 1 Step 9: 38 mg of 3-(cyclopropyl(4-fluorophenyl)methyl)-5- m ethoxy- l-(l / 7-pyrazolo[3,4-Z>]pyridin-4-yl)pyrimidine-2,4( 1 / 7, 3 / 7)-di one was purified by chiral HPLC (Chiralpak IC (250x20 mm, 5 mkm) column, mobile phase: Hexane / IPA / MeOH, 60:20:20, Flow Rate: 12 mL / min) to afford : (7?)-3-(cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l-(l / 7-pyrazolo[3,4-Z>]pyridin- 4-yl)pyrimidine-2, 4(1 / 7, 3 / 7)-dione (11.8 mg, RT = 15.990 min) as a beige solid.

[0260] RT was determined by analytical HPLC (Chiralpak IC (150x4.6 mm, 5 mkm); Hexane / IPA / MeOH, 60:20:20 as a mobile phase; flow rate: 0.6 mL / min);

[0261] ‘H-NMR (DMSO-tL, 500 MHz): 5 0.55 (m, 2H), 0.89 (m, 1H), 2.11 (m, 1H), 3.13 (m, 1H), 3.63 (s, 3H), 5.12 (m, 1H), 7.10 (m, 2H), 7.48 (m, 4H), 8.01 (m, 1H), 8.61 (s, 1H), 13.82 (s, 1H); LC-MS (ESI): m / z = 408.2 [M+H]+, RT = 2.964 min;

[0262] And (5)-3-(cyclopropyl(4-fluorophenyl)methyl)-5-methoxy-l-(l / 7-pyrazolo[3,4- Z>]pyridin-4-yl)pyrimidine-2, 4(1 / 7, 3 / 7)-dione (11.8 mg, RT = 19.548 min) as a beige solid. RT was determined by analytical HPLC using the same conditions as above.

[0263] 'H-NMR (DMSO-tL, 500 MHz): 5 0.55 (m, 2H), 0.89 (m, 1H), 2.11 (m, 1H), 3.13 (m, 1H), 3.63 (s, 3H), 5.12 (m, 1H), 7.10 (m, 2H), 7.48 (m, 4H), 8.01 (m, 1H), 8.61 (s, 1H), 13.82 (s, 1H);

[0264] LC-MS (ESI): m / z = 408.2 [M+H]+, RT = 2.963 min.

[0265] EXAMPLE 3: 3-( l-(4-Cliloroplienyl)propyl)-5-niethoxy-l-( 1 -methyl- 1 / 7- pyrrolo[3,2-c]pyridin-4-yl)pyrimidine-2,4( l / / .3 / / )-dione (Final compounds 1-8)

[0266] According to Scheme 3: 4-Bromo-l -methyl- l / 7-pyrrolo[3,2-c]pyri dine (170 mg, 810 pmol), 3-(l-(4-chlorophenyl)propyl)-5-methoxypyrimidine-2, 4(1 / 7, 3 / 7)-dione (237 mg, 807 pmol), DMEDA (71.0 mg, 805 pmol), copper(I) iodide (153 mg, 808 pmol), and potassium carbonate (333 mg, 2.42 mmol) were mixed in 1,4-dioxane and stirred at 100 °C under an argon atmosphere for 1 day. After cooling the reaction mixture to rt, EtOAc was added. The organic phase was extracted, washed twice with brine, dried over Na2SC>4 and concentrated under vacuum. The resulting crude residue was purified by FCC to give 3-(l-(4-chlorophenyl)propyl)-5-methoxy-l-(l-methyl-l / 7-pyrrolo[3,2- c]pyridin-4-yl)pyrimidine-2, 4(1 / 7, 3 / 7)-dione (78.0 mg, 184 pmol, 23% yield).

[0267] 'H-NMR (DMSO-tL, 500 MHz): 5 8.15 (d, J = 5.7 Hz, 1H), 7.61 (d, J = 5.8 Hz, 1H), 7.50 (s, 1H), 7.48 (d, J = 3.2 Hz, 1H), 7.36 (s, 4H), 6.18 (s, 1H), 5.94 (s, 1H), 3.84 (s, 3H), 3.63 (s, 3H), 2.43 (d, J= 8.6 Hz, 1H), 2.26 (m, 1H), 0.92 (t, J= 7.3 Hz, 3H);

[0268] LC-MS (ESI): m / z = 425.2 [M+H]+, RT = 3.450 min.

[0269] The compounds in the following Table have been synthezised according to the same methods as previous Examples 1 to 3, as denoted in the column denoted as "Exp. nr". The compounds denoted with the asterisk (“*”) have been exemplified in the Examples.

[0270] Table 1: Compounds prepared according to the Examples.

[0271]

[0272] Physico-Chemical Data

[0273] Melting points: a) Melting point determination was performed on a Buchi B-540 apparatus. b) DSC analysis

[0274] 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.

[0275] UPLC-MS method: 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.

[0276] Mobile phases are Solvent A: MeCN / H2O / formic acid 0.1% (900: 100:2) and Solvent B: H2O / formic acid 0.1% (1000:2).

[0277] 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.

[0278] 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.

[0279] LC-MS methods:

[0280] Method 1 :

[0281] LC-MS were recorded on a Waters Micromass ZQ 2996 system by the following conditions:

[0282] 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.

[0283] Mobile phases are Solvent A: water (0.1% formic acid) and Solvent B: MeCN (0.1% formic acid).

[0284] 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.

[0285] Method 2:

[0286] 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.

[0287] Mobile phases are Solvent A: water (0.1% formic acid) and Solvent B: MeCN (0.1% formic acid).

[0288] 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.

[0289] Method 3 :

[0290] LC-MS were recorded on a Waters Micromass ZQ 2996 system by the following conditions:

[0291] Reverse phase HPLC was carried out on an Zorbax SB-Cis cartridge (1.8 pm, 4.6 x 30 mm) from Agilent, with a flow rate of 1.5 mL / min. The gradient conditions used are: 90 % A (water + 0.05 % of formic acid), 10% B (ACN + 0.05 % of formic acid) to 100 % B at 3.5 min, kept till 3.7 min and equilibrated to initial conditions at 3.8 min until 4.5 min. Injection volume 5-20 pL. ES MS detector was used, acquiring both in positive and negative ionization modes. Cone voltage was 30 V for both positive and negative ionization modes.

[0292] Preparative HPLC purification:

[0293] Purifications were run on Agilent 1290 Infinity II series preparative HPLC system (1290 Infinity II Binary pump, 1260 Infinity II Diode Array Detector, LC / MSD mass detector), Waters SunFire (Cis, 19 x 100 mm, 5 pm) or Waters XBridge (Cis, 19 x 100 mm, 5 pm) columns using H2O + 0,1 % formic acid or H2O + 0,1 % ammonia (25% ammonia in water) and ACN as eluents. Gradients used covered the range from 10% ACN to 100 % ACN.

[0294] NMR:

[0295] 1H-NMR spectra were recorded on a Bruker NMR-spectrometer Avance (600 MHz or 500 MHz), a Bruker DPX (300 MHz) or a 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).

[0296] Table 2: Physico-chemical data. (RT means retention time in minutes; [MH]+means the protonated mass of the compound (free base); nd = not determined).

[0297] PHARMACOLOGY 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 region of the receptor. In the presence of GABA or an agonist of GABAB receptor, the compounds of this invention increase the GABAB 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.

[0298] 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.

[0299] 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.

[0300] The compounds of the present invention may be utilized in combination with one or more other drugs in the treatment, prevention, control, amelioration, or reduction of risk of diseases or conditions for which compounds of Formula (I) or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone. The behavior of positive allosteric modulators, such as the ones described in Formula (I), at GAB AB receptors is shown in the following paragraph, which is suitable for the identification of such compounds.

[0301] Example A

[0302] [35S] GTPyS binding assay

[0303] 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).

[0304] 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 dose 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.

[0305] The Table 3 below represents the mean EC50 obtained from at least three independent experiments of selected molecules performed in duplicate.

[0306] Table 3: Activity data for selected compounds

[0307] *Table legend:

[0308] NA: EC5O >1O pM

[0309] (+): 1 pM < EC50<10 pM

[0310] (++): 100 nM < ECso <1 pM

[0311] (+++): EC50 < 100 nM

[0312] The results shown in Table 3 demonstrate that the compounds described in the present invention are positive allosteric modulators of human GAB AB receptors.

[0313] Example B

[0314] Citric acid-induced cough in guinea pigs

[0315] The citric acid (CA) induced cough in conscious guinea pigs is a suitable model for testing the efficacy of antitussive drugs (Cunning et al., Cough 2012, 8:7) Animals: Male Dunkin Hartley guinea pigs (400-500 g) were group-housed in pens (11125 cm2) under temperature (20.0 ± 3 °C) and humidity (40-70%) controlled facility on a normal 12h / 12h cycle (lights on 07:00-19:00 / off: 19:00-07:00). Environmental enrichment was provided in all pens. Animals had access to food and tap water ad libitum. The animals had not been subjected to other experiments before the study and were acclimated to the facility for at least 5 days before any experimentation. All experiments were performed in compliance with government regulations. Experimental protocols were approved by Animal Ethics Committees.

[0316] Compound administration and evaluation of antitussive efficacy of compounds: Test compounds were suspended in a solution of 1% CMC-Na (medium viscosity) / 0.25% Tween 80 in distilled water and were administered in guinea pigs (n=8 / group) by oral gavage (p.o.) in a volume of 5 mL / kg. Immediately after dosing animals were placed individually into whole body plethysmography chamber (20 x 15 x 15 cm) and respiratory rate was recorded for 60 to 120 min. At the end of the pretreatment period animals were exposed to aerosol of 0.5M citric acid using an ultrasonic nebulizer set at a nominal liquid consumption rate of 1.8 mL / min and airflow of 2 L / min. Coughs elicited during the 10 minutes immediately after the citric acid aerosol were recorded manually and later confirmed from the airflow pressure changes recordings. In addition to quantifying the cough frequencies and latenties to the 1stcough, respiratory rate and body temperature changes (before the treatment and at the end of the experiment) were monitored. At the end of the experiment animals were euthanized with overdose of pentobarbitone.

[0317] Statistical analyses'. The data were analyzed using analysis of variance (ANOVA), followed by a Tukey-HSD test. A difference was considered statistically significant at p < 0.05.

[0318] Example C

[0319] Acetic acid-induced writhing (AAW) test in mice

[0320] The AAW test is commonly used as an in vivo assay for measuring acute generalized visceral pain in rodents (Collier et al., Br. J. Pharmac. Chemother. 1968, 32:295-310)

[0321] Animals: Male C57B16 / J mice (24-30g) are used. Animals were group-housed (5 per cage) and kept on a 12-h light / dark cycle (lights on from 07:00 to 19:00 h) under constant temperature (22 + 2 °C) and humidity (>45%) conditions with food and water available ad libitum. Animals were acclimated for at least 10 days before experimentations. All experimental procedures and conditions were approved by the local Ethics Committee and performed in full compliance with with in compliance with government regulations.

[0322] Compound administration and evaluation of analgesic efficacy of compounds: Mice (n=12 / group), food deprived overnight before the experiment, were treated with the compound or vehicle using oral gavage (p.o.). After 60 to 120 min following treatment animals received intraperitoneal (i.p.) injection of 0.7% acetic acid before being placed individually into observation cages (modified type II cages, placed upside down and equipped with the wire mash floor and mirrors under the floor and on the side). Observation of animals began 10 min following administration of AA and lasted 10 min. The AA-induced writhe was defined as a contraction of the abdomen or stretch of the trunck with or without extension of the limbs. Writhes were counted by a trained observer blind to the treatment.

[0323] Statistical analyses'. The data were analyzed using analysis of variance (ANOVA), followed by a Tukey-HSD test. A difference was considered statistically significant at p < 0.05.

[0324] Example D

[0325] Overactive bladder (OAB) in mice

[0326] The diuretic stress incontinence model of OAB was modified from the procedure described previously in rats (Harada et al. J. Pharmacol. Toxicol. Meth., 1992, 27: 119- 126). It has been used as an in vivo screening assay, as it shows sensitivity to cholinergic antagonists, active in the clinic, such as oxybutynin (Yoshida et al., J. Pharmac. Sci. 2010, 112: 142-150)

[0327] Animals: Male C57B16 / J mice (24-30g) are used. Animals were group-housed (3-5 per cage) and kept on a 12-h light / dark cycle (lights on from 07:00 to 19:00 h) under constant temperature (22 + 2 °C) and humidity (>45%) conditions with food and water available ad libitum. Animals were acclimated for at least 10 days before experimentations. All experimental procedures and conditions were approved by the local Ethics Committee and performed in full compliance with the EU Directive for animal experiments.

[0328] Equipment: Individual micturition chambers consisted of two clear cylindrical Plexiglas observation tubes (20 cm length x 13 cm diameter), where the top tube was designed to hold the animal, while the bottom one was equipped with the urine collection and detection system comprised of omega load sensors with a plastic cup on the top to collect urine.

[0329] Experimental procedure: Mice (n=8 / group), food-deprived for 24 h prior to the study, were either left untreated, or were administered compounds or the vehicle via oral gavage(p.o.). Sixty to 120 min following treatment animals were administered 1 mL of water s.c. Within 5 min after water administration, furosemide (10 mg / mL, dissolved in water) was administered i.p. to all animals except the untreated controls. Immeidately following flurosemide injection, animals were individually placed in micturition chambers for 90 min. The following variables were quantified: total urinary events (the event was defined as production of at least 100 pL of urine in less than 1 min), latency to the first urinary event (sec), total urinary volume (mL) and average urinary volume per event (mL).

[0330] Statistical analyses'. The data were analyzed using analysis of variance (ANOVA), followed by Dunnett’s test. A difference was considered statistically significant at p < 0.05.

[0331] FORMULATION EXAMPLES

[0332] Typical examples of recipes for the formulation of the invention are as follows:

[0333] 1. Tablets

[0334] Active ingredient 5 to 50 mg

[0335] Di-calcium phosphate 20 mg

[0336] Lactose 30 mg

[0337] Talcum 10 mg

[0338] Magnesium stearate 5 mg

[0339] Potato starch ad 200 mg 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.

[0340] 2. Suspension

[0341] 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 m .

[0342] 3. Injectable

[0343] 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.

[0344] 4. Ointment

[0345] Active ingredient 5 to 1000 mg

[0346] Stearyl alcohol 3 g

[0347] Lanoline 5 g

[0348] White petroleum 15 g

[0349] Water ad 100 g

[0350] 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.

[0351] 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, -(Ci-Ce)alkyl and -(C3-C7)cycloalkyl;R2is selected from the group of hydrogen, -(Ci-Ce)alkyl, -(C3-C7)cycloalkyl and - (Ci-Ce)haloalkyl;Zi and Z2 are each independently selected from C or N;Z3 and Z4 are each independently selected from C or N; wherein when Z3 is C, Z4 is N; wherein when Z4 is C, Z3 is N; m is an integer equal to zero, 1, 2, 3 or 4; 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, -(Ci-C6)alkylene-(C3-C7)cycloalkyl, aryl, heteroaryl, heterocycle, -(Co-Ce)alkylene-OR3, -O-(C2-Ce)alkylene-OR3, -O-(C2- C6)alkylene-NR3R4, -(Co-C6)alkylene-NR3R4, -NR3(C2-C6)alkylene-OR4, -NR3- (C2-C6)alkylene-NR4R5, -(C0-C6)alkylene-OC(=O)-R3, -O-(C2-C6)alkylene- OC(=O)-R3, -NR3-(C2-C6)alkylene-OC(=O)-R4, -(C0-C6)alkylene-C(=O)-OR3, -O- (Ci-C6)alkylene-C(=O)-OR3and -NR3-(Ci-C6)alkylene-C(=O)-OR4;R3, R4and R5are each independently hydrogen or an optionally substituted radical selected from the group of -(Ci-Ce)alkyl, -(Ci-Ce)haloalkyl, -(C3-C7)cycloalkyl, -(Ci-C6)alkylene-(C3-C7)cycloalkyl, -(Co-C6)alkylene-0-(Co-Ce)alkyl and -(Co- Ce)alkylene-N-((Co-C6)alkyl)2; n is an integer equal to 1, 2, 3, 4, 5 or 6; 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, -(C3-C7)cycloalkyl, -(Ci-C6)alkylene-(C3-C7)cycloalkyl, -(Co- Ce)alkylene-OR6, -O-(C2-C6)alkylene-OR6-O-(C2-Ce)alkylene-NR6R7, -(Co- C6)alkylene-NR6R7, -NR6(C2-C6)alkylene-OR7, -NR6-(C2-C6)alkylene-NR7R8, - (C0-C6)alkylene-OC(=O)-R6, -O-(C2-C6)alkylene-OC(=O)-R6, -NR6-(C2- C6)alkylene-OC(=O)-R7, -(C0-C6)alkylene-C(=O)-OR6, -O-(Ci-C6)alkylene- C(=O)-OR6and -NR6-(Ci-C6)alkylene-C(=O)-OR7;R6, R7and R8are each independently hydrogen or an optionally substituted radical selected from the group of -(Ci-Ce)alkyl, -(Ci-Ce)haloalkyl, -(C3-C7)cycloalkyl, - (Ci-C6)alkylene-(C3-C7)cycloalkyl, -(Co-C6)alkylene-0-(Co-Ce)alkyl and -(Co- Ce)alkylene-N-((Co-C6)alkyl)2.

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, 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 R3, R4or R5.

4. The compound according to any preceding claim having the Formula (I) wherein: the cycloalkyl ring system of (B)nis selected from the group of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, and each ring of said ring system is optionally substituted independently with 1 to 3 substituents R6, R7or R8.

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, and an optionally substituted radical selected from the group of -(Ci-Ce)alkyl, - (Ci-Ce)haloalkyl and -(Co-Ce)alkylene-OR3.

6. The compound according to any preceding claim having the Formula (I), wherein: R3is hydrogen or an optionally substituted radical selected from the group of - (Ci-Ce)alkyl and -(Ci-C6)haloalkyl.

7. 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, and an optionally substituted radical selected from the group of -(Ci-Ce)alkyl, - (Ci-Ce)haloalkyl and -(C3-C7)cycloalkyl.

8. 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, and -(Co-C6)alkylene-OR3.

9. The compound according to any preceding claim having the Formula (I), wherein:R3is -(Ci-C6)alkyl.

10. The compound according to any preceding claim having the Formula (I), wherein: the or each (B)nis independently selected from the group of hydrogen and -(Ci- Ce)alkyl.

11. 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 V-oxide form thereof.

12. The compound according to any preceding claim having the Formula (III):a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof or an V-oxide form thereof wherein:R2is selected from the group of -(Ci-Ce)alkyl and -(C3-C7)cycloalkyl.

13. The compound according to any preceding claim having the Formula (IV):a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof or an TV-oxide form thereof.

14. The compound according to any one of claims 11 to 13 wherein: R2is selected from the group of ethyl, propyl and cyclopropyl.

15. The compound according to any one of claims 11 to 14 wherein: the or each (A)mis independently selected from the group of hydrogen and halogen.

16. The compound according to claims 1 to 15, 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.

17. 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.

18. The compound according to claim 17, 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 claims 18, wherein said compound is one or moreand a pharmaceutically acceptable acid or base addition salt thereof, a stereochemically isomeric form thereof or an A -oxi de 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. 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 one of claims 1 to 20.

22. The method according to claim 21 wherein the treatment or prevention is affected or facilitated by the modulatory effect of a GAB AB allosteric modulator, such as a GAB AB positive allosteric modulator.

23. 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 one of claims 1 to 20.

24. The method according to claim 23, wherein the treatment or prevention is affected or facilitated by the modulatory effect of a GABAB positive allosteric modulator.

25. A method of treating or preventing chronic cough and refractory chronic cough comprising administering to a mammalian patient in need of such treatment an effective amount of a compound / composition according to any one of claims 1 to 20.

26. A method of treating or preventing inflammatory or neuropathic pain, postoperative pain comprising administering to a mammalian patient in need of suchtreatment an effective amount of a compound / composition according to any one of claims 1 to 20.

27. A method of treating or preventing urge urinary incontinence comprising administering to a mammal in need of such treatment or prevention, an effective amount of a compound / composition according to any one of claims 1 to 20.

28. Use of a compound according to any one of claims 1 to 19 in the manufacture of a medicament.

29. 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 21 to 27.

30. A compound according to any one of claims 1 to 19 for use as a medicament.

31. A compound according to any one of claims 1 to 19 for use in a method according to any one of claims 21 to 27.

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