WO2010138833A1 - SUBSTITUTED IMIDAZO[1,5-a]QUINOXALINES AS INHIBITORS OF PHOSPHODIESTERASE 10 - Google Patents

Abstract

The invention relates to imidazo[1,5-a]quinoxaline derivatives which are inhibitors of phosphodiesterase 10 (PDE10) useful in treating central nervous system diseases such as psychosis and also in treating, for example, obesity, type 2 diabetes, metabolic syndrome, glucose intolerance, and pain.

Description

SUBSTITUTED IMIDAZO[1, 5-a]QUINOXALINES AS INHIBITORS OF PHOSPHODIESTERASE 10

Field of the Invention

The invention relates to imidazo[1 ,5-a]quinoxaline derivatives which are inhibitors of phosphodiesterase 10 (PDE10) useful in treating central nervous system diseases such as psychosis and also in treating, for example, obesity, type 2 diabetes, metabolic syndrome, glucose intolerance, and pain.

Background

Psychotic disorders, especially schizophrenia, are severe mental disorders which extremely impair daily life. The symptoms of psychosis may be divided into two fractions. In the acute phase, it is predominated by hallucinations and delusions being called the positive symptoms. When the agitated phase abates the so called negative symptoms become obvious. They include cognitive deficits, social phobia, reduced vigilance, indifference and deficits in verbal learning and memory, verbal fluency and motor function.

Although several antipsychotics are available since, the present therapy of psychosis is not satisfactory. The classic antipsychotics, such as haloperidol, with a high affinity to dopamine D2 receptor show extreme side effects, such as extrapyramidal symptoms (=EPS) and do not improve the negative symptoms of schizophrenia so that they do not enable the patient to return to everyday life.

Clozapine which has emerged as a benchmark therapeutic ameliorating positive, negative and cognitive symptoms of schizophrenia and devoid of EPS shows agranulocytosis as a major, potential lethal side-effect (Capuano et al., Curr Med Chem 9: 521-548, 2002). Besides, there is still a high amount of therapy resistant cases (Lindenmayer et al., J CHn Psychiatry 63: 931-935, 2002).

The exact pathomechanism of psychosis is not yet known. A dysfunction of several neurotransmitter systems has been shown. The two major neurotransmitter systems that are involved are the dopaminergic and the glutamatergic system. Acute psychotic symptoms may be stimulated by dopaminergic drugs (Capuano et al., Curr Med Chem 9: 521-548,

2002) and classical antipsychotics, like haloperidol, have a high affinity to the dopamine D2 receptor (Nyberg et al., Psychopharmacology 162: 37-41 , 2002). Animal models based on a hyperactivity of the dopaminergic neurotransmitter system (amphetamine hyperactivity, apomorphine climbing) are used to mimic the positive symptoms of schizophrenia.

Additionally there is growing evidence that the glutamatergic neurotransmitter system plays an important role in the development of schizophrenia (Millan, Prog Neurobiol 70: 83-244, 2005). Thus, NMDA antagonists like phencyclidine and ketamine are able to stimulate schizophrenic symptoms in humans and rodents (Abi-Saab ef al., Pharmacopsychiatry 31 Suppl 2: 104-109, 1998; Lahti ef a/., Neuropsychopharmacology 25: 455-467, 2001 ). Acute administration of phencyclidine and MK-801 induce hyperactivity, stereotypies and ataxia in rats mimicking psychotic symptoms. Moreover, in contrast to the dopaminergic models the animal models of psychosis based on NMDA antagonists do not only mimic the positive symptoms but also the negative and cognitive symptoms of psychosis (Abi-Saab ef a/., Pharmacopsychiatry 31 Suppl 2: 104-109, 1998; Jentsch and Roth, Neuropsychopharmacology 20: 201-225, 1999). Thus, NMDA antagonists, additionally induce cognitive deficits and social interaction deficits.

Eleven families of phosphodiesterases have been identified in mammals so far (Essayan, J Allergy Clin Immunol 108: 671-680, 2001 ). The role of PDEs in the cell signal cascade is to inactivate the cyclic nucleotides cAMP and/or cGMP (Soderling and Beavo, Proc Natl Acad USA 96(12):7071 -7076, 2000). Since cAMP and cGMP are important second messengers in the signal cascade of G-protein-coupled receptors, PDEs are involved in a broad range of physiological mechanisms playing a role in the homeostasis of the organism.

The PDE families differ in their substrate specificity for the cyclic nucleotides, their mechanism of regulation and their sensitivity to inhibitors. Moreover, they are differentially localized in the organism, among the cells of an organ and even within the cells. These differences lead to a differentiated involvement of the PDE families in the various physiological functions.

PDE10 (PDE10A) is primarily expressed in the brain and here in the nucleus accumbens and the caudate putamen. Areas with moderate expression are the thalamus, hippocampus, frontal cortex and olfactory tubercle (Menniti ef al., William Harvey Research Conference, Porto, December 6^th - 8^th, 2001 ). All these brain areas are described to participate in the pathomechanism of schizophrenia (Lapiz ef al., Neurosci Behav Physiol 33: 13-29, 2003) so that the location of the enzyme indicates a predominate role in the pathomechanism of psychosis.

In the striatum PDE10A is predominately found in the medium spiny neurons and they are primarily associated to the postsynaptic membranes of these neurons (Xie et al., Neuroscience 139: 597-607, 2006). By this location PDE10A may have an important influence on the signal cascade induced by dopaminergic and glutamatergic input on the medium spiny neurons two neurotransmitter systems playing a predominate role in the pathomechanism of psychosis.

Phosphodiesterase (PDE) 1 OA, in particular, hydrolyses both cAMP and cGMP having a higher affinity for cAMP (K_m = 0.05 μM) than for cGMP (K_m =3 μM) (Soderling et al., Curr. Opin. Cell Biol 12: 174-179, 1999).

Psychotic patients have been shown to have a dysfunction of cGMP and cAMP levels and its downstream substrates (Kaiya, Prostaglandins Leukot Essent Fatty Acids 46: 33-38, 1992; MuIy, Psychopharmacol Bull 36: 92-105, 2002; Garver ef a/., Life Sc/ 31 : 1987-1992, 1982). Additionally, haloperidol treatment has been associated with increased cAMP and cGMP levels in rats and patients, respectively (Leveque ef a/., J Neurosci 20: 4011-4020, 2000; Gattaz et a/., Biol Psychiatry 19: 1229-1235, 1984). As PDE10A hydrolyses both cAMP and cGMP (Kotera et a/., Biochem Biophys Res Commun 261 : 551-557, 1999), an inhibition of PDE10A would also induce an increase of cAMP and cGMP and thereby have a similar effect on cyclic nucleotide levels as haloperidol.

The antipsychotic potential of PDE 10A inhibitors is further supported by studies of Kostowski et al. (Pharmacol Biochem Behav 5: 15-17, 1976) who showed that papaverine, a moderate selective PDE10A inhibitor, reduces apomorphine-induced stereotypies in rats, an animal model of psychosis, and increases halopehdol-induced catalepsy in rats while concurrently reducing dopamine concentration in rat brain, activities that are also seen with classical antipsychotics. This is further supported by a patent application establishing papaverine as a PDE10A inhibitor for the treatment of psychosis (US Patent Application Pub. No. 2003/0032579).

In addition to classical antipsychotics which mainiy ameliorate the positive symptoms of psychosis, PDE10A also bears the potential to improve the negative and cognitive symptoms of psychosis.

Focusing on the dopaminergic input on the medium spiny neurons, PDE10A inhibitors by up-regulating cAMP and cGMP levels act as D1 agonists and D2 antagonists because the activation of Gs-protein coupled dopamine D1 receptor increases intracellular cAMP, whereas the activation of the Gi-protein coupled dopamine D2 receptor decreases intracellular cAMP levels through inhibition of adenylyl cyclase activity (Mutschler et al., Mutschler Arzneimittelwirkungen. δ"⁷ ed. Stuttgart: Wissenschaftliche Verlagsgesellschaft mbH, 2001 ).

Elevated intracellular cAMP levels mediated by D1 receptor signalling seems to modulate a series of neuronal processes responsible for working memory in the prefrontal cortex

(Sawaguchi, Parkinsonism Relat Disord 7: 9-19, 2000), and it is reported that D1 receptor activation may improve working memory deficits in schizophrenic patients (Castner et al., Science 287: 2020-2022, 2000).

Further indication of an effect of PDE1 OA inhibition on negative symptoms of psychosis was given by Rodefer et al. (Eur. J Neurosci 21 : 1070-1076, 2005) who could show that papaverine reverses attentional set-shifting deficits induced by subchronic administration of phencyclidine, an NMDA antagonist, in rats. Attentional deficits including an impairment of shifting attention to novel stimuli belongs to the negative symptoms of schizophrenia. In the study the attentional deficits were induced by administering phencyclidine for 7 days followed by a washout period. The PDE10A inhibitor papaverine was able to reverse the enduring deficits induced by the subchronic treatment.

Some example PDE10 inhibitors include those reported in U.S. Ser. Nos. 12/277,844; 12/277,961 ; and 12/323,188.

In conclusion, there is still a need for developing new antipsychotics which ameliorate positive, negative and cognitive symptoms of psychosis, as well as provide treatment for other disorders. The PDE10 inhibitors of the invention are directed toward this end.

Summary of the Invention

The present invention provides, inter alia, PDE10 inhibitors that are compounds of Formula

I or pharmaceutically acceptable salts thereof, wherein the constituent variables are defined herein.

The present invention further provides pharmaceutical compositions comprising a compound of Formula I and at least one pharmaceutically acceptable carrier. The present invention further provides methods of treating diseases associated by PDE10 hyperactivity by administering a compound of the present invention, or pharmaceutically acceptable salt thereof, to a patient in need thereof.

The present invention further provides methods of treating central nervous system disorders by administering a compound of the invention, or pharmaceutically acceptable salt thereof, to a patient in need thereof.

The present invention further provides methods of improving learning and memory capacities comprising administering to a patient in need thereof a compound of the invention, or pharmaceutically acceptable salt thereof.

The present invention further provides methods of treating obesity, type 2 diabetes, metabolic syndrome, or glucose intolerance comprising administering to a patient in need thereof a compound of the invention, or a pharmaceutically acceptable salt thereof.

The present invention further provides methods of reducing body fat or body weight in a patient comprising administering to the patient a compound of the invention, or a pharmaceutically acceptable salt thereof.

The present invention further provides methods of treating pain conditions and disorders in a patient comprising administering to the patient a compound of the invention, or a pharmaceutically acceptable salt thereof.

The present invention further provides a compound of the invention, or a pharmaceutically acceptable salt thereof, for use in therapy.

The present invention further provides use of a compound of the invention, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for use in therapy.

Detailed Description The present invention provides, inter alia, PDE10 inhibitors that are compounds of Formula

I:

I or pharmaceutically acceptable salts thereof, wherein:

R¹ is a 5-6 membered monocyclic heteroaryl group optionally substituted with 1 , 2, 3, or 4 substituents independently selected from halo, C_1-4 alkyl, and C^ haloalkyl; R² is d-₄ alkyl; R³ is Ci-₄ alkyl;

R⁴ is H, halo, C_1-4 alkyl, C_1-4 haloalkyl, or OR⁶; R⁵ is H, halo, C_1-4 alkyl, C_1-4 haloalkyl, or OR⁷; and R⁶ and R⁷ are independently selected from H, C_1-4 alkyl, C^ haloalkyl, (C_M alkyl)sulfonyl, (C_1-4 haloalkyl)sulfonyl, (C_3-7 cycloalkylJ-C^ alkyl, (C_6-10 aryl)-C_1-4 alkyl, and (C₃. ₈ heteroaryl)-Ci_₄ alkyl.

In some embodiments, R¹ is a 6-membered monocyclic heteroaryl group optionally substituted with 1 , 2, 3, or 4 substituents independently selected from halo, Ci_-4 alkyl, and C^haloalkyl.

in some embodiments, R¹ is a pyridinyl group optionally substituted with 1 , 2, 3, or 4 substituents independently selected from halo, C_1-4 alkyl, and C_1-4 haloalkyl.

In some embodiments, R¹ is a pyridin-3-yl or pyridin-4-yl group optionally substituted with 1 , 2, 3, or 4 C_1-4 alkyl.

In some embodiments, R¹ is a pyridin-3-yl or pyridin-4-yl group optionally substituted with methyl.

In some embodiments, R¹ is:

In some embodiments, R¹ is:

In some embodiments, R¹ is:

In some embodiments, R¹ is:

In some embodiments, R² is methyl.

In some embodiments, R³ is methyl.

In some embodiments, R⁴ is OR⁶.

In some embodiments, R⁴ is Ci.₄ haloalkyl. In some embodiments, R⁴ is halo. In some embodiments, R⁵ is halo. In some embodiments, R⁵ is OR⁷.

In some embodiments, R⁶ is H.

In some embodiments, R is C^₄ alkyl. In some embodiments, R⁶ is C_1-4 haloalkyl.

In some embodiments, R⁶ is (C_3-7 cycloalkyO-C^ alkyl. In some embodiments, R⁶ is (C_3-8 heteroaryl)-C_1-4 alkyl.

In some embodiments, R⁶ is pyridinylmethyl, quinolinylmethyl, or benzothiazolylmethyl. In some embodiments, R⁶ is (Cβ-ioaryl)-d-₄ alkyl.

In some embodiments, R⁶ is benzyl.

In some embodiments, R⁶ is (Ci.₄haloaikyl)sulfonyl.

In some embodiments, R⁷ is C_1-4alkyl.

In some embodiments, R⁷ is methyl.

In some embodiments, R⁷ is H.

In some embodiments, R⁷ is H, C₁^ alkyl, C₁-* haloalkyl, (C_1-4 alkyl)sulfonyl, (C_1-4 haloalkyl)sulfonyl, (C₆-io aryl)-C₁.₄alkyl, and (C_3-S heteroaryl)-Ci.₄alkyl.

In some embodiments, the compounds of the invention have Formula II:

;

Il wherein the substitutents are defined above and anywhere herein.

In some embodiments, the compounds of the invention have Formula Il wherein:

R¹ is a 6-membered monocyclic heteroaryl group optionally substituted with 1 , 2, 3, or 4 substituents independently selected from halo, C_1-4 alkyl, and d-₄ haloalkyl;

R⁴ is halo, C_1-4 alkyl, Ci_-4 haloalkyl, or OR⁶; R⁵ is halo, C_1-4 alkyl, C_1-4 haloalkyl, or OR⁷;

R⁶ is H, C_1-4 alkyl, C_1-4 haloalkyl, (C_1-4 alkyl)sulfonyl, (d.₄ haloalkyl)sulfonyl, (C_3-7 cycloalkyl)-C,_-4 alkyl, (C₆-io aryl)-d.₄ alkyl, or (C_3-8 heteroaryl)-C_1-4 alkyl; and R⁷ is H or C_1-4 alkyl.

In some embodiments, R¹ is a pyridinyl group optionally substituted with 1 , 2, 3, or 4 substituents independently selected from halo, C₁^ alkyl, and C_1-4 haloalkyl.

In some embodiments, R¹ is a pyridin-3-yl or pyridin-4-yl group, each optionally substituted with C_1-4 alkyl. In some embodiments, the compounds of the invention have Formula IHa or MIb:

Ilia MIb wherein R is Ci-₄alkyl, and wherein the remaining substitutents are defined above or anywhere herein.

In some embodiments where the compounds have Formula Ilia or IHb:

R⁴ is OH, methoxy, ethoxy, halomethyloxy, haloethyloxy, pyridinylmethyloxy, quinolinylmethyloxy, benzothiazolylmethyloxy, benzyloxy, halomethylsulfonyloxy, fluoro, chloro, or halomethyl;

R⁵ is fluoro, chloro, methoxy, or OH.

In some embodiments, R⁵ is chloro, methoxy, or OH.

In some embodiments, R is methyl.

In some embodiments, the compounds of the invention have Formula IVa, IVb, or IVc:

IVa IVb IVc.

In some embodiments where the compounds have Formula IVa, IVb, or IVc:

R⁴ is OH, methoxy, ethoxy, halomethyloxy, haloethyloxy, pyridinylmethyloxy, quinolinylmethyloxy, benzothiazolylmethyloxy, benzyloxy, halomethylsulfonyloxy, fluoro, chloro, or halomethyl;

R⁵ is fluoro, chloro, methoxy, or OH.

In some embodiments, R⁵ is chloro, methoxy, or OH. At various places in the present specification, substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges. For example, the term "C₁^ alkyl" is specifically intended to individually disclose methyl, ethyl, C₃ alkyl, C₄ alkyl, C₅ alkyl, and C₆ alkyl.

It is further intended that the compounds of the invention are stable. As used herein "stable" refers to a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and preferably capable of formulation into an efficacious therapeutic agent.

It is further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

The term "halo" refers to fluoro, chloro, bromo or iodo.

The term "alkyl" refers to a straight or branched saturated hydrocarbon radical such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, and the like.

The term "cycloalkyl" refers to a cyclic saturated or partially saturated hydrocarbon. Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

The term "cycloalkylalkyl" refers to an alkyl group substituted by a cycloalkyl group. An example cycloalkylalkyl group is cyclopropylmethyl.

As used herein, "aryl" refers to monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings) aromatic hydrocarbons such as, for example, phenyl, naphthyl, anthracenyl, phenanthrenyl, and the like. In some embodiments, an aryl group has from 6 to about 20 carbon atoms.

As used herein, "arylalkyl" refers to an alkyl group substituted by an aryl group. Example arylalkyl groups include benzyl and phenylethyl.

As used herein, a "heteroaryl" group refers to an aromatic heterocycle having at least one heteroatom ring member such as sulfur, oxygen, or nitrogen. Heteroaryl groups include monocyclic and polycyclic (e.g., having 2, 3 or 4 fused rings) systems. Any ring-forming N atom in a heteroaryl group can also be oxidized to form an N-oxo moiety. Examples of heteroaryl groups include without limitation, pyridinyl, N-oxopyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1 ,2,4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, and the like. In some embodiments, the heteroaryl group has from 1 to about 20 carbon atoms, and in further embodiments from about 3 to about 20 carbon atoms, or 3 to 8 carbon atoms. In some embodiments, the heteroaryl group contains 3 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. In some embodiments, the heteroaryl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms.

As used herein, a "heteroarylalkyl" group refers to an alkyl group substituted by a heteroaryl group. An example of a heteroarylalkyl group is pyridinylmethyl.

As used herein, a "haloalkyl" group refers to an alkyl group substituted by one or more halogens up to the maximum valency of the alkyl group. Example haloalkyl groups include trifluoromethyl and difluoromethyl.

As used herein, an "alkylsulfonyl" group refers to a sulfonyl (SO₂) that is substituted by an alkyl group.

As used herein, a "haloalkylsulfonyl" group refers to a sulfonyl (SO₂) that is substituted by a haloalkyl group.

As used herein, a "halomethyl" group refers to a methyl that is substituted with 1 , 2, or 3 halogens. In some embodiments, the halogen is F.

As used herein, a "haloethyl" group refers to an ethyl that is substituted with 1 , 2, 3, 4, or 5 halogens. In some embodiments, the halogen is F.

As used herein, a "halomethyloxy" group refers to an oxy group (O) that is substituted by a halomethyl group.

As used herein, a "haloethyloxy" group refers to an oxy group (O) that is substituted by a haloethyl group.

As used herein, a "halomethylsulfonyloxy" group refers to an oxy group (O) that is substituted by a sulfonyl group (SO₂) which in turn is substituted by a halomethyl group. As used herein, the term "substituted" refers to the replacement of a hydrogen moiety with a non-hydrogen moiety in a molecule or group. A molecule or group may be monosubstituted. A molecule or group may be also polysubstituted with the same or different substituents up to the valence of the molecule or group. In some embodiments, a polysubstituted molecule or group has 2, 3, 4 or 5 substituents. Where a list of substituent choices are provided, the polysubstituted molecule or group can be substituted with two or more substituents independently selected from the list

The present invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present invention include the conventional nontoxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17^th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

Furthermore, in the case of the compounds of the invention which contain an asymmetric carbon atom, the invention relates to the D form, the L form and D₁L mixtures and also, where more than one asymmetric carbon atom is present, to the diastereomeric forms. Those compounds of the invention which contain asymmetric carbon atoms, and which as a rule accrue as racemates, can be separated into the optically active isomers in a known manner, for example using an optically active acid. However, it is also possible to use an optically active starting substance from the outset, with a corresponding optically active or diastereomeric compound then being obtained as the end product.

Compounds of the invention also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, amide - imidic acid pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1 H- and 3H-imidazole, 1 H-, 2H- and 4H- 1 ,2,4-triazole, 1 H- and 2H- isoindole, and 1 H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.

The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms.

Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

The term "compound" as used herein is meant to include all stereoisomers, geometric iosomers, tautomers, and isotopes of the structures depicted, unless otherwise indicated.

The compounds of the invention, and pharmaceuticaly acceptable salts thereof, can be found together with other substances to make compositions or mixtures. In some embodiments, the compounds of the invention can be found together with solvent or water to form solutions or solvated or hydrated solid forms.

In some embodiments, the compounds of the invention, and salts thereof, are substantially isolated. By "substantially isolated" is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition enriched in the compound of the invention. Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compound of the invention, or salt thereof.

Pharmaceutical Methods

The compounds according to the invention have been found to have pharmacologically important properties which can be used therapeutically. The compounds of the invention can be used alone, in combination with each other or in combination with other active compounds. The compounds according to the invention are inhibitors of phosphodiesterase 10. It is therefore a part of the subject-matter of this invention that the compounds of the invention and their salts and also pharmaceutical preparations which comprise these compounds or their salts, can be used for treating or preventing disorders associated with, accompanied by and/or covered by phosphodiesterase hyperactivity and/or disorders in which inhibiting phosphodiesterase 10 is of value.

It is an embodiment of this invention, that compounds of the invention including their salts, can be used for the treatment of central nervous system disorders of mammals including a human.

More particularly, the invention relates to the treatment of neurological and psychiatric disorders including, but not limited to, (1 ) schizophrenia and other psychotic disorders; (2) mood [affective] disorders; (3) neurotic, stress-related and somatoform disorders including anxiety disorders; (4) eating disorders; sexual dysfunction comprising excessive sexual drive; (5) disorders of adult personality and behaviour; (6) disorders usually first diagnosed in infancy, childhood and adolescence; (7) mental retardation and (8) disorders of psychological development; (9) disorders comprising the symptom of cognitive deficiency in a mammal, including a human; (10) factitious disorders.

(1 ) Examples of schizophrenia and other psychotic disorders disorders that can be treated according to the present invention include, but are not limited to, continuous or episodic schizophrenia of different types (for instance paranoid, hebephrenic, catatonic, undifferentiated, residual, and schizophreniform disorders); schizotypal disorders (such as borderline, latent, prepsychotic, prodromal, pseudoneurotic pseudopsychopathic schizophrenia and schizotypal personality disorder); persistent delusional disorders; acute, transient and persistent psychotic disorders; induced delusional disorders; schizoaffective disorders of different type (for instance manic depressive or mixed type); puerperal psychosis and other and unspecified nonorganic psychosis.

(2) Examples of mood [affective] disorders that can be treated according to the present invention include, but are not limited to, manic episodes associated to bipolar disorder and single manic episodes, hypomania, mania with psychotic symptoms; bipolar affective disorders (including for instance bipolar affective disorders with current hypomanic and manic episodes with or without psychotic symptoms, bipolar I disorder or bipolar Il disorder); depressive disorders, such as single episode or recurrent major depressive disorder of the mild moderate or severe type, depressive disorder with postpartum onset, depressive disorders with psychotic symptoms; persistent mood [affective] disorders, such as cyclothymia, dysthymia; premenstrual dysphoric disorder.

(3) Examples of disorders belonging to the neurotic, stress-related and somatoform disorders that can be treated according to the present invention include, but are not limited to, phobic anxiety disorders, for instance agoraphobia and social phobia primarily but not exclusively related to psychosis; other anxiety disorders such as panic disorders and general anxiety disorders; obsessive compulsive disorder; reaction to severe stress and adjustment disorders, such as post traumatic stress disorder; dissociative disorders and other neurotic disorders such as depersonalisation-derealisation syndrome.

(5) Examples of disorders of adult personality and behavior that can be treated according to the present invention include, but are not limited to, specific personality disorders of the paranoid, schizoid, schizotypal, antisocial, borderline, histrionic, narcissistic, avoidant, dissocial, emotionally unstable, anankastic, anxious and dependent type; mixed personality disorders; habit and impulse disorders (such as trichotillomania, pyromania, maladaptive aggression); disorders of sexual preference.

(6) Examples of disorders usually first diagnosed in infancy, childhood and adolescence that can be treated according to the present invention include, but are not limited to, hyperkinetic disorders, attentional deficit/hyperactivity disorder (AD/HD), conduct disorders; mixed disorders of conduct and emotional disorders; nonorganic enuresis, nonorganic encopresis; stereotyped movement disorder; and other specified behavioural emotional disorders, such as attention deficit disorder without hyperactivity, excessive masturbation nail-biting, nose- picking and thumb-sucking; disorders of psychological development particularly schizoid disorder of childhood and pervasive development disorders such as psychotic episodes associated to Asperger's syndrome.

Exemplary neurological disorders include neurodegenerative disorders including, without being limited to, Parkinson's disease, Huntington's disease, dementia (for example Alzheimer's disease, multi-infarct dementia, AIDS-related dementia, or fronto temperal dementia), neurodegeneration associated with cerebral trauma, neurodegeneration associated with stroke, neurodegeneration associated with cerebral infarct, hypoglycemia- induced neurodegeneration, neurodegeneration associated with epileptic seizure, neurodegeneration associated with neurotoxic poisoning or multi-system atrophy.

(8) Examples of disorders of psychological development include but are not limited to developmental disorders of speech and language, developmental disorders of scholastic skills, such as specific disorder of arithmetical skills, reading disorders and spelling disorders and other learning disorders. These disorders are predominantly diagnosed in infancy, childhood and adolescence.

(9) The phrase "cognitive deficiency" as used here in "disorder comprising as a symptom cognitive deficiency" refers to a subnormal functioning or a suboptimal functioning in one or more cognitive aspects such as memory, intellect, learning and logic ability, or attention in a particular individual comparative to other individuals within the same general age population.

Examples of disorders comprising as a symptom cognitive deficiency that can be treated according to the present invention include, but are not limited to, cognitive deficits primarily but not exclusively related to psychosis including schizophrenia, depression, age-associated memory impairment, autism, autistic spectrum disorders, fragile X syndrome, Parkinson's disease, Alzheimer's disease, multi infarct dementia, spinal cord injury, CNS hypoxia, Lewis body dementia, stroke, frontotemporal dementia, progressive supranuclear palsy Huntington's disease and in HIV disease, cerebral trauma, cardiovascular disease, drug abuse, diabetes associated cognitive impairment and mild cognitive disorder.

(11 ) Additionally, the invention relates to movement disorders with malfunction of basal ganglia. Examples of movement disorders with malfunction of basal ganglia that can be treated according to the present invention include, but are not limited to, different subtypes of dystonia, such as focal dystonias, multiple-focal or segmental dystonias, torsion dystonia, hemispheric, generalised and tardive dyskinesias (induced by psychopharmacological drugs), akathisias, dyskinesias such as Huntington's disease, Parkinson's disease, Lewis body disease, restless leg syndrome, PLMS.

(12) Furthermore the invention relates to the treatment of organic, including symptomatic mental disorders, especially to organic delusional (schizophrenia-like) disorders, presenil or senile psychosis associated to dementia, to psychosis in epilepsy and Parkinson's disease and other organic and symptomatic psychosis; delirium; infective psychosis; personality and behavioural disorders due to brain disease, damage and dysfunction.

(13) The invention relates to the treatment of mental and behavioural disorders due to psychoactive compounds, more particular to the treatment of psychotic disorders and residual and late-onset psychotic disorders induced by alcohol, opioids, cannabinoids, cocaine, hallucinogens, other stimulants, including caffeine, volatile solvents and other psychoactive compounds.

(14) The invention further relates to a general improvement of learning and memory capacities in a mammal , including a human.

Compounds currently used to treat schizophrenia have been associated with several undesirable side effects. These side effects include weight gain, hyperprolactinemia, elevated triglyceride levels, metabolic syndrome (markers: diabetes, hyperlipidemia, hypertension, and obesity), glucose abnormalities (such as hyperglycemia, elevated blood glucose and impaired glucose tolerance), and the exhibition of extrapyramidal symptoms. The weight gain observed with conventional atypical antipsychotics, such as risperidone and olanzapine, has been associated with an increased risk of cardiovascular disease and diabetes mellitus.

Compounds of the present invention are useful in treating schizophrenia to effect a clinically relevant improvement such as reduction of a PANSS total score in a patient, while maintaining body weight, maintaining or improving glucose levels and/or tolerance, maintaining and/or improving triglycerides levels and/or total cholesterol levels and/or maintaining an EPS profile similar to baseline measurements before administration.

The PDE10 inhibitors of the invention are further useful in the prevention and treatment of obesity, type 2 diabetes (non-insulin dependent diabetes), metabolic syndrome, glucose intolerance, and related health risks, symptoms or disorders. As such, the compounds can also be used to reduce body fat or body weight of an overweight or obese individual. In some embodiments, the PDE10 inhibitor is selective for PDE10, meaning that it is a better inhibitor of PDE10 than for any other PDE. In some embodiments, the selective PDE10 inhibitor can reduce PDE10 activity at least 10-fold or at least 100-fold compared to other PDE's.

As used herein, the terms "overweight" and "obese" are meant to refer to adult persons 18 years or older having a greater than ideal body weight (or body fat) measured by the body mass index (BMI). BMI is calculated by weight in kilograms divided by height in meters squared (kg/m²) or, alternatively, by weight in pounds, multiplied by 703, divided by height in inches squared (lbs x 703/in²). Overweight individuals typically have a BMI of between 25 and 29, whereas obsess individuals typically have a BMI of 30 or more (see, e.g., National Heart, Lung, and Blood institute, Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults, The Evidence Report, Washington, DC:U.S. Department of Health and Human Services, NIH publication no. 98-4083,1998). Other means for indicating excess body weight, excess body fat, and obesity include direct measure of body fat and/or waist-to-hip ratio measurements.

The term "metabolic syndrome" is used according to its usual meaning in the art. The American Heart Association characterizes metabolic syndrome as having at least 3 of the 5 below symptoms: 1 ) Elevated waist circumference (>102 cm (40 inches) in men; >88 cm (35 inches) in women), 2) Elevated triglycerides (>150 mg/dL (>1.7 mmol/L) or drug treatment for elevated triglycerides), 3) Reduced HDL-C (<40 mg/dL (1.03 mmol/L) in men <50 mg/dL (1.3 mmol/L) in women or drug treatment for reduced HDL-C, 4) Elevated blood pressure (>130/85 mmHg or drug treatment for hypertension), and 5) Elevated fasting glucose (>100 mg/dL or drug treatment for elevated glucose). See, Grundy, S. M. et al., Circulation, 2005, 112 (17, e285 (online at circahajournals.org/cgi/reprint/112/17/e285)). Metabolic syndrome according to the World Health Organization (See, Alberti et al., Diabet. Med. 15, 539-553, 1998) includes individuals suffering from diabetes, glucose intolerance, low fasting glucose, or insulin resistance plus two or more of 1 ) High blood pressure (>160/90 mmHg), 2) Hyperlipdemia (triglycerides ≥150 mg/dL or HDL cholesterol <35 mg/dL in men and <39 mg/dL in women), 3) Central obesity (waist-to-hip ratio of >0.90 for men and >0.85 for women or BMI > 30 kg/m²), and 4) Microalbuminuria (urinary albumin excretion rate ≥20 μg/min or an albumin-to-creatine ratio ≥20 μg/kg).

The present methods relating to reduction of body fat or body weight, as well as the treatment or prevention of obesity, type 2 diabetes (non-insulin dependent diabetes), metabolic syndrome, glucose intolerance, and related health risks, symptoms or disorders can be carried out by the administration of one or more compounds of the present invention. In some embodiments, one or more additional therapeutic agents can be administered such as anti-obesity agents. Example anti-obesity agents include apolipoprotein-B secretion/rnicrosomal triglyceride transfer protein(apo-B/MTP) inhibitors, 11-beta- hydroxysteroid dehydrogenase-1 (1 1 beta-HSD type 1 ) inhibitors, peptide YY3-36 or analogs thereof, MCR-4 agonists, cholecystokinin-A (CCK-A) agonists, monoamine reuptake inhibitors (such as sibutramine), cannabinoid receptor-l antagonists (such as rimona an , sympathomimetic agents, P3 adrenergic receptor agonists, 5 dopamine agonists; (such as bromocriptine), melanocyte-stimulating hormone receptor analogs, 5HT₂c agonists, melanin concentrating hormone antagonists, leptin (the OB protein), leptin analogs, leptin receptor agonists, galanin antagonists, lipase inhibitors (such as tetrahydrolipstatin, i.e. orlistat), anorectic agents (such as a bombesin agonist), neuropeptide-Y receptor antagonists (e.g., NPY Y5 receptor antagonists, such as the compounds described in U.S. Patent Nos. 6,566,367; 61649,624; 61638,942; 61605,720; 61495,569; 61462,053; 61388,077; 6,335,345; and 6,326,375; US Pat. Appl. Publ. Nos. 2002/0151456 and 20031036652; and PCT Publication Nos. WO 031010175, WO 03/082190 and receptor agonists or antagonists, orexin receptor antagonists, glucagon-like peptide-1 receptor agonists, ciliary neurotrophic factors, human agouti-related proteins (AGRP), ghrelin receptor antagonists, histamine 3 receptor antagonists or inverse agonists, neuromedin U receptor agonists and the like. Other anti-obesity agents are readily apparent to one of ordinary skill in the art.

Representative methods for using PDE10 inhibitors for the reduction of body fat or body weight, as well as the treatment or prevention of obesity, type 2 diabetes (non-insulin dependent diabetes), metabolic syndrome, glucose intolerance, and related health risks, symptoms are reported in WO 2005/120514.

The present invention also includes method of treating pain conditions and disorders. Examples of such pain conditions and disorders include, but are not limited to, inflammatory pain, hyperalgesia, inflammatory hyperalgesia, migraine, cancer pain, osteoarthritis pain, post-surgical pain, non-inflammatory pain, neuropathic pain, sub-categories of neuropathic pain including peripheral neuropathic pain syndromes, chemotherapy-induced neuropathy, complex regional pain syndrome, HIV sensory neuropathy, neuropathy secondary to tumor infiltration, painful diabetic neuropathy, phantom limb pain, postherpetic neuralgia, postmastectomy pain, trigeminal neuralgia, central neuropathic pain syndromes, central poststroke pain, multiple sclerosis pain, Parkinson disease pain, and spinal cord injury pain.

In a further embodiment compounds of the present invention are administered in combination with one or more other agents effective for treating pain. Such agents include analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), opiods and antidepressants. In various embodiments, one or more agents are selected from the group consisting of buprenorphine, naloxone, methadone, levomethadyl acetate, L-alpha acetylmethadol (LAAM), hydroxyzine, diphenoxylate, atropine, chlordiazepoxide, carbamazepine, mianserin, benzodiazepine, phenoziazine, disulfuram, acamprosate, topiramate, ondansetron, sertraline, bupropion, amantadine, amiloride, isradipine, tiagabine, baclofen, propranolol, tricyclic antidepressants, desipramine, carbamazepine, valproate, lamotrigine, doxepin, fluoxetine, imipramine, moclobemide, nortriptyline, paroxetine, sertraline, tryptophan, venlafaxine, trazodone, quetiapine, Zolpidem, zopiclone, zaleplon, gabapentin, memantine, pregabalin, cannabinoids, tramadol, duloxetine, milnacipran, naltrexone, paracetamol, metoclopramide, loperamide, clonidine, lofexidine, and diazepam.

The present invention also includes methods of treating schizophrenia and other psychotic disorders, as described above, with a combination of compounds of the present invention with one or more antipsychotic agents. Examples of suitable antipsychotic agents for use in combination with the compounds of the present invention include, but are not limited to, the phenothiazine (chlorpromazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazine and trifluoperazine), thioxanthine (chlorprothixene, thiothixene), heterocyclic dibenzazepine (clozapine, olanzepine and aripiprazole), butyrophenone (haloperidol), dipheyylbutyipiperidine (pimozide) and indolone (molindolone) classes of antipsychotic agents. Other antipsychotic agents with potential therapeutic value in combination with the compounds in the present invention include loxapine, sulpiride and risperidone.

The present invention further includes methods of treating depression or treatment-resistant depression with a combination of compounds of the present invention with one or more antidepressants. Examples of suitable anti-depressants for use in combination with the compounds of the present invention include, but are not limited to, norepinephrine reuptake inhibitors (tertiary and secondary amine tricyclics), selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine, fluvoxamine, paroxetine and sertraline), monoamine oxidase inhibitors (MAOIs) (isocarboxazid, phenelzine, tranylcypromine, selegiline), reversible inhibitors of monoamine oxidase (RIMAs) (moclobemide), serotonin and norepinephrine reuptake inhibitors (SNRIs) (venlafaxine), corticotropin releasing factor (CRF) receptor antagonists, alpah-adrenoreceptor antagonists, and atypical antidepressants (bupropion, lithium, nefazodone, trazodone and viloxazine).

As used herein, the term "treating" or "treatment" refers to one or more of (1 ) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology); and (2) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology) such as decreasing the severity of disease.

In some embodiments, administration of a compound of the invention, or pharmaceutically acceptable salt thereof, is effective in preventing the disease; for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease.

Compositions and Administration

An effective dose of the compounds according to the invention, or their salts, is used, in addition to physiologically acceptable carriers, diluents and/or adjuvants for producing a pharmaceutical composition. The dose of the active compounds can vary depending on the route of administration, the age and weight of the patient, the nature and severity of the diseases to be treated, and similar factors. The daily dose can be given as a single dose, which is to be administered once, or be subdivided into two or more daily doses, and is as a rule 0.001-2000 mg. Particular preference is given to administering daily doses of 0.1 - 500 mg, e.g. 0.1-100 mg.

Suitable administration forms are oral, parenteral, intravenous, transdermal, topical, inhalative, intranasal and sublingual preparations. Particular preference is given to using oral, parenteral, e.g. intravenous or intramuscular, intranasal preparations, e.g. dry powder or sublingual, of the compounds according to the invention. The customary galenic preparation forms, such as tablets, sugar-coated tablets, capsules, dispersible powders, granulates, aqueous solutions, alcohol-containing aqueous solutions, aqueous or oily suspensions, syrups, juices or drops, are used.

Solid medicinal forms can comprise inert components and carrier substances, such as calcium carbonate, calcium phosphate, sodium phosphate, lactose, starch, mannitol, alginates, gelatine, guar gum, magnesium stearate, aluminium stearate, methyl cellulose, talc, highly dispersed silicic acids, silicone oil, higher molecular weight fatty acids, (such as stearic acid), gelatine, agar agar or vegetable or animal fats and oils, or solid high molecular weight polymers (such as polyethylene glycol); preparations which are suitable for oral administration can comprise additional flavourings and/or sweetening agents, if desired. Liquid medicinal forms can be sterilized and/or, where appropriate, comprise auxiliary substances, such as preservatives, stabilizers, wetting agents, penetrating agents, emulsifiers, spreading agents, solubilizers, salts, sugars or sugar alcohols for regulating the osmotic pressure or for buffering, and/or viscosity regulators.

Examples of such additives are tartrate and citrate buffers, ethanol and sequestering agents (such as ethylenediaminetetraacetic acid and its non-toxic salts). High molecular weight polymers, such as liquid polyethylene oxides, microcrystalline celluloses, carboxymethyl celluloses, polyvinylpyrrolidones, dextrans or gelatine, are suitable for regulating the viscosity. Examples of solid carrier substances are starch, lactose, mannitol, methyl cellulose, talc, highly dispersed silicic acids, high molecular weight fatty acids (such as stearic acid), gelatine, agar agar, calcium phosphate, magnesium stearate, animal and vegetable fats, and solid high molecular weight polymers, such as polyethylene glycol.

Oily suspensions for parenteral or topical applications can be vegetable synthetic or semisynthetic oils, such as liquid fatty acid esters having in each case from 8 to 22 C atoms in the fatty acid chains, for example palmitic acid, lauric acid, tridecanoic acid, margaric acid, stearic acid, arachidic acid, myristic acid, behenic acid, pentadecanoic acid, linoleic acid, elaidic acid, brasidic acid, erucic acid or oleic acid, which are esterified with monohydric to trihydric alcohols having from 1 to 6 C atoms, such as methanol, ethanol, propanol, butanol, pentanol or their isomers, glycol or glycerol. Examples of such fatty acid esters are commercially available miglyols, isopropyl myristate, isopropyl palmitate, isopropyl stearate, PEG 6-capric acid, caprylic/capric acid esters of saturated fatty alcohols, polyoxyethylene glycerol trioleates, ethyl oleate, waxy fatty acid esters, such as artificial ducktail gland fat, coconut fatty acid isopropyl ester, oleyl oleate, decyl oleate, ethyl lactate, dibutyl phthalate, diisopropyl adipate, polyol fatty acid esters, inter alia. Silicone oils of differing viscosity, or fatty alcohols, such as isotridecyl alcohol, 2-octyldodecanol, cetylstearyl alcohol or oleyl alcohol, or fatty acids, such as oleic acid, are also suitable. It is furthermore possible to use vegetable oils, such as castor oil, almond oil, olive oil, sesame oil, cotton seed oil, groundnut oil or soybean oil.

Suitable solvents, gelatinizing agents and solubilizers are water or water-miscible solvents. Examples of suitable substances are alcohols, such as ethanol or isopropyl alcohol, benzyl alcohol, 2-octyldodecanol, polyethylene glycols, phthalates, adipates, propylene glycol, glycerol, di- or tripropylene glycol, waxes, methyl cellosolve, cellosolve, esters, morpholines, dioxane, dimethyl sulphoxide, dimethylformamide, tetrahydrofuran, cyclohexanone, etc. Cellulose ethers which can dissolve or swell both in water or in organic solvents, such as hydroxypropylmethyl cellulose, methyl cellulose or ethyl cellulose, or soluble starches, can be used as film-forming agents.

Mixtures of gelatinizing agents and film-forming agents are also perfectly possible. In this case, use is made, in particular, of ionic macromolecules such as sodium carboxymethyl cellulose, polyacrylic acid, polymethacrylic acid and their salts, sodium amylopectin semiglycolate, alginic acid or propylene glycol alginate as the sodium salt, gum arabic, xanthan gum, guar gum or carrageenan. The following can be used as additional formulation aids: glycerol, paraffin of differing viscosity, triethanolamine, collagen, allantoin and novantisolic acid. Use of surfactants, emulsifiers or wetting agents, for example of Na lauryl sulphate, fatty alcohol ether sulphates, di-Na-N-lauryl-β-iminodipropionate, polyethoxylated castor oil or sorbitan monooleate, sorbitan monostearate, polysorbates (e.g. Tween), cetyl alcohol, lecithin, glycerol monostearate, polyoxyethylene stearate, alkylphenol polyglycol ethers, cetyltrimethylammonium chloride or mono-/dialkylpolyglycol ether orthophosphoric acid monoethanolamine salts can also be required for the formulation. Stabilizers, such as montmorillonites or colloidal silicic acids, for stabilizing emulsions or preventing the breakdown of active substances such as antioxidants, for example tocopherols or butylhydroxyanisole, or preservatives, such as p-hydroxybenzoic acid esters, can likewise be used for preparing the desired formulations.

Preparations for parenteral administration can be present in separate dose unit forms, such as ampoules or vials. Use is preferably made of solutions of the active compound, preferably aqueous solution and, in particular, isotonic solutions and also suspensions. These injection forms can be made available as ready-to-use preparations or only be prepared directly before use, by mixing the active compound, for example the lyophilisate, where appropriate containing other solid carrier substances, with the desired solvent or suspending agent.

Intranasal preparations can be present as aqueous or oily solutions or as aqueous or oily suspensions. They can also be present as lyophilisates which are prepared before use using the suitable solvent or suspending agent.

lnhalable preparations can present as powders, solutions or suspensions. Preferably, inhalable preparations are in the form of powders, e.g. as a mixture of the active ingredient with a suitable formulation aid such as lactose. The preparations are produced, aliquoted and sealed under the customary antimicrobial and aseptic conditions

As indicated above, the compounds of the invention may be administered as a combination therapy with further active agents, e g therapeutically active compounds useful in the treatment of central nervous system disorders These further compounds may be PDE10 inhibitors or compounds which have an activity which is not based on PDE10 inhibition such as dopamine D2 receptor modulating agents or NMDA modulating agents

For a combination therapy, the active ingredients may be formulated as compositions containing several active ingredients in a single dose form and/or as kits containing individual active ingredients in separate dose forms The active ingredients used in combination therapy may be co-administered or administered separately

The invention will be described in greater detail by way of specific examples The following examples are offered for illustrative purposes, and are not intended to limit the invention in any manner Those of skill in the art will readily recognize a variety of noncπtical parameters which can be changed or modified to yield essentially the same results

Examples

The compounds in Table 1 were prepared according to Scheme 1 using the corresponding bromide or iodide as alkylating agents Compound 8-(dιfluoromethoxy)-6-fluoro-3,4- dιmethyl-1-(3-methylpyπdιn-4-yl)ιmιdazo[1 ,5- a]quιnoxalιne (Ex 4) was prepared using sodium chlorodifluoroacetate as the alkylating agent

Example 1 6-Fluoro-3,4-dimethyl-1-(3-methylpyridin-4-yl)imidazo[1,5-a]quinoxalin-8-ol To a solution of 6-fluoro-8-methoxy-3,4-dimethyl-1-(3-methylpyridin-4-yl)imidazo[1 ,5- a]quinoxaline (see U.S. Ser. No. 12/277,844, which is incorporated herein by reference in its entirety) in CICH₂CH₂CI (5 ml_) was added dropwise tribromoborane (0.129 mL, 1.368 mmol) at 0 ⁰C. The resulting orange suspension was warmed to 80 ⁰C overnight. The reaction was quenched with sodium carbonate solution, extracted with ethyl acetate (3X). Evaporation of solvent followed by column chromatography (50-100% ethyl acetate in dichloromethane followed by 10% methanol in dichloromethane) provided the product 6- fluoro-3,4-dimethyl-1-(3-methylpyridin-4-yl)imidazo[1 ,5-a]quinoxalin-8-ol (80 mg, 0.248 mmol, 91 %). ¹H NMR (400 MHz, DMSO) δ ppm 10.39 (s, 1H), 8 .69 (s, 1 H), 8.61 (d, J = 4.8 Hz, 1 H), 7.45 (d, J = 5.0 Hz, 1 H), 6.72 (dd, J = 11.9, 2.5 Hz, 1 H), 6.27 (dd, J = 2.2, 1.4 Hz, 1H), 2.75 (s, 3H), 2.70 (s, 3H), 2.00 (s, 3H).

Example 2 δ^Cyclopropylmethoxy^θ-fluoro-S^-dimethyl-I^S-methylpyridin^-yOimidazofi.S- ajquinoxaline

To a mixture of 6-fluoro-3,4-dimethyl-1-(3-methylpyridin-4-yl)imidazo[1 ,5-a]quinoxalin-8-ol (60 mg, 0.186 mmol) and cesium carbonate (91 mg, 0.279 mmol) in 2 mL of DMF was added a solution of (bromomethyl)cyclopropane (40 mg, 0.296 mmol) in 1 mL of DMF. The resulting mixture was stirred at 100 ⁰C for 1 hour and cooled to rt. Standard work-up followed by column chromatography (50-80% ethyl acetate in dichloromethane) provided the product 8-(cyclopropylmethoxy)-6-fluoro-3,4-dimethyl-1 -(3-methylpyridin-4- yl)imidazo[1 ,5-a]quinoxaline (13 mg, 0.035 mmol, 18.55 %). ¹H NMR (400 MHz, DMSO) δ ppm 8 .72 (s, 1 H), 8.63 (d, J = 5.0 Hz, 1 H), 7.51 (d, J = 4.9 Hz, 1 H), 7.00 (m, 1 H), 6.22 (m, 1 H), 3,38 (m, 2H), 2.78 (s, 3H), 2.72 (s, 3H), 2.02 (s, 3H), 1.02 (m, 1 H), 0.56 (m, 2H), 0.18(m, 2H).

Examples 3-10 were prepared using methods analogous to those of Example 1 and 2.

Example 3 8-Ethoxy-6-fluoro-3,4-dimethyl-1-(3-methylpyridin-4-yl)imidazo[1,5-a]quinoxaline

¹H NMR (400MHz, DMSO) δ ppm 8.72 (s, 1 H), 8.63 (d, J = 4.9 Hz, 1 H), 7.52 (d, J = 4.9 Hz, 1H), 7.00 (dd, J = 12.1 , 2.6 Hz, 1H), 6.21 (dd, J = 2.4, 1.5 Hz, 1H), 3.61 (m, 2H), 2.78 (s, 3H), 2.72 (s, 3H), 2.02 (s, 3H), 1.10 (t, J = 7.0 Hz, 3H).

Example 4 8-(Difluoromethoxy)-6-fluoro-3,4-dimethyl-1-(3-methylpyridin-4-yl)imidazo[1,5- a]quinoxaline

¹H NMR (400 MHz, DMSO) δ ppm 8.71 (s, 1 H), 8.62 (d, J = 4.9 Hz, 1 H), 7.51 (d, J = 4.9 Hz, 1 H), 7.32 (dd, J = 10.9, 2.5 Hz, 1 H), 6.98 (t, J = 72.8 Hz, 1 H), 6.50 (d, J = 1.9 Hz, 1 H), 2.82 (s, 3H), 2.74 (s, 3H), 2.02 (s, 3H).

Example 5

6-Fluoro-3,4-dimethyl-1-(3-methylpyridin-4-yl)-8-(2,2,2-trifluoroethoxy)imidazo[1,5- a]quinoxaline

¹H NMR (400 MHz, DMSO) δ ppm 8.71 (s, 1 H), 8.63 (d, J = 4.9 Hz, 1 H), 7.52 (d, J = 4.9 Hz, 1 H), 7.26 (dd, J = 11.8, 2.7 Hz, 1H), 6.29 (d, J = 1.6 Hz, 1H), 4.50 (m, 2H), 2.79 (s, 3H), 2.73 (s, 3H), 2.03 (s, 3H).

Example 6

6-Fluoro-3,4-dimethyl-1-(3-methylpyridin-4-yl)-8-(pyridin-2-ylmethoxy)imidazo[1,5- a]quinoxaline

¹H NMR (400 MHz, DMSO) δ ppm 8.64 (s, 1 H), 8.60 (d, J = 4.9 Hz, 1 H), 8.53 (m, 1 H), 7.78 (m, 1 H), 7.48 (d, J = 4.9 Hz, 1 H), 7.32 (m, 1 H), 7.27 (d, J = 7.8 Hz, 1 H), 7.15 (m, 1 H), 6.36 (dd, J = 2.5, 1.4 Hz, 1 H), 4.82 (d, J = 13.1 Hz, 1 H), 4.76 (d, J = 13.0 Hz, 1 H), 2.78 (s, 3H), 2.72 (s, 3H), 1.97 (s, 3H).

Example 8 6-Fluoro-3,4-dimethyl-1-(3-methylpyridin-4-yl)-8-(pyridin-4-ylmethoxy)imidazo[1,5- ajquinoxaline

¹H NMR (400 MHz, DMSO) δ ppm 8.66 (s, 1 H), 8.61 (d, J = 4.7 Hz, 2H), 8.52 (dd, J = 4.4, 1.5 Hz, 1H), 7.47 (d, J = 4.9 Hz, 1H), 7.10-7.18 (m, 3H), 6.27 (dd, J = 2.4, 1.5 Hz, 1H), 4.87 (d, J = 14.0 Hz, 1 H), 4.82 (d, J = 14.1 Hz, 1H), 2.78 (s, 3H), 2.71 (s, 3H), 1.97 (s, 3H).

Example 9

6-Fluoro-3,4-dimethyl-1-(3-methylpyridin-4-yl)-8-(quinolin-2-ylmethoxy)imidazo[1,5- ajquinoxaline

¹H NMR (400 MHz, DMSO) δ ppm 8.55 (s, 2H), 8.36 (d, J = 8.5 Hz, 1 H), 7.96 (m, 2H), 7.76 (m, 1H), 7.49 (d, J = 5.0 Hz, 1 H), 7.40 (d, J = 8.5 Hz, 1 H) 7.20 (m, 1 H), 6.37 (m, 1 H), 5.05 (d, J = 13.4 Hz, 1 H), 4.96 (d, J = 13.3 Hz, 1H), 2.78 (s, 3H), 2.70 (s, 3H), 1.90 (s, 3H).

Example 10

8-(1,3-Benzothiazol-2-ylmethoxy)-6-fluoro-3,4-dimβthyl-1-(3-mβthylpyridin-4- yl)imidazo[1 ,5-a]quinoxaline

¹H NMR (400 MHz, DMSO) δ ppm 8.70 (s, 1 H), 8.65 (d, J = 5.0 Hz, 1 H), 8.09 (d, J = 7.4 Hz, 1H), 8.01 (d, J = 7.8 Hz, 1H), 7.60 (m, 1H), 7.52 (m, 1H), 7.46 (m, 1H), 7.27 (m, 1H), 6.41 (s, 1 H), 5.34 (d, J = 14.3 Hz, 1 H), 5.27 (d, J = 14.3 Hz, 1 H), 2.78 (s, 3H), 2.71 (s, 3H)₁ 1.99 (s, 3H).

The compounds in Table 2 were prepared according to Scheme 2 using the corresponding bromide or iodide as alkylating agents. Compound 8-(difluoromethoxy)-6-methoxy-3,4- dimethyl-1-(2-methylpyridin-3-yl)imidazo[1 ,5- a]quinoxaline (Ex. 13) was prepared using sodium chlorodifluoroacetate as the alkylating agent. Compound 8-(benzyloxy)-6-methoxy- 3,4-dimethyl-1-(2-methylpyridin-3-yl)imidazo[1 ,5-a]quinoxaline (Ex. 11 ) was prepared from 5-(benzyloxy)-1 ,3-difluoro-2-nitrobenzene following the same procedure for preparing 8- fluoro-6-methoxy-3,4-dimethyl-1-(3-methylpyridin-4-yl)imidazo[1 ,5-a]quinoxaline (see U.S. Ser. No. 12/277,844, which is incorporated herein by reference in its entirety).

Example 11

8-(Benzyloxy)-6-methoxy-3,4-dimethyl-1-(2-methylpyridin-3-yl)imidazo[1,5- a]quinoxaline

¹H NMR (400 MHz, DMSO) δ ppm 8 70 (m, 1 H), 7 88 (m, 1 H), 7 46 (m, 1 H), 7 32 (m, 3H), 7 18 (m, 2H), 6 71 (d, J = 2 5 Hz, 1 H), 6 09 (d, J = 2 4 Hz, 1 H), 4 62 (d, J = 11 9 Hz, 1 H), 4 58 (d, J = 11 9 Hz, 1 H), 3 86 (s, 3H), 2 74 (s, 3H), 2 70 (s, 3H), 2 14 (s, 3H)

Example 12 6-Methoxy-3,4-dimethyl-1-(2-methylpyridin-3-yl)imidazo[1,5-a]quinoxalin-8-ol

A mixture of 8-(benzyloxy)-6-methoxy-3,4-dιmethyl-1-(2-methylpyπdιn-3-yl)ιmιdazo[1 ,5- ajquinoxaline (500 mg, 1 178 mmol) and palladium on carbon (62 7 mg, 0 059 mmol) in a 250 ml_ flask was vacuumed and refilled with nitrogen Solvents of THF (8 ml.) and MeOH (8 00 mL) were added successively, followed by addition of ammonium formate (371 mg, 5 89 mmol) The final mixture was stirred at 50 °C for 2-3 hours, then cooled to room temperature and filtered through celite, extensively washed the celite pad with methanol and ethyl acetate Filtrate was evaporated to provide clean offwhite powder of 6-methoxy-3,4- dimethyl-1-(2-methylpyridin-3-yl)imidazo[1 ,5-a]quinoxalin-8-ol (362 mg, 1.083 mmol, 92 %). 1H NMR (400 MHz, DMSO) δ ppm 8.68 (m, 1 H), 8.43 (s, 1 H), 7.82 (m, 1 H), 7.41 (m, 3H), 6.46 (d, J = 2.3 Hz, 1 H), 5.95 (d, J = 2.3 Hz, 1 H), 3.82 (s, 3H), 2.71 (s, 3H), 2.68 (s, 3H), 2.12 (s, 3H).

Example 13

8-(DifIuoromethoxy)-6-methoxy-3,4-dimethyl-1-(2-methylpyridin-3-yl)imidazo[1,5- a]quinoxaline

1H NMR (400 MHz, DMSO) δ ppm 8.70 (m, 1H), 7.88 (m, 1H), 7.43 (m, 3H), 6.90 (t, J = 72.4 Hz, 1 H), 6.87 (d, J = 2.5 Hz, 1 H), 6.20 (d, J = 2.5 Hz, 1 H), 3.90 (s, 3H), 2.77 (s, 3H), 2.72 (s, 3H), 2.13 (S₁ 3H).

Example 15 8-Fluoro-3,4-dimethyl-1-(3-methylpyridin-4-yl)imidazo[1,5-a]quinoxalin-6-ol

To a mixture of 8-fluoro-6-methoxy-3,4-dimethyl-1-(3-methylpyridin-4-yl)imidazo[1 ,5- a]quinoxaline (200 mg, 0.595 mmol) (see U.S. Ser. No. 12/277,844, which is incorporated herein by reference in its entirety) in dichloroethane (10 ml_) was added boron tribromide

(0.5 mL, 5.29 mmol) at 0 ⁰C. The resulting mixture was warmed to 80 ⁰C overnight, cooled to room temperature, quenched with K₂CO3 solution, and extracted with dichloromethane.

Standard work-up followed by column purification (ethyl acetate then 4-8% MeOH in dichloromethane (DCM)) provided the product 8-fluoro-3,4-dimethyl-1-(3-rnethylpyridin-4- yl)imidazo[1 ,5-a3quinoxalin-6-ol (150 mg, 0.465 mmol, 78 %) as a light yellow powder.

MS(ESI) 323.1 [M+H]+. ¹H NMR (400 MHz, DMSO) δ ppm 8.87 (s, 1 H), 8.76 (d, J = 5.4 Hz,

1H), 7.80 (d, J = 5.3 Hz, 1H), 6.79 (dd, J = 10.5, 2.7 Hz, 1H), 6.15 (dd, J = 10.4, 1.5 Hz,

1 H), 2.87 (s, 3H), 2.74 (s, 3H), 2.14 (s, 3H).

Example 16

6-Chloro-3,4-dimethyl-1-(3-methylpyridin-4-yl)-8-(trifluoromethyl)imidazo[1,5- a]qυinoxaline The compound of Example 16 was prepared according to the process set out in Scheme 3.

Step 1. 2-Fluoro-4-(trifluoromethyl)aniline (5 g, 27.9 mmoi) [Matrix Scientific P.O. Box 25067

Columbia, SC 29224-5067 USA] was dissolved in acetonitrle (100 ml_). To this was added N-chlorosuccinamide (4g, 30.7 mmol). The reaction was heated to 75 ⁰C for 16 hrs whcih was then poured into water and extracted with ether. The organic layer was separated, washed with saturated aqueous sodium bicarbonate, washed with water, brined, and dried over MgSO₄. The resulting solution was filtered and the solvent removed under reduced pressure. 2-Chloro-6-fluoro-4-(trifluoromethyl)aniline (5.2 g) was recovered as a yellow oil. Mass spectrum [(+)ESI] m/z = 212.8 [M-H]⁺.

Step 2.

Sodium perborate tetrahydrate (7.3 g, 46.8 mmol) was suspended in glacial acetic acid (30 mL) and heated to 50 ⁰C. To this was added dropwise a solution of 2-chloro-6-fluoro-4- (trifluoromethyl)aniline (2 g, 9.37 mmol) dissolved in glacial acetic acid (20 mL). The reaction was stirred for 16 hrs at 50 ⁰C. The reaction was then poured into water and extracted with ether. The organic layer was separated and washed with water, then washed with dilute aqueous bicarbonate solution and brined. The organic layer was then dried over MgSO₄ and filtered. The solvent was removed under reduced pressure and the crude purified by flash chromatography on silica gel in hexane. 1-Chloro-3-fluoro-2-nitro-5- (trifluoromethyi)benzene (1.17 g) was recovered as a brown oil. Mass spectrum [(+)ESI] m/z = 242.8 [M-H]⁺.

Step 3.

1-Chloro-3-fluoro-2-nitro-5-(trifluoromethyl)benzene (1.1 g, 4.5 mmol) and 4-methyl-1 H- imidazole (0.371 g, 4.5 mmol) were dissolved in dimethylformamide (DMF) (10 mL). To this mixture was added potassium carbonate (1.2 g, 9.0 mmol). The reaction was left to stir at room temperature for 16 hrs. The reaction was poured into water and extracted with ethyl acetate. The organic layer was separated and washed with water then brined and dried over MgSO₄. The solution was then filtered and the solvent removed under reduced pressure. The crude was purified by flash chromatography on silica gel in 10:2 hexane/ ethyl acetate yeilding 1 -(3-Chloro-2-nitro-5-(trifluoromethyl)phenyl)-4-methyl-1 H-imidazole (0.74 g) as a tan solid. Mass spectrum [(+)ESI] m/z = 306.0 [M-H]⁺.

Step 4.

1-(3-Chloro-2-nitro-5-(trifluoromethyl)phenyl)-4-methyl-1 H-imidazole (0.74 g, 2.4 mmol) was dissolved in a solution of glacial acetic acid and ethanol (10 mL each). To this mixture was added iron powder (0.81 g, 14.4 mmol). The reaction was heated to 100 ⁰C for 1 hr. The reaction was poured into aqueous sodium hydroxide 1 N and extracted with ethyl acetate. The organic layer was separated then washed with water, brined, and dried over MgSO₄. The resulting solution was filtered and the solvent removed under reduced pressure. An off- white solid (0.68 g) was recovered yielding product 2-chloro-6-(4-methyl-1 H-imidazol-1-yi)-4- (trifluoromethyl)aniline. Mass spectrum [(+)ESI] m/z = 274.1 [M-H]⁺.

Step 5.

2-Chloro-6-(4-methyl-1 H-imidazol-1-yl)-4-(trifluoromethyl)aniline (2 g, 7.26 mmol) was dissolved in a solution of glacial acetic acid (20 mL) and acetic anhydride (10 mL). To this was then added 10 drops of concentrated sulfuric acid. The reaction was left to stir at room temperature for 48 hrs. The reaction was poured into ice water and extracted with ethyl acetate. The organic layer was separated, washed with water, washed with saturated Na₂CO₃ then water, brined, and dried over MgSCU and filtered. The solvent was removed under reduced pressure to afford a tan solid which was N-(2-chloro-6-(4-methyl-1 H- imidazol-1 -yl)-4-(trifluoromethyl)-phenyl)acetamide (1.7 g). Mass spectrum [(+)ESI] m/z = ■ 316.1 [M-H]⁺.

Step 6. N-(2-Chloro-6-(4-methyl-1 H-imidazol-1-yl)-4-(trifluoromethyl)phenyl)acetamide (1.0 g, 3.15 mmol) was suspended in phosphorousoxychloride (10 ml_). To this was added phosphorous pentoxide (3 g, 12.6 mmol). The reaction was heated to 115 ⁰C for 16 hrs. The reaction was then poured slowly into ice water/methanol and made basic with 50% sodium hydroxide. The resulting solution was extracted with ethyl acetate and the organic layer separated and washed with water, brined, and dried over MgSO₄. The solution was then filtered and the solvent removed under reduced pressure. The crude was purified by flash chromatography on silica gel in 1 :1 hexanes/ethyl acetate. A tan solid of 6-chloro-3,4- dimethyl-8-(trifluoromethyl)-imidazo[1 ,5-a]quinoxaline (0.57 g) was recovered. Mass spectrum [(+JESI] m/z = 300.0 [M-H]⁺.

Step 7.

6-Chloro-3,4-dimethyl-8-(trifluoromethyl)imidazo[1 ,5-a]quinoxaline (0.57 g, 1.902 mmol) was suspended in acetonitrle (50 mL). To this was added N-bromosuccinamide (1.3 g, 7.6 mmol). The reaction was protected from light and stirred at room temperature for 48 hrs. The reaction was then poured into water and extracted with ethyl acetate. The organic layer was separated and washed with water then brined and dried over MgSO₄ , and then filtered. The solvent was removed under reduced pressure and the crude purified by flash chromatography on silica gel in 10:2 hexane/ ethyl acetate. A tan solid (0.63 g, 1 -bromo-6- chloro-3,4-dimethyl-8-(trifluoromethyl)imidazo[1 ,5-a]quinoxaline) was collected. Mass spectrum [(+)ESI] m/z = 378.0 [M-H]⁺.

Step 8.

1-Bromo-6-chloro-3,4-dimethyl-8-(trifluoromethyl)imidazo[1 ,5-a]quinoxaline (0.1 g, 0.264 mmol) was suspended in a solution of dioxane (4 mL) and water (1 mL). To this was added potassium carbonate (71 mg, 0.53 mmol) followed by 3-methylpyridin-4-ylboronic acid (0.054 g, 0.396 mmol) [Asymchem Laboratories, Inc. 600 Airport Blvd., Suite 1000 Morrisville, NC 27560 USA]. Argon was bubbled thru the reaction and tetrakis(triphenylphosphine)palladium(0) (10%mol, 30 mg) was added. The reaction was sealed and heated to 1 10 ⁰C for 3 hrs. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was separated, brined, dried over MgSO₄, and filtered. Solvent was removed under reduced pressure. The crude was purified by flash chromatography on silica gel in ethyl acetate. The title compound was recovered as a white solid (70 mg, 45% yield). Mass spectrum [(+)ESI] m/z = 391.1 [M-H]⁺. ¹H NMR (400 MHz, DMSO) δ ppm 8.8 (d, 1 H), 8.65 (s, 1 H), 7.75 (s, 1 H), 7.4 (d, 1 H), 7.2 (s, 1 H), 3.0 (s, 3H), 2.9 (s, 3H), 2.1 (s, 3H).

The following example compounds of the invention can be made according to one or more of the above-described procedures. For example, the compounds of Examples 17-19 can be made according to the procedures for preparing the compounds of Tables 1 and 2.

Further procedures useful in preparing the compounds of the invention can also be found in

U.S. Ser. Nos. 12/277,844 and 12/277,961 , each of which is incorporated herein by reference in its entirety.

Example 17

8-(Benzyloxy)-6-methoxy-3,4-dimethyl-1-(4-methylpyridin-3-yl)imidazo[1,5- a]quinoxaline

Example 18 6-Methoxy-3,4-dimethyl-1-(4-methylpyridin-3-yl)imidazo[1,5-a]quinoxalin-8-ol

Example 19

8-(Difluoromethoxy)-6-methoxy-3,4-dimethyl-1-(4-methylpyridin-3-yl)imidazo[1,5- a]quinoxaline

The compounds of Tables 3-5 can be prepared, for example, according to the methods described in U S Ser No 12/277,961 , which is incorporated herein by reference in its entirety

Table 3

The compounds in Table 6 can be synthesized in a manner similar to the compound of Example 16 starting with 2,6-difluoro-4-trifluoromethyl aniline (see EP 315869 which is incorporated herein by reference in its entirety).

The compounds in Table 7 can be synthesized in a manner similar to Example 16 starting with 3-chloro-5-fluoroanιsole (Aldrich Chemical Company, lnc 1001 West Saint Paul Avenue Milwaukee, Wl 53233 USA)

Table 7

The compounds in Table 8 can be synthesized in a manner simmiiar to Example 16 starting with 4-chloro-2,6-dιfluoroanιlιne (ABCR GmbH & CO KG Im Schlehert 10 D-76187 Karlsruhe GERMANY)

Example A

Inhibition of PDE10 in vitro assays

Method 1

Phosphodiesterase isoenzyme 10 (PDE10) activity can be determined in preparations of rat, pig and guinea pig striatum respectively Striatum from male Wistar rats (180-200 g), male hybrid pigs (150 kg) and male guinea pigs (CRL (HA), 500 g) respectively are collected and frozen at -7O⁰C

At the day of preparation, 0 5 g of striatum is homogenised in 10 ml 50 mM Tπs/Mg-buffer at 4°C and centrifuged for one hour at 100000 g The supernatant is called the cytosohc fraction and is removed and stored on ice The pellet is resuspended in the same buffer, but containing 1 %Tπton and incubated for 45 mm at 4 ⁰C Both fractions are independently applied onto a 5 mL Hi TrapTM QHP column at the Akta-FPLC After washing the columns, the bound PDE protein is eluted with an increasing sodium chloride gradient (0 mM-500mM sodium chloride) in 50 mM Tπs/Mg-buffer at 4°C for the cytosolic fraction and in the presence of 1 % Triton for the membrane fraction The eluted and collected fractions are tested with 100 nM [^H]-CAMP for PDE10-actιvιty in the presence of and without a specific PDE-lnhibitor at a concentration where a 100% inhibition is expected The fractions with PDE10-actιvιty were pooled and frozen in aliquots until use at -20°C PDE10 activity is determined in a one step procedure in microtiter plates. The reaction mixture of 100 μL contains 50 mM Tris-HCI/5 mM MgCI₂ buffer (pH=7.4) (Sigma,

Deisenhofen, Germany; Merck, Darmstadt, Germany) 0.1 μM [³H]-CAMP (Amersham, Buckinghamshire, UK) and the enzyme. Nonspecific activity is tested without the enzyme. The reaction is initiated by addition of the substrate solution and is carried out at 37 ⁰C for 30 minutes. Enzymatic activity is stopped by addition of 25 μL YSi-SPA-beads (Amersham- Pharmacia). One hour later the mixture is measured in a liquid scintillation counter for microtiter plates (Microbeta Trilux). To pipette the incubation mixture, a robot Biomek (Fa. Beckman) is used. The determined Km-va!ues for the substrate cAMP are 78 nM for PDE10 from rat striatum, 88 nM for pig striatum, and 66.7 nM for guinea pig striatum respectively. cGMP is the second substrate for PDE10. The Km values are 1800 nM, 2200 nM and 1700 nM for PDE10 from these species. For tests with cGMP, 500 nM of this substrate is used. The optimal amount of enzyme in the assay can be determined and optimized for each enzyme preparation and substrate separately before using the enzyme in compound testing. For determination of IC₅₀ values the Hill-plot, 2-parameter-model, can be used. Specific inhibitors of other PDE-subtypes do not inhibit the PDE10 preparation significantly. Papaverine is used as the most common PDE10 inhibitor and inhibits the PDE 10 with IC50 values of 142 nM, 110 nM and 77 nM for PDE 10 from striatum of rat, pig and guinea pig respectively.

Method 2

Phosphodiesterase isoenzyme 10 (PDE10) activity was determined in preparations of human recombinant PDE10A and PDE10 from pig striatum respectively.

The DNA of PDE10A1 (AB 020593, 2340 bp) was synthesized and cloned into the vector pCFM.TOPO (Entelechon GmbH, Regensburg, Germany). The gene was than inserted into a baculovirus vector, ligated with the baculovirus DNA. The enzyme-protein was expressed in SF21 -cells. The enzyme was isolated from these cells by harvesting the cells by a centrifugation at 200 g to collect the cells. The cells were resuspended in 50 mM Tris-HCI/5 mM MgCl2 buffer (pH=7.4) and lysed by a sonication of the cells. The cytosolic PDE10A was obtained by a centrifugation at 48000 g for 1 h in the supernatant and stored at -70 ⁰C.

Striatum from male hybrid pigs (150kg) were collected and frozen at -7O⁰C. At the day of preparation 0.5 g striatum was homogenised in 10ml 5OmM Tris/Mg-buffer at 4 ⁰C and centrifuged for one hour at 100000 g. The supernatant was removed and the pellet was resuspended in the same buffer, but containing 1 %Triton and incubated for 45 min at 4 ⁰C. The membrane fraction was applied onto a 5 ml Hi TrapTM QHP column at the Akta- FPLC. After washing the column, the bound PDE protein was eluted with an increasing sodium chloride gradient (0 mM-500 mM sodium chloride) in 50 mM Tris/Mg-buffer at 4⁰C in the presence of 1 % Triton. The eluted and collected fractions were tested with 100 nM [3H]- cAMP for PDE10-activity in the presence of and without a specific PDE-lnhibitor at a concentration where a 100% inhibition is expected. The fractions with PDE10-activity were pooled and frozen in aliquots until use at -20 °C.

PDE10 activity was determined in a one step procedure in microtiterplates. The reaction mixture of 100 μL contained 50 mM Tris-HCI/5 mM MgCI2 buffer (pH=7.4) (Sigma, Deisenhofen, Germany; Merck, Darmstadt, Germany) 0.1 μM [3H]-cAMP (Amersham,

Buckinghamshire, UK) and the enzyme. Nonspecific activity was tested without the enzyme. The reaction was initiated by addition of the substrate solution and was carried out at 37 ⁰C for 30 minutes. Enzymatic activity was stopped by addition of 25 μL YSi-SPA-beads (Amersham-Pharmacia). One hour later the mixture was measured in a liquid scintillation counter for microtiterplates (Microbeta Trilux). To pipette the incubation mixture a robot

Biomek (Fa. Beckman) is used. The determined Km-values for the substrate cAMP were 88 nM for pig striatum and 130 nM for human recombinant PDE10A respectively. The optimal amount of enzyme in the assay was determined and optimized for each enzyme preparation before using the enzyme in compound testing. For determination of IC50 values the Hill-plot, 2-parameter-model, was used. Specific inhibitors of other PDE-Subtypes do not inhibit the PDE10 preparation significantly. Papaverine was used as the most common PDE10 inhibitor and inhibits the PDEIO with IC50 values of 89 nM and 103 nM for PDE10 from human recombinant PDE10A and PDE10 from striatum of pig respectively.

Certain compounds of the invention were tested for hPDEI O inhibition according to the above assay. Table 10 below sets out the inhibition (IC₅₀) data.

Table 10

Example B

Rat Model for Psychosis

Female Wistar rats (CrI: (Wl) BR, Charles River, Sulzfeld, Germany) weighing 150 to 180 g can be used for testing MK-801 -induced psychosis. Animals are housed under standard conditions in groups of five on a 12 h light/dark cycle (light on at 0600 h) with ad libitum access to food (Pellets, ssniff M/R 15, Spezialdiat GmbH, Soest/Westfalen) and water. MK- 801 (dizocilpine, MW 337.37) is obtained by Tocris, distributed by Biotrend Chemikalien GmbH, KoIn, Germany.

Compounds are freshly suspended in 0.5% hydroxyethylcellulose so that an administration volume of 0.5 ml/100 g is reached for each substance and dose. Hydroxyethylcellulose is solved in distilled water. MK-801 is dissolved in saline so that an administration volume of 0.5 ml/100 g is reached. The suspensions and solutions are placed on a magnetic stirrer before and during dosing procedures.

The behaviour induced by the NMDA antagonist MK-801 is generally accepted as a rat model of psychosis. MK-801 induces stereotyped sniffing, hyperactivity and ataxia in rats after intraperitoneal administration.

Locomotor activity of the rats is recorded by the MotiTest Apparatus (TSE, Bad Homburg, Germany). The test area consists of a squared arena (45 x 45 cm) with protective plexiglass walls (20 cm of height) where rats can freely move. Horizontal movements are recorded by 32 infrared photocells arranged along the bottom of each wall of the arena. The activity [sec] is measured by the computer program "ActiMot" (TSE, Bad Homburg, Germany).

Stereotyped sniffing is scored by the experimenter every five minutes for one hour (12 intervals) according to the method described by Andine et al. (1999). The scores of the 12 intervals are summed up at the end of the recording time.

The day of the experiment, the female rats are placed in the laboratory and receive the test compound or vehicle at the appropriate time prior to test. MK-801 0.1 mg/kg is intraperitoneal^ administered 10 minutes prior to test. At the beginning of the test the rats are placed in the center of the squared arena of the MotiTest apparatus. Behaviour of the rats is recorded for one hour. After each run, animals are removed and the boxes thoroughly cleaned and dried.

Results are analysed by one way analysis of variance (ANOVA). Tukey test can be used for individual comparison. P < 0.05 is generally regarded as significant.

Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference, including all patents, patent applications, and journal literature, cited in the present application is incorporated herein by reference in its entirety.

Claims

What is claimed is:

1. A compound of Formula (I):

I or a pharmaceutically acceptable salt thereof, wherein:

R¹ is a 5-6 membered monocyclic heteroaryl group optionally substituted with

1. 2, 3, or 4 substituents independently selected from halo, C_1-4alkyl, and C_1-4 haloalkyl;

R² is Ci-₄ alkyl;

R³ is Ci-₄ alkyl;

R⁴ is H, halo, C_L4 alkyl, C_1-4 haloalkyl, or OR⁶;

R⁵ is H, halo, C_1-4 alkyl, C_1-4 haloalkyl, or OR⁷; and

R⁶ and R⁷ are independently selected from H, Ci_-4 alkyl, Ci_-4 haloalkyl, (C_1-4 alkyl)sulfonyl, (C_1-4 haloalkyl)sulfonyl, (C_3-7 cycloalkyl)-C_1-4 alkyl, (C₆-ioaryl)-C_1-4 alkyl, and (C₃. ₈ heteroaryl)-Ci_-4 alkyl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R¹ is a 6-membered monocyclic heteroaryl group optionally substituted with 1 , 2, 3, or 4 substituents independently selected from halo, C_1-4 alkyl, and C_1-4 haloalkyl.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R¹ is a pyridinyl group optionally substituted with 1 , 2, 3, or 4 substituents independently selected from halo, Ci_-4 alkyl, and Ci_-4 haloalkyl.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R¹ is a pyridin-3-yl or pyridin-4-yl group optionally substituted with 1 , 2, 3, or 4 Ci.₄ alkyl.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R¹ is a pyridin-3-yl or pyridin-4-yl group optionally substituted with methyl.

6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R² is methyl.

7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R³ is methyl.

8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R⁴ is OR⁶.

9. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R⁴ is C_Λ.₄ haloalkyl.

10. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R⁴ is halo.

11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R⁵ is halo.

12. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R⁵ is OR⁷.

13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R⁶ is H.

14. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R⁶ is d.₄alkyl.

15. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R⁶ is C_1-4 haloalkyl.

16. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R⁶ is (C_3-7 cycloalkyl)-Ci.₄ alkyl.

17. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R⁶ is (C_3-8 heteroaryQ-C-_M alkyl.

18. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R⁶ is pyridinylmethyi, quinolinylmethyl, or benzothiazolylmethyl.

19. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R⁶ is (C₆-io

alkyl.

20. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R⁶ is benzyl.

21. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R⁶ is (C_1-4 haloalkyl)sulfonyl.

22. The compound of any one of claims 1 to 21 , or a pharmaceutically acceptable salt thereof, wherein R⁷ is Ci_-4 alkyl.

23. The compound of any one of claims 1 to 21 , or a pharmaceutically acceptable salt thereof, wherein R⁷ is methyl.

24. The compound of any one of claims 1 to 21 , or a pharmaceutically acceptable salt thereof, wherein R⁷ is H.

25. The compound of any one of claims 1 to 21 , or a pharmaceutically acceptable salt thereof, wherein R⁷ is H, C_1-4alkyl, C^ haloalkyl, (C₁^ alkyl)sulfonyl, (C_1-4 haloalkyl)sulfonyl, (C_6-io aryl)-C₁.₄ alkyl, and (C_3-8 heteroaryO-C^ alkyl.

26. A compound of claim 1 having Formula II:

or a pharmaceutically acceptable salt thereof.

27. The compound of claim 26, or a pharmaceutically acceptable salt thereof, wherein:

R¹ is a 6-membered monocyclic heteroaryl group optionally substituted with 1 , 2, 3, or 4 substituents independently selected from halo, C_1^1 alkyl, and C_1-4 haloalkyl;

R⁴ is halo, C_1-4 alkyl, C_1-4 haloaikyl, or OR⁶;

R⁵ is halo, C_1-4 alkyl, C_1-4 haloalkyl, or OR⁷;

R⁶ is H, C_1-4 alkyl, C_1-4 haloalkyl, (C_1-4 alkyl)sulfonyl, (C_1-4 haloalkyl)sulfonyl, (C_3-7 cycloalkyl)-C_M alkyl, (C₆.₁₀ aryl)-Ci.₄ alkyl, or (C₃.₈ heteroaryO-C^ alkyl; and

R⁷ is H or C_1-4 alkyl.

28. The compound of claim 27, or a pharmaceutically acceptable salt thereof, wherein R¹ is a pyridinyl group optionally substituted with 1 , 2, 3, or 4 substituents independently selected from halo, Ci.₄alkyl, and Ci-₄ haloalkyl.

29. The compound of claim 28, or a pharmaceutically acceptable salt thereof, wherein R¹ is a pyridin-3-yl or pyridin-4-yl group, each optionally substituted with C_1-4 alkyl.

30. A compound of claim 1 having Formula HIa or IMb:

HIa IHb or a pharmaceutically acceptable salt thereof, wherein R is Ci_-4 alkyl.

31. The compound of claim 30, or a pharmaceutically acceptable salt thereof, wherein:

R⁴ is OH, methoxy, ethoxy, halomethyloxy, haloethyloxy, pyridinylmethyloxy, quinolinylmethyloxy, benzothiazolylmethyloxy, benzyloxy, halomethylsulfonyloxy, fluoro, chloro, or halomethyl;

R⁵ is fluoro, chloro, methoxy, or OH.

32. The compound of claim 30 or 31 , or a pharmaceutically acceptable salt thereof, wherein R is methyl.

33. The compound of claim 1 selected from: 6-fluoro-3,4-dimethyl-1-(3-methylpyridin-4-yl)imidazo[1 ,5-a]quinoxalin-8-ol; 8-(cyclopropyimethoxy)-6-fIuoro-3,4-dimethyl-1-(3-methylpyridin-4- yl)imidazo[1 ,5-a]quinoxaline;

8-ethoxy-6-fluoro-3,4-dimethyl-1-(3-methylpyridin-4-yl)imidazo[1 ,5- ajquinoxaline;

8-(difluoromethoxy)-6-fluoro-3,4-dimethyl-1-(3-methylpyridin-4-yl)imidazo[1 ,5- a]quinoxaline;

6-fluoro-3,4-dimethyl-1-(3-methylpyridin-4-yl)-8-(2,2,2-trifluoroethoxy)- imidazo[1 ,5-a]quinoxaline; 6-fluoro-3,4-dimethyl-1-(3-methylpyridin-4-yl)-8-(pyridin-2-ylmethoxy)- imidazo[1 ,5-a]quinoxaline;

6-fluoro-3,4-dimethyl-1-(3-methylpyridin-4-yl)-8-(pyridin-3-ylmethoxy)- imidazo[1 ,5-a]quinoxaline;

6-fluoro-3,4-dimethyl-1-(3-methylpyridin-4-yl)-8-(pyridin-4-ylmethoxy)- imidazo[1 ,5-a]quinoxaline;

6-fluoro-3,4-dimethyl-1-(3-methylpyridin-4-yl)-8-(quinolin-2-ylmethoxy)- imidazo[1 ,5-a]quinoxaline; δ^i .S-benzothiazol^-ylmethoxyVβ-fluoro-S^-dimethyl-I^S-methylpyridin^- yl)imidazo[1 ,5-a]quinoxaline;

8-(benzyloxy)-6-methoxy-3,4-dimethyl-1-(2-methylpyridin-3-yl)imidazo[1 ,5- a]quinoxaline;

6-methoxy-3,4-dimethyl-1-(2-methylpyridin-3-yi)imidazo[1 ,5-a]quinoxalin-8-ol;

8-(difiuoromethoxy)-6-methoxy-3,4-dimethyl-1 -(2-methylpyridin-3- yl)imidazo[1 ,5- a]quinoxaline;

6-methoxy-3,4-dimethyl-1-(2-methylpyridin-3-yl)imidazo[1 ,5-a]quinoxalin-8-yl trifluoromethanesulfonate;

8-fluoro-3,4-dimethyl-1-(3-methylpyridin-4-yl)imidazo[1 ,5-a]quinoxalin-6-ol; δ-chloro-S^-dimethyl-I ^S-methylpyridin^-yO-δ-^rifluoromethyOimidazoti .S- a]quinoxaline;

8-(benzyloxy)-6-methoxy-3,4-dimethyl-1 -(4-methylpyridin-3-yl)imidazo[1 ,5- a]quinoxaline;

6-methoxy-3,4-dimethyl-1-(4-methylpyridin-3-yl)imidazo[1 ,5-a]quinoxalin-8-ol;

8-(difluoromethoxy)-6-methoxy-3,4-dimethyi-1-(4-methylpyridin-3- yl)imidazof 1 ,5-a]quinoxaline;

6,8-dimethoxy-4-methyl-1-(4-methylpyridin-3-yl)-3-(trifluoromethyl)imidazo[1 ,5- a]quinoxaline;

6,8-dimethoxy-4-methyl-1-(3-methylpyridin-4-yl)-3-(trifluoromethyl)imidazo[1 ,5- a]quinoxaline;

6,8-dimethoxy-4-methyl-1-(2-methylpyridin-3-yl)-3-(trifluoromethyl)imidazo[1 ,5- a]quinoxaline;

8-(difluoromethoxy)-6-methoxy-4-methyl-1-(4-methylpyridin-3-yl)-3 (trifluoromethyl)imidazo[1 ,5-a]quinoxaline;

8-(difIuoromethoxy)-6-methoxy-4-methyl-1-(3-methylpyridin-4-yl)-3- (trifiuoromethyl)imidazo[1 ,5-a]quinoxaline;

8-(difluoromethoxy)-6-methoxy-4-methyl-1-(2-methylpyridin-3-yl)-3- (trifluoromethyl)imidazo[1 ,5-a]quinoxaline;

6-methoxy-4-methyl-1 -(4-methylpyridin-3-yl)-3,8-bis(trifluoromethyl)imidazo[1 ,5- a]quinoxaline;

6-methoxy-4-methyl-1 -(3-methylpyridin-4-yl)-3,8-bis(trifluoromethyl)imidazo[1 ,5- a]quinoxaline;

6-methoxy-4-methyl-1-(2-methylpyridin-3-yl)-3,8-bis(trifluoromethyl)imidazo[1 ,5- a]quinoxaline; β-methoxy-S^-dimethyl-I ^S-methyipyridin^-yO-δ-^rifluoromethyOimidazoti .S- ajquinoxaline;

6-methoxy-3,4-dimethyl-1-(2-methylpyridin-3-yl)-8-(trifluoromethyl)imidazo[1 ,5- a]quinoxaline;

6-methoxy-3,4-dimethyl-1-(4-methylpyridin-3-yl)-8-(trifluoromethyl)imidazo[1 ,5- ajquinoxaline;

6-chloro-8-methoxy-3,4-dimethy!-1-(3-methylpyridin-4-yl)imidazo[1 ,5- a]quinoxaline;

6-chloro-8-methoxy-3,4-dimethyl-1 -(2-methylpyridin-3-yl)imidazo[1 ,5- a]quinoxaline;

6-chloro-8-methoxy-3,4-dimethyl-1-(4-methylpyridin-3-yl)imidazo[1 ,5- a]quinoxaline; δ-chloro-β-fluoro-S^-dimethyl-i-CS-methylpyridin^-yOimidazofi .S- ajquinoxaline;

8-chloro-6-fluoro-3,4-dimethyl-1 -(2-methylpyridin-3-yl)imidazo[1 ,5- a]quinoxaline; and

8-chloro-6-fluoro-3,4-dimethyl-1-(4-methylpyridin-3-yl)imidazo[1 ,5- ajquinoxaline; or a pharmaceutically acceptable salt of any of the aforementioned.

34. A pharmaceutical composition comprising a compound of any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

35. A method of treating disorders associated with phosphodiesterase 10 hyperactivity, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 33, or pharmaceutically acceptable salt thereof.

36. A method of treating central nervous system disorders in a patient in need thereof comprising, administering to said patient a therapeutically effective amount of a compound of any one of claims 1 to 33, or pharmaceutically acceptable salt thereof.

37. The method of claim 36 wherein the central nervous system disorders are selected from neurological disorders and psychiatric disorders; schizophrenia and other psychotic disorders; mood disorders; neurotic, stress-related and somatoform disorders; eating disorders; sexual dysfunction comprising excessive sexual drive; disorders of adult personality and behavior; disorders usually first diagnosed in infancy, childhood and adolescence; mental retardation; disorders of psychological development; disorders comprising the symptom of cognitive deficits; and factitious disorders.

38. The method of claim 37 wherein the neurological disorders are selected from neurodegenerative disorders; neurodegeneration associated with cerebral trauma; neurodegeneration associated with stroke; neurodegeneration associated with cerebral infarct; hypoglycemia-induced neurodegeneration; neurodegeneration associated with epileptic seizure; and neurodegeneration associated with neurotoxic poisoning or multisystem atrophy.

39. The method of claim 38 wherein the neurodegenerative disorders are selected from Parkinson's disease, Huntington's disease, and dementia.

40. The method of claim 39 wherein the dementia is selected from Alzheimer's disease, multi-infarct dementia, AIDS-related dementia, and fronto temperal dementia.

41. The method of claim 37 wherein the schizophrenia and other psychotic disorders are selected from continuous or episodic schizophrenia; schizotypal disorders; persistent delusional disorders; acute, transient and persistent psychotic disorders; induced delusional disorders; schizoaffective disorders of different types; puerperal psychosis; and other unspecified nonorganic psychosis.

42. The method of claim 37 wherein the mood disorders are selected from manic episodes associated with bipolar disorder and single manic episodes; hypomania; mania with psychotic symptoms; bipolar affective disorders; depressive disorders; persistent mood disorders; and premenstrual dysphoric disorder.

43. The method of claim 37 wherein the disorders belonging to the neurotic, stress- related and somatoform disorders are selected from phobic anxiety, panic, or general anxiety disorders; obsessive compulsive disorder; reaction to severe stress and adjustment disorders; and dissociative disorders.

44. The method of claim 37 wherein the disorders of adult personality and behavior are selected from specific personality disorders of the paranoid, schizoid, schizotypal, antisocial, borderline, histrionic, narcissistic, avoidant, dissocial, emotionally unstable, anankastic, anxious and dependent type; mixed personality disorders; habit and impulse disorders; and disorders of sexual preference.

45. The method of claim 37 wherein the disorders usually first diagnosed in infancy, childhood and adolescence are selected from hyperkinetic disorders, attentional deficit/hyperactivity disorder (AD/HD), conduct disorders; mixed disorders of conduct and emotional disorders; nonorganic enuresis, nonorganic encopresis; stereotyped movement disorder", attention deficit disorder without hyperactivity, excessive masturbation nail-biting, nose-picking and thumb-sucking; disorders of psychological development particularly schizoid disorder of childhood and pervasive development disorders.

46. The method of claim 37 wherein the disorders of psychological development are selected from developmental disorders of speech and language, developmental disorders of scholastic skills which disorders are predominantly diagnosed in infancy, childhood and adolescence.

47. The method of claim 37 wherein the disorders comprising as a symptom cognitive deficits are selected from cognitive deficits primarily but not exclusively related to psychosis; age-associated memory impairment, Parkinson's disease, Alzheimer's disease, multi infarct dementia, Lewis body dementia, stroke, frontotemporal dementia, progressive supranuclear palsy Huntington's disease and in HIV disease, cerebral trauma, drug abuse and mild cognitive disorder.

48. The method of claim 36 wherein the disorders are selected from movement disorders with malfunction of basal ganglia selected from focal dystonias, multiple-focal or segmental dystonias, torsion dystonia, hemispheric, generalised and tardive dyskinesias, akathisias, dyskinesias selected from Huntington's disease, Parkinson's disease, Lewis body disease, restless leg syndrome, and PLMS.

49. The method of claim 36 wherein the disorders are organic disorders selected from symptomatic mental disorders; organic delusional (schizophrenia-like) disorders; presenil or senile psychosis associated to dementia, to psychosis in epilepsy and Parkinson's disease and other organic and symptomatic psychosis; delirium; infective psychosis; and personality and behavioural disorders due to brain disease, damage and dysfunction.

50. The method of claim 36 wherein the disorders are mental and behavioral disorders due to psychoactive compounds, psychotic disorders, and residual and late-onset psychotic disorders induced by alcohol, opioids, cannabinoids, cocaine, hallucinogens, caffeine, volatile solvents and other psychoactive compounds.

51. A method of improving learning and memory capacities comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 33, or pharmaceutically acceptable salt thereof.

52. A method of treating obesity, type 2 diabetes, metabolic syndrome, or glucose intolerance comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 33, or pharmaceutically acceptable salt thereof.

53. The method of claim 52 wherein said patient is overweight or obese.

54. The method of claim 52 wherein the compound is a selective PDE10 inhibitor.

55. The method of claim 52 further comprising administering a further therapeutic agent.

56. The method of claim 55 wherein said further therapeutic agent is an anti- obesity agent.

57. A method of reducing body fat or body weight in a patient comprising administering to said patient in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 33, or pharmaceutically acceptable salt thereof.

58. The method of claim 57 wherein said patient is overweight or obese.

59. The method of claim 57 wherein the compound is a selective PDE10 inhibitor.

60. The method of claim 57 further comprising administering a further therapeutic agent.

61. The method of claim 60 wherein said further therapeutic agent is an anti- obesity agent.

62. A method of treating pain conditions and disorders in a patient comprising administering to said patient in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 33, or pharmaceutically acceptable salt thereof.

63. The method of claim 62 wherein the pain conditions and disorders are selected from inflammatory pain, hyperalgesia, inflammatory hyperalgesia, migraine, cancer pain, osteoarthritis pain, post-surgical pain, non-inflammatory pain, neuropathic pain, peripheral neuropathic pain syndromes, chemotherapy-induced neuropathy, complex regional pain syndrome, HIV sensory neuropathy, neuropathy secondary to tumor infiltration, painful diabetic neuropathy, phantom limb pain, postherpetic neuralgia, postmastectomy pain, trigeminal neuralgia, central neuropathic pain syndromes, central poststroke pain, multiple sclerosis pain, Parkinson disease pain, and spinal cord injury pain.

64. The method of claim 62 wherein the compound, or pharmaceutically acceptable salt thereof, is administered in combination with one or more other agents effective for treating pain.

65. The method of claim 64 wherein the one or more other agents are selected from analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), opiods and antidepressants.

66. The method of claim 64 wherein the one or more other agents are selected from buprenorphine, naloxone, methadone, levomethadyl acetate, L-alpha acetylmethadol (LAAM), hydroxyzine, diphenoxylate, atropine, chlordiazepoxide, carbamazepine, mianserin, benzodiazepine, phenoziazine, disulfuram, acamprosate, topiramate, ondansetron, sertraline, bupropion, amantadine, amiloride, isradipine, tiagabine, baclofen, propranolol, tricyclic antidepressants, desipramine, carbamazepine, valproate, lamotrigine, doxepin, fluoxetine, imipramine, moclobemide, nortriptyline, paroxetine, sertraline, tryptophan, venlafaxine, trazodone, quetiapine, Zolpidem, zopiclone, zaleplon, gabapentin, memantine, pregabalin, cannabinoids, tramadol, duloxetine, milnacipran, naltrexone, paracetamol, metoclopramide, loperamide, clonidine, lofexidine, and diazepam.

67. A pharmaceutical composition or kit which comprises at least one compound of any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, in combination with at least one further pharmaceutically active compound.

68. The composition or kit of claim 67 wherein the further active compound is a therapeutically active compound useful in the treatment of central nervous system disorders which is not based on PDE10 inhibition.