WO2009079630A1 - 4-imidazolidinones as kv1.5 potassium channel inhibitors - Google Patents

Abstract

The present teachings relate to 4-imidazolidinones of Formula (Ia) or (Ib) which are useful as Kv1.5 potassium channel inhibitors providing atrial-selective antiarrhythmic activity. The present teachings further relate to compositions and methods for treating atrial-selective antiarrhythmia.

Description

4-IMIDAZOLIDINONES AS KV1.5 POTASSIUM CHANNEL INHIBITORS

FIELD OF THE INVENTION

The present invention relates to compounds that are effective as Kv1.5 potassium channel inhibitors The present invention also relates to compositions comprising 5 certain Kv1 5 potassium channel inhibitors, and to methods for treating cardiac arrhythmia

BACKGROUND OF THE INVENTION

Atrial fibrillation (AF) is a frequently encountered cardiac arrhythmia in the clinical setting It affects nearly 3 million people in the United States and its prevalence

10 increases with the aging of the population AF is most often treated with class III antiarrhythmic agents, acting at both the atrial and ventricular levels Commonly used or prescribed antiarrhythmic drugs inhibit various potassium channels, and prolong ventricular repolarization. Prolongation of ventricular repolarization can in turn precipitate the occurrence of life-threatening-ventricular arrhythmias, mainly

15 Torsades de Pointes (TdP)

Certain atrial-selective antiarrhythmic agents offer one possibility of increased therapeutic efficacy and safety by minimizing cardiac proarrhythmia inherent in conventional antiarrhythmic therapies

There is an unmetneed to provide certain new compounds that function as effective

20 atrial-selective antiarrhythmic agents and which do not affect ventricular rhythm In addition, there is an unmet need to provide certain new compounds that function as effective atrial-selective antiarrhythmic agents and that are compatible with other cardiac devices, cardiac protocols, therapies, and medications References related to

Kv1 5 potassium channel include: Brendel, J , et al , Curr Med Chem. 2003, 1 , 273-

25 287, Firth, A L., et al , 2008, 33, 31-47; Vidaillet, H , et al , Am J. Med 2002, 113,

365-370, Tsang, T S M , et al., Am J Med 2002, 113, 432-435, Yang, Q , et al , Expert Opin. Ther Patents 2007, 17, 1443-1456, Regan, C P , et al , J Cardiovasc Pharmacol. 2007, 49, 236-245, Nattel, S. Physiol. Rev. 2007, 87, 425-456, Tombola, F , et al , Annu Rev Cell Dev Biol. 2006, 22, 23-52, and Wirth, K J , et al., J Cardiovasc Pharmacol 2007, 49, 197-206

SUMMARY OF THE INVENTION

The present invention provides compounds of Formula (Ia) or (Ib):

or pharmaceutically acceptable salts thereof,

wherein¹

Ar¹ is a C₆-C₁₀ aryl ring or a 5-14 membered heteroaryl ring, each of which is optionally substituted with 1 , 2, 3 or 4 substituents independently selected from Cr₆ alkyl, F, Cl, Br, I, C₃-₆ cycloalkyl C,-₆ alkoxy, OH, NH₂, NH(C_{1 β} alkyl), N(C_{1 e} alkyl)₂, NO₂, C_{1 3} haloalkyl, SH, SCL₆ alkyl and CN,

Ar² is a C₆-C₁₀ aryl ring or a 5-14 membered heteroaryl ring, each of which is optionally substituted with 1 , 2, 3 or 4 substituents independently selected from C_r6 alkyl, F, Cl, Br, I, C₃-₆ cycloalkyl, C_r6 alkoxy, OH, NH₂, NH(C_{1 6} alkyl), N(C_{1 6} alkyl)₂, NO₂, C_{1 3} haloalkyl, SH, -SC_{1 6} alkyl and CN,

each X is independently -CR³R⁴-,

each L is independently -CR⁵R⁶-,

R¹, R², R³, R⁴, R⁵ and R⁶ are each independently selected from H, halogen and C_1-6 alkyl optionally substituted with 1 , 2, 3 or 4 substituents independently selected from C₁-_B alkyl, F₁CI, Br, I, C_rβ alkoxy, OH, NH₂, NO₂, C_{1 3} haloalkyl, SH, S-C_{1 6} alkyl and CN;

R⁷ and R⁸ are each independently selected from H and C_r6 alkyl optionally substituted with 1 , 2, 3 or 4 substituents independently selected from F, Cl, Br, I, C_r6 alkoxy, OH, NH₂, NO₂, C_{1 3} haloalkyl, SH, -SCL₆ alkyl, CN, C₃.₁₀ cycloalkyl, a 3-10 membered heterocyclyl ring, C₆-, C₁₀-aryl ring, and a 5-10 membered heteroaryl ring;

Y is a countenon,

n is 1 , 2, 3, 4 or 5, and

p IS O, 1 , 2, 3 or 4

The present invention also provides compositions comprising an effective amount of one or more compounds of Formula (Ia) or (Ib) and one or more excipients.

The present invention also provides a method for treating or preventing cardiac arrhythmias, for example atrial arrhythmia, including but not limited to, atrial fibrillation and atrial flutter, said method comprising administering to a subject an effective amount of a compound of Formula (Ia) or (Ib) according to the present invention. The present invention also provides a method for treating or preventing cardiac arrhythmias, for example atrial arrhythmia, including but not limited to, atrial fibrillation and atrial flutter, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds of Formula (Ia) or (Ib) according to the present invention and one or more excipients.

The present invention also provides methods for treating or preventing diseases or conditions associated with cardiac arrhythmias, including but not limited to, thromboembolism, stroke, and heart failure In some embodiments, the methods comprise administering to a subject an effective amount of a compound of Formula (Ia) or (Ib) according to the present invention.

The present invention further provides methods for treating or preventing diseases or conditions associated with cardiac arrhythmias, including but not limited to, thromboembolism, stroke, and heart failure, wherein said method comprises administering to a subject a composition comprising an effective amount of one or more compounds of Formula (Ia) or (Ib) according to the present invention and one or more excipients

The present invention also provides a method for inducing cardioversion, said method comprising administering to a subject an effective amount of a compound Formula (Ia) or (Ib) according to the present invention.

The present invention also provides a method for inhibiting Kv1 5 potassium channel in a subject comprising administering a therapeutically effective amount of a compound of Formula (Ia) or (Ib) to the subject

The present invention also provides a method for treating or preventing a disorder associated with inhibition of Kv1 5 potassium channel in a subject comprising administering a therapeutically effective amount of a compound of Formula (Ia) or (Ib) to the subject As an example, these compounds are useful in treating atrial arrhythmia, thromboembolism, stroke or cardiac failure These and other objects, features, and advantages will become apparent to those skilled in the art from a reading of the following detailed description and the appended claims

DETAILED DESCRIPTION OF THE INVENTION Kv1 5 potassium channel inhibitors of the present invention are capable of treating and preventing arrhythmia in the atrial portion of the human heart or in the heart of certain animals It has been discovered that functional Kv1 5 potassium channels are found in human atrial tissue but not in human ventricular myocytes Without wishing to be limited by theory, it is believed the inhibition of the Kv1 5 voltage-gated Shaker-like potassium (K^*) ion channel can ameliorate, abate, or otherwise cause to be controlled, atrial fibrillation and flutter without prolonging ventricular repolarization

DEFINITIONS

As used herein, all percentages, ratios and proportions herein are by weight, unless otherwise specified All temperatures are in degrees Celsius (⁰C), unless otherwise specified All documents cited are in relevant part; the citation of any document is not to be construed as an admission that it is prior art with respect to the present invention.

Throughout the description, where compositions are described as having, including, or comprising specific components, or where processes are described as having, including, or comprising specific process steps, it is contemplated that compositions of the present invention also consist essentially of, or consist of, the recited components, and that the processes of the present teachings also consist essentially of, or consist of, the recited processing steps

In this specification, where an element or component is said to be included in and/or selected from a list of recited elements or components, it should be understood that the element or component can be any one of the recited elements or components and can be selected from a group consisting of two or more of the recited elements or components.

The use of the singular herein includes the plural (and vice versa) unless specifically stated otherwise In addition, where the use of the term "about" is before a quantitative value, the present invention also includes the specific quantitative value itself, unless specifically stated otherwise

It should be understood that the order of steps or order for performing certain actions is immaterial so long as the present teachings remain operable Moreover, two or more steps or actions can be conducted simultaneously.

As used herein, unless otherwise noted, "alkyl" whether used alone or as part of a substituent group refers to a saturated straight and branched carbon chain having 1 to 20 carbon atoms or any number within this range, for example, 1 to 6 carbon atoms or 1 to 4 carbon atoms. Designated numbers of carbon atoms (e.g. C_{1 6}) shall refer independently to the number of carbon atoms in an alkyl moiety or to the alkyl portion of a larger alkyl-containing substituent Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, jso-propyl, n-butyl, sec-butyl, (so-butyl, fert-butyl, and the like Where so indicated, alkyl groups can be optionally substituted. In substituent groups with multiple alkyl groups such as N(C₁.₆alkyl)₂, the alkyl groups may be the same or different

As used herein, unless otherwise noted, "alkoxy" refers to groups of formula -Oalkyl. Designated numbers of carbon atoms (e.g. -OCi ₆) shall refer independently to the number of carbon atoms in the alkoxy group Non-limiting examples of alkyl groups include methoxy, ethoxy, n-propoxy, /so-propoxy, n-butoxy, sec-butoxy, /so-butoxy, ferf-butoxy, and the like. Where so indicated, alkoxy groups can be optionally substituted

As used herein, the terms "alkenyl" and "alkynyl" groups, whether used alone or as part of a substituent group, refer to straight and branched carbon chains having 2 or more carbon atoms, preferably 2 to 20, having at least one carbon-carbon double bond ("alkenyl") or at least one carbon-carbon triple bond ("alkynyl"). Where so indicated, alkenyl and alkynyl groups can be optionally substituted Nonlimiting examples of alkenyl groups include ethenyl, 3-propenyl, 1-propenyl (also 2- methylethenyl), isopropenyl (also 2-methylethen-2-yl), buten-4-yl, and the like. Nonlimiting examples of alkynyl groups include ethynyl, prop-2-ynyl (also propargyl), propyn-1-yl, and 2-methyl-hex-4-yn-1-yl

As used herein, "cycloalkyl," whether used alone or as part of another group, refers to a non-aromatic hydrocarbon ring including cyclized alkyl, alkenyl, or alkynyl groups, e.g., having from 3 to 14 ring carbon atoms, for example, from 3 to 7 or 3 to 6 ring carbon atoms, and optionally containing one or more (e.g , 1 , 2, or 3) double or triple bonds Cycloalkyl groups can be monocyclic (e g., cyclohexyl) or polycyclic (e.g., containing fused, bridged, and/or spiro ring systems), wherein the carbon atoms are located inside or outside of the ring system Any suitable ring position of the cycloalkyl group can be covalently linked to the defined chemical structure Where so indicated, cycloalkyl rings can be optionally substituted Nonlimiting examples of cycloalkyl groups include: cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctanyl, decalinyl, octahydropentalenyl, octahydro-1H-indenyl, 3a,4,5,6,7,7a-hexahydro-3H-ιnden-4-yl, decahydroazulenyl; bιcyclo[6 2 0]decanyl, decahydronaphthalenyl, and dodecahydro-1H-fluorenyl The term "cycloalkyl" also includes carbocyclic rings which are bicyclic hydrocarbon rings, non-limiting examples of which include, bιcyclo-[2 1.1]hexanyl, bιcyclo[2 2 1]heptanyl, bιcyclo[3.1.1]heptanyl, 1 ,3-dimethyl[2.2.1]heptan-2-yl, bιcyclo[2.2.2]octanyl, and bicyclo[3 3 3]undecanyl.

"Haloalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen atoms. As used herein, halogen refers to F, Cl, Br and I Haloalkyl groups include perhaloalkyl groups, wherein all hydrogens of an alkyl group have been replaced with halogens (e g , -CF₃, -CF₂CF₃) The halogens can be the same (e g , CHF₂, -CF₃) or different (e g , CF₂CI) Where so indicated, haloalkyl groups can optionally be substituted with one or more substituents in addition to halogen. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, dichloroethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl groups

The term "aryl," wherein used alone or as part of another group, is defined herein as an aromatic monocyclic ring of 6 carbons or an aromatic polycyclic ring of from 10 to 14 carbons Aryl groups include but are not limited to, for example, phenyl or naphthyl (e.g., naphthylen-1-yl or naphthylen-2-yl) Where so indicated, aryl groups may be optionally substituted with one or more substituents Aryl groups also include, but are not limited to for example, phenyl or naphthyl rings fused with one or more saturated or partially saturated carbon rings (e g , bicyclo[4.2 0]octa-1 ,3,5- trienyl, indanyl), which can be substituted at one or more carbon atoms of the aromatic and/or saturated or partially saturated rings

The terms "heterocyclic," "heterocycle," and "heterocyclyl," whether used alone or as part of another group, are defined herein as groups having one or more rings (e g , 1 , 2 or 3 rings) and having from 3 to 20 atoms (e g , 3 to 10 atoms, 3 to 6 atoms) wherein at least one atom in at least one ring is a heteroatom selected from nitrogen (N), oxygen (O), and sulfur (S), and wherein the ring that includes the heteroatom is non-aromatic In heterocyclyl groups that include 2 or more fused rings, the non- heteroatom bearing ring may be aryl (e.g., indolinyl, tetrahydroquinolinyl, chromanyl). Exemplary heterocyclyl groups have from 3 to 14 ring atoms of which from 1 to 5 are heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S) One or more N or S atoms in a heterocyclyl group can be oxidized (e g , N→O^", S(O), SO₂) Where so indicated, heterocyclyl groups can be optionally substituted

Non-limiting examples of monocyclic heterocyclyl groups include, for example diazirinyl, aziridinyl, urazolyl, azetidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolidinyl, isothiazolyl, isothiazolinyl oxathiazolidinonyl, oxazolidinonyl, hydantoinyl, tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, piperidin-2-onyl (valerolactam), 2,3,4,5-tetrahydro-1H-azepιnyl, 2,3-dihydro-1H-ιndole, and 1 ,2,3,4-tetrahydro- quinoline. Non-limiting examples of heterocyclic groups having 2 or more rings include, for example. hexahydro-1H-pyrrolιzιnyl, 3a,4,5,6,7,7a-hexahydro-1H- benzo[d]imidazolyl, 3a,4,5,6,7,7a-hexahydro-1H-indolyl, 1 ,2,3,4-tetrahydroquinolinyl, chromanyl, isochromanyl, indolinyl, isoindolinyl, and decahydro-1H- cyclooctalbjpyrrolyl.

The term "heteroaryl," whether used alone or as part of another group, is defined herein as a single or fused ring system having from 5 to 20 atoms (e.g., 5 to 10 atoms, 5 to 6 atoms) wherein at least one atom in at least one ring is a heteroatom selected from nitrogen (N), oxygen (O), and sulfur (S), and wherein further at least one of the rings that includes a heteroatom is aromatic. In heteroaryl groups that include 2 or more fused rings, the non-heteroatom bearing ring may be a carbocycle (e g , δJ-Dihydro-SH-cyclopentapyπmidine) or aryl (e g , benzofuranyl, benzothiophenyl, indolyl). Exemplary heteroaryl groups have from 5 to 14 ring atoms and contain from 1 to 5 ring heteroatoms independently selected from nitrogen (N), oxygen (O), and sulfur (S). One or more N or S atoms in a heteroaryl group can be oxidized (e g , N→O , S(O), SO₂). Where so indicated, heteroaryl groups can be substituted Non-limiting examples of monocyclic heteroaryl rings include, for example 1 ,2,3,4-tetrazolyl, [1 ,2,3]trιazolyl, [1 ,2,4]trιazolyl, triazinyl, thiazolyl, 1H- imidazolyl, oxazolyl, furanyl, thiopheneyl, pyrimidinyl, and pyridinyl. Non-limiting examples of heteroaryl rings containing 2 or more fused rings include¹ benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztnazolyl, cinnolinyl, naphthyridinyl, phenanthridinyl, 7H-purinyl, 9H-purinyl, 5H-pyrrolo[3,2-c/]pyrimidinyl, 7H-pyrrolo[2,3- d]pyrιmιdιnyl, pyrιdo[2,3-d]pyrιmιdιnyl, 2-phenylbenzo[d]thiazolyl, 1H-ιndolyl, 4,5,6,7- tetrahydro-1-H-ιndolyl, quinoxalinyl, 5-methylquιnoxalιnyl, quinazolinyl, quinolinyl, and isoquinolinyl

One non-limiting example of a heteroaryl group as described above is C₁-C₅ heteroaryl, which is a monocyclic aromatic ring having 1 to 5 carbon ring atoms and at least one additional ring atom that is a heteroatom (preferably 1 to 4 additional ring atoms that are heteroatoms) independently selected from nitrogen (N), oxygen (O), and sulfur (S). Examples of C₁-C₅ heteroaryl include, but are not limited to for example, triazinyl, thiazol-2-yl, thιazol-4-yl, ιmιdazol-1-yl, 1H-ιmιdazol-2-yl, 1H- ιmιdazol-4-yl, ιsoxazolιn-5-yl, furan-2-yl, furan-3-yl, thιophen-2-yl, thιophen-4-yl, pyrιmidιn-2-yl, pyrimιdιn-4-yl, pyrimιdin-5-yl, pyrιdιn-2-yl, pyrιdιn-3-yl, and pyrιdιn-4-yl.

For the purposes of the present invention, fused ring groups, spirocyclic rings, bicyclic rings and the like, which comprise a single heteroatom will be considered to belong to the cyclic family corresponding to the heteroatom containing ring For example, 1 ,2,3,4-tetrahydroquιnoline having the formula

is, for the purposes of the present invention, considered a heterocyclyl group 6,7- Dihydro-δH-cyclopentapyrimidine having the formula

is, for the purposes of the present invention, considered a heteroaryl group. When a fused ring unit contains heteroatoms in both a saturated and an aryl ring, the aryl ring will predominate and determine the type of category to which the ring is assigned For example, 1 ,2,3,4-tetrahydro-[1 ,8]naphthyridine having the formula:

is, for the purposes of the present invention, considered a heteroaryl group

The terms "treat" and "treating," as used herein, refer to partially or completely alleviating, inhibiting, ameliorating and/or relieving a condition from which a patient is suspected to suffer

As used herein, "therapeutically effective" refers to a substance or an amount that elicits a desirable biological activity or effect.

Except when noted, the terms "subject" or "patient" are used interchangeably and refer to mammals such as human patients and non-human primates, as well as experimental animals such as rabbits, rats, and mice, and other animals Accordingly, the term "subject" or "patient" as used herein means any mammalian patient or subject to which the compounds of the invention can be administered. In an exemplary embodiment of the present invention, to identify subject patients for treatment according to the methods of the invention, accepted screening methods are employed to determine risk factors associated with a targeted or suspected disease or condition or to determine the status of an existing disease or condition in a subject. These screening methods include, but are not limited to for example, conventional work-ups to determine risk factors that may be associated with the targeted or suspected disease or condition. These and other routine methods allow the clinician to select patients in need of therapy using the methods and compounds of the present invention. The term "substituted" is used throughout the specification The term "substituted" is defined herein as a moiety, whether acyclic or cyclic, which has one or more (e g. 1- 10) hydrogen atoms replaced by a substituent as defined herein below. Substituents include those that are capable of replacing one or two hydrogen atoms of a single moiety at a time, and also those that can replace two hydrogen atoms on two adjacent carbons to form said substituent For example, substituents that replace single hydrogen atoms includes, for example, halogen, hydroxyl, and the like A two hydrogen atom replacement includes carbonyl, oximino, and the like Substituents that replace two hydrogen atoms from adjacent carbon atoms include, for example, epoxy, and the like When a moiety is described as "substituted" any number of its hydrogen atoms can be replaced, as described above For example, difluoromethyl is a substituted C₁ alkyl; tπfluoromethyl is a substituted C₁ alkyl, ₄-hydroxyphenyl is a substituted aryl ring, (N,N-dimethyl-5-amιno)octanyl is a substituted C₈ alkyl, 3- guanidinopropyl is a substituted C₃ alkyl, and 2-carboxypyridinyl is a substituted heteroaryl

At various places in the present specification, substituents of compounds are disclosed in groups or in ranges It is specifically intended that the description include each and every individual subcombination of the members of such groups and ranges For example, the term "C_{1 6} alkyl" is specifically intended to individually disclose C₁, C₂, C₃, C₄, C₅, Ce, C₁-Cs, C₁-Cs, C₁-C₄, C₁-C₃, C₁-C₂, C₂-C₆, C₂-C₅, C₂-C₄, C₂-C₃, C₃-C₆, C₃-C₅, C₃-C₄, C₄-C₆, C₄-C₅, and C₅-C₆ alkyl.

In one aspect, the present invention provides compounds of Formula (Ia) or (Ib)

or pharmaceutically acceptable salts thereof,

wherein.

Ar¹ is a C₆-Ci₀ aryl ring or a 5-14 membered heteroaryl ring, each of which is optionally substituted with 1 , 2, 3 or 4 substituents independently selected from C_r6 alkyl, F, Cl, Br, I, C₃-₆ cycloalkyl, C_r6 alkoxy, OH, NH₂, NH(C_{1 6} alkyl), N(C_{1 6} alkyl)₂, NO₂, C_{1 3} haloalkyl, SH, SCL₆ alkyl and CN, Ar² is a C₆-C₁₀ aryl ring or a 5-14 membered heteroaryl ring, each of which is optionally substituted with 1 , 2, 3 or 4 substituents independently selected from d-₆ alkyl, F, Cl, Br, I, C₃-₆ cycloalkyl, d-e alkoxy, OH, NH₂, NH(d.₆ alkyl), N(C_{1 6} alkyl)₂, NO₂, C_{1 3} haloalkyl, SH, -SC_{1 6} alkyl and CN,

each X is independently -CR³R⁴-,

each L is independently -CR⁵R⁶-,

R¹, R², R³, R⁴, R⁵ and R⁶ are independently selected from H, halogen and C_rβ alkyl optionally substituted with 1 , 2, 3 or 4 substituents independently selected from Cr₆ alkyl, F, Cl, Br, I, C_r6 alkoxy, OH, NH₂, NO₂, C_{1 3} haloalkyl, SH, S-C_{1 6} alkyl and CN,

R⁷ and R⁸ are each independently selected from H and C₁-_S alkyl optionally substituted with 1 , 2, 3 or 4 substituents independently selected from F, Cl, Br, I, C_r6 alkoxy, OH, NH₂, NO₂, C_{1 3} haloalkyl, SH, SC_{1 6} alkyl, CN, C_{3 10} cycloalkyl, a 3-10 membered heterocyclyl ring, C₆-, C₁₀-aryl ring, and a 5-10 membered heteroaryl ring,

Y is a countenon,

n is 1 , 2, 3, 4 or 5, and

p is O, 1 , 2, 3 or 4

According to some embodiments, Ar¹ is a substituted C₆-C₁₀-aryl ring or a 5-14 membered heteroaryl ring, each of which is substituted with at least one substituent independently selected from d-₆ alkyl, F, Cl, Br, I, C₃-₆ cycloalkyl, C₁-_O alkoxy, OH, NH₂, NH(C_{1 6} alkyl), N(C_{1 6} alkyl)₂, NO₂, C_{1 3} haloalkyl, SH, SC_{1 6} alkyl and CN In some embodiments, each aryl or heteroaryl ring is further optionally substituted with 1 , 2, 3 or 4 substituents independently selected from C_r6 alkyl, F, Cl, Br, I, C₃-₆ cycloalkyl, C_r6 alkoxy, OH, NH₂, NH(C_{1 6} alkyl), N(C_{1 6} alkyl)₂, NO₂, C_{1 3} haloalkyl, SH, SC_{1 6} alkyl and CN In some embodiments, Ar² is a C₆-C₁₀-aryl ring or a 5-14 membered heteroaryl ring, substituted with at least one substituent independently selected from C_r6 alkyl, F, Cl, Br, I, C,-₆ alkoxy, OH, NH₂, NH(C_{1 6} alkyl), N(C_{1 6} alkyl)₂, NO₂, C_{1 3} haloalkyl, SH, SC_{1 6} alkyl and CN In some embodiments, each aryl or heteroaryl ring is further optionally substituted with 1 , 2, 3 or 4 substituents independently selected from C_r6 alkyl, F, Cl, Br, I, C_r6 alkyl, OH, NH₂, NH(C_{1 6} alkyl), N(C_{1 6} alkyl)₂, NO₂, C_{1 3} haloalkyl, SH, -SC_{1 6} alkyl and CN. In some embodiments, both Ar¹ and Ar² are independently a C₆-C_1D-aryl ring or a 5-14 membered heteroaryl ring, substituted with at least one substituent independently selected from C_r6 alkyl, F, Cl, Br, I, Cr₆ alkoxy, OH, NH₂, NH(C_{1 6} alkyl), N(d.₆ alkyl)₂, NO₂, C_{1 3} haloalkyl, SH, SC₁ e alkyl and CN. In yet further embodiments, each aryl or heteroaryl ring is further optionally substituted with 1 , 2, 3 or 4 substituents independently selected from C_r6 alkyl, F, Cl, Br, I, C_r6 alkyl, OH, NH₂, NH(C_{1 6} alkyl), N(C_{1 6} alkyl)₂, NO₂, C_{1 3} haloalkyl, SH, -SC_{1 6} alkyl and CN.

In some embodiments, each R¹, R², R³ and R⁴, is H In some such embodiments, R⁵ and R⁶ are each H

In some embodiments, L is CH₂. In some further embodiments, p is 2

In some embodiments of the compounds of Formula (Ia) or (Ib), Ar¹ is phenyl optionally substituted with 1 , 2 or 3 substituents independently selected from Cr₆ alkyl, halogen, C_1-6 alkoxy, OH, NH₂, NH(C_{1 6} alkyl), N(C_{1 6} alkyl)₂, NO₂, C_{1 3} haloalkyl, SH, SC_{1 6} alkyl and CN In some embodiments, Ar¹ is phenyl optionally substituted with 1 , 2 or 3 substituents independently selected from Cr₆ alkyl, halogen, C_r6 alkoxy, OH, and CF₃ In some embodiments, Ar¹ is phenyl optionally substituted with 1 , 2 or 3 substituents independently selected from methyl, F, Cl and methoxy In some embodiments, Ar¹ is phenyl optionally substituted with 1 , 2 or 3 methoxy groups In some embodiments, Ar¹ is para-substituted phenyl In some embodiments, Ar¹ is 4-methoxyphenyl

In some embodiments of the compounds of Formula (Ia) or (Ib), Ar² is phenyl optionally substituted with 1 , 2, or 3 substituents independently selected from C_r6 alkyl, halogen, C₃-₆ cycloalkyl, C,-₆ alkoxy, OH, NH₂, NH(C_{1 6} alkyl), N(CL₆ alkyl)₂, NO₂, C_{1 3} haloalkyl, SH, -S-C_{1 6} alkyl and CN In some embodiments, Ar² is phenyl optionally substituted with 1 , 2 or 3 substitutents independently selected from C_r6 alkyl, halogen, N(C_{1 6} alkyl)₂, and CF₃. In some embodiments, Ar² is para-substituted phenyl In some embodiments, Ar² is phenyl substituted at the 4-position with methyl, ethyl, isopropyl, t-butyl, F, Cl, CF₃, dimethylamino, diethylamino, or diisopropylamino.

In some embodiments of the compounds of Formula (Ia) or (Ib), Ar² is 5-14 membered heteroaryl ring optionally substituted with 1 , 2, 3 or 4 substituents independently selected from C_r6 alkyl, halogen, C₃-₆ cycloalkyl, C₁^ alkoxy, OH, NH- ₂, NH(C_{1 6} alkyl), N(C_{1 6} alkyl)₂, NO₂, C_{1 3} haloalkyl, SH, S-C_{1 6} alkyl and CN In some such embodiments, Ar² is pyrimidinyl optionally substituted with 1 , 2, or 3 substituents independently selected from Ci-₆ alkyl, halogen, C_r6 alkoxy, OH, NH₂, NH(C_{1 6} alkyl), N(C_{1 6} alkyl)₂, NO₂, C_{1 3} haloalkyl, SH, -S-C_{1 e} alkyl and CN In some such embodiments, Ar² is pyrimidinyl optionally sibstituted with 1 , 2 or 3 substitutents independently selected from NH₂, NH(C_{1 3} alkyl), and N(C_{1 3} alkyl)₂ In some such embodiments, Ar² is pyrimιdιn-5-yl optionally substituted 1 substitutent selected from C_r6 alkyl, halogen, C_r6 alkoxy, OH, NH₂, NH(C_{1 6} alkyl), N(C_{1 6} alkyl)₂, NO₂, C_{1 3} haloalkyl, SH, -S-C_{1 6} alkyl and CN

In some embodiments of the compounds of Formula (Ia) or (Ib), Ar¹ is 5-14 membered heteroaryl optionally substituted with 1 , 2, 3 or 4 substituents independently selected from C_r6 alkyl, halogen, C_r6 alkoxy, OH, NH₂, NH(C_{1 6} alkyl), N(C_{1 6} alkyl)(C_{1 6} alkyl), NO₂, d_₃ haloalkyl, S-C_{1 6} alkyl and CN In some embodiments, Ar¹ is pyrimidinyl optionally substituted with 1 , 2, or 3 substituents independently selected from C_r6 alkyl, halogen, C_r6 alkoxy, OH, NH₂, NH(C_{1 6} alkyl), N(C_{1 6} alkyiχCi.₆ alkyl), NO₂, C_{1 3} haloalkyl, S-C_{1 6} alkyl and CN; or with 1 , 2 or 3 substitutents independently selected from Cr₃ alkyl, halogen, Cr₃ alkoxy, OH, NH₂, NH(C_{1 3} alkyl), N(C_{1 3} alkyl)(d ₃ alkyl), NO₂, and C_{1 3} haloalkyl, or with 1 , 2 or 3 substitutents independently selected from C_r3 alkyl, halogen, C_{1 2} alkoxy, OH, NH₂, NH(C_{1 6} alkyl), N(C_{1 6} alkyl)(d ₆ alkyl) and CF₃, or with 1 substitutent selected from C_r3 alkyl, halogen, -OC_{1 2} alkyl, OH, NH₂, NH(C₆ alkyl), N(C₃ alkyl)(d.₃ alkyl) and CF₃ In some embodiments, Ar¹ is pyrιmιdιn-5-yl optionally sibstituted with NH₂, NH(C₁ s alkyl), or N(C₆ alkyl)(Ci ₆ alkyl). In some embodiments, Ar¹ is pyrιmιdιn-5-yl optionally substituted with diethylamino In some embodiments, Ar¹ is pyrιmιdιn-5-yl optionally substituted with NH₂, NH(C₁-_S alkyl), or N(C_{1 6} alkyl)₂. In some embodiments, Ar¹ is pyrimidin-5-yl optionally substituted with diethylamino

In some embodiments of the compounds of Formula (Ia) or (Ib), R⁷ is H, C_1-6 alkyl optionally substituted with halogen, C_{3 10} cycloalkyl, a 3-10 membered heterocyclyl, C₆-C₁₀ aryl, or a 5-10 membered heteroaryl. In some such embodiments, R⁷ is H, C₁- ₆ alkyl or cyclopropylmethyl In some embodiments, R⁷ and R^β are each independently C_r6 alkyl R⁷ and R⁸ are each methyl. In some such embodiments, n is 1, 2, 3 or 4 In some such embodiments, R³, at each occurrence, is H, and R⁴, at each occurrence, is H.

In some embodiments of the compounds of Formula (Ia) or (Ib), p is 2, each L is - CH₂-; and Ar¹ is phenyl optionally substituted with 1 , 2 or 3 substituents independently selected from C_r6 alkyl, halogen, C_r6 alkoxy, OH, NH₂, NH(C_{1 6} alkyl), N(C_{1 6} alkyl)₂, and C₁^ haloalkyl In some such embodiments, Ar¹ is 4- methoxyphenyl, Ar² is phenyl optionally substituted with 1 , 2, 3 or 4 substituents independently selected from C_r6 alkyl, halogen, C_r6 alkoxy, OH, NH₂, NH(C_{1 6} alkyl), N(C_{1 6} alkyl)₂, NO₂, C₁^ haloalkyl, SH, S-C_{1 6} alkyl and CN. In some such embodiments, Ar² is phenyl substituted at the 4-position with methyl, ethyl, isopropyl, t-butyl, F, Cl, CF₃, dimethylamino, diethylamino, or diisopropylamino. In some embodiments, Ar² is a 5-14 membered heteroaryl ring optionally substituted with 1 , 2, 3 or 4 substituents independently selected from Cr₆ alkyl, halogen, C_r6 alkoxy, OH, NH₂, NH(C_{1 6} alkyl), N(C_{1 6} alkyl)₂, NO₂, C_{1 3} haloalkyl, SH, -S-C₆ alkyl and CN In some embodiments, Ar² is pyrimidinyl optionally substituted with 1 , 2, or 3 substituents independently selected from Ci-₆ alkyl, halogen, Cr₆ alkoxy, OH, NH₂, NH(C_{1 6} alkyl), N(CL₆ alkyl)₂, NO₂, C_{1 3} haloalkyl, SH, S-CL₆ alkyl and CN In some embodiments, R⁷ is H, C_r6 alkyl, or cyclopropylmethyl In some embodiments, R⁷ and R⁸ are each independently C₁-_I3 alkyl, n is 1 , 2, 3 or 4 In some embodiments, R³, at each occurrence, is H, and R⁴, at each occurrence, is H

Compounds described herein can contain an asymmetric atom (also referred as a chiral center), and some of the compounds can contain one or more asymmetric atoms or centers, which can thus give rise to optical isomers (enantiomers) and diastereomers. The present teachings and compounds disclosed herein include such enantiomers and diastereomers, as well as the racemic and resolved, enantiomerically pure R and S stereoisomers, as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof. Optical isomers can be obtained in pure form by standard procedures known to those skilled in the art, which include, but are not limited to for example, chiral chromatography, diastereomeric salt formation, kinetic resolution, and asymmetric synthesis. The present invention also includes cis and trans or E/Z isomers of compounds of Formula (Ia) or (Ib)contaιnιng alkenyl moieties (e g , alkenes and imines) It is also understood that the present teachings encompass all possible regioisomers, and mixtures thereof, which can be obtained in pure form by standard separation procedures known to those skilled in the art, and include, but are not limited to, column chromatography, thin-layer chromatography, and high-performance liquid chromatography

Pharmaceutically acceptable salts of compounds of the present invention, which can have an acidic moiety, can be formed using organic and inorganic bases Both mono and polyanionic salts are contemplated, depending on the number of acidic hydrogens available for deprotonation Suitable salts formed with bases include metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, or magnesium salts, ammonia salts and organic amine salts, such as those formed with morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine (e g , ethyl-tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethylpropylamine), or a mono-, dι-, or tπhydroxy lower alkylamine (e.g., mono-, dι- or triethanolamine) Specific non-limiting examples of inorganic bases include NaHCO₃, Na₂CO₃, KHCO₃, K₂CO₃, Cs₂CO₃, LlOH, NaOH, KOH, NaH₂PO₄, Na₂HPO₄, and Na₃PO₄. Internal salts also can be formed. Similarly, when a compound disclosed herein contains a basic moiety, salts can be formed using organic and inorganic acids For example, salts can be formed from the following acids acetic, propionic, lactic, benzenesulfonic, benzoic, camphorsulfonic, citric, tartaric, succinic, dichloroacetic, ethenesulfonic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, malonic, mandelic, methanesulfonic, mucic, napthalenesulfonic, nitric, oxalic, pamoic, pantothenic, phosphoric, phthalic, propionic, succinic, sulfuric, tartaric, toluenesulfonic, camphorsulfonic, carbonic, as well as other known pharmaceutically acceptable acids.

When any variable occurs more than one time in any constituent or in any formula, its definition in each occurrence is independent of its definition at every other occurrence (e g , in N(C_{1 6} alkyl)₂ , each C_{1 6} alkyl may be the same or different than the other) Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds

The compounds described herein may be administered to humans and other animals orally, parenteral!^ sublingually, by aerosohzation or inhalation spray, rectally, intracisternally, intravaginally, intraperitoneally, bucally, intrathecal^ or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired The term parenteral as used herein includes subcutaneous injection, intravenous injection, intramuscular injection, intrasternal injection, or infusion techniques Topical administration may also involve the use of transdermal administration such as transdermal patches or ionophoresis devices

Methods of formulation are well known in the art and are disclosed, for example, in Remington The Science and Practice of Pharmacy, Mack Publishing Company, Easton, Pa , 21st Edition (2005), incorporated herein by reference

Pharmaceutical compositions for use in the present invention can be in the form of sterile, non-pyrogenic liquid solutions or suspensions, coated capsules, suppositories, lyophilized powders, transdermal patches or other forms known in the art.

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenteral^ acceptable diluent or solvent

In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or di-glycerides In addition, fatty acids such as oleic acid find use in the preparation of injectables The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

Formulations comprising crystalline forms of the compositions described herein for slow absorption from subcutaneous or intramuscular injection are provided herein Additionally, delayed absorption of a parenterally administered drug form may be accomplished by dissolving or suspending the compounds in an oil vehicle Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides) Depot injectable formulations may also be prepared by entrapping the drug in liposomes or microemulsions, which are compatible with body tissues

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrohdinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, acetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like

The solid dosage forms of tablets, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art They may optionally contain opacifying agents and can also be of a composition that they release the active ιngredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner

Examples of embedding compositions that can be used include polymeric substances and waxes

The compounds described herein can also be in micro-encapsulated form with one or more excipients as noted above The solid dosage forms of tablets, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e g , tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents They may optionally contain opacifying agents and can also be of a composition that they release the active ιngredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, EtOAc, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents

Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required Ophthalmic formulations, ear drops, and the like are also contemplated as being within the scope of this invention

Compositions of the invention may also be formulated for delivery as a liquid aerosol or inhalable dry powder Liquid aerosol formulations may be nebulized predominantly into particle sizes that can be delivered to the terminal and respiratory bronchioles

Effective amounts of the compounds of the invention generally include any amount sufficient to detectably modulate Kv1 5 potassium channel activity, or to alleviate symptoms of diseases associated with Kv1 5 potassium channel activity or susceptible to Kv1 5 potassium channel activity modulation

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 It will be understood, however, that the specific dose level for any particular subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular disease undergoing therapy The therapeutically effective amount for a given situation can be readily determined by routine experimentation and is within the skill and judgment of the ordinary clinician.

In another aspect of the invention, kits that include one or more compounds of the invention are provided Representative kits include a compound described herein (e g , a compound of Formula Ia or Ib) and a package insert or other labeling including directions for treating or preventing atrial arrhythmia, thromboembolism, stroke, or cardiac failure by administering an effective amount of a compound of the present invention

In another aspect of the invention, kits that include one or more compounds of the invention are provided Representative kits include a compound described herein (e g , a compound of Formula Ia or Ib) and a package insert or other labeling including directions for inhibiting Kv1 5 potassium channel by administering an effective amount of a compound of the present invention

In another aspect of the invention, kits that include one or more compounds of the invention are provided Representative kits include a compound described herein (e g , a compound of Formula Ia or Ib) and a package insert or other labeling including directions for inducing cardioversion by administering an effective amount of a compound of the present invention

The Kv1 5 potassium channel inhibitors of the present invention are 5-spirocyclic-4- imidazolidinones, and include all enantiomeric and diasteriomeric forms and salts of compounds having the formula (Ia) or (Ib).

wherein the core scaffold is numbered in the following manner, shown for Formula (Ib) as an example

For the purposes of the present invention, a compound depicted by the racemic formula, for example

will stand equally well for either of the two enantiomers of Formula

or mixtures thereof (or in the case where a second chiral center is present, all diastereomers and mixtures thereof).

Compounds of the present invention can be prepared in accordance with the procedures outlined herein, from commercially available starting materials, compounds known in the literature, or readily prepared intermediates, by employing standard synthetic methods and procedures known to those skilled in the art Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be readily obtained from the relevant scientific literature or from standard textbooks in the field It will be appreciated that where typical or preferred process conditions (i.β , reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc ) are given, other process conditions can also be used unless otherwise stated Optimum reaction conditions can vary with the particular reactants or solvent used. Those skilled in the art will recognize that the nature and order of the synthetic steps presented can be varied for the purpose of optimizing the formation of the compounds described herein

The processes described herein can be monitored according to any suitable method known in the art For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e g , ¹H or ¹³C), infrared spectroscopy, spectrophotometry (e g , UV-visible), mass spectrometry, or by chromatography such as high-performance liquid chromatograpy (HPLC), gas chromatography (GC), gel-permeation chromatography (GPC), or thin layer chromatography (TLC)

Preparation of the compounds can involve protection and deprotection of various chemical groups The chemistry of protecting groups can be found, for example, in Greene et al., Protective Groups in Organic Synthesis, 4th Ed (John Wiley & Sons, 2007), the entire disclosure of which is incorporated by reference herein for all purposes The reactions or the processes described herein can be carried out in suitable solvents, which can be readily selected by one skilled in the art of organic synthesis Suitable solvents typically are substantially nonreactive with the reactants, intermediates, and/or products at the temperatures at which the reactions are carried out, i e , temperatures that can range from the solvent's freezing temperature to the solvent's boiling temperature A given reaction can be carried out in one solvent or a mixture of more than one solvent Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected.

The compounds of these teachings can be prepared by methods known in the art The reagents used in the preparation of the compounds of these teachings can be either commercially obtained or can be prepared by standard procedures described in the literature For example, compounds of the present invention can be prepared according to the method illustrated in Scheme 1

SCHEME 1

In Scheme I, the amine-protected amino acid A contains an -NH-PG group. Generally, the amine-protected amino acid may have the formula

where -Z is any protected amino group In the example of Scheme I, Z is -NH-PG As another example, Z may be a protected amino group of the formula

wherein PGi and PG₂ are each a protecting group,

or of the formula

wherein PG₁ and PG₂ are each a protecting group functionality, which may be, as an example, a carbonyl group. As an example, Z may be a phthalimido group.

Amine-protected amino acid A (wherein PG is an amine protecting group) is treated with amine Ar¹-(L)_P-NH₂ under amide coupling conditions. Suitable amide coupling conditions include the use of a coupling reagent such as a carbodiimide (e g , N-(3- dimethylaminopropyl)-N'-ethylcarbodnmide hydrochloride (EDAC) or dicyclohexylcarbodiimide (DCC)), or PyBOP. Optionally, the coupling conditions comprise a coupling agent and a hydroxylated moiety (e g , N-hydroxybenzotriazole (HOBt), (HOAt) or pentafluorophenol). Any suitable amide coupling conditions known in the art may be employed. Removal of the protecting group PG yields compound B Any suitable amine protecting group (e g , ferf-butoxy carbonyl, benzyloxy carbonyl, etc.) and corresponding deprotection conditions (e.g., treatment with acid (e.g., HCI, TFA) or hydrogenation (e g , palladium catalyzed hydrogenation)) may be used (see, e g , T W Greene, Protective Groups in Organic Synthesis, 4^TH Ed (John Wiley and Sons, 2007) Compound B is condensed with aldehyde Ai^-CHO in the presence of a base to produce 4-imidazolidinone C Alkylation of C yields ₄-ιmιdazolιdιnone D Any suitable alkylation conditions may be employed, including, for example, treatment with an alkyl halide (e.g., alkyl iodide, alkyl bromide, alkyl chloride) and base (e g , metal hydride, such as NaH) in a suitable solvent (e g , THF, DMF)

Compounds of formula (I) containing a quatemized N-1 nitrogen can be prepared, for example, according to Scheme 2

SCHEME 2

Compound C may be treated with an appropriate base (e g , sodium hydride) in the presence of at least two equivalents of an alkylating agent (e g , alkyl halide, alkyl sulfonate, etc ) in a suitable solvent (e g , DMF) to yield compound E Alternatively, monoalkylated 4-ιmιdazolιdιnone D may be treated with an appropriate base (e g sodium hydride) and an alkylating agent (e g alkyl halide, alkyl sulfonate, etc ) in a suitable solvent (e g DMF) to produce compound E.

EXAMPLES

The following non-limiting examples are presented merely to illustrate the presentinvention. The skilled person will understand that there are numerous equivalents and variations not exemplified but which still form part of the present teachings. Example 1 : Preparation of 6-(4-ferf-butylphenyl)-7-[2-(4-methoxyphenyl)ethyl]-5- methyl-5,7-dιazaspιro[3.4]octan-8-one (Compound #9 in Table 1)

Step 1 860 mg (4 mmol) of Boc amino acid 1 and 4-methoxyphenethyl amine (604 mg, 4 mmol) were dissolved in 10 DMF at room temperature and 2 05 g (4 mmol) of

PyBOP was added The reaction pH was adjusted to 6 0 with DIPEA and the reaction was stirred for 12 hours. The reaction was then diluted with EtOAc and H₂O

The layers were separated, and the aqueous layer was extracted with EtOAc The combined organic layers were dried with Na₂SO₄, filtered and concentrated under vacuum Chromatography with EtOAc/Hexane (0% EtOAc to 50% EtOAc/Hexane) provided 1 40 g tert-butyl 1-(4-methoxyphenethylcarbamoyl)cyclobutylcarbamate

(95%) as white solid

The white solid was dissolved in 50 ml CH₂CI₂ 13 ml trifluoroacetic acid was added and the reaction was stirred at room temperature for 3 hours The solvent was removed under vacuum to provide 1-amino-N-(4- methoxyphenethyl)cyclobutanecarboxamide trifluoroacetate 2 (2.21 g) as a light brown oil which was used without further purification.

Step 2. The light brown oil was dissolved in 20 ml of methanol, 676 mg of 4-t- butylbenzaldehyde was added, followed by 1.38 g K₂CO₃, and the reaction was heated to reflux. After 18 hours, the reaction was allowed to cool to room temperature, the solution was filtered, and the resulting solution was stripped of solvent. The residual oil was re-dissolved in EtOAc, washed with H₂O, dried over MgSO₄, filtered and the solvent was removed under vacuum Chromatography with EtOAc/Hexane (0% EtOAc to 60% EtOAc/Hexane) provided 6-(4-tert-butylphenyl)-7- (4-methoxyphenethyl)-5,7-dιazaspιro[3.4]octan-8-one as a white solid. An amount, 392 mg (1 mmol), of the white solid was dissolved in THF (20 ml) and 27 mg (1.2 mmol) of NaH was added, followed by 197 mg (1.4 mmol) of iodomethane. The reaction was stirred for 48 hours, and then the solvents were removed under vacuum The residual material was dissolved in EtOAc, washed with water, dried over Na₂SO₄, filtered and stripped of solvents. Chromatography with EtOAc/Hexane (0% EtOAc to 50% EtOAc/Hexane) provided 264 mg of the desired 6-(4-ferf- butylphenyl)-7-[2-(4-methoxyphenyl)ethyl]-5-methyl-5,7-diazaspiro[3 4]octan-8-one 3 as a clear oil

Example 2: Preparation of 5-(4-fert-butylphenyl)-6-[2-(4-methoxyphenyl)ethyl]-4,4- dιmethyl-7-oxo-6-aza-4-azonιaspιro[2.4]heptane (Compound #25 in Table 1)

DMF

A solution of 378 mg (1 mmol) of 4 (prepared according to the procedure of Example 1), 35 mg (1 5 mmol) NaH and 284 mg (2 mmol) iodomethane in DMF was stirred at room temperature for 24 hours The mixture was diluted with 100 ml of EtOAC, washed with H₂O (2 x 50 ml), dried over Na₂SO₄, filtered and stripped to an oil. Reverse phase HPLC purification with CH₃CN/H₂O 0 1% TFA provided 304 mg (60%) of the desired 5-(4-ferf-butylphenyl)-6-[2-(4-methoxyphenyl)ethyl]-4,4-dimethyl- 7-oxo-6-aza-4-azonιaspιro[2.4]heptane.

Compounds 1-25 listed in Table I were prepared according to the procedures described in Examples 1 and 2 above using the corresponding reagents (e.g., corresponding amino acid, amine, and aldehyde reagents) High-performance liquid chromatography (HPLC) was recorded with Column Aquasil C18 (Aquasil C18 HPLC column, 50 mm length x 2 mm ID, 5 micron particle) using following conditions Mobile Phase A: 10 mM NH₄OAC in 95% water / 5% CAN (Pipette 6 67 mL of 7 5 M NH₄OAC solution into 4743 mL H₂O, then add 250 mL of ACN to the solution and mixture) Mobile Phase B 10 mM NH₄OAC in 5% water / 95% CAN (Pipette 6 67 mL of 7 5 M NH₄OAC solution into 243 mL H₂O Then add 4750 mL of ACN to the solution and mixture). Flow Rate: 0.800 mL/min, Column Temperature. 4O⁰C, Injection Volume 5 mL and UV monitor 214 nm and 254 nm Gradient Table

Tιme(mιn) %B

0.0 0

10 2 5 100

4 0 100

4.1 0

5 5 0

Mass spectra were recorded using Agilent 1200 HPLC/time-of-flight mass 15 spectrometer 3x50 mm, 1.8 micron stable bond C18 column, T = 70 C, linear gradient from 70/30 (A B) to 5/95 (A B) over 1 2 minutes, A) water w/ 0 1% formic acid, B) acetonitrile w/ 0 1% formic acid. Mass spectrometer was scanned from m/z 100-1000

Table I

KV1 5 PATCH CLAMP EP

Kv1 5 currents are recorded by the whole cell mode of patch clamp electrophysiologic ^Kv1 -^{5 is} stably over expressed in HEK cells. Microelectrodes are pulled from borosilicate glass (TW150) and heat polished (tip resistance, 1 5 to 3 megaohms) The external solution is standard Tyrodes solution The internal (microelectrode) solution contained: 1 10 mM KCI, 5 mM K₂ATP, 5 mM K₄BAPTA, 1 mM MgCI₂ and 10 mM HEPES, adjusted to pH 7 2 with KOH. Command potentials are applied for 1 second to +6OmV from a holding potential of -70 mV using Axon software (pClamp 8 1) and hardware (Axopatch 1D, 200B) Compounds are prepared as 10-2OmM DMSO stocks and diluted to appropriate test concentrations After stable currents are achieved, compounds are perfused onto the cells and the cells are pulsed every 5 seconds until no further changes in current are evident at a given compound concentration Inhibition is measured at the end of the 1 second pulses and expressed relative to controls Kv1 5 inhibition is estimated by single point determinations done at 1μM Generally following this procedure, results for representative compounds according to the present invention are listed in Table Il below.

Table I

Variations, modifications, and other implementations of what is described herein will occur to those skilled in the art without departing from the spirit and the essential characteristics of the present teachings Accordingly, the scope of the present teachings is to be defined not by the preceding illustrative description but instead by the following claims, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Each of the printed publications, including but not limited to patents, patent applications, books, technical papers, trade publications and journal articles described or referenced in this specification are incorporated by reference herein, included in their entire contents

Claims

WHAT IS CLAIMED IS:

1. A compound having the Formula (Ia) or (Ib):

(Ia) (Ib)

or a pharmaceutically acceptable salt thereof,

wherein:

Ar¹ is a C₆-C₁₀ aryl ring or 5-14 membered heteroaryl ring, each aryl or heteroaryl ring of which is optionally substituted with 1 , 2, 3 or 4 substituents independently selected from C_r6 alkyl, F, Cl, Br, I, C₃-₆ cycloalkyl, C_r6 alkoxy, OH, NH₂, NH(C₁-S alkyl), N(C₁^ alkyl)₂, NO₂, C_1-3 haloalkyl, SH, SCi_-6 alkyl and CN;

Ar² is a C₆-C₁₀ aryl ring or 5-14 membered heteroaryl ring, each of which is optionally substituted with 1 , 2, 3 or 4 substituents independently selected from C_r6 alkyl, F, Cl, Br, I, C₃-₆ cycloalkyl, C_r6 alkoxy, OH, NH₂, NH(C₁^ alkyl), N(Ci_-6 alkyl)₂, NO₂, d_₃ haloalkyl, SH, SCi_-6 alkyl and CN;

each X is independently -CR³R⁴-;

each L is independently -CR⁵R⁶-; R¹ , R², R³, R⁴, R⁵ and R⁶ are each independently selected from H, F, Cl, Br, I and C_r6 alkyl optionally substituted with 1 , 2, 3 or 4 substituents independently selected from C_r6 alkyl, F, Cl, Br, I, C_r6 alkoxy, OH, NH₂, NO₂, C-I_-3 haloalkyl, SH, S-Ci_-6 alkyl and CN;

R⁷ and R⁸ are each independently selected from H and C_r6 alkyl optionally substituted with 1 , 2, 3 or 4 substituents independently selected from F, Cl, Br, I, Cr₆ alkoxy, OH, NH₂, NO₂, Ci_₃ haloalkyl, SH, SCi_₆ alkyl, CN, C₃_i₀ cycloalkyl, 3-10 membered heterocyclyl, C₆-, Ci_O-aryl, and a 5-10 membered heteroaryl ring;

Y is a counter ion;

n is 1 , 2, 3, 4 or 5; and

p is O, 1 , 2, 3 or 4.

2. The compound of claim 1 , wherein each of R¹, R², R³ and R⁴ is H.

3. The compound of claim 1 or 2, wherein p is 1.

4. The compound of claim 1 or 2, wherein p is 2.

5. The compound of any one of claims 1 to 4, wherein each L is -CH₂-.

6. The compound of any one of claims 1 to 5, wherein Ar¹ is phenyl optionally substituted with 1 , 2 or 3 substituents independently selected from C_r6 alkyl, F₁CI, Br, I, C₃-₆ cycloalkyl, C_r6 alkoxy, OH, NH₂, NH(Ci_₆ alkyl), N(Ci_₆ alkyl)₂, NO₂, Ci_₃ haloalkyl, SH, -SCi_₆ alkyl and CN.

7. The compound of claim 6, wherein Ar¹ is phenyl optionally substituted with 1 , 2 or 3 substituents independently selected from C_r6 alkyl, F, Cl, Br, I , C₃-₆ cycloalkyl, C_r6 alkoxy, OH, and CF₃.

8. The compound of claim 7, wherein Ar¹ is phenyl optionally substituted with 1 , 2 or 3 substituents independently selected from methyl, F, Cl and methoxy.

9. The compound of claim 8, wherein Ar¹ is phenyl optionally substituted with 1 , 2 or 3 methoxy groups.

10. The compound of any one of claims 1 to 9 wherein Ar¹ is para-substituted phenyl.

1 1. The compound of any one of claims 1 to 10, wherein Ar¹ is 4-methoxyphenyl.

12. The compound of any one of claims 1 to 1 1 , wherein Ar² is phenyl optionally substituted with 1 , 2, or 3 substituents independently selected from C_r6 alkyl, F, Cl, Br, I, C₃-_S cycloalkyl, C_r6 alkoxy, OH, NH₂, NH(C₁^ alkyl), N(d_₆ alkyl)₂, NO₂, Ci_-3 haloalkyl, SH, -S-C^₆ alkyl and CN.

13. The compound of claim 12, wherein Ar² is phenyl optionally substituted with

1 , 2 or 3 substitutents independently selected from C_r6 alkyl, halogen, N(C^₆ alkyl)₂, and CF₃.

14. The compound of any one of claims 1 to claim 13, wherein Ar² is para- substituted phenyl.

15. The compound of any one of claims 1 to 14, wherein Ar² is phenyl substituted at the 4-position with methyl, ethyl, isopropyl, t-butyl, F, Cl, CF₃, dimethylamino, diethylamino, or diisopropylamino.

16. The compound of any one of claims 1 to 1 1 , wherein Ar² is 5-14 membered heteroaryl optionally substituted with 1 , 2, 3 or 4 substituents independently selected from C_r6 alkyl, F, Cl, Br, I, C₃-₆ cycloalkyl, C₁-_S alkoxy, OH, NH₂, NH(C^₆ alkyl), N(C₁-S alkyl)₂, NO₂, C_1-3 haloalkyl, SH, -S-Ci_-6 alkyl and CN.

17. The compound of claim 16, wherein Ar² is pyrimidinyl optionally substituted with 1 , 2, or 3 substituents independently selected from C₁-₆ alkyl, F, Cl, Br, I, C₃-₆ cycloalkyl, C_r6 alkoxy, OH, NH₂, NH(Ci_-6 alkyl), N(Ci_-6 alkyl)₂, NO₂, d_₃ haloalkyl, SH, -S-Ci_-6 alkyl and CN.

18. The compound of claim 17, wherein Ar¹ is pyrimidinyl optionally substituted with 1 , 2 or 3 substitutents independently selected from NH₂, NH(d_₄ alkyl), and

N(CL₄ alkyl)₂.

19. The compound of claim 17, wherein Ar¹ is pyrimidin-5-yl optionally substituted with 1 substitutent selected from C_r6 alkyl, F, Cl, Br, I, C₃-₆ cycloalkyl, d-6 alkoxy, OH, NH₂, NH(Ci_-6 alkyl), N(Ci_-6 alkyl)₂, NO₂, d_₃ haloalkyl, SH, -S-Ci- ₆ alkyl and CN.

20. The compound of claim 19, wherein Ar¹ is pyrimidin-5-yl optionally substituted with NH₂, NH(Ci_-6 alkyl), or N(Ci_-6 alkyl)₂.

21. The compound of claim 20, wherein Ar¹ is pyrimidin-5-yl optionally substituted with diethylamino.

22. The compound of any one of claims 1 to 21 , wherein R⁷ is H, C_r6 alkyl optionally substituted with F, Cl, Br, I, C₃.₁₀ cycloalkyl, 3-10 membered heterocycle, C₆ or C₁₀ aryl, or 5-10 membered heteroaryl.

23. The compound of claim 22, wherein R⁷ is H, C_r6 alkyl or cyclopropylmethyl.

24. The compound of any one of claims 1 to 21 , wherein R⁷ and R⁸ are each independently C_r6 alkyl.

25. The compound of claim 24, wherein R⁷ and R⁸ are each methyl.

26. The compound of any one of claims 1 to 25, wherein n is 1.

27. The compound of any one of claims 1 to 25, wherein n is 2.

28. The compound of any one of claims 1 to 25, wherein n is 3.

29. The compound of any one of claims 1 to 25, wherein n is 4.

30. The compound of any one of claims 26 to 29, wherein R³, at each occurrence, is H, and

R⁴, at each occurrence, is H.

31. The compound of claim 1 , wherein each p is 2; L is -CH₂-; and Ar¹ is phenyl optionally substituted with 1 , 2 or 3 substituents independently selected from C_r6 alkyl, F, Cl, Br, I, C₃-₆ cycloalkyl, C_r6 alkoxy, OH, NH₂, NH(d_₆ alkyl), N(d_₆ alkyl)₂, and C_1-3 haloalkyl.

32. The compound of claim 31 , wherein Ar¹ is 4-methoxyphenyl.

33. The compound of claim 31 or 32, wherein Ar² is phenyl optionally substituted with 1 , 2, 3 or 4 substituents independently selected from C_r6 alkyl, F, Cl, Br, I, C₃-₆ cycloalkyl, C_r6 alkoxy, OH, NH₂, NH(d_₆ alkyl), N(d_₆ alkyl)₂, NO₂, d_₃ haloalkyl, SH, -S-d_₆ alkyl and CN.

34. The compound of claim 33, wherein Ar² is phenyl substituted at the 4- position with methyl, ethyl, isopropyl, t-butyl, F, Cl, CF₃, dimethylamino, diethylamino, or diisopropylamino.

35. The compound of claim 31 or 32, wherein Ar² is 5-14 membered heteroaryl optionally substituted with 1 , 2, 3 or 4 substituents independently selected from

Ore alkyl, halogen, -OC_r6 alkyl, OH, NH₂, NH(Ci_-6 alkyl), N(Ci_-6 alkyl)₂, NO₂, C₁-S haloalkyl, SH, -S-C_1-6 alkyl and CN.

36. The compound of claim 35, wherein Ar² is pyrimidinyl optionally substituted with 1 , 2, or 3 substituents independently selected from C_r6 alkyl, F, Cl, Br, I, C₃-₆ cycloalkyl, C_r6 alkoxy, OH, NH₂, NH(Ci_-6 alkyl), N(Ci_-6 alkyl)₂, NO₂, d_₃ haloalkyl,

SH, -S-Ci_-6 alkyl and CN.

37. The compound of claim 36, wherein Ar₂ is pyrimidin-5-yl optionally substituted with NH₂, NH(C_1-6 alkyl), or N(C_1-6 alkyl)₂.

38. The compound of any one of claims claim 31 to 37, wherein R⁷ is H, C₁ -₆ alkyl, or cyclopropylmethyl.

39. The compound of any one of claims 31 to 37, wherein R⁷ and R⁸ are each independently C_r6 alkyl.

40. The compound of any one of claims 31 to 39, wherein n is 1.

41. The compound of any one of claims 31 to 39, wherein n is 2.

42. The compound of any one of claims 31 to 39, wherein n is 3.

43. The compound of any one of claims 31 to 39, wherein n is 4.

44. The compound of any one of claims 40 to 43, wherein R , at each occurrence, is H, and

R⁴, at each occurrence, is H.

45. The compound of any one of claims 1 to 44, wherein X is -CR³R⁴-

46. A compound of claim 1 that is

a) 5-(4-te/?-butylphenyl)-6-[2-(4-methoxyphenyl)ethyl]-4,6- diazaspiro[2.4]heptan-7-one;

b) 5-(4-fluorophenyl)-6-[2-(4-methoxyphenyl)ethyl]-4,6-diazaspiro[2.4]heptan- 7-one;

c) 5-(4-chlorophenyl)-6-[2-(4-methoxyphenyl)ethyl]-4,6-diazaspiro[2.4]heptan- 7-one;

d) 6-[2-(4-methoxyphenyl)ethyl]-5-[4-(trifluoromethyl)phenyl]-4,6- diazaspiro[2.4]heptan-7-one;

e) 5-(4-fe/?-butylphenyl)-6-[2-(4-methoxyphenyl)ethyl]-4-methyl-4,6- diazaspiro[2.4]heptan-7-one;

T) 5-(4-fluorophenyl)-6-[2-(4-methoxyphenyl)ethyl]-4-methyl-4,6- diazaspiro[2.4]heptan-7-one;

g) 6-[2-(4-methoxyphenyl)ethyl]-4-methyl-5-[4-(trifluoromethyl)phenyl]-4,6- diazaspiro[2.4]heptan-7-one;

h) 6-(4-fe/t-butylphenyl)-7-[2-(4-methoxyphenyl)ethyl]-5,7- diazaspiro[3.4]octan-8-one;

i) 6-(4-fe/?-butylphenyl)-7-[2-(4-methoxyphenyl)ethyl]-5-methyl-5,7- diazaspiro[3.4]octan-8-one;

j) 2-(4-fe/?-butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 ,3- diazaspiro[4.4]nonan-4-one;

k) 2-(4-fe/?-butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1-methyl-1 ,3- diazaspiro[4.4]nonan-4-one;

I) 2-(4-chlorophenyl)-3-[2-(4-methoxyphenyl)ethyl]-1-methyl-1 ,3- diazaspiro[4.4]nonan-4-one;

m) 3-[2-(4-methoxyphenyl)ethyl]-1-methyl-2-[4-(trifluoromethyl)phenyl]-1 ,3- diazaspiro[4.4]nonan-4-one;

n) 2-[4-(diethylamino)phenyl]-3-[2-(4-methoxyphenyl)ethyl]-1-methyl-1 ,3- diazaspiro[4.4]nonan-4-one;

o) 2-(4-te/?-butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 ,3- diazaspiro[4.5]decan-4-one;

p) 2-(4-chlorophenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 ,3-diazaspiro[4.5]decan- 4-one;

q) 3-[2-(4-methoxyphenyl)ethyl]-2-[4-(trifluoromethyl)phenyl]-1 ,3- diazaspiro[4.5]decan-4-one;

r) 2-(4-fe/f-butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1-methyl-1 ,3- diazaspiro[4.5]decan-4-one;

s) 2-(4-chlorophenyl)-3-[2-(4-methoxyphenyl)ethyl]-1-methyl-1 ,3- diazaspiro[4.5]decan-4-one;

t) 3-[2-(4-methoxyphenyl)ethyl]-1-methyl-2-[4-(trifluoromethyl)phenyl]-1 ,3- diazaspiro[4.5]decan-4-one;

u) 2-[4-(diethylamino)phenyl]-3-[2-(4-methoxyphenyl)ethyl]-1 -methyl- 1 ,3- diazaspiro[4.5]decan-4-one;

v) 2-[2-(diethylamino)pyrimidin-5-yl]-3-[2-(4-methoxyphenyl)ethyl]-1-methyl- 1 ,3-diazaspiro[4.5]decan-4-one;

w) 1 -(cyclopropylmethyl)-2-[4-(diethylamino)phenyl]-3-[2-(4- methoxyphenyl)ethyl]-1 ,3-diazaspiro[4.5]decan-4-one;

x) 6-(4-fe/?-butylphenyl)-7-[2-(4-methoxyphenyl)ethyl]-5,5-dimethyl-8-oxo-7- aza-5-azoniaspiro[3.4]octane;

y) 5-(4-fe/?-butylphenyl)-6-[2-(4-methoxyphenyl)ethyl]-4,4-dimethyl-7-oxo-6- aza-4-azoniaspiro[2.4]heptane;

or a pharmaceutically acceptable salt thereof.

47. A pharmaceutical composition comprising one or more compounds of claim 1 and one or more excipients.

48. A method for treating or preventing atrial arrhythmia comprising administering a therapeutically effective amount of a compound of claim 1 to a subject.

49. The method of claim 48, wherein the atrial arrhythmia comprises atrial fibrillation or atrial flutter.

50. A method for treating or preventing thromboembolism, stroke, or cardiac failure comprising administering a therapeutically effective amount of a compound of claim 1 to a subject.

51. The compound of claim 1 , wherein Ar¹ is a C₆-C₁₀ aryl ring or a 5-14 membered heteroaryl ring, each aryl or heteroaryl ring having at least one substituent selected from C_r6 alkyl, F, Cl, Br, I, C₃-₆ cycloalkyl, C_r6 alkoxy Ci-e alkoxy, OH, NH₂, NH(d_₆ alkyl), N(d_₆ alkyl)₂, NO₂, C₁-_S haloalkyl, SH, SC₁-_S alkyl and CN.

52. The compound of claim 51 , wherein Ar² is a C₆-C₁₀ aryl ring or a 5-14 membered heteroaryl ring, each aryl or heteroaryl ring having at least one substituent selected from C_r6 alkyl, F, Cl, Br, I, C_r6 alkyl, OH, NH₂, NH(C₁^ alkyl), N(C₁-_S alkyl)₂, NO₂, d_₃ haloalkyl, SH, -SC₁^ alkyl and CN.

53. A method for inhibiting Kv1.5 potassium channel in a subject comprising administering a therapeutically effective amount of a compound of claim 1 or a pharmaceutical composition of claim 47 to a subject.

54. A method for treating or preventing a disorder associated with inhibition of Kv1.5 potassium channel in a subject comprising administering a therapeutically effective amount of a compound of claim 1 or a pharmaceutical composition of claim 47 to a subject.

55. The method of claim 54, wherein the disorder is selected from the group consisting of atrial arrhythmia, thromboembolism, stroke and cardiac failure.

6. A method for inducing cardioversion in a subject comprising administering a therapeutically effective amount of a compound of claim 1 or a pharmaceutical composition of claim 47 to a subject.