HK1177739B - 2-arylimidazole derivatives as pde10a enzyme inhibitors - Google Patents

Description

2-arylimidazole derivatives as PDE10A enzyme inhibitors

Technical Field

The present invention provides heterocyclic compounds which are PDE10A enzyme inhibitors, and their use for the treatment of neurodegenerative and psychiatric disorders. In particular, the invention provides compounds which are highly selective for PDE10 over other PDE isoforms. The invention also provides pharmaceutical compositions comprising the compounds of the invention and methods of treating diseases using the compounds of the invention.

Background

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

The cyclic nucleotides cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) act as second messengers within cells to regulate a large number of activities of neurons. Intracellular cAMP and cGMP are produced by adenine cyclase and guanine cyclase and are degraded by cyclic nucleotide Phosphodiesterases (PDEs). Intracellular levels of cAMP and cGMP are controlled by intracellular signal transduction, and stimulation/inhibition of adenine cyclase and guanine cyclase in response to G protein-coupled receptor (GPCR) activation is a well-defined pathway to control cyclic nucleotide concentrations (Antoni, f.a. front. neuroendicrinol. 2000, 21, 103-132). In turn, levels of cAMP and cGMP control the activity of cAMP and cGMP-dependent kinases and other proteins with cyclic nucleotide response elements that regulate key neuronal functions such as prominent transmission, neuronal differentiation and survival through subsequent protein phosphorylation and other processes.

The 21 phosphodiesterase genes can be divided into 11 gene families. There are 10 families of adenylate cyclases, 2 families of guanylate cyclases, and 11 families of phosphodiesterases. PDEs are a class of intracellular enzymes that regulate levels of cAMP and cGMP by hydrolyzing cyclic nucleotides to their respective nucleotide monophosphates. Some PDEs degrade cAMP, some cGMP, and some both cAMP and cGMP. Most PDEs, although some are more tissue specific, are widely expressed and function in a variety of tissues.

Phosphodiesterase 10A (PDE10A) is a dual specificity phosphodiesterase capable of converting both cAMP to AMP and cGMP (Loughney, K.et al; Gene 1999, 234, 109-117; Fujishige, K.et al; Eur. J. biochem. 1999, 266, 1118-1127 and Soderling, S.et al; Proc. Natl. Acad. Sci. 1999, 96, 7071-7076). PDE10A is primarily expressed by neurons of the striatum, nucleus accumbens, and olfactory tubercle (Kotera, J. et al; biochem, Biophys, Res. Comm. 1999, 261, 551-557 and Seeger, T.F. et al; Brain Research, 2003, 985, 113-126).

Mouse PDE10A is the first member of the PDE10 family of established phosphodiesterases (Fujishige, K. et al. J. biol. chem. 1999, 274, 18438-18445 and Loughney, K. et al. Gene 1999, 234,109-117), and splice variants at the N-terminus of rat and human genes have been identified (Kotera, J. et al. biochem. Biophys. Res. Comm. 1999, 261, 551-557 and Fujishige, K. et al. Eur. J. biochem. 1999, 266, 1118-1127). There is a high degree of cross-species homology. PDE10A is uniquely present in mammals relative to other PDE families. The mRNA of PDE10A is highly expressed in testis and brain (Fujishige, K. et al, Eur J biochem 1999, 266, 1118-1127; Soderling, S. et al, Proc. Natl. Acad. Sci. 1999, 96, 7071-7076 and Loughney, K. et al, Gene 1999, 234, 109-117). These studies showed that PDE10A is most highly expressed in the striatum (caudate and putamen), nucleus accumbens and olfactory tubercle in the brain. Recently, the expression patterns of PDE10A mRNA (Seeger, T.F. et al. Abst. Soc. neurosci. 2000, 26, 345.10) and PDE10A protein (Mennitii, F.S. et al. William Harvey Research Conference 'phosphorus metabolism in Health and Disease', Porto, Portugal, Dec. 5-7, 2001) in rodent brain were analyzed.

PDE10A is expressed at high levels by the caudate nucleus, the Medium Spiny Neuron (MSN) of the nucleus accumbens, and the corresponding neurons of the olfactory tubercle. These constitute the core of the basal nucleus system. MSNs play a key role in the cortical-basal ganglia-thalamocortical loop, integrating the convergent cortical/thalamic inputs, and sending this integrated information back to the cortex. MSN expresses two functional classes of neurons: expression of D₁Dopamine receptor D₁Class and expression D₂Dopamine receptor D₂And (4) class. D₁Neurones are part of the "direct" striatal output pathway, which is widely used to facilitate behavioral responses. D₂Neurones are part of an "indirect" striatal output pathway that is used to inhibit behavioral responses, competing with behavioral responses promoted via a "direct" pathway. These competing pathways act like brakes and accelerators in a car. In the simplest terms, a lack of activity in parkinson's disease is due to overactivity of the "indirect" pathway, whereas excessive movement in disease (e.g. Huntington's disease) represents overactivity of the "direct" pathway. PDE10A modulates cAMP and/or cGMP signaling within the dendritic compartments of these neurons may be involved in filtering cortical/thalamic inputs within the MSN. Moreover, PDE10A may be involved in the regulation of GABA release in substantia nigra and globus pallidus (Seeger, T.F. et al Brain Research, 2003, 985, 113-126).

Antagonism of the dopamine D2 receptor is well established in the treatment of schizophrenia. Dopamine D since the 50 s of the twentieth century₂Receptor antagonism has been the mainstay of psychiatric treatment and all potent antipsychotics antagonize D₂A receptor. D₂Probably the effects of (A) are mediated mainly by neurons of the striatum, nucleus accumbens and olfactory tubercles, since these regions receive the highest density of dopaminergic projections and have the highest probability ofStrong D₂Receptor expression (Konradi, C. and Heckers, S. Society of Biological Psychiatry, 2001, 50, 729-742). Dopamine D₂Receptor agonism causes a decrease in intracellular cAMP levels by inhibition of adenylate cyclase, which is D₂Components of Signal Transduction (Stoof, J. C.; Kebabian J.W. Nature 1981, 294, 366-368 and Neve, K.A. et al. Journal of Receptors and Signal Transduction 2004, 24, 165-205). In contrast, D₂Antagonism of the receptor effectively increases cAMP levels, which can be mimicked by inhibition of phosphodiesterases that degrade cAMP.

Most of the 21 phosphodiesterase genes are widely expressed, and thus inhibition may have side effects. Herein, because PDE10A has desirable expression profiles with high and relatively specific expression in neurons of the striatum, nucleus accumbens and olfactory tubercles, PDE10A inhibition may have similarities to D₂The effect of receptor antagonism and thus has an antipsychotic effect.

Although PDE10A inhibition is expected to partially mimic D₂Antagonism of the receptor, it is expected that it may have different characteristics. D₂The receptor has a Signal Transduction component in addition to cAMP (New, K.A. et al. Journal of Receptors and Signal Transduction 2004, 24, 165-205), and thus interfering with cAMP by PDE10A inhibition can be negatively regulated rather than by D₂The receptor directly antagonizes dopamine signaling. This can be reduced at a strong D₂Risk of extravertebral side effects seen in antagonism. Conversely, PDE10A inhibition may have some at D₂An unseen effect in receptor antagonism. PDE10A is also expressing D₁Neuronal expression of the striatum of the receptor (Seeger, T.F. et al Brain Research, 2003, 985, 113-126). Because D₁Receptor agonism causes stimulation of adenylate cyclase leading to elevated cAMP levels, PDE10A inhibition may also have a mimetic D₁Effect of receptor agonism. Finally, because PDE10A is a bispecific phosphodiesterase, PDE10A inhibition not only increases intracellular cAMP, but is also expected to increase cGThe level of MP. cGMP, like cAMP, activates a number of target proteins within the cell and also interacts with the signal transduction pathway of cAMP. In general, PDE10A inhibition may partially mimic D₂Receptor antagonism thus has antipsychotic effects, but this profile may be different from the use of classical D₂As observed for receptor antagonists.

The PDE10A inhibitor papaverine was shown to be active in several antipsychotic models. Papaverine promotes D in rats₂The systemic stiffness effect of the receptor antagonist haloperidol, but not alone (WO 03/093499). Papaverine reduced PCP-induced hyperexcitability in rats, but not significantly amphetamine-induced hyperexcitability (WO 03/093499). These models suggest that PDE10A inhibition has the traditional antipsychotic potential that would be expected from theoretical considerations. WO 03/093499 further discloses the use of selective PDE10 inhibitors for the treatment of related neurological and psychiatric disorders. In addition, PDE10A inhibition reversed sub-chronic PCP-induced deficits in rat attention-placement-metastasis (Rodefer et al Eur. J. Neurosci. 2005, 4, 1070-1076). This model suggests that PDE10A inhibition may alleviate cognitive deficits associated with schizophrenia.

The tissue distribution of PDE10A suggests that PDE10A inhibitors may be used to increase the levels of cAMP and/or cGMP within cells expressing the PDE10 enzyme, particularly neurons comprising the basal nucleus, and therefore the PDE10A inhibitors of the present invention may be used to treat a variety of related neuropsychiatric conditions involving the basal nucleus, such as neurological and psychiatric disorders, schizophrenia, bipolar disorders, obsessive compulsive disorders, and the like, and may have the advantage of being free of unwanted side effects associated with currently existing treatments on the market.

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

As regards PDE10A inhibitors, EP 1250923 discloses that selective PDE10A inhibitors in general (especially papaverine) are used for the treatment of certain neurological and psychiatric disorders.

WO 05/113517 discloses stereospecific compounds of benzodiazepine as inhibitors of phosphodiesterases (especially type 2 and 4) and for the prevention and treatment of pathological conditions involving central and/or peripheral disorders. WO 02/88096 discloses benzodiazepine derivatives and their use as phosphodiesterase (especially type 4) inhibitors in the therapeutic field. WO 04/41258 discloses benzodiazepine derivatives and their use in the therapeutic field as phosphodiesterase (especially type 2) inhibitors.

WO 05/03129 and WO 05/02579 disclose pyrrolodihydroisoquinolines and variants thereof as PDE10 inhibitors. WO 05/82883 discloses piperidinyl-substituted quinazolines and isoquinolines as PDE10 inhibitors. WO 06/11040 discloses substituted quinazoline and isoquinoline compounds as inhibitors of PDE 10. US20050182079 discloses substituted tetrahydroisoquinolinyl derivatives of quinazolines and isoquinolines as potent Phosphodiesterase (PDE) inhibitors. In particular, US20050182079 relates to said compounds which are selective PDE10 inhibitors. Similarly, US 20060019975 discloses piperidine derivatives of quinazolines and isoquinolines as potent Phosphodiesterase (PDE) inhibitors. US 20060019975 also relates to compounds that are selective PDE10 inhibitors. WO 06/028957 discloses phthalazinone derivatives as phosphodiesterase type 10 inhibitors for the treatment of psychiatric and neurological syndromes.

However, these disclosures are not relevant to the compounds of the present invention, which are structurally unrelated to any known PDE10 inhibitors (Kehler, j. et al. Expert opin. ther. Patents 2007, 17, 147-158 and Kehler, j. et al. Expert opin. Patents 2009, 19, 1715-1725), and the present inventors found that they are highly active and selective inhibitors of the PED10A enzyme.

Summary of The Invention

It is an object of the present invention to provide compounds which are selective PDE10A enzyme inhibitors.

It is a further object of the present invention to provide compounds having such activity which have improved solubility, metabolic stability and/or bioavailability compared to prior art compounds.

It is another object of the present invention to provide effective treatment, particularly long-term treatment, in human patients without causing side effects which are usually associated with existing treatments for neurological and psychiatric disorders.

Other objects of the invention will become apparent upon reading this specification.

Accordingly, one aspect of the present invention relates to compounds of formula I and tautomers, pharmaceutically acceptable salts and polymorphs thereof:

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

wherein Y may be N or CH, Z may be N or C, and wherein HET-1 may be optionally substituted with up to three substituents R7, R8, and R9, R7, R8, and R9 are independently selected from H, C₁-C₆Alkyl (e.g., methyl), halogen (e.g., chloro and bromo), cyano, halo (C)₁-C₆) Alkyl (e.g. trifluoromethyl), aryl (e.g. phenyl), alkoxy (e.g. methoxy, dimethoxy, ethoxy, methoxy-ethoxy and ethoxy-methoxy) and C₁-C₆Hydroxyalkyl (e.g. CH)₂CH₂OH), wherein x denotes the point of attachment,

-L-is selected from-S-CH₂-、-CH₂-S-、-CH₂-CH₂-, -CH = CH-anda linker of (a);

r1 is selected from H; c₁-C₆Alkyl groups such as methyl, ethyl, 1-propyl, 2-propyl, isobutyl; c₁-C₆Alkyl radical (C)₃-C₈) Cycloalkyl groups such as cyclopropylmethyl; c₁-C₆Hydroxyalkyl radicals, such as the hydroxyethyl radical; CH (CH)₂CN；CH₂C(O)NH₂；C₁-C₆Aralkyl groups such as benzyl and 4-chlorophenylmethyl; and C₁-C₆Alkyl-heterocycloalkyl, such as tetrahydroxypyran-4-yl-methyl and 2-morpholin-4-yl-ethyl;

wherein Q is phenyl, optionally substituted with 1,2 or 3 substituents or Q is a monocyclic 5-or 6-membered heteroaryl group containing 1 or 2 heteroatoms, preferably Q is selected from the structure of the formula wherein "-" denotes the point of attachment:

wherein each of R2-R6 is independently selected from H, C₁-C₆ Alkoxy (e.g., methoxy), and halo (e.g., chloro and fluoro);

in separate embodiments of the present invention, the compound of formula I is selected from the specific compounds disclosed in the experimental part of the present specification.

The invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof for use as a medicament.

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

The invention further provides the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a neurodegenerative or psychiatric disorder.

In addition, in other aspects, the invention provides a method of treating a patient suffering from a neurodegenerative disorder comprising administering to the patient a therapeutically effective amount of a compound of formula I. In other aspects, the invention provides a method of treating a patient suffering from a psychiatric disorder comprising administering to the patient a therapeutically effective amount of a compound of formula I. In another embodiment, the invention provides a method of treating a patient suffering from a drug addiction, for example, an alcohol, amphetamine, cocaine, or opiate addiction.

Detailed Description

Definition of substituents

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

The term "C₁-C₆Alkyl "refers to straight or branched chain saturated hydrocarbons having 1 to 6 (including 1 and 6) carbon atoms. Examples of such groups include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-2-propyl, 2-methyl-1-butyl, and n-hexyl. Expression "C₁-C₆Hydroxyalkyl "means C as defined above substituted by one hydroxy group₁-C₆An alkyl group. The term "halo (C)₁-C₆) Alkyl "means C as defined above₁-C₆Alkyl, substituted with up to three halogen atoms, such as trifluoromethyl.

Expression "C₁-C₆Alkoxy "means a groupStraight-chain or branched, saturated alkoxy having 1 to 6 (including 1 and 6) carbon atoms, which has an open valency on an oxygen atom. Examples of such groups include, but are not limited to, methoxy, ethoxy, n-butoxy, 2-methyl-pentoxy, and n-hexoxy.

The term "C₃-C₈Cycloalkyl "is typically intended to mean cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. Expression "C₁-C₆Alkyl radical (C)₃-C₈) Cycloalkyl "means C which is straight or branched chain₁-C₆Alkyl substituted C as defined above₃-C₈A cycloalkyl group. Examples of such groups include, but are not limited to, cyclopropylmethyl.

The term "heterocycloalkyl" refers to a 4-8 membered ring containing carbon atoms and up to 3N, O or S atoms, provided that the 4-8 membered ring does not contain an adjacent O or an adjacent S atom. The open valency is either on a heteroatom or on a carbon atom. Examples of such groups include, but are not limited to, azetidinyl, oxetanyl, piperazin-1-yl, morpholinyl, thiomorpholinyl, and [1, 4]]Diazapentyl. The term "heterocycloalkylalkyl" refers to a heterocycloalkyl group as defined above substituted with one hydroxy group. The term "C₁-C₆Alkyl-heterocycloalkyl "means substituted by C₁-C₆Alkyl-substituted heterocycloalkyl group as defined above. Examples of such groups include, but are not limited to, tetrahydroxypyran-4-yl-methyl and 2-morpholin-4-yl-ethyl.

The term "aryl" refers to a phenyl ring, optionally substituted by halogen, C, as defined above₁-C₆Alkyl radical, C₁-C₆Alkoxy or halo (C)₁-C₆) Alkyl groups are substituted. Examples of such groups include, but are not limited to, phenyl and 4-chlorophenyl.

The term "C₁-C₆Arylalkyl "means a straight or branched chain C₁-C₆Aryl as defined above substituted with alkyl. Examples of such groups include, but are not limited to, benzyl and 4-chlorophenylmethyl.

In addition, the present invention also provides certain embodiments of the invention described below.

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

HET-1 is preferably selected from heteroaryl wherein "+" denotes the point of attachment

。

In a further embodiment, one or more hydrogen atoms in the compound of formula I are replaced with deuterium. In particular when R₇-R₉When it is methyl or methoxy, the hydrogen is replaced by deuterium.

In each separate embodiment of the invention, the compound of formula I is selected from the following specific compounds, which are present in the form of their free bases, one or more tautomers or pharmaceutically acceptable salts. Table 1 lists the compounds of the invention and the corresponding IC's measured as described in the section "PDE 10A inhibition assay₅₀The value is obtained. Each compound constitutes a separate embodiment of the invention.

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

Table 1: compounds of the invention and IC₅₀Value of

In a particular embodiment of the invention, the IC of the compounds of the invention₅₀Values of less than 50nM, for example in the range of 0.2-20 nM, in particular in the range of 0.2-10 nM, for example in the range of 0.2-5 nM or in the range of 0.2-1 nM.

Pharmaceutically acceptable salts

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

Representative examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, sulfamic acid, nitric acid, and the like. Representative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, itaconic, lactic, methanesulfonic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylenesalicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids, theophylline acetic acids, and 8-halotheophyllines such as 8-bromotheophylline and the like. Examples of other pharmaceutically acceptable acid addition salts of inorganic or organic acids include the pharmaceutically acceptable salts listed in Berge, s.m. et al, j. pharm. sci. 1977, 66, 2, the contents of which are incorporated herein by reference.

In addition, the compounds of the present invention may exist in a non-dissolved form, or may exist in a dissolved form dissolved in a pharmaceutically acceptable solvent such as water, ethanol, and the like. In general, for the purposes of the present invention, a dissolved form is considered to be equivalent to a non-dissolved form.

Pharmaceutical composition

The invention also provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula I in combination with a pharmaceutically acceptable carrier or diluent. The present invention also provides pharmaceutical compositions comprising a therapeutically effective amount of one of the particular compounds disclosed in the experimental section herein, together with a pharmaceutically acceptable carrier or diluent.

The compounds of the present invention may be administered alone or in combination with a pharmaceutically acceptable carrier, diluent or excipient, in a single dose or in multiple doses. The pharmaceutical compositions of the invention may be formulated with pharmaceutically acceptable carriers or diluents and any other known adjuvants and excipients, according to conventional techniques such as Remington: science and practice of pharmacy, 19 th^thVersion, Gennaro, ed., Mack Publishing co., Easton, PA, 1995.

The pharmaceutical compositions may be specifically formulated for any suitable route such as oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal, and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous, and intradermal). It will be appreciated that the route of administration will depend on the general condition and age of the patient being treated, the nature of the condition being treated and the active ingredient.

Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. Suitably, the composition may be prepared in accordance with methods known in the art together with a coating (e.g. enteric coating) or may be formulated to provide controlled release, e.g. sustained or prolonged release, of the active ingredient. Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs. Pharmaceutical compositions for parenteral administration include sterile aqueous or non-aqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions prior to use. Other suitable forms of administration include, but are not limited to, suppositories, sprays, ointments, creams, gels, inhalants, dermal patches and implants.

Typical oral dosages range from about 0.001 to about 100mg/kg body weight per day. Typical oral dosages also range from about 0.01 to about 50mg/kg body weight per day. Typical oral dosages further range from about 0.05 to about 10mg/kg body weight per day. Oral doses are usually administered one or more times, usually 1-3 times per day. The precise dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the patient being treated, the nature and severity of the condition being treated and any concomitant diseases which require treatment, as well as other factors which will be apparent to those skilled in the art.

The formulations may also be presented in dosage unit form by methods known to those skilled in the art. For purposes of illustration, a typical orally administered dosage unit form includes from about 0.01 to about 1000mg, from about 0.05 to about 500mg, from about 0.5mg to about 200 mg.

For parenteral routes such as intravenous, intrathecal, intramuscular and similar forms of administration, the typical dose is half that used for oral administration.

The present invention also provides a process for preparing a pharmaceutical composition comprising mixing a therapeutically effective amount of a compound of formula I with at least one pharmaceutically acceptable carrier or diluent. In an embodiment of the invention, the compound used in the aforementioned method is a specific compound disclosed in the experimental section herein.

The compounds of the present invention are generally utilized as the free substance or a pharmaceutically acceptable salt thereof. An example is an acid addition salt of a compound having the function of a free base. When the compound of formula I contains a free base, such salts are obtained in a conventional manner by treating a solution or suspension of the free base of formula I with a molar equivalent of a pharmaceutically acceptable acid. Representative examples of organic and inorganic acids are described above.

For parenteral administration, sterile aqueous solutions of the compounds of formula I, aqueous propylene glycol, aqueous vitamin E or solutions of sesame or peanut oil may be used. If necessary, such aqueous solutions should be suitably buffered and the liquid diluent first treated with sufficient salt or glucose to be isotonic. The aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The compounds of formula I can be readily added to known sterile aqueous media by using standard techniques known to those skilled in the art.

Suitable pharmaceutical carriers include inactive solid diluents or fillers, sterile aqueous solutions and various organic solvents. Examples of solid carriers include lactose, terra alba, sucrose, cyclodextrin, mica, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and lower alkyl ethers of cellulose. Examples of liquid carriers include, but are not limited to, syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene, and water. Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. The pharmaceutical compositions formed by combining the compounds of formula I with a pharmaceutically acceptable carrier are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration. The formulations may conveniently be presented in dosage unit form by methods well known in the art of pharmacy.

Formulations of the invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and optionally suitable excipients. In addition, the orally available formulations may be in the form of powders or granules, solutions or suspensions in aqueous or non-aqueous liquids, or oil-in-water or water-in-oil liquid emulsions.

If the solid carrier is to be used for oral administration, the medicament may be in the form of a tablet, or in the form of a powder or minitablet placed into a hard gelatin capsule, or it may be in the form of a troche or lozenge. The amount of solid carrier varies widely, but is in the range of from about 25mg to about 1g per dosage unit. If a liquid carrier is used, the medicament may be in the form of a syrup, emulsion, soft gelatin capsule, or sterile injectable liquid such as an aqueous or nonaqueous liquid suspension or solution.

The pharmaceutical composition of the present invention may be prepared by a method conventional in the art. For example, tablets may be prepared by mixing the active ingredient with conventional adjuvants and/or diluents and compressing the mixture in a conventional tableting machine. Examples of adjuvants or diluents include: corn flour, potato flour, talcum powder, magnesium stearate, gelatin, lactose, gums, and the like. Any other adjuvant or additive commonly used for such purposes, such as coloring agents, flavoring agents, preservatives and the like, may be used so long as it is compatible with the active ingredient.

A therapeutically effective amount

As used herein, the term "therapeutically effective amount" of a compound refers to an amount sufficient to cure, alleviate or partially arrest the clinical manifestations of a given disease and its complications during a therapeutic intervention that includes the use of the combination. An amount sufficient to achieve the above goal is defined as a "therapeutically effective amount". The effective amount for different purposes depends on the severity of the disease or injury as well as the weight and general condition of the patient. It will be appreciated that determination of the appropriate dose may be achieved using routine experimentation by constructing a matrix of values and detecting the various points in the matrix, all within the general skill of a trained physician.

Herein, the terms "treatment" and "treating" mean the management and care of a patient for the purpose of combating a condition, such as a disease or disorder. The term is intended to include the complete measure of treatment of a condition suffered by a given patient, such as the use of the compound to alleviate a syndrome or complication, delay the development of a disease, disorder or condition, alleviate or ameliorate a syndrome or complication, and/or treat or eliminate a disease, disorder or condition, wherein prevention is understood to mean the treatment and care of the patient against the disease, disorder or condition, including the use of the active compound to prevent the onset of the syndrome or complication. Nevertheless, prophylactic (preventative) and therapeutic (curative) treatment are two separate parts of the present invention. The patient to be treated is preferably a mammal, in particular a human being.

Treatment of disease

As mentioned above, the compounds of formula I are PDE10A enzyme inhibitors and are therefore useful in the treatment of related neurological and psychiatric disorders.

The present invention therefore provides a compound of formula I or a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutical composition comprising the compound, for use in the treatment of a neurodegenerative disorder, a psychiatric disorder or drug addiction in a mammal, including a human; wherein the neurodegenerative disorder is selected from Alzheimer's disease, multi-infarct dementia, alcoholic dementia or other drug-related dementia, dementia with intracranial tumors or brain trauma, dementia associated with Huntington's disease or Parkinson's disease or AIDS-related dementia, delirium, amnestic disorders, post-traumatic stress disorder, mental retardation, learning disorders, such as reading disorders, mathematical disorders or writing expression disorders, attention-deficit/hyperactivity disorder, and age-related cognitive decline; wherein the psychiatric disorder is selected from the group consisting of schizophrenia, e.g. delusional, schizotypal, catatonic, undifferentiated or sequela, schizophreniform disorder, schizoaffective disorder, e.g. delusional or depressive type, delusional disorder, substance-induced psychotic disorder, e.g. alcohol, amphetamine, cannabis, cocaine, hallucinogen, inhalants, papaverine-or phencyclidine-induced psychosis, paranoid personality disorder, and schizophreniform personality disorder; wherein the drug addiction is an alcohol, amphetamine, cocaine, or opiate addiction.

The compounds of formula I or pharmaceutically acceptable salts thereof may be used in combination with one or more other drugs for the treatment of diseases or conditions in which the compounds of the invention have utility, wherein the combination of drugs is safer or more effective than either drug alone. In addition, the compounds of the present invention may be used in combination with one or more other drugs that treat, prevent, control, reduce, or reduce the risk or toxicity of side effects of the compounds of the present invention. These additional agents may be administered by a route and in a dosage regimen common to the use of the compounds of the invention, either simultaneously or sequentially. Accordingly, the pharmaceutical compositions of the present invention include those containing one or more other active ingredients in addition to the compounds of the present invention. The combination may be provided as a unit dosage combination product, or as part of a kit of drugs or therapeutic regimens in which one or more additional drugs are administered in separate dosage forms as part of a therapeutic strategy.

The present invention provides a method of treating a mammal, including a human, suffering from a neurodegenerative disorder selected from cognitive disorders or movement disorders, which method comprises administering to the patient a therapeutically effective amount of a compound of formula I.

The invention also provides a method of treating a neurodegenerative disorder or condition in a mammal (including a human) comprising administering to said mammal an amount of a compound of formula I effective to inhibit PDE 10.

The present invention also provides a method of treating a patient suffering from a psychiatric disorder comprising administering to the patient an effective amount of a compound of formula I. Examples of psychotic disorders treatable by the invention include, but are not limited to, schizophrenia, e.g., delusional, schizotypal, catatonic, undifferentiated or sequela, schizophreniform disorder, schizoaffective disorder, e.g., delusional or depressive type, delusional disorder, substance-induced psychotic disorder, e.g., alcohol, amphetamine, cannabis, cocaine, hallucinogen, inhalant, papaverine-or phencyclidine-induced psychosis, personality disorder of paranoid type, and personality disorder of schizophreniform type; specific phobias, social phobias, obsessive compulsive disorders, post-traumatic stress disorders, acute stress disorders, and generalized anxiety disorders.

It has been found that a compound of formula I or a pharmaceutically acceptable salt thereof may advantageously be used in combination with at least one neuroleptic agent, which may be a typical or atypical antipsychotic drug, to provide an improved treatment of psychotic disorders such as schizophrenia. The combinations, uses and methods of treatment of the present invention may also provide advantages in treating patients who fail to respond properly or who are resistant to other known treatments.

The present invention therefore provides a method of treating a mammal suffering from a psychotic disorder, e.g. schizophrenia, which method comprises administering to the mammal a therapeutically effective amount of a compound of formula I, alone or as a combination therapy together with at least one neuroleptic agent.

The term "psychotropic agent" as used herein refers to a class of drugs that have the cognitive and behavioral effects of antipsychotic drugs and are capable of reducing the disturbances, delusions, hallucinations and psychomotor excitation in psychotic patients. Also known as primary sedatives and antipsychotics, neuroleptics include, but are not limited to, typical antipsychotics including phenothiazines, further divided into aliphatics, piperidines and piperazines, thioxanthenes (e.g., flupentixol), butyrophenones (e.g., haloperidol), diphenoxylates (e.g., oxazapine), indolinones (molindone), diphenylbutylpiperidines (e.g., piperacillin), and atypical antipsychotics including benzisoxazoles (e.g., risperidone), schlidine, olanzapine, quetiapine, osanetant and ziprasidone.

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

The invention also provides a method of treating a patient suffering from a cognitive disorder, which comprises administering to the patient a therapeutically effective amount of a compound of formula I. Examples of cognitive disorders that can be treated by the present invention include, but are not limited to, Alzheimer's disease, multi-infarct dementia, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumors or brain trauma, dementia associated with Huntington's disease or Parkinson's disease, or AIDS-related dementia, delirium, amnestic disorders, post-traumatic stress disorder, mental retardation, learning disorders such as reading disorders, mathematical disorders or writing expression disorders, attention-deficit/hyperactivity disorder, and age-related cognitive decline.

The invention also provides a method of treating movement disorders comprising administering to a patient a therapeutically effective amount of a compound of formula I. Examples of movement disorders that can be treated by the present invention include, but are not limited to, Huntington's disease and dopamine agonist-related movement disorders. The present invention also provides a method of treating a movement disorder selected from the group consisting of Parkinson's disease and restless legs syndrome, comprising administering to a patient a therapeutically effective amount of a compound of formula I.

The invention also provides a method of treating a mood disorder comprising administering to a patient a therapeutically effective amount of a compound of formula I. Mood disorders and mood episodes that can be treated by the invention include, but are not limited to, major depressive episodes of the mild, moderate and severe types, manic or mixed mood episodes, hypomanic mood episodes, depressive episodes with typical characteristics, depressive episodes with depressive characteristics, depressive episodes with catatonic schizophrenia characteristics, postpartum-induced mood episodes, post-stroke depression, adult depressive disorders, melancholic disorders, minor depressive disorders, premenstrual dysphoric disorder, post-schizophrenic depressive disorders, component depressive disorders superimposed with psychotic disorders (e.g., delusional disorder or schizophrenia), bipolar disorders such as bipolar I and bipolar II disorders, and cyclothymic disorders. It is understood that mood disorders are mental disorders.

The invention also provides a method of treating drug addiction, for example alcohol, amphetamine, cocaine, or opiate addiction, in a mammal (including a human) which comprises administering to said mammal an amount of a compound of formula I effective in treating drug addiction.

The invention also provides a method of treating a drug addiction, for example an alcohol, amphetamine, cocaine, or opiate addiction, in a mammal, including a human, which method comprises administering to said mammal an amount of a compound of formula I effective in inhibiting PDE 10.

The term "drug addiction" as used herein means an abnormal craving for a drug and is generally characterized by an insecurity of impulsivity, such as a forced intake of the desired drug and a strong onset of drug addiction.

Drug addiction is widely recognized as a pathological condition. Addictive disorders relate to the process of acute drug application to seek development of drug behavior, the ease of relapse, and the retarded ability to respond to declining naturally beneficial stimuli. For example, the fourth edition of diagnostic and statistical manual for mental disorders (DSM-IV) divides addiction into three stages: addiction/early appearance, mania/intoxication, and withdrawal/negative effects. These phases have a persistent craving and enthusiasm for acquisition of substances, use of substances beyond what is needed to experience exciting effects, experience drug resistance, withdrawal syndromes, and a decline in motivation for normal life behavior, respectively.

The present invention also provides a method of treating a disorder including, for example, attention and/or cognitive deficit syndrome, in a mammal (including a human being), which comprises administering to said mammal an amount of a compound of formula I effective to treat said disorder.

Other disorders that can be treated by the present invention are psychogenic/behavioral obsessive compulsive disorder, Tourette's syndrome, and other tic disorders.

As used herein (unless otherwise specified): neurodegenerative diseases or conditions "refer to diseases or conditions caused by dysfunction and/or death of neurons of the central nervous system. Treatment of these diseases and conditions may be facilitated by the application of agents that prevent dysfunction or death of at-risk neurons in these diseases or conditions, and/or enhance the function of damaged or healthy neurons to compensate for loss of function caused by dysfunction or death of at-risk neurons. The term "neurotrophic agent" as used herein refers to a substance or agent having some or all of these characteristics.

Examples of neurodegenerative diseases or conditions that can be treated by the present invention include, but are not limited to, Parkinson's disease, Huntington's disease, dementias such as Alzheimer's disease, multi-infarct dementia, AIDS-related dementia, frontotemporal dementia, neurodegeneration associated with brain trauma, neurodegeneration associated with stroke, neurodegeneration associated with brain infarction, neurodegeneration induced by hypoglycemia, neurodegeneration associated with seizures, neurodegeneration associated with neurotoxin intoxication, and multiple system atrophy.

In one embodiment of the invention, the neurodegenerative disorder or condition involves neurodegeneration of medium spiny neurons of the striatum of mammals, including humans.

In further embodiments of the invention, the neurodegenerative disorder or condition is Huntington's disease.

In other embodiments, the present invention provides methods of treating a patient for reducing body fat or body weight, or for treating non-insulin requiring diabetes (NIDDM), metabolic syndrome, or glucose intolerance, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I. In a preferred embodiment, the patient is a human, the patient is overweight or obese and the oral antagonist is administered. In other preferred embodiments, the method further comprises administering to the patient a second therapeutic agent, preferably an anti-obesity agent, such as rimonabant, orlistat, sibutramine, bromocriptine, ephedrine, leptin, pseudoephedrine, or peptide YY3-36, or an analog thereof.

The term "metabolic syndrome" as used herein refers to various conditions that place a human at high risk for coronary artery disease. These conditions include type 2 diabetes, obesity, hypertension, and poor lipid profile with elevated LDL ("poor"), low HDL ("good"), and elevated triglycerides. All of these conditions are associated with high blood insulin levels. The fundamental defect in metabolic syndrome is insulin resistance in adipose tissue and muscle.

All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference in their entirety for all purposes to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein (to the maximum extent allowed by law).

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

The use of any and all examples, or exemplary language (including "such as," "for example," and "such") in the description of the invention is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed.

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

This invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law.

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

Experimental part

General procedure

Analytical liquid chromatography-mass spectrometry (LC-MS) data were obtained by using any of the methods described below

The method A comprises the following steps:

a PE Sciex API 150EX facility equipped with atmospheric pressure ionization imaging and Shimadzu LC-8A/SLC-10A LC system was used. Column: a Waters Symmetry C18 column of 4.6x30mm with a particle size of 3.5 μm; column temperature: 60 ℃; solvent system: a = water/trifluoroacetic acid (100:0.05) and B = water/acetonitrile/trifluoroacetic acid (5:95: 0.035); the method comprises the following steps: linear gradient elution was performed with a: B =90:10 to 0:100 over 2.4 min at a flow rate of 3.3 mL/min.

The method B comprises the following steps:

a PE Sciex API 300 device equipped with atmospheric pressure ionization imaging and a Waters UPLC system was used. Column: acquisty UPLC BEH C₁₈1.7 μm, 2.1 x50mm (Waters); column temperature: 60 ℃; solvent system: a = water/trifluoroacetic acid (100:0.05) and B = water/acetonitrile/trifluoroacetic acid (5:95: 0.035); the method comprises the following steps: linear gradient elution was performed with a: B =90:10 to 0:100 over 1.0 min at a flow rate of 1.2 mL/min.

The method C comprises the following steps:

a PE Sciex API 150EX facility equipped with atmospheric pressure ionization imaging and Shimadzu LC-8A/SLC-10A LC system was used. Column: a Waters Symmetry C18 column of 4.6x30mm with a particle size of 3.5 μm; column temperature: 60 ℃; solvent system: a = water/trifluoroacetic acid (99.95:0.05) and B = methanol/trifluoroacetic acid (99.965: 0.035); the method comprises the following steps: linear gradient elution was performed with a: B =83:17 to 0:100 over 2.4 minutes at a flow rate of 3.0 mL/min.

Preliminary LC-MS-purification was performed on PE Sciex API 150EX equipment with atmospheric pressure chemical ionization. Column: YMC ODS-A of 50x20mm with A particle size of 5 μm; the method comprises the following steps: linear gradient elution was performed with a: B =80:20 to 0:100 over 7 minutes at a flow rate of 22.7 mL/min. Fragment collection was performed by split-flow MS detection.

¹H Nuclear Magnetic Resonance (NMR) spectra were recorded at 500.13 MHz on a Bruker Avance AV500 instrument and at 250.13 MHz on a Bruker Avance DPX250 instrument. TMS was used as internal standard. Chemical shift values are expressed in ppm. The following abbreviations are used to indicate the varietyNMR signals: s = single peak; d = bimodal; t = triplet; q = quartet; qui = quintuple; h = heptad; dd = doublet; dt = double triplet; dq = doublet of four peaks; tt = triple peak; m = multiplet; br s = wide singlet and br = wide signal.

Abbreviations are guided by ACS type: the ACS Styleguide-author and editor's manual Janet S. Dodd, Ed. 1997, ISBN: 0841234620.

In general: p-toluenesulfonyl hydrazide (98%) was from avocado. 2-phenyl-1H-imidazole-carboxaldehyde is from ASDI.

Preparation of the Compounds of the invention

The compounds of formula I of the present invention can be prepared according to the following reaction schemes. Unless otherwise stated, HET-1, R in the reaction scheme and discussion that follows₁-R₉and-L-, Z and Y are as defined above.

As shown in scheme 1, the compound of formula I, wherein-L-is-S-CH₂-, may be prepared by coupling a nucleophile of formula V or Va with an electrophile of formula VI, wherein X is a leaving group, such as chloro, bromo, iodo, methanesulfonyl or 4-toluenesulfonyl. In the reaction of Va and VI, the alkylation of the sulfur atom of Va with VI and ring closure to form a fused bicyclic triazole ring all occur in a one-pot reaction under the same reaction conditions

。

Scheme(s) 1

The reaction is typically carried out in a solvent such as 1-propanol, toluene, DMF or acetonitrile, optionally in the presence of a carbonate base such as potassium carbonate or a tertiary amine base such as triethylamine or Diisopropylethylamine (DIPEA), at a temperature in the range of from about 0 ℃ to about 200 ℃, optionally under pressure in a closed vessel. Other suitable solvents include benzene, chloroform, dioxane, ethyl acetate, 2-propanol, and xylene. Alternatively, a mixed solvent such as toluene/2-propanol may also be used.

Compounds of formula V are either commercially available or can be prepared as described in the literature, see, e.g., Brown et al, Aust. J. chem. 1978, 31, 397-404; yutillov et al, Khim. Geter. Soedin. 1988, 799-804; wilde et al, bioorg. Med. chem. Lett. 1995, 5, 167-172; Kidwai et al, J. Korean chem. Soc. 2005, 49, 288-291. Compounds of formula Va may be prepared from the corresponding 1, 2-diaminopyridine with thiocarbonyldiimidazole in a suitable solvent (e.g. chloroform) at a suitable temperature (e.g. room temperature or +40 ℃ C.) as described in WO 96/01826. The desired 1, 2-diaminopyridine is readily obtained from the reaction of the corresponding commercially available 2-aminopyridine with a suitable N-aminating reagent (e.g.O- (tritoluensulfonyl) hydroxylamine) in a suitable solvent (e.g.chloroform) at a suitable temperature (e.g.0 ℃ C. or room temperature), see WO 96/01826.

The 2-halomethyl-4- (aryl) -1H-triazoles of formula VI can be obtained by halogenating the corresponding (2-aryl-1H-imidazol-4-yl) -methanol or (2-heteroaryl-1H-imidazol-4-yl) -methanol using a suitable reagent (e.g. thionyl chloride, phosphorus trichloride or phosphorus tribromide), optionally using a suitable solvent (e.g. dichloromethane), using methods known to the chemist in the art. The desired (2-aryl-1H-imidazol-4-yl) -methanol can be prepared by methods known in the art (see, e.g., Journal of Medicinal Chemistry 1986, 29(2), 261-267; WO-2005014588A 1). The desired (2-aryl-1H-imidazol-4-yl) -methanol or (2-heteroaryl-1H-imidazol-4-yl) -methanol can also be readily obtained by reducing the aldehyde compound XV (see scheme 4 below) by methods known to the skilled chemist, for example by reacting a compound of formula XV with a suitable reducing agent, such as sodium borohydride, in a suitable solvent, such as THF or methanol.

A compound of formula I, wherein-Lis-CH₂-S-, obtainable by coupling a nucleophile of formula XII with an electrophile of formula VIII as shown in scheme 2

。

Scheme(s) 2

Typically the reaction is carried out in a solvent such as 1-propanol, toluene, DMF or acetonitrile, optionally in the presence of a carbonate base such as potassium carbonate or a tertiary amine base such as triethylamine or Diisopropylethylamine (DIPEA), at a temperature in the range of from about 0 ℃ to about 200 ℃, optionally under pressure in a closed vessel. Other suitable solvents include benzene, chloroform, dioxane, ethyl acetate, 2-propanol, and xylene. Alternatively, solvent mixtures such as toluene/2-propanol may also be used.

Some electrophiles of formula VIII are commercially available, many others are known in the art, see, for example, JP 59176277. The electrophile VIII, wherein X is a leaving group, such as chloro, bromo, iodo, methylsulfonyl, or 4-toluenesulfonyl, can also be prepared by converting the primary alcohol of the compound of formula VII into the leaving group by methods known to the chemist in the art. For example, the process may be selected from reacting a compound of formula VII with thionyl chloride, phosphorus trichloride, phosphorus tribromide, methanesulfonyl chloride or 4-toluenesulfonyl chloride, optionally in the presence of a suitable solvent (e.g., dichloromethane or 1-2-dichloromethane), and optionally in the presence of a base (e.g., triethylamine, diisopropylethylamine or pyridine). Alternatively, electrophiles of formula VIII can be obtained by reacting a commercially available aromatic amine of formula IX with a1, 3-dihaloacetone of formula XI (e.g., 1, 3-dichloroacetone) in a suitable solvent (e.g., 1, 2-dimethoxyethane or ethanol) at a suitable temperature (e.g., room temperature or reflux temperature). Some electrophiles of formula VII are commercially available, many others are known in the art, see for example Tsuchiya, T.A., Sashida, H.J. chem. Soc., chem. Commun. 1980, 1109-1110; Tsuchiya, T.A., Sashida, H; Konoshita, A.chem. pharm. Bull. 1983, 31, 4568-4572. Alternatively, the alcohol of formula VII may be prepared by reacting a commercially available aromatic amine of formula IX with a suitable N-aminating agent (e.g. O- (tritoluensulfonyl) hydroxylamine) in a suitable solvent (e.g. chloroform) at a suitable temperature (e.g. 0 ℃ or room temperature) to produce a compound of formula X, see WO 96/01826. The compound of formula X may be converted to the compound of formula VII by reaction with methyl glycolate followed by reduction of the methyl ester to the desired alcohol using a suitable reducing agent (e.g., lithium aluminum hydride) in a suitable solvent (e.g., diethyl ether or tetrahydrofuran) by methods known to the chemist in the art.

Compounds of formula XII may be prepared as described in the literature, see, for example, Zoete, Vincent et al. Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry 1997, (20), 2983-2988.

As shown in scheme 3, compounds of formula I (wherein R1 is other than hydrogen) can be prepared by alkylation of compounds of formula I (wherein R1 is hydrogen) with an alkyl halide of formula XIII

。

Scheme(s) 3

The reaction is typically carried out in a suitable solvent (e.g., dimethylformamide, dimethylacetamide or acetonitrile) in the presence of a suitable base (e.g., a carbonate base such as potassium carbonate) or a tertiary amine base (e.g., triethylamine or Diisopropylethylamine (DIPEA)) at a temperature in the range of about 0 ℃ to about 100 ℃.

A compound of formula I wherein-L-is-CH = CH-or-CH₂-CH₂-, may be prepared by the reaction sequence shown in scheme 4

。

Scheme(s) 4

In particular, the compounds of formula I (wherein-L-is-CH)₂-CH₂-) can be prepared by the hydrogenation reduction of an olefin of formula I (wherein-L-is-CH = CH-) using a transition metal catalyst (e.g., metallic palladium) and a hydrogen source (e.g., hydrogen, ammonium bicarbonate, or cyclohexadiene). The olefin of formula I (wherein-L-is-CH = CH-) can be of formula XIVSalts with aldehydes of formula XV in a suitable solvent (e.g. tetrahydrofuran) in a suitable base (e.g. 1, 8-diazabicyclo [5.4.0 ]]Undec-7-ene) by a Wittig reaction. Of formula XIVSalts can be readily prepared by reacting a compound of formula VIII (see scheme 2 above) with triphenylphosphine using methods known to the chemist in the art. The aldehyde of formula XV can be readily prepared by oxidation of the alcohol of formula VII (see scheme 2 above) using methods known to the chemist in the art, for example by reacting the alcohol of formula VII with a suitable oxidizing agent (e.g., Dess-Martin Periodinane) in a suitable solvent (e.g., dichloromethane or 1, 2-dichloroethane). Or the aldehyde of formula XV is readily prepared by methods described in the literature (see, e.g., Dhainaut, A. et al, Journal of Medicinal Chemistry, 2000, 43, 2165-2175).

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

Preparation of intermediates

Examples 1

2- Thiophene(s) -2- Base of -1H- Imidazole -4- Formaldehyde (I)

1, 3-dihydroxy-2-propanone (11.08 g, 123.0 mmol) was added at room temperature (rt) to an agitated solution of 2-thiophenecarboxamidine hydrochloride in 12.4M aqueous ammonia (200 mL). The solution was heated at reflux for 1 h. The solution was then cooled to room temperature and extracted with EtOAc (2 × 300mL) and THF (300 mL). The combined organic phases were washed with brine (150mL) and dried (Na)₂SO₄) And evaporated in vacuo to give 6.4g of crude alcohol, which is then purified by chromatography on silica gel (eluent: 10% methanol in EtOAc). Yield: 2.00g alcohol (2-thiophen-2-yl-1H-imidazol-4-yl) -methanol) (TLC: Rf aprox 0.1 in EtOAc).

Dess-Martin Periodinane (4.71g, 11.1mmol) was added to a stirred solution of (2-thiophen-2-yl-1H-imidazol-4-yl) -methanol (2.00g, 11.1mmol) dissolved in dichloromethane (111 mL) at room temperature under an argon (Ar) atmosphere. The mixture was darkened and stirred at room temperature overnight. More DCM (100ml) and saturated NaHCO were added₃(100mL), after removing some solids by filtration, the phases were separated. The organic layer was placed on silica gel and purified by silica gel chromatography (eluent: 0-100% EtOAc/n-heptane). Yield: 0.57g of the title compound as a red solid. LC-MS m/z =178.6 (MH)⁺)，t_R=0.31 min, method C.

Examples 2

1- Methyl radical -2- Thiazoles -2- Base of -1H- Imidazole -4- Formaldehyde (I)

Using Baldwin et al inJ. Med. Chem. 1975895A, but with modifications (alkylation step before DIBAL-H reduction).

1, 1-Dibromotrifluoroacetone (26.24 g, 97.22 mmol) was added to a stirred aqueous solution of sodium acetate (16.0 g, 194 mmol) (90 mL) at room temperature. The solution was heated at reflux for 30 minutes and then cooled to room temperature. The cooled solution was added to an agitated solution of 2-formylthiazole (10.00 g, 88.39 mmol) in methanol (400mL) and 12.4M aqueous ammonia (100 mL). The solution was kept under agitation at room temperature. The solution was rotary evaporated to 190mL then water (100mL) was added. The solution was left at 4 ℃ for 30 minutes and then filtered to give an orange solid. The orange solid was warmed in water (approximately 100ml) for 5 minutes (not completely dissolved). The color changed to light brown. The solid was obtained by filtration and dried in vacuo to give 6.50g of intermediate 2- (4-trifluoromethyl-1H-imidazol-2-yl) -thiazole. H-NMR (DMSO-d6) was similar to published NMR (J. Med Chem (2000) 2165).

2- (4-trifluoromethyl-1H-imidazol-2-yl) -thiazole (6.25g, 28.5mmol) was dissolved in methanol (300mL) and 12.4M aqueous ammonia (40mL), followed by addition of water (180 mL). The solution was heated at 60 ℃ overnight. Then, ammonia (40mL) at a concentration of over 12M was added and the solution was heated at 70 ℃ for 5 hours. The reaction was rotary evaporated to a smaller volume. The yellow solid which separated out was stored at 4 ℃ for 2 h. Filtered to give a yellow powder and dried in vacuo. Yield of 2-thiazol-2-yl-1H-imidazole-4-carbonitrile: 5.54g of crude material.

Iodomethane (4.06g, 28.6mmol) dissolved in DMF (8mL) was added dropwise to an agitated solution of 2-thiazol-2-yl-1H-imidazole-4-carbonitrile (5.31g, 30.1mmol) dissolved in N, N-dimethylformamide (50mL) and potassium carbonate (4.58g,33.1 mmol). The mixture was stirred at 60 ℃ under argon for 1 h. Vacuum removalMost of the DMF, the residue was partitioned between EtOAc (150mL) and brine (50 mL). The organic phase was washed with more brine and dried (MgSO)₄). The solution was rotary evaporated and the crude product was purified by chromatography on silica gel (eluent: 20-50% EtOAc/n-heptane). Yield: 0.982g of 1-methyl-2-thiazol-2-yl-1H-imidazole-4-carbonitrile as a yellow solid. H-NMR: (DMSO-d6) delta 8.35 (s, 1H), 8.03 (d, 1H), 7.92 (d, 1H), 4.10 (s, 3H).

1.00M diisobutylaluminum hydride in toluene (7.73mL) was added to an agitated solution of 1-methyl-2-thiazol-2-yl-1H-imidazole-4-carbonitrile (0.980g, 5.15mmol) dissolved in anhydrous tetrahydrofuran (10mL) at-78 deg.C under argon. The temperature was slowly (approximately 1h) raised to-40 ℃. The ice bath tub was removed and the mixture was quenched by addition of methanol (2.6 ml). The mixture was rotary evaporated and the crude product was chromatographed on silica gel (eluent: 0-30% methanol/EtOAc) to give 0.321g of impurity. The material was purified again by silica gel chromatography (using EtOAc as eluent). 140mg of the title compound are obtained as a yellow solid. H-NMR (DMSO-d 6): δ 9.76 (s, 1H), 8.28 (s, 1H) 8.04 (d, 1H), 7.90 (d, 1H), 4.12 (s, 3H). LC-MS: m/z = 193.8 (MH)⁺), t_R=0.36 min, method C.

Examples 3

2- Thiazoles -5- Base of -1H- Imidazole -4- Formaldehyde (I)

The method described by Baldwin et al in J. Med. chem. 1975, 895 was used.

The following intermediates were prepared analogously:

2-furan-2-yl-1H-imidazole-4-carbaldehyde

2-isothiazol-5-yl-1H-imidazole-4-carbaldehyde

2-oxazol-2-yl-1H-imidazole-4-carbaldehyde

2-isoxazol-5-yl-1H-imidazole-4-carbaldehyde

2-oxazol-5-yl-1H-imidazole-4-carbaldehyde

2-thiazol-4-yl-1H-imidazole-4-carbaldehyde

2-oxazol-4-yl-1H-imidazole-4-carbaldehyde

2-isoxazol-3-yl-1H-imidazole-4-carbaldehyde

2-isothiazol-3-yl-1H-imidazole-4-carbaldehyde

2-furan-3-yl-1H-imidazole-4-carbaldehyde

。

Examples 4

1- Methyl radical -2- Thiophene(s) -2- Base of -1H- Imidazole -4- Formaldehyde (I)

Iodomethane (477mg, 3.36mmol) dissolved in DMF (0.5mL) was added dropwise to an agitated solution of 2-thiophen-2-yl-1H-imidazole-4-carbaldehyde (0.57g, 3.2mmol) and potassium carbonate (0.486g,3.52mmol)) in anhydrous N, N-dimethylformamide (6mL) at room temperature. The solution was stirred at 70 ℃ for 3 h. Most of the DMF was removed by evaporation and the residue was partitioned between EtOAc (50mL) and brine (25 mL).The phases were separated and then dried (Na)₂SO₄) The organic phase was evaporated and the solvent was removed. The crude product was purified by chromatography on silica gel (eluent: 50% -100% EtOAc/n-heptane). Yield: 211mg of the title compound in the form of an oil. H-NMR (DMSO-d 6): δ 9.71 (s, 1H), 7.80 (s, 1H) 7.54 (m, 2H), 7.17 (m, 1H), 4.14 (s, 3H). LC-MS: m/z = 192.9 (MH)⁺), t_R= 0.34 min, method C. (211mg of the fast eluting isomer (3-methyl-2-thiophen-2-yl-3H-imidazole-4-carbaldehyde) was also separated and discarded).

Examples 5

2- Chloromethyl radical -5,7- Dimethyl group -[1,2,4] Triazolo compounds [1,5-a] Pyrimidines

Hydroxylamine-2, 4, 6-trimethyl-benzenesulfonate (105 g, 488 mmol) in 300mL of CH at 0 deg.C₂A solution in Cl was added dropwise to a solution of 4, 6-dimethyl-pyrimidin-2-amine (25 g, 200 mmol) in 400mL CH₂A solution in Cl, the mixture was stirred at 0 ℃ for 1h and then filtered. The collected solid is passed through CH₂Cl₂(100mL) after washing, 2,4, 6-trimethyl-benzenesulfonic acid 1-amino-4, 6-dimethyl-1H-pyrimidin-2-ylidene-ammonium (40g, yield: 62%) was obtained.

A mixture of 2,4, 6-trimethyl-benzenesulfonic acid 1-amino-4, 6-dimethyl-1H-pyrimidin-2-ylidene-ammonium (40g, 0.1mol) and NaOH (10g, 0.2mol) in 500mL EtOH was stirred at 50-60 ℃ for 1H. After addition of methyl chloroacetate (16.6g, 0.15mol), the resulting mixture was stirred under reflux heating for 4 h. After concentration under reduced pressure, the residue was diluted with water (1000mL) and then CH₂Cl₂(300 mL. times.3) was extracted. The combined organic layers were washed with brine (200mL) and Na₂SO₄Dried, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether/EtOAc =2/1) to give 2g of 2-chloromethyl-5, 7-dimethyl- [1,2,4] in 9% yield]Triazolo [1,5-a]A pyrimidine.¹H NMR (300 MHz, DMSO-d ₆): δ8.55 (s, 1H), 6.25 (s, 2H), 4.05 (s, 3H), 3.95 (s, 3H); LC-MS (MH⁺): m/z = 196.9, t _R(minutes, method a) = 0.52.

The following intermediates were prepared similarly:

preparation of 7-chloro-2-chloromethyl-5, 8-dimethyl- [1,2, 4-dimethyl ] -2, 5-dimethyl-pyrimidin-4-amine from 6-chloro-2, 5-dimethyl-pyrimidin-4-amine prepared as described by Henze et al, J. org. Chem 1952, 17, 1320-1327]Triazolo [1,5-c]Pyrimidine, yield: 3.2%, LC-MS: m/z =231.5 (MH)⁺), t_R=1.13 min, method C.

Preparation of 2-chloromethyl-5, 8-dimethyl- [1,2,4] from 2-amino-3, 6-dimethylpyrazine]-triazolo [1,5-a]A pyrazine. Yield: 60 percent of the total weight of the mixture,¹H NMR (500 MHz, CDCl₃): δ7.91 (s,1H), 4.87 (s, 2H), 2.91 (s, 3H), 2.74 (s, 3H), LC-MS: m/z = 196.9 (MH⁺), t _R=0.64 min, method a.

Preparation of 2-chloromethyl-5, 8-dimethyl- [1,2, 4-dimethyl ] pyrimidine-4-amine from 6-chloro-5-ethyl-2-methyl-pyrimidin-4-amine]Triazolo [1,5-a]Pyridine. Yield: 21%, LC-MS:m/z = 245.0 (MH⁺), t _R= 0.72 min, method a.

Preparation of 2-chloromethyl-8-methoxy-5-methyl- [1,2, 4-d from 3-methoxy-6-methyl-pyridin-2-amine]Triazolo [1,5-a]Pyridine. The content of the raw materials is 64%,¹H NMR (500 MHz, DMSO-d ₆): δ 7.11-7.08 (d, 1H),7.01-6.98 (d, 1H), 4.93 (s, 2H), 3.98 (s, 3H), 2.61 (s, 3H)。

2-chloromethyl-8-methoxy-5-methyl- [1,2,4] triazolo [1,5-a ] pyridine was prepared from 2-amino-6-methylpyridine. LC-MS m/z =181.8 (MH +), tR =0.64 min, method a.

2-chloromethyl-8-methyl- [1,2,4] triazolo [1,5-a ] pyridine was prepared from 2-amino-3-methylpyridine.

2-chloromethyl-8-methoxy- [1,2,4] triazolo [1,5-a ] pyridine was prepared from 2-amino-3-methoxypyridine. LC-MS m/z = 197.8 (MH +), tR =0.40 min, method B.

Preparation of 2-chloromethyl-8-ethyl-5-methyl- [1,2,4] from 2-amino-3-ethyl-6-methylpyridine]Triazolo [1,5-a]Pyridine. LC-MS: m/z = 209.8 (MH)⁺), t _R=0.60 min, method B.

The following compounds are already known in the prior art:

2-chloromethyl-1-phenyl-1H-benzimidazole (JP 59176277).

1-methyl-1, 3-dihydro-benzimidazole-2-thione (Wilde et al, bioorg. Med. chem. Lett. 1995, 5, 167-172).

1-phenyl-1, 3-dihydro-benzimidazole-2-thione (Kidwai et al J. Korean chem. Soc. 2005, 49, 288-291).

[1,2,4] triazolo [1,5-a ] pyrimidine-2-thiones (Brown et al. Aust. J. chem. 1978, 31, 397-404).

1, 3-dihydro-imidazo [4,5-b ] pyridine-2-thiones (Yutillov et al, Khim. Geter. Soedin. 1988, 799-804).

Pyrazolo [1,5-a ] pyridin-2-yl-methanol (Tsuchiya, T.; Sashida, H.J. chem. Soc., chem. Commun. 1980, 1109-1110; Tsuchiya, T.; Sashida, H; Konoshita, A. chem. pharm. Bull. 1983, 31, 4568-4572).

Examples 6

(5,8- Dimethyl group -[1,2,4] Triazolo compounds [1,5-a] Pyrazine esters -2- Radical methyl )- Triphenyl radical - (ii) a Chloride compound

150mL of 2-chloromethyl-5, 8-dimethyl- [1,2,4]]Triazolo [1,5-a]A solution of pyrazine (1.351g, 6.87mmol) and triphenylphosphine (1.80g,6.87mmol) in acetonitrile was heated at reflux for 12 h. The solvent was removed in vacuo and the residue was slurried with ether, filtered and dried to give (5, 8-dimethyl- [1,2, 4) as an off-white solid]Triazolo [1,5-a]Pyrazin-2-ylmethyl) -triphenyl-(ii) a A chloride. LC-MS: M/z =423.2([ M-Cl)]⁺),t_R=0.86 min, method a.

The following intermediates were prepared analogously:

。

from 2-chloromethyl-5, 8-dimethyl- [1,2, 4%]Triazolo [1,5-a]Preparation of (5, 8-dimethyl- [1,2,4] chloride from pyridine]Triazolo [1,5-a]Pyridin-2-ylmethyl) -triphenyl-，LC-MS:m/z=422.2(MH⁺)，t_R=1.02 min, method a.

From 2-chloromethyl-8-methoxy-5-methylRadical- [1,2,4]]Triazolo [1,5-a]Preparation of (8-methoxy-5-methyl- [1,2,4] chloride from pyridine]Triazolo [1,5-a]Pyridin-2-ylmethyl) -triphenyl-，LC-MS:m/z=438.4(MH⁺), t_R=0.96 min, method a.

From 2-chloromethyl-5-methyl- [1,2,4]Triazolo [1,5-a]Preparation of (5-methyl- [1,2,4] chloride from pyridine]Triazolo [1,5-a]Pyridin-2-ylmethyl) -triphenyl-，LC-MS:m/z=408.4(MH⁺), t_R=0.88 min, method a.

From 2-chloromethyl-8-methyl- [1,2,4]Triazolo [1,5-a]Preparation of (8-methyl- [1,2,4] chloride from pyridine]Triazolo [1,5-a]Pyridin-2-ylmethyl) -triphenyl-From LC-MS: m/z = 408.2 (MH)⁺), t_R= 0.59 min, method B.

From 2-chloromethyl-5, 7-dimethyl- [1,2,4]Triazolo [1,5-a]Preparation of (5, 7-dimethyl- [1,2,4] chloride from pyrimidine]Triazolo [1,5-a]Pyrimidin-2-ylmethyl) -triphenyl-，LC-MS:m/z=423.3(MH⁺), t_R=0.85 min, method a.

From 2-chloromethyl-8-methoxy- [1,2,4]Triazolo [1,5-a]Preparation of (8-methoxy- [1,2,4] chloride from pyridine]Triazolo [1,5-a]Pyridin-2-ylmethyl) -triphenyl-，LC-MS:m/z=423.9(MH⁺), t_R=0.55 min, method B.

From 2-chloromethyl-8-ethyl-5-methyl- [1,2,4]Triazolo [1,5-a]Preparation of (8-ethyl-5-methyl- [1,2,4] chloride from pyridine]Triazolo [1,5-a]Pyridin-2-ylmethyl) -triphenyl-，LC-MS: m/z =423.9(MH⁺), t_R=0.55 min, method B.

Preparation of the Compounds of the invention

Examples 7

5,8- Dimethyl group -2-[2-(2- Phenyl radical -1H- Imidazole -4- Base of )- Ethyl radical ]-[1,2,4] Triazolo compounds [1,5-a] Pyrazine esters

1, 8-diazabicyclo [5.4.0 ]]Undec-7-ene (0.087 mL, 0.58mmol) was added to stirred (5, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a]Pyrazin-2-ylmethyl) -triphenyl-(ii) a A suspension of chloride (0.27g,0.58mmol) and 2-phenyl-1H-imidazole-4-carbaldehyde (0.100g, 0.581mmol) in dry THF (8mL) was stirred overnight at room temperature under argon. Some solids were filtered off and the solvent was removed in vacuo. The residue was dissolved in DCM and purified by chromatography on silica gel (eluent: EtOAc/n-heptane at 0-100%). Yield: 97mg of a cis/trans mixture as an oil (53%).

The material obtained above (0.090g,0.28mmol) was dissolved in DMF (8mL) and p-toluenesulfonyl hydrazide (0.16g, 0.85mmol) was added and the reaction stirred at 120 ℃ under argon for 8 h. The solution was stirred at room temperature overnight. More p-toluenesulfonyl hydrazide (0.08g) was added and the reaction mixture was kept at 120 ℃ under argon for 6 h. DMF was evaporated and the residue was dissolved in EtOAc (20mL) and taken up with saturated NaHCO₃(2 × 20 ml). The organic phase was washed with brine and dried (MgSO)₄) Then rotary evaporation. The crude product was purified by chromatography on silica gel (eluent: 0-100% EtOAc in n-heptane). Yield: 40mg (40%) of an off-white solid. LC-MS: m/z = 319.2 (MH)⁺), t_R=0.63 min, method E.¹H NMR (600 MHz, CDCl₃): δ 7.90 (m, 3H), 7.43 (m, 2H), 7.35 (m, 1H), 6.96 (s, 1H), 3.40 (m, 2H), 3.22 (m, 2H) 2.98 (s, 3H), 2.75 (s, 3H)。

The following compounds were prepared analogously:

5, 8-dimethyl-2- [2- (1-methyl-2-phenyl-1H-imidazol-4-yl) -ethyl]-[1,2,4]Triazolo [1,5-a]Pyrazine (2), LC-MS: m/z = 333.3 (MH)⁺), t_R=0.56 min, method E.

8-Ethyl-5-methyl-2- [2- (1-methyl-2-phenyl-1H-imidazol-4-yl) -ethyl]-[1,2,4]Triazolo [1,5-a]Pyrimidine (3), LC-MS: m/z =345.9 (MH)⁺), t_R=0.49 min, method C.

5, 8-dimethyl-2- [2- (1-methyl-2-thiophen-2-yl-1H-imidazol-4-yl) -ethyl]-[1,2,4]Triazolo [1,5-a]Pyrazine (4), LC-MS: m/z =338.8 (MH)⁺), t_R=0.35 min, method C.

Examples 8

5,8- Dimethyl group -2-[2-(1- Methyl radical -2- Thiazoles -2- Base of -1H- Imidazole -4- Base of )- Ethyl radical ]-[1,2,4] Triazolo compounds [1,5-a] A pyrazine.

1, 8-diazabicyclo [5.4.0 ]]Undec-7-ene (0.109mL,0.72mmol) was added to stirred (5, 8-dimethyl- [1,2, 4)]Triazolo [1,5-a]Pyrazin-2-ylmethyl) -triphenyl-A suspension of chloride (332mg,0.72mmol) and 1-methyl-2-thiazol-2-yl-1H-imidazole-4-carbaldehyde (140mg,0.72mmol) in anhydrous THF (18mL) was stirred at room temperature for 2H under argon. The solvent was removed in vacuo. The residue was dissolved in DCM and purified by silica gel chromatography (eluent: 0-10% MeOH in EtOAc). Yield: 102mg of intermediate product, whiteCis/trans mixture (42%) as a colored solid.

This material (102mg, 0.30mmol) was dissolved in DCM (5mL) and MeOH (5mL) and 10% Pd/C (35mg) were added and the reaction was hydrogenated under 1.8 bar (pressure units) in a parr shaker overnight. The catalyst was removed by filtration and the solvent was removed in vacuo. The crude product was purified by chromatography on silica gel (eluent: 0-10% MeOH/EtOAc). Yield: 80mg (78%) of the title compound as an off-white solid. LC-MS: m/z = 339.9 (MH)⁺), t_R=0.35 min, method C.¹H NMR (600 MHz, DMSO-d₆): δ 7.95 (s, 1H), 7.91 (d, 1H), 7.73 (d, 1H), 7.15 (s, 1H), 3.97 (s, 3H), 3.21 (m, 2H), 3.04 (m, 2H), 2.75 (s, 3H), 2.65 (s, 3H)。

The following compounds were prepared analogously:

8-methoxy-5-methyl-2- [2- (2-phenyl-1H-imidazol-4-yl) -ethyl]-[1,2,4]Triazolo [1,5-a]Pyridine, LC-MS: m/z =334.5 (MH)⁺), t_R=0.78 min, method E.

8-methoxy-5-methyl-2- [2- (1-methyl-2-thiophen-2-yl-1H-imidazol-4-yl) -ethyl]-[1,2,4]Triazolo [1,5-a]Pyridine (7), LC-MS: m/z =354.4 (MH)⁺),t_R=0.41 min, method C.

8-methoxy-5-methyl-2- [2- (2-phenyl-1H-imidazol-4-yl) -ethyl ] - [1,2,4] triazolo [1,5-a ] pyridine LC-MS m/z (MH +) =334.159, tR (min) =0.78, method C.

8-methoxy-5-methyl-2- [2- (1-methyl-2-phenyl-1H-imidazol-4-yl) -ethyl ] - [1,2,4] triazolo [1,5-a ] pyridine LC-MS: m/z (MH +) =348.1746, tR (min) =0.7, method C.

8-ethyl-5-methyl-2- [2- (1-methyl-2-phenyl-1H-imidazol-4-yl) -ethyl ] - [1,2,4] triazolo [1,5-a ] pyridine LC-MS: m/z (MH +) =346.1953, tR (min) =0.49, method C.

5, 8-dimethyl-2- [2- (2-phenyl-1H-imidazol-4-yl) -ethyl ] - [1,2,4] triazolo [1,5-a ] pyrazine LC-MS m/z (MH +) =319.1593, tR (min) =0.63, method C.

5, 8-dimethyl-2- [2- (1-methyl-2-phenyl-1H-imidazol-4-yl) -ethyl ] - [1,2,4] triazolo [1,5-a ] pyrazine LC-MS: m/z (MH +) =333.1749, tR (min) =0.56, method C.

8-methoxy-5-methyl-2- [2- (1-methyl-2-thiophen-2-yl-1H-imidazol-4-yl) -ethyl ] - [1,2,4] triazolo [1,5-a ] pyridine LC-MS: m/z (MH +) =354.131, tR (min) =0.41, method C.

8-methoxy-5-methyl-2- [2- (3-methyl-2-thiophen-2-yl-3H-imidazol-4-yl) -ethyl ] - [1,2,4] triazolo [1,5-a ] pyridine LC-MS: m/z (MH +) =354.2, tR (min) =0.4, method C.

5, 8-dimethyl-2- [2- (1-methyl-2-thiophen-2-yl-1H-imidazol-4-yl) -ethyl ] - [1,2,4] triazolo [1,5-a ] pyrazine LC-MS: m/z (MH +) =338.8, tR (min) =0.35, method C.

5, 8-dimethyl-2- [2- (1-methyl-2-thiazol-2-yl-1H-imidazol-4-yl) -ethyl ] - [1,2,4] triazolo [1,5-a ] pyrazine LC-MS: m/z (MH +) = 339.9, tR (min) =0.35, method C.

5, 8-dimethyl-2- [2- (2-thiazol-5-yl-1H-imidazol-4-yl) -ethyl ] - [1,2,4] triazolo [1,5-a ] pyrazine LC-MS m/z (MH +) =326.111, tR (min) =0.43, method C.

5, 8-dimethyl-2- [2- (2-thiazol-5-yl-1H-imidazol-4-yl) -ethyl ] - [1,2,4] triazolo [1,5-a ] pyridine LC-MS: m/z (MH +) =325.1157, tR (min) =0.76, method C.

5, 8-dimethyl-2- [2- (1-methyl-2-thiazol-5-yl-1H-imidazol-4-yl) -ethyl ] - [1,2,4] triazolo [1,5-a ] pyrazine LC-MS: m/z (MH +) =340.1266, tR (min) =0.45, method C.

2- [2- (2-furan-2-yl-1-methyl-1H-imidazol-4-yl) -ethyl ] -5, 8-dimethyl- [1,2,4] triazolo [1,5-a ] pyrazine LC-MS m/z (MH +) =323.1542, tR (min) =0.36, method C.

5, 8-dimethyl-2- [2- (2-thiazol-4-yl-1H-imidazol-4-yl) -ethyl ] - [1,2,4] triazolo [1,5-a ] pyrazine LC-MS m/z (MH +) =326.111, tR (min) = 0.33, method C.

5, 8-dimethyl-2- [2- (2-thiazol-4-yl-1H-imidazol-4-yl) -ethyl ] - [1,2,4] triazolo [1,5-a ] pyridine LC-MS: m/z (MH +) =325.1157, tR (min) =0.39, method C.

2- [2- (2-furan-2-yl-1-methyl-1H-imidazol-4-yl) -ethyl ] -5, 8-dimethyl- [1,2,4] triazolo [1,5-a ] pyridine LC-MS: m/z (MH +) =322, tR (min) =0.43, method C.

5, 8-dimethyl-2- [2- (2-thiophen-2-yl-1H-imidazol-4-yl) -ethyl ] - [1,2,4] triazolo [1,5-a ] pyridine LC-MS m/z (MH +) =323.9, tR (min) =0.43, method C.

5, 8-dimethyl-2- [2- (2-thiazol-2-yl-1H-imidazol-4-yl) -ethyl ] - [1,2,4] triazolo [1,5-a ] pyridine LC-MS: m/z (MH +) =324.8, tR (min) =0.4, method C.

2- [2- (2-furan-2-yl-1H-imidazol-4-yl) -ethyl ] -5, 8-dimethyl- [1,2,4] triazolo [1,5-a ] pyridine LC-MS: m/z (MH +) = 308.2, tR (min) =0.41, method C.

2- [2- (2-furan-3-yl-1H-imidazol-4-yl) -ethyl ] -5, 8-dimethyl- [1,2,4] triazolo [1,5-a ] pyridine LC-MS: m/z (MH +) = 308.2, tR (min) =0.41, method C.

5, 8-dimethyl-2- [2- (2-thiophen-2-yl-1H-imidazol-4-yl) -ethyl ] - [1,2,4] triazolo [1,5-a ] pyrazine LC-MS m/z (MH +) =325.1157, tR (min) =0.4, method C.

5, 8-dimethyl-2- [2- (2-thiazol-2-yl-1H-imidazol-4-yl) -ethyl ] - [1,2,4] triazolo [1,5-a ] pyrazine LC-MS m/z (MH +) =326.111, tR (min) =0.37, method C.

2- [2- (2-furan-3-yl-1H-imidazol-4-yl) -ethyl ] -5, 8-dimethyl- [1,2,4] triazolo [1,5-a ] pyrazine LC-MS: m/z (MH +) =309.1386, tR (min) = 0.38, method C.

2- [2- (2-furan-2-yl-1H-imidazol-4-yl) -ethyl ] -5, 8-dimethyl- [1,2,4] triazolo [1,5-a ] pyrazine LC-MS: m/z (MH +) =309.1386, tR (min) =0.32, method C.

2- [2- (1H-imidazol-4-yl) -ethyl ] -5, 8-dimethyl- [1,2,4] triazolo [1,5-a ] pyrazine LC-MS m/z (MH +) =243.3, tR (min) =0.24, method C.

5, 8-dimethyl-2- {2- [ 1-methyl-2- (5-methyl-furan-2-yl) -1H-imidazol-4-yl ] -ethyl } - [1,2,4] triazolo [1,5-a ] pyrazine LC-MS m/z (MH +) =337.1, tR (min) =0.37, method C.

5, 8-dimethyl-2- [2- (1-methyl-2-thiazol-4-yl-1H-imidazol-4-yl) -ethyl ] - [1,2,4] triazolo [1,5-a ] pyrazine LC-MS: m/z (MH +) =340.1266, tR (min) =0.61, method C.

2- {2- [2- (4-fluoro-phenyl) -1H-imidazol-4-yl ] -ethyl } -5, 8-dimethyl- [1,2,4] triazolo [1,5-a ] pyrazine LC-MS: m/z (MH +) =337.1, tR (min) =0.36, method C.

Examples 9

8- Methoxy radical -5- Methyl radical -2-[2-(1- Methyl radical -2- Phenyl radical -1H- Imidazole -4- Base of )- Ethyl radical ]-[1,2,4] Triazolo compounds [1,5-a] Pyridine compound

Methyl iodide (0.035mL,0.57mmol) was added to a stirred solution of 8-methoxy-5-methyl-2- [2- (2-phenyl-1H-imidazol-4-yl) -ethyl]-[1,2,4]Triazolo [1,5-a]Pyridine (145mg, 0.435mmol) and Cs₂CO₃(360 mg,1.1mmol) in 2-butanone (10 mL). Adding under 50 ℃ argon atmosphereThe mixture was heated for 7 h. The mixture was cooled to room temperature and the solvent was removed by evaporation. The crude product was dissolved in DCM and purified by silica gel chromatography (eluent: EtOAc/n-heptane at 0-100% and then methanol/EtOAc at 0-5%). Yield: 31mg (20%) of the title compound as an off-white solid. LC-MS m/z =348.2 (MH)⁺), t_R=0.70min, method E.

Pharmacological test

PDE10A Enzyme

Active PDE10A enzymes were prepared in a variety of ways for PDE assays (Loughney, K. et al; Gene 1999, 234, 109-117; Fujishige, K. et al; Eur J biochem 1999, 266, 1118-1127 and Soderling, S. et al. Proc. Natl. Acad. Sci. 1999, 96, 7071-7076). PDE10A may be expressed as a full-length protein or as a truncated protein, as long as it expresses the catalytic domain. PDE10A can be prepared in different cell types, such as insect cells or E.coli. An example of a method for obtaining catalytically active PDE10A is as follows: the catalytic domain of human PDE10A (amino acids 440-779 of the sequence accession NP 006652) was amplified from total human brain total RNA by standard RT-PCR and cloned into the BamH1 and Xho1 sites of pET28a vector (Novagen). Expression in E.coli was performed according to standard protocols. Briefly, the expression plasmid was transformed into BL21(DE3) E.coli strain, and 50mL of the culture incubated with cells was allowed to grow to an OD600 of 0.4-0.6 before inducing protein expression with 0.5mM IPTG. After induction, cells were incubated overnight at room temperature and then harvested by centrifugation. Cells expressing PDE10A were resuspended in 12mL (50mM TRIS-HCl-pH8.0,1mM MgCl)₂And protease inhibitors). Cells were lysed by sonication, and after all cells were lysed TritonX100 was added according to the Novagen protocol. PDE10A was partially purified on Q sepharose and most of the active fragments were collected.

PDE10AInhibition assay

For example, the PDE10A assay may be performed as follows: the assay is characterized by a fixed amount of correlationPDE enzyme (sufficient to convert 20-25% of cyclic nucleotide substrates), buffer (50mM HEPES7.6; 10mM MgCl)₂0.02% Tween20), 0.1mg/ml BSA, 225pCi³H-labeled cyclic nucleotide substrate, tritium-labeled cAMP at a final concentration of 5nM, and variable amounts of inhibitor in 60uL samples. The reaction was initiated by addition of cyclic nucleotide substrate, the reaction was carried out at room temperature for 1h, and then stopped by mixing in 15uL of 8mg/mL yttrium silicate SPA beads (Amersham). The beads were placed in a dark environment for 1h before the discs were counted in a Wallac 1450 Microbeta counter. The measured signal can be converted to activity relative to a non-inhibited control (100%) and IC calculated using Xlfit extended to EXCEL₅₀The value of (c).

Phencyclidine (PCP) Inducing hyperexcitability

Male mice (NMRI, Charles River) weighing between 20-25g were used. Each group receiving test compound (5mg/kg) plus PCP (2.3mg/kg), including vehicle plus PCP with test compound or a parallel control group receiving vehicle injection alone, used 8 mice each. The injection volume was 10 ml/kg. The experiment was performed in a quiet room under normal lighting conditions. Test substance was injected at 60 minutes per oss prior to subcutaneous injection of PCP.

Immediately after injection of PCP, mice were placed in specially designed test cages (20cm x 32cm), respectively. The activity was detected by an infrared source at 5X8, with 4cm spacing between photocells. Light crosses the cage 1.8cm above the bottom of the cage. The recording of activity counts requires the interruption of adjacent rays, thus avoiding counts induced by mouse stability activity.

Motility was recorded at 5min intervals for 1 h. The effect of the drug was calculated by recording the total counts over the 1h behavioral test period in the following manner:

the mean activity induced by carrier treatment without PCP was taken as baseline. Thus 100% PCP effect is calculated as total activity count minus baseline. The response of the test group receiving the test compound was therefore measured by subtracting the baseline from the total activity count, expressed as a percentage of similar results recorded in the parallel PCP control group. The percent response is converted to percent inhibition.

Claims (6)

1. Compounds having structure I, and tautomers and pharmaceutically acceptable salts thereof,

wherein HET-1 is selected from [1,2,4]]Triazolo [1,5-a]Pyridine and [1,2,4]]Triazolo [1,5-a]Pyrazine and wherein HET-1 may be optionally substituted with up to three substituents R7, R8 and R9, said R7, R8 and R9 being independently selected from H, C₁-C₆Alkyl and methoxy, wherein denotes the point of attachment,

q is selected from phenyl, thiazole, thiophene and furan, optionally substituted with methyl or fluorine,

-L-is-CH₂-CH₂-，

R1 is selected from H and C₁-C₆An alkyl group;

with the proviso that the compound is not 2- (5-phenyl-1H-imidazol-2-ylmethylsulfanyl) -1H-benzimidazole or 2- (5-phenyl-1H-imidazol-2-yl-sulfanyl-methyl) -1H-benzimidazole.

2. The compound of claim 1 wherein HET-1 is a [1,2,4] triazolo [1,5-a ] pyridine moiety.

3. The compound of claim 1 wherein HET-1 is a [1,2,4] triazolo [1,5-a ] pyrazine moiety.

4. The compound of any one of claims 1-3, wherein R7, R8, and R9 are all hydrogen.

5. The compound of any one of claims 1-3, wherein at least one of R7, R8, and R9 is methyl.

6. The compound of claim 1, wherein the compound is selected from the group consisting of: 5, 8-dimethyl-2- [2- (2-phenyl-1H-imidazol-4-yl) -ethyl ] - [1,2,4] triazolo [1,5-a ] pyrazine, 5, 8-dimethyl-2- [2- (1-methyl-2-phenyl-1H-imidazol-4-yl) -ethyl ] - [1,2,4] triazolo [1,5-a ] pyrazine, 8-ethyl-5-methyl-2- [2- (1-methyl-2-phenyl-1H-imidazol-4-yl) -ethyl ] - [1,2,4] triazolo [1,5-a ] pyridine, and pharmaceutically acceptable salts thereof, 5, 8-dimethyl-2- [2- (1-methyl-2-thiophen-2-yl-1H-imidazol-4-yl) -ethyl ] - [1,2,4] triazolo [1,5-a ] pyrazine, 5, 8-dimethyl-2- [2- (1-methyl-2-thiazol-2-yl-1H-imidazol-4-yl) -ethyl ] - [1,2,4] triazolo [1,5-a ] pyrazine, 8-methoxy-5-methyl-2- [2- (2-phenyl-1H-imidazol-4-yl) -ethyl ] - [1,2,4] triazolo [1,5-a ] pyridine, 8-methoxy-5-methyl-2- [2- (1-methyl-2-thiophen-2-yl-1H-imidazol-4-yl) -ethyl ] - [1,2,4] triazolo [1,5-a ] pyridine and 8-methoxy-5-methyl-2- [2- (1-methyl-2-phenyl-1H-imidazol-4-yl) -ethyl ] - [1,2,4] triazolo [1,5-a ] pyridine and pharmaceutically acceptable salts thereof.