MX2007001188A - 1,1,2,2-tetra (hetero) arylethanes or 1,1,2-tri (hetero) aryl-2-heterocyclylethanes as potassium channel inhibitors. - Google Patents

Abstract

The present invention relates to compounds having the structure Formula (I) useful as potassium channel inhibitors to treat cardiac arrhythmias.

Description

1.1.2.2-TETRA (HETERO) ARILETANOS OR 1,1,2-TRI (HETERO) ARIL-2- HETEROCICLILETANOS AS INHIBITORS OF THE POTASSIUM CHANNEL BACKGROUND OF THE INVENTION The present invention relates broadly to compounds that are useful as inhibitors of potassium channels. Compounds of this type may be useful as Kv1.5 antagonists for treating and preventing cardiac arrhythmias and the like. Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in clinical practice and it is likely that prevalence increases with the aging of the population. Although AF is rare, it can damage cardiac function and lead to complications such as the development of congestive heart failure, thromboembolism, or ventricular fibrillation. The currently available antiarrhythmic agents have been developed for the treatment of ventricular and atrial / supraventricular arrhythmias. Malignant ventricular arrhythmias are potentially life-threatening immediately and require urgent care. Pharmacological therapy for ventricular arrhythmia includes agents Class (for example, procainamide, quinidine), Class I (for example, flecainide, propafenone) and Class III (amiodarone), which have significant risk of proarrhythmia. These Class I and III drugs have been shown to convert FA to sinus rhythm and prevent recurrence of AF (Mounsey, JP, DiMarco, JP, Circulation, 102: 2665-2670), but they have an unacceptable risk of life-threatening ventricular proarrhythmia. and thus may increase mortality (Pratt, CM, Moye, LA, Am J. Cardiol., 65: 20B-29B, 1990, Waldo er al, Lancet, 348: 7-12, 1996, Torp-Pedersen er al, Expert Opin, Invest. Drugs, 9: 2695-2704, 2000). These observations demonstrate a clear unmet medical need to develop safer and more effective drugs for the treatment of atrial arrhythmias. Class III antiarrhythmic agents cause a selective prolongation of APD without significant depression of cardiac conduction or contractile function. The only selective Class III drug approved for clinical use in atrial fibrillation is dofetilide, which mediates its antiarrhythmic effects by blocking l l, the rapidly activating component found in humans in both the atrium and the atrium. ventricle (Mounsey, JP, DiMarco, JP, Circulation, 702: 2665-2670). Since L blockers increase APD and refractoriness in both the atrium and the ventricle without affecting conduction per se, they theoretically represent potentially useful agents for the treatment of arrhythmias such as AF (Torp-Pedersen, et al. al, Expert Opin, Invest. Drugs, 9: 2695-2704, 2000). However, these agents are most likely to have an increased risk of proarrhythmia at low heart rates. It has been specifically observed the K + ultrafast delayed rectifier current lKur. in the human atrium and not in the ventricle. The molecular correlation of lKur in the human atrium is the potassium channel designated Kv1.5. It is believed that l? Ur contributes significantly to the repolarization of the human atrium. Accordingly, a specific blocker of l? Ur, that is, a compound that blocks Kv1.5, would overcome the drawbacks of other compounds by prolonging refractoriness through a delay of repolarization in the human atrium without causing delays in the ventricular repolarization that arrhythmogenic patients suffer after depolarizations or acquired long QT syndrome observed during treatment with standard Class I drugs. Kv1.5 blockers having these properties have been described (Peukert et al, J. Med. Chem., 46: 486-498, 2003; Knobloch et al, Naunyn-Schmedieberg's Arch. Pharmacol. 366: 482-287, 2002; Merck &Co., Inc. WO0224655, 2002). The compounds described in this invention represent a new structural class of Kv1.5 antagonists.

BRIEF DESCRIPTION OF THE INVENTION The invention relates to compounds of the formula that antagonize the Kv1.5 potassium channel: The compounds of this invention are useful in the treatment and prevention of cardiac arrhythmias and the like. Also within the scope of this invention are pharmaceutical formulations comprising a compound of the formula I and a pharmaceutical carrier.

DETAILED DESCRIPTION OF THE INVENTION The invention relates to compounds of the formula I which antagonize the Kv1.5 potassium channel: where: A, B and C are independently selected from the group consisting of: 1) an aryl ring, and 2) a heteroaryl ring, where the point of attachment to the heteroaryl ring is a carbon atom, and the heteroaryl ring is selected from the group consisting of: a) a 5-member unsaturated monocyclic ring with 1, 2, 3 or 4 ring atoms heteroatoms selected from the group consisting of: N, O or S, b) a monocyclic unsaturated ring of 6 members with 1, 2, 3 or 4 ring atoms heteroatoms selected from the group consisting of: N , O u S, and c) an unscreened bicyclic ring of 8-, 9- or 10-membered with 1, 2, 3 or 4 ring atoms heteroatoms selected from the group consisting of: N, O or S, the aryl ring and heteroaryl is unsubstituted, monosubstituted with R 4, disubstituted with groups independently selected from R 4, trisubstituted with groups independently selected from R 4, O tetrasubstituted with groups independently selected from R 4, and wherein any heteroaryl ring or heterocyclic S or N stable atom is not substituted or is substituted with oxo, the R4 substitutions of the heteroaryl ring being on one or more carbon atoms of the heteroaryl ring; with the proviso that at least one of substituents A, B and C is a heteroaryl ring; D is selected from the group consisting of: 1) an aryl ring, 2) a heteroaryl ring, wherein the point of attachment to the heteroaryl ring is a carbon atom, and the heteroaryl ring is selected from the group consisting of: ) a 5-member unsaturated monocyclic ring with 1, 2, 3 or 4 ring atoms heteroatoms selected from the group consisting of: N, O or S, b) a monocyclic unsaturated ring of 6 members with 1, 2, 3 or 4 ring atoms heteroatoms selected from the group consisting of: N , O u S, and c) an unsaturated 8-, 9- or 10-membered bicyclic ring with 1, 2, 3 or 4 ring atoms heteroatoms selected from the group consisting of: N, O or S, and 3) a saturated heterocyclic ring of 4 to 6 members with 1, 2 or 3 ring atoms heteroatoms selected from the group consisting of: N, O and S, where the point of attachment of the heterocyclic ring is a carbon atom, the ring being aryl, heteroaryl, saturated heterocyclic, unsubstituted, monosubstituted with R 4, disubstituted with groups independently selected from R 4, trisubstituted with groups independently selected from R 4, or tetrasubstituted with groups independently selected from R 4, and wherein any ring atom has S or N stable teroaryl or heterocyclic is unsubstituted or is substituted with oxo, the R4 substitutions of the heteroaryl ring being on one or more carbon atoms of the heteroaryl ring; X and Y are independently selected from the group consisting of: H and OR5; Ra, in each case where it appears, is independently selected from the group consisting of: hydrogen, C1-C6 alkyl and halogen; R4, in each case where it appears, is independently selected from the group consisting of: hydrogen, halogen, CN, CR4 = C (R5) 2 I (CRa2) nOR5t (CRa2) nN (R5) 2, (CRa2) n C (0) R5, N (R5) C (O) R5, C (O) OR5 and N (R5) S (O) mR5; R5, in each case where it appears, is independently selected from the group consisting of: hydrogen, alkyl C1-C6 unsubstituted or substituted, C3-C10 cycloalkyl unsubstituted or substituted, unsubstituted or substituted aryl and unsubstituted or substituted heterocyclyl; m is, independently, 0, 1 or 2; and n is, independently, 0, 1, 2, 3, 4, 5 or 6. The expression "with the proviso that at least one of the substituents A, B and C is a heteroaryl ring" means that the invention is not includes compounds where A, B, and C are simultaneously aryl. The compounds of the invention include those where any one of A, B and C is a heteroaryl ring, those where two of A, B and C are heteroaryl rings, and those where the three A, B and C are heteroaryl rings. One embodiment of the invention is a compound wherein: A is a heteroaryl ring, where the point of attachment to the heteroaryl ring is a carbon atom, where the heteroaryl ring is a monocyclic 6-membered unsaturated ring with 1 or 2 atoms of ring N, the heteroaryl ring being unsubstituted, monosubstituted with R 4, disubstituted with groups independently selected from R 4, trisubstituted with groups independently selected from R 4, or tetrasubstituted with groups independently selected from R 4, and wherein any stable N atom of the heteroaryl ring is not is substituted or is substituted with oxo, the R4 substitutions of the heteroaryl ring being on one or more carbon atoms of the heteroaryl-B ring is a heteroaryl ring, where the point of attachment to the heteroaryl ring is a carbon atom, and the heteroaryl ring is a 6-membered unsaturated monocyclic ring with 1 or 2 N atoms, the heteroaryl ring is unsubstituted, monosubstituted or with R 4, disubstituted with groups independently selected from R 4, trisubstituted with groups independently selected from R 4, O tetrasubstituted with groups independently selected from R 4, and wherein any N atom of the stable heteroaryl ring is unsubstituted or is substituted with oxo, the substitutions being R4 of the heteroaryl ring on one or more carbon atoms of the heteroaryl ring; C is selected from the group consisting of: 1) an aryl ring, and 2) a heteroaryl ring, where the point of attachment to the heteroaryl ring is a carbon atom, where the heteroaryl ring is an unsaturated monocyclic 6-membered ring with 1 N atom, the aryl and heteroaryl ring is unsubstituted, monosubstituted with R 4, disubstituted with groups independently selected from R 4, trisubstituted with groups independently selected from R 4, O tetrasubstituted with groups independently selected from R 4, and wherein any stable N atom of the heteroaryl or heterocyclic ring is unsubstituted or is substituted with oxo, the R4 substitutions of the heteroaryl ring being on one or more carbon atoms of the heteroaryl ring; and D is a heteroaryl ring, where the point of attachment to the heteroaryl ring is a carbon atom, and the heteroaryl ring is a 6-membered unsaturated monocyclic ring with 1 or 2 ring N atoms, and the heteroaryl ring is unsubstituted , monosubstituted with R 4, disubstituted with groups independently selected from R 4, trisubstituted with groups independently selected from R 4, or tetrasubstituted with groups independently selected from R 4, and wherein any stable N atom of the heteroaryl ring is unsubstituted or is substituted with oxo, the R4 substitutions of the heteroaryl ring on one or more ring carbon atoms. A preferred embodiment of the invention is a compound wherein: X is selected from the group consisting of: hydrogen and OH; And it is selected from the group consisting of: hydrogen and OH; A is selected from the group consisting of: B is selected from the group < Stente of: C is selected from the group consisting of D is selected from the group consisting of: N (CH3) 2 Hz H (CH2bCH rmcHzhOH JTHz An example of a compound of the invention is a compound selected from the group consisting of: (R) -? / -. { 6- [1- (4-fluorophenyl) -2,2-dipyridin-3-ylethyl] pyridin-2-yl} methanesulfonamide, (S) -? / -. { 6- [1 - (4-fluorophenyl) -2,2-dipyridin-3-ylethyl] pyridin-2-yl} methanesulfonamide, (f?) -? / -. { 6- [1- (3-cyanophenyl) -2,2-dipyridin-3-ylethyl] pyridin-2-yl} methanesulfonamide, (S) -? / -. { 6- [1- (3-cyanophenyl) -2,2-dipyridin-3-ylethyl] pyridin-2-yl} methanesulfonamide, (/?) -? / -. { 6- [1- (6-methoxypyridin-2-yl) -2,2-dipyridin-3-ylethyl] pyridin-2-yl} methanesulfonamide, (S) -? / -. { 6- [1- (6-methoxypyridin-2-yl) -2,2-dipyridin-3-ethyl] pyridin-2-yl} methanesulfonamide, (R) -3- [1- (2-aminopyrimidin-4-yl) -2,2-dipyrdin-3-ylethyl] benzonitrile, and (S) -3- [1- (2-aminopyrimidin- 4-yl) -2,2-dipyridin-3-ylethyl] benzonitrile. The compounds listed above are active in one or more of the assays for Kv1.5 described below. Another embodiment of the invention is a method for treating or preventing a condition in a mammal, which treatment or prevention is effected or facilitated by the inhibition of Kv1.5, which comprises administering an amount of a compound of formula I which is effective for inhibit the Kv1.5 A preferred embodiment is a method of treating or preventing cardiac arrhythmias, for example atrial fibrillation, atrial flutter, atrial arrhythmia and supraventricular tachycardia in a mammal, which comprises administering a therapeutically effective amount of a compound of formula I. Another preferable embodiment is a method to prevent thromboembolic events such as stroke. Another preferred embodiment is a method to prevent congestive heart failure. Another preferred embodiment is a method of treating or preventing immunosuppression or a disorder involving immunosuppression, such as AIDS, cancer, senile dementia, trauma (including wound healing, surgery and shock), chronic bacterial infection, certain disorders of the central nervous system and conditions that include resistance to organ or tissue transplantation, graft versus host diseases caused by bone marrow transplantation. Within this embodiment is a method for treating or preventing immunosuppression by administering a compound of the invention with an immunosuppressant compound. Another preferable embodiment is a method for treating or preventing gliomas, including those of lesser or greater malignancy, preferably those of higher malignancy. Another preferable embodiment is a method for inducing in a patient having atrial fibrillation, a normal sinus rhythm state, where the rhythm induced corresponds to the rhythm that would be considered normal for an individual who shares with the patient similar characteristics of age and weight, which it comprises treating the patient with a compound of the invention. Another preferred embodiment is a method for treating tachycardia (ie, rapid heart rate, eg, 100 beats per minute) in a patient, which comprises treating the patient with an anti-tachycardia device (eg, a defibrillator or a pacemaker) in combination with a compound in accordance with the claim 1. The present invention also encompasses a pharmaceutical formulation comprising a pharmaceutically acceptable carrier and the Compound of formula I or one of its pharmaceutically acceptable crystalline or hydrate forms. A preferred embodiment is a pharmaceutical composition of the Compound of the formula I, which further comprises a second agent. The compounds of the present invention may have chiral centers, for example, a chiral center (providing two stereoisomers, (R) and (S)), or two chiral centers (providing up to four stereoisomers), (R, R), (S, S), (R, S), and (S, R)). This invention includes all optical isomers and their mixtures. As long as the isomeric composition is not specified, all possible isomers are included. Also included within the scope of the present invention are tautomers of the compounds defined in Formula I. For example, compounds that include carbonyl groups -CH2C (O) - (keto forms) can undergo tautomerism to form hydroxyl groups -CH = C (OH) - (enol forms).

Both keto and enol forms are included within the scope of the present invention. In addition, compounds with carbon-carbon double bonds can occur in Z- and E- forms with all isomeric forms of the compounds included in the present invention. List of abbreviations: AAS atomic absorption spectroscopy AIDS Acquired immunodeficiency syndrome AF atrial fibrillation ACE on angiotensin conversion APD potential duration of action Ar argon Boc butoxycarbonyl Boc2O di-tert-butyl dicarbonate CHO Chinese hamster ovary dba dibenzylidinoacetone DEA diethylamine DMF dimethylformamide DMSO dimethylsulfoxide EDTA ethylenediaminetetraacetic acid EGTA ethylenebis (oxyethylenenitrile) tetraacetic acid ESI electrospray ionization Et2O diethyl ether Et3N triethylamine EtOAc ethyl acetate Et2O diethyl ether Et3OBF4 triethyloxonium tetrafluoroborate EtOH ethanol FAAS flame atomic absorption spectroscopy FBS fetal bovine serum HBSS Hank's balanced salt solution HEPES N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid HPLC high pressure liquid chromatography HRMS high resolution mass spectrum / -PrMgCI isopropyl magnesium chloride / '- PrOH isopropanol INH inhibition LDA lithium diisopropylamide LiHMDS lithium hexamethyldisilazide LRMS low resolution mass spectrum LYS lysate MeOH methanol MS mass spectrum n-BuLi n-butyl lithium NMR nuclear magnetic resonance NSAID non-steroidal anti-inflammatory drug PBS buffered salt solution buffered with floating TAFI TAFI inhibitor of thrombin-activated fibrinolysis TFA trifluoroacetic acid THF tetrahydrofuran TsOH p-toluenesulfonic acid As used herein, except where indicated "alkyl" means that it includes both straight and branched chain saturated aliphatic hydrocarbon groups, including all isomers, having the specified number of carbon atoms. The abbreviations commonly used for alkyl groups are used throughout the specification, for example, methyl can be represented as "Me" or CH3, ethyl can be represented as "Et" or CH2CH3, propyl can be represented as "Pr" or CH2CH2CH3, butyl can be represented as "Bu" or CH2CH2CH2CH3 and so on. "Ci-6 alkyl" (or "Ci-Cß alkyl") for example, refers to straight or branched chain alkyl groups, including all isomers, having the specified number of carbon atoms. C 1-6 alkyl includes all hexyl alkyl and pentyl alkyl isomers, as well as n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl. "C 1-4 alkyl" refers to n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl. The term "alkoxy" represents a linear or branched alkyl group of the indicated number of carbon atoms attached through an oxygen bridge. The term "alkenyl" includes both groups of linear and branched unsaturated hydrocarbons containing at least two carbon atoms linked by a double bond. The ethylene alkene is represented, for example, as "CH2CH2" or, alternatively, by "H2C = CH2". "C2-5 alkenyl" (or "C2-C5 alkenyl") for example, refers to straight or branched chain alkenyl groups having from 2 to 5 carbon atoms and include all pentenyl isomers, as well as 1- butenyl, 2-butenyl, 3-butenyl, 1-propenyl, 2-propenyl and ethenyl (or ethylenyl). Similar terms such as "C2-3 alkenyl" have an analogous meaning. The term "alkynyl" includes both groups of straight and branched chain unsaturated hydrocarbons containing at least two carbon atoms attached by a triple bond. The alkyne acetylene is represented, for example, by "CHCH" or, alternatively, by "HC = CH". "C2-5 alkynyl" (or "C2-C5 alkynyl") for example, refers to straight or branched chain alkynyl groups having from 2 to 5 carbon atoms and includes all pentinyl isomers as well as 1-butynyl, 2-butynyl, 3-butynyl, 1-propynyl, 2-propynyl and ethynyl (or acetylenyl). Similar terms such as "C2-3 alkynyl" have analogous meaning. Unless specifically indicated otherwise only as "unsubstituted" or "substituted", the alkyl, alkenyl and alkynyl groups are unsubstituted or substituted with 1 to 3 substituents on each carbon atom, with halo, C1-alkyl C20, CF3, NH2, N (C- | -C6 alkyl) 2. NO2, oxo, CN, N3, -OH, -O (C -C6 alkyl), C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (Crj-Cß alkyl) S (O) ?-2-. (Crj-C6 alkyl) S (O) o-2 (C6-C6 alkyl) -, (C6-C6 alkyl) C (O) NH-, H2N-C (NH) -, -O (alkyl) C <; | - C6) CF3, (C6-C6 alkyl) C (0) -, (C6-C6 alkyl) OC (O) -, (C6-C6 alkyl) O (C- | -C6 alkyl) -, (C 1 -C 6 alkyl) C (O) i-2 (C 1 -C 6 alkyl), (C 1 -C 6 alkyl) OC (O) NH-, -NH (C 1 -C 6 alkyl) NHC (O) NH (C1-C6 alkyl), -NH (C1-C6 alkyl) NHS? 2 (C1-CQ alkyl), - (C1-C6 alkyl) NHS? 2 (C1 alkyl) -C6), aryl, aralkyl, heterocycle, heterocyclylalkyl, haloaryl, haloarylalkyl, haloheterocycle, haloheterocyclylalkyl, cyanoaryl, cyanoarylalkyl, cyanoheterocycle and cyanoheterocyclylalkyl. The term "Co" as used in expressions such as "Crj-6 alkyl" refers to a direct covalent bond. Similarly, when an integer that defines the presence of a certain number of atoms in a group is equal to zero, it means that the atoms adjacent to it are directly connected by a link. For example, in the structure ~ X ^ > in 'a clue s is an integer equal to zero, 1 or 2, the T structure Q ^ ^ | is when s is zero. T The term "C3-8 cycloalkyl" (or "C3-C8 cycloalkyl") refers to a cyclic ring of an alkane having from three to eight carbon atoms in total (ie, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl). The terms "C3-7 cycloalkyl", "C3-6 cycloalkyl", "C5-7 cycloalkyl" and the like have analogous meanings. The term "halogen" (or "halo") refers to fluorine, chlorine, bromine and iodine (alternatively termed fluorine (F), chlorine (Cl), bromine (Br) and iodine (I)). The term "C1-6 haloalkyl" (which may alternatively be referred to as "C1-C6 haloalkyl" or "halogenated C- | - C- alkyl") refers to a linear C1 to CQ alkyl group or branched as defined above with one or more halogen substituents. The term "C1-4 haloalkyl" has an analogous meaning. The term "Ci-6 fluoroalkyl" has an analogous meaning except that the halogen substituents are limited to fluorine. Suitable fluoroalkyls include the series (CH2)? -4CF3 (ie, trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoro-n-propyl, etc.).

The term "carbocycle" (and its variations such as "carbocyclic" or "carbocyclyl") as used herein, unless otherwise indicated, refers to: (i) a saturated C3 to Cß monocyclic ring or unsaturated or (ii) a saturated or unsaturated C7 to C12 bicyclic ring system. Each ring in (ii) is independent of, or is fused with, the other ring, and each ring is saturated or unsaturated. The carbocycle may be attached to the rest of the molecule at any carbon atom that produces a stable compound. Fused bicyclic carbocycles are a subset of carbocycles; that is, the term "fused bicyclic carbocycle" generally refers to a bicyclic ring system of C7 to C10 where each ring is saturated or unsaturated and for each of the rings in the ring system two atoms are shared. adjacent carbon. A bicyclic carbocycle fused where one ring is saturated and the other saturated is a saturated bicyclic ring system. A bicyclic carbocycle fused where one ring is benzene and the other is saturated is an unsaturated bicyclic ring system. A bicyclic carbocycle fused where one ring is benzene and the other is unsaturated is an unsaturated ring system. Saturated carbocyclic rings are also referred to as cycloalkyl rings, for example, cyclopropyl, cyclobutyl, etc. Unless otherwise indicated, the carbocycle is unsubstituted or substituted by Ci-6 alkyl, C- | 6-alkenyl, C-i-6 alkynyl, aryl, halogen, NH 2 or OH. A subgroup of fused bicyclic unsaturated carbocycles are the bicyclic carbocycles where one ring is a benzene ring and the other ring is saturated or unsaturated, with the binding through any carbon atom giving rise to a stable compound. Representative examples of this subgroup include the following: The term "aryl" refers to aromatic mono- and poly-carbocyclic ring systems where the individual carbocyclic rings in the polyannular systems are fused or linked together via a single bond. Suitable aryl groups include phenyl, naphthyl and biphenylenyl. The term "heterocycle" (and its various variations such as "heterocyclic" or "heterocyclyl") broadly refer to: (i) a stable saturated or unsaturated 4 to 8 membered monocyclic ring, or (ii) a system of stable 7 to 12-membered bicyclic ring, each ring in (ii) being independent of, or fused to, the other ring or rings and each ring being saturated or unsaturated, and the monocyclic ring or bicyclic ring system containing one or more heteroatoms (for example, from 1 to 6 heteroatoms, or from 1 to 4 heteroatoms) selected from N, O and S and a balance of carbon atoms (the monocyclic ring typically contains at least one carbon atom and the ring systems typically contain at least two carbon atoms), and wherein any one or more of the nitrogen and sulfur heteroatoms is optionally oxidized and any one or more of the nitrogen heteroatoms is optionally quatemized. Unless otherwise indicated, the heterocyclic ring may be attached at any heteroatom or carbon atom, provided that the binding results in the creation of a stable structure. Unless otherwise indicated, when the heterocyclic ring has substituents, it is understood that the substituents may be attached to any atom on the ring, either a heteroatom or a carbon atom, with the proviso that a structure originates. stable chemistry Unless otherwise specifically indicated as being solely "unsubstituted" or only "substituted", the cycloalkyl, aryl and heterocycle groups are unsubstituted or substituted. As used herein, the terms "substituted C3-C10 cycloalkyl", "substituted aryl" and "substituted heterocycle" are intended to include the cyclic group containing 1 to 3 substituents in addition to the point of attachment to the rest of the compound . Preferably, the substituents are selected from the group including, but not limited to, halo, C 1 -C 20 alkyl. CF3, NH2, N (C- | -C6 alkyl) 2. NO2, oxo, CN, N3, -OH, -O (C1-C6 alkyl), C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (CQ-CQ alkyl) S (O) Q-2- >; aril- S (O) 0-2- > (Co-C6 alkyl) S (O)? - 2 (Co-Cg alkyl) -, (Co-C6 alkyl) C (0) NH-, H2N-C (NH) -, -O (alkyl) Ci-C6) CF3, (C6-C6 alkyl) C (0) -f (C6-C6 alkyl) OC (O) -, (C6-C6 alkyl) O (C1-C6 alkyl) -, ( Co-C6 alkyl) C (O) i-2 (Crj-C-6 alkyl) -, (C6-C6 alkyl) OC (O) NH-, aryl, aralkyl, heteroaryl, heterocyclylalkyl, halo-aryl, halo-aralkyl, halo-heterocycle, halo-heterocyclylalkyl, cyano-aryl, cyano-aralkyl, cyano-heterocycle and cyano-heterocyclylalkyl. Saturated heterocycles form a subgroup of heterocycles; that is, the term "saturated heterocyclic" refers generally to a heterocycle as defined above where the entire ring system (whether mono- or polycyclic) is saturated. The term "saturated heterocyclic ring" refers to a 4 to 8 membered saturated monocyclic ring or to a stable 7 to 12 membered bicyclic ring system consisting of carbon atoms and one or more heteroatoms selected from N, O and S. Representative examples include piperidinyl, piperazinyl, acetyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl and tetrahydrofuryl (or tetrahydrofuranyl). Heteroaromatics form another subgroup of heterocycles; that is, the term "heteroaromatic" (alternatively "heteroaryl") generally refers to a heterocycle as defined above where the entire ring system (either mono- or polycyclic) is an aromatic ring system. The term "heteroaromatic ring" refers to a 5- or 6-membered monocyclic aromatic ring or a 7- to 12-membered bicyclic ring consisting of carbon atoms and one or more heteroatoms selected from N, O and S. In the case of rings substituted heteroaryls containing at least one nitrogen atom (e.g., pyridine), such substitutions may be those that cause the formation of an N-oxide. Representative examples of heteroaromatic rings include pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl (or thiophenyl), thiazolyl, furanyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isooxazolyl, oxadiazolyl, thiazolyl, isothiazolyl and thiadiazolyl. Representative examples of bicyclic heterocycles include benzotriazolyl, indolyl, isoindolyl, indazolyl, indolinyl, isoindolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, chromanyl, isochromanyl, tetrahydroquinolinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzo-1. , 4-dioxinyl (ie, (Y0)), f > In the case of one of your listeners, I was angry about one or two adjacent volumes. Unless expressly indicated otherwise, an "unsaturated" ring is a partially or totally unsaturated ring. For example, a "C6 monocyclic unsaturated carbocycle" refers to cyclohexene, cyclohexadiene and benzene.

Unless expressly indicated otherwise, all of the ranges cited herein are inclusive. For example, a heterocycle described as containing "1 to 4 heteroatoms" means that the heterocycle may contain 1, 2, 3 or 4 heteroatoms. When any variable appears more than once in any constituent or in any formula that represents and describes compounds of the invention, its definition in each occurrence is independent of its definition in any other of the apparitions. In addition, combinations of substituents and / or variables are allowed only if such combinations result in stable compounds. The term "substituted" (for example, as in "aryl that is optionally substituted with one or more substituents ...") includes mono- and polysubstitution by a substituent quoted to the extent that simple substitution is permitted chemically and multiple (including multiple substitution in the same place). In the compounds of the invention having portions of pyridyl N-oxide, the pyridyl-N-oxide moiety is structurally represented using conventional representations such as that have equivalent meanings For variable definitions that contain terms that have repeated terms, for example, (CRjR) r, where r is the integer 2, Rj is a defined variable, and Rj is a defined variable, the value of Rj may differ in each case where it appears and the value of Rj can differ in each case where it appears. For example, if Ri and Rj are independently selected from the group consisting of methyl, ethyl, propyl and butyl, then (CR yRJ) 2 may be: I H3CH2C-C-CH3 H3CH2CH CH2C C CH2CH2CH Pharmaceutically acceptable salts include both metal (inorganic) salts and organic salts, a listing of which is presented in Remington's Pharmaceutical Sciences, 17th Edition, page 1418 (1985). It is well known to one skilled in the art that an appropriate salt form is chosen based on its physical and chemical stability, fluidity, hygroscopicity and solubility. As will be understood by those skilled in the art, pharmaceutically acceptable salts include, but are not limited to, salts of inorganic acids such as hydrochloride, sulfate, phosphate, diphosphate, hydrobromide and nitrate or salts of an organic acid such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate or palmoate, salicylate and stearate. Likewise, pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium and ammonium (especially ammonium salts with secondary amines). The preferred salts of this invention for the reasons mentioned above include the potassium, sodium, calcium and ammonium salts. In addition, crystalline forms, hydrates and solvates of the compounds of formula I are within the scope of this invention. Methods for preparing the compounds of this invention are illustrated in the following schemes. Other synthesis protocols will be apparent to those skilled in the art. The examples illustrate the preparation of the compounds of the formula I and as such will not be considered as limiting the invention described in the claims that are attached to the present description.

SCHEME I methods of (to literature The variables A, B, C and D in the scheme are as defined in "Formula I".

EXAMPLE 1-1 (R and S) N- (6-p- (4-fluorophenyl) -212-dipyridin-3-yleopyrimid-2-yl.] Methanesulfonamide Step A 4-Fluorophenylmagnesium bromide (2M in diethyl ether, 17.27 ml) was added dropwise to a mixture of 6-bromo-2-pyridine carboxaldehyde (6.12 g)., 32.90 mmol) in anhydrous THF (150 ml) at -78 ° C under N2. The reaction was heated to 0 ° C and stirred for 1.5 hours. The reaction was quenched with saturated aqueous NH 4 Cl. The combined organics were dried (anhydrous Na 2 SO 4), filtered and concentrated to give (6-bromopyridin-2-yl) (4-fluorophenyl) methanol. 1 H NMR (500 MHz, CDCl 3) d 7.50 (t, 1 H, J = 7.7), 7.40 (d, 1 H, J = 7.8), 7.38-7.32 (m, 2H), 7.10 (d, 1 H, J = 7.6), 7.03 (t, 2H, J = 8.7), 5.73 (d, 1 H, J = 4.2), 4.43 (d, 1 H, J = 4.4), LRMS m / z (M + H) Calculated: 282.0, found: 282.0.

Step B SOCI2 (5,870 g, 49.34 mmol) was added to a mixture of (6-bromopyridin-2-yl) (4-fluorophenyl) methanol in CH 2 Cl 2 (120 mL) at 0 ° C. The mixture was allowed to warm slowly to room temperature and was stirred for 16 hours. The mixture was again cooled to 0 ° C and quenched with saturated aqueous NaHCO3. The resulting mixture was extracted 3 times with CH2Cl2. The combined organics were dried (anhydrous Na 2 SO 4), filtered and concentrated. The resulting residue was purified by chromatography on silica gel (20-30% CH2Cl2 in hexanes) to give 2-bromo-6- [chloro (4-fluorophenyl) methyl] pyridine. 1 H NMR (500 MHz, CDCl 3) d 7.58 (t, 1 H, J = 7.7), 7.51 (d, 1 H, J = 7.6), 7.47-7.39 (m, 3H), 7.04 (t, 2H, J = 8.7). 6.08 (s, 1 H), LRMS m / z (M + H) Calculated: 300.0, found: 300.0.

Step C A solution of 3- (pyridine-3-ylmethyl) pyridine (2.5 g, 14.69 mmol) in anhydrous THF (75 ml) under N2. The mixture was cooled to -78 ° C and LDA (12.24 mL, 1.8 M) was added dropwise. The mixture was stirred at -78 ° C for 1 hour and 2-bromo-6- [chloro (4-fluorophenyl) methyl] pyridine (4.64 g, 15.42 mmol) was added. The mixture was heated to 0 ° C and stirred for 2 hours. The reaction was quenched with saturated aqueous NH4CI and extracted three times with EtOAc. The combined organics were dried (anhydrous Na 2 SO 4), filtered and concentrated. The resulting residue was purified by chromatography on silica gel (1-3% MeOH in CH 2 Cl 2) to give 2-bromo-6- [1- (4-fluorophenyl) -2,2-dipyridin-3-ylethyl] pyridine. 1 H NMR (500 MHz, CDCl 3) d 8.55 (d, 1 H, J = 2.0), 8.45 (d, 1 H, J = 2.0), 8.35-8.29 (m, 2H), 7.60 (dt, 1 H, J = 7.9, 1.9), 7.49 (dt, 1 H, J = 7.9, 1.9), 7.35-7.24 (m, 3H), 7.17 (d, 1 H, J = 7.8), 7.14-7.07 (m, 2H), 7.05 (d, 1 H, J = 7.6), 6.86 (t, 2H, J = 8.7), 5.13 (d, 1H, J = 12.2), 4.78 (d, 1 H, J = 12.0) LRMS m / z ( M + H) Calculated: 434.0, found: 434.0. The racemic mixture was separated by ChiralPak AD (30% PrOH in hexane + DEA 1 ml / l). The first peak was the A-enantiomer of 2-bromo-6- [1- (4-fluorophenyl) -2,2-dipyridin-3-ylethyrpyridine; HRMS m / z (M + H) Calculated: 434.0663, found: 434.0648. And the second peak was the B-enantiomer of 2-bromo-6- [1- (4-fluorophenyl) -2,2-dipyridin-3-ylethyl] pyridine; HRMS m / z (M + H) Calculated: 434.0633, found: 434.0646.

Step D A mixture of 2-bromo-6- [1- (4-fluorophenyl) -2,2-dipyridin-3-ylethyl] (enantiomer A) (0.550 g, 1.266 mmol) was stirred in anhydrous dioxane (5 mL). , methanesulfonamide (0.144 g, 1518 mmol), Cs2CO3 (0.578 g, 1.774 mmol), Pd2 (dba) 3 (23 mg, 0.025 mmol) and xantho (44 mg, 0.076 mmol). The mixture was degassed (three pumps / N2) and heated to 100 ° C for 16 hours under N2. The mixture was cooled to room temperature, diluted with CHCl 3 and filtered through a pad of Celite. The Celite was washed with CHCl3 and EtOAc. The filtrate was concentrated and purified by chromatography on silica gel (1-5% MeOH in CH 2 Cl 2) to give the N- enantiomer A. { 6- [1- (4-fluorophenyl) -2,2-dipyridin-3-ylethyl] pyridin-2-yl} methanesulfonamide. H NMR (500 MHz, d6 DMSO) d 10.51 (s, 1 H), 8.64 (d, 1 H, J = 2.0), 8.59 (d, 1 H, J = 2.0), 8.23 (dd, 2H, J = 4.6, 1.5), 7.90 (dt, 1 H, J = 8.0, 1.9), 7.87 (d, 1 H, J = 7.8), 7.60-7.52 (m, 2H), 7.47 (t, 1 H, J = 7.8 ), 7.24-7.15 (m, 2H), 7.01 (d, 1 H, J = 7.3), 6.96 (t, 2H, J = 8.9), 6.54 (d, 1 H, J = 8.0), 5.37 (d, 1 H, J = 12.2), 5.13 (d, 1 H, J = 12.5), 3.43 (s, 3H), HRMS m / z (M + H) Calculated: 449.1442, found: 449.1450. The B-enantiomer of N-. { 6- [1 - (4-fluorophenyl) -2,2-dipyridin-3-ylethyl] pyridin-2-yl} methanesulfonamide (HRMS m / z (M + H) Calculated: 449.1442, found: 449.1459) was synthesized using the method described above except for the B-enantiomer of 2-bromo-6- [1- (4-fluorophenyl) -2.2 -dipyridin-3-ylethyl] pyridine.

EXAMPLE I-2 (R S) N- (6-ri- (3-cyanophenyl) -2,2-dipyridin-3-yl-tnpyridin-2-yl} methanesulfonamide Step A n-BuLi (10.13 ml, 2.5 M) was added dropwise to a mixture of 2,6-dibromopyridine (6 g, 25.33 mmol) in anhydrous THF (150 ml) under N2 at -78 ° C. The mixture was stirred at -78 ° C for 15 min and 3-cyanobenzaldehyde (3.32 g) was added., 25.33 mmol) in anhydrous THF (10 ml, rinsed with 5 ml). The mixture was stirred for 20 minutes at -78 ° C and then warmed to 0 ° C and stirred for 1 hour. The mixture was quenched with saturated aqueous NH CI and the resulting mixture was extracted three times with EtOAc. The combined organics were dried (anhydrous Na 2 SO 4), filtered and concentrated. The residue was purified by chromatography on silica gel (15-30% EtOAc in hexanes) to give 3 - [(6-bromopyridin-2-yl) (hydroxy) methyl] benzonitrile. LRMS m / z (M + H) Calculated: 289.0, found 289.1.

Step B SOCI2 (2.01 mL, 16.88 mmol) was added to a mixture of 3 - [(6-bromopyridin-2-yl) (hydroxy) methyl] benzonitrile (4.88 g, 16.88 mmol) in CH 2 Cl 2 (60 mL) at 0 °. C under N2. The mixture was warmed to room temperature and stirred for 48 hours. The mixture was cooled to 0 ° C and quenched with saturated aqueous sodium bicarbonate and extracted three times with CH2Cl2. The combined organics were dried (anhydrous Na 2 SO 4), filtered and concentrated. The residue was purified by chromatography on silica gel (25-50% CH 2 Cl 2 in hexanes) to give 3 - [(6-bromopyridin-2-yl) (chloro) methyl] benzonitrile. LRMS m / z (M + H) Calculated: 307.0, found: 307.0.

Step C LDA (3.43 mL, 1.8 M) was added dropwise to a mixture of 3- (pyridin-3-ylmethyl) pyridine (0.700 g, 4.11 mmol) in anhydrous THF (20 mL) at -78 ° C under N2. The mixture was stirred for 1 hour at -78 ° C, and 3 - [(6-bromopyridin-2-yl) (chloro) methyl] benzonitrile was added. The reaction was heated to 0 ° C, and stirred for 2 hours. The resulting mixture was quenched with saturated aqueous NH CI and extracted three times with EtOAc. The combined organics were dried (anhydrous Na 2 SO 4), filtered and concentrated. The residue was purified by chromatography on silica gel (1-4% MeOH in CH 2 Cl 2) to give 3- [1- (6-bromopyridin-2-y) -2,2-dipyridin-3-ylethyl] benzon. Trilémico trilo. LRMS m / z (M + H) Calculated: 441.0, found: 441.0. The racemic mixture was separated by ChiralPak AD (40% PrOH in hexanes +1 ml / 1 DEA to 80% iPrOH in hexanes + 1 ml / 1 DEA for 45 min). The first peak was the enantiomer A of 3- [1- (6-bromopyridin-2-yl) -2,2-dipyridin-3-ylethyl] benzonitrile, and the second peak was the B-enantiomer of 3- [1- ( 6-bromopyridin-2-yl) -2,2-dipyridin-3-ylethylbenzeneitrile.

Step D An enantiomer mixture of 3- [1- (6-bromopyridin-2-yl) -2,2-d-pyridin-3-ylethyl] benzonitrile was stirred in anhydrous dioxane (5 ml). (0.318 g, 0.721 mmol), methanesulfonamide (0.082 g, 0.865 mmol), Cs2CO3 (0.329 g, 1.01 mmol), Pd2 (dba) 3 (13 mg, 0.014 mmol) and xantho (25 mg, 0.043 mmol). The mixture was degassed (3 pumping / N2) and heated to 100 ° C for 16 hours under N2. The reaction was cooled to room temperature, diluted with CHCl3, and filtered through a pad of Celite. The Celite was washed with CHCl3 and EtOAc to remove the impurities. The Celite was then washed with MeOH. The filtrate was concentrated and purified by chromatography on silica gel (1-5% MeOH in CH 2 Cl 2) to give the N- enantiomer A. { 6- [1- (3-cyanophenyl) -2,2-dipyridin-3-ylethyl] pyridin-2-yl} methanesulfonamide. 1 H NMR (500 MHz d 6 DMSO) d 10.57 (s, 1 H), 8.63 (dd, 2 H, J = 5.6, 2.0), 8.29-8.20 (m, 2H), 8.04 (s, 1 H), 7.90 (d , 2H, J = 8.1), 7.84 (d, 1 H, J = 7.8), 7.55-7.45 (m, 2H), 7.35 (t, 1 H, J = 7.8), 7.20 (dd, 2H, J = 7.9 , 4.8), 7.03 (d, 1 H, J = 7.3), 6.57 (d, 1 H, J = 8.0), 5.47 (d, 1 H, J = 12.5), 5.15 (d, 1 H, J = 12.2 ), 3.46 (s, 3H), HRMS m / z (M + H) Calculated: 456.1489, found: 456.1460. The B-enantiomer of N-. { 6- [1- (3-cyanophenyl) -2,2-dipyridin-3-ylethyl] pyridin-2-yl} methanesulfonamide (HRMS m / z (M + H) Calculated: 456.1489, found: 456.1469) was synthesized using the method described above except for the B-enantiomer of 3- [1- (6-bromopyridin-2-yl) -2.2 -dipyridin-3-ylethyl] benzonitrile.

EXAMPLE 1-3 (R and S) N-. { 6-ri- (6-methoxypyridin-2-yl) -2,2-dipyridin-3-ylethylpyridin-2-dimethanesulfonamide Step A n-BuLi (11.701 ml, 2.5 M) was added dropwise to a mixture of 2-bromo-6-methoxy-pyridine (5.00 g, 26.59 mmol) in anhydrous THF (100 ml) at -78 ° C under N2 . The mixture was stirred for 20 minutes and 6-bromo-2-pyridine carboxaldehyde (4.95 g, 26.93 mmol) was added. The mixture was heated to 0 ° C and stirred for 1 hour. The resulting mixture was quenched with saturated aqueous NH4CI and extracted three times with EtOAc. The combined organics were dried (Na 2 SO 4 anhydrous), filtered and concentrated. The residue was purified by chromatography on silica gel (15% EtOAc in hexanes) to give (6-bromopyridin-2-yl) (6-methoxypyridin-2-yl) methanol. 1 H NMR (500 MHz, CDCl 3) d 7.60-7.49 (m, 3 H), 7.37 (dd, 1 H, J = 7.1, 1.5), 7.12 (d, 1 H, J = 7.3), 6.64 (d, 1 H, J = 8.3), 5.78 (d, 1 H, J = 5.4), 5.27 (d, 1 H, J = 5.4), 3.97 (s, 3H), LRMS m / z, (M + H) Calculated: 295.0, found 295.1.

Step B SOCI2 (3.09 g, 25.97 mmol) was added to a mixture of (6-bromopyridin-2-yl) (6-methoxypyridin-2-yl) methanol (5.11 g, 17.31 mmol) in CH 2 Cl 2 (56 mL) at 0 ° C under N2. The mixture was allowed to warm to room temperature and was stirred for 3 hours. The mixture was again cooled to 0 ° C and quenched with saturated aqueous sodium bicarbonate. The resulting mixture was extracted three times with CH2Cl2. The combined organics were dried (Na2SO), filtered and concentrated. The resulting residue was purified by chromatography on silica gel (25-35% CH 2 Cl 2 in hexanes) to give 2-bromo-6- [chloro (6-methoxypyridin-2-yl) methyl] pyridine. 1 H NMR (500 MHz, CDCl 3) d 7.76 (d, 1 H, J = 7.8), 7.61-7.54 (m, 2 H), 7.41 (d, 1 H, J = 7.8), 7.12 (d, 1 H, J = 7.1), 6.66 (d, 1 H, J = 8.3), 6.02 (s, 1 H), 3.86 (s, 3H), LRMS m / z (M + H) Calculated: 313.0, found: 312.9.

Step C LDA (9.79 mL, 1.8 M) was added dropwise to a mixture of 3- (pyridin-3-ylmethyl) pyridine (2 g, 11.75 mmol) in anhydrous THF (40 mL) at -78 ° C under N2. The mixture was stirred at -78 ° C for 1 hour and 2-bromo-6- [chloro (6-methoxypyridin-2-yl) methyl] pyridine was added. The mixture was heated to 0 ° C and stirred for 2 hours. The reaction was quenched with saturated aqueous NH4CI and extracted three times with EtOAc. The combined organics were dried (anhydrous Na 2 SO 4), filtered and concentrated. The residue was purified by chromatography on silica gel (1-5% MeOH in CH 2 Cl 2) to give 2-bromo-6- [1- (6-methoxypyridin-2-yl) -2,2-dipyridin-3. iletyl] pyridine. 1 H NMR (500 MHz, CDCl 3) d 8.51 (t, 2 H, J = 2.7), 8.36-8.28 (m, 2 H), 7.69 (dt, 1 H, J = 8.1, 2.0), 7.58 (dt, 1 H, J = 8.0, 1.9) 7.50 (d, 1H, J = 7.6), 7.38-7.30 (m, 2H), 7.18 (d, 1 H, J = 7.8), 7.13 (dd, 1 H, J = 7.9, 4.8 ), 7.09 (dd, 1 H, J = 7.8, 4.9), 6.86 (d, 1 H, J = 7.3), 6.45 (d, 1 H, J = 8.1), 5.27 (d, 1 H, J = 12.2 ), 5.06 (d, 1 H, J = 12.5), 3.95 (s, 3H), LRMS m / z (M + H) Calculated: 447.1, found: 447.1. The racemic mixture was separated by ChiralPak AD (40% EtOH in hexanes + DEA 1 ml / l). The first peak was the A-enantiomer of 2-bromo-6- [1- (6-methoxypyridin-2-yl) -2,2-dipyridin-3-ylethylpyridine, and the second peak was the B-enantiomer of 2-bromo- 6- [1- (6-methoxypyridin-2-yl) -2,2-dipyridin-3-ylethyl] pyridine.

Step D Three pumpings / N2 were degassed and a mixture of the enantiomer A of 2-bromo-6- [1- (6-methoxypyridin-2-yl) -2,2-dipyridin was heated to 100 ° C for 16 hours. -3-ylethyl] pyridine (1.00 g, 2.235 g), methanesulfonamide (0.255 g, 2.683 mmol), Cs2CO3 (1.02 g, 3.13 mmol), Pd2 (dba) 3 (41 mg, 0.045 mmol), and xantho (78 mg) , 0.134 mmol) in anhydrous dioxane (10 ml) under N2. The mixture was cooled to room temperature and diluted with CHCl3. The mixture was filtered through a pad of Celite and washed with CHCl3 and EtOAc. The filtrate was concentrated and purified by chromatography on silica gel (1-5% MeOH in CH 2 Cl 2). The mixture was then purified by acid reverse phase HPLC (95% H2O: 5% CH3CN to 100% CH3CN + 0.1% TFA). The fractions were concentrated and then quenched with saturated aqueous sodium bicarbonate and extracted three times with EtOAc. The combined organics were dried (anhydrous Na 2 SO 4), filtered and concentrated to give N-. { 6- [1- (6-methoxypyridin-2-yl) -2,2-dipyrdin-3-ylethyl] pyridin-2-yl} methanesulfonamide. 1 H NMR (500 MHz, d 6 DMSO) d 10.43 (s, 1 H), 8.64 (d, 2 H, J = 8.3), 8.22 (t, 2 H, J = 5.2), 7.91 (td, 2 H, J = 6.2, 1.8, 7.55-7.40 (m, 2H), 7.25-7.10 (m, 3H) 7.06 (d, 1 H, J = 7.3), 6.55 (d, 1 H, J = 7.6), 6. 44 (d, 1 H, J = 8.1), 5.43 (d, 1 H, J = 12.2), 5.39 (d, 1 H, J = 12.2), 3.82 (s, 3H), 3. 45 (s, 3H), LRMS m / z (M + H) Calculated: 462.1595, found 462.1597. The B-enantiomer of N-. { 6- [1- (6-methoxypyridin-2-yl) -2,2-dipyridin-3-ylethyl] pyridin-2-ylmethane sulfonamide (LRMS m / z (M + H) Calculated: 462.1595, found 462.1597) synthesized using the method described above except with the B-enantiomer of 2-bromo-6- [1- (6-methoxypyridin-2-yl) -2,2-dipyridin-3-ylethyljpyridine.

EXAMPLE 1-4 (R and S) -3-f1- (2-aminopyrimidin-4-yl) -2,2-dipyridin-3-ylethyl] benzonitrile Step A: / -PrMgCl (5 mL, 2.0 M, 10 mmol) was added to the solution of 4-iodo-2- (methylthio) pyrimidine (2.52 g, 10 mmol) in THF (50 mL) at 0 ° C and was added. stirred for 1 hour. 3-Cyanobenzaldehyde (1.31 g, 10 mmol) was added. The mixture was stirred at 0 ° C for 2 hours. The reaction was quenched with saturated aqueous NH 4 Cl solution and extracted with CH 2 Cl 2. The combined organic layer was dried, filtered and concentrated. The residue was purified by chromatography on silica gel (20-50% EtOAc in hexane) to give 3-. { hydroxy [2- (methylthio) pyrimidin-4-yl] methyl} benzonitrile. 1 H NMR (500 MHz, CDCl 3) d 8.46 (d, 1 H, J = 5.1), 7.72 (s, 1 H), 7.65 (d, 1 H, J = 7.9), 7.61 (d, 1 H, J = 7.8), 7.48 (t, 1 H, J = 7.6), 6.84 (d, 1 H, J = 5.1), 5.69 (d, 1 H, J = 3.7), 4.58 (d, 1 H, J = 4.1) 2.60 (s, 3H). LRMS m / z (M + H) Calculated: 258.3, found: 258.1.

Step B Triphenylphosphine (2.36 g, 8.98 mmol) was added to the solution of 3-. { hydroxy [2- (methylthio) pyrimidin-4-yl] methyl} Benzonitrile (1.65 g, 6.41 mmol) in CCI 4 (10 ml) and CH 2 Cl 2 (10 ml) and stirred for 4 h. The mixture was concentrated and the residue was purified by chromatography on silica gel (20% EtOAc EtOAc in hexane) to give 3-. { chloro [2- (methylthio) pyrimidin-4-yl] methyl} benzonitrile. 1 H NMR (500 MHz, CDCl 3) d 8.58 (d, 1 H, J = 5.1), 7.79 (s, 1 H), 7.70 (d, 1 H, J = 8.1), 7.62 (d, 1 H, J = 7.8 ), 7.49 (t, 1H, J = 7.8), 7.25 (d, 1 H, J = 4.9), 5.92 (s, 1 H), 2.51 (s, 3H). LRMS m / z (M + H) Calculated: 276.8, found: 276.0.

Step C LDA (4.4 mL, 1.8 M) was added to the solution of 3- (pyridin-3-ylmethyl) pyridine (1.24 g, 7.26 mmol) in THF (32 mL) at -78 ° C and stirred for 1 hour. . 3- was added. { chloro [2- (methylthio) pyrimidin-4-yl] methyl} Benzonitrile (2.0 g, 7.25 mmol) in THF (5 ml). The mixture was stirred at 0 ° C for 2 hours. The reaction was quenched with ice and extracted with CH2Cl2. The combined organic layer was dried, filtered and concentrated to give a solid. The solid was purified by chromatography on silica gel (3% MeOH in CH2Cl2) to give (±) -3-. { 1 - [2- (Methylthio) pyrimidin-4-yl] -2,2-dipyridin-3-ylethyl} benzonitrilo. LRMS m / z (M + H) Calculated: 410.5, found: 410.1.

Step D M-Chloroperoxybenzoic acid (0.657 g, 77%, 2.93 mmol) was added to the solution of 3-. { 1- [2- (Methylthio) pyrimidin-4-yl] -2,2-dipyridin-3-ylethyl} benzonitrile (1.2 g, 2.93 mmol) in CHCl3 (15 ml) at 0 ° C and stirred for 1 hour. The reaction mixture was concentrated and purified by chromatography on silica gel (6% MeOH in CH 2 Cl 2) to give a diastereomeric mixture of (±) -3-. { 1- [2- (Methylsulfinyl) pyrimidin-4-yl] -2,2-dipyridin-3-ylethyl} benzonitrile. LRMS m / z (M + H) Calculated: 426.6, found: 426.1.

Step E The mixture solution of diastereomers of (±) -3-. { 1- [2- (Methylsulfinyl) pyrimidin-4-yl] -2,2-dipyridin-3-ylethyl} Benzonitrile (0.11 g, 0.25 mmol) in DMSO saturated with NH3 (2 mL) was heated to 100 ° C in the microwave for 2 hours. The mixture was concentrated and the residue was purified by chromatography on silica gel (5% MeOH in CH2Cl2) to give (±) -3- [1- (2-aminopyrimidin-4-yl) -2,2-dipyridin-3 -lethyl] benzonitrile. 1 H NMR (500 MHz, DMSO-d 6) d 8.68 (d, 1 H, J = 1.5), 8.60 (d, 1 H, J = 1.5), 8.29 (d, 1 H, J = 4.6), 8.23 (d, 1 H, J = 4.6), 8.00 (d, 1 H, J = 4.8), 7.95 (s, 1 H), 7.90 (t, 2H, J = 9.4), 7.80 (d, 1 H, J = 8.0), 7.55 (d, 1 H, J = 7.6), 7.40 (t, 1 H, J = 7.8), 7.25 (dd, 1 H, J = 7.8, 4.6), 7.19 (dd, 1 H, J = 8.0, 4.6 ), 6.67 (d, 1 H, J = 5.1), 6.54 (s, 2H), 5.25 (d, 1 H, J = 12.5), 5.20 (d, 1H, J = 12.4). LRMS m / z (M + H) Calculated: 379.4, found: 379.2.

The racemic mixture was separated by Chiralcel OD (/ '- 50% PrOH in hexane). The first peak was (-) - 3- [1- (2-aminopyrimidin-4-yl) -2,2-dipyridin-3-ylethylbenzonitrile. The second peak was. (+) - 3- [1- (2-aminopyrimidin-4-yl) -2,2-dipyridin-3-ylethyl] benzonitrile.

SCHEME II The variables C and A in the scheme are as defined in the "Formula I".

EXAMPLE 11-1 - (2-Hydroxy-1-phenyl-2,2-dipyridin-3-ylethyl) pyrrolidine-1-carboxylate of (±) -tef-butyl (diastereomer A) Step A Triethyloxonium tetrafluoroborate (2.15 g) was added at 0 ° C., 11.3 mmol) was added to a solution of? / -benzylpyrrolidinone (2.18 g, 12.4 mmol) in 25 ml of ether. The reaction was allowed to warm to room temperature and was stirred for 30 minutes, during which a solid precipitated in the reaction. The ether was separated by decantation and the remaining residue was washed three times with ether. The residual solvent was removed in vacuo to give 1-benzyl-5-ethoxy-3,4-dihydro-2 / - / - pyrrolidium tetrafluoroborate.

Step B Lithium hexamethyldisilacid solution (8.39 ml of 1M in tetrahydrofuran, 8.39 mmol) was added to dry THF and cooled to -78 ° C. Methyl phenylacetate (1.15 ml, 7.99 mmol) was added dropwise and the reaction was stirred for 15 minutes. A solution of 1-benzyl-5-ethoxy-3,4-dihydro-2 / -pyrrolium tetrafluoroborate in 5 ml of tetrahydrofuran was added dropwise, and after one hour the reaction was allowed to warm to room temperature. The mixture was quenched with saturated NaHCO3 solution, warmed to room temperature and poured into water. The aqueous phase was extracted with EtOAc and the organic extract was washed with brine, dried with Na 2 SO 4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (25-30% EtOAc / hexane) to give methyl 2- (1-benzylpyrrolidin-2-ylidene) (phenyl) acetate. ESI + MS: 308.3 [M + H] +.

Step C Palladium hydroxide (II) (231 mg, 1.64 mmol) was added to a solution of methyl 2- (1-benzylpyrrolidin-2-ylidene) (phenyl) acetate (0.505 g, 1.64 mmol) in 5 mL of methanol , and the reaction was stirred in a hydrogen gas balloon. After 3 days, the mixture was filtered through Celite, the bed was rinsed with CH2Cl2 / MeOH, and the filtrate was concentrated in vacuo affording methyl phenyl (pyrrolidin-2-yl) acetate as a mixture of two diastereomers. ESI + MS: 220.2 [M + H] +.

Step D Di-tert-butyl dicarbonate (717 mg, 3.28 mmol) was added to a solution of methyl phenyl (pyrrolidin-2-yl) acetate (0.360 g, 1.64 mmol) in 5 ml of tetrahydrofuran and the reaction was stirred All night long. The mixture was concentrated in vacuo and then purified by chromatography on silica gel (20% EtOAc / hexane) to give 2- (2-methoxy-2-oxo-1-phenylethyl) pyrrolidin-1-fer-butylcarboxylate. . ESI + MS: 264.2 [M + H - isobutylene] +.

Step E: 3-Bromopyridine (0.790 mL, 8.20 mmol) was dissolved in 30 mL of Et2? dry and cooled to -78 ° C. N-butyl lithium (3.28 ml, 2.5 M solution in hexanes, 8.20 mmol) was added drop by syringe for 10 minutes. After stirring for 15 minutes, a solution of 2- (2-methoxy-2-oxo-1-phenylethyl) pyrrolidin-1-ferf-butylcarboxylate (0.524 g, 1.64 mmol) in 5 ml of ether was added dropwise. The reaction was stirred for 45 minutes at -78 ° C, quenched with saturated aqueous NaHCO3 solution and poured into saturated aqueous solution of NaHCO3 and EtOAc. The organic phase was extracted with brine, dried over Na 2 SO 4, filtered and concentrated in vacuo. The residue was purified by preparative reverse phase HPLC and the combined pure fractions were partitioned between CH2Cl2 and saturated aqueous NaHCO3 solution. The concentration of the organic fraction provided a single diastereomer of the title compound. 1 H NMR (500 MHz, CDCl 3): d 9.03 (br s, 1 H), 8.56 (br s, 1 H), 8.52 (d, J = 4.4 Hz, 1 H), 8.18 (d, J = 8.3 Hz, 1 H), 8.15 (d, J = 4.4 Hz, 1 H), 7.75 (d, J = 7.8 Hz, 1 H), 7.43 (br s, 1 H), 7.36 (dd, J = 7.8 and 4.8 Hz, 1 H), 7.06-7.12 (m, 4H), 7.02 (dd, J = 7.8 and 4.8 Hz, 1 H), 5.1 (br s, 1 H), 4.28 (d, J = 6.6 Hz, 1 H), 3.93 (s, 1 H), 3.22 (m, 1H), 2.25 (m, 1 H), 2.17 (m, 1 H), 1.96 (m, 1 H), 1.50 (m, 9H), 1.30 (m, 1H) ). HRMS [M + H] C 27 H 32 N 3 O 3 calculated 446.2438, found 446.2424.

Using the methodologies described below, the representative compounds of the invention were evaluated and found to show activity in the Kv1.5 assays, thereby demonstrating and confirming the utility of the compounds of this invention as Kv1.5 inhibitors. and antiarrhythmics. Compounds of this type may exhibit dependence on the rate of entry, blocking of the output K + currents to a greater degree or preferably at depolarization rates or faster heart rates. The compound could be identified in electrophysiological studies as described below. For example, during a train of depolarizations delivered at frequencies of 1 Hz and 3 Hz, blocking "depends on the speed" if the degree of blocking observed during a train of 10 seconds at 3 Hz is greater than at 1 Hz. of Kv1.5 can also present dependence on use, during which the blocking of K + outflows increases with the use or during the repetitive depolarization of a cardiac cell. The dependence on the use of blocking occurs to a greater degree with each successive depolarization in a train or sequence of pulses or depolarizations at a given speed or frequency. For example, during a train of 10 depolarizations at a frequency of 1 Hz, blocking "depends on use" if the degree of blockage is greater for the tenth pulse than for the first pulse of the train. A Kv1.5 blocker can have both use dependence and speed dependence.

A Kv1.5 blocker can also be identified by electrophysiological studies of native L? Ur using cardiac myocytes or other tissue from various species including, but not limited to, human, rat, mouse, dog, monkey, ferret, rabbit , guinea pig or goat. In native tissues, Kv1.5 can exist as a homo-oligomer or as a hetero-oligomer with other members of the Kv family, or it can exist in a complex with a β subunit. The compounds of this invention can block the homo- or hetero-oligomers of Kv1.5 or Kv1.5 in complexes with β subunits.

Kv1.5 Assays The high performance Kv1.5 planar patch fixation assay is a systematic primary screening. It confirms the activity and provides a functional measure of the potency of agents that specifically affect Kv1.5 potassium channels. Kiss ef al. (Assay and Drug Dev. Tech., 1 (1-2): 127-135,2003) and Schroeder et al. (J. of Biomol. Screen., 8 (1); 50-64, 2003) describe the use of this instrument for Kv1.5 as well as other ion channels regulated by voltage. Chinese hamster ovary (CHO) cells stably expressing the alpha subunit of human Kv1.5 potassium channel, cloned from human heart, develop to 90-100% confluence in Ham's F12 medium supplemented with 10% FBS, 100 U / ml penicillin, 100 μg / ml streptomycin, 1000 μg / ml G-418 sulfate. The cells are subcultured by treatment with Versene, then suspended in phosphate-buffered saline (PBS) and centrifuged. The cell pellet is resuspended in PBS and the resulting suspension is placed in a cell reservoir in the lonWorks ™ HT instrument. The electrophysiological recordings are made with intracellular solution containing (mM): K-gluconate 100, KCI 40, MgCl2 3.2, EGTA 3, acid? / - 2-hydroxylethylpiperazine- / V1-2-ethanesulfonic acid (HEPES) 5, adjusted to pH 7.3. Amphotericin (Sigma) is prepared as a stock solution of 30 mg / ml and diluted to a final working concentration of 0.1 mg / ml in internal buffer solution. The external solution is Dulbecco's PBS (Invitrogen) and contains (mM): CaCl2 0.90, KCI 2.67, K3PO4 1.47, MgCl2 0r50, NaCl 138, Na3PO4 8.10 and has a pH of 7.4. All compounds are prepared as 10 mM stock solutions in DMSO. The compounds are diluted in external regulator, then transferred from the drug tray to the patch tray during the experiment (final concentration of DMSO <0.66 vol.%). The ion currents of Kv1.5 are recorded at room temperature. The membrane currents are amplified (RMS ~ 10pA) and sampled at 10 kHz. Subtraction is performed in all experiments by applying hyperpolarization prepulses of 160 ms (10 mV) 200 ms before the test pulses to measure the leakage conductance. The patch fixation stimulation protocol is as follows: 1. The platens of the patch tray are loaded with 3.5 μl of external regulator. 2. The planar resistances of the micropipette gaps (Rp) are determined by applying a potential difference of 10 mV, 160 ms through each gap (gap test). 3. The cells are added by pipette to the patch tray and high strength seals are formed with the 1-2 μm gaps in the bottom of each platen of the patch tray. A seal test scan is carried out to determine how many patches in the patch tray have cells that have formed seals. 4. In order to increase the electrical access to the cells, an intracellular solution containing amphotericin is circulated for 4 minutes on the bottom of the patch tray. 5. The precomposed addition test pulse is applied to each platen of the patch tray. Protocol: The cells are fixed by voltage at a membrane holding potential of -80 mV for 15 seconds. This is followed by the application of a 5 Hz stimulus train (27 x 150 depolarizations up to +40 mV). The membrane potential raised to +40 mV evokes external (positive) ion currents. 6. The compound is added to each platen of the patch tray. The compounds are allowed to incubate for 5 minutes. 7. The addition test pulse protocol is applied after the compound. Protocol: The cells are fixed at a membrane holding potential of -80 mV for 15 seconds. This is followed by the application of a stimulus train at 5 Hz (27 x 150 ms depolarizations up to +40 mV). The data analysis is carried out offline. Paired comparisons are used between the additions before and after the drug to determine the inhibitory effect of each compound. The% inhibition of peak current during depolarization number 27 to +40 mV (in the 5 Hz train) is plotted as a function of antagonist concentration. The drug concentrations required to inhibit the current by 50% (IC50) are determined by fitting the Hill equation to the response data of the concentration:% Control = 100 X (1 + ([Drug] / IC50) p) "1 For each cell four arithmetic measures are obtained: 1) resistance of the seal 2) basal metric (the average current at -70 mV from 5 to 45 ms before the first depolarization to +40 mV) 3) metric of ascent of the current (amplitude of the mean current before the compound during the first depolarization to +40 mV minus the amplitude of the mean current before the compound during depolarization number 27 to +40 mV) 4) peak current (maximum current amplitude during depolarization number 27 to +40 mV during the train at 5 Hz.) All measurements are obtained during the addition traces before and after the compound.The cells are removed from a subsequent analysis if: 1) the resistance of the seal is <; 50 MO 2) the basal metric is > ± 100 pA during the time prior to compound 3) the current rise metric is > -0.2 nA 4) the metric of the peak before reading is < 400 pA. The compounds listed above provide an inhibition > 20% at a concentration of 33 μM or less in the high yield Kv1.5 planar patch fixation assay described above.

Atomic absorption spectroscopy protocol: This assay identifies agents that specifically block the human K + Kv1.5 channel expressed heterologously in CHO cells and measured by the Rb + output using Flame Atomic Absorption Spectroscopy (FAAS). The FAAS application to measure the activity of ion channels was adapted from Terstappen ef al, Anal. Biochem., 272: 149-155, 1999. CHO cells expressing human Kv1.5 are cultured as described above, then harvested with trypsin-EDTA and washed with medium. 1. 40,000 cells are seeded per stage in a 96 platinum culture dish (assay tray) and the cells are allowed to develop for 48 hours at 37 ° C. 2. Separate the medium and add 200 μl of Rb Load Buffer (Aurora Biomed, Vancouver, BC) for 3 hours at 37 ° C under 5% CO23. The cells are washed 5 times with 200 μl of Hank's Balanced Salt Solution (HBSS), followed by the addition of 100 μl of HBSS containing test compound or 0.5% DMSO. 4. After 10 min, add 100 μl of saline plugged with HEPES containing 140 mM KCI and incubate the tray at room temperature for 5 minutes, with gentle agitation. 5. Immediately afterwards, 150 μl of the float is transferred to a new 96-well tray and the remaining float is aspirated. 6. 120 μl of Cell Lysis Regulator (Aurora Biomed, Vancouver, BC) is added to the assay tray and shaken for 10 minutes before analysis. 7. The Rb content in the floating (SUP) and lysate (LYS) samples is measured using an automatic AAS ICR-8000 instrument (Aurora Biomed, Vancouver, BC). % FLOW = 100% * (SUP / (LIS + SUP)). % INH = 100% * (1- (AB) / (C-B)), where A is% FLOW in the presence of the test compound, B is% FLOW in the presence of 10 mM of (6-methoxy-2) chloride -methyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl) -? /,? / - dimethylmethanaminium, C is% FLOW in the presence of 0.25% DMSO. The compounds listed above provide an inhibition > 25% at a concentration of 25 μM or less in the AAS assay described above. The compounds of this invention can be administered for the treatment or prevention of conditions, diseases and conditions according to the invention by any means that contacts the compound of the active ingredient with the site of action in the body of a warm-blooded animal. For example, administration may be oral, topical, including transdermal, ocular, buccal, intranasal, inhalation, intravaginal, rectal, intracystemal, and parenteral. The term "parenteral" as used herein refers to modes of administration which include subcutaneous, intravenous, intramuscular, intraarticular or infusion, intrasternal and intraperitoneal injection. The compounds can be administered by any conventional means available for use in conjunction with medicaments, either in individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, although they are usually administered with a pharmaceutical carrier selected on the basis of the chosen administration route and conventional pharmaceutical practice. For the purpose of this description, a warm-blooded animal is a member of the animal kingdom that possesses a homeostatic mechanism and includes mammals and birds. The dose administered will depend on the age, health and weight of the recipient, the intensity of the disease, the kind of concurrent treatment if any, the frequency of the treatment and the nature of the desired effect. Typically, a daily dose of the compound of the active ingredient will vary from about 1 to 500 mg per day. Ordinarily, from 10 to 100 mg per day in one or more applications, it is effective to obtain the desired results.

These dosages are effective amounts for the treatment and prevention of the conditions, diseases and conditions described above, for example, cardiac arrhythmias such as atrial fibrillation., atrial flutter, atrial arrhythmia and supraventricular tachycardia, thromboembolic events such as stroke and congestive heart failure, and immunosuppression. The active ingredient can be administered orally in solid dosage forms such as capsules, tablets, troches, lozenges, granules and powders, or in liquid dosage forms such as elixirs, syrups, emulsions, dispersions and suspensions. The active ingredient can also be administered parenterally, in sterile liquid dosage forms, such as dispersions, suspensions or solutions. Other dosage forms may also be used to administer the active ingredient, such as an ointment, cream, drops, transdermal patch or powder for topical administration, such as an ophthalmic solution or suspension formulation, ie, eye drops, for ocular administration as a aerosol sprayer or powder composition for inhalation or intranasal administration, or as a cream, ointment, aerosol or suppository for rectal or vaginal administration. Gelatin capsules contain the active ingredient and powdered carriers such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid and the like. Similar diluents can be used to prepare compressed tablets. Both the capsules and the tablets can be manufactured as sustained release products to provide a continuous release of the medication over a period of hours. Compressed tablets may be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or from an enteric coating for selective disintegration in the gastrointestinal tract. Liquid dosage forms for oral administration may contain a colorant or flavor to increase patient acceptance. In general, suitable carriers for parenteral solutions are: water, a suitable oil, saline, aqueous dextrose (glucose) and solutions of related sugars and glycols such as propylene glycol or polyethylene glycols. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents and, if necessary, regulatory substances. Antioxidant agents such as sodium bisulfite, sodium sulfite or ascorbic acid, either alone or in combination, are suitable stabilizing agents. Citric acid and its salts and sodium EDTA are also used. In addition, parenteral solutions may contain preservatives, such as benzalkonium chloride, methyl- or propylparaben, and chlorobutanol. In Remington's Pharmaceutical Sciences, A. Osol, conventional reference text in this field, suitable pharmaceutical carriers are described.

For administration by inhalation, the compounds of the present invention can be conveniently delivered in the form of an aerosol spray presentation from pressurized containers or nebulizers. The compounds can also be delivered as powders that can be formulated and the powder composition can be inhaled with the aid of a powder inhalation device by insufflation. The preferred delivery system for inhalation is a metered dose inhalation aerosol (MDI) which can be formulated as a suspension or solution of a compound of formula I in suitable propellants, such as fluorocarbons or hydrocarbons. For ocular administration, an ophthalmic preparation can be formulated with a solution or suspension of the compounds of the formula I with an appropriate weight percentage in a suitable ophthalmic vehicle, so that the compound remains in contact with the ocular surface for a period of time. of sufficient time to allow the compound to penetrate the corneal and inner regions of the eye. Pharmaceutical dosage forms useful for administration of the compounds of this invention include, but are not limited to, hard and soft gelatin capsules, tablets, parenteral injectables and oral suspensions. A large number of capsule units are prepared by filling each of the conventional two-piece hard gelatin capsules with 100 mg of active ingredient powder, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate. A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump in gelatin, to form the soft gelatin capsules containing 100 mg of the active ingredient. The capsules are washed and dried. A large number of tablets are prepared by conventional methods so that the unit dose is 100 mg of active ingredient, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch and 98.8 mg of lactose. Appropriate covers can be applied to increase palatability or delay absorption. A parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of active ingredient in 10% by volume of propylene glycol. The solution is brought to its volume with water for injection and sterilized. An aqueous suspension is prepared for oral administration so that each 5 ml contains 100 mg of finely divided active ingredient, 100 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 gram of sorbitol solution, U.S.P. and 0.025 ml of vanillin. Generally the same dosage forms can be used when the compounds of this invention are administered in several stages or in conjunction with another therapeutic agent. When the drugs are administered in physical combination, the dosage form and route of administration should be selected depending on the compatibility of the combined drugs. Thus, it is understood that the term co-administration includes the administration of the two agents concomitantly or sequentially, or alternatively, as a fixed dose combination of the two active components. The compounds of the invention can be administered as a single active ingredient or in combination with a second active ingredient, including other antiarrhythmic agents having Kv1.5 blocking activities, such as quinidine, propafenone, bothilide, amiodarone, flecainide, sotalol, bretilio, dofetilide, almokalant, bepridil, clofilio, other compounds that have Kv1.5 blocking activities such as clotrimazole, ketoconazole, bupivacaine, erythromycin, verapamil, nifedipine, zatebradine, bisindolylmaleimide, or other cardiovascular agents such as, but not limited to , ACE inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril erbumine, quinapril, ramipril and trandolapril, angiotensin II antagonists such as candesartan, eprosartan, irbesartan, losarían, olmesartan, telmisartan and valsaraz, cardiac glycosides such as digoxin, blockers of the L-type calcium channels, T-type calcium channel blockers, selective and nonselective beta-blockers, an immunosuppressant compound, endothelin antagonists, thrombin inhibitors, aspirin, nonselective SAID's other than aspirin, such as naproxen, warfarin, inhibitors of factor Xa, low molecular weight heparin, unfractionated heparin, clopidogrel, ticlopidine, llb / Illa receptor antagonists such as tirofiban, 5HT receptor antagonists, integrin receptor antagonists, thromboxane receptor antagonists, TAFI inhibitors and antagonists of the P2T receiver. The compounds of the invention can also be administered as a single ingredient or in combination with a pacemaker or a defibrillator device.

Claims (8)

NOVELTY OF THE INVENTION CLAIMS

1. A compound of the formula I, or a pharmaceutically acceptable salt thereof, having the formula I:

I where: A, B and C are independently selected from the group consisting of: 1) an aryl ring; and 2) a heteroaryl ring, wherein the point of attachment to the heteroaryl ring is a carbon atom, and the heteroaryl ring is selected from the group consisting of: a) a 5-membered unsaturated monocyclic ring with 1, 2, 3 or 4 heteroatom ring atoms selected from the group consisting of: N, O or S; b) a 6-membered monocyclic unsaturated ring with 1, 2, 3 or 4 ring atoms heteroatoms selected from the group consisting of: N, O or S; and c) an unsubstituted bicyclic ring of 8-, 9- or 10-membered with 1, 2, 3 or 4 heteroatom ring atoms selected from the group consisting of: N, O or S; the aryl and heteroaryl ring is unsubstituted, monosubstituted with R 4, disubstituted with groups independently selected from R 4, trisubstituted with groups independently selected from R 4, O tetrasubstituted with groups independently selected from R 4, and wherein any heteroaryl or heterocyclic ring atom S or N stable is unsubstituted or is substituted with oxo, the R4 substitutions of the heteroaryl ring being on one or more carbon atoms of the heteroaryl ring; with the proviso that at least one of substituents A, B and C is a heteroaryl ring; D is selected from the group consisting of: 1) an aryl ring, 2) a heteroaryl ring, wherein the point of attachment to the heteroaryl ring is a carbon atom, and the heteroaryl ring is selected from the group consisting of: ) a 5-membered unsaturated monocyclic ring with 1, 2, 3 or 4 ring atoms heteroatoms selected from the group consisting of: N, O or S, b) a 6-membered unsaturated monocyclic ring with 1, 2, 3 or 4 ring atoms heteroatoms selected from the group consisting of: N, O or S, and c) an unscreened bicyclic ring of 8-, 9- or 10-membered with 1, 2, 3 or 4 ring atoms heteroatoms selected from among the group consisting of: N, O or S; and 3) a saturated 4 to 6 membered heterocyclic ring with 1, 2 or 3 ring atoms heteroatoms selected from the group consisting of: N, O and S, where the point of attachment of the heterocyclic ring is a carbon atom; the aryl, heteroaryl, saturated heterocyclic ring being unsubstituted, monosubstituted with R 4, disubstituted with groups independently selected from R 4, trisubstituted with groups independently selected from R 4, O tetrasubstituted with groups independently selected from R 4, and wherein any heteroaryl or heterocyclic ring atom S or N stable is unsubstituted or is substituted with oxo, the R4 substitutions of the heteroaryl ring being on one or more carbon atoms of the heteroaryl ring; X and Y are independently selected from the group consisting of: H and OR5; Ra, in each case where it appears, is independently selected from the group consisting of: hydrogen, C -C6 alkyl and halogen; R4, in each case where it appears, is independently selected from the group consisting of: hydrogen, halogen, CN, CR4 = C (R5) 2I (CRa2) nOR5 > (CRa2) nN (R5) 2, (CRa2) n C (O) R5, N (R5) C (O) R5, C (O) OR5 and N (R5) S (O) mR5; R5, in each case where it appears, is independently selected from the group consisting of: hydrogen, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C3-C10 cycloalkyl, unsubstituted or substituted aryl and unsubstituted heterocyclyl or replaced; m is, independently, 0, 1 or 2; and n is, independently, 0, 1, 2, 3, 4, 5 or 6. 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, further characterized in that A is a heteroaryl ring, wherein the point of attachment to the heteroaryl ring is a carbon atomwherein the heteroaryl ring is a 6 membered monocyclic unsaturated ring with 1 or 2 ring atoms N, the heteroaryl ring is unsubstituted, monosubstituted with R 4, disubstituted with groups independently selected from R 4, trisubstituted with groups independently selected from R 4, O tetrasubstituted with groups independently selected from R 4, and wherein any stable N atom of the heteroaryl ring is unsubstituted or substituted by oxo, the R 4 substitutions of the heteroaryl ring being on one or more carbon atoms of the heteroaryl ring; β is a heteroaryl ring, where the point of attachment to the heteroaryl ring is a carbon atom, and the heteroaryl ring is a 6-membered unsaturated monocyclic ring with 1 or 2 N atoms, the heteroaryl ring is unsubstituted, monosubstituted with R 4, disubstituted with groups independently selected from R 4, trisubstituted with groups independently selected from R 4, O tetrasubstituted with groups independently selected from R 4, and wherein any stable N atom of the heteroaryl ring is unsubstituted or is substituted with oxo, the R 4 substitutions being heteroaryl ring on one or more carbon atoms of the heteroaryl ring; C is selected from the group consisting of: 1) an aryl ring, and 2) a heteroaryl ring, where the point of attachment to the heteroaryl ring is a carbon atom, where the heteroaryl ring is an unsaturated monocyclic 6-membered ring with 1 N atom, the aryl and heteroaryl ring is unsubstituted, monosubstituted with R 4, disubstituted with groups independently selected from R 4, trisubstituted with groups independently selected from R 4, O tetrasustitute with groups independently selected from R 4, and wherein any stable N atom of the heteroaryl or heterocyclic ring is unsubstituted or is substituted with oxo, the R4 substitutions of the heteroaryl ring being on one or more carbon atoms of the heteroaryl ring; and D is a heteroaryl ring, wherein the point of attachment to the heteroaryl ring is a carbon atom, and the heteroaryl ring is a 6-membered monocyclic unsaturated ring with 1 or 2 ring atoms N, and the heteroaryl ring is unsubstituted , monosubstituted with R 4, disubstituted with groups independently selected from R 4, trisubstituted with groups independently selected from R 4, O tetrasubstituted with groups independently selected from R 4, and wherein any stable N atom of the heteroaryl ring is unsubstituted or is substituted with oxo, the R substitutions of the heteroaryl ring on one or more ring carbon atoms.

3. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, further characterized in that X is selected from the group consisting of: hydrogen and -OH; And it is selected from the group consisting of: hydrogen and -OH; A is selected from the group consisting of: HzN. l «* > CH ?. riHSOjCrH ,. C, Q B is selected from the group consisting of: C is selected from the group consisting of: D is selected from the group consisting of: Br N (CH 3) 2 NH 2 H (CH 2 FeCH H N = v N M- ^

4. The compound according to claim 3, or a pharmaceutically acceptable salt thereof, further characterized in that it is selected from the group consisting of: (f?) - / V-. { 6- [1- (4-fluorophenyl) -2,2-dipyridin-3-ylethyl] pyridin-2-yl} methanesulfonamide; (S) -? / -. { 6- [1- (4-fluorophenyl) -2,2-dipyridin-3-ylethyl] pyridin-2-yl} methanesulfonamide; (r?) -? / -. { 6- [1- (3-cyanophenyl) -2,2-dipyridin-3-ylethyl] pyridin-2-yl} methanesulfonamide; (S) -? / -. { 6- [1- (3-cyanophenyl) -2,2-dipyridin-3-ylethyl] pyridin-2-yl} methanesulfonamide; (F?)-?/-. { 6- [1- (6-methoxypyridin-2-yl) -2,2-dipyridin-3-ylethyl] pyridin-2-yl} methanesulfonamide; (S) -? / -. { 6- [1- (6-methoxypyri? I ..- 2-yl) -2,2-dipyridin-3-ylethyl] pyridin-2-yl} methanesulfonamide; (ft) -3- [1 - (2-aminopyrimidin-4-yl) -2,2-dipyridin-3-ylethyl] benzonitrile; and (S) -3- [1 - (2-Aminopyrimidin-4-yl) -2,2-dipyridin-3-ylethyl] benzonitrile.

5. The use of a compound according to claim 1 in the manufacture of a medicament useful for treating a condition effected or facilitated by the inhibition of K 1.5 in a mammal.

6. The use claimed in claim 5, wherein the condition is a cardiac arrhythmia. The use claimed in claim 6, wherein the cardiac arrhythmia is atrial fibrillation. 8. A pharmaceutical formulation comprising a pharmaceutically acceptable carrier and the compound according to claim 1 or a pharmaceutically acceptable crystalline form or the hydrates thereof.