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 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 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 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 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 aJ.„ Curr. Med. Chem. 2003,1, 273-287; 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 (la) or (lb):
(Formula Removed)
or pharmaceutically acceptable salts thereof,
wherein:
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 C1-6 alkyl, F, CI, Br, I, C3-6 cycloalkyl C1-6 alkoxy, OH, NH2, NH(C1-6 alkyl), N(C1-6 alkyl)2. NO2, C1-3 haloalkyl, SH, SC1-6 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 C1-6
alkyl. F, CI, Br, I, C3-6, cycloalkyl, C1-6 alkoxy, OH, NH2, NH(C1-6 alkyl), N(C1-6 alkyl)2, NO2, C1-3 haloalkyl, SH, -SC1-6, alkyl and CN;
each X is independently -CR3R4-;
each L is independently -CR5R8-;
R1, R2, R3, R4, R5 and R8 are each independently selected from H, halogen and C1-6 alkyl optionally substituted with 1,2, 3 or 4 substituents independently selected from C1-6 alkyl, F.CI, Br, I, d1-6 alkoxy. OH, NH2, NO2, C1-3 haloalkyl, SH, S-C1-6 alkyl and CN;
R7 and R8 are each independently selected from H and C1-6 alkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from F, CI, Br, I, C1-6 alkoxy, OH, NH2, NO2, C1-3 haloalkyl, SH, -SC1-6 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 counterion;
n is 1,2, 3,4 or 5; and
p is 0,1, 2, 3 or 4.
The present invention also provides compositions comprising an effective amount of one or more compounds of Formula (la) or (lb) 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 (la) or (lb) 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 (la) or (lb) 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 (la) or (lb) 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 (la) or (lb) 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 (la) or (lb) 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 (la) or (lb) 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 (la) or (lb) 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 (°C), 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. d1-6) 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, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-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. -OC1-6) shall refer independently to the number of carbon atoms in the alkoxy group. Non-limiting examples of alkyl groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, /'so-butoxy, tert-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 (a/so 2-methylethen-2-yl), buten-4-yl, and the like. Nonlimiting examples of alkynyl groups include ethynyt, 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, cyclopentathenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctanyl, decalinyl, octahydropentalenyl, octahydro-1H-indenyl, 3a,4,5,6,7,7a-hexahydrc-3H-inden-4-yl, decahydroazulenyl; bicyclo[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, bicyclo-[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, 1,3-dimethyl[2.2.1]heptan-2-yl, bicyclo[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, CI, 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[4.2.0Jocta-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-azepinyl, 2,3-dihydro-1H-indole, and 1,2,3,4-tetrahydro-
qulnotine. Non-limiting examples of heterocyclic groups having 2 or more rings include, for example: hexahydro-1H-pyrrolizinyl, 3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazolyl, 3a,4,5,6,7,7a-hexahydro-1 H-indolyt, 1,2,3,4-tetrahydroquinolinyl, chromanyl, isochromanyl, indolinyl, isoindolinyl, and decahydro-1H-cycloocta[b]pyrrolyl.
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., 6,7-Dihydro-5H-cyclopentapyrimidine) 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]triazotyt, [1,2,4]triazolyl, triazinyl, thiazotyl, 1H-imidazolyl, oxazolyl, furanyl, thiopheneyl, pyrimidinyl, and pyridinyl. Non-limiting examples of heteroaryl rings containing 2 or more fused rings include: benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, cinnolinyl, naphthyridinyl, phenanthridinyl, 7H-purinyl, 9H-purinyI, 5H-pyrrolo[3,2-rf|pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyf, 2-phenylbenzo[d]thiazolyl, 1 H-indolyl, 4,5,6,7-tetrahydro-1-H-indolyl, quinoxalinyf, 5-methylquinoxalinyl, 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, thiazol-4-yl, imidazol-1-yl, 1H-imidazol-2-yl, 1H-
imidazol-4-yl, isoxazolin-5-yl, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl.
For the purposes of the present invention, fused ring groups, spirocyclic rings, tricyclic 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-tetrahydroquinoline having the formula:
(Formula Removed)
is, for the purposes of the present invention, considered a heterocyclyl group. 6,7-Dihydro-5H-cyclopentapyrimidine having the formula:
(Formula Removed)
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:
(Formula Removed)
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, hydroxy!, 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 alkyt; trifluoromethyl is a substituted d alky); 4-hydroxyphenyl is a substituted aryl ring; (N,N-dimethyl-5-amino)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 "C1-6 alkyl" is specifically intended to individually disclose C1, C2, C3, C4, C5, C6, C1-C6, C1-C5, 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 (la) or (lb):
(Formula Removed)
or pharmaceutically acceptable salts thereof,
wherein:
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 C1-6 alkyl, F, CI, Br, I, C3-6 cycloalkyl, C1-6 alkoxy, OH, NH2. NH(C1-6 alkyl), N(C1-6 alkyl)2, NO2, C1-3 hatoalkyl, SH, SC1-6 alkyl and CN;
Ar2 is a C6-C-10 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 C1-6 alkyl, F, CI, Br, I, C3-6 cycloalkyl, C1-6 alkoxy, OH, NH2, NH(C1-6 alkyl), N(C1-6 alkyl)2, NO2, C1-3 haloalkyl, SH, -SC1-6 alky! 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 C1-6 alkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from Cm alkyl, F, CI, Br, I, C1-6 alkoxy, OH, NH2, NO2 C1-3 haloalkyl, SH, S-C1-6 alkyl and CN;
R7 and R8 are each independently selected from H and C1-6 alkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from F, CI, Br, I, Cm alkoxy, OH, NH2. NO2, C1-3 haloalkyl, SH, SC1-6 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 counterion;
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 Cm alkyl, F, CI, Br, I, C3-6 cycloalkyl, C1-6 alkoxy, OH, NH2, NH(C1-6 alkyl), N(C1-6 alkyl)2, NO2, C1-3 haloalkyl, SH, SC1-6 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 C1-6 alkyl, F, CI, Br, I, C3-6 cycloalkyl. C1-6 alkoxy, OH, NH2, NH(C1-6 alkyl). N(C1-6 alkyl)2, NO2, C10 haloalkyl, SH, SC1-6 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 C1-6 alkyl, F, CI, Br, I, C1-6 alkoxy, OH, NH2, NH(C1-6 alkyl), N(C1-6 alkyl)2, NO2, C1-3 haloalkyl, SH, SC1-6 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 C1-6 alkyl, F, CI, Br, I, C1-6 alkyl, OH, NH2, NH(C1-6 alkyl), N(C1-6 alkyl)2, NO2, C1-3 haloalkyl, SH, -SC1-6 alkyl and CN. In some embodiments, both Ar1 and Ar2 are independently a C6-C10-aryl ring or a 5-14 membered heteroaryl ring, substituted with at least one substituent independently selected from C1-6 alkyl, F, CI, Br, I, C1-6 alkoxy, OH, NH2, NH(C1-8 alkyl), N(C1-6 alkyl)2, NO2, C1-3 haloalkyl, SH, SC1-6 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 C1-6 alkyl, F, CI, Br, I, C1-6 alkyl, OH, NH2, NH(C1-6 alkyl), N(C1-6 alkyl)2, NO2, C1. 3 haloalkyl, SH, -SC1-6 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 (la) or (lb), Ar1 is phenyl optionally substituted with 1, 2 or 3 substituents independently selected from d1-6 alkyl, halogen, C1-6 alkoxy, OH, NH2, NH(C1-6 alkyl), N(C1-6, alkyl)2, NO2, C1-3 haloalkyl, SH, SC1-6 alkyl and CN. In some embodiments, Ar1 is phenyl optionally substituted with 1, 2 or 3 substituents independently selected from C1-6 alkyl, halogen, C1-6 alkoxy, OH, and CF3. In some embodiments, Ar1 is phenyl optionally substituted with 1, 2 or 3 substituents independently selected from methyl, F, CI 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 (la) or (lb), Ar2 is phenyl
optionally substituted with 1, 2, or 3 substituents independently selected from C1-6
alkyl, halogen, C3-6 cycloalkyl, C1-6 alkoxy, OH, NH2, NH(C1-6 alkyl), N(C1-6 alkyl)2,
NO2 C1-3 haloalkyl, SH, -S-C1-6 alkyl and CN. In some embodiments, Ar2 is phenyl optionally substituted with 1, 2 or 3 substituted independently selected from C1-8 alkyl, halogen, N(C14 afkyl)2, and CF3. In some embodiments, Ar2 is para-substituted phenyl. In some embodiments, Ar2 is phenyl substituted at the 4-positjon with methyl, ethyl, isopropyl, t-butyl, F, CI, CF3, dimethylamino, thethylamino, or diisopropylamino.
In some embodiments of the compounds of Formula (la) or (lb), Ar2 is 5-14 membered heteroaryl ring optionally substituted with 1, 2, 3 or 4 substituents independently selected from C1-6 alkyl, halogen, C3-6 cycloalkyl, C1-6 alkoxy, OH, NH-2, NH(C1-6 alkyl), N(C1-6 alkyl)2 NO2, C1-3 haloalkyl, SH, S-C1-6 alkyl and CN. In some such embodiments, Ar2 is pyrimidinyl optionally substituted with 1, 2, or 3 substituents independently selected from C1-6 alkyl, halogen, C1-6 alkoxy, OH, NH2, NH(C1-6 alkyl), N(C1-6 alkyl)2, NO2 C1-3 haloalkyl, SH, -S-C1-6 alkyl and CN. In some such embodiments, Ar2 is pyrimidinyl optionally sibstituted with 1, 2 or 3 substitutents independently selected from NH2, NH(C1-3 alkyl), and N(C1-3 alkyl)2. In some such embodiments, Ar2 is pyrimidin-5-yl optionally substituted 1 substitutent selected from C1-6 alkyl, halogen, C1-6 alkoxy, OH, NH2, NH(C1-6 alkyl), N(C1-6 alkyl)2, NO2 C1-3 haloalkyl, SH, -S-C1-6 alkyl and CN.
In some embodiments of the compounds of Formula (la) or (lb), Ar1 is 5-14 membered heteroaryl optionally substituted with 1, 2, 3 or 4 substituents independently selected from C1-6 alkyl, halogen, C1-6 alkoxy, OH, NH2, NH(C1-6 alkyl), N(C1-6 alkyl)(C1-6 alkyl), NO2, C1-3 haloalkyl, S-C1-6 alkyl and CN. In some embodiments, Ar1 is pyrimidinyl optionally substituted with 1, 2, or 3 substituents independently selected from C1-6 alkyl, halogen, C1-6 alkoxy, OH, NH2, NH(C1-6 alkyl), N(C1-6 alkyl)(C14 alkyl), NO2, C1-3 haloalkyl, S-C1-6 alkyl and CN; or with 1, 2 or 3 substitutents independently selected from C1-3 alkyl, halogen, C1-3 alkoxy, OH, NH2 NH(C1-3 alkyl), N(C1-3 alkyl)(C1-3 alkyl), NO2, and C1-3 haloalkyl; or with 1, 2 or 3 substitutents independently selected from C1-3 alkyl, halogen, C1-2 alkoxy, OH, NH2 NH(C1-6 alkyl), N(C1-6 alkyl)(C1-6 alkyl) and CF3; or with 1 substitutent selected from C1-3 alkyl, halogen, -OC1-2 alkyl, OH, NH2, NH(C1-6 alkyl), N(C1-6 alkyl)(C1-3 alkyl) and CF3. In some embodiments, Ar1 is pyrimidin-5-yl optionally sibstituted with NH2, NH(C1-6 alkyl), or N(C1-6 alkyl)(C1-6 alkyl). In some embodiments, Ar1 is pyrimidin-5-yl
optionally substituted with thethylamino. In some embodiments, Ar1 is pyrimidin-5-yl optionally substituted with NH2, NH(C1-6 alkyl), or N(C1-4 alkyl)2. In some embodiments, Ar1 is pyrimidin-5-yl optionally substituted with thethylamino.
In some embodiments of the compounds of Formula (la) or (lb). R7 is H, C1-6 alkyl optionally substituted with halogen, C3-10 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 R8 are each independently C1-6 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 (la) or (lb), p is 2; each L is -CH2-; and Ar1 is phenyl optionally substituted with 1, 2 or 3 substituents independently selected from C1-6 alkyl. halogen, C1-6 alkoxy, OH, NH2, NH(C1-6 alkyl), N(C1-6 alkyl)2, and C1-3 haloalkyl . In some such embodiments, Ar1 is 4-methoxyphenyl, Ar2 is phenyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from C1-6 alkyl, halogen, C1-6 alkoxy, OH, NH2. NH(C1-6 alkyl), N(C1-6 alkyl)z, NO2, C1-3 haloalkyl, SH, S-C1-6 alkyl and CN. In some such embodiments, Ar2 is phenyl substituted at the 4-position with methyl, ethyl, isopropyl, t-butyl, F, CI, CF3, dimethylamino, thethylamino, 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 C1-6 alkyl, halogen, d-e alkoxy, OH, NH2, NH(C1-6 alkyl), N(C1-6 alkyl)2, NO2, C1-3 haloalkyl, SH, -S-C1-6 alkyl and CN. In some embodiments, Ar2 is pyrimidinyl optionally substituted with 1, 2, or 3 substituents independently selected from C1-6 alkyl, halogen, C1-6 alkoxy, OH, NH2, NH(C1-6 alkyl), N(C1-6 alkyl)2, NO2, C1-3 haloalkyl, SH, S-C1-6 alkyl and CN. In some embodiments, R7 is H, C1-6 alkyt, or cyclopropylmethyl. In some embodiments, R7 and R8 are each independently C1-6 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 (la) or (lb)containing 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-, thethyl-, diisopropyl-, triethyl-, tributyl- or dimethylpropylamine), or a mono-, di-, or trihydroxy lower alkylamine (e.g., mono-, di-or triethanolamine). Specific non-limiting examples of inorganic bases include NaHCO3, Na2CO3, KHCO3, K2CO3, Cs2CO3, LiOH, NaOH, KOH, NaH2PO4, Na2HPO4, and Na3P04. 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(C1-6 alkyl)2 , each C1-6 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, parenterally, sublingually, by aerosolization or inhalation spray, rectally, intracisternally, intravaginally, intraperitoneally, bucally, intrathecally 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 parenterally 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, carboxymethyicellulose, alginates, gelatin, polyvinylpyrrolidinone, 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 steatite, 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 lactase or milk sugar as well as high molecular weight polyethylene glycols and the like.
The solid dosage forms of tablets, capsules, pills, arid granules can be prepared with coatings and shells such as enteric coatings and other coatings well kown in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingrethents) 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 ingrethent(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, com, 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 ingrethent 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, thet, 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 la or lb) 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 la or lb) 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 la or lb) 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 (la) or (lb):
(Formula Removed)
wherein the core scaffold is numbered in the following manner, shown for Formula (lb) as an example
(Formula Removed)
For the purposes of the present invention, a compound depicted by the racemic formula, for example:
(Formula Removed)
will stand equally well for either of the two enantiomers of Formula:
(Formula Removed)
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.e., 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
(Formula Removed)
In Scheme I, the amine-protected amino acid A contains an -NH-PG group. Generally, the amine-protected amino acid may have the formula
(Formula Removed)
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
(Formula Removed)
wherein PG1 and PG2 are each a protecting group, or of the formula
(Formula Removed)
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'-ethylcarbodiimide 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., tert-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, 4TH Ed. (John Wiley and Sons, 2007). Compound B is condensed with aldehyde Ar2-CHO in the presence of a base to produce 4-imidazolidinone C.
Alkylation of C yields 4-imidazolidinone 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:
(Formula Removed)
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-imidazolidinone 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-tert-butylphenyl)-7-[2-(4-methoxyphenyl)ethyl]-5-methyl-5,7-diazaspiro{3.4]octan-8-one (Compound #9 in Table 1)
(Formula Removed)
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-methoxyphenethytearbamoyl)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-diazaspiro[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-tert-butylphenyl)-7-[2-(4-methoxyphenyl)ethyl]-5-methyl-5,7-diazaspirot3.4]octan-8-one 3 as a clear oil.
Example 2: Preparation of 5-(4-tert-butylphenyl)-6-[2-(4-methoxyphenyl)ethyl]-4,4-dimethyl-7-oxo-6-aza-4-azoniaspiro[2.4]heptane (Compound #25 in Table 1)
(Formula Removed)
A solution of 378 mg (1mmol) 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-tert-butylphenyl)-6-[2-(4-methoxyphenyl)ethyl]-4,4-dimethyl-7-oxo-6-aza-4-azoniaspiro[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 H20, 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: 40°C, Injection Volume: 5 mL and UV: monitor 214 nm and 254 nm. Grathent Table:
Time(min) %B
0.0 0
2.5 100
4.0 100
4.1 0
5.5 0
Mass spectra were recorded using Agilent 1200 HPLC/time-of-flight mass spectrometer 3x50 mm, 1.8 micron stable bond C18 column, T = 70 C, linear grathent 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
(Table Removed)
KV1.5 PATCH CLAMP EP
Kv1.5 currents are recorded by the whole cell mode of patch clamp electrophysiology. 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: 110mMKCI, 5mM K2ATP, 5mMK4BAPTA, 1
mM MgCI2 and 10 mM HEPES, adjusted to pH 7.2 with KOH. Command potentials
are applied for 1 second to +60mV from a holding potential of -70 mV using Axon software (pClamp 8.1) and hardware (Axopatch 1D, 200B). Compounds are prepared as 10-20mM 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 II below.
Table II
(Table Removed)
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.

WHAT IS CLAIMED IS: -
1, A compound having the Formula (la) or (lb):
(Formula Removed)
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 C1-6 alkyl, F, CI, Br, I, C3-8 cycloalkyl, C1-6 alkoxy, OH, NH2, NH(C1-6 alkyl), N(C1-6 alkyl)2, NO2, C1-3 haloalkyl, SH, SC1-6 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 C1-6 alkyl, F, CI, Br, I, C3-6 cycloalkyl, C1-6 alkoxy, OH, NH2 NH(C1-6 alkyl), N(C1-6 alkyl)2 NO2, C1-3 haloalkyl, SH, SC1-6 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, CI, Br, I and C1-6 alkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from C1-6 alkyl, F, CI, Br, I, C1-6 alkoxy, OH, NH2, NO2, C1-3 haloalkyl, SH, S-C1-6 alkyl and CN;
R7 and R8 are each independently selected from H and C1-6 alkyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from F, CI, Br, I, C1-6 alkoxy, OH, NH2, NO2, C1-3 haloalkyl, SH, SC1-6 alkyl, CN, C3-10 cycloalkyl, 3-10 membered heterocyctyl, C6-, C10-aryt, and a 5-10 membered heteroaryl ring;
Y is a counter ion;
n is 1,2, 3, 4 or 5; and
p is 0, 1,2, 3 or 4.
2. The compound of claim 1, wherein each of R\ 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 C1-8 alkyl, F,CI, Br, I, C3-6 cycloalkyl, C1-6 alkoxy, OH, NH2, NH(C1-6 alkyl), N(C1-6 alkyl)2, NO2, C1-3 haloalkyl, SH, -SC1-6 alkyl and CN.
7. The compound of claim 6, wherein Ar1 is phenyl optionally substituted with 1, 2 or 3 substituents independently selected from C1-6 alkyl, F, CI, Br, I , C3-6 cycloalkyl, C1-6 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, CI 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.
11. 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 11, wherein Ar2 is phenyl optionally substituted with 1, 2, or 3 substituents independently selected from C1-6 alkyl, F, CI, Br, I, C3-6 cycloalkyl, C1-8 alkoxy, OH, NH2, NH(C1-6 alkyl), N(C1-6 alkyl)2, NO2, C1-3 haloalkyl, SH, -S-C1-6 alkyl and CN.
13. The compound of claim 12, wherein Ar2 is phenyl optionally substituted with 1, 2 or 3 substitutents independently selected from C1-6 alkyl, halogen, N(C1-6 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, CI, CF3,
dimethylamino, thethylamino, or diisopropylamino.
16. The compound of any one of claims 1 to 11, wherein Ar2 is 5-14 membered heteroaryl optionally substituuuuuuuted with 1, 2, 3 or 4 substituents independently selected from C1-6 alkyl, F, CI, Br, I, C3-6 cycloalkyl, C1-6 alkoxy, OH, NH2, NH(C1-6 alkyl), N(C1-6 alkyl)2, NO2 C1-3 haloalkyl, SH, -S-C1-6 alkyl and CN.
17. The compound of claim 16, wherein Ar2 is pyrimidinyl optionally substituted with 1, 2, or 3 substituents independently selected from d-s alkyl, F, CI, Br, I, C3-B cycloalkyl, C1-6 alkoxy. OH, NH2. NH(C1-6 alkyl), N(C1-6 alkyl)2, NO2, C1-3 haloalkyl, SH, -S-C1-6 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(C1-4, alkyl), and N(C1-4 alkyl)2.
19. The compound of claim 17, wherein Ar1 is pyrimidin-5-yl optionally
substituted with 1 substituted selected from C1-6 alkyl, F, CI, Br, I, C3-6 cycloalkyl,
C1-6 alkoxy, OH. NH2, NH(C1-6 alkyl), N(C1-6 alkyl)2, NO2, C1-3 haloalkyl, SH, -S-C1-
6 alkyl and CN.
20. The compound of claim 19, wherein Ar1 is pyrimidin-5-yl optionally
substituted with NH2, NH(C1-6 alkyl), or N(C1-6 alkyl)2.
21. The compound of claim 20, wherein Ar1 is pyrimidin-5-yl optionally
substituted with thethylamino.
22. The compound of any one of claims 1 to 21, wherein R7 is H, d1-6 alkyl
optionally substituted with F, CI, Br, I, C3-10 cycloalkyl. 3-10 membered
heterocycle, C8 or C10 aryl, or 5-10 membered heteroaryl.
23. The compound of claim 22, wherein R7 is H, C1-6 alkyl or cyclopropylmethyl.
24. The compound of any one of claims 1 to 21, wherein R7 and R8 are each independently C1-6 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|-B alkyl, F, CI, Br, I, C3-6 cycloalkyl, C1-6 alkoxy, OH, NH2, NH(C1-6 alkyl), N(C1-6 alkyl)2, and C1-3 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 C1-6 alkyl, F, CI, Br, l, C3-6 cycloalkyl, C1-6 alkoxy, OH, NH2, NH(C1-6 alkyl), N(C1-6 alkyl)2, NO2, C1-3 haloalkyl, SH, -S-C1-6 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, CI, CF3, dimethylamino,
thethylamino, 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
C1-6 alkyl, halogen, -OC1-6 alkyl, OH, NH2, NH(C1-6 alkyl), N(C1-6 alkyl)2, NO2, C1-3
haloalkyl, SH, -S-C1-6 alkyl and CN.
36. The compound of claim 35, wherein Ar2 is pyrimidinyl optionally substituted
with 1, 2, or 3 substituents independently selected from C1-6 alkyl, F, CI, Br, I, C3-6
cycloalkyl, C1-6 alkoxy, OH, NH2, NH(C1-6 alkyl), N(C1-6 alkyl)2, NO2 C1-3 haloalkyl,
SH, -S-C1-6 alkyl and CN.
37. The compound of claim 36, wherein Ar2 is pyrimidin-5-yl optionally
substituted with NH2, NH(C1-6 alkyl), or N(C1-6 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 C1-6 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
R3, 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-tert-butylphenyl)-6-[2-(4-rnethoxyphenyl)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)phenyn-4,6-diazaspiro[2.4]heptan-7-one;
e) 5-(4-tert-butytphenyl)-6-[2-(4-methoxyphenyl)ethyl]-4-methyl-4,6-diazaspiro[2.4]heptan-7-one;
f) 5-(4-fluorophenyl)-6-[2-(4-methoxyphenyl)ethyl]-4-methyl-4,6-diazas piro[2.4]heptan-7-one;
g) 6-[2-(4-methoxyphenyl)ethyl]-4-methyI-5-[4-(trifluoromethyl)phenyl]-4,6-diazaspiro[2.4]heptan-7-one;
h) 6-(4-tert-buty!phenyl)-7-[2-(4-methoxyphenyl)ethyl]-5,7-
diazaspiro[3.4]octan-8-one;
i) 6-(4-tert-butylphenyl)-7-[2-(4-methoxyphenyl)ethyl]-5-methyl-5,7-diazaspiro[3.4]octan-8-one;
j) 2-(4-tert-butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1,3-diazaspiro[4.4]nonan-4-one;
k) 2-(4-tert-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-(thethylamino)phenyl]-3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-1,3-diazaspiro[4.4]nonan-4-one;
o) 2-(4-tert-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)ethyI]-2-[4-(trifluoromethyl)phenyl]-1,3-diazaspiro[4.5]decan-4-one;
r) 2-(4-tert-butyiphenyl)-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 -methy!-2-[4-(trifIuoromethy!)phenyl]-1,3-diazaspiro[4.5]decan-4-orie;
u) 2-[4-(thethylamino)phenyl]-3-[2-(4-methoxyphenyl)ethyl]-1-methy!-1,3-diazaspiro[4.5]decan-4-one;
v) 2-[2-