WO2010138585A1 - Pyrimidinones as pde10 inhibitors - Google Patents

Abstract

The present invention is directed to pyrimidinone compounds of general structural formula (I) which are useful as therapeutic agents for the treatment of central nervous system disorders associated with phosphodiesterase 10 (PDE10).

Description

TITLE OF THE INVENTION PYRIMIDINONES AS PDElO INHIBITORS

FIELD OF THE INVENTION The invention relates generally to compounds which act as inhibitors of phosphodiesterase 10 (PDElO), compositions and therapeutic uses thereof.

BACKGROUND OF THE INVENTION

Schizophrenia is debilitating disorder affecting the psychic and motor functions of the brain. It is typically diagnosed in individuals in their early to mid-twenties and symptoms include hallucinations and delusions or at the other extreme, anhedonia or social withdrawal. Across the spectrum, the symptoms are indicative of cognitive impairment and functional disabilities. Notwithstanding improvements in antipsychotic treatments, current therapies, including typical (haloperidol) and atypical (clozapine or olanzapine) antipsychotics, have been less than acceptable and result in an extremely high rate of noncompliance or discontinuation of medication. Dissatisfaction with therapy is attributed to lack of efficacy or intolerable and unacceptable side affects. The side effects have been associated with significant metabolic, extrapyramidal, prolactic and cardiac adverse events. See, Lieberman et al., N. Engl. J. Med, (2005) 353: 1209-1223, citing the results of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE).

While multiple pathways are believed to be involved with the pathogenesis of schizophrenia leading to psychosis and cognition deficits, much attention has focused on the role of glutamate/NMDA dysfunction associated with cyclic guanosine monophosphate (cGMP) levels and the dopaminergic D2 receptor associated with cyclic adenosine monophosphate (cAMP). These ubiquitous second messengers are responsible for altering the function of many intracellular proteins. Cyclic AMP is thought to regulate the activity of cAMP-dependent protein kinase (PKLA), which in turns phosphorylates and regulates many types of proteins including ion channels, enzymes and transcription factors. Similarly, cGMP is also responsible for downstream regulation of kinases and ion channels. One pathway for affecting the levels of cyclic nucleotides, such as cAMP and cGMP, is to alter or regulate the enzymes that degrade these enzymes, known as 3', 5 '-cyclic nucleotide specific phosphodiesterases (PDEs). The PDE superfamily includes twenty one genes that encode for eleven families of PDEs. These families are further subdivided based on catalytic domain homology and substrate specificity and include the 1) cAMP specific, PDE4A-D, 7 A and 7B, and 8A and 8B, 2) cGMP specific, PDE 5A, 6A-C₅ and 9A, and 3) those that are dual substrate, PDE IA-C, 2A, 3 A and 3B, 1OA, and 1 IA. The homology between the families, ranging from 20% to 45% suggests that it may be possible to develop selective inhibitors for each of these subtypes.

The identification of PDElO was reported by three groups independently and was distinguished from other PDEs on the basis of its amino acid sequence, functional properties, and tissue distribution (Fujishige et al., J, Biol, Chem, (1999) 274:18438-18445; Loughney et al., Gene (1999) 234: 109-117; Soderling et al., PNAS. USA (1999) 96: 7071-7076). The PDElO subtype at present consists of a sole member, PDElOA, having alternative splice variants at both the N-terminus (three variants) and C-terminus (two variants), but that does not affect the GAF domain in the N-terminus or the catalytic site in C-terminus. The N-terminus splice variants, PDElOAl and PDE10A2, differ in that the A2 variant has a PICA phosphorylation site that upon activation, i.e. PKA phosphorylation in response to elevated cAMP levels, results in intracellular changes to the localization of the enzyme. PDEl OA is unique relative to other PDE families also having the conserved GAF domain in that its Iigand is cAMP, while for the other GAF-domain PDEs the Iigand is cGMP (Kehler et al., Expert Opin. Ther. Patents (2007) 17(2): 147-158). PDElOA has limited but high expression in the brain and testes. The high expression in the brain and, in particular, the neurons of the striatum, unique to PDElO, suggests that inhibitors thereto may be well suited from treating neurological and psychiatric disorders and conditions.

SUMMARY OF THE INVENTION

The present invention is directed to pyrimidinone compounds that are useful as therapeutic agents for the treatment of central nervous system disorders associated with phosphodiesterase 10 (PDElO). This invention also provides pharmaceutical compositions comprising a PDElO inhibitor, either alone or in combination, with one or more therapeutically active compounds and a pharmaceutically acceptable carrier.

This invention also comprises methods of treating neurological and psychiatric disorders and, in particular, schizophrenia, Huntington's disease, or psychosis associated with striatal hypofunction or basal ganglia dysfunction, with the PDElO inhibitors herein. DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to PDElO inhibitors and derivatives of structural formula I:

I or pharmaceutically acceptable salts and individual enantiomers and diasteromers thereof wherein:

A is selected from the group consisting of (1) C3_io cycloalkyl, (2) C6-lθ aryl,

(3 ) C5- 10 heteroaryl, and

(4) Cs-io heterocyclyl, wherein said cycloalkyl, aryl, heteroaryl, and heterocyclyl is each optionally substituted with 1 to 3 groups of R^a; Ar is selected from the group consisting of

(1) -(CH₂)_nC3-10 cycloalkyl,

(2) -(O)p(CH₂)_nC6-10 aryl_s

(3) -(CH2)nC5- 10 heteroaryl, and

(4) -(CH2)_nC5- \₀ heterocyclyl, wherein said cycloalkyl, aryl, heteroaryl, and heterocyclyl is each optionally substituted with 1 to 3 groups of R^a; R is selected from the group consisting of

( 1 ) -(CH2)_nC5- 10 heteroaryl,

(2) -(CH2)_nC5- 10 heterocyclyl, (3) -(CH2)_ΠNR2C(O)NR2R3, and

(4) -(CH₂)_nNR2C(O)R3, wherein each is optionally substituted with 1 to 3 groups of R^a;

R2 and R3 are each independently selected from the group consisting of (1) hydrogen,

(2) hydroxyl,

(3) -Cl -6 alkyl, which is unsubstituted or substituted with one or more halogen,

(4) -(CH2)_nCF3,

(5) -(CH₂)_nF,

(6) -C3-10 cycloalkyl,

(7) -C6-10 aryl,

(8) -C5-IO heteroaryl, and

(9) -C5-10 heterocyclyl, wherein said cycloalkyl, aryl, heterocyclyl, or heteroaryl is each optionally substituted with 1 to 3 groups of Ra;

R^a is selected from the group consisting of

(1) halogen,

(2) hydroxyl,

(3) -C 1-6 alkyl, which is unsubstituted or substituted with one or more halogen,

(4) -C3.-6 cycloalkyl.

(5) -NR2C(O)R2,

(6) -C(O)N(R2)2,

(7) -C(R2)₂OR2,

(8) -C(O)R2

(9) NO₂,

(10) -CN,

(11) -N(R2)2,

(12) -C(O)OR2,

(13) -OR2,

(14) -(CH₂)_nC5_io heterocyclyl,

(15) -(CH2)_nC6-10 aryl, and

(16) -(CH₂)nC5-10 heteroaryl, wherein said heterocyclyl, aryl, and heteroaryl are each optionally substituted with 1 to 3 groups i Of (a) halogen,

(b) hydroxyl,

(c) -Cχ-6 alkyl,

(d) -CN, (e) -(CH₂)nCF_3f or

(f) -Ce-io aiyl; n is independently 0 to 4; and p is independently 0 or 1 ; and pharmaceutically acceptable salts thereof. In a sub-embodiment, R^a is selected from the group consisting of

(1) halogen,

(2) hydroxyl,

(3) -C 1-6 alkyl, which is unsubstituted or substituted with one or more halogen,

(4) -CN, (5) -C(O)OR?,

(6) -OR.2,

(7) -(CH2)_nC5- 10 heterocyclyl,

(8) -(CH₂)_nC6-10 aiyl, and

(9) -(CH2)_nC5-10 heteroaryl, wherein said heterocyclyl, aryl, and heteroaryl are each optionally substituted with

1 to 3 groups of

(a) halogen,

(b) hydroxyl,

(c) -Ci-6 alkyl, (d) -CN₅

(e) -(CH₂)nCF3₅ or

(f) -C6-10 ayi-

In another sub-embodiment, R^a is selected from the group consisting of (1) fluorine, (2) chlorine,

(3) hydroxyl, (4) -methyl, which is unsubstituted or substituted with one or more halogen,

(5) -CN,

(6) -C(O)O-t-butyI,

(7) methoxy, (8) propoxy,

(9) phenyl ,

(10) -O(CH2)_nF, and

(11) pyridyl, wherein said pyridyl is optionally substituted with 1 to 3 groups of (a) halogen, (b) hydroxy 1,

(c) -Cμ₆ alkyl,

(d) -CN,

(e) -(CH₂)nCF₃, or

(f) -C6-10 aryl. An embodiment of the present invention includes compounds where A is

-(CH2)nC6-10 aryl optionally substituted with 1 to 3 groups of R^a and all other variables are as previously described. Another embodiment of this invention is when said aryl is phenyl.

An embodiment of the present includes compounds where A is -(CH2)nC5~10 heteroaryl optionally substituted with 1 to 3 groups of R^a and all other variables are as previously described. Another embodiment of this invention is when said heteroaryl is pyridyl.

An embodiment of the present invention includes compounds where Ar is (CH2)nC6-10^aryl optionally substituted with 1 to 3 groups of R^a and all other variables are as previously described. Another embodiment of this invention is when said aryl is phenyl. An embodiment of the present invention includes compounds where Ar is -(CH2)nC5-10 heterocyclyl optionally substituted with 1 to 3 groups of R^a and all other variables are as previously described. Another embodiment of this invention is when said heterocyclyl is selected from the group consisting of indole and indazole.

An embodiment of the present invention includes compounds where R is -(CH2)nC5-lθ heterocyclyl optionally substituted with 1 to 3 groups of R^a and all other variables are as previously described. Another embodiment of this invention is when n is 1 to 3, preferably 2, and said heterocyclyl is selected from the group consisting of (a) indole, and

(b) phthalimidyl.

An embodiment of the present invention includes compounds where R is -(CH2)nNR²C(O)NR2R3 optionally substituted with 1 to 3 groups of Ra and all other variables are as previously described. Another embodiment of this invention is when R2 is hydrogen and R3 is -Cg-Cio a*yl- Another embodiment of this invention is when said -Cg-Cio aryl is biphenyl.

An embodiment of the present invention is where A and Ar is -(CH2)nC6-10 aryl, each optionally substituted with 1 to 3 groups of Ra and all other variables are as previously described.

An embodiment of this invention is where A and Ar is phenyl and R is -(CH2)nC5-10 heterocyclyl, each optionally substituted with 1 to 3 groups of R^a and all other variables are as previously described. Another embodiment of this invention is when n is 1 to 3, preferably 2, and said heterocyclyl is selected from the group consisting of

(1) indole,

(2) phthalimidyl.

In certain embodiments of the invention is realized by structural formula Ha:

wherein:

Ar is selected from the group consisting of

(1) phenyl,

(2) indole,

(3) indazole, and

(4) biphenyl, where each is optionally substituted with 1 to 3 groups of R^a and all other variables are as previously described. Another embodiment of this invention is when R is -(CH2)nC5-10 heterocyclyl or -(CH2)_nNR²C(O)NR2R3 optionally substituted with 1 to 3 groups of Ra and all other variables are as previously described. Still another embodiment of this invention is when n is 1 to 3, preferably 2, and said heterocyclyl is selected from the group consisting of

(1) indole, and

(2) phthalimidyl. Another embodiment of the compound of formula Ha is where Ar is phenyl and R is -(CH2)_nC5-10 heterocyclyl or -(CH2)nNR²C(O)NR.2R3 optionally substituted with 1 to 3 groups of R^a and all other variables are as previously described. Still another embodiment of this invention is when n is 1 to 3, preferably 2, and said heterocyclyl is selected from the group consisting of (1) indole, and

(2) phthalimidyl.

Another embodiment of the compound of formula Ha is where Ax is indole and R is -(CH2)nC5-10 heterocyclyl or -(CH2)_ΠNR2C(O)NR2R3 optionally substituted with 1 to 3 groups of R^a and all other variables are as previously described. Still another embodiment of this invention is when n is 1 to 3, preferably 2, and said heterocyclyl is selected from the group consisting of

(1) indole, and

(2) phthalimidyl.

Another embodiment of the compound of formula Ha is where Ar is indazole and R is -(CH2)nC5-l 0 heterocyclyl or -(CH2)_nNR²C(O)NR2R3 optionally substituted with 1 to 3 groups of R^a and all other variables are as previously described. Still another embodiment of this invention is when n is 1 to 3, preferably 2, and said heterocyclyl is selected from the group consisting of

(1) indole, and (2) phthalimidyl.

Another embodiment of the compound of formula Ha is where Ar is biphenyl and R is -(CH2)_nC5- 10 heterocyclyl or -(CH2)_nNR²C(O)NR2R3 optionally substituted with 1 to 3 groups of R^a and all other variables are as previously described. Still another embodiment of this invention is when π is 1 to 3, preferably 2, and said heterocyclyl is selected from the group consisting of

(1) indole, and (2) phthalimidyl.

In a sub-embodiment, R^a is selected from the group consisting of

(1) halogen,

(2) hydroxyl, (3) -C 1-6 alkyl, which is unsubstituted or substituted with one or more halogen,

(4) -CN,

(5) -C(O)OR?,

(6) -OR2,

(7) -(CH2)nC5-10 heterocyclyl, (8) -(CH2)nC6-10 aiyl, and

(9) -(CH2)_nC5- 10 heteroaryl, wherein said heterocyclyl, aryl, and heteroaryl are each optionally substituted with 1 to 3 groups of (a) halogen, (b) hydroxyl,

(c) -Ci-6 alkyl,

(d) -CN,

(e) -(CH₂)_nCF₃, or

(f) -C6-10 aτyϊ- In another sub-embodiment, Ra is selected from the group consisting of

(1) fluorine,

(2) chlorine,

(3) hydroxyl,

(4) -methyl, which is unsubstituted or substituted with one or more halogen, (5) -CN,

(6) -C(O)O-t-butyl,

(7) methoxy,

(8) propoxy,

(9) phenyl, (10) -O(CH2)_nF, and

(11) pyridyl, wherein said pyridyl is optionally substituted with 1 to 3 groups of

(a) halogen, Φ) hydroxyl,

(C) -Ci-6 alkyl,

(d) -CN,

(e) -(CH2)nCF₃, or

(f> -Ce- 10 aryl-

In certain embodiments of the invention is realized by structural formula lib:

lib wherein:

Ar is selected from the group consisting of

(1) phenyl,

(2) indole,

(3) indazole, and (4) biphenyl where each is optionally substituted with 1 to 3 groups of R^a and all other variables are as previously described. Another embodiment of this invention is when R is -(CH2)nC5-10 heterocyclyl or -(CH2)nNR²C(O)NR2R3 optionally substituted with 1 to 3 groups of Ra and all other variables are as previously described. Still another embodiment of this invention is when n is 1 to 3, preferably 2, and said heterocyclyl is selected from the group consisting of

(1) indole, and

(2) phthalimidyl.

Another embodiment of the compound of formula lib is where Ar is phenyl and R is -(CH2)nC5-10 heterocyclyl or -(CH2)nNR²C(O)NR2R3 optionally substituted with 1 to 3 groups of R^a and all other variables are as previously described. Still another embodiment of this invention is when n is 1 to 3, preferably 2, and said heterocyclyl is selected from the group consisting of

(1) indole, and (2) phthalimidyl.

Another embodiment of the compound of formula lib is where Ar is indole and R is -(CH2)_nC5-10 heterocyclyl or -(CH2)_nNR²C(O)NR²R3 optionally substituted with 1 to 3 groups of R^a and all other variables are as previously described. Still another embodiment of this invention is when n is 1 to 3, preferably 2, and said heterocyclyl is selected from the group consisting of

(1) indole, and

(2) phthalimidyl.

Another embodiment of the compound of formula lib is where Ar is indazole and R is -(CH2)_nC5-10 heterocyclyl or -(CH2)_ΠNR²C(O)NR2R3 optionally substituted with 1 to 3 groups of R^a and all other variables are as previously described. Still another embodiment of this invention is when n is 1 to 3, preferably 2, and said heterocyclyl is selected from the group consisting of

(1) indole, and (2) phthalimidyl.

Another embodiment of the compound of formula Hb is where Ar is biphenyl and R is -(CH2)nC5-10 heterocyclyl or -(CH2)nNR²C(O)NR²R3 optionally substituted with 1 to 3 groups of R^a and all other variables are as previously described. Still another embodiment of this invention is when n is 1 to 3, preferably 2, and said heterocyclyl is selected from the group consisting of

(1) indole, and

(2) phthalimidyl.

In a sub-embodiments R^a is selected from the group consisting of (1) halogen, (2) hydroxy.,

(3) -C 1-6 alkyl, which is unsubstituted or substituted with one or more halogen,

(4) -CN,

(5) -C(O)OR²,

(6) -OR², (7) -(CH2)_nC5-10 heterocyclyl,

(8) <CH₂)_nC6-10 aryl, and (9) -(CH2)_nC5-10 heteroaryl, wherein said heterocyclyl, aryl, and heteroaryl are each optionally substituted with 1 to 3 groups of (a) halogen, (b) hydroxyl,

(c) -Ci-e alkyl,

(d) -CN₅

(e) -(CH2)nCF₃, or

(f) -C6-10 aⁱyl- In another sub-embodiment, R^a is selected from the group consisting of

(1) fluorine,

(2) chlorine,

(3) hydroxyl,

(4) -methyl, which is unsubstituted or substituted with one or more halogen, (5) -CN,

(6) -C(O)O-t-butyl,

(7) methoxy,

(8) propoxy,

(9) phenyl, (10) -O(CH2)_nF, and

(11) pyridyl, wherein said pyridyl is optionally substituted with 1 to 3 groups of

(a) halogen,

(b) hydroxyl,

(c) -Ch alky! (d) -CN,

(e) -(CH₂)nCF₃, or

(f) -C6-10 aryl.

In certain embodiments of the invention is realized by structural formula Ilia:

IHa where Ar is selected from the group consisting of

(1) phenyl, (2) indole,

(3) indazole, and

(4) biphenyl, where each is optionally substituted with 1 to 3 groups of R^a and all other variables are as previously described. A sub-embodiment of this invention is realized when R^a is selected from the group consisting of

(1) halogen,

(2) hydroxyl,

(3) -C 1-6 alkyl, which is imsubstituted or substituted with one or more halogen, (4) -CN,

(5) -C(O)OR?,

(6) -OR2_?

(7) -(CH2)nC5-10 heterocyclyl,

(8) -(CH2)nC6-10 aryl, and (9) -(CH2)_nC5-10 heteroaryl₅ wherein said heterocyclyl, aryl, and heteroaryl are each optionally substituted with 1 to 3 groups of

(a) halogen,

(b) hydroxyl, (c) -C μ6 alkyl,

(d) -CN,

(e) -(CH₂)nCF3_> or (f) -C6-10 aryl.

In another sub-embodiment, R^a is selected from the group consisting of

(1) fluorine,

(2) chlorine,

(3) hydroxyl,

(4) -methyl, which is unsubstituted or substituted with one or more halogen,

(5) -CN₅

(6) -C(O)O-t-butyϊ,

(7) methoxy,

(8) propoxy,

(9) phenyl ,

(10) -O(CH2)_nF_> and

(1 1) pyridyl, wherein said pyridyl is optionally substituted with 1 to 3 groups of

(a) halogen,

(b) hydroxyl, (C) -Ci-6 alkyl,

(d) -CN,

(e) -(CH₂)nCF3₅ or

(f) -C6-10 aryl. hi certain embodiments of the invention is realized by structural formula IHb:

nib

where Ar is selected from the group consisting of (1) phenyl,

(2) indole,

(3) indazole, and (4) biphenyl, where each is optionally substituted with 1 to 3 groups of R^a and all other variables are as previously described.

A sub-embodiment of this invention is realized when R^a is selected from the group consisting of

(1) halogen,

(2) hydroxy!,

(3) -C i_6 alkyl, which is unsubstituted or substituted with one or more halogen,

(4) -CN, (5) -C(O)ORA

(6) -OR2,

(7) -(CH2)nCs-10 heterocyclyl,

(8) -(CH₂)_nC6-10 aryl, and

(9) -(CH2)nC5-10 heteroaryl, wherein said heterocyclyl, aryl, and heteroaryl are each optionally substituted with

1 to 3 groups of

(a) halogen,

(b) hydroxyl,

(d) -Ci-6 alkyl, (d) -CN,

(e) -(CH2)_nCF3, or

(f) -C6-10 aryl.

In another sub-embodiment, R^a is selected from the group consisting of

(1) fluorine, (2) chlorine,

(3) hydroxyl,

(4) -methyl, which is unsubstituted or substituted with one or more halogen,

(5) -CN,

(6) -C(O)O-t-butyl, (7) methoxy,

(8) propoxy,

(9) phenyl, (10) -O(CH2)_nF, and

(11) pyridyl, wherein said pyridyl is optionally substituted with 1 to 3 groups of

(a) halogen,

(b) hydroxyl,

(c) -Ci-6 alkyl,

(d) -CN,

(e) -(CH₂)nCF3, or

(f) -C6-10 aryl.

Examples of compounds of the invention made according to the schemes and

Examples that follow include:

or a pharmaceutically acceptable salt, solvate or in vivo hydrolysable ester thereof.

While the invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various adaptations, changes, modifications, substitutions, deletions, or additions of procedures and protocols may be made without departing from the spirit and scope of the invention.

Specific embodiments of the present invention include a compound which is selected from the group consisting of the subject compounds of the Examples herein and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.

When any variable (e.g. aryl, heterocycle, Ra etc.) occurs more than one time in any constituent, its definition on each occurrence is independent at every other occurrence. Also, combinations of substituents or variables are permissible only if such combinations result in stable compounds.

When R^a is -O- and attached to a carbon it is referred to as a carbonyl group and when it is attached to a nitrogen (e.g., nitrogen atom on a pyridyl group) or sulfur atom it is referred to a N-oxide and sulfoxide group, respectively. As used herein, "alkyl" encompasses groups having the prefix "alk" such as, for example, alkoxy, alkanoyl, alkenyl, and alkynyl and means carbon chains which may be linear or branched or combinations thereof. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, and heptyl. "Alkenyl" refers to a hydrocarbon radical straight, branched or cyclic containing from 2 to 10 carbon atoms and at least one carbon to carbon double bond. Preferred alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl. Preferably, alkenyl is C2-C6 alkenyl. Preferred alkynyls are C2-C6 alkynyl.

"Alkenyl," "alkynyl" and other like terms include carbon chains containing at least one unsaturated C-C bond. As used herein, "fluoroalkyl" refers to an alkyl substituent as described herein containing at least one fluorine substituent.

The term "cycloalkyl" refers to a saturated hydrocarbon containing one ring having a specified number of carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The term "Ci-g" includes alkyls containing 6, 5, 4, 3, 2, or 1 carbon atoms.

The term "alkoxy" as used herein, alone or in combination, includes an alkyl group connected to the oxy connecting atom. The term "alkoxy" also includes alkyl ether groups, where the term 'alkyl' is defined above, and 'ether' means two alkyl groups with an oxygen atom between them. Examples of suitable alkoxy groups include methoxy, ethoxy, n- propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, methoxymethane (also referred to as 'dimethyl ether'), and methoxyethane (also referred to as 'ethyl methyl ether').

As used herein, "aryl" is intended to mean any stable monocyclic or bicycHc carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic. Examples of such aryl elements include phenyl, napthyl, tetrahydronapthyl, indanyl, or biphenyl. The term heterocycle, heterocyclyl, or heterocyclic, as used herein, represents a stable 5- to 7-membered monocyclic or stable 8- to 11-membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. The term heterocycle or heterocyclic includes heteroaryl moieties. Examples of such heterocyclic elements include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofαryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cϊnnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, 1,3-dioxoIanyl, ftuyl, imidazolidinyl, iniidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoqulnolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 2-oxopiperazinyϊ, 2-oxopiρerdinyl, 2-oxopyrrolidinyl, piperidyl, piperazinyl, pyridyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, qumoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tbiamorpholinyl, thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl, thienofuryl, tblenothienyl, triazolyl, and thienyl.

In certain embodiments, the heterocyclic group is a heteroaryl group. As used herein, the term "heteroaryl" refers to groups having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms; having 6, 10, or 14 π electrons shared in a cyclic array; and having, in addition to carbon atoms, between one and about three heteroatoms selected from the group consisting of N, 0, and S heteroaryl groups include, without limitation, thienyl, benzothienyl, furyl, benzofuryl, dibenzofuryl, pyrrolyl, imidazolyl, pyrazoiyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, tetrazolyl, oxazolyl, thiazolyl, and isoxazolyl.

In certain other embodiments, the heterocyclic group is fused to an aryl or heteroaryl group. Examples of such fused heterocycles include, without limitation, tetrahydroquinolinyl and dihydrobenzofuranyl.

The term "heteroaryl", as used herein except where noted, represents a stable 5- to 7-membered monocyclic- or stable 9- to 10-membered fused bicyclic heterocyclic ring system which contains an aromatic ring, any ring of which may be saturated, such as piperidinyl, partially saturated, or unsaturated, such as pyridinyl, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O and S₅ and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Examples of such heteroaryl groups include, but are not limited to, benzimidazole, benzisothiazole, benzisoxazole, benzofuran, benzothϊazole, benzothiophene, benzotriazole, benzoxazole, carboline, cinnoline, furan, furazan, imidazole, indazole, indole, indolizine, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, quinazoline, quinoline, quinoxaline, tetrazole, thiadiazole, thiazole, Ihiophene, triazine, triazole, and N-oxides thereof.

Examples of heterocycloalkyls include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, imidazolinyl, pyrolidin-2-one, piperidin-2-one, and thiomorpholinyl.

The term "heleroalom" means O, S or N, selected on an independent basis.

A moiety that is substituted is one in which one or more hydrogens have been independently replaced with another chemical substituent As a non-limiting example, substituted phenyls include 2-flurophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluoro-phenyl, 2,4- fluor-3-propylphenyl. As another non-limiting example, substituted n-octyls include 2,4 dimethyl- 5 -ethyl-octyl and 3-cyclopentyloctyl. Included within this definition are methylenes (-CH₂-) substituted with oxygen to form carbonyl (-CO-).

Unless otherwise stated, as employed herein, when a moiety (e.g., cycloalkyl, hydrocarbyl, aryl, alkyl, heteroaryl, heterocyclic, urea, etc.) is described as "optionally substituted" it is meant that the group optionally has from one to four, preferably from one to three, more preferably one or two, non-hydrogen substituents. Suitable substituents include, without limitation, halo, hydroxy, oxo (e.g., an annular -CH- substituted with oxo is -C(O)-), nitro, halohydrocarbyl, hydrocarbyl, aryl, aralkyl, alkoxy, aryloxy, amino, acylamino, alkylcarbamoyl, arylcarbamoyl, aminoalkyl, acyl₅ carboxy, hydroxyalkyl, , alkanesulfonyl, arenesulfonyl, alkanesulfonamido, arenesulfonamido, aralkylsulfonamido, alkylcarbonyl, acyloxy, cyano, and ureido groups. Preferred substituents, which are themselves not further substituted (unless expressly stated otherwise) are:

(a) halo, cyano, oxo, carboxy, formyl, nitro, amino, amidino, guanidino, and

(b) C1-C6 alkyl or alkenyl or arylalkyl imino, carbamoyl, azido, carboxamido, mercapto, hydroxy, hydroxyalkyl, alkylaryl, arylalkyl, Cj-Cs alkyl, SO2CF3, CF3, Sθ2Me, Ci-

Cg alkenyl, Cl -Cg alkoxy, Ci-Cg alkoxycarbonyl, aryloxycarbonyl, C2-C8 acyl, C2-C8 acylamino, Ci-Cs alkylthio, arylalkylthio, arylthio, Ci-Cgalkylsulfinyl, arylalkylsulfnyl, arylsulfnyl, Cl -C8 alkylsulfonyl, arylalkylsulfonyl, arylsulfonyl, Co-C(J N-alkylcarbamoyl, C2- Ci 5 N₁N dialkylcarbamoyl, C3-C7 cycloalkyl, aroyl, aryloxy, arylalkyl ether, aryl, aryl fused to a cycloalkyl or heterocycle or another aryl ring, C3-C7 heterocycle, or any of these rings fused or spiro-fused to a cycloalkyl, heterocyclyl, or aryl, wherein each of the foregoing is further optionally substituted with one more moieties listed in (a), above. "Halogen" refers to fluorine, chlorine, bromine and iodine. Compounds described herein may contain one or more double bonds and may thus give rise to cis/trans isomers as well as other conformational isomers. The present invention includes all such possible isomers as well as mixtures of such isomers unless specifically stated otherwise.

The compounds of the present invention may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within the ambit of this invention. Any formulas, structures or names of compounds described in this specification that do not specify a particular stereochemistry are meant to encompass any and all existing isomers as described above and mixtures thereof in any proportion. When stereochemistry is specified, the invention is meant to encompass that particular isomer in pure form or as part of a mixture with other isomers in any proportion. The independent syntheses of these diastereomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry may be determined by the x-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography. The coupling reaction is often the formation of salts using an enantiomerically pure acid or base. The diasteromeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue. The racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art. Alternatively, any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art. As used in this specification and the appended claims, the singular forms "a," "an" and "the" include plural references unless the content clearly dictates otherwise. Thus, for example, reference to "a primer" includes two or more such primers, reference to "an amino acid" includes more than one such amino acid, and the like. It will be understood that, as used herein, references to the compounds of structural formulas I, Ha, lib, IHa, and HIb are meant to also include the pharmaceutically acceptable salts, and also salts that are not pharmaceutically acceptable when they are used as precursors to the free compounds or in other synthetic manipulations.

The compounds of the present invention may be administered in the form of a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (cupris and cuprous), ferric, ferrous, lithium, magnesium, manganese (manganic and manganous), potassium, sodium, zinc and the like salts. Particular embodiments include the ammonium, calcium, magnesium, potassium, and sodium salts. Salts in the solid form may exist in more than one crystal structure, and may also be in the form of hydrates. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as argmine, betaine, caffeine, choline, N,N'-dibenzylethylene-diamine, diethylamine, 2-diethylaminoethanol, 2-dimethylamino-ethanol₅ ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamme, trimethylamine, tripropylamine, tromethamine, and the like. When the compound of the present invention is basic, its corresponding salt may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandeiic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like. It will be understood that, as used herein, references to the compounds of the present invention are meant to also include the pharmaceutically acceptable salts. The term "composition" as used herein is intended to encompass a product comprising specified ingredients in predetermined amounts or proportions, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. This term in relation to pharmaceutical compositions is intended to encompass a product comprising one or more active ingredients, and an optional carrier comprising inert ingredients, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. In general, pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases.

Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by combining a compound of the present invention and a pharmaceutically acceptable carrier. By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

The pharmaceutical compositions of the present invention comprise compounds of the invention (or pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally one or more additional therapeutic agents or adjuvants. Such additional therapeutic agents can include, for example, i) opiate agonists or antagonists, ii) calcium channel antagonists, iii) 5HT receptor agonists or antagonists, iv) sodium channel antagonists, v) NMDA receptor agonists or antagonists, vi) COX-2 selective inhibitors, vii) NKl antagonists, viii) non-steroidal anti-inflammatory drags ("NSAID"), ix) selective serotonin reuptake inhibitors ("SSRI") and/or selective serotonin and norepinephrine reuptake inhibitors ("SSNRI"), x) tricyclic antidepressant drugs, xi) norepinephrine modulators, xii) lithium, xiii) valproate, xiv) neurontin (gabapentin), xv) pregabalin, and xvi) sodium channel blockers. The instant compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

Exemplifying the invention are the specific compounds disclosed in the Examples and herein that can be used for treating a disease state or condition associated with a neurological or psychiatric disorder.

"Treating" or "treatment of a disease state includes: 1) preventing the disease state, i.e. causing the clinical symptoms of the disease state not to develop in a subject that may be exposed to or predisposed to the disease state, but does not yet experience or display symptoms of the disease state; 2) inhibiting the disease state, i.e., arresting the development of the disease state or its clinical symptoms; 3) or relieving the disease state, i.e., causing temporary or permanent regression of the disease state or its clinical symptoms.

The subject treated in the present methods is generally a mammal, in particular, a human being, male or female, in whom therapy is desired. The term "therapeutically effective amount" means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician. It is recognized that one skilled in the art may affect the neurological and psychiatric disorders by treating a patient presently afflicted with the disorders or by prophylactically treating a patient afflicted with such disorders with an effective amount of the compound of the present invention. As used herein, the terms "treatment" and "treating" refer to all processes wherein there may be a slowing, interrupting, arresting, controlling, or stopping of the progression of the neurological and psychiatric disorders described herein, but does not necessarily indicate a total elimination of all disorder symptoms, as well as the prophylactic therapy to retard the progression or reduce the risk of the noted conditions, particularly in a patient who is predisposed to such disease or disorder. The compounds of the invention are useful in methods of treating a neurological or psychiatric disorder associated with PDElO dysfunction in a patient such as a mammal in need of such inhibition comprising the administration of an effective amount of the compound. In addition to primates, especially humans, a variety of other mammals can be treated according to the method of the present invention. The subject compounds are useful in a method of inhibiting PDEl 0 activity in a patient such as a mammal in need of such inhibition comprising the administration of an effective amount of the compound. In addition to primates, especially humans, a variety of other mammals can be treated according to the method of the present invention. Applicants propose that inhibitors of PDElO and, in particular inhibitors of PDElOA. will provide therapeutic benefit to those individuals suffering from psychiatric and cognitive disorders. The unique and exclusive distribution of PDElOA in the medium spiny projection neurons of the striatum, which form the principle site for cortical and dopaminergic input within basal ganglia, suggests that it may be possible and desirable to identify inhibitors of PDElO to ameliorate or eliminate unwanted cellular signaling within this site. Without wishing to be bound by any theory, Applicants believe that inhibition of PDElOA in the striatum will result in increased cAMP/cGMP signaling and striatal output, which has the potential to restore behavioral inhibition that is impaired in cognitive disease such as schizophrenia. Regulation and integration of glutamatergic and dopaminergic inputs will enhance cognitive behavior, while suppressing or reducing unwanted behavior. Thus, in one embodiment, compounds of the invention provide a method for treating or ameliorating diseases or conditions in which striatal hypofunction is a prominent feature or ones in which basal ganglia dysfunction plays a role, such as, Parkinson's disease, Huntington's disease, schizophrenia, obsessive-compulsive disorders, addiction and psychosis. Other conditions for which the inhibitors described herein may have a desirable and useful effect include those requiring a reduction in activity and reduced response to psychomotor stimulants or where it would be desirable to reduce conditional avoidance responses, which is often predictive of clinical antipsychotic activity.

As used herein, the term '"selective PDElO inhibitor" refers to an organic molecule that effectively inhibits an enzyme from the PDElO family to a greater extent than enzymes from the PDE 1-9 or PDEIl families. In one embodiment, a selective PDElO inhibitor is an organic molecule having a Ki for inhibition of PDElO that is less than or about one-tenth that for a substance that is an inhibitor for another PDE enzyme. In other words, the organic molecule inhibits PDElO activity to the same degree at a concentration of about one-tenth or less than the concentration required for any other PDE enzyme. Preferably, a selective PDEl 0 inhibitor is an organic molecule, having a Ki for inhibition of PDElO that is less than or about one-hundredth that for a substance that is an inhibitor for another PDE enzyme. In other words, the organic molecule inhibits PDElO activity to the same degree at a concentration of about one- hundredth or less than the concentration required for any other PDE enzyme. A "selective PDElO inhibitor" can be identified, for example, by comparing the ability of an organic molecule to inhibit PDElO activity to its ability to inhibit PDE enzymes from the other PDE families. For example, an organic molecule may be assayed for its ability to inhibit PDElO activity, as well as PDElA, PDElB, PDElC, PDE2A, PDE3A, PDE3B, PDE4A, PDE4B, PDE4C, PDE4D, PDE5A, PDE6A, PDE6B, PDE6C, PDE7A, PDE7B, PDE8A, PDE8B, PDE9A, and/or PDEl IA.

In a specific embodiment, compounds of the present invention provide a method for treating schizophrenia or psychosis comprising administering to a patient in need thereof an effective amount of a compound of the present invention. The Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) (2000, American Psychiatric Association, Washington DC) provides a diagnostic tool that includes paranoid, disorganized, catatonic or undifferentiated schizophrenia and substance-induced psychotic disorders. As used herein, the term "schizophrenia or psychosis" includes the diagnosis and classification of these mental disorders as described in DSM-IV-TR and the term is intended to include similar disorders described in other sources. Disorders and conditions encompassed herein include, but are not limited to, conditions or diseases such as schizophrenia or psychosis, including schizophrenia (paranoid, disorganized, catatonic, undifferentiated, or residual type), schizophreniform disorder, schizoaffective disorder, for example of the delusional type or the depressive type, delusional disorder, psychotic disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition and substance-induced or drug-induced ( for example psychosis induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opioids, phencyclidine, ketamine and other dissociative anaesthetics, and other psychostimulants), psychosispsychotic disorder, psychosis associated with affective disorders, brief reactive psychosis, schizoaffective psychosis, "schizophrenia-spectrum" disorders such as schizoid or schizotypal personality disorders, personality disorder of the paranoid type, personality disorder of the schizoid type, illness associated with psychosis (such as major depression, manic depressive (bipolar) disorder, Alzheimer's disease and post-traumatic stress syndrome), including both the positive and the negative symptoms of schizophrenia and other psychoses. In another specific embodiment, the compounds of the present invention provide a method for treating cognitive disorders comprising administering to a patient in need thereof an effective amount of a compound of the present invention. The DSM-IV-TR also provides a diagnostic tool that includes cognitive disorders including dementia, delirium, amnestic disorders and age-related cognitive decline. As used herein, the term "cognitive disorders" includes the diagnosis and classification of these disorders as described in DSM-IV-TR and the term is intended to include similar disorders described in other sources. Disorders and conditions encompassed herein include, but are not limited to, disorders that comprise as a symptom a deficiency in attention and/or cognition, such as dementia (associated with Alzheimer's disease, ischemia, multi-infarct dementia, trauma, intracranial tumors, cerebral trauma, vascular problems or stroke, alcoholic dementia or other drug-related dementia, AIDS, HIV disease, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt Jacob disease, perinatal hypoxia, other general medical conditions or substance abuse), Alzheimer's disease, multi-infarct dementia, AIDS-related dementia, and Fronto temperal dementia, delirium, amnestic disorders or age related cognitive decline.

In another specific embodiment, compounds of the present invention provide a method for treating anxiety disorders comprising administering to a patient in need thereof an effective amount of a compound of the present invention. The D SM-IV-TR also provides a diagnostic tool that includes anxiety disorders as generalized anxiety disorder, obsessive- compulsive disorder and panic attack. As used herein, the term "anxiety disorders" includes the diagnosis and classification of these mental disorders as described in DSM-IV-TR and the term is intended to include similar disorders described in other sources. Disorders and conditions encompassed herein include, but are not limited to, anxiety disorders such as, acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attack, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, specific phobia, substance-induced anxiety disorder and anxiety due to a general medical condition.

In another specific embodiment, compounds of the present invention provide a method for treating substance-related disorders and addictive behaviors comprising administering to a patient in need thereof an effective amount of a compound of the present invention. The DSM-IV-TR also provides a diagnostic tool that includes persisting dementia, persisting amnestic disorder, psychotic disorder or anxiety disorder induced by substance abuse, and tolerance of, dependence on or withdrawal from substances of abuse. As used herein, the term "substance-related disorders and addictive behaviors" includes the diagnosis and classification of these mental disorders as described in DSM-IV-TR and the term is intended to include similar disorders described in other sources. Disorders and conditions encompassed herein include, but are not limited to, substance-related disorders and addictive behaviors, such as substance-induced delirium, persisting dementia, persisting amnestic disorder, psychotic disorder or anxiety disorder, drug addiction, tolerance, and dependence or withdrawal from substances including alcohol, amphetamines, cannabis, cocaine, hallucinogens, inhalants, nicotine, opioids, phencyclidine, sedatives, hypnotics or anxiolytics.

In another specific embodiment, compounds of the present invention provide a method for treating obesity or eating disorders associated with excessive food intake, and complications associated therewith, comprising administering to a patient in need thereof an effective amount of a compound of the present invention. At present, obesity is included in the tenth edition of the International Classification of Diseases and Related Health Problems (ICD- 10) (1992 World Health Organization) as a general medical condition. The DSM-IV-TR also provides a diagnostic tool that includes obesity in the presence of psychological factors affecting medical condition. As used herein, the term "obesity or eating disorders associated with excessive food intake" includes the diagnosis and classification of these medical conditions and disorders described in ICD-IO and DSM-IV-TR and the term is intended to include similar disorders described in other sources. Disorders and conditions encompassed herein include, but are not limited to, obesity, bulimia nervosa and compulsive eating disorders.

In another specific embodiment, compounds of the present invention provide a method for treating mood and depressive disorders comprising administering to a patient in need thereof an effective amount of a compound of the present invention. As used herein, the term "mood and depressive disorders" includes the diagnosis and classification of these medical conditions and disorders described in the DSM-IV-TR and the term is intended to include similar disorders described in other sources. Disorders and conditions encompassed herein include, but are not limited to, bipolar disorders, mood disorders including depressive disorders, major depressive episode of the mild, moderate or severe type, a manic or mixed mood episode, a hypomanic mood episode, a depressive episode with atypical features, a depressive episode with melancholic features, a depressive episode with catatonic features, a mood episode with postpartum onset, post-stroke depression; major depressive disorder, dysthymic disorder, minor depressive disorder, premenstrual dysphoric disorder, post-psychotic depressive disorder of schizophrenia, a major depressive disorder superimposed on a psychotic disorder such as delusional disorder or schizophrenia, a bipolar disorder, for example, bipolar I disorder, bipolar II disorder, cyclothymic disorder, depression including unipolar depression, seasonal depression and post-partum depression, premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PDD), mood disorders due to a general medical condition, and substance-induced mood disorders.

In still other specific embodiments, compounds of the invention provide methods for treating other types of cognitive, learning and mental related disorders including, but not limited to, learning disorders, such as a reading disorder, a mathematics disorder, or a disorder of written expression, attention-deficit/hyperactivity disorder, age-related cognitive decline, pervasive developmental disorder including autistic disorder, attention disorders such as attention-deficit hyperactivity disorder (ADHD) and conduct disorder; an NMDA receptor- related disorder, such as autism, depression, benign forgetfulness, childhood learning disorders and closed head injury; a neurodegenerative disorder or condition, such as neurodegeneration associated with cerebral trauma, stroke, cerebral infarct, epileptic seizure, neurotoxin poisoning, or hypoglycemia-induced neurodegeneration; multi-system atrophy; movement disorders, such as akinesias and akinetic-rigid syndromes (including, Parkinson's disease, drug-induced parkinsonism, postencephalitic parkinsonism, progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, parkinsonism- ALS dementia complex and basal ganglia calcification), medication-induced parkinsonism (such as, neuroleptic-induced parkinsonism, neuroleptic malignant syndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia, neuroleptic-induced tardive dyskinesia and medication-induced postural tremor), Huntington's disease, dyskinesia associated with dopamine agonist therapy, Gilles de Ia Tourette's syndrome, epilepsy, muscular spasms and disorders associated with muscular spasticity or weakness including tremors; dyskinesias, including tremor (such as, rest tremor, postural tremor, intention tremor and essential tremor), restless leg syndrome, chorea (such as Sydenham's chorea, Huntington's disease, benign hereditary chorea, neuroacanthocytosis, symptomatic chorea, drug-induced chorea and hemiballism), myoclonus (including, generalised myoclonus and focal myoclonus), tics (including, simple tics, complex tics and symptomatic tics), dystonia (including, generalised, iodiopathic, drug-induced, symptomatic, paroxymal, and focal (such as blepharospasm, oromandibular, spasmodic, spasmodic torticollis, axial dystonia, hemiplegic and dystonic writer's cramp)); urinary incontinence; neuronal damage (including ocular damage, retinopathy or macular degeneration of the eye, tinnitus, hearing impairment and loss, and brain edema); emesis; and sleep disorders, including insomnia and narcolepsy.

In still another specific embodiment, compounds of the present invention provide a method for treating pain comprising administering to a patient in need thereof an effective amount of a compound of the present invention. Particular pain embodiments are bone and joint pain (osteoarthritis), repetitive motion pain, dental pain, cancer pain, myofascial pain (muscular injury, fibromyalgia), perioperative pain (general surgery, gynecological), chronic pain and neuropathic pain. Of the disorders above, the treatment of schizophrenia, bipolar disorder, depression, including unipolar depression, seasonal depression and post-partum depression, premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PDD), learning disorders, pervasive developmental disorders, including autistic disorder, attention disorders including Attention-Deficit/Hyperactivity Disorder, autism, tic disorders including Tourette's disorder, anxiety disorders including phobia and post traumatic stress disorder, cognitive disorders associated with dementia, AIDS dementia, Alzheimer's, Parkinson's, Huntington's disease, spasticity, myoclonus, muscle spasm, tinnitus and hearing impairment and loss are of particular importance.

The present invention is further directed to a method for the manufacture of a medicament for treating neurological or psychiatric disorders associated with PDElO dysfunction, including those disorders and conditions listed above, in humans and animals comprising combining a compound of the present invention with one or more additional therapeutic agents, carriers, or diluents.

The present invention is also directed to compounds of the invention for use in the treatment of neurological or psychiatric disorders associated with PDElO dysfunction, including those disorders and conditions listed above, in humans and animals comprising combining a compound of the present invention with one or more additional therapeutic agents, carriers, or diluents.

The subject compounds are further useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the diseases, disorders and conditions noted herein. The subject compounds are further useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the aforementioned diseases, disorders and conditions in combination with other agents. The compounds of the present invention may be used in combination with one or more other drugs in the treatment, prevention, control, amelioration, or reduction of risk of diseases or conditions for which compounds of the present invention or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone. Such other drug(s) may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present invention. The terms "administration of and or "administering a" compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need of treatment.

When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compound of the present invention may be desirable. However, the combination therapy may also includes therapies in which the compound of the present invention and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of the present invention. The above combinations include combinations of a compound of the present invention not only with one other active compound, but also with two or more other active compounds. Likewise, compounds of the present invention may be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which compounds of the present invention are useful. Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present invention. Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention. The weight ratio of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with another agent, the weight ratio of the compound of the present invention to the other agent will generally range from about 1000:1 to about 1 : 1000, such as about 200:1 to about 1 :200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.

In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s). Accordingly, the subject compounds may be used alone or in combination with other agents which are known to be beneficial in the subject indications or other drugs that affect receptors or enzymes that either increase the efficacy, safety, convenience, or reduce unwanted side effects or toxicity of the compounds of the present invention. The subject compound and the other agent may be co-administered, either in concomitant therapy or in a fixed combination. In one embodiment, the subject compound may be employed in combination with anti- Alzheimer' s agents, beta-secretase inhibitors, gamma-secretase inhibitors, HMG-CoA reductase inhibitors, NSAID 's including ibuprofen, vitamin E, and anti-amyloid antibodies. In another embodiment, the subject compound may be employed in combination with sedatives, hypnotics, anxiolytics, antipsychotics, antianxiety agents, cyclopyrrolones, iniidazopyridines, pyrazolopyrimidines, minor tranquilizers, melatonin agonists and antagonists, melatonergic agents, benzodiazepines, barbiturates, 5HT-2 antagonists, and the like, such as: adinazolam, allobarbital, alonimid, alprazolam, amisulpride, amitriptylme, amobarbital, amoxapine, aripiprazole, atypical antipsychotics, bentazepam, benzoctamine, brotizolam, bupropion, busprione, butabarbital, butalbital, capuride, carbocloral, chloral betaine, chloral hydrate, clomipramine, clonazepam, cloperidone, clorazepate, chlordiazepoxide, clorethate, chlorpromazine, clozapine, cyprazepam, desipramine, dexclamol, diazepam, dichloralphenazone, divalproex, diphenhydramine, doxepin, estazolam, ethchlorvynol, etomidate, fenobam, flunitrazepam, flupentixol, fϊuphenazine, flurazepam, fluvoxamine, fluoxetine, fosazepam, glulethimide, halazepam, haloperidol, hydroxyzine, imipramine, lithium, lorazepam, lormetazepam, maprotiline, raecloqualone, melatonin, mephobarbital, meprobamate, methaqualone, midaflur, midazolam, nefazodone, nisobamate, nitrazepam, nortriptyline, olanzapine, oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine, perphenazine, phenelzine, phenobarbital, prazepam, promethazine, propofol, pro tripty line, quazepam, quetiapine, reclazepam, risperidone, roletamide, secobarbital, sertraline, suproclone, temazepam, thioridazine, thiothixene, tracazolate, tranylcypromaine, trazodone, triazolam, trepipam, tricetamide, triclofos, trifluoperazine, trimetozine, trimipramine, uldazepam, venlafaxine, zaleplon, ziprasidone, zolazepam, Zolpidem, and salts thereof, and combinations thereof, and the like, or the subject compound may be administered in conjunction with the use of physical methods such as with light therapy or electrical stimulation.

In another embodiment, the subject compound may be employed in combination with levodopa (with or without a selective extracerebral decarboxylase inhibitor such as carbidopa or benserazide), anticholinergics such as biperiden (optionally as its hydrochloride or lactate salt) and trihexyphenidyl (benzhexol) hydrochloride, COMT inhibitors such as entacapone, MOA-B inhibitors, antioxidants, A2a adenosine receptor antagonists, cholinergic agonists, NMDA receptor antagonists, serotonin receptor antagonists and dopamine receptor agonists such as alentemol, bromocriptine, fenoldopam, lisuride, naxagolide, pergolide and pramipexole. It will be appreciated that the dopamine agonist may be in the form of a pharmaceutically acceptable salt, for example, alentemol hydrobromide, bromocriptine mesylate, fenoldopam mesylate, naxagolide hydrochloride and pergolide mesylate. Lisuride and pramipexol are commonly used in a non-salt form. In another embodiment, the subject compound may be employed in combination with a compound from the phenothiazine, thioxanthene, heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine and ϊndolone classes of neuroleptic agent. Suitable examples of phenothiazines include chlorpromazine, mesoridazine, thioridazine, acetophenazine, fluphenazϊne, perphenazine and trifluoperazine. Suitable examples of thioxanthenes include chlorprothixene and thiothixene. An example of a dibenzazepine is clozapine. An example of a butyrophenone is haloperidol. An example of a diphenylbutylpiperidine is pimozide. An example of an indolone is molindolone. Other neuroleptic agents include loxapine, sulpiride and risperidone. It will be appreciated that the neuroleptic agents when used in combination with thesubject compound may be in the form of a pharmaceutically acceptable salt, for example, chlorpromazine hydrochloride, mesoridazine besylate, thioridazine hydrochloride, acetophenazine maleate, fluphenazine hydrochloride, flurphenazine enathate, fluphenazine decanoate, trifluoperazine hydrochloride, thiothixene hydrochloride, haloperidol decanoate, loxapine succinate and molindone hydrochloride. Perphenazine, chlorprothixene, clozapine, haloperidolj pimozide and risperidone are commonly used in a non-salt form. Thus, the subject compound may be employed in combination with acetophenazine, alentemol, aripiprazole, amisulpride, benzhexol, bromocriptine, biperiden, chlorpromazine, chlorprothixene, clozapine, diazepam, fenoldopam, fluphenazine, haloperidol, levodopa, levodopa with benserazide, levodopa with carbidopa, lisuride, loxapine, mesoridazine, molindolone, naxagolide, olanzapine, pergolide, perphenazine, pimozide, pramipexole, quetiapine, risperidone, sulpiride, tetrabenazine, trihexyphenidyl, thioridazine, thiothixene, trifluoperazine or ziprasidone.

In another embodiment, the subject compound may be employed in combination with an anti-depressant or anti-anxiety agent, including norepinephrine reuptake inhibitors (including tertiary amine tricyclics and secondary amine tricyclics), selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors (SNRIs), corticotropin releasing factor (CRF) antagonists, α-adrenoreceptor antagonists, neurokinin- 1 receptor antagonists, atypical anti-depressants, benzodiazepines, 5-HT_1A agonists or antagonists, especially 5-HT_IA partial agonists, and corticotropin releasing factor (CRF) antagonists. Specific agents include: amitriptyline, clomipramine, doxepin, imipramine and trimipramine; amoxapine, desipramine, maprotiline, nortriptyline and protriptyline; fluoxetine, fluvoxamine, paroxetine and sertraline; isocarboxazid, phenelzine, tranylcypromine and selegiline; moclobemide: venlafaxine; duloxetine; aprepitant; bupropion, lithium, nefazodone, trazodone and viloxazine; alprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam, halazepam, lorazepam, oxazepam and prazepam; buspirone, flesinoxan, gepirone and ipsapirone, and pharmaceutically acceptable sails thereof.

The compounds of the present invention may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant), by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration. In addition to the treatment of warm- blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats, monkeys, etc., the compounds of the invention are effective for use in humans.

Pharmaceutical compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. Compositions for oral use may also be presented as hard gelatin capsules wherein the active ingredients are mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil Aqueous suspensions, oily suspensions, dispersible powders or granules, oil-in-water emulsions, and sterile injectable aqueous or oleagenous suspension may be prepared by standard methods known in the art.

The subject compounds are further useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the diseases, disorders and conditions noted herein. The dose of the active ingredient in the composition may be varied, however, it is necessary that the amount of the active ingredient be such that a suitable dosage form is obtained. The active ingredient may be administered to patients (animals and human) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. The selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of the treatment. The dose will vary from patient to patient depending upon the nature and severity of disease, the patient's weight, special diets being adhered to by the patient, concurrent medication, and other factors which those skilled in the art will recognize. Generally, dosage levels between 0.01 to 10 mg/kg of body weight daily are administered to the patient, e.g., humans and elderly humans. The dosage range will generally be about 0.5 mg to 1.0 g per patient per day which may be administered in single or multiple doses. In one embodiment, the dosage range will be about 0.5 mg to 500 mg per patient per day; in another embodiment about 0.5 mg to 200 mg per patient per day; and in yet another embodiment about 5 mg to 50 mg per patient per day. Pharmaceutical compositions of the present invention may be provided in a solid dosage formulation such as comprising about 0.5 mg to 500 mg active ingredient, or comprising about 1 mg to 250 mg active ingredient. The pharmaceutical composition may be provided in a solid dosage formulation comprising about 1 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg or 250 mg active ingredient. For oral administration, the compositions may be provided in the form of tablets containing 1.0 to 1000 mg of the active ingredient, such as, 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 20O₅ 250, 300, 400, 500, 600, 750, 800, 900, and 1000 mg of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered on a regimen of 1 to 4 times per day, preferably in a regimen of once or twice per day.

The compounds of the invention had activity in inhibiting the human PDElO enzyme as described in the biological assay that follows, generally with a Ki of less than about 1 μM. Many of the compounds within the present invention had activity in inhibiting the human PDElO enzyme in the aforementioned assay, generally with a Ki of less than about 0.1 μM. Such a result is indicative of the intrinsic activity of the compounds in use as inhibitors of the PDElO enzyme. In general, one of ordinary skill in the art would appreciate that a substance is considered to effectively inhibit PDElO activity if it has a Ki of less than or about 1 μM, preferably less than or about 0.1 μM. The present invention also includes compounds within the generic scope of the invention which possess activity as inhibitors of other phosphodiesterase enzymes.

In the table that follows, the PDElO Ki is a measure of the ability of the test compound to inhibit the action of the PDEl 0 enzyme. To determine the selectivity of the test compounds for PDElO, the Ki of the compound was determined for PDEs 1-5, 7-9, and 11. In the table that follows, the selectivity is defined as the Ki of the test compound for the most potently inhibited PDE other than PDElO, divided by the Ki for PDElO. The PDE enzyme most potently inhibited other than PDElO is listed.

TABLE 2

Several methods for preparing the compounds of this invention are illustrated in the following Schemes and Examples. Starting materials and the requisite intermediates are in some cases commercially available, or can be prepared according to literature procedures or as illustrated herein. The compounds of this invention may be prepared by employing reactions as shown in the following schemes, in addition to other standard manipulations that are known in the literature or exemplified in the experimental procedures. Substituent numbering as shown in the schemes does not necessarily correlate to that used in the claims and often, for clarity, a single substituent is shown attached to the compound where multiple substituents are allowed under the definitions hereinabove. Reactions used to generate the compounds of this invention are prepared by employing reactions as shown in the schemes and examples herein, in addition to other standard manipulations such as ester hydrolysis, cleavage of protecting groups, etc., as may be known in the literature or exemplified in the experimental procedures. Starting materials are made according to procedures known in the art or as illustrated herein.

In some cases the final product may be further modified, for example, by manipulation of substituents. These manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylatϊon, and hydrolysis reactions which are commonly known to those skilled in the art. In some cases the order of carrying out the foregoing reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products. The following examples are provided so that the invention might be more fully understood. These examples are illustrative only and should not be construed as limiting the invention in any way.

While the invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various adaptations, changes, modifications, substitutions, deletions, or additions of procedures and protocols may be made without departing from the spirit and scope of the invention.

EXAMPLES The following abbreviations are used herein: Me: methyl; Et: ethyl; t-Bu: tert- butyl; Ar: aryl; Ph: phenyl; Bn: benzyl; Ac: acetyl; THF: tetrahydrofuran; DEAD: diethylazodicarboxylate; DIPEA: N,N-dϋsopropylethylamine; DMSO: dimethylsulfoxide; EDC: N-β-DimethylaminopropyO-N'-ethylcarbodiimide; HOAT: 1- hydroxy-7-aza-benzotriazole; HOBT: hydroxybenzotriazole hydrate; Boc: tert-butyloxy carbonyl; Et₃N: triethylamine; DCM: dichloromethane; DCE: dichloroethane; BSA: bovine serum albumin; TFA: trifluoracetic acid; DMF: N,N-dimethylformamide; MTBE: methyl tert-butyl ether;SOCl₂: thionyl chloride; CDI: carbonyl diimidazole; it: room temperature; HPLC: high performance liquid chromatography.

Several methods for preparing the compounds of this invention are illustrated in the following Schemes and Examples. Starting materials are made according to procedures known in the art or as illustrated herein. In some cases the final product may be further modified, for example, by manipulation of substituents. These manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, and hydrolysis reactions which are commonly known to those skilled in the art. In some cases the order of carrying out the foregoing reaction schemes and examples may be varied to facilitate the reaction or to avoid unwanted reaction products.

The following examples are provided so that the invention might be more fully understood. These examples are illustrative only and should not be construed as limiting the invention in any way.

GENERAL SCHEMES The subject compounds of the invention can be made according to the following general schemes. According to Scheme A, anthranilic acid (or alternatively a l-amino-2- carboxy-heterocycle) can be coupled in one pot to an aliphatic carboxylic acid with triphenylphosphite, followed by addition of aniline (or an amino-substituted heterocycle) to provide compounds A-I of the current invention.

Scheme A

A-1

In Scheme B, if the R group of A-I contains a phthalimide, it can be removed by refluxing in EtOH with hydrazine to provide primary amine B-I. This can be converted to substituted phthalimide B-2 by refluxing in dioxane with the appropriate phthalic anhydride. If B-2 contains a nucleophilic group (such as a phenol), it can be further functionalized by alkylation to provide B-3. If B-2 contains an arylbromide, it can be reacted under Suzuki or Stille conditions to provide B-4.

Scheme B

dioxane, reflux

B-2 (ifR = OH)

B-3

B-4

EXAMPLE 1

P(0Ph)3, pyridine, 100⁰C

A-1 2- (2- [3-(4-metfaoxyphenyl)-4-ρxo-3,4-dihydroquiiiazoliii-2-yl]etfayϊ } - 1 Jf-isoindole- 1 ,3 f 2H)- dione (A-I)

Anthranilic acid (2.0 g, 14.6 mmol), 3-phthalimidopropionic acid (3.2 g, 14.6 mmol), and triphenylphosphite (4.0 mL, 15.3 mmol) were dissolved in pyridine (20 mL) and heated in a sealed tube at 100⁰C for 2 hours. After cooling to room temperature, the tube was opened, p-anisidine (2.7 g, 21.9 mmol) was added and heating at 100°C was resumed for 4 hours. The pyridine was removed by azeotroping with toluene, and the residue was suspended in CHCI3 and toluene. The solids that crashed out were removed, and the residue was purified by silica gel chromatography with gradient elution (0 to 100% EtOAc in hexanes). A white solid precipitated from several of the fractions which was isolated by filtration to provide A-I (2.23g, 36%). Data for A-I : LRMS: calculated M + H for C25H19N3O4: 426.14; Found: 426.16.

EXAMPLE 2

dioxane, reflux

2-(2-aminoethyl)-3-(4-methoxyphenyl)qmrtazolin-4(3H)-one (B- 1 )

To a suspension of A-I (2.23 g, 5.2 mmol) in EtOH (50 mL) was added hydrazine (495 μL, 15.7 mmol) and approximately 100 μL of water and the mixture was heated at reflux for 3 hours. After cooling to room temperature, the solids were removed and the filtrate was concentrated by rotary evaporation. The residue was suspended in EtOAc (150 mL) and the solids were again filtered. The filtrate was concentrated to provide B-I (1.5 g, 97% yield) as a beige semi-solid. Data for B-I : LRMS: calculated M + H for Ci₇H_nN₃O₂: 296.13; Found:

296.25.

4-hydroxy-2- (2-[3 -f4-methoxyphenyl)-4-oxo-3 ,4-dihydroquinazoϋn~2-yl] ethyl } - 1 H-isoindple-

U(2flVdione (B-2)

To a solution of B-I (155 mg, 0.52 mmol) in 1,4-dioxane (2mL) was added 3- hydroxyphthalic anhydride (86 mg, 0.52 mmol). The vial was sealed and heated to 80⁰C overnight. The solvents were removed, the residue dissolved in CΗC13, and purified by column chromatography (0 to 100% EtOAc in hexanes) to provide B-2 (135 mg, 58%) as a pale orange solid. Data for B-2: HRMS (ES) calculated M + H for C25H19N3O5: 442.1397; Found: 442.1394.

4-methoxy-2- {2-[3-(4-methoxvphenyl)-4-oxo-3,4-dihydroqumazolin-2-yl]ethyl} - lH-isoindole- 1.3f2flVdione fB-3)

To a solution of B-2 (39 mg, 0.088 mmol) in CH₃CN (2 mL) was added K2CO3

(86 mg, 0.27 mmol) and iodomethane (8.3 μL, 0.14 mmol). The vial was sealed and heated at 65 °C for 1 hour. The solids were filtered off, the solvent removed, and the residue was dissolved in CHCI3, and purified by column chromatography (0 to 100% EtOAc in hexanes) to provide B- 3 (18 mg, 45%) as a white solid. Data for B-3: HRMS (ES) calculated M + H for C20H21N3O5: 456.1554; Found: 456.1554.

EXAMPLE 3

C-I C-2

2- ( 2- [3 -f 4-methoxyphenyl)-4-oxo-3.4-dihydroqumazolin-2-yl]ethvl } -4-( 1 ,3 -oxazol-2-y I)- 1 H- isomdole-L3(2/JVdione (C-2) A solution of C-I (50 mg, 0.1 mmol), 2-(tπ-w-butylstannyl)oxazole (43 nig, 0.12 mmol), and tetrakis(txiphenylphospine)palladium(0) (11.5 mg, 10 μmol) was sealed in a microwave vial and heated in a microwave reactor at 140⁰C for 20 minutes. The residue was loaded directly onto a silica column and purified by column chromatography (0 to 100% EtOAc in hexanes) to provide C-2 (32 mg, 66%) as a colorless taffy. Data for C-2: HRMS (ES) calculated M + H for C28H20N4O5: 493.1506; Found: 493.1515.

EXAMPLE 4

D-I D-2

P(OPh)₃, pyridine 100°C, sealed tube; then: X)Bn

D-3 D-4

H₂N'

TMSBr

TFA₁ thioanisole, 0°C

D-6

D-5

D-7 terl-butyl 3-(4-hydroxy-l ,3-dioxo-l 3-dihydro-2H-isoindol-2-yl)propanoate (D-2)

D-I (2.0 g, 11.01 mmol) and 3-hydroxyphthalic anhydride (1.9 g, 11.56 mmol) were suspended in dioxane (10 mL). TEA (4.6 mL_s 33 mmol) was added to the suspension and heated to 50⁰C overnight. After cooling, the solution was diluted with EtOAc (150 mL) and washed with water (100 mL) and concentrated brine (100 mL). The organic layer was dried over Na2SO4 and concentrated to provide D-2 (2.1g, 65.5% yield) as an off-white solid. tert-butyl 3-(4-isopropoxy-L3-dioxo-l ,3-dihydro-2/iT-isoindol-2-yl)proρanoate (D-3)

D-2 (I g, 3.43 mmol) was suspended in acetonitrile (25 ml) in a sealed tube. While stirring, 2-iodopropane (687 μL, 6.87 mmol) and cesium carbonate (3.36 g, 10.30 mmol) were added. The tube was capped and heated to 8O⁰C for 4 hours. After cooling to room temperature, the reaction was diluted with EtOAc (150 mL) and washed with water (100 mL) and concentrated brine (10OmL). The organic layer was dried over Na2SO4 and concentrated to provide crude residue which was purified by column chromatography with gradient elution (0- 100% EtOAc in Hexanes) to provide D-3 (835 g, 73.1%) as a white solid. Data for D-3: LRMS: calculated M + H for C18H23NO5: 334.38; Found: 334.49.

3 -(4-isopropoxy-l ,3-dioxo-l ,3-dihydro-2H-isoindol-2-yl)propanoic acid (D-4)

D-3 (835 g, 2.50 mmol) was dissolved in DCM (5 mL) and TFA (5 mL) and stirred at room temperature for 2 hours. Solvents were removed and the residue azeotroped with toluene. This provided D-4 (690 g, 100%) as an off-white solid. Data for D-4: LRMS: calculated M + H for C14H15NO5: 278.27; Found: 278.62.

2-(2- { 3- [4-(benzyloxy)phenyl J-4-QXQ-3 ,4-dihydroquinazolin-2-yU ethyl)-4-isopropoxy- 1 H- isoindole-1.3f2ffl-dione (D-5) Anthranilic acid (1.0 g, 7.29 mmol), D-4 (2.02 g, 7.29 mmol), and triphenylphosphite (2.01 mL, 7.66 mmol) were dissolved in pyridine (20 mL) and heated in a sealed tube at 100⁰C for 2 hours. After cooling to room temperature, the tube was opened, 4- benzyloxyaniline hydrochloride (1.89 g, 8.02 mmol) was added and heating at 100⁰C was resumed for 4 hours. The pyridine was removed by azeotroping with toluene, and the residue was suspended in CHCI3 and toluene. The solids that crashed out were removed, and the residue was purified by silica gel chromatography with gradient elution (0 to 100% EtOAc in hexanes) to provide D-5 (1.9 g, 46%) as a while solid. Data for D-5: HRMS (ES) calculated M + H for C34H29N3O5: 560.2180; Found: 560.2195.

2- { 2- [3 -(4-hydroxyphenyl)-4-oxo-3 ,4-dihydroquinazolin-2-yl]ethyl } -4-isopropoxy- 1 H-isoindole- 1.3f2ffl-dione fl>-6)

A solution of thioanisole (6 mL, 50.0 mmol) and bromotrimethylsilane (1.62 mL, 12.5 mmol) in TFA (10 mL) was prepared at O⁰C. D-5 (1.4 g, 2.5 mmol) was added and stirred at 0⁰C for 3 hours. The reaction was then warmed to room temperature and diluted with EtOAc (200 mL). After washing with 2 times with saturated NaHCO3 (250 mL) followed by saturated brine (250 mL), the organic layer was dried over Na2SO4 and concentrated to provide crude residue. This was diluted with chloroform and purified by column chromatography with gradient elution (0 to 100% EtOAc in Hexanes) to provide D-6 (.575 g, 49%) as a white solid. Data for D- 6: HRMS (ES) calculated M + H for C27H23N3O5: 470.1710; Found: 470.1720.

4-isρρro poxy-2- { 2- [3 -(4-methoxyphenyl)-4-oxo-3 ,4-dihydroq uinazolin-2-yl j ethyl }-\H- isoindole-1.3(2/fl-dione (D-7)

D-6 (35 mg, .075 mmol) was suspended in acetonitrile (2 ml) in a vial. While stirring, iodomethane (6.99 μL, .122 mmol) and cesium carbonate (73 mg, .224 mmol) were added. The vial was capped and heated to 8O⁰C for 4 hours. After cooling to room temperature, the reaction was diluted with EtOAc (30 mL), washed with water (25 mL), then brine (25 mL), dried over Na2SO4 and concentrated to provide crude material. This was diluted with chloroform and purified by column chromatography with gradient elution (0 to 100% EtOAc in Hexanes) to provide D-7 (28 mg, 76%) as a white solid. Data for D-7: HRMS (ES) calculated M + H for C28H25N3O5: 484.1867; Found: 484.1858.

EXAMPLE 5

2-methoxy-iV- { 2-[3 -(4~methoxyphenyl)-4~oxo-3 ,4-dihydroquinazolin-2-yl] ethyl I benzamide (F-I)

To a solution of B-I (43 mg, 0.15 mmol) in 1 mL DMF was added 2- methoxybenzoic acid (27 mg, 0.18 mmol), HOAT (29 mg, 0.19 mmol), triethylamine (61 μL, 0.4 mmol), and EDC (34 mg, 0.18 mmol). The mixture was stirred at 40⁰C for 3 hours, poured into EtOAc, washed with saturated aqueous NaHCθ3, washed twice with brine, dried over Na2SO4 and concentrated by rotary evaporation. The crude material was purified by reverse-phase HPLC (water/acetonitrile, 0.1% TFA), the fractions containing the product were basified with saturated aqueous NaHCO3, extracted into EtOAc, washed with brine, dried over Na2SO4 and concentrated to provide F-I as a colorless film. Data for F-I: HRMS (ES) calculated M + H for C25H23N3O4: 430.1761; Found: 430.1753.

EXAMPLE 6

tube;

G-I

G-2

2-(2-[3-(I /f-indazol-6-vI V7-methyl-4-oxo-3.4-dihvdroquinazol in-2-yl] ethvl I -4~f proρan-2- yloχy)-lH-isoindote43f2HVdione (G-I)

2-Amino-4-methylbenzoic acid (150 mg, 0.99 mmol), D-4 (275 mg, 0.99 mmol), and triphenylphosphite (286 μL, 1.1 mmol) were dissolved in 1 mL DMF, and heated in a sealed vial at 100⁰C for 2 hours. After cooling to room temperature, the tube was opened, 6- aminoindazole (132 mg, 0.99 mmol) was added and heating at 100⁰C was resumed for 4 hours. After cooling to room temperature, the reaction was partitioned between EtOAc and saturated NaHCθ3. After separation, the organic layer was washed with brine, dried over Na₂SO₄, and concentrated by rotary evaporation. The residue was purified by silica gel chromatography with gradient elution [0 to 100% 1:1 (EtOAc/20: l :l EtOHTNH₄OHZH₂O) in hexanes] to provide G-I (302 mg, 60%) as a brown solid. Data for G-I : HRMS (ES) calculated M + H for C29H25N5O4: 508.1979; Found: 508.1983.

2-12- f7-methyl-3 -( 1 -methyl- 1 H-indazol-6-γl V 4-oxo-3 ,4-dmydroquinazolin-2- vli ethvU -4- (propan-2-yloxy)- 1 /f-isoindole- 1 ,3 (2i/)-dione (G-2)

A solution of G-I (150 mg, 0.30 mmol), iodomethane (18.5 μL, 0.3 mmol) and trϊethylamine (excess) in 1 mL of DMF was heated at 4O⁰C for several hours. The crude reaction was purified by reverse phase chromatography (CH₃CN/H₂O plus TFA as modifier) to provide G-2 (26 mg, 34%), the first eluting regioisomer, as a white solid. Data for G-2: LC/MS: rt = 1.3 min; m/z (M + H) - 522.4. IH NMR (500 MHz, CDCl₃): δ 8.15 (m, IH), 8.05 (m, IH), 7.85 (m, IH), 7.55 (m, IH), 7.4 - 7.25 (m, 4H), 7.15 (m, IH), 7.05 (m, IH), 4.7 (m, IH), 4.1 (m, 2H), 4.1 (s, 3H), 2.75 (m, 2H), 2.5 (s, 3H), 1.4 (dd, 6H) ppm.

EXAMPLE 7

Biological Example - Florescence Polarization Assay

The activity of the compounds in accordance with the present invention as PDElO inhibitors may be readily determined without undue experimentation using a fluorescence polarization (FP) methodology well known in the art (Huang, W., et al., J, Biomol Screen, 2002, 7: 215). In particular, the compounds of the Examples had activity in reference assays by exhibiting their ability to inhibit the hydrolysis of the phosphate ester bond of a cyclic nucleotide. Any compound exhibiting a Ki (inhibitory constant) below 1 μM would be considered a PDElO inhibitor as defined herein.

In atypical experiment the PDElO inhibitory activity of the compounds of the present invention was determined in accordance with the following experimental method. PDE10A2 was amplified from human fetal brain cDNA (Clontech, Mountain View, CA) using a forward primer corresponding to nucleotides 56-77 of human PDEl 0A2 (Accession No. AFl 27480, Genbank Identifier 4894716), containing a Kozak consensus sequence, and a reverse primer Corresponding to nucleotides 2406-2413 of human PDE10A2 (Accession No. AF 127480, Genbank Identifier 4894716). Amplification with Easy-A polymerase (Stratagene, La Jolla, CA) was 95⁰C for 2 minutes followed by thirty three cycles of 95°C for 40 seconds, 55⁰C for 30 seconds, and 72⁰C for 2 minutes 48 seconds. Final extension was 72⁰C for 7 minutes. The PCR product was TA cloned into pcDNA3.2-TOPO (Invitrogen, Carlsbad, CA) according to standard protocol.

AD293 cells with 70-80% confluency were transiently transfected with human PDE10A2/pcDNA3.2-TOPO using Lipofectamine 2000 according to manufacturer specifications (Invitrogen, Carlsbad, CA). Cells were harvested 48 hours post-transfection and lysed by sonication (setting 3, 10 X 5 sec pulses) in a buffer containing 20 mM HEPES, 1 mM EDTA and protease inhibitor cocktail (Roche). Lysate was collected by centrifugation at 75,000 xg for 20 minutes. Supernatant containing the cytoplasmic fraction was used for evaluation of PDE10A2 activity.

The fluorescence polarization assay for cyclic nucleotide phosphodiesterases was performed using an MAP® FP kit supplied by Molecular Devices, Sunnyvale, CA (product # R8139). IMAP® technology has been applied previously to phosphodiesterase assays (Huang, W., et al., J. Biomol Screen, 2002, 7: 215). Assays were performed at room temperature in 384- well microliter plates with an incubation volume of 20.2 μL. Solutions of test compounds were prepared in DMSO and serially diluted with DMSO to yield 8 μL of each of 10 solutions differing by 3-fold in concentration, at 32 serial dilutions per plate. 100% inhibition is determined using a known PDElO inhibitor, which can be any compound that is present at 5,000 times its Ki value in the assay described as follows, such as papaverine (see Siuciak, et al. Neuropharmacology (2006) 51 :386-396; Becker, et al. Behav Brain Res (2008) 186(2): 155-60; Threlfell, et al., J Pharmacol Exp Ther (2009) 328(3):785™795), 2-{4-[pyridin-4-yl-l -(2,2,2- txifluoroethyl)-lH-pyrazol-3-yl]phenoxymethyl}quinoline succinic acid or 2-[4~(l~methyl-4- pyridin-4-yl-lH-pyrazol~3-yl)-phenoxymethyl]quinoline succinic acid (see Schmidt, et al. J Pharmacol Exp Ther (2008) 325:681-690; Threlfell, et al., J Pharmacol Exp Ther (2009) 328(3): 785-795). 0% of inhibition is determined by using DMSO (1% final concentrations).

A Labcyte Echo 555 (Labcyte, Sunnyvale, CA) is used to dispense 200 nL from each well of the titration plate to the 384 well assay plate. A solution of enzyme (1/1600 dilution from aliquots; sufficient to produce 20% substrate conversion) and a separate solution of FAM- labeled cAMP PDE from Molecular Devices (product # R7506), at a final concentration of 50 nM are made in the assay buffer (10 mM Tris HCl, pH 7.2, 10 mM MgCl2, 0.05% NaN3 0.01% Tween-20, and 1 mM DTT). The enzyme and the substrate are then added to the assay plates in two consecutive additions of 10 μL, and then shaken to mix. The reaction is allowed to proceed at room temperature for 30 minutes. A binding solution is then made from the kit components, comprised of 80% Solution A, 20% Solution B and binding reagent at a volume of 1/600 the total binding solution. The enzymatic reaction is stopped by addition of 60 μL of the binding solution to each well of the assay plates and the plates are sealed and shaken for 10 seconds. The plate was incubated at room temperature for at least one hour prior to determining the fluorescence polarization (FP).

The parallel and perpendicular fluorescence of each well of the plate was measured using a Perkin Elmer En Vision™ plate reader (Waltham, MA).

Fluorescence polarization (raP) was calculated from the parallel (S) and perpendicular (P) fluorescence of each sample well and the analogous values for the median control well, containing only substrate (So and Po), using the following equation:

Polarization (mP) - 1000*(S/So-P/Po)/(S/So+P/Po).

Dose-inhibition profiles for each compound were characterized by fitting the mP data to a four-parameter equation given below. The apparent inhibition constant (Ki), the maximum inhibition at the low plateau relative to "100% Inhibition Control" (Imax; e.g. 1=> same as this control), the minimum inhibition at the high plateau relative to the "0% Inhibition Control" (Imin, e.g. 0=> same as the no drug control) and the Hill slope (nH) are determined by a non-linear least squares fitting of the mP values as a function of dose of the compound using an in-house software program based on the procedures described by Mosser et al, JALA, 2003, 8: 54-63, using the following equation:

_ (QVotnP - 100%mP)(Imax-- Imin) ,_{ΛΛn / n} ,_{Λn/ n} i_ΛΛny_r»w,_τ ■, mP = + l00%røP + (0%mP -10O⁰AmP)(I - Imax)

The median signal of the "0% inhibition controls" (0%mP) and the median signal of the "100% inhibition controls" (100%mP) are constants determined from the controls located in columns 1-2 and 23-24 of each assay plate. An apparent (K_1n) for FAM-labeled cAMP of 150 nM was determined in separate experiments through simultaneous variation of substrate and selected drug concentrations,

EXAMPLE 8 Biological Example - Selectivity Assay

Selectivity for PDElO, as compared to other PDE families, was also assessed using the IMAP® technology. Rhesus PDE2A3 and Human PDE10A2 enzyme was prepared from cytosolic fractions of transiently transfected HEK cells. AH other PDE's were GST Tag human enzyme expressed in insect cells and were obtained from BPS Bioscience (San Diego, CA): PDElA (Cat# 60010), PDE3A (Cat# 60030), PDE4A1 A (Cat# 60040), PDE5A1 (Cat# 60050), PDE6C (Cat# 60060), PDE7A (CaI* 60070), PDE8A1 (Cat# 60080), PDE9A2 (Cat# 60090), PDEl 1 A4 (Cat# 60110).

Assays for PDE 1 through 11 were performed in parallel at room temperature in 384-well microtiter plates with an incubation volume of 20.2 μL. Solutions of test compounds were prepared in DMSO and serially diluted with DMSO to yield 30 μL of each often solutions differing by 3-fold in concentration, at 32 serial dilutions per plate. 100% inhibition was determined by adding buffer in place of the enzyme and 0% inhibition is determined by using DMSO (1% final concentrations). A Labcyte POD 810 (Labcyte, Sunnyvale, CA) was used to dispense 200 nL from each well of the titration plate to make eleven copies of the assay plate for each titration, one copy for each PDE enzyme. A solution of each enzyme (dilution from aliquots, sufficient to produce 20% substrate conversion) and a separate solution of FAM- labeled cAMP or FAM-labeled cGMP from Molecular Devices ( Sunnyvale, CA₅ product # R7506 or cGMP#R7508), at a final concentration of 50 nM were made in the assay buffer (10 mM Tris HCl, pH 7.2, 10 mM MgCl₂, 0.05% NaN₃ 0.01% Tween-20, and 1 niM DTT). Note that the substrate for PDE2 is 50 nM FAM cAMP containing 1000 nM of cGMP. The enzyme and the substrate were then added to the assay plates in two consecutive additions of 10 μL and then shaken to mix. The reaction was allowed to proceed at room temperature for 60 minutes. A binding solution was then made from the kit components, comprised of 80% Solution A, 20% Solution B and binding reagent at a volume of 1/600 the total binding solution. The enzymatic reaction was stopped by addition of 60 μL of the binding solution to each well of the assay plate. The plates were sealed and shaken for 10 seconds. The plates were incubated at room temperature for one hour, then the parallel and perpendicular fluorescence was measured using a

Tecan Genios Pro plate reader (Tecan, Switzerland). The apparent Inhibition constants for the compounds against all 11 PDE's was determined from the parallel and perpendicular fluorescent readings as described for PDElO FP assay using the following apparent K_M values for each enzyme and substrate combination: PDElA (FAM cGMP) 70 nM, rhesus PD2A3 (FAM cAMP) 10,000 nM, PDE3A (FAM cAMP) 50 nM, PDE4A1A (FAM cAMP) 1500 nM, PDE5A1 (FAM cGMP) 400 nM_s PDE6C (FAM cGMP) 700 nM, PDE7A (FAM cAMP) 150 nM, PDE8A1 (FAM cAMP) 50 nM, PDE9A2 (FAM cGMP) 60 nM, PDE10A2 (FAM cAMP) 15OnM, PDEl 1A4 (FAM cAMP) 1000 nM.

Claims

WHAT IS CLAIMED:

1. A compound of formula I:

wherein:

A is selected from the group consisting of

(1) C3_io cycloalkyl,

(2) C6-10 aryl,

(3) C5-10 heteroaryl, and (4) C5-.10 heterocyclyl; wherein said cycloalkyl, aryl, heteroaryl, and helerocyclyl is each optionally substituted with 1 to 3 groups of R^a; Ar is selected from the group consisting of

(1) -(CH₂)_nC3-10 cycloalkyl, (2) -(O)P(CH₂)_UCo-IO aTyI,

(3) -(CH2)nC5- 1 Q heteroaryl, and

(4) -(CH₂)nC5-10 heterocyclyl, wherein said cycloalkyl , aryl, heteroaryl, and heterocyclyl is each optionally substituted with 1 to 3 groups of R^a; R is selected from the group consisting of

(1) -(CH2)_nC5-10 heteroaryl,

(2) -(CH2)_nC5- 10 heterocyclyl,

(3) -(CH2)nNR2C(O)NR2R3, and

(4) -(CH₂)_nNR2C(O)R3 wherein each is optionally substituted with 1 to 3 groups of R^a;

R2 and R3 are each independently selected from the group consisting of

(1) hydrogen,

(2) hydroxyl, (3) -C 1-6 alkylj which is unsubstituted or substituted with one or more halogen,

(4) -(CH₂)nCF₃,

(5) -(CH2)nF,

(6) -Cs-io cycloalkyl, (7) -C6-lθ axyl,

(8) -C5-10 heteroaryl, and

(9) -Cs-io heterocyclyl, wherein said cycloalkyl, aryl, heterocycyl, or heteroaryl is each optionally substituted with 1 to 3 groups of Ra; R^a is selected from the group consisting of

(1) halogen,

(2) hydroxyl,

(3) -Ci _6 alkyl, which is unsubstituted or substituted with one or more halogen,

(4) -C3-6 cycloalkyl, (5) -NR2C(O)R2,

(6) -C(O)N(R2)_2}

(7) -C(R2)2OR2,

(8) -C(O)R2,

(9) -NO₂, (10) -CN,

(11) -N(R2)₂,

(12) -C(O)OR2,

(13) -OR2,

(14) -(CH₂)nC₅-10 heterocyclyl, (15) -(CH₂)_nC6-10 aryl, and

(16) -(CH₂)_nC5_ 10 heteroaryl, wherein said heterocyclyl, aryl, and heteroaryl are each optionally substituted with 1 to 3 groups of

(a) halogen, (b) hydroxyl, (C) -Ci-6 alkyl,

(d) -CN,

(e) -(CH₂)nCF₃, or

(f) -C6-10 aryl; n is independently 0 to 4; and p is independently 0 or 1 ; and pharmaceutically acceptable salts thereof.

2. A compound of claim 1 , and pharmaceutically acceptable salts thereof, wherein A and Ar is -(CH2)nC6-10 ^h^eacn optionally substituted with 1 to 3 groups of Ra and all other variables are as previously described.

3. A compound of claim 2, and pharmaceutically acceptable salts thereof, wherein n is 2 and R is -(CH2)nC5-10 heterocyclyl selected from the group consisting of (1) indole, and

(2) phthalimidyl

4. A compound of claim 1, and pharmaceutically acceptable salts thereof, wherein A is phenyl, represented by formula Ha

Ha wherein:

Ar is selected from the group consisting of

(1) phenyl, (2) indole,

(3) indazole, and

(4) biphenyl wherein each is optionally substituted with 1 to 3 groups of R^a;

R is selected from the group consisting of (1) -(CH₂)nC5-10 lieteroaryl,

(2) -(CH2)_nC5- 10 heterocyclyl, and

(3) -NR2C(O)NR2R3, where each is optionally substituted with 1 to 3 groups of R^a; R2 and R3 are each independently selected from the group consisting of

(1) hydrogen,

(2) hydroxyl,

(3) -Ci-C₆ alkyl,

(4) -(CH₂)_nCF₃, (5) -(CH2)nF,

(6) cycloalkyl, and

(7) -C6-Cio aryl, wherein said cycloalkyl or aryl is optionally substituted with 1 to 3 groups of R^; R^a is selected from the group consisting of

(1) halogen,

(2) hydroxyl,

(3) -Ci _6 alkyl,

(5) -C3-6 cycloalkyl,

(6) -NR2C(O)R2,

(8) ~C(R2)₂OR2,

(9) -C(O)R2,

(10) -(R2)₂C(O),

(H) -NO₂,

(12) -CN,

(14) -C(O)OR2,

(15) -OR2,

(16) -(CH2)nC5-10 heterocyclyl, (17) -(CH2)_nC6-10 aryl, and

(18) -(CH2)_nC5-10 heteroaryl, wherein said heterocyclyl, aryl, and (CH2)nC5-lO heteroaryl is optionally substituted with 1 to 3 groups of (a) halogen,

(b) hydroxyl,

(C) -Ci-6 alkyl,

(d) -CN₅ or

(e) (CH₂)_nCF3; and n represents 0 to 4.

5. A compound of claim 4 wherein Ar is -(CH2)nC6-10 aryl^and R is -(CH2)nC5-10 heterocyclyl, each optionally substituted with 1 to 3 groups of R^a and n is 1 to 3.

6. A compound of claim 5 wherein n is 1 to 3 and said ~(CH2)nC5-10 heterocyclyl is selected from the group consisting of

(1) indole, and

(2) phthalimidyL

7. A compound of claim 4 wherein R is (CH2)_ΠNR2C(O)NR²R3 optionally substituted with 1 to 3 groups of Ra and n is 1 to 3.

8. A compound of claim I, and pharmaceutically acceptable salts thereof, wherein A is pyridal, represented by formula lib

wherein:

Ar is selected from the group consisting of

(1) phenyl,

(2) indole, (3) indazole, and

(4) biphenyl wherein each is optionally substituted with 1 to 3 groups of R^a; R is selected from the group consisting of (1) -(CH2)nC5-10 heteroaryl> (2) -(CH2)_nC5- 10 heterocyclyl, and

(3) -NR2C(O)NR2R3, where each is optionally substituted with 1 to 3 groups of R^a; R2 and R3 are each independently selected from the group consisting of

(1) hydrogen, (2) hydroxy^

(3) -Ci-C₆ alkyl_>

(4) -CF₃,

(5) -CHF₂,

(6) -(CH2)nF₅ (7) cycloalkyl, and

(8) aryl, wherein said cycloalkyl or aryl is optionally substituted with 1 to 3 groups of R^a; R^a is selected from the group consisting of

(1) halogen, (2) hydroxyl,

(3) -Cμ₆ alkyl,

(5) -C3-6 cycloalkyl,

(6) -NR2C(O)R2,

(8) -C(R2)₂OR2, (9) ~C(O)R2,

(10) -(R2)₂C(O),

(H) -NO₂,

(12) -CN,

(14) -C(O)OR2_;

(15) -OR2_S

( 16) -(CH2)_nC5- 10 heterocyclyl ,

(17) -(CH₂)nC6-10 aryl, and (18) -(CH2)_nC5- 10 heteroaryl, wherein said heterocyclyl, aryl, and (CH2)nC5-10 heteroaryl is optionally substituted with 1 to 3 groups of

(a) halogen,

(b) hydroxyl, (c) -Ci-6 alkyl_;

(d) -CN, or

(e) (CH₂)_nCF₃; and n represents 0 to 4.

9. A compound of claim 8 wherein Ar is -(CH2)nC6-l 0 aryϊ ^d R is

-(CH2)nC5-10 heterocyclyl, each optionally substituted with 1 to 3 groups of R^a and n is 1 to 3.

10. A compound of claim 9 wherein n is 1 to 3 and said -(CH2)nC5-10 heterocyclyl is selected from the group consisting of (1) indole, and

(2) phthalimidyl.

11. A compound of claim 8 wherein R is (CH2)_ΠNR2C(O)NR2R3 optionally substituted with 1 to 3 groups of Ra and n is 1 to 3.

12. A compound which is selected from the group consisting of:

2- { 2- [3 -(4-methoxyphenyl)-4-oxo- 3 ,4-dihydropyrido [2 , 3 ~ιi]pyrimidin-2-yl] ethyl } - 1 H-isoindole- l,3(2H)-dione,

2- [2-(3~biphenyl- 3 -yl~4-oxo-3 ,4-dihydroquinazolin-2-yl)ethyl] ~ 1 H-isoindole- 1 ,3 (2H)-dione, 2- { 2- [7-chloro-3 -(4-methyϊρhenyl)-4-oxo-3 ,4-dihydroquinazolm-2-yl] ethyl } - 1 H-isoindole- l,3(2H)-dione,

2- { 2- [3 -(4-methoxypheny l)-4-oxo- 3 ,4-dihydroquinazolin-2-yl] ethyl } -4-methyl- 1 H-isoindole- l,3(2H)-dione,

2-{2-[3-(4-methoxyphenyl)-4-oxo-3_J4-dihydroquinazolin-2-yl]ethyl}-5-methyl-l/f-isoindole- l,3(2H)-dione,

2- {2- [3-(4-methoxyphenyl)-4-oxo-3 ,4-dihydroquinazolin-2-yl] ethyl } - 1 ,3-dioxoisoindoline~4- carbonitrile,

4-methoxy-2- {2- [7-methoxy- 3 -(3 -raethylphenyl)-4-oxo-3 ,4-dihydroquinazo lin-2-yl] ethyl } - IH - isoindole-1 ,3(2iT)-dione_; 4-methoxy-2- {2- [3-(4-methoxyphenyl)-7-methyl-4-oxo-3 ,4-dihydroquinazolin-2~yl] ethyl } - IH- isoindole-1 ,3(2H)-dione, ter/-butyl 3 - { 2-[3 -(4-methoxyphenyl)-4-oxo-3 ;,4-dihydroquinazolin-2-yl] ethyl } - 1 H-indole- 1 - carboxylate, iV-biphenyl-2-yl-Λ^r - { 2- [3 ~(4-methoxyphenyl)-4-oxo-3 ,4-dihydroquinazol in-2-yl]ethyl } urea, 4-isopropoxy-2- {2- [3 -(4-methoxyphenyl)-4-oxo-3 ,4-dihydropyrido [2,3-<3]pyrimidin-2-yl]ethyl } - lH-isoindole- 1 ,3 (2H)-dione,

2-(2- { 3 - [4-(2-fluoroethoxy)phenyl] -4-oxo-3 ,4-dihydroquinazolin-2-yl } ethyl)-4-i sopropoxy- 1 H- isoindole- 1 ,3 (2H)-dione,

2- {2- [3 -( 1 H-indol-6-yl)-7-methoxy-4-oxo-3 ,4-dihydroquinazolin-2-yl] ethyl } -4-isopropoxy- 1 H- isoindole- 1 ,3 (2H)-dione ,

4-isopropoxy-2-{2-[7-methoxy-3-(3"methylphenyl)-4-oxo-3,4~dihydroquinazolin-2-yl]ethyl}- lH-isoindole-1₅3(2H)-dione,

2- {2- [3 -( 1 H-indazol-6-yl)-4-oxo~3 ,4-dihydropyrido [2,3-d]pyrimidin-2-yl] ethyl } -4-isopropoxy-

1 H-isoindole- 1 β (2H)-dione, 2- {2- [3 -(4-methoxyphenyl)-4-oxo-3 ,4-dihydroquinazolin-2-yl]ethyl } -4-pyridin-4-yl- 1 H- isoindole-1 ,3(2H)-dione,

2- { [3 -(4-methoxyphenyl)-4-oxo-3 ,4-dihydroquinazolin-2-yl]methyl } - 1 H-isoindole- 1 ,3 (2H)- dione, 2- (3 -[3 -(4-methoxyphenyl)-4-oxo-3 ,4-dihydroquinazolin-2-yI] propyl } - 1 H~isoindo Ie- 1 , 3 (2H)- dione,

2- {2-[3 -(4-meilioxyphenyl)-4-oxo-3 ,4-dihydroquinazolin-2-yI] ethyl } - 1 H-isoindole- 1 ,3 (2H)- dione, 4-hydroxy~2- { 2- [3-(4-methoxyphenyl)-4-oxo-3 ,4-dihydroquinazolin-2-yl]ethyl} - 1 H-isoindole- l,3(2H)-dione,

4-methoxy-2- {2- [3 -(4-methoxyphenyl)-4-oxo-3 ,4-dihydroquinazolin-2-yl] ethyl } - 1 H-isoindole- l,3(2H)-dione,

2-{2-[3-(4-methoxyphenyl)-4-oxo-3_J4-dihydroquinazolin-2-yl]ethyl}-4-(l,3-oxazol-2-yl)-lif- isoindole-l,3(2H>dione,

2-(2- { 3 -[4-(benzyloxy)phenyl] -4-oxo-3 ,4-dihydroquinazolin-2-yl } ethyl)-4-isoρroρoxy- 1 H- isoindole- 1 ,3(2H)-dione,

2- { 2- [3 -(4-hydroxyphenyl)~4-oxo-3 ,4-dihydroquinazolin-2-yl] ethyl } -4-isoρroρoxy- 1 H-isoindole- l,3(2H)-dione, 4-isopropoxy-2- { 2- [3 -(4-methoxyphenyl)-4-oxo-3 ,4-dihydroquinazolin-2-yl] ethyl } - 1 H- isoindole- 1 ,3(2H)-dione,

4-isopropoxy-2- { 2- [3 -(4-¹¹ C-methoxyphenyl)-4-oxo-3 ,4-dihydroquinazolin-2-yl] ethyl } - 1 H- isoindole-l,3(2H)-dione, and

2-methoxy-N- { 2- [3 -(4-methoxyphenyl)-4-oxo-3 ,4-dihydroquinazolin-2-yl] ethyl } benzamide,

2- { 2- [3 -( 1 H-indazol-6-yI)-7-methyl-4-oxo-3 ,4-dihydroquinazolin-2-yl] ethyl } -4-(propan-2- yloxy)- 1 H-isoindole- 1 ,3 (2H)-dione,

2- { 2- [7-methyl-3 -(I -methyl- lH~indazol-6-yl)-4-oxo-3 ,4-dihydroquinazolin-2-yl] ethyl } -A-

(propan-2-yloxy)- 1 H-isoindole- 1_s3(2H)-dione, 2- { 2- [3 -(4-methoxyphenyl)-4-oxo-3 ,4-dihydroquinazolin-2-yl]ethyl } -4-(2,2,2-trifluoroethoxy)-

1 H-isoindole- 1 ,3 (2H)-dione,

4-(cycloproρylmethoxy)-2- {2- [3 -(4-methoxyphenyl)-4-oxo-3 ,4-dihydroquinazolin-2-yl] ethyl } -

1 Η-isoindole- 1 ,3 (2Η)-dione,

4-(cyclobutyloxy)-2-{2-[3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-lH~ isoindole- 1 , 3(2H)~dione,

2-{2-[3-(4-methoxyphenyl)-7-methyl-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl]etliyl}-4-

(2,2,2-trifluoroethoxy)-lH-isoindole-l,3(2H)-dione, 4-melhoxy-2- {2- [3-( 1 -methyl- 1 H-indazol-6-yi)~4-oxo-3 ,4-dihydroquinazolin-2-yl]ethyl } - 1 H- isoindole-1 ,3(2H)-dione,

2- { 2- [3 -(4-methoxyphenyl)-7-meihyl-4-oxo-3 , 4-dihydropyrido [2,3 -d] pyrimidin-2-yl] ethyl } -A- (propan-2-yloxy)- lH-isoindoϊe-1 ,3(2H)-dione, 2-[2-(3-cyclohexyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl]-4-(propan-2-yloxy)- 1 H-isoindole- l,3(2H)-dione, and pharmaceutically acceptable salts thereof.

13. A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and a compound of Claim 1 or a pharmaceutically acceptable salt thereof.

14. Use of a compound of Claim 1 , or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disorder selected from psychotic disorders, delusional disorders and drug induced psychosis; anxiety disorders, movement disorders, mood disorders, and neurodegenerative disorders.

15. A method for treating a neurological or psychiatric disorder associated with PDElO dysfunction in a mammalian patient in need thereof which comprises administering to the patient a therapeutically effective amount of a compound of Claim 1 or a pharmaceutically acceptable salt thereof.

16. A method for treating a neurological or psychiatric disorder associated with striatal hypofunction or basal ganglia dysfunction in a mammalian patient in need thereof which comprises administering to the patient a therapeutically effective amount of a compound of Claim 1 or a pharmaceutically acceptable salt thereof.