ES2356843T3 - TRIAZOL DERIVATIVES AS MODULATORS OF D3 DOPAMINE RECEIVERS. - Google Patents

Abstract

A compound of formula (I) or a salt thereof: in which: (R1) p GN (CHR 2) (CH 2) n XR 3 NNNG is a 5- or 6-membered heteroaromatic group, or is a bicyclic heteroaromatic group 9 or 10-member containing one or two heteroatoms independently selected from nitrogen and oxygen, in which G is not pyridyl, indazolyl or benzothiazolyl; p is an integer that varies from 0 to 4; R1 is independently selected from a group consisting of: halogen, hydroxy, cyano, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 alkanoyl or SF5; or corresponds to a group R5; R2 is hydrogen or C1-4 alkyl; n is 2 or 3; X is S or -CH2-; R3 is C1-4 alkyl; R4 is hydrogen, or a phenyl group, a heterocyclyl group, a 5- or 6-membered heteroaromatic group, or an 8 to 11-membered bicyclic group, any of the groups being 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 and C1-4 alkanoyl; R5 is isoxazolyl, -CH2-N-pyrrolyl, 1,1-dioxide-2-isothiazolidinyl, thienyl, thiazolyl, pyridyl or 2 pyrrolidinonyl, and in which each group is optionally substituted with one or two substituents selected from: halogen, cyano , C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy and C1-4 alkanoyl.

Description

The present invention relates to new compounds, the processes for their preparation, the intermediate compounds used in these processes, the pharmaceutical compositions containing them and their use in therapy, as modulators of D3 dopamine receptors.

5 WO 2002/40471 (SmithKline Beecham) describes certain benzazepine compounds that have activity at the D3 dopamine receptor.

WO2004 / 031181 describes sulfonamide derivatives of formula (I)

image 1 image 1 image 1 R2 TO R1

image 1

image 1 N

OO S

image 1

BAr2 and Ar1

N R3

which are useful as antipsychotic agents. WO2004 / 069830 describes triazole compounds of formula (I)

They are useful for treating disorders of the central nervous system. WO00 / 42036 triazole compounds of formula (I)

N R1

15 which are suitable for the treatment of diseases that respond to the influence of dopamine D3 receptor ligands. A patent application has recently been published as WO 2005/080382 and describes the following compounds of formula (I) or a salt thereof: N image2 N (CHR2) (CH2) 2 S image 1 N

(I) N

R4 (R1) p

R3

image 1

image3

image4

20 in which  G is selected from a group consisting of: phenyl, pyridyl, benzothiazolyl, indazolyl;

5

10

fifteen

twenty

25

30

35

40

 p is an integer that varies from 0 to 5;

 R1 is independently selected from a group consisting of: halogen, hydroxy, cyano, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 alkanoyl; or corresponds to a group R5;

 R2 is hydrogen or C1-4 alkyl;

 R3 is C1-4 alkyl;

R4 is hydrogen, or a phenyl group, a heterocyclyl group, a 5- or 6-membered heteroaromatic group, or an 8 to 11-membered bicyclic group, any of the groups being 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;

 R5 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 is optionally substituted with one or two substituents selected from: halogen, cyano, C1-4 alkyl, C14 haloalkyl, C1-4 alkoxy, C1-4 alkanoyl;

and when R1 is chlorine and p is 1, said R1 is not present in the ortho position with respect to the binding bond with the rest of the molecule; and when R1 corresponds to R5, p is 1.

A new class of compounds having affinity towards dopamine receptors, in particular the D3 dopamine receptor, has been discovered. These compounds have potential in the treatment of conditions in which modulation, especially antagonism / inhibition, of the D3 receptor is beneficial, for example to treat drug dependence or as antipsychotic agents.

A new class of compounds having affinity towards dopamine receptors, in particular the D3 dopamine receptor, has been discovered. These compounds have potential in the treatment of conditions in which modulation, especially antagonism / inhibition, of the D3 receptor is beneficial, for example to treat drug dependence or as antipsychotic agents.

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

NN image2 N (CHR2) (CH2) n X

(I)

N R4

(R1) p image 1 R3

in which:

G is a 5 or 6 membered heteroaromatic group, or is a 9 or 10 membered bicyclic heteroaromatic group containing one or two heteroatoms independently selected from nitrogen and oxygen, in which G is not pyridyl, indazolyl or benzothiazolyl;

p is an integer that varies from 0 to 4;

R1 is independently selected from a group consisting of: halogen, hydroxy, cyano, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 alkanoyl or SF5; or corresponds to a group R5;

R2 is hydrogen or C1-4 alkyl;

n is 2 or 3;

X is S or –CH2-;

R3 is C1-4 alkyl;

R4 is hydrogen, or a phenyl group, a heterocyclyl group, a 5- or 6-membered heteroaromatic group, or an 8 to 11-membered bicyclic group, any of the groups being 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 and C1-4 alkanoyl;

R5 is isoxazolyl, -CH2-N-pyrrolyl, 1,1-dioxide-2-isothiazolidinyl, thienyl, thiazolyl, pyridyl or 2-pyrrolidinonyl, and in which each group is optionally substituted with one or two substituents selected from: halogen, cyano, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy and C1-4 alkanoyl.

The term "5 or 6 membered heteroaromatic group" refers to an unsaturated carbocyclic ring in which one, two or three of the carbon atoms are replaced by nitrogen, sulfur and / or oxygen. Examples include pyrrolyl, pyrrolinyl, pyrazolinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, furyl, thienyl, thiadiazolyl, triazolyl, thiacinyl, triacinyl, pyridacinyl, pyrimidinyl and pyrazinyl.

The term "9 or 10-membered bicyclic heteroaromatic group containing one or two heteroatoms independently selected from nitrogen and oxygen" refers to a fused 9-membered or 10-membered bicyclic aromatic ring containing one or two heteroatoms independently selected from nitrogen and oxygen. . Examples include indolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzoxazolium, quinolinyl, isoquinolinyl, cinolinyl, phthalacinyl, quinazolinyl and quinoxalinyl.

The term "C1-4 alkyl" refers to an alkyl group having one to four carbon atoms, in all isomeric forms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secbutyl and tert-butyl. The term "n-C1-4 alkyl" refers to unbranched alkyls, as defined above.

The term "C1-4 alkoxy" refers to a straight chain or branched chain alkoxy (or "alkyloxy") group having one to four carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy , sec-butoxy and tert-butoxy.

The term "C1-4 alkanoyl" refers to an alkanoyl group having 1 to 4 carbon atoms, such as methanoyl (or "formyl"), ethanoyl (or "acetyl"), propanoyl, isopropanoyl, butanoyl, isobutanoyl and sec-butanoyl.

The term "halogen" and its abbreviation "halo" refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I). When the term "halo" is used before another group, it indicates that the group is substituted by one, two

or three halogen atoms. For example, "C1-4 haloalkyl" refers to groups such as trifluoromethyl, bromoethyl, trifluoropropyl and other groups derived from C1-4 alkyl groups, as defined above and the term "C1-4 haloalkoxy" refers to groups such as trifluoromethoxy, bromoethoxy, trifluoropropoxy and other groups derived from C1-4 alkoxy groups as defined above.

The term "5 or 6 membered heteroaromatic group" refers to a monocyclic 5 or 6 membered heterocyclic group containing 1, 2, 3 or 4 heteroatoms, for example 1 to 3 heteroatoms, selected from O, N and S. When the group contains 2-4 heteroatoms, one can be selected from O, N and S and the other heteroatoms can be N. Examples of the 5 and 6 member heteroaromatic groups include pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl , isothiazolyl, thiazolyl, furyl, thienyl, thiadiazolyl, pyridyl, triazolyl, triacinyl, pyridacinyl, pyrimidinyl and pyrazinyl.

The term "bicyclic group of 8 to 11 members" refers to a bicyclic ring system containing a total of 8, 9, 10 or 11 carbon atoms, in which 1, 2, 3 or 4 or 5 of the atoms Carbon are optionally substituted with a heteroatom independently selected from O, S and N. The term includes bicyclic systems in which both rings are aromatic, as well as bicyclic ring systems in which one of the rings is partially or completely saturated. Examples of bicyclic groups of 8 to 11 members in which both rings are aromatic include indenyl, naphthyl and azulenyl. Examples of bicyclic groups of 8 to 11 members having 1, 2, 3, 4 or 5 heteroatoms, in which both rings are aromatic, include: 6H-thieno [2,3-b] pyrrolyl, imidazo [2,1 -b] [1,3] thiazolyl, imidazo [5,1-b] [1,3] thiazolyl, [1,3] thiazolo [3,2-b] [1.2.4] triazolyl, indolyl, isoindolyl, indazolyl , benzimidazolyl, for example, benzimidazol-2-yl, benzoxazolyl, for example, benzoxazol-2-yl, bencisoxazolyl, benzothiazolyl, bencisothiazolyl, benzothienyl, benzofuranyl, naftridinyl, quinolyl, quinoxalinyl, quinolineloxy cininoyloyl. Examples of 8 to 11 membered bicyclic groups having 1, 2, 3, 4 or 5 heteroatoms, in which one of the rings is partially or completely saturated include dihydrobenzofuranyl, indanyl, tetrahydronaphthyl, indolinyl, isoindolinyl, tetrahydroisoquinolinyl, tetrahydroquinolyl, benzoxacinyl and benzoazepinyl.

The term "heterocyclyl" refers to a monocyclic group of 5 or 6 members or bicyclic of 8 to 11 members in which 1, 2, 3, 4 or 5 of the carbon atoms are replaced by a heteroatom independently selected from O, S and N and that is partially or completely saturated. Examples of "heterocyclyl" which are monocyclic 5 or 6 membered fully saturated include pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isothiazolyl, thiazolyl, tetrahydrofuranyl, dioxolanyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl, dioxanyl, tetrahydro-2H-pyranyl and dithianyl. Examples of "heterocyclyl" groups that are partially saturated 5- or 6-membered monocyclic rings include oxazolinyl, isoaxazolinyl, imidazolinyl, pyrazolinyl, 1,2,3,6-tetrahydropyridyl, and 3,6-dihydro-2H-pyranyl. Examples of "heterocyclyl" groups that are fully saturated 8 to 11-membered bicyclic rings include decahydroquinolinyl, octahydro-2H-1,4benzoxacinyl and octahydro-1H-cyclopenta- [b] pyridinyl. Examples of "heterocyclyl" groups that are 8 to 11 partially saturated bicyclic rings include 2,3-dihydro-1H-indolyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl and 2,3 , 4,5-tetrahydro-1H-3-benzazepinyl.

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, 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 acids. tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, formic, propionic, glycolic, gluconic, maleic, succinic, canforsulfuric, isotionic, mucic, gentisic, isonicotinic, saccharic, glucuronic, ascorbic, phranic, ascorbic, ascorbic 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 (Nmethylglucamine), 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, G is a 5- or 6-membered heteroaromatic group containing one or two heteroatoms independently selected from nitrogen and oxygen, which is not pyridyl.

In one embodiment, G is furanyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, oxazolyl, imidazolyl, pyrazolidinyl, isoxazolyl, pyranyl, pyridinyl, pyridacinyl, pyrimidinyl, thienyl or pyrazinyl.

In another embodiment, G is pyrimidinyl.

In one embodiment, G is a 9 or 10-membered bicyclic heteroaromatic group containing one or two heteroatoms independently selected from nitrogen and oxygen, which is not indazolyl.

or benzothiazolyl. In one embodiment, G is indolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzoxazolium, quinolinyl, isoquinolinyl, cinolinyl, phthalacinyl, quinazolinyl or quinoxalinyl. For example, G is quinolinyl or benzoxazolyl.

In another embodiment G is quinolinyl or benzoxazolyl.

In one embodiment, R1 is C1-4 alkyl.

In one embodiment, R2 is hydrogen.

In one embodiment, p is 0 or 1.

In one embodiment, n is 2.

In one embodiment, R5 is a group selected from: isoxazolyl, 2-pyrrolidinonyl, 1,1-dioxide-2-thiazolidinyl which is optionally substituted with one or two substituents selected from: halogen, cyano, C1-2 alkyl (for example, methyl) , C1-2 haloalkyl (for example, trifluoromethyl), C1-2 alkoxy (for example, methoxy) and C1-3 alkanoyl (for example, acetyl). For example, R5 is isoxazolyl, 2-pyrrolidinonyl, CH2-N-pyrrolyl, 1,1-dioxide-2-isothiazolidinyl, 2-thienyl, 2-pyridyl or 2-thiazolyl.

In one embodiment, p is 1 or 2.

In another embodiment p is 0.

In one embodiment X is -S-.

In one embodiment, R 4 is optionally substituted phenyl (e.g., phenyl, 4-trifluoromethyl-phenyl, 3,4-difluorophenyl), an optionally substituted bicyclic group such as quinolinyl (e.g., 2-methylquinoline, 8-fluoro-2- methylquinoline), an optionally substituted pyranyl (e.g., 4-tetrahydro-2H-pyranyl), an optionally substituted pyridinyl (e.g., 3-methyl-2-pyridinyl, 2-methyl-3-pyridinyl, 3- pyridinyl, 2-methyl-6-trifluoromethyl-3

5

10

fifteen

twenty

25

30

pyridinyl), an optionally substituted pyrazolyl (e.g., 5-chloro-1-methyl-1H-pyrazol-4-yl, 1-methyl-3trifluoromethyl-1H-pyrazol-4-yl, 1,5-dimethyl-1H -pyrazolyl-4-yl), an optionally substituted pyrimidyl (e.g., 5-pyrimidinyl), an optionally substituted pyridacinyl (e.g., 4-pyridacinyl), an optionally substituted pyrazinyl (e.g., 5-methyl- 2-pyrazinyl), an optionally substituted furanyl (e.g., 3-methyl-2-furanyl, 2,5-dimethyl-3-furanyl), an optionally substituted thienyl (e.g., 5-chloro-2- thienyl), an optionally substituted oxazolyl (e.g., 4-methyl-1,3-oxazol-5-yl, 2-methyl-5-trifluoromethyl-1,3-oxazol-4-yl), an optionally substituted isoxazolyl (e.g., 3-methyl-5-isoxazolyl), an optionally substituted thiazolyl (e.g., 2,4-dimethyl-1,3-thiazol-5-yl), an optionally substituted triazolyl (e.g., 1-methyl-1H-1,2,3-triazol-4-yl).

In another embodiment R4 is optionally substituted phenyl (for example phenyl, 4-trifluoromethyl-phenyl, 3,4-difluorophenyl) or optionally substituted oxazolyl (for example 4-methyl-1,3-oxazol-5-yl, 2-methyl- 5trifluoromethyl-1,3-oxazol-4-yl).

In one embodiment, R3 is methyl.

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

It will be appreciated that, as with most biologically active molecules, the level of biological activity may vary between the individual stereoisomers 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 show appropriate biological activity with reference to the procedures described herein. .

Due to the presence of the fused cyclopropane, it is believed that the compounds of formula (I) have a "cis" arrangement of the substituents (the two groups attached to the bicyclic ring system are on the same side of this bicyclic ring system). In another embodiment of the present invention, compounds of formula (I) 'are provided which correspond to compounds of formula (I) having a "cis" arrangement, represented by highlighting the links in bold:

N

image5 H image 1 N

N (CHR2) (CH2) n X

(I) 'N R4 R3

(R1) p

wherein G, p, R1, R2, R3 and R4 are as defined above for the compounds of formula (I).

The two configurations of the compounds of formula (I) ’are shown below:

image 1

In a further embodiment of the present invention, compounds of formula (IA) corresponding to the stereochemical isomers of compounds of formula (I) ’, enriched in the configuration (1S, 5R) or (1R, 5R) are provided

N image5 H 5 image 1 NN (CHR2) (CH2) n X

(IA) 1 N R4

(R1) p

R3

5

wherein G, p, X, n, R1, R2, R3, R4 and R5 are as defined above for the compounds of formula (I) 'or a salt thereof.

In a further embodiment of the present invention, compounds of formula (IB) corresponding to the stereochemical isomers of compounds of formula (I) ', enriched in configuration (1R, 5S) or (1S, 5S) are provided :

N image5 H image 1 N5 N (CHR2) (CH2) n X

(IB) 1 N R4

(R1) p

R3

wherein G, p, X, n, R1, R2, R3, R4 and R5 are as defined above for the compounds of formula (I) 'or a salt thereof.

In the context of the present invention, it is intended that stereochemical isomers

15 enriched in the configuration (1S, 5R) or (1R, 5R) of formula (IA) correspond in one embodiment to at least 90% e.e. In another embodiment, the isomers correspond to at least 95% e.e. In another embodiment, the isomers correspond to at least 99% e.e.

In the context of the present invention, it is intended that the stereochemical isomers enriched in the configuration (1R, 5S) or (1S, 5S) of formula (IB) correspond in one embodiment to at least 90% e.e. In another embodiment, the isomers correspond to at least 95% e.e. In other

embodiment, the isomers correspond to at least 99% e.e.

In another embodiment, a compound of formula (IC) or a salt thereof is provided, wherein R1, p, R3 and R4 are as defined for formula (I):

5

10

fifteen

twenty

25

30

N

image 1 image 1 N image 1 N (CH2) 3 S

image 1 (IC) N

R4 R3 image 1

N (R1) p OR

In Formula (IC), in one embodiment, R3 is methyl. R4 may be phenyl, heterocyclyl, 5- or 6-membered heteroaromatic group or a 9 to 11-membered bicyclic group, any of which is optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of: halogen, hydroxy , oxo, cyano, nitro, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 alkoxy, C 1-4 fluoroalkoxy and C 1-4 alkanoyl. Examples of R4 include optionally substituted phenyl (e.g., phenyl, 4-trifluoromethyl-phenyl, 3,4-difluorophenyl), an optionally substituted bicyclic group such as quinolinyl (e.g., 2-methylquinoline, 8-fluoro-2-methylquinoline ), an optionally substituted pyranyl (e.g., 4-tetrahydro-2H-pyranyl), an optionally substituted pyridinyl (e.g., 3-methyl-2-pyridinyl, 2-methyl-3-pyridinyl, 3-pyridinyl , 2-methyl-6-trifluoromethyl-3-pyridinyl), an optionally substituted pyrazolyl (e.g., 5-chloro-1-methyl-1H-pyrazol-4-yl, 1-methyl-3trifluoromethyl-1H-pyrazole-4- ilo, 1,5-dimethyl-1H-pyrazolyl-4-yl), an optionally substituted pyrimidyl (e.g., 5-pyrimidinyl), an optionally substituted pyridacinyl (e.g., 4-pyridacinyl), an optionally substituted pyrazinyl ( eg, 5-methyl-2-pyrazinyl), an optionally substituted furanyl (eg, 3-methyl-2-furanyl, 2,5-dimethyl-3-furanyl), an optionally substituted thienyl (e.g. eg, 5-chloro-2-thienyl), an optionally substituted oxazolyl te (e.g., 4-methyl-1,3-oxazol-5-yl, 2-methyl-5-trifluoromethyl-1,3-oxazol-4-yl), an optionally substituted isoxazolyl (e.g., 3-methyl-5-isoxazolyl), an optionally substituted thiazolyl (e.g., 2,4-dimethyl-1,3-thiazol-5-yl), an optionally substituted triazolyl (e.g., 1-methyl-1H- 1,2,3-triazol-4-yl).

In one embodiment, for the compounds of formula (IC), p is 1 and R 1 is C 1-4 alkyl (for example ethyl).

In another embodiment, a compound of formula (ID) or a salt thereof is provided, wherein R1, p, R3 and R4 are as defined for formula (I):

N

image 1 image 1 N image 1 N (CH2) 3 S

image 1 (ID) N

R4 R3 image 1

(R1) p

N

In Formula (ID), in one embodiment, R3 is methyl. R4 may be phenyl, heterocyclyl, 5- or 6-membered heteroaromatic group or a 9 to 11-membered bicyclic group, any of which is optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of: halogen, hydroxy , oxo, cyano, nitro, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 alkoxy, C 1-4 fluoroalkoxy and C 1-4 alkanoyl. Examples of R4 include those defined above for the compounds (IC).

In one embodiment, for the compounds of formula (ID), p is 1 and R 1 is C 1-4 alkyl (for example methyl).

In another embodiment, for the compounds of formula (ID), p is 0.

In another embodiment, a compound of formula (IE) or a salt thereof is provided, wherein R1, p, R3 and R4 are as defined for formula (I):

image 1

N

image 1 N image 1 N (CH2) 3 S

image 1 (IE) N

R4 image 1 N R3

(R1) p N

In Formula (IE), in one embodiment, R3 is methyl. R4 may be phenyl, heterocyclyl, 5- or 6-membered heteroaromatic group or a 9 to 11-membered bicyclic group, any of which is optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of: halogen,

5 hydroxy, oxo, cyano, nitro, C1-4 alkyl, C1-4 fluoroalkyl, C1-4 alkoxy, C1-4 fluoroalkoxy and C1-4 alkanoyl. Examples of R4 include those defined above for the compounds (IC).

In one embodiment, for the compounds of formula (IE), p is 0.

In a further embodiment of the present invention, compounds of formula (IF) corresponding to the stereochemical isomers of compounds of formula (IC), enriched in the configuration (1S, 5R) are provided:

N

image 1 image 1 image 1 NH image 1 N (CH2) 3 S

image 1 (IF) N

R4 image 1 R3

N (R1) p O

wherein R1, R2, R3 and R4 are as defined above for the compounds of formula

(I) or a salt thereof.

In a further embodiment of the present invention, compounds of formula 15 (IG) corresponding to the stereochemical isomers of compounds of formula (IC), enriched in the configuration (1R, 5S) are provided:

N

image 1 image 1 NH

image 1 N (CH2) 3 S

image 1 (IG) N

R4 R3 image 1

N (R1) p O

wherein R1, R2, R3 and R4 are as defined above for the compounds of formula

(I) or a salt thereof.

In a further embodiment of the present invention, compounds of formula (IH) corresponding to the stereochemical isomers of compounds of formula (ID), enriched in the configuration (1S, 5R) are provided:

H image 1 image 1 N

image 1 NN (CH2) 3 S

image 1 image 1 (IH) N

image 1 R4 image6 R3

(R1) p

10

fifteen

twenty

25

30

wherein R1, R2, R3 and R4 are as defined above for the compounds of formula

(I) or a salt thereof.

In a further embodiment of the present invention, compounds of formula (IL) corresponding to the stereochemical isomers of compounds of formula (ID), enriched in the configuration (1R, 5S) are provided:

image 1 H image 1 image 1 N

image 1 NN (CH2) 3 S

image 1 (IL) N

R4 R3

(R1) p

N

wherein R1, R2, R3 and R4 are as defined above for the compounds of formula

(I) or a salt thereof.

In a further embodiment of the present invention, compounds of formula (IM) corresponding to the stereochemical isomers of compounds of formula (IE), enriched in the configuration (1R, 5R) are provided:

H image 1 image 1 N

image 1 NN (CH2) 3 S

image 1

image 1 N

image 1 R4 image 1 R3

(R1) p image 1 N

image 1 N

(IM)

wherein R1, R2, R3 and R4 are as defined above for the compounds of formula

(I) or a salt thereof.

In a further embodiment of the present invention, compounds of formula (IN) corresponding to the stereochemical isomers of compounds of formula (IE), enriched in the configuration (1S, 5S) are provided:

image 1 H image 1 image 1 N

image 1 NN (CH2) 3 S

N

image 1 R4 R3

(R1) p image 1 N

image 1 N

(IN)

wherein R1, R2, R3 and R4 are as defined above for the compounds of formula

(I) or a salt thereof.

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

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

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

In addition, prodrugs are also included within the context of this invention. As used herein, the term "prodrug" refers to a compound that is converted, inside the body, for example, by hydrolysis in the blood, into its active form that has medical effects. Pharmaceutically acceptable prodrugs are described by T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and in D. Fleisher, S. Ramon and H. Barbra "Improved oral drug delivery: solubility limitations overcome by the use of prodrugs ”, Advanced Drug Delivery Reviews (1996) 19 (2) 115-130, each incorporated herein by reference.

Prodrugs are any covalently bound vehicle that releases a compound of structure (I) in vivo when said prodrug is administered to a patient. Prodrugs are generally prepared by modifying functional groups such that the modification is cleaved, by routine manipulation or in vivo, producing the parent compound. Prodrugs include, for example, compounds of this invention in which the hydroxy, amine or sulfhydryl groups are attached to any group that, when administered to a patient, is cleaved to form the hydroxy, amine groups

or sulfhydryl. Thus, representative examples of prodrugs include (but are not limited to) acetate, format and benzoate derivatives of alcohol, sulfhydryl and amine functional groups of the compounds of structure (I). In addition, in the case of a carboxylic acid (-COOH), esters, such as methyl esters, ethyl esters and the like can be used. The esters can be active by themselves and / or can be hydrolyzed under conditions in vivo in the human body. Suitable pharmaceutically acceptable in vivo hydrolyzable ester groups include those that readily degrade in the human body to leave the acid of origin or its salt.

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

Those skilled in the art will appreciate that in the preparation of the compound of the invention or one of its solvates, it may be necessary and / or desirable to protect one or more sensitive groups in the molecule to prevent undesirable side reactions. Protective groups suitable for use according to the present invention are well known to those skilled in the art and can be used in a conventional manner. 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 include acyl type protecting groups (for example, formyl, trifluoroacetyl, acetyl), aromatic urethane type protecting groups (for example, benzyloxycarbonyl (Cbz) and substituted Cbz), aliphatic urethane type protecting groups (for example, 9-fluorenylmethoxycarbonyl (Fmoc), t-butyloxycarbonyl (Boc), isopropyloxycarbonyl, cyclohexyloxycarbonyl) and alkyl-type protecting groups (for example, benzyl, trityl, chlorotrityl). Examples of suitable oxygen protecting groups may include, for example, alkylsilyl groups, such as trimethylsilyl or tert-butyldimethylsilyl; alkyl ethers, such as tetrahydropyranyl or tert-butyl; or esters such as acetate.

When a specific enantiomer of a compound of general formula (I) is required, it can be obtained, for example, by resolution of a corresponding enantiomeric mixture of a compound of formula (I) using conventional methods. Therefore, the required enantiomer can be obtained from the racemic compound of formula (I) by the use of a chiral HPLC method.

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

The compounds of the present invention and salts of said compounds containing 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 3H, 14C are incorporated, are useful in tissue distribution assays of drugs and / or substrates. Particularly preferred are tritium isotopes, i.e. 3H, and carbon-14, i.e. 14C, for their ease of preparation and detection. Isotopes 11C and 18F are particularly useful in PET (positron emission tomography), and isotope 125I 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. 2H, may provide certain therapeutic advantages resulting from greater metabolic stability, for example, a greater half-life in vivo or lower dosage requirements and, therefore, may be preferred in Some circumstances The isotope-labeled compounds of formula I and following of this invention can be prepared, in general, by performing the procedures described in the Schemes

5

10

fifteen

twenty

25

30

and / or in the Examples shown below, substituting an unlabeled reagent with isotopes for a readily available isotope labeled reagent.

In one embodiment of the present invention, compounds with a molecular weight of 800 or less are provided. In another embodiment, compounds having a molecular weight of 600 or less are provided. In general, and not limited to the same, such compounds may have greater oral bioavailability and sometimes greater solubility and / or brain penetration. The molecular weight herein refers to that of the compound as a free base without solvating, excluding any contribution to the molecular weight of the addition salts, solvent molecules (eg water), molecular parts of the prodrug cleaved in vivo, etc.

In general, it should be construed that the compounds or salts of the invention exclude compounds (if any) that are so chemically unstable, either by themselves or in water, that they are clearly unsuitable for pharmaceutical use by all routes of administration, whether oral, parenteral or in any other way. Such compounds are known to the skilled chemist. Prodrugs or compounds that are stable ex vivo and that are convertible in the body of mammals (eg, the human being) into inventive compounds are however included.

Exemplary compounds of the present invention include:

2-methyl-6 - [(1R, 5S / 1S, 5R) -3- (3 - {[4-methyl-5- (4-methyl-1,3-oxazol-5-yl) -4H-1, 2,4-triazol-3-yl] thio} propyl) -3azabicyclo [3.1.0] hex-1-yl] quinoline;

2-ethyl-5 - [(1R, 5S / 1S, 5R) -3- (3 - {[4-methyl-5- (4-methyl-1,3-oxazol-5-yl) -4H-1, 2,4-triazol-3-yl] thio} propyl) -3azabicyclo [3.1.0] hex-1-yl] -1,3-benzoxazole;

5 - [(1R, 5S / 1S, 5R) -3- (3 - {[4-methyl-5- (4-methyl-1,3-oxazol-5-yl) -4H-1,2,4- triazol-3-yl] thio} propyl) -3azabicyclo [3.1.0] hex-1-yl] quinoline;

(1S, 5S / 1R, 5R) -3- (3 - {[4-methyl-5- (4-methyl-1,3-oxazol-5-yl) -4H-1,2,4-triazol-3 -il] thio} propyl) -1- (2-pyrimidinyl) -3-azabicyclo [3.1.0] texan;

(1S, 5S / 1R, 5R) -3- (3 - {[5- (3,4-difluorophenyl) -4-methyl-4H-1,2,4-triazol-3-yl] thio} propyl) - 1- (2-pyrimidinyl) -3azabicyclo [3.1.0] hexane;

and you leave them.

The present invention also provides a process for preparing a compound of formula (I), or one thereof as defined above, said process comprising reacting a compound of formula (II):

NH

(R1) p

image2

(II) in which R1, p and G are as defined for formula (I), with a compound of formula

(III): N N

L (CHR2) (CH2) n X

N

R4

image 1 R3

(III) in which X, n, R2, R3 and R4 are as defined for formula (I) and L is a leaving group, and thereafter optionally:

(i)

 remove any protective group; I

(ii)

 form a salt; I

(iii) convert a compound of formula (I) or a salt thereof into another compound of formula (I) or a salt thereof.

The above process can be performed using conventional methods for the formation of a

5 tertiary amine. The leaving group L may be a halogen, such as chlorine. Alternatively, L may be a sulfonyloxy group such as C 1-4 alkylsulfonyloxy (for example, methanesulfonyloxy), C 1-4 alkylsulfonyloxy or C 1-4 haloalkylsulfonyloxy (for example, trifluoromethanesulfonyloxy); or arylsulfonyloxy in which the aryl is optionally substituted phenyl, an optionally substituted 5 or 6 membered heteroaromatic group or an optionally substituted bicyclic group, for example optionally substituted phenyl, wherein in each

10 case the optional substituents are one or more C alkyl groups; for example, para-toluenesulfonyloxy.

1-2

When L is a halogen, the reaction can be carried out using a base such as potassium carbonate in the presence of a iodide source such as sodium iodide in a solvent such as N, N-dimethylformamide at a suitable temperature, for example at 60 ° C.

The compounds of formula (II) can be prepared by methods well known in the art

15 (for example, J. Med. Chem. 1981, 24, 481-490; and Adv. Synth. Catal. 2001, 343 (3), 299). Interconversion of R1 groups can be accomplished by methodology well known in the art (for example, 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).

Another general route that can be used for the preparation of a compound of formula (II) is as follows:

OR

NH NH2

image5 image 1 image2 O (R1) p (R1) p (a) (IV) (V)

image5 OO NH image5 NH

image 1

O O (R1) p (R1) p (b)

(V) (VI) OR

image2 O (c) (R1) p (R1) p (II)

(SAW)

wherein step (a) means the diazotization of an aniline (IV), followed by reaction with

maleimide to provide 3-arylmaleimide (V); step (b) means the cyclopropagation of (V) for

provide the bicyclic imide (VI); and step (c) means the reduction of the imide (VI) to provide

The compounds of formula (II).

Step (a) can be performed using conventional methods for the Meerwein reaction (for example J. Am. Chem. Soc. 1955, 77, 2313 describes the formation of arylmaleimides using this approach). Alternatively, in many cases this step is properly performed by applying a procedure in which to a mixture of maleimide, an appropriate copper (II) salt such as CuCl2

NH

NH

image2

image 1

5

10

fifteen

twenty

25

30

anhydrous, and a suitable organonitrite, such as tert-butyl nitrite, in a compatible solvent, such as acetonitrile, a solution of a compound of formula (IV) is slowly added. This is followed by a period of time during which it is allowed to react as appropriate and an appropriate treatment.

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

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

An alternative synthetic process for the preparation of compounds of formula (II) is shown below:

N image 1 PG YO

R14

image 1 (R1) p

image 1 (R1) pBO

R14

N PG + (a ') (VII) (VIII) (IX)

image2

image2

image2 NPG NH

(R1) p (R1) p (b ')

image2

image 1

(IX) (X)

in which:

R1, p and G are as defined for formula (I), R14O 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 following stages:

step (a ’) means the coupling reaction of a (2,5-dihydro-1H-pyrrol-3-yl) boronate

(VII) with the halogen derivative or aromatic sulfonyloxy (VIII);

step (b ’) means the cyclopropagation of (IX) followed, if appropriate, of deprotection to provide the bicyclic amine (II).

Step (a ') can be performed using conventional Suzuki coupling methods, for example using tetrakis (triphenylphosphine) palladium (0) as a source of catalytic palladium (0) in the presence of cesium fluoride, in an appropriate solvent such as tetrahydrofuran at a suitable temperature (R14O) 2B may suitably be 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl and benzyl PG, which represents a compound of structure (X) as reported in Synlett 2.002 , 5, 829-831.

Step (b ') consists of a cyclopropane reaction carried out, for example, using the reagent generated from trimethylsulfoxonium iodide and a suitable base such as sodium hydride, in a compatible solvent, for example, dimethylsulfoxide, followed by a deprotection reaction.

Another general scheme that could be used for the preparation of a compound of formula

(II) is as follows:

image2

image2

image5

image5

image2

OR

(R1) p

Br + CO2Me CO2Me (R1) p (a ''') image 1 CO2Me CO2Me (R1) p (b ''') image 1 CO2Me CO2Me (R1) p (c ''') image 1 NH O (d ''') (R1) p image 1 NH

5

The step (a ’’ ’) is a coupling reaction, mediated, for example, by palladium using diethyl maleate or fumarate as a common reagent (e.g. Tetrahedron, 2002, 58, 6545). Stage (b ’’) is a cyclopropagation procedure, based, for example, on trimethylfulfoxonium iodide. The stage (c ’’) is an ester hydrolysis stage and post-imide cyclization, using, for example, urea. Finally, after stage (d ’’), a compound of formula (II) can be obtained after a reduction procedure based on vitride or borane.

10

A compound of formula (III), in which X is -S-, can itself be prepared by reacting a compound of formula (XII):

image7

(XII)

wherein R3 and R4 are as defined hereinbefore; with a compound of formula (XIII): L (CHR2) (CH2) 2Y 15 (XIII) in which R2 is defined as for formula (I) and L and Y are leaving groups, for example, a bromine or chlorine. Interconversion reactions between compounds of formula (I) and their salts can be performed using methods well known in the art. Examples include: (i) converting one or more of R 1 from alkoxy (eg, methoxy) into hydroxy,

(ii) converting one or more of R 1 from hydroxy to sulfonyloxy, such as alkylsulfonyloxy or haloalkylsulfonyloxy, for example methanesulfonyloxy or alkylsulfonyloxy or trifluoro-methanesulfonyloxy,

(iii) convert one or more of R 1 of halogen or perfluoroalkylsulfonyloxy into cyano;

and optionally after this forming a salt of formula (I).

It has been found that the compounds of formula (I) have affinity towards dopamine receptors, in particular the D3 receptor and can be expected to be useful in the treatment of pathological conditions that require modulation of said receptors, such as under psychotic conditions. .

Such affinity is generally calculated from the IC50 as the concentration of a compound necessary to displace 50% of the radiolabeled ligand of the receptor and is presented as a value of 30 "Ki" calculated by the following equation:

image 1

in which L = radioligand and KD = affinity of radioligand for the receptor (Cheng and Prusoff, Biochem. Pharmacol. 22: 3099, 1973).

In the context of the present invention pKi (corresponding to the Ki antilogarithm) is used in

The Ki site and the compounds of the present invention generally show a pKi greater than 6.5. In one aspect, the present invention provides compounds of formula (I) having a pKi between 6.5 and 8. In another aspect, the present invention provides compounds of formula (I) that have a pKi between 8 and 9. In a further aspect, the present invention provides compounds of formula (I) having a pKi greater than 9.

fifteen

It has also been found that many of the compounds of formula (I) have a greater affinity towards D3 dopamine receptors than towards D2 receptors. 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 recently characterized dopamine D3 receptor blockade may produce beneficial antipsychotic activity without significant episodes (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 the present invention are provided which have greater (e.g., �10x or �100x greater) affinity towards D3 dopamine receptors than towards D2 dopamine receptors (such affinity can be measured using standard methodology, for example , using cloned dopamine receptors - see here). Such compounds may conveniently be used as selective modulators of D3 receptors.

From the location of D3 receptors, it could also be considered that the compounds could also be useful for the treatment of a disorder related to a substance in which it has been suggested that D3 receptors are involved (for example, see Levant, 1997 , Pharmacol. Rev., 49, 231-252). Examples of such substance abuse include addiction to alcohol, cocaine, heroin and nicotine. The compounds of formula (I) can be used for the treatment of all aspects of drug dependence that include drug use, relapse in drug-seeking behavior after withdrawal and withdrawal symptoms from drug addiction such such as alcohol, cocaine, opiates, nicotine, benzodiazepines and inhibition of tolerance induced by opioids. In addition, the compounds of formula (I) and their salts and solvates can be used to reduce the craving for drug use and will therefore be useful in the treatment of craving for drug use. The craving for drug use can be defined as the motivation for the stimulus to administer a psychoactive substance that had previously been consumed. Three major factors are involved in the development and maintenance of the craving for drug use: (1) Dysphoric states during drug withdrawal can function as a negative enhancer that leads to the craving for drug use; (2) The environmental stimuli associated with the effects of drugs can become progressively more potent (sensitization) to control the search or craving for drug use and (3) A cognition (memory) of the ability of drugs to favor pleasant effects and relieve a dysphoric state during withdrawal. The craving for drug use may explain the difficulty that people have in abandoning drugs and, therefore, contribute significantly to the development and maintenance of drug dependence.

The compounds of formula (I) are of potential use as antipsychotic agents, for example, in the treatment of schizophrenia, schizoaffective disorders, psychotic depression, mania, paranoid and delusional disorders. In addition, they may be useful as an auxiliary therapy in Parkinson's disease, in particular with compounds such as L-DOPA and possibly dopamine agonists, to reduce the side effects experienced with these treatments in long-term use (for example, see Schwartz et al., Brain Res. Reviews, 1998, 26, 236-242). Other conditions that can be treated with the compounds include dyskinetic disorders such as Parkinson's disease, neuroleptic-induced parkinsonism, and tardive dyskinesias; depression; anxiety, cognitive impairment including memory disorders such as Alzheimer's disease, eating disorders, sexual dysfunction, sleep disorders, emesis, movement disorders, obsessivecompulsive disorders, amnesia, aggression, autism, vertigo, dementia, rhythm disorders circadian, and gastric motility disorders, for example IBS.

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

The compounds of formula (I) are also useful for the treatment of premature ejaculation.

In the context of the present invention, the terms describing 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 by 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 the diseases listed below, refer to the classification code in DSM-IV.

In the context of the present invention, the term "substance related disorder" includes:

Substance-related disorders including Substance Use Disorders such as Substance Dependence, Substance Consumption Craving and Substance Abuse; Substance Induced Disorders, such as Substance Intoxication, Substance Abstinence, Substance Induced Delirium, Persistent Substance Induced Dementia, Substance Induced Amnesic Disorder, Substance Induced Psychotic Disorder, Substance Induced Mood Disorder, Substance Induced Disorder Substance Induced Anxiety, Substance Induced Sexual Dysfunction, Substance Induced Sleep Disorder and Persistent Hallucinogenic Perception Disorder (Retrospective Scenes); Alcohol-Related Disorders such as Alcohol Dependence (303.90), Alcohol Abuse (305.00), Alcohol Poisoning (303.00), Alcohol Withdrawal (291.81), Alcohol Intoxication Delirium, Alcohol Withdrawal Delirium, Persistent Dementia Alcohol-induced, alcohol-induced persistent amnesic disorder, alcohol-induced psychotic disorder, alcohol-induced mood disorder, alcohol-induced anxiety disorder, alcohol-induced sexual dysfunction, alcohol-induced sleep disorder and unspecified another way related to alcohol (291.9); disorders related to amphetamines (or amphetamine-like substances) such as amphetamine dependence (304.40), amphetamine addiction (305.70), amphetamine poisoning (292.89), amphetamine withdrawal (292.0), amphetamine poisoning delirium, amphetamine-induced psychotic disorder, amphetamine-induced mood disorder, amphetamine-induced anxiety disorder, amphetamine-induced sexual dysfunction, amphetamine-induced sleep disorder, and unspecified amphetamine-related disorder (292.9); caffeine-related disorders such as caffeine intoxication (305.90), caffeine-induced anxiety disorder, caffeine-induced sleep disorder and unspecified caffeine-related disorder (292.9); marijuana-related disorders, such as marijuana dependence (304.30), marijuana abuse (305.20), marijuana poisoning (292.89), marijuana intoxication delirium, marijuana-induced psychotic disorder, marijuana-induced anxiety disorder and Marijuana-related disorder not otherwise specified (292.9); Cocaine-Related Disorders, such as the Cocaine Dependence (304.20), Cocaine Abuse (305.60), Cocaine Poisoning (292.89), Cocaine Withdrawal (292.0), Cocaine Intoxication Delirium, Cocaine Induced Psychotic Disorder, Cocaine Induced Emotional State Disorder, Cocaine Induced Anxiety Disorder, Cocaine Induced Sexual Dysfunction, Cocaine Induced Sleep Disorder, and Cocaine Related Disorder Not Specified Otherwise (292.9); Hallucinogen Related Disorders, such as Hallucinogen Dependency (304.50), Hallucinogen Addiction (305.30), Hallucinogen Poisoning (292.89), Hallucinogenic Disorder with Persistent Perception (Retrospective Scenes) (292.89), Intoxication Trauma, Intoxication Hallucinogen Induced Psychotic, Hallucinogen Induced Emotional State Disorder, Hallucinogen Consumption Induced Anxiety Disorder, and Hallucinogen Related Disorder Not otherwise specified (292.9); Inhaler-Related Disorders such as Inhaler Unit (304.60), Inhaler Addiction (305.90), Inhaler Poisoning (292.89), Inhaler Intoxication Delirium, Inhaler-Induced Persistent Dementia, Inhaler-Induced Psychotic Disorder, Emotional State Disorder Inhalers-Induced, Inhalers-Induced Anxiety Disorder and Inhalers-Related Disorder Not Otherwise Specified (292.9); Nicotine-Related Disorders such as Nicotine Dependence (305.1), Nicotine Withdrawal (292.0) and Nicotine-Related Disorder Not Specified Otherwise (292.9); Opioid Related Disorders, such as Opioid Dependency (304.00), Opioid Abuse (305.50), Opioid Intoxication (292.89), Opioid Withdrawal (292.0), Opioid Intoxication Delirium, Opioid Induced Psychotic Disorder, Opioid Disorder Opioid Induced Mood, Opioid Induced Sexual Dysfunction, Opioid Induced Sleep Disorder, and Opioid Related Disorder Not Specified Otherwise (292.9); Phencyclidine-Related Disorders (or Phencyclidine Analogs) such as Phencyclidine Dependency (304.60), Phencyclidine Abuse (305.90), Phencyclidine Poisoning (292.89), Phencyclidine Intoxication Delirium, Phencyclical Pituitary Disorder Mood Induced by Phencyclidine, Anxiety Disorder Induced by Phencyclidine and Disorder Related to Phencyclidine Not Specified Otherwise (292.9); Disorders Related to Sedatives, Hypnotics

or Anxiolytics, such as Sedative, Hypnotic or Anxiolytic Dependency (304.10), Sedative, Hypnotic or Anxiolytic Abuse (305.40), Sedative, Hypnotic or Anxiolytic Intoxication (292.89), Sedative, Hypnotic or Anxiolytic (29) Delirium from Sedative, Hypnotic or Anxiolytic Intoxication, Delirium from Sedative, Hypnotic or Anxiolytic Abstinence, Persistent Sedative, Hypnotic or Anxiolytic Dementia, Persistent Sedative, Hypnotic or Anxiolytic Amnestic Disorder, Hypothetical or Hypnotic, Inductant Hypnotic of Emotional State 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 or Anxiety and Relative or Relative Disorders Anxiolytics No Spec In another way (292.9); Disorder Related to Various Substances such as the Dependence of Various Substances (304.80); and other Substance Related (or Unknown) Disorders such as Anabolic Steroids, Nitrate Inhalers and Nitrous Oxide.

In the context of the present invention, the term "psychotic disorder" includes:

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

Therefore, in a further aspect, the present invention provides a method for treating a condition for which modulation [especially inhibition / antagonism (which can also translate into inverse agonism in constitutively active receptor systems)] of dopamine receptors (especially dopamine D3 receptors), which comprises administering to a mammal (eg, a human being) in need of an effective amount of a compound of formula

(I) or a pharmaceutically acceptable salt (ie, physiologically). In one embodiment, the condition is a drug-related disorder, a psychotic disorder or an obsessive-compulsive spectrum disorder or premature ejaculation.

The invention also provides the use of a compound of formula (I) or a salt thereof in the manufacture of a medicament for the treatment of a condition in a mammal for which modulation (especially antagonism / inhibition) of receptors is beneficial. of dopamine (especially D3 dopamine receptors).

The invention also provides a compound of formula (I) or a salt thereof for use in the treatment of a condition in a mammal for which modulation [especially inhibition / antagonism (which can also result in inverse agonism in constitutively active receptor systems)] of dopamine receptors (especially D3 dopamine receptors).

In one embodiment, the compounds of the present invention are used in the treatment of a substance-related disorder, a psychotic disorder, an obsessive compulsive spectrum disorder.

or premature ejaculation.

Thus, in a further aspect, the invention provides a method of treating a psychotic disorder (eg, schizophrenia), a drug-related disorder, an obsessive compulsive spectrum disorder or premature ejaculation, which comprises administering to a mammal (e.g., a human being) in need of an effective amount of a compound of formula (I) as defined herein or a salt thereof.

The use of a compound of formula (I) or a salt thereof in the manufacture of a medicament for the treatment of a psychotic disorder (eg, schizophrenia), a drug-related disorder, a spectrum disorder is also provided. obsessive compulsive or premature ejaculation.

A compound of formula (I) or a salt thereof is also provided for use in the treatment of a psychotic disorder (eg, schizophrenia), a drug-related disorder, an obsessive compulsive spectrum disorder or premature ejaculation.

A compound of formula (I) or a salt thereof is also provided for use as a therapeutic substance in a mammal, for example, for use in the treatment of any of the conditions described herein.

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

For use in medicine, the compounds of the present invention are usually administered in the form of a conventional pharmaceutical composition. Therefore, the present invention provides in a further aspect, a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically (physiologically) acceptable salt thereof and a pharmaceutically (that is, physiologically) acceptable vehicle. The pharmaceutical composition can be used in the treatment of any of the conditions described herein.

The compounds of formula (I) may be administered by any convenient method, for example, by oral, parenteral (eg, intravenous), buccal, sublingual, nasal, rectal or transdermal administration and the pharmaceutical compositions should be adapted accordingly. .

The compounds of formula (I) and their salts that are active when administered orally can be formulated as liquids or solids, for example syrups, suspensions or emulsions, tablets, capsules and tablets.

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

A tablet-shaped composition can be prepared using any pharmaceutically acceptable carrier or vehicles, commonly used to prepare solid formulations. Examples of such vehicles include magnesium stearate, starch, lactose, sucrose and cellulose.

A capsule-shaped composition can be prepared using the usual encapsulation procedures. For example, granules containing the active ingredient can be prepared using normal carriers and then loaded into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any pharmaceutically acceptable carrier or vehicles, for example, aqueous gums, celluloses, silicates or oils and then loading the dispersion or suspension into a soft gelatin capsule.

Typical parenteral compositions consist of a solution or suspension of the compound

or salt in a sterile aqueous vehicle or parenterally acceptable oil, for example, polyethylene glycol, polyvinyl pyrrolidone, lecithin, peanut oil or sesame oil. Alternatively, the solution can be lyophilized and then reconstituted with a suitable solvent just before administration.

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

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

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

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

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

Each dosage unit for oral administration contains, for example, 1 to 250 mg (and for parenteral administration it contains, for example, 0.1 to 25 mg) of a compound of the formula (I).

or a salt thereof calculated as a free base.

The pharmaceutically acceptable compounds of the invention will normally be administered in a daily dosage regimen (for an adult patient) of, for example, an oral dose of between 1 mg and 500 mg, for example between 10 mg and 400 mg, for example between 10 and 250 mg or an intravenous, subcutaneous or intramuscular dose of 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 salt thereof calculated as a free base, the compound being administered 1 to 4 times a day. Suitably, the compounds will be administered during a period of continuous therapy, for example for a week or more.

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Four. Five

Biological Test Methods

The functional potency and intrinsic activity of the compounds of this invention can be measured according to the following GTP�S scintillation proximity test (GTP�S-SPA). The cells used in the study are Chinese Hamster Ovary (CHO) cells.

Cellphone line

CHO_D2

CHO_D3

The compounds can be tested according to two alternative protocols:

a) Cell membranes are prepared as follows. The cell pellets are resuspended in 10 volumes of 50 mM HEPES, 1 mM EDTA pH 7.4, using KOH. On the same day, the following proteases are added to the buffer just before administering the homogenization buffer.

-6

Leupeptin 2.12 x 10 M (Sigma L2884) - 5,000 x stock solution = 5 mg / ml in buffer

Bacitracin 25 ug / ml (Sigma B0125) - stock solution x 1,000 = 25 mg / ml in buffer

1 mM PMSF - 100 x stock solution = 17 mg / ml in 100% ethanol

Pepstatin A 2 x 10-6M - 1,000 x stock solution = 2 mM in 100% DMSO

The cells are homogenized by 2 bursts every 15 seconds in a 1-liter Glass Waring mixer in a class two biohazard cabinet. The resulting suspension is centrifuged at 500 g for 20 min (Beckman T21 centrifuge: 162 rad / s (1,550 rpm)). The supernatant is removed with a 25 ml pipette, poured into aliquots in previously cooled centrifuge tubes and centrifuged at 48,000 g to settle the membrane fragments (Beckman T1270: 2,408 rad / s

(23,000 rpm) for 30 min). The final sediment of 48,000 g is resuspended in the Homogenization Buffer (4 x the volume of the original cell pellet). The 48,000 g sediment is resuspended by vortexing for 5 seconds and homogenized in a 10-15 beat homogenizer. The preparation is distributed in aliquots of the appropriate size, (200-1,000 ul), in polypropylene tubes and stored at -800 C. The protein content of the membrane preparations is evaluated with the Bradford protein assay.

In the assay, the final higher concentration of test drug is 3 uM and 11: serial dots dilution curves are performed in 100% DMSO using a Biomek FX. The test drug in a total test volume (TAV) of 1% is added to a solid, white 384 well test plate. 50% of the TAV of pre-coupled membranes (for 90 minutes at 4 ° C), 5 µg / well and Twinkling Beads by Proximity of Polystyrene with Wheat Germ Agglutinin (RPNQ0260, Amersham), 0.25 mg / well, is added in 20 mM HEPES pH 7.4, 100 mM NaCl, 10 mM MgCl2, 60 µg / ml saponin and GDP 30

�M. The third addition was a 20% addition of TAV buffer (agonist format) or an EC80 final test concentration of agonist, Quineloran, prepared in the assay buffer (antagonist format). The assay began by adding 29% of the final GTP� TAV [35S] 0.38 nM final (37 MBq / ml, 1,160 Ci / mmol, Amersham). After all additions, the test plates are centrifuged for 1 minute at 105 rad / s (1,000 rpm). The test plates are counted on a Viewlux 613/55 filter, for 5 min, between 2-6 hours after the final addition.

The effect of the test drug on the initial situation generates the EC50 value with an iterative adjustment program of minimum-quadratic curves, which is expressed in the table as pCE50 (ie, -log EC50). The relationship between the maximum effect of the test drug and the maximum effect of the total agonist, Quinelorano, generates the value of Intrinsic Activity (AI) (that is, AI = 1 total agonist, AI <1 partial agonist). The fpKi values of the test drug are calculated from the IC generated by the

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"antagonist format" experiment, using the Cheng & Prusoff equation: fKi = IC50 / 1 + ([A] / EC50) in which: [A] is the concentration of the 5-HT agonist in the assay and EC50 is the 5-HT EC50 value obtained in the same experiment. fpKi is defined as -logfKi.

b) Cell membranes are prepared as follows. The cell pellets are resuspended in 10 volumes of 50 mM HEPES, 1 mM EDTA pH 7.4, using KOH. On the same day, the following proteases are added to the buffer just before administering the homogenization buffer.

-4

Leupeptin 10 M (Sigma L2884)

Bacitracin 25 μg / ml (Sigma B0125) 1 mM PMSF - 100 x stock solution = 17 mg / ml in 100% ethanol

Pepstatin A 2 x 10-6M - 500 x stock solution = 1 mM in 100% ethanol

The cells were homogenized in a glass Waring mixer for 2 x 15 s in 200 ml of 50 mM HEPES + 10-4 M leupeptin + 25 ug / ml bacitracin + 1 mM EDTA + 1 mM PMSF + 2 uM Pepstatin ( the last two reagents are added as freshly prepared stock solutions x 100 and x 500, respectively, in ethanol). The mixer was immersed in ice for 5 minutes after the first burst and 10-40 minutes after the final burst to allow the foam to dissipate. The material was then centrifuged at 500 g for 20 minutes and the supernatant was centrifuged for 36 minutes at 48,000 g. The sediment was resuspended in the same buffer as before but without PMSF and Pepstatin A. The material was then forced through a 0.6 mm needle, adjusted to the required volume (usually 4 times the volume of the original cell pellet), was divided into aliquots and kept frozen at -80 ° C.

In the assay, the final higher concentration of test drug is 3 uM and 11: serial dots dilution curves are performed in 100% DMSO using a Biomek FX. The test drug in a total test volume (TAV) of 1% is added to a solid, white 384 well test plate. 50% of the TAV of pre-coupled membranes (for 60 minutes at RT), 5 µg / well and Twinkling Beads by Proximity of Polystyrene with Wheat Germ Agglutinin (RPNQ0260, Amersham), 0.25 mg / well, in HEPES is added 20 mM pH 7.4, 100 mM NaCl, 10 mM MgCl2, 60 µg / ml saponin and 30 µM GDP. The third addition was a 20% addition of TAV buffer (agonist format) or an EC80 final test concentration of agonist, Quineloran, prepared in the assay buffer (antagonist format). The assay was started by adding 29% of the final GTP TAV [35S] 0.38 nM (37 MBq / ml, 1,160 Ci / mmol, Amersham). After all additions, the test plates are centrifuged for 1 minute at 105 rad / s (1,000 rpm). The test plates are counted on a Viewlux 613/55 filter, for 5 min, 3 to 6 hours after the final addition.

The effect of the test drug on the initial situation generates the EC50 value with an iterative adjustment program of curves by least squares, which is expressed in the table as pCE50 (ie log CE50). The relationship between the maximum effect of the test drug and the maximum effect of the total agonist, Quinelorano, generates the value of Intrinsic Activity (AI) (that is, AI = 1 total agonist, AI <1 partial agonist). The fpKi values of the test drug are calculated from the IC50 generated by the "antagonist format" experiment, using the Cheng & Prusoff equation: fKi = IC50 / 1 + ([A] / EC50) in which: [ A] is the concentration of the Quinelorano agonist in the test and EC50 is the EC50 value of Quinelorano obtained in the same experiment. fpKi is defined as -logfKi.

The compounds of the invention listed above have pKi values within the range of 6.5-10.5 at the D3 dopamine receptor. In one embodiment, the compounds of the invention listed above have pKi values in the range 7.0-10.5 in the D3 dopamine receptor. The results of pKi are estimated to be accurate only at around 0.3-0.5.

The compounds of the invention listed above show selectivity on the D2 receptor.

Examples

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

All temperatures are expressed in ° C. The infrared spectra were measured on an FT-IR instrument. The compounds were analyzed by direct infusion of the sample dissolved in acetonitrile into mass spectra operated in positive ionization mode by electroatomization (ES +). Proton Magnetic Resonance (1H NMR) spectra were recorded at 400 MHz, chemical shifts are reported in ppm at low field (d) from Me4Si, used as internal standard, and are assigned as singles (s), wide singles ( bs), doublets (d), doublets of doublets (dd), triplets (t), quartets (q) or multiples (m).

Column chromatography was performed on silica gel (Merck AG Darmstaadt, Germany). In the text, the following abbreviations are used: HOBt = 1-hydroxybenzotriazole EtOAc = ethyl acetate, Et2O = diethyl ether, DMF = N, N'-dimethylformamide, MeOH = methanol, THF = tetrahydrofuran, DCC = 1,3-cyclohexyl-carbodiimide , SCX = strong cation exchanger, Tlc refers to thin layer chromatography on silica plates, and dry refers to a solution that has been dried over anhydrous sodium sulfate,

r.t. (RT) refers to room temperature, Rt = retention time, DMSO = dimethylsulfoxide; AcOEt = ethyl acetate; DCM = dichloromethane; DCE = dichloroethane; EtOH = ethyl alcohol.

Preparation 1: diethyl 2- (2-methyl-6-quinolinyl) -2-butenodioate

image8

To a stirred solution of 6-bromo-2-methylquinoline (2.89g) in DMF (70mL) at room temperature, diethyl maleate (4.85 mL), palladium acetate (0.15 g), tri are subsequently added (otolyl) phosphine (0.39 g) and potassium carbonate (3.59 g), the reaction mixture was heated to 100 ° C and stirring continued overnight. After cooling, the reaction mixture was stopped with water and extracted twice with diethyl ether. The combined organic layers were collected, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (eluting with 100 to 60% cyclohexane-ethyl acetate) to give 4 g of the title compound as a slightly yellow oil.

MS (m / z): 314 [MH] +. Preparation 2: diethyl 1- (2-methyl-6-quinolinyl) -1,2-cyclopropanedicarboxylate

image8

Sodium hydride (0.52 g) was added in small parts to a stirred suspension of trimethylsulfoxonium iodide (2.81 g) in DMSO (28 mL) at room temperature. After 0.5 h, the mixture of

The clear reaction was cooled to 0 ° C and a solution of diethyl 2- (2-methyl-6quinolinyl) -2-butenodioate (2.0 g) in DMSO (14 mL) was added quickly and stirring continued for 0.5 h after this time water (30 mL) was added. The mixture was extracted twice with ether (30 mL), the organic phase was washed with saturated ammonium chloride, dried over sodium sulfate and evaporated under reduced pressure to provide 2 g of the title product that was used without further purification. .

MS (m / z): 328 [MH] +. Preparation 3: (1R, 5S / 1S, 5R) -1- (2-methyl-6-quinolinyl) -3-azabicyclo [3.1.0] hexane-2,4-dione

To a stirred solution of diethyl 1- (2-methyl-6-quinolinyl) -1,2-cyclopropanedicarboxylate (2 g) in THF (62 mL), at room temperature, lithium hydroxide (1.62 g) was added in water (13 mL) and the reaction mixture was heated to 80 ° C and stirred for 8 h. After cooling to room temperature, 6N hydrochloric acid was added to pH 4-5 and the mixture was concentrated under reduced pressure to 1/3 of the initial volume. The aqueous solution was passed through an SCX cartridge (eluting with MeOH and 2N ammonia / MeOH), the organic phase was evaporated under reduced pressure and the rest was dried in an oven to provide the corresponding crude crude dicarboxylic acid intermediate (1.2 g). This material was suspended in xylene (30 mL), urea (0.53 g) was added and the reaction mixture was refluxed and stirred for 5 h. After cooling the reaction to room temperature, the mixture was extracted with 2% aqueous hydrochloric acid, the pH of the aqueous solution was brought to approximately 8-9 with sodium carbonate and the mixture was extracted with DCM. The organic phase was washed with water, dried over sodium sulfate and concentrated under reduced pressure to provide the crude title product (0.66 g) that was used without purification.

35 additional.

image9

MS (m / z): 253 [MH] +. Preparation 4: (1R, 5S / 1S, 5R) -6- [3-azabicyclo [3.1.0] hex-1-yl] -2-methylquinoline

H

To a stirred solution of borane-THF complex (10.5 mL, 1M / THF) at 0 ° C, a solution of 1- (2-methyl-6-quinolinyl) -3-azabicyclo [3.1.0] was added dropwise hexane-2,4-dione (0.66 g) in THF (15 mL) and the reaction mixture was allowed to reach room temperature and refluxed for 5h.

5 The reaction mixture was cooled to 0 ° C, hydrochloric acid (20 mL, 6N) was added and the mixture was stirred for 3h at room temperature. Potassium carbonate was added to a pH of about 9 and the mixture was extracted with DCM. The organic phase was washed with water, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (eluting with DCM / MeOH from 100 to 90%) to provide the title compound (0.25 g) as a yellow foam

10 clear.

image10

NMR (1H, DMSO): � 9.5 (s, 1H), 9.4 (d, 1H), 7.98 (d, 1H), NH and NH2 not observed. MS (m / z): 139 [MH] +.

Preparation 5: 3 - [(3-chloropropyl) thio] -4-methyl-5- (4-methyl-1,3-oxazol-5-yl) -4H-1,2,4-triazole

image11

Ethyl 2-Chloroacetoacetate (1 p; 1 eq, 1,000 g) was aged with formamide (0.68 vol; approx. 2.8 eq) and the resulting solution was heated to 120 ° C. After 5 hours, the mixture was allowed to cool to room temperature and allowed to age under nitrogen overnight. The mixture was treated with NaOH (3 M, 6 vol, moderately exothermic reaction) and stirred at room temperature for 4 hours. Ethyl acetate (6 vol) was added and the phases were allowed to separate. The organic layer was discarded,

20 while the aqueous was acidified with conc. Aqueous HCl. (32%) to pH 2 (approx. 2.0 vol). A precipitate began to form. The suspension was treated with AcOEt (8 vol) and stirred vigorously until the precipitated mass dissolved. The aqueous phase was further extracted with AcOEt twice (6 vol each) and the combined organic layers were distilled to a low volume (again, a suspension was observed at low volume). Fresh AcOEt (8 vol) was added and the mixture was evaporated to dryness.

The collected solid was placed in an oven at 40 ° C overnight under reduced pressure to provide 4-methyl-1,3-oxazol-5-carboxylic acid (498 g, 64.5%).

This material (498 g, 1 p) was dissolved in dry tetrahydrofuran (5 vol), under nitrogen, cooled

up to 0 ° C. DCC (1.62 p, 1 eq) was added in parts followed by HOBt (1.07 p, 1 eq). The mixture was heated

to 25 ± 2 ° C and stirred for 30 min. 4-methyl-3-thiosemicarbacid (0.83 p, 1 eq) was added and the mixture

30 was further stirred for 2 h at 25 ± 2 ° C. The mixture was filtered, and the filter cake was washed with fresh tetrahydrofuran (1 vol) and dried on the filter for a few hours. The filter cake was suspended in 1 M aqueous NaOH (13 vol) and heated to 70 ° C for 30 min. After this time, the mixture was cooled to 25 ± 2 ° C and a solid was extracted by filtration. The filter cake was washed with 1 M aqueous NaOH (10 vol). The combined mother liquors were cooled to 0 ° C and acidified

35 to approx. pH 5 with HCl (aqueous, 16%; NOTE: keep the temperature below + 10 ° C while adding HCl). The suspended product was isolated by filtration washing with water (2x3 vol). The filter cake was dried at 40 ° C for 18 h at high vacuum to obtain 4-methyl-5- (4-methyl-1,3-oxazol-5yl) -2,4-dihydro-3H-1,2,4-triazole -3-thione (respectively, a tautomeric form thereof; 290 g, 37%).

NaOEt (21% solution in EtOH, 2.08 vol, 1.1 eq) was added to EtOH (20 vol) under a

40 nitrogen atmosphere. 4-Methyl-5- (4-methyl-1,3-oxazol-5-yl) -2,4-dihydro-3H-1,2,4-triazol-3-thione (respectively, a tautomeric form of the same; 290 g, 1 p) in one portion and the resulting mixture was stirred at 25 ± 2 ° C until a clear solution was obtained. 1-Bromo-3-chloropropane (0.54 vol, 1.1 eq) was added and the solution was stirred at 40 ° C for 24 h, and then cooled to 25 ° C. After filtration, water (20 vol) was added and the ethanolic phase was removed by vacuum distillation

45 (internal temperature ~ 40 ° C). The mixture was extracted with EtOAc (41 vol). The aqueous layer was removed and the organic phase evaporated to dryness. Dichloromethane (4 vol) was added. The organic solution is purified through a short column of silica gel (18 p of silica), eluting with EtOAc (200 vol) to provide the title compound as a solid foam (267.64 g, 66%) .

NMR (1H, CDCl3): � 7.90 (s, 1H), 3.70 (s, 5H), 3.40 (t, 2H), 2.52 (s, 3H), 2.30 (m, 2H).

2. 3

Preparation 6: 4 - [(1R, 5S / 1S, 5R) -3- (trifluoroacetyl) -3-azabicyclo [3.1.0] hex-1-yl] phenol

image12

To a stirred solution of (1R, 5S / 1S, 5R) -1- [4- (methyloxy) phenyl] -3- (trifluoroacetyl) -3azabicyclo [3.1.0] hexane (0.6 g) in DCM (20 ml ), at -780C, tribromoborane (4.2 ml) was added dropwise over 5 minutes. The reaction was allowed to reach RT and stirring continued for 1 h and after this time saturated aqueous NaHCO3 (15 ml) was added. Extraction with ethyl acetate of the reaction mixture provided after flash chromatography (eluting with cyclohexane: 10% to 60% ethyl acetate) the title compound (0.54 g).

NMR (1H, DMSO-D6): � 9.3 (bs, 1H), 7.1 (m, 2H), 6.65 (d, 2H), 4.1 - 3.55 (m, 4H), 1.95 (m, 1H), 10 1.0 (m, 1H), 0.65 (m, 1H).

Preparation 7: 2-nitro-4 - [(1R, 5S / 1S, 5R) -3- (trifluoroacetyl) -3-azabicyclo [3.1.0] hex-1-yl] phenol

H

image13

To a stirred solution of 4 - [(1R, 5S / 1S, 5R) -3- (trifluoroacetyl) -3-azabicyclo [3.1.0] hex-1-yl] phenol (0.14 g) in DCM (2 ml ) at 0 ° C, dioxosilane (140 mg) and nitric acid (0.033 ml) were subsequently added.

After 1.5 h, the reaction mixture was filtered through a celite panel, the filtrate was washed with saturated aqueous NaHCO3 (10 ml) and the solvent was evaporated in vacuo to give the title compound (0, 14 g) which was used without further purification.

NMR (1H, DMSO-D6): � 7.8 (d, 1H), 7.45 (d, 1H), 7.0 (d, 1H), 4.1-3.6 (m, 4H), 2.05 (m, 1H), 1.1 (m, 1H), 0.75 (m, 1H), the phenolic proton was not observed.

Preparation 8: 2-amino-4 - [(1R, 5S / 1S, 5R) -3- (trifluoroacetyl) -3-azabicyclo [3.1.0] hex-1-yl] phenol

H

image14

A stirred mixture of 2-nitro-4 - [(1R, 5S / 1S, 5R) -3- (trifluoroacetyl) -3-azabicyclo [3.1.0] hex-1-yl] phenol

(0.24 g) and 10% palladium / C (0.048 g) in EtOH (10 ml) was hydrogenated (1 atm) for 3 h. The Pd / C was deleted

by filtration, the solid was washed with EtOH (3 x 10 ml) and the filtrate was evaporated in vacuo to provide the

The title compound (0.22 g) that was used as such.

MS (m / z): 287 [MH] +. Preparation 9: 5 - [(1R, 5S / 1S, 5R) -3-azabicyclo [3.1.0] hex-1-yl] -2-ethyl-1,3-benzoxazole

H

image15

2-amino-4 - [(1R, 5S / 1S, 5R) -3- (trifluoroacetyl) -3-azabicyclo [3.1.0] hex-1-yl] phenol (0.11 g) was added,

1,1,1-tris (ethyloxy) propane (0.216 ml) and 4-methylbenzenesulfonic acid (0.01 g) at DMF (1 ml) at RT. The reaction was stirred at 70 ° C for 2 h and at 110 ° C for a further 2 h. Ethyl acetate was added and the organic phase was washed with sat. NaHCO3. The solvent was evaporated and the rest was dissolved in MeOH / H2O (1/1, 5 ml). Potassium carbonate (0.21 g) was added and the reaction was heated to 60 ° C. After 2 h, HF (4 ml) was added and the reaction was heated at 60 ° C for a further 2 h. Water was added to RT and extraction with DCM

35 provides after removal of the solvent the title compound (0.19 g)

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MS (m / z): 325.2 [MH] +.

Preparation 10: 3- (2-methyl-5-pyrimidinyl) -1H-pyrrole-2,5-dione

N

N

image 1 OO

N

H

The title compound can be prepared by reacting 2-methyl-5-pyrimidinamine with maleimide by analogy with a conventional Meerwein reaction (J. Am. Chem. Soc. 1955, 77, 2313)

or variations (for example J. Org .. Chem., 1977, 42, 2431). To 2-methyl-5-pyrimidinamine (1 eq) a solution of hydrochloric acid (37%, 2.6 eq) and water at room temperature should be added with vigorous stirring and the precipitate formed should be allowed to stir for 30 minutes. The temperature should be reduced to 0 ° C and sodium nitrite (1.1 g) in water was added dropwise to the stirred suspension. At the end of diazotization, a clear solution should generally be obtained. Maleimide (2 eq.) In acetone should be added dropwise at 0 ° C and the pH of the solution was adjusted to 3-3.5 by the addition of sodium acetate. Copper (II) chloride (0.15 eq.) Should be added and vigorous stirring continued for 1h at 0 ° C and overnight at room temperature. Acetone should be removed in vacuo, the rest filtered and dried overnight in vacuo to provide the crude title compound.

Preparation 11: (1R, 5S / 1S, 5R) -1- (2-methyl-5-pyrimidinyl) -3-azabicyclo [3.1.0] hexane-2,4-dione

image 1 N

N OO

N

H

The title compound could be prepared according to a cyclopropane process based on trimethylsulfoxonium iodide. Ground sodium hydroxide (2 eq.) Should be added in small parts to a stirred solution of trimethylsulfoxonium iodide (2 eq.) In DMSO. The resulting mixture should be allowed to continue stirring at room temperature for 1.5 h, 3- (2-methyl-5-pyrimidinyl) -1H-pyrrole-2,5-dione (1 eq.) In DMSO is added dropwise and should be allowed that the resulting mixture continue stirring at room temperature for 20 minutes. The reaction temperature should be reduced to 0 ° C and NH4Cl (saturated aqueous solution) added slowly, followed by Et2O. The organic phase should be washed with water, dried over Na2SO4 and evaporated to provide the crude title product.

Preparation 12: (1R, 5S / 1S, 5R) -1- (2-methyl-5-pyrimidinyl) -3-azabicyclo [3.1.0] hexane

N

N

N

image 1

H

The title compound could be prepared according to a normal imide to amine reduction procedure. To a stirred solution of BH3-THF complex (1M in tetrahydrofuran, 12 eq.), At 0 ° C, add dropwise (1R, 5S / 1S, 5R) -1- (2-methyl-5-pyrimidinyl) -3-azabicyclo [3.1.0] hexane-2,4-dione (1 eq.) In THF. At the end of the addition, the resulting mixture should be allowed to reach room temperature and refluxed for 4 hours. The mixture should be cooled to 0 ° C, methanol and hydrochloric acid (6 M solution) added, followed by removal of the organic solvent in vacuo. A solution of sodium hydroxide (5 M) should be added until a pH 9-10 is reached, the mixture is extracted with Et2O and the organic phase is evaporated in vacuo to provide the crude title product.

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Preparation 13: (1- (Phenylmethyl) -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2,5-dihydro-1H-pyrrole)

OR B

image 1

image 1

OR

image 1

image 1

N

Diisopinocamfeilborane was prepared according to the procedure published in J. Org. Chem. 1984, 49, 945-947. 2 - [(1Z) -3-Chloro-1- (chloromethyl) -1-propen-1-yl] -4,4,5,5-tetramethyl-1,3,2-dioxaborolane (described above in Tetrahedron was prepared Lett. 1993, 34, 4827-4828) according to the general procedure published in Tetrahedron Lett. 1989, 30, 2929, using 1,4-dichloro-2-butyne. The material thus obtained was further converted according to the procedure published in Synlett 2002, 5, 829-831. This last procedure was modified in that the isolation of the title product was achieved (instead of by distillation) by extracting a solution of the crude reaction products in acetonitrile with cyclohexane, to provide the title compound (containing ~ 10 mol% benzylamine) after evaporating the volatiles of the cyclohexane phase.

Preparation 14: 2-methyl-5- [1- (phenylmethyl) -2,5-dihydro-1H-pyrrol-3-yl] pyrimidine

N

image 1 N

N

image 1

image 1

The title compound can be prepared through a palladium-mediated coupling reaction, for example starting from 5-bromo-2-methylpyrimidine and 1- (phenylmethyl) -3- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -2,5-dihydro-1H-pyrrole. For example, to a solution of 5-bromo-2-methylpyrimidine (1.3 eq.) In THF, 1- (phenylmethyl) -3- (4,4,5,5-tetramethyl-1,3,2 can be added -dioxaborolan-2-yl) -2,5-dihydro-1H-pyrrole (1 eq.), tetrakis (triphenylphosphine) palladium (0) (5% mol) and cesium fluoride (4 eq.) at room temperature. The resulting mixture should be stirred at 80 ° C for 1.5 hours. After cooling, the solvent should be evaporated under reduced pressure and the remainder partitioned between dichloromethane and sodium hydroxide (1M). The organic phase should be evaporated under reduced pressure and the crude product purified by flash chromatography to provide the title compound.

Preparation 15: (1R, 5S / 1S, 5R) -1- (2-methyl-5-pyrimidinyl) -3- (phenylmethyl) -3azabicyclo [3.1.0] hexane

N

image 1 N

N

image 1

image 1

The title compound can be prepared according to the procedure for the compound of Preparation 11.

Preparation 16: (1R, 5S / 1S, 5R) -1- (2-methyl-5-pyrimidinyl) -3-azabicyclo [3.1.0] hexane

H N

image 1 NH

N

image 1

The title compound can be prepared according to a normal hydrogenation reaction. A mixture of (1R, 5S / 1S, 5R) -1- (2-methyl-5-pyrimidinyl) -3- (phenylmethyl) -3-azabicyclo [3.1.0] hexane (1 eq.), Hydrochloric acid, Pd / C, in ethanol it can be hydrogenated at 1 atm until the disappearance of material begins. The mixture must be filtered on celite and the organic phase evaporated in vacuo to provide the crude title product.

image16

The title compound can be prepared through a coupling reaction mediated by

palladium, for example starting from 2-bromo-5-methylthiophene and 1- (phenylmethyl) -3- (4,4,5,5-tetramethyl-1,3,2

5 dioxaborolan-2-yl) -2,5-dihydro-1H-pyrrole. For example, to a solution of 2-bromo-5-methylthiophene (1.3 eq.)

in THF, 1- (phenylmethyl) -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2,5-dihydro-1H-pyrrole (1

eq.), tetrakis (triphenylphosphine) palladium (0) (5% mol) and cesium fluoride (4 eq.) at room temperature. The

The resulting mixture should be stirred at 80 ° C for 1.5 hours. After cooling, the solvent should

evaporate under reduced pressure and the remainder partitioned between dichloromethane and sodium hydroxide (1M). The organic phase should be evaporated under reduced pressure and the crude product purified by chromatography.

flash to provide the title compound.

Preparation 18: (1S, 5S / 1R, 5R) -1- (5-methyl-2-thienyl) -3- (phenylmethyl) -3-azabicyclo [3.1.0] hexane

H

image17

The title compound can be prepared according to a mediated cyclopropane process

15 for zinc (for example Tetrahedron, 2003, 59, 6967). For example, 3- (5-methyl-2-thienyl) -1 (phenylmethyl) -2,5-dihydro-1H-pyrrole (1 eq.) In DCM can be added to a stirred mixture of diethyl zinc (6 eq., 1M in hexanes) and diiodomethane (12 eq.) in DCM at 0oC. Stopping with NH4Cl after the disappearance of the starting material (monitored by MS) and purification of the crude product by flash chromatography should yield the title compound.

Preparation 19: (1S, 5S / 1R, 5R) -1- (5-methyl-2-thienyl) -3-azabicyclo [3.1.0] hexane

image18

The title compound can be prepared according to a benzyl removal, using for example

an acyl chloride reagent (for example: J. Med. Chem., 1989, 32, 2534). It is also possible a

hydrogenation process For example, at a solution of (1S, 5S / 1R, 5R) -1- (5-methyl-2-thienyl) -3

25 (phenylmethyl) -3-azabicyclo [3.1.0] hexane (1 eq.) In 1,2-dichloroethane, at 0 ° C, 1-chloroethyl chloroformate (1.2 eq.) Can be added. After refluxing the reaction mixture for as long as necessary (disappearance of the starting material monitored by MS), the solvent must be removed in vacuo, methanol added and the mixture refluxed for 4 hours. Solvent removal, treatment of the remainder with HCl (0.5 N) and subsequent extraction of the mixture with ether after basification with

30 NaOH should provide the crude title compound.

5

10

fifteen

twenty

25

30

Preparation 20: Diethyl 2- (6-Quinoxalinyl) -2-Butenedioate

image 1 CO2Et

image 1 N CO2Et

N

image 1

The title compound can be prepared through a palladium-mediated coupling reaction, using diethyl maleate or fumarate as a common reagent (eg Tetrahedron, 2002, 58, 6545). For example, a mixture of 6-bromoquinoxaline (1 eq.), Diethyl maleate (2.3 eq.), Palladium acetate (0.05 eq.), Tri (o-tolyl) phosphine (0.1 eq. ) and potassium carbonate (2 eq.) in DMF can be heated to 100 ° C and stirred for 16 hours. Stopping with water, extraction with diethyl ether and purification of the crude product by flash chromatography should provide the title compound.

Preparation 21: diethyl 1- (6-Quinoxalinyl) -1,2-cyclopropanedicarboxylate

image 1 CO2Et

image 1 N CO2Et

N

The title compound can be prepared through a cyclopropane process based on trimethylsulfoxonium iodide. For example, ground sodium hydroxide (2 eq.) Can be added in small parts to a stirred solution of trimethylsulfoxonium iodide (2 eq.) In DMSO. The resulting mixture can be allowed to continue stirring at room temperature for 1.5 h, diethyl 2 (6-quinoxalinyl) -2-butenodioate (1 eq.) In DMSO is added and the resulting mixture is allowed to stir at room temperature for 20 minutes. The reaction temperature should be reduced to 0 ° C and NH4Cl (saturated aqueous solution) should be added slowly, followed by Et2O. The organic phase can be washed with water, dried over Na2SO4 and evaporated to provide the crude title product.

Preparation 22: (1R, 5S / 1S, 5R) -1- (6-quinoxalinyl) -3-azabicyclo [3.1.0] hexane-2,4-dione

Or h

image 1 NN

image 1 ON

The title compound can be prepared according to an ester hydrolysis to carboxylic acid and subsequent cyclisation to imide using urea. For example, to a stirred solution of diethyl 1- (6-quinoxalinyl) -1,2-cyclopropanedicarboxylate (1 eq.) In THF, at room temperature, lithium hydroxide (2.5 eq.) Can be added in water and the mixture The reaction is heated to 80 ° C and stirred for 8 h. After cooling to room temperature, 6N hydrochloric acid can be added to pH 4-5 and the mixture concentrated under reduced pressure to 1/3 of the initial volume. The aqueous solution may be passed through an SCX cartridge (eluting with MeOH and 2N ammonia / MeOH), the organic phase evaporated under reduced pressure and the remainder dried in an oven to provide the corresponding crude crude dicarboxylic acid intermediate. This material should be resuspended in xylene, urea (2 eq.) Added and the reaction refluxed for 5 h. After extraction with 2% aqueous hydrochloric acid, basification of the aqueous mixture and extraction with DCM should provide the crude title compound.

Preparation 23: (1R, 5S / 1S, 5R) - 6- [3-azabicyclo [3.1.0] hex-1-yl] quinoxaline

image 1 NN

image 1 N

The title compound can be prepared according to a vitride based reduction procedure

or borane. For example, to a stirred solution of BH3-THF complex (1M in tetrahydrofuran, 12 eq.), At 0 ° C, one can add dropwise (1R, 5S / 1S, 5R) -1- (6-quinoxalinyl) - 3-azabicyclo [3.1.0] hexane-2,4-dione (1 eq.) In THF. At the end of the addition, the resulting mixture should be allowed to reach room temperature and refluxed for 4 hours. The mixture should be cooled to 0 ° C, methanol and hydrochloric acid (6 M solution) added, followed by removal of the organic solvent in vacuo. A solution of sodium hydroxide (5 M) should be added until a pH 9-10 is reached, the mixture is extracted with Et2O and the organic phase is evaporated in vacuo to provide the crude title product.

Preparation 24: 2- (5-Quinolinyl) -2-diethyl butenedioate (P24)

image19

To a stirred solution of 5-bromo-2-methylquinoline (2.87g) in DMF (60mL) at room temperature, diethyl maleate (5.15 mL), palladium acetate (0.16 g), tri are subsequently added (o10 tolyl) phosphine (0.42 g) and potassium carbonate (3.80 g), the reaction mixture was heated to 100 ° C and stirring continued overnight. After cooling, the reaction mixture was stopped with water and extracted twice with diethyl ether. The combined organic layers were collected, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (eluting with 100 to 60% cyclohexane-ethyl acetate) to provide 3.51 g of the compound.

15 of the title as a slightly yellow oil.

MS (m / z): 300 [MH] +. Preparation 25: diethyl 1- (5-Quinolinyl) -1,2-cyclopropanedicarboxylate (P25)

image19

Sodium hydride (0.93 g) was added in small parts to a stirred suspension of iodide of

20 trimethylsulfoxonium (5.12 g) in DMSO (50 mL) at room temperature. After 0.5 h, the clear reaction mixture was cooled to 0 ° C and a solution of diethyl 2- (5-quinolinyl) -2-butenodioate (P24, 3.48 g) in DMSO (25 mL) was added quickly and the stirring continued for 0.5 h and after this time water (30 mL) was added. The mixture was extracted twice with ether (30 mL), the organic phase was washed with saturated ammonium chloride, dried over sodium sulfate and evaporated under reduced pressure.

The crude product was purified by flash chromatography on silica gel (eluting with 100 to 70% cyclohexane-ethyl acetate) to give 3.02 g of the title compound as a slightly yellow oil.

MS (m / z): 314 [MH] +. Preparation 26: (1R, 5S / 1S, 5R) -1- (5-quinolinyl) -3-azabicyclo [3.1.0] hexane-2,4-dione (P26)

image20

To a stirred solution of diethyl 1- (5-quinolinyl) -1,2-cyclopropanedicarboxylate (P25, 3.02 g) in THF (90 mL), at room temperature, lithium hydroxide (2.31 g) was added ) in water (23 mL) and the reaction mixture was heated to 80 ° C and stirred for 8 h. After cooling to room temperature, hydrochloric acid (37%) was added to pH 4-5, the mixture was partially concentrated under reduced pressure, extracted with DCM and the organic phase was evaporated under reduced pressure to provide a

35 solid material that was dried in a vacuum oven at 1000C overnight to obtain 1.7 g as a white solid.

A part of this material (0.85 g) was suspended in xylene (65 mL), urea (1.0 g) was added and the reaction mixture was refluxed and stirred overnight. After cooling the reaction to room temperature, the mixture was extracted with 2% aqueous hydrochloric acid, the pH of the aqueous solution was brought to approximately 8 with NaHCO3 and the mixture was extracted with DCM. The organic solution was passed through an SCX cartridge (eluting with MeOH and 2N ammonia / MeOH) to provide 120 mg of the crude title compound. This procedure was repeated for the remaining part (85 mg). The two crude products were combined and purified by flash chromatography (eluting with 100% to 96% DCM / MeOH) to provide 165 mg of the title compound.

MS (m / z): 239 [MH] +. Preparation 27: 5 - [(1R, 5S / 1S, 5R) -3-azabicyclo [3.1.0] hex-1-yl] quinoline (P27)

image21

To a stirred solution of borane-THF complex (2.8 mL, 1M / THF) in THF (1 mL) at 0 ° C, a solution of 1- (2-methyl-6-quinolinyl) -3- was added dropwise azabicyclo [3.1.0] hexane-2,4-dione (P26, 165 mg) in THF (3 mL) and the reaction mixture was allowed to reach room temperature and led to

15 reflux for 3h. The reaction mixture was cooled to 0 ° C, hydrochloric acid (2N) was added and the mixture was stirred for 3h at room temperature. NaOH (1M) was added to pH of about 9, the mixture was extracted with DCM, the organic phase was washed with water, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (eluting with DCM / MeOH from 100 to 90%) to provide the title compound (28 mg) as a yellow foam

20 clear.

MS (m / z): 211 [MH] +. Preparation 28: 2- [1- (phenylmethyl) -2,5-dihydro-1H-pyrrol-3-yl] pyrimidine (P28)

image22

To a solution of 2-bromopyrimidine (0.88 g) in dry tetrahydrofuran (30 mL), 1 was added

25 (phenylmethyl) -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2,5-dihydro-1H-pyrrole (P13, 1.21 g), tetrakis (triphenylphosphine) palladium (0) (0.25 g) and cesium fluoride (2.59 g) at room temperature. The resulting mixture was stirred at 80 ° C for 6 hours. After cooling, the solvent was evaporated under reduced pressure, the remainder was partitioned between ether and water and the organic phase was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (eluting with DCM / MeOH from

100% to 96%) to provide 0.23 g of the title compound.

MS (m / z): 238 [MH] +. Preparation 29: (1S, 5S / 1R, 5R) -3- (phenylmethyl) -1- (2-pyrimidinyl) -3-azabicyclo [3.1.0] hexane (P29)

H

N

N

N

image 1

To a suspension of sodium hydride solid (80 mg) and trimethylsulfoxonium iodide (0.43 g), DMSO (anhydrous, 2.5 mL) (gas evolution) was added dropwise and the resulting mixture was allowed it was stirred at room temperature for 10 min and a solution of 2- [1- (phenylmethyl) -2,5-dihydro1H-pyrrol-3-yl] pyrimidine (P28, 0.23 g) in DMSO (anhydrous, 1) was added mL) and the reaction mixture was stirred for 0.5h at 77oC. After cooling to room temperature, water was added and the mixture was extracted with ether twice, the organic phase was washed with concentrated saline, dried over sodium sulfate and evaporated under reduced pressure to give the crude title compound ( 0.15 g) which was used without further purification.

MS (m / z): 252 [MH] +. Preparation 30: (1S, 5S / 1R, 5R) -1- (2-pyrimidinyl) -3-azabicyclo [3.1.0] hexane (P30)

H

image23

To a stirred solution of (1S, 5S / 1R, 5R) -3- (phenylmethyl) -1- (2-pyrimidinyl) -3azabicyclo [3.1.0] hexane (P29, 100 mg) in DCE (1 mL) at 0oC and under nitrogen atmosphere, 115 chloroethylchloroformate (0.052 mL) was added and after 10 min the reaction mixture was refluxed and stirred for 2.5 h. The reaction mixture was allowed to reach RT and the solvent was evaporated under reduced pressure to provide a crude product that was dissolved in methanol (4 mL), the solution was refluxed for 2.5 h. The solvent was evaporated under reduced pressure and the rest was purified by flash chromatography (eluting with 100% to 94% DCM / MeOH) to provide the compound of the

20 titer (50 mg).

MS (m / z): 162 [MH] +. Preparation 31: 3 - [(3-chloropropyl) thio] -5- (3,4-difluorophenyl) -4-methyl-4H-1,2,4-triazole (P31)

image24

The title compound was prepared as published in WO2005118549.

Example 1: 2-methyl-6 - [(1R, 5S / 1S, 5R) -3- (3 - {[4-methyl-5- (4-methyl-1,3-oxazol-5-yl)) hydrochloride 4H-1,2,4-triazol-3-yl] thio} propyl) -3-azabicyclo [3.1.0] hex-1-yl] quinoline

N

image 1 S

image 1 image 1 NN

image 1

N

image 1 OR

image25

image 1

image 1 NH Cl

A mixture of (1R, 5S / 1S, 5R) -6- [3-azabicyclo [3.1.0] hex-1-yl] -2-methylquinoline (150 mg), 3 - [(3

Chloropropyl) Thio] -4-methyl-5- (4-methyl-1,3-oxazol-5-yl) -4H-1,2,4-triazole (236 mg), potassium carbonate (110 mg) and Sodium iodide (119 mg) in anhydrous DMF (3 mL) was heated at 60 ° C for 24 h. After removal of the solvent in vacuo, the remainder was dissolved in ethyl acetate (10 mL) and the organic phase was washed with water, dried over sodium sulfate and concentrated in vacuo. The crude was purified by flash chromatography on silica gel (dichloromethane up to 10% MeOH in dichloromethane) to provide

35 150 mg of the free base of the title compound. To a solution of this material in dichloromethane (2 mL) HCl (0.13 mL, 1 M in Et2O) was added, the solvent was evaporated in vacuo and the material thus obtained was triturated with Et2O to provide 136 mg of the title compound. as a light yellow solid.

image 1

NMR (1H, CDCl3): 10.36 (bs, 1H), 8.57 (s, 1H), 8.28 (m, 1H), 7.94 (m, 1H), 7.87 (m, 1H ), 7.66 (m, 1H), 7.49 (m, 1H), 4.11 (m, 1H), 3.75 (m, 2H), 3.69 (s, 3H), 3.56 (m, 1H), 3.31 (m, 4H), 2.69 (s, 3H), 2.37 (s, 3H), 2.31 (m, 1H), 2.18 (m, 2H) , 1.67 (m, 1H), 1.26 (m, 1H).

MS (m / z): 461 [MH] +.

5 Example 2: 2-ethyl-5 - [(1R, 5S / 1S, 5R) -3- (3 - {[4-methyl-5- (4-methyl-1,3-oxazol-5-yl) hydrochloride ) 4H-1,2,4-triazol-3-yl] thio} propyl) -3-azabicyclo [3.1.0] hex-1-yl] -1,3-benzoxazol

N N S

image 1 image 1 NO

image 1

O Cl N

image 1

image 1

image 1

image 1

image 1 N

H

N

A mixture of 5 - [(1R, 5S / 1S, 5R) -3-azabicyclo [3.1.0] hex-1-yl] -2-ethyl-1,3-benzoxazole (50 mg), and 3 [(3 -chloropropyl) thio] -4-methyl-5- (4-methyl-1,3-oxazol-5-yl) -4H-1,2,4-triazole (60 mg), potassium carbonate (35 mg) 10 and sodium iodide (33 mg) in anhydrous DMF (0.2 mL) was heated at 60 ° C for 24 h. After removal of the solvent in vacuo, the remainder was dissolved in ethyl acetate (5 mL) and the organic phase was washed with water, dried over sodium sulfate and concentrated in vacuo. The crude was purified by flash chromatography on silica gel (dichloromethane up to 10% MeOH in dichloromethane) to provide 150 mg of the free base of the title compound. To a solution of this material in dichloromethane (2

15 mL) HCl (0.22 mL, 1 M in Et2O) was added, the solvent was evaporated in vacuo and the material thus obtained was triturated with Et2O to provide 12 mg of the title compound as a white hygroscopic solid.

NMR (1H, CD3OD): METHANOL-d4) � ppm 8.41 (s, 1 H), 7.67 (d, 1 H), 7.59 (d, 1 H), 7.40 (dd, 1 H), 4.17 (d, 1 H), 3.91 (d, 1 H), 3.81 (s, 3 H), 3.73 (dd, 1 H), 3.67 (d, 1 H), 3.48-3.55 (m, 2 H), 3.43 (t, 2 H), 3.02 (q, 2 H), 2.47 (s, 3 H), 2.25 - 2.34 (m, 3 H), 1.48 - 1.54 (m, 1 H), 1.45 (t, 3 H), 1.35 - 1.41 (m, 1 H), no

20 hydrochloric proton was observed.

MS (m / z): 465.5 [MH] +.

Example 3: (1R, 5S / 1S, 5R) - 6- [3- (3 - {[4-methyl-5- (4-methyl-1,3-oxazol-5-yl) -4H1.2 hydrochloride , 4-triazol-3-yl] thio} propyl) -3-azabicyclo [3.1.0] hex-1-yl] quinoxaline

H

image 1 image 1 N

image 1 S

image 1 NN

image 1

image 1 NO N

image 1 Cl N

H

image 1

image6

It is believed that the title compound can be prepared using (1R, 5S / 1S, 5R) - 6- [3azabicyclo [3.1.0] hex-1-yl] quinoxaline and 3 - [(3-chloropropyl) thio] -4 -methyl-5- (4-methyl-1,3-oxazol-5-yl) -4H-1,2,4triazole, using methods similar to the preparation of Examples 1 and 2.

Example 4: (1R, 5S / 1S, 5R) -3- (3 - {[4-methyl-5- (4-methyl-1,3-oxazol-5-yl) -4H-1,2, hydrochloride, 4triazol-3-yl] thio} propyl) -1- (2-methyl-5-pyrimidinyl) -3-azabicyclo [3.1.0] hexane

H

image 1 image 1 image 1 NS

image 1 NN

image 1 image 1 NN

OCl

H N

image 1

30

image6

It is believed that the title compound can be prepared using (1R, 5S / 1S, 5R) -1- (2-methyl-5

pyrimidinyl) -3-azabicyclo [3.1.0] hexane and 3 - [(3-chloropropyl) thio] -4-methyl-5- (4-methyl-1,3-oxazol-5-yl) -4H-1, 2.4

triazole, using methods similar to the preparation of Examples 1 and 2.

Example 5: (1S, 5S / 1R, 5R) -3- (3 - {[4-methyl-5- (4-methyl-1,3-oxazol-5-yl) -4H-1,2,435 triazole hydrochloride -3-yl] thio} propyl) -1- (5-methyl-2-thienyl) -3-azabicyclo [3.1.0] hexane

H

image 1 image 1 image 1 NS

image 1 NN

image 1 NO

image 1 Cl

SH

image 1

image6

It is believed that the title compound can be prepared using (1S, 5S / 1R, 5R) -1- (5-methyl-2-thienyl) 3-azabicyclo [3.1.0] hexane and 3 - [(3-chloropropyl) thio ] -4-methyl-5- (4-methyl-1,3-oxazol-5-yl) -4H-1,2,4-triazole, using methods similar to the preparation of Examples 1 and 2.

5 Example 6: 5 - [(1R, 5S / 1S, 5R) -3- (3 - {[4-methyl-5- (4-methyl-1,3-oxazol-5-yl) -4H1 hydrochloride, 4H1, 2,4-triazol-3-yl] thio} propyl) -3-azabicyclo [3.1.0] hex-1-yl] quinoline (E6)

H

image 1 image 1 NS

image 1 NN

image 1 image 1 NO

N H Cl

image 1

image6

A mixture of 5 - [(1R, 5S / 1S, 5R) -3-azabicyclo [3.1.0] hex-1-yl] quinoline (P27, 28 mg), 3 - [(3

10 chloropropyl) thio] -4-methyl-5- (4-methyl-1,3-oxazol-5-yl) -4H-1,2,4-triazole (P5, 47 mg), K2CO3 (22 mg) and NaI (24 mg) in DMF (anhydrous, 0.6 mL) was heated at 60 ° C for 24 h. After removal of the solvent under reduced pressure, the remainder was dissolved in ethyl acetate, the organic layer was washed with water and dried over Na2SO4 and the solvent was evaporated under reduced pressure. The crude was purified by flash chromatography (eluting with 100% to 96% DCM / MeOH) to provide 18 mg of the compound's free base.

15 of the title. To a solution of this material in dichloromethane (0.2 mL) was added HCl (1 M in Et2O, 0.038 mL), the solvent was evaporated in vacuo and the material thus obtained was triturated with Et2O to provide 18 mg of the title compound as a slightly white hygroscopic solid.

1 H NMR (400 MHz, DMSO-d6) � ppm 10.21 - 10.40 (br, s ,, 1 H) 8.85 - 9.00 (m, 1 H) 8.54 - 8.65 (m , 1 H) 8.46 - 8.55 (m, 1 H) 7.90 - 8.06 (m, 1 H) 7.68 - 7.80 (m, 2 H) 7.53 - 7.67 (m, 1 H) 4.02 - 4.16 (m, 1 20 H) 3.72 - 3.89 (m, 2 H) 3.58 - 3.66 (m, 4 H) 3.16 - 3.27 (m, 4 H) 2.28 - 2.36 (m, 3 H) 2.19 - 2.27 (m, 1 H) 2.02 - 2.17 (m, 2 H) 1, 70-1.79 (m, 1 H) 1.00 - 1.08 (m, 1 H); MS (m / z): 447 [MH] +.

Example 7: (1S, 5S / 1R, 5R) -3- (3 - {[4-methyl-5- (4-methyl-1,3-oxazol-5-yl) -4H-1,2, hydrochloride, 4triazol-3-yl] thio} propyl) -1- (2-pyrimidinyl) -3-azabicyclo [3.1.0] hexane (E7)

H image 1 N

image 1 S

image 1 N

N

N

NO N

H

Cl N

A mixture of (1S, 5S / 1R, 5R) -1- (2-pyrimidinyl) -3-azabicyclo [3.1.0] hexane (P30, 25 mg), 3 - [(3

25 chloropropyl) thio] -4-methyl-5- (4-methyl-1,3-oxazol-5-yl) -4H-1,2,4-triazole (P5, 55 mg), K2CO3 (28 mg) and NaI (27 mg) in DMF (anhydrous, 0.5 mL) was heated at 60 ° C for 24 h. After removal of the solvent under reduced pressure, the remainder was dissolved in ethyl acetate, the organic layer was washed with water and dried over Na2SO4 and the solvent was evaporated under reduced pressure. The crude was purified by flash chromatography (eluting with 100% to 90% DCM / MeOH) to provide 21 mg of the compound's free base.

30 of the title. To a solution of this material in dichloromethane (0.5 mL) was added HCl (1 M in Et2O, 0.052 mL), the solvent was evaporated in vacuo and the material thus obtained was triturated with Et2O to provide 21 mg of the title compound as a slightly white hygroscopic solid.

image 1

1 H NMR (500 MHz, DMSO-d6) � ppm 10.38 (br, s., 1 H) 8.73 (d, 2 H) 8.55 - 8.59 (m, 1 H) 7.38 ( d, 1 H) 3.92-4.03 (m, 2 H) 3.70-3.76 (m, 1 H) 3.66-3.70 (m, 3 H) 3.47-3, 54 (m, 1 H) 3.32 - 3.44 (m, 2 H) 35 3.26 (t, 2 H) 2.34 - 2.40 (m, 3 H) 2.27 - 2.33 (m, 1 H) 2.11 - 2.22 (m, 2 H) 1.74 - 1.83 (m, 1 H) 1.57 - 1.65

(m, 1 H); MS 398 (m / z): [MH] +.

Example 8: (1S, 5S / 1R, 5R) -3- (3 - {[5- (3,4-difluorophenyl) -4-methyl-4H-1,2,4-triazol3-yl] thio} hydrochloride propyl) -1- (2-pyrimidinyl) -3-azabicyclo [3.1.0] hexane (E8)

H

image 1 image 1 N

image 1 S

image 1 NNN

N F N

image 1

H

Cl F

image 1

A mixture of (1S, 5S / 1R, 5R) -1- (2-pyrimidinyl) -3-azabicyclo [3.1.0] hexane (P30, 25 mg), 3 - [(3

5-chloropropyl) thio] -5- (3,4-difluorophenyl) -4-methyl-4H-1,2,4-triazole (P31, 55 mg), K2CO3 (28 mg) and NaI (27 mg) in DMF ( anhydrous, 0.5 mL) was heated at 60 ° C for 24 h. After removal of the solvent under reduced pressure, the remainder was dissolved in ethyl acetate, the organic layer was washed with water and dried over Na2SO4 and the solvent was evaporated under reduced pressure. The crude was purified by flash chromatography (eluting with 100% to 90% DCM / MeOH) to provide 21 mg of the compound's free base.

10 of the title. To a solution of this material in dichloromethane (0.5 mL) was added HCl (1 M in Et2O, 0.052 mL), the solvent was evaporated in vacuo and the material thus obtained was triturated with Et2O to provide 21 mg of the title compound as a slightly white hygroscopic solid.

image 1

1 H NMR (500 MHz, DMSO-d6) � ppm 10.44 - 10.57 (br. S., 1 H) 8.68 - 8.77 (m, 2 H) 7.80 - 7.89 (m , 1 H) 7.62 - 7.71 (m, 1 H) 7.57 - 7.62 (m, 1 H) 7.34 - 7.42 (m, 1 H) 3.92 - 4.05 (m, 2 H) 3.67 - 3.77 (m, 1 15 H) 3.58 - 3.64 (m, 3 H) 3.19 - 3.41 (m, 5 H) 2.27 - 2.34 (m, 1 H) 2.09 - 2.23 (m, 2 H) 1.77 - 1.87 (m, 1 H) 1.55 - 1.65 (m, 1 H);

MS 429 (m / z): [MH] +.

Claims (13)

CLAIMS: 1. A compound of formula (I) or a salt thereof: N N image 1 N (CHR2) (CH2) n X (I) N R4 image2 R3 (R1) p in which: G is a 5 or 6 membered heteroaromatic group, or is a 9 or 10 membered bicyclic heteroaromatic group containing one or two heteroatoms independently selected from nitrogen and oxygen, in which G is not pyridyl, indazolyl or benzothiazolyl; p is an integer that varies from 0 to 4; R1 is independently selected from a group consisting of: halogen, hydroxy, cyano, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 alkanoyl or SF5; or corresponds to a group R5; R2 is hydrogen or C1-4 alkyl; n is 2 or 3; X is S or –CH2-; R3 is C1-4 alkyl; R4 is hydrogen, or a phenyl group, a heterocyclyl group, a 5- or 6-membered heteroaromatic group, or an 8 to 11-membered bicyclic group, any of the groups being 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 and C1-4 alkanoyl; R5 is isoxazolyl, -CH2-N-pyrrolyl, 1,1-dioxide-2-isothiazolidinyl, thienyl, thiazolyl, pyridyl or 220 pyrrolidinonyl, and in which each group is optionally substituted with one or two substituents selected from: halogen, cyano , C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy and C1-4 alkanoyl. 2. A compound according to claim 1, wherein G is quinolinyl, benzoxazolyl or pyrimidyl. 3. A compound according to claim 1 or claim 2, wherein R1 is C1-4 alkyl.

A compound according to claim 1, 2 or 3, wherein R2 is hydrogen and n is 2.

5. A compound according to any of claims 1-4, wherein X is -S-. 6. A compound according to any of claims 1-5, wherein R4 is optionally substituted phenyl (for example phenyl, 4-trifluoromethyl-phenyl, 3,4-difluorophenyl) or optionally substituted oxazolyl (for example 4-methyl-1 , 3-oxazol-5-yl, 2-methyl-5-trifluoromethyl-1,3-oxazol-4-yl).

7. A compound according to any of claims 1-6, wherein R3 is methyl.

8. A compound according to claim 1, having a formula (I) 'or a salt thereof N image3 H image2 N N (CHR2) (CH2) n X (I) 'N R4 R3 (R1) p wherein G, p, R1, R2, R3 and R4 are as defined in claim 1 for the compounds of formula (I). 9. A compound according to claim 1 having a formula (IC) or a salt thereof, wherein R1, p, R3 and R4 are as defined in any of claims 1-7: N image2 image2 N image2 N (CH2) 3 S image2 (IC) N R4 R3 image2 N (R1) p O 10. A compound according to claim 1 having a formula (ID) or a salt thereof, wherein R1, p, R3 and R4 are as defined in any of claims 1-7: N image2 image2 N image2 N (CH2) 3 S image2 (ID) N R4 R3 image2 (R1) p N 11. A compound according to claim 1 having a formula (IE) or a salt thereof, wherein R1, p, R3 and R4 are as defined in any of claims 1-7: N image2 N image2 N (CH2) 3 S image2 (IE) N R4 (R1) p image2 N R3 N A compound according to claim 1, which is: 2-methyl-6 - [(1R, 5S / 1S, 5R) -3- (3 - {[4-methyl-5- (4-methyl-1,3-oxazol-5-yl) -4H-1, 2,4-triazol-3-yl] thio} propyl) -3azabicyclo [3.1.0] hex-1-yl] quinoline; 2-ethyl-5 - [(1R, 5S / 1S, 5R) -3- (3 - {[4-methyl-5- (4-methyl-1,3-oxazol-5-yl) -4H-1, 2,4-triazol-3-yl] thio} propyl) -3azabicyclo [3.1.0] hex-1-yl] -1,3-benzoxazole; 15 5 - [(1R, 5S / 1S, 5R) -3- (3 - {[4-methyl-5- (4-methyl-1,3-oxazol-5-yl) -4H-1,2,4 -triazol-3-yl] thio} propyl) -3azabicyclo [3.1.0] hex-1-yl] quinoline; (1S, 5S / 1R, 5R) -3- (3 - {[4-methyl-5- (4-methyl-1,3-oxazol-5-yl) -4H-1,2,4-triazol-3 -il] thio} propyl) -1- (2-pyrimidinyl) -3-azabicyclo [3.1.0] texan; (1S, 5S / 1R, 5R) -3- (3 - {[5- (3,4-difluorophenyl) -4-methyl-4H-1,2,4-triazol-3-yl] thio} propyl) - 1- (2-pyrimidinyl) -320 azabicyclo [3.1.0] hexane; or a salt thereof. 13. A process for preparing a compound as defined in claim 1, the process comprising reacting a compound of formula (II): image4 (II) in which R1, p and G are as defined for formula (I), with a compound of formula (III): L (CHR2) (CH2) 2 S (III) 5 in which R2, R3 and R4 are as defined for formula (I) and L is a leaving group, and after this optionally:

(i)

 remove any protective group; I

(ii)

 form a salt; I

(iii) converting a compound of formula (I) or a salt thereof into another compound of formula (I) or a salt thereof. 14. A compound according to any of claims 1-12 for use in therapy. 15. A compound according to any of claims 1-12 for use in the treatment of a drug-related disorder, a psychotic disorder (eg, schizophrenia) or premature ejaculation. 16. A pharmaceutical composition comprising a compound according to any of claims 1-12 and a pharmaceutically acceptable carrier. 17. Use of a compound according to any of claims 1-12 in the manufacture of a medicament for the treatment of a drug-related disorder, a psychotic disorder (eg, schizophrenia) or premature ejaculation.