WO2008130853A1

WO2008130853A1 - Hydrazides and their use as metabotropic glutamate receptor potentiators - 681

Info

Publication number: WO2008130853A1
Application number: PCT/US2008/059858
Authority: WO
Inventors: Ian Egle; Abdelmalik Slassi; Methvin Isaac; Fupeng Ma; Joshua Clayton; Babu Joseph
Original assignee: Astrazeneca Ab
Priority date: 2007-04-17
Filing date: 2008-04-10
Publication date: 2008-10-30

Abstract

The present invention is directed to compounds of Formula I: wherein A and R1 to R8 are as defined in the specification.

Description

HYDRAZIDES AND THEIR USE AS METABOTROPIC GLUTAMATE RECEPTOR POTENTIATORS - 681

BACKGROUND OF THE INVENTION

The present invention relates to novel compounds that function as potentiators of glutamate receptors, methods for their preparation, pharmaceutical compositions containing them and their use in therapy.

The metabotropic glutamate receptors (mGluR) constitute a family of GTP -binding- protein (G-protein) coupled receptors that are activated by glutamate, and have important roles in synaptic activity in the central nervous system, including neural plasticity, neural development and neurodegeneration.

Activation of mGluRs in intact mammalian neurons elicits one or more of the following responses: activation of phospholipase C; increases in phosphoinositide (PI) hydrolysis; intracellular calcium release; activation of phospholipase D; activation or inhibition of adcnyl cyclase; increases or decreases in the formation of cyclic adenosine monophosphate (cAMP); activation of guanylyl cyclase; increases in the formation of cyclic guanosine monophosphate (cGMP); activation of phospholipase A₂; increases in arachidonic acid release; and increases or decreases in the activity of voltage- and ligand-gated ion channels (Schoepp et at., 1993, Trends Pharmacol. Sci., 14: 13 ; Schoepp, 1994, Neurochcm. Int., 24:439; Pin et al, 1995, Neuropharmacology 34:1; Bordi & Ugolini, 1999, Prog. Neurobiol. 59:55).

Eight mGluR subtypes have been identified, which are divided into three groups based upon primary sequence similarity, signal transduction linkages, and pharmacological profile. Group-I includes mGluRl and niGluRS, which activate phospholipase C and the generation of an intracellular calcium signal. The Group-II (mGluR2 and mGluR3) and Group-Ill (mGluR4, mGluRδ, mGluR7, and mGluR8) mGluRs mediate an inhibition of adenylyl cyclase activity and cyclic AMP levels. For a review, see Pin et at., 1999, Eur. J. Pharmacol., 375:277-294.

Activity of mGluR family receptors are implicated in a number of normal processes in the mammalian CNS, and are important targets for compounds for the treatment of a variety of neurological and psychiatric disorders. Activation of mGluRs is required for induction of hippocampal long-term potentiation and cerebellar long-term depression (Bashir et at., 1993, Nature, 363:347 ; Bortolotto et al, 1994, Nature, 368:740 ; Aiba et al, 1994, Cell, 79:365 ; Aiba et al, 1994, Cell, 79:377). A role for mGluR activation in nociception and analgesia also has been demonstrated (Meller et al, 1993, Neuroreport, 4: 879; Bordi & Ugolini, 1999, Brain Res., 871:223). In addition, mGluR activation has been suggested to play a modulatory role in a variety of other normal processes including synaptic transmission, neuronal development, apoptotic neuronal death, synaptic plasticity, spatial learning, olfactory memory, central control of cardiac activity, waiting, motor control and control of the vestibulo-ocular reflex (Nakanishi, 1994, Neuron, 13: 1031; Pin et al., 1995, Neuropharmacology, supra; Knopfel et al., 1995, J. Med. Chem., 38:1417).

Recent advances in the elucidation of the neurophysiological roles of mGluRs have established these receptors as promising drug targets in the therapy of acute and chronic neurological and psychiatric disorders and chronic and acute pain disorders. Because of the physiological and pathophysiological significance of the mGluRs, there is a need for new drags and compounds that can modulate mGluR function. SUMMARY OF THE INVENTION

We have identified a class of compounds that modulate mGluR function. In one aspect the invention provides compounds of Formula I, or a pharmaceutically acceptable salt, hydrate, solvate, optical isomer, or combination thereof:

Formula I wherein:

A is selected from the group consisting of null, alkyleiie, =CH- and =C(allcyl)-; R¹ is selected from the group consisting of H and alkyl, or is absent when A is =CH- or =C(alkyl)-; R^" is selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aiyl and heteroaryl, wherein R² may be substituted by one or more B; R³ and R⁴ are independently selected from the group consisting of H and alkyl; R⁵ is H; R⁶ is selected from the group consisting of F, Cl, Br, I, cyano, hydroxy, alkyl, O-alkyl, alkylhalo, O-alkylhalo, cycloalkyl, O-cycloalkyl, alkylenecycloalkyl, O- alkylenecycloalkyl, heterocycloalkyl, O-heterocyclo alkyl, alkyleneheterocycloalkyl,

O-alkyleneheterocycloalkyl, aryl, O-aryl, alkylenearyl, 0-alkylenearyl, heteroaiyl, O- heteroaryl, alkyleneheteroaryl and O-alkyleneheteroaryl, wherein R⁶ may be substituted by one or more B; R⁷ is H; R⁸ is selected from the group consisting of H, F, Cl, Br, I, Ci.s-alkyl, OCi.e-alkyl, C₁-₅- alkylhalo, and OCj.g-alkylhalo; R⁹ and R¹⁰ are, in each instance, independently selected from the group consisting of H, alkyl and alkylhalo; B is selected from the group consisting of hydroxy, F, Cl, Br, I, cyano, oxo, alkyl, haloalkyl, O-haloalkyl, NR¹¹R¹², NR¹¹C(O)R¹², NR^{1 1}C(O)NR¹¹R¹² and

N(R")SO₂R¹²; R¹¹ and R¹² are, in each instance, independently selected from the group consisting of H, alkyl and alkylene-aryl, wherein any aryl group may be substituted with a substituent selected from the group consisting of halo, alkyl, haloalkyl, alkoxy and haloalkoxy; or a pharmaceutically acceptable salt, hydrate, solvate, optical isomer, or combination thereof.

The invention also provides processes for the preparation of compounds of Formula I.

The invention further provides a pharmaceutical composition comprising a compound according to Formula I together with a pharmaceutically acceptable carrier or excipient; in another aspect the invention provides a method for the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction in an animal in need of such treatment. The method comprises the step of administering to the animal a therapeutically effective amount of a compound of Formula I or a pharmaceutical composition thereof.

The invention also provides for the use of a compound according to Formula I, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of any of the conditions discussed herein. Further, the invention provides a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, for use in therapy.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention is based upon the discovery of compounds that exhibit activity as pharmaceuticals, in particular as modulators of metabotropic glutamate receptors. More particularly, the compounds of the present invention exhibit activity as potentiators of the mGluR2 receptor, and are useful in therapy, in particular for the treatment of neurological and psychiatric disorders associated with glutamate dysfunction. Definitions

Unless specified otherwise within this specification, the nomenclature used in this specification generally follows the examples and rules stated in. Nomenclature of Organic Chemistry, Sections A, B, C, D, E, F, and H, Pergamon Press, Oxford, 1979, which is incorporated by references herein for its exemplary chemical structure names and rules on naming chemical structures. Optionally, a name of a compound may be generated using a chemical naming program: ACD/ChemSketch, Version 5.09/September 2001, Advanced Chemistry Development, Inc., Toronto, Canada.

The term "alkyl" as used herein means a straight- or branched-chain hydrocarbon radical having from one to six carbon atoms, and includes methyl, ethyl, propyl, isopropyl, t- butyl and the like.

The term "aikenyl" as used herein means a straight- or branched-chain alkenyl radical having from two to six carbon atoms, and includes ethenyl, 1-propenyl, 1-butenyl and the like.

The term "alkynyl" as used herein means a straight- or branched-chain alkynyl radical having from two to six carbon atoms, and includes 1 -propynyl (propargyl), 1 -butynyl and the like. The term "alkoxy" as used herein means a straight- or branched-chain alkoxy radical having from one to six carbon atoms and includes methoxy, ethoxy, propyloxy, isopropyloxy, £-butoxy and the like.

The term "halo" as used herein means halogen and includes fluoro, chloro, bromo, iodo and the like, in both radioactive and non-radioactive forms.

The term "alkylene" as used herein means a difunctional branched or unbranched saturated hydrocarbon radical having one to six carbon atoms, and includes methylene, ethylene, n-propylene, n-butylene and the like.

The term "alkenylene" as used herein means a difunctional branched or unbranched hydrocarbon radical having two to six carbon atoms and having at least one double bond, and includes ethenylene, n-propenylene, n-butenylene and the like.

The term "alkynylene" as used herein means a difunctional branched or unbranched hydrocarbon radical having two to six carbon atoms and having at least one triple bond, and includes ethynylene, n-propynylene, n-butynylene and the like.

The term "cycloalkyl" as used herein means a cyclic group (which may be unsaturated) having from three to seven carbon atoms, and includes cyclopropyl, cyclohexyl, cyclohexenyl and the like.

The term "hetero cycloalkyl" as used herein means a three- to seven-membered cyclic group (which may be unsaturated) having at least one heteroatom selected from the group consisting of N, S and O, and includes pipcridinyl, piperazinyl, pyrrolidinyl, tetrahydrofuranyl and the like.

The term "aryl" as used herein means an aromatic group having five to twelve atoms, and includes phenyl, naphthyl and the like.

The term "heteroaryl" means an aromatic group which includes at least one heteroatom selected from the group consisting of N, S and O, and includes groups and includes pyridyl, indolyl, furyl, benzofuryl, thienyl, benzothienyl, quinolyl, oxazolyl and the like.

The term "cycloalkenyl" as used herein means an unsaturated cylcloaklyl group having from four to seven carbon atoms, and includes cyclopent-1-enyl, cyclohex-1-enyl and the like. The term "pharmaceutically acceptable salt" means either an acid addition salt or a basic addition salt which is compatible with the treatment of patients.

A "pharmaceutically acceptable acid addition salt" is any non-toxic organic or inorganic acid addition salt of the base compounds represented by Formula I or any of its intermediates. Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids which form suitable salts include the mono-, di- and tricarboxylic acids. Illustrative of such acids are, for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, 2-phenoxybenzoic, p-toluenesulfonic acid and other sulfonic acids such as methanesulfonic acid and 2-hydroxyethanesulfonic acid. Either the mono- or di-acid salts can be formed, and such salts can exist in either a hydrated, solvated or substantially anhydrous form. In general, the acid addition salts of these compounds are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms. The selection criteria for the appropriate salt will be known to one skilled in the ait. Other non-pharmaceutically acceptable salts e.g. oxalates may be used for example in the isolation of compounds of Formula I for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.

A "pharmaceutically acceptable basic addition salt" is any non-toxic organic or inorganic base addition salt of the acid compounds represented by Formula I or any of its intermediates. Illustrative inorganic bases which form suitable salts include lithium, sodium, potassium, calcium, magnesium or barium hydroxides. Illustrative organic bases which form suitable salts include aliphatic, alicyclic or aromatic organic amines such as methylarnine, trimethyl amine and picoline or ammonia. The selection of the appropriate salt may be important so that an ester functionality, if any, elsewhere in the molecule is not hydrolyzed. The selection criteria for the appropriate salt will be known to one skilled in the art.

"Solvate" means a compound of Formula I or the pharmaceutically acceptable salt of a compound of Formula I wherein molecules of a suitable solvent are incorporated in a crystal lattice. A suitable solvent is physiologically tolerable at the dosage administered as the solvate. Examples of suitable solvents are ethanol, water and the like. When water is the solvent, the molecule is referred to as a hydrate.

The term "stereoisomers" is a general term for all isomers of the individual molecules that differ only in the oiientation of their atoms in space. It includes mirror image isomers (enantiomers), geometric (cis/trans) isomers and isomers of compounds with more than one chiral centre that are not mirror images of one another (diastereomers).

The term "treat" or "treating" means to alleviate symptoms, eliminate the causation of the symptoms either on a temporary or permanent basis, or to prevent or slow the appearance of symptoms of the named disorder or condition.

The term "therapeutically effective amount" means an amount of the compound which is effective in treating the named disorder or condition.

The term "pharmaceutically acceptable carrier" means a non-toxic solvent, dispersant, excipient, adjuvant or other material which is mixed with the active ingredient in order to permit the formation of a pharmaceutical composition, i.e., a dosage form capable of administration to the patient, One example of such a carrier is a pharmaceutically acceptable oil typically used for parenteral administration. Compounds

Compounds of the invention conform generally to Formula I:

Foπnula I wherein:

A is selected from the group consisting of null, alkylene, =CH- and =C(alkyl)-;

R¹ is selected from the group consisting of H and alkyl, or is absent when A is =CH- or

=C(alkyl)-;

R² is selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein R² may be substituted by one or more B; R³ and R are independently selected from the group consisting of H and alkyl;

R⁵ is H;

R⁶ is selected from the group consisting of F, Cl, Br, I, cyano, hydroxy, alkyl, O-alkyl, alkylhalo, O-alkylhalo, cycloalkyl, O-cycloalkyl, alkylenecycloalkyl, O- alkylenecycloalkyl, heterocycloalkyl, O-heterocycloalkyl, alkyleneheterocyclo alkyl,

O-alkyleneheterocycloalkyl, aiyl, O-aryl₅ alkylenearyl, O-alkylenearyl, heteroaryl, O- heteroaryl, allcyleneheteroaryl and O-alkyleneheteroaryl, wherein R⁶ may be substituted by one or more B; R⁷ is H; R⁸ is selected from the group consisting of H, F, Cl, Br, I, C_]-6-alkyl, OCi_-6-alkyl, Cj ₆- alkylhalo, and OCi.e-alkylhalo; R⁹ and R¹⁰ are, in each instance, independently selected from the group consisting of H, alkyl and alkylhalo; B is selected from the group consisting of hydroxy, F, Cl, Br, I, cyano, oxo, alkyl, haloalkyl, O-haloalkyl, NR¹¹R¹², KR¹¹C(O)R¹², NR¹¹C(O)NR¹¹R¹² and

In a particular embodiment A is null and R¹ is a phenyl group, which may be substituted; in one embodiment the substituent is a trifluoroniethoxy group. In other embodiments A is null R¹ is a cyclopropyl group or a cyclohexyl group.

In other embodiments A represents a =CH- group.

In further embodiments R⁶ is an optionally-substituted phenyl group; in another it is an optionally-substituted pyridyl group. In other embodiments the substituent is a sulphonamido group (such as -N(H)SO₂CH₃); in others it is an acylamino group (such as - N(H)C(O)CH₃). It will be understood by those of skill in the art that when compounds of the present invention contain one or more chiral centers, the compounds of the invention may exist in, and be isolated as, enantiomeric or diastereomeric forms, or as a racemic mixture. The present invention includes any possible enantiomers, diastereomers, racemates or mixtures thereof, of a compound of Formula I. The optically active forms of the compound of the invention may be prepared, for example, by chiral chromatographic separation of a racemate, by synthesis from optically active starting materials or by asymmetric synthesis based on the procedures described thereafter.

It will also be appreciated by those of skill in the art that certain compounds of the present invention may exist as geometrical isomers, for example E and Z isomers of alkenes. The present invention includes any geometrical isomer of a compound of Formula I. It will further be understood that the present invention encompasses tautomers of the compounds of Formula I.

It will also be understood by those of skill hi the art that certain compounds of the present invention may exist in solvated, for example hydrated, as well as unsolvated forms. It will further be understood that the present invention encompasses all such solvated forms of the compounds of Formula I.

Within the scope of the invention are also salts of the compounds of Formula I. Generally, pharmaceutically acceptable salts of compounds of the present invention are obtained using standard procedures well known in the art, for example, by reacting a sufficiently basic compound, for example an alkyl amine with a suitable acid, for example, HCl or acetic acid, to afford a physiologically acceptable anion. It is also possible to make a corresponding alkali metal (such as sodium, potassium, or lithium) or an alkaline earth metal (such as a calcium) salt by treating a compound of the present invention having a suitably acidic proton, such as a carboxylic acid or a phenol with one equivalent of an alkali metal or alkaline earth metal hydroxide or alkoxide (such as the ethoxide or methoxide), or a suitably basic organic amine (such as choline or meglumine) in an aqueous medium, followed by conventional purification techniques.

In one embodiment of the present invention, the compound of Formula I may be converted to a pharmaceutically acceptable salt or solvate thereof, particularly, an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, taitrate, citrate, methanesulphonate or/J-toluenesulphonate

Specific examples of the present invention include the compounds shown m the following table, their pharmaceutically acceptable salts, hydrates, solvates, optical isomers, and combinations thereof

-0X0-

o- -5 -

isomdol-5-

isomdol-5 -

- - 1 -

ahydi o-

l-

-1-oxo- -

l-oxo-

o-

- -oxo 2,3

o- 1 H

1- 1 H

Pharmaceutical Compositions

The compounds of the present invention may be formulated into conventional pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, in associaton with a pharmaceutically acceptable earner or excipient. The pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories.

A solid carrier can be one or more substances, which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or table disintegrating agents. A solid carrier can also be an encapsulating material.

In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided compound of the invention, or the active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

For preparing suppository compositions, a low-melting wax such as a mixture of fatty acid glycciϊdes and cocoa butter is first melted and the active ingredient is dispersed therein by, for example, stirring. The molten homogeneous mixture is then poured into convenient sized moulds and allowed to cool and solidify.

Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearatc, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, low-melting wax, cocoa butter, and the like.

The term composition is also intended to include the formulation of the active component with encapsulating material as a carrier providing a capsule in which the active component (with or without other earners) is surrounded by a carrier which is thus in association with it. Similarly, cachets are included. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.

Liquid form compositions include solutions, suspensions, and emulsions. For example, sterile water or water propylene glycol solutions of the active compounds may be liquid preparations suitable for parenteral administration. Liquid compositions can also be formulated in solution in aqueous polyethylene glycol solution.

Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable colorants, flavoring agents, stabilizers, and thickening agents as desired. Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art. Exemplary compositions intended for oral use may contain one or more coloring, sweetening, flavoring and/or preservative agents.

Depending on the mode of administration, the pharmaceutical composition will include from about 0.05%w (percent by weight) to about 99%w, more particularly, from about 0.10%w to 50%w, of the compound of the invention, all percentages by weight being based on the total weight of the composition.

Λ therapeutically effective amount for the practice of the present invention can be determined by one of ordinary skill in the art using known criteria including the age, weight and response of the individual patient, and interpreted within the context of the disease which is being treated or which is being prevented. Medical Use

We have discovered that the compounds of the present invention exhibit activity as pharmaceuticals, in particular as modulators of metabotropic glulamate receptors. More particularly, the compounds of the present invention exhibit activity as potentiators of the mGluR2 receptor, and are useful in therapy, in particular for the treatment of neurological and psychiatric disorders associated with glutamate dysfunction in an animal.

More specifically, the neurological and psychiatric disorders include, hut are not limited to, disorders such as cerebral deficit subsequent to cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, dementia (including AIDS-induced dementia), Alzheimer's disease, Huntington's Chorea, amyotrophic lateral sclerosis, ocular damage, retinopathy, cognitive disorders, idiopathic and drug-induced Parkinson's disease, muscular spasms and disorders associated with muscular spasticity including tremors, epilepsy, convulsions, cerebral deficits secondary to prolonged status epilepticus, migraine (including migraine headache), urinary incontinence, substance tolerance, substance withdrawal (including, substances such as opiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, hypnotics, etc.), psychosis, schizophrenia, anxiety (including generalized anxiety disorder, panic disorder, social phobia, obsessive compulsive disorder, and post-traumatic stress disorder (PTSD)), mood disorders (including depression, mania, bipolar disorders), circadian rhythm disorders (including jet lag and shift work), trigeminal neuralgia, hearing loss, tinnitus, macular degeneration of the eye, emesis, brain edema, pain (including acute and chronic pain states, severe pain, intractable pain, neuropathic pain, inflammatory pain, and post-traumatic pain), tardive dyskinesia, sleep disorders (including narcolepsy), attention deficit/hyp eractivity disorder, and conduct disorder.

The invention thus provides a use of any of the compounds according to Formula I, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of any of the conditions discussed above.

Additionally, the invention provides a method for the treatment of a subject suffering from any of the conditions discussed above, whereby an effective amount of a compound according to Formula I or a pharmaceutically acceptable salt or solvate thereof, is administered to a patient in need of such treatment. The invention also provides a compound of Formula I or pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined for use in therapy.

In the context of the present specification, the term "therapy" also includes "prophylaxis" unless there are specific indications to the contrary. The term "therapeutic" and "therapeutically" should be construed accordingly. The term "therapy" within the context of the present invention further encompasses the administration of an effective amount of a compound of the present invention, to mitigate either a pre-existing disease state, acute or chronic, or to mitigate a recurring condition. This definition also encompasses prophylactic therapies for prevention of recurring conditions and continued therapy for chronic disorders.

In use for therapy in a warm-blooded animal such as a human, the compounds of the present invention may be administered in the form of a conventional pharmaceutical composition by any route including orally, intramuscularly, subcutaneous Iy, topically, intranasally, intraperitoneally, intrathoracially, intravenously, epidurally, intrathecally, intracerebroventricularly and by injection into the joints. In preferred embodiments of the invention, the route of administration is oral, intravenous, or intramuscular.

The dosage will depend on the route of administration, the severity of the disease, age and weight of the patient and other factors normally considered by the attending physician, who determines the individual regimen and dosage level for a particular patient.

As mentioned above, the compounds described herein may be provided or delivered in a form suitable for oral use, for example, in a tablet, lozenge, hard and soft capsule, aqueous solution, oily solution, emulsion, and suspension. Alternatively, the compounds may be formulated into a topical administration, for example, as a cream, ointment, gel, spray, or aqueous solution, oily solution, emulsion or suspension. The compounds described herein also may be provided in a form that is suitable for nasal administration, for example, as a nasal spray, nasal drops, or dry powder. The compounds can be administered to the vagina or rectum in the form of a suppository. The compounds described herein also may be administered parentally, for example, by intravenous, intravesicular, subcutaneous, or intramuscular injection or infusion. The compounds can be administered by insufflation (for example as a finely divided powder). The compounds may also be administered transdermally or sublingual Iy.

In addition to their use in therapeutic medicine, the compounds of Formula I, or salts thereof, are useful as pharmacological tools in the development and standardisation of in vitro and in vivo test systems for the evaluation of the effects of inhibitors of mGluR-related activity in laboratory animals as part of the search for new therapeutics agents, Such animals include, for example, cats, dogs, rabbits, monkeys, rats and mice. Process for Preparing Compounds of the present invention can be prepared by various synthetic processes. The selection of a particular process to prepare a given compound is within the purview of the person of skill in the art. The choice of particular structural features and/or substituents may therefore influence the selection of one process over another.

Within these general guidelines, the following processes can be used to prepare exemplary subsets of compounds of this invention. Unless indicated otherwise, the variables described in the following schemes and processes have the same definitions as those given for Formula I above.

Scheme 1

a. R2-A-halide, Cs₂CO₃, CH₃CN, 70°C, 3 h b. 12 ⁰A HCI m MeOH c. Aq. NaHCO3

Scheme 2

a. Aldehyde (or ketone), Na(OAc)₃BH (or Na(CN)BH₃), Dichloroethane, CH₃COOH, RT, 0/N

Scheme 3

a. HCOOH/HCHO, 100"C, 2 h b Boronate ester, Pd(PPh₃)₄, 2M aq, Na₂CO₃, dimethoxy ethane, 1D0°C, 1 25 h

Scheme 4

Many variations of the foregoing processes and additions thereto appear throughout the examples that follow. The person of ordinary skill in the art thus will appreciate that the compounds of this invention can be prepared by following or adapting one or more of the processes disclosed herein.

The invention is further illustrated by way of the following examples, which are intended to elaborate several embodiments of the invention. These examples are not intended to, nor are they to be construed to, limit the scope of the invention. It will be clear that the invention may be practiced otherwise than as particularly described herein. Numerous modifications and variations of the present invention are possible in view of the teachings herein and, therefore, are within the scope of the invention. General methods

All starting materials are commercially available or earlier described in the literature.

The ¹H and ¹³C NMR spectra were recorded either on Bruker 300, Bruker DPX400 or Varian +400 spectrometers operating at 300, 400 and 400 MHz for ^H NMR respectively, using TMS or the residual solvent signal as reference, in deuterated chloroform as solvent unless otherwise indicated. All reported chemical shifts are in ppm on the delta-scale, and the fine splitting of the signals as appearing in the recordings (s: singlet, br s: broad singlet, d: doublet, t: triplet, q: quartet, m: multiplet).

Analytical in line liquid chromatography separations followed by mass spectra detections, were recorded on a Waters LCMS consisting of an Alliance 2795 (LC) and a ZQ single quadropole mass spectrometer. The mass spectrometer was equipped with an electrospray ion source operated in a positive and/or negative ion mode. The ion spray voltage was ±3 kV and the mass spectrometer was scanned from m/z 100-700 at a scan time of 0.8 s. To the column, X-Terra MS, Waters, C8, 2.1 x 50mm, 3.5 mm, was applied a linear gradient from 5 % to 100% acetonitrile inlO mM ammonium acetate (aq.), or in 0.1% TFA (aq.).

Preparative reversed phase chromatography was run on a Gils on autopreparative HPLC with a diode array detector using an XTerra MS C8, 19x300mm_J 7mm as column.

Purification by a chromatotron was performed on rotating silica gel / gypsum (Merck, 60 PF-254 with calcium sulphate) coated glass sheets, with coating layer of 1, 2, or 4 mm using a TC Research 7924T chiOinatotron.

Purification of products were also done using Chem Elut Extraction Columns (Varian, cat #1219-8002), Mega BE-SI (Bond Elut Silica) SPE Columns (Varian, cat # 12256018; 12256026; 12256034), or by flash chromatography in silica-filled glass columns.

Microwave heating was performed in a Smith Synthesizer Single-mode microwave cavity producing continuous irradiation at 2450 MHz (Personal Chemistry AB, Uppsala, Sweden). The pharmacological properties of the compounds of the invention can be analyzed using standard assays for functional activity. Examples of glutamate receptor assays are well known in the art as described in, for example, Aramori et al., 1992, Neuron, 8:757; Tanabe et al, 1992, Neuron, 8:169; Miller et al, 1995, J. Neuroscience, 15:6103; Balazs, et al, 1997, J. Neurochemistry, 1997,69:151, The methodology described in these publications is incoiporated herein by reference. Conveniently, the compounds of the invention can be studied by means of an assay that measures the mobilization of intracellular calcium, [Ca²⁺], in cells expressing mGluR2.

Fluorometric Imaging Plate Reader (FLIPR) analysis was used to detect allosteric activators of mGluR2 via calcium mobilization. A clonal HEK 293 cell line expressing a chimeric mGluR2/CaR construct comprising the extracellular and transmembrane domains of human mGluR2 and the intracellular domain of the human calcium receptor, fused to the promiscuous chimeric protein G_κqi5 was used. Activation of this construct by agonists or allosteric activators resulted in stimulation of the PLC pathway and the subsequent mobilization of intracellular Ca²⁺ which was measured via FLIPR analysis. At 24-hours prior to analysis, the cells were trypsinized and plated in DMEM at 100,000 cells/well in black sided, clear-bottom, collagen I coated, 96-well plates. The plates were incubated under 5% CO₂ at 37°C overnight. Cells were loaded with 6μM fluo-3 acetoxymethylester (Molecular Probes, Eugene Oregon) for 60 minutes at room temperature. All assays were performed in a buffer containing 126mM NaCl, 5mM KCl₁ ImM MgCI₂, ImM CaCl₂, 2OmM Hepes, 0.06μM DCG-IV (a Group II mGluR selective agonist), supplemented with l.Omg/rnl D-glucose and l.Omg/ml BSA fraction IV (pH 7.4).

FLIPR experiments were done using a laser setting of 0.8 W and a 0.4 second CCD camera shutter speed. Extracellular fluo-3 was washed off and cells were maintained in 160 μL of buffer and placed in the FLIPR. An addition of test compound (O.OlμM to 30μM in duplicate) was made after 10 seconds of baseline fluorescent readings were recorded on FLIPR. Fluorescent signals were then recorded for an additional 75 seconds at which point a second addition of DCG-IV (0.2μM) was made and fluorescent signals were recorded for an additional 65 seconds. Fluorescent signals were measured as the peak height of the response within the sample period. Data was analyzed using Assay Explorer, and EC₅₀ and E_max values (relative to maximum DCG-IV effect) were calculated using a four parameter logistic equation.

A [ S]-GTPyS binding assay was used to functionally assay mGluR2 receptor activation. The allosteric activator activity of compounds at the human mGluR2 receptor were measured using a [³³S]-GTPyS binding assay with membranes prepared from CHO cells which stably express the human mGluR2. The assay is based upon the principle that agonists bind to G-protein coupled receptors to stimulate GDP-GTP exchange at the G-protein. Since [ S]-GTPyS is a non-hydrolyzable GTP analog, it can be used to provide an index of GDP- GTP exchange and, thus, receptor activation. The GTPγS binding assay therefore provides a quantitative measure of receptor activation.

Membranes were prepared from CHO cells stably transfected with human mGluR2. Membranes (30 μg protein) were incubated with test compound (3nM to 300μM) for 15 minutes at room temperature prior to the addition of 1 μM glutamate, and incubated for 30 min at 30⁰C in 500 μl assay buffer (20 mM HEPES, 10OmM NaCl, 1OmM MgCk), containing 30μM GDP and 0.InM [³⁵S]-GTPyS (1250 Ci/mmol). Reactions were carried out in triplicate in 2 ml polypropylene 96-weIl plates. Reactions were terminated by vacuum filtration using a Packard 96-well harvester and Unifilter-96, GF/B filter microplates. The filter plates were washed 4 x 1.5 ml with ice-cold wash buffer (1OmM sodium phosphate buffer, pH 7.4). The filter plates were dried and 35 μl of scintillation fluid (Microscint 20) was added to each well. The amount of radioactivity bound was determined by counting plates on the Packard TopCount. Data was analyzed using GraphPad Prism, and EC₅₀ and Eiii_ax values (relative to the maximum glutamate effect) were calculated using non-linear regression.

Generally, the compounds of the present invention were active in assays described herein at concentrations (or with EC₅₀ values) less than 10 μM. For example, Compounds 9.5, 9.12, 16.1, 16.5 and 18.1 have EC50 values of 1647, 1467, 486, 385 and 24 DM, respectively. Example 1.1: 4-Bromo-2,6-dimethyl-benzonitrile

4-Bromo-2,6-dimethyl-phenylamine (49.2 g, 246.0 mmol) was suspended in 12 M hydrochloric acid (50 ml) and crushed ice (240 g) and chilled in a -12 ⁰C ice bath. A solution of sodium nitrite (17.32 g, 251.0 mmol) in water (40 niL) was added dropwise to the reaction, keeping the internal temperature below — 5 ⁰C. The reaction was allowed to stir for 45 minutes at this temperature before the reaction was neutralized with NaCO₃ (10 g). The reaction mixture was added to an ice cold solution of sodium cyanide (38.32 g, 782.0 mmol) and copper cyanide (27.68 g, 307.5 mmol) in toluene (480 mL) and water (128 mL). The reaction was stirred at 0 ⁰C for an hour and then allowed to slowly warm up to 47 ⁰C over a further 2.5 hours. The aqueous phase was extracted with portions of toluene and the combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated to afford the crude product (48.6 g, 94%). ¹H NMR (300 MHz₁ CDCl₃): δ 7.22 (s, 2H), 5.84 (br s, IH), 5.61 (br s, IH), 2.37 (s, 6H). Example 2.1: 4-Bromo-2,6-dimethyl-benzamide

4-Bromo-2,6-dimethyl-benzonitrile (48.48 g, 231.0 mmol) was suspended in a methanol (400 mL) and 6 M sodium hydroxide solution (400 mL). The mixture was heated to reflux for 17 hours. The reaction was filtered while hot, washing with portions of methanol. The filtrate was concentrated to remove much of the methanol and resulting solid was filtered and washed with methanol, water and hexanes. The resulting solid was dried under vacuum to afford the product as a beige solid (52.09 g, 98%). ¹H NMR (300 MHz, CDCl₃): δ 7.21 (s, 2H), 6.02 (br s, IH), 5.70 (br s, IH), 2.35 (s, 6H). Example 3.1: 4-Bromo-2,6-dimethyl-beπzoic acid

Nitrosyl sulfuric acid (270 niL) was added drop wise to water (115 mL) in an ice/salt bath. 4-Bromo-2,6-dimethyl-benzamide (37.30 g, 163.5 mmol) in dichloromethane (375 mL) was added as a slurry. The reaction was allowed to warm up to room temperature over 3 hours. The reaction mixture was then poured onto crushed ice (1000 mL) and stirred for 12 hours. The reaction mixture was partitioned between water and dichloromethane and the aqueous layer was extracted with portions of dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The solvent was removed under reduced pressure to afford the product (32.55 g). ¹H NMR (300 MHz, CDCl₃): δ 7.27 (s, 2H), 2.43 (s, 6H). Example 4.1: 4-Bromo-2,6-dimethylbeπzoic acid methyl ester

To a stirred solution of 4-bromo-2,6-dimethylbenzoic acid (2.81 g, 12.3 mmol) in dimethylformamide (30 mL) was added iodomethane (2.30 mL, 36.9 mmol) and potassium carbonate (5.09 g, 36.9 mmol) and reaction was stirred at room temperature for 1.5 hours. The reaction mixture was partitioned between water and ethyl acetate and the organic layer was washed with brine. The solvent was removed under reduced pressure to yield an amber oil (3.06g). ¹H NMR (300 MHz, CDCl₃): δ 7.22 (S, 2H), 3.92 (_S) 3H), 2.30 (s, 6H). Example 5.1: 4-Bromo-2-bromomethyl-6-methyIbenzoic acid methyl ester

4-Bromo-2,6-dimethylbenzoic acid methyl ester (1.2 g, 4.94 mmol), N- bromosuccinimide (1.01 g, 5.68 mmol) and benzoyl peroxide (120 mg, 0,494 mmol) in carbon tetrachloride (30 mL) was stirred at 90 ⁰C for 4.5 hours. The reaction was cooled to room temperature, filtered, washed with carbon tetrachloride and the solvent was removed under reduced pressure to provide a yellow oil (1.87 g). ¹H NMR (300 MHz, CDCl₃): 5 7.36 (d, 2H)₃ 4.51 (S₃ 2H), 3.98 (s, 3H), 2.35 (s, 3H). Example 6.1: (5-Bromo-7-methyH-oxo-l,3-dihydro-isoindol-2-yl)-carbamic acid tert- butyl ester

4-Bromo-2-biOmomethyl-6-methylbenzoic acid methyl ester (2.99 g, 9.28 mmol), hydrazinecarboxylic acid tert-butyl ester (2.45 g, 18.57 mmol), potassium carbonate (5.13 g, 37.14 mmol) and toluene/tetrahydrofuran (90 mL/10 mL) were stirred together at 85 ⁰C for 12 hours. The solid was removed by filtration and the organic phase was washed with water, brine, dried over sodium sulfate, filtered and concentrated. The product residue was purified by eluting through a solid phase extraction tube (ethyl acetate: hexanes, 5:95 to 50:50) to afford the product as a white solid (1.08 g, 33%). ¹H NMR (300 MHz, CDCl₃): δ 7.39 (d, 2H), 6.71 (br s, IH), 4.55 (s, 2H), 2.68 (s, 3H), 1.50 (s, 9H).

Example 7.1: (S-Bromo^-methyl-l-oxo-l^-dihydro-isoindol^-yty-cyclobutylmethyl- carbamic acid tert-buty! ester

(5-Bromo-7-methyl-l-oxo-l,3-dihydiO-isoindol-2-yl)-carbamic acid tert-butyl ester (0.05g, 0.146 mmol), bromomethyl cyclobutane (0.033 mL, 0.293 mmol) and cesium carbonate (0.12 g, 0.366 mmol) were stirred in acetonitrile (3 mL) at 70 ⁰C for 3 hours. The reaction mixture was partitioned with dichloromethane and water and the aqueous phase was further extracted with dichloromethane. The organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The product residue was purified by eluting through a solid phase extraction tube eluting with ethyl acetate:hexanes (2:98 to 5:95) to yield the product as a colorless oil (0.048 g, 80%). ¹H NMR (300 MHz, CDCI₃): 5 7.39 (d, 2H), 6.71 (br s, IH), 4.46 (s, 2H), 2.68 (s, 3H), 1.42 (s, 9H).

In a similar manner, the following compounds were made:

Example 8.1 : 4-(2-{24tert-ButoxyearbonyI-(4-culoro-benzγl)-ammol-7-methvl-l-oxo- 2,3-dihydro-lH-isoindoI-5-yIoxy}-ethyl)-piperidine-l-carboxylic acid tert-butyl ester

Palladium acetate (0.0012 g, 0.0054 mmol), [l,r]binaphthalenyl-2-yl-di-tert-butyl- phosphane (0.0043 g, 0.0107 mmol), cesium carbonate (0.087 g, 0.268 mmol), (5-bromo-7- methyl-l-oxo-l_;,3-dmydro-isoindol-2-yl)-(4-chloro-benzyl)-carbamic acid tert-butyl ester (0.05 g, 0.107 mmol), and 4-(2-hydroxy-ethyl)-piperidine-l-carboxylic acid tert-butyl ester (0.03 mL, 0.139 mmol) were stirred in toluene (2,0 mL) at 75 ⁰C for 5 hours. The reaction mixture was partitioned between water and ethyl acetate and the aqueous phase was extracted with ethyl acetate. The organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude residue was purified by eluting through an SPE tube with ethyl acetate :hexanes (5:95 to 15:85) to yield the product as a white foam (0.028 g, 42 %), ¹H NMR (300 MHz, CDCl₃): δ 7.30 (s, 4H), 6.70 (s, IH), 6.58 (s, IH), 5.18 (br m, 2H), 4.38 (br m, 2H), 4.09 (m, 4H), 3.80 (t, IH)₁ 2.70 (m, 5H), 1.62 (m, 6H), 1.46 (br t, 18H).

In a similar fashion, the following compounds were made:

Example 9.1: 2-Amino-5-bromo-7-methyl-2,3-dihydro-isoindol-l-one

(S-BiOmo-V-mcthyl-l-oxo-l^-dihydro-isorjidol^-y^-carbamic acid tert-butyl ester (0.345 g, 1.01 mmol) was stirred in 12-15% hydrochloric acid in methanol (20 mL) for 2 hours. The reaction mixture was concentrated, dissolved in dichlorome thane and washed with saturated sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane and concentrated to afford the product as a white solid (0.232 g). 1H NMR (300 MHz₃ CDCl₃): δ 7.39 (d, 2H)₃ 4.45 (s, 2H), 4.30 (br s, 2H), 2.69 (s, 3H).

In a similar fashion, the following compounds were made:

Example 10.1 : 5-Bromo-2-(cyclohexvlmethγIene-amino)-7-methvl-2,3-dihvdrQ-isoiπdol- 1-one

2-Amino-5-bromo-7-methyl-2,3-dihydro-isoindol-l-one (0,035 g, 0.145 mmol), cyclohexane carboxaldehyde (0.018 mL, 0.145 mmol) and sodium triacetoxyborohydride (0,05 g, 0.232 mmol) or sodium cyanoborohydride (0.435 mmol) were stirred in dichloro ethane (3 mL) and acetic acid (0.012 mL, 0.217 mmol) at room temperature for 12 hours. The reaction was quenched with saturated sodium bicarbonate solution and the aqueous phase was extracted with dichloromethane. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude residue was purified by eluting through a solid phase extraction tube with ethyl acetate: hexanes (5:95) to afford the product (0.043 g, 88.5% yield). ¹H NMR (300 MHz, CDCl₃): δ 7.38 (s, 2H), 4.76 (d, IH), 4.44 (s, 2H), 3.13 (m, IH), 2.68 (m, 3H), 1.87 (m, 3H), 1.78 (m, 3H), 1.23 (m, 6H).

In a similar fashion, the following compounds were made:

Example 11.1: 5-Bromo-7-niethyl-2-(2,2,2-trifluoro-l-metliyI-etliylideneamino)~2,3- dihydro-isoiiidol-1-one

2-Amino-5-bromo-7-methyl-2,3-dihydro-isoindol-l-one (0.05g, 0.207 mmol), 1,1,1- trifluoro-propan-2-one (0,023 mL, 0.249 mmol), magnesium sulfate (1 small scoop) and 2M hydrochloric acid in diethyl ether (7 drops) were stirred in dichloromethane (3 mL) at room temperature for 12 hours. The reaction mixture was filtered, washing with dichloromethane. The organic washings were washed with aqueous saturated sodium bicarbonate solution, brine, dried over sodium sulfate, filtered and concentrated to yield the product as a white solid (51 mg, 73%). ¹HNMR (300 MHz, CDCl₃): δ(ppm) 7.47 (s, IH), 7.42 (s, IH), 4.74 (s, 2H), 2.67 (s, 3H), 2.23 (s, 3H). Example 12.1: 5-Brorao-7-methyl-2-(2,2,2-trifluoro-l-methyl-ethylamino)-2,3-dihydro- isoindol-1-one

5-Bromo-7-methyl-2-(2,2,2-trifluoro-l-methyl-ethylideneamino)-2,3-diliydro- isoindol-1-one (0.05 g, 0.149 mmol) and sodium borohydride (0.028 g, 0.745 mmol) were stirred in methanol (4 mL) at 0 ⁰C. The reaction was stirred for 12h while warming up to RT. The reaction mixture was concentrated, then dissolved in dichloromethane. The organic phase was quenched with aqueous saturated sodium bicarbonate solution, and extracted further with dichloromethane. The organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude residue was purified by eluting through a solid phase extraction tube eluting with ethyl acetate :hexanes (7.5:92.5) to yield the product as a white solid (0.022 g, 44%). ¹H NMR (300 MHz₁ CDCl₃): δ(ppm) 7.40 (d, 2H), 4.60 (m, 2H)₃ 4.36 (m, IH), 3.75 (qd, IH), 2.68 (s, 3H), 1.43 (d, 3H). Example 13.1: 5-Br omo-2-cy clobutylamino-7-in ethy!-2,3-di hy dr o-isoindol-1-one

5-BiOmo-2-cycIobutyIideneamino-7-methyl-2,3-dihydro-isoindol-l-one (0.331 mmol) and platinum oxide (0.007 g, 0.0331 mmol) were stirred together in tetrahydrofuran (5 mL) under a hydrogen atmosphere for 1 h. The reaction mixture was filtered through C elite filtering agent, washing with dichloromethane. The organic phase was washed with saturated sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated. The crude residue was purified by eluting through a solid phase extraction tube with ethyl acetate :hexanes (2.5:97.5 to 10:90) and concentrated to yield the product as a white solid (0.067 g, 68 %). ¹H NMR (300 MHz, CDCl₃): δ(ppm) 7.35 (d, 2H), 4.98 (br s, IH), 4.41 (s, 2H), 3.72 (br t, IH), 2.67 (s, 3H), 2.18 (m, 2H), 1.95 (m, 2H)_} 1.77 (m, 2H).

In a similar fashion, the following compounds were made:

Example Structure Name Yield

Example 14.1: 5-Brorao-2-[(4-chlorophenyl)amino]-7-methylisoiudoIin-l-one

4-Bromo-2-bromomethyl-6-m.eth.ylbenzoic acid methyl ester (300 mg, 0.932 mmol), (4-chlorophenyl)hydrazjne (247 mg, 1,39 mmol) and potassium carbonate (772 mg, 5.60 mmol) were stirred in toluene (10 niL) at 100 ⁰C for 18 hours, The reaction was cooled to room temperature, partitioned between ethyl acetate and water and the organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the product was purified by column chromatography (10-50% ethyl acetate/hexanes) to afford an orange solid (89 mg). The product was used directly in the next step without further characterization.

The following compounds were made in the manner:

Example 15.1: 5-Bromo-2- (cy clohexyl-inethyl-amino)-7-methyl~2,3-dihydr o-is oin dol- 1 - one

5-Bromo-2-(cyclohexylamino)-7-methylisoindolin-l-one (400 mg, 1,24 mmol) was dissolved in formic acid (ImL) and stirred at room temperature for 0.5 hours. Formaldehyde (ImL) was then added and the mixture was heated to 100⁰C for 18 hours. The mixture was cooled to room temperature, neutralized with saturated sodium bicarbonate and extracted with dichloromethane. The organics were dried over anhydrous sodium sulfate, filtered, and concentrated. The product residue was purified by flash column chromatography to yield a yellow oil (160 mg). ¹H NMR (300 MHz, CDCl₃): δ (ppm) 7.36 (m, 2H), 4.40 (s, 2H), 3.20 (m, IH), 2.85 (s, 3H), 2.66 (s, 3H), 1.85 (d, 2H), 1.73 (m, 2H), 1.58 (m, IH), 1.20 (m, 5H).

In a similar fashion, the following compounds were made:

Example 16.1 : 2-f4-ChIoro-phenylamiDo)-7-methyl-5-pyridin-3-yl-2,3-dihydro-isoindol- 1-one

5-BiOmo-2-[(4-chlorophenyl)amino]-7-methylisoindolin-l-one (89 mg, 0.243 mmol), 3-(4,4,5,5-Tetramethyl-l,3.2-dioxaborolan-2-yl)-pyridine (75 mg, 0.365 mmol), potassium carbonate (101 mg, 0.729 mmol), l,r-bis(diphenylphosphino)-fenOcene-dichloropalladiiιm (20 mg, 0.0243 mmol), was stirred in dimethylformaπαide (3mL) at 110 ⁰C for 4 hours. The cooled reaction was concentrated and the residue was partitioned between ethyl acetate and water. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography eluting with ethyl acetate :hexanes (20:80 to 70:30) and purification by HPLC provided the title compound as a yellow oil (5 mg, 25 %). ¹H NMR (300 MHz, CDCl₃): 8.75 (br d, IH), 7.93 (d, IH), 7.49 (m, 3H), 7.21 (d, 2H), 6.74 (m, 2H), 6.46 (s, IH), 4.69 (s, 2H), 2.81 (s, 3H). In a similar fashion, the following compounds were made:

IH)₁ 7.92 (d, IH), 2.80 (s, 3H).

(m, 2H), 7.39 (m, (br d, IH), 1.24

IH), 7.89 (d, IH), 1.91 (m, 2H), 1.77

IH), 6.99 (d, IH), IH), 2.91 (s, 3H),

Example 17.1: N-{3- [2-(C yclohexyl-methyl-ami no)-7-methyl- l-oxo-2,3-dihydro-lH- isoindoI-5-yl]-phenyl}-methaαesulfoαamide

5-(3-Amino-phenyl)-2-(cyclohexyl-methyl-amino)-7-methyl-2,3-diliydiO-isoindol-l- one (25 mg, 0.0714 mmol) was dissolved in dichloromethane (3 niL) and was cooled to 0 ⁰C in an ice-bath. Diethylamine (15μL, 0.107mmol) and methane sulfonyl chloride (11 μL, 0.143 mmol) were then added and stirring continued at O⁰C for 1 hour. The solution was diluted with dichloromethane, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford 30 mg of the disulfonamide compound as a yellow solid. This was dissolved in DMF (3 mL) and a scoop of potassium carbonate was then added. The mixture stirred at 60 ⁰C for 1.5 hours and was cooled, diluted with water and extracted with ethyl acetate. The organic layer was washed with water (2x) and brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purification by flash column chromatography afforded a light yellow oil (27mg, 90%). ¹H NMR (300 MHz, CDCl₃): δ (ppm) 7.55 (m, 5H), 7.22 (m, IH), 6.92 (s, IH), 4.40 (s, 2H), 3.22 (m, IH)₅ 3.07 (s, 3H), 2.90 (s, 3H)₃ 2.77 (s, 3H), 1.89 (m, 2H), 1.77 (m, 2H)₁ 1.61 (m, IH), 1.26 (m, 5H). Example 18.1: N-{3-[2-(CyclohexylmethyIene-amino)-7-methyl-l-oxo-2,3-dihydro-lH- isoindol-5-yl]-phenyI}-methanesαlfonamide

In a vessel with a screw cap, 5-bromo-2-(cyclohexyhnethylene-amino)-7-methyl-2,3- dihydro-isoindol-l-one (0.015 g, 0.044 mol), N-[3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan- 2-yi)-phenyl]-methanesulfonamide (0.02Og, 0.067 mmol), palladium triphenylphosphine (0.005 g, 0.0044 mmol), 2M aqueous sodium carbonate (1 mL) and ethylene glycol dimethyl ether (1 mL) were stirred together at 100 ⁰C for 1.25 hours. The reaction mixture was diluted with dichloromethane and washed with, water. The aqueous phase was extracted with dichloromethane and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude residue was purified by eluting through a solid phase extraction tube with ethyl acetate: dichloromethane (2.5:97.5 to 10:90) to afford the product as a white solid (18 mg, 91%). ¹H NMR (300 MHz, CDCl₃): δ (ppm) 7.53 (s, IH), 7.43 (m, 5H), 7.30 (m, IH), 7.20 (s, IH), 4.57 (s, 3H), 3.08 (s, 3H), 2.78 (s, 3 H), 2.44 (br s, IH), 1.69-1.89 (m, 4H), 1.27 (m, 5H).

In a similar fashion, the following compounds were made:

(m, 6H), 4.55 (s, (rn, 5H).

6.92 (br s, IH), 4.85 (m, 6H), 1.20

(m, 5H), 4.80 (br (m, 611), 1.25 (m,

7.36 (m, 4H), 4.37 (s, (s, 2H), 1.82 (m, %),

6.73 (s, IH), 4,84 1.16 (d, 6H).

7.28 (d, IH), 7.21 (s, 3H), 2.76 (s, 3H),

7.29 (m, 2H), 4.97 (s, (m, 4H), 1.40 (m, 4H).

7.20 (s, III), 5.10 (br (m, 2H), 1.99 (m,

Claims

WHAT IS CLAIMED IS:

1. A compound according to Formula I:

Formula I wherein:

A is selected from the group consisting of null, alkylene, =CH- and =C(alkyl)-;

R¹ is selected from the group consisting of H and alkyl, or is absent when A is =CH- or =C(alkyl)-;

R² is selected from the group consisting of alkyl, cycloalkyl, hetcrocycloalkyl, aryl and heteroaryl, wherein R² may be substituted by one or more B;

R³ and R⁴ are independently selected from the group consisting of H and alkyl;

R⁵ is H;

R is selected from the group consisting of F, Cl, Br, I, cyano, hydroxy, alkyl, O-alkyl, alkylhalo, O-alkylhalo, cycloalkyl, O-cycloalkyl, alkylenecycloalkyl, O- alkylenecycloalkyl, heterocycloalkyl, O-heterocycloalkyl, alkyleneheterocycloalkyl, O-alkylenehetero cycloalkyl, aryl, O-aryl, alkylenearyl, O-alkylenearyl, heteroaiyl, O- heteroaiyl, alkyleneheteroaryl and O-alkyleneheteroaryl, wherein R⁶ may be substituted by one or more B;

R⁷ is H;

R⁸ is selected from the group consisting of H, F, Cl, Br, I, Ci^-alkyl, OCi-₆-alkyl, C^₆- alkylhalo, and OC [ g-alkylhalo;

R⁹ and R¹⁰ are, in each instance, independently selected from the group consisting of H, alkyl and alkylhalo; B is selected from the group consisting of hydroxy, F, Cl, Br, I, cyano, oxo, alkyl, haloalkyl, O-haloalkyl, NR^HR¹² ₅ NR^{1 1}C(O)R¹², NR^{1 1}C(O)NR^{1 1}R¹² and N(R¹ ^SO₂R¹²;

R¹¹ and R¹² are, in each instance, independently selected from the group consisting of H, alkyl and alkylene-aryl, wherein any aryl group may be substituted with a substituent selected from the group consisting of halo, alkyl, haloalkyl, alkoxy and haloalkoxy; or a pharmaceutically acceptable salt, hydrate, solvate, optical isomer, or combination thereof.

2. A compound according to claim 1 wherein A is null.

3. A compound according to claim 2 wherein R¹ is phenyl.

4. A compound according to claim 2 wherein R¹ is a cyclo alkyl group.

5. A compound according to claim 2 wherein R⁶ is a phenyl group.

6. A compound according to claim 2 wherein R⁶ is a pyridyl group.

7. A compound selected from the group consisting of:

(4-Chloro-benzyl)-(5-{3-[(4-chloro-benzyl)-methanesulfonyl-amino]-phenyl}-7-methyl-l- oxo-l,3-diliydro-isoindol-2-yl)-carbamic acid tert-butyl ester,

5-Bromo-2-(cyclobutylmethyl-amino)-7-methyl-2,3-dihydro-isoindol-lone,

N-{3-[2-(Cyclobutylmethyl-amino)-7-methyl-l-oxo-2,3-dihydro-lH-isomdoi-5-yl]-phenyl}- methanesulfonamide,

N-[3-(7-Methyl-l-oxo-2-propylamino-2,3-diliydro-lH-isoindol-5-yl)-phenyl]- methanesulfonamide,

N-[3-(7-Methyl-l-oxo-2-propylamino-2,3-drhydro-lH-isoindol-5-yl)-phenyl]-acetamide,

N-[3-(7-Methyl-2-methylamino-l-oxo-2,3-dihydro-lH-isoindol-5-yl)-phenyl]- methanesulfonamide, N-(3-{7-Mefhyl-l-oxo-2-[(tetrahydro-pyran-4-ylmethyl)-amino]-2,3-dih.ydiO-lH-isoindol-5- yl} -phenyl)-methanesulfonamide,

2-(4-Chloro-benzylamino)-7-methyl-5-(2-piperidin-4-yl-ethoxy)-2,3-dihydro-isoindol-l-one_J

N-{3-[2-(4-CHoro-benzylamino)-7-raetliyl-l-oxo-2,3-diliydro-lH-isoindol-

5-yl] -phenyl} -methanesulfonamide,

2-(Cyclohexylmethyl-amino)-7-meth.yl-5-(2-piperidin-4-yl-ethoxy)-2₎3-diliydro-isoindol-l- one,

2-(Cyclohexyl-methyl-ammo)-7-methyl-5-(2-piperidin-4-yl-ethoxy)-2,3-dULydro-isoindol-l- one,

2-(4-ChloiO-benzylamino)-7-methyl-5-(3-piperidin-4-yl-propoxy)-2,3-diliydro-isoindol-l- one; hydrochloride,

N-{3-[2-(Isopropyl-methyl-a-nmo)-7-methyl-l-oxo-2,3-dihydτO-lH-isoindol-5-yl]-phenyl}- methanesulfonamide,

N-(3-{7-Methyl-2-[]netliyl-(2,2,2-trifluoro-l-methyl-ethyl)-amino]-l-oxo-2,3-dihydro-lH- isoindol-5 -yl } -phenyl)-methanesulfonamidc,

N-(3-{7-Methyl-2-[methyl-(2,2,2-trifliioro-l-methyl-ethyl)-amino]-l-oxo-2,3-diliydro-lH- isoindol-5-yl}-phenyl)-methanesulfonamide,

N- {3-[2-(Cyclobutyl-methyl-amino)-7-methyl-l -oxo-2, 3-dihydro- lH-isoindol-5-yl]-phenyl} - methanesulfonamide,

N-{3-[2-(Cyclohexylmethyl-methyl-amino)-7-methyl-l-oxo-2,3-dihydro-lH-isoindol-5-yl]- phenyl } -melhanesulfonamide,

2-(4-Chloro-phenylamino)-7-methyl-5-pyridin-3-yl-2,3-dihydro-isoindol-l-one,

7-Methyl-5~pyridin-3-yl-2- { [4-(trifluoromethoxy)phenyl] amino } isoindolin- 1 -one,

2-Cyclohexylamino-7-methyl-5-pyridin-3-yl-2,3-dihydro-isoindol-l-one,

2-(Cyclohexyl-methyl-amiao)-7-methyl-5-pyridin-3-yl-2,3-dihydro-isoindol-l-one,

5-(3-Amino-phenyl)-2-(cyclohexyl-methyl-amino)-7-methyl-2,3-dihydro-isoindol-l-one,

N-{3-[2-(Cyclohexyl~methyl-amino)-7-methyl-l-oxo-2₎3-dihydro-lH-isomdol-5-yl]- phenyl} -methanesulfonamide,

N-{3-[2-(Cyclohexylmethylene-amino)-7-methyl-l-oxo-2, 3-dihydro- lH-isoindol-5-yl]- phenyl} -methanesulfonamide, N-[3 -^-Cyclohexylamino^-methyl- 1 -oxo-2, 3 -dihydro- 1 H-isoindol-5-yl)-phenyl] - methanesulfonamide,

N-[3 -(2-Cyclohexylamino-7-methyl- 1 -oxo-2,3 -dihydro- 1 H-isoindol-5-yl)-phenyl] -acetamide,

N-{3-[2-(Cyclohexyl-methyl-amino)-7-methyl-l-oxo-2_;,3-dihydro-lH-isoiiidol-5-yl]- phenyl} -acetamide,

N-[3-(2-Isopropylamino-7-memyl-l-oxo-2,3-dihydro-lH-isoindol-5-yI)-phenyl]- methanesulfonamide,

N-{3-[7-MethyH-oxo-2-(2,2,2-trifluoro-l-methyl-ethylamino)-2_J3-dihydro-lH-isoindol-5- y 1] -phenyl } -methanesulfonamide,

N- [ 3-(2-Cyclopentylamino-7-methyl- 1 -oxo-2, 3 -dihydro - 1 H-isoindol-5 -yl) -phenyl] - methanesulfonamide,

N-[3-(2-CyclobutyIamino-7-methyl-l-oxo-2,3-dihydro-lH-isohidol-5-yl)-phenyl]- methanesulfonamide,

N-{3-[2-(Cyclohexyhnethyl-amino)-7-methyl-l-oxo-2_:3-dihydro-lH-isoindol-5-yl]-phenyl}" methanesulfonamide,

N-{3-[2-(Cyclohexyhnethyl-amino)-7-methyl-l-oxo-2,3-dihydro-lH-isoindol-5-yl]-phenyl}- acetamide,

N-{3-[2-(Cyclobutyhnethyl-amino)-7-methyl-l-oxo-2,3-dihydro-lH-isoindol-5-yl]-phenyl}- acetamide,

N-{3-[2-(Cyclohexyhnethyl-methyI-amino)-7-melhyl-l -oxo-2,3 -dihydro-lH- isoindol-5-yl]-phenyl} -acetamide,

N-[3-(2-Dimethylamino-7-methyl-l-oxo-2,3-dihydro-lH-isoindol-5-yl)-phenyl]- methancsulfonamide,

N-{3-[2-(Cyclobutylmethyl-methyl~amino)-7-methyl-l-oxo-2,3-dihydro-lH- isoindol-5-yl]-phenyl} -methanesulfonamide,

N-{3-[2-(Cyclobutylmelhyl~methyl-amino)-7-methyl-l-oxo-2,3-dihydro-lH-isoindol-5-yl]- phenyl} -acetamide,

N-{3-[7-Methyl-2-(methyl-propyl-amino)-l-oxo-2,3-dihydro-lH-isoindol-5-yl]-phenyl}- methanesulfonamide, N-{3-[7-Methyl-2-(methyl-piOpyl-amino)-l-oxo-2,3-dihydro-lH-isoindol-5-yl]-phenyl}- acetamide,

N-(3-{7-Methyl-2-[methyl-(tetrahydro-pyran-4-ylmethyl)-amino]-l -oxo-2,

3 -dihydro- 1 H-isoindo 1-5 -yl } -phenyl)-methanesulfonamide ,

N- {3 -[2-(Cyclopentylmethyl-amino)-7-methyl- l-oxo-2,3 -dihydro - 1 H-iso indol-5 -yl] -phenyl } - methanesulfonamide,

N-[3-(2-IsobutyIamino-7-methyl-l-oxo-2,3-dihydro-lH-isoindol-5-yl)-phenyl]- methanesulfonamide,

N-{3-[2-(CyclopiOpylmethyl-amino)-7-methyl-l-oxo-2,3-dihydro-lH-isoiadol-5-yl]- phenyl} -methanesulfonamide,

N- { 3-[2-(Cyclopentylmethyl-methyl-amino)- 7-methyl- 1 -oxo -2 , 3 -dihydro- 1 H

-isoindol-5-yl] -phenyl} -methanesulfonamide, and

N- {3 -[2-(Cyclopropylmethyl-methyl-amino)-7-methyl- 1 -oxo-2,3 -dihydro- 1 H

-isoindol-5-yl]-phenyl} -methanesulfonamide,

8. A pharmaceutical composition comprising a compound according to any one of claims 1 — 7 and a pharmaceutically acceptable carrier or excipient.

9. A compound according to any one of claims 1 - 7 for use as a medicament.

10. The use of a compound according to any one of claims 1 — 7 in the manufacture of a medicament for the therapy of neurological and psychiatric disorders associated with glutamate dysfunction,

11. The use of claim 10, wherein the neurological and psychiatric disorders arc selected from cerebral deficit subsequent to cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, dementia, AIDS-induccd dementia, Alzheimer's disease, Huntington's Chorea, amyotrophic lateral sclerosis, ocular damage, retinopathy, cognitive disorders, idiopathic and drug-induced Parkinson's disease, muscular spasms and disorders associated with muscular spasticity including tremors, epilepsy, convulsions, cerebral deficits secondary to prolonged status epilepticus, migraine, migraine headache, urinary incontinence, substance tolerance, substance withdrawal, psychosis, schizophrenia, anxiety, generalized anxiety disorder, panic disorder, social phobia, obsessive compulsive disorder, and post- traumatic stress disorder (PTSD), mood disorders, depression, mania, bipolar disorders, circadian rhythm disorders, jet lag, shift work, trigeminal neuralgia, hearing loss, tinnitus, macular degeneration of the eye, emesis, brain edema, pain, acute pain, chronic pain, severe pain, intractable pain, neuropathic pain, inflammatory pain, and post-traumatic pain, tardive dyskinesia, sleep disorders, narcolepsy, attention deficit/hyperactivity disorder, and conduct disorder.

12. A method for the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction in an animal in need of such treatment, comprising the step of administering to said animal a therapeutically effective amount of a compound according to any one of claims 1 - 7.

13. A method for the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction in an animal in need of such treatment, comprising the step of administering to said animal a therapeutically effective amount of a pharmaceutical composition according to claim 8.

14. The method according to claim 12 or 13, wherein the neurological and psychiatric disorders are selected from cerebral deficit subsequent to cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, dementia, AIDS -induced dementia, Alzheimer's disease, Huntington's Chorea, amyotrophic lateral sclerosis, ocular damage, retinopathy, cognitive disorders, idiopathic and drug-induced Parkinson's disease, muscular spasms and disorders associated with muscular spasticity including tremors, epilepsy, convulsions, cerebral deficits secondary to prolonged status epilepticus, migraine, migraine headache, urinaiy incontinence, substance tolerance, substance withdrawal, psychosis, schizophrenia, anxiety, generalized anxiety disorder, panic disorder, social phobia, obsessive compulsive disorder, and posttraumatic stress disorder (PTSD), mood disorders, depression, mania, bipolar disorders, circadian rhythm disorders, jet lag, shift work, trigeminal neuralgia, hearing loss, tinnitus, macular degeneration of the eye, emesis, brain edema, pain, acute pain, chronic pain, severe pain, intractable pain, neuropathic pain, inflammatory pain, and post-traumatic pain, tardive dyskinesia, sleep disorders, narcolepsy, attention deficit/hyperactivity disorder, and conduct disorder.

15. The method according to claim 14, wherein the neurological and psychiatric disorders are selected from Alzheimer's disease, cerebral deficits secondary to prolonged status epilepticus, substance tolerance, substance withdrawal, psychosis, schizophrenia, anxiety, generalized anxiety disorder, panic disorder, social phobia, obsessive compulsive disorder, and post-traumatic stress disorder (PTSD), mood disorders, depression, mania, and bipolar disorders.