HK1169656B

HK1169656B - Substituted n-phenyl-1-(4-pyridinyl)-1h-pyrazol-3-amines

Info

Publication number: HK1169656B
Application number: HK12110507.1A
Authority: HK
Inventors: Gregor James Macdonald; Johannes Wilhelmus John F. Thuring; Frans Alfons Maria Van Den Keybus; Yves Emiel Maria Van Roosbroeck
Original assignee: Janssen Pharmaceutica Nv
Priority date: 2009-09-17
Filing date: 2010-09-16
Publication date: 2015-07-24

Description

Substituted N-phenyl-1- (4-pyridyl) -1H-pyrazol-3-amines

The present invention relates to N-phenyl-1- (4-pyridyl) -1H-pyrazol-3-amine derivatives and pharmaceutically acceptable salts thereof, processes for preparing them, pharmaceutical compositions containing them and their use in therapy. The present invention relates particularly to positive allosteric modulators of nicotinic acetylcholine receptors (nicotinic acetylcholine receptors), such positive allosteric modulators having the capability to increase the efficacy of nicotinic receptor agonists.

Background of the prior art

WO-2007/118903 discloses 1-alkyl-3-aniline-5-aryl-1, 2, 4-triazoles as positive allosteric modulators of nicotinic acetylcholine receptors, which are useful for the treatment of neurological, degenerative and psychiatric diseases.

WO-2005/051917 discloses pyrazolyl derivatives in the form of medicaments for the treatment of acute or chronic neuronal degeneration (neuronal regressions).

WO-2009/135944 discloses 1-alkyl-3-aniline-5-aryl-pyrazole derivatives as positive allosteric modulators of nicotinic acetylcholine receptors.

EP-0,248,523 discloses N- [ 4-methoxyphenyl) -1-methyl-5-phenyl-1H-pyrazol-3-amine as a broad spectrum anti-inflammatory agent.

Background

Cholinergic receptors typically bind the endogenous neurotransmitter acetylcholine (ACh), triggering the opening of ion channels. On the basis of the agonist activity of muscarine and nicotine, ACh receptors in the mammalian central nervous system can be divided into the muscarine (mAChR) and nicotinic (nAChR) subtypes, respectively. Nicotinic acetylcholine receptors are ligand-gate gated ion channels containing 5 subunits. Members of the nAChR subunit gene family are divided into two groups based on amino acid sequence; one group contains the so-called beta subunit and the second group contains the alpha subunit. When expressed alone, three of the alpha subunits, α 7, α 8 and α 9, have been shown to form functional receptors, thus inferring the formation of homo-pentameric receptors (homooligomeric pentameric receptors).

An allosteric metamorphosis model of nachrs has been developed that involves at least a resting state, an activated state, and a "desensitized" closed channel state, a process by which receptors become insensitive to agonists. Different nAChR ligands can stabilize the conformational state of the receptor to which they preferentially bind. For example, the agonists ACh and (-) -nicotine stabilize the active and desensitized states, respectively.

Alterations in nicotine receptor activity are implicated in a variety of diseases. Some of these diseases, such as myasthenia gravis and autosomal dominant nocturnal anterior lobe epilepsy (ADNFLE), are associated with a reduction in the activity of nicotine delivery due to desensitization of the reduction or increase in receptor number.

It is also hypothesized that a decrease in nicotinic receptors mediates the cognitive deficits seen in diseases such as alzheimer's disease and schizophrenia.

The nicotinic action in tobacco is also mediated by nicotinic receptors, and since the action of nicotine is to stabilize the desensitized state of the receptors, increased nicotinic receptor activity can reduce the desire to smoke.

Compounds that bind nachrs have been proposed to be useful in the treatment of a variety of disorders involving reduced cholinergic function such as learning memory deficits, cognitive deficits, attention deficit, and memory loss. Modulation of the activity of the α 7 nicotinic receptor is expected to be beneficial in the treatment of a variety of diseases including alzheimer's disease, Dementia with Lewy bodies (Dementia), attention deficit hyperactivity disorder, anxiety, schizophrenia, mania, bipolar disorders, parkinson's disease, huntington's chorea, Tourette's syndrome, brain trauma and other neurological, degenerative and psychiatric disorders in which cholinergic synapses are lost, including jetlag, nicotine addiction and pain.

However, treatment with nicotinic receptor agonists that act at the same site is problematic because ACh not only activates but also blocks receptor activity through processes including desensitization and noncompetitive blockade. In addition, prolonged activation appears to also induce long-lasting inactivation. Thus, ACh agonists are expected to reduce activity and enhance inactivation.

In general, it is noted at nicotinic receptors, especially at α 7-nicotinic receptors, that desensitization limits the duration of the agonist action administered.

Description of the invention

The present inventors have found that certain novel pyrazole derivatives can increase the efficacy of agonists at nicotinic acetylcholine receptors (nachrs). Compounds having this type of effect (hereinafter referred to as "positive allosteric modulators") may be useful for the treatment of disorders associated with reduced nicotine delivery. In a therapeutic setting, such compounds can restore normal inter-neuronal communication without affecting the immediate profile of activation. In addition, positive allosteric modulators are also expected not to produce long-term inactivation of the receptor as may occur with long-term administration of agonists.

The positive nAChR modulators of the present invention are useful for the treatment and prevention of psychiatric disorders, intellectual impairment disorders and diseases, inflammatory diseases and conditions in which modulation of the α 7 nicotinic receptor is beneficial.

The present invention relates to N-phenyl-1- (4-pyridyl) -1H-pyrazol-3-amine derivatives having positive allosteric modulator properties, in particular increasing agonist potency at the α 7 nicotinic receptor. In view of the aforementioned pharmacological properties of the derivatives of the invention, it is concluded that they are suitable for use as medicaments. The invention also relates to a preparation method thereof and a pharmaceutical composition containing the same. The invention also relates to the use of these derivatives for the preparation of medicaments for the treatment and prophylaxis of psychotic disorders, intellectual impairment disorders and diseases, inflammatory diseases and conditions in which modulation of the α 7 nicotinic receptor is beneficial. The invention also relates to these derivatives for use in the treatment and prevention of psychotic disorders, intellectual impairment disorders and diseases, inflammatory diseases and conditions in which modulation of the α 7 nicotinic receptor is beneficial.

There is an urgent need for new positive allosteric modulators with the ability to increase the efficacy of nicotinic receptor agonists, thereby opening new avenues for the treatment of psychotic disorders, intellectual impairment disorders or inflammatory diseases. It is an object of the present invention to overcome or reduce at least one of the disadvantages of the prior art, or to provide an effective alternative. It is therefore an object of the present invention to provide such novel compounds.

The compounds of the present invention differ structurally from the compounds of the prior art.

The invention relates to novel compounds of formula (I)

And stereoisomeric forms thereof, wherein

R¹And R²Each independently represents hydrogen or C_1-4An alkyl group;

R³is C optionally substituted by one or more substituents_1-6Alkyl, the substituents are independently selected from hydroxyl, cyano, C_1-6Alkoxy, benzyloxy, R^xR^yN-C (═ O) -and R^zO-C(＝O)-；

R^xAnd R^yEach independently represents hydrogen, C_1-4Alkyl, ring C_3-6Alkyl or (ring C)_3-6Alkyl) C_1-4An alkyl group;

R^zrepresents hydrogen or C_1-3An alkyl group;

R⁴、R⁵and R⁶Each independently represents hydrogen, halo, C_1-6Alkyl, cyano, trifluoromethyl, trifluoromethoxy, or methoxy; or

R⁴And R⁵When bound to 2 adjacent carbon atoms, together form the formula- -O- -CF₂-O — a divalent group;

pharmaceutically acceptable addition salts thereof, and hydrates and solvates thereof.

It will be appreciated that certain compounds of formula (I) and addition salts, hydrates and solvates thereof may contain one or more chiral centers and exist as stereoisomeric forms.

The invention will now be further illustrated. In the following paragraphs, the various aspects of the invention are defined in detail. Aspects so defined may be combined with any other single aspect or aspects unless clearly indicated to the contrary. In particular, any feature described as being preferred or advantageous may be combined with any other feature or features described as being preferred or advantageous.

Detailed Description

When describing the compounds of the present invention, the terms used are to be construed in accordance with the following definitions, unless the context indicates otherwise.

Whenever the term "substituted" is used in the present invention, it is meant that one or more hydrogens on the designated atom in the expression using "substituted" is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a chemically stable compound, i.e., a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture and formulation into a therapeutic agent.

The term "halo" as a group or part of a group is a generic term for fluoro, chloro, bromo, iodo, unless otherwise indicated or explicitly stated herein.

The term "C" as a group or part of a group_1-6Alkyl "means a group of the formula C_nH_2n+1Wherein n is a number in the range of 1 to 6. C_1-6The alkyl group contains 1 to 6 carbon atoms, especially 1 to 4 carbon atoms, more especially 1 to 3 carbon atoms, even more especially 1 to 2 carbon atoms. Alkyl groups may be straight or branched chain and may be substituted as described herein. Herein, when a subscript is used after a carbon atom, the subscript refers to the number of carbon atoms that the named group may contain. Thus, for example, C_1-6Alkyl includes all straight or branched chain alkyl groups containing 1 to 6 carbon atoms and thus includes, for example, methyl, ethyl, n-propyl, isopropyl, 2-methyl-ethyl, butyl and its isomers (e.g., n-butyl, isobutyl and tert-butyl), pentyl and its isomers, hexyl and its isomers, and the like.

The term "C" as a group or part of a group_1-4Alkyl "means a group of the formula C_nH_2n+1A hydrocarbyl group, wherein n is a number in the range of 1 to 4. C_1-4The alkyl group contains 1 to 4 carbon atoms, especially 1 to 3 carbon atoms, more especially 1 to 2 carbon atoms. C_1-4Alkyl includes all straight or branched chain alkyl groups containing 1 to 4 carbon atoms and thus includes, for example, methyl, ethyl, n-propyl, 2-methyl-ethyl, butyl and isomers thereof (e.g., n-butyl, isobutyl and tert-butyl), and the like.

The term "C" as a group or part of a group_1-3Alkyl "means a group of the formula C_nH_2n+1A hydrocarbyl group, wherein n is a number in the range of 1 to 3. C_1-3The alkyl group contains 1 to 3 carbon atoms, preferably 1 to 2 carbon atoms. C_1-3Alkyl includes all straight or branched chain alkyl groups containing 1 to 3 carbon atoms and thus includes, for example, methyl, ethyl, n-propyl, isopropyl, 2-methyl-ethyl, isomers thereof and the like.

The term "C" as a group or part of a group_1-6Alkoxy "means having the formula OR^aWherein R is^aIs C_1-6An alkyl group. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, and hexyloxy.

The term "Ring C" alone or in combination_3-6Alkyl "refers to cyclic saturated hydrocarbon groups having 3 to 6 carbon atoms. Suitable ring C_3-6Non-limiting examples of alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

The Chemical names of the compounds of the invention were generated according to the nomenclature rules approved by Chemical Abstracts Service (ACD/Name product version 10.01; Build 15494, 1.12.2006) using the naming software of Advanced Chemical Development, inc.

Certain compounds of formula (I) may also exist in their tautomeric form. Although not explicitly illustrated in the above formula, such forms are intended to be included within the scope of the present invention.

When any variable occurs more than one time in any constituent, each definition is independent.

It will be appreciated that certain compounds of formula (I) and their pharmaceutically acceptable addition salts and stereoisomeric forms may contain one or more chiral centres and exist as stereoisomeric forms.

The term "stereoisomeric forms" as used hereinbefore or hereinafter defines all the possible stereoisomeric forms which the compounds of formula (I) and their addition salts may possess. Unless otherwise stated or indicated, the chemical designation of compounds denotes all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure as well as the individual isomeric forms of formula (I) and their salts, solvates, which are substantially free, i.e. associated with less than 10%, preferably less than 5%, especially less than 2%, most preferably less than 1% of the other isomers.

For therapeutic use, salts of the compounds of formula (I) are those wherein the counterion is pharmaceutically acceptable. However, salts of acids and bases that are not pharmaceutically acceptable may also find use, for example, in the preparation or purification of pharmaceutically acceptable compounds. All salts are included within the scope of the present invention, whether or not pharmaceutically acceptable.

The pharmaceutically acceptable acid and base addition salts described hereinabove or hereinafter are intended to include the therapeutically active non-toxic acid and base addition salt forms which the compounds of formula (I) may form. Pharmaceutically acceptable acid addition salts are conveniently obtained by treating the base form with such an appropriate acid. Suitable acids include, for example, inorganic acids such as hydrohalic acids, e.g., hydrochloric or hydrobromic acids, sulfuric acid, nitric acid, phosphoric acid, and the like; or organic acids such as acetic, propionic, glycolic, lactic, pyruvic, oxalic (i.e., oxalic), malonic, succinic (i.e., succinic), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids. Conversely, the salt form can be converted to the free base form by treatment with an appropriate base.

The compounds of formula (I) containing acidic protons may also be converted into their non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases. Suitable basic salt (base salt) forms include, for example, ammonium salts, alkali and alkaline earth metal salts such as lithium, sodium, potassium, magnesium, calcium salts, and the like; salts formed from organic bases such as primary, secondary and tertiary aliphatic and aromatic amines, e.g., methylamine, ethylamine, propylamine, isopropylamine, 4 butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline; benzathine, N-methyl-D-glucamine, hydrabamine salt; and salts with amino acids such as arginine, lysine, and the like. Conversely, the salt form can be converted to the free acid form by treatment with an acid.

The term solvate includes solvent addition forms (solvent addition forms) which the compounds of formula (I) and salts thereof may form. Examples of such forms are e.g. alcoholates and the like.

The compounds of formula (I) may be synthesized as racemic mixtures of enantiomers prepared by the following methods, which may be separated from each other by resolution methods known in the art. A method of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography using a chiral stationary phase. The pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs while preserving stereochemical integrity. Preferably, if a particular stereoisomer is desired, said compound is synthesized by stereospecific methods of preparation. These methods would be advantageous to use enantiomerically pure starting materials.

Within the framework of the present application, the compounds of the invention are inherently intended to include all isotopic combinations of their chemical elements. In the framework of the present application, a chemical element, in particular when referring to a compound of formula (I), includes all isotopes and isotopic mixtures of this element. For example, when hydrogen is mentioned, it is understood to mean¹H、²H、³H and mixtures thereof.

Thus, the compounds of the present invention inherently include compounds containing one or more isotopes of one or more elements and mixtures thereof, including radiolabeled compounds in which one or more non-radioactive atoms are replaced by one of its radioactive isotopes. The term "radiolabeled compound" denotes any compound of formula (I) containing at least 1 radioactive atom or a pharmaceutically acceptable salt thereof. For example, the compounds may be labeled with positron or gamma emitting radioisotopes. In the case of the radioligand-binding technique,³h atom or¹²⁵The I atom is a substituted selected atom. For imaging, the most commonly used Positron Emission (PET) radioisotopes are¹¹C、¹⁸F、¹⁵O and¹³n, both of which are produced by accelerators, half-life20, 100, 2 and 10 minutes (min), respectively. Because the half-lives of these radioisotopes are too short, their use is only feasible on site at the facilities with accelerators used to prepare them, thus limiting their utility. Among the most widely used isotopes are¹⁸F、^99mTc、²⁰¹Tl and¹²³I. the skilled person is aware of the handling of these radioisotopes, their preparation, isolation and incorporation into molecules.

In particular, the radioactive atoms are selected from hydrogen, carbon, nitrogen, sulfur, oxygen and halogens. In particular, the radioisotope is selected from³H、¹¹C、¹⁸F、¹²²I、¹²³I、¹²⁵I、¹³¹I、⁷⁵Br、⁷⁶Br、⁷⁷Br and⁸²Br。

as used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the content clearly dictates otherwise. For example, "a compound" means 1 compound or more than 1 compound.

The above terms and other terms used in the present specification are fully understood by those skilled in the art.

The features of the preferred compounds of the invention will now be described.

The present invention relates to novel compounds of formula (I):

and stereoisomeric forms thereof, wherein

R¹And R²Each independently represents hydrogen or C_1-4An alkyl group;

R³is C optionally substituted by one or more substituents_1-6Alkyl, said substituents being independentIs selected from hydroxy, cyano, C_1-6Alkoxy, benzyloxy, R^xR^yN-C (═ O) -and R^zO-C(＝O)-；

R^zrepresents hydrogen or C_1-3An alkyl group;

R⁴And R⁵When bound to 2 adjacent carbon atoms, together form the formula- -O- -CF₂-an O-divalent group;

and pharmaceutically acceptable addition salts, and hydrates and solvates thereof.

In one embodiment, the present invention relates to those compounds of formula (I) and stereoisomeric forms thereof, wherein

R¹And R²Each independently represents hydrogen or C_1-4An alkyl group;

R^zrepresents hydrogen or C_1-3An alkyl group;

R⁴、R⁵and R⁶Each independently represents halogeno, C_1-6Alkyl, cyano, trifluoromethylTrifluoromethoxy or methoxy; or

R⁴And R⁵When bound to 2 adjacent carbon atoms, together form the formula- -O- -CF₂-an O-divalent group; or

One embodiment of the present invention relates to those compounds of formula (I) and stereoisomeric forms thereof, wherein one or more, preferably all, of the following limitations apply:

(i)R¹and R²Each independently represents hydrogen or methyl;

(ii)R³is C optionally substituted by one or more substituents_1-4Alkyl, said substituents being independently selected from hydroxy, cyano, methoxy, benzyloxy, R^xR^yN-C (═ O) -and R^zO-C(＝O)-；

(iii)R^xAnd R^yEach independently represents hydrogen, C_1-4Alkyl, ring C_3-6Alkyl or (ring C)_3-6Alkyl) C_1-4An alkyl group;

(iv)R^zrepresents hydrogen or C_1-3An alkyl group;

(v)R⁴、R⁵and R⁶Each independently represents hydrogen, halo, cyano, trifluoromethyl, trifluoromethoxy or methoxy; especially halo, cyano, trifluoromethyl, trifluoromethoxy or methoxy; or

and pharmaceutically acceptable addition salts, hydrates and solvates thereof.

One embodiment of the present invention relates to those compounds of formula (I) and the stereoisomeric forms thereof, wherein

(i)R¹And R²Each independently represents hydrogen or methyl;

(ii)R³is C optionally substituted by one or more substituents_1-4Alkyl, said substituents being independently selected from hydroxy, cyano, methoxy, benzyloxy and R^xR^yN-C(＝O)-；

(iv)R⁴、R⁵and R⁶Each independently represents hydrogen, halo, cyano, trifluoromethyl, trifluoromethoxy or methoxy; especially halo, cyano, trifluoromethyl, trifluoromethoxy or methoxy; or

and pharmaceutically acceptable addition salts, hydrates and solvates thereof.

Another embodiment of the present invention relates to those compounds of formula (I), or any subgroup thereof as described in any other embodiment, wherein one or more, preferably all, of the following limitations apply:

(i)R¹and R²Each independently represents hydrogen or methyl;

(iii)R^xRepresents hydrogen, methyl, ethyl, cyclopropylmethyl, cyclopropyl, cyclobutyl or 1-methylethyl;

(iv)R^yrepresents hydrogen or methyl;

(v)R^zrepresents hydrogen or methyl;

(vi)R⁴、R⁵and R⁶Each independently represents hydrogen, halo, cyano, trifluoromethyl, trifluoromethoxy or methoxy; especially halo, cyano, trifluoromethyl, trifluoromethoxy or methoxy; or

and pharmaceutically acceptable addition salts, hydrates and solvates thereof.

(i)R¹and R²Each independently represents hydrogen or methyl;

(ii)R³is methyl; a hydroxymethyl group; hydroxypropyl groups; (2R) -2-hydroxybutyl; (2S) -2-hydroxybutyl; a methoxymethyl group; a cyanomethyl group; a carboxymethyl group; a carboxyethyl group; 2-methoxy-2-oxoethyl; 3-methoxy-3-oxopropyl; 2-methylamino-2-oxoethyl; 2-ethylamino-2-oxoethyl; 2- [ (cyclopropylmethyl) amino group]-2-oxoethyl; 2- (cyclopropylamino) -2-oxoethyl; 2- (cyclobutylamino) -2-oxoethyl; 3- (dimethylamino) -3-oxopropyl; a benzyloxymethyl group; benzyloxypropyl or 2- [ (1-methylethyl) amino group]-2-oxoethyl;

(iii)R⁴、R⁵and R⁶Each independently represents hydrogen, chloro, fluoro, bromo, cyano, trifluoromethyl, trifluoromethoxy or methoxy; especially chloro, fluoro, bromo, cyano, trifluoromethyl, trifluoromethoxy or methoxy; or

R⁴And R⁵When bound to 2 adjacent carbon atoms, together formFormula- -O- -CF₂-an O-divalent group;

and pharmaceutically acceptable addition salts, hydrates and solvates thereof.

Another embodiment of the present invention relates to those compounds of formula (I), or any subtype thereof as set forth in any other embodiment, wherein the following restrictions apply:

R³is methyl; a hydroxymethyl group; hydroxypropyl groups; (2R) -2-hydroxybutyl; (2S) -2-hydroxybutyl; (2R) -2-hydroxypropyl; (2S) -2-hydroxypropyl; a methoxymethyl group; a cyanomethyl group; a carboxymethyl group; a carboxyethyl group; 2-methoxy-2-oxoethyl; 3-methoxy-3-oxopropyl; 2-methylamino-2-oxoethyl; 2-ethylamino-2-oxoethyl; 2- [ (cyclopropylmethyl) amino group]-2-oxoethyl; 2- (cyclopropylamino) -2-oxoethyl; 2- (cyclobutylamino) -2-oxoethyl; 3- (dimethylamino) -3-oxopropyl; a benzyloxymethyl group; benzyloxypropyl or 2- [ (1-methylethyl) amino group]-2-oxoethyl;

and pharmaceutically acceptable addition salts, hydrates and solvates thereof.

One embodiment of the present invention relates to those compounds of formula (I), or any subtype thereof as described in any other embodiment, wherein one or more of the following limitations apply:

(i)R³is C optionally substituted by one or more substituents_1-6Alkyl, said substituents being independently selected from hydroxy, cyano, methoxy, benzyloxy and R^xR^yN-C(＝O)-；

(ii)R⁴、R⁵And R⁶Each independently represents hydrogen, halo, C_1-6Alkyl, cyano, trifluoromethyl, trifluoromethoxy, or methoxy; especially halo, C_1-6Alkyl, cyano, trifluoromethyl, trifluoromethoxy, or methoxy.

(i)R³is C optionally substituted by one or more substituents_1-4Alkyl, said substituents being independently selected from hydroxy, cyano, methoxy, benzyloxy and R^xR^yN-C(＝O)-；

(ii)R⁴、R⁵And R⁶Each independently represents hydrogen, halo, cyano, trifluoromethyl, trifluoromethoxy or methoxy; especially halo, cyano, trifluoromethyl, trifluoromethoxy or methoxy.

One embodiment of the present invention relates to those compounds of formula (I), or any subtype thereof as set forth in any other embodiment, wherein the following restrictions apply: r⁶Represents hydrogen, halo, cyano, trifluoromethyl, C_1-6Alkyl, trifluoromethoxy or methoxy; especially halo, cyano, trifluoromethyl, C_1-6Alkyl, trifluoromethoxy or methoxy; and R⁴And R⁵Are bound to 2 adjacent carbon atoms and together form the formula- -O- -CF₂-O-a divalent group.

One embodiment of the present invention relates to those compounds of formula (I), or any subtype thereof as set forth in any other embodiment, wherein the following restrictions apply: r⁶Represents hydrogen, halo, cyano, trifluoromethyl, trifluoromethoxy or methoxy; especially halo, cyano, trifluoromethyl, trifluoromethoxy or methoxy; and R⁴And R⁵Are linked to 2 adjacent carbon atoms and together form the formula- -O- -CF₂-O-a divalent group.

(i)R³is C_1-6Alkyl, especially C optionally substituted by one or more substituents_1-4Alkyl, said substituents being independently selected from hydroxy and R^xR^yN-C(＝O)-；

(ii)R^xAnd R^yEach independently represents hydrogen, C_1-4Alkyl, ring C_3-6Alkyl or (ring C)_3-6Alkyl) C_1-4An alkyl group;

(iii)R⁴、R⁵and R⁶Each independently represents hydrogen, halo, trifluoromethyl, trifluoromethoxy or methoxy; especially halo, trifluoromethyl, trifluoromethoxy or methoxy; or

R⁴And R⁵When bound to 2 adjacent carbon atoms, together form the formula- -O- -CF₂-O- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -;

and pharmaceutically acceptable addition salts, hydrates and solvates thereof.

One embodiment of the present invention relates to those compounds of formula (I), or any of its subtypes described in any other embodiment, wherein R⁴、R⁵Or R⁶At least one of which is not hydrogen.

One embodiment of the present invention relates to those compounds of formula (I), or any of its subtypes described in any other embodiment, wherein R⁴、R⁵And R⁶Each independently represents hydrogen, halo, C_1-6Alkyl, cyano, trifluoromethyl, trifluoromethoxy, or methoxy; especially halo, C_1-6Alkyl, cyano, trifluoromethyl, trifluoromethoxy, or methoxy.

One embodiment of the present invention relates to those compounds of formula (I), or any of its subtypes described in any other embodiment, wherein

R⁴And R⁵Are bound to 2 adjacent carbon atoms and together form the formula- -O- -CF₂-O — a divalent group; and R⁶Is hydrogen.

In one embodiment, the compound of formula (I) is selected from:

n- (3, 4-difluorophenyl) -5-methyl-1- (2-methyl-4-pyridyl) -1H-pyrazol-3-amine,

n- (3, 4-difluorophenyl) -1- (2-methyl-4-pyridyl) -5- [ (phenylmethoxy) methyl ] -1H-pyrazol-3-amine,

3- [ (3, 4-difluorophenyl) amino ] -1- (2-methyl-4-pyridyl) -1H-pyrazole-5-methanol,

(alpha R) -3- [ (3, 4-difluorophenyl) amino ] -alpha-ethyl-1- (2-methyl-4-pyridyl) -1H-pyrazol-5-ethanol,

(alpha R) -alpha-ethyl-1- (2-methyl-4-pyridinyl) -3- [ [3- (trifluoromethyl) phenyl ] amino ] -1H-pyrazole-5-ethanol,

n- (3, 4-difluorophenyl) -5- (methoxymethyl) -1- (2-methyl-4-pyridinyl) -1H-pyrazol-3-amine,

7.3- [ (3, 4-difluorophenyl) amino ] -1- (2-methyl-4-pyridyl) -1H-pyrazole-5-acetonitrile,

(α S) - α -ethyl-1- (2-methyl-4-pyridinyl) -3- [ [3- (trifluoromethyl) phenyl ] amino ] -1H-pyrazole-5-ethanol,

9.3- [ (3, 4-difluorophenyl) amino ] -1- (2-methyl-4-pyridyl) -1H-pyrazole-5-acetic acid methyl ester HCl

3- [ (3, 4-difluorophenyl) amino ] -N-methyl-1- (2-methyl-4-pyridyl) -1H-pyrazole-5-acetamide,

11.3- [ (3, 4-difluorophenyl) amino ] -1- (2-methyl-4-pyridyl) -1H-pyrazole-5-acetic acid,

[ alpha ] S) -3- [ (3, 4-difluorophenyl) amino ] -alpha-ethyl-1- (2-methyl-4-pyridyl) -1H-pyrazol-5-ethanol,

3- [ (3, 4-difluorophenyl) amino ] -N-ethyl-1- (2-methyl-4-pyridyl) -1H-pyrazole-5-acetamide,

n- (cyclopropylmethyl) -3- [ (3, 4-difluorophenyl) amino ] -1- (2-methyl-4-pyridyl) -1H-pyrazole-5-acetamide,

n- (3, 4-difluorophenyl) -1- (2-methyl-4-pyridyl) -5- [3- (phenylmethoxy) propyl ] -1H-pyrazol-3-amine,

[ alpha ] S) -3- [ (2, 2-difluoro-1, 3-benzodioxol-5-yl) amino ] -alpha-ethyl-1- (2-methyl-4-pyridinyl) -1H-pyrazole-5-ethanol,

(α S) - α -ethyl-3- [ [ 3-methoxy-5- (trifluoromethyl) phenyl ] amino ] -1- (2-methyl-4-pyridinyl) -1H-pyrazole-5-ethanol,

[ alpha ] S) -alpha-ethyl-1- (2-methyl-4-pyridyl) -3- [ (2, 3, 4-trifluorophenyl) amino ] -1H-pyrazole-5-ethanol,

(α S) - α -ethyl-1- (2-methyl-4-pyridinyl) -3- [ [3- (trifluoromethoxy) phenyl ] amino ] -1H-pyrazole-5-ethanol,

(α S) - α -ethyl-3- [ [ 4-methoxy-3- (trifluoromethyl) phenyl ] amino ] -1- (2-methyl-4-pyridinyl) -1H-pyrazole-5-ethanol,

(alpha S) -3- [ (3-chlorophenyl) amino ] -alpha-ethyl-1- (2-methyl-4-pyridyl) -1H-pyrazole-5-ethanol,

(alpha S) -3- [ (3-chloro-5-methoxyphenyl) amino ] -alpha-ethyl-1- (2-methyl-4-pyridinyl) -1H-pyrazole-5-ethanol,

23.5-bromo-2- [ [5- [ (2S) -2-hydroxybutyl ] -1- (2-methyl-4-pyridinyl) -1H-pyrazol-3-yl ] amino ] -benzonitrile,

(α S) - α -ethyl-1- (2-methyl-4-pyridyl) -3- [ (2,4, 5-trifluorophenyl) amino ] -1H-pyrazole-5-ethanol,

(alpha S) -3- [ (3-chloro-2-fluorophenyl) amino ] -alpha-ethyl-1- (2-methyl-4-pyridyl) -1H-pyrazole-5-ethanol,

n- (2, 2-difluoro-1, 3-benzodioxol-5-yl) -1- (2-methyl-4-pyridinyl) -5- [3- (phenylmethoxy) propyl ] -1H-pyrazol-3-amine,

3- [ (3, 4-difluorophenyl) amino ] -1- (2-methyl-4-pyridyl) -1H-pyrazole-5-propanol,

28.3- [ (3, 4-difluorophenyl) amino ] -1- (2-methyl-4-pyridyl) -1H-pyrazole-5-propionic acid,

n- (3-chloro-2-fluorophenyl) -1- (2-methyl-4-pyridyl) -5- [ (phenylmethoxy) methyl ] -1H-pyrazol-3-amine,

30.3- [ (3-chloro-2-fluorophenyl) amino ] -1- (2-methyl-4-pyridyl) -1H-pyrazole-5-methanol,

31.3- [ (3-chloro-2-fluorophenyl) amino ] -1- (2-methyl-4-pyridyl) -1H-pyrazole-5-acetonitrile,

32.3- [ (3, 4-difluorophenyl) amino ] -N, N-dimethyl-1- (2-methyl-4-pyridyl) -1H-pyrazole-5-propionamide,

n, N-dimethyl-1- (2-methyl-4-pyridinyl) -3- [ [3- (trifluoromethyl) phenyl ] amino ] -1H-pyrazole-5-propanamide,

34.3- [ [ 3-methoxy-5- (trifluoromethyl) phenyl ] amino ] -1- (2-methyl-4-pyridinyl) -1H-pyrazole-5-propanol,

35.3- [ (3-chloro-2-fluorophenyl) amino ] -1- (2-methyl-4-pyridyl) -1H-pyrazole-5-acetic acid methyl ester,

36.1- (2-methyl-4-pyridyl) -5- [3- (phenylmethoxy) propyl ] -N- [3- (trifluoromethyl) phenyl ] -1H-pyrazol-3-amine,

n- [ 3-methoxy-5- (trifluoromethyl) phenyl ] -1- (2-methyl-4-pyridyl) -5- [3- (phenylmethoxy) propyl ] -1H-pyrazol-3-amine,

38.3- [ (3-chloro-2-fluorophenyl) amino ] -N-methyl-1- (2-methyl-4-pyridyl) -1H-pyrazole-5-acetamide,

39.3- [ (3-chloro-2-fluorophenyl) amino ] -N-ethyl-1- (2-methyl-4-pyridyl) -1H-pyrazole-5-acetamide,

40.3- [ (2, 2-difluoro-1, 3-benzodioxol-5-yl) amino ] -1- (2-methyl-4-pyridinyl) -1H-pyrazole-5-propanol,

41.3- [ (3-chloro-2-fluorophenyl) amino ] -N- (cyclopropylmethyl) -1- (2-methyl-4-pyridyl) -1H-pyrazole-5-acetamide,

n- (2, 2-difluoro-1, 3-benzodioxol-5-yl) -1- (2-methyl-4-pyridinyl) -5- [ (phenylmethoxy) methyl ] -1H-pyrazol-3-amine,

43.1- (2-methyl-4-pyridinyl) -3- [ [3- (trifluoromethyl) phenyl ] amino ] -1H-pyrazole-5-acetonitrile,

44.1- (2-methyl-4-pyridyl) -5- [ (phenylmethoxy) methyl ] -N- [3- (trifluoromethyl) phenyl ] -1H-pyrazol-3-amine,

45.1- (2-methyl-4-pyridinyl) -3- [ [3- (trifluoromethyl) phenyl ] amino ] -1H-pyrazole-5-methanol,

46.3- [ [ 3-methoxy-5- (trifluoromethyl) phenyl ] amino ] -N, N-dimethyl-1- (2-methyl-4-pyridinyl) -1H-pyrazole-5-propanamide,

47.3- [ (3-chloro-2-fluorophenyl) amino ] -N, N-dimethyl-1- (2-methyl-4-pyridyl) -1H-pyrazole-5-propionamide,

48.3- [ [ 3-methoxy-5- (trifluoromethyl) phenyl ] amino ] -1- (2-methyl-4-pyridinyl) -1H-pyrazole-5-propionic acid,

49.1- (2-methyl-4-pyridinyl) -3- [ [3- (trifluoromethyl) phenyl ] amino ] -1H-pyrazole-5-acetic acid methyl ester,

n-methyl-1- (2-methyl-4-pyridinyl) -3- [ [3- (trifluoromethyl) phenyl ] amino ] -1H-pyrazole-5-acetamide,

n-ethyl-1- (2-methyl-4-pyridinyl) -3- [ [3- (trifluoromethyl) phenyl ] amino ] -1H-pyrazole-5-acetamide,

n- (cyclopropylmethyl) -1- (2-methyl-4-pyridinyl) -3- [ [3- (trifluoromethyl) phenyl ] amino ] -1H-pyrazole-5-acetamide,

53.N- [ 3-methoxy-5- (trifluoromethyl) phenyl ] -1- (2-methyl-4-pyridyl) -5- [ (phenylmethoxy) methyl ] -1H-pyrazol-3-amine,

54.3- [ (2, 2-difluoro-1, 3-benzodioxol-5-yl) amino ] -N, N-dimethyl-1- (2-methyl-4-pyridinyl) -1H-pyrazole-5-propionamide,

55.3- [ (3-chloro-2-fluorophenyl) amino ] -N-cyclopropyl-1- (2-methyl-4-pyridyl) -1H-pyrazole-5-acetamide,

56.3- [ (3-chloro-2-fluorophenyl) amino ] -N-cyclobutyl-1- (2-methyl-4-pyridyl) -1H-pyrazole-5-acetamide,

57.3- [ (2, 2-difluoro-1, 3-benzodioxol-5-yl) amino ] -1- (2-methyl-4-pyridinyl) -1H-pyrazole-5-propionic acid,

58.3- [ (2, 2-difluoro-1, 3-benzodioxol-5-yl) amino ] -1- (2-methyl-4-pyridinyl) -1H-pyrazole-5-methanol,

59.3- [ (2, 2-difluoro-1, 3-benzodioxol-5-yl) amino ] -1- (2-methyl-4-pyridinyl) -1H-pyrazole-5-acetonitrile,

60.3- [ (2, 2-difluoro-1, 3-benzodioxol-5-yl) amino ] -1- (2-methyl-4-pyridinyl) -1H-pyrazole-5-acetic acid methyl ester,

61.N- (cyclopropylmethyl) -3- [ (2, 2-difluoro-1, 3-benzodioxol-5-yl) amino ] -1- (2-methyl-4-pyridinyl) -1H-pyrazole-5-acetamide,

62.1- (2-methyl-4-pyridinyl) -3- [ [3- (trifluoromethyl) phenyl ] amino ] -1H-pyrazole-5-propanol,

63.1- (2-methyl-4-pyridinyl) -3- [ [3- (trifluoromethyl) phenyl ] amino ] -1H-pyrazole-5-propanoic acid methyl ester,

64.1- (2-methyl-4-pyridinyl) -3- [ [3- (trifluoromethyl) phenyl ] amino ] -1H-pyrazole-5-propanoic acid,

65.3- [ [ 3-methoxy-5- (trifluoromethyl) phenyl ] amino ] -1- (2-methyl-4-pyridinyl) -1H-pyrazole-5-methanol,

66.3- [ [ 3-methoxy-5- (trifluoromethyl) phenyl ] amino ] -1- (2-methyl-4-pyridinyl) -1H-pyrazole-5-acetonitrile,

67.3- [ (2, 2-difluoro-1, 3-benzodioxol-5-yl) amino ] -N-ethyl-1- (2-methyl-4-pyridyl) -1H-pyrazole-5-acetamide,

68.3- [ (3-chloro-5-methoxyphenyl) amino ] -N, N-dimethyl-1- (2-methyl-4-pyridyl) -1H-pyrazole-5-propionamide,

69.3- [ [ 3-methoxy-5- (trifluoromethyl) phenyl ] amino ] -1- (2-methyl-4-pyridinyl) -1H-pyrazole-5-acetic acid methyl ester,

70.3- [ [ 3-methoxy-5- (trifluoromethyl) phenyl ] amino ] -N-methyl-1- (2-methyl-4-pyridinyl) -1H-pyrazole-5-acetamide,

71.N- (3-chloro-2-fluorophenyl) -1- (2-methyl-4-pyridyl) -5- [3- (phenylmethoxy) propyl ] -1H-pyrazol-3-amine,

72.3- [ (3-chloro-2-fluorophenyl) amino ] -1- (2-methyl-4-pyridyl) -1H-pyrazole-5-propanol,

73.3- [ (3-chloro-2-fluorophenyl) amino ] -1- (2-methyl-4-pyridyl) -1H-pyrazole-5-propionic acid,

n- (3-chloro-5-methoxyphenyl) -1- (2-methyl-4-pyridyl) -5- [ (phenylmethoxy) methyl ] -1H-pyrazol-3-amine,

75.3- [ (3-chloro-5-methoxyphenyl) amino ] -1- (2-methyl-4-pyridinyl) -1H-pyrazole-5-methanol,

76.3- [ (3-chloro-5-methoxyphenyl) amino ] -1- (2-methyl-4-pyridinyl) -1H-pyrazole-5-acetonitrile,

77.3- [ (3-chloro-5-methoxyphenyl) amino ] -1- (2-methyl-4-pyridyl) -1H-pyrazole-5-acetic acid methyl ester,

78. N-ethyl-3- [ [ 3-methoxy-5- (trifluoromethyl) phenyl ] amino ] -1- (2-methyl-4-pyridinyl) -1H-pyrazole-5-acetamide,

79.3- [ (3-chloro-5-methoxyphenyl) amino ] -N-methyl-1- (2-methyl-4-pyridinyl) -1H-pyrazole-5-acetamide,

80.3- [ (3-chloro-5-methoxyphenyl) amino ] -N-ethyl-1- (2-methyl-4-pyridinyl) -1H-pyrazole-5-acetamide,

81.3- [ (3-chloro-5-methoxyphenyl) amino ] -N- (cyclopropylmethyl) -1- (2-methyl-4-pyridinyl) -1H-pyrazole-5-acetamide,

82.3- [ (3-chloro-5-methoxyphenyl) amino ] -N-cyclopropyl-1- (2-methyl-4-pyridinyl) -1H-pyrazole-5-acetamide,

83.3- [ (3-chloro-5-methoxyphenyl) amino ] -N-cyclobutyl-1- (2-methyl-4-pyridinyl) -1H-pyrazole-5-acetamide,

n- (cyclopropylmethyl) -3- [ [ 3-methoxy-5- (trifluoromethyl) phenyl ] amino ] -1- (2-methyl-4-pyridinyl) -1H-pyrazole-5-acetamide,

85. N-cyclobutyl-3- [ [ 3-methoxy-5- (trifluoromethyl) phenyl ] amino ] -1- (2-methyl-4-pyridinyl) -1H-pyrazole-5-acetamide,

86.1- (2-methyl-4-pyridyl) -5- [ (phenylmethoxy) methyl ] -N- [3- (trifluoromethoxy) phenyl ] -1H-pyrazol-3-amine,

n-cyclopropyl-3- [ [ 3-methoxy-5- (trifluoromethyl) phenyl ] amino ] -1- (2-methyl-4-pyridinyl) -1H-pyrazole-5-acetamide,

88.N- (3-chloro-5-methoxyphenyl) -1- (2-methyl-4-pyridyl) -5- [3- (phenylmethoxy) propyl ] -1H-pyrazol-3-amine,

89.3- [ (3-chloro-5-methoxyphenyl) amino ] -1- (2-methyl-4-pyridinyl) -1H-pyrazole-5-propanol,

90.3- [ (3-chloro-5-methoxyphenyl) amino ] -1- (2-methyl-4-pyridinyl) -1H-pyrazole-5-propionic acid,

n-cyclopropyl-3- [ (2, 2-difluoro-1, 3-benzodioxol-5-yl) amino ] -1- (2-methyl-4-pyridinyl) -1H-pyrazole-5-acetamide,

92. N-cyclobutyl-3- [ (2, 2-difluoro-1, 3-benzodioxol-5-yl) amino ] -1- (2-methyl-4-pyridyl) -1H-pyrazole-5-acetamide,

93.3- [ (2, 2-difluoro-1, 3-benzodioxol-5-yl) amino ] -N-methyl-1- (2-methyl-4-pyridinyl) -1H-pyrazole-5-acetamide,

94.1- (2-methyl-4-pyridinyl) -3- [ [3- (trifluoromethoxy) phenyl ] amino ] -1H-pyrazole-5-acetonitrile,

95.1- (2-methyl-4-pyridinyl) -3- [ [3- (trifluoromethoxy) phenyl ] amino ] -1H-pyrazole-5-acetic acid methyl ester,

96.1- (2-methyl-4-pyridinyl) -3- [ [3- (trifluoromethoxy) phenyl ] amino ] -1H-pyrazole-5-methanol,

n-methyl-1- (2-methyl-4-pyridinyl) -3- [ [3- (trifluoromethoxy) phenyl ] amino ] -1H-pyrazole-5-acetamide,

98.N- (cyclopropylmethyl) -1- (2-methyl-4-pyridinyl) -3- [ [3- (trifluoromethoxy) phenyl ] amino ] -1H-pyrazole-5-acetamide,

99. N-cyclopropyl-1- (2-methyl-4-pyridinyl) -3- [ [3- (trifluoromethoxy) phenyl ] amino ] -1H-pyrazole-5-acetamide,

n-ethyl-1- (2-methyl-4-pyridinyl) -3- [ [3- (trifluoromethoxy) phenyl ] amino ] -1H-pyrazole-5-acetamide,

n-cyclobutyl-1- (2-methyl-4-pyridinyl) -3- [ [3- (trifluoromethoxy) phenyl ] amino ] -1H-pyrazole-5-acetamide,

n- (3-chloro-2-fluorophenyl) -1- (2, 6-dimethyl-4-pyridyl) -5- [ (phenylmethoxy) methyl ] -1H-pyrazol-3-amine,

103.3- [ (3-chloro-2-fluorophenyl) amino ] -1- (2, 6-dimethyl-4-pyridyl) -1H-pyrazole-5-methanol,

104.3- [ (3-chloro-2-fluorophenyl) amino ] -1- (2, 6-dimethyl-4-pyridyl) -1H-pyrazole-5-acetonitrile,

105.3- [ (3-chloro-2-fluorophenyl) amino ] -1- (2, 6-dimethyl-4-pyridyl) -1H-pyrazole-5-acetic acid methyl ester

106.3- [ (3-chloro-2-fluorophenyl) amino ] -N- (cyclopropylmethyl) -1- (2, 6-dimethyl-4-pyridyl) -1H-pyrazole-5-acetamide,

107.3- [ (3-chloro-2-fluorophenyl) amino ] -1- (2, 6-dimethyl-4-pyridyl) -N-ethyl-1H-pyrazole-5-acetamide,

108.3- [ (3-chloro-2-fluorophenyl) amino ] -N-cyclopropyl-1- (2, 6-dimethyl-4-pyridyl) -1H-pyrazole-5-acetamide,

n- (1-methylethyl) -1- (2-methyl-4-pyridinyl) -3- [ [3- (trifluoromethoxy) phenyl ] amino ] -1H-pyrazole-5-acetamide,

110.1- (2, 6-dimethyl-4-pyridyl) -5- [ (phenylmethoxy) methyl ] -N- [3- (trifluoromethoxy) phenyl ] -1H-pyrazol-3-amine,

111.1- (2, 6-dimethyl-4-pyridinyl) -3- [ [3- (trifluoromethoxy) phenyl ] amino ] -1H-pyrazole-5-acetonitrile,

112.1- (2, 6-dimethyl-4-pyridinyl) -3- [ [3- (trifluoromethoxy) phenyl ] amino ] -1H-pyrazole-5-acetic acid methyl ester,

113.1- (2, 6-dimethyl-4-pyridinyl) -N-methyl-3- [ [3- (trifluoromethoxy) phenyl ] amino ] -1H-pyrazole-5-acetamide,

114.1- (2, 6-dimethyl-4-pyridinyl) -N-ethyl-3- [ [3- (trifluoromethoxy) phenyl ] amino ] -1H-pyrazole-5-acetamide,

n- (cyclopropylmethyl) -1- (2, 6-dimethyl-4-pyridinyl) -3- [ [3- (trifluoromethoxy) phenyl ] amino ] -1H-pyrazole-5-acetamide,

n-cyclopropyl-1- (2, 6-dimethyl-4-pyridinyl) -3- [ [3- (trifluoromethoxy) phenyl 1 amino ] -1H-pyrazole-5-acetamide,

117.1- (2, 6-dimethyl-4-pyridinyl) -N- (1-methylethyl) -3- [ [3- (trifluoromethoxy) phenyl ] amino ] -1H-pyrazole-5-acetamide,

(α S) - α -ethyl-1- (2-methyl-4-pyridyl) -3- [ (3, 4, 5-trifluorophenyl) amino ] -1H-pyrazole-5-ethanol,

(alpha R) -alpha-ethyl-1- (2-methyl-4-pyridyl) -3- [ (3, 4, 5-trifluorophenyl) amino ] -1H-pyrazole-5-ethanol,

(alpha R) -3- [ (3-chloro-2-fluorophenyl) amino ] -alpha-ethyl-1- (2-methyl-4-pyridyl) -1H-pyrazole-5-ethanol,

(alpha R) -alpha-ethyl-1- (2-methyl-4-pyridyl) -3- [ (2, 3, 4-trifluorophenyl) amino ] -1H-pyrazole-5-ethanol,

(α R) - α -ethyl-3- [ [ 3-methoxy-5- (trifluoromethyl) phenyl ] amino ] -1- (2-methyl-4-pyridinyl) -1H-pyrazole-5-ethanol,

(alpha R) -3- [ (3-chloro-5-methoxyphenyl) amino ] -alpha-ethyl-1- (2-methyl-4-pyridinyl) -1H-pyrazole-5-ethanol,

(alpha R) -3- [ (3-chloro-5-fluorophenyl) amino ] -alpha-ethyl-1- (2-methyl-4-pyridyl) -1H-pyrazole-5-ethanol,

including any stereochemically isomeric form thereof, and the pharmaceutically acceptable addition salts and solvates thereof.

Preparation of the Compounds

The compounds of the invention can generally be prepared by a series of steps, each of which is known to the skilled person. Specifically, the compounds of the present application may be prepared according to one or more of the following preparation methods. In the following schemes, all variables are used as defined in formula (I), unless otherwise indicated.

Reaction scheme 1

Scheme 1

The compounds of formulae (I-a), (I-b), (I-c), (I-d) and (I-e) of the present invention can be prepared by any of several standard synthetic methods commonly used by those skilled in the art of organic chemistry.

In the first step, the intermediate of formula (IV) is generally prepared by carrying out a ring closure reaction between the intermediate of formula (II) and the intermediate of formula (III) under known technical conditions. The conversion is usually carried out in a protic solvent, especially an alcohol such as ethanol (EtOH), in the presence of a strong base such as sodium ethoxide or metallic sodium. Stirring and elevated temperature can increase the reaction rate. The intermediates of formula (II) and (III) are commercially available or can be readily prepared by one skilled in the art.

In the second step, the intermediate of formula (VI) may be prepared by performing a coupling reaction between the amino derivative of formula (IV) and the intermediate of formula (V) using a transition metal catalyst. LG is defined as a leaving group, for example Cl, Br, I, tosylate, mesylate or triflate (triflate), especially F, Cl, Br or I, more especially Cl, Br or I, even more especially Br. Typically, palladium catalysts such as Pd₂(dba)₃For this type of reaction. Usually in bidentate phosphine ligands such as [1, 1' -binaphthyl]-2, 2' -diylbis [ diphenylphosphine](BINAP) and the like and a strong inorganic base such as potassium or sodium tert-butoxide (NaOtBu). This type of reaction can be successfully carried out in aprotic solvents such as Tetrahydrofuran (THF) and the like, at elevated temperatures, especially between 100 ℃ and 130 ℃. Intermediates of formula (V) are commercially available or can be readily prepared by one skilled in the art.

Can be carried out in an oxidizing agent such as MnO₂The intermediate of formula (VI) is reacted in the presence of a suitable solvent, such as Dichloromethane (DCM), to synthesize the compound of formula (I-e).

Can be prepared by reaction with a suitable dealkylating agent such as BBr in the presence of a suitable solvent such as DCM or Dichloroethane (DCE)₃Reacting to convert the compound of formula (I-e) into a compound of formula (I-d). Alternatively, the compounds of formula (I-d) may be prepared by catalytic hydrogenation of the compounds of formula (I-e). Pd/C isUsed as a catalyst. In a source of hydrogen such as H₂Or hydrazine and a solvent such as an alcohol, typically MeOH or EtOH. Stirring and elevated temperature can increase the reaction rate.

The compound of formula (I-c) can then be prepared by treating the compound of formula (I-d) in the first step with a sulfonyl halide, such as methanesulfonyl chloride or toluenesulfonyl chloride, in the presence of an amine base, such as triethylamine. The reaction can be carried out in a suitable solvent, such as THF in general. In the second step of the reaction, a cyanide source, such as an alkali metal cyanide, usually NaCN, and an organic solvent, such as dimethyl sulfoxide (DMSO), are added together.

In the next reaction step, the compound of formula (I-c) is subjected to hydrolysis and then Fischer esterification to give the compound of formula (I-b). Typically, this type of reaction is carried out in aqueous acid, such as aqueous HCl, at elevated temperatures, such as 70 ℃ to reflux temperature. The carboxylic acid derivative formed in this reaction is then subjected to an acid-catalyzed condensation with the desired alcohol (methanol (MeOH), ethanol (EtOH), etc.) in the presence of an acid, such as typically HCl.

Finally, the compound of formula (I-b) may be further reacted with an amine of formula (VII) to give the compound of formula (I-a). Depending on the amine chosen, a suitable solvent may be used in the reaction. Preferred solvents are protic solvents, such as lower alkyl alcohols, e.g. MeOH, and the like. The reaction can be carried out by using reaction conditions well known to those skilled in the art, depending on the amine selected.

Reaction scheme 2

Scheme 2

Alternatively, compounds of formula (I-e) can be prepared from intermediates of formula (VIII) according to the reaction scheme described in scheme 2.

Can be carried out in an oxidizing agent such as MnO₂In the presence of a suitable solvent such as Dichloromethane (DCM), the intermediate of formula (IV) is reacted to synthesize the intermediate of formula (VIII).

The compound of formula (I-e) may then be prepared by performing a coupling reaction between the amino derivative of formula (VIII) and the intermediate of formula (V) using a transition metal catalyst. LG is defined as a leaving group, for example Cl, Br, I, tosylate, mesylate or triflate (triflate), especially F, Cl, Br or I, more especially Cl, Br or I, even more especially Br. Typically, palladium catalysts such as Pd₂(dba)₃For this type of reaction. Usually in bidentate phosphine ligands such as [1, 1' -binaphthyl]-2, 2' -diylbis [ diphenylphosphine](BINAP) and the like and a strong inorganic base such as potassium or sodium tert-butoxide (NaOtBu). Such reactions can be successfully carried out in aprotic solvents such as Tetrahydrofuran (THF) and the like, at elevated temperatures, especially between 100 ℃ and 130 ℃.

Reaction scheme 3

Scheme 3

In the first step of scheme 3, by treatment in a strong acid such as H₂SO₄In the presence of an aprotic solvent, e.g. DMF and the like, with an oxidizing agent, e.g. bipyridyl dichromate(dipyridiniumchloride) (PDC), converting the alcohol of formula (I-d) into a compound of formula (I-g).

Alternatively, the compounds of formula (I-g) can also be prepared according to the reaction procedures described in scheme 1. Hydrolyzing the compound of formula (I-c) to obtain a compound of formula (I-g).

Finally, the formula (A)I-g) with a primary or secondary amine of formula (VII) to give a compound of formula (I-f). The reaction can be carried out by known methods, usually in a conventional amide coupling reagent such as HBTU (O-benzotriazole-N, N, N ', N' -tetramethylurea)Hexafluorophosphate), EDCI or EDAC, in an aprotic solvent such as DCM, or more preferably in a polar aprotic solvent such as THF or DMF, in the presence of an amine base additive such as Diisopropylethylamine (DIPEA). In some cases, HOBT is preferred as an additive.

Reaction scheme 4

Scheme 4

Intermediates of formula (XII) are synthesized by reacting an intermediate of formula (X) (3- [ [ (1, 1-dimethylethyl) dimethylsilyl ] oxy ] -pentanal) with a cyano derivative of formula (XI) (diethyl cyanomethanephosphonate) in the presence of a strong inorganic base such as NaH and the like and a solvent such as THF. Intermediates of formula (X) and intermediates of formula (XI) can be readily prepared by those skilled in the art.

Intermediates of general formula (XIV) can then be obtained by carrying out a ring closure reaction between an intermediate of formula (XII) and an intermediate of formula (II) under known technical conditions. The conversion is usually carried out in a protic solvent, especially an alcohol such as ethanol (EtOH), in the presence of a strong base such as sodium ethoxide or metallic sodium. Stirring and elevated temperature can increase the reaction rate. The intermediates of formula (II) are commercially available or can be readily prepared by one skilled in the art.

In a next step, a coupling reaction between the amino derivative of formula (XIV) and the intermediate of formula (V) may be carried out using a transition metal catalyst to prepare the compound of formula (IX). LG is defined as a leaving groupGroups, such as Cl, Br, I, tosylate, mesylate or triflate, especially F, Cl, Br or I, more especially Cl, Br or I, even more especially Br. Typically, palladium catalysts such as Pd₂(dba)₃For this type of reaction. Usually in bidentate phosphine ligands such as [1, 1' -binaphthyl]-2, 2' -diylbis [ diphenylphosphine](BINAP) and the like and a strong inorganic base such as potassium or sodium tert-butoxide (NaOtBu). This type of reaction can be successfully carried out in aprotic solvents such as Tetrahydrofuran (THF) and the like, at elevated temperatures, especially between 100 ℃ and 130 ℃.

Can be carried out in an oxidizing agent such as MnO₂The intermediate of formula (IX) is reacted in the presence of a suitable solvent, such as Dichloromethane (DCM), to synthesize an intermediate of formula (XIII).

The skilled person will note that the order of the first 2 steps of the reaction may be changed, which would also give an intermediate of formula (XIII).

Finally, the silyl protecting group can be removed at the end of the sequence shown in scheme 4 using known technical conditions in the presence of a desilylating agent such as a quaternary ammonium fluoride (TBAF). Typically, this reaction is carried out in a suitable solvent such as THF.

Analogues of the compounds of formula (I-I) wherein the hydroxyl group is located at another position on the alkyl chain or/and wherein the alkyl chain (R) is prepared by using variants of the intermediates of formula (X), such variants also being commercially available or being easily prepared by a person skilled in the art³) Is C_1-3An alkyl group.

Pharmacology of

The compounds of the present invention were found to be positive allosteric modulators of the α 7 nicotinic receptor. The alpha 7 nicotinic receptors (alpha 7nAChR) belong to the cys-loop, ionotropic ligand-gated ion channel superfamily, which include 5-HT₃、GABA_AAnd the glycine receptor family. It is activated by acetylcholine and its breakdown product choline, the main characteristic of the alpha 7nAChRThe characteristic is rapid desensitization in the continued presence of agonist. It is the second most abundant nicotinic receptor subtype in the brain and is an important regulator of the release of various neurotransmitters. It is distributed in several brain structures associated with attention and cognitive processes, such as the hippocampus and prefrontal cortex, and is associated with a variety of human mental and neurological disorders. It is also associated with cholinergic inflammatory pathways.

Genetic evidence associated with schizophrenia can be found in the form of a high correlation between schizophrenia markers (sensory gating defects) and polymorphisms at the α 7 locus on 15q 13-14 and the nuclear promoter region of the α 7 gene.

Pathological evidence indicates that α 7 immunoreactivity and α -Btx-binding are lost in hippocampus, frontal and cingulate slices of the brain in schizophrenia, in parkinson's disease and alzheimer's disease, in paraventricular and junctional nuclei (nucleous reunites) in autism.

Pharmacological evidence, such as significant smoking habits of schizophrenic patients over normal, is interpreted as an attempt by the patients to self-medicate to compensate for the deficiency in alpha 7 nicotinic delivery. In both animal models and humans, the defect in transient normalization in sensory gating after administration of nicotine (prepulse inhibition, PPI) and the temporary restoration of normal sensory gating when the current brain cholinergic activity is low (e.g., phase 2 sleep) in schizophrenic patients are explained as a result of transient activation of the α 7 nicotinic receptor followed by desensitization.

Thus, there is good reason to conclude that α 7 nachrs should have a beneficial therapeutic effect in the management of a variety of CNS (psychiatric and neurological) disorders.

As already described, α 7 nachrs rapidly desensitize in the sustained presence of the natural transmitter acetylcholine and exogenous ligands such as nicotine. In the desensitized state, the receptor remains ligand-bound but functionally inactive. This is not a big problem for natural transmitters such as acetylcholine and choline, since these transmitters are substrates for very powerful breakdown (acetylcholinesterase) and clearance (choline transporter) mechanisms. These transmitter breakdown/clearance mechanisms may maintain a balance between activating and desensitizing α 7 nachrs within a physiologically effective range. However, synthetic agonists that are not substrates of the natural breakdown and clearance mechanisms were found to have the potential to overstimulate and drive the equilibrium of the α 7nAChR population toward a sustained desensitized state, which is undesirable in conditions where defects in α 7nAChR expression or function play a role. By their nature, agonists must target the ACh binding pocket, which is highly conserved between different nicotinic receptor subtypes, resulting in the potential for adverse reactions to non-specifically activate other nicotinic receptor subtypes. Therefore, to avoid these potential trends, an alternative therapeutic strategy to α 7 agonism is to enhance the receptor response to natural agonists with Positive Allosteric Modulators (PAMs). PAM is defined as an agent whose binding site differs from that of an agonist, and therefore would be expected to have no agonist or desensitizing properties, but to enhance the responsiveness of the α 7nAChR to natural transmitters. The value of this strategy is that for a given amount of transmitter, the magnitude of the α 7nAChR response is increased in the presence of PAM relative to the level of transmission possible in the absence of PAM. PAM-induced increases in α 7 nicotinic transmission may therefore be beneficial for conditions in which the α 7nAChR protein is defective. Since PAM relies on the presence of natural transmitters, the potential for overstimulation is limited by the breakdown/clearance mechanisms of the natural transmitters.

The compounds of the invention were classified as type 0-4 based on quantitative kinetic properties as determined by whole cell voltage clamp recording. This classification is based on the effect of the α 7PAM compounds described hereinbefore on the signal induced by agonist administration. In particular, the agonist is choline at a concentration of 1 mM. In a preferred experimental setting, the α 7PAM compound and choline are administered simultaneously to the cells described below. Desensitization is defined as receptor closure upon activation during administration of agonist, as measured by the decrease in outward current following initial activation by agonist in whole cell voltage clamp electrophysiological measurements.

The definition of PAM types 0-4 is illustrated below:

the magnitude of the effect of the type 0 compound in enhancing the current induced by 1mM choline was minimal.

Type 1 compounds enhanced the magnitude of the effect of 1mM choline-induced current but minimal changes in receptor kinetics. In particular, the rate and extent of desensitization by the agonist is not affected. Thus, in the absence of the α 7PAM compound, the compound modulated response to 1mM choline approached the linear scale of the 1mM choline response.

Type 2 compounds enhance the magnitude of the effect of 1mM choline-induced current while reducing the rate and/or extent of desensitization.

The magnitude of the effect of type 3 compounds in enhancing the current drawn by 1mM choline. They completely inhibited desensitization when tested at higher concentrations up to 10 μ M, especially when administered 1mM choline for 250 milliseconds.

Type 4 compounds desensitize the receptor for the first time and then reopen the receptor during agonist administration. At low potency concentrations of the α 7PAM compound, agonist-induced activation (which subsequently leads to desensitization) can still be separated from compound-induced reopening as the maximum initial internal current. At higher potency concentrations of the α 7PAM compound, reopening occurs faster than closing due to desensitization, so that the maximum initial current disappears.

This compound is considered to have interesting PAM-like activity when the potential difference phenomenon of the peak current is at least 200% relative to the control choline response (═ 100%). In the experimental part, the class of such compounds belongs to a specific PAM type. Compounds that do not meet this condition are not classified as belonging to a particular PAM type.

It is therefore an object of the present invention to provide a method of treatment comprising either administering a positive allosteric modulator as the only active substance, thereby modulating the activity of an endogenous nicotinic receptor agonist, such as acetylcholine or choline, or administering a positive allosteric modulator together with a nicotinic receptor agonist. In a particular form of this aspect of the invention, the method of treatment comprises treatment with a positive allosteric modulator of the α 7 nicotinic receptor described herein and an α 7 nicotinic receptor agonist or partial agonist. Examples of suitable compounds having alpha 7 nicotinic receptor agonistic activity include

-1, 4-diazabicyclo [3.2.2] nonane-4-carboxylic acid, 4-bromophenyl ester, monohydrochloride (SSR 180711A);

- (-) -spiro [ 1-azabicyclo [2.2.2.]Octane-3, 5-Oxazolidines]-a 2' -ketone;

-3- [ (2, 4-dimethoxy) benzylidene ] -anabasine (anabasine) dihydrochloride (GTS-21);

- [ N- [ (3R) -1-azabicyclo [2.2.2] oct-3-yl ] -4-chlorobenzamide hydrochloride ] PNU-282987;

-nicotine;

-varenicline;

-MEM3454；

-AZD-0328；

-MEM63908；

- (+) -N- (1-azabicyclo [2.2.2] oct-3-yl) benzo [ b ] furan-2-carboxamide;

-A-582941；

-AR-R17779；

-TC-1698；

-PHA-709829；

-tropisetron;

-WAY-317538；

-EVP-6124; and

-TC-5619。

in particular, examples of suitable compounds having α 7 nicotinic receptor agonistic activity include

1, 4-diazabicyclo [3.2.2]Nonane-4-carboxylic acid, 4-bromophenyl ester, monohydrochloride (SSR 180711A); (-) -spiro [ 1-azabicyclo [ 2].2.2.]Octane-3, 5-Oxazolidines]-a 2' -ketone; 3- [ (2, 4-dimethoxy) benzylidene]-anabasine dihydrochloride (GTS-21); [ N- [ (3R) -1-azabicyclo [2.2.2] s]Oct-3-yl]-4-chlorobenzamide hydrochloride]PNU-282987; nicotine; (ii) Vancklan; MEM 3454; AZD-0328; and MEM 63908.

The positive nAChR modulators of the present invention are useful for treating or preventing psychotic disorders, intellectual impairment disorders or diseases or conditions in which modulation of α 7 nicotinic receptor activity is beneficial. A particular aspect of the methods of the invention is a method of treating the following diseases; learning deficit, cognition deficit, attention deficit hyperactivity disorder or memory deficit, psychotic disorders, inflammatory disorders in which modulation of α 7 nicotinic receptor activity is desired in favor of a variety of diseases including alzheimer's disease, dementia with lewy bodies, attention deficit hyperactivity disorder, anxiety, schizophrenia, mania, manic depression, parkinson's disease, huntington's chorea, Tourette's syndrome, brain trauma or other neurological disorders in which there is loss of cholinergic synapses, degenerative or psychiatric disorders including jetlag, nicotine addiction, pain;

a more particular aspect of the methods of the invention is a method of treating a psychotic disorder, intellectual impairment disorder or an inflammatory disease.

The invention also relates to a method of treating a disease or disorder described above or below in a patient, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier.

The compounds have also found therapeutic use as anti-inflammatory agents, since the nicotinic acetylcholine receptor alpha 7 subunit is crucial for inhibiting cytokine synthesis through the cholinergic inflammatory pathway. Examples of indications that can be treated by the compounds are endotoxemia, endotoxic shock, sepsis, rheumatoid arthritis, asthma, multiple sclerosis, psoriasis, urticaria, inflammatory bowel disease, inflammatory biliary disease (inflimatory bile disease), crohn's disease, ulcerative colitis, post-operative ileus, pancreatitis, heart failure, acute lung injury, and allograft rejection.

The compounds of the invention find therapeutic use for the following indications; such as cognition in schizophrenia, cognition in Alzheimer's disease, mild cognitive impairment, Parkinson's disease, attention deficit hyperactivity disorder, ulcerative colitis, pancreatitis, arthritis, sepsis, post-operative ileus, and acute lung injury.

In view of the above pharmacological properties, the compounds of formula (I) or any of its subtypes, their pharmaceutically acceptable addition salts, quaternary amines and stereochemically isomeric forms, are useful as medicaments. In particular, the compounds of the invention may be used for the preparation of a medicament for the treatment or prevention of psychotic disorders, intellectual impairment disorders or diseases or conditions in which modulation of the α 7 nicotinic receptor is beneficial.

In view of the above pharmacological properties, the compounds of formula (I) or any of its subtypes, their pharmaceutically acceptable addition salts, quaternary amines and stereochemically isomeric forms, are useful for the treatment or prevention of psychotic disorders, intellectual impairment disorders or diseases or conditions in which modulation of the α 7 nicotinic receptor is beneficial.

In one embodiment, the invention relates to compounds of formula (I) for use in the treatment or prevention of psychotic disorders, intellectual impairment disorders or diseases or conditions in which modulation of the α 7 nicotinic receptor is beneficial.

In one embodiment, the invention relates to compounds of formula (I) for use in the treatment or prevention, in particular in the treatment of Alzheimer's disease, dementia with Lewy bodies, attention deficit hyperactivity disorder, anxiety, schizophrenia, mania, manic depression, Parkinson's disease, Huntington's chorea, Tourette's syndrome, brain trauma or other neurological, degenerative or psychiatric disorders in which loss of cholinergic synapses is present, including jetlag, nicotine addiction, pain, endotoxemia, endotoxic shock, sepsis, rheumatoid arthritis, asthma, multiple sclerosis, psoriasis, urticaria, inflammatory bowel disease, inflammatory biliary disease, Crohn's disease, ulcerative colitis, post-operative bowel disease, pancreatitis, heart failure, acute lung injury, allograft rejection, cognition in schizophrenia, stroke, neuro, Cognition in alzheimer's disease, mild cognitive impairment, parkinson's disease, attention deficit hyperactivity disorder, ulcerative colitis, pancreatitis, arthritis, sepsis, post-operative ileus, and acute lung injury.

In one embodiment, the invention relates to compounds of formula (I) for use in the treatment or prophylaxis, in particular in the treatment of psychotic disorders, intellectual impairment disorders or diseases or conditions in which modulation of the α 7 nicotinic receptor is beneficial.

In one embodiment, the present invention relates to compounds of formula (I) for use in the treatment or prophylaxis, in particular in the treatment of psychotic disorders, intellectual impairment disorders or inflammatory diseases.

In one embodiment, the present invention relates to compounds of formula (I) for use in the treatment or prevention, in particular in the treatment of said diseases or disorders.

In view of the utility of the compounds of formula (I), there is provided a method of treating, or preventing the development of, a disease in a warm-blooded animal, including a human, in which modulation of the α 7 nicotinic receptor is beneficial, such as schizophrenia, mania and manic depression, anxiety, alzheimer's disease, learning deficit, cognition deficit, attention deficit, memory loss, lewy body dementia, attention deficit hyperactivity disorder, parkinson's disease, huntington's chorea, tourette's syndrome, brain trauma, jetlag, nicotine addiction and pain. Said method comprising the administration, i.e. systemic or local administration, preferably oral administration, of an effective amount of a compound of formula (I), including all stereochemically isomeric forms, pharmaceutically acceptable addition salts, solvates or quaternary amines thereof, to warm-blooded animals, including humans.

One skilled in the art will appreciate that a therapeutically effective amount of a PAM of the present invention is an amount sufficient to modulate the activity of the alpha 7 nicotinic receptor and that this amount may vary depending on, among other things, the type of disease, the concentration of the compound in the therapeutic formulation and the condition of the patient. Generally, the amount of PAM administered as a therapeutic agent for the treatment of diseases in which modulation of the α 7 nicotinic receptor is beneficial, such as schizophrenia, mania and manic depression, anxiety, alzheimer's disease, learning deficit, cognition deficit, attention deficit, memory loss, lewy body dementia, attention deficit hyperactivity disorder, parkinson's disease, huntington's chorea, tourette's syndrome, brain trauma, jet lag, nicotine addiction and pain will be determined by the attending physician on a case by case basis.

Generally, a suitable dose is one that results in a concentration of PAM at the treatment site in the range of 0.5nM to 200. mu.M, and more typically in the range of 5nM to 50. mu.M. To achieve these therapeutic concentrations, 0.01mg/kg to 2.50mg/kg body weight, especially 0.1mg/kg to 0.50mg/kg body weight, will be administered to the patient in need of treatment. The amount of a compound of the invention (also referred to herein as an active ingredient) required to achieve a therapeutic effect will, of course, vary with the case, the particular compound, the route of administration, the age and condition of the recipient, and the particular disorder or disease being treated. The method of treatment may further comprise administering the active ingredient on a dosing schedule of 1-4 doses per day. In these methods of treatment, it is preferred to formulate the compounds of the invention prior to administration. Suitable pharmaceutical formulations are formulated by known methods using well known and readily available ingredients, as described below.

The invention also provides compositions for the prevention or treatment of diseases in which modulation of the α 7 nicotinic receptor is beneficial, such as schizophrenia, mania and manic depression, anxiety, alzheimer's disease, learning deficit, cognition deficit, attention deficit, memory loss, lewy body dementia, attention deficit hyperactivity disorder, parkinson's disease, huntington's chorea, tourette's syndrome, brain trauma, jet lag, nicotine addiction and pain. The compositions comprise a therapeutically effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier or diluent.

Although the active ingredient may be administered alone, it is preferably administered as a pharmaceutical composition. Accordingly, the present invention also provides a pharmaceutical composition comprising a compound of the present invention in combination with a pharmaceutically acceptable carrier or diluent. A carrier or diluent must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.

The Pharmaceutical compositions of the present invention may be prepared by any of the methods well known in the Pharmaceutical arts, such as those described in Gennaro et al, Remington's Pharmaceutical Sciences (18 th edition, Mack Publishing Company, 1990, see especially section 8: Pharmaceutical preparations and the human Manufacture). A therapeutically effective amount of the particular compound, in base form or addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. Preferably, these pharmaceutical compositions are adapted for preferably systemic administration, e.g. oral, transdermal or parenteral administration; or topically, e.g., by inhalation, nasal spray, eye drops, or by unit dosage forms of ointments, gels, shampoos, and the like. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or in the case of powders, pills, capsules and tablets, the pharmaceutical media are solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case pharmaceutical carriers are obviously employed. For parenteral compositions, at least a majority of the carrier will typically comprise sterile water, although other ingredients, such as ingredients to aid solubility, may be included. For example, injectable solutions can be prepared in which the carrier comprises saline solution, dextrose solution, or a mixture of saline and dextrose solution. Injectable suspensions may also be formulated in which case appropriate liquid carriers, suspending agents and the like may be employed. In compositions suitable for transdermal administration, the carrier optionally comprises a penetration enhancer and/or a suitable wetting agent, optionally in combination with a small proportion of suitable additives of any nature, which do not cause any significant deleterious effect on the skin. The additives may aid in the administration of the drug to the skin and/or may aid in the preparation of the desired composition. These compositions can be administered in various ways, for example, as a transdermal patch, as a spot-on, or as an ointment.

It is particularly advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.

Because the compounds of the present invention are potent orally administered compounds, pharmaceutical compositions containing the compounds are particularly advantageous for oral administration.

To improve the solubility and/or stability of the compounds of formula (I) in pharmaceutical compositions, it may be advantageous to use α -, β -or γ -cyclodextrins or their derivatives, especially hydroxyalkyl-substituted cyclodextrins, for example 2-hydroxypropyl- β -cyclodextrin or sulfobutyl- β -cyclodextrin. Co-solvents such as alcohols may also improve the solubility and/or stability of the compounds of the present invention in pharmaceutical compositions.

The exact dose and frequency of administration will depend upon the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight, sex, extent of the condition and general physical condition of the particular patient and other drugs which may be used by the individual, as is well known to those skilled in the art. In addition, it will be apparent that the effective daily dose may be reduced or increased depending on the response of the patient being treated and/or on the evaluation of the physician prescribing the compounds of the instant invention.

Depending on the mode of administration, the pharmaceutical composition will contain from 0.05 to 99% by weight, preferably from 0.1 to 70% by weight, more preferably from 0.1 to 50% by weight of the active ingredient and from 1 to 99.95% by weight, preferably from 30 to 99.9% by weight, more preferably from 50 to 99.9% by weight of a pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition.

The compounds of the invention may be used for systemic administration, e.g. oral, transdermal or parenteral administration; or topically, e.g., by inhalation, nasal spray, eye drops, or by ointment, gel, shampoo, and the like. Preferably, the compounds are administered orally. The exact dose and frequency of administration will depend upon the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight, sex, extent of the condition and general physical condition of the particular patient and other drugs which may be used by the individual, as is well known to those skilled in the art. In addition, it will be apparent that the effective daily dose may be reduced or increased depending on the response of the patient being treated and/or depending on the evaluation of the physician prescribing the compounds of the instant invention.

The compounds of formula (I) may also be used in combination with other conventional alpha 7 nicotinic receptor agonists or partial agonists, such as, for example, 1, 4-diazabicyclo [3.2.2]Nonane-4-carboxylic acid, 4-bromophenyl ester, monohydrochloride (SSR 180711A); (-) -spiro [ 1-azabicyclo [2.2.2.]Octane-3, 5-Oxazolidines]-a 2' -ketone; 3- [ (2, 4-dimethoxy) benzylidene]-anabasine dihydrochloride (GTS-21); [ N- [ (3R) -1-azabicyclo [2.2.2] s]Oct-3-yl]-4-chlorobenzamide hydrochloride]PNU-282987; nicotine; (ii) Vancklan; MEM 3454; AZD-0328; MEM 63908; (+) -N- (1-azabicyclo [2.2.2] s]Oct-3-yl) benzo [ b]Furan-2-carboxamide; a-582941; AR-R17779; TC-1698; PHA-709829; tropisetron; WAY-317538; EVP-6124; and TC-5619.

The compounds of formula (I) may also be used in combination with conventional alpha 7 nicotinic receptor agonists,such agonists are, for example, 1, 4-diazabicyclo [3.2.2]Nonane-4-carboxylic acid, 4-bromophenyl ester, monohydrochloride (SSR 180711A); (-) -spiro [ 1-diazabicyclo [2.2.2.]Octane-3, 5-Oxazolidines]-a 2' -ketone; 3- [ (2, 4-dimethoxy) benzylidene]-anabasine dihydrochloride (GTS-21); [ N- [ (3R) -1-azabicyclo [2.2.2] s]Oct-3-yl]-4-chlorobenzamide hydrochloride]PNU-282987; nicotine; (ii) Vancklan; MEM 3454; AZD-0328 and MEM 63908.

Thus, the invention also relates to a combination of a compound of formula (I) and an alpha 7 nicotinic receptor agonist. The combination is useful as a medicament. The invention also relates to products containing (a) a compound of formula (I) and (b) an alpha 7 nicotinic receptor agonist, as a combined preparation for simultaneous, separate or sequential use in the treatment of a disease in which modulation of the alpha 7 nicotinic receptor is beneficial, e.g. a psychotic disorder, a intellectual impairment disorder or an inflammatory disease. The different drugs may be combined in a single formulation with a pharmaceutically acceptable carrier.

Examples

Hereinafter, the term "DCM" refers to dichloromethane; "MeOH" refers to methanol; "EtOH" refers to ethanol; ' Pd₂(dba)3 "refers to tris (dibenzylideneacetone) dipalladium; "NH₄OAc "refers to ammonium acetate; "BINAP" refers to [1, 1' -binaphthyl]-2, 2' -diylbis [ diphenylphosphine](racemic); "NaOtBu" refers to sodium tert-butoxide; "BDS" refers to (Base Deactivated Silica); "THF" refers to tetrahydrofuran; "HPLC" refers to high performance liquid chromatography; "iPrOH" refers to 2-propanol; "NaOEt" refers to sodium ethoxide; "PDC" refers to bipyridine dichromate(ii) a "r.t." means room temperature; "HOBT" refers to 1-hydroxy-1H-benzotriazole; "DMSO" refers to dimethylsulfoxide; "EDCI" refers to N' - (ethylcarbamimidoyl)) -N, N-dimethyl-1, 3-propanediamine monohydrochloride; "RP" meansInverting; "DMAP" refers to 4- (dimethylamino) pyridine; "min" means minutes; "TPAP" refers to tetrapropylammonium perruthenate; "h" means hours; "q.s." means appropriate amounts; "i.d." means inner diameter; "Et₂O "means diethyl ether; "EtOAc" refers to ethyl acetate; "Et₃N "refers to triethylamine; "TBAF" refers to tetrabutylammonium fluoride; "DIPEA" refers to diisopropylethylamine; "EtOH" refers to ethanol; "eq" refers to equivalent; "r.m." means the reaction mixture; "DIPE" refers to diisopropyl ether; and "DMF" refers to N, N-dimethylformamide;

A. preparation of intermediates

Example A1

a)Preparation of intermediate 1

In N₂NaH (60%) (8g, 200mmol) was stirred in THF (250ml) at 0-5 ℃ under an atmosphere. A solution of diethyl cyanomethanephosphonate (35.386g, 200mmol) in THF (250ml) was added dropwise at 0-5 deg.C, and the resulting mixture was stirred at 0-5 deg.C for 15 min. Then, a solution of 2- (phenylmethoxy) acetaldehyde (30g, 200mmol) was added dropwise at 0-5 ℃. The reaction mixture was stirred at room temperature for 1H and then poured into H₂And (4) in O. The aqueous mixture was extracted with DIPE. The separated organic layer was dried (MgSO)₄) Filtered and concentrated by evaporation. The crude product was purified over silica gel (eluent: DCM). The pure fractions were collected and the solvent was evaporated. Obtaining: 23g of intermediate 1 (yield 66%).

b) Preparation of intermediate 2

In N₂A mixture of 4-chloro-2-methylpyridine (10g, 78.4mmol), hydrazine hydrate 100% (4.311g, 86.2mmol) and iPrOH (30ml) was reacted at 150 ℃ for 1h under an atmosphere. The reaction mixture was then diluted with DIPE (30ml) and cooled to-15 ℃. The precipitate was filtered off and dried at 40 ℃. Obtaining: 10.7g of intermediate 2 were used as such in the next reaction step.

c) Preparation of intermediate 3

At 50 ℃ under N₂Sodium (4.48g, 194.8mmol, 2.2eq) was stirred in EtOH (200ml) under an atmosphere. Intermediate 2(14.13g, 88.53mol, 1eq) was added at room temperature and the mixture was refluxed for 30 min. Then intermediate 1(23g, 132.8mmol, 1.5eq) was added at room temperature and the reaction mixture was stirred at 50 ℃ overnight. Then, the solvent was evaporated. H is to be₂O was added to the residue, and the aqueous mixture was extracted with EtOAc. The separated organic layer was dried (MgSO)₄) Filtered and the solvent evaporated. The product is removed from Et₂O (q.s.) crystal. The crystals are filtered off and dried. Obtaining: 18.6g of intermediate 3 (yield 71%).

d) Preparation of intermediate 4

3-methoxy-5- (trifluoromethyl) aniline (benzzenamine) (20g, 104.6mmol) was added in portions to NaNO₂(7.392g, 107.1mmol) of H₂SO₄(74ml) and CH₃COOH (88ml) in cold solution. The mixture was added dropwise to a solution of CuBr (18g, 62.8mmol) in 48% HBr (200ml) at 0 ℃ with vigorous stirring. Mixing the reactionThe mixture was stirred at room temperature for 45min and then poured into ice water. The aqueous mixture was extracted with DCM. The separated organic layer was dried (MgSO)₄) Filtered and the solvent evaporated at low temperature. The residue is taken up in NaHCO₃The solution was stirred and extracted with DIPE. The separated organic layer was dried (MgSO)₄) Filtered and the solvent evaporated. Obtaining: 12.7g of intermediate 4 (yield 48%).

e) Preparation of intermediate 5

Intermediate 3(5g, 16.87mmol) was stirred in THF (100 ml). Intermediate 4(6.607g, 25.9mmol), Pd₂(dba)₃(1.4g), BINAP (1.9g) and NaOtBu (4g) were added to the mixture. The reaction mixture was stirred in a microwave oven for 2h at 110 ℃. Then, EtOAc (800ml) and brine (200ml) were added and the mixture was stirred. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue is removed from CH₃And (4) crystallizing in CN. The product was filtered off and dried to yield 5.7g of intermediate 5. When desired, additional amounts of product may be obtained by evaporation of the filtrate and purification (by, e.g., reverse phase HPLC) of the resulting residue.

Example A2

a)Preparation of intermediate 6

NaH (60%) (7g, 181.8mmol) was washed with heptane (q.s.) under N₂The mixture was stirred in THF (150ml) at 0-5 ℃ under an atmosphere. Diethyl cyanomethanephosphonate (32.202g, 181.8mmol) was dissolved in THF (150ml) and the solution was stirredThe solution is added dropwise at 0-5 ℃. The mixture was stirred for 15 min. Then, 4- (phenylmethoxy) -butyraldehyde (32.4g, 181.8mmol) was dissolved in THF (100ml), and the solution was added dropwise at 0-5 ℃. The reaction mixture was stirred at room temperature for 1H and then poured into H₂And (4) in O. The aqueous mixture was extracted with DIPE. The separated organic layer was dried (MgSO)₄) Filtered and concentrated by evaporation. The residue was purified by HPLC to give 18.6g of intermediate 6 (yield 51%).

b) Preparation of intermediate 7

In N₂A solution of 21% NaOEt in EtOH (35ml) was stirred in EtOH (110ml) under an atmosphere. Intermediate 2(10.4g, 53.04mmol) was added dropwise at room temperature and the mixture was stirred at 70 ℃ for 1 h. The mixture was then cooled and intermediate 6(13.563g, 67.39mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2h, then at 45 ℃ for 2 days. The reaction mixture was then filtered and the filtrate was concentrated by evaporation. The residue was dissolved in EtOAc (800ml) and the solution was washed with brine (200 ml). The organic layer was dried (MgSO₄) Filtered and concentrated by evaporation. The residue was purified by column chromatography over silica gel (eluent: from DCM/MeOH 98/2 to 85/15). The desired fractions were collected. Obtaining: 2.6g of crude intermediate 7 were used as such in the next reaction step. Can be obtained by RP HPLC (RP Shandon Hyperprep C18BDS-8 μm, 250g, I.D.5 cm; mobile phase: 0.25% NH)₄HCO₃An aqueous solution; MeOH + CH₃CN) further purified the less pure stream to yield more product. The desired fractions were collected and worked up to give 5g of intermediate 7.

c) Preparation of intermediate 15

Intermediate 7(8.2g, 25.275mmol) and MnO₂A mixture of (21.974g, 252.754mmol) in DCM was stirred at room temperature for 16 h. The reaction mixture was then filtered through celite and the solvent was evaporated. The residue was purified by silica gel column chromatography (DCM/MeOH from 98/2 to 85/15). The desired fractions were collected and the solvent was evaporated. The residue was further purified by RP HPLC (RP Shandon Hyperprep C18BDS-8 μm, 250g, I.D.5 cm; mobile phase: 0.25% NH)₄HCO₃/H₂O；MeOH+CH₃CN). Collecting the required fraction, and performing post-treatment to obtain: 980mg of intermediate 15 (yield 12%).

Example A3

a) Preparation of intermediate 8

A mixture of methyl (3R) -3-hydroxypentanoate (20g, 151.33mmol), 1H-imidazole (22.66g, 332.93mmol), DMAP (1.85g, 15.13mmol) and DMF (800ml) was stirred at 0 ℃. Chloro (1, 1-dimethylethyl) dimethylsilane (27.37g, 181.60mmol) was added, and the mixture was stirred at room temperature overnight. Evaporating the solvent to remove H₂O was added to the residue. The aqueous mixture was extracted with DIPE. The separated organic layer was dried (MgSO)₄) Filtered and the solvent evaporated. Obtaining: 24g of intermediate 8 (yield 64%; R-enantiomer).

b) Preparation of intermediate 9

At room temperatureNext, LiBH is added₄(2.14g, 97.40mmol) was stirred in THF (70 ml). A solution of intermediate 8(24g, 97.39mmol) in THF (70ml) was added over 5min and the reaction mixture was heated to reflux temperature and refluxed for 2 h. Then, Et was added at 0 deg.C₂O (200ml) and saturated NH₄And (4) Cl solution. The reaction mixture was stirred at 0 ℃ for 30 min. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue was dissolved in DCM and the solution was taken up with H₂And O washing. The organic layer was dried (MgSO₄) Filtered and the solvent evaporated. Obtaining: 15g of intermediate 9 (yield 71%; R enantiomer).

c) Preparation of intermediate 10

In N₂A mixture of intermediate 9(14.5g, 66.40mmol), N-methylmorpholine-N-oxide (12.5g, 103.82mmol), molecular sieve powder (33.4g) and DCM (700ml) was stirred at room temperature for 30min under an atmosphere. TPAP (1.25g) was added and the mixture was stirred for 1 h. The mixture was filtered through a glass filter containing a silica gel layer and a top layer of diatomaceous earth. The filter was washed with DCM. The filtrate was evaporated. Obtaining: 10.5g of intermediate 10 (73% yield; R enantiomer).

d) Preparation of intermediate 11

NaH (60%) (2.03g, 50.83mmol) was washed with heptane, then under N₂Stirring was carried out in THF (100ml) at 0-5 ℃ under an atmosphere. A solution of diethyl cyanomethanephosphonate (9.005g, 50.83mmol) in THF (100ml) was added dropwise at 0-5 deg.C. The mixture was stirred for 15 min. Then, intermediate 10(11g, 50.83mmol) in THF (100ml) was added dropwise at 0-5 deg.CAnd (4) liquid. The mixture was stirred at room temperature for 1H, H was added₂O, the product was extracted with DIPE. The separated organic layer was dried (MgSO)₄) Filtered and the solvent evaporated. The residue was purified over silica gel (eluent: DCM). The desired fractions were collected and the solvent was evaporated. Obtaining: 9.4g of intermediate 11 (yield 77%; R enantiomer).

e) Preparation of intermediate 12

At 50 ℃ under N₂Na (1.35g, 58.5mmol) was dissolved in EtOH (50ml) under an atmosphere. Intermediate 2(3.735g, 23.4mmol) was added portionwise at room temperature. The mixture was stirred, refluxed for 30min, and then cooled to room temperature. Intermediate 11(8.4g, 35.08mmol) was added dropwise and the reaction mixture was stirred at 50 ℃ overnight. Then, the solvent is evaporated, H₂O and EtOAc were added to the residue. The organic layer was separated and dried (MgSO)₄) Filtered and the solvent evaporated. The residue was subjected to RP HPLC (Shandon Hyperprep)C18BDS 8 μm, 250g, I.D.5 cm; mobile phase: 90% 0.5% NH₄Aqueous OAc + 10% CH₃CN；CH₃CN) purification. The desired fractions were collected and the solvent was evaporated. DCM was added and the solution was washed with NaHCO₃And (4) washing the solution. The organic layer was dried (MgSO₄) Filtered and the solvent evaporated. Obtaining: 1.5g of intermediate 12 (yield 12%).

f) Preparation of intermediate 13

Under microwave irradiation, intermediate 12 (70)0mg, 1.93mmol), 4-bromo-1, 2-difluorobenzene (558.87mg, 2.90mmol), Pd₂(dba)₃A mixture of (196mg), BINAP (266mg) and NaOtBu (560mg) in THF (5ml) was stirred at 110 ℃ for 2 h. Evaporating the mixture with H₂Wash with O and extract with DCM. Drying (MgSO)₄) The organic layer was separated, filtered and the solvent was evaporated. The product was passed through silica gel (eluent: DCM/MeOH (NH) from 90/10 to 80/20₃) Purification). The desired fractions were collected and the solvent was evaporated. Obtaining: 1g of intermediate 13 (quantitative yield).

g) Preparation of intermediate 14

Intermediate 13(1g, 2.107mmol) was stirred in DCM (400ml) at room temperature. Adding MnO₂(2.5g), the mixture was stirred for 2 h. The mixture was then filtered through celite and the filtrate was evaporated. The product was chromatographed over a silica gel column (eluent: DCM/MeOH (NH)₃) 99/1-98/2). The pure fractions were collected and the solvent was evaporated. Obtaining: 440mg of intermediate 14 (yield 44%).

Example A4

Preparation of intermediate 16

Intermediate 12(8g, 22.063mmol) was stirred in DCM (q.s.). Adding MnO in portions₂(20g) The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was then filtered through celite and the filtrate was concentrated by evaporation. The residue was subjected to RP preparative HPLC (ShandonHyperprep)C18BDS 8 μm, 250g, I.D.5 cm; mobile phase: 0.25% NH₄HCO₃/H₂O，MeOH+CH₃CN) purification. The desired fractions were collected and the solvent was evaporated to yield 3g of intermediate 16 (yield 38%).

B. Preparation of the Compounds

Example B1

a) Preparation of Compound 1

Intermediate 5(5.7g, 12.12mmol) was stirred in DCM (1 l). Adding MnO₂(17g) The reaction mixture was stirred at room temperature for 6 h. The mixture was then filtered through celite and the filtrate was concentrated by evaporation. The residue was purified by column chromatography over silica gel (eluent: DCM/MeOH 98/2). The desired fractions were collected and the solvent was evaporated. Obtaining: 4.1g Compound 1 (yield 72%).

b) Preparation of Compound 2

At-10 ℃ under N₂Compound 1(4g, 8.54mmol) was stirred in DCM (250ml) under an atmosphere. Dropwise add 1M BBr₃Was added to the reaction solution (11ml), and the reaction mixture was stirred for 30 min. Then, an additional amount of 1M BBr is added₃Was added to the reaction solution (3ml), and the reaction mixture was stirred for 30 min. Adding saturated NaHCO₃Solution (100ml) and the mixture was stirred. The organic layer was separated and purified by silica gel column chromatography (eluent: DCM/MeOH from 100/0 to 90/10)And (4) transforming. The desired fractions were collected and the solvent was evaporated. Obtaining: 3.2g Compound 2.

c) Preparation of Compound 3

Compound 2(3.2g, 8.46mmol) and Et₃N (3g) was stirred in THF (400 ml). Methanesulfonyl chloride (1.453g, 12.69mmol) was added dropwise. The mixture was stirred at room temperature for 1 h. Then add an additional amount of Et₃N (1g) and methanesulfonyl chloride (1g), the mixture was stirred at room temperature for 1 h. Finally, add more Et₃N (1g) and methanesulfonyl chloride (1g), the mixture was stirred at room temperature for a further 1 h. DMSO (200ml) and NaCN (4g) were then added in N₂The reaction mixture was stirred at reflux temperature for 1 h. Then, THF was removed by evaporation at 70 ℃ and the mixture was concentrated by evaporation. The residue was stirred in EtOAc and taken up with H₂And O washing the mixture. The organic layer was dried (MgSO₄) Filtered and concentrated by evaporation. The residue is purified by column chromatography (eluent: DCM/MeOH 95/5). The desired fractions were collected and the solvent was evaporated to give 2.7g of crude product. The crude product was crystallized from diethyl ether and the product was filtered off. Obtaining: 2.0g of Compound 3.

d) Preparation of Compound 4

Compound 3(1.3g, 3.35mmol) and HCl 37% (200ml) were stirred at 70 ℃ for 3 h. The mixture was then concentrated by evaporation. The residue was stirred in DIPE and the precipitate was filtered off. The precipitate was stirred in MeOH (200ml) and HCl (5 ml). On a cooling bath, the reaction mixture was neutralized with DIPEA (q.s.). The mixture was then concentrated by evaporation and the residue was dissolved in DCM. Subjecting the solution to H₂O (q.s.) and dried (MgSO)₄) Filtered and concentrated by evaporation. The residue was purified by column chromatography over silica gel (eluent: DCM/MeOH 95/5). The desired fractions were collected and the solvent was evaporated. Obtaining: 1g of Compound 4 (yield 71%).

e) Preparation of Compound 5

Compound 4(0.2g, 0.476mmol) was stirred in cyclopropylmethylamine at room temperature for 6 h. The mixture was then concentrated by evaporation and the residue was dissolved in DCM. Subjecting the organic solution to H₂O washing and drying (MgSO)₄) Filtered and concentrated by evaporation. The residue was subjected to RP HPLC (RP ShandonHyperprep C18BDS-8 μm, 250g, I.D.5 cm; mobile phase: 0.25% NH)₄HCO₃H of (A) to (B)₂O solution; MeOH + CH₃CN) purification. The desired fractions were collected and worked up. Obtaining: 0.109g of Compound 5 (yield 50%).

Example B2

a) Preparation of Compound 6

Intermediate 15(0.98g, 3.04mmol) was stirred in THF (20 ml). Add intermediate 4(1.163g, 4.56mmol), Pd₂(dba)₃(360mg), BINAP (480mg) and NaOtBu (960mg), the reaction mixture was stirred at 110 ℃ for 2h under microwave irradiation. Then, EtOAc (200ml) and brine (40ml) were added to the reaction mixture and the mixture was stirred. The organic layer was separated and dried (MgSO)₄) Filtered and concentrated by evaporation. The residue was chromatographed on a silica gel column (Wash)Liquid removal: DCM/MeOH 100/0-90/10). The desired fractions were collected and the solvent was evaporated. Obtaining: 2.2g of Compound 6 (quantitative yield).

b) Preparation of Compound 7

In N₂MeOH (150ml) was added to Pd/C10% (1g) under an atmosphere. Add Compound 6(2.2g, 4.43mmol) in H₂The mixture was stirred at 50 ℃ under an atmosphere until 1 equivalent of hydrogen was absorbed. The mixture was then filtered through celite. The product was purified by silica gel column chromatography (DCM/MeOH from 100/0 to 90/10). The desired fractions were collected and the solvent was evaporated. Obtaining: 105mg of Compound 7 (yield 6%).

c) Preparation of Compound 8

Compound 7(105mg, 0.26mmol) was dissolved in DMF (10 ml). The solution was cooled to 0 ℃ and PDC (1l6.64mg, 0.31mmol) and 98% H were added₂SO₄(0.05 ml). The reaction mixture was stirred at room temperature for 16 h. The mixture was then poured into H₂O, extracted with EtOAc. Drying (MgSO)₄) The separated organic layer was filtered and concentrated by evaporation. Obtaining: 129mg of Compound 8.

d) Preparation of Compound 9

Compound 8(230mg, 0.55mmol) was dissolved in DMF (10 ml). Adding hydrochloric acid IIMethylamine (178.46mg, 2.19mmol), HOBT (221.78mg, 1.64mmol), EDCI (254.80mg, 1.64mmol) and DIPEA (282.85mg, 2.19mmol) were added to the solution. The reaction mixture was stirred at room temperature overnight and then poured into H₂In O, extract with DCM (2 × 20 ml). The combined organic layers were washed with brine and dried (MgSO)₄) Filtered and the solvent evaporated. The residue was subjected to RP HPLC (RP Shandon Hyperprep C18BDS-8 μm, 250g, I.D.5 cm; mobile phase: 0.25% NH)₄HCO₃H of (A) to (B)₂O solution; MeOH + CH₃CN) purification. The desired fractions were collected and worked up. Obtaining: 31.8mg of Compound 9 (yield 13%).

Example B3

Preparation of Compound 10

A mixture of intermediate 14(410mg, 0.867mmol) and 1M TBAF solution in THF was stirred at room temperature for 2 h. Adding saturated NH₄Cl solution and the mixture was extracted with EtOAc. The separated organic layer was dried (MgSO)₄) Filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: DCM/MeOH 96/4). The desired fractions were collected and the solvent was evaporated. The residue was dissolved in 1N HCl solution and the solution was washed with DCM. The aqueous layer was basified and extracted with DCM. The organic layer was dried (extreme)) Filtered and the solvent evaporated. Obtaining: 116mg of Compound 10 (yield 37%).

Example B4

a) Compound 11 preparation of

A mixture of compound 32 (prepared by an analogous protocol to that described in example B2. b) (80mg, 0.213mmol) was dissolved in DMF (10 ml). The solution was cooled to 0 ℃ and PDC (95.956mg, 0.255mmol) and 98% H were added₂SO₄(0.05 ml). The reaction mixture was stirred at room temperature for 2h (LCMS showed formation of crude compound 12). The mixture was evaporated and the residue was purified by column chromatography over silica gel (eluent: DCM/MeOH 98/2-85/15). The desired fractions were collected and the solvent was evaporated. The product was converted to the methyl ester. Obtaining: 119mg of Compound 11.

b) Preparation of Compound 12

A mixture of Compound 11(119mg, 0.294mmol) was dissolved in MeOH (10ml) and H was added₂O (10ml), LiOH (30mg, 0.214mmol) were added to the solution and the reaction mixture was stirred at room temperature for 1 h. The mixture was worked up to give 159mg of compound 12.

Example B5

Preparation of Compound 13

Under microwave irradiation, intermediate 16(320mg, 0.887mmol), 1-bromo-2, 3, 4-trifluorobenzene (280.86mg, 1.331mmol), Pd₂(dba)₃A mixture of (90mg), BINAP (120mg) and NaOtBu (257mg) in THF (15ml) was stirred at 110 ℃ for 1 h. The mixture was then poured into saturated NH₄To the Cl solution, EtOAc was added and the reaction mixture was stirred at room temperature. The organic layer was separated and dried (MgSO)₄) Filtered and concentrated by evaporation. The residue was dissolved in THF (50ml), and a 1M solution of TBAF in THF (10ml) was added. The reaction mixture was stirred at room temperature for 2 h. Then, saturated NH was added₄Cl solution (75 ml). The mixture was stirred and extracted with EtOAc. The separated organic layer was dried (MgSO)₄) Filtered and concentrated by evaporation. The residue was dissolved in EtOAc and the solution was taken up in H₂O washes (3X), dried (MgSO)₄) Then evaporating and concentrating. The residue was subjected to RP preparative HPLC (RP Vydac DenaliC18-10 μm, 250g, I.D.5 cm; mobile phase: 0.25% NH)₄HCO₃H of (A) to (B)₂O solution; MeOH + CH₃CN) purification. The desired fractions were collected and worked up. Obtaining: 102mg of Compound 13 (yield 31%; R enantiomer).

Compounds 1-124 in tables 1a, 1b, 1c, 1d, 1e and 1f list compounds prepared by analogy to one of the above examples. If no salt form is specified, the compound is obtained in the form of the free base. 'Pr.' refers to the example number according to the division in which the compound was synthesized. No.' represents compound number.

To obtain the HCl salt form, several methods known to those skilled in the art are used.

TABLE 1a

TABLE 1b

TABLE 1c

TABLE 1d

TABLE 1e

TABLE 1f

Analysis section

LCMS(liquid chromatography/Mass Spectrometry)

General procedure A

LC measurements were performed using an Acquity UPLC (Ultra Performance Liquid Chromatography) (Waters) system including a binary pump, sample aligner (samplerganizer), column heater (temperature set at 55 ℃), Diode Array Detector (DAD) and columns described below in relation to the methods. The liquid flowing from the column was split to a MS spectrophotometer. The MS detector was configured with an electrospray ionization source. A sampling time of 0.02 seconds was used by scanning from 100 to 1000 in 0.18 seconds to acquire a mass spectrum. The capillary tip voltage was 3.5kV and the source temperature was maintained at 140 ℃. N is a radical of₂Used as a nebulizer gas. Data were collected using a Waters-MicromassMassLynx-Openlynx data System.

General procedure B

HPLC measurements were carried out with the Alliance HT 2790(Waters) system, whereuponThe system contains a four-way pump with degasser, autosampler, column oven (set at 45 ℃ C. unless otherwise noted), DAD and columns described in the related methods below. The liquid flowing out of the column was split to an MS spectrometer. The MS detector was configured with an electrospray ionization source. A sampling time of 0.1 seconds was used by scanning from 100 to 1000 in 1 second to acquire mass spectra. The capillary tip voltage was 3kV and the source temperature was maintained at 140 ℃. N is a radical of₂Used as a nebulizer gas. Data were collected using a Waters-MicromassMassLynx-Openlynx data System.

LCMS method 1

In addition to general procedure a; reverse phase UPLC was performed on a bridged ethylsiloxane/hybrid silicon (BEH) C18 column (1.7 μm, 2.1X 50 mm; Waters Acquity) at a flow rate of 0.8 ml/min. With 2 mobile phases (25mM NH)₄OAc at H₂O/CH₃In CN 95/5; mobile phase B: CH (CH)₃CN) gradient conditions were run from 95% a and 5% B to 5% a and 95% B over 1.3 minutes (min), held for 0.3 min. A sample volume of 0.5. mu.l was used. For positive ionization mode, the cone voltage is 10V; for negative ionization mode, the cone voltage is 20V.

LCMS method 2

In addition to general procedure a; reverse phase UPLC was performed on a BEH C18 column (1.7 μm, 2.1X 50 mm; WatersACQUITY) at a flow rate of 0.8 ml/min. With 2 mobile phases (mobile phase A: 0.1% formic acid in H)₂O/MeOH 95/5; mobile phase B: MeOH) gradient conditions were run from 95% a and 5% B to 5% a and 95% B over 1.3min, held for 0.2 min. A sample volume of 0.5. mu.l was used. For positive ionization mode, the cone voltage is 10V; for negative ionization mode, the cone voltage is 20V.

LCMS method 3

Except for general procedure B; reverse phase HPLC was performed on an Atlantis C18 column (3.5 μm, 4.6X 100mm) at a flow rate of 1.6 ml/min. With 2 mobile phases (mobile phase A: 70% MeOH + 30% H)₂O; mobile phase B: 0.1% formic acid in H₂O/MeOH 95/5) run a gradient from 100% B to 5% B + 95% A over 9min, maintaining thisThese conditions were 3 min. A sample volume of 10. mu.l was used. For positive ionization mode, the cone voltage is 10V; for negative ionization mode, the cone voltage is 20V.

LCMS method 4

Except for general procedure B; the column heater was set at 60 ℃. Reverse phase HPLC was performed on a Xterra MS C18 column (3.5 μm, 4.6X 100mm) with a flow rate of 1.6 ml/min. Using these mobile phases (mobile phase A: 95% 25mM NH)₄OAc+5％CH₃CN; mobile phase B: CH (CH)₃CN; mobile phase C: MeOH) gradient conditions were run from 100% a to 50% B and 50% C over 6.5min, then from 0.5min to 100% B, these conditions were held for 1min, and re-equilibrated with 100% a for 1.5 min. A sample volume of 10. mu.l was used. For positive ionization mode, the cone voltage is 10V; for negative ionization mode, the cone voltage is 20V.

LCMS method 5

Except for general procedure B; the column heater was set at 40 ℃. Reverse phase HPLC was performed on a Xterra MS C18 column (3.5 μm, 4.6X 100mm) with a flow rate of 1.6 ml/min. With 3 mobile phases (mobile phase A: 95% 25mM NH)₄OAc+5％CH₃CN; mobile phase B: CH (CH)₃CN; mobile phase C: MeOH) gradient conditions were run from 100% a to 1% a, 49% B and 50% C over 6.5min, then 1min to 1% a and 99% B, these conditions were held for 1min, and re-equilibrated with 100% a for 1.5 min. A sample volume of 10. mu.l was used. For positive ionization mode, the cone voltage is 10V; for negative ionization mode, the cone voltage is 20V.

Melting Point

For some compounds, melting points (m.p.) were determined using DSC823e (Mettler-Toledo). The melting point is determined with a temperature gradient of 30 ℃/min. The maximum temperature was 400 ℃. The value is the peak value.

The analytical measurement results are shown in table 2.

TABLE 2: retention time (R)_t) In terms of min, [ M + H]⁺Peak (protonated molecule), LCMS method and m.p. (melting point in ° c.) (n.d. indicates no detectable change)Detection)

Optical activity

Optical rotation was measured with a Perkin Elmer 341 polarimeter. [ alpha ] to]_D ²⁰Represents the optical rotation measured at a temperature of 20 ℃ with light at the D-line wavelength (589nm) of sodium. The path length of the cuvette was 1 dm. After the actual values, the solution concentration and the solvent used for measuring the optical rotation are shown. The results are shown in Table 3.

TABLE 3

Comp.No.	[α]_D ²⁰	Concentration of	Solvent(s)
				19	-11.23°	0.2938w/v％	MeOH
59	-9.69°	0.3510w/v％	MeOH
				13	-8.09°	0.3338w/v％	MeOH
36	-7.88°	0.3682w/v％	MeOH
				62	-8.73°	0.4468w/v％	MeOH
60	-10.64°	0.4134w/v％	MeOH

NMR

For some compounds, recordings were made on a Bruker DPX-360 or Bruker DPX-400 spectrophotometer¹H NMR spectra, using standard pulse sequences, operating at 360MHz and 400MHz respectively, using DMSO-d₆(deuterated DMSO, dimethyl)The radical-d 6 sulfoxide) as solvent. Chemical shifts (δ) are reported in parts per million (ppm) relative to Tetramethylsilane (TMS), which is used as an internal standard.

Compound 1:¹H NMR(360MHz)δppm 2.50(s，3H)3.83(s，3H)4.62(s，2H)4.72(s，2H)6.29(s，1H)6.67(t，J＝1.8Hz，1H)7.28-7.40(m，5H)7.42(t，J＝1.8Hz，1H)7.44-7.49(m，2H)7.54(d，J＝1.8Hz，1H)8.49(d，J＝5.9Hz，1H)9.38(s，1H).

compound 3:¹H NMR(360MHz)δppm 2.54(s，3H)3.83(s，3H)4.54(s，2H)6.23(s，1H)6.68(s，1H)7.39(s，1H)7.42(dd，J＝5.5，2.2Hz，1H)7.46(t，J＝2.2Hz，1H)7.48(d，J＝1.8Hz，1H)8.55(d，J＝5.5Hz，1H)9.39(s，1H).

compound 5:¹H NMR(360MHz)δppm 0.09-0.17(m，2H)0.36-0.43(m，2H)0.75-0.96(m，1H)2.51(s，3H)2.94(t，J＝6.2Hz，2H)3.79(s，2H)3.82(s，3H)6.11(s，1H)6.65(t，J＝1.8Hz，1H)7.39(s，1H)7.43(dd，J＝5.5，2.2Hz，1H)7.45-7.48(m，2H)8.28(t，J＝5.7Hz，1H)8.49(d，J＝5.9Hz，1H)9.28(s，1H).

compound 7:¹H NMR(400MHz)δppm 1.73-1.82(m，2H)2.52(s，3H)2.89(t，J＝7.7Hz，2H)3.47(t，J＝6.2Hz，2H)3.82(s，3H)5.99(s，1H)6.63(t，J＝1.8Hz，1H)7.36-7.42(m，2H)7.43-7.49(m，2H)8.49(d，J＝5.9Hz，1H)9.21(s，1H).

compound 9:¹H NMR(360MHz)δppm 2.53(s，3H)2.73(t，J＝7.1Hz，2H)2.82(s，3H)2.99(s，3H)3.05(t，J＝7.1Hz，2H)3.81(s，3H)6.00(s，1H)6.64(t，J＝1.8Hz，1H)7.37(t，J＝1.8Hz，1H)7.42(dd，J＝5.5，2.2Hz，1H)7.45(t，J＝1.8Hz，1H)7.49(d，J＝2.2Hz，1H)8.52(d，J＝5.5Hz，1H)9.24(s，1H).

compound 10:¹H NMR(400MHz)δppm 0.86(t，J＝7.5Hz，3H)1.27-1.52(m，2H)2.53(s，3H)2.75-2.98(m，2H)3.57-3.71(m，1H)4.78(d，J＝5.5Hz，1H)6.04(s，1H)7.09-7.20(m，1H)7.21-7.35(m，1H)7.43(dd，J＝5.5，1.8Hz，1H)7.48(d，J＝1.8Hz，1H)7.61(ddd，J＝13.9，7.1，2.7Hz，1H)8.50(d，J＝5.5Hz，1H)9.01(s，1H).

compound 13:¹H NMR(360MHz)δppm 0.86(t，J＝7.3Hz，3H)1.27-1.52(m，2H)2.53(s，3H)2.73-2.97(m，2H)3.53-3.68(m，1H)4.81(d，J＝5.9Hz，1H)6.18(s，1H)7.12-7.30(m，1H)7.44(dd，J＝5.7，1.6Hz，1H)7.49(d，J＝1.6Hz，1H)7.97-8.15(m，1H)8.49(d，J＝5.5Hz，1H)8.81(s，1H).

D. pharmacological examples

Example d.1: ca ²⁺ Flux imaging (FDSS)

Material

a) Assay buffer

Supplemented with 10mM HEPES (Invitrogen, Belgium) to a final concentration of 5mM CaCl₂0.1% bovine serum albumin (Sigma-Aldrich NV, Belgium) in Hanks buffered saline (HBSS, Invitrogen, Belgium).

b) Calcium sensitive dye-Fluo-4 AM

Fluo-4AM (Molecular Probes, USA) was dissolved in DMSO (Molecular Probes, USA) containing 10% Pluronic acid (Pluronic acid) to give a stock solution, which was diluted with assay buffer supplemented with 5mM probenecid (Sigma, Aldrich NV, Belgium) to give a final concentration of 2. mu.M.

c)384 orifice plate

Black 384 well plates, black/transparent plates, precoated PDL (Corning, Incorporated, USA)

d) Calcium flux measurement

Intracellular calcium-free flux signals were measured with a functional drug screening system (FDSS, Hamamatsu).

Method of producing a composite material

Monolayers of h α 7-wt nAChR-expressing cells are grown in multi-well plates, particularly poly-D-lysine coated black-sided, clear-bottomed 384-well plates for 24 hours, then loaded with a fluorescent calcium indicator, in one particular embodiment, fluo-4AM, for up to 120 minutes.

PAM activity was detected in real time during continuous monitoring of cellular fluorescence with FDSS by loading the test compound onto the cells along with an α 7 nicotinic receptor agonist. Compounds that give a peak fluorescence response greater than that produced by agonist alone are considered to be α 7nAChR PAMs. In a particular embodiment, the alpha 7 nicotinic receptor agonist is choline, and in a more particular embodiment, choline is administered at a sub-maximal concentration of 100 μ M. In yet another context of the invention, the test compound is administered prior to the α 7 nicotinic receptor agonist, and in a particular embodiment, up to 10 minutes prior to administration of the agonist.

Control responses to choline were calculated as the difference in peak fluorescence of wells containing either choline or assay buffer alone in each plate. The compounds of the invention were tested at concentrations ranging from 0.01. mu.M to 30. mu.M. Compounds are considered to have meaningful activity when they enhance choline signal by at least 200% at a concentration of 30 μ M (potency of 100 μ M choline is defined as 100% in the absence of PAM). When a well-defined sigmoidal curve with a top plateau (top plateau) is obtained, the EC is measured as the concentration relative to half the maximal effect₅₀(or pEC)₅₀). EC if the activity of the compound does not reach the upper plateau at the maximum concentration₅₀(or pEC)₅₀) Defined as less than the maximum concentration (shown as "< 5" in table 4).

The compounds also have an enhancing effect on the choline response in GH4C1 cells stably overexpressing the human wild-type α 7 receptor, as measured by whole cell patch clamp electrophysiology.

Example d.2: patch clamp current recording

Patch-clamp recordings of mammalian cells provide a powerful method for evaluating the function of membrane-bound proteins, which are thought to be subunits of ligand-gated ion channels. Activation of such proteins by endogenous or exogenous ligands causes the receptor-associated pores to open, through which ions flow down their electrochemical gradient. In the case of the GH4C1 recombinant cell line expressing the h α 7-wt nAChR, the preferential permeability of the receptor to calcium indicates calcium influx into the cell when activated by ACh, choline and other nicotinic ligands that cause calcium flux. Because the receptor is rapidly desensitized in the presence of agonist, it is important to use an administration system that can switch solutions very rapidly (< 100ms) to prevent partial or full desensitization of the receptor response from occurring simultaneously with agonist administration. Thus, a second convenient technique to assess the enhancement of nicotine potency is patch-clamp recording of h α 7-wt nAChR expressing GH4C1 cells in combination with a rapid administration system.

Material

a) Assay buffer

The external recording solution was prepared from 152mM NaCl, 5mM KCl, 1mM MgCl₂1mM calcium, 10mM HEPES; pH 7.3. The internal recording solution was prepared from 140mM CsCl, 10mM HEPES, 10mM EGTA, 1mM MgCl₂pH 7.3.

b) Patch-clamp recordings were performed using a patch-clamp amplifier (multiclad 700A, Axon Instruments, CA, USA). GH4C1 cells expressing h.alpha.7-wt nAChR were patch-clamped in a whole-cell configuration (Hamill et al, 1981) and the borosilicate glass electrodes had a tip resistance of 1.5-3 M.omega when filled with the internal recording solution. Cells with membrane resistance > 500 M.OMEGA.and more preferably 1 G.OMEGA.and series resistance < 15 M.OMEGA.with at least 60% series electrical compensation were recorded. The membrane potential was locked at-70 mV (clamped).

c) Agonists

ACh, choline were purchased from Sigma-Aldrich NV, Belgium.

d) Compound application

A 16-channel dynaflowdf-16 microfluidics system (Cellectricon, Sweden) for fast switching solutions (switching resolution time < 100ms) was used to apply control, agonist and PAM compounds to GH4C1 cells expressing h α 7-wt nachrs.

Method of producing a composite material

GH4C1 cells expressing h.alpha.7-wt nAChR were seeded in Dynaflow perfusion chambers containing external recording solution and allowed to sink for up to 20 minutes. The cells formed a whole cell patch which was gently lifted off the bottom of the chamber with a patch pipette and placed in a perfusate stream of continuously flowing external recording fluid (12. mu.l/min). PAM activity was recorded in real time during continuous monitoring of cell membrane currents by pre-administration of test compounds to the loaded cells followed by administration of an alpha 7 nicotinic receptor agonist. Compounds that give a current response greater than that of agonist alone are considered to be α 7nAChR PAMs. In a particular embodiment, the alpha 7 nicotinic receptor agonist is activated by a non-selective nicotinic agonist, in a more particular embodiment the agonist is choline, and in an even more particular embodiment choline is administered at a sub-maximal concentration of 1 mM. In yet another context of the present invention, the test compound is administered prior to the alpha 7 nicotinic receptor agonist, in a more particular embodiment up to 30 seconds prior to the agonist, even more particularly 5 seconds prior to the agonist. Control responses were calculated from the area under the curve of the current drawn by each cell 250ms after administration of sub-maximal choline. The area under the curve is the integral of the net current over time and is a common representation of the total ion flux through the channel. The increase in agonist potency that would be caused by a positive allosteric modulator was calculated as the percent enhancement in the "area under the curve" (AUC) of the agonist response. The enhancement of AUC by the compounds of the invention above the control indicates that they are expected to have effective therapeutic activity. EC was estimated with GraphPad Prism (GraphPad Software, Inc., San Diego, Calif.) by fitting the data to a logistic equation₅₀Value (potency), maximum effect (% potency) and Hill slope.

Table 4:potency (pEC) of various Compounds₅₀) And efficacy%

pEC₅₀And% potency values are from Ca as described in D.1²⁺Those values obtained in the assay. PAM type was obtained from patch clamp current recordings as described earlier).

Composition examples

The "active ingredient" (a.i.) as used in all of these examples relates to a compound of formula (I), including any stereochemically isomeric form thereof, a pharmaceutically acceptable salt thereof or a solvate thereof, particularly any one of the exemplified compounds.

Examples of typical formulations for use in the formulations of the present invention are as follows:

1. tablet formulation

2. Suspension

An aqueous suspension for oral administration is prepared so that 1 to 5mg of active ingredient, 50mg of sodium carboxymethylcellulose, 1mg of sodium benzoate, 500mg of sorbitol and water are added to 1ml per ml.

3. Injection solution

Parenteral compositions are prepared by stirring 1.5% (weight/volume) of the active ingredient in 0.9% NaCl solution or 10% by volume of propylene glycol in water.

4. Ointment formulation

In this example, the active ingredient may be replaced by the same amount of any of the compounds of the invention, in particular by the same amount of any of the exemplified compounds.

Reasonable variations are not to be regarded as a departure from the scope of the invention. It will be obvious to those skilled in the art that the invention thus described may be varied in many ways.

Claims

1. A compound according to formula (I)

Or a stereochemically isomeric form thereof, wherein

R¹And R²Each independently represents hydrogen or C_1-4An alkyl group;

R³is optionally substituted by one or more substituentsC_1-6Alkyl, the substituents are independently selected from hydroxyl, cyano, C_1-6Alkoxy, benzyloxy, R^xR^yN-C (= O) -and R^zO-C(=O)-；

R^zrepresents hydrogen or C_1-3An alkyl group;

R⁴And R⁵When bound to 2 adjacent carbon atoms, together form a compound of the formula-O-CF₂-a divalent radical of O-; or

A pharmaceutically acceptable addition salt thereof.

2. The compound according to claim 1 or a stereoisomeric form thereof, wherein

R¹And R²Each independently represents hydrogen or methyl;

R³is C optionally substituted by one or more substituents_1-4Alkyl, said substituents being independently selected from hydroxy, cyano, methoxy, benzyloxy, R^xR^yN-C (= O) -and R^zO-C(=O)-；

R^zrepresents hydrogen or C_1-3An alkyl group;

R⁴、R⁵and R⁶Each independently represents hydrogen, halo, cyano, trifluoromethyl, trifluoromethoxy or methoxy; or

A pharmaceutically acceptable addition salt thereof.

3. The compound according to claim 1, wherein

R⁴、R⁵And R⁶Each independently represents halogeno, C_1-6Alkyl, cyano, trifluoromethyl, trifluoromethoxy, or methoxy; or

R⁴And R⁵When bound to 2 adjacent carbon atoms, together form a compound of the formula-O-CF₂A divalent group of-O-.

4. The compound according to claim 1 or a stereoisomeric form thereof, wherein

R¹And R²Each independently represents hydrogen or methyl;

R³is methyl; a hydroxymethyl group; hydroxypropyl groups; (2R) -2-hydroxybutyl; (2S) -2-hydroxybutyl; a methoxymethyl group; a cyanomethyl group; a carboxymethyl group; a carboxyethyl group; 2-methoxy-2-oxoethyl; 3-methoxy-3-oxopropyl; 2-methylamino-2-oxoethyl; 2-ethylamino-2-oxoethyl; 2- [ (cyclopropylmethyl) amino group]-2-oxoethyl; 2- (cyclopropylamino) -2-oxoethyl; 2- (cyclobutylamino) -2-oxoethyl; 3- (dimethylamino) -3-oxopropyl; a benzyloxymethyl group; benzyloxypropyl or 2- [ (1-methylethyl) amino group]-2-oxoethyl;

R⁴、R⁵and R⁶Each independently represents hydrogen, chloro, fluoro, bromo, cyano, trifluoromethyl, trifluoromethoxy or methoxy; or

A pharmaceutically acceptable addition salt thereof.

5. A compound according to claim 1, or a stereoisomeric form thereof, wherein R⁴、R⁵Or R⁶At least one of which is not hydrogen.

6. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound as defined in any one of claims 1 to 5.

7. A process for the preparation of a composition as claimed in claim 6, characterized in that a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of a compound as defined in any one of claims 1 to 5.

8. A product comprising

(a) A compound of formula (I) as defined in claim 1, and

(b) an alpha 7 nicotinic receptor agonist selected from

1, 4-diazabicyclo [3.2.2] nonane-4-carboxylic acid, 4-bromophenyl ester, monohydrochloride;

(-) -spiro [ 1-azabicyclo [2.2.2] s]Octane-3, 5-Oxazolidines]-a 2' -ketone;

(+) -N- (1-azabicyclo [2.2.2] oct-3-yl) benzo [ b ] furan-2-carboxamide;

3- [ (2, 4-dimethoxy) benzylidene ] -anabasine dihydrochloride;

[ N- [ (3R) -1-azabicyclo [2.2.2] oct-3-yl ] -4-chlorobenzamide hydrochloride ] PNU-282987; nicotine; (ii) Vancklan; a-582941; AR-R17779; TC-1698; PHA-709829; tropisetron; WAY-317538; TC-5619; and AZD-0328 as a combined preparation for simultaneous, separate or sequential use in the prevention or treatment of a psychotic disorder, a intellectual impairment disorder or an inflammatory disease.

9. The use of a compound as defined in any one of claims 1 to 5 in the manufacture of a medicament for the treatment or prophylaxis of psychotic disorders, intellectual impairment disorders or inflammatory diseases.

10. The use according to claim 9, wherein the medicament is for the treatment or prevention of alzheimer's disease or dementia.

11. Use of a pharmaceutical composition comprising a compound as defined in any one of claims 1 to 5 and a pharmaceutically acceptable carrier for the manufacture of a medicament for the treatment of a psychotic disorder, intellectual impairment disorder or inflammatory disease in a patient.