WO2006090273A2 - [1,8]naphthyridin-2-ones and related compounds with keto or hydroxyl linkers for the treatment of schizophrenia - Google Patents

Abstract

Compounds of formula (I) are disclosed. A of formula 1 is -(CH2)mCO- or -(CH2)mCOH-, wherein m is an integer from 2 to 5 and wherein one or two of the carbon atoms can be substituted as described in the specification. G, D, Z, Q, X, Y, R1, and R4 through R7 of formula 1 are defined in the specification. Also provided are descriptions of processes for preparing compounds of formula 1, intermediates used in making the same, and pharmaceutical compositions containing such compounds and their use in the treatment of central nervous system disorders and other disorders.

Description

[l,8]NAPHTHYRIDIN-2-ONES AND RELATED COMPOUNDS WITH KETO OR HYDROXYL LINKERS FOR THE TREATMENT OF SCHIZOPHRENIA

BACKGROUND OF THE INVENTION

This invention relates to [l,8]naphthyridin-2-ones and related compounds with keto or hydroxyl linkers, methods of making such compounds, pharmaceutical compositions containing them, and their use for the treatment of schizophrenia and other central nervous system (CNS) disorders.

The [l,8]naphthyridin-2-ones and related compounds of this invention bind to dopamine D₂ receptors. Some exhibit activity as partial agonists of D₂ receptors, while others exhibit activity as antagonists of such receptors. Other heterocyclic derivatives that are useful for the treatment of schizophrenia are referred to in United States patent 5,350,747, which issued on September 27, 1994; in United States patent 6,127,357, which issued on October 3, 2000; in WO 93/04684, which published on March 18, 1993; and European patent application EP 402644A, which was published on December 19, 1990. The foregoing patents and patent applications are incorporated herein by reference in their entireties.

SUMMARY OF THE INVENTION

The present invention relates to compounds of the formula 1

(i) (ϋ)

A is -(CH₂)_mC0-, or -(CH₂)_mCOH-, wherein m is an integer from 2 to 5 and wherein one or two of the carbon atoms of A can be substituted, optionally and independently, with one or two substituents that are selected, independently, from fluoro and methyl, or with two substituents attached to the same carbon atom that form, together with the carbon to which they are attached, a spirocyclopropyl or spirocyclobutyl ring;

D is N, C, or CH, provided that when D is N, each carbon atom attached to D is attached through a single bond;

J and K are independently selected from N, CH, and C, provided that at least one of J and K is N;

Z and Q are independently selected from N, C, and CH, provided that at least one of Z and Q is N;

-X=T- is -CH₂-CH₂-, -CH=CH-, -CH₂-NH-, -NH-CH₂-, -N=CH-, -CH=N-, -0-CH₂-, or -CH₂-O-, wherein -X^^^Υ- can optionally be substituted, at any available bonding site, by one to four substituents R², R² , R³ and R³ ;

V and W are independently N, C, or CH; ring AA is a saturated or unsaturated 5- 6- or 7-membered carbocyclic ring wherein one, two or three of the carbon atoms of ring AA that are not shared with the benzo ring of group (ii) can be replaced, optionally and independently, by a nitrogen, oxygen or sulfur atom;

R¹ is hydrogen, -C(=O)CH₃, or (C₁-C₃) alkyl;

R , R , R and R are independently selected from hydrogen, halo, cyano, oxo, hydroxy, -C(=O)CH₃, (C₁-C₄) alkyl, and (C₁-C₄) alkoxy, wherein the alkyl moieties of the (C₁-C₄) alkyl, (C₁-C₄) alkoxy, and -C(=O)CH₃ groups can be optionally substituted with from one to three fluoro atoms and can also be optionally substituted with an amino or hydroxy substituent;

R⁴ and R⁵ are independently selected from hydrogen, halo, cyano, hydroxy, -C(=O)CH₃, (C₁-C₄) alkyl, and (C₁-C₄) alkoxy, wherein the alkyl moieties of the (C₁-C₄) alkyl, (C₁-C₄) alkoxy, and -C(=O)CH₃ groups can be optionally substituted with from one to three fluoro atoms and can also be optionally substituted with an amino or hydroxy substituent;

R⁶ and R⁷ are selected, independently, from hydrogen and methyl; R⁸, R⁹, R¹⁰, R¹¹, and R¹² are independently selected from hydrogen, halo, -

C(=O)CH₃, (C₁-C₄) alkyl, and (C₁-C₄) alkoxy, aryl, and aryloxy, wherein the alkyl moieties of the (C₁-C₄) alkyl, (C₁-C₄) alkoxy, and -C(=O)CH₃ groups and the aryl and aryloxy moieties can be optionally substituted with from one to three fluoro atoms and can also be optionally substituted with an amino or hydroxy substituent;

R¹³ and R¹⁴ are independently selected from hydrogen, halo, cyano, oxo, hydroxy, -C(=O)CH₃, (C₁-C₄) alkyl, and (C₁-C₄) alkoxy, wherein the alkyl moieties of the (C₁-C₄) alkyl, (C₁-C₄) alkoxy, and -C(=O)CH₃ groups can be optionally substituted with from one to three fluoro atoms and can also be optionally substituted with an amino or hydroxy substituent; and the pharmaceutically acceptable salts of such compounds. This invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

The compounds of formula 1 have useful pharmaceutical and medicinal properties.

The invention also relates to a pharmaceutical composition for treating a disorder or condition selected from single episodic or recurrent major depressive disorders, dysthymic disorders, depressive neurosis and neurotic depression, melancholic depression; atypical depression; bipolar disorder; cyclothymic disorder; conduct disorder; disruptive behavior disorder; attention deficit hyperactivity disorder; behavioral disturbances associated with mental retardation, autistic disorder, and conduct disorder; anxiety disorders; borderline personality disorder; schizophrenia and other psychotic disorders; delirium, dementia, and amnestic and other cognitive or neurodegenerative disorders; movement disorders, dyskinesias; extra-pyramidal movement disorders; chemical dependencies and additions; behavioral addictions; and ocular disorders, comprising a therapeutically effective amount of a compound of formula 1, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

The invention further relates to a pharmaceutical composition for treating a disorder or condition selected from those enumerated above, comprising: (a) a compound of formula 1, or a pharmaceutically acceptable salt thereof; and (b) an antidepressant or an anti-anxiety agent; and (c) a pharmaceutically acceptable carrier; wherein the active agents (a) and (b) are not the same and are present in amounts that render the combination of the two active agents effective in treating said disorder or condition.

This invention also relates to a method of treating a disorder or condition selected from those listed above, comprising administering to a mammal in need of such treatment an amount of a compound of formula 1, or a pharmaceutically acceptable salt thereof, that is effective in treating the disorder or condition. The invention also relates to a method of treating a disorder or condition listed above, comprising administering to a mammal in need of such treatment: (a) a compound of formula 1, or a pharmaceutically acceptable salt thereof; and (b) an antidepressant or an anti-anxiety agent, wherein the active agents (a) and (b) are not the same and wherein said active agents are present in amounts that render the combination of both active agents effective in treating said disorder or condition.

The term "alkyl", as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof. Examples of "alkyl" groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, iso- sec- and tert-butyl, pentyl, hexyl, heptyl, 3-ethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and the like. The term "alkoxy", as used herein, unless otherwise indicated, means "alkyl-O-", wherein "alkyl" is as defined above. Examples of "alkoxy" groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy and pentoxy.

The term "aryl", as used herein, unless otherwise indicated, includes an aromatic ring system with no heteroatoms as ring members, which can be either unsubstituted or substituted with one, two or three substituents selected from the group consisting of halo, (C₁-C₄)alkyl optionally substituted with from one to three fluorine atoms and (C₁-C₄)alkoxy optionally substituted with from one to three fluorine atoms. The term "aryloxy", as used herein, unless otherwise indicated, means

"aryl-O-", wherein "aryl" is as defined above.

The term "one or more substituents", as used herein, refers to a number of substituents that equals from one to the maximum number of substituents possible based on the number of available bonding sites. The terms "halo" and "halogen", as used herein, unless otherwise indicated, include, fluoro, chloro, bromo and iodo.

The term "therapeutically effective amount," as used herein, refers to a quantity of active agent sufficient to treat one or more of the disorders or conditions referred to above, when one or more doses of a pharmaceutical composition of the invention are administered to a subject with one or more of the disorders or conditions. In determining what constitutes a therapeutically effective amount of an active agent in a composition or delivered in a method of the present invention, a number of factors will generally be considered, including the experience of the medical practitioner or veterinarian administering the composition, published clinical studies, the subject's age, sex, weight and general condition, as well as the type and extent of the disorder or condition being treated, and the use of other medications, if any, by the subject. Determination of a proper dose for a particular situation, and preparation of a pharmaceutical composition containing a suitable dose of active agent for that situation, is within the skill of the medical or veterinary arts.

The term "treating", as used herein, refers to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or preventing one or more symptoms of such condition or disorder. The term "treatment", as used herein, refers to the act of treating, as "treating" is defined immediately above.

The compounds of formula 1, and the pharmaceutically acceptable salts of these compounds are referred to herein, collectively, as the "novel compounds of this invention" and the "active compounds of this invention".

DETAILED DESCRIPTION OF THE INVENTION

Preferred embodiments of this invention relate to compounds of the formula 1, and their pharmaceutically acceptable salts, wherein G is a group of the formula ii and ring AA is a benzo ring. Other preferred embodiments of this invention relate to compounds of the formula 1, and their pharmaceutically acceptable salts, wherein A is -(CH₂)₄CO- or -(CEb)₄COH.

Other preferred embodiments of this invention relate to compounds of the formula 1, and their pharmaceutically acceptable salts, wherein -X⁼⁼⁼Y- is -CH₂-NH-.

Other preferred embodiments of this invention relate to compounds of formula 1 and their pharmaceutically acceptable salts, wherein G is naphthyl, and R¹³ and R¹⁴ are independently hydrogen or fluoro.

Other preferred embodiments of this invention relate to compounds of formula 1 and their pharmaceutically acceptable salts, wherein at least one of R¹³ or R¹⁴ is fluoro or methoxy.

Other preferred embodiments of this invention relate to compounds of the formula 1, and their pharmaceutically acceptable salts, wherein G is a group of a formula selected from:

Other preferred embodiments of this invention relate to compounds of the formula 1, and their pharmaceutically acceptable salts, wherein G is 2,3- dichlorophenyl.

Other preferred embodiments of this invention relate to compounds of the formula 1, and their pharmaceutically acceptable salts, wherein W and V are C or CH.

Other preferred embodiments of this invention relate to compounds of formula 1 and their pharmaceutically acceptable salts, wherein D is N, Q is N, Z is

CH, -X=T- is -CH₂-CH₂- or -CH=CH-. and R¹, R⁴, and R⁵ are hydrogen.

Other preferred embodiments of this invention relate to compounds of formula 1 and their pharmaceutically acceptable salts, wherein W and V are each, independently, C or CH, or wherein one of W and V is N and the other is C or CH.

Other preferred embodiments of this invention relate to compounds of formula 1 and their pharmaceutically acceptable salts, wherein Q and Z are both N.

Other preferred embodiments of this invention relate to compounds of the formula 1, and their pharmaceutically acceptable salts, wherein R⁴ and R⁵ are hydrogen.

Other preferred embodiments of this invention relate to compounds of the formula 1, and their pharmaceutically acceptable salts, wherein D is N. Other preferred embodiments of this invention relate to compounds of the formula 1, and their pharmaceutically acceptable salts, wherein Q is N and Z is C or CH.

Other preferred embodiments of this invention relate to compounds of the formula 1, and their pharmaceutically acceptable salts, wherein Q is N and Z is N.

Other preferred embodiments of this invention relate to compounds of the formula 1, and their pharmaceutically acceptable salts, wherein -X^^Y- is -CH₂-CH₂- or -CH=CH-.

Other preferred embodiments of this invention relate to compounds of the formula 1, and their pharmaceutically acceptable salts, wherein R is hydrogen.

Other embodiments of this invention relate to compounds of the formula 1, and their pharmaceutically acceptable salts, wherein Q is C or CH, and Z is N.

Other embodiments of this invention relates to compounds of the formula 1, and their pharmaceutically acceptable salts, wherein -X^zr=rY- is -O-CH₂-. Other embodiments of this invention relates to compounds of the formula 1, and their pharmaceutically acceptable salts, wherein -X=^Y- is -CH₂-O-.

Other embodiments of this invention relate to compounds of the formula 1 and their pharmaceutically acceptable salts, wherein G is a group of the formula (i) and W and V are both N, or W is N and V is C or CH. Specific embodiments of the invention relate to compounds of formula 1 and their pharmaceutically acceptable salts. These embodiments include the following compounds and their pharmaceutically acceptable salts. Procedures for synthesis of each of these compounds are illustrated in the Examples section, below. 7-[4-(4-Naphthalen-l-yl-piperazin-l-yl)-butyryl]-3,4-dihydro-lH-

[l,8]naphthyridin-2-one

7-[5-(4-Naphthalen-l-yl-piperazin-l-yl)-pentanoyl]-3,4-dihydro-lH- [1 ,8]naphthyridin-2-one

7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-l-yl]-pentanoyl}-3,4-dihydro-lH- [l,8]naphthyridin-2-one

7- { 5-[4-(7-Methoxy-naphthalen- 1 -yl)-piperazin- 1 -yl] -pentanoyl } -3 ,4- dihydro-lH-[l,8]naphthyridin-2-one 7-{5-[4-(7-Fluoro-naphthalen-l-yl)-piperazin-l-yl]-pentanoyl}-3,4-dihydro- lH-[l,8]naphthyridin-2-one

7- [5-(4-Indan-4-yl-piperazin- 1 -yl)-pentanoyl] -3 ,4-dihydro- IH- [ 1 ,8]naphthyridin-2-one 7- { 5-[4-(6-Isopropyl-pyridin-2-yl)-piperazin- 1 -yl] -pentanoyl } -3 ,4-dihydro-

IH-[1 ,8]naphthyridin-2-one

7-{5-[4-(5,6,7,8-Tetrahydro-naphthalen-l-yl)-piperazin-l-yl]-pentanoyl}- 3,4-dihydro- lH-[ 1 ,8]naphthyridin-2-one

7- { 5-[4-(7-Fluoro-naphthalen- 1 -yl)-piperazin- 1 -yl] - 1 -hydroxy-pentyl } -3 ,4- dihydro-lH-[l,8]naphthyridin-2-one

(+)7- { 5- [4-(7-Fluoro-naphthalen- 1 -yl)-piperazin- 1 -yl]- 1 -hydroxy-pentyl } - 3,4-dihydro-lH-[l,8]naphthyridin~2-one

(-)7-{5-[4-(7-Fluoro-naphthalen-l-yl)-piperazin-l-yl]-l-hydroxy-pentyl}- 3,4-dihydro-lH-[l,8]naphthyridin-2-one 7- { 5-[4-(2,3-Dichloro-phenyi)-piperazin-l -yl] - 1 -hydroxy-pentyl } -3 ,4- dihydro- IH-[1 ,8]naphthyridin-2-one

7- { 1 -Hydroxy-5-[4-(7-methoxy-naphthalen- 1 -yl)-piperazin- 1 -yl]-pentyl } - 3,4-dihydro-lH-[l,8]naphthyridin-2-one

Compounds of the formula 1 may contain chiral centers and therefore may exist in different enantiomeric and diastereomeric forms. This invention relates to all optical isomers and all stereoisomers of compounds of the formula 1, both as racemic mixtures and as individual enantiomers and diastereoisomers of such compounds, and mixtures thereof, and to all pharmaceutical compositions and methods of treatment defined above that contain or employ them, respectively. Individual isomers can be obtained by known methods, such as optical resolution, fractional crystallization, optically selective reaction, or chromatographic separation in the preparation of the final product or its intermediate. Individual enantiomers of the compounds of formula 1 may have advantages, as compared with the racemic mixtures of these compounds, in the treatment of various disorders or conditions. In so far as the compounds of formula 1 are basic compounds, they are all capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate the base compound from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert to the free base compound by treatment with an alkaline reagent and thereafter convert the free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent or in a suitable organic solvent, such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is readily obtained. The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds of this invention are those which form non-toxic acid addition salts, Le₁, salts containing pharmaceutically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bi-tartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (Le₁, l,l'-methylene-bis-(2- hydroxy-3-naphthoate)) salts.

The present invention also includes isotopically labeled compounds, which are identical to those of formula 1, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹¹C, ¹⁴C, ¹⁵N, ¹⁸0, ¹⁷0, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively. Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically labeled compounds of the present invention, for example those into which radioactive isotopes such as ³H and ¹⁴C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, UJ₁, ³H, and carbon- 14, i^, ¹⁴C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, Le₁, ²H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds of formula 1 and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

The pharmaceutical compositions and methods of the present invention are suitable for use in treatment of a disease or disorder selected from single episodic or recurrent major depressive disorders, dysthymic disorders, depressive neurosis and neurotic depression, melancholic depression including anorexia, weight loss, insomnia, early morning waking or psychomotor retardation; atypical depression

(or reactive depression) including increased appetite, hypersomnia, psychomotor agitation or irritability, seasonal affective disorder and pediatric depression; bipolar disorders or manic depression, for example, bipolar I disorder, bipolar II disorder and cyclothymic disorder; conduct disorder; disruptive behavior disorder; attention deficit hyperactivity disorder (ADHD); behavioral disturbances associated with mental retardation, autistic disorder, and conduct disorder; anxiety disorders such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobias, for example, specific animal phobias, social anxiety, social phobia, obsessive-compulsive disorder, stress disorders including post-traumatic stress disorder and acute stress disorder, and generalized anxiety disorders; borderline personality disorder; schizophrenia and other psychotic disorders, for example, schizophreniform disorders, schizoaffective disorders, delusional disorders brief psychotic disorders, shared psychotic disorders, psychotic disorders with delusions or hallucinations, psychotic episodes of anxiety, anxiety associated with psychosis, psychotic mood disorders such as severe major depressive disorder; mood disorders associated with psychotic disorders such as acute mania and depression associated with bipolaf disorder; mood disorders associated with schizophrenia; delirium, dementia, and amnestic and other cognitive or neurodegenerative disorders, such as Parkinson's disease (PD), Huntington's disease (HD), Alzheimer's disease, senile dementia, dementia of the Alzheimer's type, memory disorders, loss of executive function, vascular dementia, and other dementias, for example, due to HTV disease, head trauma, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt- Jakob disease, or due to multiple etiologies; movement disorders such as akinesias, dyskinesias, including familial paroxysmal dyskinesias, spasticities, Tourette's syndrome, Scott syndrome, PALSYS and akinetic-rigid syndrome; extra-pyramidal movement disorders such as medication- induced movement disorders, for example, neuroleptic-induced Parkinsonism, neuroleptic malignant syndrome, neuroleptic-induced acute dystonia, neuroleptic- induced acute akathisia, neuroleptic-induced tardive dyskinesia and medication- induced postural tremor; chemical dependencies and addictions (e.g., dependencies on, or addictions to, alcohol, heroin, cocaine, benzodiazepines, nicotine, or phenobarbitol) and behavioral addictions such as an addiction to gambling; and ocular disorders such as glaucoma and ischemic retinopathy in a mammal in need of such treatment, including a human, comprising an amount of a compound of the formula 1, or a pharmaceutically acceptable salt thereof, that is effective in treating such disorder or condition, and a pharmaceutically acceptable carrier.

In a specific embodiment of the methods or pharmaceutical compositions of the present invention, the disorder or condition treated is selected from major depression, single episode depression, recurrent depression, child abuse induced depression, postpartum depression, dysthymia, cyclothymia and bipolar disorder. In another more specific embodiment of the methods or pharmaceutical compositions of the present invention, the disorder or condition treated is selected from schizophrenia, schizoaffective disorder, delusional disorder, substance- induced psychotic disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition, and schizophreniform disorder.

In another more specific embodiment of the methods or pharmaceutical compositions of the present invention, the disorder or condition that is being treated is selected from autism, pervasive development disorder, speech impediments such as stuttering, and attention deficit hyperactivity disorder. In another more specific embodiment of the methods or pharmaceutical compositions of this invention, the disorder or condition that is being treated is selected from generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder, and phobias, including social phobia, agoraphobia, and specific phobias.

In another more specific embodiment of the methods or pharmaceutical compositions of this invention, the disorder or condition that is being treated is selected from movement disorders such as akinesias, dyskinesias, including familial paroxysmal dyskinesias, spasticities, Tourette's syndrome, Scott syndrome, PALSYS and akinetic-rigid syndrome; and extra-pyramidal movement disorders such as medication-induced movement disorders, for example, neuroleptic-induced Parkinsonism, neuroleptic malignant syndrome, neuroleptic- induced acute dystonia, neuroleptic-induced acute akathisia, neuroleptic-induced tardive dyskinesia and medication-induced postural tremor.

In another more specific embodiment of the methods or pharmaceutical compositions of this invention, the disorder or condition that is being treated is selected from delirium, dementia, and amnestic and other cognitive or neurodegenerative disorders, such as Parkinson's disease (PD), Huntington's disease (HD), Alzheimer's disease, senile dementia, dementia of the Alzheimer's type, memory disorder, vascular dementia, and other dementias, for example, due to HTV disease, head trauma, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt- Jakob disease, or due to multiple etiologies. In another more specific embodiment of the methods of the present invention, the compound of formula 1 is administered to a human for the treatment of any two or more comorbid disorders or conditions selected from those disorders and conditions referred to in any of the above methods.

In embodiments of the pharmaceutical compositions of the present invention, comprising (a) a compound of formula 1, or a pharmaceutically acceptable salt thereof, and (b) an antidepressant or an anti-anxiety agent, as described above, or in methods of the present invention comprising administering active agents (a) and (b), examples of classes antidepressants suitable for use in the invention include norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs), NK-I receptor antagonists, monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase (REVIAs), serotonin and noradrenaline reuptake inhibitors (SNRIs), corticotropin releasing factor (CRF) antagonists, α-adrenoreceptor antagonists, and atypical antidepressants. Suitable norepinephrine reuptake inhibitors include tertiary amine tricyclics and secondary amine tricyclics. Suitable tertiary amine tricyclics and secondary amine tricyclics include amitriptyline, clomipramine, doxepin, imipramine, trimipramine, dothiepin, butripyline, iprindole, lofepramine, nortriptyline, protriptyline, amoxapine, desipramine and maprotiline. Suitable selective serotonin reuptake inhibitors include fluoxetine, fluvoxamine, paroxetine and sertraline. Examples of monoamine oxidase inhibitors include isocarboxazid, phenelzine, and tranylcyclopramine. Suitable reversible inhibitors of monoamine oxidase include moclobemide. Suitable serotonin and noradrenaline reuptake inhibitors of use in the present invention include venlafaxine. Suitable CRF antagonists include those compounds described in International Patent Application Nos. WO 94/13643, WO 94/13644, WO 94/13661, WO 94/13676 and WO 94/13677. Suitable atypical anti-depressants include bupropion, lithium, nefazodone, trazodone and viloxazine. Suitable NK-I receptor antagonists include those referred to in World Patent Publication WO 01/77100.

Suitable classes of anti-anxiety agents that can be used in combination with the compounds of formula 1 in the pharmaceutical compositions and methods of this invention include benzodiazepines and serotonin IA (5-HT_1A) agonists or antagonists, especially 5-HT_1A partial agonists, and corticotropin releasing factor (CRF) antagonists. Suitable benzodiazepines include alprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam, halazepam, lorazepam, oxazepam, and prazepam. Suitable 5-HT_1A receptor agonists or antagonists include buspirone, flesinoxan, gepirone and ipsapirone. The compounds of this invention may be prepared as described below.

Unless otherwise indicated, in the reaction schemes and discussion that follow, A, Z, D, W, Q, ring AA, G, X, Y, R¹ through R¹⁴, formula 1, the dotted line connecting X and Y, and groups of the formulas (i) and (H) are defined as above. Scheme A

oxidation

1A

Scheme A illustrates a method for preparing compounds of the formula 1 wherein A is -(CH₂)_mCO-, optionally substituted as indicated in the definition of formula 1 above (also referred to as compounds of the formula IA). This method involves oxidation of a compound of the formula 2 with Dess-Martin Periodinane or another suitable oxidizing agent such as IBX (o-iodoxybenzoic acid), oxalyl chloride in dimethyl sulfoxide (DMSO) (Swera oxidation) or PCC (pyridinium chlorochromate) to form the corresponding aldehyde of formula 3. This reaction may be carried out in dichloromethane (CH₂Cl₂), tetrahydrofuran (THF), DMSO, or a combination of two or more of these solvents. Reductive amination of a G- substituted piperidine or piperizine, as shown in Scheme A, using methods well known to those of skill in the art, with a compound of formula 3 yields the corresponding compound of formula IA. The reductive amination can be performed, for example, utilizing catalytic hydrogenation methods or using a hydride reducing agent such as sodium triacetoxyborohydride (NaBH(OAc)₃) or sodium cyanoborohydride. The reaction solvent can be 1,2-dichloroethane, tetrahydrofuran, acetonitrile, dimethylformamide (DHF), or a combination of two or more of these solvents, with the optional addition of 1-10 equivalents of acetic acid. When the piperazine or piperidine hydrochloride or hydrobromide salt is used, a base such as triethylamine is typically added. Scheme B

reduction

1A 1B

Scheme B illustrates a method for preparing compounds of the formula IB. Compounds of the formula IA can be reduced with a reducing agent such as sodium borohydride, aluminum isopropoxide, sodium, zinc, or through hydrogenation with a palladium catalyst, preferably with sodium borohydride. Solvents such as THF, DMF, methanol, methylene chloride and ethanol (EtOH) can be used, preferably methanol to yield compounds of the formula IB.

Scheme C

Conversion to the

Weinreb Amide

8

Scheme C illustrates a method for preparing compounds of the formula 8. Alkoxycarbonylation of a compound of the formula 5, wherein R₁₃ is chloro, bromo, iodo or triflate, in methanol using iron containing palladium catalysts, such as l,r-bis(diphenylphosphino)ferrocene(dppf) like bis(dppf)palladium(π)chloride dichloromethane complex (either formed in situ via ligand exchange or pre-formed), or nickel complexes provides the corresponding compound of formula 6. R₁₃ is most preferably chloro and the catalyst is most preferably bis(dppf)palladium(II)chloride dichloromethane complex. This reaction is conducted sometimes in the presence of a base such as triethyl amine, Hunig's base, or diisopropyl ethylamine. The temperature of the reaction may vary from about ambient temperature to about the reflux temperature of the solvent used and carbon monoxide gas is added under pressure (for example, at 500 psi). The reaction of the compound of formula 6 with a base like potassium hydroxide, sodium hydroxide, or lithium hydroxide yields the compound of formula 7, as described above, is preferably conducted using potassium hydroxide. Suitable solvents for this reaction are methanol, THF, dioxane, dimethylformamide or N-methylpyrrolidinone.

Compounds of the formula 7 are converted to the acid chloride using conventional conditions of oxalyl chloride, thionyl chloride, or phosgene with catalytic organic bases like triethyl amine or Hunig's base in organic solvent, preferably methylene chloride or THF. The resulting acid chloride is treated with N,O-dimethyl hydroxylamine in methylene chloride, THF, or dioxane to yield the weinreb amide or compounds of formula 8.

Scheme D

deprotection

2 Scheme D illustrates a method for preparing compounds of the formula 2.

Compounds of formula 8 are treated with the protected alkyl lithium reagent, Li(CHa)_nO-TBS, wherein TBS is tert-butyldimethylsilyl-, and n is an integer from 1 to 4, under dry conditions in THF or dioxane, preferably THF. Where the lithium reagent is not commercially available, it is made in situ using lithium wire and the appropriate alkyl chloride at temperatures from -30 °C to ambient temperature. The temperature of the coupling reaction may vary from about ambient temperature to -78 °C. The resulting compounds of the formula 9 are then deprotected to yield the corresponding compounds of formula 2. This reaction is typically run in the presence of a fluorine source like tetrabutyl ammonium fluoride (TBAF), potassium fluoride, pyridine-HF, triethylamine-HF or HF, preferably TBAF. Typical solvents include acetonitrile, water, THF, dioxane, chloroform, cyclohexane, methanol or ethanol, preferably THF. Catalytic acetic acid or 18-crown-6 in the case of potassium fluoride helps to increase yields. The temperature of the reaction can range from about ambient temperature to about the reflux temperature of the solvent.

Scheme E

Scheme E illustrates an alternative method for preparing compounds of the formula 5A (1) (J. Org. Chem. 1990, 55, 4744). (Compounds of the formula 5A (1) are compounds of the formula 5 wherein X is CR³, Y is CR² and there is a double bond between X and Y). Ortho metalation of compounds of the formula 14 and subsequent treatment with electrophiles having the formula shown in Scheme F results in compounds of the formula 15. Condensation of compounds of the formula 15 with the enolates of the alkyl esters having the formula shown in Scheme E provides the corresponding compounds of formula 16. Refluxing compounds of the formula 16 in aqueous acid such as 3N hydrochloric acid, with the optional use of a co-solvent such as dioxane, generates the corresponding compounds of formula 5A (1). Scheme F

Scheme F illustrates a method for preparing compounds of the formula 5B-1, 5B-2 and 5B-3. Ortho metalation of compounds of the formula 14, as described in Scheme E, and subsequent treatment with 3-oxopropionic acid esters of the formula shown in Scheme F above provides the corresponding compounds of formula 19. The reaction can be conducted in a solvent such as tetrahydrofuran at temperatures ranging from about -78°C to about ambient temperature, preferably from about -78°C to about -20⁰C. Refluxing compounds of the formula 19 in an aqueous acid such as 3N hydrochloric acid, with the optional use of a co-solvent such as dioxane, generates the corresponding compounds of formula 5B-1. Compounds of the formula 5B-2 can be prepared by treating the corresponding compounds of the formula 5B-1 with triethylsilane in trifluoroacetic acid at a temperature from about room temperature to the reflux . temperature of the solvent. Compounds of the formula 5B-3 can be prepared by treating compounds of the formula 5B-1 with an oxidizing agent such as Dess Martin periodinane, EBX or PCC at about ambient temperature in a solvent such as dichloromethane, dichloroethane, THF or DMSO, or a combination of two or more of these solvents. Scheme G

20

X = O, S, NH

Scheme G illustrates a method for preparing compounds of the formula 5B

(4) (see PCT Patent Application WO 02/056882). Alkylation of compounds of the formula 20 with an ester of the formula shown in Scheme G (L = Br, I, Cl, OMs, OTs) yields the corresponding compounds of formula 21. This reaction is typically run in the presence of a base such as potassium carbonate or sodium hydride, in a solvent such as acetonitrile, THF, dioxane, acetone, methyl isobutyl ketone, benzene, toluene or DMF, or a combination of two or more of these solvents. The temperature of the reaction may vary from about ambient temperature to about the reflux temperature of the solvent. The nitro group of compounds of the formula 21 can be reduced with iron powder and acetic acid, with or without the addition of a solvent such methanol or water, at temperatures from about room temperature to about the reflux temperature of the solvent mixture used. These conditions also result in ring closure to yield compounds of the formula 5B (4).

Scheme H

X^^NH ₂

Scheme H illustrates a method for preparing compounds of the formula 5B-5. Compounds of the formula 22 can be heated with liquid ammonia in a sealed reaction vessel at temperatures of about 40⁰C to about 100°C, in a solvent such as THF, to yield compounds of the formula 23. Reduction of the ester of compound 23 to the corresponding alcohol, using lithium aluminum hydride (LiAlH₄), under conventional conditions well known to those of skill in the art, followed by oxidation of the alcohol with an oxidizing agent such as barium manganate, manganese dioxide, IBX, Dess Martin periodinane, or PCC, in a solvent such as dichloromethane, THF, or DMSO, or a combination of two or more of these solvents, yields the corresponding aldehydes of formula 24. Compounds of the formula 24 can then be reacted with (carbethoxymethylene)triphenylphosphorane or a similar Wittig reagent in a solvent such as dichloromethane, chloroform, THF, benzene or toluene, at a temperature from about room temperature to about the reflux temperature of the solvent, to give the corresponding compounds of formula 25. In the case of barium manganate, the oxidation and the Wittig reaction can be carried out using a one-pot procedure (/. Org. Chem. 1998, 63, 4489). Hydrogenation of compounds of the formula 25, using methods known to those skilled in the art, for example, as described above, preferably using palladium on barium sulfate in a solvent such as THF, provides the corresponding amino esters. The resulting amino esters can be cyclized to give compounds of the formula 5B(5) by heating at a temperature from about 50°C to about the reflux temperature of the solvent, in a solvent such as ethanol, methanol or isopropanol, preferably with a catalytic amount of acid (i.e., TsOH) or base (i.e., DBU).

The preparation of other compounds of the formula 1 not specifically described in the foregoing experimental section can be accomplished using combinations of the reactions described above that will be apparent to those skilled in the art.

In each of the reactions discussed or illustrated above, pressure is not critical unless otherwise indicated. Pressures from about 0.5 atmospheres to about 5 atmospheres are generally acceptable, and ambient pressure, Le₁, about 1 atmosphere, is preferred as a matter of convenience.

The compounds of the formula 1 and the intermediates shown in the above reaction schemes can be isolated and purified by conventional procedures, such as recrystallization or chromatographic separation. he compounds of the formula 1 and their pharmaceutically acceptable salts, can be administered to mammals via either the oral, parenteral (such as subcutaneous, intravenous, intramuscular, intrasternal and infusion techniques), rectal, buccal or intranasal routes. In general, these compounds are most desirably administered in doses ranging from about 3 mg to about 600 mg per day, in single or divided doses (i.e., from 1 to 4 doses per day), although variations will necessarily occur depending upon the species, weight and condition of the patient being treated and the patient's individual response to said medicament, as well as on the type of pharmaceutical formulation chosen and the time period and interval at which such administration is carried out. However, a dosage level that is in the range of about 10 mg to about 100 mg per day is most desirably employed. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effects, provided that such higher dose levels are first divided into several small doses for administration throughout the day. he novel compounds of the present invention may be administered alone or in combination with pharmaceutically acceptable carriers or diluents by any of the routes previously indicated, and such administration may be carried out in single or multiple doses. More particularly, the novel therapeutic agents of this invention can be administered in a wide variety of different dosage forms, ij^, they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, suppositories, jellies, gels, pastes, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc. Moreover, oral pharmaceutical compositions can be suitably sweetened and/or flavored. In general, the weight ratio of the novel compounds of this invention to the pharmaceutically acceptable carrier will be in the range from about 1:6 to about 2:1, and preferably from about 1:4 to about 1:1. For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.

For parenteral administration, solutions of a compound of the present invention in either sesame or peanut oil or in aqueous propylene glycol may be employed. The aqueous solutions should be suitably buffered (preferably pH greater than 8) if necessary and the liquid diluent first rendered isotonic. These aqueous solutions are suitable for intravenous injection purposes. The oily solutions are suitable for intra-articular, intra-muscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art. his invention relates to methods of treating anxiety, depression, schizophrenia and the other disorders referred to in the description of the methods of the present invention, wherein a novel compound of this invention and one or more of the other active agents referred to above (e.g., an NKl receptor antagonist, tricyclic antidepressant, 5HT1D receptor antagonist, or serotonin reuptake inhibitor) are administered together, as part of the same pharmaceutical composition, as well as to methods in which such active agents are administered separately as part of an appropriate dose regimen designed to obtain the benefits of the combination therapy. The appropriate dose regimen, the amount of each dose of an active agent administered, and the specific intervals between doses of each active agent will depend upon the subject being treated, the specific active agent being administered and the nature and severity of the specific disorder or condition being treated. In general, the novel compounds of this invention, when used as a single active agent or in combination with another active agent, will be administered to an adult human in an amount from about 3 mg to about 300 mg per day, in single or divided doses, preferably from about 10 to about 100 mg per day. Such compounds may be administered on a regimen of up to 6 times per day, preferably 1 to 4 times per day, especially 2 times per day and most especially once daily. Variations may nevertheless occur depending upon the species of animal being treated and its individual response to said medicament, as well as on the type of pharmaceutical formulation chosen and the time period and interval at which such administration is carried out. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day.

A proposed daily dose of a 5HT reuptake inhibitor, preferably sertraline, in the combination methods and compositions of this invention, for oral, parenteral or buccal administration to the average adult human for the treatment of the conditions referred to above, is from about 0.1 mg to about 2000 mg, preferably from about 1 mg to about 200 mg of the 5HT reuptake inhibitor per unit dose, which could be administered, for example, 1 to 4 times per day. A proposed daily dose of a 5HT1D receptor antagonist in the combination methods and compositions of this invention, for oral, parenteral, rectal or buccal administration to the average adult human for the treatment of the conditions referred to above, is from about 0.01 mg to about 2000 mg, preferably from about 0.1 mg to about 200 mg of the 5HT1D receptor antagonist per unit dose, which could be administered, for example, 1 to 4 times per day.

For intranasal administration or administration by inhalation, the novel compounds of the invention are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurized container or nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch. Formulations of the active compounds of this invention for treatment of the conditions referred to above in the average adult human are preferably arranged so that each metered dose or "puff of aerosol contains 20 μg to 1000 μg of active compound. The overall daily dose with an aerosol will be within the range 100 μg to 10 mg. Administration may be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1, 2 or 3 doses each time.

The ability of the novel compounds of this invention to bind to the dopamine D₂ receptor can be determined using conventional radioligand receptor binding assays. All receptors can be heterologously expressed in cell lines and experiments conducted in membrane preparations from the cell lines using procedures outlined below. IC₅₀ concentrations can be determined by nonlinear regression of concentration-dependent reduction in specific binding. The Cheng- Prussoff equation can be used to convert the IC₅₀ to Ki concentrations.

Dopamine D? Receptor Binding Assay:

[³H]Spiperone binding to a membrane preparation from CHO-hD₂L cells is carried out in 250 μl of 50 mJVI Tris-HCl buffer containing 100 mM NaCl, 1 mM MgCl₂ and 1% DMSO at pH 7.4. Duplicate samples containing (in order of addition) the test compounds, 0.4 nM [³H]spiperone and approximately 12 μg protein are incubated for 120 minutes at room temperature. Bound radioligand is separated by rapid filtration under reduced pressure through Whatman GF/B glass fiber filters previously treated with 0.3% polyethyleneimine. Radioactivity retained on the filter is determined by liquid scintillation spectrophotometry. Title compounds of the Examples, below, were tested using the above assay, in which specific binding determined in the presence of 1 mM haloperidol was 95%. All of the title compounds exhibited Ki values less than or equal to 75 nM (see Tables 1 and 2, below). Preferred embodiments of compounds of the present invention preferably exhibit Ki values of no more than 100 nM, more preferably no more than 50 nM, even more preferably no more than 25 nM, most preferably no more than 10 nM.

D₂ intrinsic activity of title compounds of the Examples, below, was determined using the [³H] thymidine uptake assay described below.

[³H1Thvmidine Uptake Assay for D? Intrinsic Activity Cells are serum deprived by washing twice with 200 μl of serum-free media. 90 μl serum-free media was added to each well. The plates ware incubated for two to three hours. 10 μl of serum-containing media, as a positive control, vehicle (serum-free media), negative control (an antagonist) or test compounds and standards (10 μl of a 10 μM solution for a final concentration of 1 μM) in serum- free media were added to wells. The plates are returned to the incubator. Eighteen hours later [³H]thymidine is added (0.5 μCi/well in 10 μl of serum-free media) and the plates are returned to the incubator. Four hours later trypsin (0.25%) is added (100 μl/well). The plates are returned to the incubator, once again. One hour later the assay is terminated by rapid filtration through Whatman GF/C glass fiber filters. Filters are washed four times with 500 ml of 50 mM Tris-HCl pH 7.0 buffer, for example, using a Brandel MLR-96T cell harvester. Radioactivity remaining on the filters are estimated, for example, with a Wallac 1205 Betaplate liquid scintillation counter (50% efficiency). Intrinsic activity is defined as total uptake (1 μM

Quinpirole) minus serum-free media (no uptake). Test compounds are compared to 1 μM Quinpirole (full DA agonist), which was classified as 100% intrinsic activity. AU assays are preferably performed in triplicate, with each drug occupying one full column (8 wells) per plate. Compounds of the present invention preferably exhibit at least 1 % to up to

90% intrinsic activity, more preferably at least 10% to up to 90% activity, more preferably at least 10% to up to 80% activity, more preferably at least 20% to up to 60% intrinsic activity, even more preferably at least 30% to up to 50% intrinsic activity. Each of the title compounds produced as described in the Examples, below, were also tested using the above assay. See Table 1, below, for results obtained from each of the compounds tested. TABLE l

The following Examples illustrate the preparation of several compounds of the present invention. Melting points are uncorrected. NMR data are reported in parts per million and are referenced to the deuterium lock signal from the sample solvent. Any reference to a "title compound" in an example, below, refers to the compound named in the title of that particular example.

EXAMPLES

EXAMPLE 1

7-Oxo-5 ,6,7,8-tetrahydro-ri,81naphthyridine-2-carboxylic acid methyl ester

7-Chloro-lH-[l,8]naphthyridin-2-one (2 g, 11 mmol) was combined with triethylamine (1.1 g, 11 mmol) and bis (dppf) Pd (II) dichloride-dichloromethane complex (0.84 g, 1.0 mmol) in a 100 cc ss-reactor, purged with nitrogen and then with carbonmonoxide, pressurized to 500 psi, stirred and heated to 100 ⁰C for 15 h. The solution was purged with nitrogen and concentrated then triturated in ethanol. The product was isolated as a solid, (2.1 g, 10 mmol, 92.9%). MS: APCI: M+l: 205.1 (Exact Mass: 204.2). 7-Oxo-5,6,7, 8-tetrahydro-[l,81naphthyridine-2-carboxylic acid

7-Oxo-5,6,7,8-tetrahydro-[l,8]naphthyridine-2-carboxylic acid methyl ester (9.71 g, 47.1 mmol) and LiOH (3.9 g, 164 mmol) were stirred overnight in THF at room temperature. TLC showed disappearance of starting material so the reaction was concentrated and the residue was poured over ice water and neutralized with

HCl then NH₄OH. The solid that formed was collected via vacuum filtration and dried in vacuo then concentrated in toulene to remove water. The product was isolated as a white solid (8.56 g, 44.54 mmol, 94.5%). MS: APCI: M+l: 193.0 (Exact Mass: 192.17).

7-Oxo-5,6,7,8-tetrahvdro-ri ,81naphthyridine-2-carboxylic acid methoxy-methyl- amide

7-Oxo-5,6,7,8-tetrahydro-[l,8]naphthyridine-2-carboxylic acid (8.0 g, 41.6 mmol) was dilluted in 10 mL of CH₂Cl₂ with a drop of DMF, and oxalyl chloride (31.7 g, 249.8 mmol) was added at 0 ⁰C. The reaction was allowed to warm up to room temperature. LC-MS was taken of a small aliquot quenched in ethanol. Once the acid chloride had completely formed, after about 1 hour (h), the mixture was concentrated to remove excess oxalyl chloride then dilluted in CH₂Cl₂ and triethylamine was added dropwise at 0 °C and the N,O-dimethylhydroxylamine hydrochloride (4.46 g, 45.79 mmol) was added. The reaction mixture stirred for 1 h. The mixture was washed with 0.5 N HCl, brine, 5% sat. sodium bicarbonate, and brine. The organic layers were collected and dried over Na₂SO₄, filtered and concentrated. The crude product was purified using medium pressure liquid chromatography (MPLC) and a gradient of 100% CH₂Cl₂ to 100% ethyl acetate over 1 h. The product was isolated as a white powder, (3.92 g, 16.7 mmol, 40%).

MS: APCI: M+l: 236.1 (Exact Mass: 235.2).

7-r4-(tert-Butyl-dimethyl-silanyloxy)-butyrvn-3,4-dihvdro-lH-rL81naphthyridin-2- one 7-Oxo-5,6,7,8-tetrahydro-[l,8]naphthyridine-2-carboxylic acid methoxy-methyl- amide (2 g, 8.5 mmol) was dissolved in anhydrous THF (10 mL) in a dried 3 necked flask under nitrogen and cooled to - 78 ⁰C in an acetone dry ice bath before dropwise addition of 3-(t-butyldimethylsilyloxy)-l-propyllithium in cyclohexane (46.92 g, 51.0 mmol), (kept temperature below - 40 ⁰C during addition, reaction mixture turned brown). The reaction was monitored at - 78 deg and TLC was compared to the authentic sample. After 2 h the reaction mixture was warmed to 0 ⁰C and quenched with 50 mL sat. NH₄Cl. The organics were removed in vacuo and the residue was taken up in CH₂Cl₂, and washed with brine. The organic layer was collected and dried over Na₂SO₄, filtered and concentrated. The compound was purified using MPLC and a gradient of 100% CH₂Cl₂ to 100% ethyl acetate solution over 1 h. The compound was isolated as a white solid (2.31 g, 6.09 mmol, 71%). MS: APCI: M+l: 349.1 (Exact Mass: 348.5).

7-(4-Hvdroxy-butyryl)-3,4-dihvdro-lH-π,81naphthyridin-2-one

Tetrabutyl ammonium fluoride, (TBAF), (0.803 g, 3.070 mmol) was added slowly to a stirring solution of 7-[4-(tert-butyl-dimethyl-silanyloxy)-butyryl]-3,4- dihydro-lH-[l,8]naphthyridin-2-one (1.07 g, 3.07 mmol) and acetic acid (0.184 g,

3.07 mmol) in THF (30 mL) at 0 ⁰C. The reaction mixture stirred for 1 h and was followed by TLC. Product formed and the reaction was concentrated, washed with hexane; the residue was taken up in methylene chloride/ethyl acetate and put directly on the MPLC using a gradient of 100% CH₂Cl₂ to 100% ethyl acetate over 1 h. The compound was isolated as a white powder, (0.170 g, 0.725 mmol, 23.6%).

MS: APCI: M-I: 233.0 (Exact Mass: 234.2).

4-Oxo-4-(7-oxo-5,6,7,8-tetrahvdro-ri,81naphthyridin-2-yl)-butyraldehvde

7-(4-Hydroxy-butyryl)-3,4-dihydro-lH-[l,8]naphthyridin-2-one (140 mg, 0.59 mmol) was dissolved in DMSO (5 mL) and IBX (502 mg, 1.79 mmol) was added. The vial was heated to 80 °C and stirred for 1 h. The DMSO was poured into water and the mixture was extracted into ether and 1:1 ethyl acetate to ether. The organic layers were combined and purified using the MPLC and a gradient of 100% CH₂Cl₂ to 10% Methanol in ethyl acetate solution over 1 h. Isolated product (50 mg, 0.215 mmol, 36%). MS: APCI: M+l: 233.1 (Exact Mass: 232.2). EXAMPLE 2

7- r4-(4-NaphthaIen- 1 -yl-piperazin- 1 -vD-butyryll -3 ,4-dihydro- IH- F 1 ,81naphthyridin-2-one

The 4-Oxo-4-(7-oxo-5,6,7,8-tetrahydro-[l,8]naphthyridin-2-yl)- butyraldehyde (50 mg, 0.21 mmol) and 1-naphthalen-l-yl-piperazine hydrochloride

(53 mg, 0.21 mmol) were combined in methylene chloride and stirred in a vial over sieves for 10 min. Sodium triacetoxy borohydride (63 mg, 0.30 mmol) was added and the reaction stirred overnight. The mixture was complete by TLC and MS so the vial was quenched slowly with water and filtered. The residue was extracted in CH₂Cl₂ and washed with water. The organic was dried over Na₂SO₄, filtered and concentrated. The crude product was purified using the MPLC and a gradient of 100% CH₂Cl₂ to 10% Methanol in ethyl acetate solution over 1 h. The product was a low melting solid so it was taken up in a HCl saturated methanol solution and concentrated. The yellow powder was triturated in ether and isolated as the hydrochloride salt then dried in vacuo (31 mg, 0.06 mmol, 30%). MS : APCI: M+l :

429.2 (Exact Mass: 428.5). IH NMR (400 MHz, DMSO-D6) d ppm 2.1 (m, 2 H) 2.5 (m, 2 H) 2.9 (t, 7=7.4 Hz, 2 H) 3.2 (m, 6 H) 3.4 (d, 7=12.0 Hz, 4 H) 3.6 (d, 7=11.2 Hz, 2 H) 7.1 (d, 7=7.3 Hz, 1 H) 7.4 (t, 7=7.7 Hz, 1 H) 7.5 (m, 3 H) 7.6 (d, 7=8.1 Hz, 1 H) 7.8 (d, 7=7.6 Hz, 1 H) 7.9 (m, 1 H) 8.1 (d, 7=9.8 Hz, 1 H).

EXAMPLE 3

7- r5-(tert-Butyl-dimethyl-silanyloxV)-pentanoyH -3 ,4-dihydro- IH- f 1 ,8]naphthyridin-2-one

Tert-butyl(4-chlorobutoxy)dimethylsilane (4.26 g, 19.1 mmol) was dissolved in anhydrous THF (20 mL) in a dried 2 necked flask under nitrogen and cooled to - 78 °C using an acetone dry ice bath. The lithium metal (lithium wire 3.2 mm, high sodium content- 0.5-1%, 45 mg/cm = 15.7 cm, 0.265 g) was added (wiped off oil with paper towel, cut the wire in small tubes under postive nitrogen pressure into the reaction mixture) and stirred under -20 °C for 3 h to form the organolithium. The lithium became shiny and dissolved in the solution to some extent; the solution turned a bluish color. In another dried flask at -78 deg C was prepared with the 7-oxo-5,6,7,8-tetrahydro-[l,8]naphthyridine-2-carboxylic acid methoxy-methyl-amide (1.5 g, 6.37 mmol) in THF (10 mL) and the organolithium was added via filtered cannula slowly. The cannula side in the organolithium flask was coated in filter paper and the needle was sealed with teflon tape. The reaction warmed to 0 ⁰C and was monitored by TLC and MS. After two hours the reaction mixture was quenched with 50 mL sat. NH₄CI. The organics were removed in the rotovap and the residue was taken up in CH₂Cl₂, and washed with brine. The organic layer was collected and dried over Na₂SO₄, filtered and concentrated. The compound was purified using the MPLC and a gradient of 100% CH₂Cl₂ to 100% ethyl acetate solution over 1 h. The product was isolated as a white solid, (840 mg, 2.31. mmol, 36%). MS: APCI: M+l: 363.1 (Exact

Mass: 362.5).

7-(5-Hydroxy-pentanoylV3,4-dihydro-lH-ri,81naphthyridin-2-one

TBAF (0.908 g, 3.47 mmol) was added slowly to a stirring solution of the 7-[5-(tert-butyl-dimethyl-silanyloxy)-pentanoyl]-3,4-dihydro-lH-

[l,8]naphthyridin-2-one (0.84 g, 2.32 mmol) and acetic acid (0.139 g, 2.31 mmol) in THF (30 mL) at 0 °C. The reaction mixture stirred for 72 h at room temperature and was followed by TLC. The mixture was concentrated, washed with hexane, then the residue was taken up in methylene chloride and put directly on the MPLC using a gradient of 100% CH₂Cl₂ to 100% ethyl acetate over 1 h.

The compound was isolated as a white powder, (0.27 g, 1.08. mmol, 46%). MS: APCI: M-I: 247.1 (Exact Mass: 248.2).

5-Oxo-5-(7-oxo-5,6,7,8-tetrahvdro-rL81naphthyridm-2-yl)-pentanal IBX (439 mg, 1.57 mmol) was stirred in a 50 mL round bottom flask in

DMSO (5 mL) until a solution formed (30 min). 7-(5-Hydroxy-pentanoyl)-3,4- dihydro-lH-[l,8]naphthyridin-2-one (260 mg, 1.047 mmol) was added while the reaction mixture stirred at room temperature. The mixture stirred overnight and MS showed that the reaction was complete. 200 mL of CH₂Cl₂ was added and the mixture was washed with sat. NaHCO₃ then brine. The organic was dried over

Na₂SO₄, filtered and concentrated. The product was an off-white solid (257 mg, 1.04 mmol, 100%). MS: APCI: M+l: 247.0 (Exact Mass: 246.26). EXAMPLE 4

7-F5-(4-Naphthalen- 1 - yl-piperazin- 1 -vD-pentanoyll -3 ,4-dihydro- IH- [ 1 ,8^"|naphthyridin-2-one

5-Oxo-5-(7-oxo-5,6,7,8-tetrahydro-[ 1 ,8]naphthyridin-2-yl)-pentanal (257 mg, 1.04 mmol) and 1-naphthalen-l-yl-piperazine hydrochloride (265 mg, 1.06 mmol) were combined in methylene chloride and stirred in a vial over sieves for 10 min. Sodium triacetoxy borohydride (310 mg, 1.48) was added and the reaction stirred overnight. The mixture was complete by TLC and MS so the vial was quenched slowly with water and filtered. The residue was extracted in CH₂Cl₂ and washed with water. The organic was dried over Na₂SO₄, filtered and concentrated. The crude product was purified using the MPLC and a gradient of 100% CH₂Cl₂ to 10% Methanol in ethyl acetate solution over 1 h. The product was isolated as a white foam (174 mg, 0.39 mmol, 37%), MS: APCI: M+l: 443.3 (Exact Mass: 442.6), IH NMR (400 MHz, CHLOROFORM-D) d ppm 1.7 (d, 7=6.6 Hz, 2 H) 1.8 (m, 2 H) 2.5 (m, 2 H) 2.7 (m, 6 H) 3.0 (t, 7=7.4 Hz, 2 H) 3.1

(m, 6 H) 7.1 (d, 7=7.1 Hz, 1 H) 7.4 (t, 7=7.8 Hz, 1 H) 7.4 (m, 2 H) 7.5 (m, 2 H) 7.7 (d, 7=7.6 Hz, 1 H) 7.8 (d, 7=8.1 Hz, 1 H) 8.2 (d, 7=7.3 Hz, 1 H) 8.3 (s, 1 H).

EXAMPLE 5 7-{5-r4-(2,3-Dichloro-phenyl)-piperazin-l-vn-pentanovU-3,4-dihvdro-lH- n ,81naphthyridin-2-one

Starting from 5-oxo-5-(7-oxo-5,6,7,8-tetrahydro-[l,8]naphthyridin-2-yl)- pentanal (250 mg, 1.01 mmol) and l-(2,3-dichloro-phenyl)-piperazine hydrochloride (277 mg, 1.04 mmol) and following the procedure as outlined in example 1, the title compound was obtained as a white foam, (280 mg, 0.607 mmol, 59%), MS: APCI: M+2: 463.1 (Exact Mass: 461.4), IH NMR (400 MHz, DMSO-D6) d ppm 1.5 (dq, 7=7.4, 7.2 Hz, 2 H) 1.6 (qd, 7=7.4, 7.2 Hz, 2 H) 2.3 (t, 7=7.1 Hz, 2 H) 2.5 (d, 7=8.1 Hz, 6 H) 2.9 (t, 7=7.3 Hz, 6 H) 3.1 (t, 7=7.2 Hz, 2 H) 7.1 (dd, 7=6.1, 3.4 Hz, 1 H) 7.3 (m, 2 H) 7.5 (d, 7=7.6 Hz, 1 H) 7.7 (d, 7=7.8 Hz, 1 H). EXAMPLE 6

7- { 5- r4-(7-Methoxy-naphthalen- 1 - yl)-piperazin- 1 - yli -pentanoyl } -3 ,4-dihydro- IH- π ,81naphthyridin-2-one

Starting from 5-oxo-5-(7-oxo-5,6,7,8-tetrahydro-[l,8]naphthyridin-2-yl)- pentanal (250 mg, 1.01 mmol) and l-(7-methoxy-naphthalen-l-yl)-piperazine, trifluoro-acetic acid salt (369 mg, 1.04 mmol) and following the procedure as outlined in example 1, the title compound was obtained as a white foam, (206 mg, 0.435 mmol, 42.9%), MS: APCI: M+l: 473.1 (Exact Mass: 472.6), IH NMR (400 MHz, DMSO-D6) d ppm 1.5 (m, 2 H) 1.6 (qd, /=7.4, 7.2 Hz, 2 H) 2.4 (t, /=7.1 Hz, 4 H) 2.5 (d, /=8.1 Hz, 4 H) 2.9 (m, 6 H) 3.1 (t, /=7.2 Hz, 2 H) 3.8 (s, 3 H) 7.0

(d, /=8.3 Hz, 1 H) 7.1 (dd, /=9.0, 2.7 Hz, 1 H) 7.2 (m, 1 H) 7.4 (d, /=2.7 Hz, 1 H) 7.5 (m, 2 H) 7.8 (m, 2 H).

EXAMPLE 7 7- { 5-[4-(7-Fluoro-naphthalen- l-yl)-piperazin- 1-yll-pentanoyl I -3 ,4-dihydro- IH-

F 1 ,81naphthyridin-2-one

Starting from 5-oxo-5-(7-oxo-5,6,7,8-tetrahydro-[l,8]naphthyridin-2-yl)- pentanal (250 mg, 1.01 mmol) and l-(7-fluoro-naphthalen-l-yl)-piperazine, trifluoro-acetic acid salt (357 mg, 1.04 mmol) and following the procedure as outlined in example 1, the title compound was obtained as a white powder, (335 mg, 0.727 mmol, 71.7%), MS: APCI: M+l: 461.1 (Exact Mass: 460.5), IH NMR (400 MHz, DMSO-D6) d ppm 1.5 (m, 2 H) 1.6 (dq, /=7.4, 7.3 Hz, 2 H) 2.4 (m, 2H) 2.5 (m, 2 H), 2.6 (m, 4H) 2.9 (m, 6 H) 3.1 (t, /=7.2 Hz, 2 H) 7.2 (d, /=7.3 Hz, 1 H) 7.4 (m, 2 H) 7.5 (d, /=7.6 Hz, 1 H) 7.7 (m, 2 H) 7.7 (d, /=7.6 Hz, 1 H) 8.0 (dd, /=8.9, 6.0 Hz, 1 H) 10.6 (s, 1 H).

EXAMPLE 8

7-r5-(4-Indan-4-yl-piperazin-l-yl)-pentanoyll-3,4-dihvdro-lH-ri,81naphthyridin-2- one Starting from 5-oxo-5-(7-oxo-5,6,7,8-tetrahydro-[l,8]naphthyridin-2-yl)- pentanal (59 mg, 0.25 mmol) and l-indan-4-yl-piperazine hydrochloride (60 mg, 0.24 mmol) and following the procedure as outlined in example 1, the title compound was obtained as a white foam, (69 mg, 0.159 mmol, 65.5%), MS: APCI: M+l: 433.2 (Exact Mass: 432.6), IH NMR (400 MHz, DMSO-D6) d ppm 1.5 (qd, J=IA, 7.2 Hz, 2 H) 1.6 (m, J=7.4, 7.4, 7.4, 7.4 Hz, 2 H) 1.9 (dd, 7=14.4, 7.3 Hz, 2 H) 2.3 (t, 7=7.2 Hz, 2 H) 2.5 (d, J=8.1 Hz, 6 H) 2.7 (t, /=7.0 Hz, 2 H) 2.8 (t, 7=7.2 Hz, 2 H) 2.8 (s, 2 H) 2.9 (t, 7=7.6 Hz, 2 H) 3.1 (t, 7=7.1 Hz, 2 H) 3.3 (m, 2H) 6.6 (d, 7=8.1 Hz, 1 H) 6.8 (d, 7=7.3 Hz, 1 H) 7.0 (t, 7=7.6 Hz, 1 H) 7.5 (s, 1 H) 7.7 (d,

7=7.6 Hz, 1 H) 10.6 (s, 1 H).

EXAMPLE 9

7-|5-r4-(6-Isopropyl-pyridin-2-yl)-piperazin-l-yll-pentanoyl}-3,4-dihvdro-lH- [ 1 ,8^"|naphthyridin-2-one

Starting from 5-oxo-5-(7-oxo-5,6,7,8-tetrahydro-[l ,8]naphthyridin~2-yl)- pentanal (51 mg, 0.25 mmol) and l-(6-isopropyl-pyridin-2-yl)-piperazine (60 mg, 0.24 mmol) and following the procedure as outlined in example 1, the title compound was obtained as a solid, (56 mg, 0.128 mmol, 52.8%), MS: APCI: M+l: 436.3 (Exact Mass: 435.6), IH NMR (400 MHz, DMSO-D6) d ppm 1.1 (d, 7=6.8

Hz, 6 H) 1.5 (m, 2 H) 1.6 (m, 2 H) 2.3 (t, 7=7.0 Hz, 2 H) 2.4 (s, 4 H) 2.5 (d, 7=8.1 Hz, 2 H) 2.8 (dt, 7=13.7, 6.8 Hz, 1 H) 2.9 (t, 7=7.4 Hz, 2 H) 3.1 (t, 7=7.2 Hz, 2 H) 3.4 (s, 4 H) 6.5 (d, 7=7.3 Hz, 1 H) 6.5 (d, 7=8.5 Hz, 1 H) 7.4 (m, 1 H) 7.5 (d, 7=7.6 Hz, 1 H) 7.7 (d, 7=7.6 Hz, 1 H) 10.6 (s, 1 H).

EXAMPLE 10

7-{5-r4-(5,6,7,8-Tetrahvdro-naphthalen-l-yl)-piρerazin-l-yll-pentanoyl)-3,4- dihvdro-lH-rL81naphthyridin-2-one

Starting from 5-oxo-5-(7-oxo-5,6,7,8-tetrahydro-[l,8]naphthyridin-2-yl)- pentanal (63 mg, 0.25 mmol) and l-(5,6,7,8-tetrahydro-naphthalen-l-yl)-piperazine hydrochloride (60 mg, 0.24 mmol) and following the procedure as outlined in example 1, the title compound was obtained as a solid, (68 mg, 0.152 mmol, 62.5%), MS: APCI: M+l: 447.3 (Exact Mass: 446.6), IH NMR (400 MHz, DMSO-D6) d ppm 1.2 (m, 2H) 1.5 (m, 2 H) 1.6 (m, 6 H) 2.3 (t, 7=7.0 Hz, 2 H) 2.5 (d, 7=8.1 Hz, 2 H) 2.6 (t, 7=6.0 Hz, 2 H) 2.7 (t, 7=6.2 Hz, 2 H) 2.7 (s, 4 H) 2.9

(t, 7=7.7 Hz, 2 H) 3.1 (t, 7=7.2 Hz, 2 H) 3.3 (m, 2H) 6.7 (d, 7=7.8 Hz, 1 H) 6.8 (d, 7=7.3 Hz, 1 H) 7.0 (t, 7=7.7 Hz, 1 H) 7.5 (d, 7=7.3 Hz, 1 H) 7.7 (d, 7=7.8 Hz, 1 H) 10.6 (s, 1 H). EXAMPLE 11

7-15-F4-(7-Fluoro-naphthalen- 1 -yl)-piperazin- 1 -yli - 1 -hydrox y-pentyl } -3 ,4-dihydro- lH-ri,81naphthyridin-2-one

7- { 5- [4-(7-Fluoro-naphthalen- 1 -yl)-piperazin- 1 -yl] -pentanoyl } -3 ,4- dihydro-lH-[l,8]naphthyridin-2-one (130 mg, 0.28 mmol) was dissolved in methanol and cooled in an ice bath. Sodium borohydride (12.8 mg, 0.34 mmol) was added in portions. The reaction mixture stirred for 30 min then was concentrated. The residue was taken up in water and extracted into CH₂Cl₂. The organic was dried over Na₂SO₄, filtered and concentrated. The product was isolated using the MPLC and a gradient of 100% CH₂Cl₂ to 100% of the mixture of 100:8:1 CH₂Cl^EtOKNH₄OH over 1 h. The product was isolated as a foam (52 mg, 0.11 mmol, 39 %), MS: APCI: M+l: 463.1 (Exact Mass: 462.56), IH NMR (400 MHz, CHLOROFORM-D) d ppm 1.5 (m, 2 H) 1.6 (m, 2 H) 1.8 (m, 2 H) 2.5 (t, /=7.4 Hz, 2 H) 2.7 (m, 6H) 2.9 (t, 7=7.4 Hz, 2 H) 3.1 (s, 4 H) 4.7 (dd, J=7.7, 4.8 Hz, 1 H) 7.0 (d, /=7.6 Hz, 1 H) 7.1 (d, J=7.6 Hz, 1 H) 7.2 (dd, J=8.5,

2.2 Hz, 1 H) 7.3 (t, 7=7.8 Hz, 1 H) 7.5 (m, 2 H) 7.8 (m, 2 H) 8.5 (s, 1 H).

EXAMPLE 12

(+)7-{5-r4-(7-Fluoro-naphthalen-l-yl)-piperazin-l-yl1-l-hvdroxy-pentyl|-3,4- dihvdro-lH-rL81naphthyridin-2-one

The (+) enantiomer was isolated via HPLC resolution of racemic 7-{5-[4- (7-fluoro-naphthalen- 1 -yl)-piperazin- 1 -yl] - 1 -hydroxy-pentyl } -3 ,4-dihydro- IH- • [l,8]naphthyridin-2-one (289 mg, 0.63 mmol). This was dissolved in ethanol and injected into a Chiralcel OD 250 x 4.6 mm column. A mixture of hexane and ethanol 80:20, at a flow rate of 0.8 ml/min, was used as the eluent. 95 mg, (0.21 mmol, 32 %) of the title compound was isolated, R/ (hexane/ethanol, 8:2 v/v) = 14.74, UV detection: 254 nm, [α]_D + 17.7 (c = 0.005, CHCl₃) at 20 ⁰C. MS: APCI: M+l: 463.2 (Exact Mass: 462.56), IH NMR (400 MHz, CHLOROFORM- D) d ppm 1.5 (m, 2 H) 1.6 (m, 2 H) 1.8 (m, 2 H) 2.5 (t, 7=7.6 Hz, 2 H) 2.7 (m, 4 H) 2.7 (m, 2 H) 2.9 (t, 7=7.6 Hz, 2 H) 3.1 (s, 4 H) 4.7 (dd, 7=8.1, 4.6 Hz, 1 H) 7.0

(d, 7=7.6 Hz, 1 H) 7.1 (d, 7=7.6 Hz, 1 H) 7.2 (m, 1 H) 7.3 (t, 7=7.8 Hz, 1 H) 7.5 (m, 2 H) 7.8 (m, 2 H) 8.4 (s, 1 H). EXAMPLE 13

(-)7-{5-[4-(7-Fluoro-naphthalen-l-yl)-piperazin-l-yll-l-hydroxy-pentyl|-3,4- dihydro-lH-ri,81naphthyridin-2-one

The (-) enantiomer was isolated via HPLC resolution of racemic 7-{5-[4-(7- fluoro-naphthalen- 1 -yl)-piperazin- 1 -yl] - 1 -hydroxy-pentyl } -3 ,4-dihydro- IH-

[l,8]naphthyridin-2-one (289 mg, 0.63 mmol). This was dissolved in ethanol and injected into a Chiralcel OD 250 x 4.6 mm column. A mixture of hexane and ethanol 80:20, at a flow rate of 0.8 ml/min, was used as the eluent. 97 mg, (0.21 mmol, 33%) of the title compound was isolated, Rf (hexane/ethanol, 8:2 v/v) = 44.81, UV detection: 254 nm, [αfo -15.89 (c = 0.005, CHCl₃) at 20 ⁰C. MS:

APCI: M+l: 463.2 (Exact Mass: 462.56), IH NMR (400 MHz, DMSO-D6) d ppm 1.4 (m, 2 H) 1.5 (t, 7=11.0 Hz, 2 H) 1.7 (m, 2 H) 2.3 (d, 7=7.1 Hz, 2 H) 2.4 (m, 4 H) 2.6 (dd, /=14.7, 8.5 Hz, 4 H) 2.8 (t, 7=7.4 Hz, 2 H) 3.0 (s, 4 H) 4.4 (dd, 7=8.1, 4.4 Hz, 1 H) 7.0 (d, 7=7.6 Hz, 1 H) 7.2 (d, 7=7.8 Hz, 1 H) 7.4 (t, 7=7.7 Hz, 2 H) 7.5 (d, 7=7.8 Hz, 1 H) 7.6 (m, 2 H) 8.0 (dd, 7=9.0, 5.9 Hz, 1 H).

EXAMPLE 14

7-15-r4-(2,3-Dichloro-phen yl)-piperazin- 1 -yli- 1 -hvdroxy-pentyl I -3 ,4-dihydro- 1 H- [ 1 ,8^~|naphthyridin-2-one Starting from 7-{ 5-[4-(2,3-dichloro-phenyl)-piperazin-l-yl]-pentanoyl }-3,4- dihydro-lH-[l,8]naphthyridin-2-one (250 mg, 0.54 mmol) and following the procedure as outlined in example 9, the title compound was obtained as a solid, (253 mg, 0.54 mmol, 99%), MS: APCI: M+2: 465.1 (Exact Mass: 463.4), IH NMR (400 MHz, CHLOROFORM-D) d ppm 1.5 (dd, 7=15.0, 7.9 Hz, 2 H) 1.6 (m, 2 H) 1.8 (m, 2 H) 2.4 (t, 7=7.2 Hz, 2 H) 2.6 (s, 2 H) 2.6 (dd, 7=14.8, 7.4 Hz, 4

H) 2.9 (t, 7=7.4 Hz, 2 H) 3.0 (s, 4 H) 4.7 (dd, 7=7.3, 4.9 Hz, 1 H) 6.9 (d, 7=7.6 Hz, 2 H) 7.1 (d, 7=6.3 Hz, 2 H) 7.5 (d, 7=7.6 Hz, 1 H) 8.5 (s, 1 H).

EXAMPLE 15 7-{ l-Hvdroxy-5-r4-(7-methoxy-naphthalen-l-yl)-piperazin-l-yll-pentyl|-3,4- dihvdro-lH-r 1 ,81naphthyridin-2-one Starting from 7-{5-[4-(7-Methoxy-naphthalen-l-yl)-piperazin-l-yl]- pentanoyl}-3,4-dihydro-lH-[l,8]naphthyridin-2-one (160 mg, 0.34 mmol) and following the procedure as outlined in example 9, the title compound was obtained as a foam, (75 mg, 0.15 mmol, 45 %), MS: APCI: M+l: 475.1 (Exact Mass: 474.6), IH NMR (400 MHz, CHLOROFORM-D) d ppm 1.5 (m, 2 H) 1.6 (td, /=14.2, 7.1 Hz, 2 H) 1.8 (m, 2 H) 2.5 (t, /=7.6 Hz, 2 H) 2.7 (m, 4 H) 2.9 (t, /=7.7 Hz, 4 H) 3.1 (s, 4 H) 3.9 (s, 3 H) 4.7 (dd, /=8.1, 4.6 Hz, 1 H) 7.0 (d, /=7.6 Hz, 1 H) 7.1 (dd, /=18.3, 8.1 Hz, 2 H) 7.2 (d, /=15.4 Hz, 1 H) 7.5 (m, 3 H) 7.7 (d, /=8.8 Hz, 1 H) 8.4 (s, 1 H).

Claims

CLAIMSWhat is claimed is:

1. A compound of formula 1

wherein G is

(i) (ϋ)

A is -(CH₂)_mCO-, or -(CH₂)_mCOH-, wherein m is an integer from 2 to 5 and wherein one or two of the carbon or nitrogen atoms of A can be substituted, optionally and independently, with one or two substituents that are selected, independently, from fluoro and methyl, or with two substituents attached to the same carbon atom that form, together with the carbon to which they are attached, a spirocyclopropyl or spirocyclobutyl ring;

D is N, C, or CH, provided that when D is N each carbon atom attached to D is attached through a single bond;

J and K are independently selected from N, CH, and C, provided that at least one of J and K is N; Z and Q are independently selected from N, C, and CH, provided that at least one of Z and Q is N;

-X=Y- is -CH₂-CH₂-, -CH=CH-, -CH₂-NH-, -NH-CH₂-, -N=CH-, -CH=N-, -0-CH₂-, or -CH₂-O-, wherein -X^^r:Υ- can optionally be substituted, at any available bonding site, by one to four substituents R², R² , R³ and R³ ;

V and W are independently N, C, or CH; ring AA is a saturated or unsaturated 5- 6- or 7-membered carbocyclic ring wherein one, two or three of the carbon atoms of ring AA that are not shared with the benzo ring of group (ii) can be replaced, optionally and independently, by a nitrogen, oxygen or sulfur atom;

R¹ is hydrogen, -C(=O)CH₃, or (C₁-C₃) alkyl;

R², R² , R³ and R³ are independently selected from hydrogen, halo, cyano, oxo, hydroxy, -C(=0)CH₃, (C₁-C₄) alkyl, and (C₁-C₄) alkoxy, wherein the alkyl moieties of the (C₁-C₄) alkyl, (C₁-C₄) alkoxy, and -C(=O)CH₃ groups can be optionally substituted with from one to three fluoro atoms and can also be optionally substituted with an amino or hydroxy substituent;

R⁴ and R⁵ are independently selected from hydrogen, halo, cyano, hydroxy, -C(=O)CH₃, (C₁-C₄) alkyl, and (C₁-C₄) alkoxy, wherein the alkyl moieties of the (C₁-C₄) alkyl, (C₁-C₄) alkoxy, and -C(=O)CH₃ groups can be optionally substituted with from one to three fluoro atoms and can also be optionally substituted with an amino or hydroxy substituent;

R⁶ and R⁷ are selected, independently, from hydrogen and methyl; R⁸, R⁹, R¹⁰, R¹¹, and R¹² are independently selected from hydrogen, halo, -C(=O)CH₃, (C₁-C₄) alkyl, and (C₁-C₄) alkoxy, aryl, and aryloxy, wherein the alkyl moieties of the (C₁-C₄) alkyl, (C₁-C₄) alkoxy, and -C(=0)CH₃ groups and the aryl and aryloxy moieties can be optionally substituted with from one to three fluoro atoms and can also be optionally substituted with an amino or hydroxy substituent;

R¹³ and R¹⁴ are independently selected from hydrogen, halo, cyano, oxo, hydroxy, -C(=O)CH₃, (C₁-C₄) alkyl, and (C₁-C₄) alkoxy, wherein the alkyl moieties of the (C₁-C₄) alkyl, (C₁-C₄) alkoxy, and -C(=O)CH₃ groups can be optionally substituted with from one to three fluoro atoms and can also be optionally substituted with an amino or hydroxy substituent; and the pharmaceutically acceptable salts of such compounds.

2. The compound or salt of claim 1, wherein Q is N and Z is CH, or both Q and Z are N.

3. The compound or salt of claim 1, wherein -X=^=Y- is -CH₂-CH₂-, -CH=CH-, or -CH₂NH-.

4. The compound or salt of claim 1, wherein G is a group of formula:

5. The compound or salt of claim 1, wherein G is the group of formula (ii) and all atoms in ring AA are carbon atoms.

6. The compound or salt of claim 5, wherein ring AA is benzo.

7. The compound or salt of claim 1, selected from the group consisting of: 7-[4-(4-Naphthalen-l-yl-piperazin-l-yl)-butyryl]-3,4-dihydro-lH-

[l,8]naphthyridin-2-one;

7-[5-(4-Naphthalen-l-yl-piperazin-l-yl)-pentanoyl]-3,4-dihydro-lH- [l,8]naphthyridin-2-one; 7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-l-yl]-pentanoyl}-3,4-dihydro-lH-

[1 ,8]naphthyridin-2-one; 7- { 5- [4-(7-Methoxy-naphthalen- 1 -yl)-piperazin- 1 -yl] -pentanoyl } -3 ,4- dihydro-lH-[l,8]naphthyridin-2-one; 7-{5-[4-(7-Fluoro-naphthalen-l-yl)-piperazin-l-yl]-pentanoyl}-3,4-dihydro-

IH-[1 ,8]naphthyridin-2-one; 7-[5-(4-Indan-4-yl-piperazin-l-yl)-pentanoyl]-3,4-dihydro-lH-

[ 1 ,8]naphthyridin-2-one;

7-{5-[4-(6-Isopropyl-pyridin-2-yl)-piρerazin-l-yl]-pentanoyl}-3,4-dihydro- lH-[l,8]naphthyridin-2-one;

7-{5-[4-(5,6,7,8-Tetrahydro-naphthalen-l-yl)-piperazin-l-yl]-pentanoyl}-

3,4-dihydro-lH-[l,8]naphthyridin-2-one; 7- { 5-[4-(7-Fluoro-naphthalen- 1 -yl)-piperazin- 1 -yl] - 1 -hydroxy-pentyl } -3 ,4- dihydro- IH-[1 ,8]naphthyridin-2-one; (+)7- { 5-[4-(7-Fluoro-naphthalen-l -yl)-piperazin-l -yl]-l -hydroxy-pentyl } -

3,4-dihydro-lH-[l,8]naphthyridin-2-one; (-)7- { 5-[4-(7-Fluoro-naphthalen- 1 -yl)-piperazin- 1 -yl] - 1 -hydroxy-pentyl } -

3,4-dihydro-lH-[l,8]naphthyridin-2-one;

7-{5-[4-(2,3-Dichloro-phenyl)-piperazin-l-yl]-l-hydroxy-pentyl}-3,4- dihydro-lH-[l,8]naphthyridin-2-one; and

7- { l-Hydroxy-5-[4-(7-methoxy-naphthalen- 1 -yl)-piperazin- 1 -yl] -pentyl } - 3,4-dihydro-lH-[l,8]naρhthyridin-2-one

8. A pharmaceutical composition, comprising:

(a) a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and

(b) a pharmaceutically acceptable carrier.

9. A pharmaceutical composition for treating a disorder or condition in a mammal, wherein the disorder or condition is selected from the group consisting of single episodic or recurrent major depressive disorders, dysthymic disorders, depressive neurosis and neurotic depression, melancholic depression; atypical depression; bipolar disorder; cyclothymic disorder; conduct disorder; disruptive behavior disorder; attention deficit hyperactivity disorder; behavioral disturbances associated with mental retardation, autistic disorder, and conduct disorder; anxiety disorders; borderline personality disorder; schizophrenia and other psychotic disorders; delirium, dementia, and amnestic and other cognitive or neurodegenerative disorders; movement disorders, dyskinesias; extra-pyramidal movement disorders; chemical dependencies and additions; behavioral addictions; and ocular disorders, comprising administering to the mammal:

(a) a compound according to claim 1, or a pharmaceutically acceptable salt thereof; (b) an antidepressant or an anti-anxiety agent, or a pharmaceutically acceptable salt thereof; and

(c) a pharmaceutically acceptable carrier; wherein the active agents (a) and (b) are present in amounts that render the combination effective in treating such disorder or condition.

10. A method for treating a disorder or condition in a mammal, wherein the disorder or condition is selected from the group consisting of single episodic or recurrent major depressive disorders, dysthymic disorders, depressive neurosis and neurotic depression, melancholic depression; atypical depression; bipolar disorder; cyclothymic disorder; conduct disorder; disruptive behavior disorder; attention deficit hyperactivity disorder; behavioral disturbances associated with mental retardation, autistic disorder, and conduct disorder; anxiety disorders; borderline personality disorder; schizophrenia and other psychotic disorders; delirium, dementia, and amnestic and other cognitive or neurodegenerative disorders; movement disorders, dyskinesias; extra-pyramidal movement disorders; chemical dependencies and additions; behavioral addictions; and ocular disorders, comprising: administering to the mammal in need of such treatment an amount of compound according to claim 1, or a pharmaceutically acceptable salt thereof, that is effective in treating the disorder or condition.

11. The method of claim 10, wherein the disorder or condition is selected from the group consisting of: schizophrenia, schizoaffective disorder, delusional disorder, substance-induced psychotic disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition, and schizophreniform disorder.

12. A compound according to claim 1 for use as a medicament.

13. A compound according to claim 1 for use in the treatment of a disorder or condition selected from the group consisting of single episodic or recurrent major depressive disorders, dysthymic disorders, depressive neurosis and neurotic depression, melancholic depression; atypical depression; bipolar disorder; cyclothymic disorder; conduct disorder; disruptive behavior disorder; attention deficit hyperactivity disorder; behavioral disturbances associated with mental retardation, autistic disorder, and conduct disorder; anxiety disorders; borderline personality disorder; schizophrenia and other psychotic disorders; delirium, dementia, and amnestic and other cognitive or neurodegenerative disorders; movement disorders, dyskinesias; extra-pyramidal movement disorders; chemical dependencies and additions; behavioral addictions; and ocular disorders.

14. Composition comprising a compound according to claim 1 for use a medicament.

15. Composition comprising a compound according to claim 1 for use in the treatment of a disorder or condition selected from the group consisting of single episodic or recurrent major depressive disorders, dysthymic disorders, depressive neurosis and neurotic depression, melancholic depression; atypical depression; bipolar disorder; cyclothymic disorder; conduct disorder; disruptive behavior disorder; attention deficit hyperactivity disorder; behavioral disturbances associated with mental retardation, autistic disorder, and conduct disorder; anxiety disorders; borderline personality disorder; schizophrenia and other psychotic disorders; delirium, dementia, and amnestic and other cognitive or neurodegenerative disorders; movement disorders, dyskinesias; extra-pyramidal movement disorders; chemical dependencies and additions; behavioral addictions; and ocular disorders.