WO2012047703A2

WO2012047703A2 - Cyclopropyl-spiro-piperidines useful as sodium channel blockers

Info

Publication number: WO2012047703A2
Application number: PCT/US2011/053817
Authority: WO
Inventors: Ginny D. Ho; Deen Tulshian; Charles R. Heap
Original assignee: Schering Corporation
Priority date: 2010-10-04
Filing date: 2011-09-29
Publication date: 2012-04-12
Also published as: WO2012047703A3

Abstract

Cyclopropyl-spiro-piperidine compounds represented by Formulas (I)-(III) or pharmaceutically acceptable salts thereof, are blockers of voltage-gated sodium channels. Pharmaceutical compositions comprise an effective amount of the instant compounds, either alone, or in combination with one or more other therapeutically active compounds, and a pharmaceutically acceptable carrier. Methods of treating conditions associated with, or caused by, voltage-gated sodium channel activity, including, for example, acute pain, chronic pain, visceral pain, inflammatory pain, neuropathic pain, epilepsy or epilepsy conditions, irritable bowel syndrome, depression, anxiety, bipolar disorder, neurodegenerative disorders, psychiatric disorders, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, neuropathy and tinnitus, comprise administering an effective amount of the present compounds, either alone, or in combination with one or more other therapeutically active compounds. A method of administering local anesthesia comprises administering an effective amount of a compound of the instant invention, either alone, or in combination with one or more other therapeutically active compounds, and a pharmaceutically acceptable carrier.

Description

TITLE OF THE INVENTION

CYCLOPROPYL-SPIRO-PTPERIDINES USEFUL AS SODIUM CHANNEL BLOCKERS

FIELD OF THE INVENTION

The present invention relates to compounds useful as blockers of ion channels. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders.

BACKGROUND OF THE INVENTION

Voltage-gated ion channels allow electrically excitable cells to generate and propagate action potentials and therefore are crucial for nerve and muscle function. Sodium channels play a special role by mediating rapid depolarization, which constitutes the rising phase of the action potential and in turn activates voltage-gated calcium and potassium channels. Voltage-gated sodium channels represent a multigene family. Nine sodium channel subtypes have been cloned and functionally expressed to date. [Clare, J. J., et al, Drug Discovery Today, 2000, 5: 506- 520], They are differentially expressed throughout muscle and nerve tissues and show distinct biophysical properties. All voltage-gated sodium channels are characterized by a high degree of selectivity for sodium over other ions and by their voltage-dependent gating. [Catterall, W. A., Current Opinion in Neurobiology, 1991, 1 : 5-13]. At negative or hyperpolarized membrane potentials, sodium channels are closed. Following membrane depolarization, sodium channels open rapidly and then inactivate. Sodium channels only conduct currents in the open state and, once inactivated, have to return to the resting state, favored by membrane hyperpolarization, before they can reopen. Different sodium channel subtypes vary in the voltage range over which they activate and inactivate as well as in their activation and inactivation kinetics.

Sodium channels are the target of a diverse array of pharmacological agents, including neurotoxins, antiarrhythmics, anticonvulsants and local anesthetics. [Clare, J. J., et al., supra], Several regions in the sodium channel secondary structure are involved in interactions with these blockers and most are highly conserved. Indeed, most sodium channel blockers known to date interact with similar potency with all channel subtypes. Nevertheless, it has been possible to produce sodium channel blockers with therapeutic selectivity and a sufficient therapeutic window for the treatment of epilepsy (e.g. lamotrigine, phenytoin and carbamazepine) and certain cardiac arrhythmias (e.g. lignocaine, tocainide and mexiletine).

It is well known that the voltage-gated Na+ channels in nerves play a critical role in neuropathic pain. Injuries of the peripheral nervous system often result in neuropathic pain persisting long after the initial injury resolves. Examples of neuropathic pain include, but are not limited to, postherpetic neuralgia, trigeminal neuralgia, diabetic neuropathy, chronic lower back pain, phantom limb pain, pain resulting from cancer and chemotherapy, chronic pelvic pain, complex regional pain syndrome and related neuralgias. It has been shown in human patients as well as in animal models of neuropathic pain that damage to primary afferent sensory neurons can lead to neuroma formation and spontaneous activity, as well as evoked activity in response to normally innocuous stimuli. [Carter, G.T. and Galer, B.S., Physical Medicine and

Rehabilitation Clinics of North America, 2001, 12(2): 447-459]. The ectopic activity of normally silent sensory neurons is thought to contribute to the generation and maintenance of neuropathic pain. Neuropathic pain is generally assumed to be associated with an increase in sodium channel activity in the injured nerve. [Baker, M.D. and Wood, J.N., TRENDS in Pharmacological Sciences, 2001, 22(1): 27-31],

Indeed, in rat models of peripheral nerve injury, ectopic activity in the injured nerve corresponds to the behavioral signs of pain. In these models, intravenous application of the sodium channel blocker and local anesthetic lidocaine can suppress the ectopic activity and reverse the tactile allodynia at concentrations that do not affect general behavior and motor function. [Mao, J. and Chen, L.L., Pain, 2000, 87: 7-17], These effective concentrations were similar to concentrations shown to be clinically efficacious in humans. [Tanelian, D.L. and Brose, W.G., Anesthesiology. 1991, 74(5): 949-951]. In a placebo-controlled study, continuous infusion of lidocaine caused reduced pain scores in patients with peripheral nerve injury, and in a separate study, intravenous lidocaine reduced pain intensity associated with postherpetic neuralgia (PHN). [Mao, J. and Chen, L.L., supra; Anger, T., et al., J. Med. Chert 2001, 44(2): 115-137]. Lidoderm^®, lidocaine applied in the form of a dermal patch, is currently the only FDA approved treatment for PHN. [Devers, A. and Galer, B.S., Clinical J. Pain, 2000,16(3): 205- 208].

In addition to neuropathic pain, sodium channel blockers have clinical uses in the treatment of epilepsy and cardiac arrhythmias, Recent evidence from animal models suggests that sodium channel blockers may also be useful for neuroprotection under ischaemic conditions caused by stroke or neural trauma and in patients with multiple sclerosis (MS). [Clare, J. J., et al. and Anger, T., et al., supra].

See also, International Patent Publication WO 00/57877; International Patent Publication WO 01/68612; International Patent Publication WO 99/32462; International Patent Publication 03/0955427; Us Patent 3,939,159; Artico, et al., J. Heterocyclic Chem.. 1992, 29: 141-245.

However, there remains a need for novel compounds and compositions that

therapeutically block neuronal sodium channels with less side effects and higher potency than currently known compounds.

SUMMARY OF THE INVENTION

The present invention is directed to cyclopropyl-spiro-piperidine compounds which are sodium channel blockers useful for the treatment of chronic and neuropathic pain. The compounds of the present invention are also useful for the treatment of other conditions, including disorders of the CNS such as epilepsy, manic depression and bipolar disorder. This invention also provides pharmaceutical compositions comprising a compound of the present invention, either alone, or in combination with one or more therapeutically active compounds, and a pharmaceutically acceptable carrier.

This invention further comprises methods for the treatment of acute pain, chronic pain, visceral pain, inflammatory pain, neuropathic pain and disorders of the CNS including, but not limited to, epilepsy, manic depression, depression, anxiety and bipolar disorder comprising administering the compounds and pharmaceutical compositions of the present invention.

DETAILED DESCRIPTION OF THE I VENTION

The present invention is directed to sodium channel blockers and derivatives of structural Formula I:

or pharmaceutically acceptable salts and individual enantiomers and diastereomers thereof wherein:

Z is selected from the group consisting of

(1) bond, (2) -C1-C6 alkyl,

(3) -C(O)-,

(4) -C(0)0-,

(5) -C(0)N-, and

(6) -S(0)2-,

wherein said alkyl may be optionally substituted with 1 to 4 groups of R^A;

R1 is selected from the group consisting of

(1) hydrogen,

(2) -C6-Cio aryl, and

(3) -C5-C10 heteroaryl,

wherein said aryl and heteroaryl may be optionally substituted with 1 to 4 groups of R^A; R2 is selected from the group consisting of

(1) hydrogen,

(3) -C(0)NR3R4,

(4) -(CH2)n 5-Cio heterocyclyl, which may be optionally substituted with 1 to 4 groups of R^A; and

(5) -NR3C(0)0R4

R3 is selected from the group consisting of

(1) hydrogen,

(2) -Ci-Cio alkyl

(3) -C5-C 1Q heterocyclyl,

(4) -(CH₂)_nC6-Cio aryl, and

(5) -S(0)2,

wherein said alkyl, heterocyclyl, and aryl may be optionally substituted with 1 to 4 groups of R^A;

R4 is selected from the group consisting of

(1) hydrogen,

(2) -(CH₂)nC6"Cl0 ryl,

(3) -C(0)R3,

(4) X_rC₆ alkyl,

(5) -CJ-CJ O heterocyclyl,

(6) -S(0)₂R3, and

(7) -C₃-C₁₀ cycloalkyl,

wherein said aryl, alkyl, heterocyclyl, and cycloalkyl may be optionally substituted with

1 to 4 groups of R^A;

R5 is selected from the group consisting of

(1) hydrogen,

(2) -C6-CioaryL

(3) -C1-C10 alkyl and

(4) -CF3,

wherein said aryl and alkyl may be optionally substituted with 1 to 4 groups of R^A; ^A is selected from the group consisting of

(1) hydrogen,

(2) halogen,

(3) -Ci-Cio alkyl,

(4) -(CH₂)nC3-Cl0 cycloalkyl,

(5) -C6-Cio aryl,

(6) -C5-C10 heteroaryl,

(7) -C5-C10 heterocyclyl,

(10) -C(0)NR5_s

(11) -C(0)₂R5,

(12) -CN,

(13) -CF3, and

(14) -NO2,

wherein said alkyl, cycloalkyl, aryl, heteroaryl_> and heterocyclyl may be optionally substituted with 1 to 4 groups of C1-C6 alkyl;

n is 0 to 4; and

wherein the compounds of said Formula I do not include the compounds of Table 1.

Table 1

Another embodiment of the invention is realized b compounds of structural Formula Ila:

or pharmaceutically acceptable salts and individual enantiomers and diastereomers thereof, wherein R.3, R4_; and R^A are as previously described.

In another embodiment, compounds of Formula Ila are realized when

R3 is selected from the group consisting of

(1) hydrogen, and

(2) -Cl-ClO alkyl, which may be optionally substituted with 1 to 4 groups of R^A;

R4 is Cg-Cio aryl, and all other variables are as described above. In still another embodiment, compounds of formula Ila are realized when said alkyl is methyl and said aryl is phenyl.

Another embodiment of the invention is realized by compounds of structural Formula

Ob:

or pharmaceutically acceptable salts and individual enantiomers and diastereomers thereof wherein Ra is as previously described.

In another embodiment, compounds of Formula Ob are realized when

Ra is selected from the group consisting of

(1) -OR5_f and

(2) -CF₃.

IHa

or pharmaceutically acceptable salts and individual enantiomers and diastereomers thereof wherein R^a is as previously described.

In another embodiment, compounds of Formula Ilia are realized when R^a is selected from the group consisting of

(1) halogen, and

(2) -N(CH₃)2.

In still another embodiment, compounds of formula Ilia are realized when said halogen is fluoride.

Another embodiment of the invention is realized by compounds of structural Formula Illb:

or pharmaceutically acceptable salts and individual enantiomers and diastereomers thereof wherein R3 and R^a are as previously described. in another embodiment, compounds of Formula Illb are realized when

R3 is Cg-Cio aryl, which may be optionally substituted with 1 to 4 groups of Ra; and

R^a is selected from the group consisting of

(1) hydrogen,

(2) -N(CH3)2,

(3) -F, and

(4) -0(CH3)2.

In still another embodiment, compounds of formula Mb are realized when said aryl is naphthalene, which may be optionally substituted with 1 to 4 groups of Ra.

IIIc:

or pharmaceutically acceptable salts and individual enantiomers and diastereomers thereof wherein R4 and Ra are as previously described.

In another embodiment, compounds of Formula IIIc are realized when

R4 is selected from the group consisting of

(1) -Ci -C6 alkylenyl,

(2) -C3-C10 cycloalkyl, which is optionally substituted with 1 to 4 groups R^a, and

(3) -S(0)₂R3;

R3 is Cg-Cio aryl, which may be optionally substituted with 1 to 4 groups of R ; and

R^a is selected from the group consisting of

(1) -CN,

(2) -Ci-Ce alkyl, and

(3) -C6-Cio aryl.

In still another embodiment, compounds of formula IIIc are realized when said aryl is phenyl.

Specific embodiments of the compounds of the invention and methods of making them, as examples of compounds of the invention made according to the Examples that follow, include the compounds in Table 2 or a pharmaceutically acceptable salt, solvate, or in vivo hydrolysable ester thereof.

-8-

Specific embodiments of the present invention include a compound of the Examples or made according to the methods therein and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.

When any variable (e.g. aryl, heterocycle, R^aetc.) 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 -O- is 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, alkylenyl, alkoxy, alkanoyl, alkenyl, and alkynyl and means carbon chains which may be linear or branched or combinations thereof. The term "Ci-g" includes alkyls containing 6, 5, 4, 3, 2, or 1 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, and heptyl. "Alkylenyl" refers to an alkyl have substitutions at both ends. "Alkoxy" refers to an alkyl group connected to the oxy connecting atom and 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 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'). "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. Exemplary alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl.

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.

As used herein, "aryl" is intended to mean any stable monocyclic or bicyclic 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, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl,

dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, 1,3-dioxolanyI, furyl,

imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 2-oxopiperazinyl, 2-oxopiperdinyl, 2-oxopyrrolidinyl, piperidyl, piperazinyl, pyridyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyridazinyl, pyrirnidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuryl,

tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl, thienofuryl, thienothienyl, triazolyl and thienyl.

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 and four heteroatoms selected from the group consisting of N, O, and S, 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, benzothiazole, 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, thiophene, 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 "heteroatom" means O, S or N, selected on an independent basis.

The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

A group which is designated as being substituted with substituents, may be substituted with multiple numbers of such substituents, which may be the same or different, for example, with one to four groups of Ra. A group which is designated as being independently substituted with substituents may be independently substituted with multiple numbers of such substituents.

The compounds of the present invention may contain one or more asymmetric centers. Compounds with asymmetric centers give rise to enantiomers (optical isomers), diastereomers (configurational isomers) or both, and it is intended that all of the possible enantiomers and diastereomers in mixtures and as pure or partially purified compounds are included within the scope of this invention. The present invention is meant to encompass all such isomeric forms of the compound of formulas (I)-(ill). Compounds of formulas (I)-(III) are shown above without a definite stereochemistry. The present invention includes all stereoisomers of formulas (I)-(III) and pharmaceutically acceptable salts thereof.

The independent syntheses of the enantiomerically or diastereomerically enriched compounds, or their chromatographic separations, may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration and by appropriate modification of the methodology disclosed herein as known in the art. Their absolute stereochemistry may be determined by the x-ray crystallography of crystalline products or crystalline intermediates that 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 or diastereomers 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 diastereomeric 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 using chiral stationary phases, which methods are well known in the art.

During any of the above synthetic sequences it may be necessary or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J .F. W. McOmie, Plenum Press, 1 73, and T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1 99. The protecting groups may be removed at a convenient sequent stage using methods known from the art,

In the compounds of formulas (I )- (III), the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present invention is meant to include all suitable isotopic variations of the compounds of generic formulas (I) - (III). For example, different isotopic forms of hydrogen (H) include protium (^H) and deuterium (2H), Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.

Isotopically-enriched compounds within generic formulas (I) - (III) can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.

The term "substantially pure" means that the isolated material is at least 90% pure, and preferably 95% pure, and even more preferably 99% pure as assayed by analytical techniques known in the art.

The term "substituted" means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

By "stable compound' or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

The term "optionally substituted" means optional substitution with the specified groups, radicals or moieties,

The term "purified", "in purified form" or "in isolated and purified form" for a compound refers to the physical state of said compound after being isolated from a synthetic process (e.g. from a reaction mixture), or natural source or combination thereof. Thus, the term "purified", "in purified form" or "in isolated and purified form" for a compound refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan (e.g., chromatography, recrystallization and the like), in sufficient purity to be character izable by standard analytical techniques described herein or well known to the skilled artisan.

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 including inorganic or organic bases and inorganic or organic acids. The compounds of the invention may be mono, di or tris salts, depending on the number of acid functionalities present in the free base form of the compound. Free bases and salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like.

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 arginine, betaine, caffeine, choline, Ν,Ν'-dibenzylethylene-diamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethyl enediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, 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, triftuoroacetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, para-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 term "pharmaceutical composition" of the present invention

encompasses any composition made by combining a compound of the present invention and a pharmaceutically acceptable agent, including another active agent, carrier or diluent. 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 a compound 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) N 1 antagonists, viii) non-steroidal anti-inflammatory drugs ("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, and xiv) neurontin (gabapentin). 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.

The term "pharmaceutical composition" is also intended to encompass both the bulk composition and individual dosage units comprised of more than one (e.g., two) .

pharmaceutically active agents such as, for example, a compound of the present invention and an additional agent selected from the lists of the additional agents described herein, along with any pharmaceutically inactive excipients. The bulk composition and each individual dosage unit can contain fixed amounts of the afore-said "more than one pharmaceutically active agents". The bulk composition is material that has not yet been formed into individual dosage units. An illustrative dosage unit is an oral dosage unit such as tablets, pills and the like. Similarly, the herein-described method of treating a patient by administering a pharmaceutical composition of the present invention is also intended to encompass the administration of the afore-said bulk composition and individual dosage units.

It will also be appreciated that certain of the compounds of present invention can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative thereof. According to the present invention, a pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or any other adduct or derivative which upon administration to a patient in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof. 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 compound, which is a compound of formulae (I) to (IV), 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 admixing a compound of the present invention and a pharmaceutically acceptable carrier.

The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). Thus, the

pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil- in- water emulsion or as a water-in-oil liquid emulsion. In addition to the common dosage forms set out above, the compounds of the invention, or pharmaceutically acceptable salts thereof, may also be administered by controlled release means and/or delivery devices.

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 may contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. 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.

A tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Each tablet preferably contains from about 0.1 mg to about 500 mg of the active ingredient and each cachet or capsule preferably containing from about 0.1 mg to about 500 mg of the active ingredient.

Compositions for oral use may also be presented as hard gelatin capsules wherein the active ingredient is 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.

Other pharmaceutical compositions include aqueous suspensions, which contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. In addition, oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may also contain various excipients. The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions, which may also contain excipients such as sweetening and flavoring agents.

The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension, or in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi.

Pharmaceutical compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, or the like.

Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared via conventional processing methods. As an example, a cream or ointment is prepared by mixing hydrophilic material and water, together with about 5 wt% to about 10 wt% of the compound, to produce a cream or ointment having a desired consistency.

Pharmaceutical compositions of this invention can also be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art.

It will also be appreciated that the compounds and pharmaceutically acceptable compositions of the present invention can be employed in combination therapies, that is, the compounds and pharmaceutically acceptable compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures. The particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder (for example, an inventive compound may be administered concurrently with another agent used to treat the same disorder), or they may achieve different effects (e.g., control of any adverse effects). As used herein, additional therapeutic agents which are normally administered to treat or prevent a particular disease, or condition, are known as "appropriate for the disease, or condition, being treated". For example, exemplary additional therapeutic agents include, but are not limited to: nonopioid analgesics (indoles such as Etodolac, Indomethacin, Su!indac, Tolmetin; naphthylalkanones such as Nabumetone; oxicams such as Piroxicam; para-aminophenol derivatives, such as

Acetaminophen; propionic acids such as Fenoprofen, Flurbiprofen, Ibuprofen, Ketoprofen, Naproxen, Naproxen sodium, Oxaprozin; salicylates such as Aspirin, Choline magnesium trisalicylate, Diflunisal; fenamates such as meclofenamic acid, Mefenamic acid; and pyrazoles such as Phenylbutazone); or opioid (narcotic) agonists (such as Codeine, Fentanyl,

Hydromorphone, Levorphanol, Meperidine, Methadone, Morphine, Oxycodone, Oxymorphone, Propoxyphene, Buprenorphine, Buiorphano!, Dezocine, Nalbuphine, and Pentazocine).

Additionally, nondrug analgesic approaches may be utilized, in conjunction with administration of one or more compounds of the invention. For example, anesthesiology (intraspinal infusion, neural blocade), neurosurgical (neurolysis of CNS pathways), neurostimulatory (transcutaneous electrical nerve stimulation, dorsal column stimulation), physiatric (physical therapy, orthotic devices, diathermy), or psychologic (cognitive methods-hypnosis, biofeedback, or behavioral methods) approaches may also be utilized. Additional appropriate therapeutic agents or approaches are described generally in The Merck Manual, Seventeenth Edition, Ed. Mark H. Beers and Robert Berkow, Merck Research Laboratories, 1999, and the Food and Drug

Administration website, www.fda.gov, the entire contents of which are hereby incoiporated by reference.

The amount of additional, therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably, the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.

Accordingly, the present invention additionally provides any one of the aforementioned, methods further comprising administering to said patient an amount effective to treat said disease or disorder of at least one additional therapeutic agent, wherein the additional therapeutic agent(s) is/are selected from the group consisting of therapeutic agents known to be useful to treat said disease or disorder.

In one embodiment of this combination therapy method, the additional therapeutic agent(s) is/are selected from the group consisting of opiate agonists, opiate antagonists, calcium channel antagonists, 5HT receptor agonists, 5HT receptor antagonists, sodium channel antagonists, NMDA receptor agonists, NMDA receptor antagonists, COX-2 selective inhibitors, NK1 antagonists, non-steroidal anti-inflammatory drugs, selective serotonin reuptake inhibitors, selective serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressants,

norepinephrine modulators, lithium, valproate, neurontin and pregabalin.

The terms "administration of or "administering a" compound should be understood to mean providing a compound of the invention to the individual in need of treatment in a form that can be introduced into that individual's body in a therapeutically useful form and therapeutically useful amount, including, but not limited to: oral dosage forms, such as tablets, capsules, syrups, suspensions, and the like; injectable dosage forms, such as IV, IM, or IP, and the like;

transdermal dosage forms, including creams, jellies, powders, or patches; buccal dosage forms; inhalation powders, sprays, suspensions, and the like; and rectal suppositories.

The terms "effective amount" or "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.

As used herein, the term "treatment" or "treating" means any administration of a compound of the present invention and includes (1) inhibiting the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., arresting further development of the pathology and/or symptomatology), or (2) ameliorating the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., reversing the pathology and/or symptomatology).

The compositions containing compounds of the present invention may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. The term "unit dosage form" is taken to mean a single dose wherein all active and inactive ingredients are combined in a suitable system, such that the patient or person

administering the drug to the patient can open a single container or package with the entire dose contained therein, and does not have to mix any components together from two or more containers or packages. Typical examples of unit dosage forms are tablets or capsules for oral administration, single dose vials for injection, or suppositories for rectal administration. This list of unit dosage forms is not intended to be limiting in any way, but merely to represent typical examples of unit dosage forms.

The compositions containing compounds of the present invention may conveniently be presented as a kit, whereby two or more components, which may be active or inactive ingredients, carriers, diluents, and the like, are provided with instructions for preparation of the actual dosage form by the patient or person administering the drug to the patient. Such kits may be provided with all necessary materials and ingredients contained therein, or they may contain instructions for using or making materials or components that must be obtained independently by the patient or person administering the drug to the patient.

When treating or ameliorating a disorder or disease for which compounds of the present invention are indicated, generally satisfactory results are obtained when the compounds of the present invention are administered at a daily dosage of from about 0.1 mg to about 100 mg per kg of animal body weight, preferably given as a single daily dose or in divided doses two to six times a day, or in sustained release form. The total daily dosage is from about 1.0 mg to about 2000 mg, preferably from about 0.1 mg to about 20 mg per kg of body weight. In the case of a 70 kg adult human, the total daily dose will generally be from about 7 mg to about 1,400 mg. This dosage regimen may be adjusted to provide the optimal therapeutic response. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day,

The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for the oral administration to humans may conveniently contain from about 0.005 mg to about 2.5 g of active agent, compounded with an appropriate and convenient amount of carrier material. Unit dosage forms will generally contain between from about 0.005 mg to about 1000 mg of the active ingredient, typically 0.005, 0.01 mg, 0.05 mg, 0.25 mg, 1 mg, 5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg, administered once, twice or three times a day.

It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.

The pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracistemally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the l ike, depending on the severity of the infection being treated. In certain

embodiments, the compounds of the invention may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.

The inventive compounds and pharmaceutical composition of the invention have been found to modulate voltage-gated sodium channels. Accordingly, an aspect of this invention is the treatment of mammals of maladies that are amenable to amelioration through blocking, inhibiting, or any other form of modulating a voltage-gated sodium channel for therapeutic effect, including, but not limited to, acute pain, chronic pain, neuropathic pain, or inflammatory pain, arthritis, migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy or epilepsy conditions, neurodegenerative disorders, psychiatric disorders, such as, anxiety and depression, myotonia, arrhythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, nociceptive pain, breakthrough pain, postsurgical pain, tinnitus, or cancer pain by administering an effective amount of a compound of this invention. The term "mammal" includes humans, as well as other animals, such as, for example, dogs, cats, horses, pigs and cattle. Accordingly, it is understood that the treatment of mammals other than humans refers to the treatment of clinical conditions in non-human mammals that correlate to the above recited conditions.

In another aspect, this invention provides a method of treating a disease or disorder, including those disorders and conditions listed above, in a patient in need of such treating, wherein the method comprises administering to said patient an amount effective to treat said disease or disorder of a compound of this invention, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceuticall acceptable salt or solvate of said prodrug.

The present invention is further directed to a method for that manufacture of a

medicament for treating a disease or disorder, including those disorders and conditions listed above, in humans and animals comprising a compound of the present invention either alone or in combination 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 a disease or disorder associated with, the dysfunction of a voltage-gated sodium channel, including those disorders and conditions listed above, in humans and animals comprising a compound of the present invention either alone or in combination with one or more additional therapeutic agents, carriers, or diluents.

As described generally above, the compounds of the invention are useful as blockers of voltage-gated sodium channels. In one embodiment, the compounds and pharmaceutical compositions of the invention are blockers of one or more of NaVl .1, NaVl .2, NaV1.3, NaVl .4, NaVl .5, NaVl .6, NaVl .7, NaVl .8, or NaVl .9, and thus, without wishing to be bound by any particular theory, the compounds and pharmaceutical compositions are particularly useful for treating or lessening the severity of a disease, condition, or disorder where activation or hyperactivity of one or more of NaV 1.1 , NaV 1.2, NaV 1.3, NaV 1.4, NaV 1.5, NaVl .6, NaV 1.7, NaVl .8, or NaV 1.9 is implicated in the disease, condition, or disorder. When activation or hyperactivity of NaVl J, NaV1.2, NaVl .3, NaV 1.4, NaV 1.5, NaVl .6, NaVl .7, NaV 1.8, or NaV 1.9 is implicated in a particular disease, condition, or disorder, the disease, condition, or disorder may also be referred, to as a "NaVl.l , NaV 1.2, NaV 1.3, NaV 1.4, NaVl .5, NaVl .6, NaVl .7, NaVl .8 or NaV 1 ,9-mediated disease, condition or disorder." Accordingly, in another aspect, this invention provides a method for treating or lessening the severity of a disease, condition, or disorder where activation or hyperactivity of one or more of NaV 1.1, NaV 1.2, NaVl .3, NaVl .4, NaVl.5, NaVl .6, NaVl .7, NaVl .8 , or is implicated in the disease state.

The activity of a compound utilized in this invention as a blocker of NaVl.l , NaVl ,2, NaVl .3, NaVl .4, NaVl .5, NaVl ,6, NaVl .7, NaV1.8, or NaVl .9 may be assayed according to methods described generally in the Examples herein, or according to methods available to one of ordinary skill in the art. In certain exemplary embodiments, compounds of the invention are useful as blockers of NaVl .7. 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.

The compounds of the invention may be prepared according to the following reaction schemes, in which variables are as defined before or are derived, using readily available starting materials, from reagents and conventional synthetic procedures. It is also possible to use variants which are themselves known to those of ordinary skill in organic synthesis art, but are not mentioned in greater detail.

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.

EXAMPLES

The following abbreviations are used herein: ACN: acetonitrile; AcOH: acetic acid; Aq: aqueous; Boc: tert-butoxycarbonyl; Boc20: Boc anhydride; °C: degrees Celsius; calcd:

calculated; Cbz: Car bo benzyloxy : CbzCI: benzyl chloroformate; CDI: carbonyldiimidazole; DCE: 1,2-dichloroethane; DCM: dichloromethane; DIPEA: diisopropylethylamine; DMAP: 4- dimethylaminopyridine; DME: dimethoxyethane; DMF: Ν,Ν-dimethylformamide; DMSO:

methylsulfoxsde; EDCT: l-(3-di.methylaminopropyl)-3-ethylcarbodiimide hydrochloride; El: electron ionization; Eq: equivalents; EtOAc: ethyl acetate; EtOH: ethanol; g: grams; h: hours; ^lH: proton; HC1: hydrogen chloride; hex: hexanes; HOAT: l-hydroxy-7-aza-benzotriazole;

HOBT: 1-hydroxybenzotriazoIe; HPLC: high pressure liquid chromatography; LAH: lithium aluminum hydride; LCMS: liquid chromatography mass spectroscopy; M: molar; mM:

miilimolar; mmol: millimoles; Me: methyl; MeCN: acetonitrile; MeOH: methanol; min: minutes; mg: milligrams; MHz: megahertz; mL: milliliter; MPLC: medium pressure liquid

chromatography; MS: mass spectroscopy; N: normal; NaHC03: sodium bicarbonate; Na2SC>4: sodium sulfate; NMR: nuclear magnetic resonance; Obsd: observed; ON: overnight; Ph: phenyl; Py: pyridine; rt: room temperature; Satd: saturated; sgc: silica gel 60 chromatography; soln: solution; TEA: triethylamine; TFA: trifiuoroacetic acid; THF: tetrahydrofuran; TLC: thin layer chromatography; tj^: retention time: UV254 _nm: ultraviolet light 254 nm.

NMR spectra were acquired on the following instrument: 300 MHZ NMR (B raker) using CD3OD, CDCI3 or DMSO-d₆ as the solvent. LC-MS data were obtained using a PESciex API 150EX quadropole mass spectrometer using electrospray ionization or a Waters Acquity UPLC system with a Waters SQ Detector BEH CI 8 1.7 um. 2.1 x 50 mm.

Purification via reverse phase chromatography (Varian) was accomplished using a CI 8 reverse phase column with a gradient of (0.1 % TFA) 5:95 to 90: 10 acetonitrile: water, at a flow rate of 25 mL/min. Samples were collected using UV detection.

Normal phase silica gel chromatography was either accomplished by hand-packed silica columns or on an ISCO CombiFIash Rf system using RediSep Rf silica gel columns.

Several methods for preparing the compounds of this invention are illustrated in the following 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.

Example 1

N-(6-phenyI-6-azaspiro[2.5]octan- l~yl> 1 -naphthamide (1)

A. Preparation of ethyl 2-(l-phenylpiperidin-4-ylidene)acetate (lb)

Sodium hydride (1.10 g, 60% dispersion, 27.4 mmol) was added to ethyl 2- (diethoxyphosphoryl)acetate (6.14 g, 27.4 mmol) in DMF (9 mL) at 0°C portion-wise over 10 minutes. The mixture was stirred for 45 minutes at 0°C and then 15 minutes at room

temperature, l-phenylpiperidin-4-one (3.20 g, 18.3 mmol) in DMF (9 mL) was added drop-wise over 10 minutes and the resulting mixture was stirred at room temperature for 1.25 hours and then quenched with aqueous potassium hydrogen sulfate (50 mL, 5% solution), The mixture was neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried with sodium sulfate, and purified by flash column chromatography (silica gel, 7% EtOAc/hexanes) to afford lb (2,43 g, 54%) as a clear, yellow oil. MS (ESI): 246 (M + H)^÷

B. Preparation of ethyl 6-phenyl-6-azaspiro[2.5]octane-l-carboxylate (lc)

Potassium tert-butoxide (3.42 g, 30.6 mmol) was added portion-wise over 20 minutes to a suspension of trimethylsulfonium iodide (6.73 g, 30.6 mmol) in DMSO (8 mL) at room temperature. The mixture was stirred at room temperature for 45 minutes. Ethyl 2-(l- phenylpiperidin-4-ylidene) acetate (3.00 g, 12.2 mmol) in DMSO (31 mL) was added drop-wise over 30 minutes. The reaction was stirred at room temperature for 14 hours, cooled to 0°C, and quenched with brine. The reaction mixture was extracted with petroleum ether and the combined extracts were dried with sodium sulfate, filtered, and concentrated in vacuo to afford lc (1.88 g, 59%) as a clear, yellow oil. MS (ESI): 260 (M + H)⁺

C. Preparation of 6-phenyl-6-azaspiro[2.5]octane-l-carboxylic acid (Id)

Lithium hydroxide monohydrate (1,52 g, 36.3 mmol) was added to a solution of ethyl 6- phenyl-6-azaspiro[2,5]octane-l-carboxylate (lc) (1.88 g, 7.26 mmol) in THF (16 mL) and water (8 mL). The reaction was stirred at 60° C for 24 hours and then at room temperature for 2 days. Additional lithium hydroxide monohydrate (1.0 g, 24 mmol) was added and the reaction was heated to 60°C for 8 hours. The mixture was cooled to room temperature, diluted with water, and washed with EtOAc. The pH of the aqueous solution was adjusted to less than 4 with 10% aqueous citric acid and the resultant solution was extracted with methylene chloride. The organic extracts were dried with sodium sulfate, filtered, and concentrated in vacuo to afford Id (1.39 g, 83%) as a white solid. MS (ESI): 232 (M + H)⁺

D. Preparation of benzyl 6-phenyl-6-azaspiro[2.5]octan-l-ylcarbamate (le)

Diphenylphosphorylazide (1.56 mL, 7,22 mmol) in toluene (5 mL) was added drop- wise over ten minutes to a solution of 6-phenyl-6-azaspiro[2.5]octane-l-carboxylic acid (Id) (1.39 g, 6.02 mmol) and diisopropylethylamine (1.26 mL, 7.22 mmol) in toluene at room temperature. The reaction was stirred at room temperature for 30 minutes followed by 45 minutes at 90°C. Benzyl alcohol (0.78 mL, 7.22 mmol) in toluene (5 mL) was added and the reaction was heated to 1 10°C for 3 hours. The reaction was cooled to room temperature and partitioned between water and methylene chloride. The aqueous layer was extracted twice with methylene chloride and the combined extracts were dried with sodium sulfate, concentrated, and purified by flash column chromatography (silica gel, 2% methanol/methylene chloride) to afford le (2.02 g, 100%) as a clear, brown oil. MS (ESI): 337(M + H)⁺

The compounds in Table 3 were prepared according to the method of Example l .D.

Table 3

E. Pre

Purge a solution of benzyl 6-phenyl-6-azaspiro[2,5]octan-l-ylcarbamate (le) (2.02 g, 6.02 mmol) in ethanol (50 mL) with nitrogen for 10 minutes. Add palladium on carbon (10% Pd/C, 50% water, 330 mg), bubble hydrogen into the reaction mixture, and stir the reaction rapidly under a hydrogen atmosphere for 8 hours. Purge the reaction with nitrogen, filter through diatomaceous earth, such as Celite® (World Minerals, Inc., Santa Barbara, CA), and purify by flash column chromatography on silica gel to afford If (740 mg, 61%) as a clear, brown oil. MS (ESI): 203 (M + H)⁺

The compounds in Table 4 were prepared according to the method of Example I .E.

Table 4

4-3 221 ( + H)⁺

4-4 239 (M + H)⁺

F

F. Preparation of 6-(4-bromophenyl)-6-azaspiro[2.5]octan-l -amine (lh)

Add trifluoroacetic acid (0.2 mL) to a solution of tert-butyl 6-(4-bromophenyl)-6- azaspiro[2.5]octan-l-ylcarbamate (lg) (68 mg_} 0.18 mmol) in methylene chloride (1 mL) at 0°C. Stir the reaction at 0°C for 20 minutes, then at room temperature for 2.5 hours. Quench with saturated aqueous sodium bicarbonate and extract with methylene chloride. Dry the combined organic extracts with sodium sulfate, filter, and concentrate in vacuo to afford lh (44 mg_f 88%) as a yellow film. MS (ESI): 281 (M + H)⁺

G. Preparation of (SjS-Dimethoxypheny^iT'-methoxy-S'H-spirotpiperidine^^'-pyrrolotl^- a] quinoxaline] - 1 -yl)methanone hydrochloride (1)

1 -Naphthoic acid (84 mg, 0-49 mmol), EDCI (94 mg_; 0.49 mmol), HOAt (67 mg, 0.49 mmol), DMAP (40 mg, 0.33 mmol) and diisopropylethylamine (0.17 mL, 1.0 mmol) were combined with a solution of 6-phenyl-6-azaspiro[2.5]octan-l-amine (66 mg, 0.33 mmol) in methylene chloride (1 mL) and the reaction was stirred at room temperature for sixteen hours. The reaction mixture was loaded directly onto silica gel and eluted with 1 ,5%

methanol/methylene chloride. The desired fractions were concentrated and lyophilized from aqueous HCl/acetonitrile to afford 1 (91 mg, 78%) as a tan solid. MS (ESI): 357 (M + H)⁺ The compounds of Table 5 were prepared according to the method of Example 1.G.

Table 5

5-23 428 (M + H)

5-24 402 (M + H)

H. Preparation of 7^!-methoxy-5'H-spiro[piperidine-4,4'-pyrrolo[l _J2-a]quinoxaline] (5-25)

Imidazole (8 mg, 0.1 mmol) and potassium carbonate (28 mg, 0.20 mmol) were added to a solution of 4-fluoro-N-(6-phenyl-6-azaspiro[2.5]octan-l-yl)-l-naphthamide (5-11) (40 mg, 0.10 mmol) in DMSO (0.2 mL). The reaction was heated to 125°C for 21 hours, cooled to room temperature, and diluted with EtOAc. The organic solution was washed with brine, dried with sodium sulfate, and purified by flash column chromatography (silica gel, 2-7.5%

methanol/methylene chloride). The desired fractions were concentrated in vacuo and lyophiiized from water and acetomtrile to afford 5-25 (26 mg, 62%). MS (ESI): 423(M + H)⁺

Example 2

N-( 6-phenyl-6-azaspiro f2.5 ] octan- 1 -yl)-3,4-dihydroquinoime- 1 (2H)-carboxamide (2

Diisopropylethylamine (0.20 mL, 1.2 mL), DMAP (72 mg, 0.59 mmol), and 3,4- dihydroquinoline-l(2H)-carbonyl chloride (150 mg, 0.77 mmol) were added to a solution of 6- phenyl-6-azaspiro[2.5]octan-l-amine (If) (120 mg, 0.59 mmol) in methylene chloride (3 mL) at room temperature. The reaction was stirred overnight at room temperature, purified directly by flash column chromatography (silica gel, 25-35% EtOAc/hexanes), and the desired fractions lyophilized from acetonitrile and water to afford 2 (61 mg, 29%) as a light brown solid. MS (ESI): 362 (M + H)⁺

Example 3

N-(6-(3 -nitrophenyl)-6-azaspiro [2.5 Joctan- 1 -yl)- 1 -naphthamide (3)

A. Preparation of N~(6-azaspiro[2.5)octan-l-yl)-l-naphthamide (3a)

Trifluoroacetic acid (1.0 mL) is added to a solution of tert-butyl l~(l~naphthamido)-6- azaspiro[2.5]octane-6-carboxylate (5-1) (2.26 g, 5.97 mmol) in methylene chloride (30 mL) at 0°C. The reaction is stirred for 30 minutes at 0°C, then 1 hour at room temperature. The reaction mixture is applied directly to SCX bondesil resin (Varian). The resin is washed with methanol and then the product is eluted with 2 M ammonium hydroxide in methanol. The methanol solution is concentrated in vacuo to afford 3a.

B. Preparation of N-(6-(3-nitrophenyl)-6-azaspiro [2.5] octan-l-yl)-l -naphthamide (3)

Potassium carbonate (74 mg, 0.54 mmol) and l-fluoro-3 -nitrobenzene (50 mg, 0.36 mmol) are added to a solution of N-(6-azaspiro[2.5]octan-l-yl)-l-naphthamide (100 mg, 0.36 mmol) in DMSO (0.7 mL) at room temperature. The reaction mixture is heated to 90°C for 6 hours, cooled to room temperature, and diluted with EtOAc. The EtOAc solution is washed with brine, dried with sodium sulfate, and concentrated in vacuo. The residue is purified by flash column chromatography (silica gel, 2% methanol/methylene chloride). The desired fractions are concentrated in vacuo and triturated from acetonitrile to afford 3. The compounds of Table 6 were prepared according to the method of Example 3.B. Table 6

C. Preparation of N-(6-(4-chlorophenyl)-6-azaspiro[2,5]octan-l-yl)-l-naphthamide (6-6)

Copper(II) acetate (80 mg, 0.44 mmol), 4-chlorophenylboronic acid (113 mg, 0.72), and 4A powdered molecular sieves (300 mg) were added to a solution of N-(6-azaspiro[2.5]octan-l- yl)-l-naphthamide (3a) (100 mg, 0,36 mmol) in methylene chloride (1.5 mL). The suspension was stirred rapidly, opened to the air, for 36 hours, then filtered through diatomaceous earth, such as Celite® (Mineral Worlds, Inc., Santa Barbara, CA) and purified by flash column chromatography followed by passage through SCX resin. The solution was concentrated in vacuo and lyophilized from acetonitrile and water to afford 6-6 (12 mg, 9%) as a white solid. MS (ESI): 391 (M + H)⁺

The compounds of Table 7 were prepared according to the method of Example 3.C.

Table 7

Example 4

l-(l-naphthamido)-N-phenyl-6-a2aspiro|^'2.51octane-6-carboxamide (4)

N-(6-azaspiro[2.5]octan-l-yl)-l-naphthamide (3a) (50 mg, 0.178 mmol) and TEA (0.05 mL, 0.356 mmol) were combined in 2 mL acetonitrile, cooled to 0°C, and phenyl isocyanate (0.04 mL, 0.356 mmol) was added. The reaction was allowed to room temperature over 18 hours. The product was isolated by filtration from the reaction mixture and oven dried to afford 4 (47.5 mg, 75%) as a white solid. MS (ESI): 400 (M + H)⁺

The compounds of Table 8 were prepared according to the method of Example 4.

Table 8

Example 5

N-(6-benzoyl-6-azaspiro[2.5 octan-l-yl -l-naphthamide (5)

Benzoic acid (33 mg, 0.268 mmol), EDCI (52 mg, 0.268 mmol), HOAt (37 mg, 0.268 mmol), DMAP (33 mg, 0.268 mmol) and diisopropylethylamine (0.07 mL, 0.535 mmol) were combined with a solution of N-(6-azaspiro[2.5]octan-l-yl)-l-naphthamide (3a) (50 mg, 0.178 mmol) in methylene chloride (2 mL) and the reaction was stirred at room temperature for 1 hours. The reaction mixture was loaded directly onto silica gel and eluted with 0-20% methanol/methylene chloride. The desired jfractions were concentrated then co-evaporated with diethyl ether to afford 5 (46.4 mg, 68%) as a white solid. MS (ESI): 385 (M + H)⁺

The compounds of Table 9 were prepared according to the method of Example 5. Table 9

N-(6-benzyl-6-azaspiro [2.5] octan- 1 -yl)- 1 -naphthamide hydrochloride^)

Benzyl chloride (35 mg, 0.268 mmol) and DIPEA (0.07 mL, 0.535 mmol) were combined with a solution of N-(6-azaspiro [2.5] octan- l-yl)-l -naphthamide (3a) (50 mg, 0.178 mmol) in methylene chloride (2 mL) and the reaction was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and purified by preparatory reverse-phase HPLC. The desired fractions were concentrated and lyophilized from aqueous HCl/acetonitrile to afford 6 (8.7 mg, 14%) as a white solid. MS (ESI): 371 (M + H)⁺ The compounds of Table 10 were prepared according to the method of Example 6.

Table 10

Example 7

6-benzoyl-N-f 2- f piperidin- 1 - yl )phenyl)-6-azaspiro[2.5 ] octane- 1 -carboxamide (7)

A. Preparation of ethyl 6-azaspiro[2.5]octane-l-carboxylate (7b)

7a 7b

TFA (3.5 mL) was added to a solution of 6-tert-butyl 1 -ethyl 6-azaspiro[2.5]octane-l,6- dicarboxylate (7a) (1.0 g, 3.5 mmol) in methylene chloride (18 mL) at 0 °C, The reaction was stirred at 0°C for 30 minutes and then at room temperature for 1 hour. The reaction was quenched with saturated aqueous sodium bicarbonate and extracted with methylene chloride. The combined organic extracts were dried with sodium sulfate and concentrated in vacuo to afford 7b (590 mg, 91%) as a clear, yellow oil. MS (ESI): 184 (M + H)⁺

B. Preparation of ethyl 6-benzoyl-6-azaspiro[2.5]octane-l-carboxylate (7c)

EDCI (920 mg, 4.8 mmol), HOAt (660 mg, 4.8 mmol), DMAP (390 mg, 3.2 mmol), and benzoic acid (510 mg, 4.2 mmol) were added to a solution of ethyl 6-azaspiro[2.5]octane-l- carboxylate (7b) (590 mg, 3.2 mmol) in methylene chloride (16 mL). DIPEA (1.7 mL, 9.7 mmol) was added and the reaction was stirred at room temperature for 16 hours. The reaction mixture was diluted with methylene chloride and washed with 1 M HC1, saturated aqueous sodium bicarbonate, and brine. The organic solution was dried with sodium sulfate, concentrated in vacuo, and purified by flash column chromatography (silica gel, 1.5% methanol/methylene chloride) to afford 7c (870 mg, 94%) as a clear, yellow oil. MS (ESI): 288

(M + H)⁺

C. Preparation of 6-benzoyl-6-azaspiro[2.5]octane-l-carboxylic acid (7d)

7d Lithium hydroxide monohydrate (1 0 mg, 3.7 mmol) was added to a solution of ethyl 6- benzoyl-6-azaspiro[2.5)octane-l-carboxylate (7c) (350 mg, 1.2 mmol) in THF (4.5 mL) and water (1.5 mL). The reaction was stirred for 20 hours at room temperature and then additional lithium hydroxide monohydrate (75 mg, 1.7 mmol) was added and stirring continued for 28 hours. The reaction quenched with HCl (2 M aqueous) and extracted with methylene chloride. The combined extracts were dried with sodium sulfate and concentrated in vacuo to afford 7d (320 mg, 100%) as an off-white solid. MS (ESI): 260 (M + H)⁺

D. Preparation of 6-benzoyl-N-(2-(piperidin- 1 -y l)phenyl)-6-azaspiro [2.5] octane- 1 -carboxamide (7)

EDCI (44 mg, 0.23 mmol), HOAt (32 mg, 0.23 mmol), DMAP (18 mg, 0.15 mmol), and 2-(piperidin-l-yl)aniline (41 mg, 0.23 mmol) were added to a solution of 6-benzoyl-6- azaspiro[2.5]octane-l-carboxylic acid (7d) (40 mg, 0.15 mmol) in methylene chloride (0.8 mL). DIPEA (0.080 mL, 0.46 mmol) was added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was loaded directly onto silica gel and eluted with 2% methanol/methylene chloride. The fractions of interest were concentrated in vacuo and lyophilized from acetonitrile and aqueous HCl to afford 7 (69 mg, 95%) as a white solid. MS (ESI): 418 (M + H)⁺

The compounds of Table 11 were prepared according to the method of Example 7.

Table 11

Example 8

Assay Methods

A. Cell Culture

The pore-forming subunits of human voltage gated sodium channels were stably expressed in either HEK 293 cells of CHO-K1 cells. Cells were maintained in standard growth media containing 10% heat-inactivated fetal bovine serum and a selection antibiotic. The cells were grown at 37°C in a humidified tissue culture incubator with the carbon dioxide

concentration regulated at 5%.

B. FLIPR evaluation of sodium channel activity

A FLIPR assay using a membrane potential dye (Molecular Devices Corporation, blue no wash voltage-sensitive dye) was used to screen for sodium channel activity of compounds. Cells were plated onto black- walled 384 well plates with poly-lysine-coated glass bottoms 24 hours prior to evaluation on the FLIPR. On the day of experiment, the growth medium was removed and replaced with a physiological saline solution containing voltage-sensitive dye and compounds of interest. After dye loading for 60 minutes, cell depolarization was evoked on the FLIPR by the addition of veratridine. Maximum veratridine-induced increase in fluorescence intensity from baseline was used to plot concentration-effect curves. Non-linear regression analysis was used to generate IC50 values.

Compounds according to the invention showed greater than 30% activity at 30 μΜ. C. Voltage clamp measurement of sodium channel activity

Standard ruptured whole cell patch clamp techniques were used to measure sodium channel blocking activity. All studies were conducted at room temperature using a flowing extracellular solution containing (mM concentrations): 129 NaCl, 20 tetraethylammonium chloride, 3.25 C1, 2 CaCl2, 2 MgCl2, 10 glucose, 10 HEPES-NaOH (pH 7.35). The glass whole cell patch electrodes for these studies had tip resistances of approximately 1.5 ΜΩ when filled with the following intracellular solution (mM concentrations): 120 CsF, 10 NaCl, 10 tetraethylammonium chloride, 11 EGTA, 1 CaCi₂, 1 MgCl₂, 10 HEPES-CsOH (pH 7.3).

Currents were evoked with 50 millisecond voltage steps from a holding potential of -120 mV to a potential corresponding to the peak of the transient inward current- voltage relationship of the subtype of voltage-gated sodium current being studied. The stimulation frequency was 10 Hz unless noted otherwise. The fraction of baseline current remaining after exposure to compound was used to construct concentration-effect curves which were fit by non-linear regression analysis to generate IC50 values.

Compounds according to the present invention showed activity in the foregoing assays in the range of 100 nM to 30000 nM. Compounds of the invention have an IC50 of less than 1000 nM. Activity for representative compounds of the invention are shown in Table 12,

Table 12

-9 6-azaspiro[2.5] octane- 1 - 822.65 methanamine, n-(l- ethynylcyclohexyl)-6- phenyl-

-6 4-(dimethylarnino)-n-(6- 98.33 phenyl-6-azaspiro[2.5]oct-l - yl)-l- naphthalenecarboxamide -4 N - [6-(3 -fluorophenyl)-6- 650.01 azaspiro [2.5] oct- -yl] - 1 - naphthaienecarboxamide

-1 1 4-fluoro-n-(6~phenyl-6- 188.52 azaspiro [2.5] oct- 1 -yl)- 1 - naphthaienecarboxamide -12 4₅7-dimethoxy-n-(6~phenyl- 232.59

6-azaspiro[2.5]oct-l-yl)-l- naphthalenecarboxamide

-7 5-(dimethyIamino)-n-(6- 237.63 phenyl-6-azaspiro [2.5] oct- 1 - yl)-l- naphthaienecarboxamide 2-58 4- ( 1 h-imidazol- 1 -y l)-n-(6- 780.99 phenyl-6 -azaspiro [2.5 ] oct- 1 - yl)-l- naphthalenecarboxamide

10-2 N-[6-[[4- 706.23

1 1 1 (trifluoromethyI)phenyl]meth

yl] -6-azaspi ro[2.5 ] oct- 1 -y 1] - 1 -naphthalenecarboxamide

10-1 N-[6-[(3,5- 977.33 dimethoxyphenyl)niethyl]-6- azaspiro [2.5 ]oct-l -yl] - 1 - naphthalenecarboxamide

5-21 N-[6-(3,5-difluorophenyl)-6- 151.225 azaspiro[2.5]oct-l -yl]-4- (dimethylamino)- 1 - naphthalenecarboxamide

The present invention is not to be limited by the specific embodiments disclosed in the examples that are intended as illustrations of a few aspects of the invention and any

embodiments that are functionally equivalent are within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art and are intended to fall within the scope of the appended claims.

Claims

WHAT IS CLAIMED:

1. A compound of structural Formula I:

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

Z is selected from the group consisting of

(1) a bond,

(2) -C1-C6 alkyl,

(3) -C(OK

(4) -C(0)0-,

(5) -C(0)N-, and

(6) -S(0)2-,

wherein said alkyl may be optionally substituted with 1 to 4 groups of R^a;

Rl is selected from the group consisting of

(1) hydrogen,

(2) -C6-Cio aryl, and

(3) -C5-Cio heteroaryl,

wherein said aryl and heteroaryl may be optionally substituted with 1 to 4 groups of R^a;

R2 is selected from the group consisting of

(1) hydrogen,

(3) -C(0)NR3R4

(4) -(CH2)nC5-Cio heterocyclyl, which may be optionally substituted with 1 to 4 groups of R^a, and

(5) -NR3C(0)OR4;

R3 is selected from the group consisting of

(1) hydrogen,

(2) -Ci-Cio alkyl,

(3) -C5-C10 heterocyclyl,

(4 CH2)_nC6-Cio aryl,

(5) -S(0)2, and

wherein said alkyl, heterocyclyl, and aryl may be optionally substituted with 1 to 4 groups of R^a; R4 is selected from the group consisting of

(1) hydrogen,

(2) -(CH2)_nC6-Cio aryL

(3) -C(0)R3, (4) _C_rC₆ alkyl,

(5) -C5-C10 heterocyclyl,

(6) -S(0)₂ 3, and

(7) -C₃-C₁₀ cycloalkyl,

wherein said aryl, alkyl, heterocyclyl, and cycloalkyl may be optionally substituted with 1 to 4 groups of R^a;

R5 is selected from the group consisting of

(1) hydrogen,

(2) -C6-Cio aryl,

(3) -C1-C10 alkyl, and

(4) -CF_3j

wherein said aryl and alkyl may be optionally substituted with 1 to 4 groups of R^a;

R^a is selected from the group consisting of

(1) hydrogen,

(2) halogen,

(3) -C1-C10 alkyl,

(4) -(CH2)n C₃-Cio cycloalkyl,

(5) -C6-Cio ryI,

(6) -C5-C10 heteroaryl,

(7) -C5-C10 heterocyclyl,

(12) -CN,

(13) -CF3, and

(14) ~N0₂,

wherein said alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl may be optionally substituted with 1 to 4 groups of Ci-Cg alkyl;

n is 0 to 4; and

2. A compound according to claim 1 represented by structural Formula Ila:

Ila or pharmaceutically acceptable salts and individual enantiomers and diastereomers thereof wherein:

R.3 is selected from the group consisting of

(1) hydrogen, and

(2) ~Ci-Cio alkyl, which may be optionally substituted with 1 to 4 groups of R^a; and R4 is Cg-Cio aryl.

3. A compound according to claim 2 wherein said alkyl is methyl and said aryl is phenyl

4. A compoun Formula Ob:

Ra is selected from the group consisting of

(1) -OR5, and

(2) -CF₃.

5. A Formula Ilia:

R^a is selected from the group consisting of

(1) halogen, and

(2) -N(CH₃)2.

A compound of claim 5 wherein said halogen is fluoride.

A compound according to claim 1 represented by structural Formula Illb:

I S is C^-Cio aryl, which may be optionally substituted with 1 to 4 groups of and

R^a is selected from the group consisting of

(1) hydrogen,

(2) -N(CH₃)2,

(3) -F, and

(4) -0(CH₃)2-

8. A compound according to claim 7 wherein said aryl is naphthalene, which may be optionally substituted with 1 to 4 groups of R^a.

9. A comp by structural Formula IIIc:

IIIc

R4 is selected from the group consisting of

(1) -Ci-C₆ alkyl,

(2) -C3-C10 cycloalkyl, which is optionally substituted with 1 to 4 groups Ra,

(3) -S(0)₂R3;

R3 is Cg-Cjo aryl, which may be optionally substituted with 1 to 4 groups of R¾; and

R^a is selected from the group consisting of

(1) -CN,

(2) -Ci-C6 alkyl, and

(3) -C6-C10 aryl.

10. A compound according to claim 9 wherein said aryl is phenyl,

1 1 , A compound according to claim 1 selected from the group consisting of:

6-azaspiro[2.5]octane-l -methanamine, 6-(phenylmethyl)-n-[2-(l -piperidinyl)phenyl]-,

6-azaspiro [2.5] octane- 1 -methanamine, n-ethy l-n-(3 -methylpheny l)-6-(pheny lmethy 1)-,

1 -naphthalenecarboxamide, n-(6~phenyl-6-azaspiro[2.5]oct- 1 -yl)-₅

6-azaspiro[2.5]octane, 6-benzoyM-[[[2-(l-piperidinyl)phenyl]amino]methyl]-,

6-azaspiro [2.5] octane- 1 -methanamine, n-(l ,2-diphenylethyl)-6-phenyl-,

6-azaspiro[2.5]octane- 1 -methanamine, 6-phenyl-n-[(2s)-2-phenylpropyl]-,

6-azaspiro[2.5]octane, 1 -[[4-(cyclohexylmethyl)- 1 -piperazinyl]methyl]-6-(phenylsulfonyl)-, 1 (2h)-quinolinecarboxamide, 3 ,4-dihydro~n-(6-phenyl-6-azaspiro [2.5] oct- 1 -yl)-, Benzenesulfonamide, 2,3 ,5,6-tetramethyl-n-(6-phenyl-6-azaspiro[2.5]oct-l -yl)-, 6-azaspiro[2.5]octane-l-methanamine, n-(l-ethynylcyclohexyl)-6-phenyl-_f

4-(diraethylamino)-n-(6-phenyl-6-azaspiro[2.5]oct-l-yl)-l-naphthalenecarboxamide_i

N- [6-(3 -fluorophenyl )-6-azaspiro [2 , 5 ] oct- 1 -yl]- 1 -naphthaleneoarboxamide ,

4-fluoro-n-(6-phenyl-6-azaspiro[2.5]oct-l -yi)-l -naphthalenecarboxamide,

4,7-dimethoxy-n-(6-phenyl-6-azaspiro[2.5]oct-l-yl)-l-naphthalenecarboxamide,

5 -(dimethy lamino)-n- (6-pheny 1-6-azaspiro [2.5]oct- 1 -y 1)- 1 -naphthalenecarboxamide,

4 -( 1 h-imidazo 1- 1 -y 1 )-n-(6-phenyl-6-azaspiro [2.5] oct- 1 -y 1)- 1 -naphthalenecarboxami de , N-[6-[[4-(trifluoromethyl)phenyl3methyl3-6-azaspiro[2.5]oct- 1 -yl]- 1 -naphthalenecarboxamide, N-[6-[(3,5-dimethoxyphenyl)methyl]-6-azaspiro[2.5]oct-l-yl]-l-naphthalenecarboxamide, and N-[6-(3,5-difluorophenyl)-6-azaspiro[2.5]oct- 1 -yl]-4-(dimethylamino)- 1 - naphthalenecarboxamide.

12. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 1 or a pharmaceutically acceptable salt thereof.

13. Use of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of chronic and neuropathic pain.

14. A method for treating a disorder or condition associated with dysfunction of a voltage- gated sodium channel 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.

15. A method for treating a disorder or condition of claim 14 wherein said voltage- gated sodium channel is Nav 1.7.