ES2361201T3 - DERIVATIVES OF AZABICICLO [3.1.0] HEXANO AS MODULATORS OF D3 DOPAMINE RECEPTORS. - Google Patents

Abstract

Compound of formula (I) 'or a salt thereof: ** (See formula) ** in which- G is selected from a group consisting of: phenyl or a 5- or 6-membered monocyclic heteroaryl group or a heteroaryl group bicyclic of 8 to 11 members; - p is an integer that varies from 0 to 5; - R1 is halogen, hydroxy, cyano, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 alkanoyl and SF5; or corresponds to a group R8; and when p is an integer that varies from 2 to 5, each R1 can be the same or different; - R2 is hydrogen or C1-4 alkyl; - n is 3, 4, 5 or 6; - R3 is selected from the group consisting of: hydrogen, halogen, hydroxy, cyano, C1-4 alkyl, C3-7 cycloalkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 alkanoyl and NR ' R ''; or R3 is a phenyl group, a 5-14 membered heterocyclic group; and any of said phenyl or heterocyclic groups is optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of: halogen, cyano, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 alkanoyl and SF5; - R4 is selected from the group consisting of: hydrogen, halogen, hydroxy, cyano, C1-4 alkyl, C3-7 cycloalkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 alkanoyl and NR ' R ''; or R3 is a phenyl group, a 5-14 membered heterocyclic group; and any of said phenyl or heterocyclic groups is optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of: halogen, cyano, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 alkanoyl and SF5; - R5 is selected from the group consisting of: hydrogen, halogen, hydroxy, cyano, C1-4 alkyl, C3-7 cycloalkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 alkanoyl and NR ' R ''; or R3 is a phenyl group, a 5-14 membered heterocyclic group; and any of said phenyl or heterocyclic groups is optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of: halogen, cyano, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 alkanoyl and SF5; - R6 is selected from the group consisting of: hydrogen, halogen, hydroxy, cyano, C1-4 alkyl, C3-7 cycloalkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 alkanoyl and NR ' R ''; or R3 is a phenyl group, a 5-14 membered heterocyclic group; and any of said phenyl or heterocyclic groups is optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of: halogen, cyano, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 alkanoyl and SF5; - R7 is hydrogen or C1-2 alkyl; - R8 is a moiety selected from the group consisting of: isoxazolyl, -CH2-N-pyrrolyl, 1,1-dioxide-2-isothiazolidinyl, thienyl, thiazolyl, pyridyl, 2-pyrrolidinonyl, and said group R8 is optionally substituted with one or two substituents selected from: halogen, cyano, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 alkanoyl; - R 'is H, C1-4 alkyl or C1-4 alkanoyl; - R '' is defined as R '; - R 'and R' 'taken together with the interconnecting nitrogen atom can form a saturated, unsaturated, 5-6 membered heterocyclic ring; wherein at least one of R3, R4, R6 and R5 is hydrogen; and in which only one R2 group may be different from hydrogen.

Description

Derivatives azabicyclo [3.1.0] hexane as modulators of D3 dopamine receptors.

The present invention relates to new compounds, to the processes for their preparation, to the intermediates used in these processes, to the pharmaceutical compositions that contain and for use in therapy, as receptor modulators D_ {3} of dopamine.

Recently, a request for patent as document WO2005 / 080382 and describes the compounds of the following formula or salts thereof:

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one

in the that

?

G is selected from a group that it consists of: phenyl, pyridyl, benzothiazolyl, indazolyl;

?

p is an integer that varies from 0 to 5;

?

R_ {1} is selected independently of a group consisting of: halogen, hydroxy, cyano, C 1-4 alkyl, haloalkyl C 1-4, C 1-4 alkoxy, C 1-4 haloalkoxy, alkanoyl C 1-4; or corresponds to a group R5;

?

R2 is hydrogen or alkyl C 1-4;

?

R 3 is alkyl C 1-4;

?

R 4 is hydrogen, or a group phenyl, a heterocyclyl group, a heteroaromatic group of 5 or 6 members, or a bicyclic group of 8 to 11 members, being any of the groups optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of: halogen, cyano, C 1-4 alkyl, haloalkyl C 1-4, C 1-4 alkoxy, C 1-4 alkanoyl;

?

R_ {5} is a selected remainder from the group consisting of: isoxazolyl, -CH2 -N-pyrrolyl, 1,1-dioxide-2-isothiazolidinyl, thienyl, thiazolyl, pyridyl, 2-pyrrolidinonyl, and said group is optionally substituted with one or two substituents selected from: halogen, cyano, alkyl C 1-4, C 1-4 haloalkyl, C 1-4 alkoxy, alkanoyl C 1-4;

and when R_ {1} is chlorine and p is 1, said R_ {1} is not present in the ortho position with respect to the link of union with the rest of the molecule; and when R_ {1} corresponds to R 5, p is 1.

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A new class of compounds has been discovered that have affinity for dopamine receptors, in particular the dopamine receptor D3. These compounds have potential in the treatment of conditions in which modulation of the D3 receptor is beneficial, especially the antagonism / inhibition, e.g. ex. to treat dependence on drugs or as antipsychotic agents.

The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:

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2

in the that

?

G is selected from a group that consists of: phenyl, a monocyclic heteroaryl group of 5 or 6 members or a bicyclic heteroaryl group from 8 to 11 members;

?

p is an integer that varies from 0 to 5;

?

R1 is halogen, hydroxy, cyano, C 1-4 alkyl, haloalkyl C 1-4, C 1-4 alkoxy, C 1-4 haloalkoxy, alkanoyl C 1-4 and SF 5; or corresponds to a group R 8; and when p is an integer that varies from 2 to 5, each R1 may be the same or different;

?

R2 is hydrogen or alkyl C 1-4;

?

n is 3, 4, 5 or 6;

?

R_ {3} is selected from the group consisting of: hydrogen, halogen, hydroxy, cyano, alkyl C 1-4, C 3-7 cycloalkyl, C 1-4 haloalkyl, alkoxy C 1-4, C 1-4 haloalkoxy, C 1-4 alkanoyl and NR'R ''; or R_ {3} is a group phenyl, a 5-14 membered heterocyclic group; Y any of said phenyl or heterocyclic groups is substituted optionally with 1, 2, 3 or 4 substituents selected from the group consisting of: halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, alkoxy C 1-4, C 1-4 alkanoyl and SF5;

?

R_ {4} is selected from the group consisting of: hydrogen, halogen, hydroxy, cyano, alkyl C 1-4, C 3-7 cycloalkyl, C 1-4 haloalkyl, alkoxy C 1-4, C 1-4 haloalkoxy, C 1-4 alkanoyl and NR'R ''; or R_ {3} is a group phenyl, a 5-14 membered heterocyclic group; Y any of said phenyl or heterocyclic groups is substituted optionally with 1, 2, 3 or 4 substituents selected from the group consisting of: halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, alkoxy C 1-4, C 1-4 alkanoyl and SF5;

?

R_ {5} is selected from the group consisting of: hydrogen, halogen, hydroxy, cyano, alkyl C 1-4, C 3-7 cycloalkyl, C 1-4 haloalkyl, alkoxy C 1-4, C 1-4 haloalkoxy, C 1-4 alkanoyl and NR'R ''; or R_ {3} is a group phenyl, a 5-14 membered heterocyclic group; Y any of said phenyl or heterocyclic groups is substituted optionally with 1, 2, 3 or 4 substituents selected from the group consisting of: halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, alkoxy C 1-4, C 1-4 alkanoyl and SF5;

?

R_ {6} is selected from the group consisting of: hydrogen, halogen, hydroxy, cyano, alkyl C 1-4, C 3-7 cycloalkyl, C 1-4 haloalkyl, alkoxy C 1-4, C 1-4 haloalkoxy, C 1-4 alkanoyl and NR'R ''; or R_ {3} is a group phenyl, a 5-14 membered heterocyclic group; Y any of said phenyl or heterocyclic groups is substituted optionally with 1, 2, 3 or 4 substituents selected from the group consisting of: halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, alkoxy C 1-4, C 1-4 alkanoyl and SF5;

?

R 7 is hydrogen or alkyl C 1-2;

?

R_ {8} is a selected remainder from the group consisting of: isoxazolyl, -CH2 -N-pyrrolyl, 1,1-dioxide-2-isothiazolidinyl, thienyl, thiazolyl, pyridyl, 2-pyrrolidinonyl, and said group R 8 is optionally substituted with one or two substituents selected from: halogen, cyano, alkyl C 1-4, C 1-4 haloalkyl, C 1-4 alkoxy, alkanoyl C 1-4;

?

R 'is H, alkyl C 1-4 or alkanoyl C 1-4;

?

R '' is defined as R ';

?

R 'and R' 'taken together with the interconnecting nitrogen atom can form a ring heterocyclic, saturated or unsaturated, 5 or 6 members;

in which at least one of R 3, R 4, R 6 and R 5 is hydrogen; and in which only one group R_ {2} It may be different from hydrogen.

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Due to the presence of cyclopropane condensed, it is believed that the compounds of formula (I) have a "cis" arrangement of the substituents (the two groups united to the bicyclic ring system are on the same side of this bicyclic ring system).

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In an embodiment of the present invention, provide compounds of formula (I) 'that correspond to the compounds of formula (I), or salts thereof, which have arrangement "cis", represented by highlighting the links in bold

3

in which G, p, n, R_ {1}, R 2, R 3, R 4, R 5, R 6 and R 7 are as defined above for compounds of formula (I), or a salt from East.

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It will be appreciated that the compounds of formula (I) ' they have at least two chiral centers, specifically in position 1 and 5 in the portion 3-azabicyclo [3.1.0] hexane molecule. Due to the fixed cis arrangement, the compounds may exist in two stereoisomers that are enantiomers with respect to the chiral centers of cyclopropane. It will also be appreciated that, as with most biologically active molecules, the level of biological activity may vary between stereoisomers individual of a given molecule. It is intended that the scope of the invention include all individual stereoisomers (diastereoisomers and enantiomers) and all mixtures thereof, which include, but are not limited to, racemic mixtures, which demonstrate appropriate biological activity with reference to procedures described herein.

In the compounds of formula (I) 'exist at minus two chiral centers, which are in the portion cyclopropane, as depicted below (highlighted in Bold links indicate the configuration "cis"); by half of the optical resolution of a mixture that contains the two stereoisomers that are enantiomers with respect to the centers cyclopropane chiral, stereoisomers can be obtained compounds of formula (I) 'as shown in following scheme:

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4

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The absolute configuration of the chiral center in the position called 1 and 5 can be assigned using the nomenclature of Cahn-Ingold-Prelog based on group priorities.

In an embodiment of the present invention, provide compounds of formula (IA) that correspond to the stereochemical isomers of the compounds of formula (I) ', enriched in the configuration shown in the following figure in the chiral centers of positions called 1 and 5:

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5

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in which G, p, n, R_ {1}, R 2, R 3, R 4, R 5, R 6 and R 7 are as defined above for compounds of formula (I), or a salt from East.

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It is intended in the context of this invention that the stereochemical isomers of formula (IA) enriched in a configuration in centers called 1 and 5, correspond in one embodiment with at least 90% e.e. (excess enantiomeric). In another embodiment, the isomers correspond to the less with 95% of e.e. In another embodiment, the isomers are correspond at least 99% of e.e.

In another embodiment of the present invention, provide compounds of formula (IH) that correspond to stereochemical isomers of the compounds of formula (I) ', configuration rich (1S, 5R) or (1R, 5R)

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6

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in which G, A, p, n, R_ {1}, R 2, R 3, R 4, R 5 and R 6 are as they have been defined above for compounds of formula (I) and R 7 is hydrogen, or a salt of East.

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A different nomenclature can be generated to the absolute configuration assigned to the chiral center called 1 [(1R) or (1S)] using the different meanings for the group G.

For example, when group G is a group phenyl, the nomenclature of the absolute configuration for Compounds of formula (IH) is (1S, 5R).

It is intended in the context of this invention that stereochemical isomers enriched in configuration (1S, 5R) or (1R, 5R) of formula (IH) correspond in an embodiment with at least 90% e.e. (enantiomeric excess). In another embodiment, the isomers correspond to at least 95% of e.e. In another embodiment, the isomers correspond at least with 99% of e.e.

In another embodiment of the present invention, provide configuration-enriched stereochemical isomers (1R, 5S).

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In another embodiment of the present invention, provide compounds of formula (IL) that correspond to stereochemical isomers of compounds of formula (I) ', enriched in the configuration shown in the following figure in the centers chiral positions called 1 and 5:

7

in which G, A, p, n, R_ {1}, R 2, R 3, R 4, R 5, R 6 and R 7 are as defined above for compounds of formula (I), or a salt from East.

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The term "alkyl C_ {1-4} ", as used herein memory, as a group or as part of the group, refers to a group linear or branched alkyl containing from 1 to 4 carbon atoms; Examples of such groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl.

The term "cycloalkyl group C_ {3-7} ", as used herein memory means a monocyclic hydrocarbon ring not aromatic of 3 to 7 carbon atoms such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; while unsaturated cycloalkyl include cyclopentenyl and cyclohexenyl, and the like.

The term "alkoxy group C_ {1} -_ {4} ", as used herein memory, it can be a straight or branched chain alkoxy group, for example methoxy, ethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy or methylprop-2-oxy and the like.

The term "alkanoyl group C_ {1-4} ", as used herein memory, it can be a straight or branched chain alkanoyl group, for example acetyl, ethylcarbonyl, n-propylcarbonyl, i-propylcarbonyl, n-butylcarbonyl or t-butylcarbonyl and the like.

The term "halogen", as used in This specification refers to a fluorine, chlorine, bromine or iodine.

The term "haloalkyl C_ {1-4} "as used herein memory means an alkyl group that has one or more atoms of carbon and in which at least one hydrogen atom is replaced by halogen, such as for example, a trifluoromethyl group and Similar.

The term "haloalkoxy group C_ {1-4} "as used herein memory may be a C 1-4 alkoxy group such and as defined above, substituted with at least one halogen, preferably fluorine, such as OCHF2 or OCF3. He term "aryl", as used herein, means an aromatic carbocyclic moiety, such as phenyl, biphenyl or naphthyl.

The term "monocyclic heteroaryl of 5.6 members ", as used herein, means a 5 or 6 membered monocyclic, aromatic heterocycle ring, which has at least one heteroatom selected from nitrogen, oxygen and sulfur, and containing at least 1 carbon atom.

The monocyclic heteroaryl groups of 5-6 representative members include (but are not limited to): furyl, thiophenyl, pyrrolyl, pyridyl, oxazolyl, isooxazolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, triazolyl and tetrazolyl

The term "bicyclic heteroaryl of 8.11 members ", as used herein, means a heterocyclyl, bicyclic, aromatic ring, 8 to 11 members, which has at least one heteroatom selected from nitrogen, oxygen and sulfur, and containing at least 1 carbon atom.

Bicyclic heteroaryl groups from 8 to 11 Representative members include (but are not limited to): benzofuranyl, benzothiophenyl, indolyl, isoindolyl, azaindolyl, quinolinyl, isoquinolinyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, quinazolinyl and phthalazinyl.

The term 5-14 heterocycle members means a heterocycle ring, monocyclic from 5 to 7 members or polycyclic from 7 to 14 members, which is saturated, unsaturated or aromatic, and containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and in which the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized, including bicyclic rings in which any of the above heterocycles is condensed to a benzene ring, as well as tricyclic heterocyclic rings (and superior). The heterocycle can be attached through any heteroatom or carbon atom. Heterocycles include the heteroaryls that have been defined above. In this way, In addition to the aromatic heteroaryls indicated above, heterocycles also include (but are not limited to) morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, hydantoinyl, valerolactamayl, oxyranyl, oxetanyl, tetrahydrofuranoyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl and Similar.

Any of these groups can be attached to the rest of the molecule in any suitable position.

As used herein, the term "salt" refers to any salt of a compound according to the present invention, prepared from an inorganic or organic acid or base, quaternary ammonium salts and internally formed salts. Physiologically acceptable salts are particularly suitable for medical applications due to their greater aqueous solubility with respect to the original compounds. Such salts must clearly have a physiologically acceptable anion or cation. Suitably, the physiologically acceptable salts of the compounds of the present invention include acid addition salts formed with inorganic acids, such as hydrochloric, hydrobromic, iohydric, phosphoric, metaphosphoric, nitric and sulfuric acids, and with organic acids, such as tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, formic, propionic, glycolic, gluconic, maleic, succinic, canforsulfuric, isotionic, mucic, gentisic, isonicotinic, saccharic, glucuronic, ascorbic, ascorbic acid , salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, stearic, sulfinyl, alginic, galacturonic and arylsulfonic, for example, benzenesulfonic acid and p-toluenesulfonic acid; base addition salts formed with alkali metals and alkaline earth metals and organic bases such as N, N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumaine (N-methylglucamine), lysine and procaine; and salts formed internally. Salts having an anion or cation that is not physiologically acceptable are within the scope of the invention as useful intermediates for the preparation of physiologically acceptable salts and / or for use in non-therapeutic situations, for example, in vitro .

In one embodiment, R1 is halogen, cyano, acetyl, trifluoromethyl, trifluoromethoxy.

In one embodiment, R2 is hydrogen. In another embodiment R2 is C1-4 alkyl (e.g. ex. methyl).

In one embodiment R 3 may be hydrogen, C 1-4 alkyl, haloalkyl C 1-4, C 1-4 alkoxy, C 1-4 haloalkoxy, alkanoyl C 1-4 or halogen.

In one embodiment R 4 may be hydrogen, C 1-4 alkyl, haloalkyl C 1-4, C 1-4 alkoxy, C 1-4 haloalkoxy, alkanoyl C 1-4 or halogen.

In one embodiment R 5 may be hydrogen, C 1-4 alkyl, haloalkyl C 1-4, C 1-4 alkoxy, C 1-4 haloalkoxy, alkanoyl C 1-4 or halogen.

In one embodiment R 6 may be hydrogen, C 1-4 alkyl, haloalkyl C 1-4, C 1-4 alkoxy, C 1-4 haloalkoxy, alkanoyl C 1-4 or halogen.

In one embodiment, R 7 is hydrogen or methyl.

In one embodiment, R_ {8} is a group selected from: isoxazolyl, 2-pyrrolidinonyl, -CH2 -N-pyrrolyl, 1,1-dioxide-2-isothiazolidinyl, 2-thienyl, 2-pyridyl, 2-thiazolyl which is optionally substituted with one or two substituents selected from: halogen, cyano, alkyl C 1-2 (eg methyl), haloalkyl C 1-2 (eg trifluoromethyl), alkoxy C 1-2 (eg methoxy), alkanoyl C_ {1-3} (eg acetyl).

In one embodiment, p is 0, 1 or 2.

In another embodiment p is 1.

In one embodiment, n is 3 or 4.

In one embodiment, n is 3. In another embodiment, n is 4.

In another embodiment, R_ {1} is trifluoromethyl.

In another embodiment, R2 is hydrogen.

In another embodiment, R 3 and R 4 are hydrogen or methyl

In one embodiment, R 3 is hydrogen, C 1-4 alkyl, cyano, alkoxy C 1-4 or a 5-6 membered heteroaryl group optionally substituted.

In another embodiment, R 3 is hydrogen, methyl, optionally substituted pyridyl, substituted pyrimidyl optionally, methoxy or cyano.

In one embodiment, R 4 is hydrogen or methyl.

In another embodiment, R 5 and R 6 are hydrogen.

In another embodiment, R 7 is hydrogen:

In another embodiment, R 8 is isoxazolyl, 2-pyrrolidinonyl, 1,1-dioxide-2-isothiazolidinyl.

In one embodiment, G is a phenyl group.

In one embodiment, a compound is provided of formula (IB) or a salt thereof, in which R_ {1}, p, n, R_ {3}, R 4, R 5, R 6 and R 7 are as defined for the formula (I):

8

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In Formula (IB), in one embodiment, n can be 3 or 4, p is 1, R 1 is trifluoromethyl, R 2 is hydrogen, R 3 and R 4 can be hydrogen or methyl, R 5 and R 6 they are hydrogen and R 7 is hydrogen.

In Formula (IB), in another embodiment, n can be 3 or 4, p is 1, R 1 is trifluoromethyl, R 2 is hydrogen, R 3 can be hydrogen, methyl, substituted pyridyl optionally, optionally substituted pyrimidyl, methoxy or cyano, R 4 can be hydrogen or methyl, R 5 and R 6 are hydrogen and R 7 is hydrogen.

The absolute configuration of the compounds of the present invention can be assigned according to the method described in the PCT International Publication WO2005 / 080382.

Other embodiments of the present invention are compounds of formula (IB) 'that correspond to the isomers stereochemicals of the compounds of formula (IB) as they have been defined above, enriched in configuration (1S, 5R).

In one embodiment, an isomer is provided. stereochemical enriched in the configuration (1S, 5R) of formula (IB) 'or a salt thereof, wherein R_ {1}, p, n, R_ {3}, R_ {4}, R 5, R 6 and R 7 are as defined for the formula (I):

9

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In Formula (IB) ', in one embodiment, n can be 3 or 4, p is 1, R 1 is trifluoromethyl, R 2 is hydrogen, R 3 and R 4 can be hydrogen or methyl, R 5 and R 6 they are hydrogen and R 7 is hydrogen.

In Formula (IB) ', in another embodiment, n it can be 3 or 4, p is 1, R 1 is trifluoromethyl, R 2 is hydrogen, R 3 may be hydrogen, methyl, substituted pyridyl optionally, optionally substituted pyrimidyl, methoxy or cyano, R 4 can be hydrogen or methyl, R 5 and R 8 are hydrogen and R 7 is hydrogen.

Certain compounds of the invention may form acid addition salts with one or more equivalents of the acid. The The present invention includes within its scope all forms Stoichiometric and non-stoichiometric possible.

Salts can also be prepared pharmaceutically acceptable from other salts, including other pharmaceutically acceptable salts of the compound of formula (I), using conventional methods.

The experts in the technique of organic chemistry they will appreciate that many organic compounds can form complexes with solvents in which they are reacted or in which precipitate or crystallize. These complexes are known as "solvates." For example, a complex with water is known as "hydrate". The solvates of the compound of the invention are within the scope of the invention. The compounds of formula (I) can easily be isolated associated with solvent molecules by crystallization or evaporation of an appropriate solvent, to provide the corresponding solvates.

In addition, some of the crystalline forms of compounds of structure (I) may exist as polymorphs, which are included in the present invention.

Hereinafter, the compounds of formula (I) and its pharmaceutically acceptable salts and solvates, defined in any aspect of the invention (except the compounds intermediates in chemical processes) are referred to as "compounds of the invention ".

Those skilled in the art will appreciate that in the preparation of the compounds of the invention, it may be necessary and / or desirable to protect one or more sensitive groups in the molecule to Avoid undesirable side reactions. The protective groups suitable for use according to the present invention are well known by those skilled in the art and can be used in a manner conventional. See, for example, "Protective groups in organic synthesis ", by T.W. Greene and P.G.M. Wuts (John Wiley & sons, 1991), or "Protecting Groups", by P.J. Kocienski (Georg Thieme Verlag, 1994). Examples of suitable amino protecting groups they include acyl type protecting groups (eg formyl, trifluoroacetyl, acetyl), urethane type protecting groups aromatic (eg benzyloxycarbonyl (Cbz) and substituted Cbz), aliphatic urethane type protecting groups (e.g. 9-fluorenylmethoxycarbonyl (Fmoc), t-butyloxycarbonyl (Boc), isopropyloxycarbonyl, cyclohexyloxycarbonyl) and alkyl-type protecting groups (e.g. benzyl, trityl, chlorotrityl). Examples of protective groups suitable for oxygen may include, for example, groups alkylsilyl, such as trimethylsilyl or tert-butyldimethylsilyl; alkyl ethers, such as tetrahydropyranyl or tert-butyl; or esters such as acetate.

The present invention also includes compounds marked with isotopes, which are identical to those indicated in the formula (I) and following, except for the fact that one or more atoms are replaced by an atom that has an atomic mass or mass number different from the atomic mass or mass number that normally found naturally. Examples of isotopes that they can be incorporated into the compounds of the invention and salts Pharmaceutically acceptable of these include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I and 125 I.

The compounds of the present invention and non-pharmaceutically acceptable salts thereof that contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present invention. The isotope-labeled compounds of the present invention, for example those in which radioactive isotopes such as 3 H, 14 C are incorporated, are useful in tissue distribution assays of drugs and / or substrates. Particularly preferred are tritium isotopes, i.e. 3 H, and carbon-14, that is, 14 C, for their ease of preparation and detection. The 11 C and 18 F isotopes are particularly useful in PET (positron emission tomography), and the 125 I isotope is particularly useful in SPECT (single photon emission computed tomography), all useful in brain imaging. In addition, substitution with heavier isotopes, such as deuterium, i.e. 2 H, can provide certain therapeutic advantages resulting from greater metabolic stability, for example, a greater in vivo half-life or lower dosage requirements and, therefore, , may be preferred in some circumstances. The isotope-labeled compounds of the present invention and non-pharmaceutically acceptable salts thereof can be prepared, in general, by performing the procedures described in the Schemes and / or in the Examples shown below, substituting an unlabeled reagent with isotopes for a Easily available isotope labeled reagent.

Certain groups / substituents included in the Present invention may be present as isomers. The present invention includes within its scope all racemates, enantiomers, tautomers and mixtures thereof. Some of the groups substituted heteroaromatics included in the compounds of formula (I) may exist in one or more tautomeric forms. The present invention includes within its scope, all these forms tautomers, including mixtures.

The example compounds of the invention include:

3-methyl-1- (4 - {(1S, SR) -1- [4- (trifluoromethyl) phenyl] -3-azabicyclo [3.1.0] hex-3-yl} butyl) -2 (1H) -pyridinone ;

4-methyl-1- (4 - {(1S, 5R) -1- [4- (trifluoromethyl) phenyl] -3-azabicyclo [3.1.0] hex-3-yl} butyl) -2 (1H) -pyridinone ;

or a pharmaceutically acceptable salt of these.

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Additional examples of the invention include:

6'-methyl-1- (4 - {(1S, 5R) -1- [4- (trifluoromethyl) phenyl] -3-azabicyclo [3.1.0] hex-3-yl} butyl) -3,3'- bipyridin-2 (1H) -one;

2'-fluoro-1- (4 - {(1S, 5R) -1- [4- (trifluoromethyl) phenyl] -3-azabicyclo [3.1.0] hex-3-yl} butyl) -3,4'- bipyridin-2 (1H) -one;

2'-fluoro-1- (4 - {(1S, 5R) -1- [4- (trifluoromethyl) phenyl] -3-azabicyclo [3.1.0] hex-3-yl} butyl) -3,3'- bipyridin-2 (1H) -one;

6'-fluoro-1- (4 - {(1S, SR) -1- [4- (trifluoromethyl) phenyl] -3-azabicyclo [3.1.0] hex-3-yl} butyl) -3,3'- bipyridin-2 (1H) -one;

3- (5-pyrimidinyl) -1- (4 - {(1S, 5R) -1- [4- (trifluoromethyl) phenyl] -3-azabicyclo [3.1.0] hex-3-yl} butyl) -2 ( 1H) -pyridinone;

3- (methyloxy) -1- (4 - {(1S, 5R) -1- [4- (trifluoromethyl) phenyl] -3-azabicyclo [3.1.0] hex-3-yl} butyl) -2 (1H) -pyridinone;

2-oxo-1- (4 - {(1S, 5R) -1- [4- (trifluoromethyl) phenyl] -3-azabicyclo [3.1.0] hex-3-yl} butyl) -1,2-dihydro- 3-pyridinecarboni-
trilo;

3-methyl-1- (4 - {(1S, 5R) -1- [4- (trifluoromethyl) phenyl] -3-azabicyclo [3.1.0] hex-3-yl} butyl) -2 (1H) -pyridinone ;

4-methyl-1- (4 - {(1S, 5 R ) -1- [4- (trifluoromethyl) phenyl] -3-azabicyclo [3.1.0] hex-3-yl} butyl) -2 (1 H ) -pyridinone;

3-methyl-1- (3 - {(1S, 5R) -1- [4- (trifluoromethyl) phenyl] -3-azabicyclo [3.1.0] hex-3-yl} propyl) -2 (1H) -pyridinone ;

or a pharmaceutically acceptable salt of these.

       \ vskip1.000000 \ baselineskip
    

In another embodiment, the compounds of formula (I) are selected from the group consisting of hydrochloride salts of The compounds listed below:

6'-methyl-1- (4 - {(1S, 5R) -1- [4- (trifluoromethyl) phenyl] -3-azabicyclo [3.1.0] hex-3-yl} butyl) -3,3'- bipyridin-2 (1H) -one;

2'-fluoro-1- (4 - {(1S, 5R) -1- [4- (trifluoromethyl) phenyl] -3-azabicyclo [3.1.0] hex-3-yl} butyl) -3,4'- bipyridin-2 (1H) -one;

2'-fluoro-1- (4 - {(1S, 5R) -1- [4- (trifluoromethyl) phenyl] -3-azabicyclo [3.1.0] hex-3-yl} butyl) -3,3'- bipyridin-2 (1H) -one;

6'-fluoro-1- (4 - {(1S, 5R) -1- [4- (trifluoromethyl) phenyl] -3-azabicyclo [3.1.0] hex-3-yl} butyl) -3,3'- bipyridin-2 (1H) -one;

3- (5-pyrimidinyl) -1- (4 - {(1S, 5R) -1- [4- (trifluoromethyl) phenyl] -3-azabicyclo [3.1.0] hex-3-yl} butyl) -2 ( 1H) -pyridinone;

3- (methyloxy) -1- (4 - {(1S, 5R) -1- [4- (trifluoromethyl) phenyl] -3-azabicyclo [3.1.0] hex-3-yl} butyl) -2 (1H) -pyridinone;

2-oxo-1- (4 - {(1S, 5R) -1- [4- (trifluoromethyl) phenyl] -3-azabicyclo [3.1.0] hex-3-yl} butyl) -1,2-dihydro- 3-pyridinecarboni-
trilo;

3-methyl-1- (4 - {(1S, 5R) -1- [4- (trifluoromethyl) phenyl] -3-azabicyclo [3.1.0] hex-3-yl} butyl) -2 (1H) -pyridinone ;

4-methyl-1- (4 - {(1S, 5 R ) -1- [4- (trifluoromethyl) phenyl] -3-azabicyclo [3.1.0] hex-3-yl} butyl) -2 (1 H ) -pyridinone;

3-methyl-1- (3 - {(1S, 5R) -1- [4- (trifluoromethyl) phenyl] -3-azabicyclo [3.1.0] hex-3-yl} propyl) -2 (1H) -pyridinone .

       \ vskip1.000000 \ baselineskip
    

Some of the compounds herein invention can be prepared by following some of the procedures described in PCT International Publication WO2005 / 080382.

The present invention also provides a process for preparing a compound of formula (I) 'or a salt thereof as defined above, which comprises the steps of:

a) reacting a compound of formula (II):

10

in which R_ {1}, R_ {7} and p are as defined for formula (I), with a compound of formula (III):

eleven

in which R 2, R 3, R 4, R 5, R 6 and n are as defined for the formula (I) and X is a group outgoing,

or

b) reacting a compound of formula (II), as defined above:

12

with a compound of formula (IV)

13

in which R 2, R 3, R 4, R 5, R 6 and n are as defined for the formula (I); and then optionally for the process (a) or the process (b):

(i)

delete any group or groups protectors; I

(ii)

form a salt; I

(iii)

convert a compound of formula (I) 'or a salt thereof in another compound of formula (I)' or a salt of this one.

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The process (a) can be performed using methods conventional for the formation of a tertiary amine. The group protrusion X may be halogen such as chlorine. Alternatively, X may be a sulfonyloxy group such as alkyl C 1-4 -sulfonyloxy (e.g., methanesulfonyloxy), C 1-4 alkyl sulfonyloxy or C 1-4 haloalkyl sulfonyloxy (e.g., trifluoromethanesulfonyloxy); or arylsulfonyloxy, in which the group aryl is optionally substituted phenyl, a heteroaromatic group 5 or 6 members optionally substituted or a bicyclic group optionally substituted, for example, substituted phenyl optionally, in which in each case the optional substituents they are one or more C 1-2 alkyl groups; for example para-toluenesulfonyloxy. When X is a halogen, the reaction can be performed using a base such as carbonate potassium in the presence of a iodide source, such as iodide of sodium in a solvent such as N, N-dimethylformamide at a suitable temperature, e.g. ex. 60 ° C

The process (b) can be performed using methods conventional for the formation of a tertiary amine by means of reductive amination For example, when, for the compounds of formula (IV) R2 is hydrogen, the reaction can be carried out using sodium triacetoxyborohydride in a suitable solvent such as 1,2 dichloroethane at 0 ° C.

In another embodiment, the present invention provides a process for the preparation of compounds of formula (Ia), that is to say a compound of formula (I) 'in which p is 1 or 2 and a group R1 is a group R6, which comprises the steps following:

c) react a compound of formula (V):

14

in which R_ {1} and R_ {7} are as defined for formula (I), Pg is a protecting group of suitable amine, such as a group tert-butoxycarbonyl, p is 0 or 1 and Y is halogen, a perfluoroalkylsulfonyloxy group (eg trifluoromethylsulfonyloxy), or Y is a group M selected from a boron derivative (eg a boronic acid function B (OH) 2) or a function metal such as trialkylstannil (eg SnBu 3), halide of zinc or magnesium halide; with a compound of formula R_ {6} -Y_ {1}, in which R_ {6} is a group isoxazolyl, thienyl, thiazolyl or optionally substituted pyridyl, Y1 is halogen when Y is a group M; or, when Y is halogen or a perfluoroalkylsulfonyloxy group, Y1 is an M group as has previously defined or hydrogen that can be activated with a suitable base (eg Cs_ {CO 2}) in the presence of a metal adequate transition (eg Pd); "outgoing group" is like the understand an expert chemist, that is, a group that can be displaced by a nucleophile, e.g. ex. in a type reaction S_ {N} 2, S_ {1} or S_ {Ar};

to form a compound of formula (XXXIV)

fifteen

in which R_ {1} and R_ {7} are as defined for formula (I), Pg is a protecting group of suitable amine, such as a group tert-butoxycarbonyl, p is 0 or 1 and R 6 is a isoxazolyl, thienyl, thiazolyl or substituted pyridyl group optionally;

d) delete the group Pg;

e) react the product obtained with a compound of formula (III) or (IV), as defined above, under the conditions described for processes a) or b);

and after this optionally:

(i)

delete any group or groups protectors; I

(ii)

form a salt; I

(iii)

convert a compound of formula (Ia) or a salt thereof in another compound of formula (Ia) or a salt of this one.

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The reaction of a compound of formula (V) with R 1 -Y 1 according to the process (c) can be carried out in the presence of a transition metal, e.g. eg, a palladium catalyst such as bis- triphenylphosphine palladium dichloride, tetrakis- triphenylphosphine palladium (0) or the complex formed in situ from tris (dibenzylidenacetone) dipaladium (0) and 4,5-bis (diphenylphosphino) -9, 9-dimethylxanthene. When M is a boronic acid function such as B (OH) 2, the reaction can be carried out under basic conditions, for example, using aqueous sodium carbonate in a suitable solvent, such as dioxane. When M is trialkylstannil, the reaction can be carried out in an inert solvent, such as xylene or dioxane optionally in the presence of LiCl. When M is a zinc or magnesium halide, the reaction can be carried out in an aprotic solvent, such as tetrahydrofuran. When M is hydrogen which can be activated with a suitable base (eg Cs2CO3) in the presence of a suitable transition metal (eg Pd) the reaction can be carried out in an inert solvent, such as dioxane in the presence of a suitable base such as Cs2CO3. The substituent Y may be halogen such as bromine or a sulfonyloxy group, such as trifluoromethylsulfonyloxy; and Y1 may be a group M, such as hydrogen which may be activated with a suitable base (eg Cs2CO3) in the presence of a suitable transition metal (eg Pd ).

The compounds of formula (II) can be prepared by methods well known in the art (eg J. Med. Chem. 1981, 24, 481-490 or PCT International Publication WO2005 / 080382). The interconversion of groups R_ {1} can be carried out by methodology well known in the art (e.g. demethylation of a methoxy group that produces a hydroxy group using a suitable Lewis acid reagent, such as boron tribromide in an inert solvent such as dichloromethane).

In one aspect of the present invention, provides a process for the preparation of compounds of formula (IIa), that is to say a compound of general formula (II) in which R 7 is hydrogen and G is a phenyl group and R 1 is defined as for compounds of formula (I).

16

The process can be conveniently carried out. also to prepare compounds of formula (IIb), in which the phenyl moiety of compound (IIa) is replaced by pyridine. This process comprises the following stages:

17

at that:

the stage means the diazotization of an aniline (VI) followed by reaction with maleimide to provide 3-arylmaleimide (VII);

the stage (b ') means the cyclopropagation of (VII) to provide the imide bicyclic (VIII);

the stage (c ') means reduction of imide (VIII) to provide compounds of formula (IIIa).

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Step (a ') can be performed using methods Conventional methods for the Meerwein reaction (eg J. Am. Chem. Soc. 1955, 77, 2313, describes the formation of arylmaleimides using this approach). Alternatively, in many cases this stage is properly performed by applying a procedure in which to a maleimide mixture, an appropriate copper (II) salt such as Anhydrous CuCl2, and a suitable organonitrite, such as nitrite tert-butyl, in a compatible solvent, such as acetonitrile, a solution of a compound of slowly added formula (VI). This is followed by a period of time during the which is allowed to react as appropriate and a final treatment suitable.

Step (b ') consists of the slow addition of a solution of the compound of formula (VII) purified, or mixtures containing a compound of formula (VII), dissolved in a suitable solvent such as dimethyl sulfoxide, to a solution of trimethylsulfoxonium iodide in a suitable solvent such as dimethylsulfoxide and a suitable base, such as sodium hydride. This is followed by a period of time during which it is left. react as appropriate and an appropriate final treatment.

Step (c ') can be performed using an agent suitable reducer in a compatible solvent, such as borane in tetrahydrofuran or Red-Al® in toluene at one appropriate temperature, such as at 65 ° C in the case of borane as a reducing agent. This is followed by a final treatment. suitable.

In another aspect of the present invention, provides an alternative synthetic process for the preparation of compounds of formula (II). This process includes the stages following:

18

at that:

R_ {1}, p and G are as defined for formula (I), R 8 O is a suitable alkoxy group, PG is an appropriate protecting group and Y can be halogen such as bromine, or a sulfonyloxy group such as trifluoromethylsulfonyloxy, and comprises the steps following:

the stage (a '') means the coupling reaction of a (2,5-dihydro-1H-pyrrol-3-yl) boronate (IX) with the halogen derivative or aromatic sulfonyloxy (X);

the stage (b '') means the cyclopropagation of (XI) followed, if appropriate, of deprotection to provide the bicyclic amine (II).

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Step (a '') can be performed using methods conventional for Suzuki coupling, p. ex. using tetrakis (triphenylphosphine) palladium (0) as source of catalytic palladium (0), in the presence of fluoride cesium in an appropriate solvent, such as tetrahydrofuran at a adequate temperature (R 8 O) 2 B can be so adequate 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl and PG benzyl, which represents a compound of structure (X) such as It is reported in Synlett 2002, 5, 829-831.

Step (b '') consists of a reaction of cyclopropagation performed, for example, using the generated reagent from trimethylsulfoxonium iodide and a suitable base such as sodium hydride. This is followed by a reaction of check out

In another aspect of the present invention, provides a synthetic process for the preparation of compounds of formula (IIc), that is, compounds of general formula (II) in the that R 7 is C 1-2 alkyl and G is a group phenyl. This process includes the following stages:

19

at that:

the stage (a '') means bromination of compound (XV) to provide the compound (XVI);

the stage (b '') means the reaction of compound (XVI) with a benzyl amine (prone to produce benzyl cleavage under acidic conditions) to provide imide (XVII);

the stage (c '') means the coupling of compound (XVII) with an acid arylboronic to provide the compound (XVIII);

the stage (d '') means the removal of the benzyl protecting group of the compound (XVIII) to provide the compound (XIX);

the stage (e '') means the cyclopropagation of (XIX) to provide the imide bicyclic (XX);

the stage (f '') means reduction of imide (XX) to provide compounds of formula (IIc).

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Step (a '') can be performed using bromine in presence of AlCl3, and heating the mixture at a temperature elevated, suitably 120 ° C.

Stage (b '') can be performed by heating the compound (XVI) together with an appropriate benzyl amine (suitably as 3,4- (dimethoxy) benzylamine or 2,4- (dimethoxy) benzylamine) in the presence of AcONa and AcOH.

       \ newpage
    

Step (c '') can be performed using methods conventional for Suzuki coupling, p. ex. using Pd (PPh 3) 2 Cl 2 as a source of palladium catalytic (0) in the presence of cesium fluoride, BnEt3 NCl and a generic arylboronic acid in an appropriate solvent mixture, (such as 1: 1 toluene / H2O) at a suitable temperature (such as 90 ° C).

Stage (d '') can be carried out through a appropriate method for acid cleavage of the benzyl protecting group, such as one of those mentioned in "Protective groups in organic synthesis "by T.W. Greene and P.G.M. Wuts (John Wiley & sons 1991) or "Protecting Groups" by P.J. Kocienski (Georg Thieme Verlag 1994). Suitably, if the benzyl group is represented by 3,4- (dimethoxy) benzyl, protection can be removed by reaction of compound (XVIII) with TFA and anisole in the presence of sulfuric acid.

Stage (e '') consists of the slow addition of a solution of the compound of formula (XIX) purified, or mixtures containing a compound of formula (XIX), dissolved in a suitable solvent such as dimethyl sulfoxide, to a solution of trimethylsulfoxonium iodide in a suitable solvent such as dimethylsulfoxide and a suitable base, such as sodium hydride. This is followed by a period of time during which it is left. react as appropriate and an appropriate final treatment.

Step (f ') can be performed using an agent suitable reducer in a compatible solvent, such as borane in tetrahydrofuran or Red-Al® in toluene at one appropriate temperature, such as at 65 ° C in the case of borane as a reducing agent. This is followed by a final treatment. suitable.

A compound of formula (III) can be prepared he himself reacting a compound of formula (XXI):

       \ vskip1.000000 \ baselineskip
    

twenty

       \ vskip1.000000 \ baselineskip
    

wherein R_ {3}, R_ {4}, R_ {5} and R_ {6} are as defined for formula (I) '' with a compound of formula (XIII):

\hskip0.3cm

X(XIII) L (CHR2) n

 \ hskip0.3cm 

X

in which R_ {2} is as it has been defined for formula (I), X is as defined above and L is a group outgoing.

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The leaving group L may be halogen, such as chlorine. Alternatively, L may be a sulfonyloxy group such as C 1-4 alkyl sulfonyloxy (e.g. methanesulfonyloxy), C 1-4 alkyl sulfonyloxy or C 1-4 haloalkyl sulphonyloxy (e.g. trifluoromethanesulfonyloxy); or arylsulfonyloxy, in which the group aryl is optionally substituted phenyl, a heteroaromatic group 5 or 6 members optionally substituted or a bicyclic group optionally substituted, for example, substituted phenyl optionally, in which in each case the optional substituents they are one or more C 1-2 alkyl groups; for example para-toluenesulfonyloxy. When L is a halogen, the reaction can be performed using a base such as carbonate potassium in the presence of a iodide source, such as iodide of sodium in a solvent such as N, N-dimethylformamide at a suitable temperature, e.g. eg, 60 ° C.

A compound of formula (IV) can be prepared same through the following stages:

f) reacting a compound of formula (XXI):

       \ vskip1.000000 \ baselineskip
    

twenty-one

       \ newpage
    

wherein R_ {3}, R_ {4}, R_ {5} and R 6 are as defined for formula (I), with a compound of formula (XXII)

\hskip0.3cm

X(XXII) MCR2 (CHR2) n-1

 \ hskip0.3cm 

X

in which R_ {2} is defined as for formula (I), X is as defined above and M is an appropriate carbonyl protecting group (for example, dimethylacetal or dioxalan);

and then

g) excision of the protective group.

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The cleavage of the protective group can be performed under appropriate conditions known to the person skilled in the art. For example, when M is dimethylacetal, excision can be performed. by treatment with a dilute solution of hydrochloric acid in dioxane or methanol with gentle heating (e.g., 60 ° C).

The compound of formula (III), as has been defined above, it can be prepared through the stages following:

h) reacting a compound of formula (XXI), as defined above:

22

with a compound of formula (XXIII)

\hskip0.3cm

X(XXIII) NCR2 (CHR2) n-1

 \ hskip0.3cm 

X

in which R_ {2} is defined as for formula (I), X is as defined above and N is a protected alcoholic function (for example: terbutyldimethylsilyl);

and then

i) excision of the protective group under conditions appropriate known to those skilled in the art and subsequent oxidation of the free alcoholic function obtained to provide a carbonyl group.

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For example, when N is a protective group terbutyldimethylsilyl, excision can be performed by treatment with a 1 N solution of hydrochloric acid in dioxane at 0 ° C for 1 hour. The appropriate conditions for the oxidation stage they comprise periodynan-mediated oxidation of Dess-Martin in dry THF as solvent at 0 ° C for 1 hour.

Alternatively, the compounds of formula (IIIa), that is, the compounds of formula (III) in which R 3 it is a 5.6-membered heteroaryl, they can be prepared through following stages:

m) reacting a compound of formula (XXIV)

2. 3

in which R_ {4}, R_ {5} and R 6 are as defined for formula (I), with a compound of formula (XIII) under alkylation conditions standard

and then

n) coupling of the product obtained from the formula (XXV), in which n, R_ {4}, R_ {5} and R_ {6} are as they have been defined for formula (I) and X is as defined above for the compounds of formula (XIII),

24

with the acid or ester heteroarylboronic appropriate.

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Stage (n) can be performed properly using a conventional method for Suzuki coupling, using for example Pd (OAc) 2 as a source of palladium catalytic (0), in the presence of Na2CO3 as a base and a heteroaryl boronic acid or boronic ester suitable in a solvent appropriate, such as nPrOH.

The compounds of formula (XIII), (XXII) and (XXIII) are available in the market or can be prepared by reactions known in the literature.

The compounds of formula (XXI) are commercially available or can be prepared by reactions known in the literature or through the procedures that are described herein below.

The compounds of formula (Ic), that is, the compounds of formula (I) in which R 1, R 2, R 3, R 4, R 5, R 6, R 7, n, G and p are as they have been defined above and A is a group P1, can be prepared by reacting a compound of formula (XIV):

25

in which R_ {1}, R2_, R 7, G, n and p are as defined for formula (I) and X it is a leaving group, with a compound of formula (XXI) as it has been definite previously:

26

A compound of formula (XIV) in which R 1, R 7, G and p are as defined for formula (I), X is a leaving group and R2 is hydrogen and n is 3, can be prepared by alkylation of a compound of formula (II) in the presence of a base suitable such as a tertiary amine, for example diisopropylethylamine, with a propyl derivative having two leaving groups preferably of differential reactivity in the positions 1 and 3, for example 1-Bromo-3-chloropropane.

Interconversion reactions between compounds of formula (I) 'and salts thereof can be made using methods well known in the art. The examples include:

(i)

convert one or more R 1 of alkoxy (eg methoxy) in hydroxy,

(ii)

convert one or more R_ {1} of hydroxy in sulfonyloxy, such as alkylsulfonyloxy or haloalkylsulfonyloxy, e.g. ex. methanesulfonyloxy or alkylsulfonyloxy or trifluoromethanesulfonyloxy,

(iii)

convert one or more R_ {1} of halogen or perfluoroalkylsulfonyloxy in cyano; and optionally after this form a salt of formula (I) '.

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When an enantiomer or specific diastereoisomer of a compound of formula (I) or salts from it, this can be obtained, for example, by resolution of a corresponding enantiomeric or diastereoisomeric mixture using conventional methods In this way, for example, specific enantiomers or diastereoisomers of the compounds they can be obtained from the enantiomeric mixture or corresponding diastereoisomer using chromatographic methods chiral such as, for example, chiral HPLC.

Alternatively, a specific enantiomer or diastereoisomer of a compound of formula general (I), or salts thereof, from the intermediates appropriate optically active using any of the processes generals described herein.

It has been found that the compounds of formula (I) or pharmaceutically acceptable salts thereof, show affinity for dopamine receptors, in particular the D3 receptor, and are expected to be useful in the treatment of diseases that they require modulation of said receptors, such as conditions psychotic

It has also been found that many of the compounds of formula (I) or pharmaceutically acceptable salts thereof have a greater affinity for dopamine D3 receptors than for D2. It is believed that, in general, the therapeutic effect of currently available antipsychotic agents (neuroleptics) is exerted by blocking D2 receptors; However, it is also believed that this mechanism is responsible for undesirable extrapyramidal side effects ("eps"), associated with many neuroleptic agents. It has been suggested that blocking of the recently characterized dopamine D3 receptor may produce beneficial antipsychotic activity without significant eps (see, for example, Sokoloff et al ., Nature, 1990; 347: 146-151; and Schwartz et al. ., Clinical Neuropharmacology, Vol. 16, No. 4, 295-314, 1993). In one embodiment, compounds of formula (I) or salts thereof having a higher affinity (e.g., ≥10 times or ≥100 times) are provided for the dopamine D3 receptor than for the dopamine receptor D 2 (said affinity can be measured using the standard methodology - see here).

The compounds of the invention can be used suitably as selective receptor modulators D_ {3}.

By the location of the receptors D3, it can also be expected that the compounds also could be useful for substance abuse treatment, in which has been suggested that D3 receptors are involved (e.g., see Levant, 1997, Pharmacol. Rev., 49, 231-252). Examples of such substance abuse They include the abuse of alcohol, cocaine, heroin and nicotine. Other conditions that can be treated by the compounds include substance-related disorders, dyskinetic disorders such as Parkinson's disease, parkinsonism induced by neuroleptics and tardive dyskinesias; depression; anxiety, deterioration Cognitive including memory disorders such as disease of Alzheimer's, sexual dysfunction, sleep disorders, emesis, amnesia, aggression, vertigo, dementia, rhythm disorders circadian and gastric motility disorders, p. ex. IBS

A wide range of psychiatric disorders and neuropsychiatric appear to be related to the disorder Obsessive-Compulsive, and constitute a family of related disorders called spectrum disorders obsessive-compulsive (OC). The compounds of the invention can be used for the treatment of a disorder of obsessive-compulsive spectrum, including disorders somatoforms such as body dysmorphic disorder and hyperchondria, bulimia nervosa, anorexia nervosa, disorder binge eating, paraphilia and non-paraphilic sexual addictions, Korea's Sydeham, torticollis, autism, Diogenes syndrome and disorders of the movement, including Tourette's syndrome. As used in this report, it is understood that the phrase "disorder of obsessive-compulsive spectrum "includes the Obsessive-Compulsive Disorder.

The compounds of the invention are also Useful for the treatment of premature ejaculation.

The terms that describe the indications used herein are classified in the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, published by the American Psychiatric Association (DSM-IV) and / or the International Classification of Diseases, 10th Edition (ICD-10). Various subtypes of disorders mentioned herein are contemplated as part of the present invention The numbers in parentheses after diseases listed below, refer to the code of classification in DSM-IV.

The term "psychotic disorder" It includes:

Schizophrenia including Type subtypes Paranoid (295.30), Disorganized Type (295.10), Type Catatonic (295.20), Non-Differentiated Type (295.90) and Type Residual (295.60); Schizophreniform Disorder (295.40); Disorder Schizoaffective (295.70), which includes the subtypes of Bipolar Type and Depressive Type; Delusional Disorder (297.1) that includes Subtypes of Erotomanic Type, Delirium of Greatness Type, Celotypy, Persecutory Type, Somatic Type, Mixed Type and of Unspecified Type; Brief Psychotic Disorder (298.8); Shared Psychotic Disorder (297.3); Psychotic Disorder Due to a General Medical Condition that includes subtypes with Delusions and with hallucinations; Substance Induced Psychotic Disorder, which includes subtypes with Delusions (293.81) and Hallucinations (293.82); and Psychotic Disorder Not Specified Other Way (298.9).

The term "disorder related to substances "includes:

Substance-related disorders including Substance Use Disorders such as the Substance Dependence, Craving for Substance Consumption and Substance abuse; Substance Induced Disorders, such as Substance Poisoning, Substance Withdrawal, Delirium Substance Induced, Persistent Dementia Induced by Substances, Persistent Induced Substance-Induced Disorder, Substance Induced Psychotic Disorder, State Disorder Mood Induced by Substances, Anxiety Disorder Induced by Substances, Substance Induced Sexual Dysfunction, Disorder Sleep Induced by Substances and Disorder with Hallucinogenic Perception Persistent (Retrospective Scenes); Disorders Related to Alcohol such as Alcohol Dependence (303.90), Abuse of Alcohol (305.00), Alcohol poisoning (303.00), Abstinence from Alcohol (291.81), Delirium from Alcohol Poisoning, Delirium from Alcohol Abstinence, Alcohol-Induced Persistent Dementia, Persistent Amnesic Disorder Induced by Alcohol, Disorder Alcohol Induced Psychotic, Mood Disorder Alcohol Induced, Alcohol Induced Anxiety Disorder, Alcohol Induced Sexual Dysfunction, Induced Sleep Disorder For Alcohol and Unspecified Disorder in Other Related Way with Alcohol (291.9); Amphetamine Related Disorders (or Amphetamine-like Substances) such as the Unit of Amphetamines (304.40), Amphetamine Abuse (305.70), Poisoning by Amphetamines (292.89), Amphetamine Withdrawal (292.0), Amphetamine Intoxication Delirium, Psychotic Disorder Induced by Amphetamines, Mood Disorder Induced by Amphetamines, Amphetamine Induced Anxiety Disorder, Amphetamine Induced Sexual Dysfunction, Sleep Disorder Induced by Amphetamines and Unspecified Disorder Related to Amphetamines (292.9); Caffeine Related Disorders such as Caffeine Poisoning (305.90), Disorder Caffeine Induced Anxiety, Sleep Disorder Induced by Caffeine and Unspecified Caffeine-Related Disorder (292.9); Cannabis-related disorders, such as Cannabis Unit (304.30), Cannabis Abuse (305.20), Cannabis Poisoning (292.89), Intoxication Delirium with Cannabis, Psychotic Disorder Induced by Cannabis, Disorder Cannabis Induced Anxiety and Disorder Related to Cannabis Not Specified Other Way (292.9); Disorders Cocaine related, such as the Cocaine Unit (304.20), Cocaine Abuse (305.60), Cocaine Poisoning (292.89), Cocaine Withdrawal (292.0), Intoxication Delirium with Cocaine, Cocaine Induced Psychotic Disorder, Emotional State Induced by Cocaine, Anxiety Disorder Cocaine Induced, Cocaine Induced Sexual Dysfunction, Cocaine Induced Sleep Disorder and Related Disorder Cocaine Not Specified in Other Way (292.9); Disorders Hallucinogen-related, such as the Unit of Hallucinogens (304.50), Hallucinogens Abuse (305.30), Hallucinogen Poisoning (292.89), Hallucinogenic Disorder with Persistent Perception (Retrospective Scenes) (292.89), Delirium by Hallucinogen Poisoning, Psychotic Disorder Induced by Hallucinogens, Emotional State Disorder Induced by Hallucinogens, Anxiety Disorder Induced by Consumption of Hallucinogens and Hallucinogen-Related Disorder No Specified in another way (292.9); Related Disorders Inhalers such as the Inhalers Unit (304.60), Abuse of Inhalers (305.90), Intoxication with Inhalers (292.89), Delirium for Inhaler Poisoning, Persistent Dementia Induced by Inhalers, Psychotic Disorder Induced by Inhalers, Emotional State Disorder Induced by Inhalers, Anxiety Induced Disorder and Inhaler-Related Disorder Not Specified Otherwise (292.9); Nicotine-related disorders, such as Nicotine dependence (305.1). Nicotine withdrawal (292.0) and Other Unspecified Nicotine-Related Disorder Way (292.9); Opioid Related Disorders, such as Opioid Unit (304.00), Opioid Abuse (305.50), Opioid poisoning (292.89), Opioid withdrawal (292.0), Delusion of Opioid Poisoning, Induced Psychotic Disorder by Opioids, Mood Disorder Induced by Opioids, Opioid Induced Sexual Dysfunction, Sleep Disorder Opioid Induced and Opioid Related Disorder no Specified Other Way (292.9); Disorders Related to Phencyclidine (or Similar to Phencyclidine) such as Dependence on Phencyclidine (304.60), Abuse of Phencyclidine (305.90), Fenciclidine poisoning (292.89), Intoxication delirium with Phencyclidine Phencyclidine-induced Psychotic Disorder, Emotional State Disorder Induced by Phencyclidine, Anxiety Disorder Induced by Phencyclidine and Disorders Related to Unspecified Phencyclidine in Another Way (292.9); Disorders Related to Sedatives, Hypnotics or Anxiolytics, such as the Sedative, Hypnotic or Dependency Unit Anxiolytics (304.10), Sedative Abuse, Hypnotics or Anxiolytics (305.40), Sedative, Hypnotic or Poisoning Anxiolytics (292.89), Sedative, Hypnotic or Abstinence Anxiolytics (292.0), Intoxication Delirium with Sedatives, Hypnotics or Anxiolytics, Sedation Abstinence Delirium, Hypnotics or Anxiolytics, Persistent Sedative Dementia, Hypnotics or Anxiolytics, Persistent Amnesic Disorder for Sedatives, Hypnotics or Anxiolytics, Induced Psychotic Disorder by Sedatives, Hypnotics or Anxiolytics, State Disorder Emotional Induced by Sedatives, Hypnotics or Anxiolytics, Anxiety Disorder Induced by Sedatives, Hypnotics or Anxiolytics, Sexual Dysfunction Induced by Sedatives, Hypnotics or Anxiolytics, Sleep Disorder Induced by Sedatives, Hypnotics o Anxiolytics and Sedative, Hypnotic Related Disorder or Anxiolytics Not Specified Other Way (292.9); Disorder Related to Polisustances such as Dependency of Polysubstances (304.80); and other Disorders Related to Substances (or Unknown) such as Anabolic Steroids, Nitrate and Nitrous Oxide Inhalers.

The compounds of the invention may be useful. for the treatment of cognitive impairment.

The term "cognitive impairment" includes cognitive impairment in other diseases such as schizophrenia, bipolar disorders, depression, other psychiatric disorders and psychotic conditions associated with cognitive impairment, e.g. eg, the Alzheimer disease.

Therefore, in an additional aspect, the The present invention provides compounds of formula I 'for use in a method to treat a condition for which the modulation of dopamine receptors (especially those dopamine D3 receptors), which comprises administering to a mammal (eg a human being) who needs an amount effective of a compound of the invention.

Modulation, as used herein memory, refers especially to inhibition / antagonism (which it can also translate into inverse agonism in systems of constitutively active receptors).

In one embodiment, the condition is a disorder. substance-related, a psychotic disorder, a disorder of obsessive-compulsive spectrum or ejaculation early, precocious, premature.

The invention also provides a compound of The invention for use in therapy.

The invention also provides a compound of the invention for use in treating a condition in a mammal for which receptor modulation is beneficial dopamine (especially dopamine D3 receptors).

The invention also provides the use of a compound of the invention in the manufacture of a medicament for the treatment of a condition in a mammal for which it is beneficial modulation of dopamine receptors (especially dopamine D3 receptors).

In one embodiment, the compounds of the invention are used in the treatment of psychosis such as schizophrenia, in the treatment of substance abuse, in the spectrum disorder treatment obsessive-compulsive and in the treatment of premature ejaculation

The use of a compound of the invention in the manufacture of a medicament for the treatment of a psychotic condition, substance abuse in a mammal, obsessive-compulsive spectrum disorders and premature ejaculation

A compound of the invention for use in the treatment of a psychotic condition (e.g. ex. schizophrenia), substance abuse, spectrum disorders obsessive-compulsive and premature ejaculation in a mammal.

A compound of the invention for use as an active therapeutic substance in a mammal, for example for use in the treatment of any of the conditions described herein.

"Treatment" includes prophylaxis, when it is appropriate for the condition (s) relevant.

For use in medicine, the compounds of the present invention are usually administered as a composition Standard Pharmaceutical Therefore, in an additional aspect, the The present invention provides a pharmaceutical composition that comprises a compound of the invention and a vehicle pharmaceutically acceptable. The pharmaceutical composition can be use in the treatment of any of the conditions described herein.

The compound of the invention can be administered by any convenient method, for example by administration oral, parenteral (eg intravenous), buccal, sublingual, nasal, rectal or transdermal and pharmaceutical compositions can adapt according to this.

The compound of the invention that is active when administered orally it can be formulated as liquids or solids, for example, syrups, suspensions or emulsions, tablets, capsules and dragees.

A liquid formulation will generally consist of a suspension or solution of the compound or a salt pharmaceutically acceptable in a vehicle or liquid vehicles suitable, for example, an aqueous solvent such as water, ethanol or glycerin, or a non-aqueous solvent, such as polyethylene glycol or a oil. The formulation may also contain an agent of suspension, preservative, flavoring or coloring.

A composition in the form of a tablet is can prepare using any vehicle or pharmaceutical vehicles suitable, commonly used to prepare solid formulations. Examples of such vehicles include magnesium stearate, starch, lactose, sucrose and cellulose.

A composition in the form of a capsule is can prepare using encapsulation procedures usual. For example, granules containing the active ingredient using standard vehicles and then loading them in a hard gelatin capsule; alternatively, it you can prepare a dispersion or suspension using any vehicle or suitable pharmaceutical vehicles, for example, aqueous gums, celluloses, silicates or oils and then load the dispersion or suspension in a soft gelatin capsule.

Typical parenteral compositions consist of in a solution or suspension of the compound or a salt pharmaceutically acceptable in a sterile aqueous vehicle or in oil acceptable parenterally, for example, polyethylene glycol, polyvinylpyrrolidone, lecithin, peanut oil or sesame. Alternatively, the solution can be lyophilized and then reconstitute with a suitable solvent just before the administration.

Compositions for nasal administration they can be conveniently formulated as aerosols, drops, gels and powder. Aerosol formulations typically comprise a solution or a fine suspension of the active substance in a pharmaceutically acceptable aqueous or non-aqueous solvent, and they usually occur in amounts of an individual dose or multiple doses in sterile form in a sealed container, which can be in the form of a cartridge or refill for use with a device atomization. Alternatively, the sealed container may be a unit dispensing device such as a nasal inhaler of individual doses or an aerosol dispenser equipped with a metering valve that is intended to be discarded once it is The contents of the container have ended. When the way to Dosage comprises an aerosol dispenser, will contain a propellant which can be a compressed gas such as compressed air or an organic propellant such as a fluorochlorohydrocarbon. The aerosol dosage forms may also have the form of A pump atomizer.

Compositions suitable for administration buccal or sublingual include tablets, dragees and pills, in the that the active ingredient is formulated with a vehicle such as sugar and gum arabic, tragacanth or gelatin and glycerin.

Compositions for rectal administration they are conveniently in the form of suppositories that contain a conventional suppository base such as cocoa butter.

Compositions suitable for administration Transdermal include ointments, gels and patches.

In one embodiment, the composition is in shape. unit dose such as a tablet, capsule or blister.

Each unit dosage for oral administration contains for example from 1 to 250 mg (and for parenteral administration contains for example 0.1 to 25 mg) of a compound of the invention calculated as the free base.

The compounds of the invention are usually administered in a daily dosage regimen (for a patient adult) of, for example, an oral dose between 1 mg and 500 mg, per example between 10 mg and 400 mg, for example between 10 and 250 mg or a intravenous, subcutaneous, or intramuscular dose between 0.1 mg and 100 mg, for example between 0.1 mg and 50 mg, for example between 1 and 25 mg of the compound of formula (I) or a pharmaceutically acceptable salt of this calculated as the free base, the compound being administered 1 to 4 times per day. Suitably, the compounds are administered during a period of continuous therapy, for example for a week or more.

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Biological test methods

The functional potency of the compounds of this invention can be measured by the following proximity test of GTPS scintillation (GTPS-SPA). The cells used in The study is Chinese Hamster Ovary (CHO) cells.

Cellphone line

CHO_D2

CHO_D3

Dopamine CHO D 3 (Biocat No. 1060) transduced with G bacmam G0 protein (Biocat No. 97886).

All stages are performed at 4 ° C. The Cell membranes are prepared as follows. They resuspend cell pellets in 10 volumes of 50 mM HEPES, 1 mM EDTA pH 7.4, using KOH.

The cells are homogenized in a mixer glass with 2 bursts of 15 seconds in 200 ml of buffer (50 mM HEPES, 1 mM leupeptin, 25 µg / ml bacitracin, 1 mM EDTA, 1 mM PMSF, 2 µM Pepstatin A). (The last 2 reagents were added as recent x100 and x 500 mother solutions respectively in ethanol). The mixer is immersed in ice for 5 minutes later of the first burst and 10-40 minutes after the final burst to allow the foam to dissipate. The material then centrifuged at 500 g for 20 minutes and the supernatant centrifuge for 36 minutes at 48,000 g. The sediment is resuspended in the same buffer as indicated above but without PMSF or Pepstatin A. The material is then passed through of a 0.6 mm needle, is carried to the required volume (usually 4 times the volume of the original cell pellet), they are prepared aliquots and stored frozen at -80 ° C.

In the trial, the final higher concentration of Test drug is 3 µM and 1: 4 dilution curves are performed in series of 11 points in 100% DMSO using a Biomek FX. It adds the test drug at 1% (0.5 µL) of the total test volume (TAV) to a 384 well polypropylene Greiner test plate solid white 50% TAV (25 µL) of pre-coupled membranes is added (for 60 mins at RT), 5 µg / well, and Polystyrene beds with Wheat Germ Agglutinin for Scintillation Assay by Proximity (RPNQ0260, Amersham), 0.25 mg / well, in 20 mM HEPES (pH 7.4, 100 mM NaCl, 10 mM MgCl2), 60 µg / mL saponin and 30uM GDP The third addition is a 20% addition of TAV (10 µL) buffer (agonist format) or a final test concentration Agonist CE80, Quinelorano, prepared in assay buffer (antagonist format). The test is started by adding 29% TAV (15 µL) of GTP [35S] 0.38 nM final (37 MBq / ml, 1,160 Ci / mmol, Amersham). After all the additions, the plates Test were centrifuged for 1 minute at 1,000 rpm. The mixture of final test (45.5 µL) is incubated at room temperature to balance for 3-6 hours before performing reading on a ViewLux ™ luminescence imaging apparatus (filter 613/55), 5 min / plate.

The effect of the test drug on the value baseline generates fpKi values of the test drug that are calculated at from the IC_ {50} generated by the experiment of "format antagonist ", using the equation of Cheng and Prusoff: fKi = IC50 / 1 + ([A] / EC50) in which: [A] is the concentration of the agonist Quinelorano in the test and EC50 is the EC50 value of Quinelorano obtained in the same experiment. fpKi is defined as -logfKi.

It is estimated that the results of pKi have a accuracy only about 0.3-0.5.

In the context of the present invention, it is used the functional pKi (fpKi, corresponding to the negative logarithm of fKi) instead of functional Ki (fKi) and the compounds of formula (I) and the salts thereof typically show a value of fpKi for the D3 receptors between approximately 7.0 and 8.5.

Below is a list of examples showing at least 20 times greater selectivity for D3 receptors with respect to D2: E1 receptors. E2, E3, E4

Below is a list of examples that did not show any activity in the trial GTPS-SPA of D2 up to the highest concentration tested (3 µM) and, therefore, are considered selective for D3 receptors with respect to D2 receptors: E8 and E9.

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Examples

The invention is further illustrated by the following non-limiting examples.

In the procedures shown at then, after each starting material, typically refers by number to a Preparation or Example. This is It merely provides as an aid to the expert chemist. He starting material may not necessarily have been prepared to from the indicated lot.

When reference is made to the use of a "similar" procedure, as those skilled in the art will appreciate, such a procedure may involve a minimal variation, for example the reaction temperature, the amount of reagent / solvent, the reaction time, the treatment conditions, or chromatographic purification conditions
fica.

Compounds can be named using software of chemical named ACD / Name PRO 6.02 (Advanced Chemistry Development Inc., Toronto, Ontario, M5H2L3, Canada) or ISIS / Draw 2.5 SR 2 Autonom (MDL Information System, Inc)

All temperatures are indicated in ºC.

Typically, Resonance spectra Proton Magnetic (NMR) can be registered in instruments They vary at 300, 400 or 500 MHz, or on a Bruker instrument at 300 and 400 MHz. Chemical shifts are presented in ppm (δ) using the residual solvent line as an internal standard. The disintegration patterns are called s, singlet; d, double up; t triplet; c, quadruplet; m, multiplet; b, width The spectra of NMR can be recorded at temperatures ranging from 25 to 90 ° C. When more than one conformer was detected, the Chemical shifts for the most abundant.

Typically, mass spectra (MS) can collected in a 4 quadrupole Mass Spectrometer 4 II (Micromass UK) or on an Agilent MSD 1100 Mass Spectrometer, which works in ES (+) and ES (-) ionization mode or in a Spectrometer Agilent LC / MSD 1100, which works in ES ionization mode (+) and ES (-) coupled with an Agilent 1100 HPLC instrument Series In the mass spectra, only one peak appears in the group of molecular ions.

For reactions that involve irradiation of microwave, Personal Chemistry EmrysTM Optimizer can be used or Biotage Initiator 60.

Flash chromatography on silica gel can be performed on 230-400 mesh silica gel (supplied by Merck AG Darmstadt, Germany) or in cartridges prepackaged Varian Mega Be-Si or in cartridges of Biotage silica prepackaged.

In a series of preparations, purification can be done using manual flash chromatography systems Biotage (Flash +) or automatic flash chromatography (Horizon). All these instruments work with Biotage Silica cartridges.

Optical rotations can be measured using a polarimeter (Perkin Elmer Model 241) operating at 589 nm (source of Sodium). Measurements are made using a 1 decimeter microcell thermostated at 23 ° C. Concentrations are typically 10 mg / ml. (c = 0.01). For initial OR assignments, the Dalton Quantum Chemistry Program.

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Column chromatography was performed on gel silica (Merck AG Darmstaadt, Germany). In the text, the following abbreviations: EtOAc = ethyl acetate, Et2O = ether diethyl, THF = tetrahydrofuran, Tlc refers to chromatography in thin layer in silica plates and dried refers to a solution dried over anhydrous sodium sulfate, r.t. (RT) refers to room temperature, Rt = retention time, DMSO = dimethylsulfoxide; DMF = N, N'-dimethylformamide, DCM = dichloromethane, TEA = triethylamine, SPE Cartridge = Cartridge Solid Phase Extraction; SCX Cartridge = Exchange Cartridge Strong cationic

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Preparation 1 3- [4- (trifluoromethyl) phenyl] -1H-pyrrole-2,5-dione (Prep1)

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27

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A mixture of hydrochloric acid (37% in water, 285 mL) and water (190 mL) was added to 4- (trifluoromethyl) aniline (150 g, 116 mL) at room temperature with vigorous stirring and the formed precipitate was allowed to stir for an additional 30 minutes. The temperature was reduced to 0 ° C and the stirred suspension was added dropwise sodium nitrite (70.6 g) in 180 mL of water. At the end of the diazotation, a light yellow solution was obtained. Was added dropwise maleimide (180 g) in acetone (1.1 L) at 0 ° C, and then adjusted the pH of the solution to 3-3.5 by adding sodium acetate To the vigorously stirred mixture was added copper (II) chloride (18.8 g). After a few minutes, he started peel off a gas (visible foam formation). The mixture of reaction was allowed to stir at 0 ° C for 1 h and overnight at room temperature. The acetone was removed in vacuo and the rest was filtered and dried overnight under vacuum to provide the title compound (155 g) as a light brown solid.

MS ( m / z ): 242.2 [MH] +.

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Preparation 2 (1 R , 5S / 1S, 5 R ) -1- [4- (trifluoromethyl) phenyl] -3-azabicyclo [3.1.0] -hexane-2,4-dione (Prep2)

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28

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Ground sodium hydroxide (40 g) was added in small portions to a stirred solution of trimethylsulfoxonium iodide (219 g) in DMSO (anhydrous, 2 L). The resulting mixture was allowed to stir at room temperature for 1.5 h. Then, 3- [4- (trifluoromethyl) phenyl] -1 H -pyrrol-2,5-dione (Prep1, 120 g) dissolved in DMSO (anhydrous, 0.5 L) was added dropwise and the resulting mixture was left under stirring at room temperature for 20 minutes. Then, the temperature was reduced to 0 ° C and saturated aqueous NH 4 Cl (2 L) was added slowly, followed by Et 2 O (1 L). After separation of the two phases, the aqueous layer was repeatedly extracted with Et2O (3 x 1 L). The combined organic layers were washed with concentrated saline (2 x 1 L) and then dried over Na2SO4. Evaporation of the solvent provided a light brown solid that was suspended in 1 L of dichloromethane and 1 L of cyclohexane. The mixture was allowed to stir at room temperature for 45 minutes and then filtered to provide the title compound (116 g) as a white solid.

MS ( m / z ): 256.1 [MH] +.

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Preparation 3 (1 R , 5 S / 1 S , 5 R ) -1- [4- (trifluoromethyl) phenyl] -3-azabicyclo [3.1.0] -hexane (Prep3)

29

Borane (1 M in tetrahydrofuran, 1.4 L) was charged in a 5 L reactor under N 2 and cooled to 0 ° C. Then (1 R , 5 S / 1 S , 5 R ) -1- [4- (trifluoromethyl) phenyl] -3-azabicyclo [3.1.0] hexane-2,4-dione (Prep2, 101) was added dropwise g) dissolved in anhydrous THF (1 L) with vigorous stirring so that the temperature was kept constantly below 5 ° C, and the evolution of gas was monitored. At the end of the addition, the resulting mixture was left under stirring at 0 ° C for 1 h and then at room temperature overnight. Then, the mixture was cooled to 0 ° C and methanol (200 mL) was carefully added followed by a 6 M aqueous solution of hydrochloric acid (0.8 L) controlling gas evolution. Then, THF was removed in vacuo, the rest was cooled to 0 ° C and a 5M aqueous solution of sodium hydroxide was added until a pH value of 9-10 was reached. The aqueous layer was extracted with Et2O (3 x 1 L). Removal of the solvent in vacuo provided the title compound (140 g) as a colorless oil.

MS ( m / z ): 228.1 [MH] +.

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Preparation 4 (1 S , 5 R ) -1- [4- (trifluoromethyl) phenyl] -3-azabicyclo [3.1.0] hexane (Prep4)

30

(S) - (+) - Mandelic acid (94 g) was added portionwise to a stirred solution of (1 R , 5S / 1S, 5 R ) -1- [4- (trifluoro-
methyl) phenyl] -3-azabicyclo [3.1.0] hexane (Prep3, 140 g) in 1.4 L of THF. The resulting mixture was stirred at room temperature for 2 h until a white precipitate formed. Then, the mixture was heated to reflux temperature, stirred for 45 minutes and then slowly cooled to room temperature. The white solid was collected by filtration and dried in vacuo. This material was recrystallized 4 times in THF (10 volumes) to provide 32.5 g of a white solid. This material was then suspended in sodium hydroxide (1 M solution, 400 mL) and Et 2 O (400 mL) and allowed to stir at room temperature until the solution was complete. After separation of the two phases, the aqueous layer was extracted again with Et2O (3 x 250 mL). The combined organic layers were washed with 1 M aqueous solution of sodium hydroxide (3 x 200 mL) and dried over Na2SO4. Evaporation of the solvent in vacuo provided the title compound (19 g) as a white solid. The absolute configuration of the optical isomers was assigned as described in PCT International Publication Document WO2005 / 080382. NMR (1 H, CDCl 3): δ 7.51 (d, 2H), 7.25 (d, 2H), 3.20 (d, 1H), 3.0-3.1 (m, 3H), 1.69 (m, 1H), 0.8-1.0 (m, 2H), N H not observed. MS ( m / z ): 228.1 [MH] +.

Analytical chromatography

Column:

chiralcel OD 10 um, 250 x 4.6 mm

Mobile phase:

A: n-hexane; B: Isopropanol + 0.1% isopropylamine

Gradient:

2% isocratic B

Flow:

1 mL / min

UV wavelength range: 200-400 nm.

Analysis duration 25 min

100

Specific Optical Rotation: [α] D = -10 ° (CDCl 3, T = 20 ° C, c 0,00 0.004 g / 0.8 mL).

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Preparation 5 1- (4-Chlorobutyl) -3-methyl-2 (1H) -pyridinone (Prep5)

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31

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At a dissolution of 3-methyl) -2 (1H) -pyridinone (commercial aldrich) (200 mg, 1.85 mmol), in dry DMF (5 mL), is they added K 2 CO 3 (0.51 g) and 1-Bromo-3-Chlorobutane (0.32 mL) and the resulting mixture was heated at 90 ° C for 5 hours. After removal of the solvent under reduced pressure, the The residue was diluted with ethyl acetate and washed once with water and once with concentrated saline solution. The organic phase dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by gel chromatography of silica eluting with cyclohexane / EtOAc 8: 2 to provide the title compound as a colorless oil (0.24 g).

MS (m / z): 200 [MH] +.

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Preparation 6 1- (4-Chlorobutyl) -4-methyl-2 (1H) -pyridinone (Prep6)

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32

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The title compound was prepared with a 46% yield using a procedure similar to that shown previously in Prep5 starting from 4-methyl-2 (1H) -pyridinone (commercial aldrich) (200 mg, 1.85 mmol). MS (ES) 200 m / z: [MH +); C 10 H 14 ClNO requires 199.68.

1 H NMR (400 MHz, CHLORFORM- d ) δ ppm 7.14 (d, 1 H) 6.38 (dd, 1 H) 6.01 (dd, 1 H) 3.95 (t, 2 H) 3 , 58 (t, 2 H) 2.16-2.21 (m, 3 H) 1.78-1.96 (m, 4 H).

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Preparation 7 3-Bromo-1- (4-chlorobutyl) -2 (1H) -pyridinone (P7)

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33

At a dissolution of 3-Bromo-2 (1H) -pyridinone (commercial source: Alfa Aesar) (5 g, 28.7 mmol) in DMF (130 mL) K2CO3 (4.8 g, 34.5 mmol) was added. Reaction mixture stirred at room temperature for 1 hour, was added 1-Bromo-4-Chlorobutane (3.3 ml, 28.7 mmol) and the reaction mixture was stirred for 18 hours at room temperature. The DMF was evaporated, water was added to the Raw product and organic layers were extracted with DCM. The organic layers were combined, dried over Na2SO4, dried filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with a gradient of methanol in DCM (0 to 5%) to yield the compound of title (4.82 g, 63%).

1 H NMR (400 MHz, CHLORFORM- d ) δ ppm 7.73 (d, 1 H) 7.29 (dd, 1 H) 6.10 (t, 1 H) 4.04 (t, 2H) 3, 58 (t, 2H) 1.90-2.01 (m, 2H) 1.79-1.89 (m, 2H).

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Preparation 8 1- (4-Chlorobutyl) -6'-methyl-3,3'-bipyridin-2 (1H) -one (Prep8)

3. 4

Was added 3-Bromo-1- (4-chlorobutyl) -2 (1H) -pyridinone (400 mg, 1.51 mmol and then 627 mg, 4.54 mmol) at a solution of acid (6-methyl-3-pyridinyl) boronic (Synchem OHG commercial product list) (311 mg, 2.27 mmol) in dioxane (5 K 2 CO 3 mL). The mixture was degassed by bubbling N2 for 10 'and triphenylphosphine (120 mg, 0.45) mmol) and palladium (II) acetate (34 mg, 0.15 mmol). The mixture of reaction was stirred at reflux for 5 h and then at temperature ambient for 18 hours. More acid was added (6-methyl-3-pyridinyl) boronic (Synchem OHG product list) (60 mg, 0.43 mmol), triphenylphosphine (78 mg, 0.3 mmol) and palladium (II) acetate (22 mg, 0.1 mmol) and the reaction was stirred for an additional 4 hours at 80 ° C The reaction was cooled and concentrated by removing the solvent. under reduced pressure. Water was added to the crude product and the layers Organic were extracted with DCM. The organic layers were combined, dried over Na2SO4, filtered and concentrated on empty. The crude product was purified by column chromatography on silica gel eluting with a gradient of methanol in DCM (from 0 to 5%) to yield the title compound (280 mg, 67%).

1 H NMR (400 MHz, CHLORFORM- d ) δ ppm 8.64 (br, s ,, 1 H) 7.99-8.06 (m, 1 H) 7.59-7.69 (m, 1 H ) 7.23-7.33 (m, 1 H) 7.11-7.20 (m, 1 H) 6.20-6.34 (m, 1 H) 3.94-4.07 (m, 2 H) 3.49-3.60 (m, 2 H) 2.5 (s, 3 H) 1.71-2.02 (m, 4 H).

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Preparation 9 1- (4-Chlorobutyl) -6'-fluoro-3,3'-bipyridin-2 (1H) -one (Prep9)

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35

The title compound was prepared in 82% yield using a procedure similar to that shown previously in Prep8 starting from 3-bromo-1- (4-chlorobutyl) -2 (1H) -pyridinone (Prep7) (400 mg , 1.51 mmol), (6-fluoro-3-pyridinyl) boronic acid (commercial Alfa Aesar) (426 mg, 3.02 mmol), K 2 CO 3 (627 mg, 4.54 mmol) , triphenylphosphine (200 mg, 0.75 mmol) and palladium (II) acetate (68 mg, 0.30 mmol) dissolved in dioxane
(5 mL).

1 H NMR (400 MHz, CHLORFORM- d ) δ ppm 8.40 (d, 1 H) 8.22-8.28 (m, 1 H) 7.50 (dd, 1 H) 7.35 (dd, 1 H) 6.94 (dd, 1 H) 6.30 (t, 1 H) 4.04 (t, 2 H) 3.57 (t, 2 H) 1.90-2.01 (m, 2 H) 1.79-1.90 (m, 2 H).

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Preparation 10 1- (4-Chlorobutyl) -2'-fluoro-3,4'-bipyridin-2 (1H) -one (Prep10)

36

The title compound was prepared with a 53% yield using a procedure similar to that shown previously in Prep8 starting from 3-Bromo-1- (4-chlorobutyl) -2 (1H) -pyridinone (Prep7) (400 mg, 1.51 mmol), acid (6-fluoro-3-pyridinyl) boronic (Synchem OHG commercial product list) (426 mg, 3.02 mmol), K 2 CO 3 (627 mg, 4.54 mmol), triphenylphosphine (200 mg, 0.75 mmol) and palladium (II) acetate (68 mg, 0.30 mmol) dissolved in dioxane (5 mL).

1 H NMR (400 MHz, CHLORFORM- d ) δ ppm 8.15 (d, 1 H) 7.60 (dd, 1 H) 7.49 (dt, 1 H) 7.41 (dd, 1 H) 7 , 34-7.38 (m, 1 H) 6.29 (t, 1 H) 4.01 (t, 2 H) 3.53 (t, 2 H) 1.86-1.97 (m, 2 H) 1.75-1.85 (m, 2 H).

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Preparation 11 1- (4-Chlorobutyl) -2'-fluoro-3,3'-bipyridin-2 (1H) -one (Prep11)

37

The title compound was prepared in 79% yield using a procedure similar to that shown previously in Prep8 starting from 3-bromo-1- (4-chlorobutyl) -2 (1H) -pyridinone (Prep7) (400 mg , 1.51 mmol), (6-fluoro-3-pyridinyl) boronic acid (commercial Alfa Aesar) (426 mg, 3.02 mmol), K 2 CO 3 (627 mg, 4.54 mmol) , triphenylphosphine (200 mg, 0.75 mmol) and palladium (II) acetate (68 mg, 0.30 mmol) dissolved in dioxane
(5 mL).

1 H NMR (400 MHz, CHLORFORM- d ) δ ppm 8.07-8.19 (m, 2 H) 7.54-7.61 (m, 1 H) 7.35-7.40 (m, 1 H) 7.20-7.27 (m, 1 H) 6.30 (t, 1 H) 4.04 (t, 2 H) 3.58 (t, 2 H) 1.92-2.04 ( m, 2 H) 1.78-1.91 (m, 2 H).

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Preparation 12 1- (4-Chlorobutyl) -3- (5-pyrimidinyl) -2 (1H) -pyridinone (Prep12)

38

The title compound was prepared with a 51% yield using a procedure similar to that shown previously in Prep8 starting from 3-bromo-1- (4-chlorobutyl) 2 (1H) -pyridinone (Prep7) (400 mg, 1.51 mmol), acid (6-fluoro-3-pyridinyl) boronic (commercial Apollo Scientific Intermediates for Research and Development) (426 mg, 3.02 mmol), K 2 CO 3 (627 mg, 4.54 mmol), triphenylphosphine (200 mg, 0.75 mmol) and palladium acetate (II) (68 mg, 0.30 mmol) dissolved in dioxane (5 mL).

1 H NMR (400 MHz, CHLORFORM- d ) δ ppm 9.06 (br, s ,, 1 H) 9.01 (br, s ,, 2 H) 7.52 (dd, 1 H) 7.37 ( dd, 1 H) 6.29 (t, 1 H) 4.00 (t, 2 H) 3.52 (t, 2 H) 1.70-1.96 (m, 4 H).

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Preparation 13 1- (4-Chlorobutyl) -3- (methyloxy) -2 (1H) -pyridinone (Prep13)

39

The title compound was prepared with a 42% yield using a procedure similar to that shown previously in Prep7 starting from 3- (methyloxy) -2 (1H) -pyridinone (commercial Aldrich) (0.54 g, 4.31 mmol).

1 H NMR (400 MHz, CHLORFORM- d ) δ ppm 6.88 (dd, 1 H) 6.60 (dd, 1 H) 6.11 (t, 1 H) 4.01 (t, 2 H) 3 , 80-3.83 (m, 3 H) 3.57 (t, 2 H) 1.87-1.97 (m, 2 H) 1.76-1.86 (m, 2 H).

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Preparation 14 1- (4-Chlorobutyl) -2-oxo-1,2-dihydro-3-pyridinecarbonitrile (Prep14)

40

The title compound was prepared with a 65% yield using a procedure similar to that shown previously in Prep7 starting from 2-oxo-1,2-dihydro-3-pyridinecarbonitrile (commercial RC Biomedical Research Chemicals) (0.36 g, 1.71 mmoles).

MS (ES) 211 m / z: [MH +]; C 10 H 11 CIN 2 O requires 210.66.

1 H NMR (400 MHz, CHLORFORM- d ) δ ppm 7.83 (dd, 1 H) 7.57 (dd, 1 H) 6.30 (t, 1 H) 4.05 (t, 2 H) 3 , 60 (t, 2 H) 1.91-2.03 (m, 2 H) 1.79-1.90 (m, 2 H).

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Example 1 Hydrochloride 3-methyl-1- (4 - {(1S, 5R) -1- [4- (trifluoromethyl) phenyl] -3-azabicyclo [3.1.0] hex-3-yl) butyl) -2 (1H) -pyridinone (E1)

41

A mix of 1- (4-Chlorobutyl) -3-methyl-2 (1H) -pyridinone (Prep5, 40 mg), (1S, 5R) -1- [4- (trifluoromethyl) phenyl] -3-azabicyclo [3.1.0] hexane (Prep4, 30 mg, reference procedure for preparation indicated in WO 2005080382), K2CO3 (36 mg) and Nal (33 mg) in DMF (anhydrous, 0.5 mL) was heated at 70 ° C for 18 h. After the solvent removal under reduced pressure, the rest is dissolved in ethyl acetate and the organic layer was washed with water and dried over Na2SO4. This solution was filtered and the Filtrate was concentrated in vacuo. The crude product was purified by flash chromatography (dichloromethane at 5% MeOH / 0.5% hydroxide ammonium [33% w / w] in dichloromethane) to provide 30 mg of the free base of the title compound. To a dissolution of this dichloromethane material (0.2 mL) 0.08 mmol of HCl (1 M solution in Et2O), the solvent was evaporated in vacuo and the material obtained was triturated with Et2O to provide 27 mg of the title compound as a slightly white solid Hygroscopic (48% yield).

NMR (1 H, DMSO): δ 10.36 (br. S., 1 H), 7.69 (d, 2 H), 7.54 (d, 1 H), 7.48 (d, 2 H), 7.29 (d, 1 H), 6.14 (t, 1 H), 4.03 (dd, 1 H), 3.89 (t, 2 H), 3.69 (dd, 1 H), 3.58-3.65 (m, 1 H), 3.45-3.51 (m, 1 H), 3.17-3.25 (m, 2 H), 2.25-2.32 (m, 1 H), 1.96-2.01 (m, 3 H), 1.61-1.73 (m, 5H), 1.16-1.22 (m, 1 H).

MS (m / z): 391 [MH] +.

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Example 2 Hydrochloride 4-methyl-1- (4 - {(1S, 5R) -1- [4- (trifluoromethyl) phenyl] -3-azabicyclo [3.1.0] hex-3-yl} butyl) -2 (1H) -pyridinone (E2)

42

The title compound was prepared using a procedure similar to that shown above in Example 1 with a yield of 40 mg as a slightly hygroscopic white solid starting from 30 mg of (1 S , 5 R ) -1- (4- ( trifluoromethyl) phenyl) -3-azabicyclo [3.1.0] hexane.

NMR (1 H, DMSO): δ 10.46-10.61 (m, 1 H), 7.72 (d, 2 H), 7.59 (d, 1 H), 7.50 (d, 2 H), 6.19-6.22 (m, 1 H), 6.11 (dd, 1 H), 4.04 (dd, 1 H), 3.86 (t, 2 H), 3.70 (dd, 1 H), 3.59-3.66 (m, 1 H), 3.47-3.53 (m, 1 H), 3.17-3.27 (m, 2 H), 2.28-2.31 (m, 1 H), 2.12-2.14 (m, 3H), 1.73-1.78 (m, 1 H), 1.68-1.74 (m, 2 H), 1.62-1.69 (m, 2 H), 1.17-1.23 (m, 1 H).

MS (m / z): 391 [MH] +.

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Example 3 Dihydrochloride 6'-methyl-1- (4 - {(1S, 5R) -1- [4- (trifluoromethyl) phenyl] -3-azabicyclo [3.1.0] hex-3-yl} butyl) -3,3'- bipyridin-2 (1H) -one (E3)

43

Stage to

TEA (0.056 ml, 0.4 mmol) was added to a solution of 1- (4-chlorobutyl) -6'-methyl-3,3'-bipyridin-2 (1H) -one (55 mg, 0.2 mmol , Prep8) and (1S, 5R) -1- [4- (trifluoromethyl) phenyl] -3-azabicyclo [3.1.0] hexane (Prep4, 70 mg, 0.31 mmol, reference procedure for the preparation also indicated in WO 2005080382) in anhydrous DMF (2 mL). The reaction mixture was heated at 90 ° C for 1 hour and then at 100 ° C for 24 hours, stopped with water and extracted with ethyl acetate. The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The crude product was purified with an SCX cartridge (eluting with methanol followed by a 2N solution of ammonia in methanol) and then with an SPE cartridge eluting with a gradient of methanol in DCM (0 to 5%) to yield the free base of the title compound (19 mg, 20%).

1 H NMR (400 MHz, CHLORFORM- d ) δ ppm 8.69 (d, 1 H) 8.10 (dd, 1 H) 7.50-7.56 (m, 3 H) 7.34 (dd, 1 H) 7.18-7.25 (m, 3 H) 6.31 (t, 1 H) 4.05 (t, 2 H) 3.36 (d, 1 H) 3.12 (d, 1 H) 2.58-2.61 (m, 3 H) 2.52-2.58 (m, 3 H) 2.45-2.50 (m, 1 H) 1.82-1.91 (m , 2 H) 1.74-1.80 (m, 1 H) 1.55-1.59 (m, 2 H) 1.48-1.52 (m, 1 H) 0.82-0.87 (m, 1 H).

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Stage b

The free base of E3 (19 mg, 0.041 mmol) is dissolved in DCM (1 ml) and treated with HCl (0.071 ml of a 1.25 M solution in methanol, 0.092 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. Solvent evaporation and trituration with diethyl ether (2 x 2 ml) provided the title compound (E3) (16 mg) as a solid.

MS (ES) 468 m / z: [MH +]; C 27 H 28 F 3 N 3 O requires 467.5.

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Examples E4-E10

The following examples (E4-E10) they were prepared using a procedure similar to that shown earlier in Example 3.

The free bases of the title compounds (data shown in the table below) were obtained using a similar procedure to the one shown above in Example 3, Stage a starting from the appropriate pyridazinone (selected from Prep9-Prep14) and (1S, 5R) -1- [4- (trifluoromethyl) phenyl] -3-azabicyclo [3.1.0] hexane (reference procedure for the preparation indicated in WO 2005080382).

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44

Four. Five

The title compounds (data shown in the table below) were obtained using a procedure similar to that shown above in Example 3, Step b starting from the free bases of the title compounds. For compounds containing a pyridine ring, 2.2 eq of HCl from a 1.25 M solution in methanol was added, in other cases 1.1 eq of HCl from a 1.25 M solution in methanol was added.

46

47

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Example 10 Hydrochloride 3-methyl-1- (3 - {(1S, 5R) -1- [4- (trifluoromethyl) phenyl] -3-azabicyclo [3.1.0] hex-3-yl} propyl) -2 (1H) -pyridinone (E10)

48

Stage to

3-methyl-2 (1H) -pyridinone (commercial source: Aldrich) (17 mg, 0.16 mmol), (1S, 5R) -1- [4- (trifluorome-)
til) phenyl] -3-azabicyclo [3.1.0] hexane (40 mg, 0.13 mmol, reference procedure for the preparation indicated in WO 2005080382), K 2 CO 3 (27.6 mg, 0 , 02 mmol), Nal (33.2 mg, 0.2 mmol) in DMF (1 mL) overnight at 80 ° C. The reaction was stopped with a saturated solution of NaHCO3 and extracted with ethyl acetate. The organic layers were combined, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography eluting with a gradient of methanol in DCM (0 to 30%) with 5% NH3 to yield the free base of the title compound (30 mg, 61%).

1 H NMR (400 MHz, CHLORFORM- d ) δ ppm 7.53 (d, 2 H) 7.16-7.26 (m, 4 H) 6.09 (t, 1 H) 4.02 (t, 2H) 3.32-3.45 (m, 1 H) 3.10-3.21 (m, 1 H) 2.43-2.68 (m, 4 H) 2.13-2.20 (m , 3 H) 1.89-2.05 (m, 2 H) 1.75-1.85 (m, 1 H) 1.46-1.66 (m, 1 H) 0.78-0.96 (m, 1 H).

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Stage b

The free base of E10 (30 mg, 0.08 mmol) was dissolved in DCM (1 ml) and treated with HCl (0.08 ml of a 1M solution in ether at room temperature. The resulting mixture was stirred at temperature ambient for 1 hour Evaporation of the solvent and trituration with diethyl ether (3 x 2 ml) gave the title compound
(27 mg).

MS (ES) 377 m / z: [MH +]; C 21 H 23 F 3 N 2 O requires 376.42.

It should be appreciated that the present invention includes all combinations of particular groups described earlier in this memory.

The request they are part of is description and claims can be used as a basis for priority over any subsequent request. The claims of such a subsequent application may be directed to any feature or combination of features described In the present memory. They may have the form of claims of product, composition, process or use and may include, to by way of example and without limitation, the claims following.

Claims (9)

1. Compound of formula (I) 'or a salt of East: 49 in the that

?

G is selected from a group that consists of: phenyl or a monocyclic heteroaryl group of 5 or 6 members or a bicyclic heteroaryl group from 8 to 11 members;

?

p is an integer that varies from 0 to 5;

?

R1 is halogen, hydroxy, cyano, C 1-4 alkyl, haloalkyl C 1-4, C 1-4 alkoxy, C 1-4 haloalkoxy, alkanoyl C 1-4 and SF 5; or corresponds to a group R 8; and when p is an integer that varies from 2 to 5, each R1 may be the same or different;

?

R2 is hydrogen or alkyl C 1-4;

?

n is 3, 4, 5 or 6;

?

R_ {3} is selected from the group consisting of: hydrogen, halogen, hydroxy, cyano, alkyl C 1-4, C 3-7 cycloalkyl, C 1-4 haloalkyl, alkoxy C 1-4, C 1-4 haloalkoxy, C 1-4 alkanoyl and NR'R ''; or R_ {3} is a group phenyl, a 5-14 membered heterocyclic group; Y any of said phenyl or heterocyclic groups is substituted optionally with 1, 2, 3 or 4 substituents selected from the group consisting of: halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, alkoxy C 1-4, C 1-4 alkanoyl and SF5;

?

R_ {4} is selected from the group consisting of: hydrogen, halogen, hydroxy, cyano, alkyl C 1-4, C 3-7 cycloalkyl, C 1-4 haloalkyl, alkoxy C 1-4, C 1-4 haloalkoxy, C 1-4 alkanoyl and NR'R ''; or R_ {3} is a group phenyl, a 5-14 membered heterocyclic group; Y any of said phenyl or heterocyclic groups is substituted optionally with 1, 2, 3 or 4 substituents selected from the group consisting of: halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, alkoxy C 1-4, C 1-4 alkanoyl and SF5;

?

R_ {5} is selected from the group consisting of: hydrogen, halogen, hydroxy, cyano, alkyl C 1-4, C 3-7 cycloalkyl, C 1-4 haloalkyl, alkoxy C 1-4, C 1-4 haloalkoxy, C 1-4 alkanoyl and NR'R ''; or R_ {3} is a group phenyl, a 5-14 membered heterocyclic group; Y any of said phenyl or heterocyclic groups is substituted optionally with 1, 2, 3 or 4 substituents selected from the group consisting of: halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, alkoxy C 1-4, C 1-4 alkanoyl and SF5;

?

R_ {6} is selected from the group consisting of: hydrogen, halogen, hydroxy, cyano, alkyl C 1-4, C 3-7 cycloalkyl, C 1-4 haloalkyl, alkoxy C 1-4, C 1-4 haloalkoxy, C 1-4 alkanoyl and NR'R ''; or R_ {3} is a group phenyl, a 5-14 membered heterocyclic group; Y any of said phenyl or heterocyclic groups is substituted optionally with 1, 2, 3 or 4 substituents selected from the group consisting of: halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, alkoxy C 1-4, C 1-4 alkanoyl and SF5;

?

R 7 is hydrogen or alkyl C 1-2;

?

R_ {8} is a selected remainder from the group consisting of: isoxazolyl, -CH2 -N-pyrrolyl, 1,1-dioxide-2-isothiazolidinyl, thienyl, thiazolyl, pyridyl, 2-pyrrolidinonyl, and said group R 8 is optionally substituted with one or two substituents selected from: halogen, cyano, alkyl C 1-4, C 1-4 haloalkyl, C 1-4 alkoxy, alkanoyl C 1-4;

?

R 'is H, alkyl C 1-4 or alkanoyl C 1-4;

?

R '' is defined as R ';

?

R 'and R' 'taken together with the interconnecting nitrogen atom can form a ring heterocyclic, saturated or unsaturated, of 5, 6 members;

in which at least one of R 3, R 4, R 6 and R 5 is hydrogen; and in which only one group R_ {2} It may be different from hydrogen.

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2. A compound according to claim 1, which it is a compound of formula (IA) fifty in which G, A, p, n, R_ {1}, R 2, R 3, R 4, R 5, R 6 and R 7 are as have defined for the compounds of formula (I) ', or salts of these.

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3. A compound of formula (I) ', according to a any one of claims 1 or 2, selected from the group that consists in: 6'-methyl-1- (4 - {(1S, 5R) -1- [4- (trifluoromethyl) phenyl] -3-azabicyclo [3.1.0] hex-3-yl} butyl) -3,3'- bipyridin-2 (1H) -one; 2'-fluoro-1- (4 - {(1S, 5R) -1- [4- (trifluoromethyl) phenyl] -3-azabicyclo [3.1.0] hex-3-yl} butyl) -3,4'- bipyridin-2 (1H) -one; 2'-fluoro-1- (4 - {(1S, 5R) -1- [4- (trifluoromethyl) phenyl] -3-azabicyclo [3.1.0] hex-3-yl} butyl) -3,3'- bipyridin-2 (1H) -one; 6'-fluoro-1- (4 - {(1S, SR) -1- [4- (trifluoromethyl) phenyl] -3-azabicyclo [3.1.0] hex-3-yl} butyl) -3,3'- bipyridin-2 (1H) -one; 3- (5-pyrimidinyl) -1- (4 - {(1S, 5R) -1- [4- (trifluoromethyl) phenyl] -3-azabicyclo [3.1.0] hex-3-yl} butyl) -2 ( 1H) -pyridinone; 3- (methyloxy) -1- (4 - {(1S, SR) -1- [4- (trifluoromethyl) phenyl] -3-azabicyclo [3.1.0] hex-3-yl} butyl) -2 (1H) -pyridinone; 2-oxo-1- (4 - {(1S, 5R) -1- [4- (trifluoromethyl) phenyl] -3-azabicyclo [3.1.0] hex-3-yl} butyl) -1,2-dihydro- 3-pyridinecarboni-
trilo; 3-methyl-1- (4 - {(1S, 5R) -1- [4- (trifluoromethyl) phenyl] -3-azabicyclo [3.1.0] hex-3-yl} butyl) -2 (1H) -pyridinone ; 4-methyl-1- (4 - {(1S, 5 R ) -1- [4- (trifluoromethyl) phenyl] -3-azabicyclo [3.1.0] hex-3-yl} butyl) -2 (1H) - pyridinone; 3-methyl-1- (3 - {(1S, 5R) -1- [4- (trifluoromethyl) phenyl] -3-azabicyclo [3.1.0] hex-3-yl} propyl) -2 (1H) -pyridinone ; and you get out of these.

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4. A compound, according to any one of the claims 1 to 3, or a pharmaceutically acceptable salt of this one for use in therapy. 5. A compound, according to any one of the claims 1 to 3, or a pharmaceutically acceptable salt of this, for use in the treatment of a condition in a mammal for which the modulation of the receptors of dopamine D 3. 6. A compound, according to any one of the claims 1 to 3, or a pharmaceutically acceptable salt of this, for use in the treatment of psychosis or a condition psychotic, substance abuse or premature ejaculation. 7. Use of a compound, according to any one of claims 1 to 3, or a pharmaceutically acceptable salt of this, in the manufacture of a medicament for the treatment of a condition in a mammal for which modulation of the dopamine D 3 receptors. 8. Use according to claim 7, wherein the condition is psychosis or a psychotic condition, substance abuse or premature ejaculation. 9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable vehicle.