US009018217B2

(12) United States Patent (10) Patent No.: US 9,018,217 B2 Ritzen et al. (45) Date of Patent: Apr. 28, 2015

(54) PHENY LIMIDAZOLE DERIVATIVES AS 8,841,297 B2 9/2014 Ritzen et al. PDE10A ENZYME INHIBITORS 2008/0090891 A1 4/2008 Zelle 2012/0135987 A1 5, 2012 Ritzen et al. (71) Applicant: H. Lundbeck A/S, Valby-Copenhagen (DK) FOREIGN PATENT DOCUMENTS TW 2007/036246 A 10/2007 (72) Inventors: Andreas Ritzen, Copenhagen V. (DK); WO 2004/005290 A1 1, 2004 Morten Langgard, Glostrup (DK); Jan WO 2005/003129 A1 1, 2005 Kehler, Lyngby (DK); Jacob Nielsen, WO 2005/082883 A2 9, 2005 WO 2006/070284 A1 T 2006 Copenhagen V. (DK); John Paul WO 2007/077490 A2 7/2007 Kilburn, Haslev (DK); Mohamed M. WO 2007/098169 A1 8, 2007 Farah, Birmingham (GB) WO 2008.001182 A1 1, 2008 WO 2009/023179 A2 2, 2009 (73) Assignee: H. Lundbeck A/S, Valby (DK) WO 2010, 145668 12/2010 (*) Notice: Subject to any disclaimer, the term of this OTHER PUBLICATIONS patent is extended or adjusted under 35 Taiwan Examination report issued Jan. 13, 2014 in TW Application U.S.C. 154(b) by 0 days. No. 0981 19876 filed Jun. 15, 2009. International Search Report and Written Opinion issued Jul. 27, 2010 (21) Appl. No.: 14/488,554 for International Application No. PCT? DK2010/050 147 filed Jun. 17, 2010. (22) Filed: Sep. 17, 2014 Geyer et al., 2002, "Animal Models Relevant to Schizophrenia Dis orders'. Neuropsychopharmacology: The Fifth Generation of (65) Prior Publication Data Progress, pp. 689-701. Kehler, J., et al., 2007. “The potential therapeutic use of US 2015/OO25081 A1 Jan. 22, 2015 phosphodiesterase 10 inhibitors'. Expert Opinion in Ther. Patents 17(2), p. 147-158. Related U.S. Application Data CAS Registry No. 348125-42-8: Jul. 25, 2001. CAS Registry No. 939690-18-3; Jun. 27, 2007. (60) Continuation of application No. 13/365,504, filed on CAS Registry No. 938887-78-6; Jun. 25, 2007. Feb. 3, 2012, now Pat. No. 8,865,711, which is a CAS Registry No. 530 154-74-6; Jun. 13, 2003. division of application No. 12/487,694, filed on Jun. CAS Registry No. 442570-89-0; Aug. 5, 2002. CAS Registry No. 296791-07-6; Oct. 18, 2000. 19, 2009, now Pat. No. 8,133,897. International Search Report and Written Opinion issued Dec. 23. (60) Provisional application No. 61/171,523, filed on Apr. 2009 for International Application PCT/DK2009/050 134 filed Jun. 22, 2009, provisional application No. 61/162,761, 19, 2009. filed on Mar. 24, 2009, provisional application No. 61/074,226, filed on Jun. 20, 2008. Primary Examiner — James O Wilson Assistant Examiner — Oluwafemi Masha (51) Int. Cl. (74) Attorney, Agent, or Firm — Mary Catherine Di Nunzio CO7D 239/42 (2006.01) CO7D 23L/TO (2006.01) (57) ABSTRACT CO7D 487/04 (2006.01) This invention is directed to compounds, which are PDE10A CO7D 47L/04 (2006.01) enzyme inhibitors. The invention provides a pharmaceutical A6 IK3I/437 (2006.01) composition comprising atherapeutically effective amount of A6 IK3I/4985 (2006.01) a compound of the invention and a pharmaceutically accept A6 IK 45/06 (2006.01) able carrier. The present invention also provides processes for (52) U.S. Cl. the preparation of the compounds of formula I. The present CPC ...... C07D 487/04 (2013.01); C07D 471/04 invention further provides a method of treating a subject (2013.01); A61 K3I/437 (2013.01); A61 K Suffering from a neurodegenerative disorder comprising 3 1/4985 (2013.01); A61K 45/06 (2013.01) administering to the subject a therapeutically effective (58) Field of Classification Search amount of a compound of formula I. The present invention USPC ...... 514/256; 548/373.1 also provides a method of treating a Subject Suffering from a See application file for complete search history. drug addiction comprising administering to the Subject a therapeutically effective amount of a compound of formula I. (56) References Cited The present invention further provides a method of treating a Subject Suffering from a psychiatric disorder comprising U.S. PATENT DOCUMENTS administering to the subject a therapeutically effective 4,036,840 A 7, 1977 O’Brien et al. amount of a compound of formula I. 7,897,619 B2 3/2011 Zeng et al. 8,133,897 B2 3/2012 Ritzen et al. 29 Claims, No Drawings US 9,018,217 B2 1. 2 PHENYLMDAZOLE DERVATIVES AS striatum, n. accumbens and in the olfactory tubercle (Kotera, PDE10A ENZYME INHIBITORS J. et al. Biochem. Biophys. Res. Comm. 1999, 261, 551-557 and Seeger, T. F. et al. Brain Research, 2003,985, 113-126). CROSS-REFERENCE TO RELATED Mouse PDE10A is the first identified member of the APPLICATIONS PDE10 family of phosphodiesterases (Fujishige, K. et al. J. Biol. Chem. 1999, 274, 18438-18445 and Loughney, K. et al. The present application is a continuation of U.S. applica Gene 1999, 234, 109-117) and N-terminal splice variants of tion Ser. No. 13/365,504, filed Feb. 3, 2012, which is a divi both the rat and human genes have been identified (Kotera, J. sional of U.S. application Ser. No. 12/487,694, filed Jun. 19. et al. Biochem. Biophys. Res. Comm. 1999, 261,551-557 and 2009, now U.S. Pat. No. 8,133,897, which claims benefit of 10 Fujishige, K. et al. Eur: J. Biochem. 1999, 266, 1118-1127). U.S. Provisional Application No. 61/171,523 filed Apr. 22, There is a high degree of homology across species. PDE10A 2009, and claims priority of U.S. Provisional Application No. is uniquely localized in mammals relative to other PDE fami 61/162,761 filed Mar. 24, 2009, and claims benefit of U.S. Provisional Application No. 61/074.226 filed Jun. 20, 2008. lies. mRNA for PDE10 is highly expressed in testis and brain 15 (Fujishige, K. et al. EurJ Biochem. 1999, 266, 1118-1127: Each of these applications is hereby incorporated by refer Soderling, S. et al. Proc. Natl. Acad. Sci. 1999,96, 7071-7076 ence in its entirety. and Loughney, K. et al. Gene 1999, 234, 109-117). These FIELD OF THE INVENTION studies indicate that within the brain, PDE10 expression is highest in the striatum (caudate and putamen), n. accumbens The present invention provides compounds that are and olfactory tubercle. More recently, an analysis has been PDE10A enzyme inhibitors, and as such are useful to treat made of the expression pattern in rodent brain of PDE10A neurodegenerative and psychiatric disorders. Especially, the mRNA (Seeger, T. F. et al. Abst. Soc. Neurosci. 2000, 26, invention provides compounds that are highly selective for 345.10) and PDE10A protein (Menniti, F. S. et al. William PDE10 over other PDE subtypes. The present invention also Harvey Research Conference Phosphodiesterase in Health provides pharmaceutical compositions comprising com 25 and Disease, Porto, Portugal, Dec. 5-7, 2001). pounds of the invention and methods of treating disorders PDE10A is expressed at high levels by the medium spiny using the compounds of the invention. neurons (MSN) of the caudate nucleus, the accumbens nucleus and the corresponding neurons of the olfactory BACKGROUND OF THE INVENTION tubercle. These constitute the core of the basal ganglia sys 30 tem. The MSN has a key role in the cortical-basal ganglia Throughout this application, various publications are ref thalamocortical loop, integrating convergent cortical/tha erenced in full. The disclosures of these publications are lamic input, and sending this integrated information back to hereby incorporated by reference into this application to the cortex. MSN express two functional classes of neurons: describe more fully the state of the art to which this invention the D class expressing D dopamine receptors and the D. pertains. 35 class expressing D. dopamine receptors. The D class of neu The cyclic nucleotides cyclic-adenosine monophosphate rons is part of the direct striatal output pathway, which (cAMP) and cyclic-guanosine monophosphate (cGMP) func broadly functions to facilitate behavioral responses. The D. tion as intracellular second messengers regulating a vastarray class of neurons is part of the indirect striatel output path of processes in neurons. Intracellular cAMP and ccjMP are way, which functions to suppress behavioral responses that generated by adenyland guanyl cyclases, and are degraded by 40 compete with those being facilitated by the direct pathway. cyclic nucleotide phosphodiesterases (PDEs). Intracellular These competing pathways act like the brake and accelerator levels of cAMP and coMP are controlled by intracellular in a car. In the simplest view, the poverty of movement in signaling, and stimulation/repression of adenyl and guanyl Parkinson's disease results from over-activity of the indi cyclases in response to GPCR activation is a well character rect pathway, whereas excess movement in disorders such as izedway of controlling cyclic nucleotide concentrations (An 45 Huntington's disease represent over-activity of the direct toni, F. A. Front. Neuroendocrinol. 2000, 21, 103-132). pathway. PDE10A regulation of cAMP and/or cGMP signal cAMP and coMP levels in turn controlactivity of cAMP-and ing in the dendritic compartment of these neurons may be cGMP-dependent kinases as well as other proteins with involved in filtering the cortico/thalamic input into the MSN. cyclic nucleotide response elements, which through Subse Furthermore, PDE10A may be involved in the regulation of quent phosphorylation of proteins and other processes regu 50 GABA release in the Substantia nigra and globus pallidus late key neuronal functions such as Synaptic transmission, (Seeger, T. F. et al. Brain Research, 2003,985, 113-126). neuronal differentiation and survival. Dopamine D receptor antagonism is well established in There are 21 phosphodiesterase genes that can be divided the treatment of schizophrenia. Since the 1950s, dopamine into 11 gene families. There are ten families of adenylyl D. receptor antagonism has been the mainstay in psychosis cyclases, two of guanylyl cyclases, and eleven of phosphodi 55 treatment and all effective antipsychotic drugs antagonise D esterases. PDEs area class of intracellular enzymes that regu receptors. The effects of D, are likely to be mediated prima late levels of cAMP and coMP via hydrolysis of the cyclic rily through neurons in the striatum, n. accumbens and olfac nucleotides into their respective nucleotide monophosphates. tory tubercle, since these areas receive the densest dopamin Some PDEs degrade cAMP, some coMP and some both. ergic projections and have the strongest expression of D. Most PDEs have a widespread expression and have roles in 60 receptors (Konradi, C. and Heckers, S. Society of Biological many tissues, while some are more tissue-specific. Psychiatry, 2001, 50, 729-742). Dopamine D, receptor ago Phosphodieasterase 10A (PDE10A) is a dual-specificity nism leads to decrease in cAMP levels in the cells where it is phosphodiesterase that can convert both cAMP to AMP and expressed through adenylate cyclase inhibition, and this is a cGMP to GMP (Loughney, K. etal. Gene 1999,234, 109-117: component of D signalling (Stoof. J. C.; Kebabian J. W. Fujishige, K. etal. Eur:J. Biochem. 1999, 266, 1118-1127 and 65 Nature 1981, 294, 366-368 and Neve, K. A. et al. Journal of Soderling, S. et al. Proc. Natl. Acad. Sci. 1999, 96, 7071 Receptors and Signal Transduction 2004, 24, 165-205). Con 7076). PDE10A is primarily expressed in the neurons in the versely, D receptor antagonism effectively increases cAMP US 9,018,217 B2 3 4 levels, and this effect could be mimicked by inhibition of With respect to inhibitors of PDE10A, EP 1250923 dis cAMP degrading phosphodiesterases. closes the use of selective PDE10 inhibitors in general, and Most of the 21 phosphodiesterase genes are widely papaverine in particular, for the treatment of certain neuro expressed; therefore inhibition is likely to have side effects. logic and psychiatric disorders. Because PDE10A, in this context, has the desired expression 5 WO 05/113517 discloses benzodiazepine stereospecific profile with high and relatively specific expression in neurons compounds as inhibitors of phosphodiesterase, especially in striatum, n. accumbens and olfactory tubercle, PDE10A types 2 and 4, and the prevention and treatment of pathologies inhibition is likely to have effects similar to D, receptor involving a central and/or peripheral disorder. WO 02/88.096 antagonism and therefore have antipsychotic effects. discloses benzodiazepine derivatives and their uses as inhibi While PDE10A inhibition is expected to mimic D. recep 10 tors of phosphodiesterase, especially type 4 in the therapeutic torantagonism in part, it might be expected to have a different field. WO 04/41258 discloses benzodiazepinone derivatives profile. The D receptor has signalling components besides and their uses as inhibitors of phosphodiesterase, especially cAMP (Neve, K. A. et al. Journal of Receptors and Signal type 2 in the therapeutic field. Transduction 2004, 24, 165-205), wherefore interference 15 Pyrrdodihydroisoquinolines and variants thereof are dis with cAMP through PDE10A inhibition may negatively closed as inhibitors of PDE10 in WO 05/03129 and WO modulate rather than directly antagonise dopamine signaling 05/02579. Piperidinyl-substituted quinazolines and isoquino through D receptors. This may reduce the risk of the extrapy lines that serve as PDE10 inhibitors are disclosed in WO rimidal side effects that are seen with strong Dantagonism. 05/82883. WO 06/11040 discloses substituted quinazoline Conversely, PDE10A inhibition may have some effects not and isoquinoline compounds that serve as inhibitors of seen with D, receptor antagonism. PDE10A is also expressed PDE10. US 20050182079 discloses substituted tetrahy in D receptors expressing striatal neurons (Seeger, T. F. etal. droisoquinolinyl derivatives of quinazoline and isoquinoline Brain Research, 2003,985, 113-126). Since D, receptorago that serve as effective phosphodiesterase (PDE) inhibitors. In nism leads to stimulation of adenylate cyclase and resulting particular, US 20050182079 relates to said compounds, increase in cAMP levels, PDE10A inhibition is likely to also 25 which are selective inhibitors of PDE10. Analogously, US have effects that mimic D receptor agonism. Finally, 20060019975 discloses piperidine derivatives of quinazoline PDE10A inhibition will not only increase cAMP in cells, but and isoquinoline that serve as effective phosphodiesterase might also be expected to increase coMP levels, since (PDE) inhibitors. US 20060019975 also relates to com PDE10A is a dual specificity phosphodiesterase.cCMP acti pounds that are selective inhibitors of PDE10. WO 06/028957 vates a number of target protein in cells like cAMP and also 30 discloses cinnoline derivatives as inhibitors of phosphodi interacts with the cAMP signalling pathways. In conclusion, esterase type 10 for the treatment of psychiatric and neuro PDE10A inhibition is likely to mimic D. receptor antagonism logical syndromes. in part and therefore has antipsychotic effect, but the profile However, these disclosures do not pertain to the com might differ from that observed with classical D receptor pounds of the invention, which are structurally unrelated to antagonists. 35 any of the known PDE10 inhibitors (Kehler, J. et al. Expert The PDE10A inhibitor papaverine is shown to be active in Opin. Ther. Patents 2007, 17, 147-158), and which have now several antipsychotic models. Papaverine potentiated the been found by the inventors to be highly active and selective cataleptic effect of the D receptor antagonist haloperidol in PDE10A enzyme inhibitors. rats, but did not cause catalepsy on its own (WO 03/093499). The compounds 2-(5-Phenyl-1H-imidazol-2-ylmethylsul Papaverine reduced hyperactivity in rats induced by PCP. 40 fanyl)-1H-benzoimidazole (CAS Registry no. 348125-42-8) while reduction of amphetamine induced hyperactivity was and 2-(5-Phenyl-1H-imidazol-2-yl-sulfanylmethyl)-1H-ben insignificant (WO 03/093499). These models suggest that Zoimidazole (CAS Registry no. 296791-07-6) appear in the PDE10A inhibition has the classic antipsychotic potential chemical libraries of Scientific Exchange, Inc. and Zelinsky that would be expected from theoretical considerations. WO Institute of Organic Chemistry, respectively, but no pharma 03/093499 further discloses the use of selective PDE10 45 cological data appear to have been published. The compounds inhibitors for the treatment of associated neurologic and psy are both disclaimed from the scope of the present invention. chiatric disorders. Furthermore, PDE10A inhibition reverses The compounds of the invention may offer alternatives to subchronic PCP-induced deficits in attentional set-shifting in current marketed treatments for neurodegenerative and/or rats (Rodeferetal. Eur:J. Neurosci. 2005, 4, 1070-1076). This psychiatric disorders, which are not efficacious in all patients. model suggests that PDE10A inhibition might alleviate cog 50 Hence, there remains a need for alternative methods of treat nitive deficits associated with Schizophrenia. ment. The tissue distribution of PDE10A indicates that PDE10A inhibitors can be used to raise levels of cAMP and/or cGMP SUMMARY OF THE INVENTION within cells that express the PDE10 enzyme, especially neu rons that comprise the basal ganglia, and the PDE10A inhibi 55 The objective of the present invention is to provide com tors of the present invention would therefore be useful in pounds that are selective PDE10A enzyme inhibitors. treating a variety of associated neuropsychiatric conditions A further objective of the present invention is to provide involving the basal ganglia Such as neurological and psychi compounds which have such activity, and which have atric disorders, Schizophrenia, bipolar disorder, obsessive improved solubility, metabolic stability and/or bioavailability compulsive disorder, and the like, and may have the benefit of 60 compared to prior art compounds. not possessing unwanted side effects, which are associated Another objective of the invention is to provide an effective with the current therapies on the market. treatment, in particular long-term treatment, of a human Furthermore, recent publications (WO 2005/120514, WO patient, without causing the side effects typically associated 2005012485, Cantin et al. Bioorganic & Medicinal Chemis with current therapies for neurological and psychiatric disor try Letters 17 (2007) 2869-2873) suggest that PDE10A 65 ders. inhibitors may be useful for treatment of obesity and non Further objectives of the invention will become apparent insulin dependent diabetes. upon reading the present specification. US 9,018,217 B2 5 6 Accordingly, in one aspect the present invention relates to thereof, for the preparation of a medicament for the treatment compounds of formula I: of a neurodegenerative or psychiatric disorder. Furthermore, in yet another aspect, the present invention provides a method of treating a Subject Suffering from a neurodegenerative disorder, comprising administering to the R3 Subject a therapeutically effective amount of a compound of R2 formula I. In a still further aspect, the present invention pro vides a method of treating a subject Suffering from a psychi atric disorder, comprising administering to the Subject a N R5 10 therapeutically effective amount of a compound of formula I. In another embodiment, the present invention provides a HEI-1-( R6 method of treating a subject Suffering from a drug addiction, N sh Such as an alcohol, amphetamine, cocaine, or opiate addic R1 tion. 15 wherein HET is a heteroaromatic group of formula II con DETAILED DESCRIPTION OF THE INVENTION taining from 2 to 4 nitrogen atoms: Definition of Substitutents As used in the context of the present invention, the terms II “halo' and “halogen' are used interchangeably and refer to fluorine, chlorine, bromine or iodine. The term "C-C alkyl” refers to a straight-chain or branched saturated hydrocarbon having from one to six car 25 bon atoms, inclusive. Examples of Such groups include, but are not limited to, methyl, ethyl, 1-propyl. 2-propyl, 1-butyl, whereinY can be Nor CH, Z can be Nor C, and wherein HET 2-butyl, 2-methyl-2-propyl, 2-methyl-1-butyl, and n-hexyl. may optionally be substituted with up to three substituents The expression "C-C hydroxyalkyl” refers to a C-C alkyl R7, R8 and R9 individually selected from H; C-C alkyl such group as defined above which is substituted with one hydroxy as Me: halogen Such as chlorine and bromine; cyano; halo 30 group. The term "halo(C-C)alkyl” refers to a C-C alkyl (C-C)alkyl Such as trifluoromethyl: aryl Such as phenyl: group as defined above which is substituted with up to three alkoxy, preferably C-C alkoxy, such as methoxy, halogen atoms, such as trifluoromethyl. dimethoxy, ethoxy, methoxy-ethoxy and ethoxy-methoxy, The expression"C-C alkoxy” refers to a straight-chain or and C-C hydroxyalkyl such as CHCH-OH, and wherein * branched Saturated alkoxy group having from one to six car denotes the attachment point, 35 bon atoms, inclusive, with the open Valency on the oxygen. -L- is a linker selected from —S—CH2—, —CH2—S—, Examples of Such groups include, but are not limited to, —CH2—CH2—, or —CH=CH , methoxy, ethoxy, n-butoxy, 2-methyl-pentoxy and n-hexy R1 is selected from H; C-C alkyl such as methyl, ethyl, loxy. 1-propyl, 2-propyl, isobutyl, C-C alkyl (C-C)cycloalkyl The term "C-C cycloalkyl typically refers to cyclopro Such as cyclopropylmethyl, C-C hydroxyalkyl such as 40 pyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or hydroxyethyl: CHCN; CHC(O)NH; C-C arylalkyl such cyclooctyl. The expression "C-C alkyl (C-C)cycloalkyl as benzyl and 4-chlorobenzyl; and C-C alkyl-heterocy refers to a C-C cycloalkyl as defined above which is substi cloalkyl Such as tetrahydropyran-4-yl-methyl and 2-morpho tuted with a straight-chain or branched C-C alkyl. lin-4-yl-ethyl: Examples of Such groups include, but are not limited to, 45 cyclopropylmethyl. R2-R6 are each selected independently from H; C-C alkoxy The term "heterocycloalkyl refers to a four to eight mem Such as methoxy; and halogen such as chlorine or fluorine; bered ring containing carbon atoms and up to three N, O or S and tautomers and pharmaceutically acceptable acid addition atoms, provided that the four to eight membered ring does not salts thereof, and polymorphic forms thereof, with the pro contain adjacent 0 or adjacent Satoms. The open Valency is on viso that the compound is not 2-(5-Phenyl-1H-imidazol-2- 50 either the heteroatom or carbon atom. Examples of such ylmethylsulfanyl)-1H-benzoimidazole or 2-(5-Phenyl-1H groups include, but are not limited to, aZetidinyl, oxetanyl. imidazol-2-yl-sulfanylmethyl)-1H-benzoimidazole piperazinyl, morpholinyl, thiomorpholinyl and 1.4 diazepa In a particular embodiment, the invention relates to a com nyl. The term “hydroxyheterocycloalkyl refers to a hetero pound of formula I in the form of a single tautomer or a cycloalkyl as defined above which is substituted with one polymorph. 55 hydroxy group. The term "C-C alkyl-heterocycloalkyl In separate embodiments of the invention, the compound of refers to a heterocycloalkyl as defined above which is substi formula I is selected among the specific compounds disclosed tuted with a C-C alkyl group. Examples of Such groups in the Experimental Section herein. include, but are not limited to, tetrahydropyran-4-yl-methyl The invention further provides a compound of formula I, or and 2-morpholin-4-yl-ethyl. a pharmaceutically acceptable acid addition salt thereof, for 60 The term “aryl” refers to a phenyl ring, optionally substi use as a medicament. tuted with halogen, C-C alkyl, C-C alkoxy or halo (C-C) In another aspect, the present invention provides a phar alkyl as defined above. Examples of such groups include, but maceutical composition comprising a therapeutically effec are not limited to, phenyl and 4-chlorophenyl. tive amount of a compound of formula I and a pharmaceuti The term "C-Carylalkyl refers to an aryl as defined cally acceptable carrier, diluent or excipient. 65 above which is substituted with a straight-chain or branched The invention further provides the use of a compound of C-C alkyl. Examples of Such groups include, but are not formula I, or a pharmaceutically acceptable acid addition salt limited to, benzyl and 4-chlorobenzyl. US 9,018,217 B2 7 8 Additionally, the present invention further provides certain embodiment, HET is 5-methyl-imidazo 1,2-alpyridine. In embodiments of the invention, which are described below. another specific embodiment, HET is 5-trifluoromethyl-imi In one embodiment of the invention, HET is a heteroaro dazo[1,2-alpyridine. In another specific embodiment, HET is matic group of formula II containing 2 nitrogen atoms. In 6-Bromo-5,7-dimethyl-1,2,4-triazolo 1.5-alpyridine. In another embodiment of the invention, HET is a heteroaro another specific embodiment, HET is 6-bromo-7-methyl-1, matic group of formula II containing 3 nitrogenatoms. In yet 2.4 triazolo 1.5-alpyridine. In another specific embodiment, another embodiment of the invention, HET is a heteroaro HET is 6-chloro-8-methyl-1,2,4-triazolo 1.5-apyridine. In matic group of formula II containing 4 nitrogen atoms. another specific embodiment, HET is 6-chloro-imidazol-2- HET is preferably chosen among the following heteroaro apyridine. In another specific embodiment, HET is 7-me matic groups, wherein “” denotes the attachment point: 10 thyl-1,2,4-triazolo 1.5-alpyridine. In another specific embodiment, HET is 8-methyl-imidazo 1,2-alpyridine. In another specific embodiment, HET is imidazo 1,2-alpyri 21 dine-7-carbonitrile. In another specific embodiment, HET is 5,7-Dimethyl-1,2,4-triazolo 1.5-alpyrimidine. 15 Typically, HET is 5,7-dimethyl-imidazo 1,2-alpyrimidine H N or 1,2,4-Triazolo 1,5-cpyrimidine or 1,2,4-Triazolo 1.5-a a NN Y. 21 N : 21 2N. : pyrazine. In another embodiment of the invention, -L- is O) S- CX —S—CH2—. In a further embodiment. -L- is —CH2—S-. N In yet another embodiment. -L- is —CH2—CH2—. In a still further embodiment, -L- is —CH=CH-. In a further embodiment of the invention, R is H. In another embodiment, R is C-C straight or branched chain 25 alkyl. In another embodiment, R is C-C hydroxyalkyl. In In a further embodiment, the heteroaromatic group HET is another embodiment, R is C-C alkyl (C-C)cycloalkyl. In substituted with one substituent R7 selected from H; C-C, a further embodiment, R is C-C alkyl-heterocycloalkyl. In alkyl Such as methyl; halogen Such as chlorine or bromine; another embodiment, R is C-C arylalkyl. In a further cyano; halo(C-C)alkyl Such as trifluoromethyl, aryl Such as embodiment, R is CHCN. In a still further embodiment, R phenyl; and C-C hydroxyalkyl such as CHCH-OH. In 30 is CHC(O)NH. another embodiment, HET is substituted with two substitu In a specific embodiment, R is methyl. In another specific ents R7 and R8 individually selected from H; C-C alkyl embodiment, R is ethyl. In another specific embodiment, R Such as methyl; halogen Such as chlorine or bromine; cyano; is 1-propyl. In another specific embodiment, R is 2-propyl. halo(C-C)alkyl Such as trifluoromethyl, aryl Such as phe In another specific embodiment, R is isobutyl. In another nyl; and C-C hydroxyalkyl such as CHCH-OH. Inafurther 35 specific embodiment, R is hydroxyethyl. In another specific embodiment, HET is substituted with three substituents R7, embodiment, R is cyclopropylmethyl. In another specific R8 and R9 individually selected from H; C-C alkyl such as embodiment, R is tetrahydropyran-4-yl-methyl. In another methyl; halogen Such as chlorine or bromine; cyano; halo(C- specific embodiment, R is 2-morpholin-4-yl-ethyl. In C.)alkyl Such as trifluoromethyl: aryl Such as phenyl; and another specific embodiment, R is benzyl. In another specific C-C hydroxyalkyl such as CHCH-OH. 40 embodiment, R is 4-chlorobenzyl. In another specific In a specific embodiment, R-7, Rs and Ro are all hydrogen. embodiment, R is CHCN. In another specific embodiment, In a different embodiment, at least one of R. R. and R is R is CHC(O)NH. C-C alkyl Such as methyl. In a further embodiment, at least In one embodiment of the invention, R. R. R. Rs and R. one of R7, Rs and Ro is halogen Such as chlorine or bromine. are all hydrogen. In another embodiment, at least one of R, Specific embodiments of the compound for which the HET 45 R. R. Rs and R is C-C alkoxy such as methoxy. In a radical is derived are given below. further embodiment of the invention, at least one of R. R. In a specific embodiment, HET is imidazo 1,2-alpyrimi R. Rs and R is halogen such as chlorine or fluorine. dine. In a second specific embodiment, HET is 1.2.4 triazolo In one embodiment of the invention, R is hydrogen. In 1.5-alpyridine. In a third specific embodiment, HET is imi another embodiment, R is C-C alkoxy such as methoxy. In dazo[1,2-alpyridine. In a fourth specific embodiment, HET is 50 a further embodiment, R is halogen Such as chlorine or imidazo[4,5-b]pyrimidine. In a fifth specific embodiment, fluorine. HET is pyrazolo 1.5-alpyridine. In a sixth specific embodi In one embodiment of the invention, R is hydrogen. In ment, HET is 1,2,4-Triazolo 1.5-alpyrimidine. In a seventh another embodiment, R is C-C alkoxy such as methoxy. In specific embodiment, HET is 1.2.4 Triazolo 1.5-cpyrimi a further embodiment, R is halogen such as chlorine or dine. In an eight specific embodiment, HET is 1,2,4-Triazolo 55 fluorine. 1.5-alpyrazine. In one embodiment of the invention, R is hydrogen. In In another specific embodiment, HET is 1.2.4 triazolo1, another embodiment, R is C-C alkoxy such as methoxy. In 5-alpyrimidine. In another specific embodiment, HET is 1.2, a further embodiment, R is halogen Such as chlorine or 4triazolo 1.5-alpyridine-6-carbonitrile. In another specific fluorine. embodiment, HET is 1-methyl-1H-benzoimidazole. In 60 In one embodiment of the invention, Rs is hydrogen. In another specific embodiment, HET is 1-phenyl-1H-ben another embodiment, Rs is C-C alkoxy such as methoxy. In Zoimidazole. In another specific embodiment, HET is 2-(6- a further embodiment, Rs is halogen Such as chlorine or chloro-benzoimidazol-1-yl)-ethanol. In another specific fluorine. embodiment, HET is 5,7-dimethyl-1,2,4-triazolo 1.5-apy In one embodiment of the invention, R is hydrogen. In ridine. In another specific embodiment, HET is 5,7-dimethyl 65 another embodiment, R is C-C alkoxy such as methoxy. In imidazol-2-alpyridine. In another specific embodiment, a further embodiment, R is halogen Such as chlorine or HET is 5-chloro-imidazo 1,2-alpyridine. In another specific fluorine.

US 9,018,217 B2 13 14 Results of the experiments showed that the tested com colic, p-aminobenzoic, glutamic, benzenesulfonic, p-tolu pounds of the invention are in Vivo active compounds that enesulfonic acids, theophylline acetic acids, as well as the reverse the PCP induced hyperactivity to the % shown in the 8-halotheophyllines, for example 8-bromotheophylline and table. the like. Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharma TABLE 2 ceutically acceptable salts listed in Serge, S. M. et al., J. Pharm. Sci. 1977, 66, 2, the contents of which are hereby Reversal of PCP induced hyperactivity incorporated by reference. % reversal of Furthermore, the compounds of this invention may exist in PCP induced 10 unsolvated as well as in Solvated forms with pharmaceutically Compound hyperactivity acceptable solvents such as water, ethanol and the like. In 8-Methyl-2-[2-(1-methyl-4-phenyl-1H-imidazol-2-yl)- 69 general, the Solvated forms are considered equivalent to the ethyl-1,2,4-triazolo15-apyridine 5-Methyl-2-[2-(1-methyl-4-phenyl-1H-imidazol-2-yl)- 66 unsolvated forms for the purposes of this invention. ethyl-1,2,4-triazolo15-apyridine 15 Pharmaceutical Compositions 5,7-Dimethyl-2-[2-(1-methyl-4-phenyl-1H-imidazol- 84 The present invention further provides a pharmaceutical 2-yl)-ethyl-1,2,4-triazolo 1.5-apyrimidine composition comprising atherapeutically effective amount of 5,7-Dimethyl-2-[2-(4-phenyl-1H-imidazol-2-yl)-ethyl- 38 1,2,4-triazolo15-apyrimidine a compound of formula I and a pharmaceutically acceptable 5,8-Dimethyl-2-[2-(1-methyl-4-phenyl-1H-imidazol- 67 carrier or diluent. The present invention also provides a phar 2-yl)-ethyl-1,2,4-triazolo 1.5-apyridine maceutical composition comprising a therapeutically effec 5-Methyl-2-[2-(1-methyl-4-phenyl-1H-imidazol-2-yl)- 17 ethyl-7-morpholin-4-yl-1,2,4-triazolo.1,5-apyrimidine tive amount of one of the specific compounds disclosed in the Diisopropyl-(2-2-[2-(5-methyl-1,2,4-triazolo 1.5-a) 27 Experimental Section herein and a pharmaceutically accept pyridin-2-yl)-ethyl-4-phenyl-imidazol-1-yl)- able carrier or diluent. ethyl)-amine 8-Methoxy-2-(1-methyl-4-phenyl-1H-imidazol-2- 26 The compounds of the invention may be administered ylsulfanylmethyl)-1,2,4-triazolo 1.5-apyridine 25 alone or in combination with pharmaceutically acceptable 5,6,7-Trimethyl-2-[2-(1-methyl-4-phenyl-1H- 14 carriers, diluents or excipients, in either single or multiple imidazol-2-yl)-ethyl-1,2,4-triazolo15-apyrimidine doses. The pharmaceutical compositions according to the 2-4-(3-Methoxy-phenyl)-1-methyl-1H-imidazol-2- 36 ylmethylsulfanyl-5,7-dimethyl-1,2,4-triazolo.1,5-a invention may be formulated with pharmaceutically accept pyrimidine able carriers or diluents as well as any other known adjuvants (2-2-[2-(5,7-Dimethyl-1,2,4-triazolo 1.5-alpyrimidin- 14 30 and excipients in accordance with conventional techniques 2-yl)-ethyl-4-phenyl-imidazol-1-yl-ethyl)- such as those disclosed in Remington: The Science and Prac diisopropyl-amine 5,7-Dimethyl-2-[2-(4-phenyl-1-propyl-1H-imidazol- 3 tice of Pharmacy, 19" Edition, Gennaro, Ed., Mack Publish 2-yl)-ethyl-1,2,4-triazolo 1.5-apyrimidine ing Co., Easton, Pa., 1995. 1-2-[2-(5,7-Dimethyl-1,2,4-triazolo 1.5-a) 15 The pharmaceutical compositions may be specifically for pyrimidin-2-yl)-ethyl-4-phenyl-imidazol-1-yl)- 35 mulated for administration by any suitable route such as oral, propan-2-o 8-methoxy-5-methyl-2-(2-(1-methyl-4-phenyl-1H- 57 rectal, nasal, pulmonary, topical (including buccal and Sub imidazol-2-yl)ethyl)-1,2,4-triazolo15-apyridine lingual), transdermal, intracisternal, intraperitoneal, vaginal 1-2-[2-(5,7-Dimethyl-1,2,4-triazolo 1.5-alpyrimidin- 33 and parenteral (including Subcutaneous, intramuscular, 2-yl)-ethyl-4-phenyl-imidazol-1-yl)-2-methyl intrathecal, intravenous and intradermal) routes. It will be propan-2-o 40 8-Ethyl-5-methyl-2-[2-(1-methyl-4-phenyl-1H- 85 appreciated that the route will depend on the general condi imidazol-2-yl)-ethyl-1,2,4-triazolo 1,5-cpyrimidine tion and age of the subject to be treated, the nature of the 5,8-Dimethyl-2-[2-(1-methyl-4-phenyl-1H-imidazol- 99 condition to be treated and the active ingredient. 2-yl)-ethyl-1,2,4-triazolo 1.5-apyrazine Pharmaceutical compositions for oral administration 7-Isopropyl-5-methyl-2-[2-(1-methyl-4-phenyl-1H- 30 imidazol-2-yl)-ethyl-1,2,4-triazolo15-apyrimidine include Solid dosage forms such as capsules, tablets, dragees, 7-Methoxy-5,8-dimethyl-2-[2-(1-methyl-4-phenyl-1H- 41 45 pills, lozenges, powders and granules. Where appropriate, the imidazol-2-yl)-ethyl-1,2,4-triazolo 1,5-cpyrimidine compositions may be prepared with coatings Such as enteric 5,8-Dimethyl-2-[2-(1-methyl-4-phenyl-1H-imidazol- 96 coatings or they may be formulated so as to provide con 2-yl)-ethyl-1,2,4-triazolo.1,5-cpyrimidine 8-Ethyl-5-methyl-2-[2-(1-methyl-4-phenyl-1H- 31 trolled release of the active ingredient such as Sustained or imidazol-2-yl)-ethyl-1,2,4-triazolo15-apyridine prolonged release according to methods well known in the 50 art. Liquid dosage forms for oral administration include solu tions, emulsions, Suspensions, syrups and elixirs. Pharmaceutically Acceptable Salts Pharmaceutical compositions for parenteral administra The present invention also comprises salts of the com tion include sterile aqueous and nonaqueous injectable solu pounds, typically, pharmaceutically acceptable salts. Such tions, dispersions, Suspensions or emulsions as well as sterile salts include pharmaceutically acceptable acid addition salts. 55 powders to be reconstituted in sterile injectable solutions or Acid addition salts include Salts of inorganic acids as well as dispersions prior to use. Other suitable administration forms organic acids. include, but are not limited to, Suppositories, sprays, oint Representative examples of Suitable inorganic acids ments, creams, gels, inhalants, dermal patches and implants. include hydrochloric, hydrobromic, hydroiodic, phosphoric, Typical oral dosages range from about 0.001 to about 100 Sulfuric, Sulfamic, nitric acids and the like. Representative 60 mg/kg body weight per day. Typical oral dosages also range examples of Suitable organic acids include formic, acetic, from about 0.01 to about 50 mg/kg body weight per day. trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, Typical oral dosages further range from about 0.05 to about citric, fumaric, glycolic, itaconic, lactic, methanesulfonic, 10 mg/kg body weight per day. Oral dosages are usually maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, administered in one or more dosages, typically, one to three salicylic, succinic, methane Sulfonic, ethanesulfonic, tartaric, 65 dosages per day. The exact dosage will depend upon the ascorbic, pamoic, bismethylene Salicylic, ethanedisulfonic, frequency and mode of administration, the sex, age, weight gluconic, citraconic, aspartic, Stearic, palmitic, EDTA, gly and general condition of the Subject treated, the nature and US 9,018,217 B2 15 16 severity of the condition treated and any concomitant diseases lozenge. The amount of solid carrier will vary widely but will to be treated and other factors evident to those skilled in the range from about 25 mg to about 1 g per dosage unit. If a art. liquid carrier is used, the preparation may be in the form of a The formulations may also be presented in a unit dosage syrup, emulsion, soft gelatin capsule or sterile injectable liq form by methods known to those skilled in the art. For illus uid Such as an aqueous or non-aqueous liquid Suspension or trative purposes, a typical unit dosage form for oral adminis Solution. tration may contain from about 0.01 to about 1000 mg, from The pharmaceutical compositions of the invention may be about 0.05 to about 500 mg. or from about 0.5 mg to about 200 prepared by conventional methods in the art. For example, ng. tablets may be prepared by mixing the active ingredient with For parenteral routes such as intravenous, intrathecal, 10 ordinary adjuvants and/or diluents and Subsequently com intramuscular and similar administration, typical doses are in the order of half the dose employed for oral administration. pressing the mixture in a conventional tabletting machine The present invention also provides a process for making a prepare tablets. Examples of adjuvants or diluents comprise: pharmaceutical composition comprising admixing a thera corn Starch, potato starch, talcum, magnesium Stearate, gela peutically effective amount of a compound of formula I and at 15 tin, lactose, gums, and the like. Any other adjuvants or addi least one pharmaceutically acceptable carrier or diluent. In an tives usually used for Such purposes such as colorings, fla embodiment, of the present invention, the compound utilized Vorings, preservatives etc. may be used provided that they are in the aforementioned process is one of the specific com compatible with the active ingredients. pounds disclosed in the Experimental Section herein. Treatment of Disorders The compounds of this invention are generally utilized as As mentioned above, the compounds of formula I are the free Substance or as a pharmaceutically acceptable salt PDE10A enzyme inhibitors and as such are useful to treat thereof. One example is an acid addition salt of a compound associated neurological and psychiatric disorders. having the utility of a free base. When a compound of formula The invention thus provides a compound of formula I or a I contains a free base Such salts are prepared in a conventional pharmaceutically acceptable acid addition salt thereof, as manner by treating a solution or Suspension of a free base of 25 well as a pharmaceutical composition containing such a com formula I with a molar equivalent of a pharmaceutically pound, for use in the treatment of a neurodegenerative disor acceptable acid. Representative examples of Suitable organic der, psychiatric disorder or drug addiction in mammals and inorganic acids are described above. including humans; wherein the neurodegenerative disorder is For parenteral administration, Solutions of the compounds selected from the group consisting of Alzheimer's disease, of formula I in Sterile aqueous Solution, aqueous propylene 30 glycol, aqueous vitamin E or sesame or peanut oil may be multi-infarct dementia, alcoholic dementia or other drug employed. Such aqueous solutions should be suitably buff related dementia, dementia associated with intracranial ered if necessary and the liquid diluent first rendered isotonic tumors or cerebral trauma, dementia associated with Hun with Sufficient saline or glucose. The aqueous solutions are tington's disease or Parkinson's disease, or AIDS-related particularly Suitable for intravenous, intramuscular, Subcuta 35 dementia; delirium; amnestic disorder, post-traumatic stress neous and intraperitoneal administration. The compounds of disorder; mental retardation; a learning disorder, for example formula I may be readily incorporated into known sterile reading disorder, mathematics disorder, or a disorder of writ aqueous media using standard techniques known to those ten expression; attention-deficit/hyperactivity disorder; and skilled in the art. age-related cognitive decline; and wherein the psychiatric Suitable pharmaceutical carriers include inert solid dilu 40 disorder is selected from the group consisting of schizophre ents or fillers, sterile aqueous solutions and various organic nia, for example of the paranoid, disorganized, catatonic, Solvents. Examples of Solid carriers include lactose, terra undifferentiated, or residual type; schizophreniform disorder; alba, Sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, schizoaffective disorder, for example of the delusional type or magnesium Stearate, Stearic acid and lower alkyl ethers of the depressive type; delusional disorder; Substance-induced cellulose. Examples of liquid carriers include, but are not 45 psychotic disorder, for example psychosis induced by alco limited to, syrup, peanut oil, olive oil, phospholipids, fatty hol, amphetamine, cannabis, cocaine, hallucinogens, inhal acids, fatty acid amines, polyoxyethylene and water. Simi ants, opioids, or phencyclidine; personality disorder of the larly, the carrier or diluent may include any Sustained release paranoid type; and personality disorder of the Schizoid type; material known in the art, Such as glyceryl monostearate or and wherein the drug addiction is an alcohol, amphetamine, glyceryl distearate, alone or mixed with a wax. The pharma 50 cocaine, or opiate addiction. ceutical compositions formed by combining the compounds The compounds of formula I or pharmaceutically accept of formula I and a pharmaceutically acceptable carrier are able salts thereof may be used in combination with one or then readily administered in a variety of dosage forms Suit more other drugs in the treatment of diseases or conditions for able for the disclosed routes of administration. The formula which the compounds of the present invention have utility, tions may conveniently be presented in unit dosage form by 55 where the combination of the drugs together are safer or more methods known in the art of pharmacy. effective than either drug alone. Additionally, the compounds Formulations of the present invention suitable for oral of the present invention may be used in combination with one administration may be presented as discrete units such as or more other drugs that treat, prevent, control, ameliorate, or capsules or tablets, each containing a predetermined amount reduce the risk of side effects or toxicity of the compounds of of the active ingredient, and optionally a suitable excipient. 60 the present invention. Such other drugs may be administered, Furthermore, the orally available formulations may be in the by a route and in an amount commonly used therefore, con form of a powder or granules, a solution or Suspension in an temporaneously or sequentially with the compounds of the aqueous or non-aqueous liquid, or an oil-in-water or water present invention. Accordingly, the pharmaceutical composi in-oil liquid emulsion. tions of the present invention include those that contain one or If a solid carrier is used for oral administration, the prepa 65 more other active ingredients, in addition to the compounds of ration may be tabletted, placed in a hard gelatin capsule in the present invention. The combinations may be administered powder or pellet form or it may be in the form of a troche or as part of a unit dosage form combination product, or as a kit US 9,018,217 B2 17 18 or treatment protocol wherein one or more additional drugs Zisoxazoles (e.g., risperidone), sertindole, olanzapine, que are administered in separate dosage forms as part of a treat tiapine, osanetant and Ziprasidone. ment regimen. Particularly preferred neuroleptic agents for use in the The present invention provides a method of treating a invention are sertindole, olanzapine, risperidone, quetiapine, mammal, including a human, Suffering from a neurodegen aripiprazole, haloperidol, clozapine, Ziprasidone and osanet erative disorder selected from a cognition disorder or move ant. ment disorder, which method comprises administering to the The present invention further provides a method of treating Subject a therapeutically effective amount of a compound of a subject Suffering from a cognition disorder, which method formula I. 10 comprises administering to the Subject a therapeutically This invention further provides a method of treating a effective amount of a compound of formula I. Examples of neurodegenerative disorder or condition in a mammal, cognition disorders that can be treated according to the including a human, which method comprises administering present invention include, but are not limited to, Alzheimer's to said mammal an amount of a compound of formula I disease, multi-infarct dementia, alcoholic dementia or other effective in inhibiting PDE10. 15 drug-related dementia, dementia associated with intracranial This invention also provides a method of treating a subject tumors or cerebral trauma, dementia associated with Hun Suffering from a psychiatric disorder, which method com tington's disease or Parkinson's disease, or AIDS-related prises administering to the Subject a therapeutically effective dementia; delirium; amnestic disorder, post-traumatic stress amount of a compound of formula I. Examples of psychiatric disorder; mental retardation; a learning disorder, for example reading disorder, mathematics disorder, or a disorder of writ disorders that can be treated according to the present inven ten expression; attention-deficit/hyperactivity disorder; and tion include, but are not limited to, Schizophrenia, for age-related cognitive decline. example of the paranoid, disorganized, catatonic, undifferen This invention also provides a method of treating a move tiated, or residual type; schizophreniform disorder, Schizoaf 25 ment disorder, which method comprises administering to the fective disorder, for example of the delusional type or the Subject a therapeutically effective amount of a compound of depressive type; delusional disorder, Substance-induced psy formula I. Examples of movement disorders that can be chotic disorder, for example psychosis induced by alcohol, treated according to the present invention include, but are not amphetamine, cannabis, cocaine, hallucinogens, inhalants, 30 limited to, Huntington's disease and dyskinesia associated opioids, or phencyclidine; personality disorder of the para with dopamine agonist therapy. This invention further pro noid type; and personality disorder of the schizoid type; and vides a method of treating a movement disorder selected from the anxiety disorder is selected from panic disorder; agora Parkinson's disease and restless leg syndrome, which com phobia; a specific phobia; Social phobia; obsessive-compul prises administering to the Subject a therapeutically effective sive disorder, post-traumatic stress disorder; acute stress dis 35 amount of a compound of formula I. order, and generalized anxiety disorder. This invention also provides a method of treating a mood It has been found that the compounds of formula I or disorder, which method comprises administering to the Sub pharmaceutically acceptable salts thereof may advanta ject a therapeutically effective amount of a compound of geously be administered in combination with at least one formula I. Examples of mood disorders and mood episodes neuroleptic agent (which may be a typical or an atypical 40 that can be treated according to the present invention include, antipsychotic agent) to provide improved treatment of psy but are not limited to, major depressive episode of the mild, chiatric disorders such as Schizophrenia. The combinations, moderate or severe type, a manic or mixed mood episode, a uses and methods of treatment of the invention may also hypomanic mood episode; a depressive episode with a typical provide advantages in treatment of patients who fail to 45 features; a depressive episode with melancholic features; a respond adequately or who are resistant to other known treat depressive episode with catatonic features; a mood episode mentS. with postpartum onset; post-stroke depression; major depres The present invention thus provides a method of treating a sive disorder; dysthymic disorder; minor depressive disorder; mammal Suffering from a psychiatric disorder, such as premenstrual dysphoric disorder, post-psychotic depressive Schizophrenia, which method comprises administering to the 50 disorder of schizophrenia; a major depressive disorder Super mammalatherapeutically effective amount of a compound of imposed on a psychotic disorder Such as delusional disorder formula I, either alone or as combination therapy together or schizophrenia; a bipolar disorder, for example bipolar I with at least one neuroleptic agent. disorder, bipolar II disorder, and cyclothymic disorder. It is The term “neuroleptic agent” as used herein refers to drugs, 55 understood that a mood disorder is a psychiatric disorder. which have the effect on cognition and behaviour of antipsy This invention further provides a method of treating a drug chotic agent drugs that reduce confusion, delusions, halluci addiction, for example an alcohol, amphetamine, cocaine, or nations, and psychomotor agitation in patients with psycho opiate addiction, in a mammal, including a human, which ses. Also known as major tranquilizers and antipsychotic method comprises administering to said mammal an amount drugs, neuroleptic agents include, but are not limited to: typi 60 of a compound of formula I effective in treating drug addic cal antipsychotic drugs, including phenothiazines, further tion. divided into the aliphatics, piperidines, and piperazines, This invention also provides a method of treating a drug thioxanthenes (e.g., cisordinol), butyrophenones (e.g., halo addiction, for example an alcohol, amphetamine, cocaine, or peridol), dibenzoxazepines (e.g., loxapine), dihydroindolo 65 opiate addiction, in a mammal, including a human, which nes (e.g., molindone), diphenylbutylpiperidines (e.g., method comprises administering to said mammal an amount pimozide), and atypical antipsychotic drugs, including ben of a compound of formula I effective in inhibiting PDE10. US 9,018,217 B2 19 20 The term "drug addiction', as used herein, means an abnor Sibutramine, bromocriptine, ephedrine, leptin, pseudoephe mal desire for a drug and is generally characterized by moti drine, or peptide YY3-36, or analogs thereof. Vational disturbances such a compulsion to take the desired The term “metabolic syndrome' as used herein refers to a drug and episodes of intense drug craving. constellation of conditions that place people at high risk for Drug addiction is widely considered a pathological state. coronary artery disease. These conditions include type 2 dia The disorder of addiction involves the progression of acute betes, obesity, high blood pressure, and a poor lipid profile drug use to the development of drug-seeking behavior, the with elevated LDL (“bad”) cholesterol, low HDL (“good”) Vulnerability to relapse, and the decreased, slowed ability to cholesterol, and elevated triglycerides. All of these conditions respond to naturally rewarding stimuli. For example, The 10 are associated with high blood insulin levels. The fundamen Diagnostic and Statistical Manual of Mental Disorders, tal defect in the metabolic syndrome is insulin resistance in Fourth Edition (DSM-IV) has categorized three stages of both adipose tissue and muscle. addiction: preoccupation/anticipation, binge/intoxication, All references, including publications, patent applications and withdrawal/negative affect. These stages are character and patents, cited herein are hereby incorporated by reference ized, respectively, everywhere by constant cravings and pre 15 in their entirety and to the same extent as if each reference occupation with obtaining the Substance; using more of the were individually and specifically indicated to be incorpo Substance than necessary to experience the intoxicating rated by reference and were set forth in its entirety (to the effects; and experiencing tolerance, withdrawal symptoms, maximum extent permitted by law). and decreased motivation for normal life activities. Headings and Sub-headings are used herein for conve This invention further provides a method of treating a nience only, and should not be construed as limiting the disorder comprising as a symptom a deficiency in attention invention in any way. and/or cognition in a mammal, including a human, which The use of any and all examples, or exemplary language method comprises administering to said mammal an amount (including “for instance”, “for example”, “e.g., and “as of a compound of formula I effective in treating said disorder. such') in the present specification is intended merely to better Other disorders that can be treated according to the present 25 invention are obsessive/compulsive disorders, Tourette's Syn illuminate the invention, and does not pose a limitation on the drome and other tic disorders. Scope of invention unless otherwise indicated. As used herein, and unless otherwise indicated, a “neuro The citation and incorporation of patent documents herein degenerative disorder or condition” refers to a disorder or is done for convenience only, and does not reflect any view of condition that is caused by the dysfunction and/or death of 30 the validity, patentability and/or enforceability of such patent neurons in the central nervous system. The treatment of these documents. disorders and conditions can be facilitated by administration The present invention includes all modifications and of an agent which prevents the dysfunction or death of neu equivalents of the Subject-matter recited in the claims rons at risk in these disorders or conditions and/or enhances appended hereto, as permitted by applicable law. the function of damaged or healthy neurons in Such a way as 35 to compensate for the loss of function caused by the dysfunc tion or death of at-risk neurons. The term “neurotrophic Experimental Section agent as used herein refers to a Substance or agent that has Some or all of these properties. Preparation of the Compounds of the Invention Examples of neurodegenerative disorders and conditions 40 that can be treated according to the present invention include, but are not limited to, Parkinson's disease: Huntington's dis ease; dementia, for example Alzheimer's disease, multi-inf arct dementia, AIDS-related dementia, and Fronto temporal R3 Dementia; neurodegeneration associated with cerebral 45 trauma; neurodegeneration associated with Stroke, neurode generation associated with cerebral infarct; hypoglycemia induced neurodegeneration; neurodegeneration associated with epileptic seizure; neurodegeneration associated with neurotoxin poisoning; and multi-system atrophy. 50 In one embodiment of the present invention, the neurode generative disorder or condition involves neurodegeneration of striatal medium spiny neurons in a mammal, including a human. In a further embodiment of the present invention, the neu 55 Compounds of the general formula I of the invention may rodegenerative disorder or condition is Huntington's disease. be prepared as described in the following reaction schemes. In another embodiment, the invention provides a method of Unless otherwise indicated, in the reaction schemes and dis treating a subject to reduce body fat or body weight, or to treat cussion that follow, HET, R-R-L-, Z and Y are as defined non-insuline demanding diabetes mellitus (NIDDM), meta above. bolic syndrome, or glucose intolerance, comprising adminis 60 Compounds of formula I, wherein-L-is—S-CH2—, can tering to a subject in need thereof a therapeutically effective be prepared by the coupling of a nucleophile of formula III or amount of a compound of formula I. In preferred embodi IIIa with an electrophile of formula IV, where X is a leaving ments, the Subject is human, the Subject is overweight or group, e.g. Cl, Br, I, methanesulfonyl, 4-toluenesulfonyl, as obese and the antagonist is administered orally. In another shown in scheme 1. In the reaction between IIIa and IV. preferred embodiment, the method further comprising 65 alkylation of the sulfur atom of IIIa with IV and ring closure administering a second therapeutic agent to the Subject, pref to form the triazole ring both take place under the same erably an anti-obesity agent, e.g., rimonabant, orlistat, reaction conditions in a one-pot procedure. US 9,018,217 B2 21 22

Scheme 1. R3 R4 R2

-- X N R5 \ { R6

R1N IV I

R3 R7 NH R4 e S R2

R-tS4 S1 N NN l -- R9 H N1\ X N R5 S.N/ \ ( R6

IIIa R1 IV

30 This reaction is typically carried out in a solvent such as or +40° C. The requisite 1,2-diaminopyridines are readily 1-propanol, toluene, DMF, or acetonitrile, optionally in the available from the corresponding commercially available presence of a carbonate base Such as potassium carbonate or 2-aminopyridines by reaction with a suitable N-amination a tertiary amine base such as triethylamine or diisopropyl reagent, such as O-(mesitylsulfonyl)hydroxylamine, in a Suit ethylamine (DIPEA), at a temperature ranging from about 0° 35 able solvent, Such as chloroform, at a suitable temperature, C. to about 200° C., optionally under pressure in a closed such as 0° C. or room temperature, see WO96/01826. vessel. Other suitable solvents include benzene, chloroform, 2-Halomethyl-4-(aryl)-1H-imidazoles of formula IV can dioxane, ethyl acetate, 2-propanol and Xylene. Alternatively, be prepared by halogenation of the corresponding 2-hy Solvent mixtures such as toluenef2-propanol can be used. 40 droxymethyl-4-(aryl)-1H-imidazoles using a suitable Compounds of formula III are either commercially avail reagent, e.g. thionyl chloride, phosphorous trichloride, or able or can be prepared as described in the literature, see for phosphorous tribromide, optionally using a suitable solvent example Brown et al. Aust. J. Chem. 1978, 31, 397-404; Such as dichloromethane, using methods well known to chemists skilled in the art. The requisite 2-hydroxymethyl-4- Yutilov et al. Khim. Geter. Soedin. 1988,799-804; Wide et al. (aryl)-1H-imidazoles can be prepared by methods known in Bioorg Med. Chem. Lett. 1995, 5, 167-172; Kidwai et al. J. 45 the art (see for example Magdolen, P:Vasella, A. Helv. Chim. Korean Chem. Soc. 2005, 49, 288-291. Compounds of for Acta 2005, 88,2454-2469; Song, Z. etal. J. Org. Chem. 1999, mula IIIa can be prepared as described in WO96/01826 from 64, 1859-1867). the corresponding 1,2-diaminopyridines by reaction with Compounds of formula I, wherein-L- is —CH2—S—, can thiocarbonyldlimidazote in a suitable solvent, such as chlo be prepared by the coupling of a nucleophile of formula X roform, at a Suitable temperature, such as room temperature with an electrophile of formula VI as shown in scheme 2.

Scheme 2. R3 R4

H HET -v HET -v -- N R5 Base I OH X s={ R6 VI R1N US 9,018,217 B2 24 -continued O

1. HOCH2COMe, base 2. Ester reduction X X IX R7 R7 -Y NH2 -Y. Y Xa n N Y N-amination Y x n N R8- a R8 YS/ Ysa Ro1 Y NH Ro1 Y NH2

VIII X = Cl, Br, I, OMs, OTs

This reaction is typically carried out in a solvent such as Compounds of formula X are either commercially avail 1-propanol, toluene, DMF, or acetonitrile, optionally in the able or can be prepared as described in the literature, see e.g. presence of a carbonate base Such as potassium carbonate or Kjellin, G: Sandström, J. Acta Chem. Scand. 1969, 23, 2879 a tertiary amine base such as triethylamine or diisopropyl 2887: Laufer, S. A. et al. Synthesis 2008, 253-266. ethylamine (DIPEA), at a temperature ranging from about 0° Compounds of formula I, wherein R1 is not hydrogen, can C. to about 200° C., optionally under pressure in a closed 25 be prepared by the alkylation of a compounds of formula I, vessel. Other suitable solvents include benzene, chloroform, dioxane, ethyl acetate, 2-propanol and Xylene. Alternatively, wherein R1 is hydrogen, with an alkylhalide of formula XI as Solvent mixtures such as toluenef2-propanol can be used. shown in Scheme 3. Some electrophiles of formula VI are commercially avail able, and many others are known in the art, see for example JP 30 Scheme 3. 59176277. The electrophile VI, where X is a leaving group, e.g. Cl, Br, I, methanesulfonyl, 4-toluenesulfonyl, can also be R3 prepared by conversion of the primary alcohol of compounds R4 of formula V to said leaving group by methods known to R2 35 chemists skilled in the art. Said methods can for example be R5 R1-X --> selected from reacting compounds of formula V with thionyl N chloride, phosphorous trichloride, phosphorous tribromide, methanesulfonyl chloride, or 4-toluenesulfonyl chloride HET--( R6 optionally in the presence of a Suitable solvent. Such as N H dichloromethane or 1,2-dichloroethane, and optionally in the I XI presence of a base, such as triethylamine, diisopropylethy lamine, or pyridine. Alternatively, electrophiles of formula VI R3 can be prepared by reacting commercially available aromatic R4 amines of formula VII with 1,3-dihaloacetones of formula IX, 45 e.g. 1,3-dichloroacetone, in a Suitable solvent, Such as 1.2- R2 dimethoxyethane or ethanol, at a suitable temperature. Such R5 as room temperature or reflux. Some electrophiles of formula N V are commercially available, and many others are known in 50 HET--( R6 the art, see for example Tsuchiya, T.; Sashida, H. J. Chem. N Soc., Chem. Commun. 1980, 1109-11 10: Tsuchiya, T.; M H Sashida, H. Konoshita, A. Chem. Pharm. Bull. 1983, 31, R1 I 4568-4572. Alternatively, alcohols of formula V can be pre pared by reacting commercially available aromatic amines of 55 formula VII with a suitable N-amination reagent, such as (where R1 = H) O-(mesitylsulfonyl)hydroxylamine, in a suitable solvent, such as chloroform, at a suitable temperature, such as 0°C. or room temperature, see WO96/01826, to yield compounds of This reaction is typically carried out in a suitable solvent, 60 Such as dimethylformamide, dimethylacetamide, or acetoni formula VIII. Said compounds of formula VIII can be con trile, in the presence of a suitable base Such as a carbonate verted into compounds of formula V by reaction with methyl base, e.g. potassium carbonate, or a tertiary amine base, e.g. glycolate followed by reduction of the methyl ester to the triethylamine or diisopropylethylamine (DIPEA), at a tem requisite alcohol using a suitable reducing agent Such as perature ranging from about 0°C. to about 100° C. lithium aluminium hydride in a suitable solvent Such as 65 Compounds of formula I, wherein-L- is —CH=CH- or diethyl ether or tetrahydrofuran using methods known to —CH2—CH2— can be prepared by the reaction sequence chemists skilled in the art. shown in Scheme 4. US 9,018,217 B2 25 26

Scheme 4.

HET-/ PPh3 HET - /

VI XII XIII

Base

R3 R3 R4 R4 R2 R2 R5 Reduction R5 HET \ (N R6 HET \ (N R6 N N A M R1 I R1 I

(where -L- = -CH-CH (where -L- = -CH=CH and HET is as shown) and HET is as shown)

Specifically, compounds of formula I, wherein -L- is Method B: —CH2—CH2—can be prepared by reduction of analkene of An Agilent 1100 LCMS system with a G1946C or a formula I, wherein -L- is —CH=CH by hydrogenation 35 G1946A mass detector was used. Column: 2.0x50mm YMC using a transition metal catalyst, such as palladium metal, ODS-AO with 5 um particle size; Column temperature: 50° together with a hydrogen source, such as hydrogen gas, C.; Solvent system: A water/trifluoroacetic acid (99.9:0.1) and B-acetonitrile/trifluoroacetic acid (99.95:0.05); Method: ammonium hydrogen carbonate, or cyclohexadiene. Saidalk Linear gradient elution with A:B=95:5 to 0:100 in 3.5 minutes enes of formula I, wherein -L- is —CH=CH can be pre 40 and with a flow rate of 0.8 mL/min. pared by the Wittig reaction between a phosphonium salt of Method C: formula XII and an aldehyde of formula XIII in a suitable A PE Sciex API300 instrument equipped with atmospheric Solvent. Such as tetrahydrofuran, in the presence of a Suitable pressure photo ionisation and a Waters UPLC system was base, such as 1,8-diazabicyclo[5.4.0]undec-7-ene. Phospho used. Column: Acquity UPLC BEHCs 1.7 um, 2.1 x50 mm nium salt of formula XII are readily available by reaction of 45 (Waters); Column temperature: 60° C.; Solvent system: compounds of formula VI (see scheme 2 above) with triph A water/trifluoroacetic acid (100:0.05) and B-waterfaceto enylphosphine by methods known to chemists skilled in the nitrile/trifluoroacetic acid (5:95:0.035); Method: Linear gra art. Aldehydes of formula XIII are readily available by oxi dient elution with A:B=90:10 to 0:100 in 1.0 minutes and with dation of alcohols of formula V (see scheme 2 above) by a flow rate of 1.2 mL/min. methods known to chemists skilled in the art, e.g. by reacting 50 Method D: alcohols of formula V with a suitable oxidizing agent, such as An Agilent 1100 LCMS system with a G1946C or a Dess-Martin periodinane, in a suitable solvent, Such as G1946A mass detector was used. Column: 2.0x50mm YMC dichloromethane or 1,2-dicholorethane. ODS-AO with 5 um particle size; Column temperature: 50° The invention disclosed herein is further illustrated by the C.; Solvent system: A water/trifluoroacetic acid (99.9:0.1) following non-limiting examples. 55 and B-acetonitrile/trifluoroacetic acid (99.95:0.05); Method: General Methods Linear gradient elution with A:B=90:10 to 0:100 in 3.4 min Analytical LC-MS data were obtained using one of the utes and with a flow rate of 0.8 mL/min. following methods. Method E: Method A: A PE Sciex API 150EX instrument equipped with atmo A PE Sciex API 150EX instrument equipped with atmo 60 spheric pressure photo ionisation and a Shimadzu LC-8A/ spheric pressure photo ionisation and a Shimadzu LC-8A/ SLC-10A LC system was used. Column: 4.6x30mm Waters SLC-10A LC system was used. Column: 4.6x30mm Waters Symmetry C18 column with 3.5 um particle size; Column Symmetry C18 column with 3.5 um particle size; Column temperature: 60°C.; Solvent system: A water/trifluoroacetic temperature: 60°C.; Solvent system: A water?trifluoroacetic acid (99.95:0.05) and B-methanol/trifluoroacetic acid acid (100:0.05) and B-waterfacetonitrile/trifluoroacetic acid 65 (99.965:0.035); Method: Linear gradient elution with (5:95:0.035); Method: Linear gradient elution with A:B=90: A:B=83:17 to 0:100 in 2.4 minutes and with a flow rate of 3.0 10 to 0:100 in 2.4 minutes and with a flow rate of 3.3 mL/min. mL/min. US 9,018,217 B2 27 28 Preparative LC-MS-purification was performed on a PE addition funnel while maintaining the reaction temperature Sciex API 150EX instrument with atmospheric pressure between 60° C. and 68°C. A nitrogen sweep was employed to chemical ionization. Column: 50x20 mm YMCODS-A with remove the dimethyl sulfide as it was formed. Once the HBr 5 um particle size; Method: Linear gradient elution with addition was complete, the internal temperature was main A:B=80:20 to 0:100 in 7 minutes and with a flow rate of 22.7 tained at 65° C. with external heating until the reaction was mL/minute. Fraction collection was performed by split-flow complete. The reaction was quenched by pouring the reaction MS detection. mixture into water, extracted by ethyl acetate and afforded 'HNMR spectra were recorded at 500.13 MHzona Bruker 2,2-dihydroxy-1-phenyl-ethanone 2. The reaction was moni Avance AV500 instrument or at 250.13 MHZ on a Bruker tored by TLC. Avance DPX250 instrument. TMS was used as internal ref 10 To a round-bottom flask charged with methyl 2-hydroxy erence standard. Chemical shift values are expressed in ppm. 2-methoxyacetate (2.14 g. 25.9 mmol) and ammonium The following abbreviations are used for multiplicity of NMR acetate (4.108 g. 52 mmol) in methanol (30 mL), acetic acid signals: S-singlet, d=doublet, t-triplet, q quartet, (30 mL) was added dropwise, followed by the addition of a qui-quintet, h-heptet, dd-double doublet, dt double triplet, 15 Solution of 2,2-dihydroxy-1-phenylethanone 2 (2 g, 13 dq=double quartet, tt=triplet of triplets, m-multiplet, br mmol) in methanol with stirring. After 1.5 hours, the reaction s—broad singlet and br–broad signal. mixture was concentrated in vacuo and was then mixed with Abbreviations are in accordance with to the ACS Style 0.5N hydrochloric acid. The solution was washed with ethyl Guide: “The ACS Styleguide—A manual for authors and acetate. The aqueous layer was basified with 5N sodium editors Janet S. Dodd, Ed. 1997, ISBN: 0841234620 O hydroxide to pH-9 and extracted with ethyl acetate 3 times. Preparation of Intermediates The combined organic layer was dried over NaSO. The Solution was concentrated to dryness to give the compound 4-Phenyl-1H-imidazole-2-carboxylic acid methyl ester 3. O - DMSO -- aq. HBr To a solution of compound 3 (1.0 g, 5 mmol) in DMF (20 60-80° C. 25 mL) was added iodomethane (4 mL, 7.5 mmol) and KCO (1.0 g, 7.5 mmol), and the mixture was stirred at 60° C. for 1 hour until TLC (petroleum ether/EtOAc=5/1) showed that compound 3 was consumed completely. The reaction mixture 19 OH was diluted with brine (20 mL) and was extracted with ethyl O 30 acetate (2x10 mL). The combined organic layers were dried O o1 over anhydrous NaSO filtered, and concentrated under OH vacuum to afford compound 4 (0.83 g, 78%). "H NMR (400 MHz, CDC1): 8 7.81-7.78 (m, 2H), 7.39-7.35 (m, 2H), 7.32 OH (s, 1H), 7.29-7.25 (m, 1H), 4.05 (s.3H), 3.97 (s.3H). 35 To a solution of compound 4 (0.8 g., 3.7 mmol) in THF (8 2 mL) was added LiAlH4 (0.21 g, 5.5 mmol) at -5°C. under N. O The mixture was stirred at -10° C. for 2 hours and was quenched by aqueous NHCl solution at 0° C. until pH CHI NS O He reached 6. The resulting mixture was extracted with EtOAc NS 40 (3x20 mL), and the combined organic layers were washed with brine (30 mL), dried over NaSO filtered, and concen ( ) (O. trated under reduced pressure to afford compound 5 (0.5 g. 3 75%). "H NMR (400 MHz, DMSO-d): 8 7.69-7.67 (m, 2H), O 7.53 (s, 1H), 7.30 (t, J=7.6 Hz, 2H), 7.15-7.12 (m. 1H), 5.30 45 (t, J–5.6 Hz, 1H), 4.48 (d. J=5.6 Hz, 2H), 3.65 (s.3H). To a solution of (1-Methyl-4-phenyl-1H-imidazol-2-yl)- s LiAlH4 methanol 5 (0.2g, 0.097 mmol) was added SOC1 (0.14 g. ( ). KC\-N i 0.121 mmol), and the mixture was stirred at room temperature 4 overnight. The mixture was evaporated to afford 2-Chlorom 50 N ethyl-1-methyl-4-phenyl-1H-imidazole 6, which was used s OH SOCl without purification. H NMR (400 MHz, DMSO-d): 88.24 N N CHCl2 (s, 1H), 7.87 (d. J=6.8 Hz, 2H), 7.54-7.49 (m, 2H), 7.43-7.41 N (m. 1H), 5.24 (s. 2H), 3.89 (s.3H). 5 The following intermediates were prepared in a similar 55 way: 2-Chloromethyl-1-ethyl-4-phenyl-1H-imidazole 95% yield, 'H NMR (400 MHz, DMSO-d): 88.36 (s, 1H), 7.92-7.89 (m, 2H), 7.51-7.47 (m, 2H), 743-7.39 (m, 1H), 5.26 (s. 2H), 4.24 (q, J=7.2 Hz, 2H), 1.46 (t, J–7.2 Hz, 3H). 60 2-Chloromethyl-1-isopropyl-4-phenyl-1H-imidazole 100% yield, "H NMR (400 MHz, DMSO-d): 88.54 (s, An adaptation of the method described by Song et al., J. 1H), 7.93 (d. J=7.6 Hz, 2H), 7.52-7.29 (m,3H), 5.28 (s. 2H), Org. Chem. 1999, 64, 1859 was used. To a round-bottom flask 4.84-4.75 (m. 1H), 1.50 (d. J=6.8 Hz, 6H). equipped with a nitrogen inlet, a gas outlet to a bleach scrub 2-chloromethyl-4-(2-fluorophenyl)-1-methyl-1H-imidazole ber and a temperature probe was charged DMSO (113 mL) 65 80% yield, 'H NMR (400 MHz, DMSO-d): 8 8.06-8.02 and acetophenone 1 (10 g, 83.2 mmol). The solution was (m. 1H), 7.91 (d. J=3.2 Hz, 1H), 741-7.38 (m. 1H), 7.34-7.29 heated to 60°C., and aqueous HBr was added slowly via an (m. 2H), 5.12 (s. 2H), 3.84 (s.3H).

US 9,018,217 B2 31 32 An adaptation of the method described in WO 96/01826 The following intermediate was prepared analogously: was used. To a solution of ethyl O-mesitylsulfonylacetohy 4-Phenyl-1,3-dihydro-imidazole-2-thione droxamate 7 (1.7 g. 6.0 mmol) in 1,4-dioxane (10 mL) cooled 80% yield, H NMR (500 MHz, DMSO-d): & 12.53 (brs, in an ice bath (freezes at 8-9°C.) was added 70% perchloric 1H), 12.15 (brs, 1H), 7.69-7.65 (m, 2H), 741-7.35 (m, 3H) acid (7.5 mL) dropwise over 15 minutes, maintaining internal 5 7.27 (t, J=74 Hz, 1H). temperature below 15°C. The mixture was then diluted with ice water (100 mL) to precipitate the product O-(mesitylsul fonyl)hydroxylamine 8 which was filtered off, washed thor O oughly with water, and immediately dissolved in chloroform H -- (10 mL) while still wet (CAUTION. 8 is explosive when 10 dry). The organic layer was separated and was passed through a plug of Na2SO4 in a fritted Syringe to remove water. O The so obtained solution of O-(mesitylsulfonyl)hydroxy H lamine 8 was added dropwise to a solution of 2-amino-4,6- 15 dimethylpyridine 9 (0.611 g, 5.00 mmol) in chloroform (10 -O o " NHOAc Her mL) cooled in an ice bath. The mixture was then warmed to room temperature and was stirred for 2 hours to effect con 10 version to intermediate 10. Into the reaction mixture was then added 1,1'-thiocarbonyldimidazole 11 (1.16 g. 6.5 mmol) and the resulting mixture was stirred at 40°C. overnight. Volatiles were evaporated and the residue was chromatographed on silica gel (gradient elution with heptane:ethyl acetate 100: 0->0:100) to yield imidazole-1-carbothioic acid (2-imino-4, 6-dimethyl-2H-pyridin-1-yl)-amide 12 as an off-white solid 25 W - (0.50 g, 40%) containing a minor amount of residual imida O zole. H NMR (500 MHz, DMSO-d): 87.88 (s, 1H), 7.64 (s, 1H), 7.42 (brs, 2H), 6.93 (s, 1H), 6.69 (s, 1H), 6.67 (s, 1H), A solution of phenylglyoxal monohydrate (102 g, 0.67 2.28 (s.3H), 2.27 (s.3H). mol) and glyoxal dimethyl acetal (60% solution in water, 232 The following intermediates were prepared analogously, 30 mL, 1.54 mol) in methanol (1.1 L) was treated with a solution except that they were used for the preparation of final com of ammonium acetate 8202 g, 2.61 mol) in methanol (1.1 L) pounds without prior purification or characterization: and the resulting solution stirred at RT for 16 h. The volatiles Imidazole-1-carbothioic acid (5-bromo-2-imino-4-methyl were removed in vacuo and the residue slurried in 2N HCl 2H-pyridin-1-yl)-amide 35 solution (1.1 L) and heated at 80°C. for 30 min. The cooled Imidazole-1-carbothioic acid (5-bromo-2-imino-4,6-dim solution was extracted with EtOAc (200 mL) and the sepa ethyl-2H-pyridin-1-yl)-amide rated aqueous layer was basified to pH 9 with 9N NaOH Imidazole-1-carbothioic acid (5-chloro-2-imino-3-methyl solution. The solids were filtered, washed with water and 2H-pyridin-1-yl)-amide dried in vacuo to yield the title compound (97.2g, 84%) as a Imidazole-1-carbothioic acid (5-cyano-2-imino-2H-pyridin 40 light brown solid. LC-MS: m/z -173.0 (MH), t-0.66 min, 1-yl)-amide method C

N 45 H HCI KSCN ( ) { HOAc

50

An adaptation of the method reported by Kjellin and Sand ström, Acta Chem. Scand. 1969, 23, 2879-2887 was used. A 55 mixture of 2-methylamino-1-phenyl-ethanone hydrochloride (0.754g, 4.06 mmol) (see e.g. Hyde et al. J. Am. Chem. Soc. 1928, 50, 2287-2292; Shang et al. Chem. Eur: J. 2007, 13, 7780-7784) and potassium thiocyanate (0.434g, 4.46 mmol) HO in acetic acid (12 mL) was heated at 140°C. for 10 minutes 60 using a microwave synthesizer. Dilution with water (50 mL) and cooling in an ice bath caused the product to precipitate. It was collected by filtration, washed with water, and vacuum dried to yield the title compound (0.365g, 47%) pure as an In a closed vessel a slurry of 4-phenyl-1H-imidazole-2- off-white solid. "H NMR (500 MHz, DMSO-d): 812.66 (br 65 carbaldehyde (200 mg, 1.16 mmol) and sodium carbonate (60 s, 1H), 7.65 (d. J=7.6 Hz, 2H), 7.60 (s, 1H), 7.39 (I,J=7.8 Hz, mg, 0.6 mmol) in ethanol (4 mL) was treated with propylene 2H), 7.27 (t, J=7.4 Hz, 1H), 3.49 (s.3H). oxide (170 uL., 2.4 mmol) and heated at 100° C. for 3 h. The US 9,018,217 B2 33 34 cooled solution was filtered and the solids washed with DCM. -continued The volatiles were removed in vacuo to yield the crude title compound which was used without further purification (250 mg, 63%). LC-MS: m/Z 231.5 (MH), t-0.41 min, method 21 -NH. A 5 O The following intermediates were prepared analogously, 2+ except that they were used for the preparation of final com s NH Nulls o1 pounds without prior purification or characterization: O (S)-1-(2-Hydroxypropyl)-4-Phenyl-1H-imidazole-2-carbal 10 || dehyde O-S (R)-1-(2-Hydroxypropyl)-4-Phenyl-1H-imidazole-2-carbal O dehyde 1-Amino-4,6-dimethyl-1H-pyrimidin-2- 1-(2-Hydroxy-2-methyl-propyl)-4-phenyl-1H-imidazole-2- 15 ylidene-ammonium 2,4,6-Trimethyl carbaldehyde from 1-chloro-2-methyl-2-propanol. benzenesulfonate

O

N1 N DME, -- EtOH -e- 2 C C 2-Chloromethyl-5,7- HN N dimethyl-1,2,4 25 triazolo 1,5-apyrimidine

To a solution of 4,6-Dimethyl-pyrimidin-2-ylamine (25 g, 200 mmol) in 400 mL of CHCl was added dropwise a solution of hydroxylamine-2,4,6-Trimethyl-benzene 30 sulfonate (105 g, 488 mmol) in 300 mL of CHC1 at 0°C., and the mixture was stirred at 0°C. for 1 hand filtered. The solid collected was washed with CHCl (100 mL) to give 1-Amino-4,6-dimethyl-1H-pyrimidin-2-ylidene-ammonium 35 2.4.6-Trimethyl-benzenesulfonate (40 g, yield: 62%). A mixture of 1-Amino-4,6-dimethyl-1H-pyrimidin-2- A solution of 2-amino-4,6-dimethylpyrimidine (2.46 g, ylidene-ammonium 2.4.6-Trimethyl-benzenesulfonate (40 g, 20.0 mmol) and 1,3-dichloro-2-propanone (2.67 g. 21.0 0.1 mol) and NaOH (10g, 0.2 mol) in 500 mL of EtOH was mmol) in 1,2-dimethoxyethane (20 mL) was stirred at 45° C. stirred at 50-60° C. for 1 hour. After chloroacetic acid methyl overnight. A precipitate formed, and this was collected by 40 ester (16.6 g., 0.15 mol) was added, the resultant mixture was filtration, and was then refluxed with ethanol (15 mL) for 2 stirred at reflux for 4 hours. After being concentrated under hours. After cooling to room temperature, the product pre reduce pressure, the residue was diluted with water (1000 cipitated as white needles which were collected by filtration mL) and extracted with CHCl (300 mLX3). The combined and vacuum dried to yield the title compound pure as its organic layers were washed with brine (200 mL), dried over hydrochloride salt (883 mg, 19%). "H NMR (500 MHz, 45 NaSO filtered, and concentrated under vacuum. The resi DMSO-d): 87.84 (s, 1H), 6.88 (s, 1H), 4.84 (s. 2H), 2.60 (s, due was purified by column chromatography on silica gel 3H), 2.49 (s.3H). (petroleum ether/EtOAc=2/1) to give 2 g of 2-Chloromethyl The following intermediate was prepared analogously, but 5,7-dimethyl-1,2,4-triazolo 1.5-alpyrimidine in 9% yield. with a 90° C. reaction temperature for the first step: 50 "H NMR (300 MHz, DMSO-d): 88.55 (s, 1H), 6.25 (s. 2H), 2-Chloromethyl-imidazo[1,2-alpyrimidine hydrochloride 4.05 (s, 3H), 3.95 (s, 3H). LC-MS (MH): m/z =196.9, to (min, method A)=0.52 62% yield, LC-MS: m/z =168.2 (MH"), t-O.13 min, The following intermediates were prepared analogously: method A. 7-Chloro-2-chloromethyl-5,8-dimethyl-1,2,4-triazolo 1.5- 55 cpyrimidine from 6-Chloro-2,5-dimethyl-pyrimidine-4- ylamine prepared as described by Henzeetal. J. Org. Chem HN O 1952, 17, 1320-1327. 3.2% yield, LC-MS: m/z–231.5 V || (MH"), t1.13 min, method E O-S 2-Chloromethyl-5,8-dimethyl-1,2,4-triazolo 1.5-alpyra O 60 zine from 2-amino-3,6-dimethylpyrazine. 60% yield, "H NMR (500 MHz, CDC1): 87.91 (s, 1H), 4.87 (s. 2H), 2.91 CHCl2 (s, 3H), 2.74 (s, 3H), LC-MS: m/z =196.9 (MH"), t-O.64 min, method A 2-Chloromethyl-5,8-dimethyl-1,2,4-triazolo 1.5-alpyridine 4,6-Dimethyl 65 from 6-Chloro-5-ethyl-2-methyl-pyrimidin-4-ylamine. pyrimidin-2-ylamine 21% yield, LC-MS: m/z.245.0 (MH), t-O.72 min, method A US 9,018,217 B2 35 36 2-Chloromethyl-8-methoxy-5-methyl-1,2,4-triazolo 1.5-a excess SOCl was evaporated under vacuum to yield the title pyridine from 3-Methoxy-6-methyl-pyridin-2-ylamine compound as a crude product, which was used for the prepa ration of final compounds without purification or character ization. O The following compounds are known in the art: N1 N DME, 2-Chloromethyl-1-phenyl-1H-benzoimidazole -- EtOH (JP 59176277). 21 1-Methyl-1,3-dihydro-benzoimidazole-2-thione (Wilde et al. HN C C C Bioorg Med. Chem. Lett. 1995, 5, 167-172). 10 1-Phenyl-1,3-dihydro-benzoimidazole-2-thione (Kidwal et \ { N al. J. Korean Chem. Soc. 2005, 49, 288-291). N21Ne. 1.2.4 Triazolo 1.5-alpyrimidine-2-thione (Brown et al. Aust. J. Chem. 1978, 31,397-404). The method of Vanelle et al. Tetrahedron 1991, 47,5173 15 1,3-Dihydro-imidazo[4,5-b]pyridine-2-thione (Yutilov et al. 5184 was used. To a solution of 1,3-dichloro-2-propanone Khim. Geter. Soedin. 1988, 799-804). (2.69 g, 21.2 mmol) in 1,2-dimethoxyethane (5 mL) was Pyrazolo 1.5-alpyridin-2-yl-methanol (Tsuchiya, T.; added 2-aminopyridine and the mixture was stirred at room Sashida, H. J. Chem. Soc., Chem. Commun. 1980, 1109 temperature for 2 hours. During this time a thick precipitate 1110: Tsuchiya, T.; Sashida, H. Konoshita, A. Chem. Pharm. formed, and this was collected by filtration. The precipitate Bull. 1983, 31, 4568-4572). was refluxed in absolute ethanol for 2 hours after which Preparation of the Compounds of the Invention volatiles were removed by evaporation. The residue was dis solved in water (30 mL) and solid NaHCO was added to neutralize the mixture. A white precipitate formed, and this was collected by filtration, washed with water and vacuum 25 dried to yield the title compound pure as a cream white solid (1.43 g, 42%). "H NMR (500 MHz, CDC1): 88.08 (d. J=6.7 HZ, 1H), 7.62 (s, 1H), 7.58 (d. J=9.0 Hz, 1H), 7.17-7.22 (m, 1H), 6.80 (t, J=6.8 Hz, 1H), 4.78 (s. 2H). The following intermediate was prepared analogously: 30 s C 1-Propanol 2-Chloromethyl-8-methyl-imidazo[1,2-alpyridine 53% yield, "H NMR (500 MHz, CDC1): 8 7.95 (d, J=6.9 N HZ, 1H), 7.61 (s, 1H), 6.97 (dt, J–7.0 Hz, 1.1 Hz, 1H), 6.70 (t, J=6.8 Hz, 1H), 4.80 (s. 2H), 2.60 (s, 3H). 35 4n-N / {7 H HOCH2CO.Me, X- N 2N. N Norf N NN/ S / EtOH 40 HN 21 An adaptation of the method described in WO 96/01826 was used. Imidazole-1-carbothioic acid (2-imino-2H-pyri din-1-yl)-amide (200 mg, 1.37 mmol) and 2-chloromethyl-1- H c N SOCl. 45 methyl-4-phenyl-1H-imidazole 6 (300 mg, 1.46 mmol) were N21Ne. dissolved in 1-propanol (25 mL) and the mixture was heated to reflux for 2 hours. The solvent was removed under reduced pressure and the residue dissolved in dichloromethane. The Solution was washed with water and the organic layer was 50 dried over NaSO and concentrated. The residue was puri fied by chromatography on silica gel to afford the title com pound (273 mg, 62%) as a yellow solid. LC-MS: m/z 322.1 (MH), to 2.29 min, method B. To a solution of 0.79g of sodium hydroxide in ethanol (20 The following compounds of the invention were prepared mL) was added 2-imino-4,6-dimethyl-2H-pyridin-1-ylamine 55 analogously: (1.7g, 0.012 mol: obtained by HPLC purification of interme 7-Methyl-2-(1-methyl-4-phenyl-1H-imidazol-2-ylmethyl diate 10). After being stirred at 50-60° C. for 1 hour, methyl sulfanyl)-1.2.4 triazolo 1.5-alpyridine (from imidazole glycolate (1.4g, 0.016 mop was added, and the resulting 1-carbothioic acid (2-imino-4-methyl-2H-pyridin-1-yl)- mixture was stirred at reflux for 6 hours. After removal of the amide (see WO96/01826) and 2-chloromethyl-1-methyl solvent under reduced pressure, the residue was purified by 60 4-phenyl-1H-imidazole 6). LC-MS: m/z 336.5 (MH"), column chromatography on silica gel (ethyl acetate) to afford t=0.71 min, method A. (5,7-Dimethyl-1,2,4-triazolo 1.5-alpyridin-2-yl)-methanol 5,7-Dimethyl-2-(1-methyl-4-phenyl-1H-imidazol-2-ylmeth (0.2g, 10%); H NMR (300 MHz, DMSO-d): 8 7.39 (s, 1H), ylsulfanyl)-1,2,4-triazolo 1.5-alpyridine (from imida 6.87 (s, 1H), 5.38 (t, J=6.3 Hz, 1H), 4.59 (d. J=6.3 Hz, 2H), Zole-1-carbothioic acid (2-imino-4,6-dimethyl-2H-pyri 2.64 (s.3H), 2.38 (s.3H). A mixture of this compound (31 mg, 65 din-1-yl)-amide 12 and 2-chloromethyl-1-methyl-4- 0.175 mmol) and SOCl (10 mL) in dry CHCl (10 mL) was phenyl-1H-imidazole 6). LC-MS: m/z. 350.3 (MH), stirred at room temperature for 2 hours. The solvent and t=0.79 min, method A.

US 9,018,217 B2 39 40 The following compound of the invention was prepared 2-(1-Methyl-4-phenyl-1H-imidazol-2-ylsulfanylmethyl)- analogously: imidazo[1,2-alpyridine-7-carbonitrile. LC-MS: 2-(1-Methyl-4-phenyl-1H-imidazol-2-ylmethylsulfanyl)-1- m/Z. 34.6.2 (MH), to 0.66 min, method A. phenyl-1H-benzoimidazole. LC-MS: m/z 396.9 (MH"), t=0.65 min, method C. 2-4-(3-Methoxy-phenyl)-1-methyl-1H-imidazol-2-ylmeth ylsulfanyl-5,7-dimethyl-1,2,4-triazolo 1.5-alpyrimi dine, LC-MS (MH): m/z 381.5, t (min, methodA)=0.68 ( y ( 5,7-Dimethyl-2-(1-methyl-4-phenyl-1H-imidazol-2-ylmeth ylsulfanyl)-1.2.4 triazolo 1.5-alpyrimidine, LC-MS 10 (MH): m/z 351.4, t (min, method A)=0.62 /

N 15 Hops 2 FC N NH2 c. H N A mixture of 2-chloromethyl-5,7-dimethyl-imidazo 1,2-a X=s pyrimidine (1.55 g, 0.8 mmol), 1-methyl-4-phenyl-1,3-dihy 21 N N dro-imidazole-2-thione (1.5 g. 0.8 mmol) and KCO (3.31 g, 2.4 mmol) in dry DMF (20 mL) was stirred under N at room 25 temperature overnight. After removal of the solvent under N-N C vacuum, the residue was purified by preparative HPLC to afford the title compound (1.31 g, 47%) as a white solid. CF LC-MS: m/z. 350.2 (MH), to 2.14 min, method D. The following compounds of the invention were prepared NS1S 30 analogously: 5,7-Dimethyl-2-(1-methyl-4-phenyl-1H-imidazol-2-ylsulfa nyl methyl)-1,2,4-triazolo 1.5-alpyridine. LC-MS: m/z. 350.3 (MH), to 0.76 min, method A. Vy- ?coCF 2-(1-Methyl-4-phenyl-1H-imidazol-2-ylsulfanylmethyl)-1- 35 phenyl-1H-benzoimidazole (This reaction was run using DIPEA as base). LC-MS: m/z 396.8 (MH"), to 0.60 min, 1,3-dichloroacetone (0.01 mL, 0.11 mmol) was added method C. dropwise to a solution of 6-trifluoromethyl-pyridin-2- 2-(1-Methyl-4-phenyl-1H-imidazol-2-ylsulfanylmethyl)- ylamine (0.016 g., 0.10 mmol) in 1,2-dimethoxyethane (1.0 imidazo[1,2-alpyrimidine (This reaction was run at 70° C. mL), and the mixture was left to stir at room temperature for 40 overnight using DIPEA as base). LC-MS: m/z 322.1 2 h. The solvent was removed in vacuo and the resulting (MH), t0.36 min, method C. residue re-dissolved in ethanol (1.0 mL). The reaction mix 8-Methyl-2-(1-methyl-4-phenyl-1H-imidazol-2-ylsulfanyl ture was subsequently heated under reflux for 2 h, and the methyl)-imidazol-2-alpyridine (This reaction was run at solvent was removed under reduced pressure. DIPEA (0.05 60° C. for 1 h using DIPEA as base). LC-MS: m/z 335.3 mL, 0.25 mmol) and 1-methyl-4 phenyl-1,3-dihydro-imida 45 (MH), t0.55 min, method A. Zole-2-thione (0.017 g., 0.09 mmol) were sequentially added 2-(1-Methyl-4-phenyl-1H-imidazol-2-ylsulfanylmethyl)- to a solution of the crude product in DMF (1.0 mL). The imidazo[1,2-alpyridine (This reaction was run at 60° C. for reaction mixture was then heated at 60°C. for 2 hafter which 1 h using DIPEA as base). LC-MS: m/z 321.0 (MH"), LC-MS showed complete consumption of the starting mate t=0.47 min, method A. rials. The solvent was removed under reduced pressure and 50 8-Methyl-2-(4-phenyl-1H-imidazol-2-ylsulfanylmethyl)- the crude product purified using preparative LC-MS to yield imidazo[1,2-alpyridine (This reaction was run at 60° C. for the title compound. LC-MS: m/z 389.1 (MH"), t-O.52 min, 1 h using DIPEA as base). LC-MS: m/z 321.2 (MH"), method C. t=0.48 min, method A. The following compounds of the invention were prepared 2-4-(3-Methoxy-phenyl)-1-methyl-1H-imidazol-2-ylsulfa analogously: 55 nylmethyl-5,7-dimethyl-imidazo 1,2-alpyrimidine (This 5-Methyl-2-(1-methyl-4-phenyl-1H-imidazol-2-ylsulfanyl reaction was run at 60° C. for 2 h using DIPEA as base). methyl)-imidazo[1,2-alpyridine. LC-MS: m/z 335.4 LC-MS: m/z 380.6 (MH"), to O.65 min, method A. (MH), t-0.54 min, method A. 5,7-Dimethyl-2-(4-phenyl-1H-imidazol-2-ylsulfanylm 5,7-Dimethyl-2-(1-methyl-4-phenyl-1H-imidazol-2-ylsulfa ethyl)-imidazol-2-alpyrimidine (This reaction was run at nylmethyl)-imidazo 1,2-alpyridine. LC-MS: m/z 349.1 60 70° C. for 1 h using DIPEA as base). LC-MS: m/z 336.3 (MH"), to 0.61 min, method A. (MH"), t-0.54 min, method A. 5-Chloro-2-(1-methyl-4-phenyl-1H-imidazol-2-ylsulfanyl 5,7-Dimethyl-2-(4-phenyl-1H-imidazol-2-ylsulfanylm methyl)-imidazo[1,2-alpyridine. LC-MS: m/z. 355.4 ethyl)-1,2,4-triazolo 1.5-alpyrimidine, LC-MS (MH): (MH), t-0.69 min, method A. m/Z 337.4, t (min, method A)=0.58 6-Chloro-8-methyl-2-(1-methyl-4-phenyl-1H-imidazol-2- 65 5,7-Dimethyl-2-(1-methyl-4-phenyl-1H-imidazol-2-ylsulfa ylsulfanylmethyl)-imidazol-2-alpyridine. LC-MS: nylmethyl)-1,2,4-triazolo 1.5-alpyrimidine, LC-MS m/Z369.2 (MH"), to 0.76 min, method A. (MH"): m/z 351.4, t (min, method A)=0.58

US 9,018,217 B2 49 50 8-methoxy-5-methyl-2-(2-(1-methyl-4-phenyl-1H-imida PDE10A inhibition Assay zol-2-yl)ethyl)-1,2,4-triazolo 1.5-alpyridine, LC-MS: A PDE10A assay may for example, be performed as fol m/Z348.4 (MH"), to 0.77 min, method E. lows: The assay is performed in 60 u, Samples containing a 8-fluoro-2-(2-(1-methyl-4-phenyl-1H-imidazol-2-yl)ethyl)- fixed amount of the relevant PDE enzyme (sufficient to con 1.2.4 triazolo 1.5-alpyridine, LC-MS: m/Z322.4 5 vert 20-25% of the cyclic nucleotide substrate), a buffer (50 (MH), t-0.60 min, method A. mM HEPES7.6; 10 mMMgCl; 0.02% Tween20), 0.1 mg/ml 8-Ethyl-5-methyl-2-2-(1-methyl-4-phenyl-1H-imidazol-2- BSA, 225 pCi of H-labelled cyclic nucleotide substrate, yl)-ethyl-1,2,4-triazolo 1.5-cpyrimidine, LC-MS: tritium labeled cAMP to a final concentration of 5 nM and m/Z=347.4 (MH"), to 0.67 min, method A. varying amounts of inhibitors. Reactions are initiated by 5-Methyl-2-2-(1-methyl-4-phenyl-1H-imidazol-2-yl)- 10 addition of the cyclic nucleotide Substrate, and reactions are ethyl-7-propyl-1,2,4-triazolo 1.5-alpyrimidine, LC-MS: allowed to proceed for one hr at room temperature before m/Z361.5 (MH), to 0.74 min, method A. being terminated through mixing with 15 uL 8 mg/mL 7-Methoxy-5-methyl-2-[2-(1-methyl-4-phenyl-1H-1-imida yttrium silicate SPA beads (Amersham). The beads are Zol-2-yl)-ethyl-1,2,4-triazolo 1.5-cpyrimidine, allowed to settle for one hr in the dark before the plates are LC-MS: m/z 349.4 (MH"), t-O.63 min, method A. 15 counted in a Wallac 1450 Microbeta counter. The measured 7-Isopropyl-5-methyl-2-[2-(1-methyl-4-phenyl-1H-imida signal can be converted to activity relative to an uninhibited Zol-2-yl)-ethyl-1,2,4-triazolo 1.5-alpyrimidine, control (100%) and ICs values can be calculated using the LC-MS: m/z. 361.5 (MH"), t-O.74 min, method A. Xlfit extension to EXCEL. 2-2-4-(2,4-Difluoro-phenyl)-1-methyl-1H-imidazol-2-yl)- In the context of the present invention the assay was per ethyl-5,7-dimethyl-1,2,4-triazolo 1.5-alpyrimidine, formed in 60 uL assay buffer (50 mM HEPES pH 7.6; 10 mM LC-MS: m/z. 369.4 (MH), t-0.64 min, method A. MgCl; 0.02% Tween20) containing enough PDE10A to con 7-Methoxy-5,8-dimethyl-2-[2-(1-methyl-4-phenyl-1H-imi vert 20-25% of 10 nM H-cAMP and varying amounts of dazol-2-yl)-ethyl-1,2,4-triazolo 1.5-cpyrimidine, inhibitors. Following a 1 hour incubation the reactions were LC-MS: m/z. 363.4 (MH"), t-O.78 min, method A. terminated by addition of 15uIL 8 mg/mLyttrium silicate SPA 5.8-Dimethyl-2-[2-(1-methyl-4-phenyl-1H-imidazol-2-yl)- 25 beads (Amersham). The beads were allowed to settle for one ethyl-1,2,4-triazolo 1.5-cpyrimidine, LC-MS: hr in the dark before the plates were counted in a Wallac 1450 m/z–333.4 (MH"), to 0.58 min, method A. Microbeta counter. ICs values were calculated by nonlinear 2-(2-4-(2-Methoxy-phenyl)-1-methyl-1H-imidazol-2-yl)- regression using XLfit (IDBS). ethyl-5,7-dimethyl-1,2,4-triazolo 1.5-alpyrimidine, Results of the experiments showed that the tested com LC-MS: m/z. 363.4 (MH), t-0.62 min, method A. 30 pounds of the invention inhibit the PDE10A enzyme with {5-Methyl-2-[2-(1-methyl-4-phenyl-1H-imidazol-2-yl)- ICs values below 700 nM. ethyl-1,2,4-triazolo 1.5-alpyrimidin-7-yl)-methanol, Results of the experiments showed that the majority of the LC-MS: m/z 349.4 (MH), t-0.47 min, method A. compounds of the invention had ICs values of <1500 nM, 8-Ethyl-5-methyl-2-2-(1-methyl-4-phenyl-1H-imidazol-2- many compounds <100 nM, some compounds <50 nM and yl)-ethyl-1,2,4-triazolo 1.5-alpyridine, LC-MS: 35 some had ICs values <10 nM. m/z–346.4 (MH"), to 0.93 min, method E. Phencyclidine (PCP) Induced Hyperactivity 5.8-Dimethoxy-2-2-(1-methyl-4-phenyl-1H-imidazol-2- Male mice (NMRI, Charles River) weighing 20-25 g are yl)-ethyl-1,2,4-triazolo 1.5-alpyridine, LC-MS: used. Eight mice are used in each group receiving the test m/Z364.4 (MH"), to 0.70 min, method E. compound (5 mg/kg) plus PCP (2.3 mg/kg) including the Pharmacological Testing 40 parallel control groups receiving the vehicle of the test com PDE10A Enzyme pound plus PCP or vehicle injections only. The injection Active PDE10A enzyme is prepared in a number of ways Volume is 10 ml/kg. The experiment is made in normal light for use in PDE assays (Loughney, K. et al. Gene 1999, 234, conditions in an undisturbed room. The test Substance is 109-117: Fujishige, K. etal. EurJ Biochem. 1999,266, 1118 injected per oss 60 min before injection of PCP, which is 1127 and Soderling, S. et al. Proc. Natl. Acad. Sci. 1999, 96, 45 administered Subcutaneous. 7071-7076). PDE10A can be expressed as full-length pro Immediately after injection of PCP the mice are placed teins or as truncated proteins, as long as they express the individually in special designed test cage (20 cmx32 cm). The catalytic domain. PDE10A can be prepared in different cell activity is measured by 5x8 infrared light sources and photo types, for example insect cells or E. coli. An example of a cells spaced by 4 cm. The light beams cross the cage 1.8 cm method to obtain catalytically active PDE10A is as follows: 50 above the bottom of the cage. Recording of a motility count The catalytic domain of human PDE10A (amino acids 440 requires interruption of adjacent light beams, thus avoiding 779 from the sequence with accession number NP006652) is counts induced by stationary movements of the mice. amplified from total human brain total RNA by standard Motility is recorded in 5 min intervals for a period of 1 RT-PCR and is cloned into the BamPH1 and Xhol sites of the hour. The drug effect is calculated on the total counts during pET28a vector (Novagen). Expression in coli is performed 55 the 1 hour behavioral test period in the following manner: The according to standard protocols. Briefly, the expression plas mean motility induced by vehicle treatment in the absence of mids are transformed into the BL21 (DE3) E. coli strain, and PCP is used as baseline. The 100 percent effect of PCP is 50 mL cultures inoculated with the cells allowed to grow to an accordingly calculated to be total motility counts minus base OD600 of 0.4–0.6 before protein expression is induced with line. The response in groups receiving test compound is thus 0.5 mM IPTG. Following induction, the cells are incubated 60 determined by the total motility counts minus baseline, overnight at room temperature, after which the cells are col expressed in percent of the similar result recorded in the lected by centrifugation. Cells expressing PDE10A are resus parallel PCP control group. The percent responses are con pended in 12 mL (50 mM TRIS-HC1-pH8.0, 1 mM MgCl, verted to percent inhibition. and protease inhibitors). The cells are lysed by sonication, Results of the experiments showed that the tested com and after all cells are lysed, TritonX100 is added according to 65 pounds of the invention are in Vivo active compounds that Novagen protocols. PDE10A is partially purified on Q inhibit the PCP induced hyperactivity to the '% shown in table Sepharose and the most active fractions were pooled. 2 above.