Novel dioxane derivatives

Abstract

The present invention relates to substituted dioxane derivatives, pharmaceutical compositions containing them, and their use in therapy, in particular in the treatment and / or prophylaxis of neuronal and non-neuronal conditions associated with mGluR4 function.

Description

TECHNICAL FIELD

[0001] The present invention relates to substituted dioxane derivatives, pharmaceutical compositions containing them, and their use in therapy, in particular in the treatment and / or prevention of neuronal and non-neuronal conditions associated with mGluR4 function. BACKGROUND ART

[0002] L-glutamic acid (referred to as glutamic acid in this application) is one of the most abundant excitatory neurotransmitters in the vertebrate brain. Malfunctions of the brain glutamic acid system usually cause neurological or psychiatric disorders. Therefore, modulating the glutamatergic system is regarded as an attractive therapeutic direction.

[0003] Glutamic acid acts via different types of glutamate receptors located on the cell surface. Glutamate receptors include AMPA receptors, kainate receptors, NMDA receptors, and metabotropic glutamate receptors. Metabotropic glutamate receptors (mGluRs) exert their action by coupling with G proteins and activating second messenger systems.

[0004] mGluR subtypes are classified into three groups (distinguished by sequence homology, pharmacology, and second messenger systems), where Group III is the largest group (mGluR4, mGluR6, mGluR7, mGluR8) [Conn and Pin, Annu Rev Pharmacol Toxicol, 1997, 37:205-237]. Group III mGlu receptors are mainly expressed presynaptically (Schoepp, Pharmacol Exp Ther, 2001, 299:12-20), where they regulate glutamatergic as well as GABAergic transmission. Activation of Group III receptors, including mGluR4, reduces neurotransmitter release due to their activation of Gαi / o, thereby attenuating adenylate cyclase activity.

[0005] The mGluR4 receptor is mainly located in the presynaptic terminals of nerve endings. It has been confirmed that mGluR4 is expressed in multiple brain regions, with high expression in brain regions such as the basal ganglia and cerebellum. Due to the expression of mGluR4 in relevant brain circuits and its role in regulating neurotransmitter release, mGluR4 modulators are considered to have an impact on motor control (including Parkinson's disease), impulse control, learning and memory, cognition, anxiety, pain, cerebellar function, epilepsy, and the regulation of excitatory / inhibitory balance, which is crucial for information processing (Marino et al., Ann NY Acad Sci, 2003, 1003:435 - 437; Isherwood et al., Neuropharmacology 2017, 123:249 - 260; Makoff et al., Mol Brain Res, 1996, 37:239 - 248; Davis et al., Neuropharmacology 2013, 66:365 - 372; Iscru et al., Genes Brain Behav. 2013, 12:615 - 625; Szczurowska and PhysiolRes, 2012, 61:619 - 628), but not limited to these effects.

[0006] Since it has been reported that mGluR4 is also expressed in peripheral tissues such as islets of Langerhans, antagonists of mGluR4 function are considered to have therapeutic effects on disorders including but not limited to metabolic disorders, gastrointestinal diseases, and cancer (Chang et al., Clin Cancer Res. 2005, 11:3288 - 3295; Uhera et al., Diabetes 2004, 53:998 - 1006; Nunez - Salces et al., Neurogastroenterol Motil 2020, 32).

[0007] Since it has been reported that mGluR4 is also expressed in vagal afferents as well as in central satiety pathways and brain circuits (but not limited to these), antagonists of mGluR4 function are considered to have therapeutic effects on disorders including but not limited to overweight and obesity (Blackshow et al., Front Neurosci 2011, 5:40; 1 - 7; Page et al., Br JPharmacol. 2012, 166:1537 - 1558).

[0008] WO21028512 describes arylsulfonamides as mGluR4 NAMs. However, the activity of those compounds appears to be too low to be useful as drugs, especially since acidic arylsulfonamides may additionally efflux at the blood-brain barrier, which limits their brain exposure for CNS applications. Detailed Description

[0009] The present invention provides novel substituted dioxane derivatives which are unexpectedly potent negative modulators of mGluR4.

[0010] The compounds of the present invention are potent negative modulators of mGluR4 which inhibit the function of mGluR4, thereby blocking glutamate-induced intracellular cAMP decrease.

[0011] Accordingly, the present invention provides compounds for the treatment of mGluR4-mediated disorders.

[0012] The present invention further provides a method of treating an mGluR4-mediated disorder in a human subject, which comprises administering to the subject a compound of the present invention or a composition of the compound or a pharmaceutically acceptable salt thereof.

[0013] In one aspect, the present invention relates to a method of treating a condition in which a decrease in mGluR4 can alleviate the severity of the condition, by administering a compound that inhibits the function of mGluR4, such as a compound that inhibits glutamate-induced intracellular cAMP decrease as described in the present application. The present application describes the following compounds, which are antagonists of mGluR4 function, with an IC 50 at a concentration of 100 nanomolar, preferably 50 nM or lower.

[0014] In another aspect, the compounds described in the present application as antagonists of mGluR4 function can be used to inhibit the function of mGluR4, such as mGluR4-mediated glutamate-induced intracellular cAMP decrease. In some embodiments, the compounds described in the present application can be used to inhibit mGluR4-mediated glutamate-induced intracellular cAMP decrease in vitro (e.g., in cells in culture medium). In other embodiments, the compounds described in the present application can be used to inhibit mGluR4-mediated glutamate-induced intracellular cAMP decrease in vivo.

[0015] Definitions

[0016] Terms not specifically defined in the present application should be given the meaning that would be ascribed to them by one of ordinary skill in the art in light of the disclosure and the context.

[0017] The terms "negative modulator", "antagonist", and "inhibitor" are used interchangeably to denote a reagent that reduces or inhibits biological activity (e.g., reduces the activity of a receptor), and includes negative allosteric modulators (NAMs). The mGluR4 receptors described in the present application include homomeric and heteromeric structures (e.g., homomeric mGluR4 and heteromeric mGluR4-mGluR2). Inhibitors of mGluR4 function include inhibitors having any combination of the structural and / or functional properties disclosed in the present application.

[0018] For methods of inhibition or treatment of a subject, an "effective amount" of an (mGluR4) antagonist is the amount of antagonist in a formulation that, when administered as part of a desired dosage regimen, produces the desired clinical or functional result. Without being bound by theory, an effective amount of an mGluR4 antagonist for the methods of the present invention includes an amount of an mGluR4 antagonist that effectively reduces one or more in vitro or in vivo functions of the mGluR4 receptor. Exemplary functions include, but are not limited to, altering intracellular cAMP or synaptic neurotransmitter release, or altering neuronal activity, or modulating impulsive behavior. Compounds that antagonize mGluR4 function include compounds that antagonize the in vitro or in vivo functional activity of mGluR4. When a particular functional activity is only readily observable in an in vitro assay, the ability of a compound to inhibit mGluR4 function in that in vitro assay serves as a reasonable indicator of the activity of the compound. In certain embodiments, the effective amount is an amount sufficient to inhibit mGluR4-mediated cellular function.

[0019] The mGluR4 antagonists used in the methods of the present invention can be characterized according to their activity or lack of activity against one or more receptors. When referring to other receptors, inhibition of the function of such other receptors is defined in a similar manner. For example, inhibition of a receptor or receptor activity means that the antagonist inhibits one or more functional activities of another receptor. Such functions include, for example, transmembrane signal transduction and / or changes in the intracellular concentration of intracellular substances (such as cAMP) mediated by a particular receptor and subsequent functions (such as neurotransmitter release).

[0020] The terms "compound" and "reagent" are used interchangeably to denote the negative modulators of the present invention.

[0021] In the groups, radicals or moieties defined below, the number of carbon atoms is usually specified before the group, for example, C1-6 alkyl represents an alkyl group or alkyl radical having 1 to 6 carbon atoms. Generally, for a group containing two or more sub-groups, the last-mentioned sub-group is the group attachment point, for example, the substituent "aryl-C1-3 alkyl-" represents an aryl group bonded to C1-3 alkyl-, and the latter is bonded to the core or to the group to which the substituent is attached.

[0022] If the compounds of the present invention are described in chemical name and chemical formula form, in case of any discrepancy, the chemical formula shall prevail.

[0023] An asterisk may be used in the sub-formula to indicate the bond connecting to the defined core molecule.

[0024] Stereochemistry / Solvate / Hydrate

[0025] The compounds described in this application may be chiral (e.g., having one or more stereocenters). Unless otherwise indicated, all stereoisomers are represented, such as enantiomers and diastereomers. The compounds of the present invention containing asymmetrically substituted carbon atoms can be isolated in optically active form or racemic form. Methods for preparing optically active forms from optically active starting materials are known in the art, for example, by resolution of racemic mixtures or enantioselective synthesis.

[0026] Resolution of the racemic mixture of the compound can be carried out by any of the numerous methods known in the art. An example method includes fractional recrystallization using a "chiral resolving agent", which is an optically active salt-forming organic acid. Resolving agents suitable for the fractional recrystallization method are, for example, optically active acids such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or various optically active camphorsulfonic acids (e.g., β-camphorsulfonic acid). Other resolving agents suitable for the fractional crystallization method include stereochemically pure forms of α-methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine and 1,2-diaminocyclohexane.

[0027] Resolution of the racemic mixture can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoyl-phenylglycine). Suitable elution solvent compositions can be determined by those skilled in the art. The compounds of the present invention also include tautomeric forms, such as keto-enol tautomers.

[0028] Unless otherwise indicated, throughout the specification and the appended claims, a given chemical formula or name shall encompass its tautomers and all stereoisomers, optical isomers and geometric isomers (e.g., enantiomers, diastereomers, E / Z isomers) and racemates, as well as mixtures of individual enantiomers in different proportions, mixtures of diastereomers, or any form of mixtures of the foregoing forms in which such isomers and enantiomers are present.

[0029] Compounds of the present invention may also include all isotopes of atoms that occur in the intermediates or final compounds. For example, compounds of the present invention may be radiolabeled with radioactive isotopes (e.g., tritium ( 3 H) or carbon-14 ( 14 C)). All isotopic variants, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

[0030] Salt

[0031] The phrase "pharmaceutically acceptable" is used in this application to denote those compounds, materials, compositions and / or dosage forms that are suitable for use within the scope of reasonable medical judgment, without undue toxicity, irritation, allergic response, or other problems or complications, and commensurate with a reasonable benefit / risk ratio.

[0032] As used in this application, "pharmaceutically acceptable salt" refers to derivatives of the disclosed compounds in which the parent compound is combined with an acid or a base to form a salt.

[0033] Examples of acids that form pharmaceutically acceptable salts with parent compounds containing a basic moiety include inorganic acids or organic acids, such as benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gentisic acid, hydrobromic acid, hydrochloric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4-methyl-benzenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid and tartaric acid. Also included are salts of amino acids such as arginine, and salts of organic acids such as glucuronic acid or galacturonic acid (see, for example, Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19).

[0034] The neutral form of the compounds of the present invention is preferably regenerated by contacting the salt with a base or an acid and isolating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise, for the purposes of the present invention, the salt is equivalent to the parent form of the compound.

[0035] The terms "mGluR4", "mGluR4 protein", and "mGluR4 receptor" are used interchangeably throughout the application. Unless otherwise stated explicitly, the term mGluR4 includes homomeric structures (e.g., homomeric mGluR4) and heteromeric structures (e.g., heteromeric mGluR4-mGluR2).

[0036] Bioassay

[0037] The biological activity of the compounds was determined by the following methods:

[0038] A. In vitro test of mGluR4 potency

[0039] The in vitro activity of the compounds according to the present invention can be studied as follows:

[0040] HEK293 cells overexpressing the human metabotropic glutamate 4 receptor were thawed at 37 °C and immediately diluted with cell culture medium. After centrifugation, the cell pellet was resuspended in the medium and then dispensed from a stirred spinner flask into the wells of a assay plate. The plate was incubated at room temperature for one hour and then at 37 °C / 5% CO2 for 24 hours. After washing the cells in the plate three times with 80 μL of HBSS / HEPES buffer (10 μL of buffer remained in the wells after washing), the compounds diluted in HBSS / HEPES buffer containing 0.2% BSA (final concentration: 0.1%) and 1 mM IBMX (final concentration: 0.5 mM) were added to the wells of the assay plate at 5 μL / well. Thereafter, L-glutamate (final concentration: 10 μM), forskolin (final concentration: 1 μM), and 1 mM IBMX (final concentration: 0.5 mM) dissolved in HBSS / HEPES buffer containing 0.2% BSA (final concentration: 0.1%) were added to the assay plate at 5 μL / well (final DMSO concentration: 1%). Several wells of the assay plate were used for positive and negative controls or for the cAMP standard curve. The assay plate was incubated at room temperature for 30 minutes. Then, 5 μl / well of the anti-cAMP-antibody-d2 solution and 5 μl / well of the cAMP-europium cryptate dilution were added to all wells of the plate, and the plate was incubated at room temperature in the dark for another 60 minutes. Measured the emission at 615 nm and 665 nm (excitation wavelength: 320 nm) on an EnVision TM Reader (PerkinElmer). Calculate the ratio of the emission at 665 nm to the emission at 615 nm by the reader. The whole assay was carried out in the dark or under green light.

[0041] cAMP standards were prepared by diluting the cAMP stock solution with HBSS / Hepes buffer: The cAMP dilution (in HBSS / Hepes buffer containing 1 mM IBMX and 0.2% BSA - final concentration: 0.5 mM IBMX and 0.1% BSA) was added to the following wells of the assay plate at 5 μl / well, 10 μl / well of HBSS / Hepes buffer plus 5 μl / well of HBSS / Hepes solution containing 4% DMSO with 0.2% BSA (final DMSO concentration: 1% - same as in the wells containing the compound). The final cAMP concentrations in the assay plate were: 0 nM, 0.17 nM, 0.69 nM, 2.78 nM, 11.1 nM, 44.5 nM, 178 nM, and 712 nM (two wells / cAMP concentration).

[0042] Each assay microtiter plate also contained: wells with vehicle control instead of compound, as a control for the L - glutamate - induced signal (negative control; 100% CTL; 10 μM L - glutamate + 1 μM forskolin + 0.5 mM IBMX + 1% DMSO); and wells with vehicle control and no L - glutamate, as a control for non - specific changes in the signal (positive control; 0% CTL; 0 μM L - glutamate + 1 μM forskolin + 0.5 mM IBMX + 1% DMSO).

[0043] Data analysis was performed by calculating the ratio of the emission at 665 nm to the emission at 615 nm (Em665 / Em615 ratio). Subsequently, the signal of the compound was normalized using the positive and negative controls by the following formula:

[0044] PoC = 100×((signal sample - positive control) / (negative control - positive control))

[0045] B. Assessment of metabolic stability in human liver microsomes (human MST)

[0046] The metabolic stability of the compounds according to the present invention can be studied as follows:

[0047] The metabolic degradation of the test compound was determined using pooled human liver microsomes at 37°C. The final incubation volume of 100 μL for each time point contained: TRIS buffer pH 7.6 (0.1 M) at room temperature, MgCl 2(5 mM), microsomal protein (1 mg / mL), and the test compound at a final concentration of 1 μM. After a short pre-incubation period at 37 °C, the reaction was initiated by adding reduced form of β-nicotinamide adenine dinucleotide phosphate (NADPH, 1 mM), and terminated by transferring aliquots to the solvent at different time points. After centrifugation (10,000 g, 5 minutes), the amount of the parent compound in the supernatant aliquots was determined by LC-MS / MS. The half-life (t 1 / 2 ) was determined by the slope of the semi-logarithmic plot of the concentration-time curve.

[0048] C. Assessment of efflux in Madin-Darby canine kidney (MDCK) cells transfected with the human MDR1 gene

[0049] The apparent permeability coefficient (PE) of the compound across the MDCK-MDR1 cell monolayer was measured in the apical-to-basal (AB) and basal-to-apical (BA) transport directions (pH 7.4, 37 °C). AB permeability (PEAB) represents drug absorption from blood to brain, and BA permeability (PEBA) represents drug efflux from brain back to blood, which occurs via both passive permeability and active transport mechanisms mediated by efflux and uptake transporters expressed on MDCK-MDR1 cells, mainly by overexpressed human MDR1 P-gp. Compounds were classified into permeability / absorption categories by comparing the AB permeability of the compound with that of a reference compound with known in vitro permeability and human oral absorption. Similar or identical permeabilities in both transport directions indicate passive permeability, while vectorial permeability indicates additional active transport mechanisms. Higher PEBA than PEAB indicates active efflux mediated by MDR1 P-gp. Active transport can be saturated concentration-dependently.

[0050] MDCK-MDR1 cells (1 - 2×10e 5 cells / 1 cm 2 area) were seeded on filter inserts (Costar transwell polycarbonate or PET filters, 0.4 μm pore size) and cultured (DMEM) for 7 days. Then, MDR1 expression was enhanced by culturing the cells with 5 mM sodium butyrate in complete medium for 2 days. The compound was dissolved in an appropriate solvent (such as DMSO, 1 - 20 mM stock solution). HTP-4 buffer (128.13 mM NaCl, 5.36 mM KCl, 1 mM MgSO 4 , 1.8 mM CaCl2 , 4.17 mM NaHCO 3 , 1.19 mM Na 2 HPO 4 ×7H 2 O, 0.41 mM NaH 2 PO 4 ×H 2 O, 15 mM HEPES, 20 mM glucose, 0.25% BSA, pH 7.4) to dilute the stock solution to prepare the transport solution (0.1 - 300 μM compound, final DMSO ≤ 0.5%). The transport solution (TL) was applied to the apical or basolateral donor side for measuring A - B permeability or B - A permeability, respectively (3 filter membrane replicates). The receptor side contained the same buffer as the donor side. Samples were collected from the donor side at the start and end of the experiment and from the receptor side at different time intervals up to 2 hours for concentration measurement by HPLC - MS / MS or scintillation counting. The sampled receptor volume was replaced with freshly made receptor solution.

[0051] D. Evaluate the efficacy on impulsive behavior tested in the five - choice serial reaction time task (5 - CSRTT) in rats

[0052] The efficacy on motor impulsive behavior can be studied as follows:

[0053] The 5 - CSRTT task training was conducted according to a standard protocol (Isherwood et al., Neuropharmacology 2017, 123:249 - 260). Briefly, rats were trained to nose - poke at the location of a light cue presented at one of 5 positions on the curved wall of an operant chamber (Med Associates Inc, St. Albans, Vermont). If a nose - poke occurred at the illuminated location during or up to 1 second after the stimulus presentation, a sugar pellet was delivered to a reward container located across the chamber. Infrared beams in each choice aperture and the reward container allowed precise detection of the rats during this task - relevant operation. Motor impulsive behavior was defined as a response (premature response) occurring at any nose - poke aperture before the onset of the light cue.

[0054] After achieving stable behavioral performance, a new analytical method was applied that revealed the trait - like (long - term) stability of the number of premature responses made by individual animals over several months. Typically, this analysis enabled animals to be robustly classified into high - impulsive and low - impulsive groups based on a longitudinal assessment of the number of premature responses of the animals during training.

[0055] The experiments were conducted in a crossover manner such that all experimental subjects received the vehicle and the compound simultaneously on different dates, with an approximate 2-week interval between each administration. The order of vehicle and compound administration was randomized within the experimental subjects, while a third group served as a technical control and received atomoxetine on both experimental days.

[0056] As a standardized numerical threshold for the level of impulsivity, animals with >40 and <40 premature responses (out of 200 initiation trials) in the vehicle were labeled as high-impulsive and low-impulsive, respectively. Importantly, this numerical-threshold-based labeling overlapped >80% with the longitudinal analysis of the training data (as described above). This high convergence of the two approaches towards stratification enabled us to make a powerful comparison of compound effects between stable high-impulsive and stable low-impulsive rats in the 5-CSRTT.

[0057] Biological data

[0058] Table 1: In vitro potency of the structurally closest compounds disclosed in WO2019 / 138017 (determined in Assay A)

[0059]

[0060]

[0061] The compounds of the present invention differ structurally from the structurally closest compounds in the prior art (i.e., Examples 8, 12, 125, and Intermediate 250 in WO2019 / 138017) in that the hetero-monocyclic ring to which the formamide is bonded is a pyrazine (6-membered heteroaryl) group, rather than a pyrazole or isoxazole moiety (5-membered heteroaryl). Although the structurally closest compounds disclosed in WO2019 / 138017 are immunomodulators (IL-17 modulators) disclosed in that patent application, the compounds of the present invention are unexpectedly highly potent negative mGluR4 modulators (see Table 2). The structurally closest compounds disclosed in WO2019 / 138017 were tested in Assay A and were found to have no therapeutically relevant activity as mGluR4 modulators (Table 1). Unexpectedly, the compounds of the present invention are >100-fold more potent in Assay A. (Compare the data in Tables 1 and 2).

[0062] Table 2: In vitro potency of the compounds of the present invention determined in Assay A

[0063]

[0064]

[0065]

[0066] For treatment / Method of use

[0067] The present invention relates to compounds for the treatment and / or prevention of diseases, disorders and conditions in which inhibition of mGluR4 activity is therapeutically beneficial, including but not limited to the treatment of psychiatric and neurological conditions associated with impulse control deficits or maladaptive impulsive behavior. Such impulse control deficits are seen in: addiction, including substance use disorders; personality disorders, such as borderline personality disorder, antisocial personality disorder, conduct disorder; eating disorders, such as bulimia nervosa; attention deficit hyperactivity disorder; bipolar disorder; stress-related disorders, such as post-traumatic stress disorder; tic disorders, such as Tourette's syndrome; other movement disorders, such as restless legs syndrome. According to another aspect of the present invention, the compounds of the present invention are used for the treatment of mGluR4-related pathophysiological disorders, cognition, motivated behavior / reward, mood and stress, aggression. Additionally, there is a therapeutic benefit in cancers and related disorders (such as osteosarcoma) associated with maladaptive tumorigenesis. According to another aspect of the present invention, the compounds of the present invention are used for the treatment of metabolic disorders by modulating satiety pathways and / or signaling related to mGluR4 to treat disorders including but not limited to obesity.

[0068] In view of their pharmacological actions, the compounds of the present invention are suitable for the treatment and / or prevention of diseases or conditions selected from the list consisting of:

[0069] (1) Conditions associated with impulse control dysfunction, such as pathological gambling, trichotillomania, intermittent explosive disorder, conduct disorder, antisocial personality disorder, kleptomania, pyromania, compulsive shopping, internet addiction, sexual compulsivity, sexual disorders, sexual dysfunction, sexual psychological disorders, eating disorders (such as bulimia nervosa, binge eating disorder, anorexia nervosa, other specified eating disorders), obesity, overweight, cachexia, appetite / taste disorders, vomiting, nausea, Prader-Willi syndrome, binge eating disorder, appetite / taste disorders, bipolar disorder, post-traumatic stress disorder;

[0070] (2) Substance abuse / dependence / seeking or addiction and relapse prevention (including but not limited to drugs, such as cocaine, opioid drugs such as morphine, barbiturates, benzodiazepines, amphetamines, nicotine / tobacco and other psychostimulants), alcoholism and alcohol-related disorders, drug abuse or addiction or relapse, tolerance to anesthetics or anesthetic withdrawal;

[0071] ​(3) Psychiatric and neurological conditions, such as attention deficit hyperactivity disorder, conduct disorder, attention problems and related disorders, sleep disorders, anxiety disorders (e.g., generalized anxiety disorder), panic disorder, phobias, post-traumatic stress disorder, schizophrenia, Alzheimer's disease, Parkinson's disease, Huntington's disease, and Gilles de la Tourette syndrome, restless legs syndrome, dementia, movement disorders, severe mental retardation, neurodegenerative diseases, including disease entities such as disinhibition-dementia-parkinsonism-amyotrophy complex, pallido-pontine-nigral degeneration, mood disorders, bipolar disorder, mania, depression, manic-depressive disorder, borderline personality disorder, antisocial personality disorder, aggression (e.g., impulsive aggression), suicidal tendencies, frontotemporal dementia, obsessive-compulsive disorder, delirium, affective neurosis / disorder, depressive neurosis / disorder, anxiety neurosis, dysthymic disorder, neurological diseases, such as cerebral edema and angioedema, brain dementia such as Parkinson's disease and Alzheimer's disease, senile dementia; multiple sclerosis, epilepsy, temporal lobe epilepsy, drug-resistant epilepsy, seizures, stroke, myasthenia gravis, brain and meninges infections (such as encephalomyelitis, meningitis), HIV, and schizophrenia, delusional disorder, autism, affective disorder, and tic disorders, including but not limited to Tourette syndrome, and other movement disorders, epilepsia, chronic pain;

[0072] (4) Cognitive dysfunction in psychiatric or neurological disorders, cognitive impairment associated with schizophrenia, Alzheimer's disease, and other neurological and psychiatric disorders;

[0073] (5) Personality disorders, such as borderline personality disorder, antisocial personality disorder, paranoid personality disorder, schizotypal and schizoid personality disorders, histrionic personality disorder, narcissistic personality disorder, avoidant personality disorder, dependent personality disorder, other specified and unspecified personality disorders;

[0074] (6) Sleep disorders, such as narcolepsy, jet lag, sleep apnea, insomnia, parasomnia, circadian and diurnal rhythm disorders, sleep disturbances associated with psychiatric and neurological disorders;

[0075] (7) Non-neuronal conditions, including metabolic conditions such as diabetes, insulin resistance, metabolic syndrome, overweight, obesity, and for weight loss, cosmetic weight loss, prevention of relapse during or after obesity treatment, weight maintenance, vomiting, disorders associated with cardiovascular-vascular system dysfunction, and conditions associated with maladaptive blood pressure control (such as hypertension or hypotension);

[0076] (8) Cancers and related disorders associated with maladaptive tumorigenesis, such as osteosarcoma, breast cancer, ependymoma, bladder cancer, colorectal cancer.

[0077] The applicable daily dose of the compounds of the present invention can be from 0.1 mg to 2000 mg.

[0078] The actual pharmaceutically effective amount or therapeutic dose will depend on factors known to those skilled in the art, such as the age and weight of the patient, the route of administration, and the severity of the disease. In any case, the dosage and mode of administration of the drug substance are allowed to deliver a pharmaceutically effective amount suitable for the patient's condition.

[0079] Combination therapy

[0080] The compounds according to the present invention can be combined with other treatment options known in the art that can be used in the treatment of any indication of interest in the treatment of the present invention.

[0081] Such active pharmaceutical ingredients or treatment options considered suitable for combination with the compounds and treatments according to the present invention include antidepressants, mood stabilizers, typical and atypical antipsychotics, anxiolytics, antiepileptic drugs, antiparkinsonian drugs, sleeping pills, cognitive enhancers, stimulants, drugs for attention deficit hyperactivity disorder, other psychoactive drugs, anti-inflammatory drugs, analgesics, chemotherapeutic drugs, and combinations with treatment options for metabolic disorders, liver diseases, and kidney diseases.

[0082] Experimental section

[0083] List of abbreviations:

[0084] % Sol Solvent percentage, solvent %

[0085] μL Microliter

[0086] ACN Acetonitrile

[0087] AcOH Acetic acid

[0088] aq. Aqueous solution

[0089] Boc tert-Butoxycarbonyl

[0090] Boc 2 O Di-tert-butyl dicarbonate

[0091] chir. chiral

[0092] CIP 2-Chloro-1,3-dimethyl-2-imidazolinium hexafluorophosphate

[0093] conc. concentrated

[0094] d dextro-

[0095] DA Diode array

[0096] DAD Diode array detector

[0097] DCM Dichloromethane

[0098] DMF N,N-Dimethylformamide

[0099] ELSD Evaporative light scattering detector

[0100] EtOAc Ethyl acetate

[0101] ETOH Ethanol

[0102] g gram

[0103] h hour

[0104] half-conc. semi-concentrated

[0105] HPLC High performance liquid chromatography

[0106] i.vac. in vacuo

[0107] IPA Isopropyl alcohol

[0108] M Molarity

[0109] MeOH Methanol

[0110] MEOH Methanol

[0111] mg milligram

[0112] min minute

[0113] ml milliliter

[0114] mL milliliter

[0115] MS Mass spectrometer

[0116] N Normality

[0117] NBS N-Bromo-succinimide

[0118] NMM N-Methyl-morpholine

[0119] NMP N-Methylpyrrolidone

[0120] PE Petroleum ether

[0121] PPA 1-Phosphonopropane cyclic anhydride

[0122] prep. Preparative

[0123] PSI Pound per square inch

[0124] quant. Quantitative

[0125] Rf Retarding front

[0126] RT Retention time

[0127] sat. Saturated

[0128] scCO2 Supercritical carbon dioxide

[0129] SFC Supercritical fluid chromatography

[0130] TBTU O-(Benzotriazol-1-yl)-N,N,N,N-tetramethyl Tetrafluoroborate

[0131] TEA Triethylamine

[0132] Temp. Temperature

[0133] tert. Tertiary

[0134] TFA Trifluoroacetic acid

[0135] THF Tetrahydrofuran

[0136] wt Weight

[0137] X-Phos G1 Chloro-(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)-phenyl)]-palladium(II)

[0138] Method:

[0139] HPLC-MS Method:

[0140] Method A

[0141]

[0142] Method B

[0143]

[0144] Method C

[0145]

[0146]

[0147] Chiral SFC analysis method: Method 1:

[0148]

[0149] Method 2:

[0150]

[0151] Method 3:

[0152]

[0153]

[0154] Method 4:

[0155]

[0156] Method 5:

[0157]

[0158] Method 6:

[0159]

[0160] Method 7:

[0161]

[0162] Method 8:

[0163]

[0164] Method 9:

[0165]

[0166] Method 10:

[0167]

[0168] Method 11:

[0169]

[0170] Method 12:

[0171]

[0172] Method 13:

[0173]

[0174] Method 14:

[0175]

[0176] Method 15:

[0177]

[0178] Method 16:

[0179]

[0180]

[0181] Method 17:

[0182]

[0183] Method 18:

[0184]

[0185] Method 19:

[0186]

[0187] Method 20:

[0188]

[0189]

[0190] Method 21:

[0191]

[0192] Method 22:

[0193]

[0194] Method 23:

[0195]

[0196] Method 24:

[0197]

[0198]

[0199] Method 25:

[0200]

[0201] Method 26:

[0202]

[0203] Method 27:

[0204]

[0205] Method 28:

[0206]

[0207] Method 29:

[0208]

[0209] Method 30:

[0210]

[0211] Method 31:

[0212]

[0213] Method 32:

[0214]

[0215] Method 33:

[0216]

[0217] Method 34:

[0218]

[0219] Method 35:

[0220]

[0221] Method 36:

[0222]

[0223] Method 37:

[0224]

[0225]

[0226] Method 38:

[0227]

[0228] Method 39:

[0229]

[0230] Method 40:

[0231]

[0232] Method 41:

[0233]

[0234]

[0235] Method 42:

[0236]

[0237] Method 43

[0238]

[0239] Method 44:

[0240]

[0241] Method 45:

[0242]

[0243]

[0244] Method 46:

[0245]

[0246] Method 47:

[0247]

[0248] Method 48:

[0249]

[0250] Method 49:

[0251]

[0252]

[0253] Method 50:

[0254]

[0255] Method 51:

[0256]

[0257] Method 52:

[0258]

[0259] Method 53:

[0260]

[0261] Method 54:

[0262]

[0263]

[0264] Method 55:

[0265]

[0266] Method 56:

[0267]

[0268] Method 57:

[0269]

[0270] Method 58:

[0271]

[0272]

[0273] Method 59:

[0274]

[0275] Method 60:

[0276]

[0277] Method 61:

[0278]

[0279] Method 62:

[0280]

[0281]

[0282] Method 63:

[0283]

[0284] Method 64:

[0285]

[0286] Method 65:

[0287]

[0288] Method 63:

[0289]

[0290] Method 64:

[0291]

[0292] Method 65:

[0293]

[0294] Method 66:

[0295]

[0296] Method 67:

[0297]

[0298] Method 68:

[0299]

[0300]

[0301] Method 69:

[0302]

[0303] Method 70:

[0304]

[0305] Method 71

[0306]

[0307] Method 72

[0308]

[0309]

[0310] Method 73

[0311]

[0312] Method 74

[0313]

[0314] Method 75

[0315]

[0316] Method 76

[0317]

[0318] Method 77

[0319]

[0320] Method 78

[0321]

[0322] Method 79

[0323]

[0324] Method 80

[0325]

[0326] Method 81

[0327]

[0328]

[0329] Method 82

[0330]

[0331] Method 83

[0332]

[0333] Method 84

[0334]

[0335] Method 85

[0336]

[0337]

[0338] Method 86

[0339]

[0340] Method 87

[0341]

[0342] Method 88

[0343]

[0344] Method 89

[0345]

[0346] Method 90

[0347]

[0348] NMR method: The NMR spectra were recorded on a Bruker AVANCE III HD 400 MHz instrument using TopSpin 3.2 pl6 software. Chemical shifts are given in parts per million (ppm) downfield from an internal reference (such as trimethylsilane and / or water and / or solvent (e.g., d6-DMSO)), in units of δ. The selected data were reported as follows: chemical shift (multiplet, coupling constant (J), number of hydrogens). Abbreviations are as follows: s (singlet), d (doublet), t (triplet), q (quartet), spt (septet), m (multiplet), br (broad peak).

[0349] Example

[0350] Example 1:

[0351]

[0352] Step 1:

[0353] Sodium (0.95 g, 41.2 mmol) was placed into 80 mL of EtOH, and the mixture was cooled to no more than 35 °C and stirred for 45 minutes. N1-Methyl-4-(trifluoromethyl)-benzene-1,2-diamine (2.50 g, 12.9 mmol) and ethyl diethoxyacetate (4.15 mL, 23.2 mmol) in 20 mL of EtOH were added, and the mixture was heated to reflux and maintained for 20 hours. Then, 200 mL of saturated NH 4 Cl aqueous solution was added, the mixture was concentrated in vacuo, the residue was diluted with 250 mL of water and extracted with ethyl acetate. The combined organic layers were dried over MgSO 4 and concentrated in vacuo. The residue was dissolved (take up) in THF / MeOH and purified by column chromatography (XBridge C18, 10 μm, eluent gradient: (H 2 O + 0.15% NH 3 ): ACN: 56:44 -> 36:64). The fractions containing the product were combined and lyophilized. The solid was dissolved in DCM and concentrated in vacuo.

[0354] Yield: 1.78 g (5.89 mmol; 46%) Int-1a

[0355] MS (ESI+ ):(M+H) + 303; HPLC: RT = 1.05 minutes, method: Z011_S03

[0356] Step 2:

[0357] A mixture of Int-1a (12.8 g, 42.3 mmol) and hydrochloric acid (4N; 128 mL, 512 mmol) in dioxane was stirred and heated to reflux for 1.5 hours. Heating was removed, and the mixture was poured into a mixture of 800 mL of water and 500 mL of saturated NaHCO 3 aqueous solution. The mixture was stirred for 5 minutes and filtered. The solid was washed with water and dried in vacuo. The residue was dissolved in n-butyl acetate and concentrated in vacuo.

[0358] Yield: 9.33 g (40.1 mmol; 95%) of Int-1b

[0359] MS (ESI + ):(M+H) + 229; HPLC: RT = 0.88 minutes, method: Z011_S03

[0360] Step 3:

[0361] Int-1b (23.2 g, 99.6 mmol), (S)-(-)-2-methyl-2-propanesulfinamide (13.3 g, 105 mmol) and Cs 2 CO 3 (42.2 g, 130 mmol) in 370 mL of DCM were stirred under reflux for 1.25 hours. Then heating was removed, MgSO 4 was added, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in DCM and diisopropyl ether and concentrated in vacuo. The solid formed was filtered and collected. The filtrate was further concentrated in vacuo, and the residue was purified by column chromatography (silica gel; eluent gradient: petroleum ether:EtOAc: 80:20 -> 45:55). The fractions containing the product were combined and concentrated in vacuo. The residue was combined with the solid collected.

[0362] Yield: 31.6 g (95.4 mmol; 96%) of Int-1c

[0363] MS (ESI + ):(M+H) + 332; HPLC: RT = 1.07 minutes, method: Z018_S04

[0364] Chiral SFC Rt 4.27 min (Method: I_SA_10_IPA_NH3_003)

[0365] Step 4:

[0366] Under an argon atmosphere and in an additionally dried glassware, 1,4-dioxane (17.18 mL, 211.25 mmol) in 150 mL of THF was cooled to -35 °C, and n-hexyllithium (2.45 N in hexane; 76.98 mL, 188.52 mmol) was added while maintaining the temperature below -30 °C. Then the cooling was removed and the mixture was allowed to warm to 20 °C. The mixture was immediately cooled to 0 °C and stirred at this temperature for 30 minutes. Then the mixture was cooled to -65 °C and added to a mixture of Int-1c (50 g, 150.89 mmol) in 500 mL of THF in an additionally dried glassware under argon at -75 °C in such a way that the temperature of the mixture was kept below -70 °C. Then the mixture was stirred at -70 °C for 20 minutes. Then the mixture was poured into 650 mL of saturated NH 4 Cl aqueous solution. tert-Butyl methyl ether (650 ml) was added and the mixture was warmed to room temperature with stirring. The aqueous layer was extracted with tert-butyl methyl ether, and the combined organic layers were washed with brine, dried over MgSO 4 and concentrated in vacuo. EtOAc (70 ml) was added to the residue. The mixture was filtered and washed with EtOAc, and the solid was collected. The resulting product contained only one stereoisomer.

[0367] Yield: 38.5 g (92 mmol; 61%) of Int-1d. Chiral SFC Rt 5.38 min (Method: I_IH_15_IPA_NH3_003)

[0368] Step 5:

[0369] To Int-1d (15.4 g, approximately 90%, 33.2 mmol) in 347 mL of MeOH at 10 °C was added hydrogen chloride (4 N, 18.3 mL, 73.0 mmol) in dioxane. After 5 minutes, the cooling was removed and the mixture was stirred at ambient temperature for 22 hours. Then concentrated NH 3 aqueous solution was added to adjust the pH to 7.5, and the mixture was concentrated in vacuo. The residue was adjusted to pH 8 by adding concentrated NH 3 aqueous solution, 300 mL of water was added and the mixture was extracted with DCM. The aqueous layer was adjusted to pH 10 by adding Na 2 CO 2 solution (aqueous solution, 2 N) and extracted with EtOAc. The organic layer was washed with water, combined, dried over MgSO 4 and concentrated in vacuo.

[0370] Yield: 12.4 g (content about 75%; 29.8 mmol; 90%) Int-1e

[0371] MS (ESI + ): (M+H) + 314; HPLC: RT = 0.87 min, method: Z011_S03

[0372] Chiral SFC Rt 3.51 min (method: I_IG_20_IPA_NH3_003)

[0373] Step 6:

[0374] Add Boc 2 O (8.3 g, 38.0 mmol) to Int-1e (12.4 g, about 75%, 29.8 mmol) in 250 mL of DCM containing TEA (8.8 mL, 63.3 mmol). Stir the mixture at ambient temperature for 15.5 h. Wash the organic layer with water, dry over MgSO 4 and concentrate in vacuo. Then purify it by chromatography (silica gel, eluent gradient: petroleum ether:EtOAc 75:25 -> 45:55). Combine the fractions containing the product and concentrate in vacuo.

[0375] Yield: 9.82 g (23.7 mmol; 75%) Int-1f. MS (ESI + ): (M+H) + 414 Chiral SFC Rt 4.64 min (method: I_IG_10_IPA_NH3_003)

[0376] Step 7:

[0377] Mix Int-1f (8.8 g, 21.3 mmol) in 300 mL of THF with palladium on carbon (10%, 1.3 g). Hydrogenate the mixture at 60 psi in a hydrogen atmosphere for 22 h, then add palladium on carbon (10%, 1 g) and continue hydrogenation for 5 h, then add palladium on carbon (10%, 0.5 g) and continue hydrogenation for 3 h. Let the mixture stand overnight, then filter and concentrate in vacuo. Obtain the product as a mixture of stereoisomers, which is used further without separation. Only the major isomer is depicted in the synthetic scheme. Yield: 8.76 g (21.1 mmol; 99%) Int-1g

[0378] MS (ESI + ): (M+H) + 416; HPLC: RT = 1.04 min, method: Z011_S03

[0379] Stereoisomer 1: Chiral SFC Rt 2.69 min (Method: I_IG_10_IPA_NH3_003)

[0380] Stereoisomer 2: Chiral SFC Rt 3.33 min (Method: I_IG_10_IPA_NH3_003)

[0381] Step 8:

[0382] At 5 °C, TFA (14.3 mL, 186 mmol) was added to Int-1g (7.7 g, 18.7 mmol) in 65 mL of DCM. The cooling was removed and the mixture was stirred at ambient temperature for 3.8 h. 150 g of ice was added and the mixture was adjusted to pH ~10 by addition of concentrated NH 3 aqueous solution. The aqueous layer was extracted with DCM and the combined organic layers were dried over MgSO 4 and concentrated in vacuo.

[0383] Yield: 5.92 g (18.7 mmol; quantitative) Int-1h

[0384] Chiral SFC Rt 2.57 min (Method: I_SA_10_MEOH_NH3_003)

[0385] Step 9:

[0386] To a mixture of Int-1h (5.9 g, 18.7 mmol) and NMM (5.1 mL, 46.8 mmol) in 59 mL of EtOAc was added 5-methylpyrazine-2-carboxylic acid (3.2 g, 22.6 mmol) and the mixture was cooled to 0 °C with stirring. Then PPA (50% in EtOAc; 14.5 mL, 24.3 mmol) was added dropwise while maintaining the temperature below 10 °C. After 5 min the cooling was removed and the mixture was stirred at ambient temperature for 75 min. Water was added and the mixture was adjusted to pH 9 by addition of NMM. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with semi-concentrated brine, charcoal was added, stirred and dried over MgSO 4 After filtration, the mixture was concentrated in vacuo, the residue was dissolved in EtOAc and purified via chromatography (silica gel, eluent: EtOAc:EtOH 97:3). The fractions containing the product were combined and concentrated in vacuo. The product was obtained as a mixture of two stereoisomers and was purified by chiral SFC.

[0387] Yield: 4.05 g (9.30 mmol) of Example 1 and 0.71 g (1.63 mmol) of Example 1-1

[0388]

[0389]

[0390] Example 2:

[0391]

[0392] Step 1:

[0393] To Int-3b (1.30 g, 4.4 mmol) in 30 mL of ACN and 10 mL of water was added cerium(IV)-ammonium nitrate (3.62 g, 6.6 mmol), and the mixture was stirred at ambient temperature for 3 h. Then, the mixture was concentrated in vacuo, and the residue was dissolved in water and extracted with EtOAc. The combined organic layers were dried over Na 2 SO 4 and concentrated in vacuo. The residue was dissolved in 3 mL of THF and 10 mL of TEA, Boc 2 O (3.48 g, 6.4 mmol) was added, and the mixture was stirred at ambient temperature for 3 h. Then, the mixture was concentrated in vacuo.

[0394] Yield: 0.80 g (2.8 mmol; 63%) of Int-2a

[0395] MS (ESI + ): (M+H) + 290

[0396] Step 2:

[0397] LiOH (0.10 g, 4.2 mmol) was added to Int-2a (0.80 g, 2.8 mmol) in 10 mL of MeOH and 3 mL of water, and the mixture was stirred at ambient temperature for 3 h. Then the mixture was concentrated in vacuo and purified by preparative HPLC.

[0398] Yield: 0.60 g (2.3 mmol, 82%) of Int-2b, as a mixture of stereoisomers

[0399] MS (ESI + ): (M+H) + 262

[0400] Step 3:

[0401] In the presence of K 2 CO 3A mixture of 1,4-difluoro-2-nitrobenzene (100 g; 0.63 mol) and 2,2-difluoroethylamine (266 mL; 3.8 mol) in 800 mL of ACN (400 g; 1.3 mol) was stirred at 80 °C for 2 days. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was used without further purification.

[0402] R f : 0.4 (PE / EtOAc 85:15)

[0403] Yield: 105 g (0.48 mol; 76%) Int-2c

[0404] MS (ESI + ): (M+H) + 221; HPLC: RT = 1.00 min, method: Z018_S04

[0405] Step 4:

[0406] A mixture of Int-2c (50 g, 0.23 mol) in 500 mL of MeOH and 10 g of Raney-nickel was hydrogenated at ambient temperature at 50 psi (hydrogen) for 4 h. Then, the mixture was filtered, washed with EtOAc and concentrated in vacuo. The residue was used without further purification.

[0407] R f : 0.4 (PE / EtOAc 85:15)

[0408] Yield: 45 g (0.22 mol; 98%) Int-2d

[0409] MS (ESI + ): (M+H) + 191; HPLC: RT = 0.71 min, method: Z018_S04

[0410] Step 5:

[0411] At 0 °C, PPA (50% in EtOAc; 1.3 mL, 2.2 mmol) was added to a mixture of Int-2d (280 mg, 1.4 mmol), Int-2b (377 mg, 1.4 mmol) and NMM (0.95 mL, 8.7 mmol) in 3 mL of DCM. After stirring at 0 °C for 2 h, the mixture was concentrated in vacuo. Then 2.1 g of acetic acid was added and the mixture was stirred at 50 °C for 8 days. The mixture was concentrated in vacuo. The mixture contained four stereoisomers, which were separated into two pairs of enantiomers by preparative HPLC (C-18 Sunfire 10 μm, eluent gradient (water + 0.15% TFA): ACN 64:36 -> 44:56). The fractions containing the product were combined and lyophilized. Only one pair of enantiomers (Int-2e) was used in step 6, which is depicted in the reaction scheme.

[0412] Stereoisomer pair 1: Int-2e as a mixture of enantiomers: Yield: 119 mg (0.29 mmol; 20%)

[0413] MS (ESI + ): (M+H) + 416; HPLC: RT = 0.98 min, method: Z018_S04

[0414] Stereoisomer pair 2, as a mixture of enantiomers: Yield: 104 mg (0.25 mmol; 17%)

[0415] MS (ESI + ): (M+H) + 416; HPLC: RT = 0.97 min, method: Z018_S04

[0416] Step 6:

[0417] Int-2e (119 mg, 0.29 mmol) was stirred in HCl (4N; 3.0 mL, 12 mmol) in dioxane at ambient temperature for 2 h. The mixture was concentrated in vacuo.

[0418] Yield: 111 mg (0.29 mmol; quantitative) Int-2f as a mixture of enantiomers

[0419] MS (ESI + ):(M+H) + 316

[0420] Step 7:

[0421] Stir a mixture of Int-2f (111 mg, 0.29 mmol), 5-methyl-pyrazine-2-carboxylic acid (39 mg, 0.29 mmol), and NMM (189 μL, 1.7 mmol) in 3.5 mL of DCM at 0 °C. Add PPA (50% in EtOAc; 0.3 mL, 0.5 mmol), and stir the mixture at 0 °C for 1 h. Concentrate the mixture in vacuo, dissolve it in ACN, filter, and purify the filtrate by preparative HPLC (C-18 X-Bridge 10 μm, eluent gradient (water + 0.15% NH 3 ): ACN 71:29 -> 51:49). Combine the fractions containing the product and lyophilize. Then perform chiral SFC to obtain the desired enantiomers (Example 2 and 2-1).

[0422] Yield: 28 mg of Example 2 and 25 mg of Example 2-1

[0423]

[0424]

[0425] Example 3:

[0426]

[0427] Step 1:

[0428] Stir a mixture of 4-methoxy-aniline (10 g, 81 mmol), glyoxylic acid ethyl ester in polymeric form (47% in toluene, 17 mL, 81 mmol), and MgSO 4 (24 g, 203 mmol) in 125 mL of DCM at 40 °C for 3 h. Filter the mixture and evaporate the filtrate at 25 °C. Use the residue without further purification. Yield: 20.8 g (approx. 80% content; 81 mol; quantitative) Int-3a

[0429] MS (ESI + ): (M+H) + 208; HPLC: RT = 0.90 min, method: Z011_S03

[0430] Step 2:

[0431] Degas Int-3a (21 g, 80% content, 81 mmol) in 150 mL of dioxane (without stabilizer) and keep under nitrogen. Add copper(II) chloride (0.54 g, 4 mmol) and tert-butyl hydroperoxide (5.5 M in decane; 17.5 mL, 96 mmol), and stir the mixture at 50 °C for 16 h. Concentrate the mixture in vacuo and purify by flash column chromatography (silica gel, PE / EtOAc gradient 9:1 -> 4:1, then 7:3, then 4:1, combining the fractions containing the product and concentrating in vacuo before each next purification).

[0432] Yield: 6.4 g (22 mmol; 27%) of Int-3b as a mixture of stereoisomers

[0433] MS (ESI + ): (M+H) + 296; HPLC: RT = 0.90 min, method: Z011_S03

[0434] Step 3

[0435] Stir Int-3b (300 mg, 1.02 mmol) in 10 mL of CAN and 3 mL of water together with ammonium cerium(IV) nitrate (835 mg, 1.6 mmol) at ambient temperature for 3 h. Then, filter the mixture and concentrate in vacuo.

[0436] Yield: 300 mg (purity: ca. 33%; 0.53 mmol; 52%) of Int-3c as a mixture of stereoisomers

[0437] MS (ESI + ): (M+H) + 190; TLC: Rf = 0.5 (eluent: DCM:MeOH 95:5)

[0438] Step 4:

[0439] Add Boc-anhydride (5.2 g; 24 mmol) to a mixture of Int-3c (3.0 g; 16 mmol) and TEA (8.0 g; 79 mmol) in 15 mL of THF, stir the mixture at ambient temperature for 18 h, then concentrate in vacuo and purify via silica gel column chromatography (eluent gradient: hexane:EtOAc 100:0 -> 60:40).

[0440] Yield: 1.0 g (purity: ca. 65%; 2.2 mmol; 9%) of Int-3d as a mixture of stereoisomers

[0441] MS (ESI + ): (M+H)+ 234; TLC: Rf = 0.5 (eluent: hexane:EtOAc 7:3)

[0442] Step 5:

[0443] LiOH (100 mg; 4.2 mmol) was added to Int-3d (0.8 g, 2.8 mmol) in 10 mL of MeOH and 3 mL of water. The mixture was stirred at ambient temperature for 3 h, concentrated in vacuo, and purified by preparative HPLC.

[0444] Yield: 0.5 g (1.9 mmol; 68%) of Int-3e as a mixture of stereoisomers

[0445] MS (ESI + ): (M+H) + 262; TLC: Rf = 0.5 (eluent: DCM:MeOH 95:5)

[0446] Step 6:

[0447] Ethylamine (2 M in THF; 15.7 mL, 31.4 mmol) was added to 1-fluoro-2-nitro-4-trifluoromethyl-benzene (2.2 mL; 15.7 mmol) in 100 mL of DCM. The mixture was stirred at ambient temperature for 20 h. 100 mL of DCM was added and the mixture was extracted with 100 mL of water. The organic layer was collected, dried over Na 2 SO 4 dried, filtered and concentrated in vacuo.

[0448] Yield: 3.30 g (14.1 mmol; 90%) of Int-3f

[0449] MS (ESI + ): (M+H) + 235; HPLC: RT = 1.10 min, method: Z017_S04

[0450] Step 7:

[0451] Int-3f (200 mg, 0.85 mmol) was mixed with palladium on carbon (10%, 50 mg) in 20 mL of MeOH and hydrogenated at 50 psi hydrogen pressure for 3.5 h. The mixture was then filtered and concentrated in vacuo.

[0452] Yield: 170 mg (0.83 mol; 97%) of Int-3g

[0453] MS (ESI + ): (M+H) +205; HPLC: RT = 0.86 min, method: Z018_S04

[0454] Step 8:

[0455] Int-3e (210 mg, 0.80 mmol), Int-3g (170 mg, 0.83 mmol) in 5 mL DCM and 350 μL NMM were stirred at ambient temperature, and PPA (50% in EtOAc; 600 μL, 1.0 mmol) was added. After stirring at ambient temperature for 16 h, water was added and the mixture was stirred at ambient temperature for 20 min. Then 5 mL AcOH was added and the mixture was stirred at 50 °C for 3 h, at ambient temperature for 16 h, and at 80 °C for 2 h. The mixture contained four stereoisomers, which were separated into two pairs of enantiomers by HPLC (at 50 °C, C-18 Sunfire, eluent gradient (water + 0.15% TFA): ACN 58:42 -> 38:62). The fractions containing the product were combined and lyophilized. Only one pair of enantiomers (Int-60h) was used in Step 9, which is depicted in the reaction scheme.

[0456] Stereoisomer pair 1: Yield: 70 mg (0.13 mmol; 16%) as a mixture of enantiomers of Int-3h

[0457] MS (ESI + ): (M+H) + 430; HPLC: RT = 1.03 min, method: Z018_S04

[0458] Stereoisomer pair 2: Yield: 120 mg, as a mixture of enantiomers

[0459] MS (ESI + ) : (M+H) + 430; HPLC: RT = 1.04 min, method: Z018_S04

[0460] Step 9:

[0461] Int-3h (70 mg, 0.13 mmol) in 4 mL hydrochloric acid (4 M in dioxane) was stirred at ambient temperature for 1 h. The mixture was concentrated in vacuo.

[0462] Yield: 52 mg (0.13 mmol; quantitative) as a mixture of enantiomers of Int-3i

[0463] MS (ESI + ) : (M+H) + 330; HPLC: RT = 0.77 min, method: Z018_S04

[0464] Step 10:

[0465] A mixture of Int-3i (52 mg, 0.13 mmol), 5-methyl-pyrazine-2-carboxylic acid (22 mg, 0.16 mmol), TBTU (44 mg, 0.14 mmol) and TEA (100 μL, 0.72 mmol) in 4.0 mL of DMF was stirred at ambient temperature for 15 minutes. Water was added and the mixture was purified by preparative HPLC (at 50 °C, C-18 X-Bridge, eluent gradient (water + 0.15% NH 3 ): ACN 61:39 -> 41:59). The fractions containing the product were combined and lyophilized. Then chiral SFC was performed to obtain the desired stereoisomer.

[0466] Yield: 15 mg (0.033 mol; 36%) Example 3

[0467]

[0468]

[0469] Examples 4 and 5:

[0470] Similar to Example 1 (see below), using 4-chloro-1-fluoro-2-nitrobenzene as the starting material and except for Step 7, the following compounds were obtained:

[0471] (Example 1)

[0472]

[0473] Examples 4 and 5:

[0474]

[0475] Step 7:

[0476] A mixture of Int-4f (2.9 g, 6.75 mmol) and Wilkinson's catalyst (950 mg, 1.03 mmol) in ethanol (145 ml) was hydrogenated under a hydrogen atmosphere at 40 psi and 40 °C for 22 hours. The mixture was filtered and concentrated in vacuo. The residue was dissolved in THF / MeOH and purified by column chromatography (XBridge C18, 10 μm, eluent gradient: (H2O + 0.1% NH4OH): 58:42 -> 38:62 I). The fractions containing the product were combined and concentrated in vacuo. The product was separated as a mixture of stereoisomers and used as such in the following step.

[0477] Yield: 2.05 g (4.74 mmol; 70.4%) Int-4g

[0478] MS (ESI + ): (M+H) + 432; HPLC: RT = 1.03 minutes, method: Z011_S03

[0479] Chiral SFC Rt stereoisomer 1: 0.66 minutes (method: I_AC_10_IPA_NH3_002)

[0480] Chiral SFC Rt stereoisomer 2: 0.86 minutes (method: I_AC_10_IPA_NH3_002)

[0481] Step 8:

[0482] Synthesis was carried out from Inter-4g similar to Step 8 of Example 1 to obtain the title compound as a mixture of stereoisomers, which was used as such in the next step.

[0483] Yield: 1.18 g (3.56 mmol; 76.8%) Int-4h

[0484] MS (ESI + ): (M+H) + 332; HPLC: RT = 0.84 minutes, method: Z011_S03

[0485] Chiral SFC Rt diastereomer 1: 1.23 minutes (method: I_IG_20_MEOH_NH3_002)

[0486] Chiral SFC Rt diastereomer 2: 1.56 minutes (method: I_IG_20_MEOH_NH3_002)

[0487] Step 9:

[0488] Synthesis was carried out from Int-4h similar to Step 9 of Example 1 to obtain Examples 4 and 5 as a mixture of stereoisomers, which were separated by chiral SFC.

[0489] Yield: 1.18 g (3.56 mmol; 76.8%) Examples 4 and 5

[0490] MS (ESI + ): (M+H) + 332; HPLC: RT = 0.84 minutes, method: Z011_S03

[0491]

[0492]

[0493] Similar to Example 1, using 2-fluoro-1-nitro-4-(trifluoromethyl)benzene as the starting material, the following compound was obtained. The product is a mixture of two stereoisomers. One stereoisomer was isolated: Example 6

[0494]

[0495]

[0496] Similar to Example 1, using 2-fluoro-1-nitro-4-(trifluoromethyl)benzene as the starting material, the following compound was obtained. The product is a mixture of two stereoisomers separated by chiral SFC: Example 7, Example 7-1

[0497]

[0498]

[0499] Similar to Example 1, using 2,4-difluoro-1-nitrobenzene as the starting material, the following compound was obtained. The product is a mixture of two stereoisomers separated by chiral SFC: Example 8, Example 8-1

[0500]

[0501]

[0502] Similar to Example 1, using 1,2,4-trifluoro-5-nitrobenzene as the starting material, the following compound was obtained. The product is a mixture of two stereoisomers separated by chiral SFC: Example 9, Example 9-1

[0503]

[0504]

[0505] Examples 10 and 11:

[0506] Similar to Example 1 (see below) except for step 8, the following compound was obtained. In step 8, the product consisting of 2 stereoisomers was purified by crystallization to obtain a single stereoisomer.

[0507] (Synthesis of Example 1)

[0508]

[0509] Examples 10 and 11:

[0510]

[0511] Intermediate 10g was synthesized in a similar manner to Intermediate 1g using 1,4-difluoro-2-nitrobenzene as the starting material.

[0512]

[0513] Step 8:

[0514] TFA (5.083 ml, 65.88 mmol) was added to Int-10g (2.5 g, 6.589 mmol) in 30 ml of DCM at 5 °C. The cooling was removed and the mixture was stirred at ambient temperature for 6.5 h. DCM (50 ml) was added to the mixture, followed by water (150 ml). The organic phase was extracted twice with water (100 ml). The combined aqueous phases were adjusted to pH ca. 10 by adding concentrated NH 3 aqueous solution. The aqueous layer was extracted with ethyl acetate (250 ml). The combined organic layers were dried over MgSO 4 and concentrated in vacuo. Ethanol (11.75 ml) and water (0.62 ml) were added to the residue (1.67 g). The mixture was heated at 70 °C. Then 5-methylpyrazine-2-carboxylic acid (0.775 g, 5.612 mmol) was added. Ethanol (5.87 ml) and water (0.31 ml) were added to the mixture and the mixture was heated at 70 °C for 1 h. Thereafter, the mixture was slowly cooled to room temperature. Then the mixture was cooled to 20 °C within 1 min. The mixture was filtered, washed with ethanol (3 ml), and dried in a dry gun at 50 °C.

[0515] Yield: 1.81 g (4.33 mmol; 73%) of Int-10h, as the salt formed with 5-methylpyrazine-2-carboxylic acid

[0516] Step 9:

[0517] A mixture of Int-10h (0.55 g, 1.32 mmol), NMM (0.581 mL, 5.27 mmol) in 5.5 ml of EtOAc and 5-methylpyrazine-2-carboxylic acid (90.9 mg, 0.66 mmol) as the salt formed with 5-methylpyrazine-2-carboxylic acid was cooled to 0 °C with stirring. Then PPA (50% in EtOAc; 1.165 mL, 1.97 mmol) was added. The cooling was removed after 10 min and the mixture was stirred at ambient temperature for 45 min. Ethyl acetate (20 ml) was added to the mixture and then it was extracted twice with sodium bicarbonate solution. The combined organic phases were dried over MgSO 4Drying. After filtration, the mixture was concentrated in vacuo, the residue was dissolved in THF / MeOH and purified via chromatography (XBridge C18, 10, (H2O + 0.1% NH4OH + 28 - 48% ACN)). The fractions containing the product were combined and concentrated in vacuo. The product was obtained as a single stereoisomer.

[0518] Yield: 0.461 mg (1.15 mmol; 87%) Example 10.

[0519]

[0520]

[0521] Similar to Example 10, the following compound was obtained, Example 11.

[0522] Intermediate 11g was synthesized similar to Intermediate 1g and using 1,2,4-trifluoro-5-nitrobenzene as the starting material.

[0523]

[0524]

Claims

1. A compound selected from the group consisting of:

2. A pharmaceutically acceptable salt of the compound according to claim 1.

3. The compound according to claim 1 or the pharmaceutically acceptable salt according to claim 2, for use as a medicament.

4. A pharmaceutical composition comprising the compound according to claim 1 or the pharmaceutically acceptable salt according to claim 2.

5. The compound according to claim 1 or the pharmaceutically acceptable salt according to claim 2, for the treatment and / or prevention of a disease or disorder, wherein inhibition of the activity of metabotropic glutamate receptor subtype 4 (mGluR4) has a therapeutic benefit.

6. The compound according to claim 1 or the pharmaceutically acceptable salt according to claim 2, for use according to the use of claim 5, wherein the disease or disorder is a psychiatric, neurological, neurodegenerative, non-neuronal or metabolic disease, cancer or related disorder.

7. The compound according to claim 1 or the pharmaceutically acceptable salt according to claim 2, for use according to any one of claims 5 or 6, wherein the disease or disorder is selected from the group consisting of: psychiatric and neurological conditions associated with impulse control deficits or maladaptive impulsive behavior; substance use disorders; personality disorders such as borderline personality disorder, antisocial personality disorder, conduct disorder; eating disorders such as bulimia nervosa; attention deficit hyperactivity disorder; bipolar disorder; stress-related disorders such as post-traumatic stress disorder; tic disorders such as Tourette's syndrome; movement disorders such as restless legs syndrome; cognitive dysfunction in psychiatric or neurological disorders, cognitive impairment associated with schizophrenia, Alzheimer's disease and other neurological and psychiatric disorders; overweight, obesity; cancers and related disorders associated with maladaptive tumorigenesis such as osteosarcoma.

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