WO2013107856A1 - Imidazole derivatives as pde10a enzyme inhibitors - Google Patents

Description

Imidazole derivatives as PDE10A enzyme inhibitors

Field of the Invention

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

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 nucleotides 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 nucleotide phosphodiesterases (PDEs) via hydrolysis of the cyclic nucleotides into their respective nucleotide monophosphates.

Phosphodieasterase 10A (PDE10A) is a dual-specificity phosphodiesterase that can convert both cAMP to AMP and cGMP to GMP (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, 1 13-126). Studies indicate that within the brain, PDE10 expression is expressed at high levels by the medium spiny neurons (MSN) of the caudate nucleus, the accumbens nucleus and the corresponding neurons of the olfactory tubercle. MSN express two functional classes of neurons: the Di class expressing Di dopamine receptors and the D₂ class expressing D₂ dopamine receptors. The Di class of neurons is part of the '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.

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 all effective antipsychotic drugs antagonise D₂ receptors. The effects of D₂ are likely to be mediated primarily through neurons in the striatum, nucleus accumbens and olfactory tubercle, since these areas receive the densest dopaminergic projections and have the strongest expression of D₂ receptors (Konradi, C. and Heckers, S. Society of Biological Psychiatry, 2001 , 50, 729-742). Because PDE10A, in this context, has the desired expression profile with high and relatively specific expression in neurons in striatum, nucleus accumbens and olfactory tubercle, PDE10A inhibition is likely to have effects similar to D₂ receptor antagonism and therefore have antipsychotic effects. While PDE10A inhibition is expected to mimic D₂ receptor antagonism in part, it might be expected to have a different profile. The D₂ receptor has signaling components besides cAMP (Neve, K. A. et al. Journal of Receptors and Signal Transduction 2004, 24, 165-205), wherefore interference with cAMP through PDE10A inhibition may reduce the risk of the extrapyramidal side effects that are seen with strong D₂ antagonism. Conversely, PDE10A inhibition may have some effects not seen with D₂ receptor antagonism. PDE10A is also expressed in Di receptors expressing striatal neurons (Seeger, T. F. et al. Brain Research, 2003, 985, 1 13-126).

Further, since Di receptor agonism leads to stimulation of adenylate cyclase and resulting increase in cAMP levels, PDE10A inhibition is likely to also have effects that mimic Di receptor agonism. Finally, PDE10A inhibition will not only increase cAMP in cells, but might also be expected to increase cGMP levels, since PDE10A is a dual specificity phosphodiesterase. cGMP activates a number of target protein in cells like cAMP and also interacts with the cAMP signaling 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 reduction of amphetamine induced hyperactivity was insignificant (WO 03/093499). These models suggest that PDE10A inhibition has the classic antipsychotic potential that would be expected from the theoretical considerations outlined above. WO 03/093499 further discloses the use of selective PDE10 inhibitors for the treatment of associated neurologic and psychiatric disorders. Furthermore, PDE10A inhibition reverses subchronic PCP-induced deficits 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 deficits associated with schizophrenia.

The tissue distribution of PDE10A indicates that PDE10A inhibitors can be used to raise levels of cAMP and/or cGMP within cells that express the PDE10A enzyme, especially neurons that comprise the basal ganglia, and the PDE10A inhibitors of the present invention would therefore be useful in treating a variety of associated neuropsychiatric conditions involving the basal ganglia such as neurological and psychiatric disorders, schizophrenia, bipolar disorder, psychosis and obsessive compulsive disorder, and may have the benefit of not possessing unwanted side effects, which are associated with the current therapies on the market.

Furthermore, recent publications (WO 2005/120514, WO 2005012485, Cantin et al, Bioorganic & Medicinal Chemistry Letters 17 (2007) 2869-2873) suggest that PDE10A inhibitors may be useful for treatment of obesity and non-insulin dependent diabetes.

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

With respect to inhibitors of PDE10A, EP 1250923 discloses the use of selective PDE10 inhibitors in general, and papaverine in particular, for the treatment of certain neurologic and psychiatric disorders.

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 06/1 1040 discloses substituted quinazoline and isoquinoline compounds that serve as inhibitors of PDE10. US 20050182079 discloses substituted tetrahydroisoquinolinyl derivatives of quinazoline and isoquinoline that serve as effective phosphodiesterase (PDE) inhibitors. In particular, US 20050182079 relates to said compounds, which are selective inhibitors of PDE10. Analogously, US 20060019975 discloses piperidine derivatives of quinazoline and isoquinoline that serve as effective phosphodiesterase (PDE) inhibitors. US 20060019975 also relates to compounds that are selective inhibitors of PDE10. WO 06/028957 discloses cinnoline derivatives as inhibitors of PDE10 for the treatment of psychiatric and neurological syndromes. WO09/152825 discloses phenylimidazole derivatives as compounds that serve as inhibitors of PDE10.

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

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

Summary of the Invention

The objective of the present invention is to provide compounds that are selective PDE10A enzyme inhibitors.

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 therapies for neurological and psychiatric disorders.

Further objectives of the invention will become apparent upon reading the present specification. Accordingly, in a first embodiment (E1 ) the present invention relates to compounds of formula I (Compound I)

wherein

n is 0 or 1 ;

X is selected from the group consisting of CH, CF, COCH3, COH, and N; with the limitation that no more than one X is N;

R5 and R6 are each selected independently from the group consisting of H; C1 - C6 alkyl such as methyl, ethyl, 1 -propyl, 2-propyl, isobutyl; C1 -C6 alkyl(C3- C8)cycloalkyl such as cyclopropylmethyl; C1 -C6 hydroxyalkyl such as hydroxyethyl; C1 -C6 alkoxy such as methoxy and ethoxy; CH2CN; CH2C(O)NH2 ;C1 -C6 arylalkyi such as benzyl and 4-chlorobenzyl; and C1 -C6 alkyl-heterocycloalkyl such as tetrahydropyran-4-yl-methyl and 2-morpholin-4-yl- ethyl; halogen such as F; and hydroxy;

R7 and R8 are each selected independently from the group consisting of H, OH, F, CH3, and OCH3;

L is a linker of the form -C(R1 )(R2)-C(R3)(R4)- wherein R1 , R2, R3 and R4 independently of each other are selected from the group consisting of hydrogen, methyl and fluorine with the limitation that at least one of R1 , R2, R3 and R4 is methyl or fluorine;

HET 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

HET optionally can be substituted with up to three substituents R9, R10 and R1 1 individually selected from the group consisting of H; C1 -C6 alkyl such as methyl; halogen such as chlorine, flour or bromine; cyano; halo(C1 -C6)alkyl such as trifluoromethyl; aryl such as phenyl; alkoxy, preferably C1 -C6 alkoxy, such as methoxy, dimethoxy, ethoxy, methoxy-ethoxy and ethoxy-methoxy, and C1 -C6 hydroxyalkyl such as CH₂CH₂OH; and

"^*" denotes the attachment point and a pharnnaceutically acceptable acid addition salt of Connpound I, a racemic mixture of Compound I, or the corresponding enantiomer and/or optical isomer of Compound I, and polymorphic forms of Compound I as well as tautomeric forms of Compound I. Detailed Description of the Invention

Embodiments of the invention

In a first embodiment (E1 ) the present invention relates to compounds of formula I (Compound I)

wherein

n is 0 or 1 ;

X is selected from the group consisting of CH, CF, COCH3, COH, and N; with the limitation that no more than one X is N;

R5 and R6 are each selected independently from the group consisting of H; C1 - C6 alkyl such as methyl, ethyl, 1 -propyl, 2-propyl, isobutyl; C1 -C6 alkyl(C3- C8)cycloalkyl such as cyclopropylmethyl; C1 -C6 hydroxyalkyl such as hydroxyethyl; C1 -C6 alkoxy such as methoxy and ethoxy; CH2CN; CH2C(O)NH2 ;C1 -C6 arylalkyl such as benzyl and 4-chlorobenzyl; and C1 -C6 alkyl-heterocycloalkyl such as tetrahydropyran-4-yl-methyl and 2-morpholin-4-yl- ethyl; halogen such as F; and hydroxy; R7 and R8 are each selected independently from the group consisting of H, OH, F, CH3, and OCH3;

L is a linker of the form -C(R1 )(R2)-C(R3)(R4)- wherein R1 , R2, R3 and R4 independently of each other are selected from the group consisting of hydrogen, methyl and fluorine with the limitation that at least one of R1 , R2, R3 and R4 is methyl or fluorine;

HET 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

HET optionally can be substituted with up to three substituents R9, R10 and R1 1 individually selected from the group consisting of H; C1 -C6 alkyl such as methyl; halogen such as chlorine, flour or bromine; cyano; halo(C1 -C6)alkyl such as trifluoromethyl; aryl such as phenyl; alkoxy, preferably C1 -C6 alkoxy, such as methoxy, dimethoxy, ethoxy, methoxy-ethoxy and ethoxy-methoxy, and C1 -C6 hydroxyalkyl such as CH₂CH₂OH; and

"^*" denotes the attachment point

and a pharmaceutically acceptable acid addition salt of Compound I, a racemic mixture of Compound I, or the corresponding enantiomer and/or optical isomer of Compound I, and polymorphic forms of Compound I as well as tautomeric forms of Compound I. In an embodiment (E2) of (E1 ) n=0.

In an embodiment (E3) of (E1 ) or (E2) R5 and R6 are hydrogen.

In an embodiment (E4) of (E1 ) to (E3) and X is CH, CF or N.

In an embodiment (E5) of (E4) X is selected from the group consisting of CH, CF and N; and HET is selected from the group consisting of:

wherein "^*" denotes the attachment point.

When X is CH the compound of embodiment (E5) is a compound of formula (III):

In an embodiment (E6) of (E1 ) to (E5) HET is selected from the group consisting of [1 ,2,4]triazolo[1 ,5-a]pyrazine, [1 ,2,4]triazolo[1 ,5-a] pyridine, imidazo[1 ,2-a]pyridine, imidazo[4,5-b]pyrimidine; pyrazolo[1 ,5-a] pyridine, [1 ,2,4]Triazolo[1 ,5-a]pyrimidine, [1 ,2,4]Triazolo[1 ,5-c]pyrimidine, and imidazo[1 ,2-a]pyrimidine.

In an embodiment (E7) of (E6) HET is selected from the group consisting of 5,8- Dimethyl-[1 ,2,4]triazolo[1 ,5-a]pyrazine; 5,8-Dimethyl-[1 ,2,4]triazolo[1 ,5-c]pyrazine, 5,8- Dimethyl-[1 ,2,4]triazolo[1 ,5-a]pyridine, 5-methyl-[1 ,2,4]triazolo[1 ,5-a]pyridine, and (5- Methyl-[1 ,2,4]triazolo[1 ,5-a]pyrazin-8-yl)-methanol.

In an embodiment (E8) of any of the previous embodiments R1 is methyl and R2, R3 and R4 are hydrogen.

In an embodiment (E9) of any of the previous embodiments R1 and R2 are methyl and R3 and R4 are hydrogen.

In an embodiment (E10) of any of the previous embodiments R1 , R2 and R3 are methyl and R4 is hydrogen. In an embodiment (E1 1 ) of any of the previous embodiments R1 , R2, R3 and R4 are methyl.

In an embodiment (E12) of any of the previous embodiments R1 is hydrogen and R2, R3 and R4 are methyl.

In an embodiment (E13) of any of the previous embodiments R1 and R2 are hydrogen, R3 and R4 are methyl.

In an embodiment (E14) of any of the previous embodiments R1 , R2 and R3 are hydrogen and R4 is methyl.

In an embodiment (E15) of any of the previous embodiments R1 and R4 are methyl and R2 and R3 are hydrogen.

In an embodiment (E16) of any of the previous embodiments R1 is flourine and R2, R3 and R4 are hydrogen.

In an embodiment (E17) of any of the previous embodiments R1 and R2 are flourine and R3 and R4 are hydrogen.

In an embodiment (E18) of any of the previous embodiments R1 , R2 and R3 are flourine and R4 is hydrogen.

In an embodiment (E19) of any of the previous embodiments R1 , R2, R3 and R4 are flourine.

In an embodiment (E20) of any of the previous embodiments R1 is hydrogen and R2, R3 and R4 are flourine.

In an embodiment (E21 ) of any of the previous embodiments R1 and R2 are hydrogen, R3 and R4 are flourine.

In an embodiment (E22) of any of the previous embodiments R1 , R2 and R3 are hydrogen and R4 is flourine.

In an embodiment (E23) of any of the previous embodiments R1 and R4 are flourine and R2 and R3 are hydrogen.

In an embodiment (E24) of any of the previous embodiments R1 is methyl and R2, R3 and R4 are flourine.

In an embodiment (E25) of any of the previous embodiments R1 , R2 and R3 are flourine and R4 is methyl.

In an embodiment (E26) of any of the previous embodiments R1 and R2 are fluorine, R3 are methyl and R4 is hydrogen. In an embodiment (E27) of any of the previous embodiments R1 and R3 are fluorine, R2 is hydrogen and R4 is methyl.

In an embodiment (E28) of any of the previous embodiments R1 is hydrogen, R2 is methyl, and R3 and R4 are flourine.

In an embodiment (E29) of any of the previous embodiments R1 and R2 are flourine, R3 and R4 are methyl.

In an embodiment (E30) of any of the previous embodiments R1 and R2 are methyl, R3 and R4 are flourine.

In an embodiment (E31 ) of any of the previous embodiments R1 and R3 are methyl, R2 and R4 are fluorine.

In an embodiment (E32) of any of the previous embodiments R1 is fluorine, R2 is hydrogen, R3 and R4 are methyl.

In an embodiment (E33) of any of the previous embodiments R1 is flourine, R2 and R3 are methyl, and R4 is hydrogen.

In an embodiment (E34) of any of the previous embodiments R1 is hydrogen, R2 and R3 are methyl and R4 is flourine.

In an embodiment (E35) of any of the previous embodiments R1 and R2 are methyl, R3 is flourine and R4 is hydrogen.

In an embodiment (E36) of any of the previous embodiments R1 is flourine, R2 R3 and R4 are methyl.

In an embodiment (E37) of any of the previous embodiments R1 , R2 and R3 are methyl and R4 is fluorine.

In an embodiment (E38) of any of the previous embodiments the compound of formula I or a pharmaceutically acceptable acid addition salt thereof is for use as a medicament. An embodiment (E39) of any of the previous embodiments provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I and a pharmaceutically acceptable carrier, diluent or excipient.

An embodiment (E40) provides the use of a compound of formula I, or a pharmaceutically acceptable acid addition salt thereof, for the preparation of a medicament for the treatment of a neurodegenerative or psychiatric disorder.

An embodiment (E41 ) 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 present invention provides a method of treating a subject suffering from a psychiatric disorder, comprising administering to the subject a therapeutically effective amount of a compound of formula I. In another embodiment, the present invention provides a method of treating a subject suffering from a drug addiction, such as an alcohol, amphetamine, cocaine, or opiate addiction.

In separate embodiments of the invention, the compound of formula I is selected amon the following specific compounds:

In separate embodiments of the invention, the compound of formula I is selected the group of compounds consisting of 2-[(R)-2-(5,8-Dimethyl-[1 ,2,4]triazolo[1 ,5-a]pyrazin-2- yl)-propyl]-5H-imidazo[2,1 -ajisoindole; 2-[(S)-2-(5,8-Dimethyl-[1 ,2,4]triazolo[1 ,5- a]pyrazin-2-yl)-propyl]-5H-imidazo[2,1 -ajisoindole; 2-[(R)-2-(5,8-Dimethyl- [1 ,2,4]triazolo[1 ,5-a]pyrazin-2-yl)-1 -methyl-ethyl]-5H-imidazo[2,1 -ajisoindole

2-[(S)-2-(5,8-Dimethyl-[1 ,2,4]triazolo[1 ,5-a]pyrazin-2-yl)-1 -methyl-ethyl]-5H-imidazo[2,1 - ajisoindole; 2-[(1 S,2S)-2-(5,8-Dimethyl-[1 ,2,4]triazolo[1 ,5-a]pyrazin-2-yl)-1 -methyl- propyl]-5H-imidazo[2,1 -a]isoindole; 2-[(1 R,2R)-2-(5,8-Dimethyl-[1 ,2,4]triazolo[1 ,5- a]pyrazin-2-yl)-1 -methyl-propyl]-5H-imidazo[2,1 -a]isoindole; 2-[(1 S,2R)-2-(5,8-Dimethyl- [1 ,2,4]triazolo[1 ,5-a]pyrazin-2-yl)-1 -methyl-propyl]-5H-imidazo[2,1 -a]isoindole; 2- [(1 R,2S)-2-(5,8-Dimethyl-[1 ,2,4]triazolo[1 ,5-a]pyrazin-2-yl)-1 -methyl-propyl]-5H- imidazo[2,1 -a]isoindole; 2-[(R)-2-(5,8-Dimethyl-[1 ,2,4]triazolo[1 ,5-a]pyrazin-2-yl)-2- fluoro-ethyl]-5H-imidazo[2,1 -a]isoindole; 2-[(S)-2-(5,8-Dimethyl-[1 ,2,4]triazolo[1 ,5- a]pyrazin-2-yl)-2-fluoro-ethyl]-5H-imidazo[2,1 -a]isoindole; 2-[(R)-2-(5,8-Dimethyl- [1 ,2,4]triazolo[1 ,5-a]pyrazin-2-yl)-1 -fluoro-ethyl]-5H-imidazo[2,1 -a]isoindole; 2-[(S)-2- (5,8-Dimethyl-[1 ,2,4]triazolo[1 ,5-a]pyrazin-2-yl)-1 -fluoro-ethyl]-5H-imidazo[2,1 - a]isoindole; 2-[(1 S,2S)-2-(5,8-Dimethyl-[1 ,2,4]triazolo[1 ,5-a]pyrazin-2-yl)-1 ,2-difluoro- ethyl]-5H-imidazo[2,1 -a]isoindole; 2-[(1 S,2R)-2-(5,8-Dimethyl-[1 ,2,4]triazolo[1 ,5- a]pyrazin-2-yl)-1 ,2-difluoro-ethyl]-5H-innidazo[2,1 -a]isoindole; 2-[2-(5,8-Dimethyl- [1 ,2,4]triazolo[1 ,5-a]pyrazin-2-yl)-2,2-difluoro-ethyl]-5H-innidazo[2,1 -a]isoindole; and 2- [2-(5,8-Dimethyl-[1 ,2,4]triazolo[1 ,5-a]pyrazin-2-yl)-1 ,1 -difluoro-ethyl]-5H-imidazo[2,1 - a]isoindole.

In an embodiment of any of the previously mentioned embodiments one or more of the hydrogen atoms of the compound are replaced by deuterium. Definition of Substituents

As used in the context of the present invention, the terms "halo" and "halogen" are used interchangeably and refer to fluorine, chlorine, bromine or iodine.

R1 -R1 1 is short notation for the group consisting R1 , R2, R3, R4, R5, R6, R7, R8, R9, R10 and R1 1 .

Subsets of R1 -R1 1 are defined similarly, e.g. R5-R7 means the group consisting R5, R6, and R7.

The numbering of the substituents R1 -R1 1 may also be specified by subscript, i.e. Rr R₇. Similarly the number of atoms (e.g. carbon atoms) may either be indicated by C1 - C6 or by C₁ -C6, i.e. one to six carbon atoms. The term "C1-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 n-hexyl. The expression "C1-C6 hydroxyalkyl" refers to a C1-C6 alkyl group as defined above which is substituted with one hydroxy group. The term "halo(Ci-C6)alkyl" refers to a C1-C6 alkyl group as defined above which is substituted with up to three halogen atoms, such as trifluoromethyl.

The expression "C1-C6 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" includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. The expression "C1-C6 alkyl(C3-C8)cycloalkyl" refers to a C3- Cs cycloalkyl as defined above which is substituted with a straight-chain or branched C1-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. 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 "C1-C6 alkyl-heterocycloalkyl" refers to a heterocycloalkyl as defined above which is substituted with a C1-C6 alkyl group. Examples of such groups include, but are not limited to, tetrahydropyran-4-yl-methyl and 2-morpholin-4-yl-ethyl.

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

The term "C1-C6 arylalkyi" refers to an aryl as defined above which is substituted with a straight-chain or branched C1-C6 alkyl. Examples of such groups include, but are not limited to, benzyl and 4-chlorobenzyl.

Additionally, the present invention further provides certain embodiments of the invention, which are described below.

Table 1 lists compounds of the invention and the corresponding IC₅0 values determined as described in the section "PDE10A inhibition assay". Each of the compounds constitutes an individual embodiment, of the present invention:

Table 1 : Compounds of the invention and IC₅0 values

In a particular embodiment of the present invention the compounds of the present invention have an IC₅0 value of less than 20 nM, such as in the range of 0.1 - 20 nM, particularly in the range of 0.1 - 10 nM, such as in the range of 0.1 - 5 nM or in the range of 0.1 - 1 nM.

Pharmaceutically Acceptable Salts

The present 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.

Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, sulfamic, nitric acids and the like. Representative 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. Sci. 1977, 66, 2, the contents of which are hereby incorporated by reference.

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

Pharmaceutical compositions

The present 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 present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of one of the specific 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 parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) routes. It will be appreciated that the route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient.

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 ingredient such as sustained or prolonged release according to methods well known in the art. Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.

Pharmaceutical compositions for parenteral administration include sterile aqueous and nonaqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile 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 depend upon the frequency and mode of administration, the sex, age, 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 evident 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 parenteral routes such as intravenous, intrathecal, intramuscular and similar administration, typical doses are in the order of half the dose employed for oral administration. The present invention also provides a process for making a pharmaceutical composition comprising admixing a therapeutically effective amount of a compound of formula I and at least one pharmaceutically acceptable carrier or diluent. In an embodiment, of the present invention, the compound utilized in the aforementioned process is one of the specific compounds disclosed in the Experimental Section herein.

The compounds of this invention are generally utilized as the free substance or as a pharmaceutically acceptable salt thereof. One example is an acid addition salt 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 equivalent of a pharmaceutically acceptable acid. Representative examples of suitable organic and inorganic acids are described above.

For parenteral administration, solutions of the compounds of formula I in sterile 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 isotonic with sufficient saline or glucose. The aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The compounds of formula I may be readily incorporated into known sterile aqueous media using standard techniques known to those skilled in the art.

Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. Examples of solid carriers include lactose, terra alba, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, 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 present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, 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 emulsion. If a solid carrier is used for oral administration, the preparation 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 preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.

The pharmaceutical compositions of the invention may be prepared by conventional methods in the art. For example, tablets may be prepared by mixing the active ingredient with ordinary adjuvants and/or diluents and subsequently compressing the mixture in a conventional tabletting machine prepare tablets. Examples of adjuvants or diluents comprise: corn starch, potato starch, talcum, magnesium stearate, 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 ingredients. 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 psychiatric disorders.

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

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

In an embodiment the psychiatric disorder is selected from the group consisting of schizophrenia, for example of the paranoid, disorganized, catatonic, undifferentiated, or residual type; schizophreniform disorder; schizoaffective disorder, for example of the delusional type or the depressive type; delusional disorder; substance-induced psychotic disorder, for example psychosis induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opioids, or phencyclidine; personality disorder of the paranoid type; and personality disorder of the schizoid type.

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

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 episodes 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 preoccupation with obtaining the substance; using more of the substance than necessary to experience the intoxicating effects; and experiencing tolerance, withdrawal symptoms, and decreased motivation for normal life activities.

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

The compounds of formula I or pharmaceutically acceptable salts thereof may be used in combination with one or more other drugs (including typical and atypical antpsychotic agent) in the treatment of diseases or conditions for which the compounds of the present invention have utility, where the combination of the drugs together are safer or more effective than either drug alone. Additionally, the compounds of the present invention may be used in combination with one or more other drugs that treat, prevent, control, ameliorate, or reduce the risk of side effects or toxicity of the compounds of the present invention. 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 resistant to other known treatments.

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

The term "neuroleptic agent" as used herein refers to drugs, which have 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., risperidone), sertindole, olanzapine, quetiapine, osanetant and ziprasidone. Particularly preferred neuroleptic agents for use in the invention are sertindole, olanzapine, risperidone, quetiapine, aripiprazole, haloperidol, clozapine, ziprasidone and osanetant.

As used herein, and unless otherwise indicated, a "neurodegenerative disorder or condition" refers to a disorder or condition that is caused by the dysfunction and/or death of neurons in the central nervous system. The treatment of these disorders and conditions can be facilitated by administration of an agent which prevents the dysfunction or death of neurons at risk 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 all of these properties.

All 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 all examples, or exemplary language (including "for instance", "for example", "e.g.", and "as such") in the present specification 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.

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

The present invention includes all modifications and equivalents of the subject-matter recited in the claims appended hereto, as permitted by applicable law. Experimental Section

Preparation of the compounds of the invention

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

Compounds of formula I where R1 and R3 can be hydrogen, methyl or fluorine can be prepared by hydrogenation of the corresponding alkene of formula IV as shown in scheme 1 .

Scheme 1 Alkenes of formula IV can be prepared by wittig reactions by reaction of appropriately substituted phosphonium salts with appropriately substituted heteroaromatic imidazo aldehydes in a fashion similar to methods described in the literature, see e.g. WO 201 1072697, WO 201 1072696, US 20100016303 and WO 2009152825. Compounds of formula I where R1 or R2 can be hydrogen or fluorine can be prepared by conversion of a hydroxyl group as in compounds of formula V using an electrophilic flurorinating reagent like e.g. Diethylaminosulfur trifluoride (DAST) as described in scheme 2.

Scheme 2

Hydroxycompounds of formula V can be prepared by standard reactions described in the art like reduction of the corresponding ketone by e.g. sodium borohydride or by addition of an appropriately substituted organometallic reagent to the appropriately substituted heteroaromatic carbaldehyde or can be prepared by standard methods as described in standard works like and Houben-Weyl, Methoden der organischen Chemie (Methods of Organic Chennistry), Georg-Thieme-Verlag, Stuttgart and Organic Reactions, John Wiley & Sons, Inc. New York.

Compounds of formula I where R3 or R4 can be hydrogen or fluorine can be prepared by conversion of a hydroxyl group as in compounds of formula VI using an electrophilic flurorinating reagent like e.g. Diethylaminosulfur trif!uoride (DAST) as described in scheme 3.

Scheme 3

Hydroxycompounds of formula VI can be prepared by standard reactions described in the art like reduction of the corresponding ketone by e.g. sodium borohydride or by addition of an appropriately substituted organometallic reagent to the appropriately substituted heteroaromatic imidazo carbaldehyde or can be prepared by standard methods as described in standard works like and Houben-Weyl, Methoden der organischen Chemie (Methods of Organic Chemistry), Georg-Thieme-Verlag, Stuttgart and Organic Reactions, John Wiley & Sons, Inc. New York.

Compounds of formula I where R3 and R4 can be geminal fluorine can be prepared by conversion of a keto group as in compounds of formula VII using an electrophilic flurorinating reagent like e.g. Diethylaminosulfur trifluoride (DAST) as described in scheme 4.

Scheme 4 Ketones of fomula VII can be prepared by standard reactions described in the art like oxidation of the corresponding alhohol of fornnula VI by e.g. er periodinate oxidation reagent or by addition of an appropriately substituted organometallic reagent to the appropriately substituted heteroaronnatic innidazo ester or weinreb annide or can be prepared by standard methods as described in standard works like and Houben-Weyl, Methoden der organischen Chemie (Methods of Organic Chemistry), Georg-Thieme- Verlag, Stuttgart and Organic Reactions, John Wiley & Sons, Inc. New York.

Compounds of formula I where R1 and R2 can be geminal fluorine can be prepared by conversion of a keto group as in compounds of formula VIII using an electrophilic flurorinating reagent like e.g. Diethylaminosulfur trif!uoride (DAST) as described in scheme 5.

Scheme 5

Ketones of fomula VIII can be prepared by standard reactions described in the art like oxidation of the corresponding alhohol of formula V by e.g. er periodinate oxidation reagent or by addition of an appropriately substituted organometallic reagent to the appropriately substituted heteroaromatic carboxylic ester or weinreb amide or can be prepared by standard methods as described in standard works like and Houben-Weyl, Methoden der organischen Chemie (Methods of Organic Chemistry), Georg-Thieme- Verlag, Stuttgart and Organic Reactions, John Wiley & Sons, Inc. New York

General Methods

Analytical LC-MS data were obtained using the following method: A PE Sciex API 150EX instrument equipped with atmospheric pressure photo ionisation and a Shimadzu CBM-20A system was used. Column: 4.6 x 30 mm Waters Symmetry C18 column with 3.5 micro m particle size; Column temperature: 60°C; Solvent system: A = water/trifluoroacetic acid (99.95:0.05) and B = methanol/trifluoroacetic acid (99.95:0.05); 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/minute.

Preparative LC-MS-purification was performed on a PE Sciex API 150EX instrument with atmospheric pressure chemical ionization. Column: 50 X 20 mm YMC ODS-A with 5 micro m 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 detection.

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

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

Preparation of intermediates

2-(1 -Chloro-ethyl)-5,8-dimethyl-[1 ,2,4]triazolo[1,5-a]pyrazine

To a solution of Ethyl O-mesitylsulfonylacetohydroxamate (5.00 g, 17.5 mmol) in

1 ,4-Dioxane (29 mL, 380 mmol) cooled in an ice bath (freezes at 8-9 °C) was added 70% Perchloric acid (17.73 mL, 293.7 mmol) dropwise over 15 minutes, maintaining internal temperature below 15 °C. The mixture was then diluted with ice water (120 mL) to precipitate the product O-(mesitylsulfonyl)hydroxylamine which was filtered off, washed thoroughly with water, and immediately dissolved in (DCM 50 mL) while still wet (CAUTION! Explosive when dry). The organic layer was dried with MgSO4 and filtered.

The obtained solution of O-(mesitylsulfonyl)hydroxylamine was added dropwise to a solution of 3,6-Dimethyl-pyrazin-2-ylamine (2.07 g, 1 1 .7 mmol) in DCM (100 mL) cooled in an ice bath. The mixture was then warmed to room temperature over 15 minutes. LCMS indicated almost complete conversion to the aminated intermediate.

The solvent was evaporated and the residue was dissolved in Methanol (60 mL, 1000 mmol) followed by the addition of 1 ,8-Diazabicyclo[5.4.0]undec-7-ene (3.1620 mL, 21 .144 mmol) . The solution was stirred at RT for 5 mins where methyl 2- chloropropionate (1 .26 mL, 1 1 .7 mmol) was added and the solution stirred at RT for 48 hrs. The volatiles were removed in vacuo. Water was added and the organics extracted with EtOAc. The combined organics were washed with water, brine, dried (MgSO4) filtered and the volatiles removed in vacuo.

The residue was purified by flash chromatography Eluent EtOAc:Heptane, 1 :1 and the product fractions collected and evaporated to yield 2-(1 -Chloro-ethyl)-5,8- dimethyl-[1 ,2,4]triazolo[1 ,5-a]pyrazine (1 .52 g; Yield = 61 .0%; Purity = 99.3%).

[1 -(5,8-Dimethyl-[1,2,4]triazolo[1 ,5-a]pyrazin-2-yl)-ethyl] riphenyl^hosphonium chloride

2-(1 -Chloro-ethyl)-5,8-dimethyl-[1 ,2,4]triazolo[1 ,5-a]pyrazine (1 .52 g, 7.22 mmol) and Triphenylphosphine (2.10 g, 8.01 mmol) was dissolved in Acetonitrile (100 mL, 2000 mmol) and the mixture was dissolved in CH3CN (10 ml) and microwaved for 4 hours at 200 °C. Full conversion. (Yield: 4.04g, 55.7%)

2-[(E)-2-(5,8-Dimethyl-[1,2,4]triazolo[1 ,5-a]pyrazin-2-yl)^ropenyl]-5H-imidazo[2,1- a isoindole

To [1 -(5,8-Dimethyl-[1 ,2,4]triazolo[1 ,5-a]pyrazin-2-yl)-ethyl]-triphenyl-phosphonium; chloride (617 mg, 0.718 mmol) and 5H-lmidazo[2,1 -a]isoindole-2-carbaldehyde (130 mg, 0.72 mmol) in Ethanol (10 mL, 200 mmol) was added 1 ,8-diazabicyclo[5.4.0]undec- 7-ene (120 uL, 0.79 mmol), the reaction was stirred at RT for 48h. LCMS showed good conversion, purification by flash chromatography (Combi Flash) using a gradient of AcOEt to 5%Et3N/10%MeOH/85%AcOEt.fractions containing the product were isolated, pooeled and evaporated in vacuo to give the product (Yield: 95 mg; 92.8%) The following intermedicates can be prepared in a similar fashion:

2-[(E)-2-(5,8-Dimethyl-[1 ,2,4]triazolo[1 ,5-a]pyrazin-2-yl)-1 -methyl-vinyl]-5H-imidazo[2,1 - a]isoindole

Syntheses of compounds of the invention

Example 1

2-[2-(5,8-Dimethyl-[1 ,2,4]triazolo[1,5-a]pyrazin-2-yl)-propyl]-5H-imidazo[2,1 - a isoindole

2-[(E)-2-(5,8-Dimethyl-[1 ,2,4]triazolo[1 ,5-a]pyrazin-2-yl)-propenyl]-5H-imidazo[2,1 - a]isoindole (95 mg, 0.26 mmol) was dissolved in Methanol (9 mL, 200 mmol), Methylene chloride (1 mL, 20 mmol) and Acetic acid (1 mL, 20 mmol), and 10% Pd/C (1 :9, Palladium:carbon black, 30 mg) was added before the reaction was hydrogenated on Parr apparatus, 1 -3 bar. Filtered and concentrated and the product purified by silicagel chromatography on a Combi Flash. Fractions containing the product were combined to give 2-[2-(5,8-Dimethyl-[1 ,2,4]triazolo[1 ,5-a]pyrazin-2-yl)-propyl]-5H- imidazo[2,1 -a]isoindole (100%) 75 mg.

The following compounds can be prepared in an analogues fashion:

2-[2-(5,8-Dimethyl-[1 ,2,4]triazolo[1 ,5-a]pyrazin-2-yl)-1 -methyl-ethyl]-5H-imidazo[2,1 - a]isoindole

2-[2-(5,8-Dimethyl-[1 ,2,4]triazolo[1 ,5-a]pyrazin-2-yl)-2-fluoro-ethyl]-5H-imidazo[2,1 - a]isoindole

2-[2-(5,8-Dimethyl-[1 ,2,4]triazolo[1 ,5-a]pyrazin-2-yl)-1 -fluoro-ethyl]-5H-imidazo[2,1 - a]isoindole

2-[2-(5,8-Dimethyl-[1 ,2,4]triazolo[1 ,5-a]pyrazin-2-yl)-1 -methyl-propyl]-5H-imidazo[2,1 - a]isoindole Example 2

2-[2-(5,8-Dimethyl-[1 ,2,4]triazolo[1 ,5-a]pyrazin-2-yl)-2-fluoro-ethyl]-5H-imidazo[2,1 - a]isoindole and

2-[2-(5,8-Dimethyl-[1 ,2,4]thazolo[1 ,5-a]pyrazin-2-yl)-1 -fluoro-ethyl]-5H-imidazo[2,1 - a]isoindole

To a stirred solution of a mixture of 1 -(5,8-Dimethyl-[1 ,2,4]triazolo[1 ,5-a]pyrazin-2-yl)-2- (5H-imidazo[2,1 -a]isoindol-2-yl)-ethanol and 2-(5,8-Dimethyl-[1 ,2,4]triazolo[1 ,5- a]pyrazin-2-yl)-1 -(5H-imidazo[2,1 -a]isoindol-2-yl)-ethanol (1 mmol) in dichloromethane (10 mL) is added dropwise DAST (2 mmol) in dichloromethane (5 mL) at 0 °C. After addition, the reaction mixture is stirred at 25 °C for 24 h, and then the reaction is quenched by the slow addition of aqueous NaHCO3 solution until effervescence is completed. The dichloromethane layer is separated, dried over anhydrous Na2CO3, and filtered. The solvent is evaporated under reduced pressure, to obtain the corresponding compounds 2-[2-(5,8-Dimethyl-[1 ,2,4]triazolo[1 ,5-a]pyrazin-2-yl)-2-fluoro-ethyl]-5H- imidazo[2,1 -a]isoindole and 2-[2-(5,8-Dimethyl-[1 ,2,4]triazolo[1 ,5-a]pyrazin-2-yl)-1 - fluoro-ethyl]-5H-innidazo[2,1 -a]isoindole , which were isolated as solids by filtration and purified by simple washing with cold ethanol.

Example 3

2-[2-(5,8-Dimethyl-[1 ,2,4]triazolo[1 ,5-a]pyrazin-2-yl)-2,2-difluoro-ethyl]-5H-imidazo[2,1 - a]isoindole and

2-[2-(5,8-Dimethyl-[1 ,2,4]triazolo[1 ,5-a]pyrazin-2-yl)-1 ,1 -difluoro-ethyl]-5H-imidazo[2,1 - a]isoindole

To a stirred solution of a mixture of 1 -(5,8-Dimethyl-[1 ,2,4]triazolo[1 ,5-a]pyrazin-2-yl)-2- (5H-imidazo[2,1 -a]isoindol-2-yl)-ethanone and 2-(5,8-Dimethyl-[1 ,2,4]triazolo[1 ,5- a]pyrazin-2-yl)-1 -(5H-imidazo[2,1 -a]isoindol-2-yl)-ethanone (1 mmol) in

dichloromethane (10 mL) is added dropwise DAST (2 mmol) in dichloromethane (5 mL) at 0 °C. After addition, the reaction mixture is stirred at 25 °C for 24 h, and then the reaction is quenched by the slow addition of aqueous NaHCO₃ solution until

effervescence is completed. The dichloromethane layer is separated, dried over anhydrous Na2CO3, and filtered. The solvent is evaporated under reduced pressure, to obtain the corresponding compounds 2-[2-(5,8-Dimethyl-[1 ,2,4]triazolo[1 ,5-a]pyrazin-2- yl)-2,2-difluoro-ethyl]-5H-imidazo[2,1 -a]isoindole and 2-[2-(5,8-Dimethyl- [1 ,2,4]triazolo[1 ,5-a]pyrazin-2-yl)-1 ,1 -difluoro-ethyl]-5H-imidazo[2,1 -a]isoindole, which were isolated as solids by filtration and purified by simple washing with cold ethanol.

Example 4

2-r2-(5,8-Dimethyl-rt2,41triazolon,5-alpyrazin-2-yl)-1,2-difluoro-ethvn-5H- imidazor2,1 -alisoindole

To a stirred solution of a 1 -(5,8-Dimethyl-[1 ,2,4]triazolo[1 ,5-a]pyrazin-2-yl)-2-(5H- imidazo[2,1 -a]isoindol-2-yl)-ethane-1 ,2-diol (1 mmol) in dichloromethane (10 mL) is added dropwise DAST (2 mmol) in dichloromethane (5 mL) at 0 °C. After addition, the reaction mixture is stirred at 25 °C for 24 h, and then the reaction is quenched by the slow addition of aqueous NaHCO3 solution until effervescence is completed. The dichloromethane layer is separated, dried over anhydrous Na2CO3, and filtered. The solvent is evaporated under reduced pressure, to obtain the corresponding compound 2-[2-(5,8-Dimethyl-[1 ,2,4]triazolo[1 ,5-a]pyrazin-2-yl)-1 ,2-difluoro-ethyl]-5H-imidazo[2,1 - a]isoindole, which were isolated as solids by filtration and purified by simple washing with cold ethanol. Pharmacological 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, 109-1 17; Fujishige, K. et al. Eur J Biochem. 1999, 266, 1 1 18-1 127 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 overnight at room temperature, after which the cells are collected by centrifugation. Cells expressing PDE10A are resuspended in 12 mL (50 mM TRIS-HCI- pH8.0, 1 mM MgC and protease inhibitors). The cells are lysed by sonication, and after all cells are lysed, TritonXI OO 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 (sufficient to convert 20-25% of the cyclic nucleotide substrate), a buffer (50 mM HEPES7.6; 10mM MgCI₂; 0.02% Tween20), 0.1 mg/ml BSA, 225 pCi of ³H-labelled cyclic nucleotide substrate, tritium labeled cAMP to a final concentration of 5 nM and varying amounts of inhibitors. Reactions are initiated by addition of the cyclic nucleotide substrate, and reactions are allowed to proceed for one hr at room temperature 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 IC₅o values can be calculated using the Xlfit extension to EXCEL. In the context of the present invention the assay was performed in 60 uL assay buffer (50 mM HEPES pH 7.6; 10mM MgCI₂; 0.02% Tween20) containing enough PDE10A to convert 20-25% of 10 nM ³H-cAMP and varying amounts of inhibitors. Following a 1 hour incubation the reactions were terminated by addition of 15 uL 8 mg/mL yttrium silicate SPA beads (Amersham). The beads were allowed to settle for one hr in the dark before the plates were counted in a Wallac 1450 Microbeta counter. IC₅o values were calculated by non linear regression using XLfit (IDBS).

Results of the experiments showed that the tested compounds of the invention inhibit the PDE10A enzyme with IC₅o values below 10 nM.

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 special 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 of the 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 result recorded in the parallel PCP control group. The per cent responses are converted to per cent inhibition.

Results of the experiments showed that the tested compound 2-[2-(5,8-dimethyl- [1 ,2,4]triazolo[1 ,5-a]pyrazin-2-yl)-ethyl]-5H-imidazo[2,1 -a]isoindole is an in vivo active compound that inhibits the PCP induced hyperactivity

ED50 = 0.2 mg/kg;

Inhibition is 100% at 5 mg/kg.

Claims

Claims compounds of formula I (Compound I)

wherein

n is 0 or 1 ; X is selected from the group consisting of CH, CF, COCH3, COH, and N; with the limitation that no more than one X is N;

R5 and R6 are each selected independently from the group consisting of H; C1 - C6 alkyl such as methyl, ethyl, 1 -propyl, 2-propyl, isobutyl; C1 -C6 alkyl(C3- C8)cycloalkyl such as cyclopropylmethyl; C1 -C6 hydroxyalkyl such as hydroxyethyl; C1 -C6 alkoxy such as methoxy and ethoxy; CH2CN; CH2C(O)NH2 ;C1 -C6 arylalkyi such as benzyl and 4-chlorobenzyl; and C1 -C6 alkyl-heterocycloalkyl such as tetrahydropyran-4-yl-methyl and 2-morpholin-4-yl- ethyl; halogen such as F; and hydroxy;

R7 and R8 are each selected independently from the group consisting of H, OH, F, CH3, and OCH3;

L is a linker of the form -C(R1 )(R2)-C(R3)(R4)- wherein R1 , R2, R3 and R4 independently of each other are selected from the group consisting of hydrogen, methyl and fluorine with the limitation that at least one of R1 , R2, R3 and R4 is methyl or fluorine; HET 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

HET optionally can be substituted with up to three substituents R9, R10 and R1 1 individually selected from the group consisting of H; C1 -C6 alkyl such as methyl; halogen such as chlorine, flour or bromine; cyano; halo(C1 -C6)alkyl such as trifluoromethyl; aryl such as phenyl; alkoxy, preferably C1 -C6 alkoxy, such as methoxy, dimethoxy, ethoxy, methoxy-ethoxy and ethoxy-methoxy, and C1 -C6 hydroxyalkyl such as CH₂CH₂OH; and "^*" denotes the attachment point and a pharmaceutically acceptable acid addition salt of Compound I, a racemic mixture of Compound I, or the corresponding enantiomer and/or optical isomer of Compound I, and polymorphic forms of Compound I as well as tautomeric forms of Compound I.

2. The compound according to claim 1 wherein n=0.

3. The compound of claims 1 or 2 in which R5 and R6 are hydrogen.

4. The compound of claims 1 to 3 in which X is selected from the group consisting of CH, CF and N.

5. The compound of any one of claims 1 to 4 wherein X is selected from the group consisting of CH, CF and N, and wherein HET is chosen among the following heteroaromatic groups, wherein "^*" denotes the attachment point:

6. The compound of claim 5 wherein X is CH, that is a compound of the form

7. The compound of any of claims 1 to 6 wherein HET is selected from the group consisting of [1 ,2,4]triazolo[1 ,5-a]pyrazine, [1 ,2,4]triazolo[1 ,5-a] pyridine, imidazo[1 ,2-a]pyridine, imidazo[4,5-b]pyrimidine; pyrazolo[1 ,5-a] pyridine, [1 ,2,4]Triazolo[1 ,5-a]pyrimidine, [1 ,2,4]Triazolo[1 ,5-c]pyrimidine, and imidazo[1 ,2- a]pyrimidine.

8. The compound of claim 7 wherein HET is selected from the group consisting of 5,8-Dimethyl-[1 ,2,4]triazolo[1 ,5-a]pyrazine; 5,8-Dimethyl-[1 ,2,4]triazolo[1 ,5- c]pyrazine; 5,8-Dimethyl-[1 ,2,4]triazolo[1 ,5-a]pyridine, 5-methyl-

[1 ,2,4]triazolo[1 ,5-a]pyridine, and (5-Methyl-[1 ,2,4]triazolo[1 ,5-a]pyrazin-8-yl)- methanol.

9. The compound of any of claims 1 to8 wherein R1 , R2, R3 and R4 are selected from the group consisting of hydrogen and methyl, with the proviso that at least one of R1 , R2, R3 and R4 are methyl.

10. The compound of any of claims 1 to 8 wherein R1 , R2, R3 and R4 are selected from the group consisting of hydrogen and flourine, with the proviso that at least one of R1 , R2, R3 and R4 are flourine.

1 1 . The compound of any of claims 1 to 8 wherein R1 , R2, R3 and R4 are selected from the group consisting of hydrogen, methyl and flourine, with the proviso that at least one of R1 , R2, R3 and R4 are fluorine and at least one of R1 , R2, R3 and R4 are methyl.

12. A compound of any one of claims 1 to 1 1 as a medicament.

13. A compound of any one of claims 1 to 1 1 for use in the treatment of a neurodegenerative or psychiatric disorder, alone or in combination with one or more neuroleptic agents such as sertindole, olanzapine, risperidone, quetiapine, aripiprazole, haloperidol, clozapine, ziprasidone and osanetant, wherein the neurodegenerative disorder is Huntington's disease, and the psychiatric disorder is selected from the group consisting of schizophrenia, for example of the paranoid, disorganized, catatonic, undifferentiated, or residual type; schizophreniform disorder; schizoaffective disorder, for example of the delusional type or the depressive type; delusional disorder; bipolar disorder, for example bipolar I disorder, bipolar II disorder, and cyclothymic disorder.

14. A compound of any one of claims 1 to 1 1 , for the preparation of a medicament for use in the treatment of a neurodegenerative or psychiatric disorder, wherein the neurodegenerative disorder is Huntington's disease, and the psychiatric disorder is selected from the group consisting of schizophrenia, for example of the paranoid, disorganized, catatonic, undifferentiated, or residual type; schizophreniform disorder; schizoaffective disorder, for example of the delusional type or the depressive type; delusional disorder; bipolar disorder, for example bipolar I disorder, bipolar II disorder.

15. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1 to 1 1 , and one or more pharmaceutically acceptable carriers, diluents and excipients.