RESVERATROL ANALOGS AND THERAPEUTIC USES

THEREOF

FIELD OF THE INVENTION

[0001] The present invention relates to the field of cardiac disease and, in particular, to compounds for use in the treatment and prevention of atrial fibrillation and stroke.

BACKGROUND OF THE INVENTION

[0002] Atrial fibrillation (AF) is by far the most common type of cardiac electrical rhythm disturbance. It is estimated that 250,000 Canadians have AF and the incidence of AF is increasing with an aging population in most developed countries. While AF does not generally induce sudden cardiac death (as is the case for ventricular arrhythmias), AF is the primary cause of 15% of strokes and can also cause remodelling of the heart leading to heart failure. Furthermore, 30-40% of patients undergoing coronary artery by-pass graft surgery develop transient post-operative AF and this may develop into permanent AF.

[0003] Over the last decade the cellular pathways for AF have been investigated and have revealed potential therapeutic targets for the development of anti-AF drugs. One important target is Kvl.5 (IKr), a potassium channel expressed in the atria, but not the ventricle. In addition to Kvl.5, oxidative stress, late sodium current and activation of the nuclear factor of activated T-cells (NFAT) have been implicated in the development of AF and heart failure.

[0004] Several compounds that inhibit Kvl.5 have been developed. AVE0118 (2'- {[2-(4-methoxy-phenyl)-acetylamino]-methyl}-biphenyl-2-carbo xylic acid (2-pyridin- 3-yl-ethyl)-amide) is a Kvl.5 channel blocker that also shows strong atrial antiarrythmic efficacy (Wirth, et ah, 2003, Cardiovascular Res., 60:298-306). AVE0118 has also been shown to block Kvl.3, Kv2.1, Kv3.1 and Kv4.3 channels with equal potency to Kvl.5 (Decher, et al, 2006, Molec. Pharmacol, 70(4): 1204-1211). [0005] Resveratrol, a polyphenolic anti-oxidant found in red grape products such as red wine, has been shown to preferentially inhibit late sodium current and to be anti- hypertrophic via inhibition of the NFAT pathway (see Wallace CH, et al., 2006, Br J Pharmacol, 149(6):657-665; Chan AY, et al, 2008, J Biol Chem., 283(35):24194- 24201, and Dolinsky VW, et al, 2009, Circulation, 119(12):1643-1652). Preliminary testing of resveratrol on cloned human atrial Kvl.5 channel currents revealed that it is a poor inhibitor of Kvl.5.

[0006] U.S. Patent Nos. 6,531,495 and 6,686,395 describe 2'-substituted 1,1'- biphenyl-2-carboxamides and their use as antiarrythmic compounds, for example, in the treatment and prophylaxis of atrial arrythmias, such as atrial fibrillation or atrial flutter.

[0007] U.S. Patent No. 6,794,377 describes ortho, ortho-substituted nitrogen- containing bisaryl compounds and their use as antiarrhythmic compounds.

[0008] This background information is provided for the purpose of making known information believed by the applicant to be of possible relevance to the present invention. No admission is necessarily intended, nor should be construed, that any of the preceding information constitutes prior art against the present invention.

SUMMARY OF THE INVENTION

[0009] The present invention relates to resveratrol analogs and therapeutic uses thereof. In accordance with one aspect, the invention relates to a compound of general Formula (I):

or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: R ¹ is substituted or unsubstituted aryl, substituted or unsubstituted 5- to 9- membered heteroaryl in which the one or more heteroatoms are each N, substituted or unsubstituted naphthyl, substituted or unsubstituted biphenylyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, substituted or unsubstituted C3-C11 cycloalkyl, or substituted or unsubstituted Ci-Ce alkyl; CF ₃ , OCF ₃ , C ₂ F ₅ , C ₃ F ₇ , CH ₂ F, CHF ₂ or S0 ₂ Me;

R ² and R ³ are each independently -H, -OH, halo, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C1-C4 alkyl, -0(CO)R ⁿ or -NR ¹² R ¹³ ;

R ⁴ is -H or substituted or unsubstituted C1-C4 alkyl;

Y is -C=0 or -S0 ₂ ;

X is absent, -C(R R ⁷ ) _m -, -0-, -0(CH ₂ ) _p - or -NR ⁸ -, wherein when Y is -S0 ₂ , X is absent or -C(R R ⁷ ) _m -;

R ⁶ , R ⁷ , R ⁸ , R ¹¹ , R ¹² , R ¹³ , R ²⁵ and R ²⁶ are each independently -H or C1-C4 alkyl;

R 21 , R 22 , R 2"3 and 24 are each independently -H or halo; n is 0-2; m is 1-4, and p is 1-2.

[0010] In accordance with another aspect, the invention relates to a compound of general Formula (IA):

or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: R ¹ is substituted or unsubstituted aryl, substituted or unsubstituted 5- or 6- membered heteroaryl in which the one or more heteroatoms are each N, substituted or unsubstituted C5-C6 cycloalkyl, or substituted or unsubstituted d- C ₄ alkyl;

R ² and R ³ are each independently -H, -OH, halo, substituted or unsubstituted Ci-C ₄ alkoxy, substituted or unsubstituted d-C ₄ alkyl, -0(CO)R ⁿ or -NR ¹² R ¹³ ;

R ⁴ is -H or substituted or unsubstituted Ci-C ₄ alkyl;

Y is -C=0 or -S0 ₂ ;

X is absent, -C(R R ⁷ ) _m -, -0-, -0(CH ₂ ) _p - or -NR ⁸ -, wherein when Y is -S0 ₂ , X is absent or -C(R R ⁷ ) _m -;

R ⁶ , R ⁷ , R ⁸ , R ¹¹ , R ¹² and R ¹³ are each independently -H or C C ₄ alkyl;

R ²¹ and R ²² are each independently -H or halo; n is 0-2; m is 1-4, and p is 1-2.

[0011] In accordance with another aspect, the invention relates to a compound, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein the compound is selected from the group consisting of:

12









61

[0012] In accordance with another aspect, the invention relates to a pharmaceutical composition comprising a compound as described in any one of the above aspects, and a pharmaceutically acceptable carrier, diluent or excipient.

[0013] In accordance with another aspect, the invention relates to a use of a compound as described in any one of the above aspects, for the manufacture of a medicament.

[0014] In accordance with another aspect, the invention relates to a use of a compound as described in any one of the above aspects to inhibit Kvl.5 channels.

[0015] In accordance with another aspect, the invention relates to a compound as described in any one of the above aspects for use to inhibit Kvl.5 channels.

[0016] In accordance with another aspect, the invention relates to a use of a compound as described in any one of the above aspects for the treatment or prevention of atrial arrhythmia in a subject in need thereof.

[0017] In accordance with another aspect, the invention relates to a compound as described in any one of the above aspects for use to treat or prevent atrial arrhythmia in a subject in need thereof.

[0018] In accordance with another aspect, the invention relates to a use of a compound as described in any one of the above aspects for reducing the risk of stroke in a subject in need thereof. [0019] In accordance with another aspect, the invention relates to a compound as described in any one of the above aspects for use to reduce the risk of stroke in a subject in need thereof.

[0020] In accordance with another aspect, the invention relates to a method of inhibiting Kvl.5 channels comprising contacting the Kvl.5 channels with an effective amount of a compound as described in any one of the above aspects.

[0021] In accordance with another aspect, the invention relates to a method for treating or preventing atrial arrhythmia in a subject in need thereof comprising administering to the subject an effective amount of a compound as described in any one of the above aspects.

[0022] In accordance with another aspect, the invention relates to a method for reducing the risk of stroke in a subject in need thereof comprising administering to the subject an effective amount of a compound as described in any one of the above aspects.

[0023] In accordance with another aspect, the invention relates to a kit comprising a compound as described in any one of the above aspects and instructions for use.

BRIEF DESCRIPTION OF THE DRAWINGS

[0024] These and other features of the invention will become more apparent in the following detailed description in which reference is made to the appended drawings. [0025] Figure 1 presents a graph showing inhibition of cloned human atrial Kvl.5 channel currents by resveratrol: IC5 ₀ = 66 μΜ

[0026] Figure 2 presents an exemplary synthetic pathway for the preparation of Compound 21: i) Boc ₂ 0, Et ₃ N, CH ₂ C1 ₂ , 0 °C→ rt, then 2 h, 84%; ii) a, 1.4 M MeLi in Et ₂ 0, THF, -78 °C, 1 h; b, 1.6 M ί-BuLi in hexanes, -78 °C, 1 h; c, B(0/-Pr ₃ ), rt, overnight, 98%; iii) 1,2-dibromobenzene, Pd(PPh ₃ ) ₄ , NaC0 ₃ , DME, reflux, 72 h, 38%; iv) a, TFA, anisole, CH C1 ₂ , rt, 3 h; then Na C0 ₃ ; b, 4-methoxyphenylacetic acid, CDI, THF, rt, 3 h; then add product from a, rt, overnight, 51%; v) a, 1.4 M MeLi in Et 0, THF, -78 °C, 5 min; w-BuLi in hexanes -78 °C, 15 min; I ₂ , THF -78 °C→ rt, 66%; vi) a, NaH, DMSO, reflux, 45 min; b, methyltriphenylphosphonium bromide, 0 °C, 15 min; c, 4-hydroxybenzaldehyde, rt, 5 h, 24%; vii) Et ₃ N, CH ₂ C1 ₂ , Ac ₂ 0, DMAP, rt, 30 min, 24%; viii) (l,3-bis(2,4,6-trimethylphenyl)-2- imidazolidinylidene)dichloro(phenylmethylene) (tricyclohexylphosphine)ruthenium, (Grubbs 2 ^nd generation catalyst), 4,4,5,5-tetramethyl-2-vinyl-l,3,2-dioxaborolane, CH ₂ C1 ₂ , reflux, 12 h, 31%; ix) 2M Na ₂ C0 ₃ , Pd(PPh ₃ ) ₄ , DME, reflux, 27 h, 51%.

[0027] Figure 3 presents an exemplary synthetic pathway for the preparation of Compound 22: i) a, Amberlite IR 120 plus, 4A molecular sieves; b, CH(OEt) ₃ , benzene; ii) a, NaH, DMSO; b, Ph ₃ P=CH ₂ , DMSO; iii) (l,3-bis(2,4,6-trimethylphenyl)- 2-imidazolidinylidene)dichloro(phenylmethylene) (tricyclohexylphosphine)ruthenium, (Grubbs 2 ^nd generation catalyst), 4,4,5,5-tetramethyl-2-vinyl-l,3,2-dioxaborolane, CH ₂ C1 ₂ ; iv) 2M Na ₂ C0 ₃ , Pd(PPh ₃ ) ₄ , DME; v) TsOH, MeOH, H ₂ 0.

[0028] Figure 4 presents an exemplary synthetic pathway for the preparation of Compound 23 and Compound 24: i) H S0 ₄ , MeOH, reflux, 1 h, 64%; ii) precursor 2, 1,2-dimethoxyethane (DME), Pd(PPh ₃ ) ₄ , Na ₂ C0 ₃ , reflux, 18 h, 73%; iii) a, 3/1 CH ₂ C1 ₂ /TFA, rt, 3 h; (b) THF, 4-methoxyphenylacetic acid, CDI, rt, overnight, 51%; iv) LiOH, MeOH, H 0, rt, 3 h v) THF, 1,1-carbonyldiimidazole (e) 4-aminophenol, CDI, THF, rt, overnight, 27%; vi) tyramine, CDI, THF, rt, overnight, 31%.

[0029] Figure 5 presents Kvl.5 inhibition and IC5 ₀ data for Compounds 21-24 generated using whole-cell patch clamp technique to record whole-cell Kvl.5 currents from tsA201 cell stably expressing the human Kvl.5 gene. Compounds 21-24 were applied to the outside of cells at varying concentrations and the effects on current inhibition were used to generate the IC5 ₀ data.

[0030] Figure 6 presents results showing that (A) Compound 21 and (B) Compound 25 display greater inhibitory potency when Kvl.5 currents are elicited at 3 Hz vs 1 Hz. The whole-cell patch clamp technique was used to record whole-cell Kvl.5 currents from tsA201 cell stably expressing the human Kvl.5 gene.

[0031] Figure 7 presents results showing that Compound 21 ("CI") is an effective inhibitor of IKur (Kvl.5) currents recorded from atrial myocytes enzymatically isolated from atrial appendage tissue obtained during cardiac surgery. [0032] Figure 8 presents results showing that Compound 21 possesses similar antioxidant properties (reducing potential) to resveratrol when compared to AVE0118, a known Kvl.5 inhibitor, when tested using diphenylpicrylhydrazyl (DPPH).

[0033] Figure 9 presents results showing that Compound 21 ("CI") displays preferential inhibition of late sodium current vs peak sodium current (ICso _s are 1 and 3 μΜ respectively). The whole-cell patch clamp technique was used to record whole-cell sodium channel currents TsA201 cells expressing Navl.5 cloned human heart. Late sodium current was induced by 100 nM ATXII.

[0034] Figure 10 presents results showing that Compound 21 displays similar NFAT inhibitory properties to resveratrol (ICso _s ~ 1 μΜ) when measured in neonatal rat ventricular myocytes infected with an adenovirus encoding the luciferase gene under the control of the NFAT promoter.

[0035] Figure 11 presents results showing that Compound 21 ("CI") is a weak inhibitor of the hERG channel. Whole-cell recordings were made from tsA201 cells expressing the hERG A channel clone. Identity of hERG channels was confirmed by inhibition with the hERG channel inhibitor E-4031 (panel A).

[0036] Figure 12 presents results showing that Compound 21 ("CI;" 3 μΜ) did not alter either single ventricular myocyte contractility (A) or calcium transient signaling (B). Rat right ventricular myocytes were enzymatically isolated from adult rat hearts and contractility and calcium transients measured using an edge-detector or calcium- green fluorescence respectively.

[0037] Figure 13 presents results showing the effect of Compound 21 ("CI") on inducible AF in dogs: (A) Control ECG (EKG) trace showing multiple P waves - indicative of AF, (B) Sample trace of AF induction by burst pacing at 800 min ^"1 . Expanded trace shows multiple P waves, (C) IV injection of lmg/kg Compound 21 prior to burst pacing significantly reduced the incidence of inducible AF, (D) Grouped data. * denotes a significant difference of P <0.01 and ** P<0.001. Data is from 4 separate dogs. [0038] Figure 14 presents a graph showing that Compound 21 ("CI") displays selectivity for Kvl.5 and late sodium (late INa) inhibition over peak sodium current and HERG channel inhibition. Concentration response curves for Compound 21 were plotted on the same graph for illustrative purposes. Data was taken from the preceding figures.

[0039] Figure 15 presents a graph showing the inhibition of CYP 3A4 mediated testosterone and midazolam metabolism by Compound 21.

[0040] Figure 16 presents results showing the extent of inhibition of hERG channels by Compound 25.

DETAILED DESCRIPTION OF THE INVENTION [0041] The present invention relates to resveratrol analogs of general Formula (I), described below. Exemplary compounds of general Formula (I) are shown herein to display properties desirable for the treatment of atrial fibrillation (AF), including inhibition of Kvl.5 channels.

[0042] In certain embodiments, the present invention thus relates to the use of resveratrol analogs of Formula (I) to inhibit Kvl.5 channels. Such compounds have therapeutic potential for the treatment or prevention of AF and thus also for the prevention of stroke.

Definitions

[0043] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0044] The term "C1-C4 alkyl" refers to a straight chain or branched hydrocarbon chain of one to four carbon atoms. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl (t-butyl).

[0045] The term "C1-C4 alkoxy" refers to the group -OR, where R is C1-C4 alkyl. [0046] The term "aryl" refers to an aromatic carbocyclic group having a single aromatic ring.

[0047] The term "heteroaryl" refers to an aromatic carbocyclic group having one or more than one hetero atom, such as N, O or S, within the ring. [0048] The term "inhibit" and grammatical variations thereof, as used herein, means to reduce, halt or hold in check. Inhibition may thus be complete or partial and may be of short or long term duration. The term may be used in the context of inhibiting a process or action already begun or it may be used in the context of inhibiting initiation of a process or action. [0049] The terms "therapy" and "treatment" and grammatical variations thereof, as used herein, refer to an intervention performed with the intention of alleviating the symptoms associated with, preventing the development of, or altering the pathology of a disease, disorder or condition. Thus, in various embodiments, the terms therapy and treatment may include the prevention (prophylaxis), moderation, reduction, or curing of a disease, disorder or condition at various stages. In various embodiment, therefore, those in need of therapy/treatment may include those already having the disease, disorder or condition and/or those prone to, or at risk of developing, the disease, disorder or condition and/or those in whom the disease, disorder or condition is to be prevented. [0050] The term "subject" or "patient," as used herein, refers to a mammal in need of treatment.

[0051] Administration of compounds of the invention "in combination with" one or more further therapeutic agents, is intended to include simultaneous (concurrent) administration and consecutive administration. Consecutive administration is intended to encompass various orders of administration of the therapeutic agent(s) and the compound(s) to the subject.

[0052] The term "plurality," as used herein, means more than one, for example, two or more, three or more, four or more, and the like. [0053] The use of the word "a" or "an" when used herein in conjunction with the term "comprising" may mean "one," but it is also consistent with the meaning of "one or more," "at least one" and "one or more than one."

[0054] As used herein, the term "about" refers to an approximately +/-10% variation from a given value. It is to be understood that such a variation is always included in any given value provided herein, whether or not it is specifically referred to.

[0055] As used herein, the terms "comprising," "having," "including" and "containing," and grammatical variations thereof, are inclusive or open-ended and do not exclude additional, unrecited elements and/or method steps. The term "consisting essentially of when used herein in connection with a composition, use or method, denotes that additional elements and/or method steps may be present, but that these additions do not materially affect the manner in which the recited composition, method or use functions. The term "consisting of when used herein in connection with a composition, use or method, excludes the presence of additional elements and/or method steps. A composition, use or method described herein as comprising certain elements and/or steps may also, in certain embodiments consist essentially of those elements and/or steps, and in other embodiments consist of those elements and/or steps, whether or not these embodiments are specifically referred to.

[0056] It is contemplated that any embodiment discussed herein can be implemented with respect to any of the disclosed methods, uses or compositions of the invention, and vice versa.

RESVERA TROL ANALOGS

[0057] In accordance with certain embodiments, the invention relates to "resveratrol analogs" having general Formula (I):

[0058] or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:

R ¹ is substituted or unsubstituted aryl, substituted or unsubstituted 5- to 9- membered heteroaryl in which the one or more heteroatoms are each N, substituted or unsubstituted naphthyl, substituted or unsubstituted biphenylyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, substituted or unsubstituted C3-C11 cycloalkyl, or substituted or unsubstituted Ci-Ce alkyl; CF ₃ , OCF ₃ , C ₂ F ₅ , C ₃ F ₇ , CH ₂ F, CHF ₂ or S0 ₂ Me;

R ² and R ³ are each independently -H, -OH, halo, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C1-C4 alkyl, - 0(CO)R ⁿ or -NR ¹² R ¹³ ;

R ⁴ is -H or substituted or unsubstituted C1-C4 alkyl;

Y is -C=0 or -S0 ₂ ;

X is absent, -C(R R ⁷ ) _m -, -0-, -0(CH ₂ ) _p - or -NR ⁸ -, wherein when Y is -S0 ₂ , X is absent or -C(R R ⁷ ) _m -; R ⁶ , R ⁷ , R ⁸ , R ¹¹ , R ¹² , R ¹³ , R ²⁵ and R ²⁶ are each independently -H or C1-C4 alkyl;

R ²¹ , R ²² , R ²³ and R ²⁴ are each independently -H or halo; n is 0-2; m is 1 -4, and p is 1-2.

[0059] In certain embodiments, in the resveratrol analogs of general Formula (I): R ¹ is substituted or unsubstituted aryl, substituted or unsubstituted 5- to 9-membered heteroaryl in which the one or more heteroatoms are each N, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted C1-C6 alkyl. [0060] In certain embodiments, in the resveratrol analogs of general Formula (I): R ²⁵ and R ²⁶ are each independently -H or -CH ₃ . [0061] In certain embodiments, in the resveratrol analogs of general Formula (I): R ¹ is substituted or unsubstituted aryl, substituted or unsubstituted 5- or 6-membered heteroaryl in which the one or more heteroatoms are each N, substituted or unsubstituted C5-C6 cycloalkyl, or substituted or unsubstituted C1-C4 alkyl; and R ²⁵ and R ²⁶ are each independently -H or -CH ₃ .

[0062] In certain embodiments, in the resveratrol analogs of general Formula (I): R ¹ is substituted or unsubstituted aryl, substituted or unsubstituted 5- or 6-membered heteroaryl in which the one or more heteroatoms are each N, substituted or unsubstituted C5-C6 cycloalkyl, or substituted or unsubstituted C1-C4 alkyl; R ²⁵ and R ²⁶ are each independently -H or -CH ₃ , and R ²³ and R ²⁴ are each -H.

[0063] In certain embodiments, in the resveratrol analogs of general Formula (I), a substituted group may be substituted with one or more of -OH, halo, C1-C4 alkoxy, Ci-

C ₄ alkyl, -CF ₃ , -0(CO)R ¹⁴ , -NR ¹⁵ R ¹⁶ or -0(CH ₂ ) _q NR ¹⁷ R ¹⁸ , wherein R ¹⁴ , R ¹⁵ , R ¹⁶ , R and R ¹⁸ are each independently H or C1-C4 alkyl, and q is 1-4. [0064] In certain embodiments, the invention relates to resveratrol analogs having general Formula (IA):

[0065] or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:

R is substituted or unsubstituted aryl, substituted or unsubstituted 5- or 6- membered heteroaryl in which the one or more heteroatoms are each N, substituted or unsubstituted C5-C6 cycloalkyl, or substituted or unsubstituted C1-C4 alkyl; R ² and R ³ are each independently -H, -OH, halo, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C1-C4 alkyl, - 0(CO)R ⁿ or -NR ¹² R ¹³ ;

R ⁴ is -H or substituted or unsubstituted C1-C4 alkyl;

Y is -C=0 or -S0 ₂ ;

X is absent, -C(R R ⁷ ) _m -, -0-, -0(CH ₂ ) _p - or -NR ⁸ -, wherein when Y is -S0 ₂ , X is absent or -C(R R ⁷ ) _m -;

R ⁶ , R ⁷ , R ⁸ , R ¹¹ , R ¹² and R ¹³ are each independently -H or C1-C4 alkyl; and R are each independently -H or halo; n is 0-2; m is 1 -4, and p is 1-2.

[0066] In certain embodiments, in the resveratrol analogs of general Formula (IA), a substituted group may be substituted with one or more of -OH, halo, C1-C4 alkoxy, Ci- C ₄ alkyl, -CF ₃ , -0(CO)R ¹⁴ , -NR ¹⁵ R ¹⁶ or -0(CH ₂ ) _q NR ¹⁷ R ¹⁸ , wherein R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁸ are each independently H or C1-C4 alkyl, and q is 1-4.

[0067] In certain embodiments, in resveratrol analogs of general Formula (IA): X is absent or -C(R R ⁷ ) _m -.

[0068] In certain embodiments, in resveratrol analogs of general Formula (IA): R ¹ is substituted or unsubstituted aryl, substituted or unsubstituted pyndinyl or substituted or unsubstituted cyclohexyl.

[0069] In certain embodiments, in resveratrol analogs of general Formula (IA): R ¹² and R ¹³ are each independently H, -CH ₃ or -(¾(¾.

[0070] In certain embodiments, in resveratrol analogs of general Formula (IA): R ³ is

H. [0071] In certain embodiments, in resveratrol analogs of general Formula (IA): R ⁴ is H.

[0072] In certain embodiments, in resveratrol analogs of general Formula (IA): R ¹ is substituted or unsubstituted aryl, substituted or unsubstituted pyndinyl or substituted or unsubstituted cyclohexyl; and X is absent or -C(R R ⁷ ) _m -.

[0073] In certain embodiments, in resveratrol analogs of general Formula (IA): n is 0 or 1.

[0074] In certain embodiments, in resveratrol analogs of general Formula (IA): Y is

C=0. [0075] In certain embodiments, in resveratrol analogs of general Formula (IA): R and R ²² are each -H.

[0076] In certain embodiments, in resveratrol analogs of general Formula (IA): X is absent or -CH ₂ -.

[0077] In certain embodiments, the resveratrol analogs of general Formula (IA) have general F ormula (II) :

1 2 3 4 21 22

wherein R , R , R R R , R , n and X are as defined above for Formula

[0079] In certain embodiments, in resveratrol analogs of general Formula (II): X is absent or -C(R R ⁷ ) _m -.

[0080] In certain embodiments, the resveratrol analogs of general Formula (IA) have general Formula (III):

[0081] wherein R ¹ , R ² , R ³ , R ⁴ , R ²¹ , R ²² and n are as defined above for Formula (IA), and

X is absent or -C(R R ⁷ ) _m -. [0082] In certain embodiments, in resveratrol analogs of general Formula (II) or (III): R ¹ is substituted or unsubstituted aryl, substituted or unsubstituted pyridinyl or substituted or unsubstituted cyclohexyl.

[0083] In certain embodiments, in resveratrol analogs of general Formula (II): R ³ is H. [0084] In certain embodiments, in resveratrol analogs of general Formula (II): R ⁴ is H.

[0085] In certain embodiments, in resveratrol analogs of general Formula (II) or (III): n is 0 or 1.

[0086] In certain embodiments, in resveratrol analogs of general Formula (II) or (III): R ²¹ and R ²² are H.

[0087] In certain embodiments, in resveratrol analogs of general Formula (II) or (III): X is absent or -CH ₂ -.

[0088] In certain embodiments, in resveratrol analogs of general Formula (II) or (III): R ¹ is substituted or unsubstituted aryl or substituted or unsubstituted pyridinyl; R ³ is H; R ⁴ is H; and n is 0 or l .

[0089] In certain embodiments, the resveratrol analogs of general Formula (IA) have general Formula (IV):

[0090] wherein R ^z , R\ R , R ^zz and n are as defined above for Formula (IA); t is 0-2, and

Ar is substituted or unsubstituted aryl, or substituted or unsubstituted 5- or 6-membered heteroaryl in which the one or more heteroatoms are each N.

[0091] In certain embodiments, in resveratrol analogs of general Formula (IV), R 21 and R are H.

[0092] In certain embodiments, the resveratrol analogs of general Formula (IA) have general Formula (V):

[0093] wherein R ² , R ⁴ and n are as defined above for Formula (IA); t is 0-2, and

R is H, -OH, halo, substituted or unsubstituted C1-C4 alkoxy, substituted or unsubstituted C1-C4 alkyl, -CF ₃ , -NR ¹⁵ R ¹⁶ or -0(CH ₂ ) _q NR ¹⁷ R ¹⁸ , wherein R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁸ are each independently H or C1-C4 alkyl, and q is 1-4.

[0094] In certain embodiments, in resveratrol analogs of general Formula (V), R is H, halo, C1-C4 alkoxy, -NR ¹⁵ R ¹⁶ or -0(CH ₂ ) _q NR ¹⁷ R ¹⁸ . [0095] In certain embodiments, the resveratrol analogs of general Formula (IA) have general Formula (VI):

[0096] wherein R ² , R ⁴ and n are as defined above for Formula (IA); one of Zi, Z ₂ , Z3, Z ₄ and Z5 is CR ²³ and the remainder are each independently N or CH, wherein between one and three of Zi, Z , Z ₃ , Z ₄ and Z ₅ are N; t is 0-2, and

R ²³ is H, -OH, halo, substituted or unsubstituted Ci-C ₄ alkoxy, substituted or unsubstituted d-C ₄ alkyl, -CF ₃ , -NR ¹⁵ R ¹⁶ or -0(CH ₂ ) _q NR ¹⁷ R ¹⁸ , wherein

R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁸ are each independently H or Ci-C ₄ alkyl, and q is 1-4.

[0097] In certain embodiments, in resveratrol analogs of general Formula (VI), between one and two of Zi, Z , Z ₃ , Z ₄ and Z ₅ are N.

[0098] In certain embodiments, in resveratrol analogs of general Formula (VI), one of Zi, Z ₂ , Z ₃ , Z ₄ and Z ₅ is N.

[0099] In certain embodiments, in resveratrol analogs of general Formula (VI), R ²³ is H, -OH, halo, Ci-C ₄ alkoxy or Ci-C ₄ alkyl.

[00100] In certain embodiments, in resveratrol analogs of general Formula (IV), (V) or (VI), n is 1.

[00101] In certain embodiments, in resveratrol analogs of general Formula (IV), (V) (VI), t is 1. [00102] In certain embodiments, in resveratrol analogs of general Formula (IV), (V) or (VI), R ² is -H, -OH, halo, substituted or unsubstituted C1-C4 alkoxy or -NR ¹² R ¹³ .

[00103] In certain embodiments, in resveratrol analogs of general Formula (IV), (V) or (VI), R ⁴ is -H. [00104] In certain embodiments, the resveratrol analogs of general Formula (IA) have general Formula (VII):

[00105] wherein R ¹ , R ² , R ³ , R ⁴ and X are as defined above for Formula (IA).

[00106] In certain embodiments, in resveratrol analogs of Formula (VII): X is absent or -C(R R ⁷ ) _m -.

[00107] In certain embodiments, in resveratrol analogs of Formula (VII): R ¹ is substituted or unsubstituted aryl, substituted or unsubstituted pyndinyl or substituted or unsubstituted cyclohexyl.

[00108] In certain embodiments, in resveratrol analogs of general Formula (VII): R ³ is H.

[00109] In certain embodiments, in resveratrol analogs of general Formula (VII): R ⁴ is H.

[00110] In certain embodiments, in resveratrol analogs of general Formula (VII), R ² is -H, -OH, halo, substituted or unsubstituted C1-C4 alkoxy or -NR ¹² R ¹³ . [00111] In certain embodiments, in resveratrol analogs of Formula (VII): R ¹ is substituted or unsubstituted aryl, substituted or unsubstituted pyndinyl or substituted or unsubstituted cyclohexyl, and X is absent or -C(R R ⁷ ) _m -. [00112] In certain embodiments, in resveratrol analogs of general Formula (IV): R ¹ is substituted or unsubstituted aryl or substituted or unsubstituted pyridinyl; R ³ is H; R ⁴ is H, and X is absent or -C(R R ⁷ ) _m -.

[00113] In certain embodiments, the resveratrol analogs of general Formula (IA) have general Formula (VIII):

[00114] wherein R ¹ , R ² , and R ⁴ are as defined above for Formula (IA).

[00115] In certain embodiments, in resveratrol analogs of Formula (VIII): R ¹ is substituted or unsubstituted aryl, substituted or unsubstituted pyridinyl or substituted or unsubstituted cyclohexyl.

[00116] In certain embodiments, in resveratrol analogs of general Formula (VIII): R ⁴ is

H.

[00117] In certain embodiments, in resveratrol analogs of Formula (VIII): R ¹ is substituted or unsubstituted aryl. [00118] In certain embodiments, in resveratrol analogs of Formula (VIII): R ¹ is substituted or unsubstituted pyridinyl.

[00119] In certain embodiments, in resveratrol analogs of Formula (VIII): R ² is -H, - OH, halo, Ci-C ₄ alkoxy, C1-C4 alkyl, -CF ₃ , -0(CO)R ⁿ , -NR ¹² R ¹³ or -0(CH ₂ ) _r NR ¹⁹ R ² °, wherein R , R and R are as defined for Formula (IA), R and R are each independently -CH ₃ or -CH ₂ CH ₃ , and r is 1 -4.

[00120] In certain embodiments, the resveratrol analogs of general Formula (IA) have general Formula (IX):

[00121] wherein R ² and R ⁴ are as defined above for Formula (IA), and

Ar is substituted or unsubstituted aryl, or substituted or unsubstituted 5- or 6- membered heteroaryl in which the one or more heteroatoms are each N. [00122] In certain embodiments, in resveratrol analogs of Formula (IX): R ⁴ is H.

[00123] In certain embodiments, in resveratrol analogs of Formula (IX): R ¹ is substituted or unsubstituted aryl or substituted or unsubstituted pyridinyl.

[00124] In certain embodiments, in resveratrol analogs of Formula (IX): R ¹ is substituted or unsubstituted aryl. [00125] In certain embodiments, in resveratrol analogs of Formula (IX): R ¹ is substituted or unsubstituted pyridinyl.

[00126] In certain embodiments, in resveratrol analogs of Formula (IX): R ² is -H, -OH, halo, Ci-C ₄ alkoxy, C1-C4 alkyl, -CF ₃ , -0(CO)R ⁿ , -NR ¹² R ¹³ or -0(CH ₂ ) _r NR ¹⁹ R ² °, wherein R 11 , R12 and R 13 are as defined for Formula (IA), R 19 and R 20 are each independently -CH ₃ or -CH ₂ CH ₃ , and r is 1-4.

[00127] In certain embodiments, in resveratrol analogs of Formula (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX), a substituted group may be substituted with one or more of - OH, halo, C1-C4 alkoxy, C1-C4 alkyl, -CF ₃ , -0(CO)R ¹⁴ , -NR ¹⁵ R ¹⁶ or -0(CH ₂ ) _q NR ¹⁷ R ¹⁸ , wherein R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁸ are each independently H or C1-C4 alkyl, and q is 1- 4.

[00128] It is to be understood that the present invention further relates to combinations of the embodiments described above with respect to each of Formulae (I), (IA), (II),

(III), (IV), (V), (VI), (VII), (VIII) and (IX). [00129] In certain embodiments, the resveratrol analogs are selected from:





61

[00130] It is to be understood that reference to resveratrol analogs of general Formula (I) throughout the following disclosure, includes in various embodiments, resveratrol analogs of general Formulae (IA), (II), (III), (IV), (V), (VI), (VII), (VIII) and (IX), to the same extent as if embodiments reciting each of these formulae individually were specifically recited.

[00131] In certain embodiments, the resveratrol analogs may possess a sufficiently acidic group, a sufficiently basic group, or both functional groups, and accordingly react with a number of organic and inorganic bases, or organic and inorganic acids, to form pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" as used herein, refers to a salt of a resveratrol analog, which is substantially non-toxic to living organisms. Typical pharmaceutically acceptable salts include those salts prepared by reaction of the resveratrol analog with a pharmaceutically acceptable mineral or organic acid or an organic or inorganic base. Such salts are known as acid addition and base addition salts. [00132] Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulphonic acid, methanesulphonic acid, oxalic acid, p-bromophenylsulphonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. Examples of such pharmaceutically acceptable salts are the sulphate, pyrosulphate, bisulphate, sulphite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylenesulphonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, methanesulphonate, propanesulphonate, naphthalene- 1 -sulfonate, napththalene-2- sulfonate, mandelate and the like. Pharmaceutically acceptable acid addition salts of particular interest are those formed with mineral acids such as hydrochloric acid and hydrobromic acid (forming hydrochlorides and hydrobromides), and those formed with organic acids such as maleic acid and methanesulphonic acid (forming maleates and methanesulphonates). [00133] Salts of amine groups may also comprise quarternary ammonium salts in which the amino nitrogen carries a suitable organic group such as an alkyl, lower alkenyl, substituted lower alkenyl, lower alkynyl, substituted lower alkynyl, or aralkyl moiety.

[00134] Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like. Bases useful in preparing pharmaceutically acceptable salts thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like. [00135] One skilled in the art will understand that the particular counterion forming a part of a pharmaceutically acceptable salt is usually not of a critical nature, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole.

[00136] In some embodiments, the present invention further encompasses pharmaceutically acceptable solvates of a resveratrol analog of general Formula (I), in which a resveratrol analog is combined with a solvent such as water, methanol, ethanol or acetonitrile to form a pharmaceutically acceptable solvate such as the corresponding hydrate, methanolate, ethanolate or acetonitrilate.

[00137] Certain resveratrol analogs of general Formula (I) may have one or more asymmetric (chiral) centres and/or one or more unsaturated bonds. As a consequence, these compounds can be present as racemates, individual enantiomers, mixtures of enantiomers, individual diastereomers, mixtures of diastereomers, individual isomers and mixtures of isomers. Certain embodiments of the invention relate to resveratrol analogs of Formula (I) in an enantiomeric, diastereomeric or isomeric form, or as mixtures of enantiomers, diastereomers or isomers. [00138] In certain embodiments, the invention provides for prodrugs of the resveratrol analogs of general Formula (I). The term "prodrug" as used herein refers to a compound that has undergone a chemical derivation such as substitution or addition of a further chemical group to change (for pharmaceutical use) one or more of its physico- chemical properties, and that yields the active compound per se by one or a series of metabolic transformations after administration to a subject. Physico-chemical properties that may be changed by conversion of the compound into a prodrug form include, for example, solubility, bioavailability, absorption, distribution, site specificity, stability, release characteristics, toxicity, and the like. Examples of chemical derivatives that may be prepared in order to convert a compound into a prodrug include, but are not limited to, ester derivatives, ether derivatives, carbamate derivatives, amide derivatives, imine derivatives, and derivatization with an appropriate carrier moiety directly or via a linker group. Examples of prodrugs and methods of producing a prodrug of a given acting compound are well known to those skilled in the art and can be found, for example, in Krogsgaard-Larsen et ah, (Textbook of Drug Design and Discovery, Taylor & Francis, New York, NY (April 2002)). [00139] The preparation of salts, solvates and prodrugs can be carried out by methods known in the art. It will be appreciated that non-pharmaceutically acceptable salts, solvates or prodrugs also fall within the scope of the invention since those may be useful in the preparation of pharmaceutically acceptable salts, solvates or prodrugs. PREPARA TION OF THE RES VERA TROL ANALOGS

[00140] The resveratrol analogs described herein may be prepared by conventional synthetic organic chemistry methods known in the art using readily available starting materials. Exemplary non-limiting synthetic pathways are outlined in Figures 2 and 3, and in the Examples. [00141] In all procedures, it may be appropriate to temporarily protect functional groups in the molecule in certain reaction steps. Such protective group techniques are familiar to the person skilled in the art. The choice of a protective group for groups under consideration and the processes for their introduction and removal are described in the literature and can if necessary readily be adapted to the individual case by the skilled worker.

A CTIVITY OF THE RES VERA TROL ANALOGS

[00142] Resveratrol analogs of the present invention preferably inhibit Kvl .5 channels. The ability of resveratrol analogs of general Formula (I) to inhibit Kvl .5 channels may be tested by standard protocols known in the art, including the exemplary methods described in the Examples provided herein.

[00143] In some embodiments, the resveratrol analogs may exhibit one or more of the following properties: frequency dependent Kvl.5 inhibition; IKr inhibition in human atrial tissue; anti-oxidant properties; late sodium current inhibition; NFAT inhibition; lack of inhibition of the hERG channel; little or no effect on ventricular function at concentrations effective for Kvl.5 inhibition, and/or functional efficacy in a large animal model of inducible AF.

[00144] The above properties can be tested using standard protocols known in the art, including the exemplary methods described in the Examples provided herein. PHARMACEUTICAL COMPOSITIONS

[00145] Resveratrol analogs of general Formula (I) are typically formulated for therapeutic use. In certain embodiments, the present invention thus relates to pharmaceutical compositions comprising a resveratrol analog of general Formula (I) and a pharmaceutically acceptable carrier, diluent, or excipient. The pharmaceutical compositions are prepared by known procedures using well-known and readily available ingredients.

[00146] Pharmaceutical compositions comprising the resveratrol analogs may in various embodiments be formulated for administration orally (including, for example, buccally or sublingually), topically, parenterally, by inhalation or spray, or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intradermal, intra-articular, intravenous, intramuscular, intravascular, intrasternal, intrathecal injection or infusion techniques. [00147] Compositions intended for oral use may be prepared in either solid or fluid unit dosage forms. Fluid unit dosage form can be prepared according to procedures known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents such as sweetening agents, flavouring agents, colouring agents and/or preserving agents in order to provide pharmaceutically elegant and palatable preparations. An elixir is prepared by using a hydroalcoholic (for example, ethanol) vehicle with suitable sweeteners such as sugar and saccharin, together with an aromatic flavoring agent. Suspensions can be prepared with an aqueous vehicle with the aid of a suspending agent such as acacia, tragacanth, methylcellulose or the like. [00148] Solid formulations such as tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets or other solid formulations. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate: granulating and disintegrating agents for example, corn starch, or alginic acid: binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc and other conventional ingredients such as dicalcium phosphate, magnesium aluminum silicate, calcium sulfate, starch, lactose, methylcellulose, and functionally similar materials. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.

[00149] Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil. Soft gelatin capsules are prepared by machine encapsulation of a slurry of the compound with an acceptable vegetable oil, light liquid petrolatum or other inert oil.

[00150] Aqueous suspensions contain active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxylmethylcellulose, methyl cellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia: dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example hepta-decaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or w-propyl-p-hydroxy benzoate, one or more colouring agents, one or more flavouring agents or one or more sweetening agents, such as sucrose or saccharin.

[00151] Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavouring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid. [00152] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavouring and colouring agents, may also be present.

[00153] Pharmaceutical compositions may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, for example olive oil or peanut oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents. [00154] The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to known art using those suitable dispersing or wetting agents and suspending agents that have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or a suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution, for example. In addition, sterile, fixed oils may be employed as a solvent or suspending medium. For this purpose, various bland fixed oils known in the art may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may find use in the preparation of injectables. Adjuvants such as local anaesthetics, preservatives and buffering agents may optionally also be included in the injectable solution or suspension.

[00155] Other pharmaceutical compositions and methods of preparing pharmaceutical compositions are known in the art as described, for example, in "Remington: The Science and Practice of Pharmacy ^' " (formerly "Remingtons Pharmaceutical Sciences ^' "); Gennaro, A., Lippincott, Williams & Wilkins, Philidelphia, PA (2000).

USES

[00156] The resveratrol analogs of general Formula (I) are preferably capable of inhibiting Kvl.5 channels. Certain embodiments of the invention thus relate to methods and uses of the resveratrol analogs for inhibiting the activity of Kvl.5 channels in vitro or in vivo.

[00157] Therapeutic uses of the resveratrol analogs in diseases or disorders associated with abnormal Kvl.5 channel activity, methods of treatment using the resveratrol analogs and uses of the resveratrol analogs to prepare medicaments for therapeutic use are also contemplated in certain embodiments of the invention. Certain embodiments relate to the therapeutic use of the resveratrol analogs in humans.

[00158] Compounds capable of inhibiting Kvl.5 channels have therapeutic potential for the treatment or prevention of atrial arrhythmias, for example, atrial fibrillation (AF) or atrial flutters. [00159] In certain embodiments, therefore, the present invention relates to methods and uses of resveratrol analogs of general Formula (I) for the treatment of AF in a subject. In certain embodiments, the subject is a human subject.

[00160] AF is known to be a major cause of stroke. For example, individuals with AF have a risk of stroke that is 3 to 5 times greater than those without AF. In certain embodiments, therefore, the invention relates to methods and uses of resveratrol analogs of general Formula (I) to reduce the risk of stroke in a subject. In certain embodiments, therefore, the invention relates to methods and uses of resveratrol analogs of general Formula (I) to prevent stroke in a subject. In certain embodiments, the invention relates to methods and uses of resveratrol analogs of general Formula (I) to reduce the risk of, or prevent, stroke in a subject with AF.

[00161] Certain embodiments of the invention contemplate the use of the resveratrol analogs of general Formula (I) in combination therapies with other pharmaceutically active compounds. For example, for the treatment of AF, the resveratrol analogs may be used in combination therapies with substances having cardiovascular activity such as, class I, class II or class III antiarrhythmics, including IKs or IK _r channel blockers (for example, dofetilide); hypotensive drugs, such as ACE inhibitors (for example, enalapril, captopril, ramipril); angiotensin antagonists; K ⁺ channel activators; alpha- and beta-receptor blockers; sympathomimetic compounds; compounds having adrenergic activity; Na ⁺ /H ⁺ exchange inhibitors; calcium channel antagonists; phosphodiesterase inhibitors and other substances having a positive inotropic action, such as, digitalis glycosides or diuretics.

KITS [00162] Certain embodiments of the invention relate to pharmaceutical packs or kits containing one or more resveratrol analogs of general Formula (I). In those embodiments in which the resveratrol analogs of general Formula (I) are intended for use as part of a combination therapy, the kit may optionally contain the other therapeutic(s) that makes up the combination. [00163] In certain embodiments, one or more of the components of the kit can be lyophilized and the kit can additionally contain a suitable solvent for reconstitution of the lyophilized components. Individual components of the kit would typically be packaged in separate containers and, associated with such containers, can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, for use or sale for human or animal administration.

[00164] In certain embodiments, the resveratrol analogs are provided in the kit in the form of pharmaceutical compositions suitable for administration to a subject. In this case, if desired, the container may itself be an inhalant, syringe, pipette, eye dropper, or other such like apparatus, from which the composition may be administered to the subject.

[00165] To gain a better understanding of the invention described herein, the following examples are set forth. It will be understood that these examples are intended to describe illustrative embodiments of the invention and are not intended to limit the scope of the invention in any way.

EXAMPLES EXAMPLE 1: Synthesis of Compound 21

[00166] Compound 21 was synthesized by conventional synthetic organic chemistry methods following the scheme provided in Figure 2. [00167] 7V-(tert-Butoxycarbonyl)-2-bromobenzylamine (precursor 1). 2-

Bromobenzylamine hydrochloride (9.66 g, 43.4 mmol) was mixed with anhydrous CH ₂ CI ₂ (108 mL) under a nitrogen atmosphere to form a slurry. The slurry was cooled to 0 °C and Et ₃ (13.3 mL, 95.4 mmol) was then added using a syringe. The resulting solution was stirred for 5 minutes and then di-teri-butyl dicarbonate (10.42 g, 47.7 mmol) was added. The resulting solution was stirred at room temperature for 2 hours. The mixture was extracted with CH ₂ CI ₂ and the organic layer was washed with water, saturated ammonium chloride, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was then dried with sodium sulphate and concentrated in vacuo. Recrystallization from hot hexanes gave the title compound: yield 84%. [00168] 2-(tert-Butoxycarbonylaminomethyl)phenylboronic Acid (precursor 2).

Precursor 1 (4.28 g, 15.0 mmol) was added to anhydrous THF (15 mL) under a nitrogen atmosphere and cooled to -78 °C. 1.4 M of MeLi in ether (13.4 mL, 18.75 mmol) was then added via syringe and the resulting mixture was stirred for 1 hour, after which 1.6 M tert-BuLi in hexanes (22.5 mL, 36 mmol) was added and the resulting solution was stirred for an additional hour. Triisopropyl borate (13.85 mL, 60 mmol) was then added and the solution was then allowed to warm to room temperature. The reaction mixture was stirred overnight at room temperature and then diluted with 1M HC1 to a pH of 6. The reaction mixture was then extracted with CH2CI2 and the organic phase was washed with water and saturated NaCl. The organic layer was then dried using sodium sulfate and concentrated in vacuo to give the title compound: yield 98%.

[00169] 2'-(tert-butoxycarbonylaminomethyl)-biphenyl-2-bromide (precursor 3).

1 ,2-Dimethoxyethane (DME, 40 mL) was purged with nitrogen. Ρά(ΡΡ1¾) ₄ (462 mg, 0.40 mmol) and 1,2 dibromobenzene (1.93 mL. 16 mmol) were added and the reaction mixture was stirred at room temperature for 10 min. Precursor 2 (2.04 g, 8 mmol) and 2 M sodium carbonate solution (8 mL) were added and then the mixture was heated and stirred at reflux 72 hours under a nitrogen atmosphere. After cooling the mixture was extract with (¾(¾ and the organic phase was washed with water and saturated NaCl. The solution was dried over sodium sulfate and concentrated in vacuo. Purification of the residue by column chromatography gave the title compound: yield 38%. H NMR (300 MHz, CDC1 ₃ , δ): 7.68-7.64 (m, 1H), 7.48-7.28 (m, 4H), 7.27-7.20 (m, 2H), 7.16- 7.13 (m, 1H), 4.68 (bs, 1H), 4.18-4.05 (m, 2H), 1.42 (s, 9H).

[00170] 2'-{[(4-Methoxy-phenyl)-acetylamino]-methyl}biphenyl-2-bromi de (precursor 4). Two part reaction done simultaneously. Part one Boc group removal. Precursor 3 (100 mg, 0.28 mmol) was added to a mixture of ϋ¾(¾ (7 mL), excess anisole, and trifluroacetic acid (TFA, 2.3 mL). The resulting mixture was stirred at room temperature for 3 hours. The mixture was the concentrated in vacuo and the resulting residue was co-evaporated with toluene. ϋ¾(¾ (50 mL) was added and the pH was adjusted to 12 using 2 M sodium carbonate. The resulting layers were separated and the organic layer was concentrated in vacuo. Part two. 1,1-carbonyldiimidazole (1.01 g, 6.22 mmol) was added to a solution of 4-methoxyphenylacetic acid (1.03 g, 6.22 mmol) in THF (8.3 mL). The resulting reaction mixture was stirred at room temperature for 2 hours and then the product from part one was added. The solution was stirred at room temperature overnight and then quenched with water (20 mL). The mixture was extracted with ethyl acetate (EtOAc) and the organic fraction was washed with water and saturated NaCl solution. The organic layer was dried with sodium sulfate and then concentrated in vacuo. The residue was purified by column chromatography to give the title compound: yield 51%>. 1H NMR (300 MHz, CDCI ₃ , δ): 7.63-7.59 (m, 1H), 7.37-7.27 (m, 4H), 7.24-7.20 (m, 1H), 7.14-7.08 (m, 4H), 6.87-6.83 (m, 2H), 5.52 (bs, 1H), 4.25-4.05 (m, 2H), 3.81 (s, 3H), 3.46 (s, 2H). [00171] 2'-{[(4-Methoxy-phenyl)-acetylamino]-methyl}biphenyl-2-iodid e

(precursor 5). Under a nitrogen purged environment precursor 4 (250 mg, 0.611 mmol) was dissolved in THF (350 μί) at -78°C. 1.4 M MeLi in Et ₂ 0 (0.611 mmol) was added and the reaction mixture was stirred for 5 min. 1.6 M w-butyl lithium in hexanes (0.611 mmol) was then added and the reaction was stirred at -78°C for 15 min until brown spots were observed. A solution of iodine (1.22 mmol) dissolved in a minimum volume of THF was added and the reaction mixture mixture was allowed to warm to room temperature. The reaction was quenched with water and the mixture was extracted with diethyl ether. The organic fraction was washed with sodium thiosulfate solution, water, and saturated NaCl solution. The organic layer was dried with sodium sulphate and then concentrated in vacuo to give the title compound: yield 66%. H NMR (300 MHz, CDC1 ₃ , δ): 7.92-7.88 (m, 1H), 7.39-7.30 (m, 5H), 7.15-7.08 (m, 2H), 7.07-7.01 (m, 2H), 6.87-6.81 (m, 2H), 5.55 (bs, 1H), 4.25-4.05 (m, 2H), 3.81 (s, 3H), 3.48 (s, 2H). HRMS-ES (w/z): [M + Naf calcd for C22H ₂ o 0 ₂ INa, 480.0431; found, 480.0431.

[00172] 4-Hydroxystyrene (precursor 6). Sodium hydride in mineral oil (9.01 mmol) was added to a nitrogen purged flask and washed with hexane to remove the mineral oil. DMSO (5.8 mL, 10 eq) was added and the mixture was refluxed until H ₂ production stops (45 min). After cooling the mixture in an ice bath a solution of methyltriphenylphosphonium bromide (3.22 mg, 9.01 mmol) in DMSO (18.5 mL) was added and the resulting reaction mixture was stirred for 15 minutes. 4- Hydroxybenzaldehyde (1.00 g, 8.19 mmol) in a minimum of DMSO (3 mL) was added and the resulting mixture was stirred at 23 °C for 5 hours. The reaction was quenched with water and the mixture was extracted with pentane three times and then once with ethyl acetate. The organic fractions were collected and concentrated in vacuo. The resulting residue was purified by column chromatography to give the title compound: yield 24%.

[00173] 4-Acetylstyrene (precursor 7). Precursor 6 (100 mg, 0.832 mmol) CH ₂ C1 ₂ (10 mL) was added to a mixture of triethylamine (1.16 mL), acetic anhydride (83 and DMAP (100 mg) under an atmosphere of N ₂ . The mixture was stirred at 23°C for 30 minutes and then diluted with CH ₂ C1 ₂ (20 mL). The organic layer was washed with water 3 times and then once with saturated aHC03 solution. The organic layer was dried (MgS0 ₄ ) and concentrated in vacuo. Purification by column chromatography gave the title compound: yield 24%. *H NMR (300 MHz, CDC1 ₃ , δ): 7.42-7.40 (m, 2H), 7.07-7.02 (m, 2H), 6.71 (dd, J = 16, 9 Hz, 1H), 5.71 (d, J = 16 Hz, 1H), 5.25 (d, J = 9 Hz, 1H), 2.28 (s, 3H). [00174] fraws-2-(4-acetylphenyl)vinylboronic acid pinacol ester (precursor 8).

Grubbs 2 ^nd generation catalyst (45 mg, 0.05 mmol) and CH2CI2 (10 mL) were added to a dry round bottom flask that was purged with argon. Precursor 7 (324 mg, 2.0 mmol) followed by pinacol vinylboronate (308 mg, 2.0 mmol) were then added via syringe. The resulting reaction mixture was refluxed with stirring for 12 hours then dissolved in toluene. After concentration in vacuo the residue was purified by chromatography to give the title compound: yield 31%. ^l H NMR (300 MHz, CDC1 ₃ , δ): 7.52-7.47 (m, 2H), 7.39 (d, J = 18 Hz, 1H), 7.06-7.01 (m, 2H), 6.12 (d, J = 18 Hz, 1H), 2.28 (s, 3H), 1.33 (s, 12H).

[00175] 2'-[(4-Methoxybenzoylamino)methyl]biphenyl-2-ira«s-(4-hydro xystyrene) (compound 21). Ethylene glycol dimethyl ether (700 μΐ,), Pd(PPh ₃ ) ₄ (4.0 mg, 0.0035 mmol), and precursor 5 (32 mg, 0.07 mmol) were mixed together for 10 minutes in a 2 purged reaction vessel. Precursor 8 (40.3 mg, 0.14 mmol) and 2 M a ₂ C0 ₃ (70 uL) was added to the reaction mixture and the resulting mixture was refluxed for 27 hours. The mixture was then diluted with CH2CI2 and the mixture was washed with water 3 times. The organic phase was dried with sodium sulphate and concentrated in vacuo. The residue was purified with chromatography to give the title compound: yield 51%. ln NMR (400 MHz, CDC1 ₃ , δ): 7.71-7.69 (m, 1H), 7.38-7.31 (m, 4H), 7.24-7.12 (m, 4H), 7.06-7.03 (m, 1H), 6.99-6.96 (m, 2H), 6.95-6.91 (m, 1H), 6.79-6.73 (m, 4H), 6.56- 6.52 (m, 1H), 5.96 (bs, 1H), 5.55-5.53 (m, 1H), 4.21-4.19 (m, 2H), 3.87 (s, 3H), 3.29 (s, 2H). HRMS-ES (w/z): [M + Naf calcd for C ₃ oH ₂ 7N0 ₃ Na, 472.188; found, 472.188.

[00176] Additional properties of Compound 21 were investigated and are summarized in Table 1 below.

Table 1: Properties and Characteristics of Compound 21

EXAMPLE 2: Synthesis of Compound 22

[00177] Compound 22 was synthesized by conventional synthetic organic chemistry methods following the scheme provided in Figure 3. [00178] 2-Ethoxy-l,3-benzodioxole-5-carbaldehyde (precursor 9). 1H NMR (300 MHz, CDC1 ₃ , δ): 9.85 (s, 1H), 7.48-7.45 (m, 1H), 7.41-7.39 (m, 2H), 7.00-6.99 (m, 1H), 6.95 (s, 1H), 3.72 (q, J = 7.5 Hz, 2H), 1.25 (t, J = 7.5 Hz, 3H). [00179] 5-Ethenyl-2-ethoxy-l,3-benzodioxole (precursor 10). H NMR (300 MHz, CDC1 ₃ , δ): 7.05-7.00 (m, 1H), 6.89-6.86 (m, 1H), 6.87 (s, 1H), 6.82-6.79 (m, 1H), 6.63 (dd, J = 14, 7.4 Hz, 1H), 5.59 (d, J = 14 Hz, 1H), 5.17 (d, J = 7.4 Hz, 1H), 3.78 (q, J = 7.5 Hz, 2H), 1.25 (t, J = 7.5 Hz, 3H). [00180] iraws-5-(-2-Ethoxy-l,3-benzodioxole)vinylboronic acid pinacol ester (precursor 11). *H NMR (300 MHz, CDC1 ₃ , δ): 7.31 (d, J = 18.4 Hz, 1H), 7.08-7.06 (m, 1H), 7.00-6.88 (m, 1H), 6.87 (s, 1H), 6.82-6.80 (m, 1H), 5.99 (d, J = 18.4 Hz, 1H), 3.77 (q, J = 7.5 Hz, 2H), 1.32 (s, 12H), 1.23 (t, J = 7.5 Hz, 3H).

[00181] 7V-({2'-[ira«s-5-(-2-Ethoxy-l,3-benzodioxole)vinyl]biphenyl -2-yl}methyl)- (4-methoxyphenyl)acetamide (precursor 12). H NMR (300 MHz, CDC1 ₃ , δ): 7.72- 7.67 (m, 1H), 7.39-6.78 (m, 16H), 6.53 (d, J = 15 Hz, 1H), 5.37 (bs, 1H), 4.19-4.15 (m, 2H), 3.78 (s, 3H), 3.72-3.66 (m, 2H), 3.30 (bs, 2H), 1.23-1.20 (m, 3H).

[00182] 2'-[(4-Methoxybenzoylamino)methyl]biphenyl-2-ira«s-(3,4- dihydroxystyrene) (compound 22). HRMS-ES (m/z): [M + Na] ⁺ calcd for C ₃ oH ₂₇ N0 ₄ Na, 488.1832; found, 488.1834.

EXAMPLE 3: Synthesis of Compounds 23 and 24

[00183] Compounds 23 and 24 were synthesized by conventional synthetic organic chemistry methods following the scheme provided in Figure 3.

[00184] Methyl-2-bromobenzoate (precursor 13). Concentrated sulphuric acid (-94%, 1.5 mL) was added slowly down the side of the flask to a solution of 2- bromobenzoic acid (10.0 g, 49.75 mmol) in methanol (20 mL) with stirring. The reaction mixture was then refluxed for one hour and then allowed to cool to room temperature. The mixture was extracted with CH ₂ CI ₂ (30 mL) and the organic fraction was washed with water (10 mL) and then twice with 5% sodium carbonate solution (10 mL). The solution was concentrated in vacuo to give the title compound: yield 64%. Product characterized by ^-NMR.

[00185] 2'-(tert-butoxycarbonylaminomethyl)-biphenyl-2-methyl ester (precursor

14). Pd(PPh ₃ ) ₄ (462 mg, 0.40 mmol) and precursor 13 (1.68 mL, 12 mmol) were added to 1,2-dimethoxyethane (DME, 40 mL) that was purged with nitrogen. The mixture was then stirred at room temperature for 10 min. Precursor 2 (2.04 g, 8 mmol) and 2 M sodium carbonate solution (8 mL) were added and the mixture was refluxed with stirring for 18 hours under a nitrogen atmosphere. After cooling the mixture was extracted with CH2CI2 and the organic layer was washed with water and saturated NaCl. The solution was dried using sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography to give the title compound: yield 73%. Product characterization by ^-NMR.

[00186] 2'-{[(4-Methoxy-phenyl)-acetylamino]-methyl}biphenyl-2-methy l ester (precursor 15). Two part, one-pot procedure, a) Precursor 14 (1.06 g, 3.11 mmol) was added to a solution of CH2CI2 (75 mL) and TFA (25 mL). The reaction mixture was stirred at room temperature for 3 hours and concentrated in vacuo. The residue was co- evaporated with toluene. CH2CI2 (50 mL) was then added and the pH was adjusted to 12 using 2 M sodium carbonate. The layers were separated and the organic layer was concentrated in vacuo, b) 1,1-Carbonyldiimidazole (1.01 g, 6.22 mmol) was added to a solution of 4-methoxyphenylacetic acid (1.03 g, 6.22 mmol) in THF (8.3 mL) and the mixture was stirred at room temperature for 2 hours. The product from part a was added and the mixture was stirred at room temperature overnight. The reaction was quenched with water (20 mL) and then extracted with ethyl acetate (EtOAc). The organic fraction was washed with water and saturated NaCl solution. The organic fraction was dried with sodium sulfate and then concentrated in vacuo. The residue was purified by column chromatography to give the title compound: yield 51%. Product characterized

[00187] 2'-{[(4-Methoxy-phenyl)-acetylamino]-methyl}biphenyl-2-carbo xylic acid (precursor 16). 1 M LiOH (13.4 mL) was added to a solution of precursor 15 (419 mg, 1.08 mmol) in methanol (18.4 mL) with stirring. The solution was stirred at room temperature for 3 hours or until all original starting material had been consumed, as determined by TLC. The mixture was then diluted with EtOAc (40 mL) and the pH adjusted to ~2 using 1 M HC1. The aqueous layer was extracted with EtOAc (40 mL) and the organic layers were combined, washed with water and then brine. The organic layer was then dried on sodium sulfate and then concentrated in vacuo to give the title compound as a crude product that was characterized by ^-NMR. [00188] 2'-{[(4-Methoxy-phenyl)-acetylamino]-methyl}biphenyl-2-carbo xylic acid 4-phenolamide (Compound 23). 1,1-Carbonyldiimidazole (12 mg, 0.074 mmol) was added to a solution of precursor 16 (26 mg, 0.067 mmol) in THF (0.2 mL) and the resulting mixture was stirred at room temperature for 2 hours. 4-Aminophenol (14.6 mg, 0.134 mmol) was added and the mixture was stirred overnight at room temperature. The reaction was quenched with water (2 mL) and extracted with EtOAc (5 mL) twice. The organic fractions were collected and washed with water (5 mL) and saturated NaCl solution (5 mL). The organic layer was concentrated in vacuo and the residue was purified by column chromatography. Further purification with HPLC gave the title compound: yield 27%. Compound was characterized by ^-NMR and HRMS.

[00189] 2'-{[(4-Methoxy-phenyl)-acetylamino]-methyl}biphenyl-2-carbo xylic acid (4-phenol-ethyl)amide (Compound 24). All procedures the same as for Compound 23 except precursor 16 (24.7 mg, 0.063 mmol), 1,1-carbonyldiimidazole (11.3 mg, 0.069 mmol), and tyramine (17.3 mg, 0.126 mmol) of instead of 4-aminophenol: yield 31%. EXAMPLES 4-12: MATERIALS AND METHODS

[00190] For Examples 4 to 12 and 19 below, the following materials and methods were used.

Human Kvl.5 stable cell line.

[00191] The human Kvl.5 gene was isolated from human left atrial appendage tissue excised during CABG surgery. Total RNA extraction was performed and the Kvl.5 gene was isolated and amplified. The Kvl.5 gene identity was confirmed by sequencing with multiple primers and then sub-cloned into the pcDNA 3.1 zeo vector. The Kvl.5 stable line was then generated in the tsA201 cell line. In brief, the Kvl.5pcDNA3.lzeo vector was transfected into tsA201 cells and cultured in DMEM supplemented with varying concentrations of Zeocin. Cells were plated in 300ml culture flasks and individual colonies of Zeocin resistant cells were isolated, expanded and tested for stable expression of large (>300 pA) Kvl.5 currents. A Kvl.5 positive cell line with robust and stable Kvl.5 expression was then cultured or frozen down for subsequent use in the patch-clamp experiments. Cell culture and transfection

[00192] The Kvl.5 cell line was cultured in DMEM supplemented with 10% (vol/vol) FBS, 1% glutamine and 200 nM zeocin, and tsA201 cells were cultured in DMEM 10% FBS, 1% glutamine and 1% penicillin-streptomycin in a humidified 5% C(¾ incubator at 37 °C. Na _v 1.5 and HERG gene expression vectors were generously provided for unrestricted use by Dr. Arthur Brown (Cleveland University) and Dr. Henry Duff (University of Calgary) respectively. These expression vectors were co-transfected into tsA201 cells with a GFP expression vector using the calcium phosphate precipitation technique. Transfected cells were used within 48 hrs of the initial transfection. Transfected cells were identified by GFP fluorescence.

Patch-clamp electrophysiology

[00193] Standard whole-cell patch-clamp techniques were used to measure Kvl.5, Na _v 1.5 and HERG channel currents from either the Kvl.5 stable cell line or the transiently transfected tsA201 cells expressing Na _v 1.5 or HERG channels (Wallace CH, et ah, 2006, Br J Pharmacol., 149(6):657-65; Light PE, et ah, 2003, Circulation, 107(15):1962-5; Kikuchi K, et ah, 2005, Br J Pharmacol., 144(6):840-8).

Recording of Kvl.5 currents in the stable Kvl.5 tsA 201 cell line.

[00194] Cells were cultured in Dulbecco's modified Eagle's medium supplemented with 5% FBS and zeocin (200 ng / ml) at 37°C in 5% CO ₂ . Cells were dissociated with 0.25% trypsin then plated at 10 - 30% confluence onto microscope cover slips (Fisher Scientific) and maintained in the same medium as above described at 30°C in 5% CO ₂ until whole-cell patch-clamp recording. Single cells were used for whole-cell recording during the subsequent 30-h period. Pipettes were pulled from borosilicate glass capillary tubing (Warner instruments, Hamden, CT USA) using a p-87 micropipette puller (Sutter instruments, Novato, CA, USA) and tips were fire-polished, producing resistances of 1 - 3 ΜΩ. The pipette solution contained (in mM): 140 KC1, 1 CaCl2 , 1 MgC , 10 2-[4-(2-hydroxyethyl)-l-piperazinyl]ethanesulphonic acid (HEPES) and 10 ethylene glycol-bis-(2-aminoethyl etherl-N^N^N'-tetraacetic acid (EGTA). The pH was adjusted to 7.3 with KOH. 2 mM MgATP was added immediately before use. Cells were bathed in extracellular solution contained (in mM): 135 NaCl, 5.4 KC1, 1 CaCl ₂ , 1.2 MgCl ₂ , 10 HEPES and 5 Glucose (pH adjusted to 7.4 with NaOH). Solutions were applied to cells using a multi-input perfusion pipette (switch time < 2 s). Once a giga- seal was formed, the patch was ruptured and the whole-cell voltage-clamp technique was used to record Kvl .5 currents. Currents were elicited by 120 ms duration test pulses to +40 mV from a holding potential of -100 mV with a cycle length of 0.3 Hz, 1 Hz or 3 Hz respectively. Data were acquired using an Axopatch 200B patch-clamp amplifier and Clampex 8.2 software (Axon Instruments, Foster City, CA, USA).

Recording ofNavl.5 currents

[00195] tsA201 cells were maintained in Dulbecco's modified Eagle's medium supplemented with 2 mM L-glutamine, 10% foetal calf serum and 0.1% penicillin/streptomycin at 37°C in 5% C(¾. Cells were plated at 60-80% confluence onto 35 mm culture dishes 6-8 h prior to transfection. Mammalian expression vectors encoding the human heart ay 1.5 and green fluorescent protein (pGL, Life Technologies, Burlington, Canada), were co-transfected into cells using the calcium phosphate precipitation technique. Cells were plated at 20-30% confluence onto cover slips 30^12 h after transfection. Single cells were used for whole-cell recording during the subsequent 30-h period. Cells were bathed with HEPES-buffered saline solution containing (in mM): 140 NaCl, 10 HEPES, 1 CaCl ₂ , 1.4 MgCl ₂ , 5 KC1 and 10 glucose, pH 7.2. Pipette solution contained (in mM): 130 CsCl, 5 NaCl, 5 tetraethylammonium (TEA)-Cl, 2.5 HEPES, and 1 EGTA (pH was adjusted to 7.2 with CsOH). 2 mM MgATP was added immediately before use. Data acquisition, pipette pulling and superfusate solutions were same as described above for Kvl .5, with the exception that 50 ms duration test pulses were to -20 mV from a holding potential of -100 mV with a cycle length of 0.2 Hz. ATXII (3 nM) was used to induce late /NE(4). Voltage steps from a holding potential of -120 mV to 40 mV every lOmV was used to generate the current-voltage (I -V) relationship for peak Ι^ _Ά ,

Recording ofHERG currents

[00196] tsA201 cells were transfected with the HERGA channel clone mammalian expression vector in a similar way as described for Navl .5 and currents were recorded using previously published protocols (Kikuchi K, et ah, 2005, ibid). Recording of IKurfrom human atrial myocytes

[00197] For experiments on human atrial IKur (Kvl.5), atrial appendage samples were collected from the operating room at the University Hospital, Edmonton and enzymatically dissociated into single atrial myocytes. IKur currents were then measured using a modification of the whole-cell recording technique previously published (Gong D, et al, 2008, Cell Physiol Biochem., 21(5-6):385-94).

Cell shortening and calcium transient recordings

[00198] These were measured in rat ventricular myocytes using standard procedures previously published (Wallace CH, et at, 2006, ibid., Baczko I, et at, 2005, FASEB J., 19(8):980-2).

A nti-oxidant Assay

[00199] Diphenylpicrylhydrazyl (DPPH) is extensively used to examine a compound's propensity to donate a labile hydrogen atom to free radicals and render them inert. As DPPH is a stable free radical that has a noticeable change in coloration from purple to yellow when it sequesters a labile H atom from an antioxidant, it can be used to determine the antioxidant efficacy of a test compound.

[00200] A solution of ¾(¾ at a concentration of 200nM was mixed with DPPH and either resveratrol, AVE0118 or compound 21 at various concentrations (Figure 7). The absorbances of these solutions were measured at 517nm, with a lower absorbance representing an increase in anti-oxidant ability.

In vivo electrophysiology

[00201] All experiments were carried out in compliance with the Guide for the Care and Use of Laboratory Animals (USA NIH publication No 85-23, revised 1996).

[00202] Adult male Beagle dogs (14-16 kg) were anesthetized with ketamine (induction: 10 mg kg ^"1 , maintenance: 2 mg kg ^"1 every 20 min) and xylazine (induction: 1 mg kg ^"1 , maintenance: 0.2 mg kg ^"1 every 20 min) and were mechanically ventilated (Dog Ventilator UB 5025, Harvard Apparatus, USA). Following the implantation of two bipolar pacemaker electrodes into the right atrial appendage and apex of the right ventricle under fluoroscopic guidance the electrodes were connected to pacemakers (Biotronik, Hungary) in subcutaneous pockets in the neck area, radiofirequency catheter ablation of the AV node was performed to avoid high atrial pacing rates propagating into the ventricles. The ventricular pacemaker was set between 80 to 90 beats min ^"1 , following the baseline heart rate of the dog before the operation. [00203] Following recovery from surgery (3 days), high frequency right atrial pacing was started at 400 beats min ^"1 , maintained for 6 to 7 weeks before the experiments to allow electrical remodeling of the atria (monitored by the measurement of the right atrial effective refractory period (AERP) every second day). The AERPs were measured at basic cycle lengths (BCL) of 150 and 300 ms with a train of 10 stimuli (Si) followed by an extra stimulus (S ₂ ), with the AERP defined as the longest S ₁ S ₂ interval that did not produce a response. AERP shorter than 80 ms could not be measured in conscious animals (pacemaker measurement limit).

[00204] On the day of the experiment, atrial pacing was stopped, continuous recording of the electrocardiogram commenced using precordial leads (SPEL Haemosys software v3.0, Experimetria Ltd., Budapest, Hungary) and the AERP was measured. A control set (25 times) of 10-second long rapid atrial bursts (800 beats min ^"1 , at twice threshold) were performed in order to induce atrial fibrillation in conscious dogs preceded by a bolus infusion of vehicle (20 mL of a mixture of DMSO + β-hydroxypropyl- cyclodextrin + saline (all from Sigma, St. Louis, USA), DMSO concentration less than 0.1%, infused in 15 min) using an infusion pump (Terufusion TE-3, Terumo Europe, Leuven, Belgium). During the control 25 bursts and subsequent AF episodes, a continuous infusion of vehicle was maintained (in a volume of 1.7 mL kg ^"1 min ^"1 ). Following the measurement of AERP, Compound 21 was infused in a dose of 0.3 mg kg ^"1 (in 15 min bolus + maintenance) and AF was again induced 25 times. An identical procedure was repeated in every dog with 1 mg kg ^"1 dose of Compound 21. The incidence of AF, the total duration of AF, the average duration of AF episodes were measured along with changes in atrial refractory period and QT interval. QT intervals were measured before the 12th burst and were not corrected for heart rate since QT measurements were made at heart rate set to 80 beats min ^"1 by the ventricular pacemaker in each animal. Importantly, the present in vivo dog atrial fibrillation experiments were done in freely moving conscious dogs so that any interference from anesthetics could be ruled out. [00205] The total duration of AF and the average duration of AF episodes were expressed in seconds and data were normalized by logio-transformation. Data were expressed as mean ± S.E.M. As each animal served as its own control, after one-way analysis of variance, the groups were compared in pairs by means of Student's i-test. A level ofp<0.05 was considered to be significant.

EXAMPLE 4: Kvl.5 Inhibitory Potency of Compounds 21-24

[00206] Compounds 21, 22, 23 and 24 all demonstrated inhibition of cloned human atrial Kvl.5 channels. ICso's were: compound 21 = 340 nM; compound 22 = 8.3μΜ; compound 23 = 10.9μΜ; and compound 24 = 11.2μΜ. Compound 21 possessed the highest potency for inhibition (see Figure 5; compare to resveratrol (Figure 1) with an ICso = 66μΜ).

EXAMPLE 5: Frequency-Dependent Inhibition of Kvl.5 by Compound 21

[00207] Compound 21 displayed greater inhibitory potency when Kvl.5 currents were elicited at 3 Hz vs. 1 Hz (see Figure 6). This is a desirable property as AF is defined by rapidly firing action potentials in the atria.

EXAMPLE 6: Inhibition of IKr (Kvl.5) from Human Atrial Myocytes by Compound 21

[00208] Compound 21 is an effective inhibitor of IKr (Kvl.5) currents recorded from atrial myocytes enzymatically isolated from atrial appendage tissue obtained during cardiac surgery (see Figure 7). At a concentration of 300 nM, compound 21 inhibited IKr by over 50%.

EXAMPLE 7: Anti-Oxidant Properties of Compound 21

[00209] Compound 21 possesses similar anti-oxidant properties (reducing potential) to resveratrol when compared to AVE0118, a known Kvl.5 inhibitor, when measured using DPPH (see Figure 8). EXAMPLE 8: Late Sodium Current Inhibition by Compound 21

[00210] Compound 21 displays preferential inhibition of late sodium current vs. peak sodium current (ICso _s are 1 and 3 μΜ respectively) (see Figure 9). Sodium currents were recorded from cloned human heart sodium channels (Navl.5) expressed in tsA201 cells. Late sodium current was induced by 100 nM ATXII.

EXAMPLE 9: Nuclear Factor of Activated T-cells (NFAT) Inhibition by Compound 21

[00211] Compound 21 displays similar NFAT inhibitory properties to resveratrol (ICsos ~ 1 μΜ) (see Figure 10). [00212] Activation of NFAT in AF leads to abnormal gene expression and resultant deleterious re-modeling of the atria that worsens AF and may also lead to heart failure. Inhibition of NFAT is thus a desirable activity for potential AF drugs.

EXAMPLE 10: Lack of HERG Channel Inhibition by Compound 21

[00213] Significant inhibition of HERG channels may cause drug-induced (acquired) Long QT syndrome, leading to torsades de pointes ventricular arrhythmias. Lack of HERG channel inhibition is thus a desirable activity for potential AF drugs. At low micromolar concentrations (shaded bar) compound 21 does not inhibit HERG channels. ICso ~ 30 μΜ (see Figure 11).

[00214] Whole-cell recordings were made from tsA201 cells expressing the human HERG A channel clone. Identity of HERG channels was confirmed by inhibition with the HERG channel inhibitor E-4031 (panel A).

EXAMPLE 11: Lack of Effects of Compound 21 on Ventricular Myocyte Function

[00215] A highly desirable property of any small molecule for the treatment of AF is atrial selectivity; i.e. no effect on ventricular cells. Therefore, the effects of Compound 21 on rat ventricular myocyte contraction and calcium transient signaling were tested. It was found that at 3 μΜ, compound 21 did not have any effect. [00216] The results are shown in Figure 12. Compound 21 (3 μΜ) did not alter either single ventricular myocytecontractility (A) or calcium transient signaling (B).

EXAMPLE 12: Functional Anti-AF Efficacy of Compound 21 in a Large Animal Model of Inducible AF [00217] Using a large animal (conscious dog) model of inducible AF (Figure 13A,B), intravenous injection of lmg/kg compound 21 significantly reduced the total AF duration and the episode duration of AF (Figure 13C,D).

[00218] In summary, Examples 4 to 12 demonstrate that at concentrations in the 300 nM to ~1 μΜ range, the small molecule compound 21 is a selective Kvl.5 inhibitor with late sodium channel blocking actions and importantly lacks any significant inhibition of the HERG channel (see Figure 14).

[00219] In addition, compound 21 is similar in antioxidant capacity to resveratrol, inhibits NFAT activation and does not affect either the contractility or calcium handling in rat ventricular cells. Taken together, these properties of compound 21 are highly desirable for an ideal drug for the prevention of AF and this has been confirmed in the best animal model available - the conscious dog model of inducible AF (Figure 13).

[00220] Therefore, compound 21 represents a novel multifunctional lead small molecule for the treatment of AF.

EXAMPLE 13: Synthesis of Precursor Vinyl Boronate Esters

[00221] 2-(Dichloromethyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (2): To a cooled (-100 °C) solution of dichloromethane (55 mmol, 3.53 mL) in THF (110 mL) was added 2.5 M w-BuLi in hexanes (51.5 mmol, 20.6 mL) dropwise over 30 min. The resulting suspension was stirred for an additional 30 min at -100 °C then trimethylborate (55 mmol, 6.25 mL) was added in one portion. After 30 min, the reaction was quenched with 5 M HC1 (10 mL) and the organic layer was separated. The aqueous layer was extracted with ether (2 x 25 mL) and the combined organic layers were concentrated. The crude material was redissolved in benzene (110 mL) and pinacol (55 mmol, 6.5 g) was added in one portion. The reaction was refluxed under argon for 48 h. Fractional distillation afforded 4.64 g (40%) of the desired product as a clear oil. H NMR (400 MHz, CDC1 ₃ ) δ 5.37 (s, 1H), 1.36 (s, 12H).

[00222] (E)-4-[2-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)vinyl] phenol (3):

To a suspension of chromium(II) chloride (32.8 mmol, 4.0 g) in anhydrous THF (30 mL) under argon was added a solution of 4-hydroxybenzaldehyde (4.1 mmol, 500 mg) and 2-(dichloromethyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (8.2 mmol, 1.7 g) in THF (5 mL) followed by a solution of lithium iodide (16.4 mmol, 2.2 g) in THF (5 mL). The reaction was excluded from light and stirred under argon at room temperature overnight. The reaction mixture was partitioned between Et ₂ 0 and water and the aqueous layer was further extracted with Et ₂ 0 (2 x 50 mL). The combined organic layers was washed with brine, dried over Na ₂ S0 ₄ , and concentrated to give 1.2 g of product which was used in the subsequent step without any further purification.

[00223] (E)-4-[(2-(4,4,5,5-tetramethylTetramethyl-l,3,2-dioxaborolan -2- yl)vinyl])phenyl acetate (4): To a solution of (E)-4-(2-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)vinyl)phenol (~4.1 mmol, 1.2 g) in DCM (10 mL) was added Et ₃ N (4.1 mmol, 0.57 mL) and acetic anhydride (4.1 mmol, 0.43 mL). The reaction was stirred at room temperature for 5 h. The reaction mixture was concentrated and the resultant crude material was purified by automated flash chromatography (5% to 40% EtOAc in hexanes) to give 870 mg (74%, 2 steps) of the desired product as a pale yellow solid. ^l H NMR (400 MHz, CDC1 ₃ ) δ 7.51 (d, J = 8.5 Hz, 2H), 7.39 (d, J = 18.4 Hz, 1H), 7.09 (d, J = 8.6 Hz, 2H), 6.13 (d, J = 18.4 Hz, 1H), 2.32 (s, 3H), 1.34 (s, 12H). EXAMPLE 14: Synthesis of Biphenyl Core

[00224] The transformation of 5 to 7 was performed as described in Example 1 above (compound 5 = 2-bromobenzylamine hydrochloride, compound 6 = precursor 1, and compound 7 = precursor 2; see also Figure 2).

[00225] tert-Butyl (2'-bromobiphenyl-2-yl)methylcarbamate (8): A mixture of boronic acid 7 (150 mg, 0.6 mmol), 1,2-dibromobenzene (200 mg, 0.9 mmol), Na ₂ C03 (1M aqueous solution, 1.5 mL, 1.5 mmol) in ACN (2 mL) was purged with argon for 10 minutes followed by the addition of Pd(PPli ₃ )2Ci2 catalyst (20 mg, 0.03 mmol). The mixture was heated in a sealed tube with microwaves at 100 °C for 1 h and then partitioned between EtOAc and FLO. The organic phase was washed with brine, dried over anhydrous Na ₂ S0 ₄ and concentrated. The crude product was purified by automated flash chromatography to give compound 8 (132 mg, 61%).

EXAMPLE 15: Synthesis of Resveratrol Analogs - Route A [00226] Compounds 12, 18-21, 25, 26 and 30-41 were prepared as follows.

[00227] (E)-tert-Butyl [2'-(4-hydroxystyryl)biphenyl-2-yl]methylcarbamate (29) and (E)-4-(2-{2'-[(tert-butoxycarbonylamino)methyl]biphenyl-2-yl }vinyl)phenyl acetate (10): A mixture of 8 (105 mg, 0.29 mmol), boronate 4 (95 mg, 0.33 mmol), Na2C(¾ (1M aqueous solution, 0.45 mL, 0.45 mmol) in ACN (4 mL) was purged with argon for 10 minutes followed by the addition of Pd(PPh3) ₂ C¾ catalyst (13 mg, 0.02 mmol). The mixture was heated in a sealed tube with microwaves at 100 °C for lh and then partitioned between EtOAc and ¾0. The organic phase was washed with brine, dried over anhydrous Na ₂ S0 ₄ and concentrated. The crude product was purified by automated flash chromatography to give compounds 29 (32 mg, 27%) and 10 (81 mg, 63%). 29: H NMR (400 MHz, MeOD) δ 7.79 (d, J = 7.5 Hz, 1H), 7.48 - 7.27 (m, 5H), 7.19 - 7.10 (m, 4H), 7.00 (d, J = 16.3 Hz, 1H), 6.68 (d, J= 8.6 Hz, 2H), 6.59 (d, J = 16.4 Hz, 1H), 4.05 - 3.92 (m, 2H), 1.38 (s, 9H). ¹³ C NMR (101 MHz, MeOD) δ 158.45, 158.21, 141.43, 140.69, 138.49, 137.43, 131.26, 130.99, 130.72, 130.43, 128.93, 128.84, 128.23, 127.91, 127.88, 125.81, 124.67, 122.88, 116.39, 80.07, 43.18, 28.72. Mass calculated for (C ₂ 6H ₂ 7N0 ₃ +H) ⁺ 402.2, found 402.2.

[00228] (E)-4-{2-[2'-(Aminomethyl)biphenyl-2-yl]vinyl}phenyl acetate (11):

Compound 10 (70 mg, 0.158 mmol) was dissolved in DCM (2 mL) and treated with anisole (172 ^L, 1.58 mmol) followed by TFA (1.37 mL). The reaction was stirred at room temperature for 3 h, after which the reaction was concentrated. The residue was dissolved in toluene (5 mL) and re-concentrated to afford compound 11 as a brown oil that was used in the subsequent step without any further purification.

[00229] (E)-4-[2-(2'-{[2-(4-Methoxyphenyl)acetamido]methyl}biphenyl- 2- yl)vinyl] phenyl acetate (12): Compound 11 (-0.158 mmol) was dissolved in DCM (2 mL) and treated with DIPEA (137 μί, 0.787 mmol) followed by 4- methoxyphenylacetic acid (26 mg, 0.158 mmol). After stirring for 5 minutes, HATU (78 mg, 0.205 mmol) was added to the mixture and the reaction was stirred at room temperature. After 4 h, the reaction was concentrated and the crude product was purified by automated flash chromatography (25 to 100% EtOAc in hexane) to afford 12 (72 mg, 93 %) as a white solid. H NMR (400 MHz, CDC1 ₃ ) δ = 7.73 (d, J = 7.7 Hz, 1H), 7.40-7.31 (m, 4H), 7.28-7.23 (m, 3H), 7.17-7.15 (m, 1H), 7.07 (dd, J = 7.6, 1.2 Hz, 1H), 7.02-6.95 (m, 5H), 6.80 (d, J = 8.6 Hz, 2H), 6.66 (d, J = 16.3 Hz, 1H), 5.50 (t, J = 5.7 Hz, 1H), 4.19 (d, J = 3.7 Hz, 1H), 4.17 (d, J = 3.7 Hz, 1H), 3.77 (s, 3H), 3.33 (s, 2H), 2.28 (s, 3H). ¹³ C NMR (100 MHz, CDC1 ₃ ) δ = 171.0, 169.4, 158.8, 150.2, 140.0, 139.6, 136.4, 135.4, 135.0, 130.5, 130.4, 130.0, 129.0, 128.7, 128.1, 128.0, 127.6, 127.5, 127.4, 126.9, 126.8, 125.3, 121.9, 114.4, 55.3, 42.7, 41.8, 21.2.

[00230] (E)-7V-{[2'-(4-Hydroxystyryl)biphenyl-2-yl]methyl}-2-(4- methoxyphenyl)acetamide (21): Compound 12 (41 mg, 0.0834 mmol) was dissolved in MeOH (1 mL), treated with NaOH (2 M, 70 μί, 0.140 mmol) and stirred at room temperature. After 30 min the reaction was quenched by adding Amberlite IR120 H ⁺ resin until the pH was acidic. The resin was filtered away, the mixture was concentrated and the product was isolated by automated flash chromatography (25 to 100% EtOAc in hexanes) to afford 21 (34 mg, 91 %) as a white solid. H NMR (400 MHz, CDC1 ₃ ) δ = 7.70 (d, J = 7.8 Hz, 1H), 7.48 (s, 1H), 7.36-7.31 (m, 4H), 7.22-7.16 (m, 2H), 7.09 (d, J = 8.6 Hz, 2H), 7.03 (dd, J = 7.6, 1.2 Hz, 1H), 6.95 (d, J = 8.6 Hz, 2H), 6.93 (d, J = 16.0 Hz, 1H), 6.76 (d, J = 8.7 Hz, 2H), 6.70 (d, J = 8.6 Hz, 2H), 6.52 (d, J = 16.3 Hz, 1H), 5.54 (t, J = 5.8 Hz, 1H), 4.19 (d, J = 5.9 Hz, 2H), 3.74 (s, 3H), 3.28 (s, 2H). ¹³ C NMR (100 MHz, CDC1 ₃ ) δ = 171.9, 158.9, 156.8, 140.4, 139.2, 136.2, 136.1, 130.6 ^χ 2, 130.0, 129.9, 129.3, 129.0, 128.1, 128.0 ^χ 2, 127.7, 127.1, 126.4, 125.1, 123.8, 115.9, 114.5, 55.4, 42.6, 42.2. [00231] The following compounds were synthesized following the procedure for the conversion of 11 to 21, substituting alternative carboxylic acids in the HATU coupling.

[00232] (E)-2-(4-Fluorophenyl)-7V-{[2'-(4-hydroxystyryl)biphenyl-2- yl] methyl} acetamide (31)

[00233] *H NMR (400 MHz, CDC1 ₃ ) δ = 7.70 (d, J = 7.7 Hz, 1H), 7.38-7.32 (m, 4H), 7.24-7.18 (m, 3H), 7.09-7.04 (m, 3H), 6.98-6.86 (m, 5H), 6.69 (d, J = 8.6 Hz, 2H), 6.53 (d, J = 16.3 Hz, 1H), 5.54 (t, J = 5.8 Hz, 1H), 4.25 (dd, J = 14.8, 6.2 Hz, 1H), 4.14 (dd, J = 14.8, 5.6 Hz, 1H), 3.25 (s, 2H). ¹³ C NMR (100 MHz, CDC1 ₃ ) δ = 171.1, 163.3, 160.9, 156.7, 140.5, 139.2, 136.1, 136.0, 131.0, 130.9, 130.5, 130.2, 130.2, 130.0, 129.9, 129.2, 129.1, 128.2, 128.1, 128.0, 127.8, 127.2, 125.1, 123.9, 115.9, 115.7, 42.6, 42.2.

[00234] (E)-7V-{[2'-(4-Hydroxystyryl)biphenyl-2-yl]methyl}-4-methoxy benzamide (39)

[00235] H NMR (500 MHz, CDC1 ₃ ) δ = 7.72 (d, J = 7.8 Hz, 1H), 7.51-7.48 (m, 2H), 7.39-7.33 (m, 5H), 7.30-7.27 (m, 1H), 7.26-7.24 (m, 1H), 7.21-7.20 (m, 1H), 7.07 (d, J = 8.6 Hz, 2H), 6.93 (d, J = 16.3 Hz, 1H), 6.71 (d, J = 8.6 Hz, 2H), 6.66-6.62 (m, 3H), 6.18-6.15 (m, 1H), 4.61 (dd, J = 14.6, 7.0 Hz, 1H), 4.16 (dd, J = 14.6, 4.7 Hz, 1H), 3.71 (s, 3H). ¹³ C NMR (125 MHz, CDC1 ₃ ) δ = 167.2, 162.2, 156.9, 140.6, 139.5, 136.8, 136.1, 130.3, 130.2 x 2, 129.6, 129.0, 128.7, 128.3, 128.2, 128.1, 127.8, 127.3, 125.9, 125.1, 123.7, 116.0, 113.7, 55.4, 42.2. [00236] (E)-7V-{[2'-(4-Hydroxystyryl)biphenyl-2-yl]methyl}-2-phenyla cetamide (30)

[00237] *H NMR (400 MHz, CDC1 ₃ ) δ = 7.70 (d, J = 7.8 Hz, 1H), 7.36-7.32 (m, 4H), 7.26-7.15 (m, 6H), 7.08 (d, J = 8.6 Hz, 2H), 7.05-7.01 (m, 3H), 6.92 (d, J = 16.3 Hz, 1H), 6.69 (d, J = 8.6 Hz, 2H), 6.52 (d, J = 16.3 Hz, 1H), 5.52 (t, J = 5.8 Hz, 1H), 4.18 (dd, J = 5.9, 1.2 Hz, 2H), 3.33 (s, 2H). ¹³ C NMR (100 MHz, CDC1 ₃ ) δ = 171.3, 156.6, 140.5, 139.2, 136.2, 136.1, 134.5, 130.5, 130.0, 129.9, 129.5, 129.3, 129.1, 129.0, 128.1 2, 128.0, 127.7, 127.4, 127.2, 125.1, 123.8, 115.9, 43.6, 42.2. [00238] (E)-2-(4-Chlorophenyl)-N-((-{[2'-(4-hydroxystyryl)biphenyl-2 - yl)] methyl)} acetamide (32)

[00239] *H NMR (400 MHz, CDC1 ₃ ) δ = 7.73 (d, J = 8.0 Hz, 1H), 7.41 - 7.35 (m, 3H), 7.28 - 7.17 (m, 4H), 7.12 (d, J = 8.6 Hz, 2H), 7.10 - 7.05 (m, 2H), 6.98 - 6.92 (m, 3H), 6.72 (d, J = 8.6 Hz, 2H), 6.56 (d, J = 16.3 Hz, 1H), 5.54 (t, J = 5.8 Hz, 1H), 4.29 (dd, J = 14.7, 6.2 Hz, 1H), 4.16 (dd, J = 15.0, 5.3 Hz, 1H), 3.26 (s, 3H). ¹³ C NMR (100 MHz, CDC1 ₃ ) δ = 170.7, 156.6, 140.5, 139.2, 136.1, 136.0, 133.3, 132.9, 130.7, 130.6, 130.0, 129.9, 129.3, 129.2, 129.1, 128.2, 128.1, 128.0, 127.8, 127.3, 125.2, 123.9, 115.9, 42.7, 42.3. [00240] (E)-7V-{[2'-(4-Hydroxystyryl)biphenyl-2-yl]methyl}-2-[4- (trifluoromethyl)phenyl] acetamide (33)

[00241] *H NMR (400 MHz, CDC1 ₃ ) δ = 7.73 (d, J = 7.8 Hz, 1H), 7.48 (d, J = 8.0 Hz, 2H), 7.41 - 7.36 (m, 4H), 7.27 - 7.21 (m, 2H), 7.16 - 7.08 (m, 5H), 6.96 (d, J = 16.3 Hz, 1H), 6.91 (s, 1H), 6.71 (d, J = 8.6 Hz, 2H), 6.58 (d, J = 16.4 Hz, 1H), 5.58 (t, J = 5.8 Hz, 1H), 4.32 (dd, J = 14.7, 6.4 Hz, 1H), 4.14 (dd, J = 14.2, 6.3 Hz, 1H), 3.30 (s, 2H).

[00242] (E)-2-(-[4-(Dimethylamino)phenyl])-N-((-{[2'-(4-hydroxystyry l)biphenyl- 2-yl)]methyl)}acetamide (34)

[00243] *H NMR (400 MHz, CDC1 ₃ ) δ = 7.71 (d, J = 7.7 Hz, 1H), 7.37 - 7.30 (m, 4H), 7.22 - 7.16 (m, 2H), 7.09 (d, J = 8.6 Hz, 2H), 7.03 (dd, J = 7.6, 1.2 Hz, 1H), 6.96-9.89 (m, 3H), 6.70 (d, J = 8.6 Hz, 2H), 6.61 (d, J = 8.7 Hz, 2H), 6.52 (d, J = 16.3 Hz, 1H), 5.59 (t, J = 5.9 Hz, 1H), 4.25 (dd, J = 15.0, 6.1 Hz, 1H), 4.15 (dd, J = 15.3, 5.3 Hz, 1H), 3.30 (s, 2H), 2.90 (s, 6H). ¹³ C NMR (100 MHz, CDC1 ₃ ) δ = 172.5, 156.8, 149.9, 140.4, 139.2, 136.2, 136.1, 130.6, 130.3, 130.0, 129.9, 129.2, 128.8, 128.1, 128.0, 128.0, 127.5, 127.0, 125.1, 123.7, 122.0, 115.9, 113.3, 42.6, 42.1, 40.8.

[00244] (E)-2-CyclohexyWV-{[2'-(4-hydroxystyryl)biphenyl-2- yl] methyl} acetamide (35)

[00245] ^l n NMR (400 MHz, CDC1 ₃ ) δ = 7.75 (d, J = 7.7 Hz, 1H), 7.48 - 7.36 (m, 5H), 7.32 (td, J = 7.4, 1.2 Hz, 1H), 7.27 - 7.23 (m, 1H), 7.20 (dd, J = 7.6, 1.2 Hz, 1H), 7.14 (d, J = 8.6 Hz, 2H), 6.98 (d, J = 16.3 Hz, 1H), 6.75 (d, J = 8.6 Hz, 2H), 6.61 (d, J = 16.3 Hz, 1H), 5.64 - 5.59 (m, 1H), 4.42 (dd, J = 14.6, 6.9 Hz, 1H), 4.00 (dd, J = 14.6, 4.8 Hz, 1H), 1.71 (t, J = 7.4 Hz, 2H), 1.64 - 1.46 (m, 6H), 1.22 - 1.01 (m, 3H), 0.79 - 0.63 (m, 2H). ¹³ C NMR (100 MHz, CDC1 ₃ ) δ = 172.8, 156.9, 140.5, 139.5, 136.8, 136.2, 130.4, 130.3, 130.2, 129.4, 129.1, 128.3, 128.2, 128.0, 127.7, 127.3, 125.1, 124.1, 116.0, 44.7, 41.7, 35.3, 33.1, 32.9, 26.2, 26.1, 26.0.

[00246] (E)-7V-{[(2'-(4-Hydroxystyryl)biphenyl-2-yl]methyl}-2-(6-met hoxypyridin- 3-yl)acetamide (25)

[00247] H NMR (400 MHz, CDC1 ₃ ) δ = 7.77 (d, J = 2.0 Hz, 1H), 7.74 (bs, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.38-7.30 (m, 5H), 7.23 (ddd, J = 7.1, 7.4, 1.1 Hz, 1H), 7.20-7.18 (m, 1H), 7.11-7.07 (m, 3H), 6.93 (d, J = 16.3 Hz, 1H), 6.70 (d, J = 8.6 Hz, 2H), 6.61 (dd, J = 8.5, 0.5 Hz, 1H), 6.55 (d, J = 16.4 Hz, 1H), 5.63 (t, J = 5.8 Hz, 1H), 4.29 (dd, J = 14.7, 6.4 Hz, 1H), 4.08 (dd, J = 14.7, 5.4 Hz, 1H), 3.87 (s, 3H), 3.12 (s, 2H). ¹³ C NMR (100 MHz, CDC1 ₃ ) δ = 170.6, 163.5, 156.9, 146.8, 140.4, 139.9, 139.3, 136.2, 136.0, 130.5, 130.1, 129.9, 129.2, 129.1, 128.2, 128.1, 128.0, 127.8, 127.2, 125.1, 124.0, 123.2, 116.0, 111.1, 53.7, 42.2, 39.4.

[00248] (E)-7V-{[(2'-(4-Hydroxystyryl)biphenyl-2-yl]methyl}-3-methox ybenzamide (40)

[00249] *H NMR (400 MHz, CDC1 ₃ ) δ = 7.73 (d, J = 7.8 Hz, 1H), 7.53 - 7.49 (m, 1H), 7.42 - 7.35 (m, 3H), 7.30 (td, J = 7.4, 1.2 Hz, 1H), 7.27 - 7.21 (m, 2H), 7.17 (dd, J = 2.5, 1.6 Hz, 1H), 7.09 - 7.02 (m, 3H), 6.94 - 6.87 (m, 2H), 6.84 (ddd, J = 7.6, 1.5, 1.0 Hz, 1H), 6.69 (d, J = 8.6 Hz, 2H), 6.62 (t, J = 8.2 Hz, 2H), 6.17 (t, J = 5.7 Hz, 1H), 4.55 (dd, J= 14.7, 6.5 Hz, 1H), 4.27 (dd, J = 14.7, 5.2 Hz, 1H), 3.72 (s, 3H). ^1J C NMR (100 MHz, CDC1 ₃ ) δ = 167.3, 159.8, 156.4, 140.6, 139.5, 136.5, 136.1, 135.4, 130.4, 130.2, 130.1, 129.48, 129.46, 129.4, 128.31, 128.25, 128.1, 127.8, 127.3, 125.2, 123.8, 118.5, 118.0, 115.9, 112.3, 55.4, 42.4. [00250] (E)-7V-{[2'-(4-Hydroxystyryl)biphenyl-2-yl]methyl}benzamide (38)

[00251] H NMR (400 MHz, CDC1 ₃ ) δ = 7.75 (d, J= 7.8 Hz, 1H), 7.56 - 7.51 (m, 1H), 7.47 - 7.37 (m, 5H), 7.37 - 7.30 (m, 2H), 7.30 - 7.18 (m, 4H), 7.10 (d, J = 8.6 Hz, 2H), 6.95 (d, J = 16.4 Hz, 2H), 6.73 (d, J= 8.6 Hz, 2H), 6.67 (d, J = 16.3 Hz, 1H), 6.24 (t, J = 5.7 Hz, 1H), 4.63 (dd, J = 14.6, 6.8 Hz, 1H), 4.25 (dd, J = 14.6, 4.9 Hz, 1H). ¹³ C NMR (100 MHz, CDC1 ₃ ) δ = 167.5, 156.6, 140.6, 139.5, 136.6, 136.1, 133.9, 131.6, 130.4, 130.20, 130.18, 129.5, 129.3, 128.5, 128.3, 128.3, 128.1, 127.8, 127.3, 126.9, 125.2, 123.9, 115.9, 42.3.

[00252] (E)-7V-{[2'-(4-Hydroxystyryl)biphenyl-2-yl]methyl}-2-p-tolyl acetamide (36)

[00253] ^l n NMR (400 MHz, CDC1 ₃ ) δ = 7.70 (d, J= 7.9 Hz, 1H), 7.38 - 7.31 (m, 5H), 7.22 - 7.15 (m, 2H), 7.09 (d, J= 8.6 Hz, 2H), 7.06 - 7.01 (m, 3H), 6.96 - 6.90 (m, 3H), 6.70 (d, J= 8.6 Hz, 2H), 6.52 (d, J= 16.3 Hz, 1H), 5.53 (t, J= 5.8 Hz, 1H), 4.19 (d, J = 6.0 Hz, 2H), 3.31 (s, 2H), 2.29 (s, 3H). ¹³ C NMR (100 MHz, CDC1 ₃ ) δ = 171.7, 156.7, 140.4, 139.2, 137.1, 136.2, 136.1, 131.3, 130.5, 130.0, 129.9, 129.8, 129.4, 129.3, 128.9, 128.1, 128.0, 128.0, 127.6, 127.1, 125.1, 123.8, 115.9, 43.2, 42.2, 21.2. [00254] (E)-2-(-{4-(-[2-(Diethylamino)ethoxy)]phenyl)-}-N-((-{[2'-(4 - hydroxystyryl)biphenyl-2-yl)] methyl)}acetamide (26)

[00255] H NMR (400 MHz, CDC1 ₃ ) δ = 7.80 (bs), 7.77 (d, J = 7.7 Hz, 1H), 7.43 - 7.34 (m, 4H), 7.32 - 7.26 (m, 1H), 7.22 - 7.18 (m, 1H), 7.16 (dd, J = 7.6, 1.2 Hz, 1H), 7.03 (d, J = 8.6 Hz, 2H), 6.98 (d, J = 16.3 Hz, 1H), 6.87 (d, J = 8.7 Hz, 2H), 6.75 (d, J = 8.6 Hz, 2H), 6.52 - 6.45 (m, 3H), 5.39 - 5.35 (m, 1H), 4.43 (dd, J = 14.8, 7.0 Hz, 1H), 4.19 - 3.97 (m, 3H), 3.38 (d, J = 16.1 Hz, 1H), 3.19 (d, J = 16.2 Hz, 1H), 3.20 - 3.05 (m, 2H), 3.05 - 2.90 (m, 4H), 1.24 (t, J = 7.2 Hz, 6H). ¹³ C NMR (100 MHz, CDC1 ₃ ) δ = 171.0, 157.7, 157.1, 140.6, 139.2, 136.3, 135.8, 130.7, 130.5, 130.0, 129.8, 129.0, 128.6, 128.1, 128.1, 128.0, 127.6, 127.2, 127.1, 124.8, 123.4, 116.4, 114.8, 64.5, 51.5, 46.8, 42.8, 41.9, 9.4.

[00256] (E)-N-((-{[2'-(4-Hydroxystyryl)biphenyl-2-yl)]methyl)-}-6- methox nicotinamide (41)

[00257] H NMR (400 MHz, CDC1 ₃ ) δ = 8.27 (dd, J = 2.5, 0.6 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.57 (dd, J = 8.7, 2.5 Hz, 1H), 7.51 (dd, J = 5.5, 3.6 Hz, 1H), 7.42 - 7.35 (m, 3H), 7.31 (td, J = 7.4, 1.2 Hz, 1H), 7.27 - 7.19 (m, 2H), 7.04 (d, J = 8.6 Hz, 2H), 6.91 (d, J = 16.3 Hz, 1H), 6.80 (s, 1H), 6.67 (d, J = 8.6 Hz, 2H), 6.60 (d, J = 16.4 Hz, 1H), 6.52 (dd, J = 8.7, 0.7 Hz, 1H), 6.09 (t, J = 5.7 Hz, 1H), 4.56 (dd, J = 14.6, 6.7 Hz, 1H), 4.23 (dd, J = 14.6, 5.1 Hz, 1H), 3.89 (s, 3H). ¹³ C NMR (100 MHz, CDC1 ₃ ) δ = 165.9, 165.5, 156.5, 146.5, 140.6, 139.5, 137.4, 136.5, 136.0, 130.4, 130.1, 130.1, 129.6, 129.2, 128.3, 128.3, 128.0, 127.9, 127.4, 125.2, 123.9, 123.1, 115.9, 110.5, 54.0, 42.4. [00258] (E)-7V-{[2'-(4-Hydroxystyryl)biphenyl-2-yl]methyl}-2-methyl- 2- phenylpropanamide (37)

[00259] *H NMR (400 MHz, CDC1 ₃ ) δ = 7.70 (d, J = 7.9 Hz, 1H), 7.38 - 7.16 (m, 11H), 7.09 (d, J = 8.5 Hz, 2H), 6.97 (dd, J = 7.6, 1.1 Hz, 1H), 6.91 (d, J = 16.3 Hz, 1H), 6.73 (d, J = 8.6 Hz, 2H), 6.52 (d, J = 16.3 Hz, 1H), 6.40 (s, 1H), 5.30 (t, J = 5.7 Hz, 1H), 4.22 (dd, J = 15.0, 6.0 Hz, 1H), 4.14 (dd, J = 15.2, 5.4 Hz, 1H), 1.46 (s, 3H), 1.45 (s, 3H). ¹³ C NMR (100 MHz, CDC1 ₃ ) δ = 177.6, 156.2, 144.9, 140.3, 139.2, 136.4, 136.0, 130.5, 129.9, 129.9, 129.7, 128.8, 128.8, 128.6, 128.1, 128.0, 127.5, 127.1, 127.1, 126.4, 125.2, 123.8, 115.8, 47.0, 42.2, 27.1, 26.9.

[00260] (E)-7V-{[2'-(4-Hydroxystyryl)-(l,l'-biphenyl)-2-yl]methyl}-2 -(pyridin-2- yl)acetamide (18)

[00261] H NMR (400 MHz, CDC1 ₃ ) δ 8.40 (ddd, J= 4.8, 1.8, 0.9 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.58 (td, J = 7.7, 1.9 Hz, 1H), 7.42 - 7.31 (m, 4H), 7.23 (dd, J = 7.4, 1.2 Hz, 1H), 7.18 - 7.10 (m, 6H), 6.90 (d, J = 16.3 Hz, 1H), 6.69 (d, J = 8.6 Hz, 2H), 6.56 (d, J = 16.3 Hz, 1H), 5.41 (s, 1H), 4.22 (d, J = 5.9 Hz, 2H), 3.56 (s, 2H). ¹³ C NMR (126 MHz, MeOD) δ 171.71, 158.49, 156.66, 149.74, 141.77, 140.53, 138.64, 137.41, 137.37, 131.42, 131.02, 130.80, 130.37, 129.06, 128.97, 128.89, 128.82, 128.24, 127.88, 125.86, 125.52, 124.57, 123.49, 116.43, 45.32, 42.61. Mass calculated for (C ₂₈ H24N ₂ 02+H) ⁺ 421.2, found 421.2 [00262] (£)-7V-{[2'-(4-Hydroxystyryl)-(l,l'-biphenyl)-2-yl]methyl}- 2-(pyridin-3- yl)acetamide (19)

[00263] H NMR (500 MHz, MeOD) δ 8.38 (d, J = 4.8 Hz, 1H), 8.35 (s, 1H), 7.75 (d, J = 1.9 Hz, 1H), 7.63 (d, J = 7.9 Hz, 1H), 7.39 - 7.29 (m, 5H), 7.23 (t, J= 7.4 Hz, 1H), 7.15 (t, J= 8.3 Hz, 2H), 7.10 (d, J= 8.6 Hz, 2H), 6.98 (d, J= 16.3 Hz, 1H), 6.67 (d, J = 8.6 Hz, 2H), 6.56 (d, J = 16.3 Hz, 1H), 4.13 (s, 2H), 3.40 (s, 2H). ¹³ C NMR (126 MHz, MeOD) δ 172.14, 158.53, 150.46, 148.35, 141.90, 140.51, 138.92, 137.34, 133.57, 131.50, 131.02, 130.82, 130.36, 129.18, 128.98, 128.91, 128.82, 128.36, 127.87, 125.85, 125.07, 124.59, 116.46, 42.74, 40.33. Mass calculated for (C ₂₈ H24 ₂ 02+H) ⁺ 421.2, found 421.2.

[00264] (£)-7V-{[2'-(4-Hydroxystyryl)-(l,l'-biphenyl)-2-yl]methyl}- 2-(pyridin-4- yl)acetamide (20)

[00265] H NMR (500 MHz, MeOD) δ 8.37 (d, J = 5.9 Hz, 2H), 7.74 (d, J = 7.9 Hz, 1H), 7.40 - 7.31 (m, 4H), 7.22 (dd, J = 12.2, 6.1 Hz, 3H), 7.18 - 7.11 (m, 2H), 7.09 (d, J = 8.6 Hz, 2H), 6.98 (d, J = 16.3 Hz, 1H), 6.67 (d, J = 8.6 Hz, 2H), 6.57 (d, J = 16.3 Hz, 1H), 4.13 (d, J = 1.2 Hz, 2H), 3.41 (s, 2H). ¹³ C NMR (126 MHz, MeOD) δ 171.40, 158.54, 149.89, 147.34, 141.88, 140.49, 137.34, 137.27, 131.51, 131.02, 130.82, 130.33, 129.19, 128.99, 128.91, 128.83, 128.37, 127.88, 126.13, 125.86, 124.57, 116.46, 42.74, 42.66. Mass calculated for (C ₂₈ H24N ₂ 02+H) ⁺ 421.2, found 421.2.

EXAMPLE 16: Synthesis of Resveratrol Analogs - Route B

[00266] Compounds 43 and 44 were prepared as follows.

44: R=F

43: R=NMe ₂

[00267] Compound 14 was synthesized from compound 8 by following the procedure for the conversion of compound 10 to compound 12 (see Example 15). Compounds 43 and 44 were prepared by following the procedure for the conversion of compound 8 to compound 10 (see Example 15). The vinyl boronate esters were prepared by using a method analogous to the conversion of 1 to 4 (see Example 13).

[00268] (£)-7V-{[2'-(4-Fluorostyryl)-(l,l'-biphenyl)-2-yl]methyl}-2 -(4- methoxyphenyl)acetamide (44)

[00269] H NMR (400 MHz, CDC1 ₃ ) δ 7.74 (d, J = 7.9 Hz, 1H), 7.42 - 7.33 (m, 4H), 7.29 - 7.17 (m, 4H), 7.08 (dd, J = 7.6, 1.1 Hz, 1H), 7.03 - 6.93 (m, 5H), 6.81 (d, J = 8.7 Hz, 2H), 6.63 (d, J = 16.3 Hz, 1H), 5.41 (t, J = 5.1 Hz, 1H), 4.24 (dd, J = 14.9, 6.0 Hz, 1H), 4.16 (dd, J = 14.9, 5.8 Hz, 1H), 3.79 (s, 3H), 3.35 (s, 2H). ¹³ C NMR (101 MHz, CDC1 ₃ ) δ 170.84, 162.36 (d, J _C,F = 247.6 Hz), 158.76, 140.02, 139.44, 136.33, 135.36, 133.33 (d, J _C ,F = 3.4 Hz), 130.42, 130.38, 129.89, 128.71, 128.08, 128.00, 127.95, 127.52, 127.39, 126.63, 126.24 (d, J _C,F = 2.5 Hz), 125.17, 115.73, 115.52, 114.34, 55.25, 42.72, 41.79. Mass calculated for (C ₃ oH ₂₆ F 0 ₂ +H) ⁺ 452.2, found 452.2. [00270] (E)-N-({2 '- [(4-(Dimethylamino)styryl] -(1 ,1 '-biphenyl)-2-yl} methyl)-2-(4- methoxyphenyl)acetamide (43)

[00271] H NMR (400 MHz, CDC1 ₃ ) δ 7.74 (d, J = 7.9 Hz, 1H), 7.44 - 7.32 (m, 4H), 7.25 - 7.17 (m, 4H), 7.08 (dd, J = 7.6, 1.1 Hz, 1H), 7.02 - 6.94 (m, 3H), 6.80 (d, J = 8.7 Hz, 2H), 6.65 (d, J = 8.9 Hz, 2H), 6.53 (d, J = 16.3 Hz, 1H), 5.52 (t, J = 5.5 Hz, 1H), 4.28 (dd, J = 14.7, 6.3 Hz, 1H), 4.13 (dd, J = 14.7, 5.6 Hz, 1H), 3.80 (s, 3H), 3.27 (s, 2H), 2.96 (s, 6H). ¹³ C NMR (101 MHz, CDC1 ₃ ) δ 170.92, 158.74, 150.34, 140.53, 139.08, 136.73, 136.36, 130.46, 130.44, 130.19, 129.92, 129.12, 128.00, 127.94, 127.74, 127.45, 126.97, 126.72, 125.51, 124.80, 122.32, 114.32, 112.48, 55.35, 42.73, 41.87, 40.47. Mass calculated for (C ₃ 2H ₃ 2 ₂ 0 ₂ +H) ⁺ 477.3, found 477.3.

EXAMPLE 17: Synthesis of Compound 42

42

[00272] (E)-tert-Butyl(2'-{4-[2-(diethylamino)ethoxy]styryl}biphenyl -2- yl)methylcarbamate (15)

[00273] To a stirred solution of 9 (61 mg, 0.15 mmol) in DMF (3 mL) was added 2- chloro-N,N-diethylethanamine hydrochloride (40 mg, 0.23 mmol) and K ₂ CO ₃ (70 mg, 0.51 mmol). The mixture was stirred at rt for 16h and then partitioned between EtOAc and H ₂ 0. The organic phase was washed with brine, dried over anhydrous a ₂ S0 ₄ and concentrated. The crude product was purified by automated flash chromatography to give compound 15 (64 mg, 84%). [00274] Compound 42 was prepared from compound 15 by following the procedure for the conversion of compound 10 to 12 (see Example 15).

[00275] (£ -7V-[(2'-{4-[2-(Diethylamino)ethoxy]styryl}-(l,l'-biphenyl)- 2- yl)methyl]-2-(4-methoxyphenyl)acetamide (42) [00276] H NMR (500 MHz, CDC1 ₃ ) δ 7.74 (d, J = 7.8 Hz, 1H), 7.41 - 7.33 (m, 4H), 7.29 - 7.17 (m, 4H), 7.08 (d, J = 6.7 Hz, 1H), 7.00 (d, J= 8.6 Hz, 2H), 6.97 (d, J = 16.4 Hz, 1H), 6.83 (d, J = 8.7 Hz, 2H), 6.80 (d, J = 8.6 Hz, 2H), 6.59 (d, J = 16.3 Hz, 1H), 5.51 (t, J = 5.6 Hz, 1H), 4.24 - 4.15 (m, 2H), 4.05 (t, J = 6.3 Hz, 2H), 3.79 (s, 3H), 3.30 (s, 2H), 2.89 (t, J = 6.3 Hz, 2H), 2.66 (q, J = 7.1 Hz, 4H), 1.08 (t, J = 7.1 Hz, 6H). ¹³ C NMR (126 MHz, CDC1 ₃ ) δ 170.93, 158.80, 158.77, 140.28, 139.30, 136.53, 135.87, 130.45, 130.43, 129.96, 129.94, 129.58, 128.90, 128.06, 127.97, 127.83, 127.44, 127.17, 126.81, 125.05, 124.43, 114.84, 114.35, 66.61, 55.32, 51.78, 47.92, 42.73, 41.84, 11.87. Mass calculated for (C ₃₆ H4oN ₂ 0 ₃ +H) ⁺ 549.3, found 549.4.

EXAMPLE 18: Synthesis of Compounds 27 and 28

[00277] (E)-4-(2-{2'-[(Benzyloxycarbonylamino)methyl]biphenyl-2- yl}vinyl)phenyl acetate (16)

[00278] To a stirred solution of 11 (43 mg, 0.13 mmol) and benzyl chloroformate (25 μί, 0.17 mmol) in DCM (3 mL) was added DIPEA (100 μί, 0.58 mmol). The mixture was stirred at rt for 16 h and then concentrated. The crude product was purified by automated flash chromatography to give compound 16 (34 mg, 57%).

[00279] Compound 17 was prepared in a similar manner to compound 16. [00280] Compounds 27 and 28 were prepared from compounds 16 and 17 by using the procedure for the conversion of compound 12 to compound 21 (see Example 15).

[00281] (E)-Benzyl {[2'-(4-hydroxystyryl)-(l,l'-biphenyl)-2-yl]methyl}carbamate (27) [00282] *H NMR (500 MHz, MeOD) δ 7.77 (d, J = 7.9 Hz, 1H), 7.46 - 7.22 (m, 10H), 7.16 (t, J = 8.6 Hz, 2H), 7.11 (d, J = 8.4 Hz, 2H), 7.07 - 6.94 (m, 2H), 6.68 (d, J = 8.4 Hz, 2H), 6.59 (d, J = 16.3 Hz, 1H), 4.98 (s, 2H), 4.07 (s, 2H). ¹³ C NMR (126 MHz, MeOD) δ 158.62, 158.42, 141.51, 140.59, 138.22, 138.14, 137.42, 131.31, 130.99, 130.76, 130.42, 129.37, 128.92, 128.87, 128.82, 128.75, 128.39, 128.03, 127.94, 127.86, 125.82, 124.63, 116.40, 67.44, 43.69. Mass calculated for (C29H ₂ 5 0 ₃ +H) ⁺ 436.2, found 436.2.

[00283] (E)-l-{[2'-(4-Hydroxystyryl)-(l,l'-biphenyl)-2-yl]methyl}-3- phenylurea (28)

[00284] *H NMR (500 MHz, MeOD) δ 7.76 (d, J = 7.9 Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.35 (q, J = 8.4 Hz, 2H), 7.30 - 7.12 (m, 7H), 7.09 (d, J = 8.5 Hz, 2H), 6.98 (d, J = 16.3 Hz, 1H), 6.92 (t, J = 7.3 Hz, 1H), 6.65 (d, J = 8.6 Hz, 2H), 6.59 (d, J = 16.3 Hz, 1H), 4.12 (s, J = 5.4 Hz, 2H). ¹³ C NMR (126 MHz, MeOD) δ 158.43, 157.92, 141.56, 140.75, 140.65, 138.69, 137.42, 131.35, 131.02, 130.78, 130.42, 129.70, 128.95, 128.92, 128.81, 128.68, 128.04, 127.89, 125.89, 124.60, 123.38, 120.20, 116.40, 42.65. Mass calculated for (C ₂₈ H24N ₂ 02+H) ⁺ 421.2, found 421.2.

EXAMPLE 19: Kvl.5 Inhibitory Activity of Representative Compounds of General Formula (I)

[00285] The ability of compounds 12, 21, 29-32, 35, 39 and 42 at a concentration of 3μΜ to inhibit cloned human atrial Kvl.5 channels was evaluated as described above in Example 4. The results are provided in Table 6. EXAMPLE 20: Pharmacokinetic Study of Compound 21 Administered Intravenously or Orally in Mice

[00286] 33 Female CD-I mice, 5 weeks of age (3 per group) were acclimatized for approximately 1 week. Compound 21 formulated as described below was administered by intravenous injection (IV) or by oral gavage (PO) and the animals terminated at the time points indicated in Table 2. Plasma, heart, brain and liver samples were collected and frozen until analyzed to determine concentration of test compounds.

Table 2: Study Grouping

[00287] Formulation: The formulations for PO and IV administration of Compound 21 were based on VitE-TPGS, a frequently used oral vitamin E-based lipid excipient. A concentrated stock formulation was prepared by the solvent injection/dilution method. Briefly, a solution of Compound 21 in ethanol at a concentration of 45 mg/mL was slowly added to a 15% (w/v) VitE-TPGS solution (VitE-TPGS was dissolved in water), followed by 60 minutes of sonication in a bath sonicator at 60°C. The formulation was then diluted with water to 6.5% (w/v) VitE-TPGS and sonicated for an additional 15 minutes at 30°C. Isotonicity of the formulation was adjusted by adding an appropriate aliquot of a 1.2 M sodium chloride solution. The formulations for PO and IV administration were adjusted to the target concentrations of 0.1 mg/mL and 0.5 mg/mL Compound 21 by diluting the formulation stock solution with physiological saline solution. The formulations were sterile-filtered using 0.2 μιη filters.

[00288] Results: The purpose of this study was to assess the plasma concentrations of Compound 21 after oral or IV administration and to compare the resulting concentration vs time profiles to assess bioavailability. [00289] Compound 21 given intravenously was well tolerated at the nominal dose of 1 mg/kg and was cleared from the circulation with an elimination half-life of 38 minutes. The mean C _max of Compound 21 given at this dose was 439.8 ng/mL of plasma, the clearance 108.8 mL/min/kg, the AUCi _as t was 9204 ng-min/mL and the Vss 1944 mL/kg. The mean concentration of Compound 21 measured in the heart was 1473 ng/g tissue at 5 minutes after administration and decreased rapidly thereafter, dropping below the lower limit of quantitation at 30 minutes after drug administration. [00290] Compound 21 given by oral gavage at a nominal dose of 5 mg/kg had a lower mean C _max of 26.4 ng/mL, the AUQ _as t was calculated to be 510.9 ng-min/mL and the apparent elimination half-life was 33.7 minutes. The mean concentrations of Compound 21 measured in the heart were very low in all cases and mostly below the lower limit of quantitation. [00291] Estimation of the oral bioavailability of Compound 21 from the plasma AUCiast values indicated an apparent oral bioavailability of 1.2%.

EXAMPLE 21: Preparation of Additional Compounds of General Formula (I)

[00292] The following compounds were prepared following the reaction schemes described in Example 15 or 16, as indicated. [00293] (E)-2-(4-fluorophenyl)-N-((2'-(4-fluorostyryl)biphenyl-2- yl)methyl)acetamide (45)

: Prepared according to Example 16.

[00294] *H NMR (400 MHz, CDC1 ₃ ) δ = 7.74 (d, J = 7.9 Hz, 1H), 7.43 - 7.34 (m, 4H), 7.31-7.18 (m, 4H), 7.11 (dd, J = 7.6, 1.2 Hz, 1H), 7.08 - 7.02 (m, 2H), 7.02 - 6.91 (m, 5H), 6.64 (d, J = 16.4 Hz, 1H), 5.40 (s, 1H), 4.21 (d, J = 5.9 Hz, 2H), 3.33 (s, 2H). ¹³ C NMR (100 MHz, CDC1 ₃ ) δ = 170.3, 163.8, 163.3, 161.3, 160.9, 140.2, 139.6, 136.4, 135.5, 133.4, 133.4, 131.0, 130.9, 130.5, 130.5, 130.0, 129.0, 128.9, 128.9, 128.3, 128.2, 128.2, 128.1, 127.7, 127.7, 126.3, 126.3, 125.3, 115.9, 115.9, 115.7, 115.7, 42.8, 42.0. [00295] (E)-N-((2'-(4-fluorostyryl)biphenyl-2-yl)methyl)-6-methoxyni cotinamide (48)

; Prepared according to Example 16.

[00296] H NMR (400 MHz, CDC1 ₃ ) δ = 8.27 (d, J = 2.0 Hz, 1H), 7.78 (d, J = 7.3 Hz, 1H), 7.68 (dd, J = 8.7, 2.5 Hz, 1H), 7.57 (dd, J = 7.3, 1.6 Hz, 1H), 7.47 - 7.35 (m, 4H), 7.29 - 7.25 (m, 2H), 7.22 - 7.17 (m, 2H), 7.00 - 6.91 (m, 3H), 6.72 (d, J = 16.4 Hz, 1H), 6.57 (d, J = 8.7 Hz, 1H), 6.01 (t, J = 5.4 Hz, 1H), 4.53 (dd, J = 14.6, 6.4 Hz, 1H), 4.28 (dd, J = 14.6, 5.2 Hz, 1H), 3.94 (s, 3H). ¹³ C NMR (100 MHz, CDC1 ₃ ) δ = 165.9,

165.2, 163.8, 161.3, 146.3, 140.4, 139.9, 137.5, 136.6, 135.5, 133.1, 133.1, 130.4, 130.2, 129.6, 129.1, 128.4, 128.3, 128.2, 128.1, 127.9, 127.8, 126.2, 126.2, 125.3,

123.3, 115.9, 115.7, 110.6, 53.9, 42.2.

[00297] (E)-2-(5-Huoropyridin-2-yl)-N-((2'-(4-hydroxystyryl)biphenyl -2- yl)methyl)acetamide (49)

: Prepared according to Example 16. [00298] H NMR (400 MHz, CDC1 ₃ ) δ = 8.34 (d, J = 2.9 Hz, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.53 - 7.43 (m, 4H), 7.41 - 7.29 (m, 3H), 7.27 - 7.17 (m, 2H), 7.16 (d, J = 8.6 Hz, 2H), 7.01 (d, J = 16.3 Hz, 1H), 6.74 (d, J = 8.6 Hz, 2H), 6.65 (d, J = 16.3 Hz, 1H), 4.36 (dd, J = 5.3, 5.3 Hz, 2H), 3.61 (s, 2H). ¹³ C NMR (100 MHz, CDC1 ₃ ) δ = 169.4, 159.9, 157.4, 156.7, 151.2, 151.1, 140.5, 139.3, 137.3, 137.0, 136.2, 136.1, 130.6, 130.0, 129.8, 129.2, 128.8, 128.1, 128.0, 128.0, 127.5, 127.0, 125.3, 125.2, 125.0, 124.3, 124.1, 123.8, 115.8, 44.0, 42.1. [00299] (E)-N-((2'-(4-hydroxystyryl)biphenyl-2-yl)methyl)-2-(lH-imid azol-5- yl)acetamide (50)

: Prepared according to Example 15.

[00300] *H NMR (400 MHz, d ₄ -MeOH) δ = 7.77 (d, J = 7.5 Hz, 1H), 7.58 (d, J = 0.9 Hz, 1H), 7.44 - 7.33 (m, 4H), 7.26 (td, J = 7.5, 1.2 Hz, 1H), 7.19 - 7.08 (m, 4H), 6.99 (d, J = 16.3 Hz, 1H), 6.86 (s, 1H), 6.69 (d, J = 8.6 Hz, 2H), 6.57 (d, J = 16.3 Hz, 1H), 4.15 (d, J = 3.5 Hz, 2H), 3.41 (s, 2H). ¹³ C NMR (100 MHz, cU-MeOH) δ = 172.6, 158.5, 141.7, 140.5, 137.5, 137.4, 136.4, 131.4, 131.0, 130.8, 130.4, 129.0, 128.9, 128.9, 128.8, 128.2, 127.9, 125.8, 124.5, 123.3, 118.2, 116.4, 42.6, 35.3. [00301] ( ?^)-7V-((2'-(4-Hydroxystyryl)-[l,l'-biphenyl]-2-yl)methyl)-2 - phenylbutanamide (52)

: Prepared according to Example 15.

[00302] H NMR performed at room temperature indicated that compound 52 exists as a mixture of rotamers, making the NMR spectra difficult to analyse. For this compound, therefore, H NMR was performed at 80°C to simplify the analysis.

[00303] H NMR (500 MHz, DMSO) δ 9.34 (d, J = 2.0 Hz, 1H), 8.06 (bs, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.39 (q, J = 7.5 Hz, 1H), 7.34 - 7.09 (m, 13H), 7.01 (d, J = 16.3 Hz, 1H), 6.70 (d, J = 8.1 Hz, 2H), 6.51 (dd, J = 16.3, 4.4 Hz, 1H), 4.04 - 3.88 (m, 2H), 3.36 (t, J = 7.5 Hz, 1H), 1.97 - 1.88 (m, 1H), 1.67 - 1.57 (m, 1H), 0.80 (t, J = 7.2 Hz, 3H). Mass calculated for (C ₃ iH ₂₉ N02+H) ⁺ 448.2, found 448.3. [00304] (E)-2-(4-methoxyphenyl)-N-((2'-styryl-[l,l'-biphenyl]-2- yl)methyl)acetamide (53)

: Prepared according to Example 16.

[00305] H NMR (400 MHz, CDC1 ₃ ) δ 7.76 (d, J = 7.9 Hz, 1H), 7.43 - 7.29 (m, 8H), 7.28 - 7.17 (m, 3H), 7.09 (dd, J = 7.6, 1.1 Hz, 1H), 7.06 - 6.96 (m, 3H), 6.79 (d, J = 8.7 Hz, 2H), 6.72 (d, J = 16.3 Hz, 1H), 5.40 (s, 1H), 4.20 (d, J = 5.9 Hz, 2H), 3.79 (s, 3H), 3.31 (s, 2H). ¹³ C NMR (101 MHz, CDC1 ₃ ) δ 170.90, 158.74, 140.09, 139.52, 137.13, 136.41, 135.52, 130.42, 130.40, 129.98, 129.92, 128.87, 128.73, 128.08, 127.96, 127.82, 127.53, 127.42, 126.69, 126.56, 126.55, 125.26, 114.33, 55.26, 42.68,

41.79.

[00306] (E)-2-(4-methoxyphenyl)-N-((2'-(4-methoxystyryl)-[l,l'-biphe nyl]-2- yl)methyl)acetamide (54)

: Prepared according to Example 16.

[00307] H NMR (400 MHz, CDC1 ₃ ) δ 7.73 (d, J = 7.7 Hz, 1H), 7.43 - 7.31 (m, 4H), 7.27 - 7.16 (m, 4H), 7.07 (dd, J = 7.5, 1.1 Hz, 1H), 7.03 - 6.93 (m, 3H), 6.82 (dd, J = 15.6, 8.7 Hz, 4H), 6.58 (d, J = 16.3 Hz, 1H), 5.41 (s, 1H), 4.20 (dd, J = 5.9, 3.2 Hz, 2H), 3.81 (s, 3H), 3.79 (s, 3H), 3.31 (s, 2H). ¹³ C NMR (101 MHz, CDC1 ₃ ) δ 170.89, 159.46, 158.72, 140.24, 139.26, 136.47, 135.80, 130.41, 130.39, 129.94, 129.88, 129.49, 128.88, 128.02, 127.92, 127.79, 127.40, 127.14, 126.74, 124.99, 124.44, 114.31, 114.18, 55.31, 55.26, 42.68, 41.80. [00308] (E)-N-((2'-(4-(dimethylamino)styryl)biphenyl-2-yl)methyl)-2- (4- fluorophenyl)acetamide (56)

: Prepared according to Example 16.

[00309] H NMR (400 MHz, CDC1 ₃ ) δ = 7.71 (d, J = 7.9 Hz, 1H), 7.41 - 7.33 (m, 4H), 7.24 - 7.15 (m, 4H), 7.07 (dd, J = 7.6, 1.2 Hz, 1H), 7.00 - 6.87 (m, 5H), 6.62 (d, J = 8.9 Hz, 2H), 6.50 (d, J = 16.3 Hz, 1H), 5.47 (s, 1H), 4.32 (dd, J = 14.6, 6.7 Hz, 1H), 4.03 (dd, J = 14.6, 5.2 Hz, 1H), 3.19 (d, J = 2.0 Hz, 2H), 2.94 (s, 6H). ¹³ C NMR (100 MHz, CDC1 ₃ ) δ = 170.2, 163.3, 160.8, 150.4, 140.6, 139.2, 136.7, 136.4, 130.9, 130.8, 130.8, 130.7, 130.4, 130.3, 130.0, 129.4, 128.1, 128.1, 127.8, 127.6, 126.8, 125.4, 124.8, 122.4, 115.8, 115.6, 112.5, 42.7, 42.0, 40.5.

[00310] (E)-N-((2'-(4-(dimethylamino)styryl)biphenyl-2-yl)methyl)-6- methoxynicotinamide (57)

; Prepared according to Example 16.

[00311] H NMR (400 MHz, CDC1 ₃ ) δ = 8.33 (d, J = 2.1 Hz, 1H), 7.74 (d, J = 7.7 Hz, 1H), 7.56 - 7.53 (m, 1H), 7.48 (dd, J = 8.7, 2.5 Hz, 1H), 7.43 - 7.35 (m, 3H), 7.32 - 7.20 (m, 3H), 7.12 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 16.3 Hz, 1H), 6.59 (d, J = 16.3 Hz, 1H), 6.57 (d, J = 8.8 Hz, 2H), 6.44 (d, J = 8.7 Hz, 1H), 6.09 - 6.05 (m, 1H), 4.62 (dd, J = 14.5, 7.0 Hz, 1H), 4.15 (dd, J = 14.3, 4.6 Hz, 1H), 3.90 (s, 3H), 2.94 (s, 6H). ¹³ C NMR (100 MHz, CDC1 ₃ ) δ = 165.7, 165.2, 150.4, 146.9, 140.8, 139.3, 137.1, 137.0, 136.4, 130.5, 130.3, 130.2, 129.7, 128.2, 128.2, 127.8, 127.8, 126.9, 125.1, 124.9, 123.3, 122.0, 112.5, 110.4, 53.9, 42.1, 40.4. [00312] (E)-N-((2'-(4-hydroxystyryl)biphenyl-2-yl)methyl)-3-(4- methoxyphenyl)propanamide (59)

; Prepared according to Example 15.

[00313] H NMR (400 MHz, CDC1 ₃ ) δ = 7.71 (d, J = 7.6 Hz, 1H), 7.41 - 7.30 (m, 3H), 7.29 - 7.24 - 7.19 (m, 4H), 7.13 - 7.06 (m, 3H), 6.93 (d, J = 11.4 Hz, 1H), 6.92 - 6.88 (m, 2H), 6.74 (d, J = 8.7 Hz, 2H), 6.70 (d, J = 8.6 Hz, 2H), 6.57 (d, J = 16.3 Hz, 1H), 5.51 (t, J = 5.7 Hz, 1H), 4.30 (dd, J = 14.7, 6.6 Hz, 1H), 4.01 (dd, J = 14.7, 5.2 Hz, 1H), 3.75 (s, 3H), 2.69 (t, J = 8.0 Hz, 2H), 2.12 (t, J = 7.6 Hz, 2H). ¹³ C NMR (100 MHz, CDC1 ₃ ) δ = 172.5, 158.1, 156.7, 140.4, 139.4, 136.5, 136.1, 132.7, 130.3, 130.1, 130.1, 129.4, 129.2, 128.2, 128.2, 128.0, 127.7, 127.2, 125.1, 124.0, 116.0, 114.0, 55.4, 41.8, 38.5, 30.7.

[00314] (S,£)-7V-((2'-(4-Hydroxystyryl)-[l,l'-biphenyl]-2-yl)methyl )-2- phenylbutanamide (61)

: Prepared according to Example 15.

[00315] H NMR performed at room temperature indicated that compound 52 exists as a mixture of rotamers, making the NMR spectra difficult to analyse. For this compound, therefore, H NMR was performed at 80°C to simplify the analysis.

[00316] H NMR (500 MHz, DMSO) δ 9.35 (d, J = 4.9 Hz, 1H), 8.08 (bs, 1H), 7.79 (d, J = 7.9 Hz, 1H), 7.38 (q, J = 7.6 Hz, 1H), 7.33 - 7.08 (m, 13H), 7.01 (d, J = 16.3 Hz, 1H), 6.70 (d, J = 8.3 Hz, 2H), 6.51 (dd, J = 16.3, 5.0 Hz, 1H), 4.04 - 3.88 (m, 2H), 3.36 (t, J = 7.5 Hz, 1H), 1.98 - 1.89 (m, 1H), 1.66 - 1.58 (m, 1H), 0.79 (t, J = 7.3 Hz, 3H). Mass calculated for (C ₃ iH ₂₉ N02+H) ⁺ 448.2, found 448.4. EXAMPLE 22: Preparation of Additional Compounds of General Formula (I)

51

[00317] 2'-bromo-[l,l']-biphenyl]-2-amine (C). 2-iodoaniline (348 mg, 1.0 eq) and

2-bromophenylboronic acid (367 mg, 1.15 eq) were dissolved in DME (4.5 mL) and treated with NaHC0 ₃ (0.4 g) and Pd(PPh ₃ ) ₄ (55 mg). After 5 minutes of stirring, H ₂ 0 (2.3 mL) was added and the reaction was bubbled with argon for 10 minutes. The temperature was increased to 90 °C and the reaction was stirred for 3 h. The reaction was quenched by adding additional water and extracting with Et20. The combined organic layers were dried over Na ₂ S0 ₄ , filtered and concentrated and the crude product was purified by flash chromatography to afford compound C (350 mg, 89 %) as a yellow oil. Spectral data agreed with that found in the literature.

[00318] Compound D was prepared following the procedure for the conversion of 11 to 12 in Example 15. Compound E was prepared following the procedure for the conversion of 8 to 10 in Example 15. Compound 51 was prepared following the procedure for the conversion of compound 12 to 21 in Example 15.

[00319] (E)-N-(2'-(4-hydroxystyryl)biphenyl-2-yl)-2-(4-methoxyphenyl )acetamide (51)

[00320] H NMR (400 MHz, CDC1 ₃ ) δ = 8.30 (d, J = 7.9 Hz, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.43 - 7.38 (m, 1H), 7.35 (td, J = 7.8, 1.0 Hz, 1H), 7.21 - 7.11 (m, 5H), 7.00 (dd, J = 7.6, 1.2 Hz, 1H), 6.95 (s, 1H), 6.85 (d, J = 16.3 Hz, 1H), 6.79 (d, J = 8.6 Hz, 2H), 6.77 - 6.73 (m, 3H), 6.60 (d, J = 8.6 Hz, 2H), 6.43 (d, J = 16.3 Hz, 1H), 3.79 (s, 3H), 3.48 (d, J _AB = 16.8 Hz, 1H), 3.43 (d, J _AB = 16.8 Hz, 1H). ¹³ C NMR (100 MHz, CDC1 ₃ ) δ = 170.3, 158.8, 156.5, 136.1, 135.8, 135.2, 131.3, 130.6, 130.5, 130.4, 130.3, 129.4, 128.7, 128.4, 128.2, 127.5, 125.4, 125.0, 124.6, 122.9, 121.0, 115.9, 114.7, 55.3, 44.0.

[00321] The following compounds were synthesized following the procedure for the synthesis of compound 51, substituting alternative carboxylic acids in the HATU coupling.

[00322] (E)-N-(2'-(4-hydroxystyryl)biphenyl-2-yl)-4-methoxybenzamide (55)

[00323] *H NMR (400 MHz, CDC1 ₃ ) δ = 8.39 (d, J = 8.1 Hz, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.63 (s, 1H), 7.51 - 7.45 (m, 2H), 7.39 (t, J = 7.5 Hz, 3H), 7.35 - 7.25 (m, 3H), 7.14 (d, J = 8.6 Hz, 2H), 7.00-6.92 (m, 2H), 6.82 - 6.68 (m, 5H), 3.80 (s, 3H). ¹³ C NMR (100 MHz, CDC1 ₃ ) δ = 165.5, 162.5, 156.5, 136.7, 136.2, 135.6, 131.6, 131.2, 130.9, 130.6, 129.3, 128.9, 128.9, 128.8, 128.2, 127.8, 127.0, 125.3, 124.6, 123.3, 121.8, 115.8, 114.0, 55.5. [00324] (E)-N-(2'-(4-hydroxystyryl)biphenyl-2-yl)-3-(4-methoxyphenyl ) propanamide (60)

[00325] H NMR (400 MHz, CDC1 ₃ ) δ = 8.19 (d, J = 8.2 Hz, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.46 - 7.39 (m, 2H), 7.32 (td, J= 7.5, 0.9 Hz, 1H), 7.25 - 7.16 (m, 5H), 7.04 (d, J = 16.3 Hz, 1H), 6.93 (s, 1H), 6.91 - 6.85 (m, 3H), 6.75 (d, J = 8.6 Hz, 2H), 6.71 (d, J = 8.6 Hz, 2H), 6.62 (d, J = 16.3 Hz, 1H), 3.72 (s, 3H), 2.78 - 2.59 (m, 2H), 2.38 - 2.31 (m, 2H). ¹³ C NMR (100 MHz, CDC1 ₃ ) δ = 171.1, 158.1, 156.7, 136.5, 136.1, 135.1, 132.4, 131.5, 131.2, 130.8, 130.5, 129.2, 129.2, 128.8, 128.7, 128.2, 127.7, 125.1, 124.8, 123.4, 122.1, 115.9, 114.1, 55.3, 39.7, 30.4.

EXAMPLE 23: Preparation of Additional Compounds of General Formula (I)

[00326] Compound 46 was prepared according to the procedures described in Example 14 and Example 15, using appropriately fluorinated starting materials in place of the starting materials used in those Examples. [00327] (£ -7V-((4,4'-Difluoro-2'-(4-hydroxystyryl)-[l,l'-biphenyl]-2-y l)methyl)-2- (4-methoxyphenyl)acetamide (46)

^l n NMR (400 MHz, CDC1 ₃ ) δ 7.39 (dd, J = 10.4, 2.6 Hz, 1H), 7.12 (dd, J = 9.8, 4.6 Hz, 3H), 7.08 - 6.88 (m, 8H), 6.82 (d, J = 8.7 Hz, 2H), 6.74 (d, J = 8.6 Hz, 2H), 6.44 (dd, J = 16.3, 1.5 Hz, 1H), 5.58 (t, J = 6.0 Hz, 1H), 4.14 (d, J = 6.1 Hz, 2H), 3.79 (s, 3H), 3.39 (s, 2H). ¹³ C NMR (101 MHz, CDC1 ₃ ) δ 171.93, 162.56 (d, J _c ,F = 246.0 Hz), 162.37 (d, J C,F = 247.1 Hz), 158.93, 156.74, 138.79 (d, J _c ,F = 7.2 Hz), 138.38 (d, J _c ,F = 8.2 Hz), 134.96 (d, J C,F = 3.3 Hz), 133.89 (d, J _c ,F = 3.0 Hz), 132.20 (d, J _c ,F = 8.3 Hz), 131.52 (d, J C,F = 8.1 Hz), 131.16, 130.47, 128.75, 128.13, 126.07, 122.44 (s, J _c ,F = 2.3 Hz), 115.83, 115.19 (d, J _c ,F = 22.0 Hz), 114.50, 114.38 (d, J _c ,F = 21.1 Hz), 114.01 (d, J _c ,F = 21.7 Hz), 111.31 (d, J _c ,F = 22.1 Hz), 55.27, 42.53, 41.66. Mass calculated for (C ₃ oH25F ₂ 0 ₃ +H) ⁺ 486.2, found 486.3.

EXAMPLE 24: Preparation of Additional Compounds of General Formula (I)

[00328] Compounds 47 and 58 were prepared as follows:

[00329] (E)-l-(4-fluorophenyl)-N-((2'-(4-hydroxystyryl)biphenyl-2- yl)methyl)methanesulfonamide (47): A solution of 11 (0.102 mmol) was treated with DIPEA (89 uL, 0.511 mmol) and 4-fluorobenzylsulfonyl chloride (23 mg, 0.122 mmol). The reaction was stirred for 24 h, after which another aliquot of 4- fluorobenzylsulfonyl chloride (23 mg, 0.122 mmol) was added. After a further 24 h, the reaction was filtered through a plug of silica and the volatile components were removed by evaporation. The resulting crude material was dissolved in MeOH (1 mL) and treated with 1 M NaOH (204 uL, 0.204 mmol) and stirred at room temperature. After 1 h, the solvents were removed by evaporation and the crude product was purified by flash chromatography to afford 47 (24 mg) as a white solid. H NMR (400 MHz, CDC1 ₃ ) δ = 7.78 (d, J = 7.8 Hz, 1H), 7.51 - 7.39 (m, 4H), 7.32 (td, J = 7.5, 1.1 Hz, 1H), 7.27 - 7.24 (m, 1H), 7.14 (d, J = 8.6 Hz, 2H), 7.08 (dd, J = 7.6, 1.2 Hz, 1H), 7.05 - 7.00 (m, 2H), 6.99 - 6.89 (m, 3H), 6.73 (d, J = 8.6 Hz, 2H), 6.54 (d, J = 16.3 Hz, 1H), 5.75 (bs, 1H), 4.02 - 3.89 (m, 4H). ¹³ C NMR (100 MHz, CDC1 ₃ ) δ = 171.7, 164.2, 161.7, 156.0, 140.5, 138.8, 136.0, 135.3, 132.3, 132.3, 130.6, 130.3, 130.0, 129.7, 129.0, 128.4, 128.4, 128.3, 128.1, 127.4, 125.3, 124.9, 124.8, 123.9, 116.0, 115.8, 115.8, 58.4, 45.6.

[00330] Compound 58 was prepared in a similar manner to compound 47 above. [00331] (E)-N-((2'-(4-hydroxystyryl)biphenyl-2-yl)methyl)-l- phenylmethanesulfonamide (58): H NMR (400 MHz, CDC1 ₃ ) δ = 7.77 ⁽ d, J = 7.9 Hz,

1H), 7.52 - 7.39 (m, 4H), 7.34 - 7.23 (m, 5H), 7.14 (d, J = 8.5 Hz, 2H), 7.09 - 7.04 (m, 3H), 6.95 (d, J = 16.3 Hz, 1H), 6.74 (d, J = 8.6 Hz, 2H), 6.55 (d, J = 16.3 Hz, 1H), 5.21 (bs, 1H), 4.05 - 3.94 (m, 4H). ¹³ C NMR (100 MHz, CDC1 ₃ ) δ = 155. ⁸ ' 140.5, 138.9, 136.0 _, 135.3, 130.6, 130.6, 130.2, 130.1, 129.9, 129.2, 129.1, 128.9, 128.7, 128.4, 128.2, 128.2, 127.4, 125.4, 124.1, 115.8, 59.1, 45.6.

EXAMPLE 25: Inhibition of CYP 3A4 Mediated Testosterone and Midazolam Metabolism by Compound 21 [00332] Test compounds were incubated with human liver microsomes, and CYP3A4 activity was measured by monitoring the formation of metabolites of known CYP3A4 substrates (midazolam and testosterone) after 30 minutes of incubation. CYP3A4 inhibition was assessed in an 100 μL· reaction consisting of 70 μL· microsome reaction mixture (61.77 H ₂ 0, 7.5 1M KH ₂ P0 ₄ , 0.33 1M MgCl ₂ , 0.4 μΐ, 20 mg/mL human liver microsome suspension per reaction), \0 μL· substrate (either testosterone or midazolam), 10 μL· Compound 21 ("CI") or ketoconazole (known inhibitor of CYP3A4) intermediate dilutions or 1% DMSO stock solution, and 10 of 10 mM NADPH. Final concentrations of ketoconazole were 0.01, 0.1 and 1.0 μΜ; final concentrations of Compound 21 were 0.1, 1.0 and 10 μΜ. Reactions were initiated by the addition of 10 μί of 10 mM NADPH and gentle vortexing. Time 0 samples were terminated by adding 100 μL· ice-cold quench solution prior to the addition of NADPH, whereas 30 minute samples were terminated after incubation at 37°C for 30 minutes, with gentle vortexing every 10 minutes in between. After termination of all samples, the assay sample plate was centrifuged at 2500 x g for 10 minutes at 4°C; 100 μL· of the supernatants were transferred to a new Waters HPLC sample plate and sealed with a cap mat for UPLC/MS/MS analysis.

[00333] The results of this study are shown in Figure 15 and show that Compound 21 was approximately 100-fold less potent than ketoconazole at inhibiting CYP3A4; the % inhibition caused by ketoconazole at 0.01 μΜ was greater than that caused by Compound 21 at the 100-fold higher concentration of 1.0 μΜ for both CYP3A4 substrates of midazolam and testosterone. EXAMPLE 26: Plasma Concentrations of Compound 21 after Intravenous Administration

[00334] Blood samples were collected from the vena cephalica from the right foreleg of dogs treated with Compound 21 as described in Example 12, before and after administration of Compound 21 infusion at designated time points for later determination of the plasma levels of Compound 21 by HPLC. For each time point (5 min before the administration of 0.3 mg/kg Compound 21, 30 min after the administration of 0.3 and 1 mg/kg Compound 21) 4 mL of blood was taken into tubes containing lithium heparin. The tubes were immediately centrifuged at 4°C for 15 min at 3000g and the separated plasma was stored in a freezer at -20°C.

[00335] For each sample, 100 μΐ _^ of plasma was combined with 100 μΐ _^ of deionized water and the entire volume was loaded into individual wells of a 96-well Isolute SLE+ (supported liquid extraction) plate from Biotage (PN 820-00200-P01; Charlotte, NC, USA). The samples were eluted into a 96-well collection plate using 1 ml of tert-butyl methyl ether. The solvent was completely evaporated using a TurboVap 96 and samples were reconstituted in 200 μL· of 0.1% formic acid in a 50/50 water/acetonitrile mixture. Analysis was performed using an Acquity UPLC-TQD (Waters) in multiple reaction monitoring mode (positive electrospray).

[00336] HPLC analysis of blood plasma collected within 5 min of i.v. bolus injection showed that concentration ranges of 0.32-0.79 and 0.7-3.0 μηιοΐ-ί ^-1 for the 0.3 and 1 mg-kg ^-1 doses respectively were obtained (Table 3).

Table 3: Compound 21 concentration in dog plasma after IV administration

Subjects:

EXAMPLE 27: Pharmacokinetic Study of Compounds 21 and 25 in Rats

[00337] For intravenous (IV) administration, Compounds 21 and 25 were prepared in a vehicle comprised of 1.5% d-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS) and 0.4% ethanol in saline. For oral administration, Compounds 21 and 25 were prepared in a vehicle comprised of 4% TPGS and 1.2% ethanol in saline.

[00338] Female Sprague Dawley rats, 8-10 weeks old and approximately 200 grams, were administered intravenously, via tail vein injection, with Compound 21 or 25 at a dose of 1 mg/kg. For oral administration, Compounds 21 and 25 were given at 5 mg/kg by gavage. At various times after administration, blood was collected by saphenous vein bleed, the plasma separated by centrifugation using standard techniques and then the plasma concentrations of Compounds 21 and 25 were determined using UPLC/MS- MS analysis. Pharmacokinetic parameters (T _max , C _max and AUQ _as t) were calculated using Phoenix WinNonlin pharmacokinetic software (ver. 6.2). The results for Compound 21 (Table 4) and Compound 25 (Table 5) show that these compounds have an oral bioavailability of 13.2% and 7.52% respectively. Table 4: Compound 21 - Summary of PK Parameters

[00339] Oral Bioavailability (%) = 100*(AUC _O rai/AUCiv)*(Doseiv/Doseorai)

[00340] Compound 21 Oral Bioavailability (%) = 13.2

Table 5: Compound 25 - Summary of PK Parameters

[00341] Oral Bioavailability (%) = 100*(AUC _O rai/AUCiv)*(Doseiv/Doseorai)

[00342] Compound 25 Oral Bioavailability (%) = 7.52 EXAMPLE 28: Frequency Dependence of Kvl.5 Inhibition by Compound 25

[00343] The dose dependence of the inhibition of cloned human atrial Kvl.5 channels by Compound 25 was investigated following the protocol of Example 5. The results are shown in Figure 6B and show that Compound 25, like Compound 21, displays greater inhibitory potency when Kvl.5 currents are elicited at 3 Hz vs 1 Hz.

EXAMPLE 29: hERG Inhibition by Compound 25

[00344] The ability of Compound 25 to inhibit hERG channels was investigated in tsA201 cells expressing the hERG A channel clone as described in Example 10. The results are shown in Figure 16 and demonstrate that compound 25 is a weak inhibitor of hERG channels when compared to Kvl .5 inhibitory potency.

EXAMPLE 30: Activity and ADME Data for Compounds of General Formula (I)

[00345] A summary of activity and ADME (absorption, distribution, metabolism, and excretion) data generated for compounds of general Formula (I) is provided below and in Tables 6 and 7.

[00346] Kvl.5 channel inhibition was measured as described in Example 4. In addition to the results shown in Table 6, IC5 ₀ concentrations were determined for the following compounds:

Compound 21: 343 nM

Compound 25: 34 nM

Compound 41: 100 nM

[00347] NFAT inhibition was measured as described in Example 9 and determined for the following compounds (% Activity at 1 μΜ test compound):

Compound 21: 72%

Compound 31: 40%

Compound 25: 68%

Compound 41: 46%

Compound 44: 50% Compound 26: 53%

[00348] Caco-2 permeability (Table 6) was measured as follows. The permeability of compounds across a Caco-2 cell monolayer was conducted after a differentiation period of three weeks. Caco-2 cells were seeded into transwell plates and allowed to proliferate to form intact epithelial barriers, requiring 21-28 days growth, which can be used to assess the permeability of test articles across the gut epithelium. Permeability was evaluated solely in the apical-to-basal direction and initiated by the addition of the test compound to the apical chamber at a final concentration of 10 μΜ in 1% DMSO. Propranolol was used as positive controls. Lucifer Yellow was utilized as a marker of membrane integrity; it has poor permeability and remains in the apical chamber unless the integrity of the cell monolayer is compromised. Trans-epithelial electrical resistance (TEER) values were also measured prior to and post-treatment of test compounds to confirm the integrity of the Caco-2 cell monolayer. At various times after test compound addition to the apical chamber, aliquots were recovered from the basal chamber and analyzed for the amount of compound that had crossed the Caco-2 monolayer. Compounds were measured using liquid chromatography-mass spectrometry (LC/MS/MS) analysis and the Apparent permeability coefficients (P _app ) was calculated using standard methods.

[00349] Oral bioavailability (Table 7) was measured as described in Examples 20 and 23.

[00350] Microsomal stability (Table 7) was measured as follows. The in vitro metabolic stabilities of the test compounds were evaluated in rat and human microsomes. The substrate depletion method was used in NADPH-fortified rat and human micosome suspensions. Low concentration of test compound (final concentration of 1 μΜ obtained from a 25 mM stock solution in DMSO) was incubated with microsomes (at 0.5 mg microsomal protein/mL) suspended in buffer and reactions were initiated with the addition of the cofactor NADPH. Reactions were terminated at 0, 5 and 30 minutes or 0, 5, 15 and 30 minutes with the addition of acetonitrile with 0.1% formic acid and an internal standard. The percent remaining was calculated by comparing the measured levels at each time point to time zero. Compounds were measured using liquid chromatography-mass spectrometry (LC/MS/MS) analysis. [00351] Hepatocyte stability (Table 7) was measured as follows. The in vitro metabolic stabilities of test compounds were evaluated rat hepatocytes. The substrate depletion method was used to measure of in vitro metabolic stability in cryopreserved hepatocyte suspensions. Low concentrations of test compound (final concentration of 1 μΜ obtained from a 25 mM stock solution in DMSO) were incubated with rat hepatocytes in buffer (at 0.5xl0 ⁶ cells/mL). Reactions were terminated at 0, 5, 15, 30, 60 and 90 minutes and the percent of test compound remaining was calculated by comparing the quantitated levels at each time point to that at time zero. Reactions were terminated at 0, 5 and 30 minutes or 0, 5, 15 and 30 minutes with the addition of acetonitrile with 0.1% formic acid and an internal standard. The percent remaining was calculated by comparing the measured levels at each time point to time zero. Compounds were measured using liquid chromatography-mass spectrometry (LC/MS/MS) analysis.

[00352] The disclosures of all patents, patent applications, publications and database entries referenced in this specification are hereby specifically incorporated by reference in their entirety to the same extent as if each such individual patent, patent application, publication and database entry were specifically and individually indicated to be incorporated by reference.

[00353] Although the invention has been described with reference to certain specific embodiments, various modifications thereof will be apparent to those skilled in the art without departing from the spirit and scope of the invention. All such modifications as would be apparent to one skilled in the art are intended to be included within the scope of the following claims.

Table 6: Summary of Activity and ADME Data for Compounds of General Formula (I)

Kvl.5 % Aqueous Perm

Inhibition Solubility CaCO

Compound Structure (3μΜ) (μΜ), (i<r ⁶

2.5% cm/sec)

DMSO

36 68.89 3 0.105

40 74.96 5 3.18

38 73.07 1 <0.450

43 84.65 4 0.969

37 65.36 7 0.133

27 74.55 7 0.0737

44 73.96 5 7.47

26 79.79 218.34 <0.183

45 77.91 6 <0.103 Kvl.5 % Aqueous Perm

Inhibition Solubility CaCO

Compound Structure (3μΜ) (μΜ), (i<r ⁶

2.5% cm/sec)

DMSO

54 0.416

Table 7: Summar of ADME Data for Compounds of General Formula (I)

% Oral Bioavailability Microsomal Stability (% Hepatocyte Stability (ti/ ₂ , remaining at 30 min) min)

Compound Structure

Rat Mouse Human Rat Mouse Rat

47 57 ± 1 87 ± 3