WO2014012563A1 - Compounds for enhancing the cognitive function - Google Patents

Description

COMPOUNDS FOR ENHANCING THE COGNITIVE FUNCTION

FIELD OF THE INVENTION

The invention relates to 2-oxo-1 -pyrrolidinyl cyanopyrazole derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals for enhancing the cognitive function or to counteract cognitive decline in a mammal.

BACKGROUND OF THE INVENTION

Cognitive disorders, i.e. impairments of memory and learning processes, have a significant detrimental effect on the quality of life of patients affected by it. Clinically recognized cognitive disorders vary from mild cognitive impairment through to dementia of varying severity.

Mild cognitive impairment ("MCI") is believed to be a transition stage between the cognitive changes of normal aging and the more serious problems caused by Alzheimer's disease. Dementia is a clinically recognized broad-spectrum syndrome entailing progressive loss of cognitive capabilities. Dementia can be one of many symptoms of various neurological diseases or the main abnormality associated with the disease, as it is the case in Alzheimer's disease. Most common causes of dementia include cerebral atrophy associated with Alzheimer's disease, Lewy-bodies disease, front-temporal lobe degeneration, Pick's disease, vascular narrowing or blockage in the brain (i.e. vascular dementia also known as multi-infarct dementia), Huntington's disease, Parkinson's disease, head trauma, HIV infection or Down's syndrome.

Alzheimer's disease (AD) is a progressive degenerative disease of the brain primarily associated with aging. AD is one of several disorders that cause the gradual loss of brain cells and is one of and possibly the leading cause of dementia. Clinical presentation of AD is characterized by loss of memory, cognition, reasoning, judgment, and orientation. Mild cognitive impairment (MCI) is often the first identified stage of AD. As the disease progresses, motor, sensory, and linguistic abilities also are affected until there is global impairment of multiple cognitive functions. These cognitive losses occur gradually, but typically lead to severe impairment, and the disease leads eventually to death in the range of three to twenty years. Currently there are only a few medications that have been shown to afford at most a modest, mostly transient benefit to the patients suffering from cognitive impairment. Cholinesterase inhibitors (anticholinesterases), such as donepezil (Aricept®), galanthamine (Razadyne®, Razadyne ER®, Reminyl®, Nivalin®) and rivastigmine tartrate (Exelon®) have been shown to be efficacious in mild to moderate Alzheimer's disease dementia. Exelon® has recently been approved for the treatment of mild to moderate dementia associated with Parkinson's disease. Memantine, a NMDA receptor antagonist, is the first approved Alzheimer's disease medication acting on the glutamatergic system (Axura®, Akatinol®, Namenda®, Ebixa®). These drugs however have not only proven limited efficacy but also considerable side effects which in some cases lead to discontinuation of the therapy. With the increase in the life span and general aging of the population there is a need to develop drugs which could delay or alleviate the cognitive function in aging patients.

Levetiracetam or (S)-(-)-alpha-ethyl-2-oxo-1 -pyrrolidine acetamide, is a laevorotatory compound, disclosed in the European patent No. EP 0 162 036 B as being a protective agent for the treatment and the prevention of hypoxic and ischemic type aggressions of the central nervous system. Levetiracetam has the following structure:

Levetiracetam has been approved, and is marketed as Keppra®, in many countries including the European Union and the United States for the treatment of various forms of epilepsy, a therapeutic indication for which it has been demonstrated that its dextrorotatory enantiomer (R)-(+)-alpha-ethyl-2-oxo-1 -pyrrolidine acetamide completely lacks activity (Gower et al., Eur. J. Pharmacol. 222: 193-203 (1992)).

It has been repeatedly reported however that levetiracetam has no impact on the cognitive function both in animals as well as in humans (Lamberty et al, Epilepsy & Behavior 1 , 333- 342 (2000); Klitgaard et al. Epilepsy Research 50, 55-65 (2002); Shannon H & Love, P. Epilepsy & Behavior 7, 620-628 (2005); Higgins et al. Psychopharmacology 207, 513-527 (2010)).

Further racetam-type drugs include piracetam, oxiracetam, aniracetam, pramiracetam and phenylpiracetam, which have been used in humans and some of which are available as dietary supplements. Of these, oxiracetam and aniracetam are no longer in clinical use. Pramiracetam reportedly improved cognitive deficits associated with traumatic brain injuries. Although piracetam exhibited no long-term benefits for the treatment of mild cognitive impairments, recent studies demonstrated its neuroprotective effect when used during coronary bypass surgery. It was also effective in the treatment of cognitive disorders of cerebrovascular and traumatic origins; however, its overall effect on lowering depression and anxiety was higher than improving memory. As add-on therapy, it appears to benefit individuals with myoclonus epilepsy and tardive dyskinesia. Phenylpiracetam is more potent than piracetam and is used for a wider range of indications. In combination with a vasodilator drug, piracetam appeared to have an additive beneficial effect on various cognitive disabilities.

Pyrrolidone derivatives in particular for the treatment of epilepsy are disclosed in WO 2006/128693 :

In said formula

• R³ may be - among others - either of a 1 H-pyrazol-4-yl or a 1 H-pyrazol-5-yl and

• R⁴ may be a substituted or unsubstituted aryl.

SUMMARY OF THE INVENTION

The present invention relates to compounds, compositions and methods for the treatment of conditions associated with enhancement or improvement of cognitive ability or to counteract cognitive decline.

A further aspect of the present invention consists in pharmaceutical compositions containing a compound which has been identified pursuant to the above set out method and which may furthermore contain a pharmaceutically acceptable excipient.

Further aspects of the invention will become apparent from the detailed specification. DETAILED DESCRIPTION OF THE INVENTION

The compounds and their tautomers, isomers and salts useful for the treatment of conditions associated with enhancement or improvement of cognitive ability or to counteract cognitive decline are of those of formula (I)

wherein

R¹ is a fluorine atom;

n is equal to 1 , 2 or 3; and

R² is a cyano group of formula -CN.

In one embodiment the 4-phenyl of formula (I) is in the 4R configuration. In another, it is in the 4S configuration.

In a further embodiment, n is 1 , 2 or 3, preferably 2 or 3, most preferably 3.

In a preferred embodiment the 4-phenyl moiety is a 3,4,5-trifluorophenyl moiety.

Specific compounds of the present invention are those selected from the group consisting of:

· 4-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1 -yl]methyl}-1 H-pyrazole-3-carbonitrile;

• (+)-4-{[(4R)-2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1 -yl]methyl}-1 H-pyrazole-5- carbonitrile; and

• (-)-4-{[4-(2,4-difluorophenyl)-2-oxopyrrolidin-1 -yl]methyl}-1 H-pyrazole-3-carbonitrile.

The compounds of formula (I) according to the invention can be prepared analogously to conventional methods as understood by the person skilled in the art of synthetic organic chemistry.

According to one embodiment, compounds having the general formula I may be prepared by deprotection of a compound of formula II according to the equation:

wherein R¹ , R² and n have the same definitions as defined above for compounds of formula I, and R³ is a protecting group, preferably a tetrahydro-2H-pyran-2-yl group.

This reaction may be performed for example at room temperature in absolute methanol in the presence of an acid such as HCI, or according to any method known to the person skilled in the art.

Some compounds of formula II may be prepared by condensation of a compound of formula V with an aldehyde of formula VI according to the equation:

wherein R¹ , R², R³ and n have the same definitions as defined above.

This reaction may be performed in two steps comprising the reduction of a nitro derivative of formula V followed by a reductive amination with an aldehyde of formula VI.

The first step may be performed for example by using ammonium formate and Palladium as catalyst in methanol, or according to any method known to the person skilled in the art.

The second step may be performed by using for example sodium triacetoxyborohydride (STAB) in dichloroethane according to the methods described in PCT patent application WO2006/128693, or according to any other method known to the person skilled in the art.

Compounds of formula V may be prepared according to procedures described in Bioorg. Med. Chem. Letters (2009), 19(1 1 ), 31 18-3121 , or according to any other method known to the person skilled in the art. The synthesis of aldehyde VI may be performed in a two-steps procedure involving the protection of 4-bromo-1 H-pyrazole-5-carbonitrile with a protecting group, for example with tetrahydro-2H-pyran-2-yl under acidic conditions, followed by a carbonylation, using for example ethyl formate and n-butyl lithium. These steps may be performed according to any method known to the person skilled in the art.

Some compounds of formula II may be prepared by reaction of a pyrrolidone of formula III with a compound of formula IV according to the equation:

wherein R¹ , R², R³ and n have the same definitions as defined above.

This reaction may be performed in two steps involving the conversion of 4-(hydroxymethyl)- 1 -(tetrahydro-2H-pyran-2-yl)-1 H-pyrazole-5-carbonitrile into its mesyl derivative followed by a nucleophilic substitution with a pyrrolidone of formula III in presence of sodium hydride at room temperature, or according to any method known to the person skilled in the art.

The synthesis of compounds of formula III can be performed using procedures described in the literature (for example in PCT patent application WO2006/128693) or according to any method known to the person skilled in the art.

Alcohol of formula IV may be obtained by reduction at room temperature of aldehyde of formula VI using sodium borohydride, or according to any other method known to the person skilled in the art. In another embodiment, the present invention includes the synthesis of the following intermediates:

• 4-formyl-1 -(tetrahydro-2H-pyran-2-yl)-1 H-pyrazole-5-carbonitrile;

• 1 -(tetrahydro-2H-pyran-2-yl)-1 H-pyrazole-5-carbonitrile;

• ethyl (2E)-3-(3,4,5-trifluorophenyl)prop-2-enoate;

• ethyl 4-nitro-3-(3,4,5-trifluorophenyl)butanoate; • 4-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1 -yl]methyl}-1 -(tetrahydro-2H-pyran-2-yl)- 1 H-pyrazole-5-carbonitrile;

• 4-(hydroxymethyl)-1 -(tetrahydro-2H-pyran-2-yl)-1 H-pyrazole-5-carbonitrile;

• tert-butyl 4-(2,4-difluorophenyl)-2-oxopyrrolidine-1 -carboxylate;

· tert-butyl 4-(2,4-difluorophenyl)-2-oxopyrrolidine-1 -carboxylate, enantiomer A;

• tert-butyl 4-(2,4-difluorophenyl)-2-oxopyrrolidine-1 -carboxylate, enantiomer B;

• 4-(2,4-difluorophenyl)pyrrolidin-2-one, enantiomer A;

• 4-(3,4,5-trifluorophenyl)pyrrolidin-2-one and enantiomers; and

• 4-{[4-(2,4-difluorophenyl)-2-oxopyrrolidin-1 -yl]methyl}-1 -(tetrahydro-2H-pyran-2-yl)- 1 H-pyrazole-5-carbonitrile, enantiomer A.

The "pharmaceutically acceptable salts" according to the invention include therapeutically active, non-toxic acid or base salt forms which the compounds of formula I are able to form.

The acid addition salt form of a compound of formula I that occurs in its free form as a base can be obtained by treating the free base with an appropriate acid such as an inorganic acid, for example, a hydrohalic such as hydrochloric or hydrobromic, sulfuric, nitric, phosphoric and the like; or an organic acid, such as, for example, acetic, trifluoroacetic, hydroxyacetic, propanoic, lactic, pyruvic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p- aminosalicylic, pamoic and the like.

The compounds of formula I containing acidic protons may be converted into their therapeutically active, non-toxic base addition salt forms, e.g. metal or amine salts, by treatment with appropriate organic and inorganic bases. Appropriate base salt forms include, for example, ammonium salts, alkali and earth alkaline metal salts, e.g. lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. N-methyl-D- glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.

Conversely said salt forms can be converted into the free forms by treatment with an appropriate base or acid.

Compounds of the formula i and their saits can be in the form of a solvate, which is included within the scope of the present invention. Such solvates include for example hydrates, alcoholates and the like. Compounds of formula I and some of their intermediates have at least one stereogenic center in their structure. This stereogenic center may be present in a R or a S configuration, said R and S notation is used in correspondence with the rules described in Pure Appl. Chem., 45 (1976) 11-30.

The invention also relates to all enantiomeric forms of the compounds of formula I or mixtures thereof (including all possible mixtures of stereoisomers).

With respect to the present invention reference to a compound or compounds is intended to encompass that compound in each of its possible isomeric forms and mixtures thereof, unless the particular isomeric form is referred to specifically.

The expression "enantiomerically pure" as used herein refers to compounds which have enantiomeric excess (ee) greater than 95%.

Compounds according to the present invention may exist in different polymorphic forms. Although not explicitly indicated in the above formula, such forms are intended to be included within the scope of the present invention.

The compounds of the present invention are for use as a medicament, in the treatment of conditions associated with enhancement or improvement of cognitive ability or to counteract cognitive decline.

The methods of the invention comprise administration to a mammal (preferably a human) suffering from above mentioned conditions or disorders, of a compound according to the invention in an amount sufficient to alleviate or prevent the disorder or condition.

The compound is conveniently administered in any suitable unit dosage form, including but not limited to one containing 0.1 to 2000 mg, preferably 0.1 to 1000 mg, more preferably 0.1 to 500 mg of active ingredient per unit dosage form.

The terms "treatment of conditions associated with enhancement or improvement of cognitive ability" or "to counteract cognitive decline" or "treatment of a cognitive disorder" or "improving the cognitive function" or "counteracting the decline of the cognitive function" used throughout this specification shall mean promoting cognitive function (affecting impaired cognitive function in the subject so that it more closely resembles the function of an aged-matched normal, unimpaired subject, including affecting states in which cognitive function is reduced compared to a normal subject) and preserving cognitive function (affecting normal or impaired cognitive function such that it does not decline or does not fall below that observed in the subject upon first presentation or diagnosis, e.g. to the extent of expected decline in the absence of treatment). The suitability of the compounds according to the present invention for conditions associated with enhancement or improvement of cognitive ability may be tested through assays that are well known in the art. Such assays include in particular the novel object recognition test (NOR) set out in Example 3 as well as the Y-maze test set out in Example 4.

In one embodiment of the invention, the mammal has normal cognitive function which is improved.

In a further embodiment the mammal exhibits cognitive impairment associated with aging.

In still a further embodiment the mammal is a human with cognitive impairment associated with a disease or disorder such as autism, dyslexia, attention deficit hyperactivity disorder, schizophrenia, obsessive compulsive disorders, psychosis, bipolar disorders, depression, Tourette's syndrome and disorders of learning in children, adolescents and adults, Age Associated Memory Impairment, Age Associated Cognitive Decline, Parkinson's Disease, Down's Syndrome, traumatic brain injury Huntington's Disease, Progressive Supranuclear Palsy (PSP), HIV, stroke, vascular diseases, Pick's or Creutzfeldt-Jacob diseases, multiple sclerosis (MS), other white matter disorders and drug-induced cognitive worsening.

In still a further embodiment, the impairment of cognitive function is caused by, or attributed to, Alzheimer's disease. In another embodiment, the impairment of cognitive function is caused by, or attributed to, mild cognitive impairment (MCI).

The compounds according to the present invention may be used for the manufacture of a pharmaceutical composition for the treatment of a cognitive disorder or for improving the cognitive function or counteracting the decline of the cognitive function. Such compositions typically contain the active pharmaceutical ingredient and a pharmaceutically acceptable excipient.

Suitable diluents and carriers may take a wide variety of forms depending on the desired route of administration, e.g., oral, rectal, parenteral or intranasal.

Pharmaceutical compositions comprising compounds according to the invention can, for example, be administered orally, parenterally, i.e., intravenously, intramuscularly or subcutaneously, intrathecally, transdermal^ (patch), by inhalation or intranasally.

Pharmaceutical compositions suitable for oral administration can be solids or liquids and can, for example, be in the form of tablets, pills, dragees, gelatin capsules, solutions, syrups, chewing-gums and the like. To this end the active ingredient may be mixed with an inert diluent or a non-toxic pharmaceutically acceptable carrier such as starch or lactose. Optionally, these pharmaceutical compositions can also contain a binder such as microcrystalline cellulose, gum tragacanth or gelatine, a disintegrant such as alginic acid, a lubricant such as magnesium stearate, a glidant such as colloidal silicon dioxide, a sweetener such as sucrose or saccharin, or colouring agents or a flavouring agent such as peppermint or methyl salicylate.

The invention also contemplates compositions which can release the active substance in a controlled manner. Pharmaceutical compositions which can be used for parenteral administration are in conventional form such as aqueous or oily solutions or suspensions generally contained in ampoules, disposable syringes, glass or plastics vials or infusion containers.

In addition to the active ingredient, these solutions or suspensions can optionally also contain a sterile diluent such as water for injection, a physiological saline solution, oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents, antibacterial agents such as benzyl alcohol, antioxidants such as ascorbic acid or sodium bisulphite, chelating agents such as ethylene diaminetetraacetic acid, buffers such as acetates, citrates or phosphates and agents for adjusting the osmolarity, such as sodium chloride or dextrose.

Also comprised by the present invention are pharmaceutical compositions containing the compound of the present invention in the form of a pharmaceutically acceptable co-crystal.

Such pharmaceutical compositions may furthermore contain known or marketed therapeutic agents used in the treatment of cognitive or a neurological disorders (AD) including donepezil (Aricept®), galanthamine (Razadyne®, Razadyne ER®, Reminyl®, Nivalin®), rivastigmine tartrate (Exelon®), memantine (Axura®, Akatinol®, Namenda®, Ebixa®).

The pro-cognitive activity of the compounds according to the present invention in particular of formula I, or their pharmaceutically acceptable salts, may be determined by a variety of preclinical tests and models known to a skilled person in the art. Such tests may challenge the efficacy on multiple memory phases and types. In contrast to challenging a particular memory type or phase, the cognitive models test the ability of a compound to prevent or reverse a memory deficit in a given brain pathway, system, or function.

!n pre-c!inica! animal models, the compounds according to the present invention improve cholinergic memory deficit induced by scopolamine, a muscarinic receptor antagonist. They also improve the memory deficit induced by beta-amyloid. Memory deficits in Alzheimer's disease may have both a cholinergic origin as a consequence of specific cholinergic degeneration during disease progression, and an amyloid origin as a consequence of beta- amyloid increase in the brain. Therefore, it is believed that the compounds according to the present invention have a strong potential to improve cognitive deficits in Alzheimer's disease.

The compounds according to the present invention show a strong efficacy to improve two phases of memory: acquisition, and consolidation. They improve the acquisition phase of short and long term memory as seen by reversing the scopolamine induced deficit in the novel object recognition and passive avoidance, respectively. They improve the consolidation of spatial reference learning as seen by improved amyloid-induced memory deficit in the Morris water maze. Efficacy to improve retention might also be found in the inhibitory avoidance or active avoidance test.

EXAMPLES The following examples illustrate how the compounds covered by formula (I) may be synthesized. They are provided for illustrative purposes only and are not intended, nor should they be construed, as limiting the invention in any manner. Those skilled in the art will appreciate that routine variations and modifications of the following examples can be made without exceeding the spirit or scope of the invention. NMR spectra are recorded on a BRUKER AVANCE 400 NMR Spectrometer fitted with a Linux workstation running XWIN NMR 3.5 software and a 5 mm inverse 1 H/BB probehead, or BRUKER DRX 400 NMR fitted with a SG Fuel running XWIN NMR 2.6 software and a 5 mm inverse geometry ¹ H/^{1 3}C/¹9F triple probehead. The compound is studied in d6-dimethylsulfoxide (or d3-chloroform) solution at a probe temperature of 313 K or 300 K and at a concentration of 10 mg/ml. The instrument is locked on the deuterium signal of ds-dimethylsulfoxide (or d3-chloroform). Chemical shifts are given in ppm downfield from TMS (tetramethylsilane) taken as internal standard.

HPLC analyses are performed using one of the following systems:

- an Agilent 1 100 series HPLC system mounted with an INERTSIL ODS 3 C18, DP 5 μιτι, 250 X 4.6 mm column. The gradient runs from 100 % solvent A (acetonitrile, water, phosphoric acid (5/95/0.001 , v/v/v)) to 100 % solvent B (acetonitrile, water, phosphoric acid (95/5/0.001 , v/v/v)) in 6 min with a hold at 100 % B of 4 min. The flow rate is set at

2.5 ml/min. The chromatography is carried out at 35°C.

- a HP 1090 series HPLC system mounted with a HPLC Waters Symetry C18, 250 X

4.6 mm column. The gradient runs from 100 % solvent A (methanol, water, phosphoric acid (15/85/0.001 M, v/v/M)) to 100 % solvent B (methanol, water, phosphoric acid

(85/15/0.001 M, v/v/M)) in 10 min with a hold at 100 % B of 10 min. The flow rate is set at 1 ml/min. The chromatography is carried out at 40°C.

Mass spectrometric measurements in LC/MS mode are performed as follows:

HPLC conditions

Analyses are performed using a WATERS Alliance HPLC system mounted with an

INERTSIL ODS 3, DP 5 μπι, 250 X 4.6 mm column.

The gradient runs from 100 % solvent A (acetonitrile, water, trifluoroacetic acid (10/90/0.1 , v/v/v)) to 100 % solvent B (acetonitrile, water, trifluoroacetic acid (90/10/0.1 , v/v/v)) in 7 min with a hold at 100 % B of 4 min. The flow rate is set at 2.5 ml/min and a split of 1/25 is used just before API source.

MS conditions

Samples are dissolved in acetonitrile/water, 70/30, v/v at the concentration of about 250 pg/ml. API spectra (+ or -) are performed using a FINNIGAN LCQ ion trap mass spectrometer. APCI source operated at 450°C and the capillary heater at 160°C. ESI source operated at 3.5 kV and the capillary heater at 210°C.

Mass spectrometric measurements in DIP/EI mode are performed as follows: samples are vaporized by heating the probe from 50°C to 250°C in 5 min. El (Electron Impact) spectra are recorded using a FINNIGAN TSQ 700 tandem quadrupole mass spectrometer. The source temperature is set at 150°C.

Mass spectrometric measurements on a TSQ 700 tandem quadrupole mass spectrometer (Finnigan MAT) in GC/MS mode are performed with a gas chromatograph model 3400 (Varian) fitted with a split/splitless injector and a DB-5MS fused-silica column (15 m x 0.25 mm I.D., 1 μιη) from J&W Scientific. Helium (purity 99.999 %) is used as carrier gas. The injector (CTC A200S autosampler) and the transfer line operate at 290 and 250°C, respectively. Sample (1 μΙ) is injected in splitless mode and the oven temperature is programmed as follows: 50°C for 5 min., increasing to 280°C (23°C/min) and holding for 10 min. The TSQ 700 spectrometer operates in electron impact (El) or chemical ionization (CI/CH4) mode (mass range 33 - 800, scan time 1.00 sec). The source temperature is set at 150°C. High resolution mass spectrometry measurements are run on a Waters LCT Time of flight mass spectrometer equipped with an ESI source and a Waters Acquity UPLC (column: BEH C18 (1 .7μιτι, 2.1 x 50 mm)) with diode array detector. The gradient runs from 98 % solvent A (aqueous ammonium formate (63 mg/l), 30% aqueous ammonia (50 μΙ/Ι)) to 95 % acetonitrile and back in 6 min. The source parameters are as follows: ESI capillary voltage 2.5 kV, cone voltage 135 V, source block temperature 135°C, desolvation temperature 350°C, cone gas flow 20 IJHr (Nitrogen), desolvation Gas flow 800 UHr. The detector is set with a flight tube at 7.2 KV and an MCP detector at 2,500 V. Specific rotation is recorded on a Perkin-Elmer 341 polarimeter. The angle of rotation is recorded at 25°C on 1 % solutions in methanol, at 589 nm.

Melting points are determined on a Btichi 535 or 545 Tottoli-type fusionometre, and are not corrected, or by the onset temperature on a Perkin Elmer DSC 7.

Preparative chromatographic separations are performed on silicagel 60 Merck, particle size 15-40 μητι, reference 1 .1511 1.9025, using Novasep axial compression columns (80 mm i.d.), flow rates between 70 and 150 ml/min. Amount of silicagel and solvent mixtures as described in individual procedures. Reverse phase separations are carried out using 500 g of either Kromasil C18 10 μιτι silicagel (acidic or neutral conditions) or Phenomenex Gemini C18 10 μΜ (basic conditions) in 8-cm ID columns with a flow rate of 150 ml/min. Products are detected at 215 nm unless otherwise specified.

Preparative Chiral Chromatographic separations are performed on a DAICEL

Chiralpak AD 20 μπι, 100*500 mm column using an in-house build instrument with various mixtures of lower alcohols and C5 to C8 linear, branched or cyclic alkanes at ± 350 ml/min. Solvent mixtures as described in individual procedures.

The following abbreviations are used in the description:

DCE 1 ,2-dichloroethane

DBU 1 ,8-diazabicyclo[5.4.0]undec-7-ene

DCM dichloromethane

THF tetrahydrofuran

DIPEA diisopropyl ethylamine Example 1 : Synthesis of 4-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1 H- pyrazole-3-carbonitrile 1 and (+)-4-{[(4R)-2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]- methyl}-! H-pyrazole-5-carbonitrile 2.

1.1 Synthesis of 4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1 H-pyrazole-5-carbonitrile a2.

The reaction should be carried out in the absence of moisture. 4-Bromo-1 H-pyrazole- 5-carbonitrile a1 (1.0 g, 5.8 mmol) and 3,4-dihydro-2H-pyran (DHP) (1.06 mL, 1 1.6 mmol) are suspended in dry DCE (4 mL). One drop of trifluoroacetic acid (TFA) is added. The reaction mixture is stirred at room temperature, whereupon all of compound a1 is gradually dissolved, and a homogeneous solution formed. After 24 h, the reaction mixture is diluted with DCM (25 mL), washed with a 10% solution of NaHCC>3 (2 x 15 mL), brine (15 mL), dried with anhydrous Na2SC>4, and evaporated in vacuum. The residual yellowish oil is extracted with hexane. The combined extracts are evaporated to afford 1 .50 g of 4-bro o-1 - (tetrahydro-2H-pyran-2-yl)-1 H-pyrazole-5-carbonitrile a2 as a colourless oil.

Yield: 100%. 1 H NMR (DMSO) δ 8.01 (s, 1 H), 5.70 (dd, J = 9.0, 3.0 Hz, 1 H), 3.85 (dt, J = 9.0, 3.0, 3.0 Hz, 1 H), (ddd, J = 12.0, 8.0, 4.0 Hz, 1 H), 2.15 (m, 1 H), 1.95 (m, 2 H), 1.7 (m, 1 H), 1.58 (m, 3 H).

1.2. Synthesis of 4-formyl-1-(tetrahydro-2H-pyran-2-yl)-1 H-pyrazole-5-carbonitrile a3.

The reaction should be carried out under a flow of argon. 4-bromo-1 -(tetrahydro-2H- pyran-2-yl)-1 H-pyrazole-5-carbonitrile a2 (0.51 g, 2.0 mmol) is dissolved in absolute THF (15 mL). A 1.6 M solution of n-BuLi in hexane (1.30 mL, 2.1 mmol) is added dropwise for 10 min at -93°C under stirring so that the temperature of the reaction mixture would not exceed -88°C. The reaction mixture is stirred at -90°C for 25 min. Ethyl formate (0.49 mL, 6.0 mmol) is quickly added. The mixture is stirred at -90°C for 20 min then decomposed by the addition of a THF/water mixture (10 mL, 1 :1 ). The cooling bath is removed. The reaction mixture is allowed to heat up to room temperature and diluted with ethyl acetate (25 mL). Solid NaCI is added. The organic layer is separated, dried with anhydrous a2S04, and evaporated in vacuum to give 0.42 g of a light-yellow liquid as a mixture of 4-formyl-1 - (tetrahydro-2H-pyran-2-yl)-1 H-pyrazole-5-carbonitrile a3 and 1 -(tetrahydro-2H-pyran-2-yl)- 1 H-pyrazole-5-carbonitrile a4 (respectively in a 5 to 1 ratio). This crude product is used for the next step without any further purification.

Yield: 99%.

H NMR (DMSO) δ 9.90 (s, 1 H), 8.15 (s, 1 H), 5.78 (dd, J = 9.0, 3.0 Hz, 1 H), 3.74

(t, J = 6.0 Hz, 1 H), 2.50 (m, 1 H), 2.21 (m, 2 H), 1.99 (m, 1 H), 1.69 (m, 3 H).

1.3 Synthesis of ethyl (2E)-3-(3,4,5-trifluorophenyl)prop-2-enoate a6.

3,4,5-Trifluorobenzaldehyde a5 (700 g, 4.37 mol, 1 eq) is dissolved in THF (1 L). The temperature of the mixture is brought to 5°C by the use of an ice bath. In another flask, carbethoxymethylene triphenyl phosphorane (1550 g, 4.44 mol, 1.017 eq) is dissolved in dichloromethane (3 L). This yellow solution is added to the reaction mixture in 1.5 h (T°<16°C). After 1 h at 5°C, the starting product is completely consumed and the solution is concentrated to dryness at 45°C. Hexane (5 L) is added to the white residue and the suspension is stirred for 4h at room temperature. The solid is filtered and the filtrate evaporated yielding a solid. This resulting solid is dissolved in dichloromethane (3 L) and silicagel (500 g) is added. The mixture is stirred at room temperature for 2 h and filtered on a path oi siiicagei (300 g) that is further washed with dichloromethane (2 L). Evaporation affords 977.5 g of crude (2E)-3-(3,4,5-trifluorophenyl)prop-2-enoate a6 (containing 15% of the Z isomer) as a white solid which is used in the next step without any further purification.

Yield: 97%.

H NMR (CDCI₃) δ 7.51 (d, J = 16.0 Hz, 1 H), 7.14 (dd, J = 8.0, 6.6 Hz, 2 H), 8.15 (s, 1 H), 7.51 (d, J = 16.0 Hz, 1 H), 4.27 (q, J = 7.1 Hz, 2 H), 1.34 (t, J = 8.8 Hz, 3 H).

1.4 Synthesis of ethyl 4-nitro-3-(3,4,5-trifluorophenyl)butanoate a7.

Nitromethane (1 L) is placed in the reaction vessel and cooled to -19°C. DBU (1095 mL, 1 eq) is added rapidly while keeping the temperature below -5°C. At -21 °C, (2E)- 3-(3,4,5-trifluorophenyl)prop-2-enoate a6 (1656 g, 7.20 mol) is added while keeping the temperature below -12°C. The reaction mixture is stirred at -15°C for 2 h. A small quantity of solid stays in suspension so the mixture is brought to 0°C until completion of the reaction. Water (2 L) is added while maintaining the temperature around 10°C. The pH is brought to 1 by adding HCI 6N (1.6 L). The color turns from orange to yellow. The mixture is extracted with diisopropyl ether (2 L), the organic phase is washed with HCI 1 N (2 x 2 L then with brine (2 L). The organic phase is dried over MgSC>4, filtered, and concentrated to afford 1905 g of ethyl 4-nitro-3-(3,4,5-trifluorophenyl)butanoate a7 as an orange oil which crystallizes on standing. This crude mixture is used in the next step without any further purification.

Yield: 91 %.

¹ H NMR (CDCI3) δ 6.89 (dd, J = 8.0, 6.4 Hz, 2 H), 4.72 (dd, J = 12.9, 6.3 Hz, 1 H), 4.58 (dd, J = 12.9, 8.4 Hz, 1 H), 5.12 (dq, J = 7.2, 1.2 Hz, 2 H), 3.94 (t, J = 7.8 Hz, 1 H), 2.71 (t, J = 7.0, 2 H), 1.22 (t, J = 7.1 , 3 H).

1.5 Synthesis of 4-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1-(tetra- hydro-2H-pyran-2-yl)-1 H-pyrazole-5-carbonitrile a8.

The reaction should be carried out in a flow of argon. Ethyl 4-nitro-3-(3,4,5- trifluorophenyl)butanoate a7 (0.66 g, 2.25 mmol) is dissolved in absolute methanol (5 mL). Then 10% Pd/C (0.30 g) and ammonium formate (1.0 g, 15.8 mmol) are added under stirring. The reaction mixture is vigorously stirred for 30 min at room temperature, diluted with dry ether (40 mL), and filtered through Celite. The resulting mixture is transferred into a solution of the mixture of 4-formyl-1 -(tetrahydro-2H-pyran-2-yl)-1 H-pyrazole-5-carbonitrile a3 and 1 -(tetrahydro-2H-pyran-2-yl)-1 H-pyrazole-5-carbonitrile a4 obtained in example 1.2 (0.42 g, 1.5 mmol) in absolute methanol (5 mL). The reaction mixture is stirred for 30 min and evaporated in vacuum. The residue is coevaporated 3 times with dry DCE then dissolved in dry DCE (15 mL). NaBH(OAc)3 (STAB) (0.5 g, 2.4 mmol) is added at 0-5 °C. The mixture is stirred at room temperature for 18h. Then STAB (0.15 g, 0.75 mmol) is added again and the resulting mixture is stirred for an additional 6 h. The mixture is diluted with DCM (100 ml_), washed with a 10% KOH solution (2 50 ml_), dried over Na2SC>4, and evaporated in vacuum. The residue is purified by chromatography over silica gel (60 g; gradient: hexane/ethyl acetate 1 :1 to 2:3) to afford 220 mg of 4-{[2-oxo-4-(3,4,5- trifluorophenyl)pyrrolidin-1 -yl]methyl}-1 -(tetrahydro-2H-pyran-2-yl)-1 H-pyrazole-5-carbonitrile a8.

Yield: 36%.

LC-MS (MH+): 405. 1.6 Synthesis of 4-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1 H-pyra- zole-3-carbonitrile 1 and (+)-4-{[(4R)-2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1- yl]methyl}-1 H-pyrazole-5-carbonitrile 2.

The reaction should be carried out in the absence of moisture. 4-{[2-oxo-4-(3,4,5- trifluorophenyl)pyrrolidin-1 -yl]methyl}-1 -(tetrahydro-2H-pyran-2-yl)-1 H-pyrazole-5-carbonitrile a8 (200 mg, 0.494 mmol) is dissolved in absolute ethanol (6 ml_). A solution of HCI in ethanol (obtained from 280 μL· of acetyl chloride and 4 ml_ of absolute ethanol) is added to this solution. The reaction mixture is stirred at room temperature for 18 h and evaporated in vacuum. The residual colorless oil is subjected three times to coevaporation with absolute ether, mixed with some ether, and left in an ultrasound bath until a white solid formed. The latter is filtered off, washed with ether, and dried in vacuum to afford 1 13.5 mg of 4-{[2-oxo- 4-(3,4,5-trifluorophenyl)pyrrolidin-1 -yl]methyl}-1 H-pyrazole-3-carbonitrile 1 as a white powder.

Yield: 72%.

LC-MS (MH+): 321.

H NMR (DMSO) δ 13.93 (s, 1 H), 8.04 (s, 1 H), 7.32 (dd, J = 9.2, 6.8 Hz, 2 H), 4.47

(d, J = 15.3 Hz, 1 H), 4.37 (d, J = 15.3 Hz, 1 H), 3.63 (m, 2 H), 3.25 (m, 1 H), 2.67 (m, 1 H), plus 1 H under DMSO peak.

The separation of enantiomers is performed with 300 mg of 4-{[2-oxo-4-(3,4,5- trifluorophenyl)pyrrolidin-1 -yl]methyl}-1 H-pyrazole-3-carbonitrile 1 that are obtained as described previously. The enantiomers are resolved by chiral chromatography (chiralpak AD 100^*500 mm, eluent: MeOH/EtOH/benzine/DEA 8/2/90/0.1 v/v/v/v) to afford 77 mg of (+)-4- {[(4R)-2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1 -yl]methyl}-1 H-pyrazole-5-carbonitrile 2 as a white solid with an enantiomeric excess of 100%. Yield: 26%.

LC-MS (MH+): 321.

¹ H NMR (DMSO) δ 13.91 (m, 1 H), 8.02 (s, 1 H), 7.31 (dd, J = 9.3, 7.0 Hz, 2 H), 4.42 (m, 2 H), 3.62 (m, 2 H), 3.25 (m, 1 H), 2.68 (m, 1 H) plus 1 H under DMSO peak.

alpha_D (MeOH, 25°C): +15.1 °.

Example 2. Synthesis of (-)-4-{[4-(2,4-difluorophenyl)-2-oxopyrrolidin-1-yl]methyl}-1 H- pyrazole- -carbonitrile 3.

2.1 Synthesis of 4-(hydroxymethyl)-1-(tetrahydro-2H-pyran-2-yl)-1 H-pyrazole-5- carbonitrile a9.

Solid sodium borohydride (0.43 g, 0.5 eq., 11.4 mmol) is added at room temperature to a solution of 4-formyl-1 -(tetrahydro-2H-pyran-2-yl)-1 H-pyrazole-5-carbonitrile a3 in THF (100 mL). After 1 h stirring, the mixture is quenched with water (10 mL). The reaction mixture is diluted with AcOEt (100 mL), washed with brine, dried over anhydrous MgS04 ^ar|d evaporated in vacuum to afford 4.93 g of crude 4-(hydroxymethyi)-l-(tetrahydro-2H-pyran-2- yl)-1 H-pyrazole-5-carbonitrile a9. This crude product is used in the next step without any further purification. Yield: 100%.

LC-MS (MH+): 208.

2.2 Synthesis of tert-butyl 4-(2,4-difluorophenyl)-2-oxopyrrolidine-1 -carboxylate a12 and enantiomers a12-A and a12-B. To a solution of tert-butyl 2-oxo-2,5-dihydro-1 H-pyrrole-1 -carboxylate a10 (15 g, 81.9 mmol) in dioxane/water (300 mL/90 mL) are added at room temperature (2,4- difluorophenyl)boronic acid a11 (25.9 g, 163.7 mmol), cesium fluoride (37.3 g, 245.6 mmol), 2,2'-bis(diphenyl-phosphino)-1 ,1 '-binaphthyl (2.3 g, 3.7 mmol), potassium carbonate (1 1.3 g, 81.9 mmol) and chloro(1 ,5-cyclooctadiene)rhodium(l)dimer (0.6 g, 1.2 mmol). The mixture is heated at 1 10°C for 2 h. The reaction mixture is then diluted with AcOEt (300 mL), washed with brine, dried over anhydrous MgSC>4 and evaporated in vacuum. The residue is purified by chromatography over silicagel (CH2Cl2/MeOH/NH40H 99.5/0.45/0.05 v/v/v) to afford tert- butyl 4-(2,4-difluorophenyl)-2-oxopyrrolidine-1 -carboxylate a12. The enantiomers are resolved by chiral chromatography (chiralpak IC, 80^*380 mm, eluent: heptane/ethanol 70/30 v/v) to afford the 2.88 g of enantiomer A a12-A (first eluted) and 3.1 g of enantiomer B a12-B (second eluted) as white solids.

Compound a12-A:

Yield: 12%.

LC-MS (MH+): 298.

Compound a12-B:

Yield: 13%.

LC-MS (MH+): 298.

2.3 Synthesis of 4-(2,4-difluorophenyl)pyrrolidin-2-one, enantiomer A a13-A.

At room temperature, a saturated solution of HCI in ethanol (20 mL) is added to tert- butyl 4-(2,4-difluorophenyl)-2-oxopyrrolidine-1 -carboxylate, enantiomer A a12-A (2.9 g, 10.43 mmol). The mixture is stirred at room temperature for 2 h. Then, the solvent is removed under reduced pressure. The crude mixture is poured in an aqueous saturated solution of NaHCC>3 (100 mL) and extracted with AcOEt (3^*200 mL). The combined organic extracts are dried over MgS04 and concentrated under reduced pressure. The conversion is total and the evaporation affords 1.57 g of 4-(2,4-difluorophenyl)pyrrolidin-2-one, enantiomer A a13-A, which is used in the next step without any further purification.

Yield: 83%. LC-MS (MH+): 198.

4-(3,4,5-trifluorophenyl)pyrrolidin-2-one and enantiomers may be synthesized according to the same method.

LC-MS (MH+): 216.

2.4 Synthesis of 4-{[4-(2,4-difluorophenyl)-2-oxopyrrolidin-1-yl]methyl}-1-(tetra- hydro-2H-pyran-2-yl)-1 H-pyrazole-5-carbonitrile, enantiomer A a14-A.

Solution A: at 0°C, DIPEA (6.6 mL, 39.8 mmol) and methanesulfonyl chloride (0.7 mL, 8.7 mmol) are added to a solution of 4-(hydroxymethyl)-1 -(tetrahydro-2H-pyran-2-yl)-1 H- pyrazole-5-carbonitrile a9 (1.65 g, 7.96 mmol) in CH2CI2 (20 mL). The mixture is stirred for 30 minutes at 0°C.

Solution B: at the same time, solid NaH (60%, 0.95 g, 23.9 mmol) is added at room temperature to a solution of 4-(2,4-difluorophenyl)pyrrolidin-2-one, enantiomer A a13-A (1 .57 g, 7.96 mmol) in THF (20 mL). The mixture is stirred for 30 minutes at room temperature.

After 30 minutes, the solution A is added to the solution B. The mixture is stirred overnight at room temperature, then quenched with water (10 mL). The reaction mixture is diluted with AcOEt (100 mL), washed with a saturated solution of NaCI, dried over MgSC<4 and evaporated in vacuum to afford 3.3 g of crude 4-{[4-(2,4-difluorophenyl)-2-oxopyrrolidin- 1 -yl]methyl}-1 -(tetrahydro-2H-pyran-2-yl)-1 H-pyrazole-5-carbonitrile, enantiomer A a14-A. The crude product is used in the next step without any further purification.

Yield: 100%.

2.5 Synthesis of (-)-4-{[4-(2,4-difluorophenyl)-2-oxopyrrolidin-1-yl]methyl}-1 H-pyra- zole-3-carbonitrile 3. Crude 4-{[4-(2,4-difluorophenyl)-2-oxopyrrolidin-1 -yl]methyl}-1-(tetrahydro-2H-pyran-

2-yl)-1 H-pyrazole-5-carbonitrile, enantiomer A a14-A (3.3 g, 8.6 mmol) is dissolved in a solution of HCI in ethanol (20 mL, prepared from a saturated solution of HCI in ethanol that is diluted 5 times in ethanol). The mixture is stirred overnight at room temperature and then evaporated in vacuum. The residue is poured in an aqueous saturated solution of NaHC03 (100 mL) and extracted with AcOEt (3 x 200 mL), the combined organic extracts are dried over MgS04 and after filtration, concentrated under reduced pressure. The conversion is total and the evaporation affords 2.5 g of crude compound that is first purified by chromatography over silicagel (C^C^/MeOH/NI-^OH 97/2.7/0.3 v/v/v) and then triturated in diethyl ether/methanol (10 mLJ5 drops) to afford 0.9 g of pure (-)-4-{[4-(2,4-difluorophenyl)- 2-oxopyrrolidin-1-yl]methyl}-1 H-pyrazole-3-carbonitrile 3 as white solid.

Yield: 35%.

LC-MS (MH+): 303.

H NMR (DMSO) δ 14.68 (m, 1 H), 8.81 (s, 1 H), 8.22 (m, 1 H), 8.02 (m, 1 H), 7.85 (td, J = 8.5, 2.3 Hz, 1 H), 5.23 (m, 2 H), 4.57 (quint, J = 8.3 Hz, 1 H), 4.46 (t, J = 8.8 Hz, 1 H), 4.07 (dd, J = 9.0, 7.5 Hz, 1 H), 3.49 (dd, J = 16.6, 9.0 Hz, 1 H); 1 H is under the DMSO peak

alphao (MeOH, 22°C): -17.7°.

Example 3: In vivo model for assessing the efficacy of a test compound in learning and memory disorders (novel object recognition test; NOR)

Evaluation of promnesiant properties in the mouse model of 2-trial novel object recognition in a situation of scopolamine induced memory deficit: the two-trial object recognition paradigm, initially developed by Ennaceur and Delacour (1988) in the rat, can be considered as a model of episodic-like memory. This learning and memory paradigm is based on spontaneous exploratory activity of rodents and does not involve rule learning or reinforcement. The object recognition paradigm has been shown to be sensitive to the effects of ageing and cholinergic dysfunction (Scali et al, 1994; Bartolini et al, 1996). This model has been adapted to mice and validated using pharmacological agents (Bertaina- Anglade et al, 2003).

The purpose of the study is to evaluate the ability of test compounds to reverse the experimental deficit induced by scopolamine. The experiments was carried out using male C57BIJ6J mice (Centre d'Elevage R. Janvier, BP. 55, 53940 Le Genest-Saint-lsle, F.), weighing 20-35 g (10-14 weeks old) at their arrival that should meet inclusion criteria described in the experimental procedure. The animals were housed in groups of 4-9 in polypropylene cages (floor area = 777 cm2) under standard conditions: room temperature (22±2°C), light/dark cycle (12h/12h), water and food (SAFE A04) ad libitum. The experimental arena is a square wooden box (40x40x40 cm) painted in dark blue, with 8 ^* 8 cm black painted squares under a clear plexiglass floor. The arena was placed in a dark room illuminated only by lamps giving a uniform dim light in the box (around 60 lux). The day before the test, mice were habituated to the environment for a maximum of 30 min. On experimental day, mice were submitted to two trials spaced by an intertrial interval of 60 min. During the first trial (acquisition trial, T1), mice were placed in the arena containing 2 identical objects and time required by each animal to complete 20 s of object exploration was determined with a cut-off time of 12 min. Exploration was considered to be directing the nose at a distance less than 2 cm from the object and/or touching the object. For the second trial (testing trial, T2), one of the objects presented in the first trial was replaced by an unknown object (novel object), mice were placed back in the arena for 5 min and exploration of each object together with locomotor activity was determined. A criterion of minimal level of object exploration was used in the study to exclude animals with naturally low levels of spontaneous exploration: only animals having a minimal level of object exploration of 3 s during the testing trial (Novel + Familiar > 3 s ) were included in the study. The following parameters were measured: time required to achieve 20 s of object exploration on T1 (s), locomotor activity on T1 (number of crossed lines), time spent in active exploration of the familiar object on T2 (s), time spent in active exploration of the novel object on T2 (s), locomotor activity on T2 (number of crossed lines). The intraperitoneal route of administration was used to evaluate the promnesiant effects. Vehicle, or the compounds of formula I were administered 40 min before T1. Scopolamine was administered 30 min before T1.

Compounds of formula (I) according to the invention, tested according to the above protocol, displayed typically an activity of 50 mg/kg or less. Example 4: Y-maze test

A non transgenic model of amyloid-induced memory deficit is used comprising : a bolus intracerebral injection of the aggregated β25-35 amyloid peptide into the lateral ventricle of mouse. Such injection induced 7-12 days later Congo-red stained amyloid-like deposits in the hippocampus and cortex. It also induced a variety of memory deficits observed in the spontaneous alternation, the inhibitory avoidance, or the Morris water maze task.

The spontaneous alternation in rat and mice refers to the spontaneous behavior of rodent to alternate in a Y or T-maze. Spontaneous alternation behavior has been ascribed to the operation of a variety of mechanism, but regardless of his ethological function, it is evident that the animal must remember which arm it had entered on a previous occasion to enable it to alternate its choice on a following trial. Therefore, spontaneous alternation has been embraced by behavioral pharmacologists as a quick and relatively simple test of memory devoid of fear, reward or re-enforcers. A single unilateral intracerebral injection with 9 nmole aggregated β25-35 amyloid peptide was administered in the right lateral ventricle according to the technique of Maurice et al. (Brain Research. 1996;706:181-193).

The Y-maze was a three equal-size-arm maze (39 cm long) made of white PVC. The arms were oriented at 60 angles from each other. The Y-maze test was done 7-12 days post-amyloid administration under moderate lighting condition (200 lux), with moderate background music and mild eucalyptus odor. Compounds were given intraperitoneally 40 min before Y-maze trial.

Young Male Swiss mice began the single trial at the end of one arm, and were allowed to freely explore the Y-maze during 8 min. Number and sequence of arm visits was recorded. Alternation was defined as "a consecutive entry in three different arms". The alternation percentage was computed with the following formula: "number of alternation" divided by "total number of arm visit" minus 2.

The test compounds displayed typically an activity at 30 mg/kg or less.

Claims

1. A compound of formula (I)

wherein

R¹ is a fluorine atom;

n is equal to 1 , 2 or 3; and

R² is a cyano group of formula -CN.

as well as its tautomers, isomers and salts.

2. A compound according to claim 1 , wherein the 4-phenyl of formula (I) is in a 4R configuration.

3. A compound according to claim 1 , wherein the 4-phenyl of formula (I) is in a 4S configuration.

4. A compound according to any of claims 1 to 3, wherein n is 2 or 3.

5. A compound according to any of claims 1 to 4, wherein the 4-phenyl moiety is a 3,4,5- trifluorophenyl moiety.

6. A compound according to any of the preceding claims, selected from the group comprising :

4-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrroridin-1 -yl]methyl}-1 H-pyrazole-3-carbonitrile; (+)-4-{[(4R)-2-oxo-4-(3,4,5-trifiuorophenyl)pyrrolidin-1 -yl]methyl}-1 H-pyrazole-5- carbonitrile; and (-)-4-{[4-(2,4-difluorophenyl)-2-oxopyrrolidin-1 -yl]methyl}-1 H-pyrazole-3-carbonitri

7. A compound according to any of the preceding claims for use as a medicament.

8. A compound according to any of the claims 1 to 6, for use as a medicament in the treatment of a cognitive disorder.

9. A pharmaceutical composition containing a compound according to any of claims 1 to 6, as well as a suitable pharmaceutically acceptable excipient.