HK1227395A1 - Mglu2/3 antagonists for the treatment of intellectual disabilities - Google Patents

Description

MGLU2/3 antagonists for the treatment of intellectual disabilities

SUMMARY

The present invention relates to novel pharmaceutical uses of certain chemical compounds and pharmaceutical compositions containing said compounds. The present invention relates to compounds that are mGlu2/3 negative allosteric modulators for the treatment of intellectual disabilities. In another aspect, the invention relates to a pharmaceutical composition for the treatment of intellectual disabilities comprising a compound according to the invention and a pharmaceutically acceptable carrier.

Background

L-glutamate, the most common neurotransmitter in the CNS, plays an important role in a number of physiological processes. Glutamate-dependent stimulus receptors fall into two main classes. The first major class forms ligand-controlled ion channels. Metabotropic glutamate receptors (mGluRs) form the second major class and also belong to the G-protein coupled receptor family.

Currently, eight distinct members of these mglurs are known, and some of these members even have subtypes. These eight receptors can be subdivided into three subgroups, according to structural parameters, different effects on the synthesis of intracellular signaling molecules and different affinities for low molecular weight chemical compounds: mGlu1 and mGlu5 belong to group I, mGlu2 and mGlu3 belong to group II, and mGlu4, mGlu6, mGlu7 and mGlu8 belong to group III.

Ligands of metabotropic glutamate receptors belonging to group II are known to be useful for the treatment or prevention of acute and/or chronic neurological disorders such as psychosis, schizophrenia, major depression and alzheimer's disease.

Preferred compounds for use according to the invention are those described in the following documents as mGlu2/3 negative allosteric modulators: WO 01/29011¹，WO 01/29012²，WO 02/083652³，WO 02/083665⁴，WO03/066623⁵，WO 2005/014002⁶，WO 2005/040171⁷，WO 2005/123738⁸，WO 2006/084634⁹，WO2006/099972¹⁰，WO 2007/039439¹¹，WO 2007/110337¹²And WO 2008/119689¹³。

Currently there is no effective biological/drug therapy for ID (Diagnostic and Statistical Manual of Mental Disorders 5)¹⁴And Srivastava and the like¹⁵。

Detailed Description

The terms "intellectual disability" and "intellectual development disorder" summarize the disorders characterized by significant limitations in intellectual functioning such as reasoning, learning, problem solving, and adaptive behavior (including a variety of daily social and practical skills). ID occurs during developmental stages and is characterized by sub-average mental functional deficits in at least 2 areas of adaptive behavior such as communication, self-care, family life, social skills, self-guidance, leisure, and work and learning.

The following definitions apply to general terms used in the present specification, regardless of whether the terms appear alone or together with other groups.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below.

Unless otherwise indicated, the nomenclature used in this application is based on the IUPAC systematic nomenclature.

The term "modulator" refers to a molecule that interacts with a target receptor. Such interactions include, for example, agonistic, antagonistic, or inverse agonistic activity.

The term "allosteric modulator" refers to a compound that binds to a receptor at a site different from the agonist binding site ("allosteric site"). It induces a conformational change in the receptor which alters the activation of the receptor in the presence of an endogenous ligand or agonist. A "positive allosteric modulator" increases the affinity and/or activity of an agonist, while a "negative allosteric modulator" (NAM) decreases the activity and/or affinity (and thus activity) of an agonist for a receptor.

The term "C_1-6-alkyl ", alone or in combination with other groups, represents a hydrocarbon radical which may be linear or branched, with single or multiple branches, wherein alkyl generally comprises from 1 to 6 carbon atoms, such as, for example, methyl (Me), ethyl (Et), propyl, isopropyl (i-propyl), n-butyl, i-butyl (isobutyl), 2-butyl (sec-butyl), t-butyl (tert-butyl), isopentyl, 2-ethyl-propyl, 1, 2-dimethyl-propyl, and the like. In particular "C_1-6Alkyl "has 1 to 4 carbon atoms. A particular group is CH₃。

The term "halogen-C_1-6-alkyl "or" C_1-6-haloalkyl ", alone or in combination with other groups, means C as defined herein_1-6Alkyl substituted by one or more halogens, in particular 1 to 5 halogens, more particularly 1 to 3 halogens ("halogen-C)_1-3-alkyl "), a particular group has 1 halogen or 3 halogens. Particular halogen is fluorine ("fluoro-C)_1-6-alkyl "). A particular "halogen-C_1-6-alkyl "is fluoro-C_1-6-Alkyl, more particularly CF₃。

The term "C_2-6-alkenyl "means a straight or branched chain unsaturated hydrocarbon group having 2 to 6 carbon atoms, preferably having 2 to 4 carbon atoms, such as vinyl or propenyl.

The term "C_2-6-alkoxy- (ethoxy)_r"(r is 1, 2, 3 or 4) means through 1 to 4-CH₂-CH₂Lower alkoxy residues in the sense of the above definitions bound by an-O-group, such as 2-methoxy-ethoxy.

The term "amino", alone or in combination with other groups, means NH₂。

The term "cyano", alone or in combination with other groups, refers to N ≡ C- (NC-).

The term "nitro", alone or in combination with other groups, means NO₂。

The term "hydroxy", alone or in combination with other groups, refers to-OH.

The term "halogen" or "halo", alone or in combination with other groups, refers to chloro (Cl), iodo (I), fluoro (F), and bromo (Br). Particular "halogens" are Cl and F. In particular F.

The term "aryl", alone or in combination with other groups, refers to an aromatic carbocyclic group containing 6 to 14, especially 6 to 10 carbon atoms and having at least one aromatic ring or multiple fused rings in which at least one ring is aromatic. Examples of "aryl" include benzyl, diphenyl, indanyl, naphthyl, phenyl (Ph), and the like. A particular "aryl" group is phenyl.

The term "heteroaryl", alone or in combination with other groups, refers to an aromatic carbocyclic group having a single 4 to 8 membered ring or multiple fused rings containing 5 to 14, especially 5 to 12 ring atoms and containing 1, 2 or 3 heteroatoms selected individually from N, O and S, especially N and O, in which at least one heterocyclic ring is aromatic. "six-membered aromatic heterocycle" refers to a single aromatic ring containing 1-3 nitrogens or pyridine-N-oxide. Examples of "heteroaryl" include: benzofuranyl, benzimidazolyl, 1H-benzimidazolyl, benzoAzinyl radicals, benzoOxazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, furyl, imidazolyl, indazolyl, 1H-indazolyl, indolyl, isoquinolyl, isothiazolylAzolyl group,Azolyl, pyrazinyl, pyrazolyl, 1H-pyrazolyl, pyrazolo [1, 5-a ]]Pyridyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl, thiazolyl, thienyl, triazolyl, 6, 7-dihydro-5H- [1]Azoindenyl, and the like. Particular "heteroaryl" groups are pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, pyridazin-2-yl, pyridazin-3-yl, thiazol-2-yl, thiazol-5-yl and thiophen-2-yl.

The term "pyridine-N-oxide" or "pyridine-1-oxide" refers to a compound having the formula:

the term "heteroaryloxy", alone or in combination with other groups, refers to a "heteroaryl" group as described herein, linked via an-O-.

The term "alkylthio" means C in the sense of the above definition bound via a sulfur atom_1-6Alkyl residues, such as methylsulfanyl.

The term "carbamoyloxy" refers to the group-O-CO-NH₂。

The term "C_1-6-alkoxy ", alone or in combination with other groups, denotes-O-C which may be linear or branched, with a single or multiple branching_1-6An alkyl group, wherein the alkyl group typically comprises 1 to 6 carbon atoms, e.g. methoxy (OMe, MeO), ethoxy (OEt), propoxy, isopropoxy (i-propoxy), n-butoxy, i-butoxy (isobutoxy), 2-butoxy (sec-butoxy), t-butoxy (tert-butoxy), isopentyloxy (i-pentyloxy), and the like. In particular "C_1-6-alkoxy "is a group having 1 to 4 carbon atoms.

The term "haloelement-C_1-6-alkoxy "or" C_1-6-haloalkoxy ", alone or in combination with other groups, means C as defined herein_1-6-alkoxy substituted by one or more halogens, in particular fluorine. Particular "halogen-C_1-6-alkoxy "is fluoro-C_1-6-alkoxy groups.

The term "C_3-8-cycloalkyl "refers to a monovalent saturated monocyclic or bicyclic hydrocarbon group having 3 to 8 ring carbon atoms. Bicyclic means consisting of two saturated carbocyclic rings sharing one or more carbon atoms. In particular C_3-8-Cycloalkyl groups are monocyclic. Other particular groups being "C_3-6-cycloalkyl "and" C_3-4-cycloalkyl "groups. Examples of monocyclic cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. An example of a bicyclic cycloalkyl is bicyclo [2.2.1]Heptyl, or bicyclo [2.2.2]And (4) octyl. A specific example is cyclopentyl.

The term "heterocycloalkyl" refers to a 3 to 7 membered heterocyclic ring containing at least one heteroatom, such as N, O or S, the number of N atoms is 0, 1, 2 or 3, and the number of O and S atoms is each 0, 1 or 2. The term "5 or 6 membered heterocycloalkyl" refers to a 5 or 6 membered heterocyclic ring as described herein. Examples of heterocyclic groups include pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyridinyl, tetrahydropyrrolyl, azetidinyl, thiazolidinyl,oxazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, azepinyl, diazepanyl, oxazepinyl, and the like.

The term "optionally substituted" means C_a-Alkyl or C_b-An alkyl group which may be unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of: OH, halogen, cyano, halogen-C_1-6-alkoxy and C_1-6-an alkoxy group; or cycloalkyl, which may be unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of: OH, halogen, cyanogenBase, C_1-6Alkyl, halogen-C_1-6Alkyl, halogen-C_1-6-alkoxy and C_1-6-alkoxy groups.

The term "pharmaceutically acceptable salt" refers to salts suitable for use in contact with the tissues of humans and animals. Examples of suitable salts with inorganic and organic acids are, but not limited to: acetic acid, citric acid, formic acid, fumaric acid, hydrochloric acid, lactic acid, maleic acid, malic acid, methanesulfonic acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, succinic acid, sulfuric acid (sulfuric acid), tartaric acid, trifluoroacetic acid, and the like. Particular acids are formic acid, trifluoroacetic acid and hydrochloric acid. In particular hydrochloric acid, trifluoroacetic acid and fumaric acid.

The terms "pharmaceutically acceptable carrier" and "pharmaceutically acceptable auxiliary substance" refer to carriers and auxiliary substances such as diluents or excipients that are compatible with the other ingredients of the formulation.

The term "prodrug" refers to a structural derivative of a drug that must be chemically converted in vivo to the drug in order to exert its pharmacological or therapeutic effect (see Patrick)¹⁶Or Ganellin et al¹⁷)。

The term "pharmaceutical composition" includes a product comprising the specified ingredients in predetermined amounts or proportions, as well as any product which results, directly or indirectly, from combining the specified ingredients in the specified amounts. In particular, it comprises: a product comprising one or more active ingredients and an optional carrier comprising inert ingredients, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from decomposition of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.

By "therapeutically effective amount" is meant the amount of a compound that, when administered to a patient to treat a disease state, is sufficient to effect such treatment for the disease state. The "therapeutically effective amount" will vary depending on the compound, the disease state being treated, the severity or disease being treated, the age and relative health of the patient, the route and form of administration, the judgment of the attending physician or veterinary practitioner, and other factors.

The terms "as defined herein" and "as described herein" when referring to a variable are incorporated by reference to the broad definition of the variable as well as the specific, more specific and most specific definitions, if any.

The terms "treating", "contacting" and "reacting", when referring to a chemical reaction, mean adding or mixing two or more reagents under suitable conditions to produce the indicated and/or desired product. It will be appreciated that the reaction that produces the indicated and/or desired product may not necessarily be the result of a combination of the two reagents from the initial addition, i.e., more than one intermediate produced may be present in the mixture that ultimately results in the formation of the indicated and/or desired product. Treatment includes prophylactic treatment and acute relief of symptoms.

The term "aromaticity" means as in the literature, in particular in IUPAC¹⁸The general meaning of aromaticity as defined in (1).

The term "pharmaceutically acceptable excipient" means any ingredient which is not therapeutically active and which is non-toxic, such as disintegrants, binders, fillers, solvents, buffers, tonicity agents, stabilizers, antioxidants, surfactants or lubricants used in formulating pharmaceutical products.

The corresponding pharmaceutically acceptable salts with acids can be obtained by standard methods known to those skilled in the art, e.g. by dissolving a compound of formula I in a suitable solvent such as e.g. diAlkane or THF, and the appropriate amount of the corresponding acid was added. The product can usually be isolated by filtration or chromatography. The conversion of a compound of formula (I) or (II) into a pharmaceutically acceptable salt with a base may be carried out by treating said compound with said base. One possible method of forming the salt is, for example, by adding 1/n equivalent of a basic salt to a solution of the compound in a suitable solvent (e.g., ethanol-water mixture, tetrahydrofuran-water mixture)Such as, for example, M (OH)_nWherein M is the metal or ammonium cation and n is the number of hydroxide anions, and removing the solvent by evaporation or lyophilization.

The present invention relates to mGlu2/3 negative allosteric modulators for the treatment and/or prevention of intellectual disabilities.

A particular embodiment of the present invention relates to mGlu2/3 negative allosteric modulators as described herein, selected from compounds of formula (I) and formula (II):

wherein

Or E and J are N, G is C and one of L or M is N and the other is CH;

or L and G are N, E is C, and J and M are CH;

or J, G and L is N, E is C and M is CH;

or E and L are N, J and M are CH and G is C;

a is selected from the group consisting of: phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, pyridazin-2-yl, pyridazin-3-yl, thiazol-2-yl, thiazol-5-yl and thiophen-2-yl, optionally substituted with one to four R^aSubstitution;

b is selected from the group consisting of: imidazolyl group, [1, 2, 4 ]]Oxadiazolyl, pyrrolyl, 1H-pyrazolyl, pyridinyl, [1, 2, 4 ]]Triazolyl, thiazolyl, pyrimidinyl and thienyl, each of which is optionally substituted by C_1-6-alkyl substitution;

c is optionally substituted aryl or optionally substituted 5 or 6 membered heteroaryl, wherein the substituents are selected from the group consisting of:

i. the halogen(s) are selected from the group consisting of,

ii a nitro group, and (iii) a nitro group,

c optionally substituted with hydroxy_1-6-an alkyl group,

iv.NR^aaR^bbwherein R is^aaAnd R^bbIndependently is H, C_1-6-alkyl or- (CO) -C_1-6-an alkyl group,

v.-S-C_1-6-an alkyl group,

vi.-(SO₂)-OH，

vii-(SO₂)-C_1-6-an alkyl group,

viii.-(SO₂)-NR^ccR^ddwherein R is^ccAnd R^ddIndependently are:

a.H，

b. c optionally substituted by hydroxy_1-6-an alkyl group,

c.C_1-6-a halogenated alkyl group,

d.C_1-6-an alkoxy group,

e. optionally is covered with C_1-6-alkoxy substituted- (CO) C_1-6-an alkyl group,

f.-(CH₂CH₂O)_nCHR^eewherein R is^eeIs H or CH₂OH and n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10,

g.-(CH₂)_m-aryl, wherein m is 1 or 2 and said aryl is optionally substituted by halogen or C_1-6-an alkoxy group substitution,

h.-(CH₂)_p-C_3-6-cycloalkyl, wherein p is 0 or 1,

i.5 or a 6-membered heterocycloalkyl group,

ix.-(SO₂)-NR^ffR^ggwherein R is^ffAnd R^ggTogether with the nitrogen atom to which they are attached form a 4, 5 or 6 membered heterocycloalkyl ring, optionally containing another heteroatom selected from nitrogen, oxygen, sulfur or SO₂Wherein the 4, 5 or 6 membered heterocycloalkyl ring is optionally substituted with a substituent selected from the group consisting of: hydroxy, C_1-6-alkyl, C optionally substituted by hydroxy_1-6-alkoxy and 5-or 6-membered heteroaryloxy,

x.NHSO₂-C_1-6-alkyl, and

xi.NHSO₂-NR^hhRⁱⁱwherein R is^hhAnd RⁱⁱIndependently is H, C_1-6Alkyl, - (CO) O-C_1-6-alkyl, or R^hhAnd RⁱⁱTogether with the nitrogen atom to which they are attached form a 4, 5 or 6 membered heterocycloalkyl ring, the ring of which optionally contains another heteroatom selected from nitrogen, oxygen or sulfur, wherein said 4, 5 or 6 membered heterocycloalkyl ring is optionally substituted by C_1-6-alkyl substitution;

R¹is H, halogen, CF₃、CHF₂Or C_1-6-an alkyl group;

R²is H, halogen, C_1-6Alkyl radical, C_1-6-alkoxy, CF₃Or CHF₂；

R³Is H, -C (CH)₃)₂OH; straight chain C_1-4-alkyl or C_3-4-cycloalkyl optionally substituted with one or more substituents selected from the group consisting of 1 to 6F and 1 to 2 OH;

R⁴is H, halogen, C optionally substituted by hydroxy_1-6Alkyl radical, C_1-6-alkoxy, C_1-6-haloalkyl group, C_3-6-a cycloalkyl group;

R⁵is H, cyano, halogen, C_1-6-haloalkyl group, C_1-6-alkoxy, C_1-6-haloalkoxy, C_1-6-alkyl or C_3-6-a cycloalkyl group;

R⁶is halogen, H, C_1-6-alkoxy, C_1-6-haloalkyl group, C_1-6Alkyl radical, C_3-6-cycloalkyl, C_1-6-haloalkoxy, or is NR^jjR^kkWherein R is^jjAnd R^kkIndependently selected from the group consisting of: H. c_3-8-cycloalkyl, aryl, heteroaryl with 5 to 12 ring atoms and C optionally substituted by one or more substituents selected from the group consisting of_1-6-an alkyl group: halogen, hydroxy, C_3-8-cycloalkyl, aryl, heteroaryl with 5 to 12 ring atoms and-NR^llR^mmWherein R is^llAnd R^mmIndependently selected from the group consisting of H and C_1-6-alkyl groups;

or R^jjAnd R^kkCapable of forming, together with the nitrogen atom to which they are attached, an optionally substituted heterocyclic group comprising 5 to 12 ring atoms, optionally containing another heteroatom selected from nitrogen, oxygen or sulfur, wherein the heteroaryl group is optionally substituted with one, two, three, four or five substituents selected from the group consisting of: halogen, hydroxy, C_1-6-alkyl and C_1-6-a haloalkyl group;

or R⁵And R⁶Can form together a dioxo bridge;

R⁷is H or halogen;

R^ais halogen; a hydroxyl group; a cyano group; CF (compact flash)₃；NR^eR^f(ii) a C optionally substituted by amino or by hydroxy_1-6-an alkyl group; c_1-6-an alkoxy group; c_3-4-a cycloalkyl group; CO-NR^bR^c，SO₂-NR^bR^c(ii) a Or SO₂-R^d；

R^bAnd R^cMay be the same or different and is selected from the group consisting of:

i.H；

ii linear or branched C optionally substituted with one or more substituents selected from the group consisting of_1-6-an alkyl group:

iii.F, cyano, hydroxy, C_1-6-alkoxy, -NH-C (O) -O-C₁-₆Alkyl, amino, (C)_1-6-alkyl) amino, di (C)_1-6-alkyl) amino, C_3-6-cycloalkyl, heterocycloalkyl having 5 or 6 ring atoms, aryl or 5 or 6 membered heteroaryl;

iv.C_3-6-a cycloalkyl group;

v. aryl; or

A heteroaryl group;

or R^bAnd R^cMay be taken together with the nitrogen atom to which they are attached to form a radical which may be substituted by hydroxyl or by C_1-6-an alkyl-substituted heterocycle of 4 to 6 ring members;

R^dis OH or C_1-6-an alkyl group;

R^eand R^fIs H, C optionally substituted by hydroxy_1-6Alkyl, -C (O) -C_1-6-an alkyl group; s (O)₂-C_1-6-an alkyl group;

and pharmaceutically acceptable salts thereof.

A particular embodiment of the present invention relates to mGlu2/3 negative allosteric modulators as described herein, selected from compounds of formula (I) and formula (II), wherein

E and J are N, G is C, L is N and M is CH;

a is selected from the group consisting of: phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, pyridazin-2-yl, pyridazin-3-yl, thiazol-2-yl, thiazol-5-yl, and thiophen-2-yl;

b is selected from the group consisting of: imidazolyl group, [1, 2, 4 ]]Oxadiazolyl, pyrrolyl, 1H-pyrazolyl, pyridinyl, [1, 2, 4 ]]Triazolyl, thiazolyl, pyrimidinyl and thienyl, each of which is optionally substituted by C_1-6-alkyl substitution;

c is optionally substituted aryl, wherein the substituents are selected from the group consisting of:

i. the halogen(s) are selected from the group consisting of,

ii a nitro group, and (iii) a nitro group,

c optionally substituted with hydroxy_1-6-an alkyl group,

iv.NR^aaR^bbwherein R is^aaAnd R^bbIndependently is H, C_1-6-alkyl or- (CO) -C_1-6-an alkyl group,

v.-S-C_1-6-an alkyl group,

vi.-(SO₂)-OH，

vii-(SO₂)-C_1-6-an alkyl group,

viii.-(SO₂)-NR^ccR^ddwherein R is^ccAnd R^ddIndependently are:

a.H，

b. c optionally substituted by hydroxy_1-6-an alkyl group,

c.C_1-6-a halogenated alkyl group,

d.C_1-6-an alkoxy group,

e. optionally is covered with C_1-6-alkoxy substituted- (CO) C_1-6-an alkyl group,

R¹is CF₃；

R²Is H;

R³is selected freelyStraight chain C substituted with one or more substituents of the group consisting of 1 to 6F and 1 to 2 OH_1-4-an alkyl group;

R⁴is C_1-6-an alkyl group;

R⁵is C_1-6-a haloalkyl group;

R⁶is H;

R⁷is H;

and pharmaceutically acceptable salts thereof.

A particular embodiment of the present invention relates to mGlu2/3 negative allosteric modulators as described herein, selected from compounds of formula (I) and formula (II), wherein

E and J are N, G is C, L is N and M is CH;

a is pyridin-2-yl;

b is a pyridyl group, and B is a pyridyl group,

c is SO-substituted₂NH₂Substituted phenyl;

R¹is CF₃；

R²Is H;

R³is CF₃；

R⁴Is CH₃；

R⁵Is CF₃；

R⁶Is H;

R⁷is H;

and pharmaceutically acceptable salts thereof.

A particular embodiment of the present invention relates to mGlu2/3 negative allosteric modulators as described herein, which are compounds of formula (Ia) or pharmaceutically acceptable salts thereof.

A particular embodiment of the present invention relates to mGlu2/3 negative allosteric modulators as described herein, which are compounds of formula (IIa) or (IIb) or pharmaceutically acceptable salts thereof.

A particular embodiment of the present invention relates to mGlu2/3 negative allosteric modulators as described herein, which are compounds of formula (IIa) or pharmaceutically acceptable salts thereof.

A particular embodiment of the present invention relates to mGlu2/3 negative allosteric modulators as described herein, which are compounds of formula (IIb) or pharmaceutically acceptable salts thereof.

A particular embodiment of the present invention relates to the use of mGlu2/3 negative allosteric modulators for the treatment, prevention and/or delay of progression of central nervous system disorders caused by neurodevelopmental defects leading to excessive mGlu2/3 receptor activation in the central nervous system, particularly but not exclusively in the cortical region and hippocampus, and/or corrected by negative allosteric modulation via mGlu2/3 receptor activation.

A particular embodiment of the present invention relates to the use of mGlu2 negative allosteric modulators for the treatment, prevention and/or delay of progression of central nervous system disorders caused by neurodevelopmental defects that lead to excessive mGlu2 receptor activation in the central nervous system, particularly but not exclusively in the cortical region and hippocampus, and/or which can be corrected by negative allosteric modulation of mGlu2 receptor activation.

A particular embodiment of the present invention relates to the use of mGlu3 negative allosteric modulators for the treatment, prevention and/or delay of progression of central nervous system disorders caused by neurodevelopmental defects that lead to excessive mGlu3 receptor activation in the central nervous system, particularly but not exclusively in the cortical region and hippocampus, and/or which can be corrected by negative allosteric modulation of mGlu3 receptor activation.

A particular embodiment of the present invention relates to the use of mGlu2/3 negative allosteric modulators for the treatment, prevention and/or delay of progression of central nervous system disorders caused by neurodevelopmental defects leading to excessive mGlu2/3 inhibition in the cortex and hippocampus.

A particular aspect of the invention relates to the use as described herein, wherein the central nervous system disorder is intellectual disability.

A particular aspect of the invention relates to the use as described herein, wherein the mGlu2/3 negative allosteric modulator is selected from the group consisting of a compound of formula (I) and formula (II),

wherein

Or E and J are N, G is C and one of L or M is N and the other is CH;

or L and G are N, E is C, and J and M are CH;

or J, G and L are N, E is C and M is CH;

or E and L are N, J and M are CH and G is C;

a is selected from the group consisting of: phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, pyridazin-2-yl, pyridazin-3-yl, thiazol-2-yl, thiazol-5-yl, and thiophen-2-yl, optionally substituted with one to four R^aSubstitution;

b is selected from the group consisting of: imidazolyl, [1, 2, 4 ]]Oxadiazolyl, pyrrolyl, 1H-pyrazolyl, pyridinyl, [1, 2, 4 ]]Triazolyl, thiazolyl, pyrimidinyl and thienyl, each of which is optionally substituted by C_1-6-alkyl substitution;

c is optionally substituted aryl or optionally substituted 5 or 6 membered heteroaryl, wherein the substituents are selected from the group consisting of:

i. the halogen(s) are selected from the group consisting of,

ii a nitro group, and (iii) a nitro group,

c optionally substituted with hydroxy_1-6-an alkyl group,

iv.NR^aaR^bbwherein R is^aaAnd R^bbIndependently is H, C_1-6-alkyl or- (CO) -C_1-6-an alkyl group,

v.-S-C_1-6-an alkyl group,

vi.-(SO₂)-OH，

vii-(SO₂)-C_1-6-an alkyl group,

viii.-(SO₂)-NR^ccR^ddwherein R is^ccAnd R^ddIndependently are:

a.H，

b. c optionally substituted by hydroxy_1-6-an alkyl group,

c.C_1-6-a halogenated alkyl group,

d.C_1-6-an alkoxy group,

e. optionally is covered with C_1-6-alkoxy substituted- (CO) C_1-6-an alkyl group,

f.-(CH₂CH₂O)_nCHR^eewherein R is^eeIs H or CH₂OH and n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10,

g.-(CH₂)_m-aryl, wherein m is 1 or 2 and said aryl is optionally substituted by halogen or C_1-6-an alkoxy group substitution,

h.-(CH₂)_p-C_3-6-cycloalkyl, wherein p is 0 or 1,

i.5 or a 6-membered heterocycloalkyl group,

ix.-(SO₂)-NR^ffR^ggwherein R is^ffAnd R^ggTogether with the nitrogen atom to which they are attached form a 4, 5 or 6 membered heterocycloalkyl ring, optionally containing another heteroatom selected from nitrogen, oxygen, sulfur or SO₂Wherein the 4, 5 or 6 membered heterocycloalkyl ring is optionally substituted with a substituent selected from the group consisting of: hydroxy, C_1-6-alkyl, C optionally substituted by hydroxy_1-6-alkoxy and 5-or 6-membered heteroaryloxy,

x.NHSO₂-C_1-6-alkyl, and

xi.NHSO₂-NR^hhRⁱⁱwherein R is^hhAnd RⁱⁱIndependently is H, C_1-6Alkyl, - (CO) O-C_1-6-alkyl, or R^hhAnd RⁱⁱTogether with the nitrogen atom to which they are attached form a 4, 5 or 6 membered heterocycloalkyl ring, the ring of which optionally contains another heteroatom selected from nitrogen, oxygen or sulfur, wherein said 4, 5 or 6 membered heterocycloalkyl ring is optionally substituted by C_1-6-alkyl substitution;

R¹is H, halogen, CF₃、CHF₂Or C_1-6-an alkyl group;

R²is H, halogen, C_1-6Alkyl radical, C_1-6-alkoxy, CF₃Or CHF₂；

R³Is H, -C (CH)₃)₂OH; straight chain C_1-4-alkyl or C_3-4-cycloalkyl optionally substituted with one or more substituents selected from the group consisting of 1 to 6F and 1 to 2 OH;

R⁴is H, halogen, C optionally substituted by hydroxy_1-6Alkyl radical, C_1-6-alkoxy, C_1-6-haloalkyl group, C_3-6-a cycloalkyl group;

R⁵is H, cyano, halogen, C_1-6-haloalkyl group, C_1-6-alkoxy, C_1-6-haloalkoxy, C_1-6-alkyl or C_3-6-a cycloalkyl group;

R⁶is halogen, H, C_1-6-alkoxy, C_1-6-haloalkyl group, C_1-6Alkyl radical, C_3-6-cycloalkyl, C_1-6-haloalkoxy, or is NR^jjR^kkWherein R is^jjAnd R^kkIndependently selected from the group consisting of: H. c_3-8-cycloalkyl, aryl, heteroaryl with 5 to 12 ring atoms and C optionally substituted by one or more substituents selected from the group consisting of_1-6-an alkyl group: halogen, hydroxy, C_3-8-cycloalkyl, aryl, heteroaryl with 5 to 12 ring atoms and-NR^llR^mmWherein R is^llAnd R^mmIndependently selected from the group consisting of H and C_1-6-alkyl groups;

or R^jjAnd R^kkCapable of forming, together with the nitrogen atom to which they are attached, an optionally substituted heterocyclic group comprising 5 to 12 ring atoms, optionally containing another heteroatom selected from nitrogen, oxygen or sulfur, wherein the heteroaryl group is optionally substituted with one, two, three, four or five substituents selected from the group consisting of: halogen, hydroxy, C_1-6-alkyl and C_1-6-a haloalkyl group;

or R⁵And R⁶Can form together a dioxo bridge;

R⁷is H or halogen;

R^ais halogen; a hydroxyl group; a cyano group; CF (compact flash)₃；NR^eR^f(ii) a Optionally substituted by amino or by hydroxyC_1-6-an alkyl group; c_1-6-an alkoxy group; c_3-4-a cycloalkyl group; CO-NR^bR^c，SO₂-NR^bR^c(ii) a Or SO₂-R^d；

R^bAnd R^cMay be the same or different and is selected from the group consisting of:

i.H；

ii linear or branched C optionally substituted with one or more substituents selected from the group consisting of_1-6-an alkyl group:

iii.F, cyano, hydroxy, C_1-6-alkoxy, -NH-C (O) -O-C_1-6Alkyl, amino, (C)_1-6-alkyl) amino, di (C)_1-6-alkyl) amino, C_3-6-cycloalkyl, heterocycloalkyl having 5 or 6 ring atoms, aryl or 5 or 6 membered heteroaryl;

iv.C_3-6-a cycloalkyl group;

v. aryl; or

A heteroaryl group;

or R^bAnd R^cMay be taken together with the nitrogen atom to which they are attached to form a radical which may be substituted by hydroxyl or by C_1-6-an alkyl-substituted heterocycle of 4 to 6 ring members;

R^dis OH or C_1-6-an alkyl group;

R^eand R^fIs H, C optionally substituted by hydroxy_1-6Alkyl, -C (O) -C_1-6-an alkyl group; s (O)₂-C_1-6-an alkyl group;

and pharmaceutically acceptable salts thereof.

A particular aspect of the invention relates to the use as described herein, wherein the mGlu2/3 negative allosteric modulator is selected from compounds of formula (I) and formula (II) and prodrugs thereof.

A particular aspect of the invention relates to the use as described herein wherein the mGlu2/3 negative allosteric modulator is selected from the group consisting of compounds of formula (I) and formula (II), wherein

E and J are N, G is C, L is N and M is CH;

a is selected from the group consisting of: phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, pyridazin-2-yl, pyridazin-3-yl, thiazol-2-yl, thiazol-5-yl, and thiophen-2-yl;

b is selected from the group consisting of: imidazolyl group, [1, 2, 4 ]]Oxadiazolyl, pyrrolyl, 1H-pyrazolyl, pyridinyl, [1, 2, 4 ]]Triazolyl, thiazolyl, pyrimidinyl and thienyl, each of which is optionally substituted by C_1-6-alkyl substitution;

c is optionally substituted aryl, wherein the substituents are selected from the group consisting of:

i. the halogen(s) are selected from the group consisting of,

ii a nitro group, and (iii) a nitro group,

c optionally substituted with hydroxy_1-6-an alkyl group,

iv.NR^aaR^bbwherein R is^aaAnd R^bbIndependently is H, C_1-6-alkyl or- (CO) -C_1-6-an alkyl group,

v.-S-C_1-6-an alkyl group,

vi.-(SO₂)-OH，

vii-(SO₂)-C_1-6-an alkyl group,

viii.-(SO₂)-NR^ccR^ddwherein R is^ccAnd R^ddIndependently are:

a.H，

b. optionally substituted by hydroxyRadical substituted C_1-6-an alkyl group,

c.C_1-6-a halogenated alkyl group,

d.C_1-6-an alkoxy group,

e. optionally is covered with C_1-6-alkoxy substituted- (CO) C_1-6-an alkyl group,

R¹is CF₃；

R²Is H;

R³is a straight chain C substituted by one or more substituents selected from the group consisting of 1 to 6F and 1 to 2 OH_1-4-an alkyl group;

R⁴is C_1-6-an alkyl group;

R⁵is C_1-6-a haloalkyl group;

R⁶is H;

R⁷is H;

and pharmaceutically acceptable salts thereof.

A particular aspect of the invention relates to the use as described herein, wherein the mGlu2/3 negative allosteric modulator is selected from a compound of formula (I) and formula (II), wherein

E and J are N, G is C, L is N and M is CH;

a is pyridin-2-yl;

b is a pyridyl group, and B is a pyridyl group,

c is SO-substituted₂NH₂Substituted phenyl;

R¹is CF₃；

R²Is H;

R³is CF₃；

R⁴Is CH₃；

R⁵Is CF₃；

R⁶Is H;

R⁷is H;

and pharmaceutically acceptable salts thereof.

A particular aspect of the present invention relates to the use as described herein, wherein the mGlu2/3 negative allosteric modulator is a compound of formula (Ia) or a pharmaceutically acceptable salt thereof.

A particular aspect of the invention relates to the use as described herein, wherein the mGlu2/3 negative allosteric modulator is a compound of formula (Ia) or a prodrug thereof.

A particular aspect of the present invention relates to the use as described herein, wherein the mGlu2/3 negative allosteric modulator is a compound of formula (IIa) or (IIb), or a pharmaceutically acceptable salt thereof.

A particular aspect of the present invention relates to the use as described herein, wherein the mGlu2/3 negative allosteric modulator is a compound of formula (IIa) or a pharmaceutically acceptable salt thereof.

A particular aspect of the invention relates to the use as described herein, wherein the mGlu2/3 negative allosteric modulator is a compound of formula (IIa) or a prodrug thereof.

A particular aspect of the present invention relates to the use as described herein, wherein the mGlu2/3 negative allosteric modulator is a compound of formula (IIb) or a pharmaceutically acceptable salt thereof.

A particular aspect of the present invention relates to the use as described herein, wherein the mGlu2/3 negative allosteric modulator is a compound of formula (III) or a pharmaceutically acceptable salt thereof.

Wherein

X is a single bond or an acetylenediyl group; and wherein

In the case where X is a single bond,

R⁸is a hydrogen atom, and is,

the cyano group(s),

the halogen(s) are selected from the group consisting of,

C_1-6-an alkyl group,

C_1-6-an alkoxy group,

fluorine-C_1-6-an alkyl group,

fluorine-C_1-6-an alkoxy group,

pyrrol-1-yl, or

A phenyl group which is unsubstituted or substituted with one or two substituents selected from the group consisting of: halogen, C_1-6-alkyl or fluoro-C_1-6-an alkyl group;

or in the case where X is an ethynyl diradical,

R⁸is phenyl, which is unsubstituted or substituted with one or two substituents selected from the group consisting of: halogen, C_1-6-alkyl or fluoro-C_1-6-an alkyl group;

and wherein

R⁹Is a hydrogen atom, and is,

C_1-6-an alkyl group,

C_2-6-alkenyl

C_1-6-alkoxy radical，

The halogen(s) are selected from the group consisting of,

-NR’R”，

a pyrrolidin-1-yl group which is,

a piperidin-1-yl group,

a group of morpholine-4-yl and a group of morpholine-4-yl,

fluorine-C_1-6-an alkyl group,

fluorine-C_1-6-alkoxy, or

C_1-6-alkoxy- (ethoxy) r and r is 1, 2, 3 or 4;

r' is hydrogen, C_1-6-alkyl or C_3-6-a cycloalkyl group;

r' is hydrogen, 1C_1-6-alkyl or C_3-6-a cycloalkyl group;

y is-CH or-N-;

R¹⁰is a six-membered aromatic heterocyclic ring containing 1 to 3 nitrogen atoms or pyridine-N-oxide, said ring being unsubstituted or substituted by one or two substituents selected from the group consisting of

The halogen(s) are selected from the group consisting of,

fluorine-C_1-6-an alkyl group,

fluorine-C_1-6-an alkoxy group,

the cyano group(s),

an amino group, a carboxyl group,

C_1-6-an alkylamino group,

C_1-6-alkoxy-C_1-6-an alkylamino group,

C_1-6-hydroxy-C_1-6-an alkylamino group,

-(CH₂)_q-C(O)-OR”，

-(CH₂)_q-C(O)-NR'R”，

-(CH₂)_q-SO₂-NR'R”，

-(CH₂)_q-C(NH₂)＝NR”，

a hydroxyl group(s),

C_1-6-an alkoxy group,

C_1-6-an alkylthio group,

C_3-6-a cycloalkyl group, and

C_1-6-alkyl optionally substituted by fluoro, -NR' R ", hydroxy, C_1-6-alkoxy, pyrrolidin-1-yl, azetidin-1-yl, cyano or carbamoyloxy, wherein R' and R "have the meanings indicated above; and is

q is 0, 1, 2, 3 or 4.

A particular aspect of the invention relates to a method for the treatment, prevention and/or delay of progression of intellectual disability in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a mGlu2/3 negative allosteric modulator as described herein.

A particular aspect of the invention relates to a pharmaceutical composition comprising a mGlu2/3 negative allosteric modulator as described herein in a pharmaceutically acceptable form for the treatment, prevention and/or delay of progression of intellectual disabilities.

A particular aspect of the invention relates to a pharmaceutical composition comprising a mGlu2/3 negative allosteric modulator as described herein in a pharmaceutically acceptable form for the treatment, prevention and/or delay of progression of intellectual disabilities.

A particular aspect of the invention relates to mGlu2/3 negative allosteric modulators, as described herein, for use in the treatment, prevention and/or delay of progression of intellectual disabilities.

A particular aspect of the present invention relates to mGlu2/3 negative allosteric modulators as described herein for the preparation of medicaments for the treatment, prevention and/or delay of progression of intellectual disabilities.

A particular aspect of the invention relates to the use of a mGlu2/3 negative allosteric modulator, as described herein, for the preparation of a medicament for the treatment, prevention and/or delay of progression of intellectual disabilities.

Pharmaceutical composition

The compounds of formulae I-III and pharmaceutically acceptable salts thereof may be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, for example, in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. However, administration can also be effected rectally, for example in the form of suppositories, or parenterally, for example in the form of injection solutions.

The compounds of formulae I-III and pharmaceutically acceptable salts thereof can be processed with pharmaceutically inert, inorganic or organic excipients for the preparation of tablets, coated tablets, dragees and hard gelatine capsules. For example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used as such excipients for tablets, dragees and hard gelatine capsules. Suitable excipients for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like.

Suitable excipients for the preparation of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like. Suitable excipients for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils and the like. Suitable excipients for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols and the like.

In addition, the pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They may also contain other therapeutically valuable substances.

The dosage may vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, in the case of oral administration, a daily dose of about 10 to 1000 mg/human of a compound of formula I-III should be appropriate. However, the upper limit may be exceeded when necessary.

Examples of compositions according to the invention are, but are not limited to:

example A

Tablets of the following composition were made in the usual manner:

table 1: possible tablet compositions

Manufacturing process

1. Ingredients 1, 2, 3 and 4 were mixed and granulated with pure water.

2. The granules were dried at 50 ℃.

3. The particles are passed through a suitable milling apparatus.

4. Add ingredient 5 and mix for three minutes; pressing on a suitable press.

Example B-1

Capsules of the following composition were prepared:

table 2: possible capsule ingredient composition

Manufacturing process

1. Ingredients 1, 2 and 3 were mixed in a suitable mixer for 30 minutes.

2. Ingredients 4 and 5 were added and mixed for 3 minutes.

3. Filling into suitable capsules.

The compounds of formulae I-III, lactose and corn starch are first mixed in a mixer and then mixed in a mill. Returning the mixture to the mixer; talc was added thereto and mixed well. The mixture is filled by machine into suitable capsules, for example hard gelatin capsules.

Example B-2

Soft gelatin capsules of the following composition were prepared:

composition (I)	mg/capsule
		Compounds of formula I-III	5
Yellow wax	8
		Hydrogenated soybean oil	8
Partially hydrogenated vegetable oils	34
		Soybean oil	110
Total of	165

Table 3: possible soft gelatin capsule ingredient compositions

Composition (I)	mg/capsule
		Gelatin	75
Glycerin 85%	32
		Karion 83	8 (Dry matter)
Titanium dioxide	0.4
		Iron oxide yellow	1.1
Total of	116.5

Table 4: possible soft gelatin capsule compositions

Manufacturing process

The compounds of formulae I-III are dissolved in a warm melt of the other ingredients and the mixture is filled into soft gelatin capsules of appropriate size. The filled soft gelatin capsules were processed according to the general procedure.

Example C

Suppositories of the following composition were prepared:

composition (I)	mg/suppository
		Compounds of formula I-III	15
Suppository block	1285
		Total of	1300

Table 5: possible suppository composition

Manufacturing process

The suppository blocks were melted in a glass or steel vessel, mixed well and cooled to 45 ℃. Subsequently, the finely powdered compound of formula I or II is added thereto and stirred until it is completely dispersed. Pouring the mixture into suppository molds with proper size, standing and cooling; the suppositories are then removed from the moulds and individually packaged in waxed paper or metal foil.

Example D

Injection solutions of the following composition were prepared:

composition (I)	mg/injection solution
		Compounds of formula I-III	3
Polyethylene glycol 400	150
		Acetic acid	Appropriate amount to pH5.0
Water for injection solution	To 1.0ml

Table 6: possible injection solution compositions

Manufacturing process

The compounds of formulae I-III are dissolved in a mixture of polyethylene glycol 400 and water for injection (part). The pH was adjusted to 5.0 by acetic acid. The volume was adjusted to 1.0ml by adding the balance of water. The solution was filtered, filled into vials with the appropriate excess and sterilized.

Example E

Sachets (sachets) of the following composition were manufactured:

composition (I)	mg/sachet
		A compound of formula I or II	50
Lactose, fine powder	1015
		Microcrystalline cellulose (AVICEL PH102)	1400
Sodium carboxymethylcellulose	14
		Polyvinylpyrrolidone K30	10
Magnesium stearate	10
		Flavoring additive	1
Total of	2500

Table 7: possible sachet composition

Manufacturing process

The compounds of formulae I-III are mixed with lactose, microcrystalline cellulose and sodium carboxymethylcellulose and granulated with a mixture of polyvinylpyrrolidone in water. The granules were mixed with magnesium stearate and flavouring additives and filled into sachets.

Examples

Example 1: cognitive experiments in the Shank3KO mouse model with reported ASD for cognitive impairment

Patient's health

11-12C 57B16/J background female wild type and Shank3KO mice were from F.Hoffmann La Roche feedlots and were 10 weeks old at the start of the study. 20 male Nlgn3 knockout rats and 20 littermate naive wild type controls (background: Sprague Dawley) were from F.Hoffmann La Roche farms. All rats and mice were housed in groups in a holding room at controlled temperature (20-22 ℃), humidity (55-65%) and 12-h light/dark cycle (light on 06: 00 h). All animals were allowed free access to food and water. The experimental procedure used in this study was subject to prior approval from the City of base cancer indication Committee based on adherence to federal and local regulations.

Medicine

According to methods known in the art¹²II-a was synthesized in F.Hoffmann-La Roche Ltd. Both compounds were prepared as suspensions in 0.3% Tween80 v/v 0.9% saline and administered orally (os) by gavage using a dosing volume of 5ml/kg (rat) or 10ml/kg (mouse). The fixed pretreatment time for II-a was 180min and 90min, respectively. All doses reported in this study are expressed as free base equivalents.

Experimental plan for Shank3KO mouse

Treatment group

On days 1-7, II-a or vehicle (WT: n-12; KO: n-12) was administered orally at 10mg/kg (WT: n-11; KO: n-12) once daily, 3 hours before day 1 of the water maze test until the last day of the test. The dose of II-a was reduced to 7mg/kg on days 8-16. The water maze was performed on days 1-12 of treatment and was used for "shaping" 2 days before starting the drug treatment. Combing/digging tests (sanding/digging test) were performed on days 15-16.

Water maze scheme

The water maze consisted of an annular pool (1m diameter) containing water that was rendered opaque with a white artificial opacifier (E-308; Inuchem, Voletski, Switzerland) and a maze cue around the annular pool. The water temperature (21. + -. 1 ℃ C.) was constant throughout the experiment. The maze is arbitrarily divided into four quadrants: NE, NW, SE, SW; and a clear plexiglas ring platform (d ═ 10cm) was placed in the center of one of the quadrants, 1-2cm below the water surface. Each mouse swim path was analyzed online using a computer tracking system (HVS Image ltd. Each mouse started at sequential positions for each trial and the maximum duration of each trial was 60 s. The platform position is assigned at the beginning of the detection of the entire treatment group and then shifted to the opposite quadrant position in antiphase. If the mouse finds a platform during the trial, it is left on the platform for 15 s. If the mouse did not find the platform until the end of the trial, the mouse was guided towards the platform, allowed to climb onto the platform and there for 15 s. The inter-trial interval (ITI) was 10min during which the animals returned to their cages.

Probing (Acquisition): mice were trained to find hidden platform positions with 4 trials each day for 5 days, after which probing trials (probe trials) (platform removal) were performed at the end of all trials on the fifth day to assess the extent of spatial learning.

Reverse learning: two days later, the mouse returned to the water maze and learned to locate the platform hidden at a new location in the maze. This testing period consisted of 4 trials (lasting 5 days) per day, followed by a probe trial on the fifth day.

And (3) data analysis: mean latency (latency), path length and swimming speed were evaluated during probing and reverse learning. In the probe test, the percentage of time spent on the platform before searching in each quadrant (left, platform, right, and opposite) and the number of times the platform was traversed was measured.

Self-combing/planing table

Self-carding: after acclimation to the room for 30 to 60min, each mouse was tested for 5min in a clean makrolon type II (350cm3) cage (illuminated at about 40 Lux) without sawdust bedding. Two mice were tested simultaneously at each stage.

Digging: approximately two minutes after the self-combing test, mice were then placed in similar cages with a 5em pad of fresh sawdust. Two mice were tested simultaneously at each stage.

And (3) data analysis: during the self-combing test, the parameters were recorded directly by using a stopwatch: self combing duration, self combing frequency. During the dig test, parameters of dig laterals, duration and frequency were measured. After the self-combing and planing test, the parameters were measured: self-grooming duration, self-grooming frequency, digging duration and frequency.

Drawings

FIGS. 1 and 2: mean latency and pathlength assessment during probing and reverse learning in 48 female SHANK3-KO (10 weeks old, group cage) with predominantly C57BL/6j background, vehicle (0.3% tween80 in 0.9% NaCl) or mGluR2 antagonist II-a 10mg/kg, chronic by mouth (po). No learning deficit was observed in KO, and II-a produced some improvement in latency to platform only in KO mice (apparent block 7, latency and path length)

Fig. 3 and 4: mean latency and pathlength assessment during probing and reverse learning in 48 female SHANK3-KO (10 weeks old, group cage) with predominantly C57BL/6j background, vehicle (0.3% tween80 in 0.9% NaCl) or mGluR2 antagonist II-a 10mg/kg, chronic by mouth (po). Statistics are repeated measures analysis of changes. KO-Veh had a marked memory impairment compared to WT-Veh, an improvement being observed with mGluR2 antagonist II-a.

¹WO 01/29011

²WO 01/29012

³WO 02/083652

⁴WO 02/083665

⁵WO 03/066623

⁶WO 2005/014002

⁷WO 2005/040171

⁸WO 2005/123738

⁹WO 2006/084634

¹⁰WO 2006/099972

¹¹WO 2007/039439

¹²WO 2007/110337

¹³WO 2008/119689

¹⁴http：//www.dsm5.org/documents/intellectual％20disability％20fact％20sheet.pdf

¹⁵Neurosci Biobehav Rev.2014Apr 4.pii：S0149-7634(14)00077-3

¹⁶G L Patrick，An Introduction to Medicinal Chemistry.SecondEdition.pages 239-250

¹⁷Ganellin and Roberts，Medicinal Chemistry：The role of OrganicChemistry in Drug Research，Second Edition，Academic Press Ltd(1993)，Chapter 4

¹⁸Compendium of Chemical Terminology，2nd，A.D.McNaught&A.Wilkinson(Eds).Blackwell Scientific Publications，Oxford(1997)

Claims (13)

1. A mGlu2/3 negative allosteric modulator for the treatment and/or prevention of intellectual disabilities.

2. The mGlu2/3 negative allosteric modulator according to claim 1 selected from the group consisting of compounds of formula (I) and formula (II):

wherein

Or E and J are N, G is C and one of L or M is N and the other is CH;

or L and G are N, E is C, and J and M are CH;

or J, G and L is N, E is C and M is CH;

or E and L are N, J and M are CH and G is C;

a is selected from the group consisting of: phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, pyridazin-2-yl, pyridazin-3-yl, thiazol-2-yl, thiazol-5-yl and thiophen-2-yl, optionally substituted with one to four R^aSubstitution;

b is selected from the group consisting of: imidazolyl group, [1, 2, 4 ]]Oxadiazolyl, pyrrolyl, 1H-pyrazolyl, pyridinyl, [1, 2, 4 ]]Triazolyl, thiazolyl, pyrimidinyl and thienyl, each of which is optionally substituted by C_1-6-alkyl substitution;

c is optionally substituted aryl or optionally substituted 5 or 6 membered heteroaryl, wherein the substituents are selected from the group consisting of:

a halogen,

a nitro group,

xiv. C optionally substituted with hydroxy_1-6-an alkyl group,

xv.NR^aaR^bbwherein R is^aaAnd R^bbIndependently is H, C_1-6-alkyl or- (CO) -C_1-6-an alkyl group,

xvi.-S-C_1-6-an alkyl group, a carboxyl group,

xvii.-(SO₂)-OH，

xviii.-(SO₂)-C_1-6-an alkyl group,

xix.-(SO₂)-NR^ccR^ddwherein R is^ccAnd R^ddIndependently are:

j.H，

k. c optionally substituted by hydroxy_1-6-an alkyl group,

l.C_1-6-a halogenated alkyl group,

m.C_1-6-alkanesThe oxygen radical is selected from the group consisting of oxygen radicals,

n. optionally substituted by C_1-6-alkoxy substituted- (CO) C_1-6-an alkyl group,

o.-(CH₂CH₂O)_nCHR^eewherein R is^eeIs H or CH₂OH and n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10,

p.-(CH₂)_m-aryl, wherein m is 1 or 2 and said aryl is optionally substituted by halogen or C_1-6-an alkoxy group substitution,

q.-(CH₂)_p-C_3-6-cycloalkyl, wherein p is 0 or 1,

r.5 or a 6-membered heterocycloalkyl group,

xx.-(SO₂)-NR^ffR^ggwherein R is^ffAnd R^ggTogether with the nitrogen atom to which they are attached form a 4, 5 or 6 membered heterocycloalkyl ring, optionally containing another heteroatom selected from nitrogen, oxygen, sulfur or SO₂Wherein the 4, 5 or 6 membered heterocycloalkyl ring is optionally substituted with a substituent selected from the group consisting of: hydroxy, C_1-6-alkyl, C optionally substituted by hydroxy_1-6-alkoxy and 5-or 6-membered heteroaryloxy,

xxi.NHSO₂-C_1-6-alkyl, and

xxii.NHSO₂-NR^hhRⁱⁱwherein R is^hhAnd RⁱⁱIndependently is H, C_1-6Alkyl, - (CO) O-C_1-6-alkyl, or R^hhAnd R^llTogether with the nitrogen atom to which they are attached form a 4, 5 or 6 membered heterocycloalkyl ring, optionally containing another heteroatom selected from nitrogen, oxygen or sulfur, wherein said 4, 5 or 6 membered heterocycloalkyl ring is optionally substituted with C_1-6-alkyl substitution;

R¹is H, halogen, CF₃、CHF₂Or C_1-6-an alkyl group;

R²is H, halogen, C_1-6Alkyl radical, C_1-6-alkoxy, CF₃Or CHF₂；

R³Is H, -C (CH)₃)₂OH; straight chain C_1-4-alkyl or C_3-4-cycloalkyl optionally substituted with one or more substituents selected from the group consisting of 1 to 6F and 1 to 2 OH;

R⁴is H, halogen, C optionally substituted by hydroxy_1-6Alkyl radical, C_1-6-alkoxy, C_1-6-haloalkyl group, C_3-6-a cycloalkyl group;

R⁵is H, cyano, halogen, C_1-6-haloalkyl group, C_1-6-alkoxy, C_1-6-haloalkoxy, C_1-6-alkyl or C_3-6-a cycloalkyl group;

R⁶is halogen, H, C_1-6-alkoxy, C_1-6-haloalkyl group, C_1-6Alkyl radical, C_3-6-cycloalkyl, C_1-6-haloalkoxy, or is NR^jjR^kkWherein R is^jjAnd R^kkIndependently selected from the group consisting of: H. c_3-8-cycloalkyl, aryl, heteroaryl with 5 to 12 ring atoms and C optionally substituted by one or more substituents selected from the group consisting of_1-6-an alkyl group: halogen, hydroxy, C_3-8-cycloalkyl, aryl, heteroaryl with 5 to 12 ring atoms and-NR^llR^mmWherein R is^llAnd R^mmIndependently selected from the group consisting of H and C_1-6-alkyl groups;

or R^jjAnd R^kkCapable of forming, together with the nitrogen atom to which they are attached, an optionally substituted heterocyclic group comprising 5 to 12 ring atoms, optionally containing another heteroatom selected from nitrogen, oxygen or sulfur, wherein the heteroaryl group is optionally substituted with one, two, three, four or five substituents selected from the group consisting of: halogen, hydroxy, C_1-6-alkyl and C_1-6-a haloalkyl group;

or R⁵And R⁶Can form together a dioxo bridge;

R⁷is H or halogen;

R^ais halogen; a hydroxyl group; a cyano group; CF (compact flash)₃；NR^eR^f(ii) a C optionally substituted by amino or by hydroxy_1-6-an alkyl group; c_1-6-an alkoxy group; c_3-4-a cycloalkyl group; CO-NR^bR^c，SO₂-NR^bR^c(ii) a Or SO₂-R^d；

R^bAnd R^cMay be the same or different and is selected from the group consisting of:

vii.H；

a straight or branched chain C optionally substituted with one or more substituents selected from the group consisting of_1-6-an alkyl group:

ix.F, cyano, hydroxy, C_1-6-alkoxy, -NH-C (O) -O-C_1-6Alkyl, amino, (C)_1-6-alkyl) amino, di (C)_1-6-alkyl) amino, C_3-6-cycloalkyl, heterocycloalkyl having 5 or 6 ring atoms, aryl or 5 or 6 membered heteroaryl;

x.C_3-6-a cycloalkyl group;

xi, aryl; or

xii, heteroaryl;

or R^bAnd R^cMay be taken together with the nitrogen atom to which they are attached to form a radical which may be substituted by hydroxyl or by C_1-6-an alkyl-substituted heterocycle of 4 to 6 ring members;

R^dis OH or C_1-6-an alkyl group;

R^eand R^fIs H, C optionally substituted by hydroxy_1-6Alkyl, -C (O) -C_1-6-an alkyl group; s (O)₂-C_1-6-an alkyl group;

and pharmaceutically acceptable salts thereof.

3. The mGlu2/3 negative allosteric modulator according to any one of claims 1-2 selected from the group consisting of compounds of formula (I) and formula (II),

wherein

E and J are N, G is C, L is N and M is CH;

a is selected from the group consisting of: phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, pyridazin-2-yl, pyridazin-3-yl, thiazol-2-yl, thiazol-5-yl, and thiophen-2-yl;

b is selected from the group consisting of: imidazolyl group, [1, 2, 4 ]]Oxadiazolyl, pyrrolyl, 1H-pyrazolyl, pyridinyl, [1, 2, 4 ]]Triazolyl, thiazolyl, pyrimidinyl and thienyl, each of which is optionally substituted by C_1-6-alkyl substitution;

c is optionally substituted aryl, wherein the substituents are selected from the group consisting of:

ix, a halogen,

x, a nitro group,

xi. C optionally substituted by hydroxy_1-6-an alkyl group,

xii.NR^aaR^bbwherein R is^aaAnd R^bbIndependently is H, C_1-6-alkyl or- (CO) -C_1-6-an alkyl group,

xiii.-S-C_1-6-an alkyl group,

xiv.-(SO₂)-OH，

xv.-(SO₂)-C_1-6-an alkyl group,

xvi.-(SO₂)-NR^ccR^ddwherein R is^ccAnd R^ddIndependently are:

f.H，

g. c optionally substituted by hydroxy_1-6-an alkyl group,

h.C_1-6-a halogenated alkyl group,

i.C_1-6-an alkoxy group,

j. optionally is covered with C_1-6-alkoxy substituted- (CO) C_1-6-an alkyl group,

R¹is CF₃；

R²Is H;

R³is a straight chain C substituted by one or more substituents selected from the group consisting of 1 to 6F and 1 to 2 OH_1-4-an alkyl group;

R⁴is C_1-6-an alkyl group;

R⁵is C_1-6-a haloalkyl group;

R⁶is H;

R⁷is H;

and pharmaceutically acceptable salts thereof.

4. The mGlu2/3 negative allosteric modulator according to any one of claims 1-3 selected from the group consisting of compounds of formula (I) and formula (II) wherein

E and J are N, G is C, L is N and M is CH;

a is pyridin-2-yl;

b is a pyridyl group, and B is a pyridyl group,

c is SO-substituted₂NH₂Substituted phenyl;

R¹is CF₃；

R²Is H;

R³is CF₃；

R⁴Is CH₃；

R⁵Is CF₃；

R⁶Is H;

R⁷is H;

and pharmaceutically acceptable salts thereof.

5. The mGlu2/3 negative allosteric modulator according to any one of claims 1-4, which is a compound of formula (Ia):

6. the mGlu2/3 negative allosteric modulator according to any one of claims 1-5, being a compound of formula (IIa) or (IIb):

7. a method for the treatment, prevention and/or delay of progression of intellectual disability in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a mGlu2/3 negative allosteric modulator of any one of claims 1-9.

8. A pharmaceutical composition comprising mGlu2/3 negative allosteric modulator according to any one of claims 2-7 in a pharmaceutically acceptable form for the treatment, prevention and/or delay of progression of intellectual disabilities.

9. A pharmaceutical composition comprising mGlu2/3 negative allosteric modulator according to any one of claims 2-7 in a pharmaceutically acceptable form for the treatment, prevention and/or delay of progression of intellectual disabilities.

10. A mGlu2/3 negative allosteric modulator according to any one of claims 2-7 for use in the treatment, prevention and/or delay of progression of intellectual disabilities.

11. A mGlu2/3 negative allosteric modulator according to any one of claims 2-7 for the preparation of medicaments for the treatment, prevention and/or delay of progression of intellectual disabilities.

12. Use of mGlu2/3 negative allosteric modulators according to any one of claims 2-7 for the preparation of medicaments for the treatment, prevention and/or delay of progression of intellectual disabilities.

13. The invention as described above.