OA16934A

OA16934A - Quinoline derivatives as PDE10A enzyme inhibitors.

Info

Publication number: OA16934A
Application number: OA1201400275
Authority: OA
Inventors: John Paul Kilburn; Morten LANGGÅRD; Jan Kehler; Jacob Nielsen; Ask Püschl
Original assignee: H. Lundbeck A/S
Priority date: 2011-12-21
Filing date: 2012-12-21
Publication date: 2016-01-25

Abstract

The present invention provides quinoline derivatives of formula (I) that are PDE10A enzyme inhibitors, and as such are useful to treat neurodegenerative and psychiatric disorders. Especially, the invention provides compounds that are highly selective for PDE10 over other PDE subtypes. The present invention also provides pharmaceutical compositions comprising compounds of the invention and methods of treating disorders using the compounds of the invention.

Description

Qulnollne derlvatlves as PDE10A enzyme Inhibitors

Field of the Invention

The présent Invention provides quinoline dérivatives that are PDE10A enzyme inhibitors, and as such are useful to treat neurodegenerative and psychiatrie disorders· Especially, the Invention provides compounds that are htghly sélective for PDE10 over other PDE subtypes. The présent invention also provides pharmaceutical compositions comprising compounds of the invention and methods of treating disorders using the compounds of the Invention.

Background of the Invention

The cyclic nucléotides cyclic-adenosine monophosphate (cAMP) and cyclic-guanosine monophosphate (cGMP) function as intracellular second messengers regulating a vast array of processes In neurons. intracellular cAMP and cGMP are generated by adenyl and guanyl cyclases, and are degraded by cyclic nucléotide phosphodiesterases (PDEs) via hydrolysis of the cyclic nucléotides Into their respective nucléotide monophosphates.

Phosphodieasterase 10A (PDE10A) is a dual-specificity phosphodiesterase that can convert both cAMP to AMP and cGMP to GMP (Soderling, S. ef a/. Proc. Natl. Acad. Sci. 1999, 96, 7071-7076), PDE10A is primarily expressed in the neurons In the striatum, n. accumbens and In the olfactory tubercle (Kotera, J. étal. Biochem. Biophys. Res. Comm. 1999, 261, 551-557 and Seeger, T.F. et a!. Brain Research, 2003, 985,113-126).

Studies indicate that within the brain, PDE10 expression is expressed at high levels by the medium spiny neurons (MSN) of the caudate nucléus, the accumbens nucléus and the corresponding neurons of the olfactory tuberde. MSN express two functional classes of neurons: the Di class expressing Di dopamine receptors and the D₂ class expressing D₂ dopamine receptors. The Di class of neurons is part of the ‘direct¹ striatal output pathway, which broadly fonctions to facilitate behavioral responses. The D₂ class of neurons is part of the 'indirect' striatal output pathway, which fonctions to suppress behavioral responses that compete with those being facilitated by the 'direct* pathway.

Dopamine D₂ receptor antagonism Is well established in the treatment of schizophrenia. Since the 1950’s, dopamine D₂ receptor antagonism has been the mainstay in psychosis treatment and ail effective antipsychotic drugs antagonise D₂ receptors. The effects of D₂ are likely to be mediated primarily through neurons ln the striatum, nucléus accumbens and olfactory tubercle, since these areas receive the densest dopaminergic projections and hâve the strongest expression of D₂receptors (Konradi, C. and Heckers, S. Society ofBiological Psychlatry, 2001, 50, 729-742).

Because PDE10A, in this context, has the desired expression profile with high and relatively spécifie expression in neurons in striatum, nucléus accumbens and olfactory tubercle, PDE10A inhibition is likely to hâve effects similar to D₂ receptor antagonism and therefore hâve antipsychotic effects.

While PDE10A Inhibition is expected to mimic D₂ receptor antagonism in part, it might be expected to hâve a different profile. The D₂ receptor has signaling components besides cAMP (Neve, K. A. et al. Journal of Receptors and Signal Transduction 2004, 24, 165-205), wherefore interférence with cAMP through PDE10A inhibition may reduce the risk of the extrapyramidal side effects that are seen with strong D₂ antagonism. Conversely, PDE10A inhibition may hâve some effects not seen with D₂ receptor antagonism. PDE10A is also expressed in Di receptors expressing striatal neurons (Seeger, T. F. et al. Brain Research, 2003, 985,113-126).

Further, since Di receptor agonism leads to stimulation of adenylate cyclase and resulting increase ln cAMP levels, PDE10A inhibition is likely to also hâve effects that mimic Di receptor agonism.

Finally, PDE10A Inhibition will not only increase cAMP in cells, but might also be expected to increase cGMP levels, since PDE10A is a dual specificity phosphodiesterase. cGMP activâtes a number of target protein in cells like cAMP and also interacts with the cAMP signaling pathways.

ln conclusion, PDE10A inhibition is likely to mimic D₂ receptor antagonism in part and therefore has antipsychotic effect, but the profile might differ from that observed with classical D₂ receptor antagonists.

The PDE10A inhibitor papaverine is shown to be active in several antipsychotic models.

Papaverine potentiated the cataleptic effect of the D₂ receptor antagonist haloperidol in rats, but did not cause catalepsy on its own (WO 03/093499), Papaverine redueed hyperactivity in rats induced by PCP, while réduction of amphétamine induced hyperactivity was Insignificant (WO 03/093499).

These models suggest that PDE10A inhibition has the classic antipsychotic potential that would be expected from the theoretical considérations outlined above. WO 03/093499 further disdoses the use of sélective PDE10 inhibitors for the treatment of associated neurologie and psychiatrie disorders. Furthermore, PDE10A Inhibition reverses subchnonic PCP-Induced déficits in attentional set-shiftîng In rats (Rodefer et a/. Eur. J. Neurosci. 2005, 4, 1070-1076). This model suggests that PDE10A Inhibition might alleviate cognitive déficits associated with schizophrenia.

The tissue distribution of PDE10A indicates that PDE10A Inhibitors can be used to raise levels of cAMP and/or cGMP within cells that express the PDE10A enzyme, especially neurons that comprise the basal ganglia, and the PDE10A Inhibitors of the présent invention would therefore be usefui in treating a variety of associated neuropsychiatrie conditions Invoiving the basal ganglia such as neurological and psychiatrie disorders, schizophrenia, bipolar disorder, psychosis, obsessive compulsive disorder and addiction, and may hâve the benefit of not possessing unwanted side effects, which are associated with the current thérapies on the market.

Furthermore, recent publications (WO 2005/120514, WO 2005012485, Cantin et ai, Bioorganic & Médicinal Chemistry Letters 17 (2007) 2869-2873) suggest that PDE10A inhibitors may be usefui for treatment of obesity and non-lnsulin dépendent diabètes.

Furthermore, recent publications suggest that PDE10A Inhibitors may be usefui for the treatment of Huntingtons Disease (Giampa et al. PLoS One 2010, 5(10), Giampa et al. Neurobioiogy of Disease (2009), 34(3), 450-456, Hebb et al. Current Opinion in Pharmacology 2007, 7(1), 86-92.)

Pyrrolodihydroisoquinolines and variants thereof are disclosed as inhibitors of PDE10 In WO 05/03129 and WO 05/02579. Piperidlnyl-substituted quinazolines and Isoquinolines that serve as PDE10 Inhibitors are disclosed ln WO 05/82883. WO 06/11040 disdoses substituted quinazoline and Isoquinoline compounds that serve as Inhibitors of PDE10. US 20050182079 disdoses substituted tetrahydroisoquinolinyl dérivatives of quinazoline and Isoquinoline that serve as effective phosphodiesterase (PDE) Inhibitors. ln particular, US 20050182079 relates to said compounds, which are sélective inhibitors of PDE10. Analogously, US 20060019975 disdoses piperidine dérivatives of quinazoline and isoquinoline that serve as effective phosphodiesterase (PDE) inhibitors. US 20060019975 also relates to compounds that are sélective Inhibitors of PDE10. WO 06/028957 disdoses dnnoline dérivatives as inhibitors of PDE10 for the treatment of psychiatrie and neurological syndromes. WO09/152825 discloses phenylimidazole dérivatives as compounds that serve as inhibitors of PDE10.

However, these disclosures do not pertain to the compounds of the Invention, which are structurally unrelated to any of the known PDE10 inhibitors (Kehler, J. et al. Expert Opin. Ther. Patents 2007, 17, 147-158), and which hâve now been found by the inventors to be highly active and sélective PDE10A enzyme inhibitors.

The présent invention provides compounds that are PDE10A enzyme inhibitors and thus useful for treatment for neurodegenerative and/or psychiatrie disorders, which are not efficacious in ail patients. Hence, there remains a need for alternative methods of treatment.

Summary of the Invention

The objective of the présent invention is to provide compounds that are sélective PDE10A enzyme inhibitors.

A further objective of the présent invention is to provide compounds which hâve such activity, and which hâve improved solubility, metabolic stability and/or bioavailability compared to prior art compounds.

Another objective of the invention is to provide an effective treatment, in particular long-term treatment, of a human patient, without causing the side effects typically associated with current thérapies for neurological and psychiatrie disorders.

Further objectives ofthe invention will become apparent upon reading the présent spécification.

Detalled description of the Invention

Embodiments ofthe Invention in a first embodiment (E1) the présent invention relates to compounds of formula I:

wherein R1, R2, R3, R4, R5 and R6 are Indivldually selected from the group consisting of hydrogen, hydroxyl, cyano, CrCe alkyl; C_rC_e alkoxy, halogen, methylenedioxy, diflouromethylenedioxy and ethylenedioxy wherein -L- Is a linker seiected from -CH2-CH2- and -CH=CHwherein HET Is selected from the group consisting of

wherein one or more of the carbon-bound hydrogen In the HET optionally may be substituted with up to three substituents R7, R8 and R9 Individually selected from C_rC_e alkyl; halogen; cyano, halo(CrCe)alkyl; aryl, alkoxy and C_rCe hydroxyalkyl and wherein * dénotés the attachment point, and tautomers and pharmaceutically acceptable salts thereof, and polymorphie forms thereof.

In an embodiment (E2) of embodiment (E1) one or more of R1-R6 Is selected from the group consisting of 0,-03 alkyl substituted with one or more F and unsubstituted C1-C3 alkyl.

In an embodiment (E3) of embodiment (E1 ) or (E2) one or more of R1-R6 Is selected from the group consisting of methyl, ethyl, propyl, isopropyl, monoflouromethyl, diflouromethyl and triflouromethyl.

In an embodiment (E4) of embodiment (E1 ) one or more of R1-R6 Is selected from the group consisting of methoxy, diflouromethoxy and triflouromethoxy.

In an embodiment (E5) of embodiment (E1) one or more of R1-R6 is selected from the group consisting of fluorine and chlorine.

in an embodiment (E6) of any of embodiments (E1) to (E5) -L- is -CH2-CH2In an embodiment (E7) of any of embodiments (E1) to (E5) -L- is -CH=CHIn an embodiment (E8) of any of embodiments (E1 ) to (E7) HET is selected from the group consisting of *

wherein HET optionaily is substituted with one or more of R7-R9, and wherein * dénotés the attachment point.

In an embodiment (E9) of any of embodiments (E1) to (E8) HET Is substituted with one substituent R7 selected from the group consisting of 0,-(% alkyl, such as methyl; halogen, such as chlorine or bromlne; cyano; halo(Ci-C_e)alkyl, such as trifluoromethyl; aryl such as phenyl; and Ci-Ce hydroxyalkyl such as CH2CH2OH.

In an embodiment (E10) of any of embodiments (E1) to (E8), HET is substituted with two substituents R7 and R8 individualiy selected from C_rCe alkyl, such as methyl; halogen, such as chlorine or bromine; cyano; halo(CrC_e)alkyl, such as trifluoromethyl; aryl, such as phenyl; and CtCe hydroxyalkyl, such as CH2CH2OH.

In an embodiment (E11) of any of embodiment (E1) to (E8), HET Is substituted with three substituents R7, R8 and R9 individualiy selected from Ci-Ce alkyl, such as methyl; halogen, such as chlorine or bromine; cyano; haloiCj-Ceïalkyl, such as trifluoromethyl; aryl, such as phenyl; and CtCe hydroxyalkyl, such as CH2CH2OH.

In an embodiment (E12) of any of embodiments (E1) to (E8) HET is unsubstituted.

In an embodiment (E13) of any of embodiments (E1 ), (E9), (E10) and (E11 ) HET Is substituted with at least one Ct-Ce alkyl, such as methyl

In an embodiment (E14) of any of embodiments (E1) to (E11) HET Is selected from the group consisting of (5,7-Dimethyl-lmidazo[1,2-a]pyrimidin-2-yl), 5,7-Dimethyl-[1,2,4]triazolo[1,5a]pyrimldin-2-yl), (5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl), (8-Methoxy-5-methyl[1,2,4]triazolo[1,5-a]pyridin-2-yl) and 5,8-Dlmethyl-[1,2,4]trlazolo[1,5-a]pyrldin-2-yl).

In a spécifie embodiment (E15) of embodiment (E1) the compound is selected from the group of compounds listed in Table 1.

In an embodiment (E16) of any of the embodiments (E1) to (E15) the invention provides a compound of formula I, or a pharmaceutically acceptable sait thereof, for use as a médicament.

In an embodiment (E17) of any of the embodiments (E1) to (E15) the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I and a pharmaceutically acceptable carrier, diluent or excipient.

In an embodiment (E18) of any of the embodiments (E1) to (E15) the présent invention provides the use of a compound of formula I, or a pharmaceutically acceptable sait thereof, for the préparation of a médicament for the treatment of a neurodegenerative or psychiatrie disorder.

Furthermore, in an embodiment (E19) of any of the embodiments (E1) to (E15) the présent Invention provides a method of treating a subject suffering from a neurodegenerative disorder, comprising administering to the subject a therapeutically effective amount of a compound of formula I.

In an embodiment (E20) of any of the embodiments (E1) to (E15) the présent Invention provides a method of treating a subject suffering from a psychiatrie disorder, comprising administering to the subject a therapeutically effective amount of a compound of formula I.

In an embodiment (E21) of any ofthe embodiments (E1) to (E15) the présent Invention provides a method of treating a subject suffering from a drug addiction, such as an alcohol, amphétamine, cocaïne, or opiate addiction.

In an embodiment (E22) the présent Invention relates to compounds of formula I:

wherein R1-R6 and HET are as described In any ofthe previous embodiments (E1) to (E14) and L- Is a linker selected from -S-CH₂-, -CH₂-S- and ~^c=c“ .

Définition of substltutents

As used in the context of the présent Invention, the terms “halo and “halogen are used Interchangeably and refer to fluorine, chlorine, bromine or lodine.

The term Cj-Ce alkyl refers to a straight-chain or branched saturated hydrocarbon having from one to six carbon atoms, Inclusive. Exemples of such groups Include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl, 2-methyl-l-butyl, and n-hexyl. The expression “Ct-Ce hydroxyalkyl refers to a C_rC_e alkyl group as defined above which is substituted with one hydroxy group. The term “halo(Ci-C_e)alkyT refers to a CrC_e alkyl group as defined above which is substituted with up to three halogen atoms, such as trifluoromethyl.

The expression “CrCe alkoxy” refers to a straight-chain or branched saturated alkoxy group having from one to six carbon atoms, inclusive, with the open valency on the oxygen. Examples of such groups include, but are not limited to, methoxy, ethoxy, n-butoxy, 2-methyl-pentoxy and n-hexyfoxy. The alkoxy may optionally be substituted with up to three halogen atoms, such as trifluoromethoxy.

The term “C3-C_e cycloalkyl* typicaliy refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. The expression CrCe alkyJ(C3-C_B)cycloalkyl refers to a C3-C_e cycloalkyl as defined above which is substituted with a straight-chain or branched CrCe alkyl. Examples of such groups include, but are not limited to, cyclopropylmethyl.

The term “heterocycloalkyl refers to a fourto eight membered ring containing carbon atoms and up to three N, O or S atoms, provided that the four to eight membered ring does not contain adjacent O or adjacent S atoms. The open valency is on either the heteroatom or carbon atom. Examples of such groups include, but are not limited to, azetidinyl, oxetanyl, piperazinyl, morpholinyl, thiomorpholinyl and [1,4]diazepanyl. The term “hydroxyheterocycloalkyl refers to a heterocycloalkyl as defined above which is substituted with one hydroxy group. The term Cj-Ce alkyl-heterocycloalkyl refers to a heterocycloalkyl as defined above which Is substituted with a C,Ce alkyl group. Examples of such groups Include, but are not limited to, tetrahydropyran-4-yl-methyl and 2-morpholin-4-yl-ethyl.

The term “aryl refers to a phenyl ring, optionally substituted with halogen, C_rCe alkyl, C_rCe alkoxy or halofCrCeJalkyl as defined above. Examples of such groups include, but are not limited to, phenyl and 4-chlorophenyl.

The term C_rC_earylalkyl refers to an aryl as defined above which Is substituted with a stralghtchain or branched Ci-C_e alkyl. Examples of such groups include, but are not limited to, benzyl and

4-chlorobenzyl.

In a further embodiment one or more of the hydrogen atoms of the compound of formula I hâve been substituted by deuterium.

In the context of this application is should be understood that the meaning of R1-R6, R1 to R6 and *R1, R2, R3, R4, R5 and R6’ is the same.

Additionally, the présent invention further provides certain embodiments of the invention, that are described below.

In separate embodiments of the invention, the compound of formula I is selected among the following spécifie compounds listed In Table 1, in the form of the free base, one or more tautomers thereof or a pharmaceutically acceptable sait thereof. Table 1 lists compounds of the invention and the corresponding IC» values determined as described in the section “PDE10A Inhibition assay. Each ofthe compounds constitutes an individual embodiment, ofthe présent Invention.

It should be understood that the various aspects, embodiments, implémentations and features of the invention mentioned herein may be daimed separately, or in any combination, as illustrated by the following non-limiting examples.

Table 1: Compounds ofthe Invention and ICso values

Compound	IC50 (nM)
2-[(E)-2-(5,7-Dimethyl-imidazo[1,2-a]pyrimidin-2-yl)-vinyi]-qulnoline	320
2-[(Z)-2-(5,7-Dîmethyl-imidazo[1,2-a]pyrimldln-2-yl)-vinyl]-qulnoline	240
2-[2-(5,7-Dimethyl-lmidazo[1,2-a]pyrimidin-2-yl)-ethyl]-quinoline	310

Compound	IC50 (nM)
2-[2-(5_l7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)-ethyl]-quinoline	72
2-(2-(5,8-D imethy1-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-ethyl]-quinolÎne	19
2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1_l5-a]pyrazin-2-yl)-ethyl]-quinoline	7,4
2-(2-(5,7-Dimethy!-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)-ethy!]-6methoxy-quinoline	170
2-[2-(8-Methoxy-5-methyl-[1,2,4]triazolo[1,5-a]pyrid in-2-y!)-ethyl]quinoline	12
2-[2-(8-Ethyl-5-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-ethyl]-6-fluoroquinoline	25
6-Fluoro-2-[2-(8-methoxy-5-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-y!)ethyl]-qulnoline	34
2-[2-(5,8-Dimethy!-[1,2_l4]triazolo[1,5-a]pyridin-2-yl)-ethyl]-quinoline	24
2-[2-(6-Fluoro-quinolin-2-yl)-ethyl]-5-methyl-[1,2,4]triazolo[1,5a]pyridin-8-ol	85
2-(2-(5,8-Dimethyl-[1,2,4]triazolo[1_l5-a]pyrazin-2-yl)-ethyl]-4-methylquinoline	18
2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-ethy!]-4-methoxyquinoline	12
4-Methoxy-2-[2-(5-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-ethyl]quinoline	190
4-Methoxy-2-[2-(8-methoxy-5-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)ethy!]-quinoline	35
4-Methy!-2-[2-(5-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-ethy1]quinoline	140
2-(2-(8-Methoxy-5-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-y!)-ethy!]-4methyl-qutnoline	42

Compound	IC50 (nM)
4-Chloro-8-fluoro-2-[(E)-2-(8-methoxy-5-methyl-[1,2,4]triazo lo[1,5a]pyridin-2-yl)-vinyl]-quinoline	270
8-Fluoro-2-[2-(8-methoxy-5-methyl-[1,2_l4]triazolo[1,5-a]pyridin-2-yl)ethyl]-quinoline	150
2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-ethyl]-7-fluoro- quinoline	15
2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-ethyl]-6-fluoroquinoline	24
2-[2-( 5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-ethyl]-6-fluoroquinoline	26
2-[2-(5,8-DÎmethyl-[1,2_l4]triazolo[1,5-alpyrazin-2-yl)-ethyl]-4-fluoro- quinoline	28
2-[(E)-2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-alpyrazin-2-yi)-vinyll-6-fluoro- quinoline	190
2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-ethyl]-7-fluoro-4methoxy-quinollne	28
2-[2-(5,8-Dîmethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-ethyl]-7-fluoro- quinolin-4-ol	500
2-[(E)-2-(5_l8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-vinyl]-7trifluoromethyl-quinoline	550
2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-ethyl]-6-fluoro-4methoxy-quinolîne	14
2-[2-(5,8-Dimethyl-[ 1,2,4]triazolo[1,5-a]pyrazin-2-yl)-ethyl]-7trifluoromethyl-quinoline	240
2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1_l5-a]pyrazÎn-2-yl)-ethyl]-6-fluoro- quinolin-4-ol	410

Compound	IC50 (nM)
2-[2-(5,8-Dimethyb[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-ethyl]-5-fluoroquinoline	120
7-Chloro-2-[2-(5,8-dÎmethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-y1)-ethy1]- quinoline	52
2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)-ethyt]-6isopropyt-quinoline	61
2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-ethyl]-5_l7-difluoroquinolïne	110
2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-ethyl]-5,6,8trifluoro-quinoline	360
2-[2-{5,8-DimethyL[1 Æ^triazoloIl.S-aJpyrazin^-yO-ethylj-e.e-difluoroquinoline	300
6-[2-(5,8-DÎmethyl-[1,2,4]triazolo [1,5-a]pyrazin-2-yl)-ethyl][1,3]dioxolo[4,5-g]quinoline	13
2-[2-(5,8-Dimethy1-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-ethyl]-6-fluoro-8methyl-quinoline	2000
2-[2-(5,8-Dim ethyl- [1,2,4]triazolo[1,5-a]pyrazin-2-yl)-ethyt]-6-fluoro-7methyl-quinoline	8,8
6-[2-(5,8-Dimethyl-[1_l2_l4]triazolo[1,5-a]pyrazin-2-yl)-ethyt]-2,2-difluoro- [1,3]dioxolo[4,5-g]qulnoline	520
7-Chloro-2-[2-t5,8-dimethy1-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-ethyl]qulnoline-6-carbonïtrile	59
7-[2-(5,8-Dimethyl-[1,2_l4]triazolo[1_>5-a]pyrazin-2-yl)-ethyl]-2_t3-dihydro[1 ,4]dioxino[2,3-g]quinoline	4
6-Chloro-2-[2-(5,8-dlmethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-ethy1]quinoline	42

Compound	IC50 (nM)
6-Chloro-2-[2-(5,8-dimethy1-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-ethy1]-8fluoro-quinoline	240
8-Chloro-2-[2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-ethyl]-6methyl-quinoline	290
5,7-Dichloro-2-[2-(5,8-di methyl-[1,2,4]triazolo[ 1,5-a]pyrazin-2-yl )-e t hyl] quinoline	39
2-[(E)-2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-vinyl]-6trifluoromethoxy-quinoline	2800
2-[(EJ-2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-vÎnyl]-6trifluoromethyl-qulnoline	490
2-[(E)-2-(5,8-Dimethy1-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-vinyl]-6-cyanoqulnoline	2100
2-[(E)-2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-vlnyl]-7methoxy-quinoline	13
2-[(E )-2-(5,8-Di methyl-[ 1,2,4]triazolo[1,5-a]pyrazin-2-yl)-vinyl]-5methoxy-quinoline	19

ln a particular embodiment of the présent invention the compounds of the présent invention hâve an IC50 value of less than 50 nM, such as in the range of 0.2 - 20 nM, particularly in the range of 0.2-10 nM, such as in the range of 0.2 - 5 nM.

Pharmaceutically Acceptable Salts

The présent invention also comprises salts of the compounds, typically, pharmaceutically acceptable salts. Such salts include pharmaceutically acceptable add addition salts. Acid addition salts include salts of inorganic acids as well as organic acids.

Représentative examples of suitable inorganic acids Indude hydrochloric, hydrobromlc, hydroiodic, phosphoric, sulfuric, sulfamic, nltric adds and the like. Représentative examples of suitable organic acids include formic, acetic, trichloroacetic, tri fluoro a ce tic, propionic, benzoic, cinnamic, citric, fuma rie, glycolic, itaconic, lactic, methanesulfonic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicyîic, succinic, methane sulfonic, ethanesulfonic, tartane, ascorbic, pamoic, bismethylene salicyîic, ethanedisulfonlc, gluconïc, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids, theophyüine acetic acids, as well as the 8-halotheophyüines, for example 8-bromotheophyiline and the like. Further examples of pharmaceutically acceptable Inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in Berge, S.M. et al., J. Pharm. Sci. 1977, 66, 2, the contents of which are hereby incorporated by reference.

Furthermore, the compounds of this invention may exist in unsolvated as well as in solvated forms with pharmaceutically acceptable solvents such as water, éthanol and the like. In general, the solvated forms are considered équivalent to the unsolvated forms for the purposes of this invention.

Pharmaceutical compositions

The présent invention further provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula i and a pharmaceutically acceptable carrier or diluent. The présent invention also provides a pharmaceutical composition comprising a therapeutically effective amount of one of the spécifie compounds disclosed ln the Experimental Section herein and a pharmaceutically acceptable carrier or diluent.

The compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers, diluents or excipients, in either single or multiple doses. The pharmaceutical compositions according to the invention may be formuiated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, ΙΟ* Edition, Gennaro, Ed., MackPublishing Co., Easton, PA, 1995.

The pharmaceutical compositions may be specifically formulated for administration by any suitable route such as oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracistemal, intraperitoneal, vaginal and parentéral (including subeutaneous, intramuscular, intrathecal, intravenous and intradermal) routes. It will be appreciated that the route will dépend on the general condition and âge of the subject to be treated, the nature of the condition to be treated and the active Ingrédient.

Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pilis, lozenges, powders and granules. Where appropriate, the compositions may be prepared with coatings such as enteric coatings or they may be formulated so as to provîde controlled release of the active Ingrédient such as sustained or prolonged release according to methods well known in the art. Liquid dosage forms for oral administration include solutions, émulsions, suspensions, syrups and élixirs.

Pharmaceutical compositions for parentéral administration include stérile aqueous and nonaqueous Injectable solutions, dispersions, suspensions or émulsions as well as stérile powders to be reconstituted in stérile Injectable solutions or dispersions prior to use. Other suitable administration forms include, but are not limited to, suppositories, sprays, ointments, creams, gels, inhalants, dermal patches and implants.

Typical oral dosages range from about 0.001 to about 100 mg/kg body weight per day. Typical oral dosages also range from about 0.01 to about 50 mg/kg body weight per day. Typical oral dosages further range from about 0.05 to about 10 mg/kg body weight per day. Oral dosages are usually administered in one or more dosages, typically, one to three dosages per day. The exact dosage will dépend upon the frequency and mode of administration, the sex, âge, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors évident to those skilled in the art.

The formulations may also be presented in a unit dosage form by methods known to those skilled in the art. For illustrative purposes, a typical unit dosage form for oral administration may contain from about 0.01 to about 1000 mg, from about 0.05 to about 500 mg, or from about 0.5 mg to about 200 mg.

For parentéral routes such as intravenous, intrathecal, intramuscular and similar administration, typical doses are in the order of half the dose employed for oral administration.

The présent Invention also provides a process for making a pharmaceutical composition comprising admixing a therapeutically effective amount of a compound of formula I and at least one pharmaceutically acceptable carrier or diluent. In an embodiment, of the présent invention, the compound utilized in the aforementioned process Is one of the spécifie compounds disclosed In the Experimental Section herein.

The compounds of this invention are generally utilized as the free substance or as a pharmaceutically acceptable sait thereof. One example is an add addition sait of a compound having the utility of a free base. When a compound of formula I contains a free base such salts are prepared In a conventional manner by treating a solution or suspension of a free base of formula ! with a molar équivalent of a pharmaceutically acceptable acid. Représentative examples of suitable organic and inorganic adds are described above.

For parentéral administration, solutions of the compounds of formula I In stérile aqueous solution, aqueous propylene glycol, aqueous vitamin E or sesame or peanut oil may be employed. Such aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonie with sufficient saline or glucose. The aqueous solutions are particularly suitable for Intravenous, Intramuscular, subeutaneous and intraperitoneal administration. The compounds of formula I may be readily incorporated into known stérile aqueous media using standard techniques known to those skilled in the art.

Suitable pharmaceutical carriers include inert solid diiuents or fillers, stérile aqueous solutions and various organic solvents. Examples of solid carriers indude lactose, terra aiba, sucrose, cydodextrin, talc, gelatin, agar, pectin, acada, magnésium stéarate, stearic add and lower alkyl ethers of cellulose. Examples of liquid carriers indude, but are not limited to, syrup, peanut oil, olive oil, phospholiplds, fatty acids, fatty add amines, polyoxyethylene and water. Similariy, the carrier or diluent may indude any sustained release material known In the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. The pharmaceutical compositions formed by comblnlng the compounds of formula I and a pharmaceutically acceptable carrier are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration. The formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy.

Formulations of the présent invention suitable for oral administration may be presented as discrète units such as capsules or tablets, each containing a predetermined amount of the active ingrédient, and optionally a suitable excipient. Furthermore, the orally available formulations may be In the form of a powder or granules, a solution or suspension in an aqueous or non-aqueous liquid, or an oil-ln-water orwater-ln-oil liquid émulsion.

If a solid carrier is used for oral administration, the préparation may be tabletted, placed in a hard gelatin capsule in powder or pellet form or It may be In the form of a troche or lozenge. The amount of solid carrier will vary widely but will range from about 25 mg to about 1 g per dosage unit. If a liquid carrier Is used, the préparation may be In the form of a syrup, émulsion, soft gelatin capsule or stérile Injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.

The pharmaceutical compositions of the invention may be prepared by conventional methods in the art. For example, tablets may be prepared by mixing the active ingrédient with ordinary adjuvants and/or diluents and subsequently compressing the mixture in a conventional tabletting machine préparé tablets. Examples of adjuvants or diluents comprise: corn starch, potato starch, talcum, magnésium stéarate, gelatin, lactose, gums, and the like. Any other adjuvants or additives usually used for such purposes such as colorings, flavorings, preservatîves etc. may be used provided that they are compatible with the active Ingrédients.

Therapeutically effective amount

In the présent context, the term therapeutically effective amount of a compound means an amount sufficient to cure, alleviate or partially arrest the clïnical manifestations of a given disease and its complications In a therapeutic Intervention comprising the administration of said compound. An amount adéquate to accomplish this is defined as therapeutically effective amount. Effective amounts for each purpose will dépend on the severity of the disease or injury as well as the weight and general state of the subject. It will be understood that determining an appropriate dosage may be achieved using routine expérimentation, by constructing a matrix of values and testing different points In the matrix, which is ail within the ordinary skills of a trained physicien.

In the présent context, the term treatment and treating means the management and care of a patient for the purpose of combating a condition, such as a disease or a disorder. The term is intended to include the full spectrum of treatments for a given condition from which the patient Is suffering, such as administration ofthe active compound to alleviate the symptoms or complications, to delay the progression of the disease, disorder or condition, to alleviate or relief the symptoms and complications, and/or to cure or eliminate the disease, disorder or condition as well as to prevent the condition, wherein prévention is to be understood as the management and care of a patient for the purpose of combating the disease, condition, or disorder and includes the administration of the active compounds to prevent the onset of the symptoms or complications. Nonetheless, prophylactic (préventive) and therapeutic (curative) treatments are two separate aspects of the Invention. The patient to be treated is preferably a mammal, in particular a human being.

Treatment of Disorders

As mentioned above, the compounds of formula I are PDE10A enzyme inhibitors and as such are useful to treat associated neurological and psychiatrie disorders.

The invention thus provides a compound of formula I or a pharmaceutically acceptable acid addition sait thereof, as well as a pharmaceutical composition containing such a compound, for use In the treatment of a neurodegenerative disorder, psychiatrie disorder or drug addiction In humans.

In one embodiment of the présent invention, the neurodegenerative disorder or condition involves neurodegeneration of striatal medium spiny neurons in a human. in a spécifie embodiment of the présent Invention, the neurodegenerative disorder or condition is Huntington's disease. In a further embodiment the disorder Is dyskinesia associated with dopamine agonist therapy.

In an embodiment the psychiatrie disorder is selected from the group consisting of schizophrenia, for example of the paranoid, disorganlzed, catatonie, undifferentiated, or residual type; schizophreniform disorder; schizoaffective disorder, for example of the delusional type or the dépressive type; delusional disorder; substance-induced psychotic disorder, for example psychosis Induced by alcohol, amphétamine, cannabis, cocaïne, haliucinogens, Inhalants, opioids, or phencyclidine; personality disorder of the paranoid type; and personality disorder of the schizoid type.

This Invention further provides a method of treating a drug addiction, for example an alcohol, amphétamine, cocaïne, or opiate addiction, in a human, which method comprises administering to said human an amount of a compound of formula I effective in treating addiction, such as drug addiction.

The term drug addiction, as used herein, means an abnormal desire for a drug and is generaily characterized by motivational disturbances such a compulsion to take the desired drug and épisodes of intense drug craving.

Other disorders that can be treated according to the présent invention are obsessive/compulsive disorders, non-insuline demanding diabètes mellitus (NIDDM), and Tourette's syndrome and other tic disorders as well as Attention Defidt/Hyperactivity Disorder (ADHD).

The compounds of formula I or pharmaceutically acceptable salts thereof may be used in combination with one or more other drugs (including typical and atypical antpsychotic agent) In the treatment of diseases or conditions for which the compounds of the présent invention hâve utility, where the combination of the drugs together are safer or more effective than either drug alone. Additionally, the compounds of the présent invention may be used in combination with one or more other drugs that treat, prevent, control, ameliorate, or reduce the risk of side effects or toxicity of the compounds of the présent invention. The combinations, uses and methods of treatment of the invention may also provide advantages In treatment of patients who fait to respond adequately or who are résistant to other known treatments.

Such other drugs may be administered, by a route and In an amount commonly used therefore, contemporaneously or sequentially with the compounds of the présent Invention. Accordingly, the pharmaceutical compositions of the présent invention include those that contain one or more other active ingrédients, in addition to the compounds of the présent invention. The combinations may be administered as part of a unit dosage form combination product, or as a kit or treatment protocol wherein one or more additional drugs are administered in separate dosage forms as part of a treatment regimen.

The term neuroleptic agent as used herein refers to drugs, which hâve the effect on cognition and behaviour of antipsychotic agent drugs that reduce confusion, delusions, hallucinations, and psychomotor agitation in patients with psychoses. Also known as major tranquilizers and antipsychotic drugs, neuroleptic agents include, but are not limited to: typical antipsychotic drugs, including phenothiazines, further divided Into the aliphatics, piperidines, and piperazines, thioxanthenes (e.g., dsordinol), butyrophenones (e.g., haioperidol), dibenzoxazepines (e.g., loxaplne), dihydroindolones (e.g., molindone), dïphenylbutylpiperidines (e.g., pimozlde), and atypical antipsychotic drugs, Including benzisoxazoles (e.g., rispéridone), sertindole, olanzapine, quetiapine, osanetant and ziprasidone.

Partîcularly preferred neuroleptic agents for use in the invention are sertindole, olanzapine, rispéridone, quetiapine, ariplprazole, haioperidol, dozapine, ziprasidone and osanetant.

As used herein, and unless otherwise indicated, a neurodegenerative disorder or condition refers to a disorder or condition that Is caused by the dysfunction and/or death of neurons in the central nervous system. The treatment of these disorders and conditions can be facilitated by administration of an agent which prevents the dysfunction or death of neurons at risk ln these disorders or conditions and/or enhances the function of damaged or healthy neurons in such a way as to compensate for the loss of fonction caused by the dysfunction or death of at-risk neurons, The term neurotrophlc agent as used herein refers to a substance or agent that has some or ail of these properties.

Ail référencés, Including publications, patent applications and patents, cited herein are hereby incorporated by reference ln their entirety and to the same extent as If each reference were indivldually and specifically indicated to be incorporated by reference and were set forth ln Its entirety (to the maximum extent permitted by law).

Headings and sub-headings are used herein for convenience only, and should not be construed as limiting the Invention in any way.

The use of any and ail examples, or exemplary language (including for Instance, for example, e.g., and as such) in the présent spécification is intended merely to better illuminate the invention, and does not pose a limitation on the scope of invention unless otherwise Indicated.

The citation and incorporation of patent documents herein is done for convenience only, and does not reflect any view of the validity, patentabiiity and/or enforceability of such patent documents.

The présent invention includes ail modifications and équivalents of the subject-matter recited in the claims appended hereto, as permitted by applicable law.

The Invention disclosed herein is further illustrated by the following non-limiting examples.

Experimental Section

Préparation of the compounds of the Invention

Compounds of the general formula I of the invention may be prepared as described in the following reaction schemes.

Compounds of formula I, wherein L is -CH=CH- or -CHî-CHr- can be prepared by the reaction sequence shown in scheme 1.

O R6
L HET—	PPh₃	n PPh,L HET^ + R1^X	Q		_XR5
			^R4
III		IV	R2 V	R3

Base

I (where-L-=-CH₂-CH₂-)

I (where -L- = -CH=CH-)

Scheme 1.

Spedficaîly, compounds of formula I, wherein L is -CHî-CHr- can be prepared by réduction of an alkene of formula I, wherein L is -CH=CH-, by hydrogénation using a transition métal catalyst, such as palladium métal, together with a hydrogen source, such as hydrogen gas, ammonium hydrogen carbonate, or cyclohexadiene. Said alkenes of formula I, wherein L is -CH=CH- can be prepared by the Wittig reaction between a phosphonium sait of formula IV and an aldéhyde of formula V in a suitabie solvent, such as tetrahydrofuran, in the presence of a suitabie base, such as 1,8-diazabicyclo[5.4.0]undec-7-ene. Phosphonium salts of formula IV are readily available by reaction of compounds of formula IV (see scheme 1 above) with triphenylphosphlne by methods known to chemists skilled in the art and as described in e.g. WO-2011072696, WO-2011072694 and WO-2009152825. Aldéhydes of formula V are commercially available or available by methods described in the literature see e.g. Organometallics (2011), 30(5), 1008-1012, Journal of

Médicinal Chemistry (2010), 53(24), 8663-8678.ChemicalCommunications(2010),46(35)_l65546556, Journal of Médicinal Chemlstry (2010), 53(5), Science of Synthesis (2005), 15 389-549. Journal of the Chemical Society (1932), Journal of the American Chemical Society (1941), 63 2654-5.

General Methods

Analytlcal LC-MS data were obtained using the following method:

Method 111:

LC-MS were run on a Sciex API150EX equipped with APPI-source operating in positive ion mode. The HPLC consisted of Shimadzu LC10-ADvp LC pumps. SPD-M20A PDA UV-detector (operating at 254 nM) and shimadzu CBM-20A system controller. Autosampler was Gilson 215. Colomn oven was a Metalox model 200-C and column température: 60*C. injecton Gilson model 841 (1 mlcroliter loop).

ELS detector was a Sedere Sedex 85.

LC-conditions: The column was a Waters Symmetry C-18. 4.6 x 30 mm. 3.5Dm operating at 60 °C with 3.3 ml/min of a binary gradient consisting of Solvent A: 100% H2O 0.05% TFA and Solvent B:

95% ACN 5% H2O 0.035% TFA

Injection vol: 10μΙ (1 μΙ Injected on the column)

Gradient: 10% B to 100% B in 2.4 min

10% B In 0.4 min.

Total run time: 2.8 min

Method 131:

LC-MS were run on a Sciex API150EX equipped with APPI-source operating in positive ion mode. The HPLC conslsted of Shimadzu LC10-ADvp LC pumps. SPD-M20A PDA UV-detector (operating at 254 nM) and shimadzu CBM-20A system controller. Autosampler was Gilson 215. Colomn oven was a Jones Chromatography 7990R and column température: 60°C.

ELS detector was a Sedere Sedex 85.

LC-conditions: The column was a Waters Symmetry C-18.4.6 x 30 mm. 3.5Dm operating at 60 °C with 3.0 ml/min of a binary gradient consisting of Solvent A: H2O with 0.05% v/v TFA and Solvent B: Methanoi with 0.05% TFA

Injection vol: 10μΙ (1 μΙ injected on the column)

Gradient:

0.01min 17% B (v/v)

0.27 min 28% B (v/v)

0.53 min 39% B (v/v)

0.80 min 50% B (v/v)

1.07 min 59% B (v/v)

1.34 min 68% B (v/v)

1.60 min 78% B (v/v)

1.87 min 86% B (v/v)

2.14 min 93% B (v/v)

2.38 min 100% B (v/v)

2.40 min 17% B (v/v)

2.80 min 17% B (v/v)

Total run time: 2.8 min

Method 132

LC-MS were run on a Sdex AP1150EX equipped with APPI-sourca operating in positive ion mode. The HPLC consisted of Shimadzu LC10-ADvp LC pumps. SPD-M20A PDA detector (operating at 254 nM) and SCL-10A System controller. Autosampler was Gilson 215. Colomn oven was a Jones Chromatography 7990R and ELS detector was a Sedere Sedex 85.

LC-conditions: The column was a Waters Symmetry C-18.4.6 x 30 mm. 3.5D operating at 60 °C with 2.5 ml/min of a binary gradient consisting of water + 0.05 % TFA (A) and méthanol + 0.05 % TFA (B).

Gradient:	0.01 min.	5% B
	2.38 min.	100% B
	2.40 min.	5% B
	2.80 min.	5% B

Total run time: 2.8 minutes

Method 350

LC-MS were run on a Sdex API300 equipped with APPI source operating In positive ion mode. The UPLC consisted of Waters Aquity Including column mamager. binary solvent manager, sample organizer. PDA detector (operating at 254 nM) and ELS detector.

LC-conditions: The column was a Waters Aquity UPLC BEH C-18. 2.1 x 50 mm. 1.7 dm operating at 60 °C with 1.2 ml/min of a binary gradient consisting of water + 0.05 % TFA (A) and 95 % acetonitrile containing 5 % water + 0.03 % TFA (B).

Gradient: Time (min.) %B

0.0010.0

1.00100.0

1.0110.0

1.1510.0

Total run time 1.15 min

Préparative LC-MS-purification was performed on a PE Sdex API 150EX Instrument with atmospheric pressure chemical ionization. Column: 50 X 20 mm YMC ODS-A with 5 micro m particle slze; Method: Linear gradient elution with A:B » 80:20 to 0:100 In 7 minutes and with a flow rate of 22,7 mL/minute. Fraction collection was performed by split-flow MS détection.

¹H NMR spectra were recorded at 500.13 MHz on a Bruker Avance AV500 instrument or at 600.16 MHz on a Bruker Avance Ultrashield plus instrument TMS was used as Internai référencé standard. Chemical shift values are expressed in ppm. The following abbreviations are used for multiplidty of NMR signais: s ~ singlet, d = doublet, t - triplet, q - quartet, qui » quintet, h = heptet, dd = double doublet, dt - double triplet, dq - double quartet, td - triplet of doublets, tt - triplet of triplets, m ~ multiplet, br s - broad singlet and br - broad signal.

Abbreviations are in accordance with to the ACS Style Guide: The ACS Styleguide - A manual for authors and editors” Janet S. Dodd, Ed. 1997, ISBN: 0841234620

Préparation of Intermediates

Phosphonium salts of formula IV shown in scheme 1 are readily avallable by reaction of compounds of formula IV (see scheme 1 above) with triphenylphosphine by methods known to chemlsts skilled in the art and as described In e.g. WO-2011072696, WO-2011072694 and WO2009152825. Aldéhydes of formula V are commercially available or available by methods described in the literature see e.g. Organometallics (2011), 30(5), 1008-1012, Journal of Médicinal

Chemistry (2010), 53(24), 8663-8678. Chemical Communications (2010), 46(35), 6554-6556, Journal of Médicinal Chemistry (2010), 53(5), Science of Synthesis (2005), 15 389-549. Journal of the Chemical Society (1932), Journal of the American Chemical Society (1941), 63 2654-5.

2-[(E)-2-(5,8-Dimethyl-[1,2₍4]trlazolo[1,5-a]pyrazln-2-yl)-vinyl]-qulnoline-6-carbonitrlle +

To a suspension of (5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-ylmethyl)-triphenyl-phosphonium; chloride (0.222 g, 0.483 mmol) and 2-Formyl-quinoline-6-carbonitrile (80 mg, 0.4 mmol) in dry Tetrahydrofuran (6 mL, 80 mmol) was added 1,8-Diazabicyclo[5.4,0]undec-7-ene (66 uL, 0.44 mmol) (réaction mixture tums slightly yellow for a while and précipitation changes character) and the mixture was stirred at room température under an atmosphère of Argon ovemight. The mixture was rotovaped and the THF was evaporated off. The solid was dissolved in DCM and was chromatographed on silicagel (0-30% MeOH in EtOAc). Pure product 2-[(E)-2-(5,8-Dimethyl-[1 ,2,4]triazolo(1,5-a]pyrazin-2-yl)-vinyl]-quinoline-6-carbonitrile précipitâtes in one of the fractions (10): Isolated by filtration. Yield: 6 mg white solid.

The following Intermediates were made in a similar way:

2-[2-(5_l7-Dimethyl-lmidazo[1,2-a]pyrimidin-2-yl)-vinyl]-quinoline

2-(2-(5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)-vinyl]-quÎnolÎne

2-(2-(5,8-Dimethyl-[1,2,4]triazolo(1,5-a]pyrazin-2-yl)-vinyl]-quinoline

2-(2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-vinyl]-quinoline

2-(2-(5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimldin-2-yl)-vinyl]-6-methoxy-quinolÎne 2-(2-(8-Methoxy-5-methy1-{1,2,4]triazolo[1,5-a]pyridïn-2-yl)-vinyl]-quinoline 2-(2-(8-Ethyl-5-methy1-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-vinyl]-6-fluoro-quinoline

6-Fluoro-2-[2-(8-methoxy-5-methy1-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-viny1]-qulnolÎne 2-(2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-vinyl]-quinoline 2-[2-(6-Fluoro-qulnolin-2-yl)-vinyl]-5-methy1-[1,2,4]triazolo[1,5-a]pyridin-8-ol 2-(2-(5,8-Dimethyl-(1,2,4]triazolo(1,5-a]pyrazïn-2-yl)-vinyl]-4-methyl-quinoline 2-(2-(5,8-Dimethyl-[1,2,4]triazolo(1,5-a]pyrazin-2-yl)-vinyl]-4-methoxy-quinoline 4-Methoxy-2-[2-(5-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-vinyl]-quinoline 4-Methoxy-2-[2-(8-methoxy^5-methy1-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-viny1]-quÎnoline 4-Methy1-2-[2-(5-methyl-[1,2_l4]triazolo[1,5-a]pyridïn-2-yl)-vînyl]-quinoline 2-[2-(8-Methoxy-5-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-vinyl]-4-methy1-qulnoline 4-θΝθΓθ-8-ίΙυοΓθ-2-((Ε)-2-(8-πιβΙΙιοχν-5-ΓηβΑψΙ-[1,2,4]ίιί3ζοΙο[1,5-3]ρ^ΐη-2-ν1)-νΐη^]-ςυ!ηοΙΐη6 8-Fluoro-2-(2-(8-methoxy-5-methyl-(1,2,4]triazolo[1,5-a]pyridin-2-y1)-vinyl]-quinolÎne

2-(2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-vinyl]-7-fluoro-quinoline

2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-vinyl]-6-fluoro-quinoline

2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-vinyl]-6-fluoro-quinolÎne

2-[2-(5,8-Dimethyl-[1,2_l4]triazolo[1_l5-a]pyrazÎn-2-yl)-vinyl]-4-fluoro-quinoline

2-[(E)-2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-vinyl]-6-fluoro-quinoline

2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-vinyl]-7-fluoro-4-methoxy-quinoline

2-(2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-vinyl]-7-fluoro-quinolin-4-ol

2-[(E)-2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-vinyl]-7-trifluoromethyl-quinoline

2-[2-(5₍8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-vinyl]-6-fluoro-4-methoxy-quinoline

2-[2-(5,8-Dimethyl-[1_I2,4]triazolo[1,5-a]pyrazin-2-yl)-vinyl]-7-trifluoromethyl-quinolÎne

2-[2-(5_l8-DimethyL[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-vinyl]-6-fluoro-quinolin-4-ol

2-(2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-vinyl]-5-fluoro-quinoline

7-Chloro-2-[2-(5,8-dimethyl-[1,2,4]triazolo[1₍5-a]pyrazin-2-yl)-vinyl]-quinoline

2-[2-(5,8-Dimethyl-[1₍2,4]triazolo[1,5-c]pyrimidin-2-yl)-vinyl]-6-lsopropyl-quinoline

2-(2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-vinyl]-5,7-difluoro-quinoline

Z-IZ-ÎS.e-Dimethyl-tl^XltriazoloIl.S-aJpyraan-Z-yQ-vinyll-S.e.e-trifluoro-quinoline

2-(2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-vinyl]-6_l8-difluoro-quInoline

6-[2-(5,8-Dimethyl-[1,2,4]triazo lo [1,5-a]pyrazin-2-yl)-vinyl]-[1,3]dioxolo[4,5-g]quinoline

2-(2-(5,8-Dlmethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-vinyl]-6-fluoro-8-methyl-quinoline

2-[2-(5,8-DImethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-vinyl]-6-fluoro-7-methyl-quinoline

6- (2-(5,8-DimethyL[1,2,4]triazolo[1,5-a]pyrazln-2-yl)-vinyl]-2,2-difluoro-[1,3]dioxolo[4,5-g]quinoline

7- Chloro-2-[2-(5_l8-dimethyl-[1_I2,4]triazolo[1,5-a]pyrazin-2-yl)-vinyl]-quinoline-6-carbonitrile

7-[2-(5₍8-Dimethyl-[1,2_I4]triazolo[1,5-a]pyrazin-2-yl)-vinyl]-2,3-dihydro-[1,4]dioxino[2,3-g]quinoline

6-Chloro-2-[2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-vinyl]-quinolÎne

6-Chloro-2-[2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-vinyl]-8-fluoro-quinolÎne e-Chloro-Z-p-ÎS.e-dimethyHl^^jtriazolotl.S-alpyrazin-Z-ylJ-vinyll-e-niethyl-quinoline 5_l7-Dichloro-2-[2-(5,8-<iimethyl-[1_l2,4]triazolo[1,5-a]pyrazin-2-yl)-vinyl]-quinoline

Préparation of compounds ofthe invention

Example 1: a-KEÎ-a-tS.e-Dimethyl-II^^JtrlazoloIl.S-aJpyrazIn^-yO-vInylJ-e-trlfluoromethyl qulnollne

To a solution of (5_l8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-ylmethyl)-triphenyl-phosphonium; chloride (0.48 g, 1.0 mmol) and 6-Trifluoromethyl-qulnoline-2-carbaldehyde (0.24 g, 1.0 mmol) In dry N.N-Dimethylformamlde (25 mL, 320 mmol) was added 1,8-Diazabicyclo[5.4.0]undec-7ene (0.16 mL, 1.0 mmol) (reaction mixture tums more dark) and the mixture was stirred at room température under an atmosphère of Argon overnight. The reaction mixture shows précipitation the day after.

Précipitation filtered of. Washed with water and and diethyl ether. Dried on filter by vacuum, then in vacuo for 2 hours at 60 ^eC. Filtercake: Giving a white solid containing the final product 2[(E)-2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-vinyl]-6-trifluoromethyl-quinolÎne. LC-MS: m/z =369.7 (MH+). Rt = 1.96min., method = 131.

The following compounds were made in a similar way: 2-[(E)-2’(5,7-Dimethyl-imidazo[1,2-a]pyrimidîn-2-yl)-vinyl]-quinoline LC-MS: m/z = 301.1 (MH+). Rt = 0.55 min., method = 111.

2-[(E)-2-(5,8-Dimethyl-[1,2_l4]triazolo[1,5-a]pyrazin-2-yl)-vinyl]-6-trifluoromethoxy-quïnoline

LC-MS: m/z = 386.1, Rt = 1,97 min, method = 131

2-[(E)-2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-vinyl]-6-cyano-quinoline LC-MS: m/z s 327.3, Rt = 1,97 min, method = 131

2-[(E)-2-(5,8-Dimethyl-[ 1,2,4]triazolo[1,5-a]pyrazin-2-yl)-vlnyl]-7-methoxy-quinoline LC-MS: m/z = 332.1, Rt = 1,22 min, method = 131

2-[(E)-2-(5,8-Dimethyl-[1,2_l4]triazolo[1,5-a]pyrazin-2-yl)-vinyl]-5-methoxy-quinoiine LC-MS: m/z = 332.2, Rt = 1,41 min, method = 131

Example 2: 6-(2-(5,8-Dlmethy1-[1,2,4]trlazolo[1,5-a]pyrazln-2-yl)-ethyl]-1,3-dloxolo[4,5gjqulnoline

6-[(E)-2-(5,8-Dimethyl-[1,2,4]triazolo(1,5-a]pyraztn-2-yl)-viny1]-1,3-dioxolo[4,5-g]quinolÎne (0.183 g, 0.530 mmol) was dissolved In Ν,Ν-Dimethylformamide (11 mL, 140 mmol). [B] pToluenesulfonylhydrazide (0.296 g, 1.59 mmol; Supplier = Avocado) was added and the reaction was stirred at 130 C under an atmosphère of Argon ON. LCMS was done and showed almost complété conversion. 0.100 g [B] was added to the mixture was stirred 2 days at 130 C.

DMF was evaporated. The solid was dissolved In 50 mL EtOAc and extracted with 2 x 25 mL sat. NaHCO3 and washed with 50 mL brine. The organic phase was rotovaped and chromatographed on silicagel using EtOAc: heptane (1:1 ) and then 0-30% MeOH in EtOAc. Yield: 40 mg solid. LCMS: m/z =348.4 (MH+). Rt = 0.34 min., method = 350.

The following compounds were prepared In a similar way:

2-[2-(5,7-Dimethyl-imidazo[1,2-a]pyrimidin-2-yl)-ethyl]-quÎnolÎne LC-MS: m/z = 303,4 (MH+). Rt = 0,34 min., method =111 2-[2-(5,7-Dimethy1-[1,2_l4]triazolo[1,5-a]pyrimidin-2-y1)-ethyl]-quinoline LC-MS: m/z= 304,3 (MH+). Rt = 0,46 min., method = 111 2-[2-(5,8-Dimethyl-[1,2_l4]triazolo[1_l5-a]pyrazin-2-yl)-ethyl]-quinoline LC-MS: m/z = 304,3 (MH+). Rt = 0,61 min., method = 131 2-[2-(5,7-Dimethy1-[1,2,4]triazolo(1,5-a]pyrimidin-2-y1)-ethyl]-6-methoxy-quinoline LC-MS: m/z =

334,5 (MH+). Rt = 0,62 min., method = 131 2-[2-(8-Methoxy-5-methyl-[1,2_l4]triazolo[1,5-a]pyridin-2-yl)-ethyl]-quinoline LC-MS: m/z = 319,1 (MH+). Rt = 0,71 min., method =131

2-[2-(8-Ethyl-5-methyl-[1,2,4]triazolo(1,5-a]pyridin-2-yl)-ethyl]-6-fluoiO-quinoline LC-MS: m/z =

335.2 (MH+). RI = 1,12 min., method = 131

6-Fluoro-2-[2-(8-methoxy-5-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-ethyl]-quinoline LC-MS: m/z =

337,5 (MH+). Rt = 0,96 min., method = 131

2-(2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-ethyl]-quinoline LC-MS: m/z = 303,5 (MH+). Rt = 0,76 min., method = 131 2-[2-(6-Fluoro-quinolin-2-yl)-ethyî]-5-methyl-[1,2,4]triazolo[1,5-a]pyridin-8-ol LC-MS: m/z = 323,1 (MH+). Rt “ 0,41 min., method = 350

2-(2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-ethyt]-4-methyl-quînoiine LC-MS: m/z = 318,2 (MH+). Rt = 0,83 min., method = 131

2-(2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-ethyî]-4-methoxy-quinoline LC-MS: m/z= 334,5 (MH+). Rt = 0,9 min., method = 131 4-Methoxy-2-[2-(5-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl}-ethyl]-quinoline LC-MS: m/z = 319,2 (MH+). Rt = 0,93 min., method = 131

4-Methoxy-2-[2-(8-methoxy-5-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-ethyî]-quinoline LC-MS: m/z = 349,1 (MH+). Rt = 1,01 min., method =131 4-Methyl-2-(2-(5-methyl-[1,2_t4]triazolo[1,5-a]pyridin-2-yl)-ethyl]-quinoline LC-MS: m/z = 303,4 (MH+). Rt = 0,85 min., method = 131

2-(2-( 8-Methoxy-5-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-ethyl]-4-methyl-quinoline LC-MS: m/z =

333.2 (MH+). Rt = 0,95 min., method = 131 4-Chloro-8-fluoro-2-[(E)-2-(8-methoxy-5-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-vinyl]-quinoline LCMS: m/z = 369,2 (MH+). Rt = 1,98 min., method = 131

8-Fluoro-2-[2-(8-methoxy-5-methyl-I1,2,4]triazolo[1,5-a]pyridin-2-yl)-ethyl]-quinoline LC-MS: m/z =

337,5 (MH+). Rt = 1,32 min., method = 131

2-(2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-ethyl]-7-fluoro-qulnolÎne LC-MS: m/z = 321,8 (MH+). Rt = 0,43 min., method = 350 2-I2-(5_t8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-ethyl]-6-fluoro-quinoline LC-MS: m/z = 322,1 (MH+). Rt = 0,44 min., method = 350

2-(2-( 5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-ethyl]-4-fluoro-quinoline LC-MS: m/z = 321,9 (MH+). Rt = 0,44 min., method = 350

2-(2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-ethyl]-7-fluoro-4-methoxy-quinoline LC-MS: m/z = 352,3 (MH+). Rt = 0,87 min., method =131

2-[2-(5_l8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-ethyl]-7-fluoro-quinolin-4-ol LC-MS: m/z =

338,4 (MH+). Rt = 1,08 min., method = 131

2-[(E)-2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-vinyl]-7-trifluoromethyl-quinoline LC-MS: m/z = 370,2 (MH+). Rt = 0,79 min., method = 350

2-(2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-ethyl]-6-fluoro-4-methoxy-quinoline LC-MS: m/z = 352,3 (MH+). Rt = 0,9 min., method = 131

2-(2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-ethyl]-7-trifluoromethyl-quinoline LC-MS: m/z =

372.3 (MH+). Rt = 0,61 min., method = 350

2-(2-(5,8-Dimethyl-[1,2_l4]triazolo[1,5-a]pyrazin-2-yl)-ethyl]-6-fluoro-quinolin-4-ol LC-MS: m/z =

338.1 (MH+). Rt = 1,05 min., method = 131

2-(2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-ethyl]-5-fluoro-quinoline LC-MS: m/z = 322,1 (MH+). Rt = 1,25 min., method = 131

7-Chloro-2-[2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-ethyl]-quÎnoline LC-MS: m/z = 338,3 (MH+). Rt = 1,82 min., method = 132

2-(2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)-ethyl]-6-isopropyl-quinoline LC-MS: m/z =

346.2 (MH+). Rt = 0,47 min., method = 350

2-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazîn-2-yl)-ethyl]-5,7-difluoro-quinoline LC-MS: m/z =

339,8 (MH+). Rt = 0,57 min., method = 350

2-(2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-ethyl]-5,6,8-trifluoro-quinoline LC-MS: m/z =

358.4 (MH+). Rt = 0,67 min., method = 350

2-(2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-ethyl]-6,8-difluoro-quinoline LC-MS: m/z =

339,7 (MH+). Rt = 0,6 min., method = 350

6-(2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-ethyl]-[1,3]dioxolo[4,5-g]quinoline LC-MS: m/z = 348,4 (MH+). Rt = 0,34 min., method = 350

2-(2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-ethyl]-6-fluoro-8-methyl-quinoline LC-MS: m/z = 336,3 (MH+). Rt = 0,57 min., method = 350

2-(2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-ethyl]-6-fluoro-7-methyl-quinoline LC-MS: m/z = 336,3 (MH+). Rt = 0,41 min., method = 350

6- [2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-ethyl]-2,2-difluoro-i1,3]dioxolo[4,5-g]quinoline LC-MS: m/z = 384,2 (MH+). Rt = 1,6 min., method = 131

7- Chloro-2-[2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-ethyl]-quinoline-6-carbonitrile LC-MS: m/z = 363,2 (MH+). Rt = 1,61 min., method =131

7- [2-(5,8-Dimethyl-[1,2_l4]triazolo[1,5-a]pyrazin-2-yl)-ethyl]-2,3-dihydro-[1,4]dioxino[2_l3-g]quinoline LC-MS: m/z = 362,3 (MH+). Rt = 0,82 min., method = 131

6-Chloro-2-[2-(5,8-dimethyl-[1,2_l4]triazoîo[1_l5-a]pyrazin-2-yl)-ethyl]-quinoline LC-MS: m/z= 338,3 (MH+). Rt = 1.31 min., method = 131 6-Chloro-2-[2-(5,8-dimethyl-[1,2,4]triazoîo[1_l5-a]pyrazin-2-yl)-ethyl]-8-fluoro-quinoline LC-MS: m/z =

356,2 (MH+). Rt = 1,72 min., method = 131

8- Chloro-2-[2-(5_l8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-ethyl]-6-methyl-quinoline LC-MS: m/z = 352,4 (MH+). Rt = 1,7 min., method = 131

5,7-Dichloro-2-[2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-ethyl]-quinoline LC-MS: m/z = 372,0 (MH+). Rt = 2,01 min., method = 131

Pharmacoloqlcal Testlnq

PDE10A enzyme

Active PDE10A enzyme Is prepared in a number of ways for use In PDE assays (Loughney, K. et al. Gene 1999, 234, 109-117; Fujishige, K. et al. Eur J Biochem. 1999, 266, 1118-1127 and Soderiing, S. étal. Proc. Natl. Acad. Sci. 1999, 96, 7071-7076). PDE10A can be expressed as fulllength proteins or as truncated proteins, as long as they express the catalytic domain. PDE10A can be prepared In different celî types, for example Insect cells or E. coli. An example of a method to obtain catalytically active PDE10A Is as follows: The catalytic domain of human PDE10A (amino acids 440-779 from the sequence with accession number NP 006652) is ampîified from total human braln total RNA by standard RT-PCR and Is cloned into the BamH1 and Xho1 sites of the pET28a vector (Novagen). Expression in coli Is performed according to standard protocols. Briefly, the expression piasmids are transformed Into the BL21(DE3) E. coli strain, and 50 mL cultures Inoculated with the cells allowed to grow to an OD600 of 0.4-0.6 before protein expression is induced with 0.5mM IPTG. Following induction, the cells are incubated overnight at room température, after which the cells are collected by centrifugation. Cells expressing PDE10A are resuspended in 12 mL (50 mM TRIS-HCI-pH8.0, 1 mM MgCI₂ and protease Inhibitors). The cells are lysed by sonication, and after ail cells are lysed, TritonXIOO is added according to Novagen protocols. PDE10A is partially purified on Q sepharose and the most active fractions were pooled.

PDE10A Inhibition assay

A PDE1 OA assay may for example, be performed as follows: The assay Is performed ln 60 uL samples containing a fixed amount of the relevant PDE enzyme (sufficlent to convert 20-25% of the cyclic nudeotide substrate), a buffer (50 mM HEPES7.6; 10mM MgCI₂; 0.02% Tween20), 0.1 mg/ml BSA, 225 pCi of ³H-labelled cyclic nudeotide substrate, tritium labeled cAMP to a final concentration of 5 nM and varying amounts of inhibitors. Reactions are initiated by addition of the cydic nudeotide substrate, and reactions are allowed to proceed for one hr at room température before being terminated through mixing with 15 uL 8 mg/mL yttrium silicate SPA beads (Amersham). The beads are allowed to settle for one hr in the dark before the plates are counted in a Wallac 1450 Microbeta counter. The measured signal can be converted to activity relative to an uninhibited control (100 %) and IC» values can be calculated using the Xlfit extension to EXCEL

Phencyclldine (PCP) induced hyperactivity

Male mice (NMRI, Charles River) weighing 20-25g are used. Eight mice are used in each group receiving the test compound (5 mg/kg) plus PCP (2.3 mg/kg) Induding the parallel control groups receiving the vehide of the test compound plus PCP or vehide injections only. The Injection volumen is 10 ml/kg. The experiment is made in normal light conditions ln an undisturbed room. The test substance Is Injected per oss 60 min before Injection of PCP, which Is administered subcutaneous.

Immediately after injection of PCP the mice are placed individually in spécial designed test cage (20 cm x 32 cm). The activity ls measured by 5X8 infrared light sources and photocells spaced by 4 cm. The light beams cross the cage 1.8 cm above the bottom of the cage. Recording of a motility count requires interruption of adjacent light beams, thus avoiding counts induced by stationary movements of the mice.

Motiiity ls recorded in 5 min Intervals for a period of 1 hour. The drug effect is calculated on the total counts during the 1 hour behavioral test period in the foilowing manner

The mean motility induced by vehicle treatment In the absence of PCP is used as baseline. The

100 per cent effect of PCP is accordingly calculated to be total motility counts minus baseline. The response ln groups receiving test compound Is thus determined by the total motility counts minus baseline, expressed in per cent of the similar resuit recorded ln the parallel PCP control group. The 5 per cent responses are converted to per cent Inhibition.

Claims

1. A compound having the structure of formula I:

R4 wherein R_b R₂, R3, R4· Rs and Re are Individually selected from the group consisting of hydrogen, hydroxyl, cyano, Ci-Ce alkyl; CrCe alkoxy, halogen, methylenedioxy, diflouromethylenedÎoxy and ethylenedioxy wherein -L- Is a linker selected from -CH_rCH₂- and -CH=CHwherein HET Is selected from the group consisting of wherein one or more of the carbon-bound hydrogen In the HET optionally may be substituted with up to three substituents R7, R8 and R9 individually selected from CrCe alkyl; halogen; cyano, halo(CrCe)alkyl; aryl, alkoxy and CrCe hydroxyalkyl and wherein * dénotés the attachment point, and tautomers and pharmaceutically acceptable salts thereof, and polymorphie forms thereof.

2. The compound of claim 1 wherein one or more of R1 to R6 is selected from the group consisting of C1-C3 alkyl substituted with one or more F and unsubstituted C1-C3 alkyl.

3. The compound of claim 1 wherein one or more or R1-R6 is selected from the group consisting of methoxy, diflouromethoxy and triflouromethoxy.

4. The compound of claim 1 wherein one or more of R1-R6 is seiected form the group consisting of fluorine and chlorine.

5. The compound of claim 1 wherein -L- Is -CH2-CH2-

6. The compound of claim 1 wherein -L- Is -CH=CH-

7. The compound of any of claims 1 to 6 wherein HET is selected from the group consisting of wherein * dénotés the attachment point.

8. The compound of claim 1 wherein HET is substituted with one substituent R7 selected from the group consisting of C,-Ce alkyl, such as methyl; halogen, such as chlorine or bromine; cyano; halo(C_rCe)alkyl, such as trifluoromethyl; aryl such as phenyl; and C_rCe hydroxyalkyl such as CH2CH2OH.

9. The compound of daim 1 or 8 wherein HET is substituted with two substituents R7 and R8 individually selected from the group consisting of Ci-C® alkyl, such as methyi; halogen, such as chlorine or bromine; cyano; halotCrCeJalkyl, such as trifluoromethyl; aryl such as phenyl; and Ο,-Ce hydroxyalkyl such as CH₂CH₂OH.

10. The compound of daim 1 or 8 wherein HET is substituted with three substituents R7, R8 and R9 individually selected from the group consisting of C,-C« alkyl, such as methyi; halogen, such as chlorine or bromine; cyano; halo(Ci-Ce)alkyl, such as trifluoromethyl; aryl such as phenyl; and CrCe hydroxyalkyl such as CH₂CH₂OH.

11. The compound of daim 1 or 8 wherein HET ls unsubstituted.

12. The compound of daim 1 wherein HET is selected from the group consisting of (5,7Dimethyl-imidazo[1,2-a]pyrimidin-2-yl), 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl), (5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl), (8-Methoxy-5-methyl-[1,2,4]triazoio[1,5a]pyridin-2-yl) and 5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl).

13. The compound of any of claim 1 to 12, or a pharmaceutically acceptable sait thereof, for use as a médicament.

14. A pharmaceutical composition comprising a therapeutîcally effective amount of the compound of any of claims 1-12 and a pharmaceutically acceptable carrier, diluent or excipient.

15. The use of the compound of any of daims 1-12, or a pharmaceutically acceptable sait thereof, for the préparation of a médicament for the treatment of a neurodegenerative or psychiatrie disorder.