IL243676A

1,2,4-triazolo[4,3-a]pyridine compounds and their use as positive allosteric modulators of mglur2 receptors

Abstract

This record has no abstract on file.

IL243676A, drawing sheet 1 — Sheet 1 of 53

Term

No projected expiry on record.

14 claims: 2 independent, 12 dependent

1
A compound of Formula (I) or a stereo chemically isomeric form thereof, wherein R1 is selected from the group consisting of Ci_6alkyl, (C3-8cycloalkyl)Ci_3alkyl, and (C i_3alkyloxy)C i_3alkyl;each R2 is independently selected from F, Cl, Ci-3alkyl, Ci-3alkyloxy, mono- or polyhaloCi_3alkyl, and mono- or polyhaloCi-3alkyloxy;n is an integer selected from 1, 2, and 3;or a pharmaceutically acceptable salt or solvate thereof.
14
A product comprising (a) a compound as defined in any one of claims 1 to 6;and (b) an mGluR2 orthosteric agonist, as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of a central nervous system disorder selected from the group of schizophrenia (in particular, negative symptoms or residual symptoms thereof), generalized anxiety disorder, bipolar disorder (I or II), migraine, behavioral and psychological symptoms of dementia, epilepsy or convulsive disorders, panic disorder, mixed anxiety and depression, and agoraphobia.

Independent claims2

722 paragraphs in 141 sections, as filed

The present invention relates to novel l,2,4-triazolo[4,3-a]pyridine compounds as positive allosteric modulators (PAMs) of the metabotropic glutamate receptor subtype 2 (“mGluR2”). The invention is also directed to pharmaceutical compositions comprising such compounds, to processes for preparing such compounds and compositions, and to the use of such compounds and compositions for the prevention or treatment of disorders in which mGluR2 subtype of metabotropic receptors is involved.

BACKGROUND OF THE INVENTION

Glutamate is the major amino acid neurotransmitter in the mammalian central nervous system. Glutamate plays a major role in numerous physiological functions, such as learning and memory but also sensory perception, development of synaptic plasticity, motor control, respiration, and regulation of cardiovascular function. Furthermore, glutamate is at the centre of several different neurological and psychiatric diseases, where there is an imbalance in glutamatergic neurotransmission.

Glutamate mediates synaptic neurotransmission through the activation of ionotropic glutamate receptor channels (iGluRs), and the NMDA, AMP A and kainate receptors which are responsible for fast excitatory transmission.

In addition, glutamate activates metabotropic glutamate receptors (mGluRs) which have a more modulatory role that contributes to the fine-tuning of synaptic efficacy.

Glutamate activates the mGluRs through binding to the large extracellular amino-terminal domain of the receptor, herein called the orthosteric binding site. This binding induces a conformational change in the receptor which results in the activation of the G-protein and intracellular signaling pathways.

The mGLuR2 subtype is negatively coupled to adenylate cyclase via activation of Gai-protcin, and its activation leads to inhibition of glutamate release in the synapse. In the central nervous system (CNS), mGlu2 receptors arc abundant mainly throughout cortex, thalamic regions, accessory olfactory bulb, hippocampus, amygdala, caudate-putamen and nucleus accumbens.

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- 2 Activating mGluR2 was shown in clinical trials to be efficacious to treat anxiety disorders (for studies with orthosteric mG1u2/3 agonists, see Michelson et al. Neuropharmacology 2005, 49(S1), 84-257; Dunayevich et al. Neuropsychopharmacology 2008, 33(7), 1603-10), LY354740 had been previously evaluated in non-clinical and clinical model systems predicting utility in the treatment of anxiety disorders beyond generalized anxiety depression (G AD), e.g. panic (see Dunayevich et al. 2008). Non-clinical studies, suggest a role for both mGlu2 and mGlu3 receptors in anxiolysis (Linden et al. Ncuropharmacology 2005, 49, 120-134) whilst it has been suggested that positive allosteric modulation of the mGluR2 may be sufficient for an anxiolytic effect (Johnson et al. Psychopharmacology (Bcrl) 2005, 179(1),271-283).

In addition, activating mGluR2 was shown to be potentially efficacious for the treatment of (a) schizophrenia (Patil et al. Nat Med 2007, 13(9), 1102-7); later studies however, do not support treatment of acute exacerbations of schizophrenia with an mGluR2 agonist or allosteric modulator (Adams et al. BMC Psychiatry 2013, 13(1), 143; Kinon et al. J Clin Psychopharmacol. 2013, 31(3), 349-55; Litman et al. (2013) NCDEU Meeting (abstract)) but do not exclude application for other specific symptom clusters (e.g. negative symptoms (Kent et al. “Safety, tolerability and potential therapeutic efficacy of a novel glutamate modulator as adjunctive treatment in patients with schizophrenia” abstract No. 3160 and poster NR10-47, American Psychiatric Association 166th Annual Meeting 2013 (APA 2013), May 18-22, 2013, San Francisco, California, USA)) or for other phases in the disease (e.g. residual symptoms);

(b) epilepsy, based on acute non-clinical studies with mixed mGlu2/3 receptor agonists 25 (Moldrich et al. Eur J Pharmacol. 2003, 476, 3-16; Barton et al. Epilepsy Research

2003, 56, 17-26); continued administration of an mGlu2/3 agonist paradoxically induced seizure activity in long-term toxicology studies (Dunayevich et al. (2008), this paradoxical effect may be related, to agonist-induced changes in the sensitivity of the receptor systems (tachyphylaxis); positive allosteric modulators, in contrast, modulate 30 ongoing neurotransmission but are not directly stimulatory, thereby reducing the risk for tachyphylaxis;

2008; Foster, Curr Drug Abuse Rev 2009, 2, 83-98);

(d) Parkinson’s disease (see for example Johnson et al. CNS Neurol Disord Drug

Targets 2009, 8, 475-491; Konicczny ct al. Naunyn Schmiedebergs Arch. Pharmacol.

1998, 358 (4), 500-502);

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PCT/EP2014/068676 (e) pain (Chiechio and Nicoletti, Curr Opm Pharmacol 2012, 12, 28-34; Jones et al. Neuropharmacology 2005, 49, 206-21 8; Neugebauer, [Review] Pain 2002, 98 (1-2), 1-8; Simmons et al. Pharmacology, Biochemistry and Behavior 2002, 73, 419-427);

(f) sleep disorders (Ahnaou et al. European Journal of Pharmacology 2009, 603, 6272);

(f) Huntington’s disease (based on a potential disease modifying effect (Schiefcr et al. Brain Res 2004, 1019, 246 - 254) which is to be confirmed further); and (g) depression (although no efficacy signal was detected on the primary outcome measure, adjunctive administration of JNJ-40411813/ADX71149 in the dose range tested in a multi center, double-blind, placebo-controlled study in adults with major depressive disorder with anxiety symptoms showed efficacy signals on several secondary outcome measures of both depression and anxiety (Kent et al. “Efficacy and Safety of a Novel mGlu2 Receptor Positive Allosteric Modulator as an Adjunctive Treatment to an SSRI/SNR1 in the Treatment of Anxious Depression”, Abstract to poster and oral presentation, American Society of Clinical Psychopharmacology (ASCP) 2014 Annual Meeting, June 16-19, 2014 Westin Diplomat, Hollywood, Florida)).

A new avenue for developing selective compounds acting at mGluRs is to identify compounds that act through allosteric mechanisms, modulating the receptor by binding to a site different from the highly conserved orthosteric binding site.

Positive allosteric modulators of mGluRs have emerged recently as novel pharmacological entities offering this attractive alternative.

It was demonstrated that such compounds do not activate the receptor by themselves. Rather, they enable the receptor to produce an increased response to a concentration of gl utamate, which by itself induces a minimal response. Mutational analysis has demonstrated unequivocally that the binding of mGluR2 positive allosteric modulators does not occur at the orthosteric site, but instead at an allosteric site situated within, the seven transmembrane region of the receptor.

Animal data suggest that positive allosteric modulators of mGluR2 have effects in anxiety and psychosis models similar to those obtained with orthosteric agonists. Allosteric modulators of mGluR2 were shown to be active in fear-potentiated startle (Johnson et al. J Med Chcm 2003, 46, 3189-3192; Johnson et al. Psychopharmacology 2005, 179, 271-283), and in stress-induced hyperthermia models of anxiety (Johnson et al. 2005). Furthermore, such compounds were shown to be active in reversal of ketamine- (Govek et al. Bioorg Med Chcm Lett 2005, 15(18), 4058-4072) or

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amphetamine- (Galici et al. JPharmExp Ther 2005, 315(3), 1181-1187) induced hyperlocomotion, and in reversal of amphetamine-induced disruption of prepulse inhibition of the acoustic startle effect (Galici et al. 2005) models of schizophrenia.

JNJ-40411813/ADX71149, an mGlu2 PAM (which in rat also displays 5-ΗΤ2Λ antagonism activity due to a rat-specific metabolite) has undergone clinical trials for the treatment of schizophrenia, and anxiety-depression (see for instance www. Clinicaltrials.gov). Non-clinical data in the lactate-induced panic model in rodents suggests that it could have potential in the treatment of further anxiety disorders such as panic disorder and phobias, such as agoraphobia (Shekhar et al. Neuropsychopharmacology 2013, 38, S435-S593 (W220). JNJ-40411813 was also observed to reduce craving and improve smoking cessation-induced deficits in attention and episodic memory versus placebo (Salih et al. Journal of Psychopharmacology, submitted) and showed an efficacy signal in S-ketamine-induced negative symptoms in healthy volunteers and patients with predominant negative symptoms of schizophrenia (De Boer et al. Society of Biological Psychiatry 68th Annual Scientific Convention of Society of Biological Psychiatry, May 16-18, 2013, Hilton Union Square, San Francisco, California, Abstract 2013-P-1060-SOBP).

Positive allosteric modulators enable potentiation of the glutamate response, but they have also been shown to potentiate the response to orthosteric mGluR2 agonists such as LY379268 or DCG-1V. These data provide evidence for yet another novel therapeutic approach to treat the above mentioned neurological and psychiatric diseases involving mGluR2, which would use a combination of a positive allosteric modulator of mGluR2 together with an orthosteric agonist of mGluR2.

Various compounds have been described as mGluR2 positive allosteric modulators. WO2010/1.30424, WO201.0/130423, WO2010/130422, and WO2012/062750, WO2012/062751, and WO2012/062759, published on 18 November 20.10 and 18 May 2012, respectively, disclose l,2,4-triazolo[4,3-a]pyridi.nc derivatives as mGluR2 positive allosteric modulators.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to potent mGluR2 PAM compounds with an advantageous balance of properties. Thus, the present invention is directed to 1,2,4triazolo[4,3-a]pyridine derivatives of Formula (1)

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and the stereochemically isomeric forms thereof, wherein

R1 is selected from the group consisting of Ci^alkyl, (C3_scycloalkyl)Ci.3alkyl, and (CK3alkyloxy)Ci.3alkyl;

each R2 is independently selected from F, Cl, Chalky], Ci^alkyloxy, mono- or polyhaloCi_3alkyl, and mono- or polyhaloCi^alkyloxy;

n is an integer selected from 1, 2, and 3;

and the pharmaceutically acceptable salts and the solvates thereof.

The present invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) and a pharmaceutically acceptable carrier or excipient.

Additionally, the invention relates to a compound of Formula (I) for use as a medicament and to a compound of Formula (I) for use as a medicament for the treatment or prevention of neurological and psychiatric disorders in which mGluR2 is involved.

The invention also relates to the use of a compound according to Formula (I) or a pharmaceutical composition according to the invention for the manufacture of a medicament for treating or preventing neurological and psychiatric disorders in which mGluR2 is involved.

Additionally, the invention relates to the use of a compound of Formula (I) in combination with an additional pharmaceutical agent for the manufacture of a medicament for treating or preventing neurological and psychiatric disorders in which mGluR2 is involved.

Furthermore, the invention relates to a process for preparing a pharmaceutical composition according to the invention, characterized in that a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of a compound of Formula (1).

The invention also relates to a product comprising a compound of Formula (I) and an additional pharmaceutical agent, as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of neurological or psychiatric disorders and diseases.

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-6The present invention relates m particular to compounds or Formula (I) as defined hereinabove, and stereoisomeric forms thereof, wherein

R1 is selected from the group consisting of CH3CH2, CH3CH2CH2, (cyclopropyl)methyl, (cyclobutyl)mcthyl, cthyloxymethyl and methyloxymethyl; and the rest of variables are as defined herein; and the pharmaceutically acceptable salts and the solvates thereof.

In a further embodiment, the present invention relates to compounds of Formula (1) as defined hereinabove, and stereoisomeric forms thereof, wherein

R1 is selected from the group consisting of CH3CH2, (cyclopropyl)methyl, (cyclobutyl)methyl and mcthyloxymcthyl; and the rest of variables arc as defined herein; and the phannaceutically acceptable salts and the solvates thereof.

In a further embodiment, the present invention relates to compounds of Formula (1) as defined hereinabove, and stereoisomeric forms thereof, wherein

R1 is selected from the group consisting of CH3CH2, (cyclopropyl)m ethyl, (cyclobutyl)methyl and ethyloxymethyl; and the rest of variables are as defined herein; and the pharmaceutically acceptable salts and the solvates thereof.

In an additional embodiment, the invention relates to a compound of Formula (I) as defined hereinabove, and stereoisomeric forms thereof wherein each R2 is independently selected from F, Cl, CH3, CH3O and CF3; and the pharmaceutically acceptable salts and the solvates thereof.

In a further embodiment, the present invention relates to compounds of Formula (1) as defined herein having the Formula (la) (la) wherein, the variables arc as defined in Formula (1) herein, and the pharmaceutically acceptable salts and the solvates thereof.

In a further embodiment, the present invention relates to compounds of Formula (1) as defined herein having the Formula (lb)

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(lb) wherein the variables are as defined in Formula (I) herein, and the pharmaceutically acceptable salts and the solvates thereof.

Particular compounds may be selected from the group of

-(Cyclopropylmethyl )-7- [ 1 -(4-fluorophenoxy)cthyl]-8 (trifiuor omc thyl)[ 1,2,4]triazolo [4,3 -a] pyridine;

3-(Cyclopropylmethyl)-7-[(l *R)-l-(4-fluorophenoxy)cthyl]-8(trifluoromcthyl)[ 1,2,4]triazolo[4,3-a]pyridine;

3-(Cyclopropylmethyl)-7-[(1*S)-l-(4-fluorophenoxy)ethyl]-8(trifluoromethyl)[l,2,4]triazolo[4,3-a]pyridme;

3-(Cyclopropylmethyl)-7-[(lS)-l-(2,4-difluorophenoxy)ethyl]-8(trifluoromethyl)[ 1,2,4] triazolo [4,3 -a]pyridine;

3-(Cyclopropylmethyl)-7-[(lR)-1 -(2,4-difluorophenoxy)ethyl]-8(trifluoromethyl)[l,2,4]triazolo[4,3-a]pyridine;

-(Cyclopropylmethyl)-7- [ 1 -(2,4-difluorophenoxy)ethy 1] - 8 (tri fluoromethyl)[ 1,2,4]triazolo [4,3 -ajpyridine;

-(Cyclopropylmethyi)-7 - [(1S)-1 -(3,5 -difluorophenoxy)ethy 1] -8(tri fl uorom ethyl) [ 1,2,4]triazo lo [4,3-ajpyridmc;

-(Cyclopropyl methyl)- 7 - [(1S) -1 -(3,4-difluoroph cnoxy)ethyl ]-8(trifluoromethyl)[l,2,4]triazolo[4,3-a]pyridinc;

3-(Cyclopropylmethyl)-7-[(l S)-1-(2,3-difluorophcnoxy)ethyl]-8(trifluoromethyl)[ 1,2,4]triazolo[4,3-a]pyridine;

-(Cyclop ropy Imethy I )-7- [(1S)-1 -(2,5 -difluo rophenoxy)cthyl] -8(trifluoromethyl) [ 1,2,4] tri azo lo [4,3 -ajpyridine;

3-(Cyclopropylmethyl)-7-[( 1 S)-l -(2,6-difluorophenoxy)ethyl]-8(trifluoromcthyl)[ 1,2,4]triazolo[4,3-a]pyridine;

3-(Cyclopropylmcthyl)-7-[(lS)-l-(4-fluoro-2-methoxyphenoxy)ethyl]-8(trifluoromethyl)[l,2,4]triazolo[4,3-a]pyridine;

-(Cy clobutylmethyl)- 7-[ 1 -(2,4-difluo rophenoxy)ethy 1 ] -8 (trifluoromethyl)[ 1,2,4 ]triazolo[4,3-a]pyridine;

7-[( 1S)-1 -(2-Chloro-4-methylphcnoxy)cthyl]-3-(cyclopropylmethyl)-8(trifluoromethyl)[l ,2,4] triazol o[4,3-a]pyridine;

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- 8 3-(Cyclopropyhnethyl)-7-[(lS)-l-(4-fluoro-2-methylphenoxy)ethylJ-8(tri fluoromethyl)[ 1,2,4 Jtriazo lo [4,3 - a ] pyridine;

-(Cy cl opropylmethy 1)- 8 -(trifluoromethyl)- 7- [(1S)-1 -(2,4,6trifluorophenoxy)ethyl][l,2,4]triazolo[4,3-a]pyridine;

7-[l-(2,4-Difluorophenoxy)ethyl]-3-(ethoxymethyl)-8(trifluoromethyl)(l,2,4]triazolo[4,3-a]pyridine;

3-Ethyl-8-(trifluoromethyl)-7-[l-(2,4,6-trifluorophenoxy)ethyl](l,2,4]triazolo[4,3ajpyridine;

7-(1-(2,4-Difluorophenoxy)ethyl]-3-ethyl-8-(trifluoiOmethyl)(l,2,4]triazolo(4,3ajpyridinc;

3-(Cyclobutylmethyl)-7-[(l*R)-l-(2,4-difluorophenoxy)ethyl]-8(trifluoromcthyl)[l ,2,4]triazolo[4,3-ajpyridine;

3-(Cyclobutylmcthyl)-7-[(l *S)-1-(2,4-di fluorophenoxy)ethyl]-8(trifluoromcthyl) [ 1,2,4 Jtriazolo [4,3 -ajpyridin e;

3-(Ethoxymethyl)-8-(trifluoiOmethyl)-7-[(l *R)-1 -(2,4,6trifluorophenoxy)ethylj(l ,2,4]triazolo[4,3 -ajpyridine;

3-(Ethoxymethyl)-8-(trifluoromethyl)-7-((l*S)-l-(2,4,6trifluorophenoxy)ethyl] [ 1,2,4 Jtriazolo[4,3 -ajpyridine;

7-((1 * S )-1 -(2,4-D ifluorophenoxy) ethyl] -3 -(ethoxymethyl)-8(trifluoromethyl)[ 1,2,4]triazolo[4,3-a]pyridine;

7-((1 *R)-l-(2,4-Difluorophenoxy)ethyl]-3-(ethoxymethyl)-8(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine;

7-((1 *R)-1 -(2,4-Difluorophenoxy)ethyl]-3-ethyl-8(trifluoromcthyl)[ 1,2,4]triazolo[4,3-a]pyridine;

7- [(1 * S)-1 -(2,4-D Ϊ fluo roph enoxy)ethy I] -3 -ethyl -8 (trifluororn ethyl) [ 1,2,4]triazolo[4,3-ajpyridine;

7-(1-(2,4-Difluorophcnoxy)ethyl]-3-propyl-8-(trifluoroniethyl)[l ,2,4]triazolo[4,3ajpyridine;

3-Ethyl-8-(trifluoromcthyl)-7-[(l*R)-1-(2,4,6-trifluorophenoxy)ethyl][ 1,2,4]triazolo [4,3 -ajpyridine;

3-Ethyl - 8-(trifluoromethyl)-7-[(1 * S) -1 - (2,4,6-trifluoroph cnoxy)cthy I][1,2,4Jtriazolo(4,3-a]pyridine;

- [(i * R)-(2,4-d i fl uoroph eno xy)ethy 1]-3-propy 1 - 8 - (trifluoromethyl)[1,2,4Jtriazolo[4,3-aJpyridine; and

7-((1 *S)-(2,4-difluorophenoxy)ethyl]-3-propyl-8-(trifTuoromethyl)[l,2,4]triazolo[4,3-ajpyridine.

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-9Included within the scope of this list are stereoisomeric forms, the pharmaceutically acceptable salts and the solvates thereof.

In an additional embodiment, the compound may be selected from

-(Cy clopropy lmethyl)-7 - [(1S)-1 -(2,4-d ifluorophenoxy)ethyl ] - 8 (tri fl uoromethyl) [ 1,2,4] tri azo 1 o [4,3 -a] pyridine hy drochlo r ide s al t.

The names of the compounds of the present invention were generated according to the nomenclature rules agreed upon by the Chemical Abstracts Service (C.A.S.) using Advanced Chemical Development, Inc., software (ACD/Name product version 10.01.0.14105, October 2006). In case of tautomeric forms, the name of the depicted tautomeric form of the structure was generated. However it should be clear that the other non-depicted tautomeric form is also included within the scope of the present invention.

Definitions

The notation “Ci^alkyl” or “Ci-ealkyl” as used herein alone or as part of another group, defines a saturated, straight or branched, hydrocarbon radical having, unless otherwise stated, from 1 to 3 or 1 to 6 carbon atoms, such as methyl, ethyl,

1-propyl, 1-methylethyl, butyl, 1-methyl-propyl, 2-methyl-l-propyl, 1,1-dimethylethyl, 3-methyl-1-butyl, 1-pentyl, 1-hexyl and the like.

The notation “C3.8cycloaikyl” as used herein alone or as part of another group, defines a saturated, cyclic hydrocarbon radical having from 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. The notation “halogen” or “halo” as used herein alone or as part of another group, refers to fluoro, chloro, bromo or iodo, with fluoro or chloro being preferred.

The notation “mono- and polyhaloCi^alkyl” as used herein alone or as part of another group, refers to Cualkyl as defined before, substituted with 1, 2, 3 or where possible with more halo atoms as defined before.

Whenever the term “substituted” is used in the present invention, it is meant, unless otherwise is indicated or is clear from the context, to indicate that one or more hydrogens, preferably from 1 to 3 hydrogens, more preferably from 1 to 2 hydrogens, more preferably 1 hydrogen, on the atom or radical, indicated in the expression using “substituted” are replaced with a selection, from the indicated group, provided that the normal valency is not exceeded, and that the substitution results in a chemically stable compound, i.c. a compound that is sufficiently robust to survive isolation to a useful degree of purity from, a reaction mixture, and formulation into a therapeutic agent.

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- 10The term subject as used herein, refers to an animal, preferably a mammal, most preferably a human, who is or has been the object of treatment, observation or experiment.

The term therapeutically effective amount as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other cl inician, which includes alleviation of the symptoms of the disease or disorder being treated.

As used herein, the term composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.

It will be appreciated that some of the compounds of Formula (I) and their pharmaceutically acceptable addition salts and sol vates thereof may contain one or more centres of chirality and exist as stereoisomeric forms.

The term “compounds of the invention” as used herein, is meant to include the compounds of Formula (I), and the salts and solvates thereof.

As used herein, any chemical formula with bonds shown only as solid lines and not as solid wedged or hashed wedged bonds, or otherwise indicated as having a particular configuration (e.g. R, S) around one or more atoms, contemplates each possible stereoisomer, or mixture of two or more stereoisomers.

Hereinbefore and hereinafter, the term “compound of Formula (1)” is meant to include the stereoisomers thereof and the tautomeric forms thereof.

The terms “stereoisomers”, “stereoisomeric forms” or “stereochemically isomeric forms” hereinbefore or hereinafter arc used interchangeably.

The invention includes all stereoisomers of the compounds of the invention either as a pure stereoisomer or as a mixture of two or more stereoisomers.

Enantiomers are stereoisomers that arc non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a racemate or racemic mixture.

Diastereomers (or diastereoisomers) are stereoisomers that are not enantiomers, i.e. they arc not related as mirror images. If a compound contains a double bond, the substituents may be in the E or the Z configuration. Substituents on bivalent cyclic (partially) saturated radicals may have either the cis- or trans-configuration; for example if a. compound contains a disubstituted cycloalkyl group, the substituents may be in the cis or trans configuration.

Therefore, the invention, includes enantiomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof, whenever chemically

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- 11 possible.

The meaning of all those terms, i.e. enantiomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof are known to the skilled person.

The absolute configuration is specified according to the Cahn-Ingold-Prelog system. The configuration at an asymmetric atom is specified by either R or S. Resolved stereoisomers whose absolute configuration, is not known can be designated by (+) or (-) depending on the direction in which they rotate plane polarized light. For instance, resolved enantiomers whose absolute configuration is not known can be designated by 10 (+) or (-) depending on the direction in which, they rotate plane polarized light.

When a specific stereoisomer is identified, this means that said stereoisomer is substantially free, i.e. associated with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, in particular less than 2% and most preferably less than 1%, of the other isomers. Thus, when a compound of

Formula (I) is for instance specified as (R), this means that the compound is substantially free of the (S) isomer; when a compound of Formula (I) is for instance specified as Ε, this means that the compound is substantially free of the Z isomer; when a compound of Formula (I) is for instance specified as cis, this means that the compound is substantially free of the trans isomer.

Some of the compounds according to Formula (I) may also exist in their tautomeric form.. Such forms in so far as they may exist, although not explicitly indicated in the above formula are intended to be included within the scope of the present invention. It follows that a single compound may exist in both, stereisomeric and tautomeric forms.

For therapeutic use, salts of the compounds of Formula (I) are those wherein the counterion is pharmaceutically acceptable. However, salts of acids and bases which arc non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. AU salts, whether pharmaceutically acceptable or not, are included within the ambit of the present invention.

The pharmaceutically acceptable acid and base addition salts as mentioned hereinabove or hereinafter arc meant to comprise the therapeutically active non-toxic acid and base addition salt forms which the compounds of Formula (I) arc able to form. The pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrobalic acids, e.g. hydrochloric or hydrobromic

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- 12 acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids. Conversely said salt forms can be converted by treatment with an appropriate base into the free base form.

The compounds of Formula (1) containing an acidic proton may also be converted into their non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. primary, secondary and tertiary aliphatic and aromatic amines such as methylamine, ethylamine, propylamine, isopropylamine, the four butylaminc isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-w-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline; the benzathine, A-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like. Conversely the salt form can be converted by treatment with acid into the free acid form.

The term solvate comprises the solvent addition forms as well as the salts thereof, which the compounds of Formula (I) are able to form. Examples of such solvent addition forms are e.g. hydrates, alcoholates and the like.

In the framework of this application, an clement, in particular when mentioned in relation to a compound according to Formula (I), comprises all isotopes and isotopic mixtures of this element, either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form. Radiolabelled compounds of Formula (I) may comprise a radioactive isotope selected from the group of 3H, nC, 1SF, l22l,1231, 1251, 1311, 75Br, 76Br, 77Br and 82Br. Preferably, the radioactive isotope is selected from, the group of 3H, nC and l8F.

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- 13 Preparation

The compounds according to the invention can generally be prepared by a succession of steps, each of which is known to the skilled person. In particular, the compounds can be prepared according to the following synthesis methods.

The compounds of Formula (1) may be synthesized in the form of racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures. The racemic compounds of Formula (1) may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid.

Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali. An alternative manner of separating the enantiomeric forms of the compounds of Formula (!) involves liquid chromatography or supercritical fluid chromatography (SFC) using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereo specifically.

A. Preparation of the final compounds

Final compounds according to Formula (I), can be prepared by reacting an intermediate compound of Formula (II) with a compound of Formula (III) according to 20 reaction scheme (1), a reaction that is performed under classical Mitsunobu conditions. The reaction is preferably conducted with a phosphine and an azodicarboxylic ester or amide in tetrahydrofuran, 1,4-dioxane, diethyl ether, toluene, benzene, dichloromethane, or mixtures thereof, at -30 to 150°C, under thermal heating or microwave irradiation. Phosphines often used are triphenylphosphine and tributylphosphine which are usually combined with dimethyl azo di carboxylate, diethyl azodicarboxylate, diisopropyl azodi carboxylate, di-(4-chlorobenzyl) azodi carboxylate, dibenzyl azodicarboxylate, di-tert-butyl azo di carboxylate, azodicarboxylic acid bis(dimethyylamide), azodicarboxylic acid dipiperidide, or azodicarboxylic acid dimorpholidc. In reaction scheme (1), all variables are as defined in Formula (I)

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B, Preparation of the intermediates

Experimental procedure 2

Intermediate compounds according to Formula (II) can be prepared by subjecting an intermediate of Formula (IV) to conditions that are known to those skilled in the art. This is illustrated in reaction scheme (2) wherein all variables are defined as mentioned hereabove. Methods accomplishing these transformations are well known to those skilled in the art. Treatment of the aldehyde of formula (IV) with an organometallic such as methyl lithium or methyl magnesium bromide gives a compound of formula (II). A suitable solvent for this reaction is an ether such as tetrahydrofuran and the reaction is usually carried out at a temperature between -78°C and 40°C. In reaction scheme (2), all variables are defined as in Formula (1).

Reaction Scheme 2

<td> %</td><td> N-N</td><td> MeMgX</td><td></td><td rowspan="2"> F no</td><td> n-n iT</td>

Experimental procedure 3

Intermediate compounds according to Formula (IV) can be prepared by reacting an intermediate of Formula (V) under dihydroxylation and oxidative cleavage conditions that arc known to those skilled in the art and can be realized for example with oxonc, osmium tetroxide. The process may be carried out optionally in a solvent such as 1,4-dioxane, water and generally at temperatures between about -100°C and about 100l'C. A summary of such methods is found in “Comprehensive Organic Transformations”, VCH Publishers, (1989), R.C.Larock, pp.595-596. This is illustrated in reaction scheme (3) wherein all variables are defined as mentioned hereabove.

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- 15 Reaction Scheme 3

F N-N

(V)

F N-N

(IV)

Experimental procedure 4

Intermediate compounds according to Formula (V) can be prepared by coupling reactions, such as Stille or Suzuki reactions of an intermediate of Formula (VI) with a compound of Formula (VII) under conditions that are known to those skilled in. the art. The process may be carried out optionally in a solvent such as 1,4-dioxane, water and generally at temperatures between about r.t and about 200°C in the presence of a base. This is illustrated in reaction scheme (4) wherein all variables are defined as mentioned hereabove, wherein M is trialkyltin, boronic acid or boronate ester, and a palladium catalyst and halo is chloro, bromo or iodo.

<td> F A</td><td> n-n /A</td><td> Reaction Scheme 4 (VO)</td>

<td> halo''</td><td> (VI)</td><td> Palladium catalyst</td>

Experimental procedure 5

Intermediate compounds according to Formula (VI) can be prepared following art known procedures by cyclization of an intermediate compound of Formula (VUI) in the presence of a halogenating agent such as for example phosphorus (V) oxychloride (POClrf in a suitable solvent such as, for example, dichloroethanc, stirred under microwave irradiation, for a suitable period of time that allows the completion of the reaction, as for example 5 min at a temperature between 140-200 °C. In reaction scheme (5), R1 is defined as in Formula (!) and halo is chloro, bromo or iodo.

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- 16Reaction Scheme 5

Experimental procedure 6

Intermediate compounds according to Formula (VIII) can be prepared by art known procedures by reaction of a hydrazine intermediate of Formula (IX) with acid halides of Formula (X). The reaction can be carried out using an inert-solvent, such as for example DCM, in the presence of a base such as for example triethyl amine, for example at r.t, for a suitable period of time that allows completion of the reaction, for example 20 min. In reaction scheme (6), R1 is defined as in Formula (1).

Reaction Scheme 6

Experimental procedure 7

Intermediate compounds according to Formula (IX) can be prepared by reacting an intermediate compound of Formula (XI) with hydrazine according to reaction, scheme (7), a reaction that is performed in a suitable reaction-inert solvent, such as, for example, ethanol, THF or 1,4-dioxanc under thermal conditions such as, for example, heating the reaction mixture for example at 160 °C under microwave irradiation for 30 min or classical thermal heating at 70°C for 16 h. Tn reaction scheme (7), halo is chloro, bromo or iodo.

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Experimental procedure 8

Intermediate compounds according to Formula (XI) can be prepared by reacting an intermediate compound of Formula (XII) with benzyl alcohol according to reaction scheme (8), a reaction that is performed in a suitable reaction-inert solvent, such as, for example, zV,7V~dimcthylformamide in the presence of a suitable base, such as for example sodium hydride at r.t. for a suitable period of time that allows the completion 10 of the reaction, such as for example 1 h. In reaction scheme (8), halo is chloro, bromo or iodo.

Reaction Scheme 8

Experimental procedure 9

Intermediate compounds of Formula (ΧΓΙ), can be prepared by reacting an intermediate of Formula (XIII), with a suitable trifluoromethylating agent, such as for example fluorosulfonyl(difluoro)acetic acid methyl ester, according to reaction scheme (9). This reaction is performed in a suitable reaction-inert solvent such as, for example, 20 AfAMimethylformamide in the presence of a suitable coupling agent such as for example, copper(l) iodide, under thermal conditions such, as, for example, heating the reaction mixture for example at 160 °C under microwave irradiation for 45 min. In reaction scheme (9), halo is chloro, bromo or iodo.

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- 18Reaction Scheme 9

o o

The starting materials according to Formulae (II), (Vll) (X) or (XIII) arc compounds that are either commercially available or may be prepared according to conventional reaction procedures generally known to those skilled in the art.

Pharmacology

The compounds provided in this invention are positive allosteric modulators (PAMs) of metabotropic glutamate receptors, in particular they are positive allosteric modulators of mGluR2. The compounds of the present invention do not appear to bind to the glutamate recognition site, the orthosteric ligand site, but instead to an allosteric site within the seven transmembrane region of the receptor. In the presence of glutamate or an agonist of mGluR2, the compounds of this invention increase the mGluR2 response. The compounds provided in this invention are expected to have their effect at mGluR2 by virtue of their ability to increase the response of such receptors to glutamate or mGluR2 agonists.

As used herein, the term “treatment” is intended to refer to all processes, wherein there may be a slowing, interrupting, arresting or stopping of the progression of a disease or an alleviation of symptoms, but does not necessarily indicate a total elimination of all symptoms.

Hence, the present invention relates to a compound according to the general Formula (I), the stereoisomeric forms and the tautomers thereof and the pharmaceutically acceptable acid or base addition salts and the solvates thereof, for use as a medicament.

The invention also relates to the use of a compound according to the general Formula (I), the stereoisomeric forms and the tautomers thereof and the pharmaceutically acceptable acid or base addition salts and the solvates thereof, or a pharmaceutical composition according to the invention, for the manufacture of a medicament.

The invention also relates to a compound according to the general Formula (I), the stcrcoi.som.cric forms and the tautomers thereof and the pharmaceuti cally acceptable

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- 19acid or base addition salts and the solvates thereof, or a pharmaceutical composition according to the invention for use in the treatment or prevention of, in particular treatment of, a condition in a mammal, including a human, the treatment or prevention of which is affected or facilitated by the neuromodulatory effect of allosteric modulators of mGluR2, in particular positive allosteric modulators thereof.

The present invention also relates to the use of a compound according to the general Formula (1), the stereoisomeric forms and the tautomers thereof and the pharmaceutically acceptable acid or base addition salts and the solvates thereof, or a pharmaceutical composition according to the invention for the manufacture of a medicament for the treatment or prevention of, in particular treatment of, a condition in a mammal, including a human, the treatment or prevention of which is affected or facilitated by the neuromodulatory effect of allosteric modulators of mGluR2, in particular positive allosteric modulators thereof.

The present invention also relates to a compound according to the general Formula (I), the stereoisomeric forms and the tautomers thereof and the pharmaceutically acceptable acid or base addition salts and the solvates thereof, or a pharmaceutical composition according to the invention for use in the treatment, prevention, amelioration, control or reduction of the risk of various neurological and psychiatric disorders associated with glutamate dysfunction in a mammal, including a human, the treatment or prevention of which is affected or facilitated by the neuromodulatory effect of positive allosteric modulators of mGluR2.

Also, the present invention relates to the use of a compound according to the general Formula (I), the stereoisomeric forms and the tautomers thereof and the pharmaceutically acceptable acid or base addition salts and the solvates thereof, or a pharmaceutical composition according to the invention for the manufacture of a medicament for treating, preventing, ameliorating, controlling or reducing the risk of various neurological and psychiatric disorders associated with glutamate dysfunction in a mammal, including a human, the treatment or prevention of which is affected or facilitated by the neuromodulatory effect of positive allosteric modulators of mGluR2.

In particular, the neurological and psychiatric disorders associated with glutamate dysfunction, include one or more of the following conditions or diseases: acute neurological and psychiatric disorders such as, for example, cerebral deficits subsequent to cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, dementia (including AIDS-induced dementia), Alzheimer’s disease,

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-20Huntington’s Chorea, amyotrophic lateral sclerosis, ocular damage, retinopathy, cognitive disorders, idiopathic and drug-induced Parkinson’s disease, muscular spasms and disorders associated with muscular spasticity including tremors, epilepsy, convulsions, migraine (including migraine headache), urinary incontinence, substance depen.den.ce/abuse, substance withdrawal (including substances such as, for example, opiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, hypnotics, etc.), psychosis, schizophrenia, anxiety (including generalized anxiety disorder, panic disorder, and obsessive compulsive disorder), mood disorders (including depression, major depressive disorder, treatment resistant depression, mania, bipolar disorders, such as bipolar mania), posttraumatic stress disorder, trigeminal neuralgia, hearing loss, tinnitus, macular degeneration of the eye, emesis, brain edema, pain (including acute and chronic states, severe pain, intractable pain, neuropathic pain, and post-traumatic pain), tardive dyskinesia, sleep disorders (including narcolepsy), attention deficit/hyper activity disorder, and conduct disorder.

In particular, the condition or disease is a central nervous system disorder selected from the group of anxiety disorders, psychotic disorders, personality disorders, substance-related disorders, eating disorders, mood disorders, migraine, epilepsy or convulsive disorders, childhood disorders, cognitive disorders, neurodegeneration, autistic disorders, neurotoxicity and ischemia.

In particular, the central nervous system disorder is an anxiety disorder, selected from the group of agoraphobia, generalized anxiety disorder (GAD), mixed anxiety and depression, obsessive-compulsive disorder (OCD), panic disorder, posttraumatic stress disorder (PTSD), social phobia and other phobias. An additional anxiety disorder is panic attack.

In particular, the central nervous system disorder is a psychotic disorder selected from the group of schizophrenia, delusional disorder, schizoaffective disorder, schizophreniform disorder and substance-induced psychotic disorder; more in particular, negative symptoms or residual symptoms of schizophrenia. Such disorders manifest psychosis as a prominent symptom. Therefore, the invention also relates to a compound according to the general Formula (1), the stereoisomeric forms and the tautomers thereof and the pharmaceutically acceptable acid or base addition salts and the solvates thereof, or a pharmaceutical composition according to the invention for use in the treatment, prevention, amelioration, control or reduction of psychosis.

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-21 In particular, the central nervous system disorder is a personality disorder selected from the group of obsessive-compulsive personality disorder, borderline personality disorder and schizoid, schizotypal disorder.

In particular, the central nervous system disorder is a substance abuse or substance-related disorder selected from the group of alcohol abuse, alcohol addiction, alcohol dependence, alcohol withdrawal, alcohol withdrawal delirium, alcohol-induced psychotic disorder, amphetamine addiction, amphetamine dependence, amphetamine withdrawal, cocaine addiction, cocaine dependence, cocaine withdrawal, nicotine addiction, nicotine dependence, nicotine withdrawal, opioid dependence and opioid withdrawal. The treatment or prevention of the substance abuse or substance-related disorders referred to herein may involve relapse prevention thereof.

In particular, the central nervous system, disorder is an eating disorder selected from the group of anorexia nervosa and bulimia nervosa.

In particular, the central nervous system disorder is a mood disorder selected from the group of bipolar disorders (I & II), cyclothymic disorder, depression, dysthymic disorder, major depressive disorder, treatment resistant depression, bipolar depression, and substance-induced mood disorder.

In particular, the central nervous system disorder is migraine.

In particular, the central nervous system disorder is epilepsy or a convulsive disorder selected from the group of generalized nonconvulsive epilepsy, generalized convulsive epilepsy, petit mal status epilepticus, grand mal status epilcpticus, partial epilepsy with or without impairment of consciousness, infantile spasms, epilepsy partialis continua, and other forms of epilepsy. Additional disorders encompassed under epilepsy or convulsive disorder include any disorder in which a subject (preferably a human adult, child or infant) experiences one or more seizures and / or tremors. Suitable examples include, but are not limited to, epilepsy (including, but not limited to, localization-related epilepsies, generalized epilepsies, epilepsies with both generalized and local seizures, and the like), partial-onset seizures with or without generalization, myoclonic seizures, primary generalized, tonic-clonic seizures in particular in patients with idiopathic generalized epilepsy, seizures associated with Lcnnox-Gastaut syndrome, seizures as a complication of a disease or condition (such as seizures associated with encephalopathy, phenylketonuria, juvenile Gaucher’s disease, Lundborg’s progressive myoclonic epilepsy, stroke, head trauma, stress, hormonal changes, drug use or withdrawal, alcohol use or withdrawal, sleep deprivation, fever, infection, and the like), status epilepticus (convulsive or non convulsive), essential

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-22tremor, restless limb syndrome, and the like. Preferably, the disorder is selected from epilepsy (regardless of type, underlying cause or origin), essential tremor or restless limb syndrome. More preferably, the disorder is epilepsy (regardless of type, underlying cause or origin) or essential tremor. In particular, the disorder is epilepsy (regardless of type, underlying cause or origin). A more particular example of epilepsy is refractory epilepsy, also referred to as treatment or therapy resistant epilepsy. This term is often used when patients have failed three or more anti-epileptic drugs (AEDs). Refractory epilepsy also includes refractory partial epilepsy and refractory generalized epilepsy (including idiopathic or symptomatic).

Tn particular, the central nervous system disorder is attention-deficit/hyperactivity disorder.

In particular, the central nervous system disorder is an autistic disorder selected from autism and autism spectrum disorders, such as Asperger’s syndrome.

In particular, the central nervous system disorder is a cognitive disorder selected from the group of delirium, substance-induced persisting delirium, dementia, dementia due to HIV disease, dementia due to Huntington's disease, dementia due to Parkinson's disease, dementia of the Alzheimer's type, behavioral and psychological symptoms of dementia, substance-induced persisting dementia and mild cognitive impairment.

Particular examples of behavioral and psychological symptoms of dementia (BPSD) include, but are not limited to, aggression, agitation and psychosis.

In particular, the central nervous system disorder is selected from the group of schizophrenia, behavioral and psychological symptoms of dementia, major depressive disorder, treatment resistant depression, bipolar depression, anxiety, depression, generalised anxiety disorder, post-traumatic stress disorder, bipolar mania, epilepsy, attention-deficit/hyperactivity disorder, substance abuse and mixed anxiety and depression.

In particular, the central nervous system disorder is selected from the group of schizophrenia, epilepsy, obsessive compulsive disorder, alcohol addiction, cocaine addiction, nicotine addiction, borderline personality disorder, bipolar disorder, behavioral and psychological symptoms of dementia, Asperger’s syndrome, major depressive disorder, treatment resistant depression, anxiety, depression, generalised anxiety disorder, and mixed anxiety and. depression.

In particular, the central nervous system disorder is selected from the group of schizophrenia (in particular, negative symptoms or residual symptoms thereof),

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-23 generalized anxiety disorder, bipolar disorder (I or II), migraine, behavioral and psychological symptoms of dementia, epilepsy or convulsive disorders, panic disorder, mixed anxiety and depression, and agoraphobia.

In particular, the central nervous system disorder is selected from the group of schizophrenia (in particular, negative symptoms or residual symptoms thereof), generalized anxiety disorder, bipolar disorder (I or II), migraine, epilepsy, panic disorder, mixed anxiety and depression, and agoraphobia. Of the disorders mentioned above, the treatment of psychosis, schizophrenia, behavioral and psychological symptoms of dementia, major depressive disorder, treatment resistant depression , bipolar depression, anxiety, depression, generalised anxiety disorder, post-traumatic stress disorder, bipolar mania, substance abuse and mixed anxiety and depression, are of particular importance.

Of the disorders mentioned above, the treatment of generalized anxiety disorder, bipolar disorder (I or Π), epilepsy, panic disorder, and agoraphobia are of particular 15 importance.

Of the disorders mentioned above, the treatment of anxiety, schizophrenia, migraine, depression, and epilepsy are of particular importance.

Of the disorders mentioned above, the treatment of anxiety and epilepsy are of particular importance.

At present, the fourth edition of the Diagnostic & Stati stical Manual of Mental

Disorders (DSM-IV) of the American Psychiatric Association provides a diagnostic tool for the identification of the disorders described herein. The person skilled in the art will recognize that alternative nomenclatures, nosologies, and classification systems for neurological and psychiatric disorders described herein exist, and that these evolve with 25 medical and scientific progresses.

A skilled person will be familiar with alternative nomenclatures, nosologies, and classification systems for the diseases or conditions referred to herein. For example, the “American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA, American Psychiatric Association, 30 2013” (DSM-51M) utilizes terms such as anxiety disorders, in particular, agoraphobia, generalized anxiety disorder, panic disorder, social anxiety disorder (social phobia), and panic attack; schizophrenia spectrum and other psychotic disorders, in particular, schizophrenia, delusional disorder, schizoaffective disorder, schizophreniform disorder, substancc/medication-induccd and psychotic disorder; personality disorders, in particular, obsessive-compulsive personality disorder, borderline personality disorder,

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-24schizoid personality disorder, and schizotypal personality disorder; sub stance-related and addictive disorders, in particular, alcohol use disorder, alcohol withdrawal, opioid use disorder, opioid withdrawal, stimulant (amphetamine-type substance, cocaine) use disorder, stimulant (amphetamine-type substance, cocainc) withdrawal, tobacco use 5 disorder, and tobacco withdrawal; depressive disorders, in particular, major depressive disorder, persistent depressive disorder (dysthymia), and substance/medication-induced depressive disorder; bipolar and related disorders, in particular, bipolar I disorder, bipolar 11 disorder, cyclothymic disorder, substance/medication-induced bipolar and related disorder; obsessive-compulsive disorder and related disorders, in particular, 10 obsessive-compulsive disorder; trauma- and stressor-related disorders, in particular, posttraumatic stress disorder, and acute stress disorder; neuro developmental disorder, in particular, autism spectrum disorder, and attention-deficit/hyperactivity disorder; neurocognitive disorders (NCDs) (both major and mild), in particular, delirium, substance intoxication delirium, NCD due to Alzheimer’s disease, NCD due to HIV 15 infection, NCD due to Huntington’s disease, NCD due to Parkinson’s disease, and substance/medication-induced NCD. Such terms may be used by the skilled person as an alternative nomenclature for some of the diseases or conditions referred to herein.

Therefore, the invention also relates to a compound according to the general Formula (I), the stereoisomeric forms and the tautomers thereof and the pharmaceutically acceptable acid or base addition salts and the solvates thereof, for use in the treatment of any one of the diseases mentioned hereinbefore.

The invention also relates to a compound according to the general Formula (I), the stereoisomeric forms and the tautomers thereof and the pharmaceutically acceptable acid or base addition salts and the solvates thereof, for use in treating any one of the 25 diseases mentioned hereinbefore.

The invention also relates to a compound according to the general Formula (I), the stereoisomeric forms and the tautomers thereof and the pharmaceutically acceptable acid or base addition salts and the solvates thereof, for the treatment or prevention, in particular treatment, of any one of the diseases mentioned hereinbefore.

The invention also relates to the use of a compound according to the general

Formula (I), the stereoisomeric forms and the tautomers thereof and the pharmaceutically acceptable acid or base addition salts and the solvates thereof, for the manufacture of a medicament for the treatment or prevention of any one of the disease conditions mentioned hereinbefore.

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-25 The invention also relates to the use of a compound according to the general Formula (I), the stereoisomeric forms and the tautomers thereof and the pharmaceutically acceptable acid or base addition sails and the solvates thereof, for the manufacture of a medicam ent for the treatment of any one of the disease conditions 5 mentioned hereinbefore.

The compounds of the present invention can be administered to mammals, preferably humans, for the treatment or prevention of any one of the diseases mentioned hereinbefore.

In view of the utility of the compounds of Formula (I), there is provided a method of treating warm-blooded animals, including humans, suffering from any one 1 of the diseases mentioned hereinbefore, and a method of preventing in warm-blooded animals, including humans, any one of the diseases mentioned hereinbefore.

Said methods comprise the administration, i.e. the systemic or topical administration, preferably oral administration, of a therapeutically effective amount of a 15 compound of Formula (I), a stereoisomeric form or a tautomer thereof and a pharmaceutically acceptable addition salt or solvate thereof, to warm-blooded animals, including humans.

Therefore, the invention also relates to a method for the prevention and/or treatment of any one of the diseases mentioned hereinbefore comprising administering 20 a therapeutically effective amount of a compound according to the invention to a patient in need thereof.

One skilled in the art will recognize that a therapeutically effective amount of the PAMs of the present invention is the amount sufficient to modulate the activity of the mGluR2 and that this amount varies inter alia, depending on the type of disease, the 25 concentration of the compound in the therapeutic formulation, and the condition of the patient. Generally, an amount of PAM to be administered as a therapeutic agent for treating diseases in which modulation of the mGluR2 is beneficial, such as the disorders described herein, will be determined on a case by case by an attending physician.

Generally, a suitable dose is one that results in a concentration of the PAM. at the treatment site in the range of 0.5 nM. to 200 μΜ, and more usually 5 nM to 50 μΜ. To obtain these treatment concentrations, a patient in need of treatment likely will be administered an effective therapeutic daily amount of about 0.01 mg/kg to about 50 mg/kg body weight, preferably from about 0.01 mg/kg to about 25 mg/kg body weight, 35 more preferably from about 0.01 mg/kg to about 10 mg/kg body weight, more

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-26preferably from about 0.01 mg/kg to about 2.5 mg/kg body weight, even more preferably from about 0.05 mg/kg to about 1 mg/kg body weight, more preferably from, about 0.1 to about 0.5 mg/kg body weight. The amount of a compound according to the present invention, also referred to here as the active ingredient, which is required to achieve a therapeutically effect will, of course vary on. case-by-case basis, vary with the particular compound, the route of administration, the age and condition of the recipient, and the particular disorder or disease being treated. A method of treatment may also include administering the active ingredient on a regimen of between one and four intakes per day. In these methods of treatment the compounds according to the invention are preferably formulated prior to admission. As described herein below, suitable pharmaceutical formulations are prepared by known procedures using well known and readily available ingredients.

Because such positive allosteric modulators of mGluR2, including compounds of Formula (I), enhance the response of mGluR2 to glutamate, it is an advantage that 15 the present methods utilize endogenous glutamate.

Because positive allosteric modulators of mGluR2, including compounds of Formula (I), enhance the response of mGluR2 to agonists, it is understood that the present invention extends to the treatment of neurological and psychiatric disorders associated with glutamate dysfunction by administering an effective amount of a 20 positive allosteric modulator of mGluR2, including compounds of Formula (I), in combination with an mGluR2 agonist (or mGluR2/3 agonist). Examples of mGluR2/mGluR2/3 agonists include, for example, LY-379268; DCG-IV; LY-354740; LY-404039; LY-544344; LY-2140023; LY-181837; LY-389795; LY-446433; LY450477; talaglumetad; MGS0028; MGS0039; (-)-2-oxa-4-aminobicyclo[3.1.0]hexane25 4,6-dicarboxylate; (+)-4-amino-2-sulfonylbicyclo[3.1.0]hcxane-4,6-dicarboxylic acid;

(+)-2-amino-4-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid; lS,2R,5S,6S-2-amino-6-fluoro-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylic acid; lS,2R,4S,5S,6S-2-amino-6-fluoro-4hydroxybicyclo[3.1.0]hexanc-2,6-dicarboxylic acid; lS,2R,3R,5S,6S-2-amino-330 fluorobicyclo[3.1,0]hexane-2,6-dicarboxylic acid; 1 S,2R,3S,5S,6S-2-amino-6-fluoro-3hydroxybicyclo[3.1,0]hexane-2,6-dicarboxylic acid; (+)-4-amino-2-sul.fonylbicyclo[3.1.0]hexanc-4,6-dicarboxylic acid; (+)-2-amino-4-f1uorobicyclo[3.1.0]hcxane-2,6dicarboxylic acid; 1 S,2R,5S,6S-2-amino-6-fluoro-4-oxobicyclo[3.1.0]hcxane-2,6dicarboxylic acid; lS,2R,4S,5S,6S-2-a.mino-6-fluoro-4-hydroxybicyclo[3.1.0]hcxane35 2,6-dicarboxylic acid; lS,2R,3R,5S,6S-2-amino-3~fluorobicyclo[3.1.0]hexanc-2,6dicarboxylic acid; or lS,2R,3S,5S,6S-2-amino-6-fluoro-3-hydroxybicycloWO 2015/032790

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-27[3.1.0]hexane-2,6-dicarboxylic acid. More preferable mGluR2 agonists include LY379268; DCG-IV; LY-354740; LY-404039; LY-544344; or LY-2140023.

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 (1) or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone.

Pharmaceutical compositions

The present invention also provides compositions for preventing or treating diseases in which modulation of the mGlu2 receptor is beneficial, such as the disorders described herein. While it is possible for the active ingredient to be administered alone, it is preferable to present it as a pharmaceutical composition. Accordingly, the present invention also relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and, as active ingredient, a therapeutically effective amount of a compound according to the invention, in particular a compound according to Formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof or a stereochemically isomeric form or a tautomer thereof. The carrier or diluent must be “acceptable” in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipients thereof.

The compounds according to the invention, in particular the compounds according to Formula (I), the pharmaceutically acceptable salts thereof, the solvates and the stereochemically isomeric forms and the tautomers thereof, or any subgroup or combination thereof may be formulated into various pharmaceuti cal forms for administration purposes. As appropriate compositions there may be cited all compositions usually employed for systemically administering drugs.

The pharmaceutical compositions of this inven tion may be prepared by any methods well known in the art of pharmacy, for example, using methods such as those described in Gennaro et al. Remington’s Pharmaceutical Sciences (18th ed., Mack Publishing Company, 1990, sec especially Part 8: Pharmaceutical preparations and their Manufacture). To prepare the pharmaceutical compositions of this invention, a. therapeutically effective amount of the particular compound, optionally in salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier or diluent, which carrier or diluent may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical

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-28 compositions are desirable m unitary dosage form suitable, in particular, for oral, topical, rectal or percutaneous administration, by parenteral injection or by inhalation. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as, for example, suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as, for example, starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of the ease in administration, oral administration is preferred, and tablets and capsules represent the most advantageous oral dosage unit forms in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, surfactants, to aid solubility, may be included. Injectable solutions, for example, maybe prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment.

It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form as used herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions and the like, tcaspoonfuls, tablespoonfuls, and segregated multiples thereof.

Since the compounds according to the invention are orally administrable compounds, pharmaceutical compositions comprising aid compounds for oral administration arc especially advantageous.

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-29In order to enhance the solubility and/or the stability of the compounds of Formula (I) in pharmaceutical compositions, it can be advantageous to employ α-, β- or γ-cyclodextrins or their derivatives, in particular hydroxyalkyl substituted cyclodextrins, e.g. 2-hydroxypropyl-^-cyclodextrin or sulfobutyl^-cyclodextrin. Also co-solvents such as alcohols may improve the solubility and/or the stability of the compounds according to the invention in pharmaceutical compositions.

The exact dosage and frequency of administration depends on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight, sex, extent of disorder and general physical condition of the particular patient as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention.

Depending on the mode of administration, the pharmaceutical composition will comprise from 0.05 to 99 % by weight, preferably from 0.1 to 70 % by weight, more preferably from 0.1 to 50 % by weight of the active ingredient, and, from 1 to 99.95 % by weight, preferably from 30 to 99.9 % by weight, more preferably from 50 to 99.9 % by weight of a pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition.

The amount of a compound of Formula (I) that can be combined with a carrier material to produce a single dosage form will vary depending upon the disease treated, the mammalian species, and the particular mode of administration. However, as a general guide, suitable unit doses for the compounds of the present invention can, for example, preferably contain between 0.1 mg to about 1000 mg of the active compound. A preferred unit dose is between 1 mg to about 500 mg. A more preferred unit dose is between 1 mg to about 300 mg. Even more preferred unit dose is between 1 mg to about 100 mg. Such unit doses can be administered more than once a day, for example, 2, 3, 4, 5 or 6 times a day, but preferably 1 or 2 times per day, so that the total dosage for a 70 kg adult is in the range of 0.001 to about 15 mg per kg weight of subject per administration. A preferred dosage is 0.01 to about 1.5 mg per kg weight of subject per administration, and such therapy can extend for a number of weeks or months, and in some cases, years. It will be understood, however, that the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the individual being treated; the time and route of administration; the rate of excretion;

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-30other drugs that have previously been administered; and the seventy of the particular disease undergoing therapy, as is well understood by those of skill in the area.

A typical dosage can be one I mg to about 100 mg tablet or 1 mg to about 300 mg taken once a day, or, multiple times per day, or one time-release capsule or tablet taken once a day and containing a proportionally higher content of active ingredient. The time-release effect can be obtained by capsule materials that dissolve at different pH values, by capsules that release slowly by osmotic pressure, or by any other known means of controlled release.

It can be necessary to use dosages outside these ranges in some cases as will be apparent to those skilled in the art. Further, it is noted that the clinician or treating physician will know how and when to start, interrupt, adjust, or terminate therapy in conjunction with individual patient response.

As already mentioned, the invention also relates to a pharmaceutical composition comprising the compounds according to the invention and one or more other drugs for use as a medicament or for use 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. The use of such a composition for the manufacture of a medicament as well as the use of such a composition for the manufacture of a medicament 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 are also contemplated. The present invention also relates to a combination of a compound according to the present invention and an mG1uR2 orthosteric agonist (or a mGluR2/3 orthosteric agonist). The present invention also relates to such a combination for use as a medicine. The present invention also relates to a product comprising (a) a compound according to the present invention, a pharmaceutically acceptable salt thereof or a solvate thereof, and (b) a mGluR2 orthosteric agonist (or a mGluR2/3 orthosteric agonist), as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of a condition in a mammal, including a human, the treatment or prevention of which is affected or facilitated by the ncuromodulatory effect of mGluR2 allosteric modulators, in particular positive mGluR2 allosteric modulators. The different drugs of such a combination or product may be combined in a single preparation together with pharmaceutically acceptable carriers or diluents, or they may each be present in a separate preparation together with pharmaceutically acceptable carriers or diluents.

The following examples are intended to illustrate but not to limit the scope of the

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-31 present invention.

Chemistry

Several methods for preparing the compounds of this invention are illustrated in the following Examples. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification.

Hereinafter, “aq.” means aqueous; “DCE” means 1,2-dichloroethane, “DCM” means dichloromethane; “DIPE” means diisopropylethcr; “DIPEA” means N,N~ diisopropyl ethylamine; “DMF” means N, A-dimcthylform amide; “ES” means electrospray; “EtsN” means triethyl amine; “Et2O” means diethyl ether; “EtOAc” means ethyl acetate; “h” means hours; “HPLC” means high performance liquid chromatography; “HRMS” means high-resolution mass spectra/spectrometry; “1” or “L” means liter; “LRMS” means low-resolution mass spectrometry/spectra; “MeOH” means methanol; “min” means minute(s); “mp” means melting point; “Pd(PPh3)4” means tetrakis(triphenylphosphine)palladium(0); “RP” means reverse phase; “r.t.” means room temperature; “s” means seconds; “sat.” means saturated; “SFC” means supercritical fluid chromatography; “sol.” means solution; “THF” means tetrahydrofuran.

Microwave assisted reactions were performed in a single-mode reactor: Initiator™ Sixty EXP microwave reactor (Biotage AB), or in a multimode reactor: MicroSYNTH Labstation (Milestone, Tnc.).

Thin layer chromatography (TLC) was carried out on silica gel 60 F254 plates (Merck) using reagent grade solvents. Open column chromatography was performed on silica gel, particle size 60 A, mesh = 230-400 (Merck) using standard techniques. Automated flash column chromatography was performed using rcady-to-connect cartridges from Merck, on irregular silica gel, particle size 15-40 pm (normal phase disposable flash columns) on a SPOT or LAFLASH system from Armen Instrument.

The absolute stereochemical configuration for some of the compounds was determined using vibrational circular dichroism (VCD). They were measured on a Bruker Equinox 55 equipped with a PMA 37, in a KBr liquid cell using CD2CI2 as solvent (PEM: l350cm-l, L1A: ImV, resolution: 4 cm). A description on the use of VCD for the determination of absolute configuration can be found in Dyatkin A.B. ct. al, Chirality, 14:215-219 (2002).

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-32Whenever the notation “RS” is indicated herein, it denotes that the compound is a racemic mixture, unless otherwise indicated. The stereochemical configuration for some compounds has been designated “A” or “5”’ when the mixture was separated; for some compounds, the stereochemical configuration has been designated as “*7?” or “*5 when the absolute stereochemistry is undetermined although the compound itself has been isolated as a single stereoisomer and is enantiomerically pure. The enantiomeric excess of compounds reported herein was determined by analysis of the racemic mixture by supercritical fluid chromatography (SFC) followed by SFC comparison of the separated enantiomer(s).

Preparation of intermediates

Description 1 - Intermediate 1

Cyclopropylacetic acid ([CAS 5239-82-7], 50 g, 500 mmol) was dissolved in CELCL (300 mL) then SOC12 (100 mL) was added. The reaction mixture was stirred at 60 °C for 2 h and then the solvent was evaporated to yield intermediate 1 (53 g, 90%), which was used without further purification.

Description 2 - Intermediate 2

To a solution of 2,4-dichloro-3-iodopyridine ([CAS 343781-36-2], 290 g, 1058 mmol) in DMF (1.7 L) was added methyl 2,2-difluoro-2-(f!uorosulfonyl)acetate ([CAS 68015-9], 403 g, 2098 mmol) and Cui (403 g, 2.13 mol), the reaction was then heated at 100 °C for 5 h.

The reation was cooled and filtered. The filtrate was diluted with H2O and extracted with Et2O and washed with a NH3 solution. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to yield intermediate 2 (160 g), which was used without further purification.

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-33 Description 3 - Intermediate 3

To a solution of NaH (60% in oil, 24 g, 600 mmol) in DMF (2 L) at 0 °C was added benzyl alcohol (35 g, 325 mmol), then the reaction was stirred for 2 min. Intermediate 2 (160 mg, 741 mmol) was added in one portion, and stirred at 0 °C for 1 h. The reaction was diluted by the addition of ILO and extracted with Et2O. The organic layer was dried (JS^SCfi), filtered and concentrated in vacuo. The residue was purified by column chromatography over silica gel (eluent: petroleum ether/EtOAc = 20/1). The pure fractions were collected and the solvent was evaporated to yield intermediate 3 (100 g, 38%).

Description 4 - Intermediate 4

F

To a solution of intermediate 3 (100 g, 277 mmol) in 1,4-dioxane (1.5 L) was added NH2NH2 hydrate (85% solution in water, 300 g, 9.11 mol), the reaction was then heated in sealed tube at 160 °C for 2 h. The mixture was concentrated in vacuo, dissolved in DCM washed with NaHCCh. The organic layer was dried (Na^SO/i), filtered and concentrated in vacuo to yield intermediate 4 (90 g, 90%), which was used without further purification.

Description 5 - Intermediate 5

To a solution of intermediate 4 (90 g, 318 mmol) in CH2CI2 (1.5 L) was added tricthylamine (64.3 g, 636 mmol), the mixture was cooled to 0 °C, then a solution of intermediate .1 (53 g, 449 mmol) in CH2CI2 was added. The solution was stirred at RT for 1 h. The reaction mixture was washed with a sat. aq. sol. of NaHCOi, and extracted

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-34with CH2CI2. The organic layer was dried (Na2SC>4), filtered and concentrated in vacuo to yield intermediate 5 (104.4 g, 90%).

The following intermediates were synthesized following a synthetic sequence analogous to that reported in Description 5 (D5).

<td colspan="3"> Intermediate</td><td> Acid chloride</td><td> Conditions</td>

<td colspan="2"> F</td><td> o II</td><td> propionyl chloride</td><td> Addition run at</td>

<td> Intermediate 6</td><td></td><td></td><td></td><td></td>

<td> 1X1 s</td><td>XF</td><td></td><td> cyclobutaneacetyl</td><td> Conditions as in</td>

<td></td><td>XF</td><td> NH VV\</td><td> chloride ([CAS</td><td> D5.</td>

<td> Intermediate 7</td><td></td><td></td><td></td><td></td>

<td> Z;\</td><td> F</td><td>0 ></td><td> 2-ethoxy-acetyl</td><td> Conditions as in</td>

<td></td><td></td><td> it ' N</td><td> chloride ([CAS</td><td> D5.</td>

<td> Intermediate 8</td><td></td><td></td><td></td><td></td>

<td></td><td> V</td><td> 0</td><td> butyryl chloride</td><td> Conditions as in</td>

<td> Intermediate 25</td><td></td><td></td><td></td><td></td>

Description 6 (a) Intermediate 9

To a solution of intermediate 5 (101 g, 277 mmol) in CHjCN (1.2 L) were added phosphorus(V) oxychloride (84.7 g, 553 mmol) and N,jV-diisopropylethylamine (71.3

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-35g, 553 mmol). The reaction mixture was stirred at 90 °C for 38 h. The reaction was then diluted with DCM and washed with a Na2CO3 solution. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography over silica gel (eluent: petroleum ether/EtOAc = 4/1). The 5 pure fractions were collected and the solvent was evaporated to yield intermediate 9 (31.39 g, 41%).

(b) Intermediate 10

The reaction was performed in 4 batches then combined for work up and purification.

To a solution of intermediate 6 (7 g, 20.6 mmol) in DCE (50 mL), was added N,N~ diisopropyl ethylamine (3.96 mL, 22.69 mmol) and then phosphorus oxychloride (2.12 mL, 22.69 mmol) and the reaction mixture was heated in a microwave at 150 °C for 5 min. Then DCM was added and the organic layer was washed with a sat. sol. of NaHCOa, dried (Na2SO4) and concentrated in vacuo to afford the desired compound, which was purified by column chromatography (gradient elution: DCM 100% to MeOH.NEL 2% in DCM) to yield intermediate 10 (2.5 g, 49%).

The following intermediates were synthesized following a synthetic sequence analogous to that reported in Description 6(a) or (b).

<td> Intermediate</td><td> Starting material</td><td> Conditions</td>

<td> F N-N Intermediate 11</td><td> Intermediate 7</td><td> Reaction performed as in (a) but in CH3CN. After the reaction was complete, the reaction mixture was poured into ice/water then washed withNaHCO3 sat. sol. And extracted with DCM, dried (Na2SO4), filtered and con centrated. Puri fication was performed in Spot (Si cartridge, eluent DCM/EtOAc up to 10-20%).</td>

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<td> Intermediate</td><td> Starting material</td><td> Conditions</td>

<td> F N_-N Intermediate 12</td><td> Intermediate 8</td><td> Reaction performed as in (b). Purification by flash column chromatography (silica; EtOAc in DCM 0/100 to 40/60).</td>

<td> F N—N, /--- Intermediate 26</td><td> Intermediate 25</td><td> Reaction performed as in (a). Purification by flash column chromatography (silica; MeOH in CH2C12, from 0/100 to 4/96).</td>

Description 7 - Intermediate 13

(PhsP^Pd (2.096 g, 1.81 mmol) was added to a stirred solution of intermediate 9 (10 g, 36.28 mmol) and 4,4,5,5-tetramethyl-2-vinyl-l,3,2-dioxoborolane ([CAS 75927-49-0],

7.77 mL, 43.53 mmol) in deoxygenated dioxane (30 mL) and a deoxygenated NaHCO3 saturated solution (30 mL) under nitrogen. The mixture was stirred at 100 °C for 18 h. The mixture was diluted with EtOAc/water and filtered through a pad of diatomaceous earth. The filtrate was treated with brine and extracted with EtOAc. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; EtOAc in CH2C12 0/100 to 5/95). The desired fractions were collected and concentrated in vacuo to yield intermediate 13 (6.08, 63%) as a yellow solid.

The following intermediates were synthesized following a synthetic sequence analogous to that reported in Description 7.

<td> Intermediate</td><td> Starting material</td><td> Conditions</td>

<td> F N-N^ Intermediate 14</td><td> Intermediate 10</td><td> Reaction performed at 150 °C. Purification by flash column chromatography (silica; 7N solution of ammonia in methanol in DCM 0/100 to 1/9).</td>

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<td colspan="2"> Intermediate</td><td> Starting material</td><td> Conditions</td>

<td colspan="2"> F n-N Π</td><td> Intermediate 11</td><td> Extraction with DCM,</td>

<td></td><td rowspan="2"> ii</td><td></td><td> purification by flash column</td>

<td> Γ</td><td></td><td> chromatography (silica;</td>

<td colspan="2"> Intermediate 15</td><td></td><td></td>

<td> f</td><td> - κι—-N O—</td><td> Intermediate 12</td><td> Purification by flash column</td>

<td> s</td><td></td><td></td><td> chromatography (silica;</td>

<td></td><td></td><td></td><td> EtOAc in DCM 0/100 to</td>

<td colspan="2"> Intermediate 16</td><td></td><td></td>

<td colspan="2"> F NN. /-- F 1 II \\ /</td><td> Intermediate 26</td><td> Reaction mixture performed</td>

<td> F></td><td></td><td></td><td> at 150 °C in micro wave.</td>

<td></td><td></td><td></td><td> Purification by flash column chromatography (silica; EtOAc in DCM 0/100 to</td>

<td colspan="2"> Intermediate 27</td><td></td><td rowspan="2"> 10/90).</td>

Description 8 (a) Intermediate 17

Osmium tetraoxide (2.5% in t-BuOH, 10.103 mL, 0.781 mmol) and then, sodium periodate 12.53 g, 58.58 mmol) in water (48.5 mL) were added to a suspension of Intermediate 13 (6.08 g, 20.02 mmol) in dioxane (192 mL). The mixture was stirred at room temperature for 2 h.

The mixture was treated with water and EtOAc and it was filtered off through a pad of 10 diatomaceous earth. The filtrate was extracted with EtOAc. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude

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-38product was washed with Et2O and it was filtered and dried to yield intermediate 17

A suspension of sodium periodate (5.04 g, 23.54 mmol) in distilled water (19 mL) was added to a stirred solution of osmium tetraoxide (2.5% in t-BuOH, 4.06 mL, 0.31 mmol) and intermediate 14 (2.08 g, 7.85 mmol) in dioxane (75 mL). The mixture was stirred at room temperature for 150 min, and then the mixture was treated with sat NaHCCL and brine, and extracted with DCM. The organic layer was separated, dried (Na2SO4), filtered and concentrated in vacuo. The product was triturated with Et2O and filtered in vacuo, and finally put in desiccator at 50 °C for 18 h, to yield intermediate 18 (1.6 g, 80%) as a brown solid.

The following intermediates were synthesized following a synthetic sequence analogous to that reported in Description 8.

<td> Intermediate</td><td> Starting material</td><td> Conditions</td>

<td> F N-N 0 Intermediate 19</td><td> Intermediate 15</td><td> Procedure as in (a).</td>

<td> F N— N O—/ 0 Intermediate 20</td><td> Intermediate 16</td><td> Procedure as in (a).</td>

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<td> Intermediate</td><td> Starting material</td><td> Conditions</td>

<td> F N-N O Intermediate 28</td><td> Intermediate 27</td><td> Procedure as in (a), order of addition: osmium tetroxide was added to a stirred solution, of intermediate 27 in 1,4-dioxane, then a suspension of sodium periodate in water was added and the reaction mixture was stirred for 2 h at RT. No filtration through a pad of diatomaceous earth.</td>

Description 9 (a) Intermediates 21a, 21b and 21c

Intermediate 21a

Intermediate 21b

Intermediate 21c

Methylmagnesium bromide (1.4 M in THF, 12.40 mL, 17.37 mmol) was added dropwise to a stirred suspension of intermediate 17 (4.25 g, 15.79 mmol) in THF (281.07 mL) at -20 °C under N2 atmosphere. The mixture was stirred at -20 °C for 45 minutes. The crude was treated with a sat. sol. of NH4CI and extracted with EtOAc.

The organic layer was separated, dried (IS^SCL), filtered and concentrated in vacuo.

The residue was purified by flash column chromatography (silica; MeOH in DCM

0/100 to 4/96). The desired fractions were collected and concentrated in vacuo to yield intermediate 21a (racemic mixture) (2.96 g, 66%). Intermediate 21a (1.82 g) was purified by chiral SFC: [Stationary phase: CHIRALPAK AD-H (5pm 250 x20 mm), Mobile phase: 80% CO2, 20% EtOH] yielding 21b (R-enantiomer) (0.453 g, 10%) as a pale grey solid and intermediate 21c (S-enantiomer) (0.439 g, 10%).

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-40(b) Intermediate 22

Methylmagnesium bromide (1.4 M in THF, 3.97 mL, 5.56 mmol) was added drop wise to a stirred suspension of intermediate 18 (1.23 g, 5.06 mmol) in THF (90 mL) at

-20 °C under N2 atmosphere. The mixture was stirred at -20 °C for 45 minutes. The crude was treated with a sat. sol. of NH4CI and extracted with EtOAc. The organic layer was separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica; MeOH in DCM 0/100 to 4/96). The desired fractions were collected and concentrated in vacuo. The residue thus obtained was triturated with Et2O to yield intermediate 22 (620 mg, 35%) as a pale yellow solid.

The following intermediates were synthesized following a synthetic sequence analogous to that reported in Description 9.___________________________________________

<td colspan="2"> Intermediate</td><td> Starting material</td><td> Conditions</td>

<td> F C Inte</td><td> n-n to RS DH rmediate 23</td><td> Intermediate 19</td><td> Procedure (b).</td>

<td> FX < Inte</td><td> LX to RS )H rmediate 24a</td><td> Intermediate 20</td><td> Procedure (b).</td>

<td> Inte</td><td> N— /0 RS 7H rmediate 29</td><td> Intermediate 28</td><td> Procedure (b).</td>

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-41 Intermediate 24a was further separated into Intermediate 24b and Intermediate 24c:

<td> F N-N / F'T'''rp OH Intermediate 24b</td><td> F N-N / 1 Ji :¾ Is OH Intermediate 24c</td>

<td colspan="2"> Chiral SFC conditions: Stationary phase Chiralpak AJ )-H 5 pm 250*30 mm; Mobile phase: 80% CO2, 15% EtOH</td>

Preparation of the final compounds

Example 1 (a) Synthesis of compounds 4, 6 and 5

Compound 5

DIAD (2.07 mL, 10.52 mmol) was added dropwise to a stirred solution of intermediate 21a (2 g, 7.01 mmol), 2,4-difluorophenol (1.00 mL, 10.52 mmol) and triphenylphosphine (2.76 g, 10.52 mmol) in THF (74.18 mL) at 0 °C and under nitrogen atmosphere. The mixture was stirred at 100 °C for 10 minutes under microwave irradiation. The mixture was diluted with EtOAc and washed with a sat. sol. of NaHCOa- The organic layer was separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica; MeOH in DCM 0/100 to 97/3). The desired fractions were collected and concentrated in vacuo.

The residue was triturated with D1PE to give compound 4 (1.46 g, 52%) as a white solid, which was purified by chiral SFC [Stationary phase: Chiralpak AD (5pm 250*30 mm, Mobile phase: 85% CO2, 15% iPrOH)], yielding compound 6 (0.659 g, 24%) and compound 5 (0.693 g, 25%).

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-42(b) Alternative synthesis of compound 6

DIAD (31.06 pL, 0.16 mmol) was added dropwise to a stirred solution of intermediate 21b (30 mg, 0.11 mmol), 2,4-difluorophenol (15.07 pL, 0.16 mmol) and triphenylphosphine (41.38 mg, 0.16 mmol) in THF (1.11 mL) at 0 °C and under nitrogen atmosphere. The mixture was stirred at 100 °C for 10 minutes under microwave iiTadiation. The mixture was diluted with EtOAc and washed with a sat. sol. of N'aHCOv The organic layer was separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica; MeOH in DCM 0/100 to 97/3). The desired fractions were collected and concentrated in vacuo. The residue was triturated with DIPE to give compound 6 (40 mg, 96%) as a white solid.

DIAD (207.06 pL, 1.05 mmol) was added dropwise to a stirred solution of intermediate 21b (200 mg, 0.70 mmol), 2,4-difluoroph.enol (100.45 pL, 1.05 mmol) and triphenylphosphine (275.84 mg, 1.0516 mmol) in THF (4 mL) at 0 °C and under nitrogen atmosphere. The mixture was stirred at 100 °C for 15 minutes under microwave irradiation. The mixture was diluted with EtOAc and washed with a sat. sol. of NaHCO3. The organic layer was separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by RP HPLC (Stationary phase: Cl 8 XBridge 30 x 100 mm 5 pm, Mobile phase: Gradient from 60% 0.1% NH4CO3H/NH4OH pH 9 solution in Water, 40% CH3CN to 43% 0.1% NH4CO3H/NH4OH pH 9 solution in Water, 57% CH3CN), yielding a white solid residue that was dissolved in Et2O (8 mL) and 1,4-dioxane (0.5 mL). To the solution thus obtained HC1 (4M in dioxane, 200 pL) was added dropwise. The white solid precipitate was filtered, washed with Et2O, dried (Na2SO4) and evaporated under vacuum. The white residue thus obtained was triturated with Et2O to give compound 6 .HC1 (110 mg, 36%) as a white solid.

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-43 The following compounds were synthesized following a synthetic sequence analogous to that reported in Example 1(b), starting from intermediate 21b.

(R)n-

Example 2 - Synthesis of compound 7

Procedure (a): DIAD (31.06 μΤ. 0.158 mmol) was added dropwise to a stirred solution of intermediate 21b (30 mg, 0.105 mmol), 3,5-difluorophenol (20.52 mg, 0.158 mmol)

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-44and triphenylphosphine (41.38 mg, 0.158 mmol) in THF (1.113 mL) at 0 °C and under nitrogen atmosphere. The mixture was stirred at 100 °C for 10 minutes under microwave irradiation. The mixture was diluted with EtOAc and washed with a sat. sol. of NaHCO3. The organic layer was separated, dried (NfoSOA filtered and concentrated 5 in vacuo. The residue was purified by flash column chromatography (silica; MeOH in

DCM 0/100 to 96/4). The desired fractions were collected and concentrated in vacuo. The residue was triturated with DIPE to give compound 7 (21 mg, 50%) as a white solid.

Procedure (b): Alternatively, compound 7 was also synthesized following a synthetic sequence analogous to that reported in Example 1 (b), starting from intermediate 21b.

Example 3 - Synthesis of compound 8

O

Procedure (a): DIAD (31.06 pL, 0.158 mmol) was added drop wise to a stirred solution of intermediate 21b (30 mg, 0.105 mmol), 3,4-difluorophenol (20.52 mg, 0.158 mmol) 15 and triphenylphosphine (41.38 mg, 0.158 mmol) inTHF (1.11 mL) at 0 °C and under nitrogen atmosphere. The mixture was stirred at 100 °C for 10 minutes under microwave irradiation. The mixture was diluted with EtOAc and washed with a sat. sol. of NaHCO3. The organic layer was separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica; MeOH in 20 DCM 0/100 to 96/4). The desired fractions were collected and concentrated in vacuo.

The residue was triturated with DTPE to give compound 8 (10.6 mg, 25%) as a white solid.

Procedure (b): Alternatively, compound 8 was also synthesized following a synthetic sequence analogous to that reported in Example 1(b), starting from intermediate 21b.

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Example 4 - Synthesis of compound 15

Procedure (a): DIAD (155.3 pL, 0.789 mmol) was added dropwise to a stirred solution of intermediate 21b (150 mg, 0.526 mmol), 2,4,6-trifluorophenol (116.8 mg, 0.789 mol) and triphenylphosphine (206.88 mg, 0.789 mmol) in THF (5.56 mL) at 0 °C and under nitrogen atmosphere. The mixture was stirred at 100 °C for 10 minutes under microwave. The mixture was diluted with DCM and washed with a sat. sol. of NalICCh. The organic layer was separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica; MeOH/NH3 7 N in DCM 0/100 to 90/10). The desired fractions were collected and concentrated in vacuo, then purified by RP HPLC (Stationary phase: Cl 8 XBridge 30 x 100 mm 5 pm, Mobile phase; Gradient from 54% 0.1% NH4CO3H/NH4OH pH 9 solution in Water, 46% CH3CN to 64% 0.1% NH4CO3H/NH4OH pH 9 solution in Water, 36% CH3CN) yielding a colourless oil that was crystallized upon standing (2 days). The solid was triturated with heptane to give compound 15 (129.8 mg, 59%) as a white solid. Procedure (b): Alternatively, compound 15 was also synthesized following a synthetic sequence analogous to that reported in Example 1 (b), starting from intermediate 21b.

Example 5 - Synthesis of compounds 1, 2 and 3

Compound 3

Compound 2

Compound 1

Compounds 1, 2 and 3 were synthesized following the procedure described in Example 1(a). Thus, reaction of DIAD (500.05 pL, 2.54 mmol), intermediate 21a (483 mg, 1.69 mmol), 4-fluorophenol (227.77 mg, 2.03 mmol) and triphcnylphosphine (666.14 mg, 2.54 mmol) in THF (17.91 mL) as described in Example 1(a) yielded a residue that was purified by flash column chromatography (silica; EtOAc in DCM 0/100 to 90/10). The

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-46desired fractions were collected and concentrated in vacuo. The resulting residue was triturated with DIPE to yield compound 1 (320 mg, 50%) as a white solid, which was purified by chiral SFC [Stationary phase: Chiralpak AD (5pm 250*30 mm, Mobile phase: 77% CO2, 23% MeOH)], yielding compound 2 (131mg, 20%) and compound 3 (129 mg, 20%) as white solids.

Example 6 - Synthesis of compounds 24, 26, and 27

Compound 26

Compound 27

Compound 24

Compounds 24, 26 and 27 were synthesized following the procedure described in Example 1(a). Thus, reaction of DIAD (364.57 pL, 1.85 mmol), intermediate 22 (320 mg, 1.23 mmol), 2,4-difluorophenol (176.86 pL, 1.85 mmol) and triphenylphosphine (485.67 mg, 1.85 mmol) in THF (13.06 mL) as described in Example 1(a) yielded a residue that was purified by flash column chromatography (silica; MeOH in DCM 0/100 to 96/4). The desired fractions were collected and concentrated in vacuo to yield a colourless oil that crystallized with DIPE to give compound 24 as a white solid, which was purified by RP HPLC (Stationary phase: C18 XBridge 30 x 100 mm 5 pm; mobile phase: Gradient from 54% 0.1% NH4CO2H/NH4OH pH 9 solution in Water, 46% CH3CN to 64% 0.1% NH4CO3H/NH4OH pH 9 solution in Water, 36% CH3CN) yielding a colourless oil that was crystallized upon trituration with heptane to give 240 mg (52%) of compound 24 as a white solid, which was then purified by chiral SFC (Stationary phase: CHIRALPAK AD-H 5pm 250x20mm; mobile phase: 85% CO2, 15% iPOH (0.3% iPrNH2)), yielding compound 26 (103 mg, 22%) and compound 27 (107 mg, 23%).

The following compounds were obtained following a synthetic sequence similar to that reported in Example 1(a).

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Compound 25

Compound 28

Compound 29

Starting material: Intermediate 22

Chiral SFC conditions: Stationary phase: Chiralpak AD-H 5μτη 250 x 20 mm); Mobile phase: 85% CO2, 15% mixture of EtOH/iPrOH 50/50 v/v (+0.3% iPrNH2)

Compound 16

Compound 17

Compound 18

Starting material: Intermediate 23

Chiral SFC conditions: Stationary phase: Chiralpak AD-H (5 pm 250*30 mm); Mobile phase: 80% CO2,20% mixture MeOH/iPrOH 50/50 v/v (+0.3% iPrNH2)

The following compounds were synthesized following a synthetic sequence analogous to that reported in Example 1(b), starting from the indicated intermediates.

Compound 20; obtained from intermediate 24c

Compound 21; obtained from intermediate 24b

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Compound 19; obtained from intermediate 24a

Compound 22; obtained from intermediate 24c

Compound 30;

obtained from intermediate 29

Compound 23; obtained from

Starting material: Intermediate 30

Chiral SFC conditions: Stationary phase: Chiralpak AD-H 5 gm 250 x 20 mm); Mobile phase: 85% CO2; 15% iPrOH.

Tabic 1 below lists additional compounds of Formula (I) which were prepared by analogy to the above examples (Exp. no.).

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-49Table 1 : Example compounds according to Formula (I).

# indicates that the experimental procedure is described in. the examples.

<td> Co. no.</td><td> Exp no.</td><td> R1</td><td colspan="2"> Ar</td><td> Stereo-chem.</td>

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<td> Co. no.</td><td> Exp no.</td><td> R1</td><td> Ar</td><td> Stereo-chem.</td>

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<td> Co. no.</td><td> Exp no.</td><td> R1</td><td> Ar</td><td> Stereo-chem.</td>

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<td> Co. no.</td><td> Exp no.</td><td> R1</td><td> Ar</td><td> Stereo-chem.</td>

Analytical part

Optical Rotations

Optical rotations were measured on a Perkin-Elmer 341 polarimeter with a sodium lamp and reported as follows: [α]° (λ, c g/lOOml, solvent, T’C).

[a]^1 = (100a) / (/ x c) : where I is the path length in dm and c is the concentration in g/100 ml for a sample at a temperature T (°C) and a wavelength λ (in nm). Tf the wavelength of light used is 589 nm. (the sodium D line), then the symbol D might be used instead. The si gn of the rotation (+ or -) should always be given. When using this equation the concentration and solvent are always provided in parentheses after the rotation. The rotation is reported using degrees and no units of concentration are given (it is assumed to be g/100 ml).

LCMS

For (LC)MS-characterization of the compounds of the present invention, the following 15 methods were used.

General procedure

The High Performance Liquid Chromatography (HPLC) measurement was performed using a LC pump, a diode-array (DAD) or a UV detector and a column as specified in

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-53 the respective methods. If necessary, additional detectors were included (see table of methods below).

Flow from the column was brought to the Mass Spectrometer (MS) which was configured with an atmospheric pressure ion source. It is within the knowledge of the skilled person to set the tune parameters (e.g. scanning range, dwell time..,) in order to obtain ions allowing the identification of the compound’s nominal mono isotopic molecular weight (MW). Data acquisition was performed with appropriate software. Compounds are described by their experimental retention times (Rt) and ions. If not specified differently in the table of data, the reported molecular ion corresponds to the 10 [M+H]+ (protonated molecule) and/or (deprotonated molecule). In case the compound was not directly ionizable the type of adduct is specified (i.e. [M+NH4]', [M+HCOO], etc...). For molecules with multiple isotopic patterns (Br, Cl..), the reported value is the one obtained for the lowest isotope mass. All results were obtained with experimental uncertainties that are commonly associated with the method used.

Hereinafter, “SQD” means Single Quadrupole Detector, “RT” room temperature, “BEH” bridged ethylsiloxane/silica hybrid, “HSS” High Strength Silica, “DAD” Diode Array Detector.

Table 2. LCMS Method codes (Flow expressed in mL/min; column temperature (T) in °C; Run time in minutes).

<td> Instru- ment</td><td> Column</td><td> Mobile phase</td><td> Gradient</td><td> Flow Col T</td><td> Run time</td><td> LCMS Method</td>

<td> Waters: Acquity® UPLC®DAD and SQD</td><td> Agilent: Eclipse Plus Cl 8 RRHD (1.8pm, 2.1x50mm)</td><td> A: 95% CH3COONH4 6.5mM + 5% CH3CN, B: ch3cn</td><td> From 95% A to 5% A in 4.6min, held for 0.4min</td><td> 1 50</td><td> 5</td><td> 1</td>

<td> Waters: Acquity® UPLC® DAD and SQD</td><td> Waters: CSH™C18 (1.7pm, 2.1x50mm)</td><td> A: 95% CH3COONH4 6.5mM + 5% CH3CN, B: CH3CN</td><td> From 95% A to 5% A in 4.6min, held for 0.4min</td><td> 1 50</td><td> 5</td><td> 2</td>

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<td> Instru- ment</td><td> Column</td><td> Mobile phase</td><td> Gradient</td><td> Flow Col T</td><td> Run time</td><td> LCMS Method</td>

<td> Waters: Acquity uplC®D AD and Quatfro Micro™</td><td> Waters: BEH C18 (1.7pm, 2.1x100mm)</td><td> A: 95% CH3COONH4 7mM / 5% CHsCN, B: CH3CN</td><td> 84.2% A for 0.49min, to 10.5% Ain 2.18min, held for l,94min, back to 84.2% A in 0.73min, held for 0.73min.</td><td> 0.343 40</td><td> 6.2</td><td> 3</td>

<td> Waters: Acquity® UPLC®DAD and SQD</td><td> Waters: CSH™C18 (1.7pm, 2.1x50mm)</td><td> A: 95% CH3COONH4 6.5mM + 5% CH3CN, B: CH3CN</td><td> From 95% A to 5% A in 7.8min, held for 1,2min</td><td> 1 50</td><td> 9</td><td> 4</td>

Melting points

Values are peak values, and are obtained with experimental uncertainties that are commonly associated with this analytical method.

Mettler FP 81HT / FP90 apparatus

For a number of compounds, melting points were determined in open capillary tubes on a FP 81HT / FP90 apparatus (Mettler-Toledo). Melting points were measured with a temperature gradient of 1, 3, 5 or 10 °C/minute. Maximum temperature was 300 °C. The melting point was read from a digital display.

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-55Table 3 : Physico-chemical data for some compounds, retention time (Rt) in min, [M+H]+ peak (protonated molecule), LCMS method and mp (melting point in °C).

(n.d. = not determined).

<td> Co. no.</td><td> Mp (°O</td><td> Rt (min)</td><td> [MH+]</td><td> LCMS method</td><td> Optical Rotation</td>

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<td> Co. no.</td><td> Mp (°C)</td><td> Rt (min)</td><td> [MH+]</td><td> LCMS method</td><td> Optical Rotation</td>

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-57SFC-MS

General procedure

The SFC measurement was performed using Analytical system from Berger instrument comprising a FCM-1200 dual pump fluid control module for delivering carbon dioxide (CO2) and modifier, a CTC Analytics automatic liquid sampler, a TCM-20000 thermal control module for column heating from room temperature to 80°C. An Agilent 1100 UV photodiode array detector equipped with a high-pressure flow cell standing up to 400 bars was used. Flow from the column was split to a MS spectrometer. The MS detector was configured with an atmospheric pressure ionization source.The following ionization parameters for the Waters ZQ mass spectrophotometer are; corona: 9pa, source temp: 140°C, cone: 30 V, probe temp 450°C, extractor 3 V, desolvatation gas 400L/hr, cone gas 70 L/hr. Nitrogen was used as the nebulizer gas. Data acquisition was performed with a Waters-Micromass MassLynx-Openlynx data system.

Method I: In addition to the general procedure: The analytical chiral separation in SFCMS was carried out on a CHIRALPAK AD DAICEL column (10 pm, 4.6 x 250 mm) at 35 °C with a flow rate of 3.0 ml/min. The mobile phase is 85% CO2, 15% iPrOH (+ 0.3% iPrNH2) hold 7 min in isocratic mode.

Method 2: In addition to the general procedure: The analytical chiral separation in SFCMS was carried out on a CHIRALPAK AD DAICEL column (10 pm, 4.6 x 250 mm) at 35 °C with a flow rate of 3.0 ml/min. The mobile phase is 75% CO2, 15% iPrOH (+ 0.3% iPrNH2) hold 7 min in isocratic mode.

Method 3: In addition to the general procedure: The analytical chiral separation in SFCMS was carried out on a CHIRALPAK AD DAICEL column (10 pm, 4.6 x 250 mm) at 35 °C with a flow rate of 3.0 ml/min. The mobile phase is 80% CO2, 10%> Methanol + 10% iPrOH (+ 0.3% iPrNH2) hold 7 min in isocratic mode.

Table 4: Analytical SFC data - Rt means retention time (in minutes), [M+H]+ means the protonated mass of the compound, method refers to the method used for SFC/MS analysis of enantiomerically pure compounds. The measurement was compared against the mixture.

<td> Co. Nr.</td><td> Rt</td><td> |M+H]+</td><td> UV Area %</td><td> Method</td><td> Isomer Elution Order*</td>

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<td> Co. Nr.</td><td> Rt</td><td> [MTH]+</td><td> UV Area %</td><td> Method</td><td> Isomer Elution Order*</td>

*A means the first isomer that elutes. B means the second isomer that elutes.

Nuclear Magnetic Resonance (NMR)

For a number of compounds, ]H NMR spectra were recorded either on a Bruker DPX400 or on a Bruker AV-500 spectrometer with standard pulse sequences, operating at 5 400 MHz and 500 MHz respectively. Chemical shifts (δ) are reported in parts per million (ppm) downfield from tetramethylsilane (TMS), which was used as internal standard.

Co. No. 6: JH NMR (400 MHz, CDCI3) δ ppm 0.30 - 0.38 (m, 2 H), 0.59 - 0.68 (m, 2 H), 1.14-1.22 (m, 1 H), 1.72 (d, 7=6.5 Hz, 3 H), 3.02 - 3.14 (m, 2 H), 5.84 (q, 7=6.3

Hz, 1 H), 6.67 - 6.73 (m, 1 H), 6.80 - 6.89 (m, 2 H), 7.30 (d, 7=7.4 Hz, 1 H), 8.11 (d, 7=7.4 Hz, 1 H)

Co. No. 7: JH NMR (400 MHz, CDC13) δ ppm 0.30 - 0.39 (m, 2 H), 0.59 - 0.68 (m, 2 H), 1.11 - 1.23 (m, 1 H), 1.70 (d, 7=6.5 Hz, 3 H), 3.01 - 3.14 (m, 2 H), 5.83 (q, 7=6.2

Hz, 1 H), 6.35 - 6.45 (m, 3 H), 7.13 (d, 7=7.2 Hz, 1 H), 8.08 (d, 7=7.4 Hz, 1 H)

Co. No. 8: ’H NMR (400 MHz, CDC13) δ ppm 0.30 - 0.38 (m, 2 H), 0.58 - 0.68 (m, 2 H), 1,11 - 1.22 (m, 1 H), 1.69 (d, 7=6.2 Hz, 3 H), 3.01-3.13 (m, 2 H), 5.79 (q, 7=6.2 Hz, 1 H), 6.53 (dtd, 7=9.2, 3.1, 3.1, 1.7 Hz, 1 H), 6.72 (ddd, 7=11.6, 6.5, 3.1 Hz, 1 H), 20 6.95 - 7.04 (m, 1 H), 7.15 (d, 7=7.4 Hz, 1 H), 8.07 (d, 7=7.4 Hz, 1 H)

Co. No. 15: 'H NMR (500 MHz, CDC13) δ ppm 0.30 - 0.41 (m, 2 H), 0.59 - 0.71 (m, 2 H), 1.16-1.25 (m, 1 H), 1.70 (d, 7=6.4 Hz, 3 H), 3.05 - 3.16 (m, 2 H), 5.80 (q, 7=6.4 Hz, 1 H), 6.62 6.70 (m, 2 H), 7.45 (d, 7=7.5 Hz, 1 H), 8.16 (d, 7=7.2 Hz, 1 H)

Co. No. 13: !H NMR (500 MHz, CDC13) δ ppm 0.27 - 0.39 (m, 2 H), 0.58 - 0.67 (m, 2 H), 1.12 - 1.21 (m, 1 H), 1.73 (d, 7=6.4 Hz, 3 H), 2.22 (s, 3 H), 3.06 (qd, 7=15.4, 6.6

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- 59Hz, 2 H), 5.92 (q, 7=6.4 Hz, 1 H), 6.71 (d, 7=8.4 Hz, 1 H), 6.89 (dd, 7=8.4, 1.4 Hz, 1 H), 7.18 (d, 7=1.7 Hz, 1 H), 7.32 (d, 7=7.2 Hz, 1 H), 8.07 (d, 7=7.2 Hz, 1 H)

Co. No. 14: 3H NMR (500 MHz, CDC13) δ ppm 0.28 - 0.39 (m, 2 H), 0.57 - 0.69 (m, 2 H), 1.12 - 1.21 (m, 1 H), 1.70 (d, 7=6.6 Hz, 3 H), 2.31 (s, 3 H), 3.01 - 3.12 (m, 2 H), 5.79 (q, 7=6.6 Hz, 1 H), 6.55 (dd, 7=9.0, 4.3 Hz, 1 H), 6.69 (td, 7=8.5, 3.0 Hz, 1 H), 6.87 (dd, 7=9.0, 2.9 Hz, 1 H), 7.17 (d, 7=7.5 Hz, 1 H), 8.06 (d, 7=7.2 Hz, 1 H)

Co. No. 2G: 3H NMR (500 MHz, CDCI3) δ ppm 1.22(t,7=7.1 Hz, 3 H), 1.72 (d,7=6.4 Hz, 3 H), 3.58 (q, 7=7.1 Hz, 2 H), 5.03 - 5.10 (m, 2 H), 5.84 (q, 7=6.5 Hz, 1 H), 6.67 6.74 (m, 1 H), 6.81 - 6.88 (m, 2 H), 7.34 (d, 7=7.2 Hz, 1 H), 8.40 (d, 7=7.5 Hz, 1 H)

Co. No. 22: M NMR (500 MHz, CDCI3) δ ppm 1.23 (t, 7=6.9 Hz, 3 H), 1.70 (d, 7=6.4 Hz, 3 H), 3.58 (q, 7=7.0 Hz, 2 H), 5.05 - 5.12 (m, 2 H), 5.81 (q, 7=6.6 Hz, 1 H), 6.62 6.70 (m, 2 H), 7.48 (d, 7=7.5 Hz, 1 H), 8.45 (d, 7=7.2 Hz, 1 H)

Co. No. 31: rH NMR (400 MHz, CDCI3) δ ppm 1.07 (t, 7=7.40 Hz, 3 Η) 1.72 (d, 7=6.24 Hz, 3 H) 1.92 (sxt, 7=7.63 Hz, 2 H) 2.98 - 3.14 (m, 2 H) 5.84 (q, 7=6.47 Hz, 1 H) 6.65 - 6.74 (m, 1 H) 6.78 - 6.89 (m, 2 H) 7.29 (d, 7=7.40 Hz, 1 H) 8.02 (d, 7=7.40 Hz, 1 H).

Pharmacological examples

A) In vitro pharmacology

The compounds provided in the present invention are positive allosteric modulators of mGluR2. These compounds appear to potentiate glutamate responses by binding to an allosteric site other than the glutamate binding site. The response of mGluR2 to a concentration of glutamate is increased when compounds of Formula (I) are present. Compounds of Formula (I) are expected to have their effect substantially at mGluR2 by virtue of their ability to enhance the function of the receptor. The effects of positive allosteric modulators tested at mGluR2 using the [35S]GTPyS binding assay method described below and which is suitable for the identification of such compounds, and more particularly the compounds according to Formula (1), are shown in Table 5. |~35SlGTPyS binding assay

The [35S]GTPyS binding assay is a functional membrane-based assay used to study G-protcin coupled receptor (GPCR) function whereby incorporation of a

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-60non-hydrolysable form of GTP, [35S]GTPyS (guanosine 5’-triphosphate, labelled with gamma-emitting 35S), is measured. The G-protein a subunit catalyzes the exchange of guanosine 5’-diphosphate (GDP) by guanosine triphosphate (GTP) and on activation of the GPCR by an agonist, [35S]GTPyS, becomes incorporated and cannot be cleaved to 5 continue the exchange cycle (Harper (1998) Current Protocols in Pharmacology

2.6.1-10, John Wiley & Sons, Inc.). The amount of radioactive [35S]GTPyS incorporation is a direct measure of the activity of the G-protein and hence the activity of the agonist can be determined. mGlu2 receptors are shown to be preferentially coupled to Gai-protein, a preferential coupling for this method, and hence it is widely 10 used to study receptor activation of mGlu2 receptors both in recombinant cell lines and in tissues. Here we describe the use of the [35S]GTPyS binding assay using membranes from cells transfected with the human mGlu2 receptor and adapted from Schaffhauser el al. (Molecular Pharmacology, 2003, 4:798-810) for the detection of the positive allosteric modulation (PAM) properties of the compounds of this invention.

Membrane preparation

CHO-cells were cultured to pre-confluence and stimulated with 5 mM butyrate for 24 h. Cells were then collected by scraping in PBS and cell suspension was centrifuged (10 min at 4000 RPM in benchtop centrifuge). Supernatant was discarded and pellet gently resuspended in 50 mM Tris-HCl, pH 7.4 by mixing with a vortex and 20 pipetting up and down. The suspension was centrifuged at 16,000 RPM (Sorvall RC-5C plus rotor SS-34) for 10 minutes and the supernatant discarded. The pellet was homogenized in 5 mM Tris-HCl, pH 7.4 using an ultra-turrax homogenizer and centrifuged again (18,000 RPM, 20 min, 4 °C). The final pellet was resuspended in 50 mM Tris-HCl, pH 7.4 and stored at -80 °C in appropriate aliquots before use. Protein 25 concentration was determined by the Bradford method (Bio-Rad, USA) with bovine serum albumin as standard.

[35S]GTPyS binding assay

Measurement of mGluR2 positive allosteric modulatory activity of test compounds was performed as follows. Test compounds and glutamate were diluted in 30 assay buffer containing 10 mM HEPES acid, 10 mM HEPES salt, pH 7.4, 100 mM NaCl, 3 mM MgCE and .10 μΜ GDP. Human mGlu2 receptor-containing membranes were thawed on ice and diluted in assay buffer supplemented with 14 pg/ml saponin. Membranes were pre-incubated with compound alone or together with a predefined (~EC2o) concentration of glutamate (PAM assay) for 30 min at 30 °C. After addition of 35 [35S]GTPyS (f.c. 0.1 nM), assay mixtures were shaken briefly and further incubated to allow [35S]GTPyS incorporation on activation (30 minutes, 30 °C). Final assay

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-61 mixtures contained 7 pg of membrane protein in 10 mM HEPES acid, 10 mM HEPES salt, pH 7.4, 100 mM NaCl, 3 mM MgCL, 10 pM GDP and 2 pg/ml saponin. Total reaction volume was 200 pl. Reactions were terminated by rapid filtration through Unifllter-96 GF/B plates (Perkin Elmer, Massachusetts, USA) using a 96-well filtermate universal harvester. Filters were washed 6 times with ice-cold 10 mM NaH2PO4/l 0 mM Na2HPO4, pH 7.4. Filters were then air-dried, and 40 pl of liquid scintillation cocktail (Microscint-O) was added to each well. Membrane-bound radioactivity was counted in a Microplate Scintillation and Luminescence Counter from Perkin Elmer.

Data analysis

The cone entration-response curves of representative compounds of the. present invention -obtained in the presence of EC2o of mGluR2 agonist glutamate to determine positive allosteric modulation (PAM)- were generated using the Lexis software interface (developed at J&J). Data were calculated as % of the control glutamate response, defined as the maximal response that is generated upon addition of glutamate alone. Sigmoid concentration-response curves plotting these percentages versus the log concentration of the test compound were analyzed using non-linear regression analysis. The concentration producing half-maximal effect is then calculated as EC5o. The pECso values below were calculated as the -log EC50, when the EC50 is expressed in M. Emax is defined as relative maximal effect (i.e. maximal % effect relative to the control glutamate response).

Table 5 below shows the pharmacological data obtained for compounds of Formula (I). Table 5 . Pharmacological data for compounds according to the invention.

<td> Co. No.</td><td> GTPyS hmGluR2 PAM pECso</td><td> GTPyS hmGluR2 PAM Emax</td>

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<td> Co. No.</td><td> GTPyS - hmGluR2 PAM pECso</td><td> GTPyS - hmGIuR2 PAM Emax</td>

n.c. means that the pECso could not be calculated pEC<o values were not calculated in cases where the concentration-response curve did not reach a plateau level.

All compounds were tested in presence of mGluR2 agonist glutamate at a predetermined EC20 concentration, to determine positive allosteric modulation. pECso values were calculated from a concentration-response experiment of at least 8 concentrations.

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-63B) In vivo pharmacology

Motor Activity ('Video tracking)

Apparatus and General Procedure

On the day of experiments, the mice were brought into the procedural room. They were housed individually and allowed to acclimate for at least a half hour prior to testing. Although the studies were conducted during the light cycle (from 8:00 to 16:00 h), the procedure room was only sparsely lit (3 to 30 LUX) to provide better contrast for the video tracking. Local lighting was used for the injection procedures. During each trial, an individual mouse was placed in an open field arena (grey PVC cylinder with a height of 40 cm and a diameter of 22.5 cm). Each arena was placed on an infrared LED (8 x 8 LEDs)-lit box (white PVC squared box; 40 x 40 cm2; height 12.5 cm). Each mouse was placed in the center of the arena and allowed to explore freely for 30 min. After each trial, the arena was cleaned with a wet and subsequently with a dry cleaning cloth. An infrared sensitive tube camera and a white light source (in arena: 4-7 LUX) were mounted to the ceiling above the observation chamber to record and input activity to a computer. Animal behavior was recorded and analyzed using the Noldus Ethovision XT Video Tracking System (Version 3.1; Noldus, Wageningen, The Netherlands). The total distance traveled (cm) was calculated. Data were then exported to data management systems for further analysis and reporting.

1) Phencyclidine (PCP)-induced Hyperlocomotion in Mice

Test compound or solvent was administered at a pre-defined time before measurement (standard: 30 min) to male NMRI mice that were challenged with phencyclidine (PCP;

mg/kg, s.c.) 30 min before measurement. Activity was measured for a period of 30 min. Criterion for drug-induced inhibition of hyper locomotion: total distance < 5500 counts (3.9% false positives in controls; n = 154).

2) Conditioned avoidance response (CAR) test in Rats

Apparatus

The apparatus consisted of an inner box surrounded by an outer box. The inner box was composed of four walls of transparent, synthetic material (length x width x height: 30 x 30 x 30 cm), an open top, and a grid floor made of 15 pairs of iron bars (2 mm diameter; 6 mm inter-bar distance). Odd and even bars were connected with a source of alternative current (1.0 mA; Coulboum Instruments Solid State Shocker/Distributor), which could be interrupted by a switch. The outer box was composed of the same material (length x width x height: 40 x 40 x 36 cm), also with an open top, with a

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-64distance of 5 cm between the inner and outer box on all sides. To decrease the amount of environmental stimuli, three walls of the outer box were made non-transparent. The front wall was left transparent to allow the necessary inspection of the animal during the test. The upper edge of the outer and inner box served as a target for the rats on which to jump with fore- and hind-paws, respectively.

Avoidance Conditioning and Selection of Animals

From their arrival in the laboratory on the experimental day, male Wiga Wistar rats (230 ± 30 g) were housed in individual cages provided with bedding material. The rats received 5 training sessions at 15-min time intervals over a 1-h period during which, the rats were conditioned to avoid an electric shock: the rat was placed on the nonelectrificd grid floor and the grid was electrified 10 s later for not more than 30 s, if the rat did not jump out of the box. Only rats that showed correct avoidance responses in all the last 3 training sessions were included for further experiments, and received the test compound or solvent immediately after the last training session.

Experimental Sessions

The rats were tested 3 times, i.e. at 60, 90 and 120 min after the injection of test compound or solvent. Latency to avoidance was recorded. The median avoidance response obtained over the three experimental sessions for each rat were used for further calculations. A median avoidance latency > 8 s was selected as an all-or-none criterion for drug-induced inhibition of avoidance (occurring in only 1.5% of solventpretreated control rats; n = 66).

The results of tests 1) and 2) are shown in table 6 below.

Table 6. Pharmacological data for compounds according to the invention in tests 1) and 2) described above. PCP means Drug-induced inhibition of PCP-induced hyperlocomotion; CAR means Conditioned avoidance response; ED50 means median effective dose; PO means oral route.

<td rowspan="2"> Co. No.</td><td rowspan="2"> Route</td><td colspan="2"> ED50 (mg/kg)</td>

* compound 6 was in suspension in 20% hydroxypropyl-b-cyclodextrin containing 1% polysorbate 80.

WO 2015/032790

PCT/EP2014/068676

3) Anticonvulsant Studies

Preparation of Test Article and Controls

Test compounds were administered using an optimal fluid volume to body fluid ratio.

Test compounds were administered to mice in a volume of 0.01 ml/g of body weight (White, H.S., et al., General principles: Experimental selection, quantification, and evaluation of antiepileptic drugs, in Antiepileptic Drugs, Fourth Edition, R.H. Levy, R.H. Mattson, and B.S. Meldrum, Editors. 1995, Raven Press, Ltd.: New York. p. 99110). The test compound number 6 was administered orally (p.o.). For each of the tests performed on the test compound, a 40% Hydroxypropyl-β-cyclodextrin (Ηρ-β-CD) 10 stock solution was first prepared and utilized for formulating the test compound number 6 at the desired concentrations for testing via the oral (p.o.) route. Final compound concentrations were administered as suspensions in 20% Ηρ-β-CD. A 20% Ηρ-β-CD solution was used for the vehicle groups.

Critical Reagents

a) Vehicle Solutions

40% Hydroxypropyl-β-cyclodextrin (Ηρ-β-CD) stock solution

b) Miscellaneous Solutions

Tetracaine (0.5% solution w/v) was added drop wise from a plastic dropper bottle onto 20 the eyes of all animals that would subsequently receive electrical stimulation via corneal electrodes.

Animals and animal husbandry

Adult male CF No 1 albino mice (26-35 g) were obtained from Charles River, Portage, Michigan. The animals were maintained on an adequate diet (Prolab RMH 3000) and 25 allowed free access to food and water, except during the short time they were removed from their cage for testing. Animals newly received in the laboratory were allowed sufficient time to correct for possible food and water restriction incurred during transit before being employed in testing. All mice were housed in plastic cages in specially constructed rooms with controlled humidity, exchange of air and controlled lighting (12 30 hours on - 12 hours off). The animals were housed, fed, and handled in a manner consistent with the recommendations in the National Council Publication, Guide for the Care and Use of Laboratory animals.”

Experimental Design

General Methods

Minimal Motor Impairment (MMI): Acute MMI was assessed by a combination of direct observations of the animal for overt symptoms of the animal’s neurological or

WO 2015/032790

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-66muscular function. In mice, the rotarod procedure was used to disclose minimal muscular or neurological impairment. When a mouse is placed on a rod that rotates at a speed of 6 rpm, the animal can maintain its equilibrium for long periods of time. The animal was considered toxic if it fell off this rotating rod three times during a 1 min period.

TPE Determination: Groups of four animals each were administered test compounds and each group was tested at one of five time points: 0.25, 0.5, 1,2, or 4h posttreatment (White et al. 1995). TPE was determined using the 6Hz (32mA) assay. The 10 time (0.25, 0.5, 1, 2, or 4h post-treatment) at which maximal protection was observed was considered the Time of Peak Effect (TPE).

At the TPE determined for this study, or determined previously, compounds were tested in the 6Hz assay (32 and/or 44 mA), across several doses and comprising doses that elicited little or no protection to full protection. An ED50 and 95% confidence 15 interval (CI) were calculated using Probit analysis on a computer program provided in the laboratory (Finney “Probit Analysis” 34d ED 1971, London: Cambridge University Press).

Serum Collection for pK/pD Analysis: In various tests, animals were sacrificed following testing, and trunk blood and/or brain tissue (whole brains) was collected for quantification of drug levels. Immediately after testing, animals were decapitated and trunk blood was collected into a BD Vacutainer® tube containing K2EDTA and chilled on ice until centrifugation. Following centrifugation (13000 - 18000 rpm, 5-7 min), the plasma was removed and transferred to a labeled micro centrifuge tube and stored at

-80 °C. For brain tissue collection, brains were removed immediately following decapitation and flash frozen. The frozen sample was placed in a labeled centrifuge tube and stored at -80 °C.

Hz Psychomotor Seizure Test in Mice

The 6Hz seizure test is used as a model of pharmacoresistant limbic seizures. The 6Hz seizure displays a resistance to phenytoin, carbamazepine, lamotrigine, and topiramate (Barton et al. “Pharmacological characterization of the 6 Hz psychomotor seizure model of partial epilepsy” Epilepsy Research 2001, Vol. 47, pp. 217-222).

Method for 6 Hz Psychomotor Seizure Test

Focal seizures were induced in mice via corneal stimulation (6Hz, 0.2 msec rectangular pulse, 3 see duration; Barton et al. 2001). Mice were tested at either 32mA or 44mA. Prior to stimulation, drops of 0.5% tetracaine were applied to each eye. The seizures

WO 2015/032790

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-67that arise from comeal stimulation in this assay are characterized by a minimal clonic phase followed by stereotyped automatistic behaviors including stun, forelimb clonus, twitching of the vibrissae, and Straub-tail. Animals not displaying these behaviors were considered protected.

Table 7: Time-to-Peak Effect Determination for Co. No. 6 (p.o.) in the 6HZ (32mA) Assay.

<td> Dose (mg/kg, p.o.)</td><td> Time (h)</td><td> # protected / # tested</td><td> # rotarod motor impairment / # tested</td>

TPE determined to be 0.5h.

Table 8: Dose-Response Study for Co. No. 6 in the 6Hz Assay (32mA and 44mA;

0.5h TPE).

<td> Test</td><td> Dose (mg/kg, p.o.)</td><td> # protected / # tested</td><td> # rotarod motor impairment / # tested</td>

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PCT/EP2014/068676

Prophetic composition examples “Active ingredient” as used throughout these examples relates to a final compound of Formula (1), the pharmaceutically acceptable salts thereof, the solvates and the stereo chemically isomeric forms and the tautomers thereof.

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

1, Tablets

Active ingredient 5 to 50mg

Di-calcium phosphate20 mg

Lactose30 mg

Talcum10 mg

Magnesium stearate5 mg

Potato starch ad 200mg

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.

2. Suspension

An aqueous suspension is prepared for oral administration so that each 1 milliliter contains 1 to 5 mg of one of the active compounds, 50 mg of sodium carboxymethyl cellulose, 1 mg of sodium benzoate, 500 mg of sorbitol and water ad 1 ml.

3. Injectable

A parenteral composition is prepared by stirring 1.5 % by weight of active ingredient of the invention in 10% by volume propylene glycol in water.

4, Ointment

Active ingredient Stearyl alcohol Lanoline

White petroleum

Water to 1000 mg g

5g g

ad 100 g

WO 2015/032790 PCT/EP2014/068676

-69In. this Example, active ingredient can be replaced with the same amount of any of the compounds according to the present invention, in particular by the same amount of any of the exemplified compounds.

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

Contents141

192 members in 34 offices

This recordMember, by publication datePriority claim24 more offices are in the list below

Priority claims9

Priority claims
Document	Office	Kind	Date
13183427	European Patent Office (EPO)	A	2013-09-06
14153887	European Patent Office (EPO)	A	2014-02-04
2014068676	European Patent Office (EPO)	W	2014-09-03
131834277	–	–	–
141538876	–	–	–
EP20130183427	–	–	–
EP20140153887	–	–	–
PCTEP2014068676	–	–	–
WO2014EP68676	–	–	–

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CA2918669A1	Canada	A1	2015-03-12
WO2015032790A1	World Intellectual Property Organization (WIPO)	A1	2015-03-12
TW201518299A	Taiwan Province of China	A	2015-05-16
CA2933394A1	Canada	A1	2015-07-30
WO2015110435A1	World Intellectual Property Organization (WIPO)	A1	2015-07-30
AU2014317157A1	Australia	A1	2016-02-11
IL243676A0	Israel	A0	2016-02-29
IL243676D0	Israel	D0	2016-02-29
AR097566A1	Argentina	A1	2016-03-23
SG11201601397VA	Singapore	A	2016-03-30
CN105518006A	China	A	2016-04-20
KR20160050029A	Republic of Korea	A	2016-05-10
PH12016500312A1	Philippines	A1	2016-05-16
PH12016500312B1	Philippines	B1	2016-05-16
MX2016002925A	Mexico	A	2016-06-06
AU2015208233A1	Australia	A1	2016-06-16
TW201620513A	Taiwan Province of China	A	2016-06-16
US2016194318A1	United States of America	A1	2016-07-07
EP3041839A1	European Patent Office (EPO)	A1	2016-07-13
CL2016000482A1	Chile	A1	2016-08-19
PH12016501213A1	Philippines	A1	2016-08-22
PH12016501213B1	Philippines	B1	2016-08-22
SG11201605742TA	Singapore	A	2016-08-30
IL246802A0	Israel	A0	2016-08-31
IL246802D0	Israel	D0	2016-08-31
KR20160108359A	Republic of Korea	A	2016-09-19
JP2016529302A	Japan	A	2016-09-23
MX2016009471A	Mexico	A	2016-10-13
CN106061504A	China	A	2016-10-26
EA201690535A1	Eurasian Patent Organization (EAPO)	A1	2016-10-31
EP3096790A1	European Patent Office (EPO)	A1	2016-11-30
US2016367554A1	United States of America	A1	2016-12-22
EA201691467A1	Eurasian Patent Organization (EAPO)	A1	2016-12-30
JP2017503825A	Japan	A	2017-02-02
CL2016001815A1	Chile	A1	2017-04-21
HK1222657A	Hong Kong, China	A	2017-07-07
HK1222657A1	Hong Kong, China	A1	2017-07-07
US9708315B2	United States of America	B2	2017-07-18
EP3041839B1	European Patent Office (EPO)	B1	2017-07-26
BR112016016390A2	Brazil	A2	2017-08-08
DK3041839T3	Denmark	T3	2017-09-18
LT3041839T	Lithuania	T	2017-09-25
PT3041839T	Portugal	T	2017-10-02
HRP20171311T1	Croatia	T1	2017-10-20
ES2639746T3	Spain	T3	2017-10-30
SI3041839T1	Slovenia	T1	2017-10-30
MA39209A1	Morocco	A1	2017-10-31
PL3041839T3	Poland	T3	2017-11-30
RS56247B1	Serbia	B1	2017-11-30
EA029177B1	Eurasian Patent Organization (EAPO)	B1	2018-02-28
CY1119449T1	Cyprus	T1	2018-03-07
AU2014317157B2	Australia	B2	2018-03-29
AU2014317157A8	Australia	A8	2018-04-05
AU2014317157B8	Australia	B8	2018-04-05
HUE035882T2	Hungary	T2	2018-05-28
ME02953B	Montenegro	B	2018-07-20
CN105518006B	China	B	2018-07-31
AU2014317157C1	Australia	C1	2018-09-27
MA43290A1	Morocco	A1	2018-11-30
MA43291A1	Morocco	A1	2018-11-30
TWI644914B	Taiwan Province of China	B	2018-12-21
EA201891617A2	Eurasian Patent Organization (EAPO)	A2	2018-12-28
EP3424535A1	European Patent Office (EPO)	A1	2019-01-09
JP6449297B2	Japan	B2	2019-01-09
EP3431106A1	European Patent Office (EPO)	A1	2019-01-23
JO3367B1	Jordan	B1	2019-03-13
EA201891617A3	Eurasian Patent Organization (EAPO)	A3	2019-04-30
MA43290B1	Morocco	B1	2019-05-31
MA43291B1	Morocco	B1	2019-05-31
MX365438B	Mexico	B	2019-06-03
UA119446C2	Ukraine	C2	2019-06-25
EP3096790B1	European Patent Office (EPO)	B1	2019-07-10
CN109999025A	China	A	2019-07-12
CN109999033A	China	A	2019-07-12
JP2019123723A	Japan	A	2019-07-25
JP2019123724A	Japan	A	2019-07-25
IL243676AThis record	Israel	A	2019-07-31
IL243676B	Israel	B	2019-07-31
IL266622D0	Israel	D0	2019-07-31
IL266624A	Israel	A	2019-07-31
IL266624D0	Israel	D0	2019-07-31
AU2019208178A1	Australia	A1	2019-08-08
AU2019208181A1	Australia	A1	2019-08-08
AU2015208233B2	Australia	B2	2019-08-29
CN106061504B	China	B	2019-09-06
MX2019008632A	Mexico	A	2019-09-19
MX2019008633A	Mexico	A	2019-09-19
DK3096790T3	Denmark	T3	2019-10-07
LT3096790T	Lithuania	T	2019-10-10
TWI674095B	Taiwan Province of China	B	2019-10-11
PT3096790T	Portugal	T	2019-10-15
TW201940168A	Taiwan Province of China	A	2019-10-16
TW201940168A	Taiwan Province of China	A	2019-10-16
TW201940196A	Taiwan Province of China	A	2019-10-16
TW201940196A	Taiwan Province of China	A	2019-10-16
RS59302B1	Serbia	B1	2019-10-31
NZ722385A	New Zealand	A	2019-11-29
SI3096790T1	Slovenia	T1	2019-11-29
EA033889B1	Eurasian Patent Organization (EAPO)	B1	2019-12-05
HRP20191646T1	Croatia	T1	2019-12-13

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