JP2009509921A - Substituted isoindolones and their use as metabotropic glutamate receptor potentiators - Google Patents

Abstract

The present invention is directed to formula (I):
{Wherein R ¹ is a ring, R ⁵ is a specific substituent, and n is 1 to 8}. The invention also relates to the use of the present compounds as therapeutic, particularly metabotropic glutamate receptor modulators in neurological and psychiatric disorders.

Description

Detailed Description of the Invention

RELATED APPLICATION This application is related to PCT International Patent Application No. PCT / US05 / 28760, filed Aug. 12, 2005, which is hereby incorporated by reference in its entirety.

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

  Metabotropic glutamate receptors (mGluR) build a family of GTP-binding proteins (G-protein) -coupled receptors that are activated by glutamate, and synaptic activity in the central nervous system such as neuroplasticity, neurogenesis and neurodegeneration It plays an important role.

Activation of mGluR in intact mammalian neurons elicits one or more of the following responses: activation of phospholipase C; increased phosphoinositide (PI) hydrolysis; intracellular calcium release; activation of phospholipase D; adenyl cyclase Activation or inhibition; increased or decreased formation of cyclic adenosine monophosphate (cAMP); activation of guanylyl cyclase; increased formation of cyclic guanosine monophosphate (cGMP); activation of phospholipase A ₂ ; arachidonic acid release And increased or decreased activation of voltage-dependent and ligand-dependent ion channels (Schoepp et al., 1993, Trends Pharmacol. Sci, 14:13; Schoepp, 1994, Neurochem. Int., 24: 439; Pin et al., 1995, Neuropharmacology 34: 1; Bordi and Ugolini, 1999, Prog. Neurobiol. 59:55).

  Eight types of mGluR subtypes have been identified and divided into three groups based on major sequence similarity, signal transduction binding and pharmacological profile. Group I includes mGluR1 and mGluR5, which activate the generation of phospholipase C and intracellular calcium signals. Group II (mGluR2 and mGluR3) and Group III (mGluR4, mGluR5, mGluR7, and mGluR8) mGluR mediate inhibition of adenylyl cyclase activity and cyclic AMP levels. Pin et al., 1999, Eur. J. See Pharmacol, 375: 277-294.

  The activity of mGluR family receptors is involved in many processes in the mammalian CNS and is an important target for compounds for the treatment of various neurological and neurological diseases. Activation of mGluR is required for induction of hippocampal long-term potentiation and cerebellar long-term depression (Bashir et al., 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 pain and analgesia has also been shown (Meller et al., 1993, Neuroreport, 4: 879; Bordi and Ugolini, 1999, Brain Res., 871: 223). Furthermore, mGluR activation is involved in various normal processes such as synaptic transmission, neurodevelopment, apoptotic neuronal death, synaptic plasticity, spatial learning, olfactory memory, central control of cardiac activity, arousal, motor control, and control of vestibulo-ocular reflexes. Have been suggested (Nakanishi, 1994, Neuron, 13: 1031; Pin et al., 1995, Neuropharmacology, supra; Knopfel et al., 1995, J. Med. Chem., 38: 1417).

  With recent advances in elucidating the neurophysiological role of mGluR, these receptors have been established as promising drug targets in the treatment of acute and chronic nervous system diseases and psychosis and chronic and acute pain disorders. ing. Due to the physiological and pathophysiological significance of mGluR, there is a need for new drugs and compounds that can modulate mGluR function.

Summary of the Invention Applicants have identified compounds that modulate mGluR function. In one aspect, the present invention provides compounds of formula I:

{Wherein R ¹ is a 3- to 7-membered ring optionally containing one or more heteroatoms independently selected from the group consisting of N, O and S, wherein the ring is one Optionally substituted by more than one A;
R ² and R ³ are independently H, C _1-6 -alkyl, C _2-6 -alkenyl, C _2-6 -alkynyl, aryl, heteroaryl, heterocycloalkyl, C _3-8 -cycloalkyl, Selected from the group consisting of C _1-6 -alkyl-aryl, C _1-6 -alkyl-heteroaryl, C _1-6 -alkyl-heterocycloalkyl, and C _1-6 -alkyl-C _3-8 -cycloalkyl Wherein R ² and R ³ may be substituted by one or more A;
R ⁴ and R ⁶ are independently H, hydroxy, F, Cl, Br, I, nitro, cyano, C _1-6 -alkyl, C _1-6 -alkylhalo, OC _1-6 -alkyl, OC _{1- 6} - alkylhalo, C _2-6 - alkenyl, OC _2-6 - alkenyl, C _2-6 - alkynyl, OC _2-6 - alkynyl, C _3-8 - cycloalkyl, C _1-6 - alkyl -C _{3- 8} -cycloalkyl, OC _0-6 -alkyl-C _3-8 -cycloalkyl, aryl, C _1-6 -alkylaryl, OC _0-6 -alkylaryl, (CO) R ¹⁰ , O (CO) R ¹⁰ , O (CO) OR ¹⁰ , C (O) OR ¹⁰ , O (CNR ¹⁰ ) OR ¹¹ , C _1-6 -alkyl OR ¹⁰ , OC _2-6 -alkyl OR ¹⁰ , C _1-6 -alkyl (CO) R ¹⁰ , OC _1-6 -alkyl (CO) R ¹⁰ , C _0-6 -alkylCO ₂ R ¹⁰ , OC _1-6 -alkyl CO ₂ R ¹⁰ , C _1-6 -alkylcyano, OC _2-6- Alkyl cyano, C _0-6 -alkyl NR ¹⁰ R ¹¹ , OC _2-6 -alkyl NR ¹⁰ R ¹¹ , C _1-6 -alkyl (CO) NR ¹⁰ R ¹¹ , OC _1-6 -alkyl (CO) NR ¹⁰ R ¹¹ , C _0-6 -alkyl NR ^{1 0} (CO) R ¹¹ , OC _2-6 -alkyl NR ¹⁰ (CO) R ¹¹ , C _0-6 -alkyl NR ¹⁰ (CO) NR ¹⁰ R ¹¹ , C _0-6 -alkyl SR ¹⁰ , OC _2-6 -Alkyl SR ¹⁰ , C _0-6 -alkyl (SO) R ¹⁰ , OC _2-6 -alkyl (SO) R ¹⁰ , C _0-6 -alkyl SO ₂ R ¹⁰ , OC _2-6 -alkyl SO ₂ R ¹⁰ , C _0-6 -alkyl (SO ₂ ) NR ¹⁰ R ¹¹ , OC _2-6 -alkyl (SO ₂ ) NR ¹⁰ R ¹¹ , C _0-6 -alkyl NR ¹⁰ (SO ₂ ) R ¹¹ , OC _2-6 -Alkyl NR ¹⁰ (SO ₂ ) R ¹¹ , C _0-6 -alkyl NR ¹⁰ (SO ₂ ) NR ¹⁰ R ¹¹ , OC _2-6 -alkyl NR ¹⁰ (SO ₂ ) NR ¹⁰ R ¹¹ , (CO) NR ¹⁰ R ¹¹ , O (CO) NR ¹⁰ R ¹¹ , NR ¹⁰ OR ¹¹ , C _0-6 -alkyl NR ¹⁰ (CO) OR ¹¹ , OC _2-6 -alkyl NR ¹⁰ (CO) OR ¹¹ , SO ₃ R ¹⁰ , And selected from the group consisting of 5- to 7-membered rings optionally containing one or more heteroatoms independently selected from the group consisting of N, O and S, wherein R ⁴ and R ⁶ May be substituted by one or more A, where any cycloalkyl or aliquot May be fused to a 5- to 7-membered ring which may contain one or more heteroatoms independently selected from the group consisting of C, N, O and S;
R ⁵ is CN, OC _0-6 -alkyl, C _3-8 cycloalkyl, C _1-6 -alkyl-C _3-8 -cycloalkyl, OC _0-6 -alkyl-C _3-8 -cycloalkyl, C _0-6 -alkylaryl, OC _0-6 -alkylaryl, C _0-6 -alkylheteroaryl, OC _0-6 -alkylheteroaryl, heterocycloalkyl, C _1-6 -alkylheterocycloalkyl, OC ₀ Selected from the group consisting of _-6 -alkylheterocycloalkyl and C (O) R ₁₀ , wherein any cyclic moiety is substituted by one or more B;
R ⁷ is H, F, Cl, Br, I, nitro, cyano, OC _1-4 -alkyl, C _1-6 -alkyl, C _1-6 -alkylhalo, OC _1-6 -alkylhalo, C _2-6 Selected from the group consisting of -alkenyl, OC _2-6 -alkenyl, C _2-6 -alkynyl, OC _2-6 -alkynyl, and C _3-8 -cycloalkyl;
R ⁸ and R ⁹ are independently H, F, Cl, Br, I, nitro, cyano, C _1-6 -alkyl, C _1-6 -alkylhalo, OC _1-6 alkyl, OC _1-6 -alkylhalo, Selected from the group consisting of C _2-6 -alkenyl, OC _2-6 -alkenyl, C _2-6 -alkynyl, and OC _2-6 -alkynyl, or when n is greater than 1, on adjacent carbon atoms In the absence of two or more R ⁸ and / or R ⁹ can form an alkenyl or alkynyl moiety;
R ¹⁰ and R ¹¹ are independently H, hydroxy, oxo, F, Cl, Br, I, nitro, cyano, C _1-6 -alkyl, C _1-6 alkylhalo, OC _1-6 -alkyl, OC _{1 -6} - alkylhalo, C _2-6 - alkenyl, OC _2-6 - alkenyl, C _2-6 - alkynyl, OC _2-6 - alkynyl, C _3-8 - cycloalkyl, C _1-6 - alkyl -C _{3 -8} -cycloalkyl, OC _0-6 -alkyl-C _3-8 -cycloalkyl, aryl, C _1-6 -alkylaryl, OC _0-6 -alkylaryl, C _0-6 -alkyl-heterocycloalkyl, From the group consisting of OC _1-6 -alkyl-heterocycloalkyl, heteroaryl, C _1-6 alkylheteroaryl, heterocycloalkyl-C _1-6 -alkylaryl and heterocycloalkyl-C _{1-6 -alkylheteroaryl} Wherein any cyclic moiety is one or more he selected independently from the group consisting of C, N, O, and S. It may be fused to a 5- to 7-membered ring which may contain a rho atom, any cyclic moiety being a substituent selected from alkyl, halo, hydroxyl, O alkyl, haloalkyl and O haloalkyl. Optionally substituted;
A is H, hydroxy, F, Cl, Br, I, nitro, cyano, oxo, C _1-6 -alkyl, C _1-6 -alkylhalo, OC _1-6 alkyl, OC _1-6 -alkylhalo, C _{2 -6} -alkenyl, OC _2-6 -alkenyl, C _2-6 -alkynyl, OC _2-6 -alkynyl, C _3-8 -cycloalkyl, C _1-6 -alkyl-C _3-8 -cycloalkyl, OC _0-6 - alkyl -C _3-8 - cycloalkyl, aryl, C _1-6 - alkyl aryl, OC _0-6 - alkyl aryl, C _1-6 - alkyl - heterocyclyl, C _1-6 - alkyl - Heterocycloalkyl, OC _0-6 -alkyl-heterocycloalkyl, (CO) R ¹⁰ , O (CO) R ¹⁰ , O (CO) OR ¹⁰ , O (CNR ¹⁰ ) OR ¹¹ , C _1-6 -alkyl OR ¹⁰ , OC _2-6 -alkyl OR ¹⁰ , C _1-6 -alkyl (CO) R ¹⁰ , OC _1-6 -alkyl (CO) R ¹⁰ , C _0-6 -alkylCO ₂ R ¹⁰ , OC _1-6 -Alkyl CO ₂ R ¹⁰ , C _1-6 -alkyl cyano, OC _2-6 -alkyl cyano, C _0-6 -alkyl NR ¹⁰ R ¹¹ , C _{2- 6} -alkyl NR ¹⁰ R ¹¹ , C _0-6 -alkyl (CO) NR ¹⁰ R ¹¹ , OC _1-6 -alkyl (CO) NR ¹⁰ R ¹¹ , C _0-6 -alkyl NR ¹⁰ (CO) R ¹¹ , OC _2-6 -alkyl NR ¹⁰ (CO) R ¹¹ , C _0-6 -alkyl NR ¹⁰ (CO) NR ¹⁰ R ¹¹ , C _0-6 -alkyl SR ¹⁰ , OC _2-6 -alkyl SR ¹⁰ , C _{0 -6} -alkyl (SO) R ¹⁰ , OC _2-6 -alkyl (SO) R ¹⁰ , C _1-6 -alkylSO ₂ R ¹⁰ , OC _2-6 -alkylSO ₂ R ¹⁰ , C _0-6 -alkyl (SO ₂ ) NR ¹⁰ R ¹¹ , OC _2-6 -alkyl (SO ₂ ) NR ¹⁰ R ¹¹ , C _0-6 -alkyl NR ¹⁰ (SO ₂ ) R ¹¹ , OC _2-6 -alkyl NR ¹⁰ (SO ₂ ) R ¹¹ , C _0-6 -alkyl NR ¹⁰ (SO ₂ ) NR ¹⁰ R ¹¹ , OC _2-6 -alkyl NR ¹⁰ (SO ₂ ) NR ¹⁰ R ¹¹ , (CO) NR ¹⁰ R ¹¹ , O (CO) NR ¹⁰ R ¹¹ , NR ¹⁰ OR ¹¹ , C _0-6 -alkyl NR ¹⁰ (CO) OR ¹¹ , OC _2-6 -alkyl NR ¹⁰ (CO) OR ¹¹ , SO ₃ R ¹⁰ , and N, O and S Selected from the group consisting of 5- to 7-membered rings which may contain one or more heteroatoms independently selected from the group consisting of 7-membered ring may be substituted by one or more of R ¹⁰ and R ^11;
B is C _0-6 -alkyl-C _3-8 -cycloalkyl, OC _0-6 -alkyl-C _3-8 -cycloalkyl, C _0-6 -alkylaryl, OC _0-6 -alkylaryl, C _1-6 -alkylheterocycloalkyl, OC _{0-6 -alkylheterocycloalkyl} , C _1-6 -alkylheteroaryl and OC _1-6 -alkylheteroaryl, wherein any cyclic moiety Is substituted with at least one substituent selected from the group consisting of halo, alkyl, alkylhalo, alkoxy, oxo, COR, CO ₂ R, SO ₂ R and CN;
R is selected from the group consisting of H and alkyl; and
n is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8}, or a pharmaceutically acceptable salt, hydrate, solvate, optical isomer thereof Or provide a combination.

  The present invention also provides a process for preparing a compound of formula I.

  The present invention further provides a pharmaceutical composition comprising a compound of formula I together with a pharmaceutically acceptable carrier or excipient. In another aspect, the invention provides methods for treating or preventing such diseases in animals in need of treatment for neurological and psychiatric disorders associated with glutamate dysfunction. The method comprises administering to the animal a therapeutically effective amount of a compound of formula I or a pharmaceutical composition thereof.

  The present invention also provides the use of a compound of 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. The present invention further provides a compound of formula I, or a pharmaceutically acceptable salt or solvate for use in therapy.

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

Definitions Unless otherwise stated herein, the nomenclature used herein is generally Nomenclature of Organic Chemistry, Chapters A, B, C, D, E, F and H, Pergamon Press, Oxford, Follow the examples and rules described in 1979. This exemplary chemical structure name and chemical structure naming convention are included herein by reference. In some cases, the compound name is the compound naming program: ACD / ChemSketch, version 5.09 / September 2001, Advanced Chemistry Development, Inc. Can be attached using Toronto, Canada.

  As used herein, the term “alkyl” refers to a straight or branched hydrocarbon group having, for example, 1 to 6 carbon atoms, including methyl, ethyl, propyl, isopropyl, t-butyl, and the like. It is done.

  As used herein, the term “alkenyl” refers to a straight or branched alkenyl group having, for example, 2 to 6 carbon atoms, and includes ethenyl, 1-propenyl, 1-butenyl, and the like.

  As used herein, the term “alkynyl” refers to a straight or branched alkynyl group having, for example, 2 to 6 carbon atoms, and includes 1-propynyl (propargyl), 1-butynyl and the like.

  As used herein, the term “cycloalkyl” refers to a cyclic group (which may be unsaturated) having, for example, 3-7 carbon atoms, such as cyclopropyl, cyclohexyl, cyclohexenyl, and the like. Can be mentioned.

  The term “heterocycloalkyl” as used herein refers to, for example, a 3-7-membered cyclic group (unsaturated) having at least one heteroatom selected from the group consisting of N, S and O. And may include piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrofuranyl and the like.

  As used herein, the term “alkoxy” refers to a straight or branched alkoxy group having, for example, 1 to 6 carbon atoms, including methoxy, ethoxy, propyloxy, isopropyloxy, t-butoxy, and the like. Can be mentioned.

  The term “halo” as used herein refers to halogen and includes both radioactive and non-radioactive forms of fluoro, chloro, bromo, iodo and the like.

  As used herein, the term “aryl” means an aromatic having, for example, 5 to 12 atoms, and includes phenyl, naphthyl, and the like.

  The term “heteroaryl” refers to an aromatic group containing at least one heteroatom selected from the group consisting of N, S and O and is pyridyl, indolyl, furyl, benzofuryl, thienyl, benzothienyl, quinolyl, And oxazolyl.

  As used herein, the term “alkanoyl” means a straight or branched alkanoyl group having, for example, 2 to 7 atoms, and includes acetyl, propionyl, butyryl and the like.

  The term “cycloalkenyl” as used herein refers to an unsaturated cycloalkyl group having, for example, 4 to 7 carbon atoms, and includes cyclopent-1-enyl, cyclohex-1-enyl, and the like.

  The terms “alkylaryl”, “alkylheteroaryl” and “alkylcycloalkyl” refer to an alkyl group substituted with an aryl, heteroaryl or cycloalkyl group, including 2-phenethyl, 3-cyclohexylpropyl, and the like.

  “5- to 7-membered ring optionally containing one or more heteroatoms independently selected from N, O and S” includes aromatic and heteroaromatic rings, and saturated. Carbocyclic and heterocyclic rings which may be unsaturated or unsaturated, such as furyl, isoxazolyl, oxazolyl, pyrazoloyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, thiazolyl, thienyl, imidazolyl, triazolyl, morpholinyl, piperazinyl, piperidinyl , Homopiperidinyl, tetrahydropyranyl, phenyl, cyclohexyl, cycloheptyl, cyclopentyl, cyclohexanyl and the like.

  The term “pharmaceutically acceptable salts” refers to either acid or base addition salts that are compatible with the treatment of patients.

  The term “pharmaceutically acceptable acid addition salt” is any non-toxic organic or inorganic acid addition salt of a basic compound represented by Formula I or any of its intermediates.

  Representative inorganic acids that form suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, and acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. . Representative organic acids that form suitable salts include mono-, di-, and tricarboxylic acids. Representative of such acids are, for example, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, There are benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, 2-phenoxybenzoic acid, p-toluenesulfonic acid, and other sulfonic acids such as methanesulfonic acid and 2-hydroxyethanesulfonic acid. Either mono-acid or di-acid salts can be formed, and such salts must exist in either hydrated, solvated or substantially anhydrous forms. Can do. Usually, acid addition salts of these compounds are easily dissolved in water and various hydrophilic organic solvents, and usually show a higher melting point than their free base forms. The selection criteria for suitable salts are known to those skilled in the art. Other pharmaceutically unacceptable salts, such as oxalate, can be isolated in the isolation of compounds of formula I for use in the laboratory or subsequent conversion to pharmaceutically acceptable acid addition salts. Can be used.

  A “pharmaceutically acceptable base addition salt” is any non-toxic organic or inorganic base addition salt of an acid compound represented by Formula I or any of its intermediates. Representative inorganic bases that form suitable salts include lithium, sodium, potassium, calcium, manganese, or barium hydroxide. Representative organic bases that form suitable salts include aliphatic, alicyclic or aromatic organic amines such as methylamine, trimethylamine and picoline or ammonia. The choice of a suitable salt is important so that it does not hydrolyze the ester functionality if it is elsewhere in the molecule. The selection criteria for suitable salts are known to those skilled in the art.

  “Solvate” means a compound of formula I or a pharmaceutically acceptable salt of a compound of formula I, wherein the molecules of a suitable solvent are incorporated within the crystal lattice. Suitable solvents are physiologically tolerable at doses administered as solvates. Examples of suitable solvents include ethanol, water and the like. When water is the solvent, the molecule is called a hydrate.

  The term “stereoisomer” is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. This includes enantiomers (enantiomers), geometric (cis / trans) isomers, and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereomers).

  The terms `` treat '' or `` treating '' alleviate symptoms, remove the cause of the symptoms temporarily or permanently, or prevent or slow the named disease or symptom from appearing. It means to do.

  The term “therapeutically effective amount” means an amount of a compound that is effective in treating the named disease or condition.

  The term “pharmaceutically acceptable carrier” refers to non-toxic solvents, dispersants, excipients, adjuvants or the like that are mixed with an active ingredient to form a pharmaceutical composition, ie, a dosage form that can be administered to a patient. Means the substance. An example of such a carrier is a pharmaceutically acceptable oil normally used for parenteral administration.

Compounds Compounds of the present invention are typically of formula I:

{Wherein R ¹ is a 3- to 7-membered ring optionally containing one or more heteroatoms independently selected from the group consisting of N, O and S, wherein the ring is one Optionally substituted by more than one A;
R ² and R ³ are independently H, C _1-6 -alkyl, C _2-6 -alkenyl, C _2-6 -alkynyl, aryl, heteroaryl, heterocycloalkyl, C _3-8 -cycloalkyl, Selected from the group consisting of C _1-6 -alkyl-aryl, C _1-6 -alkyl-heteroaryl, C _1-6 -alkyl-heterocycloalkyl, and C _1-6 -alkyl-C _3-8 -cycloalkyl Wherein R ² and R ³ may be substituted by one or more A;
R ⁴ and R ⁶ are independently H, hydroxy, F, Cl, Br, I, nitro, cyano, C _1-6 -alkyl, C _1-6 -alkylhalo, OC _1-6 -alkyl, OC _{1- 6} - alkylhalo, C _2-6 - alkenyl, OC _2-6 - alkenyl, C _2-6 - alkynyl, OC _2-6 - alkynyl, C _3-8 - cycloalkyl, C _1-6 - alkyl -C _{3- 8} -cycloalkyl, OC _0-6 -alkyl-C _3-8 -cycloalkyl, aryl, C _1-6 -alkylaryl, OC _0-6 -alkylaryl, (CO) R ¹⁰ , O (CO) R ¹⁰ , O (CO) OR ¹⁰ , C (O) OR ¹⁰ , O (CNR ¹⁰ ) OR ¹¹ , C _1-6 -alkyl OR ¹⁰ , OC _2-6 -alkyl OR ¹⁰ , C _1-6 -alkyl (CO) R ¹⁰ , OC _1-6 -alkyl (CO) R ¹⁰ , C _0-6 -alkylCO ₂ R ¹⁰ , OC _1-6 -alkyl CO ₂ R ¹⁰ , C _1-6 -alkylcyano, OC _2-6- Alkyl cyano, C _0-6 -alkyl NR ¹⁰ R ¹¹ , OC _2-6 -alkyl NR ¹⁰ R ¹¹ , C _1-6 -alkyl (CO) NR ¹⁰ R ¹¹ , OC _1-6 -alkyl (CO) NR ¹⁰ R ¹¹ , C _0-6 -alkyl NR ^{1 0} (CO) R ¹¹ , OC _2-6 -alkyl NR ¹⁰ (CO) R ¹¹ , C _0-6 -alkyl NR ¹⁰ (CO) NR ¹⁰ R ¹¹ , C _0-6 -alkyl SR ¹⁰ , OC _2-6 -Alkyl SR ¹⁰ , C _0-6 -alkyl (SO) R ¹⁰ , OC _2-6 -alkyl (SO) R ¹⁰ , C _0-6 -alkyl SO ₂ R ¹⁰ , OC _2-6 -alkyl SO ₂ R ¹⁰ , C _0-6 -alkyl (SO ₂ ) NR ¹⁰ R ¹¹ , OC _2-6 -alkyl (SO ₂ ) NR ¹⁰ R ¹¹ , C _0-6 -alkyl NR ¹⁰ (SO ₂ ) R ¹¹ , OC _2-6 -Alkyl NR ¹⁰ (SO ₂ ) R ¹¹ , C _0-6 -alkyl NR ¹⁰ (SO ₂ ) NR ¹⁰ R ¹¹ , OC _2-6 -alkyl NR ¹⁰ (SO ₂ ) NR ¹⁰ R ¹¹ , (CO) NR ¹⁰ R ¹¹ , O (CO) NR ¹⁰ R ¹¹ , NR ¹⁰ OR ¹¹ , C _0-6 -alkyl NR ¹⁰ (CO) OR ¹¹ , OC _2-6 -alkyl NR ¹⁰ (CO) OR ¹¹ , SO ₃ R ¹⁰ , And selected from the group consisting of 5- to 7-membered rings optionally containing one or more heteroatoms independently selected from the group consisting of N, O and S, wherein R ⁴ and R ⁶ Is optionally substituted by one or more A, where any cycloalkyl or aryl May be fused to a 5- to 7-membered ring which may contain one or more heteroatoms independently selected from the group consisting of C, N, O and S;
R ⁵ is CN, OC _0-6 -alkyl, C _3-8 cycloalkyl, C _1-6 -alkyl-C _3-8 -cycloalkyl, OC _0-6 -alkyl-C _3-8 -cycloalkyl, C _0-6 -alkylaryl, OC _0-6 -alkylaryl, C _0-6 -alkylheteroaryl, OC _0-6 -alkylheteroaryl, heterocycloalkyl, C _1-6 -alkylheterocycloalkyl, OC ₀ Selected from the group consisting of _-6 -alkylheterocycloalkyl and C (O) R ₁₀ , wherein any cyclic moiety is substituted by one or more B;
R ⁷ is H, F, Cl, Br, I, nitro, cyano, OC _1-4 -alkyl, C _1-6 -alkyl, C _1-6 -alkylhalo, OC _1-6 -alkylhalo, C _2-6 Selected from the group consisting of -alkenyl, OC _2-6 -alkenyl, C _2-6 -alkynyl, OC _2-6 -alkynyl, and C _3-8 -cycloalkyl;
R ⁸ and R ⁹ are independently H, F, Cl, Br, I, nitro, cyano, C _1-6 -alkyl, C _1-6 -alkylhalo, OC _1-6 alkyl, OC _1-6 -alkylhalo, Selected from the group consisting of C _2-6 -alkenyl, OC _2-6 -alkenyl, C _2-6 -alkynyl, and OC _2-6 -alkynyl, or when n is greater than 1, on adjacent carbon atoms In the absence of two or more R ⁸ and / or R ⁹ can form an alkenyl or alkynyl moiety;
R ¹⁰ and R ¹¹ are independently H, hydroxy, oxo, F, Cl, Br, I, nitro, cyano, C _1-6 -alkyl, C _1-6 alkylhalo, OC _1-6 -alkyl, OC _{1 -6} - alkylhalo, C _2-6 - alkenyl, OC _2-6 - alkenyl, C _2-6 - alkynyl, OC _2-6 - alkynyl, C _3-8 - cycloalkyl, C _1-6 - alkyl -C _{3 -8} -cycloalkyl, OC _0-6 -alkyl-C _3-8 -cycloalkyl, aryl, C _1-6 -alkylaryl, OC _0-6 -alkylaryl, C _0-6 -alkyl-heterocycloalkyl, From the group consisting of OC _1-6 -alkyl-heterocycloalkyl, heteroaryl, C _1-6 alkylheteroaryl, heterocycloalkyl-C _1-6 -alkylaryl and heterocycloalkyl-C _{1-6 -alkylheteroaryl} Wherein any cyclic moiety is one or more he selected independently from the group consisting of C, N, O, and S. It may be fused to a 5- to 7-membered ring which may contain a rho atom, any cyclic moiety being a substituent selected from alkyl, halo, hydroxyl, O alkyl, haloalkyl and O haloalkyl. Optionally substituted;
A is H, hydroxy, F, Cl, Br, I, nitro, cyano, oxo, C _1-6 -alkyl, C _1-6 -alkylhalo, OC _1-6 alkyl, OC _1-6 -alkylhalo, C _{2 -6} -alkenyl, OC _2-6 -alkenyl, C _2-6 -alkynyl, OC _2-6 -alkynyl, C _3-8 -cycloalkyl, C _1-6 -alkyl-C _3-8 -cycloalkyl, OC _0-6 - alkyl -C _3-8 - cycloalkyl, aryl, C _1-6 - alkyl aryl, OC _0-6 - alkyl aryl, C _1-6 - alkyl - heterocyclyl, C _1-6 - alkyl - Heterocycloalkyl, OC _0-6 -alkyl-heterocycloalkyl, (CO) R ¹⁰ , O (CO) R ¹⁰ , O (CO) OR ¹⁰ , O (CNR ¹⁰ ) OR ¹¹ , C _1-6 -alkyl OR ¹⁰ , OC _2-6 -alkyl OR ¹⁰ , C _1-6 -alkyl (CO) R ¹⁰ , OC _1-6 -alkyl (CO) R ¹⁰ , C _0-6 -alkylCO ₂ R ¹⁰ , OC _1-6 -Alkyl CO ₂ R ¹⁰ , C _1-6 -alkyl cyano, OC _2-6 -alkyl cyano, C _0-6 -alkyl NR ¹⁰ R ¹¹ , C _{2- 6} -alkyl NR ¹⁰ R ¹¹ , C _0-6 -alkyl (CO) NR ¹⁰ R ¹¹ , OC _1-6 -alkyl (CO) NR ¹⁰ R ¹¹ , C _0-6 -alkyl NR ¹⁰ (CO) R ¹¹ , OC _2-6 -alkyl NR ¹⁰ (CO) R ¹¹ , C _0-6 -alkyl NR ¹⁰ (CO) NR ¹⁰ R ¹¹ , C _0-6 -alkyl SR ¹⁰ , OC _2-6 -alkyl SR ¹⁰ , C _{0 -6} -alkyl (SO) R ¹⁰ , OC _2-6 -alkyl (SO) R ¹⁰ , C _1-6 -alkylSO ₂ R ¹⁰ , OC _2-6 -alkylSO ₂ R ¹⁰ , C _0-6 -alkyl (SO ₂ ) NR ¹⁰ R ¹¹ , OC _2-6 -alkyl (SO ₂ ) NR ¹⁰ R ¹¹ , C _0-6 -alkyl NR ¹⁰ (SO ₂ ) R ¹¹ , OC _2-6 -alkyl NR ¹⁰ (SO ₂ ) R ¹¹ , C _0-6 -alkyl NR ¹⁰ (SO ₂ ) NR ¹⁰ R ¹¹ , OC _2-6 -alkyl NR ¹⁰ (SO ₂ ) NR ¹⁰ R ¹¹ , (CO) NR ¹⁰ R ¹¹ , O (CO) NR ¹⁰ R ¹¹ , NR ¹⁰ OR ¹¹ , C _0-6 -alkyl NR ¹⁰ (CO) OR ¹¹ , OC _2-6 -alkyl NR ¹⁰ (CO) OR ¹¹ , SO ₃ R ¹⁰ , and N, O and S Selected from the group consisting of 5- to 7-membered rings which may contain one or more heteroatoms independently selected from the group consisting of 7-membered ring may be substituted by one or more of R ¹⁰ and R ^11;
B is C _0-6 -alkyl-C _3-8 -cycloalkyl, OC _0-6 -alkyl-C _3-8 -cycloalkyl, C _0-6 -alkylaryl, OC _0-6 -alkylaryl, C _1-6 -alkylheterocycloalkyl, OC _{0-6 -alkylheterocycloalkyl} , C _1-6 -alkylheteroaryl and OC _1-6 -alkylheteroaryl, wherein any cyclic moiety Is substituted with at least one substituent selected from the group consisting of halo, alkyl, alkylhalo, alkoxy, oxo, COR, CO ₂ R, SO ₂ R and CN;
R is selected from the group consisting of H and alkyl; and
n is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8} or a pharmaceutically acceptable salt, hydrate, solvate, optical isomer thereof or According to the combination, except
The compound is not selected from the group consisting of:
5- (4-benzyl-piperazine-1-carbonyl) -7-methyl-2- (4-trifluoromethoxy-benzyl) -2,3-dihydro-isoindol-1-one,
7-methyl-5- (4-pyridin-4-ylmethyl-piperazine-1-carbonyl) -2- (4-trifluoromethoxy-benzyl) -2,3-dihydro-isoindol-1-one,
7-Methyl-5- [4- (2-pyridin-4-yl-ethyl) piperazine-1-carbonyl] -2- (4-trifluoromethoxy-benzyl) -2,3-dihydro-isoindole-1- on,
4- {4- [7-Methyl-1-oxo-2- (4-trifluoromethoxy-benzyl) -2,3-dihydro-1H-isoindol-5-ylmethyl] -piperidin-1-ylmethyl} -benzo Nitrile,
2-benzyl-1-oxo-2,3-dihydro-1H-isoindole-5-carbonitrile,
7-chloro-1-oxo-2- (4-trifluoromethoxy-benzyl) -2,3-dihydro-1H-isoindole-5-carbonitrile,
7-methyl-1-oxo-2- (4-trifluoromethoxy-benzyl) -2,3-dihydro-1H-isoindole-5-carbonitrile,
7-methyl-1-oxo-2- (4-chloro-benzyl) -2,3-dihydro-1H-isoindole-5-carbonitrile,
1-oxo-2- (4-trifluoromethoxy-benzyl) -7-trifluoromethyl-2,3-dihydro-1H-isoindole-5-carbonitrile,
3-oxo-2- (4-trifluoromethoxy-benzyl) -2,3-dihydro-1H-isoindole-4,6-dicarbonitrile,
7-iodo-5-methoxy-2- (4-trifluoromethoxy-benzyl) -2,3-dihydro-isoindol-1-one,
2-benzyl-5-methoxy-2,3-dihydro-isoindol-1-one, and
7-Chloro-5-methoxy-2- (4-trifluoromethoxy-benzyl) -2,3-dihydro-isoindol-1-one.

  When a compound of the present invention contains one or more chiral centers, it will be understood by those skilled in the art that the compound of the present invention may exist and be isolated as an enantiomer or diastereoisomer form or as a racemic mixture. . The present invention includes all possible enantiomers, diastereoisomers, racemates or mixtures of the compounds of formula I. Optically active forms of the compounds of the invention can be prepared, for example, by chiral chromatographic resolution of racemates, by synthesis from optically active starting materials, or by asymmetric synthesis based on the procedures described below.

  It will be appreciated by those skilled in the art that certain compounds of the present invention may exist as geometric isomers, for example E and Z isomers of alkenes. The present invention includes all geometric isomers of the compounds of formula I. It will be further understood that the present invention includes tautomers of compounds of formula I.

  It will also be appreciated by those skilled in the art that certain compounds of the present invention may exist in solvated forms, such as hydrated forms, as well as unsolvated forms. It will also be understood that the invention encompasses all such solvated forms of the compounds of formula I.

  Also within the scope of the invention are salts of the compounds of formula I. In general, pharmaceutically acceptable salts of compounds of the present invention can be obtained by standard procedures known in the art, eg, a sufficiently basic compound, such as an alkylamine and a suitable acid, such as HCl or Reaction with acetic acid can yield a physiologically acceptable anion. A compound of the invention having a suitable acidic proton, such as a carboxylic acid or phenol, and an alkali metal or alkaline earth metal hydroxide or alkoxide (eg ethoxide or methoxide) or a suitably basic organic amine (eg choline or Reaction with 1 equivalent of meglumine) in an aqueous medium followed by the formation of the corresponding alkali metal (eg sodium, potassium or lithium) or alkaline earth metal (eg calcium) salt by conventional purification methods. Is possible.

  In one embodiment of the invention, the compound of formula I is a pharmaceutically acceptable salt or solvate thereof, in particular an acid addition salt, such as the hydrochloride, hydrobromide, phosphate, acetate, fumaric acid It can be converted to a salt, maleate, tartrate, citrate, methanesulfonate, p-toluenesulfonate, or the like.

In a particular embodiment of the invention, R ⁵ is selected from the group consisting of heterocycloalkyl and C _1-6 alkylheterocycloalkyl.

In a particular embodiment of the invention, B is selected from the group consisting of C _0-6 alkylaryl, C _1-6 alkylheteroaryl and C _{0-6 alkylheterocycloalkyl} .

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

Pharmaceutical Compositions The compounds of the present invention are formulated into conventional pharmaceutical compositions comprising a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable carrier or excipient. obtain. Pharmaceutically acceptable carriers can be either solid or liquid. Examples of solid formulations include, but are not limited to, powders, tablets, dispersible particles, capsules, cachets and suppositories.

  A solid carrier can be one or more substances, which also function as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders or tablet disintegrating agents. The solid carrier also functions as an encapsulant.

  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 ingredient is mixed with the carrier having the necessary binding properties in suitable proportions and compressed into the desired shape and size.

  For preparing suppository compositions, a low-melting wax such as a mixture of fatty acid glycerides 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 conventional sized forms and allowed to cool and solidify.

  Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, sodium methylcellulose, a low melting wax, cocoa butter, and the like.

  The term composition is also intended to include a combination of an encapsulant and an active ingredient as a carrier that provides a capsule surrounded by the associated carrier (optionally including other carriers). Similarly, cachets are included.

  Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration.

  Liquid compositions include solutions, suspensions and emulsions. For example, a solution of the active compound in sterile water or water propylene glycol may be a liquid formulation suitable for parenteral administration. The liquid composition can also be formulated as a solution in an aqueous polyethylene glycol solution.

  Aqueous solutions for oral compositions can be prepared by dissolving the active component in water and adding the desired suitable colorants, flavors, stabilizers, and thickening agents. Aqueous suspensions for oral use contain finely divided active ingredients together with viscous materials such as synthetic natural rubber, resins, methylcellulose, sodium carboxymethylcellulose, and other suspending agents known in the pharmaceutical formulation industry. It can be produced by dispersing in water. Exemplary compositions for oral use can include one or more colorants, flavors, and / or preservatives.

  Depending on the dosage form, the pharmaceutical composition comprises from about 0.05% to about 99% by weight, in particular from about 0.10% to 50% by weight of a compound of the invention. All weight percentages are based on the total weight of the composition.

  A therapeutically effective amount for practicing the present invention can be determined by one of ordinary skill in the art using known criteria such as the age, weight and response of an individual patient, and is interpreted within the disease to be treated or prevented Can do.

Medical Use The Applicant has found that the compounds of the present invention are active as drugs, particularly as modulators of metabotropic glutamate receptors. In particular, the compounds of the present invention exhibit activity as mGluR2 receptor potentiators and are useful in therapy, particularly in the treatment of neurological and psychiatric disorders associated with glutamate dysfunction in animals.

  More specifically, neurological and psychiatric disorders include brain damage secondary to cardiac bypass surgery and transplantation, stroke, cerebral ischemia, spinal cord injury, skull injury, perinatal hypoxia, heart failure, hypoglycemic nerve injury, cognition (Including AIDS-induced dementia), Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis, eye damage, retinopathy, cognitive impairment, idiopathic and drug-induced Parkinson's disease, muscle spasm and trembling, epilepsy , Muscle spasms and disorders related to muscle spasm such as convulsions, cerebral deficits secondary to prolonged status epilepticus, migraine, migraine (including migraine headache), urine Incontinence, substance tolerance, substance withdrawal (including drugs such as opium, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, analgesics, hypnotics), psychosis Schizophrenia, anxiety (including generalized anxiety disorder, panic disorder, interpersonal phobia, obsessive compulsive disorder, and traumatic stress disorder (PTSD)), mood disorders (including depression, epilepsy, bipolar disorder), Circadian rhythm disorders (including jet lag and shift work), trigeminal neuralgia, hearing loss, tinnitus, macular degeneration of eyes, vomiting, cerebral edema, pain (acute and chronic pain, severe pain, intractable pain, neuropathic pain, Including, but not limited to, inflammatory pain and post-traumatic pain), delayed dyskinesia, sleep disorders (including narcolepsy), attention deficit / hyperactivity disorder, and behavioral disorders.

  Thus, the present invention provides the use of any of the compounds of formula I, pharmaceutically acceptable salts or solvates thereof for the manufacture of a medicament for the treatment of any of the above conditions.

  Furthermore, the present invention provides a method for treating a patient suffering from any of the above conditions, whereby an effective amount of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof is administered. Administer to patients as needed. The present invention also provides a compound of formula I as defined above or a pharmaceutically acceptable salt or solvate thereof for use in therapy.

  In this specification, the term “treatment” also includes “prophylaxis” unless stated to the contrary. The terms “therapeutic” and “therapeutically” should be understood accordingly. The term “treatment” in the context of the present invention further administers an effective amount of a compound of the present invention to reduce either pre-existing acute or chronic symptoms, or recurrent symptoms. Including that. This definition also includes prophylactic treatment to prevent recurrent symptoms and continuous treatment of chronic diseases.

  For therapeutic use in warm-blooded animals such as humans, the compounds of the invention can be administered orally, intramuscularly, subcutaneously, topically, intranasally, intraperitoneally, intrathoracically, intravenously, intradurally, intrathecally, intraventricularly, And can be administered in the form of conventional pharmaceutical compositions by any route, such as joint injection. In preferred embodiments of the invention, the route of administration is oral, intravenous, or intramuscular.

  The dose will depend on the route of administration, the severity of the disease, the age and weight of the patient, as well as other factors normally considered by the attending physician to determine the individual dosing regimen and the particular patient dose level.

  As noted above, the compounds described herein can be provided or delivered in forms suitable for oral use, such as tablets, lozenges, hard and soft capsules, aqueous solutions, oily solutions, emulsions and suspensions. Alternatively, the compound can be formulated in a topical application form such as a cream, ointment, gel, spray, or aqueous solution, oily solution, emulsion or suspension. The compounds described herein can also be provided in forms suitable for intranasal administration, such as nasal sprays, nasal drops or dry powders. The compound can be administered to the vagina or rectum in the form of a suppository. The compounds described herein can also be administered parenterally, for example, by intravenous, intravesical, subcutaneous or intramuscular injection or infusion. The compound can be administered by inhalation (eg, as a fine powder). The compound can also be administered transdermally or sublingually.

  In addition to its use in therapeutics, compounds of formula I, or salts thereof, are used in-vitro to evaluate the effects of inhibitors of mGluR-related activity in research animals as part of a search for new therapeutics. And as a pharmacological tool in the development and standardization of in-vivo test systems. Such animals include cats, dogs, rabbits, monkeys, rats and mice.

Production Methods The compounds of the present invention can be produced by various synthetic methods. The selection of specific methods for producing a given compound is within the skill of the art. The selection of specific structural features and / or substituents will affect the choice of one method over other methods.

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

  In one method, for example the formula Ia:

The compound of is cyclized in the presence of an amine of formula R ¹ (CR ⁸ CR ⁹ ) _n NH ₂ to give formula Ib

Gives:

The compound of formula Ib is then cross-coupled with a suitable reagent having R ⁵ to give a compound of formula Ic:

To produce the compound

In one embodiment of this method, 5-substituted-7-methylisoindolone is synthesized as shown in Scheme 1 below. 4-Bromo-2,6-dimethylaniline is converted to the corresponding nitrile under Sandmeyer reaction conditions. The nitrile is then hydrolyzed to the acid stepwise. Amides can be obtained by base hydrolysis. The amide is then diazotized with nitrososulfate and hydrolyzed to give benzoic acid, which is subsequently protected as a methyl ester using standard conditions. The benzylic methyl group is monobrominated with N-bromosuccinimide using benzoyl peroxide as radical initiator. The resulting intermediate is cyclized to isoindolone with a suitable amine in the presence of a base such as potassium carbonate. Finally, the substituent R ⁵ was introduced into C 5 of isoindolone using typical Buchwald, Suzuki or Stille cross coupling reaction conditions and reagents.

In another embodiment of this method, 5-substituted-7-chloroisoindolone is synthesized as shown in Scheme 2 below. 4-Bromo-2-methylbenzoic acid is chlorinated in the ortho position relative to the acid using N-chlorosuccinimide and a palladium catalyst. When this acid was esterified, brominated, and cyclized in the same manner as described above (Scheme 1), an isoindolone intermediate was obtained. The substituent R ⁵ is introduced in the same way.

  In yet another embodiment of this method, isoindolone substituted with an amide at C5 can be prepared as shown in Scheme 3 below. That is, a suitably substituted 5-bromoisoindolone is converted to the corresponding nitrile using zinc cyanide in the presence of a palladium catalyst. The nitrile was then hydrolyzed under basic conditions to provide benzoic acid, which was then coupled with various amines using methods known in the art to provide the final compound.

In yet another aspect, the method can be applied for the production of amino-propargyl and amino-alkylisoindolone. Thus, suitable 5-bromoisoindolone is first exposed to Sonogashira coupling conditions with various propargylamines as shown in Scheme 4. The resulting alkyne can be hydrogenated using routine methods to provide an amino-alkyl substituted product. In Scheme 4, R and R ′ correspond to the substituents defined herein for R ¹⁰ and R ¹¹ .

  In another method of the invention, some of the previous synthetic methods are adapted for the preparation of compounds having N-propargyl substituents. Thus, the formula Ia:

A compound of formula Id in the presence of propargylamine:

Is cyclized to

Coupling a compound of formula Id with a reagent having R ¹ gives formula Ie:

Is obtained.

R ¹ is preferably an aryl group. The compound of formula Ie is then cross-coupled with a reagent having R ⁵ to give the formula If:

To produce the compound

One embodiment of this method is shown in Scheme 5 below. The terminal alkyne is coupled with various aryl groups using standard Sonogashira coupling conditions. Finally, the substituent R ⁵ was introduced into C5 using typical Buchwald, Suzuki or Stille cross coupling reaction conditions as shown in Scheme 5.

  Another method of the invention contemplates the preparation of compounds of formula I that are not substituted on the isoindolone aromatic ring. This subset of compounds is prepared briefly as shown in Scheme 6. Thus, phthalimide is reduced with tin, for example under acidic conditions, to provide isoindolinone. This intermediate is alkylated with various electrophiles under basic conditions to provide the desired final product. In Scheme 6, X may be any suitable leaving group such as halo such as bromo and iodo and tosylate.

  Various variations of the above method and additions appear throughout the examples below. One skilled in the art will appreciate that the compounds of the present invention can be prepared by following or adapting one or more of the methods disclosed herein.

  The invention is further illustrated by the following examples, which detail several aspects of the invention. These examples do not limit the scope of the invention and should not be construed as limiting. It will be apparent that the invention may be practiced unless specifically described herein. Many modifications and variations of the present invention are possible in accordance with the teachings of the invention and are within the scope of the invention.

General methods All starting materials are commercially available or have already been described in the literature.

¹ H and ¹³ C-NMR spectra, unless otherwise stated, use deuterated chloroform as solvent, TMS or residual solvent signal as reference, and for ¹ H-NMR operating at 300, 400 and 400 MHz, respectively. Recorded on either a Bruker 300, Bruker DPX400 or Varian + 400 spectrometer. All reported chemical shifts are expressed in delta-scale ppm and fine signal splits are noted in the recording (s: singlet; br s: broad singlet; d: doublet; t: triplet; q : Quadruple line; m: multiple line).

  Liquid chromatographic separation followed by line analysis of mass spectral detection was recorded on a Waters LCMS consisting of an Alliance 2795 (LC) and a ZQ single quadropole mass spectrometer. The mass spectrometer is equipped with an electrospray ion source that is operated in positive and / or negative ion modes. The ion spray voltage was ± 3 kV, and the mass spectrometer was scanned from m / z 100-700 with a scan time of 0.8 seconds. To this column was applied a linear gradient of 5% to 100% acetonitrile in 10 mM ammonium acetate (aq) or 0.1% TFA (aq) X-Terra MS, Waters, C8, 2.1 x 50 mm, 3.5 mm.

  Preparative reverse phase chromatography was performed on a Gilson automated preparative HPLC with a diode array detector using an Xterra MS C8, 19 × 300 mm, 7 mm column.

  Purification by chromatotron was performed on a rotating silica gel / gypsum (Merck, 60 PF-254, calcium sulfate) coated glass sheet. The coating layer was 1, 2 or 4 mm and a TC Research 7924T chromatotron was used.

  Does the product purification use Chem Elut Extraction Columns (Varian, catalog number 1219-8002), Mega BE-SI (Bond Elut Silica) SPE columns (Varian, catalog numbers 12256018; 12256026; 12256034)? , Performed by flash chromatography on a glass column packed with silica gel.

  Microwave heating was performed in a Smith synthesizer single-mode microwave cavity (Personal Chemistry AB, Uppsala, Sweden) generating continuous illumination at 2450 MHz.

The pharmacological properties of the compounds of the invention were analyzed using standard assays for functional activity. Examples of glutamate receptor assays are described in, for example, Aramori et al., 1992, Neuron, 8: 757; Tanabe et al., 1992, Neuron, 8: 169; Miller et al., 1995, J. Am. Neuroscience, 15: 6103; Balazs et al., 1997, J. Biol. It is known in the art as described in Neurochemistry, 1997, 69: 151. The methods described in these publications are included herein by reference. Conveniently, the compounds of the invention can be studied in cells expressing mGluR2 by assays that measure the movement of intracellular calcium, [Ca ²⁺ ] i.

A fluorescent image plate reader (FLIPR) assay was used to detect allosteric activators of mGluR2 by calcium mobilization. A clone HEK293 cell line expressing a chimeric mGluR2 / CaR containing the extracellular and transmembrane domains of human mGluR2 and the intracellular domain of the human calcium receptor fused to the promiscuous chimeric protein G _αqi5 was used. . Activation of this construct by agonists or allosteric activators stimulated the PLC pathway followed by intracellular Ca ²⁺ migration. This was measured by FLIPRA analysis. Cells were trypsinized 24 hours prior to analysis and plated in DMEM at 10,000 cells / well in a collagen I-coated 96-well plate with black sides and clear bottom. The plate was incubated overnight at 37 ° C. with 5% CO ₂ . Cells were loaded with 6 μM fluo-3 acetoxymethyl ester (Molecular Probes, Eugene Oregon) for 60 minutes at room temperature. All assays consisted of 126 mM NaCl, 5 mM KCl, 1 mM MgCl ₂ , 1 mM CaCl ₂ , supplemented with 1.0 mg / ml D-glucose and 1.0 mg / ml BSA Fraction IV (pH 7.4). It was carried out in a buffer containing 20 mM Hepes, 0.06 μM DCG-IV (group II mGluR selective agonist).

The FLIPR experiment was performed using a 0.8 W laser setting and a 0.4 second CCD camera shutter speed. Extracellular fluo-3 was washed away and the cells were kept in 160 μL of buffer and placed on the FLIPR. Test compounds (0.01 μM-30 μM, duplex) were added 10 seconds after the baseline fluorescence reading was recorded on the FLIPR. The fluorescence signal was then recorded for an additional 75 seconds, at which time DCG-IV (0.2 μM) was added a second time and the fluorescence signal was measured for an additional 65 seconds. The fluorescence signal was measured at the peak height of the response within the sample period. Data was analyzed using Assay Explorer and EC ₅₀ and E _max values (for maximum DCG-IV effect) were calculated using a four parameter logistic equation.

A [ ³⁵ S] -GTPγS binding assay was used to functionally assay GluR2 receptor activation. The activity of the allosteric activator of the compounds at the human mGluR2 receptor was measured using a [ ³⁵ S] -GTPγS binding assay using membranes made from CHO cells stably expressing human mGluR2. This assay is based on the principle that agonists bind to G-protein coupled receptors to stimulate GDP-GTP exchange in G-proteins. Since [ ³⁵ S] -GTPγS is a non-hydrolyzable GTP analog, it can be used to give an index of GDP-GTP exchange and an index of receptor activation. The GTPγS binding assay thus provides a quantitative measure of receptor activation.

Membranes were produced from CHO cells stably transfected with human GluR2. Incubate membrane (30 μg protein) with test compound (3 nM-300 μM) for 15 minutes at room temperature, then add 1 μM glutamate, 500 μl containing 30 μM GDP and 0.1 nM [ ³⁵ S] -GTPγS (1250 Ci / mmol) Incubation was carried out in assay buffer (20 mM HEPES, 100 mM NaCl, 10 mM MgCl ₂ ) at 30 ° C. for 30 minutes. Reactions were performed in triplicate in 2 ml polypropylene 96-well plates. The reaction was stopped by vacuum filtration using a Packard 96-well harvester and Unifilter-96, GF / B filter microplate. The filter plate was washed four times with 1.5 ml of ice water buffer (10 mM sodium phosphate buffer, pH 7.4). The filter plate was 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 Packard TopCount. Data was analyzed using GraphPad Prism and EC ₅₀ and E _max values (relative to maximum glutamate action) were calculated using non-linear regression.

In general, the compounds of the invention were active in the assays described herein at concentrations (or EC ₅₀ values) of less than 10 μM. For example, the compounds of Examples 8.3, 10.4, 11 and 13.7 had EC50 values of 75, 230, 84 and 28 nM, respectively.

  Example 1: 4,4-Difluorocyclohexanecarboxamide

A suspension of ethyl 4,4-difluorocyclohexanecarboxylate (2500 mg, 13 mmol) in ammonium hydroxide (28%, 50 ml) was stirred at 60 ° C. overnight. After removing the solvent, the residue was washed with water. A precipitate was obtained as product (white solid, 800 mg). ¹ H-NMR (300 MHz, CDCl ₃ ): δ5.31-5.45 (br, 2H), 2.02-2.27 (m, 3H), 1.92-2.02 (m, 2H), 1.72-1.87 (m, 4H). The mother liquor was acidified with 1N HCl to pH <1. The compound was extracted with EtOAc. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated. 4,4-Difluorocyclohexanecarboxylic acid was obtained as a white solid 1200 mg. This was further converted to 4,4-difluorocyclohexanecarboxamide by the following procedure.

  To a solution of 4,4-difluorocyclohexanecarboxylic acid (1.35 g, 8.22 mmol) in THF (50 ml) was added 4-methylmorpholine (831 mg, 8.22 mmol) at −70 ° C., followed by isobutyl chloride ( isobutyl chloride carbonate) (1140 mg, 8.22 mmol) was added. After 10 minutes, ammonium hydroxide (28%, 10 ml) was added. The resulting mixture was allowed to warm to 0 ° C. After all the solvent was removed, the residue was washed with water and hexane to give 1.06 g of white solid. This was 4,4-difluorocyclohexanecarboxamide. The overall yield was 82%.

  Example 2: [(4,4-Difluorocyclohexyl) methyl] amine

  4,4-Difluorocyclohexanecarboxamide (1.32 g, 8.10 mmol) was stirred overnight in a solution of lithium borohydride (1M, 30 ml) under a nitrogen atmosphere. The reaction mixture was then refluxed for 4 hours. After cooling to room temperature, it was slowly poured into ice water. After filtration, the product was extracted from the filtrate with dichloromethane. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated to give 934 mg of colorless oil (82%). δ2.53 (d, 2H), 1.98-2.09 (m, 2H), 1.73-1.82 (m, 6H), 1.17-1.29 (m, 3H).

  Example 3: tert-butyl 4-fluorocyclohexanecarboxylate

To a solution of tert-butyl 4-hydroxycyclohexanecarboxylate (1500 mg, 7.45 mmol) in dichloromethane (anhydrous, 20 ml) was added DAST (1571 mg, 22.4 mmol) at 0 ° C. The resulting mixture was stirred at 0 ° C. for 3 hours. The mixture was diluted with dichloromethane and quenched with sodium bicarbonate. The organic layer was separated and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with water and brine and dried over anhydrous sodium sulfate. The product was purified (flash chromatography, 10-20% EtOAc / hexanes) to yield 210 mg (25%) of a yellow oil. ¹ H-NMR (300 MHz, CDCl ₃ ): δ 5.60-5.80 (m, 1H), 4.99-5.09 (m, 2H), 4.73 (d, 2H), 3.34 (br, 2H), 2.29-2.32 (m , 2H), 1.44-1.46 (m, 9H).

  Example 4: 5-Bromo-7-chloro-2-[(4,4-difluorocyclohexyl) methyl] isoindoline-1-one

4-Bromo-2-bromomethyl-6-chlorobenzoic acid methyl ester (3.5 g, 9.35 mmol), (4,4-difluorocyclohexyl) methylamine (1.7 g, 11.39 mmol) and K ₂ CO ₃ (3.15 g, 22.78) mmol) was stirred in toluene (10 mL) at 95 ° C. for 12 hours. The reaction was partitioned between ethyl acetate and water and the organic layer was washed with brine and dried over anhydrous Na ₂ SO ₄ . The solvent was removed under reduced pressure and the product was purified by column chromatography (10-25% EtOAc / hexanes) to give the title compound as a yellow foam (2.2 g, 45%). ¹ H NMR (300 MHz, CDCl ₃ ): 7.58 (s, 1H), 7.50 (s, 1H), 4.36 (s, 2H), 3.48 (d, 2H), 2.10-2.14 (m, 2H), 1.64-1.82 (m, 5H), 1.35-1.447 (m, 2H).

  Example 5: 7-Chloro-2-[(4,4-difluorocyclohexyl) methyl] -1-oxoisoindoline-5-carbonitrile

5-Bromo-7-chloro-2-[(4,4-difluorocyclohexyl) methyl] isoindoline-1-one (1.14 g, 3.01 mmol) was stirred in DMF (10 mL) under argon and Zn (CN ) ₂ (389 mg, 3.31 mmol) and Pd (PPh ₃ ) ₄ (347 mg, 0.3 mmol) were added. The reaction was stirred at 80 ° C. for 1.5 hours. The reaction was partitioned between ethyl acetate and water and the organic layer was washed with brine and dried over anhydrous Na ₂ SO ₄ . The solvent was removed under reduced pressure and the product was purified by column chromatography (40% EtOAc / hexane) to give the title compound (60 mg, 80%) as a yellow foam. ¹ H NMR (300 MHz, CDCl ₃ ): 7.72 (s, 1H), 7.65 (s, 1H), 4.45 (s, 2H), 3.53 (d, 2H), 2.11-2.15 (m, 2H), 1.66-1.91 (m, 5H), 1.41-1.50 (m, 2H).

  Example 6: 7-Chloro-5- [5- (chloromethyl) -1,2,4-oxadiazol-3-yl] -2-[(4,4-difluoro-cyclohexyl) methyl] isoindoline- 1-on

7-Chloro-N-hydroxy-1-oxo-2-[(4,4-difluorocyclohexyl) methyl] -2,3-dihydro-1H-isoindole-5-carboxamidine (450 mg, 1.26 mmol) in acetonitrile (10 ml ) Was added chloroacetyl chloride (170 mg, 1.51 mmol) followed by K ₂ CO ₃ (260 mg, 1.89 mmol). The mixture was stirred overnight. After dilution with EtOAc (20 ml), washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a yellow foam. The foam was stirred in DMF (2 ml) at 140 ° C. for 3 hours. After cooling to room temperature, it was diluted with water (5 ml). The product was extracted with EtOAc. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated. The product was purified by column chromatography (40-60% EtOAc in hexanes) to give the title compound as a white solid.

  Example 7.1: 7-Chloro-N-hydroxy-1-oxo-2- (4-trifluoromethoxy-benzyl) -2,3-dihydro-1H-isoindole-5carboxamidine

To a suspension of 7-chloro-1-oxo-2- [4- (trifluoromethoxy) benzyl] isoindoline-5-carbonitrile (500 mg, 1.36 mmol) in ethanol (2 ml) was added 8-hydroxyquinoline ( 495 mg, 3.41 mmol), followed by a solution of hydroxylamine hydrochloride (199 mg, 2.86 mmol) in water (1 ml) and sodium carbonate (230 mg, 2.2 mmol) in water (1 ml). The resulting mixture was refluxed for 4 hours. After removing the solvent, the residue was loaded onto flash chromatography. The product was purified (20% EtOAc / hexanes to 2% ammonia in MeOH / EtOAc) to give 500 mg (90%) of a greenish foam. ¹ H NMR (300 MHz, CDCl ₃ ): δ 10.04 (s, 1H) 7.48-7.61 (m, 2H), 7.28-7.36 (m, 2H), 7.17-7.21 (m, 2H), 6.04 (br, 1H ), 4.77 (s, 2H), 4.22 (s, 2H).

  The following compounds were prepared by a similar method.

  Example 8.1: 7-chloro-5- [5- (4-hydroxy-piperidin-1-ylmethyl)-[1,2,4] oxadiazol-3-yl] -2- (4-trifluoromethoxy- (Benzyl) -2,3-dihydro-isoindol-1-one

4-hydroxypiperidine (9.9 mg, 0.098 mmol), 7-chloro-5-chloromethyl- [1,2,4] oxadiazol-3-yl) -2- (4-trifluoromethoxy-benzyl) -2 To a mixture of, 3-dihydro-isoindol-1-one (30 mg, 0.065 mmol) and potassium carbonate (27 mg, 0.195 mmol) was added acetonitrile (3.0 mL). The mixture was stirred at room temperature overnight. Water (2.0 mL) was added and the product was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate, filtered and concentrated. Column chromatography gave 16.7 mg (49%) of the title compound as a yellow oil. ¹ H NMR (300 MHz, CDCl ₃ ): δ8.20 (s, 1H), 8.04 (s, 1H), 7.38-7.41 (m, 2H), 7.20-7.23 (m, 2H), 4.82 (s, 2H) , 4.34 (s, 2H), 3.95 (s, 2H), 3.75 (br, 1H), 2.90-2.93 (m, 2H), 2.42-2.50 (m, 2H), 1.94-1.99 (m, 2H), 1.64 -1.74 (m, 3H).

  The following compounds were prepared by a similar method:

  Example 9.1: 4- (2-Cyclopropylmethyl-7-methyl-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl) -piperidine-1-carboxylic acid tert-butyl ester

9-BBN (11.32 mL, 5.66 mmol) was added to an (argon) purged sample of 4-methylene-piperidine-1-carboxylic acid tert-butyl ester (727 mg, 3.68 mmol). The mixture was stirred at 60 ° C. for 2 hours. After cooling to room temperature, the solution was 5-bromo-7-methyl-2-cyclopropylmethyl-2,3-dihydro-isoindol-1-one (794 mg, 2.83 mmol), Pd (dppf) Cl ₂ (115 mg, 0.142 mmol), DMF (25 mL), potassium carbonate (1.17 g, 8.49 mmol) and water (2.5 mL). The mixture was stirred at 75 ° C. for 1.5 hours. The mixture was then cooled to room temperature and poured into water (3 mL). The product was extracted with ethyl acetate. The combined organic layers were washed 3 times with water, brine, dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (30% ethyl acetate / hexane) gave the title compound (777 mg, 53%) as a pale yellow oil. ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.01 (s, 1H), 6.94 (s, 1H), 4.39 (s, 2H), 3.42 (d, 2H), 2.68 (s, 3H), 2.57 (s , 2H), 2.54 (d, 2H), 1.70-1.62 (m, 4H), 1.43 (s, 9H), 1.09 (d, 1H), 1.01 (m, 1H), 0.56-0.5 (m, 2H), 0.31-0.29 (m, 2H).

  The following compounds were prepared by a similar method:

  Example 10.1: 2-Cyclopropylmethyl-7-methyl-5-piperidin-4-ylmethyl-2,3-dihydro-isoindol-1-one

4- [7-Methyl-1-oxo-2-cyclopropylmethyl-2,3-dihydro-1H-isoindol-5-yl] -piperidine-1-carboxylic acid tert-butyl ester (777 mg, 1.95 mmol) Dissolved in formic acid (10 mL) and stirred at room temperature for 0.5 hour. Formic acid was removed under reduced pressure and the product was neutralized with NaHCO ₃ and extracted with CH ₂ Cl ₂ . The organic layer was washed with water, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give the title compound (578 mg, 99%) as a brown oil. ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.02 (s, 1H), 6.95 (s, 1H), 4.40 (s, 2H), 3.43 (d, 2H), 3.07-3.03 (d, 2H), 2.69 (s, 3H), 2.56-2.38 (m, 4H), 2.38 (brs, 1H), 1.64-1.61 (m, 4H), 1.19-1.15 (m, 2H), 1.02 (m, 1H), 0.57-0.53 (m, 2H), 0.34-0.30 (m, 2H).

  The following compounds were prepared in a similar manner:

  Example 11. 2-Cyclopropylmethyl-5- [1- (2-fluorobenzyl) -piperidin-4-ylmethyl] -7-methyl-2,3-dihydro-isoindol-1-one

2-Fluorobenzyl bromide (47 μL, 0.377 mmol), 7-methyl-5-piperidin-4-ylmethyl-2-cyclohexylpropyl-2,3-dihydro-isoindol-1-one (75 mg, 0.251 mmol) and potassium carbonate To a mixture of (104 mg, 0.753 mmol), acetonitrile (3.0 mL) was added. The mixture was heated to 80 ° C. for 4 hours, a spoonful of sodium tert-butoxide (˜200 mg) was added and stirring was continued at 80 ° C. overnight. The mixture was cooled to room temperature, water (2.0 mL) was added and the product was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate, filtered and concentrated. Column chromatography gave the title compound (6.6 mg, 6%) as a yellow oil. ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.38 (m, 1H), 7.23-7.13 (m, 1H), 7.11-7.00 (m, 3H), 6.96 (s, 1H), 4.41 (s, 2H) , 3.61 (s, 2H), 3.46-3.44 (d, 2H), 2.95-2.92 (d, 2H), 2.70 (s, 3H), 2.59-2.57 (d, 2H), 2.01-1.98 (t, 2H) 1.65-1.61 (m, 3H), 1.38-1.27 (m, 2H), 1.04 (m, 1H), 0.60-0.55 (m, 2H), 0.36-0.32 (m, 2H).

  Example 12.1: 2-cyclohexylmethyl-7-methyl-5- (1-pyrimidin-2-ylmethyl-piperidin-4-ylmethyl) -2,3-dihydro-isoindol-1-one

2-Chloromethylpyrimidine (32 mg, 0.247 mmol), 2-cyclohexylmethyl-7-methyl-5-piperidin-4-ylmethyl-2,3-dihydro-isoindol-1-one (56 mg, 0.164 mmol) and cesium carbonate Acetonitrile (3.0 mL) was added to a mixture of (160 mg, 0.492 mmol). The mixture was stirred overnight at room temperature. Water (2.0 mL) was added and the product was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate, filtered and concentrated. Column chromatography gave the title compound (48 mg, 69%) as a yellow oil. ¹ H NMR (300 MHz, CDCl ₃ ): δ8.76-8.72 (d, 2H), 7.18 (t, 1H), 6.99 (s, 1H), 6.95 (s, 1H), 4.30 (s, 2H), 3.78 (s, 2H), 3.40-3.37 (d, 2H), 2.97-2.93 (d, 2H), 2.70 (s, 3H), 2.58-2.56 (d, 2H), 2.10-2.05 (t, 2H) 1.71- 1.42 (m, 10H), 1.26-1.13 (m, 4H), 1.09-0.98 (m, 2H).

  The following compounds were prepared in a similar manner:

  Example 13.1: 2-Cyclopropylmethyl-5- [1- (3-fluoro-benzyl) -piperidin-4-ylmethyl] -7-methyl-2,3-dihydro-isoindol-1-one

To a solution of 2-cyclopropylmethyl-7-methyl-5-piperidin-4-ylmethyl-2,3-dihydro-isoindol-1-one (30 mg, 0.101 mmol) in methanol (2 mL) is slowly added acetic acid (1 mL). ) Was added. After stirring at room temperature for 5 minutes, 3-fluoro-benzaldehyde (12.8 μL, 0.121 mmol) and sodium cyanoborohydride (8 μL, 0.11 mmol) were added dropwise. The mixture was stirred at room temperature for 2 hours and neutralized with saturated sodium bicarbonate (10 mL). The aqueous mixture was extracted with dichloromethane and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. Purification by column chromatography (10-40% ethyl acetate in hexane) gave the title compound as a yellow oil. ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.70-7.23 (m, 1H), 7.09-7.03 (m, 3H), 6.97-6.92 (m, 2H), 4.41 (s, 2H), 3.48-3.44 ( m, 4H), 2.88-2.85 (d, 2H), 2.71 (s, 3H), 2.60-2.57 (d, 2H), 1.93 (t, 2H), 1.64-1.50 (m, 3H), 1.36-1.28 ( m, 2H), 1.04 (m, 1H), 0.60-0.55 (m, 2H), 0.34-0.32 (m, 2H).

  The following compounds were prepared in a similar manner:

  Example 14: 2-Cyclopropylmethyl-5-iodo-7-methyl-2,3-dihydro-isoindol-1-one

To a solution of 5-bromo-7-methyl-2-cyclopropylmethyl-2,3-dihydro-isoindol-1-one (1.0 g, 3.56 mmol) in butanol (10 ml), (1R, 2R) -N , N'-dimethylcyclohexane-1,2-diamine (204 mg, 1.42 mmol), copper (I) iodide (140 mg, 0.714 mmol) and sodium iodide (1.08 g, 14.3 mmol) were added. The resulting mixture was stirred at 120 ° C. overnight. After cooling, the mixture was diluted with ethyl acetate, washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (30% EtOAc / hexane) gave the title compound (1.07 g, 92%) as a colorless solid. ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.65 (s, 1H), 7.59 (s, 1H), 4.42 (s, 2H), 3.46-3.44 (d, 2H), 2.70 (s, 3H), 1.04 -1.02 (m, 1H), 0.61-0.57 (m, 2H), 0.34-0.31 (m, 2H).

  Example 15: 5- (1-Benzyl-pyrrolidin-3-ylamino) -7-methyl-2- (4-trifluoromethoxy-benzyl) -2,3-dihydro-isoindol-1-one

3-Amino-1-benzyl-pyrrolidine (57 mg, 0.325 mmol), 5-bromo-7-methyl-2- (4-trifluoromethoxybenzyl) -2,3-dihydro-isoindol-1-one (100 mg, 0.25 mmol), NaO ^t Bu (168 mg, 1.75 mmol), BINAP (16 mg, 0.025 mmol) and Pd ₂ (dba) ₃ (23 mg, 0.025 mmol) were dissolved in anhydrous toluene (5 mL). This mixture was immersed in an oil bath at 110 ° C. After 18 hours, the reaction was cooled, poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO ₄ , filtered and concentrated. The compound was purified by column chromatography (50% EtOAc / hexane) to give the title compound (87 mg, 70%) as a yellow gum. ¹ H NMR (300 MHz, CDCl ₃ ): δ7.24-7.34 (m, 7H), 7.18 (d, 2H), 6.34 (d, 2H), 4.72 (s, 2H), 4.33 (d, 1H), 4.12 (s, 2H), 4.04 (m, 1H), 3.64 (decay dd, 2H), 2.75.2.83 (m, 2H), 2.66 (s, 3H), 2.58 (dd, 1H), 2.45 (ddd, 1H) 2.32-2.42 (m, 1H), 1.67-1.70 (m, 1H).

  Example 16.1: 7-methyl-5- [5- (4-methyl-piperazin-1-ylmethyl) -pyridin-3-yl] -2- (4-trifluoromethoxybenzyl) -2,3-dihydro-iso Indol-1-one

Methanesulfonic acid 5- [7-methyl-1-oxo-2- (4-trifluoromethoxy-benzyl) -2,3-dihydro-1H-isoindol-5-yl] -pyridin-3-ylmethyl ester ( 36 mg, 0.071 mmol) was dissolved in THF (5 mL). N-methylpiperazine (24 μL, 0.213 mmol) was added and the mixture was stirred at 50 ° C. for 18 hours. The mixture was cooled, diluted with water and extracted with ethyl acetate. The organics were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (5% 2M NH _{3 in} MeOH / CH ₂ Cl ₂ ) afforded the title compound (24 mg, 67%) as a yellow oil. ¹ H NMR (300 MHz, CDCl ₃ ): δ 8.73 (s, 1H), 8.56 (s, 1H), 7.86 (s, 1H), 7.42 (d, 2H), 7.37 (d, 2H), 7.19 (d , 2H), 4.82 (s, 2H), 4.32 (s, 2H), 3.60 (s, 2H), 2.85 (s, 3H), 2.52-2.42 (brs, 8H), 2.30 (s, 3H).

  The following compounds were prepared in a similar manner:

  Example 17.1: 4- {4- [7-chloro-1-oxo-2- (4-trifluoromethoxy-benzyl) -2,3-dihydro-1H-isoindol-5-ylmethyl] -piperidine-1- Ilmethyl} -benzonitrile

4-cyano-benzyl bromide (12 mg, 0.06 mmol), 7-chloro-5-piperidin-4-ylmethyl-2- (4-trifluoromethoxy-benzyl) -2,3-dihydro-isoindol-1-one ( Acetonitrile (3.0 mL) was added to a mixture of 30.0 mg, 0.06 mmol) and potassium carbonate (42 mg, 0.3 mmol). The mixture was stirred at room temperature overnight. Water (2.0 mL) was added and the product was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate, filtered and concentrated. Column chromatography gave the title compound (39.0 mg, 99%) as a brown oil. ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.60 (d, 2H), 7.27-7.59 (m, 4H), 7.17-7.20 (m, 3H), 7.05 (s, 1H), 4.77 (s, 2H) , 4.22 (s, 2H), 3.53 (s, 2H), 2.80-2.84 (m, 2H), 2.58-2.60 (m, 2H), 1.91 (t, 2H), 1.56-1.62 (m, 3H), 1.27 -1.34 (m, 2H).

  The following compounds were prepared in a similar manner:

  Example 18.1: 4- {4- [7-chloro-1-oxo-2- (4-trifluoromethoxy-benzyl) -2,3-dihydro-1H-isoindol-5-ylmethyl] -piperazine-1- Methyl} -nicotinonitrile

4- (Piperazin-1-ylmethyl) benzonitrile (30 mg, 0.094 mmol) was dissolved in dichloromethane (2.0 mL) and 7-chloro-1-oxo-2- (4-trifluoromethoxy-benzyl) -2,3 -Dihydro-1H-isoindole-5-carbaldehyde (20.0 mg, 0.054 mmol) was added. The mixture was stirred for 10 minutes, sodium triacetoxyborohydride (16.1 mg, 0.076 mmol) was added and the reaction was stirred overnight. The reaction was then diluted with dichloromethane, washed with saturated sodium bicarbonate and brine, dried over sodium sulfate, filtered and concentrated. Column chromatography (20% MeOH / EtOAc) gave the title compound (17.9 mg, 32%) as a yellow oil. ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.60-7.63 (m, 2H), 7.34-7.47 (m, 5H), 7.27-7.28 (m, 1H), 7.18-7.21 (m, 2H), 4.78 ( m, 2H), 4.24 (s, 2H), 3.55-3.57 (m, 4H), 2.48-2.53 (m, 8H).

  The following compounds were prepared in a similar manner:

  Example 19: 7-Chloro-2-cyclopropylmethyl-1-oxo-2,3-dihydro-1H-isoindole-5-carbonitrile

5-Bromo-7-chloro-2-cyclopropylmethyl-2,3-dihydro-isoindol-1-one (360 mg, 1.20 mmol) was stirred in DMF (15 mL) under argon and Zn (CN) ₂ (154 mg, 1.32 mmol) and Pd (PPh ₃ ) ₄ (139 mg, 0.12 mmol) were added. The reaction was stirred at 80 ° C. for 1.5 hours. The reaction was partitioned between ethyl acetate and water and the organic layer was washed with brine and dried over anhydrous Na ₂ SO ₄ . The solvent was removed under reduced pressure and the product was purified by column chromatography (40% EtOAc / hexane) to give a yellow solid (142.6 mg, 82%). ¹ H NMR (300 MHz, CDCl ₃ ): δ 7.53 (s, 2H), 7.36 (d, 2H), 7.22 (s, 2H), 4.80 (s, 2H), 4.30 (s, 2H), 2.81 (s , 3H).

  Example 20: 7-trifluoromethyl-5-methoxy-2- (4-trifluoromethoxy-benzyl) -2,3-dihydro-isoindol-1-one

7-trifluoromethyl-5-bromo-2- (4-trifluoromethoxy-benzyl) -2,3-dihydro-isoindol-1-one (0.060 g, 0.15 mmol) and 30% in methanol (4 mL) A mixture of sodium methoxide-methanol (0.21 mL) was stirred at 100 ° C. for 1 hour. 7-trifluoromethyl-5-methoxy-2- (4-trifluoromethoxy-benzyl) -2,3-dihydro-isoindol-1-one by work-up and column chromatography using 30% ethyl acetate in hexane (0.043 g, 70%) was obtained. ¹ H NMR (300 MHz, CDCl ₃ ): δ (ppm) 3.88 (s, 3H), 4.25 (s, 2H), 4.76 (s, 2H), 7.02 (s, 1H), 7.17 (d, 2H), 7.28 (s, 1H), 7.37 (d, 2H).

  Example 21: 5,7-dimethoxy-2- (4-trifluoromethoxy-benzyl) -2,3-dihydro-isoindol-1-one

A solution of 4-bromo-5,7-dimethoxy-2- (4-trifluoromethoxy-benzyl) -2,3-dihydro-isoindol-1-one (0.200 g, 0.45 mmol) in benzene under N2 atmosphere 2,2′-azobis (2-methylproponitrile) AIBN (5.0 mg) was added followed by tributyltin hydride (0.238 mL, 0.9 mmol). The resulting mixture was refluxed in an oil bath for 2 hours. The reaction was monitored by GC-MS for disappearance of starting material. The reaction mixture was cooled to room temperature and stirred with potassium fluoride (200 mg) for 45 minutes. The solid was filtered and the filtrate was concentrated. The resulting material is purified using column chromatography (usually 40% ethyl acetate in hexane) to give 5,7-dimethoxy-2- (4-trifluoromethoxy-benzyl) -2,3-dihydro-iso Indol-1-one (0.106 g, 64%) was obtained. ¹ H NMR (300 MHz, CDCl ₃ ): δ (ppm) 3.82 (s, 3H), 3.95 (s, 3H), 4.17 (s, 2H), 4.72 (s, 2H), 6.43 (d, 2H), 7.16 (d, 2H), 7.32 (d, 2H). GC-MS: m / z 367 (M) ⁺ , 349 (M-18) ⁺ .

  Example 22: 5,7-Dimethoxy-2- (4-chloro-benzyl) -2,3-dihydro-isoindol-1-one

A solution of 4-bromo-5,7-dimethoxy-2- (4-chloro-benzyl) -2,3-dihydro-isoindol-1-one (0.100 g, 0.25 mmol) in benzene under N2 atmosphere. 2,2′-azobis (2-methylproponitrile) AIBN (5.0 mg) followed by tributyltin hydride (0.132 mL, 0.5 mmol). The resulting mixture was refluxed in an oil bath for 2 hours. The reaction was monitored by GC-MS for disappearance of starting material. The reaction mixture was cooled to room temperature and stirred with potassium fluoride (200 mg) for 45 minutes. The solid was filtered and the filtrate was concentrated. The resulting material was purified by column chromatography (usually 40% ethyl acetate in hexane) to give 5,7-dimethoxy-2- (4-chloro-benzyl) -2,3-dihydro-isoindol-1-one ( 0.035 g, 44%) was obtained. ¹ H NMR (300 MHz, CDCl ₃ ): δ (ppm) 3.82 (s, 3H), 3.95 (s, 3H), 4.15 (s, 2H), 4.69 (s, 2H), 6.43 (d, 2H), 7.25 (m, 4H). GC-MS: m / z 317 (M) ⁺ , 299 (M-18) ⁺ .

  Example 23: 5,7-dimethoxy-2- [1- (4-chloro-phenyl) -ethyl] -2,3-dihydro-isoindol-1-one

Solution of 4-bromo-5,7-dimethoxy-2- [1- (4-chloro-phenyl) -ethyl] -2,3-dihydro-isoindol-1-one (0.112 g, 0.27 mmol) in benzene Was added 2,2′-azobis (2-methylproponitrile) AIBN (5.0 mg) followed by tributyltin hydride (0.145 mL, 0.55 mmol) under N 2 atmosphere. The resulting mixture was refluxed in an oil bath for 2 hours. The reaction was monitored by GC-MS for disappearance of starting material. The reaction mixture was cooled to room temperature and stirred with potassium fluoride (200 mg) for 45 minutes. The solid was filtered and the filtrate was concentrated. The resulting material is purified by column chromatography (usually 40% ethyl acetate in hexane) to yield 5,7-dimethoxy-2- [1- (4-chloro-phenyl) -ethyl] -2,3-dihydro-iso Indole-1-one (0.056 g, 63%) was obtained. ¹ H NMR (300 MHz, CDCl ₃ ): δ (ppm) 1.43 (d, 3H), 3.63 (s, 3H), 3.68 (d, 1H), 3.74 (s, 3H), 3.99 (d, 1H), 5.53 (q, 1H), 6.23 (dd, 2H), 7.15 (m, 4H). GC-MS: m / z 331 (M) ⁺ , 316 (M-15) ⁺ .

Claims (10)

Formula I:

{Wherein R ¹ is a 3- to 7-membered ring optionally containing one or more heteroatoms independently selected from the group consisting of N, O and S, wherein the ring is one Optionally substituted by more than one A;
R ² and R ³ are independently H, C _1-6 -alkyl, C _2-6 -alkenyl, C _2-6 -alkynyl, aryl, heteroaryl, heterocycloalkyl, C _3-8 -cycloalkyl, Selected from the group consisting of C _1-6 -alkyl-aryl, C _1-6 -alkyl-heteroaryl, C _1-6 -alkyl-heterocycloalkyl, and C _1-6 -alkyl-C _3-8 -cycloalkyl Wherein R ² and R ³ may be substituted by one or more A;
R ⁴ and R ⁶ are independently H, hydroxy, F, Cl, Br, I, nitro, cyano, C _1-6 -alkyl, C _1-6 -alkylhalo, OC _1-6 -alkyl, OC _{1- 6} - alkylhalo, C _2-6 - alkenyl, OC _2-6 - alkenyl, C _2-6 - alkynyl, OC _2-6 - alkynyl, C _3-8 - cycloalkyl, C _1-6 - alkyl -C _{3- 8} -cycloalkyl, OC _0-6 -alkyl-C _3-8 -cycloalkyl, aryl, C _1-6 -alkylaryl, OC _0-6 -alkylaryl, (CO) R ¹⁰ , O (CO) R ¹⁰ , O (CO) OR ¹⁰ , C (O) OR ¹⁰ , O (CNR ¹⁰ ) OR ¹¹ , C _1-6 -alkyl OR ¹⁰ , OC _2-6 -alkyl OR ¹⁰ , C _1-6 -alkyl (CO) R ¹⁰ , OC _1-6 -alkyl (CO) R ¹⁰ , C _0-6 -alkylCO ₂ R ¹⁰ , OC _1-6 -alkyl CO ₂ R ¹⁰ , C _1-6 -alkylcyano, OC _2-6- Alkyl cyano, C _0-6 -alkyl NR ¹⁰ R ¹¹ , OC _2-6 -alkyl NR ¹⁰ R ¹¹ , C _1-6 -alkyl (CO) NR ¹⁰ R ¹¹ , OC _1-6 -alkyl (CO) NR ¹⁰ R ¹¹ , C _0-6 -alkyl NR ^{1 0} (CO) R ¹¹ , OC _2-6 -alkyl NR ¹⁰ (CO) R ¹¹ , C _0-6 -alkyl NR ¹⁰ (CO) NR ¹⁰ R ¹¹ , C _0-6 -alkyl SR ¹⁰ , OC _2-6 -Alkyl SR ¹⁰ , C _0-6 -alkyl (SO) R ¹⁰ , OC _2-6 -alkyl (SO) R ¹⁰ , C _0-6 -alkyl SO ₂ R ¹⁰ , OC _2-6 -alkyl SO ₂ R ¹⁰ , C _0-6 -alkyl (SO ₂ ) NR ¹⁰ R ¹¹ , OC _2-6 -alkyl (SO ₂ ) NR ¹⁰ R ¹¹ , C _0-6 -alkyl NR ¹⁰ (SO ₂ ) R ¹¹ , OC _2-6 -Alkyl NR ¹⁰ (SO ₂ ) R ¹¹ , C _0-6 -alkyl NR ¹⁰ (SO ₂ ) NR ¹⁰ R ¹¹ , OC _2-6 -alkyl NR ¹⁰ (SO ₂ ) NR ¹⁰ R ¹¹ , (CO) NR ¹⁰ R ¹¹ , O (CO) NR ¹⁰ R ¹¹ , NR ¹⁰ OR ¹¹ , C _0-6 -alkyl NR ¹⁰ (CO) OR ¹¹ , OC _2-6 -alkyl NR ¹⁰ (CO) OR ¹¹ , SO ₃ R ¹⁰ , And selected from the group consisting of 5- to 7-membered rings optionally containing one or more heteroatoms independently selected from the group consisting of N, O and S, wherein R ⁴ and R ⁶ May be substituted by one or more A, where any cycloalkyl or aliquot May be fused to a 5- to 7-membered ring which may contain one or more heteroatoms independently selected from the group consisting of C, N, O and S;
R ⁵ is CN, OC _0-6 -alkyl, C _3-8 cycloalkyl, C _1-6 -alkyl-C _3-8 -cycloalkyl, OC _0-6 -alkyl-C _3-8 -cycloalkyl, C _0-6 -alkylaryl, OC _0-6 -alkylaryl, C _0-6 -alkylheteroaryl, OC _0-6 -alkylheteroaryl, heterocycloalkyl, C _1-6 -alkylheterocycloalkyl, OC ₀ Selected from the group consisting of _-6 -alkylheterocycloalkyl and C (O) R ₁₀ , wherein any cyclic moiety is substituted by one or more B;
R ⁷ is H, F, Cl, Br, I, nitro, cyano, OC _1-4 -alkyl, C _1-6 -alkyl, C _1-6 -alkylhalo, OC _1-6 -alkylhalo, C _2-6 Selected from the group consisting of -alkenyl, OC _2-6 -alkenyl, C _2-6 -alkynyl, OC _2-6 -alkynyl, and C _3-8 -cycloalkyl;
R ⁸ and R ⁹ are independently H, F, Cl, Br, I, nitro, cyano, C _1-6 -alkyl, C _1-6 -alkylhalo, OC _1-6 alkyl, OC _1-6 -alkylhalo, Selected from the group consisting of C _2-6 -alkenyl, OC _2-6 -alkenyl, C _2-6 -alkynyl, and OC _2-6 -alkynyl, or when n is greater than 1, on adjacent carbon atoms In the absence of two or more R ⁸ and / or R ⁹ can form an alkenyl or alkynyl moiety;
R ¹⁰ and R ¹¹ are independently H, hydroxy, oxo, F, Cl, Br, I, nitro, cyano, C _1-6 -alkyl, C _1-6 alkylhalo, OC _1-6 -alkyl, OC _{1 -6} - alkylhalo, C _2-6 - alkenyl, OC _2-6 - alkenyl, C _2-6 - alkynyl, OC _2-6 - alkynyl, C _3-8 - cycloalkyl, C _1-6 - alkyl -C _{3 -8} -cycloalkyl, OC _0-6 -alkyl-C _3-8 -cycloalkyl, aryl, C _1-6 -alkylaryl, OC _0-6 -alkylaryl, C _0-6 -alkyl-heterocycloalkyl, From the group consisting of OC _1-6 -alkyl-heterocycloalkyl, heteroaryl, C _1-6 alkylheteroaryl, heterocycloalkyl-C _1-6 -alkylaryl and heterocycloalkyl-C _{1-6 -alkylheteroaryl} Wherein any cyclic moiety is one or more he selected independently from the group consisting of C, N, O, and S. It may be fused to a 5- to 7-membered ring which may contain a rho atom, any cyclic moiety being a substituent selected from alkyl, halo, hydroxyl, O alkyl, haloalkyl and O haloalkyl. Optionally substituted;
A is H, hydroxy, F, Cl, Br, I, nitro, cyano, oxo, C _1-6 -alkyl, C _1-6 -alkylhalo, OC _1-6 alkyl, OC _1-6 -alkylhalo, C _{2 -6} -alkenyl, OC _2-6 -alkenyl, C _2-6 -alkynyl, OC _2-6 -alkynyl, C _3-8 -cycloalkyl, C _1-6 -alkyl-C _3-8 -cycloalkyl, OC _0-6 - alkyl -C _3-8 - cycloalkyl, aryl, C _1-6 - alkyl aryl, OC _0-6 - alkyl aryl, C _1-6 - alkyl - heterocyclyl, C _1-6 - alkyl - Heterocycloalkyl, OC _0-6 -alkyl-heterocycloalkyl, (CO) R ¹⁰ , O (CO) R ¹⁰ , O (CO) OR ¹⁰ , O (CNR ¹⁰ ) OR ¹¹ , C _1-6 -alkyl OR ¹⁰ , OC _2-6 -alkyl OR ¹⁰ , C _1-6 -alkyl (CO) R ¹⁰ , OC _1-6 -alkyl (CO) R ¹⁰ , C _0-6 -alkylCO ₂ R ¹⁰ , OC _1-6 -Alkyl CO ₂ R ¹⁰ , C _1-6 -alkyl cyano, OC _2-6 -alkyl cyano, C _0-6 -alkyl NR ¹⁰ R ¹¹ , C _{2- 6} -alkyl NR ¹⁰ R ¹¹ , C _0-6 -alkyl (CO) NR ¹⁰ R ¹¹ , OC _1-6 -alkyl (CO) NR ¹⁰ R ¹¹ , C _0-6 -alkyl NR ¹⁰ (CO) R ¹¹ , OC _2-6 -alkyl NR ¹⁰ (CO) R ¹¹ , C _0-6 -alkyl NR ¹⁰ (CO) NR ¹⁰ R ¹¹ , C _0-6 -alkyl SR ¹⁰ , OC _2-6 -alkyl SR ¹⁰ , C _{0 -6} -alkyl (SO) R ¹⁰ , OC _2-6 -alkyl (SO) R ¹⁰ , C _1-6 -alkylSO ₂ R ¹⁰ , OC _2-6 -alkylSO ₂ R ¹⁰ , C _0-6 -alkyl (SO ₂ ) NR ¹⁰ R ¹¹ , OC _2-6 -alkyl (SO ₂ ) NR ¹⁰ R ¹¹ , C _0-6 -alkyl NR ¹⁰ (SO ₂ ) R ¹¹ , OC _2-6 -alkyl NR ¹⁰ (SO ₂ ) R ¹¹ , C _0-6 -alkyl NR ¹⁰ (SO ₂ ) NR ¹⁰ R ¹¹ , OC _2-6 -alkyl NR ¹⁰ (SO ₂ ) NR ¹⁰ R ¹¹ , (CO) NR ¹⁰ R ¹¹ , O (CO) NR ¹⁰ R ¹¹ , NR ¹⁰ OR ¹¹ , C _0-6 -alkyl NR ¹⁰ (CO) OR ¹¹ , OC _2-6 -alkyl NR ¹⁰ (CO) OR ¹¹ , SO ₃ R ¹⁰ , and N, O and S Selected from the group consisting of 5- to 7-membered rings which may contain one or more heteroatoms independently selected from the group consisting of 7-membered ring may be substituted by one or more of R ¹⁰ and R ^11;
B is C _0-6 -alkyl-C _3-8 -cycloalkyl, OC _0-6 -alkyl-C _3-8 -cycloalkyl, C _0-6 -alkylaryl, OC _0-6 -alkylaryl, C _1-6 -alkylheterocycloalkyl, OC _{0-6 -alkylheterocycloalkyl} , C _1-6 -alkylheteroaryl and OC _1-6 -alkylheteroaryl, wherein any cyclic moiety Is substituted with at least one substituent selected from the group consisting of halo, alkyl, alkylhalo, alkoxy, oxo, COR, CO ₂ R, SO ₂ R and CN;
R is selected from the group consisting of H and alkyl; and
n is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8}, or a pharmaceutically acceptable salt, hydrate, solvate, optical isomer thereof Or a combination, but
The compound is not selected from the group consisting of:
5- (4-benzyl-piperazine-1-carbonyl) -7-methyl-2- (4-trifluoromethoxy-benzyl) -2,3-dihydro-isoindol-1-one,
7-methyl-5- (4-pyridin-4-ylmethyl-piperazine-1-carbonyl) -2- (4-trifluoromethoxy-benzyl) -2,3-dihydro-isoindol-1-one,
7-Methyl-5- [4- (2-pyridin-4-yl-ethyl) piperazine-1-carbonyl] -2- (4-trifluoromethoxy-benzyl) -2,3-dihydro-isoindole-1- on,
4- {4- [7-Methyl-1-oxo-2- (4-trifluoromethoxy-benzyl) -2,3-dihydro-1H-isoindol-5-ylmethyl] -piperidin-1-ylmethyl} -benzo Nitrile,
2-benzyl-1-oxo-2,3-dihydro-1H-isoindole-5-carbonitrile,
7-chloro-1-oxo-2- (4-trifluoromethoxy-benzyl) -2,3-dihydro-1H-isoindole-5-carbonitrile,
7-methyl-1-oxo-2- (4-trifluoromethoxy-benzyl) -2,3-dihydro-1H-isoindole-5-carbonitrile,
7-methyl-1-oxo-2- (4-chloro-benzyl) -2,3-dihydro-1H-isoindole-5-carbonitrile,
1-oxo-2- (4-trifluoromethoxy-benzyl) -7-trifluoromethyl-2,3-dihydro-1H-isoindole-5-carbonitrile,
3-oxo-2- (4-trifluoromethoxy-benzyl) -2,3-dihydro-1H-isoindole-4,6-dicarbonitrile,
7-iodo-5-methoxy-2- (4-trifluoromethoxy-benzyl) -2,3-dihydro-isoindol-1-one,
2-benzyl-5-methoxy-2,3-dihydro-isoindol-1-one, and
7-Chloro-5-methoxy-2- (4-trifluoromethoxy-benzyl) -2,3-dihydro-isoindol-1-one. The following:
7-chloro-2-[(4,4-difluorocyclohexyl) methyl] -1-oxoisoindoline-5-carbonitrile,
7-Chloro-5- [5- (4-hydroxy-piperidin-1-ylmethyl)-[1,2,4] oxadiazol-3-yl] -2- (4-trifluoromethoxy-benzyl) -2 , 3-dihydro-isoindol-1-one,
7-Chloro-5- [5- (4-oxo-piperidin-1-ylmethyl)-[1,2,4] oxadiazol-3-yl] -2- (4-trifluoromethoxy-benzyl) -2 , 3-dihydro-isoindol-1-one,
7-Chloro-5- [5- (4-fluoro-piperidin-1-ylmethyl)-[1,2,4] oxadiazol-3-yl] -2- (4-trifluoromethoxy-benzyl) -2 , 3-dihydro-isoindol-1-one,
7-Chloro-2- (4,4-difluoro-cyclohexyl-methyl) -5- [5- (4-fluoro-piperidin-1-ylmethyl)-[1,2,4] oxadiazol-3-yl] -2,3-dihydro-isoindol-1-one,
4- {5- [7-Methyl-1-oxo-2- (4-trifluoromethoxy-benzyl) -2,3-dihydro-1H-isoindol-5-yl]-[1,2,4] oxa Diazol-3-ylmethyl} -piperazine-1-carbaldehyde,
2-cyclopropylmethyl-5- [1- (2-fluorobenzyl) -piperidin-4-ylmethyl] -7-methyl-2,3-dihydro-isoindol-1-one,
7-Methyl-5- [3- (4-methyl-piperazin-1-ylmethyl)-[1,2,4] oxadiazol-5-yl] -2- (4-trifluoromethoxy-benzyl) -2 , 3-dihydro-isoindol-1-one,
4- {5- [7-Methyl-1-oxo-2- (4-trifluoromethoxy-benzyl) -2,3-dihydro-1H-isoindol-5-yl]-[1,2,4] oxa Diazol-3-ylmethyl} -piperazine-1-carboxylic acid tert-butyl ester,
2-cyclopropylmethyl-5- [1- (3-fluoro-benzyl) -piperidin-4-ylmethyl] -7-methyl-2,3-dihydro-isoindol-1-one,
2-cyclopropylmethyl-5- [1- (2-methoxy-benzyl) -piperidin-4-ylmethyl] -7-methyl-2,3-dihydro-isoindol-1-one,
2-cyclopropylmethyl-5- [1- (3-methoxy-benzyl) -piperidin-4-ylmethyl] -7-methyl-2,3-dihydro-isoindol-1-one,
2-cyclopropylmethyl-5- [1- (4-methoxy-benzyl) -piperidin-4-ylmethyl] -7-methyl-2,3-dihydro-isoindol-1-one,
2-cyclopropylmethyl-5- [1- (4-fluoro-benzyl) -piperidin-4-ylmethyl] -7-methyl-2,3-dihydro-isoindol-1-one,
2-cyclohexylmethyl-5- [1- (3-fluoro-benzyl) -piperidin-4-ylmethyl] -7-methyl-2,3-dihydro-isoindol-1-one,
2-cyclohexylmethyl-5- [1- (4-fluoro-benzyl) -piperidin-4-ylmethyl] -7-methyl-2,3-dihydro-isoindol-1-one,
2-cyclopropylmethyl-5- [1- (3-fluoro-benzyl) -piperidin-4-ylmethoxy] -7-methyl-2,3-dihydro-isoindol-1-one,
2-cyclopropylmethyl-5- [1- (4-methoxybenzyl) -piperidin-4-ylmethoxy] -7-methyl-2,3-dihydro-isoindol-1-one,
5- (1-benzyl-pyrrolidin-3-ylamino) -7-methyl-2- (4-trifluoromethoxy-benzyl) -2,3-dihydro-isoindol-1-one,
7-Methyl-5- [5- (4-methyl-piperazin-1-ylmethyl) -pyridin-3-yl] 2- (4-trifluoromethoxy-benzyl) -2,3-dihydro-isoindole-1- on,
7-Methyl-5- [6- (4-methyl-piperazin-1-ylmethyl) -pyridin-3-yl] -2- (4-trifluoromethoxy-benzyl) -2,3-dihydro-isoindole-1 -on,
4- {4- [7-Chloro-1-oxo-2- (4-trifluoromethoxy-benzyl) -2,3-dihydro-1H-isoindol-5-ylmethyl] -piperidin-1-ylmethyl} -benzo Nitrile,
4- [4- (7-chloro-2-cyclopropylmethyl-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl) -piperidin-1-ylmethyl] -benzonitrile,
4- {4- [7-chloro-2- (4-chloro-benzyl) -1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl] -piperidin-1-ylmethyl} -benzonitrile,
4- {4- [7-Chloro-2- (4-difluoromethoxy-benzyl) -1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl] -piperidin-1-ylmethyl} -benzonitrile ,
4- {4- [7-chloro-2- (4-ethyl-benzyl) -1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl] -piperidin-1-ylmethyl} -benzonitrile,
4- {4- [7-Chloro-1-oxo-2- (4-trifluoromethoxy-benzyl) -2,3-dihydro-1H-isoindol-5-ylmethyl] -piperazine-1-methyl} -nicoti Nononitrile,
3- {3- [1- (7-Chloro-2-cyclopropylmethyl-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl) -piperidin-4-yl] -propyl} -benzo Nitrile,
7-chloro-2-cyclopropylmethyl-1-oxo-2,3-dihydro-1H-isoindole-5-carbonitrile,
5-fluoro-2- (4-ethyl-benzyl) -7-trifluoromethyl-2,3-dihydro-isoindol-1-one,
5,7-dimethoxy-2- (4-trifluoromethoxy-benzyl) -2,3-dihydro-isoindol-1-one,
5,7-dimethoxy-2- (4-chloro-benzyl) -2,3-dihydro-isoindol-1-one, and
5,7-dimethoxy-2- [1- (4-chloro-phenyl) -ethyl] -2,3-dihydro-isoindol-1-one;
A compound selected from the group consisting of: or a pharmaceutically acceptable salt, hydrate, solvate, optical isomer, or combination thereof.   A pharmaceutical composition comprising a compound according to claim 1 or 2 and a pharmaceutically acceptable carrier or excipient.   3. A compound according to claim 1 or 2 for use as a medicament.   Use of a compound according to claim 1 or 2 in the manufacture of a medicament for the treatment of neurological and psychiatric disorders associated with glutamate dysfunction.   The neurological and psychiatric disorders are secondary to brain bypass surgery and transplantation, stroke, cerebral ischemia, spinal cord injury, skull injury, perinatal hypoxia, heart failure, hypoglycemic nerve injury, dementia, AIDS-induced cognition Related to muscle spasm, such as symptom, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, eye damage, retinopathy, cognitive impairment, idiopathic and drug-induced Parkinson's disease, muscle spasm and tremor, epilepsy, spasm Muscle spasms and disorders, brain disorders secondary to long-term status epilepticus, migraine, migraine, urinary incontinence, drug resistance, drug withdrawal, psychosis, schizophrenia, anxiety, generalized anxiety disorder, panic disorder, interpersonal Phobia, obsessive-compulsive disorder, and traumatic stress disorder (PTSD), mood disorder, depression, epilepsy, bipolar disorder, circadian rhythm disorder, jet lag, shift work, trigeminal neuralgia, hearing loss, tinnitus, macular degeneration of the eyes, vomiting Brain edema, pain, acute pain, chronic pain, acute pain, intractable pain, neuropathic pain, inflammatory pain, and post-traumatic pain, delayed dyskinesia, sleep disorders, narcolepsy, attention deficit / hyperactivity disorder, and 6. Use according to claim 5, selected from behavioral disorders.   3. A method for the treatment or prevention of such neurological and psychiatric disorders associated with glutamate dysfunction in animals in need of treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction comprising the compounds of claim 1 or 2 Administering a therapeutically effective amount of to the animal.   A method for treating or preventing such neurological and psychiatric disorders associated with glutamate dysfunction in animals in need of treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction, comprising: Administering a therapeutically effective amount of to the animal.   The neurological and psychiatric disorders are brain disorders, stroke, cerebral ischemia, spinal cord injury, skull injury, perinatal hypoxia, heart failure, hypoglycemic nerve injury, which are secondary to cardiac bypass surgery and transplantation. , Dementia, AIDS-induced dementia, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, eye damage, retinopathy, cognitive impairment, idiopathic and drug-induced Parkinson's disease, muscle spasm and trembling, epilepsy, Muscle spasms and disorders related to muscle spasm such as convulsions, brain disorders secondary to long-term status epilepticus, migraine, migraine, urinary incontinence, drug resistance, drug withdrawal, psychosis, schizophrenia, anxiety, general Sexual anxiety disorder, panic disorder, interpersonal phobia, obsessive compulsive disorder, and traumatic stress disorder (PTSD), mood disorder, depression, epilepsy, bipolar disorder, circadian rhythm disorder, jet lag, shift work, trigeminal neuralgia, hearing loss Tinnitus, macular degeneration of eyes, vomiting, brain edema, pain, acute pain, chronic pain, severe pain, intractable pain, neuropathic pain, inflammatory pain, and posttraumatic pain, late-onset dyskinesia, sleep disorder, narcolepsy, 9. A method according to claim 7 or 8, selected from attention deficit / hyperactivity disorder and behavioral disorder.   The neurological and psychiatric disorders are Alzheimer's disease, brain disorders secondary to long-term status epilepticus, drug resistance, drug withdrawal, psychosis, schizophrenia, anxiety, generalized anxiety disorder, panic disorder, interpersonal phobia, obsession 10. The method of claim 9, wherein the method is selected from sexual disorders and post traumatic stress disease (PTSD), mood disorders, depression, epilepsy, and bipolar disorder.