OA18246A

OA18246A - Heteroaromatic Aryl Triazole Derivatives as PDE10A Enzyme Inhibitors.

Info

Publication number: OA18246A
Application number: OA1201200270
Authority: OA
Inventors: John Paul Kilburn; Jan Kehler; Ask Püschl; Jacob Nielsen; Mauro Marigo; Morten LANGGÅRD
Original assignee: H. Lundbeck A/S
Priority date: 2009-12-17
Filing date: 2010-12-15
Publication date: 2018-09-17

Abstract

This invention is directed to compounds (Formula 1),

Description

The présent invention provides heteroaromatic compounds that are PDE10A enzyme inhibitors, and as such are useful to treat neurodegenerative and psychiatrie disorders. 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

Throughout this application, various publications are referenced in full. The disclosures of these publications are hereby incorporated by reference into this application to describe more fully the state of the art to which this invention pertains.

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). Intracellular levels of cAMP and cGMP are controlled by intracellular signaling, and stimulation/repression of adenyl and guanyl cyclases in response to GPCR activation is a well characterized way of controlling cyclic nucléotide concentrations (Antoni, F.A. Front. Neuroendocrinol. 2000, 21, 103132). cAMP and cGMP levels in turn control activity of cAMP- and cGMP-dependent kinases as well as other proteins with cyclic nucléotide response éléments, which through subséquent phosphorylation of proteins and other processes regulate key neuronal functions such as synaptic transmission, neuronal différentiation and survival.

There are 21 phosphodiesterase genes that can be divided into 11 gene families. There are ten families of adenylyl cyclases, two of guanylyl cyclases, and eleven of phosphodiesterases. PDEs are a class of intracellular enzymes that regulate levels of cAMP and cGMP via hydrolysis of the cyclic nucléotides into their respective nucléotide monophosphates. Some PDEs dégradé cAMP, some cGMP and some both. Most PDEs hâve a widespread expression and hâve rôles in many tissues, while some are more tissue-specific.

Phosphodieasterase 10A (PDE10A) is a dual-specificity phosphodiesterase that can convert both cAMP to AMP and cGMP to GMP (Loughney, K. et al. Gene 1999, 234, 109-117; Fujishige, K. et al. Eur. J. Biochem. 1999, 266, 1118-1127 and Soderling, S. et al. 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. et al. Biochem. Biophys. Res. Comm.

1999, 261, 551-557 and Seeger, T.F. et al. Brain Research, 2003, 985, 113-126).

Mouse PDE10A is the first identified member of the PDE10 family of phosphodiesterases (Fujishige, K. et al. J. Biol. Chem. 1999, 274, 18438-18445 and Loughney, K. et al. Gene 1999, 234, 109-117) and N-terminal splice variants of both the rat and human genes hâve been identified (Kotera, J. et al. Biochem. Biophys. Res. Comm. 1999, 261, 551-557 and Fujishige, K. et al. Eur. J. Biochem. 1999, 266, 1118-1127). There is a high degree of homology across species. PDE10A is uniquely localized in mammals relative to other PDE families. mRNA for PDE10 is highly expressed in testis and brain (Fujishige, K. et al. Eur J Biochem. 1999, 266, 1118-1127; Soderling, S. étal. Proc. Natl. Acad. Sci. 1999, 96, 7071-7076 and Loughney, K. et al. Gene 1999, 234,109-117). These studies indicate that within the brain, PDE10 expression is highest in the striatum (caudate and putamen), n. accumbens and olfactory tubercle. More recently, an analysis has been made of the expression pattern in rodent brain of PDE10A mRNA (Seeger, T.F. et al. Abst. Soc. Neurosci. 2000, 26, 345.10) and PDE10A protein (Menniti, F.S. et al. William Harvey Research Conférence 'Phosphodiesterase in Health and Disease¹, Porto, Portugal, Dec. 5-7, 2001).

PDE10A 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 tubercle. These constitute the core of the basal ganglia system. The MSN has a key rôle in the corticalbasal ganglia-thalamocortical loop, integrating convergent cortical/thalamic input, and sending this integrated information back to the cortex. MSN express two functional classes of neurons: the Di class expressing D-i dopamine receptors and the D₂ class expressing D₂ dopamine receptors. The D! class of neurons is part of the ‘direct’ striatal output pathway, which broadly functions to facilitate behavioral responses. The D₂ class of neurons is part of the 'indirect' striatal output pathway, which functions to suppress behavioral responses that compete with those being facilitated by the ‘direct’ pathway. These competing pathways act like the brake and accelerator in a car. In the simplest view, the poverty of movement in Parkinson’s disease results from over-activity of the ‘indirect’ pathway, whereas excess movement in disorders such as Huntington’s disease represent over-activity of the direct pathway. PDE10A régulation of cAMP and/or cGMP signaling in the dendritic compartment of these neurons may be involved in filtering the cortico/thalamic input into the MSN. Furthermore, PDE10A may be involved in the régulation of GABA release in the substantia nigra and globus pallidus (Seeger, T.F. et al. Brain Research, 2003, 985, 113-126).

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 in the striatum, n. accumbens and olfactory tubercle, since these areas receive the densest dopaminergic projections and hâve the strongest expression of D₂ receptors (Konradi, C. and Heckers, S. Society of Biological Psychiatry, 2001, 50, 729-742). Dopamine D₂ receptor agonism leads to decrease in cAMP levels in the cells where it is expressed through adenylate cyclase inhibition, and this is a component of D₂ signalling (Stoof, J. C.; Kebabian J. W. Nature 1981, 294, 366-368 and Neve, K. A. et al. Journal of Receptors and Signal Transduction 2004, 24, 165-205). Conversely, D₂ receptor antagonism effectively increases cAMP levels, and this effect could be mimicked by inhibition of cAMP degrading phosphodiesterases.

Most of the 21 phosphodiesterase genes are widely expressed; therefore inhibition is likely to hâve side effects. Because PDE10A, in this context, has the desired expression profile with high and relatively spécifie expression in neurons in striatum, n. 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 signalling 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 negatively modulate ratherthan directly antagonise dopamine signaling through D₂ receptors. This may reduce the risk of the extrapyrimidal 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 Dt receptors expressing striatal neurons (Seeger, T. F. et al. Brain Research, 2003, 985, 113-126). Since Di receptor agonism leads to stimulation of adenylate cyclase and resulting increase in cAMP levels, PDE10A inhibition is likely to also hâve effects that mimic D-j 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 signalling pathways. In 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 reduced 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 theoretical considérations. WO 03/093499 further discloses the use of sélective PDE10 inhibitors for the treatment of associated neurologie and psychiatrie disorders. Furthermore, PDE10A inhibition reverses subchronic PCP-induced déficits in attentional set-shifting in rats (Rodefer et al. 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 PDE10 enzyme, especially neurons that comprise the basal ganglia, and the PDE10A inhibitors ofthe présent invention would therefore be useful in treating a variety of associated neuropsychiatrie conditions involving the basal ganglia such as neurological and psychiatrie disorders, schizophrenia, bipolar disorder, obsessive compulsive disorder, and the like, 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 al, Bioorganic & Médicinal Chemistry Letters 17 (2007) 2869-2873) suggest that PDE10A inhibitors may be useful for treatment of obesity and non-insulin dépendent diabètes.

With respect to inhibitors of PDE10A, EP 1250923 discioses the use of sélective PDE10 inhibitors in general, and papaverine in particular, for the treatment of certain neurologie and psychiatrie disorders.

WO 05/113517 discloses benzodiazépine stereospecific compounds as inhibitors of phosphodiesterase, especially types 2 and 4, and the prévention and treatment of pathologies involving a central and/or peripheral disorder. WO 02/88096 discloses benzodiazépine dérivatives and their uses as inhibitors of phosphodiesterase, especially type 4 in the therapeutic field. WO 04/41258 discloses benzodiazepinone dérivatives and their uses as inhibitors of phosphodiesterase, especially type 2 in the therapeutic field.

Pyrrolodihydroisoquinolines and variants thereof are disclosed as inhibitors of PDE10 in WO 05/03129 and WO 05/02579. Piperidinyl-substituted quinazolines and isoquinolines that serve as PDE10 inhibitors are disclosed in WO 05/82883. WO 06/11040 discloses substituted quinazoline and isoquinoline compounds that serve as inhibitors of PDE10. US 20050182079 discloses substituted tetrahydroisoquinolinyl dérivatives of quinazoline and isoquinoline that serve as effective phosphodiesterase (PDE) inhibitors. In particular, US 20050182079 relates to said compounds, which are sélective inhibitors of PDE10. Analogously, US 20060019975 discloses 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 discloses cinnoline dérivatives as inhibitors of phosphodiesterase type 10 for the treatment of psychiatrie and neurological syndromes.

However, these disclosures do not pertain to the compounds of the invention, which are structurally unrelated to any ofthe known PDE10 inhibitors (Kehler, J. et al. Expert Opin. Ther. Patents 2007, 17, 147-158 and Kehler, J. et al. Expert Opin. Ther. Patents 2009, 19, 17151725), and which hâve now been found by the inventors to be highly active and sélective PDE10A enzyme inhibitors.

Compounds comprising a -CH₂-S- linker and where further HET-1 is either imidazo[1,2ajpyridine or imidazo[1,2-a]pyrimidine are disclosed in publicly available chemical libraries. These compounds are therefore disclaimed.

The compounds of the invention may offer alternatives to current marketed treatments 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 of the invention will become apparent upon reading the présent spécification.

Accordingly, in one aspect the présent invention relates to compounds of formula I:

/

R1

I wherein HET-1 is a heteroaromatic group of formula II containing from 2 to 4 nitrogen atoms:

II wherein Y can be N or CH, Z can be N or C, and wherein HET-1 may optionally be substituted with up to three substituents R7, R8 and R9 individually selected from H; CrCs alkyl such as Me; halogen such as chlorine and bromine; cyano; halo(C_rC₆)alkyl such as trifluoromethyl; aryl such as phenyl; alkoxy, such as methoxy, dimethoxy, ethoxy, methoxy-ethoxy and ethoxymethoxy, and Ci-C₆ hydroxyalkyl such as CH₂CH₂OH, and wherein * dénotés the attachment point,

-L- is a linker selected from -S-CH₂-, -CH₂-S-, -CH₂-CH₂-, -CH=CH-, and ~^c=^c_ ;

R1 is selected from H; C_rC_B alkyl such as methyl, ethyl, 1-propyl, 2-propyl, isobutyl; C^Cg alkyl(C₃-C₈)cycloalkyl such as cyclopropylmethyl; C_rC₆ hydroxyalkyl such as hydroxyethyl; CH₂CN; CH₂C(O)NH₂; C_rC₆ arylalkyl such as benzyl and 4-chlorobenzyl; and C_rC₆ alkylheterocycloalkyl such as tetrahydropyran-4-yl-methyl and 2-morpholin-4-yl-ethyl;

wherein Q is a phenyl, optionally substituted with 1, 2 or three substituents or Q is a monocyclic 5-membered or 6-membered heteroaromatic group containing 1 or 2 heteroatoms, preferred Q is chosen among structures of the formula, wherein “*” dénotés the attachment point:

R2

R3

R5

R4

R6

*

Wherein R2-R6 are each selected independently from H; C_rC₆ alkoxy such as methoxy; and halogen such as chlorine or fluorine;

with the proviso that the compound is not 1H-Benzimidazole, 2-[[(3-phenyl-1 H-1,2,4-triazol-5yl)thio]methyl]-; 1 H-Benzimidazole, 2-[[[3-(2-pyrazinyl)-1 H-1,2,4-triazol-5-yl]methyl]thio]-; 1HBenzimidazole, 2-[[(3-phenyl-1 H-1,2,4-triazol-5-yl)methyl]thio]-; 1 H-Benzimidazole, 1-ethyl-5-(1piperidinylsulfonyl)-2-[[[3-(2-thienyl)-1 H-1,2,4-triazol-5-yl]thio]methyl]-; 1 H-Benzimidazole, 6methyl-2-[[(3-phenyl-1 H-1,2,4-triazol-5-yl)thio]methyl]-; 1 H-Benzimidazole, 2-[[[3-(3-pyridinyl)1 H-1,2,4-triazol-5-yl]methyl]thio]-; lmidazo[1,2-a]pyridine, 8-methyl-2-[[(3-phenyl-1 H-1,2,4triazol-5-yl)thio]methyl]-; lmidazo[1,2-a]pyridine, 6-chloro-2-[[[3-(2-thienyl)-1 H-1,2,4-triazol-5yl]thio]methyl]-; 1 H-Benzimidazole, 2-[[[3-(4-pyridinyl)-1 H-1,2,4-triazol-5-yl]methyl]thio]-; lmidazo[1,2-a]pyridine, 6-methyl-2-[[(3-phenyl-1 H-1,2,4-triazol-5-yl)thio]methyl]-; 1HBenzimidazole, 2-[[[3-(2-pyridinyl)-1 H-1,2,4-triazol-5-yl]methyl]thio]-; lmidazo[1,2-a]pyridine, 6chloro-2-[[(3-phenyl-1 H-1,2,4-triazol-5- yl)thio]methyl]-; 3H-lmidazo[4,5-b]pyridine, 2-[[(3-phenyl1 H-1,2,4-triazol-5-yl)thio]methyl]-; or 1 H-Benzimidazole, 2-[[[3-(2-furanyl)-1 H-1,2,4-triazol-5yl]methyl]thio]-;

and tautomers and pharmaceutically acceptable salts thereof, and polymorphie forms thereof.

in separate embodiments of the invention, the compound of formula I is selected among the spécifie compounds disclosed in the Experimental Section herein.

The invention further provides a compound of formula I, or a pharmaceutically acceptable sait thereof, for use as a médicament.

In another aspect, the présent invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I and a pharmaceutically acceptable carrier, diluent or excipient.

The invention further provides the use of a compound of formula l, or a pharmaceutically acceptable sait thereof, for the préparation of a médicament for the treatment of a neurodegenerative or psychiatrie disorder.

Furthermore, in yet another aspect, 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 a still further aspect, 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 another embodiment, the présent invention provides a method of treating a subject suffering from a drug addiction, such as an alcohol, amphétamine, cocaïne, or opiate addiction.

Detailed Description ofthe Invention

Définition of Substitutents

As used in the context of the présent invention, the terms “halo” and “halogen are used interchangeably and refer to fluorine, çhlorine, bromine or iodine.

The term Ci-C₆ alkyl” refers to a straight-chain or branched saturated hydrocarbon having from one to six carbon atoms, inclusive. Examples 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-1-butyl, and nhexyl. The expression “C_rC₆ hydroxyalkyl” refers to a C^Ce alkyl group as defined above which is substituted with one hydroxy group. The term “halo(Ci-C₆)alkyl’’ refers to a C_rC₆ alkyl group as defined above which is substituted with up to three halogen atoms, such as trifluoromethyl.

The expression “CpCe 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-hexyloxy.

The term “C₃-C₈ cycloalkyl” typically refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. The expression “C_rC₆ alkyl(C₃-C₈)cycloalkyl” refers to a C₃-C₈cycloalkyl as defined above which is substituted with a straight-chain or branched C-|-C₆ alkyl. Examples of such groups include, but are not limited to, cyclopropylmethyl.

The term “heterocycloalkyl refers to a four to 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 “C-iC₆ alkyl-heterocycloalkyl” refers to a heterocycloalkyl as defined above which is substituted with a C_rC₆ alkyl group. Examples of such groups include, but are not limited to, tetrahydropyran-4yl-methyl and 2-morpholin-4-yl-ethyl.

The term “aryl refers to a phenyl ring, optionally substituted with halogen, Ο-|-Ο₆ alkyl, Ci-C₆alkoxy or halo(C₁-C₆)alkyl as defined above. Examples of such groups include, but are not limited to, phenyl and 4-chlorophenyl.

The term “Ci-C₆arylalkyl” refers to an aryl as defined above which is substituted with a straightchain or branched CrC₆ alkyl. Examples of such groups include, but are not limited to, benzyl and 4-chlorobenzyl.

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

In one embodiment ofthe invention, HET-1 is a heteroaromatic group of formula II containing 2 nitrogen atoms. In another embodiment of the invention, HET-1 is a heteroaromatic group of formula II containing 3 nitrogen atoms. In yet another embodiment of the invention, HET-1 is a heteroaromatic group of formula II containing 4 nitrogen atoms.

HET-1 is preferably chosen among the following heteroaromatic groups, wherein dénotés the attachment point:

N ln a further embodiment one or more of the hydrogen atoms of the compound of formula I hâve been substituted by deuterium. ln particular hydrogen has been replaced by deuterium when

R₇- R₉ is methyl or methoxy.

ln separate embodiments of the invention, the compound of formula I is selected among the following spécifie compounds, 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 IC₅₀ 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 claimed separately, or in any combination, as illustrated by the following non-limiting examples.

Table 1: Compounds ofthe invention and IC₅₀ values

Compound	IC50 (nM)
8-Methoxy-5-methyl-2-(5-phenyl-2H-[1,2,4]triazol-3-ylsulfanylmethyl)- [1,2,4]triazolo[1,5-a]pyridine	52
5-Methyl-2-(5-phenyl-2H-[1,2,4]triazol-3-ylsulfanylmethyl)- [1,2,4]triazolo[ 1,5-a]pyridine	200
5-Methyl-2-(1 -methyl-5-phenyl-1 H-[1,2,4]triazol-3-ylsulfanylmethyl)- [1,2,4]triazolo[1,5-a]pyridine	280
8-Methoxy-5-methyl-2-[2-(2-methyl-5-phenyl-2H-[1,2,4]triazol-3-yl)-ethyl]- [1,2,4]triazolo[1,5-a]pyridine	25
8-Methyl-2-[2-(2-methyl-5-phenyl-2H-[1,2,4]triazol-3-yl)-ethyl]- [1,2,4]triazolo[1,5-a]py ridine	170
5,7-Dimethyl-2-[2-(2-methyl-5-phenyl-2H-[1,2,4]triazol-3-yl)-ethyl]- [1,2,4]triazolo[1,5-a]pyrimidine	59
5,8-Dimethyl-2-[2-(2-methyl-5-phenyl-2H-[1_I2,4]triazol-3-yl)-ethyl]- [1,2,4]triazolo[1,5-a]pyrazine	15
8-Methoxy-5-methyl-2-[2-(5-phenyl-2-propyl-2H-[1,2,4]triazol-3~yl)-ethyl]- [1,2,4]triazolo[1,5-a]pyridine	37
8-Methoxy-5-methyl-2-{2-[5-phenyl-2-(2,2,2-trifluoro-ethyl)-2H- [1,2,4]triazol-3-yl]-ethyl}-[1,2,4]triazolo[1,5-ajpyridine	180
5-Methyl-2-[2-(2-methyl-5-phenyl-2H-[1,2,4]triazol-3-yl)-ethyl]- [1,2,4]triazolo[1,5-a] pyridine	220
8-Methoxy-2-[2-(2-methyl-5-phenyl-2H-[1,2,4]triazol-3-yl)-ethyl]- [1,2,4]triazolo[1,5-a]py ridine	560
{5-[2-(8-Methoxy-5-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-ethyl]-3phenyl-[1,2,4]triazol-1-yl}-acetic acid ethyl ester	81
2-{5-[2-(8-Methoxy-5-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-ethyl]-3- pheny l-[1,2,4]tri azo I-1 -yl}-ethanol	23
5,8-Dimethyl-2-[2-(2-methyl-5-phenyl-2H-[1,2,4]triazol-3-yl)-ethyl]- [1,2,4]triazolo[1,5-a]pyridine	6.7
5,8-Dimethyl-2-[2-(2-methyl-5-phenyl-2H-[1,2,4]triazol-3-yl)-ethyl]- [1,2,4]triazolo[1,5-c]pyrimidine	36

8-Ethyl-5-methyl-2-[2-(2-methyl-5-phenyl-2H-[1,2,4]triazol-3-yl)-ethylJ- [1,2,4]triazolo[1,5-a]pyridine	7,5
8-Ethyl-5-methyl-2-[2-(5-phenyl-2-propyl-2H-[1,2,4]triazol-3-yl)-ethyl]- [1,2,4]triazolo[1,5-a]pyridine	10
8-Ethyl-2-[2-(2-isopropyl-5-phenyl-2H-[1,2,4]triazol-3-yl)-ethyl]-5-methyl- [1,2,4]triazolo[1,5-a]pyridine	40
3-{5-[2-(8-Methoxy-5-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yI)-ethyl]-3- phenyl-[1,2,4]triazol-1-yl}-propionitrile	45
3-{5-[2-(8-Ethyl-5-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-ethyl]-3-phenyl- [1,2,4]triazol-1-yl}-propionitrile	14
2-[2-(2-lsopropyl-5-phenyl-2H-[1,2_I4]triazol-3-yl)-ethyl]-8-methoxy-5methyl-[1,2,4]triazolo[1,5-a] py ridine	56
3-{5-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-ethyl]-3-phenyl- [1,2,4]triazol-1 -y l}-propio nitrile	25
3-{2-[2-(8-Ethyl-5-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-ethyl]-4-phenyl- imidazol-1-yl}-propylamine	150
3-{5-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-ethyl]-3-phenyl- [1,2,4]triazol-1 -yl}-propylamine	100
2-{2-[2-(2-Methoxy-ethyl)-5-phenyl-2H-[1,2,4]triazol-3-yl]-ethyl}-5,8dimethy l-[1,2,4]triazolo[1,5-a]pyrazine	14
8-Methoxy-2-{2-[2-(2-methoxy-ethyl)-5-phenyl-2H-[1,2,4]triazol-3-yl]ethyl}-5-methyl-[1,2,4]triazolo[1,5-a]py ridine	62
5,8-Dimethyl-2-[2-(2-methyl-5-thiophen-3-yl-2H-[1,2,4]triazol-3-yl)-ethyl]f 1,2,4]triazo lo[ 1,5-a]pyrazine	5.3
2-[2-(5-Furan-2-yl-1 -methyl-1 H-[1,2,4]triazol-3-yl)-ethyl]-5,8-dimethyl- [1,2,4]triazolo[1,5-a]pyrazine	38
2-[(E)-2-(5-Furan-2-yl-1-methyl-1H-[1,2,4]triazol-3-yl)-vinyl]-5_l8-dimethyl- [1,2,4]triazolo[1,5-a]pyrazine	60
5,8-Dimethyl-2-[2-(2-methyl-5-thiazol-4-yl-2H-[1,2,4]triazol-3-yl)-ethyl]- [1,2,4]triazolo[1,5-a]pyrazine	25
5,8-Dimethyl-2-{2-[2-methyl-5-(5-methyl-thiazol-2-yl)-2H-[1,2,4]triazol-3- yl]-ethyl}-[1,2,4]triazolo[1,5-a]pyrazine	120

5,8-Dimethyl-2-{2-[2-methyl-5-(4-methyl-thiazol-2-yl)-2H-[1,2,4]triazol-3yl]-ethyl}-[1,2,4]triazolo[1,5-a]pyrazine	76
5,8-Dimethyl-2-[2-(2-methyl-5-oxazol-2-yl-2H-[1_l2_l4]triazol-3-yl)-ethyl]- [1,2,4]triazolo[1,5-a]pyrazine	120
5₎8-Dimethyl-2-[2-(2-methyl-5-thiophen-2-yl-2H-[1_l2,4]triazol-3-yl)-ethyl]- [1,2,4]triazolo[1,5-a]pyrazine	5.6
5,8-Dimethyl-2-[2-(2-methyl-5-pyrimidin-2-yl-2H-[1,2,4]triazol-3-yl)-ethyl]- [1,2,4]triazolo[1,5-a]pyrazine	53
5,8-Dimethyl-2-[2-(2-methyl-5-pyridin-2-yl-2H-[1,2,4]triazol-3-yl)-ethylJ- [1,2,4]triazolo[1,5-a]pyrazine	39
5,8-Dimethyl-2-[2-(2-methyl-5-thiazol-5-yl-2H-[1,2,4]triazol-3-yl)-ethyl]- [1,2,4]triazolo[1,5-a]pyrazine	26
5,8-Dimethyl-2-[2-(2-methyl-5-thiazol-2-yl-2H-[1,2,4]triazol-3-yl)-ethylJ- [1,2,4]triazolo[1,5-a]pyrazine	36
5,8-Dimethyl-2-[2-(2-methyl-5-pyridin-3-yl-2H-[1,2,4]triazol-3-yl)-ethyl]- [1,2,4]triazolo[1,5-a]pyrazine	110
2-[2-(5-Furan-2-yl-2-methyl-2H-[1,2,4]triazol-3-yl)-ethyl]-5,8-dimethyl- [1,2,4]triazolo[1,5-a]pyrazine	4.6
5,8-Dimethyl-2-(5-phenyl-2H-[1,2,4]triazol-3-ylsulfanylmethyl)- [1,2,4]triazolo[1,5-a]pyrazine	53
2-{5-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-ethyl]-3-phenyl- [1,2,4]triazol-1-yl}-ethanol	69

In a particular embodiment ofthe présent invention the compounds ofthe 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 or in the range of 0.2 - 1 nM.

Pharmaceutically Acceptable Salts

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

Représentative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, sulfamic, nitric acids and the like. Représentative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, itaconic, lactic, methanesulfonic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methane sulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids, theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromotheophylline 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. Soi. 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.

Therapeutically effective amount ln the présent context, the term therapeutically effective amount of a compound means an amount sufficient to cure, alleviate or partially arrest the clinical 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 ofthe 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 physician.

ln 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 ofthe 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 ofthe active compounds to prevent the onset ofthe 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.

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 in 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 formulated 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, 19^th Edition, Gennaro, Ed., Mack Publishing 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, intracisternal, 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, pills, 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 provide 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 mixing a therapeutically effective amount of a compound of formula 1 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 acid 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 I with a molar équivalent of a pharmaceutically acceptable acid. Représentative examples of suitable organic and inorganic acids are described above.

For parentéral administration, solutions of the compounds of formula 1 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 diluents or fillers, stérile aqueous solutions and various organic solvents. Examples of solid carriers include lactose, terra alba, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnésium stéarate, stearic acid and lower alkyl ethers of cellulose. Examples of liquid carriers include, but are not limited to, syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water. Similarly, the carrier or diluent may include 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 combining 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-in-water or water-in-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 ofthe 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 tableting 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, preservatives etc. may be used provided that they are compatible with the active ingrédients.

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 mammals including humans; wherein the neurodegenerative disorder is selected from the group consisting of Alzheimer's disease, multi-infarct dementia, alcoholic dementia or other drug related dementia, dementia associated with intracranial tumors or cérébral trauma, dementia associated with Huntington's disease or Parkinson's disease, or AIDS-related dementia; delirium; amnestic disorder; post-traumatic stress disorder; mental retardation; a learning disorder, for example reading disorder, mathematics disorder, or a disorder of written expression; attention-deficit/hyperactivity disorder; and age-related cognitive décliné; and wherein the psychiatrie disorder is selected from the group consisting of schizophrenia, for example of the paranoid, disorganized, 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, ***e, hallucinogens, inhalants, opioids, or phencyclidine; personality disorder of the paranoid type; and personality disorder of the schizoid type; and wherein the drug addiction is an alcohol, amphétamine, ***e, or opiate addiction.

The compounds of formula I or pharmaceutically acceptable salts thereof may be used in combination with one or more other drugs 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 ortoxicity ofthe compounds ofthe présent invention. 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 présent invention provides a method of treating a mammal, including a human, suffering from a neurodegenerative disorder selected from a cognition disorder or movement disorder, which method comprises administering to the subject a therapeutically effective amount of a compound of formula I.

This invention further provides a method of treating a neurodegenerative disorder or condition in a mammal, including a human, which method comprises administering to said mammal an amount of a compound of formula I effective in inhibiting PDE10.

This invention also provides a method of treating a subject suffering from a psychiatrie disorder, which method comprises administering to the subject a therapeutically effective amount of a compound of formula I. Examples of psychiatrie disorders that can be treated according to the présent invention include, but are not limited to, schizophrenia, for example of the paranoid, disorganized, 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, hallucinogens, .inhalants, opioids, or phencyclidine; personality disorder of the paranoid type; and personality disorder of the schizoid type; and the anxiety disorder is selected from panic disorder; agoraphobia; a spécifie phobia; social phobia; obsessive-compulsive disorder; post-traumatic stress disorder; acute stress disorder; and generalized anxiety disorder.

It has been found that the compounds of formula I or pharmaceutically acceptable salts thereof may advantageously be administered in combination with at least one neuroleptic agent (which may be a typical or an atypical antipsychotic agent) to provide improved treatment of psychiatrie disorders such as schizophrenia. The combinations, uses and methods of treatment of the invention may also provide advantages in treatment of patients who fail to respond adequately or who are résistant to other known treatments.

The présent invention thus provides a method of treating a mammal suffering from a psychiatrie disorder, such as schizophrenia, which method comprises administering to the mammal a therapeutically effective amount of a compound of formula I, either alone or as combination therapy together with at least one neuroleptic agent.

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., cisordinol), butyrophenones (e.g., haloperidol), dibenzoxazepines (e.g., loxapine), dihydroindolones (e.g., molindone), diphenylbutylpiperidines (e.g., pimozide), and atypical antipsychotic drugs, including benzisoxazoles (e.g., rispéridone), sertindole, olanzapine, quetiapine, osanetant and ziprasidone.

Particularly preferred neuroleptic agents for use in the invention are sertindole, olanzapine, rispéridone, quetiapine, aripiprazole, haloperidol, clozapine, ziprasidone and osanetant.

The présent invention further provides a method of treating a subject suffering from a cognition disorder, which method comprises administering to the subject a therapeutically effective amount of a compound of formula I. Examples of cognition disorders that can be treated according to the présent invention include, but are not limited to, Alzheimer's disease, multiinfarct dementia, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumors or cérébral trauma, dementia associated with Huntington's disease or Parkinson's disease, or AIDS-related dementia; delirium; amnestic disorder; post-traumatic stress disorder; mental retardation; a learning disorder, for example reading disorder, mathematics disorder, or a disorder of written expression; attention-deficit/hyperactivity disorder; and age-related cognitive décliné.

This invention also provides a method of treating a movement disorder, which method comprises administering to the subject a therapeutically effective amount of a compound of formula I. Examples of movement disorders that can be treated according to the présent invention include, but are not limited to, Huntington's disease and dyskinesia associated with dopamine agonist therapy. This invention further provides a method of treating a movement disorder selected from Parkinson's disease and restless leg syndrome, which comprises administering to the subject a therapeutically effective amount of a compound of formula I.

This invention also provides a method of treating a mood disorder, which method comprises administering to the subject a therapeutically effective amount of a compound of formula I. Examples of mood disorders and mood épisodes that can be treated according to the présent invention include, but are not limited to, major dépressive épisode of the mild, moderate or severe type, a manie or mixed mood épisode, a hypomanie mood épisode; a dépressive épisode with a typical features; a dépressive épisode with melancholic features; a dépressive épisode with catatonie features; a mood épisode with postpartum onset; post-stroke dépréssion; major dépressive disorder; dysthymie disorder; minor dépressive disorder; premenstrual dysphorie disorder; post-psychotic dépressive disorder of schizophrenia; a major dépressive disorder superimposed on a psychotic disorder such as delusional disorder or schizophrenia; a bipolar disorder, for example bipolar I disorder, bipolar II disorder, and cyclothymie disorder. lt is understood that a mood disorder is a psychiatrie disorder.

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

This invention also provides a method of treating a drug addiction, for example an alcohol, amphétamine, cocaïne, or opiate addiction, in a mammal, including a human, which method comprises administering to said mammal an amount of a compound of formula I effective in inhibiting PDE10.

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

Drug addiction is widely considered a pathological state. The disorder of addiction involves the progression of acute drug use to the development of drug-seeking behavior, the vulnerability to relapse, and the decreased, slowed ability to respond to naturally rewarding stimuli. For example, The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) has categorized three stages of addiction: preoccupation/anticipation, binge/intoxication, and withdrawal/negative affect. These stages are characterized, respectively, everywhere by constant cravings and préoccupation with obtaining the substance; using more of the substance than necessary to expérience the intoxicating effects; and experiencing tolérance, withdrawal symptoms, and decreased motivation for normal life activities.

This invention further provides a method of treating a disorder comprising as a symptom a deficiency in attention and/or cognition in a mammal, including a human, which method comprises administering to said mammal an amount of a compound of formula I effective in treating said disorder.

Other disorders that can be treated according to the présent invention are obsessive/compulsive disorders, Tourette's syndrome and other tic disorders.

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 in 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 function caused by the dysfunction or death of at-risk neurons. The term neurotrophic agent” as used herein refers to a substance or agent that has some or ail of these properties.

Examples of neurodegenerative disorders and conditions that can be treated according to the présent invention include, but are not limited to, Parkinson’s disease; Huntington's disease;

dementia, for example Alzheimer's disease, multi-infarct dementia, AIDS-related dementia, and Fronto temperal Dementia; neurodegeneration associated with cérébral trauma; neurodegeneration associated with stroke, neurodegeneration associated with cérébral infarct; hypoglycemia-induced neurodegeneration; neurodegeneration associated with epileptic seizure; neurodegeneration associated with neurotoxin poisoning; and multi-system atrophy.

In one embodiment of the présent invention, the neurodegenerative disorder or condition involves neurodegeneration of striatal medium spiny neurons in a mammal, including a human.

In a further embodiment of the présent invention, the neurodegenerative disorder or condition is Huntington’s disease.

In another embodiment, the invention provides a method of treating a subject to reduce body fat or body weight, or to treat non-insuline demanding diabètes mellitus (NIDDM), metabolic syndrome, or glucose intolérance, comprising administering to a subject in need thereof a therapeuticaliy effective amount of a compound of formula I. In preferred embodiments, the subject is human, the subject is overweight or obese and the antagonist is administered orally. In another preferred embodiment, the method further comprising administering a second therapeutic agent to the subject, preferably an anti-obesity agent, e.g., rimonabant, orlistat, sibutramine, bromocriptine, ephedrine, leptin, pseudoephedrine, or peptide YY3-36, or analogs thereof.

The term “metabolic syndrome as used herein refers to a constellation of conditions that place people at high risk for coronary artery disease. These conditions include type 2 diabètes, obesity, high blood pressure, and a poor lipid profile with elevated LDL (bad) cholestérol, low HDL (good) cholestérol, and elevated triglycérides. Ail of these conditions are associated with high blood insulin levels. The fundamental defect in the metabolic syndrome is insulin résistance in both adipose tissue and muscle.

Ail references, including publications, patent applications and .patents, cited herein are hereby incorporated by reference in their entirety and to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in 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, patentability 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.

Experimental Section

Préparation of the compounds ofthe invention

HET

R1

Compounds of the general formula I of the invention may be prepared as described in the following reaction schemes. Unless otherwise indicated, in the reaction schemes and discussion that follow, HET-1, R1-R9, -L-, Z and Y are as defined above.

Compounds of formula I, wherein -L- is -S-CH₂-, can be prepared by the coupling of a nucleophile of formula V or Va with an electrophile of formula VI, where X is a leaving group, e.g. Cl, Br, I, methanesulfonyl, 4-toluenesulfonyl, as shown in scheme 1. In the reaction between Va and VI, alkylation ofthe sulfur atom of Va with VI and ring closure to form the fused bicyclic triazole ring both take place under the same reaction conditions in a one-pot procedure.

VI

This reaction is typically carried out in a solvent such as 1-propanol, toluene, DMF, or acetonitrile, optionally in the presence of a carbonate base such as potassium carbonate or a tertiary amine base such as triethylamine or diisopropylethylamine (DIPEA), at a température ranging from about 0° C to about 200° C, optionally under pressure in a closed vessel. Other suitable solvents include benzene, chloroform, dioxane, ethyl acetate, 2-propanol and xylene.

Alternatively, solvent mixtures such as toluene/2-propanol can be used.

Compounds of formula V are either commercially available or can be prepared as described in the literature, see for example Brown et al. Aust. J. Chem. 1978, 31, 397-404; Yutilov et al. Khim. Geter. Soedin. 1988, 799-804; Wilde et al. Bioorg. Med. Chem. Lett. 1995, 5, 167-172; Kidwai et al. J. Korean Chem. Soc. 2005, 49, 288-291. Compounds of formula Va can be prepared as described in WO 96/01826 from the corresponding 1,2-diaminopyridines by reaction with thiocarbonyldiimidazole in a suitable solvent, such as chloroform, at a suitable température, such as room température or +40 °C. The requisite 1,2-diaminopyridines are readily available from the corresponding commercially available 2-aminopyridines by reaction with a suitable /V-amination reagent, such as O-(mesitylsulfonyl)hydroxylamine, in a suitable solvent, such as chloroform, at a suitable température, such as 0 °C or room température, see WO 96/01826.

2-Halomethyl-4-(aryl)-1H-triazoles of formula Vl can be prepared by halogénation of the corresponding 2-hydroxymethyl-4-(aryl)-1H-triazoles using a suitable reagent, e.g. thionyl chloride, phosphorous trichloride, or phosphorous tribromide, optionally using a suitable solvent such as dichloromethane, using methods well known to chemists skilled in the art. The requisite

2-hydroxymethyl-4-(aryl)-1 H-imidazoles can be prepared by methods known in the art (see for example Browne, E. J.; Australien Journal of Chemistry 1971, 24(2), 393-403.; Browne, E. J.; Nunn, E. E.; Polya, John B. Journal of the Chemical Society [Section] C: Organic 1970, (11), 1515-18. Becker, Heinz G. O.; Goermar, G.; Timpe, Hans J. Journal für Praktische Chemie (Leipzig) 1970, 312(4), 610-21. Behringer, Hans; Ramert, Reiner. Justus Liebigs Annalen der Chemie 1975, (7-8), 1264-71. Moderhack, Dietrich, Liebigs Annalen der Chemie 1984, (1), 4865.).

Compounds of formula I, wherein -L- is -CH₂-S -, can be prepared by the coupling of a nucleophile of formula XII with an electrophile of formula VIII as shown in scheme 2.

HET1

->

HET1

OH

VII

X

VIII il ^SV R1

XII

Base

----->- I

Scheme 2.

A/-amination <------------

1. HOCH₂CO₂Me, base

2. Ester réduction

X = Cl, Br, I, OMs, OTs

This reaction is typically carried out in a solvent such as 1-propanol, toluene, DMF, or acetonitrile, optionally in the presence of a carbonate base such as potassium carbonate or a tertiary amine base such as triethylamine or diisopropylethylamine (DIPEA), at a température ranging from about 0° C to about 200° C, optionally under pressure in a closed vessel. Other suitable solvents include benzene, chloroform, dioxane, ethyl acetate, 2-propanol and xylene. Alternatively, solvent mixtures such as toluene/2-propanol can be used.

Some electrophiles of formula VIII are commercially available, and many others are known in the art, see for example JP 59176277. The electrophile VIII, where X is a leaving group, e.g. Cl, Br, I, methanesulfonyl, 4-toluenesulfonyl, can also be prepared by conversion of the primary alcohol of compounds of formula VII to said leaving group by methods known to chemists skilled in the art. Said methods can for example be selected from reacting compounds of formula VII with thionyl chloride, phosphorous trichloride, phosphorous tribromide, methanesulfonyl chloride, or 4-toluenesulfonyl chloride optionally in the presence of a suitable solvent, such as dichloromethane or 1,2-dichloroethane, and optionally in the presence of a base, such as triethylamine, diisopropylethylamine, or pyridine. Alternatively, electrophiles of formula VIII can be prepared by reacting commercially available aromatic amines of formula IX with 1,3dihaloacetones of formula XI, e.g. 1,3-dichloroacetone, in a suitable solvent, such as 1,2dimethoxyethane or éthanol, at a suitable température, such as room température or reflux. Some electrophiles of formula VII are commercially available, and many others are known in the art, see for example Tsuchiya, T.; Sashida, H. J. Chem. Soc., Chem. Commun. 1980, 11091110; Tsuchiya, T.; Sashida, H; Konoshita, A. Chem. Pharm. Bull. 1983, 31, 4568-4572. Alternatively, alcohols of formula VII can be prepared by reacting commercially available aromatic amines of formula IX with a suitable /V-amination reagent, such as O(mesitylsulfonyl)hydroxylamine, in a suitable solvent, such as chloroform, at a suitable température, such as 0 °C or room température, see WO 96/01826, to yield compounds of formula X. Said compounds of formula X can be converted into compounds of formula VII by reaction with methyl glycolate followed by réduction of the methyl ester to the requisite alcohol using a suitable reducing agent such as lithium aluminium hydride in a suitable solvent such as diethyl ether or tetrahydrofuran using methods known to chemists skilled in the art.

Compounds of formula XII are either commercially available or can be prepared as described in the literature, see e.g. Hoggarth, Eric. Journal ofthe Chemical Society 1949, 1160-3. Losse, Gunter; Hessler, Willi; Barth, Alfred. Chemische Berichte 1958, 91, 150-7. Potts, K. T; Burton, H. R.; Roy, S. K. Journal of Organic Chemistry 1966, 31(1), 265-73. ale, Harry L.; Piala, Joseph J.; Journal of Médicinal Chemistry 1966, 9(1), 42-6. Lalezari, I.; Sharghi, N. Journal of Heterocyclic Chemistry 1966, 3(3), 336-7. Durant, Graham J. Journal ofthe Chemical Society [Section] C: Organic 1967, (1), 92-4. US-3962237. Barnikow, Guenter; Ebeling, Horst. Zeitschrift für Chemie 1980, 20(2), 55-6. WO-2009087218. US-2003162812. WO-2000012489. Baxter, Andrew; et. al. Bioorganic & Médicinal Chemistry Letters 2003, 13(16), 2625-2628. Dhiman, A. M.; Wadodkar, K. N.; Patil, S. D. Indian Journal of Chemistry, Section B: Organic Chemistry Including Médicinal Chemistry 2001, 40B(7), 636-639.

Compounds of formula I, wherein R1 is not hydrogen, can be prepared by the alkylation of a compounds of formula I, wherein R1 is hydrogen, with an alkyl halide of formula XIII as shown in scheme 3.

* ^HET1-^L^X

RÏ

I ^HET1-^L~V

H

I (where RI = H)

R1—X

XIII

Scheme 3.

This reaction is typically carried out in a suitable solvent, such as dimethylformamide, dimethylacetamide, or acetonitrile, in the presence of a suitable base such as a carbonate base, e.g. potassium carbonate, or a tertiary amine base, e.g. triethylamine or diisopropylethylamine (DIPEA), at a température ranging from about 0° C to about 100° C.

Compounds of formula I, wherein -L- is -CH=CH- or -CH₂-CH₂- can be prepared by the reaction sequence shown in scheme 4.

—C—C—

Compounds where -L- is can be prepared by the reaction sequence shown in scheme 4

RÏ

Réduction

I (where -L- = -CH₂-CH₂and HET1 and ARYL is as shown)

I (where -L- = -CH=CHand HET1 and ARYL is as shown)

Scheme 4.

Specifically, compounds of formula I, wherein -L- is -CH₂-CH₂- 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 XIV and an aldéhyde of formula XV in a suitable solvent, such as tetrahydrofuran, in the presence of a suitable base, such as 1,8-diazabicyclo[5.4.0]undec-7-ene. Phosphonium sait of formula XIV are readily available by reaction of compounds of formula VIII (see scheme 2 above) with triphenylphosphine by methods known to chemists skilled in the art. Aldéhydes of formula XV are readily available by oxidation of alcohols of formula VII (see scheme 2 above) by methods known to chemists skilled in the art, e.g. by reacting alcohols of formula VII with a suitable oxidizing agent, such as Dess-Martin periodinane, in a suitable solvent, such as dichloromethane or 1,2-dicholorethane.

Compounds of formula I, wherein L is a triple bond (etynylene), can be prepared by a coupling reaction between an triazolyl alkyne of formula XVII with an heteroaryl halide of formula XVI or by the reverse coupling between an heteroaryl alkyne of formula XVIII with an triazolyl halide of formula XIX as shown in scheme 5.

XVI XVII

Scheme 5.

This reaction is typically carried out in a suitable solvent, such as tetrahydrofuran and performed by mixing the heteroarl halide with the heteroaryl alkyne together with a suitable catalyst e.g. Copper(l) iodide with a phosphine ligand e.g. 1,1'-bis(diphenylphosphino)ferrocenepalladium(ii)dichloride dichloromethane complex and and organic base like triethylamine and tyhen heating the reaction in a sealed vial at 120 °C for 15 minutes (MicroWave).

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

General Methods

Analytical LC-MS data were obtained using one of the following methods.

Method A:

A PE Sciex API 150EX instrument equipped with atmospheric pressure photo ionisation and a Shimadzu LC-8A/SLC-10A LC system was used. Column: 4.6 x 30 mm Waters Symmetry C18 column with 3.5 pm particle size; Column température: 60 °C; Solvent system: A = water/trifluoroacetic acid (100:0.05) and B = water/ acetonitrile/trifluoroacetic acid (5:95:0.035); Method: Linear gradient elution with A:B = 90:10 to 0:100 in 2.4 minutes and with a flow rate of 3.3 mL/min.

Method B:

A PE Sciex API 300 instrument equipped with atmospheric pressure photo ionisation and a Waters UPLC system was used. Column: Acquity UPLC BEH Ci₈ 1.7 pm, 2.1 x 50 mm (Waters); Column température: 60 °C; Solvent system: A = water/trifluoroacetic acid (100:0.05) and B = water/acetonitrile/trifluoroacetic acid (5:95:0.035); Method: Linear gradient elution with A:B = 90:10 to 0:100 in 1.0 minutes and with a flow rate of 1.2 mL/min.

Method C:

A PE Sciex API 150EX instrument equipped with atmospheric pressure photo ionisation and a Shimadzu LC-8A/SLC-10A LC system was used. Column: 4.6 x 30 mm Waters Symmetry C18 column with 3.5 pm particle size; Column température: 60 °C; Solvent system: A = water/trifluoroacetic acid (99.95:0.05) and B = methanol/trifluoroacetic acid (99.965:0.035); Method: Linear gradient elution with A:B = 83:17 to 0:100 in 2.4 minutes and with a flow rate of 3.0 mL/min.

Préparative LC-MS-purification was performed on a PE Sciex ÂPI 150EX instrument with atmospheric pressure chemical ionization. Column: 50 X 20 mm YMC ODS-A with 5 pm particle size; 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 250.13 MHz on a Bruker Avance DPX250 instrument. TMS was used as internai reference standard. Chemical shift values are expressed in ppm. The following abbreviations are used for multiplicity of NMR signais: s = singlet, d = doublet, t = triplet, q = quartet, qui = quintet, h = heptet, dd = double doublet, dt = double triplet, dq = double quartet, 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

General: p-Toluene-sulfonyl hydrazide (98%) was from Avocado.

Préparation of intermediates

2-Methyl-5-phenyl-2H-1,2,4-triazo)e-3-carbaidehyde

N-Methylhydrazine (1.46 mL, 27.5 mmol) was added to a stirred solution of 2-Phenyl-oxazol-4one (4.03 g, 25.0 mmol) (prepared as described in Yushiyuki et al. Synthesis. 2004, 1359-1363) in abs Ethanol (12 mL) at rt under Ar. Exothermic reaction. The reaction mixture was stirred at rt 1 h. The solvent was evaporated off to produce 4.64 g of a yellow/white solid of crude 2-Methyl5-phenyl-2H-1,2,4-triazol-3-yl)-methanol.

Dess-Martin periodinane (11.3 g, 26.7 mmol) was added in one portion to (2-Methyl-5-phenyl2H-1,2,4-triazol-3-yl)-methanol (4.60 g, 24.3 mmol) dissolved in Methylene chloride (72 mL) at 0 °C under Ar. After 2h, the reaction was diluted with DCE (100 ml) and extracted with sat NaHCO3 (100 ml). The aq phase was discarded and the organic phase was washed with brine and was rotovaped. The crude product was purified by silica gel cromatography (Eluent: 2050% EtOAc in heptane). Yield: 3.20 g ofthe title compound as a solid. H-NMR: (CDCI₃) δ 10.08 (s, 1 H), 8.13 (m, 2H), 7.50-7.42 (m, 3H), 4.26 (s, 3H).

The Following compounds were prepared analogously:

2-Ethyl-5-phenyl-2H-1,2,4-triazole-3-carbaldehyde from Ethyl-hydrazine and 2-Phenyloxazol-4-one. H-NMR: (DMSO-d₆) <510.01 (s, 1H), 8.07 (d, 2H), 7.50 (m, 3H), 4.59 (q, 2H), 1.42 (t, 3H).

5-Phenyl-2-propyl-2H-1,2,4-triazole-3-carbaldehyde, from Propyl-hydrazine and 2-Phenyloxazol-4-one. H-NMR: (CDCI₃) δ 10.07 (s, 1H), 8.17 (d, 2H), 7.48 (m, 3H), 4.59 (m, 2H), 1.95 (m, 2H) 1.00 (t, 3H).

2-lsopropyl-5-phenyl-2H-1,2,4-triazole-3-carbaldehyde, from Isopropyl-hydrazine and 2Phenyl-oxazol-4-one. H-NMR: (DMSO-d₆) δ 10.02 (s, 1H), 8.08 (d, 2H), 7.50 (m, 3H), 5.37 (m, 1H), 1.51 (d, 6H).

5-Phenyl-2-(2,2,2-trifluoro-ethyl)-2H-1,2,4-triaz ole-3-carbaldehyde, from (2,2,2-Trifluoroethyl)-hydrazine and 2-Phenyl-oxazol-4-one. H-NMR: (CDCI₃) δ 10.07 (s, 1H), 8.18 (d, 2H), 7.50 (m, 3H), 5.28 (m, 2H).

3-(5-Formyl-3-phenyl-1,2,4-triazol-1-yl)-propionitrile, from 3-Hydrazino-propionitrile and 2Phenyl-oxazol-4-one. H-NMR: (DMSO-d₆) δ 10.03 (s, 1H), 8.08 (d, 2H), 7.52 (m, 3H), 4.86 (t, 2H), 3.20 (t, 2H).

(5-Formyl-3-phenyI-1,2,4-triazol-1-yl)-acetic acid ethyl ester, from Hydrazino-acetic acid ethyl ester and 2-Phenyl-oxazol-4-one. H-NMR: (CDCI₃) δ 10.05 (s, 1H), 8.15 (d, 2H), 7.50 (m, 3H), 5.38 (s, 2H), 4.28 (m, 2H), 1.32 (t, 3H).

Example 2 2-(2-Methoxy-ethyl)-5-phenyl-2H-[1,2,4]triazoie-3-carbaldehyde

2-HYDROXYETHYLHYDRAZINE (1.60 g, 21.0 mmol) was added to a stirred solution of 2Phenyl-oxazol-4-one (3.08 g, 19.1 mmol) in Ethanol (9.6 mL) at rt under Ar. Exothermic reaction. The reaction mixture was stirred at rt ON. The solvent was evaporated off. Yield: 4.24 g of 2-(5-Hydroxymethyl-3-phenyl-1,2,4-triazol-1-yl)-ethanol.

Sodium hydride (60% in minerai oil) (60:40, Sodium hydride:Mineral Oil, 1.36 g) was added in portions, to a stirred solution of 2-(5-Hydroxymethyl-3-phenyl-1,2,4-triazol-1-yl)-ethanol (2.92 g, 13.3 mmol) in N,N-Dimethylformamide (100 mL) at rt. The reaction was stirred at rt 5 min under Ar. Benzyl bromide (1.35 mL, 11,3 mmol) was added and the solution was stirred at rt under Ar 1 h. The reaction mixture was quenched by adding conc HCl (1 ml) and then EtOAc (200 ml) and brine (100 ml). The phases were separated and the org phase was rotovaped and the crude product was purified by silica gel cromatography (Eluent: 20-50% EtOAc in heptane). Yield: 1.39 g of 2-(5-Benzyloxymethyl-3-phenyl-[1,2,4]triazol-1-yl)-ethanol as an oil.

Sodium hydride (60% in minerai oil) (60:40, Sodium hydride:Mineral Oil, 197.7 mg) was added in portions, to a stirred solution of 2-(5-Benzyloxymethyl-3-phenyl-1,2,4-triazol-1-yl)-ethanol (1.39 g, 4.49 mmol) in N,N-Dimethylformamide (45 mL) at rt. The reaction was stirred at rt 5 min under Ar. Methyl iodide (0.3077 mL, 4.942 mmol) was added and the solution was stirred at rt under Ar 1 h. More NaH (200 mg) and Mel (0.1 ml) was added. This addetion was repeated after aprox 1 h.

EtOAc (100 ml) and brine (100 ml) was added and the phases were separated. The org phase was washed with more brine, dried (Na2SO4) and the solvent evaporated of. The crude product was purified by silica gel cromatography (20-100% EtOAc in heptane). Yield: 1.23 g of 5Benzyloxymethyl-1-(2-methoxy-ethyl)-3-phenyl-1H -1,2,4-triazole as an oil.

Pd/C (10%) (9:1, carbon black:Palladium, 250 mg) was added, to a solution of 5Benzyloxymethyl-1-(2-methoxy-ethyl)-3-phenyl-1H-1,2,4-triazole (1.23 g, 3.80 mmol) in Methanol (72 mL) and TFA (2 ml) at rt. The reaction was hydrogenated at 3 bar using a Parr shaker ON. More catalyst (200 mg) was added and the hydrogénation was cont ON. The catalyst was filtered off and the solvent was evaporated off. The crude product was purified by silica gel cromatography (25-100% EtOAc in heptane). Yield: 0.84 g of [2-(2-Methoxy-ethyl)-5phenyl-2H-1,2,4-triazol-3-yl]-methanol as an oil.

Dess-Martin periodinane (1530 mg, 3.60 mmol) was added to a stirred suspension of [2-(2Methoxy-ethyl)-5-phenyl-2H-1,2,4-triazol-3-yl]-methanol (840 mg, 3.6 mmol) dissolved in Methylene chloride (36.0 mL) at rt under Ar. The solution was stirred ON. Some solid was filtered off and discarded. Sat NaHCO3 (35 ml) and more DCM (35 ml) were added to the DCM solution. The solvent was evaporated off and the crude product was purified by silica gel cromatography (Eluent: 50% EtOAc in heptane). Yield: 0.76 g ofthe title compound as an oil. H-NMR: (CDCls) δ 10.04 (s, 1H), 8.13 (m, 2H), 7.45 (m, 3H), 4.82 (t, 2H), 3.83 (t, 2H), 3.32 (s, 3H).

Préparation of other intermediates

2-Chloromethyl-5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine

4,6-Dimethyl-pyrimidin-2-ylamine

1-Amino-4,6-dimethyl-1H-pyrimidin-2

-ylidene-ammonium 2,4,6-Trimethyl-benzenesulfonate

2-Chloromethyl-5,7-dimethyl-[1,2,4] triazolo[1,5-a]pyrimidine

To a solution of 4,6-Dimethyl-pyrimidin-2-ylamine (25 g, 200 mmol) in 400 mL of CH₂CI₂was added dropwise a solution of hydroxylamine-2,4,6-Trimethyl-benzenesulfonate (105 g, 488 mmol) in 300 mL of CH₂CI₂ at 0°C, and the mixture was stirred at 0°C for 1 hour and filtered. The solid collected was washed with CH₂CI₂ (100 mL) to give 1-Amino-4,6-dimethyl-1Hpyrimidin-2-ylidene-ammonium 2,4,6-Trimethyl-benzenesulfonate (40 g, yield:62%).

A mixture of 1-Amino-4,6-dimethyl-1H-pyrimidin-2-ylidene-ammonium 2,4,6-Trimethylbenzenesulfonate (40 g, 0.1 mol) and NaOH (10 g, 0.2 mol) in 500 mL of EtOH was stirred at 50~60°C for 1 hour. After chloroacetic acid methyl ester (16.6 g, 0.15 mol) was added, the résultant mixture was stirred at reflux for 4 hours. After being concentrated under reduce pressure, the residue was diluted with water (1000 mL) and extracted with CH₂CI₂ (300 mLx3). The combined organic layers were washed with brine (200 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography on silica gel (petroleum ether/EtOAc = 2/1) to give 2 g of 2-Chloromethyl-5,7-dimethyl-[1,2,4]triazolo[1,5ajpyrimidine in 9% yield. ¹H NMR (300 MHz, DMSO-d6)’· δ 8.55 (s, 1H), 6.25 (s, 2H), 4.05 (s, 3H), 3.95 (s, 3H); LC-MS (MH⁺): m/z = 196.9, tR (min, method A) =0.52

The following intermediates were prepared analogously:

7-Chloro-2-chloromethyl-5,8-dimethyl-[1,2,4]triazoio[1,5-c]pyrimidine from 6-Chloro-2,5dimethyl-pyrimidine-4-ylamine prepared as described by Henze et al. J. Org. Chem 1952, 17,

1320-1327. 3.2% yield, LC-MS: m/z = 231.5 (MH⁺), t_R = 1.13 min, method C

2-Chloromethyl-5,8-dimethyl-[1,2,4]-triazolo[1,5-a]pyrazine from 2-amino-3,6-dimethylpyrazine. 60% yield, ¹H NMR (500 MHz, CDCI3): 07.91 (s,1H), 4.87 (s, 2H), 2.91 (s, 3H), 2.74 (s, 3H), LCMS: m/z = 196.9 (MH⁺), tR = 0.64 min, method A

2-Chloromethyl-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine from 6-Chloro-5-ethyl-2-methylpyrimidin-4-ylamine. 21 % yield, LC-MS: m/z = 245.0 (MH⁺), t_R = 0.72 min, method A

2-Chloromethyl-8-methoxy-5-methyl-[1,2,4]triazolo[1,5-a]pyridine from 3-Methoxy-6-methylpyridin-2-ylamine. 64%, ¹H NMR (500 MHz, DMSO-d₆): δ 7.11-7.08 (d, 1H), 7.01-6.98 (d, 1H), 4.93 (s, 2H), 3.98 (s, 3H), 2.61 (s, 3H)

2-Chloromethyl-8-methoxy-5-methyl-[1,2,4]triazolo[1,5-a]pyridine from 2-AMINO-6METHYLPYRIDINE, LC-MS: m/z =181.8 (MH⁺), t_R = 0.64 min, method A.

2-Chloromethyl-8-methyl-[1,2,4]triazolo[1,5-a]pyridine from 2-AMINO-3-METHYLPYRIDINE, LCMS: m/z = xx (MH⁺), t_R = xx min, method xx. CHINA!

2-Chloromethyl-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine from 2-AMINO-3-METHOXYPYRIDINE, LC-MS: m/z = 197.8 (MH⁺), f_R = 0.40 min, method B.

2-Chloromethyl-8-ethyl-5-methyl-[1,2,4]triazolo[1,5-a]pyridine from 2-AMINO-3-ETHYL-6METHYLPYRIDINE, LC-MS: m/z = 209.8 (MH⁺), f_R = 0.60 min, method B.

(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-ylmethyl)-triphenyl-phosphonium; chloride

A solution of 2-chloromethy!-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazine (1.351 g, 6.87 mmol) and triphenylphosphine (1.80 g, 6.87 mmol) in acetonitrile 150 mL was heated at reflux for 12 h. The solvents were removed in vacuo and the residue slurried in ether, filtered and dried to yield (5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-ylmethyl)-triphenyl-phosphonium; chloride as an off white solid (2.412 g, 74.9%). LC-MS: m/z = 423.2 ([M-CIf), f_R = 0.86 min, method A.

The following intermediates were prepared analogously:

(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylmethyl)-triphenyl-phosphonium chloride from 2Chloromethyl-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine, LC-MS: m/z = 422.2 (MH⁺), f_R = 1.02 min, method A

(8-Methoxy-5-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylmethyl)-triphenyl-phosphonium chloride from 2-Chloromethyl-8-methoxy-5-methyl-[1,2,4]triazolo[1,5-a]pyridine, LC-MS: m/z = 438.4 (MH⁺), t_R = 0.96 min, method A

(5-Methyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylmethyl)-triphenyl-phosphonium chloride from 2-Chloromethyl-5-methyl-[1,2,4]triazolo[1,5-a]pyridine, LC-MS: m/z = 408.4 (MH⁺), f_R =

0.88 min, method A

(8-Methyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylmethyl)-triphenyl-phosphonium chloride from 2Chloromethyl-8-methyl-[1,2,4]triazoio[1,5-a]pyridine, LC-MS: m/z = 408.2 (MH⁺), f_R = 0.59 min, method B.

(5,7-Dimethyi-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-triphenyl-phosphonium chloride from2Chloromethyl-5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine, LC-MS: m/z = 423.3 (MH⁺), f_R = 0.85 min, method A

(8-Methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-ylmethyl)-triphenyl-phosphonium chloride from 2Chloromethyl-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine, LC-MS: m/z = 423.9 (MH*), t_R = 0.55 min, method B

(8-Ethyl-5-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylmethyl)-triphenyl-phosphonium chloride from 2-Chloromethyl-8-ethyl-5-methyl-[1,2,4]triazolo[1,5-a]pyridine, LC-MS: m/z = 423.9 (MH⁺), t_R = 0.55 min, method B

Préparation ofthe compounds ofthe invention

Example 1

5-Methyl-2-(5-phenyl-2H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]triazolo[1,5-a]pyridine

Triethylamine (0.7602 mL, 5.454 mmol) was added to a solution of [2-Chloromethyl-5-methyl- [1,2,4]triazolo[1,5-a]pyridine (495 mg, 2.73 mmol) in N,N-Dimethylformamide (12 mL, 150 mmol) and the solution was stirred aprox 2 mins. 5-Phenyl-2H-1,2,4-triazole-3-thiol (532 mg, 3.00 mmol) was added to the mixture as a solid. The reaction mixture was subsequently heated at 60 °C for 0.5 hours. The mixture was rotovaped. EtOAc (60 mL) and sat. bicarbonate (20 mL) were added to the residue and the phases were separated. The organic phase was washed with brine (20 mL). After drying (MgSO4), the solvent was removed under reduced pressure. The crude product was purified by siiica gel chromatography (Eluent: EtOAC:N-heptane 50-100%). This afforded 542 mg (61%) ofthe title compound as a white solid. LC-MS: m/z = 323.1 (MH⁺), tR = 0.52 min, Method B. ¹H NMR (600 MHz, DMSO-d6): δ 7.96 (d, 2H), 7.63 (m, 1H), 7.60 (t, 1H) 7.50 (m, 3H), 7.06 (d, 1H), 4.68 (s, 2H), 2.67 (s, 3H).

The following compound was prepared analogously:

8-Methoxy-5-methyl-2-(5-phenyl-2H-[1,2,4]triazol-3-y Isu If any lmethyl)-[1,2,4]triazolo[1,5a]pyridine (2), LC-MS: m/z = 353.4 (MH⁺), f_R = 0.57 min, Method B.

Example 2

5-Methyl-2-(2-methyl-5-phenyl-2H-[1,2,4]triazoI-3-ylsulfanylmethyl)-[1,2,4]triazolo[1,5ajpyridine

Methyl iodide (142 mg, 1.00 mmol) dissolved in DMF (0.5 ml) was added to a stirred suspension of 5-Methyl-2-(5-phenyl-2H-1,2,4-triazol-3-ylsulfanylmethyl)-[1,2,4]triazolo[1,5-a]pyridine (322 mg, 1.00 mmol) and Potassium carbonate (276 mg, 2.0 mmol) in N,N-Dimethylformamide (3.5 mL) at rt, under Ar. The solution was stirred at 3 h and then quenched by adding Sat bicarbonate sol and extracting with EtOAc. The Organic phase was dried (MgSO4) and was rotovaped. The crude product was purified by HPLC. This afforded 10 mg ofthe title compound. LC-MS: m/z = 337.1 (MH⁺), tR = 0.63 min, Method B. ¹H NMR (600 MHz, DMSO-d6): 5 7.96 (d, 2H), 7.63 (d, 1H), 7.60 (t, 1H) 7.50-7.40 (m, 3H), 7.07 (d, 1H), 4.68 (s, 2H), 2.66 (s, 3H).

The following compound was synthesized analogously:

5,8-Dimethyl-2-(5-phenyl-2H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]triazolo[1,5-a]pyrazine LCMS: m/z = 338.1 (MH⁺), t_R = 1.38 minutes, Method C

Example 3

5,8-Dimethyl-2-[2-(2-methyl-5-phenyl-2H-[1,2,4]triazol-3-yl)-ethyl]-[1,2,4]triazolo[1,5ajpyrazine

mixture of cis and trans

DCM, MeOH

1,8-Diazabicyclo[5.4.0]undec-7-ene (0.16 mL, 1.07 mmol) was added to a stirred suspension of (5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-ylmethyl)-triphenyl-phosphonium; chloride (0.490 g, 1.07 mmol) and 2-Methyl-5-phenyl-2H-1,2,4-triazole-3-carbaldehyde (0.200 g, 1.07 mmol) in Tetrahydrofuran (6.9 mL) in dry THF (8 mL) and the mixture was stirred at room température under an atmosphère of Argon overnight. DCM (50 ml) was added and the organic phase was extracted with water (2 x 50 ml), dried (MgSO4) and the solvent was evaporated off.

The remanens was dissolved in DCM, and purified by silica gel chromatography (Eluent: EtOAc). Yield: 270 mg (76%) mg ofthe intermediate as a cis/trans mixture.

This material (270 mg, 0.81 mmol) was dissolved in DCM (10 mL) and MeOH (80 ml). The solution was filtered and was hydrogenated at rt on an H-cube through a Pd/C CatCart column at 1 bar hydrogen pressure. The solvent was evaporated off, and the crude product was purified by silica gel chromatography (Eluent: EtOAc). Yield: 138 mg (51%) ofthe title compound as a solid. LC-MS: m/z = 334.5 (MH⁺), fR = 1.16 min, Method C. ¹H NMR (600 MHz, DMSO-d6): δ 8.0-7.9 (m, 3H), 7.45-7.35 (m, 3H), 3.90 (s, 3H), 3.44 (t, 2H), 3.35 (t, 2H), 2.74 (s, 3H), 2.64 (s, 3H).

The following compounds were prepared analogously: 8-Methyl-2-[2-(2-methyl-5-phenyl-2H-[1,2,4]triazol-3-yl)-ethyl]-[1,2,4]triazolo[1,5-a]pyridine dihydrochloride, LC-MS: mlz = 318.9 (MH⁺), t_R = 0.52 min, Method B.

5,7-Dimethyl-2-[2-(2-methyl-5-phenyl-2H-[1,2,4]triazol-3-yl)-ethyl]-[1,2,4]triazolo[1,5ajpyrimidine, LC-MS: mlz = 334.5 (MH⁺), t_R = 1.05 min, Method C.

8-Methoxy-5-methyl-2-[2-(5-phenyl-2-propyl-2H-[1,2,4]triazol-3-yl)-ethyl]-[1,2,4]triazolo[1,5ajpyridine dihydrochloride, LC-MS: mlz = 377.5 (MH⁺), t_R = 0.66 min, Method B.

8-Methoxy-5-methyl-2-{2-[5-phenyl-2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-ethyl}- [1,2,4]triazolo[1,5-a]pyridine, LC-MS: mlz = 416.4 (MH⁺), t_R = 0.71 min, Method B. 8-Methoxy-5-methyl-2-{2-[5-phenyl-2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-ethyl}- [1,2,4]triazolo[1,5-a]pyridine, LC-MS: m/z= 319.2 (MH⁺), t_R= 1.14 min, Method C.

8-Methoxy-2-[2-(2-methyl-5-phenyl-2H-[1,2,4]triazol-3-yl)-ethyl]-[1,2,4]triazolo[1,5-a]pyridine, LC-MS: m/z = 335.3 (MIT), t_R = 1.09 min, Method C.

5-[2-(8-Methoxy-5-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-ethyl]-3-phenyl-[1,2,4]triazol-1-yl}acetic acid ethyl ester, LC-MS: m/z = 420.6 (MIT), f_R = 0.65 min, Method B.

5.8- Dimethyl-2-[2-(2-methyl-5-phenyl-2H-[1,2,4]triazol-3-yl)-ethyl]-[1,2,4]triazolo[1,5-a]pyridine, LC-MS: m/z = 333.2 (MIT), t_R = 1.24 min, Method C.

5.8- Dimethyl-2-[2-(2-methyl-5-phenyl-2H-[1,2,4]triazol-3-yl)-ethyl]-[1,2,4]triazolo[1,5c]pyrimidine, LC-MS: m/z = 334.5 (MIT), f_R = 1.18 min, Method C.

5.8- Dimethyl-2-[2-(2-methyl-5-thiophen-3-yl-2H-[1,2,4]triazol-3-yl)-ethyl]-[1,2,4]triazolo[1,5a]pyrazine LC-MS: m/z = 340,1 (MH+), tR = 1,29 min, Method C.

2-[2-(5-Furan-2-yl-1-methyl-1H-[1,2,4]triazol-3-yl)-ethyl]-5,8-dimethyl-[1,2,4]triazolo[1,5a]pyrazine LC-MS: m/z = 324,1 (MH+), tR =1,17 min, Method C.

2-[(E)-2-(5-Furan-2-yl-1-methyl-1 H-[1,2,4]triazol-3-yl)-vinyl]-5,8-dimethyl-[1,2,4]triazolo[1,5a]pyrazine LC-MS: m/z = 322,1 (MH+), tR = 1,46 min, Method C.

5.8- Dimethyl-2-[2-(2-methyl-5-thiazol-4-yl-2H-[1,2,4]triazol-3-yl)-ethyl]-[1,2,4]triazolo[1,5ajpyrazine LC-MS: m/z = 341,1 (MH+), tR = 0,97 min, Method C.

5.8- Dimethyl-2-{2-[2-methyl-5-(5-methyl-thiazol-2-yl)-2H-[1,2,4]triazol-3-yl]-ethyl}- [1,2,4]triazolo[1,5-a]pyrazine LC-MS: m/z = 355,1 (MH+), tR = 1,21 min, Method C.

5.8- Dimethyl-2-{2-[2-methyl-5-(4-methyl-thiazol-2-yl)-2H-[1,2,4]triazol-3-yl]-ethyl}- [1,2,4]triazolo[1,5-a]pyrazine LC-MS: m/z = 355,1 (MH+), tR = 1,18 min, Method C.

5.8- Dimethyl-2-[2-(2-methyl-5-oxazol-2-yl-2H-[1,2,4]triazol-3-yl)-ethyl]-[1,2,4]triazolo[1,5ajpyrazine LC-MS: m/z = 325,1 (MH+), tR = 0,87 min, Method C.

5.8- Dimethyl-2-[2-(2-methyl-5-thiophen-2-yl-2H-[1,2,4]triazol-3-yl)-ethyl]-[1,2,4]triazolo[1,5ajpyrazine LC-MS: m/z = 340,1 (MH+), tR = 1,24 min, Method C.

5.8- Dimethyl-2-[2-(2-methyl-5-thiophen-2-yl-2H-[1,2,4]triazol-3-yl)-ethyl]-[1,2,4]triazolo[1,5ajpyrazine LC-MS: m/z = 340,1 (MH+), tR = 1,26 min, Method C.

5.8- Dimethyl-2-[2-(2-methyl-5-pyrimidin-2-yl-2H-[1,2,4]triazol-3-yl)-ethyl]-[1,2,4]triazolo[1,5ajpyrazine LC-MS: m/z = 336,2 (MH+), tR = 0,79 min, Method C.

5.8- Dimethyl-2-[2-(2-methyl-5-pyridin-2-yl-2H-[1,2,4]triazol-3-yl)-ethyl]-[1,2,4]triazolo[1,5ajpyrazine LC-MS: m/z = 335,2 (MH+), tR = 0,78 min, Method C.

5.8- Dimethyl-2-[2-(2-methyl-5-thiazol-5-yl-2H-[1,2,4]triazol-3-yl)-ethyl]-[1,2,4]triazolo[1,5ajpyrazine LC-MS: m/z = 341,1 (MH+), tR = 1.0 min, Method C.

5.8- Dimethyl-2-[2-(2-methyl-5-thiazol-2-yl-2H-[1,2,4]triazol-3-yl)-ethyl]-[1,2,4]triazolo[1,5ajpyrazine LC-MS: m/z = 341,1 (MH+), tR= 1,01 min, Method C.

5.8- Dimethyl-2-[2-(2-methyl-5-pyridin-3-yl-2H-[1,2,4]triazol-3-yl)-ethyl]-[1,2,4]triazolo[1,5ajpyrazine LC-MS: m/z = 335,2 (MH+), tR = 0,7 min, Method C.

2-[2-(5-Furan-2-yl-2-methyl-2H-[1,2,4]triazol-3-yl)-ethyl]-5,8-dimethyl-[1,2,4]triazolo[1,5ajpyrazine LC-MS: m/z = 324,1 (MH+), tR = 1,09 min, Method C.

2-[2-(5-Furan-2-yl-2-methyl-2H-[1,2,4]triazol-3-yl)-ethyl]-5,8-dimethyl-[1,2,4]triazolo[1,5ajpyrazine LC-MS: m/z = 324,1 (MH+), tR = 1,08 min, Method C.

5,8-Dimethyl-2-(5-phenyl-2H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]triazolo[1,5-a]pyrazine LCMS: m/z = 338,1 (MH+), tR = 1,38 min, Method C.

2-{5-[2-(5,8-D imethy l-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-ethyl]-3-phenyl-[1,2,4]triazol-1 -yl}-ethanol LC-MS: m/z = 364,2 (MH+), tR = 1,3 min, Method C.

Example 4

8-Ethyl-2-(2-{5-[(Z)-1 -eth-(E)-ylidene-penta-2,4-dienyl]-2-propyl-2H-[

1,2,4]triazoi-3-yl}-ethyl)-5-methyl-[1,2,4]triazolo[1,5-a]pyridine

1,8-Diazabicyclo[5.4.0]undec-7-ene (0.150 mL, 1.00 mmol) was added to a stirred suspension of 8-Ethyl-5-methyl-[1,2,4]triazolo [1,5-a]pyridin-2-ylmethyl)-tripheny l-phosphonium; chloride (472 mg, 1.00 mmol) and 5-Phenyl-2-propyl-2H-1,2,4-triazole-3-carbaldehyde (215 mg, 1.00 mmol) in dry THF (20 mL) and the mixture was stirred at room température under an atmosphère of Argon 2 days. The solvent was removed in vac. The remanens was dissolved in DCM, and purified by silica gei chromatography (Eluent: 0-100% EtOAc in n-heptane). Yield: 290 mg of the intermediate (as a single isomer) as a white solid (78%). LC-MS: m/z = 373.5 (MH⁺), t_R = 0.93 min, Method B.

This material (290 mg, 0.78 mmol) was dissolved in DMF (7.8 mL) and pToluenesulfonylhydrazide (430 mg, 2.3 mmol) was added and the reaction was stirred at 120 °C 8h under Ar. The solution was allowed to reach room température and stirred overnight. More pToluenesulfonyl hydrazide (0.08 g) was added, and the reaction mixture was at 120 °C ON under Ar. DMF was evaporated and the residue was dissolved in EtOAc (50 ml) and extracted with sat NaHCO3 (2 x 25 ml). The organic phase was washed with brine, dried (MgSO4) and was rotovaped. The crude product was purified by silica gel chromatography (Eluent: 50-100% EtOAc in n-heptane). Yield: 140 mg (48%). ofthe title compound as a solid. LC-MS: m/z = 375.3 (MH⁺), tR = 1.68 min, Method C. ¹H NMR (600 MHz, CDCI3): δ 8.08 (d, 2H), 7.40 (d, 2H), 7.34 (m, 1H), 7.17 (d, 1H), 6.70 (d, 1H), 4.12 (m,2H), 3.55 (m, 2H), 3.38 (m, 2H), 3.00 (m, 2H), 2.68 (s, 3H), 1.88 (m, 2H), 1.34 (t, 3H), 0.93 (t, 3H).

The following compounds were prepared analogously:

8-Methoxy-5-methyl-2-[2-(2-methyl-5-phenyl-2H-[1,2,4]triazol-3-yl)-ethyl]-[1,2,4]triazolo[1,5a]pyridine, LC-MS: m/z = 349.5 (MH⁺), t_R = 0.59 min, Method B.

8-Ethyl-5-methyl-2-[2-(2-methyl-5-phenyl-2H-[1,2,4]triazol-3-yl)-ethyl]-[1,2,4]triazolo[1,5a]pyridine, LC-MS: m/z = 347.1 (MH⁺), t_R = 0.59 min, Method B.

8-Ethyl-2-[2-(2-isopropyl-5-phenyl-2H-[1,2,4]triazol-3-yl)-ethyl]-5-methyl-[1,2,4]triazolo[1,5ajpyridine, LC-MS: m/z = 375.2 (MH⁺), t_R = 1.67 min, Method C.

3-{5-[2-(8-Methoxy-5-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-ethyl]-3-phenyl-[1,2,4]triazol-1-yl}propionitrile, LC-MS: m/z = 388.5 (MIT), t_R = 1.18 min, Method C.

3-{5-[2-(8-Ethyl-5-methy l-[1,2,4]triazolo[1,5-a]py ridin-2-yl)-ethyl]-3-phenyl-[1,2,4]triazol-1 -yl}propionitrile, LC-MS: m/z = 386.6 (MH⁺), i_R = 1.32 min, Method C.

2- [2-(2-lsopropyl-5-phenyl-2H-[1,2,4]triazol-3-yl)-ethyl]-8-methoxy-5-methyl-[1,2_l4]triazolo[1_l5ajpyridine, LC-MS: m/z = 377.4 (MH⁺), t_R = 1.45 min, Method C.

3- {5-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-ethyl]-3-phenyl-[1,2,4]triazol-1-yl}propionitrile, LC-MS: m/z = 373.4 (MH⁺), f_R = 0.56 min, Method B.

2-{2-[2-(2-Methoxy-ethyl)-5-phenyl-2H-[1,2,4]triazol-3-yl]-ethyl}-5,8-dimethyl-[1,2,4]triazolo[1,5ajpyrazine, LC-MS: m/z = 378.6 (MH⁺), t_R = 1.42 min, Method C. Mp = 141-143 C.

Example 5

2-{5-[2-(8-Methoxy-5-methyl-[1,2,4]triazoIo[1,5-a]pyridin-2-yl)-ethyl]-3-phenyl-[1,2,4]triazol1-yl}-ethanol

1M of Lithium tetrahydroaluminate in Tetrahydrofuran (5.0 mL) was added to a stirred solution of {5-[2-(8-Methoxy-5-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-ethyl]-3-phenyl-1,2,4-triazol-1-yl}acetic acid ethyl ester (950 mg, 2.2 mmol) in Tetrahydrofuran (3 mL) at rt. The reaction is exothermic. The solution was stirred at rt under Ar 3 h. The solution was diluted with THF (10 ml) and quenched by adding wet Na2SO4. The solution was filtered through dry Na2SO4, and was rotovaped. The crude product was purified by silica gel chromatography (Eluent: 0-30% MeOH in EtOAc). Yield: 710 mg (75%) ofthe title compound as a clear oil. LC-MS: m/z = 379.4 (MH⁺), f_R = 0.51 min, Method B.

The following compound was prepared analogously:

Example 6

3-{5-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yI)-ethyl]-3-phenyI-[1,2,4]triazol-1 -yl}propylamin

3-{5-[2-(5,8-Dimethy l-[1,2,4]triazolo[1,5-a] py razin-2-y l)-ethyl]-3-pheny 1-1,2,4-triazoM -yl}propionitrile (28 mg, 0.075 mmol) was dissolved in 2 M of Ammonia in Methanol (15 mL) and hydrogenated on an H-cube through a column of Raney-Nickel (50 bar hydrogen, rt). The solvent was evaporated off. The crude product was purified by silica gel chromatography (Eluent: 10% MeOH, 10% triethylamine, 80% EtOAc). Yield: 10 mg (35%) ofthe title compound as a clear oil. LC-MS: m/z = 377.3 (MH⁺), f_R = 0.81 min, Method C.

The following compound was prepared analogously:

3-{5-[2-(8-Ethyl-5-methyl-[1,2,4]tri azolo[1,5-a] py rid i n-2-y |)-ethy l]-3-pheny l-[1,2,4]triazol-1 -yl}propylamine, LC-MS: m/z = 390.2 (MH⁺), t_R = 0.48 min, Method B.

Example 7

2-{5-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-ethyl]-3-phenyl-[1,2,4]triazol-1 -yl}ethanol

OH

I lodotrimethylsilane (92.0 uL, 0.646 mmol) was added to a stirred solution of 2-{2-[2-(2-Methoxyethyl)-5-phenyl-2H-1,2,4-triazol-3-yl]-ethyl}-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazine (61 mg, 0.16 mmol) in Chloroform (5 mL) under an atmosphère of Argon at rt. The solution was stirred at rt 4h. More lodotrimethylsilane (184 uL, 1.29 mmol) was added and the mixture was stirred at rt ON. MeOH (10 ml) and solid sodium sulfite (0.5 g) was added and the mixture was stirred 30 min, filtered and evaporated. The crude product was purified by silica gel chromatography (Eluent: 0-5% MeOH in EtOAc). Yield: 27 mg (46%) of the title compound as a solid. LC-MS: m/z = 364.5 (MH⁺), f_R = 1.30 min, Method C.

Pharmacoloqical Testing

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. étal. Eur J Biochem. 1999, 266, 1118-1127 and Soderling, S. et al. Proc. Natl. Acad. Sci. 1999, 96, 7071-7076). PDE10A can be expressed as full-length proteins or as truncated proteins, as long as they express the catalytic domain. PDE10A can be prepared in different cell 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 amplified from total human brain 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 plasmids 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 ovemight 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 MgCI₂and 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 PDE10A assay may for example, be performed as follows: The assay is performed in 60 uL samples containing a fixed amount of the relevant PDE enzyme (suffirent to convert 20-25% of the cyclic nucléotide substrate), a buffer (50 mM HEPES7.6; 10mM MgCI₂; 0.02% Tween20), 0.1 mg/ml BSA, 225 pCi of ³H-labelled cyclic nucléotide substrate, tritium labeled cAMP to a final concentration of 5 nM and varying amounts of inhibitors. Reactions are initiated by addition of the cyclic nucléotide 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 IC₅₀ values can be calculated using the Xlfit extension to EXCEL.

Phencyclidine (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) including the parallel control groups receiving the vehicle of the test compound plus PCP or vehicle injections only. The injection volumen is 10 ml/kg. The experiment is made in normal light conditions in 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 is 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 ofthe mice.

Motility is 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 following 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 in groups receiving test compound is thus determined by the total motility counts minus baseline, expressed in per cent of the similar resuit recorded in the parallel PCP control group. The per cent responses are converted to per cent inhibition.

Claims

1. A compound having the structure I wherein HET-1 is a heteroaromatic group of formula II containing from 2 to 4 nitrogen atoms:

II wherein Y can be N or CH, Z can be N or C, and wherein HET-1 may optionally be substituted with up to three substituents R2-R4 individually selected from hydrogen, C_rC₆alkyl; halogen; cyano, halo(C₁-C₆)alkyl; aryl, alkoxy and C_rC₆ hydroxyalkyl, and wherein * dénotés the attachment point,

Q is a is phenyl, optionally substituted with one to five substituents, or a monocyclic 5membered or 6-membered heteroaromatic group containing 1 or 2 heteroatoms

-L- is a linker selected from -S-CH₂-, -CH₂-S-, -CH₂-CH₂-, -CH=CH-, and C—C

Ri is selected from H, C_rC₆ alkyl; C_rC₆ alkyl(C₃-C₈)cycloalkyl; C_rC₆ hydroxyalkyl, CH₂CN, CH₂C(O)NH₂, Cf-C₆ arylalkyl, and C_rC₆ alkyl-heterocycloalkyl, with the proviso that the compound is not 1 H-Benzimidazole, 2-[[(3-phenyl-1 H-1,2,4-triazol5-yl)thio]methyl]-; 1 H-Benzimidazole, 2-[[[3-(2-pyrazinyl)-1 H-1,2,4-triazol-5-yl]methyl]thio]-; 1H-Benzimidazole, 2-[[(3-phenyl-1 H-1,2,4-triazol-5-yl)methyl]thio]-; 1 H-Benzimidazole, 1ethyl-5-(1-piperidinylsulfonyl)-2-[[[3-(2-thienyl)-1 H-1,2,4-triazol-5-yl]thio]methyl]-; 1HBenzimidazole, 6-methyl-2-[[(3-phenyl-1 H-1,2,4-triazol-5-yl)thio]methyl]-; 1 H-Benzimidazole, 2-[[[3-(3-pyridinyl)-1 H-1,2,4-triazol-5-yl]methyi]thio]-; lmidazo[1,2-a]pyridine, 8-methyl-2-[[(3 phenyl-1 H-1,2,4-triazol-5-yl)thio]methyl]-; lmidazo[1,2-a]pyridine, 6-chloro-2-[[[3-(2-thienyl)1 H-1,2,4-triazol-5-yl]thio]methyl]-; 1 H-Benzimidazole, 2-[[[3-(4-pyridinyl)-1 H-1,2,4-triazol-5yl]methyl]thio]-; lmidazo[1,2-a]pyridine, 6-methyl-2-[[(3-phenyl-1 H-1,2,4-triazol-5yl)thio]methyl]-; 1 H-Benzimidazole, 2-[[[3-(2-pyridinyl)-1 H-1,2,4-triazol-5-yl]methyl]thio]-; lmidazo[1,2-a]pyridine, 6-chloro-2-[[(3-phenyl-1H-1,2,4-triazol-5- yl)thio]methyl]-; 3Hlmidazo[4,5-b]pyridine, 2-[[(3-phenyl-1 H-1,2,4-triazol-5-yl)thio]methyl]-; or 1HBenzimidazole, 2-[[[3-(2-furanyl)-1 H-1,2,4-triazol-5-yl]methyl]thio]-;

and tautomers and pharmaceutically acceptable salts thereof, and polymorphie forms thereof, with the proviso that when the linker (L) is -CH₂-S- then HET-1 is neither imidazo[1,2-a]pyridine nor imidazo[1,2-a]pyrimidine.

2. The compound of Claim 1 in which HET-1 is an imidazo[1,2-a]pyrimidine moiety.

3. The compound of Claim 1 in which HET-1 is a [1,2,4]triazolo[1,5-a]pyridine moiety.

4. The compound of Claim 1 in which HET-1 is an imidazo[1,2-a]pyridine moiety.

5. The compound of Claim 1 in which HET-1 is an imidazo[4,5-b]pyrimidine moiety.

6. The compound of Claim 1 in which HET-1 is a pyrazolo[1,5-a]pyridine moiety.

7. The compound of Claim 1 in which HET-1 is a [1,2,4]Triazolo[1,5-a]pyrimidine moiety.

8. The compound of Claim 1 in which HET-1 is a [1,2,4]Triazolo[1,5-a]pyrazine moiety.

9. The compound of Claim 1 in which HET-1 is a [1,2,4]Triazolo[1,5-c]pyrimidine moiety.

10. The compound of any of claim 1-9 wherein Q is selected from the group consisting of phenyl, thiophene, furane, thiazole, pyrazole, pyridine, pyrimidine and pyrazine.

11. The compound of any one of Claim 1-10 wherein -L- is -S-CH₂-

12. The compound of any one of Claim 1-10 wherein -L- is -CH₂-S-

13. The compound of any one of Claim 1-10 wherein -L- is -CH₂-CH₂-

14. The compound of any one of Claim 1-10 wherein -L- is -CH=CH-

-C—C-

15. The compound of any of Claim 1-10 wherein-L-is

16. The compound of any one of Claim 1-15 wherein R1 is hydrogen

17. The compound of any one of Claim 1-15 wherein R1 is not hydrogen

18. The compound of any one of Claim 1-17 wherein R₂, R₃, R₄, R₅ and R₆ are ail hydrogen.

19. The compound of any one of Claim 1-17 wherein at least one of R₂, R₃, R₄, Rs and R₆ is Cr

C₆ alkoxy such as methoxy.

20. The compound of any one of Claim 1-17 wherein at least one of R₂, R₃, R₄, R₅ and R₆ is halogen such as chlorine or fluorine.

21. The compound of any one of Claim 1-20 wherein R2, R3 and R4 are ail hydrogen.

22. The compound of any one of Claim 1-20 wherein at least one of R2, R3 and R4 is Cf-C₆alkyl such as methyl.

23. The compound of any one of Claim 1-20 wherein at least one of R2, R3 and R4 is halogen such as chlorine or bromine.

24. The compound of claim 1, wherein the compound is selected from the group consisting of: 8-Methoxy-5-methyl-2-(5-phenyl-2H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]triazolo[1,5a]pyridine; 5-Methyl-2-(5-phenyl-2H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]triazolo[1,5ajpyridine; 5-Methyl-2-(1-methyl-5-phenyl-1 H-[1,2,4]triazol-3-ylsulfanylmethyl)- [1.2.4] triazolo[1,5-a]pyridine; 8-Methoxy-5-methyl-2-[2-(2-methyl-5-phenyl-2H-[1,2,4]triazol3-yl)-ethyl]~[1,2,4]triazolo[1,5-a]pyridine; 8-Methoxy-5-methyl-2-[2-(2-methyl-5-phenyl-2H- [1.2.4] triazol-3-yl)-ethyl]-[1,2,4]triazolo[1,5-a]pyridine; 8-Methyl-2-[2-(2-methyl-5-phenyl-2H- [1.2.4] triazol-3-yl)-ethyl]-[1,2,4]triazolo[1,5-a]pyridine; 5,7-Dimethyl-2-[2-(2-methyl-5-phenyl2H-[1,2,4]triazol-3-yl)-ethyl]-[1,2,4]triazolo[1,5-a]pyrimidine; 5,8-Dimethyl-2-[2-(2-methyl-5phenyl-2H-[1,2,4]triazol-3-yl)-ethyl]-[1,2,4]triazolo[1,5-a]pyrazine; 8-Methoxy-5-methyl-2-[2(5-phenyl-2-propyl-2H-[1,2,4]triazol-3-yl)-ethyl]-[1,2,4]triazolo[1,5-a]pyridine; 5-Methyl-2-[2(2-methyl-5-phenyl-2H-[1,2,4]triazol-3-yl)-ethyl]-[1,2,4]triazolo[1,5-a]pyridine; 8-Methoxy-2[2-(2-methyl-5-phenyl-2H-[1,2,4]triazol-3-yl)-ethyl]-[1,2,4]triazolo[1,5-a]pyridine; {5-(2-(8Methoxy-5-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-ethyl]-3-phenyl-[1,2,4]triazol-1-yl}-acetic acid ethyl ester; 2-{5-[2-(8-Methoxy-5-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-ethyl]-3phenyl-[1,2,4]triazol-1-yl}-ethanol; 5,8-Dimethyl-2-[2-(2-methyl-5-phenyl-2H-[1,2,4]triazol-3yl)-ethyl]-[1,2,4]triazolo[1,5-a]pyridine; 5,8-Dimethyl-2-[2-(2-methyl-5-phenyl-2H- [1.2.4] triazol-3-yl)-ethyl]-[1,2,4]triazolo[1,5-c]pyrimidine; 8-Ethyl-5-methyl-2-[2-(2-methyl-5phenyl-2H-[1,2,4]triazol-3-yl)-ethyl]-[1,2,4]triazolo[1,5-a]pyridine; 8-Ethyl-5-methyl-2-[2-(5phenyl-2-propyl-2H-[1,2,4]triazol-3-yl)-ethyl]-[1,2,4]triazolo[1,5-a]pyridine; 8-Ethyl-2-[2-(2isopropyl-5-phenyl-2H-[1,2,4]triazol-3-yl)-ethyl]-5-methyl-[1,2,4]triazolo[1,5-a]pyridine; 3-{5[2-(8-Methoxy-5-methyl-[1,2,4]triazolo[1,5-a]py ridi n-2-y l)-ethy l]-3-pheny l-[ 1,2,4]triazol-1 -yl}propionitrile; 3-{5-[2-(8-Ethyl-5-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-ethyl]-3-phenyl- [1.2.4] triazol-1-yl}-propionitrile; 2-[2-(2-lsopropyl-5-phenyl-2H-[1,2,4]triazol-3-yl)-ethyl]-8methoxy-5-methyl-[1,2,4]triazolo[1,5-a]pyridine; 3-{5-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5a]pyrazin-2-yl)-ethyl]-3-phenyl-[1,2,4]triazol-1-yl}-propionitrile; 3-{2-[2-(8-Ethyl-5-methyl- [1.2.4] triazolo[1,5-a]pyridin-2-yl)-ethyl]-4-phenyl-imidazol-1-yl}-propylamine; 3-{5-[2-(5,8Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-ethyl]-3-phenyl-[1,2,4]triazol-1-yl}-propylamine; 2{2-[2-(2-Methoxy-ethyl)-5-phenyl-2H-[1,2_l4]triazol-3-yl]-ethyl}-5,8-dimethyl-[1,2,4]triazolo[1,5a]pyrazine; and 8-Methoxy-2-{2-[2-(2-methoxy-ethyl)-5-phenyl-2H-[1,2,4]triazol-3-yl]-ethyl}5-methyl-[1,2,4]triazolo[1,5-a] py ridi ne and pharmaceutically acceptable salts thereof.

25. A compound of any one of claims 1 to 24, but without proviso, for use as a médicament.

26. A compound of any one of claims 1 to 24 but without proviso, for use in the treatment of a neurodegenerative or psychiatrie disorder, alone or in combination with one or more neuroleptic agents such as sertindole, olanzapine, rispéridone, quetiapine, aripiprazole, haloperidol, clozapine, ziprasidone and osanetant, wherein the neurodegenerative disorder is selected from the group consisting of Alzheimer's disease, multi-infarct dementia, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumors or cérébral trauma, dementia associated with Huntington's disease or Parkinson’s disease, or AIDS-related dementia; delirium; amnestic disorder; post-traumatic stress disorder; mental retardation; a learning disorder, for example reading disorder, mathematics disorder, or a disorder of written expression; attention-deficit/hyperactivity disorder; and age-related cognitive décliné, and the psychiatrie disorder is selected from the group consisting of schizophrenia, for example of the paranoid, disorganized, catatonie, undifferentiated, or residual type; schizophreniform disorder; schizoaffective disorder, for example of the delusional type or the dépressive type; delusional disorder; substanceinduced psychotic disorder, for example psychosis induced by alcohol, amphétamine, cannabis, cocaïne, hallucinogens, inhalants, opioids, or phencyclidine; personality disorder ofthe paranoid type; and personality disorder ofthe schizoid type.

27. A compound of any one of claims 1 to 24 but without proviso, for use in the treatment of a drug addiction in a mammal, including a human, such as an alcohol, amphétamine, cocaïne, or opiate addiction.

28. A compound of any one of claims 1 to 24 but without proviso, for the préparation of a médicament for use in the treatment of a drug addiction in a mammal, including a human, such as an alcohol, amphétamine, cocaïne, or opiate addiction.

29. A compound of any one of claims'1 to 24 but without proviso, for the préparation of a médicament for use in the treatment of a neurodegenerative or psychiatrie disorder, wherein the neurodegenerative disorder is selected from the group consisting of Alzheimer's disease, multi-infarct dementia, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumors or cérébral trauma, dementia associated with Huntington's disease or Parkinson's disease, or AIDS-related dementia; delirium; amnestic disorder; post-traumatic stress disorder; mental retardation; a learning disorder, for example reading disorder, mathematics disorder, or a disorder of written expression; attention-deficit/hyperactivity disorder; and age-related cognitive décliné, and the psychiatrie disorder is selected from the group consisting of schizophrenia, for example of the paranoid, disorganized, catatonie, undifferentiated, or residual type; schizophreniform disorder; schizoaffective disorder, for example ofthe delusional type or the dépressive type;

delusional disorder; substance-induced psychotic disorder, for example psychosis induced by alcohol, amphétamine, cannabis, cocaïne, hallucinogens, inhalants, opioids, or

5 phencyclidine; personality disorder of the paranoid type; and personality disorder of the schizoid type.

30. A compound for the préparation of a médicament for use in the treatment according to claim 25 wherein the treatment of psychiatrie disorders comprises co-administration of a

10 neuroleptic agent such as sertindole, olanzapine, rispéridone, quetiapine, aripiprazole, haloperidol, clozapine, ziprasidone and osanetant.

31. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1 to 24 but without proviso, and one or more pharmaceutically

15 acceptable carriers, diluents and excipients.